Pd-Catalyzed Arylation of 1,2-Amino Alcohol Derivatives via β-Carbon Elimination

Abstract

Herein, we describe a Pd-catalyzed arylation of 1,2-amino alcohols with aryl halides enabled by a retroallylation manifold. This protocol constitutes a new entry point to β-arylated aldehydes via the intermediacy of in situ generated enamine intermediates. The protocol is characterized by its exquisite regioselectivity profile and broad substrate scope – including challenging substrate combinations – even in an enantioselective manner.

Key words

palladium - cross-coupling - arylation - C–C cleavage

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• 17 Unfortunately, the utilization of E isomers failed to provide even traces of the targeted compound. These results can be rationalized on the basis of steric hindrance between the Pd center and the trans substituent of the homoallylic alcohol at the chairtype transition state required for the retroallylation to occur.
• 18 The utilization of Pd(PPh₃)₄ resulted in 73% yield of 3a.
• 19 Representative Procedure An oven-dried Schlenk tube containing a stirring bar was charged with 1a (75 mg, 0.234 mmol), Cs₂CO₃ (1.3 equiv), and 2a (48 mg, 0.234 mmol). The Schlenk tube was then evacuated and backfilled with argon (this sequence was repeated three times). Then, a solution of Pd(OAc)₂ (2 mol%) and PPh₃ (4 mol%) in THF (1.0 mL) was subsequently added by syringe. The mixture was warmed up to 90 °C and stirred for 12–16 h. Then, AcOEt (10 mL) was added, and the mixture was filtered through a pad of Celite, and the crude was purified by conventional flash chromatography (hexanes/diethyl ether), providing 39.5 mg (85% yield) of 2a as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 9.75 (t, J = 2.0 Hz, 1 H), 7.84–7.78 (m, 3 H), 7.67–7.64 (m, 1 H), 7.50–7.41 (m, 2 H), 7.40–7.35 (m, 1 H), 3.54 (h, J = 7.0 Hz, 1 H), 2.86 (ddd, J = 16.7, 7.0, 2.0 Hz, 1 H), 2.75 (ddd, J = 16.7, 7.0, 2.0 Hz, 1 H), 1.42 (d, J = 7.0 Hz, 3 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 201.7, 142.8, 133.5, 132.3, 128.4, 127.6, 126.1, 125.5, 125.4, 124.9, 51.6, 34.3, 22.1 ppm.
• 20 See the Supporting Information for details.