Highly stereo- and regioselective hydrostannylation of internal alkynes promoted by simple boric Acid in air

Facile hydrostannylation of alkynes in air: The ability to prepare vinylstannanes of high regio- and sterochemical fidelity in a safe manner employing a simple operational set up, especially on a large scale, has remained elusive. This study has shown that all of the autoxidation products of Et(3) B and boronic acids are capable of promoting hydrostannylation. Most importantly, simple boric acid itself can also promote the hydrostannylation of highly functionalized internal alkynes with complete selectivity under very mild conditions (RT to 80?°C) in air.     

A novel titanium tetrahalide-mediated carbon-carbon bond-forming reaction: regioselective synthesis of substituted (E,Z)-1,5-dihalo-1,4-dienes

Reactions of aldehydes with 2 equiv of alkyne in the presence of TiX(4) (X = Cl, Br) regioselectively generated 1,5-dihalo-1,4-dienes in moderate to good yields with high (E,Z)-stereoselectivity. [reaction: see text]     

Reactions of lithiated (E)-3-halo-1-phenylsulfonylprop-1-enes and (Z)-1-halo-3-phenylsulfonylprop-1-enes with aldehydes

(E)-3-Chloro-1-phenylsulfonylprop-1-ene and its iodo- and bromo-analogues, (Z)-1-iodo-3-phenylsulfonylprop-1-ene and (Z)-1-bromo-3-phenylsulfonylprop-1-ene, have each been successfully converted into lithiated carbanions which react regioselectively with aromatic aldehydes to give gamma-alkylated products whose nature depends upon the halogen substituent: the chloro-sulfones yield (2Z)-1-aryl-2-chloro-4-phenylsulfonylbut-2-en-1-ols but the bromo- and iodo-derivatives behave differently, yielding (1E)-trans-4-aryl-3,4-epoxy-1-phenylsulfonylbut-1-enes. In sharp contrast, the same lithiated sulfones react with aliphatic aldehydes to give anti-configured beta-hydroxysulfones which are formed via diastereoselective alpha-alkylation reactions.     

A new synthesis of 1,3-difunctionalized 2-sulfonamidopropane derivatives via regioselective ring opening reactions of 2-(bromomethyl)-1-sulfonylaziridines by substituted arylsulfonamides

The novel functionalized N,N′-[2-(arylsulfonamido)propane-1,3-diyl]bis(N-allylarylsulfonamide) and N,N′-[2-(methylsulfonamido)propane-1,3-diyl]bis(N-benzylarylsulfonamide) derivatives have been prepared from 2-(bromomethyl)-1-sulfonylaziridines for the first time using substituted arylsulfonamides in the presence of sodium methoxide under catalyst-free condition in good yields.     

Cesium-catalyzed highly regioselective synthesis of (Z)-vinylic selenosulfides via thioselenation of alkynes with unsymmetrical diorganoyl dichalcogenides

A novel one-pot approach for the synthesis of (Z)-vinylic selenosulfides is demonstrated through the thioselenation of a wide range of alkynes with unsymmetrical diorganoyl dichalcogenides (RSSePh) catalyzed by cesium hydroxide monohydrate, avoiding the use of the transition metal catalyst and the previous preparation of chalcogen alkynes. Other outstanding features include mild reaction conditions, high regio- and stereo-selectivity, excellent yields and wide functional group tolerance.     

Cesium hydroxide-catalyzed hydrothiolation of alkynyl selenides to highly stereo- and regioselectively synthesize(Z)- -organoseleno-2-arylthio-1-alkenes

In the presence of catalytic amount of cesium hydroxide the hydrothiolation of alkynyl selenides occurred at room temperature in DMF under nitrogen atmosphere to give exclusive(Z)-1-organoseleno-2-arylthio-1-alkene in excellent yields.It could provide a new and expedient way for the preparation of(Z)-1-arylseleno-2-arylthio-1-alkene.     

Highly stereo- and regioselective synthesis of (Z)-trisubstituted alkenes via 1-bromo-1-alkyne hydroboration-migratory insertion-Zn-promoted iodinolysis and Pd-catalyzed organozinc cross-coupling

Hydroboration of 1-bromo-1-alkynes with dibromoborane followed by addition of 3 or 4 equiv of Me2Zn provides an efficient and selective route to (Z)-2-alkenyldimethylboranes (3) or (Z)-2-alkenylmethylzincs (4), respectively, which have been successfully applied to one-pot Suzuki (B-I) or Negishi (Zn-I) coupling in some less demanding cases. However, in more demanding cross-coupling reactions, only the use of either (Z)-2-alkenyliodides (5) or the alkenylzincs prepared from lithiation and then zincation of 5 proves to be highly satisfactory (Zn-II or Zn-III protocol). On the contrary, the corresponding organoboron coupling under B-II or B-III protocol appears to be less satisfactory. Preliminary studies indicate that certain substituents proximal to trisubstituted alkenes seriously affect the course of the desired alkenylboron cross-coupling.     

Facile isocyanide-based one-pot three-component regioselective synthesis of highly substituted pyridin-2(1H)-one derivatives at ambient temperature

A novel one-pot three-component regioselective synthesis of highly substituted pyridin-2-one derivatives starting from simple and readily available starting materials is described. The reactive zwitterionic intermediate generated by the addition of an isocyanide to dimethyl acetylenedicarboxylate (DMAD) was trapped with N-arylidene-2-cyanoacetohydrazides to afford the title compounds in moderate to good yields at room temperature without using any catalyst and other additives.     

Unusual sterically controlled regioselective lithiation of 3-bromo-5-(4,4'-dimethyl)oxazolinylpyridine. Straightforward access to highly substituted nicotinic acid derivatives

[Structure: see text] Lithiation of 5-bromonicotinic acid protected as secondary or tertiary amide as well as (4,4'-dimethyl)oxazoline with lithium amides is reported. The unusual C-2 and C-4 regioselective lithiation of 3-bromo-5-(4,4'-dimethyl)oxazolinylpyridine using LTMP versus LDA was observed, providing a new route to substituted nicotinic acid scaffolds. The methodology was applied to the synthesis of novel C-4 and C-6 arylated 5-bromonicotinic acids.     

Novel 1,4-dihydropyridine calcium antagonists. I. Synthesis and hypotensive activity of 4-(substituted pyridyl)-1,4-dihydropyridine derivatives

A series of 4-(substituted pyridyl)-1,4-dihydropyridine derivatives were synthesized and their hypotensive effects examined. Several compounds, 2-(N-benzyl-N-methylamino)ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitro-2-pyridyl)-3,5-pyridinedicarboxylate (2b), its 4-(4-nitro-2-pyridyl) analogue (2g), 4-(3-trifluoromethyl-2-pyridyl) analogue (2c), 4-(2-trifluoromethyl-3-pyridyl) analogue (3e), 4-(4-cyano-2-pyridyl) analogue (2e), 4-(2-cyano-3-pyridyl) analogue (3d), and 4-(6-bromo-2-pyridyl) analogue (2i), were found to have a hypotensive activity parallel to that of nicardipine; 2c and 3e, in particular, had approximately twice the duration of nicardipine, and 2e had the most potent hypotensive activity of all the derivatives synthesized.     

Mild and selective palladium-catalyzed dimerization of terminal alkynes to form symmetrical (Z,Z)-1,4-dihalo-1,3-dienes

A regioselective and stereoselective palladium-catalyzed dimerization of terminal alkynes method for the synthesis of symmetrical (Z,Z)-1,4-dihalo-1,3-dienes is presented. In the presence of a catalytic amount of PdX(2) and 3 equiv of CuX(2) (X = Cl and Br), terminal alkynes were dimerized to afford (Z,Z)-1,4-dihalo-1,3-dienes in good yields. The results showed that the effect of solvent had a fundamental influence on the chemoselectivity of the dimerization reaction. The mechanism of the palladium-catalyzed dimerization reaction is also discussed.     

General and regioselective synthesis of substituted pyrroles by metal-catalyzed or spontaneous cycloisomerization of (Z)-(2-en-4-ynyl)amines

A general and regioselective synthesis of substituted pyrroles 2 by cycloisomerization of readily available (Z)-(2-en-4-ynyl)amines 1 is reported. Spontaneous cycloisomerization leading to 2 occurred in the course of preparation of enynamines bearing a terminal triple bond or a triple bond substituted with a phenyl or a CH2OTHP group. When the triple bond was substituted with an alkyl or alkenyl group, enynamines were stable and could be converted into the corresponding pyrroles by metal catalysis. CuCl2 was found to be an excellent catalyst for cycloisomerization of substrates substituted at C-3, while PdX2 in conjunction with KX (X = Cl, I) turned out to be a superior catalyst for the reaction of enynamines unsubstituted at C-3.     

A new glycociamidine ring precursor: syntheses of (Z)-hymenialdisine, (Z)-2-debromohymenialdisine, and (+/-)-endo-2-debromohymenialdisine

[chemical reaction: see text]. The synthesis of the C11H5 marine sponge alkaloids, (Z)-hymenialdisine and (Z)-2-debromohymenialdisine, is described. A key step was the condensation between aldisine or its monobromo derivative and a new, efficient imidazolinone-based glycociamidine precursor. In the first case, the main product turned out to be the unprecedented (+/-)-endo-2-debromohymenialdisine.     

Synthesis and stereochemical stability of new atropisomeric 1-(substituted phenyl)pyrrole derivatives

Addition of organometallic reagents to optically active methyl 1-(2-methoxycarbonyl-6-trifluoromethylphenyl)pyrrole-2-carboxylate provided the corresponding tetrasubstituted diols and/or pyrrolo[1,2-a]benzoxazepines as pure enantiomers or racemates depending on the organometallic reagents used. Rotational energy barriers around the interconnecting C-N bonds were estimated by molecular modeling calculations and NMR measurements with the aim of clarifying the stereochemical stability order of the new atropisomeric compounds. NMR methods for the determination of the enantiomeric purity of the new compounds are proposed.     

Palladium-catalyzed highly regio- and stereoselective synthesis of (1E)- or (1Z)-1,2-dihalo-1,4-dienes via haloallylation of alkynyl halides

A highly efficient and selective synthesis of (1E)- or (1Z)-1,2-dihalo-1,4-dienes via Pd-catalyzed coupling of haloalkynes and allylic halides is described. The (1E)-1,2-dihalo-1,4-dienes were generated in good yields with excellent stereoselectivities (1E/1Z up to >98/2), while (1Z)-1,2-dihalo-1,4-dienes were produced in excellent yields and stereoselectivities (1Z/1E up to >98/2) by simply adding stoichiometric lithium halides.     

Design,synthesis and evaluation of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives as a new class of falcipain-2 inhibitors

The cysteine protease, falcipain-2 is an important drug target in human malaria parasite Plasmodium falciparum. A new series of 2-(4-(substituted benzoyl)-1,4-diazepan-1-yl)-N-phenylacetamide derivatives 5(a–t) were designed as per pharmacophoric requirements of falcipain-2 inhibitors using ligand-based approach. The target compounds were synthesized from the key intermediate, 2-(1,4-Diazepan-1-yl)-N-phenylacetamide, by coupling it with appropriate carboxylic acids using carbodiimide chemistry. Structural features of target compounds were characterized by spectral data (¹H NMR, and mass) and elemental analyses. The purity of the final compounds was confirmed by HPLC. The compounds were tested for their in vitro falcipain-2 inhibitor activity on recombinant falcipain-2 enzyme. Five compounds 5b, 5g, 5h, 5j, 5k showed good inhibitory activity (>60%), against falcipain-2 at 10 μM concentration, and fifteen compounds showed weak to moderate inhibitor activity. Compound 5g, the most potent compound from this series showed 72% inhibition at 10 μM concentrations.