Microwave-assisted solid-phase synthesis of hydantoin derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.05.084

A microwave-assisted synthesis of 3,5- and 1,3,5-substituted hydantoins starting from various resins for solid-phase combinatorial chemistry has been developed. The hydantoins were synthesized from pre-loaded resins with amino acids via treatment with isocyanate or phenylisocyanate and subsequent intramolecular cyclization. Both reactions were performed under microwave irradiation. We studied the cyclative cleavage leading to hydantoin compounds dependent on the nature of the amino acid and the nucleofuge properties of the resin.

Full text of DOI:10.1016/j.tetlet.2007.05.084

Tetrahedron Letters 48 (2007) 5317–5320
Microwave-assisted solid-phase synthesis of hydantoin derivatives
Evelina Colacino, Fr e´ d e´ ric Lamaty, Jean Martinez and Isabelle Parrot*
Institut des Biomol e´ cules Max Mousseron, UMR 5247 CNRS-Universit e´ s Montpellier 1 et 2, Pl. Eug e` ne, Bataillon,
3
4095 Montpellier Cedex 5, France
Received 5 March 2007; revised 2 May 2007; accepted 15 May 2007
Available online 18 May 2007
Abstract—A microwave-assisted synthesis of 3,5- and 1,3,5-substituted hydantoins starting from various resins for solid-phase com-
binatorial chemistry has been developed. The hydantoins were synthesized from pre-loaded resins with amino acids via treatment
with isocyanate or phenylisocyanate and subsequent intramolecular cyclization. Both reactions were performed under microwave
irradiation. We studied the cyclative cleavage leading to hydantoin compounds dependent on the nature of the amino acid and
the nucleofuge properties of the resin.
ꢀ
2007 Elsevier Ltd. All rights reserved.
Hydantoin moiety constitutes an attractive pharmaco-
logical scaffold present in several drugs. This small
transform electromagnetic radiation into heat. The short
reaction times and expanded reaction range offered by
microwave-assisted chemistry in conjunction with the
well-known advantages of solid-phase chemistry could
allow us to generate hydantoin leads efficiently.
Although several synthetic methods are described for
the preparation of hydantoin libraries, including micro-
wave-assisted liquid-phase combinatorial synthesis,
none of them combines solid-phase and microwave syn-
1
and rigid heterocyclic backbone, presenting three points
of diversity, could act on various pharmacological tar-
gets. Especially, hydantoin nucleus could be found in a
broad range of biological active compounds displaying
neuroprotective, antiarrhythmic, anticonvulsant, anti-
hypertensive, anti-inflammatory, analgesic, antidiabetic,
antiandrogen, antibacterial, antiviral, antifungal, or
diuretic activities as well as herbicidal or fungicidal
1
,20,21
thesis, to the best of our knowledge.
The novel part
2
–10
properties.
Various alkaloid compounds from mar-
of this paper is the use of microwave energy/heating, but
combined with solid-phase technology this would have
to be the most efficient route in terms of reaction time
taken, product purity, and yield that can be achieved.
ine organisms or bacteria contain also an hydantoin
1
moiety. Moreover, hydantoins are the key intermedi-
ates during the synthesis of optically pure natural and
unnatural amino acids especially those involved on
metabotropic ligands.11–13
Since the first report of solid-phase synthesis of hydan-
2
2
toin libraries by DeWitt et al., several synthetic meth-
2
3–27
In order to quickly generate large libraries of hydanto-
ins, we expected that the combination of the solid-phase
tool and the microwave technology will be useful for the
development of efficient methodologies for the produc-
tion of hydantoin scaffolds for drug discovery. Micro-
wave irradiation technology in organic synthesis has
now become an integrated part of combinatorial chem-
ods have been developed on resins or PEG.
We were
especially interested by base-catalyzed cyclative cleavage
strategies allowing both cyclization and cleavage in one
2
8
step. The hydantoin formation via solid-phase intra-
molecular cyclization is well represented in the litera-
ture. The major advantage of this strategy resides in
the fact that products which are not capable of cycli-
zation remain attached to the solid support leading
1
4–19
istry and drug discovery process.
Microwave irradi-
ation heats the reaction contents directly by taking
advantage of the ability of some liquids and solids to
R
N
2
O
O
H
N
O
OCNR
2
O
Base
NH
2
O
O
Keywords: Hydantoin; Solid-phase synthesis; Microwave irradiation;
O
HN
R
1
HN
R
1
Cyclative cleavage.
R
2
R
1
*
Corresponding author. Tel.: +33 (0) 4 67144986; fax: +33 (0) 4
7144866; e-mail: isabelle.parrot@univ-montp2.fr
6
Scheme 1.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.084

5318
E. Colacino et al. / Tetrahedron Letters 48 (2007) 5317–5320
generally to highly pure compounds. The rate of cycliza-
tion is then dependent on the nature of the side chains
R and R attached to the cyclic compound in formation,
but also dependent on the nucleofuge property of the
resin under the same basic conditions (Scheme 1).
For the synthesis of hydantoin libraries on solid sup-
port, one of the most powerful methods could be the
use of commercially available pre-loaded resins with
N-protected amino acids. Suitable N-deprotection of
the amino acid followed by reaction of the resin with
1
2
Table 1. Hydantoins produced via Scheme 2
a
Entry
Resins (1)
1
aa (R )
R
2
Yield % (4)
R
1
Phe
Phe
Ala
Val
Glu(OBz)
Ile
Ph
H
Ph
Ph
Ph
Ph
95
90
90
75
85
80
NHBoc
1
O
O
Boc-aa-Merrifield resin
O
2
Gly
Phe
Phe
Ile
Val
Leu
Ala
Pro
Ph
Ph
H
Ph
Ph
Ph
Ph
Ph
Ph
H
70
100
90
85
80
75
75
90
95
90
O
O
NHFmoc
R
1
Fmoc-aa-Wang resin
Glu(Ot-Bu)
Glu(Ot-Bu)
R
1
NH
2
3
O
Pro
Glu(Ot-Bu)
Ph
Ph
90
75
O
Cl
aa-2-ClTrt resin
R
1
NHBoc
O
O
4
Ala
Ph
Ph
Ph
60
10
40
HN
O
Boc-aa-PAM resin
5
Ala
NH
O
R
1
BocHN
Boc-aa-MBHA resin
PEG
HN
O
O
6
Glu(Ot-Bu)
ꢁ
O
O
FmocHN
R
1
Fmoc-aa-NovaSyn TGA resin
a
Yields determined by weighing of crude sample (95–100% purity determined by HPLC analysis).

E. Colacino et al. / Tetrahedron Letters 48 (2007) 5317–5320
5319
R
2
O
R
1
R1
R
1
O
N
i
ii
iii
linker
O
PG
linker
O
linker
O
R2
NH
N
NH2
N
N
MW
O
H
MW
H
H
O
O
O
R
1
1
2
3
4
Scheme 2. Reagents and conditions: (i) 20% piperidine in DCM, 20 min, rt or 50% TFA in DCM, 1 h, rt, then Et
irradiation power 300 W, 10 min; and (iii) Et N, THF/DMF (4:1 v/v), MW irradiation power 300 W, 15 min.
3 2
N, (ii) R NCO, THF, MW
3
an isocyanate could generate the corresponding urea
Scheme 1). Treatment of this intermediate with a base
tional solid-phase synthesis. All the tested resins were
found to resist under microwave irradiation. However,
the amide bound resins, less sensitive to cleavage due
to their poor nucleofuge potential, released hydantoin
compounds with lower yields (Table 1, entries 5 and
6). We reasoned that an ester linkage is more suitable
for cyclative cleavage, following our general basic proto-
col under microwave irradiation.
(
leads to nucleophilic attack on the ester (or amide)
allowing the release of the hydantoin product. Under
these basic conditions, urea will undergo cleavage, while
unreacted amino acid will remain on the sup-
2
1,23,24,26,27,29–32
port.
After cleavage, only the desired
product is released in the solution, therefore facilitating
significantly the purification step.
The results from the solid-phase synthesis of hydantoins
by cyclorelease strategy clearly demonstrate that micro-
wave irradiation offers an effective and attractive tech-
nique to produce a library of hydantoins with short
reaction times, in high yields, and with high purity com-
pared to conventional classic thermal described in the
literature. Microwave-assisted heating should prove
highly practical for combinatorial solid-phase synthesis
of hydantoins or other heterocyclic scaffolds.
In order to determine the most suitable resin for such
transformation under microwave heating, we studied
and compared the performance of various resins under
the same microwave conditions. For this purpose, reac-
tions were performed using various combinations of
resins, spacers, linkers, or amino acids (Table 1). The
general synthetic route toward the targeted molecules
is shown in Scheme 2. After N-deprotection of the
anchored amino acid (Boc or Fmoc protecting group,
except in the case of aa-2-ClTrt resin, entry 3) at room
temperature, the two other steps were carried out under
microwave conditions using a single mode cavity synthe-
sizer to ensure reproducibility. At each step, the reaction
conditions were optimized under microwave irradiation
using various experimental conditions such as tempera-
ture, reaction time, power of the irradiation, solvent,
and concentration of starting materials. The reaction
progress was monitored by IR of the resin (urea FTIR
Acknowledgements
We thank the CNRS and the ‘Ligue Contre le Cancer’
for financial support.
À1
1
References and notes
at 1656 cm ) and by LC/MS and H NMR analyses
of the final hydantoin. The treatment of the free amine
moiety of the solid-phase bound amino acid (1.0 g,
1
2
. Meusel, M.; Gutschow, M. Org. Prep. Proced. Int. 2004,
6, 391–443.
. 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.
3
0
.76 mmol, 0.76 mmol/g) with isocyanate (3.04 mmol)
was achieved in THF (5 mL) in a microwave reactor
at 60 ꢂC for 10 min. A control reaction for isocyanate
coupling was performed in parallel, at room tempera-
ture in THF, for 10 h to achieve the same completion.
The resin was then washed, dried and treated with
3. Matsugi, T.; Kageyama, M.; Nishimura, K.; Giles, H.;
Shirasawa, E. Eur. J. Pharmacol. 1995, 275, 245–250.
4
5
6
. Osz, E.; Somsak, L.; Szilagyi, L.; Kovacs, L.; Docsa, T.;
Toth, B.; Gergely, P. Bioorg. Med. Chem. Lett. 1999, 9,
Et N (0.43 mL, 3.04 mmol) in THF/DMF (5 mL, 4:1
3
1
385–1390.
v/v) in a microwave reactor at 110 ꢂC for 15 min. Higher
temperatures did not give any additional improvements.
A control reaction for cyclative cleavage was also per-
formed under normal thermal heating in refluxing
THF for 12 h to achieve the same completion. Under
optimal conditions, hydantoins were obtained from 2
in 25 min instead of 22 h under conventional well-
known conditions.
. Schelkun, R. M.; Yuen, P. W.; Serpa, K.; Meltzer, L. T.;
Wise, L. D.; Whittemore, E. R.; Woodward, R. M. J.
Med. Chem. 2000, 43, 1892–1897.
. Scicinski, J. J.; Barker, R. D.; Murray, P. J.; Jarvie, E. M.
Bioorg. Med. Chem. Lett. 1998, 8, 3609–3614.
7. Stilz, H. U.; Guba, W.; Jablonka, B.; Just, M.; Klingler,
O.; Konig, W.; Wehner, V.; Zoller, G. J. Med. Chem.
2
001, 44, 1158–1176.
8
. Kuang, R. Z.; Epp, J. B.; Ruan, S. M.; Yu, H. Y.; Huang,
P.; He, S.; Tu, J.; Schechter, N. M.; Turbov, J.; Froelich,
C. J.; Groutas, W. C. J. Am. Chem. Soc. 1999, 121, 8128–
This general protocol33 could be applied to all the previ-
ously described pre-loaded resin with an ester linkage
between the amino acid and the resin (Table 1, entries
8
129.
9
. Kuang, R. Z.; Epp, J. B.; Ruan, S.; Chong, L. S.;
Venkataraman, R.; Tu, J.; He, S.; Truong, T. M.;
Groutas, W. C. Biorg. Med. Chem. 2000, 8, 1005–1016.
1
–4) allowing the synthesis of a library of various hyd-
antoins with good to excellent yields. We were able to
provide for a diverse set of amino acids, heterocyclic
compounds with yields in the same order to conven-
10. Ohta, H.; Jikihara, T.; Wakabayashi, K.; Fujita, T. Pestic.
Biochem. Phys. 1980, 14, 153–160.

5320
E. Colacino et al. / Tetrahedron Letters 48 (2007) 5317–5320
1
1. Monn, J. A.; Valli, M. J.; Massey, S. M.; Wright, R. A.;
25. Stadlwieser, J.; Ellmerer-Muller, E. P.; Tako, A.; Mas-
louh, N.; Bannwarth, W. Angew. Chem., Int. Ed. 1998, 37,
1402–1404.
26. Boeijen, A.; Kruijtzer, J. A. W.; Liskamp, R. M. J. Bioorg.
Med. Chem. Lett. 1998, 8, 2375–2380.
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.
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.; Wright, R. A.; 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. Tellier, F.; Acher, F.; Brabet, I.; Pin, J. P.; Azerad, R.
Biorg. Med. Chem. 1998, 6, 195–208.
27. Park, K.-H.; Kurth, M. J. Tetrahedron Lett. 2000, 41,
7409–7413.
28. James, I. W. Tetrahedron 1999, 55, 4855–4946.
29. Albericio, F.; Garcia, J.; Michelotti, E. L.; Nicolas, E.;
Tice, C. M. Tetrahedron Lett. 2000, 41, 3161–3163.
30. Wu, S. D.; Janusz, J. M. Tetrahedron Lett. 2000, 41, 1165–
1169.
31. Lamothe, M.; Lannuzel, M.; Perez, M. J. Comb. Chem.
2002, 4, 73–78.
32. Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetrahe-
dron Lett. 1996, 37, 937–940.
1
1
1
1
1
1
1
2
2
2
4. Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225–9283.
5. Hayes, B. L.; Collins, M. J. Abstr. Paper Am. Chem. Soc.
004, 227, U207.
6. Larhed, M.; Hallberg, A. Drug Discovery Today 2001, 6,
06–416.
7. Majetich, G.; Hicks, R. J. Microw. Power Electromagn.
Energy 1995, 30, 27–45.
2
33. General procedure for the synthesis of hydantoins. All the
microwave-assisted reactions were performed at 300 W in
4
ꢁ
a 20 mL vial with a Biotage Initiator 60 EXP . Temper-
ature was measured with an IR sensor on the outer surface
of the reaction vial.
8. Majetich, G.; Hicks, R. Radiat. Phys. Chem. 1995, 45,
567–579.
After suitable conventional N-deprotection of the pre-
loaded resin 1, the resulting DCM-swollen resin 2 (1.0 g,
0.76 mmol, 0.76 mmol/g) was treated with isocyanate
(3.04 mmol) in THF (5 mL) in a microwave reactor at
60 ꢂC for 10 min. The solvent was removed by filtration
and the resin was washed with THF (2 · 10 mL), DMF
(2 · 10 mL), MeOH (2 · 10 mL), DCM (2 · 10 mL), and
9. Loupy, A. Microwaves in Organic Synthesis; Wiley–VCH:
Weinheim, 2002.
0. Faghihi, K.; Zamani, K.; Mobinikhaledi, A. Turk. J.
Chem. 2004, 28, 345–350.
1. Lee, M. J.; Sun, C. M. Tetrahedron Lett. 2004, 45, 437–
440.
2. Dewitt, S. H.; Kiely, J. S.; Stankovic, C. J.; Schroeder, M.
C.; Cody, D. M. R.; Pavia, M. R. Proc. Natl. Acad. Sci.
U.S.A. 1993, 90, 6909–6913.
dried. This resin 3 was then treated with Et N (0.43 mL,
3
3.04 mmol) in THF/DMF (5 mL, 4:1 v/v) in a microwave
reactor at 110 ꢂC for 15 min. The solvent was removed by
filtration and the resin was washed with THF (2 · 10 mL)
and DCM (2 · 10 mL). Combined filtrates were dried to
obtain the desired product 4 in a crude yield calculated on
the basis of the initial loading support.
2
2
3. Kim, S. W.; Ahn, S. Y.; Koh, J. S.; Lee, J. H.; Ro, S.; Cho,
H. Y. Tetrahedron Lett. 1997, 38, 4603–4606.
4. Hanessian, S.; Yang, R.-Y. Tetrahedron Lett. 1996, 37,
5835–5838.