5-Bromotryptamines. preparation

The medicinal importance of 2-aryltryptamines led Chu and co-workers to develop an efficient route to these compounds (130) via a Pd-catalyzed cross-coupling of protected 2-bromotryptamines 128 with arylboronic acids 129 [137]. Several Suzuki conditions were explored and only a partial listing of the arylboronic acids is shown here. In addition, boronic acids derived from naphthalene, isoquinoline, and indole were successfully coupled with 128. The C-2 bromination of the protected tryptamines was conveniently performed using pyridinium hydrobromide perbromide (70-100%). 2-Phenyl-5-(and 7-)azaindoles have been prepared via a Suzuki coupling of the corresponding 2-iodoazaindoles [19]. 

The requisite bis-Boc-protected 4-bromotryptamine 1459 was available in four steps from 4-bromoindole (Scheme 1.374). The other component of the biaryl coupling, the boronic acid 1460, was prepared from 2-(allyloxy)-bromobenzene. Suzuki coupling of 1459 and 1460 proceeded in excellent yield to afford 1461, which was elaborated to the ot-diazo-p-ketoester 1462. It required some experimentation to prepare 1462. Dirhodium(II) acetate-catalyzed N-H insertion of 1462 with (5)-benzyloxycarbonylvalinamide, followed by cyclodehydration, gave 1463, albeit in low overall yield (13%, two steps). Nonetheless, the authors had prepared a highly functionalized 4-aryltryptamine analog that could serve as a precursor to construct the B, E, and H rings. 

Preparation of (5)-6-bromo-8-(3-prenyl)-3a-(3-oxo-propyl)-3,3a,8,8a-tetrahydro-2//-pyrrolo[2,3-6)indole-l-carboxylic acid tert-butyl ester (222) from A -lO-BOC-l-prenyl-6-bromotryptamine (220), acrolein (213), and MacMillan catalyst 211A... 

In an elegant synthesis of the marine alkaloid flustramine B, MacMillan and coworkers have used catalyst 2 to promote the first organocatalytic addition/ cyclization process that allows the preparation of the chiral pyrroloindoline motif in a single step [82]. The transformation occurs between 6-bromotryptamine derivative 90 and acrolein via the intermediary formation of indolium ion 91, which is in turn readily trapped in an intramolecular way by the Boc-amino group, giving rise to intermediate 92 (Scheme 35.24). Then, six further additional steps were necessary to accomplish the synthesis of (—)-flustramine B. 

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