Multicomponent synthesis of N-carbamoyl hydantoin derivatives

Article abstract of DOI:10.1055/s-0032-1318432

A novel, three-component process for the preparation of a small library of unprecedented nonracemic N-carbamoyl hydantoins under very mild conditions, as well as the hypothetic mechanism, are presented. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318432

LETTER
▌727
lMetteur lticomponent Synthesis of N-Carbamoyl Hydantoin Derivatives
Synthesis of N-Carbamoyl Hydantoin Derivatives
Maria Cristina Bellucci,a Massimo Frigerio,b Tommaso Marcelli,b Alessandro Volonterio*b
a
Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Via Celoria 2, 20133 Milano, Italy
b
Department of Chemistry, Materials, and Chemical Engineer ‘Giulio Natta’, Politecnico di Milano, Via Mancinelli 7, 20131 Milano, Italy
Fax +39(02)23993180; E-mail: alessandro.volonterio@polimi.it
Received: 21.12.2012; Accepted after revision: 19.02.2013
situ prepared carbodiimides.4 The same process has been
Abstract: A novel, three-component process for the preparation of
further used for the preparation of glyco-hydantoin conju-
a small library of unprecedented nonracemic N-carbamoyl hydanto-
gates starting from carbodiimide bearing a sugar moiety.5
ins under very mild conditions, as well as the hypothetic mecha-
Since it has been demonstrated that the hydantoin ring is
able to induce conformational restriction in the backbone
of peptidomimetics being, for instance, a suitable scaffold
for the design of β-strand mimic structures,6 we became
interested in the preparation of hydantoin-based peptido-
mimetics starting from carbodiimides bearing an amino
acid. Following our chemistry, such carbodiimides could
have been prepared from Staudinger reaction between α-
azido esters and isocyanates (Scheme 1, path a).
nism, are presented.
Key words: domino reaction, multicomponent reaction, hetero-
cycles, hydantoins, Staudinger reaction
During the last years, multicomponent (MC) reactions
have been often involved in combinatorial and diversity-
oriented synthesis programs, becoming an extremely
powerful tool in medicinal chemistry.1 Indeed, MC reac-
tions have different advantages compared to the tradition-
al multistep reaction sequences, mainly considering the
operational simplicity, bond-forming efficiency, highly
flexibility, easily achievement of molecular complexity,
and all the economical and environmental aspects associ-
ated with the minimization of waste production and man-
power. Although MC processes have been applied with
success to the synthesis of different kind of scaffolds,
many of them have been developed for the efficient con-
struction of even simple heterocycles.2 For all these rea-
sons, the design and the application of novel MC reactions
for the construction of suitably functionalized heterocy-
clic scaffolds is a very active area of research both in aca-
demia and in industry. Among the various heterocycles,
the hydantoin ring could be considered a ‘privileged’ scaf-
fold since it has been widely used in numerous pharma-
ceutical applications.3
However, by reacting α-azido ester 1a with one equivalent
of benzyl isocyanate 2a in acetonitrile at room tempera-
ture and in the presence of Ph3P, we did not detect the for-
mation of the expected carbodiimide 3a, but we recovered
a product that, after careful analysis, we hypothesized to
be the N-carbamoyl hydantoin 4a (Scheme 1, path b).7 It
is worth noting that hypothetic N-carbamoyl hydantoin 4a
contains two equivalents of benzyl isocyanate, thus the
yields obtained carrying out the reaction with only one
equivalent of isocyanate 2a (43%) are very promising. In
order to verify the structure assigned, we checked the lit-
erature and, to our big surprise, we did not find any exam-
ple of nonracemic N-carbamoyl hydantoin derivative.
Thus we decided to synthesize 4a through the sequence
depicted in Scheme 2.
Hydantoin 6 has been synthesized as described by Cuny et
al., namely the preparation of phenylalanine benzyl amide
by reaction of phenylalanine methyl ester 5 with benzyl
amine, following by cyclization promoted by triphos-
gene.8 Thus, carbamoylation of 6 has been obtained by de-
In this context, we have recently discovered a MC sequen-
tial domino process for the synthesis of differently substi-
tuted hydantoins under mild conditions starting from in
Ph
Ph
a
N
C
N
MeOOC
Ph
3a (0%)
Ph3P
(1 equiv)
+
Ph
NCO
O
MeCN
r.t.
MeOOC
N3
Ph
Ph
b
H
N
N
1a (1 equiv)
2a (1 equiv)
Ph
N
O
O
4a (43%)
Scheme 1 Synthesis of N-carbamoyl hydantoin 3a
SYNLETT 2013, 24, 0727–0732
Advanced online publication: 06.03.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318432; Art ID: ST-2012-D1087-L
© Georg Thieme Verlag Stuttgart · New York

728
M. C. Bellucci et al.
LETTER
O
N
O
N
Ph
MeOOC
5
Ph
Ph
Ph
1) NaH, DMF
2) PhCH2NCO
Ph
ref. 7
H
N
Ph
N
NH
NH2
O
O
O
6
4a (52%)
Scheme 2 Multistep synthesis of N-carbamoyl hydantoin 3a
protonation with NaH followed by reaction with benzyl three-step sequence with the last step arising in moderate
isocyanate, producing derivative 4a in 52% yield. By yields.
comparing the 1H NMR and 13C NMR spectra of the two
Thus our methodology looks particularly suitable and ef-
structures, we confirmed that the product obtained by our
ficient for the preparation of such unprecedented com-
methodology was effectively the N-carbamoyl hydantoin
pounds.
4a. Unfortunately, the latter was found to have an enantio-
To determine the scope and limits of this methodology,
meric excess of almost 60%, thus a partial epimerization
we decided to study more in depth such MC processes
starting from different α-azido esters 1 and isocyanates 2
(Table 1).10,11
occurred during our process.9 However, it is worth noting
that the synthetic plan depicted in Scheme 2 consists in a
Table 1 Synthesis of N-Carbamoyl Hydantoins
O
R2
R2
R2
Ph3P
H
R3
N
R3 NCO
N
C
N
R3
+
or
N
N
O
R3
R1
N3
MeCN
r.t.
R1OOC
O
O
O
1
2
3
4
Entry R1
R2
α-Azido esters
R3
Isocyanate
Product
Yield
(%)a
Ph
O
O
N
NCO
MeO
1
Me Bn
N3
N3
N3
Bn
90
H
N
N
2a
1a
O
O
4a
MeO
Ph
O
O
NCO
OMe
MeO
2
Me Bn
4-MeOC6H4CH2
92
MeO
H
N
N
N
2b
1a
O
O
4b
Ph
O
O
N
MeO
NCO
3
Me Bn
Et
91
H
N
N
2c
1a
O
O
4c
Synlett 2013, 24, 727–732
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of N-Carbamoyl Hydantoin Derivatives
729
Table 1 Synthesis of N-Carbamoyl Hydantoins (continued)
O
R2
R2
R2
Ph3P
H
R3
N
R3 NCO
N
C
N
R3
+
or
N
N
O
R3
R1
N3
MeCN
r.t.
R1OOC
O
O
O
1
2
3
4
Entry R1
R2
α-Azido esters
R3
Isocyanate
Product
Yield
(%)a
Ph
O
O
N
MeO
4
Me Bn
N3
c-Hex
76
H
NCO
N
N
2d
O
O
N
1a
4d
Ph
Ph
Ph
MeO
N
N
C
C
N3
NCO
5
6
Me Bn
t-Bu
71
73
MeOOC
O
2e
2f
3a
1a
Ph
MeO
N
N3
Me Bn
Ph
NCO
MeOOC
O
3b
1a
O
N
NCO
MeO
1b
H
N3
68b
N
N
7
Me s-Bu
Bn
O
O
O
2a
4e
O
N
NCO
O
H
N
N3
N
8
9
t-Bu i-Bu
Bn
Et
21c
O
O
O
2a
2c
1c
4f
O
BnO
N3
H
N
NCO
N
N
Bn
H
H
89
O
O
O
1d
4g
MeO
O
EtO
OMe
NCO
N3
H
N
10
Et
4-MeOC6H4CH2
85
O
N
MeO
N
1e
2b
O
O
4h
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 727–732

730
M. C. Bellucci et al.
LETTER
Table 1 Synthesis of N-Carbamoyl Hydantoins (continued)
O
N
R2
O
R2
R2
Ph3P
H
R3
N
C
N
R3
R3 NCO
+
or
N
N
O
R3
R1
N3
MeCN
r.t.
R1OOC
O
O
1
2
3
4
Entry R1
R2
α-Azido esters
R3
Isocyanate
Product
Yield
(%)a
COOBn
H
O
N
COOBn
MeO
NCO
N3
11
Me CH2CO2Bn
Et
N
68
N
O
O
O
2c
O
O
1f
4i
OBn
OBn
N3
O
N
MeO
H
N
NCO
N
12
13
Me CH2OBn
Et
76
73
2c
O
O
1g
4j
OBn
OBn
N3
O
N
NCO
MeO
H
N
N
Me CH2OBn
Bn
O
O
2a
1g
4k
OBn
O
OBn
N3
H
MeO
N
N
N
14
Me CH2OBn
c-Hex
70
NCO
O
O
O
2d
1g
4l
a Isolated yields.
b The corresponding carbodiimide was isolated in10% yield.
c The corresponding carbodiimide was isolated in 64% yield.
First, we checked the efficiency of the process by increas- dantoin derivative, was obtained performing the reaction
ing the amount of the isocyanate. Gratifyingly, by carry- with aromatic isocyanates (Table 1, entry 6). Probably,
ing out the reaction of α-azido ester 4a with 2.5 the nucleophilic character of the amino moiety on the iso-
equivalents of 2a under the same conditions described cyanate reactant plays an important role on the outcome of
above, namely room temperature and MeCN as solvent, the process and neither bulky tert-butyl nor electron-with-
we obtained the formation of hydantoin 4a in almost drawing phenyl substituents are suitable to trigger the
quantitative yields (Table 1, entry 1). The process worked mechanism which promotes the formation of the N-car-
very efficiently with either primary and secondary alkyl bamoyl hydantoin. On the contrary, the steric hindrance of
isocyanates. Indeed, the same α-azido ester 4a reacted the α-azido ester side chain has minor influence on the
smoothly with 4-methoxybenzyl (2b), ethyl (2c), and cy- yields of the process. Indeed, azido isoleucine methyl es-
clohexyl isocyanate (2d) giving rise to the formation of ter (1b) reacted with benzyl isocyanate (2a) producing the
the corresponding N-carbamoyl hydantoin 4b–d, respec- expected hydantoin derivative 4e in good yields (Table 1,
tively, in excellent yields (Table 1, entries 2–4). Unfortu- entry 7). As expected, since one step of the process is
nately, the reaction with tertiary alkyl isocyanates, such as clearly a nucleophilic attack to the ester moiety of the
tert-butyl isocyanate (2e), did not afford the expected hy- starting azide, the reaction between α-azidovaline tert-bu-
dantoin derivative, but the corresponding carbodiimide 3a tyl ester (1c) and benzyl isocyanate (2a) lead to the forma-
in good yields (Table 1, entry 5). The same result, namely tion of hydantoin 4f in low yields (Table 1, entry 8). On
the production of the carbodiimide 3b instead of the hy- the contrary, either α-azidoglycine benzyl ester (1d) and
Synlett 2013, 24, 727–732
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of N-Carbamoyl Hydantoin Derivatives
731
R2
Ph
P
O
R2
Ph
Ph
R3
Ph
Ph
Ph
Ph3P
R3NCO
R1OOC
N P
N
N
O
R1OOC
N3
MeCN
r.t.
R2
7
8
1
OR1
R3NCO
– Ph3PO
R2
R1OOC
N
C
N
R3
3
Ph
P
O
C
Ph
O
Ph
R1O
R2
N
Ph
P
O
N
R3
Ph
R1O
Ph
N
O
N
R2
O
N
R3
O
N
R3
H
hydrolysis
R3
N
N
9
R3
R2
O
O
N
4
O
R3
10
Scheme 3 Proposed mechanism for the MC synthesis of N-carbamoyl hydantoin 3
ethyl ester (1e) reacted straightforwardly with ethyl isocy- The same behavior, namely the formation of the carbo-
anate (2c) and 4-methoxybenzyl isocyanate (2b) produc- diimide, was observed when the amino moiety of the iso-
ing N-carbamoyl hydantoins 4g,h, respectively, in very cyanate was poorly nucleophilic such as in
good yields (Table 1, entries 9 and 10). Finally, we ex- phenylisocyanate. However, when heterocycle 9 is
plored the reaction with other starting α-azido esters, such formed, it reacts with a second equivalent of isocyanate 2
as α-azido aspartic acid derivative 1f and α-azido serine leading to the formation of intermediate 10 which readily
derivative 1g with good results. Indeed 1f reacted with hydrolyzes to the final N-carbamoyl hydantoin 4.
ethyl isocyanate (2c) producing hydantoin derivative 4i in
satisfactory yields (Table 1, entry 11), while 1g was treat-
ed with isocyanates 2a,c,d giving rise to the efficient for-
In order to prove the enantiomeric excesses of the N-car-
bamoyl hydantoins obtained and that some of them could
be selectively functionalized, the ester moiety of com-
mation of products 4j–l, respectively (Table 1, entries 12–
pound 4i was hydrolyzed by catalytic hydrogenation and
14).
the resulting acid coupled with (S)-H-Phe-OBn achieving
In agreement with all the experimental results described the formation of 11 in very good overall yields as an al-
above, we suggest that our process proceeds through the most 80:20 mixture (60% ee of the starting hydantoin) of
mechanism portrayed in Scheme 3.
diastereoisomers (Scheme 4).12
Phosphazene 7, obtained by reaction between α-azido es- In conclusion, starting from easily accessible α-azido es-
ter 1 and Ph3P, reacts with the first equivalent of isocya- ters and isocyanates, we have developed a novel three-
nate 2 leading to the formation of zwitterionic component process for the synthesis of unprecedented
intermediate 8, which likely undergoes cyclization pro- nonracemic N-carbamoyl hydantoins incorporating two
ducing the heterocyclic intermediate 9. When such cycli- equivalents of the isocyanate. When the reaction is not
zation is hampered by steric factors, mainly due to the hampered by steric factors or poor nucleophilicity of the
isocyanate and the ester substituents rather than the R2 isocyanate amino moiety, the process works very well,
group, the intermediate 8 can rearrange through the clas- producing the target compounds in high yields and under
sical mechanism of the Staudinger reaction producing car- very mild conditions, that is, room temperature without
bodiimide 3 as the main, if not the sole reaction product. the need of bases or acids. The synthesis of N-carbamoyl
H
COOBn
Ph
N
COOBn
H
O
O
N
O
N
1) Pd/C, H2 (1 atm), MeOH
2) H-Phe-OBn, EDC, HOBt
TMP, DMF
N
N
H
N
N
O
O
O
O
11 (89%)
4i
Scheme 4 Synthesis of 11
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 727–732

732
M. C. Bellucci et al.
LETTER
Marcelli, T.; Volonterio, A. Org. Biomol. Chem. 2012, 10,
9538.
(5) Bellucci, M. C.; Ghilardi, A.; Volonterio, A. Org. Biomol.
Chem. 2011, 9, 8379.
(6) (a) Vazquez, J.; Garcia-Jareño, A.; Mondragon, L.; Rubio-
Martinez, J.; Perez-Paya, E.; Albericio, F. ChemMedChem
2008, 3, 979. (b) Jamieson, A. G.; Russell, D.; Hamilton, A.
D. Chem. Commun. 2012, 48, 3709. (c) Sutherell, C. L.;
Thompson, S.; Scott, R. T. W.; Hamilton, A. D. Chem.
Commun. 2012, 48, 9834.
hydantoins incorporating two different isocyanates, the
reactivity of carbodiimides 3, as well as the application of
the process for the solid-phase and combinatorial synthe-
sis of libraries of N-carbamoyl hydantoins is currently in
progress in our laboratories.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(7) Characterization of Compound 4a
Rf = 0.43 (hexane–EtOAc, 60:40); [a]D20 +33.3 (c 1.0,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.17 (t, J = 5.6 Hz,
1 H), 7.38–6.97 (m, 15 H), 4.83 (dd, J = 5.6, 2.4 Hz, 1 H),
4.62 (dd, J = 14.8, 6.0 Hz, 1 H), 4.52 (d, J = 14.8 Hz, 1 H),
4.50 (dd, J = 14.8, 6.8 Hz, 1 H), 3.70 (dd, J = 14.0, 5.6 Hz,
1 H), 3.30 (dd, J = 14.0, 2.4 Hz, 1 H). 13C NMR (125.7 MHz,
CDCl3): δ = 170.5, 155.3, 151.1, 138.0, 133.3, 129.7, 128.7,
128.6, 128.5, 128.2, 128.0, 127.6, 127.4, 59.9, 43.9, 42.4,
34.9. ESI-MS: m/z (%) = 259.1 (100), 436.2 (38) [M+ + H].
Anal. Calcd for C25H23N3O3: C, 72.62, H, 5.61, N, 10.16.
Found: C, 72.67, H, 5.64, N, 10.11.
References and Notes
(1) For some reviews on MC reactions, see: (a) Armstrong, R.
M.; Combs, A. P.; Brown, P. A.; Keating, T. A. Acc. Chem.
Res. 1996, 29, 123. (b) Bienaymé, H.; Hulme, C.; Oddon,
G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321. (c) Dömling,
A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3169.
(d) Dömling, A. Curr. Opin. Chem. Biol. 2000, 4, 318.
(e) Dömling, A. Chem. Rev. 2006, 106, 17. (f) Isambert, N.;
Lavilla, R. Chem. Eur. J. 2008, 14, 8444. (g) Ganem, B. Acc.
Chem. Res. 2009, 42, 463. (h) Ruijter, E.; Scheffelaar, R.;
Orru, R. V. Angew. Chem. Int. Ed. 2011, 50, 6234.
(i) Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012,
112, 3083.
(8) Zhang, D.; Xing, X.; Cuny, G. D. J. Org. Chem. 2006, 71,
1750.
(9) The ee was determined by chiral HPLC (see Supporting
Information). In this regard, we would like to acknowledge
the referee who suggested we check the ee of the N-
carbamoyl hydantoins obtained by our process.
(10) The starting α-azido esters 1 were prepared from the
corresponding α-amino esters by diazotransfer reaction
promoted by imidazole-1-sulfonyl azide hydrochloride:
Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797.
(11) General Procedure for the Preparation of N-Carbamoyl
Hydantoins 4
(2) For some reviews, see: (a) Orru, R. V. A.; de Greef, M.
Synthesis 2003, 1471. (b) Sunderhaus, J. D.; Martin, S. F.
Chem. Eur. J. 2009, 15, 1300. (c) Jiang, B.; Rajale, T.;
Wever, W.; Tu, S.-J.; Li, G. Chem. Asian J. 2010, 5, 2318.
(d) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44,
1156. (e) Eckert, H. Molecules 2012, 17, 1074.
(3) (a) Ware, E. Chem. Rev. 1950, 46, 403. (b) Gerona-Navarro,
G.; Gonzalez-Muñiz, R.; Fernandez-Carvajal, A.; Gonzalez-
Ros, J. M.; Ferrer-Montiel, A.; Carreño, C.; Albericio, F.;
Royo, M. ACS Comb. Sci. 2011, 13, 458.
(4) (a) Volonterio, A.; Ramirez de Arellano, C.; Zanda, M. J.
Org. Chem. 2005, 70, 2161. (b) Olimpieri, F.; Volonterio,
A.; Zanda, M. Synlett 2008, 3016. (c) Marcelli, T.;
Olimpieri, F.; Volonterio, A. Org. Biomol. Chem. 2011, 9,
5156. (d) Bellucci, M. C.; Volonterio, A. Eur. J. Org. Chem.
2009, 6179. (e) Bellucci, M. C.; Marcelli, T.; Volonterio, A.
RSC Adv. 2011, 1, 1250. (f) Olimpieri, F.; Bellucci, M. C.;
To a stirred solution of α-azido ester 1 (1equiv) and
isocyanate 2 (2.5 equiv) in MeCN (0.1 M solution), solid
Ph3P (1equiv) was added and the solution stirred at r.t. for 3
h. The solvent was removed under reduced pressure and the
crude purified by flash chromatography.
(12) Since both N-carbamoyl hydantoins 4a and 4i have ca. 60%
ee, we assume that also N-carbamoyl hydantoins 4b–f,k–l
posses the same ee since the process was run under the same
conditions, i.e., in MeCN at r.t. for 3 h.
Synlett 2013, 24, 727–732
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.