3-Alkenylated indoles

Copper(II) chloride was found to be the best oxidant for the system and a range of esters could be formed if ten equivalents of the corresponding alcohol was added to a THF solution. A range of substituted indoles were subjected to the reaction conditions and furnished both 6- and 7-membered annulation products, in good to excellent yields, 58-91%. 3-Alkenyl indoles were also effective substrates, under going cyclization onto the less nucleophilic C2 position in good yield albeit requiring extended reaction time (Scheme 44). 

Itahara et al. [9] found that A-2,6-dichlorobenzoylindole (13) was oxidatively coupled with methyl acrylate (4b) in the presence of stoichiometric Pd(OAc)2 in acetic acid, affording the 3-alkenylated product 14 in 25% yield. Similarly, A-tosylindole (15) reacted with ethyl acrylate (4c) to generate the 3-alkenylated indole 16 in 48% yield (Scheme 9.2) [10]. Unlike what Fujiwara et al. [8b] had observed in the reaction with A-acetylindole (8) and methyl acrylate (4b), both cases did not produce any 2-alkenylated indoles, presumably due to the steric hindrance of the relatively bulky 2,6-dichlorobenzoyl and tosyl groups. 

Kong, A., Han, X. and Lu, X. (2006) Highly efficient constmction of benzene ring in carbazoles by palladium-catalyzed endo-mode oxidative cyclization of 3-(3 -alkenyl)indoles. Org. Lett., 8, 1339-A2. 

Keywords Indoles, 1,3-dicarbonyl compounds, iodine, solvent-free, room temperature, ctni-densation, 3-alkenylated indoles, bis(indolyl)carbonyl compounds... 

A mixture of indole derivative (1 1 mmol), 1,3-dicarbonyl compound (2 1 mmol) and molecular iodine (10 mol%) was stirred at room temperature in a round-bottom flask for 2-3 h. After completion of the reaction (as monitored by TLC) a saturated aqueous solution of Na2S203 (2x5 mL) was added, and the mixture was extracted with EtOAc (3x5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude product of 3-alkenylated indole (3)/3-alkylated indole (4) which was then purified using column chromatography. Each of the products (3 and 4) was characterized on the basis of spectral and elemental analyses. 

Singh, N., and Singh, K. N. (2012). Iodine-catalyzed highly efficient synthesis of 3-alkylated/3-alkenylated indoles from 1,3-dicarbonyl compounds. Synlett, 23, 2116-2120. 

Keywords 2-Azido-3-arylacrylates, terminal alkenes, dichloromethane, palladium acetate, tri-fluoroacetic acid (TEA), oxygen-atmosphere, room temperature, domino reaction, intramolecular cyclization followed by olefination, 3-alkenyl indoles... 

A mixture of 2-azido-3-arylacrylate (1 0.3 mmol), terminal alkene (2 0.9 mmol), Pd(OAc)2 (0.03 mmol), TFA (2.4 mmol) was stirred in anhydrous dichloromethne (3 mL) under oxygen atmosphere at room temperature for 8 h. The reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The concentrated crude residue was purified by column chromatography using petrol ether-ethyl acetate mixture as eluent to furnish 3-alkenyl indoles 3 with 55-83% yield. All the products were are characterized by detailed spectral studies. 

When 3-(3-alkenyl)indoles 92 was heated at 80 "C in the presence of a catalytic amount of Pd(OAc)2 and stoichiometric benzoquinone, carbazoles 93 were produced (Scheme 22.22) [44]. Alkenyl palladium 94 was proposed to undergo Heck-type cyclization to give 96, whose dehydrogenation with benzoquinone resulted in the formation of 93. 

SCHEME 22.22 Intramolecular oxidative coupling of 3-(3-alkenyl)indoles. 

Af-Substituted indoles bearing Af-2,6-dichlorobenzoyl, N-phenylsulfo-nyl, or Af-methyl groups undergo coupling reactions with aciylates at the 3-position of indole (Scheme 2.25). The coupling reaction in AcOH also occurs at the 3-position of indole to give 3-alkenylated indoles. 

Knochel demonstrated the effectiveness of soluble potassium or cesium alkoxides such as KO Bu or CsO Bu as well as KH in iV-methylpyrrolidinone (NMP) for promoting the 5-endo-dig cyclizations of 2-alkynylanilines to 2-substituted indoles in solution or the solid-phase <00AG(E)2488>. Alternatively, Cacchi coupled a palladium-catalyzed cyclization of o-alkynyltrifluoroacetanilides with the addition of benzyl bromide or ethyl iodoacetate to afford 2-substituted-3-benzyl or 3-indolylcarboxylate esters, respectively <00SL394>. Yamamoto reported a new palladium catalyzed indole synthesis in which 2-(l-alkynyl)-Ar-alkylideneanilines 117 give 2-substituted-3-(l-alkenyl)indoles 118 directly from the imine by the in situ coupling of an aldehyde with the alkynylaniline <00JA5662>. 

Platinum(ii)-catalyzed cyclization of 2-alkenyl indoles forms tetrahydrocarbazole 535 and related derivatives (Scheme 108), but all efforts to realize the platinum-catalyzed cyclization-carboalkoxylation of 2-alkenyl indoles have been unsuccessful <2004JA3700>. In an optimized procedure l-methyl-2-(4-pentenyl)indole 534 gave tetrahydrocarbazole 536 in 83% yield as a single regioisomer (Scheme 108) <2004JA10250>. Unprotected, electron-rich, and electron-poor 2-(4-alkenyl)indoles underwent efficient palladium-catalyzed cyclization-carboalkoxylation. 

Palladium-catalyzed cyclization-carboalkoxylation of alkenyl indoles tolerated substitution along the alkenyl chain and at the internal and tfr-terminal olefinic position. In addition to 2-(4-alkenyl)indoles, 2-(3-alkenyl)-, 2-(5-hexenyl)-, 3-(3-butenyl)-, and 3-(4-pentenyl)indoles also underwent efficient palladium-catalyzed cyclization-carboalkoxylation to form the corresponding tricyclic indole derivatives in moderate to good yield with excellent regioselectivity. By employing this procedure, efficient palladium-catalyzed cyclization-carboalkoxylation of 2-(4-pentenyl)indole with ethanol, 1-octanol, 2-propanol, and cyclohexanol was achieved. 

A similar Pd-catalyzed cyclization-caiboalkoxylation of several alkenyl indoles has been described by Widenhoefer, one of which is shown [62]. 

Scheme 44 Widenhoefer s cyclization/carboxylation of alkenyl indoles...

Interestingly, Widenhoefer reported a similar palladium(II) catalyzed cycliza-tion of indoles onto alkenes (Scheme 58) [72]. This mild protocol for cyclization/ carboxylation of 2-alkenyl indoles makes possible catalytic addition of a carbon-nucleophile and carbonyl group across a C-C bond. The mechanism, however, is thought to involve outer-sphere attack of indole onto a palladium-olefin complex rather than the electrophilic C-H activation of the indole C(3)-H bond, exhibited by the Stoltz carbocyclization. 

Intramolecular cyclization of alkynes with imines offers a new synthetic method for indoles [75], Reaction of 2-(l-alkynyl)-A-alkylideneaniline 245 catalyzed by Pd(OAc)2 and P(n-Bu)3 afforded 2-alkyl-3-(l-alkenyl)indole 246. The reaction starts by insertion of triple bond to H-Pd-OAc to generate 247, followed by insertion of C=N bond to afford 248. Finally, y3-H elimination provides the indole... 

However, these directing groups limit the utility of the method because of their irremovability. The authors succeeded in selectively synthesizing C2-alkenylated indoles from indole-3-carboxylic acids through the carboxyl-directed alkenyla-tion/decarboxylation sequence (Scheme 18.50) [49]. This reaction seems to proceed via coordination of a carboxylic oxygen to a Pd(II) species, directed palladation at the C2 position, alkene insertion, and -hydrogen elimination. After the C2-alkenylation, decarboxylation may occur smoothly to produce a 3-unsubstituted 2-alkenylindole derivative. 

Scheme 4.9 6-exo-dig versus 1-endo-dig cyclization of alkenyl indoles ni-9... 

Treatment of indole-3-carboxylic acids with alkenes in the presence of Pd(OAc)2 (5mol%), Cu(0Ac)2 H20 (2equiv.), and LiOAc (3equiv.) in DMAc at 140 C gives rise to C2-alkenylated indoles through carboxylic group directed... 

Recently, palladium(II)-catalyzed arylation/carboxylation reactions were reported for the synthesis of carbazoles starting from 2-alkenyl indoles. These reactions employ the electron-rich C-3 carbon atom of the indole nucleus as carbon nucleophile in cyclization/carboalkoxylation reactions. The conditions that proved effective for 2-(2,3 or 5-alkenyl)-3-unsubstituted indoles are similar to those reported for the cyclization ofalkenes and alkynes bearing tethered heteronucleophiles. In particular, the best results has been obtained using PdCl2(CH3CN)2, CuCl2 in methanol under CO (latm). Under these conditions methyl (9-methyl-2,3,4,9-tetrahydro-4-carbazolyl)acetate 86 was isolated in 94% yield (Scheme 13.53) (100,101]. 

Liu, C. and Widenhoefer, R.A. (2004) Palladium-catalyzed cyclization/ carboalkoxylation of alkenyl indoles. Journal of the American Chemical Society, 126, 10250-10251. 

The formation of disubstituted alkynes by coupling of terminal alkynes, followed by intramolecular attack of an alcohol or amine, is used for the preparation of benzofurans and indoles. The benzo[il)]furan 356 can be prepared easily by the reaction of o-iodophenol with a terminal alkyne[262]. The 2-substituted indole 358 is prepared by the coupling of 2-ethynylaniline (357) with aryl and alkenyl halides or triflates, followed by Pd(ll)-catalyzed cycliza-tion[263]. 

Pyrrole derivatives are prepared by the coupling and annulation of o-iodoa-nilines with internal alkynes[291]. The 4-amino-5-iodopyrimidine 428 reacts with the TMS-substituted propargyl alcohol 429 to form the heterocondensed pyrrole 430, and the TMS is removed[292]. Similarly, the tryptophane 434 is obtained by the reaction of o-iodoaniline (431) with the internal alkyne 432 and deprotection of the coupled product 433(293]. As an alternative method, the 2,3-disubstituted indole 436 is obtained directly by the coupling of the o-alky-nyltrifluoroacetanilide 435 with aryl and alkenyl halides or triflates(294]. 

There are reports of an increasing number of palladium-assisted reactions, in some of which the palladium has a catalytic function. Thus furan and thiophene undergo facile palladium-assisted alkenylation giving 2-substituted products. Benzo[6 Jfuran and TV- acetyl-indole yield cyclization products, dibenzofurans and carbazoles respectively, in addition to alkenylated products (8UOC851). The arylation of pyrroles can be effected by treatment with palladium acetate and an arene (Scheme 86) (81CC254). 

The Cacchi group [85] developed a Pd-catalyzed domino process between o-alky-nyltrifluoroacetanilides as 6-157 and aryl or alkenyl halides, which leads to substituted pyrroles within an indole system. This scheme was successfully applied to the preparation of indolo[2,3-a]carbazoles as 6-158 using N-benzyl-3,4-dibro-momaleimide (Scheme 6/1.42). The indolocarbazole is found in several bioactive natural products as arcyriaflavin A and the cytotoxic rebeccamycin. 

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