A general and highly selective method for the asymmetric synthesis of trifluoromethyl-substituted α- And β-aminophosphonates

Article abstract of DOI:10.1002/cjoc.201300344

A highly selective method for the asymmetric formation of trifluoromethyl-substituted α- and β-aminophosphonates was described. The reaction proceeded with high yields and good to excellent diastereoselectivity. The product can be easily converted into corresponding trifluoromethyl-substituted aminophosphoric acids. A highly selective method for the asymmetric formation of trifluoromethyl-substituted α- and β-aminophosphonates was described. The reaction proceeded with high yields and good to excellent diastereoselectivity. The product can be easily converted into corresponding trifluoromethyl-substituted aminophosphoric acids. Copyright

Full text of DOI:10.1002/cjoc.201300344

FULL PAPER
DOI: 10.1002/cjoc.201300344
A General and Highly Selective Method for the Asymmetric
Synthesis of Trifluoromethyl-Substituted α- and
β-Aminophosphonates
Lijing Wang, Qilong Shen, and Long Lu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
A highly selective method for the asymmetric formation of trifluoromethyl-substituted α- and β-aminophos-
phonates was described. The reaction proceeded with high yields and good to excellent diastereoselectivity. The
product can be easily converted into corresponding trifluoromethyl-substituted aminophosphoric acids.
Keywords trifluoromethyl, aminophosphonate, asymmetric, fluorine
Introduction
chiral center containing a trifluoromethyl group,[9]
herein we reported a general and highly selective
method for the asymmetric synthesis of trifluoromethyl-
substituted α- and β-aminophosphonates with a more
challenging chiral quaternary carbon center using
N-tert-butylsulfinylimines[9] as chiral templates.
Aminophosphonates[1] are isosteric and bioisosteric
analogues of amino acids,[2] which are key structural
units in peptides, proteins, and enzymes that constitute
the basis of the living system. The unique properties of
aminophosphonates have attracted intense interest in the
preparation of aminophosphonates and further evaluaing
their biological activities that are important for the
phamaceutical and agrochemical industries.[3] Interest-
ingly, although the beneficial effects of the fluorine on
the drug molecules that might enhance their binding
selectivity, lipophilicity and metabolic stability were
well-documented,[4] very few methods for the prepara-
tion of optically pure trifluoromethyl-substituted α- and
β-aminophosphonates have been reported previously.[5]
In 1997, Vaubaillon and coworkers reported the first
asymmetric synthesis of trifluoromethyl-substituted
α-aminophosphonates with 96% ee via a chemoenzy-
matic resolution strategy.[6] Shortly after, Yuan reported
an alternative method for the preparation of trifluoro-
methyl-substituted α- and β-aminophosphonates by a
base-catalyzed [1.3]-proton shift reaction of dialkyl
1-imino-2,2,2-trifluoroethane phosphonate or 2-imino-
3,3,3-trifluoropropane phosphonate.[7] However, only
moderate enantioselectivity was achieved under these
conditions. More recently, Soloshonok reported a highly
selective asymmetric synthesis of trifluoromethyl-sub-
stituted α- and β-aminophosphonates from N-tert-but-
anesulfinyl aldimine, which formed a trifluoromethyl-
substituted chiral tertiary carbon center.[8] As part of our
ongoing programs with the aim to develop high regio-
and enantioselective methods for the construction of a
Experimental
General experimental procedures
The reagents were purchased and used without fur-
ther purification unless otherwise stated. 1H, 13C and 19
F
NMR spectra were recorded on a Bruker AV-400 MHz
spectrometer in CDCl3. Mass spectra were performed on
a Micromass GCT-MS.
General procedure for the synthesis of trifluoro-
methyl-substituted α-aminophosphonates
Ti(OPr-i)4 (1.2 mL, 4.0 mmol) was added dropwise
to a mixture of 2,2,2-trifluoro-1-phenylethanone (554
mg, 2.00 mmol) and N-tert-butylsulfinylimine (363 mg,
3.00 mmol) in 21.0 mL of hexane/toluene (20/1, V/V) at
room temperature under argon. The mixture was stirred
at room temperature before cooled to −40 ℃. Diethyl-
phosphinate (828 g, 6.00 mmol) was added and the
mixture was stirred for 5 min. The starting material dis-
appeared as determined by 19F NMR spectroscopy. Wa-
ter (10 mL) was added and the mixture was warmed to
room temperature and filtered through a short plug of
Celite. Ethyl acetate (50 mL) was added and the organic
layer was separated. The aqueous phase was extracted
by ethyl acetate (15 mL×2). The combined organic
*
E-mail: lulong@sioc.ac.cn; Tel.: 0086-21-54925199
Received April 24, 2013; accepted June 24, 2013; published online July 19, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201300344 or from the author.
892
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 892—900

Asymmetric Synthesis of Trifluoromethyl-Substituted α- and β-Aminophosphonates
Scheme 1 Strategies for the preparation of optically pure trifluoromethyl-substituted α- and β-aminophosphonates
Previous work
O
CF3
PO(OH)2
O
H
CF3
Enzyme
(1)
PhCH2
N
PhCH2
N
PO(OH)2
H
H
96% ee
(2)
H
Ph
Ph
H
NH2
N
N
2 mol/L HCl
Et2O, r.t.
Et3N
OR
OR
H
P
O
OR
OR
F3C
P
OR
OR
F3C
P
F3C
O
O
42% - 67% ee
Ph
Ph
Me
O
P
2 mol/L HCl
Et2O, r.t.
O
H
N
H
H
N
H2N
Et3N
OR
OR
OR
OR
P
P
F3C
F3C
OR
F3C
OR
O
60% - 83% ee
(3)
S
S
S
O
N
O
HN
O
HN
F3C
F3C
F3C
H
P(O)(OR)2
CH2P(O)(OEt)2
68% - 88% de
90% - 95% de
NH2
NH2
F3C
P(O)(OH)2
F3C
CH2P(O)(OHt)2
This work
S
S
CH2P(O)(OEt)2
R
S
NH
F3C
P(O)(OEt)2
R
O
N
O
NH
O
F3C
F3C
R
H2N
P(O)(OH)2
R
H2N CH2P(O)(OH)2
F3C
F3C
R
layer was dried over Na2SO4, filtered, concentrated un-
der vacuum. The residue was then purified by flash
column chromatography (Elite: petroleum ether/ethyl
acetate＝2∶1, V∶V) to give diethyl (S)-1-((R)-tert-
butylsulfinamido)-2,2,2-trifluoro-1-phenylethyl phos-
phonate (2a) (623 mg, 75%) as a white solid. M.p. 51－
126.7 (q, J＝213.0 Hz), 68.6 (dq, J＝107.0, 20.9 Hz),
64.8 (d, J＝5.6 Hz), 64.3 (d, J＝5.6 Hz), 57.9, 22.2 (d,
J＝7.8 Hz), 16.0 (d, J＝4.0 Hz), 15.8 (d, J＝4.0 Hz);
31P NMR (121 MHz, CDCl3) δ: 18.0 (q, J＝3.4 Hz); IR
(thin film) νmax: 3510, 3292, 2985, 1476, 1257, 1161,
977, 811 cm−1; MS (ESI) m/z: 416 [M＋H＋]; HRMS
calcd for C16H25NO4F3PSNa [M＋Na ＋]: 438.1092,
found 438.1080.
1
53 ℃; [α]2D0 ＝＋21.8 (c 1.0, CHCl3); H NMR (300
MHz, CD3COCD3) δ: 7.85－7.83 (m, 2H), 7.46－7.43
(m, 3H), 4.21－4.05 (m, 2H), 3.94－3.54 (m, 2H), 1.30
(t, J＝7.2 Hz, 3H), 1.28 (s, 9H), 1.08 (t, J＝7.2 Hz, 3H);
19F NMR (282 MHz, CD3COCD3) δ: −63.82 (d, J＝4.8
Hz); 13C NMR (75 MHz, CDCl3) δ: 130.9 (d, J＝4.0
Hz), 129.2, 128.8 (d, J＝1.6 Hz), 127.8 (d, J＝1.1 Hz),
Diethyl
(S)-1-((R)-tert-butylsulfinamido)-2,2,2-
trifluoro-1-p-tolylethyl phosphonate (2b) 65%, col-
orless oil. [α]2D0 ＝＋13.9 (c 1.8, CHCl3); 1H NMR (300
MHz, CD3COCD3) δ: 7.72－7.70 (d, J＝7.8 Hz, 2H),
7.27－7.24 (d, J＝9.0 Hz, 2H), 4.96－4.92 (d, J＝12.3
Chin. J. Chem. 2013, 31, 892—900
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893

Wang, Shen & Lu
FULL PAPER
Hz, 1H), 4.22－4.07 (m, 2H), 3.95－3.57 (m, 2H), 2.05
(s, 3H), 1.31 (t, J＝6.6 Hz, 3H), 1.26 (s, 9H), 1.09 (t,
J＝6.6 Hz, 3H); 19F NMR (282 MHz, CD3COCD3) δ:
−64.20 (d, J＝4.5 Hz); 13C NMR (75 MHz, CDCl3) δ:
138.8 (d, J＝1.6 Hz), 129.2, 128.6 (d, J＝1.1 Hz), 127.7
(d, J＝4.2 Hz), 121.4 (q, J＝213.0 Hz), 68.4 (dq, J＝
107.8, 20.7 Hz), 64.8 (d, J＝5.6 Hz), 64.3 (d, J＝5.6
Hz), 57.8, 22.2, 20.7, 16.0 (d, J＝4.2 Hz), 15.8 (d, J＝
4.2 Hz); IR (thin film) νmax: 3292, 2985, 1616, 1476,
1257, 1163, 1021, 823 cm−1; MS (ESI) m/z: 430 [M＋
H＋]; HRMS calcd for C17H27NO4F3PSNa [M＋Na＋]:
452.1238, found 452.1248.
J＝3.2 Hz); IR (thin film) νmax: 3285, 2932, 1469, 1257,
1169, 1089, 1022, 793 cm−1; MS (ESI) m/z: 424.2 [M＋
H＋]; HRMS calcd for C16H33NO4F3PSNa [M＋Na＋]:
446.1712, found 446.1718.
Diethyl (S)-2-((R)-tert-butylsulfinamido)-1,1,1-tri-
fluorohexan-2-yl phosphonate (2f) 73%, colorless
1
oil. [α]2D0 ＝−51.7 (c 1.7, CHCl3); H NMR (300 MHz,
CDCl3) δ: 4.45 (d, J＝9.1 Hz, 1H), 4.30－4.16 (m, 4H),
2.21－2.11 (m, 2H), 1.68－1.51 (m, 4H), 1.36 (t, J＝6.6
Hz, 6H), 1.22 (s, 9H), 0.90 (t, J＝6.6 Hz, 3H); 19F NMR
(282 MHz, CDCl3) δ: −70.20 (d, J＝3.9 Hz); 13C NMR
(75 MHz, CDCl3) δ: 124.6 (q, J＝212.9 Hz), 64.4 (d,
J＝5.5 Hz), 63.8 (d, J＝5.5 Hz), 63.4 (dq, J＝131.6,
20.3 Hz), 57.0, 30.7, 25.4 (d, J＝2.0 Hz), 22.9, 22.1,
16.0 (d, J＝4.4 Hz), 13.4 (d, J＝7.6 Hz); 31P NMR (121
Diethyl
(S)-1-((R)-tert-butylsulfinamido)-2,2,2-
trifluoro-1-(4-methoxyphenyl)ethylphosphonate (2c)
1
75%, colorless oil. [α]2D0 ＝＋14.5 (c 1.0, CHCl3); H
NMR (300 MHz, CD3COCD3) δ: 7.79 (d, J＝7.8 Hz,
2H), 7.02 (d, J＝6.9 Hz, 2H), 4.22－4.13 (m, 2H), 4.00
－3.92 (m, 1H), 3.87 (s, 3H), 3.73－3.64 (m, 1H), 1.32
(t, J＝7.5 Hz, 3H), 1.30 (s, 9H), 1.15 (t, J＝7.5 Hz, 3H);
19F NMR (282 MHz, CD3COCD3) δ: −64.50 (d, J＝3.4
Hz); 13C NMR (75 MHz, CDCl3) δ: 159.6 (d, J＝1.5
Hz), 130.6, 124.1 (q, J＝213.1 Hz), 122.2 (d, J＝4.1
Hz), 113.0 (d, J＝1.0 Hz), 67.8 (dq, J＝129.2, 20.9 Hz),
64.6 (d, J＝5.6 Hz), 64.1 (d, J＝5.6 Hz), 57.6, 54.7,
22.0, 15.8 (d, J＝4.5 Hz), 15.7 (d, J＝4.5 Hz); 31P NMR
(121 MHz, CDCl3) δ: 18.0 (q, J＝3.2 Hz); IR (thin film)
νmax: 3503, 3292, 2985, 1612, 1517, 1258, 835, 799
MHz, CDCl3) δ: 20.1 (d, J＝3.0 Hz); IR (thin film) νmax:
3497, 3286, 2965, 1637, 1471, 1253, 1021, 581 cm−1;
MS (ESI) m/z: 396.2 [M＋H＋]; HRMS calcd for
＋
C14H29NO4F3PSNa [M ＋ Na ]: 418.1404, found
418.1405.
Diethyl (S)-2-((R)-tert-butylsulfinamido)-1,1,1-tri-
fluoropentan-2-yl phosphonate (2g) 77%, colorless
oil. [α]2D0 ＝−61.2 (c 0.95, CHCl3); 1H NMR (300 MHz,
CDCl3) δ: 4.48－4.45 (d, J＝9.3 Hz, 1H), 4.32－4.17
(m, 4H), 2.21－2.11 (m, 2H), 1.75－1.53 (m, 2H), 1.37
(t, J＝6.9 Hz, 6H), 1.25 (s, 9H), 0.97 (t, J＝7.5 Hz, 3H);
19F NMR (282 MHz, CDCl3) δ: −70.27 (d, J＝3.7 Hz);
13C NMR (75 MHz, CDCl3) δ: 124.6 (q, J＝212.7 Hz),
64.3 (d, J＝4.1 Hz), 63.9 (d, J＝4.1 Hz), 63.4 (dq, J＝
90.9, 20.5 Hz), 57.0, 33.0 (d, J＝8.7 Hz), 22.2 (d, J＝
12.9 Hz), 17.0 (d, J＝1.5 Hz), 16.0 (d, J＝4.2 Hz), 14.2;
31P NMR (121 MHz, CDCl3) δ: 20.2 (q, J＝3.2 Hz); IR
(thin film) νmax: 3502, 3285, 2980, 1735, 1470, 1255,
1172, 579 cm−1; MS (ESI) m/z: 382.2 [M＋H＋]; HRMS
calcd for C13H27NO4F3PSNa [M＋Na ＋]: 404.1252,
found 404.1248.
cm−1; MS (ESI) m/z: 446 [M＋H＋]; HRMS calcd for
＋
C17H27NO5F3PSNa [M ＋ Na ]: 468.1190, found
468.1197.
Diethyl
(S)-1-(4-chlorophenyl)-1-((R)-tert-butyl
(2d)
sulfinamido)-2,2,2-trifluoroethylphophonate
1
71%, colorless oil. [α]2D0 ＝＋13.9 (c 0.6, CHCl3); H
NMR (300 MHz, CD3COCD3) δ: 7.74 (d, J＝8.1 Hz,
2H), 7.74 (d, J＝8.7 Hz, 2H), 4.16－4.00 (m, 2H), 3.92
－3.58 (m, 2H), 1.19 (t, J＝7.2 Hz, 3H), 1.15 (s, 9H),
1.02 (t, J ＝7.2 Hz, 3H); 19F NMR (282 MHz,
CD3COCD3) δ: −63.95 (d, J＝5.6 Hz); 13C NMR (75
MHz, CDCl3) δ: 135.2 (d, J＝2.4 Hz), 130.9, 129.7 (d,
J＝3.8 Hz), 128.1 (d, J＝1.4 Hz), 124.1 (q, J＝213.2
Hz), 67.5 (dq, J＝129.2, 20.9 Hz), 65.0 (d, J＝5.6 Hz),
64.6 (d, J＝5.6 Hz), 58.0, 22.2, 16.0 (d, J＝4.2 Hz),
15.9 (d, J＝4.2 Hz); 31P NMR (121 MHz, CDCl3) δ:
17.5 (q, J＝4.2 Hz); IR (thin film) νmax: 3357, 2985,
2872, 1498, 1257, 1165, 1016, 831 cm−1; MS (ESI) m/z:
450.0 [M＋H＋]; HRMS calcd for C16H24NO4F3PSClNa
[M＋Na＋]: 472.0695, found 472.0702.
Diethyl (S)-2-((R)-tert-butylsulfinamido)-1,1,1-tri-
fluorobutan-2-yl phosphonate (2h) 90%, colorless
1
oil. [α]2D0 ＝−52.4 (c 1.1, CHCl3); H NMR (300 MHz,
CDCl3) δ: 4.47 (d, J＝9.3 Hz, 1H), 4.33－4.19 (m, 4H),
2.35－2.25 (m, 2H), 1.37 (t, J＝6.9 Hz, 6H), 1.25 (s,
9H), 1.22 (t, J＝7.5 Hz, 3H); 19F NMR (282 MHz,
CDCl3) δ: −70.09 (d, J＝5.9 Hz); 13C NMR (75 MHz,
CDCl3) δ: 124.8 (q, J＝213.0 Hz), 64.6 (d, J＝5.5 Hz),
64.5 (d, J＝5.5 Hz), 64.4 (dq, J＝113.1, 20.4 Hz), 57.2,
24.3, 22.3, 16.1 (d, J＝4.4 Hz), 8.6; 31P NMR (121
MHz, CDCl3) δ: 20.3 (q, J＝3.4 Hz); IR (thin film) νmax
:
Diethyl (S)-2-((R)-tert-butylsulfinamido)-1,1,1-tri-
fluorooctan-2-yl phosphonate (2e) 73%, colorless oil.
3285, 2986, 1393, 1258, 1176, 1087, 1021, 590 cm−1;
MS (ESI) m/z: 368.2 [M＋H＋]; HRMS calcd for
＋
1
[α]2D0 ＝−51.3 (c 2.4, CHCl3); H NMR (300 MHz,
C12H25NO4F3PSNa [M ＋ Na ]: 390.1098, found
390.1092.
CD3COCD3) δ: 4.32－4.16 (m, 4H), 2.22－2.11 (m,
2H), 1.78－1.59 (m, 2H), 1.38－1.31 (m, 12H), 1.23 (s,
9H), 0.91 (t, J＝7.2 Hz, 3H); 19F NMR (282 MHz,
CDCl3) δ: −69.94 (d, J＝3.1 Hz); 13C NMR (75 MHz,
CDCl3) δ: 125.8 (q, J＝218.6 Hz), 64.1 (d, J＝5.4 Hz),
63.6 (d, J＝5.4 Hz), 63.2 (dq, J＝76.2, 20.4 Hz), 56.7,
30.8, 29.3, 23.0 (d, J＝1.9 Hz), 22.0, 21.9, 15.8 (d, J＝
4.2 Hz), 13.4; 31P NMR (121 MHz, CDCl3) δ: 20.2 (q,
Diethyl (S)-2-((R)-tert-butylsulfinamido)-1,1,1-tri-
fluoropropan-2-yl phosphonate (2i) 48%, colorless
1
oil. [α]2D0 ＝−74.2 (c 1.6, CHCl3); H NMR (300 MHz,
CDCl3) δ: 4.43 (d, J＝8.7 Hz, 1H), 4.34－4.21 (m, 4H),
1.81 (d, J＝15.3 Hz, 3H), 1.38 (t, J＝6.6 Hz, 6H), 1.25
(s, 9H); 19F NMR (282 MHz, CDCl3) δ: −73.97 (d, J＝
2.3 Hz); 13C NMR (75 MHz, CDCl3) δ: 124.6 (q, J＝
894
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Chin. J. Chem. 2013, 31, 892—900

Asymmetric Synthesis of Trifluoromethyl-Substituted α- and β-Aminophosphonates
211.7 Hz), 65.1 (d, J＝5.1 Hz), 64.0 (d, J＝5.6 Hz),
59.8 (dq, J＝114.5, 21.4 Hz), 56.9, 22.3, 16.2 (d, J＝4.6
Hz), 14.9; 31P NMR (121 MHz, CDCl3) δ: 20.1 (q, J＝
2.4 Hz); IR (thin film) νmax: 2986, 2873, 1459, 1275,
1179, 1082, 1020, 980 cm−1; MS (ESI) m/z: 354.2 [M＋
H＋]; HRMS calcd for C11H23NO4F3PSNa [M＋Na＋]:
376.0934, found 376.0935.
MHz, CDCl3) δ: 7.51 (d, J＝8.1 Hz, 2H), 7.19 (d, J＝
7.8 Hz, 2H), 4.33 (s, 1H), 3.85 (quintet, J＝7.2 Hz, 1H),
3.72 (quintet, J＝7.2 Hz, 1H), 2.39 (s, 3H), 1.33 (t, J＝
7.2 Hz, 3H), 1.29 (s, 9H); 19F NMR (282 MHz, CDCl3)
δ: −79.08; 13C NMR (75 MHz, CDCl3) δ: 140.2, 131.2,
129.5, 127.5, 122.7 (q, J＝213.8 Hz), 89.8 (q, J＝22.3
Hz), 59.2, 57.1, 22.3, 21.1, 14.7; IR (thin film) νmax
:
3289, 2999, 1614, 1365, 1171, 1093, 917, 734 cm−1; MS
(ESI) m/z: 360.0 [M＋H＋]; HRMS calcd for C15H22N-
O2F3SNa [M＋Na＋]: 360.1221, found 360.1222.
General procedure for the preparation of CF3-sub-
stituted hemiaminal ether
Ti(OPr-i)4 (1.2 mL, 4.0 mmol) was added dropwise
to a mixture of 2,2,2-trifluoro-1-phenylethanone (554
mg, 2.00 mmol) and N-tert-butylsulfinylimine (363 mg,
3.00 mmol) in 20.0 mL of hexane at room temperature
under argon. The mixture was stirred at room tempera-
ture for 12 h before cooled to 0 ℃. NaOEt (136.0 mg,
2.0 mmol) in EtOH (2.0 mL) was added and the mixture
was stirred for 5 min. The starting material disappeared
as determined by 19F NMR spectroscopy. Water (10 mL)
was added and the mixture was warmed to room tem-
perature and filtered through a short plug of Celite.
Ethyl acetate (50 mL) was added and the organic layer
was separated. The aqueous phase was extracted by
ethyl acetate (15 mL×2). The combined organic layer
was dried over Na2SO4, filtered, concentrated under
vacuum. The residue was then purified by flash column
chromatography (Elite: petroleum ether/ethyl acetate＝
8∶1, V/V) to give (S)-N-((R)-1-ethoxy-2,2,2 trifluoro-
1-phenylethyl)-tert-butylsulfinamide (4a) (310 mg, 48%
as a colorless oil and (S)-N-((S)-1-ethoxy-2,2,2-trifluo-
ro-1-phenyl ethyl)-tert-butylsulfinamide (4a') (142 mg,
22%) as a colorless oil.
(S)-N-((R)-1-Ethoxy-2,2,2-trifluoro-1-phenyl ethyl)-
tert-butylsulfinamide (4a) [α]2D0 ＝＋27.2 (c 0.8,
CHCl3); 1H NMR (300 MHz, CDCl3) δ: 7.52－7.42 (m,
5H), 4.33 (s, 1H), 3.90－3.85 (m, 1H), 3.42－3.38 (m,
1H), 1.33－1.27 (m, 12H); 19F NMR (282 MHz, CDCl3)
δ: −79.72; 13C NMR (75 MHz, CDCl3) δ: 134.2, 130.1,
128.8, 127.6, 122.6 (q, J＝284.8 Hz), 89.8 (q, J＝29.9
Hz), 59.3, 57.2, 22.3, 14.7; IR (thin film) νmax: 3277,
2995, 1450, 1288, 1171, 1079, 969, 716 cm−1; MS (ESI)
m/z: 346.2 [M＋Na＋]; HRMS calcd for C14H20NO2-
F3SNa [M＋Na＋]: 346.1045, found 346.1064.
(S)-N-((S)-1-Ethoxy-2,2,2-trifluoro-1-p-tolylethyl)-
tert-butylsulfinamide (4b') 12%, colorless oil. [α]D20
＝＋70.0 (c 2.2, CHCl3); 1H NMR (300 MHz, CDCl3) δ:
7.41 (d, J＝8.4 Hz, 2H), 7.26 (t, J＝8.4 Hz, 2H), 4.33 (s,
1H), 3.87 (quintet, J＝7.2 Hz, 1H), 3.42 (quintet, J＝7.2
Hz, 1H), 2.39 (s, 3H), 1.35 (t, J＝7.2 Hz, 3H), 1.33 (s,
9H); 19F NMR (282 MHz, CDCl3) δ: −78.71; 13C NMR
(75 MHz, CDCl3) δ: 139.7, 130.0, 129.0, 128.7, 123.2
(q, J＝216.1 Hz), 89.5 (q, J＝21.2 Hz), 60.2, 57.3, 22.7,
21.1, 15.0; IR (thin film) νmax: 3337, 3205, 2982, 1616,
1271, 1162, 974, 733 cm−1; MS (ESI) m/z: 360.0 [M＋
Na＋]; HRMS calcd for C15H22NO2F3SNa [M＋Na＋]:
360.1221, found 360.1230.
(S)-N-((S)-1-Ethoxy-2,2,2-trifluoro-1-(4-methoxy-
phenyl)ethyl)-tert-butylsulfinamide (4c) 48%, col-
orless oil. [α]2D0 ＝＋19.3 (c 0.7, CHCl3); 1H NMR (300
MHz, CDCl3) δ: 7.46－7.43 (d, J＝9.0 Hz, 2H), 6.98－
6.95 (d, J＝9.0 Hz, 2H), 4.30 (s, 1H), 3.89－3.40 (m,
5H), 1.35－1.30 (m, 12H); 19F NMR (282 MHz, CDCl3)
δ: −86.91; 13C NMR (75 MHz, CDCl3) δ: 160.8, 129.1,
126.0, 122.7 (q, J＝284.7 Hz), 114.1, 89.8 (q, J＝29.1
Hz), 59.2, 57.1, 55.32, 22.3, 14.7; IR (thin film) νmax
:
3345, 3228, 2982, 1706, 1612, 1514, 1172, 835 cm−1;
MS (ESI) m/z: 376.0 [M＋Na＋]; HRMS calcd for
＋
C10H19NO3F3PNa [M ＋ Na ]: 376.1170, found
376.1174.
(S)-N-((S)-1-Ethoxy-2,2,2-trifluoro-1-(4-methoxy-
phenyl)ethyl)-tert-butylsulfinamide (4c') 13%, col-
orless oil. [α]2D0 ＝＋12.4 (c 1.2, CHCl3); 1H NMR (300
MHz, CDCl3) δ: 7.51－7.48 (m, J＝8.7 Hz, 2H), 6.86－
6.83 (m, J＝9.0 Hz, 2H), 4.51 (s, 1H), 3.81－3.64 (m,
5H), 1.29－1.23 (m, 12H); 19F NMR (282 MHz, CDCl3)
δ: −78.77; 13C NMR (75 MHz, CDCl3) δ: 160.5, 130.6,
124.8, 123.3 (q, J＝287.2 Hz), 121.4, 113.3, 89.4 (q,
J＝29.0 Hz), 60.2, 57.3, 55.2, 22.7, 15.1; IR (thin film)
νmax: 3234, 2964, 1707, 1603, 1380, 1168, 1031, 616
(S)-N-((S)-1-Ethoxy-2,2,2-trifluoro-1-phenylethyl)-
tert-butylsulfinamide (4a') [α]2D0 ＝＋11.5 (c 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3) δ: 7.67－7.36 (m,
5H), 4.63 (s, 1H), 3.87 (quintet, J＝7.2 Hz, 1H), 3.41
(quintet, J＝7.2 Hz, 1H), 1.37－1.30 (m, 12 H); 19F
NMR (282 MHz, CDCl3) δ: −78.45; 13C NMR (75 MHz,
CDCl3) δ: 133.1, 129.7, 129.1, 127.9, 123.2 (q, J＝
240.5 Hz), 89.5 (q, J＝28.7 Hz), 60.3, 57.4, 22.6, 15.0;
IR (thin film) νmax: 3234, 2983, 1720, 1366, 1174, 1031,
941, 711 cm−1; MS (ESI) m/z: 346.2 [M＋Na＋]; HRMS
calcd for C14H20NO2F3SNa [M＋Na＋]: 346.1065, found
346.1065.
cm−1; MS (ESI) m/z: 376.0 [M＋Na＋]; HRMS calcd for
＋
C15H22NO3F3SNa [M ＋ Na ]: 376.1170, found
376.1168.
(S)-N-((R)-1-Ethoxy-2,2,2-trifluoro-1-(3-methoxy-
phenyl)ethyl)-tert-butylsulfinamide (4d) 48%, light
yellow oil. [α]2D0 ＝＋21.5 (c 0.4, CHCl3); IR (thin film)
νmax: 3223, 2983, 1604, 1491, 1262, 1181, 987, 727
1
cm−1; H NMR (300 MHz, CDCl3) δ: 7.38－6.95 (m,
4H), 4.41 (s, 1H), 3.91－3.80 (m, 4H), 3.46－3.40 (m,
1H), 1.34－1.19 (m, 12 H); 19F NMR (282 MHz, CDCl3)
δ: −78.78; 13C NMR (75 MHz, CDCl3) δ: 159.9, 135.8,
129.9, 122.6 (q, J＝285.2 Hz), 119.1, 115.0, 114.1, 89.8
(S)-N-((R)-1-Ethoxy-2,2,2-trifluoro-1-p-tolylethyl)-
tert-butylsulfinamide (4b) 44%, white solid. M.p. 81
1
－83 ℃; [α]2D0 ＝＋60.4 (c 2.5, CHCl3); H NMR (300
Chin. J. Chem. 2013, 31, 892—900
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Wang, Shen & Lu
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(q, J＝29.6 Hz), 59.4, 57.3, 55.3, 22.4, 14.8; MS (ESI)
m/z: 376.1 [M＋Na＋]; HRMS calcd for C15H22NO3-
F3SNa [M＋Na＋]: 376.1170, found 376.1171.
film) νmax: 3489, 3194, 2960, 1616, 1517, 1241, 1074,
1
824 cm−1; H NMR (300 MHz, CDCl3) δ: 7.70 (d, J＝
8.4 Hz, 2H), 7.43 (d, J＝8.4 Hz, 2H), 6.80 (s, 1H), 3.98
(d, J＝11.4 Hz, 3H), 3.92 (d, J＝11.4 Hz, 3H), 3.14－
2.90 (m, 2H), 2.58 (s, 3H), 1.42 (s, 9H); 19F NMR (282
MHz, CDCl3) δ: −75.37; 13C NMR (75 MHz, CDCl3) δ:
139.4, 130.6 (d, J＝15.1 Hz), 129.0, 128.9, 128.7 (q,
J＝146.3 Hz), 64.8 (dq, J＝2.9, 24.7 Hz), 56.8, 53.3 (d,
J＝5.5 Hz), 52.2 (d, J＝6.9 Hz), 31.6 (d, J＝140.9 Hz),
22.6, 21,1; 31P NMR (121 MHz, CDCl3) δ: 28.8; MS
(ESI) m/z: 438.0 [M＋Na＋]; HRMS calcd for C16H25N-
O4F3PSNa [M＋Na＋]: 438.1092, found 438.1092.
(S)-N-((S)-1-Ethoxy-2,2,2-trifluoro-1-(3-methoxy-
phenyl)ethyl)-tert-butylsulfinamide (4d') 14%, light
1
yellow oil. [α]2D0 ＝＋79.3 (c 1.0, CHCl3); H NMR
(300 MHz, CDCl3) δ: 7.34－7.21 (m, 3H), 6.97－6.93
(m, 1H), 4.61 (s, 1H), 3.91－3.74 (m, 5H), 1.37－1.26
(m, 12H); 19F NMR (282 MHz, CDCl3) δ: −77.11; 13C
NMR (75 MHz, CDCl3) δ: 159.2, 134.6, 128.9, 123.1 (q,
J＝216.7 Hz), 121.4, 115.3, 114.9, 89.4 (q, J＝21.8 Hz),
60.4, 57.4, 55.2, 22.7, 15.1; IR (thin film) νmax: 2983,
2245, 1604, 1492, 1268, 1159, 911, 734 cm−1; MS (ESI)
m/z: 376.0 [M＋Na＋]; HRMS calcd for C15H22NO3-
F3SNa [M＋Na＋]: 376.1170, found 376.1179.
Dimethyl (S)-2-((S)-tert-butylsulfinamido)-3,3,3-
trifluoro-2-(4-methoxyphenyl)propylphophonate (5c)
80%, colorless oil. [α]2D0 ＝＋44.7 (c 0.4, CHCl3); IR
(thin film) νmax: 3650, 3192, 2960, 1612, 1517, 1240,
1179, 840 cm−1; 1H NMR (300 MHz, CDCl3) δ: 7.71 (d,
J＝8.7 Hz, 2H), 7.13 (d, J＝8.7 Hz, 2H), 6.76 (s, 1H),
4.02 (s, 3H), 3.96 (d, J＝11.4 Hz, 3H), 3.91 (d, J＝11.4
Hz, 3H), 3.16－2.86 (m, 2H), 1.50 (s, 9H); 19F NMR
(282 MHz, CDCl3) δ: −75.54; 13C NMR (75 MHz,
CDCl3) δ: 160.2, 130.5, 128.0 (q, J＝183.7 Hz), 125.3
(d, J＝13.3 Hz), 113.5, 64.5 (dq, J＝2.9, 24.7 Hz), 56.8,
55.2, 53.3 (d, J＝5.6 Hz), 52.3 (d, J＝6.9 Hz), 31.6 (d,
J＝140.9 Hz), 22.8; 31P NMR (121 MHz, CDCl3) δ:
General procedure for the synthesis of trifluoro-
methyl-substituted β-aminophosphonates
A solution of nBuMgBr in THF (0.5 mol/L, 2.4 mL)
was added dropwise to (S)-N-((R)-1-ethoxy-2,2,2-
trifluoro-1-phenylethyl)-2-methylpropane-2-sulfinamide
4a (323 mg, 1.00 mmol) in 30.0 mL of dichloromethane
at 0 ℃ under argon. The mixture was stirred at 0 ℃
for 0.5 h before cooled to −78 ℃. In a separated vessel,
a solution of LiHMDS in THF (1.0 mol/L, 2.0 mL) was
added dropwise to dimethyl methylphosphonate (248
mg, 2.0 mmol) in THF (5.0 mL) at −78 ℃. The mixture
was stirred for 0.5 h before being transferred to the ves-
sel containing the in situ formed CF3-substituted imine.
The resulting mixture was allowed to stir for another 1 h
at −78 ℃. The peak corresponding to the imine disap-
peared as determined by 19F NMR spectroscopy. Aque-
ous NH4Cl (10 mL) was added and the mixture was
warmed to room temperature. Ethyl acetate (50 mL)
was added and the organic layer was separated. The
aqueous phase was extracted by ethyl acetate (15 mL×
2). The combined organic layer was dried over Na2SO4,
filtered, concentrated under vacuum. The residue was
then purified by flash column chromatography (Elite:
petroleum ether/ethyl acetate＝2/1, V/V) to give di-
methyl (S)-2-((S)-1,1-dimethylethyl sulfinamido)-3,3,3-
trifluoro-2-phenylpropylphosphonate 5a (322 mg, 80%)
as a colorless oil. M.p. 83－85 ℃; [α]2D0 ＝＋76.2 (c
1.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ: 7.65－7.41
(m, 5H), 6.62 (s, 1H), 3.77 (d, J＝11.4 Hz, 3H), 3.68 (d,
J＝11.4 Hz, 3H), 3.00－2.70 (m, 2H), 1.33 (s, 9H); 19F
NMR (282 MHz, CDCl3) δ: −74.59; 13C NMR (75 MHz,
CDCl3) δ: 133.8 (d, J＝12.4 Hz), 129.4, 129.1, 128.2,
125.5 (q, J＝231.0 Hz), 65.1 (dq, J＝2.9, 24.8 Hz), 57.0,
53.4 (d, J＝5.5 Hz), 52.3 (d, J＝6.5 Hz), 31.7 (d, J＝
140.9 Hz), 22.8; 31P NMR (121 MHz, CDCl3) δ: 28.6;
IR (thin film) νmax: 3233, 2976, 1459, 1244, 1179, 1068,
1027, 820 cm−1; MS (ESI) m/z: 402.2 [M＋H＋]; HRMS
calcd for C15H23NO4F3PSNa [M＋Na ＋]: 424.0945,
found 424.0943.
28.8; MS (ESI) m/z: 454.0 [M＋Na＋]; HRMS calcd for
＋
C16H25NO5F3PSNa [M ＋ Na ]: 454.1041, found
454.1039.
Dimethyl (S)-2-((S)-tert-butylsulfinamido)-3,3,3-
trifluoro-2-(3-methoxyphenyl)propylphosphonate
(5d) 81%, colorless oil. [α]2D0 ＝＋84.8 (c 0.5, CHCl3);
IR (thin film) νmax: 3484, 3198, 2961, 1605, 1467, 1241,
1
1031, 787 cm−1; H NMR (300 MHz, CDCl3) δ: 7.54－
7.11 (m, 4H), 6.75 (s, 1H), 4.01 (s, 3H), 3.94 (d, J＝
11.4 Hz, 3H), 3.83 (d, J＝11.4 Hz, 3H), 3.16－2.83 (m,
2H), 1.50 (s, 9H); 19F NMR (282 MHz, CDCl3) δ:
−74.71; 13C NMR (75 MHz, CDCl3) δ: 159.4, 135.5 (d,
J＝14.0 Hz), 129.2, 127.5 (q, J＝200.5 Hz), 121.1,
115.6, 114.8, 65.3 (q, J＝25.5 Hz), 57.1, 55.4, 53.4 (d,
J＝5.4 Hz), 52.3 (d, J＝7.1 Hz), 31.9 (d, J＝141.9 Hz),
22.9; 31P NMR (121 MHz, CDCl3) δ: 28.5; MS (ESI)
m/z: 432.0 [M＋H＋]; HRMS calcd for C16H25NO5F3P-
SNa [M＋Na＋]: 454.1041, found 454.1042.
Results and Discussion
We recently reported that reaction of chiral
CF3-substituted (R)-N-tert-butylsulfinylketimine with
TMSCN occurred under mild conditions to afford the
Strecker reaction products in excellent yield with an
excellent diastereoselectivity.[9e] Inspired by these re-
sults, we wondered if a lithium salt of dialkylphospho-
nate or dialkyl methylphosphonate instead of TMSCN
could be used as a nucleophile, a highly selective
method for the asymmetric synthesis of trifluoromethyl-
substituted α- and β-aminophosphonates could be real-
ized. With this thought in mind, we initially tested the
reaction of the isolated CF3-substituted (R)-N-tert-
Dimethyl (S)-2-((S)-tert-butylsulfinamido)-3,3,3-
trifluoro-2-p-tolylpropylphosphonate (5b)
72%,
colorless oil. [α]2D0 ＝＋83.3 (c 0.4, CHCl3); IR (thin
896
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Chin. J. Chem. 2013, 31, 892—900

Asymmetric Synthesis of Trifluoromethyl-Substituted α- and β-Aminophosphonates
butylsulfinylketimine 1 with diethylphosphonate in the
presence of different base in THF at −78 ℃. Surpris-
ingly, only moderate yields (30%－40%) were observed
when n-butyl lithium, lithium di-iso-propylamide (LDA)
or sodium hydride was used as the base. Interestingly,
when in situ formed CF3-substituted (R)-N-tert-butyl-
sulfinylketimine was used, the yield of the product was
improved to 70% albeit with a 4.5/1 ratio of diastereo-
selectivity (Table 1, Entry 1).
toluene was used as the solvent, reaction occurred to full
conversion to give the product in 60% yield with a 3.5/1
ratio of diastereoselectivity (Table 1, Entry 6). The di-
astereoselectivity increased from 4.5/1 to 11/1 when
hexane was used as the solvent and the reaction tem-
perature was lowered from room temperature to −10 ℃
(Table 1, Entries 8－12). Finally, it was found that
when a mixed solvents of hexane/toluene (20/1, V/V)
was used at −40 ℃, the reaction occurred to full con-
version after 1 min to give the corresponding product in
75% yield with a 14.5/1 ratio of diastereoselectivity
(Table 1, Entry 13). No conversion was observed when
the reaction was conducted at −78 ℃ (Table 1, Entry
14). The absolute configuration of the stereogenic center
(S) in compound 2a was determined by X-ray crystallo-
graphic analysis of a single crystal (Figure 1).
Table1 Optimization of the reaction conditions for the reaction
of CF3-substituted (R)-N-tert-butylsulfinylketimine with dialkyl-
phosphonatea
O
S
(EtO)2P(O)H
(2.0 equiv.)
t-Bu
NH2
O
(1.2 equiv.)
F3C
Ph
T (oC)
Ti(OPr-i)4
solvent
12 h
<1.0 min
O
O
P(OEt)2
S
P(OEt)2
S
NH
F3C
O
NH
F3C
O
+
R
R
2
2'
Entry
1
Solvent
Hexane
Et2O
Temp./℃
r.t.
2/2'b
4.5/1
－
Yieldc/%
80
2
r.t.
－
3
CH2Cl2
THF
r.t.
－
－
4
r.t.
－
－
5
DMF
r.t.
－
－
6
Toluene
Toluene
Hexane
Hexane
Hexane
Hexane
Hexane
r.t.
3.5/1
－
60
Figure 1 The ORTEP view of compound 2a.
7
－
−78
0
8
8/1
77
On the basis of the results summarized in Table 1,
the reaction conditions of Entry 13 in Table 1 were
chosen to study the scope of the addition reactions of
diethyl phosphonate with a variety of trifluoromethy-
lated (R)-N-tert-butylsulfinylketimine, and the results
are summarized in Table 2. In general, reactions of both
alkyl and aryl-substituted ketimines generated trifluoro-
methyl-substituted α-amino phosphonates in good to
excellent yields. Reaction of alkyl substituted ketimines
generated the corresponding products in higher di-
astereoselectivities than those of aryl-substituted keti-
mines. Reactions of ethyl or propyl substituted (R)-N-
tert-butylsulfinylketimine gave almost exclusively the
desired product with a 99/1 ratio of diastereoselectivity.
The trifluoromethyl-substituted α-aminophospho-
nates obtained from the asymmetric addition reaction
can be easily converted into the optically pure trifluoro-
methyl-substituted α-aminophosphoric acids in almost
quantitative yields (Eq. 1) after refluxing in 6.0 mol/L
HCl aqueous solution and workup.
9
－5
－10
－15
－20
－40
－78
8/1
80
10
11
12
13
14
11/1
10/1
－
75
81
－
Hexane/Toluened
Hexane/Toluenee
14.5/1
－
75
－
a
Reaction conditions: 1 (1.0 mmol), (R)-N-tert-butylsulfinyl-
ketimine (1.5 mmol), Ti(OPr-i)4 (2.0 mmol) in solvent for 12 h at
room temperature, followed by the addition of diethylphospho-
nate at −40 ℃ for 1.0 min; b Determined by 19F NMR analysis
of the crude reaction mixture; c Determined by 19F NMR analysis
of the crude reaction mixture with an internal standard; d Hex-
ane/toluene＝20/1 (V/V).
The reaction conditions were then further optimized
in term of solvent and temperature. Reactions conducted
in solvent such as Et2O, CH2Cl2, THF, DMF led to less
then 5% conversion (Table 1, Entries 2－5). When
Chin. J. Chem. 2013, 31, 892—900
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Wang, Shen & Lu
FULL PAPER
Table 2 Scope of the reaction of CF3-substituted (R)-N-tert-
miaminal ether with nBuMgBr in CH2Cl2 at 0 ℃ for
0.5 h formed the trifluoromethyl-substituted (S)-N-tert-
butylsulfinylketimine in 92% yield as determined by 19F
NMR spectroscopy. The in situ formed trifluoromethyl-
substituted (S)-N-tert-butylsulfinylketimine was then
allowed to react with diethyl methylphosphonate in the
presence of lithium hexamethyldisilylamide as the base
at −78 ℃ for 5 min to give the corresponding
CF3-substituted β-aminophosphonate in excellent yields
(88%) and good diastereoselectivity (11∶1). Several
other aryl-substituted hemiaminal ether was formed un-
der the same conditions and reactions of these ketimines
generated CF3-substituted β-aminophosphonate in ex-
cellent yields (72%－81%) and good diastereoselectiv-
ity (8/1－12/1) (Eq. 3). The absolute configuration of
the stereogenic center (S) in compound 5a was deter-
mined by X-ray crystal graphic analysis of a single
crystal (Figure 2).
butylsulfinylketimine with diethylphosphonatea
O
S
(EtO)2P(O)H
(2.0 equiv.)
t-Bu
NH2
O
(1.2 equiv.)
T (oC)
F3C
Ph
Ti(OPr-i)4
solvent
12 h
<1.0 min
O
O
S
P(OEt)2
S
NH
P(OEt)2
O
NH
F3C
O
+
F3C
R
R
2
2'
Entry
R
Product
2a
2/2'b
Yieldc/%
84
1
2
3
4
5
6
7
8
9
Ph
14.5/1
10/1
8/1
p-Me-C6H4
p-MeO-C6H4
p-Cl-C6H4
n-C6H13
n-C4H9
n-C3H7
Et
65
2b
75
2c
1) Ti(i-OPr)4, hexane
O
S
O
r.t., 6 h
8/1
71
2d
+
t-Bu
F3C
Ph
NH2
2) NaOEt, 1 min
43/1
78/1
99/1
99/1
99/1
73
2e
70% (4/4' = 1:1)
73
2f
77
2g
S
O
NH
S
90
2h
OEt
Ph
O
NH
+
OEt
Ph
(2)
Me
48
2i
F3C
F3C
a
Reaction conditions: 1 (1.0 mmol), (S)-N-tert-butylsulfinyl
4
4'
ketimine (1.5 mmol), Ti(OPr-i)4 (2.0 mmol) in solvent for 12 h at
room temperature, followed by the addition of diethylphospho-
b
nate at −40 ℃ for 1.0 min; Determined by 19F NMR analysis
O
of the crude reaction mixture; c Isolated yield.
S
S
i
NH
ii
O
N
Bu-t
OEt
Ar
F3C
F3C
Ar
O
O
S
6.0 mol/L HCl
reflex, 10 h
P(OH)2
P(OEt)2
H2N
F3C
NH
F3C
(1)
O
O
R
R
O
S
S
NH
CH2PH(OMe)2
NH
O
O
CH2P(OMe)2
Ar
2
3
(3)
+
R = Ph, 3a, 98%
F3C
Ar
F3C
R = p-ClC6H4, 3b, 95%
R = C6H13, 3c, 99%
5'
5
Ar = Ph, 5a/5a', 80%, dr = 11/1
Ar = p-MeC6H4, 5b/5b', 72%, dr = 8/1
Ar = p-OMeC6H4, 5c/5c', 80%, dr = 12/1
Ar = m-MeC6H4, 5d/5d', 81%, dr = 8/1
Encouraged by excellent results by the reaction of
(R)-N-tert-butylsulfinylketimine with diethylphospho-
nate, we next studied the reaction of the (S)-N-tert-
butylsulfinylketimine with dimethyl methylphosphonate
in the presence of various bases such as n-butyl lithium,
lithium di-iso-propylamide (LDA), lithium hexamethyl-
disilylamide (LiHMDS) or sodium hydride. Although
excellent yield was observed when n-butyl lithium was
used as the base at −78 ℃, the diastereoselectivity of
the reaction was disappointedly low (3/1). Reaction of
the in situ formed (S)-N-tert-butylsulfinylketimine re-
sulted in low yield. Interestingly, it was found that addi-
tion of excess NaOEt into the Ti(OPr-i)4-mediated keti-
mine forming reaction mixture generated a stable he-
miaminal ether which could be isolated by flash chro-
matography in 70% yield (Eq. 2). Treatment of the he-
Conditions: (i) n-BuMgBr, toluene, 0 ℃, 0.5 h; (ii) MeP(O)(OMe)2,
LiHMDS (3.0 equiv.), toluene, −78 ℃, 5 min.
Mechanistically, we proposed that the reaction of the
in situ formed CF3-substituted (R)-N-tert-butylsul-
finylketimine 1 with diethylphosphonate was mediated
by the titanium complexes since the selectivity of reac-
tion was higher than those from the isolated CF3-sub-
stituted (R)-N-tert-butylsulfinylketimine. The high di-
astereoselectivity of the reaction can be rationalized by
a seven-membered chair-like transition state. Because of
the n-p repulsion between the lone pair electron of the
sulfinyl group and the CF3 group, the CF3 group
898
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 892—900

Asymmetric Synthesis of Trifluoromethyl-Substituted α- and β-Aminophosphonates
fluoromethyl-substituted α-aminophosphonates were
successfully converted into optically pure trifluoro-
methyl-substituted α-aminophosphoric acids in quanti-
tative yields. Evaluation of the bioactivity of the tri-
fluoromethyl-substituted α-aminophosphoric acids is
undergoing currently in our laboratory.
Acknowledgement
The authors gratefully acknowledge the financial
support from National Basic Research Program of
China (Nos. 2012CB821600, 2010CB126103), the Key
Program of the National Natural Science Foundation of
China (No. 21032006), National Natural Science Foun-
dation of China (Nos. 21172244/21172245/B020304),
Agro-scientific Research in the Public Interest (No.
201103007), the National Key Technologies R&D Pro-
gram (No. 2011BAE06B05), and Shanghai Scientific
Research Program (No. 10XD1405200).
Figure 2 The ORTEP view of compound 5a.
preferred to be placed in the equatorial position of the
transition state which led to the product with S-configu-
ration. Similarly, the reaction with methyl diethylphos-
phosphonate also proceeded via lithium-mediated six-
membered chair-like transition state to give the product
with S-configuration (Scheme 2).
References
[1] (a) Palacios, F.; Alonso, C.; De Los Santos, J. Chem. Rev. 2005, 105,
899; (b) Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. Rev. 2004,
104, 6177; (c) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon
Relat. Elem. 1991, 63, 193; (d) Smith, A. B., III; Yager, K. M.;
Taylor, C. M. J. Am. Chem. Soc. 1995, 117, 10879; (e) Allen, M. C.;
Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M. J. Med. Chem. 1989,
32, 1652; (f) Ding, J.; Fraser, M. E.; Meyer, J. H.; Bartlett, P. A.;
James, M. N. G. J. Am. Chem. Soc. 1998, 120, 4610; (g) Smith, W.
W.; Bartlett, P. A. J. Am. Chem. Soc. 1998, 120, 4622; (h) Bird, J.;
Mello, R. C. D.; Harper, G. P.; Hunter, D. J.; Karran, E. H.;
Markwell, R. E.; Miles-Williams, A. J.; Rahman, S. S.; Ward, R. W.
J. Med. Chem. 1994, 37, 158.
Scheme 2
O
O
S
S
(EtO)2P(O)H
O
NH2
N
F3C
R
F3C
R
[2] Berg, J. M.; Tymoczko, J. L.; Stryer, L. Biochemistry, W. H. Free-
man, New York, 2012.
O
R
P
S
P(OEt)2
NH
F3C
O
S
[3] (a) Kolodiazhnyi, O. I. Tetrahedron: Asymmetry 1998, 9, 1279; (b)
Davis, F. A.; Lee, S.; Yan, H. X.; Titus, D. D. Org. Lett. 2001, 3,
1757; (c) Moonen, K.; Laureyn, L.; Stevens, C. V. Chem. Rev. 2004,
104, 6177; (d) Moonen, K.; Dieltiens, N.; Stevens, C. V. J. Org.
Chem. 2006, 71, 4006; (e) Chen, Q. Y.; Yuan, C. Y. Synthesis 2007,
3779.
[4] (a) Umemoto, T. In Fluorine-Containing Synthons, Ed.: Soloshonok,
V. A., ACS, Washington, DC, 2005; (b) Hu, J.-B.; Zhang, W.; Wang,
F. Chem. Commun. 2009, 7465; (c) Cahard, D.; Xu, X.;
Couve-Bonnaire, S.; Pannecoucke, X. Chem. Soc. Rev. 2010, 39,
558; (d) Ma, J.-A.; Cahard, D. Chem. Rev. 2004, 104, 6119; (e) Ma,
J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1; (f) Nie, J.; Guo, H.-C.;
Cahard, D.; Ma, J.-A. Chem. Rev. 2011, 111, 455; (g) Shibata, N.;
Mizuta, S.; Kawai, H. Tetrahedron: Asymm. 2008, 19, 2633; (h)
Ramachandran, P. V. In Asymmetric Fluoroorganic Chemistry:
Synthesis, Applications, and Future Directions, American Chemical
Society Symposium Series 746, American Chemical Society,
Washington DC, 2000; (i) Zhu, S.-F.; Pan, W.; Xing, C.-H.; Zhu,
S.-Z. Chin J. Chem. 2007, 25, 233.
N
CF3
OEt
R
Ti
O
O
OEt
2 (Rs, S)
T1
O
S
O
O
S
C4H7MgBr
NH
OEt
R
4
LiCH2P(OMe)2
N
F3C
F3C
R
S
O
S
O
O
N
O
NH
CH2P(OMe)2
Li
CF3
R
P
MeO
F3C
Ar
OMe
T2
5 (Ss, S)
[5] (a) Flynn, G. A.; Beight, D. W. Tetrahedron Lett. 1985, 26, 285; (b)
Markovskii, L. N.; Shermolovich, Y. G.; Barashenkov, G. G.; Kuk-
har', V. P.; Soloshonok, V. A.; Rozhenko, A. B. J. Gen. Chem.
USSR. 1990, 60, 2005; (c) Osipov, S. N.; Artyushin, O. I.; Kolomi-
ets, A. F.; Bruneau, C.; Picquet, M.; Dixneuf, P. H. Eur. J. Org.
Chem. 2001, 3891; (d) Cen, W. B.; Shen, Y. C. J. Fluorine Chem.
1995, 72, 107; (e) Huang, W. S.; Yuan, C. Y. Phosphorus Sulfur
Silicon Relat. Elem. 1995, 106, 163; (f) Sergeeva, N. N.; Golubev, A.
Conclusions
In summary, we have developed a general and
highly selective method for the preparation of optically
active trifluoromethyl-substituted α- and β-aminophos-
phonates by employing (R)- or (S)-N-tert-butanesul-
finylimine as auxiliary. As a demonstration, the tri-
Chin. J. Chem. 2013, 31, 892—900
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
899

Wang, Shen & Lu
FULL PAPER
S.; Hennig, L.; Burger, K. Synthesis 2003, 915.
V. P.; Rozhenko, A. B.; Soloshonok, V. A.; Sorochinsky, A. E.
Chem. Commun. 2012, 48, 111519.
[6] Vaubaillon, D.; Giraud, V.; Rabiller, C.; Gruss, U.; Haas, A.; Hagele,
G. Phosphorus, Sulfur Silicon Relat. Elem. 1997, 126, 177.
[7] (a) Xiao, J. B.; Zhang, X. M.; Yuan, C. Y. Heteroatom Chem. 2000,
11, 536; (b) Xiao, J. B.; Yuan, C. Y. Heteroatom Chem. 2000, 11,
541.
[8] (a) Roschenthaler, G.-V.; Kukhar, V. P.; Kulik, I. B.; Belik, M. Y.;
Sorochinsky, A. E.; Rusanov, E. B.; Soloshonok, V. A. Tetrahedron
Lett. 2012, 53, 539; (b) Turcheniuk, K. V.; Poliashko, K. O.; Kukhar,
[9] (a) Wen, L.; Shen, Q.; Lu, L. Org. Lett. 2010, 12, 4655; (b) Wen, L.;
Shen, Q.; Wan, X.; Lu, L. J. Org. Chem. 2011, 76, 2282; (c) Zhang,
H.-H.; Shen, Q.; Lu, L. Tetrahedron Lett. 2011, 52, 349; (d) Wang,
H.; Zhao, X.-M.; Li, Y.-H.; Lu, L. J. Org. Chem. 2006, 71, 3278; (e)
Wang, H.; Zhao, X.-M.; Li, Y.-H.; Lu, L. Org. Lett. 2006, 8, 1379.
[10] Ellman, J. A.; Owens, T.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984.
(Zhao, X.)
900
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 892—900