The first synthesis of 2,2′:5′,2″-terthiazole

Article abstract of DOI:10.1055/s-0028-1083533

2,2′:5′,2″-Terthiazole, a previously unknown terthiazole isomer, was prepared by copper-mediated oxidative coupling of 2-lithiothiazole. The yield was improved in the presence of equimolar 2,2′-bithiazole. The 5,5″-positions were cleanly lithiated by lithium diisopropylamide, which demonstrates its potential in the extension of π-systems. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083533

2882
LETTER
The First Synthesis of 2,2¢:5¢,2¢¢-Terthiazole
S
ynthesis of 2,2
¢
:5
i
¢
,2¢¢-T
e
r
rthiazoleoyuki Kurata,* Hideki Takakuwa, Kouzou Matsumoto, Takeshi Kawase,1 Masaji Oda
Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
Fax +81(6)68505387; E-mail: kurata@chem.sci.osaka-u.ac.jp
Received 17 June 2008
There have been a number of reports on the synthesis of
2,2¢-bithiazole via coupling reactions of thiazole deriva-
tives, for example, Ullman coupling,8 nickel- or palladi-
um-mediated homocoupling of 2-bromothiazole,9 and
Abstract: 2,2¢:5¢,2¢¢-Terthiazole, a previously unknown terthiazole
isomer, was prepared by copper-mediated oxidative coupling of
2-lithiothiazole. The yield was improved in the presence of equimo-
lar 2,2¢-bithiazole. The 5,5¢¢-positions were cleanly lithiated by lith-
ium diisopropylamide, which demonstrates its potential in the Stille coupling of 2-stannylthiazole and 2-bromothiazole.4
extension of p-systems.
Although copper-mediated oxidative coupling of thienyl-
lithiums has often been used for the synthesis of
bithiophene derivatives,10 there have been no reports on
the use of this method for the synthesis of the parent 2,2¢-
bithiazole.11 We therefore examined the coupling reaction
of 2-lithiothiazole with CuCl2 (Scheme 1).
Key words: thiazole, copper, coupling, lithiation, oligomer
Molecules containing two or more thiazole (1,3-thiazole)
rings play important roles in both biochemistry2 and ma-
terial science.3 Although there are 28 potential isomers of
the parent terthiazoles, only three isomers have been pre-
pared to date: 4,2¢:5¢,4¢¢-terthiazole (1), 4,2¢:4¢,5¢¢-terthia-
zole (2), and 5,2¢:5¢,5¢¢-terthiazole (3).4 These three
compounds (Figure 1) were synthesized by Stille cou-
pling of trimethylstannylthiazoles and dibromothiazoles.
Surprisingly, 2,2¢:5¢,2¢¢-terthiazole (4), which is consid-
ered to be one of the most conventional structures among
the terthiazoles, is still an unknown compound. According
to the literature, an attempt to synthesize 4 via Stille cou-
pling of 2,5-dibromothiazole with 2-tributylstannylthia-
zole failed.5 Recently, synthesis of halogenated bithiazole
derivatives by Suzuki–Miyaura coupling has been report-
ed.6 Synthesis of 4 by this method, however, is highly im-
practical because of the lack of availability of the required
2-thiazoleboronic acid.5,6 In the course of our studies con-
cerning thiazole extended p-systems,7 we discovered a
simple synthesis of 4 by copper-mediated oxidative cou-
pling of lithiothiazoles. We here report the first synthesis
of 4.
N
1) 1.0 equiv n-BuLi,
Et2O, –78 °C, 1 h
N
S
S
Br
2) CuCl2
S
N
5
+
N
S
S
S
N
N
4
Scheme 1
Table 1 Synthesis of 2,2 ¢-Bithiazole (5) and Terthiazole 4 via
CuCl2-Mediated Oxidative Couplinga
Entry CuCl2 (equiv) Temp (°C)b Time (h)b
Yield (%)c
5
4
1
2
3
4
5
6
7
1.1
1.1
1.1
2.0
1.0
0.9
0.9d
25
0
15
6
3
5
0
0
3
2
3
4
5
–78
–78
–78
–78
–78
6
39
46
42
52
46
S
N
3
S
S
N
N
N
S
3
N
N
S
S
2
1
3
N
N
3
S
S
S
S
S
a Reaction details are described in the experimental section.
b After addition of CuCl2.
S
N
N
N
N
c Isolated yield.
4
3
d CuCl2 was added in two portions with 1 h interval.
Figure 1 Known terthiazoles 1–3 and 2,2¢:5¢,2¢¢-terthiazole (4)
The results are summarized in Table 1. It was found that
the reaction temperature after addition of CuCl2 was a key
factor in obtaining coupling products. When the reaction
was carried out at 0 °C or room temperature, similar to the
synthesis of 2,2¢-bithiophene, 2,2¢-bithiazole (5) was ob-
tained in only 3–5% yield (entries 1 and 2). However,
SYNLETT 2008, No. 18, pp 2882–2884
Advanced online publication: 15.10.2008
DOI: 10.1055/s-0028-1083533; Art ID: U06308ST
© Georg Thieme Verlag Stuttgart · New York
1
4
.1
1
.2
0
0
8

LETTER
Synthesis of 2,2¢:5¢,2¢¢-Terthiazole
2883
when the reaction was carried out at –78 °C, compound 5 Compound 4 is a pale yellow powder possessing both air
was obtained in moderate yield, and the formation of ter- and thermal stability. Terthiazole 4 is more soluble in
thiazole 4 was observed (entry 3). Excess CuCl2 did not common organic solvents than 2,2¢:5¢,2¢¢-terthiophene.
affect the yield of 5 (entry 4), but a slightly reduced Lithiation and functionalization of 4 was examined for its
amount of CuCl2 improved the yields of 5 (entry 6).
utility in extending p-systems. Treatment of 4 with 2.2
equivalents of lithium diisopropylamide, followed by re-
action with 2,6-di-tert-butylbenzoquinone, afforded bis-
quinol 6 in 77% yield (Scheme 3). Successive reduction
of 6 with Zn and pyridine–water13 gave bisphenol 7 in
83% yield. Compound 7 is an important synthetic inter-
mediate in the relation of our recent studies on extended
quinines incorporated with a thiazole7 and bithiazole
rings.14
It was remarkable that terthiazole 4 was prepared, even at
such low yield. To confirm the reproducibility of this re-
action, we examined the reaction under the same condi-
tions of entry 6 for six times, and we always obtained 4 in
2–4% yield. The mechanism of formation of 4 is unclear,
but 5-lithio-2,2¢-bithiazole is most likely generated in situ,
probably caused by the incompleteness of the reaction of
2-lithiothiazole with CuCl2. We thus added CuCl2 in two
portions with a one-hour interval, the yield of 4 did not in- In conclusion, we prepared 2,2¢:5¢:2¢¢-terthiazole (4), a
crease so much (entry 7). Furthermore, we examined the previously unknown terthiazole isomer, by CuCl2-mediat-
coupling reaction in the presence of equimolar 2,2¢-bithia- ed oxidative coupling of a lithiated mixture of thiazole
zole 5 to generate 5-lithio-2,2¢-bithiazole under these re- and 2,2¢-bithiazole. Although the yield is low, this method
action conditions. As expected, the yield of 4 increased to is quite simple compared to Stille coupling or Suzuki–
17% (Scheme 2).12
Miyaura coupling reactions reported for known terthia-
zole derivatives. Due to its facile lithiation and function-
alization, compound 4 will be a good building block for
new extended p-systems containing terthiazole skeletons.
N
Br
N
1) 2.0 equiv n-BuLi,
Et2O, –78 °C, 1 h
S
S
S
+
S
2) 0.9 equiv CuCl2,
–78 °C, 3 h
N
N
N
CuCl2-Mediated Oxidative Coupling of 2-Lithiothiazole:
Synthesis of 2,2¢-Bithiazole 5 and 2,2¢:5¢:2¢¢-Terthiazole (4)
To a solution of 2-bromothiazole (3.0 mL, 33 mmol) in anhyd Et2O
(70 mL) was added dropwise a 1.5 M solution of n-BuLi in hexane
(23 mL, 34 mmol) at –78 °C for 1 h, anhyd CuCl2 (4.0 g, 30 mmol)
was added in one portion. The mixture was stirred at –78°C for 3 h,
then filtered through a Celite pad to remove inorganic materials
(eluent: CH2Cl2). The filtrate was evaporated and the residue was
purified by SiO2 (80 g) column chromatography. From the first frac-
tion eluted with 10% EtOAc–hexane, 2,2¢-bithiazole 5 was obtained
as a pale yellow powder (1.3 g, 52%), and from the second fraction
eluted with 20% EtOAc–hexane, 2,2¢:5¢,2¢¢-terthiazole (4) was ob-
tained as a yellow powder (87 mg, 4%).
S
4
17%
S
N
5
Scheme 2
N
S
S
S
N
N
4
1) 2.2 equiv LDA, THF
–70 °C, 1 h
2) 2.5 equiv 2,6-di-tert-
butylbenzoquinone
2,2¢-Bithiazole (5)
1
Pale yellow powder. H NMR (270 MHz, CDCl3): d = 7.90 (d,
J = 3.1 Hz, 2 H), 7.44 (d, J = 3.1 Hz, 2 H). 13C NMR (67.8 MHz,
CDCl3): d = 161.66, 143.90, 120.92.
77%
t-Bu
t-Bu
O
N
O
2,2¢:5¢,2¢¢-Terthiazole (4)
S
S
Yellow crystals (benzene–hexane); mp 146–147 °C. MS (EI): m/z =
251 [M+]. 1H NMR (400 MHz, CDCl3): d = 8.24 (s, 1 H), 7.93 (d,
J = 3.1 Hz, 1 H), 7.86 (d, J = 3.3 Hz, 1 H), 7.49 (d, J = 3.1 Hz, 1 H),
7.37 (d, J = 3.3 Hz, 1 H). 13C NMR (67.8 MHz, CDCl3): d = 162.21,
161.03, 157.99, 144.26, 143.94, 142.00, 134.56, 121.62, 119.48.
UV/Vis (CH2Cl2): lmax (log e) = 389 (sh, 4.15), 365 (4.41), 351 (sh,
4.35) nm. IR (KBr): n = 3103 (m), 1538 (w), 1504 (w), 1469 (m),
1374 (m), 1314 (w), 1271 (w), 1242 (m), 1150 (m), 1051 (w), 929
(m), 866 (m), 740 (m), 631 (m), 611 (m), 473 (w) cm–1. Anal. Calcd
for C9H5N3S3: C, 43.01; H, 2.00; N, 16.71. Found: C, 43.33; H,
1.92; N, 16.62.
S
HO
HO
N
t-Bu
t-Bu
N
6
Zn, pyridine–H2O
reflux, 1 h
83%
t-Bu
t-Bu
HO
N
OH
S
S
N
S
t-Bu
t-Bu
N
Synthesis of 4 in the Presence of 5
To a solution of 2-bromothiazole (0.1 mL, 1.0 mmol) and 2,2¢-
bithiazole (5, 168 mg, 1.0 mmol) in anhyd Et2O (15 mL) was added
dropwise a 1.5 M solution of n-BuLi in hexane (1.3 mL, 2.0 mmol)
at –78 °C under nitrogen atmosphere. After stirring at –78 °C for
1 h, anhyd CuCl2 (121 mg, 0.9 mmol) was added in one portion. The
mixture was stirred at –78 °C for 3 h, then filtered through a Celite
7
Scheme 3
Synlett 2008, No. 18, 2882–2884 © Thieme Stuttgart · New York

2884
H. Kurata et al.
LETTER
pad to remove inorganic materials (eluent: CH2Cl2). The filtrate was
evaporated and the residue was purified by SiO2 (30 g) column
chromatography. Bithiazole 5 (121 mg) was recovered from the
first fraction (eluent: 10% EtOAc–hexane), and the terthiazole 4 (42
mg, 17%) was obtained from the second fraction (eluent: 20%
EtOAc–hexane), as a pale yellow powder.
References and Notes
(1) Present address: Department of Materials Science and
Chemistry, Graduate School of Engineering, University of
Hyogo, 2167 Shosha, Himeji, Hyogo 671-2201, Japan.
(2) (a) Ma, Q.; Xu, Z.; Schroeder, B. R.; Sun, W.; Wei, F.;
Hashimoto, S.; Konishi, K.; Leitheiser, C. J.; Hecht, S. M.
J. Am. Chem. Soc. 2007, 129, 12439. (b) Claussen, C. A.;
Long, E. C. Chem. Rev. 1999, 99, 2797. (c) Ninomiya, K.;
Satoh, H.; Sugiyama, T.; Shinomiya, M.; Kuroda, R. Chem.
Commun. 1996, 1825.
(3) (a) Kobatake, S.; Takami, S.; Muto, H.; Ishikawa, T.; Irie,
M. Nature (London) 2007, 446, 778. (b) Kojima, T.;
Nishida, J.; Toshito, S.; Tada, H.; Yamashita, Y. Chem.
Commun. 2007, 1430. (c) Ando, S.; Murakami, R.; Nishida,
J.; Tada, H.; Inoue, Y.; Tokito, S.; Yamashita, Y. J. Am.
Chem. Soc. 2005, 127, 14996. (d) Wakamiya, A.;
Taniguchi, T.; Yamaguchi, S. Angew. Chem. Int. Ed. 2006,
45, 3170. (e) Nakagawa, T.; Atsumi, K.; Nakashima, T.;
Hasegawa, Y.; Kawai, T. Chem. Lett. 2007, 36, 372.
(f) MacLean, B. J.; Pickup, P. G. J. Mater. Chem. 2001, 11,
1357. (g) Mitschke, U.; Debaerdemaeker, T.; Bäuerle, P.
Eur. J. Org. Chem. 2000, 425.
Lithiation and Functionalization of 4 – Synthesis of Bisquinol 6
To a solution of diisopropylamine (0.15 mL, 1.1 mmol) in anhyd
THF (10 mL) was added dropwise a 1.6 M solution of n-BuLi in
hexane (0.7 mL, 1.1 mmol) at –70 °C under nitrogen atmosphere.
After stirring at 0 °C for 1 h, a solution of 4 (126 mg, 0.5 mmol) in
THF (5 mL) was added dropwise at –70 °C, and the mixture were
stirred at –70 °C for 1 h. 2,6-Di-tert-butylbenzophenone (275 mg,
1.25 mmol) in THF (5 mL) was added dropwise at –70 °C, and the
mixture were stirred at 0 °C for 1.5 h. The mixture was quenched by
sat. NH4Cl solution, extracted with EtOAc (3 × 20 mL), washed
with H2O, brine, and dried with anhyd Na2SO4. The solution was
evaporated and the residue was purified by SiO2 (50 g) column
chromatography (eluent: 5% EtOAc–benzene) to give bisquinol 6
(268 mg, 77%) as a yellow powder. This compound was used for the
next reaction without further purification.
(4) Dondoni, A.; Fogagnolo, M.; Medici, A.; Negrini, E.
Synthesis 1987, 185.
(5) Gronowitz, S.; Peters, D. Heterocycles 1990, 30, 645.
(6) Stanetty, P.; Schnürch, M.; Mihovilovic, M. D. J. Org.
Chem. 2006, 71, 3754.
Compound 6
Yellow powder. 1H NMR (270 MHz, CDCl3): d = 8.16 (s, 1 H), 7.72
(s, 1 H), 7.61 (s, 1 H), 6.69 (s, 2 H), 6.68 (s, 2 H), 1.72 (s, 2 H), 1.25
(s, 36 H).
(7) Kurata, H.; Takakuwa, H.; Imai, N.; Matsumoto, K.;
Kawase, T.; Oda, M. Bull. Chem. Soc. Jpn. 2007, 80, 1402.
(8) Erlenmeyer, H.; Schmid, E. H. Helv. Chim. Acta 1939, 22,
698.
Synthesis of Bisphenol 7
To a solution of 6 (268 mg, 0.4 mmol) in pyridine (8 mL) and H2O
(0.8 mL) was added zinc powder (1.01 g, 15.5 mmol), and the mix-
ture was refluxed for 1.5 h. After cooling to r.t., the mixture was
passed through a Celite pad to remove zinc powder. The filtrate was
extracted with EtOAc (3 × 20 mL), washed with 1% HCl, sat.
NaHCO3 solution, brine, and dried with anhyd Na2SO4. The solu-
tion was evaporated and the residue was purified by SiO2 (40 g) col-
umn chromatography (eluent: 10% EtOAc–hexane) to give
bisphenol 7 (213 mg, 83%) as an orange powder.
(9) (a) Forst, Y.; Becker, S.; Caubere, P. Tetrahedron 1994, 50,
11893. (b) Craig, D. C.; Goodwin, H. A.; Onggo, D.; Rae,
A. D. Aust. J. Chem. 1988, 41, 1625. (c) Hassan, J.;
Lavenot, L.; Gozzi, C.; Lemaire, M. Tetrahedron Lett. 1999,
40, 857. (d) Xie, Y.; Tan, G. K.; Yan, Y. K.; Vittal, J. J.; Ng,
S. C.; Hor, T. S. A. J. Chem. Soc., Dalton Trans. 1999, 773.
(10) (a) Kauffmann, T. Angew. Chem., Int. Ed. Engl. 1974, 13,
291. (b) Kauffmann, T. Angew. Chem., Int. Ed. Engl. 1979,
18, 1. (c) Kabir, S. M. H.; Miura, M.; Sasaki, S.; Harada, G.;
Kuwatani, Y.; Yoshida, M.; Iyoda, M. Heterocycles 2000,
52, 761.
(11) Neidlein et al. has reported synthesis of 4,4¢-dibromo-2,2¢-
bithiazole from 2-lithio-4-bromothiazole with CuCl2. See:
Nussbaumer, T.; Neidlein, R. Heterocycles 2000, 52, 349.
(12) We also examined this reaction by using 3.0 equivalents of
CuCl2, and the yield of 4 was 15%.
Compound 7
Orange crystals (CH2Cl2–hexane); mp 280–281 °C. MS (EI): m/z =
659 [M+]. 1H NMR (400 MHz, CDCl3): d = 8.21 (s, 1 H), 7.95 (s,
1 H), 7.86 (s, 1 H), 7.44 (s, 2 H), 7.38 (s, 2 H), 5.43 (s, 1 H), 5.41 (s,
1 H), 1.50 (s, 18 H), 1.49 (s, 18 H). 13C NMR (100 MHz, CDCl3):
d = 162.16, 158.33, 155.59, 154.94, 154.75, 143.69, 141.60, 141.55,
138.54, 138.10, 136.96, 136.93, 134.65, 124.12, 124.08, 122.13,
34.45, 30.18. UV/Vis (CH2Cl2): lmax (log e) = 427 (4.67), 274
(4.17) nm. IR (KBr): n = 3615 (s), 2955 (s), 2910 (m), 2870 (m),
1433 (s), 1405(s), 1387 (s), 1302 (m), 1223 (s), 1135 (m), 1116 (m),
1050 (w), 928 (s), 902 (m), 880 (m), 853 (m), 820 (m), 769 (w), 703
(w), 608 (m) cm–1. HRMS: m/z calcd for C37H45N3O2S3: 659.2674;
found: 659.2701.
(13) Tsuda, K.; Ohki, E.; Nozoe, S. J. Org. Chem. 1963, 28, 783.
(14) Oxidation of 7 and the properties of the oxidized species will
be reported elsewhere.
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