Diethyl N-Benzylideneaminomethylphosphonate

[50917-73-2]  · C12H18NO3P  · Diethyl N-Benzylideneaminomethylphosphonate  · (MW 255.25)

(reagent for preparation of b-lactams1 and a-aminophosphonic acids;3 agent for quaternary carbon formation4)

Physical Data: bp 145-149 °C/0.05 mmHg.

Solubility: sol most organic solvents.

Form Supplied in: light yellow oil.

Analysis of Reagent Purity: readily ascertained by NMR.

Preparative Methods: 1,3,5-tribenzylhexahydro-s-triazine is reacted with Diethyl Phosphonite at 100 °C to yield N-benzylaminomethylphosphonate. N-Debenzylation with H2-Palladium on Carbon and subsequent Schiff base formation with PhCHO affords the title reagent in virtually quantitative yield.1a Alternatively, the reagent may be prepared from the N,N-bis(TMS)aminomethylphosphonate and PhCHO in the presence of a catalytic amount of Trimethylsilyl Trifluoromethanesulfonate.2 A different approach to the aminomethylphosphonate intermediate starts with conversion of N-hydroxymethylphthalimide to the N-bromomethyl compound followed by an Arbuzov reaction with Triethyl Phosphite. Treatment of the resultant phthalimidomethylphosphonate with Hydrazine yields diethyl aminomethylphosphonate which is then subjected to imine formation with PhCHO.4a

Purification: distillation at reduced pressure.

Handling, Storage, and Precautions: stable to air and moisture. Conveniently stored under N2 at ambient temperature or lower. Shelf life undetermined.


Diethyl N-benzylidineaminomethylphosphonate (1) has served as a starting point in three approaches to b-lactam antibiotics. Deprotonation and acylation (eq 1) yields phosphonoacetate (2) which is utilized in the preparation of a-thioformamido(diethylphosphono)acetates (3). These serve as key intermediates for further elaboration to 6-H cephalosporins (4) (eq 2).1a An attempt to extend this approach to carbapenem ring systems was unsuccessful due to the instability of later intermediates.1b

An example of a novel synthesis of substituted b-lactams was demonstrated by photolytic decomposition of chromium carbene complex (5) in the presence of (1) to afford the trisubstituted lactam (6) with a high degree of stereoselectivity and in 90% yield (eq 3).1c

a-Aminophosphonic Acids.

Alkylation of the anion prepared by deprotonation of (1) provides, after hydrogenolysis of the benzylidene group and hydrolysis of the phosphonate esters, convenient access to a-aminophosphonic acids (7) (eq 4).3a Yields of alkylated product are generally quite high (>80%) and suitable electrophiles include primary, allylic, and benzylic halides as well as a-BrCH2CO2Et and halomethylpyridines.3b,3c The 1-amino-2-arylethylphosphonic acids can be viewed as phosphorus-based phenylalanine analogs.

Quaternary Carbon Formation.

Probably the most innovative use of (1) has been in the preparation of quaternary carbon centers via geminal acylation-alkylation at a carbonyl center.4a,4b Lithiation of (1) followed by condensation with a carbonyl substrate affords, upon warming, the azadiene (8) (eq 5). Regioselective addition of n-Butyllithium to (8) generates a metalloenamine which, on alkylation followed by hydrolysis of the resultant imine, gives products of general structure (9) (eq 6). The entire sequence may be conveniently carried out in a single reaction vessel without isolation of intermediates with moderate to high overall yields. Judicious choice of electrophile in the alkylation may introduce functionality suitable for subsequent elaboration to 4,4-disubstituted cyclopentenones or 4,4-disubstituted cyclohexenones.4b This strategy has been a key feature in the syntheses of mesembrine and various Amaryllidaceae alkaloids.4c-e


The anion of (1) undergoes Michael addition to ethylidenebisphosphonate (10), affording functionalized gem-bisphosphonates (11) (eq 7).5a

Conjugate addition of the anion of (1) to acrylates affords D1-pyrrolines by intramolecular cyclization via nucleophilic addition of the resultant enolate to the imine moiety (eq 8).5b The reaction is regioselective and stereospecific and the product distribution depends on reaction conditions and the steric nature of the substrate.

1. (a) Ratcliffe, R. W.; Christensen, B. G. TL 1973, 4645. (b) Herdewijn, P.; Claes, P. J.; Vanderhaeghe, H. NJC 1983, 7, 691. (c) Hegedus, L. S.; Schultze, L. M.; Toro, J.; Yijun, C. T 1985, 41, 5833.
2. Morimoto, T.; Sekiya, M CL 1985, 1371.
3. (a) Dehnel, A.; Lavielle, G. BSF(2) 1978, 95. (b) Maier, L. PS 1990, 53, 43. (c) Maier, L.; Diel, P. J. PS 1991, 62, 15.
4. (a) Davidsen, S. K.; Phillips, G. W.; Martin, S. F. OS 1987, 65, 119. (b) Martin, S. F.; Phillips, G. W.; Puckette, T. A.; Colapret, J. A. JACS 1980, 102, 5866. (c) Martin, S. F.; Puckette, T. A.; Colapret, J. A. JOC 1979, 44, 3391. (d) Martin, S. F.; Davidsen, S. K.; Puckette, T. A. JOC 1987, 52, 1962. (e) Martin, S. F.; Campbell, C. L. JOC 1988, 53, 3184.
5. (a) Sturtz, G; Guervenou, J. S 1991, 661. (b) Dehnel, A.; Kanabus-Kaminska, J. M.; Lavielle, G. CJC 1988, 66, 310.

Carlton L. Campbell

DuPont Agricultural Products, Newark, DE, USA

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