Traceless synthesis of hydantoin by focused microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2003.10.123

An efficient, microwave-assisted method for the liquid-phase combinatorial synthesis of 1,3-disubstituted hydantoin has been developed. Chloroacetyl chloride was directly anchored to HO-PEG-OH and subsequently reacted with various primary amines in a microwave cavity. The PEG bound secondary amine coupled with isocyanates and concomitant cyclization-cleavage step occurred in mild basic conditions by microwave flash heating. The desired products were then liberated from the soluble matrix in modest yield and high purity.

Full text of DOI:10.1016/j.tetlet.2003.10.123

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 437–440
Traceless synthesis of hydantoin by focused microwave irradiation
Ming-Juan Lee and Chung-Ming Sun*
Department of Chemistry, National Dong Hwa University, Shou-Feng, Hualien 974, Taiwan
Received 11 September 2003; revised 16 October 2003; accepted 17 October 2003
Abstract—An efficient, microwave-assisted method for the liquid-phase combinatorial synthesis of 1,3-disubstituted hydantoin has
been developed. Chloroacetyl chloride was directly anchored to HO–PEG–OH and subsequently reacted with various primary
amines in a microwave cavity. The PEG bound secondary amine coupled with isocyanates and concomitant cyclization–cleavage
step occurred in mild basic conditions by microwave flash heating. The desired products were then liberated from the soluble matrix
in modest yield and high purity.
ꢀ
2003 Elsevier Ltd. All rights reserved.
Because many potential drug targets have been identi-
fied through deciphering protein function with small
molecules, there is an urgent need to find efficient ways
to synthesize biologically active compounds. Combina-
torial chemistry provides a fast access to large quantities
of structurally diverse libraries to fuel the chemical
genetics. Solid-phase combinatorial synthesis has been
successfully developed to overcome tedious work-up,
purification problems arising from conventional
based chemistry to be performed with favorable reaction
kinetics and product purification is just like that
of solid-phase reactions. Furthermore, monitoring
the progress of reactions on the support is signifi-
cantly simplified by using conventional analytical
methods.
Hydantoin analogs have shown versatile therapeutic
applications and some of them have been approved by
1;2
4–9
synthesis.
However, solid-phase chemistry suffers
FDA as drugs. For example, Fosphenytoin as a so-
from various problems such as heterogeneous 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 con-
structing diverse multifunctional libraries. Liquid-
phase synthesis is a complementary type of solid-phase
synthesis, since this strategy enables standard solution-
dium channel antagonist is used for the treatment of
epilepsy. Phenytoin has antiarrhythmic, anticonvulsant,
and antineuralgic activities. Ethotoin and Mephenytoin
both show anticonvulsant effect. Nilutamide is a non-
steroidal orally active antiandrogen in combination with
surgical castration for the treatment of stage D2 meta-
static prostate cancer (Fig. 1). Moreover, hydantoins
also serve as intermediates for producing optically pure
3
O
O
O
O
CF3
CH3
O
O
H
H
CH3
N
N
OH
N
NH
O
H
HN
N
O
P
N
N
NO2
O
H C
3
OH
HN
H C
N
O
O
3
CH O
3
Fosphenytoin
Phenytoin
Ethotoin
Mephenytoin
Nilutamide
Figure 1. Examples of biologically active hydantoins.
Keywords: Hydantoin; Combinatorial chemistry; Microwave irradiation; Traceless synthesis.
*
Corresponding author. Tel.: +886-3-863-3583; fax: +886-3-863-0110; e-mail: cmsun@mail.ndhu.edu.tw
0
040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.123

438
M.-J. Lee, C.-M. Sun / Tetrahedron Letters 45 (2004) 437–440
natural and unnatural a-aminoacids, especially in me-
tabotropic receptor research.
solvent washing and drying of PEG bound secondary
amines 2, various isocyanates (3 equiv) were incorpo-
rated through microwave irradiation (100 W) within
5 min togive urea intermediates 3. The large excess of
isocyanates used to drive reactions to completion will
complicate final product purification. The control reac-
tion was also performed under normal thermal heating
in refluxing methylene chloride for 7 h to achieve the
same completion. When we compared both MW results
and conventional pre-heated oil bath results, we
observed that there is a clear improvement in yield and
reaction time by using MW heating. A similar
enhancement was also observed in other steps of the
current reaction sequence.
10–12
In order to quickly generate a compound library of in-
creasing molecular diversity, it would be favorable to
develop methods that combine the expediency of
microwave energy with the flexibility of soluble polymer-
supported combinatorial chemistry. The practicality of
microwave irradiation in chemical reaction enhance-
ment has been recognized for increasing reaction rates
13
and formation of cleaner products. It is clear that the
synergistic application of microwave technology to
rapidly synthesize biologically significant molecules on
1
4;15
the support
library generation. Although a number of hydantoin
would be of great benefit for accelerated
16–26
synthetic strategies have been reported,
application
The cyclization-assisted cleavage of polymer support
combined linker cleavage and ring formation in one-step
was conducted in mild basic conditions (K CO ) with
2 3
of microwave technology to multistep hydantoin syn-
thesis has not been demonstrated. We adapted herein a
hybrid strategy using both combinatorial and micro-
wave approach from readily available building blocks to
the expeditious synthesis of 1,3-disubstituted hydan-
toins.
100 W microwave flash heating for 5 min. The repre-
sentative library of 1,3-disubstituted hydantoins and
27
analytical results are listed in Table 1.
The major advantage of cyclorelease strategy is the fact
that only the desired compound is released into the
The general synthetic route toward the targeted mole-
cules is given in Scheme 1. Soluble polymer support
28
solution. Upon completion of the reaction, the polymer
support was removed from the homogeneous solution
by precipitation and filtration to provide the corre-
sponding crude products 4 in 70–94% yield calculated
on the basis of the initial loading to the support. The
desired compounds were obtained with 83–97% purity
as assessed by HPLC (Table 1). Structural character-
ization 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.
(
HO–PEG–OH, MWꢀ6000) dissolved in dichloro-
methane was reacted with chloroacetyl chloride in micro-
wave cavity for 10 min. For comparison to the
conventional thermal heating, coupling reaction was
also carried out by refluxing methylene chloride (pre-
heated oil bath) for 10 min, using the same stoichio-
metry. However, the reaction did not proceed at all in
the first 10 min time period. Reaction mixtures were
purified through a simple precipitation and filtration to
remove un-reacted reagents and side products. The same
work-up precipitation has been followed at every step of
the present reaction sequence. Nucleophilic substitution
of polymer immobilized chloroacetyl ester 1 with several
primary amines was carried out by microwave exposure
In summary, we have successfully combined the
advantages of microwave technology with liquid-phase
(
100 W) for 15 min in dimethylformamide. Following
O
Cl
(
3 eq.)
Cl
HO
OH
O
O
n
O
Cl
O
Cl
n
CH Cl
2
2
O
O
PEG-6000
MW (100 W), 10 m
1
R NH ( 4 eq.)
R NCO ( 3 eq.)
2
1
2
R1
R1
O
O
n
N
H
O
N
DMF
MW(100 W), 15 m
H
CH Cl
2 2
MW(100 W), 5m
O
O
2
O
O
R2
O
R2
O
O
n
R2
K CO (5 eq), CH Cl
2 3 2 2
N
N
R1
O
N
R1
N
H
N
H
N
O
O
R1
MW (100 W), 5 m
O
3
4
Scheme 1. Microwave-assisted synthesis of hydantoin on soluble polymer support.

M.-J. Lee, C.-M. Sun / Tetrahedron Letters 45 (2004) 437–440
Table 1. Representative products and results of hydantoins
439
a
b
Entry
R
1
NH
2
R
2
NCO
LRMS
Yield
Purity
4
a
b
O
O
341
88
91
O
2
N
NCO
NH
2
2
4
NCO
276
86
96
NH
4
4
c
NH2
NH2
NCO
232
246
90
93
86
96
d
NCO
Br
4
e
NH2
NH2
310
89
95
NCO
4
4
4
4
f
O
NCO
276
263
301
300
83
90
81
70
97
96
97
92
g
h
i
NH2
O N
NCO
NCO
2
O N
2
O
NH
2
O
NCO
O
O
NH
2
F
4j
274
80
83
NH
2
NCO
4
4
4
4
4
k
l
O N
NCO
312
311
281
329
348
94
76
78
71
70
96
96
94
97
95
2
N
NH
NH
NH
2
2
2
O
NCO
N
N
m
n
o
NCO
N
N
NH
2
N
O N
2
NCO
NCO
NH
2
O N
2
O
a
Crude yields determined by weight of crude sample (%).
Purity determined by HPLC analysis (UV detection at k ¼ 254 nm), Hypersil silica column, 250 · 4.6 mm, 5 l.
b
combinatorial chemistry to optimize 1,3-disubstituted
hydantoins synthesis. Purification steps are minimized,
analytical methods are significantly simplified and very
defined products are yielded. Microwave irradiation is a
powerful tool for accelerating reaction rate dramati-
cally. Compared to conventional thermal heating,
microwave irradiation decreased the reaction time on the
support from several days to several minutes. It is also
worth noting that the polymer-supported intermediates
and polymer support itself remain stable under micro-
wave 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.

440
M.-J. Lee, C.-M. Sun / Tetrahedron Letters 45 (2004) 437–440
Acknowledgements
15. Microwave-assisted solid-phase combinatorial synthesis:
a) Stadler, A.; Kappe, C. O. J. Comb. Chem. 2001, 3, 624–
30; (b) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin,
(
6
We gratefully acknowledge the National Science
Council (NSC 92-2751-B-001-014-Y) of Taiwan for the
financial support.
R. A. J. Comb. Chem. 2002, 4, 95–105; (c) Swamy, K. M.
K.; Lin, M. J.; Yeh, W. B.; Sun, C. M. Curr. Med. Chem.,
2
003, 10, 2403–2424.
1
6. DeWitt, S. W.; Kiely, J. S.; StanKovic, C. J.; Schroeder,
M. C.; Reynolds Cody, D. M.; Pavia, M. R. Proc. Natl.
Acad. Sci. 1993, 90, 6909–6913.
References and Notes
1
7. Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetrahe-
dron Lett. 1996, 37, 937–940.
1
. (a) Czarnik, A. W.; DeWitt, S. H. A Practical Guide to
Combinatorial Chemistry; American Chemical Society:
Washington, DC, 1997; (b) Fenniri, H. Combinatorial
Chemistry; Oxford: New York, 2000; (c) Seneci, P. Solid-
Phase Synthesis and Combinatorial Technologies; John
Wiley: New York, 2000.
18. Hanessian, S.; Yang, R. Y. Tetrahedron Lett. 1996, 37,
937–940.
19. Sim, M. M.; Lee, C. L.; Ganesan, A. J. Org. Chem. 1997,
62, 9358–9360.
20. Kim, S. W.; Ahn, S. Y.; Koh, J. S.; Lee, J. H.; Ro, S.; Cho,
H. Y. Tetrahedron Lett. 1997, 38, 4603–4606.
2
. Franz ꢀe n, R. J. Comb. Chem. 2000, 2, 195–214.
3
. Reviews see: (a) Sun, C. M. Comb. Chem. High Through-
put Scr. 1999, 2, 299–318; (b) Toy, P. H.; Janda, K. D.
Acc. Chem. Res. 2000, 33, 546–554; (c) Sun, C. M. In
Combinatorial Chemistry Methods and Protocols; Bella-
vance, L., Ed.; Methods in Molecular Biology Series; The
Humana: New Jersey, 2002; Chapter 10, pp 345–371.
. Brouillette, W. J.; Jestkov, V. P.; Brown, M. L.; Akhtar,
M. S.; DeLorey, T. M.; Brown, G. B. J. Med. Chem. 1994,
21. Smith, R. J.; Bratovanov, S.; Bienz, S. Tetrahedron 1997,
53, 13695–13702.
22. Boeijen, A.; Kruijtzer, J. A. W.; Liskamp, R. M. J. Bioorg.
Med. Chem. 1998, 8, 2375–2380.
23. Chong, P. Y.; Petillo, P. A. Tetrahedron Lett. 1999, 40,
2493–2496.
24. (a) Gong, Y. D.; Sohn, H. Y.; Kurth, M. J. J. Org. Chem.
1998, 63, 4854–4856; (b) Park, K. H.; Kurth, M. J.
Tetrahedron Lett. 2000, 41, 7409–7413.
4
37, 3289–3293.
5
. Matsugi, K.; Kageyama, M.; Nishimura, K.; Giles, H.;
Shirasawa, E. Eur. J. Pharm. 1995, 275, 245–250.
. Osz, E.; Somsak, L.; Szilagyi, L.; Kovacs, L.; Docsa, T.;
Toth, B.; Gergely, P. Bioorg. Med. Chem. Lett. 1999, 9,
25. Nefzi, A.; Giulianotti, M.; Truong, L.; Rattan, S.; Ostresh,
J. M.; Houghten, R. A. J. Comb. Chem. 2002, 4, 175–
178.
6
26. Zhang, W.; Lu, Yimin Org. Lett. 2003, 5, 2555–2558.
27. All the microwave-assisted polymer-supported reactions
described here were performed in a 50 mL round bottom
flask (attached tothe reflux c no denser) 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 (746 mg) and 4-nitrophenyl isocyanate (3 equiv) in
10 mL of dichloromethane was irradiated under a micro-
wave cavity with an output at 100 W for 5 min. Upon
completion of reaction, ether (30 mL) was added to the
reaction mixture at ice-water bath to precipitate out PEG-
bound urea compound 3a. The precipitate was then
collected on a sintered glass funnel and thoroughly
washed with diethyl ethyl (10 mL · 3) following filtration.
Finally, the desired hydantoin 4a was released from the
support in the microwave cavity with an output at 100 W
for 5 min by using K CO (5 equiv) in dichloromethane.
1
385–1390.
7
8
9
. Schelkun, R. M.; Yuen, P. W.; Sperpa, K.; Meltzer, L. T.;
Wise, L. D. J. Med. Chem. 2000, 43, 1892–1897.
. Scicinski, J. J.; Barker, M. D.; Murray, P. J.; Jarvie, E. M.
Bioorg. Med. Chem. Lett. 1998, 8, 3609–3614.
. Stilz, H. U.; Guba, W.; Jablonka, B.; Just, M.; Klingler,
O.; Konig, W.; Wehner, V.; Zoller, G. J. Med. Chem.
2
0. Monn, J. A.; Valli, M. J.; Massey, S. M.; Wright, R. A.;
Salhoff, C. R.; Johnson, B. G.; Howe, T.; Alt, C. A.;
Rhodes, G. A.; Robey, R. L.; Griffey, K. R.; Tizzano, J.
P.; Kallman, M. J.; Helton, D. R.; Schoepp, D. D. J. Med.
Chem. 1997, 40, 528–537.
001, 44, 1158–1176.
1
1
1. Tellier, F.; Acher, F.; Brabet, I.; Pin, J. P.; Azerad, R.
Bioorg. Med. Chem. 1998, 6, 195–208.
1
2. Monn, J. A.; Valli, M. J.; Massey, S. M.; Hansen, M. M.;
Kress, T. J.; Wepsiec, J. P.; Harkness, A. R.; Grutsch, J.
L.; Johnson, B. G.; Andis, S. L.; Kingston, A.; Tomlinson,
R.; Lewis, R.; Griffey, K. R.; Tizzano, J. P.; Schoepp, D.
D. J. Med. Chem. 1999, 42, 1027–1040.
3. For reviews of microwave-assisted reactions in solution
phase and solvent-free condition: (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; (d) Loupy, A.; Perreux, L. Tetra-
hedron 2001, 57, 9199–9223; (e) Lidstr o€ m, P.; Tierney, J.;
Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225–
2
3
The same work-up procedure has been followed by
precipitation to separate the desired product and polymer
support. The combined filtrate was dried to obtain 4a in
88% crude yield calculated on the basis of the initial
loading to the support. 1-(4-Methoxyphenyl)-3-(4-nitro-
1
1
phenyl)-imidazolidine-2,4-dione 4a: H NMR (300 MHz,
CDCl ): d 8.32 (d, J ¼ 9:3 Hz, 2H), 7.77 (d, J ¼ 9:3 Hz,
3
2H), 7.25 (d, J ¼ 8:7 Hz, 2H), 6.29 (d, J ¼ 8:7 Hz, 2H), 4.6
1
3
(s, 2H), 3.93 (s, 2H), 3.82 (s, 3H); C-NMR (75 MHz,
CDCl ): d 168.0, 159.8, 154.4, 146.3, 137.6, 129.9, 126.7,
3
þ
9
283.
4. (a) Larhed, M.; Hallberg, A. Drug Discov. Today 2001, 6,
06–416; (b) Wathey, B.; Tierney, J.; Lidstr o€ m, P.;
Westman, J. Drug Discov. Today 2002, 7, 373–380.
125.7, 124.3, 114.5, 55.4, 48.8, 46.5; MS (FAB ) m=z 342
(M+1).
1
4
28. Traceless solid-phase synthesis: Blaney, P.; Grigg, R.;
Sridharan, V. Chem. Rev. 2002, 102, 2607–2624.