Palladium-catalyzed cyclization/carboalkoxylation of alkenyl indoles

Reaction of 1-methyl-2-(4-pentenyl)indole with a catalytic amount of PdCl2(CH3CN)2 (5 mol %) and a stoichiometric amount of CuCl2 (3 equiv) in methanol under CO (1 atm) at room temperature for 30 min led to cyclization/carboalkoxylation to form the corresponding tetrahydrocarbazole in 83% isolated yield as a single regioisomer. Palladium-catalyzed cyclization/carboalkoxylation of 2-(4-pentenyl)indoles tolerated substitution along the alkenyl chain and at the internal and cis-terminal olefinic positions. Palladium-catalyzed cyclization/carboalkoxylation tolerated a range of alcohols and was effective for the cyclization of 2-(3-butenyl)indoles, 3-(3-butenyl)indoles, 3-(4-pentenyl)indoles, and 2-(5-hexenyl)indoles.     

Palladium-catalyzed functionalization of indoles with 2-acetoxymethyl-substituted electron-deficient alkenes

New functionalizations of indoles via palladium-catalyzed reaction of indoles and 2-acetoxymethyl-substituted electron-deficient alkenes are reported. It was found that for N-protected indoles the reaction proceeded smoothly in the presence of 5 mol % of Pd(acac)2 and 10 mol % of PPh3 at 80 degrees C in HOAc, while for N-unprotected indoles, the reaction was carried out by using 5 mol % of Pd(dba)2 or 2.5 mol % of Pd2(dba)3.CHCl3 with 10 mol % of 2,2'-bipyridine as the catalyst in toluene. This strategy allows the selective installation of electron-deficient olefin functionality at the 3-position of indoles, which might be difficult to obtain by other methods and can be further elaborated.     

Solventless clay-promoted Friedel-Crafts reaction of indoles with alpha-amido sulfones: unexpected synthesis of 3-(1-arylsulfonylalkyl) indoles

Friedel-Crafts reaction of indoles with alpha-amido sulfones in the presence of montmorillonite K-10 leads unexpectedly to 3-(1-arylsulfonylalkyl) indoles in good yield. The obtained products can be further desulfonylated under reductive or alkylative conditions giving linear and branched 3-substituted indoles.     

Simplified synthesis of 3-(1-arylsulfonylalkyl) indoles and their reaction with Reformatsky reagents

A simple procedure for the preparation of 3-(1-arylsulfonyl-alkyl) indoles by three-component condensation of indoles, carbonyls, and arenesulfinic acids is presented. The obtained products undergo a Reformatsky reaction leading to alkyl 3-(3-indolyl) alkanoates and (3-indolyl) ketones.     

A mild, efficient and improved protocol for the synthesis of novel indolyl crown ethers, di(indolyl)pyrazolyl methanes and 3-alkylated indoles using H4[Si(W3O10)3]

Efficient electrophilic substitution reactions of indoles with various aldehydes proceed smoothly in acetonitrile using heteropoly acid (H₄[Si(W₃O₁₀)₃]) to afford the corresponding new indolyl crown ethers and di(indolyl)pyrazolyl methanes. H₄[Si(W₃O₁₀)₃] is also found to catalyze the Michael addition of indoles to ,β-unsaturated compounds for the synthesis of 3-alkylated indoles.     

Synthetic applications of 3‐(cyanoacetyl)indoles and related compounds

Various synthetic applications of 3‐(cyanoacetyl)indoles, as well as syntheses of some related indoles, have been investigated. Diethyl 2‐(1H‐indol‐3‐yl)‐2‐oxoethylphosphonate and a methyl derivative thereof have been prepared in one step from indole. Moreover, it was demonstrated that 3‐(cyanoacetyl)indoles are useful starting materials for the preparation of for example 3‐(1H‐indol‐3‐yl)‐3‐oxopropanamides, 3‐heteroarylindoles or 3‐heteroaroylindoles.     

New Synthesis of 1-Substituted 3-(2-Aminoethyl)indoles

A number of 1-substituted 3-(2-aminoethyl) indoles were prepared, in one step, by alkylation of the corresponding 3-(2-aminoethyl)indoles (tryptamines) in the presence of NaH.     

Gold(I)-catalyzed intermolecular hydroarylation of alkenes with indoles under thermal and microwave-assisted conditions

An efficient method for intermolecular hydroarylation of aryl and aliphatic alkenes with indoles using a combination of [(PR(3))AuCl]/AgOTf as catalyst under thermal and microwave-assisted conditions has been developed. The gold(I)-catalyzed reactions of indoles with aryl alkenes were achieved in toluene at 85 degrees C over a reaction time of 1-3 h with 2 mol% of [(PR(3))AuCl]/AgOTf as catalyst. This method works for a variety of styrenes bearing electron-deficient, electron-rich, and sterically bulky substituents to give the corresponding products in good to high yields (60-95%). Under microwave irradiation, coupling of unactivated aliphatic alkenes with indoles gave the corresponding adducts in up to 90% yield. Selective hydroarylation of terminal C=C bond of conjugated dienes with indoles gave good product yields (62-81%). On the basis of deuterium-labeling experiments, a reaction mechanism involving nucleophilic attack of Au(I)-coordinated alkenes by indoles is proposed.     

Preparation of 3-arylmethylindoles as selective COX-2 inhibitors

The 3-arylmethylation of indoles using TMSOTf/Et₃SiH with a wide variety of substituted benzaldehydes has been accomplished. Under these mild Lewis acid mediated reductive conditions, it was demonstrated that indoles bearing both 6-MeSO₂ and 2-methyl substituents could be 3-arylmethylated in good to excellent yields to afford the corresponding 3-arylmethyl indoles, effective as selective COX-2 inhibitors. In addition, the viability of this method for the reductive alkylation of indoles by ketones was demonstrated and shown to be C-3 regioselective. For indoles bearing both a 6-MeSO₂ and 2-cyano substituent where this indole reductive alkylation methodology was unsuccessful, an unprecedented Pd(0) mediated arylorganozinc coupling with the requisite substituted 3-methylcarbonatomethylindole proved successful in affording the desired 2-cyano-6-MeSO₂-3-arylmethylindoles effective as selective COX-2 inhibitors.     

Synthesis of 3-(2-N,N-diethylaminoethoxy)indoles as potential 5-HT6 receptor ligands

The synthesis of new pharmaceutically interesting 3-(2-N,N-diethylaminoethoxy)indole derivatives is described. Starting from 3-silyloxy-2-methylindoles, deprotection and in situ aminoalkylation provided 3-(2-N,N-diethylaminoethoxy)indoles in good yield. Further sulfonylation of these novel indoles gave access to potential 5-HT(6) receptor ligands.     

Direct synthesis of 3-arylindoles via annulation of aryl hydroxylamines with alkynes

3-Arylindoles are produced in moderate to excellent yields from the reaction between aryl hydroxylamines and alkynes catalyzed by 10 mol % iron(II) phthalocyanine [Fe(Pc)]. Terminal and internal alkynes afford 3-aryl substituted indoles exclusively. Electron-donating and -withdrawing groups are tolerated on the aryl hydroxylamine. A few bioactive indoles are synthesized as well as several new indoles using this one-step intermolecular annulation procedure.     

无金属参与的二乙酸碘苯促进吲哚C3—H乙酸化反应

研究了无金属参与的二乙酸碘苯和吲哚的C3—H乙酸化反应,通过对取代基效应、温度以及二乙酸碘苯用量等因素的考察,建立了反应的最佳条件:反应温度60℃,乙酸(HOAc)为溶剂.在无需任何添加剂条件下,以中等到良好的收率获得一系列C3位乙酸化的吲哚衍生物.采用红外光谱、核磁共振波谱、高分辨质谱及X射线单晶衍射分析对目标化合物进行了结构表征,并推测了可能的反应机理.该催化体系对于克量级规模反应均能获得很好的结果.     

Lewis acid catalyzed direct cyanation of indoles and pyrroles with N-cyano-N-phenyl-p-toluenesulfonamide (NCTS)

BF(3)·OEt(2)-catalyzed direct cyanation of indoles and pyrroles using a less toxic, bench-stable, and easily handled electrophilic cyanating agent N-cyano-N-phenyl-para-toluenesulfonamide (NCTS) affords 3-cyanoindoles and 2-cyanopyrroles in good yields with excellent regioselectivity. The substrate scope is broad with respect to indoles and pyrroles.     

疏水作用对光化学和光物理过程的影响——Ⅷ.N-烷基吲哚在不良溶剂中的簇集及其荧光光谱

本文研究了链长不同的N-烷基吲哚和3-甲基-N-烷基吲哚在二甲基亚砜-水(DMSO-H_2O)混合溶剂中的稳态和时间分辩荧光光谱, 发现随混合溶剂中水的体积分数增大、短链吲哚衍生物的荧光峰位置红移。荧光寿命增长、而长链吲哚衍生物荧光峰位置明显兰移、荧光寿命变短。表明长链吲哚衍生物在混合溶剂中发生簇集,簇集体中微环境的极性和环己烷相似, 利用时间分辨荧光光谱计算出长链吲哚衍生物在溶液本体相和簇集体中的分布。     

A new approach to difficult Fischer synthesis: the use of zinc chloride catalyst in triethylene glycol under controlled microwave irradiation

[reaction: see text]. Application of triethylene glycol with catalytic quantity of zinc chloride (ZnCl2/TEG) is described as a new and efficient reaction medium for a difficult Fischer synthesis, leading to sensitive indoles. Transformation of the 3-acetyl-1-methylthiocycloalka[c]pyridine phenylhydrazones and p-methoxyphenylhydrazones into the 2-(2-pyridyl)indoles and 5-methoxy-2-(2-pyridyl)indoles, which are the synthons in our total synthesis of the sempervirine-type alkaloids, is carried out under controlled microwave irradiation in dry zinc chloride solution (0.16 M) in TEG. This protocol produces indoles from acetophenone or cyclohexanone via their phenylhydrazones in excellent yields.     

Gold(I)-catalyzed rearrangement of 3-silyloxy-1,5-enynes: an efficient synthesis of benzo[b]thiophenes, dibenzothiophenes, dibenzofurans, and indole derivatives

With the IPr ligand (IPr=1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene) on gold(I) excellent yields in the benzanellation of 2-substituted thiophenes, benzothiophenes, pyrroles, benzofurans, and indoles were achieved. The 1-siloxybut-3-ynyl side chains, incorporated in the anellation, are easily accessible by the addition of a propargyl metal reagent to a formyl group and silylation of the alcohol. This conveniently allows an anellation at the position of the formyl group under mild conditions. All reactions involve a 2,3-shift of the side chain in the anellation step and thus, provide an easy access to specific substitution patterns. Only in the case of 2-substituted indoles with their highly nucleophilic 3-position a direct hydroarylation without shift is observed. On the other hand, 3-substituted indoles give the same products as 2-substituted indoles. Then, a 3,2-shift in the indole ring system has to be involved.     

Scope and mechanism of the Pd(II)-catalyzed arylation/carboalkoxylation of unactivated olefins with indoles

Treatment of 1-methyl-2-(4-pentenyl)indole (5) with a catalytic amount of [PdCl2(MeCN)2] (2; 5 mol %) and a stoichiometric amount of CuCl2 (3 equiv) in methanol under CO (1 atm) at room temperature for 30 min gives methyl (9-methyl-2,3,4,9-tetrahydro-4-carbazolyl)acetate (6), which was isolated in 83% yield. A number of 2- and 3-alkenyl indoles undergo a similar palladium-catalyzed cyclization/carboalkoxylation to give the corresponding polycyclic indole derivatives in moderate to excellent yields with excellent regio- and diastereoselectivity. Under similar conditions, vinyl arenes undergo intermolecular arylation/carboalkoxylation with indoles to give 3-(1-aryl-2-carbomethoxyethyl) indoles in moderate yield with high regioselectivity. Stereochemical analyses of the palladium-catalyzed cyclization/carboalkoxylation of both 2- and 3-alkenyl indoles are in agreement with mechanisms involving outer-sphere attack of the indole on a palladium-olefin complex followed by alpha-migratory insertion of CO and methanolysis of the resulting acyl palladium intermediate. CuCl2 functions as the terminal oxidant in this palladium-catalyzed cyclization/carboalkoxylation of alkenyl indoles and also significantly increases the rate of reaction of 2 with the alkenyl indole to form the corresponding acyl palladium complex. Spectroscopic studies are in agreement with the intermediacy of a heterobimetallic Pd/Cu complex as the active catalyst in this reaction.     

The Michael addition of indoles to alpha,beta-unsaturated ketones catalyzed by CeCl3.7H2O-NaI combination supported on silica gel

Alkylation of indoles by means of the Michael addition has been the subject of a number of investigation. It is well established that regioselectivity in the additions of indoles to electron-deficient alkenes is strongly controlled by the reaction medium. In a continuation of the work on developing greener and cleaner technologies, the cerium(III) chloride heptahydrate and sodium iodide combination supported on silica gel catalyzes the alkylation of various indoles with alpha,beta-unsaturated ketones giving 3-(3-oxoalkyl)indole derivatives in good yields. The substitution on the indole nucleus occurred exclusively at the 3-position, and N-alkylation products have not been observed.     

Efficient synthesis of 3-substituted indoles through a domino gold(I) chloride catalyzed cycloisomerization/C3-functionalization of 2-(alkynyl)anilines

An efficient synthesis of 3-substituted indoles by a sequential approach involving gold(I) chloride catalyzed cycloisomerization/bis-addition and conjugate addition of 2-(alkynyl)anilines has been accomplished. A variety of 2-(alkynyl)anilines, aldehydes, isatins and nitroolefins undergo this overall process in good to excellent yields. This methodology represents an effective alternative to the classical C3-functionalization of indoles.     

Ruthenium(II)‐Catalyzed C−H Activation of Imidamides and Divergent Couplings with Diazo Compounds: Substrate‐Controlled Synthesis of Indoles and 3H‐Indoles

Indoles are an important structural motif that is commonly found in biologically active molecules. In this work, conditions for divergent couplings between imidamides and acceptor–acceptor diazo compounds were developed that afforded NH indoles and 3H‐indoles under ruthenium catalysis. The coupling of α‐diazoketoesters afforded NH indoles by cleavage of the C(N₂)?C(acyl) bond whereas α‐diazomalonates gave 3H‐indoles by C?N bond cleavage. This reaction constitutes the first intermolecular coupling of diazo substrates with arenes by ruthenium‐catalyzed C?H activation.