An efficient preparation of 2-imidazolines and imidazoles from aldehydes with molecular iodine and (diacetoxyiodo)benzene

Article abstract of DOI:10.1055/s-2005-923604

2-Imidazolines were easily prepared in quite good yields from the reaction of aldehydes and ethylenediamine with molecular iodine in the presence of potassium carbonate. Moreover, 2-imidazolines obtained were smoothly oxidized to the corresponding imidazoles in good yields using (diacetoxyiodo)benzene at room temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-923604

LETTER
227
An Efficient Preparation of 2-Imidazolines and Imidazoles from Aldehydes
with Molecular Iodine and (Diacetoxyiodo)benzene
P
reparationof 2-Imida
i
zolines
d
a
ndImidazo
o
les ri Ishihara,a Hideo Togo*a,b
a
Graduate School of Science and Technology, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
b
Faculty of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
E-mail: togo@faculty.chiba-u.jp
Received 17 October 2005
tive, but molecular iodine is much more efficient in view
of the operational utility of the reagent and the yield ob-
tained (entry 5). The same treatment of p-tolualdehyde
with DIB, instead of molecular iodine, gave a complicated
Abstract: 2-Imidazolines were easily prepared in quite good yields
from the reaction of aldehydes and ethylenediamine with molecular
iodine in the presence of potassium carbonate. Moreover, 2-imid-
azolines obtained were smoothly oxidized to the corresponding
imidazoles in good yields using (diacetoxyiodo)benzene at room reaction mixture, and 2-(4-methylphenyl)imidazoline was
temperature.
not formed at all. Based on these results, various alde-
hydes were treated with ethylenediamine and molecular
iodine under the same conditions to provide the corre-
sponding 2-substituted imidazolines in quite good yields,
as shown in Table 2. Thus, aromatic aldehydes bearing
electron-donating substituents and electron-withdrawing
substituents can be converted to the corresponding 2-
arylimidazolines in quite good yields. However, the reac-
tion of aliphatic aldehyde under the same conditions gave
the corresponding 2-alkylimidazoline in moderate yields
(entries 8, 9).
Key words: 2-imidazoline, imidazole, iodine, (diacetoxyiodo)ben-
zene, aldehyde, ethylenediamine
Synthetic study of 2-imidazoline units and imidazole units
is very important due to their potent biological activity1
and synthetic utility.2 To date, there are several synthetic
methods for 2-imidazolines starting from mainly nitriles
and esters.3 Recently, Kita et al. reported an efficient one-
pot preparation of 2-imidazolines from aldehydes and
ethylenediamine with NBS.4 Once 2-imidazolines are
formed, they can be smoothly oxidized to the correspond-
ing imidazoles by oxidants such as MnO2,5a Pd/C,5b
KMnO4,5c trichloroisocyanuric acid,5d (COCl)2–DMSO,5e
and IBX,5f etc. However, there are still several drawbacks
to these methods, i.e., preparation of 2-imidazolines and
imidazoles requires toxic or explosive oxidant, or multi-
step operation. Recently, synthetic use of hypervalent
iodines for organic synthesis has been investigated widely
because of their efficient oxidizing ability and less toxi-
city.6 Especially, (diacetoxyiodo)benzene (DIB), iodosyl-
benzene, and [hydroxy(tosyloxy)iodo]benzene (HTIB)
are the most popular and useful trivalent iodine reagents
for organic synthesis.7
Table 1 Formation of 2-(p-Tolyl)imidazoline from p-Tolualdehyde
with Ethylenediamine and Iodine
H2N
NH
2 (1.1 equiv)
H
N
I2 and K2CO3 (3.0 equiv)
CH3
CH3
CHO
t-BuOH, 70 °C, 3 h
N
Entry
I2 (equiv)
0.75
Yield (%)
82
1
2
3
4
5
1.00
89
1.25
100
1.50
100
Here, as a part of our basic study of molecular iodine for
organic synthesis,8 we would like to report a useful oxida-
tive conversion of aldehydes to 2-imidazolines with ethyl-
enediamine and iodine, and then to imidazoles with DIB.
Thus, the addition of molecular iodine to a mixture of
p-tolualdehyde and ethylenediamine in the presence of
K2CO3 provided the corresponding 2-(4-methyl-
phenyl)imidazoline, and the use of 1.25 equivalents of
molecular iodine gave the product quantitatively as shown
in Table 1 (entry 3).9 According to our previous reported
reaction conditions using molecular iodine,8b t-BuOH was
used as a solvent in the present reaction. ICl is also effec-
2.5a
83
a ICl was used in place of I2.
Then, the oxidation of 2-(4-methylphenyl)imidazoline to
2-(4-methylphenyl)imidazole in the presence of K2CO3,
using less-toxic iodine reagents such as molecular iodine
or hypervalent iodine reagents, was carried out as shown
in Table 3.10 Though it is well-known that molecular io-
dine has moderate oxidizing ability, unfortunately 2-(4-
methylphenyl)imidazoline could not be oxidized by io-
dine under any conditions. However, hypervalent iodine
reagents such as DIB, iodosylbenzene, and HTIB oxidize
it to 2-(4-methylphenyl)imidazole in DMSO at room tem-
perature, and DIB showed the most effective reactivity
among them, to give the product in good yield (entry 5).
SYNLETT 2006, No. 2, pp 0227–0230
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Advanced online publication: 23.12.2005
DOI: 10.1055/s-2005-923604; Art ID: U28905ST
© Georg Thieme Verlag Stuttgart · New York

228
M. Ishihara, H. Togo
LETTER
Table 2 Preparation of 2-Substituted Imidazolines from Aldehydes
Table 4 Oxidation of 2-Substituted Imidazolines to 2-Substituted
with Ethylenediamine and Iodine
Imidazoles with DIB
H
N
H
N
DIB (1.1 equiv), K2CO3 (1.1 equiv)
DMSO, r.t., 24 h
H2N
NH2 (1.1 equiv)
H
N
R
R
I2 (1.25 equiv) , K2CO3 (3.0 equiv)
N
N
R
CHO
R
t-BuOH, 70 °C, 3 h
N
Entry
1
R =
Yield (%)
Entry
1
R =
Yield (%)
75
83
76
73
79
100
97
2
3
4
5
Br
2
3
4
5
Br
MeO
O2N
100
99
MeO
O2N
NC
Cl
98
NC
6
70
Cl
6
99
7
8
70
38
S
7
8
94
53
S
9
41
9
50
Ph
Ph
H2N
NH
2 (1.1 equiv)
Table 3 Oxidation of 2-(p-Tolyl)imidazoline to 2-(p-Tolyl)imid-
azole with DIB
I2 (1.25 equiv), K2CO3 (3.0 equiv)
CH3
CHO
t-BuOH, 70 °C, 3 h
reagent (1.1 equiv),
K2CO3 (1.1 equiv)
H
N
H
N
DIB (1.1 equiv),
K2CO3 (1.1 equiv)
H
CH3
CH3
Ph
Ph
N
DMSO, r.t., 24 h
N
N
Yield (%)
0
CH3
DMSO, r.t., 24 h
N
92%
Entry
Reagent
H
Ph
Ph
N
1
2
3
I2
CH3
N
73%
a
I2–H2O2
0
0
a
KI–H2O2
Scheme 1
4
5
36
81
I
O
oxidized to the corresponding 2-substituted imidazoles in
good yields as shown in Table 4. However, the same treat-
ment of 2-alkylimidazoline with DIB gave the corre-
sponding 2-alkylimidazole in low yields (entries 8, 9).
Finally, the same treatment of p-tolualdehyde with (R,R)-
(+)-diphenylethylenediamine, instead of ethylenedi-
amine, provided the corresponding (R,R)-2-(p-tolyl)-3,4-
diphenylimidazoline in 92% yield, and the oxidation with
DIB produced the corresponding 2-(p-tolyl)-3,4-di-
phenylimidazole in 73% yield (Scheme 1). A plausible
reaction mechanism for imidazolines and imidazoles is
shown in Scheme 2.
I(OAc)2 (DIB)
OH
6
23
(HTIB)
I
OTs
a H2O2 (3.0 equiv) was added.
Acetonitrile and DMF, instead of DMSO, also gave 2-(4-
methylphenyl)imidazole under the same conditions; how-
ever, the yield was much decreased. Based on these re-
sults, various 2-substituted imidazolines were efficiently
Synlett 2006, No. 2, 227–230 © Thieme Stuttgart · New York

LETTER
Preparation of 2-Imidazolines and Imidazoles
229
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N
(a)
+
H2N
NH2
R
R
CHO
NH2
(– H2O)
I
H
N
N
N
I2
(– HI)
H
R
R
R
R
(– HI)
N
H
N
H
N
H
N
N
+
(b)
PhI(OAc)2
R
(– AcOH)
N
I
N
H
H
Ph
(4) Fujioka, H.; Murai, K.; Ohba, Y.; Hiramatsu, A.; Kita, Y.
Tetrahedron Lett. 2005, 46, 2197.
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OAc
(– PhI)
(– AcOH)
N
N
N
R
R
N
H
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Scheme 2 Plausible reaction mechanisms for imidazoline (a) and
imidazole (b)
In summary, 2-imidazolines could be easily obtained in
quite good yields by the reaction of aldehydes and ethyl-
enediamine with molecular iodine in the presence of po-
tassium carbonate under warming conditions. Then, 2-
imidazolines obtained could be smoothly oxidized to the
corresponding imidazoles in good yields using (diacet-
oxyiodo)benzene at room temperature. Both reactions
proceed under environmentally benign conditions, i.e.,
without using any toxic reagents. Further synthetic study
of the present reactions is underway in this laboratory.
(6) Varvoglis, A. Hypervalent Iodine in Organic Synthesis;
Academic Press: San Diego, 1997.
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(b) Moriarty, R. M.; Vaid, R. K. Synthesis 1990, 431.
(c) Moriarty, R. M.; Vaid, R. K.; Koser, G. F. Synlett 1990,
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96, 1123. (h) Umemoto, T. Chem. Rev. 1996, 96, 1757.
(i) Kita, Y.; Takada, T.; Tohma, H. Pure Appl. Chem. 1996,
68, 627. (j) Togo, H.; Hoshina, Y.; Nogami, G.; Yokoyama,
M. Yuki Gosei Kagaku Kyokaishi 1997, 55, 90.
Acknowledgment
Financial support in the form of a Grant-in-Aid for Scientific Re-
search (No. 16655012) from the Ministry of Education, Science,
Sports, and Culture of Japan is gratefully acknowledged.
(k) Varvoglis, A. Tetrahedron 1997, 53, 1179.
(l) Zhdankin, V. V. Rev. Heteroat. Chem. 1997, 17, 133.
(m) Muraki, T.; Togo, H.; Yokoyama, M. Rev. Heteroat.
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Y.; Egi, M.; Takada, T.; Tohma, H. Synthesis 1999, 885.
(s) Wirth, T.; Hirt, U. H. Synthesis 1999, 1271. (t) Ochiai,
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References and Notes
(1) (a) Grimmett, M. R. Comprehensive Heterocyclic
Chemistry, Vol. 5; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon: Oxford, 1984, 345–498. (b) Grimmett, M. R.
Comprehensive Heterocyclic Chemistry II, Vol. 3;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Elsevier Science: Oxford, 1996, 77–220. (c) The
Pharmacological Basis of Therapeutics, 10th ed.; Gilman,
A. G.; Goodman, L. S., Eds.; Macmillan: New York, 2001.
(d) Prisinano, T.; Law, H.; Dukat, M.; Slassi, A.; MaClean,
N.; Demchyshyn, L.; Glennon, R. A. Bioorg. Med. Chem.
2001, 9, 613.
(2) For examples see: (a) Jones, R. C. F.; Nichols, J. R.
Tetrahedron Lett. 1990, 31, 1771. (b) Langlois, Y.; Dalko,
P. I. J. Org. Chem. 1998, 63, 8107. (c) Menges, F.;
Neuburger, M.; Pfaltz, A. Org. Lett. 2002, 4, 4713.
(d) Meiere, S. H.; Valahovic, M. T.; Harman, W. D. J. Am.
Chem. Soc. 2002, 124, 15099. (e) Bhor, S.; Anilkumar, G.;
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(9) Typical Procedure for Preparation of 2-Imidazolines
from Aldehydes: To a solution of p-tolualdehyde (120.2
mg, 1 mmol) in t-BuOH (10 mL) was added
ethylenediamine (66.1 mg, 1.1 mmol). The obtained mixture
was stirred at r.t. under an argon atmosphere for 30 min, and
then K2CO3 (414.6 mg, 3 mmol) and I2 (317.3 mg, 1.25
mmol) were added to the mixture and stirred at 70 °C. After
3 h, the mixture was quenched with sat. aq Na2SO3 until the
Synlett 2006, No. 2, 227–230 © Thieme Stuttgart · New York

230
M. Ishihara, H. Togo
LETTER
atmosphere. After the reaction, the reaction mixture was
iodine color almost disappeared, and was extracted with
CHCl3. The organic layer was washed with sat. aq NaHCO3
and brine, and dried over Na2SO4. After filtration, the
mixture was evaporated in vacuo to provide 160.2 mg of 2-
(4-methylphenyl)imidazoline in 100% yield in an almost-
pure state. Mp 181–182 °C (lit.11 mp 181 °C). IR (KBr):
3140, 2925, 1600, 1495, 985, 830 cm–1. 1H NMR (400 MHz,
CDCl3): d = 2.38 (s, 3 H), 3.77 (s, 4 H), 7.21 (d, J = 8.3 Hz,
2 H), 7.67 (d, J = 8.3 Hz, 2 H).
diluted with sat. aq NaHCO3 and EtOAc, and was stirred for
5 min. The mixture was extracted with EtOAc and the
organic layer was dried over Na2SO4. After filtration, the
mixture was evaporated in vacuo. The residue was
chromatographed on neutral silica gel (EtOAc–MeOH,
30:1) to give 128.1 mg of 2-(4-methylphenyl)imidazole in
81% yield in an almost-pure state. Mp 217–218 °C (lit.5d mp
218–220 °C). IR (KBr): 3460, 1515, 1445, 1100, 820, 730
cm–1. 1H NMR (400 MHz, DMSO-d6): d = 2.31 (s, 3 H), 6.97
(br s, 1 H), 7.19 (br s, 1 H), 7.21 (d, J = 8.2 Hz, 2 H), 7.81 (d,
J = 8.2 Hz, 2 H), 12.38 (s, 1 H).
(10) Typical Procedure for Oxidation of 2-Imidazolines to
Imidazoles: To a mixture of 2-(4-methylphenyl)imidazoline
(160.2 mg, 1 mmol) and K2CO3 (152.0 mg, 1.1 mmol) in
DMSO (10 mL) was added DIB (354.3 mg, 1.1 mmol). Then
the mixture was stirred for 24 h at r.t. under an argon
(11) Levesque, G. Synthesis 1981, 963.
Synlett 2006, No. 2, 227–230 © Thieme Stuttgart · New York