Diethyl Isocyanomethylphosphonate

[41003-94-5]  · C6H12NO3P  · Diethyl Isocyanomethylphosphonate  · (MW 177.14)

(reagent for the elongation of aldehydes and ketones with a one-carbon unit;1 connective reagent;2,3 N,P-acetals;3 reagent for the conversion of nitroalkenes into 2-pyrrolephosphonates4)

Physical Data: bp 90 °C/0.2 mmHg.

Form Supplied in: commercially available as a nearly odorless, colorless liquid.

Analysis of Reagent Purity: IR (neat) 2140 (N=C), 1300-1250 (P=O), 1040-1010 cm-1 (P-O); 1H NMR (CCl4) d 3.9 (d, JH -P = 16 Hz, CH2).

Preparative Method: by dehydration of N-(diethoxyphosphorylmethyl)formamide.5

Handling, Storage, and Precautions: can be stored for long periods of time at 0 °C or below.

Introduction.

Diethyl isocyanomethylphosphonate (1), a reagent developed in 1973 by Schöllkopf et al.,5 belongs to the category of (hetero)-substituted derivatives of methyl isocyanide, which includes p-Tolylsulfonylmethyl Isocyanide (TosMIC), p-Tolylthiomethyl Isocyanide, Methyl N-(p-Tolylsulfonylmethyl)thiobenzimidate (a TosMIC derivative), and Ethyl Isocyanoacetate. Aldehydes and ketones are the main substrates in the reactions of (1), which result in the formation of three different types of products, wherein the phosphonate group may or may not be retained.

Horner-Wadsworth-Emmons Reactions.

Horner-Wadsworth-Emmons (HWE) type reactions of (1) with aldehydes and ketones provide vinyl isocyanides,1 which have been used as intermediates in the synthesis of erbstatin (eq 1)1a,b and of homologous aldehydes (eq 2).1c,d

Knoevenagel Condensation Products.

A method has been developed, which avoids the HWE reaction of (1) (eqs 1 and 2), to prepare (formal) Knoevenagel products (2) by elimination of water (eq 3).3a Compound (2) has been converted into progesterone by reduction of the C17-C20 double bond, followed by C20 methylation and acid hydrolysis of (EtO)2P(O)CR(Me)NC(R = 3-methoxyandrosta-3,5-dien-17-yl) (N,P-acetal behavior; eq 3).3a In these processes, (1) is used as a connective reagent to form a CO bridge between Me and a 17-steroidal group, as in eq 3. Partial hydrolysis of disubstituted derivatives of (1) [(EtO)2P(O)CR1R2NC] provides a-aminomethylphosphonic acids (esters).

The HWE reaction of Knoevenagel products (2) with aldehydes, followed by acid hydrolysis to D16-steroids, provides another example of the use of (1) as a connective reagent (eq 4).2

Oxazolines and Derivatives.

The first part of eq 3 (i.e. the formation of 2) proceeds via oxazolines (3) (eq 5), which have been hydrolyzed to a-amino-b-hydroxyalkylphosphonic acids,6a and which have been subjected to base-induced electrocyclic ring opening to the formamide precursors (4) of isocyanides of type (2).6a

The reaction to give compounds of type (3) has been carried out with high asymmetric induction (>98%) using a chiral ferrocenylphosphine-gold complex as catalyst.6b,c

Miscellaneous.

(1) has been used in Passerini-type reactions,7 and in a recent synthesis of pyrroles from nitroalkenes (eq 6).4

Several derivatives of (1) have also been used as reagents. For example, (EtO)2P(O)CR1R2NC: (i) R1 = H, R2 = Me in the synthesis of corticosteroids;8 (ii) R1 = H, R2 = Cl in the synthesis of indisodine;9 (iii) R1 = H, R2 = S-aryl in the synthesis of ketene N,S-acetals.10


1. Leading refs: (a) Burke, T. R., Jr. OPP 1991, 23, 127. (b) Stoelwinder, J.; van Leusen, A. M. S 1990, 568. (c) Moskal, J.; van Leusen, A. M. RTC 1987, 106, 137. (d) Rachon, J. C 1982, 36, 462. (e) Hoppe, I.; Schöllkopf, U. LA 1984, 600.
2. Stoelwinder, J.; van Leusen, A. M. JOC 1993, 58, 3687.
3. (a) Stoelwinder, J.; van Zoest, W. J.; van Leusen, A. M. JOC 1992, 57, 2249. (b) See footnote 4 in Ref. 3a.
4. Yuan, C.; Huang, W. S 1993, 473 (cf. Hees, U.; Schneider, J.; Wagner, O.; Regitz, M. S 1990, 834).
5. Rachon, J.; Schöllkopf, U.; Wintel, T. LA 1981, 709, and footnotes 10 and 11 therein.
6. (a) Schöllkopf, U.; Wintel, T. S 1984, 1033 and references cited therein. (b) Togni, A.; Pastor, S. D. TL 1989, 30, 1071. (c) Sawamura, M.; Ito, Y.; Hayashi, T. TL 1989, 30, 2247.
7. (a) Moran, E. J.; Armstrong, R. W. TL 1991, 32, 3807. (b) Seebach, D.; Adam, G.; Gees, T.; Schiess, M.; Weigand, W. CB 1988, 121, 507. (c) Rachon, J. C 1983, 37, 299.
8. Barton, D. H. R.; Motherwell, W. B.; Zard, S. Z. NJC 1982, 6, 295.
9. Isshiki, K.; Takahashi, Y.; Sawa, T.; Naganawa, H.; Takeuchi, T.; Umezawa, H.; Tatsuta, K. J. Antibiot. 1987, 40, 1202.
10. van Leusen, A. M.; Wildeman, J.; Moskal, J.; van Hemert, A. W. RTC 1985, 104, 177.

Albert M. van Leusen & Daan van Leusen

Groningen University, The Netherlands



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