Synthesis of Thiazoles and Isothiazoles via Three-Component Reaction of Enaminoesters, Sulfur, and Bromodifluoroacetamides/Esters

Article abstract of DOI:10.1021/acs.orglett.0c01275

A three-component strategy for the synthesis of thiazoles and isothiazoles has been developed by employing enaminoesters, fluorodibromoiamides/ester, and sulfur. The thiazoles and isothiazoles were formed via two C-F bond cleavages along with the formation of new C-S, C-N, and N-S bonds. The strategy provides high selectivity for the synthesis of thiazoles/isothiazoles, which have vital applications in drug discovery and development.

Full text of DOI:10.1021/acs.orglett.0c01275

pubs.acs.org/OrgLett
Letter
Synthesis of Thiazoles and Isothiazoles via Three-Component
Reaction of Enaminoesters, Sulfur, and Bromodifluoroacetamides/
Esters
Xingxing Ma, Xiaoxia Yu, Hua Huang, Yao Zhou, and Qiuling Song*
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ABSTRACT: A three-component strategy for the synthesis of
thiazoles and isothiazoles has been developed by employing
enaminoesters, fluorodibromoiamides/ester, and sulfur. The
thiazoles and isothiazoles were formed via two C−F bond
cleavages along with the formation of new C−S, C−N, and N−S
bonds. The strategy provides high selectivity for the synthesis of
thiazoles/isothiazoles, which have vital applications in drug
discovery and development.
elieved to be an important chemical feedstock, with more
than 60 million tons produced annually, S8 is employed in
various fields, such as organic chemistry, inorganic chemistry,
as well as polymer chemistry.1 Meanwhile, S-containing
molecules widely exist in polymeric materials, natural products,
pharmaceuticals, and agrochemicals (Figure 1).2 Despite
different roles, such as the difluoroalkyl radical, difluorocarbene
precursors, and C1 and C2 synthons.6−9 In a continuation of
our ongoing interest in the development of new reactivity of
bromodifluoroalkyl compounds as well as heteroatom
chemistry,7−9 we envisioned that S8 as a substrate could
react with certain amines and halodifluoroalkyl reagents and
eventually be introduced into the final product to render N,S-
heterocycles. However, there are challenges involved in the
divergent synthesis of these heterocycles: (1) On the basis of
previous work, S8 acted only as a catalyst,9b and the
incorporation of it into the target molecules is problematic.
(2) S8 reacts with difluorocarbene to generate thiocarbonyl
fluoride, and thus suppressing the generation of the F2CS
intermediate3b from readily accessible difluorocarbene species
under basic conditions is a big issue. (3) There are many
possible side reactions, and hence precise control of the
reaction is highly challenging.
B
Herein we report the synthesis of thiazoles and isothiazoles
involving the reaction of enaminoesters10 with bromodifluor-
oalkyl compounds. Besides the side reactions between the
amines and bromodifluoroalkyl reagents, such as the
generation of isocyanides and isothiocyanates,9a,c the for-
mylation of amines9d as well as self-attack yielding amidine
derivatives9e are well avoided (Scheme 1).
Figure 1. S-Containing superpolymer as well as pharmaceutical
examples containing thiazoles and isothiazoles scaffolds.
considerable developments in S8-involved transformations,3,4
the regioselective installation of elemental sulfur into the
various target molecules has not been supplemented.
Commercially available halodifluoroalkyl reagents (XCF2R,
X = F, Cl, Br) displaying versatile reactivities, represent one of
the significant synthetic building blocks and key subunits of
pharmaceutically active molecules.5 Among the well-known
organofluorine species, bromodifluoroalkyl compounds are one
of the most popular reagents to forge valuable molecules in
Received: April 11, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01275
© XXXX American Chemical Society
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A

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a
Scheme 1. Three-Component Reaction of Enaminoesters,
Scheme 2. Scope of the Synthesis of Thiazoles 3
Sulfurs, and Bromodifluoroacetamides/Esters
To verify the postulation, we reacted ethyl 3-amino-3-phenyl
acrylate (1a), 2-bromo-2,2-difluoro-N-isopropylacetamide
(2a), and S8 to optimize the conditions for the assembly of
the thiazoles (Table 1). To our delight, the desired product 3a
Table 1. Optimization of Reaction Conditions for the
a
Synthesis of Thiazole 3a
b
entry
base
solvent
T (°C)
yield of 3a (%)
1
2
3
4
5
6
7
8
9
10
11
12
Cs2CO3
Na2CO3
K2CO3
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
THF
dioxane
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
110
110
110
110
110
110
110
110
110
110
110
120
90
58
32
19
0
DBU
tBuONa
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
0
0
a
Reaction condition 1: 1 (0.1 mmol), 2 (1.5 equiv), S8 (60 mol %),
Cs2CO3 (5.0 equiv), and CH3CN (2.5 mL) under N2 at 90 °C for 48
50
26
40
38
52
29
b
h. 1a (1 mmol).
c
d
e
reaction conditions to afford the desired products (3a−h) in
good yields. A large-scale synthesis was further carried out
under the standard conditions for the construction of 3a.
Gratifyingly, the efficiency was not significantly affected by the
scale-up, and 3a was obtained in 53% yield. (See the
Supporting Information (SI) for details.) BrCF2COOEt
could also react with ethyl 3-amino-3-phenyl acrylate (1a),
and the corresponding product 3i was obtained in 45% yield,
lower than its amide counterparts, probably due to the fact that
BrCF2COOEt easily decomposed into difluorocarbene under
t h e b a s i c c o n d i t i o n s . H o w e v e r , d i e t h y l
(bromodifluoromethyl)phosphonate did not give the corre-
sponding thiazole compound (3j). Subsequently, the substrate
scope with respect to the R1 and the electron-withdrawing
group (EWG) on enaminoesters were also investigated
(Scheme 2). Various enaminoesters with different electronic
and steric properties of substituents were compatible in the
process. The corresponding thiazoles (3k−x) were obtained in
moderate to good yields under the conditions. Surprisingly,
when methyl ester 1y was used as a substrate, the
deesterification product 3y was obtained in 76% yield.
e
e
f
13
14
76 (69)
68
e
80
a
Reaction conditions: 1a (0.1 mmol), 2-bromo-2,2-difluoro-N-
isopropylacetamide (2a, 1.5 equiv), S8 (60 mol %), base (5.0
equiv), and CH3CN (2 mL) under N2 at 90 °C for 48 h. GC yield.
CH3CN (1.0 mL). CH3CN (1.5 mL). CH3CN (2.5 mL). Isolated
b
c
d
e
f
yield.
could be isolated in 58% yield when the reaction was
conducted using Cs2CO3 as the base in CH3CN at 110 °C
(Table 1, entry 1). To enhance the yield of the desired
product, we screened various bases, such as Na2CO3, K2CO3,
DBU, and t-BuONa. It turned out that Cs2CO3 was the
optimal base (entries 2−5). We then examined the effect of
solvents; however, no superior results were achieved (Table 1,
entries 6−8). After screening the reaction concentrations and
the temperatures (Table 1, entries 9−14), we found that the
yield of thiazole 3a was increased to 76% when 2.5 mL of
CH3CN was added, and the reaction was conducted at 90 °C
for 48 h (Table 1, entry 13).
Compared with bromodifluoroamides, BrCF2COOEt deliv-
ered the corresponding thiazoles in relatively low yields,
probably owing to the lower stability of BrCF2COOEt
compared with its counterpart amides (3z−aj in Scheme 2;
also see 3i). Specifically, the steric hindrance (3p−s, 3ac−af)
With the optimal conditions in hand, we explored the
substrate scope for the synthesis of various substituted
thiazoles, as shown in Scheme 2. A variety of bromodifluor-
oamides were tested with enaminoester 1a under the standard
B
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a
and different substituents on the aryl ring of enaminoesters
have a slight effect on this transformation, furnishing the
corresponding targeted thiazoles in decent yields. In addition,
the absolute structure of product 3ac was unambiguously
determined by X-ray crystallography.
Scheme 3. Scope for the Synthesis of Isothiazoles 4
The success of the above transformation prompted us to
investigate the feasibility of the formation of isothiazoles with
the same substrates by selectively controlling the reaction
conditions. The enaminoester ethyl 3-amino-3-phenyl acrylate
(1a), BrCF2COOEt, and S8 were chosen as substrates to
optimize the reaction conditions for forging such a product
(Table 2). When the reaction was conducted in CH3CN at 110
a
Table 2. Optimization of the Reaction for Compounds 4
a
b
entry
variation from the standard conditions
4a (%)
Reaction conditions: 2:1 (0.3 mmol), 2 (3.0 equiv), S8 (60 mol %),
Cu (80 mol %), 1,10-phen (20 mol %), Na3PO4 (3.0 equiv), and
CH3CN (2 mL) under N2 at 90 °C for 20 h. 2 is ethyl
difluoroiodoacetate.
1
2
3
4
5
6
7
8
none
66
72
40
b
CuI instead of CuBr
CuCl instead of CuBr
Cu instead of CuBr
L
Na3PO4 instead of Na2CO3
at 90 °C
c
d
f
53(71) (76)
40(80) (10)
84
88
substitution on the aromatic ring of β-enaminoesters, ortho-
and meta-substituted enaminoesters were also compatible in
the reaction, affording the corresponding isothiazoles (4j−q)
in up to 74% yield. Heterocyclic-substituted enamine esters
also led to the formation of 4r and 4s in 58 and 70% yield,
respectively. Besides the aromatic enamine esters, alkyl-
substituted enaminoesters under the same reaction conditions
furnished the expected isothiazoles 4t and 4u in modest yields.
To further broaden the scope of the method, several other
enaminoesters were tested in the transformation. The
corresponding isothiazoles (4v−x) were furnished in 68, 65,
and 62% yield. The structure of 4v was unequivocally
confirmed by X-ray diffraction analysis.
e
under air
trace
a
Reaction conditions: 1a (0.3 mmol), 2a (3.0 equiv), S8 (60 mol %
equiv), CuBr (10 mol %), L1 (20 mol %), Na2CO3 (5.0 equiv), and
CH3CN (2.5 mL) under N2 at 110 °C for 12 h. Isolated yield, N.R.
= no reaction. Cu: 50 mol %. Cu: 80 mol %. L3 instead of L1. L4
instead of L1.
b
c
d
e
f
To shed light on the mechanism of the reaction, a sequence
of control experiments was performed (Schemes 4 and 5).
°C under a nitrogen atmosphere by using CuBr as the catalyst
and Na2CO3 as the base, the isothiazole 4a was obtained in
66% yield (Table 1, entry 1). Subsequently, a range of Cu salts
and copper catalysts were screened, and it was found that Cu
powder displayed the best reactivities. Thus we carried out a
series of experiments and found that 80 mol % of Cu powder is
the best choice (Table 1, entry 2). 1.10-Phen (L3) was proven
to be the optimal ligand among the ligands tested (Table 1,
entry 5). The marginal improvements in yield of the product
were achieved when Na2CO3 was replaced by inorganic base
Na3PO4. To our delight, the yield of the desired product 4a
was slightly raised to 88% when the reaction was conducted at
90 °C (entry 7). No product was obtained when the reaction
was conducted under air (entry 8). (See the SI for details.)
After the optimized reaction condition was identified, the
generality of this transformation to afford isothiazoles was
investigated (Scheme 3). The enaminoesters having neutral
and electron-donating groups on the aromatic ring displayed
good reactivities, producing 3,4-diester 5-arylisothiazole (4a−
d) in decent yields. In addition, when BrCF2COOEt was
replaced with ICF2COOEt, the desired product 4a was
obtained in 80% yield. The aromatic ring of electron-
withdrawing and halo-substituted enaminoesters was also
amenable, delivering the corresponding isothiazoles (4e−i)
in 28−78% yield. The structure of 4e was unequivocally
confirmed by X-ray diffraction analysis. In addition to para
Scheme 4. Control Experiments for the Formation of
Thiazoles 3
First, a control experiment was conducted by using ethyl 3-
amino-3-phenyl acrylate (1a) as a substrate and 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) or 2,6-ditertbutyl-4-
methylphenol (BHT) as the radical inhibitor. In this case, the
desired product thiazole 3a was isolated in 58 and 62% yield
(Scheme 4, eq 1), which indicated that a single-electron-
transfer (SET) pathway was not involved in the formation of
thiazoles 3. Second, no target product 3a or compound 7 was
formed when S8 was replaced with K2S or Na2S (Scheme 4, eqs
2 and 3), and the above results suggested that sulfion was not
C
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(Scheme 6, eqs 3 and 4). It was found that active intermediate
10 was detected in this transformation by HRMS, and
compound 11 was also detected, whereas compound 9 was
not detected in the absence of Cu powder (Scheme 6, eqs 3
and 4). To further verify the possibility of compounds 10 and
11 as potential key intermediates in the isothiazole formation,
we conducted the formation of isothiazole 4a in a two-step
one-pot strategy, and the corresponding target products were
obtained in variable yields at different reaction times; these
results provided solid information about the existence of
intermediates 10 and 11 in the above two transformations.
(See the SI for details.) Moreover, isothiazole 4a could be
readily accessed when we added Cu(I) instead of Cu powder,
disclosing that Cu(I) might be the active catalytic species in
this transformation system. (See the SI for details.)
In terms of the mechanism of the Cu-mediated synthesis of
isothiazoles, first, Cu reacts with S8 to access complex E (Cu(I)
species). We believe that CuII radical complex F is furnished in
the presence of BrCF2COOEt and S8, which quickly
experiences S8-promoted defluorination to provide copper−
thiocarbonyl compound G under basic conditions. Next,
intermediate G is attacked by the C2 of enamine 1 to afford
CuIII complex H. Alternatively, intermediate G could undergo
hydrolysis to form ethyl 2-thioxoacetate K. Intermediate H
further converts into intermediate I to render species J. Finally,
the desired product 4 is delivered via reductive elimination,
regenerating the active species Cu(I) for the next catalytic
cycle (Scheme 7).
Scheme 5. Possible Reaction Pathway for the Formation of
Thiazoles
generated or involved in the construction of thiazoles 3. We
conducted multiple reactions in the absence of BrCF2COOEt;
no desired compound 7 was ever detected by GCMS, HRMS,
or NMR (see SI for details), which demonstrated that the
formation of the compound 7 must be associated with
bromodifluoroalkyl reagents.
On the basis of the previously described experimental results
and the previous work,9a,b,d the plausible mechanism for S8-
involved thiazole formation is depicted in Scheme 5. Initially,
enaminoester 1 attacks S8, rendering intermediate A. Then, the
NH2 of complex A works with bromodifluoroacetamides/
esters to provide active species B, which further undergoes the
S8-promoted defluorination along with desulfuration to
generate the active compound C, which is sensitive to basic
conditions. Finally, the target products 3 are obtained via SNAr
substitution.9d Meanwhile, enaminoesters might undergo self-
aminolysis to deliver the dimeric product D as the main
byproduct (Scheme 5), which has been detected by GC−MS
during the transformation.
Scheme 7. Possible Reaction Pathway for the Formation of
Isothiazoles
Subsequently, the reactions for the construction of
isothiazoles 4 were performed without S8, and no correspond-
ing compound 8 was observed (Scheme 6, eq 1). In addition,
Scheme 6. Control Experiments for the Formation of
Isothiazoles 4
when radical scavenger was added to this reaction, the desired
product 8 was not delivered, and the TEMPO−CF2COOEt
adduct was detected by GCMS (Scheme 6, eq 2). These
results suggested that the CF2COOEt radical was generated in
the construction of isothiaozles 4, yet substrate 1a will not
directly react with this radical. No reaction was observed when
Na2S was used instead of elemental sulfur, indicating that the
negative divalent sulfur was noneffective for the transformation
of 4 (Scheme 6, eq 2). The previously described results
prompted us to probe the role of S8 and BrCF2COOEt
In conclusion, we disclosed expedient S8-involved trans-
formations of bromodifluoroalkyl compounds and enaminoest-
ers, rendering the divergent assembly of isothiazoles and
thiazoles via [3 + 1 + 1] cyclization. These strategies provide
straightforward and simple protocols to access a wide range of
N,S-containing compounds via the selective cleavage of
D
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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■
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General experimental procedures and spectroscopic data
for the corresponding products, characterization data,
and NMR spectra (PDF)
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Accession Codes
CCDC 1913896, 1913900, and 1996766 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Qiuling Song − Institute of Next Generation Matter
Transformation, College of Materials Science & Engineering,
Huaqiao University, Xiamen, Fujian 361021, China;
orcid.org/0000-0002-9836-8860; Email: qsong@
hqu.edu.cn; Fax: 86-592-6162990
Authors
Xingxing Ma − Institute of Next Generation Matter
Transformation, College of Materials Science & Engineering,
Huaqiao University, Xiamen, Fujian 361021, China
Xiaoxia Yu − Institute of Next Generation Matter
Transformation, College of Materials Science & Engineering,
Huaqiao University, Xiamen, Fujian 361021, China
Hua Huang − Institute of Next Generation Matter
Transformation, College of Materials Science & Engineering,
Huaqiao University, Xiamen, Fujian 361021, China
Yao Zhou − College of Chemistry and Chemical Engineering,
Hubei Normal University, Huangshi, Hubei 435002, China;
orcid.org/0000-0002-3500-7355
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01275
Notes
The authors declare no competing financial interest.
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2019, 21, 8869−8873.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation (21772046, 21931013) is gratefully acknowledged.
We also thank the Instrumental Analysis Center of Huaqiao
University for analysis support.
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