Selective synthesis of (1: H-benzo [d] imidazol-2-yl)(phenyl)methanone and quinoxaline from aromatic aldehyde and o-phenylenediamine

Article abstract of DOI:10.1039/c9ob00531e

We have designed a general, inexpensive, and versatile method for the synthesis of (1H-benzo[d]imidazol-2-yl)(phenyl)methanone and the formation of C-N bonds via an aromatic aldehyde and o-phenylenediamine. In the presence of N,N-dimethylformamide/sulfur, (1H-benzo[d]imidazol-2-yl)(phenyl)methanone was obtained; however, in the absence of sulfur, quinoxaline was obtained in 1,4-dioxane. A wide range of quinoxalines and (1H-benzo[d]imidazol-2-yl)(phenyl)methanones was obtained under mild conditions.

Full text of DOI:10.1039/c9ob00531e

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C9OB00531E
ARTICLE
Selective synthesis of (1H-benzo[d]imidazol-2-yl)(phenyl)-
methanone and quinoxaline from aromatic aldehyde and o-
phenylenediamine
Received 00th January 20xx,
Accepted 00th January 20xx
Zhenzhen Zhan, Haojie Ma, Xinfeng Cui, Pengbo Jiang, Jinghong Pu, Yixin Zhang, Guosheng Huang*
DOI: 10.1039/x0xx00000x
We have designed
a general, inexpensive, and versatile method for the synthesis of (1H-benzo[d]imidazol-2-
yl)(phenyl)methanone and formation of C−N bonds via aromatic aldehyde and o-phenylenediamine. In the presence of N,
N-dimethylformamide/sulfur, (1H-benzo[d]imidazol-2-yl)(phenyl)methanone was obtained, however, in absence of sulfur,
quinoxaline was collected in 1,4-dioxane. A wide range of quinoxaline and (1H-benzo[d]imidazol-2-yl)(phenyl)methanone
was obtained under mild conditions.
Provious works
N
Introduction
Cs2CO3 or Pd catalyst
DMF, 90oC
O
O
N
Cancer is the worldwide health problem and the most
frightening disease of human. Innovation and development of
new antimicrobial and anticancer inhibitors are fundamental
goals of medicinal chemistry.1 Benzimidazole is a privileged
pharmacophore encountered in a number of fundamental
cellular components and bioactive molecules.2 Owing to the
importance of benzimidazole derivatives ranging from natural
products to pharmaceuticals, the synthesis of benzimidazole
derivatives attracts a lot of interest.3 Indeed, a number of
important drugs used in different therapeutic areas contain a
benzimidazole moiety.4 The importance of heterocyclic
compounds is directly correlated with structures as they are
used in many biologically and pharmaceutically active
compounds.5 They shows significant biological activities, such as
antimicrobial,6 anticancer,7 analgesic,8 antispastic, antiallergic,9
N
H
N
H
N
N
Co catalyst
N
H
N
H
O
N
pyridine, NaOH
O
N
Cl
N
reflux
N
H
H
NH2
NH2
N
N
Ar1
Ar2
O
Rose Bengal sodium salt
LED bulb,RT,
Ar1
N
anxiolytic10
and
antithrombotic.11
Moreover,
(1H-
Ar2
benzoimidazol-2-yl)(phenyl)methanone compounds shows
anxiolytic and neuroprotective activities in human clinical
testing.12 However, it is difficult to achieve one-step synthesis
of (1H-benzo[d]imidazol-2-yl)(phenyl)methanone by simple
compound. Quinoxaline is a well-known and important nitrogen
heterocyclic compound with a wide range of biological and
pharmaceutical properties.13 In recent years, a large number of
literatures have reported its synthesis and application.14
Our works
O
N
S8 DMF
NH2
NH2
N
H
CHO
N
Ar
Base
1,4-dixoane
N
Scheme1: Representative strategies for the synthesis of (1H-
benzo[d]imidazol-2-yl)(phenyl)methanone and quinoxaline.
yl)(phenyl)methanone by Co/NHPI catalysts and 2-benzyl-1H-
benzo[d]imidazole.16 In 2010, Seref Demirayak et al got the
product through benzimidazole and acid chloride by pyridine,
base and reflux.17 Recently, many methods for the synthesis of
quinoxaline derivatives are reported.18 These quinoxaline
derivative moieties were synthesized by the condensation of o-
phenylenediamine with arylacetyl bromide or alkynes.19
However, some of them required longer reaction time, harsh
conditions, metal based catalyst and gives low yield of the
Owing to their importance, numerous benzimidazole
derivatives and quinoxaline derivatives were synthesized in the
last decades.15 In 2013, Laurent El Kaïm et al obtained (1H-
benzo[d]imidazol-2-yl)(phenyl)methanone
derivatives
by
metal-free aerobic oxidation of benzazole derivatives, then in
2017, Shannon S. Stahl collected (1H-benzo[d]imidazol-2-
a. State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous
Metal Chemistry and Resources Utilization of Gansu Province Department of
Chemistry Lanzhou University Lanzhou (P. R. China) E-mail:hgs@lzu.edu.cn
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Page 2 of 5
ARTICLE
desired products. Wan and wen et al completed the synthesis
of quinoxalin derivatives with enaminone and o- Table 1. Optimization of reaction conditions
phenylenediamine.20 Although several strategies for the
Journal Name
View Article Online
DOI: 10.1039/C9OB00531E
a
NH2
O
N
CHO
synthesis of (1H-benzo[d]imidazol-2-yl)(phenyl)methanone
catalyst
N
H
derivatives have been reported, the research for
environmentally benign and synthetically efficient protocols is
NH2
solvent
1a
2a
3aa
still highly desirable. So, finding a new way for efficient
Entr Cata(equiv. Additive(equiv. Solvent/atmos Yiel
synthesis of quinoxalinone cores is still under consideration. In
this work, we synthesized (1H-benzo[d]imidazol-2-
yl)(phenyl)methanone derivatives by the sulfur-promoted
phenyl acetaldehydes with o-phenylenediamine. Compared to
previous work, our work can be completed by one step without
transition metal catalyst.
y
)
)
-
-
phere
d
(%)
41
nr
nr
1
2
3
S8(3.0)
no
S8(3.0)
DMSO/air
DMSO/air
1,4-
dioxane/air
DMF/air
DMF/air
4
5
6
7
S8(3.0)
S8(3.0)
S8(3.0)
S8(3.0)
-
52
40
32
trac
e
H2O2(2.0)
Results and discussion
CH3COOH(2.0) DMF/air
Na2CO3(2.0) DMF/air
Initially, phenylacetaldehyde and o-phenylenediamine were
taken as the model for the chemical reaction. The reaction
between o-phenylenediamine (1a) and phenylacetaldehydes
(2a) was first examined under air to optimize the sulfur
promoted reaction conditions by using different solvents
(Table 1). The initial step was performed in DMSO at 80 oC for
20 h, then the product 3aa was isolated in 41% yield (entry 1).
When the reaction was performed in DMSO/air absence of S8,
the product 3aa was not collected (entry 2). However, no
product was detected when the reaction was performed in 1,4-
dioxane at the same conditions (entry 3). When the reaction
was performed in DMF, the yield of product 3aa was improved
to 52% (entry 4) which shows that the reaction was performed
well in the polar solvents (DMSO, DMF). In order to further
optimize the reaction, we attempt to use some additives (H2O2,
CH3COOH, Na2CO3) when the reaction was performed in DMF.
With H2O2 (2.0 equiv.) or CH3COOH (2.0 equiv.) as the additives,
the product 3aa gives 40% and 32% yields, respectively (entries
5 and 6). With Na2CO3 (2.0 equiv.) little product 3aa was
obtained and another product 4aa was collected (entry 7). A
similar result was obtained after carrying out the reaction by
changing the dosages of additives (entries 8 and 9). At the same
time, with sulfur (2.0 equiv.), the product 3aa was collected with
28% yield (entry 10). By increasing the dosage of sulfur, the
yield of 3aa was not improved (entry 11). In absence of sulfur
another product 4aa was collected (entry 12). In order to get
the excellent yield then the reaction was performed in N2 and
O2 atmosphere (entries 13 and 14). However, the yield of
product 3aa was not improved. What is important, we couldn’t
collected the product 3aa when the reaction was carried in N2
8
9
S8(3.0)
S8(3.0)
S8(2.0)
S8(4.0)
no
S8(3.0)
S8(3.0)
S8(3.0)
S8(3.0)
CH3COOH(1.0) DMF/air
CH3COOH(3.0 ) DMF/air
32
33
28
34
nr
10
11
12
13
14
15b
16c
-
-
-
-
-
-
-
DMF/air
DMF/air
DMF/air
DMF/N2
DMF/O2
DMF/air
DMF/air
nr
48
48
85
aReaction conditions: o-phenylenediamine (0.2 mmol),
phenylacetaldehydes (0.24 mmol) and sulfur (3.0 equiv.) in 1.5
mL of DMF in the air for 20 h at 80 oC.
bo-phenylenediamine (0.2 mmol), phenylacetaldehydes (0.24
mmol) and sulfur (3.0 equiv.) in 1.5 mL of DMF in the air for 20
h at 60 oC.
co-phenylenediamine (0.2 mmol), phenylacetaldehydes (0.24
mmol) and sulfur (3.0 equiv.), reaction was performed in 1.5 mL
of DMF in the air at 100 oC for 10 h
o
atmosphere. Then when the reaction was performed at 60 C,
the 3aa was produced with 48% (entries 15) and when the
temperature is set to 100 oC, the reaction time is reduced to 10
h and the yield is increased to 85%. (entry16). By comparing
with the effect of reaction time and additives, the suitable
temperature exhibits more efficiency to adjust the product
yield. At the end, the optimized reaction conditions for the
reaction are as follows: sulfur (3.0 equiv.), o-phenylenediamine
(1.0 equiv.), phenylacetaldehydes (1.2 equiv.) in 1.5 mL of DMF
at 100 oC. The corresponding single crystal diffraction structure
is shown in Figure 1.
Fig.1: X-ray crystal structure of 3aa.
With the optimized conditions, we investigated the
compatibility of phenylacetaldehydes and o-phenylenediamine
bearing diverse substituents. The results are summarized in
Scheme 2. Firstly, the reactions of o-phenylenediamine (1a)
with several phenylacetaldehydes having electron-donating
groups on the benzene ring (such as 4-CH3, 3-CH3, 3-OCH3)
2 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
NH2
NH2
The further optimization of the product 4aa was performed and
View Article Online
O
N
CHO
S(3.0 equiv.)
DMF/air
R1
the result was shown in Table 2. FirstlDy,OtI:h1e0.1r0e3a9c/Cti9oOnBs00w5e3r1eE
performed in DMF, under the Na2CO3 and sulfur, the
corresponding product (4aa) was obtained with 37% yield (entry
1). Then the reaction was performed in the absence of sulfur,
the desired product (4aa) was collected with 45% yield (entry
2). Next, the reaction was carried in DMF without catalyst and
additive, the yield of product 4aa was 30% (entry3). We further
performed experiments in different solvent respectively. It was
noticed that, the yield of product was improved to 60% when
the reaction was performed in 1, 4-dioxane (entry 5). With other
additives such as (NaHCO3, DBU, KOH), the product was
collected with 70%, 66% and 30% yield, respectively (entries 7-
9). By increasing or decreasing the dosage of NaHCO3 or united
equal amount of NaHCO3 and DBU, the yield of 3a was not
improved (entries 10- 12). Additionally, the reaction was
performed at 60 oC and 100 oC, the 4aa was produced with 48%
and 64% yield, respectively (entries 13 and 14). When the
reactions were performed in N2 and O2 atmosphere, the yield of
product (4aa) was improved to 83%(entry16).
R2
R1
R2
N
H
1
2
3a
O
N
O
N
O
O
N
N
N
H
OCH3
N
H
N
H
N
H
3ac,60%
3aa,85%
3ad,65%
3ab,71%
O
O
N
N
F
F
O
O
N
N
N
H
N
H
N
H
N
H
F
Cl
O
3af,52%
3ah,63%
3ag,74%
3ae,44%
Cl
Cl
O
N
N
O
N
O
N
H3
C
H3
C
F
N
H
N
N
H
N
H
H
3aj,80%
3ak,78%
3ai,40%
3al,80%
O
N
O
N
Cl
Br
N
H
N
H
3am,70%
3an,86%
Scheme2. Sulfur-promoted synthesis of various (1H-
benzo[d]imidazol-2-yl)(phenyl)methanones 3aa-3an.
Table 2. Optimization of reaction conditions a
showed 60-71% yields for the desired products (3ab-3ad).
However, the 1a with phenylacetaldehydes bearing electron-
withdrawing groups (4-F and 4-Cl) gives corresponding products
(3ae-3af) with 44% and 52% yields, respectively. It is worth
noting the electron donating group exhibits a better effect than
the electron donating group for substituents on
phenylacetaldehyde. What’more, the same substituent in
different sites on aryl-ring shows diverse results (3ab, 3ac),
indicates that the steric effect could also plays an important
part in the reaction. Subsequently, the scope of the reaction
was investigated by varying the substituents on the benzene
ring of o-phenylenediamine. When o-phenylenediamines which
bears two electron-withdrawing groups on the benzene ring
(4,5- difluoro or 4,5- dichloro) was reacted with
phenylacetaldehyde, the products (3ah, 3ai) were obtained
with 63%, 40% yields, respectively. However, the product (3ag)
was collected with 74% yield when the phenylenediamines
which bears two electron-donating groups on the benzene ring
(4,5-dimethyl). The o-phenylenediamine which shows electron-
withdrawing group (4-fluoro, 4-chloro) gives the desired
products (3al-3am) with 70-80% yields, however, the reactions
between o-phenylenediamine when substituted with (4-
bromine) and phenylacetaldehyde gives the 86% yield for the
desired product (3an). To further investigate the versatility of
the reaction, the o-phenylenediamine (3-methyl, 4-methyl)
reacts with phenylacetaldehyde gives the 78-82% yields for the
desired products (3aj-3ak). When the phenylacetaldehyde was
reacted with o-phenylenediamine having only one substituent
group gives two products (3aj-3an). Finally, we replaced the
phenylacetaldehyde with an alkyl aldehyde such as n-
valeraldehyde and n-octanal, but did not obtain the
corresponding product.
NH2
CHO
N
base
NH2
Entr
y1a
C
ata.(e Additive(equisvo.lvenStolvent/atmosNp
Yiel
d
2a
quiv.)
)
here
4aa
(%)
37
45
30
40
60
30
70
66
30
60
53
63
48
64
no
83
1
2
3
4
5
6
7
8
S8(3.0)
Na2CO3(2.0)
Na2CO3(2.0)
no
Na2CO3(2.0)
Na2CO3(2.0)
Na2CO3(2.0)
NaHCO3(2.0)
DBU(2.0)
DMF/air
DMF/air
DMF/air
Toluene/air
1,4-dioxane/air
DMSO/air
1,4-dioxane/air
1,4-dioxane/air
1,4-dioxane/air
1,4-dioxane/air
1,4-dioxane/air
1,4-dioxane/air
1,4-dioxane/air
1,4-dioxane/air
1,4-dioxane/N2
1,4-dioxane/O2
9
KOH(2.0)
10
11
12
13b
14c
15
16
NaHCO3+DBU
NaHCO3(1.0)
NaHCO3(3.0)
NaHCO3(2.0)
NaHCO3(2.0)
NaHCO3(2.0)
NaHCO3(2.0)
aReaction conditions: o-phenylenediamine (0.2 mmol),
phenylacetaldehydes (0.24 mmol) and sulfur (3.0 equiv.) in 1.5
mL of DMF in the air for 4 h at 80 oC.
o-phenylenediamine (0.2 mmol), phenylacetaldehydes (0.24
mmol) and sulfur (3.0 equiv.), reaction was performed in 1.5Ml
of 1,4-dioxane at 60 oC for 4h.
co-phenylenediamine (0.2 mmol), phenylacetaldehydes (0.24
mmol) and sulfur (3.0 equiv.), reaction was performed in 1.5Ml
of 1,4-dioxane at 100 oC for 4h.
b
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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ARTICLE
Journal Name
O
N
NH2
CHO
ViNew Article Online
R
S8
TEMPO
DMF
NH2
NH2
N
CHO
N
H
NaHCO3(2.0equiv.)
1,4-dioxane, O2
DOI: 10.1039/C9OB00531E
NH2
R
R
N
R
48%
51%
N
4a
2
1
NH2
NH2
N
CHO
CHO
S8
2h
DMF
N
F
H
N
N
N
N
N
N
N
OCH3
NH2
NH2
N
N
O
N
NaHCO3
1,4-dioxane
4ac,76%
4ab,90%
4ad,25%
4aa,83%
N
N
TEMPO
H
83%
0%
N
N
F
F
N
Cl
N
N
standard condition
N
Cl
N
O
N
N
N
N
H
4ag,67%
4ah,15%
4af,95%
N
H
4ae,60%
quant.
Scheme 4. Some controlled experiments
N
N
F
N
N
corresponding result are shown in Scheme 4. It is possible that
the reaction was not involved with radical reactions. At the
same time, we used GC-MS to detect during the reaction. We
found that 2-benzyl-1H-benzo[d]imidazol were present in the
reaction, but when the reaction was thorough, we could not
H3
C
N
N
N
F
N
4ah',60%
4ai,70%
4aj',65%
4aj,20%
N
Br
N
Cl
N
N
N
Br
N
N
Cl
N
detect the compounds. In the end
， 2-benzyl-1H-
4al,28%
4al',40%
4ak',63%
4ak,33%
benzo[d]imidazole was used for reaction under standard
conditions, After a period of reaction, we could get a lot of
products.
Scheme 3. Synthesis of various quinoxalines 4aa-4al.
We further explored the scope and limitations of the developed
methodology with respect to the o-phenylenediamine and
phenylacetaldehydes in the presence of NaHCO3 at O2
atmosphere, and the results are shown in Scheme 3. The
So we presented a possible mechanism for the synthesis of
quinxaline and (1H-benzo[d]imidazol-2-yl)(phenyl)methanones.
The specific path is shown in scheme 5. For the quinoxaline, the
base B was synthesized by the reaction of o-phenylenediamine.
with phenylacetaldehydes. The product is formed through the
tautomerization of B to C which upon further oxidation leads to
reactions
of
o-phenylenediamine
(1a)
with
phenylacetaldehydes bearing electron-withdrawing groups on
the benzene ring (such as 4-F,) gives the desired products (4ad)
with 25% yield. However, 1a with phenylacetaldehydes bearing
electron-donating groups (4-CH3, 3-OCH3) provides
corresponding products (4ab-4ac) with 90%, 76% yields,
respectively. Next, several disubstituted o-phenylenediamines
(4,5-dimethyl, 4,5-difluoro and 4,5-dichloro) were performed at
optimal condition, the corresponding products were collected
with 60-95% yield. For substituents on phenylacetaldehyde, the
electron donating group exhibits a better effect than the
electron donating group.oups for the desired products. The o-
phenylenediamine having 4-fluoro,4-chloro and 4-bromine
groups on the benzene ring, the mixture of desired products
(4aj-4al) were formed with 68-96% yields. However, the
reactions between o-phenylenediamine with substituented
groups (3-methyl, 4-methyl) and phenylacetaldehyde gives the
desired product (4ah-4ai) with 75% and 70% yields. When the
phenylacetaldehyde was performed with o-phenylenediamine
bearing only one substituent group gives the mixture of two
products (4ah-4al). All these regioisomers expect 4ai shows that
was easily separated by column chromatography and
characterized by spectroscopic methods. At the same time, we
performed the reaction with an alkyl aldehyde such as n-
valeraldehyde and n-octanal instead of phenylacetaldehyde,
but did not obtain the corresponding product.
quinoxaline.21
For
(1H-benzo[d]imidazol-2-
yl)(phenyl)methanone, From the results of GC-MS test, we can
speculate that o-phenylenediamine and phenylacetaldehyde
were formed into 2-benzylbenzimidazole, followed by the
formation of the corresponding product under the action of
sulfur and O2 in solvent.16
N
NH2
H
N
Ph
OHC
Ph
Ph
NH2
NH2
NH2
B
C
O2
H
N
H
N
N
N
Ph
Ph
N
H
Ph
NH2
4aa
NH2
NH2
OHC
N
Ph
O
N
sulfur [O2
]
N
Ph
N
H
N
H
NH2
B
3aa
Scheme 5. Proposed mechanism for quinoxaline (4aa) and (1H-
benzo[d]imidazol-2-yl)(phenyl)methanone (3aa) formation.
Conclusions
In conclusion, a different pathway to synthesize the quinoxaline
and (1H-benzo[d]imidazol-2-yl)(phenyl)methanone from o-
phenylenediamine and phenylacetaldehyde was developed,
which avoided the use of metal catalyst. At the same time, this
transformation provides a general method for the synthesis of
heterocyclic molecules and materials. (1H-benzo[d]imidazol-2-
In order to further state the possible reaction mechanism, we
did some controlled experiments. With the standard conditions,
the reaction of o-phenylenediamine with phenylacetaldehydes
was performed in the presence of radical inhibitors 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) respectively, the
4 | J. Name., 2012, 00, 1-3
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ARTICLE
12. Sharma, D.; Narasimhan, B.; Kumar, P.; Judge, V.; Narang, R.; De
Clercq, E.; Balzarini, J., Journal of Enzyme IDnhOiIb: i1t0io.1n03a9n/Cd9MOBe0d0ic5i3n1aEl
Chemistry 2009, 24, 1161-1168.
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M.; Gee, C. E.; Jacobson, L. H.; Laue, G.; Ofner, S.; Chaudhari, V.;
Badiger, S.; Pandit, C.; Wagner, J.; Hoyer, D., J. Med. Chem. 2013, 56,
7590-607.
yl)(phenyl)methanone was collected by the oxidative
rearranging of 2-benzylbenzimidazole under N, N-
dimethylformamide/sulfur combination. The two different
products were obtained when the reaction was performed in
two different solvents.
View Article Online
Conflicts of interest
There are no conflicts to declare.
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Commun. 2018, 54, 1379-1382; Li, C.; Duan, R.; Liang, B.; Han, G.;
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