A mild and efficient one-pot synthesis of 2-dihydroimidazoles from aldehydes

Article abstract of DOI:10.1016/j.tetlet.2005.02.025

The reactions of various aldehydes and 1,2-diamines followed by NXS treatment proceed at 0°C-rt to give the corresponding dihydroimidazoles in high yields. The reaction is mild, and many functional groups such as halogens, nitriles, and esters can exist.

Full text of DOI:10.1016/j.tetlet.2005.02.025

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2197–2199
A mild and efficient one-pot synthesis of 2-dihydroimidazoles
from aldehydes
Hiromichi Fujioka,* Kenichi Murai, Yusuke Ohba, Atsushi Hiramatsu and Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
Received 6 January 2005; revised 3 February 2005; accepted 7 February 2005
Abstract—The reactions of various aldehydes and 1,2-diamines followed by NXS treatment proceed at 0 °C–rt to give the corre-
sponding dihydroimidazoles in high yields. The reaction is mild, and many functional groups such as halogens, nitriles, and esters
can exist.
Ó 2005 Elsevier Ltd. All rights reserved.
The importance of dihydroimidazole units especially in
biochemistry is recently increasing, since they are found
in many biologically active compounds.1 They are also
used in organic synthesis as synthetic intermediates,2
chiral auxiliaries,3 and chiral ligands.4 Therefore, several
methodologies for synthesizing them have already been
developed, mainly using nitriles5 and esters6 as the start-
ing substrates. However, these previous methods have
several drawbacks, namely the need for a high reaction
temperature, acidic conditions, and the use of metal cya-
nide for preparation of the nitrile compounds that limit
their uses. Although several new methods have been re-
cently developed,7 they need rather special starting
materials such as azalactones,7a 2-aryl-1,1-dibromo-
ethanes,7b and amino amides.7c The development of
mild and efficient methods is still strongly desirable.
We present here a novel mild and efficient method,
which overcomes the drawbacks of the previous
reactions.
General procedure is as follows. Namely, a solution of 1
(1.0mmol) in CH 2Cl2 (10mL) and ethylenediamine
(1.05 mmol) were mixed and stirred at 0 °C for 20min,
and NBS (1.05 mmol) was added to the mixture and
the resulting solution was allowed to warm to rt and stir-
red overnight. NaOH (10%) aq or sat NaHCO3 was
added to the reaction mixture to make sure the solution
is alkaline. The mixture was extracted with CH2Cl2. The
organic layer was dried over Na2SO4, and evaporated in
vacuo. The residue was purified by SiO2 column chro-
matography9 to give 2.
This reaction is rationalized as follows (Scheme 1). First,
imidazolidine i is formed by the condensation of 1 and
ethylenediamine without any catalysts. Its formation
1
was confirmed by a H NMR experiment. Second, the
reaction of i and N-halosuccinimide afforded the halo-
amine ii. Third, the elimination of HX then afforded
the salt 2ÆHX.10 Alkaline work-up afforded the dihydro-
imidazole 2. In the reaction, the succinimide anion
formed by the loss of the halonium ion would assist in
N-Iodosuccinimide (NIS) treatment of the mixture of
8
benzaldehyde 1 and ethylenediamine in CH2Cl2 affor-
Table 1.
ded the dihydroimidazole 2 in excellent yield at 0 °C–
rt. Other halogenating reagents, N-bromosuccinimide
(NBS) and N-chlorosuccinimide (NCS), gave the same
results (Table 1). The following experiments were then
done using the cheapest NBS.
(1.05eq)
H2N
NH2
H
N
then NXS (1.05eq)
Ph
Ph-CHO
CH2Cl2
0oC-rt.
N
1
2
Entry
NXS
Yield (%)
Keywords: Dihydroimidazole; Aldehyde; 1,2-Diamine; N,N-Acetal;
N-Halosuccinimide; Mild reaction.
1
2
3
NIS
99
99
99
NBS
NCS
*
Corresponding authors. Tel.: +81 668 798225; fax: +81 668 798229;
e-mail addresses: fujioka@phs.osaka-u.ac.jp; kita@phs.osaka-u.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.025

2198
H. Fujioka et al. / Tetrahedron Letters 46 (2005) 2197–2199
X
N
H
N
alkaline
work-up
N
H
H2N
NH2
NXS
HX
2
Ph-CHO
Ph
Ph
N
H
N
H
2
Ph
N
H
1
i
ii
HX
Scheme 1.
the elimination, because the use of bromine only in place
of NBS did not give 2.
The generality of the reaction was next examined. Table
2 shows the results using aromatic aldehydes. The result
of benzaldehyde is shown for comparison (entry 1). The
reactions well proceed in spite of an electron-donating
substituents, a methoxy group (entries 2–4), and elec-
tron-withdrawing substituents such as chloro, nitrile,
ester, and fluoro groups (entries 5–9), whereas the o-
substituted ones gave products in rather lower yields
than those of the m- and p-substituted ones (entries 4,
5). These facts suggest that the steric factor is more
important than the electronic factor in this reaction. It
is noteworthy that the nitrile and ester groups remain in-
tact under this reaction condition, although they were
used for the formation of dihydroimidazole compounds
in the previous reports. The pyridine aldehyde also gives
the desired compound in a quantitative yield without
any problem (entry 10).
Table 2.
(1.05eq)
H2N
NH2
H
N
then NBS (1.05eq)
Ar-CHO
Ar
CH2Cl2
0oC-rt.
N
Entry
Ar–CHO
Yield (%)
99
CHO
1
CHO
2
94
Table 3 shows the results of the aliphatic aldehydes. The
method works well not only for simple primary alde-
hydes (entry 1) but also for unsaturated aldehydes and
secondary aldehydes (entries 2–4). The method is also
available for aldehyde having an ester (entry 5).
OMe
CHO
3
4
5
96
69
83
MeO
CHO
MeO
The use of a chiral diphenylethyldiamine in place of eth-
ylenediamine was next studied (Table 4), since the appli-
cation of chiral dihydroimidazoles as chiral ligands has
been recently increasing. The aromatic aldehyde (entry
1), pyridine aldehyde (entry 2), and aliphatic aldehydes
(entries 3, 4) afforded the corresponding chiral dihydro-
imidazole in high yields.
CHO
Cl
CHO
In conclusion, we have developed a mild and effective
method for producing dihydroimidazoles from alde-
6
7
8
99
95
94
Table 3.
Cl
(1.05eq)
CHO
H2N
NH2
H
N
then NBS (1.05eq)
R
R CHO
CH2Cl2
0oC-rt.
N
CN
CHO
Entry
R–CHO
Yield (%)
96
CHO
Ph
1
CHO
Ph
COOMe
2
3
87
94
CHO
F
BnO
9
96
CHO
4
5
85
98
Ts
N
CHO
10
100
N
CHO
BzO(CH2)8CHO

H. Fujioka et al. / Tetrahedron Letters 46 (2005) 2197–2199
2199
Table 4.
Rettori, M. C.; Renard, P. Bioorg. Med. Chem. 2001, 9,
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Tetrahedron Lett. 1990, 31, 1771–1774; (b) Jung, M. E.;
Huang, A. Org. Lett. 2000, 2, 2659–2661.
Ph
Ph
(1.05eq)
H2N
NH2
H
N
Ph
Ph
then NBS (1.05eq)
3. For examples, see: (a) Jones, R. C. F.; Turner, I.; Howard,
K. J. Tetrahedron Lett. 1993, 34, 6329–6332; (b) Langlois,
Y.; Dalko, P. I. J. Org. Chem. 1998, 63, 8107–8117.
4. For examples, see: (a) Morimoto, T.; Tachibana, K.;
Achiwa, K. Synlett 1997, 783–785; (b) Davinport, A. J.;
Davies, D. L.; Fawcett, J.; Russell, D. R. J. Chem. Soc.,
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Carotti, A.; Dontenwill, M.; Giannella, M.; Moriconi, R.;
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Bioorg. Med. Chem. 1997, 5, 833–841; (e) Mitchell, J. M.;
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R
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CH2Cl2
0oC-rt.
N
Entry
R–CHO
Yield (%)
CHO
1
92
96
2
N
CHO
CHO
3
4
87
95
Ts
N
CHO
hydes and 1,2-diamines. This method works at low tem-
perature, 0 °C–rt, and many functional groups such as
halogens, esters, and nitriles can exist without any prob-
lem. Furthermore, since the aldehyde is a popular func-
tional group, the method here is considered useful in
organic synthesis.
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Tetrahedron 2004, 60, 9857–9862; (c) You, S.-L.; Kelly, J.
W. Org. Lett. 2004, 6, 1681–1683.
References and notes
8. Among the examined reaction solvents, toluene, CH2Cl2,
AcOEt, and THF, CH2Cl2 gave the best results (99% yield
of 2), whereas other three solvents afforded 2 in decreased
yields (toluene, 75% of 2; AcOEt, 73% of 2; THF, 76%
yield of 2).
9. Eluent for the compounds in entries 1, 3, 5–9 in Table 2:
AcOEt/Et3N system; eluent for the compounds in entries
2, 4, 10in Table 2 and entries 1, 2 in Table 3: CH2Cl2/
MeOH/Et3N system; eluent for the compounds in entries
3–5 in Table 3: CH2Cl2/MeOH/Et3N system; eluent for the
compounds in Table 4: hexane/AcOEt/Et3N system.
10. Transformation of C–N single bond to C–N double bond
from N-chloroamine, see: Scully, F. E., Jr.; Davis, R. C. J.
Org. Chem. 1978, 43, 1467–1468.
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