One-pot condensation-oxidation of glyoxamide with 1,2-diamines providing imidazolines and benzimidazoles

Article abstract of DOI:10.1055/s-0029-1217120

A novel method for the preparation of imidazolines and benzimidazoles bearing an amide at the 2-position, is described. The reactions of the glyoxamide with aliphatic and aromatic 1,2-diamines were found to form five-membered imidazolines and benzimidazoles by a one-pot condensation-oxidation procedure.

Full text of DOI:10.1055/s-0029-1217120

520
PAPER
One-Pot Condensation–Oxidation of Glyoxamide with 1,2-Diamines Providing
Imidazolines and Benzimidazoles
S
ynthesis of Imida
e
zolines and
n
Benzimidaz
i
oles chi Murai, Nobuhiro Takaichi, Yusuke Takahara, Shunsuke Fukushima, Hiromichi Fujioka*
Graduate School of Pharmaceutical Science, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
Fax +81(66)8798229; E-mail: fujioka@phs.osaka-u.ac.jp
Received 7 September 2009; revised 7 October 2009
Although various aromatic and aliphatic aldehydes have
Abstract: A novel method for the preparation of imidazolines and
benzimidazoles bearing an amide at the 2-position, is described.
The reactions of the glyoxamide with aliphatic and aromatic 1,2-di-
amines were found to form five-membered imidazolines and benz-
imidazoles by a one-pot condensation–oxidation procedure.
been used to generate a range of imidazolines and benzim-
idazoles, there are few reports on the use of aldehydes
having a-carbonyl moieties despite the fact that such
structural motifs may give rise to potentially interesting
biological activities.6 We have already reported that the
reaction of 3-indolylglyoxal and aliphatic 1,2-diamines
with NCS afforded keto-imidazoline in the total synthesis
of spongotine A (Scheme 2),4 however, this is the only ex-
ample of the use of an aldehyde with an a-carbonyl group
in oxidative imidazoline synthesis.
Key words: imidazolines, benzimidazolines, one-pot reaction, oxi-
dations, amide
Imidazolines and benzimidazoles are some of the most
important heterocyclic rings found in pharmaceutical and
biologically active compounds, and numerous synthetic
methods for their preparation have been developed.
Among them, the oxidative synthesis from aldehydes with
diamines is considered to be a useful transformation. In
the case of bezimidazoles, this transformation has been
widely used for a long time;1 however, for imidazolines,
this transformation had not been reported until recently
and the first oxidative synthesis was developed by us.2
Our developed reaction involved the condensation of al-
dehydes and diamines without any catalyst and subse-
quent oxidation by NBS to give imidazolines in a one-pot
operation (Scheme 1). This reaction has several advantag-
es: it proceeds under mild conditions at low temperature
(0 °C to room temperature) using an almost neutral re-
agent. Furthermore, functional groups such as esters and
nitriles are tolerated in this approach, whereas they have
been used for constructing imidazoline rings in previous
methods.3
O
O
H2N
NH2
N
H
then NCS
Br
N
MeCN
Ts
H
N
O
N
N
H
Br
N
R
2 N NaOH (aq)
MeOH, reflux
(2 steps, 51%)
R = Ts
spongotine A: R = H
Scheme 2 Total synthesis of spongotine A4
Generally, the reaction between 1,2-diamines and alde-
hydes having an a-carbonyl group, can be used to gener-
R2
H
N
ate
a range of nitrogen-containing six-membered
R1
R2
N
H2N
NHR3
NBS
heterocycles: glyoxylates can be used to generate
pyrazinones7 and quinoxalinones8 (Scheme 3, equation
1), and a-keto aldehydes can be used to synthesize
dihydropyrazines9 and quinoxalines10 (Scheme 3, equa-
tion 2). On the other hand, the reaction of glyoxamides
with 1,2-diamines have not previously been much ex-
plored for the synthesis of heterocyclic compounds. To
expand the scope of the oxidative synthesis of imidazo-
lines and benzimidazoles, and to establish the reactivity
trend of a-carbonyl aldehydes with 1,2-diamines, which
are important for heterocyclic and medicinal chemistries,
herein, we report a one-pot condensation–oxidation of
glyoxamides and 1,2-diamines; the method provides a
range of imidazolines and benzimidazoles having an
amide group at their 2-position (Scheme 3, equation 3).
R1CHO
R1
R2
N
R1 = aromatic
aliphatic
R3
N
R3
aminal
imidazoline
Scheme 1 Our previous work2
The utility of this reaction has been shown in the total syn-
thesis of a natural product by us4 and in the preparation of
biologically active compounds and chiral ligands by other
groups.5 However, it is still important to investigate the
scope and limitations of this reaction.
SYNTHESIS 2010, No. 3, pp 0520–0526
Advanced online publication: 13.11.2009
x
x
.
x
x
.2
0
0
9
DOI: 10.1055/s-0029-1217120; Art ID: F18309SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Imidazolines and Benzimidazoles
521
general reactions of glyoxylates and glyoxals with diamines
ane was used, 4a was obtained in excellent yield (93%,
entry 6). Among the halosuccinimides (NBS, NCS, and
NIS) tested, NBS was found to be the best oxidant (entries
6–8). Although the solvent effect of the reaction is not
clear at this time, we assume that the appropriate Lewis
basisity of the ether-type solvents might work well, since
HBr is generated along with the oxidation of aminals to
the imidazolines.
N
NH2
O
O
(1)
(2)
N
H
O
R
OR
O
NH2
NH2
N
O
NH2
R
N
Table 1 Optimization Conditionsa
this work: reaction of glyoxamides with diamines
NH2
H
N
H
N
Ph
Ph
Ph
O
N
O
N
2a (0.55 equiv) then
NXS (1.1 equiv)
H
1a
H
N
N
O
N
N
[Ox]
NH2
solvent, r.t.
Ph
O
(3)
NR1R2
N
4a
O
N
5
O
NR1R2
H
Entry
Solvent
NXS
Yield (%)
Combinedb 4ac
NR1R2
one-pot condensation-oxidation
5c
Scheme 3
1
2
3
4
5
6
7
8
CH2Cl2
NBS
NBS
NBS
NBS
NBS
NBS
NCS
NIS
66
64
44
80
79
94
83
62
60
52
31
75
79
93
74
60
6
MeOH
12
11
5
Initially, the reaction of 1,2-diphenylethylenediamine
(1a) and glyoxamide hemihydrate 2a was investigated
and the H NMR spectrum of the reaction mixture in
MeCN
1
CHCl3
CDCl3 was measured. Hemihydrate was used because of
its stability and ease of handling. Since a signal from the
proton on the aminal carbon was observed in the 1H NMR
spectrum, whereas no imine proton signal was seen, it can
be reasoned that the reaction between 1a and 2a did not af-
ford the six-membered pyrazinone ring, but instead gave
the five-membered aminal ring (Scheme 4), probably due
to the relatively low reactivity of the amide carbonyl.11–13
THF
trace
1
1,4-dioxane
1,4-dioxane
1,4-dioxane
9
2
a 0.14 mmol of 1a was used.
b Combined yield of 4a and 5.
c Determined by 1H NMR.
O
O
N
H
N
2a
Ph
Ph
O
N
Bn
OH
Ph
Ph
H
2
Ph
O
N
O
N
N
N
N
H
4a 93%
4b 70%
H2N
NH2
CDCl3
N
N
Ph
Bn
1a
3
Scheme 4
Bn
Bn
O
N
O
N
N
N
Next, according to the method developed by our group,2a
the one-pot condensation–oxidation protocol was applied
to the reaction of 1a and 2a. Thus, a mixture of 1a and 2a
was stirred for one hour in dichloromethane and then N-
bromosuccinimide (NBS) was added. To our delight, the
desired product 4a was obtained in 60% yield, along with
a minor amount of imidazole 5 that was produced by over-
oxidation with NBS (Table 1, entry 1). Although further
attempts at optimizing the reaction by changing the oxi-
dant, additives, and temperatures (NCS, NIS, t-BuOCl,
Dess–Martin reagent, Et3N, K2CO3, 5Å or 4Å MS, 0 °C,
r.t., or reflux)14 did not improve the yield of 4a, it was
found that the ether-type solvents were most effective for
this transformation (entries 1–6). Thus, when tetrahydro-
furan was used as solvent, the desired imidazoline 4a was
obtained in 79% yield (entry 5), whereas, when 1,4-diox-
4c 75%
4e 85%
4g 99%
4d 58%
4f 95%
4h 75%
N
N
H
N
H
N
O
O
N
NHBn
N
NBn2
H
N
H
N
O
N
O
N
N
NBn2
Figure 1 Although one isomer is shown for 4h, the position of the
C=N double bond was not determined due to tautomerization of 4h
Synthesis 2010, No. 3, 520–526 © Thieme Stuttgart · New York

522
K. Murai et al.
PAPER
R1
N
The generality of this reaction can be summarized by list-
ing the products obtained (Figure 1). The condensation of
glyoxamides and 1,2-diamines, with subsequent oxida-
tion, selectively afforded the imidazolines and not the six-
membered-ring product. Imidazolines 4b–d were ob-
tained from the corresponding N-benzylethylenediamines
in moderate to good yields, although the use of bulky di-
amines resulted in lower yields, perhaps due to steric rea-
sons. Nevertheless, even the reaction of a diamine bearing
a quaternary carbon gave the expected imidazoline 4d in
reasonable yield (58%). In addition, the reactions of the
glyoxamides derived from secondary, primary, and aro-
matic amines (dibenzylamine, benzylamine, and indoline)
with ethylenediamine all afforded the corresponding imi-
dazolines 4e–g in very good yields. The use of 1,2-diami-
no-2-methylpropane as the diamine reagent, which has the
potential to produce regioisomeric products depending on
the position of the C=N double bond, was also investigat-
ed and the product 4h was obtained in acceptable yield.
However, because the tautomerization of HN–C=N was
very fast, the product was observed as a single compound
in 1H and 13C NMR (25 °C), and the ratio of regioisomers
was not determined.
NHR1
NH2
O
glyoxamide
urea⋅H2O2
NR2R3
N
40 °C, MeOH
6
H
O
N
N
H
N
O
N
N
NBn2
6a 70%
6b 58%
Me
N
O
N
Me
N
O
N
N
NHBn
6c 90%
6d 77%
Me
N
Ph
N
O
N
O
N
N
N
6e 78%
6f 88%
Finally, the reactions of a range of N-substituted 1,2-phe-
nylenediamines with glyoxamide were examined; these
reactions were also found to afford the expected benzimi-
dazole-2-carboxylic acid amides (Scheme 5). When the
reaction was carried out with NBS, 6a was obtained in
26% yield in 1,4-dioxane and 48% yield in dichlo-
romethane, however, the use of urea hydrogen peroxide as
the oxidant in methanol was more efficient for this trans-
formation, giving the expected product in 70% yield.15 As
Scheme 5
Melting points are uncorrected. 1H and 13C NMR spectra were mea-
sured using JEOL JNM-ECS 400 or JEOL JNM-AL 300 spectrom-
eters with TMS as an internal standard. IR spectra were recorded
with a Shimadzu FTIR 8400 spectrometer using diffuse reflectance
measurement of samples dispersed in KBr powder. High resolution
mass spectra and elemental analysis were performed by the Elemen-
shown in Scheme 5, the reactions of a range of glyoxam- tal Analysis Section of Osaka University. Column chromatography
was performed with SiO2 [Merck Silica Gel 60 (230–400 mesh) or
ide derivatives with secondary, primary, and aromatic
Kanto Chemical Silicagel 60 (spherical, 63–210 mm)]. Oxo(pyrroli-
amines afforded the desired products 6a–f in moderate to
din-1-yl)acetaldehyde18a and N-benzyl-2-oxoacetamide18b were
synthesized as reported in the literature. N,N-Dibenzyl-2-oxoacet-
amide and (2,3-dihydroindol-1-yl)oxoacetaldehyde were prepared
good yields. 1,2-Phenylenediamine derivatives that have
a substituent on the nitrogen atom, such as methyl or phe-
nyl groups, gave better results; these reactivity trends
were similar to the reaction of 1,2-phenylenediamine de-
by oxidative cleavage of the corresponding acrylamide with OsO4
and NaIO4 (see typical procedure below). The hemihydrate of
rivatives and usual aromatic aldehydes.16 The facile prep- oxo(pyrrolidin-1-yl)acetaldehyde, N,N-dibenzyl-2-oxoacetamide,
and (2,3-dihydroindol-1-yl)oxoacetaldehyde were obtained by ex-
posing a mixture of the corresponding hydrate form to air.
aration of such compounds is noteworthy, since these
types of structures have been found in a wide range of
biologically active compounds;3 previously reported syn-
Synthesis of (2,3-Dihydroindol-1-yl)oxoacetaldehyde; Typical
Procedure
thetic methods typically require several steps starting
from 1,2-phenylenediamines, need harsh reaction condi-
tions, or can only be used with a limited range of starting
materials.3,17
To a solution of indoline (200 mg, 1.68 mmol) and Et3N (0.47 mL,
3.4 mmol) in CH2Cl2 (16.8 mL), was added acryloyl chloride (0.20
ml, 2.5 mmol) at –78 °C. The reaction mixture was stirred at r.t. for
2 h then the reaction was quenched by the addition of H2O (20 mL).
The aqueous layer was extracted with CH2Cl2 (2 × 20 mL), dried
over Na2SO4, and evaporated in vacuo. The residue was purified by
SiO2 column chromatography (hexane–EtOAc, 3:1) to give 1-(2,3-
In summary, we have developed a novel method for the
preparation of imidazolines and benzimidazoles with an
amide group at the 2-position. In contrast to the corre-
sponding reactions performed with glyoxylates and gly- dihydroindol-1-yl)propenone.
oxals, one-pot condensation–oxidation of glyoxamides
with aliphatic and aromatic 1,2-diamines formed five-
membered imidazolines and benzimidazoles rather than
the six-membered-ring heterocycles. The fundamental
trend seen in the reactivities of a-carbonyl aldehydes with
1,2-diamines is important and useful for the syntheses of
nitrogen-containing heterocycles.
Yield: 538 mg (87%); colorless solid; mp 72 °C.
1H NMR (300 MHz, CDCl3): d = 8.30 (d, J = 7.5 Hz, 1 H), 7.26–
7.18 (m, 2 H), 7.03 (dt, J = 0.9, 8.1 Hz, 2 H), 6.63–6.48 (m, 2 H),
5.80 (dd, J = 9.3, 3.3 Hz, 1 H), 4.17 (t, J = 8.7 Hz, 2 H), 3.24–3.18
(m, 2 H).
13C NMR (100.5 MHz, CDCl3): d = 142.8, 131.5, 129.0, 128.9,
127.6, 124.5, 124.0, 99.9, 48.0, 28.0.
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Synthesis of Imidazolines and Benzimidazoles
523
HRMS (FAB): m/z [M + H]+ calcd for C11H12NO: 174.0919; found:
174.0912.
1H NMR (300 MHz, CDCl3): d = 7.37–7.22 (m, 10 H), 6.08 (br s, 1
H), 5.11 (d, J = 9.0 Hz, 1 H), 4.64 (d, J = 9.0 Hz, 1 H), 4.12–3.98
(m, 2 H), 3.65–3.61 (m, 2 H), 1.98–1.79 (m, 4 H).
13C NMR (100.5 MHz, CDCl3): d = 159.0, 158.6, 142.9, 142.6,
128.8, 128.6, 127.7, 127.4, 126.8, 126.2, 82.0, 68.7, 49.3, 47.2,
26.4, 23.7.
To a solution of 1-(2,3-dihydroindol-1-yl)propenone (1.75 g, 10.1
mmol) in a mixture of THF–H2O (3:1, 40 mL), was added OsO4
(cat.) and NaIO4 (4.54 g, 21.2 mmol) at r.t. and the mixture was
stirred for 6.5 h. The reaction was quenched by the addition of sat.
aq Na2S2O5 (20 mL), H2O (100 mL) was added to the mixture, and
the solution was extracted with CH2Cl2 (3 × 40 mL). The organic
layer was dried over Na2SO4, and evaporated in vacuo. The residue
was purified by SiO2 column chromatography (hexane–EtOAc, 1:1)
to give a mixture of the hydrate form of (2,3-dihydroindol-1-
yl)oxoacetaldehyde. Exposure to air for 3 d gave the hemihydrates
(a small amount of other hydrate forms remained).
Anal. Calcd for C20H21N3O: C, 75.21; H, 6.63; N, 13.16. Found: C,
75.01; H, 6.66; N, 13.01.
Imidazoline 4b
The reaction was carried out for 2 h according to the typical proce-
dure with N-benzylethylenediamine (30.8 mg, 0.205 mmol),
oxo(pyrrolidin-1-yl)acetaldehyde hemihydrate (31.9 mg, 0.117
mmol), and NBS (39.1 mg, 0.220 mmol) in 1,4-dioxane (2.0 mL) to
give 4b after SiO2 column chromatography (EtOAc–MeOH–Et3N,
20:1:1).
Yield: 1.49 g (57%); pale-pink solid.
1H NMR (400 MHz, CDCl3): d = 8.15 (d, J = 8.4 Hz, 2 H), 7.24–
7.18 (m, 4 H), 7.10–7.05 (m, 2 H), 5.72 (d, J = 10.0 Hz, 2 H), 5.31
(d, J = 10.0 Hz, 2 H), 4.40–4.33 (m, 2 H), 4.15–4.08 (m, 2 H), 3.24–
3.18 (m, 4 H).
13C NMR (100.5 MHz, CDCl3): d = 165.2, 142.0, 131.7, 127.6,
125.1, 124.8, 117.3, 87.1, 46.9, 28.1.
Yield: 36.8 mg (70%); pale-yellow oil.
IR (KBr): 1641, 1600 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.36–7.25 (m, 5 H), 4.38 (s, 2 H),
3.84 (t, J = 10.2 Hz, 2 H), 3.56–3.49 (m, 4 H), 3.15 (t, J = 10.2 Hz,
2 H), 1.90–1.83 (m, 4 H).
HRMS (FAB): m/z [M + H]+ calcd for C20H21N2O5: 369.1450;
found: 369.1454.
13C NMR (75.5 MHz, CDCl3): d = 160.8, 160.5, 137.3, 128.5,
127.9, 127.4, 53.5, 50.9, 49.4, 47.8, 45.4, 25.7, 24.0.
Oxo(pyrrolidin-1-yl)acetaldehyde Hemihydrate
Pale-yellow solid; mp 127–128 °C.
IR (KBr): 3319, 1643, 1481, 1410, 1336, 1132, 997, 653, 619 cm–1.
HRMS (FAB): m/z [M + H]+ calcd for C15H20N3O: 258.1606;
found: 258.1608.
1H NMR (300 MHz, CDCl3): d = 5.52 (d, J = 9.9 Hz, 2 H), 5.12 (d,
J = 9.9 Hz, 2 H), 3.72–3.63 (m, 2 H), 3.56–3.42 (m, 6 H), 1.99–1.85
(m, 8 H).
13C NMR (67.8 MHz, CDCl3): d = 165.9, 86.7, 46.4, 45.7, 25.8,
23.9.
HRMS (FAB): m/z [M + H]+ calcd for C12H21N2O5: 273.1450;
found: 273.1460.
Imidazoline 4c
The reaction was carried out for 2.5 h according to the typical pro-
cedure with 2-amino-1-(N-benzylamino)-3-phenylpropane (32.8
mg, 0.136 mmol), oxo(pyrrolidin-1-yl)acetaldehyde hemihydrate
(20.4 mg, 0.075 mmol), and NBS (26.7 mg, 0.150 mmol) in 1,4-di-
oxane (1.36 mL) to give 4c after SiO2 column chromatography
(EtOAc to EtOAc–Et3N, 15:1).
Yield: 35.6 mg (75%); colorless oil.
Anal. Calcd for C12H20N2O5: C, 52.93; H, 7.40; N, 10.29. Found: C,
52.75; H, 7.24; N, 10.09.
IR (KBr): 3026, 2877, 1643, 1596, 1494, 1454, 1398, 1222, 1107,
746, 700 cm–1.
N,N-Dibenzyl-2-oxoacetamide Hemihydrate
A small amount of other hydrate forms remained.
1H NMR (300 MHz, CDCl3): d = 7.34–7.15 (m, 10 H), 4.42–4.27
(m, 3 H), 3.59–3.43 (m, 4 H), 3.30 (t, J = 9.6 Hz, 1 H), 3.12 (dd,
J = 13.8, 5.1 Hz, 1 H), 3.05 (t, J = 9.0 Hz, 1 H), 2.70 (dd, J = 13.8,
8.7 Hz, 1 H), 1.89–1.82 (m, 4 H).
13C NMR (75.5 MHz, CDCl3): d = 160.7, 159.5, 138.3, 137.2,
129.2, 128.5, 128.3, 127.7, 127.4, 126.2, 66.3, 53.5, 50.6, 47.8,
45.4, 41.7, 25.7, 24.0.
Pale-yellow solid.
1H NMR (400 MHz, CDCl3): d = 7.38–7.29 (m, 12 H), 7.21–7.17
(m, 8 H), 5.79 (d, J = 10.0 Hz, 2 H), 5.26 (d, J = 10.0 Hz, 2 H), 4.81
(ABq, J = 15.2 Hz, 2 H), 4.73 (ABq, J = 16.4 Hz, 2 H), 4.46 (ABq,
J = 15.2 Hz, 2 H), 4.32 (ABq, J = 16.4 Hz, 2 H).
13C NMR (100.5 MHz, CDCl3): d = 168.2, 135.8, 135.4, 128.9,
128.8, 128.0, 127.7, 127.3, 86.4, 48.6, 48.3.
HRMS (FAB): m/z [M + H]+ calcd for C22H26N3O: 348.2076;
found: 348.2081.
HRMS (FAB): m/z [M + H]+ calcd for C32H33N2O5: 525.2389;
found: 525.2363.
Imidazoline 4d
The reaction was carried out for 2.5 h according to the typical pro-
cedure with 2-amino-1-(N-benzylamino)-2-methylpropane (25.5
mg, 0.190 mmol), oxo(pyrrolidin-1-yl)acetaldehyde hemihydrate
(28.5 mg, 0.104 mmol), and NBS (37.2 mg, 0.209 mmol) in 1,4-di-
oxane (1.9 mL) to give 4d after SiO2 column chromatography
(EtOAc–Et3N, 20:1).
Synthesis of Imidazoline 4a; Typical Procedure
(dl)-1,2-Diphenylethylenediamine (1a; 30.2 mg, 0.142 mmol) and
glyoxamide hemihydrate (2a; 22.6 mg, 0.083 mmol) were dissolved
in dioxane (1.4 mL) and stirred for 1 h at r.t. under N2. NBS (27.7
mg, 0.155 mmol) was added to the resulting solution, which was
then stirred for 3 h. After the reaction was complete (judged by
TLC), sat. aq Na2S2O3 (2 mL) and sat. aq NaHCO3 (15 mL) were
added and the mixture was extracted with CH2Cl2 (3 × 15 mL). The
organic layer was dried over Na2SO4 and evaporated in vacuo. The
residue was purified by SiO2 column chromatography (hexane–
EtOAc, 1:2) to give imidazoline 4a.
Yield: 31.5 mg (58%); colorless oil.
IR (KBr): 2960, 1643, 1598, 1494, 1457, 1404, 1307, 1278, 740
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.33–7.25 (m, 5 H), 4.37 (s, 2 H),
3.57–3.52 (m, 2 H), 3.51–3.47 (m, 2 H), 3.07 (s, 2 H), 1.88–1.84 (m,
4 H), 1.26 (s, 6 H).
Yield: 42.2 mg (93%); pale-yellow solid; mp 168–169 °C.
IR (KBr): 3286, 1629, 1593, 1577, 1491, 1423, 754, 704 cm–1.
13C NMR (75.5 MHz, CDCl3): d = 160.9, 156.9, 137.4, 128.5,
127.8, 127.3, 65.6, 61.5, 50.6, 47.7, 45.3, 28.6 (2 C), 25.7, 24.1.
Synthesis 2010, No. 3, 520–526 © Thieme Stuttgart · New York

524
K. Murai et al.
PAPER
HRMS (EI): m/z [M]+ calcd for C17H23N3O: 285.1841; found:
and NBS (33.3 mg, 0.187 mmol) in 1,4-dioxane (1.7 mL) to give 4h
285.1836.
after SiO2 column chromatography (hexane–EtOAc, 1:3).
Yield: 41.0 mg (75%); colorless oil.
Imidazoline 4e
IR (KBr): 3327, 2964, 2926, 2864, 1643, 1600, 1494, 1454, 1184,
962, 700 cm–1.
1H NMR (400 MHz, CD3OD): d = 7.27–7.73 (m, 10 H), 4.53 (s, 2
H), 4.41 (s, 2 H), 3.31 (s, 2 H), 1.16 (s, 6 H).
13C NMR (100.5 MHz, CD3OD): d = 165.4, 159.4, 137.1, 137.0,
129.9, 129.7, 129.4, 129.1, 128.7, 52.2, 47.8, 28.3.
The reaction was carried out for 1 h according to the typical proce-
dure with 1,2-ethylenediamine (29.0 mg, 0.483 mmol), N,N-diben-
zyl-2-oxoacetamide hemihydrate (149 mg, 0.284 mmol), and NBS
(97.7 mg, 0.549 mmol) in 1,4-dioxane (5.0 mL) to give 4g after
SiO2 column chromatography (EtOAc–Et3N, 40:1).
Yield: 116.0 mg (82%); colorless solid; mp 127–128 °C.
HRMS (FAB): m/z [M + H]+ calcd for C20H24N3O: 322.1919;
found: 322.1925.
IR (KBr): 3315, 1658, 1614, 1494, 1452, 1429, 1180, 1031, 731,
698 cm–1.
1H NMR (270 MHz, CDCl3): d = 7.38–7.21 (m, 10 H), 5.46 (br s, 1
Imidazole 5
Colorless solid.
H), 5.07 (s, 2 H), 4.53 (s, 2 H), 4.00 (br s, 2 H), 3.49 (br s, 2 H).
13C NMR (67.8 MHz, CDCl3): d = 161.8, 159.9, 136.6, 136.1,
128.7, 128.6, 128.2, 127.9, 127.6, 127.5, 50.7, 47.5.
HRMS (FAB): m/z [M + H]+ calcd for C18H20N3O: 294.1606;
found: 294.1618.
IR (KBr): 3180, 1599, 1519, 1471, 1444, 1427, 1384, 1226, 1199,
767, 698 cm–1.
1H NMR (400 MHz, CD2Cl2): d = 12.05 (br s, 1 H), 7.62 (d, J = 7.3
Hz, 2 H), 7.50 (dd, J = 5.0, 2.3 Hz, 2 H), 7.38–7.21 (m, 6 H), 4.30
(t, J = 6.8 Hz, 2 H), 3.48 (t, J = 6.8 Hz, 2 H), 2.00 (quint, J = 6.8 Hz,
2 H), 1.85 (quint, J = 6.8 Hz, 2 H).
13C NMR (100.5 MHz, CD2Cl2): d = 157.8, 141.1, 138.5, 134.8,
130.7, 129.5, 128.63, 128.56, 128.3, 127.6, 127.0, 49.2, 47.2, 26.7,
23.7.
Imidazoline 4f
The reaction was carried out for 4 h according to the typical proce-
dure with 1,2-ethylenediamine (40 mL, 0.598 mmol), N-benzyl-2-
oxoacetamide (110.8 mg, 0.679 mmol), and NBS (117 mg, 0.658
mmol) in 1,4-dioxane (6.0 mL) to give 4f after SiO2 column chro-
matography (EtOAc–MeOH–Et3N, 15:1:1).
HRMS (FAB): m/z [M + H]+ calcd for C20H20N3O: 318.1606;
found: 318.1615.
Yield: 115.5 mg (95%); colorless solid; mp 186 °C.
IR (KBr): 3302, 3161, 1664, 1599, 1500, 1296, 1276, 977, 746, 715,
694 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.92 (t, J = 6.4 Hz, 1 H), 7.31–
7.19 (m, 5 H), 6.95 (s, 1 H), 4.30 (d, J = 6.4 Hz, 2 H), 3.54 (br s, 4
Synthesis of Benzimidazole 6a; Typical Procedure
1,2-Phenylenediamine (14.5 mg, 0.134 mmol) and glyoxamide
hemihydrate (2a; 20.1 mg, 0.074 mmol) was dissolved in MeOH
(1.35 mL) and stirred at r.t. for 1 h. To the resulting solution, urea
hydrogen peroxide (25.2 mg, 0.268 mmol) was added and the reac-
tion was stirred for 22 h at 40 °C. After the reaction was complete
(judged by TLC), sat. aq Na2S2O3 (2 mL) and H2O (20 mL) were
added and the reaction mixture was extracted with CH2Cl2 (3 × 15
mL). The organic layer was dried over Na2SO4, and evaporated in
vacuo. The residue was purified by SiO2 column chromatography
(EtOAc) to give benzimidazole 6a.
H).
13C NMR (100.5 MHz, DMSO-d6): d = 160.0, 159.2, 139.1, 128.2,
127.3, 126.8, 42.0.
HRMS (FAB): m/z [M + H]+ calcd for C11H14N3O: 204.1137;
found: 204.1136.
Imidazoline 4g
The reaction was carried out for 1 h according to the typical proce-
dure with 1,2-ethylenediamine (30.4 mg, 0.506 mmol), (2,3-dihy-
droindol-1-yl)oxoacetaldehyde hemihydrate (101.1 mg, 0.275
mmol), and NBS (97.7 mg, 0.549 mmol) in 1,4-dioxane (5.0 mL) to
give 4g after SiO2 column chromatography (EtOAc–MeOH–Et3N,
20:1:1).
Yield: 20.1 mg (70%); colorless solid; mp 238 °C.
IR (KBr): 3180, 1604, 1529, 1491, 1448, 1435, 1404, 748 cm–1.
1H NMR (300 MHz, CDCl3): d = 12.0 (br s, 1 H), 7.85 (d, J = 9.0
Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.38–7.26 (m, 2 H), 4.38 (t,
J = 6.9 Hz, 2 H), 3.84 (t, J = 6.9 Hz, 1 H), 2.13–1.94 (m, 4 H).
13C NMR (75.5 MHz, CDCl3): d = 158.4, 145.9, 143.6, 133.3,
124.7, 122.7, 120.9, 112.0, 49.4, 47.7, 26.6, 23.7.
HRMS (FAB): m/z [M + H]+ calcd for C12H14N3O: 216.1137;
found: 216.1160.
Yield: 108.3 mg (99%); pale-pink solid; mp 106–107 °C.
IR (KBr): 1643, 1593, 1483, 1402, 912, 742 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.25 (d, J = 8.7 Hz, 1 H), 7.26–
7.20 (m, 2 H), 7.09 (t, J = 0.9 Hz, 1 H), 5.58 (br s, 1 H), 4.59 (t,
J = 8.1 Hz, 2 H), 4.09 (br s, 2 H), 3.49 (br s, 2 H), 3.17 (t, J = 8.1
Hz, 2 H).
13C NMR (67.8 MHz, CDCl3): d = 160.8, 158.3, 142.7, 132.6,
127.3, 124.8, 124.7, 118.0, 50.4, 28.5.
HRMS (FAB): m/z [M + H]+ calcd for C12H14N3O: 216.1137;
found: 216.1116.
Benzimidazole 6b
The reaction was carried out for 8 h according to the typical proce-
dure with 1,2-phenylenediamine (14.4 mg, 0.133 mmol), N,N-
dibenzyl-2-oxoacetamide hemihydrate (38.4 mg, 0.073 mmol), and
urea hydrogen peroxide (25.1 mg, 0.267 mmol) in MeOH (1.3 mL)
to give 6b after SiO2 column chromatography (hexane–EtOAc,
3:1).
Anal. Calcd for C12H13N3O: C, 66.96; H, 6.09; N, 19.52. Found: C,
66.83; H, 6.09; N, 19.46.
Yield: 26.5 mg (58%); colorless solid; mp 173 °C.
IR (KBr): 3281, 1614, 1516, 1406, 1319, 1244, 972, 738 cm–1.
Imidazoline 4h
1H NMR (300 MHz, CD2Cl2): d = 11.79 (br s, 1 H), 7.75–7.72 (m,
1 H), 7.48–7.23 (m, 13 H), 5.78 (s, 2 H), 4.79 (s, 2 H).
The reaction was carried out for 6 h according to the typical proce-
dure with 1,2-diamino-2-methylpropane (15.0 mg, 0.170 mmol),
N,N-dibenzyl-2-oxoacetamide hemihydrate (49 mg, 0.094 mmol),
Synthesis 2010, No. 3, 520–526 © Thieme Stuttgart · New York

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Synthesis of Imidazolines and Benzimidazoles
525
13C NMR (100.5 MHz, CD2Cl2): d = 160.5, 145.8, 143.7, 137.5,
136.9, 133.5, 129.1, 129.0, 128.4, 128.3, 127.93, 127.88, 125.3,
123.3, 121.2, 112.3, 51.4, 49.3.
Anal. Calcd for C17H15N3O: C, 73.63; H, 5.45; N, 15.15. Found: C,
73.60; H, 5.58; N, 15.17.
Benzimidazole 6f
HRMS (FAB): m/z [M + H]+ calcd for C22H20N3O: 342.1606;
The reaction was carried out for 23 h according to the typical pro-
cedure with N-phenyl-1,2-phenylenediamine (36.1 mg, 0.196
mmol), oxo(pyrrolidin-1-yl)acetaldehyde hemihydrate (29.3 mg,
0.108 mmol), and urea hydrogen peroxide (36.9 mg, 0.392 mmol)
in MeOH (2.0 mL) to give 6f after chromatographic purification on
two SiO2 columns (hexane–EtOAc, 1:1, then CH2Cl2–EtOAc, 1:1).
found: 342.1601.
Anal. Calcd for C22H19N3O: C, 77.40; H, 5.61; N, 12.31. Found: C,
77.53; H, 5.80; N, 12.31.
Benzimidazole 6c
The reaction was carried out for 4.5 h according to the typical pro-
cedure with N-methyl-1,2-phenylenediamine (23.4 mg, 0.192
mmol), oxo(pyrrolidin-1-yl)acetaldehyde hemihydrate (28.7 mg,
0.106 mmol), and urea hydrogen peroxide (36.1 mg, 0.384 mmol)
in MeOH (1.9 mL) to give 6c after SiO2 column chromatography
(hexane–EtOAc, 1:1→1:3).
Yield: 50.1 mg (88%); colorless solid; mp 128 °C.
1H NMR (300 MHz, CDCl3): d = 7.88–7.85 (m, 1 H), 7.57–7.26 (m,
8 H), 3.82 (t, J = 6.6 Hz, 2 H), 3.57 (t, J = 6.6 Hz, 2 H), 1.95–1.88
(m, 4 H).
13C NMR (100 MHz, CDCl3): d = 159.0, 146.2, 141.8, 136.2, 135.7,
129.5, 128.6, 126.4, 124.6, 123.3, 120.7, 111.0, 48.6, 46.2, 26.1,
24.0.
IR (KBr): 1649, 1518, 1498, 1431, 1373, 765, 750 cm–1.
HRMS (FAB): m/z [M + H]+ calcd for C18H18N3O: 292.1450;
Yield: 39.6 mg (90%); colorless solid; mp 73 °C.
IR (KBr): 2926, 1631, 1504, 1460, 1414, 1369, 1330, 742 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.80 (d, J = 7.8 Hz, 1 H), 7.44–
7.29 (m, 3 H), 4.05 (s, 3 H), 4.03–3.99 (m, 2 H), 3.73–3.69 (m, 2 H),
2.00–1.95 (m, 4 H).
found: 292.1450.
13C NMR (75.5 MHz, CDCl3): d = 159.4, 145.5, 141.5, 135.6,
124.2, 122.8, 120.7, 110.0, 49.4, 46.6, 31.7, 26.4, 24.0.
Anal. Calcd for C18H17N3O: C, 74.20; H, 5.88; N, 14.42. Found: C,
74.29; H, 5.99; N, 14.45.
HRMS (FAB): m/z [M + H]+ calcd for C13H16N3O: 230.1293;
found: 230.1287.
Acknowledgment
Benzimidazole 6d
This work was financially supported by a Grant-in-Aid for Scienti-
fic Research (B) and for Young Scientists (B).
The reaction was carried out for 5 h according to the typical proce-
dure with N-methyl-1,2-phenylenediamine (20.0 mg, 0.164 mmol),
N-benzyl-2-oxoacetamide (29.4 mg, 0.180 mmol), and urea hydro-
gen peroxide (30.0 mg, 0.328 mmol) in MeOH (1.65 mL) to give 6d
after SiO2 column chromatography (hexane–EtOAc, 4:1).
References
(1) For recent examples, see: (a) Curini, M.; Epifano, F.;
Montanari, F.; Rosati, O.; Taccone, S. Synlett 2004, 1832.
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Yield: 33.4 mg (77%); colorless solid; mp 140 °C.
IR (KBr): 3338, 1668, 1535, 1464, 1394, 746, 729 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.16 (br s, 1 H), 7.74 (d, J = 7.5
Hz, 1 H), 7.45–7.25 (m, 8 H), 4.64 (d, J = 6.0 Hz, 2 H), 4.25 (s, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 159.7, 143.2, 140.9, 137.6,
136.9, 128.7, 127.8, 127.6, 124.6, 123.4, 120.5, 110.4, 43.3, 32.0.
HRMS (FAB): m/z [M + H]+ calcd for C16H16N3O: 266.1293;
found: 266.1297.
Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found: C,
72.33; H, 5.83; N, 15.87.
(3) For recent reviews, see: (a) Crouch, R. D. Tetrahedron
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Benzimidazole 6e
The reaction was carried out for 6.75 h according to the typical pro-
cedure with N-methyl-1,2-phenylenediamine (24.3 mg, 0.199
mmol), (2,3-dihydroindol-1-yl)oxoacetaldehyde hemihydrate (40.3
mg, 0.109 mmol), and urea hydrogen peroxide (37.4 mg, 0.398
mmol) in MeOH (2.0 mL) to give 6e after SiO2 column chromatog-
raphy (hexane–EtOAc, 7:1).
(4) Murai, K.; Morishita, M.; Nakatani, R.; Kubo, O.; Fujioka,
H.; Kita, Y. J. Org. Chem. 2007, 72, 8947.
(5) For examples, see: (a) Nakahara, T.; Okamoto, N.; Suzuki,
K.; Kanie, O. Carbohydr. Res. 2008, 343, 1624.
(b) Nakamura, S.; Hyodo, K.; Nakamura, Y.; Shibata, N.;
Toru, T. Adv. Synth. Catal. 2008, 350, 1443.
(6) For examples, see: (a) Valdez-Padilla, D.; Rodoríguez-
Morales, S.; Hernández-Campos, A.; Hernández-Luis, F.;
Yépez-Mulia, L.; Tapia-Contreras, A.; Castillo, R. Bioorg.
Med. Chem. 2009, 17, 1724. (b) Guo, Q.; Chandrasekhar, J.;
Ihle, D.; Wustrow, D. J.; Chenard, B. L.; Krause, J. E.;
Hutchison, A.; Alderman, D.; Cheng, C.; Cortight, D.;
Broom, D.; Kershaw, M. T.; Simmermacher-Mayer, J.;
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Grice, C. A.; Jablonowski, J. A.; Shah, C. R.; Kwok, A. K.;
Yield: 42.8 mg (78%); pale-red solid; mp 145 °C.
IR (KBr): 1639, 1595, 1502, 1479, 1460, 1398, 1375, 1323, 771,
758, 738 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.33 (d, J = 8.1 Hz, 1 H), 7.83 (d,
J = 8.1 Hz, 1 H), 7.46–7.25 (m, 5 H), 7.12 (d, J = 7.5 Hz, 1 H), 4.65
(t, J = 8.4 Hz, 2 H), 4.07 (s, 3 H), 3.20 (t, J = 8.4 Hz, 2 H).
13C NMR (75.5 MHz, CDCl3): d = 158.8, 145.3, 142.7, 141.4,
135.7, 132.6, 127.4, 124.83, 124.80, 124.5, 123.1, 120.9, 117.9,
110.1, 50.9, 31.8, 28.5.
HRMS (FAB): m/z [M + H]+ calcd for C17H16N3O: 278.1293;
found: 278.1296.
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526
K. Murai et al.
PAPER
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Synthesis 2010, No. 3, 520–526 © Thieme Stuttgart · New York