Total synthesis of (-)-cocaine and (-)-ferruginine

Total synthesis of tropane alkaloids (-)-cocaine and (-)-ferruginine were accomplished in nine steps each and in 55% and 46% overall yields, respectively, starting from the known Betti base derivative (+)-(7aR,10R,12S)-10-(1H-benzotriazol-1-yl)-7a,8,9,10-tetrahydro-12-phenyl-12H-naphtho[1,2-e]pyrrolo[2,1-b][1,3]oxazine. In this novel route, RCM reaction and 1,3-dipolar cycloaddition were employed as key steps for the enantioselective construction of tropane skeleton and the regioselective introduction of 3-bromo-2-isoxazoline ring as masked cis-2,3-disubstituents. To obtain the desired precursor (2S,5R)-2-allyl-5-vinylpyrrolidine for RCM reaction, we developed a general and practical method for the preparation of enantiopure cis-2,5-disubstituted pyrrolidines bearing alkene- and/or alkyne-containing substituents. We also offered two highly efficient pathways for the conversion of the 3-bromo-2-isoxazoline ring into the desired cis-2,3-disubstituted groups in (-)-cocaine and (-)-ferruginine.     

Palladium-catalyzed carbonylative synthesis of N-(2-cyanoaryl)benzamides and sequential synthesis of quinazolinones

A convenient procedure for the synthesis of N-(2-cyanoaryl)benzamides has been developed. Using aryl bromides and 2-aminobenzonitriles as the substrates, Mo(CO)₆ as the CO source, the desired amides were produced in good yields. Quinazolinones were produced in good yields in a sequential manner as well.     

A practical and expedient synthesis of 2-heterocycle (C-N bond) substituted 4-oxo-4-arylbutanoates

A practical and expedient synthesis of the titled compounds is described. Using the same simple procedure (DBU was reacted with the mixture of an alkynol and a nitrogen heterocycle in CH₂Cl₂ at rt for 16 h), a wide variety of diverse NH-containing nucleophiles such as pyrazoles, indazoles, indoles, imidazoles and benzoimidazole, oxazolidinone and benzooxazolone, triazoles, phthalimides, and N-formyl anilines, have been reacted with 4-aryl-4-hydroxy-alkynyl esters to afford good yields of desired products. This reaction proceeded by the DBU catalyzed redox isomerization of ethyl 4-aryl-4-hydroxybut-2-ynoate to (E)-ethyl 4-aryl-4-oxobut-2-enoate, followed by the DBU catalyzed aza-Michael reactions with the isomerized product in one-pot.     

Selective base-promoted synthesis of substituted selenophenes by carbocyclization of (Z)-benzylselenoenynes

We herein described the synthesis of several 3-benzyl-2,5-diarylselenophene derivatives in moderate to good yields using (Z)-benzylselenoenynes as starting material in carbocyclization reactions. The reactions were carried out under mild conditions using only t-BuOK as base, in the complete absence of transition metals or additives. The cyclized 3-benzyl-2,5-diarylselenophenes obtained in the current protocol appear highly promising and attractive intermediates for the synthesis of polysubstituted selenophenes. For instance, 3-benzyl-2,5-diphenylselenophene was treated with Br(2) provided the corresponding 3-benzyl-4-bromo-2,5-diphenylselenophene in high yield. 4-Bromoselenophene derivative was applied as substrate in the palladium catalyzed cross-coupling reactions with boronic acids to give the Suzuki type products in excellent yields.     

Synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-ones via Pd-catalyzed regioselective cross-coupling reaction and cyclization

An efficient and novel route for the synthesis of 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 via palladium-catalyzed site-selective cross-coupling reaction and cyclization process was described. Reaction of 3-bromo-4-trifloxy-quinolin-2(1H)-one 3 with arylboronic acid catalyzed by PdCl₂(PPh₃)₂ afforded 3-bromo-4-aryl-quinolin-2(1H)-one 4, which then reacted with 2-ethynylaniline 5 via Pd-catalyzed Sonogashira coupling and CuI-mediated cyclization leading to the desired 1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-one 1 in good yields.     

One-pot,microwave-assisted synthesis of polymethylene-bridged bis(1H-1,2,4-triazol-5(3)-amines) and their tautomerism

A highly selective and efficient method for the synthesis of 3,3′(5,5′)-polymethylene-bis(1H-1,2,4-triazol-5(3)-amines) was developed using the reaction of dicarboxylic acids and aminoguanidine in an aqueous medium. This one-pot, microwave-promoted method was proved to be scalable affording the desired products in good yields and purity. The scope of the method was successfully explored by the preparation of a small library of polymethylene-bis(1H-1,2,4-triazol-5(3)-amines) with different alkyl chain linkers. The annular prototropic tautomerism in the prepared compounds was studied using NMR spectroscopy and X-ray crystallography.     

Suzuki route to regioregular polyalkylthiophenes using Ir-catalysed borylation to make the monomer, and Pd complexes of bulky phosphanes as coupling catalysts for polymerisation

We have applied palladium complexes of bulky, electron-rich phosphane ligands as catalysts for the Suzuki synthesis of highly head-to-tail regioregular polyalkylthiophenes from 2-(5-bromo-4-n-alkyl-thiophen-2-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane. The monomer can be prepared in high yield by Ir-catalysed borylation of 2-bromo-3-hexylthiophene, without the need for organolithium reagents or strong bases.     

Efficient synthesis of 3,3′,5,5′-tetra(p-X-phenylethynyl)biphenyl (X: NMe2; OMe) by homocoupling of 1-bromo-3,5-di(p-X-phenylethynyl)benzene or by heterocoupling of 3,3′,5,5′-tetraethynylbiphenyl with p-X-phenylbromobenzene with nickel or palladium complexes, respectively

The conjugated 3,3′,5,5′-tetra(p-X-phenylethynyl)biphenyl derivatives were efficiently obtained by homocoupling of 1-bromo-3,5-di(p-X-phenylethynyl)benzene mediated by zero-valent nickel complexes.The 1-bromo-3,5-di(p-X-phenylethynyl)benzene was previously prepared by heterocoupling between 1-bromo-3,5-di(ethynyl)benzene and p-X-iodobenzene (X: NMe₂; OMe) catalysed by the palladium/copper system in good yield. The necessary 1-bromo-3,5-di(ethynyl)benzene was obtained by heterocoupling between 1,3,5-tribromobenzene and 2-methyl-3-butyn-2-ol catalysed by palladium and successive treatment with sodium hydroxide in dry toluene, in good yield.The same 3,3′,5,5′-tetra(p-X-phenylethynyl)biphenyl (X: NMe₂; OMe) derivatives were alternatively synthesised in highest yield by heterocoupling between 3,3′,5,5′-tetra(ethynyl)biphenyl and p-X-bromobenzene (X: NMe₂; OMe) catalysed by palladium in excellent yields. Previously, 3,3′,5,5′-tetra(ethynyl)biphenyl was obtained in practically quantitative yield by homocoupling of 1-bromo-3,5-di[4-(2-methyl-3-butyn-2-ol)] benzene mediated by the zero-valent nickel complex to the 3,3′,5,5′-tetra{di[4-(2-methyl-3-butyn-2-ol)]}biphenyl followed the treatment with sodium hydroxide.     

Chemoselective synthesis of 3H-pyrrolo[2,3-c]quinolin-4(5H)-one derivatives from 3-phenacylideneoxindoles and substituted tosylmethyl isocyanide (TosMIC)

A simple and convenient synthetic approach to access of 3H-pyrrolo[2,3-c]quinolin-4(5H)-one derivatives by the reaction of (Z)-3-(2-oxo-2-ethylidene)indolin-2-one derivatives 1 with functionalized TosMICs under basic conditions has been reported. The desired products were obtained in good to excellent yields (82–94%). The easy accessibility of the starting materials, simple and mild reaction conditions, short reaction time, and good to excellent chemical yields make this methodology highly efficient.     

Regioselective synthesis of cytotoxic 4-(1-alkynyl)-substituted 2-(5H)-furanones

4-(1-Alkynyl)-3-bromo- and 4-(1-alkynyl)-3-chloro-2(5H)-furanones have been regioselectively synthesized in moderate to good yields by a new version of the Pd/Cu-catalyzed Sonogashira reaction involving treatment of 1-alkynes with 3,4-dibromo- and 3,4-dichloro-2(5H)-furanone, respectively, in the presence of KF as a base. 4-(1-Alkynyl)-3-bromo-2(5H)-furanones have been found to be able to undergo Stille-type and Suzuki-type reactions with aryl(tributyl)tins and arylboronic acids, respectively, to give 4-(1-alkynyl)-3-aryl-2(5H)-furanones in modest to satisfactory yields. Some 4-(1-alkynyl)-substituted 2(5H)-furanones so prepared have been found to exhibit significant cytotoxic activities, especially against human leukemia cell lines.     

Syntheses of various 5-(bromoaryl)-substituted uracils

The Suzuki Pd(0)-catalyzed coupling between arylboronic acids and aryl bromides or iodides in weakly alkaline medium, previously further developed by us, has been used for regioselective preparation of 5-(2′-bromo-5′-furyl)-, 5-(2′-bromo-4′-furyl)-, 5-(2′-bromo-5′-thienyl)-, 5-(2′-bromo-4′-thienyl)-, 5-(4′-bromo-2′-thiazolyl)-, 5-(3′-bromophenyl)-, 5-(6′-bromo-2′-pyridyl)- and 5-(4′-bromo-2′-pyrimidyl)-substituted 2,4-di-t-butoxypyrimidines. In the coupling between 2,4-di-t-butoxy-5-pyrimidineboronic acid and the nine different aryl dibromides that were tried as coupling partners, only the 2,4- and 2,5-dibromothiazoles did not give satisfactory yields, 15% and 0%, respectively. The other seven aryl dibromides gave the desired 5-(bromoaryl)-2,4-di-t-butoxypyrimidines in 58-89% yield. Attempts to synthesise 2,4-di-t-butoxy-5-(2′-bromo-4′-thienyl)pyrimidine from 2-bromo-4-iodothiophene failed. Dealkylation of the 5-(bromoaryl)-2,4-di-t-butoxypyrimidines in 2.5 M hydrochloric acid gave the corresponding 5-(bromoaryl)uracils in almost quantitative yields.     

Study of cyclyzation of o-(1-Alkynyl)- and o-(1,3-Butadiynyl)aryltriazenes under the action of acids

The investigation of Richter cyclization of o-(1-alkynyl)- and o-(1,3-butadiynyl)arenediazonium salts generated by acid cleavage of triazenes was carried out by the methods of NMR and ESI MS (Electrospray Ionization Mass Spectrometry). The effect was shown of the substituents at the carbon atom of the triple bond and in the aromatic ring, of the solvent, temperature, and the reagents ratio on the rate of the cyclization and the yield of its products, 4-bromo-3-alkyl- and 4-bromo-3-ethynylcinnolines; the conditions of their synthesis were optimized. The possibility to use 4-bromo-3-ethynylcinnolines as substrates of electrophilic cyclization was demonstrated.     

Solid-phase synthesis of hydroxypiperazine derivatives using phenethylamine linker by oxidation-Cope elimination

A general method is reported for the parallel solid-phase synthesis of hydroxypiperazine derivatives based on the oxidation-Cope elimination of polymer-bound phenethylamine linker with m-CPBA. The key intermediate of phenethylamine N-oxide resins was separable on solid-phase for subsequent β-elimination, from which the desired hydroxypiperazine products could be obtained in high purities and yields without any significant contamination at 90 °C for 2 h. The utility of the methodology for solid-phase synthesis of general hydroxylamines was also investigated using the same linker. The progress of reactions could be monitored on polymer bound intermediates by ATR-FTIR spectroscopy on single bead. The desired products were obtained in good six-step overall yields upon cleavage from the resins and were characterized by LC/MS, ¹H NMR, and ¹³C NMR spectroscopy.     

An efficient synthesis of 2-bromo(chloro)-3-selenyl(sulfenyl)indoles via tandem reactions of 2-(gem-dibromo(chloro)vinyl)anilines with diselenides(disulfides)

A novel and efficient synthesis of 2-bromo(chloro)-3-selenyl(sulfenyl)indoles through tandem reactions of 2-(gem-dibromo(chloro)vinyl)-N-methylsulfonylanilines with diselenides and disulfides in the presence of t-BuOLi and I(2) (10 mol%) in DMSO was developed. The reactions generated the desired products in good yields with high regio-selectivity under transition-metal-free conditions in one-pot.     

Facile,catalyst-free,microwave-assisted access toward the synthesis of 2-aryl/alkyl-3-(1H-benzo[d]imidazol-2-yl)-2, 3-dihydroquinazolin-4(1H)-ones

An efficient, catalyst-free, microwave-assisted approach has been developed for the synthesis of 2-aryl/alkyl-3-(1H-benzo[d]imidazol-2-yl)-2,3-dihydroquinazolin-4(1H)-one derivatives by condensing 2-aminobenzamides with various aliphatic, aromatic, and heterocyclic aldehydes. This catalyst-free approach exhibited good functional group compatibility and produced the desired products in good to excellent yields in just 10–20?min. This approach can be seen as a better alternative of the metal-catalyzed protocols used for the synthesis of this class of compounds. The formation of desired compound has also been confirmed by X-ray analysis.     

Enantioselective synthesis of butadien-2-ylcarbinols via (silylmethyl)allenic alcohols from chromium-catalyzed additions to aldehydes utilizing chiral carbazole ligands

The synthesis of chiral, nonracemic butadienylcarbinols by employing intermediate (trimethylsilyl)methylallenic alcohols is described. Allenic alcohols are obtained by treatment of aldehydes with (4-bromobut-2-ynyl)trimethylsilane in the presence of a catalytic amount of CrCl₃ or CrCl₂. Several new tridentate bis(oxazolinyl)carbazole ligands were synthesized and evaluated as the source of chirality. The synthesis of chiral allenic alcohols can be achieved in good yields (58-88%) and enantioselectivities (55-78% ee). Allenic alcohols may be treated with TBAF or 2 M HCl to provide the desired dienes in 43-86% yields. Alternatively, the (trimethylsilyl)methyl allenic alcohols afford iodobutadienyl carbinols when treated with N-iodosuccinimide.     

A diastereoselective synthesis 1-trimethylsilyl-(E)-1,3-alkenynes and a simple synthesis of alkyl trimethylsilylethynyl ketones via organoboranes

A convenient, novel diastereoselective synthesis of 1-trimethylsilyl-(E)-1,3-alkenynes and a convenient synthesis of alkyl trimethylsilylethynyl ketones based on Z-1-bromo-1-alkenylboronate esters are developed. α-Bromo-(Z)-1-alkenylboronate esters readily available using literature procedures smoothly undergo a reaction with trimethylsilylethynyllithium (derived from the deprotonation of trimethylsilylethyne with n-butyllithium) in tetrahydrofuran to provide the corresponding ‘ate’ complexes. These ‘ate’ complexes undergo intramolecular nucleophilic substitution reactions to afford the corresponding (E)-1-alkenylboronate esters containing trimethylsilylethynyl moiety which upon protonolysis with acetic acid provide the corresponding 1-trimethylsilyl-(E)-1,3-alkenynes in good yields (70-82%) and in high stereochemical purities (>98%). These intermediates upon oxidation with hydrogen peroxide and sodium acetate afford the corresponding alkyl trimethylsilylethynyl ketones in good yields (66-78%).     

One-pot synthesis of alkyl 3-aryl-2-(4-phenyl-1<Emphasis Type="Italic">H</Emphasis>-1,2,3-triazol-1-yl)propanoates

Reaction of 3-aryl-2-bromopropanoic acids esters, products of the Meerwein arylation, with sodium azide afforded alkyl 2-azido-3-arylpropanoates. The latter react with ethyl acetoacetate and phenylacetylene to form 1,2,3-triazole derivatives. A one-pot method for the synthesis of 3-aryl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-propanoic acid esters via a tricomponent reaction of alkyl 2-bromo-3-arylpropanoates, sodium azide, and phenylacetylene in the presence of CuI was developed.     

Facile synthesis of dihaloheterocycles via electrophilic iodocyclization

An efficient and facile electrophilic iodocyclization for the synthesis of various O-, N-, and S-containing dihaloheterocycles has been developed. A wide range of the substituted propargyl alcohols having -OH, -NTs, and -SAc functional groups reacted with molecular iodine or bromoiodine at ambient temperature to produce the corresponding dihalogenated O-, N-, and S-containing five- and six-membered heterocycles in good to high yields; Under optimized solvent conditions, the reactions of various substituted but-2-yn-1-ones bearing -OH, -NTs, and -SAc functional groups at C4-position, with iodine or bromoiodine at ambient temperature afforded the corresponding 3,4-diiodo- and 3-bromo-4-iodo-substituted furans, pyrroles, and thiophenes in good to high yields. Further transformation of the resulting iodine- or bromine-containing products to polyaromatics potentially of useful as organo-material intermediates has been investigated.