Stereoselective synthesis of α-difluoromethyl-β-amino alcohols via nucleophilic difluoromethylation with Me3SiCF2SO2Ph

Article abstract of DOI:10.1016/j.tetlet.2008.01.034

A facile synthesis of anti-α-(difluoromethyl)-β-amino alcohols was accomplished by using a nucleophilic difluoromethylation strategy with Me₃SiCF₂SO₂Ph reagent. Good to excellent chemical yields as well as modest to good d

Full text of DOI:10.1016/j.tetlet.2008.01.034

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Tetrahedron Letters 49 (2008) 1605–1608
Stereoselective synthesis of a-difluoromethyl-b-amino alcohols
via nucleophilic difluoromethylation with Me3SiCF2SO2Ph
Jun Liu, Chuanfa Ni, Fang Wang , Jinbo Hu *
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
Received 30 November 2007; revised 28 December 2007; accepted 9 January 2008
Available online 12 January 2008
Abstract
A facile synthesis of anti-a-(difluoromethyl)-b-amino alcohols was accomplished by using a nucleophilic difluoromethylation strategy
with Me3SiCF2SO2Ph reagent. Good to excellent chemical yields as well as modest to good diastereoselectivity were achieved in these
reactions. We found that the solvent played a crucial role in controlling the diastereoselectivity of the reaction, and an apolar solvent
such as toluene helps to improve the diastereoselectivity of the reaction. The anti-a-(difluoromethyl)-b-amino alcohol 3a was demon-
strated to be a useful synthetic intermediate to synthesize difluoromethylated oxazolidinone 9.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Fluorine; Difluoromethylation; Amino alcohol; Stereoselective
As the incorporation of fluorine atom(s) can often have
profound effects on the target molecules, stereoselective
introduction of the fluoroalkyl groups into the a-position
of b-amino alcohols has attracted much attention.1 a-Fluo-
roalkyl-b-amino alcohols have been used as peptidometics
and transition state mimics in drug design,2 as well as chiral
auxiliaries or as ligands in asymmetric synthesis.3 During
the past two decades, a number of synthetic methods for
the synthesis of a-trifluoromethyl-b-amino alcohols have
been reported,4 including the direct trifluoromethylation
of homochiral a-amino aldehydes with Ruppert–Prakash
reagent (Me3SiCF3).5 On the other hand, the stereoselec-
tive synthesis of a-difluoromethyl-b-amino alcohols
was less explored, probably due to less availability of
difluoromethylated precursors and difluoromethylating
reagents.6 All of the previous reports are based on
the synthetic elaboration of difluoromethyl-containing
substrates,7–11 and we are not aware of any report on the
stereoselective synthesis of a-difluoromethyl-b-amino alco-
hols via nucleophilic difluoromethylation strategy. In this
Letter, we wish to report a stereoselective synthesis of a-
difluoromethyl-b-amino alcohols via nucleophilic difluoro-
methylation of homochiral a-amino aldehydes using
Me3SiCF2SO2Ph reagent.
Based on our previous experience in using difluoro-
methyl phenyl sulfone (PhSO2CF2H, 1) as a robust
difluoromethylating agent,12,13 first of all, we tested the
nucleophilic (phenylsulfonyl)difluoromethylation reaction
between 1 and a-amino aldehyde 2a (Scheme 1). It turned
out that, in the presence of 2 equiv of LHMDS in THF at
O
OH
CF2SO2Ph
PhSO2CF2H (1)
Ph
H
Ph
LHMDS, solvent
NBn2
NBn2
°
0 C, 6~7 h
anti-3a
syn-3a
2a
*
Corresponding author. Tel.: +86 21 54925174; fax: +86 21 64166128.
solvent = THF, yield = 46%, syn/anti = 33:67
solvent = toluene, yield = 52%,syn/anti = 33:67
E-mail address: jinbohu@mail.sioc.ac.cn (J. Hu).
Fang Wang was a visiting undergraduate student from Zhejiang
University.
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.034

1606
J. Liu et al. / Tetrahedron Letters 49 (2008) 1605–1608
0 °C, the reaction between 1 equiv of 2a and 1.2 equiv of 1
only gave low yield (46%) of product 3a with syn/anti
ratio = 33:67. When toluene was used as the solvent, a sim-
ilar result was obtained (Scheme 1). We envisioned that
since LHMDS is a strong base, the low yield of product
3a was probably caused by the enolization of 2a and the
resulting aldol-type side reactions.14
With reagent 4 in hand, we chose compound 2a as a
model compound to examine the fluoride-induced (phenyl-
sulfonyl)difluoromethylation, and the results are shown in
Table 1. Tetrabutylammonium triphenyldifluorosilicate18
(TBAT, 5 mol %) was used as a fluoride initiator for the
reaction. Different solvents such as THF, toluene, DMF,
n-hexane, acetonitrile, and dichloromethane were used. In
all cases, excellent overall yields (92–96%) of syn-3a and
anti-3a were obtained, with the anti-isomer being the major
one. It turned out that better diastereoselectivity could be
obtained in apolar solvents (such as toluene and n-hexane),
and the best diastereomeric ratio was observed in toluene
(dr = 11:89, see entry 2). We further tried to lower the reac-
tion temperature to ꢀ35 °C, but no improvement of diaste-
reoselectivity was observed. Other fluoride initiators such
as tetrabutylammonium fluoride (TBAF) and tetramethyl-
ammonium fluoride (TMAF) were also tried (instead of
TBAT), but chemical yields decreased.
Previously, we had developed [(phenylsulfonyl)difluoro-
methyl]trimethylsilane (Me3SiCF2SO2Ph, 4) as an alter-
native nucleophilic (phenylsulfonyl)difluoromethylating
agent.15 Unlike PhSO2CF2H (1), which usually needs a
ꢀ
strong base to generate the PhSO2CF2 intermediate,
reagent 4 needs only a catalytic amount of mild Lewis base
(such as a fluoride ion) to accomplish the nucleophilic
transfer of PhSO2CF2 group to carbonyl compounds.15
Me3SiCF2SO2Ph (4) was first prepared in 2003 via
mCPBA-mediated oxidation of Me3SiCF2SPh (5) in 51%
yield.16 In 2005, we improved the synthesis of reagent 4
(with 78% isolated yield) by the reaction of PhSO2CF2Br
(1 equiv), n-BuLi (1.8 equiv), and Me3SiCl (1.5 equiv) in
THF at ꢀ78 °C.15 After further optimization of the reac-
tion conditions, we found that when the reactant ratio
was changed to PhSO2CF2Br/n-BuLi/Me3SiCl = 1.0:
1.1:1.5 and a subsequent acid-quenching procedure was
used, an excellent yield of 4 (87–98%) could be obtained
(Scheme 2).17
By using the optimized reaction condition (Table 1,
entry 2), we studied the scope of the nucleophilic difluoro-
Table 2
Stereoselective (phenylsulfonyl)difluoromethylation of a-dibenzylamino
aldehydes
OH
R
CF2SO2Ph
NBn2
syn-
(1) TBAT(5 mol %)
O
3
°
toluene, 0 C
R
+
Me3SiCF2SO2Ph
+
H
(1) n-BuLi (1.1 equiv)
(2) TBAF, H2O
OH
CF2SO2Ph
NBn2
Me3SiCl (1.5 equiv)
O
O
O
O
R
°
2
4
THF, -78 C
S
S
Ph
CF2SiMe3
Ph
CF2Br
NBn2
anti-3
(2) cold 1 M HCl (aq.)
87%
4
Entry Substrate
Producta
Yieldb (%) drc
Scheme 2.
CHO
NBn2
Ph
1
syn-3a + anti-3a 92
syn-3b + anti-3b 86
11:89
2a
CHO
NBn2
Table 1
Survey of reaction conditions
2
3
13:87
47:53
OH
CF2SO2Ph
2b
Ph
Ph
CHO
NBn2
syn-3c + anti-3c
72
NBn2
syn-3a
+
OH
2c
(1) TBAT (5 mol %)
O
°
0
C
Me3SiCF2SO2Ph
+
H
Ph
(2) TBAF, H2O
CHO
NBn2
4
5
6
7
syn-3d + anti-3d 88
6:94
9:91
2d
2a
4
NBn2
CHO
Ph
CF2SO2Ph
NBn2
anti-3a
syn-3e + anti-3e
syn-3f + anti-3f
85
83
2e
NBn2
Entrya
Solvent
Time (h)
Yieldb (%)
drc
H3CH2C(H3C)HC
CHO
NBn2
1
2
3
4
5
6
a
THF
Toluene
DMF
6
10
6
12
6
93
92
94
93
96
92
17:83
11:89
28:72
16:84
25:75
20:80
6:94
2f
CHO
NBn2
n-Hexane
CH3CN
CH2Cl2
TBDMSO
syn-3g + anti-3g 78
20:80
2g
8
a
The absolute configurations of syn-3a were determined by single-
In all cases, reagent 4 (2.0 equiv) was added to a mixture of 2a
(1.0 equiv) and TBAT (0.05 equiv) at 0 °C.
crystal X-ray analysis; the others were assigned by analogy.
b
b
Yield of isolated analytically pure material.
Diastereomeric ratios (syn/anti) were determined by 19F NMR
Isolated yield.
c
Diastereomeric ratios (syn/anti) were determined by 19F NMR
c
spectroscopy on samples from the crude reaction mixture.
spectroscopy on samples from the crude reaction mixture.

J. Liu et al. / Tetrahedron Letters 49 (2008) 1605–1608
1607
methylation between homochiral a-dibenzylamino alde-
hydes 2 and Me3SiCF2SO2Ph (4).19 The results are summa-
rized in Table 2. In all cases, good to excellent yields
(72–93%) of products 3 were obtained. Good diastereo-
selectivities were generally observed except for the reaction
with 2c (Table 2, entry 3). The absolute configuration of
syn-3a was determined by single-crystal X-ray analysis
(Fig. 1), and the other structures were assigned by analogy.
It is remarkable that, excellent diastereoselectivities were
observed in the cases of 2d and 2f (dr = 6:94 and 6:94,
respectively; see entries 4 and 6). Compound 5 (the enantio-
mer of 2a) was also used to react with reagent 4 under
similar reaction conditions (Scheme 3), and similar good
result was obtained (93% yield, dr = 11:89).
catalyst,20 compound anti-3a was transformed into anti-a-
(difluoromethyl)-b-amino alcohol 8. Intermediate 8 was
then treated with triphosgene and triethylamine in CH2Cl2
leading to difluoromethylated oxazolidinone 9.21
In summary, we have demonstrated a facial synthesis of
anti-a-(difluoromethyl)-b-amino alcohols using a nucleo-
philic difluoromethylation strategy with Me3SiCF2SO2Ph
reagent. Good to excellent chemical yields as well as mod-
est to good diastereoselectivity were achieved in these reac-
tions. We found that the solvent played a crucial role in
controlling the diastereoselectivity of the reaction. Apolar
solvent such as toluene helps to improve the diastereoselec-
tivity of the reaction. The anti-a-(difluoromethyl)-b-amino
alcohol 3a was demonstrated to be a useful synthetic inter-
mediate to synthesize difluoromethylated oxazolidinone 9.
As shown in Scheme 4, upon reductive desulfonylation
by using our previously developed Mg/HOAc/NaOAc sys-
tem15 and debenzylation by hydrogenolysis on Pearlman’s
Acknowledgments
We gratefully thank the National Natural Science Foun-
dation of China (20502029, 20772144), Shanghai Rising-
Star Program (06QA14063), and the Chinese Academy of
Sciences (Hundreds-Talent Program and Knowledge Inno-
vation Program) for financial support.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.01.034.
References and notes
Fig. 1. Single-crystal X-ray structure of syn-3a.
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°
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O
syn-6
(2) TBAF, H2O
Me3SiCF2SO2Ph
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Ph
H
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4
CF2SO2Ph
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anti-6
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OH
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OH
CF2H
Mg, HOAc-NaOAc
Ph
Ph
DMF, r.t.
86%
NBn2
NBn2
anti-3a
7
H2, Pd(OH)2/C
CH3OH, r.t.
95%
O
O
OH
NH
Bn
(CCl3O)2CO
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Asymmetry 1993, 4, 835–838.
10. Prakash, G. K. S.; Mandal, M.; Schweizer, S.; Petasis, N. A.; Olah, G.
A. J. Org. Chem. 2002, 67, 3718–3723.
Ph
CF2H
NEt3, CH2Cl2
r.t.
HF2C
NH2
8
9
71%
Scheme 4.
11. Li, G.; van der Donk, W. A. Org. Lett. 2007, 9, 41–44.

1608
J. Liu et al. / Tetrahedron Letters 49 (2008) 1605–1608
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14. Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Eur. J. Org. Chem.
2005, 2218–2223.
then quenched by the addition of saturated NaCl aqueous solution
(10 mL). After warming to room temperature, the solution mixture
was extracted with diethyl ether (25 mL ꢁ 3), and the combined
organic phase was washed with brine and dried with anhydrous
MgSO4. The solvents were removed under vacuum and the residue
was purified by flash chromatography (silica gel; petroleum ether/
ethylacetate (12:1)) to give product syn-3a (27 mg) and anti-3a
(212 mg) as white solid, total yield: 92%. Characterization data for
25
syn-3a: white solid. Mp 136–138 °C. ½aꢂD 25:68 (c 1.07, CHCl3). 1H
15. Ni, C.; Hu, J. Tetrahedron Lett. 2005, 46, 8273–8277.
16. Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68, 4457–
4463.
NMR: d 7.90 (d, J = 8.1 Hz, 2H), 7.69 (t, J = 7.5 Hz, 1H), 7.54 (t,
J = 7.2 Hz, 2H), 7.11–7.39 (m, 15H), 5.18 (s, 1H), 4.29 (dd, J = 19.5,
7.5 Hz, 1H), 3.84 (d, J = 13.2 Hz, 2H), 3.51–3.61 (m, 1H), 3.36 (d,
J = 12.3 Hz, 2H), 3.12 (dd, J = 15.0, 9.3 Hz, 1H), 2.99 (dd, J = 14.4,
4.2 Hz, 1H). 19F NMR: d ꢀ105.2 (d, J = 236.1 Hz, 1F), ꢀ116.9 (dd,
J = 235.5, 19.5 Hz, 1F). 13C NMR: d 139.1, 137.7, 135.2, 133.5, 130.8,
129.4, 129.3, 129.2, 128.8, 128.5, 127.5, 126.9, 122.1 (dd, J = 298.8,
289.4 Hz), 68.1 (dd, J = 24.9, 21.3 Hz), 57.7, 54.3, 34.7 (d, J =
3.3 Hz). IR (KBr): 3301, 1584, 1448, 1347, 1164, 1092, 992, 755,
586 cmꢀ1. Elemental Anal. Calcd for C30H29F2NO3S: C, 69.08; H,
5.60; N, 2.69. Found: C, 68.87; H, 5.58; N, 2.58; MS (ESI, m/z): 522.2
(M++1). Characterization data for anti-3a: white solid. Mp 42–44 °C.
17. Improved preparation of Me3SiCF2SO2Ph (4): Under N2 atmosphere,
n-BuLi (hexane solution, 1.6 M, 15.8 mL, 25 mmol) was added to the
solution of PhSO2CF2Br (6.0 g, 22 mmol) and chlorotrimethylsilane
(4.5 mL, 33 mmol) in THF (105 mL) at ꢀ78 °C. After the addition of
n-BuLi (over a period of 1.5 h), the reaction mixture was stirred for
additional 2 h at ꢀ78 °C. Then the reaction mixture was carefully
added into a cold aqueous HCl solution (1 M). The mixture was
extracted with Et2O (70 mL ꢁ 3), and the combined organic phase was
washed with brine, water, and then dried over Na2SO4. After the
removal of the solvent under vacuum, 5.73 g of crude product was
obtained (yield 98.1%). The crude product was further fractionally
distilled to afford 5.10 g (yield 87%) of product 4 as a colorless liquid.
1H NMR (CDCl3): d 0.42 (s, 9H), 7.60 (t, J = 7.5 Hz, 2H), 7.73 (t,
J = 7.5 Hz, 1H), 7.94 (d, J = 8.0 Hz, 2 H). 19F NMR (CDCl3): d
ꢀ112.9 (s). The data were consistent with the previous report (Ref. 16).
18. (a) Pilcher, A. S.; Ammon, H. L.; DeShong, P. J. Am. Chem. Soc.
1995, 117, 5166–5167; (b) Pilcher, A. S.; DeShong, P. J. Org. Chem.
1996, 61, 6901–6905; (c) Handy, C. J.; Lam, Y.-F.; DeShong, P. J.
Org. Chem. 2000, 65, 3542–3543.
19. Typical procedure for the stereoselective nucleophilic (phenylsulfon-
yl)difluoromethylation of a-amino aldehydes with reagent 4: Under N2
atmosphere, a solution of Me3SiCF2SO2Ph (4) (265 mg, 1.0 mmol) in
4 mL toluene was added to a solution of amino aldehyde 2a
(0.5 mmol, 165 mg) and TBAT (14 mg, 0.025 mmol) in toluene
(6 mL) at 0 °C. The mixture was then stirred at that temperature
for about 10 h. Subsequently, TBAF (32 mg, 0.1 mmol) was added,
and the reaction mixture was stirred at room temperature for 1 h and
25
½aꢂD 20:50 (c 0.93, CHCl3). 1H NMR: d 8.01 (d, J = 7.2 Hz, 2H), 7.74
(t, J = 7.5 Hz, 1H), 7.60 (t, J = 8.1 Hz, 2H), 6.96–7.26 (m, 15H), 5.03–
5.17 (m, 1H), 3.97 (d, J = 14.1 Hz, 2H), 3.47 (d, J = 14.1 Hz, 2H),
3.39–3.4 (m, 1H), 3.25 (d, J = 5.4 Hz, 1H), 3.05–3.17 (m, 1H), 2.82–
2.92 (m, 1H). 19F NMR: d ꢀ104.7 (d, J = 234.1 Hz, 1F), ꢀ116.9 (dd,
J = 234.1, 24.6 Hz, 1F). 13C NMR: d 139.5, 139.1, 135.7, 132.6, 130.8,
129.7, 129.5, 128.7, 128.2, 128.1, 126.9, 126.1, 121.6 (dd, J = 299.6,
289.2 Hz), 66.1 (dd, J = 25.6, 20.7 Hz), 58.4, 54.1, 32.7. IR (KBr):
3528, 3028, 1496, 1334, 1159, 1097, 743, 698, 587 cmꢀ1. Elemental
Anal. Calcd for C30H29F2NO3S: C, 69.08; H, 5.60; N, 2.69. Found C,
69.30; H, 5.46; N, 2.55. MS (ESI, m/z): 522.2 (M++1).
20. (a) Mori, Yoshikazu; Seki, Masahiko Org. Synth. 2007, 84, 285–294;
(b) Yu, J. Q.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 3232–3233; (c)
Bernotas, Ronald C.; Cube, Rowena V. Synth. Commun. 1990, 20,
1209–1212.
21. Sham, H. L.; Betebenner, D. A.; Wideburg, N. E.; Kempf, D. J.;
Plattner, J. J.; Norbeck, D. W. J. Fluorine Chem. 1995, 73, 221–
224.