An efficient protocol for solid phase aminothiazole synthesis

Article abstract of DOI:10.1016/j.tetlet.2006.06.169

An efficient synthesis of 2,4-diamino-5-ketothiazoles under solid phase conditions has been achieved by the reaction of polymer supported amidinothioureas with α-haloketones. This novel synthetic approach involving traceless cleavage from the support is s

Full text of DOI:10.1016/j.tetlet.2006.06.169

Tetrahedron Letters 47 (2006) 6179–6182
An efficient protocol for solid phase aminothiazole synthesis
Kumaran G. Sreejalekshmi, Satyabhama K. C. Devi and Kallikat N. Rajasekharan*
Department of Chemistry, University of Kerala, Trivandrum, Kerala 695 581, India
Received 19 May 2006; revised 20 June 2006; accepted 30 June 2006
Abstract—An efficient synthesis of 2,4-diamino-5-ketothiazoles under solid phase conditions has been achieved by the reaction of
polymer supported amidinothioureas with a-haloketones. This novel synthetic approach involving traceless cleavage from the sup-
port is suited for automation, and allows solid phase combinatorial synthesis of 2,4-diamino-5-ketothiazoles in good yields and
purities.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The utility of solid phase reactions in combinatorial
library synthesis depends largely upon the efficiency of
the synthetic route selected and the availability of re-
agents. Since attractive targets for combinatorial synthe-
sis are often small organic molecules1 with useful
bioactivity profiles, rapid synthesis through simple
routes has great appeal. Aminothiazoles, with a wide
spectrum of well established bioactivity,2 are being con-
tinually investigated for newer therapeutic applications.
We have reported3 on the solution phase synthesis of
2,4-diamino-5-ketothiazoles 1 and their cytotoxic prop-
erties.4 Moreover, thiazole derivatives of type 1 are
reported to be potential inhibitors of cyclin-dependent
kinases (CDKs)5 and glycogen synthase kinase-3
(GSK-3).6
reagent in a solid phase thiocarbamoylamidine transfer
protocol.
The design of the solid phase route was based on a retro-
synthesis, which is outlined in Scheme 1. We proposed
to access the target 1 through a [4+1] ring construction
approach in which the C–N–C–S unit for the thiazole
H2N
N
R2
NHR1
S
O
1
NH
S
The increasing appearance of aminothiazole motifs in
potential drug candidates has resulted in the design of
solid phase routes7 to these molecules. A literature sur-
vey revealed only two reports8 on the solid phase synthe-
sis of 2,4-diamino-5-ketothiazoles. As part of our efforts
to develop versatile solid phase routes to these scaffolds,
we earlier reported the design and synthesis of a novel
thiocarbamoylamidine transfer reagent.9 We now report
an efficient, two-step procedure for the solid phase
synthesis of 2,4-diamino-5-ketothiazoles starting from
aminomethylpolystyrene and employing the above
R2COCH2X
+
R3HN
N
H
NHR1
3
2
NH
S
N
N
N
H
NHR1
R3NH2
+
4
5
HN
N
NH2
N
R1NCS
+
Keywords: Solid phase synthesis; 2,4-Diamino-5-ketothiazoles; Thio-
carbamoylamidine transfer; Traceless cleavage; Aminomethyl-
polystyrene.
6
7
*
Corresponding author. Tel.: +91 471 255 2986; fax: +91 471 244
5947; e-mail: rajkn_1951@yahoo.com
Scheme 1. Retrosynthesis of 2,4-diamino-5-ketothiazoles 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.169

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K. G. Sreejalekshmi et al. / Tetrahedron Letters 47 (2006) 6179–6182
Table 1. Sulfur analysis data of polymer bound amidinothioureas 9a–d
ring would be derived from an amidinothiourea 2 and
the remaining C atom from an a-haloketone 3. It was
decided to anchor the amidinothiourea unit onto a solid
support using the thiocarbamoylamidine transfer
protocol. The transfer reagents 5 required for this step
could be synthesized easily from commercially available
1-amidino-3,5-dimethylpyrazole 6 and isothiocyanates
7, as reported earlier, as a prelude to the present
work.9
Amidinothiourea 9
R1
S capacity (%)
a
b
c
C6H5
0.80
1.50
0.70
1.40
4-ClC6H4
4-CH3C6H4
4-CH3OC6H4
d
NH
The first step in the synthesis involved the development
of polymer anchored amidinothioureas 9 (Scheme 2).
This required the selection of amino polymer 8,10,11
which could be reacted with 5 to access polymer an-
chored amidinothioureas 9 which are analogous to 2.
Prior to this step, the reaction conditions for the thio-
carbamoylamidine transfer were optimized using pilot
reactions in solution phase conditions. For the optimiza-
tion step, various primary amines 4 and differently
substituted thiocarbamoylamidine transfer reagents 5
were employed.12 The conditions for the reaction be-
tween polymer 8 and transfer reagents 5 were also inves-
tigated in a number of trials, and the optimized
conditions were identified by evaluating the extent of
thiocarbamoylamidine transfer reaction13 by varying
the reagent concentrations and the reaction time or tem-
perature. Thus, two equivalents of transfer reagent 5a–d
was added to aminomethylpolystyrene beads swelled in
acetonitrile in four separate reaction vessels based on
the amino group capacity of the resin. The reaction
flasks were kept at 70–75 ꢁC in a constant temperature
bath and the reactions proceeded in a parallel fashion.
The resin, after work up,14 was subjected to sulfur anal-
ysis (Table 1) and was assigned structure 9 based on IR
NH
S
N
H2N
R2COCH2Br 3
DMF, Et3N
R2
N
H
N
H
NHR1
NR1
S
O
9
NH
H2N
NH
H2N
N
N
R2
R2
−
NR1
H2N
NHR1
S
S
H
O
O
N
NH2
−
R2
NHR1
S
O
1
Scheme 3. Solid phase synthesis of 2,4-diamino-5-ketothiazoles 1.
studies as well as on the results from solution phase
model reactions.
The next step was the reaction of polymer anchored
amidinothioureas 9 with various a-haloketones 3. It
was decided to employ a-bromoketones as the active
methylene compounds in view of the greater reactivity
of these compounds in nucleophilic substitution reac-
tions as well as their commercial availability. The reac-
tion of resins 9 with 3 in DMF15 proceeded through
an acyclic S-alkylisothiourea intermediate, which
cyclized to a thiazoline. This underwent eliminative
aromatization to afford tracelessly, 2,4-diamino-5-
ketothiazoles 1 (Scheme 3), after work-up,16 in good
yields and purities. The generality of the synthetic route
was evaluated by employing both aryl and heteroaryl
substituted haloketones 3, and the representative com-
pounds thus synthesized are summarized in Table 2.
The crude yields of 1 were in the range of 88–92% and
the purities of the crude samples17 were in the range
85–90%. After purification by column chromatography
on silica, the pure thiazoles were obtained in 60–73%
yields.
S
NH
N
R1HN
N
H
N
NH2
+
8
5
CH3CN;
70-75 oC;
12-15 h
5, 9
a; R1= C6H5
b; R1= 4-ClC6H4
c; R1= 4-CH3C6H4
d; R1= 4-CH3OC6H4
NH
S
N
H
N
H
NHR1
9
Scheme 2. Synthesis of polymer bound amidinothioureas 9 using
thiocarbamoylamidine transfer reagents 5.
Table 2. 2,4-Diamino-5-ketothiazoles 1a–h
Thiazole 1
R1
R2
Yield (%)
Mp (ꢁC)
Lit. mp (ꢁC)
a
C6H5
C6H5
C6H5
C6H5
C6H5
4-ClC6H4
2-C10H7
Indol-3-yl
Coumarin-3-yl
65
73
68
67
72
70
67
60
186–87
200–01
155–56
205–06
196–98
221–23
258–59
>320
18619
200–019
155–5619
205–0619
1969
—
—
—
b
4-ClC6H4
4-CH3C6H4
4-CH3OC6H4
C6H5
C6H5
4-ClC6H4
4-ClC6H4
c
d
e
f20
g21
h22

K. G. Sreejalekshmi et al. / Tetrahedron Letters 47 (2006) 6179–6182
6181
11. Mathew, B.; Pillai, V. N. R. Eur. Polym. J. 1994, 30, 61–
65.
In conclusion, a simple, efficient, two-step synthesis of
2,4-diamino-5-ketothiazoles suited to solid phase combi-
natorial synthesis has been achieved. This synthetic
route allows easy amplification of molecular diversity
in the target core structure by varying the isothiocya-
nates and a-haloketones, many of which are commer-
cially available. The reaction conditions are mild,
work-up is simple, and the steps are automation-
friendly. The reuse of the spent resin was also investi-
gated.18 Further studies on the mechanistic aspects as
well as the construction of combinatorial libraries are
in progress and will be reported in due course.
12. Solution phase pilot reactions on individual n-alkylamines
with thiocarbamoyl transfer reagent 5a in acetonitrile at
50–55 ꢁC afforded the corresponding 1-(N-alkylamidino)-
3-phenylthioureas as major products in good yields.
13. The sulfur capacities of the resins were measured after
each reaction to evaluate the extent of thiocarbamoylam-
idine transfer. When transfer reagent 5 (R1 = alkyl) was
used, the extent of thiocarbamoylamidine transfer was
found to be low.
14. Each vessel was charged with 1.5 g of resin 8 swelled in
acetonitrile (10 mL) followed by the thiocarbamoylami-
dine transfer reagent 5 (2 M equiv based on the amino
group capacity of the resin) and kept at 70–75 ꢁC for 12–
15 h with occasional mixing. The suspension was then
filtered while hot. The resin beads were washed in
succession with the following warm solvents: acetonitrile
(5 mL · 3); petroleum ether (2 mL · 3); acetonitrile
(5 mL · 2); ethanol (95%, 5 mL · 3) and finally methanol
(5 mL · 2). The resin was then dried under vacuum.
15. Devi, S. K. C.; Rajasekharan, K. N. Synth. Commun.
2002, 32, 1523–1528.
Acknowledgements
K.G.S. acknowledges a Junior Research Fellowship
from the University Grants Commission, Govt. of
India. The authors thank RRL, Trivandrum, and
CDRI, Lucknow, for spectral and analytical data.
16. To resin 9a (2.5 g, S capacity 0.8%), pre-swelled in DMF
(10 mL), a-bromoketone 3a (1 M equiv) was added and
the suspension was heated at 60 ꢁC with occasional
shaking for 30 min. After adding triethylamine (1.1 equiv)
which acts as a catalyst as well as a quench for the
generated HBr, the suspension was kept at 60 ꢁC for
another 30 min and then left at room temperature
overnight. The resulting orange-yellow mixture was fil-
tered and the resin beads were washed with DMF
(2 mL · 2). The filtrate and washings were combined and
slowly added to ice-water (75 mL) with rapid stirring. This
afforded a yellow solid (86%). To obtain a pure sample for
analysis, the crude product was purified on a silica gel (60–
120 mesh) column using ethyl acetate–petroleum ether
(3:1) mixture as eluent to obtain 1a (65%).
References and notes
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Storer, R.; Watson, S. P. Bioorg. Med. Chem. Lett. 1996,
6, 1409–1414; (b) Hargrave, K. D.; Hess, F. K.; Oliver, J.
T. J. Med. Chem. 1983, 26, 1158–1163; (c) Tsuji, K.;
Ishikawa, H. Bioorg. Med. Chem. Lett. 1994, 4, 1601–
1606; (d) Gorczynski, M. J.; Leal, R. M.; Mooberry, S. L.;
Bushweller, J. H.; Brown, M. L. Bioorg. Med. Chem. Lett.
2004, 12, 1029–1036; (e) Guba, W.; Neidhart, W.;
Nettekoven, M. Bioorg. Med. Chem. Lett. 2005, 15,
1599–1603.
17. The crude product was analyzed by HPLC using a
Shimadzu ODS column (25 cm · 4.6 mm) using a 1%
TFA water–acetonitrile gradient.
3. Rajasekharan, K. N.; Nair, K. P.; Jenardanan, G. C.
Synthesis 1986, 353–355.
4. Sengupta, S.; Smitha, S. L.; Thomas, N. E.; Santhosh-
kumar, T. R.; Devi, S. K. C.; Sreejalekshmi, K. G.;
Rajasekharan, K. N. Br. J. Pharmacol. 2005, 145, 1076–
1083.
5. Rosania, G. R.; Chang, Y.-T. Expert Opin. Ther. Patents
2000, 10, 215–230.
6. Dorronsoro, I.; Castro, A.; Martinez, A. Expert Opin.
Ther. Patents 2002, 12, 1527–1536.
7. (a) Katritzky, A. R.; Cai, X.; Rogovoy, B. V. J. Comb.
Chem. 2003, 5, 392–399; (b) Kazzouli, S. E.; Raboin, S. B.;
Mouaddib, A.; Guillaumet, G. Tetrahedron Lett. 2002, 43,
3193–3196; (c) Steiber, F.; Mazitschek, R.; Soric, N.;
Giannis, A.; Waldmann, H. Angew. Chem., Int. Ed. 2002,
41, 4757–4761; (d) Goff, D.; Fernandez, J. Tetrahedron
Lett. 1999, 40, 423–426; Kearney, P. C.; Fernandez, M.;
Flygare, J. A. J. Org. Chem. 1998, 63, 196–200.
8. (a) Baer, R.; Masquelin, T. J. Comb. Chem. 2001, 3, 16–19;
(b) Lee, I. Y.; Lee, J. Y.; Lee, H. J.; Gong, Y.-D. Synlett
2005, 16, 2483–2485.
18. The reuse of spent resin was explored by thoroughly
washing it with a variety of solvents, drying and then
taking it through the synthetic cycle as described above.
As a typical example, thiazole 1b was obtained in 68%
crude and 47% purified yield. Further repetition of the
cycle deleteriously affected the yield and purity of the
product.
19. Binu, R.; Thomas, K. K.; Jenardanan, G. C.; Rajasekh-
aran, K. N. Org. Prep. Proced. Int. 1998, 30, 93–96.
20. Compound 1f: IR (KBr) mmax: 3467, 3267, 1622, 1528, 1445,
824, 741 cmÀ1; 1H NMR (270 MHz, DMSO-d6): d 7.20 (t,
J 7.8 Hz, 1H, ArH), 7.48 (t, J 8.1 Hz, 2H, ArH), 7.71–7.77
(m, 4H, ArH), 7.89 (dd, J 8.53, 1.73 Hz, 1H, ArH), 8.08–
8.18 (m, 3H, ArH), 8.39 (br, 2H, ArH and NH), 10.92 (s,
1H, NH); 13C NMR (67.5 MHz, DMSO-d6): d 92.65,
119.05, 123.42, 124.33, 126.86, 127.47, 127.71, 128.15,
132.17, 133.72, 139.31, 139.62, 167.27, 182.61. Anal. Calcd
for C20H15N3OS: C, 69.54; H, 4.38; N, 12.17. Found: C,
69.29; H, 4.62; N, 12.05.
21. Compound 1g: IR (KBr) mmax: 3392, 3298, 2993, 1635,
1584, 1490, 1452, 1315, 1242, 1177, 1012, 823, 757,
676 cmÀ1 1H NMR: (200 MHz, DMSO-d6 + CDCl3): d
;
9. Jenardanan, G. C.; Francis, M.; Deepa, S.; Rajasekharan,
K. N. Synth. Commun. 1997, 27, 3457–3462.
7.15–7.22 (m, 2H, ArH), 7.27 (d, J 5.9 Hz, 2H, ArH), 7.34
(br, 2H, NH2), 7.42 (d, J 5.1 Hz, 1H, ArH), 7.59 (d, J
5.9 Hz, 2H, ArH), 7.79 (d, J 1.9 Hz, 1H, ArH), 8.31 (d, J
5.1 Hz, 1H, ArH), 10.28 (s, 1H, NH), 11.06 (s, 1H, NH);
13C NMR (75 MHz, DMSO-d6 + CDCl3): d 92.67, 111.2,
117.41, 119.85, 120.57, 121.53, 122.23, 126.11, 127.09,
10. Aminomethylpolystyrene 8 was prepared from Merrifield
resin (Sigma, 1% DVB cross-linked, 200–400 mesh, 0.9–
1.1 mmole Cl/g) using the literature method11 and its
amino capacity was estimated to be 0.90 mmole NH2/g by
titrimetry.

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K. G. Sreejalekshmi et al. / Tetrahedron Letters 47 (2006) 6179–6182
127.83, 128.40, 135.92, 138.18, 163.32, 165.59, 179.71;
DMSO-d6): d 7.20–7.89 (m, 8H, ArH), 8.16 (br, 2H, NH),
8.27 (s, 1H, ArH), 10.93 (br, 1H, NH); EIMS: m/z (%):
399 (M+2, 20), 398 (M+1, 39), 397 (M+, 65), 396 (100),
395 (68), 394 (47), 360 (15), 218 (8), 188 (13), 173 (52), 147
(72), 145 (18), 127 (70). Anal. Calcd for C19H12ClN3O3S:
C, 57.36; H, 3.04; N, 10.56. Found: C, 57.20; H, 2.92; N,
10.62.
EIMS: m/z (%): 370 (M+2, 6), 368 (M+, 12), 367 (7), 353
(7), 351 (15), 153 (4), 145 (10), 144 (100), 116 (26), 111 (3),
89 (24). Anal. Calcd for C18H13ClN4OS: C, 58.61; H, 3.55;
N, 15.19. Found: C, 58.56; H, 3.70; N, 15.28.
22. Compound 1h: IR (KBr) mmax: 3400, 3300, 1720, 1600,
1520, 1465, 1160, 1040, 820, 750 cmÀ1; 1H NMR (90 MHz,