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Journal of the Brazilian Chemical Society

Print version ISSN 0103-5053

J. Braz. Chem. Soc. vol.23 no.1 São Paulo Jan. 2012

http://dx.doi.org/10.1590/S0103-50532012000100024 

SHORT REPORT

 

Metal chloride hydrates as Lewis acid catalysts in multicomponent synthesis of 2,4,5-triarylimidazoles or 2,4,5-triaryloxazoles

 

 

Marcelo V. MarquesI, II; Marcelo M. RuthnerIII; Luiz A. M. FontouraI, III,; Dennis RussowskyII,*

IDepartamento de Engenharia de Processos, Fundação de Ciência e Tecnologia, 94930-230 Cachoeirinha-RS, Brazil
IILaboratório de Sínteses Orgânicas, Instituto de Química, Universidade Federal do Rio Grande do Sul, 91501-970 Porto Alegre-RS, Brazil
IIICurso de Química, Universidade Luterana do Brasil, 92452-900 Canoas-RS, Brazil

 

 


ABSTRACT

A series of nine metal chloride hydrates (ZnCl2.2H2O, SnCl2.2H2O, CdCl2.2H2O, MnCl2.4H2O, CoCl2.6H2O, SrCl2.6H2O, NiCl2.6H2O, CrCl3.6H2O and CeCl3.7H2O) was investigated as mild and inexpensive Lewis acid catalysts to promote the multicomponent synthesis of triarylimidazoles. Reactions starting from benzil showed the best results when SnCl2.2H2O was used, while for benzoin as the starting material, CeCl3.7H2O was more efficient. All reactions were performed in EtOH as solvent. These catalysts were also successfully employed in the synthesis of triaryloxazoles.

Keywords: triarylimidazoles, triaryloxazoles, multicomponent reaction, metal halide hydrates, Lewis acids, Radziszewski reaction, benzil, benzoin


RESUMO

Uma série de nove hidratos de cloretos metálicos (ZnCl2.2H2O, SnCl2.2H2O, CdCl2.2H2O, MnCl2.4H2O, CoCl2.6H2O, SrCl2.6H2O, NiCl2.6H2O, CrCl3.6H2O e CeCl3.7H2O) foi investigada como catalisadores ácidos de Lewis brandos e baratos na síntese multicomponente de triarilimidazóis. O melhor catalisador para as reações com benzila foi o SnCl2.2H2O, enquanto que para as reações com benzoína, o CeCl3.7H2O foi mais eficiente. Todas as reações foram efetuadas em EtOH como solvente. Estes catalisadores também foram empregados igualmente com sucesso na síntese de triariloxazóis.


 

 

Introduction

Imidazole is a five-membered ring heteroaromatic compound with two nitrogen atoms at 1 and 3 positions.1 This type of compound is known to exhibit a broad range of pharmaceutical and industrial applications. For instance, the imidazole core unity is present in many compounds with pronounced biologic activities such as angiotensin inhibitors,2 anti-inflammatory,3 glucagon antagonist,4 antiviral,5 antimicrobial,6 fungicidal7 and high cytotoxicity, which has indicated them as new candidates in cancer therapy.8

A particular class of triarylimidazoles, the pyridinyl arylimidazoles 1, 2 and 3 have been recognized as a potent p38 mitogen-activated protein (MAP) kinase inhibitors and emerged as possible therapeutic drugs in the treatment of various diseases such as cancer and as anti-inflammatory agent, combating the associated pain with osteoarthritis (Figure 1).9 Beyond the pharmacological applications, arylimidazoles have been used in the industry as chemiluminescent10 and chromotropic materials11 due to their optic and electronic properties.12

 

 

The synthesis of triarylimidazoles from the three-component reaction of 1,2-dicarbonyl compounds, aldehyde and ammonia was independently discovered by Japp and Robinson13 in 1882 and Radziszewski.14 However, long periods of time and harsh conditions were frequently associated with low yields of production. Davidson et al.15 showed to be possible to reduce the reaction times using acetic acid as solvent and ammonium acetate instead of ammonia. This last protocol became usual and default procedure for the synthesis of triarylimidazoles.

Recently, Kamijo and Yamamoto16 have reviewed the progress on the synthesis of imidazoles through catalyzed process. Besides other methods using Brønsted catalysis of p-toluenesulfonic acid (p-TSA),17 heteropolyacids,18 oxalic acid19 and phosphomolybdic acid20 were developed. Heterogeneous catalysts based on silica-supported Brønsted or Lewis acids, such as HClO4/SiO2,21 H2SO4/SiO2,22 BF3/SiO2,23 NaHSO4/SiO224 or zeolites HY-type,25 were successfully employed. Microwave,26 ultrasound irradiation27 and ionic liquids28 were also reported as efficient promoters to the synthesis of arylimidazoles. Other solid catalysts, such as NaHSO329 or I230 and proline31 or tetrabutylammonium bromide (TBAB)32 as organocatalysts, were also effective. Although many catalysts have been employed in the Radziszewski reaction, the use of Lewis acid catalysts such as metal triflates as Yb(OTf)3,33 metal halides as ZrCl4,34 Zn(acac)427 or cerium ammonium nitrate35 are rare. Additionally, few examples of metal halide hydrates like InCl3.3H2O36 and NiCl2.6H2O/Al2O337 were reported for the synthesis of these compounds.

The previous experience of our research group on the use of highly moisture sensitive metal halides as Lewis acid catalysts in organic reactions38 prompt us to investigate the similar ability of the metal halide hydrates, which are cheaper, easily handled and compatible moisture. Fortunately, our group discovered that SnCl2.2H2O was successfully employed in the Biginelli reaction,39 Friedlander condensation40 and in conjugate Friedel-Crafts reaction.41 In the present work, we explore the ability of a series of metal chloride hydrates (SnCl2.2H2O, ZnCl2.2H2O, CdCl2.2H2O, MnCl2.4H2O, CoCl2.6H2O, SrCl2.6H2O, NiCl2.6H2O, CrCl3.6H2O and CeCl3.7H2O) as mild and inexpensive Lewis acid catalysts in the multicomponent Radziszewski reaction. Besides the search for catalyst efficiency, variables such as protic/aprotic solvents and molar ratio of reagents and catalyst were investigated towards the optimization of a general and useful protocol.

 

Results and Discussion

Catalysts

To investigate the abilities of metal chloride hydrates as Lewis acid catalysts, lophine (2,4,5-triphenyl-1H-imidazole) (8a) was chosen as the model compound. In a first example, the reaction of benzil (4a, 1.0 mmol), benzaldehyde (6a, 1.0 mmol ), NH4OAc (7, 4.0 mmol) and SnCl2.2H2O (0.10 mmol) was carried out in gently refluxing EtOH. The course of the reaction was monitored by thin layer chromatography (TLC) and after a period of 4 h, the starting materials were consumed. After this time, the reaction was stopped and the crude product was isolated (Table 1, entry 2). Therefore, this time was chosen as default for comparison with other catalysts (Scheme 1).

 

 

 

 

The same conditions were applied for the reactions with benzoin (5, 1.0 mmol) instead of benzil, and the results are shown in the Table 1. In all cases, the metal chloride hydrates showed catalytic activity affording lophine in variable yield. It should be noted that in the absence of the catalyst, the yield was drastically reduced, evidencing the metal halide activity (see Table 1, entry 1). The best results (higher than 80% yield) starting from benzil (4) were found in the presence of SnCl2.2H2O and MnCl2.2H2O (entries 2 and 3, respectively). On the other hand, the optimum result with benzoin (5) was achieved in the presence of CeCl3.7H2O (entry 10). The decrease in the catalyst amount from 0.10 to 0.05 mmol afforded worse results for both starting ketones (entries 11 and 12). Finally, the reactions that were carried out for 2 h caused a decrease in the yield of the product, while an increase of 6 h in the time of the reaction led only to a small improvement (cf. entries 10 and 14, respectively). Therefore, it was decided to explore the use of SnCl2.2H2O and CeCl3.7H2O (0.10 mmol) as the main catalysts and the time of 4 h as default.

Different mechanistic pathways have been proposed for this multicomponent reaction having the benzil or benzoin as starting materials.15,28,33 The proposed rationale by Kokare et al.19 seems to be in accordance with the results in Table 1 (Scheme 2). The authors suggested the initial formation of N,N-ketal (9) under Brønsted acidic catalysis from benzaldehyde (6a) and 2 equivalents of NH4OAc (7). It was assumed that the same activation occurs in the Lewis catalysis. Therefore, the condensation of 9 with benzil (4a) after losing 2 equivalents of water, leads to the conjugate intermediate 10 which rearranges via a [1,5]-sigmatropic proton shift to afford the corresponding lophine (8a).

 

 

On the other hand, starting from benzoin, the cyclization of intermediate imino-alcohol (11) should occur by an intramolecular attack of nitrogen in a more hindered and saturated carbon to afford the dihydroimidazole intermediate (12) (Scheme 3). Additionally, the needed oxidation step to produce the conjugated intermediate (10) could be corroborating to explain the minor reactivity that is observed in reactions starting from benzoin. The intermediate (10) is suggested as common specie in both mechanistic pathways.

 

 

Solvent

Despite the use of H2O,42 MeOH, EtOH, i-PrOH, CH2Cl2, THF, 1,4-dioxane43 or CH3CN34 as solvents has already been reported in presence of different catalysts, the relative influence of alcoholic solvents in the Radziszewski reaction was not well studied. For this purpose, were investigated the reactions of benzil (4a, 1 mmol) or benzoin (5, 1 mmol), benzaldehyde (6a, 1.0 mmol), NH4OAc (7, 4.0 mmol) and the catalyst (0.10 mmol) carried out in MeOH, EtOH, n-PrOH, CH3CN and THF (tetrahydrofuran) promoted by SnCl2.2H2O or CeCl3.7H2O for the synthesis of lophine (8a, Scheme 4). The results are shown in the Table 2, bellow.

 

 

Table 2 shows the solvents, their dipole moments (µ) and relative dielectric constants (ε).44 The reaction from benzyl in the presence of SnCl2.2H2O seems to be more influenced by the solvent (Table 2, entries 1-5). Aprotic solvents led to poorer yields. In the case of CH3CN (the most polar between them), the solvent might be associating to the catalyst in a stronger way than the other ones do, reducing more significantly the reaction rate (entry 4). On the other hand, from benzoin and CeCl3.7H2O, the yields are essentially the same for all the solvents, protic or aprotic (entries 6-10). The effect of CH3CN is not observed, which might be attributed to the metal volume, making their association more difficult (entry 9). Besides the effects of polarity of the solvents, their ability in acting as "hydrogen bond donors" can be considered. This new principle can be evidenced in the activation process through the hydrogen bonding between the solvent and reactants on organocatalyzed reactions, as recently reviewed by Akiyama.45 Therefore, based on the results above discussed and on economical and ambient sustainability reasons, lower toxicity and easy availability, ethanol becomes more advantageous solvent and was chosen as a default solvent in our present study.

Molar ratio of NH4OAc

Next, it was investigated the influence of the molar ratio of NH4OAc on the synthesis of lophine under catalysis of SnCl2.2H2O and CeCl3.7H2O. The molar ratio of benzil (4a, 1.0 mmol) or benzoin (5, 1.0 mmol), benzaldehyde (6a, 1.0 mmol) and catalyst (0.10 mmol) were the same for all performed assays. The results are shown in Table 3. From substrates, 4a or 5, the increase in the NH4OAc amount from 2 to 4 mmol was followed by an improvement on the reaction yield (cf. entries 1, 2 and 4, 5, respectively).

 

 

From substrates, benzyl or benzoin, the increase in the NH4OAc amount from 2 to 4 mmol was followed of an improvement on the reaction yield (cf. entries 1, 2 and 4, 5, respectively). Using 10 mmol of NH4OAc, a little improvement from benzyl was observed (entry 3). In contrast, a poorer yield from benzoin (entry 6) was achieved. In summary, 4 mmol (2 molar equivalents) were considered the optimum amount of this reagent. This developed protocol was applied to the reaction of benzils (4a-c) and benzoin (5) with aldehydes (6a-k) to afford a library of triarylimidazoles (8a-p) (Scheme 5). The results are show in the Table 4.

 

 

Pyrazine and triaryloxazoles

The decrease in the yield when 10 mmol of NH4OAc was employed with benzoin (5, see Table 3, entry 6) was attributed to the formation of pyrazine (13) as a byproduct (identified by GC-MS analysis).

Similar observation was already reported in the literature.15 Intending to confirm this hypothesis, it was performed the reaction of benzoin (5, 2.0 mmol), NH4OAc (7, 4.0 mmol) under refluxing of ethanol and CeCl3.7H2O (0.10 mmol) over 4 h in absence of the aldehyde. After this time, the pyrazine (13) was isolated in 87% yield (Scheme 6).

 

 

On the other hand, the reaction of benzil (4a, 2.0 mmol) with ammonium acetate (7, 4.0 mmol) under refluxing of ethanol and SnCl2.2H2O (0.10 mmol) over 4 h afforded the triaryloxazole (10a) in 74% yield (Scheme 7).

 

 

Davidson et al.15 early reported the formation of 2,4,5-trifenyloxazole as a lateral product in the Radziszewski reaction under acetic acid media. By the proposed mechanistic pathway suggested by Davidson et al.,15 it is clear the aid of acetic acid as a Brønsted acid catalyst. Triaryloxazoles are structurally similar to triarylimidazoles and also have some of their properties, but have been less studied so far. Due to their broad application (for example, in nonlinear optical devices46 or as biologically active compounds),47 it was decided to investigate the ability of metal chloride hydrates such as NiCl2.6H2O, ZnCl2.2H2O, MnCl2.4H2O and SnCl2.2H2O to participate as Lewis acid catalysts in the synthesis of triaryloxazoles. The results are shown in Table 5.

The reactions were carried out as described in the synthesis of lophine (see Table 1). In the absence of the catalyst (Table 5, entry 1), 10a was only isolated in a poor yield. The same result was observed when NiCl2.6H2O or MnCl2.4H2O was added (entries 2 and 3). Changing the catalyst to ZnCl2.2H2O, an increase in the yield was observed. In the presence of SnCl2.2H2O, a reasonable yield (78%) was achieved (entries 4 and 5, respectively). Other solvents were also investigated. The reactions were carried out under reflux. In MeOH, a decrease in the yield was observed, while the use of n-PrOH permitted to isolate the product in a yield of 73% (entries 6 and 7, respectively). On the other hand, in CH3CN and THF (aprotic polar solvents), benzyl was recovered after the work up (entries 8 and 9, respectively). So, EtOH was considered to be the best solvent. After that, the amount of catalyst was diminished from 10 to 5 mol% (cf. entries 5 and 10, respectively) and no significant decrease in the yield was observed, therefore, this new condition was set as default.

Finally, the increase in the reaction times also caused an increase in the yield of triaryloxazole (14a), 84 and 94% (entries 11 and 12, respectively). The use of benzyl (4c) under the optimized protocol afforded the triaryloxazole (14b) in good yield, confirming the applicability of this protocol.

 

Conclusions

We found that the metal halide hydrates were active as Lewis acid catalyst to prepare 2,4,5-triarylimidazoles in reasonable to good yields through the Radziszewski multicomponent synthesis. These catalysts were effective starting from benzoin, as well as from benzils. The SnCl2.2H2O showed the best results in reactions from benzyl, while CeCl3.7H2O was more effective with benzoin. Additionally, we demonstrate that the molar ratio of NH4OAc is important to improve the yields of the products and the large excess of them can leads to the formation of 1,2,4,5-tetraarylpyrazines. The SnCl2.4H2O was also effective to promote the reaction of benzils with NH4OAc to afford the respective triaryloxazoles in good yields.

 

Experimental

General considerations

The solvents and reagents were used without previous treatment, except for benzaldehyde, anisaldehyde and furfural, which were distilled prior to use. The reactions were monitored by thin layer chromatography (TLC) on ALUGRAM® SIL G/UV 254 Macherey-Nagel silicagel plates. A mixture CH2Cl2/AcOEt in 98:2 ratios was used as eluent. The plates were visualized in alcoholic solution of 2,4-dinitrofenilidrazine or under UV light (254 nm). The 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded in DMSO-d6 using a Varian VNMRS or a Varian Mercury spectrometers at 300/400 MHz and 75/100 MHz, respectively. The chemical shifts (δ) are reported in parts per million (ppm) relative to DMSO-d6 at δ 2.50 ppm for 1H NMR and the line at δ 39.5 ppm for 13C NMR. The coupling constants J are reported in Hz. The following abbreviations are used for the multiplicities: s (singlet), d (doublet), dd (double of doublets), t (triplet), q (quartet), m (multiplet) and br s (broad singlet). The infrared (IR) spectra were recorded on a Perkin-Elmer Spectrum One, between 4000 and 600 cm-1 (Nujol). The melting points (mp) were measured on an Uniscience Brazil fusing equipment (model 498) and are uncorrected. The mass spectra (MS) were recorded on a GC-MS QP 2010 Shimadzu (EI, 70 eV).

General procedures

Synthesis of 2,4,5-triarylimidazoles (8a-p) from benzyls (4a-c)

A 10 mL round-bottom flask equipped with magnetic stirrer was charged with benzyls (4a-c) (1.0 mmol), aldehydes (6a-k) (1.0 mmol), NH4OAc (7, 4.0 mmol) and SnCl2.2H2O (0.10 mmol), followed by EtOH (4 mL). The reaction mixture was stirred and gently refluxed for 4 h. After the completion of the reaction with the monitoring of TLC, 4 mL of water were added. The solid was filtered under reduced pressure and washed with small portions of a mixture of cooled EtOH/H2O (1:1, v:v). The crude product was recrystallized from acetone/water 9:1 or toluene.

Synthesis of 2,4,5-triarylimidazoles (8a-k) from the benzoin (5)

A 10 mL round-bottom flask equipped with magnetic stirrer was charged with benzoin (5) (1.0 mmol), aldehydes (6a-k) (1.0 mmol), NH4OAc (7, 4.0 mmol) and CeCl3.7H2O (0.10 mmol), followed by EtOH (4 mL). The reaction mixture was stirred and gently refluxed for 4 h. After the completion of the reaction with the monitoring of TLC, 4 mL of water were added. The solid was filtered under reduced pressure and washed with small portions of a mixture of cooled EtOH/H2O (1:1, v:v). The crude product was recrystallized from acetone/water 9:1 or toluene.

Synthesis of 2,4,5-triaryloxazoles (14a, b) from benzyls (4a, c)

A 10 mL round-bottom flask equipped with magnetic stirrer was charged with benzyls (4a,c) (1.0 mmol), NH4OAc (7, 5.0 mmol) and SnCl2.2H2O (0.05 mmol), followed by EtOH (4 mL). The reaction mixture was stirred and gently refluxed for 4 h. After the completion of the reaction with the monitoring of TLC, 4 mL of water were added. The solid was filtered under reduced pressure and washed with small portions of a mixture of cooled EtOH/H2O (1:1, v:v). The crude product was recrystallized from acetone/water 9:1 or toluene.

 

Supplementary Information

Supplementary data (spectral data of compounds 8a-p and 10a, b and spectra) are available free of charge at http://jbcs.org.br as PDF file.

 

Acknowledgments

The authors would like to acknowledge FAPERGS (Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul) and CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnológico, Grant 2007-6/484615) for financial support and graduate fellowship (M. V. M).

 

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Submitted: July 6, 2011
Published online: October 11, 2011

 

 

* e-mail: dennis@iq.ufrgs.br

 

 

Supplementary Information

Spectral characterization of compounds 8a-p and 10a, b

2,4,5-Triphenyl-1H-imidazole (lophine) (8a): solid; mp 278-279 ºC;1 1H NMR (300 MHz, DMSO-d6) δ 12.71 (br s, 1H, NH), 8.09 (d, 2H, J 7.0 Hz), 7.14-7.70 (m, 13H); 13C NMR (75 MHz, DMSO-d6) δ 145.4, 137.0, 135.1, 131.0, 130.2, 128.6, 129.5, 128.4, 128.2, 128.1, 127.7, 127.0, 126.4, 125.1; IR (Nujol) νmax/cm-1 1600, 1503, 1128, 966, 916; GC-MS (IE, 70 eV) m/z (%) 296 (M+, 100.0), 165 (48.0), 148 (12.6), 89 (17.1), 77 (7.0), 63 (7.3), 51 (4.0).

4-(4,5-Diphenyl-1H-imidazol-2-yl)phenol (8b): solid; mp 262-263 ºC;2 1H NMR (400 MHz, DMSO-d6) δ 9.61 (br s, 1H, NH), 7.89 (d, 2H, J 8.3 Hz), 7.05-7.70 (m, 10H), 6.84 (d, 2H, J 8.8 Hz); 13C NMR (100 MHz, DMSO-d6) δ 157.6, 145.9, 126.6, 121.5. 115.2; IR (Nujol) νmax/cm-1 1643, 1613, 1546, 1506, 1490, 1240, 764, 698; GC-MS (IE, 70 eV) m/z (%) 312 (M+, 100.0), 165 (39.0), 89 (8.9), 77 (8.9), 51 (3.0), 39 (2.9).

2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (8c): solid; mp 233-234 ºC;1 1H NMR (400 MHz, DMSO-d6) δ 12.45 (br s, 1H, NH), 8.01(d, 2H, J 8.8 Hz), 7.15-7.62 (m, 10H), 7.04 (d, 2H, J 8.8 Hz), 3.82 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 55.1, 59.4, 145.6, 128.2, 126.6, 123.1, 114.0; IR (Nujol) νmax/cm-1 1614, 1546, 1248, 765, 696; GC-MS (IE, 70 eV) m/z (%) 326 (M+, 100.0), 311 (22.4), 165 (14.0), 89 (6.3), 77 (6.3), 63 (3.0), 51 (2.9), 39 (1.8).

2-(3,4-Dimethoxyphenyl)-4,5-diphenyl-1H-imidazole (8d): solid; mp 250-251 ºC;1 1H NMR (400 MHz, DMSO-d6) δ 12.46 (br s, 1H, NH), 7.16-7.77 (m, 12H), 7.06 (d, 1H, J 8.3 Hz), 3.86 (s, 3H), 3.82 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 55.4, 55.5, 149.0, 148.7, 148.1, 145.5, 137.8, 129.4, 128.4, 128.2, 128.1, 127.9, 127.4, 126.9, 126.2, 123.1, 117.8, 111.8, 108.9; IR (Nujol) νmax/cm-1 1606, 1495, 765, 696; GC-MS (IE, 70 eV) m/z (%) 326 (M+, 100.0), 165 (12.6), 89 (5.2),77 (4.8), 63 (5.2), 51 (2.1).

2-(1-Naphtalen-1-yl)-4,5-diphenyl-1H-imidazole (8e): solid; mp 273-275 ºC;3 1H NMR (400 MHz, DMSO-d6) δ 12.71 (br s, 1H, NH), 8.01 (d, 2H, J 7.8 Hz), 7.98 (dd, 1H, J 7.3 and 1.0 Hz), 7.50-7.65 (m, 7H), 7.20-7.47 (m, 7H); 13C NMR (100 MHz, DMSO-d6) δ 145.4, 137.9, 137.0, 135.2, 133.5, 130.9, 130.2, 129.4, 128.7, 128.4, 128.2, 128.0, 127.7, 127.5, 127.3, 127.0, 126.5, 126.4, 126.3, 125.9, 125.0; IR (Nujol) νmax/cm-1 1596, 1500, 764, 695; GC-MS (IE, 70 eV) m/z (%) 326 (M+, 100.0), 165 (37.4), 139 (9.3), 89 (6.0), 77 (4.1), 63 (3.3), 51 (1.9).

4-(4,5-Diphenyl-1H-imidazol-2-yl)benzonitrile (8f): solid; mp 248-250 ºC; 1H NMR (300 MHz, DMSO-d6) δ 13.03 (br s, 1H, NH), 8.26 (d, 2H, J 8,2 Hz), 7.93 (d, 2H, J 8.2 Hz), 7.18-7.70 (m, 10 H); 13C NMR (75 MHz, DMSO-d6) δ 143.6, 138.0, 134.6, 134.2, 132.7, 130.5, 129.5, 128.6, 128.4, 128.2, 128.0, 127.0, 126.7, 125.4, 118.8, 110.0; IR (Nujol) νmax/cm-1 2227, 1610, 1490, 766, 696; GC-MS (IE, 70 eV) m/z (%) 321 (M+, 100.0), 165 (47.7), 89 (12.0), 77 (5.3), 63 (7.4), 51 (4.0); HRMS (ESI, w/H+) calcd. 321.13387, found 322.13394.

2-(3-Nitrophenyl)-4,5-diphenyl-1H-imidazole (8g): solid; mp 315-317 ºC;4 1H NMR (300 MHz, DMSO-d6) δ 13.11 (br s, 1H, NH), 8.96 (s, 1H), 8.52 (d, 1H, J 7.7 Hz), 8.21 (dd, 1H, J 8.2 Hz), 7.77 (t, 1H, J 8.0 Hz), 7.22-7.64 (m, 10H); 13C NMR (75 MHz, DMSO-d6) δ 148.3, 143.4, 137.7, 134.7, 131.8, 131.2, 130.6, 130.4, 129.2, 128.7, 128.4, 128.3, 128.1, 127.1, 126.8, 122.6, 119.4; IR (Nujol) νmax/cm-1 1541, 1523, 1348, 777, 699; GS-MS (IE, 70 eV) m/z (%) 341 (M+, 100.0), 311 (47.8), 295 (21.1), 165 (42.6), 89 (22.0), 77 (13.2), 63 (3.3), 43 (2.2).

2-(2-Nitrophenyl)-4,5-diphenyl-1H-imidazole (8h): solid; mp 224-225 ºC;5 1H NMR (300 MHz, DMSO-d6) δ 12.98 (sl, 1H, NH), 8.00 (d, 1H, J 7.6 Hz), 7.93 (d, 1H, J 8.2 Hz), 7.79 (t, 1H, J 7.6 Hz), 7.64 (t, 1H, J 7.6 Hz), 7.35-7.60 (m, 8H), 7.31 (t, 1H, J 7.0 Hz), 7.23 (t, 1H, J 7.0 Hz); 13C NMR (75 MHz, DMSO-d6) δ 148.2, 140.9, 137.4, 134.6, 132.0, 130.5, 129.7, 129.4, 128.7, 128.6, 128.2, 128.1, 127.9, 126.9, 126.6, 123.9,123.3; IR (Nujol) νmax/cm-1 1601, 1524, 1502, 1364, 724, 694; GC-MS (IE, 70 eV) m/z (%) 341 (M+, 59.7), 311 (100.0), 207 (15.0), 165 (40.1), 147 (14.2), 135 (21.3), 104 (79.0), 89 (46.3), 77 (25.6), 63 (13.8), 51 (11.4).

2-(Furan-2-yl)-4,5-diphenyl-1H-imidazole (8i): solid; mp 229-230 ºC;6 1H NMR (300 MHz, DMSO-d6) δ 12.85 (br s, 1H, NH), 7.81 (d, 1H, J 1.6 Hz), 7.36-7.75 (m, 10H), 6.98 (d, 1H, J 3.4 Hz), 6.65 (dd, 1H, J 3.4 and 1.8 Hz); 13C NMR (75 MHz, DMSO-d6) δ 148.3, 145.7,143.1, 138.6, 138.0, 129.6, 128.5, 128.3, 127.7, 111.9, 107,5; IR (Nujol) νmax/cm-1 1602, 1500, 764, 696; GC-MS (IE, 70 eV) m/z (%) 286 (M+, 100.0), 257 (9.4), 165 (22.0), 143 (6.1), 128 (8.6), 89 (3.7), 77 (9.0), 63 (2.8), 51 (12.1).

4,5-Diphenyl-2-(thiophen-2-yl)-1H-imidazole (8j): solid; mp 255-256 ºC;1 1H NMR (300 MHz, DMSO-d6) δ 12.79 (br s, 1H, NH), 7.69 (d, 1H, J 3.5 Hz), 7.25-7.51 (m, 11H), 7.15 (dd, 1H, J 4.7 and 3.5 Hz); 13C NMR (75 MHz, DMSO-d6) δ 124.1, 126.2, 126.5, 127.0, 127.8, 128.1, 128.6, 130.8, 133.9, 134.7, 136.6, 141.5; IR (Nujol) νmax/cm-1 1594, 1493, 765, 695; GC-MS (IE, 70 eV) m/z (%) 304 (6.77), 302 (M+, 100.0), 165 (39.7), 151 (8.7), 95 (7.4), 89 (5.8), 77 (6.3), 69 (6.5), 63 (4.1), 51 (4.3).

4,5-Diphenyl-2-(thiophen-3-yl)-1H-imidazole (8k): solid; mp 257-259 ºC; 1H NMR (300 MHz, DMSO-d6) δ 12.63 (br s, 1H, NH), 8.04 (dd, 1H, J 2.9 and 1.3), 7.71 (dd, 1H, J 5.0 and 1.2 Hz), 7.65 (dd, 1H, J 5.0 and 2.9 Hz), 7.31-7.53 (m, 10H); 13C NMR (75 MHz, DMSO-d6) δ 142.7, 132.5, 128.4, 127.7,127.0, 125.9, 121.8; IR (Nujol) νmax/cm-1 1593, 1493, 765, 697; GC-MS (IE, 70 eV) m/z (%) 304 (6.64), 302 (M+, 100.0), 165 (46.6), 151 (8.9), 89 (10.3), 77 (6.5), 63 (5.2), 51 (4.2); HRMS (ESI, w/H+) calcd. 303.09505, found 303.09518.

4,5-Bis(4-methoxyphenyl)-2-(thiophen-3-yl)-1H-imidazole (8l): solid; mp 199-201 ºC;7 1H NMR (400 MHz, DMSO-d6) δ 12.35 (br s, 1H, NH), 7.97 (dd, 1H, J 2.9 and 1.5 Hz), 7.68 (dd, 1H, J 4.8 and 1.1 Hz), 7.62 (dd, 1H, J 5.5 and 2.9 Hz), 6.80-7.50 (m, 8H), 3.75 (s, 3H), 3.79 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 148.3, 143.4, 137.7, 134.7, 131.8, 131.2, 130.6, 130.4, 129.2, 128.7, 128.4, 128.3, 128.1, 127.1, 126.8, 122.6, 119.4; IR (Nujol) νmax/cm-1 3391, 1655, 1600, 1573, 1508, 1259, 1163, 842, 832; GC-MS (IE, 70 eV) m/z (%) 362 (M+, 100.0), 347 (28.4), 275 (4.1), 181 (5.7).

4,5-Bis(4-fluorophenyl)-2-phenyl-1H-imidazole (8m): solid; mp 255-257 ºC;8 1H NMR (400 MHz, DMSO-d6) δ 12.67 (br s, 1H, NH), 8.07 (dd, 2H, J 8.4 and 1.1 Hz), 7.50-7.60 (m, 4H), 7.48 (t, 2H, J 7.5 Hz), 7.38 (t, 1H, J 7.3 Hz), 7.29 (t, 2H, J 8.8 Hz), 7.14 (t, 2H, J 8.8 Hz); 13C NMR (100 MHz, DMSO-d6) δ 161.5 (d, 1JCF 245.7 Hz), 160.9 (d, 1JCF 243.4 Hz), 145.4, 136.1, 131.4 (d, 4JCF 3.1 Hz), 130.4 (d, 3JCF 8.4 Hz), 130.1, 128.7 (d, 3JCF 7.6 Hz), 128.5, 128.1, 128.0, 127.2 (d, 4JCF 3.1 Hz), 126.9, 125.0, 115.5 (d, 2JCF 21.4 Hz), 114.9 (d, 2JCF 21.4 Hz); IR (Nujol) νmax/cm-1 1606, 1590, 1537, 1514, 1595, 1226, 1156, 835; GC-MS (IE, 70 eV) m/z (%) 332 (M+, 100.0), 201 (44.1), 89 (9.6), 77 (3.0), 63 (4.6), 51 (2.2), 39 (2.0).

4-[4,5-Bis(4-fluorophenyl)-1H-imidazol-2-yl)]benzonitrile (8n): solid; mp 272-274 ºC; 1H NMR (400 MHz, DMSO-d6) δ 12.98 (br s, 1H, NH), 8.23 (d, 2H, J 8.3 Hz), 7.93 (d, 2H, J 8.3 Hz), 7.55 (d, 2H, J 8.8 Hz), 7.54 (d, 2H, J 8.8 Hz), 7.00-7.40 (m, 4H); 13C NMR (100 MHz, DMSO-d6) δ 143.5, 134.0, 132.6, 128.7, 128.0, 125.4, 125.1, 118.6, 110.0; IR (Nujol) νmax/cm-1 2229, 1608, 1516, 1497, 1223, 1161, 847, 837; GC-MS (IE, 70 eV) m/z (%) 357 (M+, 100.0), 201 (42.5), 107 (13.3); HRMS (ESI, w/H+) calcd. 358.11522, found 358.11503.

4,5-Bis(4-fluorophenyl)-2-(furan-2-yl)-1H-imidazole (8o): solid; mp 223-225 ºC; 1H NMR (400 MHz, DMSO-d6) δ 12.81 (br s, 1H, NH), 7.79 (dd, 1H, J 1.8 and 0.7 Hz), 7.42-7.58 (m, 4H), 7.27 (t, 2H, J 9.0 Hz), 7.14 (t, 2H, J 9.0 Hz), 6.96 (dd, 1H, J 3.3 and 0.7 Hz), 6.64 (dd, 1H, J 3.3 and 1.8 Hz); 13C NMR (100 MHz, DMSO-d6) δ 161.6 (d, 1JCF 244.1 Hz), 161.0 (d, 1JCF 241.9 Hz), 145.5, 143.0, 138.4, 136.8, 136.0, 130.4 (d, 3JCF 8.4 Hz), 128.9 (d, 3JCF 8.4 Hz), 127.0 (d, 4JCF 3.1 Hz), 126.3, 115.6 (d, 2JCF 22.1 Hz), 115.0 (d, 2JCF 21.4 Hz), 111.7, 107.4; IR (Nujol) νmax/cm-1 1606, 1529, 1514, 1496, 1228, 1158, 836, 738; GC-MS (IE, 70 eV) m/z (%) 322 (M+, 100.0), 293 (11.8), 201 (18.8), 107 (3.9); HRMS (ESI, w/H+) calcd. 323.09905, found 323.09912.

4,5-Bis(4-fluorophenyl)- 2-(thiophen-3-yl)-1H-imidazole (8p): solid; mp 255-256 ºC; 1H NMR (400 MHz, DMSO-d6) δ 8.17 (dd, 1H, J 2.9 and 1.5 Hz), 7.76 (dd, 1H, J 5.1 and 1.5 Hz), 7.69 (dd, 1H, J 5.1 and 2.9 Hz), 7.54 (dd, 4H, J 9.2 e 5.5 Hz Hz), 7.24 (t, 4H, J 8.8 Hz); 13C NMR (100 MHz, DMSO-d6) δ 166.6 (d, 1JCF 248.0 Hz), 166.0 (d, 1JCF 255.6 Hz), 162.6, 160.2, 141.9, 132.8, 132.7, 132.6, 129.8 (d, 3JCF 8.4 Hz), 128.1, 127.1, 152.7, 123.2, 116.5 (d, 2JCF 22.1 Hz), 115.3 (d, 2JCF 21.4 Hz); IR (Nujol) νmax/cm-1 3467, 1650, 1598, 1501, 1227, 1156, 835; GC-MS (IE, 70 eV) m/z (%) 338 (M+, 100.0), 201 (43.7), 107 (11.4), 95 (9.6); HRMS (ESI, w/H+) calcd. 339.07620, found 339.07639.

2,4,5-Triphenyl-1,3-oxazole (10a): solid; mp 111-113 ºC;9 1H NMR (200 MHz, DMSO-d6) δ 8.4-8.0 (m, 2H), 7.3-7.15 (m, 13H); 13C NMR (50 MHz, DMSO-d6) δ 159.9, 145.7, 136.5, 132.3, 131.3, 129.7, 129.5, 129.2, 129.0, 128.6, 128.1, 127.0, 126.6; IR (Nujol) νmax/cm-1 3060, 2000-1700, 1600, 1590, 1500, 1490, 700, 690; GC-MS (IE, 70 eV) m/z (%) 297 (M+, 100.0), 269 (28.7), 165 (92.9). 105 (9.5), 89 (27.7), 77 (22.7), 63 (14.1), 51 (10.4)

2,4,5-Tris(4-fluorophenyl)-1,3-oxazole (10b): solid; mp 154-157°C; 1H NMR (200 MHz, DMSO-d6) δ 8.3-7.9 (m, 2H), 7.8-7.1 (m, 10H); 13C NMR (50 MHz, DMSO-d6) δ 164.2, 162.9, 162.6, 116.9, 116.8, 166.4, 130.4, 129.6, 129.3, 128.7, 125.1, 123.7; IR (Nujol) νmax/cm-1 3060, 2100-1700, 1600, 1520, 1500, 1200, 820; GC-MS (IE, 70 eV) m/z (%) 351 (M+, 86.6), 323 (18.6), 201 (100.0), 123 (10.5), 107 (28.9), 95 (19.3), 81 (4.4), 51(1.1); HRMS (ESI, w/H+) calcd. 352.09922, found 352.0979.

 

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