Synthesis of 1-Thio-Substituted Isoquinoline Derivatives by Tandem Cyclization of Isothiocyanates

Article abstract of DOI:10.1021/acs.joc.6b02605

A copper-catalyzed tandem arylation-cyclization process to access 1-(arylthio)isoquinolines from isothiocyanates and diaryliodonium salts is described. It is the first general method to construct the potentially useful 1-(arylthio)isoquinoline derivatives. Moreover, 1-(methylthio)isoquinoline derivatives were also achieved successfully with MeOTf instead of diaryliodonium salts under metal-free conditions. Mechanistic studies reveal that these two processes proceed in different routes. This method has been successfully applied to the synthesis of quinazolinone alkaloid rutaecarpine.

Full text of DOI:10.1021/acs.joc.6b02605

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Article
Synthesis of 1-Thio-substituted Isoquinoline
Derivatives by Tandem Cyclization of Isothiocyanates
Li-Rong Wen, Qian Dou, Yuan-Chao Wang, Jinwei Zhang, Wei-Si Guo, and Ming Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02605 • Publication Date (Web): 16 Jan 2017
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Synthesis of 1-Thio-substituted Isoquinoline Derivatives by Tandem
Cyclization of Isothiocyanates
†,‡
†
†
‡
,†,‡
,†
LiꢀRong Wen, Qian Dou, YuanꢀChao Wang, JinꢀWei Zhang, WeiꢀSi Guo,* Ming Li*
†
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State Key Laboratory Base of EcoꢀChemical Engineering, College of Chemistry and Molecular
Engineering, Qingdao University of Science and Technology, Qingdao 266042, P. R. China
‡
State Key Laboratory for Marine Corrosion and Protection, Luoyang Ship Material Research
Institute (LSMRI), Qingdao 266101, P. R. China
Eꢀmail: liming928@qust.edu.cn, nick8110@163.com
A
copperꢀcatalyzed
ꢀ(arylthio)isoquinolines from isothiocyanates and diaryliodonium salts is described.
It is the first general method to construct the potentially useful
ꢀ(arylthio)isoquinoline derivatives. Moreover, 1ꢀ(methylthio)isoquinoline derivatives
tandem
arylationꢀcyclization
process
to
access
1
1
were also achieved successfully with MeOTf instead of diaryliodonium salts under
metalꢀfree conditions. Mechanistic studies reveal that these two processes proceed in
different routes. This method has been successfully applied to the synthesis of
quinazolinone alkaloid rutaecarpine.
TOC Graphic
INTRODUCTION
Isoquinoline is an important heteroaromatic scaffold existing in natural products,
1
2
pharmaceuticals, and functional materials, such as berberine alkaloids,
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antispasmodic drug papaverine, and cytotoxic alkaloid quinocarcin (Figure 1). Thus,
diverse synthetic methods have been developed for constructing isoquinoline
derivatives. However, classical methods of isoquinoline synthesis, involving
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Bischler−Napieralski and Pictet−Spengler reactions, require harsh acidic conditions
which limited their usage. Recently, many efficient methods have been reported to
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construct isoquinolines through annulation reactions catalyzed by transition metals,
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such as palladium, nickel, silver, copper, rhodium, and ruthenium. Although
significant advances have been made toward isoquinoline construction, to the best of
our knowledge, it has been no general method to synthesize 1ꢀ(arylthio)isoquinoline
derivatives. Given that the increasing prevalence of sulfurꢀcontaining compounds in
1
4
pharmaceuticals, introducing arylthio or methylthio group into isoquinoline motif
would be of great synthetic value.
Figure 1. Representative bioactive isoquinoline natural products
Recently, the arylationꢀcyclization process based on diaryliodonium salts has
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become a powerful strategy for the construction of heterocycles. Various substrates,
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such as alkenes, alkynes, nitriles, can be easily arylated with diaryliodonium salts
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to generate carbocation intermediates, which undergo cyclization to obtain
structureꢀdivergent molecules. Isothiocyanates, as versatile synthetic intermediates,
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have been widely used in the construction of heterocyclic compounds.
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Traditionally, reactions occurred at the C atom of isothiocyanates, i.e. the ꢀNCS group
was applied as an electrophile. Recently, tandem radical cyclization reactions
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involving isothiocyanates have received more attentions. However, reactions
2
1
induced by S atom of isothiocyanate have been much less reported. Moreover,
βꢀarylethyl isothiocyanates and vinyl isothiocyanates, as potentially synthetic useful
2
2
intermediates, are seldom applied for the synthesis of heterocycles. As our
continuing interests in using isothiocyanates as the starting materials for the
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construction of heterocycles, herein, we report a new efficient tandem reaction to
synthesize 1ꢀ(arylthio) and 1ꢀ(methylthio)isoquinoline derivatives through
isothiocyanates with diaryliodonium salts and methyl triflate, respectively.
RESULTS AND DISCUSSION
Considering many natural isoquinoline alkaloids containing 3,4ꢀdimethoxy or
3
,4ꢀmethylenedioxy
groups
(Figure
1),
4ꢀ(2ꢀisothiocyanatoethyl)ꢀ1,2ꢀ
dimethoxybenzene 1a was chosen as a model substrate to react with
23a
diphenyliodonium salt 2a (Table 1). Initially, our previous optimized conditions
were used and the desired product 1ꢀ(phenylthio)ꢀ3,4ꢀdihydroisoquinoline 3a was
obtained in 34% yield (entry 1). This result motivated us to test different copper
2 2
catalysts. However, other copper salts such as Cu(OTf) , Cu(OAc) , CuBr, CuTC, and
CuI did not improve the yield of 3a (entries 2ꢀ6). In addition, compound 3a was not
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observed in the absence of copper salt (entry 7). When hexafluorophosphate (PF )
−
was used as an anion instead of OTf , 3a was obtained in excellent yield (entry 8),
−
4
whereas lower yield was provided with tetrafluoroborate (BF
) (entry 9), which
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showed that the anions of diaryliodonium salts had dramatically influence on the
reaction. Additionally, screening some other solvents, such as THF and toluene,
revealed that DCE was the best choice (entries 10 and 11). The yield of 3a decreased
o
o
with elevating the temperature to 100 C or decreasing to 60 C (entries 12 and 13).
When 5 mol % CuCl was used as catalyst, the yield of 3a dropped to 39% (entry 14).
A slightly lower yield was observed when the reaction was conducted under the air
atmosphere. Finally, the optimal conditions were established as follows: 1a and 2a (X
o
= PF
6
) in a ratio of 1:1.5, CuCl (10 mol %), DCE (0.2 M) at 80 C for 2 h.
a
Table 1. Optimization of the reaction conditions
o
b
Entry
Catalyst (mol %)
CuCl (10)
X
Solvent
T [ C]
Yield [%]
1
2
OTf
OTf
OTf
OTf
OTf
OTf
OTf
PF6
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
80
80
80
80
80
80
80
80
80
80
80
34
28
12
26
28
32
0
Cu(OTf)
2
(10)
(10)
3
Cu(OAc)
2
4
CuBr (10)
CuTC (10)
CuI (10)
5
6
7
none
8
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
90
18
50
83
9
BF
4
10
PF
PF
6
6
11
toluene
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1
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CuCl (10)
CuCl (10)
CuCl (5)
PF
PF
PF
PF
6
6
6
6
DCE
DCE
DCE
DCE
100
60
77
75
39
78
13
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80
c
1
5
CuCl (10)
80
a
b
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Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), solvent (1 mL), 2 h, N . Isolated yield based
on 3a. Under an air atmosphere.
2
c
Under the optimized reaction conditions, the scope of substrates was investigated
(
Table 2). The 1ꢀ(arylthio)ꢀ3,4ꢀdihydroisoquinolines 3a-f were generated in good to
excellent yields (72ꢀ96%) from isothiocyanate 1a and diaryliodonium salts 2, except
the paraꢀOMe substrate 2c (64% yield). The desired products 3g-l were also formed
in moderated to good yields when 3,4ꢀmethylenedioxy substituted isothiocyanate 1b
was used instead of 1a. In addition, disubstituted diaryliodonium salts, such as
2,4ꢀdimethyl substituted compound 2m, was also compatible to the reaction and
product 3m was obtained in 82% yield. Disappointingly, no cyclization products were
formed when monoꢀsubstituted substrates 1 (4ꢀMe, 4ꢀOMe, 4ꢀFꢀphenyl) were used.
To further extend the scope of the protocol, several vinyl isothiocyanates were
synthesized and reacted with diaryliodonium salts 2. The reaction proceeded smoothly,
and isoquinolines 3n-q were provided in moderate yields. The reason may be subject
to the electronꢀwithdrawing COOEt group, which makes the carbon atom of NCS
group more electronꢀdeficient to facilitate the electrophilic cyclization. The structures
of 3 were unambiguously confirmed by Xꢀray crystallographic analysis of compound
3
a (See Figure S1).
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a,b
Table 2. The Synthesis of Isoquinoline Derivatives 3
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3g: R3 = H,
3h: R3 = 4-Me,
3i: R3 = 4-OMe, 73%
3j: R3 = 4-F,
52%
50%
MeO
MeO
3a: R3 = H,
90%
96%
O
O
3
3
b: R = 4-F,
N
N
3
3c: R = 4-OMe, 64%
3
S
3d: R = 4-Me, 88%
S
68%
74%
69%
3
R3 3k: R3 = 2-F,
3l: R3 = 3-F,
R3
3e: R = 2-Me, 81%
f: R3 = 3-Me, 72%
3
COOEt
O
O
COOEt
N
N
N
Me
Me
S
S
S
Me
3
m: 82%
3n: 46%
3o: 58%
COOEt
COOEt
N
N
Me
MeO
S
S
OMe
3
p: 60%
3q: 63%
a
Reaction conditions: 1 (0.4 mmol), 2 (0.6 mmol), CuCl (0.04 mmol), DCE (2 mL), 2 h ,
b
N
2
. Isolated yield .
a,b
Table 3. The Synthesis of Isoquinoline Derivatives 4
a
Reaction conditions: 1 (0.4 mmol), MeOTf (0.6 mmol), DCE (2 mL), 2
b
h , N2
。
Isolated yield .
Considering aryl carbocations generated from 2 could react with isothiocyanates 1,
we envisioned that methyl carbocation may proceed a similar process to form
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ꢀ(methylthio)isoquinoline derivatives. To test the idea, methyl triflate (MeOTf) was
chosen to react with isothiocyanates 1 under the above conditions without copper
catalyst (Table 3). To our delight, 1ꢀ(methylthio)ꢀ3,4ꢀdihydroisoquinolines 4a-f
were obtained in 51ꢀ86% yields. The reactions showed obvious electron effects,
higher yield was obtained with highly electron rich substrate (4f, 86%), whereas the
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electron deficient 4ꢀCF
3
substrate provided lower yield (4e, 51%). Notably,
heterocyclic thiophene and indole substrates were also suitable for the reaction, the
desired products 4g and 4h were obtained in 60% and 84% yields, respectively.
Scheme 1. Comparative Experiments of Diphenyliodonium Salt and MeOTf
Interestingly, when vinyl isothiocyanate 1n was used to react with MeOTf,
1
ꢀ(methylthio)isoquinoline 4i was not obtained; whereas 1ꢀ(phenylthio)isoquinoline
3
n was provided in 46% yield (Scheme 1). Furthermore, 4b was produced in 72%
yield when isothiocyanate 1r was used, whereas 3r was not formed. These
phenomena suggested that the two reactions maybe proceed through different
pathways.
In order to explain these phenomena, a series of control experiments were
conducted (Scheme 2). Isothiocyanate 1r could be cyclized smoothly to provide
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thioamide 5 in the presence of trifluoromethanesulfonic acid (TfOH) (eq.1). Then, the
reaction of 5 with 2a was performed under the standard conditions, and the
dihydroisoquinoline 3r was obtained in 79% yield (eq.2). However, when the reaction
of 1r with 2a was directly performed under the standard conditions, no cyclized
product 3r was obtained, but thiocarbamate 6 was formed in 68% yield (eq.3). Based
on the above results, we performed eq.1 and eq.2 in oneꢀpot in the presence of
stoichiometric TfOH (eq.4), and 3r was obtained albeit in low yield of 24%.
Considering a trace amount of TfOH is sufficient to initiate the intramolecular
electrophilic cyclization, 0.5 mol% TfOH was added in the reaction mixture, to our
delight, the yield of 3r increased to 75%. Thus, a cyclization/arylation process was
proposed for the synthesis of monosubstituted product 3r.
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Otherwise, 4b was generated in 80% yield from 5 under the standard conditions
(eq.5). When vinyl isothiocyanate 1n was used under the same conditions as eq.1, the
thioamide was not obtained and only starting material 1n was recovered (eq.6). These
results indicated that the cyclization would occur prior to the methylation for the
reactions of isothiocyanates with MeOTf, which was probably due to a trace amount
of TfOH involving in MeOTf (MeOTf easily hydrolyzes to form TfOH). To verified
this hypothesis, the reaction of 1r with MeOTf was conducted with 10 mol%
2,6ꢀdiꢀtertꢀbutylpyridine as a base, and it was completely prevented. These results
confirmed that TfOH should play an important role in the cyclization process.
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Scheme 2. Control Experiments
TfOH (1.0 equiv.)
NH
eq.1
eq.2
NCS
Me
Me
Me
DCE, 80 oC, 2 h
S
1
5
r
5, 64%
CuCl (10 mol%)
DCE, 80 oC, 2 h
10
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Ph
I
PF6
N
NH
Me
Ph
S
S
2a
Ph
3r, 79%
Ph
I
PF6 CuCl (10 mol%)
DCE, 80 oC, 2 h
N
HN
S
Me
Me
eq.3
Ph
NCS
NCS
Ph
2a
Me
Me
S
O
1r
1r
Ph
N
3
r, 0%
6, 68%
CuCl (10 mol%)
PF6
Ph
I
Me
eq.4
Ph
2a
DCE, 80 oC, 2 h
S
3r
Ph
TfOH (1.0 equiv.)
TfOH (0.5 mol%)
24%
75%
MeOTf
DCE, 80 oC, 2 h
N
NH
Me
eq.5
eq.6
Me
S
S
5
4b
,
Me
80%
COOEt TfOH (1.0 equiv.)
COOEt
NH
X
NCS
DCE, 80 oC, 2 h
1
n
S
To further examine the generality of the reaction in Scheme 2, eq.4, other
monosubstituted substrates (4ꢀOMe, 4ꢀF, 3ꢀOMe) were investigated (Table 4), the
results showed that the reactions could proceeded smoothly and the cyclized
monosubstituted products 3s-u were formed in good yields.
a,b
Table 4. The Synthesis of Monoꢀsubstituted Derivatives 3
a
Reaction conditions: 1 (0.4 mmol), 2 (0.6 mmol), CuCl (0.04 mmol), TfOH (0.002
b
mmol), DCE (2 mL), 2 h , N
2
. Isolated yield .
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On the basis of the above results, a possible mechanism is proposed in Scheme 3.,
2 6
In path 1, when Ar IPF reacts with isothiocyanate 1 in the absence of TfOH, the
sulfonium intermediate A is formed initially through Sꢀarylation of the generated aryl
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carbocation.
Friedel−Craftsꢀtype cyclization, followed by deprotonation to provide the desired
ꢀ(arylthio)isoquinolines 3a-q (path 1). In path 2, when MeOTf reacts with 1, the
Subsequently, the intermediate A undergoes intramolecular
1
NCS group is initially protonated, followed by cyclization to generate intermediate D.
Finally, a methylation of D with MeOTf gives products 4. The reaction mechanism for
the synthesis of 3r-u is similar to compounds 4.
Scheme 3. Proposed Reaction Mechanism
The quinazolinone alkaloid rutaecarpine, isolated in 1915 from Evodia rutaecarpa,
was used in Traditional Chinese Medicine for the treatment of inflammationꢀrelated
24
disorders. To further illustrate the potential utility of this new method, a concise total
synthesis of rutaecarpine was explored (Scheme 4). Initially, isothiocyanate 8 was
synthesized from commercially available tryptamine 7. Under the above standard
cyclization conditions, the methylthio substituted 3,4ꢀdihydroꢀβꢀcarboline 9 was
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generated in 90% yield. Finally, annulation with 2ꢀaminobenzoic acid afforded the
24b
natural alkaloid rutaecarpine. The facile synthetic route could provide a pathway
for rutaecarpine analogues synthesis.
10
11
12
13
14
15
16
17
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19
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59
60
Scheme 4. Application in the Synthesis of Rutaecarpine
CONCLUSION
In summary, we have developed a new tandem reaction to synthesize
1
ꢀthioꢀsubstituted isoquinolines from isothiocyanates with diaryliodonium salts or
methyl triflate under mild conditions. Control experiments suggest that two
mechanistically different pathways might be involved. To the best of our knowledge,
this is the first general method to construct 1ꢀ(arylthio)isoquinolines. In addition, the
method was applied as a key step to the short synthesis of alkaloid rutaecarpine.
Further studies to explore new synthetic methods using isothiocyanates are in
progress.
EXPERIMENTAL SECTION
General information. All airꢀ or moistureꢀsensitive reactions were conducted
2
under a nitrogen atmosphere. DCE was distilled from CaH . Unless noted, all
commercial reagents were used without further purification. Melting points were
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2
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2
2
2
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3
3
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1
recorded on a microscopic melting apparatus and uncorrected. H NMR spectra were
1
3
recorded at 500 MHz and C NMR spectra were recorded at 125 MHz in CDCl
3
or
DMSOꢀd . Chemical shifts were reported in parts per million (δ) relative to
6
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
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6
7
8
9
0
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6
7
8
9
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3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
tetramethylsilane (TMS). HRMS were obtained on a spectrometer with an ESI source.
The Xꢀray singleꢀcrystal diffraction was performed on a CCD area detector. Silica gel
(
200–300 mesh) was used for column chromatography and silica GF254 for TLC.
25
Preparation of starting materials. Diaryliodonium salts were prepared
26
according to previously published procedures. The (2ꢀisothiocyanatoethyl) benzenes
2
2a
and ethyl (Z)ꢀ2ꢀisothiocyanatoꢀ3ꢀ phenylacrylates were also synthesized according
to previously published procedures.
General procedure for the synthesis of compounds 3 (3a for example). Under
N
2
atmosphere, to a dry Schlenk tube was charged with a mixture of
4ꢀ(2ꢀisothiocyanatoethyl)ꢀ1,2ꢀdimethoxybenzene 1a (90 mg, 0.40 mmol),
diphenyliodonium salt 2a (256 mg, 0.60 mmol), CuCl (4.0 mg, 0.04 mmol) and DCE
(2.0 mL). The mixture was allowed to stir at 80 °C for 2 h. After completion, the
mixture was cooled to room temperature, quenched with saturated NaHCO
extracted with EtOAc (10 mL × 3). The organic layer was washed with saturated
NaCl and dried over anhydrous MgSO . Evaporation of the solvent followed by
purification on silica gel (petroleum ether/ethyl acetate) provided product 3a.
3
and
4
6
,7-Dimethoxy-1-(phenylthio)-3,4-dihydroisoquinoline (3a). Isolated yield 108 mg (90%);
1
white solid; mp 86−88 °C; R 0.20 (petroleum ether/ethyl acetate = 4:1 v/v). H NMR (CDCl , 500
f
3
MHz):
δ
2.68 (t, J = 7.4 Hz, 2H), 3.66 (t, J = 7.4 Hz, 2H), 3.92 (s, 3H), 3.94 (s, 3H), 6.72 (s, 1H),
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4
3
.31 (s, 1H), 7.36−7.42 (m, 3H), 7.57 (d, J = 7.1 Hz, 2H); C NMR (CDCl , 125 MHz): δ 25.9,
8.6, 55.9, 56.1, 108.6, 110.1, 121.5, 128.5, 128.9, 129.8, 131.1, 134.8, 147.3, 151.1, 163.3;
+
HRMS (ESIꢀTOF, [M + H] ): calcd for C17
H
17NO
2
S, 300.1053, found 300.1054
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
-((4-Fluorophenyl)thio)-6,7-dimethoxy-3,4-dihydroisoquinoline (3b). Isolated yield 122 mg
1
(
f
96%); white solid; mp 105−106 °C; R 0.24 (petroleum ether/ethyl acetate = 4:1 v/v). H NMR
(
CDCl
3
, 500 MHz):
.70 (s, 1H), 7.09 (t, J = 8.6 Hz, 2H), 7.28 (s, 1H), 7.51−7.54 (m, 2H); C NMR (CDCl
, 125
3
δ 2.65 (t, J = 7.4 Hz, 2H), 3.63 (t, J = 7.2 Hz, 2H), 3.92 (s, 3H), 3.93 (s, 3H),
13
6
2
MHz):
δ
26.0, 48.6, 56.0, 56.1, 108.3, 110.1, 116.2 (d, JCꢀF = 21.9 Hz), 121.5, 124.6, 131.1, 137.2
1
+
(
d, JCꢀF = 248.3 Hz), 147.4, 151.2, 162.1, 163.1, 164.0; HRMS (ESIꢀTOF, [M + H] ): calcd for
17 2
C H16FNO S, 318.0959, found 318.0956.
6,7-Dimethoxy-1-((4-methoxyphenyl)thio)-3,4-dihydroisoquinoline (3c). Isolated yield 85
1
mg (64%); white solid; mp 138−140 °C; R
f
0.10 (petroleum ether/ethyl acetate = 4:1 v/v). H
NMR (CDCl
3
, 500 MHz):
δ
2.64 (t, J = 7.0 Hz, 2H), 3.62 (t, J = 7.0 Hz, 2H), 3.82 (s, 3H), 3.92 (s,
13
3
H), 3.93 (s, 3H), 6.69 (s, 1H), 6.93 (d, J = 7.9 Hz, 2H), 7.31 (s, 1H), 7.47 (d, J = 7.9 Hz, 2H); C
NMR (CDCl
3
, 125 MHz):
δ
26.1, 48.63, 55.27, 56.0, 56.2, 108.6, 110.2, 114.8, 120.0, 121.8,
+
1
31.1, 136.8, 147.5, 151.2, 160.2; HRMS (ESIꢀTOF, [M + H] ): calcd for C H NO S, 330.1164,
1
8
19
3
found 330.1152.
6,7-Dimethoxy-1-(p-tolylthio)-3,4-dihydroisoquinoline (3d). Isolated yield 110 mg (88%);
1
white solid; mp 129−131 °C; R
f
0.22 (petroleum ether/ethyl acetate = 4:1 v/v). H NMR (CDCl
3
,
5
00 MHz):
δ 2.36 (s, 3H), 2.65 (t, J = 7.4 Hz, 2H), 3.64 (t, J = 7.2 Hz, 2H), 3.91 (s, 3H), 3.92 (s,
1
3
3H), 6.69 (s, 1H), 7.21 (d, J = 7.9 Hz, 2H), 7.30 (s, 1H), 7.43 (d, J = 8.0 Hz, 2H); C NMR
(
CDCl
3
, 125 MHz):
δ
21.3, 26.0, 48.6, 56.0, 56.1, 108.4, 110.0, 121.6, 125.9, 130.0, 131.1, 135.0,
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3
3
3
3
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5
5
5
5
5
6
+
1
38.8, 147.3, 151.0, 163.5; HRMS (ESIꢀTOF, [M + H] ): calcd for C H NO S, 314.1210, found
18
19
2
314.1212.
6
,7-Dimethoxy-1-(o-tolylthio)-3,4-dihydroisoquinoline (3e). Isolated yield 101 mg (81%);
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
white solid; mp 94−96 °C; R
f
0.23 (petroleum ether/ethyl acetate = 4:1 v/v). H NMR (CDCl
3
, 500
MHz):
δ
2.43 (s, 3H), 2.65 (t, J = 7.4 Hz, 2H), 3.62 (t, J = 7.2 Hz, 2H), 3.92 (s, 6H), 6.70 (s, 1H),
13
7
2
1
3
.20−7.23 (m, 1H), 7.30−7.32 (m, 3H), 7.55 (d, J = 7.6 Hz, 1H); C NMR (CDCl
3
, 125 MHz):
δ
0.9, 26.0, 48.6, 55.9, 56.1, 108.6, 110.1, 121.7, 126.5, 128.9, 129.4, 130.6, 131.1, 136.2, 142.6,
+
47.4, 151.0, 162.5; HRMS (ESIꢀTOF, [M + H] ): calcd for C18
2
H19NO S, 314.1210, found
14.1211.
6
,7-Dimethoxy-1-(m-tolylthio)-3,4-dihydroisoquinoline (3f). Isolated yield 90 mg (72%);
1
white solid; mp 93−95 °C; R 0.24 (petroleum ether/ethyl acetate = 4:1 v/v). H NMR (CDCl , 500
f
3
MHz):
6.70 (s, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.26−7.30 (m, 2H), 7.35−7.37 (m, 2H); C NMR (CDCl
25 MHz): 21.3, 26.0, 48.6, 56.0, 56.1, 108.6, 110.1, 121.6, 128.8, 129.3, 129.5, 131.1, 132.0,
δ 2.36 (s, 3H), 2.66 (t, J = 7.4 Hz, 2H), 3.65 (t, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.92 (s, 3H),
13
3
,
1
δ
+
135.4, 138.7, 147.4, 151.1, 163.4; HRMS (ESIꢀTOF, [M + H] ): calcd for C18
found 314.1214.
2
H19NO S, 314.1210,
5-(Phenylthio)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline (3g). Isolated yield 59 mg (52%);
1
white solid; mp 154−156 °C; R
f
0.39 (petroleum ether/ethyl acetate = 4:1 v/v). H NMR (CDCl
3
,
500 MHz):
δ
2.63 (t, J = 7.3 Hz, 2H), 3.60 (t, J = 7.3 Hz, 2H), 6.00 (s, 2H), 6.68 (s, 1H), 7.31 (s,
13
1
H), 7.34−7.41 (m, 3H), 7.55 (d, J = 6.9 Hz, 2H); C NMR (CDCl
3
, 125 MHz):
δ
26.7, 48.4, 80.7,
84.1, 101.4, 105.9, 107.8, 122.9, 128.6, 129.0, 133.0, 135.0, 146.4, 149.5, 163.2; HRMS
+
(
ESIꢀTOF, [M + H] ): calcd for C16
H13NO
2
S, 284.0745, found 284.0752.
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-(p-Tolylthio)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline (3h). Isolated yield 60 mg (50%);
1
white solid; mp 161−163 °C; R
f
0.40 (petroleum ether/ethyl acetate = 4:1 v/v). H NMR (CDCl
3
,
5
1
δ
00 MHz):
δ 2.36 (s, 3H), 2.61 (t, J = 7.3 Hz, 2H), 3.59 (t, J = 7.3 Hz, 2H), 5.99 (s, 2H), 6.67 (s,
10
11
12
13
14
15
16
17
18
19
20
21
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23
24
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28
29
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31
32
33
34
35
36
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45
46
47
48
49
50
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52
53
54
55
56
57
58
59
60
1
3
H), 7.20 (d, J = 7.8 Hz, 2H), 7.31 (s, 1H), 7.43 (d, J = 7.9 Hz, 2H); C NMR (CDCl
3
, 125 MHz):
26.7, 48.5, 101.4, 105.9, 107.8, 130.0, 125.8, 129.9, 130.0, 135.2, 138.8, 146.3, 149.3, 163.3;
+
HRMS (ESIꢀTOF, [M + H] ): calcd for C H NO S, 298.0902, found 298.0912.
17
15
2
5-((4-Methoxyphenyl)thio)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline (3i). Isolated yield
1
9
1 mg (73%); white solid; mp 153−155 °C; R
f
0.28 (petroleum ether/ethyl acetate = 4:1 v/v). H
NMR (CDCl , 500 MHz):
δ
2.61 (t, J = 7.3 Hz, 2H), 3.58 (t, J = 7.3 Hz, 2H), 3.82 (s, 3H), 5.99 (s,
3
13
2
H), 6.67 (s, 1H), 6.94 (d, J = 8.9 Hz, 2H), 7.31 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H); C NMR
(
CDCl
3
, 125 MHz):
δ
26.8, 48.5, 55.3, 101.4, 105.8, 107.8, 114.8, 119.8, 123.0, 133.0, 137.0,
+
1
46.4, 149.3, 160.2, 163.6; HRMS (ESIꢀTOF, [M + H] ): calcd for C17
H
15NO
3
S, 314.0851, found
314.0862.
5-((4-Fluorophenyl)thio)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline (3j). Isolated yield 82
1
mg (68%); white solid; mp 156−158 °C; R
f
0.62 (petroleum ether/ethyl acetate = 4:1 v/v). H
3
NMR (CDCl , 500 MHz): δ 2.62 (t, J = 7.3 Hz, 2H), 3.58 (t, J = 7.3 Hz, 2H), 6.00 (s, 2H), 6.68 (s,
1
3
3
1H), 7.09 (t, J = 8.9 Hz, 2H), 7.28 (s, 1H), 7.50−7.52 (m, 2H); C NMR (CDCl , 125 MHz): δ
2
2
6.7, 48.5, 101.4, 105.7, 107.9, 116.2 (d, JCꢀF = 21.9 Hz), 122.8, 124.6, 133.0, 137.2, 137.3,
1
+
146.4, 149.5, 162.9, 163.1 (d, JCꢀF = 248.3 Hz); HRMS (ESIꢀTOF, [M + H] ): calcd for
16 2
C H12FNO
S, 302.0651, found 302.0659.
5-((2-Fluorophenyl)thio)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline (3k). Isolated yield 89
1
mg (74%); white solid; mp 159−161 °C; R
f
0.52 (petroleum ether/ethyl acetate = 4:1 v/v). H
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2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NMR (CDCl
3
, 500 MHz):
δ
2.64 (t, J = 7.3 Hz, 2H), 3.61 (t, J = 7.3 Hz, 2H), 6.02 (s, 2H), 6.70 (s,
1
3
3
1H), 7.15−7.22 (m, 2H), 7.40−7.44 (m, 1H), 7.58 (t, J = 6.7 Hz, 1H); C NMR (CDCl , 125
2
2
MHz):
δ
26.6, 48.5, 101.4, 105.9, 107.8, 116.0 (d, JCꢀF = 22.7 Hz), 117.0 (d, JCꢀF = 18.1 Hz),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
122.7, 124.5, 131.3, 133.0, 137.2, 146.4, 149.5, 161.3, 162.7 (d, JCꢀF = 253.0 Hz); HRMS
+
(
ESIꢀTOF, [M + H] ): calcd for C16
2
H12FNO S, 302.0651, found 302.0661.
5-((3-Fluorophenyl)thio)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline (3l). Isolated yield 72
1
f
mg (60%); white solid; mp 125−127 °C; R 0.58 (petroleum ether/ethyl acetate = 4:1 v/v). H
NMR (CDCl
3
, 500 MHz):
δ 2.64 (t, J = 7.4 Hz, 2H), 3.62 (t, J = 7.4 Hz, 2H), 6.00 (s, 2H), 6.68 (s,
13
1
1
1
H), 7.05 (t, J = 8.1 Hz, 1H), 7.28−7.35 (m, 4H); C NMR (CDCl , 125 MHz):
δ
26.6, 48.5,
3
2
2
01.4, 105.9, 107.9, 115.6 (d, JCꢀF = 21.1 Hz), 121.6 (d, JCꢀF = 22.9 Hz), 122.8, 130.0, 131.8,
1
+
33.1, 146.5, 149.6, 162.4, 162.5 (d, J =247.3 Hz); HRMS (ESIꢀTOF, [M + H] ): calcd for
CꢀF
C
16
H
12FNO
2
S, 302.0651, found 302.0648.
5-((2,4-Dimethylphenyl)thio)-7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline (3m). Isolated
f
yield 102 mg (82%); white solid; mp 118−120 °C; R 0.40 (petroleum ether/ethyl acetate = 4:1
1
v/v). H NMR (CDCl
3
, 500 MHz):
δ
2.36 (s, 3H), 2.40 (s, 3H), 2.62 (t, J = 7.3 Hz, 2H), 3.59 (t, J
=
7.3 Hz, 2H), 6.02 (s, 2H), 6.70 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 7.38 (s, 1H), 7.45
13
(d, J = 7.8 Hz, 1H); C NMR (CDCl
3
, 125 MHz):
δ
20.8, 21.3, 48.5, 101.3, 105.9, 107.8, 123.0,
+
125.1, 127.4, 131.5, 132.9, 136.4, 139.6, 142.6, 146.3, 149.3, 162.5; HRMS (ESIꢀTOF, [M + H] ):
2
calcd for C18H17NO S, 312.1058, found 312.1062.
Ethyl 1-(phenylthio)isoquinoline-3-carboxylate (3n). Isolated yield 63 mg (51%); white solid;
1
mp 63−65 °C; R
f
0.68 (petroleum ether/ethyl acetate = 10:1 v/v). H NMR (CDCl
3
, 500 MHz):
δ
1
.33 (t, J = 7.2 Hz, 3H), 2.40 (q, J = 7.1 Hz , 2H), 7.38−7.44 (m, 3H), 7.69−7.78 (m, 4H), 7.93 (d,
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7
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1
3
J = 8.0 Hz, 1H), 8.29 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H); C NMR (CDCl
3
, 125 MHz): δ 14.1, 29.6,
6
1.3, 121.5, 124.9, 128.1, 128.5, 128.8, 129.4, 129.9, 131.0, 134.6, 135.5, 141.0, 159.6, 165.5;
+
2
HRMS (ESIꢀTOF, [M + H] ): Calcd for C18H15NO S, 310.0902, found 310.0914.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 7-methyl-1-(phenylthio)isoquinoline-3-carboxylate (3o). Isolated yield 75 mg (58%);
1
white solid; mp 84−86 °C; R
f
0.56 (petroleum ether/ethyl acetate = 10:1 v/v). H NMR (CDCl
3
,
5
7
1
1
00 MHz): δ 1.32 (t, J = 7.3 Hz, 3H), 2.60 (s, 3H), 4.32 (q, J = 7.2 Hz, 2H), 7.38−7.44 (m, 3H),
.59 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 7.9 Hz，2H), 7.82 (d, J =7.9 Hz, 1H)，8.14 (s, 1H)，8.26 (s,
13
H); C NMR (CDCl
3
, 125 MHz):
δ
14.1, 22.2, 61.2, 121.4, 124.0, 127.2, 128.4, 128.5, 128.8,
+
30.0, 133.1, 133.6, 134.6, 140.1, 140.3, 158.5, 165.6; HRMS (ESIꢀTOF, [M + H] ): calcd for
19 2
C H17NO S, 324.1058, found 324.1049.
Ethyl 7-methoxy-1-(phenylthio)isoquinoline-3-carboxylate (3p). Isolated yield 82 mg (60%);
1
white solid; mp 112−114 °C; R
f
0.50 (petroleum ether/ethyl acetate = 10:1 v/v). H NMR (CDCl
3
,
500 MHz):
δ
1.33 (t, J = 7.0 Hz, 3H), 2.60 (s, 3H), 4.33 (q, J = 7.1 Hz, 2H), 7.35−7.42 (m, 4H),
13
7
.56 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 9.2 Hz, 1H), 8.27 (s, 1H); C NMR (CDCl
3
,
125 MHz): δ 14.1, 55.6, 61.2, 121.6, 123.7, 128.2, 128.8, 129.9, 130.3, 130.8, 134.0, 139.4, 157.1,
+
1
60.3, 165.6; HRMS (ESIꢀTOF, [M + H] ): calcd for C H NO S, 340.1007, found 340.1012.
19 17 3
Ethyl 1-((4-methoxyphenyl)thio)-7-methylisoquinoline-3-carboxylate (3q). Isolated yield 89
1
mg (63%); white solid; mp 89−91 °C; R
f
0.55 (petroleum ether/ethyl acetate = 10:1 v/v). H NMR
(CDCl , 500 MHz):
δ
1.32 (t, J = 7.3 Hz, 3H), 2.60 (s, 3H), 3.84 (s, 3H), 4.30 (q, J = 7.2 Hz, 2H),
3
6
.99 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 7.9 Hz，
1
3
1H), 8.13 (s, 1H)，8.22 (s, 1H); C NMR (CDCl , 125 MHz):
δ
14.0, 22.1, 55.3, 61.1, 114.5,
3
1
20.1, 121.0, 123.8, 128.0, 128.5, 133.0, 133.5, 136.9, 139.9, 140.3, 159.4, 160.2, 165.7; HRMS
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
(
ESIꢀTOF, [M + H] ): calcd for C H NO S, 354.1158, found, 354.1171.
20 19 3
General procedure for the synthesis of compounds 4 (4a for example). To a dry
Schlenk tube was charged with a mixture of (2ꢀisothiocyanatoethyl) benzene 1c (66
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mg, 0.40 mmol), methyltriflate (99 mg, 0.60 mmol) and DCE (2.0 mL). The mixture
was allowed to stir at 80 °C for 2 h under N
cooled to room temperature, quenched with saturated NaHCO
EtOAc (10 mL × 3). The organic layer was washed with saturated NaCl and dried
over anhydrous MgSO . Evaporation of the solvent followed by purification on silica
2
atomsphere. After that, the mixture was
3
and extracted with
4
gel (petroleum ether/ethyl acetate) provided the product 4a.
22b
1
-(Methylthio)-3,4-dihydroisoquinoline (4a). Isolated yield 46 mg (64%); colorless oil; R
f
1
0
.48 (petroleum ether/ethyl acetate = 10:1 v/v). H NMR (CDCl
3
, 500 MHz):
δ
2.44 (s, 3H), 2.74
(
t, J = 7.3 Hz, 2H), 3.76 (t, J = 7.3 Hz, 2H), 7.19 (d, J = 7.3 Hz, 1H), 7.28 (t, J = 7.3 Hz, 1H), 7.36
13
(t, J = 7.6 Hz, 1H), 7.66 (d, J = 7.3 Hz, 1H); C NMR (CDCl
3
, 125 MHz): δ 12.2, 26.5, 48.2,
+
1
24.7, 126.9, 127.3, 129.3, 130.8, 136.8, 164.0; HRMS (ESIꢀTOF, [M + H] ): calcd for C10
H11NS,
178.0685, found 178.0689.
7
-Methyl-1-(methylthio)-3,4-dihydroisoquinoline (4b). Isolated yield 55 mg (72%); colorless
1
oil; R
f
0.43 (petroleum ether/ethyl acetate = 10:1 v/v). H NMR (CDCl
3
, 500 MHz):
δ
2.36 (s, 3H),
2
.44 (s, 3H), 2.68 (t, J = 7.3 Hz, 2H), 3.74 (t, J = 7.3 Hz, 2H), 7.04 (d, J = 7.6 Hz, 1H), 7.17 (d, J
13
= 7.5 Hz, 1H), 7.47 (s, 1H); C NMR (CDCl , 125 MHz):
δ
12.2, 21.2, 26.2, 48.5, 125.3, 127.2,
3
+
1
29.2, 131.5, 133.8, 136.5, 164.1; HRMS (ESIꢀTOF, [M + H] ): calcd for C11
H14NS, 192.0841,
found 192.0837.
7
-Methoxy-1-(methylthio)-3,4-dihydroisoquinoline (4c). Isolated yield 62 mg (75%);
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colorless oil; R
f
0.40 (petroleum ether/ethyl acetate = 10:1 v/v). H NMR (CDCl
3
, 500 MHz):
δ
2
1
4
.44 (s, 3H), 2.66 (t, J = 7.3 Hz, 2H), 3.73 (t, J = 7.3 Hz, 2H), 3.82 (s, 3H), 6.92 (q, J = 3.7 Hz,
1
3
H), 7.11 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H); C NMR (CDCl
3
, 125 MHz):
δ
12.4, 25.7,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
8.7, 55.5, 110.0, 116.7, 128.2, 129.0, 130, 158.5, 164.0; HRMS (ESIꢀTOF, [M + H] ): calcd for
11
C H13NOS, 208.0791, found 208.0795.
7-Fluoro-1-(methylthio)-3,4-dihydroisoquinoline (4d). Isolated yield 44 mg (56%); white
1
solid; mp 49−51 °C; R
f
0.50 (petroleum ether/ethyl acetate = 10:1 v/v). H NMR (CDCl
3
, 500
MHz):
δ 2.44 (s, 3H), 2.70 (t, J = 7.0 Hz, 2H), 3.75 (t, J = 7.3 Hz, 2H), 7.07 (td, J = 7.9, 2.4 Hz,
1
3
1H), 7.16 (t, J = 7.0 Hz, 1H), 7.37 (dd, J = 9.2, 2.4 Hz, 1H); C NMR (CDCl , 125 MHz):
δ
12.4,
3
2
2
3
2
5.8, 48.4, 111.9 (d, JCꢀF = 23.3 Hz), 117.6 (d, JCꢀF = 20.9 Hz), 128.7 (d, JCꢀF = 7.0 Hz), 130.4
3
4
1
(
d, J = 7.0 Hz), 132.4 (d, J = 3.0 Hz), 161.5 (d, J = 245.3 Hz), 163.1; HRMS (ESIꢀTOF,
CꢀF CꢀF CꢀF
+
[
M + H] ): calcd for C10H10FNS, 196.0591, found 196.0594.
1-(methylthio)-7-(trifluoromethyl)-3,4-dihydroisoquinoline (4e). Isolated yield 50 mg
1
(51%); white solid; mp 46−48 °C; R
f
0.46 (petroleum ether/ethyl acetate = 10:1 v/v). H NMR
3
(CDCl , 500 MHz): 2.45 (s, 3H), 2.79 (t, J = 7.0 Hz, 2H), 3.78 (t, J = 7.3 Hz, 2H), 7.32 (d, J = 7.9
13
3
Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.89 (s, 1H); C NMR (CDCl , 125 MHz): δ 12.3, 26.5, 47.8,
1
2
121.7, 123.8 (d, J = 272.1 Hz), 127.3, 127.9, 129.2 (d, J = 32.7 Hz), 129.5, 140.7, 162.9; HRMS
+
(
ESIꢀTOF, [M + H] ): calcd for C11
H
11
F
3
NS, 246.0559, found 246.0557
2
2b
6,7-dimethoxy-1-(methylthio)-3,4-dihydroisoquinoline (4f). Isolated yield 82 mg (86%);
1
white solid; mp 92−94 °C; R
f
0.37 (petroleum ether/ethyl acetate = 10:1 v/v). H NMR (CDCl
3
,
2
2b
500 MHz)
:
δ
2.43 (s, 3H), 2.65 (t, J = 7.3 Hz, 2H), 3.71 (t, J = 7.0 Hz, 2H), 3.90 (s, 6H), 6.68 (s,
13
1
H), 7.17 (s, 1H); C NMR (CDCl
3
, 125 MHz):
δ
12.3, 26.2, 48.3, 55.9, 56.1, 108.1, 110.0, 122.1,
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
1
30.4, 147.5, 151.0, 163.4; HRMS (ESIꢀTOF, [M + H] ): calcd for C H NO S, 238.0896, found
12
16
2
2
38.0894.
-(Methylthio)-6,7-dihydrothieno[3,2-c]pyridine (4g).
27
4
Isolated yield 44 mg (60%);
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
colorless oil; R 0.65 (petroleum ether/ethyl acetate = 10:1 v/v). H NMR (CDCl , 500 MHz):
δ
f
3
2
.44 (s, 3H), 2.86 (t, J = 7.9 Hz, 2H), 3.85 (t, J = 7.9 Hz, 2H), 7.07 (d, J = 5.5 Hz, 1H), 7.15 (d, J
13
=
5.5 Hz, 1H); C NMR (CDCl
3
, 125 MHz):
NS
-Methyl-1-(methylthio)-4,9-dihydro-3H-pyrido[3,4-b]indole (4h). Isolated yield 78 mg
δ
11.8, 22.8, 49.0, 122.2, 123.3, 131.1, 141.9, 160.2;
+
HRMS (ESIꢀTOF, [M + H] ): calcd for C
8
H
9
2
, 184.0249, found 184.0252.
9
1
(
f
84%); white solid; mp 55−58 °C; R 0.60 (petroleum ether/ethyl acetate = 4:1 v/v). H NMR
(
3
CDCl , 500 MHz): δ 2.54 (s, 3H), 2.85 (t, J = 7.6 Hz, 2H), 3.87 (t, J = 7.6 Hz, 2H), 4.04 (s, 3H),
13
7
.14−7.18 (m, 1H), 7.34 (d, J = 3.7 Hz, 2H), 7.61 (d, J = 7.9 Hz, 1H); C NMR (CDCl , 125
3
MHz):
δ
12.2, 20.0, 32.5, 49.6, 110.2, 117.4, 119.9, 120.0, 124.2, 124.3, 130.0, 138.5, 156.4;
+
HRMS (ESIꢀTOF, [M + H] ): calcd for C13
H
14
N
2
S, 231.0950, found 231.0956.
Procedure for the synthesis of compound 5. Under N atmosphere, to a dry
2
Schlenk tube was charged with a mixture of 1ꢀ(2ꢀisothiocyanatoethyl)ꢀ4ꢀ
methylbenzene 1r (71 mg, 0.40 mmol), TfOH (90 mg, 0.60 mmol) and DCE (2.0 mL).
The mixture was allowed to stir at 80 °C for 2 h. After completion, the mixture was
cooled to room temperature, neutralized with saturated NaHCO
EtOAc (10 mL × 3). The organic layer was washed with saturated NaCl and dried
over anhydrous MgSO . Evaporation of the solvent followed by purification on silica
3
and extracted with
4
gel (petroleum ether/ethyl acetate) provided the product 5 as an oily yellow solid.
28
7
-Methyl-3,4-dihydroisoquinoline-1(2H)-thione (5). Isolated yield 45 mg (64%); oily
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yellow solid; R
f
0.40 (petroleum ether/ethyl acetate = 4:1 v/v). H NMR (CDCl
3
, 500 MHz):
δ
2
8
.38 (s, 3H), 2.96 (t, J = 6.8 Hz, 2H), 3.50ꢀ3.54 (m, 2H), 7.05 (d, J = 7.9 Hz, 1H), 7.24 (s, 1H),
.33 (s, 1H), 8.43 (br s, 1H).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the synthesis of compound 3r-u (3r for example). Under
2
N atmosphere, to a dry Schlenk tube was charged with a mixture of 1r (71 mg, 0.40
mmol), diphenyliodonium salt 2a (256 mg, 0.60 mmol), CuCl (4 mg, 0.04 mmol),
TfOH (0.18 ꢁL, 0.002 mmol) and DCE (2.0 mL). The mixture was allowed to stir at
8
0 °C for 2 h. After completion, the mixture was cooled to room temperature,
quenched with saturated NaHCO and extracted with EtOAc (10 mL × 3). The organic
3
4
layer was washed with saturated NaCl and dried over anhydrous MgSO . Evaporation
of the solvent followed by purification on silica gel (petroleum ether/ethyl acetate)
provided the product 3r as a colorless oil (76 mg, 75%).
7-Methyl-1-(phenylthio)-3,4-dihydroisoquinoline (3r). Isolated yield 76 mg (75%); colorless
1
oil, R 0.62 (petroleum ether/ethyl acetate = 10:1 v/v). H NMR (DMSOꢀd , 500 MHz):
δ 2.37 (s,
f
6
3H), 2.62 (t, J = 7.2 Hz, 2H), 3.50 (t, J = 7.3 Hz, 2H), 7.20 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 7.6
13
Hz, 1H), 7.41 (m, 3H), 7.51 (m, 3H); C NMR (DMSOꢀd
6
, 125 MHz):
δ
21.2, 25.7, 48.4, 115.7,
122.8, 125.0, 125.1, 127.8, 128.1, 128.5, 129.2, 129.4, 129.6, 129.8, 132.3, 132.5, 134.6, 135.7,
+
1
36.8, 162.5; HRMS (ESIꢀTOF, [M + H] ): calcd for C16
H16NS, 254.0998, found 254.0997.
7-Methoxy-1-(phenylthio)-3,4-dihydroisoquinoline (3s). Isolated yield 83 mg (77%); white
1
solid; mp 75−77 °C; R
0.47 (petroleum ether/ethyl acetate = 10:1 v/v). H NMR (CDCl
, 500
f
3
MHz):
δ
2.65 (t, J = 7.3 Hz, 2H), 3.65 (t, J = 7.0 Hz, 2H), 3.84 (s, 3H), 6.94 (d, J = 7.9 Hz, 1H),
13
7
.12 (d, J = 7.9 Hz, 1H), 7.34 (s, 1H), 7.39 (q, J = 8.1 Hz, 3H), 7.56 (d, J = 6.7 Hz, 2H).
C
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NMR (CDCl
3
, 125 MHz):
δ
25.5, 48.9, 55.5, 110.3, 117.0, 128.3, 128.6, 129.0, 129.5, 135.1,
+
158.4, 163.6. HRMS (ESIꢀTOF, [M + H] ): calcd for C16
H16NOS, 270.0947, found 270.0947.
7
-Fluoro-1-(phenylthio)-3,4-dihydroisoquinoline (3t). Isolated yield 74 mg (72%); white
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
solid; mp 89−91 °C; R
f
0.58 (petroleum ether/ethyl acetate = 10:1 v/v). H NMR (CDCl
3
, 500
MHz):
δ
2.70 (t, J = 7.0 Hz, 2H), 3.68 (t, J = 7.3 Hz, 2H), 7.11 (td, J = 8.3, 2.3 Hz, 1H), 7.20 (t, J
13
=
6.7 Hz, 1H), 7.37ꢀ7.45 (m, 3H), 7.53 (dd, J = 9.0, 2.2 Hz, 1H), 7.58 (d, J = 6.5 Hz, 2H).
C
2
2
NMR (CDCl
3
, 125 MHz):
δ 25.6, 48.7, 112.2 (d, J = 23.3 Hz), 117.8 (d, J = 21.2 Hz), 128.9,
1
+
129.1, 130.0, 133.0, 134.7, 135.2, 161.5 (d, J = 242.7 Hz), 162.8. HRMS (ESIꢀTOF, [M + H] ):
calcd for C15H13FNS, 258.0747, found 258.0746.
6
-Methoxy-1-(phenylthio)-3,4-dihydroisoquinoline (3u). Isolated yield 86 mg (80%);
1
white solid; mp 102−104 °C; R 0.53 (petroleum ether/ethyl acetate = 10:1 v/v). H NMR (CDCl ,
f
3
500 MHz):
δ 2.72 (t, J = 7.3 Hz, 2H), 3.66 (t, J = 7.3 Hz, 2H), 3.86 (s, 3H), 6.74 (s, 1H), 6.82 (dd,
1
3
J = 8.5, 2.2 Hz, 1H), 7.36ꢀ7.42 (m, 3H), 7.58 (d, J = 7.3 Hz, 2H), 7.76 (d, J = 8.5 Hz, 1H).
C
NMR (CDCl , 125 MHz):
δ
26.9, 48.4, 55.4, 111.8, 111.9, 122.4, 127.0, 128.9, 135.0, 139.7, 161.5,
3
+
163.3. HRMS (ESIꢀTOF, [M + H] ): calcd for C16
H16NOS, 270.0947, found 270.0948.
2
Procedure for the synthesis of compound 6. Under N atmosphere, to a dry
Schlenk
tube
was
charged
with
(71
a
mixture
0.40
of
1
ꢀ(2ꢀisothiocyanatoethyl)ꢀ4ꢀmethylbenzene
1r
mg,
mmol),
diphenyliodonium salt 2a (256 mg, 0.60 mmol), CuCl (4 mg, 0.04 mmol) and DCE
2.0 mL). The mixture was allowed to stir at 80 °C for 2 h. After completion, the
mixture was cooled to room temperature, quenched with saturated NaHCO and
(
3
extracted with EtOAc (10 mL × 3). The organic layer was washed with saturated
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NaCl and dried over anhydrous MgSO
4
. Evaporation of the solvent followed by
purification on silica gel (petroleum ether/ethyl acetate) provided the product 6 as a
white solid (62 mg, 68%).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
S-Phenyl 4-methylphenethylcarbamothioate (6). Isolated yield 62 mg (68%); White solid;
1
mp 71−73 °C; R
f
0.45 (petroleum ether/ethyl acetate = 4:1 v/v). H NMR (CDCl
3
, 500 MHz):
δ
2
.33 (s, 3H), 2.74 (s, 2H), 3.49 (d, J = 6.9 Hz, 2H), 5.29 (brs, 1H), 6.98 (d, J = 6.4 Hz, 2H), 7.08
13
(
d, J = 6.8 Hz, 2H), 7.38 (m, 3H), 7.49 (d, J = 6.8 Hz, 2H); C NMR (CDCl
3
, 125 MHz):
δ
21.0,
+
3
5.0, 42.5, 128.5, 129.4 129.5, 129.6, 135.1, 135.5, 136.1, 166.1; HRMS (ESIꢀTOF, [M + H] ):
calcd for C16H17NOS, 272.1109, found 272.1112.
Procedure for the synthesis of rutaecarpine. A roundꢀbottom flask was charged
with a mixture of 2ꢀ(1Hꢀindolꢀ3ꢀyl)ethanꢀ1ꢀamine 7 (0.80 g, 5.0 mmol), DABCO
(
2
4.40 g, 20.0 mmol) and toluene (25 mL). To the stirred mixture, CS (1.52 g, 20.0
mmol) was added dropwise, and the mixture was stirred for overnight at room
temperature. Then the dithiocarbamate salt was filtered and washed with toluene. To a
roundꢀbottom flask was added the dithiocarbamate salt and CHCl
3
(15 mL). The
) was added
mixture was cooled to 0 °C and BTC (0.50 g, dissolved in CHCl
3
dropwise. The mixture was stirred for 1 h at 0 °C and refluxed for 2 h at 80 °C. After
completion, the mixture was evaporated under reduced pressure and purified by silica
gel column chromatography (petroleum ether/ethyl acetate) to obtain the
3
ꢀ(2ꢀisothiocyanatoethyl)ꢀ1Hꢀindole 8.
2
9
3-(2-Isothiocyanatoethyl)-1H-indole (8). Isolated yield 858 mg (85%); white solid; mp
1
4
5−47 °C (lit. mp 46−47 °C); R
f
0.58 (petroleum ether/ethyl acetate = 4:1 v/v). H NMR (CDCl
3
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4
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4
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5
5
5
5
6
5
00 MHz):
δ
3.16 (t, J = 6.8 Hz, 2H), 3.76 (t, J = 6.7 Hz, 2H), 7.09 (s, 1H), 7.15 (t, J = 7.3 Hz,
1
H), 7.22 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 8.04 (br s, 1H).
To a Schlenk tube was charged with 8 (122 mg, 0.60 mmol), methyltriflate (148 mg,
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
.90 mmol) and DCE (3 mL). The mixture was stirred for 2 h at 80 °C under N . After
2
completion, the mixture was cooled to room temperature, quenched with saturated
NaHCO and extracted with EtOAc (10 mL × 3). The organic layer was washed with
saturated NaCl and dried over anhydrous MgSO . Evaporation of the solvent followed
3
4
by purification on silica gel (petroleum ether/ethyl acetate) provided the product 9 as
a white solid.
1-(Methylthio)-4,9-dihydro-3H-pyrido[3,4-b]indole (9). Isolated yield 117 mg (90%); white
1
solid; mp 136−138 °C; R 0.36 (petroleum ether/ethyl acetate = 4:1 v/v). H NMR (CDCl , 500
f
3
MHz):
δ 2.53 (s, 3H), 2.90 (t, J = 8.2 Hz, 2H), 3.95 (t, J = 8.0 Hz, 2H), 7.16 (t, J = 7.3 Hz, 1H),
1
3
7.29 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 8.29 (br s, 1H);
C
NMR (CDCl , 125 MHz):
δ
11.4, 19.7, 49.8, 112.0, 116.2, 120.1, 120.5, 124.7, 125.5, 128, 136.4,
3
+
156.2; HRMS (ESIꢀTOF, [M + H] ): calcd for C12
H
12
N
2
S, 217.0799, found 217.0792.
To a roundꢀbottom flask was charged with a mixture of anthranilic acid (69 mg, 0.5
mmol), 9 (108 mg, 0.5 mmol) and acetic acid (5 mL). The mixture was refluxed under
stirring for 12 h. After cooling and evaporation of the solvent, the crude product was
recrystallized from EtOH to furnish the rutaecarpine as a white solid.
30
Rutaecarpine. Isolated yield 115 mg (80%); white solid; mp 259−261°C (lit. 259−260 °C); R
f
1
0.56 (petroleum ether/ethyl acetate = 2:1 v/v). H NMR (DMSOꢀd
6
, 500 MHz):
δ
3.18 (t, J = 6.8
Hz, 2H), 4.45 (t, J = 6.8 Hz, 2H), 7.09 (t, J = 7.4 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.46−7.50 (m,
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H), 7.64 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.81 (t, J = 7.0 Hz, 1H), 8.16 (d, J = 8.0 Hz,
1H), 11.88 (s, 1H).
1
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Supporting Information Available: Xꢀray data for 3a in CIF format; H and
C
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NMR spectra of all new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
ACKNOWLEDGEMENTS
This work was financially supported by the National Natural Science Foundation of
China (21372137 and 21572110), the Natural Science Foundation of Shandong
Province (ZR2014BM006), the Science and Technology Development Project in
University of Shandong Province (J16LC12), the Applied Basic Research Project
(Youth Special) of Qingdao (16ꢀ5ꢀ1ꢀ98ꢀjch), and the Research Fund of State Key
Laboratory for Marine Corrosion and Protection of Luoyang Ship Material Research
Institute (No. KF160404).
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