I2/TBHP-Mediated tandem cyclization and oxidation reaction: Facile access to 2-substituted thiazoles and benzothiazoles

Article abstract of DOI:10.1039/c8ob02826e

The efficient synthesis of 2-substituted thiazoles and benzothiazoles has been accomplished employing readily available cysteine esters and 2-aminobenzenethiols as N and S sources. The reaction proceeds under an I₂/TBHP system and involves a on

Full text of DOI:10.1039/c8ob02826e

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I2/TBHP-Mediated tandem cyclization and
oxidation reaction: Facile access to 2-substituted
Cite this: DOI: 10.1039/c8ob02826e
thiazoles and benzothiazoles†
Received 13th November 2018,
Accepted 9th December 2018
a
a
a
a
a
b
Li Liu, Chen Tan, Rong Fan, Zihan Wang, Hongguang Du, * Kun Xu * and
a
DOI: 10.1039/c8ob02826e
Jiajing Tan
*
rsc.li/obc
5
2
The efficient synthesis of 2-substituted thiazoles and benzothia- with various oxidants including MnO , DDQ, etc. In spite of
zoles has been accomplished employing readily available cysteine some advantages, the methods described above often encoun-
esters and 2-aminobenzenethiols as N and S sources. The reaction ter certain limitations including harsh reaction conditions,
proceeds under an I /TBHP system and involves a one-pot tandem expensive toxic metals/oxidants, tedious synthetic procedures
2
cyclization and oxidation sequence. A diverse range of aldehydes is toward starting materials, and release of toxic by-products.
amenable for this transition-metal-free protocol, which provides Therefore, the pursuit of alternative efficient protocols to
an alternative method to rapidly access thiazole-containing obtain thiazoles has never ceased.
molecules.
Given our group’s long-term interest in heterocyclic chem-
istry and green chemistry, we questioned whether simple
6
Thiazole and its derivatives are ubiquitous components of bio-
logical natural products. Based on extensive research by med-
icinal chemists, many thiazole-containing molecules have dis-
played promising pharmacological activities. These valuable
natural amino acids could be employed as the nitrogen and
sulfur sources for thiazole synthesis. More specifically, we
planned to realize the synthesis by developing a tandem imine
1
2
7
formation, intermolecular cyclization and oxidation protocol.
structural subunits are also broadly employed in the develop-
ment of novel active pharmaceutical ingredients due to their
unique ability to impact therapeutic potency, drug lipophili-
Furthermore, the ester group could serve as a useful synthetic
handle to accomplish the facile synthesis of other useful thia-
zole-based derivatives. Nevertheless, a critical task for develop-
ing this protocol would be the identification of compatible
2
city, etc. For instance, febuxostat, a drug used in the treatment
of chronic gout and hyperuricemia, functions as a selective
inhibitor of xanthine oxidase, whereas thiomuracin GZ, a
member of the thiopeptide antibiotic family with potent
activity toward Gram-positive drug-resistant bacteria, possesses
8
cyclization and oxidation conditions for this transformation.
Also, the employment of transition metals and toxic oxidants
should also be avoided. Despite these challenges, we herein
would like to report our recent efforts in developing an
3
several distinct thiazole scaffolds (Scheme 1). Moreover, they
also play an increasingly important role in materials chemistry
as the core components of materials with optical or electronic
4
properties.
The strong demand for this heterocyclic scaffold has stimu-
lated much effort. Classical methods to assemble such motifs
rely on the cyclization strategy, and are exemplified by
Hantzsch’s synthesis, the Gabriel synthesis, and the Cook–
1
Heilbron synthesis. Besides, the direct oxidation of pre-syn-
thesized thiazolines to substituted thiazoles was also reported
a
Department of Organic Chemistry, College of Science, Beijing University of Chemical
Technology, Beijing 100029, P. R. China. E-mail: dhg@mail.buct.edu.cn,
tanjj@mail.buct.edu.cn
b
College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University,
Nanyang, Henan 473061, P. R. China. E-mail: xukun@nynu.edu.cn
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02826e
Scheme 1 Thiazole-based bioactive molecules.
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efficient tandem cyclization/oxidation protocol employing I
2
Given these results, we next explored the substrate scope of
and tert-butyl hydroperoxide (TBHP) to synthesize thiazole aldehyde components using the optimized reaction conditions
derivatives. This methodology was amenable for a large range (Table 2). A wide range of aromatic aldehydes were found to
9
of readily available aldehydes. Due to the immense usefulness display comparable reactivities to benzaldehydes, giving the
of 2-substituted thiazole motifs, this protocol in principle desired substituted thiazoles in good yields (3b–3p). In
1
0
should be of great interest to the community.
general, the electron-donating groups are well tolerated provid-
To investigate our proposed reaction, initial studies focused ing the structurally diverse thiazoles in good yields, whereas
on the reaction between L-cysteine ethyl ester hydrochloride the electron-withdrawing substitution groups gave slightly
(
1a) and benzaldehyde (2a), as shown in Table 1. We were lower yields. Notably, the sulfide functionality was well toler-
delighted to discover that the ethyl 2-phenylthiazole-4-carboxy- ated due to which 3q was produced with a yield of 78%, even
late (3a) is formed in the presence of potassium iodide and though sulfides are known to be easily converted into sulfox-
1
1
tert-butyl hydroperoxide (TBHP) in 41% yield (entry 1). Other ides under oxidative conditions. Furthermore, aldehydes
iodine-based catalysts were also evaluated, and the yields bearing poly-aromatic rings and conjugated systems were also
could be improved to 58% when employing iodine as the cata- compatible with this transformation, giving the thiazole pro-
lyst (entries 2–5). Oxidants including benzoyl peroxide, di-tert- ducts (3r–3v) in good yields. Given the importance of hetero-
butyl peroxide and hydrogen peroxide were evaluated sub- cycles in the production of functional molecules, we were
sequently, but none of them afforded more satisfactory results delighted to find that 2-thienylaldehyde and 2-pyridinecarbox-
(entries 6–8). Additional assessment of the base effect indi-
cated that potassium carbonate was the best condition for this
transformation, providing a higher chemical yield (entry 2 vs. Table 2 Substrate scope
entries 9 and 10). A significant increase in the reaction
outcome was observed upon switching the solvent to 1,4-
dioxane. Other commonly used solvents (entries 12 and 13)
showed no improvements. Next, the essential roles of the cata-
lyst and oxidant were demonstrated by control experiments,
wherein minimal amounts of 3a were detected (entries 14 and
a,b
1
5). Finally, the investigation revealed that the chemical yield
of 3a could be improved to 90% under a nitrogen atmosphere
entry 16).
(
a
Table 1 Reaction condition optimization
b
Entry
Catalyst
KI
Oxidant
Solvent
Yield
1
2
3
4
5
6
7
8
TBHP
TBHP
TBHP
TBHP
TBHP
BPO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
1,4-Dioxane
DMSO
CH CN
3
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
41%
58%
44%
39%
46%
44%
52%
53%
27%
37%
85%
22%
43%
7%
I
2
NH
4
I
NaI
NIS
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
DTBP
H O
2 2
c
9
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
—
d
10
11
12
13
14
15
16
—
I
I
2
Trace
90 (88%)
e
f
2
TBHP
a
1
a (0.4 mmol), 2a (0.1 mmol), I
2
(0.03 mmol), TBHP (0.4 mmol),
b
K
2
CO
3
(0.3 mmol), 4 Å MS (0.2 g) and solvent (0.5 mL) for 12 h. Yield
1
determined by H NMR with 1,3,5-trimethoxybenzene as an internal
standard. NaHCO
atmosphere. Isolated yield (NIS: N-iodosuccinimide; BPO: benzoyl
peroxide; DTBP: di-tert-butyl peroxide).
c
d
e
a
3
was used instead. Cs
2
CO
3
was used instead.
N
2
2
1a (0.8 mmol), 2 (0.2 mmol), I (0.06 mmol), TBHP (0.8 mmol),
f
K
2
CO
3
(0.6 mmol), 4 Å MS (0.4 g) and 1,4-dioxane (1 mL) under a N
2
b
atmosphere, 70 °C, 12 h. Isolated yield.
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aldehyde readily participate in this reaction to give the desired
products in 66% and 30% yield, respectively. When the ali-
phatic aldehyde such as isobutyraldehyde was employed, no
desired product was observed, which demonstrated a limit-
ation of our protocol.
Although initial studies focused on using cysteine as the N
and S sources for thiazole synthesis, we next wondered
whether 2-aminobenzenethiol would be a suitable reaction
component (Table 3). Indeed, this domino process could also
furnish the benzothiazoles (5a–5p) in good yields under
similar reaction conditions. Noteworthily, a similar trend of
electronic effects was observed in which aldehydes with elec-
tron-withdrawing substitution groups gave slightly lower yields
than those with electron-donating groups. Aliphatic aldehydes,
on the other hand, proved to be tolerated for benzothiazole
synthesis due to which products 5n–5p were obtained in good
yields. Given the fact that thiazoles and benzothiazoles are
commonly found in pharmaceutically relevant compounds,
1
0,12
our protocol should be attractive to the community.
This thiazole synthesis protocol is amenable for scale-up
preparation (Scheme 2). We reacted 1.0 mmol of 2a with excess
1
3
a or 4a under the standard reaction conditions, and products Scheme 2 Synthetic applications.
a and 5a were produced in 85% and 98% yields, respectively.
The functionalization of 4a has also been successfully achieved
to provide the thiazole-containing products 6–9. These deriva-
tizations could further offer pathways to a number of useful
thiazole-containing compounds, further highlighting the syn-
1
thetic advantages of our method.
To gain insights into the reaction mechanism, control
experiments were performed accordingly (Scheme 3). When
a,b
Table 3 Substrate scope
Scheme 3 Mechanistic studies.
excess radical scavenger BHT was added to the model reaction,
the desired thiazole product was obtained with only 8% yield,
indicating that our method might take place through a radical
pathway. Compound C could be obtained under the sole basic
conditions via cyclization. Besides, in the absence of iodine,
3a was not obtained, whereas NIS as the catalyst gave the
desired thiazole product with 46% yield (Table 1, entries 5 and
a
4
2
a (0.8 mmol), 2 (0.2 mmol), I
CO (0.6 mmol), 4 Å MS (0.4 g) and DMF (0.4 mL) at 120 °C for 12 h.
Isolated yield.
2
(0.06 mmol), DTBP (0.8 mmol),
+
14). Therefore, an I
2
–I redox process might be involved in our
K
3
b
13
protocol. Based on these results and literature reports,
a
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plausible mechanistic pathway for our I
2
/TBHP-promoted ring
Allergy Drug Discovery, 2007, 1, 69; (d) K. Okamoto,
B. T. Eger, T. Nishino, S. Kondol and E. F. Pai, J. Biol.
Chem., 2003, 278, 1848; (e) N. Mahanta, Z. G. Zhang,
G. A. Hudson, W. A. van der Donk and D. A. Mitchell,
J. Am. Chem. Soc., 2017, 139, 4310.
cyclization and oxidation reaction cascade is depicted in
Scheme 3. In the presence of potassium carbonate, the
cysteine ester initially underwent tandem imine formation and
cyclization to give intermediate C. Under the I /TBHP catalyst
2
system, compound C is converted to give partially oxidized
intermediate F via a sequence of hydrogen abstraction, single
electron transfer with I and elimination. Next, the I species,
generated by the oxidation of iodine, could react with inter-
mediate F and subsequent elimination of G to give the final
product 3a.
4 (a) A. Srivastava, G. Shukla, D. Yadav and M. S. Singh,
J. Org. Chem., 2017, 82, 10846; (b) T. Miura, Y. Funakoshi,
Y. Fujimoto, J. Nakahashi and M. Murakami, Org. Lett.,
2015, 17, 2454; (c) P. Hrobárik, V. Hrobáriková, V. Semak,
P. Kasak, E. Rakovsky, I. Polyzos, M. Fakis and
P. Persephonis, Org. Lett., 2014, 16,, 6358; (d) T. Tao,
B.-B. Ma, Y.-X. Peng, X.-X. Wang, W. Huang and X.-Z. You,
J. Org. Chem., 2013, 78, 8669; (e) Q. Shi, H. J. Fan, Y. Liu,
J. M. Chen, L. C. Ma, W. P. Hu, Z. G. Shuai, Y. F. Li and
X. W. Zhan, Macromolecules, 2011, 44, 4230; (f) T. Murai,
F. Hori and T. Maruyama, Org. Lett., 2011, 13, 1718;
+
+
Conclusions
In summary, we developed an efficient one-pot cascade cycliza-
tion/oxidation approach to synthesize substituted thiazoles
and benzothiazoles from readily available starting materials.
This catalytic protocol avoids using transition metal oxidants
and shows a broad substrate scope, providing consistently
good yields of thiazole products. Remarkably, the reaction
proved to be not only efficient in scale-up reactions, but
further functionalization was also easily possible, setting the
base for rapidly accessing medicinally relevant thiazole deriva-
tives. In comparison with the classical approaches, we antici-
pate that our method should provide a potential alternative.
(
g) A. Job, A. Wakamiya, G. Kehr, G. Erker and
S. Yamaguchi, Org. Lett., 2010, 12, 5470; (h) S. Caron,
R. W. Dugger, S. G. Ruggeri, J. A. Ragan and D. H. B. Ripin,
Chem. Rev., 2006, 106, 2943; (i) S. Ando, R. Murakami,
J. Nishida, H. Tada, Y. Inoue, S. Tokito and Y. Yamashita,
J. Am. Chem. Soc., 2005, 127, 14996.
5
(a) Y. Y. Wang, Z. Y. Li, Y. Huang, C. H. Tang, X. M. Wu and
J. Y. Xu, Tetrahedron, 2011, 67, 7406; (b) J. Deeley,
A. Bertram and G. Pattenden, Org. Biomol. Chem., 2008, 6,
1994; (c) P. Merino, T. Tejero, F. J. Unzurrunzaga, S. Franco,
U. Chiacchio, M. G. Saita, D. Iannazzo, A. Piperno and
G. Romeo, Tetrahedron: Asymmetry, 2005, 16, 3865;
Conflicts of interest
(
d) G. Serra, G. Mahler and E. Manta, Heterocycles, 1998, 48,
035; (e) T. Aoyama, N. Sonoda, M. Yamauchi, K. Toriyama,
M. Anzai, A. Ando and T. Shioiri, Synlett, 1998, 35;
f) D. R. Williams, P. D. Lowder, Y. G. Gu and D. A. Brooks,
2
There are no conflicts to declare.
(
Tetrahedron Lett., 1997, 38, 331; (g) A. I. Meyers and
F. Tavares, Tetrahedron Lett., 1994, 35, 2481;
Acknowledgements
(
2
2
h) X. Fernandez and E. Duñach, Tetrahedron: Asymmetry,
001, 12, 1279; (i) S. Kumar and R. Aggarwal, ARKIVOC,
018, 3, 354; ( j) A. N. Christ, L. Labzin, G. T. Bourne,
J. J. T. is grateful for the support of the National Natural
Science Foundation of China (21702013), the Beijing Natural
Science Foundation (2184115) and the Fundamental Research
Funds for the Central Universities (XK1802-6, buctrc201721) at
the BUCT. K. X. is grateful to the National Natural Science
Foundation of China (21602119 and U1504208).
H. Fukunishi, J. E. Weber, M. J. Sweet, M. L. Smythe and
J. U. Flanagan, J. Med. Chem., 2010, 53, 5536; (k) A. Okabe,
A. Ito, K. Okumura and C.-G. Shin, Chem. Lett., 2001, 5,
3
2
80; (l) K. Okumura, T. Suzuki and C.-G. Shin, Heterocycles,
000, 53, 765.
6
(a) R. Fan, B. Liu, T. Y. Zheng, K. Xu, C. Tan, T. L. Zeng,
S. S. Su and J. J. Tan, Chem. Commun., 2018, 54, 7081;
(b) T. Y. Zheng, J. J. Tan, R. Fan, S. S. Su, B. Liu, C. Tan and
K. Xu, Chem. Commun., 2018, 54, 1303; (c) H. Q. Wang,
J. Zhang, J. J. Tan, L. L. Xin, Y. P. Li, S. Zhang and K. Xu,
Org. Lett., 2018, 20, 2505; (d) J. J. Tan, T. Y. Zheng, Y. Q. Yu
and K. Xu, RSC Adv., 2017, 7, 15176; (e) J. J. Tan,
T. Y. Zheng, K. Xu and C. Y. Liu, Org. Biomol. Chem., 2017,
15, 4946; (f) J. J. Tan, B. Liu and S. S. Su, Org. Chem. Front.,
2018, 5, 3093.
Notes and references
1
J. A. Joule and K. Mills, Heterocyclic Chemistry, 5th edn,
Blackwell, Oxford, U.K., 2010.
2
(a) J. J. Li and O. Chemie, Heterocyclic chemistry in drug dis-
covery, John Wiley
& Sons, 2013; (b) T. J. Ritchie,
S. J. F. Macdonald, R. J. Young and S. D. Pickett, Drug
Discovery Today, 2011, 16, 164.
3
(a) N. M. Haste, W. Thienphrapa, D. N. Tran, S. Loesgen,
P. Sun, S. J. Nam, P. R. Jensen, W. Fenical, G. Sakoulas,
V. Nizet and M. E. Hensler, J. Antibiot., 2012, 65, 593;
7 (a) A. Behr, A. J. Vorholt, K. A. Ostrowski and
T. Seidensticker, Green Chem., 2014, 16, 982;
(b) H. Pellissier, Chem. Rev., 2013, 113, 442; (c) X. M. Zeng,
Chem. Rev., 2013, 113, 6864.
(
b) Y. Yu, L. Duan, Q. Zhang, R. J. Liao, Y. Ding, H. X. Pan,
E. W. Pienkowski, G. T. Tang, B. Shen and W. Liu, ACS
Chem. Biol., 2009, 4, 855; (c) K.-H. Yu, Recent Pat. Inflamm
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2018

View Article Online
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Communication
8
9
D.-S. Kim, W.-J. Park and C.-H. Jun, Chem. Rev., 2017, 117, 11 (a) L. Wang, H. L. Yue, D. S. Yang, H. Cui, M. H. Zhu,
8
977.
For selected reports on I
Z.-Z. Zhou, Y.-T. He, L.-H. Li, J.-W. Ma, Y.-F. Qiu, P.-X. Zhou,
J. Wang, W. Wei and H. Wang, J. Org. Chem., 2017, 82,
6857; (b) Y. J. Wang, W. Jiang and C. D. Huo, J. Org. Chem.,
2017, 82, 10628.
2
/TBHP chemistry, see: (a) L. Zheng,
X.-Y. Liu, P.-F. Xu and Y.-M. Liang, J. Org. Chem., 2016, 81, 12 (a) T. D. Bradshaw and A. D. Westwell, Curr. Med. Chem.,
6
6; (b) Z. K. Chen, H. L. Li, W. P. Dong, M. Z. Miao and
2014, 11, 1009; (b) Q. Sun, R. Z. Wu, S. T. Cai, Y. Lin,
L. Sellers, K. Sakamoto, B. He and B. R. Peterson, J. Med.
Chem., 2011, 54, 1126.
H. J. Ren, Org. Lett., 2016, 18, 1334; (c) X. R. Zhong, J. Lv
and S. Z. Luo, Org. Lett., 2016, 18, 3150; (d) J. Y. Lai,
L. M. Chang and G. Q. Yuan, Org. Lett., 2016, 18, 3194; 13 (a) J.-C. Xiang, Z.-X. Wang, Y. Cheng, J.-T. Ma, M. Wang,
e) H. Aruri, U. Singh, S. Kumar, M. Kushwaha, A. P. Gupta,
R. A. Vishwakarma and P. P. Singh, Org. Lett., 2016, 18,
(
B.-C. Tang, Y.-D. Wu and A.-X. Wu, J. Org. Chem., 2017, 82,
13671; (b) X. Wu, X. Geng, P. Zhao, J. J. Zhang, Y.-D. Wu
and A.-X. Wu, Chem. Commun., 2017, 53, 3438; (c) L. Y. Liu
and Z. Y. Wang, Green Chem., 2017, 19, 2076; (d) Y. Z. Yan
and Z. Y. Wang, Chem. Commun., 2011, 47, 9513;
(e) J.-C. Xiang, J. C. Xiang, Y. Cheng and A.-X. Wu, Org.
Lett., 2016, 18, 24; (f) Y.-D. Wu, X. Geng, Q. H. Gao,
J. Zhang, X. Wu and A.-X. Wu, Org. Chem. Front., 2016, 3,
1430; (g) Y.-L. Zhu, B. Jiang, W.-J. Hao, A.-F. Wang,
J.-K. Qiu, P. Wei, D.-C. Wang, G. G. Li and S.-J. Tu, Chem.
Commun., 2016, 52, 1907; (h) J. J. Chen, Y. Shao, H. Zheng,
J. Cheng and X. B. Wan, J. Org. Chem., 2015, 80, 10734;
(i) Y. Z. Yan, Y. H. Zhang, Z. G. Zha and Z. Y. Wang, Org.
Lett., 2013, 15, 2274; ( j) J. Zhang, J. W. Jiang, Y. L. Li,
Y. Zhao and X. B. Wan, Org. Lett., 2013, 15, 3222;
(k) Y. Z. Yan, Y. H. Zhang, C. T. Feng, Z. G. Zha and
Z. Y. Wang, Angew. Chem., Int. Ed., 2012, 51, 8077;
(l) W.-J. Xue, Q. Li, Y.-P. Zhu, J.-G. Wang and A.-X. Wu,
Chem. Commun., 2012, 48, 3485; (m) W. Wei, C. Zhang,
Y. Xu and X. B. Wan, Chem. Commun., 2011, 47, 10827;
(n) C. F. Wan, L. F. Gao, Q. Wang, J. T. Zhang and
Z. Y. Wang, Org. Lett., 2010, 12, 3902.
3
8
638; (f) P. S. Volvoikar and S. G. Tilve, Org. Lett., 2016, 18,
92; (g) G. C. Senadi, W.-P. Hu, T.-Y. Lu, A. M. Garkhedkar,
J. K. Vandavasi and J.-J. Wang, Org. Lett., 2015, 17, 1521;
h) D. Beukeaw, K. Udomsasporn and S. Yotphan, J. Org.
(
Chem., 2015, 80, 3447; (i) W.-C. Gao, F. Hu, Y.-M. Huo,
H.-H. Chang, X. Li and W.-L. Wei, Org. Lett., 2015, 17, 3914;
(
j) R. N. Reddi, P. K. Prasad and A. Sudalai, Org. Lett., 2014,
6, 5674; (k) F. H. Xiao, H. Chen, H. Xie, S. Q. Chen, L. Yang
1
and G.-J. Deng, Org. Lett., 2014, 16, 50; (l) Z.-J. Cai, X.-M. Lu,
Y. Zi, C. Yang, L.-J. Shen, J. Li, S.-Y. Wang and S. J. Ji, Org.
Lett., 2014, 16, 5108; (m) Z.-J. Cai, S.-Y. Wang and S.-J. Ji,
Org. Lett., 2013, 15, 5226; (n) Y. Z. Yan and Z. Y. Wang,
Chem. Commun., 2011, 47, 9513; (o) Q. Wang, C. F. Wan,
Y. Gu, J. T. Zhang, L. F. Gao and Z. Y. Wang, Green Chem.,
2
011, 13, 578; (p) H. F. Jiang, H. W. Huang, H. Cao and
C. R. Qi, Org. Lett., 2010, 12, 5561; (q) J. T. Zhang, D. P. Zhu,
C. M. Yu, C. F. Wan and Z. Y. Wang, Org. Lett., 2010, 12,
2
0 P. Arora, R. Narang, S. K. Nayak and S. K. Singh,
Med. Chem. Res., 2016, 25, 1717.
841.
1
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