Ivan A. Bidusenko

Base-catalyzed domino cyclization of acetylenes with ketones to functionalized cyclopentenes.

Acetylene reacts with methylaryl(hetaryl)ketones in the presence of 6.5 mol % KOH in DMSO to give diastereoselectively in single operationally functionalized cyclopentenes. This domino cyclization involving two molecules of acetylene and two molecules of ketone proceeds with the formation of four C-C bonds. The complementary assembly of the cyclopentenes with similar functionalities from acetylenes and 1,5-diketones has been developed.

Furans Conjugated with Bulky Aromatic Systems: One‐Pot Synthesis from Ketones and Acetylene

Ketones with bulky aromatic, heteroaromatic and ferrocene substituents react with acetylene in the presence of a KOH/DMSO super-base suspension (90 °C, 15 min) to give polysubstituted furans in up to 86 % isolated yields in a one-pot fashion. This assembly of the furan scaffold involves a domino sequence in which one molecule of ketone reacts with two molecules of acetylene.

Decorated Cyclopentadienes from Acetylene and Ketones in Just Two Steps

The products of the one-pot assembly of acetylene and ketones in the KOH/DMSO system, 7-methylene-6,8-dioxabicyclo[3.2.1]octanes, undergo an acid-catalyzed (CF3COOH, room temperature) rearrangement to rarely substituted cyclopentadienes in good-to-excellent yields. The mechanism of the rearrangement has been supported by the isolation and corresponding transformations of two intermediates.

Formation of 2-methyl-3,5-diphenylfuran from chalcone and acetylene in the system KOH–DMSO

Chalcone reacted with acetylene in a suspension of KOH in DMSO at 90°C (30 min) to give 36% of 2-methyl-3,5-diphenylfuran.

Alkanethiol-promoted stereoselective radical rearrangement of 7-methylidene-6,8-dioxabicyclo[3.2.1]octanes to 2-acetyl-3,4-dihydropyrans

We have recently discovered diastereoselective self-assembly of ketones with acetylene in superbasic systems MOH‒DMSO (M = K, Cs; 80°C, 1 h,) to produce 7-methylidene-6,8-dioxabicyclo[3.2.1]octanes 1 [1] (Scheme 1) that are close structural analogs of insect pheromones [2, 3] and mammalian hormones [4, 5]. This one-pot transformation of simple and readily accessible reagents to complex functionalized heterocyclic systems combining bicyclic acetal and vinyl ether moieties in a single molecule opens unexpected prospects for the development of organic synthesis where the synthon (building block) approach is now increasingly used for the design of molecular systems with a desired structure. While performing a systematic study of the synthetic potential of 7-methylidene-6,8-dioxabicyclo[3.2.1]octanes 1 that have become readily accessible we revealed their unusual reaction with alkanethiols under radical initiation conditions. It is known that radical addition of thiols to vinyl ethers leads to the formation of the corresponding anti-Markovnikov adducts [6, 7]. However, contrary to expectations, 7-methylidene-6,8-dioxabicyclo[3.2.1]octanes 1a–1d in the reaction with propane-1-thiol in the presence of azobis(isobutyronitrile) (AIBN; 60–65°C, 4 h) were stereoselectively and almost quantitatively converted into 2-acetyl-3,4-dihydropyrans 2a–2d without addition of the thiol (Scheme 2).

Diastereoselective self-organization of acetylene and acetophenone molecules into 1-benzoyl-3-hydroxy-cyclopentene in the presence of potassium hydroxide

We have recently found that acetylene and alkyl aromatic and alkyl heteroaromatic ketones in the superbasic system KОН–DMSO (80С, 1 h) underwent instead of Favorskii reaction a unique selective tandem reaction leading in a single preparative stage to the formation of complex functionalized heterocyclic systems with a frontalin scaffold, 7-methylene-6,8dioxabicyclo[3.2.1]octanes in up to 86% yield [1]. Since frontalin and its analogs are well known insect pheromones [2, 3] and mammal hormones [4, 5], this easy stereoselective (a single diastereomer forms among many possible) and one-pot approach to their derivatives opens new opportunities for the development of their preparative chemistry. At the same time the yet unknown aspect of acetylene reactivity has been unexpectedly revealed: Its capability in the presence of strong bases to undergo self-assembly with the capture of suitable nucleophiles into complex difficultly available functionalized molecules often structurally close to naturally occurring substances. Here we preliminary report that at the systematic investigation of the above mentioned reaction by an example of acetophenone we have found an entirely new direction of self-assembly of two acetylene and two acetophenone molecules affording along with the expected 7-methylene-6,8-bicyclo[3.2.1]octane (I) also 1-benzoyl-3-hydroxycyclopentene (II), also in the form of a single diastereomer (Scheme 1). The preparative yield of structural isomers I and II was 43 and 46% respectively at the acetophenone conversion 46% (the conditions were not yet optimized).

Features of the base-catalyzed reaction of 1-vinyl-4,5-dihydro-1H-benzo[g]indole-2-carbaldehyde with phenylacetylene

The current chemistry of pyrrolecarbaldehydes is one of the fundamental areas of fine organic synthesis. Pyrrolecarbaldehydes are used as building blocks in the preparation of porphyrins [1, 2], ligands for metal complexes [3, 4], medications [5], and precursors of optoelectronic materials [6-8]. Transformations of pyrrolecarbaldehydes give carbolines [9], cyanopyrroles [10], and divinylpyrroles [11]. The high synthetic potential of a carbonyl group in combination with the biological importance of pyrroles ensures a steady interest in this class of compounds. There has recently been developed a preparative method for the preparation of 1-vinylpyrrole2-carbaldehydes by the formylation of 1-vinylpyrroles [12, 13], which are readily obtained from ketones (via ketoximes) and acetylene [14, 15]. It is known that aldehydes react with acetylenes in the presence of a base, giving secondary acetylenic alcohols (the Favorsky reaction) [16, 17]. However, examples of pyrrolecarbaldehyde ethynylation using acetylenes have not been reported in the literature. The use of 1-vinylpyrrole-2-carbaldehydes as starting material in the synthesis of acetylenic alcohols could even further broaden their synthetic potential, thanks to the combination of ethynylcarbinol and vinylpyrrole fragments in a single molecule. Continuing our studies in this area, we have found that 1-vinyl-4,5-dihydro-1H-benzo[g]indole-2-carbaldehyde (1) reacts with phenylacetylene (2) in a suspension of KOH–DMSO (20oC, 1.5 h), forming the E-configured ,-ethylenic ketone 5 in a non-optimized yield of 24%, rather than the expected acetylenic alcohol 3. It should be noted that the ketone 5 was obtained exclusively as the E-isomer. The analogous Z-configured product could not be identified by NMR spectroscopy or by GLC, even in the reaction mixture. The formation of ketone 5 evidently begins with a nucleophilic addition of phenylacetylene 2 to the carbonyl group of the pyrrolecarbaldehyde 1, to give the secondary acetylenic alcohol 3, which prototropically rearranges via the allenic alcohol 4 into the ,-ethylenic ketone 5.

Unexpected reaction of 9-acetylanthracene with acetylene in a suspension of potassium hydroxide in DMSO

We have recently described a diastereoselective assembly of two ketone molecules and two acetylene molecules in a suspension of KOH in DMSO under mild conditions (80°C, 1 h), which afforded complex bicyclic systems, 7-methylidene-6,8-dioxabicyclo[3.2.1]octanes [1]. While attempting to extend this reaction to fused aromatic ketones we have found that 9-acetylanthracene 1 reacts with acetylene in KOH– DMSO (90°C, 15 min) to give 5-(anthracen-9-yl)-2,3dimethylfuran (2, unoptimized yield 24%) instead of expected bicyclooctane derivative 3 (Scheme 1). Presumably, intermediate A (Scheme 2) cannot take up the second molecule of deprotonated ketone 1 for steric reasons, so that 7-methylidene-6,8-dioxabicyclo[3.2.1]octane 3 is not formed. Instead, the addition of acetylide ion to the activated double bond of A yields enolate B which undergoes cyclization to 2-methylidene-2,3-dihydrofuran C (intramolecular nucleophilic addition of oxygen-centered anion to the triple bond). The subsequent prototropic isomerization yields compound 2. We believe that this reaction may also be typical of other ketones with bulky aromatic fragments, which could provide a simple one-pot synthetic route to promising components of materials for optoelectronics. This assumption is now under verification.

Cascade assembly of frontalin derivatives from cyclohexanone and acetylene in the system KOH-DMSO

Frontalin and structurally related brevicomin and multistriatin are insect pheromones [1] and mammalian hormones [2] which can be synthesized according to multistep schemes from difficultly accessible starting compounds [3, 4]. We have recently reported [5] that new frontalin derivatives, 1,5-diaryl-3-methyl-7-methylidene-6,8-dioxabicyclo[3.2.1]octanes can be obtained with high diastereoselectivity in one step from fatty aromatic ketones and acetylene. Cascade selfassembly of two ketone and two acetylene molecules was accomplished under superbasic conditions (MOH‒ DMSO, M = K, Cs). Under analogous conditions, from acetone and acetylene we obtained a complex mixture of products, among which the expected frontalin derivative was identified only by spectral methods (~10%). It seemed improbable that such reaction with aliphatic ketones would be of preparative importance. However, this assumption turned out to be premature. While continuing studies in this line, we have found that a cycloaliphatic ketone, cyclohexanone (1), reacts with acetylene in a suspension of potassium hydroxide in dimethyl sulfoxide to afford tetracyclic system 2 which may be regarded as a frontalin framework fused to two cyclohexane rings (Scheme 1). As in reactions with fatty aromatic ketones, molecule 2 is built up from two cyclohexanone and two acetylene molecules. It is assembled under mild conditions (70°C, 1 h) at a 1-to-KOH molar ratio of 1 : 1. Compound 2 was isolated in 43% yield. According to the H and C NMR data, the product was a mixture of several isomers, mainly of three ones at a ratio of 3 : 2 : 2. Presumably, isomers of 2 differ by the modes of junction of the cyclohexane and frontalin fragments (by analogy with cisand trans-decalins [6]). A probable reaction scheme is shown in Scheme 2. It includes nucleophilic addition of carbanion derived from cyclohexanone to acetylene, prototropic isomerization of adduct A, addition of the second cyclohexanone molecule to isomer B, Favorskii ethynylation of 1,5-diketone C, intramolecular hemiacetalization of acetylenic hydroxy ketone D, and intramolecular nucleophilic addition of the hydroxy group of hemiacetal E to the triple bond (Scheme 2). There are reasons to believe that the described cascade assembly is applicable to other cycloaliphatic ketones. It opens the possibility of developing one-pot syntheses of previously unknown frontalin derivatives via cascade CH-functionalizations with ketones and acetylene that are simple and readily accessible compounds. 7-Methyl-15-methylidene-14,16-dioxatetracyclo[11.2.1.0.0]hexadecane (2). A 250-mL Paar 4576A reactor was charged with a mixture of 5 g (50 mmol) of cyclohexanone (1) and 3.26 g (50 mmol) of finely powdered KOH · 0.5 H2O in 100 mL of DMSO (containing ~0.2% of water). The reactor was purged with acetylene under pressure to expel air, acetylene was then supplied to an initial pressure of 10 atm (during the process, the acetylene pressure did not exceed 12 atm), and the reactor was heated to 70°C ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 12, pp. 1799–1800.