1. Introduction

2. Methods and Approaches

2.1. Models for the Description of Superbasic Media

2.2. Calculation Procedure

3. Formation of Pyrroles and Pyrrole-Fused Heterocycles

3.1. Trofimov Reaction

3.2. Self-assembly of 2,5-Dimethyl-1-phenyl-1H-pyrrole from Aniline and Acetylene

3.3. Formation of Pyrrolo[2,1-c][1,4]oxazines

4. Reactions of Ketones with Acetylenes

4.1. Assemblies of 7-Methylidene-6,8-dioxabicyclo[3.2.1]octanes and Cyclopentenols

4.2. Assembly of Substituted Furans

4.3. Assembly of Δ2-Isoxazolines

5. Reactions of Imines with Acetylenes

5.1. Formation of Imidazopyridines

5.2. Formation of Pyrrolines

6. Conclusions

1. INTRODUCTION

The unique properties of acetylene and its deriva­tives give rise to a diversity of reactions with their participation, thus providing the basis for the develop­ment of new reactions and new routes for the synthesis of complex compounds [1–3]. An important and actively developing field of research in this area is the chemistry of acetylene in superbasic media based on suspensions and solutions of alkali metal hydroxides or alkoxides in dimethyl sulfoxide (DMSO) [4]. These systems most clearly revealed the dual nature of acetylene capable of acting as both nucleophile in ethynylation reactions and electrophilic substrates in vinylation reactions. In addition, by the action of strong bases, alkynes can undergo acetylene–allene rearrange­ment to give highly reactive allene structures, as well as fast multi-position migration of the triple bond along the carbon chain.

A striking example of the dual nature of acetylene is its reactions with ketones. The classical ethynylation of ketones with the formation of propargyl alcohols is easy to accomplish but is reversible, and the products dissociate into the initial acetylene and ketone as the temperature rises. On further raising the temperature in superbasic medium, deprotonation of ketone and its addition to the triple bond becomes possible with the formation of β,γ-unsaturated ketones which then can be converted to α,β-unsaturated isomers [5]. This unique reaction gave rise to a huge diversity of assemblies of complex molecular structures from several acetylene and ketone molecules, sometimes with the participation of other nucleophiles (such as hydrazine, hydroxyl­amine, guanidine, etc.), where acetylene alternately acts as electrophile and nucleophile [6].

Recently, it was shown that nitrogen analogs of ketones, ketimines, can be involved in the ethynylation reaction in the presence of superbases with the forma­tion of terminal and internal propargylamines (aza-Favorsky reaction) [7, 8]. The synthetic potential of the reaction of imines with acetylenes is just begins to be revealed, but today it is already possible to synthesize in one pot valuable 1- and 2-azadienes [9, 10], 1-pyr­rolines, 1H- and 2H-pyrroles [11, 12], imidazopyridines [13], etc., depending on the C=N bond nature.

It is difficult to study mechanisms of these reactions by experimental methods because of their multistage nature and high reactivity of compounds involved therein. Therefore, high-level quantum chemical cal­cula­tions, followed by detailed analysis of the results of calculations and experimental data, are necessary to understand their mechanistic features. The present review considers recent results of joint studies per­formed at the Irkutsk Institute of Chemistry (Siberian Branch, Russian Academy of Sciences) and Laboratory of Quantum Chemistry of the Irkutsk State University.

2. METHODS AND APPROACHES

2.1. Models for the Description of Superbasic Media

One of the models of superbasic media used in our studies is based on the concept that a superbase is a complex of an ionized strong base with a ligand which specifically interacts with the base cation in a medium weakly solvating anions (generally, in a polar aprotic solvent) [14]. In this case, reactions can be approximately considered as the transformations with the participation of anions without taking into account interaction with strongly solvated cation. The advantage of this “anionic” model is its compact­ness, which allows it to be applied to fairly large systems. It can also be used to assess the reliability of selected approximations by comparing with the results of preci­sion approaches by example of the simplest reactions for the classes of compounds under study.

Weak solvation of anions is related to the reduced degree of dissociation of salts and bases in DMSO. According to conductometric measurements, the dis­sociation constant of t-BuOK in DMSO is as low as 3.7×10–3, and it decreases to 10–6 in going to t-BuONa; whereas alkali metal methoxides in DMSO dissociate even to a lesser extent [15], and KKOH = 7.9×10–4 [16]. Therefore, we proposed a model of the superbase center including a non-dissociated molecule of alkali metal hydroxide or alkoxide [17]. The formation of the first solvation shell (specific solvation) consisting of five solvent molecules in the case of KOH and t-BuOK or four solvent molecules in the case of NaOH and t-BuONa is accompanied by significant elongation of the M–O bond (M = Na, K). The effect of the remaining part of the solvent (nonspecific solvation) is considered in terms of the continuum model IEF PCM [18]. Analysis of typical ethynylation and vinylation reac­tions in the framework of such pentasolvate (for KOH and t-BuOK) model showed that these reactions gen­erally occur at the periphery of the reaction complex, which rationalizes the suitability in some cases of a simple anionic model. It should be noted that the reacting system remains in contact with the cation tightly surrounded by solvent molecules. Therefore, it is possible, if necessary, to make a correction for the cation nature.

For obvious reasons, the pentasolvate model proved to be quite resource-intensive, and a monosolvate model was proposed for the cases when the inclusion of a cation is necessary. This model comprises one solvent molecule in the explicit form and, in com­bina­tion with PCM, considers both specific and nonspecific solvation [17, 19] with simultaneous saving of com­putational resources. A feature of the monosolvate model is the necessity of considering solvation effects even at the geometry optimization stage, whereas the pentasolvate and anionic models often satisfactorily interpret the geometric structure and normal vibration frequencies for all stationary points, including transi­tion states, even at the gas-phase level.

In the following discussion, we will use the designa­tions PENTA, MONO, and ANION for the above three models with the subscripts indicating inclusion of solva­tion effects at the optimization stage, e.g., PENTAGAS or MONOPCM.

2.2. Calculation Procedure

In our studies, we mainly used the density func­tional method B3LYP/6-31+G* [20, 21] to optimize the geometric parameters and calculate vibrational cor­rec­tions with energy refinement in terms of the double hybrid functional B2PLYP [22] with a dispersion correction [23, 24] and extended basis set 6-311+G**. The combined B2PLYP-D/6-311+G**//B3LYP/ 6-31+G* approach provides good agreement with the results of precision CCSD(T)/6-311+G**//CCSD/ 6-31+G* and CBS-Q//B3 computations of basic acetylene reactions, ethynylation, and vinylation, and also successfully handles such traditionally difficult for popular DFT- and MP2-based approaches problems as the characterization of the propyne–allene rearrange­ment [25–27] and the aldol reaction [28].

Solvation effects were taken into account using the IEFPCM model [18] in combination with the B3LYP/6-31+G* method, which provided fairly consistent description of neutral and anionic species involved in reactions. Furthermore, two additional factors were included to correctly describe free energies in solution, namely change in the entropy in going from an ideal gas to a 1 M solution [ΔS = Rln(1/22.4) = –25.86 J mol–1 K–1] and change of the translational and rotational contributions to the entropy. The latter were estimated on the assumption that different compounds lose the same fraction of entropy while being transferred from the gas phase to the same solvent [29, 30]; this also applies to the solvation of ions [29]. Following the protocol given in [31], for a 1 M solution at 300 K, we eventually obtained Ssol = 0.74Sharm – 3.2 cal mol–1 K–1 [32]. It should be noted that such consideration of the solvent effect in com­bina­tion with the calculation of gas-phase free energies at the B2PLYP-D/6-311+G**//B3LYP/6-31+G* level assesses the CH, NH, OH, and SH acidities with an average error not exceeding two pKa units (in this case, the scaling factor α = 1.35 [33] was used in the IEFPCM model).

The calculations were carried out using Gaussian 09 [34], Gaussian 16 [35], and GAMESS [36] quantum chemical software packages.

3. FORMATION OF PYRROLES AND PYRROLE-FUSED HETEROCYCLES

3.1. Trofimov Reaction

The Trofimov reaction is a classic example of the assembly of heterocyclic compounds from acetylene in superbasic medium. Reactions of acetylene with ketoximes that are easily available from ketones and hydroxylamine provide a straightforward and efficient route to 2,3-substituted 1H-pyrroles [37]. Reaction mechanism suggested by experimental studies was confirmed by the isolation of presumed intermediates; however, some of the postulated inter­mediate products, such as vinyloxyamine and imino­aldehyde, have not yet been detected experimentally. Although this reac­tion was discovered more than 40 years ago, it still attracts researchersʼ attention. A series of theoretical studies of the mechanism of Trofimov reaction have been performed [38–42]; however, these studies were concerned only with separate reaction stages, which did not allow to obtain an integral interaction pattern. As an example of the assembly of 4,5,6,7-tetrahydro-1H-indole from acetylene 1 and cyclohexanone oxime 2 and its subsequent vinylation with acetylene, we studied for the first time all stages of the Trofimov reaction at a uniform theoretical level (B2PLYP/ 6-311+G**//B3LYP/6-31+G*) using the ANIONPCM model [43] (Fig. 1).

Fig. 1.
figure 1

Free energy profile of the Trofimov reaction and N-vinylation of pyrroles; main steps and intermediates are shown.

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It was shown that the most favorable is the fol­low­ing transformation sequence: O-vinylation of ket­oxime 2, 1,3-prototropic rearrangement of O-vinyl oxime 3 to vinyloxyamine 4, [3,3]-sigmatropic shift leading to iminoaldehyde 5, cyclization of 5 to 5-hy­droxy­pyr­roline 6, O-vinylation of 6 to give 5-vinyloxy­pyr­roline 8, formation of 3H-pyrrole 7 through hy­droxide ion-assisted elimination of acetaldehyde mole­cule, and rearrangement to 1H-pyrrole 9. The steps of O-vinyla­tion of ketoxime 2 (2 → 3, ΔG‡ = 24.9 kcal× mol–1) and 5-hydroxypyrroline 6 (6 → 8, ΔG‡ = 24.3 kcal/mol) required the highest energy barrier to be overcome. Vinyloxyamine 4 and iminoaldehyde 5 were found to be unstable compared to the preceding and sub­sequent intermediates, which is responsible for the absence of these structures among those isolated experimentally.

Several versions of the transition of 5-hydroxy­pyr­roline to 3H-pyrrole were proposed. The dehydration of 5-hydroxypyrroline to 3H-pyrrole (6 → 7) was found to be impossible under experimental conditions due to the high activation barrier (ΔG‡ = 46.5 kcal× mol–1). Therefore, 5-vinyloxypyrroline 8 becomes one of the main intermediates; in this case, the high-barrier dehydration of 5-hydroxypyrroline can be avoided, and the reaction can follow more energetically favorable routes through vinylation of 6 and subsequent elimination of acetaldehyde molecule (ΔG‡ ≈ 18.5– 20.5 kcal/mol). Further vinylation of 4,5,6,7-tetrahydro-1H-indole (in the presence of excess acetylene) is characterized by a higher activation barrier than that of its formation step which is the rate-determining step. This is qualitatively consistent with the results of kinetic studies [44]. Our theoretical study significantly supplemented the data on the Trofimov reaction mechanism.

3.2. Self-assembly of 2,5-Dimethyl-1-phenyl-1H-pyrrole from Aniline and Acetylene

The recently discovered one-pot self-assembly of 2,5-dimethyl-1-phenyl-1H-pyrrole from acetylene and aniline in the presence of KOH/DMSO [45] was studied by quantum chemical methods [B2PLYP(D3)/ 6-311+G**//B3LYP/6-31+G* + IEFPCM] using PENTAGAS and MONOPCM models [46]. Two mecha­nisms were proposed. The first mechanism involved triggering of the process by the addition of one acetylene molecule to another with the formation of vinylacetylene 10. In the second mechanism, the reaction is triggered by the addition of aniline 11 to acetylene 1 with the formation of N-vinylaniline 12 (Scheme 1).

Scheme
scheme 1

1.

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Modeling of the addition of anions derived from aniline and acetylene to acetylene using PENTAGAS (Fig. 2) showed a significant kinetic preference of the N-vinylation (ΔΔG‡ = 5.1 kcal/mol). A similar dif­ference (ΔΔG‡ = 3.6 kcal/mol) was obtained using the MONOPCM model. Thus, the mechanism involving N-vinylaniline 12 as intermediate is discussed below as more probable. All subsequent steps were simulated using MONOPCM.

Fig. 2.
figure 2

Transition state structures for the addition of aniline and acetylene anions to acetylene in the presence of the superbase complex KOH·5DMSO.

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The stage of aniline vinylation with acetylene is followed by enamine–imine isomerization (12 → 13) and ethynylation of aldimine 13 at the C=N bond (aza-Favorsky reaction). N-(But-3-yn-2-yl)aniline 14 thus formed can directly add another acetylene molecule at the triple bond (propargyl pathway) or rearrange to N-(buta-2,3-dien-2-yl)aniline 15 which then undergoes ethynylation (allenyl pathway). At the ethynylation step involving 14 or 15, the route through the propargyl structure (14 → 16) is kinetically preferred. The result­ing N-(hex-3-en-5-yn-2-yl)aniline 16 can be converted into both N-(hex-2-en-5-yn-2-yl)aniline 17 and N-(hexa-2,4,5-trien-2-yl)aniline 18 via 1,3-prototropic shift. In contrast, in the final cyclization step, the allenyl pathway for the formation of pyrrole 19 (18 → 19) with regeneration of the superbase complex KOH·DMSO becomes kinetically preferred (ΔΔG‡ = 9.4 kcal/mol) with respect to the propargyl pathway (17 → 19).

The entire cascade self-assembly of 2,5-dimethyl-1-phenyl-1H-pyrrole in the presence of KOH/DMSO includes two rate-limiting steps with similar energy barriers: vinylation of aniline (1 + 11 → 12, ΔG‡ = 22.6 kcal/mol) and ethynylation of intermediate pro­pargyl­amine (14 + 1 → 16, ΔG‡ = 22.8 kcal/mol). The simulated pathways for the formation 2,5-dimethyl-1-phenyl-1H-pyrrole demonstrate the ability of acetylene to act as both electrophile and nucleophile within the same assembly; they also explain the absence of isolable intermediate products in the cascade assembly.

3.3. Formation of Pyrrolo[2,1-c][1,4]oxazines

A promising line of research in organic synthesis in the field of design of pyrrole-fused heterocycles is related to the introduction of an allenyl group into position 1 and an aldehyde group into position 2 of 1H-pyrrole molecule. The reduction of 1H-pyrrole-2-carbaldehyde gave (1H-pyrrol-2-yl)methanol 20 pos­sessing two potential nucleophilic centers, OH oxygen atom and pyrrole nitrogen atom. The reaction of 20 with propargyl chloride 21 could give rise to a variety of products via further reactions of the introduced propargyl group (Scheme 2; 20 + 21 → 22). The latter can easily isomerize to allenyl group under superbasic conditions (22 → 23), and each of these forms can be in­volved in cyclization through the addition of an O-nu­cleophile to the terminal carbon atom (22 → 25, 23 → 27) with the formation of seven-membered oxazepane ring or to the internal carbon atom (22 → 24, 23 → 26) with the formation of six-membered oxazine ring. In addition, the possibility of formation of disubstituted products (22 → 28, 23 → 29) was studied.

Scheme
scheme 2

2.

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Joint theoretical (ANIONGAS, CBS-Q//B3) and experimental studies made it possible to determine most probable chemical transformation pathways for compounds 20a and 21a [47]. It was found that the first step in the superbasic system is exclusively genera­tion of the N-anion while deprotonation of the hydroxy group does not occur. This follows from the higher acidity of 1H-pyrrole compared to methanol in DMSO. Nucleophilic substitution of chlorine by pyrrolide ion to form (N-propargyl-1H-pyrrol-2-yl)­methanol 22a turned out to be the rate-determining step (ΔG‡ = 21.5 kcal/mol). Analysis of further transforma­tions showed that the most probable is isomerization of the propargyl group to allenyl (ΔG‡ = 11.0 kcal/mol) followed by bifurcation. (N-Allenyl-1H-pyrrol-2-yl)­methanol 23a can cyclize to 3-methyl-1H-pyrrolo­[2,1-c][1,4]oxazine 26a (ΔG‡ = 13.2 kcal/mol) and/or attack another propargyl chloride molecule to form disubstituted derivative 29a (ΔG‡ = 12.0 kcal/mol). Due to similarity of the activation barriers, the forma­tion of several products simultaneously is possible. As shown experimentally by our colleagues at the Irkutsk Institute of Chemistry (Siberian Branch, Russian Academy of Sciences), the reaction can be controlled, and each of the three compounds, 23a, 26a, and 29a, can be obtained with high selectivity.

As part of further comprehensive study of this reaction, we examined the effect of substituents on the energy characteristics of particular steps [48]. Intro­duction of a phenyl group into the 5-position of the pyrrole ring (20b) decreased the barrier to cyclization to pyrrolooxazine 26b by 1.3 kcal/mol (ΔG‡ = 11.7 kcal/mol), whereas the barrier to the competing formation of disubstituted product 29b increased by 1.0 kcal/mol (ΔG‡ = 13.0 kcal/mol). According to the experimental data, the reaction with aryl-substituted pyrroles selectively afforded pyrrolooxazines 26.

The presence of a methyl group at the triple bond of propargyl chloride (21c) not only increases the activa­tion barrier at the key reaction steps by 2–5 kcal/mol but also leads to almost complete loss of selectivity due to leveling of the activation barriers for the formation of pyrrolooxazine 26c and pyrrolooxazepine 27c from allenyl structure 23c. It is worth noting that we found no examples in the literature of the formation of pyrrolooxazines from structures with an alkyl group at a multiple bond [49, 50]. We have shown that the synthesis of such fused structures by the above method is not promising due to the low selectivity.

4. REACTIONS OF KETONES WITH ACETYLENES

4.1. Assemblies of 7-Methylidene-6,8-dioxa­bicyclo[3.2.1]octanes and Cyclopentenols

The assembly of 7-methylidene-6,8-dioxabicyclo[3.2.1]octanes was achieved by the superbase-catalyzed (KOH/DMSO) reaction between two acetylene and two ketone molecules [6] (Scheme 3). We performed quantum chemical modeling of the mechanism of this reaction using the ANIONGAS model and aceto­phenone/acetylene (a) [17, 51] and cyclohexanone/ace­tylene (b) systems [52] as examples. In the first system, dioxabicyclo[3.2.1]octanes were formed diastereo­selec­tively (the product molecule can possess up to five asymmetric centers), while in the second, the reaction was not diastereoselective, and mixtures of (usually three) stereoisomeric dioxabicyclo[3.2.1]octanes (tetracyclic frontalins) were formed, one of which prevailed. The assembly of dioxabicyclo[3.2.1]octanes has a cascade nature and is triggered by the C-vinylation of ketones with acetylene 1 (addition of ketone carbanion 30 to acetylene) with the formation of β,γ-unsaturated ketones 31 which then underwent hydroxide ion-promoted barrierless 1,3-prototropic rearrangement to α,β-unsaturated ketones 33 through dienolate ions 32 (Scheme 4). The C-vinylation step has the highest activation barrier and leads to a signif­icant decrease of the free energy (system a: ΔG‡ = 22.5 kcal/mol, ΔG = –24.6 kcal/mol; system b: ΔG‡ = 18.7 kcal/mol, ΔG = –29.1 kcal/mol).

Scheme
scheme 3

3.

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Scheme
scheme 4

4.

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In subsequent steps (Fig. 3), which include the addition of the second ketone carbanion 30 to the β-carbon atom of 33 with the formation of 1,5-diketone 34 (Michael reaction), addition of ethynide ion 35 to the carbonyl group of diketone 34 to give hemiketal anion 36 (ethynylation), and intramolecular O-vinyla­tion in anion 36 with the formation of target dioxabicy­clo[3.2.1]octane 37, chiral centers arise. The dia­stereoisomeric composition of dioxabicyclo[3.2.1]octanes obtained from alkyl aryl ketones and acetylene is formed at the final step, i.e., intramolecular O-vinyla­tion (TS36a→37a), and the experimentally ob­served diastereoselectivity is ensured due to significant differences in the activation barriers to this step for different diastereomers.

Fig. 3.
figure 3

Reaction profile of the formation of four out of eight possible diastereoisomeric tetracyclic frontalins in the system cyclohexanone/acetylene (b).

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In the assembly of tetracyclic frontalins, the dia­stereoisomer ratio is determined already at the stage of ethynylation of intermediate 1,5-diketone 34b (TS34b→36b). Herein, comparable activation barriers and reaction rates for different diastereoisomers are responsible for the lack of diastereoselectivity (Fig. 3).

Along with dioxabicyclo[3.2.1]octanes, cyclo­pen­tenols can be stereoselectively formed in the reaction of methyl aryl ketones with acetylenes [6] (Scheme 5). The key intermediate products in this cascade assembly are 1,5-diketones 34. The addition of ethynide ion 35 to the carbonyl group of 34 gives a structural isomer of hemiketal anion 36, δ-acetylenic enolate ion 38 (Fig. 4). The latter undergoes intramolecular C-vinyla­tion to form methylidenecyclopentanol which is converted to cyclopentenol 39 through 1,3-prototropic rearrangement.

Scheme
scheme 5

5.

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Fig. 4.
figure 4

Reaction profile of the formation of the R,R,S-dia­stereo­isomer of dioxabicyclo[3.2.1]octane and S,S-diastereo­isomer of cyclopentenol in the system acetophenone/ace­tylene (a).

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Using the ANIONGAS model, we showed [17, 51] that δ-acetylenic enolate ion 38a is more thermo­dynamically stable than hemiketal anion 36a and that anion 38a is relatively easily formed from the O-cen­tered anion derived from tertiary acetylenic alcohol (precursor to 36a). The ratio of dioxabicyclo[3.2.1]octanes and cyclopentenols in the mixture of products of cascade assembly of alkyl aryl ketones and acetylene is determined by differences in the activation barriers of the last steps of their assembly, intramolecular O- (TS36a→37a) and C-vinylation (TS38a→39a), respec­tively (Fig. 4). When R = Ph (system a), the activation barriers to these steps are ΔG‡ = 15.9 and 18.2 kcal× mol–1, respectively, i.e., the assembly of dioxabicyclo­octane is kinetically preferred, which is consistent with its 86% yield. For the system 2-acetylthiophene/ace­tylene (c, R = thiophen-2-yl), the ratio of the activa­tion barriers changes to the opposite, ΔG‡ = 19.1 and 17.8 kcal/mol, respectively, and the experimental yields of dioxabicyclooctane and cyclopentenol are 34 and 55%.

It was shown that the diastereoselectivity in the assembly of cyclopentenols is determined at the final intramolecular C-vinylation step due to difference (ΔΔG‡ = 1.6 kcal/mol) in the activation barriers for the formation of different diastereoisomers.

4.2. Assembly of Substituted Furans

Ketones with bulky substituents at the carbonyl group (R1) or at the α-carbon atom (R2) reacted with acetylene in a different way with the formation of substituted furans [6] (Scheme 6). The branch point arises here from the competition between ethynide ion 35 and ketone carbanion 30 in the addition to the activated C=C bond of α,β-unsaturated ketone 33 (Michael reaction). The addition of ethynide ion 35 gives β-acetylenic enolate 40 which undergoes intra­molecular O-vinylation, yielding methylidenedihydro­furan carbanion 41, and the latter is converted to substituted furan 42 via prototropic rearrangements (Scheme 7).

Scheme
scheme 6

6.

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Scheme
scheme 7

7.

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Comparison of the thermodynamic characteristics of the assemblies of dioxabicyclo[3.2.1]octanes, cyclo­pentenols, and furans showed that the assembly of substituted furans is most thermodynamically favorable (ΔG = –29.7 to –34.6 kcal/mol). The formation of di­oxa­bicyclo[3.2.1]octanes from ketones with bulky sub­stituents (R1 = Mes, R2 = H; R1 = Ph, R2 = Bn) is com­pletely unfavorable (ΔG = 10.0 and 2.0 kcal/mol) [53]. Apart from the thermodynamic factor, the key role is played by the ratio of activation barriers for the Michael reaction. When R1 = Ph, R2 = H (a), the activation barrier for the addition of ketone carbanion is lower by 1.7 kcal/mol than that for the addition of ethynide ion, and the Michael reaction produces inter­mediate 1,5-diketone 34. In contrast, in the addition of ethynide ion to ketone with R1 = Mes, R2 = H (d), the activation barrier is lower by 3.1 kcal/mol than that for the addition of ketone carbanion [17, 53]. It was shown that the preference of the addition of ketone carbanion or ethynide ion to the C=C double bond of unsaturated ketone can be predicted on the basis of combined reactivity indices. These indices are defined as the product of the local electrophilicity index ω+ of substrate and the multiphilicity index Δωk of ketone carbanion for the reaction with ketone carbanions and the product of the charge of the β-carbon atom multiplicated by the global electrophilicity of substrate [q(β)×ω] and the multiphilicity index Δωk of ethynide ion for the reaction with ethynide ion [53].

The entire mechanism of furan assembly was studied using the ANIONGAS model and mesityl methyl ketone as an example [17, 53]. The highest energy barrier was found for the step of intramolecular O-vinylation of 40d with the formation of dihydrofuran 41d, and its value was well consistent with the harsh conditions of the assembly of furans (90°C) compared to dioxabicyclo[3.2.1]octanes and cyclopentenols.

4.3. Assembly of Δ 2 -Isoxazolines

The synthetic potential related to the initial forma­tion of unsaturated ketones can be extended by involving one more nucleophile in the reaction. The mechanism of the reaction of ketones with aryl­acetylenes and hydroxylamine in the presence of t-BuOK/DMSO, followed by treatment of the reaction mixture with H2O and KOH and leading to the forma­tion of Δ2-isoxazolines (Scheme 8), was studied using the assembly of (4R,5S)-5-benzyl-4-ethyl-3-methyl-4,5-dihydro-1,2-oxazole from pentan-2-one, phenyl­acetylene, and hydroxylamine as an example [54].

Scheme
scheme 8

8.

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We estimated the energies of activation for the following consecutive steps: generation of ketone carbanion and its addition to the triple bond (vinyla­tion); addition of hydroxylamine to the carbonyl group and dehydration of the resulting carbinolamine (oximation); base-catalyzed E/Z isomerization of the oxime; supposed prototropic rearrangement of β,γ-un­saturated oxime to α,β-unsaturated isomer; and, finally, intramolecular nucleophilic addition to the double bond with closure of five-membered heterocycle.

Both C1- and C3-centered anions can be formed at the stage of vinylation of pentan-2-one with phenyl­acetylene. In the gas phase, proton abstraction from C3 of pentan-2-one is more thermodynamically favorable by 0.9 kcal/mol. In contrast, in DMSO solution, deprotonation of the methyl group is more favorable by 0.7 kcal/mol. On the other hand, the addition of C3-carbanion to phenylacetylene is characterized by a lower activation barrier (ΔG‡ = 14.3 kcal/mol), which is responsible for the observed [55] vinylation ex­clusively at C3 of pentan-2-one with the formation of (4E)-3-ethyl-5-phenylpent-4-en-2-one.

The oximation step (Scheme 9), i.e., the addition of hydroxylamine to (4E)-3-ethyl-5-phenylpent-4-en-2-one, involves an eight-membered cyclic transition state with participation of water and tert-butyl alcohol molecules (ΔG‡ = 18.8 kcal/mol). The most favorable is the participation of water as a proton donor and of tert-butyl alcohol as a proton acceptor. In this case, the activation barrier for the subsequent dehydration of the resulting carbinolamine also decreases to ΔG‡ = 18.4 kcal/mol. It is worth noting that the dehydration stage involves intermediate formation of nitrone which isomerizes into (2E,4E)-3-ethyl-N-hydroxy-5-phenyl­pent-4-en-2-imine with an activation barrier of ΔG‡ = 6.0 kcal/mol (Scheme 10). The difference in the activation energies for the formation of (2E,4E)- and (2Z,4E)-isomers of β,γ-unsaturated oxime is respon­sible for the experimentally observed [55] completely selective formation of (2E,4E)-isomers from dialkyl ketones.

Scheme
scheme 9

9.

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Scheme
scheme 10

10.

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The ease of proton detachment from the C3 atom of (2E,4E)-3-ethyl-N-hydroxy-5-phenylpent-4-en-2-imine provides the possibility of its conversion into the (2Z,4E)-isomer (Scheme 11). The prototropic rear­range­ment of the β,γ-unsaturated oxime into α,β-un­saturated (2Z,3Z)-3-ethyl-N-hydroxy-5-phenylpent-3-en-2-imine, which was presumed initially [55], is thermodynamically unfavorable, whereas the cycliza­tion of the corresponding O-anion requires a high energy (ΔG‡ = 27.9 kcal/mol). In contrast, the cycliza­tion of β,γ-unsaturated oximate ion (Scheme 12) is easy to occur (ΔG‡ = 16.3 kcal/mol). The subsequent protonation of the intermediate carbanion completes the assembly of 5-benzyl-4-ethyl-3-methyl-4,5-dihy­dro-1,2-oxazole.

Scheme
scheme 11

11.

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Scheme
scheme 12

12.

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5. REACTIONS OF IMINES WITH ACETYLENES

5.1. Formation of Imidazopyridines

The recently discovered aza-Favorsky reaction has opened new prospects for constructing nitrogen-con­taining heterocyclic systems. In particular, ethynylation of N-(pyridin-2-yl)(het)arylmethanimines with (het)­arylacetylenes unexpectedly afforded imidazopyridine derivatives [13] (Scheme 13).

Scheme
scheme 13

13.

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As shown by NBO (B3LYP/6-31+G*) analysis, the negative charge in propargylamine anion 45 generated by the action of phenylethynide 44 on N-(pyridin-2-yl)­phenylmethanimine 43 is distributed between the endo- and exocyclic nitrogen atoms to form a diazatriene system which undergoes intramolecular N-vinylation leading to imidazopyridine structure (Scheme 14). Using the B2PLYPD/6-311+G**//B3LYP/6-31+G* ap­proach and ANIONGAS model, we estimated the relative thermodynamic stabilities of propargylamine anion 45 and its allenyl isomer 46 and studied the entire mechanism of imidazopyridine assembly [13].

Scheme
scheme 14

14.

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Allenyl structure 46 turned out to be more stable than its propargyl isomer 45 by ΔΔG = 8.8 kcal/mol, and the barrier to intramolecular addition to the pyri­dine nitrogen atom of 46 with the formation of benzyl­imidazopyridine anion 47 is as low as ΔG‡ = 4.6 kcal× mol–1. In the next stage, a competition appears between the protonation of anion 47 by tert-butyl alcohol with the formation of benzylimidazopyridine 48 and the addition of 47 to another molecule of imine 43 to produce (Z)-stilbene/imidazopyridine ensemble 51 through intermediate anionic adducts 49 and 50. This stage determines the final composition of products and their ratio. The results of our research showed that the addition to imine 43 is preferred both kinetically and thermodynamically (Fig. 5). This is consistent with the experimental data, according to which stilbene 51 pre­dominated over benzylimidazopyridine 48 in the reac­tion products at an equimolar ratio of the initial imine and acetylene, as well as an increase in the yield of benzylimidazopyridines with a deficiency of imine 43.

Fig. 5.
figure 5

Reaction profile of the competing protonation of benzyl­imidazopyridine anion and its addition to initial imine with the formation of benzylimidazopyridine and (Z)-stil­bene/imidazopyridine ensemble.

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The pathway leading to stilbene 51 includes a high-barrier step (ΔG‡ = 15.8 kcal/mol), isomerization of 49 into 50 with the participation of t-BuOH. As the number of proton carriers increases, this step becomes faster, which explains the experimentally observed change of the product ratio toward stilbene 51 upon addition of methanol or tert-butyl alcohol.

5.2. Formation of Pyrrolines

N-Benzyl imines showed no expected electrophil­icity in reactions with acetylenes and did not undergo ethynylation, since their acidity in DMSO exceeds the acidity of acetylene and phenylacetylene by several orders of magnitude [56, 57]. Deprotonation of N-benzyl imines by superbases gives highly reactive azaallyl anions which react with acetylene to produce 2-azabutadienes [10, 57]. The addition of arylacety­lenes to such azaallyl anions leads to the formation of mixtures of pyrrolines [11, 12] (Scheme 15).

Scheme
scheme 15

15.

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The mechanism of the pyrroline assembly from N-benzyl-1-phenylmethanimine 52 and phenyl­acety­lene 53 was studied using the ANIONGAS and PENTAGAS models [58]. It was found that the con­certed mechanism of cycloaddition rather than stepwise one is kinetically preferred. The concerted cycload­dition requires stabilization of the azaallyl anion in the transition state via hydrogen bonding with t-BuOH or DMSO (solvent). The descent from the transition state occurs through not only [3+2]-cycloaddition but also protonation of the emerging nitrogen-centered anion with tert-butyl alcohol, which eventually leads to 3-pyr­roline 54. A series of subsequent prototropic rearrangement gives a mixture of target pyrrolines 55 and 56 (Fig. 6) with predominance of the former due to its higher thermodynamic stability.

Fig. 6.
figure 6

Reaction profile of the formation of 1-pyrrolines and byproducts.

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Mild conditions of the assembly of 1-pyrrolines (60°C, 15 min) are determined by the low activation barrier at the cycloaddition step (ΔG‡ = 11.6 kcal/mol), which is achieved due to formation of solvate com­plexes where the azaallyl anion is more accessible to the attack of phenylacetylene molecule (Fig. 7).

Fig. 7.
figure 7

Structure of solvate complex formed by the azaallyl anion.

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On the other hand, the step of C-vinylation of aldimine 52 with the formation of 2-azapenta-1,4-diene anion 57 is characterized by a close energy of activa­tion. As shown by theoretical and experimental methods, anion 57 is formed as an intermediate in the side processes leading to triarylpyridines 58 through the concerted cycloaddition of another phenylacetylene molecule and to 1,3-diarylpropan-1-ones 59 as a result of hydrolysis.

6. CONCLUSIONS

To conclude, we can state with certainty that the chemistry of acetylene in superbasic media endows synthetic chemists with a great potential and provides extensive material for research to theoretical chemists. The sharp increase in computational facilities over the past two decades has made it possible to take full advantage of using additional tools provided by quantum chemistry for studying mechanisms of chemical reactions.

The present review summarizes recent advances in studying the mechanisms of assemblies of carbo- and heterocycles based on reactions of acetylenes in superbasic media. We succeeded in creating models of superbasic centers to describe vinylation, ethynylation, 1,3-prototropic rearrangements, and Michael reactions typically occurring in such media and successfully applying these models to study the mechanisms of various reactions, including a number of fast elemen­tary steps. We hope that the presented results will favor better understanding of peculiar features of these interesting complex transformations.