Synthesis of Isothiazole via the Rhodium-Catalyzed Transannulation of 1,2,3-Thiadiazoles with Nitriles

Article abstract of DOI:10.1021/acs.orglett.6b02499

A synthetic method for obtaining a wide variety of isothiazoles by the Rh-catalyzed transannulation of 1,2,3-thiadiazoles with alkyl, aryl, and heteroaryl nitriles, which proceeds via an α-thiavinyl Rh-carbenoid intermediate, was developed. The results suggest that during its reaction with nitriles, the α-thiavinyl carbene acts as an umpolung 1,3-dipole equivalent, in contrast to its behavior during its reaction with alkynes. The developed method was successfully employed to synthesize pentaoligomeric arylene compounds consisting of three benzene and two isothiazole rings.

Full text of DOI:10.1021/acs.orglett.6b02499

Letter
pubs.acs.org/OrgLett
Synthesis of Isothiazole via the Rhodium-Catalyzed Transannulation
of 1,2,3-Thiadiazoles with Nitriles
Boram Seo, Ya Gob Kim, and Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 24341, Republic of Korea
S
* Supporting Information
ABSTRACT: A synthetic method for obtaining a wide variety of isothiazoles by the Rh-catalyzed transannulation of 1,2,3-
thiadiazoles with alkyl, aryl, and heteroaryl nitriles, which proceeds via an α-thiavinyl Rh-carbenoid intermediate, was developed.
The results suggest that during its reaction with nitriles, the α-thiavinyl carbene acts as an umpolung 1,3-dipole equivalent, in
contrast to its behavior during its reaction with alkynes. The developed method was successfully employed to synthesize
pentaoligomeric arylene compounds consisting of three benzene and two isothiazole rings.
Scheme 1. 1,3-Dipole Equivalents Generated from Triazoles
and Thiadiazoles
ecause isothiazoles are valuable structural motifs found in
Bmany natural products, pharmaceutical compounds, and
functional materials,1 streamlined methods for their synthesis
from readily available compounds must be developed.2
Recently, N-sulfonyl-1,2,3-triazoles were easily prepared from
1-alkynes and N-sulfonyl azides and employed as convenient α-
imino carbene precursors.3 This study demonstrated that the α-
imino carbene acts as a 1,3-dipole equivalent in transannulation
reactions with unsaturated compounds. Thus, the trans-
annulation of N-sulfonyl-1,2,3-triazoles has become a valuable
approach for synthesizing a wide variety of five-membered
heterocycles (Scheme 1a).4 More recently, the Rh-catalyzed
transannulation of 1,2,3-thiadiazoles with alkynes was reported
to give thiophenes with high regioselectivity via an α-thiavinyl
carbene (Scheme 1b).5 These results indicate that the carbene
carbon in the generated complex is electrophilic and the α-
thiavinyl sulfur is nucleophilic. Accordingly, it was hypothesized
that a Rh catalyst could be used in the transannulation of
thiadiazoles with nitriles to obtain thiazoles. However, no
thiazoles were observed, and isothiazoles were unexpectedly
produced instead, indicating that the carbene carbon is
nucleophilic and the α-thiavinyl sulfur is electrophilic. These
results suggest that the α-thiavinyl carbene acts as an umpolung
1,3-dipole equivalent when reacting with a nitrile, in contrast to
its reaction with an alkyne. Herein, we report for the first time
new 1,3-dipole equivalents generated from thiadiazoles in the
presence of a Rh catalyst and a method for synthesizing a wide
variety of isothiazoles by the Rh-catalyzed transannulation of
1,2,3-thiadiazoles with alkyl, aryl, and heteroaryl nitriles via an
α-thiavinyl Rh-carbenoid intermediate (Scheme 1c).
product was not detected (entry 1). Rh2(esp)2 was also unable
to catalyze the transannulation reaction (entry 2). However,
Rh(PPh3)3Cl and the [Rh(COD)Cl]2 (2 mol %) and DPPF (5
mol %) system gave the transannulation product in 66% (entry
3) and 80% (entry 4) yields, respectively. Lower yields were
achieved with the Ph3P, DPPE, XantPhos, and DPEPhos
ligands than with DPPF (entries 5−8). The highest trans-
Initially, the transition metal-catalyzed transannulation of
ethyl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1a) with benzo-
nitrile (2a) was examined (Table 1). When 1a was reacted with
2a in the presence of [Ir(COD)Cl]2 (2 mol %) and DPPF (5
mol %) in chlorobenzene at 130 °C for 1 h, the transannulation
Received: August 20, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02499
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a
a
Table 1. Reaction Optimization
Scheme 2. Nitrile Substrate Scope
b
entry
1
cat. (mol %)
ligand (mol %)
yield (%)
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
[Ir(COD)Cl]2 (2)
Rh2(esp)2 (2)
DPPF (5)
DPPF (5)
DPPF (5)
DPPF (5)
PPh3 (10)
DPPE (5)
XantPhos (5)
DPEPhos (5)
DPPF (12)
DPPF (12)
0
0
3
Rh(PPh3)3Cl (2)
[Rh(COD)Cl]2 (2)
[Rh(COD)Cl]2 (2)
[Rh(COD)Cl]2 (2)
[Rh(COD)Cl]2 (2)
[Rh(COD)Cl]2 (2)
[Rh(COD)Cl]2 (5)
[Rh(COD)Cl]2 (5)
3aa
3aa
66
80
0
4
5
6
0
7
0
8
3aa
3aa
3ba
14
c
9
99 (99)
c
10
90 (89)
a
Reaction conditions: 1 (0.2 mmol), 2a (2 mmol), the catalyst (2−5
mol %) and the ligand (5−12 mol %) were reacted at 130 °C for 1 h in
chlorobenzene under N2. NMR yield using CH2Br2 as an internal
standard. Isolated yields.
b
c
a
1a (0.2 mmol), 2 (2 mmol), [Rh(COD)Cl]2 (5 mol %), and DPPF
b
c
(12 mol %) were reacted at 130 °C for 1 h. 0.4 mmol of 2. 1 mmol
of 2. After 1a (0.2 mmol) was reacted with 2 (2 mmol) in the
d
presence of [Rh(COD)Cl]2 (2.5 mol %) and DPPF (6 mol %) at 130
°C for 1 h, more [Rh(COD)Cl]2 (2.5 mol %) and DPPF (6 mol %)
were added to the reaction mixture, which was then stirred at 130 °C
for 1 h.
annulation product yield, which was quantitative, was obtained
with [Rh(COD)Cl]2 (5 mol %) and DPPF (12 mol %) in
chlorobenzene at 130 °C for 1 h (entry 9). The product was
initially expected to be the thiazole 4aa. However, after 1b was
reacted with 2a in the presence of [Rh(COD)Cl]2 (5 mol %)
and DPPF (12 mol %), X-ray crystallography revealed that the
product was the isothiazole 3ba (89%). The catalyst, solvent,
and stoichiometry of the reaction of 1a with 2a were optimized
as shown in the Supporting Information.
(6.0 mol %) to the reaction mixture twice; see the Supporting
Information) increased the 3al yield to 68%. Likewise, although
it was sterically hindered, 2-methylbenzonitrile (2k) reacted
with 1a under the modified conditions to give the desired
isothiazole 3ak in 50% yield. 4-Methylbenzonitrile (2m) and 4-
methoxybenzonitrile (2n) were smoothly converted to 3am
and 3an, respectively, in quantitative yields. To examine the
scope and limitations of this method, the transannulation of 1a
with aliphatic nitriles was performed under the optimized
conditions. Transannulation with acetonitrile (2o), butyroni-
trile (2p), and 4-phenylbutyronitrile (2q) led to the
corresponding products 3ao, 3ap, and 3aq, respectively, in
good to excellent yields (73−93%). However, isobutyronitrile
(2r) was less reactive due to steric effects. Remarkably,
heterocyclic nitriles, such as 2-cyanopyridine and 2-thiophe-
neacetonitrile, reacted with 1a to give 3as in 94% yield and 3at
in 83% yield, respectively. Furthermore, benzoyl cyanide and
ethyl cyanoformate were converted to the desired products 3au
(95%) and 3av (72%), respectively, via the Rh-catalyzed
transannulation reaction. Cyanosulfoximines with 3-methyl and
3-chloro substituents on the phenyl ring (2w and 2x,
respectively) were transannulated to afford the desired
isothiazoles 3aw (97%) and 3ax (68%), respectively. To
demonstrate the feasibility of applying this method on a larger
scale, 1.0 g (4.3 mmol) of ethyl 5-phenyl-1,2,3-thiadiazole-4-
carboxylate (1a) was reacted with benzonitrile (2a) under the
optimized conditions to give the desired isothiazole 3aa (1.2 g,
3.8 mmol) in 88% yield, which is comparable to that obtained
in the small-scale experiment.
Next, ethyl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1a) was
reacted with several aromatic and aliphatic nitriles (2) to
demonstrate the scope and efficiency of this Rh-catalyzed
transannulation reaction (Scheme 2). Although 2-fluorobenzo-
nitrile (2b) was transannulated to 3ab in only 57% yield due to
steric hindrance, 4-fluorobenzonitrile (2c) was smoothly
converted to the corresponding isothiazole (3ac) in quantita-
tive yield. Transannulation with 3- and 4-chlorobenzonitriles
(2d and 2e, respectively) was also possible, leading to the
corresponding isothiazoles (3ad and 3ae, respectively) in
excellent yields. Cyclization with 4-bromobenzonitrile (2f) and
3-iodobenzonitrile (2g) gave the isothiazoles 3af and 3ag,
respectively, in quantitative yields. Transannulation with a
benzonitrile (2h) bearing a labile acetyl group proceeded
smoothly to afford 3ah in 98% yield. The monoisothiazole 3ai
was selectively obtained in 95% yield from 1,4-dicyanobenzene
(2i) under the optimized reaction conditions. The benzonitrile
(2j) with the strongly electron-withdrawing 4-nitro group gave
the desired product 3aj in moderate yield. However, because
benzonitriles with electron-donating groups, such as methyl and
methoxy groups, are less reactive, the reaction conditions were
slightly modified. Although 3-methylbenzonitrile (2l) reacted
with 1a to produce the desired isothiazole 3al in 54% yield
under the optimized conditions, modifying the reaction
conditions (adding the Rh catalyst (2.5 mol %) and DPPF
B
DOI: 10.1021/acs.orglett.6b02499
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Based on these results, a wide range of thiadiazoles (1) were
transannulated with benzonitrile (2a), 4-bromobenzonitrile
(2f), and 1,4-dicyanobenzene (2i) (Scheme 3). Ethyl 5-aryl-
Scheme 4. Competition Experiments between Various
Benzonitriles
a
a
Scheme 3. Thiadiazole Substrate Scope
a
1 (0.2 mmol), 2 (nitrile, 0.4 mmol each), [Rh(COD)Cl]2 (5 mol %),
b
and DPPF (12 mol %) were reacted at 130 °C for 1 h. NMR yield
using CH2Br2 as an internal standard.
production of the isothiazoles 3af in quantitative yield. In the
benzonitrile and butyronitrile competition experiment, the
isothiazole 3aa produced by transannulation with benzonitrile
was the major product (entry 3).
After many isothiazoles 3 were efficiently synthesized in this
study, oligomeric arylene compounds consisting of benzene and
isothiazole rings were prepared using the developed reaction.
For example, the isothiazole 3ai produced by the trans-
annulation of ethyl 5-phenyl-1,2,3-thiadiazole-4-carboxylate
(1a) with 1,4-dicyanobenzene (1i) was further reacted with
1a to give the (benzene/isothiazole) pentaoligomer 5a(ai) in
82% yield under the modified optimum conditions (Scheme
5a). Pentaoligomers with a different connectivity of nitrogen
a
1 (0.2 mmol), 2 (2 mmol), [Rh(COD)Cl]2 (5 mol %), and DPPF
b
c
(12 mol %) were reacted at 130 °C for 1 h. 1 mmol of 2. After 1 (0.2
mmol) was reacted with 2 (2 mmol) in the presence of [Rh(COD)-
Cl]2 (2.5 mol %) and DPPF (6 mol %) at 130 °C for 1 h, more
[Rh(COD)Cl]2 (2.5 mol %) and DPPF (6 mol %) were added to the
reaction mixture, which was then stirred at 130 °C for 1 h.
Scheme 5. Synthesis of Pentaoligomeric Arylene
Compounds
1,2,3-thiadiazole-4-carboxylates with an electron-withdrawing
bromo group or electron-donating methyl or methoxy group on
the aryl ring efficiently reacted with 2a, providing the desired
isothiazoles 3ba, 3ca, and 3da, respectively, in good to excellent
yields (89−99%) under the optimized conditions. The
transannulation of the thiadiazole 1b with 1,4-dicyanobenzene
(2i) produced the corresponding isothiazole 3bi in quantitative
yield. The thiadiazoles with a 2-thienyl and methyl group at R2
were also converted to the desired isothiazoles 3ea and 3fa in
excellent yields. Diethyl 1,2,3-thiadiazole-4,5-dicarboxylate (1g)
was also transannulated by the developed reaction to afford the
isothiazole 3ga in 78% yield. When the thiadiazole 1h was
employed in the reaction with 4-bromobenzonitrile (2f), the
corresponding isothiazole 3hf was obtained in 83% yield. When
4,5-diphenyl-1,2,3-thiadiazole (1i) was reacted with 2a and 2f,
the corresponding isothiazoles 3ia and 3if were obtained in
94% and 91% yields, respectively.
Competition experiments between various aryl and alkyl
nitriles were also performed (Scheme 4). Ethyl 5-phenyl-1,2,3-
thiadiazole-4-carboxylate (1a) was simultaneously reacted with
4-methoxybenzonitrile and 4-chlorobenzonitrile (2 equiv each),
which resulted in the formation of the isothiazoles 3ae as the
major product, indicating that the electron-deficient aryl nitrile
is more reactive than the electron-rich aryl nitrile. Similarly,
simultaneous transannulation with 4-methoxybenzonitrile and
4-bromobenzonitrile (2 equiv each) resulted in the selective
and sulfur bond in two isothiazole rings were also synthesized
(Scheme 5b). When 1,4-di(thiadiazolyl)benzene 1j was reacted
with 3-iodobenzonitrile (2g), the desired penta(arylene) 3jg
consisting of three benzene and two isothiazole rings was
obtained in 68% yield. The structures of 3ja and 3jf were
confirmed by X-ray crystallography (see the Supporting
Information).
A possible reaction mechanism for the transannulation of
thiadiazole 1 with nitrile 2 is proposed in Scheme 6. First, a
reversible ring−chain tautomerization of thiadiazole 1 affords
the α-diazo thiocarbonyl A. The α-thiavinyl Rh-carbenoid B is
subsequently generated from the denitrogenation of A with
C
DOI: 10.1021/acs.orglett.6b02499
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Scheme 6. Possible Mechanism
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: phlee@kangwon.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a National Research Foundation
(NRF) of Korea grant funded by the Korean government
(MSIP) (2011-0018355) and 2015H1C1A1035955. We also
thank Prof. Kang Mun Lee (KNU) for X-ray analyses.
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dipole equivalent in its reaction with nitriles, in contrast to its
transannulation with alkynes. This method was employed to
efficiently synthesize pentaoligomeric arylene compounds
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02499.
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Experimental procedures, characterization data, X-ray
crystallography data (3ba, 3ja, and 3jf) (PDF)
Crystallography data for 3ja (CIF)
Crystallography data for 3jf (CIF)
Crystallography data for 3ba (CIF)
NMR spectra of all the products (ZIP)
D
DOI: 10.1021/acs.orglett.6b02499
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