Thiazolobenzyne: A versatile intermediate for multisubstituted benzothiazoles

Article abstract of DOI:10.1039/c6cc05112j

Thiazolobenzyne, which is a benzyne species fused with a thiazole ring, was efficiently generated via an iodine-magnesium exchange reaction of an ortho-iodoaryl triflate-type precursor using a trimethylsilylmethyl Grignard reagent as an activator. A wide range of arynophiles reacted efficiently with the thiazolobenzynes generated by this method to afford various multisubstituted benzothiazoles.

Full text of DOI:10.1039/c6cc05112j

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. Yoshida, T.
Yano, Y. Nishiyama, Y. Misawa, M. Kondo, T. Matsushita, K. Igawa, K. Tomooka and T. Hosoya, Chem.
Commun., 2016, DOI: 10.1039/C6CC05112J.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemcomm

Page 1 of 5
ChemComm
View Article Online
DOI: 10.1039/C6CC05112J
ChemCommun
RSCPublishing
COMMUNICATION
Thiazolobenzyne: A versatile intermediate for
multisubstituted benzothiazoles
Cite this: DOI: 10.1039/x0xx00000x
Suguru Yoshida,a Takahisa Yano,a Yoshitake Nishiyamaa, Yoshihiro Misawa,a
Masakazu Kondo,b Takeshi Matsushita,b Kazunobu Igawa,c Katsuhiko Tomookac and
Takamitsu Hosoya*a
Received 00th xxxxx 201x,
Accepted 00th xxxxx 201x
DOI: 10.1039/x0xx00000x
www.rsc.org/
Thiazolobenzyne, which is a benzyne species fused with a
thiazole ring, was efficiently generated via an iodine–
magnesium exchange reaction of an ortho-iodoaryl triflate-
type precursor using a trimethylsilylmethyl Grignard reagent
as an activator. A wide range of arynophiles reacted
efficiently with the thiazolobenzynes generated by this
method to afford various multisubstituted benzothiazoles.
Fig. 1 Various benzothiazole derivatives.
Benzothiazole is a heterocycle that is often contained as a core
skeleton in a wide range of molecules. These include natural products,
such as firefly luciferin, and imaging probes, such as Pittsburgh
compound B, which is used as a diagnostic agent for Alzheimer's
disease (Fig. 1).1 Despite the increasing importance of benzothiazoles,
methods for synthesizing multisubstituted benzothiazoles are limited.1
In accordance with our studies to develop selective protein kinase
inhibitors such as INDY and TG003,2 we faced a problem in preparing
multisubstituted benzothiazoles.
We assumed that the application of aryne chemistry could be one
of the solutions to address this issue because arynes are highly
reactive intermediates that are useful for synthesizing diverse
aromatic compounds (Fig. 2).3–9 These include ringꢀfused
multisubstituted arenes that are difficult to prepare using
conventional methods (Fig. 2A and 2B). In particular, the chemistry
of heterocyclic arynes, such as pyridynes and indolynes, has been
wellꢀstudied in recent years and a broad range of multisubstituted
heteroarenes has become readily accessible.6,7 We anticipated that
thiazoleꢀfused benzyne, i.e., thiazolobenzyne, could be a useful
intermediate for preparing multisubstituted benzothiazoles (Fig.
2C).9 However, despite the potential usefulness of thiazolobenzyne,
neither the generation nor the synthetic application of this species
has been reported. Moreover, we became interested in the reactivity
of thiazolobenzyne, particularly in the characteristic difference
Fig. 2 Thiazolobenzynes: new entries as ringꢀfused benzynes.
indolyne7 and 3,4ꢀcyclobutabenzyne,8 with various arynophiles have
been reported (Fig. 2B), we hypothesized that thiazolobenzynes also
react with arynophiles in a regioselective manner. Herein, we report
an efficient method for the generation of thiazolobenzynes and their
use in the synthesis of multisubstituted benzothiazoles.
As precursors for 6,7ꢀ and 4,5ꢀthiazolobenzynes, we chose orthoꢀ
iodoaryl triflates10 because they were expected to be easily
synthesized. Indeed, thiazolobenzyne precursors 1a and 1b with a 4ꢀ
fluorophenyl group at the 2ꢀposition (Scheme 1) were easily prepared
from the corresponding 6ꢀ and 4ꢀmethoxybenzothiazole, respectively.
For example, thiazolobenzyne precursor 1a was efficiently prepared
from 6ꢀmethoxybenzothiazole in three steps: orthoꢀiodination,
between thiazolo[5,4ꢀc]benzyne
I
(6,7ꢀthiazolobenzyne) and
thiazolo[4,5ꢀc]benzyne II (4,5ꢀthiazolobenzyne) (Fig. 2C). Because
regioselective reactions of 3,4ꢀringꢀfused arynes, such as 6,7ꢀ
This journal is © The Royal Society of Chemistry 201x
Chem. Commun., 201x, 00, 1-4 | 1

ChemComm
Page 2 of 5
View Article Online
COMMUNICATION
ChemCommun
DOI: 10.1039/C6CC05112J
demethylation, and triflylation.11 Our initial attempts showed that Table 2 Cycloadditions of 6,7ꢀthiazolobenzyne
generating thiazolobenzynes from these precursors via iodine–metal
exchange reaction triggered by treatment with an organometallic
reagent was possible (Scheme 1). However, these attempts also
indicated difficulty in achieving an efficient transformation via these
species. For example, the treatment of 1a with isopropylmagnesium
chloride–lithium chloride complex in the presence of 2,5ꢀ
dimethylfuran (2) in THF at −78 °C afforded the desired cycloadduct
3a only in low yield (Scheme 1A). After careful investigation of the Entry
products, we identified a side product 4, which was probably formed
via nucleophilic addition of THF to 6,7ꢀthiazolobenzyne. This result
Arynophile
Product
Yielda (%)
86
1
1a
1a
5
7
6
indicated the particularly high electrophilicity and instability of
thiazolobenzyne species. Similarly, the reaction using 4,5ꢀ
thiazolobenzyne precursor 1b under the same conditions afforded the
desired cycloadduct 3b in moderate yield (Scheme 1B).
2
t-Bu
96b
8
+
8’
N
O
(80:20)
Ph
70b,c,d
10
+
10’
3
1a
1a
9
(94:6)
73b
12
+
12’
4
11
(91:9)
Scheme 1 Initial attempts.
OMe
OMe
82e
1a
1c
13
9
14
15
5
Table 1 Optimization of reaction conditions
75b,c,f
(86:14)
6
aIsolated yields, unless otherwise noted. Ratio of regioisomers shown in
parentheses. bYields as a mixture of regioisomers. cYield based on 1H NMR
analysis. dThe major product was isolated in 66% yield. eRegioisomer was
not detected. fThe major product was isolated in 56% yield.
Entry
R–Mtl
nꢀBuLi
Temp. (°C)
−78
Yielda (%)
1
2
3
4
5
49
53
46
27
37
nꢀBuMgBr
iꢀPrMgCl
tꢀBuMgCl
PhMgBr
−78
Under optimized conditions, various ringꢀfused benzothiazoles
were efficiently prepared from 6,7ꢀthiazolobenzyne precursor 1a
(Table 2). The Diels–Alder reaction of 6,7ꢀthiazolobenzyne with Nꢀ
phenylpyrrole (5) (entry 1) and [2+3] and [2+2] cycloadditions with
a variety of arynophiles, such as nitrone 7, azides 9 and 11, and
ketene acetal 13, proceeded with high efficiencies (entries 2–5).
High regioselectivities observed in these cases indicated that the
most nucleophilic atom of the arynophiles predominantly attacked
the 6ꢀposition of 6,7ꢀthiazolobenzyne to form new bonds. The
structure of the major isomer of the triazoleꢀfused product 10 was
confirmed by Xꢀray crystallographic analysis.11 Notably, 6,7ꢀ
thiazolobenzyne bearing a bromo group at the 2ꢀposition was also
successfully generated from precursor 1c, leaving the organometallic
reagentꢀsusceptible bromo group intact, as demonstrated in the
reaction with azide 9 (entry 6). The obtained cycloadduct 15 would
be further transformed to various C2ꢀsubstituted benzothiazoles by
taking advantage of the C2ꢀbromo group, easily widening the
available benzothiazoles by this method.
−78
−78
−78
6
TMSCH2MgCl
−78
67
7
8
TMSCH2MgCl
TMSCH2MgCl
−30
0
85
91 (89)b
aYields based on 1H NMR analysis. bIsolated yields in parentheses.
To improve the efficiency of the reaction between 1a and 2, we aimed
for better conditions (Table 1). After extensive screening of activators,
the trimethylsilylmethyl Grignard reagent delivered the best result
among various organometallic reagents examined (entries 1–6). Similar
to our previous reports, the modest ability of the trimethylsilylmethyl
Grignard reagent for iodine–magnesium exchange due to its low
nucleophilicity must have contributed to the significant improvement of
the reaction efficiency via the generation of aryne species with
particularly high reactivity.5 Further improvement in the yield of
cycloadduct 3a was achieved by performing the reaction at higher
temperatures (entries 7 and 8); the best result was obtained when the
reaction was performed at 0 °C (entry 8).
The method was also applicable for the generation and
cycloaddition of 4,5ꢀthiazolobenzyne bearing an aryne triple bond
adjacent to the nitrogen atom (Table 3). Using the same conditions
for the generation of 6,7ꢀthiazolobenzyne from 1a, various ringꢀ
fused benzothiazoles were prepared from the 4,5ꢀthiazolobenzyne
2 | Chem. Commun., 201x, 00, 1-4
This journal is © The Royal Society of Chemistry 201x

Page 3 of 5
ChemCommun
ChemComm
View Article Online
COMMUNICATION
DOI: 10.1039/C6CC05112J
precursor 1b in high yields with high regioselectivities (entries 1–5).
Notably, the reaction of 2ꢀmethylꢀ4,5ꢀthiazolobenzyne, which was
generated from 1d, with azide 20 proceeded smoothly without
affecting the methyl and ester groups, demonstrating the mildness of
the reaction conditions (entry 6).
Table 3 Cycloadditions of 4,5ꢀthiazolobenzyne
Scheme 2 Addition of an amine to thiazolobenzynes. N =
piperidinyl.
Entry 1 Arynophile
Product
Yielda (%)
91
1
2
1b
1b
2
5
3b
16
78
t-Bu
17
+
17’
94b
(93:7)
N
3
4
5
1b
1b
1b
7
9
O
Ph
18
+
18’
85b
(87:13)
Scheme 3 Diversification of a simple thiazolobenzyne precursor.11
19
+
19’
94b
(89:11)
OMe
OMe
13
21
+
21’
93b
(77:23)
6
1d
20
aIsolated yields. Ratio of regioisomers shown in parentheses. bYields as a
mixture of regioisomers.
Generation of thiazolobenzyne from 1a or 1b in the presence of
piperidine (22) afforded 6ꢀ or 5ꢀpiperidinobenzothiazole, 23a or 24a,
respectively, as a major product, indicating that the addition of the
nucleophile predominantly proceeded at the 6ꢀ or 5ꢀposition of 6,7ꢀ
or 4,5ꢀthiazolobenzyne, respectively (Scheme 2). These results were
in good agreement with regioselectivities observed in cycloadditions
of thiazolobenzynes with unsymmetrical arynophiles (Table 2,
entries 2–5 and Table 3, entries 3–6).
Derivatization of a simple thiazolobenzyne precursor further
expanded the scope of synthesizable benzothiazole derivatives by
this method. For example, modification of the C2ꢀmethyl group of
4,5ꢀthiazolobenzyne precursor 1d via metalation and subsequent
reaction of generated carbanion III with an electrophile rendered
functionalized thiazolobenzyne precursors such as 1e and 1f easily
available (Scheme 3). Thiazolobenzynes bearing a hydroxy or styryl
group were efficiently generated from these precursors and reacted
successfully with an arynophile, demonstrating the synthetic utility
of this method.
Fig. 3 Computational studies using a DFT method (M11ꢀL/6ꢀ
31G(d)).11 (A) Optimized structures of 6,7ꢀthiazolobenzyne (Ia) and
4,5ꢀthiazolobenzyne (IIa). The numbers denotes the charge
distribution of Ia and IIa. (B) Analysis of the reaction pathway for
cycloadditions of Ia and IIa with methyl azide.
Theoretical studies based on density functional theory (DFT)
provided insights into the particularly high reactivity of
thiazolobenzynes and the regioselectivity observed in their reactions
with arynophiles (Fig. 3). Using the GAMESSꢀUS program package,12
we analyzed the geometric/electronic structures of thiazolobenzynes
and their reactivity with methyl azide at the M11ꢀL/6ꢀ31G(d) level of
the theory.11 Optimized geometry structures of thiazolobenzynes Ia
and IIa were in good agreement with those previously reported by
Paton, Houk, Garg, and coworkers;13 the calculated values of the
internal angles at C6 and C5 in the optimized structures of 6,7ꢀ
thiazolobenzyne (Ia) and 4,5ꢀthiazolobenzyne (IIa) were larger than
that of C7 and C4, respectively, indicating that the structures of these
arynes are highly distorted (Fig. 3A). Furthermore, population
This journal is © The Royal Society of Chemistry 201x
Chem. Commun., 201x, 00, 1-4 | 3

ChemComm
Page 4 of 5
View Article Online
COMMUNICATION
ChemCommun
DOI: 10.1039/C6CC05112J
analysis11,14 revealed that C6 of Ia and C5 of IIa are the more
electrophilic carbons. The considerable distortion of Ia bearing the
aryne triple bond adjacent to the sulfur atom can be attributed to the
electronic effect derived from the increased pꢀcharacter of the C–S
bond15 as well as the strain effect elicited by the fused ring, which is
similar to the case of cyclobutabenzyne proposed by Suzuki and
coworkers.8a For the case of IIa bearing the aryne triple bond adjacent
to the nitrogen atom, in addition to the strain effect, the
electronnegativity of the nitrogen atom must have contributed to
eliciting the distortion, as with the case of 6,7ꢀindolyne.7
Transition state (TS) structures for the cycloadditions of Ia and
IIa with methyl azide were obtained at the same level of the theory
(Fig. 3B). The difference in the calculated activation energies for the
distal cycloadditions via TS1 or TS3 was 2.1 or 0.4 kcal/mol less,
respectively, than the proximal cycloadditions via TS2 or TS4,
which was in good agreement with the observed selectivity (Table 2,
entry 3 vs Table 3, entry 4).
In summary, we have developed an efficient method for
generating thiazolobenzynes. The method has been applied to the
synthesis of various multisubstituted benzothiazoles. Further studies
to expand the scope of the method and its application to the synthesis
of bioactive compounds are now in progress.
The authors thank Dr. Hiroyuki Masuno at Tokyo Medical and
Dental University for HRMS analysis and Central Glass Co., Ltd. for
their generous gift of Tf2O. This work was supported by the Platform
for Drug Discovery, Informatics, and Structural Life Science from
MEXT and AMED, Japan; CREST from JST and AMED, Japan;
JSPS KAKENHI Grant Numbers 15H03118 (B; T.H.), 16H01133
(Middle Molecular Strategy; T.H.) and 26350971 (C; S.Y.); and the
Cooperative Research Program of "Network Joint Research Center
for Materials and Devices".
T. Hamura, Y. Chuda, Y. Nakatsuji and K. Suzuki, Angew. Chem., Int.
Ed., 2012, 51, 3368; (c) T. R. Hoye, B. Baire, D. Niu, P. H. Willoughby
and B. P. Woods, Nature, 2012, 490, 208; (d) S. Yoshida and T. Hosoya,
Chem. Lett., 2013, 42, 583; (e) S. Y. Yun, K.ꢀP. Wang, N.ꢀK. Lee, P.
Mamidipalli and D. Lee, J. Am. Chem. Soc., 2013, 135, 4668; (f) Y.
Nagashima, R. Takita, K. Yoshida, K. Hirano and M. Uchiyama, J. Am.
Chem. Soc., 2013, 135, 18730; (g) H. Yoshida, R. Yoshida and K.
Takaki, Angew. Chem., Int. Ed., 2013, 52, 8629; (h) Y. Sumida, T. Kato
and T. Hosoya, Org. Lett., 2013, 15, 2806; (i) S. Yoshida, K. Uchida and
T. Hosoya, Chem. Lett., 2014, 43, 116; (j) V. G. Pandya and S. B.
Mhaske, Org. Lett., 2014, 16, 3836; (k) Y. Sumida, R. Harada, T. Katoꢀ
Sumida, K. Johmoto, H. Uekusa and T. Hosoya, Org. Lett., 2014, 16
,
6240; (l) S. Yoshida, F. Karaki, K. Uchida and T. Hosoya, Chem.
Commun., 2015, 51, 8745; (m) M. Pawliczek, L. K. B. Garve and D. B.
Werz, Org. Lett., 2015, 17, 1716; (n) S. Yoshida, Y. Hazama, Y. Sumida,
T. Yano and T. Hosoya, Molecules, 2015, 20, 10131; (o) S. Yoshida, K.
Shimomori, T. Nonaka and T. Hosoya, Chem. Lett., 2015, 44, 1324; (p)
S. Yoshida, T. Yano, Y. Misawa, Y. Sugimura, K. Igawa, S. Shimizu, K.
Tomooka and T. Hosoya, J. Am. Chem. Soc., 2015, 137, 14071; (q) E.
Demory, K. Devaraj, A. Orthaber, P. J. Gates and L. T. Pilarski, Angew.
Chem., Int. Ed., 2015, 54, 11765; (r) C. M. Holden, S. M. A. Sohel and
M. F. Greaney, Angew. Chem., Int. Ed., 2016, 55, 2450; (s) M.
Thangaraj, S. S. Bhojgude, M. V. Mane and A. T. Biju, Chem. Commun.
2016, 52, 1665; (t) T. Ikawa, S. Masuda, A. Takagi and S. Akai, Chem.
Sci., 2016, , 5206.
5 (a) S. Yoshida, T. Nonaka, T. Morita and T. Hosoya, Org. Biomol. Chem.
,
7
,
2014, 12, 7489; (b) S. Yoshida, K. Uchida, K. Igawa, K. Tomooka and T.
Hosoya, Chem. Commun., 2014, 50, 15059; (c) S. Yoshida, K. Uchida
and T. Hosoya, Chem. Lett., 2015, 44, 691; (d) S. Yoshida, T. Morita and
T. Hosoya, Chem. Lett., 2016, 45, 726.
6 For selected reviews on heterocyclic arynes, see: (a) T. Kauffmann,
Angew. Chem., Int. Ed. Engl., 1965,
4, 543; (b) M. G. Reinecke,
Tetrahedron, 1982, 38, 427; (c) A. E. Goetz, T. K. Shah and N. K. Garg,
Chem. Commun., 2015, 51, 34.
7 (a) S. M. Bronner, K. B. Bahnck and N. K. Garg, Org. Lett., 2009, 11
,
1007; (b) P. H.ꢀY. Cheong, R. S. Paton, S. M. Bronner, G.ꢀY. J. Im, N. K.
Garg and K. N. Houk, J. Am. Chem. Soc., 2010, 132, 1267; (c) G.ꢀY. J.
Im, S. M. Bronner, A. E. Goetz, R. S. Paton, P. H.ꢀY. Cheong, K. N.
Houk and N. K. Garg, J. Am. Chem. Soc., 2010, 132, 17933; (d) S. M.
Notes and references
aLaboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University, 2ꢀ3ꢀ10 KandaꢀSurugadai, Chiyodaꢀku,
Tokyo 101ꢀ0062, Japan. Eꢀmail: thosoya.cb@tmd.ac.jp
Bronner, A. E. Goetz and N. K. Garg, J. Am. Chem. Soc., 2011, 133
3832; (e) A. E. Goetz and N. K. Garg, Nat. Chem., 2013, , 54.
8 (a) T. Hamura, Y. Ibusuki, K. Sato, T. Matsumoto, Y. Osamura and K.
Suzuki, Org. Lett., 2003, , 3551; (b) T. Hamura, Y. Ibusuki, H. Uekusa,
,
b
5
Ichihara Research Center, JNC Petrochemical Corporation, 5ꢀ1 Goikaigan,
Ichihara, Chiba 290ꢀ8551, Japan
c
5
Institute for Materials Chemistry and Engineering, Kyushu University, 6ꢀ1
T. Matsumoto and K. Suzuki, J. Am. Chem. Soc., 2006, 128, 3534; (c) T.
Hamura, Y. Ibusuki, H. Uekusa, T. Matsumoto, J. S. Siegel, K. K.
Baldridge and K. Suzuki, J. Am. Chem. Soc., 2006, 128, 10032; (d) S.
Shinozaki, T. Hamura, Y. Ibusuki, K. Fujii, H. Uekusa and K. Suzuki,
Angew. Chem., Int. Ed., 2010, 49, 3026.
Kasugaꢀkoen, Kasuga, Fukuoka 816ꢀ8580, Japan Laboratory of Chemical
Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and
Dental University, 2ꢀ3ꢀ10 KandaꢀSurugadai, Chiyodaꢀku, Tokyo 101ꢀ0062, Japan
† Electronic supplementary information (ESI) available: Experimental
procedures, characterization data including copies of NMR spectra,
details for computational studies, and the Xꢀray crystallographic data for
10 (CCDC 1481578). See DOI: 10.1039/c000000x/
9 For an excellent approach to 2,4ꢀdisubstituted benzothiazoles via domino
reaction of 3ꢀtriflyloxybenzyne with protected thioamides, see: J. Shi, D.
Qiu, J. Wang, H. Xu, Y. Li, J. Am. Chem. Soc., 2015, 137, 5670.
10 For orthoꢀiodoaryl triflates as aryne precursors, see: T. Matsumoto, T.
Hosoya, M. Katsuki and K. Suzuki, Tetrahedron Lett., 1991, 32, 6735.
See also, Refs 3e, 5, 8 and references cited therein.
1 (a) A. Martinez and C. Gil, in Privileged Scaffolds in Medicinal
Chemistry: Design, Synthesis, Evaluation, ed. S. Bräse, Royal Society of
Chemistry, Cambridge, 2015, pp. 245–248; (b) N. P. Prajapati, R. H.
11 See Supporting Information for details.
Vekariya, M. A. Borad and H. D. Patel, RSC Adv. 2014, 4, 60176.
12 M. W. Schmidt, K. K. Baldridge, J. A. Boatz, S. T. Elbert, M. S. Gordon,
J. H. Jensen, S. Koseki, N. Matsunaga, K. A. Nguyen, S. Su, T. L.
Windus, M. Dupuis and J. A. Montgomery Jr., J. Comput. Chem., 1993,
14, 1347.
2 (a) M. Muraki, B. Ohkawara, T. Hosoya, H. Onogi, J. Koizumi, T.
Koizumi, K. Sumi, J. Yomoda, M. V. Murray, H. Kimura, K. Furuichi,
H. Shibuya, A. R. Krainer, M. Suzuki and M. Hagiwara, J. Biol. Chem.
,
2004, 279, 24246; (b) Y. Ogawa, Y. Nonaka, T. Goto, E. Ohnishi, T.
13 For the comprehensive assessment of stability of heterocyclic arynes,
including thiazolobenzynes, and prediction of regioselectivities for their
reactions by the computational method, see: A. E. Goetz, S. M. Bronner,
J. D. Cisneros, J. M. Melamed, R. S. Paton, K. N. Houk and N. K. Garg,
Angew. Chem., Int. Ed., 2012, 51, 2758.
Hiramatsu, I. Kii, M. Yoshida, T. Ikura, H. Onogi, H. Shibuya, T.
Hosoya, N. Ito and M. Hagiwara, Nat. Commun., 2010, 1, 86; (c) S.
Masaki, I. Kii, Y. Sumida, T. KatoꢀSumida, Y. Ogawa, N. Ito, M.
Nakamura, R. Sonamoto, N. Kataoka, T. Hosoya and M. Hagiwara,
Bioorg. Med. Chem., 2015, 23, 4434.
14 (a) T. Ikawa, A. Takagi, M. Goto, Y. Aoyama, Y. Ishikawa, Y. Itoh, S.
Fujii, H. Tokiwa and S. Akai, J. Org. Chem., 2013, 78, 2965; (b) A.
Takagi, T. Ikawa, Y. Kurita, K. Saito, K. Azechi, M. Egi, Y. Itoh, H.
Tokiwa, Y. Kita and S. Akai, Tetrahedron, 2013, 69, 4338; (c) T. Ikawa,
H. Kaneko, S. Masuda, E. Ishitsubo, H. Tokiwa and S. Akai, Org.
Biomol. Chem., 2015, 13, 520.
15 M. B. Smith, in March’s Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure, 7th ed., John Wiley & Sons, New Jersey,
2013, pp. 25–27.
3 For some recent reviews on arynes, see: (a) H. Yoshida and K. Takaki,
Synlett, 2012, 23, 1725; (b) A. Bhunia, S. R. Yetra and A. T. Biju, Chem.
Soc. Rev., 2012, 41, 3140; (c) C. M. Gampe and E. M. Carreira, Angew.
Chem., Int. Ed., 2012, 51, 3766; (d) P. M. Tadross and B. M. Stoltz,
Chem. Rev., 2012, 112, 3550; (e) S. Yoshida and T. Hosoya, Chem. Lett.
,
2015, 44, 1450.
4 For some recent aryne chemistries, see: (a) D. A. Candito, D.
Dobrovolsky and M. Lautens, J. Am. Chem. Soc., 2012, 134, 15572; (b)
4 | Chem. Commun., 201x, 00, 1-4
This journal is © The Royal Society of Chemistry 201x

Page 5 of 5
ChemCommun
ChemComm
View Article Online
COMMUNICATION
DOI: 10.1039/C6CC05112J
Graphical abstract for the contents page
xxx
Thiazolobenzyne: A versatile intermediate for
multisubstituted benzothiazoles
Suguru Yoshida, Takahisa Yano, Yoshitake Nishiyama,
Yoshihiro Misawa, Masakazu Kondo, Takeshi
Matsushita, Kazunobu Igawa, Katsuhiko Tomooka and
Takamitsu Hosoya*
Thiazolobenzynes were efficiently generated via an iodine–
magnesium exchange reaction of ortho-iodoaryl triflate-type
precursors using a trimethylsilylmethyl Grignard reagent as an
activator, which enabled facile synthesis of various
multisubstituted benzothiazoles.
This journal is © The Royal Society of Chemistry 201x
Chem. Commun., 201x, 00, 1-4 | 5