Microwave-assisted solvent-free regiospecific synthesis of 5-alkylidene and 5-arylidenehydantoins

Article abstract of DOI:10.1080/00397910600589007

Hydantoins have become a well-known class of structures that have found significant applications as agrochemicals and therapeutics. This structural motif is of interest in the synthesis of small building blocks suitable for the preparation of potentially

Full text of DOI:10.1080/00397910600589007

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Microwave‐Assisted Solvent‐Free
Regiospecific Synthesis of 5‐Alkylidene and
5‐Arylidenehydantoins
M. Lamiri a , K. Bougrin a , B. Daou a , M. Soufiaoui a , E. Nicolas b & E. Giralt
b
a Laboratoire de Chimie des Plantes et de Synthèse Organique et
Bio‐Organique, Université Mohammed V‐Agdal, Faculté des Sciences, Rabat,
Morocco
b Department of Organic Chemistry, Universitat de Barcelona, Barcelona,
Spain
Version of record first published: 21 Aug 2006.
To cite this article: M. Lamiri, K. Bougrin, B. Daou, M. Soufiaoui, E. Nicolas & E. Giralt (2006):
Microwave‐Assisted Solvent‐Free Regiospecific Synthesis of 5‐Alkylidene and 5‐Arylidenehydantoins, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:11,
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Synthetic Communicationsw, 36: 1575–1584, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600589007
Microwave-Assisted Solvent-Free
Regiospecific Synthesis of 5-Alkylidene
and 5-Arylidenehydantoins
M. Lamiri, K. Bougrin, B. Daou, and M. Soufiaoui
`
Laboratoire de Chimie des Plantes et de Synthese Organique et
´ ´
Bio-Organique, Universite Mohammed V-Agdal-Faculte des Sciences,
Rabat, Morocco
E. Nicolas and E. Giralt
Department of Organic Chemistry, Universitat de Barcelona,
Barcelona, Spain
Abstract: Hydantoins have become a well-known class of structures that have found
significant applications as agrochemicals and therapeutics. This structural motif is of
interest in the synthesis of small building blocks suitable for the preparation of poten-
tially bioactive molecules. In this sense, 5-alkylidene and 5-arylidenehydantoins con-
stitute nice examples of precursors of synthetic a-amino acids. The microwave-assisted
synthesis of these compounds under green chemistry conditions is reported in this
article. The method has proved to afford yields of 74–96%.
Keywords: 5-Alkylidenehydantoins, 5-arylidenehydantoins, microwave irradiation,
organic synthesis, sodium acetate/alumina, solvent free
INTRODUCTION
Microwave (MW) irradiation has become a widely accepted energy source for
performing chemical synthesis. Since the pionering works of Gedye et al.[1]
Received in Poland October 21, 2005
Address correspondence to K. Bougrin, Laboratoire de Chimie des Plantes et de
`
´
´
Synthese Organique et Bio-Organique, Universite Mohammed V-Agdal, Faculte des
Sciences, B.P. 1014, Morocco. Tel.: þ212 37 26 44 18; Fax: (þ212) 37 77 54 40;
E-mail: kbougrin@yahoo.fr
1575

1576
M. Lamiri et al.
and Giguere et al.,[2] this mode of activation has attracted a considerable
amount of attention in the green chemistry field as a tool for speeding up
chemical reactions under conditions compatible with environmental protection
requirements.[3] With this aim, several years ago we started a research line
devoted to the application of nonclassical modes of activation in the
synthesis of heterocyclic scaffolds of interest in drug design, following eco-
friendly approaches.[4] The present study reports an efficient microwave-
assisted synthetic protocol for the preparation of 5-alkyl and 5-arylidenehydan-
toins with the aim of using these derivatives in the preparation of a-amino acids.
The hydantoin moiety can be considered a privileged structure because
of the wide range of biological activities that its derivatives have in
medicinal[5] and agrochemical[6] applications. In this sense, 5-alkylidene[7]
and 5-arylidene[6b,7,8] derivatives are among the hydantoins with potential
bioactivity. They have been demonstrated to possess antimicrobial,[7a]
antioxidative,[8a] anticonvulsant,[8b,8c] antitumor,[8d] tubulin inhibitory,[7b]
and antifungal[6b] activities. Moreover, hydantoins are also intermediates for
producing optically active natural and synthetic a-amino acids[9] for use in
drug discovery fields such as metabotropic receptor research[10] or the
design of bioactive peptides,[11] among others. In this context, 5-alkyl and
5-arylidenehydantoins are potentially useful starting materials for the prep-
aration of a-amino acids because a broad range of synthetic methodologies
can be used to modify the exocyclic double bond to produce structural diversity.
Several reports have appeared in the literature concerning the synthesis of
5-alkyl and 5-arylidenehydantoins that follow classical protocols that obtain
these products in variable yields. These methodologies include the use of
piperidine,[12] AcONa in glacial AcOH[13] or NaHCO3/ethanolamine in
water/EtOH[6b] under refluxing conditions, or fused ZnCl2.[14] However, the
preparation of these derivatives under microwave conditions has not been
explored much. Thus, only the synthesis of 5-arylidenehydantoins using
microwaves following a protocol where NH4OAc is utilized with ethylengly-
col as solvent has been described.[15] That moved us to seek more environmen-
tally friendly solvent-free synthetic alternatives. These solvent-free MW-
assisted conditions have gained popularity because they provide the
potential to work with open vessels and scaling the reactions. The develop-
ment of solvent-free techniques, which have improved the safety aspects,
are mostly of interest because of the shorter reactions times.
RESULTS AND DISCUSSION
In general, basic catalysis is required for the preparation of 5-alkyl and 5-ary-
lidenehydantoins. That prompted us to explore methodologies that involve the
use of mineral-supported bases to adapt the conventional protocol to one
suitable for the use of MW irradiation as energy source in dry media. It has
been shown that solvent-free conditions are especially adapted to MW

Synthesis of 5-Alkylidene and 5-Arylidenehydantoins
1577
activation as reactions can be run safely under atmospheric pressure.[16] In this
context, mineral oxides such as alumina (Al2O3) have proved to be very
efficient MW absorbents, allowing a very rapid and homogeneous heating
that results in faster reactions and less degradation of final products when
compared to classical heating.[17] Among the different procedures described
so far, we focused our attention on the use of acetate salts in the presence
of alumina. Thus, we demonstrated that CH3CO2Na absorbs MWs strongly
when impregnated on alumina. This particular behavior proved to be
suitable for the efficient preparation in a domestic oven of alkyl esters from
alkyl halides using the acetate as nucleophilic reagent.[18] In our particular
case, 5-alkyl and 5-arylidenehydantoins were obtained in excellent yields
when an equimolar mixture of hydantoin 1 and aldehyde 2 in the presence
of CH3CO2Na was subjected to MW irradiation on alumina using an unmodi-
fied household microwave oven (Pmax ¼ 1250 W) (Table 1). Reactions were
carried out in open vessels, which were placed in the highest irradiation
locations within the oven determined using CoCl2 in order to optimize MW
absorption.[19] The structures of hydantoin derivatives 3a–m were clearly
Table 1. Preparation of 5-alkylidenehydantoins and 5-arylidenehydantoins
Hydantoin
derivative
Yield
(%)
R
3a
3b
3c
3d
3e
3f
C6H5
86a
92
p-MeOC6H4
p-MeC6H4
o-ClC6H4
90
85b
96c
88
p-ClC6H4
p-NO2C6H4
3,4,5-(MeO)3C6H2
C6H5CH55CH
C6H5CH55C(Me)
n-Propyl
3 g
3 h
3i
79
84
82
78
3j
3 k
3l
(Me)2CH55CH(CH2)2C(Me)55CH
(m-MeO-p-OH)C6H3
6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl
74
82d
76
3 m
aLit.[15] 94%.
bLit.[15] 95%.
cLit.[15] 94%.
dLit.[15] 88%.

1578
M. Lamiri et al.
established by NMR spectroscopy and they were assigned to the Z-isomers by
comparison with those structures reported in the literature.[8b,12c,15,20]
Conventional heating of reagents under similar conditions to those
described yielded traces of the desired products, probably as a consequence
of the poor thermal conductivity of alumina, which is a barrier for thermal acti-
vation of the reaction, whereas MWs are easily transmitted. On the other hand,
a complex mixture of products was obtained with prolonged reaction times. It
is interesting to note that the use of alumina alone or CH3CO2Na alone with
MWs were also far less effective, resulting in no reaction. The same result
was obtained when reagents 1 and 2 were irradiated on acidic montmorillonites
KSF and K-10. Moreover, bases such as KOH, Ba(OH)2, or KF on alumina or
with Aliquat 336 as phase-transfer agent[21] furnished degradation products of
the hydantoin and by-products resulting from cross-Cannizzaro reactions and
aldol condensations of aromatic and aliphatic aldehydes, respectively.
The efficiency of acetate to absorb MWs when impregnated on alumina
has been explained in terms of variations in the dielectric properties of the
medium in relation to specific interactions between alumina and the salt that
could provoque desegregation and partial ionic dissociation of CH3CO2Na,
resulting in anionic activation of the salt.[18b] In this context, similar results
to those obtained with alumina (79–95%) were achieved when a homo-
geneous mixture of 1 and 2 with CH3CO2Na in DMF was irradiated with
MWs. In this case, MW irradiation had to be carried out during 1 min
because the maximum temperature reached at this time was higher than that
reached with alumina and near to the boiling point of the solvent (145–
1518C), as a consequence of the highly microwave sensitivity of the polar
DMF (e ¼ 36.7).[22] These results could also be interpreted in this case
according to an enhanced dissociation degree of the salt mediated by DMF
under MW conditions.
CONCLUSION
We have developed an original, alumina-supported, simple, high-yielding,
expeditious, and ecofriendly synthetic protocol for the preparation of 5-alkyl
and 5-arylidenehydantoins from hydantoin and aldehydes under solvent-free
MW irradiation. The reaction time is reduced from hours to minutes and
affords clean products high in yields and selectivity. This efficient methodology
may find application in combinatorial strategies that seek for hydantoin deriva-
tives of relevant therapeutically interest or as precursors of novel a-amino acids.
EXPERIMENTAL
A microwave of frequency 2.45 GHz, 1250 W, equipped with thermometer
and timer (Philco) was used in all irradiation experiments. Melting points

Synthesis of 5-Alkylidene and 5-Arylidenehydantoins
1579
were determined on a kofler melting-point apparatus and are uncorrected.
Reactions were monitored by TLC on 0.2-mm silica-gel plates (Merck)
using hexane/ethylacetate (80/20 v/v) mixtures as eluents, and compounds
were visualized with UV light (254 and 365 nm) and iodine. NMR spectra
were determined on Bruker W spectrometer at 300 MHz (1H NMR) and at
75 MHz (13C NMR). Chemical shifts are reported as d values (ppm) relative
to the solvent peak of DMSO-d6 set at d ¼ 2.5 (1H NMR) or d ¼ 39.5
(13C NMR) with tetramethylsilane as internal standard. Mass spectra were
recorded on a Hewlet Packard 5971 spectrometer in positive mode with EI
(70 eV). IR spectra were recorded on a Perkin Elmer 1600 FTIR spectropho-
tometer in KBr. Elemental analyses were performed on a Carlo-Erba 1106
Elemental Analysis instrument. All solvents used in reactions were freshly
distilled from appropriate drying agents. All other reagents were recrystallized
or distilled when necessary.
Preparation of Sodium Acetate/Alumina
Sodium acetate (22 g) is added to distilled water (200 mL), and the mixture is
stirred vigorously in the presence of air for ꢀ4 min until complete dissolution
of the crystals of sodium acetate. After a short time, alumina (20 g) is added in
small amounts and stirring is continued for another 4 min. The resulting sus-
pension is placed in a rotary evaporator, and the water is eliminated under
reduced pressure on a water bath at 50 8C. After 15 min, the dry solid crust
adhering to the walls of the flask is flaked off with a spatula, and solvent evap-
oration is resumed for another 15 min. This procedure yields about 42 g of a
sodium acetate-alumina; the resulting solid is dried at 110 8C for 24 h and
can be kept for several months in a nonhermetic powder box.
General Procedure for the Synthesis of Hydantoin
Derivatives 3a–3m
The CH3CO2Na/Al2O3 (5 g, 1:1 w/w proportion) was added to a solution of
hydantoin 1 (2 mmol) and the aldehyde derivative 2 (2 mmol) in 15 mL of
CH2Cl2 under atmosphere pressure. The resulting suspension was stirred at
room temperature, and the CH2Cl2 was removed under vacuum. Also, the
reaction of 1 and 2 can be completed, by adding the sodium acetate/DMF
(5 g, 4:1 w/w proportion). The resulting solid was exposed to MW irradiation
for 2 min in the case of sodium acetate-alumina, and 1 min in sodium acetate/
DMF conditions, with a final temperature of 130–140 8C. Completion of the
reaction was generally revealed by TLC, and after cooling, CH2Cl2
(2 ꢀ 15 mL) was added to the mixture and the solids were filtered off. The
solvent was evaporated in vacuum to give the pure product (74–96%).

1580
M. Lamiri et al.
Data
5-Benzalhydantoin (3a): Yield 86%. Mp: 224–226 8C. IR (KBr): 3529, 3455,
3289, 2763, 2359, 1742, 1717, 1657cm21; 1H NMR (DMSO-d6): d 11.1 (s, 1H),
9.91 (s, 1H), 7.60–7.27 (m, 5H), 6.39 (s, 1H); 13C NMR (DMSO-d6): d 165.2,
156.1, 133.3, 129.7–128.3, 108.7. MS m/z: 188 (Mþ). Anal. calcd. for
C10H8N2O2: C, 63.82; H, 4.28; N, 14.89. Found C, 63.62; H, 4.36; N, 14.99.
5-(4-Methoxybenzal)hydantoin (3b): Yield 92%. Mp: 250–252 8C. IR
1
(KBr): 3235, 3012, 1732, 1669, 1603 cm21. H NMR (DMSO-d6): d 11.1
(s, 1H), 9.94 (s, 1H), 7.94 (d, 2H), 7.55 (d, 2H), 6.39 (s, 1H), 3.77 (s, 3H);
13C NMR (DMSO-d6): d 166, 159.8, 156, 131.1, 126.5, 125.8, 114.7, 109.6,
55.6. MS m/z: 218 (Mþ). Anal. calcd. for C11H10N2O3: C, 60.55; H, 4.62;
N, 12.84. Found C, 60.67; H, 4.70; N, 12.90.
5-(4-Methylbenzal)hydantoin (3c): Yield 90%. Mp: 273–275 8C. IR (KBr):
3515, 3295, 3216, 2695, 1763, 1717, 1661 cm21. 1H NMR (DMSO-d6): d 11.1
(s, 1H), 9.95 (s, 1H), 7.49 (d, 2H), 7.18 (d, 2H), 6.36 (s, 1H), 2.48 (s, 3H). 13
C
NMR (DMSO-d6): d 165.9, 156, 138.5, 130.5, 129.7, 127.6, 109.6, 21.3. MS
m/z: 202 (Mþ). Anal. calcd. for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85.
Found C, 65.44; H, 4.88; N, 13.72.
5-(2-Chlorobenzal)hydantoin (3d): Yield 85%. Mp: 272–274 8C. IR (KBr):
3465, 3177, 3056, 2766, 1782, 1732, 1663 cm21. 1H NMR (DMSO-d6): d 11.1
(s, 1H), 9.99 (s,1H), 7.67-7.34 (m, 4H), 6.53 (s, 1H). 13C NMR (DMSO-d6):
d 165.6, 156, 133.5, 131.3, 130.5, 130.4–127.9, 103.3. MS m/z: 222 (Mþ).
Anal. calcd. for C10H7ClN2O2:C, 53.82; H, 3.17; N, 12.58. Found C, 53.63;
H, 3.24; N, 12.44.
5-(4-Chlorobenzal)hydantoin (3e): Yield 96%. Mp: 291–294 8C. IR (KBr):
3226, 3010, 2693, 2008, 1796, 1736, 1667 cm21. 1H NMR (DMSO-d6): d 11.1
(s, 1H), 9.98 (s,1H), 7.53 (d, 2H), 7.41 (d, 2H), 6.38 (s, 1H). 13C NMR
(DMSO-d6): d 165.8, 156.1, 133.2, 132.1, 131.4, 129, 128.9, 107.2. MS m/
z: 222 (Mþ). Anal. calcd. for C10H7ClN2O2: C, 53.82; H, 3.17; N, 12.58.
Found C, 53.69; H, 3.14; N, 12.43.
5-(4-Nitrobenzal)hydantoin (3f): Yield 88%. Mp: 302–303 8C. IR (KBr):
1
3328, 2363, 2850, 1779, 1732, 1665 cm21. H NMR (DMSO-d6): d 11.1
(s, 1H), 10 (s,1H), 7.94 (d, 2H), 7.55 (d, 2H), 6.46 (s, 1H). 13C NMR
(DMSO-d6): d 165.6, 156, 146.6, 140.4, 131.2, 130.5, 124.1, 105.5. MS m/
z: 233 (Mþ). Anal. calcd. for C10H7N3O4: C, 51.51; H, 3.03; N, 18.02.
Found C, 51.56; H, 3.10; N, 17.98.
5-(3,4,5-Trimethoxybenzal)hydantoin (3 g): Yield 79%. Mp: 266–268 8C.
IR (KBr): 3162, 3062, 2836, 2741, 1771, 1725, 1657 cm21 1H NMR
.

Synthesis of 5-Alkylidene and 5-Arylidenehydantoins
1581
(DMSO-d6): d 11.2 (s, 1H), 10 (s, 1H), 6.82 (s, 2H), 6.35 (s, 1H), 3.82 (s, 9H).
13C NMR (DMSO-d6): d 165.9, 156.2, 153.1, 138.4, 128.9, 127.6, 107.4, 60.5,
56.5. MS m/z: 278 (Mþ). Anal. calcd. for C13H14N2O5: C, 56.11; H, 5.07; N,
10.07. Found C, 56.20; H, 5.10; N, 10.01.
5-Cinnamalhydantoin (3h): Yield 84%. Mp: 285–2888C. IR (KBr): 3531,
1
3448, 3224, 3029, 2755, 1755, 1707, 1647, 1613 cm21. H NMR (DMSO-
d6): d 11.2 (s, 1H), 9.97 (s, 1H), 7.50–7.26 (m, 6H), 6.93 (d, 1H), 6.23
(d, 1H). 13C NMR (DMSO-d6): d 165.1, 154.9, 137.1, 130, 129.2, 128.8,
127, 122.9, 109.2. MS m/z: 214 (Mþ). Anal. calcd. for C12H10N2O2: C,
67.28; H, 4.71; N, 13.08. Found C, 67.48; H, 4.75; N, 13.28.
5-(2-Methylcinnamal)hydantoin 3i: Yield 82%. Mp: 246–2488C. IR (KBr):
1
3170, 3052, 2763, 1761, 1726, 1643 cm21. H NMR (DMSO-d6): d 11.2
(s, 1H), 9.98 (s,1H), 7.37–7.23 (m, 5H), 6.83 (s, 1H), 6.14 (s, 1H), 2.11
(s, 3H). 13C NMR (DMSO-d6): d 165.9, 155.8, 137.2, 135.3, 132.4, 129.5–
127.6, 127.6, 114.3, 17.3. MS m/z: 228 (Mþ). Anal. calcd. for C13H12N2O2:
C, 68.41; H, 5.30; N, 12.27. Found C, 68.56; H, 5.37; N, 12.43.
5-(n-Propylidene)hydantoin (3j): Yield 78%. Mp: 220–2228C. IR (KBr):
1
3316, 3108, 2967, 2930, 2865, 1917, 1713, 1645 cm21. H NMR (DMSO-
d6): d 10 (s, 1H), 8.84 (s, 1H), 6.63 (s, 1H), 1.92–1.84 (m, 7H). 13C NMR
(DMSO-d6): d 174.7, 153.4, 122, 110.1, 65.4, 34.31, 25.92. MS m/z: 154
(Mþ). Anal. calcd. for C7H10N2O2: C, 54.54; H, 6.54; N, 18.17. Found C,
54.35; H, 6.58; N, 18.26.
5-(2,6,6-Trimethylhexa-1,5-dienylidene)hydantoin (3k): Yield 74%. Mp:
176–1788C. IR (KBr): 3855, 3185, 3050, 2969, 2927, 1767, 1713, 1647,
1624 cm21 1H NMR (DMSO-d6): d 11.1 (s, 1H), 9.98 (s, 1H), 6.15
.
(m, 2H), 5.07 (s, 1H), 2.11 (s, 3H), 1.83–1.63 (m, 4H), 1.58 (s, 6H). 13C
NMR (DMSO-d6): d 165.4, 154.9, 146.6, 131.7, 128.1, 123.9, 118.7, 105.8,
26.32, 25.86, 17.85, 17.28. MS m/z: 234 (Mþ). Anal. calcd. for
C13H18N2O2: C, 66.64; H, 7.74; N, 11.96. Found C, 66.76; H, 7.73; N, 12.01.
5-(3-Methoxy-4-hydroxybenzal)hydantoin (3l): Yield 82%. Mp: 270–
2718C. IR (KBr): 3627, 3513, 3355, 3083, 2718, 1742, 1713, 1657 cm21
.
1H NMR (DMSO-d6): d 11.1 (s, 1H), 9.97 (s, 1H), 9.40 (s, 1H), 7.09–7.03
(m, 2H), 6.76 (d, 1H), 6.34 (s, 1H), 3.82 (s, 3H). 13C NMR (DMSO-d6):
d 166, 156.1, 148.1, 148, 128.9, 125.8, 124.7, 123.9, 116.1, 56.20. MS m/z:
234 (Mþ). Anal. calcd. for C11H10N2O4: C, 56.41; H, 4.30; N, 11.96. Found
C, 56.54; H, 4.37; N, 12.02.
5-(6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-ylidene)hydantoin (3m): Yield
1
76%. Mp: 218–2208C. IR (KBr): 3314, 2917, 1765, 1728, 1653 cm21. H
NMR (DMSO-d6): d 11.1 (s, 1H), 9.90 (s, 1H), 6.10 (s, 1H), 5.80 (s, 1H),

1582
M. Lamiri et al.
2.49–2.35 (m, 6H), 1.24 (s, 3H), 0.78 (s, 3H). 13C NMR (DMSO-d6): d 166.1,
156.8, 129.9, 126, 118.8, 109.8, 44.07, 40.33, 37.42, 32.15, 31.09, 25.73,
20.89. MS m/z: 232 (Mþ). Anal. calcd. for C13H16N2O2: C, 67.22; H, 6.94;
N, 12.06. Found C, 67.28; H, 7.00; N, 12.18.
ACKNOWLEDGMENTS
´
Financial support by the Agencia Espan˜ola de Cooperacion Internacional
(AECI, Programa de Cooperacion Interuniversitaria entre Espan˜a y
´
Marruecos, 21/03/AC) is gratefully acknowledged.
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