Synthesis 2018; 50(02): 361-370
DOI: 10.1055/s-0036-1588585
paper
© Georg Thieme Verlag Stuttgart · New York

Copper-Catalyzed Simultaneous Activation of C–H and N–H Bonds: Three-Component One-Pot Cascade Synthesis of Multi­substituted Imidazoles

Sachin D. Pardeshi
a  National Centre for Nanosciences and Nanotechnology, University of Mumbai, Vidyanagari, Kalina Campus, Santacruz (East), Mumbai-400098, India   Email: [email protected]
,
Pratima A. Sathe
a  National Centre for Nanosciences and Nanotechnology, University of Mumbai, Vidyanagari, Kalina Campus, Santacruz (East), Mumbai-400098, India   Email: [email protected]
,
Kamlesh S. Vadagaonkar
b  Department of Dyestuff Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga (East), Mumbai-400019, India
,
Lucio Melone*
c  Dipartimento di Chimica, Materiali ed Ingegneria Chimica, ‘G. Natta’, Politecnico Di Milano, via L. Mancinelli, 7, 20131 Milano, Italy   Email: [email protected]
,
Atul C. Chaskar*
a  National Centre for Nanosciences and Nanotechnology, University of Mumbai, Vidyanagari, Kalina Campus, Santacruz (East), Mumbai-400098, India   Email: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 11 September 2017

Accepted after revision: 12 September 2017

Publication Date:
10 October 2017 (online)

 


§ Authors contributed equally to this work.

Abstract

A copper-catalyzed expedient, practical, and straightforward approach for the one-pot three-component modular synthesis of multisubstituted imidazoles has been described by using arylacetic acids, N-arylbenzamidines, and nitroalkanes. The reaction involves simultaneous activation of C–H and N–H bonds of arylacetic acids and N-arylbenzamidines, respectively. The use of inexpensive copper sulfate as a catalyst, readily available starting materials, and Celite-free workup makes this protocol economically viable. Multisubstituted imidazoles were obtained in moderate to good yields with significant functional group tolerance and high regioselectivity.


#

In recent years, C–H functionalization has become a widely admired, elegant tool in organic synthesis due to selective construction of new bonds and rapid assembly of complex molecular framework from easily available simple starting materials. The mechanistic understanding of C–H functionalization has enabled extensive efforts for carbon–carbon and carbon–heteroatom bonds formation which has prompted the development of innovative synthetic strategies.[1] [2] Obviously, identifying a specific method is always a crucial starting point. Among various transition elements, copper has extensively been employed for C–H functionalization due to its variable oxidation states. Indeed, multicomponent-based target-oriented cascade strategies provided an efficient entry to nitrogen heterocycles owing to their multiple bond breaking and bond forming ability within a single step. A steady growth in their development bears witness to their usability.

Imidazole is a widely explored nitrogen heterocycle owing to its existence in many natural products[3] and pharmaceutical compounds.[4] Imidazole derivatives are known to exhibit a wide range of medicinal properties,[5] such as antifungal,[6] antitumor,[7] antibacterial,[8] antiplasmodium,[9] and anti-inflammatory.[10] Furthermore, they are also key constituents of numerous functional materials,[11] such as organic semiconductors,[12] dyes,[13] optoelectronic materials,[14] etc. In addition to this, imidazole salts are considered as elegant materials due to their liquid nature at room temperature and have been extensively used as catalysts and/or green reaction media as well as electrolytes for solar cells and batteries. These significant potential applications have led to the development of various methods for the synthesis of imidazole scaffolds with wide substitution patterns. Beside the classical and simple one-pot synthesis of imida­zoles by using 1,2-diketones/α-hydroxy ketones/α-halo ketones/α-amino ketones, primary amine, an aldehyde, and ammonium acetate, several novel protocols, such as aldimine cross-coupling,[15] catalyst-free domino reaction of 2-azido acrylates and nitrones,[16] cycloaddition of amidines and nitroolefins,[17] the three-component reaction,[18] Ni-catalyzed dehydrogenation of benzylic-type imines,[19] and Zn-catalyzed cyclization of 2-(tetrazol-5-yl)-2H-azirines and imines,[20] have been reported. Moreover, Chiba and Chen synthesized imidazole from oximes by ­using copper(I) iodide and K3PO4.[21] Mirzaei and co-workers also reported the synthesis of N-substituted 2,4-diarylimidazoles via a multicomponent reaction,[22] while Meille and co-workers synthesized imidazoles through FeCl3-mediated ring opening of 2H-azirines.[23]

Amidines have been widely employed synthetic precursors due to their easy availability and ability to furnish multisubstituted imidazoles via [3+2] cycloaddition reaction or radical pathway. In this context, Chen and co-workers reported the synthesis of trisubstituted imidazoles from acetophenones[24] by using a combination of I2 with zinc iodide as catalysts, whereas Mandal and co-workers[25] synthesized imidazoles from phenacyl bromide by using ­KHCO3 as a base. An iron-catalyzed protocol was established for aldehydes[18c] while [3+2] cycloaddition of nitro­vinylbenzene was accomplished by using copper(I) ­iodide.[17a] Moreover, Neuville and Li have described the synthesis of trisubstituted imidazoles from phenylacetylene by using copper chloride as a catalyst over a period of 24 hours[26] while Mahajan and co-workers used nitrosovinylbenzene in dichloromethane to form imidazoles.[27] 1,3-Dicarbonyl compounds, ketones, and chalcones are successfully used along with amidines for the synthesis of imida­zoles.[28]

Despite the proven useful track record of previously reported methods, the requirements for functionalized substrates, high catalyst loading, long reaction times, and low yields of products limit their wider applicability. Indeed, our interest in metal-catalyzed C–H functionalization mediated tandem synthesis of N-heterocycles[29] has led us to the one-pot, three-component synthesis of multisubstituted imidazoles using arylacetic acids, N-arylbenzamidines, and nitroalkanes under aerobic oxidative conditions through simultaneous C–H and N–H bond activation. An easy sp3 C–H bond activation followed by decarboxylation under mild reaction conditions is the key factor behind the selection of arylacetic acids.

Table 1 Optimization of the Reaction Conditionsa

Entry

Catalyst (mol%)

Ligand (mol%)

Solvent

Yield (%)b

 1

CuSO4 (10)
CuSO4 (5)

DMF/CH3NO2

20
10

 2

CuSO4 (10)

bipy (20)
bipy (10)

DMF/CH3NO2

80
60

 3

CuSO4 (10)

bipy (20)

DMF/CH3NO2

80
50c
44d
20e

 4

CuSO4 (10)

bipy (20)

DMF/CH3NO2

60f
20g

 5h

CuSO4 (10)

bipy (20)

DMF/CH3NO2

n.r.

 6

CuI (10)

bipy (20)

DMF/CH3NO2

25

 7

CuCl (10)

bipy (20)

DMF/CH3NO2

32

 8

CuCl2 (10)

bipy (20)

DMF/CH3NO2

40

 9

CuBr (10)

bipy (20)

DMF/CH3NO2

28

10

CuBr2 (10)

bipy (20)

DMF/CH3NO2

43

11

Cu(OAc)2 (10)

bipy (20)

DMF/CH3NO2

54

12

CuSO4 (10)

o-Phen (20)

DMF/CH3NO2

37

13

CuSO4 (10)

Ph3P (20)

DMF/CH3NO2

23

14

CuSO4 (10)

8-hydroxyquinoline (20)

DMF/CH3NO2

31

15

CuSO4 (10)

bipy (20)

DMF/CH3NO2

49

16

CuSO4 (10)

bipy (20)

1,2-DCE/CH3NO2

41

17

CuSO4 (10)

bipy (20)

1,4-dioxane/CH3NO2

55

18

CuSO4 (10)

bipy (20)

DMI/CH3NO2

52

a Reaction conditions: phenylacetic acid (1a, 1.5 mmol), N-phenylbenzamidine (1b, 1.0 mmol), catalyst (10 mol%), ligand (20 mol%), solvent (2.0 mL), 130 °C, 8 h, under O2 atmosphere.

b Yield of isolated product after column chromatography.

c Reaction performed at 120 °C.

d Reaction performed at 110 °C.

e Reaction performed at 90 °C.

f Phenylacetic acid (1.0 mmol).

g Phenylacetic acid (0.5 mmol).

h Reaction performed under N2 atmosphere or argon atmosphere.

We anticipated phenylacetic acid (1a) as the most suitable starting arylacetic acid for fine-tuning the reaction parameters to accomplish highest yield of imidazole scaffold. When the reaction of phenylacetic acid (1a, 1.5 equiv) with N-phenylbenzamidine (2a, 1.0 equiv) was performed in the presence of 5 mol% of CuSO4 as a catalyst in DMF/CH3NO2 solvent system under an oxygen atmosphere at 130 °C, the desired 1,2,4-triphenyl-1H-imidazole (3aa) was isolated in only 10% yield, but the yield was enhanced to 20% when catalyst loading was increased to 10 mol% (Table [1], entry 1). Nitromethane acted as a single carbon synthon. We were delighted to find a great increase in the yield when 2,2′-bipyridyl (bipy) was used as a ligand along with 10 mol% of CuSO4 (entry 2), this could be attributed to the stabilization of Cu2+ species by the 2,2′-bipyridyl ligand. This encouraging result prompted us to focus our attention on screening different parameters encompassing temperature, catalyst and ligand loading, substrate concentration, and solvent system in order to explore the optimal reaction conditions. The detrimental role of temperature and concentration of phenylacetic acid was noticed as the yield of imidazole diminished with lower temperature (entry 3) as well as concentration of phenylacetic acid (entry 4). Notably, no reaction occurred under nitrogen or argon atmosphere (entry 5). Various copper catalysts were tested, but they failed to provide an improved outcome (entries 6–11). Various ­ligands were also screened under standard conditions, however, they gave lower yields of 3aa when compared to 2,2′-bipyridyl (entries 12–14). Moreover, different solvent systems, DMSO/CH3NO2, 1,2-DCE/CH3NO2, 1,4-dioxane/CH3NO2, 1,3-dimethylimidazolidin-2-one ­(DMI)/CH3NO2, were also screened, but unfortunately lower yields of the product were observed (entries 15–18). All these observations implied that the best conditions are: phenylacetic acid (1a, 1.5 equiv), N-phenylbenzamidine (2a, 1.0 equiv), CuSO4 (10 mol%), 2,2′-bipyridyl (bipy, 20 mol%), DMF/CH3NO2, 130 °C, under oxygen. A Celite-free workup, unlike FeCl3-catalyzed reactions, leads to enhancement of the yield which apparently demonstrates the potential applicability of this protocol for large-scale synthesis.

Zoom Image
Scheme 1 Scope of various arylacetic acids in the copper-catalyzed synthesis of imidazoles. Reagents and conditions: arylacetic acid 1 (1.5 mmol), N-phenylbenzamidine (2a, 1.0 mmol), CuSO4 (10 mol%), 2,2′-bipyridyl (20 mol%), DMF/CH3NO2 (1.5:0.5 mL), 130 °C, 8 h, under O2 atmosphere; isolated yields are given.
Zoom Image
Scheme 2 Scope of various N-substituted amidines in the copper-­catalyzed synthesis of imidazoles. Reagents and conditions: phenylacetic acid (1a, 1.5 mmol), N-arylbenzamidine 2 (1.0 mmol), CuSO4 ­(10 mol%), 2,2′-bipyridyl (20 mol%), DMF/CH3NO2 (1.5:0.5 mL), 130 °C, 8 h, O2 atmosphere; isolated yields are given.

With these optimized conditions in hand, we evaluated the substrate scope of this method by using various aryl­acetic acids, N-arylbenzamidines, and nitroalkanes as generalization with respect to different substituents and substitution pattern is mandatory for the wider acceptability of process. At the outset, diverse arylacetic acids 1ai were screened under the optimized conditions and it was found that nature of the substituents govern the yield of the product (Scheme [1]). N-Phenylbenzamidine (2a) on reaction with phenylacetic acid (1a) afforded 1,2,4-triphenyl-1H-imidazole (3aa) in 80% yield. 3-Chloro- 1b and 4-bromo-substituted phenylacetic acid 1c gave imidazoles 3ba and 3ca in moderate yields. Notably, 4-methyl- 1d and 4-meth­oxy-substituted arylacetic acid 1e gave the corresponding imidazoles 3da and 3ea in 70% and 71% yields, respectively. Arylacetic acid 1f bearing an electron-withdrawing 4-CN group gave desired imidazole 3fa in 69% yield. Along with this we further screened naphthalene-1-acetic acid (1g) and naphthalene-2-acetic acid (1h) which furnished product 3ga and 3ha with moderate yields 51% and 47%, respectively. Moreover, we carried out the reaction of heterocyclic acetic acid, thiophene-2-acetic acid (1i) with N-phenylbenz­amidine (2a) resulting in product 3ia in 45% yield.

Zoom Image
Scheme 3 Scope of benzamidines and nitroethane in the copper-­catalyzed synthesis of imidazoles. Reagents and conditions: arylacetic acid 1 (1.5 mmol), N-arylbenzamidine 2 or benzamidine 4 (1.0 mmol), CuSO4 (10 mol%), 2,2′-bipyridyl (20 mol%), DMF/CH3NO2 or DMF/EtNO2 (2 mL), 130 °C, 8 h, O2 atmosphere; isolated yields are given.

Furthermore, we assessed the use of various N-aryl­benzamidines 2al bearing substituents of varying electronic character and steric effect on both the phenyl rings with phenylacetic acid (1a) (Scheme [2]). Indeed, N-phenylbenzamidines bearing halogen substituents (3-Cl 2b and 4-Cl 2c) as well as electron-donating substituents (3-Me 2d, 4-Me 2e, and 4-OMe 2f) gave imidazoles 3abaf in moderate to good yields (52–75%). However, an N-phenylbenzamidine bearing NO2 group (not shown) did not react with phenylacetic acid under the same reaction conditions. Similarly, the effects of the substituents on the N-phenyl ring of the N-arylbenzamidine were also investigated. A moderate yields (45–62%) of imidazoles 3agaj were observed for N-arylbenzamidines bearing halogen substituents (2-F 2g, 2-Cl 2h, 3-Cl 2i, and 4-Cl 2j). N-Arylbenzamidines bearing electron-donating substituents (4-Me 2k and 4-OMe 2l) gave the corresponding imidazoles 3ak and 3al in 72% and 77% yields. No product formation was observed for N-arylbenzamidines bearing a NO2 substituent.

Encouraged by these results, we next turned our attention to the synthesis of disubstituted and tetrasubstituted imidazoles by exploring the use of benzamidine and nitro­ethane, respectively (Scheme [3]). The use of arylacetic acids bearing electron-donating (4-Me 1d and 4-OMe 1e) substituents with benzamidine (4) afforded respective disubstituted imidazoles 5a and 5b in 74% and 76% yields, respectively. An arylacetic acid 1j with an electron-withdrawing (3-CF3) substituent with benzamidine (4) produced corresponding disubstituted imidazoles 5c in 68% yield. N-Phenyl­benzamidine (2a) bearing an electron donating (2-Me) group on reaction with phenylacetic acid (1a) in the presence of DMF/nitroethane solvent system afforded tetrasubstituted imidazole 5d in 65% yield.

Zoom Image
Scheme 4 Control experiments

To gain insight on the role of CuII(Ln) and endorse our hypothesis, a few controlled experiments were conducted. Initially, when a mixture of phenylacetic acid (1a), CuSO4, and 2,2′-bipyridyl was heated in DMF at 130 °C for 2 hours under an O2 atmosphere, 95% conversion into benzaldehyde (A) was observed [Scheme [4] (a)]. The same reaction failed to give benzaldehyde (A) in the presence of radical inhibitor TEMPO [Scheme [4] (b)]. This clearly indicated that reaction has proceeded by following single electron transfer (SET) pathway owing to CuII(Ln). Similarly no product was observed when CuII(Ln)-catalyzed reaction of phenylacetic acid (1a) and N-phenylbenzamidine (2a) was carried out in the presence of TEMPO [Scheme [4] (c)]. In order to confirm that the reaction proceeds through the formation of an α-keto acid, we carried out the reaction of α-keto acid 6 with N-phenylbenzamidine (2a) under the optimized reaction conditions [Scheme [4] (d)] and found that the reaction produced imidazole 3aa in 75% yield, thereby indicating the formation of an α-keto acid as an intermediate in this reaction.

A plausible mechanism, developed from these results and the literature reports, is depicted in Scheme [5]. Initially, CuII(Ln) E catalyzed C–H activation of arylacetic acid 1 occurs in the presence of oxygen via peroxide linkage formation to afford α-keto acid,[30] [31] which on oxidative decarboxylation gives aromatic aldehyde A. Further, N-arylbenzamidine 2 in the presence of CuII(Ln) E ­undergoes auto-oxidation to generate a stable biradical via N–H activation.[17a] [32] This, on nucleophilic substitution reaction with aromatic aldehyde, yields intermediate B. Then nitroalkane (Michael donor) undergoes regioselective ­Michael addition[33] [34] with intermediate B to form basic skeleton C which forms thermodynamically stable intermediate having a five-membered ring D. The stereoelectronic effect of C drives radical 5-exo-trig cyclization[35] due to better orbital overlapping to give intermediate D, which in the presence of CuII(Ln) E complex undergoes β-hydride elimination to give substituted imidazole 3 as the desired product with the liberation of nitroxyl gas.

Zoom Image
Scheme 5 Proposed reaction mechanism

We have developed a copper-catalyzed efficient protocol for the synthesis of multisubstituted imidazoles via ­simultaneously C–H and N–H activation of easily available arylacetic acids and N-arylbenzamidines. Also we report phenylacetic acid as an alternative to benzaldehyde since it offer advantages like wide substrate scope, stable and robust nature, etc. We strongly believe that this method will open a new avenue for the synthesis of biologically important multisubstituted imidazoles and should find broad application in modern synthetic chemistry as well as medicinal chemistry.

N-Arylbenzamidines were synthesized according to a literature procedure.[36] Chemical reagents were purchased from commercial suppliers. All the solvents were purchased from Spectrochem and were used as received. DMF was dried by using vacuum distillation and was stored over 4–Å molecular sieves before use. All reactions were performed in a round-bottom flask and monitored by TLC performed on aluminum plates (0.25 mm, E. Merck) precoated with silica gel (Merck 60 F-254). Developed TLC plates were visualized under a short-wavelength UV lamp. Reactions were conducted under open air and O2 atmosphere. Yields refer to spectroscopically (1H, 13C NMR) homo­geneous material obtained after column chromatography performed on silica gel (230–400 mesh) supplied by Avra laboratories, India. ­Petroleum ether = PE. 1H and 13C NMR were recorded in CDCl3 on a Bruker 400 and 300 MHz spectrometer relative to TMS (δ = 0.0) as an internal standard. High-resolution mass spectra (HRMS) were obtained by using positive electrospray ionization (ESI) and the time-of-flight (TOF) method. Melting points were recorded on a standard melting point apparatus from Sunder Industrial Product, Mumbai and are uncorrected.


#

Multisubstituted Imidazoles 3 and 5; General Procedure

A round-bottom flask was charged with arylacetic acid 1 (1.5 mmol), N-arylbenzamidine 2 or 4 (1.0 mmol), CuSO4 (10 mol%), and 2,2′-bipyridyl (20 mol%). A pre-oxygen degassed solvent system of DMF/nitroalkane (1.5:0.5 mL) was added to above mixture. The resulting mixture was heated at 130 °C for 8 h. The reaction progress was monitored by using TLC. After completion of the reaction, water was added to the mixture and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (anhyd Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography (230–400 mesh silica gel, EtOAc/n-hexane) to afford imidazoles 3 or 5.


#

1,2,4-Triphenyl-1H-imidazole (3aa)[18c]

Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil; yield: 120 mg (80%).

1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 8 Hz, 2 H), 7.47–7.45 (m, 3 H), 7.43–7.39 (m, 5 H), 7.33 (s, 1 H), 7.28–7.24 (m, 5 H).

13C NMR (100 MHz, CDCl3): δ = 147.4, 142.1, 138.8, 134.2, 130.6, 129.9, 129.2, 129.0, 128.9, 128.6, 127.4, 126.4, 126.2, 125.5, 118.9.

HRMS (ESI): m/z [M + H]+ calcd for C21H17N2: 297.1392; found: 297.1390.


#

4-(3-Chlorophenyl)-1,2-diphenyl-1H-imidazole (3ba)

Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil; yield: 83 mg (54%).

1H NMR (400 MHz, CDCl3): δ = 7.90–7.87 (m, 1 H), 7.75–7.73 (m, 1 H), 7.47–7.38 (m, 6 H), 7.31–7.21 (m, 7 H).

13C NMR (100 MHz, CDCl3): δ = 140.5, 138.3, 135.7, 134.7, 130.0, 129.6, 128.9, 128.7, 128.4, 128.4, 128.4, 128.3, 127.0, 125.9, 125.2, 123.1, 119.1.

HRMS (ESI): m/z [M + H]+ calcd for C21H16ClN2: 331.1002; found: 331.1005.


#

4-(4-Bromophenyl)-1,2-diphenyl-1H-imidazole (3ca)[23]

Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil; yield: 95 mg (60%).

1H NMR (300 MHz, CDCl3): δ = 7.79–7.74 (tt, J = 3 Hz, 2 H), 7.54–7.49 (tt, J = 3 Hz, 2 H), 7.46–7.39 (m, 6 H), 7.28–7.24 (m, 5 H).

13C NMR (75 MHz, CDCl3): δ = 147.7, 141.8, 136.4, 133.8, 131.8, 130.7, 130.2, 129.4, 128.6, 128.3, 128.1, 127.8, 127.0, 125.1, 118.5.

HRMS (ESI): m/z [M + H]+ calcd for C21H16BrN2: 375.0497; found: 375.0495.


#

1,2-Diphenyl-4-(p-tolyl)-1H-imidazole (3da)[24]

Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil; yield: 107 mg (70%).

1H NMR (300 MHz, CDCl3): δ = 7.91–7.88 (m, 2 H), 7.49–7.46 (m, 2 H), 7.42–7.37 (m, 3 H), 7.29–7.24 (m, 4 H), 7.21 (s, 1 H), 7.18 (s, 1 H), 7.16–7.12 (m, 2 H), 2.39 (s, 3 H).

13C NMR (75 MHz, CDCl3): δ = 146.9, 141.8, 138.6, 136.7, 131.1, 130.4, 129.5, 129.3, 128.8, 128.4, 128.2, 128.1, 125.9, 125.0, 118.1, 21.3.

HRMS (ESI): m/z [M + H]+ calcd for C22H19N2: 311.1548; found: 311.1545.


#

4-(4-Methoxyphenyl)-1,2-diphenyl-1H-imidazole (3ea)[18c]

Purified by column chromatography (EtOAc/PE 1:9) as a light yellow oil; yield: 109 mg (71%).

1H NMR (400 MHz, CDCl3): δ = 7.84–7.81 (distorted t, J = 3.2, 2.0 Hz, 2 H), 7.46–7.44 (m, 2 H), 7.39–7.35 (m, 4 H), 7.28–7.23 (m, 5 H), 6.97–6.93 (tt, J = 3.2, 2.0 Hz, 2 H), 3.82 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 158.9, 146.9, 141.6, 138.6, 134.3, 131.8, 129.6, 128.5, 128.3, 126.4, 125.9, 124.6, 120.5, 117.7, 114.1, 55.4.

HRMS (ESI): m/z [M + H]+ calcd for C22H19N2O: 327.1497; found: 327.1499.


#

4-(1,2-Diphenyl-1H-imidazol-4-yl)benzonitrile (3fa)[18c]

Purified by column chromatography (EtOAc/PE 1:9) as a pale yellow solid; yield: 106 mg (69%); mp 198–200 °C.

1H NMR (400 MHz, CDCl3): δ = 7.89–7.88 (m, 1 H), 7.86 (d, J = 4.0 Hz, 1 H), 7.66 (d, J = 1.2 Hz, 1 H), 7.64 (s, 1 H), 7.56 (t, J = 4 Hz, 1 H), 7.54 (t, J = 1.6 Hz, 1 H), 7.52–7.47 (m, 4 H), 7.40 (t, J = 1.6 Hz, 1 H), 7.38 (s, 1 H), 7.36 (t, J = 1.6 Hz, 1 H), 7.18–7.14 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 145.9, 142.0, 138.3, 133.7, 131.5, 130.3, 129.8, 129.3, 128.7, 128.6, 127.2, 125.9, 125.1, 122.9, 120.0, 118.9.

HRMS (ESI): m/z [M + H]+ calcd for C22H16N3: 322.1344; found: 322.1347.


#

4-(Naphthalen-1-yl)-1,2-diphenyl-1H-imidazole (3ga)

Purified by column chromatography (EtOAc/PE 3:7) as a yellow oil; yield: 79 mg (51%).

1H NMR (300 MHz, CDCl3): δ = 7.93 (s, 1 H), 7.74–7.71 (m, 3 H), 7.51 (d, J = 7.5 Hz, 3 H), 7.46–7.37 (m, 4 H), 7.32 (t, J = 7.5 Hz, 3 H), 7.22 (d, J = 8.1 Hz, 2 H), 7.15 (s, 1 H), 7.04 (t, J = 7.5 Hz, 1 H).

HRMS (ESI): m/z [M + H]+ calcd for C22H19N2: 347.1548; found: 347.1550.


#

4-(Naphthalen-2-yl)-1,2-diphenyl-1H-imidazole (3ha)

Purified by column chromatography (EtOAc/PE 3:7) as a yellow oil; yield: 73 mg (47%).

1H NMR (300 MHz, CDCl3): δ = 8.03 (s, 1 H), 7.80–7.82 (m, 4 H), 7.63 (d, J = 7.8 Hz, 3 H), 7.51 (t, J = 2.7 Hz, 1 H), 7.48 (t, J = 1.2 Hz, 1 H), 7.45–7.40 (m, 3 H), 7.34 (t, J = 8.1 Hz, 3 H), 7.13 (t, J = 7.5 Hz, 2 H).

HRMS (ESI): m/z [M + H]+ calcd for C22H19N2: 347.1548; found: 347.1546.


#

1,2-Diphenyl-4-(thiophen-2-yl)-1H-imidazole (3ia)

Purified by column chromatography (EtOAc/PE 4:6) as a yellow oil; yield: 70 mg (45%).

1H NMR (300 MHz, CDCl3): δ = 7.99 (s, 1 H), 7.86 (d, J = 6.9 Hz, 2 H), 7.64 (t, J = 7.8 Hz, 3 H), 7.53–7.43 (m, 4 H), 7.35 (t, J = 8.1 Hz, 3 H), 7.14 (t, J = 7.5 Hz, 1 H).

HRMS (ESI): m/z [M + H]+ calcd for C19H15N2S: 303.0950; found: 303.0958.


#

2-(3-Chlorophenyl)-1,4-diphenyl-1H-imidazole (3ab)[23]

Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil; yield: 80 mg (52%).

1H NMR (400 MHz, CDCl3): δ = 7.87–7.84 (m, 2 H), 7.55 (t, J = 2.0 Hz, 1 H), 7.43–7.41 (m, 4 H), 7.39–7.36 (m, 2 H), 7.27–7.24 (m, 3 H), 7.18 (t, J = 1.6 Hz, 1 H), 7.15 (s, 1 H), 7.13 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 145.5, 142.0, 138.2, 134.4, 133.7, 132.0, 129.7, 129.4, 128.9, 128.8, 128.6, 128.6, 127.3, 126.8, 125.9, 125.1, 119.0.

HRMS (ESI): m/z [M + H]+ calcd for C21H16ClN2: 331.1002; found: 331.0998.


#

2-(4-Chlorophenyl)-1,4-diphenyl-1H-imidazole (3ac)[37]

Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil; yield: 100 mg (65%).

1H NMR (400 MHz, CDCl3): δ = 7.88–7.85 (m, 2 H), 7.45–7.38 (m, 8 H), 7.33 (t, J = 2.0 Hz, 1 H), 7.31–7.29 (m, 1 H), 7.27–7.25 (m, 2 H), 7.24 (s, 1 H).

13C NMR (75 MHz, CDCl3): δ = 145.9, 142.0, 138.3, 133.7, 131.5, 130.3, 129.8, 129.3, 128.7, 128.6, 127.2, 125.9, 125.1, 122.9, 118.9.

HRMS (ESI): m/z [M + H]+ calcd for C21H16ClN2: 331.1002; found: 331.0999.


#

1,4-Diphenyl-2-(m-tolyl)-1H-imidazole (3ad)[37]

Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil; yield: 108 mg (71%).

1H NMR (300 MHz, CDCl3): δ = 7.89–7.86 (m, 2 H), 7.43–7.37 (m, 6 H), 7.33 (d, J = 6.0 Hz, 2 H), 7.28–7.26 (m, 2 H), 7.24 (s, 1 H), 7.06 (d, J = 6.0 Hz, 2 H), 2.31 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 147.2, 141.6, 138.7, 138.5, 134.0, 129.6, 129.5, 129.3, 129.0, 128.8, 128.7, 128.2, 127.5, 127.0, 125.9, 125.1, 118.4, 21.4.

HRMS (ESI): m/z [M + H]+ calcd for C22H19N2: 311.1548; found: 311.1545.


#

1,4-Diphenyl-2-(p-tolyl)-1H-imidazole (3ae)[17b]

Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil; yield: 110 mg (73%).

1H NMR (400 MHz, CDCl3): δ = 7.89–7.87 (m, 2 H), 7.43–7.35 (m, 7 H), 7.34 (t, J = 2.0 Hz, 1 H), 7.32 (t, J = 2.0 Hz, 1 H), 7.28–7.25 (m, 3 H), 7.24 (s, 1 H), 2.31 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 147.3, 141.6, 138.7, 138.5, 134.0, 129.5, 129.0, 128.8, 128.7, 128.2, 127.5, 127.0, 125.9, 125.1, 118.4, 21.4.

HRMS (ESI): m/z [M + H]+ calcd for C22H19N2: 311.1548; found: 311.1549.


#

2-(4-Methoxyphenyl)-1,4-diphenyl-1H-imidazole (3af)[37]

Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil; yield: 116 mg (75%).

1H NMR (300 MHz, CDCl3): δ = 7.84–7.80 (distorted t, J = 2.1, 1.5 Hz, 3 H), 7.64 (d, J = 5.7 Hz, 1 H), 7.44–7.36 (m, 5 H), 7.26–7.22 (m, 4 H), 6.96–6.92 (distorted tt, J = 2.1, 1.5 Hz, 2 H ), 3.81 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 158.9, 146.9, 141.6, 138.6, 131.8, 129.6, 128.9, 128.3, 128.2, 127.2, 126.4, 125.9, 124.6, 117.7, 114.1, 55.4.

HRMS (ESI): m/z [M + H]+ calcd for C22H19N2O: 327.1497; found: 327.1494.


#

1-(2-Fluorophenyl)-2,4-diphenyl-1H-imidazole (3ag)

Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil; yield: 69 mg (45%).

1H NMR (400 MHz, CDCl3): δ = 7.91–7.89 (m, 1 H), 7.76–7.74 (tt, J = 1.2 Hz, 1 H), 7.45–7.37 (m, 7 H), 7.29–7.24 (m, 6 H).

13C NMR (100 MHz, CDCl3): δ = 147.4, 142.0, 138.8, 134.2, 134.1, 130.6, 129.9, 129.2, 129.0, 128.9, 128.7, 128.6, 127.4, 126.4, 126.2, 125.5, 118.9.

HRMS (ESI): m/z [M + H]+ calcd for C21H16FN2: 315.1298; found: 315.1301.


#

1-(2-Chlorophenyl)-2,4-diphenyl-1H-imidazole (3ah)

Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil; yield: 74 mg (48%).

1H NMR (400 MHz, CDCl3): δ = 7.89–7.86 (m, 2 H), 7.44 (s, 2 H), 7.39 (d, J = 7.6 Hz, 2 H), 7.36 (distorted t, J = 2.0, 1.2 Hz, 1 H), 7.34–7.28 (m, 6 H), 7.25 (s, 1 H), 7.11–7.09 (distorted tt, J = 1.6, 1.2 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 146.9, 141.9, 139.4, 135.0, 133.4, 131.4, 130.4, 129.8, 128.8, 128.7, 128.6, 128.3, 127.1, 125.8, 125.0, 124.1, 118.1.

HRMS (ESI): m/z [M + H]+ calcd for C21H16ClN2: 331.1002; found: 331.1005.


#

1-(3-Chlorophenyl)-2,4-diphenyl-1H-imidazole (3ai)[37]

Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil; yield: 86 mg (56%).

1H NMR (400 MHz, CDCl3): δ = 7.89–7.86 (m, 2 H), 7.46–7.35 (m, 6 H), 7.33–7.25 (m, 6 H), 7.11–7.08 (distorted tt, J = 1.6, 1.2 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 147.3, 142.0, 138.8, 134.4, 133.6, 130.6, 129.9, 129.2, 129.0, 128.9, 128.7, 128.6, 127.4, 126.4, 126.2, 125.5, 118.9.

HRMS (ESI): m/z [M + H]+ calcd for C21H16ClN2: 331.1002; found: 331.0997.


#

1-(4-Chlorophenyl)-2,4-diphenyl-1H-imidazole (3aj)[24]

Purified by column chromatography (EtOAc/PE 1:9) as a yellow oil; yield: 95 mg (62%).

1H NMR (300 MHz, CDCl3): δ = 7.93–7.89 (m, 2 H), 7.54–7.51 (tt, J = 0.9 Hz, 1 H), 7.47–7.43 (m, 2 H), 7.41–7.36 (m, 5 H), 7.34–7.32 (m, 2 H), 7.27–7.24 (m, 3 H).

13C NMR (75 MHz, CDCl3): δ = 147.7, 141.8, 136.4, 133.8, 131.8, 130.7, 130.2, 129.4, 128.6, 128.3, 128.1, 127.8, 127.0, 125.1, 118.5.

HRMS (ESI): m/z [M + H]+ calcd for C21H16ClN2: 331.1002; found: 331.1004.


#

2,4-Diphenyl-1-(p-tolyl)-1H-imidazole (3ak)[18c]

Purified by column chromatography (EtOAc/PE 1:9) as a light yellow oil; yield: 110 mg (72%).

1H NMR (300 MHz, CDCl3): δ = 7.91–7.88 (m, 2 H), 7.49–7.46 (m, 2 H), 7.42–7.37 (m, 3 H), 7.29–7.25 (m, 4 H), 7.21 (s, 1 H), 7.18 (s, 1 H), 7.16–7.12 (m, 2 H), 2.39 (s, 3 H).

13C NMR (75 MHz, CDCl3): δ = 147.0, 141.5, 138.2, 136.0, 133.8, 130.3, 130.1, 128.8, 128.6, 128.4, 128.2, 127.0, 125.6, 125.1, 118.7, 21.1.

HRMS (ESI): m/z [M + H]+ calcd for C22H19N2: 311.1548; found: 311.1552.


#

1-(4-Methoxyphenyl)-2,4-diphenyl-1H-imidazole (3al)[17b]

Purified by column chromatography (EtOAc/PE 1:9) as a light yellow oil; yield: 118 mg (77%).

1H NMR (400 MHz, CDCl3): δ = 7.90–7.87 (m, 2 H), 7.49–7.45 (m, 2 H), 7.42–7.37 (m, 3 H), 7.27–7.23 (m, 4 H), 7.20–7.15 (distorted tt, J = 4.4, 2.8 Hz, 2 H), 6.92–6.87 (distorted tt, J = 4.4, 2.8 Hz, 2 H), 3.82 (s, 3 H).

13C NMR (75 MHz, CDCl3): δ = 159.3, 147.1, 141.9, 134.0, 131.5, 130.4, 128.7, 128.6, 128.3, 128.2, 127.1, 126.9, 125.0, 118.9, 114.6, 55.5.

HRMS (ESI): m/z [M + H]+ calcd for C22H19N2O: 327.1497; found: 327.1500.


#

2-Phenyl-4-(p-tolyl)-1H-imidazole (5a)[38]

Purified by column chromatography (EtOAc/PE 3:7) as a white solid; yield: 105 mg (74%); mp 156–158 °C.

1H NMR (400 MHz, CDCl3): δ = 9.17 (br s, 1 H), 7.83–7.81 (dd, J = 7.3, 3.6 Hz, 2 H), 7.52–7.50 (d, J = 8.0 Hz, 2 H), 7.18–7.12 (m, 3 H), 7.09 (s, 1 H), 7.03 (d, J = 7.9 Hz, 1 H), 2.22 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 146.3, 137.6, 129.5, 128.8, 128.3, 128.1, 127.9, 126.1, 125.3, 116.9, 21.3.

HRMS (ESI): m/z [M + H]+ calcd for C16H15N2: 235.1230; found: 235.1231.


#

4-(4-Methoxyphenyl)-2-phenyl-1H-imidazole (5b)[39]

Purified by column chromatography (EtOAc/PE 3:7) as a white solid; yield: 108 mg (76%); mp 260–262 °C.

1H NMR (400 MHz, CDCl3): δ = 8.58 (br s, 1 H), 7.80–7.73 (m, 2 H), 7.50 (d, J = 8.7 Hz, 1 H), 7.29–7.09 (m, 5 H), 6.97 (s, 1 H), 6.72 (d, J = 8.7 Hz, 1 H), 3.65 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 159.1, 146.4, 137.6, 130.5, 129.1, 128.7, 126.6, 125.9, 125.6, 114.1, 113.2, 55.3.

HRMS (ESI): m/z [M + H]+ calcd for C16H15N2O: 251.1179; found: 251.1180.


#

2-Phenyl-4-[3-(trifluoromethyl)phenyl]-1H-imidazole (5c)[39]

Purified by column chromatography (EtOAc/PE 3:7) as a yellow solid; yield: 101 mg (68%); mp 264–266 °C.

1H NMR (400 MHz, CDCl3): δ = 9.94 (br s, 1 H), 7.94 (s, 1 H), 7.83 (distorted t, J = 8.8, 7.3 Hz, 3 H), 7.46 (d, J = 7.6 Hz, 1 H), 7.39 (t, J = 7.7 Hz, 1 H), 7.28–7.25 (m, 4 H).

13C NMR (100 MHz, CDCl3): δ = 147.9, 138.5, 133.4, 131.4–130.5 [q, J = 32.2 Hz, 1 C (-CF3)], 129.2, 129.1, 128.8, 128.3, 125.8, 125.5, 123.6, 122.8, 120.1, 117.0.

HRMS (ESI): m/z [M + H]+ calcd for C16H12F3N2: 289.0947; found: 289.0948.


#

5-Methyl-1,4-diphenyl-2-(o-tolyl)-1H-imidazole (5d)

Purified by column chromatography (EtOAc/PE 1:9) as a colorless oil; yield: 103mg (65%).

1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 7.6 Hz, 2 H), 7.47 (distorted t, J = 8.1, 7.3 Hz, 5 H), 7.33 (distorted t, J = 8.0, 5.6 Hz, 3 H), 7.24–7.22 (m, 2 H), 7.03 (d, J = 8.0 Hz, 2 H), 2.29 (s, 3 H), 2.28 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 146.4, 138.0, 137.4, 135.0, 132.2, 129.7, 129.5, 129.2, 129.0, 128.9, 128.8, 128.7, 128.5, 128.4, 126.5, 126.1.

HRMS (ESI): m/z [M + H]+calcd for C23H21N2: 325.1699; found: 325.1701.


#
#

Acknowledgment

S.D.P thanks Department of Science and Technology, New Delhi, India for providing a DST-PURSE fellowship. K.S.V. and A.C.C. thank DST-SERB­, India (sanction No. SB/FT/CS-147/2013) for financial support. Authors thank Prof. A. K. Srivastava, Director National Centre for Nano­sciences and Nanotechnology, University of Mumbai for his generous support. Authors gratefully acknowledge V.N.K., A.A.C. and ORL, Department of Chemistry, University of Mumbai for their generous help and support.

Supporting Information

  • References

    • 2a Tietze LF. Brasche G. Gericke K. Domino Reactions in Organic Synthesis . Wiley-VCH; Weinheim: 2014
    • 2b Pellissier H. Chem. Rev. 2013; 113: 442
    • 2c Tietze LF. Kinzel T. Brazel CC. Acc. Chem. Res. 2009; 42: 367
    • 2d Tietze LF. Rackelmann N. Pure Appl. Chem. 2004; 76: 1967
    • 3a Jin Z. Nat. Prod. Rep. 2009; 26: 382
    • 3b Forte B. Malgesini B. Piutti C. Quartieri F. Scolaro A. Papeo G. Mar. Drugs 2009; 7: 705
    • 3c Midoux P. Pichon C. Yaouanc J.-J. Jaffrès P.-A. Br. J. Pharmacol. 2009; 157: 166
    • 3d Xiong F. Chen X.-X. Chen F.-E. Tetrahedron: Asymmetry 2010; 21: 665
    • 4a Lee JC. Laydon JT. McDonnell PC. Gallagher TF. Kumar S. Green D. McNulty D. Blumenthal MJ. Heys JR. Landvatter SW. Strickler JE. McLaughlin MM. Siemens IR. Fisher SM. Livi GP. White JR. Adams JL. Young PR. Nature (London) 1994; 372: 739
    • 4b de Laszlo SE. Hacker C. Li B. Kim D. MacCoss M. Mantlo N. Pivnichny JV. Colwell L. Koch GE. Cascieri MA. Hagmann WK. Bioorg. Med. Chem. Lett. 1999; 9: 641
    • 4c Antolini M. Bozzoli A. Ghiron C. Kennedy G. Rossi T. Ursini A. Bioorg. Med. Chem. Lett. 1999; 9: 1023
    • 4d Wang L. Woods KW. Li Q. Barr KJ. McCroskey RW. Hannick SM. Gherke L. Credo RB. Hui Y.-H. Marsh K. Warner R. Lee JY. Zielinski-Mozng N. Frost D. Rosenberg SH. Sham HL. J. Med. Chem. 2002; 45: 1697
    • 4e Dietrich J. Gokhale V. Wang X. Hurley LH. Flynn GA. Bioorg. Med. Chem. 2010; 18: 292
    • 4f Cho HJ. Gee HY. Baek K.-H. Ko S.-K. Park J.-M. Lee H. Kim N.-D. Lee MG. Shin I. J. Am. Chem. Soc. 2011; 133: 20267
    • 5a Bonezzi K. Taraboletti G. Borsotti P. Bellina F. Rossi R. Giavazzi R. J. Med. Chem. 2009; 52: 7906
    • 5b Sadek B. Pharma Chem. 2011; 3: 410
    • 5c Jin CH. Krishnaiah M. Sreenu D. Subrahmanyam VB. Rao KS. Lee HJ. Park SJ. Park HJ. Lee K. Sheen YY. Kim DK. J. Med. Chem. 2014; 57: 4213
    • 5d Zhang L. Peng X.-M. Damu GL. V. Geng R.-X. Zhou C.-H. Med. Res. Rev. 2014; 34: 340
    • 6a Wolff DJ. Datto GA. Samatovicz RA. J. Biol. Chem. 1993; 268: 9430
    • 6b Sennequier N. Wolan D. Stuehr DJ. J. Biol. Chem. 1999; 274: 930
    • 6c Koga H. Nanjoh Y. Makimura K. Tsuboi R. Med. Mycol. 2009; 47: 640
    • 6d Röhrig UF. Majjigapu SR. Chambon M. Bron S. Pilotte L. Colau D. Van den Eynde BJ. Turcatti G. Vogel P. Zoete V. Michielin O. Eur. J. Med. Chem. 2014; 84: 284
    • 7a Fukui M. Inaba M. Tsukagoshi S. Sakural Y. Cancer Res. 1982; 42: 1098
    • 7b Atwell GJ. Fan J.-Y. Tan K. Denny WA. J. Med. Chem. 1998; 41: 4744
    • 7c Al-Raqa SY. ElSharief AM. S. Khalil SM. E. Al-Amri AM. Heteroat. Chem. 2006; 17: 634
    • 8a Vijesh AM. Isloor AM. Telkar S. Peethambar SK. Rai S. Isloor N. Eur. J. Med. Chem. 2011; 46: 3531
    • 8b Choi JY. Plummer MS. Starr J. Desbonnet CR. Soutter H. Chang J. Miller JR. Dillman K. Miller AA. Roush WR. J. Med. Chem. 2012; 55: 852
    • 8c Yurttaş L. Duran M. Demirayak Ş. Gençer HK. Tunalı Y. Bioorg. Med. Chem. Lett. 2013; 23: 6764
  • 9 Vlahakis JZ. Lazar C. Crandall IE. Szarek WA. Bioorg. Med. Chem. 2010; 18: 6184
    • 10a Adams JL. Boehm JC. Gallagher TF. Kassis S. Webb EF. Hall R. Sorenson M. Garigipati R. Griswold DE. Lee JC. Bioorg. Med. Chem. Lett. 2001; 11: 2867
    • 10b Husain A. Drabu S. Kumar N. Alam MM. Bawa S. J. Pharm. BioAllied Sci. 2013; 5: 154
    • 11a Maeda Y. Nishimura T. Uemura S. Bull. Chem. Soc. Jpn. 2003; 76: 2399
    • 11b Asensio JA. Gómez-Romero P. Fuel Cells 2005; 5: 336
    • 11c Singh N. Jang DO. Org. Lett. 2007; 9: 1991
    • 11d Nagarajan N. Velmurugan G. Prakash A. Shakti N. Katiyar M. Venuvanalingam P. Renganathan R. Chem. Asian J. 2014; 9: 294
    • 11e Kwon JE. Park S. Park SY. J. Am. Chem. Soc. 2013; 135: 11239
    • 11f Yuan Y. Chen J.-X. Lu F. Tong Q.-X. Yang Q.-D. Mo H.-W. Ng T.-W. Wong F.-L. Guo Z.-Q. Ye J. Chen Z. Zhang X.-H. Lee C.-S. Chem. Mater. 2013; 25: 4957
    • 11g Jeżewski A. Hammann T. Cywiński PJ. Gryko DT. J. Phys. Chem. B 2015; 119: 2507
    • 12a Mowry DT. Chem. Rev. 1948; 42: 189
    • 12b Ellis GP. Romney-Alexander TM. Chem. Rev. 1987; 87: 779
    • 12c Bacon RG. R. Hill HA. O. J. Chem. Soc. 1964; 1097
    • 12d Sandmeyer T. Ber. Dtsch. Chem. Ges. 1884; 17: 2650
    • 12e Koelsch CF. Whitney AG. J. Org. Chem. 1941; 6: 795
    • 13a Mori K. Yamaguchi K. Mizugaki T. Ebitani K. Kaneda K. Chem. Commun. 2001; 461
    • 13b Yamaguchi K. Mizuno N. Angew. Chem. Int. Ed. 2003; 42: 1480
    • 13c Kotani M. Koike T. Yamaguchi K. Mizuno N. Green Chem. 2006; 8: 735
    • 13d Li F. Chen J. Zhang Q. Wang Y. Green Chem. 2008; 10: 553
    • 13e Zhang Y. Xu K. Chen X. Hu T. Yu Y. Zhang J. Huang J. Catal. Commun. 2010; 11: 951
    • 14a Capdevielle P. Lavigne A. Sparfel D. Baranne-Lafont J. Nguyen KC. Maumy M. Tetrahedron Lett. 1990; 31: 3305
    • 14b Tang R. Diamond SE. Neary N. Mares F. J. Chem. Soc., Chem. Commun. 1978; 562
    • 14c Porta F. Crotti C. Cennini S. J. Mol. Catal. 1989; 50: 333
    • 14d Bailey AJ. James BR. Chem. Commun. 1996; 2343
  • 15 Kison C. Opatz T. Chem. Eur. J. 2009; 15: 843
  • 16 Hu B. Wang Z. Ai N. Zheng J. Liu X.-H. Shan S. Wang Z. Org. Lett. 2011; 13: 6362
    • 17a Tang D. Wu P. Liu X. Chen Y.-X. Guo S.-B. Chen W.-L. Li J.-G. Chen B.-H. J. Org. Chem. 2013; 78: 2746
    • 17b Liu X. Wang D. Chen B. Tetrahedron 2013; 69: 9417
    • 17c Mitra S. Bagdi AK. Majee A. Hajra A. Tetrahedron Lett. 2013; 54: 4982
    • 17d Kumar T. Verma D. Menna-Barreto RF. S. Valença WO. da Silva Júnior EN. Namboothiri IN. N. Org. Biomol. Chem. 2015; 13: 1996
    • 18a Nie Y.-B. Wang L. Ding M.-W. J. Org. Chem. 2012; 77: 696
    • 18b Jiang Z. Lu P. Wang Y. Org. Lett. 2012; 14: 6266
    • 18c Liu X. Wang D. Chen Y. Tang D. Chen B. Adv. Synth. Catal. 2013; 355: 2798
    • 18d Chen C.-Y. Hu W.-P. Yan P.-C. Senadi GC. Wang J.-J. Org. Lett. 2013; 15: 6116
    • 18e Pusch S. Opatz T. Org. Lett. 2014; 16: 5430
    • 18f Aly S. Romashko M. Arndtsen BA. J. Org. Chem. 2015; 80: 2709
  • 19 Tlahuext-Aca A. Hernández-Fajardo O. Arévalo A. García JJ. Dalton Trans. 2014; 43: 15997
  • 20 Cardoso AL. Lemos A. Pinho e Melo TM. V. D. Eur. J. Org. Chem. 2014; 5159
  • 21 Chen H. Chiba S. Org. Biomol. Chem. 2014; 12: 42
  • 22 Adib M. Ansari S. Feizi S. Damavandi JA. Mirzaei P. Synlett 2009; 3263
  • 23 Auricchio S. Truscello AM. Lauria M. Meille SV. Tetrahedron 2012; 68: 7441
  • 24 Qu J. Wu P. Tang D. Meng X. Chen Y. Guo S. Chen B. New J. Chem. 2015; 39: 4235
  • 25 Hota PK. Vijaykumar G. Pariyar A. Sau SC. Sen TK. Mandal SK. Adv. Synth. Catal. 2015; 357: 3162
  • 26 Li J. Neuville L. Org. Lett. 2013; 15: 1752
  • 27 Sharma AK. Mazumdar SN. Mahajan MP. J. Chem. Soc., Perkin Trans. 1 1997; 3065
    • 28a Zhou X. Ma H. Shi C. Zhang Y. Liu X. Huang G. Eur. J. Org. Chem. 2017; 237
    • 28b Zhu Y. Li C. Zhang J. She M. Sun W. Wan K. Wang Y. Yin B. Liu P. Li J. Org. Lett. 2015; 17: 3872
    • 29a Kalmode HP. Vadagaonkar KS. Murugan K. Chaskar AC. New J. Chem. 2015; 39: 4631
    • 29b Kalmode HP. Vadagaonkar KS. Murugan K. Prakash S. Chaskar AC. RSC Adv. 2015; 5: 35166
    • 29c Vadagaonkar KS. Kalmode HP. Prakash S. Chaskar AC. New J. Chem. 2015; 39: 3639
    • 29d Vadagaonkar KS. Kalmode HP. Murugan K. Chaskar AC. RSC Adv. 2015; 5: 5580
    • 29e Vadagaonkar KS. Murugan K. Chaskar AC. Bhate PM. RSC Adv. 2014; 4: 34056
  • 30 Chen X. Chen T. Ji F. Zhou Y. Yin S.-F. Catal. Sci. Technol. 2015; 5: 2197
  • 31 Yang D. Yan K. Wei W. Tian L. Shuai Y. Li R. You J. Wang H. Asian J. Org. Chem. 2014; 3: 969
  • 32 Gandeepan P. Rajamalli P. Cheng C.-H. Asian J. Org. Chem. 2014; 3: 303
  • 33 Mahmudov KT. Kopylovich MN. Haukka M. Mahmudova GS. Esmaeila EF. Chyragov FM. Pombeiro AJ. L. J. Mol. Struct. 2013; 1048: 108
  • 34 Jalal S. Sarkar S. Bera K. Maiti S. Jana U. Eur. J. Org. Chem. 2013; 4823
  • 35 Maiti S. Biswas S. Jana U. J. Org. Chem. 2010; 75: 1674
  • 36 Cooper FC. Partridge MW. Org. Synth. 1956; 36: 64
  • 37 Tang D. Guo X. Wang Y. Wang J. Li J. Huang Q. Chen B. Tetrahedron Lett. 2015; 56: 5982
  • 38 Gopi E. Kumar T. Menna-Barreto RF. S. Valença WO. da Silva Júnior EN. Namboothiri IN. N. Org. Biomol. Chem. 2015; 13: 9862
  • 39 Zuliani V. Cocconcelli G. Fantini M. Ghiron C. Rivara M. J. Org. Chem. 2007; 72: 4551

  • References

    • 2a Tietze LF. Brasche G. Gericke K. Domino Reactions in Organic Synthesis . Wiley-VCH; Weinheim: 2014
    • 2b Pellissier H. Chem. Rev. 2013; 113: 442
    • 2c Tietze LF. Kinzel T. Brazel CC. Acc. Chem. Res. 2009; 42: 367
    • 2d Tietze LF. Rackelmann N. Pure Appl. Chem. 2004; 76: 1967
    • 3a Jin Z. Nat. Prod. Rep. 2009; 26: 382
    • 3b Forte B. Malgesini B. Piutti C. Quartieri F. Scolaro A. Papeo G. Mar. Drugs 2009; 7: 705
    • 3c Midoux P. Pichon C. Yaouanc J.-J. Jaffrès P.-A. Br. J. Pharmacol. 2009; 157: 166
    • 3d Xiong F. Chen X.-X. Chen F.-E. Tetrahedron: Asymmetry 2010; 21: 665
    • 4a Lee JC. Laydon JT. McDonnell PC. Gallagher TF. Kumar S. Green D. McNulty D. Blumenthal MJ. Heys JR. Landvatter SW. Strickler JE. McLaughlin MM. Siemens IR. Fisher SM. Livi GP. White JR. Adams JL. Young PR. Nature (London) 1994; 372: 739
    • 4b de Laszlo SE. Hacker C. Li B. Kim D. MacCoss M. Mantlo N. Pivnichny JV. Colwell L. Koch GE. Cascieri MA. Hagmann WK. Bioorg. Med. Chem. Lett. 1999; 9: 641
    • 4c Antolini M. Bozzoli A. Ghiron C. Kennedy G. Rossi T. Ursini A. Bioorg. Med. Chem. Lett. 1999; 9: 1023
    • 4d Wang L. Woods KW. Li Q. Barr KJ. McCroskey RW. Hannick SM. Gherke L. Credo RB. Hui Y.-H. Marsh K. Warner R. Lee JY. Zielinski-Mozng N. Frost D. Rosenberg SH. Sham HL. J. Med. Chem. 2002; 45: 1697
    • 4e Dietrich J. Gokhale V. Wang X. Hurley LH. Flynn GA. Bioorg. Med. Chem. 2010; 18: 292
    • 4f Cho HJ. Gee HY. Baek K.-H. Ko S.-K. Park J.-M. Lee H. Kim N.-D. Lee MG. Shin I. J. Am. Chem. Soc. 2011; 133: 20267
    • 5a Bonezzi K. Taraboletti G. Borsotti P. Bellina F. Rossi R. Giavazzi R. J. Med. Chem. 2009; 52: 7906
    • 5b Sadek B. Pharma Chem. 2011; 3: 410
    • 5c Jin CH. Krishnaiah M. Sreenu D. Subrahmanyam VB. Rao KS. Lee HJ. Park SJ. Park HJ. Lee K. Sheen YY. Kim DK. J. Med. Chem. 2014; 57: 4213
    • 5d Zhang L. Peng X.-M. Damu GL. V. Geng R.-X. Zhou C.-H. Med. Res. Rev. 2014; 34: 340
    • 6a Wolff DJ. Datto GA. Samatovicz RA. J. Biol. Chem. 1993; 268: 9430
    • 6b Sennequier N. Wolan D. Stuehr DJ. J. Biol. Chem. 1999; 274: 930
    • 6c Koga H. Nanjoh Y. Makimura K. Tsuboi R. Med. Mycol. 2009; 47: 640
    • 6d Röhrig UF. Majjigapu SR. Chambon M. Bron S. Pilotte L. Colau D. Van den Eynde BJ. Turcatti G. Vogel P. Zoete V. Michielin O. Eur. J. Med. Chem. 2014; 84: 284
    • 7a Fukui M. Inaba M. Tsukagoshi S. Sakural Y. Cancer Res. 1982; 42: 1098
    • 7b Atwell GJ. Fan J.-Y. Tan K. Denny WA. J. Med. Chem. 1998; 41: 4744
    • 7c Al-Raqa SY. ElSharief AM. S. Khalil SM. E. Al-Amri AM. Heteroat. Chem. 2006; 17: 634
    • 8a Vijesh AM. Isloor AM. Telkar S. Peethambar SK. Rai S. Isloor N. Eur. J. Med. Chem. 2011; 46: 3531
    • 8b Choi JY. Plummer MS. Starr J. Desbonnet CR. Soutter H. Chang J. Miller JR. Dillman K. Miller AA. Roush WR. J. Med. Chem. 2012; 55: 852
    • 8c Yurttaş L. Duran M. Demirayak Ş. Gençer HK. Tunalı Y. Bioorg. Med. Chem. Lett. 2013; 23: 6764
  • 9 Vlahakis JZ. Lazar C. Crandall IE. Szarek WA. Bioorg. Med. Chem. 2010; 18: 6184
    • 10a Adams JL. Boehm JC. Gallagher TF. Kassis S. Webb EF. Hall R. Sorenson M. Garigipati R. Griswold DE. Lee JC. Bioorg. Med. Chem. Lett. 2001; 11: 2867
    • 10b Husain A. Drabu S. Kumar N. Alam MM. Bawa S. J. Pharm. BioAllied Sci. 2013; 5: 154
    • 11a Maeda Y. Nishimura T. Uemura S. Bull. Chem. Soc. Jpn. 2003; 76: 2399
    • 11b Asensio JA. Gómez-Romero P. Fuel Cells 2005; 5: 336
    • 11c Singh N. Jang DO. Org. Lett. 2007; 9: 1991
    • 11d Nagarajan N. Velmurugan G. Prakash A. Shakti N. Katiyar M. Venuvanalingam P. Renganathan R. Chem. Asian J. 2014; 9: 294
    • 11e Kwon JE. Park S. Park SY. J. Am. Chem. Soc. 2013; 135: 11239
    • 11f Yuan Y. Chen J.-X. Lu F. Tong Q.-X. Yang Q.-D. Mo H.-W. Ng T.-W. Wong F.-L. Guo Z.-Q. Ye J. Chen Z. Zhang X.-H. Lee C.-S. Chem. Mater. 2013; 25: 4957
    • 11g Jeżewski A. Hammann T. Cywiński PJ. Gryko DT. J. Phys. Chem. B 2015; 119: 2507
    • 12a Mowry DT. Chem. Rev. 1948; 42: 189
    • 12b Ellis GP. Romney-Alexander TM. Chem. Rev. 1987; 87: 779
    • 12c Bacon RG. R. Hill HA. O. J. Chem. Soc. 1964; 1097
    • 12d Sandmeyer T. Ber. Dtsch. Chem. Ges. 1884; 17: 2650
    • 12e Koelsch CF. Whitney AG. J. Org. Chem. 1941; 6: 795
    • 13a Mori K. Yamaguchi K. Mizugaki T. Ebitani K. Kaneda K. Chem. Commun. 2001; 461
    • 13b Yamaguchi K. Mizuno N. Angew. Chem. Int. Ed. 2003; 42: 1480
    • 13c Kotani M. Koike T. Yamaguchi K. Mizuno N. Green Chem. 2006; 8: 735
    • 13d Li F. Chen J. Zhang Q. Wang Y. Green Chem. 2008; 10: 553
    • 13e Zhang Y. Xu K. Chen X. Hu T. Yu Y. Zhang J. Huang J. Catal. Commun. 2010; 11: 951
    • 14a Capdevielle P. Lavigne A. Sparfel D. Baranne-Lafont J. Nguyen KC. Maumy M. Tetrahedron Lett. 1990; 31: 3305
    • 14b Tang R. Diamond SE. Neary N. Mares F. J. Chem. Soc., Chem. Commun. 1978; 562
    • 14c Porta F. Crotti C. Cennini S. J. Mol. Catal. 1989; 50: 333
    • 14d Bailey AJ. James BR. Chem. Commun. 1996; 2343
  • 15 Kison C. Opatz T. Chem. Eur. J. 2009; 15: 843
  • 16 Hu B. Wang Z. Ai N. Zheng J. Liu X.-H. Shan S. Wang Z. Org. Lett. 2011; 13: 6362
    • 17a Tang D. Wu P. Liu X. Chen Y.-X. Guo S.-B. Chen W.-L. Li J.-G. Chen B.-H. J. Org. Chem. 2013; 78: 2746
    • 17b Liu X. Wang D. Chen B. Tetrahedron 2013; 69: 9417
    • 17c Mitra S. Bagdi AK. Majee A. Hajra A. Tetrahedron Lett. 2013; 54: 4982
    • 17d Kumar T. Verma D. Menna-Barreto RF. S. Valença WO. da Silva Júnior EN. Namboothiri IN. N. Org. Biomol. Chem. 2015; 13: 1996
    • 18a Nie Y.-B. Wang L. Ding M.-W. J. Org. Chem. 2012; 77: 696
    • 18b Jiang Z. Lu P. Wang Y. Org. Lett. 2012; 14: 6266
    • 18c Liu X. Wang D. Chen Y. Tang D. Chen B. Adv. Synth. Catal. 2013; 355: 2798
    • 18d Chen C.-Y. Hu W.-P. Yan P.-C. Senadi GC. Wang J.-J. Org. Lett. 2013; 15: 6116
    • 18e Pusch S. Opatz T. Org. Lett. 2014; 16: 5430
    • 18f Aly S. Romashko M. Arndtsen BA. J. Org. Chem. 2015; 80: 2709
  • 19 Tlahuext-Aca A. Hernández-Fajardo O. Arévalo A. García JJ. Dalton Trans. 2014; 43: 15997
  • 20 Cardoso AL. Lemos A. Pinho e Melo TM. V. D. Eur. J. Org. Chem. 2014; 5159
  • 21 Chen H. Chiba S. Org. Biomol. Chem. 2014; 12: 42
  • 22 Adib M. Ansari S. Feizi S. Damavandi JA. Mirzaei P. Synlett 2009; 3263
  • 23 Auricchio S. Truscello AM. Lauria M. Meille SV. Tetrahedron 2012; 68: 7441
  • 24 Qu J. Wu P. Tang D. Meng X. Chen Y. Guo S. Chen B. New J. Chem. 2015; 39: 4235
  • 25 Hota PK. Vijaykumar G. Pariyar A. Sau SC. Sen TK. Mandal SK. Adv. Synth. Catal. 2015; 357: 3162
  • 26 Li J. Neuville L. Org. Lett. 2013; 15: 1752
  • 27 Sharma AK. Mazumdar SN. Mahajan MP. J. Chem. Soc., Perkin Trans. 1 1997; 3065
    • 28a Zhou X. Ma H. Shi C. Zhang Y. Liu X. Huang G. Eur. J. Org. Chem. 2017; 237
    • 28b Zhu Y. Li C. Zhang J. She M. Sun W. Wan K. Wang Y. Yin B. Liu P. Li J. Org. Lett. 2015; 17: 3872
    • 29a Kalmode HP. Vadagaonkar KS. Murugan K. Chaskar AC. New J. Chem. 2015; 39: 4631
    • 29b Kalmode HP. Vadagaonkar KS. Murugan K. Prakash S. Chaskar AC. RSC Adv. 2015; 5: 35166
    • 29c Vadagaonkar KS. Kalmode HP. Prakash S. Chaskar AC. New J. Chem. 2015; 39: 3639
    • 29d Vadagaonkar KS. Kalmode HP. Murugan K. Chaskar AC. RSC Adv. 2015; 5: 5580
    • 29e Vadagaonkar KS. Murugan K. Chaskar AC. Bhate PM. RSC Adv. 2014; 4: 34056
  • 30 Chen X. Chen T. Ji F. Zhou Y. Yin S.-F. Catal. Sci. Technol. 2015; 5: 2197
  • 31 Yang D. Yan K. Wei W. Tian L. Shuai Y. Li R. You J. Wang H. Asian J. Org. Chem. 2014; 3: 969
  • 32 Gandeepan P. Rajamalli P. Cheng C.-H. Asian J. Org. Chem. 2014; 3: 303
  • 33 Mahmudov KT. Kopylovich MN. Haukka M. Mahmudova GS. Esmaeila EF. Chyragov FM. Pombeiro AJ. L. J. Mol. Struct. 2013; 1048: 108
  • 34 Jalal S. Sarkar S. Bera K. Maiti S. Jana U. Eur. J. Org. Chem. 2013; 4823
  • 35 Maiti S. Biswas S. Jana U. J. Org. Chem. 2010; 75: 1674
  • 36 Cooper FC. Partridge MW. Org. Synth. 1956; 36: 64
  • 37 Tang D. Guo X. Wang Y. Wang J. Li J. Huang Q. Chen B. Tetrahedron Lett. 2015; 56: 5982
  • 38 Gopi E. Kumar T. Menna-Barreto RF. S. Valença WO. da Silva Júnior EN. Namboothiri IN. N. Org. Biomol. Chem. 2015; 13: 9862
  • 39 Zuliani V. Cocconcelli G. Fantini M. Ghiron C. Rivara M. J. Org. Chem. 2007; 72: 4551

Zoom Image
Scheme 1 Scope of various arylacetic acids in the copper-catalyzed synthesis of imidazoles. Reagents and conditions: arylacetic acid 1 (1.5 mmol), N-phenylbenzamidine (2a, 1.0 mmol), CuSO4 (10 mol%), 2,2′-bipyridyl (20 mol%), DMF/CH3NO2 (1.5:0.5 mL), 130 °C, 8 h, under O2 atmosphere; isolated yields are given.
Zoom Image
Scheme 2 Scope of various N-substituted amidines in the copper-­catalyzed synthesis of imidazoles. Reagents and conditions: phenylacetic acid (1a, 1.5 mmol), N-arylbenzamidine 2 (1.0 mmol), CuSO4 ­(10 mol%), 2,2′-bipyridyl (20 mol%), DMF/CH3NO2 (1.5:0.5 mL), 130 °C, 8 h, O2 atmosphere; isolated yields are given.
Zoom Image
Scheme 3 Scope of benzamidines and nitroethane in the copper-­catalyzed synthesis of imidazoles. Reagents and conditions: arylacetic acid 1 (1.5 mmol), N-arylbenzamidine 2 or benzamidine 4 (1.0 mmol), CuSO4 (10 mol%), 2,2′-bipyridyl (20 mol%), DMF/CH3NO2 or DMF/EtNO2 (2 mL), 130 °C, 8 h, O2 atmosphere; isolated yields are given.
Zoom Image
Scheme 4 Control experiments
Zoom Image
Scheme 5 Proposed reaction mechanism