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.     

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.     

N-alkenyl indoles as useful intermediates for alkaloid synthesis

A mild cross-coupling reaction to access several N-alkenyl-substituted indoles has been developed. The coupling procedure involves treating a NH-indole with various alkenyl bromides using a combination of 10 mol % of copper(I) iodide and 20 mol % of ethylenediamine as the catalyst in dioxane at 110 °C in the presence of K(3)PO(4) as the base. When treated with acid, these unique enamines produce a dimeric product derived from a preferred protonation reaction at the enamine π-bond. A cationic cyclization reaction of the readily available 2-(2-(1H-indol-1-yl)allyl)cyclopentanol was utilized to construct tetracyclic indole derivatives with a quaternary stereocenter attached to the C(2)-position of the indole ring. An alternative strategy for selective functionalization at the C(2)-position of a N-alkenyl-substituted indole derivative that was also studied involves a radical cyclization of a xanthate derivative. The work described provides an attractive route to the tetracyclic core of some vinca alkaloids, including the tetrahydroisoquinocarbazole RS-2135.     

Platinum-catalyzed multistep reactions of indoles with alkynyl alcohols

PtCl2 effectively catalyzes the multistep reaction of N-methyl indole (1 a) with pent-3-yn-1-ol (2 a) in THF at room temperature for 2 h to give indole derivative 3 a, which contains a five-membered cyclic ether group at C3 in 93% yield. Under similar reaction conditions, various substituted N-methyl indoles 1 b-h and indole (1 i) reacted efficiently with 2 a to afford the corresponding indole derivatives 3 b-h and 3 i in 48-91 and 72% yields. The results showed that N-methyl indoles with electron-donating substituents were more reactive affording higher product yields than those with electron-withdrawing groups. Likewise, various substituted but-3-yn-1-ols 2 b-e and other longer chain alkynyl alcohols 2 f-i also underwent a cyclization-addition reaction with N-methyl indole (1 a) to provide the corresponding cyclization-addition products 3 j-m and 3 a, 3 j, and 3 n-o in good to excellent yields. The present platinum-catalyzed cyclization-addition reaction can be further extended into N-methyl pyrrole. Mechanistically, the catalytic reaction proceeds by an intramolecular hydroalkoxylation of alkynyl alcohol to afford cyclic enol ether followed by the addition of the C--H bond of indole to the unsaturated moiety of cyclic enol ether providing the final product. Experimental evidence to support this proposed mechanism is provided.     

Assembly of conjugated enynes and substituted indoles via CuI/amino acid-catalyzed coupling of 1-alkynes with vinyl iodides and 2-bromotrifluoroacetanilides

Cross-coupling of 1-alkynes with vinyl iodides occurs at 80 degrees C in dioxane catalyzed by CuI/N,N-dimethylglycine to afford conjugated enynes in good to excellent yields. Heating a mixture of 2-bromotrifluoroacetanilide, 1-alkyne, 2 mol % of CuI, 6 mol % of L-proline, and K(2)CO(3) in DMF at 80 degrees C leads to the formation of the corresponding indole. This conversion involves a CuI/L-proline-catalyzed coupling between aryl bromide and the 1-alkyne followed by a CuI-mediated cyclization process. An ortho-substituent effect directed by NHCOCF3 enables the reaction to proceed under these mild conditions. Both aryl acetylenes and O-protected propargyl alcohol can be applied, leading to 5-, 6-, or 7-substituted 2-aryl and protected 2-hydroxymethyl indoles in good yields. With simple aliphatic alkynes, however, lower yields were observed.     

A bimetallic catalyst and dual role catalyst: synthesis of N-(alkoxycarbonyl)indoles from 2-(alkynyl)phenylisocyanates

3-allyl-N-(alkoxycarbonyl)indoles are synthesized via the reaction of 2-(alkynyl)phenylisocyanates and allyl carbonates in the presence of Pd(PPh(3))(4) (1 mol %) and CuCl (4 mol %) bimetallic catalyst. It is most probable that Pd(0) acts as a catalyst for the formation of a pi-allylpalladium alkoxide intermediate and Cu(I) behaves as a Lewis acid to activate the isocyanate, and the cyclization step proceeds with a cooperative catalytic activity of Pd and Cu. On the other hand, N-(alkoxycarbonyl)indoles are produced via the reaction of 2-(alkynyl)phenylisocyanates and alcohols under a catalytic amount of Na(2)PdCl(4) (5 mol %) or PtCl(2) (5 mol %). Pd(II) or Pt(II) catalyst exhibits dual roles; it acts as a Lewis acid to accelerate the addition of alcohols to isocyanates and as a typical transition-metal catalyst to activate the alkyne for the subsequent cyclization.     

Control of the regioselectivity of sulfonamidyl radical cyclization by vinylic halogen substitution

The radical cyclization reactions of unsaturated sulfonamides were investigated. The photolysis of N-(4-halo-4-pentenyl)sulfonamides (X=I, Br, or Cl) with (diacetoxyiodo)benzene (DIB) and iodine at room temperature afforded exclusively the corresponding piperidines in 73-98% yield via 6-endo radical cyclization. On the other hand, the reactions of N-(5-halo-4-pentenyl)sulfonamides with DIB/I2 led to the only formation of the pyrrolidine products in 84-99% yield via 5-exo radical cyclization. The vinylic halogen substitution not only successfully inhibits the competing ionic iodocyclization process to allow the radical cyclization to proceed smoothly but also shows a remarkable effect in controlling the regioselectivity of cyclization.     

Platinum-catalyzed intramolecular asymmetric hydroarylation of unactivated alkenes with indoles

[reaction: see text] A 1:1 mixture of the platinum bis(phosphine) complex [(S)-4]PtCl2 [(S)-4 = (S)-3,5-t-Bu-4-MeO-MeOBIPHEP] catalyzes the intramolecular asymmetric hydroarylation of 2-(4-pentenyl)indoles in moderate to good yield with up to 90% ee.     

About the synthesis of [1,2]diazepinoindole derivatives from ethyl 2-(1-methylindole)acetate, 2-indole and 3-indoleacetohydrazones

The Vilsmeier-Haack reaction with ethyl 2-(1-methylindole)acetate and N,N-Dimethylamides/phosphorus oxychloride gave (65–85%) of ethyl 2-(3-acyl-1-methylindole)acetates 2 , which when boiled with hydrazine yielded about 90% of 4,5-dihydro-6-methyl-4-oxo-3H[1,2]diazepino[5,6-b]indoles 3. The attempted cyclization of 2-(1-methylindole)acetohydrazones 6 with acyl (acetyl and benzoyl) chlorides/triethylamine, to [1,2]diazepino[5,6-b]indole derivatives was fruitless and the bis(acyl)hydrazones 9 were obtained. Several transformations of 9 are reported. Similarly, the attempted cyclization of 3-indoleacetohydrazones 14 with acetyl chloride/triethylamine to [1,2]diazepino[4,5-b]indole derivatives was also fruitless and the bis(acyl)hydrazones 16 were again obtained.     

Indole synthesis by radical cyclization of o-alkenylphenyl isocyanides and its application to the total synthesis of natural products

Development of indole synthesis by tin-mediated radical cyclization of o-alkenylphenyl isocyanide is described. Upon heating o-alkenylphenyl isocyanide in the presence of tri-n-butyltin hydride and AIBN, 2-stannyl-3-substituted indole was formed via 5-exo-trig cyclization of the imidoyl radical intermediate. After acidic workup, 3-substituted indoles were isolated. For substrates bearing simple alkyl groups, a substantial amount of tetrahydroquinoline derivatives were generated through 6-endo-trig cyclization. This undesired cyclization was suppressed by using an excess amount (five equivalents based on o-alkenylphenyl isocyanide) of ethanethiol instead of tri-n-butyltin hydride. The 2-stannylindole intermediates proved to be a suitable substrate for Stille coupling, giving 2,3-disubstituted indoles in a one-pot procedure. In addition, the 2-stannylindole intermediates could be converted to 2-iodoindoles by treatment with iodine or N-iodosuccinimide. The 2-iodoindoles thus obtained served as good substrates for Heck reactions, Stille couplings, Suzuki couplings, and palladium-mediated carbonylations, to afford a variety of 2,3-disubstituted indoles. The utility of this protocol was demonstrated by application to synthetic studies on gelsemine and discorhabdin A, and the total synthesis of an aspidosperma alkaloid, (-)-vindoline.     

The synthesis of 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles,11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles and 1,2,4-triazolo[3,4-f]-1,2,4-triazino[4,5-a]indoles

This paper describes the synthesis of the previously unknown 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles (2) and 11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles (3) from 4-hydrazino-5H-pyridazino[4,5-b]indoles (1) , as well as the synthesis of 1,2,4-triazolo[3,4-f]-1,2,4-triazino-[4,5-a]indoles (10) from 2-indolecarbohydrazide (4) . Compounds 2 were obtained by acylation of compounds 1 , followed of thermal cyclization and compounds 3 by treating compounds 1 with nitrous acid. The reactions of compound 4 with formic acid or ethyl orthoformiate gave 1,2-dihydro-1-oxo-1,2,4-triazino[4,5-a]indole (6) . Treating this last compound with phosphorus oxychloride or phosphorus pentasulfide, followed by hydrazine, gave 1-hydrazino-1,2,4-triazino-[4,5-a]indole (9) . Acylation of this last compound, followed of cyclization gave compounds 10 . All the compounds were characterized by elemental analysis and ir and ¹H-nmr spectra.     

Palladium-catalyzed intramolecular oxidative alkylation of 4-pentenyl beta-dicarbonyl compounds

Reaction of 8-nonene-2,4-dione with a catalytic amount of [PdCl2(CH3CN)2] (2; 5 mol %) and a stoichiometric amount of CuCl2 (2.5 equiv) at room temperature for 3 h led to oxidative alkylation and formation of 2-acetyl-3-methyl-2-cyclohexenone in 80 % isolated yield. The oxidative alkylation of 4-pentenyl beta-diketones tolerated a number of terminal acyl groups and substitution at the C1 and C3 carbon atoms of the 4-pentenyl chain. Likewise, 4-pentenyl beta-keto esters that possessed geminal disubstitution at the C1, C2, or C3 carbon atom of the 4-pentenyl chain cyclized to form 2-carboalkoxy-2-cyclohexenones in moderate to good yield as the exclusive cyclized product. Deuterium-labeling experiments provided information regarding the mechanism of the palladium-catalyzed oxidative alkylation of 4-pentenyl beta-dicarbonyl compounds.     

Development of an efficient procedure for indole ring synthesis from 2-ethynylaniline derivatives catalyzed by CuII salts and its application to natural product synthesis

The development of efficient methods for the indole synthesis catalyzed by Cu(II) salts and its applications were investigated. Cu(OAc)(2) has been proved to be the best catalyst for the synthesis of various 1-p-tolylsulfonyl or 1-methylsulfonylindoles, which have both electron-withdrawing and electron-donating groups on the aromatic ring and C2 position of indoles. For the primary aniline derivatives, Cu(OCOCF(3))(2) showed good activities, while Cu(OAc)(2) was a good catalyst for the cyclization of secondary anilines. This methodology could be applied to the sequential cyclization reaction for the compounds which have the electrophilic part in the same molecule. By prior treatment with KH, the sequential cyclization was realized to provide the tricyclic ring systems, but it was limited to five- and six-membered rings for the second cyclization. Finally, formal and total synthesis of hippadine with the Cu(II)-promoted indole synthesis as the key step was accomplished.     

Highly active Au(I) catalyst for the intramolecular exo-hydrofunctionalization of allenes with carbon, nitrogen, and oxygen nucleophiles

Reaction of benzyl (2,2-diphenyl-4,5-hexadienyl)carbamate (4) with a catalytic 1:1 mixture of Au[P(t-Bu)2(o-biphenyl)]Cl (2) and AgOTf (5 mol %) in dioxane at 25 degrees C for 45 min led to isolation of benzyl 4,4-diphenyl-2-vinylpyrrolidine-1-carboxylate (5) in 95% yield. The Au(I)-catalyzed intramolecular hydroamination of N-allenyl carbamates tolerated substitution at the alkyl and allenyl carbon atoms and was effective for the formation of piperidine derivatives. gamma-Hydroxy and delta-hydroxy allenes also underwent Au-catalyzed intramolecular hydroalkoxylation within minutes at room temperature to form the corresponding oxygen heterocycles in good yield with high exo-selectivity. 2-Allenyl indoles underwent Au-catalyzed intramolecular hydroarylation within minutes at room temperature to form 4-vinyl tetrahydrocarbazoles in good yield. Au-catalyzed cyclization of N-allenyl carbamates, allenyl alcohols, and 2-allenyl indoles that possessed an axially chiral allenyl moiety occurred with transfer of chirality from the allenyl moiety to the newly formed stereogenic tetrahedral carbon atom.     

Indole derivatives

The Fischer cyclization of arylhydrazones of 4-thiepanone leads to 1, 3, 6H, 4, 5-dihydrothiepino[4, 3-c]indoles, while the cyclization of arylhydrazones of the S, S-dioxide of 4-thiepanone forms 6H-1, 2, 4, 5-tetrahydrothiepino[5, 4-c]indole.For communication XXIV, see [1].     

A practical synthetic route to functionalized THBCs and oxygenated analogues via intramolecular Friedel-Crafts reactions

A practical catalytic approach to the synthesis of 4-substituted 1,2,3,4-tetrahydro-beta-carbolines (THBCs, 1) and 1,2,3,9-tetrahydropyrano[3,4-b]indoles (2) via InBr3-catalyzed intramolecular Friedel-Crafts (F-C) cyclization is described. The use of cross-metathesis reaction represents a direct route to the cyclization precursors and the use of InBr3 (5 mol%) allowed polycyclic indole compounds to be isolated in high yields under mild reaction conditions (rt, DCM, minutes). Finally, efforts toward the development of a stereocontrolled version of the present cyclization are presented, highlighting [salenAlCl] and bimetallic [(salenAlCl)2-InBr3] system as promising chiral Lewis acids (ee up to 60%).     

Thiol-mediated radical cyclization: regioselective formation of indole-annulated sulfur heterocycles by tandem cyclization

Indole-2-yl-prop-2-ynyl sulfides, under thiophenol-mediated alkenyl radical cyclization conditions, afforded exclusively 4-thiophenyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indoles or 3-thiophenylmethyl-2,3,8-trihydrothieno[2,3-b]indoles depending on the substituent at the indole nitrogen.     

Regioselective unusual formation of spirocyclic 4-{2'-benzo(2',3'-dihydro)furo}- 9-methyl-2,3,9-trihydrothiopyrano[2,3-b]indole by 4-exo-trig aryl radical cyclization and rearrangement

4-(2'-Bromoaryloxymethylene)-9-methyl-2,3,9-trihydrothiopyrano[2,3-b]indoles under tri-n-butyltin hydride mediated aryl radical cyclization furnished exclusively the 4-{2'-benzo(2',3'-dihydro)furo}-9-methyl-2,3,9-trihydrothiopyrano[2,3-b]indoles in excellent yield (75-80%) via 4-exo-trig cyclization, opening of the oxetene ring, and 5-endo-trig cyclization.     

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.     

Development of highly regioselective amidyl radical cyclization based on lone pair-lone pair repulsion

The substituent effect on the reactivity and regioselectivity of N-(4-pentenyl)amidyl radical cyclization was investigated. Exclusive 6- endo cyclization was observed for N-(4-pentenyl)amidyl radicals with internal vinylic heteroatom substitution (Cl, Br, I, OMe, SEt). The substituent on the carbonyl group also showed a significant influence on the reactivity of amidyl radicals, which increases in the order of Ph < Me < OEt. As a result, the photostimulated reactions of N-(4-halopent-4-enyl)amides and carbamates (X = Cl, Br, I) with DIB/I 2 or Pb(OAc) 4/I 2 led to the efficient and exclusive formation of the corresponding piperidines while those of N-(5-halopent-4-enyl)amides afforded the pyrrolidine products only. The halogen-substitution effect also allowed the 6- exo and 7- endo amidyl radical cyclization to proceed in a highly regioselective manner. The above experimental results, in combination with theoretical analyses, revealed that the lone pair-lone pair repulsion between the nitrogen radical and the vinylic heteroatom played an important role in controlling the regioselectivity of cyclization.