Synthesis of enantiopure 1-substituted, 1,2-disubstituted, and 1,4,5-trisubstituted imidazoles from 1,2-amino alcohols

Article abstract of DOI:10.1016/j.tet.2006.05.079

A highly versatile method for the preparation of enantiopure 1-substituted, 1,2-disubstituted, and 1,4,5-trisubstituted imidazoles was developed by using the cyclocondensation reaction of a 1,2-dicarbonyl compound, an aldehyde, a 1,2-amino alcohol, and ammonium acetate.

Full text of DOI:10.1016/j.tet.2006.05.079

Tetrahedron 62 (2006) 8199–8206
Synthesis of enantiopure 1-substituted, 1,2-disubstituted, and
1,4,5-trisubstituted imidazoles from 1,2-amino alcohols
*
Yuki Matsuoka, Yasuhiro Ishida, Daisuke Sasaki and Kazuhiko Saigo
*
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo Hongo,
Bunkyo-ku, Tokyo 113-8656, Japan
Received 30 January 2006; revised 23 May 2006; accepted 29 May 2006
Available online 19 June 2006
Abstract—A highly versatile method for the preparation of enantiopure 1-substituted, 1,2-disubstituted, and 1,4,5-trisubstituted imidazoles
was developed by using the cyclocondensation reaction of a 1,2-dicarbonyl compound, an aldehyde, a 1,2-amino alcohol, and ammonium
acetate.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
usually used for this reaction, such as alkyl halides, alcohols,
and epoxides, are not so easy to obtain in an enantiopure
form and in a large amount. In addition, this method is obvi-
ously disadvantageous for the preparation of N-substituted
imidazoles with a stereogenic carbon at the a-position of
the imidazole N(1), especially when a bulky substituent is
placed on the carbon. The efficiency of N-alkylation is sig-
nificantly influenced by the steric hindrance of the carbon
at which a nucleophilic attack occurs. Furthermore, the ste-
reochemistry of the stereogenic carbon in the electrophile is
not necessarily preserved during the reaction.
Imidazole and its derivatives play an important role in the
fields of biology and pharmacology as well as chemistry.1–5
Imidazole ring systems are frequently found in numerous
naturally occurring1 and synthetic molecules such as fungi-
cides, herbicides,2 and therapeutic agents.3 Recently, an
interest to these heteroaromatic systems has been further
expanded as the precursors of imidazolium-based ionic
liquids4 and N-heterocyclic carbenes (NHCs).5 Among
them, imidazole derivatives having a N-substituent with
stereogenic center(s) have attracted special attention, be-
cause of their potential utility in a wide range of fields related
to chiral recognition and asymmetric catalysis.6,7
On the other hand, the cyclocondensation of ring fragments
established by Gridnev and Mihaltseva9a has been applied
for the preparation of various N-substituted imidazoles.9,10
By using an enantiopure amine as a primary amine fragment
in this method, imidazoles with a stereogenic N-substituent
can be prepared in one step. Because stereogenic carbon
does not directly participate in the cyclocondensation, there
is little risk for the racemization/epimerization of the stereo-
genic carbon. Furthermore, enantiopure amines are easily
available in a large scale. Considering the application of
N-substituted imidazoles as the building blocks of biologi-
cally active compounds, asymmetric catalysts, and chiral
ionic liquids, the introduction of a functional group as well
as a stereogenic center adjacent to the five-membered ring
core would be advantageous from the viewpoints of further
derivatization and chiral recognition/induction. Therefore,
the development of a novel method for the preparation of
1-substituted imidazoles with a functional group and a
stereogenic center on the substituent is an important subject.
Synthetic strategies for the preparation of imidazoles with
a stereogenic N-substituent are classified into two cate-
gories; (i) the alkylation of an imidazole nitrogen with enan-
tiopure electrophiles and (ii) the cyclocondensation of ring
fragments, typically the combination of glyoxal, ammonia,
an aldehyde, and an enantiopure primary amine. The alkyla-
tion method is quite straightforward to access target mole-
cules, because imidazole is commercially available and
the N-alkylation of imidazole is a well-established reaction
with very low possibility of complicated side reactions. In
fact, several methods based on the alkylation approach
have been recently reported, in which various enantiopure
electrophiles were employed.8 However, the alkylation
method still possesses serious limitations: electrophiles
Keywords: 1,2-Amino alcohol; Chiral pool; Cyclocondensation; Enantio-
pure; N-Substituted imidazole.
In the course of our ongoing studies on the design and syn-
thesis of chiral ionic liquids based on imidazoliums,11 the
* Corresponding authors. Tel.: +81 3 5841 7266; fax: +81 3 5802 3348;
e-mail: saigo@chiral.t.u-tokyo.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.079

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Y. Matsuoka et al. / Tetrahedron 62 (2006) 8199–8206
synthesis of 1-substituted and 1,2-disubstituted imidazoles
from 1,2-amino alcohols was highly required. Although
there have been a large number of reports on the synthesis
of imidazoles by the cyclocondensation of four components
(glyoxal, ammonia, an aldehyde, and an amine including
enantiopure one), little is concerned with the thorough
examination of the optimal conditions for the cycloconden-
sation of glyoxal, ammonia, an aldehyde, and a 1,2-amino
alcohol.9,10 Here we report an efficient and practical method
for the preparation of 1-substituted, 1,2-disubstituted, and
1,4,5-trisubstituted imidazoles with a hydroxy group and
a stereogenic center on the substituent.
Table 1, the amounts of these reagents were another crucial
factor to determine the yield of 2a, especially when ammo-
nium acetate was used as an ammonia source. By increasing
the amounts of glyoxal, formaldehyde, and ammonium ace-
tate from 1.0 equiv to 2.0 equiv, the yield of 2a was signifi-
cantly improved (entries 5 and 6). However, the yield did not
increase any longer by using further excess amounts
(4.0 equiv each) of these reagents (entry 7). Contrary to
this, when ammonium chloride was employed as an ammo-
nia source, the yield was slightly diminished by using excess
amounts of these ring fragments (entry 4). Although the use
of the ring fragments in excess resulted in the formation of
several undesired by-products, they could be easily removed
from the desired product through the work-up process
because of their high volatility and/or polarity. Thus, the
conditions adopted in entries 3 and 6 (Table 1) seem to be
suitable for this cyclocondensation. Worth noting is the
fact that the amount of imidazole (3) generated through
the reaction was surprisingly small, although the ring frag-
ments for the construction of 3 adequately existed under
the conditions of entries 2, 4, 6, and 7; when the reactions
were conducted under the conditions of these entries, only
less than 5% of 3 was generated with respect to 2a. It means
that the 1-substituted imidazole formation is much faster
than the imidazole formation.
2. Results and discussion
2.1. Optimization of the reaction conditions
(S)-2-Amino-1-phenylethanol (1a) was chosen as an enan-
tiopure primary 1,2-amino alcohol for the study on the
reaction conditions, because of its easy availability from
(R)-mandelic acid and the detectability of the products,
developed on a TLC plate, by UV absorption.12
For the imidazole formation by cyclocondensation, pH is
known to be one of the most crucial factors to determine
the yield.9a,b Therefore, we at first investigated the effect
of an ammonia source on the efficiency of this cyclocon-
densation; the 1,2-amino alcohol 1a, glyoxal (40% aqueous
solution, 1.0 equiv), formaldehyde (37% aqueous solution,
1.0 equiv) were allowed to react in the presence of ammonia
(28% aqueous solution, 1.0 equiv), ammonium chloride,
or ammonium acetate in methanol (Table 1, entries 1, 3,
and 5). Comparing the yields of the product 2a, it could be
clearly deduced that acidic conditions were favorable
for the cyclocondensation. This observation is in good
agreement with the result in the report of Gridnev and
Mihaltseva.9a
In the next stage, we examined the solvent effect for the re-
action using ammonium acetate as an ammonia source. The
use of water in the place of methanol caused a considerable
diminish in the yield of 2a; a notable amount of precipitates
was generated just after the reaction was started, which
might arise from hydrophobicity of an intermediate derived
from 1a and glyoxal (Table 1, entry 8). Contrary to this,
ethanol and 2-propanol dissolved all of the four components
and maintained the homogeneity of the system throughout
the reaction, as did methanol. However, the yields observed
by using ethanol and 2-propanol were lower than that
achieved by using methanol (entries 9 and 10). These obser-
vations indicate that the dielectric constant of the reaction
medium is also an important factor for the present cyclocon-
densation; polar solvents are fundamentally favorable as far
as the substrate and intermediate are adequately soluble in
the reaction media.
Considering the availability of each ring fragment, the first
priority should be given to the conversion of the 1,2-amino
alcohol unit. Therefore, we then conducted the reactions us-
ing excess amounts of the other ring fragments. As shown in
Table 1. Synthesis of 1-substituted imidazole 2a from (S)-2-amino-1-phe-
nylethanol (1a)
2.2. Synthesis of various 1-substituted imidazoles
We then carried out the reactions of various enantiopure 1,2-
amino alcohols (Table 2). Under the conditions of entry 4 in
Table 1 (method A), the enantiopure 1,2-amino alcohols
1a–f could be successfully converted to the corresponding
N-substituted imidazoles without the loss of enantiopurity
(entries 1, 3, 5, 7, 9, and 10). The fact that the yield of 2a
(entry 1) was comparable to that of the reaction of 2-phenyl-
ethylamine (1g) under the same conditions (entry 10)
strongly indicates that the hydroxy group in the 1,2-amino
alcohols was likely to bring little influence on this reaction.
Furthermore, the reaction of (S)-tyrosinol (1f) afforded the
corresponding 1-substituted imidazole 2f in the yield com-
parable to those of the other reactions, which clearly shows
that this cyclocondensation is tolerant to a phenol moiety
(entry 9). Worth noting is the fact that the reaction proceeded
efficiently even when a bulky substituent was introduced at
the a-position of the amino group (entries 3, 5, and 7). Thus,
HCHO
(n equiv.)
OHC–CHO (n equiv.)
NH3 source (n equiv.)
H
OH
N
N
N
+
80 °C (oil bath), 5 h
H2N
OH
1a
N
2a
3
Entry
NH3 source
n/eq.
Solvent
Isolated yield
1
2
3
4
5
6
7
8
9
10
28% NH3 aq
28% NH3 aq
NH4Cl
1
2
1
2
1
2
4
2
2
2
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Water
20
44
69
63
53
71
72
45
51
44
NH4Cl
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
Ethanol
2-Propanol

Y. Matsuoka et al. / Tetrahedron 62 (2006) 8199–8206
8201
Table 2. Synthesis of 1-substituted imidazoles 2a–g from various 1,2-amino
alcohols 1a–g
reaction can be conducted under almost neutral conditions,
which might be advantageous for the reaction of amines
bearing a functional group unstable under acidic conditions.
Thus, the method A is concluded to be the most favorable for
the cyclocondensation.
R2
R1
HCHO
(n equiv.)
R1
H2N
R2
OHC–CHO (n equiv.)
NH3 source (n equiv.)
OH
N
OH
MeOH, 80 °C (oil bath), 5 h
N
In order to demonstrate the applicability of this procedure in
a large scale, we then conducted the reaction in a multi-gram
scale under the same conditions and attempted to isolate the
target N-substituted imidazoles by a method other than col-
umn chromatography. For example, when the reaction of
3.00 g of 1d (29 mmol) was carried out under the same
conditions of the method A, 3.69 g of the corresponding 1-
substituted imidazole 2d (24 mmol, 82% yield) was isolated
with satisfactory purity by Kugelrohr distillation (3 mmHg,
170 ꢀC). This preparative method is undoubtedly more effi-
cient, compared with the conventional method reported by
Bao et al.;10b 2d was prepared in three reaction steps, all
of which required chromatographic purification. On the
other hand, for the isolation of less volatile 1-substituted imi-
dazoles such as 2e, crystallization was found to be effective;
when 4.54 g of 1e (30 mmol) was treated under the same
conditions, 2.97 g of 2e (15 mmol, 50% yield) was isolated
by simple crystallization from ethyl acetate/hexane.
1a–g
2a–g
Entry
Primary amine 1
Methoda
Isolated
yield (%)
ee (%)b
1
2
A
B
71
69
>99
>99
1a
H2N
OH
3
4
A
B
65
61
>99
>99
1b
H2N
OH
5
6
A
B
65
>99c
>99c
61d
1c
H2N
OH
7
8
A
B
69
>99
>99
1d
54e
H2N
OH
2.3. Synthesis of 1,2-disubstituted and 1,4,5-tri-
substituted imidazoles
In general, the introduction of a substituent at the C(2) posi-
tion of 1-substituted imidazoles and 1,3-disubstituted imida-
zolium salts brings a considerable effect on the properties of
the resultant imidazoles/imidazolium salts. Especially in the
cases of ionic liquids consisting of 1,3-dialkylimidazolium
salts, the alkylation at the C(2) position makes these ionic
liquids applicable under basic conditions, because the easy
formation of undesired carbene species from 1,3-disubsti-
tuted imidazoliums by the action of a base can be pre-
vented.13 Usually, such a substituent at the C(2) position
as well as at the C(4) and/or C(5) positions is introduced
by the lithiation of a 1-substituted imidazole, followed by
treatment with an electrophile.14 On the other hand, there
has been only a few reports on the preparation of 1,2-disub-
stituted and 1,4,5-trisubstituted imidazoles by the cyclocon-
densation, although this route seems to be more convenient
compared with conventional methods.9b,9e–g,15
1e
9
A
55
>99
H2N
OH
OH
10
A
A
63
63
n.d.
1f
H2N
H2N
OH
11
1g
a
Method A: n¼2; NH3 source, NH4OAc. Method B: n¼1; NH3 source,
NH4Cl.
Estimated by a chiral HPLC analysis.
b
c
d
e
Estimated by 1H NMR.
As a mixture with the 1,2-amino alcohol 1c (2c:1c¼61:19).
As a mixture with imidazole (3) (2d:3¼54:5).
With the optimized conditions for the cyclocondensation of
a 1,2-amino alcohol, formaldehyde, glyoxal, and an ammo-
nia source in hand, we then attempted to apply the cyclocon-
densation reaction to the formation of highly substituted
imidazoles by replacing formaldehyde and glyoxal with
other aldehydes and 1,2-diketones, respectively. At first,
we attempted to synthesize 1,2-disubstituted imidazoles by
using various aldehydes in the place of formaldehyde (Table
3, entries 1–6).
a highly convenient and efficient method for the synthesis of
imidazoles possessing a stereogenically pure OH-pendant
N-substituent was established.
The reaction conditions of entry 3 in Table 1 (method B)
were also applied to the cyclocondensation of several amino
alcohols (1a–d: Table 2, entries 2, 4, 6, and 8). The method B
realized yields comparable to or slightly lower than those by
the method A for the reactions of 1a–c. However, for the
reaction of 1d, the yield achieved by the method B was ob-
viously lower than that accomplished by the method A. This
means that the method A is suitable for the reaction of steri-
cally hindered amino alcohols such as 1d; ammonium
acetate is better than ammonium chloride as the ammonium
source. Furthermore, by using ammonium acetate, the
When 1a, glyoxal (2.0 equiv), acetaldehyde (2.0 equiv), and
ammonium acetate (2.0 equiv) were allowed to react with
each other in methanol (method A), the target imidazole
4a was obtained, as was expected, accompanying the forma-
tion of two kinds of by-products, 2a and 11, having no sub-
stituent at the C(2) and N(1) positions, respectively (Table 3,
entry 1). Although such by-products 2a and 11 were formed,

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Y. Matsuoka et al. / Tetrahedron 62 (2006) 8199–8206
Table 3. Synthesis of 1,2-disubstituted and 1,4,5-trisubstituted imidazoles from (S)-2-amino-1-phenylethanol (1a) and (S)-valinol (1d)
R2
R2
R3CHO
(n equiv.)
R1
R1
R4COCOR4 (n equiv.)
NH3 source (n equiv.)
H
R4
R4
R4
R4
R4
R4
R1
R2
OH
R3
OH
R4
N
N
N
N
N
R3
+
+
MeOH, 80 °C (oil bath), 5 h
H2N
OH
N
entry
1,2-amino alcohol
aldehyde
R3 = CH3
product-2
product-3
1,2-diketone
R4 = H
product-1
1a: R1 = H, R2 = Ph
1a: R1 = H, R2 = Ph
1a: R1 = H, R2 = Ph
4a
5a
6a
4d
2a
2a
2a
2d
11
12
13
11
1, 2
3
4
R3 = (CH2)2Ph R4 = H
R
R
3 = Ph
R
R
4 = H
4 = H
i
1d: R1 = Pr, R2 = Ph
5
3 = CH3
1a: R1 = H, R2 = Ph
1a: R1 = H, R2 = Ph
7a
8a
8d
9a
10a
10d
14
15
15
6
7
8
R3 = H
3 = H
R3 = H
R
R
4 = Me
4 = Ph
R
i
1d: R1 = Pr, R2 = Ph
R4 = Ph
Entry
Methoda
Ratio of the productsb (prdct-1:prdct-2:prdct-3)
Yieldc
1
2
A
B
1.00:0.31:0.17
1.00:0.77:0.18
50 (41)
29 (22)
4a
OH
N
N
3
4
5
6
5a
A
A
A
A
1.00:0.58:0.65
1.00:0.50:0.58
51 (43)
48 (40)
OH
N
N
OH
6a
N
N
1.00:1.10:0.69
1.00:0.16:0.60d
27 (26)
OH
34 (34)d
4d
N
N
1.00:<0.01:<0.01
30 (30)
7a
OH
N
N
OH
N
7e
A
A
1.00:<0.01:<0.01
1.00:<0.01:0.07
83 (83)
8a
N
OH
N
8e
85 (52)
8d
N
a
Method A: n¼2; NH3 source, NH4OAc. Method B: n¼1; NH3 source, NH4Cl.
Estimated by 1H NMR.
b
c
d
e
Yield based on 1H NMR (in a parenthesis, isolated yield).
Glyoxal (1.0 equiv) was used.
Reaction time, 9 h.

Y. Matsuoka et al. / Tetrahedron 62 (2006) 8199–8206
8203
the target 1,2-disubstituted imidazole 4a was isolated by alu-
mina column chromatography in moderate yield (50% yield
by a 1H NMR analysis, 41% isolated yield). The cyclocon-
densation was found to be tolerant to other aldehyde compo-
nents; the reaction conditions optimized for the formation of
4a were successfully applied to the reactions involving an al-
iphatic or aromatic aldehyde, such as 3-phenylpropanal or
benzaldehyde, as the C(2) provider, and the corresponding
1,2-disubstituted imidazoles 5a and 6a were obtained in
yields comparable to that of 4a (entries 3 and 4).
the formation of the sterically crowded product possessing
a C(2) substituent. However, by reducing the amount of
glyoxal from 2.0 equiv to 1.0 equiv, the formation of the
undesired by-product 2d could be efficiently suppressed to
improve the yield of 4d. Contrary to the case of the synthesis
of 4d, the formation of a 1,4,5-trisubstituted imidazole was
hardly influenced by a substituent on a primary amine
unit; the cyclocondensation of 1d, benzyl (2.0 equiv), form-
aldehyde (2.0 equiv), and ammonium acetate (2.0 equiv)
proceeded smoothly, and only a small amount of 15 was
afforded as a by-product. As a result, the yield of the target
1,4,5-trisubstituted imidazole 8d was comparable to that of
8a from 1a (entry 8).
The formation of 11–13 is reasonable, because all of the ring
fragments for the formation of 11–13 (glyoxal, acetalde-
hyde, and ammonium acetate) were excessively used. On
the other hand, the C(2) of 2a was most likely provided by
formaldehyde or its equivalent, which would be generated
in situ from glyoxal under the reaction conditions; the
primary amine 1a should be consumed for the formation
of 2a to diminish the yield of 4a–6a.16 The same side reac-
tion could be considered to occur during the 1-substituted
imidazole formation using formaldehyde (Tables 1 and 2)
but might bring little effect on the yield of the target imi-
dazole, because the side reaction afforded the same product.
Noteworthy, the pH of the reaction mixture was again found
to be an important factor to determine the yield and selectiv-
ity of the reaction; when ammonium chloride was used in the
place of ammonium acetate, the ratio of the undesired 2a
considerably increased to lower the yield of 4a (method B,
entry 2).
3. Conclusion
We developed a highly versatile method for the preparation
of 1-substituted imidazoles by the cyclocondensation of
glyoxal, ammonium acetate, formaldehyde, and a 1,2-amino
alcohol. The choice of an ammonium source, which gives
significant influence on the pH of the reaction mixture,
was found to be an important factor to determine the effi-
ciency and selectivity of the reaction. The protocol opti-
mized here was applicable to the transformation of various
enantiopure 1,2-amino alcohols, including sterically hin-
dered 1,2-amino alcohols, to the corresponding enantiopure
1-substituted imidazoles with maintaining the enantiopurity.
By this method, target imidazoles could be prepared in
multi-gram scales and easily isolated in satisfactorily pure
forms without resorting column chromatography. Further-
more, the procedure was successfully applied to the synthe-
sis of 1,2-disubstituted and 1,4,5-trisubstituted imidazoles
by the proper choice of an aldehyde and a 1,2-dicarbonyl
compound. The synthetic procedure established here is
expected to contribute to the development of enantiopure
imidazole/imidazolium-based molecules, such as bioactive
reagents, ionic liquids, NHC ligands, and NHC catalysts.
The successful results described above prompted us to apply
the cyclocondensation to the formation of 1,4,5-trisub-
stituted imidazoles, because several 4,5-diaryl-substituted
imidazoles have been attracted recent attention as potent
inhibitors of p38 MAP kinase.17 We therefore conducted
the cyclocondensation reaction of a 1,2-diketone, ammo-
nium acetate, formaldehyde, and 1a under the conditions
of the method A. To our delight, the reaction proceeded
smoothly to afford the target 1,4,5-trisubstituted imidazoles
7a and 8a in moderate to good yields (Table 3, entries 6 and
7). Contrary to the case of the reactions using glyoxal, these
1,2-diketones did not act as imidazole C(2) providers; the
formation of 1,2,4,5-tetrasubstituted imidazoles 9a and
10a was not observed. Furthermore, another kind of possible
by-products, 4,5-disubstituted imidazoles (14 and 15) were
not detected in both of the reactions of the 1,2-diketones.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on a Varian Mercury
300 operating at 300 and 75 MHz, respectively. IR spectra
were recorded on a JASCO model FT/IR-480plus. High-
resolution FABMS spectra were recorded on a JEOL JMS-
HX110 spectrometer using 3-nitrobenzyl alcohol matrix.
Melting points were determined on a Yamato MP-21.
For the synthetic method to prepare 1,2-disubstituted and
1,4,5-trisubstituted imidazoles thus established, the scope
of the primary amine component was investigated. As a
primary amine unit, (S)-valinol (1d) was used in the place
of (S)-2-amino-1-phenylethanol (1a), because 1d with a
sterically congested amino group seemed to be suitable to
evaluate the effect of the substituent neighboring an amino
group on the efficiency of the reaction. In the cycloconden-
sation of 1d, glyoxal (2.0 equiv), acetaldehyde (2.0 equiv),
and ammonium acetate (2.0 equiv), the target 1,2-disubsti-
tuted imidazole 4d was obtained, but considerable amounts
of the by-products 2d and 11 were generated to diminish the
yield of 4d (entry 5). The ratio of the by-product lacking
a C(2) substituent significantly increased compared with
the case of 1d (entry 1 vs entry 5), most likely because the
isopropyl group on 1d brought an unfavorable effect on
4.2. Synthesis and characterization of imidazoles.
General procedure
A methanol solution (6 mL) of aqueous glyoxal (40%
w/v, 0.87 g, 6.0 mmol) or a 1,2-dicarbonyl compound
(6.0 mmol), ammonium acetate (0.46 g, 6.0 mmol), aqueous
formaldehyde (36% w/v, 0.50 g, 6.0 mmol) or an aldehyde
(6.0 mmol), and a 1,2-amino alcohol (3.0 mmol) was re-
fluxed for 5 h. Unless otherwise noted, the reaction mixture
was treated as follows: The reaction mixture was concen-
trated under reduced pressure. The resultant residue was
treated with 2 M aqueous KOH solution (100 mL) and
extracted with CH2Cl2 (4ꢁ100 mL). The combined organic

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Y. Matsuoka et al. / Tetrahedron 62 (2006) 8199–8206
layers were dried over anhydrous Na2SO4 and concentrated
under reduced pressure.
found: 155.1186. Anal. Calcd for C8H14N2O: C, 62.31; H,
9.15; N, 18.17. Found: C, 62.19; H, 9.32; N, 18.14.
4.2.1. Imidazole 2a. Purified by silica gel (deactivated with
10 wt % water) column chromatography eluted with
CH2Cl2/MeOH (100:0–95:5, v/v). Mp 147.5–150.5 ꢀC.
[a]2D5 +45.3 (c 1.2, MeOH). IR (KBr): 3120, 2891, 2850,
Analytical chiral HPLC: column, CHIRALCEL OD-H
(0.46ꢁ25 cm); eluent, hexane/2-propanol¼90:10, v/v;
flow, 1.0 mL/min; (R) 18.0 min, (S) 32.4 min.
1
2788, 1636, 1601, 1513, 1449 cmꢂ1. H NMR (CDCl3):
4.2.5. Imidazole 2e. Purified by silica gel (deactivated with
10 wt % water) column chromatography eluted with
CH2Cl2/MeOH (99:1–95:5, v/v). Mp 86.0–87.5 ꢀC. [a]D25
ꢂ114.7 (c 1.1, MeOH). IR (KBr): 3157, 3113, 2962, 2933,
d 4.04–4.17 (m, 2H), 4.93 (dd, J1¼7.2 Hz, J2¼4.5 Hz,
1H), 6.89 (s, 1H), 6.94 (s, 1H), 7.26–7.41 (m, 6H). 13C
NMR (CDCl3): d 54.27, 72.62, 119.60, 125.64, 127.51,
128.05, 128.11, 137.38, 141.55. HRMASS calcd for
[M+H]+ C11H13N2O: 189.1028, found: 189.1021. Anal.
Calcd for C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found:
C, 70.24; H, 6.60; N, 14.88.
1
2833, 1963, 1886, 1653, 1604, 1590, 1505 cmꢂ1. H NMR
(CDCl3): d 2.99 (dd, J1¼13.8 Hz, J2¼8.4 Hz, 1H), 3.15
(dd, J1¼13.8 Hz, J2¼6.5 Hz, 1H), 3.83–3.85 (m, 2H),
4.21–4.26 (m, 1H), 6.89–6.91 (m, 2H), 7.00–7.03 (m 2H),
7.19–7.27 (m, 4H). 13C NMR (CDCl3): d 38.41, 62.26,
64.21, 117.61, 126.99, 128.59, 128.76, 128.90, 136.47,
137.10. HRMASS calcd for [M+H]+ C12H15N2O:
203.1184, found: 203.1182. Anal. Calcd for C12H14N2O: C,
71.26; H, 6.98; N, 13.85. Found: C, 71.27; H, 7.20; N, 13.81.
Analytical chiral HPLC: column, CHIRALCEL OD-H
(0.46ꢁ25 cm); eluent, hexane/2-propanol ¼ 85:15, v/v;
flow, 1.0 mL/min; (R) 21.1 min, (S) 23.7 min.
4.2.2. Imidazole 2b. Purified by silica gel column chromato-
graphy eluted with CH2Cl2/MeOH (99:1–95:5, v/v). Mp
117.5–120.0 ꢀC. [a]D25 +25.9 (c 1.3, MeOH). IR (KBr):
3148, 3108, 3033, 2958, 2925, 2859, 2652, 1984, 1961,
1882, 1812, 1685, 1601, 1583, 1495, 1460, 1451, 1410,
Analytical chiral HPLC: column, CHIRALCEL OD-H
(0.46ꢁ25 cm); eluent, hexane/2-propanol ¼ 90:10, v/v;
flow, 1.0 mL/min; (R) 24.5 min, (S) 37.2 min.
1
1371 cmꢂ1. H NMR (CDCl3): d 4.13–4.25 (m, 2H), 5.27
4.2.6. Imidazole 2f. The reaction mixture was concentrated
under reduced pressure. The resultant residue was dissolved
in water (6 mL), and the aqueous solution was neutralized by
the addition of solid NaHCO3 until the pH reached at 7.0–
8.0. The resultant mixture was extracted with 1-butanol
(6ꢁ2 mL), and the organic layers combined were washed
with brine (6 mL). The organic solution was concentrated
under reduced pressure, and the resultant residue was sub-
jected to silica gel (deactivated with 10 wt % water) column
chromatography eluted with CH2Cl2/MeOH (90:10, v/v).
The separated product was crystallized from CHCl3/
MeOH to give 2f. Mp 175.5–180.5 ꢀC. [a]D25 ꢂ133.2 (c
1.1, MeOH). IR (KBr): 3142, 3124, 3023, 2931, 2806,
2677, 1614, 1593, 1515, 1504, 1454, 1386, 1373,
(dd, J1¼7.8 Hz, J2¼4.8 Hz, 1H), 6.94–6.96 (m, 2H), 7.15–
7.18 (m, 2H), 7.31–7.35 (m, 3H), 7.51 (s, 1H). 13C NMR
(CDCl3): d 63.81, 64.42, 118.77, 127.04, 128.48, 128.53,
129.04, 136.84, 137.53. HRMASS calcd for [M+H]+
C11H13N2O: 189.1028, found: 189.1024. Anal. Calcd for
C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C, 70.00;
H, 6.58; N, 14.73.
Analytical chiral HPLC: column, CHIRALCEL OD-H
(0.46ꢁ25 cm); eluent, hexane/2-propanol ¼ 80:20, v/v;
flow, 1.0 mL/min; (R) 9.5 min, (S) 12.7 min.
4.2.3. Imidazole 2c. Purified by silica gel (deactivated with
10 wt % water) column chromatography eluted with
CH2Cl2/MeOH (100:0–95:5, v/v) followed by crystalliza-
tion from EtOAc. Mp 161.5–163.0 ꢀC. [a]D25 ꢂ37.6 (c 2.1,
MeOH). IR (KBr): 3098, 2933, 2841, 1971, 1904, 1832,
1709, 1685, 1636, 1602, 1586, 1508, 1493, 1451,
1
1234 cmꢂ1. H NMR (CD3OD): d 2.89 (dd, J1¼14.2 Hz,
J2¼9.3 Hz, 1H), 3.06 (dd, J1¼14.2 Hz, J2¼5.7 Hz, 1H),
3.77–3.85 (m, 2H), 4.25–4.34 (m, 1H), 6.59–6.64 (m, 2H),
6.82–6.87 (m, 2H), 6.92 (m, 1H), 7.16 (m, 1H), 7.47 (s,
1H). 13C NMR (CD3OD): d 39.27, 64.36, 65.79, 117.08,
119.85, 129.57, 130.27, 131.76, 139.00, 158.09. HRMASS
calcd for [M+H]+ C12H15N2O2: 219.1134, found:
219.1139. Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47;
N, 12.84. Found: C, 65.87; H, 6.45; N, 12.58.
1
1397 cmꢂ1. H NMR (CDCl3): d 5.23 (d, J¼6.9 Hz, 1H),
5.41 (d, J¼6.9 Hz, 1H), 6.89–6.90 (m, 2H), 7.14–7.18 (m,
2H), 7.26–7.31 (m, 5H), 7.34–7.38 (m, 4H). 13C NMR
(CDCl3): d 67.81, 75.14, 118.67, 126.50, 128.28, 128.49,
128.53, 128.62, 128.71, 136.15, 136.75, 141.10. HRMASS
calcd for [M+H]+ C17H17N2O: 265.1341, found: 265.1359.
Anal. Calcd for C17H16N2O: C, 77.25; H, 6.10; N, 10.60.
Found: C, 77.12; H, 6.12; N, 10.45.
4.2.7. Imidazole 2g. Purified by silica gel (deactivated with
10 wt% water) column chromatography eluted with CH2Cl2/
MeOH (99:1–95:5, v/v) followed by Kugelrohr distillation
(3 mmHg, 160 ꢀC). Colorless oil. IR (NaCl): 3111, 3028,
1
4.2.4. Imidazole 2d. Purified by silica gel (deactivated with
10 wt % water) column chromatography eluted with
CH2Cl2/MeOH (99:1–97:3, v/v). Mp 106.5–111.5 ꢀC.
[a]2D5 ꢂ27.1 (c 1.6, MeOH). IR (KBr): 3112, 3090, 2957,
2928, 1672, 1604, 1508, 1455 cmꢂ1. H NMR (CD3OD):
d 3.04 (t, J¼7.2 Hz, 2H), 4.16 (t, J¼7.2 Hz, 2H), 6.83 (m,
1H), 7.02–7.07 (m, 3H), 7.24–7.32 (m, 4H). 13C NMR
(CD3OD): d 38.14, 48.80, 119.06, 127.28, 128.89, 129.06,
129.69, 137.38, 137.74. HRMASS calcd for [M+H]+
C11H13N2: 173.1078, found: 173.1072.
1
2926, 2856, 2726, 1691, 1599, 1504, 1494 cmꢂ1. H NMR
(CDCl3): d 0.74 (d, J¼6.6 Hz, 3H), 1.03 (d, J¼6.6 Hz,
3H), 2.07–2.14 (m, 1H), 3.64–3.71 (m, 1H), 3.85–3.91 (m,
2H), 6.92 (m, 2H), 7.32 (s, 1H). 13C NMR (CDCl3):
d 19.31, 20.01, 30.01, 62.69, 67.09, 118.15, 128.26,
136.81. HRMASS calcd for [M+H]+ C8H15N2O: 154.1184,
4.2.8. Imidazole 4a. Purified by alumina column chromato-
graphy eluted with hexane/CH2Cl2 (33:67–0:100, v/v). Mp
145.5–150.0 ꢀC. [a]D25 +23.6 (c 1.2, MeOH). IR (KBr):

Y. Matsuoka et al. / Tetrahedron 62 (2006) 8199–8206
8205
3111, 2846, 1654, 1532, 1505, 1436 cmꢂ1
.
1H NMR
217.1364. Anal. Calcd for C13H16N2O$1/4H2O: C, 70.66;
H, 7.47; N, 12.68. Found: C, 70.84; H, 7.48; N, 12.54.
(CDCl3): d 2.12 (s, 3H), 3.98–4.01 (m, 2H), 4.90 (t,
J¼5.9 Hz, 1H), 6.72 (d, J¼1.4 Hz, 1H), 6.81 (d, J¼1.4 Hz,
1H), 7.26–7.37 (m, 5H). 13C NMR (CDCl3): d 12.79,
53.80, 73.33, 120.00, 125.99, 126.49, 128.21, 128.72,
141.59, 145.20. HRMASS calcd for [M+H]+ C12H15N2O:
203.1184, found: 203.1180. Anal. Calcd for C12H14N2O$1/
6H2O: C, 70.21; H, 6.99; N, 13.65. Found: C, 70.08; H,
6.97; N, 13.15.
4.2.13. Imidazole 8a. Purified by silica gel (deactivated with
10 wt % water) column chromatography eluted with
CH2Cl2/MeOH (100:0–95:5, v/v). Mp 223.0–223.5 ꢀC.
[a]2D5 +63.2 (c 1.2, CHCl3). IR (KBr): 3117, 3060, 2892,
2847, 2722, 1952, 1896, 1643, 1603, 1508, 1496, 1480,
1
1444 cmꢂ1. H NMR (CDCl3): d 3.58 (dd, J1¼14.1 Hz,
J2¼2.2 Hz, 1H), 3.74 (dd, J1¼14.1 Hz, J2¼9.6 Hz, 1H),
4.63 (dd, J1¼9.6 Hz, J2¼2.2 Hz, 1H), 6.67 (d, J¼6.9 Hz,
2H), 7.10–7.14 (m, 2H), 7.18–7.42 (m, 11H), 7.81 (s, 1H).
13C NMR (CDCl3): d 54.04, 72.48, 125.99, 126.76,
127.01, 128.02, 128.27, 128.77, 128.86, 129.08, 130.48,
131.70, 134.87, 137.35, 138.32, 141.63, 144.75. HRMASS
calcd for [M+H]+ C23H31N2O: 341.1654, found: 341.1658.
Anal. Calcd for C23H30N2O: C, 81.15; H, 5.92; N, 8.23.
Found: C, 81.00; H, 6.06; N, 8.08.
4.2.9. Imidazole 4d. Purified by alumina column chromato-
graphy eluted with hexane/CH2Cl2/MeOH (25:75:0–0:99:1,
v/v/v). Viscous oil. [a]D25 ꢂ20.4 (c 3.3, MeOH). IR (NaCl):
3156, 2963, 1529, 1498, 1421, 1278, 1147, 1083, 1028,
990, 747, 680 cmꢂ1 1H NMR (CDCl3): d 0.73 (d,
.
J¼6.6 Hz, 3H), 1.06 (d, J¼6.6 Hz, 3H), 1.96–2.08 (m,
1H), 2.35 (s, 3H), 3.68–3.75 (m, 1H), 3.79–3.85 (m, 1H),
3.93–3.97 (m, 1H), 6.83 (d, J¼1.5 Hz, 1H), 6.85 (d,
J¼1.5 Hz, 1H). 13C NMR (CDCl3): d 13.7, 19.9, 20.3,
30.7, 63.4, 65.2, 116.0, 127.3, 145.7. HRMASS calcd for
[M+H]+ C9H17N2O: 169.1341, found: 169.1341.
4.2.14. Imidazole 8d. Purified by silica gel (deactivated with
10 wt % water) column chromatography eluted with
CH2Cl2/MeOH (100:0–99:1, v/v). Mp 161.0–163.0 ꢀC.
[a]2D5 ꢂ55.9 (c 1.8, MeOH). IR (KBr): 3127, 2964, 1894,
4.2.10. Imidazole 5a. Purified by alumina column chroma-
tography eluted with hexane/CH2Cl2/MeOH (33:67:0–
0:98:2, v/v/v). Viscous oil. [a]2D5 +11.7 (c 1.0, MeOH). IR
(KBr): 3061, 3027, 2931, 1952, 1881, 1811, 1671, 1603,
1
1820, 1773, 1602, 1506 cmꢂ1. H NMR (CD3OD): d 0.75
(d, J¼6.6 Hz, 3H), 0.95 (d, J¼6.6 Hz, 3H), 2.17–2.29 (m,
1H), 3.56–3.63 (m, 1H), 3.85 (dd, J1¼11.7 Hz, J2¼3.3 Hz,
1H), 3.97 (dd, J1¼11.7 Hz, J2¼6.6 Hz, 1H), 7.12–7.22 (m,
3H), 7.30–7.39 (m, 4H), 7.45–7.54 (m, 3H). 13C NMR
(CDCl3): d 20.95, 32.56, 64.22, 65.76, 128.34, 128.89,
129.93, 130.84, 130.95, 132.23, 132.83, 133.77, 136.49,
137.64, 138.88. HRMASS calcd for [M+H]+ C20H23N2O:
307.1810, found: 307.1806. Anal. Calcd for C20H22N2O:
C, 78.40; H, 7.24; N, 9.14. Found: C, 78.27; H, 7.34; N, 8.97.
1
1528, 1493, 1453 cmꢂ1. H NMR (CDCl3): d 2.71–2.77
(m, 2H), 2.98 (t, J¼7.8 Hz, 2H), 3.87–3.90 (m, 2H), 4.76
(t, J¼5.9 Hz, 2H), 6.84 (d, J¼1.4 Hz, 1H), 6.91 (d,
J¼1.4 Hz, 1H), 7.09–7.12 (m, 2H), 7.16–7.37 (m, 9H). 13C
NMR (CDCl3): d 28.38, 34.18, 53.14, 72.91, 119.97,
125.90, 126.12, 126.27, 127.95, 128.36, 128.39, 128.51,
141.15, 141.87, 147.75. HRMASS calcd for [M+H]+
C19H21N2O: 293.1654, found: 293.1659.
4.2.11. Imidazole 6a. Purified by alumina column chroma-
tography eluted with hexane/CH2Cl2/MeOH (33:67:0–
0:99:1, v/v/v). Mp 152.5–153.5 ꢀC. [a]D25 ꢂ3.6 (c 1.0,
MeOH). IR (KBr): 3121, 3061, 3031, 2933, 2885, 2835,
2760, 1957, 1896, 1820, 1604, 1577, 1537, 1508, 1492,
Acknowledgements
A part of this work was financially supported by a Grants-in-
Aid for Young Scientists (No. 14750674) from the Ministry
of Education, Culture, Sports, Sciences and Technology, and
Japan Interaction in Science and Technology Forum.
1474, 1447, 1425 cmꢂ1 1H NMR (CDCl3): d 4.15 (d,
.
J¼6.0 Hz, 2H), 4.86 (t, J¼6.0 Hz, 1H), 7.01 (d, J¼1.4 Hz,
1H), 7.08 (d, J¼1.4 Hz, 1H), 7.14–7.17 (m, 2H), 7.26–
7.29 (m, 3H), 7.35–7.43 (m, 5H). 13C NMR (CDCl3):
d 53.89, 73.33, 121.55, 125.88, 127.87, 128.13, 128.48,
128.64, 128.80, 129.28, 130.46, 144.40, 148.04. HRMASS
calcd for [M+H]+ C17H17N2O: 265.1341, found: 265.1341.
Anal. Calcd for C17H16N2O$H2O: C, 72.26; H, 6.38; N,
9.92. Found: C, 72.91; H, 5.95; N, 9.91.
References and notes
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with 10 wt % water) column chromatography eluted with
CH2Cl2/MeOH (100:0–90:10, v/v) followed by aluminum
column chromatography eluted with hexane/CH2Cl2/
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1598, 1558, 1541, 1506, 1496, 1451, 1386, 1344 cmꢂ1. H
NMR (CDCl3): d 2.00 (s, 3H), 2.09 (s, 3H), 3.83–3.99 (m,
2H), 4.87 (dd, J1¼8.4 Hz, J2¼3.5 Hz, 1H), 7.28–7.42 (m,
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acylamides. See: Grimmett, K. R. Imidazoles and their
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Reactions, Synthesis, and Uses of Heterocyclic Compounds;
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