Conformational preferences in 2-alkyl, 2-alkanoyl and 2-aroyl-2-oxo-1,3,2-oxazaphosphorinanes

Article abstract of DOI:10.1016/S0040-4039(00)02050-5

A series of 2-alkyl-, 2-alkonyl- 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.

Full text of DOI:10.1016/S0040-4039(00)02050-5

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

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K. Afarinkia et al. / Tetrahedron Letters 42 (2001) 743–746
Scheme 2.
Figure 1.
Figure 2.

K. Afarinkia et al. / Tetrahedron Letters 42 (2001) 743–746
745
Table 1.
4a
7b
4c
7c
8
7d
ÚC4ꢀNꢀP (°)
ÚZꢀNꢀP (°)
ÚC4ꢀNꢀZ (°)
ÚOꢀPꢀN (°)
ÚOꢁPꢀN (°)
ÚOꢁPꢀO (°)
ÚOꢁPꢀC (°)
ÚOꢀPꢀC (°)
ÚNꢀPꢀC (°)
ÚC6ꢀOꢀP (°)
118(0.5)
117(0.5)
115(0.5)
103(0.2)
113(0.4)
112(0.6)
112(0.0)
104(0.0)
110(0.9)
119(0.1)
1.47(8)
119(0.4)
120(0.9)
119(0.3)
105(0.4)
114(0.9)
113(0.5)
113(0.0)
103(0.0)
105(0.9)
121(0.9)
1.46(9)
114(0.7)
132(0.0)
114(0.0)
101(0.1)
115(0.0)
116(0.3)
114(0.4)
98(0.4)
109(0.7)
115(0.4)
1.47(1)
1.59(5)
1.67(6)
117(0.0)
124(0.6)
114(0.2)
103(0.6)
118(0.9)
111(0.0)
113(0.5)
100(0.9)
106(0.8)
125(0.6)
1.46(7)
120(0.7)
117(0.0)
120(0.9)
105(0.6)
114(0.6)
112(0.4)
114(0.4)
100(0.7)
107(0.9)
122(0.8)
1.47(0)
120(0.7)
121(0.3)
117(0.9)
106(0.0)
115(0.4)
113(0.4)
110(0.0)
101(0.6)
108(0.4)
119(0.9)
1.47(3)
,
PꢁO (A)
,
PꢀO (A)
1.60(1)
1.66(6)
1.80(1)
0.06(4)
1.57(4)
1.64(1)
1.86(4)
0.07(5)
1.59(0)
1.64(7)
1.88(8)
1.58(1)
1.64(0)
1.87(2)
0.07(7)
1.57(5)
1.62(8)
1.87(0)
0.10(0)
,
PꢀN (A)
,
PꢀC (A)
1.79(1)
Dev.a PNC5C6 (A)
,
Dev.a OC6NC4 (A)
0.02(1)
0.00(2)
0.00(3)
0.04(1)
,
Dev.a OPNC4 (A)
0.07(3)
0.10(7)
NA
0.00(3)
0.12(8)
156(0.8)
,
Dev.a OC4C5C6 (A)
,
Dih.b OꢁPꢀCꢁO (°)
NA
132(0.1)
176(0.0)
115(0.0)
a Deviation from plane.
b Dihedral angle.
Scheme 3.
phosphorinane bearing an N-trityl substituent, 4c, was
similarly prepared from 1-bromopropane and the corre-
sponding 2-ethoxy-oxazaphosphorinane.1,2
length is quite similar in 7a–d and 13 (where it is 1.850
5
,
A) suggesting no significant interaction between the
respective lone pairs on nitrogen and oxygen with |* of
P(O)ꢀC(O) bonds.
Drawings of the solid state conformations of a selection
of these compounds are shown (Figs. 1 and 2, phenyl
groups are omitted for clarity) and a selection of bond
angels, dihedral angels and bond lengths are given
(Table 1). In all cases, the N(3) atom is planar and the
bond angles about the O(1) atom suggests that this
atom is also trigonal. This observation is in direct
contrast to that observed by Denmark for compound
1,1 but in agreement with that reported by Bentrude for
compounds such as 10 and 11.3a,c
Furthermore, the P(O)ꢀC(O) bond length is slightly
longer than that of P(O)ꢀCH2, presumably due to
repulsion between bonded pairs, but nevertheless sug-
gesting no significant interaction between the respective
y or y* systems of the CꢁO and PꢁO bonds.
One of the most important differences in these systems
arises from the ring conformation of the N-benzyl and
N-benzhydryl derivatives, and that of the N-trityl
derivatives. In the N-benzyl (including a-methylbenzyl)
and N-benzhydryl derivatives, the oxazaphosphorinane
ring adopts a pseudo-chair conformation (Scheme 3).
The deviation from the true chair conformation arises
from the planarity of the nitrogen atom and, to a lesser
extent, the oxygen atom. Consequently, O(1)ꢀN(3)ꢀ
(C4)ꢀC(6) are near planar (deviation from plane ca.
In all compounds synthesised by us, whether P-alkyl,
P-alkanoyl or P-aroyl, the PꢁO bond is placed in an
equatorial position. The equatorial preference for the
PꢁO bond was previously observed by Bentrude3e for
compounds such as 12, and was attributed in this
compound to an endo anomeric effect arising from
overlap of the N(3) p orbital and PꢀX anti-bonding
(|*) orbital. Interestingly, our observation suggests that
an equatorial preference for the PꢁO bond is also
applicable when X is not an electronegative atom, for
instance carbon. Furthermore, the P(O)ꢀC(O) bond
,
0.002 A for 7b). However, in N-trityl derivatives, the
conformation is pseudo-boat with P(2)ꢀO(1)ꢀN(3)ꢀ(C4)
,
near planar (deviation from plane ca. 0.003 A for 7c).
In other words, the introduction of a bulkier N-trityl
substituent forces the relative position of C(5) and C(6)

746
K. Afarinkia et al. / Tetrahedron Letters 42 (2001) 743–746
atoms to change, resulting in a conformational change
in the oxazaphosphorinane ring.
References
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Finally, it should be noted that all 2-alkanoyl- and
2-aroyl-2-oxo-1,3,2-oxazaphosphorinanes analysed dur-
ing this work had a gauche or anti relationship between
the PꢁO and CꢁO bonds. This is presumably to min-
imise dipolar interactions between the two bonds as
observed in a-diketones.
Acknowledgements
We thank EPSRC and GlaxoWellcome for an indus-
trial CASE award to J.L. and EPSRC for a project
studentship to C.L.J. We are grateful to Professor
David Williams and Dr. Andrew White (Imperial Col-
lege, London) and Dr. Jon. W. Steed (King’s College,
London) for X-ray crystallography.
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