Synthesis, reactivity and stereochemistry of new phosphorus heterocycles with 5- or 6-membered rings

Article abstract of DOI:10.1016/j.jorganchem.2004.11.035

Syntheses of novel phosphorus heterocycles containing α-amino or α-hydroxyphosphonic or phosphinic acids motifs are developed. 2,3-dihydro-1,3-oxaphospholes (1) and 1,4,2-oxazaphosphinanes (2) exhibit a reactive part, respectively the enolether moiety and the P-H bond, which allows various structural modifications: (i) for 1a, by introduction of amino substituents, (ii) for 2a, by hydroxy- or aminoalkylation, by Michael addition or by P-arylation. These reactions present generally a good or even an excellent kinetic diastereoselectivity which can often be predicted by molecular models of the transition states.

Full text of DOI:10.1016/j.jorganchem.2004.11.035

Journal of Organometallic Chemistry 690 (2005) 2472–2481
www.elsevier.com/locate/jorganchem
Synthesis, reactivity and stereochemistry of new
phosphorus heterocycles with 5- or 6-membered rings
,a
a,
a
Henri-Jean Cristau , Jean-Luc Pirat ,a, David Virieux , Jerome Monbrun ,
*
*
*
´ ˆ
b
Ciptadi Ciptadi , Yves-Alain Bekro
c
a
´
Laboratoire de Chimie Organique, UMR 5076 CNRS, Ecole Nationale Superieure de Chimie de Montpellier, 8, Rue de l’Ecole Normale,
34296 Montpellier Cedex 5, France
b
Department of Chemistry, Palangkaraya University, Jalan Yos Sudarso, Palangkaraya 73112, Indonesia
c
´ ´ ´ ˆ
Universited’Abobo-Adjame, 02BP801, Abidjan 02, Republique de Cote d’Ivoire
Received 26 July 2004; accepted 9 November 2004
Available online 19 January 2005
Abstract
Syntheses of novel phosphorus heterocycles containing a-amino or a-hydroxyphosphonic or phosphinic acids motifs are devel-
oped. 2,3-dihydro-1,3-oxaphospholes (1) and 1,4,2-oxazaphosphinanes (2) exhibit a reactive part, respectively the enolether moiety
and the P–H bond, which allows various structural modifications: (i) for 1a, by introduction of amino substituents, (ii) for 2a, by
hydroxy- or aminoalkylation, by Michael addition or by P-arylation. These reactions present generally a good or even an excellent
kinetic diastereoselectivity which can often be predicted by molecular models of the transition states.
Ó 2004 Elsevier B.V. All rights reserved.
Keywords: Phosphorus heterocycles; 1,3-oxaphosphole; 1,4,2-oxazaphosphinane; Stereoselective synthesis
1. Introduction
ꢀ the 2,3-dihydro-1,3-oxaphospholes (1), five-mem-
bered heterocycles with a P–C–O design,
Phosphorus compounds with a nitrogen or oxygen
heteroatom on the carbon a to phosphorus very often
exhibit interesting biological properties, as exemplified
by the following compounds (Scheme 1).
ꢀ the 1,4,2-oxazaphosphinanes (2), six-membered het-
erocycles with a P–C–N design.
2. Results and discussion
As a part of our search for new biologically active
compounds in the fields of human health or plant pro-
tection, we are interested in introducing such P–C-het-
eroatom pattern into heterocyclic structures. Very few
such phosphorus heterocycles are investigated in the lit-
erature. The results presented in this account concern
two different heterocycles (Scheme 2):
2.1. 2,3-Dihydro-1,3-oxaphospholes (1) [1]
For the synthesis of compounds 1, we considered a
simple retrosynthesis involving a double disconnection
of the P–C and C–O bonds (Scheme 3).
The resulting synthons are:
(i) A dianionic structure, of which the mesomeric eno-
late form affords a simple synthetic equivalent with
the corresponding malonic diester in presence of
two equivalents of base,
*
Corresponding author. Tel.: +33 46 714 4314; fax: +33 46 714
4319.
E-mail address: virieux@cit.enscm.fr (D. Virieux).
0022-328X/$ - see front matter Ó 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2004.11.035

H.-J. Cristau et al. / Journal of Organometallic Chemistry 690 (2005) 2472–2481
2473
(ii) A dicationic phosphorus synthon, corresponding to
simple dielectrophilic synthetic equivalent
O
P
a
X
obtained by introducing a good leaving group, such
as chloride, both on the phosphorus and on the a-
carbon atoms.
(X = O or N)
O
P
O
P
Thus, according to the disconnection approach, the
direct synthesis of 2,3-dihydro-1,3-oxaphospholes (1)
can be achieved by reaction of a-chloroalkylphosphinic
or phosphonic chlorides 3 with malonic diester in pres-
ence of two equivalents of base.
OH
NH2
O
P
NH2
HO
HO
NH
CO2H
N
N
The phosphorus precursors 3 are easily prepared
according to the literature in satisfactory yields about
70% (Scheme 4). For the phosphinic compounds, an
Abramov addition of the P–H bond of phosphinous
acids on aldehydes in acidic medium affords first the cor-
responding a-hydroxylalkylphosphinic acids which un-
dergo a double chlorination of both hydroxy groups at
phosphorus and at a-carbon atom using an excess of
thionyl chloride. For the phosphonic derivatives, the
starting material is diethyl phosphite, and after addition
on aldehydes in basic medium, the chlorination occurs
first with AppelÕs reagent and then with P(O)Cl3.
The phosphinic or phosphonic chlorides 3 were then
successfully transformed into the corresponding 5-
alkoxy-2,3-dihydro-1,3-oxaphospholes 1 by reaction
with diethyl malonates in presence of two equivalents
of sodium hydride (Scheme 5). The yields of isolated
heterocycles are satisfactory, up to 70%.
Glyphosate (herbicide)
(Round-Up®, Monsanto)
O
P
HO
HO
O
O
HO
PMEA - anti HIV
P
NH
HO
O
Alafosfaline (antibiotic)
(Hoffman La Roche)
Ph
OH
H
Val
N
N
P
Val
O
MeO
O
OH
H
P
NH
Ph
Ph
Ph
N
US5663139 (1997) - anti HIV
O
C
O
Val-Val
HIV - protease inhibitor
Scheme 1.
O
O
P
R"
O
P
R"
O
R
O
P
X
NH
R"
R
R'
R'
2
1
(X = O or N)
2,3-Dihydro-1,3-oxaphospholes
1,4,2-oxazaphosphinanes
Scheme 2.
O
RO2C
O
R
RO2C
+
_
R
P
P
+
O _
RO
R'
+
RO
O
R'
O
P
O
C
O
C
RO2C
RO
R
_
_
Cl
2 eq. Base +
RO
OR
R'
H
H
Cl
O
3
R =Alk, Ar, OEt
R' = H,Alk, Ar
Scheme 3.

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H.-J. Cristau et al. / Journal of Organometallic Chemistry 690 (2005) 2472–2481
O
OH
O
R
OH
H
O
Cl
HCl, H2O
80˚C, 20h
5 eq SOCl2
80˚C, 10h
P
P
(CH2O)n
+
P
R'
CH2OH
R"
CH2Cl
3
R = H
R = Ph
R' = CH2OH
R = Ph
R" = CH2Cl (70% Yield)
R" = Ph
(71% Yield)
O
OEt
O
OEt
O
Cl
O
OEt
Ph3P
CCl4
cat. NEt3
100˚C, 1h30
P(O)Cl3
P
P
P
P
+ RCHO
EtO
CH2Cl
R
EtO
CHOH
R
EtO
CH2Cl
R
EtO
H
3
R = H (94%)
R = Ph (63%)
R = Me (99%)
(77%)
(79%)
(54%)
(70%)
(--)
(31%)
Scheme 4.
O
P
O
R"O2C
R"O
R"O2C
Cl
R
R'
a) 2 NaH, THF, -10 to 0˚C
b) 20˚C or reflux, 2h30 - 4h
R'
P
Cl
+
R"O2C
R
O
R = H, Me
R' = CH2Cl, Ph, OEt
1: 25-70% Yield
R" = Me, Et
Scheme 5.
It is likely that the mechanism of formation involves
first, a monodeprotonation resulting in the formation of
malonic enolate which gives a nucleophilic substitution
at phosphorus to afford a malono-intermediate 4 with
P–C bond formation (Scheme 6). There was no evidence
of P–O bond formation in the crude 31P NMR spectra
of reaction mixtures. The intermediate 4 could be iso-
lated in a separate experiment (R0 = CH2Cl) using only
one equivalent of sodium hydride and is fully character-
ized by its NMR data. In the last step of synthesis, a sec-
ond deprotonation occurs on intermediate 4 and results
in the intramolecular O-alkylation of the enolate, afford-
ing the heterocycle 1.
R00 = CH2Cl) shows that the 5-membered ring is almost
flat with values of 7° 5 and 112° 2 for the OPCH dihe-
dral angle, which are in good agreement with the corre-
2
sponding JPH coupling constants (respectively ꢁ9.4 Hz
and +0.3 Hz) (Scheme 7) [2].
Noteworthy are the values of the shifts (174.9 and
71.4 ppm), in the 13C NMR spectra, for the two sp2 car-
bon atoms, which indicate a strong polarization of the
C@C double bond: indeed, the C@C double bond be-
longs to the capto-dative class of olefins, with two elec-
tron-withdrawing groups on one side, and two donating
groups on the other side.
Indeed, the 5-alkoxy substituted heterocycles 1 react
easily with primary amines to afford the corresponding
5-amino substituted heterocycles 5 (Scheme 8) [3]. For
From a structural point of view, a crystal X-ray anal-
ysis of compound 1a (R = CO2Me, R0 = OMe,
O
P
O
O
P
EtO2C
EtO2C
HC
EtO2C
EtO2C
_
Cl
NaH
_
R'
•
R'
P
Cl
R'
CH
•
EtO
C
CH2 Cl
EtO2C
(- H2)
CH2Cl
•
R
O
•
4
R' = CH2Cl 93% Yield
NaH (- H2)
EtO2C
δ31 = 40.6 ppm
P
O
δH = 11.95 ppm
RO2C
RO
R'
P
CH2
EtO2C
R
O
1
Scheme 6.

H.-J. Cristau et al. / Journal of Organometallic Chemistry 690 (2005) 2472–2481
2475
Scheme 7.
O
EtO2C
R'
CH2Cl2, 40˚C, 2-3 h
(- EtOH)
R
NH2
P
(R' = CH2Cl, OEt)
R
NH
5: 75-100% Yield
O
O
P
EtO2C
EtO
R'
(R = Et, n-C12H25, i-Bu, t-Bu, PhCH2, Ph2CH, PhCH2CH2)
(R = CH2CH2OH, CH2CO2Et, NH2, NHMe)
EtO2C
O
1
O
P
R'
PhMe, 110˚C, 2-3 h
(- EtOH)
Ar NH2
(R' = CH2Cl)
Ar NH
O
(Ar = Ph, p-Tol, 2-Pyr, β-Nap)
5: 30-70% Yield
Scheme 8.
aliphatic amines, the reaction occurs easily in refluxing
dichloromethane and affords high yields in isolated com-
pounds 5, between 75% and 100%. In the case of the less
reactive aromatic amines, the reaction occurs at higher
temperature in refluxing toluene and the yields range
from 30% up to 70%.
It is likely that the substitution of the alkoxy group
by amino group on the dihydro-oxaphosphole 1, pro-
ceeds through an addition–elimination process as illus-
trated in Scheme 9.
Finally, concerning this family of heterocycles, we
succeed in applying the substitution reaction to func-
tional primary amines (1,2-ethanolamine, ethyl glycinate,
mono- or di-methylhydrazine). Investigations on the pos-
sible building of a second fused cycle by intramolecular
reaction between the ester group and the functional R
nitrogen substituent are now in progress.
2.2. 1,4,2-oxazaphosphinanes (2) [4]
From the beginning, to build such 6-membered
rings with a PCN design, we chose to use 1,2-dipheny-
lethanolamine (R@R0@Ph), which presents two com-
plementary advantages in the resulting heterocycle 2
(Scheme 10):
ꢀ firstly, the presence of benzylic C–O and C–N bonds
should allow their cleavage by hydrogenolysis in
order to obtain the corresponding free a-amino alkyl-
phosphinic or phosphonic acids.
ꢀ secondly, the 1,2-diphenylethanolamine pattern is
chiral and the use of one pure enantiomer
would introduce asymmetric inductions in the
ring building and further in the reactivity at
phosphorus.

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H.-J. Cristau et al. / Journal of Organometallic Chemistry 690 (2005) 2472–2481
O
P
O
P
O
P
EtO2C
EtO2C
EtO
EtO2C
_
R'
R'
R'
addition
NH2
elimination
- EtOH
EtO
••
R
R
N
H
O
O
O
••
+
H
NH
R
Scheme 9.
O
O
*
O
P
*
R
Ph
Ph
Ph
Ph
OH
R
HO
P
*
*
*
*
*
*
N
R'
NH2
H2N
R'
H
2
Scheme 10.
2.2.1. Synthesis of ( ) 1,4,2-oxazaphosphinanes (2)
The synthesis of the 5,6-diphenyl-1,4,2-oxazaphos-
phinanes (2) has been achieved by cyclisation at phos-
phorus of an open chain precursor 6 (Scheme 11),
through a base catalysed transesterification, which af-
fords the cycle 2 in 65% yield. The precursors are, on
one side, the imine of the racemic 1,2-diphenyl ethanol-
amine with benzaldehyde, and, on the other side, methyl
phosphinate obtained from hypophosphorous acid
esterified by trimethyl orthoformate.
the result of a rapid epimerisation at phosphorus in the
basic conditions used for the cyclisation by
transesterification.
The u,l,u structure [5] of the major isomer 2a was
determined by a monocrystal X-ray analysis which indi-
cated further the twisted boat structure of the heterocy-
1
cle [4]. Finally, H NMR chemical shifts and coupling
constants of 2a are in good agreement with those ob-
served by Juaristi et al. for the 2-ethoxy-2-oxo-1,4,2-
oxazaphosphinanes (Scheme 13) [6].
From a stereochemical point of view, four diastereo-
isomers could be formed in the first addition step, be-
cause there are two new stereogenic centres created.
Actually, four diastereoisomers are detected by 31P
NMR for the open chain intermediate, in the ratio
shown in Scheme 12. But, only two diastereoisomers (ra-
tio 75/25) are obtained after the second step, probably as
We could not obtain suitable crystals of the second
diastereoisomer 2b for X-ray analysis, but the u,u,u
structure could be ascertained indirectly from stereose-
lective reactivities.
Concerning the diastereoselectivity observed, the dia-
stereoisomeric ratio for compounds 2a and 2b is directly
related to the ratio of the open intermediates 6 showing
Ph
Ph
OH
Ph
Ph
OH
N
PhCHO, CH2Cl2
H
O
MgSO4, 20˚C, 18h
(88%)
Ph
Ph
O
H
NH2
Ph
THF, 20˚C, 24h
P
OMe
Ph
N
H
O
H
H
O
4 eq. HC(OMe)3
H
6
P
P
PhMe - THF
0˚C- 20˚C
(96%)
H
OH
OMe
THF
0.1 eq. t-BuOK
0˚C-20˚C, 18h
(65%)
O
H
Ph
Ph
O
N
P
Ph
H
2
Scheme 11.

H.-J. Cristau et al. / Journal of Organometallic Chemistry 690 (2005) 2472–2481
2477
H
H
P
H
O
Ph
Ph
O
O
Ph
Ph
O
O
Ph
Ph
O
H
Ph
( ) u
Ph
OH
N
P
P
*
*
+
OMe
Ph
N
H
Ph
N
H
Ph
N
Ph
H
+ H2PO2Me or H3PO2
6
2a (75)
u,l,u
2b (25)
u,u,u
4 diastereoisomers
[(40/33) / (12/15)]
Scheme 12.
Scheme 13.
that the carbon chirality a to phosphorus is determined
in the first step. Indeed, we could show in competition
experiments that the P–C bond formation is irreversible
in this step, and, in a separate experiment, that no C–H
epimerisation takes place in the reaction conditions.
Therefore, the diastereoselectivity is under kinetic con-
trol and results from the favoured addition of the methyl
phosphinate anion on the Si side of the imine, as shown
in Scheme 14. The proposed structure of the transition
state involving the anti configuration of the imine and
hydrogen bonding between the free hydroxyl group
and the polar phosphorus reagent accounts well for
the preferential formation of the u,l,u diastereoisomer.
2.2.2.1. Addition on aldehydes [7]. Abramov [8] or
Pudovik [9] reactions of compound 2a with aldehydes
afford good yields in a-hydroxyalkyl derivatives phosp-
hoaldol adducts [10], which exhibit an interesting N–C–
P–C–O framework (Scheme 15).
The reaction is easier with aliphatic aldehydes in pres-
ence of tertiary amines than with aromatic aldehydes
which need catalysis by potassium tert-butoxide. But
concerning the diastereoselectivity obtained in the crea-
tion of the new carbon chiral center, the de are moderate
(lower than 40%) with aliphatic aldehydes while the de
come up to 84% with aromatic ones.
It was possible to obtain suitable single crystal for X-
ray analysis of the major isomer of the adduct 7a from
furfuraldehyde, which appears to be the u,u,l,u isomer
(Scheme 16).
2.2.2. Reactivity of 2-hydrogeno-1,4,2-oxazaphosphinanes
(2a)
The reactivity of 2-hydrogeno-1,4,2-oxazaphosphin-
anes (2) was investigated on the pure major isomer 2a,
which can be easily isolated by preferential crystallisa-
tion, and concerns mainly the reactivity of the P–H
bond.
In agreement with the literature for a similar case
[11], we could ascertain, through competition reactions,
that the phosphoaldol reaction is under kinetic control
in our reaction conditions. Actually, two possible transi-
tion states result from the attack of the phosphinate
Si
Ph
O
OMe (H)
H
OMe (H)
Ph
Ph
OH
THF
P
H
H
Ph
:P
O
H (OMe)
Ph
O
H
N
H (OMe)
Ph
N
H
S
Scheme 14.

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H.-J. Cristau et al. / Journal of Organometallic Chemistry 690 (2005) 2472–2481
R
OH
*
CH
H
P
2 eq. RCHO, 1eq. Et3N
CH2Cl2, 48h, 20˚C
Ph
Ph
O
O
Ph
Ph
O
O
P
or
N
H
Ph
N
H
Ph
3 eq.
CHO, 0.1 eq. t-BuOK
Ar
CH2Cl2, 20˚C
2a (u,l,u)
7: ~ 70% Yield
Scheme 15.
Scheme 16.
anion on the Si side or the Re side of the aldehyde with
retention of configuration at phosphorus. Examinating
the molecular models of the transition states in which
the carbonyl oxygen is coordinated to the potassium cat-
ion together with the two oxygen atoms linked to the
phosphorus, it appears that the steric hindrance between
the phenyl ring a to oxygen and the incoming furyl
groups, accounts well for the observed diastereoselectiv-
ity (Scheme 17).
the diastereoisomeric excess are moderate (35–50%),
but the diastereoselectivity can be increased up to 90%
using one equivalent of zinc chloride. This excellent dia-
stereoselectivity is probably the result of a more rigid
transition state formed by a double coordination of
the zinc cation with the imino and the phosphoryl
groups.
2.2.2.3. Addition to Michael olefins [13,14]. Com-
pounds 2a reacts also easily with activated C@C double
bonds, a,b-unsaturated ester or ketones, in Michael
additions catalysed by potassium tert-butoxide. The
reactions afford excellent yields in the corresponding ad-
ducts which can have two new stereogenic centres a and/
or b to phosphorus, depending on the nature of R and
R0 substituents (Scheme 19). The diastereoisomeric ex-
cess is in the range between 30% and 80%.
2.2.2.2. Addition on imines [7]. Kabachnik–Fields
reactions [12] of compounds 2a with aliphatic or aro-
matic imines afford the corresponding a-aminoalkyl
derivatives, with a NCPCN pattern.
Activation of the C@N double bond with Lewis
Acids affords excellent yields of the corresponding ad-
ducts (Scheme 18). In presence of boron trifluoride,
+
+
(S)
K
Fur
H
HO
K
C
_
O
_
O
Ph
Ph
O
Fur
N
Ph
O
O
O
H
Ph
Ph
O
H
N
H
O
P
R
R
Fur
Ph
Ph
Ph
N
H
Ph
S
S
H
7a (u,u,l,u)
R / Si
R / Re
Scheme 17.

H.-J. Cristau et al. / Journal of Organometallic Chemistry 690 (2005) 2472–2481
2479
R
NH R'
*
H
P
CH
BF3.Et2O or ZnCl2
CH2Cl2, 20˚C
Ph
O
O
Ph
Ph
O
O
R
P
C
N
+
R' Ph
N
H
Ph
N
H
Ph
8: ~ 95% Yield
Scheme 18.
R
*
CH
R'
*
CH
H
GA
0.1 eq. t-BuOK
CH2Cl2, -5˚C to 20˚C
Ph
O
O
Ph
Ph
O
O
GA
P
P
C
+
Ph
N
N
H
Ph
Ph
R'
R
H
2a
(GA = CO2R", CN, COR")
9: ~ 80% Yield
Scheme 19.
Ar
P
H
P
OH
O
Ar
0.05 to 0.1 eq. Pd(PPh3)4
Et3N, PhMe
Ph
Ph
O
N
O
Ph
Ph
O
O
Ar
X
+
4h, 80˚C or 110˚C
N
H
Ph
N
H
Ph
H
Ar = Ph, C6H3F2
2a
10: 70-75% Yield
Scheme 20.
2.2.2.4. P-Arylation of 1,4,2-oxazaphosphinane (2a)
[15]. The structural analogy between arylmorpholinols
[16], which exhibit interesting antidepressant activities,
and the P-arylated 1,4,2-oxazaphosphinanes 10 led us to
investigate the P-arylation of compounds 2a (Scheme 20).
The direct arylation of the P–H bond was performed
with aryliodides or bromides, catalysed by 5% mol
Pd(PPh3)4, in presence of triethylamine, in refluxing tol-
uene. The yields are good, between 70% and 75%, and
the reaction can also be applied to heteroarylation with
derivatives of thiophene or pyridine.
From the stereochemical point of view, the reaction
affords only one compound, demonstrating a full diaste-
reoselectivity in the P–Ar bond formation. In good
agreement with the literature [17], we could prove the
complete retention of configuration at phosphorus, in
the arylation compound 2a with 2-bromopyridine. In
this case, both structures of the starting compound 2a
(Scheme 13) and the arylated product 10 (Ar = 2-pyr-
idyl) (Scheme 21) were determined by crystal X-ray
analysis showing unambiguously the retention of config-
uration at phosphorus.
Scheme 21.

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H.-J. Cristau et al. / Journal of Organometallic Chemistry 690 (2005) 2472–2481
2.2.2.5. Hydrogenolysis of 5,6-diphenyl-1,4,2-oxazaphos-
phinanes. In the various derivatives obtained from
1,4,2-oxazaphosphinane (2a) by Abramov–Pudovik
hydroxyalkylations, by Kabachnik–Fields aminoalkyla-
tions or by Michael additions, the diastereoselectivity in
the formation of the new stereogenic centres was in-
duced by the chiral 1,2-diphenylethanolamine auxiliary,
chosen for the possibility of subsequent cleavage by
hydrogenolysis.
Our model 1,4,2-oxazaphosphinane (2a) was built
deliberately, from the beginning, with a third phenyl
ring a to phosphorus in order to check the likelihood
of double deprotection at oxygen and at nitrogen. More-
over, we investigated the hydrogenolysis on compound
10b (Ar@Ph) which exhibits a fourth phenyl substituent
on the phosphorus. Therefore compound 10b can virtu-
ally undergo five different hydrogenolyses of benzylic or
pseudo-benzylic heteroatomic bonds, corresponding to
cleavages a–e (Scheme 22). As expected, the pseudoben-
zylic P–O or P–C bonds were not cleaved in our exper-
iments, but the cleavage of benzylic C–O or C–N bonds
occurred resulting in two different deprotected products:
(i) the target a-amino-benzyl phenylphosphinic acid 11
(cleavage a, b) and (ii) the unsubstituted benzyl phenyl-
phosphinic acid 12 (cleavages a and c). The ratio of
products depends on the hydrogen source and on the
e
Ph
a
Ph
P
Ph
P
Ph
Ph
O
O
HO
O
HO
O
P
"H2", cat.
d
N
H
Ph
H2N
Ph
Ph
c
11 (a,b)
12 (a,c)
b
H2 (1 atm), Pd(OH)2
18h, 20˚C
12%
88%
H2 (1 atm), Pd/C
18h, 20˚C
86%
14%
--
HCO2H (MeOH), Pd/C
18h, 20˚C
100%
Scheme 22.
H
O
a) H2PO2Me
THF, PhMe, 18h
R
Ph
Ph
OH
N
R
S
Ph
Ph
O
P
R
b) 0.1 eq. t-BuOK
36h, 20˚C
Ph
N
H
Ph
S
S
- [α]D = -15 (CHCl3)
(+)[α]D = + 46 (CHCl3)
CO2Me
2 eq.
Ph
0.3 eq. t-BuOK
CH2Cl2, 20˚C, 36h
Ph
CH2CO2Me
CH
O
OH
Ph
Ph
O
O
P
HCO2H, Pd/C
Ph
S
P
CO2Me
Ph
N
H
Ph
NH2
13
92% Yield
(d.e. = 70%)
(-) [α]2D0 = -146 (CHCl3)
Scheme 23.

H.-J. Cristau et al. / Journal of Organometallic Chemistry 690 (2005) 2472–2481
2481
nature of the catalyst. As shown in Scheme 22, the pure
a-aminobenzyl phenylphosphinic acid 11 is obtained
using formic acid in presence of palladium on charcoal.
Acknowledgements
This work was supported by the SSTD-KBRI-
SFERE program, the EGIDE program, the Centre Na-
´
tional de la Recherche Scientifique and the Ministere de
lÕEducation Nationale de lÕEnseignement Superieur et de
la Recherche.
2.2.3. Synthesis from enantiopure 1(S),2(R)-
diphenylethanolamine [14]
´
Based on the chemistry developed in the preceding
part from the racemic starting material, we are now
elaborating the synthesis of diastereoisomerically and
enantiomerically pure functional a-aminophosphinic
acids (Scheme 23).
References
Starting from the enantiomerically pure 1(S),2(R)-
diphenylethanolamine, the formation of the corresponding
imine with benzaldehyde occurs almost quantitatively.
Then the base-catalysed addition of methyl phosphinate
followed by cyclisation through transesterification af-
fords two diastereoisomers (ratio 75/25), and the major
dextrogyre product can be isolated by crystallisation. Its
Michael addition on the trans methyl cinnamate affords
also two diastereoisomers (ratio 85/15), which can be
separated chromatographically.
[1] D. Virieux, C. Ciptadi, Y.A. Bekro, H.J. Cristau, Eur. J. Org.
Chem. (2004) 3205.
[2] C. Ciptadi, H.J. Cristau, Y.A. Bekro, M. Tillard, D. Virieux,
Acta Cryst. E 60 (2004) 99.
[3] D. Virieux, C. Ciptadi, H.J. Cristau, Synthesis, in preparation.
[4] H.J. Cristau, J. Monbrun, M. Tillard, J.L. Pirat, Tetrahedron
Lett. 44 (2003) 3183.
[5] V. Prelog, D. Seebach, Angew. Chem. Int. Ed. Engl. 21 (1982)
654.
[6] I. Linzaga, J. Escalante, M. Mun˜oz, Z. Juaristi, Tetrahedron 58
(2002) 8973.
[7] J.L. Pirat, J. Monbrun, D. Virieux, H.J. Cristau, in
preparation.
Our next step will be the O- and N-deprotections by
hydrogenolysis to obtain the enantiomeric pure like and
unlike compounds 13.
[8] (a) V.S. Abramov, Dokl. Akad. Nauk SSSR 95 (1954) 991;
(b) V.S. Abramov, Zh. Obshch. Khim. 22 (1952) 647.
[9] (a) A.N. Pudovik, B.A. Arbuzov, Dokl. Akad. Nauk SSSR 73
(1950) 327;
(b) A.N. Pudovik, B.A. Arbuzov, Zh. Obshch. Khim. 21 (1951)
382.
3. Conclusion
[10] T.P. Kee, T.D. Nixon, Top. Curr. Chem. 223 (2003) 45.
[11] V.J. Blazis, K.J. Koeller, C.D. Spilling, J. Org. Chem. 60
(1995) 931.
In order to obtain novel phosphorus heterocycles
containing a P–C–O or P–C–N motif in their cyclic
framework, we developed new syntheses of 2,3-dihy-
dro-1,3-oxaphospholes 1 and of 1,4,2-oxazaphosphin-
anes 2. In both cases, the parent compounds 1a and
2a contain a reactive part, respectively the enolether
moiety and the P–H bond. This allows various struc-
tural modifications: (i) for 1a, by introduction of amino
substituents, (ii) for 2a, by hydroxy- or aminoalkylation,
by Michael addition or by P-arylation.
[12] (a) M.I. Kabachnik, T.Y. Medved, Dokl. Akad. Nauk SSSR 83
(1952) 689;
(b) E.K. Fields, J. Am. Chem. Soc. 74 (1952) 1528;
(c) M.I. Kabachnik, T.Y. Medved, Izv. Akad. Nauk SSSR (1953)
868.
[13] R. Engel, Org. React. 36 (1988) 175.
[14] H.J. Cristau, J. Monbrun, D. Virieux, J.L. Pirat, in
preparation.
[15] H.J. Cristau, J. Monbrun, M. Tillard, D. Virieux, J.L. Pirat, in
preparation.
These reactions exhibit generally a good to excellent
kinetic diastereoselectivity which can often be predicted
by molecular models of the transition states.
[16] P.F. Morgan, D.L. Musso, J.J. Partridge, Glaxo Group Limited
WO9937305, 1999 (CA 131:111445).
[17] Y. Xu, J. Zhang, J. Chem. Soc. Chem. Commun. (1986) 1606.