High throughput synthesis of 2,3,6-trisubstituted-5,6-dihydroimidazo[2,1-b] thiazole derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.12.006

A facile approach to the synthesis of 2,3,6-trisubstituted-5,6- dihydroimidazo[2,1-b]thiazole was reported. A resin bound cyclic thiourea was formed by the treatment of a resin bound diamine with 1,1′- thiocarbonyldiimidazole, and then reacted with a α-ha

Full text of DOI:10.1016/j.tetlet.2010.12.006

Tetrahedron Letters 52 (2011) 696–698
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
High throughput synthesis of 2,3,6-trisubstituted-5,6-dihydroimidazo
[2,1-b]thiazole derivatives
⇑
Yangmei Li, Marc Giulianotti, Richard A. Houghten
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A
facile approach to the synthesis of 2,3,6-trisubstituted-5,6-dihydroimidazo[2,1-b]thiazole was
reported. A resin bound cyclic thiourea was formed by the treatment of a resin bound diamine with
1,10-thiocarbonyldiimidazole, and then reacted with a
-haloketone to generate a resin bound isothiou-
Received 8 November 2010
Revised 30 November 2010
Accepted 1 December 2010
Available online 7 December 2010
a
rea. HF treatment of the resin bound isothiourea resulted in the cleavage of the product and simultaneous
formation of an enamine bond. This led to the formation of the 2,3,6-trisubstituted-5,6-dihydroimi-
dazo[2,1-b]thiazole in high yield and purity.
Ó 2010 Elsevier Ltd. All rights reserved.
Heterocyclic compounds have been found to have multiple
applications in the treatment of human diseases.1 Imidazole and
thiazole are among the most common heterocycles currently
utilized in medicinal science and drug discovery.2 Imidazole- and
thiazole-containing structures have been found in many developed
drugs, as well as in many bioactive natural products and synthetic
compounds.3 From the well-known natural drugs penicillin and
vitamin B, to the synthetic drugs Meloxicam, Cimetidine, Metroni-
dazole, and Eprosartan, these important drugs are either imidaz-
ole- or thiazole-containing compounds.4 Imidazothiazole, which
consists of an imidazole-ring fused with a thiazole-ring, has been
reported to have excellent immunostimulating properties and
anti-inflammation activities.5 Levamisole, a marketed anthelmin-
thic and immunomodulator belongs to this class. Levamisole is also
used in combination with other forms of chemotherapy for cancer
treatment.6
bound amino acid 2. After removal of the Boc-group, the resin
bound 2 was reduced by exhaustive borane reduction to yield
the resin bound diamine 3. The resin bound diamine 3 was treated
with 1,10-thiocarbonyldiimidazole, forming the resin bound cyclic
thiourea 4. An
a-haloketone was then coupled to yield the resin
bound isothiourea 5. The resin bound isothiourea 5 was then trea-
ted with anhydrous HF at 0 °C to release the products from the
polymer support. Simultaneous ring closure was carried out by
enamine formation, generating the second thiazole-ring, and even-
tually resulting in the 2,3,6-trisubstituted-5,6-dihydroimidazo[2,1-
b]thiazole derivatives 6 (Table 1, 6a–j).
H
N
N
S
Imidazothiazoles have generally been synthesized from starting
materials that already contain a heterocyclo—either an ethylen-
ethiourea (Scheme 1, method (i)) or a thiazole (Scheme 1, method
(ii)).7 The limited accesses of commercially available starting
heterocycles restrict the high throughput synthesis of multiple-
substituted imidazothiazole compounds. In order to overcome
these drawbacks, herein, we report a facile approach to the high
throughput synthesis of 2,3,6-trisubstituted-5,6-dihydroimi-
dazo[2,1-b]thiazole derivatives through the use of a solid-phase
synthetic method.
Levamisole
method i
S
Ra
O
Rb
N
Rb
Ra
+
HN
NH
N
S
N
X
method ii
Rb
O
H
N
Rb
Ra
The synthesis was based on the reaction of a cyclic thiourea
Ra
+
+
NH
with an
a
-haloketone. The cyclic thiourea was generated through
N
S
S
X
OH
the solid-phase synthetic method described below (Scheme 2).8
Starting from MBHA resin 1, a Boc-amino acid was coupled on
the resin using a standard DIC/HOBt protocol to generate the resin
Ra
N
Rb
N
S
Rb
Ra
X
N
S
NH2
⇑
Corresponding author. Tel.: +1 772 345 4580; fax: +1 772 345 3649.
E-mail addresses: yli@tpims.org (Y. Li), houghten@tpims.org (R.A. Houghten).
Scheme 1. Structure of levamisole and general routes to synthetic imidazothiazole.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.006

Y. Li et al. / Tetrahedron Letters 52 (2011) 696–698
697
O
S
NH2
NH2
c
b
a
NH2
N
H
N
H
N
NH
R1
R1
R1
4
1
2
3
O
S
R2
R3
R2
d
e
N
R1
R3
N
N
N
S
R1
6
5
Scheme 2. Synthesis of 2,3,6-trisubstituted-5,6-dihydroimidazo[2,1-b]thiazole derivatives. (a) Boc-AA-OH (5 equiv), DIC (5 equiv), HOBt (5 equiv); 55% TFA/DCM; (b)
BH3ꢁTHF (40 equiv), 65 °C, 72 h; piperidine, 65 °C, overnight; (c) 1,10-thiocarbonyldiimidazole (5 equiv) in CH2Cl2, overnight; (d)
(e) anhydrous HF, 0 °C, 1.5 h.
a-haloketone (5 equiv) in DMF, 65 °C, 24 h;
Table 1
Individual
derivatives
Development, National Science Foundation (R.A.H. CHE 0455072),
1P41GM079590, 1P41GM081261, and U54HG03916-MLSCN.
products
R1
of 2,3,6-trisubstituted-5,6-dihydroimidazo[2,1-b]thiazole
Entry
R2
R3
Purity %a
Yield %b
References and notes
6a
6b
6c
6d
6e
6f
6g
6h
6i
–CH3
–CH3
–CH3
–CH3
–CH2CH(CH3)2
–CH2C6H5
–CH2C6H5
–CH2CH(CH3)2
–CH(CH3)2
–CH2C6H5
–C6H5(4-F)
–C6H5
–C6H5
1-Adamantyl
2-Naphthyl
–C6H5
–CH3
–C(CH3)3
–C6H5
–H
85
98
90
95
75
80
95
75
60
90
87
85
98
98
68
90
98
84
80
90
1. (a) Krchnák, V.; Holladay, M. W. Chem. Rev. 2002, 102, 61; (b) Nefzi, A.; Ostresh, J.
M.; Houghten, R. A. Chem. Rev. 1997, 97, 449; (c) Cassels, B. K.; Bermúdez, I.;
Dajas, F.; Abin-Carriquiry, J. A.; Susan, W. Drug Discov. Today 2005, 10, 1657.
2. (a) Marsilje, T. H.; Roses, J. B.; Calderwood, E. F.; Stroud, S. G.; Forsyth, N. E.;
Blackburn, C.; Yowe, D. L.; Miao, W. Y.; Drabic, S. V.; Bohane, M. D.; Daniels, J. S.;
Li, P.; Wu, L. J.; Patane, M. A.; Claiborne, C. F. Bioorg. Med. Chem. Lett. 2004, 14,
3721; (b) Townsend, L. B. Chem. Rev. 1967, 67, 533; (c) Silvestri, R.; Artico, M.; La
Regina, G.; Di Pasquali, A.; De Martino, G.; D’Auria, F. D.; Nencioni, L.; Palamara,
A. T. J. Med. Chem. 2004, 47, 3926; (d) Sanfilippo, P. J.; Jetter, M. C.; Cordova, R.;
Noe, R. A.; Chourmouzis, E.; Lau, C. Y.; Wang, E. J. Med. Chem. 1995, 38, 1057; (e)
van Muijlwijk-Koezen, J. E.; Timmerman, H.; Vollinga, R. C.; Frijtag von Drabbe
Künzel, J.; de Groote, M.; Visser, S.; Ijzerman, A. P. J. Med. Chem. 2001, 44, 749.
3. (a) De Luca, L. Curr. Med. Chem. 2006, 13, 1; (b) Jin, Z. Nat. Prod. Rep. 2006, 23,
464.
–C6H5
–CH3
–H
–H
–CH3
–CH3
–H
–H
–H
6j
–C6H5(4-OCH3)
a
Purity (in %) is determinate by the peak area of HPLC at 214 nm.
Yields (in %) are based on the weight of crude product and are relative to the
substitution of the resin (1.1 mmol/g).
b
4. Eicher, T.; Hauptmann, S. In The Chemistry of Heterocycles, 2nd ed.; WILEY-VCH,
2003; p 173.
5. (a) Raeymaekers, A. H. M.; Roevens, L. F. C.; van Laerhoven, W. J. C.; van Wauwe,
J. P. F. U.S. Patent, 1996; 5527915.; (b) Nishio, K.; Chiyomaru, I.; Anma, K.;
Yamamoto, K.; Ohno, H.; Takayanagi, N. U.S. Patent, 1985; 4556669.; (c)
Yamamoto, I.; Matsunari, K.; Nitta, K.; Shibata, K.; Takayanaqi, N. U.S. Patent,
1990; 4910315.; (d) Scribner, A.; Meitz, S.; Fisher, M.; Wyvratt, M.; Penny, L.;
Liberatoe, P.; Gurnett, A.; Brown, C.; Mathew, J.; Thompson, D.; Schmatz, D.;
Biftu, T. Bioorg. Med. Chem. Lett. 2008, 18, 5263.
6. Moertel, C. G.; Fleming, T. R.; Macdonald, J. S.; Haller, D. G.; Laurie, J. A.; Tangen,
C. M.; Ungerleider, J. S.; Emerson, W. A.; Tormey, D. C.; Glick, J. H.; Veeder, M. H.;
Mailliard, J. A. Ann. Intern. Med. 1995, 122, 321.
7. For method i: (a) Debre, S.; Lecat-Guillet, N.; Pillon, F.; Ambroise, Y. Bioorg. Med.
Chem. Lett. 2009, 19, 825; (b) Lecat-Guillet, N.; Ambroise, Y. ChemMedChem
2008, 1211; (c) Varma, R. S.; Kumar, D.; Liesen, P. J. J. Chem. Soc. Perk. T. 1. 1998,
4093; (d) Dianov, V. M.; Zeleev, M. K.; Spirikhin, L. V. Russ. J. Org. Chem. 2005, 41,
153; For method ii: (e) Li, L.; Chang, L.; Pellet-Rostaing, S.; Liger, F.; Lemaire, M.;
Buchet, R.; Wu, Y. Bioorg. Med. Chem. 2009, 17, 7290; (f) Birman, V.; Li, X. Org.
Lett. 2006, 7, 1351.
A variety of different
described conditions. Generally, linear
the desired product with good-to-excellent yield and purity.
However attempts made with -halocycloketones such as
2-bromocyclohexanone, 2-chlorocyclopentanone, and 2-bromo-1-
indanone did not yield the desired imidazothiazole products
under the current conditions. The main products obtained after
HF cleavage were identical to the products obtained from resin
bound 4. This indicates that the resin bound isothiourea did not
a
-haloketones were examined under the
a-haloketone generated
a
form after the resin bound cyclic thiourea 4 reacted with the
a-
halocycloketone. This is probably caused by the stereo hindrance
of both structurally rigid reactants—the resin bound cyclic thiourea
and the
a-halocycloketone. This problem was not solved by
8. General procedure for the synthesis of 5,6-dihydroimidazo[2,1-b]thiazole
increasing the reaction time or raising the temperature to 90 °C.
In summary, a novel strategy for the high throughput synthesis
of 2,3,6-trisubstituted-5,6-dihydroimidazo[2,1-b]thiazole deriva-
tives has been reported by the use of a solid-phase synthetic
method. The resin bound cyclic thiourea was straightforwardly
generated from the resin bound amino acid and was reacted with
derivatives. 100 mg MBHA resin was sealed within
a polypropylene mesh
packet. Reactions were carried out in polypropylene bottles. A solution of N-Boc-
amino acid (5 equiv, 0.10 M in DMF), HOBt (5 equiv, 0.10 M in DMF), and DIC
(5 equiv, 0.10 M in DMF) was added to the reaction vessel. The reaction mixture
was shaken at room temperature for 2 h, followed by washing with DMF (3
times). Upon removal of the Boc-group with 55% TFA in DCM at room
temperature for 30 min, the resin was washed and neutralized with 5% DIEA
in DCM. After washing with DCM (2 times), DMF (1 time), DCM (2 times), and air
dried, the resin bound amino acids were reduced with borane in THF at 65 °C for
72 h, followed by treatment with piperidine at 65 °C overnight. The resin bound
diamines were then reacted with 1,10-thiocarbonyldiimidazole (5 equiv, 0.10 M
the linear
a-haloketone to form the resin bound isothiourea. The
HF cleavage and simultaneous formation of the enamine lead to
the final products, the 2,3,6-trisubstituted-5,6-dihydroimidazo
[2,1-b]thiazole derivatives. This strategy provides for the facile
high throughput preparation of structurally-diverse imidazothiaz-
ole derivatives.
in DCM) overnight. After washing with DCM, a-bromoketone (5 equiv, 0.10 M in
DMF) was added to the reaction vessel. The reaction was performed at 65 °C for
24 h. The resin packet was then washed with DMF (3 times), DCM (3 times) and
MeOH (3 times). The cleavage of the product was carried out by the treatment
with anhydrous HF at 0 °C for 90 min, followed by nitrogen gas flow to remove
the HF. The product was extracted by 95% acetic acid. After lyophilization, the
product of 2,3,6-trisubstituted-5,6-dihydroimidazo[2,1-b]thiazole was obtained.
The product was characterized by LC–MS under ESI conditions and NMR
spectroscopy. For representative product 6b: separation yield: 63%; HPLC column
condition: CH3CN(+0.05% formic acid) in H2O (+0.05% formic acid), 5–95% in
Acknowledgment
This work was supported by the State of Florida, Executive
Officer of the Governor’s Office of Tourism, Trade and Economic
6 min; column: luna C18, 5
lm, 50 ꢀ 4.60 mm, detection 254 nm, tR = 2.41 min;

698
Y. Li et al. / Tetrahedron Letters 52 (2011) 696–698
ESI-MS (m/z): 293.1 [M+H]; 1H NMR (500 MHz, CDCl3) d: 0.93 (d, 3H, J = 6 Hz),
[M+H]; 1H NMR (500 MHz, CDCl3) d: 2.00 (s, 3H), 2.07 (s, 3H), 2.87 (dd, 1H,
J = 9.2, 13.6 Hz), 3.06 (dd, 1H, J = 4.3, 13.6 Hz), 3.97 (dd, 1H, J = 3.9, 12.8 Hz), 4.11
(dd, 1H, J = 9.3, 12.8 Hz), 4.41–4.46 (m, 1H), 7.17 (d, 2H, J = 7.1 Hz), 7.27–7.36
(m, 3H).
3.83 (dd, 1H, J = 3.3, 12 Hz), 4.39 (dd, 1H, J = 9.5, 12 Hz), 4.42–4.44 (m, 1H), 7.06–
7.08 (m, 2H), 7.16–7.18 (m, 3H), 7.31–7.33 (m, 2H), 7.38–7.42 (m, 3H). 13C NMR
(250 MHz, CDCl3) d: 19.9, 56.5, 63.6, 127.8, 128.3, 128.9, 129.4, 129.5, 129.8. For
compound 6g: separation yield: 72%; HPLC: tR = 2.07 min; ESI-MS (m/z): 245.0