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

Christian V. Stevens; Gino Van Heecke; Carmen Barbero; Krystyna Patora; Norbert De Kimpe; Roland Verhé

doi:10.1055/s-2002-32587

LETTER

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

Christian V. Stevens*, Gino Van Heecke, Carmen Barbero, Krystyna Patora, Norbert De Kimpe, Roland Verhé
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological, Sciences, Ghent University, Coupure links 653,9000 Gent, Belgium
Fax: +32(9)2646243; e-Mail: Chris.Stevens@rug.ac.be;

Abstract

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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

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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.

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.

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.

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.

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.

<TD VALIGN="TOP"> Entry </TD><TD VALIGN="TOP"> X </TD><TD VALIGN="TOP"> K 1/mol.s </TD><TD VALIGN="TOP"> Rel. K </TD><TD VALIGN="TOP"> a </TD><TD VALIGN="TOP"> Br </TD><TD VALIGN="TOP"> 95.8 × 10^-6 </TD><TD VALIGN="TOP"> 1.00 </TD><TD VALIGN="TOP"> a′ </TD><TD VALIGN="TOP"> Cl^a </TD><TD VALIGN="TOP"> 57.6 × 10^-6 </TD><TD VALIGN="TOP"> 0.60 </TD><TD VALIGN="TOP"> b </TD><TD VALIGN="TOP"> Br </TD><TD VALIGN="TOP"> 6.6 × 10^-3 </TD><TD VALIGN="TOP"> 68.89 </TD><TD VALIGN="TOP"> c </TD><TD VALIGN="TOP"> Br </TD><TD VALIGN="TOP"> 33.2 × 10^-3 </TD><TD VALIGN="TOP"> 346.56 </TD><TD VALIGN="TOP"> d </TD><TD VALIGN="TOP"> Br </TD><TD VALIGN="TOP"> 28.9 × 10^-6 </TD><TD VALIGN="TOP"> 0.30 </TD><TD VALIGN="TOP"> e </TD><TD VALIGN="TOP"> Br </TD><TD VALIGN="TOP"> 8.2 × 10^-6 </TD><TD VALIGN="TOP"> 0.19 </TD><TD VALIGN="TOP"> f </TD><TD VALIGN="TOP"> Br </TD><TD VALIGN="TOP"> 14.6 × 10^-6 </TD><TD VALIGN="TOP"> 0.15 </TD><TD VALIGN="TOP"> g </TD><TD VALIGN="TOP"> Br </TD><TD VALIGN="TOP"> 176.1 × 10^-6 </TD><TD VALIGN="TOP"> 2.88 </TD><TD VALIGN="TOP"> h </TD><TD VALIGN="TOP"> Br </TD><TD VALIGN="TOP"> 139.0 × 10^-6 </TD><TD VALIGN="TOP"> 1.45 </TD><TD VALIGN="TOP"> I </TD><TD VALIGN="TOP"> Br </TD><TD VALIGN="TOP"> 16.1 × 10^-6 </TD><TD VALIGN="TOP"> 0.17 </TD><TD COLSPAN="20">

</TD></TR><TR><TD VALIGN="TOP" COLSPAN="4"> ^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]
</TD>