A facile synthesis of 1,3,5-trisubstituted hydantoins via Ugi four-component condensation

Article abstract of DOI:10.1055/s-2005-922745

A facile access to 1,3,5-trisubstituted hydantoins is achieved by combining an Ugi four-component condensation with a base-induced cyclization. This two-step sequence, which differs from any other method, is experimentally simple and allows a wide variety

Full text of DOI:10.1055/s-2005-922745

LETTER
3051
A Facile Synthesis of 1,3,5-Trisubstituted Hydantoins via Ugi
Four-Component Condensation
Synthesis
o
of 1,3,5-Tris
s
ubstituted
é
H
ydantoins Miguel Ignacio,a,1 Sonia Macho,a,1 Stefano Marcaccini,*a Roberto Pepino,a Tomás Torrobab
a
Dipartimento di Chimica Organica ‘Ugo Schiff’, Università di Firenze, via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax +39(055)4573531; E-mail: stefano.marcaccini@unifi.it
b
Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Plaza Misael Bañuelos s/n, 09001 Burgos, Spain
Received 5 September 2005
In a previous paper8 we reported that the Ugi-4CC adducts
1 arising from primary amines, aldehydes, isocyanides,
and chloroacetic acid underwent a ring-closure reaction to
2,5-diketopiperazines 2 upon treatment with potassium
Abstract: A facile access to 1,3,5-trisubstituted hydantoins is
achieved by combining an Ugi four-component condensation with
a base-induced cyclization. This two-step sequence, which differs
from any other method, is experimentally simple and allows a wide
variety in the substitution pattern. In this synthesis the acid compo- hydroxide. The key step is the formation of the internal
nent, namely trichloroacetic acid, acts as a carbonic acid equivalent.
nucleophile by deprotonation of the amide nitrogen
(Scheme 1).
Key words: Ugi four-component condensation (U-4CC), isocyan-
ides, heterocycles, cyclizations, multicomponent reactions
In principle, an Ugi-4CC adduct 3 arising from primary
amines, aldehydes, isocyanides, and carboxylic acids may
undergo an intramolecular nucleophilic attack in basic
medium, but the low electrophilic strength of the a-acyl-
amino group prevents it (Scheme 2).
The synthesis of iminohydantoins2 and iminothio-
hydantoins3 is one of the earlier achievements of the Ugi
four-component condensation.4 The preparation of these
heterocyclic systems, apart from the synthetic interest, is
a remarkable example of the versatility of the Ugi reaction
with respect to the variation of the components: imino-
hydantoins and iminothiohydantoins are obtained by em-
ploying cyanic and thiocyanic acid as the acid component,
respectively.
R1
R1
O
O
R
R
Base
– H+
N
N
Products
_
HN
O
R2
N
O
R2
R3
R3
3
Scheme 2 Hypothetical reactivity of Ugi 4-CC adducts 3
Although a wide variety of heterocyclic systems is obtain-
able by means of the Ugi reaction, either directly5 or by
post-condensation modifications,6 only one report dealing
with the synthesis of hydantoins via isocyanide-based
multicomponent reactions has appeared in the literature.7
In this paper a very elegant route to the desired products
via a Ugi five-component condensation followed by a
BOC-deprotection and cyclization is described.
Keeping in mind the above results we decided to prepare
a number of Ugi-4CC in which the electrophilic strength
of the a-acylamino group is enhanced. In order to achieve
this goal we reacted primary amines 4, aldehydes 5,
trichloroacetic acid (6), and isocyanides 7. The reaction
took place smoothly in methanol at room temperature to
afford the expected adducts 8 in low to good yields.9 A
strong yield improvement for compounds 8c,d was
achieved by performing the Ugi reaction with the pre-
formed imine in Et2O (Table 1, entries 3, 4).10 With the
exception of compounds 8g,i the Ugi adducts precipitated
from the reaction mixture in a pure form. The structure of
compounds 8 was confirmed by analytical and spectral
data. In the IR spectra the amide NH and the CCl3 ab-
sorptions were detected at 3256–3368 cm–1 and 697–846
cm–1, respectively. In most of the spectra the trichloro-
acetamide and the amide carbonyl groups gave two well-
separated peaks at 1654–1694 cm–1 and 1651 cm–1, re-
spectively. Furthermore, when n-hexyl- and cyclohexyl
isocyanide were employed as the starting isocyanide, a
strong absorption at about 2920 cm–1, due to the C–Haliph
stretching was detected. In the 1H NMR spectra of 8, the
proton in the position a to the amide group was detected
at d = 5.70–6.17.
R1
R
NH2
O
KOH
R1 CHO
R2 NC
R
O
N
HN
R2
Cl
CO2H
Cl
1
R1
R1
O
R
O
R
O
N
N
N
R2
_
– H+
– Cl
N
O
R2
Cl
2
Scheme 1 Formation of 2,5-diketopiperazines 2 from Ugi-4CC
adducts 1
SYNLETT 2005, No. 20, pp 3051–3054
1
9
.1
2
.2
0
0
5
Advanced online publication: 28.11.2005
DOI: 10.1055/s-2005-922745; Art ID: G27105ST
© Georg Thieme Verlag Stuttgart · New York

3052
J. M. Ignacio et al.
LETTER
Upon treatment with sodium ethoxide in ethanol or meth- The fact that hydantoins 9g,i were obtained without iso-
anol, compounds 8 underwent a ring-closure reaction to lating the Ugi adducts 8g,i shows that the synthesis of
give hydantoins 9 in good yields. A possible mechanism hydantoins 9 from primary amines 4, aldehydes 5, trichlo-
is reported in Scheme 3.
roacetic acid (6), and isocyanides 7 can be performed by a
simple one-pot, two-step procedure.12
R
NH2 (4)
R1
O
Table 1 Prepared Ugi-4CC Products 8a–f,h,j
R1 CHO (5)
R
O
N
HN
R2
Entry
Product
8a
Mp (°C)a
186–187
171–172
187–188
119–120
201–202
141–142
208–209
126–127
Yield (%)b Yield (%)c
Cl3C CO2H (6) MeOH, r.t., 2 d
30–88%
R2 NC (7)
CCl3
1
2
3
4
5
6
7
8
58
54
8
8b
R1
R
N
O
R
N
O
R1
EtONa
8c
33
30
88
65
67
65
75
70
_
–
N
R2
– CCl3
31–89%
EtOH or MeOH, r.t.
N
8d
O
R2
CCl3
O
8e
9
R1
C6H5
7
a
R2
8f
4
a
b
c
d
R
5
c-C6H11
n-C6H13
C6H5
a
b
c
d
8h
b
c
d
4-ClC6H4
4-CH3C6H4
C6H4CH2
4-CH3C6H4
4-ClC6H4
2-Pyridyl
4-(Phenylazo)phenyl
4-CH3C6H4
8j
a Solvent: i-PrOH.
b Reaction performed in MeOH.
R1
R2
8,9
a
b
c
d
e
f
R
c Reaction performed with the preformed imine in Et2O.
C6H5
C6H5
c-C6H11
c-C6H11
c-C6H11
n-C6H13
4-ClC6H4
4-ClC6H4
4-ClC6H4
C6H5
4-CH3C6H4
C6H5
Table 2 Prepared Hydantoins 9a–j11
C6H5
C6H5
4-(Phenylazo)phenyl
n-C6H13
Entry
Product
9a
Base (equiv)a Mp (°C)b
Yield (%)
4-CH3C6H4 4-ClC6H4
g
h
i
C6H4CH2
C6H5
4-CH3C6H4
4-CH3C6H4
2-Pyridyl
n-C6H13
1
2
1.21
0.67
1.18
0.58
2.00
0.31
1.42
0.36
0.52
0.08
130–131
180–181
191–192
105–106
222–223
83–84
77
89
85
69
52
72
33
57
31
45
4-CH3C6H4
c-C6H11
C6H5
9b
9c
j
4-ClC6H4
2-Pyridyl
n-C6H13
3
Scheme 3 Two-step route towards 1,3,5-trisubstituted hydantoins 9
4
9d
9e
5
The presence of chloroform, arising from the reaction of
the CCl3 anion with a proton source, was confirmed in
–
6
9f
earlier experiments by GCMS of the crude reaction
mixture. With regard to the cyclization step, it was essen-
tial to add the sodium ethoxide solution to a suspension of
8 in a relatively quick manner, until a clear solution result-
ed. In this case hydantoins 9 precipitated from the mother
liquors in an almost pure form, otherwise, mixtures of
hydantoins and the starting Ugi products were always
obtained (Table 2).
7
9g
144–145
145–146
131–132
101–102
8
9h
9i
9
10
9j
a Equivalents of EtONa employed for the cyclization of 8.
b Solvent: i-PrOH.
Again, the IR spectra gave useful information about the
structure of compounds 9. In fact, the absorptions due to
the amide NH and to the CCl3 group were not detected.
Furthermore, a CO peak at 1766–1781 cm–1 was found, in
agreement with the presence of a cyclic urea moiety. The
CO absorptions due to the g-lactam and the amide moi-
eties were overlapped and a unique peak at 1699–1722
cm–1 was observed. As expected, neither the NH proton
signal in the 1H NMR spectra nor the CCl3 carbon signal
The synthesis of 1,3,5-trisubstituted hydantoins is usually
accomplished by reacting N-substituted a-amino acids or
their esters with isocyanates, either in solution13 or in solid
phase.14 A viable route consists of the N-alkylation of
mono- and disubstituted hydantoins.15 Methods based on
the ring transformation of 5-bromobarbituric acid,16
imidazo[3,4-a]quinazoline,17 and benzoxazol-2-one
derivatives18 are less important. Other methods, such as
the irradiation of 1,2-dihydropyrazol-3-one derivatives19
and the hydrolysis of their 5-phenylimino derivatives20
have occasionally been used.
1
in the 13C NMR was detected. Furthermore, in the H
NMR spectra of compounds arising from n-hexyl and
cyclohexyl isocyanide, a lower multiplicity of the signals
attributable to the proton(s) linked to the carbon adjacent
to the nitrogen was seen.
Synlett 2005, No. 20, 3051–3054 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,3,5-Trisubstituted Hydantoins
3053
2-(N-Phenyl-N-trichloroacetyl)amino-2-phenylacetic
Acid N-Cyclohexyl Amide (8a).
Recently, a very elegant and straightforward three-com-
ponent synthesis of 1,3,5-trisubstituted hydantoins based
on the reaction of N,N¢-disubstituted ureas with carbon
monoxide and aldehydes in the presence of a palladium
catalyst under high pressures has been reported.21
IR (KBr): n = 3275, 3062, 2930, 1688, 1651, 697 cm–1. 1H
NMR (200 MHz, CDCl3): d = 7.25–7.10 (m, 10 H), 5.81 (s,
1 H), 5.41 (d, J = 8.00 Hz, 1 H), 3.94–3.77 (m, 1 H), 1.98–
0.89 (m, 10 H) ppm. 13C NMR (50 MHz, CDCl3): d =
167.46, 160.66, 138.20, 133.28, 132.40, 130.46, 128.70,
128.44, 128.34, 127.53, 93.01, 69.87, 48.76, 32.60, 32.55,
25.28, 24.69, 24.57 ppm.
The synthesis described in the present note is advanta-
geous with respect to the known methods since the
starting products are commercially available or easily ob-
tainable. Furthermore, neither expensive catalysts nor
special apparatus are required. The simple experimental
procedure, the possibility of employing reagents and sol-
vents as supplied, and the facile isolation of the products
from the reaction medium represent additional advantages
of this new route to 1,3,5-trisubstituted hydantoins.
(10) Improved Procedure for the Synthesis of Ugi Adducts
8c,d.
A mixture of 4-chloroaniline (4b, 549 mg, 4.3 mmol),
benzaldehyde (5a, 456 mg, 4.3 mmol), CHCl3 (10 mL) and
anhyd Na2SO4 (900 mg) was stirred for 4 h at r.t. and then
filtered. The collected solid was washed with CHCl3 (5 mL).
The filtrate was evaporated to dryness and the residue
dissolved in Et2O (10 mL). The above solution was cooled at
10 °C and treated under stirring with a solution of isocyanide
7 (4.3 mmol) in Et2O (5 mL) and then with trichloroacetic
acid (6, 703 mg, 4.3 mmol). The solution turned violet and
the precipitation of the reaction product began within 1 h.
After 24 h stirring the reaction mixture was filtered to give
almost pure 8. Another crop was obtained by evaporating the
filtrate and stirring the residue with i-PrOH (3–4 mL).
2-[N-(4-Chlorophenyl)-N-trichloroacetyl]amino-2-
phenylacetic Acid N-Cyclohexyl Amide (8c).
References
(1) Present address: Departamento de Química, Facultad de
Ciencias, Universidad de Burgos, Spain.
(2) Ugi, I.; Offermann, K. Chem. Ber. 1964, 97, 2276.
(3) Ugi, I.; Rosendahl, F. K.; Bodesheim, F. Liebigs Ann. Chem.
1963, 666, 61.
(4) For two excellent reviews on the isocyanide
multicomponent reactions see: (a) Dömling, A.; Ugi, I.
Angew. Chem. Int. Ed. 2000, 39, 3168. (b) Ugi, I.; Werner,
B.; Dömling, A. Molecules 2003, 8, 53.
(5) See for example: (a) Short, K. M.; Ching, B. W.; Mjalli, A.
M. M. Tetrahedron 1997, 53, 6653. (b) Hanusch-Kompa,
C.; Ugi, I. Tetrahedron Lett. 1998, 39, 2725. (c) Zhang, J.;
Jacobson, A.; Rusche, J. R.; Herlihy, W. J. Org. Chem. 1999,
64, 1074. (d) Marcaccini, S.; Miguel, D.; Torroba, T.;
García-Valverde, M. J. Org. Chem. 2003, 68, 3315.
(6) See for example: (a) Lee, D.; Sello, J. K.; Schreiber, S. L.
Org. Lett. 2000, 2, 709. (b) Nixey, T.; Tempest, P.; Hulme,
C. Tetrahedron Lett. 2002, 43, 1637. (c) Tempest, P.;
Pettus, L.; Gore, V.; Hulme, C. Tetrahedron Lett. 2003, 44,
1947. (d) Faggi, C.; García-Valverde, M.; Marcaccini, S.;
Pepino, R.; Pozo, M. C. Synthesis 2003, 1553.
IR (KBr): n = 3268, 3064, 2927, 1691, 1651, 748 cm–1; 1H
NMR (200 MHz, CDCl3): d = 7.26–6.94 (m, 9 H), 5.88 (s, 1
H), 5.39 (d, J = 8.40 Hz, 1 H), 3.85–3.76 (m, 1 H), 1.97–0.96
(m, 10 H) ppm. 13C NMR (50 MHz, CDCl3): d = 167.29,
160.61, 136.38, 134.45, 134.06, 132.98, 130.51, 128.99,
128.52, 127.67, 92.84, 69.26, 48.87, 32.60, 25.28, 24.69
ppm.
(11) Synthesis of Hydantoins 9a–f,h,i. General Procedure.
A 1.0 M ethanolic solution of NaOEt was dropped into a
well-stirred suspension of 8 (1.0 mmol) in EtOH (4–5 mL)
until a clear solution was obtained. Within a few minutes the
precipitation of a solid product commenced. The suspension
was cooled at 0 °C and filtered to give almost pure 9.
Analytical samples were obtained from i-PrOH.
1-(4-Chlorophenyl)-3-cyclohexyl-5-phenylhydantoin
(9a).
(e) Marcaccini, S.; Pepino, R.; Pozo, M. C.; Basurto, S.;
García-Valverde, M.; Torroba, T. Tetrahedron Lett. 2003,
44, 3999. (f) Beck, B.; Picard, A.; Herdtweck, E.; Dömling,
A. Org. Lett. 2004, 6, 39. (g) For a recent review see:
Marcaccini, S.; Torroba, T. In Multicomponent Reactions;
Zhu, J.; Bienaymé, H., Eds.; Wiley-VCH: Weinheim, 2005,
33.
IR (KBr): n = 3031, 2928, 1773, 1704 cm–1. 1H NMR (200
MHz, CDCl3): d = 7.49–7.03 (m, 10 H), 5.36 (s, 1 H), 4.09–
3.97 (m, 1 H), 2.26–1.17 (m, 10 H) ppm. 13C NMR (50 MHz,
CDCl3): d = 169.85, 154.51, 136.51, 133.33, 129.14, 128.94,
128.90, 126.58, 124.45, 120.17, 63.52, 52.05, 29.26, 29.11,
25.75, 25.72, 24.92 ppm. Anal. Calcd for C21H22N2O2
(334.41): C, 75.42; H, 6.63; N, 8.38. Found: C, 75.71; H,
6.81; N, 8.12.
(7) (a) Hulme, C.; Ma, L.; Romano, J. J.; Morton, G.; Tang, S.-
Y.; Cherrier, M.-P.; Choi, S.; Salvino, J.; Labaudiniere, R.
Tetrahedron Lett. 2000, 41, 1889. (b) The conversion of
iminohydantoins into hydantoins was accomplished by
hydrolysis in harsh conditions, whereas the conversion of
iminothiohydantoins into hydantoins was achieved via
KMnO4 oxidation and alkaline hydrolysis. These
transformations were used by Ugi and co-workers (see ref. 1
and 2) as structural proof of the Ugi-4CC adducts.
(8) Marcaccini, S.; Pepino, R.; Pozo, M. C. Tetrahedron Lett.
2001, 42, 2727.
(9) Synthesis of Ugi Adducts 8a–f,h,j. General Procedure.
A solution of the amine 4 (12 mmol) in MeOH (10 mL) was
treated with aldehyde 5 (finely powdered if solid; 12 mmol),
a solution of isocyanide 7 (12 mmol) in MeOH (5 mL), and
trichloroacetic acid (6, 1.96 g, 12 mmol) in the order given.
The reaction mixture was stirred for 2 d at r.t. and then
cooled at 0 °C and filtered. The collected solid was washed
with a little cold i-Pr2O and then with pentane and dried to
give almost pure 8. Analytical samples were obtained from
i-PrOH.
(12) Synthesis of Hydantoins 9g,i. General Procedure.
Supporting Ugi reagents were allowed to react as described
in ref. 11, general procedure. The clear reaction mixture was
treated with 1.0 M ethanolic NaOEt and stirred for 15 min at
r.t. The resulting suspension was cooled at 0 °C and filtered
to give almost pure 9g,i. Analytical samples were obtained
from i-PrOH.
1-Benzyl-3-hexyl-5-(4-methylphenyl)hydantoin (9g).
IR (KBr): n = 3033, 2929, 1766, 1698 cm–1. 1H NMR (200
MHz, CDCl3): d = 7.32–7.02 (m, 9 H), 5.11 (d, J = 14.7 Hz,
1 H), 4.53 (s, 1 H), 4.03–3.94 (m, 1 H), 3.68 (d, J = 14.7 Hz,
1 H), 2.37 (s, 3 H), 2.25–1.15 (m, 10 H) ppm. 13C NMR (50
MHz, CDCl3): d = 171.25, 156.33, 138.92, 135.50, 129.79,
128.65, 128.21, 127.77, 127.24, 62.02, 44.14, 29.32, 29.15,
25.72, 25.68, 24.82, 21.00 ppm. Anal. Calcd for C23H28N2O2
(364.48): C, 75.79; H, 7.74; N, 7.69. Found: C, 75.88; H,
7.41; N, 7.95.
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3054
J. M. Ignacio et al.
LETTER
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Synlett 2005, No. 20, 3051–3054 © Thieme Stuttgart · New York