Augmented indoles

Abstract

The indole ring presents a good platform for synthesis because of its nucleophilic capacity at C3, to a lesser extent at C2, and also through the indole anion at N1. The development of new indoles with strategically placed methoxy groups at C4 and C6, or C5 and C7, provides even better platforms not only through increased general activation, but also through specific activation at C7 and C4 respectively. As a result of this multi-faceted activity, it is possible to generate a variety of additional rings fused to the indole platform. This rather general strategy of molecular augmentation leads to new types of indole structures, some of which bear resemblance to natural indole alkaloids. A selection of examples is presented.

Bis- and Trisindolylmethanes (BIMs and TIMs)

“…The presence of the two substituted OMe groups on the benzene ring should also activate position C4. 562 Isomeric BIM 400 was isolated from the reaction of yohimbine 399 and 4-dimethylaminobenzaldehyde in the presence of methanolic hydrogen choloride (Scheme 124). 563 Black et al have focused on the synthesis of calix[n]indoles.…”

“…598 A rare example of 3,4′,4′′-TIMs 431 has been reported by the Black group. 562 3,4′,4′′-TIM 431 was obtained in excellent yield from methyl carboxylate 395 and 3-formylindole in acidic methanol (Scheme 137). For more details of the reaction, see also Scheme 123.…”

“…This lack of activity at the C3 position may be due to the presence of the methyl carboxylate group that will deactivate the pyrrolic ring. The presence of the two substituted OMe groups on the benzene ring should also activate position C4 …”

Comparative reactivity of 5,7-dimethoxyindoles with aldehydes and ketones

“…Column chromatography was carried out using Merck 230-400 mesh silica gel or Merck 70-230 mesh silica gel, whilst preparative TLC was performed using Merck 60GF254 silica gel. X-ray crystallography was conducted with a suitable single crystal and crystallographic data excluding structure factors have been deposited with the Cambridge Crystallographic Data Centre: Compound 44 -Deposition Number 2004528 Methyl 1-(tert-butyloxycarbonyl)-4-formyl-5,7-dimethoxyindole-2-carboxylate (12). A suspension of methyl 4-formyl-5,7-dimethoxyindole-2-carboxylate (11) (0.49 g, 1.85 mmol), di-tert-butyl dicarbonate (0.79 g, 3.62 mmol) and N,N-dimethylaminopyridine (48 mg) in anhydrous acetonitrile (12.0 mL) was stirred at room temperature, under nitrogen, for 70 min.…”