Three-component, one-pot sequential synthesis of 1,3-disubstituted 5-arylhydantoins

Article abstract of DOI:10.1055/s-0028-1087352

Reaction of carbodiimides with α-Br(Cl)-aryl acetic acids produces N,N′-substituted 5-arylhydantoins under very mild conditions and high yields. When the carbodiimides are generated in situ by Staudinger reaction, the process becomes a one-pot, three-component sequential synthesis of libraries of differently substituted 5-arylhydantoins. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087352

3016
LETTER
Three-Component, One-Pot Sequential Synthesis of 1,3-Disubstituted
5-Arylhydantoins
Synthesis of
1
r
,3-Disub
a
stituted 5-A
n
rylhydantoin
c
s
esca Olimpieri,a Alessandro Volonterio,*a,b Matteo Zanda*b
a
Dipartimento di Chimica, Materiali e Ingegneria Chimica ‘Giulio Natta’, Politecnico di Milano, Via Mancinelli 7, 20131 Milano, Italy
Fax +39(02)23993080; E-mail: alessandro.volonterio@polimi.it
b
C.N.R., Istituto di Chimica del Riconoscimento Molecolare, Sezione ‘A. Quilico’, Via Mancinelli 7, 20131 Milano, Italy
Received 6 August 2008
Recently, we demonstrated that carbodiimides, when
treated with suitable carboxylic acids in the absence of a
nucleophile, are useful reagents for the multicomponent
synthesis of small heterocycles.10 Herein we show that
Abstract: Reaction of carbodiimides with a-Br(Cl)-aryl acetic ac-
ids produces N,N¢-substituted 5-arylhydantoins under very mild
conditions and high yields. When the carbodiimides are generated
in situ by Staudinger reaction, the process becomes a one-pot, three-
component sequential synthesis of libraries of differently substitut- differently substituted carbodiimides 2 smoothly react
ed 5-arylhydantoins.
with easily accessible a-halo-arylacetic acids 1 leading to
the formation of N,N¢-disubstituted 5-arylhydantoins 3
under very mild conditions (Scheme 1). The reaction se-
quence involves initial addition of 1 to 2 to form the reac-
tive O-acyl isourea 5 which readily cyclizes to the
intermediate 6 through an intramolecular nucleophilic
displacement of the halide. The following O→N acyl mi-
gration gives rise to the formation of the hydantoin 3. In
some cases, the O→N acyl migration is competitive with
the cyclization, leading to the formation of the N-acyl ure-
as 4 as a byproduct or even as the main product. However,
N-acyl ureas 4 can be convergently transformed into the
target hydantoins 3 by in situ treatment with a suitable
base. When the carbodiimides 2 are prepared in situ from
the corresponding azides and isocyanates through the
Staudinger (aza-Wittig) reaction, the process becomes a
Key words: heterocycles, multicomponent reactions, combinatori-
al chemistry, carbodiimides, sequential synthesis
While the past 50 years have witnessed extraordinary
progress in the discovery of new reagents, reactions, and
synthetic strategies,1 the tools of synthetic organic chem-
istry are often found inadequate when confronted with the
challenge of preparing even modestly elaborate molecules
in a practical fashion. One powerful approach toward this
goal is to combine two or more distinct reactions into a
single transformation, thereby producing a sequential re-
action process.2 Efficiency is also being pursued, when
possible, by implementation of classical multicomponent
(MC) reactions,3 as well as by the invention of new ones.
In this context ‘one-pot’ MC sequential syntheses feature
a high degree of reaction mass efficiency4 and are espe-
cially suitable in combinatorial chemistry and diversity-
oriented synthesis programs. Traditionally, methods
based on MC reactions have proved quite efficient for the
construction of many different types of heterocycles.5
R1
Br
Br
O
N
R1
N
C
N
R2
+
Ar
Ar
COOH
H
O
N
R2
2
1
5
5-Arylhydantoins have shown versatile therapeutic appli-
cations and some of them have been approved by the FDA
as therapeutics.6 Moreover, 5-arylhydantoins are impor-
tant building blocks for the synthesis of enantiomerically
pure phenylglycine derivatives by dynamic kinetic resolu-
tion of the racemate. The feasibility of this method was
demonstrated on an industrial scale by Ajinomoto and
Kanegafuchi for the production of D-p-hydroxyphenyl-
glycine.7 Since 1,3,5-substituted hydantoins were previ-
ously prepared by multistep synthesis starting from the
appropriate amino acids,8 or by palladium-catalyzed car-
bonylation reaction,9 we decided to develop a new synthe-
sis of libraries of 1,3-disubstituted 5-arylhydantoins that
was practical, experimentally simple, and suitable for the
one-pot generation of several new chemical bonds.
– HBr
N→O acyl
R2
migration
N
R1
N
O
Br
R2
N
H
Ar
N
O
Ar
R1
6
O
O
4
N→O acyl
migration
base
– HBr
R1
O
N
O
N
R2
Ar
3
SYNLETT 2008, No. 19, pp 3016–3020
x
x
.x
x
.2
0
0
8
Advanced online publication: 12.11.2008
DOI: 10.1055/s-0028-1087352; Art ID: D29408ST
Scheme 1 Synthesis of 5-arylhydantoins 3
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 1,3-Disubstituted 5-Arylhydantoins
3017
three-component, one-pot sequential synthesis of libraries try 9). Finally, 2f reacted with 1a leading to the exclusive
of structurally diverse 5-arylhydantoins.
formation of the N-acyl urea 4f (entry 10).11
To determine the best conditions for the reaction, we first Also in this case, in situ addition of a 2 M aqueous NaOH
examined the condensation of a-bromo-phenylacetic acid solution to 4f led to the formation of the hydantoin 3f in
(1a) with different carbodiimides 2, namely N,N¢-dialkyl- very good yield (entry 11).
carbodiimides 2a–d, N-alkyl- N¢-arylcarbodiimide 2e, and
N,N¢-diarylcarbodiimide 2f (Scheme 1, Table 1).
Next, we investigated the use of the Staudinger reaction in
order to develop a three-component, one-pot sequential
Hydantoins 3a–d were readily obtained, as the only prod- process starting from easily accessible azides 7, isocya-
ucts, upon treatment of 1a with 2a–d in the presence of 1 nates 8, and a-halo-arylacetic acids 1, without isolation of
equivalent of TMP at room temperature. The yields were the intermediate carbodiimides 2 (Table 2). Symmetrical
dependent on the solvent: the best results were obtained N,N¢-dibenzylcarbodiimide, generated from benzyl azide
with less polar CH2Cl2 (entries 3 and 5, Table 1); whereas 7a and isocyanate 8a in CH2Cl2 at room temperature, re-
more polar solvents such as dioxane (entries 2 and 4) and acted in situ with the acid 1a and a-bromodiphenylacetic
MeCN (entry 1) gave lower yields. As expected,10a when acid (1c) affording the hydantoins 3aa (entry 1, Table 2)
the two carbodiimide alkyl substituents R1 and R2 were and 3ah (entry 8), respectively, in good yields. As expect-
sterically very different – such as in 2d where R1 = tert- ed, when 1a and a-bromo-p-fluorophenylacetic acid (1b)
butyl and R2 = p-methoxybenzyl – the reaction was re- were treated with the asymmetric dialkylcarbodiimide
giospecific leading to the exclusive formation of the re- generated from 7a and tert-butylisocyanate 8b, hydanto-
gioisomer 3d (entry 7). In contrast, carbodiimide 2c, ins 3ab (entry 2) and 3ae (entry 5) were, respectively,
where R1 and R2 have similar steric bulk, afforded 3c as formed as the only regioisomers.12 The carbodiimide pre-
an equimolecolar mixture of the two regioisomers (entry pared in situ from 7b and 8a reacted with 1a and 1b af-
6). Carbodiimide 2e afforded a 2:1 mixture of hydantoin fording mixtures of the corresponding hydantoins and N-
3e and N-acyl urea 4e, as single regioisomers, upon treat- acyl ureas, which were converted to the regioisomers 3ac
ment with 1a (entry 8). However, in situ addition of a 2 M (entry 3) and 3af (entry 6), respectively, upon treatment
aqueous NaOH solution promoted the cyclization of 4e with a 2 M aqueous NaOH solution. The three-component
under Schotten–Bauman conditions, leading to the exclu- process worked well even with aryl azide 7c and aryl iso-
sive formation of the hydantoin 3e in excellent yield (en- cyanate 8c when reacted with acids 1a–c, leading to the
N,N¢-diarylhydantoins 3ad (entry 4), 3ag (entry 7) and 3ai
Table 1 Reaction between Acid 1a and Differently Substituted Carbodiimides
Br
R1
N
R1
N
COOH
Br
R1
N
O
O
H
1a
O
O
N
TMP
2N NaOH
R2
N
N
+
+
R2
R2
solvent
O
O
B
R1
N C N
R2
4
3
A
3
2
Entry
Carbodiimide R1
R2
Solvent
MeCN
Procedure
Hydantoin, yield (%) N-Acylurea, yield (%)
1
2
2a
2a
2a
2b
2b
2c
2d
2e
2e
2f
c-Hex
c-Hex
c-Hex
c-Hex
i-Pr
A
3a (33)
3a (57)
3a (100)
3b (45)
3b (100)
3c (93)a
3d (85)
3e (62)
3e (87)
–
–
c-Hex
c-Hex
i-Pr
dioxane
CH2Cl2
dioxane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
dioxane
dioxane
A
–
3
A
–
4
A
–
5
i-Pr
i-Pr
A
–
6
Me
PMB
PMB
PMB
PMB
p-Tol
p-Tol
A
–
7
t-Bu
PMP
PMP
p-Tol
p-Tol
A
–
8
A
4e (31)
9
A + B
A
–
10
11
4f (85)
2f
A + B
3f (81)
–
a Equimolar ratio of the two regioisomers 3c and 3c¢.
Synlett 2008, No. 19, 3016–3020 © Thieme Stuttgart · New York

3018
F. Olimpieri et al.
LETTER
(entry 9), respectively, after cyclization promoted by the philic acid 1e reacted with in situ generated N-alkyl, N¢-
NaOH solution. Highly electrophilic a-chloro-2,2-diphe- aryl, and N,N¢-diarylcarbodiimides affording the corre-
nylacetic acid (1d) reacted smoothly when submitted to sponding hydantoins 3al (entry 12) and 3am (entry 13),
the three-component process with N-alkyl, N¢-aryl, and respectively, in acceptable yields.
N,N¢-diarylcarbodiimides, directly affording the hydanto-
ins 3aj (entry 10) and 3ak (entry 11), respectively, in good
yields. Finally, quite surprisingly, even the less electro-
Table 2 The Three-Component One-Pot Sequential Synthesis of 5-Arylhydantoin 3
X
R1
Ar
COOH
R3
N
O
O
1) Ph3P, CH2Cl2
1
R1N3
2 N NaOH
R1
N C N
R2
3 + 4
N
2) R2NCO 8
R2
TMP
B
Ar
7
R3
A
3
Entry Azide, R1
Isocyanate, R2
Acid
Method Hydantoin
Product,
yield (%)
1
7a, Bn
8a, Bn
1a
A
3aa, 61
O
N
N
O
2
3
4
7a, Bn
8b, t-Bu
1a
1a
1a
A
3ab, 55
3ac, 83
3ad, 69
O
N
N
O
7b, 4-CbzNHC6H4 8a, Bn
A + B
O
N
N
NHCbz
O
7c, 4-MeOC6H4
8c, 4-MeOC6H4
A + B
MeO
O
N
N
OMe
O
5
6
7a, Bn
8b, t-Bu
A
3ae, 51
3af, 90
O
Br
N
N
COOH
N
F
O
O
1b
F
F
7b, 4-CbzNHC6H4 8a, Bn
1b
A + B
N
NHCbz
O
Synlett 2008, No. 19, 3016–3020 © Thieme Stuttgart · New York

LETTER
Synthesis of 1,3-Disubstituted 5-Arylhydantoins
3019
Table 2 The Three-Component One-Pot Sequential Synthesis of 5-Arylhydantoin 3 (continued)
X
R1
N
Ar
COOH
R3
O
O
1) Ph3P, CH2Cl2
1
R1N3
2 N NaOH
R1
N C N
R2
3 + 4
N
2) R2NCO 8
R2
TMP
B
Ar
7
R3
A
3
Entry Azide, R1
Isocyanate, R2
Acid
Method Hydantoin
Product,
yield (%)
7
8
7c, 4-MeOC6H4
8c, 4-MeOC6H4
1b
A + B
3ag, 72
MeO
O
N
N
OMe
O
F
7a, Bn
8a, Bn
A
3ah, 63
Br
O
COOH
N
N
O
1c
1c
9
7c, 4-MeOC6H4
8c, 4-MeOC6H4
A + B
3ai, 95
MeO
O
N
N
OMe
O
10
11
7c, 4-MeOC6H4
7c, 4-MeOC6H4
8a, Bn
A
A
3aj, 62a
O
Cl
N
COOH
N
OMe
Ph
Ph
O
1d
1d
8c, 4-MeOC6H4
3ak, 69a
MeO
O
N
N
OMe
Ph
Ph
O
12
13
7c, 4-MeOC6H4
7c, 4-MeOC6H4
8d, 4-MeOC6H3CH2
8c, 4-MeOC6H4
A
A
3al, 45
Br
O
COOH
N
N
OMe
MeO
MeO
Ph
O
1e
1e
3am, 40
O
N
N
OMe
Ph
O
a Yield calculated with respect to the azide.
Synlett 2008, No. 19, 3016–3020 © Thieme Stuttgart · New York

3020
F. Olimpieri et al.
LETTER
In conclusion, we have developed a novel and efficient
process for the synthesis of libraries of 1,3-disubstituted
5-arylhydantoins having a high degree of diversity
through a three-component sequential reaction involving
simple and readily accessible starting materials. The oper-
ational simplicity and the good chemical yields, combined
with favorable atom-economy aspects and a small number
of synthetic steps, render this new synthetic strategy at-
tractive and promising for the preparation of hydantoins
and useful derivatives such as unnatural a-amino acids.
References and Notes
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General Procedure for the Synthesis of 5-Arylhydantoins 3
Starting from a-Bromo Arylacetic Acids 1 and Carbodiimides 2
To a stirred solution of 1 (1 equiv) in CH2Cl2 (0.1 M solution) car-
bodiimide 2 (1.5 equiv), followed by TMP (1 equiv), was added at
r.t., and the mixture was stirred overnight. When needed, a 2 N
NaOH aq solution (10% in volume) was added and the mixture
stirred for 2 h. Afterwards, 1 N HCl aq solution was added, and the
resulting mixture extracted with CH2Cl2. The combined organic
layers were dried over anhyd Na2SO4, filtered, and concentrated un-
der vacuum. The crude material was purified by flash chromatogra-
phy.
General Procedure for the Synthesis of 5-Arylhydantoins 3 under
the Three-Component, One-Pot Sequential Process
To a stirred solution of the azide 7 (1.5 equiv) in anhyd CH2Cl2 (0.1
M) a solution of Ph3P in anhyd CH2Cl2 was added dropwise at r.t.
After 4 h the isocyanate 8 (1.5 equiv) was added, and the reaction
stirred for 3 h. Finally, TMP (1 equiv), followed by the acid 1 (1
equiv), was added and the solution stirred overnight. When needed,
a 2 M NaOH aq solution (10% in volume) was added and the mix-
ture stirred for 2 h. Afterwards, 1 M HCl aq solution was added and
the resulting mixture extracted with CH2Cl2. The combined organic
layers were dried over anhyd Na2SO4, filtered, and concentrated un-
der vacuum. The crude material was purified by flash chromatogra-
phy.
(7) (a) Yokozeki, K.; Kubota, K. Agric. Biol. Chem. 1987, 51,
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Chem. Int. Ed. 1999, 38, 1454.
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J. Org. Chem. 2005, 70, 2161. (b) Volonterio, A.; Zanda,
M. Org. Lett. 2007, 5, 841.
1,3-Dicyclohexyl-5-phenylimidazolidine-2,4-dione (3a)
Rf = 0.43 (hexane–EtOAc, 90:10). FTIR (Nujol): n = 1700, 1684
cm–1. 1H NMR (400 MHz, CDCl3): d = 7.39 (m, 5 H), 5.43 (s, 1 H),
4.00 (m, 1 H), 3.66 (m, 1 H), 2.32 (m, 2 H), 1.76 (m, 8 H), 1.36 (m,
10 H). 13C NMR (100.6 MHz, CDCl3): d = 170.7, 145.8, 134.5,
129.2, 128.9, 126.1, 79.1, 53.7, 53.1, 34.4, 34.3, 28.5, 28.4, 25.9,
25.8, 25.7, 25.1, 24.7, 24.6. ESI-MS: m/z (%) = 363.1 (86) [M+ +
Na], 341.1 (100) [M+ + 1].
(11) The reaction was carried out in dioxane because
Acknowledgment
carbodiimide 2f was insoluble in CH2Cl2.
Politecnico di Milano (Progetto Giovani Ricercatori) and CNR are
gratefully acknowledged for economic support.
(12) The lower yields obtained with N,N¢-dialkylcarbodiimides in
the three-component process are probably due to lower
yields in the Staudinger reaction.
Synlett 2008, No. 19, 3016–3020 © Thieme Stuttgart · New York