Nickel-catalyzed synthesis of 1,3,5-trisubstituted hydantoins from acrylates and isocyanates

Article abstract of DOI:10.1021/ol200957y

One molecule of acrylate reacts with two molecules of isocyanate in the presence of a nickel(0)/SIPr catalyst to give a 1,3,5-trisubstituted hydantoin. Two processes operate in sequence, the first, regioselective formation of N-substituted fumaramate from acrylate and isocyanate and, the second, ring closure of the fumaramate with incorporation of another molecule of isocyanate.

Full text of DOI:10.1021/ol200957y

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3560–3563
Nickel-Catalyzed Synthesis of
1,3,5-Trisubstituted Hydantoins from
Acrylates and Isocyanates
Tomoya Miura, Yusuke Mikano, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University,
Katsura, Kyoto 615-8510, Japan
murakami@sbchem.kyoto-u.ac.jp
Received April 11, 2011
ABSTRACT
One molecule of acrylate reacts with two molecules of isocyanate in the presence of a nickel(0)/SIPr catalyst to give a 1,3,5-trisubstituted
hydantoin. Two processes operate in sequence, the first, regioselective formation of N-substituted fumaramate from acrylate and isocyanate and,
the second, ring closure of the fumaramate with incorporation of another molecule of isocyanate.
A hydantoin (imidazolidine-2,4-dione) skeleton1 is an
important structural motif found in a number of pharma-
ceutically active compounds,2 such as phenytoin and fo-
sphenytoin which are in practical use for the treatment of
epilepsy. In addition, substituted hydantoins act as valu-
able intermediates for the synthesis of enantiomerically
pure amino acids through dynamic kinetic resolution using
hydantoinase biocatalysis.3 Therefore, the development
of efficient methods for rapid construction of hydantoin
skeletons from simple and inexpensive starting materials
is highly desired. Various preparative methods based on
transition-metal catalysts have been reported. A formal
intermolecular [2 þ 2 þ 1] cycloaddition reaction of one
molecule of phenylacetylene and two molecules of isocya-
nate is catalyzed by iron,4 ruthenium,5 and manganese6
complexes, leading to the formation of 5-benzylidene-
1,3-disubstituted hydantoins. A copper-catalyzed CꢀH
R-amination reaction of esters with di-tert-butyldiaziridi-
none affords 1,3,5-trisubstituted hydantoins.7 A palladium-
catalyzed carbonylation reaction of aldehydes with ureas
and carbon monoxide furnishes 5-, 3,5-, and 1,3,5-substi-
tuted hydantoins.8 However, there has been no report
on the hydantoin synthesis starting from acrylates and
isocyanates. We now report the synthesis of 1,3,5-trisub-
stituted hydantoins9 from one molecule of acrylate and
two molecules of isocyanate by use of nickel catalysis.
€
(1) For a review of hydantoin chemistry, see: Meusel, M.; Gutschow,
M. Org. Prep. Proced. Int. 2004, 36, 391.
(6) Kuninobu, Y.; Kikuchi, K.; Takai, K. Chem. Lett. 2008, 37, 740.
(7) Zhao, B.; Du, H.; Shi, Y. J. Am. Chem. Soc. 2008, 130, 7220.
(8) Beller, M.; Eckert, M.; Moradi, W. A.; Neumann, H. Angew.
Chem., Int. Ed. 1999, 38, 1454.
(2) (a) Last-Barney, K.; Davidson, W.; Cardozo, M.; Frye, L. L.;
Grygon, C. A.; Hopkins, J. L.; Jeanfavre, D. D.; Pav, S.; Qian, C.;
Stevenson, J. M.; Tong, L.; Zindell, R.; Kelly, T. A. J. Am. Chem. Soc.
2001, 123, 5643. (b) Stilz, H. U.; Guba, W.; Jablonka, B.; Just, M.;
(9) For recent examples of the synthesis of 1,3,5-substituted hydan-
toins without the use of transition-metal catalysts, see: (a) Sim, M. M.;
Ganesan, A. J. Org. Chem. 1997, 62, 3230. (b) Matthews, J.; Rivero,
R. A. J. Org. Chem. 1997, 62, 6090. (c) Kim, S. W.; Ahn, S. Y.; Koh, J. S.;
Lee, J. H.; Ro, S.; Cho, H. Y. Tetrahedron Lett. 1997, 38, 4603. (d)
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. (e) Zhang, W.; Lu, Y. Org. Lett. 2003, 5, 2555. (f) Ignacio, J. M.;
Macho, S.; Marcaccini, S.; Pepino, R.; Torroba, T. Synlett 2005, 3051.
(g) Volonterio, A.; de Arellano, C. R.; Zanda, M. J. Org. Chem. 2005, 70,
2161. (h) Olimpieri, F.; Volonterio, A.; Zanda, M. Synlett 2008, 3016. (i)
Attanasi, O. A.; De Crescentini, L.; Favi, G.; Nicolini, S.; Perrulli, F. R.;
Santeusanio, S. Org. Lett. 2011, 13, 353.
€
Klingler, O.; Konig, W.; Wehner, V.; Zoller, G. J. Med. Chem. 2001, 44,
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1158. (c) Somsak, L.; Kovacs, L.; Toth, M.; Osz, E.; Szilagyi, L.;
€
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Gyorgydeak, Z.; Dinya, Z.; Docsa, T.; Toth, B.; Gergely, P. J. Med.
Chem. 2001, 44, 2843. (d) Thenmozhiyal, J. C.; Wong, P. T.-H.; Chui,
W.-K. J. Med. Chem. 2004, 47, 1527. (e) Muccioli, G. G.; Fazio, N.;
Scriba, G. K. E.; Poppitz, W.; Cannata, F.; Poupaert, J. H.; Wouters, J.;
Lambert, D. M. J. Med. Chem. 2006, 49, 417.
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r
10.1021/ol200957y
Published on Web 06/14/2011
2011 American Chemical Society

nickel-catalyzed reaction of 1a with 2a using achiral
ligands as shown in Table 1.13 The cycloadduct 3aa was
scarcely obtained when phosphine ligands such as PPh3,
PCy3, and dppe were used (entries 1ꢀ3). On the contrary,
the use of N-heterocyclic carbene (NHC) ligands afforded
fairly good results (entries 4ꢀ7).14 Among them, SIPr most
effectively promoted the reaction to give 3aa in 79%
isolated yield.
Table 1. Optimization of Reaction Conditionsa
entry
ligand
X/mol %
NMR yield/%b
1
2
3
4
5
6
7
PCy3
PPh3
Dppe
IMes
SIMes
IPr
20
20
10
10
10
10
10
6
Table 2. Ni-Catalyzed Synthesis of 1,3,5-Trisubstituted
Hydantoins 3 from Acrylates 1 and Isocyanates 2a
0
1
8
82
83
SIPr
83 (79)
a All reactions were carried out on a 0.4 mmol scale. b 1H NMR yield
using CHCl2CHCl2 as an internal standard with isolated yield in
parentheses. Abbreviations: IMes = 1,3-bis(2,4,6-trimethylphenyl)imi-
dazol-2-ylidene, SIMes = 1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-
ylidene, IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, SIPr =
1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene.
entry
1 (R1)
2 (R2)
3
yield/%b
1
1a (Me)
1a
2b (Ph)
3ab
3ac
3ad
3ae
3af
75
2
2c (3-Tol)
77c
68
3
1a
2d (2-Tol)
4
1a
2e (4-MeO-C6H4 (PMP))
2f (4-Cl-C6H4)
2g (4-MeO2C-C6H4)
2h (4-CH3C(O)-C6H4)
2i (4-CF3-C6H4)
2a (4-Tol)
72c
74
We have recently developed10 a highly enantioselective
[2 þ 2 þ 2] cycloaddition reaction of one molecule of allene
and two molecules of isocyanate using a nickel(0)/(S,S)-i-
Pr-FOXAP11 catalyst. This method allowed for facile
preparation of enantiomerically enriched dihydropyrimi-
dine-2,4-diones. On the other hand, it has been reported
that the [2 þ 2 þ 2] cycloaddition reaction of one molecule
of methyl acrylate and two molecules of phenyl isocyanate
in the presence of a nickel(0)/PCy3 catalyst affords 1,3-
diphenyl-6-methoxycarbonyldihydropyrimidine-2,4-dione
in 60% yield.12 As a continuation of our study on metal-
catalyzed asymmetric cycloaddition reactions of isocya-
nates, we next examined the asymmetric version using
chiral ligands in a reaction of methyl acrylate (1a) and
4-tolyl isocyanate (2a). When 1a (1.0 equiv) was treated
with 2a (3.0 equiv) in the presence of a nickel(0)/(S,S)-i-Pr-
FOXAP11 catalyst which was effective for the allene/
isocyanate cycloaddition,10 no cycloadduct was obtained.
When (S,S)-CHIRAPHOS11 was used as the ligand, 8%
of a 1:2 acrylate/isocyanate cycloadduct was obtained
(0% ee). The structure of the cycloadduct was determined
to be 1,3-ditolyl-5-(methoxycarbonylmethyl)hydantoin
(3aa) having a five-membered ring, rather than 1,3-
ditolyl-6-methoxycarbonyldihydropyrimidine-2,4-dione
having a six-membered ring, by derivatization to the
ethoxycarbonyl compound which is known in literature.9g
This unexpected result prompted us to re-examine the
5
1a
6
1a
3ag
3ah
3ai
67c
65c,d
72
7
1a
8
1a
9
1b (Et)
1c (Bn)
1d (i-Pr)
1e (t-Bu)
3ba
3ca
3da
3ea
88
10
11
12
2a
81
2a
78
35c
2a
a The reaction was carried out with 1 (0.4 mmol), 2 (1.2 mmol),
Ni(cod)2 (10 mol %), and SIPr (10 mol %) in 1,4-dioxane (2.0 mL) at
90 °C for 18 h, unless otherwise noted. b Isolated yield. c 110 °C. d Using
1,4-dioxane (4.0 mL).
The results obtained with various combinations of
acrylates1and isocyanates2using anickel(0)/SIPrcatalyst
are summarized in Table 2. The reaction of 1a with a
sterically and electronically diverse array of aryl isocya-
nates 2bꢀi proceeded well to give the corresponding 1,3,5-
trisubstituted hydantoins 3abꢀai in yields ranging from
65% to 77% (entries 1ꢀ8). In contrast, alkyl isocyanates
gave inferior results. The reaction of 1a with n-hexyl
isocyanate or benzyl isocyanate produced large amounts
of isocyanate oligomers together with a trace amount of
the corresponding 1,3,5-trisubstituted hydantoin. Cyclo-
hexyl isocyanate and tert-butyl isocyanate gave no desired
products either. Both primary and secondary alkyl acry-
lates 1bꢀd readily reacted with 2a to afford the corre-
sponding hydantoins 3baꢀda in good yield (entries 9ꢀ11),
whereas the reaction of tert-butyl acrylate was relatively
sluggish to give the product 3ea only in 35% yield (entry
12). It was noteworthy that a spirocyclic hydantoin
(11) Abbreviations: (S,S)-i-Pr-Foxap = (S,S)-[2-(40-isopropyloxa-
zolin-20-yl)ferrocenyl]diphenylphosphine. See: Miyake, Y.; Nishibaya-
shi, Y.; Uemura, S. Synlett 2008, 1747. (S,S)-CHIRAPHOS = (2S,3S)-
bis(diphenylphosphino)butane.
(12) Hoberg, H.; Guhl, D. J. Organomet. Chem. 1989, 375, 245.
(13) When the reaction of 1a with 2b was carried out under the
reported conditions12 in our laboratory, 1,3-diphenyl-5-(methoxy-
carbonylmethyl)hydantoin (3ab) was produced in 2% NMR yield and
no formation of 1,3-diphenyl-6-methoxycarbonyldihydropyrimidine-
2,4-dione was observed in 1H NMR spectra of the reaction mixture.
(14) The asymmetric version using chiral NHC ligands was briefly
examined. However, no asymmetric induction was observed.
(15) For β-hydride elimination of a five-membered ring azanickla-
cycle in anti mode, see: Hoberg, H.; Nohlen, M. J. Organomet. Chem.
1990, 382, C6.
Org. Lett., Vol. 13, No. 14, 2011
3561

skeleton was also constructed by using 5,6-dihydro-2H-
pyran-2-one (1f) as the substrate (eq 1).15
When the nickel-catalyzed reaction of 1c(1.0 equiv) with
2a (3.0 equiv) at 90 °C was quenched after 30 min, the
fumaramate 4ca was isolated in 33% yield in addition to
3ca (20% yield). The isolated fumaramate 4ca was treated
with the isocyanate 2a (2.0 equiv) in the absence and
presence of a nickel(0)/SIPr catalyst (eq 2).
Figure 1. Time-dependent change of the reaction mixture of 1c
with 2a using a nickel(0)/SIPr catalyst. The yield of the corre-
sponding compounds (1c, blue diamond; 4ca, red square; and
3ca, green circle) was determeined by 1H NMR spectra using
2-methoxynaphthalene as an internal standard.
The resulting amide anion adds to another molecule of 2
to afford the anionic intermdiate C. Subsequent ring
closure by conjugate addition in a five-exo mode furnishes
hydantoins 3.20
Whereas essentially no reaction was observed in the
absence of a Ni(cod)2/SIPr catalyst, 3ca was formed in
90% yield in the presence of a Ni(cod)2/SIPr catalyst
(10 mol %). Furthermore, the reaction proceeded in the
presence of only SIPr (2 mol %). Even Et(i-Pr)2N(100mol%)
mediated a cyclization reaction of 4ca with 2a.
Scheme 1. Proposed Reaction Mechanism
The time-dependent change of the reaction mixture of 1c
with 2a was followed by measuring 1H NMR spectra at 10
min intervals (Figure 1). An initial increase of 3ca was
slower than the decrease of 1c. On the other hand, the
fumaramate 4ca increased up to a 52% yield after 40 min
and then gradually decreased. These results indicated that
the reaction proceeds via the formation of N-substituted
fumaramate as the key intermediate.
On the basis of these results, we propose a mechanism
for the production of 1,3,5-trisubstituted hydantoins 3
from acrylates 1 and isocyanates 2 as depicted in Scheme
1. Initially, the oxidative cyclization on nickel(0) occurs
with a heteropair of 1 and 2 to give a five-membered ring
azanickelacycle A,12 with which the ester group is bound
to the carbon R to nickel.16 We assume that a partial
negative charge developing on the R carbon is stabilized
by the ester substituent.17 Subsequent β-hydride elimina-
tion and reductive elimination results in the formation
of N-substituted fumaramates 4. Next, the amide group
of 4 is deprotonated by the NHC ligand (SIPr).18,19
Next, we examineda two-step procedurefor preparation
of a hydantoin which incorporated two different isocya-
nates. The isolated fumaramate 4ca21 was treated with
4-methoxyphenyl (PMP) isocyanate (2e, 2.0 equiv) in the
presence of SIPr (5 mol %), and 1-(4-methoxyphenyl)-
3-tolyl-5-(benzyloxycarbonylmethyl)hydantoin 3cae was
obtained in 86% yield (eq 3). This two-step procedure
would significantly expand the structural variation of the
(16) Oxidative cyclization of 1-octene and cyclohexyl isocyanate
catalyzed by a nickel(0)/IPr complex forms five-membered ring azanick-
elacycle, the alkene substituent (a hexyl group) of which is bound to a
carbon β to nickel. Schleicher, K. D.; Jamison, T. F. Org. Lett. 2007, 9,
875.
(17) For related stablization, see: Duong, H. A.; Louie, J. J. Orga-
nomet. Chem. 2005, 690, 5098.
(20) Another mechanism consisting of intermolecular addition of
NHC to isocyanate followed by conjugate addition of the resulting
nitrogen anion to 4 and subsequent ring closure is also conceivable. For
intermolecular addition of NHC to isocyanate, see: Duong, H. A.;
Cross, M. J.; Louie, J. Org. Lett. 2004, 6, 4679.
(18) It has been reported that Ni(cod)2 and IPr exist in equiblium with
Ni(IPr)2 and COD (Keq = 1). Louie, J.; Gibby, J. E.; Farnworth, M. V.;
Tekavec, T. N. J. Am. Chem. Soc. 2002, 124, 15188.
(19) For an example of NHC acting as a base, see: Phillips, E. M.;
Riedrich, M.; Scheidt, K. A. J. Am. Chem. Soc. 2010, 132, 13179.
(21) N-Substituted fumaramates can be also prepared by half-ester-
ification of fumaric acid with alcohols, followed by amidation with
aniline derivatives. See the Supporting Information for details.
(22) Yamauchi, M.; Morimoto, M.; Miura, T.; Murakami, M. J. Am.
Chem. Soc. 2010, 132, 54.
3562
Org. Lett., Vol. 13, No. 14, 2011

produced hydantoins.
In summary, a new synthetic route of 1,3,5-trisubsti-
tuted hydantoins starting from acrylates and iso-
cyanates has been developed using a nickel(0)/SIPr
catalyst. N-Substituted fumaramate is initially gener-
ated as the key intermediate, which then undergoes ring
construction with another molecule of isocyanate in a
one-pot sequence.
The removal of the PMP groups was examined. When
3ae was treated with ceric ammonium nitrate (CAN) at
ꢀ5 °C for 5 min,22 the PMP group at the N1-position was
selectively removed togive3,5-disubstitutedhydantoin5ae
in 87% yield (eq 4).7 The PMP group at the N3-position
remained even under more forcing conditions (40 °C,
20 min).
Acknowledgment. This work was supported in part by
MEXT (Grant-in-Aid for Scientific Research on Innova-
tive Areas Nos. 22105005 and 22106520, Young Scientists
(A) No. 23685019) and Asahi Glass Foundation.
Supporting Information Available. Experimental de-
tails and spectra data for new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 13, No. 14, 2011
3563