Scheme 12 Preparation of 3a-substituted pyrrolo[2,3-fc]indoles from 1-hydroxy-tryptamines bonylpyrrolo[2,3-fr]indole (96a, 92%) as a sole product. Similar reaction of 35 with NBS (0.9-mol eq.) in MeCN provides 3a-bromo-1,2,3,3a,8,8a-hexahydro-8-methoxy-1-methoxycarbonylpyrrolo[2,3-fr]indole (96b, 85%) cleanly. Treatment of 96a or 96b with silver cyanide in MeCN/H2O yields the same product, 8-acetyl-3a-hydroxy-1-methoxycarbonyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (97, 85%, 94%, respectively). Alkylation of 97 with alkyl halides and NaH affords 98.

A simple one-step synthetic method from 35 for the desired product (98) has been created as the third route [30]. Addition of iodine to the solution of 35 in morpholine and an appropriate alcohol as a solvent at room temperature generated 98a-i in excellent yields as shown in Table 4. In this reaction, use of 10-mol eq. of iodine is recommended to achieve high product yields (compare entry 2 with 1). The reagent system is selected among various trials including Br2, Br2/NaOAc, 4-dimethylaminopyridinium tribromide, NIS, iodine/triethylamine, iodine/K2CO3, iodine/NaHCO3, iodine/pyridine, iodine/Nal, iodine/NH4Cl, and iodine only in various solvents.

Although the N(1) - H compound (55) provides the 3a-alkoxypyrrolo[2,3-fr]indoles such as 99a and 99b upon the reaction with iodine/morpholine in either MeOH or EtOH, their yields are always inferior, accompanied by tar formation, to those of the 1-methoxy compound (35). Compound (99b, 96%) is also obtained by the catalytic reduction of 98b. Since the acetylation of 99b provides 95b (95%), all of the structures are correlated and determined unequivocally. These findings suggest that the presence of the methoxy oxygen at the 1-position on the indole nucleus makes the intermediate (100) more stable than the corresponding immonium salt (101).

The above iodine-morpholine reaction has been successfully applied for the preparation of optically active methyl 1,2,3,3a,8,8a-hexahydropyrrolo[2,3-fr]indole-2-carboxylates having a halogen or an oxygen functional group at the 3a-position (Scheme 13) [31].

Treatment of (S)-42 with iodine and morpholine in MeOH results in the formations of (2S,3aS,8aS)- (102a, 6%) and (2S,3a.,8a.)-methyl 1-acetyl-1,2,3,3a,8,8a-hexahydro-3a,8-dimethoxypyrrolo[2,3-fr]indole-2-carboxylates (103a, 48%). When isopropyl alcohol is employed as a solvent, 102b (6%) and 103b (34%) are obtained. The reaction of (S)-42 with NCS in MeCN generates (2S,3aS,8aS)- (102c, 42%) and (2S,3a.,8a.R)-methyl

1-acetyl-3a-chloro-1,2,3,3a, 8,8a-hexahydro-8-methoxypyrrolo[2,3-fr ]indole-

2-carboxylates (103c, 42%). Upon the reaction with NBS, (2S,3aS,8aS)- (102d,

Table 4 A novel synthetic method for 3a-alkoxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]in-doles

Entry Iodine Solvent Reaction Product Yield (%) of Recovery Total yield (mol eq.) (ROH) time (h) 98 R 98 (%) (%)
0 0

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