Diastereoselective trifluoromethylation of chiral N-(Tolylsulfinyl)imines in the presence of Lewis bases

Article abstract of DOI:10.1246/cl.2005.894

A diastereoselctive trifluoromethylation of chiral N-(tolylsulfinyl)imines with (trifluoromethyl)trimethylsilane in the presence of Lewis bases such as tetrabutylammonium acetate or phenoxide proceeded smoothly to afford the corresponding trifluoromethyla

Full text of DOI:10.1246/cl.2005.894

894
Chemistry Letters Vol.34, No.7 (2005)
Diastereoselective Trifluoromethylation of Chiral N-(Tolylsulfinyl)imines
in the Presence of Lewis Bases
Yoshikazu Kawanoy;yy and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received March 14, 2005; CL-050340)
A diastereoselctive trifluoromethylation of chiral N-(tolyl-
of chiral N-sulfinylimines, easily prepared from commercially
available sulfinamide, was studied. In this communication,
we would like to describe the trifluoromethylation of chiral N-
sulfinylimine with TMSCF3 under mild conditions by using a
Lewis base such as AcONn-Bu4.
sulfinyl)imines with (trifluoromethyl)trimethylsilane in the pres-
ence of Lewis bases such as tetrabutylammonium acetate or
phenoxide proceeded smoothly to afford the corresponding tri-
fluoromethylated adducts in good yields.
In the first place, a trifluoromethylation of (S)-N-benzyli-
dene-p-toluenesulfinamide 1a with TMSCF3 was tried in the
presence of an equimolar amount of AcOLi at 0 ꢁC in DMF
and the desired product was obtained in moderate yield with
low diastereoselectivity (Table 1). The effect of counter cations
of the acetate was also examined in order to improve the yield
and diastereoselectivity of the above reaction. As a result, it
was found that the counter cations played important roles on
yields and stereoselectivities of this reaction, and as the nucleo-
philicity of acetate anion increased, yield and diastereoselectiv-
ity of the adduct became higher (Entries 1–5). Further, various
tetrabutylammonium salts were screened and reaction conditions
were optimized in order to improve the diastereoselectivity
(Entries 6–11). The corresponding trifluoromethylated adduct
was obtained in high yield with good diastereoselectivity when
the reaction was carried out by using an equimolar amount of
tetrabutylammonium acetate (AcON-n-Bu4) at ꢂ40 ꢁC (Entry
8). On the other hand, the trifluoromethylation reactions did
The introduction of a trifluoromethyl group into organic
molecules dramatically influences on the polarity, solubility,
and biological activity of thus formed fluorinated compounds.
Trifluoromethylated amines are important building blocks for
biologically active drugs and agrochemicals, and also useful
precursors for the synthesis of ꢀ-trifluoromethyl ꢀ-amino acid
analogues. In spite of their usefulness in synthetic reaction, only
a few examples have been reported on the syntheses of trifluoro-
methylated amines including chiral ones.1–3 Prakash and co-
workers reported on the nucleophilic addition of the trifluoro-
methyl group to chiral N-sulfinylimines, that is one of the most
straightforward methods for syntheses of chiral trifluoro-
methylated amines.4
In our previous communication, a catalytic trifluoro-
methylation of various carbonyl compounds or imines with
TMSCF3 in the presence of lithium acetate was reported.5 In
order to demonstrate the utilities of these Lewis bases such as
the acetate anion in synthetic reactions, the trifluoromethylation
Table 2. Trifluoromethylation of various aldimines
O
O
Cat. (1.0 equiv.)
S
H
S
Table 1. Screening of catalysts
TMSCF3
N
p-Toly
HN
p-Toly
+
DMF, Temp.
1 h.
O
O
(1.4 equiv.)
R
R
CF3
S
H
S
Cat. (1.0 equiv.)
TMSCF3
p-Toly
p-Toly
N
HN
+
Temp. Yielda
(2.0 equiv.)
(SS,R:SS,S)b
DMF, Temp.
1 h.
Entry
R
Cat.
Ph
Ph
CF3
/ꢁC
/%
1a
2 a
1
2
3
4
5
6
7
8
9
C6H5
(2a) AcON-nBu4 ꢂ40
91
81
90
92
93
94
94
92
85
93
91
75
53
96:4
92:8c,d
95:5
96:4
95:5
95:5
94:6
96:4c
94:6
95:5
96:4
95:5e
92:8e
Entry
Cat.
Temp./ꢁC Yield/%a (SS,R:SS,S)b
4-MeOC6H4 (2b) AcON-nBu4 ꢂ20
4-MeC6H4 (2c) AcON-nBu4 ꢂ40
1
2
AcOLi
0
0
56
68
77
89
92
97
94
93
87
51
6
52:48
46:54
63:37
75:25
92:8
95:5
96:4
96:4c
94:6
95:5
96:4
—
AcONa
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
(2d) AcON-nBu4 ꢂ40
(2e) AcON-nBu4 ꢂ40
(2f) AcON-nBu4 ꢂ40
(2g) AcON-nBu4 ꢂ40
3
AcOK
0
4
AcOCs
0
5
AcON-n-Bu4
AcON-n-Bu4
AcON-n-Bu4
AcON-n-Bu4
PhON-n-Bu4
PhCO2N-n-Bu4
0
6
ꢂ20
ꢂ40
ꢂ40
ꢂ40
ꢂ40
ꢂ40
0
1-Naphthyl (2h) AcON-nBu4 ꢂ40
7
3-Pyridyl
(2i) AcON-nBu4 ꢂ40
(2j) AcON-nBu4 ꢂ40
(2k) AcON-nBu4 ꢂ40
(2l) PhON-nBu4 ꢂ40
8
10 2-Furyl
11 t-Bu
9
11
10
12
12 c-C6H5
d
SuccinN-n-Bu4
13 PhCH2CH2 (2m) PhON-nBu4 ꢂ40
none
0
aIsolated yield. Diastereomeric ratios were determined by 19F NMR
b
aYield was determined by 1H NMR analysis (270 MHz) using
1,1,2,2-tetrachloroethane as an internal standard. bDiastereomeric
ratios were determined by 19F NMR analysis. c1.4 equiv. of
analysis. Diastereomeric ratios were determined by H NMR analy-
sis. d2.0 equiv. of TMSCF3 were used. eThe combined solution of
imine and TMSCF3 in DMF was added slowly to the DMF solution
of PhON-nBu4.
c
1
d
TMSCF3 were used. Tetrabutylammonium succinimide.
Copyright ꢀ 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.7 (2005)
895
This study was supported in part by the Grant of the 21st
Century COE Program from Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan. The authors
wish to thank Mr. Masahiko Bando (Otsuka Pharmaceutical
Co., Ltd.) for his support in X-ray crystallographic analysis.
References and Notes
1
For a review on trifluoromethylation, see: a) R. P. Singh and
J. M. Shreeve, Tetrahedron, 56, 7613 (2000). b) G. K. S.
Prakash and M. Mandal, J. Fluorine Chem., 112, 123 (2001).
c) J.-A. Ma and D. Cahard, Chem. Rev., 104, 6119 (2004).
a) N. R. Patel, R. L. Kirchmeier, and J. M. Shreeve, Inorg.
Chem., 32, 4802 (1993). b) C. P. Felix, N. Khatimi, and
A. J. Laurent, Tetrahedron Lett., 35, 3303 (1994). c) J. C.
Blazejewski, E. Anselmi, and M. P. Wilmshurst, Tetrahedron
Lett., 40, 5475 (1999). d) V. A. Petrov, Tetrahedron Lett., 41,
6959 (2000). e) G. K. S. Prakash, M. Mandal, S. Schweizer,
N. A. Petasis, and G. A. Olah, Org. Lett., 2, 3173 (2000). f)
G. K. S. Prakash, M. Mandal, and G. A. Olah, Synlett, 2001, 77.
a) W. H. Prikle and J. R. Hanske, J. Org. Chem., 42, 2436
(1977). b) W. H. Prikle and J. R. Hanske, J. Org. Chem., 46,
3239 (1981). c) Y. Wang and H. S. Mosher, Tetrahedron Lett.,
32, 987 (1991). d) V. A. Soloshonok and T. Ono, J. Org. Chem.,
62, 3030 (1997). e) D. W. Nelson, J. Owens, and D. Hiraldo,
J. Org. Chem., 66, 2572 (2001).
Figure 1. An ORTEP representation of the structure of 2a.
2
O
S
NH2
CF3
HN
p-Toly
NH
2 HCl
1N HCl
MeOH
HO
O
O
*
CF3
2j (>99 %de)
CF3
O
1 step
rt
92% 3 (>99 %ee)
4
3
4
Scheme 1. Synthesis of 3,3,3-Trifluoroalanine.
not proceed effectively when the reactions were tried by using
TMSCF3 in the presence of a catalytic amount of a Lewis base.
The reason for these results is not made clear yet.
a) G. K. S. Prakash, M. Mandal, and G. A. Olah, Angew. Chem.,
Int. Ed., 40, 589 (2001). b) G. K. S. Prakash, M. Mandal, and
G. A. Olah, Org. Lett., 3, 2847 (2001) c) G. K. S. Prakash
and M. Mandal, J. Am. Chem. Soc., 124, 6538 (2002).
a) T. Mukaiyama, Y. Kawano, and H. Fujisawa, Chem. Lett.,
34, 88 (2005). b) Y. Kawano, H. Fujisawa, and T. Mukaiyama,
Chem. Lett., 34, 422 (2005).
Next, the reaction of various chiral N-sulfinylimines with
TMSCF3 was tried by using an equimolar amount of AcON-n-
Bu4 in DMF (Table 2). Aromatic aldimines having electron-
donating or -withdrawing groups reacted smoothly to afford
the trifluoromethylated adducts in high yields with good diaster-
eosectivities (Entries 1–10). Aliphatic aldimine having no ꢀ-
proton adjacent to the imino group reacted smoothly to afford
the desired adduct in high yield whereas those having ꢀ-protons
gave the adducts in low yields because the abstraction of an
ꢀ-proton took place competitively (Entry 11). However, when
the reactions were carried out in the coexistence of an equimolar
amount of PhON-n-Bu4, the corresponding trifluoromethylated
adducts were obtained in moderate yields with good diastereo-
sectivities (Entries 12 and 13).
These trifluoromethylated adducts were easily purified by
recrystallization of the crude mixture from hexane–AcOEt
and, optically pure major diastereomers were obtained (Scheme
1).6 The absolute configuration of newly formed stereogenic
carbon was determined by X-ray analysis of compound 2a7
and the configurations of 2b and 2m were assigned by compar-
ing 19F NMR chemical shifts of 2a with that of 2b and 2m
(Figure 1).8
Thus, obtained amines were known as useful precursors for
the synthesis of ꢀ-trifluoromethyl ꢀ-amino acids. Since Demir
et al. reported that 2,2,2-trifluoro-1-(furan-2-yl)ethylamine 3
was converted into 3,3,3-trifluoroalanine 4 by oxidative cleav-
age of the furan ring (Scheme 1),9 the synthesis of 3 implies a
formal synthesis of 3,3,3-trifluoroalanine.10
It is noted that AcON-n-Bu4 behaved as an effective Lewis
base catalyst in trifluoromethylation of chiral N-sulfinylimines.
This method is quite practical since the reaction proceeded by
using mild and readily available Lewis base catalysts such as
AcON-n-Bu4 and PhON-n-Bu4, and the adducts can be purified
easily by crystallization because the catalyst is removed just
by treating with water. Further study on this reaction is now in
progress.
5
6
Recrystallization of compound 2a.
O
O
S
S
p-Toly
p-Toly
Recryst.
HN
Ph
2a (>99% de)
HN
Hexane - AcOEt
CF3
Ph
H
2a (92% de)
82 %
7
Crystal data: C15H14NOF3S (FW ¼ 313:34), monoclinic, P21,
ꢀ ꢀ ꢀ
a ¼ 8:621ð1Þ A, b ¼ 8:315ð1Þ A, c ¼ 11:0901ð8Þ A, ꢁ ¼
107:489ð6Þ , V ¼ 758:2ð1Þ A , Z ¼ 2:0, Dcalcd ¼ 1:372 g cmꢂ3
,
ꢁ
ꢀ 3
T ¼ 295 K. X-ray intensities were measured on a Rigaku
AFC-5S diffractometer with graphite-monochromated Mo Kꢀ
radiation. The final R factors was 0.052 (Rw ¼ 0:101 for all
data) for 1519 reflections with I > 2ꢂðIÞ.
8
9
Structure assignment of diastereomer was based on the
19F NMR chemical shift, which resonates at a higher field in
the (Ss,R)-isomer than in the (Ss,S)-isomer.
A. S. Demir, O. Sesenoglu, and Z. Gercek-Arkin, Tetrahedron:
Asymmetry, 12, 2309 (2001).
10 Compound 3: Determined by HPLC (CHIRALCEL OD-H,
hexane/iPrOH = 50:1, flow rate = 1.0 ml/min): tR ¼ 11:3
21
min. ½ꢀꢃD ¼ ꢂ6:7 (c 1.01, MeOH).
11 Typical experimental procedure is as follows (Table 2,
Entry 1); to a stirred solution of AcON-n-Bu4 (60.3 mg,
0.2 mmol) in DMF (1.0 mL) were added successively a solution
of chiral N-benzylidene-p-toluenesulfinamide (48.7 mg, 0.2
mmol) in DMF (0.2 mL) and TMSCF3 (43.7 mL, 0.28 mmol,
95% content) at ꢂ40 ꢁC. The mixture was stirred for 1 h at
the same temperature and quenched with saturated aqueous
NH4Cl. The mixture was extracted with AcOEt and organic
layer was washed with brine and dried over anhydrous Na2SO4.
After filtration and evaporation of the solvent, the resulted
residue was purified by preparative TLC to give the desired
product (57.1 mg, 91%) as a colorless prisms.
Published on the web (Advance View) May 28, 2005; DOI 10.1246/cl.2005.894