Alkenyl indoles, cyclization

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. 

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). 

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... 

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 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... 

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

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. 

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. 

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). 

Gilchrist examined the cyclization of Af-alkenyl-2-iodoindoles with palladium [268, 269], For example, reaction of A-pentenylindole 244 under Heck conditions affords a mixture of 245 and 246 in very good yield. In the absence of TIOAc, 246 is the major product. Further exposure of 245 to Pd(OAc)2 gives 246. Reaction of l-(4-butenyl)-2-iodoindole under similar conditions affords the pyrrolo[l,2-a]indole ring system in modest yield (35%). 

Stoichiometric Pd(II)-mediated oxidative cyclization of alkenyl anilines to indoles. Cf. Wacker oxidation. 

A new benzannulation methodology was developed in order to overcome the limitations of electrocyclic ring closure of divinylindoles. The cyclization is achieved via an allene-mediated electrocyclic reaction of 2,3-difunctionalized indoles. This method is more efficient for the synthesis of highly substituted 2-methyl carbazole alkaloids (559). The 3-alkenyl-2-propargylindole 557, a precursor for the allene intermediate, was prepared from 2-formylindole over several steps using simple functional group transformations (536,537) (Scheme 5.20). 

Several (A/-alkenyl)iodoacetamides undergo cyclization when they are reacted with tetrakis(triphe-nylphosphine)palladium(O). The highest yields (which are generally only moderate) are obtained in DMF solution with 1,8-dimethylaminonaphthalene (Proton Sponge) to take up the hydrogen iodide formed. This reaction has been used to prepare piperidones, oxindoles, indolizidines, quinolizidines, pyrrolidines, indoles, quinolines53 and pyrrolizidines (equation 18).54... 

The direct alkenylation of arylamines at the ortho position has been reported in reactions of o -chloroalkenylmagnesium chloride with N-lithioarylamines.22 Use of the CuI-L-proline catalyst system in DMSO has been found to be successful in promoting reactions of aryl iodides and bromides with activated methylene compounds, such as ethyl acetoacetate and diethyl malonate.23 The same catalyst in dioxane has been used in intramolecular cyclization of ene-carbamates leading to indoles or pyrrolo[2,3-cjpyridines.24... 

The cascade sequence that affords bicyclic systems fails with the lithium derivatives of 2-bromo-iV,iV-diallylaniline. The methodology is useful for the synthesis of 3-substituted indolines and indoles, but the substrate undergoes only one anionic cyclization. Alkenyl vinyllithiums and alkenyl aryllithiums have also been employed in the preparation of alkylidenecyclopentanes and indanes. The intramolecular addition of vinyllithium reagents... 

Two type Ib approaches to indoles were reported involving tin-mediated radical cyclization reactions. Treatment of either 2-alkenylthioanilides <05H(66)241> or 2-(l-alkenyl) imidoyltellurides <05SL1893> provided 2,3-disubstituted indoles. The former precursor was also utilized in a synthesis of tetrahydro- 3-carbolines. 

Heck cyclization reactions of o-halo-A-(2-alkenyl)anilines have proven useful for the development of type Ic approaches to indoles. Recent applications include the preparation of a... 

Aromatic isonitriles, particularly orf/jo-alkenyl-substituted aryl isonitriles, were also successfully employed by Fukuyama in the synthesis of indole derivatives [19]. Cyclization of compounds 26 was accomplished with tin radicals, and 6-membered ring closure did not significantly compete except in one case (R = -Bu) where, on the other hand, this problem was interestingly alleviated by using the Z-alkene instead of the Z-analog (Scheme 11). 

Very recently, a variant of this methodology was developed by the same author through tin-radical-mediated cyclization of ort/zo-alkenyl-substituted thioanilides [20], Moreover, Rainier et al. demonstrated that a very efficient synthesis of indoles can be carried out also with urz/to-alkynyl-substituted aryl isonitriles, provided that a TMS group is linked to the alkyne moiety [21] (Scheme 13). 

Bennasar also recently extended their interest in the cyclization of A -alkenyl substituted 2-indolylacyl radicals towards the annulation of larger rings [126]. A 7-endo-mg closure was observed when brotnovinyl substituted seleno ester 237 was treated with excess tin hydride in EtaB. In addition to the desired azepino[3,2-I>] indole 238, the 6-exo cyclization product 239 was observed as the minor product, with both products showing no evidence of the bromine atom in their strucmres. Previous attempts at this cyclization using a tethered allyl moiety, rather than the 2-bromo-2-propenyl tether, also gave the azepinoindole but only as the minor product. 

The Fukuyama indole synthesis involves the intramolecular radical cyclization of 2-alkenylisocyanides, the availability of which often limits the utility of this process. In order to access a wider variety of such substrates, the author prepared the versatile Horner-Wadsworth-Emmons reagent 131 using the Pudovik reaction <01SL1403>. Reaction of 131 with a variety of aldehydes thus provides a convenient and general route to diverse alkenyl precursors 132. Additionally, instead of the standard radical conditions using tri-n-butyltin hydride, Fukuyama now finds that excess thiols arc quite effective for inducing cycliz.ation, whereupon desulfurization of the indoles 133 can be effected with Raney-Ni if desired. 

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