Regioselective Halogen-Metal Exchange Reaction of 3-Substituted 1,2-Dibromo Arenes: The Synthesis of 2-Substituted 5-Bromobenzoic Acids

Abstract

Regioselective halogen-metal exchange reactions using isopropylmagnesium chloride were carried out on 3-substituted 1,2-dibromo arenes. Eleven examples are given.A common strategy in organic synthesis is the functionalization of polyhalogenated arenes. Primarily, iodo-bromo arenes are used in the regioselective functionalization. In recent years, increasing efforts have been made to investigate the regioselective functionalization of diiodo-or dibromo arenes. [2][3][4][5] In 1,4-and 1,3-dibromo arenes, a regioselective halogen-metal exchange reaction using butyllithium is well documented. 6,7 Interestingly, there are only a few examples of the regioselective halogen-metal exchange on 1,2-dibromo arenes. 8,9 This lack of precedence may be attributed to the accessibility and availability of 1,2-dibromo arenes. 10 Additionally, vicinal bromo-lithio arenes in general tend to decompose via a well known benzyne pathway even at low temperatures. 11 In contrast, using isopropylmagnesium chloride for the halogen-metal exchange of 1,2-dibromo arenes has several advantages: (a) higher thermodynamic stability of the resulting arylmagnesium intermediate; (b) prevention of benzyne pathways at low temperatures and (c) generation of highly functionalized arylmagnesium compounds. 12In general, the regioselective functionalization of the 2-position in 3-or 3,5-substituted bromobenzene derivatives afforded mixtures of 1,3,4-and 1,2,3-or 1,2,3,4-and 1,3,4,5-bromobenzene derivatives, respectively. We envisioned that 3-substituted 1,2-dibromobenzene derivatives could be regioselective functionalized in a halogen-metal exchange reaction. In order to test our hypothesis 1,2-dibromo-3-chlorobenzene (1a) was treated with butyllithium at -78°C in tetrahydrofuran or diethyl ether (Scheme 1). 6 The halogen-metal exchange occurred exclusively at the 2-position (entries 1 and 2, Table 1). 13 However, 3-bromo-1-chlorobenzene (2a) was formed only in 75% and 67%, respectively, 14 as determined by HPLC versus a standard prepared from commercially available authenic material. When reacting isopropylmagnesium chloride with 1,2-dibromo-3-chlorobenzene (1a) at -40°C, 1-bromo-3-chlorobenzene (2a) and 1-bromo-2-chlorobenzene (3a) were afforded in 93% and 5% yields, respectively (entry 3). The high regioselectivity in the halogen-metal exchange, the high yield of 2a and the thermodynamic stability of the arylmagnesium intermediate encouraged us to study the reaction conditions using isopropylmagnesium chloride in more detail. Scheme 1 Study of reaction conditions for the regioselective halogen-metal exchange on 1,2-dibromo-3-chlorobenzene (1a)A similar regioselectivity between 2a and 3a and a lower yield of 2a were observed if the reaction was carried out at -78°C (entry 4). Both yield of 2a (71%) and regioselectivity (90:10) decreased when the halogen-metal exchange was performed at room temperature (entry 5). When the reaction mixture was kept at room temperature for 24 hours, the ratio worsened to 81:19 and a significant decrease in the yield of 2a wa...

Halogen – metal exchange of 3‐substituted 1,2‐dibromoarenes: the use of long‐range JCH coupling constants to determine regiochemistry

“…A series of 3-substituted 1,2-dibromobenzene analogs were prepared to examine the effect of R-group substitution on regioselectivity in the transmetalation. 4 To simplify the analysis, the metal analogs were quenched with carbon dioxide to provide the more stable benzoic acid analogs for product yield via HPLC analysis. NMR analysis was used to determine the regiochemistry of these analogs, which required the use of the older, more traditional 1-D technique:…”

Terminal versus Internal Diiodobenzyl Alcohol Derivatives via Regioselective Metal–Iodine Exchange of 1,2,3‐Triiodoarenes: Synthesis and Antibacterial Activity

“…8 Other pioneering work from the group of Karsten Menzel reported regioselective Metal-bromine exchange reaction of 3-substituted 1,2-dibromoarenes for the synthesis of ortho-bromobenzoic acid derivatives, the authors isolated the products in good yields and concluded that the reactivity and regioselectivity of these substrates per se are affected by the type of substituent at position 3 favoring the metal-bromine exchange reaction to occur exclusively either at position 1 or 2. 23 We envisioned that 1,2,3-triiodoarene derivatives could be regioselective functionalized in a metal-iodine exchange reaction. Having just two regiochemically distinct sites occupied with iodine, metal-iodine exchange/functionalization sequence can give rise to not more than two possible regioisomers, the terminal and the internal diiodobenzyl alcohol products as shown in Scheme 1.…”

Efficient and Selective Synthesis of α,β‐Epoxy‐γ‐Butyrolactones from 2‐Peroxy‐1,4‐Dicarbonyl Compounds

“…reported regioselective metal–bromine exchange reactions of 3‐substituted‐1,2‐dibromoarenes for the synthesis of ortho ‐bromobenzoic acid derivatives. The products were isolated in good yields and concluded that the reactivity and regioselectivity of these substrates per se are affected by the type of substituent at the C3 position, favoring the metal–bromine exchange reaction exclusively either at the C1 or C2 position 23…”