Generation of 1-(trifluoromethyl)-1,2-dihydroisoquinolines via a silver(I)-catalyzed reaction of 2-alkynylaryl aldimine with trimethyl(trifluoromethyl)silane

Article abstract of DOI:10.1016/j.tetlet.2013.12.064

A silver(I)-catalyzed reaction of 2-alkynylaryl aldimine with trimethyl(trifluoromethyl)silane is reported. This reaction proceeds efficiently under extremely mild conditions to generate 1-(trifluoromethyl)-1,2-dihydroisoquinolines in good yields. A three-component reaction of 2-alkynylbenzaldehyde, amine, with trimethyl(trifluoromethyl)silane is presented as well.

Full text of DOI:10.1016/j.tetlet.2013.12.064

Tetrahedron Letters 55 (2014) 962–964
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Tetrahedron Letters
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Generation of 1-(trifluoromethyl)-1,2-dihydroisoquinolines
via a silver(I)-catalyzed reaction of 2-alkynylaryl aldimine
with trimethyl(trifluoromethyl)silane
b,c,
Xianbo Wang a, Guanyinsheng Qiu b, Ling Zhang a, , Jie Wu
⇑
⇑
a Department of Chemistry, Nanchang University, 999 Xuefu Road, Nanchang, Jiangxi 330031, China
b Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
c State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A silver(I)-catalyzed reaction of 2-alkynylaryl aldimine with trimethyl(trifluoromethyl)silane is reported.
This reaction proceeds efficiently under extremely mild conditions to generate 1-(trifluoromethyl)-1,2-
dihydroisoquinolines in good yields. A three-component reaction of 2-alkynylbenzaldehyde, amine, with
trimethyl(trifluoromethyl)silane is presented as well.
Received 16 November 2013
Revised 6 December 2013
Accepted 17 December 2013
Available online 21 December 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
2-Alkynylaryl aldimine
Amine
Silver hexafluorostiboranuide
1-(Trifluoromethyl)-1,2-
dihydroisoquinoline
Trimethyl(trifluoromethyl)silane
Recently, the fluorine chemistry has attracted much attention
due to the importance of fluorinated small molecules in medicinal
chemistry, pharmaceuticals, and agricultural chemicals.1 For
example, more than 20% of commercial drugs contain fluorine.
Currently, organic and medicinal chemists are focusing on the
introduction of fluorine into drugs or leading compounds, with
an expectation to significantly improve their medicinal properties.2
As a part of program aiming at the incorporation of fluorine into
natural product-like compounds with privileged scaffolds, we are
interested in the synthesis of fluorinated isoquinolines and its
related library.
The skeleton of isoquinoline core could be found in many
natural products and pharmaceuticals.3–5 The application of the
fluorinated isoquinolines has been discovered as well. For instance,
some biologically active compounds (including antiproliferative
drug, myosin inhibitor, and agent for reducing intraocular pres-
sure) have been designed and synthesized by using fluorinated iso-
quinolines as building blocks.6 Thus, the development of efficient
route to fluorinated isoquinolines is highly important.7 Recently,
Liu and co-workers described the synthesis of 4-fluoroisoquino-
lines A via a silver-catalyzed intramolecular oxidative aminofluori-
nation of alkynes using NSFI as the fluorine source (Fig. 1).7a We
also discovered that, in the presence of p-methoxybenzenesulfonyl
chloride, 1-((trifluoromethyl)thio)isoquinolines B could be con-
structed through a silver(I)-catalyzed reaction of 2-alkynylbenzal-
doxime with silver trifluoromethyl)thiolate.7b Prompted by these
results and due to the importance of the trifluoromethyl group,8
we conceived that the trifluoromethyl group could be introduced
in the isoquinoline scaffold as well (compound C). We anticipated
that the library of trifluoromethyl substituted isoquinolines would
be beneficial for the subsequent biological evaluations.
Initially, we expected that 1-trifluoromethylisoquinolines could
be generated via a silver(I)-catalyzed reaction of 2-alkynylbenzal-
doxime with trifluoromethyl anion as well under the standard con-
ditions we developed.7b However, the reaction failed after detailed
investigations. Therefore, a model reaction of 2-alkynylbenzaldi-
mine 1a with trimethyl(trifluoromethyl)silane 2 was selected for
reaction development. Since 2-alkynylbenzaldimine 1a would
⇑
Corresponding authors. Tel.: +86 21 6510 2412; fax: +86 21 6564 1740.
E-mail address: jie_wu@fudan.edu.cn (J. Wu).
Figure 1. Fluorinated isoquinolines.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.064

X. Wang et al. / Tetrahedron Letters 55 (2014) 962–964
963
Table 1
Initial studies for the reaction of 2-alkynylbenzaldimine 1a with trimethyl(trifluoro-
methyl)silane 2
Entry
[M]
Solvent
Temp
Additive
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Pd(OAc)2
Pd(TFA)2
AgOTf
CuI
CuSO4
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
Toluene
DMSO
DMA
THF
Dioxane
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
80
80
80
80
80
80
80
80
80
0
25
40
60
100
25
25
25
25
25
25
25
25
25
25
25
25
25
25
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
7
10
15
Trace
nr
31
19
28
nr
25
47
40
23
29
32
19
14
Trace
26
Trace
38
Trace
18
53
88
nd
nd
73
AgSbF6
AgBF4
AgTFA
Bi(OTf)3
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
—
—
—
—
Scheme 1. Synthesis of 1-(trifluoromethyl)-1,2-dihydroisoquinolines
3 via a
—
silver(I)-catalyzed reaction of 2-alkynylbenzaldimine 1 with trimethyl(trifluoro-
methyl)silane 2.a(Isolated yield based on 2-alkynylbenzaldimine 1.)
Cs2CO3
DABCO
NaOAc
HOAc
CF3CO2H
TsOH
PhCO2H
a
Isolated yield based 2-alkynylbenzaldimine 1a.
undergo 6-endo cyclization in the presence of Lewis acid,9 this
would facilitate subsequent nucleophilic attack. Thus, different
Lewis acids were evaluated in acetonitrile at 80 °C (Table 1). At
the outset, the corresponding product 3a was obtained and iso-
lated in 7% yield when palladium acetate was used as the catalyst
(Table 1, entry 1). A similar outcome was observed when Pd(TFA)2
was utilized (Table 1, entry 2). A higher yield was obtained when
silver(I) triflate was employed in the transformation (Table 1, entry
3). However, the reaction failed when copper salts were used
(Table 1, entries 4 and 5). Interestingly, the desired 1-(trifluoro-
Scheme 2. Silver(I)-catalyzed reaction of 2-alkynylbenzaldimine
1 with tri-
methyl(trifluoromethyl)silane 2.a(Isolated yield based on 2-alkynylbenzaldimine 1.)
methyl)-1,2-dihydroisoquinoline 3a was produced in 31% yield
when the reaction was catalyzed by silver hexafluorostiboranuide
(Table 1, entry 6). The result could not be improved when other
silver salts were used as replacement (Table 1, entries 7 and 8).
Further exploration of temperature revealed that the reaction
worked efficiently at 25 °C, which afforded product 3a in 47% yield
Scheme 3. A silver(I)-catalyzed three-component reaction of 2-alkynylbenzalde-
Figure 2. X-ray ORTEP illustration of compound 3a (30% probability ellipsoids).
hyde, amine, with trimethyl(trifluoromethyl)silane.

964
X. Wang et al. / Tetrahedron Letters 55 (2014) 962–964
(Table 1, entries 10–14). The survey of solvents discovered that
acetonitrile was the best choice, and inferior yields were obtained
when the reaction was performed in other solvents (Table 1,
entries 15–21). With these results in hand, we considered to im-
prove the nucleophilicity of trimethyl(trifluoromethyl)silane 2.
Therefore, different bases were screened (Table 1, entries 22–24).
The desired product 3a was obtained in 53% yield when NaOAc
was added in the reaction. Further exploration revealed that the
reaction proceeded efficiently in the presence of 1.1 equiv of HOAc,
giving rise to the corresponding product 3a in 88% yield. We
reasoned that the presence of acetic acid might act a Brønsted acid
for the activation of the imine group. In the meantime, the struc-
ture of 1-(trifluoromethyl)-1,2-dihydroisoquinoline 3a was
illustrated by X-ray analysis (Fig. 2).
Under the optimized conditions (5 mol % of AgSbF6, 1.1 equiv of
HOAc, MeCN, 25 °C), we then explored the generality of this trans-
formation. The results are presented in Scheme 1. Various substi-
tuted 2-alkynylbenzaldimines 1 with trimethyl(trifluoromethyl)
silane 2 were evaluated. It was found that reactions of 2-alkynyl-
benzaldimines 1 with electron-donating groups attached on the
aromatic backbone afforded the expected products in excellent
yields. However, moderate yields of 1-(trifluoromethyl)-1,2-dihy-
droisoquinolines 3 were obtained when 2-alkynylbenzaldimines
1 with electron-withdrawing groups attached on the aromatic ring
were employed. For examples, the methoxy-substituted 1-(trifluo-
romethyl)-1,2-dihydroisoquinoline 3e was isolated in 91% yield,
while the chloro-substituted product 3g was furnished in 46%
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/j.tet-
let.2013.12.064. These data include MOL files and InChiKeys of
the most important compounds described in this article.
References and notes
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Moreover, it was found that the expected 1-(trifluoromethyl)-
1,2-dihydroisoquinolines 3 could be afforded via a silver(I)-cata-
lyzed three-component reaction of 2-alkynylbenzaldehyde, amine,
with trimethyl(trifluoromethyl)silane (Scheme 3). For instance, 2-
alkynylbenzaldehyde reacted with tert-butyl amine and trimethyl
(trifluoromethyl)silane leading to the corresponding product 3a
in 68% yield. When aniline was used as a replacement, the desired
product 3n was generated in 85% yield.
In conclusion, we have described a silver(I)-catalyzed reaction
of 2-alkynylaryl aldimine with trimethyl(trifluoromethyl)silane
for the synthesis of 1-(trifluoromethyl)-1,2-dihydroisoquinolines.
This transformation proceeds efficiently under extremely mild
conditions to generate the corresponding products in good yields.
A three-component reaction of 2-alkynylbenzaldehyde, amine,
with trimethyl(trifluoromethyl)silane is presented as well. The
broad reaction scope is demonstrated and the diversity could be
easily introduced.
Acknowledgment
Financial support from National Natural Science Foundation of
China (Nos. 21032007 and 21172038) is gratefully acknowledged.