Indoles benzannulation

Using a modification of Sakamoto s indole benzannulation protocol (see Scheme 5.59), Beccalli et al. reported the synthesis of the 3-methoxycarbazole alkaloids hyellazole (245) and 6-chlorohyellazole (246) (540) (Scheme 5.61). Unlike Sakamoto s methodology, this method requires a good leaving group at the 2-position of the indole moiety of the 3-(l,3-butadienyl)indoles 692 to facilitate the aromatization of the intermediate dihydrocarbazole by eliminating the dehydrogenation step. 

A different type of synthesis, which leads to a benzannulated indolo[2,3-3][l,6]naphthyridine 15, is illustrated in Scheme 3 <1999TL3797>, and the use of an azaindolone as starting material may introduce an additional heteroatom into the indole moiety of the product, as in 16 (Equation 2) <1994TL1995>. The dipyrrolo[2,3-3 2, 3 -g][l,8]naphthyridine 18 is produced by reaction of the naphthyridine 17 with ethyl glycinate in the presence of a phase-transfer catalyst (Scheme 4) <2000PS(163)29>. 

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). 

A new method for the benzannulation of indole involving the thermal cyclization of 3-buta-l,3-dienylindoles (560 and 561) was described for the synthesis of 3-methoxycarbazole alkaloids 562 (538-540). Contrary to earlier benzannulation procedures, this method involves the ring closure of a 3-buta-l,3-dienylindole without the loss of the methoxy group at the 3-position of the carbazole nucleus. The 3-buta-l,3-dienylindole required for this method was obtained by Sakamoto s procedure (538,539) starting from l-acetyl-2-methoxy-l,2-dihydroindole-3-one by... 

Mai et al. reported a new benzannulation strategy for the synthesis of murrayafoline A (7) via anionic [4+2] cycloaddition of the furoindolone 650 (583,584). Using a literature procedure, Fischer indolization of 3-(2-phenylhydrazono)-dihydrofuran-2(3H)-one (648) afforded the furoindolone 649 (583). This was... 

Mai et al. also reported a formal synthesis of murrayaquinone A (107) starting from murrayafoline A (7). However, the required murrayafoline A (7) was obtained by the benzannulation of furoindolone, which was prepared by Fischer indolization of 3-(2-phenylhydrazono)dihydrofuran-2(3H)-one (648) (see Scheme 5.46) (584) (Scheme 5.113). 

A complementary access to extended indole and carbazole systems is based on the thermal intramolecular benzannulation of ortfio-al kyn ylan i 1 i nocarbene complexes or on a photo-induced benzannulation of phenylpyrrolylcarbene complexes. The first example involves an intramolecular access to the carbazole skeleton. Refluxing a solution of orflio-alkyn yl phen yl amino carbene complex 109 in acetonitrile gave a 63 % yield of benzocarbazole 110. Less strongly coordinating solvents (TBME, THF, or di-n-butyl ether) or other substituents less bulky than 2,4,6-trimethylphenyl (for example, phenyl or 4-methylphenyl) led to a considerably reduced yield (Scheme 39) [83]. 

Merlic discovered the novel benzannulation of bi indole 261 to 262 during studies to synthesize indolocarbazoles [122b]. Several unsymmetrical biindoles were also prepared and their reactions with dimethyl acetylenedicarboxylate and related alkynes were studied. Yields of indolocarbazoles were 51-88% and some regioselectivity was observed in unsymmetrical cases (up to 80 20). 

An iodonium-mediated benzannulation approach to indoles starting from 3-alkynyl-2-pyrrole-carboxaldehydes has been reported <05ASC526>. For example, treatment of pyrrole 119 with iodine and styrene provided 4,5-disubstituted indole 120. The authors suggest a mechanism for this transformation. 2-Aminofurans have been converted into the ergoUne indole alkaloids utilizing cycloaddition chemistry <05JOC6833>. 

De-O-benzylation. The oxidative ther functional groups, including second Oxidation of aromatic and heterm methoxyarenes to afford p-quinones reqi Benzofurans and substituted indoles u -ange readily to give benzannulated lactoa malealdehyde, which can be trapped I... 

Benzofurans and substituted indoles undergo epoxidation, but the products rearrange readily to give benzannulated lactones and lactams. Furan itself is converted to malealdehyde," which can be trapped by Wittig reagents. 

Gross S, Reissig H-U (2003) Novel stereoselective syntheses of highly functionalized benzannulated pyrrolizidines and indolizidines by samarium diiodide induced cyclizations of indole derivatives. Org Lett 5 4305 307... 

Indole is the most important benzannulated (fused-ring) derivative of the l-hetero-2,4-cyclopentadienes. It forms part of many natural products, including the amino acid tryptophan... 

A novel [3-I-3]-benzannulation process occurs in the coupling of alkynylcarbene complexes (e.g., 160, Scheme 17.27) and heteroaromatic aldehyde-derived imines (e.g., 201) [83]. Furan, benzofuran, and N-substituted indole derivatives led to benzannulation products, heteroaromatic-fused benzenes (e.g., 204). The mechanism proposed involves electrophilic aromatic substitution at the 3-position of the heterocyclic ring, resulting in the complex 202, followed by a simultaneous 1,2-shift of the metal and nucleophilic addition to the iminium salt. 

Dai, W., Petersen, J.L. and Wang, K.K. (2005) Synthesis of indeno-fused derivatives of quinolizinium salts, imidazo[l,2-a]pyridine, Pyrido[l,2-a]indole, and 4ff-quinolizin-4-one via benzannulated enyne-allenes. Journal of Organic Chemistry, 70(17), 6647-6652. 

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