Highly regioselective synthesis of 2,3,4-trisubstituted 1H-pyrroles: a formal total synthesis of lukianol A

A combined use of alpha-lithiation and nucleophilic substitutions of N,N-dimethyl 3,4-bis(trimethylsilyl)-1H-pyrrole-1-sulfonamide 8c led to several 2-substituted 3, 4-bis(trimethylsilyl)-1H-pyrrole-1-sulfonamides. Utilizing the beta-effect of a trimethylsilyl group, a highly regioselective synthesis of 2,3,4-trisubstituted 1H-pyrroles 23 and 34 was accomplished. The marine natural product lukianol A (3) was prepared utilizing this strategy.     

Regiospecific Displacement of the C-B Bond of Tris[4-(substituted)furan-3-yl]boroxines with C-Sn Bond and C-O Bond: Syntheses of 3,4-Disubstituted Furans and 4-Substituted-3(2H)-furanones,

Tris[4-(substituted)furan-3-yl]boroxines 2 , prepared from the corresponding 4-(substituted)-3-(trimethylsilyl) furan 1, were converted successfully to 4-(substituted)-3-(tributylstannyl)furans 3 through palladium-catalyzed cross-coupling reactions with tributylstannyl chloride. Palladium-catalyzed cross-coupling reactions of 3 with organohalides afforded 3,4-disubstituted furans 4 . Regiospecific iodination of 4-(trimethylsilyl)-3-((tributylstannyl) furan ( 3a ) gave 4-iodo-3-(trimethylsilyl)furan ( 5 ), which reacted with excess ethyl acrylate under a common Heck-condition to produce 2,3-bis(trans-ethoxycarbonylvinyl)-4-(trimethylsilyl)furan ( 6 ). A thermal 6-electrocyclic reaction followed by dehydration converted 6 into benzo[2,3-6]furan 8 . Oxidation of 2 generated the corresponding 4-substituted-3(2H)-furanones 9 .     

Cross-coupling reaction on N-(3,5-dibromo-2-pyridyl)piperazines: regioselective synthesis of 3,5-disubstituted pyridylpiperazines

Unsymmetrical 3,5-disubstituted pyridylpiperazines were prepared from tribromopyridine in three coupling reactions. Key to the success of the syntheses is the palladium-catalyzed regioselective cross-coupling reaction in the 3-position of N-(3,5-dibromo-2-pyridyl)piperazines.     

Convenient synthesis of 2,4-disubstituted pyrido[2,3-d]pyrimidines via regioselective palladium-catalyzed reactions

A novel and effective route for the synthesis of 2,4-disubstituted pyrido[2,3-d]pyrimidines III is reported starting from the corresponding 2,4-dichloropyridopyrimidine 1 through regioselective functionalization palladium-catalyzed C–C coupling reactions, by two successive palladium-catalyzed reactions involving an original regioselective chlorine discrimination. Alternatively, type III compounds were elaborated from 2 by C-2 chlorine further displacement of the C-4 isopropylsulfanyl group, which acted as a temporary C-4 protecting group. Further Suzuki–Miyaura cross-coupling reactions led to C-2 and C-4 disubstituted compounds.     

Pd-catalyzed regiocontrolled Sonogashira and Suzuki cross-coupling reaction of 3,6-dihalogenoimidazo[1,2-a]pyridines: one-pot double-coupling approach

New and efficient regioselective Sonogashira and Suzuki-Miyaura palladium-catalyzed coupling reactions of 3,6-dihalogenoimidazo[1,2-a]pyridines followed by another cross-coupling has been successfully developed. Various solvents, palladium species and bases were tested. Scope and limitations of this regiocontrolled palladium-catalyzed reaction were investigated. The synthesis of 3,6-disubstituted imidazo[1,2-a]pyridine derivatives using one-pot regioselective double-coupling approach was developed. This procedure affords convergent syntheses of polysubstituted compounds in high yields in a very few steps.     

One-pot synthesis of 5,5′-dibromo-2,2′-dipyridylacetylene and its boronic acid derivative

5,5′-Dibromo-2,2′-dipyridylacetylene was prepared from 2,5-dibromopyridine and (trimethylsilyl)acetylene via the new one-pot synthesis approach using a regioselective palladium-catalyzed coupling reaction with a 60% yield. Several protocols of lithium-halogen exchange were then attempted to synthesize 6,6′-(1,2-ethynediyl)bis[3-pyridylboronic acid] from 5,5′-dibromo-2,2′-dipyridylacetylene. The former was successfully obtained with a 54% yield by a reverse addition method using toluene and THF and it showed potential as a useful building block for cross-coupling reactions in the formation of carbon-carbon bonds.     

Pyrrolodiazines. 6. Palladium-catalyzed arylation, heteroarylation, and amination of 3,4-dihydropyrrolo[1,2-a]pyrazines

The palladium-catalyzed Suzuki cross-coupling reaction of arylboronic acids and 6-bromo- and 6,8-dibromo-3,4-dihydropyrrolo[1,2-a]pyrazines afforded 6-substituted and 6,8-disubstituted 3,4-dihydropyrrolo[1,2-a]pyrazines in good yields. Stille and Negishi coupling reactions have been used to prepare 6-heteroaryl-substituted derivatives in moderate yields by employing heteroaryl halides and 6-metalated 3,4-dihydropyrrolo[1,2-a]pyrazines as reaction partners. A variety of cyclic secondary amines have also been incorporated at position C-6 of 6-bromo-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine in the presence of the palladium catalyst Pd(2)(dba)(3) in conjunction with BINAP as ligand. This amination reaction is one of the few reported examples of such a palladium-catalyzed transformation on a pyrrole ring, although the reaction could not be extended to less nucleophilic amines.     

Synthesis of d- and l-2,3-trans-3,4-cis-4,5-trans-3,4-dihydroxy-5-hydroxymethylproline and tripeptides containing them

Enantiomerically pure (-)-(1R,4R,5R,6S)- and (+)-(1S,4S,5S,6R)-7-(tert-butoxycarbonyl)-5,6-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]hept-2-one ((-)-3 and (+)-3) have been obtained from the Diels-Alder adduct of N-(tert-butoxycarbonyl)pyrrole and 2-bromo-1-(p-toluenesulfonyl)acetylene, including the Alexakis optical resolution of ketone (+/-)-3 via formation of cyclic aminals with (1R,2R)-diphenylethylenediamine. Compounds (-)-3 and (+)-3 were converted into d- and l-2,3-trans-3,4-cis-4,5-trans-N-(tert-butoxycarbonyl)-5-hydroxymethyl-3,4-isopropylidenedioxyprolines (-)-4 and (+)-4, respectively. Applying the Boc and Fmoc strategies of peptide synthesis, these compounds were used to construct two tripeptides containing the d- or l-2,3-trans-3,4-cis-4,5-trans-3,4-dihydroxy-5-hydroxymethylproline.     

Synthesis of 3,4-disubstituted isoquinolines via palladium-catalyzed cross-coupling of 2-(1-alkynyl)benzaldimines and organic halides

The palladium-catalyzed cross-coupling of readily available N-tert-butyl-2-(1-alkynyl)benzaldimines and aryl, allylic, benzylic, alkynyl halides, as well as a vinylic halide, provides a valuable new route to 3,4-disubstituted isoquinolines with aryl, allylic, benzylic, 1-alkynyl, and vinylic substituents, respectively, in the 4-position. The reaction appears to require an aryl group on the end of the acetylene furthest from the imine functionality. The reaction conditions have been optimized, and reasonably good yields have been obtained.     

A new catalytic cross-coupling approach for the synthesis of protected aryl and heteroaryl amidines

[reaction: see text] A new method for the synthesis of protected benzamidines is described. The commercially available 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea guanidylation reagent, after SEM-protection, functions as an amidine-forming cross-coupling partner under Liebeskind-Srogl conditions. In the presence of copper(I) thiophenecarboxylate (CuTC), the palladium-catalyzed cross-coupling of the SEM-protected thiopseudourea reagent with boronic acids affords fully protected benzamidines in good to excellent yield (40-91%).     

Regioselective functionalization of quinolin-4(1H)-ones via sequential palladium-catalyzed reactions

A practical and general synthesis of 1,3,6-trisubstituted quinolin-4(1H)-ones starting from 1-alkyl-6-bromo-3-iodoquinolin-4(1H)-one is described, based on regioselective sequential palladium-catalyzed cross-coupling reactions, namely Suzuki-Miyaura, Sonogashira and aminocarbonylation reactions, under microwave irradiation. Good substrate generality, ease of execution and practicability make this method exploitable for the generation of libraries of chemically diverse 4-quinolones.     

Synthesis of 3,5-difunctionalized 1-methyl-1H-pyrazolo[3,4-b]pyridines involving palladium-mediated coupling reactions

Indirect iodination of 2-chloro-nicotinonitrile gave 2-chloro-5-iodonicotinonitrile, which was cyclized with methylhydrazine to lead to 3-amino-5-iodopyrazolo[3,4-b]pyridine. Position 3 was then protected by pivaloyl group and the resulting 5-iodo-3-pivaloylaminopyrazolo[3,4-b]pyridine was engaged in palladium-promoted coupling reactions with various reagents to give 3-pivaloylamino-5-substituted compounds. Deprotection and iododediazoniation followed by cross-coupling reactions in position 3 afforded novel unsymmetrical 3,5-disubstituted pyrazolo[3,4-b]pyridine species.     

胺作为配体在钯催化偶联反应中应用

对近期我们研究小组及其它研究小组在利用胺作为钯催化偶联反应的配体研究进展进行了总结. 钯/胺作为催化体系主要应用的偶联反应包括: Suzuki-Miyaura交叉反应, Sonogashira交叉反应, Stille交叉反应, Hiyama交叉反应和Heck反应. 研究结果表明胺可以作为价廉和高效的配体促进钯催化交叉偶联反应.     

Regioselective Palladium-Catalyzed Cross-Coupling Reactions of 2,4,7-Trichloroquinazoline

The regioselective palladium-catalyzed cross-coupling reactions of 2,4,7-trichloroquinazoline with various aryl- and heteroarylboronic acids are reported. An efficient, sequential strategy was developed that provides access to novel, functionalized heterocycles.     

Short and flexible route to 3,4-diarylpyrrole marine alkaloids: syntheses of permethyl storniamide A, ningalin B, and lamellarin G trimethyl ether

A highly efficient route to 3,4-diarylpyrrole marine alkaloids has been developed using Hinsberg-type pyrrole synthesis and palladium-catalyzed Suzuki cross-coupling of the 3,4-dihydroxypyrrole bis-triflate derivatives as key reactions. Based on this approach, formal syntheses of permethyl storniamide A and ningalin B, and a total synthesis of lamellarin G trimethyl ether have been achieved.     

General and efficient route for the synthesis of 3,4-disubstituted coumarins via Pd-catalyzed site-selective cross-coupling reactions

Palladium-catalyzed site-selective cross-coupling reactions of 3-bromo-4-trifloxycoumarin or 3-bromo-4-tosyloxycoumarin provide an efficient and facile route for the synthesis of 3,4-disubstituted coumarins, which include 3,4-diarylcoumarins, 3-amino-4-arylcoumarins, and 3-aryl-4-aminocoumarins. The order of reactivity of the (pseudo)halide substituents in the coumarins was found to be 4-OTf > 3-Br > 4-OTs.     

Synthesis of 5-iodo-1,2,3-triazole-containing macrocycles using copper flow reactor technology

A new macrocyclization strategy to synthesize 12- to 31-membered 5-iodo-1,2,3-triazole-containing macrocycles is described. The macrocycles have been generated using a simple and efficient copper-catalyzed cycloaddition in flow under environmentally friendly conditions. This methodology also permits the facile, regioselective synthesis of 1,4,5-trisubstituted-1,2,3-triazole-containing macrocyles using palladium-catalyzed cross-coupling reactions.     

Preparation and Regioselective Magnesiation or Lithiation of Bis(trimethylsilyl)methyl‐Substituted Heteroaryls for the Generation of Highly Functionalized Heterocycles

A wide range of bis(trimethylsilyl)methyl (BTSM)‐ substituted heteroaryl derivatives has been prepared by using Kumada–Corriu or Negishi cross‐coupling reactions. The regioselective lithiation or magnesiation of these building blocks bearing a bulky BTSM group by using magnesium or lithium 2,2,6,6‐tetramethylpiperidide bases followed by quenching reactions with different electrophiles provides various functionalized N‐, O‐, or S‐heterocycles. Furthermore, the BTSM group can then be converted into formyl, methyl, or styryl groups to give access to a variety of highly functionalized heteroaromatics.     

Novel approach towards 3,7-disubstituted 1,6-naphthyridin-4(1H)-ones exploiting cross-coupling and SNAr reactions of a dihalogenated compound

A new route towards the synthesis of a series of 3,7-disubstituted 1,6-naphthyridin-4(1H)-ones in moderate to good yields is reported. The strategy involves the preparation of a 3,7-dihalogenated compound that undergoes differential functionalization using palladium-catalyzed cross-coupling and S_NAr reactions.     

Convergent stereoselective synthesis of the visual pigment A2E

[chemical reaction: see text]. A stereoselective total synthesis of the visual pigment A2E has been achieved with use of palladium-catalyzed cross-coupling reactions in all key steps: a regioselective Suzuki or Negishi coupling of 2,4-dibromopyridine, a Sonogashira reaction, and a double Stille cross-coupling to complete the bispolyenyl skeleton.