Isocyanide Addition to Acylphosphonates: A Formal Passerini Reaction of Acyl Chlorides

Abstract

Acylphosphonates behave as carbonyl components in Passerini reactions with isocyanides and carboxylic acids. Under saponification, the adducts undergo a phospha-Brook rearrangement to form α-amidophosphates. As acylphosphonates are quantitatively formed from carboxylic derivatives, this new reductive procedure allows acyl chlorides to react as aldehydes in a Passerini-type reaction.

phosphonate - isocyanide - multicomponent reaction - Passerini reaction

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15

General Procedure for the Formation of Phosphonate 5: To acyl chloride 1 (2 mmol) was added neat trialkyl phosphite (1 equiv). The mixture was stirred under argon for 30 min. Toluene (1 M), isocyanide (1 equiv) and carboxylic acid (1 equiv) were then successively added. The mixture was stirred for 24 h under argon at r.t. (for alkyl acyl chlorides) or at 80 °C (for aromatic acyl chlorides). The solvent was then removed under reduced pressure to afford Passerini products after purification by flash column chromatography on silica gel. Data for 5a: mp 72-74 °C; R _f (EtOAc-PE, 50:50): 0.1. ¹H NMR (400 MHz, CDCl₃): δ = 7.26-7.33 (m, 2 H), 7.18-7.24 (m, 3 H), 6.73 (d, J = 8.3 Hz, 1 H), 3.84-3.88 (m, 1 H), 3.88 (d, J _H-P = 10.8 Hz, 3 H), 3.84 (d, J _H-P = 10.6 Hz, 3 H), 2.69-2.80 (m, 1 H), 2.56-2.69 (m, 3 H), 2.18 (s, 3 H), 1.91-1.99 (m, 2 H), 1.68-1.78 (m, 2 H), 1.59-1.66 (m, 1 H), 1.33-1.47 (m, 2 H), 1.17-1.32 (m, 3 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 169.1 (d, J _C-P = 5.9 Hz), 165.2 (d, J _C-P = 4.4 Hz), 141.4, 129.0, 128.9, 126.5, 83.3 (d, J _C-P = 152.2 Hz), 55.1 (d, J _C-P = 6.6 Hz), 54.5 (d, J _C-P = 7.3 Hz), 49.1, 35.6, 33.2, 33.1, 30.5 (d, J _C-P = 7.3 Hz), 25.9, 25.1, 21.6. IR (thin film): 3328, 3027, 2987, 1749, 1669, 1531, 1259, 1222, 1020 cm^-1. HRMS: m/z calcd for C₂₀H₃₀NO₆P: 411.1811; found: 411.1810.
Typical Procedure for the Conversion of 5a to 6a: To a solution of LiOH (1 mmol) in anhyd THF (0.25 M) was added 5a (1 equiv). The mixture was heated for 2 d at 65 °C under argon. After evaporation of the solvent under reduced pressure, the remaining salts were removed by washing the residue with a 1:1 mixture of CH₂Cl₂ and PE followed by filtration. Evaporation of the solvent gave 6a as a yellow oil in quantitative yield. ¹H NMR (400 MHz, CDCl₃): δ = 7.22-7.30 (m, 2 H), 7.13-7.22 (m, 3 H), 6.46 (d, J = 7.6 Hz, 1 H), 4.70-4.78 (m, 1 H), 3.80 (d, J _H-P = 10.9 Hz, 6 H), 3.75-3.83 (m, 1 H), 2.65-2.76 (m, 2 H), 2.16-2.25 (m, 2 H), 1.83-1.94 (m, 2 H), 1.65-1.76 (m, 2 H), 1.55-1.65 (m, 1 H), 1.27-1.43 (m, 2 H), 1.10-1.27 (m, 3 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 168.5 (d, J _C-P = 4.4 Hz), 141.1, 128.9, 128.8, 126.5, 78.2 (d, J _C-P = 6.6 Hz), 55.2 (d, J _C-P = 6.6 Hz), 55.1 (d, J _C-P = 6.6 Hz), 48.5, 35.3 (d, J _C-P = 4.4 Hz), 33.4, 33.2, 30.8, 25.8, 25.1. IR (thin film): 3298, 2932, 2856, 1668, 1536, 1452, 1267, 1051 cm^-1. HRMS: m/z calcd for C₁₈H₂₈NO₅P: 369.1705; found: 369.1700.