Synthesis of Poly‐Substituted Benzene from Morita–Baylis–Hillman Adducts Via [3 + 1 + 2] Annulation Strategy: Palladium‐catalyzed Domino Cyclization (5‐ exo /3‐ exo ), Ring‐Expansion by Palladium Rearrangement, and Aromatization

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 numerousmethods including [4 + 2] cycloaddition, 6π-electrocyclization, [3 + 3] annulation strategy, and consecutive [3 + 1 + 2] annulation protocols. A palladiumcatalyzed synthesis of aromatic compounds from MBH adducts has been reported; however, the synthesis of poly-substituted benzenes has rarely been studied. Recently, we reported the synthesis of nicotinates by palladium-catalyzed consecutive 5-exo/3-exo cyclization, ring-expansion, and subsequent aromatization process (Scheme1).As a continuouswork,we envisaged that the synthesis of poly-substituted benzene ring could be achieved by using sulfonylacetate as an one-carbon linker, as shown in Scheme 1. The benzene ring could be constructed by a sequential introduction of sulfonylacetate at the primary position of MBH adduct, bromoallylation with 2,3-dibromoprop-1-ene, and a palladium-catalyzed domino 5-exo/3-exo carbopalladation, ring-expansion by palladium rearrangement, and an aromatization process. The preparation of starting materials 3a–k was carried out fromMBHacetates 1 by nucleophilic substitution (SN20) reaction with sulfonylacetates to form 2 and the following allylation with 2-bromoallyl bromides in good yields, as shown in Scheme 2. With compound 3a, we examined the synthesis of dimethyl isopthtalate 4a, as shown in Scheme 3. The reaction of 3a in the presence of Pd(OAc)2/PPh3 and Cs2CO3 (3.0 equiv) in DMF at 120 C afforded 4a in good yield (71%) for 2 h. The use of K2CO3 (3.0 equiv) at 120 C gave 4a in low yield (54%) for 5 h. The reactions with Cs2CO3 (3.0 equiv) and K2CO3 (3.0 equiv) at low temperature (90 C) for 5 h afforded 4a in moderate yields, 57 and 63%, respectively. It is interesting to note that cyclohexene intermediate V could be isolated in good yield (65%) when we used Et3N (2.0 equiv) as a base (120 C, 2 h). Under the conditions, 4awas not formed in any trace amount. Et3N is a weaker base than K2CO3 or Cs2CO3, and the elimination of PhSO2H might be difficult. The result also stated that the cyclohexene derivativeVwould be a reaction intermediate. Thus, the mechanism for the formation of 4a could be proposed, as shown in Scheme 3. An oxidative addition of C Br bond of 3a to Pd to form I and a subsequent 5-exo carbopalladation gave an alkylpalladium intermediate II. Because the intermediate IIhas no suitableβ-hydrogen atom that can be eliminated, a sequential 3-exo carbopalladation occurred to afford an alkylpalladium intermediate III. The presence of an ester group can stabilize both alkylpalladium intermediates II and III by chelation, and this stabilization effect might facilitate the 5-exo/3-exo cascade carbopalladations. The intermediate III has no β-hydrogen atom, thus a concomitant palladium migration/ring expansion proceeded to form intermediate IV. A subsequent syn β-H elimination of IV could occur in either direction; however, V was formed as an intermediate exclusively. A subsequent elimination of PhSO2H from V and double bond isomerization furnished 4a. Encouraged by the successful result, the reactions of 3b–k were carried out and the results are summarized in Table 1. The reactions of 1-naphthyl, 2-naphthyl, 4-biphenyl, and 5methyl-2-thienyl derivatives 3b–e produced the corresponding dimethyl isophthalates 4b–e in good yields (62–76%) in short time (1–2 h). The reactions of 3f–k showed the formation of some side products under the influence of Cs2CO3 at 120 C, and the yields of products were low to moderate. Thus, we carried out the reactions in the presence of K2CO3 at 90 C (vide supra). The reactions of acetyl derivative 3f R COOMe OAc