A novel metal-free synthesis of thiazole-substituted α-hydroxy carbonyl compounds and 2-alkenylthiazoles from thiazole N-oxides and olefins

Article abstract of DOI:10.1016/j.tetlet.2019.05.053

A metal-free and highly atom-economic synthesis of thiazole-substituted α-hydroxy carbonyl compounds has been developed. Catalyzed by 5 mol% of p-toluenesulfonic acid (TsOH), a variety of thiazole-substituted α-hydroxy carbonyl compounds were obtained in

Full text of DOI:10.1016/j.tetlet.2019.05.053

Accepted Manuscript
A novel metal-free synthesis of thiazole-substituted α-hydroxy carbonyl com-
pounds and 2-alkenylthiazoles from thiazole N-oxides and olefins
Hui Li, Juan Zhang, Yanqiu Zhang, Jiayi Wang, Gonghua Song
PII:
S0040-4039(19)30501-5
https://doi.org/10.1016/j.tetlet.2019.05.053
TETL 50825
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
9 April 2019
10 May 2019
27 May 2019
Please cite this article as: Li, H., Zhang, J., Zhang, Y., Wang, J., Song, G., A novel metal-free synthesis of thiazole-
substituted α-hydroxy carbonyl compounds and 2-alkenylthiazoles from thiazole N-oxides and olefins, Tetrahedron
Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.05.053
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Graphical Abstract
A metal-free and highly atom-economic synthesis of thiazole-substituted α-hydroxy carbonyl compounds has been
developed. Catalyzed by 5 mol% of p-toluenesulfonic acid (TsOH), a variety of thiazole-substituted α-hydroxy carbonyl
compounds were obtained in moderate to good yields via 1,3-dipolar cycloaddition of thiazole N-oxides with olefins,
followed by a ring-opening reaction. Furthermore, the corresponding 2-alkenylthiazoles could be produced in excellent yields
A novel metal-free synthesis of thiazole-
substituted α-hydroxy carbonyl compounds
and 2-alkenylthiazoles from thiazole N-
oxides and olefins
Leave this area blank for abstract info.
Hui Li, Juan Zhang, Yanqiu Zhang, Jiayi Wang, Gonghua Song
from synthesized α-hydroxy carbonyl compounds through a one-pot, two-step dehydration process.

1
Tetrahedron Letters
A novel metal-free synthesis of thiazole-substituted α-hydroxy carbonyl compounds
and 2-alkenylthiazoles from thiazole N-oxides and olefins.
Hui Li, Juan Zhang, Yanqiu Zhang, Jiayi Wang, Gonghua Song
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A metal-free and highly atom-economic synthesis of thiazole-substituted α-hydroxy carbonyl
compounds has been developed. Catalyzed by 5 mol% of p-toluenesulfonic acid (TsOH), a
variety of thiazole-substituted α-hydroxy carbonyl compounds were obtained in moderate to
good yields via 1,3-dipolar cycloaddition of thiazole N-oxides with olefins, followed by a ring-
opening reaction. Furthermore, the corresponding 2-alkenylthiazoles could be produced in
excellent yields from synthesized α-hydroxy carbonyl compounds through a one-pot, two-step
dehydration process.
Available online
Keywords:
metal-free
thiazole N-oxide
2009 Elsevier Ltd. All rights reserved.
1,3-dipolar cycloaddition
thiazole-substituted α-hydroxy carbonyl
Introduction
Thiazole is an essential scaffold in pharmaceuticals [1],
functional organic materials [2], asymmetric ligands [3] and
agrochemicals [4]. For example, among the biologically active
natural products, thiazole derivatives have been found to possess
diverse biological activities such as anti-inflammatory [5],
anticancer [6], antifungal [7], antitubercular [8] and antiparasitic
[9-10]. Thus, the synthesis and functionalization of thiazole
derivatives are highly meaningful.
The aromatic N-oxides are well-known synthetic
intermediates for the functionalization of aromatic nitrogen
heterocycles [11-12]. They have been recognized as valuable
substrates for C-H functionalization and other types of cross-
coupling reactions [13-14]. For instance, Fagnou developed a C-
H
activation reaction between thiazole N-oxides and
halogenobenzenes catalyzed by palladium (II) to give aryl
thiazoles [15]. Bering and Antonchick reported a cross-coupling
reaction of quinoline N-oxides with alkenyl boronic acids under
metal-free conditions to achieved various 2-styryl quinolines
[16]. In particular, N-oxides are easily go through nucleophilic
substitution with nucleophiles or organometallic reagents, and
they are capable of acting as dipolarophiles in 1,3-dipolar
cycloaddition [17-18]. Wang and Bower reported respectively the
synthesis of 2-alkenylquinoline derivatives from quinoline N-
oxides and different kinds of alkenes (Scheme 1a and 1b) [19-
20]. The reactions proceed via a 1,3-dipolar cycloaddition
between quinoline N-oxides and alkenes, the cleavage of N-O
bond and aromatization of the quinoline ring to give the α-
hydroxy intermediate, and finally dehydration process to generate
t—he—fin—al product. However, since the dehydration process
 Corresponding author. E-mail address: ghsong@ecust.edu.cn (G. Song).

2
Tetrahedron Letters
occurred reasonably fast, it was hard to isolate the alcoholic
[23]. However, stoichiometric metal oxidants, a transition metal
catalyst and a ligand are necessary for the accomplishment of the
transformation. Herein, we describe a novel metal-free method
for the synthesis of thiazole-substituted α-hydroxy carbonylic
compounds through a 1,3-dipolar cycloaddition of thiazole N-
oxides with olefins and followed by TsOH catalyzed ring-
opening reaction. Furthermore, corresponding 2-alkenylthiazoles
can be obtained by a one-pot, two-step dehydration process of the
α-hydroxy carbonylic compounds (Scheme 1f).
intermediate. Meanwhile, a strategy for the synthesis of α-
hydroxy carboxylic quinolines through a tandem 1,3-dipolar
cycloaddition and ring-opening process has been developed by
Sharma and Kumar (Scheme 1c) [21]. But this approach was not
applicable to thiazole N-oxides. It is worth noting that 1,3-dipolar
cycloaddition of five-membered nitrogen heterocyclic N-oxides
has also been used for the construction of new heterocyclic
systems. For example, Loska described a three component
reaction of thiazole N-oxides, 1,1-difluorostyrenes and alcohols
to prepare thiazolyl acetic acid esters (Scheme 1d) [22]. The 1,3-
dipolar cycloaddition between N-oxide and 1,1-difluorostyrene
led to the acyl fluoride intermediate, which was then quenched
by alcoholic nucleophile to form the target product.
Unfortunately, this work was not suitable for thiazole N-oxides
and phenyl vinyl ketones to form the thiazole-substituted α-
hydroxy carbonylic compounds. The final thiazolyl acetic acid
esters were obtained in only 22% yield. Up to now, the synthetic
method of thiazole-substituted α-hydroxy carbonylic compounds
has not been reported yet.
Results and discussion
The reaction of 4,5-dimethylthiazole N-oxide (1a) with phenyl
vinyl ketone (2a) was selected as the model reaction. After
keeping the reactants in DMSO at 120°C for 2h, 3a was obtained
in 43% HPLC yield (Table 1, entry 1). To promote the reaction
yield, a series of additives were then evaluated (entries 2-6). As
shown in Table 1, different acid could assist the transformation
and, among them, p-toluenesulfonic acid (TsOH) proved to be
the most effective one (entry 5). Decreasing the amount of TsOH
from 10 mol% to 5 mol% improved the yield from 84% to 85%
HPLC yield (entry 7). No further improvement was observed
when less TsOH was added (entry 8). Then we screened a variety
On the other hand, 2-alkenylthiazoles were synthesized
through the addition of thiazoles to olefins with a catalytic
system of Pd(OAc)2/AgNO3/1,10-phenanthroline (Scheme 1e)
Table 1
Optimization of reaction conditions.a
Entry
1
2a (equiv)
Additive (mol%)
none
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Time
2h
T (°C)
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
110
100
90
Yield %b
43
2
2
2
10% AcOH
10% TFA
10% MEHQ
10% TsOH
10% Et3N
5% TsOH
2% TsOH
5% TsOH
5% TsOH
5% TsOH
5% TsOH
5% TsOH
5% TsOH
5% TsOH
5% TsOH
5% TsOH
5% TsOH
5% TsOH
5% TsOH
5% TsOH
5% TsOH
5% TsOH
5% TsOH
2h
62
3
2
2h
80
4
2
2h
73
5
2
2h
84
6
2
2h
41
7
2
2h
85
8
2
2h
76
9
2
2h
88
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24d
2
Toluene
1,4- Dioxane
NMP
2h
57
2
2h
53
2
2h
50
2
Water
EtOH
2h
10
2
2h
73
2
CH3CN
DMF
2h
75
2
2h
89
2
DMF
2h
90
2
DMF
2h
85
1.1
1.5
1.1
1.1
1.1
1.1
DMF
2h
100
100
100
100
100
100
91
DMF
2h
90
DMF
1h
92
DMF
30 min
20 min
30 min
94 (85)c
DMF
83
DMF
n.d.
a Reaction conditions: 1a (0.30 mmol), 2a, additive and solvent (2 mL).
b HPLC yield (biphenyl as an internal standard).
c Isolated yield.
d 4,5-dimethylthiazole as the reactant.

3
of solvents such as DMF, toluene, 1,4- dioxane, NMP, water and
other polar solvents (entries 9-15). DMF proved to be the most
appropriate solvent for this reaction, providing 3a in 88% HPLC
yield (entry 9). After inspecting the reaction temperature between
120°C and 90°C (entries 16-18), we found that the suitable
temperature was 100°C (entry 17). Furthermore, we optimized
the reaction time and quantity of 2a to achieve better yield
(entries 19-23). The use of 1.1 equivalent of 2a led to 94% HPLC
yield of 3a in DMF at 100°C for 30 min (entry 22). A control
experiment using 4,5-dimethylthiazole instead of 4,5-
dimethylthiazole N-oxide failed to provide the product 3a. It
means N-oxide was necessary for this transformation (entry 24).)
(3o) could be obtained in 37% yield. However, the reaction
with α-methyl phenyl vinyl ketone failed to give the desired
product (3p), which might be due to the steric hindrance. It is
worth noting that the acrylic esters could also participate in this
reaction in moderate yields when prolong the reaction time to 3h
(3q-3s). As the contrast agent, styrene was also carried out in this
reaction system. The target product (3t) was obtained in only
11% yield even prolonging the reaction time to 12h. Also,
unsubstituted thiazole N-oxide could be alkylated successfully
with alkenyl ketones (3u and 3v).
The dehydration of thiazole-substituted α-hydroxy carbonyl
compounds toward corresponding 2-alkenylthiazoles was then
investigated.
Table 2
Scope of the C-2 alkylation of thiazole N-oxides with alkenyl
Table 3
ketones.a
One-pot, two-step approach to the C-2 alkenylation of
a Reaction conditions: 1 (0.30 mmol), 2 (0.33 mmol), TsOH (5 mol %), DMF
thiazole.a
a Reaction conditions: 3 (0.50 mmol), SOCl2 (1.0 mmol), DCM (5 mL), rt for
10 min, then evaporated DCM and SOCl2, added CHCl3:Et3N=3:1(v:v) at
room temperature for 3h, isolated yield.
(2 mL), heated at 100°C for 30 min, isolated yield.
b Reaction time 3h.
b The step two reacted at 50°C for 3h.
c The step two reacted at 50°C for 12h.
c Reaction time 12h.
With the optimized conditions in hand, we investigated the
substrate scope of the C-2 alkylation of 4,5-dimethylthiazole by
exploring a series of alkenes (Table 2). The phenyl vinyl ketones
with electron-withdrawing substituents at the para-position (3b,
3c, 3f and 3g) gave higher yields than those with electron-
donating substituents (3d and 3e). Substitution at the meta- or
ortho-position of the benzene ring gave similar yields to that at
the para-position (3h-3k). Furthermore, disubstituted alkenes,
heteroaryl alkenes and aliphatic alkenyl ketones were well-
tolerated. For example, 2,4-dichlorophenyl vinyl ketone, 3-
indolyl vinyl ketone and ethyl vinyl ketone could get the
corresponding C-2 alkylated products in 67%, 72% and 69%
respectively (3l-3n). Interestingly, when a methyl group was
introduced at the β-site of phenyl vinyl ketone, the target product
At first, we attempted to use sulfuric acid as the dehydrating
agent of 3a. However, after reacting in DMF at 100°C for 24h,
the isolated yield of the target product 4a was only 43%. When
SOCl2 was used and DCM as the solvent, both chlorinated and
dehydrated products of hydroxyl compounds were observed in
the reaction mixture by NMR. After evaporating the solvent, the
residual was treated with a mixture of CHCl3 and Et3N
(CHCl3:Et3N=3:1(v:v)). The target product 4a was isolated in
92% yields. The dehydration of different thiazole-substituted α-
hydroxy carbonylic compounds was then investigated (Table 3,).
The 2-alkenylthiazoles with electron-withdrawing substituents on
the phenyl ring could be gotten at room temperature, while those
with electron-donating substituents were obtained at higher
temperature with good yields (4a-4p). Unfortunately, the acrylic

4
Tetrahedron
esters and the styrene products failed to form the corresponding
References and notes
products (4q-4t). Unsubstituted 2-alkenylthiazoles could also be
prepared in moderate to good yields (4u and 4v).
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(1998) 602-617.
Furthermore, to demonstrate the utility of the strategy on a
larger scale, a gram-scale reaction of 4,5-dimethylthiazole N-
oxide (1a) and phenyl vinyl ketone (2a) was carried out. The
desired product 3a was obtained in 79% isolated yield (Scheme
10. G.T. Zitouni, M.D. Altintop, A. Ozdemir, B. Sever, C.G.
Akalin, K. Kucukoglu, Eur. J. Med. Chem. 107 (2016) 288-
294.
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McHardy, S.J. Watowich, J. Med. Chem. 60 (2017) 5015-
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Larionov, Chem. Commun. 52 (2016) 9945-9948.
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Tetrahedron Lett. 57 (2016) 5223–5226.
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3249-3254.
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Gorelsky, K. Fagnou, J. Am. Chem. Soc. 130 (2008) 3276-
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Based on the literatures [19-22], a probable mechanism for
the synthesis of 3a is proposed (Scheme 3). It is assumed that a
1,3-dipolar cycloaddition to form the isoxazolidine intermediate
A was carried out firstly. The cleavage of the N-O bond assisted
by TsOH was then followed to provide the α-hydroxy carbonyl
product 3a.
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5706-5709.
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In conclusion, we have demonstrated an efficient strategy for
the synthesis of thiazole-substituted α-hydroxy carbonyl
compounds under transition-metal-free conditions. Furthermore,
go through a one-pot, two-step dehydration process, the
corresponding thiazole C-2 alkenylation products can be obtained
in good yields.
Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
Acknowledgments
Financial support for this study from the National Key
Research and Development Plan (Grant No. 2017YFD0200504)
and the National Natural Science Foundation of China (Grant No.
21572060) is gratefully acknowledged.

5
Highlights
1. A metal-free and atom-economic synthesis of
thiazole-substituted
α-hydroxy
carbonyl
compounds has been established.
2. A domino 1,3-dipolar cycloaddition and ring-
opening aromatization reaction was involved.
3. The corresponding 2-alkenylthiazoles were
produced in excellent yields through a one-pot,
two-step dehydration process.