Hypervalent iodine-mediated efficient synthesis of imidazoles

Article abstract of DOI:10.1246/cl.2007.1270

The condensation of an α-hydroxy ketone with an aldehyde and ammonium acetate in the presence of diacetoxy iodobenzene (DIB) produced the corresponding imidazole in excellent yield. Copyright

Full text of DOI:10.1246/cl.2007.1270

1270
Chemistry Letters Vol.36, No.10 (2007)
Hypervalent Iodine-mediated Efficient Synthesis of Imidazoles
Biswanath Das,ꢀ Yallamalla Srinivas, Harish Holla, Maddeboina Krishnaiah, and Ravirala Narender
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500007, India
(Received July 31, 2007; CL-070813; E-mail: biswanathdas@yahoo.com)
The condensation of an ꢀ-hydroxy ketone with an aldehyde
and ammonium acetate in the presence of diacetoxy iodoben-
zene (DIB) produced the corresponding imidazole in excellent
yield.
NH
Ph
O
Ph
Ph
Ph
NH
N
RCHO
NH4OAc
Ph
NH2
CHR
OH
Ph
H
A
B
OAc
OAc
Ph
I
Hypervalent iodine-mediated organic syntheses have at-
tracted considerable attention in recent years.1 Various organo-
iodide(III) reagents have successfully been utilized in different
organic transformations. Recently, we applied diacetoxy iodo-
benzene (DIB) for the synthesis of isoxazolines.2 In continuation
of our work on the application of this reagent, we have discov-
ered that it can efficiently be employed for the synthesis of an
imidazole derivative by treatment of an aldehyde with an ꢀ-
hydroxy ketone and ammonium acetate (Scheme 1).
H
-PhI
Ph
Ph
Ph
Ph
N
N
H
-AcOH
R
R
N
H
N
I
Ph
OAc
C
Imidazoles exhibit various interesting biological properties
and many of them have been characterized as important thera-
peutic agents,3 fungicides and herbicides,4 and plant growth reg-
ulators.5 They have also been applied in the synthesis of ionic
liquids.6 However, the methods for the synthesis of imidazoles
starting from ꢀ-hydroxy ketones are limited.7 Moreover, long
reaction times, unsatisfactory yields, and applicability to only
aromatic aldehydes are the disadvantages of many of the report-
ed methods.
The present condensation mediated by DIB (Scheme 1) pro-
ceeded smoothly to afford the imidazoles in excellent yields
(91–98%) (Table 1).8 The conversion was complete within 30–
60 min. Both aromatic and aliphatic aldehydes were equally
utilized for the preparation of imidazoles. Aromatic aldehydes
containing electron-donating as well as electron-withdrawing
groups underwent the conversion facilely. The probable mecha-
nism of the conversion is shown in Scheme 2.
Scheme 2.
experiments.
In conclusion, we have demonstrated that an imidazole
derivative can easily be synthesized in short reaction time and
in excellent yield starting from an aldehyde (aromatic or aliphat-
ic), and an ꢀ-hydroxy ketone using NH4OAc in the presence of a
hypervalent iodine reagent, DIB. A new useful application of
this reagent is thus disclosed.
The authors thank CSIR and UGC, New Delhi for financial
assistance.
References and Notes
#
Part 153 in the series ‘‘Studies on novel synthetic methodol-
ogies.’’
The ꢀ-hydroxyketone reacts at first with NH4OAc and
its keto group is converted into =NH and the hydroxy group
into –NH2 to form the intermediate A. This intermediate
reacts with an aldehyde to furnish the corresponding imine B.
The cyclization of the imine subsequently takes place easily in
the presence of DIB to produce C. The iodine of DIB attracks
electrons of the double bond of the imine system of B followed
by the loss of an –OAc group. The subsequent deattachment of
PhI and AcOH from C affords the stable imidazole derivative.
During the preparation of the imidazoles following the present
method the formation of PhI was detected by direct comparision
of the reaction mixture with an authentic sample of PhI by TLC
1
a) V. V. Zhdankin, P. J. Stang, Chem. Rev. 2002, 102, 2523.
b) T. Wirth, Hypervalent Iodine Chemistry; Modern
Development in Organic Synthesis In Topics In Current
Chemistry, Springer, Berlin, 2003, p. 224.
B. Das, H. Holla, G. Mahender, J. Banrjee, M. R. Reddy,
Tetrahedron Lett. 2004, 45, 7347.
a) J. Heeres, L. J. J. Backx, J. H. Mostmans, J. Van Custem,
J. Med. Chem. 1979, 22, 1003. b) J. S. Kim, B. Gatto, C. Yu,
A. Liu, L. F. Liu, E. J. La Voie, J. Med. Chem. 1996, 39, 992.
c) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev.
2003, 103, 893.
T. Maier, R. Schmierer, K. Bauer, H. Bieringer, H. Buerstell,
B. Sachse, US Patent 4820335, 1989; Chem. Abstr. 1989,
111, 19494.
R. Schmierer, H. Mildenberger, H. Buerstell, German Patent
361464, 1987; Chem. Abstr. 1988, 108, 37838.
T. Welton, Chem. Rev. 1999, 99, 2071.
a) Y. Xu, L.-F. Wan, H. Salehi, W. Deng, Q.-X. Guo, Het-
erocycles 2004, 63, 1613. b) S. A. Siddiqui, U. C. Narkhede,
S. S. Palimkar, T. Daniel, R. J. Lahoti, K. V. Srinivasan,
2
3
4
5
Ph
N
NH4OAc
DIB
Ph
Ph
O
R
+
RCHO
N
EtOH, reflux
30 60 min
Ph
H
6
7
OH
91 98%
Scheme 1.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.10 (2007)
1271
Table 1. Preparation of imidazoles from aldehydes and benzoin
using DIB and NH4OAc
Tetrahedron 2005, 61, 3539. c) A. Shaabani, A. Rahmati, J.
Mol. Catal. A: Chem. 2006, 249, 246.
8
General procedure for the synthesis of imidazole: A mixture
of an aldehyde (0.5 mmol), benzoin (0.5 mmol), NH4OAc
(1.5 mmol), and DIB (0.5 mmol) in ethanol (5 mL) was
refluxed for 30–60 min. The reaction was monitored by
TLC. After completion, the mixture was cooled and the
solvent was removed under reduced pressure. Saturated aq,
NaHCO3 (10 mL) was added and the mixture was extracted
with EtOAc (3 ꢁ 10 mL). The extract was dried and concen-
trated. The residue was subjected to column chromatography
(silica gel, hexane–EtOAc) to obtain pure imidazole deriva-
tive.
Entry
Aldehyde
Producta
Time Isolated
/min yield
/%
O
Ph
Ph
N
H
1
30
98
N
H
1
O
O
Ph
Ph
N
H
H
Cl
Cl
2
3
30
30
96
95
N
H
Cl
Cl
2
The spectral (1H NMR and MS) data of some representative
imidazoles are given below.
Ph
Ph
N
Compound 2: 1H NMR (200 MHz, CDCl3): ꢁ 12.16 (1H,
brs), 8.06 (2H, d, J ¼ 8:0 Hz), 7.60–7.42 (4H, m), 7.40–
7.06 (8H, m); FAB-MS: m=z 355, 353 [M + Na]þ.
Compound 4: 1H NMR (200 MHz, CDCl3): ꢁ 12.68 (1H,
brs), 8.39–8.21 (4H, m), 7.62–7.43 (4H, m), 7.42–7.10
(6H, m); FAB-MS: m=z 364 [M + Na]þ.
N
Cl
O
H
Cl
3
Ph
Ph
N
H
H
H
H
NO2
4
5
6
7
60
30
45
45
94
98
94
92
N
H
O2N
1
4
Compound 8: H NMR (200 MHz, CDCl3): ꢁ 8.01 (2H, d,
O
O
O
J ¼ 8:0 Hz), 7.56 (4H, d, J ¼ 8:0 Hz), 7.38–7.20 (8H, m),
2.99 (1H, m), 1.25 (6H, d, J ¼ 7:0 Hz); FAB-MS: m=z 361
[M + Na]þ.
Compound 10: 1H NMR (200 MHz, CDCl3): ꢁ 7.52–7.05
(16H, m), 4.04 (2H, s); FAB-MS: m=z 333 [M + Na]þ.
Compound 11: 1H NMR (CDCl3, 200 MHz): ꢁ 7.48–7.34
(4H, m), 7.30–7.09 (6H, m), 2.62 (2H, t, J ¼ 7:0 Hz),
1.81–1.62 (2H, m), 1.40–1.24 (4H, m), 0.83 (3H, t,
J ¼ 7:0 Hz); FAB-MS: m=z 313 [M + Na]þ.
Ph
Ph
N
CH3
N
H
H3C
5
Ph
Ph
N
OMe
OMe
N
H
6
MeO
MeO
H3C
Ph
Ph
N
N
OH
H
HO
7
O
Ph
Ph
N
CH3
CH3
H
H
8
9
30
45
98
96
CH
N
H
CH3
8
O
Ph
N
N
H
9
Ph
Ph
N
H
N
H
10
11
Ph
60
60
91
94
O
10
O
Ph
Ph
N
H
N
H
11
O
Ph
Ph
N
12
60
92
H
N
H
12
aThe structures of the products were determined from spectral
(1H NMR and MS) data.
Published on the web (Advance View) September 22, 2007; doi:10.1246/cl.2007.1270