Construction of substituted imidazoles from aryl methyl ketones and benzylamines via N-heterocyclic carbene-catalysis

Article abstract of DOI:10.1016/j.catcom.2019.03.009

A novel synthetic strategy for the construction of substituted imidazoles from acetophenones and benzylamines via N-heterocyclic carbene (NHC) - catalysis was reported. This reaction can be performed under solvent-free condition without pre-functionalization of substrates. Various substituted acetophenones and benzylamines were converted to its corresponding imidazoles with good to excellent yields.

Full text of DOI:10.1016/j.catcom.2019.03.009

Accepted Manuscript
Construction of substituted imidazoles from aryl methyl ketones
and benzylamines via N-heterocyclic carbene-catalysis
A. Anitha Alanthadka, E. Sankari Devi, T. Pavithra, S. Nagarajan,
V. Sridharan, C. Uma Maheswari
PII:
S1566-7367(19)30078-0
DOI:
Reference:
https://doi.org/10.1016/j.catcom.2019.03.009
CATCOM 5647
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
29 December 2018
2 March 2019
7 March 2019
Please cite this article as: A.A. Alanthadka, E.S. Devi, T. Pavithra, et al., Construction
of substituted imidazoles from aryl methyl ketones and benzylamines via N-heterocyclic
carbene-catalysis,
Catalysis
Communications,
https://doi.org/10.1016/
j.catcom.2019.03.009
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ACCEPTED MANUSCRIPT
Construction of Substituted Imidazoles from Aryl Methyl Ketones and Benzylamines
via N-Heterocyclic Carbene-Catalysis
a
c
A. Anitha Alanthadka a, E. Sankari Devi a, T. Pavithra , S. Nagarajan b, V. Sridharan , and
C. Uma Maheswari*a
a
Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed
University, Thanjavur-613401, India.
b Department of Chemistry, National Institute of Technology-Warangal, Warangal-506004,
India.
c
Department of Chemistry and Chemical Sciences, Central University of Jammu,
Rahya-Suchani (Bagla), District-Samba, Jammu-181143, J&K, India.
Abstract
A novel synthetic strategy for the construction of substituted imidazoles from
acetophenones and benzylamines via N-heterocyclic carbene (NHC) - catalysis was reported.
This reaction can be performed under solvent-free condition without pre-functionalization of
substrates. Various substituted acetophenones and benzylamines were converted to its
corresponding imidazoles with good to excellent yields.
Keywords: N-Heterocyclic Carbene; Imidazoles; Aryl methyl ketones; Benzylamines;
Oxidation.

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1. Introduction
Imidazoles are one of the most important five membered nitrogen-heterocycle
possessing broad range of pharmaceutical and industrial applications. Imidazole nuclei are
present in many compounds with enhanced biological activities such as anti-inflammatory,
glucagon antagonist, antiviral, antimicrobial, angiotensin inhibitors, fungicidal and high
cytotoxicity, thus enabling them as them as suitable candidates for cancer therapy [1-6]. The
structures of some of the commercial imidazole-core drugs including Cimetidine (І),
Trifenager (II), Ketoconazole (III) and compound (IV) are shown in Figure 1 [7]. The high
therapeutic properties of the substituted imidazole based drugs have encouraged the synthetic
chemists to develop new strategies for the construction of chemotherapeutic agents
possessing imidazole nucleus [8-11]. There were several reports on the synthesis of imidazole
scaffolds in the past few years [12,13] employing catalysts including transition-metals [14-
16], Lewis acids [17-19] and bases [20]. In similar lines, Iodine catalysed synthesis of
substituted imidazoles was also reported [21]. But, these synthetic methods are associated
with one or more drawbacks such as use of expensive reagents, metal catalysts, complex
work-up procedures, generation of excess toxic wastes, harsh reaction conditions, poor yields
and occurrence of side reactions etc.
Fig. 1. Structures of commercial imidazole-core drugs
In this context, development of effective, economical, clean and mild environmentally
benign protocols is highly desirable for the construction of imidazole scaffolds. Among
various aspects of green chemistry, significant one is to avoid the use of metal catalysts and

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substitute it with organocatalysts. Moreover, application of organocatalysis for the synthesis
of highly substituted imidazoles has not been well explored.
Thus, there is ample scope for the development of new synthetic strategy for the
formation of substituted imidazoles employing N-heterocyclic carbenes (NHCs) as
organocatalyst. There were several reports based on N-Heterocyclic Carbenes (NHC) as an
organocatalyst [22] and unlike phosphine ligands, NHCs are found to be very stable under
oxidative conditions. Construction of oxygen containing heterocycles via C-O bond
formation under N-heterocyclic catalysis was employed for the formation of pthalimides,
pyrans and isocoumarins [23]. Similarly, construction of nitrogen containing heterocycles
like pyridinones, Oxindoles and Indole, via direct C-N bond formation was achieved
employing NHCs as organocatalysts [24-27]. In case of organocatalysed synthesis of
substituted imidazoles, Tillyer et. al have carried out thiazolium-catalyzed synthesis of
substituted imidazole from aldehydes and α-amido sulfones [28].
2. Experimental Section
General procedure for the NHC catalysed synthesis of substituted imidazoles:
Mixture of NHC pre-catalyst (0.042 g, 0.1 mmol), K2CO3 (0.013 g, 0.1 mmol),
acetophenone derivative (1a: 0.120 g, 1.0 mmol), benzylamine derivative (2a: 0.321 g, 3.0
mmol) and BF3·OEt2 (0.014 g, 10 mol%) followed by 70% TBHP in H2O (0.25 mL, 2.0
mmol) was taken in round bottom flask and stirred at 80 oC for 15 h. Progress of the reaction
was monitored by TLC. After the completion of the reaction, the mixture was washed with
plenty of water and extracted with ethyl acetate. The extract was washed with brine solution
and dried over anhydrous Na2SO4. Removal of the solvent under vacuum afforded the crude
product, which was purified by column chromatography using hexane/ethyl acetate mixture.
All the substituted imidazoles given below are synthesized using general procedure.

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3. Results and Discussion
As a part of our ongoing study on organocatalytic oxidative transformations mediated
by N-heterocyclic carbenes (NHC), we have recently reported NHC-catalysed oxidative
amidation of aldehydes with amines, benzylic sp3 C-H bond activation of alkylarenes and N-
benzylamines under metal-free conditions, and the synthesis of β-keto amines from aryl
methyl ketones and 2-aminopyridines [29]. Herein, we report a novel, efficient and practical
route for the synthesis of substituted imidazoles from aryl methyl ketones with benzylamines
catalysed by N-heterocyclic carbenes.
To begin with, when benzylamine (2a; 3.0 mmol) was treated with a mixture containing
acetophenone (1a; 1.0 mmol), NHC precatalyst A (0.1 mmol), and t-BuOK (0.1 mmol),
BF3·
OEt2 (0.1 mmol) in presence of aq. tert-butyl hydroperoxide (TBHP) as oxidant at 80 oC
under solvent free condition, the substituted imidazole 3a was obtained in 42% yield upon
isolation (Table 1, Entry 1). To improve the yield of 3a, several other NHC precatalysts from
Fig. 2. Structures of various NHC-precatalysts used for the synthesis
of imidazoles
to G were examined and among the NHCs screened, precatalysts A to C gave the moderate
yields (up to 57%; Entries 1-3). Other NHC salts D-G gave comparatively similar yield of the
desired product, and D was found to be slightly better for this oxidative cyclization (Entries
4-7).

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Table 1. Optimization condition for NHC catalysed synthesis of substituted imidazolesa
S.
NHC
pre-
Lewis acid
Base
Yield
(%)b
No
catalyst
A
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
BF3
BF3
BF3
BF3
BF3
BF3
BF3
BF3
BF3
BF3
BF3
BF3
BF3
BF3
BF3
·
·
·
·
·
·
·
·
·
·
·
·
·
·
·
OEt2
OEt2
OEt2
OEt2
OEt2
OEt2
OEt2
OEt2
OEt2
OEt2
OEt2
OEt2
OEt2
OEt2
OEt2
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
K2CO3
Cs2CO3
NaOH
42
47
57
75
66
72
61
78
66
38
53
40
38
43
71c
53
67
56
65
48
NRd
66e
64f
57g
B
C
D
E
F
G
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
Et3N
Morpholine
Piperidine
DBU
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Yb(OTf)3
Sc(OTf)3
InCl3
SnCl2
·2H2O
CAN
BF3
·
·
·
·
OEt2
BF3
BF3
BF3
OEt2
OEt2
OEt2
a Reaction conditions: Acetophenone 1a (1.0 mmol), benzylamine 2a (3.0 mmol), NHC precatalyst A-G (10 mol
o
c
%), base (10 mol%), TBHP (3.0 equiv.), Lewis acid (10 mol%), 80 C, 15 h. b Isolated yield. TBHP in decane
ο
f
as oxidant. d Reaction at rt. e Reaction at 60 C. 2.0 equiv. of oxidant used. g NHC precatalyst (5 mol%) and
Et3N (5 mol%) for 24 h.
Once the NHC precatalyst D was fixed, different bases were tested for this oxidative
coupling reaction and among inorganic bases, K2CO3 was found to be superior as compared
to NaOH and Cs2CO3 (Entries 8-10). Different organic bases such as Et3N, Morpholine,
Piperidine and 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) were also tested but yields were

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not satisfactory (Entries 11-14). Then we shifted our attention on fixing suitable oxidant for
the formation of substituted imidazoles. We found out that only THBP proved to be the
suitable oxidant and when TBHP in decane was used as the oxidant, the product was obtained
in slightly lower yield compared to aq. TBHP (Entries 8, 15). Other peroxides like aq. H2O2,
di-t-butyl peroxide (DTBP), dicumyl peroxide (DCP) and tert-butyl peroxybenzoate (TBPB)
failed to furnish the desired product.
Similarly the reaction failed with N-bromosuccinimide (NBS) and N-chlorosuccinimide
(NCS) as the oxidant. In order to examine the effect of Lewis acid for the formation of
Scheme 1. Substrate scope for oxidative synthesis of substituted imidazoles

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substituted imidazoles, various Lewis acids were screened including Yb(OTf)3 , Sc(OTf)3,
incl3, SnCl2·2H2O and ceric ammonium nitrate (CAN) (Entries 16-20). The yields were found
to be moderate but better yield was observed with BF3·OEt2 as Lewis acid (Entry 8). Effect of
temperature on the formation of imidazoles was studied and the when the reaction was
carried out at room temperature, the reaction does not proceed (Entry 21). Gradual increase in
ο
the reaction temperature increases the product production and the yield was optimal at 80 C
(Entries 22 & 8). When the reaction was carried out with 2.0 equivalent of oxidant, yield of
the desired product decreased significantly (Entry 23). When the reaction was performed with
low catalyst loading (5 mol% of d), there is a considerable decrease in the product yield
(Entry 24). Thus we arrived at the optimized reaction NHC pre-catalyst D (10 mol%), K2CO3
(10 mol%) as base, BF3·Et2O (10 mol%) as Lewis acid, TBHP in water as oxidant (3.0
o
equiv.) at 80 C for 15 h (Entry 8). With the optimal conditions, the scope and limitations of
the NHC-catalysed construction of substituted imidazoles employing several substituted aryl
methyl ketones and benzylamines were examined and the results were summarized in scheme
1.
Initially, benzylamines having different substituents at ortho, meta and para positions
were subjected to oxidative coupling with acetophenone. Irrespective of the nature of the
substituent at para position (-H, -OMe, -Me, -F), moderate to good yields were observed (3a-
3d). But when 2-methylbenzylamine was taken as the substrate, the yield of the desired
imidazole product (3e) decreased considerably to 58%. This may be due to the steric effect of
ortho substituent on the product formation. When 3-methoxybenzylamine was taken as the
substrate, only trace amount of the desired substituted imidazole was observed (3f) along
with corresponding amide and imine as the major products. Next we turned our attention to
study the scope and limitations of this NHC-catalysed process for aryl methyl ketones.
Various substituted aryl methyl ketones were reacted with benzylamine. It was found that

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irrespective of the nature of substituent present at the para position, the reaction proceeds
well to give the desired product 3g-3k in good to excellent yield. The yield was slightly
higher for halogens like chloro and bromo substituent at para position- 89% and 81%
respectively. When 2-chloroacetophenone was taken as the aryl methyl ketone variant, only
trace amount of the desired product was obtained which may be attributed to the steric factors
(3l). When 2-acetonaphthone was used as substrate for the oxidative coupling with
benzylamine, corresponding substituted imidazole was obtained in 86% yield (3m). Similarly
when heterocyclic ketone, 2-acetylthiophene was employed as the substrate, 77% of the
desired product was obtained (3n).
To probe the reaction mechanism, we have carried out following control experiments
using acetophenone and benzylamine as the model substrates (scheme 2). In the absence of
Lewis acid, the reaction failed completely and the desired imidazole was not observed (Eq.
1). Similar observation was made when the reaction was performed in absence of oxidant
Scheme 2. Control experiments

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(Eq. 2), which proves the role of Lewis acid and oxidant for the formation of imidazole.
When the reaction was performed in absence of NHC catalyst, the yield of the desired
imidazole fall sharply from 78% to mere 34% along with 52% of N-benzylbenzamide (3o) as
the major product (Eq. 3). When the reaction was performed with other Lewis acids like
Yb(OTf)3, Sc(OTf)3, InCl3, SnCl2·2H2O and in the absence of NHC, amide was observed as
the major product. These experiments signifies the importance of NHC for this reaction.
When the reaction was carried out in presence of CH3CN as the solvent, the yield of the
product decreased significantly compared to solvent free conditions, revealing that solvent
free condition is most suitable for the reaction (Eq. 4). When acetophenone was treated with
1.0 equiv. of benzylamine, the corresponding imine, N-benzyl-1-phenylethan-1-imine was
obtained as the product. To this imine, when excess benzylamine was added under our
optimized reaction condition, the desired imidazole was obtained in 82% yield, suggesting
that the imine acts as the intermediate during the course of the reaction (Eq. 5)
Based on the aforementioned results and previous reports [15, 21], a probable catalytic
cycle for this NHC-catalysed oxidative functionalization of aryl methyl ketones is outlined in
Scheme 3. Plausible reaction mechanism for NHC-catalysed construction of imidazoles

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Scheme 3. Acetophenone reacts with 1.0 equiv. of benzylamine in the presence of Lewis acid
to form imine I, which can undergo tautomerization to give the enamine II. The formation of
imine as intermediate was confirmed by the control experiment (Eq. 5). Enamine II on
oxidation in presence of oxidant forms alcohol III which rearranges to give intermediate
aldehyde IV. Formation of Breslow intermediate between the reaction of NHC and aldehydes
were well documented [30-32] and similar to the previous reports, we have proposed Breslow
intermediate V between NHC and aldehyde IV. Intermediate V on reaction with another
molecule of benzylamine gives intermediate VI with the regeneration of free carbene.
Intermediate VI on dehydration generates VII, which subsequently undergoes intramolecular
cyclization to yield VIII. Dehydrogenation of VIII in presence of oxidant leads to the desired
imidazole product 3a.
4. Conclusion
In conclusion, a novel NHC-catalysed synthesis of substituted imidazoles was
reported under solvent free conditions. This strategy eliminates the use of transition
metals and pre-functionalization of substrates which were common in conventional
methods for the synthesis of substituted imidazoles. Various substituted acetophenones
including 2-acetonaphthone, 2-acetylthiophene and benzylamines tolerated the
reaction condition to give the respective substituted imidazoles in good to excellent
yield.
Acknowledgements
Financial support from the Department of Science and Technology, DST, New Delhi for
the award of a research grant EMR/2016/002485/OC is gratefully acknowledged.
Conflict of interest
There is no conflict of interest.

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Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.doi.org/.
References
[1] A. D. Palkowitz, M. I. Steinberg, K. J. Thrasher, J. K. Reel, K. L. Hauser, K. M. Zimmerman, S. A.
Wiest, C. A. Whitesitt, R. L. Simon, W. Pfeifer, S. L. Lifer, D. B. Boyd, C. J. Barnett, T. M. Wilson, J.
B. Deeter, K. Takeuuchi, R. E. Riley, W. D. Miller, W. S. Marshall, J. Med. Chem. 37 (1994) 4508-
4521.
[2] J. I. Trujillo, J. R. Kiefer, W. Huang, A. Thorarensen, L. Xing, N. L. Caspers, J. E. Day, K. J. Mathis, K.
K. Kretzmer, B. A. Reitz, R. A. Weinberg, R. A. Stegeman, A. Wrightstone, L. Christine, R. Compton,
X. Li, Bioorg. Med. Chem. Lett. 19 (2009) 908-911.
[3] L. L. Chang, K. L. Sidler, M. A. Cascieri, S. D. Laszlo, G. Koch, B. Li, M. MacCoss, N. Mantlo, S.
O’Keefe, M. Pang, A. Rolando, W. K. Hagmann, Bioorg. Med. Chem. Lett. 11 (2001) 2549-2553.
[4] D. Sharma, B. Narasimhan, P. Kumar, V. Judge, R. Narang, E. D. Clercq, J. Balzarini, Eur. J. Med.
Chem. 44 (2009) 2347-2353.
[5] S. Kumar, J. Boehm, J. C. Lee, Nature Rev. Drug Disc. 2 (2003) 717-726.
[6] A. J. King, D. R. Patrick, R. S. Batorsky, M. L. Ho, H. T. Do, S. Y. Zhang, R. Kumar, D. W. Rusnak, A.
K. Takle, D. M. Wilson, E. Hugger, L. Wang, F. Karreth, J. C. Lougheed, J. Lee, D. Chau, T. J. Stout,
E. W. May, C. M. Rominger, M. D. Schaber, L. Luo, A. S. Lakdawala, J. L. Adams, R. G. Contractor,
K. S. M. Smalley, M. Herlyn, M. M. Morrissey, D. A. Tuveson, P. S. Huang, Cancer Res. 66 (2006)
11100-11105.
[7] M. M. Heravi, M. Daraie, V. Zadsirjan, Mol Divers 19 (2015) 577-623.
[8] A. K. Jain, V. Ravichandran, M. Sisodiya, R. K. Agrawal, Asian. Pac. J. Trop. Med. (2010) 471-474 and
references cited therein.
[9] A. Karakurt, M. Özalp, S. Işık, J. P. Stables, S. Dalkara, Bioorg. Med. Chem. 18 (2010) 2902-2911.
[10] V. Sharma, M. S. Y. Khan, Eur. J. Med. Chem. 36 (2001) 651-658.

ACCEPTED MANUSCRIPT
[11] D. Sharma, B. Narasimhan, P. Kumar, V. Judge, R. Narang, E. D. Clercq, J. Balzarini, Eur. J. Med.
Chem. 44 (2009) 2347-2353.
[12] F. Bellina, R. Rossi, Adv. Synth. Catal. 352 (2010) 1223-1276 and references cited therein.
[13] R. L. Giles, J. D. Sullivan, A. M. Steiner, R. E. Looper, Angew. Chem. Int. Ed. 48 (2009) 3116-3120.
[14] D. Tang, P. Wu, X. Liu, Y.-X. Chen, S.-B. Guo, W.-L. Chen, J.-G. Li, B.-H. Chen, J. Org. Chem. 78
(2013) 2746-2750 and references cited therein.
[15] Z.-J. Cai, S.-Y. Wang, S.-J. Ji, Org. Lett. 14 (2012) 6068-6071 and references cited therein.
[16] T. Yamauchi, F. Shibahara, T. Murai, J. Org. Chem. 79 (2014) 7185-7192.
[17] M. Kidwai, P. Mothsra, Tetrahedron Lett. 47 (2006) 5029-5031.
[18] B. Sadeghi, B. B. F. Mirjalili, M. M. Hashemi, Tetrahedron Lett. 49 (2008) 2575-2577.
[19] S. Petit, C. Fruit, L. Bischoff, Org. Lett. 12 (2010) 4928-4931.
[20] S. N. Murthy, B. Madhav, Y. V. D. Nageswar, Tetrahedron Lett. 51 (2010) 5252-5257.
[21] L. Xiang, Y. Niu, X. Pang, X. Yang, R. Yan, Chem. Commun. 51 (2015) 6598-6600.
[22] D. Enders, O. Niemeier, A. Henseler, Chem. Rev. 107 (2007) 5606-5655.
[23] J. Mahatthananchai, J. Kaeobamrung, J. W. Bode, ACS Catal. 2 (2012) 494-503 and references cited
therein.
[24] D.-L. Wang, Z.-Q. Liang, K.-Q. Chen, D.-Q. Sun, S. Ye, J. Org. Chem. 80 (2015) 5900-5905.
[25] Z.-F. Zhang, K.-Q. Chen, C.-L. Zhang, S. Ye, Chem. Commun. 53 (2017) 4327-4330.
[26] M. T. Hovey, C. T. Check, A. F. Sipher, K. A. Sceidt, Angew Chem. Int. Ed., Engl. 53 (2014) 9603-
9607.
[27] B. Wanner, J. Mahatthananchai, J. W. Bode, Org. Lett. 13 (2011) 5378-5381 and references cited
therein.
[28] D. E. Frantz, L. Morency, A. Soheili, J. A. Murry, E. J. J. Grabowski, R. D. Tillyer, Org. Lett. 6 (2004)
843-846.
[29] A. Anitha, E. S. Devi, A. Tamilselvi, S. Nagarajan, V. Sridharan, C. U. Maheswari, Adv. Synth. Catal.
359 (2017) 2369-2374 and references cited therein.

ACCEPTED MANUSCRIPT
[30] R. J. Breslow, Am. Chem. Soc. 80 (1958) 3719-3726 and references cited therein.
[31] Y.-K. Liu, R. Li, L. Yue, B.-J. Li, Y.-C. Chen, Y. Wu, L.-S. Ding, Org. Lett. 8 (2006) 1521-1524.
[32] S. D. Sarkar, A. Studer, Org. Lett. 12 (2010) 1992-1995.

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Highlights:
1. Metal & solvent free synthesis of imidazoles were achieved employing NHC catalysis
2. Imidazoles were prepared from readily available chemicals-ketones & benzylamines
3. Substrate scope include acetophenones like 2-acetonaphthone & 2-acetylthiophene
4. This strategy doesn’t employ pre-functionalization of starting materials