PdI2/I2-catalyzed thiolation-annulation of 2-alkynylbenzyl azides with disulfides: Selective synthesis of 4-sulfenylisoquinolines

Article abstract of DOI:10.1055/s-0030-1259965

A PdI₂/I₂-catalyzed thiolation-annulation route of alkynes with azides and disulfides for the synthesis of 4-sulfenylisoquinolines is described. This route allows numerous 2-alkynylbenzyl azides to react with disulfides or 1,2-diphen

Full text of DOI:10.1055/s-0030-1259965

PAPER
1219
PdI2/I2-Catalyzed Thiolation-Annulation of 2-Alkynylbenzyl Azides with
Disulfides: Selective Synthesis of 4-Sulfenylisoquinolines
S
ynthesis of 4-Sul
o
f
enylisoquino
n
lines g-Ping Zhang,a,b Xu-Heng Yang,a Peng Peng,a Jin-Heng Li*a
a
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education), Hunan Normal University,
Changsha 410081, P. R. of China
Fax +86(731)88872576; E-mail: jhli@hunnu.edu.cn
Department of Biology and Chemistry Engineering, Shaoyang University, Shaoyang 422000, P. R. of China
b
Received 7 February 2011; revised 26 February 2011
lyzed cyclization of 2-alkynylbenzyl azides leading to
1,3-disubstituted isoquinolines. Yamamoto’s group have
employed 2-alkynylbenzyl azides to construct the 1,3-di-
substituted 4-haloisoquinoline skeleton via an electrophilic
Abstract: A PdI2/I2-catalyzed thiolation-annulation route of
alkynes with azides and disulfides for the synthesis of 4-sulfenyliso-
quinolines is described. This route allows numerous 2-alkynylben-
zyl azides to react with disulfides or 1,2-diphenyldiselane leading to
the corresponding 4-chalcogen-substituted isoquinolines in moder-
ate to good yields.
Table 1 Screening of Optimal Conditions in the Reaction of 1a with
2aa
Key words: palladium, iodine, thiolation, annulation, 2-alkynyl-
benzyl azides, disulfides, isoquinolines
SPh
Ph
Ph
+
PhSSPh
N
N3
2a
3
1a
Intramolecular annulation of alkynes, particularly electro-
philic annulation of alkynes, has become one of the most Entry [Pd] (mol%) Additive
important methods in organic synthesis because it pro-
Solvent
Temp Yield
(equiv)
(°C)
80
80
80
80
80
80
80
80
80
80
80
60
100
80
80
80
80
80
80
(%)b
trace
35
vides excellent opportunities for the construction of car-
1
2
PdCl2 (5)
PdCl2 (5)
–
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
bocycles and heterocycles from readily accessible
substrates by simple initiation with excellent selectivity.1–5
This intramolecular annulation method is also applied in
the synthesis of the isoquinoline nucleus,1–6 which is
widely present in many natural products and biologically
active molecules.6 For example, Larock’s group have re-
ported that a wide range of 3,4-disubstituted isoquinolines
were synthesized by Pd-catalyzed annulation of alkynes
(or allenes) with aldehydes and tert-butylamine.2 Interest-
ingly, recent results have demonstrated that 2-alkynylben-
zyl azides were suitable substrates for the synthesis of
isoquinoline derivatives by either Lewis acid catalyzed in-
tramolecular annulation3c,g or electrophilic iodocycliza-
tion transformations.4 Liang’s group3c and Yamamoto’s
group3g independently have reported Ag or Au/Ag-cata-
I2 (2)
I2 (2)
I2 (2)
–
3
12
4
PdI2 (5)
PdI2 (5)
PdBr2 (5)
PdI2 (5)
PdI2 (5)
PdI2 (5)
PdI2 (5)
PdI2 (5)
PdI2 (5)
PdI2 (5)
PdI2 (5)
PdI2 (5)
PdI2 (5)
PdI2 (5)
PdI2 (10)
PdI2 (1)
73
5
6
6
I2 (2)
I2 (3)
I2 (1)
NIS (2)
ICl (2)
40
7
70
8
53
9
50
10
11
12
13
14
15
16
17
18
19
43
n-Bu4NI (2) MeCN
trace
64
YR4
R2
I2 (2)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
I2 (2)
MeCN
MeCN
DMSO
1,4-dioxane
DCE
R4
PdCl2, I2
2 (1)
R1
R
+
R1
61
Y
Y
MeCN, 80 °C
O
R4
OR3
36
Y = S, Se
YR3
R2
trace
60
R2
PdI2, I2
+
R3YYR3
(2)
MeCN, 80 °C
N
N3
2
R1
R1
toluene
MeCN
MeCN
60
Y = S, Se
1
75
Scheme 1 Synthesis of chalcogen-substituted compounds
28
SYNTHESIS 2011, No. 8, pp 1219–1226
Advanced online publication: 22.03.2011
DOI: 10.1055/s-0030-1259965; Art ID: H18211SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
1
a Reaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), [Pd], additive,
and solvent (2 mL) for 22 h under N2 atmosphere.
b Isolated yield.

1220
H.-P. Zhang et al.
PAPER
iodocyclization process.4 Recently, we also developed an ciency, enhancing the yield of 3 to 73% (entries 1–6). The
efficient synthesis of 3-chalcogen-benzo[b]furans via pal- results demonstrated that the amount of I2 affected the re-
ladium-promoted annulation reaction of 2-alkynylphenol action to some extent (entries 7 and 8). While identical re-
derivatives with disulfides or diselenides and iodide sults were obtained at a loading of three equivalents of I2
(Scheme 1, equation 1).7d In continuation of our interest in (entry 7), the yield was lowered to 53% using one equiv-
the synthesis of chalcogen-substituted compounds,7 we alent of I2 (entry 8). In light of these results, some other
decided to explore the feasibility of synthesizing sulfenyl- additives, such as NIS, ICl, and n-Bu4NI were subse-
isoquinolines using 2-alkynylbenzyl azides as the starting quently investigated (entries 9–11). However, the results
substrates because the S-contained group has a significant showed that they were less active than I2. Among the re-
effect on the biological activity and often manifests action temperature and solvents examined, it turned out
changes in chemical and physical properties.6 Here, we re- that the reaction in MeCN at 80 °C gave the best yields
port a new, selective protocol for the synthesis of 4-sulfe- (entries 12–17). Finally, the loading of PdI2 was evaluated
nylisoquinolines by PdI2/I2-catalyzed thiolation- (entries 18 and 19). We found that a good yield was
annulation of alkynes with azides and disulfides achieved at 10 mol% PdI2, and 1 mol% PdI2 resulted in an
(Scheme 1, equation 2).
unsatisfactory yield.
As shown in Table 1, the reaction between 1-azidometh- As shown in Table 2, the scope of both azides 1 and di-
yl-2-(phenylethynyl)benzene (1a) and 1,2-diphenyldisul- sulfides 2 was investigated under the standard reaction
fane (2a) was chosen as the model reaction to screen the conditions. The results demonstrated that disulfides 2b–d,
optimal reaction conditions. Initially, treatment of azide bearing a Me, MeO, or Cl group on the aryl moiety, were
1a with disulfide 2a under the reported reaction tolerated well in moderate to good yields (Table 2, entries
conditions7d afforded a low yield: a trace of the desired 1–3). However, disulfides 2e with an electron-deficient
product 3 was observed in the absence of I2, and 35% group displayed no activity (entry 4). It was pleasing to
yield in the presence of two equivalents of I2 (Table 1, en- note that aliphatic disulfide 2f successfully underwent the
tries 1 and 2). It is noteworthy that 12% yield was still iso- annulation with azide 1a, PdI2, and I2 in 60% yield (entry
lated using I2 alone (entry 3). After a series of trials, it was 5). To our delight, a variety of azides 1b–l were smoothly
found that PdI2 combined with I2 displayed the most effi- annulated with 1,2-diphenyldisulfane (2a), PdI2, and I2,
providing moderate to good yields of the products (entries
R
SePh
6–16). It was found that several functional groups, includ-
ing methoxy, methyl, nitro, acetyl, and chloro groups, on
the terminal alkyne were perfectly consistent with the
standard conditions, and electron-withdrawing groups fa-
vored the reaction (entries 6–12). While substrate 1b with
a methoxy group resulted in 49% yield (entry 6), nitro-
substituted substrate 1f gave the desired product 13 in
80% yield (entry 10). Aliphatic alkynes 1i and 1j were
R
PdI2, I2
+
PhSeSePh
MeCN, 80 °C, 24 h
N3
N
2g
1a R = Ph
1m R = n-C8H13
20 (80%)
21 (75%)
Scheme 2 Selenation of 2-alkynylbenzyl azides 1 with 1,2-diphe-
nyldiselane (2g)
N3
R2SSR2
I2
N2
R1
N
2
Pd(0)
IPdSR2
PdI2
R2SI
R1
N
I(R2S)Pd
A
R2SSR2
R1
2
SR2
+ H+ + N2
R2SI
I2
N2
N2
N2
N
N
N
Pd
R1
PdI
R1
R2S
S
R1
I
R2S
R2
B'
C
B
N2
N
– N2
N
R1
R1
SR2
D
SR2
Scheme 3 Possible mechanisms of thiolation-annulation reaction
Synthesis 2011, No. 8, 1219–1226 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Sulfenylisoquinolines
1221
also suitable substrates for the thiolation-annulation reac- Screening revealed that the reaction could take place in
tion with disulfide 2a, PdI2, and I2 affording the products the presence of PdI2 or I2 alone, suggesting an electro-
16 and 17 in 68% and 72% yield, respectively (entries 13 philic addition process (Table 1, entries 3 and 5). Thus,
and 14). Gratifyingly, the standard conditions were com- possible mechanisms as outlined in Scheme 3 were pro-
patible with substrates 1k,l with a MeO or OCH2O group posed. The reaction between PdI2 and R2SSR2 yields the
on the aryl ring of the benzyl azide moiety (entries 15 and Pd(SR2)I complex together with R2SI, followed by coor-
16). For example, 5-(azidomethyl)-6-(phenylethynyl)ben- dination of Pd(SR2)I with an alkyne affording the interme-
zo[d][1,3]dioxole (1l) underwent the annulation with 1,2- diate A. Thiopalladation of the alkyne takes place leading
diphenyldisulfane (2a), PdI2, and I2 to give 19 in 68% to intermediate B. Subsequently, intramolecular addition
yield (entry 16).
of Pd into the N=N bond of intermediate B gives interme-
diate C. Intermediate C undergoes reductive elimination/
deprotonation to afford the desired product, N2, HI, and
the Pd(0) species. The Pd(0) species may react with I2 or
R2SI to regenerate the corresponding active PdI2 or
Pd(SR2)I species.
Selenylation of 2-alkynylbenzyl azides 1 with 1,2-diphe-
nyldiselane (2g) was subsequently investigated in the
presence of PdI2 and I2 (Scheme 2). Treatment of 2-alky-
nylbenzyl azides 1 with 1,2-diphenyldiselane (2g), PdI2
and I2 afforded the corresponding 4-selenylisoquinoline
products 20 and 21 in 80% and 75% yield, respectively.
Table 2 Thiolation Annulation Reactions of 2-Alkynylbenzyl Azides 1 with Disulfides 2a
R2
SR3
R2
PdI2, I2
+
R3SSR3
MeCN, 80 °C
N3
N
2
R1
R1
1
Entry
Azide 1
Disulfide 2
Product (yield)b
Ph
1
2
3
4
5
1a
2b
4 (72%)
S
2
N3
N3
N3
N3
N3
Ph
Ph
Ph
Ph
1a
1a
1a
1a
2c
2d
2e
2f
5 (86%)
6 (36%)
7 (trace)
8 (60%)
MeO
Cl
S
2
S
2
O2N
S
2
S
2
OMe
6
7
1b
1c
2a
2a
9 (49%)
S
S
2
N3
10 (57%)
2
N3
Synthesis 2011, No. 8, 1219–1226 © Thieme Stuttgart · New York

1222
H.-P. Zhang et al.
PAPER
Table 2 Thiolation Annulation Reactions of 2-Alkynylbenzyl Azides 1 with Disulfides 2a (continued)
R2
SR3
R2
PdI2, I2
+
R3SSR3
MeCN, 80 °C
N3
N
2
R1
R1
1
Entry
Azide 1
Disulfide 2
Product (yield)b
8
9
1d
2a
11 (55%)
S
S
S
2
N3
1e
1f
2a
2a
12 (58%)
13 (80%)
2
N3
NO2
10
2
2
2
N3
O
11
12
1g
1h
2a
2a
14 (84%)
15 (76%)
S
S
N3
Cl
N3
N3
N3
13
14
1i
1j
2a
2a
16 (68%)
17 (72%)
S
S
2
2
Ph
15
16
1k
1l
2a
2a
18 (70%)
19 (68%)
S
S
2
2
N3
Ph
MeO
O
O
N3
a Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), PdI2 (5 mol%), I2 (2 equiv) and MeCN (2 mL) at 80 °C for 20–26 h under N2 atmosphere.
b Isolated yield.
Synthesis 2011, No. 8, 1219–1226 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Sulfenylisoquinolines
1223
1H NMR (500 MHz, CDCl3): d = 9.35 (s, 1 H), 8.41 (d, J = 8.5 Hz,
1 H), 8.21 (d, J = 8.5 Hz, 1 H), 8.02–7.92 (m, 4 H), 7.49–7.38 (m,
3 H), 6.91 (d, J = 8.0 Hz, 2 H), 6.82 (d, J = 8.0 Hz, 2 H), 2.21 (s, 3
H).
13C NMR (125 MHz, CDCl3): d = 158.2, 153.2, 140.8, 138.3, 135.1,
134.4, 131.6, 129.8, 129.7, 128.2, 128.1 (2C), 127.6, 127.4, 126.9,
126.2, 122.2, 20.8.
LRMS (EI, 70 eV): m/z (%) = 329 (M+ + 2, 20), 327 (M+, 80), 326
(20), 294 (13), 251(19), 250 (23), 235 (100).
HRMS (EI): m/z calcd for C22H17NS (M+): 327.1082; found:
327.1081.
We can not rule out that the desired product is obtained via
another electrophilic mechanism: the thionium intermedi-
ate B¢ can be generated from intermediate A with the aid
of Pd catalyst, followed by addition with a nitrogen atom
and elimination yields the desired product.
In summary, we have developed a novel PdI2/I2-catalyzed
thiolation-annulation protocol for the synthesis of 4-sulfe-
nylisoquinolines using 2-alkynylbenzyl azides and disul-
fides as the reaction partners. In the presence of PdI2 and
I2, a variety of 2-alkynylbenzyl azides were reacted with
numerous disulfides smoothly to afford the corresponding
4-sulfenylisoquinolines in moderate to good yields. More-
over, this method allows 2-alkynylbenzyl azides to react
with 1,2-diphenyldiselane giving the products in good
yields under the same conditions. Notably, several fea-
tures of the present reaction are obvious: (1) selectivity
was shifted toward to 4-sulfenylisoquinolines or 4-sele-
nylisoquinolines, and not to 4-iodoisoquinolines using the
PdI2/I2 system, (2) the reaction can take place in the pres-
ence of PdI2 or I2 alone, but PdI2 combined with I2 was the
most efficient, and (3) the electron-deficient aryl groups at
the terminal alkynes favor the reaction, however, disul-
fides with electron-deficient aryl groups are inert.
4-(4-Methoxyphenylthio)-3-phenylisoquinoline (5)
Brown solid; mp 128.6–130.1 °C.
1H NMR (500 MHz, CDCl3): d = 9.32 (s, 1 H), 8.48 (d, J = 8.5 Hz,
1 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.64–7.59
(m, 3 H), 7.43–7.38 (m, 3 H), 6.87 (d, J = 8.5 Hz, 2 H), 6.64 (d,
J = 8.5 Hz, 2 H), 3.68 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 158.0, 157.9, 152.9, 140.8, 138.2,
131.5, 129.9, 129.4, 128.3, 128.2, 128.1, 128.0, 127.6, 127.4, 126.2,
123.5, 114.6, 55.2.
LRMS (EI, 70 eV): m/z (%) = 343 (M+, 96), 342 (16), 267 (22), 236
(100), 251 (25), 223 (23), 222 (10).
HRMS (EI): m/z calcd for C22H17NOS (M+): 343.1030; found:
343.1026.
NMR spectroscopy was performed on a Bruker 500 spectrometer
operating at 500 MHz (1H NMR) and 125 MHz (13C NMR). TMS
was used an internal standard and CD3Cl was used as the solvent.
Mass spectrometric analysis was performed on a GC-MS instru-
ment (Shimadzu GCMS-QP2010 plus). All melting points are un-
corrected.
4-(4-Chlorophenylthio)-3-phenylisoquinoline (6)
Brown solid; mp 125.8–127.3 °C.
1H NMR (500 MHz, CDCl3): d = 9.38 (s, 1 H), 8.37 (d, J = 8.5 Hz,
1 H), 8.06 (d, J = 8.0 Hz, 1 H), 7.75 (t, J = 7.5 Hz, 1 H), 7.66 (d,
J = 7.5 Hz, 1 H), 7.61–7.59 (m, 2 H), 7.41–7.39 (m, 3 H), 7.07 (d,
J = 8.5 Hz, 2 H), 6.83 (d, J = 9.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 158.5, 153.6, 140.6, 138.1, 136.4,
131.9, 131.2, 129.7, 129.1, 128.3 (2C), 128.2, 128.1, 127.8, 127.7,
125.9, 121.5.
LRMS (EI, 70 eV): m/z (%) = 349 (M+ + 2, 40), 347 (M+, 98), 348
(33), 346 (21), 314 (12), 272 (41), 271 (21), 270 (40), 236 (100).
HRMS (EI): m/z calcd for C21H14ClNS (M+): 347.0536; found:
347.0532.
Palladium-Catalyzed Annulation of 2-Alkynylbenzyl Azides 1
with Disulfides 2; General Procedure
2-(Alk-1-ynyl)benzyl azide 1 (0.2 mmol), disulfide 2 (0.1 mmol),
PdI2 (5 mol%), I2 (2 equiv), and MeCN (2 mL) were added in turn
to a Schlenk tube. Then, the mixture was stirred at 80 °C under N2
atmosphere for the indicated time until complete consumption of
starting material as monitored by TLC and GC-MS analysis (ca. 20–
26 h). After completion of the reaction, the mixture was poured into
H2O (3 mL), and extracted with EtOAc (3 × 5 mL). The combined
organic layers were washed with brine (5 × 3 mL), dried (Na2SO4),
and evaporated under vacuum. The residue was purified by flash
column chromatography on silica gel (hexane–EtOAc) to afford the
desired product.
4-(Benzylthio)-3-phenylisoquinoline (8)
Brown solid; mp 126.9–128.4 °C.
1H NMR (500 MHz, CDCl3): d = 9.25 (s, 1 H), 8.62 (d, J = 8.5 Hz,
1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.78 (t, J = 7.5 Hz, 1 H), 7.64 (t,
J = 7.0 Hz, 1 H), 7.56–7.54 (m, 2 H), 7.43–7.42 (m, 3 H), 7.09–7.03
(m, 3 H), 6.75 (d, J = 7.0 Hz, 2 H), 3.69 (s, 2 H).
13C NMR (125 MHz, CDCl3): d = 157.9, 152.1, 141.0, 138.6, 137.1,
131.3, 130.1, 128.7, 128.1 (2 C), 127.8 (2C), 127.6, 127.2, 126.9,
125.9, 124.1, 40.2.
LRMS (EI, 70 eV): m/z (%) = 329 (M+ + 2, 20), 327 (M+, 80), 326
(20), 294 (13), 251 (19), 250 (100), 204 (30).
HRMS (EI): m/z calcd for C22H17NS (M+): 327.1082; found:
327.1080.
3-Phenyl-4-(phenylthio)isoquinoline (3)
Brown solid; mp 129.5–130.9 °C.
1H NMR (500 MHz, CDCl3): d = 9.37 (s, 1 H), 8.41 (d, J = 8.5 Hz,
1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.71 (t, J = 7.5 Hz, 1 H), 7.64–7.61
(m, 3 H), 7.41–7.37 (m, 3 H), 7.11 (t, J = 7.5 Hz, 2 H), 7.04 (t,
J = 7.5 Hz, 1 H), 6.92 (d, J = 8.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 158.4, 153.4, 140.7, 138.3, 138.0,
131.8, 129.7, 128.9, 128.2 (2 C), 128.1, 127.7, 127.5, 126.7, 126.2,
125.3, 121.8.
LRMS (EI, 70 eV): m/z (%) = 315 (M+ + 2, 11), 313 (M+, 58), 312
(17), 280 (10), 237 (18), 236 (100), 235 (15).
HRMS (EI): m/z calcd for C21H15NS (M+): 313.0925; found:
313.0922.
3-(4-Methoxyphenyl)-4-(phenylthio)isoquinoline (9)
Brown solid; mp 128.5–129.9 °C.
1H NMR (500 MHz, CDCl3): d = 9.36 (s, 1 H), 8.38 (d, J = 8.5 Hz,
1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.71 (t, J = 7.5 Hz, 1 H), 7.64–7.60
(m, 3 H), 7.13 (t, J = 7.5 Hz, 2 H), 7.05 (t, J = 7.0 Hz, 1 H), 6.95–
6.93 (m, 4 H), 3.84 (s, 3 H).
3-Phenyl-4-(p-tolythio)isoquinoline (4)
Brown solid; mp 126.5–127.9 °C.
Synthesis 2011, No. 8, 1219–1226 © Thieme Stuttgart · New York

1224
H.-P. Zhang et al.
PAPER
13C NMR (125 MHz, CDCl3): d = 158.0, 157.9, 152.9, 140.8, 138.2,
131.5, 129.9, 129.4, 128.3, 128.2, 128.1, 128.0, 127.7, 127.4, 126.2,
123.5, 114.6, 55.2.
LRMS (EI, 70 eV): m/z (%) = 360 (M+ + 2, 27), 358 (M+, 100), 357
(14), 311 (11), 282 (10), 281 (52), 236 (15), 235 (63).
HRMS (EI): m/z calcd for C21H14N2O2S (M+): 358.0776; found:
358.0773.
LRMS (EI, 70 eV): m/z (%) = 343 (M+, 96), 342 (16), 267 (22), 266
(100), 251 (25), 223 (23), 222 (10).
1-{4-[4-(Phenylthio)isoquinolin-3-yl]phenyl}ethanone (14)
White solid; mp 126.3.1–127.8 °C.
HRMS (EI): m/z calcd for C22H17NOS (M+): 343.1030; found:
343.1028.
1H NMR (500 MHz, CDCl3): d = 9.39 (s, 1 H), 8.43 (d, J = 8.0 Hz,
1 H), 8.08 (d, J = 8.0 Hz, 1 H), 7.98 (d, J = 8.5, 2 H), 7.78–7.66 (m,
4 H), 7.12 (t, J = 7.0 Hz, 2 H), 7.07 (t, J = 7.5 Hz, 1 H), 6.91 (d,
J = 7.5 Hz, 2 H), 2.63 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 197.9, 157.2, 153.6, 145.4, 138.3,
137.6, 136.4, 132.0, 130.1, 129.1, 128.4, 128.0, 127.8, 127.7, 126.7,
126.2, 125.5, 122.4, 26.7.
LRMS (EI, 70 eV): m/z (%) = 357 (M+ + 2, 27), 355 (M+, 92), 354
(21), 340 (19), 280 (11), 279 (19), 278 (100), 235 (44), 236 (21).
HRMS (EI): m/z calcd for C23H17NOS (M+): 355.1031; found:
355.1029.
4-(Phenylthio)-3-(p-tolyl)isoquinoline (10)
Brown solid; mp 131.8–133.3 °C.
1H NMR (500 MHz, CDCl3): d = 9.37 (s, 1 H), 8.37 (d, J = 8.5 Hz,
1 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.70 (t, J = 7.5 Hz, 1 H), 7.62 (t,
J = 7.5 Hz, 1 H), 7.55 (d, J = 8.0 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H),
7.12 (t, J = 7.0 Hz, 2 H), 7.04 (t, J = 7.5 Hz, 1 H), 6.93 (d, J = 8.5
Hz, 2 H), 2.39 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 158.5, 153.4, 138.3, 138.2, 138.0,
137.9, 131.7, 129.7, 128.9, 128.4, 128.2 (2C), 127.4, 126.6, 126.2,
125.2, 121.3, 21.3.
LRMS (EI, 70 eV): m/z (%) = 329 (M+ + 2, 20), 327 (M+, 80), 326
(20), 294 (13), 251 (19), 250 (100), 235 (23).
3-(4-Chlorophenyl)-4-(phenylthio)isoquinoline (15)
Brown solid; mp 125.4–126.9 °C.
HRMS (EI): m/z calcd for C22H17NS (M+): 327.1082; found:
327.1085.
1H NMR (500 MHz, CDCl3): d = 9.36 (s, 1 H), 8.42 (d, J = 8.0 Hz,
1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.73 (t, J = 7.5 Hz, 1 H), 7.65 (t,
J = 7.5 Hz, 1 H), 7.57 (d, J = 8.5 Hz, 2 H), 7.36 (d, J = 6.5 Hz, 2 H),
7.12 (t, J = 7.5 Hz, 2 H), 7.06 (t, J = 7.5 Hz, 1 H), 6.90 (d, J = 7.0
Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 157.1, 153.5, 139.1, 138.4, 137.7,
134.3, 131.9, 131.2, 129.0, 128.3, 128.2, 127.9, 127.8, 126.7, 126.1,
125.5, 122.0.
4-(Phenylthio)-3-o-tolylisoquinoline (11)
Brown solid; mp 130.2–131.7 °C.
1H NMR (500 MHz, CDCl3): d = 9.36 (s, 1 H), 8.42 (d, J = 8.5 Hz,
1 H), 8.07 (d, J = 8.0 Hz, 1 H), 7.74 (t, J = 7.5 Hz, 1 H), 7.66 (t,
J = 7.5 Hz, 1 H), 7.29–7.23 (m, 2 H), 7.16 (d, J = 8.5 Hz, 2 H),
7.09–7.02 (m, 3 H), 6.87 (d, J = 8.5 Hz, 2 H), 2.06 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 159.0, 153.1, 140.6, 138.0, 137.3,
135.9, 131.7, 129.9, 129.0, 128.7, 128.3, 128.2, 128.1, 127.6 (2 C),
126.0, 125.5, 125.2, 123.6, 19.8.
LRMS (EI, 70 eV): m/z (%) = 349 (M+ + 2, 40), 347 (M+, 98), 346
(21), 314 (12), 272 (41), 271 (21), 270 (100).
HRMS (EI): m/z calcd for C21H14ClNS (M+): 347.0536; found:
347.0532.
LRMS (EI, 70 eV): m/z (%) = 329 (M+ + 2, 20), 327 (M+, 80), 326
(20), 294 (13), 251 (19), 250 (100), 235 (23).
3-Cyclopropyl-4-(phenylthio)isoquinoline (16)
Colorless oil.
HRMS (EI): m/z calcd for C22H17NS (M+): 327.1082; found:
327.1081.
1H NMR (500 MHz, CDCl3): d = 9.15 (s, 1 H), 8.37 (d, J = 8.5 Hz,
1 H), 7.89 (d, J = 8.0 Hz, 1 H), 7.64 (t, J = 7.5 Hz, 1 H), 7.48 (t,
J = 7.5 Hz, 1 H), 7.15 (t, J = 7.5 Hz, 2 H), 7.07–7.03 (m, 3 H), 3.08–
3.04 (m, 1 H), 1.20–1.18 (m, 2 H), 0.99–0.97 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 160.9, 153.7, 138.4, 137.5, 131.4,
128.9, 127.9, 127.4, 126.4, 126.2, 125.1 (2C), 120.1, 15.2, 10.4.
LRMS (EI, 70 eV): m/z (%) = 279 (M+ + 2, 27), 277 (M+, 100), 236
(20), 200 (19), 127 (10).
HRMS (EI): m/z calcd for C18H15NS (M+): 277.0925; found:
277.0923.
3-(Naphthalen-1-yl)-4-(phenylthio)isoquinoline (12)
Pale yellow oil.
1H NMR (500 MHz, CDCl3): d = 9.43 (s, 1 H), 8.44 (d, J = 8.0 Hz,
1 H), 8.11 (d, J = 8.0 Hz, 1 H), 7.88 (d, J = 8.5 Hz, 2 H), 7.77 (t,
J = 7.5 Hz, 1 H), 7.70 (t, J = 8.0 Hz, 1 H), 7.47–7.40 (m, 4 H), 7.33
(t, J = 7.0 Hz, 1 H), 7.03–6.97 (m, 3 H), 6.85–6.83 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 157.9, 153.2, 138.5, 138.0, 137.5,
133.6, 131.9, 131.8, 128.7, 128.5, 128.3, 128.2, 127.8, 127.5, 126.9,
126.1, 125.7, 125.6, 125.4, 124.9, 124.8.
LRMS (EI, 70 eV): m/z (%) = 365 (M+ + 2, 27), 363 (M+, 81.5), 362
(76), 287 (24), 286 (100), 285 (19), 284 (12), 254 (37), 253 (29).
3-tert-Butyl-4-(phenylthio)isoquinoline (17)
Colorless oil.
HRMS (EI): m/z calcd for C25H17NS (M+): 363.1082; found:
363.1079.
1H NMR (500 MHz, CDCl3): d = 9.26 (s, 1 H), 8.31 (d, J = 8.5 Hz,
1 H), 7.95 (d, J = 7.5 Hz, 1 H), 7.58–7.52 (m, 2 H), 7.12 (t, J = 7.5
Hz, 2 H), 7.02 (t, J = 7.5 Hz, 1 H), 6.85 (d, J = 7.5 Hz, 2 H), 1.66
(s, 9 H).
3-(4-Nitrophenyl)-4-(phenylthio)isoquinoline (13)
Brown solid; mp 140.1–140.5 °C.
1H NMR (500 MHz, CDCl3): d = 9.39 (s, 1 H), 8.47 (d, J = 8.5 Hz,
1 H), 8.23 (d, J = 9.0 Hz, 2 H), 8.10 (d, J = 8.0 Hz, 1 H), 7.80 (t,
J = 8.5 Hz, 3 H), 7.72 (t, J = 7.5 Hz, 1 H), 7.14–7.06 (m, 3 H), 6.88
(d, J = 8.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 155.8, 153.7, 147.5, 147.1, 138.3,
137.2, 132.3, 130.8, 129.2, 128.6, 128.4, 128.3, 126.9, 126.2, 125.8,
123.1, 123.0.
13C NMR (125 MHz, CDCl3): d = 166.6, 151.8, 139.2, 138.9, 131.1,
128.9, 127.9, 127.8, 126.8, 125.8, 125.7, 124.7, 121.0, 40.3, 30.9.
LRMS (EI, 70 eV): m/z (%) = 295 (M+ + 2, 20), 293 (M+, 13), 217
(18), 216 (100), 200 (12), 175 (8).
HRMS (EI): m/z calcd for C19H19NS (M+): 293.1238; found:
293.1237.
Synthesis 2011, No. 8, 1219–1226 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Sulfenylisoquinolines
1225
7-Methoxy-3-phenyl-4-(phenylthio)isoquinoline (18)
White solid; mp 114.2–115.7 °C.
Acknowledgment
The authors thank the Scientific Research Fund of Hunan Provincial
Education Department (No. 08A037) and Natural Science Founda-
tion of China (No. 20872112) for financial support.
1H NMR (500 MHz, CDCl3): d = 9.27 (s, 1 H), 8.30 (d, J = 9.5 Hz,
1 H), 7.61 (d, J = 8.0 Hz, 2 H), 7.40–7.33 (m, 4 H), 7.29 (s, 1 H),
7.11 (t, J = 7.5 Hz, 2 H), 7.04 (t, J = 7.5 Hz, 1 H), 6.91 (d, J = 7.5
Hz, 2 H), 3.95 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 158.7, 156.6, 152.0, 140.8, 138.2,
133.9, 129.8, 129.6, 129.0, 128.0 (2C), 127.7, 126.7, 125.3, 124.7,
121.7, 105.3, 55.6.
References
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LRMS (EI, 70 eV): m/z (%) = 345 (M+ + 2, 25), 343 (M+, 100), 342
(16), 310 (13), 267 (21), 266 (88), 223 (36).
HRMS (EI): m/z calcd for C22H17NOS (M+): 343.1031; found:
343.1028.
7-Phenyl-8-(phenylthio)[1,3]dioxolo[4,5-g]isoquinoline (19)
White solid; mp 120.4–121.7 °C.
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Cook, J. M. Chem. Rev. 1995, 95, 1797. (b) Chrzanowska,
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(6) (a) The Chemistry of Hetrocyclic Compounds:
Isoquinolines, Vol. 38; Coppola, G. M.; Schuster, H. F.,
Eds.; Wiley: New York, 1981, Part 3. (b) The Chemistry
and Biology of Isoquinoline Alkaloids; Phillipson, J. D.;
Roberts, M. F.; Zenk, M. H., Eds.; Springer Verlag: Berlin,
1985. (c) Bentley, K. W. The Isoquinoline Alkaloids, Vol. 1;
Hardwood Academic: Amsterdam, 1998. (d) Kletsas, D.;
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S.; Ferry, S.; Wermuth, C. G.; Schwartz, J.-C.; Sokoloff, P.;
Stark, H. ChemBioChem 2004, 5, 508. (f) Muscarella, D.
1H NMR (500 MHz, CDCl3): d = 9.10 (s, 1 H), 7.72 (s, 1 H), 7.59–
7.57 (m, 2 H), 7.38–7.35 (m, 3 H), 7.25 (s, 1 H), 7.11 (t, J = 7.0 Hz,
2 H), 7.05 (t, J = 7.0 Hz, 1 H), 6.90 (d, J = 8.0 Hz, 2 H), 6.08 (s, 2
H).
13C NMR (125 MHz, CDCl3): d = 157.8, 152.5, 151.0, 148.6, 140.8,
137.8, 137.7, 129.6, 129.0, 128.0, 127.6, 126.5, 125.6, 125.2, 120.9,
103.5, 102.8, 101.9.
LRMS (EI, 70 eV): m/z (%) = 359 (M+ + 2, 12), 357 (M+, 100), 280
(36), 248 (13), 159 (34).
HRMS (EI): m/z calcd for C22H15NO2S (M+): 357.0824; found:
357.0822.
3-Phenyl-4-(phenylselanyl)isoquinoline (20)
Yellow oil.
1H NMR (500 MHz, CDCl3): d = 9.35 (s, 1 H), 8.44 (d, J = 8.5 Hz,
1 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.72–7.69 (m, 1 H), 7.62 (t, J = 7.5
Hz, 1 H), 7.57 (t, J = 7.5 Hz, 2 H), 7.41–7.39 (m, 3 H), 7.07–7.02
(m, 5 H).
13C NMR (125 MHz, CDCl3): d = 158.4, 153.1, 141.9, 138.6, 133.0,
131.7, 129.8, 129.6, 129.1, 128.6, 128.1, 128.1, 127.9, 127.6, 127.4,
126.1, 121.4.
LRMS (EI, 70 eV): m/z (%) = 361 (M+, 1), 284 (1), 204 (1), 176 (1),
44 (16), 40 (100).
HRMS (EI): m/z calcd for C21H15NSe (M+): 361.0370; found:
361.0368.
3-Octyl-4-(phenylselanyl)isoquinoline (21)
Black oil.
1H NMR (500 MHz, CDCl3): d = 9.25 (s, 1 H), 8.40 (d, J = 8.5 Hz,
1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.65 (t, J = 15.5 Hz, 1 H), 7.55 (t,
J = 7.5 Hz, 1 H), 7.10 (s, 5 H), 3.33 (t, J = 7.5 Hz, 2 H), 1.76–1.70
(m, 2 H), 1.39–1.34 (m, 2 H), 1.28–1.23 (m, 8 H), 0.86 (t, J = 6.5
Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 161.0, 153.5, 138.8, 132.7, 131.4,
129.2, 129.1, 128.0, 128.0, 127.7, 126.8, 126.0, 120.9, 39.2, 31.8,
30.7, 29.7, 29.4, 29.2, 22.6, 14.1.
LRMS (EI, 70 eV): m/z (%) = 397 (M+, 3), 320 (11), 299 (39), 240
(59), 218 (52), 40 (100).
HRMS (EI): m/z calcd for C23H27NSe (M+): 397.1309; found:
397.1306.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Synthesis 2011, No. 8, 1219–1226 © Thieme Stuttgart · New York

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H.-P. Zhang et al.
PAPER
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2003, 74, 66. (g) Dzierszinski, F.; Coppin, A.; Mortuaire,
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(h) Kartsev, V. G. Med. Chem. Res. 2004, 13, 325.
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(7) For papers on the use of disulfides from our group, see:
(a) Wang, Z.-L.; Tang, R.-Y.; Luo, P.-S.; Deng, C.-L.;
Synthesis 2011, No. 8, 1219–1226 © Thieme Stuttgart · New York