Iodine-mediated intramolecular oxidative cyclization of 2-(styrylthio)anilines: Synthesis of 2-substituted benzothiazoles

Article abstract of DOI:10.1055/s-0031-1289692

A novel metal-free iodine-mediated intramolecular oxidative cyclization protocol is presented, which allows for the preparation of various 2-substituted benzothiazoles. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289692

PAPER
927
Iodine-Mediated Intramolecular Oxidative Cyclization of
2-(Styrylthio)anilines: Synthesis of 2-Substituted Benzothiazoles
S
ynthesis of 2-Sub
o
stituted Benz
n
othiazoles g-Yun Zhao,a Xiao-Kang Guo,a Jin-Heng Li,*b Ri-Yuan Tang*a
a
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. of China
Fax +86(577)86689615; E-mail: try@wzu.edu.cn
b
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, P. R. of China
E-mail: jhli@hnu.edu.cn
Received 23 November 2011; revised 8 January 2012
As shown in Table 1, treatment of 2-(styrylthio)aniline
(1a) with iodine reagent was carried out to investigate the
optimal conditions. Initially, several iodide catalysts, in-
cluding I2, NIS, and ICl, were tested in DCE (1,2-dichlo-
roethane) at 80 °C (Table 1, entries 1–3). The results
disclosed that I2 is more efficient than NIS (N-iodosuccin-
imide) and ICl. In the presence of I2, the reaction fur-
nished the target product 2a in 60% yield (entry 1) while
both NIS and ICl lowered the yield to 16% and 35%, re-
spectively (entries 2 and 3). Screening revealed that the
amount of I2 affected the reaction (entries 1, 4, and 5); the
yield of 2a was decreased slightly to 51% using 0.5 equiv-
alent of I2 (entry 4), but the yield was enhanced to 71% at
1 equivalent of I2 (entry 5). Screening of reaction temper-
Abstract: A novel metal-free iodine-mediated intramolecular oxi-
dative cyclization protocol is presented, which allows for the prep-
aration of various 2-substituted benzothiazoles.
Key words: iodine, oxidation, cyclization, 2-(styrylthio)aniline,
benzothiazole
Synthesis of 2-substituted benzothiazoles have attracted
much attention due to their potential utilization in medi-
cine and therapeutic areas.1 Until now, many efficient
synthetic methods have been developed for 2-substituted
benzothiazoles including (1) intermolecular cycloconden-
sation-dehydration of o-aminothiophenol with carboxylic
acids or aldehydes,2 (2) intramolecular S-arylation–
cyclization of N-phenylthioamides via cross-coupling
reaction3 or C–H bond functionalization,4 (3) tandem re-
action of 2-halobenzenamines with isothiocyanates,5 and
(4) modification on the 2-position of benzothiazole
through C–H bond activation.6 To the best of our knowl-
edge, however, the synthesis of 2-substituted benzothiaz-
oles via an intramolecular iodoamination protocol is
unexplored.
Table 1 Screening Optimal Conditionsa
S
S
N
NH2
1a
2a
Entry
1
I source (equiv) Solvent
Isolated yield (%)
In recent years, iodine-mediated cyclization has become a
powerful tool for constructing heterocyclic compounds.7
Larock’s group and others have made significant contri-
bution to this field.8–10 Although numerous N-heterocyclic
and O-heterocyclic compounds have been synthesized by
iodocyclization protocol, the research on the formation of
thiazole ring through an iodine-mediated oxidative cy-
clization process has received less attention.11 Here, we
report a novel protocol for the synthesis of 2-substituted
benzothiazole derivatives through an iodocyclization/HI
elimination/olefin isomerization process (Scheme 1).
I2 (2)
NIS (2)
ICl (2)
I2 (0.5)
I2 (1)
I2 (1)
I2 (1)
I2 (1)
I2 (1)
I2 (1)
I2 (1)
I2 (1)
DCE
60
2
DCE
16
3
DCE
35
4
DCE
51
5
DCE
71
6b
7c
8d
9
DCE
0
DCE
54
DCE
58
R2
S
N
I2 (1 equiv)
MeCN
1,4-dioxane
DMF
trace
trace
trace
32
S
R2
R1
DCE, 80 °C, 12 h
10
11
12
R1
NH2
2
1
Scheme 1 Iodine-mediated intramolecular cyclization
CH2Cl2
a Reaction conditions: 1a (0.3 mmol) in solvent (5 mL) at 80 °C for 12
h.
SYNTHESIS 2012, 44, 927–933
x
x
.x
x
.2
0
1
2
b At room temperature.
c At 110 °C.
Advanced online publication: 06.02.2012
DOI: 10.1055/s-0031-1289692; Art ID: H109911SS
© Georg Thieme Verlag Stuttgart · New York
d NaHCO3 (2 equiv) was added.

928
D.-Y. Zhao et al.
PAPER
ature showed that the reaction at 80 °C gave the best re- vinyl amide 1h was also a suitable substrate for the reac-
sults (entries 5–7). In the presence of NaHCO3, the yield tion (entry 7). However, the reaction of substrate 1i, with
of product 2a was reduced to 58% (entry 8). Finally, a se- a pyridinyl group at the terminal alkene, could not take
ries of other solvents, MeCN, 1,4-dioxane, DMF, and place under the optimal conditions (entry 8).13 Finally,
CH2Cl2 were examined (entries 9–12). The results dis- substituents, including Me and Cl, on the aryl ring of the
closed that they displayed less efficiency for this reaction. aniline moiety were consistent with the optimal condi-
tions (entries 9–11). The result showed that methyl-substi-
With the optimal reaction conditions in hand, the scope of
tuted substrate 1j reacted with I2 to give the desired
substrates 1 was explored for the cyclization reaction
product 2j in 55% yield (entry 9). Substrates 1k and 1l
(Table 2). In the presence of I2, a variety of substrates 1b–
with a Cl group could also undergo the cyclization reac-
l underwent the cyclization reaction smoothly in moderate
tion smoothly, providing the corresponding products 2k
and 2l in 90% and 81% yield, respectively (entries 10 and
11). The electron-withdrawing effect of the Cl group on
the aniline ring may promote this oxidative cyclization re-
action leading to the observed good yields of products 2k
and 2l.
to good yields (Table 2, entries 1–11).12 The results dis-
closed that several substituted groups, such as Me, MeO,
MeS, NO2, and phenyl on the aromatic ring in styrylthio
moiety were tolerated well under the optimal conditions
(entries 1–5). Substrate 1g with an o-phenyl group, for ex-
ample, was treated with I2 smoothly providing the corre-
sponding product 2g in 65% yield (entry 6). Gratifyingly,
Table 2 Synthesis of Benzothiazole through Iodine-Mediated Oxidative Cyclizationa
R2
S
I2 (1 equiv)
S
R2
R1
DCE, 80 °C, 12 h
N
R1
NH2
1
2
Entry
1
Substrate 1
Product 2
Isolated yield (%)
64
S
N
S
1b
2b
NH2
S
N
S
2
1c
2c
50
NH2
S
N
OMe
SMe
OMe
SMe
S
3
4
1d
1e
2d
2e
46
52
NH2
S
N
S
NH2
S
N
S
5
6
1f
2f
53
65
NH2
NO2
NO2
S
N
1g
2g
S
NH2
Synthesis 2012, 44, 927–933
© Thieme Stuttgart · New York

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Synthesis of 2-Substituted Benzothiazoles
929
Table 2 Synthesis of Benzothiazole through Iodine-Mediated Oxidative Cyclizationa (continued)
R2
S
N
I2 (1 equiv)
S
R2
R1
DCE, 80 °C, 12 h
R1
NH2
2
1
Entry
7
Substrate 1
Product 2
Isolated yield (%)
S
N
S
O
HN
NH
1h
2h
71
NH2
O
S
N
S
8
1i
2i
trace
NH2
N
N
S
N
S
9
1j
2j
55
90
NH2
S
Cl
Cl
S
NH2
10
1k
2k
N
Cl
Cl
S
N
S
O
HN
NH
11
1l
2l
81
NH2
O
a Reaction conditions: 1 (0.3 mmol) and I2 (1 equiv) in DCE (5 mL) for 12 h at 80 °C.
A possible mechanism as outlined in Scheme 2 is pro- In summary, we have developed a metal-free iodine-
posed. Substrate 1 is first activated by iodine to produce mediated intramolecular oxidative cyclization method for
intermediate A, followed by nucleophilic addition to form the synthesis of 2-substituted benzothiazoles. In the pres-
intermediate B. Subsequently, HI is eliminated from inter- ence of iodine, a variety of substituted 2-(styryl-
mediate B via an oxidative process to afford intermediate thio)anilines could efficiently undergo the intramolecular
C. Finally, product 2 is obtained by the isomerization of oxidative cyclization reaction to afford the corresponding
intermediate C. Iodine may play two key roles in this re- 2-substituted benzothiazole in moderate to good yields.
action: (1) as an electrophilic reagent to activate the C=C
bond, and (2) as an oxidant to oxidize intermediate B to
intermediate C.
R2
S
S
N
I2
R1
R1
DCE, 80 °C
R2
NH2
2
1
I
S
IH
S
S
R2
R1
R1
R1
R2
R2
N
H
N
H
H
N
H
H
B
C
A
Scheme 2 Possible mechanism for the formation of 2-substituted benzothiazoles
© Thieme Stuttgart · New York
Synthesis 2012, 44, 927–933

930
D.-Y. Zhao et al.
PAPER
All melting points are uncorrected. NMR spectroscopy was per-
formed on a Bruker Avance spectrometer operating at 300 MHz (1H
NMR) and 75 MHz (13C NMR) or at 500 MHz (1H NMR) and 125
MHz (13C NMR). Mass spectrometric analysis was performed on
GC-MS analysis (Shimadzu GCMS-QP2010) and ESI-Q-TOF
(Bruker MicroQTOF-II).
1H NMR (300 MHz, CDCl3): d = 7.62 (d, J = 6.5 Hz, 1 H), 7.39 (d,
J = 7.6 Hz, 1 H), 7.27–7.24 (m, 3 H), 7.16 (t, J = 8.0 Hz, 1 H), 6.78
(d, J = 10.4 Hz, 1 H), 6.72–6.69 (m, 2 H), 6.27 (d, J = 10.4 Hz, 1 H),
4.22 (br s, 2 H), 2.44 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 147.7, 137.4, 135.2, 134.9, 130.3,
129.3, 128.8, 127.9, 126.1, 124.8, 124.6, 118.6, 117.5, 115.3, 16.0.
Substrates 1a–l were prepared following the literature procedure.12
LRMS (EI, 70 eV): m/z (%) = 150 (11), 149 (100).
(Z)-2-(Styrylthio)aniline (1a)12
Yield: 0.0508 g (56%); yellow solid; mp 56.7–57.1 °C.
(Z/E)-2-(4-Nitrostyrylthio)aniline (1f)12
Ratio Z/E = 1:1; yield: 0.0174 g (16%); rufous solid; mp 65.1–66.5
IR (KBr): 3460, 3364, 2919, 1604, 1478, 1308, 1079, 845, 758, 691
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.55 (d, J = 7.6 Hz, 2 H), 7.43–
7.36 (m, 3 H), 7.28–7.16 (m, 2 H), 6.74 (d, J = 7.9 Hz, 2 H), 6.51
(d, J = 10.8 Hz, 1 H), 6.18 (d, J = 10.8 Hz, 1 H), 4.17 (br s, 2 H).
13C NMR (75 MHz, CDCl3): d = 147.7, 136.6, 135.2, 130.4, 128.8,
128.4, 127.7, 127.0, 126.7, 118.7, 117.8, 115.3.
°C (Lit.12 mp 65.1–66.5 °C).
IR (KBr): 3437, 2924, 1599, 1493, 1337, 1206, 1096, 746, 674
cm–1.
1H NMR (300 MHz, CDCl3): d = 8.23 (d, J = 8.3 Hz, 1 H), 8.08 (d,
J = 8.3 Hz, 1 H), 7.66 (d, J = 8.3 Hz, 1 H), 7.41 (d, J = 8.3 Hz, 1 H),
7.32–7.18 (m, 2 H), 6.86 (d, J = 15.4 Hz, 0.5 H), 6.80–6.74 (m, 2
H), 6.51–6.49 (m, 1 H), 6.20 (d, J = 15.4 Hz, 0.5 H), 4.31 and 4.28
(br s, 2 H).
13C NMR (75 MHz, CDCl3): d = 148.4, 147.7, 146.1, 145.8, 143.0,
142.9, 136.4, 135.3, 134.1, 131.5, 131.1, 130.6, 129.1, 125.9, 124.1,
123.7, 118.9, 118.8, 116.6, 115.6, 115.5, 112.6.
LRMS (EI, 70 eV): m/z (%) = 227 (M+, 16), 136 (100).
(Z)-2-(2-Methylstyrylthio)aniline (1b)
Yield: 0.0434 g (45%); brown oil.
IR (KBr): 3456, 3364, 2921, 1603, 1471, 1250, 1067, 850, 749
cm–1.
LRMS (EI, 70 eV): m/z (%) = 278 (M+, 20), 136 (100).
(Z)-2-[2-(Biphenyl-2-yl)vinylthio]aniline (1g)
Yield: 0.0618 g (51%); yellow oil.
1H NMR (300 MHz, CDCl3): d = 7.62 (d, J = 7.8 Hz, 1 H), 7.41 (dd,
J = 7.8, 1.7 Hz, 1 H), 7.23–7.16 (m, 4 H), 6.75–6.71 (m, 2 H), 6.64
(d, J = 10.5 Hz, 1 H), 6.24 (d, J = 10.5 Hz, 1 H), 4.21 (br s, 2 H),
2.33 (s, 3 H).
IR (KBr): 3461, 3365, 2923, 1602, 1470, 1307, 1154, 1021, 846,
758, 628, 518 cm–1.
13C NMR (75 MHz, CDCl3): d = 147.7, 136.1, 135.3, 135.1, 130.3,
1H NMR (300 MHz, CDCl3): d = 7.87 (d, J = 7.6 Hz, 1 H), 7.47–
7.40 (m, 9 H), 7.19 (d, J = 7.8 Hz, 1 H), 6.78–6.75 (m, 2 H), 6.50
(d, J = 10.6 Hz, 1 H), 6.16 (d, J = 10.6 Hz, 1 H), 4.23 (br s, 2 H).
13C NMR (75 MHz, CDCl3): d = 147.7, 141.4, 141.0, 135.1, 134.2,
130.3, 130.1, 129.8, 129.4, 128.9, 128.1, 127.9, 127.5, 127.1, 126.6,
118.7, 117.9, 115.3.
130.2, 128.4, 128.1, 127.4, 125.6, 125.5, 118.7, 117.9, 115.3, 20.0.
LRMS (EI, 70 eV): m/z (%) = 241 (M+, 21), 136 (100).
(Z)-2-(4-Methylstyrylthio)aniline (1c)
Yield: 0.0463 g (48%); brown oil.
IR (KBr): 3459, 3365, 2920, 2864, 1604, 1476, 1249, 1071, 822,
683 cm–1.
LRMS (EI, 70 eV): m/z (%) = 303 (M+, 1), 207 (29), 179 (48), 178
(62), 125 (89).
1H NMR (300 MHz, CDCl3): d = 7.46–7.40 (m, 3 H), 7.23–7.13 (m,
3 H), 6.73 (d, J = 7.7 Hz, 2 H), 6.49 (d, J = 10.7 Hz, 1 H), 6.11 (d,
J = 10.7 Hz, 1 H), 4.23 (br s, 2 H), 2.36 (s, 3 H).
(Z)-3-(2-Aminophenylthio)-N-phenylacrylamide (1h)
Yield: 0.0562 g (52%); white solid; mp 160.1–161.2 °C.
IR (KBr): 3461, 3371, 1637, 1609, 1445, 1384, 1309, 1180, 831,
754, 691, 672 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.60–7.59 (m, 2 H), 7.41–7.18 (m,
6 H), 6.89 (d, J = 9.8 Hz, 1 H), 6.76–6.72 (m, 2 H), 6.00 (d, J = 9.8
Hz, 1 H), 4.24 (br s, 2 H).
13C NMR (75 MHz, CDCl3): d = 164.5, 148.9, 147.6, 137.9, 135.2,
130.8, 129.0, 124.3, 120.0, 118.9, 118.7, 116.2, 115.4.
13C NMR (75 MHz, CDCl3): d = 147.7, 136.9, 135.2, 133.8, 130.4,
129.1, 128.7, 126.8, 126.5, 118.7, 118.0, 115.3, 21.3.
LRMS (EI, 70 eV): m/z (%) = 241 (M+, 20), 136 (100).
(Z)-2-(2-Methoxystyrylthio)aniline (1d)
Yield: 0.0452 g (49%); yellow solid; mp 63.8–64.7 °C.
IR (KBr): 3459, 3038, 2939, 2837, 1604, 1471, 1302, 1245, 1030,
850, 751 cm–1.
LRMS (EI, 70 eV): m/z (%) = 193 (75), 149 (100).
1H NMR (300 MHz, CDCl3): d = 7.77 (d, J = 7.6 Hz, 1 H), 7.45 (d,
J = 7.9 Hz, 1 H), 7.28 (t, J = 7.8 Hz, 1 H), 7.19 (t, J = 7.8 Hz, 1 H),
7.07 (t, J = 7.9 Hz, 1 H), 6.94 (d, J = 8.2 Hz, 1 H), 6.87 (d, J = 10.7
Hz, 1 H), 6.77 (m, 2 H), 6.25 (d, J = 10.8 Hz, 1 H), 4.30 (br s, 2 H),
3.88 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 156.6, 147.7, 135.2, 130.3, 129.3,
128.6, 127.5, 125.4, 121.7, 120.2, 118.6, 118.0, 115.3, 110.5, 55.5.
(Z)-2-[2-(Pyridin-4-yl)vinylthio]aniline (1i)12
Yield: 0.0128 g (14%); yellow solid; mp 121.9–122.8 °C (Lit.12 mp
121.9–122.8 °C).
IR (KBr): 3435, 3296, 2923, 1589, 1474, 1409, 1310, 1240, 1153,
825, 744 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.62 (d, J = 6.1 Hz, 2 H), 7.43–
7.41 (m, 3 H), 7.21 (t, J = 8.1 Hz, 1 H), 6.79–6.73 (m, 2 H), 6.48 (d,
J = 10.8 Hz, 1 H), 6.41 (d, J = 10.8 Hz, 1 H), 4.29 (br s, 2 H).
LRMS (EI, 70 eV): m/z (%) = 257 (M+, 16), 136 (100).
(Z)-2-[2-(Methylthio)styrylthio]aniline (1e)
Yield: 0.0535 g (49%); yellow oil.
13C NMR (75 MHz, CDCl3): d = 149.9, 147.7, 143.6, 135.3, 134.4,
130.9, 123.6, 122.9, 118.8, 116.7, 115.4.
IR (KBr): 3459, 3361, 2918, 2852, 1916, 1602, 1443, 1307, 1052,
951, 850, 695 cm–1.
LRMS (EI, 70 eV): m/z (%) = 228 (M+, 29), 136 (100).
Synthesis 2012, 44, 927–933
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Synthesis of 2-Substituted Benzothiazoles
931
(Z)-2-Methyl-6-(styrylthio)aniline (1j)
LRMS (EI, 70 eV): m/z (%) = 239 (M+, 100), 224 (50).
Yield: 0.0299 g (31%); grey oil.
HRMS (ESI): m/z calcd for C15H13NS (M + H)+: 240.0841; found:
240.0846.
1H NMR (500 MHz, CDCl3): d = 7.48 (d, J = 7.4 Hz, 2 H), 7.35–
7.32 (m, 3 H), 7.27 (d, J = 7.7 Hz, 1 H), 7.02 (d, J = 7.6 Hz, 1 H),
6.66 (t, J = 7.6 Hz, 1 H), 6.45 (d, J = 10.7 Hz, 1 H), 6.10 (d, J = 10.7
Hz, 1 H), 3.97 (br s, 2 H), 2.18 (s, 3 H).
2-(4-Methylbenzyl)benzo[d]thiazole (2c)15
Yield: 0.0359 g (50%); brown oil.
13C NMR (125 MHz, CDCl3): d = 144.9, 132.0, 130.7, 130.4, 127.8,
1H NMR (300 MHz, CDCl3): d = 8.01 (d, J = 8.0 Hz, 1 H), 7.80 (d,
J = 7.9 Hz, 1 H), 7.45 (t, J = 8.0 Hz, 1 H), 7.35–7.26 (m, 3 H), 7.18
(d, J = 7.7 Hz, 2 H), 4.41 (s, 2 H), 2.36 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 171.6, 154.2, 137.1, 134.2, 131.4,
129.5, 129.0, 127.5, 125.9, 124.7, 121.5, 40.3, 21.3.
127.3, 127.2, 127.0, 125.9, 125.6, 122.0, 117.1, 17.0.
LRMS (EI, 70 eV): m/z (%) = 241 (M+, 21), 150 (100).
(Z)-5-Chloro-2-(styrylthio)aniline (1k)
Yield: 0.0741 g (71%); yellow solid; mp 125.7–126.8 °C.
LRMS (EI, 70 eV): m/z (%) = 239 (M+, 100).
IR (KBr): 3472, 3376, 1605, 1477, 1256, 1078, 909, 845, 772, 687,
653 cm–1.
2-(2-Methoxybenzyl)benzo[d]thiazole (2d)16
Yield: 0.0352 g (46%); brown oil.
1H NMR (300 MHz, CDCl3): d = 7.56–7.54 (m, 2 H), 7.45–7.27 (m,
4 H), 6.76–6.69 (m, 2 H), 6.56 (d, J = 10.7 Hz, 1 H), 6.12 (d,
J = 10.7 Hz, 1 H), 4.31 (br s, 2 H).
13C NMR (75 MHz, CDCl3): d = 148.4, 136.1, 136.0, 135.9, 128.6,
128.5, 128.2, 127.1, 127.0, 126.8, 118.4, 114.6.
1H NMR (300 MHz, CDCl3): d = 7.98 (d, J = 8.1 Hz, 1 H), 7.76 (d,
J = 7.9 Hz, 1 H), 7.42 (t, J = 8.0 Hz, 1 H), 7.33–7.25 (m, 3 H), 6.96–
6.90 (m, 2 H), 4.45 (s, 2 H), 3.84 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 171.8, 157.3, 153.1, 133.7, 130.8,
128.9, 127.5, 125.7, 124.5, 122.5, 121.4, 120.7, 110.7, 55.3, 35.1.
LRMS (EI, 70 eV): m/z (%) = 261 (M+, 29), 170 (100).
LRMS (EI, 70 eV): m/z (%) = 255 (M+, 18), 240 (13), 224 (100).
(Z)-3-(2-Amino-4-chlorophenylthio)-N-phenylacrylamide (1l)
Yield: 0.079 g (65%); light-yellow solid; mp 175.2–176.5 °C.
2-[2-(Methylthio)benzyl]benzo[d]thiazole (2e)
Yield: 0.0423 g (52%); brown oil.
IR (KBr): 2919, 2849, 1589, 1505, 1438 cm–1.
IR (KBr): 3471, 3376, 1625, 1567, 1309, 1024, 894, 790, 691, 624
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.64 (d, J = 7.7 Hz, 2 H), 7.32–
7.24 (m, 3 H), 7.03 (t, J = 7.4 Hz, 1 H), 6.86–6.80 (m, 2 H), 6.56
(dd, J = 8.1, 2.2 Hz, 1 H), 6.20 (d, J = 9.8 Hz, 1 H), 5.60 (br s, 2 H).
1H NMR (300 MHz, CDCl3): d = 7.98 (d, J = 8.1 Hz, 1 H), 7.75 (d,
J = 7.9 Hz, 1 H), 7.42 (t, J = 7.7 Hz, 1 H), 7.33–7.13 (m, 5 H), 4.60
(s, 2 H), 2.44 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 164.6, 150.7, 146.5, 139.7,
136.3, 135.0, 129.2, 123.5, 119.3, 117.8, 117.0, 116.5, 114.2.
13C NMR (75 MHz, CDCl3): d = 170.8, 153.2, 138.1, 135.7, 132.3,
130.4, 128.3, 127.0, 125.8, 125.6, 124.7, 122.7, 121.5, 38.5, 16.5.
LRMS (EI, 70 eV): m/z (%) = 304 (M+, 1), 161 (97), 148 (51).
LRMS (EI, 70 eV): m/z (%) = 271 (M+, 77), 224 (71), 149 (100).
HRMS (ESI): m/z calcd for C15H13NS2 (M + H)+: 272.0562; found:
272.0567.
2-Substituted Benzothiazoles; 2-Benzylbenzo[d]thiazole (2a);14
Typical Procedure
A mixture of 2-(styrylthio)aniline (1a; 68 mg, 0.3 mmol) and mo-
lecular I2 (76 mg, 0.3 mmol, 1 equiv) in DCE (5 mL) was stirred at
80 °C for the indicated time until complete consumption of starting
material as monitored by TLC (eluent: hexane–EtOAc, 10:1). After
completion of the reaction, the mixture was washed with sat. aq
Na2S2O3 (5 mL) and poured into EtOAc (20 mL), which was
washed with brine (10 mL). The aqueous layer was extracted with
EtOAc (3 × 5 mL); the combined organic layers were dried
(Na2SO4) and the solvent was evaporated under vacuum. The resi-
due was purified by flash column chromatography (hexane–EtOAc,
10:1) to afford the desired product 2a as a light-yellow oil; yield:
0.0479 g (71%).
2-(4-Nitrobenzyl)benzo[d]thiazole (2f)17
Yield: 0.0429 g (53%); brown solid; mp 91.5–92.8 °C (Lit.17 mp
115 °C).
1H NMR (300 MHz, CDCl3): d = 8.21 (d, J = 8.7 Hz, 2 H), 8.01 (d,
J = 8.1 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.54 (d, J = 8.7 Hz, 2 H),
7.48–7.38 (m, 2 H), 4.55 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 168.0, 153.1, 147.2, 144.3, 135.4,
129.9, 126.2, 125.2, 123.9, 122.9, 121.5, 39.9.
LRMS (EI, 70 eV): m/z (%) = 270 (M+, 100).
2-(Biphenyl-2-ylmethyl)benzo[d]thiazole (2g)
Yield: 0.0587 g (65%); brown oil.
IR (KBr): 2921, 1594, 1437, 1308 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.98 (d, J = 8.2 Hz, 1 H), 7.77 (d,
J = 8.1 Hz, 1 H), 7.48–7.34 (m, 11 H), 4.44 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 171.6, 153.3, 142.4, 140.9, 135.6,
134.7, 130.5, 130.4, 129.3, 128.3, 127.8, 127.4, 127.3, 125.9, 124.7,
122.8, 121.5, 37.9.
LRMS (EI, 70 eV): m/z (%) = 301 (M+, 100).
HRMS (ESI): m/z calcd for C20H15NS (M + H)+: 302.0998; found:
1H NMR (300 MHz, CDCl3): d = 8.03 (d, J = 8.1 Hz, 1 H), 7.80 (d,
J = 7.9 Hz, 1 H), 7.50–7.31 (m, 7 H), 4.46 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 171.2, 153.3, 137.2, 135.7, 129.2,
128.9, 127.4, 126.0, 124.8, 122.8, 121.5, 40.6.
LRMS (EI, 70 eV): m/z (%) = 225 (M+, 86), 224 (100).
2-(2-Methylbenzyl)benzo[d]thiazole (2b)
Yield: 0.0459 g (64%); brown oil.
IR (KBr): 2925, 2863, 1652, 1594, 1496, 1440 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.03 (d, J = 8.2 Hz, 1 H), 7.79 (d,
J = 7.9 Hz, 1 H), 7.47 (t, J = 8.0 Hz, 1 H), 7.37–7.24 (m, 5 H), 4.47
(s, 2 H), 2.37 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 171.7, 153.3, 136.9, 135.6, 131.6,
130.7, 130.2, 127.8, 126.4, 125.9, 124.7, 122.7, 121.5, 38.5, 19.6.
302.1002.
2-(Benzo[d]thiazol-2-yl)-N-phenylacetamide (2h)18
Yield: 0.0571 g (71%); yellow solid; mp 155.1–156.9 °C (Lit.18 mp
161 °C).
© Thieme Stuttgart · New York
Synthesis 2012, 44, 927–933

932
D.-Y. Zhao et al.
PAPER
Chem. Biol. Drug Des. 2008, 71, 78. (e) Kok, S. H. L.;
1H NMR (300 MHz, CDCl3): d = 9.67 (br s, 1 H), 8.06 (d, J = 8.0
Hz, 1 H), 7.90 (d, J = 7.5 Hz, 1 H), 7.58–7.28 (m, 6 H), 7.13 (t,
J = 7.4 Hz, 1 H), 4.23 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 164.7, 164.5, 152.6, 137.6, 134.8,
128.9, 126.4, 125.5, 124.5, 122.6, 121.7, 120.0, 41.5.
Gambari, R.; Chui, C. H.; Yuen, M. C. W.; Lin, E.; Wong,
R. S. M.; Lau, F. Y.; Cheng, G. Y. M.; Lam, W. S.; Chan, S.
H.; Lam, K. H.; Cheng, C. H.; Lai, P. B. S.; Yu, M. W. Y.;
Cheung, F.; Tang, J. C. O.; Chan, A. S. C. Bioorg. Med.
Chem. 2008, 16, 3626. (f) Liu, C.; Lin, J.; Pitt, S.; Zhang, R.
F.; Sack, J. S.; Kiefer, S. E.; Kish, K.; Doweyko, A. M.;
Zhang, H.; Marathe, P. H.; Trzaskos, J.; Mckinnon, M.;
Dodd, J. H.; Barrish, J. C.; Schieven, G. L.; Leftheris, K.
Bioorg. Med. Chem. Lett. 2008, 18, 1874. (g) Henriksen,
G.; Hauser, A. I.; Westwell, A. D.; Yousefi, B. H.;
Schwaiger, M.; Drzezga, A.; Wester, H. J. J. Med. Chem.
2007, 50, 1087.
LRMS (EI, 70 eV): m/z (%) = 268 (M+, 4), 149 (100).
2-Benzyl-4-methylbenzo[d]thiazole (2j)
Yield: 0.0394 g (55%); grey oil.
1H NMR (500 MHz, CDCl3): d = 7.52 (d, J = 7.2 Hz, 1 H), 7.30–
7.14 (m, 7 H), 4.40 (s, 2 H), 2.69 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 170.4, 152.2, 137.3, 135.4, 132.6,
129.2, 128.8, 127.3, 126.7, 124.7, 118.9, 40.5, 18.5.
LRMS (EI, 70 eV): m/z (%) = 239 (M+, 100), 224 (7).
HRMS (ESI): m/z calcd for C15H13NS (M + H)+: 240.0841; found:
(2) For cyclocondensation–dehydration process, see: (a) Mu,
X. J.; Zou, J. P.; Zeng, R. S.; Wu, J. C. Tetrahedron Lett.
2005, 46, 4345. (b) Bose, D. S.; Idrees, M. J. Org. Chem.
2006, 71, 8261. (c) Hioki, H.; Matsushita, K.; Kubo, M.;
Harada, K.; Kodama, M.; Fukuyama, Y. Tetrahedron 2007,
63, 11315. (d) Boger, D. E. J. Org. Chem. 1978, 43, 2296.
(e) Terashima, M.; Ishii, M.; Kanaoka, Y. Synthesis 1982,
484. (f) Ben-Alloum, A.; Bakkas, S.; Soufiaoui, M.
Tetrahedron Lett. 1997, 38, 6395. (g) Ben-Alloum, A.;
Bakkas, S.; Soufiaoui, M. Tetrahedron Lett. 1997, 38, 6395.
(h) Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.;
Tolmachev, A. A. Synthesis 2006, 3715. (i) Kawashita, Y.;
Ueba, C.; Hayashi, M. Tetrahedron Lett. 2006, 47, 4231.
(j) Li, Y.; Wang, Y. L.; Wang, J. Y. Chem. Lett. 2006, 35,
460. (k) Bahrami, K.; Khodaei, M. M.; Naali, F. J. Org.
Chem. 2008, 73, 6835. (l) Chen, Y. X.; Qian, L. F.; Zhang,
W.; Han, B. Angew. Chem. Int. Ed. 2008, 47, 9330.
(m) Metzger, J. V. In Comprehensive Heterocyclic
Chemistry, Vol. 6; Katritzsky, A. R.; Rees, C. W., Eds.;
Pergamon Press: Oxford, 1984, 322.
(3) For N-(2-haloaryl)thioamides as substrates, with Pd:
(a) Couture, A.; Granclaudon, P. Heterocycles 1984, 22,
1383. (b) Benedí, C.; Bravo, F.; Uriz, P.; Fernández, E.;
Claver, C.; Castillón, S. Tetrahedron Lett. 2003, 44, 6073.
(c) Itoh, T.; Mase, T. Org. Lett. 2007, 9, 3687. (d) Vera, M.
D.; Pelletier, J. C. J. Comb. Chem. 2007, 9, 569. With Pd or
Cu: (e) Joyce, L. L.; Evindar, G.; Batey, R. A. Chem.
Commun. 2004, 446. With Cu: (f) Evindar, G.; Batey, R. A.
J. Org. Chem. 2006, 71, 1802.
(4) For N-Arylthioamides as the substrates, with Pd/Cu:
(a) Inamoto, K.; Hasegawa, C.; Hiroya, K.; Doi, T. Org. Lett.
2008, 10, 5147. With Cu: (b) Ueda, S.; Nagasawa, H.
Angew. Chem. Int. Ed. 2008, 47, 6411.
(5) (a) Ding, Q.; He, X.; Wu, J. J. Comb. Chem. 2009, 11, 587.
(b) Pi, S. S.; Zhang, X. G.; Tang, R. Y.; Li, J. H. Synlett
2009, 3032. (c) Qiu, J.-W.; Zhang, X. G.; Tang, R. Y.;
Zhong, P.; Li, J. H. Adv. Synth. Catal. 2009, 351, 2319.
(d) Shen, G.-D.; Lv, X.; Bao, W.-L. Eur. J. Org. Chem.
2009, 5897. (e) Ding, Q.-P.; Cao, B.-P.; Liu, X.-J.; Zong, Z.-
Z.; Peng, Y.-Y. Green Chem. 2010, 12, 1607. (f) Guo, Y. J.;
Tang, R. Y.; Zhong, P.; Li, J. H. Tetrahedron Lett. 2010, 51,
649.
240.0845.
2-Benzyl-5-chlorobenzo[d]thiazole (2k)19
Yield: 0.0699 g (90%); brown solid; mp 70.1–71.5 °C (Lit.19 mp
78–79 °C).
1H NMR (300 MHz, CDCl3): d = 7.99 (d, J = 1.9 Hz, 1 H), 7.67 (d,
J = 8.5 Hz, 1 H), 7.38–7.31 (m, 6 H), 4.44 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 173.3, 154.2, 136.8, 133.9, 132.0,
129.2, 128.9, 127.5, 125.3, 122.7, 122.2, 40.7.
LRMS (EI, 70 eV): m/z (%) = 259 (M+, 99), 258 (100).
2-(5-Chlorobenzo[d]thiazol-2-yl)-N-phenylacetamide (2l)
Yield: 0.0734 g (81%); yellow solid; mp 165.1–167.2 °C.
IR (KBr): 3426, 3252, 1663, 1648, 1596, 1536, 1437, 1341, 1115,
1073, 955, 865, 736, 695 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.41 (br s, 1 H), 8.04 (d, J = 2.0
Hz, 1 H), 7.80 (d, J = 8.6 Hz, 1 H), 7.56 (d, J = 7.7 Hz, 2 H), 7.42–
7.26 (m, 3 H), 7.12 (t, J = 7.4 Hz, 1 H), 4.21 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 166.7, 164.2, 153.5, 137.5, 133.1,
132.6, 129.0, 126.1, 124.7, 122.6, 122.4, 120.1, 41.7.
LRMS (EI, 70 eV): m/z (%) = 303 (M+, 1), 175 (40), 161 (100).
HRMS (ESI): m/z calcd for C15H11ClN2OS (M + H)+: 303.0353;
found: 303.0357.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
We thank the National Natural Science Foundation of China (Nos.
20872112 and 21002010) and Zhejiang Provincial Natural Science
Foundation of China (Nos. Y407116, Y4080169 and Y4100307)
for financial support.
(6) (a) Saha, D.; Adak, L.; Ranu, B. C. Tetrahedron Lett. 2010,
51, 5624. (b) Xie, K.; Yang, Z. Y.; Zhou, X. J.; Li, X. J.;
Wang, S. Z.; Tan, Z.; An, X. Y.; Guo, C. C. Org. Lett. 2010,
12, 1564. (c) Huang, J. K.; Chan, J.; Chen, Y.; Borths, C. J.;
Baucom, K. D.; Larsen, R. D.; Faul, M. M. J. Am. Chem.
Soc. 2010, 132, 3674. (d) Hachiya, H.; Hirano, K.; Satoh,
T.; Miura, M. Org. Lett. 2009, 11, 1737. (e) Canivet, J.;
Yamaguchi, J.; Ban, I.; Itami, K. Org. Lett. 2009, 11, 1733.
(f) Derridj, F.; Roger, J.; Geneste, F.; Djebbar, S.; Doucet, H.
J. Organomet. Chem. 2009, 694, 455. (g) Alagille, D.;
Baldwin, R. M.; Tamagnan, G. D. Tetrahedron Lett. 2005,
46, 1349.
References
(1) For selected recent papers, see: (a) Wang, M.; Gao, M. Z.;
Mock, B. H.; Miller, K. D.; Sledge, G. W.; Hutchins, G. D.;
Zheng, Q. H. Bioorg. Med. Chem. 2006, 14, 8599. (b)Lion,
C. J.; Matthews, C. S.; Wells, G.; Bradshaw, T. D.; Stevens,
M. F. G.; Westwell, A. D. Bioorg. Med. Chem. Lett. 2006,
16, 5005. (c) Mortimer, C. G.; Wells, G.; Crochard, J. P.;
Stone, E. L.; Bradshaw, T. D.; Stevens, M. F. G.; Westwell,
A. D. J. Med. Chem. 2006, 49, 179. (d) Kamal, A.; Khan,
M.; Naseer, A.; Reddy, K. S.; Srikanth, Y. V. V.; Sridhar, B.
Synthesis 2012, 44, 927–933
© Thieme Stuttgart · New York

PAPER
(7) (a) Banerjee, A. K.; Laya, M. S.; Cabrera, E. V. Curr. Org.
Synthesis of 2-Substituted Benzothiazoles
933
(10) For selected recent papers on the iodocyclizations of
alkenes, see: (a) Mohapatra, D. K.; Bhimireddy, E.;
Chem. 2011, 15, 1058. (b) Mphahlele, M. J. Molecules
2009, 14, 4814. (c) Togo, H.; Iida, S. Synlett 2006, 2159.
(d) Martins da Silva, F.; Jones, J. Jr.; de Mattos, M. C. S.
Curr. Org. Synth. 2005, 2, 393. (e) Larock, R. C. In
Acetylene Chemistry; Diederich, F.; Stang, P. J.; Tykwinski,
R. R., Eds.; Wiley-VCH: Weinheim, 2005, P51–P99.
(8) For selected recent papers on N-heterocyclization via
iodocyclizations of alkynes, see: (a) Zora, M.; Kivrak, A.;
Yazici, C. J. Org. Chem. 2011, 76, 6726. (b) Ali, S.; Zhu,
H.-T.; Xia, X.-F.; Ji, K.-G.; Yang, Y.-F.; Song, X.-R.; Liang,
Y.-M. Org. Lett. 2011, 13, 2598. (c) Okitsu, T.; Sato, K.;
Potewar, T. M.; Wada, A. J. Org. Chem. 2011, 76, 3438.
(d) Ouyang, H.-C.; Tang, R.-Y.; Zhong, P.; Zhang, X.-G.;
Li, J.-H. J. Org. Chem. 2011, 76, 223. (e) Okitsu, T.; Sato,
K.; Wada, A. Org. Lett. 2010, 12, 3506. (f) Mehta, S.;
Larock, R. C. J. Org. Chem. 2010, 75, 1652. (g) Worlikar,
S. A.; Neuenswander, B.; Lushington, G. H.; Larock, R. C.
J. Comb. Chem. 2009, 11, 875. (h) Cherry, K.; Duchene, A.;
Thibonnet, J.; Parrain, J.-L.; Anselmi, E.; Abarbri, M.
Synthesis 2009, 257. (i) Choi, J.; Lee, G. H.; Kim, I. Synlett
2008, 1243. (j) Knight, D. W.; Rost, H. C.; Sharland, C. M.;
Singkhonrat, J. Tetrahedron Lett. 2007, 48, 7906.
(k) Hessian, K. O.; Flynn, B. L. Org. Lett. 2006, 8, 243.
(l) Yao, T.; Yue, D.; Larock, R. C. J. Org. Chem. 2005, 70,
9985. (m) Yue, D.; Larock, R. C. Org. Lett. 2004, 6, 1037.
(9) For selected recent papers on O-heterocyclization via
iodocyclizations of alkynes, see: (a) Cho, C.-H.; Larock, R.
C. ACS Comb. Sci. 2011, 13, 272. (b) Raffa, G.; Belot, S.;
Balme, G.; Monteiro, N. Org. Biomol. Chem. 2011, 9, 1474.
(c) Chen, Z.-W.; Huang, G.; Jiang, H.-F.; Huang, H.-W.;
Pan, X.-Y. J. Org. Chem. 2011, 76, 1134. (d) Verma, A. K.;
Rustagi, V.; Aggarwal, T.; Singh, A. P. J. Org. Chem. 2010,
75, 7691. (e) Mancuso, R.; Mehta, S.; Gabriele, B.; Salerno,
G.; Jenks, W. S.; Larock, R. C. J. Org. Chem. 2010, 75, 897.
(f) Roy, S.; Roy, S.; Neuenswander, B.; Hill, D.; Larock, R.
C. J. Comb. Chem. 2009, 11, 1128. (g) Okitsu, T.;
Krishnarao, P. S.; Das, P. P.; Yadav, J. S. Org. Lett. 2011,
13, 744. (b) Miyagawa, T.; Nagai, K.; Yamada, A.;
Sugihara, Y.; Fukuda, T.; Fukuda, T.; Uchida, R.; Tomoda,
H.; Omura, S.; Nagamitsu, T. Org. Lett. 2011, 13, 1158.
(c) Davies, D.; Fletcher, M. D.; Franken, H.; Hollinshead, J.;
Kaehm, K.; Murphy, P. J.; Nash, R.; Potter, D. M.
Tetrahedron Lett. 2010, 51, 6825. (d) Pradal, A.; Nasr, A.;
Toullec, P. Y.; Michelet, V. Org. Lett. 2010, 12, 5222.
(e) Chen, J.; Lu, L.; Ma, S. M. Tetrahedron 2008, 64, 8899.
(f) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445,
900. (g) Amjad, M.; Knight, D. W. Tetrahedron Lett. 2006,
47, 2825.
(11) (a) Downer-Riley, N. K.; Jackson, Y. A. Tetrahedron 2007,
63, 10276. (b) Il’inykh, E. S.; Kim, D. G. Chem. Heterocycl.
Compd. 2011, 47, 636. (c) Creeke, P. I.; Mellor, J. M.
Tetrahedron Lett. 1989, 30, 4435.
(12) Wang, Z. L.; Tang, R. Y.; Luo, P. S.; Deng, C. L.; Zhong, P.;
Li, J. H. Tetrahedron 2008, 64, 10670.
(13) Further investigation demonstrated that by loading bases
like NaHCO3 and K2CO3 (2 equiv), or lowering the amount
of iodine (0.5 equiv), the reactivity of substrate 1i did not
increase and only trace product was observed. For relative
references, see: (a) Huang, Q.-H.; Hunter, J. A.; Larock, R.
C. Org. Lett. 2001, 3, 2973. (b) Zhang, X. X.; Campo, M.
A.; Yao, T.-L.; Larock, R. C. Org. Lett. 2005, 7, 763.
(14) Takashi, N.; Hideki, Y.; Koichiro, O. Org. Lett. 2007, 9,
2373.
(15) Tekiner-Gulbas, B.; Filak, L.; Vasko, G. A.; Egyed, O.;
Yalcin, I. Heterocycles 2008, 75, 2005.
(16) Nutaitis, C. F.; Swartz, B. D. Org. Prep. Proced. Int. 2005,
37, 507.
(17) Hamer, F. M. J. Chem. Soc. 1956, 1480.
(18) Kendall, J. D.; Duffin, G. F. Patent GB 829832, 1960; Chem.
Abstr. 1960, 54, 91775.
(19) Cossey, H. D.; Judd, J.; Stephens, F. F. J. Chem. Soc. 1965,
Nakazawa, D.; Taniguchi, R.; Wada, A. Org. Lett. 2008, 10,
4967. (h) Waldo, J. P.; Mehta, S.; Neuenswander, B.;
Lushington, G. H.; Larock, R. C. J. Comb. Chem. 2008, 10,
658. (i) Arimitsu, S.; Jacobsen, J. M.; Hammond, G. B.
J. Org. Chem. 2008, 73, 2886. (j) Aillaud, I.; Bossharth, E.;
Conreaux, D.; Desbordes, P.; Monteiro, N.; Balme, G. Org.
Lett. 2006, 8, 1113.
954.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 927–933