Facile Construction of Hydantoin Scaffolds via a Post-Ugi Cascade Reaction

Article abstract of DOI:10.1055/s-0037-1610234

A small series of hydantoins was efficiently synthesized via a two-step Ugi/cyclization reaction sequence using alkyne group as a leaving group under basic conditions. This microwave-assisted one-pot cyclization strategy could be applicable to other multicomponent reactions (MCRs) for synthesizing bioactive and drug-like hydantoins.

Full text of DOI:10.1055/s-0037-1610234

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
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Z.-G. Xu et al.
Letter
Synlett
Facile Construction of Hydantoin Scaffolds via a Post-Ugi Cascade
Reaction
Zhi-Gang Xua◊
Yong Dinga◊
Jiang-Ping Menga
Dian-Yong Tanga
Yong Lia
Jie Leia
Chuan Xu*b
R1 NH2
O
(1) MeOH, r.t.
without purification
R1
R3
R2 CHO
R3
COOH
N
N
R
1 = Ar
N
(2) K2CO3, CH3CN
MW, 100 °C, 10 min
R2 = Ar
R2
O
R3 = Ar, Alkyl
leaving group
Microwave irradiation
One-pot protocol
Atom economy
Short reaction times
17 examples, yield 42–77%
Two steps and one purification
Zhong-Zhu Chen*a
a Chongqing Engineering Laboratory of Targeted and Innovative
Therapeutics, Chongqing Key Laboratory of Kinase Modula-
tors as Innovative Medicine, IATTI, Chongqing University of
Arts and Sciences. 319 Honghe Ave., Yongchuan, Chongqing
402160, P. R. of China
18883138277@163.com
b Department of Oncology, Sichuan Academy of Medical Sci-
ences,, Sichuan Provincial People’s Hospital, University of Elec-
tronic Science and Technology of China, Chengdu, Sichuan,
610072, P. R. of China
Xuchuan100@163.com
◊ These authors contributed equally to this work
Received: 10.07.2018
Accepted after revision: 18.07.2018
Published online: 06.09.2018
scaffolds represented by hydantoins were prepared via a
MCR, an efficient three-component reaction, domino pro-
cess for the synthesis of libraries of 1,3-disubstituted-5-
arylhydantoins with a high degree of diversity starting
from simple and easily accessible reactants.12 Similarly, a
structure of pseudopeptidic hydantoin was constructed
through a diastereoselective synthesis of helix-forming by
an Ugi/cyclization/Ugi sequence of reactions with trichloro-
acetic acid as a leaving group.13 The cost-effective and envi-
ronment-friendly conditions, short reaction steps, and sim-
ple workups would be still desirable.
DOI: 10.1055/s-0037-1610234; Art ID: st-2018-w0284-l
Abstract A small series of hydantoins was efficiently synthesized via a
two-step Ugi/cyclization reaction sequence using alkyne group as a
leaving group under basic conditions. This microwave-assisted one-pot
cyclization strategy could be applicable to other multicomponent reac-
tions (MCRs) for synthesizing bioactive and drug-like hydantoins.
Key words hydantoins, multicomponent reactions (MCRs), one-pot,
alkyne group, leaving group
We have a long-standing interest in the use of the Ugi
cascade reaction for the formation of new C–C bonds as a
general strategy for the construction of heterocycles for
drug discovery.14 In this regard, we were pleased to find
that the results of our previous work provided us with a
new opportunity to use propiolic acid, surprisingly to find
it as a leaving group to synthesize a hydantoin core
(Scheme 1).
Initially, to form the Ugi core, aniline (1a), propiolic acid
(2), benzaldehyde (3a), and phenyl isonitrile (4a) were
mixed in methanol with stirring overnight at room tem-
perature to afford compound 5a in excellent yield (Scheme
1). Unfortunately, on our first reaction conditions testing,
the subsequent cyclization under thermal conditions in the
presence of a base did not proceed to afford the anticipated
product 6a, but instead gave the unexpected hydantoin an-
alogue 7a. The structure of compound 7a was unequivocal-
ly confirmed by the NMR data from a known compound
and X-ray results (see Supporting Information).15,16 The
alkyne group was actually used as a leaving group in the
Hydantoins, an important class of versatile compounds,
has been widely investigated in medicinal and organic
chemistry.1 In recent years, the interest has been focused on
pharmacological activities like androgen receptors,2 perfo-
rin inhibitors,3 P2X7 receptor antagonists,4 mutant IDH1 in-
hibitors,5 antischistosomal,6 CB1 cannabinoid receptor an-
tagonists,7 and antagonists of leukocyte cell adhesion acting
as allosteric inhibitors.8 Various different methods for the
synthesis of hydantoins have been recently developed both
in solution and in the solid phase to improve the drawbacks
associated with reductive amination9 or Mitsunobu reac-
tion.10 However, even if some of these methods allow the
synthesis of hydantoins under milder conditions, less of
them meet the modern requirements to be ‘green’ and
‘practical’, all of them being multistep procedures.
Multicomponent reactions (MCRs) have attracted con-
siderable attention as powerful tools for the rapid construc-
tion of highly functionalized heterocyclic skeletons of
chemical and biomedical importance.11 Recently, privileged
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

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Z.-G. Xu et al.
Letter
Synlett
Entry Base
Solvent
Time
(min)MW
Temp
(°C)
Yield
(%)a
NH2
COOH
O
6
NaOEt (2 equiv)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMF
20
10
10
10
20
20
20
20
20
20
20
20
10
10
10
10
10
10
10
140
90
65
42
37
9
1a
3a
2
MeOH
r.t.
N
+
N
H
7
KOH (1 equiv)
KOH (1 equiv)
KOH (1 equiv)
KOH (2 equiv)
Na2CO3 (2 equiv)
Cs2CO3 (2 equiv)
KOAc (2 equiv)
KF (2 equiv)
N
O
CHO
8
100
110
140
140
140
140
140
100
80
4a
5a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
NR
80
85
72
77
93
60
84
93
46
94
21
70
40
37
observed
O
O
N
anticipated
N
N
N
O
O
6a
7a
K2CO3(2 equiv)
K2CO3(2 equiv)
K2CO3(2 equiv)
K2CO3(2 equiv)
K2CO3 (0.5 equiv)
K2CO3 (1.0 equiv)
K2CO3(1 equiv)
K2CO3(1 equiv)
K2CO3(1 equiv)
K2CO3 (1 equiv)
Scheme 1 Synthetic strategy of compounds 6a and 7a
90
ring-cyclization step. Although the leaving group of trichloro-
acetic acid has been reported to synthesize the hydan-
toins,15 the alkyne group would enrich this synthesis meth-
od and can be applied to other synthetic processes.
100
100
100
100
100
100
100
Optimization work was therefore conducted to improve
the yield of this reaction. To begin, we screened various
bases of triethylamine (TEA), diisopropylamine (DIPA), N,N-
diisopropylethylamine (DIPEA), and 4-dimethylaminopyri-
dine (DMAP). Pleasingly, for all of the organic bases tested
in this study, the hydantoin compound 7a could be ob-
served in 21–81% yield with microwave irradiation (Table 1,
entries 1–5). Based on these good results, some inorganic
bases were tested continually under microwave irradiation
conditions. As expected, inorganic bases still could afford
compound 7a (Table 1, entries 6–15) with higher yields
than those of organic bases, but KOH did not afford com-
pound 7a in good yield (Table 1, entries 7–10). It is note-
worthy that the microwave irradiation at 100 °C in CH3CN
for 20 min could afford the desired product 7a in 93% yield.
Gratifyingly, we also investigated the effect of the reaction
time, solvents, and equivalent of K2CO3 and found that the
optimized reaction conditions are (Table 1, entry 20) heat-
ing the reaction mixture at 100 °C under microwave irradia-
tion for 10 min in CH3CN. The synthesis of compound 7a
was tracked by the HPLC following these conditions (see
Supporting Information for details). Notably, switching the
solvent to DMSO, DMF, ethanol, or 1,4-dioxane led to the
lower yields of compound 7a (Table 1, entries 21–24).
EtOH
Diox
a Yield (%) based on peak area of the product by HPLC analysis at 254 nm.
MW = microwave.
Encouraged by the remarkable yield at the optimized
conditions, we investigated the scope of this cyclization by
varying starting materials. Propiolic acid (2) was treated
with various substituted isonitriles, amines, and benzalde-
hydes in methanol at room temperature overnight to give
the crude Ugi product 5, which was directly subjected to
cyclization reaction after the removal of solvent under a
gentle stream of nitrogen. Then, under the basic conditions,
following the intermediates 8 and 9, nucleophilic addition
and elimination reactions occurred to give product 7. A va-
riety of different starting materials were successfully em-
ployed under the optimized conditions for the construction
of structurally diverse hydantoin 7a–q with yields of 42–
77% (Scheme 2), indicating a good functional group toler-
ance. It is noteworthy that the products of the Ugi reaction
did not require purification by column chromatography,
with the crude products having no discernible impact on
the overall yield. The results further confirm the utility and
the potential broad application of this novel methodology.
In summary, we have developed an unprecedented
post-Ugi cascade reaction in one-pot for the construction of
highly functionalized hydantoins, which are important
pharmacophores and privileged structures that can be
found in many biologically important compounds in medic-
inal chemistry. The cascade cyclization using the leaving
property of alkyne group with the microwave irradiation
under basic conditions design approach would be highly
Table 1 Optimization of the Reaction Conditions for the Synthesis of 7a
Entry Base
Solvent
Time
(min)MW
Temp
(°C)
Yield
(%)a
1
2
3
4
5
TEA (2 equiv)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
20
20
20
20
20
140
140
140
140
140
81
21
73
72
62
DIPA (2 equiv)
DIPEA (2 equiv)
DMAP (2 equiv)
DBU (2 equiv)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
Z.-G. Xu et al.
Letter
Synlett
Scheme 2 Scope of the Ugi cascade reaction route leading to hydantoin 7a–q.
applicable to other MCRs such as Passerini,17 Petasis,18 Bet-
ti,19 Kabachnik–Fields,20 Mannich21, etc. This new method22
for the construction of complex heterocyclic systems could
provide a platform for the further diversification of hydan-
toin scaffolds and studies on their potent biological activity.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610234.
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References and Notes
Funding Information
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This work was supported by the Chongqing Research Program of Basic
Research and Frontier Technology (cstc2015jcyjA1328 and
cstc2015zdcy-ztzx0191) and the Scientific Research Foundation of
Chongqing University of Arts and Sciences (Grant Nos. R2013XY01
and R2013XY02).
)(
Acknowledgment
We would like to thank Ms H.Z. Liu for obtaining the LC/MS and NMR
data, Ms J. Xu for obtaining the HRMS data.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

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A solution of aniline (1.0 mmol), propiolic acid (1.0 mmol),
benzaldehyde (1.0 mmol), and isonitrile (1.0 mmol) were mixed
in methanol with stirring overnight at room temperature. The
reaction mixture was monitored by TLC. When no isonitrile was
left, the solvent was removed under a gentle stream of nitrogen.
Then, the residue was diluted with CH3CN (5.0 mL) and K2CO3
(1.0 mmol) was added. The reaction mixture was treated in
microwave at 100 °C for 10 min. After the microwave vial was
cooled to room temperature, the reaction mixture was diluted
with EtOAc (25 mL) and washed with water and brine. Then the
organic layer was dried with Na2SO4 and concentrated. The
residue was purified by silica gel column chromatography using
a gradient of EtOAc/hexane (15–30%) to afford the relative tar-
geted product 7.
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Analytical Data for Compound 7aWhite solid, 75%. 1H NMR
(400 MHz, CDCl3):  = 4.71–4.83 (q, J = 14.4 Hz, 2 H), 5.46 (s, 1
H), 7.05–7.09 (t, J = 7.6 Hz, 1 H), 7.23–7.27 (m, 2 H), 7.27–7.35
(m, 8 H), 7.43–7.47 (t, J = 8.8 Hz, 4 H). 13C NMR (100 MHz,
CDCl3):  = 169.59, 160.24, 154.41, 136.47, 135.75, 134.35,
130.37, 129.11, 128.74, 128.07, 124.75, 120.20, 119.01, 114.73,
112.21, 64.26, 42.90. HRMS (ESI): m/z calcd for C22H18N2O2+ [M +
H]+: 343.14465; found: 343.14431.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D