The Reactions of Phosphonic Acid Esters with Acid Chlorides. A Very Mild Hydrolytic Route

Abstract

The distillate, b.p. 75-80°( 0.3 mm.), 0.19 g., was analyzed by n.m.r. spectroscopy, which indicated 46.7 ± 4.1% of IV and 53.3 ± 4.1 % of III.(ti).-To 3.5 g. of iodine and 6.8 g. of potassium iodide in 60 ml. of water was added the sodium salt of XII (from 1.0 g. of XII and 1.73 g. of sodium bicarbonate) in 30 ml. of water. A heavy oil which separated was extracted with ether. The extracts were washed with sodium bisulfite solution until colorless, sodium bicarbonate solution, and water and dried. Removal of ether furnished 1.5 g. (82%) of an undistillable (dec.) noncrystallizable oil which represented the iodolactone (infrared spectrum). Hydrogenolysis with W-2 Raney nickel in ethanol and triethylamine was only partially successful, whereas hydrogenolysis with nickel and sodium bicarbonate completed removal of iodine. Infrared and n.m.r. spectra of the product indicated that it was composed of III and IV; n.m.r. analysis indicated the presence of 54.2 ± 2% III and 45.8 ± 2% IV.1-Cycloheptene-l-acetic Acid (XV) and Cycloheptane-1 '"-acetic Acid (XVI).-Dehydration of the hydroxy ester, obtained in 67% yield by the Reformatsky reaction of cycloheptanone and ethyl bromoacetate, with thionyl chloride furnished a mixture of ,ßand d.v-unsaturated ester; b.p. 71-82°( 1.5 mm.); yield, 51%; infrared bands at 1740 (ester), 1715 (conjugated ester), and 1635 cm.-1 (conjugated double bond) which contained 60% of the /3,7-unsaturated compound (v.p.c.). Hydrolysis gave a mixture of the title compounds, b.p. 110-114 (18 mm.), 74% yield, which was used directly for the following reactions.(A) .-Cyclization of the mixture with dilute sulfuric acidacetic acid for 11 hr. and work-up in the usual manner gave 57% of a neutral fraction, b.p. 68-73°( 0.15 mm.), whose n.m.r. analysis indicated that it was composed of 73.7 ± 1.6% cislactone III and 26 ± 1.6% ¿rans-lactone IV.(B) .-Iodolactonization of the mixed acids yielded 26% of a noncrystallizable oil which decomposed on attempted distillation but was a mixture of iodolactones (infrared spectrum). W-2 Raney nickel hydrogenolysis in ethanol with sodium bicarbonate gave a mixture of lactones III and IV, b.p. 88-92°( 0.6 mm.),

Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors

“…It began with the acylation of the ammonium hydrochloride salt of tyrosine O-methyl ester a with appropriate acyl chlorides followed by etherification of the free phenol with appropriate mesylates to afford the fully protected tyrosine c. Next, was the base mediated addition onto the methyl ester with the lithium anion of dimethyl methylphosphonate to achieve β-keto phosphonate dimethyl ester d. A bromotrimethylsaline mediated deprotection of the ester ensued to afford the β-keto phosphonate g. 27 Sodium borohydride reduction of d proceeded to give two possible diastereometic β-hydroxy phosphonate dimethyl esters which were separated by column chromatography. The stereochemistry determination is ongoing.…”

Synthesis of a Number of 3‐Alkyl Substituted Pyrrole Monomers

“…Gauvry 28 reported the usefulness of boron tribromide for the conversion of dialkyl phosphonates into the corresponding phosphonic acids via methanolysis. Rabinowitz, 29 McKenna 30 and others 31,32 described the conversion of dialkyl phosphonates with chloro-or bromo-trimethylsilanes into the silyl esters, thus making the corresponding phosphonic acids readily available via hydrolysis with water. After investigating the methods, we chose bromo trimethylsilane to react with compound 7 in organic solvent at 0 ℃, and the desired phosphonic acids 8 were obtained by hydrolysis of the silyl esters.…”

Synthesis of vinyl pyrophosphonate analogues of farnesyl pyrophosphate: New potential inhibitors of farnesyl protein transferase

“…phosphonates were converted to the corresponding phosphonic acids 6a, 11b, and 11c by standard treatment with bromotrimethylsilane and pyridine in CH 2 Cl 2 (84, 70, and 85% yields, respectively) [16]. SCHEME 3 Synthesis procedure of pyrophosphonates from aldehydes.…”