Allylic Substitution of Esters Derived from 2-Bromocyclohex-2-enol with Aryl Copper Reagents and Synthetic Utilization of the Derived anti SN2′ Products

Abstract

Allylic substitution of esters derived from 2-bromocyclohex-2-enol with PhMgBr-based copper reagent was investigated to find high anti S N 2′ selectivity with the diethyl phosphate, whereas other esters such as picolinate, acetate, and mesylate resulted in partial racemization or recovery of the starting esters. This protocol was applied to the copper reagent derived from 2-Me-4-MeOC 6 H 3 MgBr and CuBr·SMe 2 and the olefin part of the anti S N 2′ product was cleaved for a synthesis of patchouli alcohol.2-Bromocyclohex-2-enol (1), available as an enantiomerically enriched form by the Corey-Bakshi-Shibata (CBS) reduction of 2-bromocyclohexen-1-one, 1 is a functionalgroup-rich compound, and has been utilized for organic synthesis. 1,2 To expand a scope of utilization we envisioned allylic substitution of esters 2 with aryl reagents followed by cleavage of the olefinic C(Br)-C(H) bond to produce 4 (Scheme 1), in which functional groups X and Y are differentiated to facilitate further transformation toward several biologically active compounds such as curcumenes, heliannuols, etc. 3 In addition, coupling reactions of 3a (Ar = Ph) were studied to compare the reactivity of 3a with that of the corresponding iodide. 4 Several allylic esters 2A-E were prepared from 1 (R isomer, 94-98% ee) 1 by esterification, and allylic substitution with phenyl copper reagents derived from PhMgBr/CuBr·SMe 2 in various ratios was evaluated by chirality transfer (CT) defined as (% ee of 3a) × 100/(% ee of 2) and by yield of 3a (or conversion of the substrate). First, picolinate 2A was chosen as a substrate on the basis of the previous results from our laboratory. 5 The reaction with Ph 2 CuMgBr·MgBr 2 , however, resulted in almost complete racemization (Table 1, entry 1). On the other hand, the substitution with PhCu·MgBr 2 gave 3a through the anti S N 2′ pathway (vide infra) with 73% CT (Table 1, entry 2). To suspect a reason for the low enantiomeric excess, a structurally related picolinate 5 (94% ee) was synthesized from 1 in 87% yield by iron-catalyzed coupling 6 with MeMgBr [Fe(acac) 3 (0.5 equiv), NMP (9 equiv), THF] followed by esterification with PyCO 2 H (DCC, DMAP).As delineated in Scheme 2, the substitution of 5 proceeded with substantial racemization as in the case of 2A. These results suggest that the substituent (Br, Me) on the ring is responsible for the racemization through syn S N 2′ and/or S N 2-type mechanism or through the π-allyl copper intermediate. In relation to these results, the substitution of the iodoacetate 7a with the mixed cuprates 8 gives the S N 2 products 9a highly stereoselectively according to Knochel, who mentioned that the substitution of 7b with the Scheme 1 Aim of the research and compounds possessing the framework of 4 Br L Ar Br 3 1 (L = OH) 2A-E (L = leaving group) allylic substitution Y Ar 4 X cleavage X, Y = CH 2 OH, CHO, CO 2 Me, etc. curcumene (R = H) xanthorrhizol (R = OH) R Me OMe patchouli alchohol intermediate O OH heliannuol A OH Scheme 2 Substitution of the methyl-substituted allylic pic...

Trimethylphosphate as a Methylating Agent for Cross Coupling: A Slow-Release Mechanism for the Methylation of Arylboronic Esters

“…The reaction of Mes-Cu with PO(OMe) 3 gave no product after 20 h, but the reaction with MeI afforded Mes-Me in 20% yield after 5 h at 40 °C and 58% yield after 42 h. The analogous reactions also were conducted with the less hindered PhCu, which is not isolable but can be generated in situ. 18 The reaction of this species with PO(OMe) 3 gave no detectable product after 10 min; in contrast, the reaction with MeI occurred with a half-life of less than 2 min. These results fit our observation that the catalytic methylation reaction proceeds only in the presence of halide (Table 1, entries 8 and 9).…”

“…Thus, to understand how an aryl­copper complex would undergo methylation in this system, we first studied reactions of Mes-Cu with PO­(OMe) 3 and MeI (Scheme a). The reaction of Mes-Cu with PO­(OMe) 3 gave no product after 20 h, but the reaction with MeI afforded Mes-Me in 20% yield after 5 h at 40 °C and 58% yield after 42 h. The analogous reactions also were conducted with the less hindered PhCu, which is not isolable but can be generated in situ . The reaction of this species with PO­(OMe) 3 gave no detectable product after 10 min; in contrast, the reaction with MeI occurred with a half-life of less than 2 min.…”

Availability, Pharmaceutics, Security, Pharmacokinetics, and Pharmacological Activities of Patchouli Alcohol

“…Moreover, Srikrishna and Satyanarayana [27] synthesized PA from the readily available monoterpene (R)-carvone 8 through tandem double Michael reaction-alkylation sequence and single electron mediated 6-endo trig cyclization reaction. Recently, the characteristic of allylic substitution of esters derived from 2-bromocyclohex-2-enol 9 with PhMgBr-based copper reagent has been testified to afford the anti SN2′ products in good yields and with sufficient chirality transfer for synthesis of PA [28]. …”