Synthesis of 2-Benzylphenols: Transformation of the Baylis-Hillman Adducts Derived from 2-Cyclohexen-1-one

Abstract

an extension of the reaction, we intended to prepare acridine skeleton from the Baylis-Hillman adducts of 2-cyclohexen1-one as shown in Scheme 1. However, we could not prepare the desired compounds via the reaction scheme (vide infra). Instead, we could obtain 2-benzylphenol derivatives in good yields as shown in Scheme 2 and wish to report herein the results. The Friedel-Crafts alkylation reaction is one of the most powerful methods to form the carbon-carbon bond in organic reactions. The Friedel-Crafts benzylation reaction is of great synthetic significance in industrial processes. 3 However, synthesis of 2-benzylphenols regioselectively from phenols or benzyl phenyl ethers is difficult due to the formation of ortho-/para- mixtures. 4 Synthesis of these compounds by Fries rearrangement of phenyl phenylacylates also suffers from the formation of mixtures. 5 Ortho-specific alkylation of phenols via 1,3,2-benzodioxaborins was known. 6 1,3,2-Benzodioxaborins can be reduced to orthoalkyl phenols with tert-butylamine borane in the presence of aluminum chloride. The Baylis-Hillman reaction of 2-fluorobenzaldehyde (1a) and 2-cyclohexen-1-one (2) was carried out in aqueous THF with the aid of DMAP at room temperature to give the corresponding adduct 3a in 58% yield as reported previously. 7 Acetylation of 3a with Ac2O/DMAP gave 4a in 91% yield. Initially, we examined the reaction of 4a and ptoluenesulfonamide in the presence of K 2CO3 in DMF. However, 2-(2-fluorophenyl)methylphenol (5a) was isolated in 74% yield, unexpectedly. The formation of 5a occurred well without tosylamide. Actually, the yield of 5a was improved up to 94% without tosylamide as shown in Table 1 (entry 1). Thus, we prepared some Baylis-Hillman acetates of 2cyclohexen-1-one and examined their conversion to 2arylmethylphenols and the results are summarized in Table 1. As mentioned previously, the Baylis-Hillman reaction of 1 and 2 was carried out in aqueous THF in the presence of 0.1 equiv. of DMAP. 7 The corresponding adducts 3a-h were obtained in reasonable yields (41-64%) at room temperature. Following conversion to their acetate 4a-h was excellent in all cases (CH2Cl2, Ac2O/DMAP, rt, 90-98%). The reaction of 4a-f in DMF in the presence of K 2CO3 (1.0 equiv) gave 5a-f in good yields (89-96%) in short time (1-2 h) at 60-70 o C. 8 The formation of 5g, the quinoline derivative, was carried out at room temperature. The reaction is believed to occur as depicted in Scheme 2: potassium carbonate assisted elimination of acetic acid and the following keto-enol tautomerization and 1,5-hydrogen transfer. 9 We could not obtain the corresponding phenol derivative from the analogous reaction with 4h, derived from hexanal. Intractable mixtures were observed on tlc at 60-70 o C. Instead, we could isolate cyclohexenone derivative 6 in 40% yield at room temperature. 10 The structure of 6 was determined by 1 H, 13 C, and 1 H- 1 H COSY. 8 In conclusion we disclosed unusual transformation of the Baylis-Hillman acetates of 2-cyclohexen-1-one into 2arylmethylphenols. Further chemical transformation of the products to xanthene derivatives via the nucleophilic aromatic substitution strategy and the synthesis of acridines are underway.