Dihydroindoles, synthesis

DihydroindolesA novel synthesis of fused dihydroindoles involves [2 + 2 + 2]cycloaddition of alkynes with the 2,3-double bond of N-alkynoylated pyrroles. The reaction of 1 with bis(trimethylsilyl)ethyne results in two diaster-... 

The Heck reaction on polymer-bound iodoarenes is assisted by the addition of a catalytic amount of tetra-n-butylammonium bromide and has been employed in the synthesis of 4-carboxycinnamic esters and amides [33], and 4-aminosulphonyl-cinnamic esters [34], It has also been reported that the presence of an equimolar equivalent of benzyltriethylammonium chloride aids the Pd(II)-mediated reaction of A -acyl-2-iodoanilines with vinylidene carbonate, which leads to A -acyl-2-hydroxy-indolines providing a convenient route to the indoles (80-90%) [35], The catalysed reaction of 2-hydroxy- and 2-tosylaminoiodobenzene with 1,2-dienes produces 1,2-dihydrobenzofurans and 1,2-dihydroindoles, respectively [36]. 

Synthesis ofLysergic Acid, By reacting N-benzoyl-3-(B-carboxyethyl)-dihydroindole (see JCS, 3158 (1931) for the preparation of this compound) with thionyl chloride, followed by aluminum chloride gives l-benzoyl-5-keto-l,2,2a,3,4,5-hexahydrobenzindole. This is then brominated to give the 4-bromo-derivative, which is converted to the ketol-ketone by reacting with methylamine acetone ethylene ketol. This is then hydrolized by acid to yield the diketone and treated with sodium methoxide to convert it to the tetracyclic ketone. Acetylate and reduce this ketone with sodium borohydride to get the alcohol, which is converted to the hydrochloride form, as usual. 

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... 

Carbanions derived from side chain tertiary amides have also been cyclized to provide isoquinolones and isoindoles (equation 36).125 126 While benzyne intermediacy in the formation of the former is likely, the latter seems to arise through a SrnI reaction pathway. Synthesis of indole from the meta bromo compound (87), on the other hand, clearly involves an aryne cyclization. 27 A more versatile route to indoles is based on intramolecular addition of aminyl anions to arynes (equation 38).128 A somewhat similar dihydroindole preparation constitutes the first step in a synthesis of lycoranes (equation 39).129 The synthesis of (88) also falls in the same category of reactions, but it is noteworthy because only a few examples of ring closure of heteroarynes are mentioned in literature.27 28... 

Rezaie and Bremner reported the synthesis of tricyclic 1,4-thiazepines by ring contraction. OT-Cyclophane lactam 237 was treated with Ar-bromosuccinimide and azoisobutyronitrile to yield 47% of dihydroindole derivative 238, as the major product next to side products 239-242 (Scheme 42). The same reaction condition was applied for the ester derivative of 237 (X = COOCH3>, but with longer reaction time. This resulted in indole analogues 240-242 (X = COOCH3) without the formation of dihydroindole derivatives. Bromination on the aromatic ring was observed prior to the intramolecular cyclization. The exact mechanism has not been resolved, but a possible reaction sequence could be... 

XXVIII. Photochemical synthesis of 2,3-dihydroindoles from N-aryl enamines. 

The first, and hitherto only, synthesis of lysergic acid was effected by the research group of Kornfeld et al. (50, 26). In this particular synthesis a X-acyl-2,3-dihydroindole derivative was used as starting material, thus allowing the formation of rings C and D by classical methods. Dehydrogenation of the 2,3-dihydroindole system to the indole system was only effected in the last stage so that the formation of the benz[c,d]-indoline system was prevented. 

The synthesis of 2-vinylindoles continues to be of interest due to the vast potential of these species for further chemical elaboration. In developing a strategy for carbazole synthesis, a Michael-type addition of 4,7-dihydroindole to dimethyl acetylenedicarboxylate was employed to afford, after DDQ oxidation, functionalized 2-vinylindoles <06JOC7793>. In a metal-mediated approach, Nakao, Hiyama, and co-workers prepared propyl-substituted 2-vinylindoles from A-protected 3-cyanoindoles via treatment with 4-octyne in the presence of catalytic nickel <06JACS8146>. Aryl, vinyl, and alkynyl substituents were installed by direct coupling with an A-protected 2-trifluoromethanesulfonyloxyindole, prepared from oxindole <06S299>. 

When the central double bond is part of an aromatic ring, die ting closure is retarded and is accompanied by regeneration of die aromatic nucleus. Thus, as described earlier in this review, the dihydroniqih-thalene (34) was obtained upon thermolysis of compound (33), a product obtained by an initial electrocycliution followed by a 1,5-H shift. Similarly, a synthesis of the dihydroindole nucleus (99) makes use of the thermal (216 C) or photochemical electrocyclic ring closure of 2,3-dienylpyrroles (97) to intermediate (98) followed by a 1,5-H shift. ... 

Transannular cyclization. In a recent total synthesis of indole and dihydroindole alkaloids,3 a key step is a transannular cyclization reaction with mercuric acetate. For example, the reaction of 4/3-dihydrocleavamine (1) with mercuric acetate yields the indolenine (2), which was isolated as the more stable reduction product (3). 

In the partial synthesis of Khuong-Huu and co-workers (205), corynan-theidine (105) was reduced with NaBFL, in the presence of trifluoroacetic acid (TFA) to the corresponding 2a,7a-dihydro derivative 106, which by NaOMe/MeOH treatment was transformed to the corresponding acetal 107. Benzenesulfonylation of compound 107 afforded compound 108. Photosensitized oxidation of 108 in the presence of rose bengal and KCN yielded compound 109, which, via the corresponding iminium ion, was claimed to cyclize to Afa-benzenesulfonyl-2a,7a,19,20a-tetrahydro-10-de-soxysarpagine (110) (a dihydroindole derivative, which, however, could not be transformed to an indole derivative) (Scheme 6). It is noteworthy that... 

Other groups have reported free-radical approaches to lycoranoids less richly decorated than 66. For example, Rigby has reported a short synthesis of ot-lycorane (67) via an aryl radical-enamide cyclization that constructs the C 2a-Ci2b bond [42]. Padwa focused on the same bond construction via an aryl radical-dihydroindole cyclization in his synthesis of anhydrolycorin-7-one (68) [43]. Both Zard [44] and Cossy [45] have reported syntheses of y-lycorane (69) that involve initial construction of the N-Ci2a bond via cyclization of nitrogen-centered radicals. Both ap-... 

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