Synthesis of 1,3,4‐Trisubstituted Benzenes from Morita–Baylis–Hillman Adducts of α‐Bromocinnamaldehyde via [5+1] Annulation Strategy

The construction of suitably functionalized benzene ring in a regioselective way is important in organic synthesis. The Morita–Baylis–Hillman (MBH) adducts have been used as useful starting materials for this purpose. There have been reported numerous methods including [4+2] cycloaddition, 6π-electrocyclization, [3+3] annulation, and consecutive [3+1+2] annulation protocols. During our recent studies using the MBH adducts of cinnamaldehydes, we reasoned out that the synthesis of 1,3,4-trisubstituted benzenes 3 could be realized by [5+1] annulation protocol from the acetates of MBH adduct of α-bromocinnamaldehyde via a sequential SN20 reaction of primary nitroalkane, an intramolecular 1,6conjugate addition, and eliminations of HBr and HNO2, as shown in Scheme 1. Thus, starting materials 1a-dwere prepared from α-bromocinnamaldehydes, as shown in Scheme 2. The MBH reaction was carried out in the presence of 1,4-diazabicyclo[2.2.2] octane (DABCO) to produce the corresponding MBH adducts in good to moderate yields (45–83%), and the following acetylation (Ac2O/DMAP) afforded 1a-d in good yields (82–88%). The reaction of MBH acetate 1a and nitroethane (2a) in the presence of Cs2CO3 (3.0 equiv) in DMF at room temperature for 4 h afforded the desired product 3a in moderate yield (45%) along with a small amount (5%) of unexpected phenol 4a, as shown in Scheme 3. The use of CH3CN or K2CO3 showed a similar result. The reaction mechanism for the formation of 3awould be a sequential introduction of nitroethane at the primary position of theMBH adduct by SN20 reaction to afford I, and the following intramolecular 1,6-conjugate addition to produce II, and the final elimination of HBr and HNO2 to give 3a. For the formation of benzene ring, theMBHacetate providedfive carbons and nitroethane served one carbon.During the reaction intermediate II could be converted to IV by SN2 reaction of the nitronate anion of nitroethane, 12 and the following Hass–Bender oxidation could affordV. A subsequent elimination of HNO2 and keto-enol tautomerization would provide 4a as a minor product. However, another possibility involving sequential [2,3]-sigmatropic rearrangement of allylic nitro intermediate and the following disproportionation process cannot be ruled out completely at this stage. Encouraged by the successful results, some representative primary nitroalkanes 2b-iwere examined under the same reaction conditions, and the results are summarized in Table 1. The reactions of 1a with 1-nitropropane (2b), 1-nitrobutane (2c), 1-nitropentane (2d), 1-nitrohexane (2e), ethyl nitroacetate (2f), 2-phenylnitroethane (2g), 2-(2-thienyl)nitroethane (2h), and methyl 4-nitrobutyrate (2i) showed similar results. The corresponding benzene derivatives 3b-i were synthesized in moderate yields (40–68%) along with phenol derivatives 4b-e (5–9%) as minor products in some cases. For the reactions of 2f-i, the corresponding phenol derivatives were observed on TLC at the right position; however, they could not be separated in appreciable amount. The reaction of MBH acetate 1b with 2b and 2f also provided 3j (44%) and 3k (71%), respectively. The reaction of acetyl derivative 1c and 2f provided 3l (43%) in moderate yield. However, the reaction of nitrile derivative 1d and 2b afforded 3m in low yield (13%). As reported in many similar cases, the SN20 reaction of a nucleophile to MBH acetate produced a Z-form intermediate as a major as shown in Scheme 4, and the following 1,6-conjugate addition could Ph EWG OAc