Regioselective Allylic Rearrangement of 3‐Alkyl‐ N ‐allylindoles to 3‐Alkyl‐2‐allylindoles

Morita–Baylis–Hillman (MBH) adducts have been used extensively for the synthesis of various cyclic and acyclic compounds. Both the primary and secondary positions of MBH adducts could be selectively attached at the N-1 position of indoles to produce 1 and 2, as shown in Scheme 1. In addition, a regioselective introduction of MBH adduct at the C-3 position of indoles to form 3 and 4 has also been reported. However, an introduction of MBH adduct at the C-2 position of indoles to form 5 and 6 has not been reported, to the best of our knowledge. 2-Benzylindoles have been synthesized from Nbenzylindoles by rearrangement of the benzyl group under acidic conditions. As an example, N-benzylindole was converted to 2-benzylindole in polyphosphoric acid (PPA) in moderate yield. As compared to N-benzylindoles, the rearrangement of N-allylic indoles produced more complex mixtures of products depending on N-allylic moiety and the reaction conditions. Casnati et al. reported the rearrangement of N-crotyl or N-prenyl group of 3substituted indoles. They observed the rearrangement of the allylic moieties to the C-2 position with partial allylic rearrangement. Later, Okazaki and coworkers suggested the reaction mechanism would involve a chargeinduced [3,3]-shift of the allylic moiety from N-1 to C-3 position, following a [1,5]-shift, and subsequent enamination process. In this respect, we decided to examine the allylic rearrangement of 1a and 2a under the influence of PPA, as shown in Scheme 2. The starting materials 1a and 2a were prepared from MBH bromide or carbonate according to the reported methods. The rearrangement of 1a occurred smoothly in PPA at 70 C to afford 6a in good yield (73%) along with 5a in low yield (5%). The reaction using BF3 etherate (10 equiv) in 1,2-dichloroethane (reflux, 2 h) or trifluoroacetic acid (reflux, 2 h) showed a similar result to that of PPA. The reaction in PPA at higher temperature (100 C) was less efficient due to the formation of many intractable side products. In contrast to the selective formation of 6a from 1a, the reaction of 2a afforded 5a in good yield (64%) along with 6a in low yield (8%). Encouraged by the successful results, 1b–1f and 2b–2f were prepared according to the reported methods, and the allylic rearrangement was examined. The results are summarized in Table 1. The reaction of ethyl ester 1b (entry 3) afforded 6b as a major product in good yield (77%) along with a low yield of 5b (4%). The reaction of 2b (entry 4) gave 5b as a major product (65%) along with 6b (7%). Likewise, the reactions of p-chlorophenyl derivatives 1c (entry 5) and 2c (entry 6) or 3-ethylindole derivatives 1d (entry 7) and 2d (entry 8) showed similar results. For the reaction of naphthyl derivative 1e (entry 9), the rearranged products 5e and 6e could not be separated. Thus, 5e and 6e were obtained together as a mixture, and the ratio of 5e/6e (1:7) was determined based on its H nuclear magnetic resonance (NMR) spectrum. In addition, somewhat unusual product ratio (5e/6e = 2:3) was observed in the reaction of 2e (entry 10); however, the reason is not clear at this stage. The thiophene derivatives 1f and 2f were decomposed under a typical reaction condition (PPA, 70 C). Thus, the reactions of 1f and 2f were carried out in a mixed solvent (ClCH2CH2Cl/PPA, 1:1) at lower temperature (60 C) in short time (30 min). It is interesting to note that primary product 5f was obtained as a sole product in moderate yields (42 and 45%) irrespective of the starting materials 1f and 2f (entries 11 and 12). Based on the result of 1f (entry 11), we assumed that primary product 5f could be a thermodynamically favored one. In this context, we examined the reaction of 1f at lower temperature (30 C) in a mixed solvent (ClCH2CH2Cl/ PPA, 1:1). Surprisingly, the allylic rearrangement proceeded even at 30 C for 2 h in this case, and the secondary product 6f was formed successfully in moderate yield (38%) along with 5f (32%), as shown in Scheme 3. A plausible reaction mechanism for the rearrangement of 1a to the major product 6a is proposed in Scheme 4. As suggested by Okazaki and coworkers, a charge-induced [3,3]-shift of the allylic moiety from N-1 to C-3 position to form 3,3-disubstituted indolenine intermediate I, following a [1,5]-shift to form II, and a subsequent enamination process would produce 6a. Note