Generation and Trapping of Nitrosocarbonyl Intermediates - Chemical

Review pubs.acs.org/CR

Generation and Trapping of Nitrosocarbonyl Intermediates Misal Giuseppe Memeo and Paolo Quadrelli* Dipartimento di Chimica, Università degli Studi di Pavia, Viale Taramelli 12, 27100 Pavia, Italy S Supporting Information *

ABSTRACT: The nitrosocarbonyls (R−CONO) are highly reactive species and remarkable intermediates toward different synthetic targets. This review will cover a research area whose impact in current organic synthesis is constantly increasing in the chemical community. This review represents the first and comprehensive picture on the generation and trapping of nitrosocarbonyls and is solidly built on more than 380 papers. Six different classes of key starting materials such as hydroxamic acids, Nhydroxy carbamates, N-hydroxyureas, nitrile oxides, and 1,2,4-oxadiazole-4-oxides were highlighted. The content of the review surveys all the methods to generate the nitrosocarbonyls through different approaches (oxidative, thermal, photochemical, catalytic, aerobic, and the less common ones) in the light of efficiency, yields, and mildness. The most successful trapping agents employed to catch these fleeting intermediates are reviewed, exploiting their superior dienophilic, enophilic, and electrophilic power. The work is completed by paragraphs dedicated to the detection of the intermediates, theoretical studies, and insights about the challenges and future directions for the field.

CONTENTS 1. Introduction 1.1. Definition of “Nitrosocarbonyls” 1.2. Nitrosocarbonyls, i.e., Acyl Nitroso Compounds: Historical Survey 2. Nitrosocarbonyl Precursors, Reactivity, and Trapping 2.1. Starting Materials and their Synthesis 2.1.1. Hydroxamic Acids 2.1.2. N-Hydroxycarbamates 2.1.3. N-Hydroxyureas 2.1.4. Nitrile Oxides 2.1.5. 1,2,4-Oxadiazole-4-oxides 2.1.6. Nitrodiazoalkanes 2.2. Reactivity of Nitrosocarbonyls and Trapping Methods 3. Nitrosocarbonyl Generation Methods 3.1. Oxidative Protocols 3.1.1. From Aliphatic and Aromatic Hydroxamic Acids 3.1.2. From N-Hydroxycarbamates 3.1.3. From N-Hydroxyureas 3.1.4. From Heterocyclic Hydroxamic Acids 3.1.5. From Chiral Hydroxamic Acids 3.1.6. From Hydroxamic Acids with Intramolecular Trapping 3.1.7. From Nitrile Oxides 3.2. Photochemical Protocols 3.2.1. From 1,2,4-Oxadiazole-4-oxides 3.3. Polymer Supported Nitrosocarbonyl Intermediates 3.3.1. Oxidative and Photochemical Generation © XXXX American Chemical Society

3.4. Thermal Protocols 3.4.1. From 9,10-Dimethylanthracene Cycloadducts 3.4.2. From 1,2,4-Oxadiazole-4-oxides 3.5. Trapping of Nitrosocarbonyls with Nucleophiles 3.5.1. Aldol Reactions, Electrophilic Amination, and Hydroxymation 3.5.2. Reactions with Amines 4. Nitrosocarbonyl Detection 4.1. Spectroscopic Observations 5. Miscellaneous Generation Methods 5.1. From Nitrodiazoalkanes 5.1.1. Nitrocarbenes as Precursors of Nitrosocarbonyl Intermediates 6. Related Structures 6.1. From P-Nitrosophosphonates 6.1.1. P-Nitroso Compounds 7. Theoretical Studies 7.1. Studies on Nitroso and Nitrosocarbonyl Compounds 8. Conclusions and Perspectives Associated Content Supporting Information Author Information Corresponding Author ORCID Notes Biographies Acknowledgments

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BO Received: October 6, 2016

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DOI: 10.1021/acs.chemrev.6b00684 Chem. Rev. XXXX, XXX, XXX−XXX

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these fleeting intermediates. This review will not cover any synthetic application since recent reviews deal with these aspects: S. Iwasa, A. Fakhruddin, and H. Nishiyama published in MiniReviews in Organic Chemistry a work dealing with “recent” synthetic applications to the total synthesis of natural products,2 while M. F. A. Adamo and S. Bruschi furnished the reader an update of the most “recent” findings and applications of NC in Targets in Heterocyclic Systems.3 Recent advances in asymmetric Diels−Alder reactions involving NC intermediates were reported by Y. Yamamoto and H. Yamamoto in European Journal of Organic Chemistry in 2006.4 A review by B. S. Bodnar and M. J. Miller published in Angewandte Chemie, International Edition in 2011 describes the HDA reactions and the synthetic utility of the resulting oxazines toward the preparation of biologically active molecules,5 and finally, the last published review in Synthesis in 2014 by L. I. Palmer, C. P. Frazier, J. Read de Alaniz deals with the mild oxidation of N-substituted hydroxylamines.6 Hence, this review on the generation and trapping of NC goes deeper in the subject, giving a full picture made up of about 390 papers. The review includes six different classes of starting materials classified as shown in Table 1.

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1. INTRODUCTION The idea of this review can be symbolized by the famous Botticelli painting La Nascita di Venere (The Birth of Venus, Galleria degli Uffizi, Florence) where a wind of generation comes from the starting materials and the nitrosocarbonyls are obtained and instantly trapped by the handmaid’s wrap to keep these intermediates safe and usable by chemists. The nitrosocarbonyl (NC) intermediates R−CONO are highly reactive species that were discovered at the beginning of the 1970s. G. W. Kirby was the first to point out the powerful dienophilic activity of these transient species in 1973, and in the seminal paper in Chemical Society Reviews published in 1977, NCs were established as remarkable intermediates toward different synthetic targets.1 Nitrosocarbonyl or acylnitroso compounds attracted a great deal of attention in the area of organic synthesis during the last decades since highly functionalized molecules can be readily achieved starting from nitroso compounds through different reactions such as the hetero Diels−Alder (HDA) reactions. One of the most relevant achievements came from the synthesis of 1,4-amino alcohols, which represent the pivotal step for the total synthesis of a large number of natural products (vide infra). The range of applications of NCs in organic synthesis has been widened in recent years by the discovery of new generation methods allowing for the use of these transient species to achieve many multifunctionalized molecules. The aim of this review is to cover a research area whose impact in current organic synthesis can be evaluated from the increasing number of papers in this field, published from the very beginning up to nowadays. The interest of the chemical community in the use of these intermediates in organic syntheses and in the study of their chemical behavior in various reactions increased considerably after 1977 (Chart 1), and the majority of the about 390 papers

Table 1. Classes of Starting Materials 1 2 3 4 5 6

name

acronym

hydroxamic acids N-hydroxycarbamates N-hydroxyureas nitrile oxides 1,2,4-oxadiazole-4-oxides nitrodiazoalkanes

A C U N O NZ

The various starting compounds and the methods to generate the NC intermediates are discussed in the light of efficiency, yield, mildness, trapping agents, and the possibility of using these latter compounds as intermediates in organic syntheses. These aspects of the NC chemistry needs to be properly collected, covering the entire development of the methods for the generation of these fleeting intermediates from the very beginning up to ending in 2015, reordering all the information in a clear picture which could be of great help for a wide range of chemists. An introductory historical survey and a final section on the detection of NC intermediates will complete the work.

Chart 1. Paper Distribution from 1961 to 2015 on Nitrosocarbonyl Chemistry

1.1. Definition of “Nitrosocarbonyls”

The name “nitrosocarbonyl” does not correspond exactly to the correct definition of the species at hand and essentially indicates the presence in the molecular structure of two functional groups, directly connected to each other: a carbonyl and a nitroso group. The IUPAC rules7 for nitroso derivatives indicate the use of the prefix “nitroso” to name the compound containing the −NO group, while a carbonyl group linked to an alkyl or an arylic group defines an acyl group. Nevertheless the name “nitrosocarbonyl” is quite of general use in the literature since it refers essentially to the chemical properties of these organic compounds as a single functional group. The term “nitrosocarbonyl” appeared for the first time in 1897 in Berichte der Deutschen Chemischen Gesellschaf t by Emil Fischer and dealing with the decomposition of theobromine.8 Here it refers to an N-nitroso urea derivative where the NO group is attached to the nitrogen atom and not a carbonyl group (Figure 1).

have been published in the last 25 years (271 papers). In this count, 11 papers published from 1932 to 1968 have not been included, since the NC structure was just hypothesized by those authors who were involved in different scientific areas or who were engaged in the search of an alternative way toward common reagents. In some cases the name “nitrosocarbonyl” was attributed erroneously to other compounds. The content of this review will survey the starting materials used to generate NCs through different protocols (oxidative, thermal, photochemical, catalytic, and the less common ones) and the most successful trapping agents employed to capture B


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Figure 1. Paper published in 1897 in Berichte der Deutschen der Chemischen Gesellschaf t by Emil Fischer and dealing with the decomposition of theobromine. [Reproduced with permission from ref 8. Copyright 1897 John Wiley and Sons, Inc.]

Figure 2. First paper where the name “nitrosocarbonyl” appeared. [Reproduced with permission from ref 14. Copyright 1937 Royal Society of Chemistry.]

monoxide is allowed to be absorbed by the metal complex, followed by treatment with nitric oxide. The compounds are liquids and are purified by distillation. Their structures are mainly attributed on the basis of analytical data, and only in some cases thermal and scattering analyses as well as electron diffraction studies allow for structure determinations. In these compounds, the two functional groups, carbonyl and nitroso, are not connected to each other but both coordinate the central transition metal (Figure 2). Again these papers are the direct effect of the search on databases using the name “nitrosocarbonyl”. However, the chemistry of organometallic compounds, in particular the chemistry of iron(III) derivatives, somewhat triggered the very first discovery of metal-complexed “nitrosocarbonyl” moieties and the reaction to generate these species. In 1960 T. Emery and J. B. Neilands were studying the isolation and the general properties of ferrichrome compounds because of the wide presence of these structures in microbial species.16 The structure of ferrichrome was already been established in 1959 and published in Nature17,18 (Figure 3), where is reported as an organometallic compound having a hydroxamic acid nature. In fact, the iron-free ferrichromes are instantly oxidized by periodate and the method is mentioned as a general way for the characterization of hydroxamic acids.

Searches in chemical literature databases sometimes produce these mistakes or misunderstanding due to the old nomenclature given to completely different compounds. 1.2. Nitrosocarbonyls, i.e., Acyl Nitroso Compounds: Historical Survey

More properly, the name “nitrosocarbonyl” can be replaced with “acyl nitroso” compounds. From the IUPAC rules point of view, an “acyl nitroso” derivative is an organic molecule where the nitroso group is attached to a generic acyl group with a single bond. However, in the review by Kirby dealing with the C-nitroso compounds, the name “nitrosocarbonyl” is used to describe the structure of these intermediates and, in particular, Kirby indicates as nitrosocarbonyl-alkanes and -arenes the way to describe compounds where the −CONO moiety is linked to an aliphatic or aromatic group. As a consequence, Ph−CONO is named nitrosocarbonyl-benzene and CH3−CONO is nitrosocarbonylmethane. The name “nitrosocarbonyl” is also associated with organometallic compounds containing carbon monoxide and a nitroso group. In these cases the correct nomenclature is “metal nitrosocarbonyl” compounds. The literature around the 1930s reports the synthesis of iron and cobalt nitrosocarbonyl compounds which are usually prepared starting from metal cyanides in sodium hydroxide.9−15 To these suspensions, carbon C


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conclude the paper with these words: “It is obvious that “active acyl” compounds could be detected and determined if these were first transformed into the corresponding N-alkyl-hydroxamic acids.” The research attracted the attention of other organic chemists, and in 1964 B. Sklarz and A. F. Al-Sayyab published a paper dealing with the oxidation of hydroxamic acids for the synthesis of amides.21 The authors performed the oxidation of some hydroxamic acids with aryl and aryl-alkyl substituents in the presence of primary and secondary amines as well as some amino acids and using selected oxidants such as NaIO4, NBS, I2, and K3[Fe(CN6)]. A few amides were obtained from low to good yields (9−63%) depending upon the reaction conditions and difficulties in isolations of the final products. The authors conclude the paper by supposing that the oxidation of hydroxamic acids could lead to a hypothetical intermediate R−CO−NO which is considered to behave as an acylating entity in the periodate oxidation reactions described in the work. This can be considered the first time an NC structure of type R−CO−NO is reported as an intermediate of these organic reactions in the chemical literature, even though two years before, in 1962, the presence of an NC intermediate was postulated in the thermal decomposition reaction of tertbutyl nitrite in the presence of benzaldehyde.22 From these very first results, the oxidation of hydroxamic acids as a method to prepare esters, acids, and O-alkyl derivatives found new supporters and disciples when in 1968 a paper was published in the Australian Journal of Chemistry, in which a wide list of oxidants was proposed for hydroxamic acid oxidation.23 The authors, following previous literature suggestions, report the structure of nitrosocarbonyls R−CO−NO (see formula III in Figure 5) as intermediates of hydroxamic acid oxidation in a variety of transformations to different products.

Figure 3. Ferrichrome structure. [Reproduced with permission from ref 17. Copyright 1959 Nature Publishing Group.]

On the basis of these findings, the same authors investigated the periodate oxidation of hydroxamic acids. The results obtained in 1960 indicated that periodates rapidly and quantitatively cleave these substances to liberate the corresponding free acids (Figure 4) and that the stability of the hydroxamic function is greatly augmented by addition of ferric ion, even against periodate oxidation.19 On pursuing their research, T. Emery and J. B. Neilands tried to oxidize with periodate the benzohydroxamic acid with the aim to obtain benzoic acid and nitrous oxide.20 The N,Odibenzoylhydroxylamine was found instead. The authors

Figure 5. Nitrosocarbonyl structure and its transformations. [Reproduced with permission from ref 23. Copyright 1968 CSIRO.]

In the same paper a variety of hydroxamic acids R−CO− NHOR′ are reported in a great table along with a good number of oxidants (Figure 6). For every single starting material and oxidant the yields of the isolated products are reported, giving a general view of the applicability of the methods to obtain the desired products. Some of these oxidants will become very popular in the generation of NC intermediates in few years’ time. In the meantime, B. Sklarz and A. K. Qureshi, studying the oxidation of Δ1-pyrroline-1-oxides to afford nitrones, proposed the use of the tetraethylammonium periodate, “a potentially useful reagent soluble in various organic solvents” as the authors report in the paper,24,25 another piece which will compose the mosaic of the generation of NC intermediates. However, the 1960s went by without any proper demonstration of the existence of NC as intermediates in the organic reactions. In 1971, U. Lerch and J. G. Moffatt published a paper in The Journal

Figure 4. Reaction of hydroxamic acid with periodate. [Reproduced from ref 19. Copyright 1960 American Chemical Society.] D


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in a typical Pummerer rearrangement. Hydroxamic acids give the same reaction and the identical products are isolated from the reaction mixtures. Since the major reaction products starting from either carbocylic acids or the corresponding hydroxamic acids are the same, the authors found it interesting to “speculate” on the point at which the two reaction pathways become equivalent. A likely mechanism was proposed as reported in Scheme 1; the tetracovalent sulfur intermediate undergoes dicyclohexylurea elimination to give a sulfonium ylide whose dissociation affords dimethyl sulfide and a “nitrosocarbonyl” intermediate 1. The recombination with DMSO and loss of a proton affords the sulfonium ylide, i.e., the precursor of the MTM ester. The authors do not demonstrate the mechanism and the existence of NC intermediate 1. They wrote in the paper that “...the compound (1) has been postulated as a reactive intermediate during oxidation of hydroxamic acids with a variety of agents and thermal decomposition of nitrite esters”. The time has come! In 1973 a paper appears in Journal of the Chemical Society, Chemical Communications by G. W. Kirby and J. G. Sweeny entitled “Nitrosocarbonyl compounds as intermediates in the oxidative cleavage of hydroxamic acids”.27,28 Kirby sweeps away all the doubts and the shadows reporting his idea on the existence of these intermediates. In fact, he was studying the chemistry of nitrosyl cyanide and, in a paper published two years before, Kirby recognized its powerful dienophilic character.29 In analogy with nitrosyl cyanide, he suggested that the previously postulated NC intermdiate, though short-lived, could be efficiently trapped by conjugated dienes. Hence, benzohydroxamic acid 2 was added to an ethyl acetate solution of thebaine 3 in the presence of tetraethylammonium periodate at 0 °C and the first HDA cycloadduct 4 was isolated in 97% yield (Scheme 2). This result represents the very starting point of the chemistry of these fleeting intermediates. In a few years’ time, Kirby dedicated his research to the exploration and exploitation of the potentialities of NCs, paving the way for their use in organic synthesis and clearly pointing out that the generation and trapping of these intermediates often represent the pivotal step in many organic syntheses. He collected his scientific interests and findings in the seminal paper in Chemical Society Reviews published in 1977 under the general title of “Tilden Lecture” as an amplified version of lectures given on various occasions during 1974−1975, where the chemistry of electrophilic Cnitroso compounds is summarized for the first time.1

Figure 6. Oxidation of hydroxamic acids with several oxidants. [Reproduced with permission from ref 23. Copyright 1968 CSIRO.]

of Organic Chemistry where the mild acid-catalyzed reactions of dimethyl sulfoxide (DMSO) and dicyclohexylcarbodiimide (DCC) with carboxylic acids, hydroxamic acids, and carboxamides were studied in detail.26 It was shown that DMSO and DCC react in the presence of a mild acidic catalyst to form the oxysulfonium intermediate OS (Scheme 1). This species can be attacked by various nucleophiles such as the carboxylate anion to afford a tetracovalent sulfur intermediate which undergoes dicyclohexylurea elimination to give a sulfonium ylide. Dissociation of the ylide into the methylene methylsulfonium ion and recombination with the carboxylate anion gives the final methylthiomethyl ester (MTM) Scheme 1. DMSO-Promoted Generation of Nitrosocarbonyls

E


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group can be either halides X− or the R′O− depending upon the starting compound. These are the most used and reliable methods which are currently applied for the preparation of known as well as new hydroxamic acids. The structures of the hydroxamic acids used to generate NC intermediates will be reported in the next paragraphs; the nature of the R group will determine different sections. The syntheses will be also reported for those compounds whose preparation is not directly accounted for by the general methods of hydroxamic acid synthesis. Formates or urea derivatives and other compounds sharing the general formula R′−CO−NH−OH where R′ ≠ R are also reported in separate sections. 2.1.2. N-Hydroxycarbamates. The main synthetic protocol to carbamates is represented by the addition of alcohols to isocyanates. This is an excellent reaction of wide scope that gives good yields. The isocyanates can be generated in situ by the reaction of an amine and oxalyl chloride and subsequent reaction with HCl and then an alcohol gives the desired carbamate.34 The synthesis of N-hydroxycarbamates is accomplished by reacting the carbonates with hydroxylamine free base or alternatively functionalizing with hydroxylamine the desired chloroformates.35 2.1.3. N-Hydroxyureas. Ammonia and primary and secondary amines can be added to isocyanates to give ureas; this is again an excellent method. The methodology for obtaining of N-hydroxy ureas is simply modified by using hydroxylamine free base.36 2.1.4. Nitrile Oxides. The most important works on nitrile oxides are those dedicated to this subject by Grundmann and Grünanger37 and by Caramella and Grünanger.38 These reviews are references and canon for any synthetic approach to a variety of these 1,3-dipoles. Recently, an updated book was published dealing with the synthetic applications of 1,3-dipolar chemistry, targeting the new heterocyclic systems, obtained through the use of 1,3-dipoles for the preparation of natural compounds.39 Nitrile oxides are reactive 1,3-dipoles prepared for the first time in 1894 by Werner and Buss, who demonstrated that benzhydroximoyl chloride is easily transformed by sodium carbonate into an unstable oil which soon solidifies to the crystalline 3,4-diphenyl-1,2,5-oxadiazole-5-oxide (furoxan), the common dimer of benzonitrile oxide (BNO) (Scheme 4).40 In 1907 Wieland isolated the low-melting BNO (mp 15 °C) in pure form by Werner’s procedure, determined its molecular weight, and studied its reactivity.41 The hydroximoyl chloride synthesis was revisited in 1952 by Speroni and Bartoli in the highly cited and rich in details Nota VIII “Sopra gli ossidi di benzonitrile”, where the synthesis of a

Scheme 2. HDA Cycloaddition of Nitrosocarbonyl Benzene with Thebaine

2. NITROSOCARBONYL PRECURSORS, REACTIVITY, AND TRAPPING We have gathered the precursors of NC intermediates into six different categories of chemical compounds as previously reported, and accordingly, we can define different methods for the NC generation. The syntheses of these starting materials will be reported briefly, giving the main references for a useful approach to these compounds. 2.1. Starting Materials and their Synthesis

2.1.1. Hydroxamic Acids. The chemistry of hydroxamic acids began in 1869 when H. Lossen isolated oxalohydroxamic acid from the reaction between ethyl oxalate and hydroxylamine.30 Although these compounds have been known for over 140 years, their synthesis continues to occupy plenty of pages of scientific journals dealing with new synthetic approaches and possible applications in organic chemistry and as bioactive molecules. A number of review articles deal with the chemistry of hydroxamic acids. One of the earliest is by Lossen,31 which summarizes the status of nearly 25 years of research done by Lossen’s group. The work published in Chemical Reviews in 1943 represents the first complete review dealing with the nomenclature, synthesis, and chemistry of hydroxamic acids.32 Thirty years later, an updated chapter by Sandler and Karo was published in Organic Functional Group Preparation, a book edited by Academic Press in 1972.33 In recent years, Iwasa reported a summary of the modern methods to prepare these precursors.2 Among the several possible synthetic methods for the preparation of hydroxamic acids, two approaches, which have been used in most of the cases at hand, are (i) reaction of acyl halides with hydroxylamine and (ii) reactions of acids or esters with hydroxylamine (Scheme 3). Both synthetic pathways correspond to acyl substitution where the nucleophile is the hydroxylamine as free base and the leaving

Scheme 4. Dimerization of Nitrile Oxides to Furoxan

Scheme 3. Synthesis of Hydroxamic Acids

F


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variety of aromatic nitrile oxides is reported, although this paper is indeed hardly accessible to interested readers.42 In 1960 the cornerstone of 1,3-dipolar cycloaddition was introduced by Huisgen43 and the research in the nitrile oxide field took a sharp acceleration. The properties and synthetic potential of nitrile oxide cycloaddition were actively explored. The preparation of nitrile oxides received increased attention, and new methods were discovered. The best and most widely applied procedure for the generation of nitrile oxides remains Huisgen’s in situ dehydrohalogenation of hydroximic acid chlorides with triethylamine. The nitrile oxides became privileged precursors of the NC intermediates much later with respect to hydroxamic acids, in 1996, when reaction between them and N-oxides and in particular tertiary amine N-oxides was discovered.44,45 Alternatively, the dehydration of primary nitroalkanes can be used for the in situ generation of of aliphatic nitrile oxides.46 This technique has become a favorite route in the application of nitrile oxide cycloadditions to the synthesis of natural products.38 The structures of the nitrile oxides used to generate NC intermediates will be reported in section 2.1.5 according to the nature of the R group. The syntheses will be also reported for those 1,3-dipoles whose preparation is not directly accounted for by the general methods cited above. 2.1.5. 1,2,4-Oxadiazole-4-oxides. The first 1,2,4-oxadiazole-4-oxide was prepared by Wieland a century ago,47 but this compound remained largely a chemical curiosity until very recently. 1,2,4-Oxadiazole-4-oxides are a family of heterocycles closely related to the chemistry of nitrile oxides, which were actively studied in the past half-century and provided basic knowledge of 1,2,4-oxadiazole-4-oxides. The dimerizations of nitrile oxides under acidic or basic conditions were thoroughly studied by different research groups,48−58 and offer the more common entries to the symmetrical substituted 1,2,4-oxadiazole4-oxides (Scheme 5). A more general route to symmetrical and unsymmetrical substituted 1,2,4-oxadiazole-4-oxides is based on the nitrile oxide cycloadditions to amidoximes.59

A variety of other 1,2,4-oxadiazole-4-oxide forming reactions are also known in the literature. Many of these reactions were neither fully exploited nor mechanistically understood since they require unusual starting reagents, they are often difficult to be prepared, or because they take place affording complex mixtures of products. A recent review was dedicated to the synthesis and synthetic applications of 1,2,4,-oxadiazole-4-oxides.60 The chemistry of 1,2,4-oxadiazole-4-oxides is related to the fragility of the heterocyclic ring, which undergoes photochemical or thermal cycloreversion to nitriles and NC intermediates. Trapping of the NC takes place easily with dienes and enes, affording a variety of HDA and ene adducts, which attract great interest, not only because of their useful synthetic elaboration toward many natural products of potential pharmaceutical applications but also for the very first detection of these fleeting intermediates. The high efficiency of the photochemical cleavage of 1,2,4oxadiazole-4-oxides at room temperature or below affords the softest entry to the NCs and allows for the study of their chemistry under convenient and simple experimental conditions. The photochemical cleavage has been applied successfully to solid phase chemistry, allowing for a safe and environmentally friendly methodology for the synthesis of important intermediates. 2.1.6. Nitrodiazoalkanes. The literature concerning the generation of NC intermediates reports other rare precursors such as the nitrocarbenes, whose preparation requires starting from nitrodiazoalkanes of general formula O2NCRN N.61 These starting materials are prepared on treatment of nitrotert-butyldiazoacetate with trifluoroacetic acid in ether as the solvent. They are converted into NC intermediates through catalytic or photochemical generation methods. 2.2. Reactivity of Nitrosocarbonyls and Trapping Methods

In order to define the character of NC intermediates in terms of reactivity, it is worthwhile to focus on the title of the “Tilden Lecture”1 given by G. W. Kirby: “Electrophilic C-NitrosoCompounds”. The electrophilic properties of these fleeting intermediates are somewhat increased by the presence of an electron-withdrawing group, such as the carbonyl RCO group on the nitroso moiety, a well-known and powerful electrophilic functional group. The strong electrophilic behavior is displayed by reaction of these intermediates with three different classes of compounds, which act as trapping (T) agents and give rise to the classifications shown in Table 2. An “i” after the trapping method will indicate the “intramolecular” version of the reaction.

Scheme 5. Dimerization Paths of Nitrile Oxides

3. NITROSOCARBONYL GENERATION METHODS The generation methods of NC intermediates can be grouped under seven main headings depending upon the protocols, which transform the different starting materials into the target intermediates. The methods are listed in Table 3. Table 2. Classes of Compounds That Act as Trapping Agents compound 1 2 3 a

reaction

dienes, acyclic and cyclic, belonging to the family of the hydrocarbons and including compounds having a diene system in their skeleton (e.g., heterodienes) alkenes, acyclic and cyclic, also including those compounds having a CC double bond in their structures nucleophiles, including carbon nucleophiles and oxygen/nitrogen nucleophiles

acronym

HDA cycloaddition

TCa

ene reaction aldol reactions, electrophilic amination, and hydroxylation

TEb TNc

Trapping through cycloaddition (C) reactions. bTrapping through ene (E) reactions. cTrapping with nucleophiles (N). G


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to prepare the deformylated compound 7. Both these cycloadducts are characterized by a thermal lability (vide infra) and were used in a cycloreversion reaction to generate respectively the nitrosoformaldehyde (HCONO) 1a and the nitrosyl hydride (HNO). The reactions were conducted at 110 °C in toluene as solvent and in the presence of 1-(4-tert-butylcyclohexylidene)-4-tert-butylcyclohexane to afford the ene adducts 8a and 8b in good yields. The ene reaction reaction also represents a way of trapping NCs, and the results reported by the authors were conducted in view of attempts to have more insights into the mechanism of singlet oxygen ene reactions and nitroso derivatives and the relative stereochemical outcome. Acetohydroxamic acid 2b (entry 2) is somewhat part of the history of NCs since it was used by Kirby in 1973 in the reaction with thebaine as trapping agent and tetraethylammonium periodate as oxidant as a reference reaction to demonstrate the validity of the method to generate these fleeting intermediates (see Scheme 2).27 In the same paper Kirby reports the synthesis of the nitrosocarbonyl methane 1b HDA cycloadducts to 9,10DMA and butadiene.63 Thebaine will be used years later by Kirby to capture the nitrosocarbonyl methane 1b and nitrosocarbonyl pentane 1e (Table 4, entry 5); both corresponding cycloadducts were converted in four steps into analgesic derivatives.64 The 9,10-DMA cycloadduct of nitrosocarbonyl methane 1b was found also to decompose thermally at 60 °C in benzene in the presence of thebaine to give the corresponding cycloadduct in 96% yield.63 First-order kinetics were observed for the release of DMA, k = 4.4 × 10−5 s−1, consistent with slow dissociation of the HDA cycloadduct followed by rapid capture of 1b by thebaine. To this thermal procedure to generate the NC intermediates, a specific section will be dedicated in this review (see section 3.4). In 1977 Kirby reports the oxidation of 2b with Et4IO4 in dichloromethane (DCM) as solvent at 0 °C in the presence of a new trapping agent of the TC type, the ergosteryl acetate that captures the nitrosocarbonyl methane 1b affording the HDA product in 84% yield.65,66 In the same year Kirby collects his first results on NC chemistry in the famous review published in Chemical Society Reviews.1 The nitrosocarbonyl methane 1b however is prone to further derivatization when trapped with 9,10-DMA. The corresponding HDA cycloadduct 9 can be obtained in excellent yields (>90%), and formation of the enolate could be secured by treatment with LDA in THF−HMPA (4:1) at −78 °C, followed by quenching with 2,4-hexadienal, affording the condensation product 10 in 85% yield (Scheme 7).67 Thermolysis of 10 in benzene at reflux for 5 h then afforded, besides the DMA, a mixture of diastereoisomeric intramolecular HDA cycloadducts 11a and 11b in quantitative yields. This is a classical example proposed by G. E. Keck of dienophile transfer, using HDA cycloadducts of nitrosocarbonyl methane 1b as synthetic reagents, that allows the preparation of otherwise difficultly accessible intramolecular [4 + 2] adducts with exceptionally high efficiency. The procedure, that will be also reviewed in section 3.4.1, was successfully applied in the condensation of the enolate of the cycloadduct 9 with a variety of α,β-unsaturated aldehydes substituted with tert-butyl dimethylsilyloxy groups. The products of condensation were converted to their tert-butyl dimethylsilyl ethers 12. These new substrates were thermally submitted to intramolecular ene processes affording unsaturated pyrrolidinones 13 in quantitative yields (Scheme 8).68 The mild conditions of the processes

Table 3. Generation Methods for Nitrosocarbonyl Intermediates protocol

acronym

oxidative

Ox

photochemical thermal

Pt Th

nitrocarbenes

NZ

compound hydroxamic acid N-hydroxycarbamates N-hydroxyureas nitrile oxides 1,2,4-oxadiazole-4-oxides 9,10-dimethylanthracene cycloadducts 1,2,4-oxadiazole-4-oxides nitrodiazoalkanes

acronym AOx COx UOx NOx OPt DTh OTh NZ

On the basis of such classification different tables will collect the structural information on starting materials and reagents as well as the essential experimental conditions and the structures of the trapping agents will be commented in view of the use of the final compounds. In the Supporting Information a complete collection of structures of starting materials is reported with the generation method labels and references to tables in the text. 3.1. Oxidative Protocols

Oxidative methods rely upon the use of a variety of reagents or mixtures of compounds displaying oxidative properties whose application in the NC intermediate generation has received a continuous development by different research groups engaged in this field. When hydroxamic acids are used as precursors to promote the conversion of the NH−OH into the NO group, the most popular oxidants are undoubtedly the periodate derivatives. In fact, besides HIO4, sodium and ammonium salts were the most successful compounds used in an enormous number of cases for the efficient oxidation of hydroxamic acids. For the same purposes, we mention the use of halogens and in particular Br2 and I2 or derivatives such as NBS. Hypervalent iodine derivatives are also used in a few cases; Ph−IO and the Dess−Martin reagent are reported in the very recent literature. Another efficient protocol is represented by the Swern oxidation (oxalyl chloride in DMSO). Metal oxides such as Ag2O or PbO2 have been reported in a few cases. Finally, the use of transition metal catalysts is coupled with the use of peroxides to promote hydroxamic acid oxidation. Recently, aerobic catalytic methods and metal catalyzed protocols were introduced as valuable alternatives to classical oxidation methodologies. The nitrile oxides require the donation of a nucleophilic oxygen atom to the electrophilic carbon atom of the nitrile oxide moiety; tertiary amine N-oxides are the reagents of choice. 3.1.1. From Aliphatic and Aromatic Hydroxamic Acids. Table 4 reports the structures of aliphatic (acyclic and cyclic alkyl and alkenyl derivatives) hydroxamic acids used to generate the corresponding NC intermediates through oxidative protocols. The simplest of all the NC intermediates is nitrosoformaldehyde (HCONO) 1a readily available from formohydroxamic acid 2a (entry 1 of Table 4) that is prepared according to the reported procedures.33 The oxidation is conducted in the presence of the benzyltrimethylammonium periodate that was not purchased but was prepared by the authors starting from periodic acid as reported in the paper. The reaction smoothly proceeds at room temperature in DMF as solvent in the presence of an excess of 9,10-dimethylanthracene (9,10-DMA) in a typical HDA cycloaddition reaction, affording the N-formylnitroso derivative up to 79% yields (Scheme 6).62 Cycloadduct 6 is submitted to further treatment with Me2NH in alcoholic solution H


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Table 4. Structures of Aliphatic Hydroxamic Acids R−CO−NH−OH, Oxidants, Trapping Agents, and Reaction Conditions

a

Yields refer to the best results obtained or ranges of the best performances of the reported method.

(benzene at reflux, 5 h) make them particularly attractive for employment in natural products synthesis.69,70 The promising results obtained by Keck in the intramolecular ene reactions of NCs whose structures were modified through condensation with aldehydes of the enolates generated from cycloadduct 9 determined the further steps in the use of acylnitroso compounds in ene reactions. The main question was to find the limit of application of the entropic assistance of intramolecular effects in the ene reactions of NCs with a variety

of olefins; i.e., is it possible to perform ene reactions by generating the nitrosocarbonyl methane 1b in the presence of some alkenes, without appending an unsaturated substituent at the acylnitroso group? Keck and Yates explored three methods: (a) nitrosocarbonyl methane 1b was generated by thermal fragmentation of cycloadduct 9 at the boiling point of selected olefins (substitute cyclohexenes, 1-octene, and some other simple alkenes); (b) several reactions were carried out in benzene at reflux in the I


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Scheme 6. HDA Cycloaddition Reaction of FormoNitrosocarbonyl 1a to 9,10-DMA

presence of Mo(CO)6 to prepare 1,4-amino alcohols and amino cyclitols. This protocol to cleave the N−O bond was extensively used by M. J. Miller and co-workers to prepare the 4aminocyclopenten-1-ol derivative as a useful synthon for further synthetic transfomations.78 Valuable synthetic applications of the cyclopentadiene adduct of nitrosocarbonyl methane 1b were demonstrated by M. J. Miller and co-workers, who studied the stereo- and regioselective Pd(0)/InI-mediated allylic additions of aldehyde and ketones. In particular, the addition of benzyloxyacetaldehyde to the adduct 14 was promoted by the in situ generated Pd(0) species in the presence of InI to afford a mixture of cyclopentene derivatives 15a−15c in 55% yields (Scheme 9).77 In the reported solvent mixture the ratios of the three products are indicated in Scheme 9, and compound 15a is the major component. Upon changing the solvent mixture, a variable selectivity is observed. The method is suitable for the use of a variety of aliphatic, cyclic, unsaturated, and aromatic aldehydes affording the adducts of type 15a in valuable yields (56−65%). When N-carboxymethyl-1,2-dihydropyridine is used as an azadiene, nitrosocarbonyl methane 1b is captured to afford the HDA cycloadduct 16 in 67% yield (Scheme 10).79 Streith and coworkers have investigated the use of the acylnitroso intermediates in the synthetic approach toward aminosugars. Nitrosocarbonyl methane 1b reacted specifically with the 1,2dihydropyridine affording the syn cycloadduct 16 and the authors suggest a possible interpretation in terms of frontier molecular orbitals (FMOs): the lowest unoccupied molecular orbital (LUMO) of the acylnitroso dienophile has the largest coefficient on the oxygen atom of the nitroso group, because of the strong electron-withdrawing effect of the carbonyl moiety, similar to the LUMO of acrolein; on the basis of HOMOdiene− LUMOdienophile interaction (HOMO, highest occupied molecular orbital), the cycloaddition proceeds specifically toward the syn adduct. Cis-hydroxylation of the cycloadduct 16 with OsO4/NMO protocol in H2O/acetone as solvents afforded stereoselectively the corresponding diol; protection of the hydroxy groups

Scheme 7. Derivatization of Cycloadduct 9 with Aldehydes and Thermal Intramolecular HDA Cycloaddition

presence of the same olefins; (c) the reactions were conducted in sealed tubes with olefin concentration of 0.2 M. In all cases the thermally stable ene adducts were easily isolated in 83−95% yields and the method was for the first time introduced as direct functionalization of olefins (allylic amidation).71 Besides the use of natural compounds as trapping agents, nitrosocarbonyl methane 1b is efficiently trapped with the highly reactive cyclopentadiene affording N-acetyl-2,3-oxazanorborn-5ene in very good yield, using tetraethylammonium periodate as oxidant72−74 or sodium periodate in a water/methanol solution affording the same cycloadduct up to 99% yield, as a valuable entry to a substrate for the synthesis of conformationally restricted analogues of siderophore biosynthetases.75 To the cyclic dienes reported above, others were introduced to prepare oxazines such as 1,3-cycloheptadiene76 and 1-substituted 1,3-cyclohexadienes such as 2,2-dimethyl-3a,7a-dihydrobenzo[d][1,3]dioxole that reacted with the in situ generated nitrosocarbonyl methane 1b to give the corresponding HDA cycloadducts in 90% yield.76,80 The synthesized 1,2-oxazines were easily submitted to N−O bond reductive cleavage in the Scheme 8. Thermal Retro-DA and Intramolecular Ene Reaction

J


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Scheme 9. Stereo- and Regioselective Pd(0)/InI-Mediated Allylic Additions

Scheme 10. HDA Cycloaddition to Dihydropyridine for Aminosugar Synthesis

Scheme 11. Pummerer’s Ketone as Precursor of Diene 19 in HDA Cycloaddition with Nitrosocarbonyl 1b

through acetylation gave the derivative 17 that is the precursor of the peracetylated amino-lyxopyranose 18 through hydrogenolysis (Pd/C). The dienamine 19 of Pummerer’s ketone was used by Kirby to trap the nitrosocarbonyl methane 1b, generated in situ from the acetohydroxamic acid 2b, under typical experimental conditions (Scheme 11, entry 2 of Table 4).81,82 Pummerer’s ketone was employed as a “pharmacophoric synthon” for the synthesis of analogues of the morphine alkaloids. Here the dienamine 19 reacts with the nitrosocarbonyl methane to afford the primary HDA cycloadduct 20 that, under the reaction conditions, is hydrolyzed to give the final isolated compound 21 in 28% yield. Low chemoselectivity and reaction yields did not encourage the use of this type of trapping agent in cycloaddition reactions with NC intermediates. Nitrosocarbonyl methane 1b was generated in situ by the periodate oxidation in DCM solution in the presence of an asymmetrically substituted silyloxy-diene 22 (Scheme 12).

Scheme 12. HDA Cycloaddition to Asymmetrically Substituted Silyloxy-diene 22

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Scheme 13. Asymmetric HDA Cycloadditions to the (S)-N-(1,3-Butadienyl)pyroglutamate Methyl Ester 24

The HDA cycloaddition reaction afforded the expected regioisomeric compounds 23a and 23b in 79% overall yields and in the 1:1 ratio.83,84 No remarkable steric effect is determined by the methyl group of the NC moiety in terms of regioselectivity. In other cases, which will be examined later in this review, the regioselectivities are somewhat different, depending upon the substituent located on the acyl nitroso cycloaddend. The same authors presented the asymmetric HDA cycloadditions of nitrosocarobonyl methane to the (S)-N-(1,3butadienyl)pyroglutamate methyl ester 24, an N-dienyl lactam frequently employed in asymmetric cycloaddition reactions (Scheme 13).85,86 The reaction turned out to be regiospecific, leading to the cycloadducts 25a and 25b in 62% overall yield and in the ratio 2:1. The major cycloadduct of type 25a appears in its (6S) configuration as determined by X-ray analysis in accordance with the proposed mechanism. The asymmetric inductor can be easily recovered by catalytic hydrogenolysis. In 1999 a one-pot allylic amidation procedure, which employs the ene reaction of NC intermediates with electron-rich olefins, is presented through the generation of these intermediates from hydroxamic acids oxidized with iodosobenzene diacetate (Scheme 14). This is the first case of oxidation of hydroxamic acids without the use of periodates.

The use of the Dess−Martin periodinane represents a logical consequence of the previous results. Acetohydroxamic acid 2b is efficiently oxidized under mild conditions to the corresponding nitrosocarbonyl methane 1b and trapped in situ with cyclopentadiene to afford the HDA cycloadduct in 34% yield. Other dienes have been used, such as 1,3-cyclohexadiene and 9,10DMA, allowing isolation of the corresponding cycloadducts, both with 24% yields. The modest yields do not represent a sustainable alternative to other methods.88 The new century brings new oxidation methods, and in 2012 Read de Alaniz and co-workers describe a general and efficient aerobic oxidation of acetohydroxamic acid 2b providing a catalytic and sustainable alternative to stoichiometric oxidation methods to gain access to a range of nitroso compounds (Scheme 15).89 The reaction is promoted by CuCl/Py as the Scheme 15. Aerobic Oxidation of Acetohydroxamic Acid 2b

Scheme 14. Ene Reaction of Nitrosocarbonyl Methane with TME

catalyst in THF at room temperature and smoothly proceeds in the presence of 1,3-cyclohexadiene to afford the HDA cycloadduct in 58% yield. To conclude the performances of nitrosocarbonyl methane 1b, we report the catalytic method by Iwasa and co-workers based upon the ruthenium(II)-pyridine-2,6-dicarboxylate (pydic) of 2,6-bis(oxazolinyl)pyridine (pybox-dh) complex 28 (11 mol %) that catalyzes the hydrogen peroxide oxidation of acetohydroxamic acid 2b in the presence of cyclopentadiene to give the corresponding HDA cycloadduct 14 in 84% yield (Scheme 16).90 Some other aliphatic substituents are part of this section. Because of the ease of hydrolysis of trifluoroacetamides, Just and Cutrone studied the condensation of cyclopentadiene with nitrosocarbonyl trifluoromethane 1c (Table 4, entry 3) with the aim to prepare 2,3-oxazabicyclo[2.2.1]heptane 31 (Scheme 17).91

Iodosobenzene diacetate is an oxidizing agent operating under mild and clean in situ conditions; acetohydroxamic acid 2b is efficiently oxidized by iodosobenzene diacetate in the presence of tetramethylethylene (TME) to give the ene adduct 26 and this method avoids the formation of byproducts commonly formed because the strong oxidation power of periodates.87 L


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Scheme 16. Ru(II) (pybox-dh) (pydic) Oxidation of Acetohydroxamic Acid 2b

Scheme 18. HDA Cycloaddition of Pivalohydroxamic Acid 2d to Cyclopentadiene

Scheme 19. HDA Cycloaddition of Unsaturated Hydroxamic Acids 2f−2h to Cyclopentadiene Trifluoroacetohydroxamic acid 2c is added at −70 °C to cyclopentadiene and benzyltrimethylammonium periodate as oxidant, and the resulting product was found to be the HDA cycloadduct 29 (78%) that was reduced to the derivative 30. From this latter the 2,3-oxazabicycloheptane 31 was secured by reduction with sodium borohydride. Quite interesting is the case represented by the oxidation of pivalohydroxamic acid 2d that discloses the possibility of a different role of the corresponding NC intermediate 1d (Table 4, entry 4), i.e. the double role of the dienophile and hetero diene. The reaction is conducted in the presence of cyclopentadiene as trapping agent with the novelty of the use of silver oxide or lead dioxide as oxidants in ethyl acetate solution (Scheme 18).92 The chromatographic separation of the reaction mixture allowed isolation of the HDA cycloadduct of type 32 along with a small amount (2−10%) of a second cycloadduct which the authors identified as product 33 deriving from the formal cycloaddition of the cyclopentadiene as dienophile and the nitrosocarbonyl 1d as hetero diene. The presence of adduct 33 was justified on the basis of the known lability of the azodipivaloyl analogue; similarly, 33 can derive from 32 generated under the reaction conditions or during the workup. The presence of 33 in the reaction mixture was confirmed by analyzing the hexane extracts from the crude. The authors also tried to heat a benzene solution of cycloadduct 32 with “uncertain results”. Modest yields (45%) were obtained by using NBS as oxidant in the presence of pyridine in DCM as solvent to prepare the same product 32.92,93 Unsaturated NC intermediates were recently obtained by the research group of Vincent and Kouklovsky. The simplest one is the vinyl nitrosocarbonyl 1f (Table 4, entry 6) generated in the presence of sodium periodate in methanol/water solution at 0 °C trapped with cyclopentadiene to give the corresponding HDA cycloadduct 34f in 72%yield (Scheme 19).94,95 Homologation of the alkene side chain is also reported; allyl and 3-butenyl hydroxamic acids 2g and 2h were oxidized to afford the corresponding adducts 34g and 34h in very good

yields (Table 4, entries 7 and 8). These strained nitroso DA adducts functionalized with alkene side chains of diverse length underwent a ring-rearrangement methatesis process with external alkenes and Grubbs II or Hoveyda−Grubbs II ruthenium catalysts, under microwave irradiation or classical heating, to deliver cis-fused bicycles of various ring sizes, which contain an N−O bond. These scaffolds are of synthetic relevance for the generation of molecular diversity and to the total synthesis of alkaloids.95 Alternatively, the allyl hydroxamic acid 2g can be oxidized under the Swern conditions (oxalyl chloride/DMSO in DCM at −78 °C) in the presence of cyclopentadiene to give the expected cycloadduct 34g in 80% yield.96 Table 5 reports the structures of aromatic hydroxamic acids, or hydroxamic acids containing aromatic residues, prepared with common methods or through specific preparations, which were used to generate the corresponding NC intermediates. The simplest aromatic NC intermediate 1i bears the phenyl as substituent and was generated by the oxidation with tetraethylammonium periodate in the presence of thebaine as trapping agents as reported in a paper by Kirby in 1973 (Table 5, entry 1).27 Years later, Sheldrake reinvestigates the same reaction with the aim to cleave selectively the C5−C6 bond in the

Scheme 17. Condensation of Cyclopentadiene with Nitrosocarbonyl Trifluoromethane 1c

M


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Table 5. Structures of Aromatic Hydroxamic Acids Ar−CO−NH−OH, Oxidants, Trapping Agents, and Reaction Conditions

N


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Table 5. continued

a

Yields refer to the best results obtained or ranges of the best performances of the method. bYield refers to the sum of both regioisomers. O


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Scheme 20. Cleavage of the C5−C6 Bond in Cycloadduct of Thebaine and Nitrosocarbonyl Benzene 1i

Scheme 21. Trapping of Nitrosocarbonyl 1i with 1,3-Cyclohexadiene and N−O Bond Cleavage

Scheme 22. Trapping of Nitrosocarbonyl Benzene 1i with Ergosteryl Acetate 39

Scheme 23. HDA Cycloaddition of Nitrosocarbonyl Benzene 1i to 2-Substituted 1,3-Cyclohexadienes

hours affording the aminol 38 as a valuable synthon for model studies on Narcissus alkaloids. Besides thebaine and classical dienes, steroids such as ergosteryl acetate 39 are also used to trap the nitrosocarbonyl benzene 1i under typical experimental conditions (Et4IO4, DCM, 0 °C) to afford the regiosomeric HDA cycloadducts 40a and 40b (Scheme 22).65,66 Only the isomer 40b could be isolated in 33% yield, while 40a readily underwent a [3,3]-sigmatropic rearrangement to give 41 in 56% yield. This and other investigations on the ergosteryl acetate adducts aimed to untie the supposed dichotomy regarding the nature of NC as 2π or 4π components in HDA cycloaddition reactions. The results clearly showed that NC are dienophiles and the products of their “behavior as dienes” come from [3,3]sigmatropic rearrangements.66 The problem of the thermal instability of the nitrosocarbonyl benzene adducts to cyclopentadiene91 and 1,3-cyclohexadiene was investigated, too.72 These studies gave the opportunity to shine some light not only on the thermal generation of these

presence of SmI2 in THF solution to give novel hexahydrobenzazocine products (Scheme 20).97 Other synthetic elaborations of the thebaine cycloadduct 35 were mentioned before in the case of the methane derivative to produce analgesics through ketal synthesis.64 The nitrosocarbonyl benzene 1i, generated through NaIO4 oxidation, was also trapped with 9,10-DMA and found thermally unstable at 60 °C in benzene to release 9,10-DMA according to a first-order kinetics, k = 5.4 × 10−5 s−1, consistent with slow dissociation of the HDA cycloadduct followed by rapid capture of 1i by a suitable diene.28,63 The slow addition of a DMF solution of benzhydroxamic acid 2i to a stirred solution of 1,3-cyclohexadiane and nPr4IO4 in DMF at 23 °C under argon gave the corresponding HDA cycloadduct 37 in 70% yield (Scheme 21).98 Reductive cleavage of the N−O bond in 37 with preservation of both the carbon−carbon double bond and the amide carbonyl was readily accomplished in quantitative yield by treatment with excess aluminum amalgam in 10:1 THF−H2O at 0 °C for several P


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fleeting intermediates from HDA cycloadducts but also on the dimerization of NC in the absence of a trapping agent. From thermal retro-DA reaction of the adduct of 1i to 9,10-DMA, nitrous oxide and benzoic anhydride were detected and some hypotheses on the dimerization mechanism were inferred. Substituted 1,3-cyclohexadienes were extensively used to trap the nitrosocarbonyl benzene 1i. The 2,2-dimethyl-3a,7adihydrobenzo[d][1,3]dioxole reacted with the in situ generated nitrosocarbonyl benzene 1i to give the corresponding HDA cycloadducts in 70% yield.80 2-Substituted 1,3-cyclohexadienes gave regioisomeric mixtures of the nitrosocarbonyl benzene cycloadducts 42a and 42b in the ratio 2.8−2.9:1 (Scheme 23).99 These intermediates 42a and 42b served for the stereospecific preparation of functionalized cis-Δ6-1-octalones as a first probe of DA stereocontrol (π-facial selectivity) by allylic heteroatom substituents, utilizing a rigid cyclic dienophile.100 As mentioned before, the group of Defoin and Streith has extensively used heterocyclic dienes for the synthesis of aminosugars. Some aromatic NCs were also employed containing the phenyl and the benzyl substituents (1i and 1w), and the regioselectivity outcome was explained in light of the FMO theory.79 In particular for the aromatic substituents, it was observed that the regioselectivity is 100% in favor of the compound 43 (Scheme 24). The yields are also quantitative, and the products were synthetically elaborated to aminosugars.101

obtained along with small amounts (5%) of a second compound, 45, deriving from a slow conversion at room temperature through a [3,3]-sigmatropic process of the primary adduct (Scheme 25).102 Nitrosocarbonyl benzene 1i is also at work with the 1,3cycloheptadiene in a proposed new synthetic route to tropane alkaloids. The reaction furnishes the HDA cycloadduct 46 in 65% yield, and N−O bond cleavage is secured with Na/Hg amalgam to afford the cycloheptenol derivative 47, the key intermediate toward the synthesis of N-benzoyl nortropane 48 (Scheme 26).103−106 Similarly, 1,4-functionalization of 1,3-cyclooctadiene using the NC strategy allowed obtaining the HDA cycloadduct 49 in 46% yield. N−O bond cleavage followed by intramolecular cyclization yielded the 9-azabicyclo[4.2.1]nonane (homotropane) and the corresponding non-7-enes (homotrop-7-enes).107 Increasing the complexity of the trapping dienes, Streith reported the use of azetidinodiazepines that reacted with the phenyl and benzyl substituted NCs affording the expected regioisomeric HDA cycloadducts in good yields.108 The tridimensional structures were determined by X-ray analyses corroborating the spectroscopic data (Scheme 27). Notably, the two nitrosocarbonyls 1i and 1w (Table 5, entries 1 and 15) gave reversed selectivities: when the phenyl group is located on the NC dienophile, isomer 50a is the major one, while the benzyl nitrosocarbonyl 1w strongly prefers the addition that leaves the benzyl group opposite to the N−COOEt group of the diazepine ring as it appears in isomer 50b.108 The synthetic use of these cycloadducts has been also reported in order to obtain azetidinoribose and 4-amino-1-deoxyribose, with this latter found active against HIV.109,110 Nitrosocarbonyl benzene 1i was also generated in situ by the oxidation periodate in DCM solution in the presence of an asymmetrically substituted silyloxy-diene 22 (Scheme 28). The HDA cycloaddition reaction gave the expected regioisomeric compounds 51a and 51b in 66% overall yields and in the 2.3:1 ratio.83,84 When the benzyl substituent replaces the phenyl group, no remarkable steric effect is observed and the two regioisomer were obtained in 56% overall yield and 1:1 ratio, as in the case of the nitrosocarbonyl methane. The same authors presented the asymmetric HDA cycloadditions of nitrosocarbonyls 1i and 1w to the (S)-N-(1,3butadienyl)pyroglutamate methyl ester 24 (Scheme 29).85,86 The reaction turned out to be regioselective, leading to the cycloadducts 52a and 52b in 70% overall yield for the phenyl substituted cycloadducts and in 58% overall yield for the benzyl substituted cycloadducts, in the ratios reported in Scheme 29. The one-pot allylic amidation procedure, which employs the ene reaction of NC intermediates with electron-rich olefins, was tested to the aromatic NC intermediates 1i and 1w through oxidation with iodosobenzene diacetate (see Scheme 14 for

Scheme 24. HDA Cycloaddition of Aromatic Nitrosocarbonyls to Dihydropyridine

These observations were confirmed by Knaus, who demonstrated the strong dependence of the regioselectivity upon the electronic effects of substituents located on the dienophile, conducting the reaction with some new dihydropyridines. With nitrosocarbonyl benzene 1i, 70% yield of the compound 44 was

Scheme 25. HDA Cycloaddition of Nitrosocarbonyl Benzene 1i to Dihydropyridines

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Scheme 26. HDA Cycloaddition of Nitrosocarbonyl Benzene 1i to 1,3-Cycloheptadiene and 1,3-Cyclooctadiene

Scheme 27. HDA Cycloaddition of Aromatic Nitrosocarbonyls 1i and 1w to Azetidinodiazepine

benzyl-hydroxamic acids 2i, 2o, and 2w (Table 5, entries 1, 7, and 15) to gain access to the corresponding NC intermediates (see Scheme 15 as reference).89 The reaction nicely afforded the HDA adducts to 1,3-cyclohexadiene, respectively in 80 and 93% yields. The catalytic method by Iwasa and co-workers based upon the ruthenium(II)-pyridine-2,6-dicarboxylate (pydic) of 2,6bis(oxazolinyl)pyridine (pybox-dh) complex 28 (11 mol %) catalyzed the hydrogen peroxide oxidation of the benzhydroxamic acid 2i and tolylhydroxamic acid 2m (Table 5, entry 5) in the presence of cyclopentadiene to give the corresponding HDA cycloadducts in 90 and 92% yields, respectively (see Scheme 16 as reference).90 The theme of the double role of NC intermediates as dienophiles or hetero dienes was investigated also with help of the cyclopentadiene adducts of nitrosocarbonyl benzene 1i. The reaction is conducted in the presence of cyclopentadiene as trapping agent with NBS as oxidant in DCM solution.92,93 The HDA cycloadduct was obtained in 70% yield. These studies paved the way to intriguing investigations by changing both oxidants and dienes. Silver or lead oxides were found the most convenient and were employed in ethyl acetate (or any common aprotic solvent) solutions to oxidize the benzhydroxamic acids 2i in the presence of 2,5-dimethylfuran (Scheme 30).111,112

Scheme 28. HDA Cycloaddition to Asymmetrically Substituted Silyloxy-diene 22

reference). Benz- and benzyl-hydroxamic acids 2i and 2w were efficiently oxidized by iodosobenzene diacetate in the presence of tetramethylethylene (TME) to give the expected ene adducts in high yields.87 In parallel, the use of the Dess−Martin periodinane allowed oxidation of benz- and benzyl-hydroxamic acids 2i and 2w under mild conditions to the corresponding nitrosocarbonyls 1i and 1w that were trapped in situ with cyclopentadiene, 1,3-cyclohexadiene, and 9,10-DMA to afford the corresponding HDA cycloadducts, respectively, in 67, 51, and 33% yields.88 In 2012 Read de Alaniz and co-workers used the aerobic oxidation catalyzed by CuCl/Py of benz-, 2-hydroxyphenyl-, and

Scheme 29. Asymmetric HDA Cycloadditions of Nitrosocarbonyls 1i and 1w to the (S)-N-(1,3-Butadienyl)pyroglutamate Methyl Ester 24

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Scheme 30. HDA Cycloaddition of Nitrosocarbonyl Benzene 1i to 2,5-Dimethylfuran

2,6-bis(oxazolinyl)pyridine (pybox-dh) complex that catalyzes the hydrogen peroxide oxidation of benzhydroxamic acid 2i in the presence of (S)-N-(1,3-butadienyl)pyroglutamate methyl ester 24. The reaction gave the corresponding regioisomeric HDA cycloadducts 57a and 57b in 87% overall yield and in the regioisomeric ratio 4.9:1, respectively, and diastereomeric excess (de) of 65% (Scheme 32).114 The Ru(II)-based catalyst was found to be more efficient than the Ir(I) derivative; other pybox ligands were also tested (varying the substituent on the oxazoline ring) although with lower yields. An experimental and computational approach to understand the reactions of NC intermediates in [4 + 2] cycloadditions compares the results obtained with a variety of aromatic and heterocyclic substituents located on the NC moiety in situ generated with NaIO4 and with catalytic aerobic oxidation conditions using the 1,3-cyclohexadiene as trapping agent. Among the aromatic or phenyl group containing derivatives, we report here some results gathered in Scheme 33 (see also Table 5, entries 1 and 15−17). Periodate oxidation (method A) affords the expected HDA cycloadducts from NCs bearing phenyl, benzyl, phenylethyl, and phenylpropyl groups (Scheme 33, entries 1−4; 1i, 1w, 1x, 1y) in moderate yields (32−53%). The aerobic oxidation was performed in the same solvent (method B, MeOH) in the presence of CuCl2 (10 mol %) and 2ethyl-2-oxazoline (20 mol %).115 The results were quite disappointing since no oxidation was observed. The aerobic protocol needed to be slightly tuned up by changing the solvent to increase the reaction temperature (method C, toluene at reflux). These conditions allowed obtaining the desired HDA cycloadducts in good yields (49− 73%). The authors also investigated the same reactions with 2,3dimethylbutadiene and completed the study by mapping the reaction pathways by density functional theory (DFT) computations at the B3LYP/6-31G* level. We complete the overview on the nitrosocarbonyl benzene 1i accounting the trapping mode through ene reactions conducted by generating the intermediate by hydrogen peroxide metal complex catalyzed oxidation proposed by Iwasa and co-workers. The experimental conditions were properly tuned up and the use of 1.1 equiv of H2O2 in the presence of 2 mol % [Ir(cod)2Cl]2 as the catalyst in THF solution at 0 °C allowed running the ene reaction with 1.5 equiv of tme to obtain the ene adduct in 40% yield (Scheme 34).116 Substituted phenyl groups were also employed in the generation of NC intermediates, and we account for the best results obtained. The simplest is the perfluorinated phenyl group of the nitrosocarbonyl 1j (Table 5, entry 2) that was obtained through periodate oxidation and trapped by thebaine as already depicted in Scheme 20.97 The 4-chlorophenyl nitrosocarbonyl intermediate 1k (Table 5, entry 3) was for the first time generated from the corresponding hydroxamic acid by oxidation with Et4NIO4 and trapped with 9,10-DMA by Corrie and Kirby.28 On the other

The authors demonstrate, on the basis of their spectroscopic investigation, that compound 54 was the correct structure of the isolated product. If the oxidation is carried out at 0 °C, good yields (63%) of the unstable furo[1,4,2]dioxazine 53, the formal product of the addition of the furan to the NC behaving as heterodiene, can be isolated. It was assumed and then demonstrated that compound 53 is the precursor of the final product 54 through isomerization under the experimental conditions, presumably catalyzed by “an undefined component” as the authors reported. A possible concerted rearrangement of compound 53 or alternatively a stepwise process through a dipolar intermediate was proposed. More difficult for the authors was to say if the classical HDA cycloadduct 55 is at work as a possible precursor through [3,3]-sigmatropic rearrangement to give 53, in analogy with previous findings,92,93 and the question seems to be still open. Nitrosocarbonyl benzene 1i was used by Iwasa and co-workers to test new catalytic systems in the presence of hydrogen peroxide as oxidant and cyclopentadiene as trapping agent. The HDA cycloadduct 56 was obtained in 97% yield under the experimental condition reported in Scheme 31 with 2 mol % of catalyst used.113 Scheme 31. [Ir(coe)2Cl]2-Catalyzed Hydrogen Peroxide Oxidation of Benzhydroxamic Acid 2i

With a catalyst loading of 0.05 mol %, a maximum TON (turnover number) was attained of 740. Other solvents (MeOH, DCM, DMF, H2O) can be used but with lower yields. Good results were also obtained under the same experimental conditions for the trapping with cyclopentadiene of the 4chlorophenyloxymethyl nitrosocarbonyl 1ab (Table 5, entry 20); the HDA cycloadduct was isolated in 60% yield.113 Being this last part dedicated to alternative oxidant species, we report the catalytic method by Iwasa and co-workers based upon the ruthenium(II)- or Ir(I)-pyridine-2,6-dicarboxylate (pydic) of S


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Scheme 32. Ru(II)-Catalyzed Asymmetric HDA Cycloadditions to the (S)-N-(1,3-Butadienyl)pyroglutamate Methyl Ester 24

Scheme 33. Comparison between Periodate and Aerobic Oxidation in Nitrosocarbonyl Generation

31 with 2 mol % of catalyst used afforded the desired products in 94 and 80% yields, respectively.113 The synthesis of 1,4-benzodiazepines has received a novel contribution from suitable substituted NC intermediates, and the works published by M. J. Miller and co-workers nicely represent this strategy. The anthranilic acid 60 is the starting material for the preparation of the corresponding N-tosyl benzhydroxamic acid derivative 2r (Table 5, entry 10) that underwent periodate oxidation in the presence of cyclopentadiene to afford the expected HDA cycloadduct 61 in 79% yield (Scheme 35).117,118

Scheme 34. Hydrogen Peroxide Metal Complex Catalyzed Oxidation and Ene Trapping of Nitrosocarbonyl Benzene 1i

Scheme 35. Synthetic Strategy toward Benzodiazepines via Nitrosocarbonyl Chemistry

hand, the ergosteryl acetate 39 was used to trap, respectively, the 4-bromophenyl, 2,4,6-trimethylphenyl, 4-methoxyphenyl, and 4nitrophenyl nitrosocarbonyls 1l, 1n, 1p, and 1t (Table 5, entries 4, 6, 8, and 12) under typical experimental conditions (Et4IO4, DCM, 0 °C) to afford the regiosomeric HDA cycloadducts of type 40a and 40b as already shown in Scheme 22.66 The 4methoxyphenyl nitrosocarbonyl 1p, generated with periodates in the proper solvent at 0 °C, was also trapped with 9,10-DMA28 or thebaine.97 The 4-bromophenyl and 4-nitrophenyl nitrosocarbonyls 1l and 1t (Table 5, entries 4 and 12) can be alternatively generated by the use of silver oxide or lead dioxide as oxidants in ethyl acetate solution and efficiently trapped with cyclopentadiene as shown in Scheme 18.92,93 The [Ir(coe)2Cl]2-catalyzed hydrogen peroxide oxidation in the presence of cyclopentadiene as trapping agent allowed preparation of the HDA cycloadducts of the 4-methoxyphenyl and 3,4-dimethoxyphenyl nitrosocarbonyls 1p and 1q (Table 5, entries 8 and 9). The experimental condition reported in Scheme

Through application of Pd(0) chemistry the conversion in the final benzodiazepine 62 was accomplished in 20% yield. The efficiency of this last transformation was found to be dependent on the NH pKa of the sulfonamide cycloadduct. Nitrosocarbonyl 1s HDA cycloadduct to cyclopentadiene bearing a 3,5diaminophenyl substituent can be also obtained by catalytic T


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adduct 35 (Scheme 20) to produce analgesics, and this approach has been enriched by the introduction of other substituents on the NC moiety, in particular by generating through NaIO4 oxidation the benzyl-, 2-phenylethyl- and 3-phenylpropylnitrosocarbonyls 1w, 1x, and 1y (Table 5, entries 15−17). In all cases the elaborations provided analogues of the aminocodeinones. Miller and co-workers extensively used the benzyl nitrosocarbonyl intermediate 1w for synthetic purposes by simple generation with NaIO4 in the presence of cyclic dienes. The high yields of the protocol allowed for the use of these scaffolds to investigate different synthetic strategies. The regio- and stereoselective Fe(III)- and Pd(0)-mediated ring opening of the cyclopentadiene adducts provided anti- and syn-1,4-hydroxamic acid derived cyclopentenes, enhancing the chemical versatility of these adducts and complementing standard N−O reductive procedures.121 The protocol was implemented by the use of Cu(II) in an alcohol solvent to induce ring opening affording predominantly the anti-1,4-hydroxamic acid.122 The use of heterocyclic dienes done by the group of Defoin and Streith served for the synthesis of aminosugars.79,101 A variant of the dihydropyridine diene 68 was prepared from a regioselective introduction of a methoxycarbonyl methyl group at the C2 position of unsubstituted pyridine through Cu(II) catalysis and was employed for an expeditious entry to unconventional piperidines. Periodate generation of the nitrosocarbonyl 1w from the relative hydroxamic acid 2w with the in situ presence of the previously prepared diene afforded the regioisomeric mixture of HDA cycloadduts in 42−65% yield, depending on oxidant and solvent. The regioisomeric ratio favors compound 69a (99:1), which was converted in two steps into the desired piperidine derivative 70 (Scheme 38).123

reduction of the dinitro derivative (Table 5, entry, 11) and was found unstable upon standing in air.91 The first total synthesis of racemic neplanocin A was reported by Retey and co-workers in 1983 taking advantage of the chemistry of the 3,5-dinitrophenyl nitrosocarbonyl 1u (Table 5, entry 13) prepared from the corresponding hydroxamic acid 2u that was oxidized by periodate in the presence of cyclopentadiene as trapping agent to isolate the HDA cycloadduct 63 in 65% yield.91 Detachment of the dinitrobenzoyl group and cleavage of the N−O bond allowed obtaining the aminolic intermediate 64 that was the starting point for the linear construction of the adenine heterobase to give neplanocin A 65 (Scheme 36).119 This strategy has been applied in recent years for the preparation of novel nucleoside analogues (vide infra). Scheme 36. Synthesis of Racemic Neplanocin A through 3,5Dinitrophenyl Nitrosocarbonyl 1u

The enantiocontrolled syntheses of (+)-lycoricidine and other alkaloids were investigated by Hudlicky and co-workers. Within the scope of their experiments, the microbial oxidation with Pseudomonas putida80 of aromatic compounds allowed preparation of the diene 66 that was used as trapping agent for the capture of the NC generated through periodate oxidation from the hydroxamic acid 2v, containing a piperonyl group (Scheme 37, Table 5, entry 14).120 The synthesis was performed in nine steps demonstrating the potential viability of the NC chemistry to Narcissus alkaloids. One of the most frequently used aromatic substituents in NC chemistry is absolutely the benzyl group. We have already mentioned the synthetic elaborations of the thebaine cyclo-

Scheme 38. Generation of Benzyl Nitrosocarbonyl 1w for the Synthesis of Piperidines

Scheme 37. HDA Cycloadduct Synthesis as Intermediate to (+)-Lycoricidine

Besides the asymmetrically substituted sililoxy-diene 22 (see Scheme 28),83,84 other 1,4-disubstituted 1,3-butadienes have been used with the benzyl nitrosocarbonyl 1w. In particular, the dimethyl acetal derivative was used to capture the in situ generated nitrosocarbonyl 1w by the periodate oxidation in chloroform solution. The HDA cycloaddition proceeds regioand stereospecifically leading to the expected dihydrooxazine 71 in 61% yield (Scheme 39).124,125 cis-Glycosidation of the cycloadduct gave the dihydro derivative that is the intermediate toward the elaboration into aminodeoxyallose derivatives; this type of piperidino-deoxysugar U


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group (R′ = CH(OMe)2), the HDA cycloadducts of 1ac and 1ah are obtained in 75 and 85% yields, respectively, and the regioisomeric ratio is the same in both cases, 8:2 favoring the isomer 73a.124,125 The asymmetric HDA cycloadditions of nitrosocarbonyls 1ac (RO = MeO), 1ae (RO = TMSCH2CH2O), and 1ah (RO = PhCH2O) to the (S)-N-(1,3-butadienyl)pyroglutamate methyl ester 24, an N-dienyl lactam frequently employed in asymmetric cycloaddition reactions (Scheme 42), gives a mixture of diastereoisomeric compounds 74a and 74b in very good yields (63−80%).85,86 The relative amounts of the stereoisomers are reported in Scheme 42 and evidence the preference for compound 74a with the (S,S) configuration for all substituted dienophiles. Defoin and Streith tested also the effect of the ester substituent on the chiral center of the diene 24. The carbomethoxy group was replaced with isopropyl, tert-butyl, and the unusual, although strongly sterically demanding, cholesteryl groups. The effect compared with the previous results was minimal: the ratio in favor of the stereoisomer 74a increases up to 88:12 and the chemical yields remained good.169,170 2-Substituted 1,3-cyclohexadienes gave regioisomeric mixtures of the methoxy substituted nitrosocarbonyl 1ac. The cycloadducts 75a and 75b were isolated in very good yields, and in both cases in the ratio ca. 3:1 (Scheme 43).99,100 Thebaine is back on the scene as trapping agent with trichloroethyloxy nitrosocarbonyl 1ad (Table 5, entry 2). This substituent linked to the CO group is known by the acronym “Troc-”, and the oxidation with periodate afforded the HDA cycloadduct whose X-ray analysis was reported to corroborate the structure.126 A more classical diene 76, although inserted on a protected D-(−)-arabinose skeleton, was used to produce the oxazine required to promote ring contraction process to a pyrrole ring and subsequent elaborations to furnish pyrrolo-castanospermine derivatives. The carbamate 2ad was prepared and oxidized with periodate in the presence of the synthesized diene 76 in DCM solution at 0 °C to afford the HDA cycloadduct 77 in 72% yield (Scheme 44). The product is constituted by a mixture of regiosiomers in a 48:14:7:3 ratio with the predominant C-6 epimer.127 The same cycloadduct could also be obtained through thermal generation of the nitrosocarbonyl 1ad from the corresponding 9,10-DMA HDA cycloadduct, known to be thermally unstable and a valid precursor of these fleeting intermediates. After several synthetic steps the target compound 78 was obtained as a novel stable pyrrolo-castanospermine product. In another example the synthetic target is the maduropeptin analogues (family of enediyne antitumor antibiotics) and the fragment containing the two alkyne groups was prepared through NC chemistry. From the cis-2,3-dibromoacrylic ester 79 the diene 80 was prepared in 60% overall yield (Scheme 45). Typical periodate oxidation with the carbamate 2ad allowed isolation of the HDA cycloadduct 81 in 65% yield. Cleavage of the N−O bond under reductive conditions afforded the required aminol, a key intermediate toward the synthetic target.128 Finally, the Troc-nitroso intermediate 1ad was also generated through aerobic oxidation in the presence of CuCl (20 mol %) and pyridine (5 mol %) in THF solution at room temperature in the presence of 1,3-cyclohexadiene. The corresponding HDA cycloadduct was obtained in 87%yield.89 There is no doubt that one of the most frequently used Nhydroxycarbamates as precursors of the NC intermediates is that bearing a tert-butyloxy substituent (Table 5, entry 4). The easy

Scheme 39. Generation of the Nitrosocarbonyl 1w in the Presence of the Dimethyl Acetal of the (E,E)-2,4-Hexadienal

exhibits a strong anomeric effect with the HO−C(1) always axial.125 The presence of unsaturated functionalities within the substituent to the NC moiety has been demonstrated to be compatible with the periodate oxidation. The nitrosocarbonyls 1z and 1aa (Table 5, entries 18 and 19) were generated in DMF/ EtOAc solutions at 0 °C from the corresponding hydroxamic acids 2z and 2aa in the presence of thebaine as trapping agent.97 The HDA cycloadduct containing the styrene moiety was isolated in modest yield (38%), while that containing the 4chlorostyrene group was obtained in 90% yield. 3.1.2. From N-Hydroxycarbamates. Table 6 reports the structures of the nitrosocarbonyl intermediates obtained through oxidative protocols from a different category of starting material, the N-hydroxycarbamates of general formula RO−CO−NH− OH. In Table 6 we have collected the aliphatic and aromatic substituents linked to the oxygen atom and consequently labeled RO. The methoxy group leads the ranking of the substituents in Table 6 (entry 1), and the simplest oxidation with NaIO4 in MeOH/H2O solution allowed obtaining the corresponding nitrosocarbonyl 1ac easily trapped with cyclopentadiene to give the HDA cycloadduct in 99% yield.74 The HDA cycloadduct of the nitrosocarbonyl 1af containing a tert-butoxy group (Table 6, entry 4) was however prepared in three steps from the hydroxylamine derivative. These compounds were kinetically resolved by enzymatic acetylation and were the key intermediates for the total synthesis of phosphodiesterase inhibitors belonging to the pyrazolo[3,4-d]pyrimidine family.74,78 The N-carboxymethyl-1,2-dihydropyridine was used as a diene to trap the nitrosocarbonyl 1ac generated through nPr4NIO4 oxidation in DCM solution at 0 °C. The regioisomeric HDA cycloadducts 72a and 72b were isolated in 78% overall yield in the ratio 1:1 (Scheme 40).79,101 Asymmetrically substituted dienes of type 22 are the trapping agents for the capture of nitrosocarbonyls 1ac (RO = MeO), 1ae (RO = TMSCH2CH2O), and 1ah (RO = PhCH2O), generated in situ by the periodate oxidation in DCM solution (Scheme 41). When the diene bears a TBDM-silyloxy substituent in the position (1) of the 1,3-butadiene, the regiosiomeric HDA cycloadducts 73a and 73b were obtained in 68, 97, and 93% yields, respectively from 1ac, 1ae, and 1ah (Table 5, entries 1, 3, and 6).83,84 The regiosiomeric ratios are reported in Scheme 41, and in the case of the TMSCH2CH2O-benzyloxy substituent, isomer 73a is favored. When the butadiene is substituted with a dimethylacetal V


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Table 6. Structures of N-Hydroxycarbamates RO−CO−NH−OH, Oxidants, Trapping Agents, and Reaction Conditions

W


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Table 6. continued

X


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Table 6. continued

Y


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Table 6. continued

a Yields refer to the best results obtained or ranges of the best performances of the method. bYield refers to the sum of both regioisomers. cMajor regioisomer after osmylation reaction.

submitted to N−O bond reductive cleavage.129 The addition of azides to 82 showed that the reaction was greatly affected by the level of alkene strain and sterically demanding azides do not hinder the reaction and the subsequent elaboration into aziridine derivatives.130 Substrate 82 can be easily converted into malonate derivatives that are converted by Pd(0) catalyst into homoallylic esters.131 Again, the metal-catalyzed transformations are at work in the [RhCl(cod)]2-catalyzed ring opening reaction of 82 with arylboronic acids.132 Similarly, the reaction was conducted in

oxidation with periodate in the presence of cyclic dienes in MeOH/H2O solution allowed isolation of this valuable HDA cycloadduct 82 as intermediate for a variety of synthetic transformations.122 Miller and co-workers extensively used the product of this HDA reaction for their synthetic purposes, and Scheme 46 collects the synthetic targets obtained from the cycloadduct 82. The carbocyclic polyoxin C and its epimer were in fact prepared in racemic form in an efficient and stereodivergent fashion taking advantage of the possibility to have an amino-Boc protected group from the HDA cycloadduct, Z


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Scheme 40. HDA Cycloaddtion to Dihydropyridine

Scheme 43. HDA Cycloaddition of Nitrosocarbonyl 1ac to 2Substituted 1,3-Cyclohexadienes

Scheme 41. HDA Cycloaddition to Asymmetrically Substituted Dienes 22 The synthesis of carbocyclic nucleoside precursors found in the Pd(0)-catalyzed alkylation reaction the key step and in the cycloadduct 82 the starting material of election. The chemistry was explored in both racemic and asymmetric fashion.135 In this context, carbocyclic uracil polyoxin C analogues were prepared from 82 in fewer than nine steps using Pd(0)/InI-mediated allylation to install the β-amino acid side chain.136 The same catalytic system was used to mediate the allylation of electrophiles generated from the hydrolysis of Eschenmoser’s salt on the cycloadduct 82.137 Again, the allylation and the possibility to install a 4-hydroxyethyl group on the aminocyclopentenol prepared from compound 82 was accomplished by the use of a Pd(0)-catalyzed process.138 This allowed preparation of carbocyclic nucleosides 5′-homocarbovir and epi-4′-homocarbovir. A convergent and versatile racemic total synthesis of the antiinfluenza agent BCX-1812 was accomplished through stereoselective reactions where the key intermediate was the cycloadduct 82 and its derivative obtained from N−O bond cleavage.139 The synthesis involving N−O bond cleavage, oxidation, intermolecular cyclopropanation, Bucherer−Bergs reaction, hydrolysis, and regioselective acylation, starting from 82, furnished the analogue of LY354740, also in an optically active fashion.140 We can complete this synthetic survey with the use of 82 to prepare the cyclopentenol through N−O bond reductive cleavage as the intermediate for the synthesis of streptazolin and its dihydro derivative.141 In all the synthetic applications of the tert-butoxy nitrosocarbonyl derivative 1af reported above, the NaIO4 is the oxidant of election and it continues to operate the oxidation in the next examples. The N-Cbz-protected spiro-cyclopentadiene 83 was used to capture the nitrosocarbonyl 1af to afford the cycloadduct 84 that served as key intermediate toward an efficient conversion into the novel carbocyclic nucleoside spironoraristeromycin 85 (Scheme 47).142 The cycloadduct 84 was obtained in 61% yield, and the subsequent first synthetic step for the nucleoside preparation was the N−O bond cleavage with Mo(CO)6. The same cycloadduct 84 was also employed in a series of functionalizations at the spiropiperazinyl nitrogen atom with insertion of a variety of substituted phenyl rings, in particular bearing an oxazolidinone residue. These new compounds were evaluated against various Gram-positive and -negative bacteria, and some of them were found active against selected drug resistant microbes.143

Scheme 42. Asymmetric HDA Cycloadditions to the (S)-N(1,3-Butadienyl)pyroglutamate Methyl Ester 24

the presence of alcohols with the possibility to govern the stereochemistry by selecting the ligands around the ruthenium metal center.133 Usually, the N−O bond cleavage represents the pivotal step to several synthetic targets. Unexpectedly, an unusual bicyclic hydroxamate resulted from C−O bond cleavage of the cycloadduct 82 when treated with catalytic Brønsted acids under anhydrous conditions.134 AA


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Scheme 44. Synthesis of Pyrrolo-castanospermine Derivatives through Nitrosocarbonyl 1ad

Scheme 45. Synthesis of Maduropeptin Analogues through Nitrosocarbonyl Chemistry

Scheme 46. Synthetic Uses of Cycloadduct 82 from Nitrosocarbonyl 1af

Scheme 47. N-Cbz-Protected Spiro-Cyclopentadiene Capture of Nitrosocarbonyl 1af

The commercially available diene 86 was used as trapping agent in the reaction with 1af and 1ah to afford entirely, according to theoretical predictions, the proximal cycloadducts 87 (Scheme 48). The optimized experimental conditions allowed obtaining the cycloadducts 87 in 85 and 47% yields, respectively for the nitrosocarbonyls 1af and 1ah. These adducts were proved to be ideal α-amino acid precursors, and the efficient synthesis of the 5methyl ornithine was accomplished.144

The synthesis of 1-azaglucose analogue, in which the ring oxygen is retained and the product displayed a relative weak glucosidase inhibition, was performed by capturing the nitrosocarbonyl 1af with the pentadienol 88 (Scheme 49).145 The reaction afforded the two regioisomeric cycloadducts 89a and 89b isolated in 78% combined yields and in the ratio 2:1 in favor of the adduct 89a. A short access to silylated homocalystegine analogues was conducted by desymmetrization of a PDMS-methylcycloheptaAB


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91a and 91b in lower yields (52%) due, presumably, to inefficient oxidation and trapping. Sodium periodate was used to oxidize the carbamate 2af in the presence of the dihydropyridine 68 to give the regioisomeric cycloadducts 92a and 92b in 68% overall yields and in a nearly 1:1 ratio (Scheme 51).123

Scheme 48. HDA Cycloaddition of Nitrosocarbonyl 1af and 1ah with Diene 86

Scheme 51. HDA Cycloaddition of Nitrosocarbonyl 1af with Dihydropyridine 68

Scheme 49. HDA Cycloaddition of Nitrosocarbonyl 1af with Pentadienol 88

In this case the authors tested other oxidants; the classical Et4NIO4 in DCM solution at −78 °C determined a decrease in the overall yields (47%) without significant changes in the regioisomeric ratio. However, the CuCl2-catalyzed oxidation in the presence of hydrogen peroxide in THF at room temperature increased the reaction yields (76%). Moving to ammonium periodate salts, nBu4NIO4 in DCM solution nicely oxidized the carbamate 2af in the presence of cyclopentadiene to give the known HDA cycloadduct in 79% yield.148 From this adduct several optically active compounds were prepared through enzyme-controlled kinetic resolution. The same oxidant was chosen in a series of reactions involving the carbamate 2af in the presence of a variety of dienes. When the NC generation reaction is conducted in the presence of the silylated diene 93, a mixture of different products is obtained. The minor one (20%) is the HDA cycloadduct 94, while the major is the ene adduct 95 isolated in 26% yield (Scheme 52). Quite surprisingly, the ene reaction seems to prevail over the HDA addition, representing one of the few cases in the literature. The authors suggested a tentative rationalization by invoking a

triene using osmium-mediated dihydroxylation, followed by diol protection. The diene 90 was used in the HDA cycloaddition reaction with nitrosocarbonyl 1af to give the regioisomeric cycloadducts 91a and 91b in the ratio 3:2 and 73% combined yields (Scheme 50).146,147 The same reaction performed with nBu4NIO4 in DCM/ MeOH solution at room temperature afforded the cycloadducts Scheme 50. HDA Cycloaddition of Nitrosocarbonyl 1af with Cyclic Diene 90

Scheme 52. HDA Cycloaddition of Nitrosocarbonyl 1af with Diene 93

AC


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benefit from β-stabilization by the silyl group of the polarized diradical intermediate occurring in the reaction mechanism.149 The Boc protected 6-aminohexa-2,4-dien-1-ol 96 was used in the HDA cycloaddition to 1af affording both the proximal and distal mixture of cycloadducts 97a and 97b in 87% combined yields and a nearly 1:1 ratio (Scheme 53).150 By virtue of the NC ability to introduce an amino and hydroxyl functionalities in a cis-1,4-relationship, the isomer 97b was easily converted into the bis-Boc-δ-hydroxylysine amino acid 98. To conclude with the open dienes, we report the use of dienes of type 99 for conducting a regio- and stereochemical study of the HDA cycloaddition to 1af. Scheme 54 reports the reaction and the regioisomeric cycloadducts 100a and 100b obtained. The yields were very good, from 74 to 96%. The regioisomeric ratio varied depending on the steric hindrance of the substituent of the diene partner 99, considering that the dienophile bears a tertbutyl group, also sterically demanding.151 In the case of the simple alcohol (R = H), isomer 100a is 10fold 100b while the proportions slightly invert when bulky substituents are located on the dienes (R = Piv and TBS). The observed regioselectivities were explained both in terms of the possibility for the alcohol to establish hydrogen bonding with the dienophile and in terms of steric effects. In Scheme 54 the proximal and distal transition structures (TSs) are reported and the steric hindrance determined by the conformational array of the dienophile accounts for the lower ratio in the mixture. At variance with previous results, the 7-silylcycloheptatriene 101 was used in the reaction with nitrosocarbonyls 1af and 1ah without preliminary desymmetrization (Scheme 55). In both cases the HDA cycloadducts of type 102 were obtained in very good yields (63−81%) with a diastereomeric ratio >95:5.152 The reactions were extended by the authors to triazolindione and catalyzed cycloadditions to aldehydes and ketones.153

Scheme 55. HDA Cycloaddition of Nitrosocarbonyls 1af and 1ah with Dienes 101

We conclude with the ammonium periodate oxidation of carbamates 2af and 2ah with the reaction involving the tetrahydropyridine 103 as trapping agent (Scheme 56). The reactions afforded the expected cycloadducts 104 in 76 and 70% yields, respectively, for the nitrosocarbonyls 1af and 1ah.154 Carbamates 2af and 2ah were also tested with other oxidants, starting from the Dess−Martin periodinane that allowed obtaining the HDA cycloadducts with three dienes. From NC 1af and cyclopentadiene, the HDA cycloadduct was obtained in 50% yield while better yields were obtained with 1,3-cyclohexadiene (63%) and 9,10-DMA (61%). The reaction between NC 1ah and cyclopentadiene afforded the corresponding cycloadduct in 53% yield. The same NC with 1,3-cyclohexadiene gave the HDA cycloadduct in 76% yield, while with 9,10-DMA the yield is slightly lower (55%).88 AD


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adduct was obtained in 87% yield (see Scheme 34 for reference).116 tert-Butylperoxide is a valuable alternative to hydrogen peroxide and was used in the presence of RuCl2(PPh)4 as the catalyst (10 mol %) with 1,3-cyclohexadiene in DCM solution at room temperature to give the HDA in 69% yield.156 Reduction of the amount of catalyst at 0.1 mol % causes a dramatic drop in the yield (39%), while the absence of the catalyst allowed obtaining the HDA cycloadduct in 30% yield. Whiting and co-workers suggested the use of ruthenium(II)− salen complexes to catalyze the oxidation of carbamate 2af in the presence of tert-butylperoxide to give the HDA cycloadducts 82, 107, and 108 in variable yields. In Scheme 58 the best results are shown with the three cyclic dienes reported.157

Scheme 56. HDA Cycloaddition of Nitrosocarbonyls 1af and 1ah with Tetrahydropyridine 103

Scheme 58. HDA Cycloaddition of Nitrosocarbonyl 1af with Cyclic Dienes

The next oxidants to be discussed involve either peroxides or aerobic methods. First we report the work by Adamo and Bruschi dealing with the use of metal-catalyzed oxidation with H2O2 with a variety of dienes. Scheme 57 reports the best results in term of yields (over 70%) obtained for the acyclic and cyclic dienes sketched below along with the catalytic systems that allowed obtaining those results. The case of 2,3-dimethyl-1,3-butadiene includes three catalytic systems: copper can be used in both oxidation states with an aminol as ligand while Fe(III) was used with the ethylendiamine as ligand. With the other two dienes, Cu(II) and Fe(III) were employed with very good results. In general, the methodology is based on commercially available materials and allows performance of the HDA cycloadditions in short reaction times (30 min maximum).155 The use of H2O2 as oxidant was also employed in the oxidation of the carbamates. Ru(II)(pybox-dh)(pydic) complex catalyzed the hydrogen peroxide oxidation of 2af in the presence of cyclopentadiene in THF solution at 0 °C to give the HDA product in 99% yield.90 Upon changing the catalyst, [Ir(coe)2Cl]2, the yields remain high (92%).113 The [Ir(cod)Cl]2 catalyst was used in a different process trapping 1af with tetramethylethylene (TME) in a typical ene reaction. The ene

With other acyclic dienes the yields are less impressive (25− 42%) and the use of enantiopure catalyst does not produce any asymmetric induction, suggesting that the NC intermediate dissociates readily from the chiral complex prior to DA cycloaddition. Surprisingly, in one case a diene worked as an “ene partner” affording the adduct in just 19% yield. The HDA reaction between carbamate 2af and 1,3-cyclohexadiene was also used by the authors as a benchmark reaction to test other chiral ligands, in particular phosphines such as (R)-Tol-BINAP, (R)BINAP, (−)-DIOP, and (R)-PROPHOS in the presence of RuCl2. Unfortunately, the results were quite unsuccessful: in the case of RuCl2/(R)-PROPHOS(PPh3)-catalyzed reaction conducted at −60 °C, a 10% enantiomeric excess (ee) was obtained

Scheme 57. HDA Cycloaddition of Nitrosocarbonyl 1af with Acyclic and Cyclic Dienes

AE


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and 110b in 88% yield from 1af and in 74% yield from 1ah. The regioisomeric ratio is 85:15 in both cases (Scheme 61).114 The most recent advances in this field were reported by Read de Alaniz and co-workers. Photoredox catalysis was employed to generate the NC species 1af and 1ah under experimental conditions comparable to previously developed transition metal aerobic oxidation and amenable to a range of transformations including DA and ene reactions. Scheme 62 reports the protocol set up by the authors, who used Ru(II) complex as a good oxidant and reductant; a simple white lamp (26 W) brings the catalyst at the excited state that promotes the oxidation to the NC intermediate, and the HDA cycloadducts 82 and 107 were isolated in 89 and 77% yields for 1af, respectively, with cyclopentadiene and 1,3-cyclohexadiene. Similarly, it was done for 1ah getting the expected products 111 and 112 in 93 and 87%, respectively, with cyclopentadiene and 1,3-cyclohexadiene.160 The protocol was prone to be applied also to ene reactions with a variety of tetra-, di-, and monosubstituted alkenes to give the expected ene adducts in 34−99% yields. These and prevoious results proved the reaction conditions to be sufficiently mild so as to not decompose the delicate ene products. The phenyl hydroxycarbamate 2ag is the precursor of the phenyloxy nitrosocarbonyl 1ag (Table 6, entry 5) that was obtained through the Et4NIO4 oxidation and trapped with different cyclic and acyclic dienes. In the presence of a dihydropyridine the HDA cycloadduct 113 was obtained with modest yields (26%) (Scheme 63).102 When the acyclic azadiene 114 was used, the primary cycloadduct 115 was formed but not isolated since it was converted through desilylation in methanol into the isolable heterocyclic derivative 116 obtained in 40% yield.161 The comparison between NaIO4 and with catalytic aerobic oxidation conditions in the generation of the phenyloxy nitrosocarbonyl 1ag is proposed by Whiting and co-workers using the 1,3-cyclohexadiene as trapping agent. Periodate oxidation affords the expected HDA cycloadduct in 51% yield in methanol as solvent. The aerobic oxidation performed in the same solvent in the presence of CuCl2 (10 mol %) and 2-ethyl-2-oxazoline (20 mol %) allowed obtaining the desired product in 98% yield.115 Toluene as solvent here was inefficient. Entry 6 of Table 5 reports the results obtained in the generation of the benzyloxy nitrosocarbonyl 1ah, already discussed previously in this review. One of the first examples reported in the literature was the oxidation with NaIO4 of the carbamate 2ah in the presence of thebaine as trapping agent. The product was used in synthetic elaboration toward analgesic analogues.64 Thebaine was also used to trap 1ah in view of further transformation into different compounds via the intriguing C5−C6 bond cleavage operated in the presence of SmI2, as previously reported.97 In this case the oxidant of choice was the benzyltrimethylamonium or tetraethylamonium periodate.163 Similar experimental conditions except for the solvent, here MeOH/water, allowed obtaining the cyclopentadiene adduct of 1ah as precursor for nucleoside analogue synthesis74 or in the preparation of pyrazolo[3,4-d]pyrimidines78 as well as in the use of metal-catalyzed transformations of the bicyclic structure into cyclopentene derivatives122 and again in the concise route to (−)-kainic acid.162 In a communication published in 1983 Baldwin and coworkers presented the NC chemistry approach to the synthesis

for product 107. This very low level of asymmetric induction was explained by the authors to be because of the failure in providing discrete, stable diastereomerically pure Ru complexes, concluding that the asymmetric induction could be viewed as fortuitous.157 A new catalytic system was proposed by Lu and co-worker based on the dirhodium(II) caprolactamate (Rh2(cap)4) that was found to exhibit similar oxidative reactivity toward carbamates when tert-butylperoxide is the oxidant. Again, Scheme 59 shows the best results obtained for cyclic dienes; the yields are remarkably higher than those reported in the previous case.158 Scheme 59. HDA Cycloaddition of Nitrosocarbonyl 1af with Cyclic Dienes

It is worth noting that 9,10-DMA was also used, allowing isolating the corresponding HDA cycloadduct in 61% yield as well as acyclic diene with yields ranging from 41 to 81%, and testifying to the efficiency of the catalytic system and the wide reaction scope. The last example, in which tert-butylperoxide is employed reports a different catalyst based on copper(II) salts. CuCl2 was complexed with (7aR,11aR)-dodecahydrobenzo[e][1,4,7]oxadiazonine, and this catalytic system in the presence of oxidant and trapping agent allowed obtaining the HDA cycloadduct 107 in 69% yield (Scheme 60).159 Scheme 60. HDA Cycloaddition of Nitrosocarbonyl 1af with 1,3-Cyclohexadiene

We finally report the aerobic methods starting from the already discussed use of air/CuCl/pyridine in THF solution at room temperature. Carbamate 2af is efficiently oxidized in the presence of 1,3-cyclohexadiene to give the corresponding HDA product 107 in 96% yield. The same result was obtained in the case of the benzyloxy substituted nitrosocarbonyl 1ah.89 The asymmetric version was realized with the Ru(pyboxdh)(pydic) complex that catalyzes the hydrogen peroxide oxidation of carbamates 2af and 2ah in the presence of (S)-N(1,3-butadienyl)pyroglutamate methyl ester 24. The reaction gave the corresponding regioisomeric HDA cycloadducts 110a AF


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Scheme 61. Ru(II)-Catalyzed Asymmetric HDA Cycloadditions to the (S)-N-(1,3-Butadienyl)pyroglutamate Methyl Ester 24

Cleavage of the N−O bond in 122 and epoxidation are the key steps leading to the target product 123. The azadiene 114 was also used to trap the nitrosocarbonyl 1ah. At variance with the case of the nitrosocarbonyl 1ag, here a mixture of regioisomeric cycloadducts was obtained, being 124a the major (73%) along with 10% of 124b (Scheme 66).161 The use of silyloxy dienes in the capture of nitrosocarbonyl 1ah (Table 6, antry 6) was already cited,83,84,124,125 and in all these cases the oxidant of election was nPr4NIO4. The same oxidant was also employed in the presence of the mentioned azetidinodiazepine derivative. The reaction afforded the regioisomeric cycloadducts 125a and 125b, respectively, in 49 and 18% yields (Scheme 67).108−110 Benzyloxy nitrosocarbonyl 1ah, generated from the corresponding carbamate 2ah through nPr4NIO4 oxidation, was trapped with the (E,E)-hexadienal dimethylacetal to give the HDA cycloadducts 126a and 126b that served for the straightforward synthesis of (±)-5-amino-5,6-dideoxyallose (Scheme 68). The reaction was conducted without isolation of the primary HDA cycloadducts; treatment with OsO4/NMO afforded the regioisomeric diols 126a and 126b obtained in 52 and 17% yields.171 Further synthetic elaborations allowed the authors to prepare allosamine, allo-nijirimycin, and other derivatives.172 The synthetic studies on the narciclase alkaloids found in the HDA cycloaddition of the benzyloxy nitrosocarbonyl 1ah with a MOM-protected 1,3-cyclohexadienediol the key step for the synthesis of (±)-lycoricidine. The reaction was conducted at −15 °C in the presence of nBu4NIO4 as oxidant and afforded the expected cycloadduct 127 in 69% yield (Scheme 69).173 The hexa-2,4-dienal was condensed with (−)-ephedrine to give predominantly the oxazolidine 128 which underwent a stereoselective HDA cycloaddition with the nitrosocarbonyl 1ah

Scheme 62. Photoredox catalytic generation of Nitrosocarbonyl intermdiates

of the exotoxin from Pseudomonas tabaci (the orgamism responsible for wildfire disease of tobacco plants). The pivotal step is represented by the in situ generation of the benzyloxy nitrosocarbonyl 1ah through Et4NIO4 oxidation in the presence of the ethyl cyclohexa-1,3-dienecarboxylate in DCM solution (Scheme 64).164 The reaction affords the HDA cycloadduct 117 in 93% yield; this latter is the starting point for a sequence of synthetic elaborations, first to the intermediate 118 in which the differentiation of the carboxy groups was achieved and then the final construction of the β-lactam ring through intramolecular cyclization to get the final product 119.165 These synthetic steps were deeply investigated and detailed in several papers.166,167 The total synthesis of (±)-isonitrin B is the occasion to report the HDA cycloaddition reaction where both the diene and the dienophile are in situ generated. The synthesis of the diene starts from the cyclopentadiene, which is converted into the fulvene 120. Treatment of the bright yellow fulvene 120 with 1 equiv of p-toluensulfonic acid at −40 °C in DCM solution gave intensely red-colored 1-acetylcyclopentadiene 121. A solution of the carbamate 2ah in DCM was added to 121 followed by the slow addition of the periodate salt. The reaction afforded the HDA cycloadduct 122 in 94% yield (Scheme 65).168

Scheme 63. Generation and Trapping of Phenyloxy Nitrosocarbonyl 1ag

AG


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Scheme 64. Generation of the Benzyloxy Nitrosocarbonyl 1ah in the Presence of Ethyl Cyclohexa-1,3-dienecarboxylate

Scheme 65. Generation of the Benzyloxy Nitrosocarbonyl 1ah in the Presence of 1-Acetylcyclopentadiene

Scheme 66. Generation of Phenyloxy Nitrosocarbonyl 1ah and Trapping with Azadiene

Scheme 67. Generation of Phenyloxy Nitrosocarbonyl 1ah and Trapping with Azetidinodiazepine

Scheme 68. Generation of Phenyloxy Nitrosocarbonyl 1ah and Trapping with (E,E)-Hexadienal Dimethylacetal

to give the cycloadducts 129a and 129b in a 5:2 ratio (Scheme 70).174 Further transformations of the major cycloadduct 129a (32%) allowed preparing optically active mono- and trihydroxypiperidine derivatives. The synthesis of optically pure compounds was also secured by the use of 1-sulfinyl dienes. Compound 130 efficiently trapped the nitrosocarbonyl 1ah to give the HDA cycloadduct 131 in 54% yield with complete regioselectivity and π-facial diastereoselectivity. Sequential osmylation and protection of the resulting glycol gave the oxazine 132 that was directly transformed into the enantiomerically pure 1,4,5-trideoxy-1,4imino-L-ribitol 133 by reduction with Pd/C (Scheme 71).175 Microbial 1,2-dihydroxylation of sodium benzoate permitted the rapid construction of a novel inositol−amino acid hybrid

Scheme 69. Generation of Phenyloxy Nitrosocarbonyl 1ah and Trapping with MOM-Protected 1,3-Cyclohexadienediol

AH


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Scheme 70. Generation of Phenyloxy Nitrosocarbonyl 1ah and Trapping with Oxazolidine 128

Scheme 71. Generation of Phenyloxy Nitrosocarbonyl 1ah and Trapping with 1-p-Tolylsulfinyl-1,3-pentadiene

Scheme 72. Generation of Phenyloxy Nitrosocarbonyl 1ah and Trapping with Protected 1,3-Cyclohexadiene Carboxylate 134

Scheme 73. Generation of Phenyloxy Nitrosocarbonyl 1ah and Trapping with 1,3-Cycloheptadienes

in the enantiocontrolled synthesis of the (+)-lycoricidine and other alkaloids.80 1,3-Cycloheptadiene offers a valuable entry to tropane derivatives. The trapping of nitrosocarbonyl 1ah with this diene was proposed by Malpass and Justice to prepare 4aminocycloheptanones of type 137. The oxidation with periodate afforded the HDA cycloadduct in 97% yield (Scheme 73).177 The adduct 136 was reducted with diimide followed by reductive cleavage of the N−O bond. Reduction with LiAlH4 and Jones oxidation provided the physoperuvine 137 in 79% overall yield. With cyclohepta-3,5-dienol as trapping agent, the HDA cycloaddition reaction leads to the stereoisomeric compounds 138a and 138b, isolated in 73% yield as an inseparable mixture where the two isomers are in the ratio 35:65, being 138b the major component. The initial 1,4-functionalization of the dienol

structure. These were accessed by HDA cycloaddition of nitrosocabonyl 1ah to the protected diene 134. Oxidation with nBu4NIO4 afforded a mixture of the regioisomeric cycloadducts 135a and 135b isolated in 58 and 13% yields, respectively (Scheme 72).176 The subsequent synthetic elaboration conducted to a novel class of azacarbasugars; the authors were able to prepare the new molecules containing six contiguous stereocenters in seven steps starting from the simple sodium benzoate as precursor of the diene 134. Closely related from the structural point of view is the diene 66, already reported for aromatic hydroxamic acid as precursors of NC (see Scheme 37 for reference). The chloro-substituted diene allowed trapping of the nitrosocarbonyl 1ah (HDA cycloaddduct obtained in 54% yield) in the microbial oxidation of aromatic compounds investigated by Hudlicky and co-workers AI


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Scheme 74. Generation of Phenyloxy Nitrosocarbonyl 1ah and Trapping with Silylated 1,3-Cycloheptadienes

complex. Scheme 77 reports the best results obtained with classical cyclic dienes and an acyclic one.184

constituted the pivotal steps for the synthesis of scopine, pseudoscopine, and other nor-derivatives.178 The picture of the seven-membered ring-based dienes is completed by the silylated derivatives of type 139 able to capture the nitrosocarbonyl 1ah leading to the cycloadducts of type 140 (80−93% yields, depending from the substituent R on the diene; Scheme 74). Cleavage of the N−O bond and further transformations afforded the racemic calystegine B2 141 in good yield (72%).179 6,7-Dihydroxylated calystegines and homocalystegines were synthesized by the stereoselective dihydroxylation reactions of the HDA cycloadducts obtained from the nitrosocarbonyl 1ah and 1,3-cyclohepta- and cyclooctadienes according to the wellestablished procedure (Scheme 75).180,181

Scheme 77. Generation of Phenyloxy Nitrosocarbonyl 1ah and Trapping with Dienes

Scheme 75. Generation of Phenyloxy Nitrosocarbonyl 1ah and Trapping with 1,3-Cyclohepta- and Cyclooctadienes

Other dienes were tested but with poor results. Upon changing the catalyst [e.g., Fe(III) or Cr(III)] or the ligand (p-cymene), the yields remain well below those reported in Scheme 77 and the positive results are limited to the typical dienes; i.e., attempts to use furan or pyrrole failed. However, these results prompted further investigations on the mechanistic point of view and the activation of triphenylphosphine-ligated ruthenium−salen complexes was examined and evidence was presented for the ruthenium−oxo species involved in the oxidative process of carbamates. The observation of the lack of asymmetric induction in the intermolecular cycloaddition reaction was explained by comparison with Cu(I)/Cu(II) BINAP-based catalysts. The study was completed by an important series of experiments devoted to the mechanistic investigation in order to understand the intrinsic nature of the coordination of the reactive species to the metal centers with the aim to design a catalyst capable of promoting both oxidation and HDA reactions.185 Under aerobic conditions, the carbamate 2ah was oxidized by the O2/CuCl2/ethyl-2-oxazoline catalytic system in the presence of cyclic and acyclic dienes. Scheme 78 reports the best results for some cyclic dienes and 2,3-dimethyl-1,3-butadiene. As we can see, the yields are excellent in all cases, with the peculiarity of the

The adducts of type 136 and 142 were easily converted into the desired target compounds with satisfactory yields. Steroids represent a further enhancement of the complexity of trapping agents. Diene 143 adds the nitrosocarbonyl 1ah affording the two stereoisomeric steroids 144a and 144b in 78 and 22% yields, respectively (Scheme 76).182 Grieco and co-worker applied the same protocol for the synthesis of the highly oxygenated ergostane type steroid (+)-withanolide E.183 We leave the periodate protocols to enter the peroxide methods to oxidize the carbamate 2ah, starting from the tertbutylhydroperoxide, employed in the presence of a Ru−salen

Scheme 76. Generation of Phenyloxy Nitrosocarbonyl 1ah and Trapping with Steroid 143

AJ


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Scheme 78. Aerobic Generation of Nitrosocarbonyl 1ah and Reaction with Dienes

Scheme 79. Ene Reaction Trapping of Nitrosocarbonyl 1ah

materials are prepared with common methods and the substituents RR′N− listed in Table 7 can be both aliphatic and aromatic. The simplest intermediate is the nitrosocarbonyl bearing an NH2− group obtained by the pioneer Kirby in 1985 through the oxidation of the 1-hydroxyurea 2aj with Et4NIO4 (Table 7, entry 1). The amino nitrosocarbonyl 1aj was trapped with the classical cyclopentadiene affording the expected HDA cycloadduct 152 (Scheme 80).188 The method was extended to a variety of ureas with methylamino (2ak), dimethylamino (2al), phenylamino (2an), and diphenylamino (2ap) substituents (Table 7, entries 2, 3, 5, and 7). The only reported yield refers to the phenylamino derivative 155 (67%), but the protocol found also application in the presence of other trapping agents. The HDA cycloaddition was also performed with 2,3-dimethyl-1,3-butadiene with the same ureas reported in Scheme 80 to obtain the corresponding cycloadducts. The dimethylamino derivative was obtained in 60% yield. Two other dienes were tested with very good results: 9,10-DMA (54%) and thebaine (79%). Unfortunately, ergosteryl acetate was also used as diene but the authors did not report the obtained yields. King and co-workers conducted the oxidation of hydroxyureas with sodium periodate in the presence of 9,10-DMA to get the corresponding HDA cycloadducts 157−160 (Scheme 81). The hydroxyureas contained amino (2aj), n-butylamino (2am), phenylamino (2an), and benzylamino (2aq) substituents (Table 7, entries 1, 4, 5, and 8).189

reaction with butadiene where a competition between the HDA and ene reaction arises, with large favor for the HDA process.186 Changing the solvent (CHCl3), the yields are slightly lower and competition with the ene reaction still remains for acyclic dienes. Finally, the ene trapping was extensively applied by Read de Alaniz and co-workers by applying the air/CuCl/pyridine catalytic system to a variety of alkenes. Scheme 79 reports three examples with tetra- and trisubstituted alkenes as well as the case of the geranyl acetate containing two different ene groups. The yields are excellent; with trisubstituted enes the selectivity in the addition always proceeds according to the Markovnikov orientation.187 When two different ene groups are present in the molecule, the preferred attachment occurs to the more nucleophilic carbon atom affording product 150; the acetate group slightly decrements the nucleophilicity on the β-carbon atom and the adduct 151 is the minor component of the reaction mixture. Table 5, entry 7, reports the single case found in the literature of a substituted aromatic carbamate 2ai, 4-chlorobenzyl substituted, that was used to generate the corresponding nitrosocarbonyl 1ai with the Ru(II)(pybox-dh)(pydic) catalyst and hydrogen peroxide in the presence of cyclopentadiene in THF solution at 0 °C to give the HDA product in 76% yield.90 3.1.3. From N-Hydroxyureas. The oxidation of Nhydroxyureas with general formula RR′N−CO−NH−OH represents the third category of precursors to generate NC intermediates, and Table 7 reports the structures of the fleeting compounds obtained through this methodology. The starting AK


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Table 7. Structures of N-Hydroxyureas RN−CO−NH−OH, Oxidants, Trapping Agents, and Reaction Conditions

a

Yields refer to the best results obtained or ranges of the best performances of the method. bYield refers to the sum of both regioisomers.

The reaction yields are from good to excellent, and the HDA cycloadducts were thermally decomposed at 40 °C in MeCN/ H2O solutions to generate N2O, CO2, 9,10-DMA, and the corresponding amines. The method aimed to provide HNO at biologically relevant temperatures with a new group of nitroxyl delivery agents as a new therapy for sickle disease.190 This is the first time that the generation of HNO appears in this review, and

the methodology will be cited again below, in consideration of the relevant biological role of this small molecule with an activity comparable to NO. The 1-hydroxyurea 2aj and the 3-hydroxy-1,1-dimethylurea 2al were oxidized with nPr4NIO4 in DCM solution in the presence of the (S)-N-(1,3-butadienyl)pyroglutamate methyl ester 24, an N-dienyl lactam frequently employed in asymmetric AL


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regioisomeric HDA cycloadducts 163a and 163b were isolated in 100% overall yield in the ratio 75:25 (Scheme 83).79,101 Asymmetrically substituted dienes of type 22 are the trapping agents for the capture of nitrosocarbonyl 1al (Table 7, entry 3) generated in situ by the periodate oxidation in DCM solution (Scheme 84). When the diene had a TBDM-silyloxy substituent in the position (1) of the 1,3-butadiene, a single regiosiomeric HDA cycloadduct 164a was obtained in 85%.83,84 When the butadiene was substituted with a dimethylacetal group, the regioisomeric HDA cycloadducts were obtained in negligible yields ( 98% in accordance with previous observations.198 As to double asymmetric induction with the chiral diene with (S) configuration, it proved to be strongly dependent on the (R) or the (S) configuration of the heterocyclic NC intermediates 1av and 1ax. Asymmetric

induction turned out to be poor when the chiral diene reacted with 2av, while it was excellent with the dienophile 2ax. The authors gave a reasonable interpretation, and the inset in Scheme 91 reports the TS of the cycloaddition leading to the best asymmetric induction. The hydroxamic acid 2ax and its diphenyl substituted 2bb (Table 8, entry 8) were oxidized with Et4NIO4 in DCM solutions at 0 °C in the presence of a variety of dienes; however, the best results in terms of both yields and selectivities were obtained with 1,3-cyclohexadiene (Scheme 92).199 Increasing the bulkiness of the substituent on the pyrrole ring does not affect the chemical yields and determines a remarkable improvement of the de. AQ


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Scheme 92. Generation of Nitrosocarbonyls 1ax and 1bb and Trapping with 1,3-Cyclohexadiene

Scheme 94. Generation of Nitrosocarbonyl 1bf and Trapping with Cyclic Dienes

A new chiral heterocyclic nitrosocabonyl intermediate 1bc (Table 8, entry 9) was obtained through periodate oxidation of the corresponding hydroxamic acid prepared from a substitute pyrrolidine possessing a C2 symmetry. The HDA reaction was conducted in the presence of three cyclic dienes, and the products 183−185 were obtained in very good yields (70−88%) with remarkable de (Scheme 93).199,200 The inset in Scheme 93 rationalizes the favored approach between the addends. A structural modification was done on the hydroxamic acid 2bc by replacing the methoxy groups with tert-butyldimethylsilyloxy groups in the derivative 2bd (Table 8, entry 10). The oxidation reaction in the presence of 1,3-cyclohexadiene afforded the HDA cycloadduct in 82% yield and de >98%, not much improving previous results.199 The hydroxamic acid 2bc was also coupled with an azadiene at −25 °C in DCM solution (methanolysis done for isolation of the product) to get the derivative 186 in 70% yield and de >98%.201 We can complete this section dedicated to the heterocyclic five-membered rings with the results obtained with the hydroxamic acid derived from the oxazolidine 2be (Table 8, entry 11). The oxidation was performed with sodium periodate in methanol/water solution affording the HDA cycloadduct in 75% yield and de 43%.196 NC intermediate 1bf (Table 8, entry 12), derived from Dbornane-10,2-sultam, was generated by oxidation with Et4NIO4 in DCM solution at room temperature and trapped with cyclopentadiene and 1,3-cyclohexadiene to afford the corresponding HDA cycloadducts 187 and 188 in 91 and 94% yields, respectively (Scheme 94).199,202 The cycloadducts were obtained with better than 98% ee, and the absolute configuration of the 1,3-cyclohexadiene derivative was established by independent synthesis from known (1R,4S)-

oxazine. A comparative semiempirical and ab initio calculation study gave a theoretical framework to the experimental results, and the steric vs stereoelectronic influences of the sultam moiety on the HDA cycloaddition reactions were discussed helping for a better understanding of the rationalization of chemical transformations and in the design of new chiral auxiliaries.203 The enantiomeric hydroxamic acid 2bg was oxidized with classical periodate in DCM solution at −78 °C to produce the nitrosocarbonyl 1bg (Table 8, entry 13), trapped with 2-silyloxy1,3-cyclohexadiene to afford the HDA cycloadduct 189, found quite unstable. For the sake of isolation and stability, Mo(CO)6 reductive cleavage of the N−O bond allowed preparation of the stable compound 190 in 64% overall yield (Scheme 95).204 The HDA cycloaddition was the pivotal step toward the synthesis of (−)-epibatidine. The sterically encumbered hydroxamic acid 2bh (Table 8, entry 14) was oxidized with periodate in the presence of 1,3cyclohexadiene and a single product 191 was isolated with the stereochemistry indicated in 90% chemical yield and >99% selectivity (Scheme 96).197 (S)-1-(2,4-Hexa-2,4-dienoyl)-N-hydroxypyrrolidine-2-carboxamide 2bi (Table 8, entry 15) was prepared from L-proline and oxidized with periodate in the presence of cyclopentadiene (Scheme 97) to afford solely the corresponding HDA cycloadduct 192 in 61% yield. This latter served to prepare a chiral diketopiperazine through thermal retro-DA followed by intramolecular cyclization of the NC moiety on the pentadienyl substituent.205 The example reported in Scheme 98 deals with the Swern oxidation, the first example in the literature, of the imidazolidin2-one derivative 2bj (Table 8, entry 16) in the presence of cyclopentadiene and 1,3-cyclohexadiene. The reaction conducted in DCM solution at −60 °C afforded the HDA cycloadducts 193 and 194 in 63 and 73% yields, respectively, for the cyclopentadiene and 1,3-cyclohexadiene derivatives.206

Scheme 93. Generation of Nitrosocarbonyl 1bc and Trapping with Cyclic Dienes and Azadiene

AR


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Scheme 95. Generation of Nitrosocarbonyl 1bg and Trapping with 2-Silyloxy-1,3-cyclohexadiene

Table 9 reports the structures of the fleeting intermediates obtained through various oxidative protocols, and the dots in the structures of the chiral moieties indicate the points of attachment of the reactive NC unit. Chiral hydroxamic acids are the starting materials of election for the asymmetric HDA cycloaddition reactions of the in situ generated chiral NC intermediates with suitable dienes. One of the first examples (Table 9, entry 1) of this type of reaction was reported by Procter and co-workers, who trapped the (R)nitrosocarbonyl 1bm with cyclopentadiene or 1,3-cyclohexadiene to get as major adducts those corresponding to the structure shown in Scheme 101.208 The same results were obtained also for the chiral tert-butyl and cyclohexyl substituted nitrosocarbonyls 1bn and 1bo (Table 9, entries 2 and 3) trapped with the same dienes. These results opened the way to the use of these optically active compounds in several synthetic transformations, mainly devoted to the preparation of natural compounds and asymmetric synthesis in general.209,210 Kirby further investigated these reactions and found that conducting the reactions at 0 °C the stereoselectivity was moderate; the cycloadduct with nitrosocarbonyl 1bm and cyclopentadiene as well as that from 1bn and 1,3-cyclohexadiene were obtained in the diastereomeric ratio of about 5:1. Much higher diastereoselectivities were observed at −78 °C (10:1).211 Procter revised the experimental conditions and prepared the adduct to cyclopentadiene from the hydroxamic acid 2bm through oxidation with Et4NIO4 in methanol solution at −78 °C with 89% yield, 80% de.212 An intense work of application in asymmetric syntheses was done as a consequence, introducing the use of Pd(0)-catalyzed processes for the preparation of oxazolidinones and other synthetic intermediates.213,214 The (S)nitrosocarbonyl 1bm was also used in the presence of 1,3cyclohexadiene at −70 °C to get the diastereoisomeric mixture in the ratio 10:1.215 The same (S)-nitrosocarbonyl 1bm in the presence of 1,3-pentadiene (piperylene) afforded the four possible racemic cycloadducts.216 This type of reaction was reported by Miller and co-workers, who trapped the (R)-nitrosocarbonyl 1bm with cyclopentadiene for their regio- and stereoselective Fe(III)- and Pd(0)-mediated ring opening studies.121 Defoin and Streith employed the (R)-nitrosocarbonyl 1bm and its methoxy derivative 1bp (Table 9, entry 4) in the HDA cycloadditions with 1,3-cyclohexadiene. When the reaction of

Scheme 96. Generation of Nitrosocarbonyl 1bh and Trapping with 1,3-Cyclohexadiene

Scheme 97. Generation of Nitrosocarbonyl 1bi and Trapping with Cyclopentadiene

The stereochemical outcome was determined by NMR data, and the inset in Scheme 98 accounts for the preferred approach of the diene to the less hindered face of the dienophile. Aromatic heterocyclic substituents were rarely found in the literature. An example is represented by the 3-pyridine nitrosocarbonyl 1bk (Table 8, entry 17) that was prepared and used in a dienophile screening study, aiming to find new entries to heterocyclic products. The oxidation of the corresponding hydroxamic acid 2bk was secured with sodium periodate in the presence of the bicyclic diene 195 allowing obtaining the HDA cycloadduct 196 in 70% yield in the racemic form and 8:1 isomeric ratio (Scheme 99).207 The same hydroxamic acid 2bk and the analogue 2-pyridine substituted 2bl were tested for the aerobic protocol by Whiting and co-workers in comparison with classical periodate oxidation. However, the results were quite disappointing since only the periodate oxidation worked although affording the HDA cycloadducts 197 and 198 in modest yields (Scheme 100) while the use of the air/CuCl2/2-ethyl-2-oxazoline method failed in all the tested experimental conditions.115 3.1.5. From Chiral Hydroxamic Acids. We have already seen in many cases the asymmetric version of the HDA cycloaddition of NCs where the inducer was placed on the diene partner. This section is devoted to NC derivatives with a stereogenic center in the α position with respect to the carbonyl group; these intermediates can react with achiral or chiral dienes.

Scheme 98. Generation of Nitrosocarbonyl 1bj and Trapping with Cyclic Dienes

AS


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Scheme 99. Generation of Nitrosocarbonyl 1bk and Trapping with Diene 195

done to make a comparison with different methods of oxidation of the starting hydroxamic acid 2bp (Scheme 104).219 With cyclopentadiene as trapping agent the best oxidation protocol in terms of chemical yield (80%) was made of oxalyl chloride/DMSO/Et3N also allowing for the best selectivities when the reaction is performed at −78 °C in DCM solution. The same selectivities were obtained in methanol at −50 °C with a little decrement of the chemical yields. Protected amino acids offer a valuable chemical source for chiral hydroxamic acids, and compounds 2bq−2bt (Table 9, entries 5−8) were used to generate the corresponding NCs upon oxidation with the simple sodium periodate in methanol/water solutions at −50 °C (Scheme 105). The diastereoisomeric HDA cycloadducts were obtained in variable yields (17−80%) and de (0−72%).196 Other oxidants and experimental conditions did not improve significantly the overall results. Good yields (67%) and de (45%) were obtained from the hydroxamic acid 2bu (Table 9, entry 9). The structural similarity between β-lactam antibiotics and isoxazolidine-3,5-dicarboxylic acids led to the use of the latter for their synthesis through NC intermediates. The enantiomeric hydroxamic acids 2bv and 2bw (Table 9, entries 10 and 11) were oxidized with sodium periodate in the presence of cyclopentadiene to get the diastereoisomeric HDA cycloadducts 210a,b and 211a,b that were used for the targeted final product (Scheme 106).220 The β-lactam analogues obtained from the reported cycloadducts 210 and 211 were tested and found good inhibitors of Escherichia coli X580. (R)-1-Hydroxy-3-(1-phenylethyl)urea 2bx (Table 9, entry 12) was oxidized in two different ways. The normal sodium periodate oxidation in methanol afforded the HDA cycloadduct 212 in 42% yield. The alternative aerobic protocol, air/CuCl2/2-ethyl-2oxazoline in the same solvent, allowed getting better yields (97%); the authors did not mention the problem of diastereoselectivity (Scheme 107).115 The use of optically pure N-protected amino acids as starting materials to prepare the corresponding hydroxamic acids allowed investigating the diastereoselectivity outcome in the intermolecular HDA reactions of the derived chiral NC dienophiles. The hydroxamic acids 2by, 2bz, 2ca, 2cb, and 2cc (Table 9, entries 13−17) were derived from N-protected amino acid methyl esters hydroxylaminolyzed under standard procedures (Scheme 108).221,222 Oxidation of the starting compounds with nBu4NIO4 in methanol solutions at 0 °C in the presence of cyclopentadiene afforded mixtures of chromatographically separable diastereoisomers of the HDA cycloadducts in 65−90% yields. The ratio of the diastereoisomers, given in Scheme 108, was determined by HPLC and the absolute structure of the major compounds by X-ray analysis of the cycloadduct from 2ca. Independently from the protecting groups used in the synthesis of the hydroxamic acids, in the cases of valine and

Scheme 100. Generation of Nitrosocarbonyls 1bk and 1bl and Trapping with 1,3-Cyclohexadiene

1bm was performed in chloroform at 0 °C, the cycloadduct 200, with the configuration reported in Scheme 101, was the minor product (24%). Replacement of the OH group with OMe, as it occurs in 1bp, afforded the cycloadduct in 67% yield and a nearly 1:1 diastereomeric ratio in a reaction conducted in chloroform at room temperature.195 The same reaction with cyclopentadiene at −60 °C in DCM/MeOH solution afforded the cycloadduct with the inverted stereochemistry at the bicyclic stereocenters as the major component (90%).194 The (R)-nitrosocarbonyl 1bm was generated from the corresponding hydroxamic acid 2bm through nBu 4 NIO 4 oxidation in the presence of a substituted cyclopentadiene 201, and the HDA cycloadduct 202 was obtained in 48% yield. The SMe substituent points on the opposite side with respect to the chiral center introduced through the NC moiety (Scheme 102).217 The obtained compound has the correct orientation of substituents to be used as the intermediate for the synthesis of mannostatin A. The same authors took advantage of the substitution on the diene by replacing the SMe group with the hydroxymethylene benzyl protected −CH2OBn, suitable for further synthetic elaborations in order to prepare (+)-6epitrehazolin, a potent inhibitor of trehalase. The HDA cycloadduct of 1bm to this modified diene afforded the key intermediate with a 96% yield that was finally converted in nine steps into the desired product.218 Finally, the nitrosocarbonyl 1bm was also trapped with the chiral diene (S)-methyl 1-(buta-1,3-dien-1-yl)-5-oxopyrrolidine2-carboxylate 24. The reaction was conducted by using nPr4NIO4 as oxidant in DCM solution, and the cycloadducts 203a and 203b were obtained in 22 and 10% yields, respectively (Scheme 103).198 The inset in Scheme 103 indicates the two proposed possible TSs accounting for the obtaining of the major diestereoisomer 203a. The wide use of the (R)-nitrosocarbonyl 1bm bearing an hydroxyl group encouraged further investigations on these simple hydroxamic acids since it was clearly proved that this polar and protic substituent does not interfere with the generation of the transient species. Replacement of the hydroxyl with an OMe group as it occurs in nitrosocabonyl 1bp (Table 9, entry 4) was AT


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Table 9. Structures of Chiral Hydroxamic Acids R*−CO−NH−OH, Oxidants, Trapping Agents, and Reaction Conditions

AU


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Table 9. continued

AV


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Table 9. continued

a

Yields refer to the best results obtained or ranges of the best performances of the method. bYield refers to the sum of both regioisomers. cYields after hydrolysis of the primary cyclodducts.

alanine derivatives the reactions afforded one of the possible stereoisomers as the major component while for the optically pure phenylalanine derivative 2cb the two HDA cycloadducts 216a and 216b were obtained with a reduced diastereoselectivity (1.5:1). No data are reported for the racemic phenylalanine derivative 2cc. The cycloaddition reactions of chiral NCs afforded synthetically useful quantities of functionally rich, optically pure cycloadducts of type 214 and 215 that were used in the preparation of a variety of compounds of biological interest, such as novel hydantoin analogues of carbocyclic nucleosides,223 and the synthesis of enantiomerically pure 5′-aza-noraristeromycin analogues.224 Alanyl substituted 4-amino-2-cyclopenten-1-yl acetates, obtained from the sodium periodate oxidation of 2bz, were involved in Pd(0)-catalyzed cyclization for the preparation of oxazolines and cyclopentenol derivatives225 and in the asymmetric synthesis of important precursors to 5′-nor-nucleosides.226 The use of the

Scheme 101. Generation and Trapping of Nitrosocarbonyl 1bm

Scheme 102. Trapping of Nitrosocarbonyl 1bm with Diene 201

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Scheme 103. Double Asymmetric Induction with Nitrosocarbonyl 1bm and a Chiral Diene

Scheme 104. Generation of Nitrosocarbonyl 1bp with Different Oxidants

Scheme 105. Generation of Nitrosocarbonyls 1bq−1bu and Trapping with Cyclopentadiene

Scheme 106. Generation of Nitrosocarbonyls 1bv and 1bw and Trapping with Cyclopentadiene

Swern oxidation in the presence of cyclopentadiene227 or 1,3cycloheptadiene228 represents the single variant for the trapping of the alanine derivatives of these NC intermediates and afforded the HDA cycloadduct in 78 and 79% yields, respectively, with 6:1 and 3:1 diastereoisomeric ratios for the two cases. In the case of 1,3-cycloheptadiene as trapping agent, the complete carbon framework of enantiomerically and diastereomerically pure (2S)-

amino-(6R)-hydroxy-1,7-heptanedioic acid dimethyl ester was derived from the HDA cycloadduct obtained as described by the authors.228 On the other hand, the derivatives of the cyclopentadiene served for a conformational study on which basis an enantioselective, regiospecific synthesis of novel aminoxy transproline analogues was proposed.229 Finally, the same cycloAX


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heptadiene 219 was isolated in the ratio 92:8. This attractive choice of camphor-based NCs was considered a valuable element for conducting asymmetric cycloadditions. In close analogy, we report the case of the hydroxamic acid 2cf (Table 9, entry 20) prepared from the alcohol 220 and oxidized through the Swern protocol in the presence of several dienes. Scheme 111 reports the case of the trapping with an open-chain diene; the product was obtained in 94% yield and the diastereoselectivity was >96%.233 With cyclic dienes (cyclopentadiene and 1,3-cyclohexadiene) the yields remained high (89 and 93%, respectively) and the selectivities slightly lower (91 and 95%, respectively). Periodate oxidation protocol was used to generate the nitrosocarbonyl 1cg (Table 9, entry 21) that was trapped with cyclopentadiene and 1,3-cyclohexadiene to afford the corresponding HDA cycloadducts 222 and 223 in good yields (65 and 74%, respectively) (Scheme 112).199 However, the de’s were quite low, 12 and 20%, respectively, for the cyclopentadiene and cyclohexadiene adducts, indicating the presence of several reactive conformations in the nitrosocarbonyl dienophile 1cg. An enantioselective approach to (−)-epibatidine based on asymmetric HDA cycloaddition with an NC bearing a 8-(2naphthyl)menthol as chiral source was used by preparing the corresponding hydroxamic acid 2ch (Table 9, entry 22). The oxidation was conducted with nPr4NIO4 in chloroform solution at room temperature in the presence of 1,3-cyclohexadiene as trapping agent (Scheme 113). Yields and selectivities strongly depend on the oxidation protocol; the best results were obtained with the Swern method allowing obtaining the diastereoisomeric HDA cycloadducts 224a and 224b in 89% overall yields and in the remarkable de 1:14.234 The facial selectivity observed is consistent with the TS model represented in the inset of Scheme 113 wherein the naphthyl group shields selectively the face of the NC group in the s-cis conformation by π−π stacking interaction and forcing the diene to the endo approach from the front side. In eight steps the

Scheme 107. Generation of Nitrosocarbonyl 1bx and Trapping with 1,3-Cyclohexadiene

pentadiene cycloadduct from 1bw allowed synthesizing a segment of nucleoside Q, also known as queuosine, located in the first position of the anticodon region of Escherichia coli tRNA.230 Interesting chiral scaffolds are the bicyclic structures of norbornane or camphor type. The hydroxamic acid 2cd (Table 9, entry 18) was oxidized with Et4NIO4 in the presence of cyclopentadiene at −78 °C. The nitrosocarbonyl 1cd adds the diene from the less hindered face of the nitroso group as shown in Scheme 109, affording the diastereoisomeric mixture of HDA cycloadducts 217a and 217b in the remarkable ratio of 99:1.231 The main product was used for the asymmetric synthesis of carbanucleosides and prostanoid intermediates. Camphor-based NCs find in the ketopinic acid a good precursor that was easily converted into the desired hydroxamic acid 2ce (Table 9, entry 19). Oxidation with periodate and trapping with 1,3-cyclohexadiene and 1,3-cycloheptadiene afforded the HDA cycloadducts 218 and 219 in 81 and 78% yields, respectively (Scheme 110).232 The cycloadduct to cyclohexadiene 218 was isolated in the diastereomeric ratio of 91:9, while the cycloadduct to cyclo-

Scheme 108. Generation of and Trapping Nitrosocarbonyls 1by, 1bz, 1ca, 1cb, and 1cc

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Scheme 109. TS for the Cycloaddition of Nitrosocarbonyl 1cd to Cyclopentadiene

Scheme 110. Generation of Nitrosocarbonyl 1ce from Ketopinic Acid and Trapping with Dienes

Scheme 111. Generation of Nitrosocarbonyl 1cf and Trapping with 2,4-Hexadiene

1ci−1cm and 1,3-cyclohexadiene (Table 9, entries 23−27).235 For the sake of comparison we have also reported here the results concerning the cycloadducts 224. The oxidation protocol offers the possibility to obtain the cycloadducts in excellent yields in all cases. The selectivities seem to be strongly dependent upon the substituent. Lacking the aryl substituent as it occurs in nitrosocarbonyl 1ci, no selectivity is observed in the cycloaddition reaction. In all the other cases where a phenyl group is present, with or without a group in position 4 of the aromatic ring, the selectivities increase remarkably up to 1:22 as in the case of intermediate 1cm.235 A general approach to the cis-fused octahydroindole skeleton of representative Amaryllidaceae alkaloids relies upon the chemistry of NCs suitably substituted. The hydroxamic acid 2cn (Table 9, entry 28) is oxidized with periodate in the presence of 9,10-DMA to afford the HDA cycloadduct 230 in 85% yield (Scheme 115). The cycloadduct cycloreverts to the nitrosocarbonyl 1cn when refluxed in toluene and undergoes intramolecular ene reaction to give the indane 231 quantitatively, which represents the key intermediate for the synthesis of (±)-crinane.236 The same strategy was used for the total synthesis of mesembrine and dihydromaritidine, alkaloids of the genera Sceletium and Amaryllis. The hydroxamic acid 2co (Table 9, entry 29) is oxidized under the same experimental condition of the previous reaction, and the HDA cycloadduct 232 was obtained in 83% yield (Scheme 116).

Scheme 112. Generation of Nitrosocarbonyl 1cg and Trapping with Cyclic Dienes

synthesis of (−)-epibatidine was accomplished taking advantage of the efficient selective HDA cycloaddition of this NC intermediate. This result prompted the authors to extend the investigations of the effect on the facial selectivity of the substitution of naphthyl with other groups, increasing the reaction scope. 1,3Cyclohexadiene was the trapping agent of choice and the Swern oxidation was also selected in order to compare the new results with those reviously obtained and reported in Scheme 113. Hence, Scheme 114 reports yields and de ratios for the HDA cycloadducts 225−229 obtained from the new nitrosocarbonyls AZ


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Scheme 113. Generation of Nitrosocarbonyl 1ch and Trapping with 1,3-Cyclohexadiene

Scheme 114. Generation of Nitrosocarbonyls 1ci, 1cj, 1ck, 1cl, 1cm, and 1ch and Trapping with 1,3-Cyclohexadiene

Scheme 115. Generation of Nitrosocarbonyl 1cn, Trapping with 9,10-DMA, and Intramolecular Ene Rearrangement

Scheme 116. Generation of Nitrosocarbonyl 1co, Trapping with 9,10-DMA, and Intramolecular Ene Rearrangement

bonds in linear or cyclic moieties suitable to instantly capture the NC intermediates generated through variable methods. This is the intramolecular version of the NC chemistry where the trapping agent can be a diene (HDA cycloaddition) or a simple alkene (ene reaction). Table 10 reports the structures of the fleeting intermediates, and the dots in the structures indicate the points of attachment of the reactive NC unit. The simplest case is that reported in Table 10, entry 1, where the oxidation via periodate salt of the hydroxamic acid 2cp

The intramolecular thermal ene reaction afforded quantitatively the indane 233 whose structure was subsequently elaborated to obtain the target compounds.237 These two last reactions are reported here because the primary products of the reactions were HDA cycloadducts to dienes but somewhat represent borderline cases with the intramolecular variant of the NC reactions to which section 3.1.6 is dedicated. 3.1.6. From Hydroxamic Acids with Intramolecular Trapping. In this section we report the structures of achiral and chiral hydroxamic acids R−CO−NH−OH where the substituents R contain one or two unsaturations due to CC double BA


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Table 10. Structures of Hydroxamic Acids R−CO−NH−OH, Oxidants, and Reaction Conditions in Intramolecular Reactions

BB


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Table 10. continued

a

Yields refer to the best results obtained or ranges of the best performances of the method.

afforded 2-oxa-1-azabicyclo[4.2.0]oct-4-en-8-one 234 in modest yield (34%) (Scheme 117).238

Other oxidants, such as PhI(OAc)2, and experimental conditions were tested in the search of better yields, but the method was not reproducible because of the inherent instability and competitive reactions of the NC intermediate in situ formed. For this reasons, the authors preferred to consider a different approach to β-lactam rings. The total synthesis of alkaloids possessing saturated nitrogen heterocyclic ring systems such as the case of monomorine I 236 can be performed by taking advantage of the intramolecular HDA cycloaddition of the hydroxamic acid 2cq (Table 10, entry 2) leading to the bicyclic heterocycle 235 in excellent yield (86%) (Scheme 118).239 This strategy toward the preparation of a variety of nitrogenous natural products relies upon the intramolecular HDA cycloaddition of NC intermediates which allowed for the preparation of valuable privileged structures suitable to be differently elaborated for the synthesis of a variety of nitrogenous

Scheme 117. Synthesis of 2-Oxa-1-azabicyclo[4.2.0]oct-4-en8-one 234

Scheme 118. Synthesis of 4a,5,6,7-Tetrahydropyrido[1,2-b][1,2]oxazin-8(2H)-one 235

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Scheme 119. Synthesis of (2S,4aR)-2-Butyl-4a,5,6,7-tetrahydropyrido[1,2-b][1,2]oxazin-8(2H)-one 237

method with tBuOOH coupled with a Ru−salen catalyst was used to get the desired compound in 64% yield and 9% ee.244 Medium range bridged heterocycles were also prepared from hydroxamic acid 2cv (Table 10, entry 7) that was first oxidized with periodate in the presence of 9,10-DMA; the anthracene HDA cycloadduct was thermally decomposed to afford the desired intramolecular regioisomeric cycloadducts 242a and 242b in 60% overall yield and in the ratio 1:1 (Scheme 121). These structural studies allowed for quantification of the deformations of the bridged functionalities and provided a strategy for the stereoselective synthesis of substituted seven- and eight-membered ring lactams.245 The synthesis of a bridged bicyclic oxazinolactam with complete diastereoselectivity was obtained from the oxidation with periodate of the benzyl-substituted hydroxamic acid 2cw (Table 10, entry 8), prepared from the acid 243 as reported in Scheme 122. The HDA cycloadduct 246 was obtained in 85%

natural products, including piperidine, indolizidine, and decahydroquinoline alkaloids.240 Another example comes from the periodate oxidation of the hydroxamic acid 2cr (Table 10, entry 3) that undergoes intramolecular HDA cycloaddition to the heterocycle 237 (Scheme 119).239−242 This can be easily elaborated into the gephyrotoxin (GTX) 223AB 238 in seven steps. The synthesis of bridged oxazinolactams was accomplished by oxidizing the hydroxamic acids 2cs and 2ct (Table 10, entries 4 and 5), which contain a terminal diene moiety (Scheme 120). Scheme 120. Syntheses of Bridged Oxazinolactams 239, 240, and 241

Scheme 122. Synthesis of Cycloadduct 246 as Single Diastereoisomer

yield as a single product whose elaboration conducted the synthesis of the cis-3,7-disubstituted azocin-2-one. A rationalization of the stereoselective outcome was proposed by the authors on the basis of steric interactions of the substituent located on the alkyl chain that keeps away the NC moiety and the diene one. Some other experiments were performed to prove these assumptions. The hydroxamic acid 2cx (Table 10, entry 9)

The HDA cycloadducts 239 and 240 were obtained in very good yields (75 and 85%, respectively).243 A variant of the reported protocol was proposed by Shea and co-workers by employing the hydroxycarbamate 2cu that is oxidized with periodate to afford 241 in 85% yield. In order to evaluate the performance of ruthenium catalysts, the oxidative Scheme 121. Synthesis of Cycloadducts 242a and 242b

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bears a benzyloxy substituent in the α position to the carbonyl group, and its oxidation afforded the HDA compound 247 in 76% yield and 100% selectivity (Scheme 123).246

HDA cycloaddition to afford the diastereomeric products 254a and 254b in 88% overall yields and in the ratio 1.8:1 (Scheme 125).

Scheme 123. Effect on Diastereoselectivity of the Chain Substituent

Scheme 125. Synthesis of the Diastereomeric Compounds 254a and 254b

The reaction is the pivotal step toward the synthesis of different natural products.240 In one case the products served the preparation of (−)-nupharamine and (+)-epinupharamine, members of the family of Nuphar piperidine alkaloids.249 In another case, the total synthesis of (−)-indolizidine alkaloid, a molecule extracted from the poison arrow frog, was completed through a synthetic strategy where the nitrosocarbonyl 1de represents a key intermediate.250,251 The first asymmetric synthesis of (+)-ioline was achieved in 20 steps from (S)-(−)malic acid by a route that includes the intramolecular HDA cycloaddition of the nitrosocarbonyl 1df (Table 10, entry 17) obtained from periodate oxidation of the unsaturated hydroxamic acid 2df (Scheme 126).

Moving the substituent to the β position with respect to the carbonyl group as it occurs in nitrosocarbonyl 1cy, the intramolecular cyclization afforded two diastereoisomers 248a and 248b in 84% yield and in the ratio 4:1. Nitrosocarbonyl 1cz bears the benzyloxy substituent on the γ position of the alkyl spacer. Moving the substituent far from the NC moiety causes a decrease of the selectivity to 3.7:1 in the cycloadducts 249a/249b, while the yields remain very good (84%). The carbamates 2da−2dd (Table 10, entries 12−15) were employed in the synthesis of bicyclic heterocycles possessing cleavable tethers for possible applications in the preparation of gastroprotective agents (Scheme 124).247,248 The periodate oxidation afforded the desired HDA cycloadducts 250−252 in the reported yields. The authors suggested for the cycloadduct 253 a reasonable TS accounting for the geometry of the product (see the inset in Scheme 124). A nice example of versatility in the use of privileged structures in the synthesis of natural compunds is represented by the oxidation with periodate of the hydroxamic acid 2de (Table 10, entry 16), a chiral compound that undergoes intramolecular

Scheme 126. Synthesis of the Diastereomeric 3,6-Dihydro1,2-oxazines 255

The key step is represented in Scheme 126, and the best experimental conditions to obtain the desired diastereoisomer trans-255a were investigated through solvent and temperature effects. The best results were obtained using THF/H2O 1:1 as solvent at 0 °C, yielding 97% of the isolated products 255a and 255b in the ratio 73:27, respectively.252 Scheme 127 reports the periodate oxidation of the unsaturated hydroxamic acid 2dg (Table 10, entry 18) affording the diastereomeric pyrido[1,2-b][1,2]oxazin-8-ones 256a and 256b

Scheme 124. Syntheses of Heterocycles 250−253

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solvent at 0 °C allowed obtaining the diastereoisomeric HDA cycloadducts 259 and 260 in high yields with remarkable selectivities (Scheme 130): from compound 2dj, cycloadducts 259a and 259b were isolated in 4.4:1 ratio while from compound 2dk cycloadducts 260a and 260b were isolated in 5.0:1 ratio.255

Scheme 127. Synthesis of Diastereomeric Pyrido[1,2b][1,2]oxazin-8-ones 256

Scheme 130. Synthesis of Diastereomeric Pyrido[1,2b][1,2]oxazin-8-ones via MOM Protected Hydroxamic Acids 2dj and 2dk in 96% overall yields. This represents the pivotal step for the synthetic approach to indolizidine alkaloids. The authors set up the experimental conditions with the aim to tune the diastereoselectivity outcome of the reaction. When the reaction was performed at 0 °C, the cycloadducts were isolated in the ratio 1.2:1 respectively for 256a/256b. Decreasing the temperature at −78 °C, the diastereomeric ratio is strongly improved in favor of the compound 256a with a ratio 2.3:1.253 The structure of pyrido[1,2-b][1,2]oxazin-8-ones is prone to be synthetically elaborated toward various targets. Another example of their use is represented by the synthesis of the (−)-swainsonine. Kibayashi and co-workers used the hydroxamic acid 2dh (Table 10, entry 19) in the pivotal step. Oxidation with periodates in CHCl3 at 0 °C afforded the desired heterocycles 257a and 257b in 76% overall yield. The diastereomeric ratio was 1.3:1 in favor of isomer 257a (Scheme 128).254

The role of privileged structure of nitrosocarbonyls becomes clear in the following example. The hydroxamic acid 2dl (Table 10, entry 23) is oxidized with periodate affording the diastereomeric HDA cycloadsduct 261a and 261b in 69% overall yields and in the ratio 6.6:1, respectively (Scheme 131).258 The major diastereoisomer 261a was synthetically elaborated toward the preparation of a variety of natural compounds. (−)-Lepadin B, isolated from the tunicate Clavelina lepadiformis, exhibits significant in vitro cytotoxicity against human cancer cell lines. On the other hand, (+)-azimine and (+)-carpaine, respectively isolated from Azima tetracantha L. and Carica papaya L., were obtained from the azimic acid N-Cbz protected, directly prepared from compound 261a.259,260 An intramolecular HDA cycloadduct of an NC intermediate to the 9,10-DMA derivative was prepared as potential nitroxyl (HNO) donor. Hydroxamic acid 2dm (Table 10, entry 24) was prepared from the anthracene ester 262 and oxidized with periodate to afford the cycloadduct 263 in quantitative yield (Scheme 132). The synthetic modification introduced onto the adduct 263 by adding a nitrone moiety afforded a modified compound potentially able to act as HNO donor.261 Unfortunately, this compound did not release HNO under any of the conditions tested. A stereocontrolled approach to the proposed structure of lepadiformine was achieved employing an intramolecular HDA reaction of the NC generated through periodate oxidation of the hydroxamic acid 2dn (Table 10, entry 25) via a preliminary cycloaddition to the 9,10-DMA 264. Thermal retro-DA afforded the intramolecular cycloadducts 265a and 265b in 75% overall yields and in the ratio 5.5:1, respectively (Scheme 133). Curiously, the synthesis afforded a final compound that was not identical with that reported for the natural lepadiformine and

Scheme 128. Synthesis of Diastereomeric Pyrido[1,2b][1,2]oxazin-8-ones 257

The same authors conducted several studies on the effect of acqueous media on the HDA cycloaddition of NCs trying to improve yields and selectivities, also varying the alcoholic protecting groups. The best results in terms of chemical yields were obtained with the hydroxamic acid 2di (Table 10, entry 20) in organic solvent at 0 °C (87% overall yield) and a diastereomeric ratio of the products 258a/258b of 1.4:1 (Scheme 129).255,256 The total synthesis of (−)-pumiliotoxin C was accomplished in 13 steps by taking advantage of the intramolecular HDA of the nitrosocarbonyl 1di, starting from the regiosiomer 258a.257 Upon changing the solvent to H2O/MeOH (6:1) the selectivity was efficiently improved to 4.5:1 with a slight decrease of the chemical yields (73%). Similarly, it was done also for the reaction with the hydroxamic acid 2dh, where the selectivities were strongly improved by using water as solvent up to 4.1:1 for 257a/257b.255 The oxidation with periodate of MOM-protected hydroxamic acids 2dj and 2dk (Table 10, entries 21 and 22) in water as

Scheme 129. Synthesis of Diastereomeric Pyrido[1,2-b][1,2]oxazin-8-ones 258

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Scheme 131. Synthesis of (−)-Lepadin B, (+)-Azimine, and (+)-Carpaine

Scheme 132. Intramolecular HDA Cycloaddition of the Anthracene Nitrosocarbonyl 1dm

Scheme 133. Generation and Intramolecular Trapping of Nitrosocarbonyl 1dn

Scheme 134. Generation and Intramolecular Trapping of Nitrosocarbonyl 1do

the authors, convinced of the correctness of their synthesis,

The same authors started to study a slightly different approach to lepadiformine and other marine alkaloids, such as fasicularin, in the racemic forms. As in the previous case, the key common strategy element is the stereocontrolled intramolecular HDA

concluded that the literature proposed structure for the natural lepadiformine had to be revised.262 BG


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cycloaddition of the NC generated from the oxidation of the hydroxamic acid 2do (Table 10, entry 26) prepared for the scope. Scheme 134 reports the synthesis of the intramolecular cycloadducts 266a and 266b which were isolated in 84% overall yields and in the ratio 4.5:1, respectively. On further elaboration of the cycloadduct 266b, the two synthetic targets were achieved, and in particular the relative stereochemistry of lepadiformine, formerly assigned incorrectly, was definitively and unambiguously established.263 Table 10, entry 27, shows the hydroxamic acid 2dp that was oxidized with periodates to give the intramolecular cycloadduct 267 in 66% yield (Scheme 135). The structure was assigned

Scheme 137. Generation and Intramolecular Trapping of Nitrosocarbonyls 2dr−2dt

Scheme 135. Generation and Intramolecular Trapping of Nitrosocarbonyl 1dp

The reaction is the first example of a cyclic diene as a participant in the NC reaction. The product was isolated as a 10:1 mixture of diastereoisomers at the C10 and variation of reaction temperature resulted in a negligible effect on the selectivity. Further elaborations provided the functionalized tricyclic core suitable for the elaboration toward stenine. The hydroxamic acid 2ds (Table 10, entry 30) is similarly oxidized to get the cycloadduct 270 and from here in five steps the tricyclic core of stenine. A second generation synthesis was developed starting from the hydroxamic acid 2dt (Table 10, entry 31), oxidized at lower temperature to afford the desired cycloadduct 271 in modest yields (32−51%) but high diastereoselectivity (>10:1).267 The Cephalotaxus alkaloid cephalotaxine was synthesized in the dl form via an intramolecular HDA cycloaddition of the complex hydroxamic acid 2du (Table 10, entry 32) that was oxidized with periodate to afford the diastereoisomeric cycloadducts 272a and 272b in 71% yields (Scheme 138).268,269 Both isomers were carried on during the synthesis and the separation to the final target was performed in the last steps. The last two examples deal with the generation of NC intermediates by using hydrogen peroxide as oxidant in the presence of suitable catalysts. The hydroxamic acids 2dv and 2dw (Table 10, entries 33 and 34) were oxidized under mild simple conditions employing Fe(III) chloride as the catalyst and H2O2 in stoichiometric amounts. These conditions were found compatible with the intramolecular ene reaction allowing for the efficient conversion into the adducts 273 and 274 (Scheme 139). The reaction conducted in methanol at room temperature afforded 273 in 60% yield and 274 in 10% yield, only. Upon increasing the reaction temperature at 100 °C (iPrOH was used as solvent), 274 was isolated in 64% yield as a single product.270 The protocol was proved to be applied in other cases where the CC double bond possesses a different degree of substitution of alkyl groups. The hydroxyl-oxazolidinone core structure remained the same, and for these reason the examples were not reported here. From the hydroxamic acid 2dv, upon changing the metal cation Cu(II) in THF, the yields of 273 were improved up to 70%. 3.1.7. From Nitrile Oxides. Nitrile oxides R−CNO were introduced in recent years as starting materials for the generation

through X-ray analysis and cleavage of the tethering group and further synthetic elaboration allowed preparation of valuable heterocyclic derivatives.264 A new efficient strategy for the construction of the 6azaspiro[4,5]decane ring system was developed by Kibayashi and co-workers using the intramolecular ene reaction of the nitrosocarbonyl 1dq, obtained from periodate oxidation of the hydroxamic acid 2dq (Table 10, entry 28). The spirocyclic ene product 268 was obtained in 82% yield as a single diastereoisomer and subsequently subjected to highly stereoselective ethynylation, leading to the azaspirodecane core of halichlorine and pinnaic acid (Scheme 136).265 The hydroxamic acid 2dr (Table 10, entry 29) is oxidized with periodate to add the cyclohexadiene moiety intramolecularly and give the HDA cycloadduct 269 in 50% yield (Scheme 137).266 Scheme 136. Generation and Intramolecular Trapping of Nitrosocarbonyl 2dq

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Scheme 138. Generation and Intramolecular Trapping of Nitrosocarbonyl 2du

including carbocyclic nucleosides and biomimetic compounds.274−284 Other dienes were used to trap 1i such as 1,3-cyclohexadiene (HDA cycloadduct 37 yield: 81%)271,285,286 allowing preparation of carbocyclic nucleosides and 9,10-DMA whose HDA cycloadduct was isolated in 90% yield.271 The nitrosocarbonyl benzene 1i was extensively used to test the application of the oxidative method from nitrile oxides and NMO in the ene reactions in the presence of a variety of alkenes at different degrees of substitution on the CC double bond (Scheme 143). The results demonstrated that tetra- and trisubstituted alkenes and cyclohexene afforded the ene adducts in nearly quantitative yields. The 1,3-dipolar cycloaddition strongly competes when cyclopentene and 1,1- and 1,2-disubstituted alkenes are used as ene partners. Finally, monosubstituted alkenes such as 1-hexene or 1-octene do not react according to the ene pathway but the 1,3-dipolar cycloaddition is the only active reaction path with these alkenes.272,287,288 It is worth noting that, with alkenes where a regioselectivity outcome is expected, a single ene adduct was isolated in full accordance with the Markovnikov rule; i.e., the addition of the nitrosocarbonyl 1i occurs on the less substituted carbon atom of the alkene.287,288 The reaction of the nitrosocarbonyl benzene 1i with 3-methyl2-buten-1-ol was also investigated, and the intermediate was found to to add the less substituted carbon atom of the CC double bond in full accordance with the Markovnikov orientation (M) affording the ene adduct 284j in 50% yield, along with the product of the water elimination 284k in 8% yield (Scheme 144).289 The corresponding methyl ether and acetate ester behave similarly, and the ene adducts derived from the Markovnikov addition of 1i were isolated in 70% and 60% yield, respectively. The reactions performed with sterically demanding nitrosocarbonyls 1n (Table 11, entry 12) and 1eb (Table 11, entry 15) activate for the NC intermediates the anti-Markovnikov (AM) pathway (Scheme 145). The reactions of 1n with the 3-methyl-2-buten-1-ol methyl ether and acetate esters afforded the ene adducts of the M and AM pathways in 63%/35% (284Ml) and 56%/32% (284Mm) yields, respectively. When the simple alcohol was used, an unexpected hydroxy-isoxazolidine 284Mn was isolated in 25% yield along with 50% of the M adduct 284Ml. The formation of this heterocycle derives from an intramolecular cyclization path of not-isolable intermediates.289 The steric effect that enables the AM pathway to be competitive with the electronically favored M pathway is enforced by the use of the anthracene nitrosocarbonyl 1eb; the M ene adduct 284Al was isolated in 27% yield while the hydroxyl-isoxazolidine 284An was obtained as a major component (52% yield). These hydroxyl-isoxazolidines were

Scheme 139. Generation and Intramolecular Trapping of Nitrosocarbonyls 1dv and 1dw

of NC intermediates, and this section of the review is dedicated to this topic. Table 11 reports the structures of the fleeting intermediates bearing aliphatic and aromatic substituents, the oxidants used in the different reaction, and the trapping agents. The simplest case is that reported in Table 11, entry 1, where the nitrosocarbonyl methane 1b was obtained through oxidation with N-methyl-morpholine N-oxide (NMO) of the aliphatic nitrile oxide CH3−CNO, generated in situ from the corresponding hydroxymoyl chloride 275. The reaction along with the oxidation mechanism is reported in Scheme 140. In the presence of 1,3-cyclohexadiene, the HDA cycloadduct 27 was isolated in 57% yield along with a small amount of the cycloadduct 276 (4%) deriving from the 1,3-dipolar cycloaddition to the cyclohexadiene.271 The same nitrosocarbonyl 1b was also generated in the presence of TME to afford the ene adduct 26 in 64% yield. The reaction conducted at room temperature represents a valuable method for the C−N bond formation under mild conditions.272 Aliphatic nitrosocarbonyls 1dx and 1dy (Table 11, entries 2 and 3) were generated in situ upon oxidation of the corresponding nitrile oxides and trapped with both 1,3cyclohexadiene273 and TME272 (Scheme 141). The HDA cycloadducts 279 and 280 were obtained in very good yields along with small quantities of the 1,3-dipolar derivatives (90%) were obtained for the 1-substituted cyclohexenes reported in Scheme 157 heated in

construct allowed for the mild cleavage of the products by using 0.1 M TBAF in THF for 30 min. These results served as a benchmark for the extension to immobilized arylnitroso dienophiles that were prepared on several linkers cleavable by different cleavage reagents. The outcome of the HDA cycloadditions was evaluated for a set of 19 dienes.301 Polyethylene glycol functionalized with hydroxamic acid 311 moiety has been investigated by Read de Alaniz and co-workers as a new tool for conjugation. The oxidation was performed under aerobic conditions by using CuCl/Py as the catalyst in the presence of cyclopentadienyl end-capped polystyrene polymer 313 (Scheme 156). The oxidation proceeds at room temperature with complete conversion, and the resulting oxazine-capped polymer could be easily isolated by precipitation and fully characterized.302 Interestingly, the diene modification by introducing a triple bond allowed obtaining an oxazine-capped polymer suitable for further functionalization through click chemistry of azide polymers with intriguing perspectives for future applications.

Scheme 157. Ene Reaction from Thermal Retro-DA of Cycloadduct 9

3.4. Thermal Protocols

3.4.1. From 9,10-Dimethylanthracene Cycloadducts. In the previous sections we have already discussed the thermal generation of NC intermediates from labile adducts that contain the RCO−N−O moiety obtained through different protocols. Normally, this escamotage is used when the oxidation conditions do not permit the safe obtaining of the desired products or in case of the presence of complex and delicate functionalities within the entire molecule. One of the first examples of this methodology was reported by G. E. Keck, who prepared the HDA cycloadduct of nitrosocarbonyl methane 1b to 9,10-DMA under classical periodate oxidation of hydroxamic acid (Scheme 7). The HDA cycloadduct 9 was derivatized with a 2,4-hexadiene-1-ol substituent by aldehyde condensation on the acetyl group.67 Thermolysis of compound 10 in refluxing benzene for 5 h afforded the 9,10DMA and two intramolecular HDA cycloadducts 11a and 11b in quantitative yields. This methodology was successfully applied in the condensation of the enolate of the cycloadduct 9 with a variety of α,βunsaturated aldehydes substituted with tert-butyl dimethylsilyloxy groups. Thermolysis of the substituted cycloadducts allowed performance of ene reactions as intramolecular processes affording unsaturated pyrrolidinones in quantitative yields as shown in Scheme 8.68 The mild conditions of the thermal generation of functionalized NCs make the protocol particularly attractive for employment in natural products synthesis,69 such as

benzene at reflux with compound 9, obtaining the ene adducts 284l and 284m of the nitrosocarbonyl 1b and 9,10-DMA as byproduct. With other olefins the yields are always above 80% with the exception of 1,1-diphenyl-1-propene. The method found remarkable improvements through the functionalization of the hydroxylamine adduct to 9,10-DMA in the presence of sodium methoxide and a variety of acyl chlorides to obtain the adducts 315a−315f that were submitted to thermolysis to afford quantitatively the ene adducts 316a−316f (Scheme 158).303 Extension to other structures, not reported here, afforded the ene adducts in >75% yields as a further confirm of the general reliability of the designed protocol.304 The thermal reversibility of the HDA cycloadducts of NCs was also investigated for the cyclopentadiene adducts of type 317a− 317d, prepared through periodate oxidation of the corresponding hydroxyl-carbamates in the presence of cyclopentadiene as trapping agent. When heated at 80−111 °C, cyclopentadiene is released and the intramolecular ene reaction afforded the adducts 318a−318d in variable yields. The best results are collected in Scheme 159; other cases gave variable responses. Further examples of the valuable application of the thermolysis of the HDA cycloadducts come from the use of the stable hydroxamic acid 2ef in the synthesis of 9,10-DMA cycloadduct followed by thermal-promoted ene reaction to give the 6-endo product 319a and the 5-exo product 319b in >90% yields and 9:1 endo/exo ratio (Scheme 160).305 The major product of this BR


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Scheme 158. Ene Reaction from Thermolysis of Adducts 315

reaction was the key starting material for the first total synthesis of (−)-hosieine A.306 The transfer of the NC intermediate from the 9,10-DMA cycloadduct to other dienes is also used to prepare the HDA cycloadducts that serve for specific syntheses. This is the case represented in Scheme 161, where the 9,10DMA cycloadducts of nitrosocarbonyls 1b, 1i, and 1w were submitted to thermolysis in the presence of the phosphono diene 320 to afford the cycloadduct 321 in 95% yield.307 As a key starting material, 321 was used to prepare polyfunctionalized aminophosphonic derivatives. However, the thermal fragmentation of HDA cycloadducts of NC served other intriguing investigations, not directly connected to synthetic purposes. Kirby and co-workers used the thermolysis of the 9,10-DMA HDA cycloadducts of nitrosocarbonyls 1i, 1k, 1p, and 1t to perform a deoxygenation reaction in the presence of triphenylphosphine to prepare aromatic substituted isocyanates 323 (Scheme 162). The reaction proceeds through the intermediate 322 between the NC and the phosphine that undergoes intramolecular transposition to the isocyanates.308 The thermal retro-DA of anthracene adducts was also investigated from the theoretical point of view in order to determine if the diene is a cofactor or just a spectator in this process. Monbaliu and co-workers evidenced that the thermal process has to overcome an activation barrier of 27.6 kcal/mol and the anthracene cycloadducts slowly release the NC species in the reaction medium. This could rationalize why the NC

Scheme 159. Ene Intramolecular Reaction from Thermolysis of Cycloadducts 317

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Scheme 160. Ene Reaction from Thermolysis

Since 1978, the thermal cycloreversion of 9,10-DMA cycloadducts of nitrosocarbonyls was found to be an interesting, valuable, and promising method for generating other transition species such as HNO. In this area, Tyler and co-workers detected by microwave spectroscopy the HNO product by retro-DA reaction.311 Similarly, in 1989 Ensley and Mahadevan looked with interest at the opportunity to decompose the 9,10-DMA HDA cycloadducts of nitroso and acylnitroso derivatives, performing a retro-DA reaction with the scope to generate HNO and HCONO species to be used as dienophiles and enophiles.312 The method became applicable in various ways. In fact, the potential pharmacological activity of HNO attracted much attention and the classical 9,10-DMA cycloadducts of NC intermediates, generated through typical periodate oxidation, became the starting material to perform the HNO release via UVA irradiation. The formation of HNO was confirmed by EPR and GC−MS analyses.313 3.4.2. From 1,2,4-Oxadiazole-4-oxides. Finally, we wish to report the very last property of the 1,2,4-oxadiazole-4-oxides: the photochemical cleavage suggested to verify a potential thermal fragmentation of the heterocycle in the same manner. When the 3,5-diphenyl-1,2,4-oxadiazole-4-oxide 294 is heated at temperature above 110 °C, it undergoes thermal fragmentation to a nitrile and an NC moiety as sketched in Scheme 164.314 High boiling point alkenes, such as cyclooctene, can be used both as solvent and as trapping agent to afford the corresponding ene adduct in 81% yield. The same reaction was tested also for nitrosocarbonyl 1k, 1m, 1p, and 1n using cyclooctene as solvent and the ene adducts were obtained in 73−87% yields. For the sake of simplicity, we summarize these results in Table 12 (entries 2−5). The 3,5-diphenyl-1,2,4-oxadiazole-4-oxide 294 was also used to generate nitrogen oxides that are critical components of a number of physiological processes, gaining a wide interest with respect to the treatment of heart failure and as preconditioning agents for the mitigation of ischemia-reperfusion injury. There are a number of methods to generate HNO from different donors, such as Angeli’s salt or Piloty’s acid. Novel Nsubstituted hydroxylamines with carbon-based leaving groups have been recently synthesized, and in particular their barbituric acid and pyrazolone derivatives efficiently generated HNO at physiological conditions. Strictly related, a wide range of N,Obisacylated hydroxylamine derivatives with chloro and arene-

Scheme 161. HDA Cycloaddition to 1-Phosphono-1,3butadiene

intermediates lead more successfully to the corresponding cycloadducts of unconstrained dienes than the classical periodate oxidation of hydroxamic acids. Moreover, under these conditions, the cisoid state of the diene is more populated than the fundamental transoid one; at lower temperature, the cisoid state of the diene is not sufficiently populated and NCs do not undergo cycloaddition and accumulate in the medium, dimerizing with final degradation. The cisoid−transoid equilibrium is for the nitrosocarbonyl species fundamental for unconstrained dienes being the ratedetermining step.309 In consideration of the interest in thermal transformations of NC HDA cycloadducts, the behavior of the 2,3-oxazanorborn-5enes was investigated and novel thermolytic pathways was encountered. Scheme 163 reports the main directions the Nbenzoyl-2,3-oxazanorbor-5-ene 56 underwent when heated at 100 °C for 70 h in xylene. The retro-DA reaction proceeded to the cyclopentadiene formation and free nitrosocabonyl benzene that dimerized and degradated. The 3-phenyl-5,7a-dihydro-4aH-cyclopenta[e][1,4,2]dioxazine 324 was isolated as a rearranged product from a [3,3]-sigmatropic shift. The labile N−O and C−N bond were subjected to homolytic cleavage to the structure reported in Scheme 163 that underwent intramolecular rearrangements to the isolated compounds.310

Scheme 162. Isocyanate Synthesis through Thermolysis of HDA Cycloadducts

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Scheme 163. Thermal Fragmentation Pathways of N-Benzoyl-2,3-oxazanorbor-5-ene

Scheme 164. Thermal Fragmentation of 3,5-Diphenyl-1,2,4-oxadiazole-4-oxide 294

Scheme 165. Catalyzed O- and N-Functionalization with Nitrosocarbonyl 1af

Scheme 166. Aerobic Generation of Nitrosocarbonyl 1ah and α-Amination

The first examples of this novel synthetic procedure was presented by the Yamamoto and Read de Alaniz groups in 2012 in two papers published nearly at the same time. Yamamoto used the carbamate 2af to generate the corresponding nitrosocarbonyl 1af by using MnO2 as a mild and efficient oxidant in the presence of a Cu(II) complex with the (R,R)-PhBox ligand. The nitrosocarbonyl 1af was captured by an oxopentanoate derivative 325 to afford the O- and N-products 326a and 326b in 73% and 20:1, respectively (98% ee). These optimized conditions were applied to a variety of aldehydes, aliphatic and aromatic, with excellent results and with ee’s in the range 92−99%. Further applications were proposed by the same authors by coupling the asymmetric hydroxyamination with the Wittig reaction as a one-pot synthesis of chiral allylamines.320 The reaction shown in Scheme 169 reports the merging of aerobic conditions and enamine catalysis in the asymmetric αamination of ketoesters with NCs. The optimized conditions require the use of a chiral amine and CuCl as the catalyst. The

The new methodology harnesses the power of compounds of type 2ah as a viable electrophilic source of nitrogen in αfunctionalization reactions. Various oxopropanoate derivatives, bearing aliphatic and aromatic substituents in positions 2 and 3 of the propanoate chain, were tested under the reported conditions and the N-products were isolated in 42−92% yields. On pursuing the investigation on the ambident reactivity of NCs as electrophiles, the Read de Alaniz group extended the studies to cyclic ketoesters 329a−329c. The nitrosocarbonyl 1af was generated through aerobic conditions in the presence of Cu(I)/Cu(II) as the catalysts and 2-ethyl-2-oxazoline, getting very good results in terms of yields relative to products 330a− 330c for the α-oxygenation as reported in Scheme 167.318 Inspired by the work by Yamamoto and co-workers, Read de Alaniz and co-workers set out to control the absolute stereochemistry of the O-selective NC aldol products. The reaction can be rendered asymmetric by simply substituting the 2-ethyl-2-oxazoline with the (R,R)-PhBox ligand. The results in terms of yields were very good (74−88%) and the enantiomeric ratio was up to 99:1. BV


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Scheme 170. Aerobic Oxidation in the Presence of Cu(I)/Cu(II) Salts

Scheme 171. Enantioselective Synthesis of β-Amino Alcohol

Scheme 172. Enantioselective Hydroxymation Reaction

dearomatization reaction using properly substituted indoles. The best result was obtained for the compound 336 that was converted into the dimer 337 in 45% yield, as a product derived from a [4 + 4] cycloaddition. A highly enantioselective method for the preparation of βamino alcohols was achieved by using the readily available proline-tetrazole as the catalyst for the N-nitroso aldol reaction of aldehydes with in situ generated NC compounds. The key to success of this reaction is the use of MnO2 as an oxidant and cathecol as a Brønsted acid additive. Scheme 171 reports the best result obtained in the optimization of the method performed with the carbamate 2af with the 3-phenyl-propanal 331; subsequent reduction of the primary product afforded the compound 338 in 65% yield and 98% ee.325

yields are excellent (97%), and the N- and O-products 333a and 333b were obtained in the ratio >20:1, respectively (96% ee).321 Again, the extension to several ketoesters allowed preparation of a variety of valuable compounds in optimum yields (51−93%) and excellent ee’s (88−99%). The chemoselective control over N/O selectivity in these reactions was investigated through computational studies.322,323 A series of new pyrroloindolines was prepared by taking advantage of the aerobic oxidation of carbamate 2ah in the presence of Cu(I)/Cu(II) salts as the catalysts with protected tryptamine 334 (Scheme 170). The optimized conditions allowed obtaining the product 335 in 70% yield.324 To highlight the synthetic utility of the reaction, the authors turned their attention to the copper-catalyzed intramolecular BW


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Scheme 173. Practical Method for α-Amination

Scheme 174. Synthesis of the N-Product 344

Scheme 175. Mukaiyama Aldol Reaction

Scheme 176. Asymmetric Ene Reaction

(Scheme 173). As usual, the optimized conditions were applied to several other cases with excellent results in terms of both chemical yields (82−97%) and ee’s (85−95%). The method also provided nice access to highly substituted β-keto amino acid derivatives.328 These and previous results by the Maji and Yamamoto group were also summarized in an account dedicated to the C−X bond formation.329 A practical method for α-amination was proposed by Lu and Liang starting from the carbamate 2af in the presence of βketoesters. The oxidant used in these reactions was tBuOOH and the catalyst was the MgCl2 salt. Scheme 174 reports the best result obtained; the N-product 344 derived from the β-ketoester 343 was isolated in 99% yield. Other β-ketoesters were used with excellent yields (80−97%).330 The Mukaiyama aldol reaction found application in the chemistry of NC intermediates, and the reported examples come from the optimization of the reaction conditions for the carbamate 2ah that was oxidized to the corresponding nitrosocarbonyl 1ah with oxygen in the presence of CuCl/ pyridine as the catalyst and the silyl enol ether 345 (Scheme 175). The reaction proceeded with perfect N-selectivity (98% yield) and simultaneous N−O bond cleavage; such a cascade of C−N bond formation and N−O bond cleavage in a single step was heretofore unknown in the field of NC chemistry. A variety of

The extension to other aldehydes, bearing aliphatic, aromatic, and heterocyclic substituents, allowed for obtaining the β-amino alcohols in 51−69% yield and excellent ee (92−98%). On pursuing the studies on the use of MnO2 as an oxidant for carbamates, Maji and Yamamoto reported the α-hydroxy phosphonic acids and their derivatives can be accessed through the copper-catalyzed direct α-oxidation of β-ketophosphonates using in situ generated NC intermediates as an electrophilic source of oxygen. The optimized conditions were reported for the reaction sketched in Scheme 172 for the carbamate 2af and the compound 339. Copper triphlate complex with the (R,R)PhBox ligand allowed for obtaining the product 340 in 94% yield and 96% ee.326,327 The substrate scope and the generality of this reaction were evaluated, reporting 27 examples with excellent yields and enantioselectivities. The absolute configuration of the product was assigned to be (R) by analyzing its X-ray structure, and a reasonable mechanism was proposed following the TS reported in the inset of Scheme 172. The same authors reported also the first example of a Lewis acid catalyzed asymmetric hydroxyamination of β-ketoesters with the nitrosocarbonyl 1af generated from MnO2 oxidation. The combination of a catalytic amount of Mg(OTf)2 with a chiral N,N′-dioxide ligand provides the derivatives 342a and 342b in 91% yield and in the ratio >20:1, respectively, with 95% ee for the major compound BX


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presence of a trisubstituted alkene no traces of the ene product were detected.

silyl enol ethers was tested with excellent results (70−99% yields).331 The first example of a general asymmetric nitrosocarbonyl ene reaction was described by Read de Alaniz and co-workers using a copper-catalyzed aerobic oxidation of a commercially available chiral nitrosocarbonyl precursor 2bg. The reaction conditions were optimized for the enolsilyl ether 347 and allowed obtaining the primary ene adduct 348 that was hydrolyzed to the ketone 349, isolated in 99% yield and >95:5 dr (Scheme 176).332 Having established the optimized conditions, the reaction was also tested for a variety of cyclic aliphatic silyl enol ethers, all possessing an E-enolate geometry, getting the corresponding ene adducts in good yields and excellent diastereoselectivities. 3.5.2. Reactions with Amines. This section is dedicated to the generation of nitrosocarbonyl intermediates in the presence of nucleophiles, but contrary to the cases reported above, we refer to classical nitrogen nucleophiles, such as amines or their derivatives. Oxidation of hydroxamic acids in the presence of primary or secondary amines generates nitric oxide (N2O) and the corresponding amides. King and co-workers reported these reactions in 1996 for the hydroxamic acids 2b, 2i, and 2w. The reactions were conducted in water as solvent and afforded the amides in 16−65% yields and N2O in 42−69% yields (Scheme 177).333

4. NITROSOCARBONYL DETECTION 4.1. Spectroscopic Observations

In the “Tilden Lecture” in 1977, G. W. Kirby affirmed that “...the postulated intermediates, RCONO, have, so far, not been detected by physical methods.”1 Since that time, the detection of these fleeting intermediates has remained an open question. However, the attempts to find evidence of NCs started immediately in the scientific community and the very first investigation was reported by Forrester and co-workers in 1978. The authors treated the N-acyloxyamide 353 with di-tert-butyl peroxide, irradiating at 0−100 °C in the EPR cavity. No signals were detected, but when the lamp was masked and the solution heated at 100 °C a triplet of doublets slowly appeared. These spectra were attributed to the species 1′, as confirmed by addition of few drops of oxirane, when the spectrum was observed to intensify 5-fold (Scheme 180). This and other experiments tried to indicate indirectly the presence of the NC species.336 The 9,10-DMA adduct of nitrosocarbonyl benzene 1i was warmed to 40−80 °C in the cavity of an EPR spectrometer. The main radical detected was compound 357 derived from a source of R•. At 70 °C much weaker signals were detected and attributed to the radical structure 356 (Scheme 181).337 By the use of EPR spectroscopy, it was furtherly demonstrated that NCs can act as spin traps for short-lived radicals with formation of acyl aminoxyl radicals that appeared almost immediately when the reaction mixture was irradiated in situ in the EPR cavity with UV light.338 In the search of other techniques capable of detecting the NC intermediates, the neutral cycloadducts of 9,10-DMA to the nitrosocarbonyls 1a−1c were analyzed by neutralization− reionization mass spectrometry (NR-MS); under these conditions a beam of positive or negative ions with a given mass is generated and directed through a collision cell containing oxygen gas. An electron is transferred, neutralizing the ion. The beam of neutrals and fragment ions pass the electrode and all the charged species are deflected. The neutrals are ionized and detected. The method allowed recognition of the masses of nitrosocarbonyls 1a−1c, this being the very first experimental evidence of the existence of these transient species.339,340 An unstable neutral radical 358 was formed and detected by ESR analysis from the oxidation of the hydroxamic acid 2eh with PbO2. The reactivity of this transient species was verified by adding alcohols or phenol or water (Scheme 182).341 We have to wait until the year 2003 to find a definitive direct observation of an NC in solution by using time-resolved IR spectroscopy (TRIR). Toscano and co-workers had the intuition to use the 3,5-diphenyl-1,2,4-oxadiazole-4-oxide 294 (Wieland heterocycle) to generate photochemically the nitrosocarbonyl benzene 1i, in accordance with the protocol proposed by the Pavia group.295

Scheme 177. Amides and N2O Generation from Nitrosocarbonyls

The identification of N2O suggested the intermediacy of HNO, and the method was proposed in view of the generation of this highly reactive species. Years later, an efficient and straightforward approach for the coupling of N-protected hydroxamic acids with amino components in the presence of iodine was delineated. The iodine oxidation of hydroxamic acid 2eg in the presence of benzylamine afforded in DMSO as solvent at room temperature the amide 350 in 95% yield (Scheme 178).334 If the amine is an amino acid, the method nicely represents a protocol for new peptide bond formation. Finally, we report the condensation of nitrosocarbonyl intermediate 1aq, generated through periodate oxidation, with 2-(cyclohex-1-en-1-yl)ethanamine (Scheme 179). The reaction afforded the amide 351 as expected product in 41% yield along with the unexpected semicarbazone 352 in 43% yield. This latter is formed in the presence of excess amine and presumably comes from the isomerization of the initially generated acyl azo compound.335 Surprisingly, even in the

Scheme 178. Iodine Oxidation of Hydroxamic Acid 2eg and Trapping with Benzylamine

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Scheme 179. Trapping of Nitrosocarbonyl 1aq with 2-(Cyclohex-1-en-1-yl)ethanamine

Scheme 180. Radical Promoted Generation of Nitrosocarbonyl Intermediates

Scheme 182. PbO2 Promoted Generation of Nitrosocarbonyl 1eh

On the basis of calculations at the MP3/6-31G* level the authors were unable to locate a minimum for the oxazirine-Noxide 361 but reported that the rearrangement of the singlet nitrocarbene 360 was highly favored on thermodynamic grounds. It was also demonstrated compound 360 is a minimum and the oxazirine-N-oxide 361 is a transition structure that leads to the nitrosocarbonyl 1a. In the search for experimental evidence, tentative experiments to trap the NC from nitrocarbenes failed, and for these reasons the same authors defined the nitrocarbene 360 as an elusive species. Nevertheless, the authors were convinced that the singlet nitrocarbene was the intermediate to the NC species and found the solution to the problem from the experimental point of view. The nitrodiazomethane 359a, trifluoromethyl-nitrodiazomethane 359b, and ethyl nitrodiazoacetate 359c were treated with a catalytic amount of rhodium(II) acetate in the presence of 9,10-DMA and the HDA cycloadducts 362a−362c of the corresponding NCs were isolated in 25, 65, and 67% yields, respectively. Similar results were also obtained under mild thermal conditions in refluxing chloroform solution without a catalyst (Scheme 184).343−345 The authors affirm that this was convincing evidence that nitrocarbenes do undergo a facile [1,2] oxygen atom shift to yield NC intermediate. In 2011 Toscano and co-workers confirmed these assumptions by examining the photogeneration of NCs from nitrodiazo precursors by TRIR spectroscopy. Ethyl diazoacetate 359c provided the characteristic nitrosocarbonyl 1ei TRIR signal at

Laser photolysis (355 nm, 5 ns, 4 mJ) of a solution of the Wieland heterocycle produced the TRIR difference spectra shown in Figure 7.342 When the nitrosocarbonyl 1i is formed by photochemical cleavage of the heterocycle, the red line of the TRIR spectrum is shown; upon addition of diethylamine the signal of 1i is progressively quenched to leave the amide represented by the blue line. The stability of 1i was determined to be at least 180 μs. These results are the cornerstone and the ultimate evidence of the NC intermediates.

5. MISCELLANEOUS GENERATION METHODS 5.1. From Nitrodiazoalkanes

5.1.1. Nitrocarbenes as Precursors of Nitrosocarbonyl Intermediates. In 1988 Dailey and O’Bannon reported their studies on strained ring nitro compounds finding in the nitrodiazomethane 359 the ideal precursor, according to the observation made by other authors. A nitrocarbene 360 was expected to be generated from nitrodiazomethane; however, its failure in the addition to olefins allowed thinking of different reaction pathways that were investigated from the theoretical point of view according to ab initio calculations (Scheme 183). Scheme 181. Radical Trapping of Nitrosocarbonyl Intermediates

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Figure 7. TRIR spectrum of nitrosocarbonyl 1i. [Reproduced from ref 342. Copyright 2003 American Chemical Society.]

No other examples of NC generation from nitrodiazo compounds were reported in the literature.

Scheme 183. From Nitrodiazomethane to Nitrosocarbonyl

6. RELATED STRUCTURES 6.1. From P-Nitrosophosphonates

6.1.1. P-Nitroso Compounds. We are pleased to make a little diversion from the topic of this review by talking about the related structures of the P-nitrosophosphates because of their close resemblance to the NC intermediates, both on the starting material ground and on the oxidation methodology as well as on their reactivity. In 1999, King and Ware reported the oxidation of Nphosphinoyl-hydroxylamines 363 with nBu4NIO4 in MeOH/ DCM solution at 0 °C in the presence of cyclopentadiene or 1,3cyclohexadiene to give the HDA cycloadducts 365a and 365b in 80 and 88% yields, respectively (Scheme 186).347 The dienes are able to trap the reactive nitrosodiphenylphosphine oxide 364 in the same way they operate with NCs. Other dienes were tested, such as the 1,3-pentadiene affording the regioisomeric HDA cycloadducts 366a and 366b in 82% yield in the ratio 2.5:1, respectively. 9,10-DMA was also used to give the corresponding adduct in 73% yield. Other open dienes afforded the HDA cycloadducts in 34−81% yields as single products having the regiochemistry of compound 366a. The oxidation of N-phosphinoyl-hydroxylamines 367 with nBu4NIO4 in MeOH/DCM solution at 0 °C in the presence of cyclopentadiene or 1,3-cyclohexadiene gave the HDA cycloadducts 369a and 369b in 67 and 70% yields, respectively (Scheme 187).

Scheme 184. Synthesis of HDA Cycloadducts 362a−362c

1788 cm−1, consistent with B3LYP/6-31G* calculations. The intermediate was found stable for at least 1 ms in DCM, and nearly quantitative yields of HNO and carboxylic acid were observed following the photolysis in 75:25 MeCN/H2O (Scheme 185).346 Scheme 185. Photochemical Generation of Nitrosocarbonyl 1ei

Scheme 186. Generation and Trapping of the Nitrosodiphenylphosphine Oxide 364

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Scheme 187. Generation and Trapping of the Diethyl Nitrosophosphonate 368

Scheme 188. Generation and Trapping of the Benzyl-nitroso-phenylphosphine Oxide 372

Scheme 189. Intramolecular HDA Cycloaddition of P-Nitroso Derivatives

oxidation the intramolecular HDA cycloadduct 378 was isolated in 51% yield (Scheme 189).349 There results support the further developments of Pnitrosophosphine oxides as new synthetic reagents and intermediates for the synthesis of complex phosphorus molecules.

The cyclic dienes are able to trap the reactive diethyl nitrosophosphonate 368; other dienes were tested, such as 1methoxy-1,3-butadiene affording the regioisomeric HDA cycloadduct 370 in 76% yield as a single regioisomer. 9,10-DMA was also used to give the corresponding adduct in 36% yield, only. This adduct is thermally unstable and cycloreverts to the addends; the P-nitrosophosphate can be trapped instantly with other dienes. This is the same picture shown in the generation and chemical behavior of NCs.348 The use of asymmetric P-nitrosophosphate intermediate 371 in the presence of cyclic dienes afforded the diastereomeric HDA cycloadducts 373a,b and 374a,b. They were obtained in very high yields and with a remarkable stereoselectivity as reported in Scheme 188.349 The use of these asymmetric reactive Pnitrosophosphates allowed also investigation of the intramolecular version of the HDA cycloaddition. The 7-bromo-1,3-heptadiene 375 was converted into the phosphinic ester 376 whose basic hydrolysis and chlorination afforded the precursor 377. This was transformed into the protected hydroxylamine derivative; after deprotection and

7. THEORETICAL STUDIES 7.1. Studies on Nitroso and Nitrosocarbonyl Compounds

There are no comprehensive studies on NC intermediates from the theoretical point of view. Sometimes in the literature the structures of these fleeting species appeared in the context of more general investigations on related compounds.115,310 In this section we wish to summarize the bibliographic references where a reader can find useful suggestions on a theoretical approach to the NC chemistry. The first work reporting an NC structure was published by Wiberg and co-workers in 1992 where the structures, energies, and rotational profiles of heterobutadienes were studied according to DFT calculations. Among the structures reported, CB


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nature of nitrosocarbonyls, possibly widening their field of application and making it suitable even in unusual conditions for this king of compounds such as in biological environments.356−359

the nitrosocarbonyl OCNO was studied without any reference to possible reactions as dienophile or enophile.350 The chemistry of simple nitroso compounds RNO offered a simplified ground on which to develop theoretical studies on the reactivity of these species. Houk and co-workers deeply investigated this area starting from the reactions of nitrosyl hydride with 1,3-butadiene in HDA cycloaddition reactions.351 A single case was reported for the reaction of nitrosocarbonyl 1a with the 2-tert-butyl-1,3-butadiene.352 In 2002, Houk published DFT studies on the ene reaction of nitroso compounds with propene. In this paper the authors reported for the first time the possibility that the reaction involves a polarized diradical intermediate in a stepwise process.353 This work preluded the organic study of both DA and ene reactions with singlet oxygen, nitroso compound, and triazolinedione where the mechanisms of the three reactive species in the two reactions at hand were somewhat definitively clarified on a theoretical ground.354 Besides the specific studies done by the Pavia group in connection with ene reaction of nitrosocarbonyls 1i, 1n, and 1eb already discussed in previous sections,289,290 recently, Shea, Rychnovsky, and co-workers presented quantum mechanical calculations to investigate the intramolecular NC HDA cycloaddition to account for the origin of regio- and stereoselectivities. Scheme 190 reports the reaction and the DFT calculated TS predicting the observed selectivities.355

8. CONCLUSIONS AND PERSPECTIVES In the course of the long story of nitrosocarbonyls, some reviews, accounts, or highlights were published to present these intermediates, their chemistry, and their reactivity. Most of these publications covered the synthetic application of the nitroso group, including as a special variety the NC intermediates.360−362 These collections ware typically based on the type of reaction used to trap the NCs or on the synthetic applications of the adducts obtained from the trapping processes.363,364 Many of them, for example, were submitted to reactions in the presence of ruthenium based Grubb’s catalyst365 to perform stereodivergent syntheses of piperidine alkaloids by ringrearrangement metathesis,366 or alternatively in the presence of Pd(OAc)2 as the catalyst for the synthesis of conformationally restricted carbocyclic nucleosides.367,368 Furthermore, antimalarial drugs were prepared from suitable NCs according to ene reactions in the key steps.369 Among the variety of synthetic transformations proposed, the N−O bond cleavage represents one of the most productive and prolific reaction pathways.370,371 To this scope the cleavage could be conducted either by using the Al(Hg) amalgam in THF/H2O solution372 or by the use of SmI2/THF.373 The N−O bond cleavage found applications in the synthesis of inhibitors of 5lipooxygenase374,375 as well as in processes catalyzed by titanocene(III) chloride (Cp2TiCl),376 In(OTf)2,377 Cu(OTf)2−PPh3 for ring-opening,378,379 and many others.380,381 Nitrosocarbonyls are found in studies devoted to the biological applications of their starting materials382,383 or as generators of HNO through their dimerization and hydrolysis.384 The natural product synthesis was also extensively performed and reviewed,385,386 as well as the catalytic enantioselective C−N and/or C−O bond formation.386 In these fields the chiral version of the NC chemistry found large applications.387,388 Up to now, for a chemist, it was really difficult to extricate from the big number of papers dealing with the generation and trapping of NCs, and the state of the art on the chemistry of these intermediate was as much a fugitive as their chemical behavior. In this review, we tried to overcome this problem, collecting and organizing a comprehensive guide for the use of NCs. We collected all the possible precursors and then the reagents and experimental conditions needed to generate and efficiently trap these intermediates. In terms of precursors, we have seen the hydroxamic acids represent the most common starting material, while periodate salts are the most used oxidant for the generation of NCs. Whereas the complexity of the application increased, new solutions were developed, in order to make the use of NCs possible and easy.389,390 For example, the new aerobic generation method proposed by Read de Alaniz and Whiting, that makes the use of NCs suitable even on substrates with other delicate functional groups, is remarkable.391 For the same reasons, it is worth mentioning the photochemical generation by cleavage of the 1,2,4-oxadiazole-4-oxides, representing the mildest entry to NCs as well as the oxidation of hydroxamic acid using Rose Bengal as photosensitizer. In recent years, an increasing number of papers have been published dealing with the synthesis of optically pure products through the use of these fleeting intermediates, in the presence of chiral catalysts, further widening

Scheme 190. TS Structure for the Intramolecular HDA Cycloaddiction Reaction [Reproduced from ref 355. Copyright 2013 American Chemical Society.]

From the theoretical point of view the cycloreversion process of the 3,5-diphenyl-1,2,4-oxadiazole-4-oxide 294 was investigated by peforming DFT calculations at the B3LYP/631G(d,p) level. Figure 8 shows the enthalpic profile connecting the intermediates and the TS along with the energy values (kcal/ mol) nearby the structures.315 The photochemical fragmentation of 294 occurs at the excited state of triplet located 46.9 kcal/mol above the ground state. Then, two competitive reactions can be followed. At a higher value of activation energy (13.2 kcal/mol) a transition structure leads to the deoxygenation pathway to form 1,2,4-oxadiazole. The lower path at 3.6 kcal/mol leads to an intermediate where the N−O bond of the oxadiazole ring is broken. The open intermediate is remarkably stabilized at 28.2 kcal/mol below the triplet state and, through an easy passage located 8.6 kcal/mol above, the TS leads to the final compounds, the benzonitrile and the nitrosocarbonyl benzene 1i. DFT calculations, and in general theoretical approaches to nitrosocarbonyl chemistry, can be further exploited to better understand the behavior of these intermediates. Some effort could be done in studying the reactivity in nitroso ene reaction as well as to understand all the factors that could affect and enhance their stability. The continuous updating of modern calculation methods will certainly offer new chances to clarify the intrinsic CC


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Figure 8. Enthalpic profile of the photocatalyzed cycloreversion of 294. [Adapted with permission from ref 315. Copyright 2013 Elsevier Ltd.]

their field of applications and getting good results in terms of enantio- and diastereoselection. Besides the classical trapping with dienes and alkenes, nitrosocarbonyls were also employed in other reactions because of their electrophilic character. Aldol reactions and electrophilic amination and hydroxymation were performed with 1,3dicarbonylic compounds as nucleophiles.392 From the applicative point of view, the limitation to the use of NC intermediates arises predominantly from the short lifetime and the high competition between the behavior as π2 addend in pericyclic reaction and the strong electrophilicity at the sp2 carbon. With regard to the reactivity in the ene reaction, some effort should be made to better understand the mechanism behind the regioselectivity with substituted olefins and in particular with cyclic olefins in order to increase the application fields in the synthesis of complex molecules where the use of NCs as synthons is crucial. In the near future, the peculiar reactivity of NCs can be applied in contests where bio-orthogonal reactivity is required.393 Although the generation protocols are mature, they are mild enough to be compatible with biological conditions, hence making a transient intermediate able to perform specific reactions such as the nitroso DA and the ene reaction already used for the chemical ligation of biomolecules. Moreover, the capability of NCs to act as electrophiles with simple amines opens the way to investigate the behavior of these intermediates as acylating agents with respect to DNA bases394 with obvious consequences in the treatment of DNA-involving diseases.395 In this field a valuable suggestion for implementation of NC range of chemical activity is offered by the recent studies of other transient species, the quinone methide (QM) and the QMmodified structures containing naphthalene diimides (NDIs) targeting loop adenines in G-quadruplex.396 Protocols for the generation of transient electrophilic quinone methides merged into the recent strategies to achieve recognition and alkylation of nucleic acids. The reversibility of the DNA alkylation process by

QM was reviewed underlining the opportunities and drawbacks in the DNA targeting.397 A photoreactive molecular dye targeting the G-quadruplex nucleic acid was recently developed, as a noninvasive tool for selective nucleic acid tagging and cellular applications.398 These valuable QM applications in modern medicinal chemistry raise the question of whether NCs are able to act similarly and if there is the generation methodology for applications in biological fields. Nevertheless, NCs are somewhat excluded from the material science. SP supported studies suggested the possibility to graph these intermediates on other surfaces, but no studies at the moment can prelude possible innovations in this field. We conclude this review by summarizing the main figures that characterize the nitrosocarbonyl chemistry. We have discussed eight different structures of aliphatic nitrosocarbonyls (Table 4) and 20 aromatic nitrosocarbonyls (Table 5). Table 6 reports the structures of seven different N-hydroxycarbamates, and Nhydroxyureas were collected in Table 7 with 11 different structures. Heterocyclic substituted nitrosocarbonyl intermediates are found in Table 8 (18 structures), while Table 9 gathers 29 different structures of chiral nitrosocarbonyls, to finish with Table 10, collecting 34 different structures of hydroxamic acids suitably modified to be used in intramolecular processes. Table 11 reports 19 different structures of nitrile oxides, and Table 12 collects six different structures of 1,2,4-oxadiazole-4oxides, as alternative methods for the preparation of NCs. Solid phase chemistry applications and thermal cycloreversion of specific cycloadducts were also discussed as well as the methods for HNO generation and nuclephilic trapping processes. To finish, we have also reported some information on the detection of these transient species as well as the generation from unusual starting compounds, as in the case of the nitrodiazoalkanes. CD


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(3) Adamo, M. F. A.; Bruschi, S. Generation of Nitroso Species and Their Use as Dienophiles in the Hetero Diels-Alder Reaction. Targets Heterocycl. Syst. 2007, 11, 396−430. (4) Yamamoto, Y.; Yamamoto, H. Recent Advances in Asymmetric Nitroso Diels-Alder Reactions. Eur. J. Org. Chem. 2006, 2006, 2031− 2043. (5) Bodnar, B. S.; Miller, M. J. The Nitrosocarbonyl Hetero DielsAlder Reaction as a Useful Tool for Organic Syntheses. Angew. Chem., Int. Ed. 2011, 50, 5630−5647. (6) Palmer, L. I.; Frazier, C. P.; Read de Alaniz, J. Developments in Nitrosocarbonyl Chemistry: Mild Oxidation of N-Substituted Hydroxylamines Leads to New Discoveries. Synthesis 2014, 46, 269−280. (7) IUPAC. Rule C-851 and Rule C-403. In Nomenclature of Organic Chemistry; Pergamon Press: Oxford, U.K., 1979. (8) Fischer, E.; Frank, F. New Degradation of the Theobromine. Ber. Dtsch. Chem. Ges. 1897, 30, 2604−2618. (9) Anderson, J. S.; Hieber, W. Ube rein Fluchtiges EisenNitrosocarbonyl, Fe(CO)2(NO)2. Z. Anorg. Allg. Chem. 1932, 208, 238−248. (10) Sclecht, L.; Hamprecht, G.; Spoun, F. Herstellung von Kobaltnitrosocarbonyl. Ger. Patent DE 566448, July 26, 1931. (11) Hieber, W.; Anderson, J. S. Reaktionen und Derivate Stickoxydsubstituierter Metallcarbonyle. Z. Anorg. Allg. Chem. 1933, 211, 132− 140. (12) Improvements in the Manufacture and Production of Cobalt Nitrosocarbonyl. Br. Patent GB 396717, Aug 8, 1933; Chem. Abstr. 1934, 28, 3483. (13) Sclecht, L.; Hamprecht, G.; Spoun, F. Verfahren zur Herstellung von Gemisches aus Kobaltnitrosocarbonyl und Kobaltnitrosyl. Ger. Patent DE 613400, May 18, 1935. (14) Brockway, L. O.; Anderson, J. S. The Molecular Structures of Iron Nitrosocarbonyl Fe(CO)2(NO)2 and Cobalt Nitrosocarbonyl Co(CO)2(NO). Trans. Faraday Soc. 1937, 33, 1233−1239. (15) Ormont, B. Uber die Bildung von Nitrosylen, Nitrosocarbonylen, Nitrosocyaniden und Nitrosohalogeniden. Acta Physicochim. URSS 1940, 12, 159−175. (16) Emery, T. F.; Neilands, J. B. Contribution to the Structure of Ferrichrome Compounds: Characterization of the Acyl Moieties of the Hydroxamate Functions. J. Am. Chem. Soc. 1960, 82, 3658−3662. (17) Emery, T. F.; Neilands, J. B. The Iron-binding Centre of Ferrichrome Compounds. Nature 1959, 184, 1632−1633. (18) Emery, T. F.; Neilands, J. B. Structure of Ferrichrome Componds. J. Am. Chem. Soc. 1961, 83, 1626−1628. (19) Emery, T. F.; Neilands, J. B. Periodate Oxidation of Hydroxylamine Derivatives. Products, Scope and Application. J. Am. Chem. Soc. 1960, 82, 4903−4904. (20) Emery, T. F.; Neilands, J. B. Further Observation Concerning the Periodic Acid Oxidation of Hydroxylamine Derivatives. J. Org. Chem. 1962, 27, 1075−1077. (21) Sklarz, B.; Al-Sayyab, A. F. The Oxydation of Hydroxamic Acids: a Synthesis of Amides. J. Chem. Soc. 1964, 1318−1320. (22) Beckwith, A. L. J.; Evans, G. W. Reactions of Alkoxy-radicals. Part III. Formation of Esters from Alkyl Nitrites. J. Chem. Soc. 1962, 130− 137. (23) Rowe, J. E.; Ward, A. D. Hydroxamic Acids. The Oxidation of Hydroxamic Acids and Their O-Alkyl Derivatives. Aust. J. Chem. 1968, 21, 2761−2767. (24) Qureshi, A. K.; Sklarz, B. The Periodate Oxidation of Nitrones. J. Chem. Soc. C 1966, 412−415. (25) Bunton, C. A.; Shiner, V. J., Jr. Periodate Oxidation of 1,2-Diols, Diketones, and Hydroxyketones: the Use of Oxygen-18 as a Tracer. J. Chem. Soc. 1960, 1593−1598. (26) Moffatt, J. G.; Lerch, U. Carbodiimide-Sulfoxide Reactions. Reactions of Carboxylic Acids, Hydroxamic Acids and Amides. J. Org. Chem. 1971, 36, 3391−3400. (27) Kirby, G. W.; Sweeny, J. G. Nitrosocarbonyl Compounds as Intermediates in the Oxidative Cleavage of Hydroxamic Acids. J. Chem. Soc., Chem. Commun. 1973, 704−705.

We wish to dedicate this work to G. W. Kirby, the pioneer of the chemistry of nitrosocarbonyls, whose works were the source of inspiration for many research teams in the world. Even though the chemistry of nitrosocarbonyls has a long story, it continues to fascinate and inspire chemists in the same way the guests of the Galleria degli Uffizi in Florence are, when looking at Botticelli’s painting La Nascita di Venere.

ASSOCIATED CONTENT S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemrev.6b00684. Table containing the structures of the nitrosocarbonyl intermediates with generation and trapping methods along with references to the cited literature (PDF)

AUTHOR INFORMATION Corresponding Author

*Tel.: +39 0382 987315. Fax: +39 0382 987323. E-mail: paolo. [email protected]. ORCID

Paolo Quadrelli: 0000-0001-5369-9140 Notes

The authors declare no competing financial interest. Biographies Misal Giuseppe Memeo was born near Milan in 1986. In 2010 he received his degree in chemistry cum laude at the University of Pavia. He got the Ph.D. degree under the guidance of Prof. P. Quadrelli at the same university. He was a visiting Ph.D. student in Dr. Spring’s group at the University of Cambridge, continuing the postdoc experience in Pavia. His current research focuses on the synthesis of nucleoside analogues and peptidomimetics. orcid.org/0000-0001-9895-4432. Paolo Quadrelli was born in 1961. He received his degree in chemistry in 1986 at the University of Pavia. In 1990 he obtained the Ph.D. degree at the same university under the supervision of Prof. G. Desimoni. Then he moved to the R&D lab of the ENI group until 1992, when he returned as researcher in Prof. P. Caramella’s group. In 1996 he joined the group of Prof. R. Grigg at the University of Leeds. He is currently associate professor of organic chemistry and heterocyclic chemistry at the Department of Chemistry of the University of Pavia. His research interests are pericyclic reactions, chemistry of 1,3-dipoles, transitionmetal-catalyzed reactions, steroid synthesis, and solid phase chemistry.

ACKNOWLEDGMENTS Financial support by the University of Pavia, MIUR (PRIN 2011, CUP: F11J120002100001), is gratefully acknowledged. DEDICATION Dedicated to Prof. Paolo Grünanger, “maestro” in the nitrile oxide chemistry, on the occasion of his 90th birthday. REFERENCES (1) Kirby, G. W. Tilden Lecture. Electrophilic C-Nitroso-compounds. Chem. Soc. Rev. 1977, 6, 1−24. (2) Iwasa, S.; Fakhruddin, A.; Nishiyama, H. Synthesis of Acylnitroso Intermediates and Their Synthetic Applications. Mini-Rev. Org. Chem. 2005, 2, 157−175. CE


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