Next Article in Journal
Linearizability of 2:−3 Resonant Systems with Quadratic Nonlinearities
Next Article in Special Issue
On the Question of Stepwise [4+2] Cycloaddition Reactions and Their Stereochemical Aspects
Previous Article in Journal
iPVP-MCV: A Multi-Classifier Voting Model for the Accurate Identification of Phage Virion Proteins
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Symmetry
Volume 13
Issue 8
10.3390/sym13081509
symmetry-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Acyl(imidoyl)ketenes: Reactive Bidentate Oxa/Aza-Dienes for Organic Synthesis

by
Ekaterina A. Lystsova
,
Ekaterina E. Khramtsova
* and
Andrey N. Maslivets
*
Department of Chemistry, Perm State University, ul. Bukireva, 15, 614990 Perm, Russia
*
Authors to whom correspondence should be addressed.
Symmetry 2021, 13(8), 1509; https://doi.org/10.3390/sym13081509
Submission received: 27 July 2021 / Revised: 12 August 2021 / Accepted: 16 August 2021 / Published: 17 August 2021
(This article belongs to the Special Issue Regio- and Stereoselectivity in Cycloaddition Reactions)
Browse Figures
Versions Notes

Abstract

:
Polyfunctional building blocks are essential for the implementation of diversity-oriented synthetic strategies, highly demanded in small molecule libraries’ design for modern drug discovery. Acyl(imidoyl)ketenes are highly reactive organic compounds, bearing both oxa- and aza-diene moieties, conjugated symmetrically to the ketene fragment, enabling synthesis of various skeletally diverse heterocycles on their basis. The highlights of reactions utilizing acyl(imidoyl)ketenes are high yields, short reaction time (about several minutes), high selectivity, atom economy, and simple purification procedures, which benefits the drug discovery. The present review focuses on the approaches to thermal generation of acyl(imidoyl)ketenes, patterns of their immediate transformations via intra- and intermolecular reactions, including the reactions of cyclodimerization, in which either symmetric or dissymmetric heterocycles can be formed. Recent advances in investigations on mechanisms, identifications of intermediates, and chemo- and regioselectivity of reactions with participation of acyl(imidoyl)ketenes are also covered.

1. Introduction

Recently, diversity-oriented synthesis (DOS), a technique for transforming a group of simple and similar starting materials into a collection of more complex and diverse products [1], has become an important trend in drug discovery [1,2,3,4,5,6,7,8,9]. DOS allows us to explore wider chemistry space, including currently deficiently presented (or even vacant) space and, in perspective, space correlating best with needed properties [1]. Implementation of DOS requires available polyfunctional building blocks with studied chemical properties to predict and tune their chemical behavior in the developing strategy. Acyl(imidoyl)ketenes A are well suited to these requirements, as these molecules bear a forked diene fragment consisting of a C=C bond conjugated with geminal C=O and C=N patterns, which enables the development of DOS based on them with an emphasis on skeletal diversity (Scheme 1). Moreover, immediate reactions of some types of acyl(imidoyl)ketenes A afford the formation of symmetric products, which could possibly increase the likelihood of the occurrence of useful biological properties in them [10,11].
Acyl(imidoyl)ketenes A are compounds bearing oxa- and aza-diene reaction centers symmetrically located relative to the heterocumulene (ketene) fragment (Scheme 1), which makes them similar both to acyl- and imidoylketenes, well-studied building blocks widely used in organic synthesis [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]. Therefore, chemical transformations of such hybrid structures as acyl(imidoyl)ketenes A can involve both oxa- and aza-diene fragments.
Acyl(imidoyl)ketenes A belong to the category of highly reactive compounds. Most often, they are generated in the result of the elimination of carbon monoxide (CO) from monocyclic 4-acyl-1H-pyrrole-2,3-diones 1 or their [e]-fused analogs 2 under thermolysis conditions at temperatures above 110 °C (Scheme 2) [36,37,38,39,40]. Another approach to acyl(imidoyl)ketenes A is based on the thermolysis of (quinoxalin-2-yl)furan-2,3-diones 3 (Scheme 2) [41]. Moreover, generation of acyl(imidoyl)ketenes A is possible in the course of Gould–Jacobs reaction via the thermolysis of 2-(aminomethylene)malonates 4 [42,43].
Although acyl(imidoyl)ketenes A are highly reactive, and their isolation seems to be extremely difficult, their formation was instrumentally proven by flash vacuum thermolysis (FVT) studies of 4-acyl-1H-pyrrole-2,3-diones 1 [37,39,40,44,45]. In these experiments, the examined compounds were heated to temperatures of 500–700 °C to achieve a gas phase, and the products of their decomposition were collected by freezing on KBr windows for IR spectroscopy cooled to −196 °C by liquid nitrogen. The IR spectra of these products were registered immediately, and contained a characteristic absorption band at 2122–2140 cm−1, that corresponded to C=C=O fragment of ketenes A. This characteristic band in IR spectra disappeared as the temperature rose to between −105 and −70 °C, which demonstrated instability of acyl(imidoyl)ketenes A.
Such thermal instability of acyl(imidoyl)ketenes A is the origin of their high reactivity. In order to achieve thermodynamic stability, these compounds undergo various chemical immediate transformations, resulting in different heterocyclic compounds, which makes acyl(imidoyl)ketenes A a very interesting group of compounds from the theoretical point of view, as well as promising intermediates in the synthesis of various skeletally diverse heterocycles.
The present review summarizes patterns of immediate transformations of acyl(imidoyl)ketenes via intra- and intermolecular reactions, including the reactions of cyclodimerization, investigations on mechanisms, identifications of intermediates, and chemo- and regioselectivity of reactions with participation of acyl(imidoyl)ketenes. For the sake of simplicity, this review has been divided into three sections. The first shows general information on acyl(imidoyl)ketenes: possible applications in DOS, their structure from a symmetry point of view, approaches to their generation and data on the structure confirmation via FVT. In the second section, data on the immediate transformations of acyl(imidoyl)ketenes by intramolecular reactions are gathered and subdivided by the type of the formed heterocyclic product, while the third section contains data on intermolecular reactions and subdivided to cyclodimerization reactions and reactions with intercepting (trapping) reagents.
As acyl(imidoyl)ketenes A are highly reactive and unstable under the conditions of their generation (above 110 °C), most often, they are undetectable intermediates generated in situ. For this reason, in this review, acyl(imidoyl)ketenes A and other unstable, undetectable intermediates are given in square brackets.

2. Immediate Transformations of Acyl(imidoyl)ketenes via Intramolecular Reactions

2.1. Intramolecular Cyclization of Acyl(imidoyl)ketenes to Quinoline-4(1H)-Ones

Chemical behavior of acyl(imidoyl)ketenes A is dramatically dependent on the presence of nucleophilic centers spatial close to the ketene moiety C=C=O. In particular, substituent at nitrogen atom in imidoyl moiety C=N of acyl(imidoyl)ketenes A can be directly involved in intramolecular cyclizations, and the structure of products of such a transformation will depend on the nature of this substituent.
At thermolysis of 4-acyl-1-aryl-1H-pyrrole-2,3-diones 1.1, N-aryl substituted acyl(imidoyl)ketenes A1 are generated, which undergo intramolecular cyclization through acylation of the ortho CH group of the benzene ring at nitrogen atom by the ketene moiety to result in quinoline-4(1H)-ones 5 (Scheme 3) [36,37,38,40,46,47,48,49,50,51]. The presence of one substituent in the ortho position of the benzene ring at nitrogen atom in 4-acyl-1-aryl-1H-pyrrole-2,3-diones 1.1 and, further, in ketenes A1, does not influence the reaction mode, and does not reduce the yields of compounds 5, which reflects the ease of the intramolecular acylation process [47]. In addition, there is no noticeable effect of substituents in meta positions of the benzene ring at the nitrogen atom on the yield of the target products 5 [50].
There were attempts to trap ketenes A1 generated from monocyclic 1H-pyrrole-2,3-diones 1.1 (Scheme 3) by various reagents (p-methoxybenzaldehyde, benzonitrile, phenol, morpholine, and 2,4-dinitrophenylhydrazone of benzaldehyde) [47]. As a result, no intermolecular products were isolated, and reaction mixtures were turned into unidentified tars.
The mechanism of this transformation was studied using 13C labels under FVT conditions (650 °C, gas phase) and under melting solid conditions (250 °C, phase transition from solid to liquid) [40]. 2,3-13C-Labelled 4-benzoyl-1,5-diphenyl-1H-pyrrole-2,3-dione 1.1 was used as a starting material (Scheme 4). Under FVT conditions, a ketene–ketene rearrangement proceeding through a 1,3-shift of phenyl group with the formation of quinolones 5′, 5″ was observed. However, under common melting solid conditions of the starting pyrroledione 1.1, no rearrangement was observed, and quinolone 5‴ was a single product.

2.2. Intramolecular Cyclization of Acyl(imidoyl)ketenes to Furo[3,2-c]isoquinoline-2-Ones and 4-Aminofuran-2-Ones

Thermolysis of 4-acyl-1-benzyl-1H-pyrrole-2,3-diones 1.2 leads to the formation of acyl(N-benzylimidoyl)ketenes A2 (Scheme 5) [52]. N-Benzyl substituent plays an important role in further transformations of compounds A2 bearing it. Thus, acyl(N-benzylimidoyl)ketenes A2 undergo a [1,5]-prototropic shift (proton migrates from methylene group in benzyl moiety to the oxygen atom of acyl group) to result in hydroxyalkenyl ketenes B which undergo either intramolecular cyclization/reduction to 4-aminofuran-2-ones 6 or double intramolecular cyclization to 4,5-dihydrofuro[3,2-c]isoquinoline-2(3H)-ones C. Then, intermediates C are oxidized to furo[3,2-c]isoquinolin-2-ones 7 (Scheme 5).

2.3. Intramolecular Cyclization of Acyl(imidoyl)ketenes to Furo[3,2-b]quinoxalines

Thermolysis of N5-unsubstituted 3-acylpyrroloquinoxalinetriones 2.1 (analogs of 4-acyl-1H-pyrrole-2,3-diones 1 discussed in the above sections, in which pyrrole core is fused with quinoxaline fragment) results in the formation of N4-unsubstituted acyl(quinoxalin-2-yl)ketenes A3, in which imidoyl fragment C=N is a part of quinoxaline substituent (Scheme 6). Acyl(quinoxalin-2-yl)ketenes A3 cannot undergo intramolecular cyclization to quinoline-4(1H)-ones 5, as the ortho CH group of the benzene ring at N1 atom is spatially too far away from ketene moiety C=C=O. However, N4-unsubstituted acyl(quinoxalin-2-yl)ketenes A3 still undergo intramolecular cyclization, in contrast to their N4-substituted analogs, which are discussed below (Section 3.1.1 and Section 3.2). N4-Unsubstituted acyl(quinoxalin-2-yl)ketenes A3 exist as two tautomers, amide and hydroxyimine. Hydroxyimine form contains OH group prone to react with ketene moiety to form furo[3,2-b]quinoxalines 8 [53,54,55] (Scheme 6). It should be mentioned that there were attempts to trap ketenes A3 by various dienophiles, but all of them were unsuccessful [55].

2.4. Intramolecular Cyclization of Acyl(imidoyl)ketenes to Benzo[e]pyrazolo[5,1-b][1,3]oxazines

Installation of methyleneamino substituent at nitrogen atom of 4-acyl-1H-pyrrole-2,3-diones 1.3 enables generation of peculiar acyl(imidoyl)ketenes A4 prone to intramolecular cyclization to zwitterions D1 (their bromine-free analogs are thoroughly discussed below (Section 3.1.2 and Section 3.2)), through intramolecular attack of nitrogen atom of methyleneamino substituent on ketene moiety C=C=O (Scheme 7). As ketenes A4 bear (((2-bromophenyl)(phenyl)methylene)hydrazono) substituent, brominated zwitterions D1 undergo further intramolecular cyclization to brominated benzo[e]pyrazolo[5,1-b][1,3]oxazines E. Then, 1,3-sigmatropic shift of bromine occurs in intermediates E to result in intermediates F, which react with water to afford benzo[e]pyrazolo[5,1-b][1,3]oxazines 9 (Scheme 7) [56].
Interestingly, in the case of ketenes A4 bearing (((2-bromophenyl)(phenyl)methylene)hydrazono) substituent, formation of dimer compounds (which are discussed below (Section 3.1.2)) is not observed. In order to explain this fact, the mechanism of their transformation to compounds 9 and possible dimers was investigated by density functional theory (DFT) calculations [56]. The simplest system, A4′, was used for the modelling (Scheme 8). It was found that the two transformations (path A to the model of compounds 9 and path B to the model of dimers) had a common, intermediate zwitterion, D1′, formed via transition state TS1. Then, in path A, intermediate E′ was formed via the transition state TS2 in the result of a 6π-electrocyclic ring closure in intermediate D1′. After that, intermediate E′ underwent a [1,3]-Cl shift via the transition state TS3 to afford compound F’, the model of compounds 9. In alternative path B, zwitterion D1′ underwent dimerization in two stages. Firstly, polar dimeric structure G was formed via the transition state TS4. Secondly, structure G cyclized to form structure H, model of dimers, via the transition state TS5. The free energy barriers calculations for the two alternative modes of transformation of ketene A4′ revealed that structure F′ should be formed in the result of both the kinetical and thermodynamical control. Additionally, the formation of structure H should be an accessible process. The exclusive formation of structure F′ (Scheme 8) was explained by the lower thermodynamic stability of dimer H in relation to structure F′ and the entropic acceleration of the intramolecular cyclization process (path A) in comparison with the intermolecular dimerization (path B) [56].

2.5. Intramolecular Cyclization of Acyl(imidoyl)ketenes to 1,8-Naphthyridines and 4H-Pyrido[1,2-a]pyrimidines

Thermolysis of diethyl 2-((pyridin-2-ylamino)methylene)malonates 4 leads to acyl(imidoyl)ketenes A5, which immediately undergoes intramolecular cyclization via acylation by ketene moiety of one of two reaction centers to afford 1,8-naphthyridines 10 (attack on the ortho-CH group) and/or 4H-pyrido[1,2-a]pyrimidines 11 (attack on the ortho-N atom) (Scheme 9) [42,43]. 4H-Pyrido[1,2-a]pyrimidines 11 are major products of this transformation under FVT (gas phase, contact times of 0.3 s, 450 °C) conditions and are kinetic products. While in solution phase, the regioselectivity is highly dependent on the substituent position, as the cyclization is controlled by steric characteristics. Moreover, 1,8-naphthyridines 10 are formed as a result of thermal rearrangement of 4H-pyrido[1,2-a]pyrimidines 11 and, thus, are considered to be thermodynamic products.
In order to explain the regioselectivity of this transformation, DFT calculations of cyclization of ketene A5 were performed (Scheme 10) [43]. According to the results of DFT calculations, after the formation of ketene A5, it underwent intramolecular cyclization at the nitrogen of the pyridyl-moiety to the kinetic product 11 via the transition state TS6. Then, product 11 rearranged to intermediate I via the transition state TS7. Finally, product 11 was tautomerized to the thermodynamic product 10. It should be emphasized that ketene A5 was found to be unable to cyclize directly to intermediate I, as a corresponding intermediate or transition state were not located [43]. These results indicated that thermodynamic product 10 could only be formed from kinetic product 11.

3. Immediate Transformations of Acyl(imidoyl)ketenes via Intermolecular Reactions

Some structural features in the substituents of acyl(imidoyl)ketenes A make ketenes A unable to undergo reactions of intramolecular cyclization. In such cases, acyl(imidoyl)ketenes A become able to participate in reactions with themselves (dimerization) or other reagents (interception).

3.1. Dimerization Reactions of Acyl(imidoyl)ketenes

Depending on the structural features of the substituents in acyl(imidoyl)ketenes A, their dimerization reactions can proceed through either [4+2]-cycloaddition reactions or zwitterionic ones.

3.1.1. Cyclodimerization Reactions of Acyl(imidoyl)ketenes via [4+2]-Cycloaddition

As acyl(imidoyl)ketenes A bear C=C–C=N and C=C–C=O diene fragments, which, hypothetically, can react with one another intermolecularly, both as dienes and dienophiles, one can assume that a difficult mixture of products would be formed in such reactions. However, experimental studies of cyclodimerization reactions of acyl(imidoyl)ketenes A have shown that, in their case, the reaction proceeds selectively, where one ketene A molecule acts as C=C–C=N diene, and the other as C=C dienophile, to form corresponding pyridine derivatives 12 (Scheme 11) [57,58,59,60,61,62,63].
This pattern of cyclodimerization is a characteristic of acyl(imidoyl)ketenes A generated from 4-acyl-1H-pyrrole-2,3-diones 2 fused at [e]-side with a heterocyclic fragment. Such acyl(imidoyl)ketenes A cannot undergo intramolecular cyclization (except for some cases such as N4-unsubstituted acyl(quinoxalin-2-yl)ketenes A3, Section 2.3), as ortho CH group of the benzene ring at N1 atom or other nucleophilic centers are spatially too far away from ketene moiety C=C=O (Scheme 12). For example, such a pattern of immediate transformations is observed in the case of N4-phenyl substituted acyl(quinoxalin-2-yl)ketenes A6 generated from N5-phenyl substituted 3-acylpyrroloquinoxalinetriones 2.2 (Scheme 12) [57]. These N4-phenyl substituted acyl(quinoxalin-2-yl)ketenes A6 undergo cyclodimerization via [4+2]-cycloaddition pathway, in which one ketene molecule plays the role of aza-diene, and the other one acts as C=C dienophile, to form 9-(3-oxo-3,4-dihydroquinoxalin-2-yl)-5H-pyrido[1,2-a]quinoxaline-6,8,10(9H)-triones 12.1 (Scheme 12) [57].
Interestingly, acyl(imidoyl)ketenes A6–A8 of this type, bearing aroyl substituent COAr as acyl group, participate in the same type of cyclodimerization as their alkoxycarbonyl COOAlk analogs (structures A6, Scheme 12), but formed products 12 undergo 1,3-acylotropic shift to result in compounds 13 (Scheme 13) [58,59,60,61,62,63].

3.1.2. Dimerization Reactions of Acyl(imidoyl)ketenes via Intramolecular Cyclization of Them to Zwitterions

Immediate transformation of acyl(imidoyl)ketenes A bearing methyleneamino substituent at nitrogen atom is accompanied by the formation of zwitterions D, existing in two tautomeric forms, 1,3-CNN-dipole and 1,4-CNCO-dipole (Scheme 14) [64,65].
These types of methyleneamino substituted acyl(imidoyl)ketenes A9 are readily generated from 1-[(diphenylmethylidene)amino] substituted 4-acyl-1H-pyrrole-2,3-diones 1.4 (Scheme 15) [64,65]. Formed zwitterions D2 undergo dimerization reaction through two possible pathways in the dependence on the type of acyl substituent COR. When acyl substituent is pivaloyl (R = t-Bu), zwitterions D2 participate in [3+3]-cycloaddition reaction as 1,3-dipoles to form symmetric tetrazines 14, and when acyl substituent is aroyl (R = Ar), zwitterions D2 participate in [4+4]-cycloaddition reaction as 1,4-dipoles to form symmetric bis-pyrazolodioxadiazocines 15 (Scheme 15). Formation of compounds 15 is a reversible process, which is indicated visually by the change of their solutions’ color from colorless to dark blue when their solutions are heated, and vice versa, when cooled [64,65]. Due to this property, compounds 15 can be successfully used in synthetic procedures as a source of zwitteriones D2 [65].
It should be emphasized that formation of compounds 14, 15 is not observed in the case of similar ketenes A4 bearing (((2-bromophenyl)(phenyl)methylene)hydrazono) substituent, apparently due to the fact that corresponding zwitterions D1 quickly undergo intramolecular cyclization to benzo[e]pyrazolo[5,1-b][1,3]oxazines 9 (Scheme 9, Section 2.4) [56].
In addition, 1-diphenylamino substituted 4-acyl-1H-pyrrole-2,3-diones 1.5 do not afford acyl(imidoyl)ketenes A10 prone to formation of zwitterions (Scheme 16) [66]. Instead, when heated, compounds 1.5 undergo a kinetically controlled isomerization to 1,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-2,3-diones 16. Further heating of pyrrolo[2,3-b]indole-2,3-diones 16, which have a benzoyl substituent at C3a, results in isomerization to thermodynamically stable N-(2-(1,2-diphenyl-1H-indole-3-yl)-2-oxoacetyl)benzamide 17 (Scheme 16). However, the heating an analogous pyrrolo[2,3-b]indole-2,3-dione 16, bearing an ester group at C3a, leads to another thermolysis product, ethyl 1,2-diphenyl-1H-indole-3-carboxylate 18 (Scheme 16).

3.2. Interception Reactions of Acyl(imidoyl)ketenes

Acyl(imidoyl)ketenes A6–A9 capable to participate in dimerization reactions are able to take part in reactions with some other reagents (interception reactions) to form various heterocycles. Alkenes, imines, carbonyl compounds, nitriles, isocyanides, carbodiimides, etc. can act as interceptors (trapping reagents).

3.2.1. Interception Reactions of Acyl(imidoyl)ketenes with Alkenes

Zwitterions D2, formed as a result of intramolecular cyclization of methyleneamino substituted acyl(imidoyl)ketenes A9, react with alkenes 18 to afford pyrazolo[5,1-b][1,3]oxazines 19 (Scheme 17) [64,67]. This reaction proceeds regioselectively; zwitterions D react as 1,4-CNCO-dipoles, and alkenes 18 react as C=C dipolarophiles. Trapping reagents 18 are added to the reaction mixture after thermolysis of compounds 1.4 is finished.
There are no reports on reactions of other acyl(imidoyl)ketenes A with alkenes, as precursors of these ketenes, compounds 1, 2, react with alkenes 18 at temperatures lower than required for the generation of acyl(imidoyl)ketenes A [38,46], and carrying out this reaction by adding alkenes 18 after the generation of ketenes A is impossible due to the very short lifetime of ketenes A.

3.2.2. Interception Reactions of Acyl(imidoyl)ketenes with Carbonyl Compounds

Acyl(imidoyl)ketenes A8 generated from (quinoxalin-2-yl)furan-2,3-diones 3 react with carbonyl compounds 20 (aldehydes and ketones) to form exclusively 5-(quinoxalin-2-yl)-4H-1,3-dioxin-4-ones 21 (Scheme 18) [68,69]. Trapping reagents 20 are added directly to the reaction mixture before heating. Ketenes A react as oxa-dienes, and carbonyl compounds 20 react as oxa-dienophiles. The reaction proceeds regioselectively, and formation of alternative products, [1,3]oxazino[3,4-a]quinoxalin-3-ones J, is not observed (Scheme 18).
The reaction of acyl(imidoyl)ketenes A8 with allobetulone proceeds in a similar way to result in corresponding derivatives 21 (Scheme 18) [68]. However, a similar reaction of ketenes A8 with camphor does not produce desired derivatives 21 nor derivatives J, and instead products of dimerization of acyl(imidoyl)ketenes A8 to compounds 13.3 are observed [68]. Such a change in regioselectivity of the reaction may be caused by steric difficulties created by the three methyl groups in camphor [68].
In addition, N4-substituted acyl(quinoxalin-2-yl)ketenes A6 generated from N5-substituted 3-acylpyrroloquinoxalinetriones 2.2 do not react with carbonyl compounds 20 [70].
Acyl(imidoyl)ketenes A7 generated from 3-aroylpyrrolobenzoxazinetriones 2.3 nonselectively react with aromatic aldehydes 20 to form a mixture of 3-(4-oxo-4H-1,3-dioxin-5-yl)-2H-benzo[b][1,4]oxazin-2-ones 22 and 1H-benzo[5,6][1,4]oxazino[4,3-c][1,3]oxazine-3,5-diones 23 (Scheme 19) [71]. Trapping reagents 20 are added directly to the reaction mixture before heating. Such a change in selectivity of reaction of acyl(imidoyl)ketenes A7 [71], in comparison with acyl(imidoyl)ketenes A8 [68,69], can be caused by two factors. It can be connected to the influence of heterocyclic substituent incorporating imidoyl moiety C=N of ketenes A or to the influence of reaction temperature (it is much lower in the case of ketenes A8).
Zwitterions D2, formed as a result of intramolecular cyclization of methyleneamino substituted acyl(imidoyl)ketenes A9 or thermal dissociation of symmetric bis-pyrazolodioxadiazocines 15, react with carbonyl compounds 20 (aldehydes or ketones) to afford pyrazolo[5,1-b][1,3]oxazines 24 (Scheme 20) [64,65]. This reaction proceeds regioselectively; zwitterions D2 react as 1,4-CNCO-dipoles, and carbonyl compounds 20 react as C=O dipolarophiles. In the case of synthesis via thermolysis of compounds 1.4, trapping reagents 20 are added to the reaction mixture after thermolysis of compounds 1.4 is finished [64]. In the case of synthesis via thermal dissociation of compounds 15, trapping reagents 20 are added to the reaction before heating, and the reaction can be carried out under solvent-free conditions [65].
Synthetic approach based on generation of zwitterions D2 via intramolecular cyclization of methyleneamino substituted acyl(imidoyl)ketenes A9 obtained from thermolysis of compounds 1.4 is suitable for the reaction with aromatic aldehydes 20 [64], and the approach through thermal dissociation of symmetric bis-pyrazolodioxadiazocines 15 is suitable for reactions with ketones 20 [65]. This can be explained by the fact that products 24, derived from ketones 20, are less thermally stable than their analogs derived from aldehydes 20 and, thus, lower reaction temperatures are required for their synthesis, which is easily achieved in the approach via bis-pyrazolodioxadiazocines 15.

3.2.3. Interception Reactions of Acyl(imidoyl)ketenes with Nitriles and Isocyanides

Acyl(imidoyl)ketenes A8 generated from (quinoxalin-2-yl)furan-2,3-diones 3 react with cyanamides 25 to form 5-(quinoxalin-2-yl)-4H-1,3-oxazin-4-ones 26 as sole products (Scheme 21) [72]. Trapping reagents 25 are added directly to the reaction mixture before heating. Ketenes A8 react as oxa-dienes, and cyanamides 25 react as aza-dienophiles. The reaction proceeds regioselectively, and formation of alternative products, 3H-pyrimido[1,6-a]quinoxalin-3-ones K, is not observed (Scheme 21). It should be mentioned that ketenes A8 do not react with acetonitrile and substituted benzonitriles 27 [72]. In this case, only dimers 13.3 are isolated as products.
In addition, N4-substituted acyl(quinoxalin-2-yl)ketenes A6 generated from N5-substituted 3-acylpyrroloquinoxalinetriones 2.2 do not react with benzonitriles 27 [70]. Additionally, their reaction with cyanamides 25 proceeded before thermal decarbonylation, and unspecified adducts of compound 2.2 with cyanamides 25 were detected as the major components of the reaction mixtures [70].
Zwitterions D2, formed as a result of intramolecular cyclization of methyleneamino substituted acyl(imidoyl)ketenes A9, react with substituted benzonitriles 27 to afford 4H-pyrazolo[5,1-b][1,3,5]oxadiazines 28 (Scheme 22) [64]. This reaction proceeds regioselectively; zwitterions D2 react as 1,4-CNCO-dipoles, and benzonitriles 27 react as C≡N dipolarophiles. Trapping reagents 27 are added to the reaction mixture after thermolysis of compounds 1.4 is finished.
Similar reaction of 1-isocyanoadamantane 29 with zwittreions D2 affords pyrazolo[5,1-b]oxazoles 30 (Scheme 22) [64]. This reaction proceeds regioselectively too; zwitterions D2 react as 1,4-CNCO-dipoles, and 1-isocyanoadamantane 30 react as carbene. Trapping reagent 30 is added to the reaction mixture after thermolysis of compounds 1.4 is finished.

3.2.4. Interception Reactions of Acyl(imidoyl)ketenes with Carbodiimides and Schiff Bases

Acyl(imidoyl)ketenes A8 generated from (quinoxalin-2-yl)furan-2,3-diones 3 react as oxa-dienes with Schiff bases 31 and carbodiimides 32 to form 5-(quinoxalin-2-yl)-2,3-dihydro-4H-1,3-oxazin-4-ones 33, 34 (Scheme 23) [73]. Trapping reagents 31, 32 are added directly to the reaction mixture before heating. The reaction proceeds regioselectively, and no formation of alternative products of cycloaddition at aza-diene system of ketenes A8 is observed.
Interestingly, N4-phenyl substituted acyl(quinoxalin-2-yl)ketenes A6 generated from N5-phenyl substituted 3-acylpyrroloquinoxalinetriones 2.2 react as aza-dienes with Schiff bases 31 to form 1,2-dihydro-3H-pyrimido[1,6-a]quinoxaline-3,5(6H)-diones 35 as sole products (Scheme 24) [54]. Trapping reagents 31 are added directly to the reaction mixture before heating; the reaction can be performed in a solvent-free mode. The reaction proceeds regioselectively, and no formation of alternative products of cycloaddition at oxa-diene system of ketenes A6 is observed [54]. Such a change in regioselectivity of reaction of acyl(imidoyl)ketenes A6 [54], in comparison with acyl(imidoyl)ketenes A8 [73], can be caused rather by the influence of heterocyclic substituent incorporating imidoyl moiety C=N of ketenes A or to the influence of reaction temperature (it is lower in the case of ketenes A8).
However, N4-substituted acyl(quinoxalin-2-yl)ketenes A6 generated from N5-substituted 3-acylpyrroloquinoxalinetriones 2.2 react with carbodiimides 32 to form 1,2-dihydro-3H-pyrimido[1,6-a]quinoxaline-3,5(6H)-diones 36 or 5-(3-oxo-3,4-dihydroquinoxalin-2-yl)-2,3-dihydro-4H-1,3-oxazin-4-ones 37 in dependence on type of acyl substituent COR2 (Scheme 25) [70]. When R2 is aryl, reaction occurs at C=C–C=O system, and compounds 36 are formed, and when R2 is alkoxy or t-butyl, reaction occurs at C=C–C=N system, and compounds 37 are formed. Trapping reagents 32 are added directly to the reaction mixture before heating; the reaction can be performed in a solvent-free mode. The reaction proceeds regioselectively in both cases, and no formation of alternative products of cycloaddition is observed [54].
Such a regioselectivity switch by acyl substituents COR2 (Scheme 25) can be explained by intractability of COOAlk and COBu-t groups to participate in hetero-Diels–Alder reaction.
A similar regioselectivity switch is observed in the case of trapping of acyl(imidoyl)ketenes A7 generated from 3-aroylpyrrolobenzoxazinetriones 2.3 by Schiff bases 31 and carbodiimides 32 (Scheme 26) [61,74]. However, in this case, regioselectivity depends on the type or trapping reagent. Schiff bases 31 promote cycloaddition at C=C–C=N fragment to form 1,2-dihydrobenzo[b]pyrimido[1,6-d][1,4]oxazine-3,5-diones 38, and carbodiimides 32, at C=C–C=O fragment to form 3-(2-imino-4-oxo-3,4-dihydro-2H-1,3-oxazin-5-yl)-2H-benzo[b][1,4]oxazin-2-ones 39. Trapping reagents 31, 32 are added directly to the reaction mixture before heating.

3.2.5. Interception Reactions of Acyl(imidoyl)ketenes with Water

As acyl(imidoyl)ketenes A are highly reactive compounds, they can react with air moisture and moisture from reaction vessels which are not thoroughly dried, solvents, and reagents [54,67]. In these cases, reaction mixtures contain various side products formed as a result of hydrolysis of acyl(imidoyl)ketenes A.
Thus, zwitterions D2, formed as a result of intramolecular cyclization of methyleneamino substituted acyl(imidoyl)ketenes A9, react with water to afford pyrazolones 40 (Scheme 27) [67]. This process is accompanied by formation of benzophenone Ph2CO.
N4-Phenyl substituted acyl(quinoxalin-2-yl)ketenes A6 generated from N5-phenyl substituted 3-acylpyrroloquinoxalinetriones 2.2 react with water to result in corresponding enamines 41 (Scheme 28) [54]. The same hydrolysis pathway is likely typical for other similar ketenes A6-A8, generated from [e]-fused 1H-pyrrole-2,3-diones 2 or furan-2,3-diones 3.

4. Conclusions

There are many examples of various thermolytic reactions in a solvent medium or gas phase (FVT), enabling the generation of highly reactive compounds with symmetric but unequal reaction centers (C=C–C=O and C=C–C=N), acyl(imidoyl)ketenes, the immediate transformation of which can proceed in two patterns, intramolecular cyclization reactions, and intermolecular ones. Immediate reactions of these compounds can afford synthesis of many various heterocycles, which is a desired property for DOS of small molecule libraries for drug discovery.
This review shows that the pattern of immediate transformation of an acyl(imidoyl)ketene dramatically depends on the structure of the substituent at nitrogen atom in imidoyl C=N moiety.
Acyl(imidoyl)ketenes bearing a conformationally free substituents at nitrogen atom in imidoyl C=N moiety are prone to intramolecular cyclizations. At the same time, incorporation in this position of a methyleneamino substituent affords intramolecular cyclization of such ketenes to tautomeric zwitterions that can undergo intermolecular reactions.
Acyl(imidoyl)ketenes bearing a conformationally rigid substituent at nitrogen atom in imidoyl C=N moiety are prone to intermolecular reactions. In such reactions, in dependence on the structure of trapping reagents, such acyl(imidoyl)ketenes can react as oxa-dienes, aza-dienes, and dienophiles.
Thus, this review indicates that a relatively small amount of different types of substituents were installed into molecules of acyl(imidoyl)ketenes. However, even this small amount of substituent variants gave rise to a large number of diverse products. These make acyl(imidoyl)ketenes a promising class of chemical compounds for the development of small molecule libraries, and intriguing objects for investigations of properties of highly reactive chemical species.

Author Contributions

Writing—original draft preparation, E.A.L. and E.E.K.; writing—review and editing, E.E.K.; supervision, A.N.M. and E.E.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Russian Science Foundation, grant number 19-13-00290.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Burke, M.; Schreiber, S. A Planning Strategy for Diversity-Oriented Synthesis. Angew. Chem. Int. Ed. 2004, 43, 46–58. [Google Scholar] [CrossRef]
  2. Collins, S.; Bartlett, S.; Nie, F.; Sore, H.F.; Spring, D.R. Diversity-oriented synthesis of macrocycle libraries for drug discovery and chemical biology. Synthesis 2016, 48, 1457–1473. [Google Scholar] [CrossRef]
  3. Schneider, G. Automating drug discovery. Nat. Rev. Drug Discov. 2018, 17, 97–113. [Google Scholar] [CrossRef] [PubMed]
  4. Pavlinov, I.; Gerlacha, E.M.; Aldrich, L.N. Next generation diversity-oriented synthesis: A paradigm shift from chemical diversity to biological diversity. Org. Biomol. Chem. 2019, 17, 1608–1623. [Google Scholar] [CrossRef] [PubMed]
  5. Dandapani, S.; Marcaurelle, L.A. Current strategies for diversity-oriented synthesis. Curr. Opin. Chem. Biol. 2010, 14, 362–370. [Google Scholar] [CrossRef] [PubMed]
  6. Yi, S.; Varun, B.V.; Choi, Y.; Park, S.B. A Brief Overview of Two Major Strategies in Diversity-Oriented Synthesis: Build/Couple/Pair and Ring-Distortion. Front. Chem. 2018, 6, 507. [Google Scholar] [CrossRef] [Green Version]
  7. Kidd, S.L.; Osberger, T.J.; Mateu, N.; Sore, H.F.; Spring, D.R. Recent Applications of Diversity-Oriented Synthesis Toward Novel, 3-Dimensional Fragment Collections. Front. Chem. 2018, 6, 460. [Google Scholar] [CrossRef] [Green Version]
  8. Jiang, X.; Hao, X.; Jing, L.; Wu, G.; Kang, D.; Liu, X.; Zhan, P. Recent applications of click chemistry in drug discovery. Expert Opin. Drug. Discov. 2019, 4, 779–789. [Google Scholar] [CrossRef]
  9. Gerry, C.J.; Schreiber, S.L. Recent achievements and current trajectories of diversity-oriented synthesis. Curr. Opin. Chem. Biol. 2020, 56, 1–9. [Google Scholar] [CrossRef]
  10. Greer, A.; Wauchope, O.R.; Farina, N.S.; Haberfield, P.; Liebman, J.F. Paradigms and paradoxes: Mechanisms for possible enhanced biological activity of bilaterally symmetrical chemicals. Struct. Chem. 2006, 17, 347–350. [Google Scholar] [CrossRef]
  11. Bai, W.-J.; Wang, X. Appreciation of symmetry in natural product synthesis. Nat. Prod. Rep. 2017, 34, 1345–1358. [Google Scholar] [CrossRef] [PubMed]
  12. Bellus, D.; Aizpurua, J.M.; Kowalczyk, J.J.; Austin, W.F.; Moore, H.W.; Danheiser, R.L.; Oiarbide, M.; Dudley, G.B.; Palomo, C.; Ebner, S.; et al. Science of Synthesis, 23: Category 3, Compounds with Four and Three Carbon Heteroatom Bonds, 1st ed.; Edition Thieme Verlagsgrouppe: Stuttgart, Germany; New York, NY, USA; Rio, Brazil, 2006. [Google Scholar] [CrossRef]
  13. Tidwell, T.T. Ketenes, 2nd ed.; Wiley-Interscience: Hoboken, NJ, USA, 2006. [Google Scholar] [CrossRef]
  14. Fulloon, B.E.; Wentrup, C. Fluoroquinolones from Imidoylketenes and Iminopropadienones, R–N=C=C=C=O. Aust. J. Chem. 2009, 62, 115–120. [Google Scholar] [CrossRef]
  15. McNab, H.; Hill, L.; Imam, S.; O’Neill, W. Regioselective Synthesis of Quinolin-4-ones by Pyrolysis of Anilinomethylene Derivatives of Meldrum’s Acid. Synlett 2009, 2009, 1847–1851. [Google Scholar] [CrossRef]
  16. Presset, M.; Coquerel, Y.; Rodriguez, J. Microwave-assisted domino and multicomponent reactions with cyclic acylketenes: Expeditious syntheses of oxazinones and oxazindiones. Org. Lett. 2009, 11, 5706–5709. [Google Scholar] [CrossRef]
  17. Reber, K.P.; Tilley, S.D.; Sorensen, E.J. Bond formations by intermolecular and intramolecular trappings of acylketenes and their applications in natural product synthesis. Chem. Soc. Rev. 2009, 38, 3022–3034. [Google Scholar] [CrossRef] [Green Version]
  18. Alajarin, M.; Bonillo, B.; Sanchez-Andrada, P.; Vidal, A. Tandem 1,5-hydride shift/1,5-S,N-cyclization with ethylene extrusion of 1,3-oxathiolane-substituted ketenimines and carbodiimides. An experimental and computational study. J. Org. Chem. 2010, 75, 3737–3750. [Google Scholar] [CrossRef]
  19. Gaywood, A.P.; Hill, L.; Imam, S.H.; McNab, H.; Neumajer, G.; O’Neill, W.J.; Matyus, P. Cyclisation reactions of some pyridazinylimidoylketenes. New J. Chem. 2010, 34, 236–242. [Google Scholar] [CrossRef]
  20. Presset, M.; Coquerel, Y.; Rodriguez, J. Periselectivity switch of acylketenes in cycloadditions with 1-azadienes: Microwave-assisted diastereoselective domino three-component Synthesis of α-spiro-δ-lactams. Org. Lett. 2010, 12, 4212–4215. [Google Scholar] [CrossRef]
  21. Leber, S.; Kollenz, G.; Wentrup, C. Synthesis of functionalized macrocyclic derivatives of trioxabicyclo[3.3.0]nonadiene. Beilstein J. Org. Chem. 2012, 8, 738–743. [Google Scholar] [CrossRef]
  22. Nunes, C.M.; Reva, I.; Pinho e Melo, T.M.V.D.; Fausto, R. UV-Laser photochemistry of isoxazole isolated in a low-temperature matrix. J. Org. Chem. 2012, 77, 8723–8732. [Google Scholar] [CrossRef]
  23. Galvez, J.; Castillo, J.-C.; Quiroga, J.; Rajzmann, M.; Rodriguez, J.; Coquerel, Y. Divergent chemo-, regio-, and diastereoselective normal electrondemand povarov-type reactions with α-oxo-ketene dienophiles. Org. Lett. 2014, 16, 4126–4129. [Google Scholar] [CrossRef]
  24. Khlebnikov, A.F.; Novikov, M.S.; Pakalnis, V.V.; Iakovenko, R.O.; Yufit, D.S. Domino reactions of 2H-azirines with acylketenes from furan-2,3-diones: Competition between the formation of ortho-fused and bridged heterocyclic systems. Beilstein J. Org. Chem. 2014, 10, 784–793. [Google Scholar] [CrossRef] [Green Version]
  25. Zavyalov, K.V.; Novikov, M.S.; Khlebnikov, A.F.; Pakalnis, V.V. Selective syntheses of 2H-1,3-oxazines and 1H-pyrrol-3(2H)-ones via temperature-dependent Rh(II)-carbenoid-mediated 2H-azirinering expansion. Tetrahedron 2014, 70, 3377–3384. [Google Scholar] [CrossRef]
  26. Cookson, R.; Barrett, T.N.; Barrett, A.G.M. β-Keto-dioxinones and β,δ-diketo-dioxinones in biomimetic resorcylate total synthesis. Acc. Chem. Res. 2015, 48, 628–642. [Google Scholar] [CrossRef] [PubMed]
  27. Miyamaru, S.; Umezu, K.; Ito, A.; Shimizu, M. Synthesis of multisubstituted dihydroquinoxaline derivatives by tandem N-alkylation and addition reactions of 3-oxoquinoxaline-2-carboxylates. Eur. J. Org. Chem. 2015, 2015, 3327–3337. [Google Scholar] [CrossRef]
  28. Rezvanian, A. An expedient synthesis strategy to the 1,4-dihydropyridines and pyrido[1,2-a]quinoxalines: Iodine catalyzed one-pot four-component domino reactions. Tetrahedron 2016, 72, 6428–6435. [Google Scholar] [CrossRef]
  29. Azev, Y.A.; Kodess, M.I.; Ezhikova, M.A.; Ermakova, O.S.; Berseneva, V.S.; Bakulev, V.A. Reactions of quinoxalin-2-one with β-diketones: A new approach to 6a,7-dihydro-5H-pyrido[1,2-a]quinoxaline-6,8-diones. Mendeleev Commun. 2017, 27, 97–98. [Google Scholar] [CrossRef]
  30. Azev, Y.A.; Ermakova, O.S.; Berseneva, V.S.; Kodess, M.I.; Ezhikova, M.A.; Ganebnykh, I.N. Synthesis of the 6-oxidopyrido[1,2-a]quinoxalinium derivatives from quinoxalin-2-one and aldehydes—New examples of domino reactions. Mendeleev Commun. 2017, 27, 637–639. [Google Scholar] [CrossRef]
  31. Hu, Z.; Dong, J.; Men, Y.; Lin, Z.; Cai, J.; Xu, X. Silver-catalyzed chemoselective [4+2] annulation of two isocyanides: A general route to pyridone-fused carbo- and heterocycles. Angew. Chem. Int. Ed. 2017, 56, 1805–1809. [Google Scholar] [CrossRef]
  32. Kollenz, G.; Wentrup, C. From dipivaloylketene to tetraoxaadamantanes. Beilstein J. Org. Chem. 2018, 14, 1–10. [Google Scholar] [CrossRef] [Green Version]
  33. Soozani, A.; Keivanloo, A.; Bakherad, M. One-pot palladium-catalyzed synthesis of functionalized 10H-pyrido[1,2-a]quinoxalin-10-ones under copper-free conditions. Tetrahedron 2018, 74, 150–156. [Google Scholar] [CrossRef]
  34. Galaverna, R.; McBride, T.; Pastre, J.C.; Browne, D.L. Exploring the generation and use of acylketenes with continuous flow processes. React. Chem. Eng. 2019, 9, 1559–1564. [Google Scholar] [CrossRef]
  35. Luo, J.; Chen, G.-S.; Chen, S.-J.; Liu, Y.-L. Catalyst-free formal [4+1]/[4+2] cyclization cascade sequence of isocyanides with two molecules of acylketene formed in situ from thermal-induced Wolff rearrangement of 2-diazo-1,3-diketones. Sci. Bull. 2020, 65, 670–677. [Google Scholar] [CrossRef] [Green Version]
  36. Kollenz, G.; Igel, H.; Ziegler, E. Uber reaktionen mit cyclischen oxalylverbindungen, 6. mitt.: Synthesen von heterocyclen, 161. Mitt. Monatsh. Chem. 1972, 103, 450–459. [Google Scholar] [CrossRef]
  37. Briehl, H.; Lukosch, A.; Wentrup, C. Reactive nitrogenous molecules from Meldrum’s acid derivatives, pyrrole-2,3-diones, and isoxazolones. J. Org. Chem. 1984, 49, 2772–2779. [Google Scholar] [CrossRef]
  38. Sano, T. Syntheses of heterocyclic compounds containing nitrogen utilizing dioxopyrrolines. J. Syn. Org. Chem. JPN 1984, 42, 340–354. [Google Scholar] [CrossRef]
  39. Kappe, C.O.; Kollenz, G.; Wentrup, C. A Nitroketene to Nitrile Oxide Transformation. J. Chem. Soc. Chem. Commun. 1992, 485–486. [Google Scholar] [CrossRef]
  40. George, L.; Netsch, K.-P.; Penn, G.; Kollenz, G.; Wentrup, C. Oxoketene–oxoketene, imidoylketene–imidoylketene and oxoketenimine–imidoylketene rearrangements. 1,3-Shifts of phenyl groups. Org. Biomol. Chem. 2006, 4, 558–564. [Google Scholar] [CrossRef]
  41. Vasvari-Debreczy, L.; Hermecz, I.; Meszaros, Z.; Dvortsak, P.; Toth, G. Nitrogen bridgehead compounds. Part 6. Ring transformation. Part 3. Thermal cyclization of diethyl 2-(2-pyridylaminomethylene)-succinates and -glutarates. J. Chem. Soc. Perkin Trans. 1980, 1, 227–232. [Google Scholar] [CrossRef]
  42. Wernik, M.; Hartmann, P.E.; Sipos, G.; Darvas, F.; Boese, A.D.; Dallinger, D.; Kappe, C.O. On the Regioselectivity of the Gould−Jacobs reaction: Gasphase versus solution-phase thermolysis. Eur. J. Org. Chem. 2020, 2020, 7051–7061. [Google Scholar] [CrossRef]
  43. Kappe, C.O.; Kollenz, G.; Leung-Toung, R.; Wentrup, C. Methyleneketene-lmidoylketene-oxoketenimine rearrangements. J. Chem. Soc. Chem. Commun. 1992, 487–488. [Google Scholar] [CrossRef]
  44. Kappe, C.O.; Kollenz, G.; Netsch, K.-P.; Leung-Toung, R.; Wentrup, C. Imidoylketene-azetin-2-one-oxoketenimine rearrangement. J. Chem. Soc. Chem. Commun. 1992, 488–490. [Google Scholar] [CrossRef]
  45. Tsuda, Y.; Horiguchi, Y.; Sano, T. Diels-Alder reaction in a polar system. Thermal cycloaddition of 1-phenyl-2-ethoxycarbonyl-3-benzoyl-Δ2-pyrroline-4,5-dione with butadienes. Heterocycles 1976, 4, 1355–1360. [Google Scholar] [CrossRef]
  46. Maslivets, A.N.; Krasnykh, O.P.; Smirnova, L.I.; Andreichikov, Y.S. Five-membered dioxoheterocycles. XII. Thermolysis of 1-aryl-4-aroyl-5-methoxycarbonyl-2,3-dihydro-2,3-pyrrolediones. J. Org. Chem. USSR 1989, 25, 941–948. (In Russian) [Google Scholar]
  47. Abd EI-Nabi, H.A.; Kollenz, G. Reactions of cyclic oxalyl compounds XXXIX. Reactions of 4-ethoxycarbonyl-5-phenyl-2,3-dihydrofuran-2,3-dione with heterocumulenes and Schiff bases. Monatsh. Chem. 1997, 128, 381–387. [Google Scholar] [CrossRef]
  48. Silaichev, P.S.; Kudrevatykh, N.V.; Maslivets, A.N. Five-membered 2,3-dioxoheterocycles: LXXXIII. Synthesis and thermolysis of 1-aryl-4,5-diaroyl-1H-pyrrole-2,3-diones. Russ. J. Org. Chem. 2012, 48, 249–252. [Google Scholar] [CrossRef]
  49. Boteva, A.A.; Krasnykh, O.P.; Fefilova, I.V.; Babushkina, E.B.; Slepukhin, P.A. Methyl 3-aroyl-4-oxo-1,4-dihydroquinoline-2-carboxylates: Synthesis and molecular and crystal structures. Russ. Chem. Bull. 2014, 63, 731–738. [Google Scholar] [CrossRef]
  50. Sarıpınar, E.; Karatas, S. Synthesis and thermolysis of the 2,3-dihydro-1H-pyrole-2,3-diones, pseudopericyclic reactions of formyl(N-phenylimidoyl)ketene: Experimental data and PM3 calculations. J. Heterocycl. Chem. 2005, 42, 787–796. [Google Scholar] [CrossRef]
  51. Aliev, Z.G.; Krasnykh, O.P.; Maslivets, A.N.; Stepanov, O.S.; Andreichikov, Y.S.; Atovmyan, L.O. Chemistry of acyl(imidoyl)ketenes. 4. Synthesis and crystal and molecular structure of 3-benzoyl-4-benzylamino-5-phenyl-5H-furan-2-one. Russ. Chem. Bull. 1999, 48, 2127–2130. [Google Scholar] [CrossRef]
  52. Aliev, Z.G.; Maslivets, A.N.; Golovnina, O.V.; Krasnykh, O.P.; Atovmyan, L.O. Chemistry of acyl(imidoyl)ketenes. 6. Synthesis and the molecular structure of ethyl 2-oxo-2,5-dihydrofuro[2,3-b]quinoxaline-3-carboxylate. Russ. Chem. Bull. 2001, 50, 1317–1319. [Google Scholar] [CrossRef]
  53. Mashevskaya, I.V.; Mokrushin, I.G.; Bozdyreva, K.S.; Maslivets, A.N. Five-membered 2,3-dioxoheterocycles: LXXIII. Synthesis and thermolysis of 3-acylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones. Russ. J. Org. Chem. 2011, 47, 253–257. [Google Scholar] [CrossRef]
  54. Kasatkina, S.O.; Stepanova, E.E.; Maslivets, A.N. Synthesis of pyrimido[1,6-a]quinoxalines via intermolecular trapping of thermally generated acyl(quinoxalin-2-yl)ketenes by Schiff bases. Beilstein J. Org. Chem. 2018, 14, 1734–1742. [Google Scholar] [CrossRef]
  55. Lisowskaya, N.A.; Alajarin, M.; Sanchez-Andrada, P. New cyclization mode of [N-(diarylmethyleneamino)carbonimidoyl]ketenes: Synthesis of 9H-pyrazolo[3,2-b][1,3]benzoxazines. Eur. J. Org. Chem. 2006, 2006, 1468–1475. [Google Scholar] [CrossRef]
  56. Maslivets, A.N.; Aliev, Z.G.; Krasnykh, O.P.; Golovnina, O.V.; Atovmyan, L.O. Chemistry of acyl(imidoyl)ketenes. 8. Thermolysis of 3-Alkoxycarbonyl-5-phenyl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinoxaline-1,2,4-triones. Structure of 2-(3-oxo-4-phenyl-3,4-dihydro-2-quinoxalinyl)-2,4-di(ethoxycarbonyl)-6-phenyl-2,3,5,6-tetrahydro-1H-pyrido[1,2-a]quinoxaline-1,3,5-trione. Chem. Heterocycl. Compd. 2004, 40, 1295–1299. [Google Scholar] [CrossRef]
  57. Silaichev, P.S.; Maslivets, A.N. Two methods for generation of aroyl(quinoxalin-2-yl)ketene. Russ. J. Org. Chem. 2012, 48, 1261–1262. [Google Scholar] [CrossRef]
  58. Lisovenko, N.Y.; Krasnykh, O.P.; Aliev, Z.G.; Vostrov, E.S.; Tarasova, O.P.; Maslivets, A.N. Intermolecular cyclodimerization of aroyl(imidoyl)ketenes generated by thermolysis of 5-aryl-4-imidoyl2,3-dihydro-2,3-furandiones. Chem. Heterocycl. Compd. 2001, 37, 1314–1316. [Google Scholar] [CrossRef]
  59. Maslivets, A.N.; Lisovenko, N.Y.; Krasnykh, O.P.; Tarasova, O.P.; Aliev, Z.G.; Atovmyan, L.O. Chemistry of acyl(imidoyl)ketenes. 7. Synthesis and thermolysis of 5-aryl-4-quinoxalinyl-2,3-dihydrofuran-2,3-diones. Russ. Chem. Bull. 2002, 51, 850–853. [Google Scholar] [CrossRef]
  60. Lisovenko, N.Y.; Yukova, Y.V.; Makhmudov, R.R. Synthesis and analgesic activity of substituted pyridoquinoxalinyl arylates and their hydrolysis products. Pharm. Chem. J. 2014, 47, 593–595. [Google Scholar] [CrossRef]
  61. Maslivets, V.A.; Maslivets, A.N. Five-membered 2,3-dioxo heterocycles: LXXXVIII. Reaction of 3-aroylpyrrolo[1,2-d][1,4]benzoxazine-1,2,4(4H)-triones with N,N′-dicyclohexylcarbodiimide under thermolysis conditions. Russ. J. Org. Chem. 2012, 48, 1233–1237. [Google Scholar] [CrossRef]
  62. Bozdyreva, K.S.; Smirnova, I.V.; Maslivets, A.N. Five-membered 2,3-dioxo heterocycles: L. Synthesis and thermolysis of 3-aroyl- and 3-hetaroyl-5-phenyl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinoxalin-1,2,4-triones. Russ. J. Org. Chem. 2005, 41, 1081–1088. [Google Scholar] [CrossRef]
  63. Semenova, T.D.; Krasnykh, O.P. Chemistry of acyl(imidoyl)ketenes: IX. Synthesis and thermolysis of 3-aroyl-8-chloro-1,2-dihydro-4H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones. Russ. J. Org. Chem. 2005, 41, 1222–1227. [Google Scholar] [CrossRef]
  64. Zhulanov, V.E.; Dmitriev, M.V.; Maslivets, A.N.; Rubin, M. New method for in-situ generation of enolate-iminium 1,4-dipoles for [4+2] and [4+1] dipolar heterocycloaddition reactions. RSC Adv. 2016, 6, 90239–90247. [Google Scholar] [CrossRef] [Green Version]
  65. Zhulanov, V.Е.; Vigovskaya, V.A.; Dmitriev, M.V.; Silaichev, P.S.; Maslivets, A.N.; Rubin, M. Dipyrazolodioxadiazocines as shelf-stable “ready-to-use” precursors for an in situ generation of enolate-iminium 1,4-dipoles: A straightforward atom-economical approach to pyrazolo[5,1-d][1,3,5]dioxazines. Org. Biomol. Chem. 2020, 18, 3382–3391. [Google Scholar] [CrossRef] [PubMed]
  66. Kollenz, G. Zur Fischer-indol-umlagerung sterisch gehinderter systeme, 6. Mitt.: Reaktionen mit cyclischen oxalylverbindungen, 22. Mitt. Monatsh. Chem. 1978, 109, 249–257. [Google Scholar] [CrossRef]
  67. Zhulanov, V.E.; Dmitriev, M.V.; Maslivets, A.N. Thermolysis of 1-(methylideneamino)-1H-pyrrole-2,3-diones. Synthesis of pyrazolooxazines by [4+2]-cycloaddition of azomethine imines to alkenes. Russ. J. Org. Chem. 2017, 53, 1531–1536. [Google Scholar] [CrossRef]
  68. Nekrasov, D.D.; Obukhova, A.S.; Lisovenko, N.Y.; Roubtsov, A.E. Effect of substituents in the cumulene and aryl fragments of aroylketenes on the stereoselectivity of Diels-Alder heteroreaction with mono-, bi-, and polycyclic terpenoids containing a carbonyl group. Chem. Heterocycl. Compd. 2010, 46, 413–418. [Google Scholar] [CrossRef]
  69. Lisovenko, N.Y.; Maslivets, A.N.; Aliev, Z.G. Five-membered 2,3-dioxo heterocycles: XLVI. Reaction of 5-aryl-4-quinoxalinyl-2,3-dihydrofuran-2,3-diones with aldehydes and ketones. Molecular and crystalline structure of 5-(3-p-tolylquinoxalin-2-yl)-4H-1,3-dioxine-2-spiro-2′-adamantan-4-one. Russ. J. Org. Chem. 2004, 40, 1053–1057. [Google Scholar] [CrossRef]
  70. Kasatkina, S.; Stepanova, E.; Dmitriev, M.; Mokrushin, I.; Maslivets, A. Divergent synthesis of (quinoxalin-2-yl)-1,3-oxazines and pyrimido[1,6-a]quinoxalines via the cycloaddition reaction of acyl(quinoxalinyl)ketenes. Tetrahedron Lett. 2019, 60, 151088. [Google Scholar] [CrossRef]
  71. Maslivets, V.A.; Maslivets, A.N. Two pathways in the cycloaddition of 4-nitrobenzaldehyde to acyl(imidoyl)ketene. Russ. J. Org. Chem. 2013, 49, 1092–1093. [Google Scholar] [CrossRef]
  72. Lisovenko, N.Y.; Nekrasov, D.D.; Karmanov, V.I. Thermolytic transformations of 5-aryl-4-quinoxalin-2-ylfuran-2,3-diones in the presence of N-cyano compounds. Chem. Heterocycl. Compd. 2012, 48, 1357–1360. [Google Scholar] [CrossRef]
  73. Lisovenko, N.Y.; Maslivets, A.N.; Aliev, Z.G. Five-membered 2,3-dioxo heterocycles: LII. Reactions of 5-aryl-4-(quinoxalin-2-yl)-2,3-dihydrofuran-2,3-diones with Schiff bases and dicyclohexylcarbodiimide. Crystalline and molecular structure of substituted 2-(4-oxo-3,4-dihydro-2H-1,3-oxazin-5-yl)quinoxalines. Russ. J. Org. Chem. 2007, 43, 117–120. [Google Scholar] [CrossRef]
  74. Aliev, Z.G.; Krasnykh, O.P.; Maslivets, A.N.; Andreichikov, Y.S.; Atovmyan, L.O. Chemistry of acyl(imidoyl)ketenes. 3. Synthesis and structure of l-p-bromophenyl-2-p-methoxyphenyl-4-p-toluoyl-1,2-dihydropyrimidino[4,3-c][1,4]benzoxazine-3,5-dione. Russ. Chem. Bull. 1999, 48, 608–611. [Google Scholar] [CrossRef]
Symmetry 13 01509 sch001 550
Scheme 1. Acyl(imidoyl)ketenes A and some of their DOS possibilities.
Scheme 1. Acyl(imidoyl)ketenes A and some of their DOS possibilities.
Symmetry 13 01509 sch001
Symmetry 13 01509 sch002 550
Scheme 2. Approaches to generation of acyl(imidoyl)ketenes A.
Scheme 2. Approaches to generation of acyl(imidoyl)ketenes A.
Symmetry 13 01509 sch002
Symmetry 13 01509 sch003 550
Scheme 3. Intramolecular cyclization of acyl(imidoyl)ketenes A1 to quinoline-4(1H)-ones 5.
Scheme 3. Intramolecular cyclization of acyl(imidoyl)ketenes A1 to quinoline-4(1H)-ones 5.
Symmetry 13 01509 sch003
Symmetry 13 01509 sch004 550
Scheme 4. The reaction mechanism study using 13C labels (• = 13C; red arrows are for melting solid conditions; blue arrows are for FVT conditions; and in structures of FVT pathway, the 13C labels were in either one of the two positions indicated).
Scheme 4. The reaction mechanism study using 13C labels (• = 13C; red arrows are for melting solid conditions; blue arrows are for FVT conditions; and in structures of FVT pathway, the 13C labels were in either one of the two positions indicated).
Symmetry 13 01509 sch004
Symmetry 13 01509 sch005 550
Scheme 5. Intramolecular cyclization of acyl(imidoyl)ketenes A2 to 4-aminofuran-2-ones 6 and furo[3,2-c]isoquinoline-2-ones 7.
Scheme 5. Intramolecular cyclization of acyl(imidoyl)ketenes A2 to 4-aminofuran-2-ones 6 and furo[3,2-c]isoquinoline-2-ones 7.
Symmetry 13 01509 sch005
Symmetry 13 01509 sch006 550
Scheme 6. Intramolecular cyclization of acyl(imidoyl)ketenes A3 to furo[3,2-b]quinoxalines 8.
Scheme 6. Intramolecular cyclization of acyl(imidoyl)ketenes A3 to furo[3,2-b]quinoxalines 8.
Symmetry 13 01509 sch006
Symmetry 13 01509 sch007 550
Scheme 7. Intramolecular cyclization of acyl(imidoyl)ketenes A4 to benzo[e]pyrazolo[5,1-b][1,3]oxazines 9 via zwitterionic intermediates D1.
Scheme 7. Intramolecular cyclization of acyl(imidoyl)ketenes A4 to benzo[e]pyrazolo[5,1-b][1,3]oxazines 9 via zwitterionic intermediates D1.
Symmetry 13 01509 sch007
Symmetry 13 01509 sch008 550
Scheme 8. DFT calculations of cyclization pathways of imidoylketene A4′.
Scheme 8. DFT calculations of cyclization pathways of imidoylketene A4′.
Symmetry 13 01509 sch008
Symmetry 13 01509 sch009 550
Scheme 9. Intramolecular cyclization of acyl(imidoyl)ketenes A5 to 1,8-naphthyridines 10 and 4H-pyrido[1,2-a]pyrimidines 11.
Scheme 9. Intramolecular cyclization of acyl(imidoyl)ketenes A5 to 1,8-naphthyridines 10 and 4H-pyrido[1,2-a]pyrimidines 11.
Symmetry 13 01509 sch009
Symmetry 13 01509 sch010 550
Scheme 10. DFT calculations of cyclization of acyl(imidoyl)ketene A5.
Scheme 10. DFT calculations of cyclization of acyl(imidoyl)ketene A5.
Symmetry 13 01509 sch010
Symmetry 13 01509 sch011 550
Scheme 11. Generalized scheme of cyclodimerization of acyl(imidoyl)ketenes A.
Scheme 11. Generalized scheme of cyclodimerization of acyl(imidoyl)ketenes A.
Symmetry 13 01509 sch011
Symmetry 13 01509 sch012 550
Scheme 12. Cyclodimerization of acyl(imidoyl)ketenes A6 to 9-(3-oxo-3,4-dihydroquinoxalin-2-yl)-5H-pyrido[1,2-a]quinoxaline-6,8,10(9H)-triones 12.1.
Scheme 12. Cyclodimerization of acyl(imidoyl)ketenes A6 to 9-(3-oxo-3,4-dihydroquinoxalin-2-yl)-5H-pyrido[1,2-a]quinoxaline-6,8,10(9H)-triones 12.1.
Symmetry 13 01509 sch012
Symmetry 13 01509 sch013 550
Scheme 13. Cyclodimerization of acyl(imidoyl)ketenes A6–A8 bearing aroyl substituent COAr to compounds 13 accompanied by 1,3-acylotropic shift.
Scheme 13. Cyclodimerization of acyl(imidoyl)ketenes A6–A8 bearing aroyl substituent COAr to compounds 13 accompanied by 1,3-acylotropic shift.
Symmetry 13 01509 sch013
Symmetry 13 01509 sch014 550
Scheme 14. Immediate transformation of acyl(imidoyl)ketenes A bearing methyleneamino substituent at nitrogen atom to zwitterions D.
Scheme 14. Immediate transformation of acyl(imidoyl)ketenes A bearing methyleneamino substituent at nitrogen atom to zwitterions D.
Symmetry 13 01509 sch014
Symmetry 13 01509 sch015 550
Scheme 15. Pathways of immediate transformation of zwitterions D2 generated from acyl(imidoyl)ketenes A9 to tetrazines 14 and bis-pyrazolodioxadiazocines 15.
Scheme 15. Pathways of immediate transformation of zwitterions D2 generated from acyl(imidoyl)ketenes A9 to tetrazines 14 and bis-pyrazolodioxadiazocines 15.
Symmetry 13 01509 sch015
Symmetry 13 01509 sch016 550
Scheme 16. Thermolysis of 4-acyl-1-(diphenylamino)-5-phenyl-1H-pyrrole-2,3-diones 1.5 without formation of acyl(imidoyl)ketenes A10.
Scheme 16. Thermolysis of 4-acyl-1-(diphenylamino)-5-phenyl-1H-pyrrole-2,3-diones 1.5 without formation of acyl(imidoyl)ketenes A10.
Symmetry 13 01509 sch016
Symmetry 13 01509 sch017 550
Scheme 17. Interception of zwitterions D2, formed from methyleneamino substituted acyl(imidoyl)ketenes A9, by alkenes 18 with formation of pyrazolo[5,1-b][1,3]oxazines 19.
Scheme 17. Interception of zwitterions D2, formed from methyleneamino substituted acyl(imidoyl)ketenes A9, by alkenes 18 with formation of pyrazolo[5,1-b][1,3]oxazines 19.
Symmetry 13 01509 sch017
Symmetry 13 01509 sch018 550
Scheme 18. Interception of acyl(imidoyl)ketenes A8 by carbonyl compounds 20 with formation of 5-(quinoxalin-2-yl)-4H-1,3-dioxin-4-ones 21.
Scheme 18. Interception of acyl(imidoyl)ketenes A8 by carbonyl compounds 20 with formation of 5-(quinoxalin-2-yl)-4H-1,3-dioxin-4-ones 21.
Symmetry 13 01509 sch018
Symmetry 13 01509 sch019 550
Scheme 19. Interception of acyl(imidoyl)ketenes A7 by aromatic aldehydes 20 with formation of 3-(4-oxo-4H-1,3-dioxin-5-yl)-2H-benzo[b][1,4]oxazin-2-ones 22 and 1H-benzo[5,6][1,4]oxazino[4,3-c][1,3]oxazine-3,5-diones 23.
Scheme 19. Interception of acyl(imidoyl)ketenes A7 by aromatic aldehydes 20 with formation of 3-(4-oxo-4H-1,3-dioxin-5-yl)-2H-benzo[b][1,4]oxazin-2-ones 22 and 1H-benzo[5,6][1,4]oxazino[4,3-c][1,3]oxazine-3,5-diones 23.
Symmetry 13 01509 sch019
Symmetry 13 01509 sch020 550
Scheme 20. Interception of zwitterions D2, formed from methyleneamino substituted acyl(imidoyl)ketenes A9 or from bis-pyrazolodioxadiazocines 15, by carbonyl compounds 20 with formation of pyrazolo[5,1-d][1,3,5]dioxazines 24.
Scheme 20. Interception of zwitterions D2, formed from methyleneamino substituted acyl(imidoyl)ketenes A9 or from bis-pyrazolodioxadiazocines 15, by carbonyl compounds 20 with formation of pyrazolo[5,1-d][1,3,5]dioxazines 24.
Symmetry 13 01509 sch020
Symmetry 13 01509 sch021 550
Scheme 21. Interception of acyl(imidoyl)ketenes A8 by cyanamides 25 with formation of 5-(quinoxalin-2-yl)-4H-1,3-oxazin-4-ones 26.
Scheme 21. Interception of acyl(imidoyl)ketenes A8 by cyanamides 25 with formation of 5-(quinoxalin-2-yl)-4H-1,3-oxazin-4-ones 26.
Symmetry 13 01509 sch021
Symmetry 13 01509 sch022 550
Scheme 22. Interception of zwitterions D2, formed from methyleneamino substituted acyl(imidoyl)ketenes A9, by benzonitriles 27 and 1-isocyanoadamantane 29 with formation of 4H-pyrazolo[5,1-b][1,3,5]oxadiazines 28 and pyrazolo[5,1-b]oxazoles 30, respectively.
Scheme 22. Interception of zwitterions D2, formed from methyleneamino substituted acyl(imidoyl)ketenes A9, by benzonitriles 27 and 1-isocyanoadamantane 29 with formation of 4H-pyrazolo[5,1-b][1,3,5]oxadiazines 28 and pyrazolo[5,1-b]oxazoles 30, respectively.
Symmetry 13 01509 sch022
Symmetry 13 01509 sch023 550
Scheme 23. Interception of acyl(imidoyl)ketenes A8 by Schiff bases 31 and carbodiimides 32 with formation of 5-(quinoxalin-2-yl)-2,3-dihydro-4H-1,3-oxazin-4-ones 33, 34, respectively.
Scheme 23. Interception of acyl(imidoyl)ketenes A8 by Schiff bases 31 and carbodiimides 32 with formation of 5-(quinoxalin-2-yl)-2,3-dihydro-4H-1,3-oxazin-4-ones 33, 34, respectively.
Symmetry 13 01509 sch023
Symmetry 13 01509 sch024 550
Scheme 24. Interception of acyl(imidoyl)ketenes A6 by Schiff bases 31 with formation of 1,2-dihydro-3H-pyrimido[1,6-a]quinoxaline-3,5(6H)-diones 35.
Scheme 24. Interception of acyl(imidoyl)ketenes A6 by Schiff bases 31 with formation of 1,2-dihydro-3H-pyrimido[1,6-a]quinoxaline-3,5(6H)-diones 35.
Symmetry 13 01509 sch024
Symmetry 13 01509 sch025 550
Scheme 25. Interception of acyl(imidoyl)ketenes A6 by carbodiimides 32 with formation of 1,2-dihydro-3H-pyrimido[1,6-a]quinoxaline-3,5(6H)-diones 36 or 5-(3-oxo-3,4-dihydroquinoxalin-2-yl)-2,3-dihydro-4H-1,3-oxazin-4-ones 37.
Scheme 25. Interception of acyl(imidoyl)ketenes A6 by carbodiimides 32 with formation of 1,2-dihydro-3H-pyrimido[1,6-a]quinoxaline-3,5(6H)-diones 36 or 5-(3-oxo-3,4-dihydroquinoxalin-2-yl)-2,3-dihydro-4H-1,3-oxazin-4-ones 37.
Symmetry 13 01509 sch025
Symmetry 13 01509 sch026 550
Scheme 26. Interception of acyl(imidoyl)ketenes A7 by Schiff bases 31 and carbodiimides 32 with formation of 1,2-dihydrobenzo[b]pyrimido[1,6-d][1,4]oxazine-3,5-diones 38 or 3-(2-imino-4-oxo-3,4-dihydro-2H-1,3-oxazin-5-yl)-2H-benzo[b][1,4]oxazin-2-ones 39, respectively.
Scheme 26. Interception of acyl(imidoyl)ketenes A7 by Schiff bases 31 and carbodiimides 32 with formation of 1,2-dihydrobenzo[b]pyrimido[1,6-d][1,4]oxazine-3,5-diones 38 or 3-(2-imino-4-oxo-3,4-dihydro-2H-1,3-oxazin-5-yl)-2H-benzo[b][1,4]oxazin-2-ones 39, respectively.
Symmetry 13 01509 sch026
Symmetry 13 01509 sch027 550
Scheme 27. Interception of zwitterions D2, formed from methyleneamino substituted acyl(imidoyl)ketenes A9, by water with formation of pyrazolones 40.
Scheme 27. Interception of zwitterions D2, formed from methyleneamino substituted acyl(imidoyl)ketenes A9, by water with formation of pyrazolones 40.
Symmetry 13 01509 sch027
Symmetry 13 01509 sch028 550
Scheme 28. Hydrolysis of acyl(imidoyl)ketenes A6 with formation of enamines 41.
Scheme 28. Hydrolysis of acyl(imidoyl)ketenes A6 with formation of enamines 41.
Symmetry 13 01509 sch028
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Lystsova, E.A.; Khramtsova, E.E.; Maslivets, A.N. Acyl(imidoyl)ketenes: Reactive Bidentate Oxa/Aza-Dienes for Organic Synthesis. Symmetry 2021, 13, 1509. https://doi.org/10.3390/sym13081509

AMA Style

Lystsova EA, Khramtsova EE, Maslivets AN. Acyl(imidoyl)ketenes: Reactive Bidentate Oxa/Aza-Dienes for Organic Synthesis. Symmetry. 2021; 13(8):1509. https://doi.org/10.3390/sym13081509

Chicago/Turabian Style

Lystsova, Ekaterina A., Ekaterina E. Khramtsova, and Andrey N. Maslivets. 2021. "Acyl(imidoyl)ketenes: Reactive Bidentate Oxa/Aza-Dienes for Organic Synthesis" Symmetry 13, no. 8: 1509. https://doi.org/10.3390/sym13081509

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop