Pallado-catalysed P-arylations and P-vinylation of 2-hydrogeno-2-oxo-1,4,2- oxazaphosphinanes

Article abstract of DOI:10.1016/j.tet.2005.05.007

A simple and effective preparation of 2-aryl- (or 2-vinyl)-1,4,2- oxazaphosphinanes, phosphorus analogues of aryl-morpholinols has been developed, involving palladium catalysed coupling of aryl (or vinyl)-halides with 2-H-1,4,2-oxazaphosphinane in presenc

Full text of DOI:10.1016/j.tet.2005.05.007

Tetrahedron 61 (2005) 7029–7036
Pallado-catalysed P-arylations and P-vinylation of
2-hydrogeno-2-oxo-1,4,2-oxazaphosphinanes
*
´ ˆ
Jean-Luc Pirat, Jerome Monbrun, David Virieux and Henri-Jean Cristau
*
Laboratoire de Chimie Organique, UMR 5076, ENSCM, 8 rue de l’Ecole Normale, 34296 Montpellier Cedex 5, France
Received 18 March 2005; revised 29 April 2005; accepted 2 May 2005
Abstract—A simple and effective preparation of 2-aryl- (or 2-vinyl)-1,4,2-oxazaphosphinanes, phosphorus analogues of aryl-morpholinols
has been developed, involving palladium catalysed coupling of aryl (or vinyl)-halides with 2-H-1,4,2-oxazaphosphinane in presence of
triethylamine. A deprotection step was also proposed to afford the corresponding P-aryl-a-aminobenzylphosphinic acid.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
plant regulators.), the challenge in synthesis of phos-
phorus containing heterocycle was particularly stimulating.
Indeed, it is well known that heterocyclic compounds
received much attention of chemists due to their pharma-
ceutical importance and extensive application in organic
synthesis.2
Among various organophosphorus compounds synthesized
during the last decades, a-aminophosphinic derivatives
have shown interesting biological properties especially as
enzyme inhibitors: leucine aminopeptidase1a or isoaspartyl/
b-aspartyl zinc peptidase (A),1b HIV-1 protease (B).1c–g On
the other hand, arylphosphinic acid derivatives are also
known as agents of treating hypercholesterolemia or
atherosclerosis (C)1h or as microsomal aminopeptidase1i
and thrombin inhibitors (D) (Fig. 1).1j
In previous works, we described the synthesis of a new class
of 1,4,2-oxazaphosphinanes 1 bearing a reactive P–H bond,
and the diastereoselective additions of 1 to aldehydes
and imines.3a,b Arylation of such structure would lead to
compounds 2, phosphorus heterocycles analogues of
morpholinols derivatives 3, widely described for their
antidepressing activities (Fig. 2).4
As a part of our ongoing efforts in discovery and synthesis
of new potent organophosphorus inhibitors (virucide,
Figure 1. Various biologically active phosphinic derivatives.
Figure 2. Analogy between P-aryl1,4,2-oxazaphosphinanes and aryl-morpholinols.
Keywords: Arylphosphinate; Aminoalkylarylphosphinic acid; Vinylation; Arylation; Pallado-catalyse.
*
Corresponding authors. Tel.: C33 4 67 14 72 43; fax: C33 4 67 14 43 19 (J.-L.P.); e-mail addresses: pirat@cit.enscm.fr; cristau@cit.enscm.fr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.007

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J.-L. Pirat et al. / Tetrahedron 61 (2005) 7029–7036
Figure 3. Chiral phosphonic and phosphinic Michael-type olefins.
In addition, vinylphosphoryl derivatives5 4 and 5 (Fig. 3)
were developed to induce diastereoselective additions on
the C]C double bond, as the intracyclic phosphorus atoms
of these activated olefins is substituted by a chiral group.
Vinylation of structure 1 could also give efficient derivatives
6 for diastereoselective reactions.6
Suitable crystals for X-ray analysis (Fig. 5) were obtained
for the 2-pyridyl substituted compound 7e after crystal-
lization from chloroform. As noted above, retention of
configuration at phosphorus atom is then confirmed
(arylation occurs at the same side of the initial P–H bond).
Moreover, we can point out the intramolecular H-bond
between pyridyl nitrogen and proton of exocyclic amine.
Using racemic oxazaphosphinane 1a, both enantiomers
appear on the crystal cell (Fig. 4). It is interesting to observe
the p-stacking phenomenon between pyridyl and phenyl
substituents of each enantiomer.
To the best of our knowledge, only few papers deal with
1,4,2-oxazaphosphinane structures. One of them describes
the synthesis of a 2-phenyl-1,4,2-oxazaphosphinane ring
starting with chlorophosphines, aminophenol and various
substituted aldehydes.7 We propose herein a different
approach via a direct pallado-catalysed arylation or
vinylation of 2-hydrogeno-2-oxo-1,4,2-oxazaphosphinane
1 affording P-aryl- or P-vinyl-oxazaphosphinanes.
2. Results and discussion
2.1. Arylation of 2-hydrogeno-2-oxo-1,4,2-oxazaphos-
phinane 1a
Diastereoisomer 1a was chosen as substrate for arylation
and vinylation reactions as its relative stereochemistry was
already fully determined by X-ray analysis.3a Arylation
takes place in the conditions usually described in the
literature:8 oxazaphosphinane 1a is arylated using catalytic
amounts of tetrakis(triphenylphosphine) palladium
(10 mol%), Ar–X (1 equiv), NEt3 (3 equiv) under refluxing
toluene to give as expected, only one diastereoisomer in
good yields (69 to 75%) (Scheme 1, Table 1); indeed, these
results are in accordance with the well established
phosphorus retention of configuration during pallado-
catalysed arylation.9
Figure 4. X-ray-cell of (C)-2-pyridyl-1,4,2-oxazaphosphinane 7e.
Scheme 1. Arylation of 2-hydrogeno-2-oxo-1,4,2-oxazaphosphinanes 1a.
Table 1. Arylation of 2-H-2-oxo-1,4,2-oxazaphosphinane 1a
Figure 5. X-ray structure of 2-pyridyl-1,4,2-oxazaphosphinane 7f derived
from 1b.
The mechanism of the catalysis also fully justifies the
retention process (Scheme 2): The active catalyst PdL2, a 14
electrons complex, gives a classical oxidative addition of
the aryl halide and affords a 16 electrons intermediate.
Further, the tetracoordinated oxazaphosphinane is stereo-
selectively in equilibrium, with the tricoordinated phos-
phinite form, which can give a nucleophilic substitution of
Compound
Ar-X
Yield (%)a
7a
7b
7c
7d
7e
Ph-I
p-Br-C6H4-I
p-MeO-C6H4-Br
2-Br-thiophene
2-Br-pyridine
69
73
71
70
75
a Yield after purification by column chromatography.

J.-L. Pirat et al. / Tetrahedron 61 (2005) 7029–7036
7031
Scheme 2. Mechanism of the catalytic arylation.
halogen (iodide or bromide) on palladium, and affords after
deprotonation by the tertiary amine the metallated oxaza-
phosphinane with retention of configuration at phosphorus.
The last step of catalytic cycle occurs also by a front
reductive elimination with retention of configuration at
phosphorus.
Configurational relationship between 1a and 1b at C3
position was easily demonstrated by ring opening of each
compound with aqueous hydrochloric acid (Scheme 4):
indeed, acidic treatment removes chirality at phosphorus
center, then the C3 chiral position only remains; treatment of
a mixture of both diastereoisomers 1a and 1b leads to two
opened structures 8a and 8b, they are consequently epimers
at C3 position. However, it was impossible to assign the
stereochemistry of the phosphorus atom.
2.2. Determination of stereochemistry of 2-hydrogeno-2-
oxo-1,4,2-oxazaphosphinane 1b
The full determination of relative stereochemistry of the
second diastereoisomer 1b not only at the C3 position but
also at the phosphorus center could be made by arylation of
the second diastereoisomer with bromopyridine following
the same procedure as described for arylations of 1a. As
expected, arylation of 1b proceeds in a similar way (65%
yield after column chromatography, one diastereoisomer 7f)
In our previous work dealing with synthesis of 2-H-2-oxo-
1,4,2-oxazaphosphinane compounds,3 two diastereoisomers
1a and 1b were obtained (Scheme 3). However, although we
easily obtained suitable crystals of the diastereoisomer 1a
for X-ray analysis, we were unable to crystallize the second
one 1b.
Scheme 3. 2-Hydrogeno-1,4,2-oxazaphosphinane synthesis via an intramolecular transesterification.
Scheme 4. Acidic ring opening to settle up the relative configurations at C3 position.

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J.-L. Pirat et al. / Tetrahedron 61 (2005) 7029–7036
and we were pleased to obtain suitable crystals by crystal-
lization from chloroform for X-ray analysis, after chroma-
tographic purification (Fig. 5).
isomers: 10/90). The first experiment using the same
conditions as described above for arylation (110 8C, 4 h)
afforded only one stereoisomer (trans compound as
determined by 1H NMR coupling constants) and no cis
isomer coming from the starting b-bromostyrene is
detected. At first glance, this result seems to be in
contradiction with the well established stereospecificity of
the reaction.
As compound 7f has the pyridyl-group (P2 position) and the
phenyl-group (C3 position) anti to the phenyl-groups at C5
and C6 positions, the relative stereochemistry of 1b should
be as follows (Scheme 5).
A first explanation for the high trans stereoselectivity could
consist with a preliminary in situ isomerisation of b-bromo-
styrene. Indeed, it is known that prolonged heating can
isomerize the double bond to the thermodynamically more
stable trans-derivative.10 As a consequence, we tried to use
softer conditions (55 8C, 1 h) but no presence of cis-
derivative was detected leading us to make a NMR study of
b-bromo-styrene isomerization under these reaction con-
ditions. The reaction mixture (bromostyrene and triethyl-
amine in deuterated benzene) checked by 1H NMR analysis,
after 1 h heating at 55 8C, shown that no isomerization
occurred, even after addition of 10% Pd(PPh3)4 followed by
1 h heating.
Another explanation could consist with in situ isomerization
of vinyloxazaphosphinane due to its Michael olefin nature
and presence of an intracyclic secondary amine function
(Scheme 7). Indeed, it is well known that secondary amine
catalyse isomerization of activated double bond from cis
stereoisomer to trans one, as demonstrated for cis-
chalcone11 via Michael/retro-Michael reactions.
Scheme 5. Structure elucidation of diastereoisomer 1b.
2.3. Vinylation of 2-hydrogeno-2-oxo-1,4,2-oxaza-
phosphinane
Vinylation of oxazaphosphinane heterocycle was performed
(Scheme 6) with b-bromo-styrene (a mixture of cis/trans
2.4. Deprotection of arylated 2-hydrogeno-2-oxo-1,4,2-
oxazaphosphinane structure
Removal of the chiral inductor was carried out on the phenyl
substituted compound 7a (Scheme 8). Several ways could
be considered: hydrogenolysis catalysed by palladium
derivatives as well as oxidative cleavage by sodium
periodate (as the inductor initially used is an aminoalcohol).
The latter needs one more step for ring opening before
oxidative cleavage, but the difficulty of hydrogenolysis
consists on the regioselectivity of the cleavage due to the
presence of two benzylic C–N bonds.
Scheme 6. Pallado-catalysed vinylation of 2-H-oxazaphosphinane 1a.
Scheme 7. Possible isomerization of cis-8 catalysed by oxazaphosphinane secondary amine.

J.-L. Pirat et al. / Tetrahedron 61 (2005) 7029–7036
7033
Scheme 8. 2-Phenyl-oxazaphosphinane deprotection to free phenyl-aminobenzylphosphinic acids.
Ring-opening of compound 9a was easily obtained from
cyclic starting material 7a after acidic treatment (way a).
4. Experimental
All reactions involving air or moisture sensitive reagents or
intermediates were carried out under dry nitrogen in flame-
dried glassware. Reagents and solvents were distilled before
use and stored under nitrogen over sodium wires (THF) or
molecular sieves (dichloromethane). All reactions were
monitored by 31P NMR. Merck silica gel (35–70 mm) was
used for column chromatography. NMR spectra were
recorded on BRUKER AC 200, 250 or 400 (1H frequency:
200.13, 250.13 or 400.13 MHz; 13C frequency: 50.32, 62.89
or 100.62 MHz, 31P frequency: 81.02, 101.25, 162.04 MHz,
respectively). Chemical shifts are given in d units with
respect to TMS (1H, 13C NMR) or H3PO4 85% (31P),
coupling constants are expressed in Hz. Infrared spectra
were recorded on PERKIN-ELMER 377 or FT-NICOLET
210 spectrometer. Mass spectra were measured on JEOL
JMS DX-300 spectrometer (positive FAB ionisation and
High Resolution using p-nitrobenzyl alcohol NBA).
However, sodium periodate gave no reaction even after
several days.
Catalytic hydrogenolysis of 9a over palladium on charcoal
(way b) or palladium hydroxide (way c) (after neutralisation
by aqueous NaOH 1 N solution) under 1 atm of hydrogen
was tried but gave unfortunately the wrongly deprotected
benzyl-phenylphosphinic acid 9b, leading us to try hydro-
genolysis directly to the arylated heterocycle 7a. As above,
palladium hydroxide leads to the wrong deprotected
derivative 9b (way d). Surprisingly, palladium on charcoal
gave the expected a-aminobenzyl-phenylphosphinic acid
9c, with small amount of 9b (way e). These results incited us
to choose mild hydrogen donor as formic acid under Pd/C
catalysis: in such conditions (way f), very clean reaction
occurred affording only the correctly deprotected compound
9c with high isolated yield (75%). Petnehazy et al.
recently described12 the deprotection of N-methylbenzyl-
a-amino benzylphosphinic acid to compound 9c using Pd/C
hydrogenolysis under 10 atm of hydrogen. However,
4.1. General procedure for arylation of 2-hydrogeno-2-
oxo-1,4,2-oxazaphosphinane (7a–7f, 8)
1
according to the chemical shifts (31P and H NMR) and
In a 10 ml flask containing 675 mg of 1a (1.94 mmol)
and 224 mg of palladium-tetrakis(triphenylphosphine)
(0.194 mmol, 0.1 equiv) under N2 are added under stirring
3.7 ml of dry toluene followed by 810 mL of triethylamine
(5.82 mmol) and aryl-halide or vinyl-halide (1.94 mmol) at
room temperature. The reaction mixture is heated at 110 8C
and precipitation of triethylammonium halide occurs. After
4 h stirring at 110 8C, compound 1a was completely
consumed and heating was stopped. After cooling, the
reaction mixture is dissolved in chloroform and saturated
aqueous NaCl solution is added. After extraction with
chloroform, the organic layers are dried over Na2SO4. The
crude solution is evaporated affording a solid purified by
column chromatography (dichloromethane/ethyl acetate
gradient: 100/0 to 50/50).
melting point given, it is likely that they actually isolated
compound 9b.
3. Conclusion
In conclusion, we synthesized several aryl or heteroaryl
oxazaphosphinanes via a palladium(0) catalysed arylation
of 2-hydrogeno-1,4,2-oxazaphosphinane with aromatic or
heteroaromatic bromides or iodides affording heterocyclic
phosphorus analogues of arylated morpholinols. Further-
more, vinylation of these structures was also tried to afford
activated olefin containing chiral functionalized phosphi-
nate moiety, usable for several diastereoselective reactions
(Michael addition, Diels–Alder reactions.). Cleavage of
the chiral inductor using catalytic hydrogenolysis was
finally described opening new perspectives in the synthesis
of a-aminophosphinic derivatives.
4.1.1. (2R*,3R*,5R*,6S*)-(C/K)-2-Oxo-2,3,5,6-tetra-
phenyl-1,4,2-oxazaphosphinane 7a. White solid (570 mg,
1.34 mmol, 1 diastereoisomer), mpZ223.9 8C; yield 69%;

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J.-L. Pirat et al. / Tetrahedron 61 (2005) 7029–7036
3
3
31P NMR (81.02 MHz, CDCl3): 42.77; 1H NMR
4.84 (dd, 1H, JHHZ4.4 Hz, JHHZ4.4 Hz, NCHPh), 5.14
3
2
3
(250.13 MHz, CDCl3): 2.20 (d, 1H, JPHZ28.9 Hz, NH),
(d, 1H, JPHZ11.5 Hz, PCHPh), 6.18 (dd, 1H, JPHZ
3
4.93 (dd, 1H, JHHZ4.6, 4.6 Hz, NCHPh), 5.13 (d, 1H,
8.4 Hz, 3JHHZ5.8 Hz, OCHPh), 7.04–7.41 (m, 17H, CHar),
3 4
2JPHZ13.4 Hz, PCHPh), 6.20 (dd, 1H, JPHZ7.1 Hz,
7.68 (dd, 1H, JHHZ3.8 Hz, JHHZ3.8 Hz, SCH); 13C
3
3JHHZ5.8 Hz, OCHPh), 7.18–7.80 (m, 20H, CHar): 13C
NMR (62.90 MHz, DMSO-d6): 59.61 (d, JPCZ107.0 Hz,
1
1
2
NMR (MHz, DMSO-d6): 59.60 (d, JP2CZ106.5 Hz,
HNCHP), 63.37 (s, NCHPh), 76.48 (d, JPCZ4.8 Hz,
4
OCHPh), 127.0–129.73 (m, CHar), 136.51 (d, JPC
HNCHP), 63.36 (s, NCHPh), 76.47 (d, JPCZ4.8 Hz,
Z
2
OCHPh), 127.09–129.56 (m, CHar), 136.17 (d, JPC
Z
4.3 Hz,
SCHar),
136.17
(d,
2JPCZ6.2 Hz,
5.8 Hz, Car), 137.95 (d, 3JPCZ8.2 Hz, Car), 141.04 (s, Car),
139.19 (d, 2JPCZ9.1 Hz, PCarCHar): IR (KBr): 3440, 3280,
3080, 3020, 2840, 1590, 1480, 1450, 1230, 1200, 1180,
1125, 1060, 1030, 990, 690; HRMS (FABC): calcd for
C27H24NO2P 425.1623. Found 425.1605; 426 [MCH]C
(32%), 284 (95%), 180 (100%), 106 (21%), 91 (38%).
CarCH[(P),(NH)]), 137.95 (d, JPCZ8.6 Hz, CarCH[(O),
(CH)]), 141.04 (s, CarCHN), 139.20 (d, JPCZ11.0 Hz,
[(P),(S)]CarCH): IR (KBr): 3420, 3270, 3080, 3030, 2990,
2840, 1600, 1490, 1450, 1230, 1200, 1130, 1060, 1030, 990,
955, 700, 695; HRMS (FABC): calcd for C25H22NO2PS:
431.1187. Found: 431.1196; 432 [MCH]C (43%), 284
(100%), 180 (73%), 106 (11%), 91 (19%).
3
4
4.1.2. (2R*,3R*,5R*,6S*)-(C/K)-2-Oxo-3,5,6-triphenyl-
2-p-bromophenyl-1,4,2-oxazaphosphinane 7b. White
solid (714 mg, 1.42 mmol, 1 diastereoisomer), mpZ
228.8 8C; 73% yield; 31P NMR (81.02 MHz, CDCl3):
42.05: 1H NMR (250.13 MHz, CDCl3): 2.23 (d, 1H,
4.1.5. (2S*,3S*,5R*,6S*)-(C/K)-2-Oxo-3,5,6-triphenyl-
2-(2-pyridyl)-1,4,2-oxazaphosphinane 7e. White solid
(620 mg, 1.46 mmol, 1 diastereoisomer), mpZ221.2 8C;
75% yield: 31P NMR (81.02 MHz, CDCl3): 34.52; 1H NMR
3
3
3
3JPHZ30.3 Hz, NH), 4.91 (dd, 1H, JHHZ4.3 Hz, JHH
Z
(250.13 MHz, CDCl3): 3.47 (ddd, 1H, JPHZ20.7 Hz,
2
3
4.3 Hz, N CHPh), 5.13 (d, 1H, JPHZ13.0 Hz, PCHPh),
6.18 (dd, 1H, 3JPHZ7.3 Hz, 3JHHZ5.7 Hz, OCHPh), 7.17–
7.57 (m, 19H, CHar): 13C NMR (52.32 MHz, DMSO-d6):
3JHHZ9.2, 11.9 Hz, NH), 4.78 (dd, 1H, JHHZ6.5,
2
3
7.7 Hz, NCHPh), 5.10 (dd, 1H, JPHZ16.1 Hz, JHH
Z
Z
3
3
11.7 Hz, PCHPh), 6.21 (dd, 1H, JPHZ7.9 Hz, JHH
1
59.18 (d, JPCZ100.9 Hz, HNCHP), 62.18 (s, NCHPh),
5.7 Hz, OCHPh), 7.08–7.48 (m, 16H, CHar), 7.68 (m, 1H,
2
2
3
75.68 (d, JPCZ4.5 Hz, OCHPh), 126.19–128.58 (m,
[N,P]CarCHCHar), 7.93 (dd, 1H, JPHZ7.3 Hz, JHHZ
2
2
3
CHar), 131.04 (d, JPCZ13.0 Hz, Car), 134.37 (d, JPC
Z
7.3 Hz, [P,N]CarCHar), 7.93 (d, 1H, JHHZ4.4 Hz,
1
2
9.7 Hz, Car), 135.21 (d, JPCZ5.6 Hz, CarCH[(P),(NH)]),
137.07 (d, JPCZ8.9 Hz, CarCH[(O),(CH)]), 140.0 (s,
CarCHN), 137.07 (d, JPCZ8.9 Hz, PCarCHar): IR (KBr):
NCHar); 13C NMR (50.32 MHz, CDCl3): 58.60 (d, JPC
Z
3
83.0 Hz, HNCHP), 65.05 (d, 4JPCZ1.5 Hz, NCHPh), 76.92
2
2
(d, JPCZ6.3 Hz, OCHPh), 127.09–129.56 (m, CHar),
3
3360, 3290, 3080, 3020, 2860, 1600, 1490, 1450, 1240,
1190, 1120, 1070, 1030, 990, 960, 690; HRMS (FABC):
calcd for C27H23BrNO2P: 503.0728. Found: 503.0673; 504
[MCH]C (24%), 284 (100%), 180 (67%), 106 (20%), 91
(27%).
134.30 (d, JPCZ1.1 Hz, [P,N]CarCHarCHar), 136.52
2
3
(d, JPCZ6.3 Hz, CarCH[(P),(NH)]), 135.96 (d, JPC
10.4 Hz, CarCH[(O),(CH)]), 138.89 (s, CarCHN), 149.59
Z
3
1
(d, JPCZ19.3 Hz, NCHar), 151.86 (d, JPCZ163.0 Hz,
PCar); IR (KBr): 3420, 3270, 3080, 3020, 2920, 1590, 1490,
1450, 1250, 1230, 1185, 1155, 1090, 1060, 1010, 990, 950,
710, 690; HRMS (FABC): calcd for C26H23N2O2P:
426.1575. Found: 426.1558; 427 [MCH]C (45%), 284
(100%), 180 (54%), 106 (8%), 91 (16%).
4.1.3. (2R*,3R*,5R*,6S*)-(C/K)-2-Oxo-3,5,6-triphenyl-
2-p-methoxyphenyl-1,4,2-oxazaphosphinane 7c. White
solid (627 mg, 1.38 mmol, 1 diastereoisomer), mpZ
233.1 8C; 71% yield: 31P NMR (81.02 MHz, CDCl3):
42.95: 1H NMR (250.13 MHz, CDCl3): 2.15 (d, 1H,
3JPHZ28.4 Hz, NH), 3.80 (s, 3H, CH3), 4.86 (dd, 1H,
4.1.6. (2R*,3R*,5S*,6R*)-(C/K)-2-Oxo-3,5,6-triphenyl-
2-(2-pyridyl)-1,4,2-oxazaphosphinane 7f. White solid
(618 mg, 1.45 mmol, 1 diastereoisomer), mpZ221.2 8C;
75% yield: 31P NMR (81.02 MHz, CDCl3): 24.55; 1H NMR
(250.13 MHz, CDCl3): 3.36 (bs, 1H, NH), 4.17 (d, 1H,
3JHHZ4.5 Hz, 3JHHZ5.1 Hz, NCHPh), 5.07 (d, 1H, 2JPH
Z
Z
3
3
12.5 Hz, PCHPh), 6.16 (dd, 1H, JPHZ7.2 Hz, JHH
5.9 Hz, OCHPh), 7.14–7.59 (m, 19H, CHar); 13C NMR
1
(62.90 MHz, DMSO-d6): 56.17 (s, CH3), 60.30 (d, JPC
2
Z
Z
3JHHZ3.2 Hz, N CHPh), 4.12 (d, 1H, JPHZ19.4 Hz,
2
99.8 Hz, HNCHP), 63.27 (s, NCHPh), 76.09 (d, JPC
PCHPh), 7.15 (m, 1H, OCHPh), 7.13–7.65 (m, 18H,
CHar), 8.75 (m, 1H, NCHar): 13C NMR (62.90 MHz,
2
4.8 Hz, OCHPh), 114.41 (d, JPCZ13.9 Hz, PCarCH),
1
1
119.27 (d, JPCZ140.1 Hz, PCar), 127.09–129.56 (m,
CDCl3): 56.31 (d, JPCZ99.6 Hz, HNCHP), 61.93 (d,
3
2
CHar), 135.42 (d, JPCZ10.6 Hz, MeOCarCHar), 136.71
4JPCZ3.1 Hz, NCHPh), 86.46 (d, JPCZ10.0 Hz,
2
3
3
OCHPh), 125.44–130.59 (all CHar), 134.87 (d, JPC
(d, JPCZ5.3 Hz, CarCH[(P),(NH)]), 138.32 (d, JPC
Z
Z
2
8.2 Hz, CarCH[(O),(CH)]), 141.21 (s, CarCHN), 163.34 (d,
4JPCZ2.9 Hz, MeOCar): IR (KBr): 3270, 3080, 3020, 2960,
2820, 1600, 1490, 1450, 1260,1230, 1180, 1130, 1060,
1030, 990, 950, 700; HRMS (FABC): calcd for
C28H26NO3P: 455.1729. Found: 455.1729; 456 [MCH]C
(29%), 284 (100%), 180 (80%), 106 (10%), 91 (15%).
1.9 Hz, Car), 138.34 (d, JPCZ6.2 Hz, Car), 136.33 (d,
3
3JPCZ10.8 Hz, Car), 136.50 (s, Car), 149.61 (d, JPC
Z
1
21.5 Hz, NCHar), 154.52 (d, JPCZ166.9 Hz, PCar): IR
(KBr): 3430, 3300, 3080, 3020, 2920, 2860, 1595, 1490,
1445, 1270,1230, 1170, 1110, 1070, 1040, 1025, 970, 690;
HRMS (FABC): calcd for C26H23N2O2P 426.1575. Found:
426.1586; 427 [MCH]C (44%), 284 (80%), 180 (49%), 106
(24%), 91 (29%).
4.1.4. (2R*,3R*,5R*,6S*)-(C/K)-2-Oxo-3,5,6-triphenyl-
2-(2-thienyl)-1,4,2-oxazaphosphinane 7d. White solid
(653 mg, 1.51 mmol, 1 diastereoisomer), mpZ224.8 8C;
78% yield: 31P NMR (81.02 MHz, CDCl3): 38.39; 1H NMR
4.1.7. Vinylation of 2-hydrogeno-2-oxo-1,4,2-oxazaphos-
phinane 1a; (2R*,3R*,5R*,6S*)-(C/K)-2-oxo-3,5,6-tri-
phenyl-2-styryl-1,4,2-oxazaphosphinane 8. White solid
3
(250.13 MHz, CDCl3): 2.25 (d, 1H, JPHZ28.9 Hz, NH),

J.-L. Pirat et al. / Tetrahedron 61 (2005) 7029–7036
7035
2
(604 mg, 1.34 mmol, 1 diastereoisomer), mpZ196.4 8C;
69% yield; 31P NMR (81.02 MHz, CDCl3): 39.12; 1H NMR
(250.13 MHz, CDCl3): 2.26 (bm, 1H, 3JPHZ29.2 Hz, NH),
(250.13 MHz, CD3OD): 3.32 (d, 2H, JPHZ17.9 Hz,
PCHPh), 7.07–7.68 (m, 10H, CHar); 13C NMR
(50.32 MHz, CD3OD): 37.70 (d, 1JPCZ94.2 Hz,
3
1
HNCHP), 126.04–132.70 (all CHar), 131.40 (d, JPC
4.87 (dd, 1H, JHHZ4.1, 4.1 Hz, NCHPh), 5.01 (d, 1H,
Z
3
2JPHZ13.9 Hz, PCHPh), 5.98 (dd, 1H, JPHZ8.2 Hz,
130.6 Hz, PCar); IR (KBr): 3040, 3020, 2990, 2860, 1650,
1455,1440, 1240, 1200, 1170, 1140, 960, 700; HRMS
(FABC): calcd for C13H13O2P 233.0731. Found: 233.0735;
233 [MCH]C (100%), 91 (45%): 77 (30%).
2
3JHHZ4.1 Hz, OCHPh), 6.20 (dd, 1H, JPHZ21.5 Hz,
3JHHZ17.4 Hz, vinyl), 7.14–7.62 (m, 20H, CHar); 13C
1
NMR (50.32 MHz, DMSO-d6): 62.53 (d, JPCZ99.3 Hz,
3
HNCHP), 63.91 (d, JPCZ1.6 Hz, NCHPh), 79.57 (d,
1
2JPCZ7.5 Hz, OCHPh), 114.19 (d, JPCZ156.2 Hz,
4.2.3. a-Aminobenzyl-phenylphosphinic acid 9c. In a
10 ml flask containing 300 mg (0.71 mmol) of 7a and
300 mg of palladium catalyst (Pd/C 10% on activated
charcoal, 0.28 mmol) is added 10.6 ml of methanolic
solution of formic acid (10% vol/vol). After 3 h stirring at
55 8C, the reaction mixture is filtrated over celite, and the
filtrate evaporated. 2 ml of aqueous solute of NaOH (1 N)
are added. The suspension is then filtered and the filtrate is
evaporated. The white solid is recrystallized in methanol to
afford 9c as white crystals.
2
PCHCH), 127.54–130.56 (m, CHar), 135.99 (d, JPC
Z
3
5.9 Hz, CarCH[(P),(NH)]), 136.75 (d, JPCZ7.5 Hz,
CarCH[(O),(CH)]), 139.24 (s, CarCHN), 135.46 (d,
1
2JPCZ22.4 Hz, PCHCH), 150.56 (d, JPCZ156.2 Hz,
CHCHCar); IR (KBr): 3420, 3290, 3080, 3020, 2840,
1590, 1485, 1440, 1230, 1210, 1190, 1180, 1090, 1060,
1025, 990, 955, 700; HRMS (FABC): calcd for
C29H26NO2P 451.1779. Found: 451.1768; 452 [MCH]C
(35%), 284 (100%), 180 (58%), 106 (8%), 91 (18%).
4.2. General procedure for deprotection of arylated
2-hydrogeno-2-oxo-1,4,2-oxazaphosphinane compounds
White solid, (132 mg, 0.53 mmol, 1 diastereoisomer), mpZ
205.8 8C; 75% yield; 31P NMR (101.25 MHz, CD3OD):
32.16; 1H NMR (250.13 MHz, CD3OD): 4.27 (d, 1H,
2JPHZ12.0 Hz, PCHPh), 7.23–7.47 (m, 20H, CHar); 13C
4.2.1. a-[(2-Hydroxy-1,2-diphenyl-ethylamino)-benzyl]-
phenyl-phosphinic acid 9a. In a 250 ml flask containing
800 mg of 7a (1.75 mmol) is added 50 ml of concentrated
aqueous HCl solution (35%). Under stirring, the reaction
mixture is heating 3 days at 80 8C. Then, after cooling, the
reaction mixture is dissolved in chloroform and saturated
with aqueous NaCl solution. After extraction with chloro-
form, the organic layers are dried over Na2SO4. The crude
solution is evaporated affording a yellow-brown solid
purified by column chromatography (dichloromethane/
Ethyl acetate gradient: 100/0 to 70/30).
1
NMR (62.90 MHz, CD3OD): 57.29 (d, JPCZ96.5 Hz,
1
HNCHP), 127.24–132.28 (all CHar), 134.00 (d, JPC
Z
2
122.4 Hz, PCar), 139.01 (d, JPCZ1.9 Hz, CarCHP); IR
(KBr): 3240, 3000, 1600, 1490, 1430, 1200, 1170,1130,
1045, 1000, 690, 570, 545,490; HRMS (FABC): calcd for
C13H14NO2P 248.0840. Found 248.0848; 248 [MCH]C
(12%), 106 (33%), 77 (24%). (N8 CAS: 25891-89-8).
Acknowledgements
White solid (780 mg, 1.76 mmol, 1 diastereoisomer), mpZ
209.6 8C; 92% yield; 31P NMR (81.02 MHz, DMSO-d6):
28.93: 1H NMR (250.13 MHz, DMSO-d6): 4.45 (d, 1H,
´ ˆ
Jerome Monbrun is grateful to MRT for a scholarship and
Monique Tillard is warmly acknowledged for X-ray
analyses.
3
2JPHZ12.0 Hz, PCHPh), 4.49 (d, 1H, JHHZ2.4 Hz,
3
NCHPh), 5.53 (d, 1H, JHHZ2.4 Hz, OCHPh), 6.88–7.53
(m, 20H, CHar); 13C NMR (100.62 MHz, DMSO-d6): 60.38
1
(d, JPCZ95.8 Hz, HNCHP), 67.14 (s, NCHPh), 71.15 (s,
1
OCHPh), 125.97–132.18 (all CHar), 130.97 (d, JPC
References and notes
Z
133.9 Hz, Car), 135.92 (s, Car), 141.03 (s, Car); IR (KBr):
3260, 3130, 3040, 2920, 1585, 1490, 1440, 1425, 1450,
1220, 1190, 1070, 950, 700; HRMS (FABC): calcd for
C27H26NO3P 443.1729. Found: 443.1716; 444 [MCH]C
(21%), 887 [2MCH]C (10%), 302 (100%), 284 (51%), 180
(11%), 106 (100%).
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