C7-Derivatization of C3-Alkylindoles Including Tryptophans and Tryptamines

Abstract

A versatile strategy for C7-selective boronation of tryptophans, tryptamines, and 3-alkylindoles, by way of a single-pot C2/C7-diboronation–C2-protodeboronation sequence is described. The combination of a mild iridium-catalyzed C2/C7-diboronation followed by an in situ palladiumcatalyzed C2-protodeboronation allows efficient entry to valuable C7-boroindoles that enable further C7-derivatization. The versatility of the chemistry is highlighted by the gram-scale synthesis of C7-boronated N-Boc-L-tryptophan methyl ester and the rapid synthesis of C7-halo, C7-hydroxy, and C7-aryl tryptophan derivatives.

Direct C7 Functionalization of Tryptophan. Synthesis of Methyl ( S )‐2‐(( tert ‐Butoxycarbonyl)amino)‐3‐(7‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐1 H ‐indol‐3‐yl)propanoate

“…10 Examination of conditions for the diboronation of various N-protected tryptamines demonstrated that exposure to excess pinacolborane (5 equiv), catalytic amounts of [Ir(cod)OMe] 2 , and 4,4'-di-tert-butylbipyridine in tetrahydrofuran at 60 °C, was sufficient to ensure full boronation at C2 and C7. 9 Consistent with our C2 protodeboronation hypothesis, these 2,7-diboronated indoles can be dissolved in dichloromethane followed by addition of trifluoroacetic acid to cleanly afford the desired 7-boronated indole derivatives.…”

“…In all but one case (entry 1), a temperature of 60 °C and reaction time of 4-7 h was found to be ideal for the diboronation reactions (entries 2-5, Table 1). 9 These results highlighted the general compatibility of our protocol with alcohol, carbamate, ester, and sulfonamide functional groups. The excellent yield obtained for a C7-boronated tryptophan derivative (entry 4, Table 1) and its ready conversion to the corresponding 7-halo, 7-hydroxy and 7-aryl tryptophan derivatives (Scheme 1) further highlight the versatility of this chemistry.…”

“…By taking advantage of the more nucleophilic/basic C2 position of C3-substituted indoles, our two-step single-flask procedure provides expedient access to the corresponding C7-boronated compounds on multi-gram scale through direct C7 activation of nonfunctionalized tryptamines and tryptophans. 9 The premise behind this diboronation/ protodeboronation sequence was our recognition of the high propensity of five-membered heterocycles to undergo rapid C2 protodemetalation. 10 Examination of conditions for the diboronation of various N-protected tryptamines demonstrated that exposure to excess pinacolborane (5 equiv), catalytic amounts of [Ir(cod)OMe] 2 , and 4,4'-di-tert-butylbipyridine in tetrahydrofuran at 60 °C, was sufficient to ensure full boronation at C2 and C7.…”

“…Gratifyingly, dilution of the reaction mixture with dichloromethane followed by the addition of trifluoroacetic acid at 0 °C, led to the desired C2-protodeboronated tryptamine in 60% yield for the two-step process (entry 1, Table 1). 9 We then focused our attention on expanding the substrate scope (Table 1) to other 3-substituted indoles. In all but one case (entry 1), a temperature of 60 °C and reaction time of 4-7 h was found to be ideal for the diboronation reactions (entries 2-5, Table 1).…”

“…This product contained trace impurities (<5%) but was not subjected to further chromatographic purification due to its sensitivity toward C2 protodeboronation. For reference, data for N-Boc-2,7-diborotryptophan methyl ester (4) 9,25.2,27.4,28.2,28.5,52.3,55.5,79.4,84.0,84.6,119.4,123.1,123.2,127.0,131.9,143.1,155.9,173.7;FTIR (neat) 5 Longer exposure to these protodeboronation conditions led to isolation of trace amounts (<5%) of N-Boc-L-tryptophan methyl ester (1), resulting from proto-deboronation of product 3. 6 Flash column chromatography (9.0 cm diameter, 17 cm height) was performed using silica gel (60-Å pore size, 40-63 µm, standard grade, Zeochem).…”