Synthesis of Substituted Cyclopropylphosphonates by Michael Induced Ring Closure (MIRC) Reactions

Abstract

A variety of cyclopropylphosphonates were prepared in moderate to good yields by Michael Induced Ring Closure of trialkyl phosphites with the corresponding β-bromoalkylidene cyanoacetates and malonates.

Key words

Michael additions - ring closure - phosphorylations - cyclizations - carbocycles

References

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General Procedure for the Bromination of Alkylidenemalonates or Cyanides. A solution of 10 mmol of Knoevenagel adduct 2, 13 mmol of NBS and 10 mg of BPO in 5 mL of CCl₄ was refluxed under UV irradiation for approximately 2 hours. The end of the reaction was monitored carefully by ¹H NMR. Evaporation of the solvent gave almost pure bromoalkylidene malonates or cyanides 4 in good yields.

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Spectral data of 4k: ¹H NMR [CDCl₃, δ (ppm)]: 1.06 (6 H, t, J = 7.3 Hz, Me₂), 2.30 (4 H, m, CH₂), 3.91 (3 H, s, OMe), 7.74 (1 H, s, CH=). ¹³C NMR [CDCl₃, δ(ppm)]: 10.31 (Me), 34.06 (CΗ₂); 42.64 (CBr), 53.71 (OMe); 106.37 (=C); 113.31 (CN); 161.83 (CH=); 162.74 (COOMe). IR (cm^-1): 2231 (CN), 1740 (C=O), 1621 (C=C). MS (m/z) (%): 234 (0.5); 182(12); 181(100); 148(60); 122(12); 121(29); 107(14); 94(14); 84(13); 49(12). Anal. Calcd. for C₁₀H₁₄BrNO₂: C 46.17; H 5.42; N 5.38. Found: C 46.35; H 5.53; N 5.02.

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General Procedure for the Preparation of the Cyclopropylphosphonates. A mixture of 2.5 mmol bromoalkylidenemalonate or -cyanide 4 and 3 mmol of trialkyl phosphite was stirred under nitrogen atmosphere for the appropriate time (Table [1] ). The volatile compounds formed and the excess of phosphite were then removed by evaporation under vacuum and the mixture was purified by flash chromatography or by distillation.

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Spectral data of 7a: ¹H NMR [CDCl₃, δ (ppm)]: 1.24 (3 H, d, J= 1.3 Hz, Me); 1.58 (3 H, s, Me); 1.86 (1 H, d, J = 1.9 Hz, CH-P); 3.76 (3 H, s, OMe); 3.77 (3 H, d, J =1.9 Hz, OMe); 3.78 (3 H, d, J = 1.6 Hz, OMe); 3.81 (3 H, s, OMe). ¹³C NMR [CDCl₃, δ(ppm), J _P-C(Hz)]: 19.53 (Me, 5); 22.21 (Me, 5.1); 27.65 (CHP, 188); 30.38 (CMe₂, 3.6); 43.56 [C(COOMe]₂, 3.6); 52.15 (OMe, 6.1); 52.65 (OMe); 52.99 (OMe, 4.9); 53.03 (OMe); 166.64 (COOMe, 123.3); 167.92 (COOMe). ³¹P NMR referenced to H₃PO₄ [CDCl₃, δ(ppm)]: 25.00. IR (cm^-1): 1256 (P=O), 1733 (C=O). MS (m/z) (%): 294 (M⁺, 0.5); 235(12); 231(20); 229(30); 220(8); 203(21); 186(9); 185(86); 153(100); 125(12); 110(14); 109(18); 93(11); 79(12). Anal. Calcd. for C₁₁H₁₉O₇P: C 44.90; H 6.51.
Found: C 44.65; H 6.63.

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For details of Reaction rates see Table 2.

Table 2 Kinetic Data of the Reactions of the electrophilic Allyl Halides 4 with Trivalent Nucleophiles to 7 at 35 °C.

Entry	X	K 1/mol.s	Rel. K
a	Br	95.8 × 10-6	1.00
a′	Cla	57.6 × 10-6	0.60
b	Br	6.6 × 10-3	68.89
c	Br	33.2 × 10-3	346.56
d	Br	28.9 × 10-6	0.30
e	Br	8.2 × 10-6	0.19
f	Br	14.6 × 10-6	0.15
g	Br	176.1 × 10-6	2.88
h	Br	139.0 × 10-6	1.45
I	Br	16.1 × 10-6	0.17
a The chloro derivative was prepared according to the literature procedure by condensation of the chloroaldehyde and the malonate using titanium (IV)chloride and pyridine. [24]