Stereospecific coupling of H -phosphinates and secondary phosphine oxides with amines and alcohols: A general method for the preparation of optically active organophosphorus acid derivatives

Article abstract of DOI:10.1021/jo100473s

Figure presented The reaction of H-phosphinates and secondary phosphine oxides with amines and alcohols proceeds highly stereospecifically to give the corresponding coupling products with inversion of configuration at the phosphorus center under the Atherton-Todd reaction conditions. This finding leads to the establishment of a general and efficient method for the synthesis of a variety of optically active organophosphorus acid derivatives from the easily available chiral H-phosphinates and secondary phosphine oxides.

Full text of DOI:10.1021/jo100473s

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alkyl or aryl, R2 and R3= an alkoxy group) are important
Stereospecific Coupling of H-Phosphinates and
Secondary Phosphine Oxides with Amines and
Alcohols: A General Method for the Preparation of
Optically Active Organophosphorus Acid
Derivatives†
compounds which not only show diverse biological activi-
ties such as antibacterial, antipsoriatic, and anti-HIV ef-
fects2 but also have potential applications in asymmetric syn-
thesis.3 However, methods for their preparation are rather
limited.1a,b,4 Thus, although a few synthetic routes have been
reported by using chiral auxiliaries such as (-)-ephedrine,
L-proline or(þ)-d-glucose, the procedures were tedious, the yields
were usually poor, and the generality was rather limited.4b-e
Herein, we report a general protocol for the preparation of
optically active organophosphorus acid derivatives 2. During an
ongoing project on the preparation of optically active phos-
phorus compounds via the stereospecific transformation of the
reactive H-P bonds of the relatively easily accessible H-phos-
phonates and H-phosphinates,5 we found that 2 can be easily
generated in high yields by a stereospecific coupling of the
optically pure H-phosphinates and secondary phosphine oxides
16 with amines and alcohols under mild Atherton-Todd reac-
tion conditions (Scheme 1).7,8 To the best of our knowledge,
such a general method has not been revealed yet.
Gang Wang,‡ Ruwei Shen, Qing Xu, Midori Goto,
Yufen Zhao,*,‡,§ and Li-Biao Han*,
‡Department of Chemistry and Key Laboratory for Chemical
Biology of Fujian Province, Xiamen University, Xiamen
361005, China, §Key Laboratory of Bioorganic Phosphorus
Chemistry and Chemical Biology (Ministry of Education),
Department of Chemistry, Tsinghua University, Beijing
100084, China, and National Institute of Advanced
Industrial Science and Technology (AIST ), Tsukuba,
Ibaraki 305-8565, Japan
yfzhao@xmu.edu.cn; libiao-han@aist.go.jp
Received March 15, 2010
SCHEME 1
The reaction of H-phosphinates and secondary phos-
phine oxides with amines and alcohols proceeds highly
stereospecifically to give the corresponding coupling
products with inversion of configuration at the phos-
phorus center under the Atherton-Todd reaction condi-
tions. This finding leads to the establishment of a general
and efficient method for the synthesis of a variety of
optically active organophosphorus acid derivatives from
the easily available chiral H-phosphinates and secondary
phosphine oxides.
As demonstrated by the following experiment, this is an
easily operating and highly efficient reaction. Thus, to a
mixture of (RP)-l-menthyl phenylphosphinate (RP)-1a
(5 mmol), Et3N (10 mmol), and CCl4 (5 mL) in acetonitrile
ꢀ
(3) (a) Darcel, C.; Uziel, J.; Juge, S. In Phosphorous Ligands in Asymmetric
€
Catalysis; Borner, A., Ed.; Wiley-VCH: Weinheim, 2008; Vol. 3, pp 1211-1233.
(b) Gamble, M. P.; Smith, A. R. C.; Wills, M. J. Org. Chem. 1998, 63, 6068. (c)
Brown, J. M.; Carey, J. V.; Russel, M. J. H. Tetrahedron 1990, 46, 4877. (d)
Brunel, J. M.; Legrand, O.; Buono, G. Eur. J. Org. Chem. 2000, 3313. (e)
Legrand, O.; Brunel, J. M.; Buono, G. Tetrahedron Lett. 1998, 39, 9419. (f )
Vinci, D.; Mateus, N.; Wu, X.; Hancock, F.; Steiner, A.; Xiao, J. Org. Lett. 2006,
8, 216.
Optically active organophosphorus acid derivatives 21 such
as amidophosphinates (R1 = an alkyl or aryl, R2 = an alkoxy
group, E = an amino group) and phosphonates (R1 = an
(4) (a) Hall, C. R.; Inch, T. D. Tetrahedron 1980, 36, 2059. (b) Koizumi,
T.; Yanada, R.; Takagi, H.; Hirai, H.; Yoshii, E. Tetrahedron Lett. 1981, 22,
477. (c) Koizumi, T.; Yanada, R.; Takagi, H.; Hirai, H.; Yoshii, E. Tetra-
hedron Lett. 1981, 22, 571. (d) Cooper, D. B.; Hall, C. R.; Harrison, J. M.;
Inch, T. D. J. Chem. Soc., Perkin Trans. 1 1977, 1969. (e) Hall, C. R.; Inch,
T. D.; Peacock, G.; Pottage, C.; Williams, N. E. J. Chem. Soc., Perkin Trans.
1 1984, 669.
(5) (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.
(6) Optically pure H-P(O) compounds 1a-d can be purchased from
Katayama Chemical Industries Co. Ltd. (http://www.katayamakagaku.co.
jp). For their preparation, see: (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) Xu, Q.;
Zhao, C.-Q.; Han, L.-B. J. Am. Chem. Soc. 2008, 130, 12648.
(7) (a) Atherton, F.; Openshaw, A.; Todd, A. J. Chem. Soc. 1945, 660. (b)
Atherton, F.; Todd, A. J. Chem. Soc. 1947, 674.
† Dedicated to the memory of Professor Xian Huang.
(1) (a) Imamoto, T. In Handbook of Organophosphorus Chemistry; Engel,
R., Eds.; Marcel Dekker: New York, 1992; Charpter 1, pp 5-8. (b) Quin, L. D.
A Guide to Organophosphorus Chemistry; Wiley-Interscience: New York, 2000;
Chapter 9, pp 272. (c) Sasaki, M. In Chirality in Agrochemicals; Kurihara, N.,
Miyamoto, J., Eds.; Wiley & Sons: Chichester, U.K., 1998; p 85.
(2) (a) Kukhar, V. P.; Hudson, H. R. et al. Aminophosphonic and Aminopho-
sphinic acids Chemistry and Biological Activity; Wiley & Sons: Chichester,
U.K., 2000. (b) Sawa, M.; Tsukamoto, T.; Kiyoi, T.; Kurokawa, K.; Nakajima, F.;
Nakada, Y.; Yokota, K.; Inoue, Y.; Kondo, H.; Yoshino, K. J. Med. Chem. 2002,
45, 930. (c) Camp, N. P.; Hawkins, P. C. D.; Hitchcock, P. B.; Gani, D. Bioorg.
Med. Chem. Lett. 1992, 2, 1047. (d) Camp, N. P.; Perry, D. A.; Kinchington, D.;
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3890 J. Org. Chem. 2010, 75, 3890–3892
Published on Web 05/05/2010
DOI: 10.1021/jo100473s
r
2010 American Chemical Society

Wang et al.
JOCNote
TABLE 1. Stereospecific Coupling Reaction of H-Phosphinates and
Secondary Phosphine Oxides 1 with Amines a
FIGURE 1. Single-crystal X-ray structure of compound (Rp)-2a.
(25 mL) was added ammonia solution (28% in water, 5 mL)
at 0 °C. The mixture was stirred at room temperature over-
night to produce the expected amidophosphinate 2a in 95%
isolated yield as a single diastereomer (eq 1).
The facts that another diastereomer (SP) could not be
detected from the crude products by NMR spectroscopy and
that when a diastereomeric mixture of 1a (RP/SP = 60/40)
was employed as the substrate in the above reaction 2a was
obtained as a mixture of diastereomers in the same ratio (RP/
SP = 60/40) indicated that this reaction proceeded highly
stereospecifically. In addition, the stereochemistry at phos-
phorus in 2a was unambiguously determined by X-ray
analysis, showing that this reaction proceeded with inversion
of configuration at the phosphorus center in 1a (Figure 1).
The results compiled in Table 1 clearly demonstrate that
this stereospecific reaction is a highly general and efficient
method for the preparation of a variety of optically pure
organophosphorus acid derivatives. Thus, in addition to
ammonia, primary amines such as n-butylamine, aniline,
and benzylamine (runs 1-5) all reacted with (RP)-1a to give
the corresponding aminophospninates in high yields. Nota-
bly, the expected P-N coupling product (RP)-2c was also
obtained in high yield from 5-hydroxylpentan-1-amine and
other amines bearing an OH group, indicating the higher
reactivity of an amino group than that of a hydroxyl group
(runs 2, 10, and 16). A wide range of amino acid esters can
also be employed as substrates in the reaction with (RP)-1a,
readily yielding the corresponding optically active phosphor-
yl amino acid esters (entries 6-11). Compared to primary
amines, the reaction with secondary amines proceeded a little
slowly under the present reaction conditions. Nevertheless,
the expected products were obtained stereospecifically and in
good yields. For example, the reactions of diethylamine,
dipropylamine, and pyrrolidine with (RP)-1a afforded the
corresponding optically active phosphinylamides in 77%,
74%, and 75% yields, respectively (runs 12, 13, and 15). Note
that functionalized secondary amines such as diallylamine
and bis(2-hydroxyethyl)amine could also be used as sub-
strates to produce the corresponding products (RP)-2n and
(RP)-2p in 79% and 64% yields (runs 14 and 16). Besides
a1 mmol of 1, 2 mmol of NEt3, and 2 mmol of amine dissolved in 5 mL
of CCl4, stirred at room temperature overnight. bIsolated yield. c5 mL of
CH2Cl2 was added. d5 mL of CH3CN was added.
(RP)-l-menthyl phenylphosphinate (1a), (SP)-l-menthyl phe-
nylphosphinate (SP)-1b, (RP)-l-menthy benzylphosphinate
(1c), and bulky (SP)-tert-butylphenylphosphine oxide (1d),
all served as good substrates to produce the corresponding
optically active organophosphorus acid derivatives in high
yields (entries 17-20).
In addition to amines, other nucleophiles such as alcohols
and thiophenol could also be used as the substrates to pro-
duce the corresponding coupling compounds stereospecifi-
cally and in high yields (eq 2). However, when aliphatic
(8) For an early observation on the reaction of (R)-(-)-isopropyl methyl-
phosphinate (4.6% optically pure) with aniline, see: Reiff, L. P.; Aaron, H. S.
J. Am. Chem. Soc. 1970, 92, 5275.
(9) Aliphatic thiols themselves react with CCl4 and Et3N under the
present conditions.
J. Org. Chem. Vol. 75, No. 11, 2010 3891

Wang et al.
JOCNote
thiols, e.g., n-BuSH and n-C8H17SH, were employed, the
pressure gave the crude product. Pure (RP)-2a was obtained
by passing the crude product through a short silica gel column
using MeCN/EtOAc as eluent: 1.4 g, 95% yield; white solid; mp
143.1-143.4 °C; [R]24D = -67.9 (CHCl3, c = 0.805); 1H NMR
(CDCl3, 400 MHz) δ 7.83-7.78 (m, 2H), 7.50-7.47 (m, 1H),
7.43-7.38 (m, 2H), 4.24-4.16 (m, 1H), 3.17 (s, 2H), 2.35 (d, J =
12.1 Hz, 1H), 2.02-1.95 (m, 1H), 1.66-1.60 (m, 2H), 1.50-1.40
(m, 1H), 1.34-1.27 (m, 1H), 1.21 (q, J = 12.0 Hz, 1H),
1.01-0.86 (m, 2H), 0.92 (d, J = 6.4 Hz, 3H), 0.83 (d, J = 7.2
Hz, 3H), 0.54 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
δ 132.5 (d, JP-C = 173.1 Hz), 131.6 (d, JP-C = 2.9 Hz), 131.3 (d,
reaction did not give the corresponding products.9
In summary, we have demonstrated that a variety of
optically pure phosphorus acids derivatives can be efficiently
prepared via a simple stereospecific coupling of the corre-
sponding P(O)H-type compounds with nucleophiles under
the Atherton-Todd reaction conditions.
J
P-C = 9.3 Hz), 128.2 (d, JP-C = 14.0 Hz), 76.5 (d, JP-C = 6.5
Hz), 48.7 (d, JP-C = 6.6 Hz), 43.6, 34.1, 31.6, 25.5, 22.7, 22.0,
21.0, 15.3; 31P NMR (CDCl3, 160 MHz) δ 23.0; HRMS calcd for
C16H26NO2P 295.1701, found 295.1696.
Acknowledgment. Y.Z. acknowledges financial support
from the National Natural Science Foundation of China
(Project Nos. 20732004 and 20972130).
Experimental Section
Typical Procedure for the Synthesis of (RP)-2a. To a mixture
of (RP)-1a (5 mmol), Et3N (10 mmol), and CCl4 (5 mL) in aceto-
nitrile (25 mL) was added ammonia solution (28% in water,
5 mL) at 0 °C. The resulting mixture was allowed to stir at 0 °C
for 30 min and then warmed to room temperature. After the
mixture was stirred overnight, water was added. Extraction with
ethyl acetate and removal of the solvent under a reduced
Supporting Information Available: General experimental
procedures, spectroscopic data for compounds 2, and X-ray
data for compound (RP)-2a (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
3892 J. Org. Chem. Vol. 75, No. 11, 2010