Synthesis of 1,2-bisubstituted benzimidazole: 1,3-Shift mechanism catalyzed by acid or base

Article abstract of DOI:10.1002/jhet.531

Benzimidazole ring system is a useful nucleus in medicinal chemistry and is found in many biologically active compounds. An efficient approach for the synthesis of 1,2-bisubstituted benzimidazoles is presented in this article, and the mechanism of the con

Full text of DOI:10.1002/jhet.531

230
Synthesis of 1,2-Bisubstituted Benzimidazole: 1,3-Shift
Mechanism Catalyzed by Acid or Base
Vol 48
Ya-Mu Xia,* Jia You, and Feng-Ke Yang
College of Chemical Engineering, Qingdao University of Science and Technology,
Qingdao 266042, People’s Republic of China
*E-mail: xiaym@qust.edu.cn
Received December 8, 2009
DOI 10.1002/jhet.531
Published online 7 October 2010 in Wiley Online Library (wileyonlinelibrary.com).
Benzimidazole ring system is a useful nucleus in medicinal chemistry and is found in many biologi-
cally active compounds. An efficient approach for the synthesis of 1,2-bisubstituted benzimidazoles is
presented in this article, and the mechanism of the condensation from 2-[(2-aminophenylimino)phenyl-
methyl]-4-bromophenol, using piperdine or acetic acid as catalyst, is studied. 1,3-Shift of negative
hydrogen ion is the key step for this rearrangement reaction, and the influences of catalyst, temperature,
substrate, and solvent are also investigated.
J. Heterocyclic Chem., 48, 230 (2011).
INTRODUCTION
di-Schiff base may be conveniently prepared at room
temperature. However, in refluxing condition, it is con-
verted into the benzimidazole. Their transformations
into the corresponding benzimidazoles seemed to rest
upon the reaction temperature, but this has turned out to
be insufficient for explaining our new findings as only
di-Schiff base was obtained in the refluxing condition in
certain reactions. To gain better insight into the conden-
sation mechanism to confirm whether di-Schiff base was
the intermediate in the formation of benzimidazole, we
decided to investigate the reaction of a variety of alde-
hydes with mono-Schiff base as this would provide
more information about the mechanism.
Benzimidazoles are very useful intermediates for the
development of molecules of pharmaceutical or biologi-
cal interest [1–4]. In general, nitrogen-containing or-
ganic compounds and their metal complexes display a
wide range of biological activities [5–8]. Over the past
few years, benzimidazole derivatives have been used as
anti-inflammatory, analgesic, antifungal and antiviral
agents, and thrombin receptor antagonists [9–15]. Apart
from the above-mentioned activities, benzimidazoles
possess some interesting efficacy of antiallergic, antipro-
liferative, antitumor, anti-HIV, antibacterial, and antitu-
berculosis activities [16–21]. Because of the broad spec-
trum of activities reported in the literature so far, the
efficient synthesis of important diversely functionalized
substituted benzimidazoles has attracted recent attention
[22–27]. In particular, the discovery of 1,2-bisubstituted
benzimidazoles have increased this interest, which can
be attributed not only to their good nucleophilic abilities
but their diverse biological and pharmacological proper-
ties as well [28]. In our early study of this research, we
reported an efficient approach for the synthesis of 1,2-
bisubstituted benzimidazoles [29], and surprisingly, we
observed the cyclization of di-Schiff bases to benzimida-
zole derivatives, and such benzimidazole derivatives can
also be directly obtained by condensation of aldehydes
and mono-Schiff base under refluxing condition. This
RESULTS AND DISCUSSION
Chemistry. All compounds have been synthesized by
the reaction of Schiff base 3 with different aldehydes
under three different reaction conditions as follows and
providing various compounds in quantitative yield: (A)
using piperidine as catalyst by refluxing in ethanol; (B)
using acetic acid as catalyst at room temperature in
ethanol; and (C) using acetic acid as catalyst by reflux-
ing in ethanol. The condensed products 4 and 5 were
purified by recrystallization from a proper solution. The
1H-NMR spectra of the proton on imine C of di-Schiff
base appeared at d 8.0 ppm, whereas disappeared in its
C
V
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January 2011
Synthesis of 1,2-Bisubstituted Benzimidazole: 1,3-Shift Mechanism
Catalyzed by Acid or Base
231
Scheme 1
1
corresponding benzimidazole H-NMR spectrum, and its
proton on the asymmetric C shifted upfield to the area
of benzene proton and was hardly identified. The precur-
sor Schiff base derivative 3 was synthesized by the con-
densation of 5-bromo-2-hydroxybenzophenone 2 with
1,2-diaminobenzene, and compound 2 was synthesized
by the reaction of benzoic acid 4-bromo-phenyl ester 1
with anhydrous aluminum chloride via Fries rearrange-
ment (Scheme 1). Spectral data and elemental analyses
of compounds 1–5 fully supported the structures
assigned to them, and the structures of compounds 3,
4c, and 5g were further confirmed by X-ray crystallo-
graphic analyses (Fig. 1). The results are shown in
Table 1.
directly by the addition of acetic acid. Mono-Schiff base
3 was transformed into di-Schiff base 4 at room temper-
ature. However, higher temperature could bring about an
intramolecular rearrangement. The nitrogen atom in the
imino group attacked the secondary amine carbon to
close the five-membered ring, owing to steric hindrance
of the substituents on imino carbon. After 1,3-shift of
negative hydrogen ion, benzimidazoles 5 was obtained.
To confirm the reaction mechanism, different solvents
such as DMF, EtOH, and toluene were chosen as reac-
tion solvents. Aprotic solvent DMF showed fast reaction
rate than nonpolar solvent and protic solvent due to sol-
vent effect, and this result exhibited that the reaction in-
termediate was charged. Protic solvent EtOH also
showed good reaction rate and product yield, this was
because benzimidazoles had a poor solubility in EtOH
and thus promoted the reaction. A number of experi-
ments were conducted to verify the mechanism. For
example, the di-Schiff bases of m-nitrobenzaldehyde, p-
bromobenzaldehyde, and thiophene formaldehyde could
be conveniently prepared at room temperature, while the
corresponding benzimidazoles can be obtained at higher
temperature. Such benzimidazoles could be directly
obtained in refluxing condition. However, in none of
these cases the formation di-Schiff base was observed.
Thus, temperature had significant influence in the reac-
tion, and from the mechanism, we inferred that the two
courses are competitive and that the formation of di-
Schiff base is reversible.
The results from Table 1 showed that the reaction
gave different products because of the reaction condi-
tions and substrates we chose. The aldehydes with small
steric hindrance could easily react with Schiff base, and
the reaction finished in 3 h in high yield, while 4-ben-
zyloxy-3-methoxy-benzaldehyde on condensation with
2-[(2-aminophenylimino)phenylmethyl]-4-bromophe-
nol gave a very low product yield even at prolonged
reaction time. The reaction results were different
when catalyst changed, benzimidazole was obtained
in the presence of acetic acid and/or a higher reac-
tion temperature, while using piperidine as catalyst,
di-Schiff base or no reaction product was obtained.
The mechanism of reaction. A mechanism for the
formation of benzimidazole catalyzed by acetic acid was
proposed as illustrated in Scheme 2. First, carbonyl
group was activated to react with mono-Schiff base 3
Another probable mechanism for the formation of
benzimidazole catalyzed by piperidine is shown in
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232
Y.-M. Xia, J. You, and F.-K. Yang
Vol 48
Figure 1. X-ray ORTEP drawings of 3, 4c, and 5g.
Scheme 3. Piperidine first reacted with aldehyde to form
quaternary ammonium salt and then condensed with 2-
[(2-aminophenylimino) phenylmethyl]-4-bromophenol to
obtain di-Schiff base and then rearranged to benzimida-
zole. The di-Schiff base proved to be the intermediate,
as both of the di-Schiff base and benzimidazole were
detected in the same reaction.
hydroxy-benzaldehyde, side reactions were observed
with low yield or even no reaction product. The influ-
ence of the position of substituent should also be taken
into account. When the phenyl group had a hydroxyl
group in the ortho-position, a complex mixture was
obtained. The lack of reactivity could be explained by
the influence of hydrogen bond that was formed between
hydroxyl group and aldehyde group of salicylaldehyde.
In some cases, the impact of the site of the substituent
was even larger than steric hindrance and catalyst effect.
Finally, to clarify the issue of whether the two courses
were competitive and the formation of di-Schiff base was
reversible in the presence of acid, the di-Schiff bases
were subjected to the acidic refluxing condition to inves-
tigate the formation of all possible products (Table 2).
The substituent on aldehyde had significant impact on
the reaction kinetics. Electron-withdrawing substituent
such as nitro group and nitrile group could lower the
electron density on the oxygen atom on aldehyde group,
which could lower the alkalinity and thus lower the reac-
tivity for the condensation. However, when there is more
than one activating group on aldehyde, such as 4-ben-
zyloxy-3-methoxy-benzaldehyde and 3,5-dibromo-4-
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Synthesis of 1,2-Bisubstituted Benzimidazole: 1,3-Shift Mechanism
Catalyzed by Acid or Base
233
Table 1
Preparation of compounds 4a–h and 5a–h.
Entry
Substrate
Reaction condition
Yield (%)
Product
1
p-Bromobenzaldehyde
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
85
86
82
81
80
86
62
Di-Schiff base 4a
Di-Schiff base 4a
Benzimidazole 5a
Di-Schiff base 4b
Benzimidazole 5b
Benzimidazole 5b
Di-Schiff base 4c
–
Di-Schiff base 4c
Benzimidazole 5d
Benzimidazole 5d
Benzimidazole 5d
Benzimidazole 5e
Benzimidazole 5e
Benzimidazole 5e
Di-Schiff base 4f
—
Di-Schiff base 4f
Di-Schiff base 4g
Di-Schiff base 4g
Benzimidazole 5g
Di-Schiff base 4h
Di-Schiff base 4h
Benzimidazole 5h
2
3
4
5
6
7
8
p-Dimethylaminobenzaldehyde
Salicylaldehyde
66
80
83
87
75
70
62
43
Benzaldehyde
Furaldehyde
4-Benzyloxy-3-methoxy-benzaldehyde
Thiophene formaldehyde
m-Nitrobenzaldehyde
47
88
84
89
58
56
63
Reaction condition: (A) catalyzed by piperidine in refluxing ethanol; (B) catalyzed by acetic acid at room temperature in ethanol; (C) catalyzed by
acetic acid in refluxing ethanol.
Scheme 2
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234
Y.-M. Xia, J. You, and F.-K. Yang
Vol 48
Scheme 3
Interestingly, benzimidazoles were observed in these
firmed to be an intermediate in the presence of piperi-
dine. We also found that the reaction temperature, sol-
vent, and the structures of aldehydes exerted substantial
influences on the products.
reactions. Hence, it was reasonable to confirm that
there existed two competitive courses in the reaction
and that the formation of di-Schiff base was reversible.
The aforementioned results strongly favored this mech-
anism, particularly, if one takes into account our find-
ings that mono-Schiff base and benzimidazole were
both found when heated, the di-Schiff base was heated
at refluxing in the presence of acetic acid. 4-Bromo-2-
{[2-(2-hydroxybenzylideneamino)phenylimino] phenyl
methyl}phenol was difficult to transform into benzim-
idazole because a tetratomic ring was formed through
the reaction between the oxygen atom on hydroxyl
group and carbocation, thus lowering the electrophilic-
ity of carbocation.
EXPERIMENTAL
General. Melting points were taken on Gallenkamp melt-
ing point apparatus and are uncorrected. Infrared spectra
1
were recorded on a Nicolet NEXUS 670 FTIR. The H-NMR
and 13C-NMR spectra were recorded on Brucker AM-500
MHz spectrometers. HRMS were obtained on a Bruker Dal-
tonics APEXII47e spectrometer. Flash column chromatogra-
phy was performed on silica gel (200–300 mesh) and TLC
inspections on silica gel GF254 plates. Single crystal was
measured on an Enraf-Nonius CAD-4 diffractometer. Cell
refinement: CAD-4 software; data reduction: NRCVAX; pro-
gram(s) used to solve structure: SHELX97; program(s) used
to refine structure: SHELX97; molecular graphics:
SHELXL97/PC; software used to prepare material for publi-
cation: WinGX.
CONCLUSIONS
We have reported an efficient methodology for the
synthesis of 1,2-bisubstituted benzimidazoles by using
acetic acid and piperidine as catalysts. On this basis,
two possible mechanisms have been presented. The
mechanism of reaction involved 1,3-shift of negative
hydrogen ion. It has been confirmed that there were two
competitive courses in the synthesis of benzimidazoles
and that the formation of di-Schiff base was reversible
in the presence of acid, while di-Schiff base was con-
5-Bromo-2-hydroxybenzophenone (2). 4-Bromophenol (17.3
g, 0.1 mol) was dissolved in absolute diethyl ether (150 mL).
The appropriate pyridine (7.9 g, 0.1 mol) was added to the so-
lution, and benzoyl chloride (14.1 g, 0.1 mol) was added to
the mixture, which rapidly became hot, and the white solid
was precipitated from solution. The precipitate was filtered off
and then placed in the flask at 120ꢀC for about 10 min. The
flask was then heated to 160ꢀC. Anhydrous aluminum chloride
(20 g, 0.15 mol) was added to the flask in portions of about
Table 2
Acetic acid-catalyzed intramolecular rearrangement of di-Schiff base to benzimidazole.a
Entry
Substrate
Yieldb (%)
87
Product
1
4-Bromo-2-{[2-(4-bromo-benzylidene-amino)
phenylimino]phenylmethyl}phenol
4-Bromo-2-{[2-(4-dimethylamino-benzylideneamino)
phenylimino]phenylmethyl}phenol
4-Bromo-2-{[2-(2-thienylamino)-
4-Bromo-2-{a-[1-(4-bromo-phenyl)
benzoimidazol-2-yl]-benzyl}phenol
4-Bromo-2-{a-[1-(4-dimethylamino-phenyl)
benzoimidazol-2-yl]-benzyl}-phenol
4-Bromo-2-{a-[1-(2-thienyl)-
benzoimidazol-2-yl]-benzyl}phenol
4-Bromo-2-{a-[1-(2-nitro-phenyl)-
benzoimidazol-2-yl]-benzyl}phenol
2
3
4
85
89
79
phenylimino]phenylmethyl}phenol
4-Bromo-2-{[2-(2-nitro-benzylidene-amino)
phenylimino]phenylmethyl}phenol
a Reaction conditions: di-Schiff base (0.1 mmol), acetic acid (0.5 mmol), and heated at refluxing.
b Isolated yield.
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Synthesis of 1,2-Bisubstituted Benzimidazole: 1,3-Shift Mechanism
Catalyzed by Acid or Base
235
10 g, which rapidly became hot, evolving fumes of HCl. After
2 h, the flask was allowed to cool to room temperature. Hydro-
chloric acid (5%, 150 mL) was then poured into the flask and
was allowed to stand for 24 h. The hydrochloric acid was then
decanted from the flask. The yellow solid was washed twice
with water and then recrystallized from hot ethanol to give
compound 2 as yellow crystals in 47.5% yield. Mp 77–79ꢀC.
IR (KBr, cmꢁ1) m: 3430 (OH), 1626 (C¼¼O), 832, 768, 699.
1H-NMR(CDCl3, 500 MHz) d: 6.95–6.97 (d, 1H, CH¼¼CBr),
7.49–7.67 (m, 7H, Ar-H), 11.91 (s, 1H, Ar-OH); 13C-NMR
(CDCl3, 125 MHz) d: 110.21, 120.31, 120.43, 128.55, 129.10,
132.37, 135.33, 137.10, 138.90, 162.07, 200.46 (C¼¼O). Anal.
calcd for C13H9BrO2: C 56.35, H 3.27, Br 28.83; found: C
56.30, H 3.26, Br 28.84. HRMS calcd for C13H10BrO2
(MþHþ): 278.12; found: 278.10.
16.98, N 5.97. HRMS calcd for C26H20BrN2O2 (MþHþ):
472.34; found: 472.31. Crystal data for 4c: C26H19BrN2O2, Mr
¼ 471.34, crystal system ¼ triclinic, space group ¼ Pꢁ1, Z ¼
˚
˚
˚
2, a ¼ 9.1682 (18) A, b ¼ 9.7011 (19) A, c ¼ 12.986 (3) A, a
¼ 90.87 (3)ꢀ, b ¼ 108.79 (3)ꢀ, c ¼ 90.09 (3)ꢀ, V ¼ 1089 (4)
3
A , D ¼ 1.436 mg cmꢁ3, l ¼ 1.91 mmꢁ1, reflections meas-
˚
ured ¼ 5132, independent reflections ¼ 4348, reflections with
I > 2r(I) ¼ 3028, with Rint ¼ 0.018, T ¼ 295 (2) K, R[F2 >
2
2
´
2o(F )] ¼ 0.034, wR(F ) ¼ 0.091, S ¼ 1.03.
4-Bromo-2-{[2-(4-benzyloxy-3-methoxy-benzylideneamino)-
phenylimino]phenylmethyl}phenol (4f). Yellow solid. Mp
176–178ꢀC. IR (KBr, cmꢁ1) m: 3429 (OH), 1695 (C¼¼N), 1240
(CAO); 1H-NMR(CDCl3, 500 MHz) d: 3.95 (s, 3H, OCH3),
5.24 (s, 2H, CH2), 6.66–7.75 (m, 20H, Ar-H), 8.16 (s, 1H,
N¼¼CAH), 14.99 (s, 1H, Ar-OH). 13C-NMR (CDCl3, 125
MHz): d: 56.01, 70.87, 109.30, 109.62, 112.73, 118.32,
120.00, 121.59, 122.44, 124.25, 125.65, 126.21, 127.27,
128.07, 128.34, 128.38, 128.56, 128.71, 129.30, 130.15,
133.99, 134.12, 135.69, 136.64, 140.24, 144.00, 150.10,
151.10, 159.01, 162.07, 171.51 (N¼¼C). Anal. calcd for
C34H27BrN2O3: C 69.04, H 4.60, Br 13.51, N 4.74; found: C
2-[(2-Aminophenylimino)phenylmethyl]-4-bromophenol (3). 5-
Bromo-2-hydroxybenzophenone (27.7 g, 0.1 mol), 1,2-diami-
nobenzene (10.8 g, 0.1 mol), piperidine (10.2 g, 0.12 mol),
and triethylorthoformate (20 mL) were refluxed in absolute
ethanol (120 mL) until the red-orange crystalline product
started to precipitate from solution. The solution was allowed
to cool to room temperature, and the product was collected by
filtration and then washed twice with hot ethanol to give com-
pound 3 as red-orange crystals in 65.1% yield. Mp 193–
195ꢀC. IR (KBr, cmꢁ1) m: 3460 (OH), 3367 (NH), 1623
69.05,
H 4.64, Br 13.52, N 4.71. HRMS calcd for
C34H28BrN2O3 (MþHþ): 592.49; found: 592.44.
4-Bromo-2-{ꢀ-[1-(2-thienyl)benzoimidazol-2-yl]-benzyl}phe-
nol (5g). Orange solid. Mp 243–244ꢀC; IR (KBr, cmꢁ1) m: 3426
(OH), 1510 (C¼¼N), 1442, 1420, 1370 (thiophene), 1297 (CAN);
1H-NMR (d6-DMSO, 500 MHz) d: 6.67–7.82 (m, 16H, Ar-H,
NACH, and thiophene), 10.22 (s, 1H, Ar-OH); 13C-NMR (d6-
1
(C¼¼N), 829, 743, 704; H-NMR (CDCl3, 500 MHz) d: 6.23–
7.43 (m, 12H, Ar-H), 14.470 (s, 1H, Ar-OH); 13C-NMR
(CDCl3, 125 MHz) d: 109.71, 115.47, 118.30, 119.86, 121.45,
121.80, 126.09, 128.25 (d), 128.42 (d), 129.51, 133.39, 133.50,
134.13, 135.89, 138.84, 161.39, 174.05 (N¼¼C). Anal. calcd
for C19H15BrN2O: C 62.14, H 4.12, Br 21.76, N 7.63; found:
C 62.12, H 4.13, Br 21.75, N 7.64. HRMS calcd for
C19H15BrN2O (MþHþ): 368.23; found: 368.29. Crystal data
for 3: C19H15BrN2O, Mr ¼ 367.23, crystal system ¼ triclinic,
DMSO 125 MHz) d: 59.26 (
), 110.28, 112.62, 118.09,
119.94, 122.59, 123.13, 127.74, 128.00, 128.57, 129.57, 130.28,
131.39, 132.72, 132.82, 135.79, 137.82, 143.33, 149.02, 155.33
(N¼¼C). Anal. calcd for C24H17BrN2OS: C 62.48, H 3.71, Br
17.32, N 6.07, S 6.95; found: C 62.45, H 3.70, Br 17.30, N
6.09,
S
6.91, HRMS calcd for C24H18BrN2OS (MþHþ):
461.37; found: 461.43. Crystal data for 5g: C24H17BrN2OS, Mr
¼ 461.37, crystal system ¼ monoclinic, space group ¼ P21/c, Z
space group ¼ Pꢁ1, Z ¼ 2, a ¼ 8.4504 (17) A, b ¼ 9.4206
˚
ꢀ
ꢀ
˚
˚
(19) A, c ¼ 11.141 (2) A, a ¼ 68.94 (3) , b ¼ 85.40 (3) , c
˚
¼ 4, a ¼ 13.623 (3), b ¼ 9.6472 (19), c ¼ 16.962 (3) A, a ¼
¼ 78.31 (3) , V ¼ 810.5 (3) A , D ¼ 1.505 mg cmꢁ3, l ¼
3
ꢀ
˚
3
ꢀ
ꢀ
ꢀ
˚
90.00 , b ¼ 111.98 (3) , c ¼ 90.00 , V ¼ 2067.2 (8) A , D ¼
2.54 mmꢁ1, reflections measured ¼ 3365, independent reflec-
1.482 mg cmꢁ3, l ¼ 2.11 mmꢁ1, reflections measured ¼ 9403,
tions ¼ 2785, reflections with I > 2r(I) ¼ 2094, with Rint
¼
independent reflections ¼ 4334, reflections with I > 2r(I) ¼
0.018, T ¼ 295 (2) K, R[F2 > 2o(F )] ¼ 0.038, wR(F ) ¼
2
2
2709, with Rint ¼ 0.033, T ¼ 295 (2) K, R[F2 > 2o(F )] ¼
2
´
´
0.042, wR(F2) ¼ 0.112, S ¼ 1.02.
0.099, S ¼ 1.03.
General procedure for the preparation of the compounds
(4) and (5). To a solution of 2-[(2-aminophenylimino)phenyl-
methyl]-4-bromophenol (36.7 g, 0.10 mol) in ethanol (120 mL),
corresponding aldehyde (0.10 mmol) was added and reacted
based on the three conditions as follows: (A) piperidine (10.2 g,
0.12 mol) and triethylorthoformate (12 mL), and the mixture
was heated at refluxing; (B) acetic acid (30 g, 0.5 mmol), and it
reacted at room temperature in ethanol; (C) acetic acid (30 g,
0.5 mmol), and it was heated at refluxing. The precipitated solid
was collected by filtration and washed twice with hot ethanol.
4-Bromo-2-{[2-(2-hydroxybenzylideneamino)phenylimino]-
phenylmethyl}-phenol(4c). Yellow solid. Mp 228–230ꢀC. IR
(KBr, cmꢁ1) m: 3429 (OH), 1595 (C¼¼N); 1H-NMR (CDCl3,
500 MHz) d: 6.82–7.60 (m, 17H, Ar-H), 8.40 (s, 1H, N¼¼CH),
12.98 (s, 1H, Ar-OH). 13C-NMR (CDCl3, 125 MHz) d:
109.56, 117.42, 118.29, 118.95, 119.20, 120.14, 120.92,
122.96, 125.79, 126.97, 128.08, 128.26, 129.28, 132.79,
133.28, 133.69, 134.18, 136.06, 139.74, 141.32, 161.13,
161.67, 162.46, 173.68 (N¼¼C). Anal. calcd for C26H19BrN2O2:
C 66.25, H 4.06, Br 16.95, N 5.94; found: C 66.23, H 4.02, Br
SUPPLEMENTARY MATERIAL
Crystallographic data for the structure analysis of the
compounds have been deposited with the Cambridge
Crystallographic Data Center, CCDC No. 657790 3,
672869 4c, 651531 5g. Copies of these information may
be obtained free of charge from The Director, CCDC,
12 Union Road, Cambridge, CB2 1EZ, UK (http://
www.ccdc.cam.ac.uk).
Acknowledgment. This work was financially supported by
Taishan Scholar Project of Shandong Province (No.
2006011036), China and Specialized Research Fund for the
Doctoral Program of Higher Education of China (No.
20093719120004), and Open Foundation of Chemical Engineer-
ing Subject, Qingdao University of Science and Technology,
China.
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Y.-M. Xia, J. You, and F.-K. Yang
Vol 48
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet