Esters of heterocyclic γ-amino alcohols

Reduction of cis-3-cyano-4-hydroxypiperidines with lithium aluminum hydride (LAH) gave cis-3-aminomethyl-4-hydroxypiperidines, which were converted to cis-3-dimethylaminomethyl-4-hydroxypiperidines by methylation with formaldehyde and formic acid. Acylation of the methylated compounds with benzoyl and cinnatnoyl chlorides gave the corresponding esters. Condensation of cis-3-aminomethyl-4-hydroxypiperidines with formaldehyde gave perhydropyrido[3,4-e][1,3]oxazines, which were converted to 3-methylaminomethyl-4-hydroxypiperidines by means of LAH. The cis isomers of the corresponding O,N-diacyl derivatives of these amino alcohols were obtained by acylation with acetic anhydride and benzoyl and cinnamoyl chlorides.See [1] for communication V.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1363–1368, October, 1978.     

Synthesis of stereoisomeric 1,3-dimethyl- and 1,2,5-trimethyl-4-acyl(benzoyl)-4-piperidinols

In order to synthesize stereoisometric 4-acyl(benzoyl)-1, 3-dimethyl and-1, 2, 5-trimethyl-4-piperidinols, the reaction of the geometrical isomers of 4-cyano-1, 3-dimethyl- and -1, 2, 5-trimethyl-4-piperidinols and the amines and imidic esters corresponding to them with some alkyl- and arylmagnesium halides, leading to the corresponding isomeric piperidinic α-ketols, has been studied. The dependence of the reactivity of the geometrical isomers of the compounds studied on the spatial orientation of their functional groups has been shown.     

Synthesis of stereoisomeric 1,3-dimethyl- and 1,2,5-trimethyl-4-acyl(benzoyl)-4-piperidinols

In order to synthesize stereoisometric 4-acyl(benzoyl)-1, 3-dimethyl and-1, 2, 5-trimethyl-4-piperidinols, the reaction of the geometrical isomers of 4-cyano-1, 3-dimethyl- and -1, 2, 5-trimethyl-4-piperidinols and the amines and imidic esters corresponding to them with some alkyl- and arylmagnesium halides, leading to the corresponding isomeric piperidinic -ketols, has been studied. The dependence of the reactivity of the geometrical isomers of the compounds studied on the spatial orientation of their functional groups has been shown.     

Synthesis and steric structure of 1,3(1,5)-dimethyl-2-phenyl-and -2,4-diphenyl-4-piperidols

1,3(1,5)-dimethyl-2-phenyl- and -2,4-diphenyl-4 piperidols were respectively obtained with the reaction of 1,3-and 1,5-dimethyl-2 phenyl-4-piperidoraes with sodium borohydride and phenyllithium. The steric isomers of the compounds obtained were separated and identified by spectral methods.Moscow State Academy of Precision Chemical Technology, Moscow 117571. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 941–945, July, 1994. Original submitted July 11, 1994.     

Mannich reaction in a number of six-membered heterocyclic γ-ketones

Aminomethylation of 2,2-dimethyl-4-oxotetrahydropyran gave a number of its aminomethyl derivatives, which were converted to tertiary γ-amino alcohols by phenylation. The individual structural and geometrical isomers were isolated, and their structures were established by mass spectrometry and PMR and IR spectroscopy.     

Syntheses of benzomorphan and related compounds. Part III. An alternate synthesis of 3-substituted-1,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6,11-dimethyl-3-benzazocine

Reduction of the appropriate Schiff bases gave 5-benzylamino-3-methyl-2-pentene (XVII) and l-benzylamino-3-methylpentane (XVIII), the condensation of which with methyl 3-(4-methoxyphenyl)-2,3-epoxypropionate afforded a mixture of the isomeric 1-benzyl-2-(4-methoxy-benzyl)-3,4-dimethyl-4-hydroxypiperidines (XIXa and XIXb). The piperidinols were heated with hydrobromic acid, respectively, to afford 3-benzyl-1,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6,11-dimethyl-3-benzazocine (II). Since the conversion of II to pentazocine (Ic) had already been accomplished, an alternate synthesis of Ic was achieved.     

Synthesis of trans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidine Opioid Antagonists: Application of the Cis-Thermal Elimination of Carbonates to Alkaloid Synthesis

Improved syntheses of twotrans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists from 1,3-dimethyl-4-piperidinone are described. The 1,3-dimethyl-4-arylpiperidinol 23 was selectively dehydrated in a two step process to the 1,3-dimethyl-4-aryl-1,2,3,6-tetrahydropyridine 26 by the cis-thermal elimination of the corresponding alkyl carbonate derivative at 190 degrees C. In the presence of a basic nitrogen, the success of the elimination was found to be critically dependent upon the nature of the carbonate alkyl group, with Et, i-Bu, and i-Pr being preferred (90% yield). Alkylation of the metalloenamine, formed by deprotonation of 26 with n-BuLi, proceeded regio- and stereospecifically to give the trans-3,4-dimethyl-4-aryl-1,2,3,4-tetrahydropyridine 27, which was converted in three steps to the common intermediate, (3R,4R)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine. LY255582, a centrally-active opioid antagonist, and LY246736-dihydrate, a peripherally-active opioid antagonist, were prepared from 1,3-dimethyl-4-piperidinone in 11.8% yield (8 steps) and 6.2% yield (12 steps), respectively.     

Isomerization of perfluoro-3,3-diethylindan-1-one into perfluoro-1,3-dimethyl-4-ethyl-1 H-isochromen under the action of antimony pentafluoride

The heating of perfluoro-3,3-diethylindan-1-one with SbF₅ at 180°C after treatment of the reaction mixture with anhydrous HF afforded perfluoro-1,3-dimethyl-4-ethylisochromen, and after hydrolysis, perfluoro-1,3-dimethyl-4-ethyl-1H-isochromen-1-ol. The latter under the action of NaHCO₃ converted into 5,6,7,8-tetrafluoro-1,3-bis(trifluoromethyl)-1H-isochromen-1-ol. Both isochromenols reacted with SOCl₂ gave the corresponding polyfluoro-1-chloro-1H-isochromens. On dissolving isochromenols in CF₃SO₃H and isochromens in SbF₅ perfluoro-1,3-dimethyl-4-ethylisochromenyl and 5,6,7,8-tetrafluoro-1,3-bis(trifluoromethyl)isochromenyl cations were generated which by hydrolysis were converted into the corresponding isochromenols.     

Preparation and some properties of 2H-imidazole 1,3-dioxides,derivatives of alicyclic 1,2-dioximes

The corresponding 2H-imidazole 1,3-dioxides were obtained by the reaction of cyclohexanedione and cycloheptadione 1,2-dioximes with acetone, cyclopentanone, and methyl ethyl ketone. The reactions of these compounds with hydroxylamine hydrochloride, NaBH₄, a Grignard reagent, and acetic anhydride in the presence of H₂SO₄ were studied in the case of 2,2-dimethyl-4,5,6,7-tetrahydro-2H-benzimidazole 1,3-dioxide. Bromination of the latter and 2,2-dimethylcyclohepta-2H-imidazole 1,3-dioxide with N-bromosuccinimide gave the corresponding dibromo derivatives, the bromine atoms in which are replaced by acetoxy and hydroxy groups. 4,7-Dihydroxy-2, 2-dimethyl-4,5,6,7-tetrahydro-2H-benzimidazole 1,3-dioxide, which was obtained by oxidation with MnO₂ was converted to a quinone, viz., 2,2-dimethyl-4,7-dioxo-4,7-dihydro-2H-benzimidazole 1,3-dioxide. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 808–813, June, 1980.     

Facile syntheses of 2,2-dimethyl-6-(2-oxoalkyl)-1,3-dioxin-4-ones and the corresponding 6-substituted 4-hydroxy-2-pyrones

A variety of 2,2-dimethyl-6-(2-oxoalkyl)-1,3-dioxin-4-ones 5a-l and the corresponding 6-substituted 4-hydroxy-2-pyrones 3a-l were prepared in high yields under mild reaction conditions by the reaction of 2,2,6-trimethyl-1,3-dioxin-4-one 4 with 1-acylbenzotriazoles 9 in the presence of LDA followed by thermal cyclization of 5a-l to 3a-l. Synthesis of novel 6-(1-benzoylalkyl)-2,2-dimethyl-1,3-dioxin-4-ones 12a-c was achieved by alkylation of dioxinone 5a and their subsequent cyclization gave 5-alkyl-4-hydroxy-2-pyrones 13a-c.     

[Co(2,3-tir)(amp)Cl]ZnCl4体系中三个几何经式异构体的 识别

对[Co(2,3-tir)(amp)Cl]ZnCl42,3-tri=N-(2-aminoethyl)-1,3-propanediamine;amp=2-(aminomethyl)pyridine)体系进行了合成,分离出四个配合物。用单晶X射线衍射分析了两个结构,用二维核磁共振DQCOSY和NOESY技术联合解板了另一结构。结构解析显示它们为该体系的四个几何经式异构体(meridianisomers)。两个晶体结构都属中心对称的空间群,表明它们都是外消旋的对映体。     

Sythese von α und β-Sinensal

β-Sinensal (2,6-dimethyl-10-methylene-dodeca-2,6,11-trienal) was synthesized from the diene-aldehyde 5 . This was converted into the trans- and cis-triene-aldehydes 16 and 17 , which were condensed with the phosphorane 18 to give the corresponding two geometrical isomers ( 3 and 19 ) of β-sinensal.     

Di-4(3H)-quinazolinon-2-yl Derivatives from the Diacid Chlorides of Pinic and sym-Homopinic Acids

The corresponding diamides have been synthesized by the interaction of the diacid chlorides of cis-2,2-dimethyl-3-carboxycyclobutaneacetic acid (pinic acid) and cis-2,2-dimethylcyclobutane-1,3-diacetic acid (sym-homopinic acid) with two equivalents of anthranilic acid. Treatment of the diamides with formamide gave 2,2-dimethyl-1-[4(3H)-quinazolinon-2-yl]methyl-3-[4(3H)-quinazolinon-2-yl]cyclobutane and 2,2-dimethyl-1,3-di[4(3H)-quinazolinon-2-ylmethyl]cyclobutane respectively.     

The Use of 4-(Bromomethylene)-5,5-dimethyl-1,3-dioxolan-2-one as “Masked” α-Bromo-α'-Hydroxy Ketone in the Synthesis of Heterocyclic Systems

4-(Bromomethylene)-5,5-dimethyl-1,3-dioxolan-2-one was obtained on the basis of the readily obtainable 4-methylene-5,5-dimethyl-1,3-dioxolan-2-one. It forms 2-imidazo[1,2-a]pyridin-2-yl-2-propanol with 2-aminopyridine, 11a-hydroxy-1,1-dimethyl-3-oxo-1,5,11,11a-tetrahydro[1,3]oxazolo[3,4-a]pyrido[1,2-d]-10-pyrazinium bromide with 2-(aminomethyl)pyridine, and the corresponding derivative of 4-hydroxyoxazolidin-2-one with 2-(3,4-dimethoxyphenyl)ethylamine. The last product was converted by intramolecular amidoalkylation without isolation into 10b-(bromomethyl)-8,9-dimethoxy-1,1-dimethyl-1,5,6,10b-tetrahydro[1,3]oxazolo[3,4-a]isoquinolin-3-one.     

Stereochemistry of heterocycles

2-Methyl-and 2,5-dialkyl-5-phenoxy-1,3-dioxanes were synthesized and separated into their geometrical isomers by precision rectification. The configuration and conformations of these isomers were determined by PMR spectroscopy. It is shown that the low-boiling trans isomers exist primarily in the chair conformation with an equatorial phenoxy group, whereas the high-boiling cis isomers exist primarily in the chair conformation with an axial phenoxy group.     

3-Methyl-9-benzylidene-2-azafluorene and its analogs

The possibility of obtaining 3-methyl-2-azafluorene by dehydrocyclization of 2,5-dimethyl-4-phenylpyridine at 500–750° in the absence of a catalyst was examined. This azafluorene was condensed with aromatic aldehydes. Several transformations of the geometrical isomers of 3-methyl-9-benzylidene-2-azafluorene and its analogs were studied.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1398–1402, October, 1971.     

New Chiral Diamines of the Dioxolane Series: (+)-(4S,5S)-2,2-Dimethyl-4,5-bis(diphenylaminomethyl)- 1,3-dioxolane and (+)-(4S,5S)-2,2-Dimethyl-4,5-bis(methyl- aminomethyl)-1,3-dioxolane

The reaction of sodium diphenylamide with 2,2-dimethyl-4,5-bis(tosyloxymethyl)-1,3-dioxolane gave (+)-(4S,5S)-2,2-dimethyl-4,5-bis(diphenylaminomethyl)-1,3-dioxolane, which was brought into complex formation with cobalt chloride. Treatment of 2,2-dimethyl-4,5-bis(tosyloxymethyl)-1,3-dioxolane with sodium N-methylanilide resulted in cleavage of the SÄO bond in the p-toluenesulfonate moiety with formation of N-methyl-N-phenyl-p-toluenesulfonamide and 4,5-bis(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane disodium salt. Diethyl (4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate reacted with methylamine to give the corresponding dicarboxamide which was reduced with lithium aluminum hydride to (4S,5S)-2,2-dimethyl-4,5-bis(methylaminomethyl)-1,3-dioxolane having chiral carbon and nitrogen atoms.     

Isolation and characterization of nongeminal cyclic methylphenylphosphazene tetramers

Heating pure samples of the cyclic phosphazenes, cis- or trans-[Me(Ph)PN](3), yielded mixtures of the cis and trans isomers of the cyclic phosphazene trimers, [Me(Ph)PN](3), and all four geometric isomers of the tetramers, [Me(Ph)PN](4). Varying the temperature and heating times changes the ratio of these components. Following the thermolysis by NMR spectroscopy indicated that only a mixture of the two isomeric trimers occurred initially. Longer heating times produced mixtures of the isomers of the tetramer. Column chromatography and solubility differences were used to separate each of the isomers of the tetramer. Spectroscopic and X-ray crystallographic studies suggest that the four different geometrical isomers of the tetramer can be described as cone, partial cone, 1,2-alternate, and 1,3-alternate by analogy to calix[4]arene.     

Synthesis and Addition Reactions of 1,3-Thiazole-5(4H)-thione Oxides

1,3-Thiazole-5(4H)-thione oxides 2 were prepared by oxidation of the corresponding 1,3-thiazole-5(4H)-thiones 1 with m-chloroperbenzoic acid (Table 1). Addition reactions of 2 with organolithium and Grignard reagents yielded 4,5-dihydro-4,4-dimethyl-1,3-thiazol-5-yl methyl sulfoxides of type 4 via thiophilic attack (Table 2). Whereas the reaction with the organolithium compounds proceeded with fair-to-excellent yields, the Grignard reagents reacted only very sluggishly. The sulfoxides 4 could also be prepared via oxidation of 4,5-dihydro-4,4-dimethyl-5-(methylthio)-1,3-thiazoles of type 3 with m-chloroperbenzoic acid, together with the corresponding sulfones 5 (Scheme 1).     

Unlocking the 5-exo Pathway with the AuI-Catalyzed Alkoxycyclization of 1,3-Dien-5-ynes

The first general regio- and stereoselective 5-exo gold(I)-catalyzed alkoxycyclization of a specific class of 1,5-enynes such as 1,3-dien-5-ynes has been described, despite 1,5-enynes being known to almost invariably proceed via endo cyclizations under gold-catalysis. The configuration of the terminal alkene in the starting 1,3-dien-5-yne plays a crucial role on the regiochemical outcome of the reaction. A wide variety of interesting alkoxy-functionalized alkylidenecyclopentenes have been synthesized from 1-monosubstituted (E)-1,3-dien-5-ynes. On the contrary, the corresponding Z isomers evolve affording formal 6-endo cyclization products. In addition, mechanistic exploration supports a highly stabilized carbocation as a key intermediate instead of a highly constrained cyclopropyl gold carbene from E isomers, and also accounts for the well differentiated reactivity observed between both E/Z geometrical isomers as well as for the stereochemical outcome of the reaction.