Rearrangement of N-Oxyenamines and Related Reactions - Chemical

Review pubs.acs.org/CR

Rearrangement of N‑Oxyenamines and Related Reactions Andrey A. Tabolin* and Sema L. Ioffe N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospekt 47, Moscow 119991, Russian Federation 4.3. Formation of the N-Vinyl Motif by Tautomerization of N-Acyl Hydroxylamines 4.4. Rearrangement of N-Heterovinyl Derivatives 4.4.1. Rearrangement of N-Acyl-O-aryl Hydroxylamines 4.4.2. Rearrangement of N-Imidoyl-O-vinyl Derivatives 4.4.3. Rearrangement of N-Imidoyl-O-aryl Derivatives 4.5. Rearrangement of Oxime Derivatives Possessing Electron-Acceptor Substituents 4.6. Direct α-Oxygenation of Carbonyl Compounds 5. Boekelheide Rearrangement and Related Reactions 5.1. Boekelheide Rearrangement 5.2. Rearrangement of Nitrones and Related Compounds 6. Miscellaneous Pericyclic Reactions of N-Oxyenamines 7. Conclusions Author Information Corresponding Author Notes Biographies Acknowledgments Abbreviations References

CONTENTS 1. Introduction 2. [1,x]-Rearrangements (x = 3, 5, 7) of NOxyenamines 2.1. 1,x-Migrations 2.2. [1,3]-Rearrangement of Bis(oxy)enamineBased Oxyanions 3. [3,x]-Rearrangements (x = 3, 5) in N,ODivinylhydroxylamines 3.1. Formation of N-Vinyl Pattern by Tautomerization 3.1.1. Oxime Tautomerization 3.1.2. N-Acyl-Hydroxylamine Tautomerization 3.2. Formation of the N-Vinyl Motif by the Addition of Hydroxylamines to Acetylenes 3.3. Formation of the N-Vinyl Motif from NArylhydroxylamines 3.3.1. Bartoli Indole Synthesis 3.3.2. Vinylation of Hydroxylamines with Vinyl Acetate 3.3.3. Formation of the O-Vinyl Motif by Addition of Hydroxylamines to Multiple Bonds 3.3.4. Formation of the O-Vinyl Motif by Cycloaddition of N-Arylnitrones 3.3.5. Formation of the O-Vinyl Motif by Tautomerization of O-Acyl and OImidoyl Derivatives 3.3.6. Rearrangements of N,O-Diarylhydroxylamines 3.4. Formation of the N,O-Divinylhydroxylamine Motif from N-Vinylhydroxylamines 4. [3,x]-Rearrangements (x = 3, 5) of N-Vinyl-Oheterovinyl Hydroxylamines 4.1. Rearrangements of N-Arylhydroxylamines 4.1.1. Rearrangements of O-Acyl and O-Sulfonyl Derivatives 4.1.2. Rearrangement of O-Imidoyl Derivatives 4.1.3. Rearrangement of O-Thiocarbonyl Derivatives 4.2. Rearrangements of the Derivatives of NHydroxy-Substituted Heterocycles © 2014 American Chemical Society

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1. INTRODUCTION Hydroxylamines and their derivatives have found a wide range of applications in organic synthesis.1 In this review we hope to cover the synthetic applications of N-vinylhydroxylamine 1 rearrangements that proceed with N−O bond cleavage, in other words, N−O-cleavage-assisted rearrangements. Structures possessing an N-oxyenamine moiety CC−N−O are a priori considered as quite unstable. This is largely attributed to the presence of the weak N−O σ bond which has an average energy of ∼57 kcal/mol. This is much less than the energies of the πC−C (66 kcal/mol) and σC−X (X = C, N, O) (69−91 kcal/mol) bonds.2 The low strength of the N−O bond is explained by the repulsion of the lone electron pairs on the nitrogen and oxygen atoms. As a result, transformations leading to cleavage of this bond are favored. Most of the N-oxyenamine 1 reactions described in this review can be considered via N−O bond cleavage leading to the nitrenium cation A and some O anion B.3 These are

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Received: April 10, 2013 Published: March 14, 2014

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dx.doi.org/10.1021/cr400196x | Chem. Rev. 2014, 114, 5426−5476

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Scheme 1

appears pertinent to briefly describe processes involving paths c and d. [3,3]-Rearrangements (Scheme 1, path b) can be conveniently divided into two types as shown in Scheme 2. The products of N,O-divinylhydroxylamine rearrangements (A and B carbon atoms) are monoimines of 1,4-dicarbonyl compounds, i.e., Paal−Knorr intermediates 3-(1) (for further details of their transformation see Scheme 27).6 If the system possesses a heteroatom in the third position (A = O, N, etc. atoms, products 3-(2)) then the rearrangement leads to functionalization of the carbon backbone. Frequently, the N-oxyenamine moiety is attained in situ in the molecular structure, and the corresponding products 1 undergo spontaneous rearrangement. Hence, some serious consideration of the N-oxyenamine pattern formation appears reasonable (Scheme 3). N-Oxyenamines, possessing protons either on the nitrogen or on the oxygen, are generally unstable due to their possible tautomerization to form oximes or their corresponding ethers 7 (for NH oxyenamines) as well as to Noxides 8 (for OH oxyenamines). Four common approaches to N-oxyenamine fragment generation can be outlined. The first case involves the initially assembled CC−N−O bond system (structure 6). This is possible when the compound is not prone to tautomerization as mentioned above. This is the case for Nphenylhydroxylamines, where the C,C double bond is incorporated into the aromatic system. Additionally, rearrangement product 10 is capable of undergoing a hydrogen shift 10 → 11, which leads to restoration of the aromaticity. In the second case, oxime derivatives 7 are the starting materials. Electrophile addition with subsequent proton elimination leads to the target N-oxyenamines 1 (This is virtually the reverse for the tautomerizations 1 → 7 (for R′ = H) shown in Scheme 3). In the third case, the starting materials are N-oxides 8. This generally covers nitrones and nitrogen heterocycle N-oxides. Electrophile addition with subsequent proton elimination leads to the target N-oxyenamine 1 structure which is also the reversal of the tautomerization 1 → 8 (R = H). The fourth pathway employs substrates with an 2-azadiene-oxide 9 moiety such as an N-arylnitrone or a pyridine N-oxide. Generation of the N-oxyenamine motif is usually accomplished by cycloaddition. In summary, substrates 1 as well as their immediate precursors are rather accessible.

summarized in Scheme 1. Cation A is heteroallylic and stabilized by conjugation with the CC bond. Additionally, in N-vinylhydroxylamines it is the possible overlap of the C−C π bond with an antibonding orbital of the N−O bond (structure 1-A) that also favors N−O cleavage. There are several possible pathways for cation A transformations. In the absence of external reagents, anion B can couple to the cation A carbon atom, giving rise to imines 2 (1,3-N,C-shift, path a). However, this particular reaction pathway is not very common. More common is the case where the oxygen atom of anion B is part of heteroallylic system, and its coupling can proceed with an allylic rearrangement (path b). Such transformations can be considered either as a hetero-Cope rearrangement (1-oxa-1′aza) or as a hetero-Claisen rearrangement,4,5 and they lead to α-substituted imines 3. Another option for cation A transformation is double-bond formation giving rise to enimines 4. This can be accomplished by proton abstraction or C−C bond cleavage (path c, C−X bond cleavage). With the introduction of external reagents new pathways for cation A transformations arise. Trapping with a nucleophile usually occurs by the β-C atom (path d), leading to α-substituted imines 5. Formally this reaction can be considered as an SN′ substitution. However, it Scheme 2

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Scheme 3

This review is divided into sections covering types of transformation, the nature of the substrate, as well as Noxyenamine pattern formation. Section 2 covers [1,x]rearrangements (x = 3, 5, 7), sections 3−5 cover [3,x]rearrangements (x = 3, 5), and finally section 6 covers miscellaneous pericyclic reactions, which are analogous to the transformations described. Some relevant examples of the application of N-oxyenamine rearrangements to organic synthesis have already been described in reviews such as the one devoted to the Trofimov pyrrole synthesis7 or the Bartoli indole synthesis.8 In such cases, in order to avoid repetition, we confine our discussion in this review to some general remarks. Other reviews worthy of note are the monograph dealing with hydroxylamine, oxime, and hydroxamic acid rearrangements9 and an older review by S. Blechert4 covering some aspects of [3,3]-rearrangements.

Scheme 5

chloride (Scheme 5).12 High yields and short reaction times are achieved for bulky substituents R. These results may be explained by the fact that the reaction proceeds from the sterically favored s-trans configuration (structure A). For cyclic derivatives 16, incapable of adopting this conformation, no rearrangement was observed. Under the same conditions, Nacetoxy derivative (14, R = Me, R′ = Ac) led to nucleophilic replacement of the AcO fragment by a chloride anion (product 17). OH-group migration in N-acyl-N-phenylhydroxylamines 18 can occur under the action of Bu3P−CCl4 in acetonitrile.13 The transformation is possible with a catalytic amount of phosphine but with significant increases in reaction times. The major product results from a migration to the ortho position. Migration to the para position and substitution of the hydroxy group by a chloride anion were also observed. A proposed reaction mechanism is shown in Scheme 6. The reactions which proceed through a N−O bond cleavage and cation A formation (see Scheme 4) are usually accompanied not by rearrangement but by addition of an external nucleophile. Elimination of the oxygen substituent is promoted by Brønsted acids, as is usual under Bamberger rearrangement conditions. Recently, application of Lewis acids, such as indium triflate,14 also became popular. In the case of N-phenylhydroxylamines, generally substitution can proceed both in the ortho and in the para positions.

Scheme 4

2. [1,X]-REARRANGEMENTS (X = 3, 5, 7) OF N-OXYENAMINES 2.1. 1,x-Migrations

Hydroxyl migration to the benzene ring in N-phenylhydroxylamines is known as the Bamberger rearrangement (Scheme 4).10,11 As a result of acid action on N-phenylhydroxylamine 12 and its derivatives, migration of the hydroxyl group occurs to the para position. The key intermediate is the anilenium cation A, which interacts with water to give the rearrangement product 13. In addition to Brønsted acids, the rearrangement can also be catalyzed by Lewis acids. N-Methoxyamides 14 (R′ = Me) undergo selective MeO-group migration to the ortho position of the benzene ring under treatment with 2 equiv of aluminum 5428


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Scheme 6

Scheme 8

Scheme 7 reveal that the aryl-connected oxygen atom in azasultones 27 mostly arises from the nitrone oxygen atom (80% retention). This provides evidence of a highly synchronous rearrangement.21 The [3 + 2]-cycloaddition of in-situ-generated N-allenylnitrones 28 gave the oxazepine derivatives 29 (Scheme 11).22 The exocyclic double bond selectively formed in the E configuration. The stereochemistry of the dipolarophile selectively transferred into the product, whereas the selectivity of the C5-stereocenter varied with solvent choice. Both a [2,3]rearrangement and a [3 + 2]-cycloaddition can proceed in the absence of a catalyst. Thus, it appears that a transition metal is important for the [1,3]-rearrangement since no target oxazepine 29 was observed in the absence of the copper salt. The N-aryl-isoxazolidine fragment suffering rearrangement can be formed by nucleophilic substitution as shown in Scheme 12.23 An 1,5-N,C oxygen shift frequently accompanies 1,3-dipolar cycloaddition of pyridine-N-oxides. Interaction of 3,5-dimethylpyridine N-oxide 30 with maleimides proceeds in an exo fashion. However, the primary adduct 31 is further transformed into the rearrangement product 32 (Scheme 13).24 A similar migration accompanies pyridine N-oxides reactions with phenylisocyanate,25 nitrilium salts,26 and, to a lesser extent, dichloroketene.27 For 2-alkyl-substituted pyridines products of the type 32 undergo further transformations.24a Isoquinoline N-oxides 35 react with arynes 36 through a [3 + 2]-cycloaddition/[1,3]-rearrangement sequence as shown in eq 1, Scheme 14.28 Both reactants were prepared in situ: the isoquinoline precursor, through cyclization of alkynyl benzaldoxime 33, and the aryne, via TBAF-mediated decomposition of TMS-substituted aryl triflates 34. Good yields were achieved for the bis-aryl-substituted triple bond (R2 = Ar), whereas alkyl groups (R2 = cyclopropyl, n-hexyl) gave inferior results. Unsymmetrical arynes led largely to regioisomeric product mixtures arising from a nonselective [3 + 2]-cycloaddition. However, the dipolarophile character significantly influences the decomposition pathway of the [3 + 2]-cycloadducts. Cycloaddition of isoquinoline N-oxides with DMAD furnished isoquinoline-based ylides 38 (Scheme 14, eq 2).29 Although not discussed in the paper, presumably this resulted from the lowered stability of the O-connected CC bond. When this

Evidence points to the fact that the more asynchronous the reaction and the longer the ionic intermediate lifetime the more probable the para attack. On the other hand, treatment with thionyl chloride leads predominantly to ortho substitution (19 → 20, Scheme 7), 15,16 whereas DAST leads to para substitution.17 For interaction of N-siloxy-N-arylamines with organoaluminum reagents the ratio of substitution products in the ortho and para positions varied from 3.7:1 to 1:2. However, the authors did not consider the reasons for the observed changes.18 In a strong acid medium, N-arylhydroxylamines 21 react with aromatic compounds, giving rise to diphenylamines 22 and biphenyls 23 (Scheme 8, cf. Scheme 71, section 4.1.1).19 The ratio of C- and N-arylation is governed by steric requirements: for bulky nitrogen substituent (R1 = t-Bu) dominant formation of products 23 is observed.19 1,3-Migration can accompany the cycloaddition processes for systems possessing an N-aryl-N-oxide pattern. The primary tricyclic adducts 24 are unstable and have only rarely been isolated from the reaction mixture (Scheme 9).20 Their decomposition gives rise to cyclohexadieneimines 25, which upon further exposure and depending on the initial dipolarophile structure in turn transform in various ways. It is worth noting that related cycloadducts of the less sterically hindered nitrone 26 turned out to be stable. [3 + 2]-Cycloadducts of N-arylnitrones with sulfenes behave in a similar manner (Scheme 10). Isotope-labeling studies 5429


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Scheme 9

Scheme 10

Scheme 12

Scheme 11

Scheme 13

bond was aromatic it was found to remain intact during the reaction and hence lead to a [1,3]-rearrangement. When nonaromatic the bond participated in the transformation. Recently, an intriguing product 41 was formed in the rhodium-catalyzed reaction of N-arylnitrones 39 with vinyl diazoacetate 40, as observed by Doyle et al. (Scheme 15).30 The transformation proceeded regioselectively even for unsymmetrical N-aryl substituents (e.g., R1 = p-Me, R2 = m-Br). A remarkable diastereoselectivity was evident. The reaction mechanism proposed involved consecutive [3 + 2]-cycloadditions of the nitrone to the double bond of 40, aromatic double bond cyclopropanation, electrocyclic ring expansion, 5430


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Scheme 14

Scheme 15

Under mild heating 2-methoxy-pyrazole-1-oxides 42 were observed to undergo not only a 1,7-methyl group shift (42 ⇌ 43)31 but also a MeO-group migration to positions 3 and 5, resulting in products 44 and 45, respectively, as seen in Scheme 16.32 MeO-group migration to C-4 was not observed. In the author’s opinion, this is evidence regarding the necessary participation of a positively charged nitrogen N-1 in the transition state. Above we have largely described the transformations of Naryl-hydroxylamine derivatives. Although the reactivity of the analogous N-vinyl derivatives is also of special interest, they have been investigated to a much lesser degree due to their inaccessibility. Currently the most popular method for the synthesis of such stable N-oxy-enamines involves silylation of the corresponding N-oxides. The N-siloxy-en-nitrosoacetals 47 and 50 (Scheme 17), which are silylation products of the corresponding nitronates 46 and 49,33,34 are among the most interesting substrates. For the rearrangement of nitroso acetals 47, Lewis acid screening revealed zinc triflate as the best catalyst (eq 1).35 Also, rearrangements can be performed in situ using TMSOTf both for the synthesis and for the rearrangement, albeit in this case

Scheme 16

and, finally, a [1,7]-rearrangement of the N-oxy-trieneamine moiety. 5431


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Scheme 17

Scheme 18

the yields are somewhat lower.36 For nitroso acetals 50, the double-bond substituent R1 turned out to play the most important role with the rearrangement rate increasing with increasing electron-donating ability. It was found that some (i.e., R1 = An) nitroso acetals 50 could not be isolated;37,38 some (R1 = Me, Et, Ph) underwent rearrangement over 1 day under ambient conditions with catalytic amounts of water.37 Unsubstituted nitroso acetals 50 (R1 = H) on the other hand are stable to similar water treatment (cf. with similar tendency for O-acylated analogues, section 5.2, Scheme 115). Both substituted and unsubstituted nitroso acetals 50 underwent TFAA-mediated rearrangement. Products were deprotected in situ to form hydroxyalkyl-oxazines 51.39 Treatment of 50 with TMS halides leads to halogen insertion instead of rearrangement.40 Mono- and bis-silyl derivatives 52 (X = Me and OSiR3, respectively) can undergo radical alkylation (Scheme 18).41,42 The initial radicals can be generated by the action of triethylborane42 or distannane41,43 under irradiation and even without a promoter (for the TBDPS group).41,42 Such reactions can be used for synthesis of both ketones 54 and amides 55.43,44 Under the same conditions siloxydieneimines 56 react via their ω-C atoms.41,44 Acylation of heterocyclic N-oxides, namely, the Boekelheide rearrangement (see section 5.1), is usually employed for functionalization of the carbon side chain. Silylation of pyridine N-oxide derivatives 57 proved useful in the intramolecular trapping of the pycolylic cation A (Scheme 19).45 For this

Scheme 19

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Scheme 20

Scheme 21

aluminum atom to the double-bond β-carbon atom. Subsequent imine hydrolysis gave rise to substituted ketones 71. For

purpose di-tert-butylsilyl bis(trifluoromethanesulfonate) was used. Microwave irradiation raises the yields by 13−26%, compared to those achieved at room temperature. This reaction is suitable for preparing both ortho- and para-substituted pyridine N-oxides. Cyclic amines 59 can also be obtained. However, synthesis of the corresponding azepine derivative (n = 3) was unsuccessful. Also, lower yields were observed with the introduction of side chain substituents. In one case the side product 60 was observed, most likely arising from rearrangement of siloxyenamine 58. Treatment of pyrazole-2-oxide 61 with strong silylating agents (TMSOTf, TMSI) leads to formation of the corresponding O-silylated salts 64.46 The triflate salt was not further investigated. Pyrazole-2-oxide 61 silylation with an excess of trimethylsilyl iodide/base under harsh conditions leads to two products: the iodide 62 and the salt 63 (Scheme 20). Formation of the latter can be prevented by use of a sterically more hindered base, 1,2,2,6,6-pentamethylpiperidine. For the isomeric substrate 65, the side product 68 is presumably formed by the 1,5-N,C-siloxy-group migration in the intermediate oxy-dienamine 66. Increasing the silyl iodide amount increases the 67:68 ratio, but it is worth noting the transformation 68 → 67 was not observed in the reaction conditions. The authors found similar transformations for triazole 1-oxides.46 Introduction of nucleophiles into the α position in ketones 69 is possible with the help of N-oxyenamines. Using this strategy it is possible to achieve the umpolung of the usual carbonyl group reactivity (Scheme 21).47 Isoxazolidine-based enamines 70, formed in situ, were treated with organoaluminum reagents that led to radical transfer from the

Scheme 22

unsymmetrical ketone substrates, the reaction usually proceeded regioselectively. However, high diastereoselectivity was achieved only for aryl−aluminum reagents and not for alkyl ones. 2.2. [1,3]-Rearrangement of Bis(oxy)enamine-Based Oxyanions

For nitronates such as 72 which have a proton at C-2, abstraction of this proton leads to the anion A. This is capable of RO− elimination to give the nitrosoalkene B (Scheme 22). If the latter molecule is not stabilized then the anion eliminated is capable of Michael addition and affords the oximes 73 (Scheme 22). If the CC double bond of the nitrosoalkene B is incorporated into an aromatic system, its reaction proceeds in quite different directions. Such behavior is typical for 5433


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Scheme 23

Scheme 24a

a

i: RONa, ROH (R = Me, Et), reflux, 1 h, then 25 °C, 12 h.

Scheme 25

Scheme 26

24, eq 2).51 This is evidence that nitroso alkene attack by an external nucleophile proceeded faster than recyclization. Another path for anion A and nitrosoalkene B generation is interaction of N,N-bis(oxy)enamines with nucleophiles. Unsubstituted (R1 = H) nitroso acetals 50 suffer TBAF-triggered rearrangement, giving rise to pyranone oxime derivatives 79 (Scheme 24, eq 3).38 There are also some examples of trapping with external nucleophiles (Scheme 24, eq 4).33 Thus, reactions of the nitroso acetals 50 can lead to either oxazine ring opening or ring retention (see Scheme 17). This is achieved by altering the nucleophile or electrophile nature of the reagent. Related reactions for acyclic bis-silyl-enamines 47 have been more extensively investigated. Enamines 47 were involved in

nucleophilic additions to nitrobenzenes with subsequent trapping of the intermediate Meisenheimer complex 74 with a silyl group (Scheme 23).48 If the eliminated anion RO− remains tethered to the molecule it is expected that this should favor the rearrangement under consideration. Thus, base treatment of 3-methylfuroxane is found to give rise to isoxazoline derivatives. A typical example is the synthesis of the oxime 76 from furoxane 75 (Scheme 24, eq 1).49 Sometimes transformations of this type are called Angeli rearrangements, who described it as early as the 19th century.50 However, for benzisoxazole N-oxide 77, the action of sodium alcoholates led to the oximes 78 (Scheme 5434


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formation.64 Additional heating (110−180 °C)62,65 or microwave irradiation63 is necessary for conversion of the ethers 88

reactions with a wide range of nucleophiles, either carbon52,53 or heteroatom (Scheme 25).54−59 In most cases, addition of the silylation reagent or use of a silyl-capped nucleophile is desirable for trapping of the oximate anion, prevention of nitrosoalkene B polymerization, as well as formation of the rearrangement products 48. The interaction of the nitroalkene 81 with diethyl bromomalonate afforded the oxirane 83 instead of the expected 5-membered cyclic nitronate 82 (Scheme 26).60 Such a

Scheme 29

Scheme 27

to the target pyrroles 89. Gold cations were recently shown to be good catalysts for these reactions. Their use allows the reaction temperature to be lowered to 100 °C.61 For addition to oximes nonactivated acetylenes, on the contrary, require a superbasic medium such as KOH/DMSO as well as high temperatures. Under such conditions, in situ, the O-vinyl ether 88 tautomerizes into N,O-divinylhydroxylamine with subsequent pyrrole 89 formation. With an excess of the acetylene, the pyrrole 89 undergoes vinylation to give the products 90. This method for pyrrole synthesis from ketoximes and acetylenes is known as the Trofimov reaction.7 Another approach to O-vinyl oximes is based on isomerization of O-allylated derivatives 91 (Scheme 29). In this case good results were achieved under heating using an iridium catalyst with further conversion of the ethers 92 into pyrroles. An additional advantage is the fact that one-pot synthesis is possible combining both the isomerization and the rearrangement.66 3.1.1.2. [3,3]-Rearrangement in O-Aryl-Substituted Systems. The Paal−Knorr intermediate 3-(1), formed during the [3,3]-rearrangement of N,O-divinylhydroxylamines, can lead to two heterocyclic systems (see Scheme 27). In order to obtain the furan derivatives it is necessary to shift the keto−enol equilibrium toward enol formation. This prevents nitrogen addition to the carbonyl group and at the same time increases the nucleophilicity of the oxygen atom. Of course, the shift is favored with incorporation of the enol double bond into an aromatic system. Thus, in most cases rearrangement of Ophenylsubstituted oximes 93 affords the benzofuran derivatives 96 (Scheme 30). Typical reaction conditions for these transformations are reflux of the oxime ethers 93 with a strong acid such as hydrogen chloride,67−74 methanesulfonic acid,75,76 sulfuric acid,77 or boron fluoride etherate in acetic acid.78 This method was used for the synthesis of benzofuran-containing natural products79 as well as benzofuran-containing analogues of bioactive compounds such as naltrindole80 and betulinic acid.81 Under the reaction conditions the imine group in intermediate A can be hydrolyzed leading to 2-aryl-substituted ketones 95 (Scheme 30).75 This process becomes dominant for formation of the 2-pyridone derivatives 97.82 Milder reaction conditions (HCl in acetic acid at 20−25 °C) allows in some cases isolation of the imine salts 94.67,83 Side processes arising from the initial oxime ether 93 undergoing hydrolysis84 or other migrations75 have also been reported.

reaction mode can be attributed to the acidity of the C-4 proton in intermediate 82 whose abstraction triggers the sequence leading to product 83. It should be noted that analogous deprotonation of the 6-membered nitronates follows another pathway (see section 6, Chart 4). Scheme 28

3. [3,X]-REARRANGEMENTS (X = 3, 5) IN N,O-DIVINYLHYDROXYLAMINES As mentioned above, rearrangement of N,O-divinylhydroxylamines leads to the Paal−Knorr intermediate 3-(1) (Scheme 27). Its major transformation path is cyclization into pyrroles such as 85. Other paths can include imine group hydrolysis (product 84), cyclization to furans 86, and interactions of the carbonyl or imino group with other substrate functionalities. 3.1. Formation of N-Vinyl Pattern by Tautomerization

3.1.1. Oxime Tautomerization. 3.1.1.1. [3,3]-Rearrangement in O-Vinyl-Substituted Systems. The most common approach for synthesis of O-vinylated oximes is addition of oximes 87 to acetylenes (Scheme 28). There are two possible options depending on the nature of the acetylene. For electrondeficient ones the reaction can proceed under milder conditions and affords vinyl ethers 88.61−63 Apart from the typical bases, triphenylphosphine is also a good catalyst for this trans5435


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Scheme 30

Where there is unsymmetrical substitution in the benzene ring, mixtures of products 98 and 99 are usually observed. Dominant formation of the latter is usually explained by steric factors (Scheme 31).71,75,85,86 Formation of products resulting from enolization toward the methylene group has been reported for oximes of the type 100 (Chart 1), derived from unsymmetrical ketones.67,70,76,80 It was found that for ketones 101 the methylene group that is most remote from the heteroatom participated in the reaction.69 Rearrangements can be performed in situ for synthesis of oxime ethers from carbonyl compounds and either O-phenylhydroxylamine68,69,76 or O-aryl acetohydroximates.87 For unsymmetrical 1,3-dicarbonyl compounds such as the acetoacetic ester 10285 or the azepinediones 103,68 oximation is selective to the more reactive carbonyl group. Similarly, a keto-alkyl functional group is more active than a keto-aryl one. It was only in the case of the pyridyl-substituted diketone 104 that a small erosion of selectivity was observed, giving an isomer ratio of 93:7. Not surprisingly, tautomerization of oximes containing electronaccepting substituents such as those derived from substrates 102 and 103 involves the more acidic protons.68,69,85 A good catalyst for such substrates is the AuCl3/AgOTf system.85 Notably, with acetylacetone as a model compound the use of typical Lewis or Broensted acids (i.e., HCl, AlCl3, TfOH) afforded the target product only in low yields. T. Naito et al. demonstrated the use of strong acylating agents for conversion of oxime ethers 105 into benzofurans 107 under mild conditions (Scheme 32, eq 1).88−91 The TFAA treatment of substrates 105 lead to the dihydrobenzofurans 106. Use of the stronger trifluoroacetyl triflate in the presence of base afforded benzofurans 107 in good yields (73−99%).91 The reaction is applicable to a wide range of substituted acetoand propiophenones, except those containing a donating para-

Scheme 31

Chart 1a

a

O = Predominantly oximating carbonyl group, T = predominantly enolizing CH2 group.

Scheme 32

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Scheme 33

Scheme 34

methoxy group in the aromatic ring.89,91 This method does not require free hydroxyl group protection, since the trifluoroacetates formed during the reaction course are cleaved by chromatography on silica.90,91 Another feature is the possibility of regioselective syntheses from unsymmetrical oximes such as 108 (Scheme 32, eq (2)).92 The authors explain it as follows: in the absence of base the reaction proceeds through the more thermodynamically stable enamine A, whereas in the presence of base the kinetically more available proton is abstracted leading to the enamine B. Remarkably, cyano-substituted oximes ethers 105 (R1 = CN) do not need strong catalysts, and hydrogen bonding provided by MeOH is enough for synthesis of substituted 2,3-dyhydrobenzofurans of the type 106.93 3.1.2. N-Acyl-Hydroxylamine Tautomerization. Under acidic media various ortho-unsubstituted N-acetoacetyl-O-aryl hydroxylamines 109 undergo transformation into benzofurans 110 in high yields (Scheme 33).94 For ortho-methyl-substituted substrates, a drop in yields of up to 34−44% was observed. As has been already mentioned (see Scheme 31), meta-substituted derivatives give rise to isomeric product mixtures with the dominant migration to the less sterically hindered para position. In the case of di-ortho-substituted substrates reaction products are formed after a 1,2-shift of one of the ortho substituents. A [3,3]-rearrangement is possible for N,O-diacetyl-hydroxylamines 111. This requires enolization of both acetyl groups furnishing succinic acid derivatives 112 as the products (Scheme 34).95,96 The major side processes are O-deacetylation to give 114 and a monoenolate A rearrangement leading to the

Scheme 35

products 113. Use of equimolar amounts of base does not give 113 in a selective manner due to concomitant second deprotonation. As it is known for N-arylderivatives (see section 3.3.5) the reaction is promoted by stabilizing substituents (R1 or R2 = Ph), with a stronger influence from the R2 side. Another way to suppress side reactions is by introduction of a bulky substituent to the nitrogen (R3 = t-Bu). Here good yields of the products 112 were achieved even for substrates without stabilizing substituents (49−68% for R1 = R2 = H, Me). However, one reaction drawback is low diastereoselectivity. 5437


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Scheme 36

Scheme 37

Interaction of O-arylhydroxylamines with DMAD leads to formation of coumarin derivatives such as 124 (Scheme 37).100 However, typical conditions for nitrophenyl substituent (R = pNO2) led to low yields (10%) of the coumarin. The oxime 125, formed by tautomerization of the intermediate A, was the major product. In order to convert it into the corresponding coumarin 124 refluxing with HCl was required (cf. section 3.1.1.2).

Worthy of note is the rearrangement of vinyl and phenylacetyl substrates 115 and 116 (Scheme 35). Here not only a [3,3]but also a [3,5]-rearrangement was observed.95 The authors underline the fact that satisfactory yields of the [3,5]rearrangement were achieved only for N-methylthioacetyl derivatives. Introduction of donating substituents (116, R = OMe) helped raise the yield to 21%. 3.2. Formation of the N-Vinyl Motif by the Addition of Hydroxylamines to Acetylenes

3.3. Formation of the N-Vinyl Motif from N-Arylhydroxylamines

The solvent-free reaction of NH-hydroxylamine 117 with acetylenedicarboxylates either under conventional heating or using microwave irradiation leads to the pyrrole-tetracarboxylates 118 (Scheme 36).97 Comparable yields are achieved (80−87%) in both processes with MW reaction times being just 2−3 min. Literature data indicate that the reaction proceeds through formation of the nitrones 120 and their cycloadducts 121.98 Supporting this scheme is the fact that N,N-dialkylhydroxylamines 119 interaction with acetylenedicarboxylates leads to the nitrones 120. Presumably, this is as a result of a Michael addition and Cope elimination (Scheme 36). Under cooling to 0 °C the cycloadducts 121 were isolable. Under reflux in benzene they could be converted into the enamines 122.98 Similar pyrrole synthesis sequences have been suggested for other nitrones.99

This section covers [3,3]-rearrangements when the CC double bond connected to nitrogen is a part of an aromatic Scheme 38

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through both substituted and unsubstituted sites were observed (Scheme 41, eq 2).103 In this case the yield was low and unreacted substrate (23%) was isolated from the reaction mixture. Unfortunately, the approach described was applied only for synthesis of 2,3-unsubstituted indoles. In other words, only vinyl acetate itself was involved in the reaction. The reaction was used, however, in the total synthesis of indolecontaining natural products.102,103,108 3.3.3. Formation of the O-Vinyl Motif by Addition of Hydroxylamines to Multiple Bonds. For introduction of the O-vinyl moiety into a hydroxylamine molecule a Michael addition is used. Here two major pathways can be outlined (Scheme 42): first, addition to allenes produces 2-substituted indoles 135, whereas addition to acetylenes gives either 3- or 2,3-substituted indoles 137. Reaction of the hydroxylamine 133 salts with electrondeficient allenes proceeds at room temperature or under slight cooling (−20 °C).104,109 Counterion character (Li+, Na+, K+) in the substrate has a small influence on the reaction rate. It should be noted that for the adduct of the salt 138 with allenylphosphine oxide allylic rearrangement proceeds at a rate comparable to that of a [3,3]-rearrangement, thus affording two isomeric anilides 139 and 140 (Scheme 43).109 For N-acyl derivatives such as 133 (R = C(O)R′) the reaction stops at formation of the ketone 134. In other cases, intermediates such as 134 cannot be isolated and indole formation occurs spontaneously. The bis-ortho-disubstituted derivatives 141 give rise to anions A that are incapable of undergoing tautomerization. However, the anions A can undergo intramolecular cyclization to give the bicyclic compounds 142 (Scheme 44).110 Reaction of N-phenylhydroxylamines 133 (R = C(O)Ph, CO2Bn) with DMAD culminates with formation of the anilide 136 (Scheme 42).100 On the other hand, interaction of the arylhydroxamates 133 (R = CO2Bn) with methyl propiolates afforded the indoles 137, albeit mostly in moderate to low yields.103,111,112 For the unsubstituted derivative (X = H) the best yield was achieved in nitromethane with diisopropylethylamine as the base.111 For the unsymmetrically substituted benzene 143 only one regioisomer was observed. Even after extensive screening of the reaction conditions the authors were satisfied with the 66% yield (Scheme 45).111a The product 144 was subsequently used in the synthesis of a unit of the antibiotic CC-1065.111a In the case of the guanidine derivatives 145 reaction occurred only with the monosubstituted acetylenes: ethyl propiolate and 3-butyne-2-one, leading to the corresponding indoles.113 When disubstituted acetylenes were used keteneaminals 146 were isolated in moderate yields (Scheme 46).113a The suggested mechanism involves pyrroline ring opening by means of a retro-

Scheme 39

system. As a rule, N-phenylhydroxylamine derivatives are the initial substrates. The oxygen-connected vinyl moiety is either directly introduced into the molecule or formed by tautomerization of the corresponding O-acyl derivatives. In the same way that pyrroles are the main products for N,Odivinylhydroxylamines (see Scheme 27), rearrangement of the N-aryl-O-vinyl-hydroxylamines 126 often leads to indole derivatives. For unsymmetrically substituted substrates, as has already been shown for O-aryl-derivative rearrangements (see Scheme 31), regioisomeric mixtures are formed (Scheme 38).101−105 3.3.1. Bartoli Indole Synthesis. Reaction of the nitroarenes 127 with an excess of vinyl−magnesium halide leads to the indole derivatives 128 (Scheme 39). This synthesis method is known as the Bartoli indole synthesis. Because a review8 has already addressed this reaction, we will limit our discussion here to some general comments. Only ortho-substituted nitro derivatives can be involved in this particular reaction, and these give rise to 7-substituted indoles. Detailed investigations resulted in the following mechanism being proposed (Scheme 40).106 The first step is a Grignard reagent attack onto the nitro group oxygen atom which leads to the nitroso compounds 129. It should be noted that in the absence of an ortho substituent N-attack on the nitro group was observed, thus leading to formation of side products. Next, a second equivalent of the Grignard reagent reacts with the intermediates 129, giving rise to anion A. Then anion A undergoes a [3,3]-rearrangement and subsequent ring closure to give intermediate B. In the third step another Grignard reagent equivalent is used for proton abstraction from B. Finally, the last step, namely, indole formation, occurs under work up. Instead of nitro compounds nitroso compounds 129 can also be involved in the process, but in this case only two Grignard reagent equivalents are required. 3.3.2. Vinylation of Hydroxylamines with Vinyl Acetate. Metal-catalyzed trans-vinylation is a direct method for introduction of a vinyl moiety onto an oxygen atom.107 In such a manner N-acyl-N-phenylhydroxylamines 130 can be converted into the indoles 131 (Scheme 41, eq 1).101,103 For the ortho-substituted substrate 132, reactions proceeding Scheme 40

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Scheme 41

Scheme 42

Scheme 43

Scheme 44

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the alkynes, making it possible to use both substituted vinylacetylenes and disubstituted acetylenes.105b In the latter case, the regioselectivity of the reaction is governed both by steric and by electronic factors. A simpler gold catalyst Ph3PAuOTf was used for addition of 1-hydroxy-benzotriazoles 152 to a triple bond (Scheme 50).116 The reaction proceeded well for terminal alkynes, whereas allenes and internal alkynes gave poor results. However, other heterocycles such as 1-hydroxyindazole and N-hydroxy quinolone derivatives failed to react at all. The adducts 153 turned out to be stable under ambient conditions and underwent a [3,3]-rearrangement only at elevated temperatures. Such stability may be explained by the electronaccepting character of the nitrogen substituent in the N,Odivinyl-hydroxylamine system (cf. with the influence of the substituent characteristics on the rearrangement rate discussed in section 4.1.1). Under heating, two products 154 and 155 were formed; these correspond to two [3,3]-rearrangement pathways. It is worth noting that electron-rich acetylenes are capable of but rarely exploited in reactions with hydroxylamines (Scheme 51).117 An elegant combination of [2,3]- and [3,3]-rearrangements, which was developed by K. Majumdar, allows high-yield conversion of propargylic amines 158 into indoles 159 (Scheme 52).118,119 Introduction of a chloro-benzoic acid moiety into the product structure by means of nucleophilic addition to intermediate A occurs during the reaction. For meta-substituted substrates [3,3]-rearrangement does not occur and decomposition is observed.120 Intermediates of type A were detected by means of NMR spectroscopy121 and trapped with nucleophiles such as thiophenol, azide, and cyanide anions.121,122 Such methodology allows pyrrole ring annelation to produce derivatives of barbituric acid,123a,b coumarins,123c,d thiocoumarins,123e as well as quinolines.123f For the precursors 158 containing free hydroxyl groups dimerization of A occurs leading to the macrocycles 160.124 In a sequence similar to that described above, synthesis of 2vinyl-substituted indoles was successfully achieved (Scheme 53). Treatment of allenic amines 161 with magnesium monoperoxyphthalate triggers the reaction cascade, furnishing the indoles 162.125

Scheme 45

Claisen reaction with subsequent nucleophilic substitution at the guanidine carbon atom. Such unusual reaction behavior was attributed to the steric hindrance of the R group. Successful indole synthesis can be accomplished starting from not only N-acyl derivatives but also NH-arylhydroxylamines (Scheme 47).114 This approach leads to formation of the indoles 147 which possess a vinyl group on the nitrogen. The first reaction step is a Michael addition to nitrogen which gives intermediates A. Due to the conjugation, the nitrogen nucleophilicity in A is lowered, and this allows addition of a second acetylene molecule to the oxygen atom resulting in the [3,3]-rearrangement precursor. R. Coates described an original domino method for construction of the pyrroloindoles 149. His methodology is based on the intramolecular addition of the hydroxylamine moiety to electron-deficient acetylene (Scheme 48).115 Then the initially obtained nitrones 148 were in situ reduced with NaBH3CN, which triggered the Michael addition and [3,3]rearrangement-indole ring-closure cascade. Recently, reaction of hydroxylamines with alkyl-substituted acetylenes has been reported.105 Here triple-bond activation for nucleophilic attack was achieved using gold catalysis (Scheme 49). The gold compound (ArO)3PAuNTf2 (Ar = 2,4-di-tertbutylphenyl) turned out to be the best catalyst for Nunprotected substrates 150 (X = H).105a A slight excess of alkyne (1.8−2 equiv) is required due to the possibility of side reactions. High yields are achieved for a wide range of terminal alkyl-acetylenes. 2-Substituted indoles 151 (R3 = H) are obtained exclusively. In the case of ortho-methyl-substituted hydroxylamine 150 and for internal or aryl-acetylenes, reaction gives low yields of the target products 151. Use of N-protected N-phenylhydroxylamines 150 (X = Boc, CO2Me, Ac) and combination of zinc and gold catalysts gives greater scope for Scheme 46

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Scheme 47

Scheme 48

Scheme 49a

is achieved by use of Garner’s aldehyde derivative 167.129,133,134 The bulky nitrogen substituent PG plays an important role in creating the optical purity. It should also be noted that nitrones, which are incapable of achieving the conformation required for cycloaddition or rearrangement (i.e., 169), follow other reaction pathways.130 Dichloroketene after hydrolysis leads to the isatins 170.135 Besides ketenes, the reaction is also applicable to ketenimines,136 although in this case oxindole formation might follow a non-[3,3]-rearrangement pathway.136a,b The [3 + 2]-adducts of nitrones and acetylenes can undergo various transformations depending on the reaction conditions and substrate structure.137 One of these pathways is the [3,3]rearrangement as shown in Scheme 56. Reaction of the nitrone 171 with acetylene carboxylates furnishes the series of indoles 172.138 3.3.5. Formation of the O-Vinyl Motif by Tautomerization of O-Acyl and O-Imidoyl Derivatives. N-Aryl-Oacylhydroxylamines 173 can undergo two kinds of [3,3]rearrangements. Under either ambient conditions or heating acyloxy-group migration occurs (see section 4.1.1 for details). Enolization allows formation of the CC double bond needed to participate in the rearrangement of which anilines 174 are the primary products (Scheme 57). Enolization of the acyl moiety can be achieved by deprotonation of 17395,139,140 or deprotonation with subsequent silylation.141 In the first case the rearrangement occurs in anion mode, and the reaction mixture was treated with diazomethane in order to obtain the methyl esters of the rearrangement products.95,139 Nonpolar solvents favor rearrangement. For N-alkyl substrates (173, R1 = tert-Bu) in toluene the reaction is already complete after 1 h at −78 °C. However for N-acyl-substituted substrates temperatures of up to 0−15 °C are usually required.95,139,141 Carbamate derivatives (173, R1 = CO2Me) undergo rearrangement on treatment with KHMDS in THF at −78 °C.140 Yields of 174 vary depending on the substrate structure. Whereas N-tert-butyl derivatives 173

a

i: (ArO)3PAuNTf2 (5%), DCE, room temperature, 20 h. ii: (ArO)3PAuNTf2 (5%), Zn(OTf)2 (5−10%), toluene, 60−80 °C, 2− 18 h. Ar = 2,4-di-tert-butylphenyl. iii: IPrAuNTf2 (5%), Zn(OTf)2 (20%), touene, 60 °C, 18−30 h. IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.

3.3.4. Formation of the O-Vinyl Motif by Cycloaddition of N-Arylnitrones. [3,3]-Rearrangement precursors, similar to those described above, can be formed by [3 + 2]cycloaddition of N-arylnitrones 163 to allenes (Scheme 54).104,126,127 They undergo rearrangements giving benzoazepinones 164, which subsequently can undergo either a retroMichael reaction giving the indoles 165126,127 or a retroMannich reaction that provides the indoles 166.104,126−128 Interaction of N-arylnitrones with ketenes proceeds via a [3 + 2]-cycloaddition to a carbonyl group.129 A further reaction cascade furnishes oxindoles.130−132 In Scheme 55 is shown the recently developed asymmetric method, where chiral induction 5442


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Scheme 50a

a

i: Ph3PAuCl (5%), AgOTf (5%), DCE, room temperature, 5−10 h. ii: 1,4-dioxane, 100 °C, 2−4 h.

to good yields (Scheme 58).117 The derivatives 176 can be obtained by acylation of the corresponding N-hydroxy derivatives with diketene,117 acyl chlorides,117 or Meldrum’s acid derivatives.143 Interestingly, treatment of the arylhydroxylamines 178 with malononitriles furnishes anilides 179 by formal SN2′ substituion with simultaneous partial hydrolysis of one of the nitrile groups (Scheme 59).144 This is explained by nucleophilic addition of 178 to one of the malononitrile cyano groups, subsequent tautomerization, and then [3,3]-rearrangement. Formation of the para-substituted isomers (yields of up to 11%) is a side reaction. The β-naphthyl derivative 178 underwent exclusively a [3,3]-rearrangement into the α position. 3.3.6. Rearrangements of N,O-Diarylhydroxylamines. N,O-Diarylhydroxylamines can also participate in N−Ocleavage-assisted rearrangements. After acid work up alkaline hydrolysis of benzisoxazolone 180 afforded the biphenyl derivative 181 (Scheme 60). The reaction involves an isoxazolone ring opening and a [5,5]-rearrangement, similar to the benzidine rearrangement.145

Scheme 51

(R1 = tert-Bu) give yields of 38−75%,95,139 for N-benzoyl-Oacetyl derivatives 173 (R1 = PhC(O), R2, R3 = H) yields dropped to 8−12% as a result of O-deacylation being the major process.139,141 The presence of stabilizing substituents (R2 or R3 = Ph, SPh) is desirable with a view to increase the yield of 174.141 For N-acetyl derivatives (173, R1 = MeC(O)) the reaction is hampered by enolization of the N-acyl moiety which is followed by subsequent [3,3]-rearrangement. For more details about this rearrangement see section 3.1.2. However, this side process can be suppressed by use of the bulkier isobutyryl substituent (R1 = iso-PrC(O)).95,139 Additionally, [3,5]-rearrangement products 175 were isolated in low yields (up to 21%).95,139,142 Their formation was explained by the intermolecularity of the process or by asynchronous rearrangement in the tight ion pair. Products 174 may be cyclized to the corresponding oxindoles.140,141 These were subsequently used in the total synthesis of the alkaloid eseroline.142 An increase in enolization can be easily achieved by introduction of electron-withdrawing groups into the α position of the carbonyl function. Under reflux in toluene various derivatives 176 successively undergo enolization, rearrangement, and decarboxylation, affording anilides 177 in moderate

3.4. Formation of the N,O-Divinylhydroxylamine Motif from N-Vinylhydroxylamines

In most cases reaction of N-hydroxy indoles 182 with electrondeficient acetylenes proceeds nonselectively and affords the addition products 183 along with the indoles 184 and 185 (Scheme 61).146 Aldehydes 184 arise from a [3,3]-rearrangement of the intermediate 183. Formation of N-acylindole 185 is also explained through intermediate indoles 183: intramolecular nucleophilic attack of nitrogen onto the double bond leading to the dipole A, where proton migration occurs. Another way for enehydroxylamine moiety stabilization to occur relies on the conjugation of the CC double bond with an electron-withdrawing group. Thus, 1,3-cyclohexanedione

Scheme 52

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Scheme 53a

a

i: magnesium monoperoxyphthalate, MeOH/H2O, 25 °C, 3 h.

Scheme 54

Scheme 55

Scheme 56

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Scheme 57

Scheme 58

62).147,148 The reaction proceeds similarly with electrondeficient aromatics, 2,4-dinitrofluorobenzene, giving the derivative 187.147,148 Reaction of the substrate 189 with the allene CH2CCHSO2Ph furnishes the bicyclic derivative 190 (Scheme 63, cf. Scheme 44).4

Scheme 59

4. [3,X]-REARRANGEMENTS (X = 3, 5) OF N-VINYL-O-HETEROVINYL HYDROXYLAMINES In contrast to the [3,3]-rearrangements which were described in section 3, when heteroatoms are present only in positions 1 and 1′ introduction of a heteroatom into the position 3 (atom A in Schemes 1 and 2) allows functionalization of the carbon backbone of the starting material. Another peculiarity of such substrates is the increasing stability of the anion, generated via N−O bond heterolysis. This gives an opportunity for trapping the nitrenium cation with external nucleophiles. Various migration products can be formed from these N-aryl substrates. Scheme 64 shows an example of the meta-disubstituted benzene 191 rearrangement. There are two possible products of an ortho migration ([3,3]-processes): 192 and 193 (cf. Schemes 31 and 38). In addition, product 194 can form as a result of a para migration (a [3,5]-process). The formation of the latter sharply contrasts with the case of the N,O-divinyl system rearrangements described in section 3. In the latter the [3,5]-migrations occurred rarely and usually with low yields (see Schemes 35 and 57).

Scheme 60

4.1. Rearrangements of N-Arylhydroxylamines

4.1.1. Rearrangements of O-Acyl and O-Sulfonyl Derivatives. Although investigation into the rearrangements of O-acylated phenylhydroxylamines started more than one-half of a century ago,149,150 it was only recently that they found use in the targeted synthesis of 2-substituted anilines (Scheme 65).151−153 [3,3]-Rearrangement is favored by electrondonating substituents at the nitrogen site and electronaccepting ones on the oxygen site. Whereas acyl or carbamate derivatives 196 are isolable and their rearrangement into 197

derivatives 186 react smoothly with acetylene carboxylates, affording the pyrrolines 188. Subsequently, these can be dehydrated to form the corresponding pyrroles (Scheme 5445


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Scheme 61

Scheme 62

Scheme 63a

a

Scheme 64

i: 1. B: 2. CH2CCHSO2Ph, MeCN, 0 °C room temperature, 1 h.

requires a substantial increase in temperature (conventional heating150,151,154 or microwave irradiation152),155 sulfonate derivatives 199 on the other hand undergo [3,3]-rearrangement already in situ at room temperature150 or under mild heating.153 The latter propensity allows the facile conversion of hydroxylamines 195 into aminophenol derivatives 200.151,156 The influence of the oxygen substituent electron-accepting ability was noted in the series of chloroacetyl derivatives where their rearrangement temperature was found to be reduced with

increasing number of chlorine atoms.157 Monochloro derivatives (196, R2 = CH2Cl) were easily isolable, dichloro derivatives underwent rearrangement at temperatures higher than −10 °C, and reactions with trichloroacetyl chloride should be performed even at −40−50 °C. In this case cyclization concomitant with trichloromethyl-group elimination also furnished benzoxazolone 201 (Scheme 66). 5446


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Scheme 65

Scheme 66a

a

The concertedness of the reaction and consequently the kind of transformation was thoroughly investigated by use of isotope labeling.21,149,159−164 For example, isotope data using 18O labeling for both the N-tosyl derivative 202159,160 and the Onosyl derivative 203 (Chart 2), when rearrangement occurred in situ,149 supported a synchronous mechanism. Introduction of electron-donating nitrogen substituents and electron-accepting oxygen substituents increases the participation of ion-pair intermediates.160 Evaluation of the Hammet ρ values for rearrangement of the mesylate derivatives 204 (Chart 2) resulted in ρ = −9.24. This is strong evidence regarding the N−O bond heterolysis with formation of significant charge on the nitrogen.158 For 202 a slight increase in reaction rate (1.3fold) was observed with a change in solvent from chloroform to acetonitrile.160 For the rearrangement of 205, acetonitrile turned out to be the unique medium having negative activation entropy and decreased activation enthalpy (by ∼20 kcal/mol). Among the other solvents tried were 2-butanone, 1,4-dioxane, 1,2-dichloroethane, and DMSO. As a result of these observations the authors concluded that a synchronous

i: Cl3CC(O)Cl, NEt3, CH2Cl2, −40−50 °C.

For the ortho-substituted benzenes 195 formation of nearly equimolar product mixtures, corresponding to ortho and para migrations, is typically observed (cf. Scheme 64).151 For meta substitution the regioisomer ratio did not exceed 2.4:1 (see products 192 and 193 in Scheme 64).151−153,158 It is worth

Scheme 67

Chart 2

rearrangement was occurring in the acetonitrile medium.155a Rearrangement of the quinolone derivative 206 requires heating, and isomerization occurs primarily via a solventseparated ion pair.163 We would like to point out that reaction proceeding through an ion pair is linked with an increased contribution of rearrangement to the para position. In an extreme case the simple derivative 207 can selectively afford either the ortho-product 208 exploiting the mesyl group or the para-product 209 exploiting the more electron-accepting triflyl group (Scheme 67).165 It is interesting that under high temperatures (200 °C) there is an increase in N−O bond

noting that this approach is useful for synthesis of aminophenols possessing different protecting groups.151 Another potential use for the products 197 is their cyclization to benzoxazolones 198, which can be simply performed by additional heating. In some cases (for example, 197, R = Boc, R2 = OPh) the reaction was found to occur spontaneously152 and cleavage of the Boc group was also observed. 5447


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Scheme 68

N-Acyl-N-arylhydroxylamines and related compounds (216, 217) are formed in mammalian organisms during the metabolism of aromatic amines. Their carcinogenic properties are attributed to this fact.168 Because of this observation significant attention has been paid to the rearrangement of these substrates. Model studies involved a wide range of compounds (Scheme 70).158,169 The key intermediate is the nitrenium ion A (see the Bamberger rearrangement, Scheme 4). The rearrangement was shown to involve both the ortho and the para positions. When the reaction is carried out in a polar nucleophilic medium this leads to partial trapping of cation A by the solvent molecules. Rearrangement of 216 proceeds in a tight ion pair, and cation A trapping requires its decomposition.169a,b From a preparative point of view, it is interesting when carbon nucleophiles are involved in the reaction. The pmethoxy-phenylhydroxylamine derivative 218 reacts with electron-rich aromatics such as phenols, pyrrole, or indoles, giving [3,3]-rearrangement product 219. In addition, the products of external nucleophile addition to nitrogen (220) or ortho-carbon atoms (221) are also observed (Scheme 71).170 Selective formation of 219 can be achieved under mild heating (40 °C) of 218. Another manifestation of this reactivity is imide derivative transformation, as exemplified by 222 (Scheme 72). Because of the high stability of both the cation and the anion formed on N−O bond heterolysis and because of the high degree of charge delocalization in the cation, product mixtures including benzimidazoles such as 223 and dibenzodiazepines such as 224 were observed.164 4.1.2. Rearrangement of O-Imidoyl Derivatives. The literature contains some examples of N−O-cleavage-assisted rearrangements with O-imidoyl hydroxylamines 226 as the proposed intermediates. Treatment of N-phenylhydroxylamines 225 with imidoyl chlorides171 or trichloroacetonitrile172 in the presence of base was found to lead to the 2-aminoanilines 227 (Scheme 73). In rare cases the migrating group attaches to the meta position of the acylamino function.173 Reaction of the ortho-disubstituted substrate stops at the iminoderivatives

Scheme 69

homolysis and the contribution of a radical process in the rearrangement.150 Another indirect indication for a highly concerted process is the reaction of the amino-nitrones 210 with mesyl chloride/ triethylamine. Here mesylate 211 is a major product. The product of nitrenium cation A intramolecular trapping, namely, Scheme 70

the benzimidazole 212, was isolated in insignificant yield (Scheme 68).166 The [3,3]-rearrangement (product 214) and Polonovskii rearrangement (product 215) are co-occurring processes during acylation of the substituted aniline N-oxides 213 (Scheme 69).167 However, similar transformations have not found wide application in synthesis. Scheme 71

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Scheme 72

Scheme 73a

a

i: R3(CNR4)Cl, NaH, THF, or CCl3CN, Im, DMF, 25−40 °C.

Scheme 74

Derivatives of N-phenylhydroxylamine react with cyanogen bromide, furnishing the benzimidazolones 230 (Scheme 74, eq 1).166,175 In such a context it is worth noting that the meta-

228. 173 Treatment of the hydroxylamines 225 with Ph−NCCl2 affords the benzimidazolones 229.174 5449


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Scheme 75

Scheme 76

methyl-substituted nitrone 231 rearranged to the sterically more demanding ortho position affording benzimidazolone 232 (Scheme 74, eq 2).166 4.1.3. Rearrangement of O-Thiocarbonyl Derivatives. Introduction of sulfur-containing groups into an aromatic ring via a [3,3]-rearrangement of the corresponding arylhydroxylamines has not been widely applied. Reactions of acylhydroxylamines 233 with dimethylthiocarbamoyl chloride or thiobenzoyl chloride afford migration product mixtures,176a involving exclusive rearrangement to the para position (for Me2NC(S)−Cl) (Scheme 75, eq 1).176b A similar transformation occurs in the reaction of 233 (R = H) with phenyl isothiocyanate (Scheme 75, eq 2).177 Besides the rearrangement to the aromatic core, the product 237 was isolated. Presumably it arose from a 1,3 O → S migration in intermediate 234.176a However, in all cases product yields cannot be considered as preparatively valuable.

Scheme 77

4.2. Rearrangements of the Derivatives of N-Hydroxy-Substituted Heterocycles

derivative 240, obtained from isocarbostyril 239, undergoes rearrangement into 241 at 90 °C (Scheme 76, eq 1). An increase in reaction rate was observed with an increase in solvent polarity.163,179 When this transformation was performed in an acetonitrile−water mixture (2:1) the corresponding hydroxy-derivative 242 was produced. Just mentioned [3,3]migrations in N-acyloxy and imidoyloxy-pyridones180 and pyrazinones181 can proceed photochemically as well, albeit

If the CC−N fragment in the hydroxylamine is part of an aromatic system, then N−O bond heterolysis is favored due to stabilization of the cation formed. Consequently, the intermediate nitrenium cation can be trapped with different nucleophiles. Reactions of this kind are rather diverse, especially for N-hydroxy indoles,178 so we confine the discussion here to the rearrangements of such substrates. Thus, the tosyl 5450


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Scheme 78

An interesting transformation that can include a [3,5]rearrangement of the intermediate 253 has been described for N′-hydroxy-pyrazole N-oxide 252 (Scheme 79).184

Scheme 79

4.3. Formation of the N-Vinyl Motif by Tautomerization of N-Acyl Hydroxylamines

We already mentioned (see section 3.1.2) that in the course of the rearrangement of N,O-bis(acyl)hydroxylamines, which proceeds through the dianion B (see Scheme 34), byproducts resulting from monoenolization were observed. The same migration can be a side process for other transformations of the O-acylhydroxamic acid derivatives.185 It can be made into a major reaction path affording 2-oxy amides 256 (Scheme 80).186 The process can be induced thermally to give the products 256 in high yields (80−95%). However, that is only achieved by prolonged exposure to temperatures of 140 °C. Evidently, the transformation proceeds through the enol form A, which undergoes a [3,3]-rearrangement. Further studies showed that the reaction 255 → 256 can be catalyzed by nitrogen bases such as triethylamine or Huenig’s base. Equimolar amounts of base at room temperature or catalytic amounts under heating are required. The substrate has to possess a stabilizing substituent R1 at the N-acyl moiety (R1 = Ar, 2-thienyl, PhCHCH). Otherwise (R1 = Bu, 2-NpO), the target products were not observed. The situation changes with the use of a phosphazene base 257 (see Scheme 80). However, this narrows the possible substrate scope by the need for a bulky substituent at the nitrogen (yields ca. 75% for N-tert-butyl derivative. A similar tendency was discussed in section 3.1.2).187 It should also be pointed out that substituents R2 possessing no

with low yields. In a similar manner, the benzothiazine dioxide 243 is converted into 244 under heating (Scheme 76, eq 2).182 Acylation and successive heating of 1-hydroxy-tryptamine 245 leads to the pyrroloindoles 247 (Scheme 77).183 The reaction pathway involves a [3,3]-rearrangement of the acyl derivative 246 and addition of an amino group to the CN bond. N-Hydroxy indole 248 reacts with cyanogen bromide, affording the indoles 250 and 251 (Scheme 78).146 A suggested reaction scheme includes a [3,3]-rearrangement of 249 proceeding at both positions 3 and 7. Although the authors did not study the reaction in detail, they noted that substitution of DABCO for triethylamine increased the yield of 251 to 58%. Scheme 80

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activated α-hydrogens are desirable. This avoids primary enolization of the O-acyl moiety (see section 3.1.2, Scheme 34). Electron-withdrawing substituents R2 were found to

only. The silylketeneaminals 259 obtained undergo a [3,3]rearrangement, affording the amides 260 upon warming. The side process is the oxazolidine ring closure. However, in most cases selective synthesis of either 260 or 261 is possible by a simple variation of the amount of the silylation mixture. The authors attempted the asymmetric synthesis of 2-oxyamides using a mandelyl chiral auxiliary, but the induction turned out to be rather low. For N-oxybenzoxazinone and N-oxybenzthiazinone 262 a [3,3]-rearrangement allows functionalization of site 2 (see Scheme 82, eq 1).191−194 This was used in the synthesis of the natural product analogues containing the benzoxazine

Scheme 81

Scheme 83

accelerate the reaction. Thus, hydroxylamine 255 (R1 = PhCHCH, R2 = n-NO2C6H4−) underwent rearrangement in only 5 min at 110 °C (with a yield of 256 of 58%). On the other hand, the trichloroacetyl derivative 255 (R1 = Ph, R2 = CCl3) rearranged spontaneously, although with only a 10% yield of the targeted product.186b For base-catalyzed reactions the mechanism suggested involves not a synchronous migration but rather intermediate formation of aziridinone B and the anion R2COO− (Scheme 80).186 Direct evidence for this mechanism is formation of all four possible products in a nearly equal ratio from the reaction with two different substrates. It is noteworthy that an intermediate like B can be trapped by external nucleophiles with cleavage of the R1C−N or OC−N bond. In the latter case the reaction can be considered as an aza-Favorsky rearrangement.188,189

motif.193,194 The transformation may pass through enolization and subsequent intramolecular rearrangement. We assume this is the pathway for a nonpolar medium, because an increase in temperature when the solvent is changed from benzene191 to toluene193 leads to an increase in yield of 263 from 30% to 70%. Addition of acids such as AcOH, TFA, or HCl191,192 results in lower yields of 263 and nucleophile (acid residues, phenol, and benzene) attachment to positions 2, 4, 5, 6, or 7. For example, reflux of 262 (for X = O) in acetic acid gives exclusive migration of the acetoxy group to position 6 (yield 80%).191 Presumably, the key intermediates in these transformations are the equilibrating cations A and B (Scheme 82, eq 2). Here we should also mention the rearrangement of the carbamate derivatives 264 which affords the 2-aminoamides 265 (Scheme 83).95,195 The reaction is performed in dianion mode, as previously described for N,O-bis(acyl)substituted substrates (see section 3.1.2).

Scheme 82

4.4. Rearrangement of N-Heterovinyl Derivatives

In this section the rearrangements of N-acyl and N-imidoyl substrates with the N−CX (X = O, N) fragment as a part of the 3,3-system are summarized. Although they cannot actually be considered as true N-vinyl substrates, we believe that they merit inclusion in this review because the reactions described here are closely analogous to those described in other sections. 4.4.1. Rearrangement of N-Acyl-O-aryl Hydroxylamines. Similar to the syntheses of o-aminophenols and odiaminobenzenes, as discussed in sections 4.1.1 and 4.1.2, [3,3]rearrangements can be applied to the synthesis of ohydroxyphenols.196 O-Aryl-N-benzoylhydroxylamines 266 undergo rearrangement in a strong acid medium, affording the catechol derivatives 267 after work up (Scheme 84). In

Treatment of the hydroxamates 258 with a TMSOTf/NEt3 mixture was recently demonstrated to be an effective method for the rearrangement described in Scheme 81.190 This methodology avoids the concurrent enolization of the O-acyl moiety and does not require an activated α-hydrogen in the Nacyl moiety. Silylation of the derivatives 258 proceeds smoothly at low temperatures and selectively involves the amide function 5452


Chemical Reviews

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Scheme 84

Scheme 85

Scheme 86

Scheme 87

to imidazole synthesis.166,197,198 It requires harsh conditions such as heating in a EtOH/Ph2O mixture.198a For example, reactions of amidoxime 268 or aminonitrone 269 with methyl propiolate trigger an addition−rearrangement−cyclization

some cases migration of the benzoyl group to the adjacent hydroxyl group was also observed.196 4.4.2. Rearrangement of N-Imidoyl-O-vinyl Derivatives. Reaction of amidoximes with propiolates can be applied 5453


Chemical Reviews

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Scheme 88

Scheme 89

Scheme 90

cascade furnishing the imidazoles 270 (Scheme 85).166 Similarly, reaction of 271 with DMAD leads to pyrimidine ring closure, affording the pyrimidines 272 (Scheme 86)199,200 in addition to imidazoles (cf. Scheme 85) as side products which are formed in low yields.199 4.4.3. Rearrangement of N-Imidoyl-O-aryl Derivatives. 2-Aminophenols can be obtained from N-phenylhydroxylamine (see section 4.1.1) as well as from O-phenyl-hydroxylamine

derivatives. The latter case is similar to the one already discussed, namely, synthesis of 2-hydroxyphenols (see section 4.4.1). Treatment of the N-phenoxyureas 273 and 274 with TFA affords the ureas 275 that are further cleaved to form the 2-(N-alkylamino) phenols 277 (Scheme 87).201 In addition to a [3,3]-rearrangement N′-phenyl-ureas 274 also undergo [5,5]rearrangement to form 276.202 Its formation can be assigned both to two sequential [3,3]-rearrangements and to one [5,5]5454


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Scheme 91

Scheme 92a

a

i: R3C(O)Cl, (R3CO)2O, Py, 80−100 °C, 8−10 h (R3 = Me, Et). ii: R3C(NR4)Cl, NEt3, reflux, 12 h (R3 = Ph, R4 = Me, Ph).

Scheme 93

tion.147 The addition products 282, derived from the interaction of 278 with diethyl chlorophosphate and benzoyl chloride, undergo rearrangement only in refluxing toluene. Such group-migrating ability corroborates discussion in section 4.1.1. The [3,3]-rearrangement leading to 283 was shown to proceed intramolecularly as supported by the fact that there were no crossover products observed for the substrate 282 mixture.147 Reaction of 278 with cyanogen bromide gives imidazolinones 287 directly, whereas the phenyl isocyanate adduct 285 undergoes [3,3]-rearrangement only in an anion mode (Scheme 89).147 The yield of 286 can be increased by performing the reaction of 278 with an excess of PhNCO in the presence of NaH.147,148

rearrangement (transition state A). The reaction pathway is unimolecular, and evidence is supported by the absence of crossover products for simultaneous reaction of two substrates. 4.5. Rearrangement of Oxime Derivatives Possessing Electron-Acceptor Substituents

Enehydroxylamines are the tautomeric forms of the corresponding nitrones and oximes, with the equilibrium strongly shifted to the latter in most cases. As has been already mentioned (see section 3.4), introduction of an electronwithdrawing group into the β position of the CC bond stabilizes the enehydroxylamine moiety. The substrates 278 react with sulfonyl chlorides and thiocarbamoyl chlorides giving the rearrangement products 279 and 280, respectively (Scheme 88).147,148 Reactions of the barbituric derivatives 281 are hampered by side processes such as nucleophilic substitu5455


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Subsequently, these undergo [3,3]-rearrangement with ultimate ring closure. Reaction is facile only for α-CH2-ketone-derived oximes. Tautomerization leading to A proceeds exclusively through abstraction of the more mobile proton. Recently, a similar transformation was reported for the O-perfluorobenzoyl oxime 300 (Scheme 94).208 In this case the reaction proceeds under milder conditions than those for dimethyl carbonate. An older multistep approach to the mentioned transformation consists of oxime O-acylation, followed by Nmethylation with a Meerwein salt and subsequent proton abstraction (Scheme 95).209 This method is the predecessor for the direct α-oxygenation methodology discussed in the next section. Acid-catalyzed conversion of conjugated cyclohexenone oximes into aniline derivatives has been known since the end of the 19th century. This reaction is often referred as “Semmler−Wolff aromatization”.210,211 Typical conditions consist of treating the oximes with acetic anhydride in the presence of a strong acid such as hydrogen chloride. The reaction was used in the syntheses of substituted anilines,212 quinolines,213 and other heteroaromatics214 as well as in the total syntheses of miltirone,215 sanguinarine, and chelerythrine.216 It also proved successful for more complex targets such as pseudopteroxazole,217 penitrem D,218 and HKI 0231B.219 Ketene and 1-ethoxyvinyl acetate were found to be useful reagents for the transformation (Scheme 96, eq 1).220 Other mild reaction conditions involve treatment of 303 with acetyl chloride in toluene at 80 °C.217 One of the mechanisms proposed includes a N,O-bis(acetylation) of the starting oximes, leading to the oxy-enamines A and/or B.220 Although alternative ways involving dienimine 307221 or azirine 308 are also possible,214 acetic acid elimination from A or B affords the anilides 304. Another way for generation of the initial enoxime is the in situ enolization of the monooximes 305, which allows synthesis of the acetylated m-aminophenols 306 (eq 2).222 A substituent shift can be observed if the initial cyclohexenone oxime possesses quaternary carbon atoms.213a,214,223 In certain cases a Beckmann rearrangement is a side process in the rearrangement. However, judicious choice of reaction conditions may allow selective transformations.213a,214 Due to the acidic medium there is a high probability for formation of cationic species that can be trapped onto aromatics.224 In contrast, sometimes basic media may be preferable for aromatization,219 for example, if the cyclohexenone oxime ring possesses electron-withdrawing substituents.225

A change in rearrangement direction proved to be possible for substrates 285 and 288. This was accomplished by doublebond transposition under silylation of 285 (R = H) or 288. Subsequent [3,3]-rearrangement lead to functionalization of position 4 of the cyclohexane ring in moderate yields (Scheme 90). Note that product 289 can be directly obtained from hydroxylamine 278.147 An analogous transformation is possible for 1,3-dioximes 290 (Scheme 91).203 While rearrangement of the acylated products 291 occurs under heating, formation of sulfonate and phosphate derivatives occurs in situ. The latter is accompanied by halogen insertion, apparently via SN2′ substitution. Rearranged substrates can also be obtained from nonfunctionalized oximes, but such reports are rare (for rearrangement of nonfunctionalized nitrones see section 5.2). The N,Obis(acylation) or N,O-bis(imidoylation) of oximes 293 gave various enamides 294−296 (Scheme 92). Imidoylation was reported as giving only the 1,2-diaminoalkene derivatives 294.204 Exhaustive acylation, on the other hand, usually afforded mixtures of the regioisomeric amides 295 and 296.205,206 The unsymmetrical oximes 293 (R1 ≠ R2) could be expected to give regioisomeric products by proton Scheme 94

abstraction from either the R1CH2 or the R2CH2 group. However, some selective cases have been reported.205 The products 294 and 296 can be converted to imidazoles and oxazoles, respectively.204,205a Reaction of the oximes 297 with dimethyl carbonate in the presence of potassium carbonate under heating in an autoclave afforded N-methyloxazolones 299 in moderate yields (Scheme 93).207 The primary O-methoxycarbonylation of the initial oximes 297 has been established as leading to the target products. The intermediates 298 are further subjected to Nmethylation and thus give rise to the oxyenamines A. Scheme 95

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Scheme 96

C, R3 = Me, R4 = Ph) reacts with cyclic ketones at room temperature and with acyclic and aromatic ones under mild heating (50 °C).228 This synthesis methodology tolerates different functionalities, such as esters, acetals, or phenols. Unsymmetrical ketones give selective rise to CH2-group oxygenation in the presence of a CH3 group. Note that methyl ketones (acetone, acetophenone) fail to react. A similar reaction is applicable for synthesis of carbonates (X = C, R3 = Me, R4 = OR′)230 and carbamate derivatives (X = C, R3 = Me, R4 = NR′2) 311.231

Scheme 97

Scheme 98

Table 1. Direct Oxygenation of Carbonyl Compounds 309 with Hydroxylamines 310 310 309 aldehydes aldehydes, aldehydes, aldehydes, aldehydes,

ketones ketones ketones ketones

X

R3

R4

examples

311, %

C C SO C C

t-Bu Me Me Me Me

Ph Ph p-Tol NR′2 OR′

9 23 17 16 22

61−82 69−92 38−82a 50−88 47−84

a

Reaction conditions: MsOH, THF, or THF/toluene, room temperature to 40 °C, 24 h.

Use of N-methyl-O-tosylhydroxylamine in the presence of methanesulfonic acid converts aldehydes to the corresponding 2-tosyloxy derivatives 311 (X = SO, R3 = Me, R4 = n-Tol).232 In such a manner the functionalization of methyl ketones 309 (R1 = H) is possible but with only moderate regioselectivity (functionalization of the secondary site/primary site ≈ 2.6− 4.2:1). More electron-accepting substituents at the sulfur, such as p-nitrophenyl, lead to Beckmann-like rearrangements.233 The applicability of asymmetric reagents such as 310 was also studied.234 Substituents on both the nitrogen and the oxygen atoms, reaction temperature, solvent, and counteranion were all found to have a dramatic effect on both the yield and the asymmetric induction. After thorough screening the best

4.6. Direct α-Oxygenation of Carbonyl Compounds

Reaction of carbonyl compounds with secondary amines is a classical method for enamine synthesis.226 The enamines formed can be involved in [3,3]-rearrangements with subsequent hydrolysis, affording functionalized carbonyl compound. Thus, it seems somewhat amazing that only recently has the reaction of aldehydes and ketones 309 with N-alkyl-O-acylhydroxylamines been applied for reliable introduction of the α-hydroxyl moiety (Scheme 97, Table 1).227−229 The bulky reagent 310 (X = C, R3 = t-Bu, R4 = Ph) reacts selectively with aldehydes but is, however, unactive toward ketones.227 The less sterically demanding derivative 310 (X = 5457


Chemical Reviews

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Scheme 99

The commonly accepted mechanism and side products of the Boekelheide rearrangement are depicted in Scheme 99. The first stage is the O-acylation of the substrate 314 to give the salt A. The rate-determining step of the overall process is usually a proton abstraction from A which gives the oxy-enamine B.237,239 Isotope-labeling240−243 and external nucleophile addition244,245 studies led to the conclusion that a tight ion pair C participates in the reaction path. For the rearrangement to the para-methyl substituent (see Scheme 100) intermolecular acetate-ion attack has been suggested.245 Branched alkyl substituents afforded some low yield products which result from rearrangement in the ion pair C.241 Rate increases were observed in polar solvents such as DMF.246 It is interesting to note that the 320 (Chart 3) was proposed as the structure of one of the epothilone B N-oxide acetylation products.247 The major side processes are attachment of the acyloxy group to the C-2 position of aromatics yielding the product 316, sometimes referred as the Katada reaction,236,248 as well as acyloxy group migration to the third and fifth ring positions giving the products 317 and 318, respectively.241 Therefore, product mixtures are not unexpected, and reaction protocols may require optimization. The 3-methylisoquinoline N-oxide 321 undergoes a Boekelheide rearrangement with quite a low yield (Scheme 101).249 Presumably the low yield arises from the low stability of the respective ene hydroxylamine intermediate A. This is due to loss of aromaticity in both rings. Substrates possessing substituents in both the 2 and the 4 positions undergo preferable rearrangement to the 2 position.241,250 However, the substrate 322 gave 4-site selectivity exclusively (Scheme 102).251 This seemed to arise from the lower steric demands of the methyl group compared to that of the butyl substituent. The increased acidity from the adjacent phenyl group (in substrates 325 and 326) also favors rearrangement to the 4 position.252

Scheme 100

results to date were achieved with a TFA salt of the amine 313 in toluene (Scheme 98). Transformation of cyclohexanones 312 proceeded with moderate yields and promising ee values. Cyclic ketones of other types (5- and 7-membered, 4-aza) gave inferior results.

5. BOEKELHEIDE REARRANGEMENT AND RELATED REACTIONS 5.1. Boekelheide Rearrangement

2-Alkyl-substituted pyridine N-oxides 314 under heating with acetic anhydride undergo functionalization of the carbon side chain giving rise to the 1-acetoxy-alkyl derivatives 315 (Scheme 99). The 4-alkyl derivative 319 behaves similarly (Scheme 100). Since its discovery in the early 1950s,235,236 this transformation Chart 3

has attracted much attention.237,238 Especially noteworthy is the review by Oae and Ogino,237a which discusses in depth pertinent research on the mechanism. Scheme 101

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Scheme 102

Scheme 103

Scheme 105a

During Boekelheide rearrangements double-bond formation can be observed instead of acyloxy group migration as just Scheme 104

a

i:TFAA, CH2Cl2, room temperature, then saponification.

system of camptothecin.276 Rearrangement to the para substituent, except for pyridine substrates,277,278 was used for preparing acridine derivatives.279 In the quinoline series it was used, for example, in the total syntheses of the antibiotic dynemicin and its analogues.280 Scheme 106

discussed.241,253−255 A mechanism involving abstraction of a proton from cation C (see Scheme 99) rather than the [3,3]rearrangement−elimination sequence cannot be excluded. For instance, the tetrahydrofuran derivative 327 afforded the furan 328 under reflux in acetic anhydride (Scheme 103).254 In order to explain this and other similar results it can be assumed that an increase in elimination product yield is caused by the concomitant increase in the stability of nitrenium cation. This corroborates the increased elimination product formation for sec-alkyl-substituted substrates, although the yields are not synthetically valuable.241 Boekelheide rearrangements seem to be hampered by the increased steric demands of alkyl substituents connected to the aromatic core. Thus, while reaction of 2-n-butyl-pyrazine Noxide proceeds smoothly,256 reaction of the 2-benzyl derivative 329 affords significant amounts of the core substitution product 330 (Scheme 104).257 For the isobutyl substituent258 and other branched alkyl groups,253 yields of the normal rearrangement products are quite low. The Boekelheide rearrangement has been successfully used for functionalization of methyl and other alkyl groups in 2(arylmethyl)pyridines,259 cycloalkyl-annelated pyridines,260,261 phenanthrolines,262 quinolines,263,264 phenanthridines,265 pyrazines,266−269 pyridazines,270 pyrimidines,271,272 quinoxalines,273 and oxazoles.274 The reaction was also a part of a total synthesis of the alkaloid streptonigrine275 and the ring

Table 2. Boekelheide Rearrangement of Substituted Pyrimidine Mono-N-oxides 332

5459

no.

R1

R2

R3

333 + 334, %

333:334

1 2 3 4 5

H H H OMe H

H H H H OMe

Ph OMe Me OMe OMe

58 74 not mentioned 83 82

2:1 only 333 6:1 only 333 only 333


Chemical Reviews

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Scheme 107

Scheme 108

Scheme 109a

Application of the more active trifluoroacetic anhydride allows the rearrangement to proceed at room temperature and without the use of anhydride as a solvent.281,282 Moreover, trifluoroacetic ester cleavage can be accomplished in one pot, while acetate cleavage requires a separate step. This modification was used for preparation cycloalkyl-annelated pyridines,283 pyrimidines,284 and triazole,285 including functionalization of the tetrahydroquinoline moiety during the total syntheses of the thiostrepton family of peptide antibiotics.286 The multisubstituted substrate 331 underwent TFAAmediated rearrangement exclusively at the 2 position substituent (Scheme 105).282 Intriguing results were obtained during the rearrangement of the substituted pyrimidine 1-oxides 332 (Scheme 106, Table 2).272 The rearrangement proceeds mainly with a C-2 alkyl substituent even in the case of steric preference of a C-6 substituent (see Table 2, no. 4). Similar regioselectivity was observed for pyrimidine-1,3-dioxides287 and 2,4-dimethyl-1,3thiazole N-oxide.288 It is evident that rearrangements can be mediated by anhydrides other than acetic and trifluoroacetic. Although they are the most widely used reagents, in general any electrophile− base combination can lead to the required enehydroxylamine intermediate. However, although proton abstraction is the ratedetermining step (see above) for the overall Boekelheide reaction, instances of addition of a base to the reaction are rare. In addition to TFAA and acetic anhydride other acid anhydrides such as phenylacetic289,290 and trichloroacetic have also been used.289 Phenyl acetates possessing electron-accepting substituents in the benzene ring can be employed as acylating reagents.291 Rearrangement products were observed even during the nitration of quinaldine N-oxide with benzoyl nitrate.292 As has been demonstrated for the simplest picoline N-oxide, there is an increase in the target product (see 315, Scheme 99) yield from 71% to 88% with simultaneous diminishing of byproduct formation (cf. 317 and 318) amounts in the series acetic > propionic > butyric anhydride. This is attributed to the increase in steric hindrance of the reagents.246 Benzoic anhydride led to low yields of the target products, and succinic anhydride failed to react even at 150−160 °C.236 The active reagent is an acetic anhydride/acetyl chloride mixture.246 The methane (Ms2O) and p-toluene (Ts2O) anhydrides of sulfonic acids can also be employed.293 The potential advantage of these reagents is the synthesis of products possessing good leaving groups. For example, in a one-pot reaction the triflic

i: AcCl, NEt3, toluene, 80 °C, 2 h, then room temperature, 12 h. ii: NaOH, EtOH, reflux, 1 h. a

derivative A was subjected to elimination (Scheme 107).286a The sequence was named the Matsumura−Boekelheide rearrangement. The first cases of reactions of aromatic heterocycles N-oxides with acyl chlorides were reported as long ago as 1936.294 Nevertheless, the use of acid chlorides for Boekelheide rearrangements is much less frequent than acid anhydrides.295,296 Intrestingly, reaction of N-oxide 335 with ethyl chloroformate led not only to the normal carbonate 336 but also to the ethoxy derivative 337 (Scheme 108). Formation of the latter can be explained by decarboxylation of the ethyl carbonate anion and solvent attack onto cation A.297 The AcCl/Et3N reagent mixture was used for rearrangement of triazole-1-oxide 338 (Scheme 109).298 Recently, an acyl chloride/base mixture was used for an asymmetric Boekelheide rearrangement (Scheme 110).299 Mosher’s acid chloride was used as the acylating reagent. The best results were achieved in 2-propanol and with ethyl acetate as the solvent. A related oxidation of an aldehyde to an ester occurred under treatment of quinoxaline dioxide 340 with acetone cyanohydrin in the presence of triethylamine in methanol (Scheme 111).300 The mechanism proposed involves the oxy-enamine intermediate A whose formation is promoted by the electronaccepting cyano group. Employment of reagents containing nucleophilic moieties in the Boekelheide rearrangement can lead to nucleophile insertion into the final product molecule. The most common procedure is treatment of nitrogen heterocycle N-oxides with POCl3 that leads to chloride anion introduction (Scheme 112). The same approach was used for the transformation of pyridines, 301−303 oxazoles, 274,304 and benzisoxazoles. 305 Achievement of high yields requires addition of base, which abstracts a proton from the intermediate complex 343.301,306 In the absence of base nucleophilic substitution occurs at positions 5460


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Scheme 110

the action of tosyl chloride has also been reported.316 An important role in decreasing the chloride derivative yield may be played by inorganic bases (e.g., potassium carbonate) because it removes the chloride anion from the medium. Due to the low stability of products of the 344 type,302a their in situ involvement in nucleophilic chlorine substitution is reasonable.317 Formation of product 348, resulting from trapping of the picolylic cation A on acetonitrile, is worthy of mention. Formation of such products generated during interception with external nucleophiles such as anisole or nitriles usually occurs in low yields.245,316 A discussion regarding intramolecular trapping under silylation can be found in section 2.1. In concluding this section we should consider the possibility of introducing the amino group rather than the oxy group. Treatment of 2-picoline N-oxide 342 with N-phenylbenzimidoyl chloride afforded 2-(acylaminomethyl) derivative 349 in good yield.318 One of the mechanisms suggested involves a [3,3]-sigmatropic rearrangement of the intermediate A (Scheme 114). Addition of the base to the reaction mixture plays an important role. Otherwise, core substitution occurs (product 350).318,319 Presumably, the role of the base is in proton abstraction from the methyl group and A formation. For 4-picoline N-oxide 319 in addition to the amination product 351 the C,C-coupling product 352 was also isolated.319 Concerning the migration mechanism, both the appearance of the dimerization product 353 and evidence in the form of CIDNP signals for the C,C-coupling products combine to support the existence of a radical pathway. On the other hand, this does not exclude a contribution from a concerted mechanism, leading to C,N-coupling.320

Scheme 111

Scheme 112

5.2. Rearrangement of Nitrones and Related Compounds 253,268,302,307

2 and 4. However, there are examples of selective chlorination of the side chain.308 Useful reagents are di- and triphosgene.309 Heterocyclic substrates, possessing several alkyl groups, often led to regioselective chlorination of one of them (cf. Scheme 106).303,310 Competitive processes are the “normal” rearrangement (cf. 314 → 315, Scheme 99) and deoxygenation of the N-oxide.296 Use of acyl halides leads principally to a normal rearrangement, whereas alkylsulfonyl chlorides allow nucleophile insertion.296,311−313 In the latter case it cannot be excluded that the reaction proceeds through a normal rearrangement and subsequent nucleophilic substitution. For instance, reaction of picoline N-oxide 342 with trichloroacetyl chloride primarily gives the trichloroacetate 345, which on prolonged heating gives chloromethylpyridine 344 (Scheme 113, eq 1).314 Even in the presence of lithium chloride 2-methylquinoline N-oxide 319 under treatment with acetyl chloride gives predominantly the acetate product (cf. 315 in Scheme 99). Reaction with tosyl chloride gave a mixture of the tosylate and chloride products, while use of benzenesulfonyl chloride gave only the chloride 346 (Scheme 113, eq 2).315 On the other hand, selective formation of the tosylate 347 under

Acylation of nitrones has been less exploited than acylation of different heterocyclic N-oxides. The first general procedure was reported only in 1983.321 Treatment of the nitrones 354 with acyl halides in the presence of triethylamine gave 2acyloxyimines 355, which could be hydrolyzed to the corresponding carbonyl compounds 356321 or reduced to the amino alcohols 357 (Scheme 115).321,322 It is important to note the need of an anhydrous medium and addition of a base: otherwise, nitrone hydrolysis or a Beckmann rearrangement may occur.323 Thus, it can be concluded that for carbonyl compounds the sequence nitrone formation−acylation and rearrangement−hydrolysis leads to α-acyloxy carbonyl compounds (cf. Schemes 95 and 97). Among the acyl chlorides investigated, as a rule, pivaloyl chloride gave the best results (Scheme 115). In addition to acyl chlorides, methyl chloroformate can also be used.322 The reaction was applied to various aldonitrones and two simple ketonitrones derived from cyclohexanone and cyclopentanone.321 In most cases rearrangement proceeds spontaneously.324 Only two stable Nacyloxyenamines of type A were reported: the unsubstituted acetaldehyde derivative 358,321 which undergoes rearrangement 5461


Chemical Reviews

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Scheme 113

Scheme 114

Scheme 115

the total synthesis of fumagillol. The reaction also gave excellent diastereoselectivity.325 Reaction of ketonitrones with imidoyl chlorides includes a [3,3]-rearrangement step (Scheme 117, eq 1).326 The imidoyl chloride influences the structure of reaction product to a considerable extent. During the [3,3]-rearrangement the benzimidoyl moiety is transformed into a benzoyl group. In

under reflux in benzene, and the acetophenone derivative 359.42 The major side products are imides such as 360 (Scheme 116), formation of which can be avoided by use of bulky N-substituents (tert-butyl, cyclohexyl, etc.), which prevent proton Ha abstraction from the imine carbon atom.322 The [3,3]-rearrangement was successfully applied to 5462


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Scheme 116

Scheme 117

Scheme 118a

a

i: R4C(O)Cl. ii: R4C(O)Cl, NaH, or Py.

enamides 363. 326b The regioselectivity of the proton abstraction also deserves some attention.326b Cyclic ketone derivatives gave 2,3-diamino-alk-1-enes 363, while acyclic acetophenone and acetone derivatives 364 gave the 1,2diaminoalkenes 365 (Scheme 117, eq 2). Interestingly, the

this way the intermediates 361 can be hydrolyzed to form the 2-aminoketone derivatives 362.326a In contrast, the N-Cbztrifluoromethylimidoyl moiety resulted in formation of the mobile trifluoroacetyl group with the result that in the products 361 its migration occurred. This gave rise to the amino5463


Chemical Reviews

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cyclohexenone nitrone 366 also led to chloride introduction (product 367, Scheme 117, eq 3). Treatment of aldonitrones

Generally proton abstraction from the nitrones 368 can proceed in two directions: leading to either an endo- (371) or an exocyclic (372) enamines. The 2-methyl derivatives (368, R1 = Me) afforded products that were attributed to endocyclic enamine formation.330,331 However, a change in base to a bulky triethylamine allowed abstraction of the exocyclic hydrogen.332 4-Substituted pyrroline N-oxides 368 (R3 = Me, Ph, R2 = H) gave mostly high diastereoselectivity, e.g., sole formation of the 3,4-cis-isomer.330 With an excess of reagent the rearrangement product also underwent acylation to give the enamide 373.333 Under more harsh conditions the ketone 374 was isolated (Scheme 119).331 An analogous migration was observed for 2-aminopyrroline N-oxide 375 (Scheme 120). The first step was amino-group acylation leading to the hydroxylamine 376.334a Further acylation furnished the 3-acyloxy derivative 377.334b Reaction of the 4-membered cyclic nitrones 378 with acetyl chloride leads to chlorine insertion (products 379 and 380) instead of the expected acetoxy group (Scheme 121).335 As an explanation the authors suggested O-acylation, a 1,2-hydride shift, chloride-anion addition, and elimination of acetic acid. Usually exclusive chloride attachment to the endocyclic carbon had been observed, and only the benzyl derivative 378 (R = PhCH2) led to chloride attachment to the side chain (product 381). The absence of products containing the acetoxy group (cf. with 369, Scheme 118) is evidence against formation of Nacetoxyenamines 382, especially those possessing an endocyclic double bond. However, the enamine 383 is a possible intermediate in formation of 381. Under harsh conditions the diarylpyrroline N-oxides 384 mainly gave elimination330,336 and 2H-pyrroles 385 or 1Hpyrroles 386 could be obtained in good yields (Scheme 122).336 An analogous reaction of pyrroline N-oxides can also be made with chlorosulfonyl isocyanate.337 Note that a similar transformation is known for N-oxynitrones, in other words, nitronates.338 Nevertheless, reaction of the 5-membered cyclic nitronates 387 proceeds via base catalysis with N−O cleavage as a first step (Scheme 123).338a,b On the other hand, acyclic nitronates 388, formed in situ from the corresponding nitro compounds during silylation, can be converted into enoximes 390. The transformation in some cases proceeds via N,Nbis(siloxy)enamines 389 (Scheme 124).339

Scheme 119a

a i: BzCl, NaOH (for R = Ph), H2O, 0 °C, 15 min. ii: Ac2O (for R = Me), CCl4, −20 °C to room temperature, 21 h.

with imidoyl chlorides gave imides of the type 360 (see Scheme 116).326a Similar transformations were reported for cyclic nitrones such as the pyrroline N-oxides 368 (Scheme 118).327−330 The Scheme 120a

a i: MeCN, 0 °C to room temperature, 1 day. ii: CCl4, −20 to 0 °C, 3 days.

product yields of 369 vary greatly. Elimination leading to 370 is a competing process, the contribution of which increases with introduction of substituents in the 3 and 4 positions.327,328,330 Scheme 121

5464


Chemical Reviews

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Scheme 122

imine 400 or the sulfonyloxy derivative 401 (Scheme 128).346 The specific reaction paths are determined by the substituents in the substrate 399. The yield of 401 was increased to 58% with the use of the more nucleophilic 4-N,N-dimethylaminopyridine. The results obtained are consistent with the mechanism shown in Scheme 123. The key role is played by the intermediate N-oxy-enamine A. Of note is the fact that nitrones possessing no cross-conjugated double bonds led to either a Beckmann rearrangement or a Semmler−Wolff aromatization (see Scheme 96).223a,347 Relatively few applications of oxyenamine rearrangements in enantioselective synthesis have been reported. We already mentioned that the Boekelheide rearrangement under the action of a chiral acyl halide (see Scheme 110) proceeds with moderate selectivity. Employment of nonracemic hydroxylamine for nitrone formation is another way to promote chiral induction. Condensation of hydroxylaminoalcohols with orthoesters afforded the oxazolines 403. The latter were treated with acylating reagents in the presence of triethylamine without purification and furnished the acyloxy derivatives 404 with high diastereoselectivity (Scheme 129).348,349 Protective group cleavage in 404 leads to the corresponding α-hydroxy esters 405. It should be possible to regenerate the chiral auxiliary. The transformation occurs under the action of both acyl halides and acetic anhydride.348,349 In contrast, di-tert-butyl dicarbonate was not reactive enough.349 Also of note is the low diastereoselectivity (de = 32% for 407) achieved with benzyl chloroformate.348 Among the substrates examined the phenyl derivative (R = Ph) also failed to react. This was attributed to conjugation of the benzene ring with the double bond in intermediate A.348 Among the chiral amino alcohols the best selectivities were achieved with tert-leucinol 402349 and isoborneol derivatives 406.348 Also, these auxiliaries lead to the opposite configuration of the stereocenter formed (cf. products 404 and 407). Rearrangement diastereoselectivity is attributed to both the Z configuration of the double bond and the shielding of one double-bond face by the bulky substituent in A. It appears that a related strategy can be applied for asymmetric synthesis of α-amino acids, although until now only one achiral example has been reported (Scheme 130).345

Scheme 123

For certain cyclic substrates the rearrangement−elimination described here is similar to a Semmler−Wolff aromatization and occurs under rather acidic conditions (Scheme 125, eq 1) (see section 4.5).213b Sometimes such rearrangement−eliminations occur under very mild conditions. Thus, the products 392, formed from bis-N-oxide 391 interaction with amines, gave the benzimidazoles 393 during attempted purification by column chromatography (Scheme 125, eq 2).340 Single examples of acetic anhydride-mediated rearrangement for more rare nitrones, benzodiazepine341 or oxazoline derived,342 have also been reported. Under treatment with a mild acylating reagent the steroidal nitrone 394 allowed isolation of the intermediate 395. Under harsher reaction conditions this was converted into the standard rearrangement product 396 (Scheme 126).343 Similar products for other steroidal nitrones, analogous to 394, were observed under benzoylation or acylation conditions.344 However, rearrangement led to chlorine insertion in the case of the tosylation (cf. Scheme 113).344 Reaction of the pyrroline N-oxide 397 with N-phenylbenzimidoyl chloride afforded the rearrangement product 398, presumably through the enamine A as an intermediate (Scheme 127).345 Thus, in comparison to the benzoylation of pyrroline N-oxides (see Scheme 118), the reaction regioselectivity changed. Presumably, endocyclic proton abstraction is hampered due to steric hindrance from the adjacent methyl groups. Reaction of tosyl chloride with steroidal nitrones 399 follows two major pathways, giving either the elimination product the Scheme 124

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Scheme 125

Scheme 126

Scheme 127

Scheme 128

6. MISCELLANEOUS PERICYCLIC REACTIONS OF N-OXYENAMINES The 6-membered cyclic enehydroxylamines, 5,6-dihydro-2H1,2-oxazines 408, are thermodynamically labile and capable of undergoing [4 + 2]-cycloreversion to give rise to the enimines 409 and the carbonyl compounds 410. The fragmentation is usually referred to as the “Eschenmoser fragmentation” or the “Eschenmoser cycloreversion” (Scheme 131). The most common method of 1,2-oxazines 408 synthesis is deprotonation of the corresponding salts 411. They are usually obtained by alkylation of the oxazines 412350 or by [4 + 2]-cycloaddition of the vinyl nitrosonium cations 413 with alkenes351,352 (Scheme 131). The first example of such a [4 + 2]-cycloreversion referred to reaction of the bicyclic pyridinium salt 414 with a base (Scheme 132).353 The reaction driving force is cleavage of the weak N−O bond in 408. The temperature depends on the nature of the

substituents. Thus, the 3-cyano-substituted products 408 (R′ = 3-CN) undergo cycloreversion during work up.354 Some alkyl5466


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Scheme 129

Scheme 130

Scheme 131

enoximes.357 Fragmentation of the sterically demanding 5,5,6,6tetrasubstituted oxazines 418 required reflux in benzene.352 The stability of the propellane structures 419 increased with an increase in ring size. For n = 1 the enamine 419 at 0 °C was not observed, whereas for n = 3 the half reaction time was 1.5 h at 80 °C. This was attributed to conformational effects.358 N-Acyl 2H-dihydro-1,2-oxazines are more stable than the corresponding N-alkyl ones.359,360 Incorporation of electron-withdrawing substituents in the 4 position also increases the stability of the 2H-1,2-oxazines 408.360,361 The analogous anions 420 do not appear to undergo cycloreversion. The latter allows trapping of 420 with electrophiles (alkyl iodides, acyl chlorides)360 or tautomerization at the C-4 site.362 In the absence of electronwithdrawing groups deprotonation/alkylation should be performed at low temperatures,350a otherwise cycloreversion of 420 occurred.363 An interesting route to the 3-vinyl isoxazolidines 423 starts from the [3 + 2]-cycloaddition of 3-bromo nitronates 421 (Scheme 133).364 Loss of HBr from the bicyclic adducts 422 gave the precursors for the [4 + 2]-cycloreversion. Different dipolarophiles gave good results, whereas the choice of nitronate was somewhat limited. The enimines 409 formed during cycloreversion can undergo further transformations. The simplest is the hydrolysis of the enimine to the corresponding carbonyl compound.351,352,358 Reaction of 1,2-oxazine 424 with DMAD affords 1,3-oxazine 425 (Scheme 134).365 Performing the reaction in acetone or acetaldehyde does not result in solvent molecule incorporation into the product. Thus, the authors concluded that the reaction

Scheme 132

Chart 4

substituted 2H-oxazines 408 were observed using NMR techniques at −65 °C, but they underwent cycloreversion on warming up to −20 °C.355 The N-siloxyderivatives 416 (Chart 4) seemed to decompose already at negative temperatures.33,356 The O-anions 417 also cycloreverse to the corresponding 5467


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Scheme 133

Scheme 134

Scheme 135

Scheme 138

Scheme 136 follows path a, where the CH2O fragment, which is formally eliminated during the course of the cycloreversion, remains tethered to the rest of the molecule during the reaction. N-Acyl-benzoxazines 426, obtained from the corresponding N-chlorohydroxamates, under strong heating (melting or reflux in mesitylene) gave rise to cycloreversion, and subsequent cyclization leads to benzo-1,3-oxazines 427 in high yields (Scheme 135).366 Unfortunately, most of the products 427 decompose upon purification. Scheme 137

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Scheme 139

Scheme 140

441 into oxindoles 443 under treatment with acetylene dicarboxylates (Scheme 140).372

The 5,6-dihydro-4H-1,2-oxazines 428 afforded pyridines 429 under strong heating (Scheme 136).367 The mechanism of the process presumably involves isomerization of the 4H-1,2oxazines 428 following cycloreversion of the intermediate A. A retro-ene reaction seems to be the major decomposition path for nonaromatic N-alkoxy-enamines, which are incapable of cycloreversion. Weinreb amides 430 under treatment with TBSOTf/base undergo deoxygenation to form the amides 432 or undergo rearrangement into the amides 433 (Scheme 137).368 Substrates like 430, which do not possess an α-CH2 group, failed to react in such manner or only afforded products in low yields. These and other data support intermediate formation of oxy-enamines 431. Other examples of retro-ene reactions of N-alkoxy-enamines have also been reported.46,355,369,370 For example, the derivatives 435, formed by deprotonation of the salts 434, were observed by low-temperature NMR analysis (Scheme 138, eq 1).355 The N-alkoxyenamines 437 are the intermediates of the base-promoted decomposition of 2-alkylpyridinium salts 436 (Scheme 138, eq 2).369 Recently, a retro-ene reaction aimed at in situ generation of unstable N-acylketimines 439 with subsequent trapping with aryl−aluminum reagents (Scheme 139).371 Among the different N-alkoxy substituents examined (R3 = H, Ph, 4-CF3C6H4−, 4MeOC6H4−) the best results were obtained for the benzyl ethers. The reaction is applicable to both cyclic and acyclic enamides 438. Of note is the in situ preparation of the aryl− aluminum reagent. A complex mixture was formed when ArMgBr was used. At the same time MgBr2 is necessary for the successful retro-ene step. Electrocyclic ring opening in benzo-1,2-oxazines 442 is proposed as one of the steps in the transformation of nitrones

7. CONCLUSIONS We hope we have demonstrated that N-oxyenamine rearrangements constitute a well-studied area of organic chemistry. However, not all substrate types were studied in the depth that might prove most useful. As can be seen from this review, rearrangements of the readily available derivatives of Nphenylhydroxylamines and nitrogen heterocycle N-oxides have been the most studied. Another complicating factor is the dearth of stable N-oxyenamines, especially those possessing a N-vinyl moiety not incorporated into aromatic system. Finally, compared to [3,3]-migrations, [1,3]-migrations are far less investigated. Substrates that are incapable of [3,3]rearrangements are more prone to be trapped with external reagents. Considering the diversity of both substrates for the rearrangement and specific paths for formation of the N-vinylhydroxylamine motif, further development in N-oxyenamine rearrangements in organic synthesis can be expected in the near future. It is hoped that this hopefully comprehensive review goes some way toward stimulating interest in this fascinating field of research.373 AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. 5469


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Biographies

Cbz CIDNP DABCO DAST DCE DMAD DMAP EWG HFIP KHMDS LDA MCPBA MW Np TBAF TBDPS TBS TFA TFAA TMEDA TMS

Andrey A. Tabolin was born in Moscow in 1987. He graduated from the D. I. Mendeleev University of Chemical Technology in 2009 (faculty Higher Chemical College of the Russian Academy of Sciences). He received his Ph.D. degree from the N. D. Zelinsky Institute of Organic Chemistry in 2012 under the supervision of Professor S. L. Ioffe. Currently, he is a researcher in the same institute. His scientific interests include development of the methodology of organic synthesis, especially in the field of nitro compounds and their derivatives.

benzyloxycarbonyl chemically induced dynamic nuclear polarization 1,4-diazabicyclo[2,2,2]octane diethylaminosulfur trifluoride 1,2-dichloroethane dimethyl acetylenedicarboxylate 4-dimethylaminopyridine electron-withdrawing group 1,1,1,3,3,3-hexafluoro-2-propanol potassium hexamethyl-disilazide lithium di-isopropylamide m-chloroperbenzoic acid microwave irradiation naphthyl tetra-n-butyl ammonium fluoride tert-butyldiphenylsilyl tert-butyldimethylsilyl trifluoroacetic acid trifluoroacetic anhydride N,N,N′,N′-tetramethyl ethylene diamine trimethylsilyl

REFERENCES (1) The chemistry of hydroxylamines, oximes and hydroxamic acids; Rappoport, Z., Liebman, J. F., Eds.; John Wiley and Sons: Chichester, 2009. (2) (a) Luo, Y.-R. Comprehensive handbook of chemical bond energies; CRC Press and Taylor & Francis Group: Boca Raton, FL, 2007; p 353. (b) Smith, M. B.; March, J. March’s advanced organic chemistry: reactions, mechanisms and structure, 6th ed.; John Wiley and Sons: Hoboken, NJ, 2007; p 29. (3) In general, homolysis of the N−O bond and heterolysis leading to O-cation and N-anion cannot be excluded. (4) Blechert, S. Synthesis 1989, 71. (5) Reviews on Cope and Claisen rearrangements see, e.g.: (a) Hill, R. K. Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Kidlington, Oxford, 1991; Vol. 5, p 786. (b) Wipf, P. Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Kidlington, Oxford, 1991; Vol. 5, p 827. (c) Castro, A. M. M. Chem. Rev. 2004, 104, 2939. (d) Nubbemeyer, U. Synthesis 2003, 961. (6) Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43, 5171. (b) Gossauer, A. Die Chemie der Pyrrole; SpringerVerlag: Berlin, 1974. (7) (a) Trofimov, B. A. Advances in heterocyclic chemistry; Katrizky, A. R., Ed.; Academic Press: San Diego, CA, 1990; Vol. 51, p 178. (b) Trofimov, B. A.; Mikhaleva, A. I. Heterocycles 1994, 37, 1193. (c) Trofimov, B. A.; Mikhaleva, A. I. Zh. Org. Khim. 1996, 32, 1127− 1141; Chem. Abstr 1997, 126, 251030z. (d) Trofimov, B. A. Advances in heterocyclic chemistry; Katrizky, A. R., Ed.; Academic Press: San Diego, CA, 2010; Vol. 99, p 209. (8) Dalpozzo, R.; Bartoli, G. Curr. Org. Chem. 2005, 9, 163. (9) Pereira, M. M. A.; Santos, P. P. The chemistry of hydroxylamines, oximes and hydroxamic acids; Rappoport, Z., Liebman, J. F., Eds.; John Wiley and Sons: Chichester, England, 2009; p 343. (10) (a) Li, J. J. Name reactions in heterocyclic chemistry; John Wiley and Sons: Hoboken, NJ, 2005; p 18. (b) Shine, H. J. Aromatic rearrangements; Elsevier: New York, 1967; p 182. (11) (a) Bamberger, E. Ber. Dtsch. Chem. Ges. 1894, 27, 1347. (b) Bamberger, E. Ber. Dtsch. Chem. Ges. 1894, 27, 1548. (c) Sone, T.; Tokuda, Y.; Sakai, T.; Shinkai, S.; Manabe, O. J. Chem. Soc., Perkin Trans. 2 1981, 298. (12) Kikugawa, Y.; Shimada, M. J. Chem. Soc., Chem. Commun. 1989, 1450. (13) Kikugawa, Y.; Mitsui, K. Chem. Lett. 1993, 1369. (14) Yang, B.; Miller, M. J. Org. Lett. 2010, 12, 392.

Sema L. Ioffe was born in Moscow in 1938. He graduated from the D. I. Mendeleev Institute of Chemical Technology in 1960. Since then he has worked in the N. D. Zelinsky Institute of Organic Chemistry (from 1960 to 1963 as postgraduate student, from 1963 to 1967 as Junior Researcher, from 1967 to 1985 as Senior Researcher, and since 1985 as Principal Researcher), where he received his Ph.D. (1964) and his Dr. Sci. degrees (1980). He was appointed Professor in 1993. His scientific interests cover the chemistry of aliphatic nitro compounds and their derivatives as well as the chemistry of polynitrogen compounds. His additional interest is connected with the advanced chemical education of gifted youth in the Moscow Chemical Lyceum and various institutions of Russian Academy of Sciences.

ACKNOWLEDGMENTS The authors thankfully acknowledge the reviewers and editors for thorough reading of the manuscript and valuable suggesstions. The authors’ research on the review topic was supported by the Russian Foundation for Basic Research (grants 12-03-00278, 11-03-00737). ABBREVIATIONS Boc tert-butoxycarbonyl BSA N,O-bis(trimethylsilyl)acetamide 5470


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