Favorskii Reaction Research Articles

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).

Synthesis and Myelostimulatory Activity of 1-(2-Ethoxyethyl) Piperidine Derivatives

This study concerns the synthesis of 1-(2-ethoxyethyl)-4-oktynyl-4-hydroxypiperidine derivatives. The condensation of 1-(2-ethoxyethyl)-4-oxopiperidine with 1-oktyne by modified Favorskii reaction gave 1-(2-ethoxyethyl)-4-oktynyl-4-hydroxypiperidine. The structure of 4-alkynylpiperid-4-ol is in a good agreement with the results of elemental analysis and IR and 13C NMR spectral data. Acylation of hydroxyl group of obtained alcohol led to corresponding esters. To carry out the preliminary pharmacological study and to obtain the solid forms of new potentially biologically active piperidine derivatives their β-cyclodextrin complexes with β-cyclodextrin have been synthesized. The pharmacological activities of new compounds were predicted by PASS computer program. It has been found that 1-(2-ethoxyethyl)-4-oktynyl-4-acyloxypiperidines can exhibit anesthetic, anesthetic local, spasmolytic and immunosuppressory effects. The preliminary study of 1-(2-ethoxyethyl)-4-(oktyn-1-yl)-4-propionyloxypiperidine (BIV-71) and 1-(2-ethoxyethyl)-4-(oktyn-1-yl)-4-benzoyloxypiperidine (BIV-81) activities were carried out. It was shown that esters complexes possess a higher myelostimulatory activities compared with levamisole as standard. The acute toxicity of the β-cyclodextrin complexes is smaller than levamisole ones.

ChemInform Abstract: Improved Synthesis of Tertiary Propargyl Alcohols by the Favorskii Reaction of Alkyl Aryl (Hetaryl) Ketones with Acetylene.

AbstractTertiary propargyl alcohols bearing aryl or heteroaryl substituents are readily accessible from the corresponding ketones and acetylene under atmospheric pressure using a superbasic system.

Improved synthesis of tertiary propargyl alcohols by the Favorskii reaction of alkyl aryl (hetaryl) ketones with acetylene

Alkyl aryl (hetaryl) ketones react with acetylene under atmospheric pressure in the superbasic system KOH-EtOH-H2O-DMSO at 10–15°C (2 h) to give the corresponding tertiary propargyl alcohols in up to 91% yield. The procedure requires no large excess of KOH and low-boiling inflammable solvents, produces few wastes, and is safe and convenient on the laboratory scale; there are no limitations for its large-scale application.

ChemInform Abstract: One‐Pot Synthesis of 1‐Ethynylcyclohexyl Vinyl Ether from Cyclohexanone and Acetylene.

Vinyl ether derived from tertiary acetylenic alcohols have not been reported so far. The reason is that such alcohols are unstable on heating in the presence of bases (classical retro-Favorskii reaction) [1–3]. Nevertheless, insofar as the Favorskii reaction is reversible, we can presume that O-vinylation of a tertiary acetylenic alcohol present in the reaction mixture even at a small concentration should eventually lead to expected vinyl ether due to continuous displacement of the equilibrium (Scheme 1). Therefore, vinyl ethers of tertiary acetylenic alcohols could be obtained in one step by heating ketones with acetylene in the presence of a base. Screening of the reaction conditions and superbasic catalytic systems, as well as of ketones and acetylenic compounds used as reactants, has shown that 1-ethynylcyclohexyl vinyl ether (III) is indeed formed upon treatment of cyclohexanone (I) with acetylene in the presence of a base. In the reaction performed in a suspension of KOH in DMSO (molar ratio I–KOH 1 : 1) at 90°C under acetylene pressure the yield of vinyl ether III reached 40% (Scheme 2). An important condition is acetylene pressure which ensures its high concentration in the liquid phase and favors displacement of equilibrium toward formation of 1-ethynylcyclohexan-1-ol (II) which then undergoes vinylation (Scheme 2). ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 6, pp. 858–859. © Pleiades Publishing, Ltd., 2012. Original Russian Text © B.A. Trofimov, E.Yu. Shmidt, I.A. Bidusenko, E.V. Ivanova, N.V. Zorina, A.I. Mikhaleva, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 6, pp. 860–861.

One-pot synthesis of 1-ethynylcyclohexyl vinyl ether from cyclohexanone and acetylene

Vinyl ether derived from tertiary acetylenic alcohols have not been reported so far. The reason is that such alcohols are unstable on heating in the presence of bases (classical retro-Favorskii reaction) [1–3]. Nevertheless, insofar as the Favorskii reaction is reversible, we can presume that O-vinylation of a tertiary acetylenic alcohol present in the reaction mixture even at a small concentration should eventually lead to expected vinyl ether due to continuous displacement of the equilibrium (Scheme 1). Therefore, vinyl ethers of tertiary acetylenic alcohols could be obtained in one step by heating ketones with acetylene in the presence of a base. Screening of the reaction conditions and superbasic catalytic systems, as well as of ketones and acetylenic compounds used as reactants, has shown that 1-ethynylcyclohexyl vinyl ether (III) is indeed formed upon treatment of cyclohexanone (I) with acetylene in the presence of a base. In the reaction performed in a suspension of KOH in DMSO (molar ratio I–KOH 1 : 1) at 90°C under acetylene pressure the yield of vinyl ether III reached 40% (Scheme 2). An important condition is acetylene pressure which ensures its high concentration in the liquid phase and favors displacement of equilibrium toward formation of 1-ethynylcyclohexan-1-ol (II) which then undergoes vinylation (Scheme 2). ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 6, pp. 858–859. © Pleiades Publishing, Ltd., 2012. Original Russian Text © B.A. Trofimov, E.Yu. Shmidt, I.A. Bidusenko, E.V. Ivanova, N.V. Zorina, A.I. Mikhaleva, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 6, pp. 860–861.

Howard E. Zimmerman (1926-2012)

Howard E. Zimmerman (1926-2012)

Process Development of a Diacyl Glycerolacyltransferase-1 Inhibitor

A synthesis of a selective diacyl glycerolacyltransferase-1 (DGAT-1) inhibitor, 1, is described. The synthesis illustrates a diketone Favorskii reaction on 9 in place of the more common ketoester variant for generation of the dicarboxycyclopentane core, the development of an efficient classical resolution of a key cyclopentyl ketoacid intermediate 4, and an ambient temperature Suzuki−Miyaura coupling which avoids epimerization of the labile aryl ketone of 1.

Theoretical investigation of mono- and bi-function alkylating agents transformed from nitrosodimethylamine derivatives

In vivo, N-hydroxymethyl-methylnitrosamine (HMMN) and N-acetoxymethyl-methylnitrosamine (AMMN) are the activated derivatives of N-nitrosodimethylamine (NDMA) which is a potent carcinogen. The mechanistic pathway of the transformations of HMMN and AMMN have been investigated at B3LYP/6-311+G(d, p) level. The results show that the decomposition of HMMN to a mono-function alkylating agent proceeds through a stepwise mechanism involving isomerization and retro-ene reaction, in which the former is the rate-determining step in the gas phase with the energy barrier of about 24 kcal/mol. For the transformation of AMMN, a bi-function alkylating agent is produced via an intramolecular rearrangement mechanism which is similar to the Favorskii reaction.

Polymer-Supported Carboxylate as a New Polymeric Reagent for Synthesis of Alkyl Esters

Polymer supported reagents especially anion exchange resins have been widely applied in organic synthesis. These polymeric reagents are generally used in single step reactions. Their main advantage over monomeric reagents is their insolubility in the reaction medium and consequently the easier workup by a simple filtration. The reactions can often be driven to completion by using excess of these reagents without the fear of separating the unspent reagent from the desired products. The spent polymeric reagents can usually be removed quantitatively and regenerated. In addition, anions bound to the macroporous resin have the advantage that they often react successfully in non-polar solvents. The ester group is an important functional group that can be synthesized in a number of different ways such as acylation of alcohols, oxidation of aldehydes, addition of carboxylic acids to alkenes, reaction of carboxylic acids with diazomethane, Bayer-Villiger oxidation of ketones, reaction of organoboranes with α-halo esters, rearrangement of α-haloketones (Favorskii reaction) and especially for large scale operation by reaction of carboxylate salts or Amberlite IRA-904 supported carboxylate ion with alkyl halides or tosylates. Sodium carboxylate, however, has been the reagent most widely used. Unfortunately, each of these methods suffer from at least one of the following disadvantages: (1) the yields of the reactions are low, (2) the reaction has to be carried out in the presence of phase transfer catalyst, (3) the reaction mixture has to be acidified or the reaction has to be catalyzed by a base such as pyridine, and (4) tedious work-up procedure. Polymer-supported carboxylate ion overcomes most of the above mentioned disadvantages. In this study we wish to report an important, efficient, and easy method for preparation of alkyl acetate or alkyl formate esters from crosslinked poly(4-vinylpyridinium) acetate (I) or crosslinked poly(4-vinylpyridinium) formate (II) with alkyl halides (Scheme 1). While there are numerous applications of solid-supported reagents and scavengers only a few examples for the formation of esters were described. Solid-supported acids were used as catalysts in the esterification of carboxylic acids with alcohols. Carboxylates, generated with solidsupported organic bases, were alkylated with alkyl halides. Solid-supported organic bases were also used as scavenger resins in the esterification of benzyl alcohol with benzyl chlorides, giving clean benzyl esters in high yields. A modification of the Mitsunobu reaction with resin-bound triphenylphosphine and soluble di-t-butylazodicarboxylate was described, that allowed for the isolation of pure products without chromatography. A very recent report described the alkylation of carboxylic acids with carbenium ions, generated from polymer-supported triazines, for the ester formation. We report here a convenient and general procedure for the synthesis of esters from alkyl halides and polymer-supported carboxylate ion that readily prepared from employing the commercially available poly(4-vinylpyridine) (2% crosslinked with DVB) resin as the solid-supported condensation reagent. Crosslinked poly(N-methyl-4-vinylpyridinium) acetate (I) and crosslinked poly(N-methyl-4-vinylpyridinium) formate (II) were prepared by an exchange reaction between crosslinked poly(N-methyl-4-vinylpyridinium) iodide with a slight excess of sodium acetate or sodium formate solution in water. Using these heterogeneous reagents converted benzyl halides to benzyl acetate or benzyl formate esters in acetone under reflux condition. The advantages of this method are: 1) the reaction can be performed in non-aqueous medium; 2) an excess of the reagent can be used; 3) the product can be obtained by simple filtration and evaporation of the solvent; and 4) the polymeric reagent is easily regenerable with a sodium acetate or sodium formate solution. Crosslinked polymers (I) and (II) can be easily prepared and used as mild and efficient polymeric reagents for conversion of benzyl halides to the corresponding benzyl acetate and benzyl formates. It was proved that acetone is the best solvent for these reactions. In these conversions, the best molar ratio of reagent/substrate proved was 1.5, but

A Theoretical Study of Favorskii Reaction Stereochemistry. Lessons in Torquoselectivity

The mechanisms of the chloroenolate-->cyclopropanone step of the "normal" Favorskii rearrangement have been investigated in detail using high-level ab initio calculations. A series of simple alpha-chloroenolates, based on chloroacetone (6), all monomethyl derivatives (7-9), a dimethyl analogue (10), and 1-acetyl-1-chlorocyclohexane (11) was first used to explore and define the basic features of the mechanism, which include the finding of both an "inversion" and a "retention" transition state and that in most cases these arise from separate ground-state conformations of the chloroenolate. These theoretical studies were then extended to an isomeric pair of chloroenolates 1 and 2, the cis- and trans-2-methyl derivatives of 11, which are the reactive intermediates involved in a well-known experimental study carried out by Stork and Borowitz (S-B). Finally, three alpha-chlorocyclohexanone enolate systems 12-14 were studied, since these intermediates have a more restricted enolate geometry. The "inversion" mechanism has been described as an SN2 process but the present results, while supporting a concerted process, is better described as an oxyallyl structure undergoing concerted ring closure. The "retention" mechanism has been described as SN1-like, but the calculations show that this process is also concerted, although much less so, and again involves oxyallyl-like transition-states. The model systems 6-8, 10, and 11 with a potential plane of symmetry have two enantiomeric transition states for inversion and another two for retention of configuration (at the C-Cl center). With 9 and the S-B models 1 and 2, with no symmetry plane, there are a calculated total of four diastereomeric transition states for cyclopropanone ring closure in each case, two for inversion and two for retention. While the transition-state energies calculated for simple chloroenolates favor the inversion process, the S-B models 1 and 2 have almost equal inversion-retention transition-state energies. Solvation simulation calculations of ground states and transition states suggest that the retention mechanism becomes relatively more favored in polar solvents, in agreement with some experimental results. In the chloroenolates 12-14, both inversion and retention mechanisms were also located, these arising from two different ground-state ring conformations of the enolate. In these models, one also finds similar inversion and retention transition-state energies, but again with a small preference for the inversion process.

Synthesis, structure, and transformations of 3-(N-Cytisinyl)propyne

3-(N-Cytisinyl)propyne was synthesized, and its transformations under Favorskii reaction conditions were studied and X-ray diffraction analysis was performed.

Intramolecular ring closure via ether bond in reaction of α,α′-halogeno bicyclo[3.3.1]nonanediones under basic conditions

The stereoselectivity of halogenation of bicyclo[3.3.1]nonan-2-one 1 and bicyclo[3.3.1]nonane-2,6-dione 2 with molecular bromine and chlorine was studied. The transformation of α-bromo- and chloro-bicyclo[3.3.1]nonanones 3–5 under Favorskii reaction conditions was studied. The reaction of α,α′-dihalogeno diones in the presence of sodium methoxide, ethoxide, propoxide and potassium cyanide led to the intramolecular ring closure via C–O bond formation giving the highly functionalized chiral 2-oxatricyclo[4.3.1.03,8]decane (2-oxaprotoadamantane) structure. Enantiomers of this cage structure were resolved by chiral GLC. The intramolecular ring closure pathway involving the intermediate alkoxybicyclo[3.3.1]nonanolate structure was proposed.

Formation of 2-oxatricyclo[4.3.1.03,8]decanes in intramolecular cyclization of α-halobicyclo[3.3.1]nonanones

Transformations of α-chloro- and α-bromobicyclo[3.3.1]nonanones under conditions of the Favorskii reaction were studied. The interaction of dihalodiketones with MeONa gives 2-oxatricyclo[4.3.1.03.8]decane (oxaprotoadamantane) derivatives as a result of intramolecular cyclization, whereas 3-bromobicyclononanone undergoes only nucleophilic substitution of bromine.

ChemInform Abstract: Polycycles from 1,5‐Cyclooctadiene and Chlorocyanoketene.

AbstractChlorocyanoketene derived by method A) from (V) adds to cyclohexene (I) or cyclooctene (VI) stereoselectively to give (II) or (VII), both of which undergo Favorskii reaction to yield the bicyclic acids or esters (III)/(IV) or (VIII).

ChemInform Abstract: Favorskii Reaction of 2‐Bromobicyclo[3.3.1]nonan‐3‐one.

AbstractDie Favorskii‐Umlagerung des 2ß‐ (II) bzw. Za‐Brom‐bicyclononans (III) mit Natriummethanolat in Methanol oder Dimethoxyethan (DME) bei 0°C führt stereospezifisch zu dem exo‐ Ester (V).

ChemInform Abstract: Synthesis of Primary‐Ditertiary Enyne Triols, Their Monoethers and Their Hydrogenation.

AbstractThe condensation of the hydroxyketones (Ia) and (Ib) and of the keto ethers (Ic) and (Id) with the enyne alcohol (II) under the conditions of the Favorskii reaction affords the title compounds as separable mixtures of the cis‐compounds (III) and the trans‐compounds (IV).

Favorskii reaction of 2-bromobicyclo(3.3.1)nonan-3-one.

Both 2β-bromobicyclo[3.3.1]nonan-3-one (IIa) and its 2α- epimer (IIb) afforded methyl bicyclo[3.2.1]octane-6β-carboxylate (IIIa) stereoselectively in the Favorskii reaction using sodium methoxide in methanol. In the reaction using sodium methoxide in dimethoxyethane (DME) at room temperature, the stereoselectivity decreased and the product was contaminated with methyl bicyclo[3.2.1]octane-6α-carboxylate (IIIb). However, when the reaction in DME was carried out at 0°C, IIIa was the only product.The routes involved in these transformations were examined by using nuclear magnetic resonance spectroscopic techniques with the deuterated compounds.

Synthesis of optically active 1,2,5-trimethyl-4-ethynyl-4-piperidols and the corresponding diacetylenic glycols

The following optically active enantiomeric pairs were synthesized by the Favorskii reaction from (+)-(2S,5R)- and (−)-(2R,5S)-trans-1,2,5-trimethyl-4-piperidones: (+)-(2S,4R,5R)- and (−)-(2R,4S,5S)-trans-1,2,5-trimethyl-4-ethynyl-4-piperidol and (+)-(2S,4S,5R)- and (−)-(2R,4R,5S)-trans-1,2,5-trimethyl-4-ethynyl-4-piperidol. Optically active 1,4-bis(1,2,5-trimethyl-4-hydroxy-4-piperidyl) buta-1,3-diynes were obtained by Glaser oxidative dimerization of the enantiomeric pairs of ethynylpiperidols. The antagonistic action of the dihydrochlorides of (+)-(2S,4R,5R)- and (−)-1,4-bis[(2R,4S,5S)-1,2,5-trimethyl-4-hydroxy-4-piperidyl]buta-1,3-diyne on cell respiration was established from the results of biological tests on cultures of tobacco and Chlorella cells.

Selective Favorskii rearrangment of α,α,α′-dibromochlorocycloalkanones of medium ring size

α,α,α′-Dibromochlorocycloalkanones of medium ring size have been prepared by treatment of chlorocycloalkanones with bromine and were separated by chromatorgraphy and then submitted to Favorskii reaction. The stereoisomeric reaction products have in each case been evaluated by gas chromatography and the selectivity of bromide elimination deduced.