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

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.


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 . Therefore, chemical transformations of such hybrid structures as acyl(imidoyl)ketenes A can involve both oxa-and aza-diene fragments.

Scheme 2. Approaches to generation of acyl(imidoyl)ketenes A.
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.

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.
The mechanism of this transformation was studied using 13 C labels under FVT conditions (650 • C, gas phase) and under melting solid conditions (250 • C, phase transition from solid to liquid) [40]. 2,3-13 C-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. Scheme 4. The reaction mechanism study using 13 C labels (• = 13 C; red arrows are for melting solid conditions; blue arrows are for FVT conditions; and in structures of FVT pathway, the 13 C labels were in either one of the two positions indicated).
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  [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].

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[1,2a]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. Scheme 10. DFT calculations of cyclization of acyl(imidoyl)ketene A5.

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).

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.

oxazines 19.
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.

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- 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.
A similar regioselectivity switch is observed in the case of trapping of acyl(imidoyl) ketenes A7 generated from 3-

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.

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.