New stereoselective syntheses of cis- and trans-2-methyl-4-arylpiperidines

A stereoselective approach has been developed for the synthesis of cis- and trans-2-methyl-4-arylpiperidines from a common intermediate. The Ni-catalyzed hydrogenolysis of N-Boc-2-methyl-4-aryl-4-piperidinols, obtained by addition of organometallic reagents on N-Boc-2-methyl-4-piperidone, afforded the trans derivatives with up to 95% selectivity whereas the corresponding cis isomers were obtained in the presence of palladium catalysts.     

Syntheses of E- and Z-2- and 4-fluorourocanic acids

Horner-Wadsworth-Emmons olefination of ring-fluorinated N-trityl-imidazole carboxaldehydes with dialkyphosphonoacetic acid esters produced ring-fluorinated imidazolyl-E- and Z-acrylate esters. Stereochemistry was controlled by choice of phoshonate. Acid catalyzed removal of trityl followed by ester saponification gave the target 2- and 4-fluoro-E- and Z-urocanic acid derivatives. These are being investigated as potential mediators of photo-immunosupression.     

Facile stereoselective synthesis of cis- and trans-3-alkoxyazetidin-2-ones

A highly stereoselective synthesis of cis- and trans-3-alkoxy-3-phenyl/benzylthioazetidin-2-ones is described. The reaction of α-chlorosulfide-β-lactams with various alcohols catalyzed by a Lewis acid such as ZnCl₂ in the presence of molecular sieves (3-4 Å) leads to cis-3-alkoxy-3-phenyl/benzylthio-β-lactams whereas treatment of potassium 2-alkoxy-2-phenylthioethanoate with appropriate Schiff's base using POCl₃ in the presence of triethylamine leads to the formation of trans-3-alkoxy-3-phenylthioazetidin-2-ones as major products.     

Convenient access to C-2 or C-5 substituted 4-azaindole derivatives

Functionalization at C-2 and C-5 of N-benzenesulfonyl-4-azaindole 1 was performed by lithiation reactions and original palladium-catalyzed chemistry. It led to very useful new substituted 4-azaindole derivatives in fair to high yields.     

Specific volume of bisphenol C-2 polycarbonate

The molecular weight (M) dependence of specific volume (v_sp) for bisphenol C-2 polycarbonate (BCPC) is described. It has been confirmed that the Fox-Flory relation v_sp=A₀ + (A₁/M) is satisfied at 296 K, i.e. below the glass transition temperature of BCPC (441 K). The specific volume data for BCPC have been determined and compared with the corresponding data for bisphenol A polycarbonate.     

A vicarious synthesis of unsymmetrical meta- and para- terphenyls from 2H-pyran-2-ones

An innovative synthesis of terphenyls functionalized with electron-withdrawing or -donating substituents is described and illustrated by carbanion-induced ring transformation of 2H-pyran-2-ones with 2-methoxyacetophenone in excellent yields. The existing protocols for the synthesis of terphenyls are generally inter- and intramolecular aryl-aryl cross couplings in the presence of metal complexes. In this letter, we report a potentially useful alternative to conventional metal-catalyzed cross-coupling reactions.     

Synthesis of trans-4-aryl-3-(3-chloropropyl)azetidin-2-ones and their transformation into trans- and cis-2-arylpiperidine-3-carboxylates

Treatment of arylmethylideneamines with 5-chloropentanoyl chloride in benzene in the presence of 2,6-lutidine afforded novel trans-4-aryl-3-(3-chloropropyl)azetidin-2-ones in good yields. The latter 3-(3-chloropropyl)-β-lactams were transformed selectively into trans-methyl 1-alkyl-2-arylpiperidine-3-carboxylates in high yields and purity upon subsequent treatment with hydrogen chloride in methanol and triethylamine in dichloromethane. These trans-1-alkyl-2-arylpiperidine-3-carboxylates were easily converted into either their cis-isomers upon treatment with hydrazine monohydrate in methanol, or into the corresponding piperidine-1,3-dicarboxylates by reaction with alkyl chloroformates in benzene. Finally, 3-(3-chloropropyl)-1-(4-methoxybenzyl)-4-phenylazetidin-2-one was transformed into the corresponding trans-1-tert-butoxycarbonyl-3-(4-methoxybenzylcarbamoyl)piperidine via a three-step sequence in a good overall yield.     

Synthesis of C-2 methylene glycosides from C-2 propargyloxymethyl glycals exploiting the alkynophilicity of AuCl3

C-2 Methylene glycosides were synthesized from C-2 propargyloxymethyl glycals in a stereoselective manner using a catalytic quantity of AuCl₃. The Au-catalyzed reaction was explored using various aglycones. The current protocol enables the preparation of C-2 methylene glycosides, tolerates diverse functional groups and is fast, catalytic and mild.     

Self-assembly via intermolecular hydrogen-bonding between o-/m-/p-NH2 and BF2 groups on dipyrromethenes

Boron difluoride dipyrromethenes bearing configurationally different amine groups on a meso-phenyl ring were prepared and crystallized. The ortho- and para-amino groups allow the phenyl group to inductively release greater electron density into the dipyrromethenes resulting in relatively strong intermolecular hydrogen-bonding with the terminal BF₂ groups, whereas the meta-analog formed weaker hydrogen-bonds. The intensities of the ¹H NMR peaks in concentrated solutions all increased with F-decoupling.     

N-Polyfluoroethyl and N-2-chlorodifluorovinyl derivatives of azoles

Reactions of tetrafluoroethylene, chlorotrifluoroethylene and 1,2-dichlorodifluoroethylene with N-potassium salts of imidazole, 2-methylbenzimidazole, 3,5-dimethylpyrazole, 1,2,4-triazole, and benzotriazole lead to the formation of the corresponding N-(1,1,2,2-tetrafluoroethyl), N-(2-chloro-1,1,2-trifluoroethyl), and N-(2-chloro-1,2-difluorovinyl) azoles. Treatment of N-(2-chloro-1,2-difluorovinyl) and N-(2-chloro-1,1,2-trifluoroethyl) derivatives of azoles with tetramethylammonium fluoride is a useful synthetic method for the preparation of heterocycles with 1,2,2,2-tetrafluoroethyl group attached to nitrogen.     

A new enlargement methodology for the preparation of 2H-1- and 2H-3-benzazepin-2-one derivatives

An investigation of the one-carbon homologation of some 1-tribromomethyl-isoquinoline and 2-tribromomethyl-quinoline derivatives was conducted. Under the influence of an aqueous solution of silver nitrate in the presence of a nucleophilic species (MeOH, H₂O, EtNH₂), these derivatives led to the respective expanded heterocycles, 2H-1- and 2H-3-benzazepin-2-one derivatives. A mechanism for this novel ring enlargement involving initial formation of an aziridinium, and its subsequent opening to form a stabilized benzylic carbocation, is proposed to explain the results.     

DBU-assisted 1,3,2-oxathiaphospholane ring-opening condensation with selected O-, S-, N- and C-nucleophiles

The reactivity of protected thymidine 3′-O- and 5′-O-(2-thio-1,3,2-oxathiaphospholanes) towards various nucleophiles in the presence of DBU is presented and mechanistic implications are discussed.     

Novel N-chlorinated derivatives of 2H-1-benzopyran-2-imines

A series of new N-chlorobenzopyran-2-imines were prepared in moderate to good yields, by reacting sodium hypochlorite in an acidic medium with benzopyran-2-imines obtained via the Knoevenagel condensation. Some of the N-chlorobenzopyran-2-imines obtained are potential antiproliferating agents.     

Kinetically distinct triplets in the photorearrangement of 2-phenylcyclohexanone to cis- and trans-6-phenyl-5-hexenals

A reinvestigation of the photochemistry of 2-phenylcyclohexanone reveals that the two aldehyde products, cis- and trans-6-phenyl-5-hexanal, come from triplets of different lifetimes. That the two distinct triplets are not simply the two conformers with phenyl axial and equatorial is demonstrated by the similar behavior of cis-4-t-butyl-2-phenylcyclohexanone. The trans isomer of this ketone is photostable. It is concluded that trans-enal arises by an almost concerted out-of-plane cleavage which forms a 1,6-biradical in the perfect geometry for disproportionation to trans-enal.The precursor to cis-enal may be a minor rotamer of 1 which is forced by nonbonded interactions into a cleavage mode which twists the biradical into a geometry suitable for at least partial formation of cis-enal. In both cases biradicals must be very short-lived and not rotationally equilibrated.     

ortho-, meta- and para-nitrophenylgold(I) complexes

Treatment of [BzPh₃P][AuCl₂] with [Hg(x-C₆H₄NO₂)₂] (x = o, m, or p) gives anionic gold(I) complexes of the type [BzPh₃P][Au(R)Cl](R = o-, m- or p-C₆H₄NO₂, Bz = C₆H₅CH₂). The chloro ligand in [Au(o-C₆H₄NO₂)Cl]^? can be replaced by bromo or iodo ligands by use of NaBr or NaI. The anions [Au(R)Cl]^? react with neutral monodentate ligands, L, to give neutral mononuclear complexes [Au(R)L] (R = o-C₆H₄NO₂, L = PPh₃, AsPh₃; R = m-C₆H₄NO₂, L = PPh₃) and with 1,2-bis(diphenylphosphino)ethane (dpe) to give [Au₂(R)₂(dpe)] (R = o-C₆H₄NO₂). The corresponding [Au(p-C₆H₄NO₂)Cl]^? reacts with PPh₃ or AsPh₃ to give mixtures containing [AuClL]. The anionic ortho-nitrophenylgold(I) complex is much more stable than its meta- or para-nitrophenyl isomers. These are thought to be the first reports of nitrophenylgold(I) complexes.     

Stereoselective multigram-scale synthesis of cis- and trans-β-phenylproline derivatives

Efficient routes for the gram-scale preparation of the proline analogues that bear a phenyl substituent attached to the pyrrolidine β carbon (cis- and trans-β-phenylproline) have been developed. The cis derivative was synthesized from N-Boc-β-alanine in six steps and 78% overall yield. The generation of a vinyl triflate with full regiochemical control together with a high-yielding cross-coupling reaction and a completely stereoselective hydrogenation are at the basis of the high efficiency of the procedure. Epimerization of the cis β-phenylproline derivative with lithium bis(trimethylsilyl)amide provided access to the trans isomer.     

Synthesis of cis-3,4-diarylpiperidines and cis-3,4-diaryltetrahydropyrans

Substituted cis-3,4-diarylpiperidines and cis-3,4-diaryltetrahydropyrans are synthesized in modest overall yields starting from 4-aryl-1,2,5,6-tetrahydropyridines and 4-aryl-1,2,5,6-tetrahydropyrans via the following sequence: (1) pinacol-type ring contraction having the combination of m-chloroperoxybenzoic acid and boron trifluoride etherate, (2) Grignard addition with arylmagnesium bromide reagents and followed by boron trifluoride etherate-mediated intramolecular ring-expanded rearrangement, and (3) hydrogenation with hydrogen on 10% palladium-activated carbon. A facile synthesis of 3,4-diarylpyridines was also described by base-induced aromatization.     

Synthesis of 5-endo-, 5-exo-, 6-endo- and 6-exo-hydroxylated analogues of epibatidine

A convenient, high-yield synthesis of N-Boc-7-azabicyclo[2.2.1]hept-5-en-2-one (7) was developed by SmI₂-mediated desulfonylation of 6. Thus, 5-endo-, 5-exo-, 6-endo-, and 6-exo-hydroxylated epibatidine analogues 2a,b and 3a,b were synthesized from 7 by using a Pd(PPh₃)₄-catalyzed reductive Heck coupling reaction and SmI₂-mediated reduction of the carbonyl group as the key steps. Other reaction conditions for the reductive Heck procedure and the reduction step were also investigated.     

Conformational analysis of N-aryl-N-(2-azulenyl)acetamides

Aromatic amides bearing 2-azulenyl group on the amide nitrogen were synthesized and their structures were investigated. The π-electron density of the N-aryl group was found to influence the cis-trans conformational preferences of these compounds in solution. X-ray crystallography revealed that the plane of the 2-azulenyl ring has a strong tendency to lie coplanar with the amide plane when the azulene group is located on the same side as the amide oxygen atom.     

One-pot synthesis of meso-tris-aryl-substituted N-21-methyl- and N-21-benzyl-corroles

A simple and versatile synthesis of meso-substituted N-21-alkylcorroles was achieved directly from aldehydes, pyrrole and N-alkylpyrroles via mix-condensation. Compounds inaccessible via previous routes have been obtained in acceptable yields. It was proved that meso-substituted N-21-alkylcorroles differ from N-unsubstituted corroles in absorption spectra, stability and solubility.