Ligand-free copper-catalyzed synthesis of substituted benzimidazoles, 2-aminobenzimidazoles, 2-aminobenzothiazoles, and benzoxazoles

Article abstract of DOI:10.1021/jo901813g

(Chemical Equation Presented) The synthesis of substituted benzimidazoles, 2-aminobenzimidazoles, 2-aminobenzothiazoles, and benzoxazoles is described via intramolecular cyclization of o-bromoaryl derivatives using copper(II) oxide nanoparticles in DMSO under air. The procedure is experimentally simple, general, efficient, and free from addition of external chelating ligands. It is a heterogeneous process and the copper(II) oxide nanoparticles can be recovered and recycled without loss of activity. 2009 American Chemical Society.

Full text of DOI:10.1021/jo901813g

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Ligand-Free Copper-Catalyzed Synthesis of Substituted Benzimidazoles,
2-Aminobenzimidazoles, 2-Aminobenzothiazoles, and Benzoxazoles
Prasenjit Saha, Tamminana Ramana, Nibadita Purkait, Md Ashif Ali, Rajesh Paul, and
Tharmalingam Punniyamurthy*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati-781039, India
tpunni@iitg.ernet.in
Received August 25, 2009
The synthesis of substituted benzimidazoles, 2-aminobenzimidazoles, 2-aminobenzothiazoles, and
benzoxazoles is described via intramolecular cyclization of o-bromoaryl derivatives using copper(II)
oxide nanoparticles in DMSO under air. The procedure is experimentally simple, general, efficient,
and free from addition of external chelating ligands. It is a heterogeneous process and the copper(II)
oxide nanoparticles can be recovered and recycled without loss of activity.
Introduction
(PARP) inhibitor,5b factor Xa(FXa) inhibitor,5c histamine
H1-receptor,5d-f 5-HT3-receptor agonist 2,5d HIV reverse
Benzimidazoles,1 2-aminobenzimidazoles,2 2-aminobenzo-
thiazoles,3 and benzoxazoles4 are privileged organic
compounds due to their recognition in biological and
therapeutic activities (Figure 1). Recent medicinal chemistry
applications of these heterocyclic compounds include
5-lipoxygenase inhibitor,5a poly(ADP-ribose)polymerase
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DOI: 10.1021/jo901813g
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Published on Web 10/20/2009
J. Org. Chem. 2009, 74, 8719–8725 8719
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JOCArticle
FIGURE 1. Examples of some biologically active compounds.
transcriptase inhibitor L-697,695,5g anticancer agent NSC-
693638,4a and orexin-1 receptor antagonist SB-334867.5h
Other applications of these compounds include their use
as anti-inflammatory,6a antibacterial,2l antimicrobial,6b and
antiviral2k,4c agents. Development of general methods for the
synthesis of these compounds is thus highly relevant for drug
discovery.
The classical methods used for the preparation of these
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formation of 2-aminobenzimidazoles14 and 2-aminobenzo-
thiazoles15 via inter- as well as intramolecular cross-coupling
reactions. The synthesis of benzoxazoles is reported using
copper(I)/(II) complexes via intramolecular or inter-
followed by intramolecular cross-coupling reactions.16 More
recently, iron(III) complex has been employed for the cycli-
zation of o-bromoanilides to afford 2-arylbenzoxazoles.17
Most of these reactions function under homogeneous con-
ditions and the ligands chelated with the metals play a crucial
role in the catalysis. Among these studies, the cyclizations via
intramolecular cross-coupling reactions provide a straight-
forward route with wide substrate scope for the synthesis of
these target heterocycles in high yield.
TABLE 1. Optimization of the Reaction Conditions
Recently, we and others reported the intermolecular cross-
coupling reactions of aryl iodides with nitrogen, oxygen, and
sulfur nucleophiles using copper(II) oxide nanoparticles18
under ligand-free conditions.11w-z Since the copper(II) oxide
nanoparticles are readily accessible, air stable, recyclable,
and free from addition of external chelating ligands, we
became further interested to investigate them for the synth-
esis of important organic compounds. In this contribution,
we wish to describe a general method for the synthesis of
substituted benzimidazoles, 2-aminobenzimidazoles, 2-ami-
nobenzothiazoles, and benzoxazoles by intramolecular cy-
clization in the presence of the copper(II) oxide nano-
particles under air. The procedure is experimentally simple
and efficient to afford the heterocyclic compounds in high
yield. The reaction involves a heterogeneous process and the
copper(II) oxide nanoparticles can be recovered and recycled
without loss of activity. From an industrial standpoint, these
studies are attractive since the cost and environmental im-
pact of the process (E-factor) can be further lowered.19
aSubstrate (0.5 mmol), CuO nanoparticles (5 mol %), and KOH
(1 mmol) were stirred at 110 °C in DMSO (1 mL) under air. bSubstarte
(0.5 mmol), CuO nanoparticles (5 mol %), and KOH (0.75 mmol) were
stirred at 110 °C in DMSO (1 mL) under air. cSubstrate (0.5 mmol), CuO
nanoparticles (2.5 mol %), and K2CO3 (0.25 mmol) were stirred at 80 °C
in DMSO (1 mL) under air. dSubstrate (0.5 mmol), CuO nanoparticles
(5 mol %), and K2CO3 (0.75 mmol) were stirred at 110 °C in DMSO
(1 mL) under air. eDetermined by 1H NMR.
Results and Discussion
The optimized reaction conditions for the formation of
benzimidazoles 2a-p, 2-aminobenzimidazoles 4a-l, 2-amino-
benzothiazoles 6a-j, and benzoxazoles 8a-n via intra-
molecular cross-coupling reactions are presented in Table 1.
Both o-iodoaryl and o-bromoaryl derivatives readily under-
went cyclization to afford the heterocyclic compounds in
high yield. In contrast, o-chloroaryl derivatives were less
reactive providing the target molecules in <28% yield.
Under these conditions, the cyclization via C-H activa-
tion did not occur. The cyclization of o-haloarylamidines
and -guanidines provided the best results in the presence
of KOH, while the formation of benzothiazoles and benzox-
azoles could be accomplished with K2CO3 or Cs2CO3. The
cyclizations occurred at 80-110 °C in DMSO under air.
Solvents such as DMF (15-85%), toluene (5-10%), and
dioxane (10-66%) were less effective. Control experiments of
these reactions without copper(II) oxide nanoparticles showed
no reaction.
Synthesis of Benzimidazoles. o-Bromoarylamidines 1a-p
were prepared from the readily accessible o-bromoanilines
and amides in the presence of POCl3 in high yield.12a The
amidines 1a-p were then investigated for the cyclization
reaction under the optimized conditions, using 5 mol %
copper(II) oxide nanoparticles at 110 °C in the presence of
KOH in DMSO under air (Table 2). The reactions occurred
in an intramolecular manner to provide the corresponding
substituted benzimidazoles 2a-p in 80-97% yield. The
substrates with R3 =aryl groups 1j-p exhibited enhanced
reactivity compared to that having R3 =alkyl substituents
1a-i. These results clearly suggest that this protocol could be
used for the synthesis of the substituted 2-alkyl and 2-aryl
benzimidazoles in high yield.
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€
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TABLE 2. CuO Nanoparticles-Catalyzed Synthesis of Substituted
Benzimidazoles
TABLE 3. CuO Nanoparticles-Catalyzed Synthesis of Substituted
2-Aminobenzimidazoles
ao-Bromoarylguanidine (0.5 mmol), CuO nanoparticles (5 mol %),
and KOH (0.75 mmol) were stirred at 110 °C in DMSO (1 mL) under air.
ao-Bromoarylamidine (0.5 mmol), CuO nanoparticles (5 mol %), and
KOH (1 mmol) were stirred at 110 °C in DMSO (1 mL) under air.
b3 equiv of KOH was used.
2-aminobenzimidazoles 4a-l in 73-95% yield. Both the sub-
strates having alkyl and aryl substituents were compatible
affording the cyclized compounds with 100% selectivity. The
substrates 3a-l with R2 = aryl substituents exhibited greater
reactivity (4-5 h) compared to those containing R2 = alkyl
groups (12-24 h). This could be due to lower pKa of NH-aryl
substituents in comparison to NH-alkyl moieties.
Synthesis of 2-Aminobenzimidazoles. Reaction of o-halo-
anilines with isothiocyanate gave thioureas which were
treated with amines in the presence of HgCl2 to provide
o-haloarylguanidines 3a-l in high yield.14b Using the above
reaction conditions described for benzimidazole formation,
the intramolecular cross-coupling reaction of o-bromoaryl-
guanidines 3a-l was studied (Table 3). The cyclization
reactions proceeded efficiently to afford the substituted
Synthesis of 2-Aminobenzothiazoles. The preparation of
the cyclization precursors, o-bromoaryl thioureas 5a-j, was
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conditions were further examined for the cyclization of o-
bromophenyl benzothioamide (Scheme 1). However, both
TABLE 4. CuO Nanoparticles-Catalyzed Synthesis of 2-Aminoben-
zothiazoles
SCHEME 1. Cyclization Reaction of N-(2-Bromophenyl)benzo-
thioamide
TABLE 5. CuO Nanoparticles-Catalyzed Synthesis of 2-Arylbenzox-
azoles
ao-Bromoarylthiourea (0.5 mmol), CuO nanoparticles (2.5 mol %),
and K2CO3 (0.25 mmol) were stirred at 80 °C in DMSO (1 mL) under air.
accomplished from o-bromoaniline and isothiocynate in
high yield. The intramolecular cyclization reactions of the
substituted o-bromoaryl thioureas 5a-j were pursued at
80 °C in the presence of K2CO3 in DMSO under air
(Table 4). The cross-coupling reactions occurred readily to
afford the corresponding substituted 2-aminobenzothia-
zoles. The substrates 5a-g having R2 = alkyl groups
proceeded well to give the cyclized products 6a-g selectively
in 82-98% yield. In contrast, the substrates 5h-j containing
R2 = aryl groups were not selective affording the desired
cyclized products 6h-j in 27-37% yield.20 These reaction
ao-Bromoanilide (1 mmol), CuO nanoparticles (5 mol %), and
K2CO3 (1.5 mmol) were stirred at 110 °C in DMSO (1 mL) under air.
the blank reaction as well as the reaction with copper(II)
oxide exhibited the cyclization to afford the 2-phenylben-
zothiazole in 73% and >99% yield, respectively.21
Synthesis of Benzoxazoles. The substituted o-haloanilides
7a-o were prepared from the readily available o-haloanilines
and acid chlorides. The cyclization reactions of o-haloani-
lides 7a-o were studied at 110 °C in the presence of either
K2CO3 or Cs2CO3 in DMSO under air (Tables 5 and 6). The
reactions proceeded efficiently to afford the substituted
benzoxazoles in high yield. N-(o-Bromophenyl)benzamides
7a-e having 3-Br, 3-NO2, 4-Br, and 4-Me substituents
underwent reactions with 60-92% yield. Under these con-
ditions, o-bromoanilides 7f-h substituted with Br, Cl, OMe,
(20) The substrates undergo decomposition to give 2-bromoaniline as a
byproduct.
(21) (a) Inamoto, K.; Hasegawa, C.; Hiroya, K.; Doi, T. Org. Lett. 2008,
10, 5147. (b) Gurupadaiah, B. M.; Jayachandran, E.; Kumar, B. S.; Nagappa,
A. N.; Nargund, L. V. G. Indian J. Heterocycl. Chem. 1998, 7, 213. (c)
Kashiyama, E.; Hutchinson, I.; Chua, M. S.; Stinson, S. F.; Phillips, L. R.;
Kaur, G.; Sausville, E. A.; Bradshaw, T. D.; Westwell, A. D.; Stevens, M. F. G.
J. Med. Chem. 1999, 42, 4172. (d) Boger, D. L. J. Org. Chem. 1978, 43, 2296. (e)
Ben-Alloum, A.; Bakkas, S.; Soufiaoui, M. Tetrahedron Lett. 1997, 38, 6395. (f)
Bowman, W. R.; Heaney, H.; Smith, P. H. G. Tetrahedron Lett. 1982, 23, 5093.
(g) Ma, H. C.; Jiang, X. Z. Synlett 2008, 1335.
J. Org. Chem. Vol. 74, No. 22, 2009 8723

Saha et al.
SCHEME 2. Proposed Catalytic Cycle for Intramolecular
Cyclization Reactions
JOCArticle
TABLE 6. CuO Nanoparticles-Catalyzed Synthesis of 2-Alkylbenzox-
azoles
TABLE 7. Recyclability of CuO Nanoparticles
run
catalyst recoverability (%)
product conversion(%)a,b
1
>99
>99
99
98
98
100
100
>99
99
2c
3c
4c
5c
97
ao-Bromoanilide (1 mmol), CuO nanoparticles (5 mol %), and
Cs2CO3 (1.5 mmol) were stirred at 110 °C in DMSO (1 mL) under air.
aSubstrate 7a (2.5 mmol), CuO nanoparticles (5 mol %), and K2CO3
(3.75 mmol) were stirred at 110 °C in DMSO (2.5 mL) under air.
bDetermined by 1H NMR. cRecovered used.
and Me groups cyclized with 61-91% yield. Similarly, N-(o-
bromophenyl)alkylamides 7i-n underwent cyclization to
afford the corresponding benzoxazoles in 67-84% yield.
These results clearly reveal that the present method is general
and can be used for the synthesis of substituted 2-aryl- and 2-
alkylbenzoxazoles in high yield.
oxide nanoparticles were collected by centrifugation and
washed successively with water and acetone. After drying under
vacuum, the catalyst was reused for the cyclization of fresh o-
bromophenylbenzamide 7a. This process was repeated for five
runs and the reactions took place efficiently to afford the cross-
coupled product 8a with 97% conversion and >98% catalyst
recoverability. The TEM images and powder X-ray diffraction
peaks of the fresh and recovered copper(II) oxide nanoparticles
were found to be similar, which suggests that the nanoparticles
do not undergo significant changes during the recycling process
(see the Supporting Information).22,23
Mechanism. To reveal the leaching of the catalyst, the
copper(II) oxide nanoparticles were stirred at the reaction
temperature (110 °C) for 10 h in the presence of K2CO3 in
DMSO. The solution was then cooled to room temperature
and subjected to centrifugation. The particles were recovered
and the clear solution was investigated for the cyclization of o-
bromophenylbenzamide 7a in the presence of fresh K2CO3.
No reaction was, however, obtained and the starting o-bro-
mophenylbenzamide 7a was recovered intact. Furthermore,
atomic absorption spectroscopy (AAS) showed the amount of
copper species present in the clear solution was below the
detection limit (<0.25%). These studies suggest that the
reaction involves a heterogeneous process and the leaching
of the copper(II) oxide nanoparticles has not occurred under
these conditions. Thus, the DMSO stabilized copper(II) oxide
nanoparticles a may undergo reaction with the substrate on
their surface to generate intermediate b and the positive charge
developed could be shared among the copper oxide nanopar-
ticles present on the surface of the cluster (Scheme 2). The
intermediate b can then transform to intermediate c in the
presence of base that can complete the catalytic cycle by the
reductive elimination of the cross-coupled product.
Conclusions
The synthesis of substituted benzimidazoles, 2-aminobenzi-
midazoles, 2-aminobenzothiazoles, and benzoxazoles is de-
scribed using copper(II) oxide nanoparticles under ligand-free
conditions. The reactions are simple, general, and efficient and
the catalyst can be recovered and recycled without loss of
activity and selectivity. It is a clean technological process and
a wide range of substrates can undergo reactions in high yield.
Experimental Section
General Procedure for the Synthesis of 2-Aryl- and Alkylben-
zimidazoles. o-Bromoarylamidine (0.5 mmol), CuO nanoparti-
cles (5 mol %, 2 mg), and KOH (1 mmol, 56 mg) were stirred at
ꢀ
(22) (a) Pachon, L. D.; Rothenberg, G. Appl. Organomet. Chem. 2008, 22,
Recyclability Experiment. The copper(II) oxide nanopar-
ticles can be recovered and recycled (Table 7). After the
cyclization of the o-bromophenylbenzamide 7a, the reaction
mixture was treated with ethyl acetate and water. The copper(II)
288. (b) Gaikwad, A. V.; Holuigue, A.; Thathagar, M. B.; ten Elshof, J. E.;
Rothenberg, G. Chem.;Eur. J. 2007, 13, 6908. (c) Wang, W.; Zhan, Y.;
Wang, G. Chem. Commun. 2001, 727.
(23) (a) Yamamoto, H.; Maruoka, K. J. Am. Chem. Soc. 1981, 103, 4186.
(b) Nardi, D.; Pennini, R.; Tajana, A. J. Heterocycl. Chem. 1975, 12, 825.
8724 J. Org. Chem. Vol. 74, No. 22, 2009

Saha et al.
JOCArticle
110 °C in DMSO (1 mL) for the appropriate time (Table 2). The
progress of the reaction was monitored by TLC, using ethyl
acetate and hexane as eluent. The reaction mixtures were then
cooled to room temperature and diluted with ethyl acetate (20
mL). The organic layer was washed successively with brine (1 Â
5 mL) and water (3 Â 5 mL). Drying (Na2SO4) and evaporation
of the solvent gave a residue that was purified on silica gel
column chromatography, using ethyl acetate and hexane as
eluent.
organic layer was successively washed with brine (1 Â 5 mL) and
water (3 Â 5 mL). Drying (Na2SO4) and evaporation of the
solvent gave a residue that was purified on silica gel column
chromatography, using ethyl acetate and hexane as eluent.
N-Cyclohexylbenzo[d]thiazol-2-amine (6a):15d
.
analytical
TLC on silica gel, 1:4 ethyl acetate/hexane Rf 0.43; yellow liquid;
yield 90%; 1H NMR (CDCl3, 400 MHz) δ 7.55 (d, J = 8.0 Hz,
1H), 7.49 (d, J = 8.0 Hz, 1H), 7.25 (dt, J = 1.2 Hz, 7.2 Hz, 1H),
7.04 (dt, J = 1.2 Hz, 7.6 Hz, 1H), 5.39 (s, 1H), 3.54 (s, 1H), 2.11
1-Benzyl-2-methyl-1H-benzo[d]imidazole (2a):23a. analytical
TLC on silica gel, 1:2 ethyl acetate/hexane Rf 0.28; yellow solid;
yield 95%; mp 67 °C (lit.23b mp 68-69 °C); 1H NMR (400 MHz,
CDCl3) δ 7.73 (d, J = 8.0 Hz, 1H), 7.32-7.19 (m, 6H), 7.05 (d,
J = 8.0 Hz, 2H), 5.31 (s, 2H), 2.56 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 152.1, 142.8, 136.0, 135.6, 129.1, 128.0, 126.4, 122.4,
122.1, 119.2, 109.5, 47.2, 14.1; FT-IR (KBr) 3060, 2929, 1655,
(d, J = 3.2 Hz, 2H), 1.80-1.61 (m, 4H), 1.45-1.13 (m, 4H); 13
C
NMR (CDCl3, 100 MHz) δ 167.1, 152.5, 130.3, 126.0, 121.3,
120.9, 118.6, 54.8, 33.4, 25.6, 24.9; FT-IR (neat) 2927, 2851,
1596, 1544, 1440, 1251, 1033 cm-1. Anal. Calcd for C13H16N2S:
C, 67.20; H, 6.94; N, 12.06; S, 13.80. Found: C, 67.30; H, 6.91; N,
12.09; S, 13.70.
General Procedure for the Synthesis of Benzoxazoles. o-Ha-
loanilide (1 mmol), CuO nanoparticles (5 mol %, 4 mg), and
K2CO3 (1.5 mmol, 207 mg) were stirred at 110 °C in DMSO
(1 mL) for the appropriate time (Tables 5 and 6). The progress of
the reaction was monitored by TLC, using ethyl acetate and
hexane as eluent. The reaction mixture was then cooled to room
temperature and diluted with ethyl acetate (20 mL). The organic
layer was washed successively with brine (1 Â 5 mL) and water
(2 Â 5 mL). Drying (Na2SO4) and evaporation of the solvent
gave a residue that was purified on silica gel column chroma-
tography, using ethyl acetate and hexane as eluent.
1618, 1518, 1454, 1404, 1355, 1330, 1286, 1251, 1143, 1029 cm-1
.
Anal. Calcd for C15H14N2: C, 81.05; H, 6.35; N, 12.60. Found:
C, 81.14; H, 6.31; N, 12.55.
General Procedure for the Synthesis of 2-Aminobenzimida-
zoles. o-Bromoarylguanidine (0.5 mmol), CuO nanoparticles (5
mol%, 2 mg), andKOH(0.75 mmol,42mg) werestirredat 110°C
in DMSO (1 mL) for the appropriate time (Table 3). The progress
of the reaction was monitored by TLC, using ethyl acetate and
hexane as eluent. The reaction mixture was then cooled to room
temperature and treated with ethyl acetate (25 mL). The organic
layer was washed successively with brine (1 Â 5 mL) and water
(3 Â 5 mL). Drying (Na2SO4) and evaporation of the solvent gave
a residue that was purified on silica gel column chromatography,
using ethyl acetate and hexane as eluent.
1-(Phenylmethyl)-2-(1-pyrrolidinyl)-1H-benzo[d]imidazole (4a):.
analytical TLC on silica gel, 1:1 ethyl acetate/hexane Rf 0.42;
yellow solid; yield 73%; mp 133 °C; 1H NMR (400 MHz, CDCl3)
δ 7.54 (d, J = 8.0 Hz, 1H), 7.32-7.27 (m, 3H), 7.16-7.12 (m,
2H), 7.02-6.95 (m, 3H), 5.27 (s, 2H), 3.54 (s, 4H), 1.91 (s, 4H);
13C NMR (100 MHz, CDCl3) δ 157.3, 142.5, 137.1, 136.3,
129.0, 127.6, 125.9, 121.9, 120.1, 116.7, 108.4, 50.6, 47.9,
25.8; FT-IR (neat) 3027, 2958, 2924, 2868, 1606, 1594, 1552,
1484, 1455, 1406, 1361, 1349, 1285, 1008 cm-1. Anal. Calcd for
C18H19N3: C, 77.95; H, 6.90; N, 15.15. Found: C, 78.13, H, 6.87;
N, 15.00.
2-Phenylbenzoxazole (8a):16c. analytical TLC on silica gel,
1:20 ethyl acetate/hexane Rf 0.47; white solid; yield 95%; mp 101
°C (lit.16c mp 101-102 °C); 1H NMR (CDCl3, 400 MHz) δ
8.26-8.24 (m, 2H), 7.77-7.75 (m, 1H), 7.58-7.56 (m, 1H),
7.53-7.49 (m, 3H), 7.35-7.33 (m, 2H); 13C NMR (CDCl3, 100
MHz) δ 163.2, 150.9, 142.2, 131.7, 129.1, 127.8, 127.3, 125.3,
124.7, 120.2, 110.8; FT-IR (KBr) 3060, 2961, 1616, 1552, 1472,
1447, 1344, 1318, 1241, 1196, 1052, 1022 cm-1. Anal. Calcd for
C13H9NO: C, 79.98; H, 4.65; N, 7.17. Found: C, 80.12; H, 4.59;
N, 7.08.
Acknowledgment. This work was supported by the De-
partment of Science and Technology, New Delhi, and the
Council of Scientific and Industrial Research, New Delhi.
General Procedure for the Synthesis of 2-Aminobenzothiazole.
N-(2-Bromoaryl)thiourea (0.5 mmol), CuO nanoparticles (2.5
mol %, 1 mg), and K2CO3 (0.25 mmol, 34.5 mg) were stirred at
80 °C in DMSO (1 mL) for the appropriate time (Table 4). The
progress of the reaction was monitored by TLC, using ethyl
acetate and hexane as eluent. The reaction mixture was cooled to
room temperature and diluted with ethyl acetate (10 mL). The
Supporting Information Available: X-ray diffraction analy-
sis and TEM micrographs of fresh and recovered CuO nano-
particles, characterization data of 2b-p, 4p-l, 6b-j, and 8b-n,
and NMR spectra (1H and 13C) of 2a-p, 4a-l, 6a-j, and 8a-n.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 74, No. 22, 2009 8725