Selective 1,4-Addition of Organolithiums to Maleate Monoesters with Application for a Short Efficient Route to Azaindanones

Published as part of the Cluster Modern Heterocycle Synthesis and Functionalization

Abstract

The ability of maleate half-ester salts to serve as electrophilic partners in 1,4-conjugate addition reactions with control of regioselectivity has previously been explored in only a limited context with soft nucleophiles. We have demonstrated that benzylic anions of picolines, as well as enolates of ketones, esters, and nitriles, react with lithium 4-(tert-butoxy)-4-oxobutenoate in a completely regioselective manner. This new method was applied to an expedient two-step process for preparing a key azaindanone intermediate for the clinical-candidate drug MK-8666.

Key words

lithium butoxyoxobutenoate - maleate half esters - 1,4-addition - azaindanones

• References and Notes

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• 20 tert-Butyl 3-[(5-Bromo-2-chloropyridin-4-yl)methyl]-4-[methoxy(methyl)amino]-4-oxobutanoate (11a); Typical Procedure A 2.5 M solution of n-BuLi in hexanes (11.14 mL, 1.15 equiv, 27.8 mmol) was added to a solution of i-PrNH₂ (4.07 mL, 1.20 equiv, 29.1 mmol) in THF (12.5 mL) at –20 to –30 °C, and the mixture was aged for 20–30 min. The solution was then cooled to –78 °C and a solution of 5-bromo-2-chloro-4-methylpyridine (6; 5.0 g, 24.2 mmol) in THF (9 mL) was added. The mixture was cooled to –78 °C and aged for 1 h. A solution of lithium (Z)-4-(tert-butoxy)-4-oxobut-2-enoate (7f; 5.61 g, 1.3 equiv, 31.5 mmol) in THF (32 mL) was added by using a syringe pump over 30 min, and the resulting mixture was stirred for 30 min. The reaction was then quenched by slow addition of MsOH (5.59 g, 2.4 equiv, 58.1 mmol) over 30 min. The mixture was allowed to warm to rt, CDI (5.69 g, 1.45 equiv, 35.1 mmol) was added, and the mixture was stirred overnight at rt. N,O-Dimethylhydroxylamine hydrochloride (3.66 g, 1.55 equiv, 37.5 mmol) was then added at rt, and the mixture was stirred for 6 h while the progress of the reaction was monitored by LC/MS. The mixture was poured into aq citric acid solution to a pH of ~4.5 and extracted with EtOAc. The organic layer was washed with sat. aq NaHCO₃ and brine then dried (Na₂SO₄), filtered and concentrated. The residue was purified by column chromatography (silica gel, EtOAc–PE) to give a white solid; yield: 9.5 g (93%); mp 98 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.45 (s, 1 H), 7.19 (s, 1 H), 3.73–3.60 (m, 1 H), 3.65 (s, 3 H), 3.12 (s, 3 H), 2.97 (dd, J = 13.2, 8.5 Hz, 1 H), 2.87 (dd, J = 13.2, 6.9 Hz, 1 H), 2.79 (dd, J = 16.4, 9.1 Hz, 1 H), 2.31 (dd, J = 16.4, 5.2 Hz, 1 H), 1.43 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.83, 170.86, 151.51, 150.46, 126.56, 122.00, 81.19, 61.52, 37.58, 37.31, 36.64, 32.35, 28.24. HRMS (ESI); m/z [M + H]⁺ calcd for C₁₆H₂₃BrClN₂O₄: 421.0530; found: 421.0524.