An efficient synthesis of hydantoins via sustainable integration of coupled domino processes

Article abstract of DOI:10.1021/ol1015948

A highly efficient synthesis of hydantoins has been developed from simple and commercially available 1,3-dicarbonyl compounds, ureas, and methyl ketones or terminal aryl alkenes. This protocol involves a sustainable integration of two coupled domino processes: iodine-promoted synthesis of unsymmetrical 1,4-enediones (domino I) and the sequential transformation into hydantoins (domino II).

Full text of DOI:10.1021/ol1015948

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4026-4029
An Efficient Synthesis of Hydantoins via
Sustainable Integration of Coupled
Domino Processes
Meng Gao, Yan Yang, Yan-Dong Wu, Cong Deng, Wen-Ming Shu,
Dong-Xue Zhang, Li-Ping Cao, Neng-Fang She, and An-Xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal UniVersity, Hubei, Wuhan 430079, P. R. China
chwuax@mail.ccnu.edu.cn
Received July 10, 2010
ABSTRACT
A highly efficient synthesis of hydantoins has been developed from simple and commercially available 1,3-dicarbonyl compounds, ureas, and
methyl ketones or terminal aryl alkenes. This protocol involves a sustainable integration of two coupled domino processes: iodine-promoted
synthesis of unsymmetrical 1,4-enediones (domino I) and the sequential transformation into hydantoins (domino II).
In modern synthetic chemistry, a growing trend toward the
integration of discrete reactions in one process has been well
illustrated by domino reactions1 and one-pot multicomponent
reactions,2 which allow the direct synthesis of complex
molecules from simple substrates in a highly efficient
manner. A particularly attractive domino strategy is that
which involves a multiple use of catalysts or reagents to
promote mechanistically distinct processes. For example, the
“autotandem catalysis” strategy involves a catalyst to catalyze
two or more distinct chemical transformations in a single
flask.3 However, as many important reactions still need
“stoichiometric” reagents to guarantee their efficiency,4 new
strategies are urgent and important to improve the atom
efficiency of such reactions. During the past few years, a
chain of two or more coupled domino processes has been
linked in a one-pot operation, which is a very convenient
approach to complex architectures via a multiplicative effect.5
In this context, we hypothesized that a multiuseful reagent
could be used to promote both “stoichiometric” and “cata-
lytic” domino processes in a one-pot reaction for maximizing
synthetic efficiency.
Recently, a sustainable synthetic strategy has been pro-
posed to allow the byproducts of a stoichiometric reaction
to be internally recycled to catalyze the subsequent reaction
(3) For reviews on the “autotandem catalysis” strategy, see: (a) Shindoh,
N.; Takemoto, Y.; Takasu, K. Chem.sEur. J. 2009, 15, 12168. (b) Wasilke,
J. C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. ReV. 2005, 105, 1001.
(c) Fogg, D. E.; dos Santos, E. N. Coord. Chem. ReV. 2004, 248, 2365.
(4) For selected examples in carbon-carbon double bond formation
using “stoichiometric” reagents, see the Wittig reaction, Peterson olefination,
Julia olefination, Mcmurry reaction, and Tebbe olefination.
(5) (a) Tejedor, D.; Gonza´lez-Cruz, D.; Garc´ıa-Tellado, F.; Marrero-
Tellado, J. J.; Rodr´ıguez, M. L. J. Am. Chem. Soc. 2004, 126, 8390. (b)
Yamamoto, Y.; Hayashi, H.; Saigoku, T.; Nishiyama, H. J. Am. Chem. Soc.
2005, 127, 10804.
(1) For reviews on domino reactions, see: (a) Tietze, L. F.; Brasche,
G.; Gericke, K. Domino Reactions in Organic Synthesis; Wiley-VCH:
Weinheim, Germany, 2006. (b) Tietze, L. F. Chem. ReV. 1996, 96, 115. (c)
Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551.
(2) For reviews on multicomponent reactions, see: (a) Zhu, J. P.,
Bienayme´, H., Eds.; Multicomponent Reactions; Wiley-VCH: Weinheim,
2005. (b) Ramo´n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602.
(c) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004,
4957.
10.1021/ol1015948  2010 American Chemical Society
Published on Web 08/26/2010

in a domino process.6 For example, Alaimo et al. first
demonstrated the power of this strategy in a domino
nitroarene reduction/imine formation/aza Diels-Alder reac-
tion, which utilized the InIII byproducts generated in the
reduction step to catalyze the aza-Diels-Alder reaction.6a
Inspired by this excellent strategy and with our interests in
exploring multiuseful reagents to promote coupled domino
processes, we reported here a novel sustainable strategy,
which involves a multiuseful reagent to promote the upstream
stoichiometric domino reaction, and the excess or partly
regenerated reagent could be internally recycled to catalyze
the downstream catalytic domino reaction (Scheme 1).
oxidation step, which could be oxidized by CuO or DMSO
to regenerate at least 0.5 equiv of iodine (see Scheme 2).10
Scheme 2. Proposed Reaction Pathway
Scheme 1
.
Sustainable Integration of Coupled Domino
Processesa
On the basis of this facile access to unsymmetrical 1,4-
enediones, a potentially useful approach was proposed in
Scheme 2 for the synthesis of hydantoins. It is expected that
a consecutive Michael addition and 1,2-addition of dinu-
cleophilic ureas to unsymmetrical 1,4-enediones III would
provide the five-membered cyclic intermediate IV, which
would then undergo oxidative dehydrogenation11 and 1,2-
rearrangement12 to afford the hydantoins 5.
Considering oxidative conditions would be necessary for
the proposed domino process II, various oxidants were first
explored using the 1,4-enedione IIIa and 1,3-dimethyl urea
4a as substrates, with a goal of identifying reaction conditions
compatible with the previous domino process (Table 1).
Fortunately, the expected hydantoin 5a was obtained in 15%
isolated yield in the presence of 10 mol % of I2 at 100 °C,
which was unambiguously confirmed by X-ray diffraction.13
Much to our satisfaction, by increasing the catalyst loading
to 0.5 equiv, hydantoin 5a was obtained in 93% yield after
3 h (Table 1, entry 3).14 The presence of I2 is important for
a In the first domino process, multiuseful reagent R could promote the
reaction of substrates A and B to give intermediate C, and then the excess
or partly regenerated reagent “R” is internally recycled to catalyze the second
domino reaction of intermediate C with reactant D to afford final product
E.
Because of the pharmacological importance of hydanto-
ins,7 their efficient and elegant synthesis would be an ideal
testing ground for demonstrating the power and potential of
this strategy. Especially, as there were only very few methods
for the direct synthesis of bioactive 1,3,5,5-tetrasubstituted
hydantoins,8 a straightforward and practical methodology is
highly desirable for their synthesis.
In our previous studies, a focusing domino reaction was
proposed to synthesize unsymmetrical 1,4-enediones from
1,3-dicarbonyl compounds and methyl ketones or terminal
aryl alkenes in the presence of a stoichiometric CuO/I2 or
IBX/CuO/I2.9 In this domino process, hydrogen iodide was
generated as a byproduct in the iodination and Kornblum
(10) (a) Yin, G.; Zhou, B.; Meng, X.; Wu, A.; Pan, Y. Org. Lett. 2006,
8, 2245. (b) Yin, G.; Wang, Z.; Chen, A.; Gao, M.; Wu, A.; Pan, Y. J.
Org. Chem. 2008, 73, 3377. (c) Gao, M.; Yin, G. D.; Wang, Z. H.; Wu,
Y. D.; Guo, C.; Pan, Y. J.; Wu, A. X. Tetrahedron 2009, 65, 6047. (d)
Yin, G.; Gao, M.; She, N.; Hu, S.; Wu, A.; Pan, Y. Synthesis 2007, 3113.
(11) For reviews of oxidative dehydrogenation adjacent to carbonyl
functionalities, see: (a) Kleinman, E. F. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon Press:
Oxford, U.K., 1991; Vol. 7, pp 119-146. (b) Sommer, T. J. Synthesis 2004,
161. (c) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y. L. J. Am.
Chem. Soc. 2002, 124, 2245.
(6) (a) Alaimo, P. J.; O’Brien, R.; Johnson, A. W.; Slauson, S. R.;
O’Brien, J. M.; Tyson, E. L.; Marshall, A.-L.; Ottinger, C. E.; Chacon,
J. G.; Wallace, L.; Paulino, C. Y.; Connell, S. Org. Lett. 2008, 10, 5111.
(b) Yang, B.-L.; Weng, Z.-T.; Yang, S.-J.; Tian, S.-K. Chem.sEur. J. 2010,
16, 718. (c) Cao, J.-J.; Zhou, F.; Zhou, J. Angew. Chem., Int. Ed. 2010, 49,
4976.
(7) Reviews: (a) Meusel, M.; Gutschow, M. Org. Prep. Proced. Int.
2004, 36, 391. (b) Ware, E. Chem. ReV. 1950, 46, 403. (c) Lo´pez, C. A.;
Trigo, G. G. AdV. Heterocycl. Chem. 1985, 38, 177. (d) Volonterio, A.;
Zanda, M. Tetrahedron Lett. 2003, 44, 8549.
(12) For review on 1,2-rearragement, see :(a) Bru¨ckner, R. In AdVanced
Organic Chemistry: Reaction Mechanisms; Harcourt/Academic Press: San
Diego, 2002; pp 435-476. For selected examples in synthesis of hydantoins
involving 1,2-rearrangement reactions, see: (b) Muccioli, G. G.; Poupaert,
J. H.; Wouters, J.; Norberg, B.; Poppitz, W.; Scriba, G. K. E.; Lambert,
D. M. Tetrahedron 2003, 59, 1301. (c) Paul, S.; Gupta, M.; Gupta, R.;
Loupy, A. Synthesis 2002, 75.
(8) For examples of pharmaceutical research on tetrasubstituted hydan-
toins, see: (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. For synthesis of tetrasubstituted hydantoins, see: (b) Moskal, J.;
Moskal, A. Synthesis 1979, 794. (c) Moskal, J.; Moskal, A.; Milart, P.
Monatsh. Chem. 1984, 115, 187. (d) Meusel, M.; Ambrozˇak, A.; Hecker,
T. K.; Gutschow, M. J. Org. Chem. 2003, 68, 4684. (e) Alizadeh, A.;
Bijanzadeh, H. R. Synthesis 2004, 3023.
(13) CCDC 773974 (5a) and 777267 (8) contain the supplementary
crystallographic data for this paper.
(14) Iodine acts as a oxidation catalyst in domino process II, as its
reduction product HI could be oxidized by DMSO to regenerate iodine (see
Scheme 2).
(9) Gao, M.; Yang, Y.; Wu, Y.-D.; Deng, C.; Cao, L.-P.; Meng, X.-G.;
Wu, A.-X. Org. Lett. 2010, 12, 1856.
Org. Lett., Vol. 12, No. 18, 2010
4027

Table 1. Optimization of the Reaction Conditions for Domino IIa
Scheme 3.
Scope of Methyl Ketonesa
entry
oxidant
equiv t (h) temp (°C) yield (%)b
1
I2
I2
I2
I2
I2
0.1
0.3
0.5
0.5
1.0
-
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
6
6
3
6
6
6
6
6
6
6
6
6
6
6
100
100
100
70
15
56
93
0
2
3
4
5
70
0
6
none
100
100
100
100
100
100
100
100
100
0
0
7
CuO
8
DDQ
68
51
0
9
IBX
10
11
12
13
14
PIDA
SeO2
45
0
Mn(OAc)3·2H2O
TEMPO
H2O2
0
74
a Reaction conditions: IIIa (0.2 mmol), 4a (0.4 mmol) in 1 mL of DMSO
under an atmosphere of argon. b Isolated yields. DDQ ) 2,3-dichloro-5,6-
dicyanobenzoquinone; IBX ) 2-iodoxybenzoic acid; PIDA ) iodosoben-
zene diacetate; TEMPO ) 2,2,6,6-tetramethyl-piperidine-1-oxyl.
accelerating equilibrium toward the hydantoins; otherwise,
a mixture of products would be obtained (Table 1, entry 5).15
Employing other oxidants under this condition failed to
produce better results (Table 1, entries 6-13).
a Reaction was performed with methyl ketone 1 (1.0 mmol), 3a (1.0
mmol), CuO (1.1 mmol), and I2 (1.1 mmol) in DMSO (5 mL) at 70 °C for
12 h; then, 4a (2.0 mmol) was added, and the mixture was stirred at 100
°C for another 3-4 h. Yield of the isolated product shown.
Encouraged by the discovery that iodine could promote
both domino processes and it could be regenerated in domino
process I, we wondered whether it would be possible to
prepare hydantoins via an integration of the two coupled
domino processes in a one-pot reaction (see Scheme 2). After
some optimization studies, the feasibility of this strategy was
verified by reaction of 1.0 mmol of acetophenone 1a and
1.0 mmol of 1,3-diphenylpropane-1,3-dione 3a in the pres-
ence of 1.1 mmol of CuO and 1.1 mmol of iodine in 5 mL
of DMSO under an atmosphere of argon at 70 °C for 12 h.
After the substrates were completely consumed, 2.0 mmol
of 1,3-dimethyl urea 4a was added, and the reaction mixture
was stirred at 100 °C for 3 h. After workup, the desired
hydantoin 5a was obtained in 76% yield (Scheme 3), which
is comparable to the stepwise reaction.16
yields (44-63%; 5j-5l). However, use of unsaturated methyl
ketones was unsuccessful.17
To our delight, terminal aryl alkenes could also smoothly
react with 3a and 4a to give the desired products (Table 1).
The steric and electronic nature of the alkenes had little
influence on the reaction efficiency, and generally good yields
were obtained (56-68%; Table 2).
Table 2. Scope of Terminal Aryl Alkenesa
With this optimized result in hand, we next explored the
scope of this reaction. Pleasingly, all methyl ketones,
regardless of their electronic or steric properties, proceeded
efficiently to afford their corresponding products in moderate
to good yields (44-76%; Scheme 3). For example, electron-
neutral (H, CH3), electron-rich (OCH3), electron-deficient
(NO2), and sterically hindered (ꢀ-naphthyl) methyl ketones
all reacted efficiently to give the expected hydantoins in
excellent yields (62-76%; 5a-5e). Much to our satisfaction,
good yields were obtained with halogenated and hydroxylated
substrates (63-75%; 5f-5i). The heteroaryl methyl ketones
could also give their corresponding products in moderate
entry
2 (R1)
2a (C6H5)
2b (4-MeC6H4)
2c (4-MeOC6H4)
2d (ꢀ-naphthyl)
2e (4-ClC6H4)
2f (4-BrC6H4)
2g (4-FC6H4)
5
yield (%)b
1
2
3
4
5
6
7
5a
5b
5c
5e
5f
5g
5h
68
65
56
62
63
65
59
a Reaction was performed with terminal aryl alkene 2 (1.0 mmol), IBX
(1.2 mmol), and I2 (1.1 mmol) in DMSO (5 mL) at room temperature for
0.5 h; then 3a (1.0 mmol) and CuO (1.1 mmol) were added; and the mixture
was stirred at 70 °C for 6 h. After the substrates were completely consumed,
4a (2.0 mmol) was added, and the mixture was stirred at 100 °C for another
3-4 h. b Isolated yield.
(15) The 1H NMR of the crude reaction mixture showed that the
hydantoin 5a was not included in the mixture.
(16) The isolated yield for the 1,4-enedione IIIa was 84%, and the
overall yield for the hydantoin 5a was 78% via stepwise reaction.
4028
Org. Lett., Vol. 12, No. 18, 2010

Scheme 4. Scope of 1,3-Dicarbonyl Compounds and Ureasa
Scheme 5.
Control Experimenta
a Reaction conditions: see the Supporting Information. Yield of the
isolated product shown.
I2 to give compound 8 in 96% yield within 1.0 h. This result
clearly confirmed our suspicion that I2 could efficiently
catalyze the oxidative dehydrogenation step.
In summary, we have developed a sustainable integration
of double domino processes for the straightforward construc-
tion of tetrasubstituted hydantoins. It comprises six mecha-
nistically different reactions: iodination-Kornblum oxida-
tion-Knoevenagel condensation-dinucleophilic addition-
oxidative dehydrogenation-1,2-rearrangement reaction. The
easy generation of molecular diversity along with the
importance of tetrasubstituted hydantoins in medicinal
chemistry makes the reaction described here an appropriate
protocol for the synthesis of potentially bioactive compounds.
Further investigation into the reaction mechanism and
application of this strategy are currently underway in our
laboratory.
a Reaction conditions: see Scheme 3 or the Supporting Information.
Yield of the isolated product shown.
Using acetophenone, structural variations in the 1,3-
dicarbonyl compounds and ureas were then examined
(Scheme 4). In the case of electron-neutral (H) and electron-
deficient (NO2) 1,3-dicarbonyl compounds, a satisfactory
yield was obtained (72%, 75%; 5m, 5o). However, when
strong electron-donating groups were attached to the phenyl
ring of the 1,3-dicarbonyl compounds, the yield dropped
obviously (47%; 5n). Significantly, halogen and the hetero-
cycle containing 1,3-diketones were readily tolerated in this
transformation (66-71%; 5p-5r).18 Unfortunately, use of
aliphatic 1,3-dicarbonyl compounds was unsuccessful, which
led to a mixture of products.19 To our delight, various urea
derivatives could also complete this transformation. Although
urea gave its corresponding product in a lower yield (42%;
5s), 1,3-diethyl urea and 1,3-dipropyl urea could give their
corresponding products in good yields (65-68%; 5t-5u).
To provide insight into the oxidative dehydrogenation step
in domino process II, a control experiment was performed
(Scheme 5). When 1,4-enedione IIIa was treated with
tetrahydropyrimidin-2-one 6 in the presence of 0.5 equiv of
I2 in DMSO under argon at 100 °C for 3 h, product 8 was
obtained in 92% yield, which was unambiguously confirmed
by X-ray diffraction.13 When the reaction was conducted
without iodine, only Michael addition product 7 was obtained
in 85% yield after 3 h, which could be further oxidized by
Acknowledgment. We thank the National Natural Science
Foundation of China (Grant 20872042, 20902035 and
21032001).
Supporting Information Available: Experimental pro-
cedures and compound characterization data including X-ray
crystal data for 5a and 8. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL1015948
(17) Unsaturated methyl ketones tested include (E)-4-phenylbut-3-en-
2-one, (E)-4-(4-methoxyphenyl)but-3-en-2-one, (E)-4-(4-nitrophenyl)but-
3-en-2-one, and (3E,5E)-6-phenylhexa-3,5-dien-2-one.
(18) Compounds 5m-5r were obtained as a mixture of two racemic
diastereoisomers, while compounds 5a-5l and 5s-5u were obtained as a
racemic mixture. For more details, see the Supporting Information.
(19) Aliphatic 1,3-dicarbonyl compounds tested include pentane-2,4-
dione and ethyl 3-oxobutanoate.
Org. Lett., Vol. 12, No. 18, 2010
4029