Chemistry of Ketene N, S-Acetals: An Overview

Review pubs.acs.org/CR

Chemistry of Ketene N,S‑Acetals: An Overview Lin Zhang, Jinhuan Dong, Xianxiu Xu,* and Qun Liu* Department of Chemistry, Northeast Normal University, Changchun 130024, China ABSTRACT: Push−pull alkenes, which bear electron-donating and -accepting group(s) at both termini of a CC double bond, respectively, are of interest not only for their unique electronic properties but also for their importance as versatile building blocks in organic synthesis. In the world of ketene acetals having the push−pull alkene skeleton, ketene N,S-acetal is most likely the biggest family according to the number and types of these compounds. The first ketene N,S-acetal compound was reported in 1956. As a cyclic ketene N,S-acetal compound, nithiazine, the first lead structure of neonicotinoid insecticides, was reported in 1978. The characteristics of ketene N,S-acetals, which have the structural feature of ketene S,S-acetals and enaminones, make them versatile and easy to use, especially in cyclization and multicomponent reactions for the synthesis of various heterocyclic systems and related natural products. There has been an increasing wealth of information about the synthesis and synthetic applications of ketene N,Sacetals, especially, in recent years. This review provides comprehensive knowledge on the chemistry of ketene N,S-acetals.

CONTENTS 1. Introduction 2. General Methods for Synthesis of Functionalized Ketene N,S-Acetals 2.1. Synthesis of Ketene N,S-Acetals Based on Ketene S,S-Acetals 2.2. Synthesis of Ketene N,S-Acetals Based on Alkyl/Aryl Isothiocyanates 2.3. Synthesis of Ketene N,S-Acetals Based on Thioamides 3. Heteroannulation Reactions via Ketene N,SAcetals 3.1. Construction of Five-Membered Heterocyclic Rings 3.2. Construction of Six-Membered Heterocyclic Rings 4. Intramolecular Cyclization Reactions of Ketene N,S-Acetals 5. Functionalization and Related Reactions of Ketene N,S-Acetals 5.1. Functionalization of Ketene N,S-Acetals 5.2. Functionalization of Cyclic Ketene N,S-Acetals 5.3. Preparation of N-Alkyl/Acyl Cyclic Ketene N,S-Acetals 5.4. Synthesis of Highly Selective Probes for Parallel G4s 6. Synthesis of 4-Oxothiazolidine Derivatives and Rhodacyanine Analogues 6.1. Synthesis of 4-Oxothiazolidine Derivatives 6.2. Synthesis of Rhodacyanine Analogues 7. Annulation Reactions 7.1. [4 + 1] Annulation 7.2. [5 + 1] Annulation 7.3. [3 + 2] Annulation 7.4. [3 + 3] Annulation © 2016 American Chemical Society

8. Multicomponent Reactions 8.1. Three-Component Reactions 8.2. Four-Component Reactions 9. Perspectives and Conclusion Author Information Corresponding Authors Author Contributions Notes Biographies Acknowledgments Abbreviations References

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1. INTRODUCTION Push−pull alkenes, which bear electron-donating and -accepting group(s) at both termini of a CC double bond, respectively, are of interest not only for their unique properties but also for their importance in organic synthesis as versatile synthons and/ or synthetic intermediates. In push−pull alkenes containing alkyloxy, alkylthio, alkyl, or arylamino groups as electron donors through p−π conjugation, the synthesis and synthetic applications of ketene acetals (ketene O,O-acetals),1 ketene silyl acetals (KSA),2 ketene S,S-acetals,3−9 and ketene N,Nacetals10−12 have been widely studied and reviewed. However, the syntheses and synthetic applications of ketene N,S-acetals have not been well summarized, although several comprehensive reviews on the chemistry of ketene S,S-acetals have mentioned some of the early work before 19903−5 and a recent microreview on novel organosulfur synthons highlighted the recent research on ketene N,S-acetals by Ila and Junjappa.13 Ketene N,S-acetals, which possess structural features that enable the olefinic linkage to be activated by electron-releasing

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Received: June 26, 2015 Published: January 13, 2016 287

DOI: 10.1021/acs.chemrev.5b00360 Chem. Rev. 2016, 116, 287−322

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Scheme 34), 1,5-N,N-dinucleophiles (section 7.2, Scheme 61), 1,5-dinucleophiles (section 5.1, Table 3), C3 1,3-dielectrophiles (section 3.2, Scheme 25; section 7.3, Scheme 62), and C5 1,5dielectrophiles (section 7.2, Scheme 60), etc. (Figure 3). Moreover, it has been found that the isomerization between Z and E configurations of ketene N,S-acetals (for example C) via an imine intermediate G occurs more easily in both polar and nonpolar media58,59 under heating conditions (Scheme 29), in basic media (Schemes 38 and 71), in the presence of electrophiles (Scheme 34, Table 3), or in the presence of Lewis acids (Scheme 74). This tendency is extremely important for the cyclization reactions based on ketene N,S-acetals (due to the “equal contribution”, for example, C and H in Figure 3) and is very clear in enhancing the nucleophilicity of the carbon atom at the acceptor end of ketene N,S-acetals having an acidic NH group. Significantly, the reactivity and performance of ketene N,S-acetals are different from those of ketene O,O-, N,O-, N,N-, and S,S-acetals. Thus, the present review is to provide comprehensive knowledge on the chemistry of ketene N,Sacetals as well.

alkylthio and amino groups through p−π conjugation, are more reactive toward electrophiles than ethylene. Functionalized ketene N,S-acetals, for example C, having structural features of polarized α-oxo ketene S,S-acetals3−9,14−18 and enaminones (Figure 1),19−23 have proved to be particularly useful intermediates in organic synthesis. In addition, the incorporation of multiple reactive sites as in enaminones and ketene S,S-acetals, including a good leaving group (alkylthio group) in ketene N,Sacetals along with varied sorts of functional groups (FGs) on the carbon atom adjacent to the acetal moiety (also known simply as the acceptor end) and N-alkyl or N-aryl group, gives ketene N,Sacetals rise to a variety of chemical transformations and allows them to be used easily in the construction of a wide variety of heterocycles.4,13,24−27 Moreover, cyclic ketene N,S-acetal compounds, for instance, ralitoline and etozolin, had been registered as drugs in treatment of neurological and hypertension diseases.28,29 Nithiazine was the first lead structure of neonicotinoid insecticides, which opened the neonicotinoid era of pest management, currently the most widely used insecticides in the world;30−32 and thiazole orange (TO) and SYBR safe are the widely used probes for nucleic acids in G-quadruplex (G4) to study the interaction between G4 and its ligands (Figure 2).33−35 In recent years, along with increasing reports on the chemistry of ketene S,S-acetals as an active area in push−pull alkenes,6−9,14−18,36−52 there has been an increasing wealth of information about the syntheses and applications of ketene N,Sacetals as the second generation of versatile intermediates derived from ketene S,S-acetals via replacement of an alkylthio group by various primary or secondary aliphatic and aromatic amines (see section 2, Schemes 1 and 2).3−9,13,53 In the present review, covering a wide range of topics, we give an overview of the chemistry of ketene N,S-acetals, from the first report in 1956 by Sheehan et al.54 on the preparation of ketene N,S-acetals (see section 5.3, eq 6) to present, including general (section 2) and special (sections 5 and 6) methods for the synthesis of numerous ketene N,S-acetal compounds. We highlight the actions and reactions relating to their particular characteristics, not only the intrinsic nucleophilicity of the carbon adjacent to the acetal moiety and the nitrogen atom of the amino group (sections 5, 6, and 8) and the electrophility of the acetal carbon (sections 3, 4, 7, and 8) but also the distinctive combination of their multiple reactive sites toward attack by electrophiles, nucleophiles, and radicals. These characteristics of ketene N,S-acetals make them versatile and easy to use, especially in cyclization and multicomponent reactions (sections 7 and 8) for the synthesis of various heterocyclic systems and related natural products. According to Hall’s bond-forming initiation theory55 based on the increasing donor ability of alkenes in the sequence vinyl sulfides > vinyl ethers > vinylamines, in general, the nucleophilic reactivity of the carbon adjacent to the acetal moiety should be ketene S,S-acetals > ketene O,O-acetals > ketene N,N-acetals, though this sequence is dependent on reaction type and conditions.55−57 The reactivity and flexibility of a wide variety of functional groups and substituents in ketene N,S-acetals and equivalents allows them not only to act as a N- and/or C-nucleophile but also to act as C2 1,2-dipoles (section 7.3, Schemes 65 and 67; section 8.1, eqs 11−14, Schemes 72 and 73, etc.) and 1,4-C,Ndipoles (section 7.1, Scheme 59), potential azomethine ylides (section 7.3, Schemes 63 and 64), 1,3-C,N-dinucleophiles (section 5.2, Schemes 47 and 48; section 7.3, Table 5 and Schemes 65 and 66, etc.), 1,5-C,N-dinucleophiles (section 4,

Figure 1. Typical structures of ketene S,S-acetals, enaminones, and ketene N,S-acetals.

Figure 2. Examples of ketene N,S-acetal-containing drugs, insecticides, and probes.

Figure 3. Profile of synthetic versatility of ketene N,S-acetals. 288


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Scheme 2. Synthesis of Ketene N,S-Acetals without Addition of an External Base

2. GENERAL METHODS FOR SYNTHESIS OF FUNCTIONALIZED KETENE N,S-ACETALS Numerous ketene N,S-acetals and ketene N,S-acetal-containing compounds have been prepared for different applications. In this section, several general methods for synthesis of ketene N,Sacetals bearing one or two electron-withdrawing groups (EWGs) at the acceptor end are summarized. These methods include (1) base-mediated nucleophilic addition of an active methylene compound to alkyl/aryl isothiocyanates followed by S-alkylation (Scheme 1, method A);4 (2) S-alkylation of β-ketothioamides Scheme 1. General Synthetic Methods for Ketene N,S-Acetals

external base, the corresponding cyclic ketene N,S-acetals, including 2k and 2l, were obtained in good yields (Scheme 2).64 With primary aromatic amines as nucleophiles,64−69 the desired, more thermodynamically stable compounds 9 were obtained in high yields with the amino group cis to the alkylcarbonyl moiety of 9 due to formation of an intramolecular hydrogen bond between NH and the oxygen of carbonyl group (Scheme 3). Products 9c, 9d, and 9i showed good selectivity and

bearing a primary amino group under basic conditions (Scheme 1, method B);24 and (3) reaction of ketene S,S-acetals with stoichiometric primary or secondary amines (or 2-aminoethanethiol) through a nucleophilic addition−alkylthio elimination sequence (Scheme 1, methods C and D).4 Methods C and D are very useful for preparation of various acyclic and cyclic ketene N,S-acetals due to the ready availability of both ketene S,S-acetals3−9,14 and amines.

Scheme 3. Synthesis of Cyanoacrylate Derivatives

2.1. Synthesis of Ketene N,S-Acetals Based on Ketene S,S-Acetals

The efficiency of the reaction of ketene S,S-acetals with amines strongly depends on the electrophilicity of the acetal carbon of ketene S,S-acetals and the nucleophilicity of amines. Ketene S,Sacetals bearing two gem-electron-withdrawing substituents and nitroketene S,S-acetals are very reactive toward nucleophiles due to the enhanced push−pull effect on their CC double bond.3−9 In 1962, Gompper and Topfl53 reported the preparation of 2a by reaction of 1 with aqueous ammonia in EtOH as the solvent at reflux without addition of an external base to activate the nucleophilic amine component (Scheme 2).53 Similarly, a series of ketene N,S-acetals were synthesized in moderate to excellent yields. This method can also be applied to the synthesis of 2j by using ethyl L-prolinate as the amine component and commercially available nitroketene dimethylthioacetal60−62 as the starting material. Nitroketene N,S-acetals can be further converted to nitroacetamides by Hg2+-catalyzed hydrolysis.63 Under identical reaction conditions as above and with 1,3dinucleophilic 3 as the amine component, pyrimidino[2.lb]benzothiazoles, such as 6 and 8, were obtained when 4a and 1 were selected as the S,S-acetal components, respectively (Scheme 2).53 In these reactions, 4a and 1 play the role of C3dielectrophiles. In the case of reactions of 1 or 4a with 2aminoethanethiol in water heated to reflux in the absence of an

activity against dicotyledonous weeds.66 In addition, it was found that 9l,70 9m,71 9n,72 and 9o73 possessing E configuration can be prepared by using 2-chlorothiazol-5-amine, (6-fluoropyridin-3yl)methanamine, (6-chloropyridin-3-yl)methanamine, and [3(4-methoxyphenyl)isoxazol-5-yl]methanamine as the amine components, respectively. These compounds showed excellent herbicidal activities even at low doses. Under identical reaction conditions, Song and co-workers74 prepared 9p and analogues (24 examples, 26.9−56.5% yields), which also have the configuration with the amino group cis to the carbonyl moiety, as indicated by X-ray analysis of 9r. Compounds 9p and 9q have 289


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addition, higher reaction temperature was needed when aryl amines were applied as the amine components, due to their weaker nucleophilicity than aliphatic amines.

the same effect against tobacco mosaic virus as ningnanmycin with the structure of 10. Catalyzed by triethylamine (TEA),75 the reaction of secondary aliphatic amines with 4c can give either the desired products 11 or the unusual enaminone products 12 as the major products, depending on the amines used. Similar to 11f, 11a−e were obtained in high to excellent yields when N-methylalkylamines were applied (Scheme 4). In comparison, 11g was produced in high yield by use of the primary aliphatic amine, 2(4-fluorophenyl)ethanamine, as the nucleophile.76

Scheme 5. Reaction of 17 with Amines

Scheme 4. Reaction with Secondary Aliphatic Amines In the case of reaction of 19 with a large excess of pyrrolidine at 90 °C for 1 h, 20 was generated in good yield79 (Scheme 6; Scheme 6. Reaction with Pyrrolidine as an Nucleophile

also see Scheme 4, 11f). However, under identical reaction conditions, reaction of 19 mainly afforded diaminated product when a six-membered secondary amine was used as the amine component, due to its stronger nucleophilicity than pyrrolidine. Aziridine is a good amine component for synthesis of the corresponding ketene N,S-acetals, as described by Ila and coworkers80 using 21 as the electrophiles (Scheme 7). Scheme 7. Reaction with Aziridine as an Nucleophile

In studies on the screening of compounds with antidiabetic activity, (E)-24 was prepared from 23 in the presence of NaH as a strong base due to the relatively weak nucleophilicity of 2aminobenzothiazoles (eq 1, 11 examples, no yields were given).81 These results (Schemes 5−7 and eq 1) indicate that reactions of ketene S,S-acetals having one EWG at the acceptor end with amines may require harsher reaction conditions or the use of a strong base, depending on the nature of ketene S,Sacetals and/or amines (for a comparison, also see Scheme 2).

However, it was found that the enaminone analogue, (E)12a,75 was generated as the main product when N-ethylbenzylamine was used for the above reaction (Scheme 4). Similarly, 12b and 12c were also obtained in high yields when Nethylcyclohexanamine and N-ethylbutan-1-amine were applied, respectively. The stereochemistry of 12b was established by performing a nuclear Overhauser effect spectroscopy (NOESY) experiment. A possible mechanism for formation of 12 may involve formation of the corresponding 13 having a bulky secondary aliphatic amino group, which may undergo an intramolecular thiophilic cyclization via zwitterionic intermediate 14, followed by thiophilic attack by the in situ generated methylthiolate and subsequent elimination of the second ethylthio group.6,77 The above results75 indicate that the reaction of ketene S,S-acetals with amines can also be applied to the synthesis of enaminones through the selection of amines and reaction conditions. In comparison with the reaction of ketene S,S-acetals bearing two gem-electron-withdrawing substituents and nitroketene S,Sacetals as the electrophiles (Schemes 2−4), an excess of amine is generally required for the reaction of ketene dithioacetals bearing one electron-withdrawing group (Scheme 5).78 In

Intermolecular addition of amines to cinnamoyl ketene S,Sacetals tends to give adducts by the nucleophilic attack of amine at the β-C of the cinnamoyl moiety.7,8 However, a significantly different result was described by Suryawanshi et al.82 in the screening of antileishmanial agents. In their studies, cinnamoyl ketene N,S-acetals were produced by heating the mixture of 25 and amines in a steel bomb at high temperature (eq 2, six examples, no yields were given).

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Instead of the “desired” products, like bis(trifluoroacetyl) ketene N,S-acetals, a mixture of trifluoroacetyl ketene N,S-acetal and imino ketene N,S-acetal was afforded by reaction of 32 with aqueous methylamine in EtOH at room temperature.91,92 In this reaction, aqueous methylamine acts as either a base or a nucleophile, which might enable a base-promoted detrifluoroacetylation−nucleophilic substitution sequence to give 30b and an imination−nucleophilic substitution sequence to deliver 33 (Scheme 9). Imination of the ketone moiety with simple amines has rarely been found in the chemistry of acyl ketene S,S- and N,S-acetals, α,β-unsaturated trifluoromethyl ketones, and related compounds.6,86,87,93−96 The above results indicate that bis(trifluoroacetyl) ketene S,S-acetals have different properties compared to other ketene S,S-acetals (Schemes 2−4) due to the increased reactivity of trifluoromethylcarbonyl compounds to 1,2-nucleophilic addition.86,87 According to electron-withdrawing ability, α-oxo ketene S,Sacetals are less reactive toward nuclophiles than nitro and trifluoroacetyl ketene S,S-acetals. For the reaction of α-oxo ketene S,S-acetals, a suitable base is generally required for formation of an amine anion, as the more reactive nucleophile and to prevent the formation of undesired ketene N,N-acetals through overamination under harsh reaction conditions. By use of n-BuLi as a strong base,97 displacement of one of the methylthio groups of 35 by an in situ generated anilide anion from aniline and n-BuLi afforded the desired, more thermodynamically stable products, (E)-36, in good to high yields (Scheme 10, 23 examples, 60−93% yields). All products 36a−w

By use of microwaves (MW) as heat source,83 a series of nitroketene N,S-acetals bearing N-aryl and N-alkyl groups were prepared by reaction of 27 with the corresponding amines (Scheme 8). In comparison, no reaction occurred when 4Scheme 8. Synthesis of Nitroketene N,S-Acetals

nitroaniline and 4-(trifluoromethyl)aniline were applied, respectively, due to their weak nucleophility resulting from the strong EWG (nitro and trifluoromethyl group) on the aryl ring of the arylamine.84,85 Trifluoroacetyl is a strong EWG.86,87 Displacement of a methylthio group of trifluoroacetyl ketene dimethylthioacetal88,89 by an amine gives the desired trifluoroacetyl ketene N,Sacetals, for example 30a−f, in good to excellent yields under very mild reaction conditions (Scheme 9)90 without requirement for Scheme 9. Synthesis of Trifluoroacetyl Ketene N,S-Acetals

Scheme 10. Synthesis of α-Oxo Ketene N,S-Acetals with nBuLi as Base

were assigned as the E configuration according to formation of the intramolecular hydrogen bond between NH and oxygen of carbonyl group on the basis of 1H NMR spectra for the NH adsorption at low field; for example, δ = 14.3 ppm for 36s. Similarly, 36x−z, with δ = 13.8, 13.0, and 13.5 ppm, respectively, for their 1H NMR NH adsorption peaks, were also prepared in high yields by Junjappa, Ila, and co-workers.98 Their synthetic method provides a general and reliable procedure for preparation of a wide variety of α-oxo ketene N,S-acetals, starting from the readily available α-oxo ketene S,S-acetals. As a comparison, acid-catalyzed synthesis of ketene N,Sacetals from ketene S,S-acetals and amines has seldom been developed. Kohra et al.99 in 1993 and Yu and co-workers100

an external base. Products 30a−e are assigned as the E configuration on the basis of their 1H NMR data for NH adsorption at low field, owing to formation of the intramolecular hydrogen bond between NH and the oxygen of carbonyl group. However, no assignment existed for the configuration of 30f with a secondary amino group on the acetal carbon.90 Compounds 30 can be further converted to the corresponding bis(trifluoroacetyl) ketene N,S-acetals by trifluoroacetylation of 30 with excess trifluoroacetic anhydride as the electrophile in the presence of pyridine as an acid scavenger (Scheme 9).91 291


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recently described regioselective synthesis of 38 through BF3· Et2O-catalyzed reaction of 37 with anilines. A typical procedure for the synthesis of acyl ketene N,S-acetals in gram scale from 37 via an amine addition−methylthio elimination sequence in the presence of a catalytic amount of BF3·Et2O was also described (Scheme 11). Thus, 1.30 g (63% yield) of (E)-38a was obtained Scheme 11. Synthesis of Acyl Ketene N,S-Acetals under Acidic Conditions

Figure 4. Examples of ketene N,S-acetals prepared with phenyl isothiocyanate.

1,2-dibromoethane101,103 and 2-chloroacetyl chloride102 were applied as alkylating agents, the corresponding cyclic ketene N,Sacetals, such as 40i−m, were directly generated in moderate yields, in which an additional intramolecular N-alkylation or Nacylation was involved. Compounds 40l and 40m have the structural features of enamides, which are powerful synthetic intermediates in organic synthesis.104−106 In the presence of a relatively weak base, K2CO3,107 a series of ketene N,S-acetals including 2e (see Scheme 2) having two electron-withdrawing groups are prepared in high to excellent yields by use of the more CH-acidic methylene compounds as substrates (Scheme 12).

by reaction of 37a (1.62 g, 10 mmol) with aniline (1.40 mL, 15 mmol) in toluene (30 mL) catalyzed by BF3·Et2O (0.13 mL, 1.0 mmol) at reflux.100 The peak at δ 12.95 of 1H NMR for amino hydrogen of 38a indicates that the phenylamino group is in cis position to the acetyl group, due to formation of an intramolecular H bond. In general, an amine nucleophile is easy to deactivate under acidic conditions because of the formation of acid−base complexes. The above procedure provides an easy entry into ketene N,S-acetals via activation of ketene S,S-acetals. This method is efficient and has the advantages of simplicity and suitable for gram-scale synthesis, which deserves further investigation. In addition, the acidic conditions are important for one-pot reactions combined with further modification of ketene N,S-acetals (see sections 5 and 7).

Scheme 12. Synthesis of Acyl/Cyano Ketene N,S-Acetals

2.2. Synthesis of Ketene N,S-Acetals Based on Alkyl/Aryl Isothiocyanates

Alkyl/aryl isothiocyanates are very reactive toward nucleophilic attack. As an example of method A in Scheme 1 for synthesis of ketene N,S-acetals by base-mediated one-pot reaction of ketones or related active methylene compounds with alkyl/aryl isothiocyanates followed by S-alkylation, in 1967, Gompper and Schaefer60 reported that the reaction of nitromethane with phenyl isothiocyanate in the presence of NaH as the base in DMF (dimethylformamide), followed by S-methylation, afforded 28j in good yield (eq 3). The enamine double bond of 28j should adopt an E configuration under thermodynamic control because of intramolecular hydrogen bonding of the enamine NH proton with the nitro group. This has been demonstrated by the significant downfield shift of the NH proton in 1H NMR spectra at 11.8 ppm, although (Z)-28j was given in the report. This procedure provides efficient access to nitroketene N,S-acetals in a one-pot reaction in gram scale (20 g) from simple starting materials under mild reaction conditions and avoids the use of MW as the heating source (also see Scheme 8).

Under identical conditions as described, 43 were prepared in high yields by Yu et al.108 using β-dicarbonyl compounds as the active methylene components and bromoethane as alkylating reagent (Table 1). The reaction favored the formation of ketene N,S-acetals in Z isomers, probably due to steric hindrance operating through thermodynamic control, so that the relatively larger Ar1NH group is located in cis with the acetyl group (smaller than aroyl group), and the structure of (Z)-43a was confirmed by X-ray crystallographic analysis. As an alternative approach to α-oxo ketene N,S-acetals based on ketene S,S-acetals (see Scheme 10), aroyl ketene N,S-acetals can also be prepared in high yields through a one-pot reaction of aryl methyl ketones, aryl isothiocyanates, and methyl iodide in the presence of a strong base, NaH (Scheme 13).109,110 Cyanoketene N,S-acetals containing a benzimidazole unit can be prepared by reaction of 2-cyanomethylbenzimidazole with phenyl isothiocyanate in the presence of a base, followed by Salkylation of the resultant potassium thiolate salt 45 with methyl iodide.111 For example, treatment of a mixture of 44 and phenyl isothiocyanate with a solution of KOH at room temperature gave salt 45 (yellow crystal, mp >300 °C) in excellent yield (Scheme

By similar methods, a series of ketene N,S-acetals, including (E)-40a−c,101 (E)-40d−f,102 (Z)-40g, and (Z)-40h,103 were also synthesized in moderate to good yields (Figure 4). When 292


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Table 1. Preparation of Acetyl-Aroyl Ketene N,S-Acetals

product

Ar

Ar1

yield, %

Z/E

43a 43b 43c 43d 43e 43f 43g 43h 43i 43j 43k

4-MeC6H4 3-MeC6H4 4-MeOC6H4 Ph 4-BrC6H4 4-ClC6H4 Ph Ph Ph Ph Ph

Ph Ph Ph Ph Ph Ph 4-MeC6H4 3-MeC6H4 4-FC6H4 4-BnC6H4 2-MeC6H4

85 86 84 84 90 86 83 85 75 87 81

13:1 10:1 14:1 10:1 13:1 15:1 11:1 11:1 10:1 27:1 11:1

Scheme 15. Synthesis of Cyclic Ketene N,S-Acetals

Scheme 13. Synthesis of Aroyl Ketene N,S-Acetals

2.3. Synthesis of Ketene N,S-Acetals Based on Thioamides

In 1964, Gompper and Elser116 described the first example of synthesis of ketene N,S-acetals from thioamides bearing a secondary amino group by reaction with methyl iodide followed by base-mediated deprotonation, for example, the synthesis of 59 (Scheme 16, seven examples, no yields were given). Ynamines are synthetically useful.117−119 Treatment of 59g with a strong base enabled the formation of 60 in moderate yield.

14). Adding methyl iodide gradually to a solution of 45 in DMF afforded 46 in high yield. The 1H NMR spectrum of 46 revealed Scheme 14. Synthesis of Cyanoketene N,S-Acetals

Scheme 16. Synthesis of Ketene N,S-Acetals from Thioamides

two broad singlets at δ = 12.49 and 12.57 ppm, respectively, assignable for two NH groups. In the presence of KOH, the in situ generated potassium sulfide salts can further react with biselectrophiles to give cyclic ketene N,S-acetals.112 Reaction of 48 with phenacyl bromide as the biselectrophile afforded (Z)-49 via S-alkylation and subsequent intramolecular condensation. Compound 49 showed high potent in vitro antifungal activity with MICs (minimal inhibitory concentrations) of 6.25 mg/mL against Aspergillus fumigatus and Fusarium oxysporum. Under identical conditions, 52 was produced by using 2-chloro-N-(p-tolyl)acetamide as the biselectrophile. Clearly, an intramolecular amidation (amide exchange reaction) along with the loss of ptoluidine from alkylating intermediate 53 is involved in the latter case (Scheme 15). It has been found that, in cyclic ketene S,S-acetals, the EWGactivated 2-methylene-1,3-dithioles (for example, 55) displayed significantly different performance compared with the related 2methylene-1,3-dithiolane analogues (for instance, 56).6,113−115 Thus the synthesis and synthetic applications of 49 and analogues need to be investigated in detail.

As indicated in Scheme 1, method B, S-alkylation of βoxothioamides bearing a primary amino group under basic conditions can also be selected as an alternative method for the synthesis of α-oxo ketene N,S-acetals.24 For example, Salkylation of 61 with alkyl iodides in the presence of potassium carbonate in acetone enables the synthesis of 62a−e in high to excellent yields (Scheme 17).120 Under similar conditions, 62f− h are prepared in high yields from the corresponding βoxothioamides and methyl iodides.121 By use of KOH as a base, S-alkylation of arylhydrazonothioacetamides afforded the corresponding azo ketene N,S-acetals in good to high yields (Scheme 18, 20 examples, 58−92% yields).122,123 293


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Scheme 17. Synthesis of α-Oxo Ketene N,S-Acetals from βOxothioamides

ring closure) seems more appropriate, especially for the formation of 68p, on account of the great steric hindrance of an intermolecular SN2 at a tertiary center.114,115 Alternatively, another possibility for formation of 68p−r may occur via a sequence of acylation of the amino nitrogen of 67 by 2-chloro-2methylpropanoic acid anhydride, where the amide N atom participates in intramolecular displacement of the Cl atom to give an aziridinonium cation that is then displaced by the sulfur atom. S-alkylation reactions are required in synthetic methods A and B of Scheme 1 for preparation of ketene N,S-acetals. In these cases, a one-pot heteroannulation reaction could be created by choice of suitable alkylating reagents.112 Quenching the potassium sulfide salt 72 (generated from reaction of 71 and phenyl isothiocyanate mediated by KOH in DMF) with hydrochloric acid over crushed ice gave the thioacetanilide in equilibrium with its tautomeric thiol form 74 (Scheme 20).127

Scheme 18. Synthesis of Azo Ketene N,S-Acetals

Scheme 20. Synthesis of 1,3,4-Oxadiazol-2-yl Ketene N,SAcetals

In the case of biselectrophiles being utilized, cyclic ketene N,Sacetals can be constructed. Catalyzed by 4-dimethylaminopyridine (DMAP), [3 + 2] annulation of 67 with diethyl but-2ynedioate as the 1,2-dielectrophile via a sequential thia-Michael addition/intramolecular amidation afforded cyclic ketene N,Sacetals124−126 having the structural features of enamides104−106 in high yields (Scheme 19, 16 examples, 75−92% yields). The Scheme 19. Synthesis of Functionalized 1,3-Thiazolidin-4ones

Treatment of 72 with methyl iodide resulted in 75, which, by reaction with hydrazine hydrate or phenyl hydrazine, can be further converted to the desired 3-aminopyrazole derivatives, such as 76a and 76b. The corresponding 77 and 78 were afforded in high yields by treatment of 72 with chloroacetyl chloride and chloroacetone, respectively, under mild reaction conditions.

3. HETEROANNULATION REACTIONS VIA KETENE N,S-ACETALS In addition to heteroannulation reactions for the formation of cyclic ketene N,S-acetals (see Schemes 15, 19, and 20), the methods for synthesis of functionalized ketene N,S-acetals described in section 2 can also be used for the construction of various heterocyclic rings if a suitable alkylating reagent for method A in Scheme 1 or amine component for method C in Scheme 1 is applied (see Schemes 23 and 24 and Table 2 in section 3.1).

merit of this reaction is highlighted by its operational simplicity, short reaction time (3−10 min), very mild reaction conditions, and tolerance of a large variety of functional groups for βketothioamides.124 Similarly, 68p−r were obtained by use of αhalocarboxylic acid anhydrides [in situ generated from αhalocarboxylic acids in the presence of dicyclohexylcarbodiimide (DCC) at room temperature] as the 1,2-dielectrophiles.126 For the formation of 68p−r, a plausible mechanism involving intermolecular S N2 displacement was proposed by the authors,126 although an intramolecular SN2 displacement (for

3.1. Construction of Five-Membered Heterocyclic Rings

The electrophilicity of the carbonyl and cyano group at the acceptor end of ketene N,S-acetals makes them potentially reactive sites toward a nucleophilic center (see Scheme 2). Augustin et al.128 had attempted the reaction of aroyl or heteroaroyl acetonitriles, phenyl isothiocyanate, and α-CH-acid halo compounds as alkylating agents to form the corresponding ketene N,S-acetals in the presence of NaH as the base in DMF as 294


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the solvent. However, in most cases, the desired ketene N,Sacetals cannot be isolated, for they can be easily converted to tetrasubstituted 5-phenylaminothiophenes through base-mediated intramolecular Dieckmann-type condensation of the resultant N,S-acetal intermediate 80 (Scheme 21). Kirsch and

Scheme 23. Formation of 2-Ethylthiopyrroles and Proposed Mechanism

Scheme 21. One-Pot Synthesis of Substituted Thiophenes

the external base, both 88a and 89a were obtained. Compound 90b can be obtained and further converted to 88b. However, no 88a could be found by the reaction of 89a with 87a. A [3 + 2] annulation mechanism can be proposed that involves formation of 90a through displacement of an ethylthio group of 86a and deprotonation of 90a with base to give anion intermediate 91 in resonance with enolate anion 92, followed by nucleophilic 5-exo-dig cyclization (to give intermediate 93), base-mediated deacylation, and subsequent isomerization. In the reaction, ketene S,S-acetals act as a C2 1,2-dipole and 87a acts as a masked 1,3-N,C-dipole (Scheme 23). Accordingly, a series of 2-ethylthiopyrroles were prepared in high to excellent yields where 2.0 equiv of 87a was applied (Table 2).132

129

co-workers described similar results by using a relatively weak base, K2CO3, indicating the preferred intramolecular Dieckmann-type cyclization of ketene N,S-acetals with an active acidic SCH2 group in basic medium even at room temperature (Scheme 21, yields in parentheses). In the former case, 80f and 80g were obtained in very low yields.128 In the latter case, the corresponding thiophenes were produced in low yields when ethyl isothiocyanate was applied.129 In comparison, when NaOEt is used as the base and EtOH as the solvent,130 reaction of the active methylene compound 82 with isothiocyanates such as methyl, ethyl, allyl, adamantyl, and phenyl isothiocyanates, followed by addition of chloroacetone or chloroacetonitrile, afforded in each case the desired tetrasubstituted 4-aminothiophene-3-carboxamides, although in moderate yields (Scheme 22). In these reactions, intermediates 85

Table 2. Synthesis of Substituted Pyrroles

Scheme 22. Synthesis of 4-Aminothiophene-3-carboxamides product

R

EWG

time,a h

yield,a %

88a 88c 88d 88e 88f 88g 88h 88i 88j 88k

Me Et Me Me Me Me Me Me Me Me

MeCO EtCO C6H5NHCO 4-ClC6H4NHCO 4-MeOC6H4NHCO 2-MeOC6H4NHCO 4-MeC6H4NHCO 2-MeC6H4NHCO 2,4-Me2C6H3NHCO 2-ClC6H4NHCO

12 (12) 12 (12) 18 (20) 16 (20) 20 (30) 20 (30) 18 (30) 18 (30) 20 (30) 18 (20)

97 (93) 93 (90) 91 (90) 95 (89) 90 (86) 88 (87) 90 (85) 92 (82) 89 (60) 94 (88)

a

Reaction times and yields given in parentheses are for water as solvent.

should be involved. Compound 83d displayed significant antibacterial activity against Escherichia coli. The methods mentioned provide easy access to polysubstituted thiophenes and can also be extended to the construction of benzo[b]thiophenes and their heterofused analogues.131 In our recent research,132 we found that reaction of 86a with commercially available propargylamine in DMF in the absence of an external base can afford 88a in good yield (Scheme 23). In the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) as

Water (at reflux without an external base) has also been proven to be a suitable solvent for the above reaction (Table 2, reaction times and yields in parentheses).133 Based on either the amount of amine132,133 or the solvent applied,133 both the amine and hydroxide ion generated in situ can play the role of a nucleophile in deacylation as described in Scheme 23. 3Phenylprop-2-yn-1-amine is also a suitable choice for [3 + 2] annulation, and this reaction has been successfully expanded to 295


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having two methylthio groups, reacts faster than 106, and a ketene N,S-acetal intermediate 108 is formed for the former case.

include the conversion of vinylogous thiol esters to the corresponding substituted pyrroles.132 Further expansion of [3 + 2] annulation with a secondary amine, for example 87b, as the amine component, N-methyl 2,3dicarbonyl- and 2-acylpyrroles, instead of 2-ethylthiopyrroles, were produced in good yields with K2CO3 as the base (no reaction occurred in the absence of an external base).133 In this case, a 1,2-acyl migration process is involved (Scheme 24).

4. INTRAMOLECULAR CYCLIZATION REACTIONS OF KETENE N,S-ACETALS In ketene N,S-acetals, varied sorts of substitutes can be incorporated onto the carbon atom adjacent to the acetal moiety through the choice of starting materials or synthetic methods (section 2). Ketene N,S-acetals such as 40 (see section 2.2, Figure 4) can be used for synthesis of heterocycles via intramolecular cyclization in the presence of a base.145 Treatment of 40a (X = R = H) with NaH in DMF at elevated temperature led to the formation of 111a in excellent yield via an intramolecular SNAr reaction (Scheme 26).101 Similarly, 111b

Scheme 24. Synthesis of 2-Acylpyrroles and Proposed Mechanism

Scheme 26. Preparation of Phenylquinolin-4(1H)-ones and Phenylthieno[2,3-b]quinolin-4(9H)-ones

was prepared in excellent yield from 40f (X = Cl, R = H).106 In the cases of 40b (X = H) and 40c (X = H) having an acidic SCH alkylthio group (R = MeCO or PhCO), thieno[2,3-b]quinolines, such as 112a and 112b, were produced directly via 4-quinolone intermediates 111 by further intramolecular condensation.101,106 These methods provide efficient access to 4-quinolone and thieno[2,3-b]quinoline derivatives,146,147 respectively, depending on the substituents on the sulfur atom of ketene N,S-acetals. Direct displacement on the polarized ketene dithioacetals with tryptamine afforded 115 in high yields, which could be further converted to carbolines in good to high yields mediated by trifluoroacetic acid (TFA) through Bischler−Napieralski-type cyclization (Scheme 27).148 Treatment of 62a (see Scheme 17) with DBU leads to 2,3,5trisubstituted pyrrole in low yield via intramolecular Knoevenagel condensation (eq 4).110

This reaction presents an alternative approach for the synthesis of 2,3-dicarbonylpyrrole derivatives.134,135 In contrast with the construction of 88, in the synthesis of 95 with Nmethylprop-2-yn-1-amine as the amine component, the thiophilic nucleophilic reaction77,136−139 for formation of thiiranium intermediate 98140,141 (also see Scheme 4) should be critical for the formation of 95 via 1,2-acyl migration (Scheme 24).142 3.2. Construction of Six-Membered Heterocyclic Rings

Condensation of 5-aminopyrazoles with 1a in ethanol in the presence of a catalytic amount of TEA at reflux for 5 h yielded 105 in 32−43% yields (Scheme 25).143,144 Under identical conditions, compounds 107 were obtained (four examples, 30− 47% yields) with 106 as the 1,3-dielectrophiles. Both reactions share the same mechanism involving an addition−elimination pathway with methylthio as the leaving group. Substrate 1,

Scheme 27. Preparation of Alkylidene-1,2,3,4-tetrahydro-bcarbolines

Scheme 25. Preparation of Pyrazolo[1,5-a]pyrimidines

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Scheme 29. Synthesis of 2-(Methylthio)-N-Tosylpyrroles

In comparison, intramolecular cyclization of aroyl-aryl ketene N,S-acetals having an additional aryl group, for example, 62g (see Scheme 17), could not proceed effectively in the presence of a base.121 However, in the presence of Vilsmeier reagent (POCl3/DMF), 118a was obtained in high yield from 62g via an intramolecular condensation (Scheme 28). Under identical Scheme 28. Preparation of 3,4-Diarylpyrrole-2-carboxylates

pyridines, in high to excellent yields (Scheme 30)156 via formation of cation radical intermediate 133 followed by Scheme 30. Synthesis of 3-Aroylimidazo[1,2-a]pyridines

conditions, 118b was produced from 62h, and 118b can be further converted to the desired 3,4-diarylpyrrole-2-carboxylate by demethylthiolation with Raney Ni. For the cyclization reaction, a tandem aminomethylenation−cyclization sequence is thought to be involved, on the basis of the performance of the Vilsmeier reagent.149,150 Significantly, intramolecular cyclization of 62g can be activated by formation of the iminium intermediate 120, where the C atom is more electrophilic, allowing for a 1,4conjugate addition to the unsaturated imidate thiolester. 3,4Diarylpyrrole-2-carboxylate analogues are key intermediates in the synthesis of marine pyrrole alkaloids, such as lukianol A and lamellarin O (Scheme 28).151−153 Recently, Li and co-workers154 described a method for synthesis of 124 bearing an N-Ts group at the acetal carbon. Compounds 124 can be applied to the synthesis of 2-(methylthio)-N-tosylpyrroles through intramolecular cyclization of 127, formed probably by isomerization of 124 under heating conditions in the absence of catalysts (Scheme 29) involving a geometrically favorable 5-exo-trig process.155 Treatment of 36, having the pyridin-2-ylamino group (see Scheme 10), with cupric chloride as oxidant in THF at reflux gave the products, 2-(methylthio)-3-aroylimidazo[1,2-a]-

abstraction of hydrogen atom and intramolecular cyclization along with the release of hydrogen, keeping the methylthio group intact. Furthermore, 2-unsubstituted-3-aroyl derivatives were afforded in high yields by reductive dethiomethylation of 131 in the presence of Raney Ni in EtOH. Mediated by CuCl2,100 compounds 38 (for 38a−38r, see Scheme 11) underwent intramolecular C−H/C−H crossdehydrogenative coupling reaction to give highly functionalized indoles (Scheme 31). Under identical conditions, no reaction was observed with sterically hindered ketene N,S-acetals, such as 38s, as the substrate. It was found that indole derivatives can be prepared from 136 by Liebeskind−Srogl cross-coupling reaction157−160 (four examples, 63−79% yields).100 The aziridine ring is very reactive toward nucleophilic attack. Treatment of 22 with potassium iodide in acetone at room temperature under nitrogen atmosphere enabled the synthesis of spiro compounds 138 (Scheme 32).80 A possible mechanism for formation of 138 is likely to involve iodide ion-promoted ring opening of the aziridine ring followed by intramolecular cyclization.161 Treatment of 138a and 138c with Raney Ni in methanol led to the formation of DL-coerulescine (80% yield) 297


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Scheme 31. Synthesis of Substituted Indoles

Scheme 33. Synthesis of Quinoxalines

Scheme 32. Synthesis of Spiropyrrolidinyloxindole Alkaloids

Yu et al.108 found that under Vilsmeier reaction conditions (VR, POCl3/DMF or PBr3/DMF), 33 (see section 2.2, Table 1) acting as a 1,5-C,N-dinucleophile enabled the synthesis of halogenated pyridin-2(1H)-ones (Scheme 34, 22 examples, 74− 85% yields) via a mechanism probably involving formation of iminium species as intermediates and thus driving the intramolecular cyclization as the key step to furnish halogenated 149 (Scheme 34). In the synthesis of 149, Vilsmeier reagent plays the double roles of both a one-carbon electrophile and a halogenating agent.6,108,167 Alkenoyl (including cinnamoyl) ketene S,S-acetals, prepared by base-promoted condensation of acetyl ketene S,S-acetals with aldehydes, are useful synthetic intermediates for the synthesis of six-membered carbo- and heterocyclic compounds.7,168−172 In comparison, the synthetic applications of alkenoyl ketene N,Sacetals are rare. Recently, Yu and co-workers173 found that, upon treatment by CuX2 in the presence of LiX (X = Cl or Br) under basic conditions, 26 (also see section 2.1, eq 2) can be converted to 155 in good to excellent yields under argon atmosphere (Scheme 35, 27 examples, 57−94% yields). In this reaction, substrates 26 were prepared by BF3·Et2O-catalyzed reaction of readily available cinnamoyl ketene S,S-acetals7 with anilines as described in Scheme 1199,100 (also see Supporting Information of ref 173). The reaction can tolerate a wide range of aryl/heteroaryl groups on the cinnamoyl moiety. The structure of 155a was confirmed by X-ray crystallographic analysis. This reaction did not occur without CuCl2 (or CuBr2) or a base, and an oxygen (or air) atmosphere made the reaction less efficient. In addition, it was found that LiCl (or LiBr) can benefit the reaction, whereas TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or BHT (2,6-di-

and DL-horsfiline (75% yield), respectively, via a concomitant reductive dethiomethylation N-methylation process.80,162 When EtOH was used as the solvent at reflux, the desired (E)141 resulted from reaction of nitroketene dimethylthioacetal with the corresponding anilines.163,164 It was found that the attempted synthesis of 142a by reaction of 141a with Vilsmeier reagent as a one-carbon electrophile gave, instead of the desired 3-nitroquinoline (also see section 5.1, Table 3), a quinoxaline derivative,165 143a (Scheme 33). After optimization of reaction conditions (no DMF was required), the novel POCl3-mediated heteroannulation methodology of nitroketene N,S-acetals provides quinoxalines in moderate to high yields (13 examples, 42−80% yields)163 depending on the nature of the substituent on the aniline ring, which benefits the relatively electron-rich aniline ring. A possible mechanism for heteroannulation may involve formation of quinoxaline N-oxide intermediate 147 and subsequent chlorination followed by dehydrative aromatization.163 In a recent report by Nakamura and co-workers,166 143a was prepared in 54% yield and was further converted to 144 by oxidation with m-chloroperbenzoic acid (m-CPBA) as the oxidant (Scheme 33). They found that 144 was active against Trypanosoma cruzi Y strain, which can cause Chagas’ disease.166 298


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5.1. Functionalization of Ketene N,S-Acetals

Scheme 34. Synthesis of Halogenated Pyridin-2(1H)-ones

Treatment of 62, a precursor of substituted pyrroles (see Scheme 17), with Vilsmeier reagent, generated in situ from POCl3 and DMF, gives 156a−e in high yields via double aminomethylenation and subsequent cyclization/hydrolysis sequence (Scheme 36).176 In this process, a formyl group is Scheme 36. Synthesis of 4-Formyl-2,3,5-trisubstituted Pyrroles

tert-butyl-4-methylphenol) completely inhibited the reaction.173 Although the mechanism is not yet clear at the current stage, the synthesis of 155 provides further evidence for bond formation at the α-carbon of the cinnamoyl moiety in intramolecular cyclization.174,175

introduced to a ketene N,S-acetal in the iminium form and finally leads to 156. This reaction, together with DBU-promoted intramolecular Knoevenagel condensation (see section 4, eq 4) and POCl3-promoted tandem aminomethylenation−cyclization (see Scheme 28) based on aroyl ketene N,S-acetals, provides efficient access to polysubstituted pyrroles starting from acyclic precursors.177,178 In the presence of n-BuLi as base, displacement of one of the methylthio groups of an α-oxo ketene dimethylthioacetal by an aniline afforded the corresponding α-oxo ketene N,S-acetals, for example 36, in good to high yields (see Scheme 10). Compounds 36 can be used as the 1,5-dinucleophiles to react with Vilsmeier reagent as the one-carbon electrophile to provide convenient access to 162 via formylation followed by Friedel− Crafts cyclization (Table 3).98

5. FUNCTIONALIZATION AND RELATED REACTIONS OF KETENE N,S-ACETALS Similar to ketene S,S-acetals,6,8,9 the carbon atom adjacent to the acetal moiety of ketene N,S-acetals is very reactive toward electrophiles. This electrophilic susceptibility not only makes the functionalization of ketene N,S-acetals a convenient tool for the construction of diverse ketene N,S-acetal scaffolds but also provides efficient access to nitrogen-containing heterocycles, such as functionalized quinolines, β-lactam, thiazolo[3,2-a]pyridines, and polysubstituted pyrroles starting from acyclic precursors.120 Scheme 35. Synthesis of 4-Halo-5-alkylthio-3-pyrrolones

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Scheme 37. Electrophilic Fluorination of Ketene N,S-Acetals

Table 3. Preparation of Functionalized Quinolines and Their Benzo/Hetero-Fused Analogues

Heating a mixture of 167a−f and hydrazine hydrate in 2propanol at reflux for 2 h afforded the desired 169 in good to high yields (Scheme 38).182 Scheme 38. Synthesis of 3-Amino-4-fluoro-1H-pyrazoles

5.2. Functionalization of Cyclic Ketene N,S-Acetals

Reaction of 170 (made by reacting 2-mercaptoethylamine with 27)186,187 with N-aryl sydnones as an electrophilic aryl diazonium equivalent188,189 gave 172 in low yields when the reaction was performed in xylene or dimethoxyethane under microwave irradiation (Scheme 39).190 In comparison, the corresponding azo ketene S,S-acetals can be prepared in high yields through azolation of ketene S,S-acetals and related methods.17,191

The experimental results showed that (1) reactions of 36 without activating group on aniline are sluggish toward Vilsmeier reagent to furnish the desired quinolines (products 162a and 162h/h′); (2) 36h, having the 3-fluoroanilino group, afforded a regioisomeric mixture of 162h and 162h′; (3) reaction of 36b′ afforded the angularly fused 162i instead of the corresponding linearly fused 162i′; and (4) 36j gave 165 as the only identifiable product in 50% yield.98 On the basis of these results and related reports on Vilsmeier reagents,6,149,150,179−181 related mechanisms are proposed as described, and the formylation or acylation at the acceptor end of aroyl ketene N,S-acetals by POCl3/DMF or POCl3/DMA (where DMA = N,N-dimethylacetamide) should be the key step for construction of 162 (Table 3). Compounds 166a−e were prepared by reaction of a methyl ketone, an aryl isothiocyanate, and methyl iodide; 166f was prepared from 35a via thioacetal exchange reaction with benzylamine as the nucleophile.182 Treatment of 166a−f with the commercially available electrophilic fluorinating agent 1chloromethyl-4-fluorodiazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor)183 enables the synthesis of 167/167′a−f as a mixture of the enamine and imine forms when Selectfluor was added in portions (Scheme 37).182,184,185 When a slight excess of Selectfluor was used or Selectfluor was added in one portion, the difluorinated 168a was increasingly formed and the reaction of 166a with 2 equiv of Nfluorobenzenesulfonimide (NFSI) as the electrophilic fluorinating agent at room temperature afforded 168a in good yield (eq 5).182

Scheme 39. Preparation of Cyclic Azo Ketene N,S-Acetals

In 2004, Zhou and Pittman192 reported that 180a can be prepared from reaction of 179a with pivaloyl chloride (trimethylacetyl chloride) in the presence of TEA as base in acetonitrile. Under identical conditions, 180b and 180c were prepared, respectively, by N-acylation of 179a and its analogues (Scheme 40). This reaction provides a useful method for preparation of N-substituted cyclic ketene N,S-acetals starting from readily available 2-alkylthiazoles.193 300


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Scheme 40. Preparation of N-Acyl Cyclic Ketene N,S-Acetals

In contrast, with phenyl isothiocyanate as the electrophile to give α-thioxo cyclic ketene N,S-acetals by mono C-thioacylation, bis-adducts 184 were synthesized in excellent yields from 181 by using 2 equiv of more electrophilic phenyl isocyanates as the electrophiles via double C-acylation under very mild reaction conditions (Scheme 43).194,195 Bis-mono- and trimonoadducts 184e and 184f were obtained when 1,4-phenylene diisocyanate and 1,3,5-triisocyanatobenzene were applied as electrophile, respectively. Scheme 43. Synthesis of Carboamino Cyclic Ketene N,SAcetals

Functionalization of ketene N,S-acetals is a convenient tool for the construction of diverse functionalized ketene N,S-acetals, in which acid halides, acetic anhydrides, isocyanates, and isothiocyanates have been successfully applied as the electrophiles. With TEA as base, the reaction of 181a with pivaloyl chloride at room temperature afforded 182a in high yield via Cacylation (Scheme 41).192 A series of N-methyl acyl cyclic ketene N,S-acetals can be obtained under mild reaction conditions from the reaction of 181a and analogues with the corresponding acyl halides. Scheme 41. Acylation of N-Methyl Cyclic Ketene N,S-Acetals

In comparison, when relatively less electrophilic vinyl isocyanates are used as the electrophiles, monoadducts 185a− d were produced (Scheme 44).194 Scheme 44. Reaction with Vinyl Isocyanates

Similar to C-acylation of 181 with acyl halides,192 Cthioacylation of 181 with phenyl isothiocyanate as the electrophile in THF at room temperature furnished the corresponding 183a−d in high yields with N-arylthioamide function exclusively cis to the sulfur atom of the ketene N,Sacetal moiety based on NMR analyses (NOESY experiments) (Scheme 42).194,195 Similarly, bis-monoadduct 183e was prepared in excellent yield by use of 1,4-phenylene diisothiocyanates as the electrophile. It was also observed that 183a−d are not nucleophilic enough to react with a second equivalent of phenyl isothiocyanate to afford the corresponding diadducts at room temperature under the reaction conditions applied.

However, β-lactam derivatives, such as 189a and 189b, were formed when 188, having two germinal methyl groups on the carbon atom adjacent to the acetal moiety, was selected as the nucleophilic component and toluene was used as solvent (Scheme 45).194

Scheme 42. Synthesis of α-Thioxo Cyclic Ketene N,S-Acetals

Scheme 45. Preparation of β-Lactam Derivatives

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Benzoylation of 2-methyl-2-thiazoline with benzoyl chloride in acetonitrile at reflux afforded 192a in excellent yield (Scheme 46).196 This result indicated that formation of 192a should

Scheme 48. Synthesis of Thiazolo[3,2-c]pyrimidine Derivatives

Scheme 46. Preparation of N-Acyl Acyl Cyclic Ketene N,SAcetals

very reactive toward nucleophiles, and lower temperature and suitable solvents may be required.197,198 When α,α-disubstituted malonyl dichloride or terephthalic chloride was selected as diacylating agent, bis-ketene cyclic N,Sacetals were obtained in high yields by use of 181 as nucleophile (Scheme 49).196 Similarly, 198d can also be prepared by using 1,3,5-benzenetricarbonyl chloride as acylating reagent. Scheme 49. Synthesis of Bis- and Triketene Cyclic N,SAcetals

involve a double acylation sequence, namely, N-acylation (see Scheme 40) followed by C-acylation. It was shown that, under identical conditions, the corresponding 192b−e can be prepared from 191a and analogues in high to excellent yields by use of benzoyl and trimethylacetyl chlorides having no α-protons as the acylating reagents. In comparison, none of the desired double acylation products 192f and 192g could be obtained when acid chlorides having α-proton(s), such as propionyl chloride and isobutyryl chloride, were selected as the acylating reagents. In this case, probable formation of the corresponding ketenes for the competing base-catalyzed elimination of HCl from these acid chlorides could lead to other reactions. On the basis of synthesis of 192 via double acylation, Zhou and Pittman196 further described the preparation of 196 through intramolecular double acylation by using α,α-disubstituted diacid chlorides as the diacylating agents (Scheme 47).

Different from the sequential N- and C-acylation reactions of 191 with mono- or diacid chlorides (Schemes 46, 48, and 49), trifluoroacetylations of 191a with the electrophile trifluoroacetic anhydride gave only the mono C-trifluoroacetylation product 199 instead of the N,C-bistrifluoroacetylation product 200 (Scheme 50).199 Compound 200 cannot be obtained because Scheme 50. Synthesis of Trifluoroacetyl Cyclic Ketene N,SAcetals

Scheme 47. Synthesis of Thiazolo[3,2-a]pyridine Derivatives

the trifluoroacetamide function is very reactive toward a nucleophile. As a result, the labile N-trifluoroacetyl function is lost under the workup procedure.87,200−202 Trifluoroacetylation of 181a (generated in situ by deprotonation of the corresponding iodide salts 201) gave both mono- and bistrifluoroacetylated products, 202 and 203, respectively (also see Scheme 9 for the synthesis of bis-trifluoroacetyl ketene N,Sacetals), with the latter as the major product.

When N-(chlorocarbonyl) isocyanate was used as the dielectrophile in place of diacid chlorides, products 197 were prepared in excellent yields via N-acylation and subsequent intramolecular cyclization with 179 as 1,3-C,N-dinucleophile (Scheme 48).196 However, oxalyl chloride, phthaloyl dichloride, and phosgene as diacylating agents were found not to follow the desired cyclization reactions199 since these diacylating agents are

5.3. Preparation of N-Alkyl/Acyl Cyclic Ketene N,S-Acetals

2-Thiazoles are readily available193,203 and are useful starting materials for the synthesis of cyclic ketene N,S-acetals (Scheme 40).192 The first synthesis of 2-methyl- and 2-alkylthiazolines, for 302


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example 191, via thionation of N-(β-hydroxy)amides was reported by Wenker in 1935.204 The first (cyclic) ketene N,Sacetal compound, 204a, was synthesized by Sheehan et al.54 in 1956 and reexamined by Durst and Manoir205 in 1970 through reaction of 191a with phthaloylglycyl chloride (eq 6).

Scheme 52. Synthesis of 2-Alkylthiazolines

Pittman and Zhou prepared a series of N-methyl cyclic ketene N,S-acetals, for example 181, in moderate yields via 191 from the reaction of amino alcohols with acetyl chloride in the presence of TEA, followed by treatment of the generated 205 with P2S5 and further N-alkylation (Scheme 51).192,206,207 Similarly, 208 and 209 were prepared in good yields when methyl 2-phenylacetate and the corresponding amino alcohols were applied, respectively.208,209 Scheme 51. Synthesis of N-Methyl Cyclic Ketene N,S-Acetals

affords 216 in good to excellent yields under mild reaction conditions. Importantly, in this reaction, cyclopropyl thiazolines were formed without any detectable epimerization. In addition, no epimerization at the α-carbon of cysteine residue was detected when optically pure cysteine ethyl ester was selected as the aminothiol component. In tobacco extract, nicotine (Figure 5) had been the best available agent to prevent insects, although it is hazardous to

Figure 5. Structures of nicotine, imidacloprid, and thiacloprid.

human health. Neonicotinoids, as an alternative to nicotine alkaloid, are similar to nicotine in action as agonists of the nicotinic acetylcholine receptor (nAChR) are more toxic to insects than mammals.215 Imidacloprid and thiacloprid (Figure 5) have also been successfully developed from a systematic investigation of nithiazine (see Figure 2). As a cyclic ketene N,Sacetal compound, nithiazine had been the first neonicotinoid lead structure and opened the neonicotinoid era of pest management.30−32 As the nitroketene N,S-acetals, 220, synthesized from 217 via a three-step approach involving S-methylation, condensation with ethyl nitroacetate to form 219, and hydrolysis followed by decarboxylation (Scheme 53, overall yield not given), showed high bioactivity for typical species of lepidoptera.216 However, Rajappa and co-workers 217 found that the attempted reaction of 221 with nitromethane, for synthesis of acyclic nitroketene S,N-acetals, could not occur under identical conditions as described in Scheme 53 or by use of conventional Lewis acid or base as catalyst. Successful condensation between

Without N-alkylation, 210a and 210b, having a stereogenic center at C-4, were obtained in good yields by use of chiral amino alcohols as the reagents (Scheme 51).210 N-Benzoylation of 191 with 2-halobenzoyl chloride gave 211, which underwent stereocontrolled aryl radical cyclization in 6-endo-trig manner in the presence of azodiisobutyronitrile (AIBN) and Bu3SnH to afford pairs of tetrahydrooxazolo[3,2-b]isoquinolin-5-ones, for example, 212a and 212b (eq 7). This report represented the first example where the electron-rich double bond of a cyclic ketene N,S-acetal was used for radical cyclization.210

In a recent report, Samzadeh-Kermani211 described a one-pot procedure for preparation of 1,3-thiazolidine-2-alkylidenes from terminal alkynes, elemental sulfur, and 2-phenyl/n-Pr/TMS/-1tosylaziridines. What should be emphasized here, however, are several useful alternative methods for the synthesis of 191 and analogues, for example, from reactions of β-azido disulfide with carboxylic acid212 or primary thioamides with 2-hydroxyethylamines.213 It was described that amide can be activated by triflic anhydride (Tf2O) to give imino triflates, such as 213, in the presence of a suitable base to neutralize any adventitious acid (Scheme 52).214 Reaction of 213 with 2-aminoethanethiols

Scheme 53. Synthesis of Cyclic Nitroketene N,S-Acetals

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6. SYNTHESIS OF 4-OXOTHIAZOLIDINE DERIVATIVES AND RHODACYANINE ANALOGUES 2-Methylenethiazolidin-4-one has the structural characteristics of cyclic ketene N,S-acetals, such as the bioactive ralitoline and etozolin (Figure 2).28−32 Several synthetic methods for 2methylenethiazolidin-4-one containing compounds have been developed (also see Figure 4 in section 2.2) and are described in this section.

221 and nitromethane to produce 222g was achieved by using a rare-earth exchanged zeolite as the catalyst. Later, the zeolitecatalyzed reaction was explored for synthesis of a series of 222 with various carbonimidodithioic acid dimethyl esters as Scheme 54. Synthesis of Nitroketene S,N-Acetals

6.1. Synthesis of 4-Oxothiazolidine Derivatives

Catalyzed by K2CO3, the reaction of freshly distilled α-mercapto esters with α-acyl-substituted nitriles leads to the formation of 229 having a γ-lactam structure in good yields (Scheme 56).229,230 The configuration of 229d was confirmed by singlesubstrates (Scheme 54).218 The broad peak at about δ 10.5 of 1 H NMR for amino hydrogen of 222 indicates that the alkylamino group is in cis position to the nitro group, due to formation of an intramolecular H-bond.

Scheme 56. Synthesis of (Z)-2-[5-(2-Ethoxy-2-oxoethyl)-4oxothiazolidin-2-ylidene]acetic Acid Derivatives

5.4. Synthesis of Highly Selective Probes for Parallel G4s

In biological systems, the sequences of DNA that forms G4s are prevalent in the genome. The development of molecular probes, especially those with long wavelength for G4 recognition, is an important subject.219,220 Reaction of iodide salt 223 as the precursor of a nucleophile (also see Scheme 50) with 224 as the electrophile in the presence of a base gave salt 225, which condensed with aromatic aldehydes in the presence of a catalytic amount of piperidine to form the desired dyes, such as 226a−c (Scheme 55).221 Scheme 55. Synthesis of Isaindigotone Analogues crystal X-ray determination, and several effects including nonbonded S···O polar interactions were applied as an explanation for the configuration by the authors.230 By use of NaBH4 as the reducing reagent, the ethoxycarbonylmethyl group of 229 can be selectively converted to a hydroxyethyl group.231 In the presence of K2CO3, reaction of 229 with α,ω-dibromides gives the corresponding N-substituted alkyl bromides, such as 232, which can be further converted to fused thiazolidinecondensed five-, six-, and seven-membered heterocycles, for example, the synthesis of 233a−c through a three-step procedure (Scheme 56).232 A series of 229 have been prepared, stereoselectively, in varied yields from nitriles having an α-EWG and α-mercapto esters by conventional methods and under microwave irradiation conditions, respectively (Table 4).233 N-Alkylation of 229 has also been achieved with MeI, BnBr, Br(CH 2 ) 3 Br, or BrCH2CO2Et as alkylating reagent, separately, in moderate to high yields (17 examples, 53−97% yields) under mild conditions with K2CO3 as the base.234 Similarly to cyclic ketene S,S-acetals,6,8 229a−c can be brominated under mild reaction conditions to afford the desired bromo ketene N,S-acetals, which adopt either the Z configuration for 234a/c or the E configuration for 234b, consistent with 1H NMR data for the amino hydrogen (Scheme 57).235−237 Bromo ketene N,S-acetals can be further converted under different conditions, for example, through pyridine-assisted bromine transfer238,239 or functionalization based on DMSOassisted carbon−bromine bond cleavage.240

Compounds 226 (abbreviated as ISTO) have the structural characteristics of both TO (see Figure 1) and isaindigotone.222,223 It has been shown that 226c can be used for visual detection and differentiation of G4s.223 In addition, several cyclic ketene N,S-acetal derivatives, such as ETC,224,225 MTC,226,227 and CSTS228 (Figure 6), have also been prepared as selective probes for parallel G4s.

6.2. Synthesis of Rhodacyanine Analogues

Rhodacyanine dyes consisting of a central 4-oxothiazolidine with exocyclic CC double bond have proven to exhibit antitumor

Figure 6. Selective probes for parallel G4s. 304


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Table 4. Synthesis of 4-Oxothiazolidine Derivatives

Scheme 58. Synthesis of Rhodacyanine Analogues

By the above method, YM-08 (Figure 7), a neutral analogue of MKT-077, was prepared and it was found that YM-08 can bind to Hsp70.245 It was found that JG-98 showed improved potencies against breast cancer cells.246

7. ANNULATION REACTIONS According to the structural features of functionalized ketene N,Sacetals (Figure 1), combination of their multiple reactive sites enables them to potentially act as C2 1,2-dipoles and 1,4-C,Ndipoles, potential azomethine ylides, 1,3-C,N-dinucleophiles, 1,5-N,N-dinucleophiles, C3 1,3-dielectrophiles, and C5 1,5dielectrophiles. These structural features make them versatile building blocks for the synthesis of various heterocyclic ring systems incorporating ketene N,S-acetals and related compounds or reagents.

Scheme 57. Bromination of Cyclic Ketene N,S-Acetals

7.1. [4 + 1] Annulation

Intramolecular cyclization reactions of ketene N,S-acetals enable the synthesis of N-unsubstituted pyrroles (see sections 3 and 4, eq 4, Schemes 23 and 28, and Table 2). Acyl ketene N,S-acetals and cyano ketene N,S-acetals can be easily prepared in high to excellent yields by use of the corresponding more CH acidic methylene compounds as substrates in the presence of a relatively weak base, K2CO3. Mediated by potassium carbonate, reaction of 42 bearing two EWGs (see section 2.2, Scheme 12 and Table 1) as 1,4-C,N-dipoles with ethyl bromoacetate in acetone gave 244 in varied yields via a [4 + 1] annulation (Scheme 59).107

activity.241−243 For instance, MKT-077 (also known as FJ-776, Figure 7) is highly water-soluble and exhibits significant antitumor activity.244

Scheme 59. Synthesis of Polysubstituted Pyrroles via [4 + 1] Annulation

Figure 7. Chemical structures of MKT-077 and analogues.

Recently, Gestwicki and co-workers245,246 reported the synthesis of a series of rhodacyanine analogues, starting with cyclization of substituted anilines with potassium ethyl xanthate, followed by methylation with iodomethane to give benzothiazoles. Reaction of 239 as electrophile after activation by methyl p-toluenesulfonate (MeOTs) with N-substituted rhodanines as active methylene components afforded 241, which finally were converted to 243 via methylation with MeOTs followed by coupling with 1-ethyl-2-methylpyridin-1-ium (for example, to give MKT-077, Scheme 58). 305


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with either 254 or 255 bearing a dimethylamine group (prepared by reaction of 254 with 1 equiv of dimethylamine in benzene at room temperature) as C3 1,3-dielectrophiles (Scheme 62). In

[5 + 1] Annulation is an important and efficient method for regioselective construction of six-membered carbo- and heterocyclic compounds.7,8,167−172,247,248 Although various [5 + 1] annulation reactions, including [5C + 1C] annulation based on ketene S,S-acetals as C5 1,5-dielectrophiles,7,8,168 have been well developed in recent years, [5 + 1] annulation based on ketene N,S-acetals has been rarely explored (see Scheme 34). Singh et al.79 found that, in the presence of KOH as base in DMSO at room temperature, reaction of 20 (see section 2.1, Scheme 6) as the C5 1,5-dielectrophile with functionalized aryl/ heteroaryl methyl ketones as C1 nucleophile furnished 247 (Scheme 60).

Scheme 62. Synthesis of Methylthiopyrazoles

Scheme 60. Synthesis of Substituted Naphthalene via [5C + 1C] Annulation

the reaction of ketene N,S-acetals with hydrazines, the dimethylamine instead of the methylthio group was eliminated, probably due to elimination of the sterically hindered dimethylamino group favoring the formation of intermediate 260. In addition, in both reactions, the corresponding products, isomers 257 and 258, were not observed, showing that the reactions have high chemo- and regioselectivity. Reaction of 64, as a potential azomethine ylide (see Scheme 18), with N-methyl- and N-phenylmaleimide as dipolarophile in dry benzene at reflux leads to the corresponding pyrrolo[1,2a]azepine and pyrrolo[1,2-c][1,4]oxazine derivatives, respectively (37 examples, 45−98% yields).122 For example, 261 was obtained as an E/Z isomer mixture by treatment of (Z)-64a with N-phenylmaleimide, via tandem isomerization, azomethine ylide formation, [3 + 2] cycloaddition, and elimination of methylthiol sequence (Scheme 63).

Reaction of 250 (prepared by amination of the corresponding ketene S,S-acetal with ammonia solution in methanol;249 also see Scheme 2) with aryl aldehydes by heating under solvent and catalyst-free conditions gave 251 in varied yields (Scheme 61, Scheme 61. Synthesis of Substituted Pyrimidin-4(3H)-ones

Scheme 63. Synthesis of Pyrrolo[3,4-a]indolizine Derivatives

nine examples, from 25% up to 90% yields).27 Treatment of 250 as 1,5-N,N-dinucleophile with benzaldehyde in acetic acid at reflux afforded 252a as the precursor of substituted pyrimidin4(3H)-ones, indicating a [5 + 1] annulation from 250 to 251.

Under identical conditions as described above, [3 + 2] cycloaddition reaction of 265 as a masked 1,3-dipole with Nmethyl- or N-phenylmaleimide as dipolarophile gives 266 in high to excellent yields (Scheme 64, 22 examples, 71−95% yields).251−253 It was shown that dimethyl maleate and dimethylacetylene dicarboxylate were also effective dipolarophiles for the [3 + 2] cycloaddition with 265 as masked 1,3dipole.251 However, under similar reaction conditions, none of


[3 + 2] annulation using ketene N,S-acetals as C2 1,2-dipoles, 1,3-C,N-dinucleophiles, or C3 1,3-dielectrophiles has been widely studied. In 1970, Liljefors and Sandström250 reported the regioselective construction of 256 by reactions of hydrazines 306


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Scheme 64. Synthesis of Pyrrolo[3,4-a]pyrrolizin-4-ylidene Derivatives

Table 5. [3 + 2] Annulation with Nitroalkenes

the desired [3 + 2] adduct, such as 268, could be obtained when 267 was used, indicating that the azo function is important, acting as a base to abstract an acidic α-proton adjacent to the iminium nitrogen of intermediate 262 for in situ generation of 263 as the 1,3-dipole. In 2007, Ila and co-workers254 described an efficient route for regioselective construction of N-unsubstituted 2,3,4-trisubstituted pyrroles by 1,3-dipolar cycloaddition of readily accessible 269 (derived from reaction of polarized ketene S,S-acetals with cyclic secondary amines) as C2 1,2-dipole with carbanions derived from activated methylene isocyanides [such as ethyl isocyanoacetate to form 270a−c, tosylmethyl isocyanide (TosMIC) to form 270d, and 4-chlorobenzyl isocyanide to form 270e] (Scheme 65). This reaction allows the introduction In another case, 276c was obtained in 95% yield along with recovery of 275d [having a strong EWG (NO2) on the aryl ring] in 90% yield from the competition reaction of 275d, 275c [having a strong EDG (electron-donating group) on the aryl ring], and 36a (eq 9).255

Scheme 65. [3 + 2] Cycloaddition with Activated Methylene Isocyanides

This [3 + 2] annulation reaction has the advantages of operational simplicity, good to excellent yields, tolerance of a large variety of functional groups, and efficiency. Mechanistic studies showed that either a relatively electron-rich ketene N,Sacetal and nitroalkene are more reactive than the electron-poor ones (Table 5, eqs 8 and 9). A possible mechanism, involving Lewis acid-catalyzed tandem Michael-type addition/intramolecular cyclization/nitrous acid elimination sequence, was proposed (Scheme 66).168,255,256 Scheme 66. Proposed Mechanism for [3 + 2] Annulation of Aroyl/Heteroaroyl Ketene N,S-Acetals with Nitroalkenes of a number of functionalities, including aryl, carbalkoxy, cyano, tosyl, nitro (by reaction of 274 with TosMIC), benzoyl, acetyl, cyclic amines, etc., at the 2,3,4-positions of the resultant pyrrole ring. Catalyzed by In(OTf)3 (where OTf = triflate), the [3 + 2] annulation of 36 (see Scheme 10) as 1,3-C,N-dinucleophile with β-nitrostyrene or analogues as C2 1,2-dielectrophile enabled the synthesis of 276 in good to excellent yields under mild solventfree conditions (Table 5).255 The intermolecular competition reaction of two different aroyl ketene N,S-acetals in an equimolar ratio, containing an electron-donating and electron-withdrawing group on the aryl ring of the aroyl moiety, respectively, with (E)-(2-nitrovinyl)benzene allowed the formation of 276e as the major product (eq 8).255

In research on ketene N,S-acetals as synthetic intermediates of heterocycles,257,258 Takahata, Yamazaki, and co-workers259 found that [3 + 2] annulation of ketene N,S-acetals as C2 1,2dipoles with l,4-quinones allowed the construction of benzo[b]and naphtho[l,2-b]furans in low to moderate yields (16 examples, 8−51% yields). 307


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Recently, Zeng and co-workers260 described a simple procedure for synthesis of a series of N-alkyl ketene N,S-acetals, such as 281, which can be performed in 20 mmol scale by treatment of a ketene S,S-acetal with an aliphatic amine in toluene at reflux. With 281 as C2 1,2-dipole, the desired sulfonamidobenzofuran derivatives can be constructed by reaction with 282 (Scheme 67, 13 examples, 43−76% yields).

Under similar conditions as for synthesis of 287,262 [3 + 3] annulation of 281 with 1-chlorobenzyl isocyanates in dichloromethane at reflux gave the desired 292, and the isocyanates having an electron-poor aryl group as 1,3-dielectrophile led to higher yields of the corresponding 292 (Scheme 69).267

Scheme 67. [3 + 2] Annulation with 4-(NBenzenesulfonyl)quinone Monoamines

Scheme 69. [3 + 3] Annulation with 1-Chlorobenzyl Isocyanates

In this [3 + 2] annulation, ketene N,S-acetals might be activated by CuBr2 through coordination to the alkene double bond of 281, whereas BF3·Et2O plays the role of activating 4-(Nbenzenesulfonyl)quinone monoamines.261

A series of 3,4-dihydropyrimidin-2-ones were also prepared by displacement of the methylthio group of 292 by primary or second amines.267 In another case, the reaction of aroyl ketene N,S-acetals with in situ-generated propiolic acid chloride as the C3 1,3-dielectrophile give the corresponding 6-ethylthiosubstituted pyridin-2(1H)-ones in low to good yields, and these can be be further converted to 6-amino-substituted pyridin-2(1H)-ones by treatment with amines.268 Base-mediated [3 + 3] annulation of 170 with acryloyl or cinnamoyl chlorides as C3 1,3-dielectrophile afforded 294a−g in good to high yields (Scheme 70).269 Interestingly, in the cases


Heating the mixture of 28 (see Scheme 8) as 1,3-C,Ndinucleophile and itaconic anhydride as C3 1,3-dielectrophile in acetonitrile at reflux furnishes 287 via a Michael addition/azaannulation sequence (Scheme 68).262 Under identical reaction Scheme 68. [3 + 3] Annulation with Itaconic Anhydride

Scheme 70. Synthesis of Thiazolo[3,2-a]pyridin-5(3H)-one Derivatives

conditions, a series of 287, including 287e as the major diastereomer, were prepared in moderate to high yields by using various acyclic and cyclic α-oxo and nitro ketene N,S-acetals as 1,3-C,N-dinucleophiles. As a modification of 287, the organocopper-mediated coupling263 of 287g led to the desired product 291 via displacement of the methylthio group by a methyl group (eq 10).262 In this [3 + 3] annulation, itaconic anhydride (the anhydride of itaconic acid),264 accounting for the biomassderived building blocks,264−266 has been successfully applied as the C3 1,3-dielectrophile.

where (E)-but-2-enoyl chloride and 3-methylbut-2-enoyl chloride were used as electrophiles, N-acylation product 295 instead of the desired 294 was obtained.

8. MULTICOMPONENT REACTIONS As powerful tools in organic synthesis for the construction of complex molecules starting from simple and readily available starting materials, multicomponent reactions (MCRs) and domino reactions are cost-effective and efficient as they allow 308


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Scheme 71. Preparation of Tetrahydropyrido[2,1b][1,3]thiazine Derivatives

Scheme 74. Preparation of 4-Amino-1,2-dihydropyridines

Scheme 72. Preparation of Pyrazolo[3,4-b]pyridine Derivatives

Scheme 75. Preparation of Tetrahydrochromen-5-one Derivatives

Scheme 73. Preparation of 5-Nitro-4H-pyran-3-carbonitrile Derivatives

for more than one transformation in a single synthetic sequence.270−272 In the past decade, research on MCRs based on ketene N,Sacetals through combination of their multiple reactive sites toward attack by electrophiles and nucleophiles has emerged. In this regard, several efficient three- and four-component reactions 309


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dipole, aromatic aldehydes, and dimedone (as active methylene component) (eq 11, 10 examples, 76−86% yields) and of 281a, aromatic aldehydes, and 4-hydroxycoumarin (as active methylene component) (eq 12, six examples, 76−86% yields).275 In these reactions, 281a was taken as a two-carbon dipole.

Scheme 76. Preparation of 5-Methylthio-2,3-dihydro-1Hpyrrole and Analogues

Scheme 77. Preparation of Pyrrolo[2,3-b]pyridines, [1,8]Naphthyridines, and Pyrido[2,3-b]-azepines Catalyzed by pyrrolidine in ethanol at reflux,276 309a was obtained in good yield (68%) from the three-component, tandem Knoevenagel condensation/Michael addition/intramolecular cyclization reaction of 281a, 4-chlorobenzaldehyde, and 4-hydroxy-1-methylquinolin-2(1H)-one. In comparison, under similar reaction conditions but with the acidic catalyst ZnCl2 in place of pyrrolidine, 309a could be obtained in excellent yield (92%, eq 13). Thereby, a series of 309 were synthesized in high to excellent yields (15 examples, 85−93% yields). These results show that acidic catalysts (for instance, ZnCl2) may play multiple roles in some cases, in which not only the electrophiles (aldehydes and Knoevenagel adducts) can be activated but also the nucleophiles if all the components of a MCR are compatible with the acidic catalyst.

Catalyzed by L-proline,277 the three-component reaction of 281a, aromatic aldehydes, and 3-methyl-1-aryl-1H-pyrazol-5amines as potential active methylene components leads to 310 (22 examples, 72−83% yields) in high yields (Scheme 72). This reaction can tolerate a variety of aromatic aldehydes bearing either EWG or EDG on the aryl ring. Catalyzed by indium trichloride,278 the three-component reaction of 281a, isatins, and pyrazoles as active methylene components via a domino Knoevenagel condensation/Michael addition/intramolecular O-cyclization gives 313 in high to excellent isolated yields without column chromatographic purification (eq 14, 26 examples, 80−94% yields). However, when the model reaction for synthesis of 313a was examined in the presence of bases such as pyridine, pyrrolidine, piperidine, Lproline, DBU, K2CO3, NaOH, and DMAP in ethanol at reflux temperature, a trace of 313a was observed at longer reaction time, although 313a could be obtained in 70% yield in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) as the base catalyst.

based on nitroketene N,S-acetals and a few other ketene N,Sacetals as the versatile intermediates have been developed. 8.1. Three-Component Reactions

Most three-component reactions are based on nitroketene N,Sacetals. In these reactions, nitroketene N,S-acetals act as either a 1,3-N,C-dinucleophile or two-carbon dipoles. In addition, in situ-generated Michael acceptor is generally required. The piperidine-catalyzed one-pot reaction of commercially available nithiazine (also see Figure 2),273 ethyl cyanoacetate (as the active methylene component), and aryl aldehyde under mild reaction conditions led to formation of 299 as nithiazine analogues in high yields (Scheme 71).274 Under identical conditions, 306 were obtained by using malononitrile as the active methylene component. In this reaction, nithiazine acts the 1,3-N,C-dinucleophile, and 303 as the 1,3-carbon electrophile is formed from condensation of a methylene component with an aldehyde. Preliminary bioassays indicated that most of the nithiazine analogues showed moderate insecticidal activity against Aphis craccivora. In addition, catalyzed by piperidine in ethanol at room temperature, highly functionalized chromen-5-ones and pyrano[3,2-c]chromen-5-ones were prepared in high yields from the three-component, tandem Knoevenagel condensation/Michael addition/intramolecular cyclization reactions of 281a as C2 1,2-

Under identical conditions as described above, the threecomponent reaction of 281a, 4-bromobenzaldehyde, and 3310


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Scheme 78. Preparation of Hexasubstituted 1,4-Dihydropyridines

condensation between aldehyde and dimedone to give Knoevenagel adduct 324, Michael-type addition of 36 to 324 to generate intermediate 325,followed by intramolecular Ocyclization and elimination of MeSH, was proposed. Under similar reaction conditions as above with 4-hydroxycoumarin in place of dimedone, a series of 327 were obtained in high yields. In 2006, Müller and co-workers286 described a three-step synthesis of ketene N,S-acetals, for example 311a (Scheme 76), in moderate overall yields (35−65%) starting from 328 through thionation with Lawesson’s reagent.283−286 This procedure involves thionation of 328a to form 329a, methylation of 329a with methyl iodide to give S-alkylated iodide salt 330a, and finally treatment of 330a with potassium tert-butoxide to furnish 311a. The consecutive one-pot, three-component reaction of an electron-poor aryl/heteroaryl halide, a terminal propargyl Ntosylamine, and 331 can furnish 332, 333, and 334, respectively, in moderate to good yields (Scheme 77, 10 examples, 31−66% yields).286 The resultant heterocycles are highly fluorescent and partially pH-sensitive. A mechanism involving a Pd-catalyzed C− C coupling−isomerization−enamine addition−cyclocondensation sequence was proposed. As a three-component reaction based on 281, Rao and Parthiban287 described a one-pot pseudo-three-component reaction of 2 equiv of 281 with 1 equiv of aldehyde catalyzed by 2-aminopyridine in ethanol at reflux to give 335 in good to excellent yields (Scheme 78, 21 examples, 56−92% yields). The structure of 335i was confirmed by X-ray analysis. The resultant products 335 can precipitate out of the reaction mixture, and simple filtration is enough to gather the products without the need for workup or column chromatography. As a probe for preparation of 335a under otherwise similar conditions, it was shown that tertiary amines (DMAP, DBU, TEA), pyridine, and K2CO3 are not efficient catalysts (10−30%

cyanoacetylindole afforded the desired product, 314a, in 65% yield.279 After optimization of the reaction conditions, 314a was obtained in 93% yield when the reaction was assisted by microwave irradiation and performed under solvent-free conditions (Scheme 73). Higher product yield and shorter reaction time were observed for the substrates containing EWGs on both the aryl ring of aryl aldehydes and at the 5-position of the indole ring of 314 (Scheme 73, 16 examples, 84−93% yields). In addition, by use of 2-azidobenzaldehyde as the aryl aldehyde component, the three-component reaction led to formation of 315 in high yield (87%), which can be further converted to 317 by [3 + 2] cycloaddition with phenyl acetylenes. Catalyzed by InCl3 under solvent-free conditions, the threecomponent reaction of 36 (see Scheme 10), aryl aldehydes, and malononitrile afforded 317 in good to high yields (16 examples, 66−89% yields; the structure of 317b was confirmed by X-ray single-crystal diffraction analysis) via a tandem Knoevenagel condensation/aza-Michael addition/cyclization sequence (Scheme 74).280 A possible mechanism for the formation of 317 was given by this report, which involves a rarely known intermolecular 1,2-addition of the carbon atom at the acceptor end of ketene N,S-acetal to the cyano carbon of Knoevenagel adduct 320 generated from aldehyde and malononitrile. Because the aza-Michael addition of an amine to a Michael acceptor is general,281,282 it is possible that an intermolecular aza-Michael addition is the key step, which can further lead to the desired 1,2dihydropyridine ring by intramolecular cyclization and subsequent isomerization (see the mechanism at the bottom of Scheme 74). The one-pot three-component reaction of 36, aromatic aldehydes, and dimedone in the presence of DABCO under solvent-free conditions enables the synthesis of 323 in high yields (Scheme 75).109 A mechanism involving Knoevenagel 311


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Table 6. Synthesis of 8-Nitrothiazolo[3,2-c]pyrimidine Derivatives

condition A product

R

344a 344b 344c 344d 344e 344f 344g 344h 344i 344j 344k 344l 344m 344n 344o

(R)-(+)-1-phenylethyl (R)-(+)-1-phenylpropyl (S)-(−)-1-phenylpropyl butyl propyl cyclohexyl benzyl 3-trifluoromethylbenzyl 2-methylthienyl 4-chlorobenzyl isopropyl diphenyl benzo[d-1,3]dioxol-5-yl 4-fluorophenyl p-tolyl

condition B

time, h yield, % time, min 2.5 2.5 2.0 3.0 3.5 2.5 4.0 5.0 4.0 4.0 3.5 3.0 6.0 5.0 6.0

92 70 94 41 35 82 65 77 70 63 78 70 42 58 32

Scheme 80. Preparation of Chromenopyrazoles

5 4 4 4 4 4 4 4 4 4 4 4 7 4 4

yield, % 100 95 100 65 65 100 95 98 80 80 100 100 72 76 55

yields), while secondary amines (L-proline, piperidine, pyrrolidine) give moderate yields of 335a (36−46%). In primary amines, benzylamine, ethyl amine, aniline, and 4-aminopyridine enabled the formation of 335a in 71%, 62%, 62%, and 71% yield, respectively.287 The pseudo-three-component reaction may proceed via formation of an imine (from an aldehyde and 2aminopyridine) Mannich-type reaction to give intermediate 336. As a crucial step, formation of the relatively stable carbanion intermediate 340 seems necessary, which probably undergoes cyclization although 2-aminopyridine (or a primary amine) is not a suitable leaving group (Scheme 78). The methylthio group in products 335 can be displaced with primary or secondary aliphatic amines to give the corresponding 343 in high to excellent yields (eq 15, nine examples, 80−98% yields).287

Scheme 79. Preparation of Pyranopyrazoles

8.2. Four-Component Reactions

Very recently, several reports about four-component reactions based on functionalized ketene N,S-acetals have emerged. Promoted by microwave heating (Table 6, method B) or conventional heating (Table 6, method A),288 344 were obtained (15 examples) by a pseudo-four-component reaction of 170 (see Scheme 39), formaldehyde (37% v/v solution), and aliphatic or aromatic amines in water. In comparison, yields of 344 were higher and reaction times were much shorter with microwave heating than conventional heating. However, when amines such as thiazol-5-amine, 6-methylpyridin-2-amine, 5amino-1H-benzo[d]imidazole-2-thiol, naphthalen-1-amine, or 6-nitroquinolin-5-amine were selected as the amine component, none of the desired product can be obtained under either 312


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hydes as the aromatic aldehyde components, 353 can also be prepared in high yields via a similar mechanism for the formation of 348 but involving a preferred intramolecular phenolic Ocyclization leading to construction of the chromene ring (Scheme 80).289 A direct preparation of highly diversified thiazoloquines has recently been reported by Singh and co-workers290,291 through a four-component reaction with 357, cysteamine, aldehydes, and cyclic 1,3-diketones in water−PEG-400 [where PEG = poly(ethylene glycol)] under catalyst-free conditions (Scheme 81). This domino process can form two rings by concomitant formation of two C−C, two C−N, and one C−S bond, presumably via a sequence of N,S-acetal generation,292 Knoevenagel condensation, conjugate addition, and N-cyclization. For this four-component reaction, a broad range of substrates 357, bearing at the R1 position both electron-rich and electronpoor aryl, heteroaryl, extended aromatic, and alkyl groups, can be employed. In addition, aromatic aldehydes and 1,3-cyclohexanediones are also tolerated well. However, isobutyraldehyde is not a suitable aldehyde component for this four-component reaction (products 358u−w), although cyclohexanecarbaldehyde gives a good result (product 358t). Under identical reaction conditions, 363 were prepared in low yields from the four-component reaction with acetylacetone in place of cyclohexane-1,3-diones (Scheme 82). In these cases, most of the components remained unconsumed even after 24 h at reflux temperature. It was also mentioned that the attempted synthesis of corresponding oxazolo- and imidazoloquinolinones by treating 357 with ethanolamine and ethylenediamine, respectively, under similar reaction conditions as above could not obtain the desired cyclic O,N- and N,N-acetals.290

Scheme 81. Synthesis of Thiazoloquinolines under Catalystfree Conditions

9. PERSPECTIVES AND CONCLUSION This review was intended to provide comprehensive coverage of the chemistry of ketene N,S-acetals, which in turn enabled us to find that, in the world of acetals having the push−pull alkene skeleton, ketene N,S-acetal is most likely the biggest family according to the number and types of ketene N,S-acetal compounds. Thus, it is worthwhile to emphasize not only general methods for their synthesis, based on approaches in which various primary or secondary amino groups can be incorporated (section 2), but also diverse schemes from various starting materials, such as 2-alkylthiazolines, thiazolidine-2thiones, bis(alkylthio)-methaneimines, 2,3-dialkylbenzothiazolium halides (section 5.3), lactams (section 8.1), and other approaches including the synthesis of insecticides (section 5.3) and molecular probes (section 6). In comparison, the synthetic applications of ketene N,S-acetal has not been well explored. Taking account of the intrinsic nucleophilicity, distinctive combination of multiple reactive sites, and configurational flexiblility of ketene N,S-acetals in both polar and nonpolar media (Figure 3),58,59,182 further research on ketene N,S-acetals, as the biggest family in push−pull alkenes, may need to be focused on several topics, including (1) synthetic applications of cinnamoyl ketene N,S-acetals in annulation and multicomponent reactions, (2) biomass-derived building blocks as electrophiles, (3) synthetic applications of ketene N,S-acetals having a secondary amino group on the acetal end,132,133 (4) transition-metal-catalyzed reaction (for example, C−H functionalization at the acceptor end), and (5) enantioselective cyclization reactions. In any case, efficient synthesis and synthetic applications of new ketene N,S-acetal species (for

Scheme 82. Preparation of Thiazolopyridines

condition because these amines are more sterically hindered and/or less nucleophilic. The above experimental results support the proposed mechanism involving imine formation between a primary amine and formaldehyde followed by Mannich addition, condensation, and intramolecular aza-Mannich addition. Catalyzed by piperidine under solvent-free conditions,289 a combinatorial library of 348 was constructed in high yields by simple filtration through adding ethanol to the reaction mixture of ethyl acetoacetate, hydrazinehydrate, substituted aromatic aldehyde, and 281 as a two-carbon dipole (Scheme 79). This domino protocol generates biologically significant heterocycles with the formation of one C−C, one CC, one C−N, one C N, and one C−O bond in a single operation via a tandem [3 + 2] cyclization/Knoevenagel condensation/Michael addition/intramolecular annulation sequence. The above reaction tolerated a wide array of aromatic aldehydes, and no obvious electronic effects of the aldehydes were observed. Under identical conditions and using salicylalde313


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example, imino ketene N,S-acetals) are still the main themes of ketene N,S-acetal chemistry.

DABCO 1,4-diazabicyclo[2.2.2]octane DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC dicyclohexylcarbodiimide DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EC50 concentration for 50% of maximal effect Et ethyl EDG electron-donating group EWG electron-withdrawing group FG functional group G4s G-quadruplexes Hsp heat shock protein ISTO isaindigotone thiazole orange KSA ketene silyl acetals MCR multicomponent reaction Me methyl MeOTs methyl p-toluenesulfonate MICs minimal inhibitory concentrations Ms methanesulfonyl MW microwaves nAChR nicotinic acetylcholine receptor NFSI N-fluorobenzenesulfonimide NOESY nuclear Overhauser effect spectroscopy PEG poly(ethyleneglucol) Ph phenyl Pr propyl OTf triflate Selectfluor 1-chloromethyl-4-fluorodiazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) SET single electron transfer TEA triethylamine TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy TFA trifluoroacetic acid Tf2O triflic anhydride THF tetrahydrofuran TO thiazole orange TosMIC tosylmethyl isocyanide tosyl (Tos or Ts) p-toluenesulfonyl VR Vilsmeier reagent

AUTHOR INFORMATION Corresponding Authors

*E-mail [email protected]. *E-mail [email protected]. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest. Biographies Lin Zhang was born in Sichuan, China, in 1986. He received his B.Sc. in chemistry from Northeast Normal University, China, in 2008 and received his Ph.D. in 2014 from the same university under the supervision of Professors Qun Liu and Xihe Bi. His doctoral work mainly focused on the activation of inert chemical bonds catalyzed by transition metals. He joined Professor Bi’s group as a assistant professor to work on transition metal catalyzed transannulation reactions. Jinhuan Dong was born in Xianyang, China, in 1988. He studied chemistry in Tonghua Normal University, China, where he received his bachelor’s degree in science in 2011. He is now pursuing his doctoral studies at Northeast Normal University under the supervision of Professor Qun Liu. His research interests are in the field of synthesis of trifluoromethylated compounds based on pre/postfunctionalization methodologies. Xianxiu Xu was born in Shandong Province, China, in 1975. In 2006, he received his Ph.D. degree at Jilin University under the supervision of Professor Xu Bai. Then he moved to Northeast Normal University and became an associate professor in 2010. He spent 2011−2012 as a postdoctoral fellow in the group of Professor Guofu Zhong and CheolMin Park at Nanyang Technological University. His current research interests are focused on the development of new synthetic methodologies and applications to the synthesis of biologically active molecules. Qun Liu studied chemistry at Northeast Normal University and received his Ph.D. from this university. He spent two years (1990 and 1998) at the University of Southampton and the University of Glasgow under the supervision of Professor P. J. Kocienski. Since 1994 he has been a full professor at Northeast Normal University. His research concerns the development of new synthetic methods and strategies and investigations toward understanding the mechanism.

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ACKNOWLEDGMENTS We thank all authors whose names are listed in the references for their contributions to the chemistry described in this review. We gratefully acknowledge the financial support by the NSFC (21572031, 21502017 and 21272034), and New Century Excellent Talents in Chinese University (NCET-11-0613). ABBREVIATIONS Ar aryl AIBN azodiisobutyronitrile BHT 2,6-ditert-butyl-4-methylphenol Bn benzyl Bu butyl m-CPBA m-chloroperbenzoic acid CuTc copper(I) thiophene-2-carboxylate 314


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