KI-catalyzed arylation of benzothiazoles from the coupling of aryl aldehydes with benzothiazoles in neat water

Article abstract of DOI:10.1039/c3ob42318b

A KI-catalyzed oxidative coupling of benzothiazoles with aryl aldehydes has been developed using TBHP as an oxidant in neat water under metal free conditions. Various 2-aryl benzothiazoles were prepared in 36-79% yields for 28 examples. The mechanistic studies suggested that this transformation proceeded via a radical process. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ob42318b

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KI-catalyzed arylation of benzothiazoles from the
coupling of aryl aldehydes with benzothiazoles in
neat water†
Cite this: Org. Biomol. Chem., 2014,
12, 1044
Received 20th November 2013,
Accepted 2nd January 2014
Yuyu Gao, Qiuling Song, Guolin Cheng and Xiuling Cui*
DOI: 10.1039/c3ob42318b
www.rsc.org/obc
A KI-catalyzed oxidative coupling of benzothiazoles with aryl alde- boronic acids,7 sodium sulfinates,8 and aryl triflates9
hydes has been developed using TBHP as an oxidant in neat water (Scheme 1). Recently, Liu and co-workers reported an iron-cata-
under metal free conditions. Various 2-aryl benzothiazoles were lyzed arylation of benzothiazoles with aryl aldehydes
prepared in 36–79% yields for 28 examples. The mechanistic (Scheme 2, eqn (1)).10 The metal catalyst or organometallic
studies suggested that this transformation proceeded via a radical reagent would lead to potential metal contamination of the
process.
products that is particularly significant in the pharmaceutical
industry. Yang and co-workers described their elegant work on
the construction of 2-aryl benzothiazoles mediated by K2S2O8
oxidative condensation of benzothiazoles with aryl aldehydes
(Scheme 2, eqn (2)).11 However, this transformation proceeded
in organic solvents, and is not applicable to electron-deficient
aryl aldehydes. The development of a mild and environmen-
tally friendly approach for the direct synthesis of 2-aryl benzo-
thiazoles especially using cheap and commercially available
aryl aldehydes as an aryl source has attracted much interest.
Herein, we report an arylation of benzothiazoles with aryl alde-
hydes catalyzed by KI in neat water under metal free con-
ditions (Scheme 3).
2-Aryl benzothiazoles are highly important scaffolds in organic
and medicinal chemistry due to their diverse biological and
pharmacological properties, including antitumor, anti-convul-
sant, and anti-viral, which are exemplified in Fig. 1.1
Conventional synthetic methods, including the metal-cata-
lyzed intramolecular cyclization of thioformanilides2 and the
condensation of 2-aminothiophenol with carboxylic acids or
aldehydes,3 suffer from difficulties in preparation of the start-
ing materials due to their being easily oxidized. Alternatively,
2-aryl benzothiazoles have been successfully synthesized by
transition metal-catalyzed cross-coupling of benzothiazoles
with aryl halides,4 arylsilanes,5 aromatic carboxylic acids,6 aryl
The condensation of benzothiazole (1a) with benzaldehyde
(2a) was initially chosen as a model reaction to screen the
various reaction parameters. The arylation product was
Scheme 1 Metal catalyzed cross-coupling of benzothiazoles with pre-
functionalized arene.
Fig. 1 Examples of 2-aryl benzothiazole with bioactivities.
Engineering Research Center of Molecular Medicine, Ministry of Education,
Key Laboratory of Xiamen Marine and Gene Drugs, Institutes of Molecular Medicine
and School of Biomedical Sciences, Huaqiao University, Xiamen, 361021, China.
E-mail: cuixl@hqu.edu.cn
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ob42318b
Scheme 2 Recent development of arylation of benzothiazoles with
benzaldehydes.
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DMSO, respectively (Table 1, entries 15 and 16). Moreover, the
yields were reduced by decreasing the reaction temperature
(Table 1, entries 17 and 18). When the reaction was carried out
under the air and oxygen atmospheres, the yield decreased to
50% and 41%, respectively, perhaps due to the oxidation of
the aldehydes to the corresponding acids (Table 1, entries 19
and 20).
Under the optimal reaction conditions, the scope of sub-
strates was investigated. The results are listed in Table 2. The
reaction worked well for a wide variety of substituted benzal-
dehydes, affording the corresponding 2-aryl substituted ben-
zothiazoles in 36–79% yields for 28 examples. There were no
significant steric effects for benzaldehydes. o-, m-, and
p-Methyl benzaldehydes gave similar yields (3ab–3ad). Bulky
Scheme 3 Arylation of benzothiazoles with aryl aldehydes in water.
obtained in only 10% yield using TBHP (70% aq.) as an
oxidant at 100 °C (Table 1, entry 1). Other peroxides, such as
TBPB (tert-butyl peroxybenzoate), DTBP (di-tert-butyl peroxide),
mCPBA (3-chloroperbenzoic acid), benzoyl peroxide (50% aq.)
and TBHP in decane or in toluene, disfavoured this reaction
(Table 1, entries 2–7). The yield could reach 49% in the pres-
ence of 10 mol% KI (Table 1, entry 8) and was improved to
66% when 1 mL of water was added (Table 1, entry 9). 72%
yield could be obtained by increasing the amount of KI to
20 mol% (Table 1, entry 10). Bu4NI could also give a similar
yield (Table 1, entry 11). Transition metal salts, such as
FeCl2·4H2O and CuCl2·2H2O, only gave the desired product in
40% and 30% yields respectively (Table 1, entries 12 and 13).
I2 was also screened as a terminal oxidant. Only 43% isolated
yield was obtained with the stoichiometric amount of I2
(Table 1, entry 14). When the organic solvent was added,
which made the reaction proceed in the homogeneous solu-
tion, the yields decreased to 7% and 34% yields for MeCN and
Table 2 Arylation of benzothiazoles with various aldehydesa
Table 1 Optimization of the reaction conditions for the condensation
of benzothiazole (1a) with benzaldehyde (2a)a
Catalyst
(mol%)
T
Yieldb
Entry Oxidant
Solvent
(°C) (%)
1
2
3
4
5
TBHP (70% aq.)
TBPB
DTBP
mCPBA
Benzoyl peroxide
(50% aq.)
—
—
—
—
—
—
—
—
H2O
—
100 10
100 nr
100 nr
100
100
8
9
6
7
8
9
10
11
12
TBHP (5.5 N in decane)
TBHP (5 N in toluene)
TBHP (70% aq.)
TBHP (70% aq.)
TBHP (70% aq.)
TBHP (70% aq.)
TBHP (70% aq.)
—
—
—
—
—
H2O
H2O
100 nr
100 nr
100 49c
100 66c
100 72c
100 72c
100 40c
KI (10)
KI (10)
KI (20)
Bu4NI (20) H2O
FeCl2·4H2O H2O
(20)
CuCl2·2H2O H2O
(20)
—
13
TBHP (70% aq.)
100 30c
14
15
I2 (1.2 eq.)
TBHP (70% aq.)
H2O
100 43c
KI (20)
MeCN–H2O 100 7
(1 : 1)
16
TBHP (70% aq.)
KI (20)
DMSO–H2O 100 34
(1 : 1)
17
18
19
20
TBHP (70% aq.)
TBHP (70% aq.)
TBHP (70% aq.)
TBHP (70% aq.)
KI (20)
KI (20)
KI (20)
KI (20)
H2O
H2O
H2O
H2O
60 20c
80 59c
100 50c,d
100 41c,e
a Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), TBHP (70%
aqueous solution) (1.5 mmol), KI (0.1 mmol), H2O (1 mL), 100 °C, 8 h
under N2, isolated yield. b Reaction conditions: after 4 h, the second
part of 2 (0.75 mmol), TBHP (70% aqueous solution) (1.5 mmol) and
KI (0.1 mmol) were added.
a Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), oxidant
(1.5 mmol), solvent (1 mL), N2, 8 h. b GC yield based on 1a. c Isolated
yield based on 1a. d Air. e With oxygen balloon.
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groups, such as tert-butyl (3ag), 1-naphenyl (3ah), 2-naphenyl
(3ai), and di-methoxy (3al, 3am), could give moderate yields.
Electron-withdrawing groups such as trifluoromethyl (3at) and
cyano (3au, 3av) also afforded the corresponding 2-substituted
benzothiazoles in moderate yields. The aliphatic aldehydes
produced the desired products, but in low yields. However, the
yields could be improved by doubling the quantities of alde-
hydes and TBHP (3aw, 3ax). Benzothiazoles substituted by
withdrawing and donating groups worked well under the opti-
mized conditions (3ba–3fa, 3bp). The halogen group in either
aldehyde or benzothiazole could survive well under the stan-
dard reaction conditions and no cleavage of the C–halogen
bond was observed (3an–3as, 3ba, 3bp). While benzimidazole
and benzoxazole were decomposed under the standard con-
ditions, no product was detected.
To clarify the reaction mechanism, some controlled experi-
ments were carried out under the optimized conditions as
follows: (1) 13C-labeled benzaldehyde was used as a substrate
instead of benzaldehyde. A 13C-labeled 2-phenyl benzothiazole
was detected as a major product (>90%) by NMR (Scheme 4,
eqn (1)), which indicated that this transformation did not take
a decarbonylative or decarboxylate pathway, but might go
through a ring-opening mechanism.12 (2) Under the standard
reaction conditions, benzothiazole would remain unchanged
in the absence of aldehyde (Scheme 4, eqn (2)). Therefore,
aldehydes were proposed to promote the ring-opening process.
(3) Furthermore, CO2 was generated and caused the clear lime-
water to become cloudy (Scheme 4, eqn (3)). (4) The conden-
sation of 2-methylbenzothiazole with benzaldehyde (2b) could
not give the desired product even prolonging the reaction time
to 20 h (Scheme 4, eqn (4)). It was likely that the C2 of benzo-
thiazole was oxidated into CO2 and the 2-methyl group hin-
dered such an oxidation. (5) When 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) was added to this reaction system, the
reaction was hampered (Scheme 4, eqn (5)). This result
suggested that this transformation might go through a radical
process.
Scheme 5 Proposed reaction mechanism.
base 4. At the same time, tert-butoxyl and tert-butylperoxyl
radical were formed through the reaction of TBHP with I− or
I2.13,14 Subsequently, these radicals promoted 4 to convert into
intermediate 5 via a thio–ene radical process.3e,15 Intermediate
5 was highly reactive and would fast undergo an annulation
process to afford 6. Thereafter, 6 was oxidated by TBHP or I2
and gave the desired product 7.
Conclusion
Based on the results obtained, an aldehyde assisted ring-
opening mechanism was proposed as shown in Scheme 5.
Firstly, benzothiazole 1 reacted with water to give 2-hydroxy-
1,3-dihydrobenzothiazole 2. The NH then reacted with benz-
aldehyde to give an aminal 3. Loss of water then gave a Schiff’s
A general and efficient procedure for the direct arylation of
benzothiazoles with aryl aldehydes in neat water has been
developed, affording the arylated products in 36%–79% yields
for 28 examples. This transformation was proposed to go
through a radical mechanism by using TBHP as a stoichio-
metric oxidant and KI as a catalyst.
Acknowledgements
This work was supported by Program for Minjiang Scholar
(10BS216) and Science Research Item of Science and Techno-
logy of Xiamen City (3502z201014).
Notes and references
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