Addition of benzyltrimethylsilane to imines triggered by tetrabutylammonium fluoride

Article abstract of DOI:10.1016/j.tetlet.2006.09.062

The addition of benzyltrimethylsilane 2 to imines 1 triggered by TBAF in the presence of 4A molecular sieves gave rise to the corresponding α-benzylated amines 3 in good yields. Moderate to high diastereoselectivity was obtained in the reactions of tert-b

Full text of DOI:10.1016/j.tetlet.2006.09.062

Tetrahedron Letters 47 (2006) 8391–8393
Addition of benzyltrimethylsilane to imines triggered
by tetrabutylammonium fluoride
a,c
b
a
Wan-Xuan Zhang, Chang-Hua Ding, Zhi-Bin Luo,
a,b,
a
*
Xue-Long Hou
and Li-Xin Dai
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
54 Fenglin Lu, Shanghai 200032, China
3
b
Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
c
Faculty of Chemistry and Material Science, Hubei University, Wuhan 430062, PR China
Received 10 July 2006; revised 13 September 2006; accepted 14 September 2006
Available online 9 October 2006
Abstract—The addition of benzyltrimethylsilane 2 to imines 1 triggered by TBAF in the presence of 4A molecular sieves gave rise
to the corresponding a-benzylated amines 3 in good yields. Moderate to high diastereoselectivity was obtained in the reactions of
tert-butanesulfinyl imines with 2.
Ó 2006 Elsevier Ltd. All rights reserved.
Organosilane reagents have found their wide-range uses
R
PhCH SiMe 2
HN
1
2
2
3
in organic synthesis. Sakurai–Hosomi reaction, the
reaction of an allylsilane with a carbonyl compound
under Lewis acid conditions or in the presence of fluo-
Ar1
R
N
ð1Þ
Ph
TBAF, 4A MS
Ar1
1
3
3
ride ions, is among the most popular protocols. The
4
,5
reaction has also been extended to aza-analogies. In
spite of the success of allylation of C@N bond using
allylsilane derivatives under Sakurai–Hosomi reaction
conditions, few examples reported so far the reaction
of imines with benzylsilane 1 in the presence of fluoride
though the reaction of 1 with aldehyde catalyzed by
As it is shown in the reaction of allylsilane with imines,
the presence of a molecular sieve is crucial. No reaction
took place in the absence of it. Screening of the solvents
5
showed that many solvents are suitable (solvent, temper-
ature, yield: THF, reflux, 72%; CH Cl , reflux, 72%;
2
2
hexane, reflux, 62%; toluene, 85 °C, 59%). However,
complex products were given when the reaction was
run in DMF.
6
TBAF was investigated previously.
We have investigated the reaction of allylsilane with imi-
5
nes triggered by fluoride anion. Further studies showed
Under the above condition, several imines were tested
that benzyltrimethylsilane also reacted with imines in
the presence of n-tetrabutylammonium fluoride (TBAF)
and 4A molecular sieves to give the corresponding
benzylated products. Herein, we would like to report
our preliminary results.
(
Table 1). All N-aryl imines derived from arylaldehydes
gave good yields (entries 1–5), while imine 1f with a
benzyl substituent at N-atom failed to give the product.
The electronic property of the substituent on either
phenyl rings has little influence on the yield.
The reaction of imine 1a with benzylsilane 2 in the
presence of 5 mol % of TBAF and 4A MS in THF under
reflux provided benzylated product 3a in 72% yield
Many bioactive molecules, including some medicines,
*
7
contain BnCH –NH subunit with chiral carbon center.
2
One of the easiest ways to prepare compounds contain-
ing such a subunit is the addition of benzyl reagents to
imines. Chiral sulfinyl group as an excellent chiral auxi-
liary and activator of the C@N bond for nucleophilic
addition has widely been used in organic synthesis, since
(
Eq. 1).
*
Corresponding author. Tel.: +86 21 54925144; fax: +86 21
4925100; e-mail: xlhou@mail.sioc.ac.cn
5
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.062

8392
W.-X. Zhang et al. / Tetrahedron Letters 47 (2006) 8391–8393
Table 1. Reaction of Imines 1 with benzylsilane 2 in the presence of
TBAF
Table 2. The reaction of sulfinylimines 4 with 2 in the presence of
TBAF
a
a
b
1
2
b
e
Entry
Imine 1
Ar
R
Yield (%)
Entry Imine 4
R
R
Yield (%) de (%)
c
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Ph
p-MeOC
Ph
p-ClC H
6
Ph
Ph
Ph
p-MeOC
Ph
p-ClC
3a, 72
3b, 70
3c, 65
3d, 71
3e, 74
0
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
i-Propyl
i-Propyl
n-Propyl
s-Butyl
p-Tolyl 5a, 68
t-Butyl 5b, 63
t-Butyl 5c, 38
t-Butyl 5d, 49
t-Butyl 5e, 40
t-Butyl 5f, 31
64
85
83
63
65
86
59
77
72
86
69
c
c
c
c
c
d
d
d
6
4
6
H
4
4
6
H
4
6
H
4
2 2
PhCH CH
p-MeOC
H
Bn
t-Butyl
a
4g
4h
4i
PhCH@CH t-Butyl 5g, 68
Ph
4-F–C H
6 4
4-MeOC
2-Furyl
The reaction proceeded on a 0.5 mmol scale in 2 mL THF at reflux,
molar ratio of 1:2:TBAF = 1:1.5:0.05, and 200 mg of 4A MS was
added.
t-Butyl 5i, 85
t-Butyl 5i, 73
t-Butyl 5j, 66
t-Butyl 5k, 67
d
d
b
10
1
4j
4k
6 4
H
Isolated yield based on imine 1.
1
a
The reaction was run on a 0.25 mmol scale, molar ratio of
4:2:TBAF = 1:2:0.3, and 200 mg of 4A MS was added.
Isolated yield based on imine 4.
Davis and Ellman pioneered using chiral p-toluenesulfin-
yl and tert-butanesulfinyl groups in imine chemistry.
8
b
c
Thus, sulfinylimines 4 were tested in this fluoride-trig-
gered benzylation reaction (Eq. 2). However, sulfinyl-
imine 4a derived from racemic p-tolylsulfinamide
reacted with benzylsilane 2 in THF at 40 °C in the pres-
ence of 5 mol % TBAF gave no desired product. When
the amount of TBAF increased to 15 mol %, 20% of
product 5a as well as complex by-products was deliv-
ered, which may have produced through competitive
a-deprotonation followed by unknown transformations
Run at ꢀ60 °C in THF.
d
e
Run at ꢀ45 °C in CH
3
CN.
1
Determined by 300 MHz H NMR.
In conclusion, benzylation of imines using benzyltri-
methylsilane in the presence of TBAF has been devel-
oped. Good de was provided when sulfinimines were
used. Further studies on fluoride-initiated reactions as
well as the applications of benzylsilane in organic
synthesis are in progress.
1
1
9
under basic condition. Side-reactions were greatly
depressed and the yield of product 5a increased to
6
3
8% if the reaction run in THF at ꢀ40 °C and
1
0 mol % of TBAF was used. The H NMR spectrum
of the product showed two peaks at d 2.37 (s) and
2
.39 (s) with a ratio of 82:18, which corresponds to
Acknowledgments
6
4% de. Higher de value was provided if imine derived
from t-butylsulfinamide was used. A de value of 85%
was given when imine 4b reacted with 2 in THF at
This work was financially supported by National
Natural Science Foundation of China and Chinese
Academy of Sciences.
ꢀ
60 °C. Under this optimized condition, several sulfin-
imines were used and the results are compiled in Table 2.
References and notes
O
S
O
S
PhCH SiMe3
2
N
R2
2
HN
R1
R2
Ph
1. For some reviews Hosomi, A.; Miura, K. Bull. Chem. Soc.
Jpn. 2004, 77, 835.
2. Hosomi, A.; Shirahata, A.; Sakurai, H. Tetrahedron Lett.
ð2Þ
TBAF, 4A MS
R1
H
1
978, 19, 3043.
4
5
3
. For some examples: (a) Wadamoto, M.; Yamamoto, H.
J. Am. Chem. Soc. 2005, 127, 14556; (b) Malkov, A. V.;
Dufkova, L.; Farrugia, L.; Kocovsky, P. Angew. Chem.,
Int. Ed. 2003, 42, 3674.
4. For some of examples: (a) Kira, M.; Hino, T.; Sakurai, H.
Chem. Lett. 1991, 277; (b) Pilcher, A. S.; DeShong, P. J.
Org. Chem. 1996, 61, 6901; (c) Fernandes, R. A.;
Yamamoto, Y. J. Org. Chem. 2004, 69, 735; (d) Koba-
yashi, S.; Ogawa, C.; Konishi, H.; Sugiura, M. J. Am.
Chem. Soc. 2003, 125, 3674; (e) Yamasaki, S.; Fujii, K.;
Wada, R.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2002, 124, 6536.
It can be seen from Table 2 that good de was given for
all reactions, 86% de being the best (Table 2, entries 6
1
0
and 10). Imines derived from arylaldehydes gave the
products in higher yields than that derived from ali-
phatic aldehydes (Table 2, entries 3–6 vs entries 7–11),
even for imine 4k derived from heteroarylaldehyde
(
Table 2, entry 11). It is interesting to note that CH CN
3
is better than THF when imines derived from arylalde-
hydes were substrates (Table 2, entries 7–11). It is the
same as for the reaction of imines 1 that the electronic
property of the substituent on phenyl ring has no effect
on the yield (Table 2, entry 8 vs entries 9 and 10).
5. Wang, D. K.; Zhou, Y. G.; Tang, Y.; Hou, X. L.; Dai, L.
X. J. Org. Chem. 1999, 64, 4233.
. Bennetau, B.; Dunogues, J. Tetrahedron Lett. 1983, 4217.
. Chiral Drugs; Challener, C. A., Ed.; Wiley: New York,
6
7
2
001.
It appears that this benzylation reaction was also initi-
ated by fluoride. However, the yields of the reaction
using benzylsilane 2 were lower than that using allyl-
silane, which may reflect the difference in reactivity
between benzylsilane and allylsilane.
5
8. For a review on reaction of tert-butanesulfinyl imines: (a)
Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res.
2
002, 35, 984; For a review on reaction of p-toluenesulfinyl
imines: (b) Zhou, P.; Chen, B.-C.; Davis, F. A. Tetra-
hedron 2004, 60, 8003.

W.-X. Zhang et al. / Tetrahedron Letters 47 (2006) 8391–8393
8393
9
. Layer, R. W. Chem. Rev. 1963, 63, 489.
was purified by chromatography to give 5j in 66% yield
with 86% de. The major isomer of H NMR (300 MHz,
1
1
0. A product with 74% de was obtained when optical 4h
reacted with 2 at ꢀ20 °C.
CDCl ): d 1.13 (s, 0.63H, minor), 1.15 (s, 8.37H, major),
3
1
1. Typical procedure for benzylation of imine 4: The mixture
of imine 4j (60 mg, 0.25 mmol), benzyltrimethylsilane 2
2.98 (m, 1H), 3.28 (m, 1H), 3.49 (br, 1H), 3.78 (s, 2.79H,
major), 3.80 (s, 0.21H, minor), 4.54 (m, 1H), 6.82 (d,
1
3
(
82 mg, 0.5 mmol), and THF (1.5 mL) was added drop-
wise to the solution of 4A MS (200 mg), TBAF (75 lL of
M solution in THF), and CH
J = 9.0 Hz, 2H). 7.00 (m, 2H), 7.15–7.20 (m, 5H).
C
NMR (300 MHz, CDCl ): d 159.1, 137.6, 133.7, 129.6,
3
ꢀ
1
1
3
CN (1.5 mL) at ꢀ45 °C
128.4, 128.2, 126.4, 60.2, 55.8, 55.2, 43.5, 22.5. IR (cm ):
3142 (m, NH), 1036 (s, S@O). MS m/z (EI): 332 (M+1).
Anal. Cacld for C H NO S: C, 68.85; H, 7.60; N, 4.23.
while stirring. After the reaction was completed (moni-
tored by TLC), the reaction mixture was filtered on a short
silica gel column. The solvent was removed and the residue
1
9
25
2
Found: C, 68.76; H, 7.52; N, 4.22.