1,3,5-trisubstituted and 5-acyl-1,3-disubstituted hydantoin derivatives via novel sequential three-component reaction

Article abstract of DOI:10.1021/ol102664n

1,2-Diaza-1,3-dienes (DDs) react as Michael acceptors with primary amines to afford α-aminohydrazone derivatives that were in situ coupled with isocyanates. Intramolecular ring closure of the asymmetric urea derivatives so formed allows for a selectively

Full text of DOI:10.1021/ol102664n

ORGANIC
LETTERS
2011
Vol. 13, No. 3
353-355
1,3,5-Trisubstituted and
5-Acyl-1,3-Disubstituted Hydantoin
Derivatives via Novel Sequential
Three-Component Reaction
Orazio A. Attanasi, Lucia De Crescentini, Gianfranco Favi, Simona Nicolini,
Francesca Romana Perrulli, and Stefania Santeusanio*
Istituto di Chimica Organica, UniVersita` degli Studi di Urbino “Carlo Bo”, Via I
Maggetti 24, 61029 Urbino, Italy
stefania.santeusanio@uniurb.it
Received November 3, 2010
ABSTRACT
1,2-Diaza-1,3-dienes (DDs) react as Michael acceptors with primary amines to afford r-aminohydrazone derivatives that were in situ coupled
with isocyanates. Intramolecular ring closure of the asymmetric urea derivatives so formed allows for a selectively substituted hydantoin ring
to be obtained. The hydrazone side chain introduced by the conjugated heterodiene system at the 5-position of the heterocycle represents a
valuable functionality for accessing novel 5-acyl derivatives difficult to obtain by other methods.
Hydantoin-based scaffolds have been found to possess
significant pharmacological activities. In fact, many deriva-
tives have been identified as anticonvulsant,1 antimuscarin-
ics,2 antiulcers and antiarrhythmics,3 antivirals, antidiabetics,4
and serotonin and fibrinogen receptor antagonists.5 Moreover,
substituted hydantoins are important building blocks for the
synthesis of nonnatural amino acids by alkaline degradation.6
Therefore, many methods for the rapid acquisition of
structurally varied and functionalized hydantoins are desir-
able. The synthesis of 1,3,5-trisubstituted hydantoins is
usually accomplished by reacting N-substituted R-amino
acids or their esters with isocyanates, either in solution7 or
in solid phase.8 Other strategies for the synthesis of 1,3,5-
hydantoins have been recently reported in the literature and
are based on the reaction of N,N′-disubstituted ureas with
carbon monoxide and aldehydes,9 on a Ugi four-component
condensation10 and on the reaction between activated R,ꢀ-
unsaturated carboxylic acids and asymmetric carbodiim-
ides.11 To the best of our knowledge, there is no report on
the synthesis of 1,3,5-trisubstituted hydantoins having hy-
drazone or acyl function at the 5-position of the ring neither
(1) Thenmozhiyal, J. C.; Wong, P. T. H.; Chui, W. K. J. Med. Chem.
2004, 47, 1527.
(2) (a) Brazil, C. W.; Pedley, T. A. Annu. ReV. Med. 1998, 49, 135. (b)
Luer, M. S. Neurol. Res. 1998, 20, 178.
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Blogoeva, I. B.; Jirby, A. J.; Pojarieff, I. G. J. Chem. Soc., Perkin Trans.
2 1998, 2289. (c) Blogoeva, I. B.; Toteva, M. M.; Ouarti, N.; Ruasse, M.-
F. J. Org. Chem. 2001, 66, 2123.
(3) (a) Matzukura, M.; Daiku, Y.; Ueda, K.; Tanaka, S.; Igarashi, T.;
Minami, N. Chem. Pharm. Bull. 1992, 40, 1823. (b) Knabe, J.; Baldauf, J.;
Ahlhelm, A. Pharmazie 1997, 52, 912.
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Kim, S. W.; Ahn, S. Y.; Koh, J. S.; Lee, J. H.; Ro, S.; Cho, H. Y.
Tetrahedron Lett. 1997, 38, 4603. (c) Boeijen, A.; Kruijtzer, J. A. W.;
Liskamp, R. M. J. Bioorg. Med. Chem. Lett. 1995, 5, 47.
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Int. Ed. 1999, 38, 1454.
¨
(4) Somsa´k, L.; Kova´cs, L.; To´th, M.; Osz, E.; Szila´gyi, L.; Gyo¨rgydeak,
Z.; Dinya, Z.; Docsa, T.; To´th, B.; Gergely, P. J. Med. Chem. 2001, 44,
2843.
(5) (a) Moloney, G. P.; Robertson, A. D.; Martin, G. R.; MacLennan,
S.; Mathews, N.; Dosworth, S.; Sang, P. Y.; Knight, C.; Glen, R. J. Med.
Chem. 2001, 44, 2843. (b) Moloney, G. P.; Martin, G. R.; Mathews, N.;
Milne, A.; Hobbs, H.; Dosworth, S.; Sang, P. Y.; Knight, C.; Maxwell,
M.; Glen, R. J. Med. Chem. 1999, 42, 2504.
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Synlett 2005, 3051.
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70, 2161.
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10.1021/ol102664n  2011 American Chemical Society
Published on Web 12/27/2010

acter of the terminal carbon of 1 making it capable to undergo
nucleophilic attack, primary amines 2 constitute useful
reagents to perform an aza-Michael addition producing the
corresponding R-aminohydrazone derivatives 3.14 Subsequent
acylation of secondary amines 3 with isocyanates 4 generates
the requisite asymmetric ureas 5 to be directed to a ring
closure. Indeed, compounds 5 provide spontaneous regiose-
lective heteroring closure owing to the nucleophilic attack
of the amidic NH at the terminal ester function of the azo-
ene system, affording the hydantoin derivative 6 (Scheme
1) by loss of an alcohol molecule. This one-pot reaction
sequence represents a valuable route to variously 1,3,5-
trisubstituted hydantoins 6a-q containing an electron-
withdrawing hydrazone function at C-5 derived from the
conjugated azo-ene system of DDs. It can be easily ac-
complished in EtOH at room temperature, with satisfactory
yields (47-76%, Table 1) overcoming the drawback of
regiocontrol (i.e., 6c,d,i,p) especially when weakly asym-
metric carbodiimides are used.11
Scheme 1
.
One-Pot Synthesis of 1,3,5-Trisubstituted Hydantoins
6a-q
Although aromatic amines (i.e., 4-methoxyaniline) worked
well in the Michael addition producing R-aminohydrazones
3, unfortunately the subsequent coupling with isocyanates
(i.e., butylisocyanate) failed probably because of the poor
nucleophilicity of the amine nitrogen atom of 3 (only traces
of 5 were observed even upon prolonged reaction times).
Since the hydrazone side chain represents a protected
carbonyl function, the hydrolytic cleavage of the hydrazide
moiety under heterogeneous conditions (Scheme 2) intro-
duces a point of diversity leading to novel 5-acyl disubsti-
tuted 1,3-hydantoin scaffolds difficult to obtain from amino
acid ester building blocks8a or by other methods.9,11,12
In summary, we have demonstrated the synthetic utility
of 1,2-diaza-1,3-dienes in the construction of diversified
trisubstituted 1,3,5-hydantoins with a controlled regioselec-
tivity in the substitution at N-1 and N-3 of the heterocycle
from amino acid derivatives nor from N,N′-disubstituted
ureidomalonate building blocks.12 Indeed, by continuing our
investigations designed to develop the usefulness of the
conjugated azo-ene system of 1,2-diaza-1,3-dienes (DDs) as
building blocks in heterocyclic chemistry, the present paper
reports a synthetic strategy for regioselective trisubstituted
hydantoin derivatives bearing novel and valuable functional-
ity at the C-5 position of the hydantoin ring as a general
procedure to achieve 5-acyl derivatives.
The versatility of DDs 1 in the synthesis of useful
heterocyclic scaffolds is well documented13 and relies on
their ability to undergo 1,4-Michael additions. Our approach,
for acquiring the title compounds in a one-pot procedure,
involves the construction of N,N′-disubstituted asymmetric
urea moieties linked to suitable DD substrates. Since the
conjugated heterodiene system exalts the electrophilic char-
Table 1. Results of the Synthesis of Hydantoin Derivatives 6a-q
DD 1
amine 2
R4
n-Bu
isocyanate 4
entry
R1
R2
R3
R5
hydantoin 6
yielda (%)
1
2
3
4
5
6
7
8
1a
1b
1b
1c
1d
1a
1c
1a
1a
1e
1a
1c
1c
1f
CO2Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Ph
CH2CO2Et
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
2a
2b
2b
2b
2a
2b
2c
2d
2e
2b
2b
2d
2e
2a
2b
2e
2e
4a
4a
4b
4c
4a
4a
4a
4d
4b
4a
4d
4a
4e
4e
4a
4f
Ph
Ph
Cyclohexyl
CH2CO2Et
Ph
Ph
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
67
76
65
68
62
66
65
63
63
66
63
63
73
48
65
69
47b
CO2t-Bu
CO2t-Bu
CO2Me
CO2Bn
CO2Et
CO2Me
CO2Et
CO2Et
n-Pr
n-Pr
n-Pr
n-Bu
n-Pr
Allyl
Propargyl
Benzyl
n-Pr
Ph
3-Cl-Ph
Cyclohexyl
Ph
3-Cl-Ph
Ph
4-Cl-Ph
4-Cl-Ph
Ph
9
10
11
12
13
14
15
16
17
CO2t-Bu
CO2Et
n-Pr
CO2Me
CO2Me
CO2t-Bu
CO2t-Bu
CO2Me
CO2Me
Propargyl
Benzyl
n-Bu
n-Pr
Benzyl
Benzyl
1g
1c
1h
n-Bu
4-Cl-Ph
CO2Et
4e
a Yield of pure isolated product. b Yield referred to isolated R-aminohydrazone derivative.
354
Org. Lett., Vol. 13, No. 3, 2011

Further extension of this sequential three-component
pathway is currently being pursued in our laboratories and
will be reported in due course.
Scheme 2
Acknowledgment. Financial support from the Ministero
dell’Istruzione, dell’Universita` e della Ricerca (MIUR)-Roma
and from the University of Urbino “Carlo Bo” is gratefully
acknowledged.
Supporting Information Available: Detailed experimen-
tal procedures and full characterization for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL102664N
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with respect to that obtained when weakly asymmetric
carbodiimides are coupling with R,ꢀ-unsaturated carboxylic
acids. The one-pot procedure described here is based on
sequential aza-Michael addition/condensation reactions and
introduces a valuable hydrazone functionality at the 5-posi-
tion of the heteroring that allows access to 5-acyl hydantoins.
Noteworthily, the acyl residue directly bonded at the C-5 of
the hydantoin nucleus is not easily achievable from amino
acid esters or with ureidomalonate building blocks.
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Mantellini, F. AdV. Synth. Catal. 2009, 351, 715.
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