Facile Synthesis of 2,5-Disubstituted Thiazoles from Terminal Alkynes, Sulfonyl Azides, and Thionoesters

Article abstract of DOI:10.1021/acs.orglett.5b00960

A sequential procedure for the synthesis of 2,5-disubstituted thiazoles from terminal alkynes, sulfonyl azides, and thionoesters is reported. A copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes with sulfonyl azides affords 1-sulfonyl-1,2,3-triazoles, which then react with thionoesters in the presence of a rhodium(II) catalyst. The resulting 3-sulfonyl-4-thiazolines subsequently aromatize into the corresponding 2,5-disubstituted thiazoles by elimination of the sulfonyl group. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b00960

Letter
pubs.acs.org/OrgLett
Facile Synthesis of 2,5-Disubstituted Thiazoles from Terminal
Alkynes, Sulfonyl Azides, and Thionoesters
Tomoya Miura,* Yuuta Funakoshi, Yoshikazu Fujimoto, Junki Nakahashi, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510, Japan
S
* Supporting Information
ABSTRACT: A sequential procedure for the synthesis of 2,5-
disubstituted thiazoles from terminal alkynes, sulfonyl azides, and
thionoesters is reported. A copper(I)-catalyzed 1,3-dipolar cyclo-
addition of terminal alkynes with sulfonyl azides affords 1-sulfonyl-
1,2,3-triazoles, which then react with thionoesters in the presence of a
rhodium(II) catalyst. The resulting 3-sulfonyl-4-thiazolines sub-
sequently aromatize into the corresponding 2,5-disubstituted thiazoles by elimination of the sulfonyl group.
thiazole ring represents a privileged structural motif often
found in natural products and pharmaceutically active
electrophilic carbene carbon and a nucleophilic imino nitrogen in
the molecule. They act as the 1,3-dipoles in a formal sense in the
reactions with a variety of dipolarophiles, which include
alkynes,11 allenes,12 nitriles,13 aldehydes and imines,14 isocya-
nates and isothiocyanates,15 and indoles,16 affording the
corresponding [3 + 2] cycloadducts. In the present study, we
examined if thionoesters could serve as the suitable dipolar-
ophiles.17 First, we prepared O-methyl benzothioate (2a) from
methyl benzoate and the Lawesson’s reagent according to a
literature procedure.18 Then, 4-phenyl-1-tosyl-1,2,3-triazole (1a,
1.0 equiv) was treated with 2a (1.5 equiv) in the presence of
(tBuCO2)4Rh2 (2.0 mol %) and 4 Å molecular sieves (MS)19 in
chloroform (2 mL) at 70 °C (eq 1). The triazole 1a was
A
substances.1 Moreover, thiazoles multisubstituted with aryl
groups are core components constituting materials of interesting
optical2 and electronic properties.3 The condensation reaction of
α-halocarbonyl compounds with thioamides, named Hantzsch
thiazole synthesis, is the most widely used and reliable procedure
for their preparation.4 However, 2,5-disubstituted thiazoles are
less accessible with the Hantzsch thiazole synthesis5 because
chemically labile α-haloaldehydes are required for their synthesis.
An alternative method to synthesize those substituted thiazoles is
given by palladium-catalyzed C−H arylation reactions of
thiazoles with aryl halides, in which an aryl substituent is
installed onto a preformed thiazole core.6 On the other hand, the
synthetic methods to directly construct thiazole skeletons
possessing 2,5-disubstituents from easily available simple starting
substances are still limited.7,8 We now report a facile method to
synthesize 2,5-disubstituted thiazoles from terminal alkynes,
sulfonyl azides, and thionoesters (Figure 1). The transformation
consumed in 1 h, and after chromatographic purification using
modified silica gel, 2,5-diphenyl-2-methoxy-3-tosyl-4-thiazoline
(3a) was obtained in 91% isolated yield. The structure of 3a was
confirmed by its single-crystal X-ray analysis. The thiazoline 3a
was labile under acidic conditions to readily aromatize by
elimination of a sulfonyl group. Thus, when acidic silica gel was
directly added to the reaction mixture containing 3a, elimination
of methyl 4-methylbenzenesulfonate occurred to afford 2,5-
diphenylthiazole (4a) in 87% yield based on 1a (eq 2). 1-Mesyl-
Figure 1. Construction of 2,5-disubstituted thiazoles.
consists of two catalytic reactions; a copper(I)-catalyzed 1,3-
diploar cycloaddition of terminal alkynes with sulfonyl azides9
and a rhodium(II)-catalyzed reaction of the resulting 1-sulfonyl-
1,2,3-triazoles with thionoesters.
Recently, 1-sulfonyl-1,2,3-triazoles have received much
attention as the precursors of α-imino metal carbene
complexes.10 The generated carbene complex possesses an
Received: April 2, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00960
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Letter
substituted triazole 1b also reacted well with 2a to give a slightly
better yield of 4a (90%).
A plausible mechanism for the production of the thiazole 4a
from 1-sulfonyl-1,2,3-triazole 1 and O-methyl benzothioate (2a)
is depicted in Scheme 1. Initially, a reversible ring−chain
(entry 9), n-propyl-substituted triazole 1l afforded the product
4k in 49% yield, probably due to a 1,2-hydride shift occurring
with the rhodium carbene complex (entry 10).21
A diverse array of thionoesters was also readily prepared from
the corresponding carboxylic esters by the reaction with the
Lawesson’s reagent, and they were reacted with the triazole 1b
(Scheme 2). 2-Aryl-5-phenylthiazoles 4l−t were obtained in
Scheme 1. Proposed Mechanism for the Formation of
Thiazole 4a
Scheme 2. Rh(II)-Catalyzed Reaction of 1b with Various O-
a
Alkyl Thioates 2
tautomerization of 1 generates α-diazoimine 1′, which reacts
with rhodium(II) to afford α-imino rhodium carbene complex A
with extrusion of molecular nitrogen. The sulfur of 2a attacks the
electrophilic carbene center of A to furnish zwitterionic
intermediate B.20 The anionic rhodium releases an electron
pair, which induces the addition of the imino nitrogen to the
carbon of the oxonium ion, forming a five-membered ring. The
resulting 4-thiazoline 3 readily aromatizes upon treatment with
acidic silica gel by elimination of methyl sulfonate to give the
thiazole 4a.
A variety of triazoles 1 were subjected to the sequential
reaction with O-methyl benzothioate (2a) (Table 1). Triazoles
Table 1. Rh(II)-Catalyzed Reaction of Various Triazoles 1
a
with 2a
a
b
On a 0.20 mmol scale. TsOH·H2O was used instead of SiO2.
yields ranging from 58% to 99%. Styryl-substituted thionoester
was also effectively converted into the product 4u in 86% yield. In
the case of alkyl-substituted thionoesters, the aromatization
process from intermediate 4-thiazolines was slightly more
sluggish to afford the products 4v and 4w in moderate yields.
The synthetic usefulness of the present reaction was
demonstrated by its successful integration into a one-pot
procedure which directly started from readily available terminal
alkynes 5 (Table 2). First, a solution of 5 (1.0 equiv), mesyl azide
(1.0 equiv), and CuTC (5.0 mol %) in chloroform was stirred for
8 h at room temperature, generating 1-mesyl-substituted
triazoles 1. Second, thionoesters 2 (1.5 equiv) and
(tBuCO2)4Rh2 (2.0 mol %) were added to the same vessel,
which was then heated at 70 °C for 1 h. Finally, acidic silica gel
was added to the reaction mixture to promote deprotective
aromatization. The corresponding thiazoles 4 were obtained in
overall yields ranging from 80% to 85%. Thus, the rhodium-
catalyzed annulation reaction in the second step was barely
interupted by the copper catalyst employed in the first step. This
one-pot procedure saves a significant amount of time and
solvents for a workup/purification procedure.22
a
b
c
On a 0.20 mmol scale. Isolated yield. Ts-substituted triazole 1l and
2a (5.0 equiv) were used.
1c−i, possessing an aryl group at the 4-position, afforded the
corresponding thiazoles 4b−h in yields ranging from 67% to 96%
(entries 1−7). Notably, the aryl group tolerates a halogen atom
and a boryl group as the substituents, although the produced
halo- and boryl-substituted thiazoles are difficult to synthesize
with the previously reported palladium-catalyzed C−H arylation
reactions of thiazoles.6 Whereas 1-cyclohexenyl-substituted
triazole 1k successfully participated in the sequential reaction
The one-pot procedure was applied to steroidal substrate 6a
and δ-tocopherol-derived substrate 6b (eqs 3 and 4). The
B
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Letter
Table 2. One-Pot Synthesis of Thiazoles 4 Starting from
a
Terminal Alkynes
a
b
On a 0.20 mmol scale. Isolated yield.
corresponding thiazolyl-substituted derivatives 4x and 4y were
successfully obtained in 64% and 57% overall yields based on the
starting terminal alkynes 6a and 6b.
Quinque(arylene) 12 having a different array of two thiazole
and three benzene rings was also synthesized (eq 7). Initially, 5-
(4-iodophenyl)thiazole 10 was prepared from 5e and 2c, and
then a terminal ethynyl group was introduced on the phenyl ring
by a palladium-catalyzed coupling reaction,24 forming 11. The
second thiazole formation was carried out using 11 and 2c to
produce the quinque(arylene) 12.
Derivatization of the obtained thiazole was exemplified in eq 5.
When the palladium(0)-catalyzed conditions developed by
Quinque(thiophene/thiazole) oligomers could be efficiently
synthesized based on the present thiazole synthesis. The triazole
1m was prepared from 2-ethynylthiophene 5f and mesyl azide.
Then, thiophene-2,5-bis(carbothioate) 2d (0.1 mmol) was
reacted with 1m (0.2 mmol). Double annulation took place to
afford symmetrical quinque(thiophene/thiazole) oligomer 13 in
72% yield (eq 8).
Larock23 were applied to o-bromophenyl-substituted thiazole
4f, the carbonylative cyclization reaction took place to give 4H-
indeno[2,1-d]thiazole-4-one 7.
The terminal alkyne-based thiazole synthesis was further
extended to an iterative procedure for the synthesis of linear
oligomeric arylene compounds. For example, the ethynyl-
substituted benzothioate 2b presents a useful building block
for the iterative procedure (eq 6). The first thiazole formation
from 5d and 2b was carried out in a stepwise manner to furnish
ter(arylene) 8 possessing a terminal ethynyl group. Next, the
terminal ethynyl group of the ter(arene) 8 was utilized for the
second thiazole formation with 4-hexylbenzothioate 2c to
produce the quinque(arylene) 9 consisting of two thiazole and
three benzene rings.
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(4) For reviews, see: (a) Riego, E.; Hernan
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In summary, we have demonstrated that thionoesters can act
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2,5-disubstituted thiazoles starting from terminal alkynes. This
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S
* Supporting Information
Experimental procedures, spectral data for the new compounds,
and details of the X-ray analysis (CIF). The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.orglett.5b00960.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: tmiura@sbchem.kyoto-u.ac.jp.
*E-mail: murakami@sbchem.kyoto-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Y. Nagata (Kyoto University) for his kind help in
the X-ray analysis. This work was supported by MEXT (Scientific
Research (B)) and JST (ACT-C). Y. Funakoshi thanks the JSPS
for Yong Scientists for a Research Fellowship.
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DOI: 10.1021/acs.orglett.5b00960
Org. Lett. XXXX, XXX, XXX−XXX