Weinreb amide as an efficient reagent in the one pot synthesis of benzimidazoles and benzothiazoles

Article abstract of DOI:10.1016/j.tetlet.2013.03.075

One pot synthesis of 2-substituted benzimidazoles/benzothiazoles through condensation is followed by cyclization of Weinreb amide with o-diaminoarene or o-aminothiophenol is reported. In the presence of boron trifluoride etherate in 1,4-dioxane solvent, a high yield (75-94%) was achieved within 60 min. Weinreb amide shows high selectivity in the reaction, even in presence of other active functional groups such as carboxyl, halogen, cyano, and methoxy.

Full text of DOI:10.1016/j.tetlet.2013.03.075

Tetrahedron Letters 54 (2013) 2693–2695
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Weinreb amide as an efficient reagent in the one pot synthesis
of benzimidazoles and benzothiazoles
Yadaganahalli K. Bommegowda a, Gejjalagere S. Lingaraju a, Saji Thamas b, Koravangala S. Vinay Kumar a,
Challanayakanahally S. Pradeepa Kumara a, Kanchugarakoppal S. Rangappa a,
,
⇑
Marilinganadoddi P. Sadashiva a,
⇑
a Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India
b Jubilant Life Sciences Ltd., C-26, Sector 59, Noida 201301, India
a r t i c l e i n f o
a b s t r a c t
Article history:
One pot synthesis of 2-substituted benzimidazoles/benzothiazoles through condensation is followed by
cyclization of Weinreb amide with o-diaminoarene or o-aminothiophenol is reported. In the presence of
boron trifluoride etherate in 1,4-dioxane solvent, a high yield (75–94%) was achieved within 60 min.
Weinreb amide shows high selectivity in the reaction, even in presence of other active functional groups
such as carboxyl, halogen, cyano, and methoxy.
Received 31 December 2012
Revised 9 March 2013
Accepted 13 March 2013
Available online 23 March 2013
Keywords:
O
Weinreb amide
Benzimidazoles
Benzothiazoles
Boron trifluoride etherate
o-Diaminoarene
o-Aminothiophenol
R1
NH2
R1
N
X
BF3·OEt2
R
N
O
R
+
1,4-dioxane
X
H
100 °C
X : NH, S
R
1 : H, CH3, Br
R : Alkyl, Alkenyl, Aryl, Heteroaryl
Ó 2013 Elsevier Ltd. All rights reserved.
2-Substituted benzimidazoles and benzothiazoles have gained
importance in medicinal chemistry. They have been in use as
anti-inflammatory,1a antimicrobial,1b anti-ulcer,1c antihelmentic,1c
antihypertensive,1d anti-analgesic,1e antivirus,1f and anticancer
agents.1g The general method of synthesis of 2-substituted benzim-
idazoles involves the reaction between o-diaminoarene and a car-
boxylic acid or an acid chloride or nitrile or imadates or ortho
esters. The condensation of arenealdehyde with 1,2-diaminoben-
zene to form a Schiff base which undergoes intramolecular cycliza-
benzimidazoles through transition-metal catalyzed amination fol-
lowed by condensation has also been reported.8,9
Similarly, the classical approach for the synthesis of 2-substi-
tuted benzothiazoles is by condensation of o-aminothiophenols
with aldehydes using oxidants or oxidation process such as
MnO2/SiO2,10 silica-sulfuric acid,11a p-TsOH, or graphite on the sur-
face of solid mineral supports under microwave irradiation,11b–f I2/
DMF,12 1-phenyl-3-methylimidazolium bromide {[PmIm]Br} un-
der microwave irradiation,13 activated carbon (Shirasagi KL or Dar-
coÒ KB) under oxygen atmosphere,14 O2 or H2O2 in the presence of
Sc(OTf)3,15 ceric ammonium nitrate (CAN),16 pyridinium chloro-
chromate,17 electro oxidation,18 solvent and catalyst-free micro-
wave irradiation,19 trichloroisocyanuric acid,20 and perchloric
acid-doped polyaniline.21 However, the above mentioned methods
suffer from several disadvantages like harsh reaction conditions
(strong acid, high temperature), high catalyst cost, occurrence of
side reactions (which leads to poor yield and difficulty in isolation),
low reaction rate, additional oxidation step, tedious work-up pro-
tion generating
a
dihydrobenzimidazole which undergoes
dehydrogenation by 1,4-benzoquinone.2 Alternative oxidants that
can be used are 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ),3
manganese dioxide,4 lead tetraacetate {Pb(OAC)4},5 potassium-
monopersulfate (oxone),6 and sodium bisulfate.7 Synthesis of
⇑
Corresponding authors. Tel.: +91 821 2419661; fax: +91 821 2500846.
E-mail addresses: rangappaks@uni-mysore.ac.in, rangappaks@gmail.com (K.S.
Rangappa), mpsadashiva@gmail.com (M.P. Sadashiva).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.075

2694
Y. K. Bommegowda et al. / Tetrahedron Letters 54 (2013) 2693–2695
Table 1
Table 2
Optimization of reaction conditions for the synthesis of 2-phenyl-1H-benzimidazole
3a from N-methoxy-N-methylbenzamide 1a with o-diamino benzene 2a
The reactivity of boron trifluoride etherate in various solvents and at temperatures
during the synthesis of 2-phenyl-1H-benzimidazole 3a from N-methoxy-N-methylb-
enzamide 1a with o-diaminoarene 2a
O
Entry Equivalent Solvent
Temperature (°C) Time (min) Yielda (%)
H2N
N
Lewis acid
01
02
03
04
05
06
07
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1,4-Dioxane 100
EDC
DMF
Toluene
Benzene
THF
60
60
60
60
60
60
60
89
40
45
82
76
32
25
+
Solvent
N
O
90
100
100
90
70
90
N
H2N
H
1a
3a
2a
CH3CN
a
Isolated yields.
Entry Lewis acid (1.0 equiv) Temperature (°C) Time (min) Yielda (%)
01
02
03
04
05
06
07
08
09
ZnCl2
ZnCl2
AlCl3
FeCl3
SnCl4
BF3ÁOEt2
Sc(OTf)3
InCl3
RT
—
0
20
35
27
42
88
34
48
54
100
100
100
100
100
100
100
100
60
60
60
60
60
60
60
60
Table 3
Synthesis of 2-substituted bezimidazoles 3a–l from Weinreb amides 1a–j
Entry
R
1
R1
3
Yielda (%)
01
02
03
04
05
06
07
08
09
10
11
12
Phenyl
1a
1b
1c
1d
1e
1f
1g
1h
1a
1g
1i
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
90
81
78
75
78
80
90
89
87
84
77
86
4-Carboxyphenyl
2-Carboxyethyl
4-Pyridyl
2-(4-Pyridyl)ethyl
Allyl
PTSA
a
Isolated yield.
Me
4-Bromophenyl
Phenyl
Me
3-Pyridyl
Cyclohexylmethyl
cedure, and lack of selectivity. The present method aims at over-
coming all these problems.
CH3
Br
H
3j
3k
3l
N-Methoxy-N-methylamide is popularly known as Weinreb
amide, which Nahm and Weinreb first employed in the synthesis
of ketones from organometallics and also used as acylating agent
to synthesize ester enolate.22 Nowadays, the versatility of this re-
agent has been increased in organic synthesis for instance, in the
preparation of aldehydes,23a ketones by classical Wittig
reaction,23b Grignard reactions,24a,b organolithium additions,24c–e
lithium aluminum hydride reductions,24f acylation of oxazole,25
pyrazoles,26 nitriles,27 pyrrole carbaldehyde and pyrrolidinones,28
trifluoromethyl ketones,29 etc. The four main reasons for its in-
creased use by chemists as a reagent in organic synthesis are the
stability of Weinreb amide functionality, ease of preparation, the
scalability of reaction and predictability. As part of our research
on Weinreb amide application, we tried one pot syntheses of 2-
substituted benzimidazoles and benzothiazoles.
Weinreb amides were synthesized from the carboxylic acid by
coupling with N,O-dimethyl-hydroxyl amine.30 Optimization of
the reaction conditions and parameters were stabilized for the syn-
thesis of 2-phenyl-1H-benzimidazole (3a) by cyclization of N-
methoxy-N-methylbenzamide (1a) with o-diamino benzene (2a)
using various Lewis acids in 1,4-dioxane solvent (Table 1).
The reaction was carried out initially between 1a and 2a in the
presence of zinc chloride as Lewis acid in 1,4-dioxane at room tem-
perature, but product 3a was not obtained even after a prolonged
time of 24 h (Table 1, entry 1). When the reaction was continued
at 100 °C no improvement in yield was observed (Table 1, entry
2). Further, the reaction was done with various Lewis acids such
as AlCl3, FeCl3, SnCl4, BF3ÁOEt2, Sc(OTf)3, InCl3 and PTSA to enhance
the product yield (Table 1, entries 3–9). Among these reagents,
only BF3ÁOEt2 gave the highest product yield of 88% (Table 1, entry
6).
1j
H
a
Isolated yields.
was examined in the presence of active carboxyl, halogens, cyano,
and methoxy groups.
Weinreb amide showed high reactivity and selectively partici-
pated in the cyclization reaction to obtain a very good yield within
a short time (Table 3, entries 2 and 3)(Scheme 1).
The optimized reaction conditions were further used to synthe-
size 2-alkyl/aryl/heteroaryl benzothiazoles from Weinreb amides
by replacing o-diminoarene with o-aminothiophenol (Scheme 2).31
The reaction afforded 2-substituted benzothiazole with good yield
(Table 4, entries 1–9). Further, the reaction was carried out with o-
aminophenol with the expectation to generate 2-arylbenzoxazole,
but the yield obtained was very low (ꢀ15%) (Scheme 3). This may
be due to lower nucleophilicity of oxygen than of nitrogen and
sulfur.
In conclusion, Weinreb amide has proved to be an effective re-
agent to synthesize 2-substituted benzimidazoles and benzothiaz-
oles in the presence of boron trifluoride etherate in 1,4-dioxane
solvent at 100 °C. The optimized procedure is a one pot synthesis
and shows high selectivity, because the amide function alone par-
ticipates in the cyclization reaction even in the presence of active
functional groups like carboxyl, halogens, cyano, and methoxy on
the carbon skeleton of the Weinreb amide. This method may suc-
cessfully replace the earlier methods for the preparation of 2-
substituted benzimidazoles and benzothiazoles which are cur-
rently prepared with non-commercial and unstable or sensitive
aldehydes and acid chlorides.
The solvent and temperature factors on the cyclization reaction
between 1a and 2a in the presence of boron trifluoride etherate
were optimized (Table 2). Although most of the solvents promoted
the reaction, 1,4-dioxane and toluene were found suitable media at
100 °C conditions (Table 2, entries 1 and 4).
Finally, the optimized reaction conditions were used to study
the generality of the protocol and scope of this cyclization reaction.
We have studied the reactivity of various alkyl, alkenyl, aryl, and
hetero aryl Weinreb amides and the selectivity of Weinreb amide
R1
NH2
R1
O
R
N
BF3·OEt2
N
R
+
NH2
1,4-dioxane
N
H
O
100 °C
1a-j
3a-l
2
Scheme 1. The cyclization of o-diaminoarene 2a with various Weinreb amides 1a–j
in the presence of boron trifluoride etherate.

Y. K. Bommegowda et al. / Tetrahedron Letters 54 (2013) 2693–2695
2695
Connolly, T. M.; Condra, C. L.; Xia, M.; Cunningham, M. E.; Bednar, B.; Stump, G.
L.; Lynch, J. J.; Macaulay, A.; Wafford, K. A.; Koblan, K. S.; Liverton, N. J. J. Med.
Chem. 2004, 47, 2089; (b) Wilfred, C. D.; Taylor, R. J. K. Synlett 2004, 1628.
5. Stephens, F. F.; Bower, J. D. J. Chem. Soc. 1949, 2971.
6. Beaulieu, P. L.; Hache, B.; von Moos, E. A. Synthesis 2003, 1683.
7. Weidner-Wells, M. A.; Ohemeng, K. A.; Nguyen, V. N.; Fraga-Spano, S.;
Macielag, M. J.; Werblood, H. M.; Foleno, B. D.; Webb, G. C.; Barrett, J. F.;
Hlasta, D. J. Bioorg. Med. Chem. Lett. 2001, 11, 1545.
N
S
NH2
SH
O
R
BF3·OEt2
R
+
N
1,4-dioxane
O
100 °C
1a,b,d,f,j-n
5a
4a-i
Scheme 2. The cyclization of o-aminothiophenol 5a with various Weinreb amides
1a,b,d,f,j–n in the presence of boron trifluoride etherate.
8. (a) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem. 2007, 119, 2652. Angew. Chem., Int. Ed.
46, 2598; (b) Surpur, M. P.; Singh, P. R.; Patil, S. B.; Samant, S. D. Synth. Commun.
2007, 37, 1375.
9. (a) Massimo, C.; Francesco, E.; Francesca, M.; Ornelio, R.; Sara, T. Synlett 2004,
1832; (b) Moorthy, J. N.; Neogi, I. Tetrahedron Lett. 2011, 52, 3868.
10. Bougrin, K.; Loupy, A.; Soufiaoui, M. Tetrahedron 1998, 54, 8055.
11. (a) Patil, D. R.; Salunkhe, S. M.; Sambavekar, P. P.; Deshmukh, M. B.; Kolekar, G.
B.; Der Anbhule, P. V. Pharma Chemica 2011, 3, 189; (b) Rostamizadeh, S.;
Housaini, S. A. Gh. Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 1321; (c)
Pratap, U. R.; Mali, J. J.; Jawale, D. V.; Mane, R. A. Tetrahedron Lett. 2009, 50,
1352; (d) Guo, H. Y.; Li, J. C.; Shang, Y. L. Chin. Chem. Lett. 2009, 20, 1408; (e)
Niralwad, K. S.; Shingate, B. B.; Shingare, M. S. Bull. Korean Chem. Soc. 2010, 31,
981; (f) Algul, O.; Kaessler, A.; Apcin, Y.; Yilmaz, A.; Jose, J. Molecules 2008, 13,
736.
12. Moghaddam, F. M.; Bardajee, G. R.; Ismaili, H.; Taimoory, S. M. D. Synth.
Commun. 2006, 36, 2543.
13. Ranu, B. C.; Jana, R.; Dey, S. S. Chem. Lett. 2004, 33, 274.
14. Kawashita, Y.; Ueba, C.; Hayashi, M. Tetrahedron Lett. 2006, 47, 4231.
15. (a) Itoh, T.; Nagata, K.; Ishikawa, H.; Ohsawa, A. Heterocycles 2004, 62, 197; (b)
Itoh, T.; Nagata, K.; Ishikawa, H.; Ohsawa, A. Heterocycles 2004, 63, 2769.
16. (a) Al-Qalaf, F.; Mekheimer, R. A.; Sadek, K. U. Molecules 2008, 13, 2908; (b)
Nair, V.; Deepthi, A. Chem. Rev. 1862, 2007, 107.
Table 4
Synthesis of 2-substituted benzothiazoles 4a–i from Weinreb amides 1a,b,d,f,j–n
Entry
R
1
4
Yielda (%)
01
02
03
04
05
06
07
08
09
Phenyl
1a
1b
1k
1d
1l
1m
1n
1f
4a
4b
4c
4d
4e
4f
4g
4h
4i
94
76
81
75
89
92
94
88
89
4-Carboxyphenyl
3-Cyano phenyl
4-Pyridyl
4-Fluoro-3-methoxyphenyl
4-Ethylphenyl
Benzo[1,3]dioxolyl
Allyl
2-Carboxyethyl
1j
a
Isolated yields.
17. Praveen, C.; Hemanth kumar, K.; Muralidharan, D.; Perumal, P. T. Tetrahedron
2008, 64, 2369.
18. Okimoto, M.; Yoshida, T.; Hoshi, M.; Hattori, K.; Komata, M.; Tomozawa, K.;
Chiba, T. Heterocycles 2008, 75, 35.
19. Mukhopadhyay, C.; Datta, A. Heterocycles 1837, 2007, 71.
20. Xiao, H.-L.; Chen, J.-X.; Liu, M.-C.; Zhu, M.-C.; Ding, J.-C.; Wu, H.-Y. Chem. Lett.
2009, 38, 170.
21. Abdollahi-Alibeik, M.; Poorirani, S. Phosphorus, Sulfur Silicon Relat. Elem. 2009,
184, 3182.
O
N
O
NH2
BF3·OEt2
N
+
O
1,4-dioxane
OH
100 °C
1a
6a
7a
15%
22. Ohshima, T.; Xu, Y.; Takita, R.; Shimizu, S.; Zhong, D.; Shibasaki, M. J. Am. Chem.
Soc. 2002, 124, 14546.
23. (a) Hisler, K.; Tripoli, R.; Murphy, J. A. Tetrahedron Lett. 2006, 47, 6293; (b)
Murphy, J. A.; Commeureuc, A. G. J.; Snaddon, T. N.; McGuire, T. M.; Khan, T. A.;
Hisler, K.; Dewis, M. L.; Carling, R. Org. Lett. 2005, 7, 1427.
24. (a) Conrad, R. M.; Grogan, M. J.; Bertozzi, C. R. Org. Lett. 2002, 4, 1359; (b) Parhi,
A. K.; Franck, R. W. Org. Lett. 2004, 6, 3063; (c) Ruiz, J.; Sotomayor, N.; Lete, E.
Org. Lett. 2003, 5, 1115; (d) Davis, F. A.; Prasad, K. R.; Brad Nolt, M.; Wu, Y. Org.
Lett. 2003, 5, 925; (e) Taillier, C.; Bellosta, V.; Meyer, C.; Cossy, J. Org. Lett. 2004,
6, 2145; (f) Singh, J.; Satyamurthi, N.; Aidhen, I. S. J. Prakt. Chem. 2000, 342, 340.
25. (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815; (b) Pippel, D. J.;
Mapes, C. M.; Mani, N. S. J.Org. Chem. 2007, 72, 5828.
Scheme 3. The cyclization of o-aminophenol 6a with N-methoxy-N-methyl-benz-
amide 1a in the presence of boron trifluoride etherate.
Acknowledgements
The authors thank UGC, Govt. of India for the financial supports
to M.P.S under the projects vide F. No. 37-456/2009[SR] dated: 12-
01-2010 and UOM/IOE/RESEARCH/1/2010-11 dated: 22-04-2010.
26. Alberola, A.; Gonzalez Ortega, A.; Luisa Sádaba, M.; Sañudo, C. Tetrahedron
1999, 55, 6555.
Supplementary data
27. Suzuki, Y.; Yoshino, T.; Moriyama, K.; Togo, H. Tetrahedron 2011, 67, 3809.
28. Coffin, A. R.; Roussell, M. A.; Tserlin, E.; Pelkey, E. T. J. Org. Chem. 2006, 71, 6678.
29. Rudzinski, D. M.; Kelly, C. B.; Leadbeater, N. E. Chem. Commun. 2012, 48, 9610.
30. (a) Niu, T.; Zhang, W.; Huang, D.; Xu, C.; Wang, H.; Hu, Y. Org. Lett. 2009, 11,
4474; (b) Braun, M.; Waldmüller, D. Synthesis 1989, 856; (c) Sawamura, M.;
Nakayama, Y.; Kato, T.; Ito, Y. J. Org. Chem. 1995, 60, 1727; (d) Gibson, C. L.;
Handa, S. Tetrahedron: Asymmetry 1996, 7, 1281; (e) Angelastro, M. R.; Peet, N.
P.; Bey, P. J. Org. Chem. 1989, 54, 3913; (f) Moyer, M. P.; Shiurba, J. F.; Rapoport,
H. J. Org. Chem 1986, 51, 5106; (g) Goel, O. P.; Krolls, U.; Sterr, M.; Kesten, S. Org.
Synth. 1989, 67, 69; (h) Theisen, P. D.; Heathcock, C. H. J. Org. Chem. 1988, 53,
2374; (i) Nitz, T. J.; Volkots, D. L.; Aldous, D. J.; Oglesby, R. C. J. Org. Chem. 1994,
59, 5828; (j) Goel, O. P.; Krolls, U. Org. Prep. Proced. Int. 1987, 19, 75; (k) Basha,
A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 18, 4171; (l) Sha, C.-K.;
Huang, S.-J.; Zhan, Z.-P. J. Org. Chem. 2002, 67, 831.
Supplementary data (Supplementary data 1H NMR and 13C NMR
of the synthesized compounds described in Schemes 1 and 2 are
associated with this article are available, in the on-line version)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2013.03.075.
References and notes
1. (a) Mader, M.; de Dios, A.; Shih, C.; Anderson, B. D. Bioorg. Med. Chem. Lett. 2008,
18, 179; (b) Arjmand, F.; Mohani, B.; Ahmad, S. Eur. J. Med. Chem. 2005, 40,
1103; (c) Mavrova, A. T.; Anichina, K. K.; Vuchev, D. I.; Tsenov, J. A.; Denkova, P.
S.; Kondeva, M. S.; Micheva, M. K. Eur. J. Med. Chem. 2006, 41, 1412; (d) Kohara,
Y.; Kubo, K.; Imamiya, E.; Wada, T.; Inada, Y.; Naka, T. J. Med. Chem. 1996, 39,
5228; (e) Elmer, G. I.; Pieper, J. O.; Goldberg, S. R.; George, F. R.
Psychopharmacology (Berl.) 1995, 117, 23; (f) Gualtieri, F.; Brody, G.;
Fieldsteel, A. H.; Skinner, W. A. J. Med. Chem. 1972, 15, 420; (g) Tamm, I.
Science 1957, 126, 1235.
2. Verner, E.; Katz, B. A.; Spencer, J. R.; Allen, D.; Hataye, J.; Hruzewicz, W.; Hui, H.
C.; Kolesnikov, A.; Li, Y.; Luong, C.; Martelli, A.; Radika, K.; Rai, R.; She, M.;
Shrader, W.; Sprengeler, P. A.; Trapp, S.; Wang, J.; Young, W. B.; Mackman, R. L.
J. Med. Chem. 2001, 44, 2753.
31. General Procedure: To
a stirred solution of Weinreb amide (5 mmol), o-
diaminoarene or o-aminothiophenol (5 mmol) in 1,4-dioxane (10 mL) was
added BF3ÁOEt2 (5 mmol). The resulting mixture was heated at 100 °C under
nitrogen atmosphere for the specified time (Table 3 and 4). After completion of
the reaction as indicated by TLC, the mixture was quenched with saturated
ammonium chloride solution (40 mL) and extracted with ethyl acetate
(3 Â 25 mL). The combined organic layers were washed with water
(2 Â 25 mL), brine solution (2 Â 25 mL), dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuum. The resulting residue was purified by
column chromatography on silica gel (Merck, 60–120 mesh, appropriate ethyl
acetate and hexane mixture, 1:1 or 3:7) to afford the pure product.
3. Eynde, J. J. V.; Delfosse, F.; Lor, P.; Haverbeke, Y. V. Tetrahedron 1995, 51, 5813.
4. (a) McCauley, J. A.; Theberge, C. R.; Romano, J. J.; Billings, S. B.; Anderson, K. D.;
Claremon, D. A.; Freidinger, R. M.; Bednar, R. A.; Mosser, S. D.; Gaul, S. L.;