[41003-94-5] · C6H12NO3P · Diethyl Isocyanomethylphosphonate · (MW 177.14)
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.
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 (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
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
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
(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
Albert M. van Leusen & Daan van Leusen
Groningen University, The Netherlands