Diethyl b-(Cyclohexylimino)ethylphosphonate

[20061-84-1]  · C12H24NO3P  · Diethyl b-(Cyclohexylimino)ethylphosphonate  · (MW 261.30)

(reagent for formylalkenation at carbonyl centers1)

Physical Data: mp 58-61 °C; bp 151-152 °C/0.04 mmHg.

Solubility: sol most organic solvents.

Form Supplied in: crystalline solid.

Analysis of Reagent Purity: readily ascertained by NMR.

Preparative Methods: (EtO)2CHCH2P(O)(OEt)2 is prepared by reaction of Triethyl Phosphite with BrCH2CH(OEt)2. Acetal hydrolysis affords diethyl formylmethylphosphonate, which is combined with an equimolar quantity of cyclohexylamine in MeOH. The product is isolated by fractional distillation in the presence of K2CO3, to prevent acid-catalyzed dimerization, and at reduced pressure, followed by crystallization from cold pentane.1b Yields are 65-75%. A modified procedure for imine formation uses MeCN as solvent with isolation of product from Et2O at -40 °C to afford white crystalline material in 70% yield.3

Purification: distillation at reduced pressure. Crystallization from pentane at 0 °C.

Handling, Storage, and Precautions: crystalline material is stable for several months when stored under anhydrous conditions at 0 °C.

Homologation Reactions.

Diethyl b-(cyclohexylimino)ethylphosphonate (1) is an excellent reagent for the conversion of aldehydes and ketones to the corresponding a,b-unsaturated aldehydes.1a,1c,1d Anion generation is accomplished by treatment of (1) with 1 equiv of a strong base and a solution of the carbonyl substrate is added slowly to maintain a temperature <=5 °C. Warming to ambient temperature yields an unsaturated aldimine which is promptly hydrolyzed under biphasic conditions (aqueous Oxalic Acid or a pH 4 acetate buffer solution), thereby affording an a,b-unsaturated aldehyde of general structure (2) (eq 1).

Attributes of this Horner-Wadsworth-Emmons reaction include (1) its simplicity in operation, (2) the generally high yields of products, (3) the fact that Ph3P=CHCHO and (EtO)2P(O)CH2CH(OEt)2 do not react with ketones, and (4) the stereoselectivity for the formation of the (E)-alkene. A limitation is the slow reaction of the anion of (1) with an ester group or a free hydroxy group. Consequently, these functionalities should be masked if the substrate carbonyl is slow to react.

During spectral studies on all-trans-geranylgeraniol, (1) was utilized in the preparation of the 4-normethyl analog by reaction with trienal (3) to provide trans-enal (4) in 33% yield (eq 2).2

Homologation of the cyclopropanecarbaldehyde (5) yielded enal (6) in 68% yield (eq 3).3 Conversion of (6) to the corresponding tosylhydrazone and subsequent pyrolysis provided a carbene-based approach to C12H12 species.

Also described was the preparation of deuterated (1) (eq 4). Spectroscopic studies estimated 90% deuteration at the carbon adjacent to phosphorus in a distribution of 67% d2, 28% d1, and 5% d0.

Synthetic investigations towards preparation of stable thromboxane A2 analogs saw attempts at homologation of [3.3.1] and [3.2.1] bicyclic ketones (eqs 5 and 6).4 While reaction of (1) with bicyclo[3.3.1]nonanone (8) yields the desired product only in low yield, the corresponding bicyclo[3.2.1]octanone (10) affords product in 40% yield.

Application to the two-carbon extension of heteroaromatic aldehydes has met with limited success. Condensation of the anion of (1) with 2-thiophenecarbaldehyde affords 3-(2-thienyl)propenal in 80% yield (eq 7).5 However, treatment of 2-methyl-3-(pyrrol-2-yl)propenal (14) with the phosphonate anion produces the homologous dienal (15) in low yield (eq 8).6

The facile synthesis of dienes was demonstrated in an approach to the galanthan alkaloid ring system.7 Condensation of (1) with 2-carboxybenzaldehyde provides the substituted cinnamaldehyde (17) in 50% yield after esterification (eq 9). Peterson alkenation provides diene (18); this can be elaborated to triene (19) (eq 10) which undergoes intramolecular cycloaddition upon heating.


1. (a) Nagata, W.; Hayase, Y. TL 1968, 4359. (b) Nagata, W.; Wakabayashi, T.; Hayase, Y. OS 1973, 53, 44. (c) Nagata, W.; Wakabayashi, T.; Hayase, Y. OS 1973, 53, 104. (d) Nagata, W.; Hayase, Y. JCS(C) 1969, 460.
2. Coates, R. M.; Ley, D. A.; Cavender, P. L. JOC 1978, 43, 4915.
3. Farnum, D. G.; Ghandi, M.; Raghu, S.; Reitz, T. JOC 1982, 47, 2598.
4. Hewson, A. T.; Evans, E. H.; March, L. A.; Nowell, I. W.; Wadsworth, A. H. JCS(P1) 1987, 137.
5. Godefroi, E. F.; Janssen, C. G. M.; van Lier, P. M.; Buck, H. M. JOC 1979, 44, 4199.
6. Toube, T. P.; Badar, Y.; Chopra, A. K.; Dias, H. W.; Hursthouse, M. B.; Khokar, A. R.; Ito, M.; Weedon, B. C. L. JCS(P1) 1977, 1372.
7. Stork, G.; Morgans, D. J., Jr. TL 1979, 1959.

Carlton L. Campbell

DuPont Agricultural Products, Newark, DE, USA



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.