A convenient synthesis of 2-acyl benzothiazoles/thiazoles from benzothiazole/thiazole and N,N'-carbonyldiimidazole activated carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2019.05.043

A convenient and efficient strategy for the synthesis of 2-acyl benzothiazoles/thiazoles has been developed. The treatment of benzothiazole/thiazole with allylic Grignard reagents readily generates the corresponding 2-Grignard reagents, which is followed by a reaction with N,N'-carbonyldiimidazole activated carboxylic acids to afford various 2-acyl benzothiazoles/thiazoles products. The synthetic method is applicable to a wide array of carboxylic acids and allows easy access to 2-acyl benzothiazoles/thiazoles with considerable yields under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2019.05.043

Accepted Manuscript
A convenient synthesis of 2-acyl benzothiazoles/thiazoles from benzothiazole/
thiazole and N,N'-carbonyldiimidazole activated carboxylic acids
Tonghui Huang, Xin Wu, Yongbo Yu, Lin An, Xiaoxing Yin
PII:
S0040-4039(19)30487-3
https://doi.org/10.1016/j.tetlet.2019.05.043
TETL 50815
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 March 2019
16 May 2019
21 May 2019
Please cite this article as: Huang, T., Wu, X., Yu, Y., An, L., Yin, X., A convenient synthesis of 2-acyl benzothiazoles/
thiazoles from benzothiazole/thiazole and N,N'-carbonyldiimidazole activated carboxylic acids, Tetrahedron
Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.05.043
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Graphical Abstract
A convenient synthesis of 2-acyl benzothiazoles/
thiazoles from benzothiazole/thiazole and
Leave this area blank for abstract info.
N,N'-carbonyldiimidazole activated carboxylic acids
Tonghui Huang a,b, Xin Wu a, Yongbo Yu a, Lin An a, Xiaoxing Yin a,
S
HO
R
20 examples
67-93%
N
O
a
b
O
S
S
c
N
N
R
+
R
MgCl·LiCl
N
N
O
Conditions : (a) i-PrMgCl·LiCl, THF, -10 °C, 30 min. (b) N,N'-carbonyldiimidazole, THF, r.t., 1 h. (c) THF, -10 °C to r.t., 3 h.

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A convenient synthesis of 2-acyl benzothiazoles/thiazoles from benzothiazole/thiazole
and N,N'-carbonyldiimidazole activated carboxylic acids
Tonghui Huang a,b, Xin Wu a, Yongbo Yu a, Lin An a, Xiaoxing Yin a,
a Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221000, PR China
b Xuzhou Medical University Science Park, Xuzhou, Jiangsu 221006, PR China
———
ARTICLE INFO
ABSTRACT
 Corresponding author. e-mail: yinxx@xzhmu.edu.cn (X. Yin).
Article history:
Received
Received in revised form
Accepted
A convenient and efficient strategy for the synthesis of 2-acyl benzothiazoles/thiazoles has been
developed. The treatment of benzothiazole/thiazole with allylic Grignard reagents readily
generates the corresponding 2-Grignard reagents, which is followed by a reaction with N,N'-
carbonyldiimidazole activated carboxylic acids to afford various 2-acyl benzothiazoles/ thiazoles
products. The synthetic method is applicable to a wide array of carboxylic acids and allows easy
access to 2-acyl benzothiazoles/thiazoles with considerable yields under mild reaction
conditions.
Available online
Keywords:
2-acyl thiazoles
2-acyl benzothiazoles
Grignard reagents
Acylation
2009 Elsevier Ltd. All rights reserved.
Introduction
hydroxy-aromatic ketones, and 1-arylethanol; whereas it is worth
noting that only 2-aroyl benzothiazoles were obtained via this
Benzothiazole is a privileged heterocyclic scaffold with its
derivatives frequently found in diverse pharmacological agents,1
natural products,2 as well as synthetic intermediates.3 Studies on
benzothiazoles suggest they have various pharmacological effects,
exhibiting anticancer,4 anti-inflammatory,5 antimicrobial,6 and
antifungal activities.7 In particular, 2-acyl benzothiazoles have
attracted significant attention due to their highly effective
therapeutic activities and favorable pharmaceutical properties.8 In
our previous work, we also designed a series of 2-acyl
benzothiazoles, which could serve as a potential inhibitor toward
the herbicidal target D1 protease (CtpA).9 The extensive
biological activities of 2-acyl benzothiazoles have provided a
strong motive to achieve synthesis of this series of compounds.
method.12a Moreover, harsh reaction conditions like high reaction
temperature, long reaction times and/or tedious workup
procedure
oxidation/heterocyclization
are
indispensable
of
for
the
coupled
with
2-aminothiophenols
substrates such as phenylacetaldehydes,12b α,α-dihaloketones,12c
and aromatic ketones.12d, 12e Thus, it is worthwhile to develop a
concise and practical approach that capable of synthesizing both
alkyl benzothiazoyl ketones and aryl benzothiazoyl ketones.
S
HO
R
O
N
i-PrMgCl·LiCl
CDI
R
O
S
S
N
In the past decades, a number of approaches have been
developed for the preparation of 2-acyl benzothiazoles, mainly
including: (1) nucleophilic addition of metallized benzothiazoles
with electrophiles;10 (2) direct acylation of benzothiazoles with
carbonyl sources;11 (3) coupled oxidation/heterocyclization of 2-
aminothiophenols with diverse substrates.12 However, these
synthetic strategies remain less than ideal with some inevitable
drawbacks. For example, due to the highly reactive of lithium
salts, a very low temperature is imperative for the metallation of
benzothiazoles with n-butyllithium or other lithium reagents, as
well as the following reaction with suitable electrophiles. To the
I2/KOH synergistically promoted direct ring-opening acylation of
benzothiazoles,11a FeCl3·6H2O or copper (I) iodide catalyzed
acylation of benzothiazoles,11b, 11c only aryl ketones can serve as
carbonyl sources, which greatly limited the application of them.
N
+
N
MgCl·LiCl
R
N
O
Scheme 1. The synthetic method for 2-acyl
benzothiazoles/thiazoles.
Herein, we report a convenient and efficient approach for the
synthesis of 2-acyl benzothiazoles/thiazoles via treatment of
benzothiazole/thiazole (1.2 equiv) with i-PrMgCl·LiCl (1.3
equiv), followed by reaction with N,N'-carbonyldiimidazole (CDI,
1 equiv) activated carboxylic acids (Scheme 1). The present
method is applicable to a wide range of substrates and allows
easy access to desired products with considerable yields under
mild reaction conditions.
Results and disscussion
In contrast,
a
multipathway coupled domino strategy
Motivated by the effective preparation of 2-acyl oxazoles
through the reactions of Grignard oxazole reagents with iminium
demonstrated the ability to synthesize 2-acyl benzothiazoles from
multiform substrates including arylethenes, arylacetylenes, 2-

2
benzonitrile, (1H-imidazol-1-yl)(phenyl)methanone, and HATU
activated benzoic acid were investigated (Table 1, entry 2−7).
The optimization results revealed that (1H-imidazol-1-
yl)(phenyl)methanone was the best electrophile to provide 2a in a
yield of 83% (Table 1, entry 6), whereas only a trace amount of
2a were observed in the other five reactions. Based on this
research, an appropriate approach to generate (1H-imidazol-1-
yl)(phenyl)methanone was also designed (Table 1, entry 8). The
CDI activated benzoic acid can directly react with 2-Grignard
reagents or Weinreb amides,13 it was postulated that the 2-
Grignard benzothiazole reagents might react with carboxylic acid
derivatives in a similar fashion to yield 2-acyl benzothiazoles.
Hence,
benzothiazole,
i-PrMgCl,
and
N-Methoxy-N-
methylbenzamide were chosen as model substrates to initiate this
study (Table 1). Fortunately, the treatment of benzothiazole (1.2
equiv) with i-PrMgCl (1.3 equiv) at -10 °C in THF, followed by
reaction with the Weinreb amide of benzoic acid (1 equiv) at
room temperature for 3 h, provided the desired product 2a in
70% yield (Table 1, entry 1). Encouraged by this initial success,
attention was focused on determining an alternative electrophile,
and benzoyl chloride, ethyl benzoate, benzoic acid anhydride,
benzothiazole without purification and provided 2a in
a
comparable yield (80%).
Table 1
Optimization of reaction conditions.a
Electrophile
S
S
N
Grignard reagent
Solvent, Temp. 1
Temp. 2
N
O
2a
1
Entry
1
Electrophile
Solvent
THF
Temp. 1 (C)
-10
Temp. 2 (C)
Grignard reagent
i-PrMgCl
Yield (%)b
70
N-methoxy-N-methylbenzamide
benzoyl chloride
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
60
2
THF
-10
i-PrMgCl
Trace
Trace
Trace
Trace
83
3
ethyl benzoate
THF
-10
i-PrMgCl
4
benzoic acid anhydride
benzonitrile
THF
-10
i-PrMgCl
5
THF
-10
i-PrMgCl
6
(1H-imidazol-1-yl)(phenyl)methanone
benzoic acid + HATU
benzoic acid + CDI
THF
-10
i-PrMgCl
7
THF
-10
i-PrMgCl
Trace
80
8
THF
-10
i-PrMgCl
9
benzoic acid + CDI
diethyl ether
toluene
THF
-10
i-PrMgCl
40
10
11
12
13
14
15
16
17
18
19c
20d
21
22
benzoic acid + CDI
-10
i-PrMgCl
Trace
58
benzoic acid + CDI
0
i-PrMgCl
benzoic acid + CDI
THF
-10
i-PrMgCl
30
benzoic acid + CDI
THF
-20
r.t.
-10
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
i-PrMgCl
78
benzoic acid + CDI
THF
-10
i-PrMgCl
70
benzoic acid + CDI
THF
-10
EtMgCl
43
benzoic acid + CDI
THF
-10
n-BuMgCl
TMPMgCl·LiCl
i-PrMgCl·LiCl
i-PrMgCl·LiCl
i-PrMgCl·LiCl
i-PrMgCl·LiCl
i-PrMgCl·LiCl
64
benzoic acid + CDI
THF
-10
73
benzoic acid + CDI
THF
-10
90
benzoic acid + CDI
THF
-10
63
benzoic acid + CDI
THF
-10
65
methyl benzoyl-L-prolinate
phenyl(pyrrolidin-1-yl)methanone
THF
-10
25
THF
-10
Trace
a Reaction conditions: 1 (1.2 mmol), Grignard reagent (1.3 mmol) in solvent (8 mL) at -10 °C for 30 min, followed by electrophile (1 mmol) at r.t. for 3 h.
b Isolated yield.
c i-PrMgCl·LiCl (2 equiv) was used.
d 8 h.
With this preliminary result, the effects of different solvents
on the reaction, including THF, diethyl ether, and toluene, were
investigated. Among them, THF was the most appropriate due to
its relatively high solubility (Table 1, entry 8−10). Attempts to
increase reaction temperatures accelerated the reaction rate with
increased by-product formation and lower yields (Table 1, entry
11−12), while decreasing reaction temperatures led to a reduction
in the reaction rate (Table 1, entry 13−14). A slight decrease in
yield was observed when utilizing EtMgCl, n-BuMgCl or
TMPMgCl·LiCl to generate 2-Grignard benzothiazole (Table 1,
entry 15−17), whereas a better yield (90%) was obtained with i-
PrMgCl·LiCl (Table 1, entry 18). Furthermore, either increasing

3
the amount of i-PrMgCl·LiCl or prolonging the reaction time led
to the formation of by-products, which are unfavorable to the
yield (Table 1, entry 19−20).
reaction conditions, giving the target products in 70%−83%
yields. In general, the yields of 2-acyl thiazoles were higher than
the corresponding 2-acyl benzothiazoles.
With the optimized reaction conditions in hand (Table 1, entry
18), attention was turned to enlarging the substrate scope. As
shown in Table 2, benzoic acid derivatives (2a−2c) tolerated the
reaction well and afforded the expected 2-acyl benzothiazoles in
good to excellent yields (85−92%). Moreover, a yield of 82%
was achieved when phenoxyacetic acid was utilized (2d),
suggesting this approach is appropriate for various aromatic
carboxylic acids. Subsequently, investigations of amino acids
were conducted, which determined the Boc-protected amino
acids were adept in efficiently furnishing the corresponding
products in moderate yields (2e−2g, 75−78%). To our
satisfaction, the Boc-protected dipeptide, namely Boc-Phe-Phe-
OH, could also provide the desired product 2h, albeit with a
slightly lower yield (67%).
Table 3
Substrate scope of carboxylic acids for synthesis of 2-acyl thiazoles.a
O
S
N
S
N
i-PrMgCl·LiCl
R
R-COOH, CDI
4a-l b
3
O
O
O
O
O
S
S
S
S
N
N
N
4a
4b
4c
, 91%
, 93%
, 87%
O
O
O
O
S
S
S
Table 2
Substrate scope of carboxylic acids for synthesis of 2-acyl benzothiazoles.a
N
N
N
NO2
4f
, 84%
4e
, 80%
4d
, 85%
O
S
S
N
i-PrMgCl·LiCl
O
O
H
N
O
R
O
S
R-COOH, CDI
S
N
N
N
O
2a-h b
N
1
4i
, 80%
O
4g, 80%
O
O
4h
, 75%
O
O
O
S
S
S
O
O
O
O
O
NH
S
N
N
N
O
O
H
NH
S
N
N
O
NH
S
2b
2c
, 85%
, 92%
2a
, 90%
O
N
N
O
S
O O
O
S
N
O
O
S
N
O
4j, 83%
4l
, 70%
4k
O
, 81%
N
NH
NH
a Reaction Conditions: 3 (1.2 mmol), i-PrMgCl·LiCl (1.3 mmol) in THF (8
mL) at -10 °C for 30 min, followed by imidazole carboxamide derivatives
that obtained under the activation of CDI (1 equiv) at r.t. for 3 h.
b Isolated yield.
2d
2e
2f
, 75%
, 82%
, 78%
O
O
O
O
O
O
S
O
NH
S
N
N
NH
A major surprise during the investigation of the substrate
scope was the reaction of CDI activated Boc-Phe-Pro-OH with 2-
Grignard benzothiazole/thiazole generated unexpected principal
products (5a/6a), while the desired products (5b/6b) were not
detected (Scheme 2). A possible explanation is the L-proline
derivatives activated carboxylic acids could also react with
Grignard benzothiazole/thiazole reagents to afford corresponding
2-acyl benzothiazoles/thiazoles. To demonstrate this hypothesis,
phenyl(pyrrolidin-1-yl)methanone and methyl benzoyl-L-
prolinate were used as electrophiles to participate in the synthesis
of 2a, respectively (Table 1, entry 21 & 22). The methyl benzoyl-
NH
2g
, 78%
2h
, 67%
a Reaction Conditions: 1 (1.2 mmol), i-PrMgCl·LiCl (1.3 mmol) in THF (8
mL) at -10 °C for 30 min, followed by imidazole carboxamide derivatives
that obtained under the activation of CDI (1 equiv) at r.t. for 3 h.
b Isolated yield.
In view of the similar chemical properties between thiazole
and benzothiazole, it was hypothesized that 2-acyl thiazoles
could also be successfully obtained from thiazole under
optimized reaction conditions. As illustrated in Table 3, benzoic
acids bearing electron-neutral (4-H, 2-Me, 4-Me), electron-rich
(3,4-OMe), and electron-deficient (4-NO2) groups all participated
in the reaction well to produce the expected 2-acyl thiazoles in
moderate to excellent yields (4a−4e, 80−93%). These results
revealed this method is not sensitive to the electronic effects and
steric effect of substituents. Other aromatic carboxylic acids such
as phenoxyacetic acid (4f, 84%) and 3-phenylpropanoic acid (4g,
80%) were both able to effectively provide the corresponding
products. It is noteworthy that anthracene-9-carboxylic acid
afforded the target product 4h in a moderate yield (75%),
suggesting polycyclic aromatic carboxylic acids might also
accommodate this reaction. Moreover, the Boc-protected amino
acids and dipeptide (4i−4l) all reacted well under optimized
L-prolinate provided 2a in
a yield of 25%, with the
phenyl(pyrrolidin-1-yl)methanone gave a trace amount of 2a,
demonstrating that L-proline derivatives activated carboxylic
acids could complement the electrophiles of this reaction.
In order to evaluate the practicability of this approach, a scale-
up synthesis was conducted under the standard conditions with
benzoic acid (10 mmol, 1.23 g) and benzothiazole (12 mmol,
1.62 g) as the substrate. The target product 2a was obtained in a
moderate yield (81%), suggesting this method is practical for the
synthesis of 2-acyl benzothiazoles/thiazoles.
Based on the above experimental results,
a plausible
mechanism for the reaction was proposed (Scheme 3). Initially,
benzothiazole reacted with i-PrMgCl·LiCl to generate 2-Grignard
benzothiazole B. The negative Gibbs free energy change (ΔG)
and enthalpy change (ΔH) suggested the generation of B is

4
(b) El-Damasy AK, Lee JH, Seo SH, Cho NC, Pae AN, Keum G.
Eur J Med Chem. 2016;115:201-216;
(c) Ma H, Zhuang CL, Xu XG, et al. Eur J Med Chem.
2017;133:174-183;
spontaneously and exothermic (Scheme 3). Subsequently, B
interacted with CDI activated carboxylic acids (C) through the
nucleophilic addition to provide the cyclic intermediate D, which
finally yield the desired product 2.
(d) Shao H, Li XK, Moses MA, et al. J Med Chem. 2018;61:6163-
6177.
5. (a) Shafi S, Alam MM, Mulakayala N, et al. Eur J Med Chem.
2012;49:324-333;
S
Boc-Phe-Pro-OH
NH
O
N
S
O
N
(b) Kharbanda C, Alam MS, Hamid H, et al. Bioorgan Med Chem.
2014;22:5804-5812;
(c) Tariq S, Kamboj P, Alam O, Amir M. Bioorg Chem.
2018;81:630-641.
T H F
C D I
O
5a 6a
)
principal product (
,
T H F
5a
6a
, benzothiazole as reagent, yield: 31%
, thiazole as reagent, yield: 23%
+
6. (a) Maddili SK, Li ZZ, Kannekanti VK, et al. Bioorg Med Chem
Lett. 2018;28:2426-2431;
NH
S
N
N
MgCl.LiCl
+
N
O
S
(b) Haroun M, Tratrat C, Kositzi K, et al. Curr Top Med Chem.
2018;18:75-87;
(c) Zha GF, Leng J, Darshini N, et al. Bioorg Med Chem Lett.
2017;27:3148-3155;
(d) Alborz M, Jarrahpour A, Pournejati R, et al. Eur J Med Chem.
2018;143:283-291.
NH
O
O
O
O
N
O
O
O
N
N
5b 6b
desired product (
,
)
5b
6b
, benzothiazole as reagent, undetected
, thiazole as reagent, undetected
Scheme 2. Reactions with Boc-Phe-Pro-OH as the reagent.
7. (a) Luo B, Li D, Zhang AL, Gao JM. Molecules. 2018;23:2457-
2472;
(b) Zhao SZ, Zhao LY, Zhang XQ, et al. Eur J Med Chem.
2016;123:514-522;
(c) Al-Talib M, Al-Soud YA, Abussaud M, Khshashneh S. Arab J
Chem. 2016;9:S926-S930.
8. (a) Spadaro A, Frotscher M, Hartmann RW. J Med Chem.
2012;55:2469-2473;

S

S
N
MgCl·LiCl
H = -20.89 kcal/mol
G = -20.29 kcal/molhk
+
MgCl·LiCl
N
B
A
1

C
(b) Thanigaimalai P, Konno S, Yamamoto T, et al. Eur J Med
Chem. 2013;65:436-447;
(c) Thanigaimalai P, Konno S, Yamamoto T, et al. Eur J Med
Chem. 2013;68:372-384;
(d) Duchene D, Colombo E, Desilets A, et al. J Med Chem.
2014;57:10198-10204.
O
Cl

S
S
O
O
S
N
N
C
MgCl·LiCl
R
Li
Mg
N
N
N
R
Cl
N
B
R
N
2
D
Scheme 3. Proposed mechanism.
9. Huang T, Sun J, An L, Zhang L, Han C. Bioorg Med Chem Lett.
2016;26:1854-1859.
Conclusion
10. (a) Zhou CY, Garcia-Calvo M, Pinto S, et al. J Med Chem.
2010;53:7251-7263;
In conclusion, we have developed a convenient and efficient
approach for the synthesis of 2-acyl benzothiazoles/thiazoles via
treatment of benzothiazole/thiazole with i-PrMgCl·LiCl,
followed by a reaction with CDI activated carboxylic acids.
Various substituted carboxylic acids effectively provided the
desired products in moderate to excellent yields under mild
reaction conditions. This offers an alternative approach to access
2-acyl benzothiazoles/thiazoles and supplements the acylation
methods of benzothiazole/thiazole. Further exploration of
carbonyl sources and a thorough understanding of the mechanism
of this reaction are underway in our lab.
(b) Tang G, Nikolovska-Coleska Z, Qiu S, Yang CY, Guo J,
Wang S. J Med Chem. 2008;51:717-720;
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2012;55:2469-2473;
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3307;
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(f) Myllymaki MJ, Saario SM, Kataja AO, et al. J Med Chem.
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Ablordeppey SY. Eur J Med Chem. 2012;53:124-132.
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Acknowledgments
We are grateful to the Natural Science Foundation of Jiangsu
Province (BK20171184), Jiangsu Planned Projects for
Postdoctoral Research Funds (1701132C), Technology Plan
Projects of Xuzhou (KC17091) and Postgraduate Research &
Practice Innovation Program of Jiangsu Province (KYCX18-
2203).
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Graphical Abstract
Highlights
1. Synthesis of 2-acyl benzothiazoles/thiazoles from
various carboxylic acids.
2. Appropriate for Boc-protected amino acids and
dipeptide.
A convenient synthesis of 2-acyl benzothiazoles/
thiazoles from benzothiazole/thiazole and
Leave this area blank for abstract info.
N,N'-carbonyldiimidazole activated carboxylic acids
Tonghui Huang a,b, Xin Wu a, Yongbo Yu a, Lin An a, Xiaoxing Yin a,
S
HO
R
20 examples
67-93%
N
O
a
b
O
S
S
c
N
N
R
+
R
MgCl·LiCl
N
N
O
Conditions : (a) i-PrMgCl·LiCl, THF, -10 °C, 30 min. (b) N,N'-carbonyldiimidazole, THF, r.t., 1 h. (c) THF, -10 °C to r.t., 3 h.
3. Moderate to excellent yields under mild reaction
conditions.