Synlett 2004(14): 2576-2578  
DOI: 10.1055/s-2004-834829
LETTER
© Georg Thieme Verlag Stuttgart · New York

An Improved Protocol for the Synthesis of Allylated Isonitriles

Uli Kazmaier*, Stefanie Ackermann
Institut für Organische Chemie, Universität des Saarlandes, 66123 Saarbrücken, Germany
Fax: +49(681)3022409; e-Mail: u.kazmaier@mx.uni-saarland.de;
Further Information

Publication History

Received 10 August 2004
Publication Date:
20 October 2004 (online)

Abstract

α-Isocyanoacetates can be used as suitable nucleophiles in palladium-catalyzed allylic alkylations giving rise to α-allylated isonitriles. Best results are obtained if Cs2CO3 is used as a base to deprotonate the isonitrile, and with dppe as a ligand on palladium, which supresses decomposition of the active palladium complex.

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α-Alkylated isonitriles were probably used to avoid double allylation and epimerization if chiral substrates or ligands are used.

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General Procedure for the Allylic Alkylation of Isocyanoacetates: Cs2CO3 (1 equiv) was dissolved in anhyd THF (to make a 0.5 M solution) under Ar in a two-neck flask. Isocyanoacetate (1 equiv) was added, and the mixture was stirred for 15 min. A solution of 2 mol% [PdCl(allyl)]2, 4 mol% dppe and allyl carbonate (or phosphate, 1 equiv) was prepared in mL anhyd THF (to make a solution 0.5 M in allyl carbonate or phosphate) under argon and was stirred for 15 min before it was added slowly to the solution of the deprotonated isocyanide. The mixture was heated to reflux until all carbonate was consumed (TLC). After cooling to r.t. 1 M KHSO4 was added and the aqueous layer was extracted three times with Et2O. After drying (Na2SO4) and evaporation of the solvent, the crude product was purified by flash chromatography.
Compound 3: Substitution product 3 was obtained as major regioisomer from 2a (0.5 mmol scale) as a pale yellow oil in 93% yield. 1H NMR (500 MHz, CDCl3): δ = 1.13-1.26 (m, 6 H, 1-H, 12-H), 2.98 (m, 1 H, 2-H), 4.14-4.38 (m, 3 H, 9-H, 11-H), 6.02 (dd, 3 J 3,4 = 15.8 Hz, 3 J 3,2 = 9.9 Hz, 0.5 H, 3-H), 6.04 (dd, 3 J 3,4 = 15.8 Hz,3 J 3,2 = 9.7 Hz, 0.5 H, 3-H), 6.40 (d, 3 J 4,3 = 15.8 Hz, 0.5 H, 4-H), 6.47 (d, 3 J 4,3 = 15.8 Hz, 0.5 H, 4-H), 7.15-7.33 (m, 5 H, 6-H-8-H). 13C NMR (125 Hz, CDCl3): δ = 15.2 (C-12), 18.0 (C-1), 40.0 (C-2), 62.6 (C-9, C-11), 126.4 (C-3), 128.3 (C-7), 128.6 (C-8), 132.3 (C-6), 133.0 (C-4), 136.4 (C-5), 161.1 (C-13), 165.9 (C-10).
Compound 6: Substitution product 6 was obtained from 1 mmol carbonate 5a in 89% yield as a pale yellow oil. 1H NMR (500 MHz, CDCl3): δ = 1.04 (d, 3 J 1,2 = 6.6 Hz, 1.5 H, 1-H), 1.12 (d, 3 J 1,2 = 6.7 Hz, 1.5 H, 1-H), 1.24 (t, 3 J 10,9 = 7.3 Hz, 3 H, 10-H), 1.62 (m, 3 H, 5-H), 2.74 (m, 1 H, 2-H), 4.10 (d, 3 J 6,2 = 7.1 Hz, 1 H, 6-H), 4.18 (q, 3 J 9,10 = 7.3 Hz, 2 H, 9-H), 5.32 (m, 1 H, 4-H), 5.53 (m, 1 H, 3-H). 13C NMR (125 MHz, CDCl3): δ = 10.8 (C-10), 11.9 (C-5), 12.7 (C-1), 37.3 (C-2), 60.2 (C-6, C-9), 125.0 (C-4), 127.7 (C-3), 158.2 (C-7), 168.8 (C-8).

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Preparation of Allylic Phosphonate 7c: DMAP (122 mg, 1.0 mmol) was added to a solution of cyclohexenol (980 mg, 10.0 mmol) in pyridine (10 mL). The solution was cooled to 0 °C before diethoxyphosphoryl chloride (2.65 g, 15.4 mmol) was added slowly. The mixture was warmed to r.t. overnight and the volatile components were removed in vacuo. Hexane was added to the residue and the precipitated pyridinium hydrochloride was filtered off. The solvent was removed in vacuo and 7c was obtained in 78% yield (1.82 g, 7.76 mmol) as a pale yellow oil, which was used directly for allylic alkylations according to the general procedure. 1H NMR (500 MHz, CDCl3): δ = 1.25 (t, 3 J 8,7 = 7.0 Hz, 6 H, 8-H), 1.54-2.02 (m, 6 H, 4-H-6-H), 4.04 (q, 3 J 7,8 = 7.3 Hz, 4 H, 7-H), 4.81 (m, 1 H, 1-H), 5.72 (m, 1 H, 3-H), 5.87 (m, 1 H, 2-H). 13C NMR (125 MHz, CDCl3): δ = 16.1 (d, 4 J 8,P = 6.4 Hz, C-8), 18.4 (C-5), 29.9 (d, 3 J 6,p = 4.3 Hz, C-6), 35.2 (C-4), 63.5 (d, 2 J 7,P = 3.2 Hz, C-7), 72.1 (d, 3 J 1,P = 6.4 Hz, C-1), 126.3 (C-3), 132.7 (C-2).

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Substitution product 8 was obtained from crude 7c (2 mmol) in 91% yield as pale yellow liquid. 1H NMR (500 MHz, CDCl3): δ = 1.26 (t, 3 J 11,10 = 7.3 Hz, 3 H, 11-H), 1.56-1.97 (m, 6 H, 4-H-6-H), 2.74 (m, 1 H, 1-H), 4.07 (d, 3 J 7,1 = 5.4 Hz, 0.5 H, 7-H), 4.17 (d, 3 J 7,1 = 5.4 Hz, 0.5 H, 7-H), 4.22 (q, 3 J 10,11 = 7.3 Hz, 2 H, 10-H), 5.43 (m, 1 H, 3-H), 5.88 (m, 1 H, 2-H). 13C NMR (125 MHz, CDCl3): δ = 14.1 (C-11), 20.8 (C-6), 23.6 (C-5), 24.6 (C-4), 38.7 (C-1), 62.6 (C-7, C-10), 125.0 (C-3), 132.0 (C-2), 160.3 (C-8), 166.1 (C-9).