A novel one-pot rearrangement reaction of 2,3-epoxydiaryl ketones: Synthesis of (±)-5,5-disubstituted imidazolones and 5,5-disubstituted hydantoins

Article abstract of DOI:10.1055/s-2006-950277

A novel one-pot rearrangement reaction, involving sequential epoxide rearrangement, condensation, cyclization and phenyl migration took place when 2,3-epoxydiphenyl ketones were treated with guanidine hydrochloride or urea in the presence of a base like s

Full text of DOI:10.1055/s-2006-950277

LETTER
2723
A Novel One-Pot Rearrangement Reaction of 2,3-Epoxydiaryl Ketones: Syn-
thesis of ( )-5,5-Disubstituted Imidazolones and 5,5-Disubstituted Hydantoins
Novel One-Pot
R
i
earrang
l
ement
a
Reactiono
l
f
2,3-Epoxydi
A
aryl Ketones . Bhat,a Kanaya L. Dhar,*a Satish C. Puri,a Michael Spitellerb
a
Synthetic Chemistry Section, Regional Research Laboratory, Jammu 180001, India
E-mail: dharklrrl@rediffmail.com
b
Institute of Environmental Research, University of Dortmund, Otto-Hahn-Straße 6, 44221 Dortmund, Germany
Received 4 May 2006
interesting to note that instead of compound 4, or its dehy-
drated analogue, a new compound, 2-amino-5-benzyl-5-
phenyl-3,5-dihydro-4H-imidazol-4-one (2) was obtained
in good yield.
Abstract: A novel one-pot rearrangement reaction, involving
sequential epoxide rearrangement, condensation, cyclization and
phenyl migration took place when 2,3-epoxydiphenyl ketones were
treated with guanidine hydrochloride or urea in the presence of a
base like sodium hydride and new type of imidazolone derivatives
were obtained in good to excellent yields.
N
O
NH2
Key words: one-pot, epoxydiphenyl ketones, rearrangement,
guanidine, imidazolone
Ar2
NH2
NH
O
Ar1
a
a
N
N
2
Ar1
Ar2
O
Ar1
Ar2
With the emphasis on the search for atom-efficient trans-
formations of easily available starting materials into com-
plex organic molecules,1 reactions that provide maximum
diversity are especially desirable. In this context one-pot
synthesis of heterocycles is a powerful tool in the modern
drug-discovery process in terms of lead finding and lead
optimization.2 The range of easily accessible and func-
tionalized small heterocycles like 5,5-disubstituted imida-
zolones and 5,5-disubstituted hydantoins is rather limited.
Over the last few decades there has been considerable in-
terest in the synthesis of these scaffolds as an important
class of heterocyclic chemistry. The imidazolone scaffold
is found in a large number of natural products and phar-
macologically active compounds.3 Substituted imidazolo-
nes have received significant attention as a result of their
diverse medicinal uses.4 On the other hand, hydantoin de-
rivatives find application in pharmaceuticals,5 chemical
industry6 and polymer chemistry.7 Only a few general
methodologies exist for the assembly of such substituted
imidazolones and hydantoins.8 Therefore, the develop-
ment of new, rapid, and robust routes towards focused
libraries of such compounds is of great importance.
b
NH
O
O
OH
Ar2
4
1
N
H
Ar1
Ar1, Ar2 = substituted and unsubstituted aryls
3
Scheme 1 Reagents and conditions: (a) Guanidine hydrochloride,
NaH/THF; (b) urea, NaH/THF.
In the first step, we subjected a heterogeneous solution of
2,3-epoxydiphenyl ketone (1) and guanidine hydro-
chloride to heating at reflux temperature, and no reaction
was observed. However, when sodium hydride was added
to the reaction mixture, it was found to effect a novel
rearrangement reaction, involving sequential epoxide re-
arrangement to a 1,2-diketone, condensation, cyclization,
phenyl migration and double bond repositioning in a one-
pot procedure. To test the efficacy of the reaction under
different conditions, we examined the effect of various
bases like sodium methoxide, potassium tert-butoxide be-
sides sodium hydride. It was found that all these bases me-
diate this rearrangement, but sodium hydride was found to
be the best in terms of yield of desired compound. Reac-
tion was also carried out with different ratios of sodium
hydride and guanidine hydrochloride. The best result was
achieved by carrying out the reaction with 2:1 equivalents
of sodium hydride–guanidine hydrochloride in tetrahy-
drofuran for 6 hours. One mole of the base is utilized for
the generation of guanidine from its hydrochloride salt
and the next mole effects the reaction. It is noteworthy
that the reaction went to completion even at room temper-
ature, but this procedure required longer reaction time. It
may also be noted that when the reaction was carried out
between 2,3-epoxydiphenyl ketone and sodium hydride
alone, it formed 1,2-diketone, which when treated with
guanidine reduced the reaction time considerably. This
confirmed the formation of 1,2-diketone as the first inter-
mediate during the reaction.
As part of our research program directed towards the
design and synthesis of lead compounds for potentially
interesting drugs, 2,3-epoxydiphenyl ketones9 were taken
into consideration as a possible starting point to obtain
new substances with pharmacological and medicinal
applications. Previously we reacted 1 with hydrazine
hydrate to form the corresponding 4-hydroxypyrazole
derivatives, which are of pharmacological interest.10 In
our recent efforts aiming at synthesizing compound 4, we
treated 1 with guanidine hydrochloride in the presence of
sodium hydride in tetrahydrofuran (Scheme 1). It was
SYNLETT 2006, No. 17, pp 2723–2726
1
7
.1
0
.2
0
0
6
Advanced online publication: 09.10.2006
DOI: 10.1055/s-2006-950277; Art ID: D12706ST
© Georg Thieme Verlag Stuttgart · New York

2724
B. A. Bhat et al.
LETTER
To test this procedure, the scope of the reaction was then
investigated with various substituted 2,3-epoxydiphenyl
ketones and guanidine hydrochloride under the estab-
lished protocol. All reactions proceeded smoothly to give
the corresponding 2-amino-5-benzyl-5-phenyl-3,5-dihy-
dro-4H-imidazol-4-ones in good to excellent yields
(Table 1). Encouraged by the results obtained with guani-
dine hydrochloride, we turned our attention to urea. It fol-
lowed the same general rule as guanidine hydrochloride.
However, it is interesting to note that under the similar
conditions, the product formed was 5-benzyl-5-phenyl-
imidazolidine-2,4-diones. All these products were charac-
terized by 1H NMR, 13C NMR, IR, ESI–MS and elemental
analysis.11 Compounds 2a and 3a were additionally con-
firmed by 2D NMR techniques like HMBC and HSQC
and the structure of one of the derivatives, 2a, was also
confirmed by X-ray crystal structure analysis (Figure 1).
Figure 1 X-ray crystal structure of 2a
numerous classical base-catalyzed reactions of 2,3-ep-
oxydiphenyl ketones,12 the initial event in this reaction is
the formation of 1,2-diketones II, followed by condensa-
tion of guanidine or urea with 2-ketone to generate the rel-
atively more resonance-stabilized intermediate III.
Subsequently, the resulting intermediate III undergoes
cyclization by the second nucleophilic attack of the NH2
on the other carbonyl carbon to generate the intermediates
V and VII with guanidine and urea, respectively. The in-
termediate V undergoes the phenyl migration and double-
bond repositioning because of the electron-withdrawing
carbonyl group to give the product 2. However, in case
with urea the more stable, hydantoin derivative 3, is the fi-
nal product.
For 2,3-epoxydiphenyl ketones, the presence of electron-
withdrawing groups and electron-releasing groups on the
aromatic ring Ar2, did not exhibit significant effects on
yields or rates of reaction while as on ring Ar1, electron-
withdrawing groups like chloro and nitro slightly slows
down the reaction kinetics and yields are also low
(Tables 1 and 2).
A proposed reaction mechanism that accounts for this
rearrangement reaction is shown in Scheme 2. As in
Table 1 Reaction Time and Yields of Some Representative Examples of 2-Amino-5-benzyl-5-phenyl-3,5-dihydro-4H-imidazol-4-ones
N
NH·HCl
O
O
NH2
NaH/THF
reflux
Ar1
Ar2
NH
Ar2
Ar1
+
H2N
NH2
O
1
2
Entry
1
Ar1
Ar2
Product
2a
Time (h)
Yield (%)a
4-OMeC6H4
4-OMeC6H4
4-OMeC6H4
3,4,5-(OMe)3C6H2
4-OMeC6H4
4-FC6H4
5
5
72
77
71
75
72
74
83
79
81
82
53
40
79
80
2
2b
2c
3
6
4
3,4,5-(OMe)3C6H2
Ph
4-OMeC6H4
4-ClC6H4
4-ClC6H4
3,4-(OMe)2C6H3
4-FC6H4
2d
2e
5
5
6
6
4-OMeC6H4
4-OMeC6H4
3,4,5-(OMe)3C6H2
3,4,5-(OMe)3C6H2
4-OMeC6H4
4-ClC6H4
2f
6
7
2g
5
8
2h
2i
6
9
3,4-OMeC6H3
Ph
5
10
11
12
13
14
2j
6
Ph
2k
2l
8
2-NO2C6H4
2-MeC6H4
Ph
12
6
4-FC6H4
2m
2n
4-OMeC6H4
4-MeC6H4
4
a Isolated yield.
Synlett 2006, No. 17, 2723–2726 © Thieme Stuttgart · New York

LETTER
Novel One-Pot Rearrangement Reaction of 2,3-Epoxydiaryl Ketones
2725
Table 2 Reaction Time and Yields of Some Representative Examples of 5-Benzyl-5-phenylimidazolidine 2,4-diones
H
N
O
O
O
O
NaH/THF
reflux
Ar2
Ar2
NH
Ar1
+ H2N
NH2
O
Ar1
1
3
Entry
Ar1
Ar2
Product
3a
Time (h)
Yield (%)a
1
2
4-OMeC6H4
4-OMeC6H4
4-OMeC6H4
4-OMeC6H4
4-OMeC6H4
4-OMeC6H4
Ph
3,4,5-(OMe)3C6H2
4-FC6H4
5
7
79
73
76
77
81
70
78
44
58
76
72
3b
3c
3
4-OMeC6H4
3,4-(OMe)2C6H3
Ph
5
4
3d
3e
5
5
5
6
4-ClC6H4
3f
7
7
4-ClC6H4
3g
6
8
2-NO2C6H4
4-ClC6H4
3,4-OMeC6H3
4-OMeC6H4
Ph
3h
3i
12
12
5
9
10
11
2-MeC6H4
4-OMeC6H4
3j
2-MeC6H4
3k
5
a Isolated yield.
X
H2N
NH2
B
O
O
X
O
O
Ar2
Ar1
Ar2
Ar1
HN
Ar2
NH2
B
Ar1
Ar2
O
Ar1
H2N
H2N
N
NH
– H2O
O
X
X
I
III
II
H
H
N
Ar1
HN
O
Ar1
HN
O
N
N
O
O
NH2
NH2
X = NH
– H+
H+
Ar2
Ar2
N
Ar1
N
N
Ar1
X
Ar2
VI
HN
Ar2
IV
2
V
X = O
– H
H
Ar1
HN
O
N
O
O
H+
Ar2
Ar2
NH
N
Ar1
O
VII
3
Scheme 2 Plausible reaction mechanism
Synlett 2006, No. 17, 2723–2726 © Thieme Stuttgart · New York

2726
B. A. Bhat et al.
LETTER
(9) (a) Payne, G. B. J. Am. Chem. Soc. 1959, 81, 4901.
In conclusion, a novel and efficient one-pot rearrange-
ment reaction of 2,3-epoxydiphenyl ketones to 2-amino-
5-benzyl-5-phenyl-3,5-dihydro-4H-imidazol-4-ones and
5-benzyl-5-phenylhydantoins from guanidine hydrochlo-
ride and urea, respectively, has been developed. This
method is a convenient and high-yielding procedure for
the synthesis of synthetically and pharmacologically nov-
el 5,5-disubstituted imidazolones and 5,5-disubstituted
hydantoins.
(b) Payne, G. B. J. Org. Chem. 1959, 24, 2048. (c) Adams,
R.; Johnson, J. R.; Wilcox, C. F. Laboratory Experiments in
Organic Chemistry, 5th ed.; The Macmillan Company: New
York, 1963, 381.
(10) Bhat, B. A.; Dhar, K. L.; Puri, S. C.; Saxena, A. K.;
Shanmugavel, M.; Qazi, G. N. Bioorg. Med. Chem. Lett.
2005, 15, 3177.
(11) General Procedure for Preparation for 3,5-Disubstituted
Imidazolones: Typical experimental procedure for
synthesis of 3,5-disubstituted imidazolones as exemplified
for 2a. Guanidine hydrochloride (95.5 mg, 1 mmol) was
added to a solution of 2,3-epoxydiphenyl ketone (334 mg,
1 mmol) in anhyd THF (10 mL). To this was added NaH (48
mg, 2 mmol) at r.t. After 30 min, the reaction mixture was
stirred at reflux temperature for 5 h; TLC analysis indicated
that the reaction was complete. The reaction mixture was
filtered, solvent was removed by rotatory evaporator and the
residue passed through a silica gel column (CHCl3–MeOH)
afforded 2a (315 mg, 72%) as a white solid; mp 281–284 °C.
1H NMR (600 MHz, DMSO-d6): d = 2.97 (d, J = 13.2 Hz, 1
H), 3.11 (d, J = 13.2 Hz, 1 H), 3.57 (s, 3 H, OCH3), 3.65 (s,
6 H, 2 × OCH3), 3.72 (s, 3 H, OCH3), 6.41 (s, 2 H), 6.89 (d,
Acknowledgment
The authors are grateful to Dr. G. N. Qazi, Director RRL, for his
interest and encouragement in the research and one of the authors,
BAB is grateful to CSIR for SRF.
References and Notes
(1) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M.
Angew. Chem., Int. Ed. Engl. 1995, 34, 259. (c) Trost, B.
M. Transition Metals for Organic Synthesis; Beller, M.;
Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998, 1.
(2) (a) Weber, L. Curr. Med. Chem. 2002, 9, 1241.
(b) Bienayme, H.; Hulme, C.; Oddon, G.; Schmidt, P. Chem.
Eur. J. 2000, 6, 3321. (c) Zhu, J. Eur. J. Org. Chem. 2003,
1133. (d) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471.
(e) Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (f) Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett.
2000, 2, 709.
(3) (a) Greenlee, W. J.; Siegl, P. K. S. Ann. Rep. Med. Chem.
1992, 27, 59. (b) Shilcrat, S. C.; Mokhallalati, M. K.;
Fortunak, J. M. D.; Pridgen, L. N. J. Org. Chem. 1997, 62,
8449. (c) Rizzi, J. P.; Nagel, A. A.; Rosen, T.; McLean, S.;
Seeger, T. J. Med. Chem. 1990, 33, 2721. (d) Shapiro, G.;
Gomez-Lor, B. J. Org. Chem. 1994, 59, 5524. (e)Adams, J.
L.; Boehm, J. C.; Kassis, S.; Gorycki, P. D.; Webb, E. F.;
Hall, R.; Sorenson, M.; Lee, J. C.; Ayrton, A.; Griswold, D.
E.; Gallagher, T. F. Bioorg. Med. Chem. Lett. 1998, 8, 3111.
(4) (a) Laufer, S.; Wagner, G.; Kotschenreuther, D. Angew.
Chem. Int. Ed. 2002, 41, 2290. (b) Sarshar, S.; Zhang, C.;
Moran, E. J.; Krane, S.; Rodarte, J. C.; Benbatoul, K. D.;
Dixon, R.; Mjalli, A. M. M. Bioorg. Med. Chem. 2000, 10,
2599. (c) Zhang, C.; Sarshar, S.; Moran, E. J.; Krane, S.;
Rodarte, J. C.; Benbatoul, K. D.; Dixon, R.; Mjalli, A. M. M.
Bioorg. Med. Chem. 2000, 10, 2603. (d) Bilodeau, M. T.;
Cunningham, A. M. J. Org. Chem. 1998, 63, 2800.
(5) Lamothe, M.; Lannuzel, M.; Perez, M. J. Comb. Chem.
2002, 4, 73.
(6) Kirk-Othmer Encyclopedia of Chemical Technology, 3rd
ed., Vol. 12; John Wiley and Sons: New York, 1983, 692–
700.
(7) (a) Faghihi, K.; Mirsamie, A.; Sangi, R. Eur. Polym. J. 2002,
39, 247. (b) Faghihi, K.; Zamani, K.; Mallakpour, S. Iranian
Polym. J. 2002, 11, 339.
(8) (a) For an overview on the synthesis of imidazoles, see:
Ebel, K. In Houben-Weyl: Methoden der Organischen
Chemie, Hetarene III, 1H-Imidazole; Schaumann, E., Ed.;
Georg Thieme Verlag: Stuttgart, New York, 1994, 1–215.
For recent imidazole syntheses, see: (b) Henkel, B.
Tetrahedron Lett. 2004, 45, 2219. (c) Sezen, B.; Sames, D.
J. Am. Chem. Soc. 2003, 125, 5274. (d) Tan, K. L.;
Bergman, R. G.; Ellmann, J. A. J. Am. Chem. Soc. 2002, 124,
13964. (e) Faghihi, K.; Zamani, K.; Mobinikhaledi, A. Turk.
J. Chem. 2004, 28, 345. (f) Mahmoodi, N. O.; Khodace, Z.
Mendeleev Commun. 2004, 304.
J = 9.0 Hz, 2 H), 7.42 (d, J = 9.0 Hz, 2 H), 8.34 (s, 1 H). 13
C
NMR (125 MHz, DMSO-d6): d = 44.8, 55.8 56.3, 60.6, 70.6
108.2, 114.0, 127.4, 132.4, 33.8, 136.7, 152.6, 158.9, 171.2,
189.0. IR (KBr): 3346.2, 32.2, 1698.2, 1645.4, 1593.4,
1299.3, 1127.9, 828.4 cm–1. MS (ESI): m/z = 386.2 [M + H],
408.0 [M + Na]. Anal. Calcd for C20H23N3O5: C, 62.32; H,
6.01; N, 10.90. Found: C, 62.13; H, 6.15; N, 11.20.
2b: White solid; mp 298–302 °C. 1H NMR (200 MHz,
DMSO-d6): d = 2.99 (d, J = 13.4 Hz, 1 H), 3.21 (d, J = 13.4
Hz, 1 H), 3.67 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 6.73 (d,
J = 8.9 Hz, 2 H), 6.9 (d, J = 8.8 Hz, 2 H), 7.03 (d, J = 9.1 Hz,
2 H), 7.41 (d, J = 8.8 Hz, 2 H), 8.20 (s, 1 H). 13C NMR (125
MHz, DMSO-d6): d = 42.6, 54.8, 70.5, 113.1, 125.5, 127.0,
127.9, 128.0, 131.2, 141.0, 157.9, 170.2, 187.9. IR (KBr):
3347.6, 1698.3, 1652.2, 1613.4, 1513.4, 1257.6, 1033.7,
837.6 cm–1. MS (ESI): m/z = 325.2 [M + H]. Anal. Calcd for
C18H19N3O3: C, 66.45; H, 5.89; N, 12.91. Found: C, 66.71;
H, 6.05; N, 12.73.
3a: White solid; mp 238–241 °C. 1H NMR (600 MHz,
DMSO-d6): d = 2.88 (d, J = 13.5 Hz, 1 H), 3.35 (d, J = 13.5
Hz, 1 H), 3.59 (s, 3 H, OCH3), 3.69 (s, 6 H, 2 × OCH3), 3.73
(s, 3 H, OCH3), 6.48 (s, 2 H), 6.95 (d, J = 8.9 Hz, 2 H), 7.51
(d, J = 8.9 Hz, 2 H), 8.51 (s, 1 H), 10.46 (s, 1 H). 13C NMR
(125 MHz, DMSO-d6): d = 44.9, 55.8, 56.4, 60.5, 68.6,
108.4, 114.4, 127.5, 131.1, 132.0, 137.2, 152.9, 156.8,
159.6, 176.6. IR (KBr): 3444.1, 3342.0, 1766.7, 1709.4,
1586.6, 1241.9, 1129.9, 839.2 cm–1. MS (ESI): m/z = 385
[M – H], 409.2 [M + Na]. Anal. Calcd for C20H22N2O6: C,
62.16; H, 5.73; N, 7.25. Found: C, 62.13; H, 6.14; N, 7.36.
3b: White solid; mp 204–207 °C. 1H NMR (200 MHz,
DMSO-d6): d = 2.96 (d, J = 13.5 Hz, 1 H), 3.34 (d, J = 13.5
Hz, 1 H), 3.74 (s, 3 H, OCH3), 6.96 (d, J = 8.8 Hz, 2 H), 7.16
(m, 4 H), 7.51 (d, J = 8.8 Hz, 2 H), 8.59 (s, 1 H). 13C NMR
(125 MHz, DMSO-d6): d = 43.0, 55.6, 70.5, 113.9, 114.6,
114.8, 127.1, 132.4, 132.5, 133.5, 158.6, 160.5, 160.6,
162.6, 170.9, 188.6. IR (KBr): 3373.9, 1757.5, 1713.4,
1608.3, 1511.7, 1403.6, 1257.7, 1225.7, 845.8 cm–1. MS
(ESI): m/z = 315 [M + H]. Anal. Calcd for C17H15FN2O3: C,
64.96; H, 4.81; N, 8.91. Found: C, 65.08; H, 5.09; N, 8.97.
(12) (a) Cleeland, R. Jr.; Grunberg, E.; Leimgruber, W.; Weigele,
M. US Patent, 4045487, 1977; Chem. Abstr. 1977, 87,
167872. (b) Baranes, R. P.; Chigbo, F. E. J. Org. Chem.
1963, 28, 1644.
Synlett 2006, No. 17, 2723–2726 © Thieme Stuttgart · New York