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.     

Sc(OTf)3: A Highly Efficient and Renewable Catalyst for Michael Addition of Indoles to Nitroolefins in Water

A catalytic amount of scandium trifluoromethanesulfonate [Sc(OTf)₃] (2.5 mol%) was used to catalyze the Michael addition of indoles to nitroolefins in water to afford the corresponding 3-alkylated indoles in good to excellent yields. The short reaction times, excellent yields, and renewability of the catalyst are noteworthy.     

Base-promoted three-component cascade approach to unsymmetrical bis(indolyl)methanes

Here we report a base-catalyzed reaction of two different indoles with aldehydes under heating to produce unsymmetrical bis(indolyl)methanes (BIMs), in which one of the indole ring must be N-substituted. Mixture of EtOH-H₂O is used as solvent. The reaction did not give symmetrical BIMs of N-substituted indoles or N–H indoles. However, traces of latter were formed in few cases, especially when electron-rich aldehydes were used. Diversely substituted indoles and aldehydes were used for the reaction. The reaction proceeds via 3-indolylalcohol, which we confirmed through isolation. The method also gives good yield on multigram scale reaction.     

Indium trichloride catalyzed three component one-pot route to 1-hydroxymethyl-3-aminomethyl indoles

A one-pot synthesis of 1-hydroxymethyl-3-aminomethyl indoles 3 could be achieved in excellent yield by reacting indoles 1 with formaldehyde and secondary amines 2 in the presence of molecular sieves (3 Å) and catalytic amount of InCl₃ (10 mol %) in 1,4-dioxane at room temperature for 3-5 h.     

A new synthesis of 3-arylthioindoles as selective COX-2 inhibitors using PIFA

The direct 3-arylthiolation of 2-substituted indoles using phenyliodine(III)bis trifluoroacetate (PIFA) in (CF₃)₂CHOH with a wide variety of benzenethiols has been accomplished. In particular, indoles bearing a 6-MeSO₂ and either a 2-methyl or 2-carboxymethyl substituent could be 3-arylthiolated in good to excellent yields to afford the corresponding 3-arylthioindoles as selective COX-2 inhibitors. In a study varying the electronic nature of the 5-substituent of 2-CO₂Et indoles, it was discovered that the yield of the reaction improved as the substituent became more electron withdrawing. This result was consistent with a proposed mechanism involving benzenethiol displacement of an intermediate 3-IPh indole complex.     

Direct Catalytic Asymmetric and Regiodivergent N1- and C3-Allenylic Alkylation of Indoles

Herein we report a Pd-catalyzed asymmetric allenylic alkylation strategy for the direct functionalization of 1H-indoles by employing P-chiral BIBOP-type ligands. The regioselectivity (N1/C3) of this process can be switched efficiently. Using Cs₂CO₃ at elevated temperatures in MeCN, N1-alkylated indoles bearing axial chirality with a stereocenter non-adjacent (β) to the nitrogen are produced in good yields with high enantioselectivity and complete N1-regioselectivity regardless of the electronic properties and substitution patterns of diverse indoles. Using K₂CO₃ at room temperature in CH₂Cl₂, chiral C3-alkylated indoles can also be obtained. Notably, we introduce a new class of tri-substituted allenylic electrophiles that proceeded through different pathways from di-substituted allenylic electrophiles.     

3-(o-Trifluoroacetamidoaryl)-1-propargylic esters: common intermediates for the palladium-catalyzed synthesis of 2-aminomethyl-, 2-vinylic, and 2-alkylindoles

3-(o-Trifluoroacetamidoaryl)-1-propargylic esters have been used as common synthetic intermediates for the preparation of a variety of 3-unsubstituted 2-substituted indoles. Treating ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates unsubstituted or containing an aryl substituent at the propargylic carbon with piperazines and Pd(PPh₃)₄ in THF at 80 °C affords 2-(piperazin-1-ylmethyl)indoles in excellent yields. Good to excellent yields of 2-aminomethylindoles are also obtained with other secondary amines. Ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates bearing an alkyl substituent at the propargylic carbon and ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic acetates disubstituted at the propargylic carbon give 2-vinylic indoles with the Pd(OAc)₂/PPh₃ combination and Et₃N in THF at 80 °C. Formation of 2-vinylic indoles is quite stereoselective, generating trans vinylic derivatives, at least with the substrates that we have investigated. In the presence of formic acid, Et₃N, and Pd(PPh₃)₄ in MeCN at 80 °C, ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates afford 2-alkylindoles in good to excellent yields.     

Base-induced rearrangements of 3-(α-haloacyl)indoles : A convenient route to indole-3-acetic acids and tryptopholes

Base-induced reactions of 3-(α-haloacyl)indoles have been investigated. Rearrangement is a general reaction observed under the influence of various bases, e.g. hydroxide, hydride and Grignard reagent. Indole-3-acetic acids (20–32) are formed in fair yields when the reaction is performed with sodium hydroxide in 80% aqueous ethanol. The carbon monoxide evolved during the reaction appears to be eliminated from an intermediate cyclopropanone (33). Tryptopholes (53–55) are prepared in good yields by LiAlH₄-reduction of 3-(α-haloacyl)indoles.     

First heterogeneously palladium-catalysed fully selective C3-arylation of free NH-indoles

A simple heterogeneously palladium-catalysed procedure for the selective C3-arylation of indoles is reported. Under relatively standard reaction conditions (Pd-catalyst, K₂CO₃, dioxane, reflux), using only 1 mol % [Pd(NH₃)₄]/NaY as the catalyst, indoles substituted or not at position 2 gave up to 92% conversion (i.e., 85% isolated yield) towards the expected C3-arylated indole.     

通过η~3-苄基钯中间体零价钯催化的吲哚苄基化反应(英文)

本文报道了零价钯催化的吲哚苄基化反应,获得了优秀的区域选择性.使用Pd(PPh3)4作为催化剂,在温和反应条件下,以90%–99%的收率获得含有各类取代吲哚片段的三芳基甲烷化合物.     

Catalytic conjugate addition of heterocyclic compounds to α,β-unsaturated carbonyl compounds by hafnium salts and scandium salts

The hafnium chloride (HfCl₄) and scandium chloride (ScCl₃) catalyzed conjugate additions of heterocyclic compounds, such as indoles, pyrrole, pyrazole, and imidazole, have been demonstrated. Hafnium chloride effectively catalyzed the conjugate addition of indoles to α,β-unsaturated carbonyl compounds, and the addition product was obtained in high yield. The reaction of pyrrole was also catalyzed by HfCl₄ or ScCl₃, and produced 2,6-dialkylated pyrroles up to 99% yields. Furthermore, the conjugate addition of the 1-position of the pyrazoles and imidazole occurred, and produced several substituted heterocyclic compounds in good yields.     

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.     

Sequential alkylation/cyclization/isomerization of ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic esters: a new route to 2-acyl- and 2-ethoxycarbonyl-3-alkenyl indoles

The reaction of ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic esters with ethyl iodoacetate or α-bromoacetophenone in the presence of K₂CO₃ in DMSO provides a new simple access to 2-acyl- and 2-ethoxycarbonyl-3-alkenyl indoles.     

F-Tag Induced Acyl Shift in the Photochemical Cyclization of o-Alkynylated N-Alkyl-N-acylamides to Indoles**

A photochemical cyclization of F-tagged, o-alkynylated N-alkylamides to indoles catalyzed by [Ir(dF(CF₃)ppy)₂(dtbpy)]PF₆ is presented. This straightforward and efficient reaction involves an intramolecular rearrangement due to the presence of an electron withdrawing group in the acyl moiety and is the first example of photochemically induced 1,3-acyl shift in the cyclization towards 3-acylindoles. A four-step reaction sequence including the photoreaction as a key step to the desired indoles has been developed and optimized. The compatibility of differently substituted F-tagged precursors with the photocyclization step was investigated and the robustness of this step towards modifications could be shown. In total, 16 so far unknown derivatives with diverse modifications in positions N1 and C2, bearing a pentadecafluorooctanoyl moiety as F-tag, were synthesized in very good yields and fully characterized.     

Directly Bridging Indoles to 3,3′‐Bisindolylmethanes by Using Carboxylic Acids and Hydrosilanes under Mild Conditions

A straightforward Lewis acid‐promoted protocol for 3,3′‐bisindolylmethanes (BIMs) synthesis by reductive alkylation of indoles at the C3 position with carboxylic acids in the presence of hydrosilane was developed for the first time. Instead of aldehydes, more readily available, stable, and easy‐to‐handle carboxylic acids have been employed as alternative alkylating agents. As an efficient organocatalyst, B(C₆F₅)₃ enables the reductive alkylation of various substituted indole derivatives with carboxylic acids with up to 98 % yield at room temperature and under neat conditions. This metal‐free strategy offers an alternative approach for the direct functionalization of indoles to BIMs with carboxylic acids and such protocol allows selective reduction of carboxylic acid to aldehyde in combination with C−C bond formation.     

Cs2CO3-catalyzed alkylation of indoles with trifluoromethyl ketones

A Cs₂CO₃-catalyzed alkylation reaction of indoles with trifluoromethyl ketones was presented. Both alicyclic and aromatic trifluoromethyl ketones as well as various substituted indoles are compatible with the methodology. Good to excellent yields of the corresponding trifluoromethyl substituted tertiary alcohols 2,2,2-tritrifluoro-1-(1H-indol-3-yl)-ethan-1-ols were acquired as the sole products.     

Tandem radical addition reactions to substituted indoles under atom-transfer and oxidative conditions

The dimethyl methylmalonyl radical was generated upon photolysis of dimethyl bromomethylmalonate or treatment of dimethyl methylmalonate with Mn(OAc)₃·2 H₂O. This radical was added to an exocyclic olefin appended to 1-acyl or 3-acyl indoles, with subsequent cyclization to generate 1,2- or 2,3- fused indole derivatives, respectively.     

Palladium‐Catalyzed Direct C2 Arylation of N‐Substituted Indoles with 1‐Aryltriazenes

A novel and efficient palladium‐catalyzed C2 arylation of N‐substituted indoles with 1‐aryltriazenes for the synthesis of 2‐arylindoles was developed. In the presence of BF₃ ? OEt₂ and palladium(II) acetate (Pd(OAc)₂), N‐substituted indoles reacted with 1‐aryltriazenes in N,N‐dimethylacetamide (DMAC) to afford the corresponding aryl–indole‐type products in good to excellent yields.     

Ruthenium‐Catalyzed Alkylation of Indoles with Tertiary Amines by Oxidation of a sp3 C?H Bond and Lewis Acid Catalysis

Ruthenium porphyrins (particularly [Ru(2,6‐Cl₂tpp)CO]; tpp=tetraphenylporphinato) and RuCl₃ can act as oxidation and/or Lewis acid catalysts for direct C‐3 alkylation of indoles, giving the desired products in high yields (up to 82 % based on 60–95 % substrate conversions). These ruthenium compounds catalyze oxidative coupling reactions of a wide variety of anilines and indoles bearing electron‐withdrawing or electron‐donating substituents with high regioselectivity when using tBuOOH as an oxidant, resulting in the alkylation of N‐arylindoles to 3‐{[(N‐aryl‐N‐alkyl)amino]methyl}indoles (yield: up to 82 %, conversion: up to 95 %) and the alkylation of N‐alkyl or N‐H indoles to 3‐[p‐(dialkylamino)benzyl]indoles (yield: up to 73 %, conversion: up to 92 %). A tentative reaction mechanism involving two pathways is proposed: an iminium ion intermediate may be generated by oxidation of an sp³ C? H bond of the alkylated aniline by an oxoruthenium species; this iminium ion could then either be trapped by an N‐arylindole (pathway A) or converted to formaldehyde, allowing a subsequent three‐component coupling reaction of the in situ generated formaldehyde with an N‐alkylindole and an aniline in the presence of a Lewis acid catalyst (pathway B). The results of deuterium‐labeling experiments are consistent with the alkylation of N‐alkylindoles via pathway B. The relative reaction rates of [Ru(2,6‐Cl₂tpp)CO]‐catalyzed oxidative coupling reactions of 4‐X‐substituted N,N‐dimethylanilines with N‐phenylindole (using tBuOOH as oxidant), determined through competition experiments, correlate linearly with the substituent constants σ (R²=0.989), giving a ρ value of ?1.09. This ρ value and the magnitudes of the intra‐ and intermolecular deuterium isotope effects (k_H/k_D) suggest that electron transfer most likely occurs during the initial stage of the oxidation of 4‐X‐substituted N,N‐dimethylanilines. Ruthenium‐catalyzed three‐component reaction of N‐alkyl/N‐H indoles, paraformaldehyde, and anilines gave 3‐[p‐(dialkylamino)benzyl]indoles in up to 82 % yield (conversion: up to 95 %).     

Regioselective N- and C2-electrophilic substitution of 3-substituted indoles

The reaction of 3-substituted indoles with 2-cyclohexenone under Lewis acid mediated conditions with Bi(NO₃)₃·5H₂O has been investigated. We have demonstrated that electrophilic substitution of 3-substituted indoles with 2-cyclohexenone will readily occur at the nitrogen. Furthermore, the extent of regioselectivity is dependent on reaction solvent and the C3-substituent. Excellent conversion is obtained with good to excellent isolated yields of N- and C2-adducts. In general, more polar, aprotic solvents (CH₃CN) give greater N-selectivity whereas with polar protic solvents (CH₃OH) an increase in the C2-adduct is observed.