Bifunctionalized Allenes,Part IX: An Efficient Method for Regioselective Synthesis of 4‐Heteroatom‐Functionalized Allenecarboxylates

An efficient method for regioselective synthesis of 4‐heteroatom‐functionalized allenecarboxylates by an atom economical [2,3]‐sigmatropic rearrangement of the mediated 2‐heteroatom‐functionalized alk‐3‐ynecarboxylates is described. Alkyl 4‐(dimethoxyphosphoryl), (diphenylphosphinoyl), (benzenesulfinyl), or (methanesulfonyl)‐alka‐2,3‐dienoates can be readily prepared via reactions of alkyl 2‐hydroxy‐alk‐3‐ynoates with dimethylchlorophosphite, chlorodiphenylphosphine, benzensulfanyl chloride, or methanesulfinyl chloride, respectively, in the presence of a base.     

Selective functionalization in positions 2 and 3 of indole via an iodine-copper exchange reaction

Two selectively successive I/Cu exchange reactions performed with (Nphyl)CuLi allow the functionalization of indoles in positions 2 and 3. The 2,3-diketones prepared by this method can readily be converted to tricyclic heterocycles by standard methods.     

Methanesulfenylation of 2,3-dialkylindoles: synthesis and reactions of 3-methylthioindolenines

3-Methylthioindolenines, readily prepared from 2,3-dialkylindoles and methanesulfenyl chloride, are heat and acid labile, yielding the parent indole and methyl disulfide as the major decomposition products, and are readily reduced to the parent indoles with mercaptoacetic acid.     

Sulfenylation of some pyrroles and indoles

Methylsulfenylation of 1-substituted pyrroles and indoles was observed using 1-(methylthio)morpholine and an acid catalyst or with methylsulfenyl chloride and excess pyridine. 1-Substituents which are activating or weakly deactivating towards electrophilic substitution such as alkyl, 2-cyanoethyl, dimethylamino, trialkylsilyl, 2-chloroethyl and 2-phenylsulfonylethyl were used. The 2-chloroethyl and 2-phenylsulfonylethyl groups which can be removed with a strong base can be used to obtain 1H-methylthiopyrroles and indoles. 1-Phenylsulfonyl and 1-acetyl substituents are too strongly deactivating for these sulfenylations to be successful. Mono and disubstituted pyrroles and monosubstituted indoles can be isolated from these reactions, however, because the methylthio group is activating towards electrophilic substitution the main advantage of these reactions is the synthesis of tri and tetrasubstituted pyrroles and disubstituted indoles. 1-Methyl-2,3,4,5-tetra-methylthiopyrrole and 1-methyl-2,3-dimethylthioindole are oxidized to the corresponding 3,4-disulfoxide and 3-sulfoxide and with excess oxidizing agent to the tetrasulfone and disulfone, respectively.     

An efficient,mild and selective Ullmann‐type N‐arylation of indoles catalysed by Pd immobilized on amidoxime‐functionalized mesoporous SBA‐15 as heterogeneous and recyclable nanocatalyst

A wide range of N‐arylated indoles were selectively synthesized through intermolecular C(aryl)? N bond formation from the corresponding aryl iodides and indoles through Ullmann‐type coupling reactions in the presence of a catalytic amount of Pd immobilized on amidoxime‐functionalized mesoporous SBA‐15 (SBA‐15/AO/Pd(0)) under mild reaction conditions. These cross‐coupled products were obtained in excellent yields under mild conditions at extremely low palladium loading (ca 0.3 mol%), and the heterogeneous catalyst can be readily recovered by simple filtration and reused seven times with loss in its activity. Copyright © 2015 John Wiley & Sons, Ltd.     

A Novel Pd‐Catalysed Annulation Reaction for the Syntheses of Pyrroloindoles and Pyrroloquinolines

Pd‐catalysed annulation reactions between indole derivatives and internal alkyne esters leading to various pyrrolo[1,2‐a]indoles and pyrroloquinolines have been developed. The strategy involves an intermolecular addition of the indole nitrogen on to the internal alkyne ester followed by an intramolecular insertion of a vinyl–palladium complex into the carbonyl group. This method offers a facile and practical approach to pyrrolo[1,2‐a]indoles and pyrroloquinolines.     

Palladium‐Catalyzed Enantioselective Reductive Heck Reactions: Convenient Access to 3,3‐Disubstituted 2,3‐Dihydrobenzofuran

The first example of highly enantioselective intramolecular hydroarylation of allyl aryl ethers was realized by palladium‐catalyzed reductive heck reactions utilizing a new chiral sulfinamide phosphine ligand (N‐Me‐ XuPhos ). N‐Me‐ XuPhos can be easily prepared on gram scale from readily available starting materials in a one‐pot synthesis approach. A series of optically active 2,3‐dihydrobenzofurans bearing a quaternary stereocenter were obtained in good yields and with excellent enantioselectivities. The practicality of this reaction was validated in the straightforward synthesis of CB2 receptor agonists. Moreover, deuterium was efficiently incorporated into the products.     

Synthesis of diversely functionalized hexahydropyrrolo[2,3-b]indoles using domino reactions, olefination, isomerization and Claisen rearrangement followed by reductive cyclization

Hexahydropyrrolo[2,3-b]indoles 6 were synthesized in five steps from indolin-3-one 8 by a general and efficient method, in which elements of molecular diversity were readily added onto the 3a-position of the pyrrolo[2,3-b]indole ring system. Horner-Wadsworth-Emmons reaction of 2-allyloxyindolin-3-ones 7, derived from indolin-3-one 8 and a variety of allylic alcohols, smoothly proceeded with successive Claisen rearrangement to give the corresponding 3-allyl-3-cyanomethylindolin-2-ones 15. Indolin-2-ones 15 were converted into pyrrolo[2,3-b]indoles 6 using partial hydrolysis followed by reductive cyclization with LiAlH(4). Synthesis of N-methylated pyrrolo[2,3-b]indole derivatives 23 and 26 is also described.     

Efficient indoles and anilines syntheses employing tert-butyl sulfinamide as ammonia surrogate

tert-Butyl sulfinamide is an ammonia equivalent for the palladium-catalyzed amination of aryl bromides and aryl chlorides. Using these amine derivatives, it has been observed that indoles and anilines with sensitive functional groups can be readily prepared. This surrogate has also been used for the synthesis of indoles from 2-halophenols using palladium catalyzed cross coupling reaction as the key step.     

Synthesis,characterization and first application of chiral C2‐symmetric bis(phosphinite)–Pd(II) complexes as catalysts in asymmetric intermolecular Heck reactions

A series of new chiral C₂‐symmetric bis(phosphinite) ligands and their palladium(II) complexes have been synthesized and for the first time used as catalysts in the palladium‐catalysed asymmetric intermolecular Heck coupling reactions of 2,3‐dihydrofuran with iodobenzene or aryl triflate. Under optimized conditions, products were obtained with high conversions and moderate to good enantioselectivities. The new C₂‐symmetric bis(phosphinite) ligands and their palladium(II) complexes were characterized using multinuclear NMR and Fourier transform infrared spectroscopies and elemental analysis. Copyright © 2015 John Wiley & Sons, Ltd.     

Palladium‐Catalyzed Insertion of Isocyanides into the C−S Bonds of Heteroaryl Sulfides

Insertion of tert‐butyl isocyanide into the C(sp²)?S bonds of heteroaryl sulfides is catalyzed by a palladium diphosphine complex. Thioimidates generated through this reaction could be readily hydrolyzed under acidic conditions to yield the corresponding thioesters, which are of synthetic use. This insertion is useful because starting heteroaryl sulfides were readily prepared by either conventional ways or through sulfur‐specific extended Pummerer reactions.     

Highly Regioselective Preparation of Heteroaryl–Magnesium Reagents by Using a Br/Mg Exchange

Disubstituted thienyl‐, furyl‐ and pyridylmagnesium derivatives are regioselectively prepared from a Br/Mg exchange of the corresponding dibromo compounds by using either iPrMgCl ? LiCl or hindered arylmagnesium reagents, such as isitylmagnesium bromide ? lithium chloride (isityl=2,4,6‐triisopropyl‐phenyl) complexed with a diamine ligand, in difficult cases. The selective functionalisations of these heterocyclic scaffolds by using Negishi cross‐coupling reactions, acylations or addition to aldehydes were readily achieved.     

Formal Total Synthesis of Diazonamide A by Indole Oxidative Rearrangement

A short formal total synthesis of the marine natural product diazonamide A is described. The route is based on indole oxidative rearrangement, and a number of options were investigated involving migration of tyrosine or oxazole fragments upon oxidation of open chain or macrocyclic precursors. The final route proceeds from 7‐bromoindole by sequential palladium‐catalysed couplings of an oxazole fragment at C‐2, followed by a tyrosine fragment at C‐3. With the key 2,3‐disubstituted indole readily in hand, formation of a macrocyclic lactam set the stage for the crucial oxidative rearrangement to a 3,3‐disubstituted oxindole. Notwithstanding the concomitant formation of the unwanted indoxyl isomer, the synthesis successfully delivered, after deprotection, the key oxindole intermediate, thereby completing a formal total synthesis of diazonamide A.     

Controlled immobilization of palladium nanoparticles in two different fluorinated polymeric aggregate cores and their application in catalysis

Fluoroalkyl end-capped betaine-type cooligomeric nanocomposites-immobilized palladium nanoparticles were prepared by the reactions of palladium chloride with sodium acetate in the presence of sodium chloride and the corresponding fluorinated cooligomers. Outer blocks of poly(2,3,4,5,6-pentafluorostyrene)-containing ABA-triblock copolymeric nanocomposites-immobilized palladium nanoparticles were prepared by the use of the corresponding block copolymers under similar conditions. TEM images showed that palladium nanoparticles can be immobilized outside the fluorinated cooligomeric nanocomposite cores; in contrast, palladium nanoparticles can be effectively immobilized inside these fluorinated ABA-triblock copolymeric nanocomposite cores. Thus, these two different fluorinated copolymers enabled the controlled immobilization of palladium nanoparticles in the fluorinated nanocomposite cores. These fluorinated nanocomposites-immobilized palladium nanoparticles were also applied to the catalysts for Suzuki-Miyaura cross-coupling reaction, and the different reactivity between these nanocomposites was observed.     

Specific allylic-allylic coupling procedures effected by ligand-induced elimination from di(allylic)palladium species

Bis(allylic)palladium complexes can be induced to undergo reductive elimination by replacement of phosphine ligands in the system with π-acidic ligands. The product 1,5-diencs, formed in high yield, are predominantly the ‘head-to-head’ coupled isomers. The bis(allylic)palladium intermediatesmay be formed by addition of an allylic Grignard or trialkyl(allylic)tin reagent to an (η³-allyl)palladiuin chloride complex, or by 1,3-diene condensation. The latter process leads to cydodimerization, ‘unusual’ for palladium catalysed reactions.     

Facile access to polysubstituted indoles via a cascade Cu-catalyzed arylation-condensation process

Cu(I)/L-proline-catalyzed cross-coupling of 2-halotrifluoroacetanilides with beta-keto esters and amides followed by in situ acidic hydrolysis delivered 2,3-disubstituted indoles. The halides bearing a strong electron-withdrawing group in the 4-position can undergo in situ basic hydrolysis to provide the corresponding indoles. Polysubstituted indoles can be prepared from substituted 2-halotrifluoroacetanilides with high regioselectivity.     

The reaction of indole and the indole grignard reagent with phosgene. A facile synthesis of indole-3-carboxylic acid derivatives

Indole-3-carboxylic acid (as well as indole-3-glyoxylic acid) derivatives are readily prepared from indoles (including oxindoles) and phosgene (oxalyl chloride), respectively. The interaction of these reagents with the indole Grignard reagent afforded several products including the cyclo-tetramers, 21 and 30 . Indolo-fused heterocycles can be readily prepared from the reaction of phosgene (or oxalyl chloride) with suitable reactants. Thus e.g., phosgene and 2-(2-hydroxy-phenyl)-N-methylindole readily gave 5,6-dihydro-11-methyl-6-oxobenzo[a]pyrano[4,3-b] indole ( 33 ).     

Chemoselective functionalization of α-carbolines at the C-2, C-3, C-4, and C-6 positions using Suzuki-Miyaura reactions

The synthesis of 2-, 3-, 4-, and 6-substituted pyrido[2,3-b]indoles (α-carbolines) by palladium-catalyzed cross-coupling reactions from the corresponding halopyrido[2,3-b]indoles is described. A sequential and a one-pot chemoselective double Suzuki-Miyaura coupling route is presented for the synthesis of symmetrically and unsymmetrically disubstituted pyrido[2,3-b]indoles.     

The regioselectivity of rhodium and palladium-catalysed cyclisations of 2-bromo-1,6- and -1,7-dienes

2-Bromo-l,6-dienes are catalytically cyclised to a mixture of the corresponding 3,4-bis(methylene)cyclopentane and 5-methylenecyclohex-3-ene. Wilkinson's catalyst shows good selectivity for the 5-membered ring product whilst palladium catalysts, in general, show little selectivity, Addition of tetraethylammonium salts, especially the chloride, allow the palladium catalysed reactions to be carried out at 30°C in good yield and with high selectivity for the 5-membered ring. 2-Bromo-1,7-dienes are cyclised regio-specifically to 6-membered rings by the same catalysts although some double bond isomerisation also occurs. The mechanism of the catalytic cyclisations is discussed. The 3,4-bis(methylene) cyclopentanes undergo facile Diels-Alder reactions.     

Diversity‐Oriented Synthesis of Substituted Benzo[b]thiophenes and Their Hetero‐Fused Analogues through Palladium‐Catalyzed Oxidative CH Functionalization/Intramolecular Arylthiolation

An efficient, high yielding route to multisubstituted benzo[b]thiophenes has been developed through palladium‐catalyzed intramolecular oxidative C?H functionalization–arylthiolation of enethiolate salts of α‐aryl‐β‐(het)aryl/alkyl‐β‐mercaptoacrylonitriles/acrylates or acrylophenones. The overall strategy involves a one‐pot, two‐step process in which enethiolate salts [generated in situ through base‐mediated condensation of substituted arylacetonitriles, deoxybenzoins, or arylacetates with (het)aryl (or alkyl) dithioates] are subjected to intramolecular C?H functionalization–arylthiolation under the influence of a palladium acetate (or palladium chloride)/cupric acetate catalytic system and tetrabutylammonium bromide as additive in N,N‐dimethylformamide (DMF) as solvent. In a few cases, the yields of benzo[b]thiophenes were better in a two‐step process by employing the corresponding enethiols as substrates. In a few examples, Pd(OAc)₂ (or PdCl₂) catalyst in the presence of oxygen was found to be more efficient than cupric acetate as reoxidant, furnishing benzothiophenes in improved yields by avoiding formation of side products. The method is compatible with a diverse range of substituents on the aryl ring as well as on the 2‐ and 3‐positions of the benzothiophene scaffold. The protocol could also be extended to the synthesis of a raloxifene precursor and a tubulin polymerization inhibitor in good yields. The versatility of this newly developed method was further demonstrated by elaborating it for the synthesis of substituted thieno‐fused heterocycles such as thieno[2,3‐b]thiophenes, thieno[2,3‐b]indoles, thieno[3,2‐c]pyrazole, and thieno[2,3‐b]pyridines in high yields. A probable mechanism involving intramolecular electrophilic arylthiolation via either a Pd‐S adduct or palladacycle intermediate has been proposed on the basis of experimental studies.