Synthesis and Characterization of New Cα,α-Disubstituted (Diarylaminomethyl)-phosphonates

Abstract

A convenient and efficient three-step procedure for the preparation of N -protected or unprotected C α,α -disubstituted (diarylaminomethyl)phosphonates 1 is reported. This method allows diversification of the substituents on the carbon in the α -position to the phosphorus, as well as the protective group on the amine and the phosphonate ester group.Over the past three decades, several research projects have been directed toward the synthesis of α -aminophosphonic acids 2 and their esters, analogs of amino acids, to find new biologically active molecules. These compounds did indeed show enzyme inhibition, antibacterial, antitumoral, herbicidal and fungicidal activities. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] Recently, C. Toniolo 16 reported "the explosive interest in the study of C α,α -disubstituted amino acids" 3 . These compounds ' peptaibols ' are used as proteolytic enzyme inhibitors and exhibit several attractive biological activities, for example, against epilepsy.For these reasons, we decided to develop a convenient and efficient method for the preparation of C α,α -disubstituted (aminomethyl)phosphonates 1 , another class of new less well-known compounds.The procedure used for the synthesis of 1 is a generalization of the Kabachnik-Fields method described in the literature. 17 This method, in three steps, leads to 1 with good yields (Scheme).(Ph-and Ar-) are different, two isomers E and Z can be characterized by NMR and GC/MS; for example, with compound 4b (R' = 2-tolyl) the ratio Z / E is 40:60. The E isomer is the major product, likely for steric reasons.The second step is the protection of the amine function with different groups leading to compounds 5 . These protective groups can be released from C α,α -disubstituted (aminomethyl)phosphonates by basic and/or acidic conditions. This could be crucial for the biological activity of the C α,α -disubstituted (aminomethyl)phosphonates and in particular for the stability of these compounds in biological media. Further, the benzyloxycarbonyl protective group can be specifically cleaved by hydrogenolysis, for synthetic purpose. The yields obtained for this protection step are between 41 and 95%.The last step of the synthesis is an extension of the reactivity of phosphonate anions on imino electrophiles. This step gives 1 with good yields, between 35 and 96%. The N -protected C α,α -disubstituted (aminomethyl)phosphonates have been characterized unambiguously by IR, 31 P, 1 H, 13 C NMR spectra, elemental analyses and mass spectrometry.The results are presented in Table 1. One of the compounds 1g , characteristic of this (aminomethyl)phosphonate family, has been analyzed by X-ray diffraction (Figure). A dimer, i.e. structure, induced by intermolecular SchemeThe first step is the preparation of the imines 4 , by reacting arylmagnesium bromide with benzonitrile. The yields obtained are between 60 and 98%. When the substituents Figure. Dimer structure of compound 1gDownloaded by: University of Texas at San Antonio. Copyrighted material.

Application of Chiral Sulfides to Catalytic Asymmetric Aziridination and Cyclopropanation with In Situ Generation of the Diazo Compound

“…This study of activating groups on the nitrogen atom revealed that sulfonyl‐ or TcBoc‐activated imines provided the best combination of yield, enantioselectivity, and diastereoselectivity to date in a practical, user‐friendly catalytic process 10. These groups were therefore tested with a range of imines derived from aromatic, heteroaromatic, unsaturated, and even aliphatic aldehydes and ketones11 (Table 2). As sulfonyl‐substituted imines were easier to prepare than TcBoc‐substituted ones, most studies were conducted with the former group.…”

Reactions of an Arylrhodium Complex with Aldehydes, Imines, Ketones, and Alkynones. New Classes of Insertion Reactions

“…The aldimines ( p -tol)CHN(C 6 H 4 - p -CO 2 Me) ( 3a-Tol ), (Ph)CHN(C 6 H 4 - p -CO 2 Me) ( 3a-Ph ), (Ph)CHNPh ( 3b ), and ( p -tol)CHN(C 6 H 4 - p -OMe) ( 3c ) were prepared using procedures reported for the preparation of similar compounds . [(DPPE)Rh(μ-Cl)] 2 , 4-methylbenzophenone imine, 4,4‘-dimethylbenzophenone imine, solid p -tolyllithium, 20b , 21b , and 25 129 were prepared according to literature procedures. Compound 18b 130 was synthesized by PCC oxidation of 20b in CH 2 Cl 2 .…”

3,5,5-Triphenyl-4,5-dihydro-1,2,4-oxadiazole

“…A solution of triethylamine (0.01 mol) in diethyl ether (20 ml) was added to a stirred solution of freshly prepared benzeneoximoyl chloride, obtained from 0.01 mol of a-benzaldoxime (Baruah et al, 1988) and dissolved in diethyl ether (50 ml) at a temperature below 273 K. This was followed by the addition of a benzophenone imine (0.01 mol) (Cristau et al, 1998) solution in diethyl ether (30 ml). The resulting mixture was stirred for 24 h without cooling, extracted with water (30 ml), 15% hydrochloric acid (3 x 30 ml), and again with water.…”