A Facile Anchoring of the Bisphosphonate Moiety into Alcohols and Phenols through Copper Carbenoid Mediated O-H Insertion Reaction

Delphine Lecerclé; Frédéric Taran

doi:10.1055/s-2007-984535

LETTER

A Facile Anchoring of the Bisphosphonate Moiety into Alcohols and Phenols through Copper Carbenoid Mediated O-H Insertion Reaction

Delphine Lecerclé, Frédéric Taran*
CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, 91191 Gif sur Yvette, France
Fax: +33(1)69087991; e-Mail: Frederic.taran@cea.fr;

Abstract

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Abstract

A straightforward procedure ensuring the anchoring of bisphosphonate moiety into alcohols or phenols is described. The method uses a bisphosphonate-metal-carbenoid O-H insertion reaction for which copper(II) triflate was found to be an efficient catalyst.

Key words

carbenoids - insertions - copper - rhodium - phosphorus

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References

References and Notes

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General Procedure
To a solution of diazo bisphosphonate 1a (100 mg, 0.318 mmol) and alcohol (0.350 mmol) in 6 mL of anhyd toluene was added Cu(OTf)₂ (1.2 mg, 0.003 mmol). The mixture was heated under reflux for 8 or 12 h and then evaporated under reduced pressure. The residue was purified directly by flash chromatography on silica column (acetone-CH₂Cl₂, 1:1) to afford the desired product.
All new compounds have been characterized by ¹H NMR, ¹³C NMR, ³¹P NMR, IR, and mass spectroscopy.
Selected Data:
Compound 5b: ¹H NMR (400 MHz, CDCl₃): δ = 1.29 (t, J = 7.2 Hz, 6 H), 1.31 (t, J = 7.2 Hz, 6H), 4.04 (t, J = 17.8 Hz, 1 H), 4.08-4.20 (m, 8 H), 4.80 (s, 2 H), 7.26-7.38 (m, 5 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.32-16.41 (m), 63.16 (d, J = 3.0 Hz), 63.19 (d, J = 3.0 Hz), 63.31 (d, J = 3.0 Hz), 63.34 (d, J = 3.0 Hz), 71.50 (t, J = 157.0 Hz), 75.58 (t, J = 5.0 Hz), 128.16, 1128.26, 128.67, 136.34 ppm. ³¹P NMR (160 MHz, CDCl₃): δ = 16.09 (s, 2 P) ppm. MS (ESI/TOF): m/z = 395 [M + H]⁺.
Compound 5c: ¹H NMR (400 MHz, CDCl₃): δ = 1.29 (t, J = 7.2 Hz, 6 H), 1.32 (t, J = 7.2 Hz, 6 H), 4.18-4.30 (m, 8 H), 4.89 (t, J = 17.8 Hz, 1 H), 4.80 (s, 2 H), 7.02 (t, J = 7.6 Hz, 1 H), 7.09 (d, J = 7.6 Hz, 2 H), 7.29 (t, J = 7.6 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.26 (d, J = 2.9 Hz), 16.29 (d, J = 2.9 Hz), 16.36 (d, J = 2.9 Hz), 16.39 (d, J = 2.9 Hz), 63.50 (d, J = 3.2 Hz), 63.53 (d, J = 3.2 Hz), 63.87 (d, J = 3.2 Hz), 63.90 (d, J = 3.2 Hz), 72.35 (t, J = 157.0 Hz), 116.23, 122.64, 129.45, 158.71 (t, J = 4.5 Hz) ppm. ³¹P NMR (160 MHz, CDCl₃): δ = 14.51 (s, 2 P) ppm. MS (ESI/TOF): m/z = 381 [M + H]⁺.
Compound 5d: ¹H NMR (400 MHz, CDCl₃): δ = 1.30 (t, J = 6.8 Hz, 12 H), 4.06-4.25 (m, 11 H), 5.19-5.30 (m, 2 H), 5.79-5.88 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.24-16.31, 63.29 (d, J = 3.0 Hz), 63.32 (d, J = 3.0 Hz), 63.52 (d, J = 3.0 Hz), 63.55 (d, J = 3.0 Hz), 70.87 (t, J = 157.0 Hz), 74.72 (t, J = 4.7 Hz), 119.19, 133.13 ppm. ³¹P NMR (160 MHz, CDCl₃): δ = 16.29 (s, 2 P) ppm. MS (ESI/TOF): m/z = 345 [M + H]⁺.
Compound 5e: ¹H NMR (400 MHz, CDCl₃): δ = 1.31 (t, J = 7.2 Hz, 6 H), 1.32 (t, J = 7.2 Hz, 6 H), 4.10 (t, J = 17.2 Hz, 1 H), 4.10-4.24 (m, 8 H), 4.77 (s, 2 H), 6.34 (dd, J = 3.2, 1.2 Hz, 1 H), 6.40 (d, J = 3.2 Hz, 1 H), 7.41 (d, J = 1.2 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.30-16.41 (m), 63.17 (d, J = 3.0 Hz), 63.20 (d, J = 3.0 Hz), 63.42 (d, J = 3.0 Hz), 63.46 (d, J = 3.0 Hz), 66.11 (t, J = 5.2 Hz), 70.15 (t, J = 157.0 Hz), 110.35, 111.47, 143.37, 149.92 ppm. ³¹P NMR (160 MHz, CDCl₃): δ = 15.93 (s, 2 P) ppm. HRMS: m/z calcd for C₁₄H₂₆O₈P₂Na: 407.1001; found: 407.1014.
Compound 5f: ¹H NMR (400 MHz, CDCl₃): δ = 0.79 (s, 3 H), 1.15 (s, 3 H), 1.23-1.29 (m, 2 H), 1.31 (t, J = 7.2 Hz, 6 H), 1.32 (t, J = 7.2 Hz, 6 H), 1.58 (m, J = 8.0 Hz, 1 H), 1.67-1.76 (m, 2 H), 1.80-1.82 (m, 1 H), 1.86-1.88 (m, 1 H), 1.96-1.99 (m, 1 H), 2.28 (qt, J = 7.6 Hz, 1 H), 3.51 (d, J = 7.2 Hz, 2 H), 3.85 (t, J = 17.8 Hz, 1 H), 4.10-4.21 (m, 8 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.30-16.41 (m), 18.08, 20.04, 23.44, 23.96, 26.52, 35.97, 38.97, 40.74, 42.22, 62.97-63.17 (m), 73.47 (t, J = 157.0 Hz), 79.15 (t, J = 4.3 Hz) ppm. ³¹P NMR (160 MHz, CDCl₃): δ = 16.21 (s, 2 P) ppm. MS (ESI/TOF): m/z = 441 [M + H]⁺.

Compound 5h: ¹H NMR (400 MHz, CDCl₃): δ = 1.27-1.34 (m, 15 H), 1.41 (s, 3 H), 3.85 (dd, J = 18.0 16.0 Hz, 1 H), 3.96-4.03 (m, 2 H), 4.06-4.22 (m, 8 H), 4.59 (s, 1 H), 4.77 (d, J = 5.6 Hz, 1 H), 4.80 (d, J = 5.6 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.66-16.78 (m), 23.91, 27.06, 63.67 (d, J = 6.6 Hz), 63.79 (d, J = 6.6 Hz), 64.02 (d, J = 6.6 Hz), 73.50 (dd, J = 3.7, 5.7 Hz), 73.89 (t, J = 157.0 Hz), 75.80, 78.39, 80.82, 113.48, 174.38 ppm. ³¹P NMR (160 MHz, CDCl₃): δ = 14.41 (d, J = 28 Hz, 1 P), 15.89 (d, J = 28 Hz, 1 P) ppm. HRMS: m/z calcd for C₁₇H₃₂O₁₁P₂Na: 497.1318; found: 497.1326.
Compound 5i: ¹H NMR (400 MHz, CDCl₃): δ = 1.23 (t, J = 7.2 Hz, 6 H), 1.26 (t, J = 7.2 Hz, 6 H), 3.08 (s, 3 H), 3.65 (t, J = 5.4 Hz, 2 H), 3.89 (t, J = 18.0 Hz, 1 H), 3.95 (t, J = 5.4 Hz, 2 H), 4.06-4.18 (m, 8 H), 6.69 (d, J = 8.8 Hz, 2 H), 7.67 (d, J = 8.8 Hz, 2 H), 9.68 (s, 1 H) ppm ¹³C NMR (100 MHz, CDCl₃): δ = 16.30-16.35 (m), 39.03, 51.68, 63.18-63.32 (m), 71.97 (t, J = 4.5 Hz), 73.53 (t, J = 157.0 Hz), 110.93, 125.21, 131.90, 153.36, 190.09 ppm. ³¹P NMR (160 MHz, CDCl₃): δ = 15.72 (s, 2 P) ppm. MS (ESI/TOF): m/z = 466 [M + H]⁺.
Compound 5j: ¹H NMR (400 MHz, CDCl₃): δ = 1.32 (t, J = 7.2 Hz, 12 H), 1.56 (s, 6 H), 1.64 (s, 3 H), 1.91-1.95 (m, 2 H), 1.99-2.10 (m, 6 H), 3.99 (t, J = 17.6 Hz, 1 H), 4.16-4.26 (m, 8 H), 4.30 (d, J = 7.2 Hz, 2 H), 5.03-5.08 (m, 2 H), 5.30 (t, J = 7.2 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.86, 16.33-16.41 (m), 17.56, 25.58, 26.21, 26.60, 39.58, 63.06 (d, J = 3.0 Hz), 63.09 (d, J = 3.0 Hz), 63.28 (d, J = 3.0 Hz), 63.31 (d, J = 3.0 Hz), 69.90 (t, J = 4.7 Hz), 70.62 (t, J = 157.0 Hz), 119.28, 123.54, 124.17, 131.19, 135.33, 142.83 ppm. ³¹P NMR (160 MHz, CDCl₃): δ = 16.52 (s, 2 P) ppm. MS (ESI/TOF): m/z = 509 [M + H]⁺.
Compound 5k: ¹H NMR (400 MHz, CDCl₃): δ = 1.30 (t, J = 7.2 Hz, 6 H), 1.31 (t, J = 7.2 Hz, 6 H), 4.19-4.34 (m, 8 H), 4.89 (t, J = 17.2 Hz, 1 H), 7.15 (d, J = 8.8 Hz, 2 H), 7.29 (t, J = 7.4 Hz, 2 H), 7.39 (t, J = 7.4 Hz, 2 H), 7.50 (d, J = 8.6 Hz, 2 H), 7.52 (d, J = 7.4 Hz, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.30 (d, J = 3.0 Hz), 16.33 (d, J = 3.0 Hz), 16.39 (d, J = 3.0 Hz), 16.41 (d, J = 3.0 Hz), 63.54 (d, J = 3.0 Hz), 63.57 (d, J = 3.0 Hz), 63.87 (d, J = 3.0 Hz), 63.90 (d, J = 3.0 Hz), 72.55 (t, J = 157.0 Hz), 116.51, 126.71, 126.91, 128.09, 128.68, 135.70, 140.30, 158.25 (t, J = 4.5 Hz) ppm. ³¹P NMR (160 MHz, CDCl₃): δ = 14.41 (s, 2 P) ppm. MS (ESI/TOF): m/z = 457 [M + H]⁺.
Compound 5m: ¹H NMR (400 MHz, CDCl₃): δ = 1.33 (t, J = 7.2 Hz, 12 H), 3.55 (s, 3 H), 3.56-3.72 (m, 176.0 H), 3.79 (t, J = 4.8 Hz, 2 H), 3.91 (t, J = 4.8 Hz, 2 H), 4.08 (t, J = 17.6 Hz, 1 H), 4.18-4.26 (m, 8 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.4-16.44 (m), 58.96, 63.23 (d, J = 3.0 Hz), 63.26 (d, J = 3.0 Hz), 63.33 (d, J = 3.0 Hz), 63.36 (d, J = 3.0 Hz), 70.31-70.62 (m), 71.84, 73.43 (t, J = 157.0 Hz) ppm. ³¹P NMR (160 MHz, CDCl₃): δ = 15.99 (s, 2 P) ppm.