Access to indoles via Diels‐Alder reactions of 2‐vinylpyrroles with maleimides

Abstract

Variously substituted 2‐vinylpyrroles underwent an endo‐addition [4+2] cycloaddition reaction with maleimides followed by a spontaneous highly diastereoselective (93–98% de) isomerization to give tetrahydroindoles in moderate to excellent yield. Treatment with activated MnO2 in refluxing toluene provided the corresponding indoles in moderate to good yield. This highly convergent methodology for formation of indoles is versatile and the starting materials are conveniently prepared. J. Heterocyclic Chem., (2009).

Palladium-catalyzed oxidative annulation of in situ generated enones to pyrroles: a concise route to functionalized indoles

“…Herein, we report direct synthesis of indoles from 65 pyrroles and 3-chloropropiophenones in a one-shot style (Scheme 1c). 70 Initially, the reaction of N-methyl-2-phenylpyrrole (1a) with 3chloropropiophenone (2a) was conducted to screen the reaction conditions (Table 1). In the presence of 10 mol % Pd(OAc) 2 as the catalyst, Cu(OAc) 2 H 2 O (6.0 equiv) as the oxidant, and NaOAc (4 equiv) as the base, the target product 3a was obtained in 41% yield from the reaction in DMSO at 100 o C (Table 1, entry 1).…”

Access to Indoles via Diels-Alder Reactions of 5-Methylthio-2-vinylpyrroles with Maleimides

“…Vinylpyrroles 7 and 8 (1.1 equiv) were stirred with 4‐ethylphenylmaleimide 16 in chloroform for several days, but with TLC, no reaction was observed to occur. The vinylpyrrole was used in excess because our past experience with vinylpyrroles indicated any adduct formed would be eluted during chromatography very near to the maleimide . The reaction mixtures were refluxed for five days, but still, no new TLC spots appeared; 1 H NMR confirmed that only starting materials were present in the reaction mixture.…”

“…The crude 9 was then subjected to a Vilsmeier–Haack reaction , giving aldehyde 11 in 91% yield, which was conveniently vacuum‐distilled for purification; any N ‐methyl‐5‐methylthio‐2‐pyrrolecarboxaldehyde 12 that codistilled was easily removed by trituration with hexanes. Lastly, a Wittig reaction was performed on 11 by using potassium tert ‐butoxide in THF , which, following vacuum distillation, gave the desired 5‐methylthio‐2‐vinylpyrrole 13 in 69% yield.…”

“…Conversely, Diels–Alder reactions with N ‐(dimethylamino) 19 formed 24 (<5% yield) and the major adduct rearranged to the aromatic pyrrole structure 29 . The more basic N , N ‐dimethylaminomaleimide 19 may be able to facilitate the rearrangement to the aromatic adduct 29 by more easily enabling a 1,3‐proton shift than maleimides 15 , 16 , 17 , 18 . However, combining adduct 22 with triethylamine in chloroform for about a week produced only minimal rearrangement to the aromatic adduct 27 ; thus, we were unable to verify this theory.…”

“…We have reported that tetrahydroindoles are available via 2‐vinylpyrroles derived from acid‐catalyzed condensation of pyrrole with cyclic ketones, followed by in situ trapping by various maleimides in Diels–Alder reactions . We have reported that indoles are available from oxidation of tetrahydroindoles synthesized by Diels–Alder reactions of both N ‐H and N ‐methyl‐2‐vinylpyrroles , and of N‐p ‐toluenesulfonyl‐3‐vinylpyrroles, with N ‐substituted maleimides. In comparing the efficiency of the Diels–Alder reactions of N ‐H‐2‐vinylpyrroles and N ‐tosyl‐3‐vinylpyrrole, we were inspired by the apparent increase in efficiency caused by the use of the N ‐tosyl group, which was later able to be removed.…”