Phosphinamide-Directed ortho Metalations: Application to the Desym­metrization of the Diphenylphosphoryl Group

Abstract

Diphenylphosphinamides have been regioselectively ortho-lithiated under mild conditions providing a simple access to ortho-functionalized derivatives in good yields. The application of the methodology to the diastereoselective desymmetrization of the phosphorus atom is described for the first time.

phosphinamides - ortho lithiation - diastereoselectivity - organotin - directed metalation

References and Notes

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<A NAME="RD32106ST-12">12</A>

The analogous reaction of N,N-dialkylthiophosphinamides produced the quantitative displacement of the amino moiety. See reference 4h.

<A NAME="RD32106ST-13">13</A>

Typical Procedure for the Synthesis of 15a′
To a solution of the phosphinamide 13 (3.11·10^-4 mol) in THF (30 mL) was added a solution of n-BuLi (0.7 mL of a 1.6 M solution in cyclohexane, 10.9·10^-4 mol) at -35 °C. After 2 h of metalation was added chlorotrimethyltin (10.9·10^-4 mol). The reaction mixture was stirred at the same temperature for 30 min and then was poured into ice water and extracted with EtOAc (3 × 15 mL). The organic layers were dried over Na₂SO₄ and concentrated in vacuo. ¹H NMR, ¹H{³¹P} NMR, and ³¹P NMR spectra of the crude reaction were measured in order to determine the stereoselectivity of the process. The reaction mixture was then purified by flash column chromatography using a mixture of EtOAc-hexane (1:5) as eluent.
Spectroscopic Data of 15a′
¹H NMR (300 MHz, THF-d ₈): δ = 0.32 (s, 9 H), 1.57 (d, 3 H, J _PH = 6.8 Hz), 4.19 (m, 1 H), 5.10 (1 H, J _PH = 5.4, 10.1 Hz, NH), 7.16-7.50 (10 H), 7.80 (m, 2 H), 7.99 (m, J _PH = 11.4, 7.5 Hz). ¹³C NMR: δ = -5.32 (CH₃, J _PC = 1.2 Hz), 50.82 (CH), 125.92 (HCAr), 126.27 (HCAr), 127.50 (HCAr, J _PC = 12.2 Hz), 127.87 (HCAr), 127.93 (HCAr, J _PC = 11.9 Hz), 130.02 (HCAr, J _PC = 3.8 Hz), 131.12 (HCAr, J _PC = 2.6 Hz), 132.12 (HCAr, J _PC = 9.0 Hz), 132.17 (HCAr, J _PC = 12.8 Hz), 134.39 (C _ipso , J _PC = 127.4 Hz), 136.25 (HCAr, J _PC = 17.4 Hz), 137.74 (ipso, J _PC = 133.2 Hz), 145.69 (C _ipso , J _PC = 7.4 Hz), 151.17 (C _ipso , J _PC = 18.2 Hz). ³¹P NMR: δ = 23.58. Oil. MS (API-ES): m/z (%) = 508 (5) [M + Na], 470.1 (1009 [M - 15]. Anal. Calcd (%) for C₂₃H₂₈NOPSn: C, 57.06; H, 5.83; N, 2.89. Found: C, 57.0; H, 5.70; N, 2.97.

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<A NAME="RD32106ST-17">17</A>

The crystal data of 18′ has been deposited in CCDC with number 625923.

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<A NAME="RD32106ST-18C">18c</A>

See also ref. 4e-g.

<A NAME="RD32106ST-18D">18d</A> For other diastereoselective deprotonations of ferrocene, see: Metallinos C. Snieckus V. Org. Lett.  2002,  4:  1935 ; and references therein