Microwave-assisted traceless synthesis of thiohydantoin

Article abstract of DOI:10.1016/j.tetlet.2003.09.156

An efficient, microwave-assisted method for the liquid-phase combinatorial synthesis of 3,5-disubstituted-thiohydantoin has been developed. Fmoc-protected amino acids were coupled with HO-PEG-OH and after deprotection, reacted with various isothiocyanates

Full text of DOI:10.1016/j.tetlet.2003.09.156

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8739–8742
Microwave-assisted traceless synthesis of thiohydantoin
Mei-Jung Lin and Chung-Ming Sun*
Department of Chemistry, National Dong Hwa University, Hualien 974, Taiwan
Received 23 May 2003; revised 4 August 2003; accepted 8 September 2003
Abstract—An efficient, microwave-assisted method for the liquid-phase combinatorial synthesis of 3,5-disubstituted-thiohydantoin
has been developed. Fmoc-protected amino acids were coupled with HO-PEG-OH and after deprotection, reacted with various
isothiocyanates in microwave cavity. The PEG bound thiourea compounds underwent base mediated cyclization/cleavage step by
microwave flash heating. The desired products were then liberated from the soluble matrix in good yield and purity under
microwave exposure.
© 2003 Elsevier Ltd. All rights reserved.
With more and more therapeutic targets emerging from
chemical genomics research, combinatorial chemistry
provides a fast access to the structurally diverse
libraries to fuel the chemical genetics. Limitations in
efficiency of classical chemical synthesis resulting from
tedious work-up and purification after each reaction
step can be overcome by the solid phase synthesis due
to advantages like easy and fast purification.1 It is
expected that solid phase library synthesis, using known
solution-phase reaction conditions, will be useful to
identify novel therapeutics.2 However, solid-phase
chemistry suffers from various problems such as hetero-
geneous nature of reaction condition, reduced rate of
reactions, solvation of the bound species and mass
transport of reagents. We have been interested in
employing liquid-phase combinatorial technology as a
means of efficient construction of diverse multifunc-
tional libraries.3 This strategy enables standard solu-
tion-based chemistry to be utilized, and product
purification is just like that of solid phase reactions.
Furthermore, monitoring progress of reactions on the
support is significantly simplified by using conventional
analytical methods such as NMR, IR, HPLC and
TLC.4
toin structural motif have been identified to display a
wide range of biological activities (Fig. 1). For example,
phenytoin has many usages, such as antiarrhythmic,
anticonvulsant, antineuralgic, trigeminal neuralgia and
skeletal muscle relaxant.5,6 Sulfahydantoin has been
studied on the respect of inhibition of serine
proteases.7,8 The glucopyranosylidene-spiro-thiohydan-
toin is reported as an efficient inhibitor of muscle and
liver glycoen phosphorylases.9,10
Microwave irradiation in chemical reaction enhance-
ment has been well recognized for increasing reaction
rates and formation of cleaner products.11 In order to
quickly generate compounds of increasing molecular
diversity, the synergistic application of microwave tech-
nology to rapidly synthesize medicinally interesting
molecules on the support would be of great benefit for
accelerated library generation.12,13 Although a number
of strategies for synthesis of hydantoin analogs have
been reported,14–28 application of microwave technol-
Recently combinatorial organic synthesis has focused
on the generation of non-peptide small molecules with
potential therapeutical value. Compounds with hydan-
Figure 1. Examples of medicinally interesting hydantoin
analogs.
* Corresponding author: Fax: +(886)-3-8630110; e-mail: cmsun@
mail.ndhu.edu.tw
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.156

8740
M.-J. Lin, C.-M. Sun / Tetrahedron Letters 44 (2003) 8739–8742
The major advantage of cyclorelease strategy is the fact
that only the desired compound is released into the
solution.29 Upon completion of reaction, polymer sup-
port was removed from the homogeneous solution to
provide the corresponding products 4 in 88–99% yield
based on the initial loading to the support. The desired
compounds were obtained with 81–99% purity as
assessed by HPLC (Table 1). The structural characteriza-
tion of cleaved libraries demonstrates the success of the
major transformations described in Scheme 1. Products
from the validated libraries are characterized by mass
spectrometry and proton NMR confirming that in each
reaction the major compound has a molecular ion
corresponding to the appropriate product.
ogy to facilitate multi-step thiohydantoin synthesis is
unknown. We adopted herein a hybrid strategy using
both combinatorial and microwave approach from read-
ily available building blocks to the expeditious synthesis
of thiohydantoin derivatives.
The general synthetic route of thiohydantoins is given in
Scheme 1. Soluble polymer support (HO-PEG-OH, MW
ꢀ6000) dissolved in CH2Cl2 was coupled with Fmoc-
protected amino acids under DCC/DMAP activation by
focused microwave reactor (150 W) for 14 min. For the
comparison to the conventional thermal heating, cou-
pling reactions were also carried out in refluxing methyl-
ene chloride (preheated oil bath) for 14 min, using the
same stoichiometry. However, the reaction did not
proceed at all in the first 14 m time period. Reaction
mixtures were purified through a simple precipitation,
filtration and solvent washing to remove un-reacted
reagents and side products. The same work-up precipita-
tion has been followed at every step of the present
reaction sequence. Following deprotection of compound
1 with 10% piperidine in methylene chloride at room
temperature, various isothiocyanates were introduced
through 150 W microwave irradiation for 7 min in
methylene chloride to give thiourea intermediate 3. The
control reaction was also performed under normal ther-
mal heating in refluxing methylene chloride (preheated
oil bath) for 7 min, using identical stoichiometry. How-
ever, after cleavage we obtained only the unreacted
compound 2. The same reaction was found to complete
in three hours.
In summary, we have successfully combined the advan-
tages of microwave technology with liquid phase combi-
natorial
chemistry
to
facilitate
high-speed
3,5-disubstituted thiohydantoins synthesis. Purification
steps are minimized, analytical methods are significantly
simplified and well defined products are yielded.
Microwave irradiation is a powerful tool for accelerating
reaction rate dramatically. Compared to conventional
thermal hearting, microwave irradiation decreased the
reaction time on the support from several days to several
minutes. It should be stressed that the polymer supported
intermediates and polymer support itself remain stable
under microwave exposure. The coupling of microwave
technology with liquid-phase combinatorial synthesis
constitutes a novel and attractive avenue for the rapid
generation of structurally diverse libraries.
The cyclization/traceless cleavage step30 was complete
under mild basic condition (K2CO3) with 150 W
microwave flash heating for 7 min. The representative
library of thiohydantoins and analytical results are listed
in Table 1.
Acknowledgements
We thank the National Science Council of Taiwan for
financial support.
Scheme 1. Synthesis of 3,5-disubstituted thiohydantoins.

M.-J. Lin, C.-M. Sun / Tetrahedron Letters 44 (2003) 8739–8742
8741
Table 1. Representative products and results of 3,5-disubstituted thiohydantoins
References
5. Brouillette, W. J.; Jestkov, V. P.; Brown, M. L.; Akhtar,
M. S.; DeLorey, T. M.; Brown, G. B. J. Med. Chem.
1994, 37, 3289–3293.
6. Scicinski, J. J.; Barker, M. D.; Murray, P. J.; Jarvie, E.
M. Bioorg. Med. Chem. Lett. 1998, 8, 3609–3614.
7. Osz, E.; Somsak, L.; Szilagyi, L.; Kovacs, L.; Docsa, T.;
Toth, B.; Gergely, P. Bioorg. Med. Chem. Lett. 1999, 9,
1385–1390.
8. Kuang, R.; Epp, J. B.; Ruan, S.; Yu, H.; Huang, P.; He,
S.; Tu, J.; Schechter, N. M.; Turboy, J.; Froelich, C. J.;
Groutas, W. C. J. Am. Chem. Soc. 1999, 121, 8128–8129.
9. Kuang, R.; Epp, J. B.; Ruan, S.; Chong, L. S.;
Venkataraman, R.; Tu, J.; He, S.; Truong, T. M.;
Groutas, W. C. Bioorg. Med. Chem. 2000, 8, 1005–1016.
10. He, S.; Kuang, R.; Venkataraman, R.; Tu, J.; Truong, T.
M.; Chan, H. T.; Groutas, W. C. Bioorg. Med. Chem.
2000, 8, 1713–1717.
1. (a) Fenniri, H. Combinatorial Chemistry; Oxford Univer-
sity Press: New York, 2000; (b) Seneci, P. Solid-Phase
Synthesis and Combinatorial Technologies; John Wileys &
Sons: New York, 2000.
2. Franze´n, R. J. Comb. Chem. 2000, 2, 195–214.
3. (a) Sun, C. M. Comb. Chem. High Throughput Screening
1999, 2, 299–318; (b) Toy, P. H.; Janda, K. D. Acc.
Chem. Res. 2000, 33, 546–554; (c) Sun, C. M. In Combi-
natorial Chemistry Methods and Protocols; Bellavance, L.,
Ed.; Humana Press: New Jersey, 2002; Chapter 10, pp.
345–371; (d) Shang, Y. J.; Wang, Y. G. Tetrahedron Lett.
2002, 43, 2247–2249; (e) Lin, X. F.; Zhang, J.; Wang, Y.
G. Tetrahedron Lett. 2003, 44, 4113–4115.
4. Shey, J. Y.; Sun, C. M. Tetrahedron Lett. 2002, 43,
1725–1729.

8742
M.-J. Lin, C.-M. Sun / Tetrahedron Letters 44 (2003) 8739–8742
23. Lamothe, M.; Lannuzel, M.; Perez, M. J. Comb. Chem.
2002, 4, 73–78.
24. Nefzi, A.; Giulianotti, M.; Truong, L.; Rattan, S.;
Ostresh, J. M.; Houghten, R. A. J. Comb. Chem. 2002, 4,
175–178.
25. Hanessian, S.; Yang, R. Y. Tetrahedron Lett. 1996, 37,
5835–5838.
26. Boeijen, A.; Kruijtzer, J. A. W.; Liskamp, R. M. J.
Bioorg. Med. Chem. Lett. 1998, 8, 2375–2380.
27. Park, K. H.; Kurth, M. J. Tetrahedron Lett. 2000, 41,
7409–7413.
11. For reviews of microwave-assisted reactions in solution
phase and solvent free conditions, see: (a) Caddick, S.
Tetrahedron 1995, 51, 10403–10432; (b) Galema, S. A.
Chem. Soc. Rev. 1997, 26, 233–238; (c) Varma, R. S.
Green Chem. 1999, 1, 43–55; (c) Loupy, A.; Perreux, L.
Tetrahedron 2001, 57, 9199–9223; (d) Lidstro¨m, P.; Tier-
ney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57,
9225–9283.
12. (a) Larhed, M.; Hallberg, A. Drug Discovery Today 2001,
6, 406–416; (b) Wathey, B.; Tierney, J.; Lidstro¨m, P.;
Westman, J. Drug Discovery Today 2002, 7, 373–380.
13. For microwave-assisted solid-phase combinatorial syn-
thesis, see: (a) Stadler, A.; Kappe, C. O. J. Comb. Chem.
2001, 3, 624–630; (b) Lew, A.; Krutzik, P. O.; Hart,
M. E.; Chamberlin, R. A. J. Comb. Chem. 2002,
4, 95–105; (c) Blackwell, H. E. Org. Biomol. Chem. 2003,
1, 1251–1255; (d) Swamy, K. M. K.; Yeh, W. B.; Lin,
M. J.; Sun, C. M. Curr. Med. Chem. 2003, 10, 1241–
1263.
14. DeWitt, S. W.; Kiely, J. S.; StanKovic, C. J.; Schroeder,
M. C.; Reynolds, D. M.; Pavia, M. R. Proc. Natl. Acad.
Sci. 1993, 90, 6909–6913.
15. Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetra-
hedron Lett. 1996, 37, 937–940.
16. Sim, M. M.; Lee, C. L.; Ganesan, A. J. Org. Chem. 1997,
62, 9358–9360.
17. Kim, S. W.; Ahn, S. Y.; Koh, J. S.; Lee, J. H.; Ro, S.;
Cho, H. Y. Tetrahedron Lett. 1997, 38, 4603–4606.
18. Wu, S.; Janusz, J. M. Tetrahedron Lett. 2000, 41, 1165–
1169.
28. Lamothe, M.; Lannuzel, M.; Perez, M. J. Comb. Chem.
2002, 4, 73–78.
29. For traceless solid-phase synthesis, see: Blaney, P.; Grigg,
R.; Sridharan, V. Chem. Rev. 2002, 102, 2607–2624.
30. All the microwave-assisted polymer-supported reactions
described here were performed in a 100 mL round bot-
tom flask (attached to the reflux condenser) with CEM
Discover Microwave System at a frequency of 2450 Hz
(0–300 W). A typical procedure for the synthesis of 4a
(Table 1, entry 1): A mixture of polymer bound diamine
2a (600 mg) and n-butyl isothiocyanate (3.0 equiv.) in 5
mL of CH2Cl2 was irradiated under microwave cavity
with an output at 150 W for 7 min. Upon completion of
reaction, ether (20 mL) was added to the reaction mixture
to precipitate out PEG-bound thiourea compound 3a.
The precipitate was then collected on sintered glass fun-
nel and thoroughly washed with diethyl ether (3×20 mL)
following filtration. Finally, the desired cyclized thiohy-
dantoin 4a was released from the support in microwave
cavity with an output at 150 W for 7 min by using K2CO3
(3 equiv.) in dichloromethane. The combined filtrate was
dried to offer the corresponding crude product 4a, 3-
butyl-2-thioxoimidazolidin-4-one, in 90% yield with 81%
19. Albericio, F.; Garcia, J.; Michelotti, E. L.; Nicolas, E.;
Tice, M. Tetrahedron Lett. 2000, 41, 3161–3163.
20. Albericio, F.; Bryman, L. M.; Garcia, J.; Michelotti, E.
L.; Nicolas, E.; Tice, C. M. J. Comb. Chem. 2001, 3,
290–300.
21. Kita, R.; Svec, F.; Fre´chet, J. M. J. J. Comb. Chem. 2001,
3, 564–571.
22. Tremblay, M.; Voyer, N.; Boujabi, S.; Dewynter, G. F. J.
Comb. Chem. 2002, 4, 429–435.
1
HPLC purity: H NMR (300 MHz, CDCl3) l 4.06–4.03
(m, 2H), 3.81 (t, J = 7.5 Hz, 2H), 1.70–1.60 (m, 4H),
1.27–1.23 (m, 3H); 13C NMR (75 M Hz, CDCl3) l
183.25, 171.51, 48.34, 41.25, 29.63, 20.03, 13.68; IR
(cm−1, neat) 2956, 2911, 1713, 1506, 1434, 1345; MS (EI)
m/z 172 (M+).