TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 743–746
Conformational preferences in 2-alkyl, 2-alkanoyl and
2-aroyl-2-oxo-1,3,2-oxazaphosphorinanes
Kamyar Afarinkia,a,* Richard Angell,b Clare L. Jonesa and James Lowmana
aDepartment of Chemistry, King’s College, Strand, London WC2R 2LS, UK
bGlaxoWellcome Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, UK
Received 3 November 2000; accepted 15 November 2000
Abstract—A series of 2-alkyl-, 2-alkanoyl- and 2-aroyl-2-oxo-1,3,2-oxazaphosphorinanes bearing N-benzyl, N-benzhydryl and
N-trityl substituents are prepared and their conformational preferences in solid phase are discussed. © 2001 Published by Elsevier
Science Ltd.
Study of the conformation of 2-oxo-1,3,2-oxazaphos-
phorinanes is important for three reasons. The confor-
mation of 2-oxo-1,3,2-oxazaphosphorinanes is the basis
of a number of models which predict asymmetric reac-
tions of chiral phosphonamidates such as 11 and 2.2
Secondly, it is of basic interest to understand the effect
on the conformational properties arising from the re-
placement, and substitution, of the carbon atoms of a
cyclohexane ring by heteroatoms.3 Lastly, this ring sys-
tem is found in a number of anticancer drugs (cyclophos-
phamide 3a, isophosphamide 3b, trophophosphamide
3c) and therefore an understanding of this ring’s pre-
ferred conformation contributes to the interpretation of
these drugs’ structure–activity relationships (Scheme 1).4
phenyl or hydrogen substituents on the nitrogen atom
(which was found to be trigonal).3a,c Denmark has
reported oxazaphosphorinanes with i-Pr and t-Bu sub-
stituents on the nitrogen atom (which was found to be
pyramidal).2b In this paper, we reveal further influences
of the N-substituent and the P-substituent on the solid
state structure of this ring system.
2-Propyl-2-oxo-1,3,2-oxazaphosphorinanes bearing N-
benzyl and N-benzhydryl substituents (4a and 4b, respec-
tively) were prepared from the reaction of N-benzyl and
N-benzhydrylpropanolamine with propanephosphonic
dichloride.1,2
2-Alkanoyl- and 2-aroyl-2-oxo-1,3,2-oxazaphosphori-
nanes bearing N-benzyl, N-benzhydryl and N-trityl
substituents (6–9) were prepared by the Arbuzov reaction
of the corresponding acid chlorides and 2-ethoxy-oxaza-
phosphorinanes (Scheme 2). Intermediate 2-ethoxy-
1,3,2-oxazaphosphorinanes, such as 5, were found to be
predominantly of one configuration, presumably with the
OEt in an axial position. 2-Propyl-2-oxo-1,3,2-oxaza-
Previous studies on the solid and solution state structures
of 2-oxo-1,3,2-oxazaphosphorinanes have revealed im-
portant information about the conformational prefer-
ences of this ring system. These studies have concentrated
on ring systems in which the phosphorus atom is substi-
tuted with electronegative groups such as OMe,3a Cl,3b
and NR2.3c Bentrude has studied ring systems with
Scheme 1.
* Corresponding author. E-mail: kamyar.afarinkia@kcl.ac.uk
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(00)02050-5