Use of molecular oxygen as a reoxidant in the synthesis of 2-substituted benzothiazoles via palladium-catalyzed C-H functionalization/intramolecular C-S bond formation

Article abstract of DOI:10.1002/adsc.201000604

Molecular oxygen (O₂) was successfully employed as a reoxidant in cyclizations of thiobenzanilides 1a-s through a palladium-catalyzed C-H functionalization/intramolecular C-S bond formation process, leading to an efficient, green method for the synthesis of 2-arylbenzothiazoles 2a-s. Addition of cesium fluoride (CsF) greatly enhanced the reactions, which produced variously substituted 2-arylbenzothiazoles with good functional group tolerance. Thioureas 4a-j were also found to be suitable substrates for the cyclization process using a palladium/O₂ catalyst system, thus generating 2-aminobenzothiazoles 5a-j. One-pot syntheses of 2-aminobenzothiazoles 5a-j from aryl isothiocyanates 6 and amines 7 were also successful.

Full text of DOI:10.1002/adsc.201000604

FULL PAPERS
DOI: 10.1002/adsc.201000604
Use of Molecular Oxygen as a Reoxidant in the Synthesis of
À
2-Substituted Benzothiazoles via Palladium-Catalyzed C H
À
Functionalization/Intramolecular C S Bond Formation
Kiyofumi Inamoto,a,* Chisa Hasegawa,a Junpei Kawasaki,a Kou Hiroya,a
and Takayuki Doia,*
a
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
Fax : (+81)-22-795-6866; phone: (+81)-22-795-6864; e-mail: inamoto@mail.pharm.tohoku.ac.jp or
doi_taka@mail.pharm.tohoku.ac.jp
Received: July 29, 2010; Published online: October 12, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000604.
Abstract: Molecular oxygen (O2) was successfully strates for the cyclization process using a palladium/
employed as a reoxidant in cyclizations of thiobenz- O2 catalyst system, thus generating 2-aminobenzo-
À
anilides 1a–s through a palladium-catalyzed C H thiazoles 5a–j. One-pot syntheses of 2-aminobenzo-
À
functionalization/intramolecular C S bond formation thiazoles 5a–j from aryl isothiocyanates 6 and
process, leading to an efficient, green method for the amines 7 were also successful.
synthesis of 2-arylbenzothiazoles 2a–s. Addition of
cesium fluoride (CsF) greatly enhanced the reac-
tions, which produced variously substituted 2-aryl- Keywords: benzothiazoles; C H functionalization;
benzothiazoles with good functional group tolerance. C S bond formation; cyclization; molecular oxygen;
Thioureas 4a–j were also found to be suitable sub- palladium
À
À
Introduction
preparing 2-arylbenzothiazoles from readily available
thiobenzanilides.[3e,4–6] This method represents a rare
À
In recent years, substantial progress has been made in example of C S bond formation through transition
the development of new transformations through pal- metal-catalyzed C H functionalization [Eq. (1)]. Al-
ladium-catalyzed C H functionalization. The discov- though the method provided a step forward in ex-
ery of catalytic systems that successfully effect C C, panding the scope of palladium-catalyzed C H func-
À
À
À
À
À
À
À
C O, C X (X=halogen), and recently C N bond for- tionalization reactions, it was not an ideal solution be-
mation via C H functionalization represents a signifi- cause the process requires the use of 50 mol% of CuI
À
cant contribution to this field.[1,2] We used a palladi- along with an excess amount (200 mol%) of Bu4NBr
À
um-catalyzed C H functionalization/intramolecular in the reoxidation system for efficient formation of
À
C N bond-forming amination sequence to synthesize cyclized products.
N-heterocycles such as indazoles,[2l] indoles,[2k] and 2-
Molecular oxygen (O2) is one of the ideal oxidants
quinolinones.[2a] Recognizing the importance of sulfur in organic synthesis. It is non-toxic, readily available,
atom-containing heterocycles because of their broad
range of bioactivities and useful material properties
and wishing to further exploit the potential of the pal-
À
ladium-catalyzed C H functionalization process for
C heteroatom bond formation, we recently turned
À
À
our attention to intramolecular C S bond formation
via C H functionalization, which would result in
novel, efficient, and more straightforward cyclization
approaches to S-heterocycles.[3] Consequently, we suc-
cessfully developed a versatile synthetic method for
À
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easy-to-handle, and does not produce any environ- After extensive work, we determined the reaction
mentally hazardous by-products. Therefore, the use of conditions that would allow the use of O2 as a reoxi-
O2 has long been of interest in organic reactions, in- dant. The key to success is the addition of a basic ad-
cluding palladium-catalyzed transformations such as ditive (Table 1, entry 1 vs. 2–12). 50 mol% of CsF was
the Wacker-type process and oxidation of alcohols.[7] found to be most effective among the additives
Indeed, some groups have reported that palladium- tested;[13] cyclization of 1a proceeded smoothly in the
À
catalyzed C H functionalization effectively used O2 presence of 10 mol% of PdCl2 and 50 mol% of CsF in
as a terminal co-reoxidant of palladium.[8,9] Very re- DMSO under an O2 atmosphere, providing benzothia-
cently, Batey et al. successfully employed an O2/MnO2 zole 2a in high yield along with the formation of a
reoxidation system for Pd-catalyzed cyclization of thi- small, but still not negligible, amount of by-product
oureas, affording several kinds of 2-aminobenzothia- 3a (entry 12). Both 2a and 3a were easily purified and
zoles.[3c]
isolated by silica gel column chromatography. PdCl2
Considering the advantages of O2 as an oxidant and was the best catalyst for the process,[14] and decreasing
hoping to develop a greener, efficient, and atom-eco- the catalyst loading resulted in lower yields (entries 13
nomic system, we decided to use O2 in our 2-arylben- and 14). Essentially none of the desired cyclization
zothiazoles synthesis. However, this turned out to be occurred in the absence of palladium (entry 15). Re-
problematic (Scheme 1). When thiobenzanilide 1a placement of DMSO with other solvents led to de-
was heated in DMSO-NMP (1:1) at 1208C in the creased yields (entries 16–21). Cyclization conducted
presence of 10 mol% of PdCl2 in air, benzanilide 3a under an argon atmosphere resulted in the recovery
was produced as a major product (79%), along with a of a large amount of starting material (entry 22).
small amount of the desired benzothiazole 2a (7%). Lowering the reaction temperature provided a slightly
The same side reaction took place when a catalytic increased yield (entry 23).
amount of CuI was used instead of PdCl2, resulting in
the exclusive formation of benzanilide 3a (82%).
The catalytic activity of the system was evaluated
in the cyclization of an array of starting thiobenzani-
The conversion of thioamides into the correspond- lides 1b–s (Table 2). Reactions of substrates possess-
ing carbonyl compounds has been known to proceed ing both electron-withdrawing and electron-donating
in the presence of a variety of stoichiometric oxidants, groups on the benzene rings proceeded smoothly, and
such as inorganic metal salts and peroxidic re- the variously substituted 2-arylbenzothiazoles 2b–s
agents.[10] Molecular oxygen, with or without photo-ir- were obtained generally in good to high yields. Func-
radiation, can also be a good electrophile that is capa- tional groups such as the cyano (entries 1, 12, and 16)
ble of achieving this transformation.[11] Shibahara and and the alkoxycarbonyl (entry 2) group were well tol-
Murai recently reported the catalytic procedure for erated under the reaction conditions. It is particularly
desulfurization of thioamides using 20 mol% of CuCl noteworthy that the whole range of halogen atoms, in-
in DMSO solvent under an O2 atmosphere.[12]
cluding iodine, can be incorporated (entries 7–11, 13)
In the present study, we describe our further efforts because such compounds can be further functional-
to successfully use O2 as a reoxidant in the synthesis ized via certain synthetic methods (e.g., transition
of 2-aryl and 2-aminobenzothiazoles.
metal-catalyzed cross-coupling). In addition, sub-
strates possessing a heteroaromatic ring system (1r
and 1s) were found to be suitable for the process (en-
tries 17 and 18).
Results and Discussion
Cyclization of Thiobenzanilides for Synthesis of 2-
Arylbenzothiazoles
Cyclization of Thioureas for Synthesis of 2-
Aminobenzothiazoles
Despite our initial discouraging results (Scheme 1),
we began our investigation using thiobenzanilide (1a) 2-Aminobenzothiazoles also constitute an important
to identify the reaction conditions that would pre- class of heterocycles in medicinal chemistry.[15] Un-
dominantly produce the desired cyclized product 2a. fortunately, the above developed conditions could not
Scheme 1. Initial approach to 2-phenylbenzothiazole 2a using O2 as a reoxidant.
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Use of Molecular Oxygen as a Reoxidant in the Synthesis of 2-Substituted Benzothiazoles
À
À
Table 1. Palladium-catalyzed C H functionalization/C S bond formation for synthesis of 2-phenylbenzothiazole 2a: Effects
of reaction parameters.
Entry
PdCl2 (mol%)
Additive
Solvent
Yield [%][a,b]
2a
3a
1a
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
10
10
10
10
7.5
5
none
pyridine
(i-Pr)2NEt
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
(5)
8
54
54
56
45
53
62 (56)
14
(82)
74
31
21
33
25
30
26 (25)
57
25
(0)
0
0
0
0
8
8
0 (0)
0
0
0
0 (0)
2 (0)
0 (0)
48 (58)
2
2
11
0
55
67
(76)
0
KHMDS
KOPh
NaOMe
KO-t-Bu
NaO-t-Bu
Na2CO3
Cs2CO3
KF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
9
10
11
12
13
14
15
16
17
18
19
20
21
22[c]
23[d]
51
53
37
72 (73)
66 (63)
54 (53)
3 (0)
54
15
57
18
22
24 (20)
39 (21)
34 (32)
18 (23)
28
81
14
66
2
0
10
10
10
10
10
10
10
10
DMI
DMF
diglyme
o-xylene
PhCl
DMSO
DMSO
16
(14)
(77)
0
(0)
(20)
[a]
Determined by GC analysis versus a calibrated internal standard.
Isolated yield in parentheses.
Ar atmosphere instead of O2 atmosphere.
1008C instead of 1208C.
[b]
[c]
[d]
be applied directly to the cyclization of thioureas 4 strates.[18] Treatment of 6 with 7 in NMP at room tem-
for the synthesis of 2-aminobenzothiazoles 5.[3c] By perature followed by heating at elevated temperature
adjusting the reaction parameters, however, we were in the presence of a catalytic amount of PdCl2 result-
able to develop a method that achieves the desired ed in the successful formation of 2-aminobenzothia-
cyclization of 4a under an O2 atmosphere, producing zoles 5 (Table 4). Yields obtained from the one-pot
2-aminobenzothiazole 5a in reasonable yield synthesis were generally comparable to those from
(Scheme 2).[16] The choice of NMP as the solvent the cyclizations of thioureas
4 (Scheme 2 and
played an important role in this case. Although a rela- Table 3), thus the one-pot synthesis represents a more
tively high catalyst loading was necessary for the best efficient route to synthesizing 2-aminobenzothiazole
conversion, the simple catalytic system composed of compounds.
only a catalytic amount of palladium and O2 is partic-
ularly appealing.[17]
Several kinds of thioureas 4b–j that possess a varie- Mechanistic Considerations
ty of functional groups underwent smooth cyclization,
providing the corresponding 2-aminobenzothiazoles Several mechanistic scenarios have been proposed for
À
5b–j in moderate to fairly good yields (Table 3).
palladium-catalyzed aromatic C H functionalization
The one-pot, sequential synthesis of 2-aminobenzo- processes, including an electrophilic aromatic pallada-
thiazoles 5 from aryl isothiocyanates 6 and amines 7 tion pathway,[19] a Heck-like pathway,[20] and a s-bond
was also examined to develop a more efficient and metathesis or base-assisted deprotonative metalation
convenient approach to synthesizing this class of sub- pathway.[21]
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À
À
Table 2. Palladium-catalyzed C H functionalization/C S bond formation for synthesis of 2-arylbenzothiazoles.
Entry
1
Substrate 1
Product 2
Conditions
Yield [%][a,b]
67 (23)
1b
1c
1d
2b
2c
2d
1208C, 2h
2
3
1208C, 2h
70 (18)
61 (11)
1008C, 12h
4
5
6
7
1e
1f
1g
1h
2e
2f
2g
2h
1208C, 4h
1208C, 4h
1208C, 2h
1208C, 2h
58 (18)
78 (12)
58 (24)
69 (20)
8
1i
2i
1208C, 2h
1208C, 2h
1008C, 12h
1008C, 12h
1208C, 2h
1208C, 2h
72 (19)
69 (22)
59 (20)
66 (15)
52 (28)
46 (34)
9
1j
2j
10
11
12
13
1k
1l
2k
2l
1m
1n
2m
2n
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Use of Molecular Oxygen as a Reoxidant in the Synthesis of 2-Substituted Benzothiazoles
Table 2. (Continued)
Entry
Substrate 1
Product 2
Conditions
Yield [%][a,b]
58 (24)
14
1o
1p
1q
2o
2p
2q
1008C, 12h
15
16
17
1208C, 2h
79 (10)
59 (27)
1008C, 12h
1r
1s
2r
2s
1208C, 2h
58 (11)
53 (11)
18
1008C, 12h
[a]
Yield of isolated product from the reaction on a 0.14 mmol scale.[b] Yield of the corresponding amide in parentheses.
To obtain insight into the reaction mechanism of
the process, experiments with the isotopically labeled
substrates 1e-d and 1a-d5 were performed. As a result,
primary kinetic isotope effects (KIE, kH/kD) of 2.3 (in-
tramolecular) and 2.0 (intermolecular) were observed,
À
indicating that the cleavage of the C H bond is in-
Scheme 2. Palladium-catalyzed synthesis of 2-aminobenzo-
volved in the rate-determining step (Figure 1).[22,23]
thiazole 5a.
Investigation of the effect of the substituent on the
benzene ring is also informative. Namely, unsubstitut-
ed thiobenzanilide 1a and thiobenzanilides possessing
À
À
Table 3. Palladium-catalyzed C H functionalization/C S bond formation for synthesis of 2-aminobenzothiazoles.
5b yield: 54% (T 1208C)
5e yield: 57% (T 1408C)
5c yield: 63% (T 1208C)
5f yield: 44% (T 1008C)
5d yield:59% (T 1408C)
5g yield: 54% (T 1208C)
5h yield: 58% (T 1208C)
5i yield: 54% (T 1208C)
5j yield: 50% (T 1408C)
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Table 4. One-pot synthesis of 2-aminobenzothiazoles.
5a yield: 57% (T 1208C)
5b yield: 55% (T 1208C)
5e yield: 53% (T 1408C)
5c yield: 58% (T 1208C)
5d yield: 46% (T 1408C)
5g yield: 53% (T 1208C)
5f yield: 19% (T 1008C)
5i yield: 23% (T 1208C)
5h yield: 60% (T 1208C)
5j yield: 41% (T 1408C)
electrophilic aromatic palladation pathway is not op-
erating.
On the basis of these findings and literature prece-
dents,[19–22] a plausible reaction pathway is shown in
Figure 3. The reaction is most likely initiated by the
coordination of sulfur atom to Pd(II), leading to the
formation of the complex I. A subsequent formation
of six-membered palladacycle II followed by reduc-
tive elimination affords the desired 2-substituted ben-
zothiazole and Pd(0), which can be reoxidized to
Pd(II) by O2. Taking the observations above (positive
KIE values and the lack of an electronic effect on the
Figure 1. Observed kinetic isotope effects in 2-arylbenzo-
thiazole synthesis.
either an electron-withdrawing cyano or an electron- reactivity) into account, it seems reasonable to
donating methoxy group in the meta-position (1_3- assume that the palladacycle II is formed via s-bond
CN and 1_3-OMe) were independently reacted under metathesis or base-assisted deprotonative metala-
the optimal reaction conditions and the time-depen- tion,[21,25] rather than electrophilic aromatic pallada-
dent profiles of the reactions were obtained tion or Heck-like insertion.[26] Although a precise role
(Figure 2). Although the slightly better yield was ob- of the added base (CsF) in 2-arylbenzothiazole syn-
tained from the reaction of 1_3-OMe after 13 h com- thesis is not yet clear at present, it might aid the for-
pared to those of 1a and 1_3-CN,[24] there was not a mation of palladacycle II acting as an external base in
large difference in reactivity among these compounds, the deprotonative metalation step.[27,28]
especially at the early stage of the process (~1 h).
This observation is in sharp contrast to the related
synthesis of benzimidazoles[9b] and benzoxazoles[9a] via Conclusions
À
a copper-catalyzed C H functionalization/cyclization
process, in which an apparent reaction-accelerating In summary, we described new palladium-based cata-
effect of the electron-donating group at the meta-posi- lyst systems that successfully realize the cyclization of
tion was observed. The authors of both reports thus thiobenzanilides and thioureas to produce 2-aryl- and
concluded the possible involvement of the electrophil- 2-aminobenzothiazoles, respectively. The protocol
ic aromatic substitution mechanism. On the other allows the use of O2 alone as a reoxidant, and no
hand, the lack of an electronic effect on the reactivity other redox-active reagents are necessary for the pro-
in our benzothiazole synthesis would suggest that an cess. In the synthesis of 2-arylbenzothiazoles, the ad-
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Use of Molecular Oxygen as a Reoxidant in the Synthesis of 2-Substituted Benzothiazoles
Figure 2. Plot of yield vs. time in cyclizations of 1a, 1_3-CN, and 1_3-OMe.
Figure 3. Plausible reaction mechanisms for benzothiazole synthesis.
Sigma–Aldrich (99.5% in a SureSealTM bottle). CsF was
dition of 50 mol% of CsF turned out to be crucial for
dried under vacuum while heating. All other commercially
available materials, including thiobenzanilide (1a), N,N’-di-
phenylthiourea (4j), and PdCl2, were used as received. Syn-
thesis of starting thiobenzanilides 1b–q was described pre-
viously.[3e] Thiobenzanilides 1r and 1s were prepared accord-
ing to the literature.[29] Thioureas 4a–i were prepared by
condensation of the corresponding aryl isothiocyanates and
amines. Melting points were measured with a Yazawa micro
the best conversion. Cyclizations proceeded smoothly
with good functional group compatibility, affording a
range of products with various substitution patterns
generally in high yields. Thiourea compounds also
proved suitable for the cyclization process, giving rise
to several kinds of 2-aminobenzothiazoles. Further
studies to broaden the substrate scope and increase
the efficiency of the catalyst system are underway.
Furthermore, we are applying this approach to the
construction of other heterocyclic compounds.
1
melting point apparatus and uncorrected. H NMR spectra
were recorded on a JEOL JNM-AL400 (400 MHz) spec-
trometer. Chemical shifts (d) are given from TMS (0 ppm)
in CDCl3 and from residual non-deuterated solvent peak in
other solvents (DMSO-d6: 2.49 ppm, acetone-d6: 2.04 ppm),
and coupling constants are expressed in hertz (Hz). The fol-
lowing abbreviations are used: s=singlet, d=doublet, t=
triplet, q=quartet, dd=double doublet, m=multiplet,
br.s=broad singlet, and br=broad signal. 13C NMR spectra
were recorded on a JEOL JNM-AL400 (100 MHz) spec-
trometer and chemical shifts (d) are given from 13CDCl3
(77.0 ppm), DMSO-d6 (39.7 ppm), or acetone-d6 (29.8 ppm).
Experimental Section
General Comments
Anhydrous dimethyl sulfoxide (DMSO) was purchased from
Sigma–Aldrich (>99.5% over molecular sieve). Anhydrous
1-methyl-2-pyrrolidinone (NMP) was purchased from
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Kiyofumi Inamoto et al.
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Mass spectra and high resolution mass spectra were mea-
sured on JEOL JMS-DX303 and MS-AX500 instruments,
respectively. Elemental analyses were performed by Yanaco
CHN CORDER MT-6.
tensity %)=241 (M+, 100); HR-MS: m/z=241.0533, calcd.
for C14H11NOS: 241.0561.
5-Methoxy-2-phenylbenzothiazole (2f): mp 62.5–638C
(colorless prisms from hexane-AcOEt, lit.[33] mp 75–778C);
1H NMR (400 MHz, CDCl3): d=3.90 (3H, s), 7.03 (1H, dd,
J=8.8, 2.4 Hz), 7.46–7.49 (3H, m), 7.56 (1H, d, J=2.4 Hz),
7.73 (1H, d, J=8.8 Hz), 8.04–8.09 (2H, m); 13C NMR
(100 MHz, CDCl3): d=55.6, 105.4, 115.4, 121.7, 126.8, 127.3,
128.9, 130.7, 133.6, 155.3, 159.0, 169.1; MS: m/z (relative in-
tensity %)=241 (M+, 100); HR-MS: m/z=241.0567, calcd.
for C14H11NOS: 241.0561.
Representative Procedure for Pd-Catalyzed Synthesis
of 2-Arylbenzothiazoles (2a-s) (Tables 1 and 2):
Cyclization of Thiobenzanilide (1a) (Table 1,
entry 12)
A mixture of 1a (30.5 mg, 0.14 mmol), PdCl2 (2.5 mg,
0.014 mmol), and CsF (10.9 mg, 0.72 mmol) in DMSO
(2.9 mL, 0.05M) was stirred at 1208C for 2 h under an O2 at-
mosphere (balloon). The reaction mixture was extracted
with ethyl acetate (5 mLꢁ3) and the combined organic
layer was washed with brine (10 mL), and dried over
MgSO4. The solvent was evaporated and the residue was pu-
rified by silica gel column chromatography [hexane:ethyl
acetate (9:1)] to give 2a (yield: 22.0 mg, 73%) as a colorless
solid and 3a (yield: 5.9 mg, 20%) as a colorless solid.
4-Methyl-2-phenylbenzothiazole (2g): obtained as a pale
yellow oil; 1H NMR (400 MHz, CDCl3): d=2.73 (3H, s),
7.17–7.20 (2H, m), 7.37–7.43 (3H, m), 7.62–7.65 (1H, m),
8.01–8.04 (2H, m); 13C NMR (100 MHz, CDCl3): d=18.4,
118.9, 125.0, 126.7, 127.5, 128.9, 130.7, 133.4, 134.0, 135.0,
153.5, 166.5; MS: m/z (relative intensity %)=225 (M+, 100);
HR-MS: m/z=225.0612, calcd. for C14H11NS: 225.0612.
6-Chloro-2-phenylbenzothiazole (2h): mp 156–1578C (col-
orless prisms from hexane:AcOEt, lit.[34] mp 156.5–1578C);
1H NMR (400 MHz, CDCl3): d=7.44 (1H, dd, J=8.8,
2.2 Hz), 7.47–7.50 (3H, m), 7.86 (1H, d, J=2.2 Hz), 7.96
(1H, d, J=8.8 Hz), 8.03–8.07 (2H, m); 13C NMR (100 MHz,
CDCl3); d=121.0, 123.7, 126.9, 127.3, 128.8, 130.8, 131.0,
133.0, 136.0, 152.4, 170.8; MS: m/z (relative intensity %)=
247 (M+ +2, 41), 245 (M+, 100); HR-MS: m/z=245.0050,
calcd for C13H835ClNS 245.0066.
6-Bromo-2-phenylbenzothiazole (2i): mp 150–1518C (pale
brown prisms from hexane:AcOEt, lit.[35] mp 1508C);
1H NMR (400 MHz, CDCl3): d=7.45–7.49 (3H, m), 7.57
(1H, dd, J=8.6, 1.8 Hz), 7.90 (1H, d, J=8.6 Hz), 8.01 (1H,
d, J=1.8 Hz), 8.04–8.06 (2H, m); 13C NMR (100 MHz,
CDCl3): d=118.6, 124.0, 124.2, 127.4, 129.0, 129.7, 131.2,
133.1, 136.6, 152.9, 168.4; MS: m/z (relative intensity %)=
291 (M+ +2, 100), 289 (M+, 99); HR-MS: m/z=288.9549,
calcd. for C13H879BrNS: 288.9561.
2-Phenylbenzothiazole (2a): mp 110.5–1118C (colorless
1
prisms from hexane:AcOEt, lit.[30] mp 110–1118C); H NMR
(400 MHz, CDCl3): d=7.36 (1H, t, J=7.8 Hz), 7.46–7.49
(4H, m), 7.88 (1H, d, J=7.8 Hz), 8.06–8.09 (3H, m);
13C NMR (100 MHz, CDCl3): d=121.5, 123.1, 125.1, 126.2,
127.5, 128.9, 130.8, 133.5, 135.0, 154.0, 167.9; MS: m/z (rela-
tive intensity %)=211 (M+, 100); HR-MS: m/z=211.0444,
calcd. for C13H9NS: 211.0456.
6-Cyano-2-phenylbenzothiazole (2b): mp 195–1968C (red
plates from hexane:AcOEt); IR (film): n=2228 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=7.50–7.57 (3H, m), 7.73
(1H, d, J=8.4 Hz), 8.08–8.12 (3H, m), 8.22 (1H, s);
13C NMR (100 MHz, CDCl3): d=108.4, 118.6, 123.7, 126.2,
127.7, 129.1, 129.4, 131.9, 132.5, 135.3, 156.3, 172.0; MS: m/z
(relative intensity %)=236 (M+, 100); HR-MS: m/z=
236.0407, calcd. for C14H8N2S: 236.0408.
5-Bromo-2-phenylbenzothiazole (2j): mp 135–1368C (col-
orless plates from hexane:AcOEt); 1H NMR (400 MHz,
CDCl3): d=7.45–7.49 (4H, m), 7.73 (1H, d, J=8.4 Hz),
8.04–8.07 (2H, m), 8.20 (1H, d, J=1.6 Hz); 13C NMR
(100 MHz, CDCl3): d=119.8, 122.6, 126.0, 127.6, 128.2,
129.0, 131.3, 133.1, 133.8, 155.2, 169.6; MS: m/z (relative in-
tensity %)=291 (M+ +2, 100), 289 (M+, 97); HR-MS: m/z=
288.9550, calcd. for C13H879BrNS: 288.9561.
6-Iodo-2-phenylbenzothiazole (2k): mp 175–176.58C (pale
brown prisms from hexane:AcOEt); 1H NMR (400 MHz,
CDCl3): d=7.49–7.51 (3H, m), 7.75–7.81 (2H, m), 8.06–8.08
(2H, m), 8.23 (1H, s); 13C NMR (100 MHz, CDCl3): d=
89.4, 124.7, 127.6, 129.1, 130.1, 131.3, 133.1, 135.4, 137.1,
153.5, 168.5; MS: m/z (relative intensity %)=337 (M+, 100);
HR-MS: m/z=336.9425, calcd. for C13H8INS: 336.9422.
4-Fluoro-2-phenylbenzothiazole (2l): Obtained along with
its dehalogenated compound 2. The yield was determined
from the 1H NMR spectrum. 1H NMR (400 MHz, CDCl3):
d=7.16–7.21 (1H, m), 7.30–7.35 (1H, m), 7.47–7.50 (3H,
m), 7.65 (1H, dd, J=8.1, 0.8 Hz), 8.08–8.13 (2H, m); MS:
m/z (relative intensity)=229 (M+, 100); HR-MS: m/z=
229.0342, calcd. for C13H8FNS: 229.0362.
6-Ethoxycarbonyl-2-phenylbenzothiazole (2c): mp 196–
1978C (pale red prisms from hexane:AcOEt); IR (film): n=
1
1709, 1275 cmÀ1; H NMR (400 MHz, CDCl3): d=1.43 (3H,
t, J=7.2 Hz), 4.42 (2H, q, J=7.2 Hz), 7.48–7.51 (3H, m),
8.06–8.11 (3H, m), 8.16 (1H, dd, J=8.4, 1.4 Hz), 8.61 (1H,
d, J=1.4 Hz); 13C NMR (100 MHz, CDCl3): d=14.4, 61.3,
122.7, 123.7, 127.2, 127.5, 127.7, 129.0, 131.5, 133.1, 134.8,
156.8, 166.0, 171.3; MS: m/z (relative intensity %)=283
(M+, 85), 238 (100); HR-MS: m/z=283.0648, calcd. for
C16H13NO2S: 283.0667.
6-Nitro-2-phenylbenzothiazole (2d): mp 191–1928C (pale
orange prisms from hexane:AcOEt, lit.[31] mp 187–1888C);
1
IR (film): n=1518, 1333 cmÀ1; H NMR (400 MHz, CDCl3):
d=7.50–7.56 (3H, m), 8.09–8.12 (3H, m), 8.34 (1H, dd, J=
9.0, 2.3 Hz), 8.81 (1H, d, J=2.3 Hz); 13C NMR (100 MHz,
CDCl3): d=118.1, 121.8, 123.2, 127.8, 129.2, 132.1, 132.6,
135.2, 144.8, 157.7, 173.6; MS: m/z (relative intensity %)=
256 (M+, 100); HR-MS: m/z=256.0287, calcd. for
C13H8N2O2S: 256.0307.
6-Methoxy-2-phenylbenzothiazole (2e): mp 112–1138C
(red prisms from hexane-AcOEt, lit.[32] mp 114–1158C);
1H NMR (400 MHz, CDCl3): d=3.87 (3H, s), 7.08 (1H, dd,
J=9.1, 2.7 Hz), 7.34 (1H, d, J=2.7 Hz), 7.42–749 (3H, m),
7.94 (1H, d, J=9.1 Hz), 8.01–8.04 (2H, m); 13C NMR
(100 MHz, CDCl3): d=55.8, 104.1, 115.6, 123.6, 127.1, 128.9,
130.4, 133.7, 136.3, 148.6, 157.6, 165.4; MS: m/z (relative in-
2-(4-Cyanophenyl)benzothiazole (2m): mp 169.5–170.58C
(colorless prisms from hexane:AcOEt, lit.[36] mp 170–
1718C); IR (film): n=2228 cmÀ1
;
1H NMR (400 MHz,
CDCl3): d=7.44 (1H, t, J=8.0 Hz), 7.53 (1H, t, J=8.0 Hz),
2650
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2643 – 2655

Use of Molecular Oxygen as a Reoxidant in the Synthesis of 2-Substituted Benzothiazoles
7.75 (2H, d, J=8.0 Hz), 7.92 (1H, d, J=8.0 Hz), 8.09 (1H,
d, J=8.0 Hz), 8.17 (2H, d, J=8.0 Hz); 13C NMR (100 MHz,
CDCl3): d=114.1, 118.2, 121.8, 123.8, 126.0, 126.8, 127.9,
132.7, 135.3, 137.4, 154.0, 165.3; MS: m/z (relative intensity
%)=236 (M+, 100); HR-MS: m/z=236.0409, calcd. for
C14H8N2S: 236.0408.
2-(4-Chlorophenyl)benzothiazole (2n): mp 111.5–112.58C
(colorless prisms from hexane:AcOEt, lit.[37] mp 118–
1208C); 1H NMR (400 MHz, CDCl3): d=7.39 (1H, t, J=
7.8 Hz), 7.46 (2H, d, J=8.6 Hz), 7.49 (1H, t, J=7.8 Hz),
7.89 (1H, d, J=7.8 Hz), 8.02 (2H, d, J=8.6 Hz), 8.06 (1H,
d, J=7.8 Hz); 13C NMR (100 MHz, CDCl3): d=121.6, 123.2,
125.3, 126.4, 128.6, 129.2, 132.0, 135.0, 136.9, 154.0, 166.5;
MS: m/z (relative intensity %)=247 (M+ +2, 42), 245 (M+,
100); HR-MS: m/z=245.0049, calcd. for C13H835ClNS:
245.0066.
Representative Procedure for Preparation of
Thioureas (4a–i): N-Benzyl-N’-phenylthiourea (4a)
Phenyl isothiocyanate (2.0 g, 15.0 mmol) was added to a so-
lution of benzylamine (1.7 g, 15.8 mmol) in MeCN (20 mL)
at room temperature and the mixture was stirred for 1 h at
the same temperature. MeCN was removed under reduced
pressure and the precipitate was washed with Et2O (5 mLꢁ
3) and hexane (5 mLꢁ3). Recrystallization from hexane-
acetone gave 4a as colorless prisms; yield: 2.5 g (85%); mp
153–1548C (lit.[39] mp 151.2–151.78C); IR (film): n=1537,
1
1352, 1244 cmÀ1; H NMR (400 MHz, CDCl3): d=4.87 (2H,
d, J=5.2 Hz), 6.28 (1H, br.s), 7.21 (2H, d, J=8.0 Hz), 7.25–
7.34 (6H, m), 7.39 (2H, t, J=7.2 Hz), 8.06 (1H, br.s);
13C NMR (100 MHz, CDCl3): d=49.5, 125.2, 127.3, 127.5,
127.6, 128.7, 130.2, 135.8, 137.1, 180.7; MS: m/z (relative in-
tensity %)=242 (M+, 48), 91 (100); HR-MS: m/z=
242.0875, calcd. for C14H14N2S: 242.0878.
2-(4-Methoxyphenyl)benzothiazole (2o): mp 119–1208C
(colorless prisms from hexane:AcOEt, lit.[32] mp 121–
N-(4-Methoxybenzyl)-N’-phenylthiourea (4b): obtained as
1
1228C); H NMR (400 MHz, CDCl3): d=3.87 (3H, s), 6.99
colorless needles; yield: 86%; mp 109–1108C (lit.[40] mp
(2H, d, J=8.4 Hz), 7.34 (1H, t, J=7.6 Hz), 7.46 (1H, t, J=
7.6 Hz), 7.86 (1H, d, J=7.6 Hz), 8.01–8.03 (3H, m);
13C NMR (100 MHz, CDCl3): d=55.5, 114.3, 121.4, 122.7,
124.7, 126.1, 126.4, 129.0, 134.8, 154.1, 161.8, 167.7; MS: m/z
(relative intensity %)=241 (M+, 100); HR-MS: m/z=
241.0555, calcd. for C14H11NOS: 241.0561.
2-(3-Methoxyphenyl)benzothiazole (2p): mp 81.5–828C
(pale orange plates from hexane:AcOEt, lit.[32] mp 81–
828C); 1H NMR (400 MHz, CDCl3): d=3.90 (3H, s), 7.03
(1H, dd, J=8.3, 2.6 Hz), 7.35–7.40 (2H, m), 7.48 (1H, t, J=
7.5 Hz), 7.62–7.67 (2H, m), 7.88 (1H, d, J=7.5 Hz), 8.07
(1H, d, J=8.3 Hz); 13C NMR (100 MHz, CDCl3): d=55.5,
112.0, 117.2, 120.1, 121.5, 123.2, 125.1, 126.2, 129.9, 134.8,
135.0, 153.9, 159.9, 167.8; MS: m/z (relative intensity %) 241
(M+, 100); HR-MS: m/z=241.0532, calcd. for C14H11NOS:
241.0561.
1078C); IR (film): n=3209, 1512, 1247, 1175, 1031 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=3.77 (3H, s), 4.78 (2H, d,
J=5.2 Hz), 6.25 (1H, br.s), 6.83 (2H, d, J=8.4 Hz), 7.18–
7.30 (5H, m), 7.37 (2H, t, J=7.8 Hz), 8.26 (1H, br.s);
13C NMR (100 MHz, CDCl3): d=48.9, 55.2, 114.0, 125.0,
127.1, 128.9, 129.1, 130.0, 135.9, 159.0, 180.3; MS: m/z (rela-
tive intensity %)=272 (M+, 28), 121 (100); HR-MS: m/z=
272.0996, calcd. for C15H16N2OS: 272.0983.
N-(4-Nitrobenzyl)-N’-phenylthiourea (4c): obtained as
pale yellow prisms; yield: 87%; mp 163–1648C; IR (film):
n=3200, 1516, 1343, 1185 cmÀ1 1H NMR (400 MHz, ace-
;
tone-d6): d=5.04 (2H, d, J=6.0 Hz), 7.19 (1H, t, J=
7.7 Hz), 7.36 (2H, t, J=7.7 Hz), 7.42–7.45 (2H, m), 7.63
(2H, d, J=8.8 Hz), 7.81 (1H, br.s), 8.18 (2H, d, J=8.8 Hz),
9.08 (1H, br.s); 13C NMR (100 MHz, acetone-d6): d=48.1,
124.1, 125.4, 126.4, 129.1, 130.0, 139.2, 147.8, 148.3, 183.1;
MS: m/z (relative intensity %)=287 (M+, 38), 135 (100);
HR-MS: m/z=287.0711, calcd. for C14H13N3O2S: 287.0729;
anal. calcd. for C14H13N3O2S: C 58.52, H 4.56, N 14.62;
found: C 58.46, H 4.61, N 14.64.
6-Cyano-2-(4-methoxyphenyl)benzothiazole (2q): mp 197–
197.58C (red plates from hexane:AcOEt); IR (film): n=
2224 cmÀ1 1H NMR (400 MHz, CDCl3): d=3.90 (3H, s),
;
7.11 (2H, d, J=8.6 Hz), 7.70 (1H, dd, J=8.4, 1.4 Hz), 8.04
(2H, d, J=8.6 Hz), 8.05 (1H, d, J=8.4 Hz), 8.18 (1H, d, J=
1.4 Hz); 13C NMR (100 MHz, CDCl3): d=55.6, 107.9, 114.6,
118.8, 123.3, 125.4, 126.1, 129.4, 129.5, 135.3, 156.6, 162.7,
166.2; MS: m/z (relative intensity %)=266 (M+, 100); HR-
MS: m/z=266.0516, calcd. for C15H10N2OS: 266.0514.
N-(2-Methylbenzyl)-N’-phenylthiourea (4d): obtained as
colorless prisms; yield: 97%; mp 202–2038C (lit.[41] mp
1898C); IR (film): n=3371, 3153, 1537, 1246, 1173 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=2.31 (3H, s), 4.84 (2H, d,
J=4.8 Hz), 6.04 (1H, br.s), 7.15–7.29 (7H, m), 7.39 (2H, t,
J=7.8 Hz), 7.67 (1H, br.s); 13C NMR (100 MHz, CDCl3):
d=19.1, 47.9, 125.3, 126.2, 127.5, 128.0, 128.4, 130.3, 130.6,
134.8, 135.9, 136.4, 180.8; MS: m/z (relative intensity %)=
256 (M+, 42), 105 (100); HR-MS: m/z=256.1015, calcd. for
C15H16N2S: 256.1034; anal. calcd. for C15H16N2S: C 70.27, H
6.29, N 10.93; found: C 70.32, H 6.30, N 10.88.
2-PhenylthiazoloACHTUNGTRENNUNG[4,5-c]pyridine (2r): mp 147.5–148.58C
(pale orange prisms from hexane:AcOEt, lit.[38] mp 147–
1
1488C); H NMR (400 MHz, DMSO-d6): d=7.58–7.64 (3H,
m), 8.12 (2H, d, J=7.2 Hz), 8.22 (1H, d, J=4.8 Hz), 8.53
(1H, br), 9.32 (1H, br); 13C NMR (100 MHz, DMSO-d6):
d=117.6, 127.7, 129.7, 132.2, 132.4, 142.6, 144.0, 144.7, 150.4,
169.1; MS: m/z (relative intensity %)=212 (M+, 100); HR-
MS: m/z=212.0393, calcd. for C12H8N2S: 212.0408.
N-Benzyl-N’-(4-methoxyphenyl)thiourea (4e): obtained as
colorless needles; yield: 94%; mp 113–1148C (lit.[42] mp 108–
1098C); IR (film): n=3337, 1597, 1508, 1258, 1171 cmÀ1
;
2-PhenylthiazoloACHTUNGTRENNUNG[5,4-c]pyridine (2s): mp 136–136.58C
(colorless prisms from hexane:AcOEt, lit.[38] mp 133–
1H NMR (400 MHz, CDCl3): d=3.78 (3H, s), 4.85 (2H, d,
J=5.6 Hz), 6.08 (1H, br.s), 6.89 (2H, d, J=8.8 Hz), 7.14
(2H, d, J=8.8 Hz), 7.24–7.33 (5H, m), 7.91 (1H, br.s);
13C NMR (100 MHz, CDCl3): d=49.3, 55.5, 115.3, 127.4,
127.5, 127.6, 128.1, 128.6, 137.3, 158.9, 181.3; MS: m/z (rela-
tive intensity %)=272 (M+, 49), 91 (100); HR-MS: m/z=
272.0977, calcd. for C15H16N2OS: 272.0983.
1
1348C); H NMR (400 MHz, CDCl3): d=7.50–7.56 (3H, m),
7.93 (1H, d, J=4.8 Hz), 8.13 (2H, d, J=7.6 Hz), 8.65 (1H,
d, J=4.8 Hz), 9.20 (1H, s); 13C NMR (100 MHz, CDCl3):
d=117.3, 128.0, 129.2, 132.0, 132.1, 132.7, 144.2, 145.9, 158.8,
173.3; MS: m/z (relative intensity %)=212 (M+, 100); HR-
MS: m/z=212.0394, calcd. for C12H8N2S: 212.0408.
Adv. Synth. Catal. 2010, 352, 2643 – 2655
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2651

Kiyofumi Inamoto et al.
FULL PAPERS
N-Benzyl-N’-(4-cyanophenyl)thiourea (4f): obtained as
colorless needles; yield: 80%; mp 178–1798C; IR (film): n=
Representative Procedure for One-Pot Synthesis of
2-Aminobenzothiazoles (5a–j) (Table 4): Synthesis of
2-(Benzylamino)benzothiazole (5a)
1
3032, 2228, 1604, 1506, 1177 cmÀ1; H NMR (400 MHz, ace-
tone-d6): d=4.87 (2H, s), 7.26 (1H, t, J=7.4 Hz), 7.33 (2H,
t, J=7.4 Hz), 7.39 (2H, d, J=7.4 Hz), 7.68 (2H, d, J=
9.0 Hz), 7.86 (2H, d, J=9.0 Hz), 7.94 (1H, br.s), 9.35 (1H,
br.s); 13C NMR (100 MHz, acetone-d6): d=48.6, 107.2,
119.4, 123.0, 128.0, 128.6, 129.2, 133.5, 139.3, 144.9, 182.1;
MS: m/z (relative intensity %)=267 (M+, 15), 160 (100);
HR-MS: m/z=267.0819, calcd. for C15H13N3S: 267.0830;
anal. calcd. for C15H13N3S: C 67.39, H 4.90, N 15.72; found:
C 67.39, H 5.02, N 15.62.
A mixture of phenyl isothiocyanate (67.6 mg, 0.50 mmol)
and benzylamine (53.6 mg, 0.50 mmol) in NMP (10 mL,
0.05m) was stirred at room temperature for 1 h. PdCl2
(17.7 mg, 0.10 mmol) was added to the mixture and the
whole reaction mixture was heated at 1208C under an O2 at-
mosphere (balloon). The reaction mixture was extracted
with ethyl acetate (5 mLꢁ3) and the combined organic
layer was washed with brine (10 mL), and dried over
MgSO4. The solvent was evaporated and the residue was pu-
rified by silica gel column chromatography [hexane-ethyl
acetate (4:1)] to give 5a as a colorless solid; yield: 69.0 mg
(57%); mp 157.5–158.58C (pale brown prisms from hex-
N-Benzyl-N’-(2-methylphenyl)thiourea (4g): obtained as
colorless prisms; yield: 87%; mp 143–1448C (lit.[41] mp
1
1318C); IR (film): n=3375, 3193, 1534, 1194 cmÀ1; H NMR
(400 MHz, DMSO-d6): d=2.17 (3H, s), 4.71 (2H, d, J=
4.8 Hz), 7.14–7.32 (9H, m), 7.86 (1H, br.s), 9.18 (1H, br.s);
13C NMR (100 MHz, DMSO-d6): d=17.6, 47.4, 126.3, 126.5,
126.7, 127.3, 127.9, 128.1, 130.5, 134.8, 137.0, 139.3, 181.5;
MS: m/z (relative intensity %)=256 (M+, 55), 91 (100);
HR-MS: m/z=256.1026, calcd. for C15H16N2S: 256.1034.
N-Phenyl-N’-(1-phenylethyl)thiourea (4h): obtained as
colorless prisms; yield: 42%; mp 104–1058C (lit.[39] mp
102.3–103.88C); IR (film): n=3377, 3240, 1596, 1531, 1244,
AHCTUNGTRENNUNG
ane:AcOEt, lit.[44] mp 164–1678C); IR (film): n=3086, 2899,
1
1618, 1454, 1269, 745 cmÀ1; H NMR (400 MHz, CDCl3): d=
4.61 (2H, s), 6.80 (1H, br.s), 7.05 (1H, t, J=7.6 Hz), 7.22–
7.39 (7H, m), 7.55 (1H, d, J=7.6 Hz); 13C NMR (100 MHz,
CDCl3): d=49.4, 118.7, 120.7, 121.4, 125.9, 127.5, 127.7,
128.7, 130.2, 137.4, 152.1, 167.7; MS: m/z (relative intensity
%)=240 (M+, 100); HR-MS: m/z=240.0721, calcd. for
C14H12N2S: 240.0721; anal. calcd. for C14H12N2S: C 69.97, H
5.03, N 11.66; found: C 70.03, H 5.22, N 11.60.
1
1134 cmÀ1; H NMR (400 MHz, CDCl3): d=1.54 (3H, d, J=
6.8 Hz), 5.66 (1H, br.s), 6.26 (1H, br.s), 7.17 (2H, d, J=
7.6 Hz), 7.24–7.41 (8H, m), 7.97 (1H, br.s); 13C NMR
(100 MHz, CDCl3): d=21.5, 54.4, 125.0, 126.0, 127.1, 127.5,
128.7, 130.0, 136.1, 142.1, 179.6; MS: m/z (relative intensity
%)=256 (M+, 63), 105 (100); HR-MS: m/z=256.1023,
calcd. for C15H16N2S: 256.1034.
2-[(4-Methoxybenzyl)amino]benzothiazole (5b): mp 176–
1788C (colorless needles from hexane:AcOEt, lit.[45] mp
170–1718C); IR (film): n=3204, 1554, 1251, 1032 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=3.79 (3H, s), 4.55 (2H, s),
6.08 (1H, br.s), 6.87 (2H, d, J=8.4 Hz), 7.07 (1H, t, J=
7.7 Hz), 7.25–7.32 (3H, m), 7.46 (1H, d, J=7.7 Hz), 7.56
(1H, d, J=7.7 Hz); 13C NMR (100 MHz, CDCl3): d=48.9,
55.3, 114.2, 118.9, 120.8, 121.6, 125.9, 129.1, 129.4, 130.4,
152.3, 159.3, 167.3; MS: m/z (relative intensity %)=270
(M+, 66), 121 (100); HR-MS: m/z=270.0816, calcd. for
C15H14N2OS: 270.0827.
N-Phenylmorpholine-4-carbothioamide (4i): obtained as
colorless prisms; yield: 93%; mp 136–1378C (lit.[43] mp
130.58C); IR (film): n=3196, 3176, 1535, 1337, 1223,
1
1112 cmÀ1; H NMR (400 MHz, CDCl3): d=3.70 (4H, t, J=
5.2 Hz), 3.77 (4H, t, J=5.2 Hz), 7.12 (2H, d, J=7.7 Hz),
7.15 (1H, t, J=7.7 Hz), 7.32 (2H, t, J=7.7 Hz), 7.52 (1H,
br.s); 13C NMR (100 MHz, CDCl3): d=49.5, 66.0, 123.2,
125.3, 129.0, 139.8, 183.4; MS m/z (relative intensity %)=
222 (M+, 72), 135 (100); HR-MS: m/z=222.0826, calcd. for
C11H14N2OS: 222.0827.
2-[(4-Nitrobenzyl)amino]benzothiazole (5c): mp 177–
1788C (yellow prisms from hexane:AcOEt, lit.[46] mp 177–
1788C); IR (film): n=3388, 1515, 1344 cmÀ1
;
1H NMR
(400 MHz, CDCl3): d=4.79 (2H, s), 6.15 (1H, br.s) 7.11
(1H, td, J=7.9, 1.1 Hz), 7.29 (1H, td, J=7.9, 1.1 Hz), 7.49
(1H, d, J=7.9 Hz), 7.56–7.59 (3H, m), 8.20 (2H, d, J=
8.8 Hz); 13C NMR (100 MHz, CDCl3): d=48.3, 119.2, 120.9,
122.1, 123.9, 126.1, 128.0, 130.4, 145.2, 147.4, 151.9, 166.7;
MS: m/z (relative intensity %)=285 (M+, 100); HR-MS:
m/z=285.0572, calcd. for C14H11N3O2S: 285.0572; anal.
calcd. for C14H11N3O2S: C 58.93, H 3.89, N 14.73; found: C
58.91, H 3.95, N 14.59.
Representative Procedure for Pd-Catalyzed Synthesis
of 2-Aminobenzothiazoles (5a–j) (Scheme 2 and
Table 3): Cyclization of N-Benzyl-N’-phenylthiourea
(4a) (Scheme 2)
A mixture of 4a (34.7 mg, 0.14 mmol) and PdCl2 (5.1 mg,
0.029 mmol) in NMP (2.9 mL, 0.05M) was stirred at 1208C
for 12 h under an O2 atmosphere (balloon). The reaction
mixture was extracted with ethyl acetate (5 mLꢁ3) and the
combined organic layer was washed with brine (10 mL), and
dried over MgSO4. The solvent was evaporated and the resi-
due was purified by silica gel column chromatography
[hexane-ethyl acetate (4:1)] to give 5a as a colorless solid;
yield: 19.4 mg (57%).
2-[(2-Methylbenzyl)amino]benzothiazole (5d): mp 157–
1588C (colorless prisms from hexane:AcOEt); IR (film): n=
1
3406, 1611, 1454 cmÀ1; H NMR (400 MHz, CDCl3): d=2.38
(3H, s), 4.60 (2H, s), 6.08 (1H, br.s), 7.07 (1H, td, J=7.7,
0.7 Hz), 7.15–7.28 (4H, m), 7.35 (1H, d, J=7.7 Hz), 7.42
(1H, dd, J=7.7, 0.7 Hz), 7.56 (1H, d, J=7.7 Hz); 13C NMR
(100 MHz, CDCl3): d=19.0, 47.5, 118.9, 120.8, 121.6, 125.9,
126.3, 128.1, 128.4, 130.4, 130.6, 135.1, 136.6, 152.3, 167.2;
MS: m/z (relative intensity %)=254 (M+, 100); HR-MS:
m/z=254.0873, calcd. for C15H14N2S: 254.0878; anal. calcd.
for C15H14N2S: C 70.83, H 5.55, N 11.01; found: C 70.70, H
5.60, N 10.96.
2-Benzylamino-6-methoxybenzothiazole (5e): mp 140–
1418C (colorless prisms from hexane:AcOEt, lit.[42] mp 136–
2652
asc.wiley-vch.de
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2643 – 2655

Use of Molecular Oxygen as a Reoxidant in the Synthesis of 2-Substituted Benzothiazoles
136.58C); IR (film): n=3091, 1619, 1220, 1027 cmÀ1
;
Acknowledgements
1H NMR (400 MHz, CDCl3): d=3.80 (3H, s), 4.61 (2H, s),
5.74 (1H, br.s), 6.88 (1H, dd, J=8.8, 2.4 Hz), 7.11 (1H, d,
J=2.4 Hz), 7.28–7.41 (6H, m); 13C NMR (100 MHz, CDCl3):
d=49.4, 55.9, 105.4, 113.5, 119.3, 127.6, 127.8, 128.7, 131.4,
137.5, 146.4, 155.1, 165.5; MS: m/z (relative intensity %)=
270 (M+, 100); HR-MS: m/z=270.0841, calcd. for
C15H14N2OS: 270.0827.
This work was supported in part by a Grant-in-Aid forYoung
Scientists (B) from the Japan Society for the Promotion of
Science (JSPS).
References
2-Benzylamino-6-cyanobenzothiazole (5f): mp 222–2238C
(colorless prisms from MeOH); IR (film): n=3416, 2215,
À
[1] For recent reviews on transition metal-catalyzed C H
1
1575 cmÀ1; H NMR (400 MHz, DMSO-d6): d=4.63 (2H, d,
functionalization, see: a) L. Ackermann, Chem.
Commun. 2010, 46, 4866–4877; b) T. W. Lyons, M. S.
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J=5.2 Hz), 7.26 (1H, t, J=6.4 Hz), 7.32–7.37 (4H, m), 7.46
(1H, d, J=8.4 Hz), 7.60 (1H, dt, J=8.4, 1.6 Hz), 8.19 (1H,
d, J=1.6 Hz), 9.02 (1H, s); 13C NMR (100 MHz, DMSO-d6):
d=47.4, 102.2, 118.1, 119.5, 125.3, 127.1, 127.3, 128.3, 129.6,
131.2, 138.1, 155.9, 169.2; MS: m/z (relative intensity %)=
265 (M+, 100); HR-MS: m/z=265.0657, calcd. for
C15H11N3S: 265.0674; anal. calcd. for C15H11N3S: C 67.90, H
4.18, N 15.84; found: C 67.67, H 4.36, N 15.70.
2-Benzylamino-4-methylbenzothiazole (5g): mp 112–
1138C (colorless prisms from hexane:AcOEt); IR (film): n=
3395, 3214, 1543, 1452, 1212 cmÀ1
;
1H NMR (400 MHz,
CDCl3): d=2.56 (3H, s), 4.60 (2H, s), 5.80 (1H, br.s), 6.99
(1H, t, J=7.6 Hz), 7.10 (1H, d, J=7.2 Hz), 7.27–7.43 (6H,
m); 13C NMR (100 MHz, CDCl3): d=18.5, 49.5, 118.2, 121.4,
126.7, 127.6, 127.7, 128.7, 128.8, 130.2, 137.5, 151.2, 166.4;
MS: m/z (relative intensity %)=254 (M+, 100); HR-MS:
m/z=254.0862, calcd. for C15H14N2S: 254.0878; anal. calcd.
for C15H14N2S: C 70.83, H 5.55, N 11.01; found: C 70.61, H
5.58, N 10.84.
2-[(a-Methylbenzyl)amino]benzothiazole (5h): mp 132–
1348C (yellow prisms from hexane:acetone); IR (film): n=
3189, 2972, 1606, 1569, 1445 cmÀ1
;
1H NMR (400 MHz,
CDCl3): d=1.63 (3H, d, J=6.8 Hz), 4.81 (1H, q, J=6.8 Hz),
6.23 (1H, br.s), 7.04 (1H, td, J=7.6, 1.2 Hz), 7.23–7.29 (2H,
m), 7.32–7.41 (4H, m), 7.49–7.53 (2H, m); 13C NMR
(100 MHz, CDCl3): d=23.7, 55.4, 118.8, 120.7, 121.3, 125.8,
126.0, 127.5, 128.7, 130.5, 142.8, 151.9, 167.0; MS: m/z (rela-
tive intensity %)=254 (M+, 69), 150 (100), 105 (90); HR-
MS: m/z=254.0876, calcd. for C15H14N2S: 254.0878; anal.
calcd. for C15H14N2S: C 70.83, H 5.55, N 11.01; found: C
70.85, H 5.77, N 11.00.
À
À
À
[2] Compared to C C, C O, and C X bond formation,
À
only a few reports exist about C N bond formation via
À
palladium-catalyzed C H functionalization, see: a) K.
Inamoto, T. Saito, K. Hiroya, T. Doi, J. Org. Chem.
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2-(Morpholin-4-yl)benzothiazole (5i): mp 119–1208C (col-
orless prisms from hexane:AcOEt, lit.[47] mp 128.5–
130.3.8C); IR (film): n=2855, 1540, 1290, 1113 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=3.63 (4H, t, J=4.8 Hz),
3.84 (4H, t, J=4.8 Hz), 7.10 (1H, td, J=8.0 Hz, 0.8 Hz),
7.31 (1H, td, J=8.0 Hz, 0.8 Hz), 7.57 (1H, dt, J=8.0 Hz,
0.8 Hz) 7.61 (1H, dt, J=8.0, 0.8 Hz); 13C NMR (100 MHz,
CDCl3): d=48.5, 66.3, 119.3, 120.7, 121.6, 126.0, 130.5, 152.4,
168.9; MS: m/z (relative intensity %)=222 (M+, 100); HR-
MS: m/z=222.0664, calcd. for C11H12N2OS: 220.0670.
2-Phenylaminobenzothiazole (5j): mp 163–1648C (color-
less prisms from hexane:acetone, lit.[44] mp 159–1608C); IR
1
(film): n=3189, 2934, 1456, 1250 cmÀ1; H NMR (400 MHz,
CDCl3): d=7.13–7.19 (2H, m), 7.32 (1H, t, J=8.1 Hz), 7.40
(2H, t, J=8.1 Hz), 7.50 (2H, d, J=8.1 Hz), 7.56 (1H, d, J=
7.8 Hz), 7.62 (1H, d, J=7.8 Hz), 8.97 (1H, br.s); 13C NMR
(100 MHz, CDCl3): d=119.3, 120.4, 120.8, 122.4, 124.4,
126.1, 129.6, 129.8, 139.9, 151.4, 164.8; MS: m/z (relative in-
tensity %)=226 (M+, 100); HR-MS: m/z=226.0551, calcd.
for C13H10N2S: 226.0565.
À
À
[3] Examples of C S bond formation via catalytic C H
functionalization in the presence of transition metals
Adv. Synth. Catal. 2010, 352, 2643 – 2655
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2653

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Pd(OAc)2, Pd(acac)2, and Pd
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2A
ACHTUNGTRENNUNG
A
U
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À
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For experimental details, see Supporting Information.
[23] A study of kinetic isotope effects for 2-aminobenzo-
thiazole synthesis was also performed, which resulted
in the observation of low KIE value (intramolecular:
1.2). Further investigation is necessary to reveal the
precise reaction mechanism for this process. For experi-
mental details, see Supporting Information.
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stead of 50 mol%, gave relatively lower yields. For de-
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Adv. Synth. Catal. 2010, 352, 2643 – 2655
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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