N-Morpholinomethyldiphenylphosphine Oxide1

[20684-76-8]  · C17H20NO2P  · N-Morpholinomethyldiphenylphosphine Oxide  · (MW 301.35)

(Horner-Wittig reagent useful for the preparation of homologous aldehydes,2 their morpholino enamines,2a,b,3 and a-morpholinomethyl ketones4)

Physical Data: mp 159 °C.

Solubility: insol H2O; sol THF, CHCl3.

Form Supplied in: white crystalline solid, not commercially available.

Preparative Methods: has been prepared in several ways, most efficiently by two related sequences involving an Arbuzov reaction (eqs 1 and 2).3,5 In both approaches the crude product is sufficiently pure for use in subsequent synthesis applications.

Purification: most easily purified by recrystallization from benzene or from CH2Cl2/hexane. It can also be purified by column chromatography on silica gel.

Handling, Storage, and Precautions: stable for extended periods of storage under nitrogen; its toxicity is unknown.

Horner-Wittig Formation of Enamines.

The utility of the title reagent lies in its application as an a-amino-substituted Horner-Wittig reagent. Deprotonation with n-Butyllithium in THF at 0 °C gives a reasonably stable, orange-colored anion (1). This anion adds to aliphatic, aromatic, and a,b-unsaturated aldehydes to give good yields of the addition adducts as lithium alkoxides, which are sufficiently stable that they do not undergo direct elimination of lithium diphenylphosphinate.2a Rather, protonation yields the alcohols as diastereomeric mixtures of products (eq 3). Treatment with Potassium t-Butoxide, Potassium Hydride, or Sodium Hydride forms the corresponding potassium or sodium alkoxide which eliminates potassium or sodium diphenylphosphinate to give mixtures of (E)- and (Z)-enamines; these isomerize to the more stable (E)-enamines upon purification (eq 4).

This reagent has certain advantages over related phosphonates6 and phosphonium salts,7 both of which have shown only limited success for the synthesis of homologous enamines of aldehydes. However, the utility of this reagent is limited by the basicity of the anion (1) in that its reaction with ketones results in partial to complete enolization.2b The related reagent [(N-methylanilino)methyl]diphenylphosphine oxide has been used successfully with ketones, due to the lower basicity of its derived anion relative to (1).8

Formation of Homologous Aldehydes.

The enamines prepared with the title reagent can be readily hydrolyzed to the corresponding aldehydes (eq 5).2a Thus, the overall transformation exemplified by eqs 3-5 represents a method for the one-carbon homologation of aldehydes. Related reagents having an additional a-substituent, which can be prepared by Mannich-type condensation of Diphenylphosphine Oxide with aldehydes and morpholine,5b show promise as acyl anion equivalents.9

Formation of a-Morpholinomethyl Ketones.

The initial addition adduct of (1) with aldehydes can also be elaborated to a-morpholinomethyl ketones by heating in a protic solvent (e.g. ethylene glycol) or by heating in an aprotic solvent in the presence of a catalytic amount of p-Toluenesulfonic Acid (eq 6).4 This reaction is consistent with following an E1-type mechanism in which the b-hydroxyl group is not directly involved in the elimination step.

1. Maryanoff, B. E.; Reitz, A. B. CRV 1989, 89, 863.
2. (a) Broekhof, N. L. J. M.; van der Gen, A. RTC 1984, 103, 305. (b) Broekhof, N. L. J. M.; Jonkers, F. L.; van der Gen, A. TL 1979, 2433. (c) Nagata, R.; Kawakami, M.; Matsuura, T.; Saito, I. TL 1989, 30, 2817.
3. (a) Pindur, U.; Otto, C. CL 1992, 403. (b) Pindur, U.; Otto, C. T 1992, 48, 3515.
4. Broekhof, N. L. J. M.; van der Gen, A. TL 1981, 22, 2799.
5. (a) Arbusov, B. A. PAC 1964, 9, 307. (b) Broekhof, N. L. J. M.; van Elburg, P.; van der Gen, A. RTC 1984, 103, 312.
6. (a) Zimmer, H.; Bercz, P. C. LA 1965, 686, 107. (b) Gross, H.; Burger, W. JPR 1969, 311, 395. (c) Martin, S. F.; Chou, T. S.; Payne, C. W. JOC 1977, 42, 2520.
7. Bohme, H.; Haake, M. CB 1972, 105, 2233.
8. Broekhof, N. L. J. M.; Jonkers, F. L.; van der Gen, A. TL 1980, 21, 2671.
9. Broekhof, N. L. J. M.; van Elburg, P.; Hoff, D. J.; van der Gen, A. RTC 1984, 103, 317.

John M. Fevig

The DuPont Merck Pharmaceutical Company, Wilmington, DE, USA

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