Practical synthesis of chiral vinylphosphine oxides by direct nucleophilic substitution. Stereodivergent synthesis of aminophosphine ligands

Article abstract of DOI:10.1021/jo052575q

A practical synthesis of optically pure alkylphenylvinylphosphine oxides is described, utilizing a nucleophilic displacement at phosphorus to install the vinyl moiety. The products were used to prepare classes of P-stereogenic aminophosphine (PN) and aminohydroxyphosphine (PNO) ligands. Stereocontrol can be exerted at various stages of the synthesis, to provide specific combinations of chirality in the final product. The effect of the stereogenic phosphorus and match-mismatch of chiralities of PNO ligands were examined in the asymmetric ruthenium-catalyzed hydrogen transfer reduction of three aryl ketones.

Full text of DOI:10.1021/jo052575q

Practical Synthesis of Chiral Vinylphosphine Oxides by Direct
Nucleophilic Substitution. Stereodivergent Synthesis of
Aminophosphine Ligands
Marco Oliana,† Frank King,‡ Peter N. Horton,§ M. B. Hursthouse,§ and
King Kuok (Mimi) Hii*,|
Department of Chemistry, King’s College London, Strand, London WC2R 2LS, U.K., Johnson Matthey,
P.O. Box 1, Belasis AVenue, Billingham, CleVeland TS23 1LB, U.K., EPSRC National Crystallography
SerVice, UniVersity of Southampton, Highfield, Southampton SO17 1BJ, U.K., and Department of
Chemistry, Imperial College London, South Kensington, London SW7 2AZ, U.K.
mimi.hii@imperial.ac.uk
ReceiVed December 14, 2005
A practical synthesis of optically pure alkylphenylvinylphosphine oxides is described, utilizing a
nucleophilic displacement at phosphorus to install the vinyl moiety. The products were used to prepare
classes of P-stereogenic aminophosphine (PN) and aminohydroxyphosphine (PNO) ligands. Stereocontrol
can be exerted at various stages of the synthesis, to provide specific combinations of chirality in the final
product. The effect of the stereogenic phosphorus and match-mismatch of chiralities of PNO ligands
were examined in the asymmetric ruthenium-catalyzed hydrogen transfer reduction of three aryl ketones.
Introduction
which are impractical on a large scale, there is a general lack
of synthetic procedures for homochiral vinylphosphine oxides.
Typically, they are prepared via chiral phosphinate ester
intermediates3 that were resolved either enzymatically or by the
formation of diastereomeric menthyl esters.1j,4 Because of its
inherent reactivity, the double bond is often installed by
elimination reactions in the last stages of the synthesis. To date,
asymmetric synthesis of vinylphosphine oxides via the direct
nucleophilic substitution of a OdPXYZ compound by H2Cd
CHMgX has never been successful,5 although reactions with
other Grignard reagents are known to proceed in a highly
stereospecific manner.6 This is because the conjugate addition
of the organometallic reagent to the vinylphosphine oxide
P-Stereogenic vinylphosphine oxides can be transformed by
a variety of reactions to give structures of considerable structural
complexity, making them highly valuable as precursors for the
synthesis of phosphorus ligands for asymmetric catalysis.1
Discounting chiral resolution by preparative HPLC methods,2
† King’s College London.
‡ Johnson Matthey.
§ EPSRC National Crystallography Service.
| Imperial College London.
(1) (a) Bisaro, F.; Gouverneur, V. Tetrahedron 2005, 61, 2395. (b)
Demchuk, O. M.; Pietrusiewicz, K. M.; Michrowska, A.; Grela, K. Org.
Lett. 2003, 5, 3217. (c) Barbaro, P.; Bianchini, C.; Giambastiani, G.; Togni,
A. Chem. Commun. 2002, 2672. (d) Pietrusiewicz, K. M.; Kuznikowski,
M.; Koprowski, M. Tetrahedron: Asymmetry 1993, 4, 2143. (e) Brandi,
A.; Cicchi, S.; Goti, A.; Pietrusiewicz, K. M. Tetrahedron: Asymmetry 1991,
2, 1063. (f) Brandi, A.; Cicchi, S.; Goti, A.; Pietrusiewicz, K. M.
Tetrahedron Lett. 1991, 32, 3265. (g) Pietrusiewic, K. M.; Zablocka, M.
Tetrahedron Lett. 1988, 29, 1991. (h) Pietrusiewicz, K. M.; Zablocka, M.
Phosphorus, Sulfur Silicon Relat. Elem. 1988, 40, 4751. (i) Pietrusiewicz,
K. M.; Zablocka, M. Tetrahedron Lett. 1988, 29, 937. (j) Johnson, C. R.;
Imamoto, T. J. Org. Chem. 1987, 52, 2170.
(3) Kielbasinski, P.; Zurawinski, R.; Pietrusiewicz, K. M.; Zablocka, M.;
Mikolajczyk, M. Tetrahedron Lett. 1994, 35, 7081.
(4) (a) Bodalski, R.; Rutkowsk-Olma, E.; Pietrusiewicz, K. M. Tetra-
hedron 1980, 36, 2353. (b) Pietrusiewicz, K. M.; Zablocka, M. Tetrahedron
Lett. 1989, 30, 477. (c) Nagel, U.; Roller, C. Z. Naturforsch. B 1998, 53,
211.
(5) For example, see: Carey, J. V.; Barker, M. D.; Brown, J. M.; Russell,
M. J. H. J. Chem. Soc., Perkin Trans. 1 1993, 831.
(6) Korpiun, O.; Lewis, R. A.; Chickos, J.; Mislow, K. J. Am. Chem.
Soc. 1968, 90, 4842.
(2) Brandi, A.; Cicchi, S.; Gasparrini, F.; Maggio, F.; Villani, C.;
Koprowski, M.; Pietrusiewicz, K. M. Tetrahedron: Asymmetry 1995, 6,
2017.
10.1021/jo052575q CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/22/2006
2472
J. Org. Chem. 2006, 71, 2472-2479

StereodiVergent Synthesis of Aminophosphine Ligands
SCHEME 1. Stereodivergent Synthesis of
SCHEME 2. Synthesis of (()-Alkylphenyl and
â-Aminophosphine Ligandsa
Arylphenylphosphinic Chloridesa
a (i) Michael addition; (ii) reduction with retention of configuration; (iii)
reduction with inversion of configuration.
product is competitive under the reaction conditions required
for the nucleophilic substitution.7
a (i) MeOH, pyridine, hexane, 0 °C; (ii) RI, reflux (R ) alkyl); (iii) PCl5,
CH2Cl2, reflux; (iv) HNEt2, pyridine, THF, reflux, 3 h; (v) ArMgBr, THF,
0°C; (vi) H2O2, concentrated HCl, acetone; (vii) SOCl2.
As part of our research directed toward the catalytic applica-
tions of bidentate (PN) and terdentate (PNP, PNN, PNO)
aminophosphine ligands, we have developed a number of
methodologies for the synthesis of ligands containing stereogenic
carbon and phosphorus atoms.8,9 During the course of this work,
we became particularly interested in utilizing aza-Michael
addition as a means of accessing chiral â-aminophosphines con-
taining chirality at the N- and P-termini. By judicious selection
of the appropriate isomers of amine and vinylphosphine oxide
precursors, different structures and chirality can be assembled
in a single step. Furthermore, by choosing the appropriate re-
agents, the reduction of phosphine oxide can be achieved stereo-
specifically with either retention or inversion of configuration,
delivering great stereodiversity to the process (Scheme 1).
In our quest to develop a general route to the synthesis of
optically pure vinylphosphine oxide precursors, we were at-
tracted by a report by Khiar and Ferna´ndez et al., who described
the stereoselective synthesis of tertiary o-anisyl and n-propyl
methylphenylphosphine oxides by nucleophilic displacement of
phosphinate esters prepared from sugar derivatives.10 The
reactions with alkyl and aryl Grignard reagents were reported
to occur under very mild conditions (room temperature, 2 h),
but the reaction with vinyl Grignard reagents was not reported.
Herein, we will describe how this method can be modified to
achieve stereoselective, gram-scale synthesis of optically active
vinylphosphine oxides, which can be used in the synthesis of a
number of P-stereogenic PN and PNO ligands, containing one
SCHEME 3. Formation of Phosphinate Esters
or more stereogenic centers. Finally, some results obtained from
the application of these ligands in the asymmetric transfer
hydrogenation reactions will be discussed.
Result and Discussion
Preparation of Phosphinic Chlorides. Asymmetric phos-
phinic chlorides were prepared using established literature
procedures.6 For alkylphenylphosphinic chlorides, dichlorophen-
ylphosphine was subjected to alcoholysis to give dialkyl phos-
phonites 1. Michaelis-Arbusov reaction with the relevant alkyl
halides gave the phosphinate esters 2, which were chlorinated
to afford the phosphinic chorides 3a-c (Scheme 2). On the other
hand, aryl- and benzylphenylphosphinoyl chlorides 3d-f were
prepared by the chemoselective substitution of chlorophen-
ylphosphoramide 4, using the requisite aryl Grignard reagents.11
The resulting arylphenylphosphonamides 5d-f were promptly
oxidized and hydrolyzed in one pot, to yield asymmetric
arylphenylphosphinic acids 6d-f. Subsequent chlorination af-
forded the arylphenylphosphinic chlorides 3d-f.
Formation of Phosphinate Esters (Scheme 3, Table 1). In
the absence of detailed experimental procedures, the reaction
between 1,2:5,6-di-O-cyclohexylidene-D-glucofuranose (DCG),
7, and methylphenylphosphinic chloride 3a was reexamined.
The initial reaction was conducted in toluene at 0 °C, employing
triethylamine as the base and an excess of the methylphen-
ylphosphinic chloride 3a (10 equiv). The progress of the reaction
was monitored by TLC analysis and quenched upon complete
consumption of the chiral auxiliary. Following workup and
column chromatography, the corresponding phosphinate ester
(7) For a report of a polymerization reaction of diphenylvinylphosphine
oxide initiated by the Michael addition of vinylmagnesium bromide, see:
Collins, D. J.; Rowley, L. E.; Swan, J. M. Aust. J. Chem. 1974, 27, 841.
(8) For our previous work on achiral aminophosphines: (a) Parisel, S.
L.; Adrio, L. A.; Pereira, A. A.; Pe´rez, M. M.; Vila, J. M.; Hii, K. K.
Tetrahedron 2005, 61, 9822. (b) Parisel, S. L.; Moorcroft, N. D.; Jutand,
A.; Aldous, D. J.; Hii, K. K. Org. Biomol. Chem. 2004, 2, 301. (c) Rahman,
M. S.; Prince, P. D.; Steed, J. W.; Hii, K. K. Organometallics 2002, 21,
4927. (d) Qadir, M.; Mo¨chel, T.; Hii, K. K. Tetrahedron 2000, 56, 7975.
(e) Qadir, M.; Mo¨chel, T.; Hii, K. K. Tetrahedron 2000, 56, 7975. (f)
Rahman, M. S.; Steed, J. W.; Hii, K. K. Synthesis 2000, 1320. (g) Thornton-
Pett, M.; Jutand, A.; Tooze, R. P. Organometallics 1999, 18, 1887.
(9) For our previous work on chiral aminophosphine (oxide) ligands,
see: (a) Lam, H.; Coles, S. J.; Hursthouse, M. B.; Aldous, D. J.; Hii, K. K.
Tetrahedron Lett. 2005, 46, 8145. (b) Cheng, X.; Horton, P. N.; Hursthouse,
M. B.; Hii, K. K. Tetrahedron: Asymmetry 2004, 15, 2241. (c) Rahman,
M. S.; Oliana, M.; Hii, K. K. Tetrahedron: Asymmetry 2004, 15, 1835. (d)
Cheng, X.; Hii, K. K. Tetrahedron: Asymmetry 2003, 14, 2045. (e) Lam,
H.; Cheng, X.; Steed, J. W.; Aldous, D. J.; Hii, K. K. Tetrahedron Lett.
2002, 43, 5875.
(10) (a) Kolodiahnyi, O. I.; Grishkun, E. V. Tetrahedron: Asymmetry
1996, 7, 967. (b) Benabra, A.; Alcudia, A.; Khiar, N.; Fernandez, I.; Alcudia,
F. Tetrahedron: Asymmetry 1996, 7, 3353. (c) Fernandez, I.; Khiar, N.;
Roca, A.; Benabra, A.; Alcudia, A.; Espartero, J. L.; Alcudia, F. Tetrahedron
Lett. 1999, 40, 2029.
(11) (a) Horner, L.; Nippe, B. Chem. Ber. 1958, 91, 67. (b) Mann, F.
G.; Tong, B. P.; Wystrach, V. P. J. Chem. Soc. 1963, 1155. (c) Blicke, F.
F.; Raines, S. J. Org. Chem. 1964, 29, 204. (d) Miles, J. A.; Gribiak, R. C.;
Cummins, C. J. Org. Chem. 1982, 47, 1677.
J. Org. Chem, Vol. 71, No. 6, 2006 2473

Oliana et al.
TABLE 1. Reaction of Methylphenylphosphinic Chloride 3a with
DCGa,b
TABLE 3. Chemical Shifts, Optical Rotation, and Configurational
Assignments for 8-12
entry
equivc
base
solvent
t/h
T/°C
d.r.d
1H NMR chemical shift (ppm)a
b
1
2
3
4
5
6
7
8
9
10
3
1
1
1
1
1
1
1
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Pyr
toluene
toluene
toluene
toluene
toluene
THF
CH2Cl2
toluene
THF
8
18
24
48
15
24
24
24
24
0
0
0
95:5
95:5
95:5
95:5
compound
H-1
H-2
H-3
[R]D
assignment
c
8
5.90
5.79
5.89
5.75
5.96
5.72
5.75
5.80
5.87
5.83
5.04
4.64
5.07
4.58
5.20
4.52
4.84
4.59
5.10
4.94
4.37
4.87
4.44
4.90
4.55
4.96
4.45
4.81
4.70
4.72
-58.6
-31.5
-54.2
-27.1
-51.0
-12.3
-53.4
-17.0
-39.0d
-9.0e
SP
c
RP
-78
25
0
9
10
11
12
SP
RP
SP
RP
SP
RP
RP
SP
92:8
87:13
80:20
40:60
30:70
0
0
0
Pyr
a Scheme 3, R ) Me. b All reactions were performed using 1 equiv of
7 and 3 equiv of the appropriate base. c Equivalents of methylphenylphos-
phinic chloride 3a. d SP/RP epimeric ratio, determined by 1H NMR analysis.
a Unless otherwise stated,1H NMR (360 MHz, CDCl3) spectra were
recorded with optically pure samples (de > 99%, verified by HPLC
analysis). b Optical rotations were measured in CHCl3. c Reported absolute
configuration.10b d de ) 92%. e de ) 95%.
TABLE 2. Reaction of Racemic Phenylphosphinic Chlorides 3b-f
with 7a,b
yield
entry substrate
R
product base solvent (%)c d.r.d
reaction (Table 2). In the presence of triethylamine, the ethyl
and benzyl phosphinate esters 9 and 11 were obtained with high
diastereomeric excesses (entries 1 and 5).15 An increase in the
size of the alkyl group resulted in a decrease in stereodiffer-
entiation, as shown by the lower de obtained with the isopropyl
derivative 10 (entry 3).
The diastereomers of phosphinate esters 8-11 were separated
easily on a large scale; up to 5 g can be separated effectively
on a preparative (flash) column to afford optically pure isomers
(de > 99%, determined by HPLC).
It would appear that DCG is not a good selector for
asymmetrical diarylphosphine oxides. By replacing the alkyl
substituent on phosphorus with an aryl group, a significant drop
in stereoselectivity was observed (Table 2, entries 7-9). As a
result, the separation of the diastereomers proved to be
problematic. Despite several repeated chromatographic runs
using a variety of eluting systems and stationary phases, the
o-anisyl-substituted phosphinate ester 12 can only be obtained
in an optically enriched form (de e 95%), whereas the epimeric
separation of 13 remained elusive.
1
2
3
4
5
3b
3b
3c
3c
3f
Et
Et
i-Pr
i-Pr
Bn
Bn
9
9
Et3N toluene
Pyr THF
Et3N toluene
Pyr THF
Et3N toluene
Pyr THF
Et3N toluene
Pyr THF
Et3N toluene
Pyr THF
93
94
92
90
95
95
93
94
87
83
93:7
30:70
86:14
40:60
90:10
40:60
30:70
55:45
40:60
55:45
10
10
11
11
12
12
13
13
6
3f
7
8
9
10
3d
3d
3e
3e
o-anisyl
o-anisyl
1-naphthyl
1-naphthyl
a Scheme 3. b The reactions were performed at 0 °C using 3b-f (10
mmol), 7 (1.5 equiv), and the appropriate base (3 equiv). c Isolated yield
after column chromatography. d Determined by H NMR analysis.
1
8 can be obtained in near quantitative yields. The diastereomeric
ratio can be determined by H NMR analysis, by comparing
1
resonances of H-1, H-2, and H-3 corresponding to each epimer,
which are separated by large anisotropic shifts.12 Alternatively,
the diastereomeric excess (de) of 8 can also be determined by
HPLC analysis.13 The product was found to have a de of 90%
(Table 1, entry 1).
Contrary to a previous report,10b the diastereomeric ratio
remained unchanged when the reactants were used in equimolar
amounts, even at lower temperature (entries 2-4). At room
temperature, the reaction experienced a slight erosion of de
(entry 5). The reaction was noticeably slower in more polar
solvents (dichloromethane, THF), which also led to a reduction
in the selectivity (entries 6 and 7). The effect of the achiral
base had been identified as the most important factor that
determines the stereochemical outcome of the reaction.9b,c
Indeed, the selectivity was reversed in the presence of pyridine
(entries 8 and 9).
Key spectroscopic and optical properties of the phosphinate
esters 8-12 are presented in Table 3. The absolute configuration
of the major epimer of compound 8 obtained using triethylamine
(SP) has been previously established.10b Notably, it displayed a
distinctive distribution of proton resonances, whereby the H-3
signal (double-doublet) is shifted upfield with respect to H-2.
This is reversed for the opposite epimer (RP)-8, where the H-3
resonance is located downfield to H-2. This trend appears to be
consistent for all the alkylphenylphosphinate esters (see Sup-
porting Information). Thus, the absolute configurations of 9-11
were tentatively assigned by this analogy. These were confirmed
Subsequently, reactions of phosphinic chlorides 3b-g with
7 were performed using the two bases at 0 °C (Table 2). As
these reactions are slower, a slight excess of the DCG (1.5 equiv)
was employed.14 The phosphinate esters 9-13 were obtained
with good to excellent yields after column chromatography,
which also permitted the recovery of the excess chiral auxiliary.
Once again, the stereochemical outcome of the reactions was
directly dependent on the nature of the achiral base used in the
(14) The reaction progress was monitored by 31P-{1H} NMR analysis.
Aliquots of the reaction mixture were extracted periodically and quenched
immediately by the addition of water. Reaction was terminated upon
complete consumption of the starting phosphinic chloride (acid). The
formation of epimers was indicated by the appearance of two resonance
signals.
(15) The origin(s) of the base-directed stereoselectivity is not clear at
this juncture. However, the unchanged de at different reactant ratios (Table
1, entries 1-3) suggests that the process is unlikely to be the result of a
dynamic kinetic resolution, which would be expected to be concentration
dependent. The Et3N/toluene (strong base/nonpolar solvent) system could
generate a nucleophilic alkoxide with a different selectivity to the alcohol,
and/or, conversely, the use of pyridine/THF could alter the nature of the
electrophile; e.g., the nucleophilic pyridine can attach itself to the phosphorus
center, generating a phosphonium intermediate (stabilized by the polar
solvent).
(12) Resonances attributed to protons H-1 and H-2 appeared as distinct
doublets in the region 6.00-4.50 ppm. For the SP diastereoisomer, the H-3
resonance is shifted upfield to H-2, whereas the opposite is true for the RP
isomer (Supporting Information).
(13) HPLC conditions: Hicrom Partisil P5 Silicon column, 95:5 hexane/
i-PrOH, flow rate of 1 mL/min, tR ) 7.41 min, and tS ) 9.23 min.
2474 J. Org. Chem., Vol. 71, No. 6, 2006

StereodiVergent Synthesis of Aminophosphine Ligands
SCHEME 4. Nucleophilic Displacement of DCG by
Vinylmagnesium Bromide
later by chemical conversion of 8 and 9 into phosphine oxides
of known configuration. Although such correlations were not
achieved for 10 and 11, it is not unreasonable to assume that
the NMR assignment is consistent.
FIGURE 1. Molecular structures of alkylvinylphenylphosphine oxides
14 (left) and 15 (right) showing the requisite RP stereochemistry
(aromatic hydrogens are omitted to aid clarity).
For the arylphosphinate ester 12, the H-3 resonance signal
appeared upfield to H-2 for both epimers. For these isomers,
stereochemical assignments were made by chemical correlation
(vide infra).
(Figure 1).19 Also, although there are four different molecules
of 14 in the asymmetric unit, they only differ by the rotation of
the phenyl ring (Supporting Information).
Thus, in a predictable manner, the use of triethylamine in
the reaction between alkylphenylphosphinic chloride and 7 led
predominantly to the formation of the (SP)-phosphinate ester,
whereas pyridine promoted the formation of the opposite epimer.
When arylphenylphosphinic chlorides are employed, the (RP)-
phosphinate was obtained as the major product with triethy-
lamine and the (SP)-phosphinate was slightly preferred with
pyridine.16
Displacement of the Chiral Auxiliary: Synthesis of Enan-
tiopure Vinylphosphine Oxides (Scheme 4). In the original
reports, nucleophilic displacements of the DCG by Grignard
reagents were effected at room temperature. To suppress the
Michael addition, we conducted the reaction at much lower
reaction temperatures. After some trial and error, the optimal
temperature was found to be -40 °C, whereupon the reaction
of (SP)-8 with vinylmagnesium bromide proceeded smoothly
to give methylphenylvinylphosphine oxide 14.
The reaction is extremely sensitive to the reaction temperature.
Crucially, the Grignard reagent (3 equiv) has to be added slowly
at -78 °C, before the temperature is raised to -40 °C, where
it is maintained until all the phosphinate ester is consumed (31P
NMR).17 It is also important to quench the reaction at 0 °C.
Using this procedure, one can isolate methylphenylvinylphos-
phine oxide 14 in 80% yield after purification by column
chromatography. The product was found to have the RP
A good result was also obtained for the displacement of the
optically enriched 12 (92% de), which furnished the o-anisyl-
phenylvinylphosphine oxide 16 in 75% isolated yield. At this
point, its configuration (RP) can be established by comparison
of its optical rotation, [R]D ) +7.9°, with the reported value
([R]D ) +8.8°).1j The value is consistent with an optical purity
of 92% (0.92 × 8.8°), which confirms the stereospecificity of
the substitution reaction. Assuming that this has also proceeded
with inversion of configuration at phosphorus, it follows that
the phosphinate ester 12 has the RP configuration.
The nucleophilic substitution reactions proved to be sensitive
to the alkyl group at phosphorus. No reaction between the
isopropyl derivative 10 and vinylmagnesium bromide could be
detected (31P NMR), even when a large excess of Grignard
reagent (10 equiv) was employed. Presumably, the nucleophilic
substitution is prevented by insurmountable steric congestion
at phosphorus. Conversely, the addition of the vinyl Grignard
reagent to the benzyl phosphinate ester 11 also failed to give
the desired vinylphosphine oxide. Even though a bright red
reaction mixture was obtained, only the starting material was
recovered upon workup. We attributed this failure to the acidity
of the benzylic protons, which could be deprotonated by the
organometallic reagent. Because the Michael addition can be
suppressed under these reaction conditions, we envisage that
these problems may be circumvented by introducing the vinyl
moiety at an earlier stage, i.e., adding the benzyl or isopropyl
Grignard reagent to a diastereomerically pure sample of vinyl-
phenylphosphinate ester. Because a variety of vinylphosphine
oxides may be accessible through one common phosphinate
ester, it is also a more attractive strategy; this will be explored
in our future work.
configuration, by comparison of its optical rotation, [R]D
)
+81.7°, which was opposite in sign to the reported value of
the SP isomer ([R]D ) -80°).18 Hence, the nucleophilic
substitution had occurred with inversion of configuration at
phosphorus. Similarly, ethylphenylvinylphosphine oxide (RP)-
15 may be obtained from phosphinate (SP)-9 in 72% yield ([R]D
) +77.5°). The opposite enantiomers (SP)-14 and -15 were also
obtained from (RP)-8 and -9 in good yields.
Synthesis of Homochiral â-Aminophosphines by the Aza-
Michael Addition. The conjugate addition of amines should
proceed without loss of stereointegrity at the phosphorus atom.
Previously, Pietrusiewicz et al. demonstrated that the Michael
addition of amines to P-stereogenic vinylphosphine oxides
Slow crystallization from ether at -5 °C afforded single
crystals of (RP)-14 and -15 in sufficiently good quality to enable
the absolute configurations to be determined unequivocally
(16) Note that substitution of alkyl by aryl in these phenylphosphinate
esters neccesitates a change in the chiral descriptor; the stereoinduction of
the achiral base is unchanged for all the substrates.
(17) Side-product formation was observed at -20 °C.
(18) Pietrusiewicz, K. M.; Zablocka, M.; Monkiewicz, J. J. Org. Chem.
1984, 49, 1522.
(19) Absolute structure parameters for 14 ) 0.06(7) and 15 ) -0.06-
(9). Although the esds for the latter structure is slightly higher, the absolute
configuration of this molecule has been corroborated by comparison of its
[R]D with the reported value. The X-ray crystal structure of (S)-14 was
previously reported: Pietrusiewicz, K. M.; Zablocka, M.; Wieczorek, W.;
Brandi, A. Tetrahedron: Asymmetry 1991, 2, 419.
J. Org. Chem, Vol. 71, No. 6, 2006 2475

Oliana et al.
occurs slowly in water (7 days heating in a sealed ampule).20
We have subsequently found that the addition can be dramati-
cally accelerated in the presence of methanol. In all cases,
reaction was complete in just a few hours, even with the most
sterically demanding tert-butylamine.8f We have used the
methodology to assemble aminophosphine and aminophosphine
oxide ligands from commercially available chiral amines and
amino alcohols.9c
TABLE 4. Yields and Optical Rotations of Chiral
Aminophosphines and Aminohydroxyphosphinesa
Thus, both isomers of methylphenylvinylphosphine oxide 14
were subjected to Michael addition reactions with a number of
achiral, as well as optically active, amines and amino alcohols.
Reactions were complete in a few hours (31P NMR), to afford
P-chiral phosphine oxides 17-24 in near quantitative yields after
purification via column chromatography (Table 4). Single sets
of 1H and 31P NMR resonances were observed for the addition
of homochiral amines; thus, the optical purity of the products
were judged to be at least >95%.
The aminophosphine oxides 17, 19, and 20 were reduced
stereoselectively with inversion of configuration, using HSiCl3
and triethylamine,21 to the corresponding new P-stereogenic
phosphines 25-27 (Figure 2) in good yields (70-80%). The
optical rotary values of 25 corresponded well with those reported
for their enantiomers.20b Again, no loss of the optical purity
was observed. This was confirmed by subjecting (RP)-26 to
oxidation by H2O2 in CHCl3, which is known to occur with
retention of configuration.22 This provided (SP)-19, which
exhibited specific optical rotation equal in magnitude but
opposite in sign to its enantiomer (Table 4, entry 4). This
experiment also illustrates the versatility of the methodology,
which may be manipulated to obtain the required P-chirality in
the ligand, by choosing the appropriate reduction/oxidation
reagents. Thus, the stereochemistry can be defined in the final
transformation step, allowing simple access to P-chirality
without recourse to unnatural L-glucose.
Catalytic Studies (Scheme 5, Table 5). Previously, we have
found that hydroxyaminophosphine ligands derived from chiral
amino alcohols confer extremely catalytic activity and selectivity
in ruthenium-catalyzed asymmetric transfer hydrogenation
reactions.9b,c Herein, we disclose some preliminary catalytic
studies carried out using the P-stereogenic hydroxyaminophos-
phine ligands derived from (RP)-14. The results will be com-
pared with those obtained with the diphenylphosphines 29-31
prepared earlier (Figure 3).9c
Using the reaction conditions previously optimized for
P-N-O ligands, the asymmetric transfer hydrogenation reac-
tions of three aryl ketones (acetophenone, propiophenone, and
1-phenylbutan-1-one) were carried out at room temperature
using 2-propanol as the hydrogen source.
a Diastereomeric purity >95%, determined by 1H NMR analysis.
b Recorded in CHCl3. c Isolated yields. d Reported [R]D of the SP, SC
enantiomer20b ) +27.3 (CHCl3, c ) 5.3). e Reported [R]D of the SP, RC
enantiomer20b ) -56.1 (CHCl3, c ) 3.2).
Previously, we have established that hydroxyaminophosphine
oxide (PNO) ligands derived from ephedrine are noticeably more
stereoselective than PN ligands generated from other amines.
Furthermore, chirality at phosphorus has a small but significant
effect on the enantioselectivity. These observations are rein-
forced in the present study: Ligands 20 afforded much higher
conversion and enantioselectivity than the corresponding ligand
derived from L-alaninol (entries 1-3 vs 7-9, entries 4-6 vs
FIGURE 2. P-Stereogenic â-aminophosphines and aminohydroxy-
phosphines.
(20) (a) Maj, A. M.; Pietrusiewicz, K. M.; Suisse, I.; Agbosou, F.;
Mortreux, A. Tetrahedron: Asymmetry 1999, 10, 831. (b) Maj, A. M.;
Pietrusiewicz, K. M.; Suisse, I.; Agbosou, F.; Mortreux, A. J. Organomet.
Chem. 2001, 626, 157.
(21) (a) Naumann, K.; Zon, G.; Mislow, K. J. Am. Chem. Soc. 1969,
91, 7012. (b) Horner, L.; Balzer, W. D. Tetrahedron Lett. 1965, 6, 1157.
(22) Horner, L. Pure Appl. Chem. 1964, 9, 225.
10-12). The ligand (SP,RC,SC)-20 is particularly selective,
conferring enantiomeric excesses (ee’s) in excess of 90% for
the reduction of all three ketones. In the absence of the
stereogenic phosphorus, the ligand (RC,SC)-28 afforded products
2476 J. Org. Chem., Vol. 71, No. 6, 2006

StereodiVergent Synthesis of Aminophosphine Ligands
SCHEME 5. Asymmetric Ruthenium-Catalyzed Transfer
Hydrogenation of Aryl Ketones
3.6, H2), 5.90 (1H, d, JHH ) 3.6, H1), 7.84-7.91 (2H, m, Hmeta),
7.49-7.55 (1H, m, Hpara), 7.84-7.91 (2H, m, Hortho). δC (90.6 MHz,
CDCl3): 16.0 (d, JCP ) 105, PCH3), 23.9 (s, CH2), 24.1 (s, CH2),
24.6 (s, CH2), 24.8 (s, CH2), 25.2 (s, CH2), 25.5 (s, CH2), 35.3 (s,
CH2), 36.1 (s, CH2), 37.0 (s, CH2), 67.5 (s, C6), 72.0 (s, C5), 78.5
(d, JCP ) 7, C3), 81.1 (d, JCP ) 9, C4), 83.7 (s, C2), 105.1 (s, C1),
110.4 (s, C), 113.1 (s, C), 129.8 (d, JCP ) 13, Cmeta), 136.6 (d,
JCP ) 11, Cortho), 132.8 (d, JCP ) 134, Cipso), 133.1 (d, JCP ) 3,
with ee’s around 90% (entries 7-9). In the presence of a (RP)-
phosphine oxide moiety, ligand 20 improved the yields of the
alcohols by up to 10%. However, although the enantioselectivity
remained unchanged for the reduction of acetophenone, optical
purities of the other products were noticeably reduced (entries
10-12). By changing the chirality at phosphorus to (SP)-20,
the ee’s of the products were significantly enhanced (entries
13-15), and the catalytic activities were maintained. Hence,
there are clear cooperative effects between the stereogenic
centers on the enantioselectivity but not on the catalytic activity
of the process. The stereoinduction is unaffected by the
stereochemistry at phosphorus.
Reduction of the phosphorus moiety to the +3 oxidation state
reduced the catalytic activity of the resultant catalysts (entries
16-21). Once again, P-chirality was found to have an effect
on the enantioselectivity of the processes, but it is not significant
enough to change the overall stereoinduction.
C
para). δP (145.8 MHz, CDCl3): +46.4. νmax (KBr disk)/cm-1: 1173
(s, PdO). HRMS (EI) m/z: 501.2032 (M + Na+). Calcd for
C25H35NaO7P: 501.2018.
Dicyclohexylidene-D-glucose-(RP)-methylphenyl Phosphinate
Ester, (RP)-8. White solid, 98%, mp 49-50 °C. [R]20 -31.5° (c
D
1.0, CHCl3). δH (360 MHz, CDCl3): 1.20-1.66 (20H, m, CH2),
1.73 (3H, d, JHP ) 14.5, PCH3), 3.96 (1H, dd, JHH ) 8.6, 4.5, H6),
4.07-4.14 (2H, m, H6, H4), 4.21 (1H, ddd, JHH ) 8.6, 5.4, 4.5,
H5), 4.64 (1H, d, JHH ) 3.6, H2), 4.87 (1H, dd, JHP ) 9.1, JHH
)
2.7, H3), 5.79 (1H, d, JHH ) 3.6, H1), 7.39-7.46 (2H, m, Hmeta),
7.48-7.54 (1H, m, Hpara), 7.70-7.78 (2H, m, Hortho). δC (90.6 MHz,
CDCl3): 15.5 (d, JCP ) 95, PCH3), 23.8 (s, CH2), 24.2 (s, CH2),
24.3 (s, CH2), 24.5 (CH2), 25.2 (s, CH2), 25.5 (s, CH2), 36.0 (s,
CH2), 36.8 (s, CH2), 37.0 (s, CH2), 67.7 (s, C6), 72.6 (s, C5), 77.9
(d, JCP ) 7, C3), 81.4 (d, JCP ) 7, C4), 84.0 (s, C2), 105.3 (s, C1),
110.4 (s, C), 113.5 (s, C), 129.0 (d, JCP ) 13, Cmeta), 130.0 (d,
JHP ) 11, Cortho), 132.7 (d, JCP ) 136, Cipso), 132.9 (d, JCP
)
2, Cpara). δP (145.8 MHz, CDCl3): +45.1. νmax (KBr disk)/cm-1
:
1170 (s, PdO). HRMS (EI): 501.2007 (M + Na+). Calcd for
C25H35NaO7P: 501.2018.
Diastereomeric Mixture (SP/RP)-dicyclohexylidene-D-glucose-
(1-naphthyl)phenyl Phosphinate Ester, 13. White solid, 80%, mp
72-75 °C. δH (360 MHz, CDCl3): 1.28-1.80 (20H, m, CH2),
4.02-4.28 (3H, m, H6, H4), 4.38-4.54 (1H, m, H5), 4.97-5.01
(1H, m, H3), 5.21 (1H, d, JHH ) 3.6, H2), 5.27 (1H, d, JHH ) 3.6,
H2), 5.96 (1H, d, JHH ) 3.6, H1), 6.05 (1H, d, JHH ) 3.6, H1),
7.17-8.85 (12H, m, Ar-H). δC (90.6 MHz, CDCl3): 24.6 (s, CH2),
24.7 (s, CH2), 24.8 (s, CH2), 25.6 (s, CH2), 25.8 (s, CH2), 26.0 (s,
CH2), 26.1 (s, CH2), 67.0 (s, C6), 72.2 (s, C5), 78.0 (d, JCP ) 7,
C3), 82.1 (d, JCP ) 9, C4), 85.2 (s, C2), 105.4 (s, C1), 124.0-160.0
(Ar-C). δP (145.8 MHz, CDCl3): +35.6, +35.4. HRMS (EI):
613.2304 (M + Na+). Calcd for C34H39NaO7P: 613.2331.
General Procedure for the Displacement of Chiral Auxiliary.
Vinylmagnesium bromide (1 M solution in THF, 2 equiv) was
added dropwise, via syringe, to a solution of the corresponding
phosphinate ester (3 mmol) in THF (20 mL) at -78 °C. The mixture
was heated gradually to -40 °C and stirred until the reaction was
complete (31P NMR). The reaction mixture was quenched by
transfer via cannula into a solution of 1 M aqueous NH4Cl (100
mL) at 0 °C. Following separation, the aqueous layer was extracted
with CH2Cl2 (3 × 20 mL). The combined organic layers were
washed with brine (2 × 25 mL), dried (MgSO4), filtered, and
evaporated to furnish the crude product as an oil, which was purified
by flash chromatography on silica using CHCl3/acetone (8:2) as
the eluting system. Solid products were recrystallized from diethyl
ether.
Conclusion
A practical synthesis of optically pure alkylphenylvinylphos-
phine oxides has been achieved in five steps from dichlorophe-
nylphosphine, involving the nucleophilic displacement of a DCG
derivative by a vinyl Grignard reagent at low temperature. The
methodology proved to be well suited for large-scale preparation
of these valuable precursors. Utilizing the Michael reaction, one
can prepare a variety of optically pure aminophosphine ligands,
and stereochemistry of the ligands can be controlled in a
predictable manner. Finally, cooperative effects between donor
atoms, chirality, and oxidation state of the phosphorus moiety
are demonstrated in the ruthenium-catalyzed asymmetric transfer
hydrogenation reactions of ketones.
Experimental Section
Synthesis and Resolution of Dicyclohexylidene-D-glucose
Phosphinate Esters. Et3N (3 equiv) was added to an ice-cold
solution of the appropriate phosphinic chloride (10 mmol) in toluene
(25 mL) and stirred for 10 min. A solution of di-o-cyclohexylidene-
R-D-glucofuranose (1.2 equiv) in toluene (25 mL) was then added
slowly over 30 min. The reaction mixture was allowed to warm to
room temperature, and stirring was continued until all the phosphinic
chloride was consumed (31P NMR). The mixture was filtered, and
the solvent was removed under reduced pressure. The crude product
was purified by passing through a short silica column, eluting with
ether, to recover any unreacted alcohol (DCG). Diastereomeric
separation was achieved chromatographically on flash silica gel
using a mixture of ether/acetone (9:1). Diastereomeric excess (de)
was determined either by normal-phase HPLC (silicon column, flow
rate of 1.0 mL/min, 95:5 hexane/i-PrOH) or by reverse-phase HPLC
(C18 column, flow rate of 0.5 mL/min, MeOH/H2O, gradient 60:
40, 30 min; 95:5, 40 min; and 60:40, 30 min).
(+)-(RP)-Methylphenylvinylphosphine Oxide, (RP)-14. White
solid, 80%, mp 79-81 °C. [R]D20 +81.7° (c 2.0, CHCl3). δH (360
MHz, CDCl3): 1.77 (3H, d, JHP ) 13.2, PCH3), 6.15 (1H, ddd, JHP
) 40.6, JHH ) 12.4, 1.8, CH2), 6.22 (1H, ddd, JHP ) 22.1, JHH
)
18.6, 1.8, CH2), 6.42 (1H, ddd, JHP ) 25.1, JHH ) 18.6, 12.4, PCH),
7.44-7.54 (3H, m, Hmeta, Hpara), 7.67-7.74 (2H, m, Hortho). δC (90.6
MHz, CDCl3): 16.30 (d, JCP ) 74, PCH3), 128.6 (d, JCP ) 12,
C
meta), 130.6 (d, JCP ) 10, Cortho), 131.7 (d, JCP ) 3, Cpara), 132.5
(d, JCP ) 95, CH2), 132.9 (s, CH), 133.2 (d, JCP ) 102, Cipso). δP
(145.8 MHz, CDCl3): +27.7. νmax (KBr disk)/cm-1
1165
:
Dicyclohexylidene-D-glucose-(SP)-methylphenyl Phosphinate
Ester, (SP)-8. White solid, 98%, mp 49-51 °C. [R]20 -58.6° (c
(PdO). Anal. Calcd for C9H11OP: C, 65.06; H, 6.67. Found C,
65.27; H, 6.68%. Colorless crystals for X-ray crystallography
obtained by recrystallization from diethyl ether at -5 °C.
(-)-(SP)-Methylphenylvinylphosphine Oxide, (SP)-14.17 White
solid, 78%, mp 79-81 °C (lit. 80 °C). [R]20D -81.3° (c 2.0, CHCl3).
D
1.0, CHCl3). δH (360 MHz, CDCl3): 1.20-1.66 (20H, m, CH2),
1.65 (3H, d, JHP ) 14.5, PCH3), 3.92-3.98 (2H, m, H4, H6), 4.08
(1H, dd, JHH ) 8.6, 5.9, H6), 4.23 (1H, ddd, JHH ) 8.6, 5.4, 4.5,
H5), 4.37 (1H, dd, JHP ) 6.8, JHH ) 2.3, H3), 5.04 (1H, d, JHH
)
J. Org. Chem, Vol. 71, No. 6, 2006 2477

Oliana et al.
TABLE 5. Asymmetric Transfer Hydrogenation of Arylphenyl Ketonesa
a General reaction conditions: 2 mmol of the appropriate substrate in 2-propanol (20 mL), [Ru(cymene)Cl2]2 (0.01 mmol), appropriate ligand (0.04
mmol), base (0.1 mmol), 29 °C. Conversion and enantioselectivity were determined by GC analysis.
reaction mixture was heated in a sealed Young’s tube at 80 °C.
When the reaction was complete, the volatiles were removed under
reduced pressure. The remaining crude product was purified by
flash chromatography on silica using CHCl3/acetone/Et3N (8:2:0.5).
Method B: To a solution of the appropriate vinylphosphine oxide
(3 mmol) in 3 mL of MeOH was added the appropriate amine (0.8
equiv). The reaction mixture was heated in a sealed Young’s tube
FIGURE 3. Non-P-chiral aminohydroxyphosphines included in the
at 80 °C. After the appropriate reaction time, MeOH was removed
and the crude product was dissolved in ether (50 mL) and subjected
to an acidic work up with 1 M aqueous HCl. From the organic
phase, the unreacted vinylphosphine oxide was recovered and
purified via chromatography (CHCl3/acetone 8:2). The aqueous
phase was treated with 1 M aqueous NaOH followed by extraction
with CHCl3. The solvent was then removed, and the crude product
was purified by flash chromatography using CHCl3/acetone/Et3N
(8:2:0.5).
{2-[(RP)-Methylphenylphosphinoyl]ethyl}-(1R)-(1-phenyleth-
yl) Amine, (RP,RC)-17. Low-melting solid, 97%. [R]20D -25.5° (c
2.7, CHCl3). δH (360 MHz, CDCl3): 1.23 (3H, d, JHH ) 6.8,
CHCH3), 1.62 (3H, d, JHP ) 13.2, PCH3), 1.78 (1H, br s, NH),
1.95-2.13 (2H, m, PCH2), 2.56-2.84 (2H, m, CH2N), 3.61 (1H,
catalytic study.
δH (360 MHz, CDCl3): 1.77 (3H, d, JHP ) 13.2, PCH3), 6.15 (1H,
ddd, JHP ) 40.6, JHH ) 12.4, 1.8, CH2), 6.22 (1H, ddd, JHP ) 22.1,
JHH ) 18.6, 1.8, CH2), 6.42 (1H, ddd, JHP ) 25.1, JHH ) 18.6,
12.4, PCH), 7.44-7.54 (3H, m, Hmeta, Hpara), 7.67-7.74 (2H, m,
H
ortho). δC (90.6 MHz, CDCl3): 16.30 (d, JCP ) 74, PCH3), 128.6
(d, JCP ) 12, Cmeta), 130.6 (d, JCP ) 10, Cortho), 131.7 (d, JCP ) 3,
C
para), 132.5 (d, JCP ) 95, CH2), 132.9 (s, CH), 133.2 (d, JCP )
102, Cipso). δP (145.8 MHz, CDCl3): +27.7. νmax (KBr disk)/cm-1
1165 (PdO).
:
Synthesis of â-Aminophosphine Oxides. Method A: To a
solution of the appropriate vinylphosphine oxide (2.5 mmol) in 3
mL of MeOH was added the appropriate amine (3 equiv). The
2478 J. Org. Chem., Vol. 71, No. 6, 2006

StereodiVergent Synthesis of Aminophosphine Ligands
q, JHH ) 6.8, CHCH3), 7.08-7.23 (5H, m, Ph), 7.33-7.46 (3H,
m, Hmeta, Hpara), 7.54-7.66 (2H, m, Hortho). δC (90.6 MHz,
CDCl3): 16.4 (d, JCP ) 70, PCH3), 24.1 (s, CHCH3), 32.2 (d, JCP
) 70, PCH2), 40.9 (d, JCP ) 2, CH2N), 58.1 (s, CHCH3), 126.4 (s,
Ph), 126.9 (s, Ph), 128.3 (s, Ph), 128.6 (d, JCP ) 11, Cmeta), 129.8
(d, JCP ) 9, Cortho), 131.5 (d, JCP ) 2, Cpara), 133.7 (d, JCP ) 95,
{2-[(RP)-Methylphenylphosphanyl]ethyl}-(1S)-(1-phenyleth-
yl) Amine, (RP,SC)-25. Colorless oil, 78%. [R]20 +22.3° (c 2.5,
D
CHCl3). δH (360 MHz, CDCl3): 1.22 (3H, d, JHP ) 3.2, PCH3),
1.25 (3H, d, JHH ) 6.8, CHCH3), 1.45 (1H, br, NH), 1.66-1.88
(2H, m, PCH2), 2.43-2.61 (2H, m, CH2N), 3.68 (1H, q, JHH
)
6.8, CHCH3), 7.11-7.46 (10H, m, Ar-H). δC (90.6 MHz,
CDCl3): 10.7 (d, JCP ) 13, PCH3), 23.2 (s, CHCH3), 30.5 (d, JCP
) 12, PCH2), 43.2 (d, JCP ) 19, CH2N), 57.1 (s, CHCH3), 125.5
(s, Ph), 125.8 (s, Ph), 127.2 (s, Ph), 127.4 (s, Cpara), 127.6 (d, JCP
) 9, Cmeta), 131.7 (d, JCP ) 19, Cortho), 137.5 (d, JCP ) 12, Cipso),
144.9 (s, Ph). δP (145.8 MHz, CDCl3): -38.8. νmax (thin film)/
cm-1: 3420 (s, NH). HRMS (EI): 294.1304 (M + Na+). Calcd
for C17H22NNaP: 294.1388.
Cipso), 145.1 (s, Ph). δP (145.8 MHz, CDCl3): +37.9. νmax (thin
film)/cm-1: 3243 (s, NH), 1115 (s, PdO). HRMS (EI): 310.1322
(M + Na+). Calcd for C17H22NNaOP: 310.1337.
{2-[(RP)-Methylphenylphosphinoyl]ethyl}-(1S)-(1-phenyleth-
yl) Amine, (RP,SC)-17. Low-melting solid, 98%. [R]20D +50.7° (c
2.8, CHCl3). δH (360 MHz, CDCl3): 1.21 (3H, d, JHH ) 6.8,
CHCH3), 1.61 (3H, d, JHP ) 13.2, PCH3), 1.69 (1H, br, NH), 1.92-
2.15 (2H, m, PCH2), 2.60-2.74 (2H, m, CH2N), 3.61 (1H, q, JHH
Reduction of Aryl Ketones. A solution of [RuCl2(p-cymene)]2
(0.01 mmol, 1 mol %) and the appropriate ligand (0.04 mmol, 2
mol %) in i-PrOH (5 mL) was placed in a dry reaction tube under
argon and heated at 80 °C for 20 min, whereupon the color changed
from orange to deep red. The catalyst solution was cooled to 29
°C, before the introduction of the substrate (2 mmol) as a solution
in i-PrOH (4 mL). The reaction was initiated by the addition of a
solution of KOH (0.1 mmol) in i-PrOH (1 mL). Reaction aliquots
(0.1 mL) were extracted periodically and passed through silica,
before GLC analysis. The conversions and ee’s were determined
using a capillary column (25 m × 0.25 mm), under isothermal
conditions. Retention times: acetophenone 8.9 min, (R)-1-phenyle-
thanol 14.1 min, (S)-1-phenylethanol 17.9 min at 100 °C; pro-
piophenone 15.1 min, (R)-phenylpropanol 42.1 min, (S)-phenyl-
propanol 47.7 min at 100 °C; 2-methylpropiophenone 10.5 min,
(R)-2-methyl-1-phenylpropanol 34.6 min, (S)-2-methyl-1-phenyl-
propanol 36.8 min at 110 °C. Absolute configurations were
determined by comparing the optical rotation with reported vales.
) 6.8, CHCH3), 7.08-7.23 (5H, m, Ph), 7.33-7.46 (3H, m, Hmeta
,
H
para), 7.55-7.64 (2H, m, Hortho). δC (90.6 MHz, CDCl3): 16.5 (d,
JCP ) 70, PCH3), 24.1 (s, CHCH3), 32.1 (d, JCP ) 70, PCH2), 40.7
(d, JCP ) 3, CH2N), 58.0 (s, CHCH3), 126.3 (s, Ph), 126.7 (s, Ph),
128.5 (s, Ph), 128.6 (d, JCP ) 11, Cmeta), 129.8 (d, JCP ) 10, Cortho),
131.5 (d, JCP ) 3, Cpara), 133.4 (d, JCP ) 96, Cipso), 145.0 (s,
Ph). δP (145.8 MHz, CDCl3): +37.8. νmax (thin film)/cm-1: 3243
(s, NH), 1115 (s, PdO). HRMS (EI): exact mass calcd for
C17H22NNaOP (M+ + Na), 310.1337; found, 310.1332.
General Procedure for the Reduction of Phosphine Oxide.
The appropriate aminophosphine oxide (2 mmol) was suspended
in toluene (25 mL). Et3N (6 mL) was added, and the mixture was
stirred and cooled to 0 °C. Trichlorosilane (5 equiv) was added
dropwise by syringe, followed by gradual warming to reflux (3-4
h). After cooling to ambient temperature, the mixture was diluted
with ether (50 mL), and a few drops of aqueous Na2CO3 were added
to destroy the excess reducing agent. The mixture was filtered
through a short pad of Celite under Ar and dried over MgSO4,
before evaporating to dryness under reduced pressure, to give the
product.
Acknowledgment. We are grateful to Dr.’s Elizabeth
Rowsell and Chris Barnard (Johnson Matthey) for assistance
with ligand screening experiments. The authors thank Johnson
Matthey for studentship support and also the provision of HTE
equipment. We are also grateful to Dr. Bruno Linclau (Southamp-
ton University) for help with preparative LC separations.
{2-[(RP)-Methylphenylphosphanyl]ethyl}-(1R)-(1-phenyleth-
yl) Amine, (RP,RC)-25. Colorless oil, 81%. [R]20 +4.7° (c 2.3,
CHCl3). δH (360 MHz, CDCl3): 1.19 (3H, d, JHPD) 3.2, PCH3),
1.25 (3H, d, JHH ) 6.8, CHCH3), 1.45 (1H, br s, NH), 1.68-1.90
(2H, m, PCH2), 2.43-2.61 (2H, m, CH2N), 3.68 (1H, q, JHH
)
6.8, CHCH3), 7.11-7.46 (10H, m, Ar-H). δC (90.6 MHz,
CDCl3): 10.7 (d, JCP ) 13, PCH3), 23.2 (s, CHCH3), 30.5 (d, JCP
) 12, PCH2), 43.2 (d, JCP ) 19, CH2N), 57.1 (s, CHCH3), 125.5
(s, Ph), 125.8 (s, Ph), 127.2 (s, Ph), 127.4 (s, Cpara), 127.6 (d, JCP
) 9, Cmeta), 131.7 (d, JCP ) 19, Cortho), 137.5 (d, JCP ) 12, Cipso),
144.9 (s, Ph). δP (145.8 MHz, CDCl3): -38.9. νmax (thin film)/
cm-1: 3420 (s, NH). HRMS (EI): 294.1394 (M + Na+). Calcd
for C17H22NNaP: 294.1388.
Supporting Information Available: Experimental procedures
and characterization data for precursors 1-6, compounds 9-12,
13, 15, 16, 18-24, 26, and 27, selected NMR spectra of intermedi-
ates, X-ray crystallographic data, and cif files for compounds 14
and 15. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO052575Q
J. Org. Chem, Vol. 71, No. 6, 2006 2479