Diethyl Morpholinomethylphosphonate

[27353-29-3]  · C9H20NO4P  · Diethyl Morpholinomethylphosphonate  · (MW 237.24)

(for spiroannulation at carbonyl centers;2 formyl anion equivalent3)

Physical Data: bp 137 °C/3 mmHg.

Solubility: sol most organic solvents.

Analysis of Reagent Purity: readily ascertained by NMR.

Preparative Method: by the addition of Formaldehyde to a stirred mixture of equimolar quantities of Morpholine and Diethyl Phosphonite. Vacuum distillation affords pure product in 92% yield.1

Purification: distillation at reduced pressure.

Amino Phosphonic Acid Esters.

During investigations on the synthesis of substituted a-amino phosphonic esters, the title compound (3) was obtained in high yield, exemplifying the generality of the synthetic route presented for the preparation of a-aminophosphonates (eq 1).1

Quaternary Carbon Formation.

The utility of (3) for quaternization by geminal alkylation at a carbonyl center has been demonstrated.2 Anion formation and Horner-Emmons reaction with a ketone afforded the morpholine enamine of the homologous aldehyde (eq 2), which was shown to undergo Michael addition to methyl vinyl ketone. Subsequent acid hydrolysis of the resultant imine was accompanied by intramolecular aldol condensation and dehydration, thereby resulting in the formation of 4,4-disubstituted 2-cyclohexenones (eq 3).

This procedure was shown to be applicable to acyclic, cyclic, aromatic, and a,b-unsaturated ketones. Use of cyclic ketones illustrated the facile production of spirocyclic ring systems. For substrates possessing conformational constraints, a reasonable degree of stereoselectivity was observed (eq 4).

Enamine Synthesis.

Other investigations on enamine synthesis using reagent (3) provided an interesting but conflicting result.3 Addition of the phosphonate anion of (3) to a carbonyl substrate resulted only in isolation of the a-morpholino-b-hydroxyphosphonate addition product (10) (eq 5). Elimination to form the enamine could not be induced even upon treatment of (10) with KH. On this basis the authors suggested that the mechanism of the reaction may not be as straightforward as originally thought.


An attempt at using the morpholinophosphonate in the preparation of sulfides by displacement of the diethyl phosphinate moiety with a thiolate anion resulted instead in the mono-dealkylation of the reagent (eq 6).4

Oxidation of (3) with excess mercury(II) ion afforded the corresponding lactam but only in 7% yield (eq 7).5 Based on literature precedent and experimental investigations, the transformation was proposed to occur via an intermediate iminium ion with internal participation of the phosphonate oxygen.5

1. Fields, E. K. JACS 1952, 74, 1528.
2. Martin, S. F. JOC 1976, 41, 3337.
3. van der Gen, A.; Broekhof, N. L. J. M. RTC 1984, 103, 305.
4. Savignac, P.; Lavielle, G. BSF(2) 1974, 1506.
5. Möhrle, H.: Vetter, W. ZN(B) 1988, 43, 1662.

Carlton L. Campbell

DuPont Agricultural Products, Newark, DE, USA

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