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...

Regioselective halogen/metal exchange reactions were carried out on a series of 3-substituted- 1,2-dibromoarenes. Product mixtures were quenched with CO2 to form the corresponding benzoic acid analogs to facilitate HPLC and NMR analysis. Substitution at the 3-position could readily be assigned on the basis of 2D HMBC long-range correlations, while assignment at the 2-position was not as straightforward. The use of three-bond J(CH) coupling constant measurements, extracted from 1-D 1H coupled 13C experiments, were necessary to render unequivocal regio assignments.

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( S )‐Valinol Triethylamine Trifluoromethanesulfonic anhydride ( S )‐ N ‐Trifluoromethylsulfonyl‐2‐isopropylaziridine Benzylamine (2 S ,6 S )‐4‐Benzyl‐1,7‐bis(trifluoromethylsulfonyl)‐2,6‐disopropyll‐1,4,7‐triazaheptane Disiopropylethylamine Trimethylaluminum Acetyl bromide Hydrocinnamaldehyde (4 S )‐4‐(2‐Phenethyl)oxetane‐2‐one

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