Facile assembly of 1-[(trifluoromethyl)thio]isoquinolines through reaction of 2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolate

Article abstract of DOI:10.1002/ejoc.201301401

1-[(Trifluoromethyl)thio]isoquinolines can be assembled through silver(I)-catalyzed reaction of 2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolate in the presence of p-methoxybenzenesulfonyl chloride. The (trifluoromethyl)thio moiety (SCF₃

Full text of DOI:10.1002/ejoc.201301401

FULL PAPER
DOI: 10.1002/ejoc.201301401
Facile Assembly of 1-[(Trifluoromethyl)thio]isoquinolines through Reaction of
2-Alkynylbenzaldoxime with Silver (Trifluoromethyl)thiolate
Qing Xiao,[a] Jie Sheng,[b] Qiuping Ding,*[a] and Jie Wu*[b,c]
Keywords: Synthetic methods / Nitrogen heterocycles / Alkynes / Silver / Fluorine / Sulfur
1-[(Trifluoromethyl)thio]isoquinolines can be assembled
methoxybenzenesulfonyl chloride. The (trifluoromethyl)thio
through silver(I)-catalyzed reaction of 2-alkynylbenzaldox- moiety (SCF3) could be easily introduced into the scaffold of
ime with silver (trifluoromethyl)thiolate in the presence of p-
isoquinoline under mild conditions.
Introduction
The importance of isoquinolines in synthetic organic
chemistry and pharmaceuticals is well-recognized,[1,2] and
this privileged scaffold is present in a broad range of natural
products and drug molecules. Compounds with the core of
isoquinoline often show remarkable biological activities. In
the meantime, due to the increasing interest in fluorine
chemistry,[3] the construction of fluorinated heterocycles
has attracted growing attention recently.[4] Among the N-
heterocycles, fluorinated isoquinolines have served as build-
ing blocks for the design and synthesis of biologically active
compounds, including antiproliferative drugs, myosin inhib-
itors, and agents for reducing intraocular pressure.[5] There-
fore, continuous efforts have focused on the synthesis of
fluorinated isoquinolines.[6] For example, Liu and co-
workers reported the generation of 4-fluoroisoquinolines
through a silver-catalyzed intramolecular oxidative amino-
fluorination of alkynes by using N-fluorobenzenesulfon-
imide (NSFI) as the fluorine source (Figure 1).[6a] From the
viewpoint of studies of chemical genetics using natural
product-like compounds, a biological evaluation of the use
of diverse fluorinated isoquinolines would be beneficial.
Figure 1. Fluorinated isoquinolines.
In the past few years, the introduction of a (trifluoro-
methyl)thio moiety (SCF3) into small molecules has been a
hot field in fluorine chemistry.[7,8] The attractive intrinsic
properties of this group (such as its high lipophilicity) has
prompted its rapid development. For instance, Billard re-
ported the electrophilic trifluoromethanesulfanylation of
organometallic species with trifluoromethanesulfanamides
for C–SCF3 bond formation.[7b] Aryl trifluoromethyl thio-
ethers could be synthesized through trifluoromethylthiol-
ation of aryl boronic acids with TMSCF3 and elemental
sulfur or by using AgSCF3 in coupling reactions.[7c,7f] Be-
cause (trifluoromethyl)thio-substituted compounds are usu-
ally used as candidates in pharmaceutical and agrochemical
applications, we became interested in the introduction of
the (trifluoromethyl)thio moiety into the scaffold of iso-
quinoline (Figure 1).
Recently, the reactivity of 2-alkynylbenzaldoxime has
been extensively explored, and these studies have provided
a facile route to isoquinoline derivatives.[9] For example, 1-
aryloxyisoquinolines could be generated through silver-cat-
alyzed reaction of 2-alkynylbenzaldoxime with phenols.[9d]
During the transformation, a phosphonium salt or sulfonyl
chloride was essential for the activation of the N-oxide
formed in situ. In light of these results, we hypothesized
[a] Key Laboratory of Functional Small Organic Molecules,
Ministry of Education and College of Chemistry & Chemical
Engineering, Jiangxi Normal University,
Nanchang, Jiangxi 330022, China
E-mail: dqpjxnu@gmail.com
[b] Department of Chemistry, Fudan University,
220 Handane Road, Shanghai 200433, China
E-mail: jie_wu@fudan.edu.cn
that a silver-catalyzed reaction of 2-alkynylbenzaldoxime
http://www.chemistry.fudan.edu.cn/teacher.asp?tno=wujie
[c] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
[10]
with AgSCF3
might allow the formation of (trifluoro-
methyl)thio-substituted isoquinolines under suitable condi-
tions. The proposed synthetic route is presented in
Scheme 1.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301401.
Eur. J. Org. Chem. 2014, 217–221
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
217

Q. Xiao, J. Sheng, Q. Ding, J. Wu
FULL PAPER
was obtained in 16% yield when benzenesulfonyl chloride
was added in the reaction (Table 1, entry 5). Other sulfonyl
chlorides were then screened (Table 1, entries 6–9), and it
was found that the addition of p-MeOC6H4SO2Cl gave the
best result (27% yield; Table 1, entry 7). Further screening
of solvents revealed that the reaction proceeded efficiently
in N,N-dimethylacetamide (DMA), leading to the expected
product 3a in 55% yield (Table 1, entry 17). The reaction
was subsequently examined in the presence of various bases
(Table 1, entries 18–26). Gratifyingly, the desired product 3a
was generated in 87% yield when the reaction was per-
formed in the presence of K3PO4 (Table 1, entry 21).
Scheme 1. The proposed route to (trifluoromethyl)thio-substituted
isoquinolines.
The generality of this silver(I)-catalyzed reaction of 2-
alkynylbenzaldoxime with silver (trifluoromethyl)thiolate in
the presence of p-methoxybenzenesulfonyl chloride was
then examined under the optimized conditions. The results
are shown in Table 2. A range of 1-[(trifluoromethyl)thio]-
isoquinolines could be produced as expected. The nature of
the substituents on the triple bond of the 2-alkynylbenz-
aldoximes affected the final outcome. 2-Alkynylbenzaldox-
imes with a range of aryl groups attached on the triple bond
reacted with silver (trifluoromethyl)thiolate smoothly, giv-
ing the corresponding products in good yields. However,
the yields were low when the aryl group attached on the
triple bond was replaced by an alkyl group. For instance,
Results and Discussion
The initial studies were carried out for the reaction of 2-
alkynylbenzaldoxime 1a with AgSCF3 (2) catalyzed by
10 mol-% silver triflate in the presence of iPr2NEt (DIPEA)
in 1,4-dioxane (Table 1). Initially, a range of activators in-
cluding acid chloride, sulfonyl chloride, and phosphonyl
chloride were evaluated. However, no reaction took place
when acetic acid chloride was used (Table 1, entry 1). The
result was not improved when PhCOCl, tBuCOCl, or
Ph2POCl were employed (Table 1, entries 2–4). To our de-
light, the desired 1-[(trifluoromethyl)thio]isoquinoline 3a
cyclopropyl-substituted
1-[(trifluoromethyl)thio]isoquin-
Table 1. Initial optimization of the reaction of 2-alkynylbenzaldox-
ime 1a with AgSCF3 (2).[a]
Table 2. Synthesis of 1-[(trifluoromethyl)thio]isoquinolines through
silver-catalyzed reaction of 2-alkynylbenzaldoxime 1 with AgSCF3
(2).[a,b]
Entry RCl
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
CH3COCl
DIPEA 1,4-dioxane
DIPEA 1,4-dioxane
DIPEA 1,4-dioxane
DIPEA 1,4-dioxane
DIPEA 1,4-dioxane
DIPEA 1,4-dioxane
n.r.
5
PhCOCl
tBuCOCl
Ph2POCl
PhSO2Cl
TsCl
n.r.
n.r.
16
20
27
5
p-MeOC6H4SO2Cl DIPEA 1,4-dioxane
p-NO2C6H4SO2Cl
MsCl
DIPEA 1,4-dioxane
DIPEA 1,4-dioxane
9
10
45
44
38
35
44
26
50
55
56
44
44
87
46
50
42
39
n.r.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
p-MeOC6H4SO2Cl DIPEA CH2Cl2
p-MeOC6H4SO2Cl DIPEA DCE
p-MeOC6H4SO2Cl DIPEA THF
p-MeOC6H4SO2Cl DIPEA toluene
p-MeOC6H4SO2Cl DIPEA MeCN
p-MeOC6H4SO2Cl DIPEA DMSO
p-MeOC6H4SO2Cl DIPEA DMF
p-MeOC6H4SO2Cl DIPEA DMA
p-MeOC6H4SO2Cl Et3N
p-MeOC6H4SO2Cl Cs2CO3 DMA
p-MeOC6H4SO2Cl DBU DMA
p-MeOC6H4SO2Cl K3PO4 DMA
p-MeOC6H4SO2Cl NaOAc DMA
p-MeOC6H4SO2Cl Na2CO3 DMA
p-MeOC6H4SO2Cl NaHCO3 DMA
p-MeOC6H4SO2Cl pyridine DMA
p-MeOC6H4SO2Cl tBuOK DMA
DMA
[a] Reaction conditions: 2-alkynylbenzaldoxime 1 (0.2 mmol),
AgOTf (10 mol-%), AgSCF3 2 (0.3 mmol), K3PO4 (0.9 mmol), p-
MeOC6H4SO2Cl (0.3 mmol), DMA (2.0 mL), 25 °C. [b] Isolated
yield based on 1.
[a] Reaction conditions: 1a (0.2 mmol), AgOTf (10 mol-%),
AgSCF3 2 (0.3 mmol), base (0.9 mmol), RCl (0.3 mmol), solvent
(2.0 mL), 25 °C. [b] Isolated yield based on 1a; n.r.: no reaction.
218
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Eur. J. Org. Chem. 2014, 217–221

Facile Assembly of 1-[(Trifluoromethyl)thio]isoquinolines
13C NMR (100 MHz, CDCl3): δ = 150.7, 150.3, 139.1, 137.5, 135.3,
129.6, 129.3 (q, J = 307.2 Hz), 127.8, 127.7, 127.4, 126.7, 124.9,
oline 3f was formed in 24% yield, and compound 3g, with
an n-butyl group, was obtained in 23% yield. This might be
due to the reactivity of the alkyl-substituted substrates,
since the reaction did not go to completion and was
stopped at the isoquinoline N-oxide stage. With respect to
substrates with substituents on the aromatic ring of 2-alk-
ynylbenzaldoximes, all reactions worked well under the
standard conditions, leading to the desired products in
good yields. Interestingly, thiophenyl-incorporated sub-
strate 1m was also found to be a good reactant, affording
the corresponding product 3m in 90% yield (Scheme 2).
124.7, 115.7, 21.9 ppm. 19F NMR (378 MHz, CDCl3):
δ =
–39.07 ppm. HRMS (ESI): calcd. for C17H13F3NS+ [M + H+]
320.0715; found 320.0715.
3-(4-Methoxyphenyl)-1-[(trifluoromethyl)thio]isoquinoline
(3c):
1
Yield 60.4 mg (90%). H NMR (400 MHz, CDCl3): δ = 8.10 (m, 3
H), 7.91 (s, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.66 (t, J = 7.2 Hz, 1
H), 7.54 (t, J = 7.6 Hz, 1 H), 6.00 (d, J = 8.8 Hz, 2 H), 3.86 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.5, 150.5, 150.3,
137.6, 131.0, 130.7, 129.3 (q, J = 307.2 Hz), 128.1, 127.7, 127.5,
127.1, 124.9, 115.0, 114.2, 55.4 ppm. 19F NMR (378 MHz, CDCl3):
δ = –39.12 ppm. HRMS (ESI): calcd. for C17H13F3NOS+ [M + H+]
336.0664; found 336.0662.
3-(4-Fluorophenyl)-1-[(trifluoromethyl)thio]isoquinoline (3d): Yield
1
42.0 mg (65%). H NMR (400 MHz, CDCl3): δ = 8.14–8.07 (m, 3
H), 7.91 (s, 1 H), 7.82 (d, J = 8.0 Hz, 1 H), 7.68 (t, J = 7.2 Hz, 1
H), 7.59–7.55 (m, 1 H), 7.15 (t, J = 8.4 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 163.5 (d, J = 247.3 Hz), 150.6, 149.6, 134.2,
131.1, 129.2 (q, J = 310.9 Hz), 128.5 (q, J = 6.2 Hz), 127.9 (d, J =
18.5 Hz), 127.2, 124.7 (d, J = 20.7 Hz), 115.7 (d, J = 11.0 Hz),
115.6 (d, J = 11.5 Hz) ppm. 19F NMR (378 MHz, CDCl3): δ =
–39.13, –133.25 (Ar-F) ppm. HRMS (ESI): calcd. for
C16H10F4NS+ [M + H+] 324.0465; found 324.0458.
Scheme 2. Reaction of compound 1m with AgSCF3. Reaction con-
ditions: 3-(phenylethynyl)thiophene-2-carbaldehyde oxime (1m;
0.2 mmol), AgOTf (10 mol-%), AgSCF3 2 (0.3 mmol), K3PO4
(0.9 mmol), p-MeOC6H4SO2Cl (0.3 mmol), DMA (2.0 mL), 25 °C.
3-(4-Chlorophenyl)-1-[(trifluoromethyl)thio]isoquinoline (3e): Yield
1
42.0 mg (62%). H NMR (400 MHz, CDCl3): δ = 8.13–8.09 (m, 3
Conclusions
H), 7.98 (s, 1 H), 7.87 (d, J = 8.0 Hz, 1 H), 7.74–7.71 (m, 1 H),
7.64–7.60 (m, 1 H), 7.46–7.44 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 150.8, 149.4, 137.3, 136.5, 135.1, 131.2, 129.2 (q, J =
300.7 Hz), 129.0, 128.2, 128.0, 127.9, 124.9, 116.1 ppm. 19F NMR
(378 MHz, CDCl3): δ = –39.13 ppm. HRMS (ESI): calcd. for
C16H10ClF3NS+ [M + H+] 340.0169; found 340.0165.
We have reported a facile assembly of 1-[(trifluorometh-
yl)thio]isoquinolines through silver(I)-catalyzed reaction of
2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolate
in the presence of p-methoxybenzenesulfonyl chloride. The
(trifluoromethyl)thio moiety (SCF3) could be easily intro-
duced into the scaffold of isoquinoline under mild condi-
tions. Further exploration of the utility of AgSCF3 for the
generation of other fluorinated N-heterocycles is ongoing
in our laboratory.
3-Cyclopropyl-1-[(trifluoromethyl)thio]isoquinoline
(3f):
Yield
13.0 mg (24%). 1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J =
8.4 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.66–7.63 (m, 1 H), 7.52–
7.48 (m, 1 H), 7.46 (s, 1 H), 2.15–2.08 (m, 1 H), 1.17–1.14 (m, 2
H), 1.03–0.99 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
156.3, 137.1, 130.7, 129.6 (q, J = 300.7 Hz), 126.7, 126.6, 124.8,
117.1, 16.6, 9.7 ppm. 19F NMR (378 MHz, CDCl3):
δ =
–39.22 ppm. HRMS (ESI): calcd. for C13H11F3NS+ [M + H+]
270.0559; found 270.0552.
Experimental Section
General Procedure for the synthesis of 1-[(trifluoromethyl)thio]iso-
quinolines: 2-Alkynylbenzaldoxime 1 (0.2 mmol) was added to a
solution of AgOTf (10 mol-%) in DMA (1.0 mL) under N2. After
stirring at 70 °C for 1 h, AgSCF3 2 (0.3 mmol), K3PO4 (0.9 mmol),
and p-MeOC6H4SO2Cl (0.3 mmol) were added followed by DMA
(1.0 mL). The mixture was stirred at 25 °C until completion of reac-
tion (indicated by TLC analysis; typically overnight), then the mix-
ture was purified by flash column chromatograph (EtOAc/n-hex-
ane, 1:100) to give the desired product 3.
3-n-Butyl-1-[(trifluoromethyl)thio]isoquinoline (3g): Yield 12.5 mg
(23%). 1H NMR (400 MHz, CDCl3): δ = 8.27 (d, J = 8.4 Hz, 1 H),
7.79 (d, J = 8.0 Hz, 1 H), 7.72–7.68 (m, 1 H), 7.62–7.58 (m, 1 H),
7.50 (s, 1 H), 2.96 (t, J = 7.6 Hz, 2 H), 1.85–1.77 (m, 2 H), 1.45–
1.36 (m, 2 H), 0.95 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 156.2, 137.5, 130.7, 129.3 (q, J = 300.7 Hz), 127.4,
126.9, 125.8, 119.5, 37.4, 31.7, 22.3, 13.9 ppm. 19F NMR
(378 MHz, CDCl3): δ = –39.45 ppm. HRMS (ESI): calcd. for
C14H15F3NS+ [M + H+] 286.0872; found 286.0854.
3-Phenyl-1-[(trifluoromethyl)thio]isoquinoline (3a): Yield 53.0 mg
1
(87%). H NMR (400 MHz, CDCl3): δ = 8.20–8.15 (m, 3 H), 8.06
7-Methyl-3-phenyl-1-[(trifluoromethyl)thio]isoquinoline (3h): Yield
1
(s, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.75–7.71 (m, 1 H), 7.64–7.60
(m, 1 H), 7.53–7.50 (m, 2 H), 7.45–7.41 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 150.6, 138.0, 137.4, 131.1, 129.3 (q, J =
301.6 Hz), 129.1, 128.9, 127.9, 127.8, 126.8, 124.9, 121.6,
116.2 ppm. 19F NMR (378 MHz, CDCl3): δ = –39.13 ppm. HRMS
(ESI): calcd. for C16H10F3NS+ [M + H+] 306.0559; found 306.0586.
54.4 mg (85%). H NMR (400 MHz, CDCl3): δ = 8.16–8.14 (m, 2
H), 7.95 (s, 1 H), 7.86 (s, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 7.51–7.46
(m, 3 H), 7.40 (t, J = 7.2 Hz, 1 H), 2.53 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 149.9, 149.5, 138.3, 138.2, 135.7, 133.3,
129.4 (q, J = 300.7 Hz), 128.8, 127.6, 126.6, 123.7, 116.1, 22.0 ppm.
19F NMR (378 MHz, CDCl3): δ = –39.09 ppm. HRMS (ESI):
calcd. for C17H13F3NS+ [M + H+] 320.0715; found 320.0707.
3-(p-Tolyl)-1-[(trifluoromethyl)thio]isoquinoline (3b): Yield 53.5 mg
1
(82%). H NMR (400 MHz, CDCl3): δ = 8.07–8.03 (m, 3 H), 7.92 6-Methoxy-3-phenyl-1-[(trifluoromethyl)thio]isoquinoline (3i): Yield
1
(m, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.63 (t, J = 7.6 Hz, 1 H), 7.52 53.7 mg (80%). H NMR (400 MHz, CDCl3): δ = 8.16–8.14 (m, 2
(t, J = 7.6 Hz, 1 H), 7.26 (d, J = 7.6 Hz, 2 H), 2.39 (s, 3 H) ppm.
H), 8.04 (d, J = 9.2 Hz, 1 H), 7.92 (s, 1 H), 7.50–7.47 (m, 2 H),
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Q. Xiao, J. Sheng, Q. Ding, J. Wu
FULL PAPER
3980; Angew. Chem. Int. Ed. 2004, 43, 3890; b) J. Panteleev, L.
Zhang, M. Lautens, Angew. Chem. 2011, 123, 9255; Angew.
Chem. Int. Ed. 2011, 50, 9089; c) S. H. Kim, S. H. Park, J. H.
Choi, S. Chang, Chem. Asian J. 2011, 6, 2618; d) P. Lu, Y.
Wang, Chem. Soc. Rev. 2012, 41, 5687; e) T. Miura, M. Murak-
ami, Chem. Commun. 2007, 217; f) M. Malacria, Chem. Rev.
1996, 96, 289; g) K. C. Nicolaou, T. Montagnon, S. A. Snyder,
Chem. Commun. 2003, 551; h) K. C. Nicolaou, D. J. Edmonds,
P. G. Bulger, Angew. Chem. 2006, 118, 7292; Angew. Chem. Int.
Ed. 2006, 45, 7134; i) D. Enders, C. Grondal, M. R. M. Hüttl,
Angew. Chem. 2007, 119, 1590; Angew. Chem. Int. Ed. 2007,
46, 1570; j) L. F. Tietze, G. Brasche, K. Gericke, Domino Reac-
tions in Organic Synthesis Wiley-VCH, Weinheim, Germany,
2006; k) L. F. Tietze, M. A. Düfert, T. Hungerland, K. Oum,
T. Lenzer, Chem. Eur. J. 2011, 17, 8452.
7.43–7.39 (m, 1 H), 7.21–7.19 (m, 1 H), 7.08 (d, J = 2.4 Hz, 1 H),
3.93 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.4, 151.2,
149.6, 139.7, 138.2, 129.4 (q, J = 306.9 Hz), 129.0, 128.8, 127.0,
126.8, 123.6, 120.9, 115.9, 105.3, 55.6 ppm. 19F NMR (378 MHz,
CDCl3): δ = –39.10 ppm. HRMS (ESI): calcd. for C17H13F3NOS+
[M + H+] 336.0664; found 336.0658.
6,7-Dimethoxy-3-phenyl-1-[(trifluoromethyl)thio]isoquinoline
(3j):
1
Yield 58.6 mg (80%). H NMR (400 MHz, CDCl3): δ = 8.10 (d, J
= 7.6 Hz, 2 H), 7.86 (s, 1 H), 7.46 (t, J = 7.2 Hz, 2 H), 7.40–7.37
(m, 2 H), 7.05 (s, 1 H), 4.02 (s, 3 H), 4.00 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 153.5, 150.9, 149.8, 146.7, 138.3, 134.4,
129.5 (q, J = 307.2 Hz), 128.8, 128.7, 126.5, 124.6, 115.9, 105.5,
103.6, 56.2 ppm. 19F NMR (378 MHz, CDCl3): δ = –39.11 ppm.
HRMS (ESI): calcd. for C18H15F3NO2S+ [M + H+] 366.0770;
found 366.0774.
[3] a) R. Filler, Y. Kobayashi, in: Biomedicinal Aspects of Fluorine
Chemistry; Elsevier: Amsterdam, 1982; b) In Fluorine, in: Bio-
organic Chemistry (Eds.: J. T. Welch, S. Eswarakrishman),
Wiley: New York, 1991; c) Bioorganic and Medicinal Chemistry
of Fluorine (Eds.: J.-P. Begue, D. Bonnet-Delpon), Wiley, Ho-
boken, 2008.
[4] For some reviews on the synthesis of fluorinated heterocycles,
see: a) V. A. Petrov, in: Fluorinated Heterocyclic Compounds:
Synthesis Chemistry, and Applications, John Wiley & Sons, Inc.,
Hoboken, NJ, 2009; b) E. V. Nosova, G. N. Lipunova, V. N.
Charushin, Q. N. Chupakhin, J. Fluorine Chem. 2010, 131,
1267; c) S. Zhu, Y. Wang, W. Peng, L. Song, G. Jin, Curr. Org.
Chem. 2002, 6, 1057; d) M. J. Silvester, Aldrichim. Acta 1991,
24, 31. For some selective examples, see: e) P. Kwiatkowski,
T. D. Beeson, J. C. Conrad, D. W. C. MacMillan, J. Am. Chem.
Soc. 2011, 133, 1738; f) Y. Kishi, H. Nagura, S. Inagi, T. Fu-
chigami, Chem. Commun. 2008, 3876; g) S. Fustero, S. Catalan,
M. Sanchez-Rosello, A. Simon-Fuentes, C. del Pozo, Org. Lett.
2010, 12, 3484; h) S. Ye, J. Liu, J. Wu, Chem. Commun. 2012,
48, 5028.
[5] For some recent patents involving fluorinated isoquinolines,
see: a) R. Yamada, M. Seto, U. S. Patent 201093789, 2010; b)
Q. Zeng, C. C. Yuan, G. Yao, X. Wang, S. Tadesse, D. J. S.
Jean Jr., A. Reichelt, Q. Liu, F.-T. Hong, N. Han, C. Fotsch,
C. Davis, M. P. Bourbeau, K. S. Ashton, J. G. Allen, WO
201083246, 2010; c) K. Matsubara, A. Iesato, A. Oomura, K.
Kawasaki, R. Yamada, M. Seto, U. S. Patent 200948223 A1,
2009.
7-Fluoro-3-phenyl-1-[(trifluoromethyl)thio]isoquinoline (3k): Yield
1
57.0 mg (88%). H NMR (400 MHz, CDCl3): δ = 8.14–8.12 (m, 2
H), 8.00 (s, 1 H), 7.88–7.85 (m, 1 H), 7.79–7.76 (m, 1 H), 7.51–7.45
(m, 3 H), 7.43–7.39 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 161.1 (d, J = 250.1 Hz), 150.5, 149.5, 137.7, 134.6, 130.5 (d, J
= 8.6 Hz), 129.2, 129.1 (q, J = 307.8 Hz), 128.9, 128.5 (d, J =
8.5 Hz), 126.7, 116.2, 109.1 (d, J = 22.8 Hz) ppm. 19F NMR
(378 MHz, CDCl3): δ = –39.16, –108.8 (Ar-F) ppm. HRMS (ESI):
calcd. for C16H10F4NS+ [M + H+] 324.0465; found 324.0458.
7-Chloro-3-phenyl-1-[(trifluoromethyl)thio]isoquinoline (3l): Yield
1
51.7 mg (76%). H NMR (400 MHz, CDCl3): δ = 8.16–8.15 (m, 3
H), 78.03 (s, 1 H), 7.84 (d, J = 8.8 Hz, 1 H), 7.68–7.65 (m, 1 H),
7.53–7.49 (m, 2 H), 7.46–7.42 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 151.1, 149.5, 137.6, 135.8, 132.7, 132.2, 129.4, 129.3,
129.0 (q, J = 300.7 Hz), 128.9, 128.6, 126.8, 124.2, 115.9 ppm. 19F
NMR (378 MHz, CDCl3): δ = –39.10 ppm. HRMS (ESI): calcd.
for C16H10ClF3NS+ [M + H+] 340.0169; found 340.0155.
5-Phenyl-7-[(trifluoromethyl)thio]thieno[2,3-c]pyridine (3m): Yield
1
56.0 mg (90%). H NMR (400 MHz, CDCl3): δ = 8.10–8.07 (m, 3
H), 7.71 (d, J = 5.6 Hz, 1 H), 7.50–7.46 (m, 2 H), 7.43–7.40 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.0, 147.3, 141.8,
139.3, 138.3, 131.2, 129.3 (q, J = 308.2 Hz), 129.1, 128.9, 126.9,
124.1, 114.7 ppm. 19F NMR (378 MHz, CDCl3): δ = –38.89 ppm.
[6] a) T. Xu, G. Liu, Org. Lett. 2012, 14, 5416; b) C. Si, A. G.
Myers, Angew. Chem. 2011, 123, 10593; Angew. Chem. Int. Ed.
2011, 50, 10409.
HRMS (ESI): calcd. for C14H9F3NS2 [M + H+] 312.0123; found
+
[7] For selected examples, see: a) C. Chen, L. Chu, F.-L. Qing, J.
Am. Chem. Soc. 2012, 134, 12454; b) F. Baert, J. Colomb, T.
Billard, Angew. Chem. 2012, 124, 10528; Angew. Chem. Int. Ed.
2012, 51, 10382; c) G. Teverovskiy, D. S. Surry, S. L. Buchwald,
Angew. Chem. 2011, 123, 7450; Angew. Chem. Int. Ed. 2011,
50, 7312; d) C.-P. Zhang, D. A. Vicic, J. Am. Chem. Soc. 2012,
134, 183; e) Z. Weng, W. He, C. Chen, R. Lee, D. Tan, Z. Lai,
D. Kong, Y. Yuan, K.-W. Huang, Angew. Chem. 2013, 125,
1588; Angew. Chem. Int. Ed. 2013, 52, 1548; f) C. Chen, Y. Xie,
L. Chu, R.-W. Wang, X. Zhang, F.-L. Qing, Angew. Chem.
2012, 124, 2542; Angew. Chem. Int. Ed. 2012, 51, 2492; g) C.-
P. Zhang, D. A. Vicic, Chem. Asian J. 2012, 7, 1756; h) X. Shao,
X. Wang, T. Yang, L. Lu, Q. Shen, Angew. Chem. 2013, 125,
3541; Angew. Chem. Int. Ed. 2013, 52, 3457; i) L. D. Tran, I.
Popov, O. Daugulis, J. Am. Chem. Soc. 2012, 134, 18240.
[8] a) A. Tlili, T. Billard, Angew. Chem. 2013, 125, 6952; Angew.
Chem. Int. Ed. 2013, 52, 6818; b) Y. Yang, X. Jiang, F.-L. Qing,
J. Org. Chem. 2012, 77, 7538; c) A. Ferry, T. Billard, E. Bacqué,
B. R. Langlois, J. Fluorine Chem. 2012, 134, 160; d) A. Ferry,
T. Billard, B. R. Langlois, E. Bacqué, J. Org. Chem. 2008, 73,
9362; e) A. Ferry, T. Billard, B. R. Langlois, E. Bacqué, Angew.
Chem. 2009, 121, 8703; Angew. Chem. Int. Ed. 2009, 48, 8551;
f) A. Ferry, T. Billard, B. R. Langlois, E. Bacqué, J. Org. Chem.
2008, 73, 9362; g) Q. Xiao, J. Sheng, Z. Chen, J. Wu, Chem.
Commun. 2013, 49, 8647.
312.0114.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, 1H and 13C
NMR spectra of 3.
Acknowledgments
Financial support from the National Natural Science Foundation
of China (NSFC) (grant numbers 21032007, 21172038) is gratefully
acknowledged.
[1] a) K. W. Bentley, in: The Isoquinoline Alkaloids, Hardwood Ac-
ademic, Amsterdam, 1998; b) F. Dzierszinski, A. Coppin, M.
Mortuaire, E. Dewally, C. Slomianny, J.-C. Ameisen, F. DeBels,
S. Tomavo, Antimicrob. Agents Chemother. 2002, 46, 3197; c)
L. Kong, C. Cheng, R. Tan, Planta Med. 2001, 67, 74; d) R.
Davis, A. Carroll, G. Pierens, R. Quinn, J. Nat. Prod. 1999, 62,
419; e) E. Marco, W. Laine, C. Tardy, A. Lansiaux, M. Iwao,
F. Ishibashi, C. Bailly, F. Gago, J. Med. Chem. 2005, 48, 3796.
[2] For reviews, see: a) J. Montgomery, Angew. Chem. 2004, 116,
220
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 217–221

Facile Assembly of 1-[(Trifluoromethyl)thio]isoquinolines
[9] For selected examples, see: a) H. Ren, Y. Luo, S. Ye, J. Wu,
Org. Lett. 2011, 13, 2552; b) S. Ye, H. Wang, J. Wu, ACS Comb.
Sci. 2011, 13, 120; c) Q. Xiao, S. Ye, J. Wu, Org. Lett. 2012,
14, 3430; d) D. Zheng, Z. Chen, J. Liu, J. Wu, Org. Biomol.
Chem. 2011, 9, 4763; e) H.-S. Yeom, S. Kim, S. Shin, Synlett
2008, 924; f) Z. Huo, H. Tomeba, Y. Yamamoto, Tetrahedron
Lett. 2008, 49, 5531.
[10]
a) J. H. Clark, C. W. Jones, A. P. Kybett, M. A. Mcclinton,
J. M. Miller, D. Bishop, R. J. Blade, J. Fluorine Chem. 1990, 48,
249; b) G. Teverovskiy, D. S. Surry, S. L. Buchwald, Angew.
Chem. 2011, 123, 7450; Angew. Chem. Int. Ed. 2011, 50, 7312.
Received: September 14, 2013
Published Online: November 26, 2013
Eur. J. Org. Chem. 2014, 217–221
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