Access to 4-substituted isothiazoles through three-component cascade annulation and their application in C-H activation

Article abstract of DOI:10.1039/d0cc01100b

The use of potassium ethyl xanthate (EtOCS2k) as a sulfur atom donor enabled the transition-metal-free [3 + 1 + 1] cascade annulation of isopropene derivatives with NH4I in DMSO/H2O, affording various 4-substituted isothiazoles in moderate to good yields

Full text of DOI:10.1039/d0cc01100b

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DOI: 10.1039/D0CC01100B
Journal Name
COMMUNICATION
Access to 4-Substituted Isothiazoles through Three-Component
Cascade Annulation and Its Application in C–H Activation
Guoling Huang,a Jian Li,a Xiaoliang Ji, a Lu Chen,a Qiang Liu, a,b Xiuwen Chen, a Yubing Huang,*,a and
Yibiao Li*,a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The use of potassium ethyl xanthate (EtOCS2k) as a sulfur atom accessing 4-substituted isothiazole derivatives, most suffer
donor enabled the transition-metal-free [3+1+1] cascade from significant limitations, such as toxic and expensive
annulation of isopropene derivatives with NH4I in DMSO/H2O, reagents, multiple steps, and poor starting material
affording various 4-substituted isothiazoles in moderate to good availability. For example, rare compound 3-chloro-2-
yields with good functional group compatibility. Furthermore, the phenylpropenal was used as the raw material for the synthesis
Pd and Ag-catalyzed C5–H-selective direct oxidation dimerization of 4-substituted isothiazoles through a cyclization reaction
of 4-substituted isothiazoles afforded 5,5’-bisisothiazoles. This with ammonium thiocyanate.[9g, 11d] Furthermore, highly toxic
series of reactions included the formation of new C–S, C–N, N–S, HCN might be released during the reaction, making the
and C–C bonds via cascade addition, annulation, and direct C–H synthetic operation difficult. These problems regarding
activation under mild conditions.
isothiazole construction have greatly hindered the application
of isothiazoles in medicinal and materials chemistry.
Figure 1. Bioactive compounds containing isothiazole-based
heterocycles
The development of simple and efficient protocols for the
synthesis of heterocycle molecules is an important task in
organic synthesis. Isothiazole and isoxazole derivatives are
privileged organic compounds found in natural products and
applied in several pharmaceuticals owing to their recognized
biological and therapeutic activities.[1] In particular, substituted
isothiazoles bearing a key structural display a wide range of
biological activities, including as GPR agonists, [2] which tend to
improve the triglyceride level of cell membranes. Substituted
isothiazole rings also show a broad range of pharmacological
activities, including as tyrosine kinase c-Met inhibitors,[3]
mGluR1 antagonists,[4] and MEK-1 kinase inhibitors.[5]
Isothiazole derivatives have also been proposed for industrial
applications, such as corrosion inhibitors,[6] inkjet inks and azo
dyes,[7] and antifreeze compositions for diesel engines.[8]
Consequently, the development of rapid and efficient methods
for the construction of isothiazole skeletons has stimulated
considerable interest.[9] Unfortunately, despite synthetic
methods for benzoisothiazoles and 5-substituted, 3,5-
disubstituted, and 3,4,5-trisubstituted isothiazoles having been
N
S
O
NC
S
SMe
N
NH
OMe
N
CH3
S
MeO
OMe
EtO
MeO
poliovirus uncoating inhibitor [1g]
mGluR1 antagonists [4]
O
treating or inhibiting angiogenesis [1f]
N
S
NH
HO
H
N
O
N
H
O
NH
S
HN
CH3
HN
O
S
NH
N
S
O
H2
N
OH
MEK-1 kinase inhibitors [5]
N
CH3
GPR agonists [2]
Benzenesulfonamide [1h]
Xanthates and the related derivatives are used in organic
synthesis in several interesting and important ways.[12] As part of
our continuing research on exploiting the reactivity of EtOCS2K, we
previously reported novel and practical methods for the synthesis
of 2-acetylthienopyridine,[13a] tetrahydrothiophene,[13b] and
[13c]
thienopyridines using EtOCS2K as the sulfur donor.
Specifically,
NH4I-mediated three-component oxysulfenylation and sulfonylation
reactions of alkenes were achieved using a radical-promoted
domino reaction.[13d] Furthermore, xanthate can act as a promoter
for the semihydrogenation of alkynes to synthesize (E)-alkenes,[13e]
well developed,[10] 4-substituted isothiazoles still lack
a
[13f]
and the oxidation of alkynes to synthesize substituted benzils.
[11]
universal synthetic method.
Among reported methods for
Encouraged by these results, in this study, we report the first
synthesis of 4-substituted isothiazoles via a transition-metal-free
three-component annulation reaction of isopropene derivatives,
NH4I, and EtOCS2K. To our knowledge, the sole previous attempt to
involve isopropenes in isothiazole formation was made by Hofmann
and coworkers, who obtained only small amounts of the desired
products through the reaction of SO2 and NH3 at 300–350 oC.[14]
aSchool of Biotechnology and Health Sciences, Wuyi University, Jiangmen,
Guangdong Province 529090, China, bCenter of Basic Molecular Science,
Department of Chemistry, Tsinghua University, Beijing 100084, China. E-mail:
leeyib268@126.com; wyuchemhyb@126.com
†Electronic Supplementary Information (ESI) available: General Experimental
information, experimental procedure for product synthesis, full characterization
data, 1H and 13C NMR spectra of all products. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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The C3–H and C5–H bond on the 4-substituted isothiazole ring
DOI: 10.1039/D0CC01100B
can be converted into a more complex polysubstituted isothiazole
With optimized conditions in hand, the scope of the
synthesis of 4-substituted isothiazoles was examined using
several isopropene derivatives and EtOCS2K (Scheme 1). Both
electron-rich and electron-deficient isopropene derivatives
reacted with EtOCS2K and NH4I to give the corresponding 4-
disubstituted isothiazole products in moderate to good yields
(Scheme 1). The reaction tolerated various substituents,
including alkyl, -OMe, -Cl, -Br, -F, -I, -CF3, and naphthyl groups.
Substituents at the ortho-position of the benzyl group greatly
affected the reaction yield (Scheme 1, 2b and 3o). Notably, 5-
(prop-1-en-2-yl)benzo[d][1,3]dioxole were also successfully
converted to 4-(benzo[d][1,3]dioxol-5-yl)isothiazole 2g in 70%
View Article Online
derivative through Pd-catalyzed direct C–H functionalization
reactions. To further prove the application value of 4-substituted
isothiazoles, as shown in Scheme 3, the functionalization of 4-
substituted isothiazoles by Pd-catalyzed C–H bond activation was
18]
demonstrated.[17,
Pleasingly, a highly efficient functionalization
reaction of 4-substituted isothiazoles was achieved through
selective activation of the C5–H bond on the isothiazole
heterocycle, affording 5,5'-bisisothiazole products through Pd-
catalyzed dimerization reactions in moderate to good yields.
Initially, reaction of 4-phenyl-substituted isothiazole with an
electron-donating group on the benzene ring was tested in this
dimerization reaction. The results showed that when -Me, -OMe,
and methylenedioxyl groups were used as substituents, the
reactions proceeded smoothly, giving the desired products in good
yields (Scheme 2, 3a–3d). Electron-withdrawing groups, such as Cl,
Br, and F, were also used as substituents to test the universality of
the reaction. These reactions proceeded smoothly, giving the
desired 5,5'-bisisothiazole products in moderate to good yields
(Scheme 3, 3e–3h). Notably, a heterocycle-substituted isothiazole
also successfully underwent the dimerization reaction, affording
4,4'-di(thiophen-2-yl)-5,5'-bisisothiazole (3i) in 88% yield. Finally, a
cross-dimerization reaction also gave the corresponding 5,5'-
bisisothiazole product (3j) in an acceptable yield. Among these
products, the structure of 3k (CCDC 1978414) was confirmed by
crystal X-ray diffraction analysis.[16] Such multi-substituted
bisisothiazoles can be expected to have important roles in
materials chemistry.
yield. The structure of 2g was confirmed by crystal X-ray
[16]
diffraction analysis (CCDC 1902238).
The conditions
described also provided access to 4-substituted isothiazoles
bearing multiple fluoro-substituents, which are often highly
desirable in medicinal chemistry owing to the unique biological
properties imparted by fluorine atoms (Scheme 1, 2n–2q).
Remarkably, iodine substituents were tolerated in this
transformation, allowing further functionalization at the C–I
bond
under
transition-metal-catalyzed
cross-coupling
conditions (Scheme 1, 2r). Substrates bearing heterocycles,
such as 2-thienyl groups, also produced corresponding 4-
disubstituted isothiazole 2w in 43% yield. Interestingly, using
1,3-di(prop-1-en-2-yl)benzene resulted in formation of the
corresponding 1,3-di(isothiazol-4-yl)benzene product 2x in
41% yield as a white crystal, which enabled the reaction nature
of the annulation process to be confirmed. The molecular
structure of complex 2x was established by X-ray
crystallography (CCDC 1978413).[16] Unfortunately, the
reactions with alkyl-substituted isopropenes, such as 2-
methylpent-1-ene and pent-2-en-3-ylbenzene, only afforded a
mixture of products with a low conversion rate, while
allylbenzene was did not react.
Scheme 2. Synthesis of 5,5'-bisisothiazoles from 4-substituted
isothiazole derivatives a,b
N
R
S
S
N
Pd(OAc)2, Phen
Ag2CO3, K2CO3
Scheme 1. Synthesis of isothiazoles from isopropene derivatives a, b
toluene, 130 oC, 24h
S
R
R
S
N
DMSO, H2
130 oC, 24 h
O
S
2
3
R
R
NH4
I
+
+
N
KS
OEt
CH3
N
N
2
N
1
S
S
S
S
N
MeO
Me
S
N
S
N
S
N
OMe
Me
N
Me
S
Me
S
S
N
Me
Me
N
N
Me
2d, 81%
2a, 84%
2c, 72%
3b, 93%
3c, 86%
3a, 89%
2b, 56%
S
N
N
S
N
S
O
N
S
MeO
S
S
N
H3
C
O
O
Cl
O
O
O
Cl
CH3
2f, 78%
S
2e, 65%
2g, 70%
2h, 72%
S
Cl
N
Cl
Br
N
S
S
N
Cl
S
N
S
N
3e, 84%
3d, 56%
Cl
N
Cl
N
S
N
S
N
S
Cl
2i, 80%
2k, 61%
2j, 74%
2l, 62%
Br
F
Br
F
S
S
S
S
N
S
N
S
N
F
S
F
Br
F
N
N
N
N
F
F
3f, 85%
3g, 90%
2p, 63%
2m, 66%
2n, 78%
3h, 77%
2o, 42%
N
S
N
S
N
S
S
N
S
N
S
N
S
F3
C
I
S
N
S
S
S
Br
F3
C
S
2s, 68%
N
2t, 65%
N
2q, 54%
2r, 83%
N
3i, 88%
3j, 43%
3k, 91%
S
N
S
S
N
Ph
aReaction conditions: Isothiazole (2, 0.5 mmol), Pd(OAc)2 (10 mol%),
1,10-phenanthroline (10 mol%), Ag2CO3 (1.0 mmol), K2CO3 (1.0
mmol) in toluene (1 mL) at 130 oC for 24 h; bIsolated yield.
N
S
S
S
N
N
2w, 43%
2u, 56%
2v, 61%
2x, 41%
aReaction conditions: Alkene (1, 1.0 mmol), NH4I (2.0 mmol),
EtOCS2K (1.2 mmol), H2O (1.0 mL) in DMSO (2.0 mL) at 130 oC for 24
h; bIsolated yield.
2 | J. Name., 2015, 00, 1-3
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S
N
Scheme 4. Control experiments
View Article Online
O
DOIC:H130.1053a9, 8/9D% 0CC01100B
NH4I (3 equiv.), EtOH (0.5 mL)
(a)
O
2g
DMSO (2.5 mL), 126 oC, 24h
CH3
SMe
2a, 1 mmol
EtOCS2K (2 equiv.), NH4I (2 equiv.)
S
S
S
2a, 76%
2a, n. r
(b)
(c)
SMe
DMSO (2 mL), H2O (1 mL), 130 oC, 24h
N
N
N
2x
CH3
N
5a, 0.5 mmol
S
S
N
NH4I (2 equiv.)
SMe
DMSO (2 mL), H2O (1 mL), 130 oC, 24h
CH3
S
5a, 0.5 mmol
N
3k
Although the mechanism was difficult to clarify, the present
reaction likely proceeded through the proposed mechanism shown
in Scheme 5.[11c, 14] Initially, HI and NH3 form through the thermal
decomposition of NH4I, which can then react with DMSO to liberate
I2.[19] I2 subsequently liberates an iodine radical (I•), which activates
EtOCS2K to afford Z-S• with a simultaneous release of electrons. In
this process, the Z-S• representing any sulfur radical in the medium,
such as xanthate and sulfide, etc.[13e] The addition of Z-S• to α-
methylstyrene 1 gives intermediate alkyl radical A, which undergoes
further single-electron oxidation (SET) to afford intermediate
Figure 2. Molecular structures of 2g, 2x and 3K from Single-Crystal
X-ray diffraction analysis
As 4-substituted isothiazoles contain two active C–H bonds (C3–H
and C5–H bonds), they can undergo further selective
functionalization. First, the 5-deuterio-4-phenylthiazole 2a-D were
prepared by base-catalyzed deuteration of 4-phenylthiazole in 84%
yields. Next, 4-phenylisothiazole underwent an electrophilic
substitution reaction with N-bromosuccinimide, with bromination
occurring selectively at the para-position of the benzene ring to
afford 4-(4-bromophenyl)isothiazole 2m in 87% yield. The
isothiazole group can be used as an electron donor to direct the
electrophilic substitution reaction to the para-position.
Furthermore, Pd/Ag was found to catalyze the reaction of 4-
phenylisothiazole 2a with iodobenzene through selective C5–H
activation to prepare 4,5-diphenylisothiazole products 4a in 65%
yield. Interestingly, the methoxy group substituted 4-(4-
methoxyphenyl)isothiazole and 5-iodo-1,2,3-trimethoxybenzene
can smoothly gave the design product 4-(4-methoxyphenyl)-5-
(3,4,5-trimethoxyphenyl)isothiazole 4b in 58% yields, which can as a
potential modulators of nuclear hormone receptor function.[1f] It is
important to note that the Pd-catalyzed Sonogashira coupling
reaction between 4-(4-iodophenyl)isothiazole 2r and 7-ethynyl-4,4-
dimethylthiochromane gave the corresponding 4-(4-((4,4-
dimethylthiochroman-7-yl)ethynyl)phenyl)isothiazole 2y in 85%
yield. Then, other terminal alkynyl-containing bioactive molecules
such as Erlotinib, Ethisterone and Mestranol, can reaction with 4-(4-
iodophenyl) isothiazole 2r gave corresponding products in good
yields, which are potential valuable in biological applications.
Scheme 3. Synthetic utilization
carbocation B.[20] Carbocation
B then gives alkenyl sulfur
intermediate C through α-H elimination reaction process that
follows Zaitsev’s rule.[21] Next, intermediate C undergoes iodine
radical substitution to give allyl iodine intermediate D, followed by
nucleophilic substitution with NH3 to give allylamine E. Next, 2,3-
dihydroisothiazole F is obtained by reaction with base. Subsequent
aromatization of 2,3-dihydroisothiazole
corresponding isothiazole 2.
F
furnishes the
Scheme 5. Plausible mechanism
(1)
NH4
I
NH3
+
HI
DMS
+
DMSO
2HI
(2)
(3)
I2
+
H2O
+
S
C
S
C
+
I2
EtOCS2
K
Z
S
EtO
S
S
OEt
Ar
S
Z
S
Ar
CH3
N
1
2
S
Z
Ar
CH3
S
Ar
A
NH
SET
F
HZ
Z
S
Ar
Z
B
CH3
S
B
Ar
NH2
H+
E
S
NH3
Z
Ar
S
I2
D
CH3
Z
Ar
S
C
S
N
X
CH3ONa (1.5 eq)
CH3OD
R= H, NXS (1.2 eq)
I
N
DMF, 80 oC, 8h
OMe
D
HI
2m, X = Br, yield: 87%
2r, X = I, yield: 76%
OMe
OMe
2a-D, 84%
In conclusion, we have developed a new and efficient protocol
for the synthesis of 4-substituted isothiazoles starting from
commercially available isopropene derivatives, NH4I, and EtOCS2K,
achieving excellent chemoselectivity and good functional group
tolerance in moderate to good yields. Based on this efficient
synthesis of 4-substituted isothiazoles, the C5-selective oxidative
dimerization of 4-substituted isothiazoles has been achieved for the
first time using a Pd and Ag catalyst and 1,10-phenanthroline as
ligand. With further development, these reaction could potentially
provide an efficient route to 5,5'-bisisothiazoles and 4,5-isothiazoles
in good yields. Efforts are currently underway to further elucidate
the detailed reaction mechanism and explore the synthetic
usefulness of these compounds in advanced materials.
Iodobenzene (1.5 eq)
Pd(OAc)2 (10 mol%)
1, 10-Phen(10 mol%)
S
5-Iodo-1,2,3-trimethoxybenzene (1.5 eq)
Pd(OAc)2 (10 mol%), 1, 10-Phen(10 mol%)
R
N
S
N
S
N
Ag2CO3 (20 mol%), K2CO3 (1 eq)
m-xylene, 130 oC, 24h
Ag2CO3 (20 mol%), K2CO3 (1 eq.)
m-xylene, 130 oC, 24h
0.5 mmol
4b, yield: 58% [1f]
OMe
4a, yield: 65%
N
R = 4-I, terminal alkyne (1.3 eq)
PdCl2(PPh3 2 (10 mol%)
N
O
S
S
OMe
OMe
)
S
N
CuI (5 mol%), CH3CN, NEt3
50 oC, 12h
N
O
CH3
CH3
NH
2z, yield: 77%
2y, yield:85%
N
S
S
S
MeO
2aa, yield: 92%
O
N
N
OH
OH
CH3
2ab, yield: 83%
CH3
CH3
2ac, yield: 86%
To explore the plausible mechanism of the annulation reaction, a
series of control experiments were performed (Scheme 4). First,
since α-methylstyrene (1a) could react with DMSO under the NH4I
and be converted to methyl(2-phenylprop-1-en-1-yl)sulfane 5a in
89% yields, respectively, they were considered to be possible
reaction intermediates.[19c] When sulfane 5a and EtOCS2K were
reacted under standard conditions, the reaction gave 4-
phenylisothiazole 2a in 76% yields (Scheme 4b). The reaction did
not occur in the absence of EtOCS2K (Scheme 4c).
Conflicts of interest
There are no conflicts to declare.
This journal is © The Royal Society of Chemistry 20xx
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S. Y. Wang, S. J. Ji, J. Org. Chem. 2018, 83, 10281; (d) G.
Acknowledgements
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The authors thank the Foundation of the Department of
Education of Guangdong Province (2017KZDXM085,
2018KZDXM070 and 2019KZDXM052), Science Foundation for
Young Teachers of Wuyi University (2019td06) for financial
support.
Notes and references
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4 | J. Name., 2015, 00, 1-3
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DOI: 10.1039/D0CC01100B
TOC：
The use of EtOCS2k enabled the annulation of isopropene derivatives with NH4I,
affording various 4-substituted isothiazoles in good yields.
R
NH4I
H
S
N
KS
S
S
Pd(OAc)2
Ag2CO3
DMSO
130 o
+
OEt
N
C
N
S
R
R
CH3
R
11 examples
Up to 93% yield
24 examples
Up to 84% yield