An Improved Protocol for the Synthesis of Allylated Isonitriles

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.

isonitriles - palladium - allylic alkylation

References

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<A NAME="RG31604ST-22">22</A>

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).

<A NAME="RG31604ST-23">23</A> Tanigawa Y. Tetrahedron Lett.  1982,  5549 

<A NAME="RG31604ST-24">24</A>

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).

<A NAME="RG31604ST-25">25</A>

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).