Highly Selective Preparation of 2-(Hydroxymethyl)vinylphosphonates by Insertion of Ketones into Zirconacycle Phosphonates

Abed Al Aziz Quntar; Artem Melman; Morris Srebnik

doi:10.1055/s-2002-19322

LETTER

Highly Selective Preparation of 2-(Hydroxymethyl)vinylphosphonates by Insertion of Ketones into Zirconacycle Phosphonates

Abed Al Aziz Quntar^a, Artem Melman^b, Morris Srebnik*^a
^a Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Hebrew University, Jerusalem, 91120, Israel
^b Department of Organic Chemistry, Institute of Chemistry, Hebrew University, Jerusalem, Israel
Fax: +97(22)6758201; e-Mail: msrebni@md2.huji.ac.il;

Abstract

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Abstract

Three-member zirconacycles insert ketones exclusively at C-2 to give five-member zirconacycle phosphonates that can be hydrolyzed to give 2-(hydroxymethyl)vinylphosphonates, 2, in excellent yields. Other regioisomers were not detected. The reaction works well for both aromatic and aliphatic ketones. Competitive studies indicate that ketones and aldehydes insert at about the same rate and that both react much faster than alkynes. Compounds 2 undergo chlorination with thionyl chloride without rearrangement.

Key words

alkynylphosphonates - zirconacycles - regioselective insertion - 2-(hydroxymethyl)vinylphosphonates - chlorination

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References

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Quntar, A. A.; Srebnik, M. J. Org. Chem. in press.

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14

General Procedure: To 0.584 g(2mmol) zirconocene dichloride dissolved in 6 mL dry THF at -78 °C, 2.5 mL of 1.6 M n-BuLi (4 mmol) were added dropwise and the mixture was stirred for 3 h. Then 0.39 g (1.8 mmol) of 1-alkynylphosphonate was added and the mixture was warmed gradually to r.t. and stirred overnight. Then 1.1 mmol of freshly distilled ketone was added and the mixture was stirred for additional 24 h. The reaction mixture was worked up with dilute HCl and the product was extracted with ether and separated on a silica gel column (petroleum ether:EtOAc, 3:1). All new compounds were analyzed by NMR, LCMS and gave satisfactory elementary analysis.
Selected NMR data: 2a: ¹H NMR (300 MHz): δ = 0.77 (t, 3 H, J _HH = 7.5 Hz), 1.25 (t, 6 H, J _HH = 6.9 Hz), 1.12-1.38 (overlap, 4 H), 1.71 (s, 3 H), 2.25 (m, 2 H), 2.81 (s, 1 H), 3.97-4.10 (m, 4 H), 5.94-6.00 (d, 1 H, ² J _PH = 16.8 Hz), 7.20-7.40 (m, 5 H); ³¹P NMR (300 MHz): δ = 19.17; ¹³C NMR (75.5 MHz): δ = 170.43 (d, ² J _pc = 7.20 Hz), 145.1, 128.4, 127.6, 126.1, 109.7 (d, ¹ J _pc = 189.4 Hz), 77.1 (d, ³ J _pc" = 21.8 Hz, trans), 61.4 (d, ² J _pc = 6.0 Hz), 33.3, 31.0, (d, ³ J _PC = 8.1 Hz), 28.0, 23.7, 16.5 (d, ³ J _pc = 6.5 Hz),13.9; 2b: ¹H NMR (300 MHz): δ = 0.85 (t, 3 H, J _HH = 7.5 Hz), 1.27 (t, 6 H, J _HH = 6.9 Hz), 1.30 (s, 6 H), 1.22-1.60 (overlap, 4 H), 2.40 (m, 2 H), 3.00 (broad s, 1 H), 3.94-4.01 (m, 4 H), 6.22-6.30 (d, 1 H, ² J _PH = 17.1 Hz); ³¹P NMR (300 MHz): δ = 19.83; ¹³C NMR (75.5 MHz): δ = 172.8 (d, ² J _pc = 4.08 Hz), 108.90 d, ¹ J _pc = 186.5 Hz), 74.6 (d, ³ J _pc" = 21.2 Hz, trans), 61.3 (d, ² J _pc = 6.1 Hz), 33.3, 29.4, 23.7, 16.9 (d, ³ J _pc = 6.6 Hz), 16.2; 2c: ¹H NMR (300 MHz): δ = 0.80 (overlap, 6 H), 1.27 (t, 6 H, J _HH = 6.9 Hz), 1.23 (s, 3 H), 1.22-1.60 (overlap, 8 H), 2.20 (m, 2 H), 2.40 (m, 2 H), 2.85 (broad s, 1 H), 3.80-4.00 (m, 4 H), 5.6-5.70 (d, 1 H, ² J _PH = 17.1 Hz); ³¹P NMR (300 MHz): δ = 19.72; ¹³C NMR (75.5 MHz): δ = 172.0 (d, ² J _pc = 6.95 Hz), 109.6 (d, ¹ J _pc = 189.7 Hz), 76.5 (d, ³ J _pc" = 20.9 Hz, trans), 61.3 (d, ² J _pc = 6.0 Hz), 41.0, 33.0, 30.6 (d, ³ J _PC = 7.1 Hz), 28.0, 25.9, 23.7, 23.0, 16.4 (d, ³ J _pc = 6.6 Hz), 14.3, 13.9; 2d: ¹H NMR (300 MHz): δ = 0.84 (t, 3 H, J _HH = 67.5 Hz), 1.27 (t, 6 H, J _HH = 6.6 Hz), 1.29-1.80 (overlap, 12 H), 2.32 (m, 2 H), 2.70 (broad s, 1 H), 3.90-4.01 (m, 4 H), 5.75-5.81 (d, 1 H, ² J _PH = 17.7 Hz); ³¹P NMR (300 MHz): δ = 19.75; ¹³C NMR (75.5 MHz): δ = 170.7 (d, ² J _pc = 7.5 Hz), 109.4 (d, ¹ J _pc = 194.0 Hz), 85.1 (d, ³ J _pc" = 21.2 Hz, trans), 61.1 (d, ² J _pc = 5.7 Hz), 39.3, 33.0, 30.5 (d, ³ J _PC = 6.8 Hz, cis), 23.8, 23.3, 16.2 (d, ³ J _pc = 6.6 Hz), 13.6; 2e: ¹H NMR (300 MHz): δ = 0.84 (t, 3 H, J _HH = 7.5 Hz), 1.27 (t, 6 H, J _HH = 6.6 Hz), 1.29-1.80 (overlap, 14 H), 2.28 (broad s, 1 H), 2.42 (m, 2 H), 3.90-4.01 (m, 4 H), 5.72-5.78 (d, 1 H, ² J _PH = 17.1 Hz); ³¹P NMR (300 MHz): δ = 20.06; ¹³C NMR (75.5 MHz): δ = 173.2 (d, ² J _pc = 6.6 Hz), 109.2 (d, ¹ J _pc = 190.0 Hz), 75.4 (d, ³ J _pc" = 20.9 Hz, trans), 61.1 (d, ² J _pc = 5.7 Hz), 35.7, 33.2, 30.2 (d, ³ J _PC = 7.1 Hz, cis), 25.2, 23.5, 21.5, 16.2 (d, ³ J _pc = 6.5 Hz), 13.7; 2f: ¹H NMR (300 MHz): δ = 0.77 (t, 3 H, J _HH = 7.5 Hz), 1.27 (t, 6 H, J _HH = 6.6 Hz), 1.29-1.50 (overlap, 4 H), 1.81 (m, 2 H), 1.95 (m, 2 H), 2.42 (m, 2 H), 2.73 (broad s, 1 H), 2.65-2.80 (m, 2 H), 3.90-4.01 (m, 4 H), 5.85-5.91 (d, 1 H, ² J _PH = 17.7 Hz), 7.01-7.10 (m, 4 H); ³¹P NMR (300 MHz): δ = 19.28; ¹³C NMR (75.5 MHz): δ = 170.6 (d, ² J _pc = 7.8 Hz), 137.2, 128.7, 127.7, 127.3, 126.1, 111.7 (d, ¹ J _pc = 188.8 Hz), 76.6 (d, ³ J _pc" = 24.9 Hz, trans), 61.8 (d, ² J _pc = 5.7 Hz), 35.8, 33.7, 30.9 (d, ³ J _PC = 6.3 Hz, cis), 23.1, 18.7, 16.2 (d, ³ J _pc = 6.5 Hz), 13.4; 2g: ¹H NMR (300 MHz): δ = 0.84 (t, 3 H, J _HH = 7.5 Hz), 1.27 (t, 6 H, J _HH = 6.6 Hz), 1.29-1.99 (overlap, 10 H), 2.42 (m, 2 H), 2.50 (broad s, 1 H), 3.90-4.01 (m, 4 H), 5.47-5.51 (d, 1 H, J _HH = 9.9 Hz), 5.69-5.74 (d, 1 H, ² J _PH = 17.1 Hz), 5.88 (m, 1 H); ³¹P NMR (300 MHz): δ = 19.31; ¹³C NMR (75.5 MHz): δ = 170.96 (d, ² J _pc = 6.6 Hz), 131.3, 130.5, 111.0 (d, ¹ J _pc = 189.4 Hz), 74.3 (d, ³ J _pc" = 22.7 Hz, trans), 61.1 (d, ² J _pc = 5.7 Hz), 35.5, 33.2, 30.1 (d, ³ J _PC = 7.1 Hz, cis), 24.7, 23.4, 18.5, 16.2 (d, ³ J _pc = 6.5 Hz), 13.7; 2h: ¹H NMR (300 MHz): δ = 0.88 (t, 3 H, J _HH = 6.8 Hz), 1.00-1.07 (t, 6 H, J _HH = 6.9 Hz), 1.24 (s, 3 H), 1.25-1.50 (overlap, 6 H), 3.40(s, 1 H), 3.53-3.74 (m, 4 H), 6.19-6.25 (d, 1 H, ² J _PH = 18.3 Hz), 7.10-7.26 (m, 5 H); ³¹P NMR (300 MHz): δ = 17.99; ¹³C NMR (75.5 MHz): δ = 168.2 (d, ² J _pc = 3.8 Hz), 138.0 (d, ³ J _pc = 8.3 Hz, cis), 128.7, 127.6, 127.5, 114.6 (d, ¹ J _pc = 192.3 Hz), 76.0 (d, ³ J _pc" = 18.9 Hz, trans), 61.3 (d, ² J _pc = 6.0 Hz), 39.7, 27.6, 25.9, 23.1, 16.3 (d, ³ J _pc = 6.6 Hz); 2i: ¹H NMR (300 MHz): δ = 1.02 (t, 6 H, J _HH = 6.7 Hz), 1.64 (s, 3 H), 3.53-3.74 (m, 4 H), 4.12 (broad s, 1 H), 6.40-6.46 (d, 1 H, ² J _PH = 18.3 Hz), 7.10-7.36 (m, 10 H); ³¹P NMR (300 MHz): δ = 17.60; ¹³C NMR (75.5 MHz): δ = 166.8 (d, ² J _pc = 4.30 Hz), 137.2 (d, ³ J _pc = 8.0 Hz, cis), 129.3, 128.2, 127.1, 114.4 (d, ¹ J _pc = 192.0 Hz), 77.5 (d, ³ J _pc" = 19.2 Hz, trans), 61.4 (d, ² J _pc = 6.0 Hz), 27.6, 16.3 (d, ³ J _pc = 6.7 Hz); 2j: ¹H NMR (300 MHz): δ = 0.98 (t, 6 H, J _HH = 6.8 Hz), 1.22 (s, 6 H), 3.53-3.74 (m, 4 H), 4.12 (s, 1 H), 6.22-6.30 (d, 1 H, ² J _PH = 18.3 Hz), 7.10-7.26 (m, 5 H); ³¹P NMR (300 MHz): δ = 18.19; ¹³C NMR (75.5 MHz): δ = 169.0 (d, ² J _pc = 4.08 Hz), 137.7 (d, ³ J _pc = 8.3 Hz, cis), 128.4, 127.2, 127.1, 113.1 (d, ¹ J _pc = 192.9 Hz), 73.4 (d, ³ J _pc" = 19.2 Hz, trans), 61.3 (d, ² J _pc = 6.0 Hz), 28.4, 16.3 (d, ³ J _pc = 6.6 Hz); 2k: ¹H NMR (300 MHz): δ = 1.22 (t, 6 H, J _HH = 6.7 Hz), 1.81 (m, 4 H), 2.59 (m, 2 H), 3.38 (s, 1 H), 3.46 (t, 2 H), 3.69 (s, 3 H), 3.84-3.95 (m, 4 H), 5.67-5.75 (d, 1 H, ² J _PH = 16.2 Hz), 6.75-7.28 (m, 9 H); ³¹P NMR (300 MHz): δ = 18.35; ¹³C NMR (75.5 MHz): δ = 167.2 (d, ² J _pc = 6.9 Hz), 135.7, 130.5, 127.6, 127.3, 126.3, 111.3 (d, ¹ J _pc = 186.6 Hz), 78.8 (d, ³ J _pc" = 21.2 Hz, trans), 61.2 (d, ² J _pc = 6.0 Hz), 54.9, 45.2, 33.1, 28.4 (d, ³ J _PC = 6.6 Hz), 16.0 (d, ³ J _pc = 6.5 Hz); 2l: ¹H NMR (300 MHz): δ = 1.20 (t, 6 H, J _HH = 6.8 Hz), 1.29 (s, 6 H), 2.00 (m, 2 H), 2.53 (m, 2 H), 3.50 (broad s, 1 H), 3.51 (t, 2 H, J _HH = 5.4 Hz), 3.90-4.11 (m, 4 H), 5.74-5.80 (d, 1 H, ² J _PH = 17.1 Hz); ³¹P NMR (300 MHz): δ = 19.14; ¹³C NMR (75.5 MHz): δ = 170.9 (d, ² J _pc = 6.3 Hz), 109.8 (d, ¹ J _pc = 189.4 Hz), 74.1 (d, ³ J _pc" = 21.2 Hz, trans), 61.3 (d, ² J _pc = 6.1 Hz), 45.2, 33.4, 29.1, 27.9 (d, ³ J _PC = 7.2 Hz), 16.2 (d, ³ J _pc = 6.6 Hz); 2m: ¹H NMR (300 MHz): δ = 0.75 (m, 1 H), 1.20 (t, 6 H), 1.37 (m, 4 H), 1.76 (m, 2 H), 2.28 (t, 2 H), 3.30 (t, 2 H), 3.38 (broad s, 1 H), 3.84-3.95 (m, 4 H), 6.00-6.06 (d, 1 H, ² J _PH = 17.1 Hz), 7.14-7.42 (m, 5 H); ³¹P NMR (300 MHz): δ = 18.78; ¹³C NMR (75.5 MHz): δ = 167.1 (d, ² J _pc = 6.9 Hz), 142.6, 126.8, 126.3, 125.6, 110.1 (d, ¹ J _pc = 187.4 Hz), 75.9 (d, ³ J _pc" = 32.3 Hz, trans), 61.2 (d, ² J _pc = 6.1 Hz), 44.2, 32.2, 27.5 (d, ³ J _PC = 6.8 Hz), 17.0, 16.2 (d, ³ J _pc = 6.5 Hz); 2n: ¹H NMR (300 MHz): δ = 1.20 (t, 6 H, J _HH = 6.8 Hz), 1.61 (m, 2 H), 2.55 (m, 2 H), 3.31 (t, 2 H), 3.84-3.95 (m, 4 H), 4.17 (s, 1 H), 5.57-5.63 (d, 1 H, ² J _PH = 18.3 Hz), 7.3 (broad, 10 H); ³¹P NMR (300 MHz): δ = 17.80; ¹³C NMR (75.5 MHz): δ = 167.8 (d, ² J _pc = 7.5 Hz), 143.9, 127.8, 127.3, 126.6, 115.1 (d, ¹ J _pc = 186.7 Hz), 84.1 (d, ³ J _pc" = 23.3 Hz, trans), 61.2 (d, ² J _pc = 6.0 Hz), 45.2, 33.2, 29.3 (d, ³ J _PC = 6.9 Hz, cis), 16.2 (d, ³ J _pc = 6.4 Hz); 4: ¹H NMR (300 MHz): δ = 0.91 (overlap, 6 H), 1.27 (t, 6 H, J _HH = 6.7 Hz), 1.23 (s, 3 H), 1.22-1.80 (overlap, 8 H), 2.20 (m, 2 H), 2.70 (m, 2 H), 4.00-4.12 (m, 4 H), 5.68-5.72 (d, 1 H, ² J _PH = 13.8 Hz); ³¹P NMR (300 MHz): δ = 18.3; ¹³C NMR (75.5 MHz): δ = 172.6 (d, ² J _pc = 8.1 Hz), 112.3 (d, ¹ J _pc = 189.2 Hz), 76.5 (d, ³ J _pc" = 20.9 Hz, trans), 61.3 (d, ² J _pc = 6.0 Hz), 41.0, 33.0, 30.6 (d, ³ J _PC = 7.1 Hz), 28.0, 25.9, 23.7, 23.0, 16.4 (d, ³ J _pc = 6.6 Hz), 14.3, 13.9.