1. Introduction

2. Synthesis of 3H-Pyrroles and 5-Hydroxypyrrolines from Secondary Alkyl Ketoximes and Acetylene

3. Minor Reactions of Secondary Alkyl Ketoximes with Acetylene

4. 3H-Pyrroles and 5-Hydroxypyrrolines as 21st Century Reagents: Recent Advances

5. Conclusions

1. INTRODUCTION

Organic synthesis is a rapidly developing field of chemistry, and its practical significance is impossible to overestimate. Constantly growing social demands with simultaneous emergence of new paradigms in chemical methodologies, including the “green” chem­istry and PASE (Pot–Atom–Step Economy) paradigms, have become the major factors stimulating the develop­ment of organic synthesis in the new millennium. New requirements have been applied to the arsenal of syn­thetic chemists, including reagents and catalysts, which should provide carrying out various chemical trans­formations under mild and environmentally benign con­ditions. Undoubtedly, cascade assemblies of com­plex molecular systems on the basis of acetylene under superbasic activation, which have been discovered and are systematically explored by the scientific school un­der the guidance of Academician B.A. Trofimov [1–3], can be regarded as such chemical transformations.

In fact, acetylene is a large-scale product of hydro­carbon processing [4], and most of its reactions are addition reactions [5] that are atom-economic in essence; these reactions are accompanied by evolution of heat (i.e., they are energy-safe), and are therefore completely consistent with the modern paradigms of organic synthesis. The key role in cascade assemblies is played by the dual nature of acetylene which is capable of alternately acting as a nucleophile and electrophile. This capability is significantly enhanced in superbasic catalytic media that comprise a complex of a strongly ionized base (Brønsted base) with a ligand which specifically interacts with the cation of that base (Lewis base) in a medium weakly solvating anions (as a rule, a polar aprotic solvent) [6]. A typical and widely used example of such green catalytic medium containing no transition metal cations is potassium hydroxide in nontoxic and easily recoverable dimethyl sulfoxide which acts simultaneously as a Lewis base and a solvent.

The synthesis of pyrroles and N-vinylpyrroles from ketoximes and acetylene (Scheme 1) is historically the first example of such assemblies, which is currently known in the world literature as the Trofimov reaction and is justly considered a powerful tool in targeted organic synthesis [7].

Scheme
scheme 1

1.

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Long-term systematic studies of the Trofimov reaction not only resulted in the synthesis of a huge diversity of previously unknown pyrrole structures but also unambiguously proved the tandem character of pyrrole assembly. The transformation sequence in­cludes prototropic shift in O-vinyl ketoximes (ketoxime adducts with acetylene), [3,3]-sigmatropic rearrange­ment of N,O-dialkenyl hydroxylamines, cyclization of iminoaldehydes, dehydration of 5-hydroxypyrrolines, and aromatization of 3H-pyrroles to 1H-pyrroles (Scheme 2).

Scheme
scheme 2

2.

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In the case of secondary alkyl ketoximes, which contain only one C–H bond at the α-position with respect to the oxime group, the given sequence should be terminated at the stage of formation of 3,3-disub­stituted 3H-pyrroles whose further aromatization without C–C bond cleavage is impossible. The pos­sibility of synthesizing 3H-pyrroles by the Trofimov reaction was demonstrated in 1985 by reacting iso­propyl phenyl ketoxime with acetylene in the system KOH/DMSO (Scheme 3) [8]. The yield of 3H-pyrrole was later improved to 53%, and the corresponding conditions were applied to the reaction with isopropyl 2-thienyl ketoxime; however, the results were poorly reproducible [9]. Furthermore, some minor reaction pathways were discovered (see below), and studies of this reaction were mostly discontinued.

Scheme
scheme 3

3.

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On the other hand, 3H-pyrroles are promising reagents in organic synthesis of the 21st century due to their sufficient stability on storage and simultaneous energy richness in comparison to aromatic 1H-isomers. The latter factor is responsible for the high reactivity of 3H-pyrroles, which is a fundamental ground for the development of mild synthetic methods of their modifi­cation. It is worth noting that studies on the reactivity of 3H-pyrroles are few in number; the most com­prehensive reviews were given in [10, 11].

Guided by these ideas, about 10 years ago we initiated systematic studies of the reactivity of secon­dary alkyl ketoximes in the Trofimov reaction with the goal of obtaining previously inaccessible aza hetero­cyclic systems (3H-pyrroles and 5-hydroxypyrrolines) and exploring their synthetic potential in chemical trans­formations whose conditions meet the require­ments of modern organic synthesis. The review sum­marizes the results and prospects of studying the reactions of acetylene with secondary alkyl ketoximes containing only one C–H bond at the α-position with respect to the oxime group in superbasic catalytic media. The selective formation of key intermediate products in the pyrrole synthesis, their reactivity, and unique cascade assemblies of unpredictable products are discussed.

2. SYNTHESIS OF 3H-PYRROLES AND 5-HYDROXYPYRROLINES FROM SECONDARY ALKYL KETOXIMES AND ACETYLENE

With the goal of developing one-pot synthesis of 3H-pyrroles by the Trofimov reaction, we performed a systematic study of the reaction of secondary alkyl ketoximes with acetylene under pressure [12]. Screen­ing of the reaction conditions, including the nature of superbasic system (MOR/DMSO; M = Li, Na, K; R = H, t-Bu, ketoxime/base molar ratio, temperature, reaction time, co-solvent, and reactant concentration, showed that a series of 3H-pyrroles can be obtained in up to 33% yield using the multiphase superbasic system KOH/DMSO/hexane (Scheme 4). The role of a nonpolar solvent (hexane), which is immiscible with DMSO, is to extract products and thus prevent them from contacting the active zone of the reaction mixture and hence reduce the probability of further undesirable transformations.

Scheme
scheme 4

4.

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While studying the substrate scope, we found that secondary alkyl ketoximes with a bulky 2,5-dimethyl­phenyl substituent reacted with acetylene under standard conditions to give previously unknown inter­mediate products in the pyrrole synthesis, 5-vinyloxy­pyrrolines (Scheme 5). The latter were converted to 3H-pyrroles by further heating at 120°C for 1 h in the presence of 3.0 equiv of potassium tert-butoxide.

Scheme
scheme 5

5.

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It was found that 5-hydroxypyrroline obtained from isopropyl phenyl ketoxime does not undergo dehy­dra­tion under the optimal conditions of 3H-pyrrole syn­thesis in the absence of acetylene and is recovered virtually unchanged. On the other hand, its reaction with acetylene leads to the formation of 3H-pyrrole in 37% yield, the conversion of 5-hydroxypyrroline being complete. Thus, it was experimentally shown for the first time and subsequently confirmed by quantum chemical calculations [13] that vinylation of inter­mediate 5-hydroxypyrrolines is a necessary final step in the assembly of 3H-pyrroles from sec-alkyl ket­oximes and acetylene.

An obvious drawback of the developed method of synthesis of 3H-pyrroles, which limits its implementa­tion in the general practice of organic synthesis, is the use of special high-pressure reactors. Our further studies allowed us to remove this limitation and synthesize 3H-pyrroles by passing a stream of acety­lene through a solution of ketoxime in DMSO con­taining 1.0 equiv of potassium hydroxide at 90°C for 4 h; in these cases, the yields of the target compounds remained acceptable [14] (Scheme 6). Interestingly, a decrease in the basicity of the system by reducing the amount of potassium hydroxide to 0.5 equiv with simultaneous addition of 2 wt % of water (with respect to DMSO) completely suppressed vinylation of inter­mediate 5-hydroxypyrrolines, so that these valuable pyrroline ring carriers can be obtained in up to 44% yield with high chemoselectivity [15].

Scheme
scheme 6

6.

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An alternative selective two-step synthesis of 5-hydroxypyrrolines was proposed [16] (Scheme 7). In the first step, by analogy with the previously developed method [17], sec-alkyl ketoximes reacted with acetylene in a multiphase superbasic system under pressure to produce the corresponding O-vinyl oximes. A substantial advantage of this step is the absence of side processes and hence easy isolation of the products. O-Vinyl ketoximes were extracted from the reaction mixture with hexane, and the initial ketoxime was recovered by pouring the DMSO solution into water, followed by extraction with diethyl ether. The second step is base-catalyzed rearrangement of O-vinyl ketoximes to 5-hydroxypyrrolines, which is sufficiently effective even at room temperature. In this proce­dure, further reaction of the target product with acetylene or unreacted ketoxime is completely ruled out (cf. Scheme 6).

Scheme
scheme 7

7.

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The use of calcium carbide as a convenient and safe synthetic equivalent of acetylene gas has become one of the trends in the development of acetylene chemistry in the 21st century [18]. As applied to the reaction of sec-alkyl ketoximes with acetylene, this approach made it possible to develop technologically safe chemoselective methods for the synthesis of 3H-pyr­roles and 5-hydroxypyrrolines, which can be easily implemented in any synthetic laboratory having no facilities for working with acetylene gas [19] (Scheme 8). The chemoselectivity of the assembly was controlled by varying the amount of calcium carbide and the nature of the base. In particular, 8.0 equiv of calcium carbide and 1.0 equiv of potassium hydroxide or 4.0 equiv of calcium carbide and 1.0 equiv of sodium hydroxide were used to obtain 3H-pyrroles and 5-hydroxypyrrolines, respectively.

Scheme
scheme 8

8.

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Analysis of the entire array of experimental data on the reaction of sec-alkyl ketoximes with acetylene showed that moderate yields of 3H-pyrroles and 5-hydroxypyrrolines are the result of the ultimate use of superbasic catalytic systems at elevated temperature. On the one hand, these conditions help to overcome high activation barriers to the stages of vinylation of initial ketoximes to initiate cascade assembly and intermediate 5-hydroxypyrrolines to complete 3H-pyr­role assembly; on the other hand, they are insufficiently tolerant to the target products, thus promoting a number of minor reactions that are discussed in the next section of the review.

3. MINOR REACTIONS OF SECONDARY ALKYL KETOXIMES WITH ACETYLENE

Numerous attempts to intensify the synthesis of 3H-pyrroles from sec-alkyl ketoximes and acetylene led to the discovery of quite unexpected reaction pathways, each of which is likely to negatively affect the yield of the target products to a greater or lesser extent. However, it should be kept in mind that the discovery of minor reactions is of fundamental signif­icance, as it gives rise to new ideas and new scientific perspectives.

For example, isopropyl ketoximes containing no impurity of n-propyl isomers reacted with acetylene in the system KOH/DMSO under pressure to give 1–2% of aromatic 3-ethyl-1H-pyrroles and 5–8% of 3-ethyl-1-vinyl-1H-pyrroles in addition to the expected prod­ucts [20] (Scheme 9). It was presumed that the aromatic system is formed as a result of a two-step process including deprotonation of the methyl group in 3H-pyrrole by the action of the superbase and subse­quent migration of the second methyl group to the carbanionic center.

Scheme
scheme 9

9.

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The mechanism of formation of byproducts con­taining a 1-pyrroline fragment is more questionable [21] (Scheme 10). According to [21], 1-pyrrolines could be formed via either reduction of 3H-pyrroles with the superbase or homolysis of the C–O bond in intermediate 5-hydroxypyrrolines, followed by reduc­tion of the resulting radical. It was also noted that the obtained 1-pyrrolines contained a small amount of unidentified carbonyl compound. We believe that the latter was N-vinylpyrrolidone which was recently isolated by us as one more unusual product of cascade transformations involving sec-alkyl ketoximes and acetylene [22] (Scheme 11). This compound is likely to be formed from the corresponding pyrrolidone which is generated by 1,3-prototropic shift in 5-hy­droxy­pyrroline.

Scheme
scheme 10

10.

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Scheme
scheme 11

11.

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Thorough analysis of the reaction mixtures obtained from isopropyl phenyl ketoxime and acetylene under pressure while optimizing the synthesis of 3H-pyrrole (see Scheme 4) revealed another quite unexpected minor product, 2-(2-ethynyl-3,3-dimethyl-2-phenyl­aziridin-1-yl)-4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrole, as the only diastereoisomer [23] (Scheme 12). Presumably, the assembly of this product involves dehydration of the initial oxime (Hoch–Campbell-like reaction) or elimination of vinyl alcohol from inter­mediate O-vinyl oxime to give azirine. Ethynylation of the latter via nucleophilic addition of acetylide ion to the C=N bond produces 2-ethynylaziridine which reacts with 5-hydroxy- or 5-vinyloxypyrroline to afford final aziridinylpyrroline.

Scheme
scheme 12

12.

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2-Ethynylpyrrolines were isolated in 1–2% yield from the reaction mixtures obtained under the same conditions [24] (Scheme 13). These compounds are likely to result from attack of acetylide ion on the C=N bond of key intermediate products in the pyrrole synthesis, 5-hydroxypyrrolines, 5-vinyloxypyrrolines, and 3H-pyrroles.

Scheme
scheme 13

13.

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It should be noted that at the moment of their discovery, cascade assemblies involving addition of acetylide ion to the nitrogen–carbon double bond (Schemes 12, 13) were of fundamental importance for acetylene chemistry as the first experimental evidence of aza-Favorsky reaction. Nowadays, due to systematic studies under the leadership of B.A. Trofimov, the ideas on base-catalyzed aza-Favorsky reaction sub­stan­tially progressed from incidental observations random to a universal tool for fine organic syn­thesis [25–29].

Of particular interest is a series of studies of the reactions of acetylene with ketoximes derived from piperidinones in superbasic medium as the only example of the Trofimov reaction with cyclic sec-alkyl ketoximes. For instance, fused 3H-pyrroles were isolated in poor yields along with the expected aromatic isomers in the heterocyclization of a cyclic ketoxime with CH and CH2 groups adjacent to the oxime moiety [30] (Scheme 14).

Scheme
scheme 14

14.

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Presumably, the reaction of 2,4,6-trimethylpiperidin-4-one oxime with acetylene in KOH/DMSO also gives fused 3H-pyrrole which undergoes aromatization to 2,4,5-trimethyl-1,2,3,4-tetrahydropyrrolo[1,2-c]py­rimi­dine in 16% yield [31] (Scheme 15). The yield was later improved to 45% by using rubidium hydroxide as a component of the superbasic medium [32], and the aromatization step was shown to proceed like a retro-Mannich reaction [33].

Scheme
scheme 15

15.

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The Trofimov reaction with even more sterically crowded 2,6-dimethyl-3,5-diphenylpiperidin-4-one oxime produced a complex mixture of 21(!) compounds (according to the GC/MS data) [33]. The authors suc­ceeded in isolating 1.2% of pyrrolo[1,2-c]pyrimidine (product of rearrangement and aromatization of intermediate fused 3H-pyrrole) and four stereoisomeric acetylenic alcohols (overall yield 11%) resulting from the addition of water and acetylene to 3H-pyrrole (Scheme 16) [34].

Scheme
scheme 16

16.

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Thus, the formation of diverse and unpredictable products in the Trofimov reactions of sec-alkyl ket­oximes not only emphasizes once again that acetylene is prone to undergo unique cascade transformations under superbasic activation, but also reliably indicates high reactivity of 3H-pyrroles and 5-hydroxypyrrolines, some modern aspects of which are discussed below.

4. 3H-PYRROLES AND 5-HYDROXYPYRROLINES AS 21st CENTURY REAGENTS: RECENT ADVANCES

Despite modest yields of 3H-pyrroles and 5-hy­droxy­pyrrolines in the Trofimov reaction, the avail­ability of initial ketoximes and components of the catalytic system enabled us to successfully start a systematic study of selected heterocycles shown, e.g., in Scheme 8. Of particular importance is the fact that the developed methods (see Section 3) make it possible to synthesize a representative series of compounds containing no substituents with specific electronic or steric effects, so that these compounds are convenient subjects for studying the reactivity of the heterocyclic system itself.

On the other hand, working with these compounds requires considering their moderate storage stability. 5-Hydroxypyrrolines are crystalline solids that are fairly stable on prolonged storage (for more than a year in a refrigerator), whereas 3H-pyrroles are oily liquids in which various impurities can be detected even after storage for a month in a refrigerator. By thorough analysis of samples of 3H-pyrroles stored in sealed ampules at 5–7°C for 9.5 months, a new type of the Diels–Alder reaction was discovered, dimerization of 3H-pyrroles, where one molecule acts as an aza-diene component, and the other, as a dienophile through its carbon–carbon double bond [35]. We succeeded in improving the yield of the adducts to a preparatively significant level by heating 3H-pyrroles in the presence of a mild organocatalyst, tert-butyl alcohol [36] (Scheme 17). Presumably, the role of the catalyst consists of coordination with the dienophile molecule through hydrogen bonding with the pyridine-type nitro­gen atom, which makes the C=C double bond electron-deficient and hence more complementary to the uncoordinated electron-rich aza-diene component. From a fundamental point of view, the proposed ap­proach suggests effective ways of intensifying Diels–Alder reactions of 3H-pyrroles [10, 11], which are especially attractive as a tool for synthesizing complex natural compounds such as alkaloids [37].

Scheme
scheme 17

17.

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Compounds containing a Δ1-pyrroline fragment are widespread in natural materials and living organisms; they are used as building blocks in the synthesis of molecular switches [38], fluorescent boron complexes (boranils) [39], and biologically active compounds [40]. Obviously, reactions of nucleophiles with 3H-pyrroles (addition reactions) and 5-hydroxypyrrolines (substitu­tion reactions) provide a simple route to variously substituted Δ1-pyrrolines.

It was found that, contrary to the generally accepted views [10, 11], the aza-diene system of 3H-pyrroles is fairly inert toward nucleophilic attack provided that it is not activated by electron-withdrawing groups. A series of previously unknown pyrrolines were syn­thesized in up to 81% isolated yield by reacting 3H-pyrroles with oxygen-, nitrogen-, and sulfur-cen­tered nucleophiles on heating under solvent-free conditions in the presence of a catalytic amount of trifluoroacetic acid [41] (Scheme 18). Quantum chemical calculations showed that the addition of nucleophiles to the C=N double bond is a kinetically controlled reversible process leading to unstable adducts and that the addition to the C=C double bond, which is slightly activated toward nucleophilic attack due to inductive effect of the neighboring protonated hydrogen atom, gives stable Δ1-pyrrolines through a high-energy transition sate; elevated temperature is necessary to overcome the energy barrier.

Scheme
scheme 18

18.

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In contrast, acid-catalyzed nucleophilic substitution of the hydroxy group in 5-hydroxypyrrolines occurs under milder conditions, at room temperature or by refluxing in acetonitrile or excess nucleophile when the latter is an easily removable alcohol [42] (Scheme 19). Like 3H-pyrroles, 5-hydroxypyrrolines react with acids to give N-protonated intermediates (according to the 15N NMR data) which are capable of reversibly adding a nucleophile to the C=N double bond. Therefore, it can be concluded that the formation of O-protonated intermediates and then target Δ1-pyrrolines is a thermo­dynamically controlled reaction pathway.

Scheme
scheme 19

19.

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5-Hydroxypyrrolines efficiently reacted with weak carbon-centered nucleophiles (arenes) under conditions of superacid activation [43] (Scheme 20). As shown by experimental and theoretical methods, strong tri­fluoromethanesulfonic acid protonates initial 5-hy­droxy­pyrrolines simultaneously at the nitrogen and oxygen atoms. Elimination of neutral water molecule from the resulting dication yields C,N-centered dication which is the key intermediate toward 2,5-diaryl-sub­stituted Δ1-pyrrolines.

Scheme
scheme 20

20.

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The possibility of primary nucleophilic attack on the C=N bond was demonstrated by the results of studying acid-catalyzed reactions of 5-hydroxypyr­rolines with hydrazine derivatives [44–46]. Instead of the expected nucleophilic substitution products, these reactions afforded 1,4-dihydropyridazine derivatives that are promising analogs of antihypertensive and spasmolytic agents [47–49], fluorescent labels for proteins [50] and living cell organelles [51], and com­ponents of fluorescent chemosensors [52] and oxida­tion-resistant polymers [53]. Alkyl-, aryl-, and hetaryl­hydrazines [44], as well as semicarbazide and 4-phenylsemicarbazide [45], successfully reacted with 5-hydroxypyrrolines to give the corresponding 1,4-di­hydropyridazines in up to 95% yield (Scheme 21). The cascade assembly of 1,4-dihydropyridazines begins with protonation of the initial 5-hydroxypyrroline at the nitrogen atom with trifluoroacetic acid or hydrogen chloride (in the reactions with commercially available hydrazine derivatives as hydrochlorides). The iminium cation thus formed reacts with hydrazine to form unstable pyrrolidine which undergoes ring opening to linear intermediate, and the latter cyclizes to hy­droxytetrahydropyridazine via intramolecular nucleo­philic substitution of the amino group (probably, protonated under the given conditions) by the internal NH group of the hydrazine. The assembly of the 1,4-dihydropyridazine framework is completed by dehydration.

Scheme
scheme 21

21.

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Unlike hydrazine derivatives listed above, car­box­ylic acid hydrazides are characterized by significantly lower nucleophilicity of the NH nitrogen atom neigh­boring to the carbonyl group. As a result, under standard conditions for the assembly of 1,4-dihydro­pyridazines, the main products are highly function­alized tetrahydropyridazines originating from a com­petitive attack of the second hydrazide molecule on the linear intermediate (see Scheme 21). Further addition of excess acid within a one-pot two-step procedure provides successful elimination of the carboxylic acid hydrazide molecule to form the target 1,4-dihydro­pyridazines. The presence of additional nucleophilic functionalities in the hydrazide molecule, such as an amino group in anthranilic acid hydrazide or a hydroxy group in salicylic acid hydrazide, opens the way to more complex fused tricyclic systems [46] (Scheme 22).

Scheme
scheme 22

22.

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Due to the presence of an imino group capable of acting as an electrophile (analog of carbonyl), nucleo­phile (lone electron pair on the nitrogen atom), and dienophile, 3H-pyrroles, 5-hydroxypyrrolines, and substituted Δ1-pyrrolines obtained therefrom can be considered as promising building blocks for the syn­thesis of various fused systems.

Tertiary cyanoacetylenic alcohols reacted under mild conditions with 3H-pyrroles [54, 55] and substi­tuted Δ1-pyrrolines [56], mostly in regio- and stereo­selective manner, to produce partially hydrogenated fused pyrrolo[2,1-b]oxazoles in up to 82% yield (Scheme 23). A probable reaction mechanism involves formation of a zwitterionic intermediate via attack of the pyridine-type nitrogen atom on the electron-deficient carbon–carbon triple bond, intramolecular proton transfer from the hydroxy group to the carbanionic center, and final closure of the oxazolidine ring through addition of the oxygen-centered anion to the iminium group. The developed synthetic approach to hydrogenated pyrrolo[2,1-b]oxazoles is a special case of the general methodology for the synthesis and modification of nitrogen heterocycles based on zwitterionic intermediates. It demonstrates once again a deep genetic interrelation of the research directions developed by the scientific school under the leadership of B.A. Trofimov [57].

Scheme
scheme 23

23.

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We recently proposed a diastereoselective synthesis of tetrahydropyrrolo[1,2-d]oxadiazoles by cycload­di­tion of nitrile oxides to 3H-pyrroles and substituted Δ1-pyrrolines [58]. Nitrile oxides were generated in situ by the action of an oxidant (sodium hypochlorite) on the corresponding aldoximes in the two-phase system water–methylene chloride (Scheme 24). The reaction was equally efficient and selective for both substrates containing oxidizable groups (5-hydroxy­pyrrolines) and those possessing competitive reaction centers for cycloaddition (3H-pyrroles).

Scheme
scheme 24

24.

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The number of possible synthetic transformations of 3H-pyrroles, 5-hydroxypyrrolines, and substituted Δ1-pyrrolines derived therefrom further increases when the specific reactivity related to substituents in the heterocyclic system is taken into account. For example, rhodium-catalyzed C–H functionalization of the ortho position of aryl substituents at the imino group by the action of acetylenes and subsequent cyclization of organorhodium intermediates opens a simple route to a wide range of synthetic analogs of the alkaloid crispine B [59, 60] (Scheme 25). The nitrogen atom of the heterocyclic fragment plays a key role in the stabilization of organorhodium intermediates through coordination to the metal center. Preliminary studies of the photophysical properties of pyrrolo[2,1-a]isoquino­linium salts demonstrated prospects of using the syn­thesized systems for the design of blue organic light-emitting diodes.

Scheme
scheme 25

25.

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5. CONCLUSIONS

It seems reasonable to conclude the review by listing promising directions in studying the reaction of sec-alkyl ketoximes with acetylene. First of all, the problem of extending the substrate scope with the goal of obtaining variously functionalized 3H-pyrroles and 5-hydroxypyrrolines remains important. An example is the study of the reactivity of almost unexplored cyclic sec-alkyl ketoximes as precursors to fused 3H-pyrroles and 5-hydroxypyrrolines. In addition, the only reported example of 5-hydroxypyrroline synthesis from phenyl­acetylene [61] and considerable progress in using substituted acetylenes in related syntheses of aromatic pyrroles [7] reliably indicate successful implementation of the reaction of sec-alkyl ketoximes with substituted acetylenes. It is possible that the use of activated acetylenes will allow the transition from superbasic catalytic systems to metal complex catalysts, thus opening real prospects of stereoselective syntheses of 3H-pyrroles and 5-hydroxypyrrolines.

An equally important aspect is further study of the reactivity of 3H-pyrroles and 5-hydroxypyrrolines to develop synthetic approaches to practically significant molecular ensembles in agreement with the require­ments of modern organic synthesis. Especially prom­ising is the search for new chemical transformations involving the imino group of 3H-pyrroles and 5-hy­droxypyrrolines, as well as for transformations deter­mined by a combination of the reactivity of the heterocyclic system itself and specific reactivity of side-chain substituents.