MIDA as a Protecting Group and Iterative Cross-Coupling

By: Josephine Nakhla, ChemFiles Volume 9 Article 1

To demonstrate the efficacy of MIDA as a protecting group, Burke’s group reacted a 1:1 mixture of the MIDA boronate (698229) and 4-butylphenylboronic acid with 4-bromobenzaldehyde under Buchwald’s anhydrous Suzuki-Miyaura conditions (Scheme 1). The resultant product mixture displayed a 24:1 preference for reaction with the unprotected boronic acid. A control experiment using p-tolyl boronic acid in lieu of (698229) provided a 1:1 mixture of the two products. Additionally, when a control reaction employing the N-methyldiethanolamine adduct instead of the N-methyliminodiacetic acid was performed, no selectivity was observed, presumably due to the increased flexibility of the N-methyldiethanolamine derivative.

Scheme 1 (698229)

Various halo-containing MIDA-derivatives were prepared, cross-coupled with boronic acids, and sequentially deprotected under basic conditions to release the unprotected boronic acid, thereby demonstrating the utility towards iterative cross-coupling (Scheme 2).

Scheme 2 (701092)

The potential for iterative cross-couplings using the Burke methodology was further demonstrated in their total synthesis of ratanhine (Scheme 3). trans-1-Propen-1-ylboronic acid was coupled with the benzofuranyl MIDA boronate 1, which was deprotected and cross-coupled with the bulky aryl bromide MIDA boronate 2 at elevated temperature. The subsequent intermediate was deprotected and coupled with vinyl bromide 3 to yield the diMOM ether. Cleavage of the two MOM groups resulted in ratanhine, in seven steps in the longest linear sequence. Enabling features of this type of synthesis include the use of only a single, mild reaction to assemble a collection of easily synthesized, readily purified, and highly robust building blocks. Moreover, the short and modular nature of this pathway enables the easy preparation of analogs simply by substituting modified building blocks into the same iterative cross-coupling sequence.1

Scheme 3

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  1. Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716.

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