Reductivetrans-2,6-diallylation of pyridines with allylboranes. Synthesis oftrans- andcis-2,6-diallyl-1,2,5,6-tetrahydropyridines and their deuterated derivatives

The reductivetrans-2,6-diallylation of pyridines with triallyl- and allyl(dialkyl)boranes has been discovered. Heating (40–100 °C) of pyridine, deuteropyridine, or 3-bromopyridine complexes with triallylborane in the presence of alcohols (ROH or CH₃OD), water, or Et₂NH results in the respectivetrans-2,6-diaIlyl-1,2,5,6-tetrahydropyridines (2,3,22, or25) in 20–97 % yields. A preparative method for the isomerization oftrans-2,6-diallyl compounds2 and25 into the respectivecis-isomers4 and28 by heating them with triallyl- or allyl(dialkyl)boranes (125–150 °C) has been suggested. The hydrogenation oftrans- orcis-2,6-diallyl-1,2,5,6-tetrahydropyridines gavetrans- orcis-2,6-dipropylpiperidines, respectively. Thecis- andtrans-configurations of compounds2 and4 were established by analyzing the NMR spectra ofN-benzyl (7 and13) andN,N-dimethyl (6 and 14) derivatives of piperidine derivatives5 and8. A possible mechanism for the reductive diallylation of pyridines has been discussed.Translated fromIzyestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 693–704, April, 1994.This study was financially supported by the Russian Foundation for Basic Research (Project 93-03-18193).     

Stereoselective synthesis of (±)-indolizidines 167B and 209D and theirtrans-isomers based on the reductive allylboration of pyridine

A general method for the synthesis of 5-substituted indolizidines based on intramolecular cyclization oftrans- andcis-2-allyl-6-R-1,2,3,6-tetrahydropyridines, obtained from pyridine and triallylborane, has been elaborated. The closure of the five-membered ring is carried out by hydroboration-oxidation followed by cyclization of the resulting δ-amino alcohols in the presence of the Ph₃P−CBr₄−Et₃N system. (Pr₂BH)₂ and Pr₃B are used as the hydroborating reagents, and H₂O₂ in an acid medium is used for the oxidation of 2-[3-(dipropylboryl]-Δ²-piperideines formed. This method has been used for the synthesis of two natural alkaloids: indolizidine 209D (cis-5-hexylindolizidine) and itstrans-isomer were prepared fromcis- andtrans-2-allyl-6-hexyl-1,2,3,6-tetrahydropiridine, respectively; indolizidine 167B andtrans-5-propylindolizidine were synthesized fromcis- andtrans-2,6-diallyl-1,2,3,6-tetra-hydropyridine, respectively. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 971–979, May, 1998.     

Preparative electroreduction oftrans-2-allyl-6-methyl(phenyl)-1,2,3,6-tetrahydropyridine

Electrocatalytic hydrogenation oftrans-2-allyl-6-phenyl-1,2,3,6-tetrahydropyridine andtrans-2-allyl-6-methyl-1,2,3,6-tetrahydropyridine in 40% aqueous DMF in the presence of AcOH on a nickel cathode gavetrans-6-phenyl-2-propylpiperidine andtrans-2-methyl-6-propylpiperidine ((±)-epidihydropinidine), respectively. Direct electroreduction oftrans-2-allyl-6-phenyl-1,2,3,6-tetrahydropyridine in anhydrous DMF on a mercury cathode afforded a 7 ∶ 5 mixture oftrans- andcis-2-allyl-6-phenylpiperidine. The structure of the latter compound was confirmed by 2D NOESY spectroscopy. The possible mechanism of formation of thecis-isomer is discussed. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No.4, pp. 758–761, April, 1999.     

Transformations of pyridine and deuteropyridine under the action of trimethallylborane and alcohols. Synthesis oftrans- andcis-2,6-dimethallyl-1,2,3,6-tetrahydropyridines and theirN-derivatives

Reductivetrans-2,6-dimethallylation of pyridine and deuteropyridine with trimethallylborane in the presence of alcohols proceeds at room temperature,i.e., under substantially milder conditions than the analogous reaction with the participation of triallylborane.trans-2,6-Di(2-methylallyl)-1,2,3,6-tetrahydropyridine (3) was obtained in a yield of 87%. When heated with trimethallylborane (130–135°C, 2.5 h), compound3 underwent isomerization tocis-2,6-di(2-methylallyl)-1,2,3,6-tetrahydropyridine (4). Hydrogenation oftrans- (3) andcis-isomers (4) yieldedtrans- andcis-2,6-diisobutylpiperidines, respectively. The heterocycles obtained wereN-functionalized by reactions with MeI, PhCH₂Cl, ethylene oxide, and perfluoropropyloxirane. The stereochemistry of thecis- andtrans-isomers (3 and4) was established based on the NMR spectra of theirN,N-dimethyl salts and the products of the reaction with ethylene oxide.trans-2,6-Dimethallyl-2,3,4,5,6-pentadeutero-1,2,3,6-tetrahydropyridine and a number of its derivatives were prepared from the complex of trimethallylborane with C₅D₅N. A probable mechanism of the reductivetrans-2,6-diallylation of pyridines with allylboranes in the presence of alcohols is discussed. This article is dedicated to Prof. W. Siebert (Heidelberg) on the occasion of his 60th birthday. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1361–1370, July, 1997.     

Reductive mono- and diallylation of the bis(pyridine)dihydropyridyllithium dimer by triallylborane

Reductive allylation of the bis(pyridine)dihydropyridyllithium dimer containing the 1,2- and 1,4-dihydropyridine fragments by triallylborane results mainly in trans- and cis-2,6-diallylpiperidines (60—85%), their ratio depending on the nature of the solvent. The minor reactions products are 2-allyl-1,2,3,6-tetrahydropyridine and 4,10-diallyl-3,9-diazatricyclo[6.2.2.0^2,7]dodecane. The unexpected formation of the latter is due to hetero-Diels—Alder condensation of intermediate products formed in the allylboration of dihydropyridines. The stereochemistry of trans- and cis-2,6-diallylpiperidines was determined from the ¹H and ¹³C NMR spectra of the respective N,N-dimethylpiperidinium iodides. The structure of 4,10-diallyl-3,9-diazatricyclo[6.2.2.0^2,7]dodecane dipicrate was established by X-ray diffraction analysis.     

Preparation oftrans- andcis-2-allyl-6-alkyl(aryl)-1,2,3,6-tetrahydropyridines based on the reductivetrans-2,6-dialkylation of pyridine. Synthesis of (±)-epidihydropinidine and (±)-dihydropinidine

A general method for the preparation of unsymmetricaltrans-2-allyl-6-alkyl(aryl)-1,2,3,6-tetrahydropyridines6 based on a combination of 1,2-addition of RLi to pyridine andtrans-6-allylation with triallylborane in the presence of methanol was elaborated. It was shown thattrans-piperideines (6 (R=Alk, Ph) isomerize into the correspondingcis-2-allyl-6-alkyl(phenyl)-3-piperideines14 on heating with triallylborane followed by deboronation of aminoborane (16) with methanol and an alkali. The stereochemistry of compounds6 and14 was determined by two-dimensional NOE spectroscopy. A possible mechanism of the formation oftrans-amines6 and their transformation intocis-isomers14 is discussed. Alkaloids (±)-epidihydropinidine (trans-2-methyl-6-propylpiperidine2a, 70%) and (±)-dihydropinidine (cis-2-methyl-6-propylpiperidine1d, 71%) were synthesized by hydrogenation of compound6a (R=Me) and14a (R=Me), respectively, over Raney nickel. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 467–474, March, 1998.     

Peculiarities of electroreduction of trans-2-allyl-6-methyl(allyl,phenyl)-1,2,3,6-tetrahydropyridines

Electrochemical reduction of trans-2-allyl-6-R-1,2,3,6-tetrahydropyridines (R = Me, All, and Ph) on the mercury cathode in anhydrous DMF (with 0.1 M Bu₄NClO₄ as the supporting electrolyte) resulted in catalytic hydrogen evolution, while in the case of anhydrous DMF the electrochemical activity of the endocyclic double bond was dictated by the nature of the R substituent at the carbon atom neighboring the double bond. The electrocatalytic hydrogenation of the piperideines under study on the Ni (Ni_disp/Ni) cathode in 40% aqueous DMF in the presence of a tenfold excess of AcOH yielded the corresponding trans-2-propyl-6-R¹-piperidines (R¹ = Me, Pr, and Ph). Using trans-2,6-diallyl-1,2,3,6-tetrahydropyridine as an example, the conditions (with annealed copper as the cathode) for selective hydrogenation of the double bonds in allyl substituents with preservation of the endocyclic double bond were found.     

Synthesis of bridged azabicycles from isoquinolines via a tandem of allylboration and intramolecular metathesis

A method for the synthesis of bridged azabicyclic compounds from isoquinolines was developed. The method is based on a combination of allylboration and ruthenium-catalyzed intramolecular metathesis. Reductive 1,3-diallylation of bromoisoquinolines with triallylborane gave trans-1,3-diallyl-1,2,3,4-tetrahydroisoquinolines. When heated with triallylborane, these compounds yielded mixtures of cis-and trans-isomers in the ratio ∼1: 1. The structure of cis-1,3-diallyl-5-bromo-1,2,3,4-tetrahydroisoquinoline was confirmed by X-ray diffraction analysis. In a similar way, trans-3-allyl-1-vinyl-1,2,3,4-tetrahydroisoquinoline synthesized by sequential vinylation (with vinyllithium) and allylboration of isoquinoline, yielded a mixture of cis-and trans-isomers in the ratio 1.6: 1. Intramolecular metathesis reactions of N-Boc derivatives of cis-isomers in the presence of the Grubbs catalyst (2.0–2.5 mol.%) afforded 7,8-benzo-10-azabicyclo[4.3.1]dec-2-enes or 7,8-benzo-9-azabicyclo[3.3.1]non-2-ene in nearly quantitative yields. Dedicated to Academician V. A. Tartakovsky on the occasion of his 75th birthday. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1510–1515, August, 2007.     

Reductive allylation of pyrrole with allylboranes. Synthesis oftrans- andcis-2,5-disubstituted pyrrolidines

Pyrrole undergoes reductive mono- and diallylation on successive treatment with β,γ-unsaturated organoboron derivatives (triallylborane, allyl(dipropyl)borane, and triprenylborane) and alcohols to give 2-allylated 3-pyrrolines andtrans-2,5-diallylated pyrrolidines. The addition of both the first and second boron-allylic fragment to the heterocycle proceeds with rearrangement. A method for transformation of thetrans-2,5-diallylpyrrolidine into thecis-isomer (heating with triallylborane at 190 °C) was developed and a series ofN-substituted derivatives of these pyrrolidines was synthesized. A method for the preparative synthesis of nonsymmetrically substitutedtrans- andcis-2-alkyl(phenyl)-5-allylpyrrolidines, based on reductive allylboration of pyrrole followed by 1,2-addition of RLi to the 5-allyl-1-pyrroline that formed, was also developed. A direct confirmation of intermediate formation of 2H- and 3H-pyrrole tautomers under the action of allylboranes was obtained. The adduct of 2H-pyrrole with BF₃ was detected by NMR spectroscopy. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1718–1728, September, 1999.     

Transformation of 1,2,5,6-Tetrahydropyridines with Mycellar Fungi

It has been shown that on biotransformation of a series of 1,2,5,6-tetrahydropyridines with strains of the mycellar fungi Cunninghamella verticillata VKPM F-430, Beauveria bassiana ATCC 7159, and Penicillium simplicissimum KM-16, the culture of Cunninghamella verticillata possesses the greatest transforming activity and selectivity. With the aid of the latter practically quantitative oxidation of 1,2,5,6-tetrahydropyridines occurs into the corresponding trans-diol. The structure and spatial disposition of trans-1-benzyl-3,4-dihydroxypiperidine was demonstrated by data of chromato-mass spectrometric analysis and high resolution NMR spectra and was confirmed by comparison with an authentic sample obtained by an alternate synthesis using the oxidation of 1-benzyl-1,2,5,6-tetrahydropyridine with trifluoroperacetic acid.     

Reactions of 3-amino-1-phenyl- and 3-amino-1-(thien-2-yl)-4,4,4-trifluorobut-2-en-1-ones with 1,2-diaminopropane and 1,2-diamino-3,3,3-trifluoropropane

The reactions of 3-amino-1-phenyl-and 3-amino-1-(thien-2-yl)-4,4,4-trifluorobut-2-en-1-ones with 1,2-diaminopropane under kinetically controlled conditions afford mixtures ofcis andtrans isomers of 2-aroylmethyl-4-methyl-2-trifluoromethylimidazolidines. Analogous reactions with 1,2-diamino-3,3,3-trifluoropropane yieldcis-2-aroylmethyl-2,4-bis(trifluoro-methyl)imidazolidines. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2135–2139, November, 1999.     

Synthesis and molecular structure oftrans-2-allyl-6-phenyl-1,2,3,6-tetrahydropyridine hydrochloride

When treated with triallylborane and McOH, the product of the 1,2-addition of PhLi to pyridine transforms totrans-2-allyl-6-phenyl-1,2,3,6-tetrahydropyridine. The structure of its hydrochloride was established by X-ray structural analysis.Deceased in 1995.Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya, No. 11, pp 2736–2738, November, 1996.     

Oxidizing Reactions of Azines. 7. Imination of 4-Aryl-1,2,3,6-tetrahydropyridines by Arylamines in the Presence of Potassium Permanganate. Molecular Structure of 1-Methyl-2-(4-nitrophenylimino)-4-phenyl-1,2,5,6-tetrahydropyridine

On treating 4-aryl substituted 1-methyl-1,2,3,6-tetrahydropyridines with potassium permanganate in the presence of arylamines a previously unknown intermolecular oxidative imination reaction occurs leading to the formation of 2-(arylimino)-1,2,5,6-tetrahydropyridines. The molecular structure of 1-methyl-2-(4-nitrophenylimino)-4-phenyl-1,2,5,6-tetrahydropyridine was studied by X-ray analysis and it was shown that the hydropyridine ring of the molecule has a sofa conformation and its amidine fragment is in the E-configuration.     

High-Performance liquid chromatographic separation of enantiomers of unusual amino acids possessing cycloalkane or cycloalkene skeletons on a chiral crown ether containing stationary phase

Summary Direct reversed-phase high-performance liquid chromatographic methods were developed for the separation and identification of the enantiomers of mono- and bicyclic racemic β-amino acids:cis- andtrans-2-aminocyclopentane-1-carboxylic acids,cis- andtrans-2-aminocyclohexane-1-carboxylic acids,cis- andtrans-2-amino-4-cyclohexene-1-carboxylic acids,diendo- anddiexo-3-aminobicyclo[2.2.1]heptane-2-carboxylic acids anddiendo- anddiexo-3-amino-5-bicyclo[2.2.1]heptene-2-carboxylic acids. Enantioseparation was carried out by the application of a chiral stationary phase, Crownpak CR(+). The conditions of separation were optimized by changing the temperature, the flow rate and the pH of the mobile phase. Presented at: Balaton Symposium on High-Performance Separation Methods, Siófok, Hungary, September 3–5, 1997.     

Reaction of 2-isobutyl-5-methyl-4-phenyl-1,3,2-dioxaborinane with acetonitrile

Reaction of 2-isobutyl-5-methyl-4-phenyl-1,3,2-dioxaborinane (a mixture ofcis- andtrans-isomers in a 81 : 19 ratio) with acetonitrile yielded 2,5-dimethyl-4-phenyl-5,6-dihydro1, 3-oxazine as a mixture ofcis- andtrans-forms in a 50 : 50 ratio. The possible mechanism of this transformation is discussed.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1297–1298, May, 1996.     

Synthesis and molecular structure of 3-bromo-trans-2,6-diallyl-Δ3-piperideine hydrochloride

The structure of 3-bromo-trans-2,6-diallyl-³-piperideine hydrochloride was determined by X-ray diffraction analysis. The corresponding base was prepared by reductive diallylation of 3-bromopyridine with triallylborane. 3-Bromo-cis-2,6-diallyl-₃-piperideine3 was prepared by heatingtrans-isomer2 with triallylborane at 130 °C followed by deboronation of the resulting aminoborane with a solution of sodium hydroxide.Translated fromIzyestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 705–707, April, 1994.This work was carried out with the financial support of the Russian Foundation for Basic Research (project No 93-03-18193).     

Study of radical cations ofcis- andtrans-decalin in nonpolar solutions by the MARY and optically detected ESR spectroscopy

Radical cations ofcis- andtrans-decalin in nonpolar solvents were studied by optically detected ESR and magnetically affected reaction yield (MARY) spectroscopy. The observed differences in the spectra ofcis- andtrans-decalin are in agreement with the assumption of the existence of temperature-activated intramolecular dynamic transitions in the radical cation oftrans-decalin. Using MARY spectroscopy, the signals of the corresponding radical cations were detected at room temperature in diluted solutions containingcis- andtrans-decalin molecules as acceptors. Under these conditions, the total recovery of dynamic transitions in the radical cation oftrans-decalin is observed. Radical cations of bothcis- andtrans-decalin participate in the reaction of the ion-molecular charge transfer to a neutral molecule; the rate constant of this reaction is close to the diffusion-controlled one. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 968–973, May 1997.     

Reductivetrans-1,3-dialkylation of isoquinoline on treatment with RLi and triallylborane

The preparative synthesis oftrans-1-alkyl(aryl)-3-allyl-1,2,3,4-tetrahydroisoquinolines based on the 1,2-addition of RLi to isoquinoline andtrans-allylboration is described. Dedicated to the memory of Academician M. E. Vol'pin timed to his 75th birthday. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1206–1209, June, 1998.     

Synthesis and structures of complexes ofN-2-nitroxyethylpicolinamide and 2-(2-pyridyl)-2-oxazoline with PdCl2

The reaction ofN,N′-bis(2-nitroxyethyl)pyridine-2,6-dicarboxamide with PdCl₂ afforded previously unknowncis-(N-2-nitroxyethylpicolinamide-N,N′)dichloropalladium(II) andcis-[2-(2-pyridyl)-2-oxazoline-N,N′]dichloropalladium(II), which were isolated as a cocrystallizate of the molecular compounds. Its structure was established by X-ray diffraction analysis. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1604–1606, August, 1999.     

Efficient access to chiral trans-2,6-dialkyl-1,2,5,6-tetrahydropyridines via allylation of chiral imines and ring-closing metathesis

Enantiomerically pure trans-2,6-dialkyl-1,2,5,6-tetrahydropyridines are synthesized in five steps from Garner's aldehyde in 37-44% overall yield. This strategy is based on the allylation of chiral iminoalcohols formed in situ followed by a ring-closing metathesis.