Stereospecific nucleophilic substitution of optically pure H-phosphinates: A general way for the preparation of chiral P-stereogenic phosphine oxides

Article abstract of DOI:10.1021/ja804412k

Contrary to the generally held view, it is found that the rapid epimerization of (-)-menthyl (R_P)-phenylphosphinate under basic conditions is not due to the so far believed inherent stereolability of its corresponding anion but due to a reactio

Full text of DOI:10.1021/ja804412k

Published on Web 08/30/2008
Stereospecific Nucleophilic Substitution of Optically Pure
H-Phosphinates: A General Way for the Preparation of Chiral
P-Stereogenic Phosphine Oxides
Qing Xu, Chang-Qiu Zhao, and Li-Biao Han*
National Institute of AdVanced Industrial Science and Technology,
Tsukuba, Ibaraki 305-8565, Japan
Received December 1, 2007; E-mail: libiao-han@aist.go.jp
Abstract: Contrary to the generally held view, it is found that the rapid epimerization of (-)-menthyl (RP)-
phenylphosphinate under basic conditions is not due to the so far believed inherent stereolability of its
corresponding anion but due to a reaction of the hydrogen phosphinate ester with a metal alkoxide. This
finding successfully leads to a discovery that, by adding an H-phosphinate to organolithiums or Grignard
reagents at a low temperature, the nucleophilic substitution of the alkoxy group of the H-phosphinate with
organolithiums or Grignard reagents proceeds stereospecifically with inversion of configurations at
phosphorus to give a wide range of P-stereogenic secondary phosphine oxides and tertiary phosphine
oxides, by quenching the reaction mixture with water and alkyl halides, respectively. This finding establishes
a general protocol for the preparation of optically active secondary phosphine oxides and tertiary phosphine
oxides from the easily accessible optically pure H-phosphinates. Mechanistic studies show that the
substitution reactions of H-phosphinates with organolithiums and Grignard reagents proceed via two
competing reaction paths, that is, a two-step reaction path involving first a deprotonation of H-phosphinates
followed by a substitution of the corresponding anion with inversion of configuration at phosphorus and a
direct substitution of RM with H-phosphinates generating the SPO directly.
SPOs.4 However, progress of such studies is bottlenecked by
the limited availability of these optically pure SPOs since their
Introduction
preparations usually involve tedious procedures.1,3,4 We are
engaging in the preparation of optically active phosphorus
compound via the stereospecific transformation of the reactive
H-P bonds of the relatively easily accessible H-phosphonates
and H-phosphinates.5,6 We have revealed that a palladium-
mediated addition to alkynes and a radical or base initiated
addition to alkenes of the optically pure (-)-menthyl (RP)-
phenylphosphinate 1a could take place stereospecifically to give
high yields of (RP)-phosphinates with retention of configuration
at phosphorus (Scheme 1).6 Since the preparation of SPOs via
substitution of organolithiums or Grignard reagents with H-
phosphonates and H-phosphinates is well-known,7 we assume
that if it can proceed stereospecifically, a variety of enantio-
merically pure SPOs 2 and tertially phosphine oxides (TPOs) 3
will be readily prepared from an enantiomerically pure H-
P-Stereogenic phosphorus compounds are of importance in
organic synthesis, and asymmetric catalysis.1 The recent realiza-
tion that secondary phosphine oxides (SPOs) can serve as
ligands in metal-catalyzed reactions2 is boosting a new wave
of studies on metal-catalyzed asymmetric reactions using
unsymmetrical enantiomerically pure SPOs,3 because of the easy
operation of the metal-mediated reactions using the air-stable
(1) (a) Quin, L. D. A Guide to Organophosphorus Chemistry; Wiley-
Interscience: New York, 2000. (b) Sasaki, M. In Chirality in
Agrochemicals; Kurihara, N., Miyamoto, J., Eds.; Wiley & Sons:
Chichester, U.K. 1998; pp 85. (c) Imamoto, T. In Handbook of
Organophosphorus Chemistry; Engel, R., Ed.; Marcel Dekker: New
York, 1992; Chapter 1. (d) Crepy, K. V. L.; Imamoto, T. Top. Curr.
Chem. 2003, 229, 1.
(2) (a) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513. (b) Bigeault, J.;
Giordano, L.; Buono, G. Angew. Chem., Int. Ed. 2005, 44, 4753. (c)
Ackermann, L.; Born, R.; Spatz, J. H.; Meyer, D. Angew. Chem., Int.
Ed. 2005, 44, 7216. (d) Ackermann, L. Synthesis 2006, 1557. (e)
Ackermann, L.; Born, R.; Spatz, J. H.; Althammer, A.; Gschrei, C. J.
Pure Appl. Chem. 2006, 78, 209.
(4) Recent preparation of optically active SPOs: (a) Pietrusiewicz, K. M.;
Zablocka, M. Chem. ReV. 1994, 94, 1375. (b) Haynes, R. K.; Au-
Yeung, T.-L.; Chan, W.-K.; Lam, W.-L.; Li, Z.-Y.; Yeung, L.-Y.;
Chan, A. S. C.; Li, P.; Koen, M.; Mitchell, C. R.; Vonwiller, S. C.
Eur. J. Org. Chem. 2000, 3205. (c) Haynes, R. K.; Free Man, R. N.;
Mitchell, C. R.; Vonwiller, S. C. J. Org. Chem. 1994, 59, 2919. (d)
Wang, F.; Polavarapu, P. L.; Drabowicz, J.; Mikolajczyk, M. J. Org.
Chem. 2000, 65, 7561. (e) Drabowicz, J.; Lyzwa, P.; Omelanczuk, J.;
Pietrusiewicz, K. M.; Mikolajczyk, M. Tetrahedron: Asymmetry, 1999,
10, 2757. (f) Leyris, A.; Nuel, D.; Giordano, L.; Achard, M.; Buono,
G. Tetrahedron Lett. 2005, 46, 8677.
(3) (a) Dubrovina, N. V.; Bo¨rner, A. Angew. Chem., Int. Ed. 2004, 43,
5883. (b) Jiang, X.; Minnaard, A. J.; Hessen, B.; Feringa, B. L.;
Duchateau, A. L. L.; Andrien, J. G. O.; Boogers, J. A. F.; de Vries,
J. G. Org. Lett. 2003, 5, 1503. (c) Dai, W. M.; Yeung, K. K. Y.;
Leung, W. H.; Haynes, R. K. Tetrahedron: Asymmetry 2003, 14, 2821.
(d) Chan, E. Y. Y.; Zhang, Q.-F.; Sau, Y.-K.; Lo, S. M. F.; Sung,
H. H. Y.; Williams, I. D.; Haynes, R. K.; Leung, W. H. Inorg. Chem.
2004, 43, 4921. (e) Nemoto, T.; Jin, L.; Nakamura, H.; Hamada, Y.
Tetrahedron Lett. 2006, 47, 6577. (f) Jiang, X.; van den Berg, M.;
Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. Tetrahedron:
Asymmetry 2004, 15, 2223. (g) Jiang, X.; Minnaard, A. J.; Feringa,
B. L.; de Vries, J. G. J. Org. Chem. 2004, 69, 2327.
(5) Xu, Q.; Han, L.-B. Org. Lett. 2006, 8, 2099.
(6) (a) Han, L.-B.; Zhao, C.-Q.; Onozawa, S.; Goto, M.; Tanaka, M. J. Am.
Chem. Soc. 2002, 124, 3842. (b) Han, L.-B.; Zhao, C.-Q. J. Org. Chem.
2005, 70, 10121.
9
12648 J. AM. CHEM. SOC. 2008, 130, 12648–12655
10.1021/ja804412k CCC: $40.75
2008 American Chemical Society

Substitution of Optically Pure H-Phosphinates
A R T I C L E S
Scheme 1
Scheme 2
Scheme 3
Scheme 4
phosphinates 1 (Scheme 2).8,9 Moreover, if the two substituents
X1 and X2 on 1 can be sequentially replaced, a vast number of
the optically active SPOs can be generated by a simple
combination of R1M and R2M (Scheme 2).
However, such a stereospecific transformation has not been
discovered9 until recently by us10 and others.11 In the past,
optically active H-phosphinates were reported to rapidly epimer-
ize in the presence of a base giving racemic products.8,9,12 Thus,
Mislow and co-workers found that the anion of (RP)-1a is
stereolabile and epimerization easily took place.8a Aaron and
co-workers prepared optically active (S)-(+)-isopropyl
methylphosphinate.8b They reported that treatment of (S)-(+)-
isopropyl methylphosphinate with n-butyl lithium followed by
quenching with benzyl bromide gave only racemic methylbu-
tylbenzylphosphine oxide.8b Herein we disclose the details of
our findings on the preparation of optically pure H-phosphinates
1a-d and their conversions to optically active P-stereogenic
secondary phosphine oxides (SPOs) 2 and tertiary phosphine
oxides (TPOs) 3 via stereospecific nucleophilic substitutions of
optically pure H-phosphinates 1 with organolithiums or Grignard
reagents.
(7) (a) A general review: Organic Phosphorus Compounds; Kosolapoff,
G. M., Maier, L., Eds.; Wiley-Interscience: New York, 1972; Vol.
3,Chapter 6. See also: (b) Hays, H. R. J. Org. Chem. 1968, 33, 3690.
(c) Grim, S. O.; Satek, L. C. J. Inorg. Nucl. Chem. 1977, 39, 499. (d)
Williams, R. H.; Hamilton, L. A. J. Am. Chem. Soc. 1952, 74, 5418.
(8) Optically pure H-phosphinates 1a-d can be purchased from Katayama
Chemical Industries Co.Ltd. (http://www.katayamakagaku.co.jp). Prepa-
ration of optically active H-phosphinates: (a) Farnham, W. B.; Murray,
R. K.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 5809. (b) Reiff, L. P.;
Aaron, H. S. J. Am. Chem. Soc. 1970, 92, 5275. (c) Benschop, H. P.;
Platenburg, D. H. J. M.; Meppelder, F. H.; Boter, H. J. Chem. Commun.
1970, 33. (d) Bodalski, R.; Koszuk, J. Phosphorus, Sulfur, Silicon
Relat. Elem. 1989, 44, 99. (e) Reference 6.
(9) Early attempts to prepare chiral SPOs via similar substitution reactions
only led to the nonselective formation of racemates, see: (a) Emmick,
T. L.; Letsinger, R. L. J. Am. Chem. Soc. 1968, 90, 3459. (b) Farnham,
W. B.; Murray, R. K.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 5808.
(c) Reference 8b.
(10) Han, L.-B.; Xu, Q. Japanese Patent JP2008-69103A (filed, 25 August
2006; opened, 3 March2008).
Results and Discussion
Preparation of Optically Pure H-Phosphinates 1. As shown
in the following Schemes, optically pure H-phosphinates 1a-d
(>99% de) were easily obtained (Schemes 3 and 4). A
diastereomer mixture of (-)-menthyl phenylphosphinate 1a was
prepared from a PhPCl2 and (L)-(-)-menthol as reported
(Scheme 3).8a,9a It appeared that its preparation was first reported
by Emmick and co-workers although they failed to separate the
diastereomer mixture.9a Later Mislow et al. obtained an optically
enriched (RP)-1a (ca. RP/SP ) 95/5) by fractional recry-
stallization.8a We modified their procedure and found that pure
(RP)-1a (RP/SP > 99/1) could be easily obtained by recrystal-
lizing the RP/SP diastereomer mixtures at -30 °C.6 A similar
(11) (a) Leyris, A.; Bigeault, J.; Nuel, D.; Giordano, L.; Buono, G.
Tetrahedron Lett. 2007, 48, 5247. (b) Moraleda, D.; Gatineau, D.;
Martin, D.; Giordano, L.; Buono, G. Chem. Commun. 2008, 3031.
9
J. AM. CHEM. SOC. VOL. 130, NO. 38, 2008 12649

A R T I C L E S
Xu et al.
Table 1. Stereospecific Nucleophilic Substitution of (RP)-1a with
MeLi
to remove menthol generated and other organic substrates, and
then the aqueous phase was extracted with chloroform. Con-
sequently, a colorless oil of NMR spectroscopically pure
methylphenylphosphine oxide (2a)14 was obtained (652 mg, 4.65
mmol, 93% yield, 97% ee) (entry 1, Table 2).
As demonstrated in Table 2, a variety of organolithiums and
Grignard reagents are applicable to this reaction to produce the
corresponding SPOs in high yields with high ee. Thus, under
similar reaction conditions, primary (MeLi-LiBr, n-BuLi),
secondary (i-PrLi), and tertiary (t-BuLi) alkyllithiums produced
the corresponding optically active SPOs in 93% ee (2a), 99%
ee (2b), 97% ee (2c), and 99% ee (2d), respectively (entries
2-5). A functionalized alkylithium reagent such as Me3SiCH2Li
could also be used in the reaction to give the unsymmetrical
SPO 2e in 92% yield with 96% ee (entry 6). As to the absolute
configuration of the SPOs at phosphorus, the stereochemistry
of 2d (entry 5) was determined to be SP by comparing with the
literature data,4b indicating that this substitution takes place
through inversion of configuration at phosphorus. Under the
same reaction condition, the reaction of (SP)-1b with n-BuLi
and t-BuLi produced the corresponding RP enantiomers of 2b
and 2d in 95% ee and 93% ee, respectively (entries 7-8),
showing the substitution reaction proceeded stereospecifically.
Noteworthy, in addition to organolithiums, primary and second-
ary alkyl Grignard reagents could also be used as the substrates.
Thus, methyl, butyl, i-propyl, allyl, and benzyl Grignard reagents
all gave high yields of the products with high ee (entries 9-18).
However, sterically bulky Grignard reagents could not be used
in this reaction. For example, no substitution product was
obtained with t-BuMgCl at -80 °C.15 Although 76% yield of
2d was obtained when the reaction was conducted at 0 °C, the
ee of 2d was only 48%.
Like (RP)-1a,(-)-menthyl benzylphosphinate (RP)-1c and(-)-
menthyl mesitylphosphinate (RP)-1d reacted similarly. Thus,
(RP)-1c and (RP)-1d reacted with PhLi to give (RP)-2g and (SP)-
2h in 97% and 94% ee, respectively (entries 19-22). By
comparison of SPO (RP)-2g (entries 19-20) with its enantiomer
(SP)-2g (entry 18), the absolute configuration of 1c was deduced
to be RP at phosphorus, which is also in consistent with the
literature.8d The absolute configuration of (RP)-1d was deduced
similarly by the comparison of (SP)-2h (entries 21-22) with
(RP)-2h (entry 42). Reactions of (RP)-1c with other organolithi-
ums under similar conditions also gave the corresponding SPOs
2i-k in high ee (entries 23-25).
entry
conditionsa
yield %b
ee %c
1
2
3
4
room temperature (25 °C), 1 h
0 °C, 1 h
-80 °C, 7 h
-80 °C, 30 min; 0 °C, 30 min
99
99
84
99
60
83
97
97
a (RP)-1a (1.0 M in THF) was added to 2.1 equiv MeLi (1.0 M in
Et2O) in a Schlenk tube under N2. The reaction mixture was quenched
with saturated aqueous NH4Cl solution and slowly warmed to room
temperature. b Determined by 1H NMR of the crude mixture. c Deter-
mined by HPLC analysis (UV) on a Chiralpak AS column using hexane/
i-PrOH (1/1) as eluent (1 mL/min) at 30 °C.
method was used to prepare (SP)-1b by using (D)-(+)-menthol
instead of (L)-(-)-menthol (Scheme 3).
Other H-phosphinates 1c,d were obtained by the reactions
of the corresponding Grignard reagents with (-)-MenOPCl2
which is easily prepared from PCl3 and (L)-(-)-menthol13
(Scheme 4). After recrystallization, optically pure H-phosphi-
nates (RP)-1c and (RP)-1d were obtained (RP/SP > 99/1). The
absolute configuration of 1c was determined to be RP at
phosphorus (vide infra), which is in consistent with the literature
data.8d The stereochemistry of (RP)-1d was deduced on the basis
of the stereochemistry of the substitution products of (RP)-1d
with organolithiums (vide infra).
Stereospecific Nucleophilic Substitution of Optically Pure
H-Phosphinates 1 Affording Optically Active Phosphine Oxides.
The reaction of (RP)-1a with 2.1 equiv of MeLi was investigated
first (Table 1). At room temperature, when (RP)-1a was slowly
added to MeLi, methylphenylphosphine oxide 2a was obtained
in 99% yield with 60% ee (entry 1). When the reaction was
conducted at 0 °C, the ee of 2a was improved to 83% (entry
2), and the ee of 2a further increased to 97% at -80 °C (entry
3), though the yield of 2a slightly decreased because part of
(RP)-1a remained unreacted. A high yield (99%) and high ee
(97%) of 2a was achieved by conducting the addition of (RP)-
1a to MeLi at -80 °C and then raising the temperature to 0 °C
(entry 4). As shown below, this reaction could be easily carried
out in a relatively large scale with good reproducibility. Thus,
to MeLi (11 mmol, 1.0 M in Et2O) at -80 °C was slowly added
(RP)-1a in THF (5 mmol in 5 mL of THF). The reaction mixture
was kept at -80 °C for 30 min, and then slowly warmed to 0°.
Saturated aqueous ammonium chloride (20 mL) was then added.
The product 2a is rather soluble in water. This leads to an easy
isolation of the product by simply washing the aqueous phase
with hexane to remove menthol and other organic substrates,
followed by extraction of the product with chloroform. Thus,
the resulted reaction mixture was first washed twice with hexane
Aryllithiums also react efficiently with (RP)-1a to give the
corresponding unsymmetrical diarylphosphine oxides in high
ee (entries 26, 28, 30, 32, 34, 36, 37, 39, 40). In addition, the
lithioheterocyclic compounds such as 2-, or 3-lithiothiophene,
and 2-lithiopyridine reacted efficiently to give the corresponding
products in high ee (entries 37-41). As expected, organolithi-
ums generated by the convenient lithium-tellurium exchange
reactions of organotellurides with n-BuLi16 can also be em-
ployed in these reactions (entries 27, 29, 31, 33, 35, 38, 41-43).
Moreover, we found that the benzyl group can also be
replaced by organolithiums.19 Thus, the reaction of (RP)-2j (97%
ee) with PhLi gave (RP)-2d in a high selectivity (96% ee, entry
(12) Other early attempts to obtain chiral SPOs by reduction of the
corresponding optically active P-stereogenic precursors using alu-
minium reagents also failed, see: (a) Reference 9a. (b) Henson, P. D.;
Ockrymiek, S. B.; Markham, R. E., Jr. J. Org. Chem. 1974, 39, 2296.
(c) Wetzel, R. B.; Kenyon, G. L. J. Org. Chem. 1974, 39, 1531. It
was also reported that phosphine oxides undergo rapid stereomutation
in the presence of aluminium reagents prior to reduction, see: (d)
Henson, P. D.; Nauman, K.; Mislow, K. J. Am. Chem. Soc. 1969, 91,
5645. (e) Reference 9b.
(14) We found that although stable under basic conditions, 2a instantly
epimerizes when treated with diluted hydrogen chloride acid. Even a
trace amount of acid can cause this epimerization even at-80 °C.
Thus, all glasswares used for keeping this compound were all carefully
deacidified by washing them first with an alkaline solution and then
with water.
(13) (a) Chen, W.-P.; Xiao, J.-L. Tetrahedron Lett. 2001, 42, 2897. (b)
Yamanoi, Y.; Imamoto, T. J. Org. Chem. 1997, 62, 8560.
(15) All (RP)-1a used was recovered without epimerization.
9
12650 J. AM. CHEM. SOC. VOL. 130, NO. 38, 2008

Substitution of Optically Pure H-Phosphinates
A R T I C L E S
Table 2. Preparation of Optically Active P-Stereogenic Phosphine Oxides 2 and 317
entry
RLi or RMgX
substrate
conditionsa
E
product: R1, R2, R3
yield % ee %
1d
MeLi
(RP)-1a Et2O,-80 °C, 0.5 h;0 °C,
0.5 h
H2O
(SP)-2a: Me, Ph, H
93
97b
2d
3d
4d
5d
6d
7d
8d
9d
MeLi-LiBr
n-BuLi
i-PrLi
t-BuLi
Me3SiCH2Li
n-BuLi
(RP)-1a Et2O,-80 °C, 3 h
(RP)-1a hexane,-80 °C, 5 h
(RP)-1a pentane,-80 °C, 13 h
(RP)-1a pentane,-80 °C, 14 h
(RP)-1a pentane,-80 °C, 23 h
(SP)-1b hexane,-80 °C, 10 h
(SP)-1b pentane,-80 °C, 17 h
(RP)-1a Et2O,-80 °C, 6 h
(RP)-1a Et2O,-80 °C, 4 h
(RP)-1a Et2O,--80 °C, 14 h
(RP)-1a THF,-80 °C, 6 h
(RP)-1a THF,-80 °C, 11 h
(RP)-1a Et2O,-80 °C, 20 h
(RP)-1a THF,-80 °C, 13 h
(RP)-1a THF,-80 °C, 14 h
(RP)-1a Et2O,-80 °C, 14 h
(RP)-1a THF,-80 °C, 14 h
(RP)-1c Et2O, -80 °C, 19 h
(RP)-1c Pentane, -80 °C, 19 h
(RP)-1d Et2O, -80 °C, 17 h
(RP)-1d pentane, -80 °C, 17 h
(RP)-1c hexane,-80 °C, 14 h
(RP)-1c pentane,-80 °C, 19 h
(RP)-1c pentane,-80 °C, 25 h
(RP)-1a THF,-80 °C, 22 h
(RP)-1a THF,-80 °C, 30 h
(RP)-1a Et2O,-80 °C, 24 h
(RP)-1a Et2O,-80 °C, 17 h
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
(SP)-2a
64
99
98
95
95
99
99
82
93
78
67
99
94
93
99
99
66
50
62
93
89
99
91
98
91
99
99
92
98
96
89
81
85
93
89
71
40
91
99
99
74
89
35
93b
99b
97b
99b
96b
95b
93b
97b
92b
99b
99b
91b
91b
66b
97c
97c
87b
97b
97b
94b
94b
92b
97b
99b
98c
80c
79b
89b
92b
92b
99c
82c
92c
89c
87b
77b
77b
99c
92b
87b
64b
74b
96b
(SP)-2b: n-Bu, Ph, H
(SP)-2c: i-Pru, Ph, H
(SP)-2d: t-Bu, Ph, H
(SP)-2e: Me3SiCH2, Ph, H
(RP)-2b: Ph, n-Bu, H
(RP)-2d: Ph, t-Bu, H
(SP)-2a
(SP)-2a
(SP)-2b
(SP)-2b
(SP)-2b
(SP)-2c
(SP)-2c
(SP)-2f: allyl, Ph, H
(SP)-2f
(SP)-2g: PhCH2, Ph, H
(RP)-2g: Ph, PhCH2, H
(RP)-2g
(SP)-2h: Ph, mesityl, H
(SP)-2h
(SP)-2i: n-Bu, PhCH2, H
(RP)-2j: t-Bu, PhCH2, H
(RP)-2k: Me3SiCH2, PhCH2, H
(RP)-2l: 2-tolyl, Ph, H
(RP)-2l
(RP)-2m: 2-anisyl, Ph, H
(RP)-2m
(RP)-2n: 2,4-dimethoxy-phenyl, Ph, H
(RP)-2n
t-BuLi
MeMgI
10d MeMgBr
11d n-BuMgI
12d n-BuMgBr
13d n-BuMgCl
14d i-PrMgCl
15d i-PrMgBr
16d CH2dCHCH2MgCl
17d CH2dCHCH2MgBr
18d PhCH2MgBr
19d PhLi
20d PhLi
21d PhLi
22d PhLi
23d n-BuLi
24d t-BuLi
25d Me3SiCH2Li
26e 2-lithiotoluene
27f 2-lithiotoluene
28e 2-lithioanisole
29f 2-lithioanisole
30e 2,4-dimethoxy-phenyllithium (RP)-1a Et2O,-80 °C, 27 h
31f 2,4-dimethoxy-phenyllithium (RP)-1a Et2O,-80 °C, 50 h
32e 1-lithionaphthalene
33f 1-lithionaphthalene
34e 2-lithionaphthalene
35f 2-lithionaphthalene
36g 9-lithiophenanthrene
37e 2-lithiothiophene
38f 2-lithiothiophene
39e 3-lithiothiophene
40e 2-lithiopyridine
41f 2-lithiopyridine
42f lithiomesitylene
43f 4-lithioanisole
(RP)-1a THF,-80 °C, 22 h
(RP)-1a Et2O,-80 °C, 39 h
(RP)-1a THF,-80 °C, 18 h
(RP)-1a Et2O,-80 °C, 39 h
(RP)-1a THF,-80 °C, 16 h
(RP)-1a Et2O,-80 °C, 22 h
(RP)-1a THF,-80 °C, 21 h
(RP)-1a Et2O,-80 °C, 24 h
(RP)-1a Et2O,-80 °C, 24 h
(RP)-1a Et2O,-80 °C, 48 h
(RP)-1a THF,-80 °C, 72 h
(RP)-1a THF,-80 °C, 13 h
(RP)-2o: 1-naphthyl, Ph, H
(RP)-2o
(RP)-2p: 2-naphthyl, Ph, H
(RP)-2p
(RP)-2q: 9-phenanthryl, Ph, H
(RP)-2r: 2-thiophenyl, Ph, H
(RP)-2r
(RP)-2s: 3-thiophenyl, Ph, H
(RP)-2t: 2-pyridyl, Ph, H
(RP)-2t
(RP)-2h
(RP)-2u: 4-anisyl, Ph, H
(RP)-2d
44d PhLi
(RP)-2j cyclohexane/Et2O,-80 °C, H2O
19 h
45d n-BuLi
46d n-BuLi
(RP)-1a hexane,-80 °C, 7 h
(RP)-1a hexane,-80 °C, 7 h
MeI 0 °C, 24 h
CH2dCH-CH2Br (RP)-3b: n-Bu, Ph, Allyl
0 °C, 24 h
PhCH2Br 0 °C,
24 h
(SP)-3a: n-Bu, Ph, Me
84
86
93b
91b
47d n-BuLi
(RP)-1a hexane,-80 °C, 7 h
(RP)-3c: n-Bu, Ph, PhCH2
83
72b
a All reactions were conducted at -80 °C by slowly adding optically pure 1 (>99% de) or (RP)-2j (97% ee) (1.0 M in THF or pentane) to RM
reagents (2.1 equiv). The reaction mixture was either quenched with saturated aqueous NH4Cl solution and slowly warmed to room temperature, or
quenched with alkyl halides and stirred at 0 °C overnight. b Determined by HPLC analysis using a Chiralpak AS or AD column. c Determined by 1H or
31P NMR by adding an equimolar ratio of (R)-(+)-tert-butylphenylthiophosphinic acid.18 d Organolithiums and Grignard reagents purchased.
e Organolithiums generated from organobromides and n-butyllithium. f Organolithiums generated from butyltellurides and n-butyllithium16
nolithiums generated from 9-iodophenanthrene and n-butyllithium.
.
g Orga-
44). Given that (RP)-2j was generated from (RP)-1c via the
replacement of the menthoxyl group with t-BuLi (entry 24),
this reaction significantly expands the scope of the preparation
of optically active SPOs via stereospecific substitutions, because,
as shown in Scheme 5, the two groups (menthoxyl and benzyl)
of (RP)-1c can be sequentially replaced by organolithiums.
Finally, by switching the quenching reagent from water to
alkyl halides, the corresponding optically active tertiary phos-
phine oxides (TPOs) could also be generated in moderate to
high ee. For example, after the reaction mixture of (RP)-1a (0.2
mmol in 0.8 mL pentane) and n-BuLi (0.42 mmol in 0.26 mL
hexane) was kept at -80 °C for 7 h, MeI (0.6 mmol) was added
(-80 °C, 30 min; 0 °C, overnight). The corresponding (SP)-
methylbutylphenylphosphine oxide 3a was obtained in 84%
yield with 93% ee (entry 45). Similarly, by employing allyl-
bromide and benzylbromide as the substrate, (RP)-allylbutylphe-
9
J. AM. CHEM. SOC. VOL. 130, NO. 38, 2008 12651

A R T I C L E S
Xu et al.
Scheme 5
epimerization paths could lead to the formation of the minor
RP enantiomer. However, as experimentally confirmed below,
the possibilities of paths 2 and 3 can be excluded under the
present reaction conditions. Thus, the ee of (SP)-2a PhMeP(O)H
(95% ee), before and after being treated with an equivalent of
MeLi to generate (SP)-6a and then quenched with saturated
aqueous NH4Cl solution, was essentially the same. Treatment
of (SP)-2b and (SP)-2d with n-BuLi and t-BuLi gave the same
results, ruling out the epimerization of (SP)-6a to (RP)-6a (path
Scheme 6
3, Scheme 7) under the substitution reaction conditions.20c
A
similar deprotonation reaction of (RP)-1a with organolithiums
to generate (RP)-5a, however, can not be used for the study of
path 2, because (-)-MenOLi, generated from the substitution
reaction of (RP)-1a with the organolithium, can significantly lead
to the epimerization of 1a (vide infra). Thus the use of a bulky
base, which deprotonates (RP)-1a but does not replace (-)-
MenO group is necessary. For this purpose, t-BuMgCl and LDA
were used. We found that (RP)-1a could be recovered in >99%
yield with >99% de after treatment with t-BuMgCl at -80 °C.15
Similarly, (RP)-1a was allowed to react with LDA at -80 °C.
Quenching the reaction mixture after 4 h at -80 °C with MeI
afforded the methylation product (-)-menthyl (RP)-methylphe-
nylphosphinate 7 in 99% yield with RP/SP ) 98/2. Under similar
conditions by quenching with saturated aqueous NH4Cl, no
epimerization of 1a took place (1a was recovered in 99% yield
with RP/SP ) 99/1). By conducting a similar reaction at -40
°C for 30 min, 1a could also be recovered in 99/1 RP/SP ratio.
These results indicated that (RP)-5a is stable under these
conditions.
Indeed, (RP)-5a is stable enough to be isolated and stored at
room temperature. Treating (RP)-1a with 1 equiv of LDA in
Et2O at -80 °C followed by the removal of solvent and other
volatiles under vacuum gave a white solid at room temperature.
Hydrolysis of this solid with saturated aqueous ammonium
chloride at -80 °C gave (RP)-1a with 99/1 RP/SP ratio, while
the treatment of this solid with 1.2 equiv of n-BuLi at -80 °C
gave (SP)-2b in 80% yield and 92% ee, clearly indicating that
(a) this solid (RP)-5a is stable at room temperature and (b) (RP)-
5a readily reacts with n-BuLi with inversion of configuration
at phosphorus to give the substitution product. Therefore, it can
be concluded that, (RP)-5a is a relatively stable intermediate
and no epimerization took place under the present reaction
conditions.8a,9,11,12
In contrast to paths 2 and 3, the epimerization of (RP)-1a to
(SP)-1a (path 1, Scheme 7) does take place easily even at -80
°C in the presence of a metal alkoxide.22 Thus, (RP)-1a, when
mixed with 1 equiv of (-)-MenOLi at -80 °C for 4 h and then
quenched with saturated aqueous NH4Cl solution, gave a
diastereomers mixture of 1a (RP/SP ) 67/33 in Et2O; RP/SP )
51/49 in hexane). The epimerization of (RP)-1a can also be
confirmed by using MeI as the quenching reagent to give
diastereomers mixture of 7 (RP/SP ) 68/32 in Et2O; RP/SP )
78/22 in hexane). In addition, this epimerization was also well
reflected in the substitution reaction of (RP)-1a with n-BuLi.
Thus, after mixing (RP)-1a with (-)-MenOLi at -80 °C for
4 h, the reaction with n-BuLi (2.1 equiv) only gave 16% ee
selectivity of (SP)-2b, while under similar conditions, the
simultaneous addition of (-)-MenOLi (1 equiv) and n-BuLi (2.1
equiv) to (RP)-1a gave a 93% ee of the product, which is slightly
lower than that obtained from a reaction in the absence of (-)-
nylphosphine oxide 3b and (RP)-benzylbutylphenylphosphine
oxide 3c were obtained in 86% yield with 91% ee and 83%
yield with 72% ee, respectively (entries 46, 47).
The diverse utility of optically active phosphorus compounds
were well documented in the literature.3,4,20 For example, SPO
can readily react with sulfur stereospecifically to give the
corresponding chiral thiophosphinic acid quantitatively. Thus,
(SP)-2d (99% ee) can be easily converted to the useful chemical
shift reagent (R)-(+)-tert-butylphenylthiophosphinic acid 4 with
retention of configuration at phosphorus21 without the loss of
ee, by simply heating 2d with an equivalent sulfur in THF
(Scheme 6). Chiral thiophosphinic acid 4 is an effective chemical
shift reagent which has been prepared by a tedious separation
process.4b,c,18
Factors Affecting the ee of the Products. During the course
of this study, we noted that the following impurities from (RP)-
1a and organolithiums or Grignard reagents can significantly
decrease the ee of the products: menthol, water, and metal
alkoxide ROM (M ) Li, MgX). Thus, to get high ee of the
products, these reactions must be carried out under dry nitrogen
atmosphere, using (RP)-1a free of menthol and water and
organolithiums or Grignards without the contamination of metal
alkoxides ROM. Scheme 7 showed the possible routes for the
formation of the minor enantiomer (RP)-2 in the stereospecific
substitution of (RP)-1a with RM. In addition to the instinct
selectivity of the substitution of (RP)-5a with RM, at least three
(16) (a) Hiiro, T.; Kambe, N.; Ogawa, A.; Miyoshi, N.; Sonoda, N. Angew.
Chem., Int. Ed. 1987, 26, 1187. (b) Hiiro, T.; Morita, Y.; Inoue, T.;
Kambe, N.; Ogawa, A.; Ryu, I.; Sonoda, N. J. Am. Chem. Soc. 1990,
112, 455. (c) Hiiro, T.; Atarashi, Y.; Kambe, N.; Fujiwara, S.; Ogawa,
A.; Ryu, I.; Sonoda, N. Organometallics 1990, 9, 1355. (d) Kambe,
N.; Inoue, T.; Takeda, T.; Fujiwara, S.-i.; Sonoda, N. J. Am. Chem.
Soc. 2006, 128, 12650.
(17) See Supporting Information for a table with chemical structures of
the products.
(18) (a) Moriyama, M. J. Synth. Org. Chem. 1985, 42, 75. (b) Zhang, J.;
Xu, Y.; Huang, G.; Guo, H. Tetrahedron Lett. 1988, 29, 1955. (c)
Drabowicz, J.; Dudzinski, B.; Mikolajczyk, M. Tetrahedron: Asym-
metry 1992, 3, 1231. (d) Omelanczuk, J.; Mikolajczyk, M. Tetrahe-
dron: Asymmetry 1996, 7, 2687. (e) Drabowicz, J.; Dudzinski, B.;
Mikolajczyk, M.; Colonna, S.; Gaggero, N. Tetrahedron: Asymmetry
1997, 8, 2267. (f) Drescher, M.; Felsinger, S.; Hammerschmidt, F.;
Ka¨hlig, H.; Schmidt, S.; Wuggenig, F. Phosphorus, Sulfur, Silicon
Relat. Elem. 1998, 140, 79.
(19) Kyba, E. P. J. Am. Chem. Soc. 1976, 98, 4805.
(20) (a) Haynes, R. K.; Lam, W. W.-L.; Yeung, L.-L. Tetrahedron Lett.
1996, 37, 4729. (b) Lam, W. W.-L.; Haynes, R. K.; Yeung, L.-L.;
Chan, E. W.-K. Tetrahedron Lett. 1996, 37, 4733. (c) Haynes, R. K.;
Lam, W. W.-L.; Williams, I. D.; Yeung, L.-L. Chem.sEur. J. 1997,
3, 2052. (d) Au-Yrung, T.-L.; Chan, K.-Y.; Chan, W.-K.; Haynes,
R. K.; Williams, I. D.; Yeung, L.-L. Tetrahedron Lett. 2001, 42, 453.
(21) (a) Michalski, J.; Skrzypczyn´ski, Z. J. Organomet. Chem. 1975, 97,
C31. (b) Krawiecka, B.; Michalski, J.; Wonjna-Tadeusiak, E. J. Org.
Chem. 1986, 51, 4201.
(22) Sodium methoxide can cause the epimrization of (R)-(-)-isopropyl
methylphosphinate (ref 8b). The epimerization of (RP)-1a by t-BuONa
and EtOMgCl were also noted (ref 6b).
9
12652 J. AM. CHEM. SOC. VOL. 130, NO. 38, 2008

Substitution of Optically Pure H-Phosphinates
A R T I C L E S
Scheme 7
Scheme 8
Table 3. Reactions of H-Phenylphosphinates with 1 equiv of R1M
entry
H-phosphinate
R1M
conditionsa
yield %b
1
2
3
4
5
6
7
8
(EtO)PhP(O)H
MeLi
Et2O, 2 h
Et2O, 2 h
Et2O, 2 h
Et2O, 2 h
THF, 2 h
THF, 2 h
Et2O, 2 h
Et2O, 2 h
Et2O, 2 h
Et2O, 2 h
Et2O, 2 h
Et2O, 2 h
Et2O, 2 h
Et2O, 2 h
Et2O, 2 h
Et2O, 0.5 h
pentane, 4 h
pentane, 23 h
pentane, 19 h
THF, 18 h
THF, 14 h
THF, 22 h
THF, 22 h
89
82
81
72
79
74
60
62
60
48
37
37
40
39
42
39
46
41
43
36
22
0
n-BuLi
t-BuLi
PhLi
MeMgCl
PhMgBr
MeLi
n-BuLi
t-BuLi
PhLi
MenOLi (entry 3, Table 2). The epimerization of (RP)-1a by
(-)-MenOLi also well explained that a stepwise addition of
n-BuLi to (RP)-1a (the first 1 equiv of n-BuLi was added at
-80 °C; another equivalent of n-BuLi was then added after 4 h)
resulted in the decrease of the product’s ee (90%), because of
the formation of (-)-MenOLi by the first 1 equiv of n-BuLi
added. As expected, other metal alkoxides also cause the
epimerization of (RP)-1a.22 Thus, i-PrOLi caused a complete
epimerization of (RP)-1a under the similar condition. Note that
isopropyl phenylphosphinate 8, formed by transesterification,
was obtained in 34% yield, clearly indicating that the epimer-
ization of (RP)-1a takes place by the attack of ROM at
phosphorus.
(i-PrO)PhP(O)H
(t-BuO)PhP(O)H
(RP)-1a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
MeLi
n-BuLi
t-BuLi
PhLi
n-BuLi
MeLi
n-BuLi
t-BuLi
PhLi
MeMgCl
i-PrMgBr
t-BuMgCl
PhMgBr
Therefore, it was rationalized that in order to avoid the
epimerization of (RP)-1a, the best way for conducting this
stereospecific nucleophilic substitution reaction is to add 1 to
an excess of organolithiums or Grignard reagents (more than 2
equiv) at low temperatures.
6
a RM was added to H-phosphonate (1.0 M) at -80 °C under N2. The
reaction mixture was quenched with saturated aqueous NH4Cl solution.
b Yields determined by 31P NMR based on RM used.
Mechanistic Study on the Stereospecific Nucleophilic Sub-
stitution Reaction. As to the mechanism of the stereospecific
substitution reaction, it is generally believed that the substitution
reaction of H-phosphinates with R1M forming SPO takes place
by the deprotonation of the H-phosphinate with 1 equiv of R1M
giving the corresponding anion followed by its reaction with
another equivalent of R1M to produce the corresponding SPO
(path a, Scheme 8).7 However, as described below, contrary to
this commonly held view, we found that, to our surprise, there
is a competing direct substitution path (path b, Scheme 8)
leading to SPO, that can even be the main reaction path to SPO
depending on the substrates used. Therefore, there are two routes
leading to SPOs 2 (Scheme 8): (path a) a stereoretention
deprotonation of (RO)PhP(O)H by the first equivalent of R1M
working as a base forming (RO)PhP(OM), which is stable under
the present reaction conditions as described above, followed
by the substitution of (RO)PhP(OM) with another equivalent
of R1M to give intermediate R1PhP(OM) with inversion of
configuration at phosphorus;23 and (path b) a direct substitution
of (RO)PhP(O)H by R1M with inversion of configuration to
give the corresponding R1PhP(O)H.
give the corresponding SPO 2b with inversion of configuration
at phosphorus.23 On the other hand, clear evidence supporting
the direct substitution reaction path b was also obtained by
carrying out reactions of (RO)PhP(O)H with 1 equiv of R1M
(Table 3). As shown in Table 3, three H-phenylphosphonates
bearing sterically different alkoxy groups increasing in bulkiness
in the order of (EtO)PhP(O)H < (i-PrO)PhP(O)H < (t-BuO)-
PhP(O)H and (RP)-1a were allowed to react with an equivalent
of a variety of R1M at -80 °C. The yields of the corresponding
SPOs by the reaction of (EtO)PhP(O)H with four typical
organolithiums (MeLi, n-BuLi, t-BuLi, and PhLi) and two
Grignard reagents (MeMgCl and PhMgBr) are in a range of
74-89% (entries 1-6) all exceeding 50%, not only unambigu-
ously showing that the direct substitution path b exists but also
indicating that path b can even be the main reaction path in
this case. When similar reactions were conducted using the
bulkier (i-PrO)PhP(O)H, the yields of the corresponding SPOs
decreased (entries 7-10). However, except in the case of PhLi
(entry 10), the yields of SPOs still exceeded 50% (entries 7-9).
The yields of SPOs constantly decreased when an even bulkier
(t-BuO)PhP(O)H was used as the substrate (entries 11-14),
though a considerable amount of the corresponding SPOs were
The reactions involved in path a have been discussed as
above, confirming that 5a (M ) Li) could react with n-BuLi to
9
J. AM. CHEM. SOC. VOL. 130, NO. 38, 2008 12653

A R T I C L E S
Xu et al.
Scheme 9
still generated. These results showed that path a and path b are
two competing reaction paths involved in the reactions of
hydrogen phosphinates with organolithiums or Grignard reagents
to afford the same SPOs. Steric hindrance around phosphorus
seems to determine the participation of these two paths in the
reaction. Thus, for less bulky hydrogen phosphonates such as
(EtO)PhP(O)H, the direct substitution path b is the main reaction
path, however, the participation of the deprotonation path a
increased as the hydrogen phosphinates become bulkier.
The yield of the corresponding SPO 2b by the reaction of
(RP)-1a with BuLi was 42% yield (entry 15). This yield, lower
than that of (i-PrO)PhP(O)H (entry 8) but higher than that of
(t-BuO)PhP(O)H (entry 12), is well consistent with the order
of the steric hindrance of the substrates. Although all organo-
lithiums (MeLi, n-BuLi, t-BuLi, and PhLi) tested gave similar
yield of the corresponding SPO (entries 16-19), in the case of
alkyl Grignard reagents, the yields of SPOs did decrease as the
Grignard reagent became bulkier, since the direct substitution
path b became more difficult (entries 20-23). An extreme
example is t-BuMgCl, which does not produce any substitution
products under the present reaction conditions (entry 22).
The reaction mixture of (RP)-1a with 1 equiv of n-BuLi before
quenching with water can be determined easily by an NMR
experiment (Scheme 9). Thus, in an NMR tube, 1 equiv of
n-BuLi was added to (RP)-1a in d8-toluene at -80 °C to give a
31P NMR spectra in which (RP)-1a completely epimerized to a
RP/SP mixtures appeared at 24.3 and 21.4 ppm, their corre-
sponding anions (RP)- and (SP)-5a were observed around
165.4-177.9 ppm as a broad signal, the substitution product
2b appears at 27.3 ppm, and its corresponding anion 6a was
observed at 84.4-98.4 ppm as a broad signal. The percentages
of these phosphorus species could be obtained on the basis of
the integrations, confirming the good yield (47%) of the
substitution products (2b and 6a).
of configuration at phosphorus and (b) a direct substitution of
RM with H-phosphinates generating the corresponding SPO with
inversion of configuration at phosphorus.
Experimental Section
General. All reactions were carried out under dry nitrogen
atmosphere. Solvents were dried and purified under nitrogen before
use by standard procedure. Unless otherwise noted organolithiums
and Grignard reagents were purchased and used as received. Other
organolithiums were in situ prepared from the corresponding
arylbromides, aryliodides, or butyltellurides with n-BuLi.16 Opti-
cally pure H-phosphinates 1a and 1b were prepared according to
literature’s methods.6 1H, 13C, and 31P NMR spectra were recorded
1
on a JEOL LA-500 instrument (500 MHz for H, 125.4 MHz for
13C, and 201.9 MHz for 31P NMR spectroscopy). Unless otherwise
noted, CDCl3 was used as the solvent. Chemical shift values for
1H and 13C were referred to internal Me4Si (0 ppm), and that for
31P was referred to H3PO4 (85% solution in D2O, 0 ppm). Mass
spectra were measured on a Shimadzu GC-MS-QP2010 spec-
trometer (EI). HRMS analysis was performed by the Analytical
Center at the National Institute of Advanced Industrial Science and
Technology. The optical purity of the products were determined
by HPLC (Tosoh SC 8020 instrument) equipped with an UV
detector (254 nm) using a Chiralpak AS or AD column (eluent:
hexane/i-PrOH) or by 1H or 31P NMR using (R)-(+)-tert-butylphe-
4b,c
nyl-thiophosphinic acid
as a chemical shift reagent. Optical
rotations were recorded with a JAS CO DIP-370 Digital Polarimeter.
A Typical Procedure for the Preparation of Optically Pure
H-Phosphinates (RP)-1a and (SP)-1b. The mixture of (L)-(-)-
menthol (100 g, 641 mmol) and pyridine (51.3 mL, 641 mmol) in
Et2O (200 mL) was added dropwise with stirring to a PhPCl2 (87.2
mL, 641 mmol) solution in Et2O (400 mL) at 0 °C and then stirred
at room temperature overnight. Water (12 mL, 667 mmol) was
added, and the reaction mixture was washed with water and
extracted with hexane. The hexane layer was dried over magnesium
sulfate, filtered, and concentrated. Recrystallization of the mixture
in hexane (twice) at -30 °C gave pure (RP)-1a as a white crystal
(RP)-1a (RP/SP >99/1). (SP)-1b was prepared similarly from PhPCl2
and (D)-(+)-menthol.
(+)-Menthyl (RP)-Phenylphosphinate (1a) and (+)-Menthyl
(SP)-Phenylphosphinate (1b). 1H NMR: δ 7.83-7.79 (m, 2H),
7.64-7.61 (m, 1H), 7.56-7.52 (m, 2H), 7.68 (d, JHP ) 553 Hz,
1H), 4.31 (m, 1H), 2.28-2.18 (m, 2H), 1.75-1.68 (m, 2H),
1.54-1.45 (m, 1H), 1.27 (q, J ) 11.8 Hz, 1H), 1.09 (qd, J ) 12.6
Hz, J ) 3.4 Hz, 1H), 0.99 (d, J ) 6.7 Hz, 3H), 0.92 (d, J ) 6.4
Hz, 3H), 0.89 (d, J ) 6.4 Hz, 3H). 31P NMR: δ 24.7. The
preparation of a diastereomeric mixture of 1a9a and an optically
enriched (RP)-1a8a have been reported.
Conclusion
Contrary to the generally held view, we found that the so far
reported rapid epimerization of a chiral hydrogen phosphinate
ester under basic conditions is not due to the inherent stere-
olability of its corresponding anion but due to a transesterifi-
cation reaction of the hydrogen phosphinate ester with a metal
alkoxide. This finding successfully leads to the discovery of a
general protocol for the preparation of the highly useful optically
active secondary and tertiary phosphine oxides on the basis of
the stereospecific nucleophilic substitution reactions of optically
pure H-phosphinates with organolithiums and Grignard reagents
which proceed by inversion of configuration at phosphorus via
two competing reaction paths of (a) a two step reaction path
involving first a deprotonation of H-phosphinates followed by
a substitution of the corresponding anion by RM with inversion
Preparation of H-Phosphinates (RP)-1c and (RP)-1d. PhCH2-
MgCl (1.0 M in Et2O, 800 mL, 800 mmol) was added dropwise to
the Et2O (800 mL) solution of (-)-MenOPCl2 (206.4 g, 800 mmol)
at 0 °C and then stirred at room temperature overnight. Recrystal-
lization of the mixture at -30 °C gave pure (RP)-1c as white needles
(RP/SP >99/1). (RP)-1d was prepared similarly starting from (-)-
MenOPCl2 and mesitylmagnesium bromide.
(23) The deprotonation step has been shown to be stereoretention (ref 8a).
The reaction of the isolated solid salt of (RP)-5a with n-BuLi at low
temperature indicated that this substitution took place with inversion
ofconfigurationatphosphorusviaasimilarmechanismforphosphites:Neuffer,
J.; Richter, W. J. J. Organomet. Chem. 1986, 301, 289.
1
Optically Pure (-)-Menthyl (RP)-Benzylphosphinate 1c. H
NMR: δ 7.34-7.31 (m, 2H), 7.27-7.22 (m, 3H), 7.08 (d, JHP
)
539 Hz, 1H), 4.02 (m, 1H), 3.21-3.17 (m, 2H), 2.18 (m, 2H),
1.64-1.56 (m, 4H), 1.46-1.37 (m, 1H), 1.33-1.27 (m, 1H), 1.20
9
12654 J. AM. CHEM. SOC. VOL. 130, NO. 38, 2008

Substitution of Optically Pure H-Phosphinates
A R T I C L E S
(q, J ) 12.2 Hz, 1H), 0.98-0.78 (m, 2H), 0.89 (d, J ) 7.3 Hz,
3H), 0.78 (d, J ) 6.1 Hz, 3H), 0.59 (d, J ) 7.4 Hz, 3H). 31P NMR:
δ 37.2. The preparation of a diastereomeric mixture of 1c and
optically pure (RP)-1c has been reported.8d
(d, JHP ) 17.4 Hz, 9H). 31P NMR: δ 98.7. The absolute structure
of the product was confirmed by comparing its NMR spectra in
the presence of (S)-(-)-1-phenylethylamine (as a chemical shift
reagent) with those of an authentic sample.4b,c Optical purity of
(RP)-4 is >99% ee.
Isolation of (RP)-5a, (RP/SP)-5a, and (SP)-6a. The Et2O (2 mL)
solution of (RP)-1a (0.28 g, 1 mmol) was added dropwise with to
LDA (1 mmol) in Et2O (3 mL) at -80 °C. Et2O was then removed
under vacuum at -40 °C affording a white solid which was further
dried at room temperature. Similarly, were prepared (RP/SP)-5a and
(SP)-6a.
Optically Pure (-)-Menthyl (RP)-Mesitylphosphinate 1d. 1H
NMR: δ 8.05 (d, JHP ) 547 Hz, 1H), 6.86 (d, J ) 4.9 Hz, 2H),
4.22 (m, 1H), 2.57 (s, 6H), 2.34 (m, 2H), 2.29 (s, 3H), 2.08 (m,
1H), 1.68 (m, 2H), 1.49 (m, 1H), 1.39 (m, 1H), 1.26 (q, J ) 12.2
Hz, 1H), 1.04 (m, 1H), 0.93 (d, J ) 7.3 Hz, 3H), 0.90 (d, J ) 7.4
Hz, 3H), 0.87 (m, 1H), 0.82 (d, J ) 6.1 Hz, 3H). 31P NMR: δ
24.3.
A General Procedure for the Preparation of Chiral Second-
ary Phosphine Oxide 2 (SPO). To a Schlenk tube containing 2.1
equiv RM (M ) Li, MgX) solution kept at -80 °C was added 0.1
mmol 1 (1.0 M solution in THF or pentane). The reaction mixture
was stirred at -80 °C for the time as shown in Table 2, and was
then quenched with 1 mL saturated aqueous NH4Cl solution, and
slowly warmed to room temperature. Since the resulting SPOs are
rather soluble in water, the reaction mixture was extracted with
water and washed with hexane to remove menthol generated and
other organic substrates. The water layer was then extracted with
chloroform, dried over MgSO4, filtered, and concentrated under
vacuum to give NMR spectroscopically pure SPOs.
Preparation of Optically Active Tertiary Phosphine Oxides
3. To a Schlenk tube containing 2.1 equiv n-BuLi (in hexane) cooled
at -80 °C was added 0.2 mmol (RP)-1a (1.0 M in pentane) followed
by the addition of 3 equiv of RX after 7 h at -80 °C. The mixture
was then stirred at -80 °C for 30 min and 0 °C overnight. The
product was isolated using a preparative GPC equipment using
CHCl3 as solvent.
Typical Procedure for the Reaction of H-Phosphinates with
1 equiv of Organolithiums or Grignard Reagents. To a Schlenk
tube containing Ph(EtO)P(O)H (0.1123 g, 0.66 mmol) in Et2O (1
mL) was added 1 equiv of n-BuLi (1.65 M in hexane, 0.4 mL,
0.66 mmol) at -80 °C and stirred for 2 h at this temperature. The
reaction mixture was then slowly warmed to room temperature (20
°C) with stirring and cooled to -80 °C again followed by quenching
with 3 mL saturated aqueous NH4Cl solution. The reaction mixture
was then extracted with chloroform, dried over MgSO4, filtered,
1
concentrated under vacuum, and measured by H and 31P NMR.
Other reactions of entries 16-23 in Table 3 were conducted at -80
°C for a time shown and then quenched with saturated aqueous
NH4Cl solution followed by the same workup procedure.
Acknowledgment. We thank the Japan Society for the Promo-
tion of Science (JSPS) for the support of Grant-in-Aid for Scientific
Research (B) (Kakenhi 16350027). Thanks are due to Dr.s T. Hirai
and Y. Ono for their help performing some experiments.
Preparation of (RP)-(+)-tert-Butylphenylthiophosphinic Acid
4. A mixture of (SP)-tert-butylphenylphosphine oxide (2d) (99%
ee, 45.5 mg, 0.25 mmol) and sulfur (8 mg, 0.25 mmol) was heated
under N2 in dry THF (0.5 mL) for 1.5 h. A complete conversion of
(SP)-2d was confirmed. Solvent was pumped off. The residue was
recrystalized in hexane to give pure (RP)-(+)-tert-butylphenylth-
iophosphinic acid 4 (44 mg, 0.206 mmol, 82% yield). 1H NMR: δ
7.81-7.67 (m, 2H), 7.48-7. 44 (m, 1H), 7.39-7.36 (m, 2H), 1.16
Supporting Information Available: A list of spectroscopic
data of 2 and 3; copies of HPLC and NMR spectra of the
products; copies of 31P NMR spectra related to mechanistic
studies. This material is available free of charge via the Internet
at http://pubs.acs.org.
JA804412K
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J. AM. CHEM. SOC. VOL. 130, NO. 38, 2008 12655