Synthesis of α-substituted β-amidophosphines by diastereoselective alkylation. A new access to chiral ligands for asymmetric catalysis

Article abstract of DOI:10.1021/jo0155759

Chiral β-amidophosphine boranes 7a-f can be diastereoselectively alkylated, using O-protected amino-alcohols as chiral inducers, to furnish α-substituted β-amidophosphine boranes 8a-f and 9-12 with up to 72% diastereoisomeric excess. Selective deprotection afforded optically pure carboxylic derivative 13 which is a key intermediate for the synthesis of various potential chiral ligands for asymmetric catalysis.

Full text of DOI:10.1021/jo0155759

5566
J . Org. Chem. 2001, 66, 5566-5571
Syn th esis of r-Su bstitu ted â-Am id op h osp h in es by
Dia ster eoselective Alk yla tion . A New Access to Ch ir a l Liga n d s for
Asym m etr ic Ca ta lysis
Matthieu Le´autey, Ge´raldine Castelot-Deliencourt, Philippe J ubault,
Xavier Pannecoucke, and J ean-Charles Quirion*
Laboratoire d’He´te´rochimie Organique associe´ au CNRS, IRCOF, INSA et Universite´ de Rouen,
1 rue Tesnie`re, 76821 Mont Saint-Aignan Cedex, France
Received February 15, 2001
Chiral â-amidophosphine boranes 7a -f can be diastereoselectively alkylated, using O-protected
amino-alcohols as chiral inducers, to furnish R-substituted â-amidophosphine boranes 8a -f and
9-12 with up to 72% diastereoisomeric excess. Selective deprotection afforded optically pure
carboxylic derivative 13 which is a key intermediate for the synthesis of various potential chiral
ligands for asymmetric catalysis.
In tr od u ction
best of our knowledge, the ligands developed by Minami9
and Gilbertson10 are the only two catalysts of this series
possessing such a stereogenic center. However, these
syntheses are based on a racemic approach and need
either an optical resolution9 or the separation of a 1/1
mixture of diastereoisomers.10
The development of new R-substituted phosphine
ligands would therefore be of particular interest. Indeed,
the stereogenic R-position next to the phosphine could
be of great importance since the phosphorus atom is
directly associated with the transition metal in the
asymmetric reaction. The presence of a chiral center at
the R-position could enhance facial discrimination and
thus lead to improved levels of enantioselectivity in
catalytic asymmetric reactions.
For these reasons, we became interested in the syn-
thesis and the development of new potential ligands
possessing a stereogenic center in the R-position related
to the phosphorus atom. A few years ago, Beak11 reported
a new 1,5 diastereoselective alkylation of â-aryl second-
ary amides. The asymmetric induction was explained by
the formation of a rigid intermediate in which the
benzylic lithium was complexed by the nitrogen of the
amide. We then decided to apply this methodology to the
alkylation of phosphine-amides 1, since it is known that
phosphine-borane substrates can be easily metalated12
(Scheme 1). We supposed that the corresponding lithium
intermediate could then adopt the same conformation
and might lead to high diastereoselectivity during the
substitution step.
After deprotection and simple synthetic transforma-
tions, chiral derivatives 2 could then furnish a large
variety of ligands such as phosphine-amides, phosphine-
amines, phosphine-acids, or phosphine-alcohols. De-
scribed here is the first application of this methodology
to the synthesis of R-substituted phosphines.
The increasing practical usefulness of catalytic asym-
metric synthesis has received much attention in recent
years,1 especially in the pharmaceutical field for the
preparation of biologically active chiral compounds. For
this reason, much interest is being focused on the
synthesis and the development of new efficient chiral
ligands. During the past three decades, numerous po-
tential chiral catalysts have been synthesized and some
of them appeared to be excellent ligands (for example
DIPAMP2, DIOP3, BINAP,4 PennPHOS,5 DuPHOS,6 etc.)
and have been developed for a variety of catalytic reac-
tions. However, no structural class is universally suitable
for all transformations. Furthermore, it is generally
highly desirable to have access to a variety of ligands in
order to optimize the reaction when applied to a range
of substrates.
All these ligands can be classified into three main
families depending on the location of the stereogenic
information which can be encountered on a side chain
(VALAP,7 CHIRAPHOS8), on the phosphorus atom
(DIPAMP), or as an axial chirality (BINAP). Concerning
the first series, most of the ligands frequently used are
derived from amino acids, limiting the structural diver-
sity of the catalysts. Very few of them are obtained by
diastereoselective creation of a stereogenic center. To the
* Corresponding author. Phone: 33 (0)2 35 52 29 20. FAX: 02-35-
52-29-59. E-mail address: quirion@ircof.insa-rouen.fr.
(1) Reviews, see: (a) Ojima, I. Ed. Catalytic Asymmetric Synthesis;
VCH Publishers: Weinheim, 1993. (b) Noyori, R. Asymmetric Catalysis
in Organic Synthesis; Wiley & Sons: New York, 1994. (c) J acobsen, E.
N.; Pfaltz, A.; Yamamoto, H., Eds. Comprehensive Asymmetric Cataly-
sis; Springer-Verlag: Berlin, 1999.
(2) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106.
(3) Kagan, H. B.; Dang, T.-P. J . Am. Chem. Soc. 1972, 94, 6429.
(4) (a) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345. (b)
Noyori, R. Science 1990, 248, 1194.
(5) (a) Chen, Z.; J iang, Q.; Zhu, G.; Xiao, D.; Cao, P.; Guo, C.; Zhang,
X. J . Org. Chem. 1997, 62, 4521. (b) J iang, Q.; J iang, Y.; Xiao, D.; Cao,
P.; Zhang, X. Angew. Chem., Int. Ed. 1998, 37, 1100. (c) Zhang, Z.;
Zhu, G.; J iang, Q.; Xiao, D.; Zhang, X. J . Org. Chem. 1999, 64, 1774.
(6) Burk, M. J .; Lee, J . R.; Martinez, J . P. J . Am. Chem. Soc. 1994,
116, 10847.
(7) Moritomo, T.; Yamaguchi, Y.; Suzuki, M.; Saitoh, A. Tetrahedron
Lett. 2000, 41, 10025.
(8) Auburn, P. R.; Mackensie, P. B.; Bosnich, B. J . J . Am. Chem.
Soc. 1985, 107, 2033.
(9) Minami, T.; Okada, Y.; Otaguro, T.; Tawaraya, S.; Furuichi, T.;
Okauchi, T. Tetrahedron: Asymmetry 1995, 6, 2469.
(10) Gilbertson, S. C.; Chang, C.-W. T. J . Org. Chem. 1998, 63, 8424.
(11) Pippel, D. J .; Curtis, M. D.; Du, H.; Beak, P. J . Org. Chem. 1998,
63, 2.
(12) For recently reported representative examples of metalation-
alkylation of phosphine-boranes, see: (a) Muci, A. R.; Campos, K. R.;
Evans, D. A. J . Am. Chem. Soc. 1995, 117, 9075. (b) Yamanoi, Y.,
Imamoto, T. J . Org. Chem. 1999, 64, 2988.
10.1021/jo0155759 CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/19/2001

Synthesis of R-Substituted â-Amidophosphines
J . Org. Chem., Vol. 66, No. 16, 2001 5567
Sch em e 1
probably due to the formation of aggregates during the
metalation process. We could not raise the concentration
above 2.3 × 10-1 mol L-1 for solubility problems at the
alkylation temperature (-78 °C). To confirm this hypoth-
esis, we studied the influence of chelating agents. The
addition of lithium chloride had small effects on the de
(51%) while the addition of HMPA led to a reduced
diastereoisomeric excess (19%). Finally, we observed that
the nature of the lithiated base had no influence on
diastereoselectivity. We next examined the influence of
the chiral auxiliary as well as the nature of the protecting
groups for amino-alcohols. In addition to (R)-aminobu-
tanol, two other chiral auxiliaries were tested, (R)-
phenylglycinol and valinol. Two protecting groups were
investigated: benzyl and methyl ethyl ether (effect of the
introduction of one additional oxygen atom). The results
obtained for the methylation (Scheme 3) of phosphines-
amides 7 are collected in Table 2.
Resu lts a n d Discu ssion
In a first attempt we decided to investigate the direct
transposition of Beak’s method to substrate 7a . This
amide was synthesized in five steps from chlorodiphen-
ylphosphine using a Michael addition of diphenylphos-
phine-borane 3 to ethyl acrylate (Scheme 2). A coupling
reaction between acyl chloride 6 and (R)-R-methylben-
zylamine was then performed under standard conditions
(NaOH, CH2Cl2) leading to the expected phosphines-
amides 7a in 67% yield.
All chiral auxiliaries provided the expected products
in good yield (60-70%). The use of different amino-
alcohols with an identical O-protecting group (entries 2,
4, and 6; or entries 3 and 5) led to the same level of
diastereoselectivity, thus clearly demonstrating that the
substituent initially present on the amino-alcohol core
had no real influence on the stereochemical control.
Variations of the O-protecting group led to enhanced
diastereoselectivities (entries 2 and 3) and the methyl
ethyl ether group led to the best stereochemical control.
These last results support in favor of lithiated intermedi-
ate such as B (Scheme 4), the lithiated intermediate A
was the one fully characterized by Beak during the
asymmetric substitution of â-phenylcarboxamides.The
introduction of oxygen atoms might lead to additional
chelation effects between these atoms and the lithium
atom (compared with the case when R-methylbenzyl-
amine was used) and therefore could explain the differ-
ences observed for the stereochemical control.
Substrate 7a was reacted successively with n-BuLi and
methyl iodide to afford derivative 8a in 70% yield but
only 12% de. This result appeared to be promising as it
indicated that alkylation was totally regioselective. We
then decided to investigate the influence of the chiral
auxiliary on the diastereoselectivity. In connection with
our program aiming at the development of new diaste-
reoselective reactions using chiral amino alcohols,14 we
explored the use of these readily available auxiliaries as
chiral inducers in this particular reaction. The formation
of oxazolines during the alkylation step prevented us
from using nonprotected O-amino alcohols.15 Compounds
7b-f were prepared by condensation of acyl chloride 6
with the corresponding O-protected amino alcohols syn-
thesized following Hu’s procedure.16
We then examined several parameters to determine
the optimal conditions for this reaction. These param-
eters were: the nature of lithiated bases (n-BuLi, sec-
BuLi, tert-BuLi), the metalation and alkylation temper-
atures, the reaction time, the concentration of substrate
7, and the influence of chelating agents. For this pre-
liminary study, we decided to use O-benzylated amide
7b derived from aminobutanol and methyl iodide as an
electrophile. Concerning metalation temperature, we
observed no reaction at -78 °C, and that the best
compromise between the metalation temperature and
yield was when the deprotonation process was conducted
at -20 °C. For the alkylation step, selectivity fell when
methyl iodide was added at a temperature higher than
-78 °C. So, to summarize, the standard conditions
selected for this process are as follows: metalation
conditions (2.1 equiv of lithiated base, temperature: -20
°C, 1 h), alkylation conditions (1.1 equiv of methyl iodide,
temperature: -78 °C, 4 h). We then turned our attention
toward the influence of the concentration of 7b. The
results are collected in Table 1.
A range of electrophiles have been assayed in this
reaction using 7c (chiral vector: O-MEM amino-butanol)
as a substrate; the formation of products 9-12 is sum-
marized in Table 3. Most of these electrophilic substitu-
tions proceeded in good yields and in moderate to good
diastereoselectivities.
For the determination of the absolute configuration of
the newly created chiral center, separation of the two
diastereoisomers have been carried out by flash chroma-
tography over silica gel but single crystallization was
unsuccessful for X-ray analysis. However, deprotection
of the major diastereoisomer of 8d (Scheme 5) provided
the known 3-(diphenylphosphino)butanoic acid 13 whose
optical rotation has been given by Minami, indicating a
(S) configuration for the created center. Moreover, its
enantiomeric purity has been checked on the borane
derivative 14 by chiral HPLC (See Experimental Section).
Mech a n ism . The diastereo-determining step for these
reactions could be an asymmetric deprotonation or an
asymmetric substitution. To get information concerning
the mechanism involved during this reaction, we studied
the results of tin-lithium exchange and the sub-
sequent reaction of the two epimeric stannanes with
electrophiles. Scheme 6 outlines the preparation, trans-
metalation, and electrophilic quench of these compounds.
Phosphine-amide 7d was alkylated to a separable mix-
ture of stannanes (S,R)-15 and (R,R)-15 in 58% yield and
47% de. After separation of these diastereoisomeric
stannanes by flash chromatography over silica gel, both
The results depicted in Table 1 clearly indicated the
dramatic influence of the concentration of 7b on diaste-
reoisomeric excesses (from 9 to 60%). These results were
(13) Gilbertson, S. C.; Chen, G.; McLoughlin, M. J . Am. Chem. Soc.
1994, 116, 4481.
(14) (a) Micouin, L., J ullian, V., Quirion, J .-C., Husson, H.-P.
Tetrahedron: Asymmetry 1996, 7, 2839. (b) Marcotte, S., Pannecoucke,
X., Feasson, C., Quirion, J .-C. J . Org. Chem. 1999, 64, 8461. (c)
Castelot-Deliencourt, G., Pannecoucke, X., Quirion, J .-C. Tetrahedron
Lett. 2001, 42, 1025.
(15) Castelot-Deliencourt, G. Ph.D. Thesis, University of Rouen, Sep
11, 2000.
(16) Hu, X. E.; Cassady, J . M. Synth. Commun. 1995, 25, 907.

5568 J . Org. Chem., Vol. 66, No. 16, 2001
Le´autey et al.
Sch em e 2
Ta ble 1. In flu en ce of th e Con cen tr a tion d u r in g th e
Meth yla tion of Am id e 7b
Sch em e 4
[7b] mol L-1
8b de (%)17
5.5 × 10-2
8.8 × 10-2
1.66 × 10-1
2.30 × 10-1
9
34
51
60
Sch em e 3
Ta ble 3. Electr op h ilic Su bstitu tion of 7b w ith
Electr op h iles
entry
electrophile
product
yielda (%)
deb (%)
1
2
3
4
Bu3SnCl
Me3SiCl
BrCH2CO2Et
CH2dCHCH2I
9
10
11
12
60
60
79
85
58
46
72c
41
a
b
Isolated yield. Determined by 31P NMR on the crude mixture
of thiophosphines (See Experimental Section). c Determined by 1H
NMR on the crude mixture of phosphine-boranes.
Sch em e 5
Ta ble 2. In flu en ce of th e Ch ir a l In d u ctor on th e
Dia ster eoselective Meth yla tion (electr op h ile: CH3I) of
7a -f u n d er Op tim u m Rea ction Con d ition s
yielda deb
(%) (%)
entry subtrate
R1
R2
product
1
7a
R-methyl-
benzylamine
C2H5
C2H5
C6H5
8a
70
12
2
3
4
5
6
7b
7c
7d
7e
7f
CH2C6H5
CH2OC2H5
CH2C6H5
CH2OC2H5
CH2C6H5
8b
8c
8d
8e
8f
70
65
67
65
60
60
66
60
65
60
C6H5
(CH3)2CH
a
b
Isolated yield. Determined by 31P NMR on the crude mixture
of thiophosphines (see Experimental Section).
To conclude, we have investigated a range of chiral
auxiliaries for the distereoselective alkylation of phos-
phine-amides derived from O-protected amino-alcohols.
Using this protocol, we prepared new R-substituted
phosphines with different substituents and with modest
to reasonable levels of diastereoselectivity. The model
diastereoisomers were transmetalated with n-BuLi. Ad-
dition of MeI gave product 8d in 60% yield with a dr of
80:20 in favor of the same major diastereoisomer. This
result is the same as that obtained by the direct lithiation
of 7d (Table 2, entry 4). As far as we know, tin-lithium
exchange is known to proceed with retention of config-
uration,18 so these results establish that an asymmetric
deprotonation is not the stereochemical-controlling step
in this sequence and suggested that the substitution
proceeded via rapidly equilibrating diastereoisomeric
organolithium intermediates (S)-16 and (R)-16. Conse-
quently, the enantioselectivity is determined during the
post-deprotonation step.
(17) The diastereoisomeric excesses have been measured by three
differents methods: by 1H NMR on the methyl protons, by 31P NMR
on the corresponding thiophosphines (as phosphines-boranes exibited
broad signals), or by mass-coupled HPLC on the diastereoisomeric
phosphines-boranes. The maximum difference registered between these
three analysis methods was 2%.
(18) (a) Elworthy, T. R.; Meyers, A. I. Tetrahedron 1994, 20, 6089.
(b) Still, W. C.; Sreekumar, C. J . J . Am. Chem. Soc. 1980, 102, 1201.
(c) Sawyer, J . S.; Kucerovy, A.; Macdonald, T. L.; McGarvey, G. J . J .
Am. Chem. Soc. 1988, 110, 842.

Synthesis of R-Substituted â-Amidophosphines
J . Org. Chem., Vol. 66, No. 16, 2001 5569
Sch em e 6a
a
(a) 1. n-BuLi, THF, -20 °C. 2. Bu3SnCl, -78 °C. (b) 1. n-BuLi, THF, -20 °C. 2. CH3I, -78 °C.
and extracted with dichloromethane (3 × 20 mL). The organic
previously described by Beak cannot be used to explain
our results. We demonstrated that the chiral auxiliary
could be readily removed by treatment with acid to give
the corresponding carboxylic acid. The latter one as well
as substituted amides 8b-f can be considered as poten-
tial chiral ligands and as useful intermediates for the
preparation of chiral catalysts. Their synthesis is cur-
rently being investigated and will be soon disclosed.
layer was dried (MgSO4) and evaporated under reduced
pressure affording carboxylic acid 5 in quantitative yield as a
white powder: mp 147 °C; 1H NMR δ 0.5-1.2 (b, 3H), 2.5 (m,
4H), 7.4 (m, 6 H), 7.6 (m, 4H); 31P NMR δ 17.4; 13C NMR δ
21.3 (d, J ) 39), 27 (d, J ) 3), 128.6 (d, J ) 57.4), 129.4 (d, J
) 11), 131.9 (d, J ) 2.3), 132.6 (d, J ) 9.1), 174.2 (d, J ) 18);
IR (neat) 3037, 2924, 2342, 1711, 1437, 1263, 751 cm-1. Anal.
Calcd for C15H18BO2P (272.11): C, 66.22; H, 6.67. Found: C,
66.06; H, 6.56.
3-Bor an atodiph en ylph osph in o P r opion yl Ch lor ide (6).
To a stirred, cooled (0 °C) solution of 3-diphenylphosphino
propionic acid (5) (1.5 g, 5.5 mmol) in dichloromethane (30
mL) was added dropwise oxalyl chloride (1.4 g, 11 mmol) under
argon. The reactional mixture was stirred at room temperature
for 4 h. Removal of solvent and excess of oxalyl chloride under
reduced pressure (0.05 mmHg) afforded 6 in quantitative yield
as a red oil: 1H NMR δ 0.5-1.2 (b, 3H), 2.5 (m, 2H), 3 (m,
2H), 7.3 (m, 6H), 7.6 (m, 4H); 31P NMR δ 16.8; 13C NMR δ
21.3 (d, J ) 39), 27 (d, J ) 3), 128.6 (d, J ) 57.4), 129.4 (d, J
) 11), 131.9 (d, J ) 2.3), 132.6 (d, J ) 9.1), 174.2 (d, J ) 18).
Gen er a l P r oced u r e for th e Cou p lin g Rea ction be-
tw een O-P r otected Am in o Alcoh ols (or r-m eth ylben zyl-
a m in e) a n d 6. To a stirred solution of 3-diphenylphosphino
propionic chloride (6) (1.16 g, 3.9 mmol) and O-protected
amino-alcool or R-methylbenzylamine (3.9 mmol) in dichlo-
romethane (30 mL) was added slowly, at room temperature,
sodium hydroxyde (0.176 g, 4.39 mmol) dissolved in water (0.5
mL). The reaction mixture was stirred at room temperature
for 4 h and then washed with water (3 × 10 mL). The organic
layer was dried (MgSO4) and evaporated under reduced
pressure affording phosphine-amide boranes 7a -f. The crude
product was purified by chromatography, eluting with 20%
ethyl acetate in cyclohexane to give the pure products (7a :
67%, 7b: 72%, 7c: 50%, 7d : 67%, 7e: 57%, 7f: 47%) as white
powders.
Exp er im en ta l Section
Gen er a l. Solvents were purified by conventional methods
prior to use. TLC was performed on Merck 60F-250 silica
gel plates and column chromatography over silica gel SI 60
(230-240 mesh). Mps were taken on a Kofler apparatus and
were uncorrected. Elemental analyses were carried out on a
Carlo Erba EA 1100 analyzer. NMR spectra were recorded on
a Bruker DXP 300 spectrometer operating at 300 MHz for
proton, 75.4 MHz for carbon, and 121.5 MHz for phosphorus.
This probe is equipped with pulsed-field (z) gradients. Chemi-
1
cal shifts (δ) are expressed in ppm relative to TMS for H and
13C nuclei and to H3PO4 for 31P nuclei; coupling constants (J )
are given in Hertz; coupling multiplicities are reported using
conventional abbreviations.
3-Bor a n a tod ip h en ylp h osp h in o P r op ion ic Acid (5). To
an ice-cooled solution of 3.51 g (17.5 mmol) of diphenylphos-
phine-borane 3 in THF (50 mL) was added dropwise ethyl
acrylate (1.75 g, 17.5 mmol), then sodium hydride (700 mg,
17.5 mmol) was added portionwise at 0 °C. The mixture was
stirred at 0 °C for 2 h, after which water (10 mL) was added
and then extracted with diethyl ether (3 × 30 mL). The organic
layer was washed with brine (20 mL), dried (MgSO4), and
evaporated under reduced pressure. The crude product was
purified by chromatography, eluting with 10% diethyl ether
in cyclohexane to give the pure product 4 (4.72 g, 15.75 mmol,
90%). To this ester (4.59 g, 15 mmol) was added dropwise at
room-temperature potassium hydroxide (0.94 g, 17 mmol)
dissolved in a mixture of water (1 mL) and ethanol (2.5 mL).
The mixture was stirred for 4 h, and then ethanol was
evaporated under reduced pressure. The collected oil was
redissolved in water (5 mL) and washed with diethyl ether (3
× 20 mL). The aqueous layer was first acidified until pH ) 1
with hydrochloric acid 1 M, saturated with sodium chloride,
(R)-3-(Bor a n a t od ip h en ylp h osp h in o)-N-(1-p h en ylet h -
yl)p r op ion a m id e (7a ): mp 128 °C; [R]20 ) +62.8 (c 1.1,
D
CHCl3); 1H NMR δ 0.5-1.2 (b, 3H), 1.42 (d, J ) 6.9, 3H), 2.4-
2.45 (m, 2 H), 2.5-2.6 (m, 2H), 5 (m, 1H), 5.9 (d, J ) 7.6, 1H),
7.2-73 (m, 5H), 7.35-7.5 (m, 6H), 7.6-7.8 (m, 4H); 31P NMR
δ 17.1; 13C NMR δ 21.4 (d, J ) 39.6), 22.1, 30.2 (d, J ) 2.1),
49.5, 126.5, 127.8, 128.7 (d, J ) 55.4), 129.1, 129.3 (d, J )
10.3), 131.8 (d, J ) 2), 132.5 (d, J ) 9.2), 170.4 (d, J ) 14.9);

5570 J . Org. Chem., Vol. 66, No. 16, 2001
Le´autey et al.
IR (neat) 3270, 2968, 2393, 1644, 1541, 1435, 1108, 736 cm-1
Anal. Calcd for C23H27 BNOP (375.26): C, 73.62; H, 7.25; N,
3.73. Found: C, 75.53; H, 7.23; N, 3.63.
.
The combined organic phases were dried (MgSO4) and evapo-
rated under reduced pressure. The crude product was directly
1
analyzed by H NMR, 31P NMR, and mass-coupled HPLC. A
(R)-3-(Bor a n a t od ip h en ylp h osp h in o)-N-(1-b en zyloxy-
m eth ylp r op yl)p r op ion a m id e (7b): H NMR δ 0.5-1.2 (b,
pure mixture of diastereoisomers was obtained by chromatog-
raphy on silica gel preparative plates (cyclohexane/ethyl
acetate, 6:4).
1
3H), 0.77 (t, J ) 7.4, 3H), 1.3-1.6 (m, 2H), 2.2-2.35 (m, 2H),
2.45-2.6 (m, 2H), 3.3 (dd, J ) 3.8, J ) 9.5, 1H), 3.4 (dd, J )
3.8, J ) 9.5, 1H), 3.85 (m, 1H), 4.37 (d, J ) 12, 1H), 4.42 (d, J
) 12, 1H), 5.58 (d, J ) 8.7, 1H), 7.14-7.3 (m, 5H), 7.32-7.46
(m, 6H), 7.54-7.68 (m, 4H); 31P NMR δ 16.73; 13C NMR δ 10.2,
21.5 (d, J ) 39.6), 25.1, 30.2 (d, J ) 2.3), 51, 71.1, 73.6, 128.2,
129.5 (d, J ) 56.3), 128.8, 129.3 (d, J ) 10.3), 129.5 (d, J )
2.3), 131.8 (d, J ) 2.9), 132.5 (d, J ) 9.2), 138.4, 170.9 (d, J )
15.5); IR (neat) 3248, 2931, 2374, 1632, 1551, 1435, 1110, 739
(S,R)-3-(Bor a n a tod ip h en ylp h osp h in o)-N-(2-ben zyloxy-
1-p h en yleth yl)bu ta n a m id e (8d ): pale yellow powder; mp 70
1
°C; [R]20 ) -18.9 (c 1.1, CHCl3); H NMR δ 0.5-1.2 (b, 3H),
D
1.05 (dd, J ) 6.9, J ) 16.2, 3H), 2.1-2.2 (m, 1H), 2.25-2.4
(m, 1H), 3.1-3.3 (m, 1H), 3.6 (dd, J ) 5.2, J ) 11.7, 1H), 3.67
(dd, J ) 5.2, J ) 11.7, 1H), 4.4 (s, 2H), 5-5.2 (m, 1H), 6.1 (d,
J ) 7.7, 1H), 7.15-7.3 (m, 10H), 7.37-7.52 (m, 6H), 7.60-
7.74 (m, 4H); 31P NMR δ 24.6; 13C NMR δ 14.3 (d, J ) 2.6),
25.5 (d, J ) 39.6), 38.8 (d, J ) 5), 53.5, 72.7, 73.6, 127.3, 127.8,
128.3, 128.6 (d, J ) 55.9), 128.9, 129.4 (d, J ) 10.2), 129.6,
131.8 (d, J ) 2), 132.5 (d, J ) 9.4), 138.1, 140.1, 170.5 (d, J )
16.5); IR (neat) 3300, 2858, 2381, 1645, 1546, 1437, 1125, 737
cm-1; Anal. Calcd for C31H35BNO2P (495.44): C, 75.16; H, 7.12;
N, 2.83. Found: C, 75.13; H, 7.26; N, 2.88. Diastereoisomeric
excess determination: HPLC, ODS Inertsil 250 mm × 4.6 ×
5 µm, 0.8 mL/min, 10% water/methanol, (R,R) t1 ) 53.9 min;
(S,R) t1 ) 56.7 min.
cm-1
.
(R )-3-(B o r a n a t o d ip h e n y lp h o s p h in o )-N -(1-e t h o x y -
m eth oxym eth ylp r op yl)p r op ion a m id e (7c): 1H NMR δ
0.5-1.2 (b, 3H), 0.81 (t, J ) 7.4, 3H), 1.12 (t, J ) 7.2, 3H),
1.35-1.55 (m, 2H), 2.17-2.4 (m, 2H), 2.45-2.6 (m, 2H), 3.35
(dd, J ) 3.8, J ) 9.7, 1H), 3.45-3.6 (m, 3H), 3.77-3.9 (m, 1H),
4.56 (s, 2H), 5.67 (d, J ) 8.7, 1H), 7.3-7.48 (m, 6H), 7.53-7.7
(m, 4H); 31P NMR δ 16.73; 13C NMR δ 8.4, 13.1, 19.1 (d, J )
39.7), 22.6, 30.2, 48.5, 61.4, 66.8, 93.4, 129.2 (d, J ) 55.8), 129.4
(d, J ) 10.3), 131.8 (d, J ) 2.3), 132.55 (d, J ) 9.2), 168.4 (d,
J ) 15.5); IR (neat) 3299, 2968, 2382, 1648, 1542, 1437, 1110,
Gen er a l P r oced u r e for th e Con ver sion of 8a -f a n d
9-12 to Th eir Cor r esp on d in g Th iop h osp h in es. A solution
of 8a -f or 9-12 (100 mg) in diethylamine (3 mL) was heated
under argon at 40 °C for 8 h. Diethylamine was evaporated
under reduced pressure providing crude phosphines. THF (5
mL) was added to the crude phosphine. The solution was cooled
to 0 °C, and elemental sulfur (40 mg) was added. The reaction
mixture was stirred at 0 °C for 2 h. The solvent was removed
under reduced pressure, and the crude thiophosphines were
directly analyzed by 31P NMR.
738 cm-1
(R)-3-(b or a n a t od ip h en ylp h osp h in o)-N-(2-b en zyloxy-
1p h en yleth yl)p r op ion a m id e (7d ): mp 100 °C; [R]20
.
)
D
-36.3 (c 1.0, CHCl3); 1H NMR δ 0.5-1.2 (b, 3H), 2.3-2.45 (m,
2H), 2.5-2.6 (m, 2H), 3.6 (dd, J ) 5.2, J ) 11.7, 1H), 3.67 (dd,
J ) 5.2, J ) 11.7, 1H), 4.47 (s, 2H), 5-5.2 (m, 1H), 6.2 (d, J )
7.7, 1H), 7.15-7.3 (m, 10H), 7.37-7.52 (m, 6H), 7.60-7.74 (m,
4H); 31P NMR δ 16.7; 13C NMR δ 21.4 (d, J ) 39.6), 30.1, 53.5,
72.7, 73.6, 127.3, 127.8, 128.3, 128.6 (d, J ) 55.9), 128.9, 129.4
(d, J ) 10.2), 129.6, 131.8 (d, J ) 2), 132.5 (d, J ) 9.4), 138.1,
140.1, 171 (d, J ) 15.7); IR (neat) 3294, 2856, 2378, 1647, 1546,
1436, 1127, 736 cm-1. Anal. Calcd for C30H33 BNO2P (481.42):
C, 74.85; H, 6.91; N, 2.91. Found: C, 74.98; H, 7.04; N, 2.86.
(R )-3-(B o r a n a t o d ip h e n y lp h o s p h in o )-N -(2-e t h o x y -
m eth oxy-1-p h en yleth yl)p r op ion a m id e (7e): mp 62 °C;
[R]20D ) -41.1 (c 0.97, CHCl3); 1H NMR δ 0.5-1.2 (b, 3H), 1.12
(t, J ) 7, 3H), 2.36-2.5 (m, 2H), 2.5-2.67 (m, 2H), 3.34-3.5
(m, 2H), 3.72 (dd, J ) 4.7, J ) 10.2, 1H), 3.78 (dd, J ) 4.7, J
) 10.2, 1H), 4.58 (d, J ) 6.7, 1H), 4.62 (d, J ) 6.7, 1H), 5.0-
5.1 (m, 1H), 6.3 (d, J ) 7.4, 1H), 7.15-7.3 (m, 6H), 7.37-7.52
(m, 5H), 7.60-7.74 (m, 4H); 31P NMR δ 16.6; 13C NMR δ 15.4,
21.4 (d, J ) 39.7), 30.1, 53.4, 64, 70.8, 95.7, 127.1, 127.9, 128.3
(d, J ) 56.3), 128.9, 129.3 (d, J ) 9.8), 131.8 (d, J ) 2.3), 132.5
(d, J ) 9.2), 139.9, 170.8 (d, J ) 15.5). Anal. Calcd for C26H33
BNO3P (449.37): C, 69.5; H, 7.4; N, 3.12. Found: C, 69.76; H,
7.39; N, 2.99.
Thiophosphine of 8a : 31P NMR δ 53.87 (major), 53.85
(minor). Thiophosphine of 8b: 31P NMR δ 53.79 (major), 53.72
(minor). Thiophosphine of 8c: 31P NMR δ 53.76 (major), 53.71
(minor). Thiophosphine of 8d : 31P NMR δ 53.76 (major), 53.67
(minor). Thiophosphine of 8e: 31P NMR δ 53.76 (major), 53.68
(minor). Thiophosphine of 8f: 31P NMR δ 53.82 (major), 53.73
(minor). Thiophosphine of 9: 31P NMR δ 51.11 (major), 51.09
(minor). Thiophosphine of 10: 31P NMR δ 50.33 (major), 50.27
(minor). Thiophosphine of 11: 31P NMR δ 54.25 (major +
minor), de measured by 1H NMR. Thiophosphine of 12: 31P
NMR δ 53.39 (major), 53.45 (minor).
(S)-3-Dip h en ylp h osp h in o Bu ta n oic Acid (13). A sus-
pension of 8d (1.5 g, 3.02 mmol) in a mixture of sulfuric acid
9 M (45 mL) and dioxane (30 mL) (the solvent mixture was
degassed by three freeze-thaw cycles prior to use) was heated
at 100 °C for 3 h. The reaction mixture was then cooled to
room temperature. Degassed sodium hydroxide 15 M (50 mL)
was added, and the aqueous phase was extracted with de-
gassed dichloromethane (2 × 25 mL). The organic phases were
dried (MgSO4) and evaporated under reduced pressure giving
3-(Bor a n a t od ip h e n ylp h osp h in o)-N -(1-b e n zyloxy-2-
m eth ylp r op yl)p r op ion a m id e (7f): mp 80 °C; 1H NMR δ
0.5-1.2 (b, 3H), 0.78 (d, J ) 6.8, 3H), 0.80 (d, J ) 6.8, 3H),
1.78 (oct, J ) 6.8, 1H), 2.2-2.3 (m, 2H), 2.4-2.6 (m, 2H), 3.27
(dd, J ) 3.8, J ) 9.8, 1H), 3.45 (dd, J ) 3.8, J ) 9.8, 1H),
3.6-3.8 (m, 1H), 4.35 (d, J ) 12.1, 1H), 4.4 (d, J ) 12.1, 1H),
5.65 (d, J ) 7.7, 1H), 7.15-7.3 (m, 10H), 7.37-7.52 (m, 6H),
7.60-7.74 (m, 4H); 31P NMR δ 16.9; 13C NMR δ 19.5, 19.9,
21.5 (d, J ) 39.8), 29.8, 30.2 (d, J ) 2.3), 54.8, 70.2, 73.6, 128.2,
128.3, 128.6 (d, J ) 57.4), 129.4 (d, J ) 10.2), 129.5, 131.8 (d,
J ) 2.9), 132.6 (d, J ) 9.4), 138.4, 170.5 (d, J ) 15.5); IR (neat)
3434, 2961, 2380, 1647, 1542, 1436, 1109, 738 cm-1. Anal.
Calcd for C27H35 BNO2P (447.40): C, 72.49; H, 7.89; N, 3.13.
Found: C, 72.59; H, 8.07; N, 3.06.
Gen er a l P r oced u r e for th e Alk yla tion of P h osp h in e-
Am id e Bor a n es 7. To a stirred, cooled (-20 °C) solution of
secondary phosphine-amide boranes 7 (201 µmol) in THF (870
µmol, [7] ) 2.3 10-1 mol L-1) was slowly added n-BuLi (429
µmol, 330 µL of a 1.3 M hexane solution). The reaction mixture
was stirred at this temperature for 1 h and then cooled to -
78 °C. The alkylating agent (221 µmol) was then added, the
mixture was stirred at - 78 °C for 4 h, and then water was
added (2 mL). The organic layer was separated, and the
aqueous phase was extacted with dichloromethane (3 × 3 mL).
13 (0.7 g, 2.57 mmol, 80%). [R]20 ) +28.7 (c 1, CHCl3); 1H
D
NMR δ 1.1 (dd, J ) 14.8, J ) 6.9, 3H), 2.2 (ddd, J ) 16.4, J )
11, J ) 5.6, 1H), 2.5 (ddd, J ) 16.4, J ) 11, J ) 5.6, 1H),
2.8-3.0 (m, 1H), 7.2-7.4 (m, 6 H), 7.45-7.6 (m, 4H); 31P NMR
δ -0.275; 13C NMR δ 17.2 (d, J ) 16.6), 27.3 (d, J ) 10.3),
38.6 (d, J ) 19.5), 128.9 (d, J ) 6.9), 129 (d, J ) 7.5), 129.5,
129.6, 133.9 (d, J ) 19.5), 134 (d, J ) 18.9), 136.4 (d, J ) 14),
136.5 (d, J ) 13.8), 179.5 (d, J ) 16.1). Phenylglycinol can be
recovered by the following procedure: To the previous aqueous
phase was added sodium hydroxide 15 M (2 mL), and then it
was extracted with dichloromethane (3 × 25 mL). The organic
phases were dried (MgSO4) and evaporated under reduced
pressure giving phenylglycinol in 80% yield.
(S)-3-Bor a n a tod ip h en ylp h osp h in o Bu ta n oic Acid (14).
To 1.5 g of 13 was slowly added, at 0°C, 3.1 mL of 1 M borane-
THF complex solution. The solution was stirred at this
temperature for 30 min. Water was then added to the solution
(3 mL) and extracted with dichloromethane (3 × 5 mL). The
combined organic phases were dried (MgSO4) and evaporated
under reduced pressure to afford 14. The crude product was
purified by chromatography, eluting with 20% ethyl acetate
in cyclohexane to give 14 as a white powder in a quantitative

Synthesis of R-Substituted â-Amidophosphines
J . Org. Chem., Vol. 66, No. 16, 2001 5571
yield. Mp: 120 °C; [R]20 ) +34 (c 1, CHCl3); 1H NMR δ 0.5-
(neat) 3366, 2954, 2921, 2869, 2383, 1674, 1495, 1106, 736,
D
697 cm-1
.
1.1 (b, 3H), 1.2 (dd, J ) 16.1, J ) 6.9, 3H), 2.4-2.65 (m, 2H),
3-3.3 (m, 1H), 7.2-7.4 (m, 6 H), 7.45-7.6 (m, 4H); 31P NMR
δ 25.2; 13C NMR δ 14.7 (d, J ) 17.3), 25.5 (d, J ) 38.5), 35.9
(d, J ) 5.2), 127.9 (d, J ) 54.5), 128 (d, J ) 53.4), 129.3 (d, J
) 9.2), 129.6 (d, J ) 9.8), 131.9 (d, J ) 3.4), 132 (d, J ) 2.3),
132.9 (d, J ) 8.6), 133 (d, J ) 8.6), 178.2 (d, J ) 17.8). Anal.
Calcd for C16H20BO2P (286.12): C, 67.17; H, 7.05. Found: C,
67.31; H, 7.16. HPLC Daicel Chiralcel OJ , 1 mL/min, 4%
2-PrOH/hexane + 0.5 mL formic acid, (S) t2 ) 25.5 min (for a
mixture of enantiomers, (R) t1 ) 22.1 min; (S) t2 ) 25.5 min).
(S,R)-3-(Bor a n a tod ip h en ylp h osp h in o)-3-tr ibu tylsta n -
n yl-N-(2-b en zyloxy-1-p h en ylet h yl)p r op ion a m id e (15):
(R,R)-3-(Bor a n a tod ip h en ylp h osp h in o)-3-tr ibu tylsta n -
n yl-N-(2-b en zyloxy-1-p h en ylet h yl)p r op ion a m id e (15):
white oil; Rf ) 0.31 (cyclohexane/ethyl acetate 9:1); [R]20
)
D
-33.1 (c 1, CHCl3); 1H NMR δ 0.4-0.8 (m, 6H), 0.5-1.4 (b,
3H), 0.75 (t, J ) 7.2, 9H), 0.95-1.3 (m, 12H), 2.35-2.8 (m,
3H), 3.55-3.65 (m, 2H), 4.35 (d, J ) 15.6, 1H), 4.4 (d, J )
15.6, 1H), 4.9 (m, 1H), 9 (d, J ) 7.7, 1H), 7.1-7.4 (m, 16H),
7.7-7.9 (m, 4H); 31P NMR δ 21.4; 13C NMR δ 10.4, 11.7 (d, J
) 24.3), 12.6, 26.3, 27.9, 34.1, 53.2, 72.5, 73.4, 127.1-129,
130.8-132.1, 137.8, 139.9, 171 (d, J ) 15.4).
white oil; Rf ) 0.21 (cyclohexane/ethyl acetate 9:1); [R]20
)
D
-15.4 (c 1, CHCl3); 1H NMR δ 0.4-0.8 (m, 6H), 0.5-1.4 (b,
3H), 0.7 (t, J ) 7.2, 9H), 0.95-1.3 (m, 12H), 2.4-2.65 (m, 2H),
2.7-2.85 (m, 1H), 3.4 (dd, J ) 4.8, J ) 9.7, 1H), 3.5 (dd, J )
4.8, J ) 9.7, 1H), 4.4 (s, 2H), 4.9 (m, 1H), 5.9 (d, J ) 7.7, 1H),
7.1-7.4 (m, 16H), 7.7-7.9 (m, 4H). 31P NMR δ 21.2; 13C NMR
δ 11.8, 13.1 (d, J ) 24.7), 14, 27.7, 29.2, 34.2, 53.3, 72.4, 73.4,
127.3-129.1, 130.9-132.4, 137.9, 140.1, 171 (d, J ) 14.3); IR
Ack n ow led gm en t . This work is part of the
RINCOF/PUNCHORGA program, and we thank the
Conseil Re´gional de Basse-Normandie and the Conseil
Re´gional de Haute-Normandie for their financial sup-
port (Grants to M.L. and G.C.-D.).
J O0155759