Construction of Benzimidazoles and Benzoxazoles through the Molybdenum-Mediated Carbonylation of Aryl Halides

Article abstract of DOI:10.1002/ejoc.201500803

The facile and efficient one-pot construction of benzimidazoles and benzoxazoles through the Mo(CO)₆-mediated carbonylation of aryl halides was examined. In the process, Mo(CO)₆ acted as a convenient and safe solid source of carbon monoxide. A wide range of substrates were tolerated to provide the corresponding products in fair to good yields without the need of gaseous CO or palladium catalysts. The facile and efficient one-pot construction of benzimidazoles and benzoxazoles is described. The reaction proceeds through Mo(CO)₆-mediated carbonylation of aryl halides, in which Mo(CO)₆ acts as a convenient and safe solid source of carbon monoxide.

Full text of DOI:10.1002/ejoc.201500803

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500803
Construction of Benzimidazoles and Benzoxazoles through the Molybdenum-
Mediated Carbonylation of Aryl Halides
Eshetu Kebede,[a] Ramu Tadikonda,[a] Mangarao Nakka,[a] Bhargavi Inkollu,[a] and
Siddaiah Vidavalur*[a]
Keywords: Synthetic methods / Carbonylation / Molybdenum / Carbonyl ligands / Fused-ring systems / Nitrogen
heterocycles
The facile and efficient one-pot construction of benzimid-
azoles and benzoxazoles through the Mo(CO)6-mediated
carbonylation of aryl halides was examined. In the process,
Mo(CO)6 acted as a convenient and safe solid source of
carbon monoxide. A wide range of substrates were tolerated
to provide the corresponding products in fair to good yields
without the need of gaseous CO or palladium catalysts.
Introduction
Nitrogen-containing heterocycles are widely distributed
in nature and are essential to life; they play a vital role in
the metabolism of all living cells. Among these, benzimid-
azoles and benzoxazoles are more prominently found in
natural products and commercially available drugs (Fig-
ure 1). They are known to have a wide range of biological
activities, including anticancer,[1] antimicrobial,[2] antitu-
mor,[3] and antibacterial[4] activities in addition to enzyme
inhibition.[5] Furthermore, they have also been applied in
dyes,[6] chemosensing,[7] and fluorescence.[8]
Therefore, much effort has been devoted to their con-
struction starting from a variety of substrates, among which
2-amino/hydroxyaniline are the most typical. Benzimid-
azoles and benzoxazoles are commonly prepared by con-
densation of 2-aminoanilines and 2-aminophenols with
either carboxylic acid[9] derivatives under harsh conditions
or aldehydes[10] under strong oxidative conditions
Figure 1. Commercially available drugs containing benzimidazole
and benzoxazole moieties.
(Scheme 1, path a). To overcome these drawbacks, im- Keto esters,[14] β-keto nitriles,[15] and β-diketones[16]
proved methods have recently been reported, and these in- (Scheme 1, path c) have also been used for the synthesis of
volve the use of benzylic methylene sp3 carbon atoms as benzimidazoles and benzoxazoles. Despite these advances,
a one-carbon synthon to provide a more environmentally versatile and efficient methods for the direct construction of
friendly process (Scheme 1, path b). Benzylamine has been benzimidazoles and benzoxazoles that are compatible with
used for the synthesis benzimidazoles and benzoxazoles in various functional groups and the use of readily available
sulfur,[11] 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO),[12] starting materials remain highly desirable.
and iodine[13] catalytic systems. Very recently, the oxidation
Recently, aryl halides were used as starting materials for
of methylarenes and methylhetarenes was also applied in the direct synthesis of heterocyclic compounds through pal-
this field, which possessed a highly valuable advantage. β- ladium-catalyzed carbonylation and subsequent intramolec-
ular cyclization by using carbon monoxide (CO) as a C1
[a] Department of Organic Chemistry and FDW,
College of Science and Technology, Andhra University,
Visakhapatnam, Andhra Pradesh, India
source. Very recently, dimethylformamide was also used as
CO source at higher temperatures in the presence of a base
in the palladium-catalyzed aminocarbonylation of aryl hal-
ides. Therefore, solid reagents that can release CO in a con-
trolled manner have recently gained considerable interest as
alternatives to the use of gaseous CO.[17] Recently, group VI
E-mail: sidduchem@gmail.com
http://www.andhrauniversity.edu.in/science/organicchy/
contact.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500803.
Eur. J. Org. Chem. 2015, 5929–5933
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E. Kebede, R. Tadikonda, M. Nakka, B. Inkollu, S. Vidavalur
SHORT COMMUNICATION
Table 1. Optimization of reaction conditions for the synthesis of
benzimidazole 3a.[a]
Entry M(CO)6 (equiv.) Base
Solvent
diglyme
Time[b] [h] Yield[c] [%]
1
2
3
4
5
6
7
8
Mo(CO)6 (0.2)
Mo(CO)6 (0.2)
Mo(CO)6 (0.2)
Mo(CO)6 (0.2)
Mo(CO)6 (0.2)
W(CO)6 (0.2)
Cr(CO)6 (0.2)
Mo(CO)6 (0.2)
Mo(CO)6 (0.2)
Mo(CO)6 (0.2)
Et3N
16
12
15
15
13
16
14
14
11
12
13
11
48
32
DMAP diglyme
K2CO3 diglyme
Cs2CO3 diglyme
Bu3N
Bu3N
Bu3N
Bu3N
Bu3N
Bu3N
n.r.[d]
n.r.[d]
66
diglyme
diglyme
diglyme
DME
DMF
1,4-dioxane
DMF
25
27
45
85
31
73
85
9
10
11
12
Mo(CO)6 (0.167) Bu3N
Mo(CO)6 (0.3) Bu3N
DMF
[a] Reaction conditions: 1a (1.0 equiv.), 2a (1.2 equiv.), M(CO)6,
base (1.1 equiv.), Et4NCl (0.2 equiv.), solvent (2 mL per mmol of
1a), 150 °C. [b] Time at which TLC (EtOAc/hexane) indicated com-
plete disappearance of the starting materials. [c] Yield of isolated
product. [d] n.r.: no reaction.
Scheme 1. Different pathways for the synthesis of benzimidazoles
and benzoxazoles by using 2-amino/hydroxyaniline.
system for the synthesis of benzimidazoles and benz-
oxazoles, we then focused on the quantity of Mo(CO)6. By
decreasing the quantity of Mo(CO)6 from 0.2 to
0.167 equiv. (stoichiometric amount of CO) the yield of the
product dropped to 73% even after prolonging the reaction
time (Table 1, entry 11). In contrast, no improvement in the
yield was observed by increasing the quantity of Mo(CO)6
(Table 1, entry 12). Thus, by varying different parameters,
the optimal reaction conditions were set to be Mo(CO)6
(0.2 equiv.), Et4NCl (0.2 equiv.), and Bu3N (1.1 equiv.) in
DMF at 150 °C under a nitrogen atmosphere.
With the establishment of a viable reaction system, the
substrate scope was investigated. First, we examined the re-
action with various aryl iodides, and the results are pre-
sented in Table 2. Aryl iodides bearing electron-donating
groups such as 4-methyl (2b) and 4-methoxy (2c) reacted
smoothly with 1a to afford the desired products in yields of
90 and 92%, respectively (Table 2, entries 2 and 3). Aryl
metal carbonyl complexes such as Cr(CO)6, W(CO)6,
Co2(CO)8, and Mo(CO)6 were used as solid sources of
CO.[18] Among them, Mo(CO)6 has emerged as an ideal
candidate and has been used in several organic transforma-
tions.[19] Inspired by these advances and in continuation of
our work in the development of efficient synthetic method-
ologies for various biologically active heterocycles,[20] herein
we report for the first time the palladium-free and CO-gas-
free synthesis of benzimidazoles and benzoxazoles from
aryl halides by using Mo(CO)6 as a C1 source (Scheme 1,
path d).
Results and Discussion
We began our investigation by subjecting o-phenylenedi- iodides bearing 4-chloro (2d) and 4-fluoro (2e) substituents
amine (1a) and iodobenzene (2a) to the catalytic system of were also compatible under the optimized conditions and
Mo(CO)6, Et4NCl, and Et3N in DMF at 150 °C for 16 h, afforded the products in satisfactory yields (Table 2, en-
which gave target product 3a in 48% yield (Table 1, en- tries 4 and 5). Notably, steric bulk of the aryl iodides did
try 1). Several other bases were investigated. Among them, not affect the reactivity, and 89% yield of the desired prod-
Bu3N showed the best efficiency (Table 1, entry 5). The uct was achieved with 2-chloroiodobenzene (Table 2, en-
screening of different metal carbonyls demonstrated that try 6). However, aryl iodides having electron-withdrawing
Mo(CO)6 was the best choice for this reaction, and the cor- groups such as 4-nitro (2g) and 3-nitro (2h) were not suit-
responding product was obtained in good yield (Table 1, able coupling partners for this process (Table 2, entries 7
entries 5–7).
and 8). An appropriate reason may be attributed to the for-
Further, various solvents were screened for this reaction, mation of a complex mixture of reduced products.[21] Next,
and the results are summarized in Table 1. Finally, it was we performed the reaction with different o-phenylenediam-
found that DMF had a superior solvent effect in terms of ines. 4-Methyl-o-phenylenediamine (1b) underwent the reac-
reaction time as well as yield of the product (Table 1, en- tion smoothly to afford the corresponding products in ex-
try 9). Once we established the suitable base and solvent cellent yields (Table 2, entries 9–11), but 4-nitro-o-phenyl-
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Construction of Benzimidazoles and Benzoxazoles
enediamine (1c) was not a suitable substrate for this trans- synthesis of benzoxazoles under the optimized reaction
formation (Table 2, entry 12). Further, the reaction was per- conditions. The obtained results are presented in Table 3. It
formed by using aryl bromides in place of the aryl iodides, is evident that this methodology can be easily applied to
but lower yields were observed (Table 2, entries 13 and 14). the synthesis of various benzoxazole derivatives. This se-
quential synthesis protocol tolerates various aryl iodides to
Table 2. Synthesis of benzimidazoles.[a]
provide the corresponding benzoxazole derivatives in good
to excellent yields (Table 3).
Table 3. Synthesis of benzoxazoles.[a]
[a] Reaction conditions: o-aminophenol (1.0 equiv.), aryl halide
(1.2 equiv.), Mo(CO)6 (0.2 equiv.), tetraethylammonium chloride
(0.2 equiv.), tributylamine (1.1 equiv.), and DMF (10 mL) at
150 °C. [b] Yield of isolated product after column chromatography.
According to the literature,[19] a plausible mechanism is
[a] Reaction conditions: o-phenylenediamine (1.0 equiv.), aryl hal-
ide (1.2 equiv.), Mo(CO)6 (0.2 equiv.), tetraethylammonium chlor-
ide (0.2 equiv.), tributylamine (1.1 equiv.), and DMF (10 mL) at
150 °C. [b] Yield of isolated product after column chromatography.
proposed for this reaction as shown in Scheme 2. The plaus-
ible pathway involves oxidative addition of the aryl halide
and subsequent insertion of carbon monoxide to generate
A. Intermediate A reacts with o-phenylenediamine to form
After successfully synthesizing a wide range of benzimid- B. Intramolecular nucleophilic attack of the amine to the
azoles in good yields, we turned our attention towards the carbonyl group in B affords benzimidazole 3.
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E. Kebede, R. Tadikonda, M. Nakka, B. Inkollu, S. Vidavalur
SHORT COMMUNICATION
Scheme 2. Plausible mechanism.
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In conclusion, we developed an efficient and CO-gas-free
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Experimental Section
General Procedure:
A mixture of 2-amino/hydroxyaniline (1,
1.0 equiv.), aryl halide 2 (1.2 equiv.), Mo(CO)6 (0.2 equiv.), Et4NCl
(0.2 equiv.), and Bu3N (1.1 equiv.) in DMF (10 mL) was heated at
150 °C under a N2 atmosphere. After completion of the reaction
as monitored by TLC, the mixture was cooled to room temperature
and partitioned between water and ethyl acetate. The organic and
aqueous layers were then separated, and the aqueous layer was ex-
tracted with ethyl acetate (2ϫ). The combined organic layer was
dried with anhydrous Na2SO4, and the solvent was evaporated un-
der reduced pressure to afford the crude product. The crude mate-
rial was purified by silica gel (100–200 mesh) column chromatog-
raphy (EtOAc/hexane) to afford product 3.
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1
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Acknowledgments
The authors thank the Department of Atomic Energy (DAE),
Board of Research in Nuclear Sciences (BRNS), Mumbai for finan-
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of Education, Ethiopia for financial support to E. K. G., and the
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Received: June 17, 2015
Published Online: August 14, 2015
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