Directedortho-Metalation, a New Insight into Organosodium Chemistry

Abstract

From laboratory to industrial scale, the use of strong organoalkali metal bases is almost exclusively restricted to alkyllithium derivatives. [1] They are commercially available as 1 ± 2 m solutions, quite stable and easily generated from alkylhalides and lithium. In contrast, the synthesis of alkylsodium compounds is much more troublesome and requires high-speed mechanical stirring, low temperatures, and excess sodium. [2±6] Under classical conditions, organohalides react with sodium to give mainly Wurtz coupling products. [7,8] Moreover, alkylsodium compounds show poor stability, especially in ethereal solvents. [9,10] As a consequence, in spite of the low cost of metallic sodium and the sometimes demonstrated interesting reactivity, [11] alkylsodium compounds have not been considered so far as valuable organometallic reagents in organic synthesis.Herein we report on a straightforward and efficient one-pot ortho-metalation procedure relying on the generation of sodiated organic bases from RCl and a stoichiometric amount of metallic sodium in the presence of aromatic substrates. [12] Under these conditions, handling and storage of alkylsodium compounds is avoided and ortho-metalation is favored over usual coupling and solvolysis side reactions. [13] 1,3-Dimethoxybenzene (1,3-DMB), known to undergo ortho-metalation with alkyllithium bases in good yields, [14] was selected as a model substrate to investigate the scope of the reaction with alkylsodium compounds [Eq. (1)]. Several parameters, including solvent, temperature, and the nature of the organohalide, were varied (Table 1). All reactions were quenched by addition of dry-ice, and the yield of acid [see Eq. (1)] was considered as indicative of the metalation efficiency. [15] ZUSCHRIFTEN

Reactivity of Benzofuran Derivatives

“…Benzo[b]furan 1a with sodium sand in the presence of 1-chlorooctane gave the 2-sodium salt of benzo[b]furan, which reacted with CO 2 gave the carboxylic acid 95, [39] as shown in Scheme 31.…”

ortho-Formylation of oxygenated phenols

“…C-2 is deprotonated if phenyl lithium, n-BuLi or sodium sand is used as reagent; subsequently adding DMF or N-methyformanilide yields the C-2 formylated product. [185][186][187][188][189] While C-4 is formylated when Gattermann/Adams, 151,152 Gross,190 Vilsmeier-Haack [191][192][193] or reaction methods derived thereof 194,195 are employed. Yields are in the range of 45-99%.…”

Carbanions as Intermediates in the Formation of Grignard Reagents

“…The combination of high reactivity and selectivity of the carbanion might be explained by coordination to the (positively charged) magnesium surface, as recently proposed for the ortho metalation of anisole by sodium. 42 Thus, a high steadystate concentration of carbanions can be achieved, resulting in an enhanced possibility to react with neutral starting molecules.…”