Iodine-Mediated Difunctionalization of Imidazopyridines with Sodium

Novel iodine-induced sulfonylation and sulfenylation of imidazopyridines have been described using sodium sulfinates as the sulfur source. This strate...
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Article Cite This: J. Org. Chem. 2018, 83, 338−349

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Iodine-Mediated Difunctionalization of Imidazopyridines with Sodium Sulfinates: Synthesis of Sulfones and Sulfides Yu-Jing Guo, Shuai Lu, Lu-Lu Tian, En-Ling Huang, Xin-Qi Hao, Xinju Zhu,* Tian Shao,* and Mao-Ping Song College of Chemistry and Molecular Engineering, School of Life Sciences, Zhengzhou University, No. 100 of Science Road, Zhengzhou, Henan 450001, P. R. China S Supporting Information *

ABSTRACT: Novel iodine-induced sulfonylation and sulfenylation of imidazopyridines have been described using sodium sulfinates as the sulfur source. This strategy enables highly selective difunctionalization of imidazo[1,2-a]pyridine to access sulfones and sulfides in good yields. A wide range of substrates and functional groups were well-tolerated under optimized conditions. Moreover, control experiments have been conducted, indicating a radical pathway involved in the reaction mechanisms.

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INTRODUCTION As an important N-heterocycle, imidazopyridine is recognized as a privileged scaffold that has exhibited wide applications in pharmaceuticals and optoelectronics.1 In the past decades, significant efforts have been made for the construction of substituted imidazo[1,2-a]pyridine derivatives.2 Meanwhile, given the electron-rich nature of imidazopyrine rings, the direct C−H functionalizations, for example, hydroarylation/ annulation,3 amination,4 oxidative homocoupling,5 arylation,6 and carbonylation,7 on the C3 position have also been welldeveloped.8 Recently, sulfur-containing compounds have attracted considerable attention due to their prevalence in a variety of natural products, pharmaceuticals, and materials science.9,10 In addition, organosulfur architectures are considered as versatile precursors for further functionalizations in synthetic chemistry.11 In this context, sulfenylation of imidazo[1,2-a]pyridine heterocycles has gained much attention and been well-developed in the presence of disulfides, thiols, and elemental sulfur (Scheme 1a−c).12−14 In comparison, the employment of sulfonyl derivatives to achieve sulfenylation of imidazopyridine is relatively less investigated.15 As bench-stable and readily accessible reagents, sodium sulfinates have recently emerged as promising starting materials to form a C−S bond via sulfenylation transformations.16 Recently, the Li and Zhou group has reported sulfenylation of imidazo[1,2-a]pyridine with sodium sulfinates as the sulfur sources (Scheme 1d).17 Also, sulfonylation of indoles, alkene, and alkyne substrates could be successfully achieved by employment of sodium sulfinates.18 Despite the © 2017 American Chemical Society

above achievements, to the best of our knowledge, direct sulfonylation of imidazo[1,2-a]pyridines has not yet been reported.19 Our group has successfully achieved C−H oxidative cycloaromatization, alkylation, tosylmethylation, and biscyanation of imidazo[1,2-a]pyridines. 20 We have also developed nickel-catalyzed auxiliary-directed C(sp2)−H sulfonylation with sodium sulfinates.21 As a continuation of our previous work and recent reports, we herein disclose the first iodine-induced C−H sulfonylation of imidazo[1,2-a]pyridines with sodium sulfinates. At the same time, iodine-induced sulfenylation of imidazo[1,2-a]pyridine was also conducted under reduction conditions (Scheme 1e). For the first time, we have reported the difunctionalization of imidazo[1,2-a]pyridine to access sulfones and sulfides. Meanwhile, the utilization of Et2O and DCM allows an easier reaction workup compared with that of DMSO and DMF.

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RESULTS AND DISCUSSION Initially, 2-phenylimidazo[1,2-a]pyridine 1a and sodium benzenesulfinate 2a were utilized as the model substrates to optimize reaction conditions for direct sulfonylation of imidazopyridines. During the transformation, we noticed iodide product 4a was also isolated (Table 1). We commenced our studies by investigating various bases in a mixture solvent of H2O and PEG400 [Table S1 of the Supporting Information Received: October 28, 2017 Published: December 16, 2017 338

DOI: 10.1021/acs.joc.7b02734 J. Org. Chem. 2018, 83, 338−349

Article

The Journal of Organic Chemistry

examined, which led to inferior reactivity (Table 1, entries 9 and 10). When the volume of Et2O was reduced to 1 mL, a decreased yield was observed for 3a (Table 1, entry 11). Next, the amounts of I2 and Na2CO3 were systematically screened (Table S3, SI), and the best result of 75% yield was achieved when 1.5 equiv of I2 and 1.5 equiv of Na2CO3 were employed (Table 1, entry 12). The reaction efficiency (87%) could be further improved by using 3 equiv of sodium sulfinate (Table 1, entry 13). When the reaction was carried out in the absence of Na2CO3, a decreased yield was observed for product 3a. We assume that the addition of base may help with the elimination process (see the path I route for the sulfonylation mechanism). On the basis of the above discussion, the optimized conditions were finally chosen as shown in entry 13 of Table 1. The structure of sulfonylated product 3a was further confirmed by X-ray diffraction (see the Supporting Information). With the optimized conditions in hand (Table 1, entry 13), we investigated the substrate scope of 2-arylimidazo[1,2a]pyridines (Scheme 2). Initially, the coupling reaction

Scheme 1. Sulfuration of Imidazopyridines with Various Sulfur Sources

Scheme 2. Substrate Scope of 2-Arylimidazo[1,2a]pyridinesa

Table 1. Optimization of Sulfonylation Reaction Conditionsa

% yield entry

base (equiv)

solvent

3a

4a

1 2 3 4 5 6 7 8 9b 10c 11d 12 13e 14 15f

NaHCO3 (1) NaOAc (1) NaOH (1) Na2CO3 (1) Na2CO3 (1) Na2CO3 (1) Na2CO3 (1) Na2CO3 (1) Na2CO3 (1) Na2CO3 (1) Na2CO3 (1) Na2CO3 (1.5) Na2CO3 (1.5) − Na2CO3 (1.5)

H2O/PEG400(1/1) H2O/PEG400 (1/1) H2O/PEG400 (1/1) H2O/PEG400 (1/1) DCE DCM Et2O anisole Et2O Et2O Et2O Et2O Et2O Et2O Et2O

10 10 7 18 34 57 67 27 − − 30 75 87 32 −

7 8 3 8 47 34 32 62 8 (12g) 14 (17g) 16 13 12 8 −

a

Reaction conditions: 1 (0.2 mmol), 2a (0.6 mmol), I2 (1.5 equiv), Na2CO3 (1.5 equiv), Et2O (2 mL), 100 °C, 24 h, under air. bYield for 48 h reaction time.

a

between sodium benzenesulfinate 2a and C2-substituted imidazo[1,2-a]pyridines 1b−n was examined. In most cases, both electron-donating (R = OMe, Me, Et, and t-Bu) and electron-withdrawing (halogen and CF3) substituents on the para- and meta-positions of the phenyl ring were well-tolerated, generating the sulfonylated products 3b−l in 48−92% yields. Unfortunately, a low yield was achieved for nitro-substituted substrate 1m. For ortho-substituted substrates, only 3n was obtained in 16% yield, probably due to the steric hindrance between the sulfonyl group and ortho-substituted phenyl ring. Next, substrates 1o−ac bearing substituents on the C6, C7, and C8 positions of imidazo[1,2-a]pyridines were also

Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), I2 (1.5 equiv), base (X equiv), solvent (2 mL) at 100 °C for 24 h under air. b Tetrabutylammonium iodide (20 mol %), TBHP (2 equiv). cKI (20 mol %), TBHP (2 equiv). dEt2O (1 mL). ePhSO2Na (3 equiv, 0.6 mmol). fWithout I2. gConversion of 1a.

(SI)]. To our delight, sulfonylated product 3a was obtained in 18% yield in the presence of I2 and Na2CO3 at 100 °C for 24 h (Table 1, entry 4). Subsequently, the effects of solvents were screened, which reveals that Et2O was the optimal choice to give the product 3a in 67% yield (Table 1, entry 7). The combination of other catalytic iodide salts and oxidant was also 339

DOI: 10.1021/acs.joc.7b02734 J. Org. Chem. 2018, 83, 338−349

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The Journal of Organic Chemistry

Scheme 4. Substrate Scope of Heterocyclic Substratesa

evaluated. Similarly, it was found that moderate to good yields could be obtained for most substrates, while a strong electronwithdrawing group (CN) led to a low yield. In addition, disubstituted imidazo[1,2-a]pyridines 1ad−ah were employed under the optimal conditions, delivering the desired product 3ad−ah in 35−75% yields. Finally, imidazo[1,2-a]pyridine having naphthyl substitution on the C2 position was also found to be an ideal substrate to provide 3ai in 52% yield. However, when 2-methylimidazo[1,2-a]pyridine 1aj and imidazo[1,2a]pyridine 1ak were employed, no sulfonylated products 3aj and 3ak were obtained. Meanwhile, when a methyl substituent was installed at the C3 position of imidazopyridine (1al), no desired product was detected. To further examine the scope of the sulfonylation reaction, various sodium sulfinates were tested, as summarized in Scheme 3. A series of para-substituted sodium sulfinates

a

Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), I2 (1.5 equiv), Na2CO3 (1.5 equiv), Et2O (2 mL), 100 °C, 24 h, under air. bYield for 48 h reaction time.

Scheme 3. Substrate Scope of Sodium Sulfinatesa

phenylimidazo[1,2-a]pyridine 1a and sodium benzenesulfinate 2a were optimized (Table 2). After screening various solvents, Table 2. Optimization of Sulfenylation Reaction Conditionsa

a

Reaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), I2 (1.5 equiv), Na2CO3 (1.5 equiv), Et2O (2 mL), 100 °C, 24 h, under air.

entry

solvent

X (equiv)

Y (equiv)

7a yield (%)

1 2 3 4 5 6 7 8 9 10c 11d

H2O/PEG400b DCM DCE THF EtOH DCM DCM DCM DCM DCM DCM

1 1 1 1 1 0.5 1.5 1 1 1 1

2 2 2 2 2 2 2 1.5 2.5 2 2

64 88 70 78 61 3 (12e) 54 65 63 58 34

a

Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), I2 (X equiv), PPh3 (Y equiv), solvent (2 mL) at 100 °C for 12 h under air. bH2O/ PEG40 = 1/1 (2 mL). cPhSO2Na (0.2 mol). dPhSO2Na (0.6 mol). e Conversion of 1a.

bearing both electron-withdrawing (F, Cl, and CF3) and electron-donating (OCH3 and CH3) groups could react with imidazo[1,2-a]pyridine 1a smoothly to deliver sulfonylated products 5a−e in 39−88% yields. In addition, the bulky substrate 2-naphthylsulfinic acid sodium salt 2f also proceeded well to afford 5f in 32% yield. However, the employment of sodium methanesulfinate led to the sulfenylated product in 44% yield (not shown). Same as the above discussion, cleavage of C−halogen bonds was not observed, which could be utilized for potential transformations. Moreover, the reactivity of sodium 4-fluorobenzenesulfinate 2a was tested, which gave products 5g−l in 80−86% yields. When sodium pyridine-3sulfinate 2m was utilized, no desired sulfonylated product was isolated. The optimized reaction conditions were further applied to imidazo-containing heterocycles, which delivered the sulfonylated products 6a−e in 30−54% yields (Scheme 4). In general, compared with 2-arylimidazo[1,2-a]pyridine, lower yields were obtained for sulfonylation of heterocycles with limited substrate scope. After screening the direct sulfonylation reaction, we next sought to expand the sulfenylation of imidazopyridine derivatives. First, the sulfenylation conditions between 2-

DCM proved to be the suitable solvent to provide the desired product 7a in 88% yield in the presence of I2 (1 equiv) and PPh3 (2 equiv) (Table 2, entry 2). The attempt to modify the I2 and PPh3 loading was unsuccessful, which led to decreased yields for 7a (Table 2, entries 6−9). When the amount of benzenesulfinate 2a was either increased or decreased, a similar observation was obtained (Table 2, entries 10 and 11). Initially, a variety of imidazo[1,2-a]pyridines were explored to react with sodium benzenesulfinate (Scheme 5). Similar to the sulfonylation reaction, a para- or meta-substituted phenyl ring on the C2 position proceeded smoothly to generate the desired products 7a−j in 44−89% yields, irrespective of electronic properties. However, higher yields were also achieved for sulfenylation of ortho-substituted substrates, which is probably attributed to the less-hindering effect of sulfides compared with sulfones. Imidazo[1,2-a]pyridines bearing substituents on the C6, C7, and C8 positions were employed under the optimized conditions, providing the products 7n−w in 67−89% yields. Disubstituted and 2naphthyl-substituted imidazo[1,2-a]pyridines also coupled 340

DOI: 10.1021/acs.joc.7b02734 J. Org. Chem. 2018, 83, 338−349

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The Journal of Organic Chemistry Scheme 5. Substrate Scope for Sulfenylation Transformationa

Scheme 6. Control Experiments for Sulfonylation Transformation

optimized conditions. The reaction was completely inhibited in the presence of 1 equiv TEMPO (2,2,6,6-tetramethyl-1piperidinyloxy) and BQ (benzoquinone) (Scheme 6, eq f). Importantly, when 1 equiv of BHT (2,6-di-tert-butyl-4methylphenol) and 1,1-diphenylethylene were added, radical trapping products 8 (Figure S1, SI) and 9 (Figure S2, SI) were isolated, both in 28% yield (Scheme 6, eqs g and h). These results suggest that sulfonylation transformation proceeds via a radical pathway. Meanwhile, similar control experiments were performed to investigate the sulfenylation mechanism (Scheme 7). During

a

Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), I2 (1.0 equiv), PPh3 (2.0 equiv), DCM (2 mL), 100 °C, 12 h, under air.

with sodium benzensulfinate to give the sulfenylation products 7x−ab in 42−92% yields. Moreover, this current methodology could be further applied to 2-methylimidazo[1,2-a]pyridine and imidazo[1,2-a]pyridine, which generated products 7ac and 7ad in 65% and 21% yields, respectively. As for the previous observation, no desired product could be detected when 3methylimidazo[1,2-a]pyridine was utilized (not shown). Subsequently, the scope of sodium sulfinates, including aliphatic sodium methanesulfinate, was examined, which furnished 7ac−ak in 35−95% yields. Moreover, sulfenylation of imdazopyridine using sodium pyridine-3-sulfinate provided the desired product 7al in 18% yield. To explore the sulfonylation mechanism, a set of control experiments was performed under various reaction conditions (Scheme 6). During sulfonylation of 2-phenylimidazo[1,2a]pyridine 1a, iodide product 4a was also isolated in 12% yield (Scheme 6, eq a). Under the standard conditions, 1a itself provided iodide product 4a in 58% and 32% yield, respectively, in the presence or absence of Na2CO3 (Scheme 6, eq b). In addition, when 4a and 4-methylbenzenesulfonyl iodide22 were utilized as the substrates with 2a and 1a, the sulfonylated product 3a and 5e was obtained in 58% and 12% yields, respectively (Scheme 6, eqs c and d). Moreover, reaction between 4a and benzenesulfinic acid gave sulfenylated product 7a in 5% yield instead (Scheme 6, eq e). These results indicate that 4-methylbenzenesulfonyl iodide and 4a might be the key intermediates for the sulfonylation reaction.23 Subsequently, the radical scavenger reactions were performed under the

Scheme 7. Control Experiments for Sulfenylation Transformation

sulfenylation of 2-phenylimidazo[1,2-a]pyridine 1a, no iodide product 4a was detected (Scheme 7, eq a). Under the standard conditions, 1a itself could not afford iodide product 4a (Scheme 7, eq b). These results indicate that iodo-substituted imidazopyrine 4a might not be the intermediate for the sulfenylation reaction. Meanwhile, sulfenylation of 1a with PhSSPh and p-Me-C6H5SH afforded products 7a and 7ah in 68% and 19% yields, respectively (Scheme 7, eqs c and d). 341

DOI: 10.1021/acs.joc.7b02734 J. Org. Chem. 2018, 83, 338−349

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and sulfides conveniently using sodium sulfinates as the sulfur source.

Finally, the reaction was mostly inhibited in the presence of 3 equiv of TEMPO and BH (Scheme 7, eq e), suggesting that a radical process may be included in the sulfenylation transformation with 1,2-diphenyldisulfane as the possible intermediate. However, we were unable to detect the corresponding radical trapping products. On the basis of the above discussion and relevant literature, two possible pathways were proposed for the sulfonylation of imidazo[1,2-a]pyridines (Scheme 8). In path I, reaction of

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EXPERIMENTAL SECTION

General Information. All reactions were carried out in ovendried sealed tubes under an air atmosphere unless otherwise mentioned. Solvents were dried with standard methods and freshly distilled prior to use if needed. Melting points were determined on an XT4A melting point apparatus and are uncorrected. Flash column chromatography was performed using 200−300 mesh silica gel. Analytical and preparative thin-layer chromatography (TLC) plates coated with commercial silica gel GF254 were used to monitor the reactions and purify products. 1H and 13C NMR spectra were recorded at 400 or 600 MHz using TMS as an internal standard. Data are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration, and coupling constants (J) in hertz (Hz). HRMS were determined on a Q-Tof Micro or AB SCIEX TripleTOF 6600 MS/ MS System ESI spectrometer. The structure of bis-cyanated product 3a (CCDC file number 1574238) was further confirmed by X-ray diffraction collected on a diffractometer with graphite-monochromated Cu Kα radiation. General Procedure for Sulfonylation. To an oven-dried 15 mL sealed tube were added imidazo[1,2-a]pyridine 1a (0.2 mmol, 38.3 mg), sodium benzenesulfinate 2a (0.6 mmol, 96.7 mg), I2 (0.3 mmol, 76.2 mg), and Na2CO3 (0.3 mmol, 31.8 mg) in Et2O (2 mL) under an air atmosphere. The sealed tube was capped and heated at 100 °C for 24 h. The reaction mixture was cooled down to room temperature and directly concentrated under vacuo. The crude mixture was purified by preparative TLC (ethyl acetate/petroleum = 1/3) to afford the sulfonylated product 3a in 87% yield. General Procedure for Sulfenylation. To an oven-dried 15 mL sealed tube were added imidazo[1,2-a]pyridine 1a (0.2 mmol, 38.8 mg), sodium benzenesulfinate 2a (0.4 mmol, 64.5 mg), I2 (0.2 mmol, 50.8 mg), and PPh3 (0.4 mmol, 105.0 mg) in DCM (2 mL) under an air atmosphere. The sealed tube was capped and heated at 100 °C for 12 h. The reaction mixture was cooled down to room temperature and directly concentrated under vacuo. The crude mixture was purified by preparative TLC (ethyl acetate/petroleum = 1/5) to afford the sulfonylated product 7a in 88% yield. 2-Phenyl-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3a). Yellow solid (58.1 mg, 87% yield); mp 120−121 °C; 1H NMR (400 MHz, CDCl3) δ 9.10 (d, J = 7.0 Hz, 1H), 7.79−7.76 (m, 2H), 7.70−7.64 (m, 3H), 7.47−7.37 (m, 5H), 7.31 (t, J = 8.0 Hz, 2H), 7.00 (td, J = 7.0, 1.2 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.0, 146.7, 141.9, 133.4, 132.7, 130.5, 129.4, 129.1, 128.7, 127.8, 126.7, 126.2, 117.9, 117.4, 114.8; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H15N2O2S 335.0849, found 335.0851. 2-(4-Fluorophenyl)-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3b). Yellow solid (64.5 mg, 92% yield); mp 116−117 °C; 1H NMR (400 MHz, CDCl3) 9.11 (dt, J = 7.0, 1.1 Hz, 1H), 7.78−7.70 (m, 3H), 7.65−7.63 (m, 2H), 7.51−7.44 (m, 2H), 7.39−7.34 (m, 2H), 7.18−7.13 (m, 2H), 7.09−7.05 (m, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 164.5, 162.8, 152.0, 146.7, 141.9, 133.5, 132.6, 132.5, 129.1, 128.8, 128.7 (JC−F = 3.1 Hz), 126.8, 126.2, 118.0, 117.4, 115.0, 114.8, 114.7; 19F NMR (376 MHz, CDCl3) δ −111.70; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14FN2O2S 353.0755, found 353.0755. 2-(4-Chlorophenyl)-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3c). Brown solid (58.6 mg, 80% yield); mp 189−190 °C; 1H NMR (400 MHz, CDCl3) δ 9.10 (dt, J = 7.0, 1.0 Hz, 1H), 7.74−7.70 (m, 3H), 7.66−7.64 (m, 2H), 7.52−7.42 (m, 4H), 7.39−7.35 (m, 2H), 7.07 (td, J = 7.0, 1.2 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 151.8, 147.5, 146.8, 141.8, 138.6, 135.7, 133.5, 131.9, 131.1, 129.2, 128.8, 128.1, 126.8, 126.3, 119.7, 118.1, 117.6, 114.8, 114.1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14ClN2O2S 369.0459, found 369.0461. 3-(Phenylsulfonyl)-2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine (3d). Yellow solid (59.8 mg, 74% yield); mp 163−164 °C; 1 H NMR (400 MHz, CDCl3) 9.10 (d, J = 7.0 Hz, 1H), 7.90 (d, J =

Scheme 8. Proposed Mechanism for Sulfonylation and Sulfenylation

sodium sulfinates 2a with I2 generates iodide intermediate A,22 which undergoes homolysis to give sulfonyl radical B.24 Subsequently, sulfonyl radical B attacks imidazo[1,2-a]pyridine 1a to afford intermediate C, which reacts with an iodine radical to form intermediate D.25 Finally, elimination of intermediate D will provide the desired product 3a in the presence of Na2CO3.26 In path II, sulfonyl radical B reacts with 4a to form intermediate E,23 which releases the final product 3a via elimination of iodine radical. Meanwhile, the mechanism for sulfenylation of imidazo[1,2-a]pyridines is also illustrated in Scheme 7 via similar radical pathways.14b

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CONCLUSION In conclusion, we have developed a facile metal-free method for the difunctionalization of imidazopyridines. This strategy effciently afforded sulfones and sulfides divergently via different catalytic pathways. A wide range of imidazopyridines and sodium sulfinates proceeded smoothly under the optimized conditions. Importantly, the current investigation provided a useful approach to access imidazopyridine sulfones 342

DOI: 10.1021/acs.joc.7b02734 J. Org. Chem. 2018, 83, 338−349

Article

The Journal of Organic Chemistry

TOF) m/z [M + H]+ calcd for C19H14BrN2O2S 412.9954, found 412.9953. 3-(Phenylsulfonyl)-2-(m-tolyl)imidazo[1,2-a]pyridine (3l). Yellow solid (33.7 mg, 48% yield); mp 113−114 °C; 1H NMR (400 MHz, CDCl3) δ 9.13 (d, J = 7.0 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.66− 7.64 (m, 2H), 7.54 (d, J = 7.5 Hz, 1H),7.50−7.44 (m, 3H), 7.38−7.32 (m, 3H), 7.28 (d, J = 8.3 Hz, 1H), 7.06 (td, J = 7.0, 1.1 Hz, 1H), 2.41 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.3, 146.7, 142.1, 137.4, 133.3, 132.5, 130.9, 130.1, 129.0, 128.5, 127.7, 126.9, 126.4, 118.0, 117.4, 114.6, 21.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H17N2O2S 349.1005, found 349.1009. 2-(3-Nitrophenyl)-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3m). Yellow oil (5.5 mg, 7% yield); 1H NMR (400 MHz, CDCl3) δ 9.11 (dt, J = 7.0, 1.0 Hz, 1H), 8.60 (t, J = 1.9 Hz, 1H), 8.35 (dq, J = 8.3, 1.0 Hz, 1H), 8.19 (dt, J = 7.7, 1.3 Hz, 1H), 7.76 (dt, J = 9.0, 1.0 Hz, 1H), 7.73−7.71 (m, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.57−7.51 (m, 2H), 7.44 (t, J = 8.0 Hz, 2H), 7.14 (td, J = 7.1, 1.3 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 147.8, 146.9, 136.7, 134.3, 133.8, 129.4, 129.1, 128.9, 126.8, 126.3, 125.4, 124.1, 118.3, 115.2; HRMS (ESITOF) m/z [M + H]+ calcd for C19H14N3O4S 380.0700, found 380.0704. 2-(2-Fluorophenyl)-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3n). Yellow solid (5.5 mg, 8% yield); mp 138−139 °C; 1H NMR (400 MHz, CDCl3) δ 8.94 (dt, J = 7.0, 1.0 Hz, 1H), 7.78−7.73 (m, 3H), 7.56−7.51 (m, 2H), 7.50−7.41 (m, 4H), 7.27 (td, J = 7.6, 1.0 Hz, 1H), 7.17 (t, J = 9.1 Hz, 1H), 7.08 (td, J = 7.0, 1.2 Hz, 1H); 13 C{1H} NMR (151 MHz, CDCl3) δ 161.2, 159.6, 147.1, 146.8, 141.5, 133.5, 132.5, 131.3 (JC−F = 8.1 Hz), 129.2, 128.5, 126.6, 126.4, 123.6 (JC−F = 3.4 Hz), 121.0 (JC−F = 14.7 Hz), 118.8, 118.3, 115.6, 115.4, 114.8; 19F NMR (376 MHz, CDCl3) δ −113.03; HRMS (ESITOF) m/z [M + H]+ calcd for C19H14FN2O2S 353.0755, found 353.0757. 6-Fluoro-2-phenyl-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3o). Yellow solid (38.7 mg, 55% yield); mp 133−134 °C; 1H NMR (400 MHz, CDCl3) δ 9.16 (qd, J = 2.4, 0.6 Hz, 1H), 7.71−7.68 (m, 3H), 7.61 (dd, J = 8.2, 0.9 Hz, 2H), 7.51−7.43 (m, 4H), 7.41−7.33 (m, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 154.8, 153.7, 153.2, 144.2, 141.7, 133.6, 132.3, 130.4, 129.5, 129.1, 127.9, 126.4, 120.4, 120.3, 118.9, 118.4, 118.4 (JC−F = 8.8 Hz), 114.5, 114.2; 19F NMR (376 MHz, CDCl3) δ −135.21; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14FN2O2S 353.0755, found 353.0757. 6-Chloro-2-phenyl-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3p). Yellow solid (42.7 mg, 58% yield); mp 144−145 °C; 1H NMR (400 MHz, CDCl3) δ 9.24 (dd, J = 1.9, 0.7 Hz, 1H), 7.71−7.65 (m, 3H), 7.61 (dd, J = 8.2, 0.9 Hz, 2H), 7.51−7.41 (m, 5H), 7.35 (t, J = 8.2 Hz, 2H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.4, 144.9, 141.7, 133.6, 132.2, 130.4, 129.9, 129.6, 129.1, 127.9, 126.4, 124.9, 123.0, 118.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14ClN2O2S 369.0459, found 369.0464. 6-Bromo-2-phenyl-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3q). Yellow solid (37.5 mg, 46% yield); mp 157−158 °C; 1H NMR (400 MHz, CDCl3) δ 9.33 (q, J = 1.0 Hz, 1H), 7.69 (dd, J = 7.6, 1.4 Hz, 2H), 7.62−7.59 (m, 3H), 7.54−7.42 (m, 5H), 7.35 (t, J = 8.1 Hz, 2H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.2, 145.1, 141.7, 133.6, 132.1, 132.0, 130.4, 129.6, 129.1, 127.9, 127.0, 126.4, 118.5, 118.1, 109.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14BrN2O2S 412.9954, found 412.9956. 6-Iodo-2-phenyl-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3r). Yellow solid (40.3 mg, 44% yield); mp 141−142 °C; 1H NMR (400 MHz, CDCl3) δ 9.42 (q, J = 0.8 Hz, 1H), 7.69 (dd, J = 7.6, 1.4 Hz, 2H), 7.65−7.59 (m, 3H), 7.51−7.42 (m, 5H), 7.35 (t, J = 8.1 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ 152.9, 145.2, 141.7, 136.6, 133.6, 132.1, 131.7, 130.5, 129.6, 129.1, 127.9, 126.4, 118.9, 117.7, 77.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14IN2O2S 460.9815, found 460.9817. 2-Phenyl-3-(phenylsulfonyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (3s). White solid (57.8 mg, 72% yield); mp 145−146 °C; 1H NMR (400 MHz, CDCl3) δ 9.58 (s, 1H), 7.82 (d, J = 9.36 Hz, 1H), 7.71 (dd, J = 7.7, 1.4 Hz, 2H), 7.63−7.59 (m, 3H), 7.52−7.44 (m, 4H), 7.35 (t, J = 8.2 Hz, 2H); 13C{1H} NMR (151 MHz, CDCl3) δ

8.1 Hz, 2H), 7.75−7.72 (m, 3H), 7.67−7.65 (m, 2H), 7.52−7.47 (m, 2H), 7.38 (t, J = 8.0 Hz, 2H), 7.10 (td, J = 7.0, 1.0 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 151.3, 146.8, 141.7, 136.3, 133.6, 131.2 (JC−F = 32.7 Hz), 131.0, 129.2, 128.9, 126.8, 126.3, 124.7 (JC−F = 3.4 Hz), 124.1 (JC−F = 273.0 Hz), 118.2, 118.0, 115.1; 19F NMR (376 MHz, CDCl3) δ −62.64; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H14F3N2O2S 403.0723, found 403.0726. 2-(4-Methoxyphenyl)-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3e). Brown solid (62.5 mg, 86% yield); mp 133−134 °C; 1H NMR (400 MHz, CDCl3) δ 9.10 (dt, J = 7.0, 1.0 Hz, 1H), 7.77−7.73 (m, 2H), 7.69 (dt, J = 9.0, 1.0 Hz, 1H), 7.65−7.63 (m, 2H), 7.48−7.41 (m, 2H), 7.37−7.32 (m, 2H), 7.04−6.98 (m, 3H), 3.87 (s, 3H); 13 C{1H} NMR (151 MHz, CDCl3) δ 160.7, 153.1, 146.7, 142.1, 133.3, 132.0, 129.1, 128.6, 126.9, 126.2, 124.9, 117.8, 116.8, 114.5, 113.3, 55.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H17N2O3S 365.0954, found 365.0959. 3-(Phenylsulfonyl)-2-(p-tolyl)imidazo[1,2-a]pyridine (3f). Yellow solid (55.7 mg, 80% yield); mp 166−167 °C; 1H NMR (400 MHz, CDCl3) δ 9.10 (dt, J = 7.0, 1.0 Hz, 1H), 7.70 (dt, J = 9.0, 1.0 Hz, 1H), 7.66−7.64 (m, 4H), 7.49−7.41 (m, 2H), 7.34 (t, J = 8.1, 2H), 7.27 (t, J = 3.8 Hz, 2H), 7.03 (td, J = 7.0, 1.2 Hz, 1H), 2.43 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.4, 146.7, 142.1, 139.4, 133.3, 130.4, 129.7, 129.1, 128.6, 128.5, 126.8, 126.3, 117.9, 117.2, 114.6, 21.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H17N2O2S 349.1005, found 349.1009. 2-(4-Ethylphenyl)-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3g). Yellow solid (56.3 mg, 78% yield); mp 125−126 °C; 1H NMR (400 MHz, CDCl3) δ 9.10 (dt, J = 7.0, 1.0 Hz, 1H), 7.71−7.63 (m, 5H), 7.48−7.41 (m, 2H), 7.35−7.27 (m, 4H), 7.03 (td, J = 7.0, 1.2 Hz, 1H), 2.73 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.4, 146.7, 145.7, 142.0, 133.3, 130.5, 129.9, 129.0, 128.5, 127.4, 126.8, 126.3, 117.9, 117.1, 114.5, 28.8, 15.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H19N2O2S 363.1162, found 363.1165. 2-(4-(tert-Butyl)phenyl)-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3h). Brown oil (60.3 mg, 77% yield); 1H NMR (400 MHz, CDCl3) δ 9.11 (d, J = 7.0 Hz, 1H), 7.71−7.63 (m, 5H), 7.48−7.41 (m, 4H), 7.33 (t, J = 8.1 Hz, 2H), 7.03 (td, J = 7.0, 1.2 Hz, 1H), 1.37 (s, 9H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.2, 152.5, 147.5, 146.7, 142.0, 138.5, 133.3, 130.2, 129.6, 129.0, 128.5, 126.9, 126.4, 124.8, 119.6, 117.9, 117.1, 114.5, 114.1, 34.8, 31.3; HRMS (ESITOF) m/z [M + H]+ calcd for C23H23N2O2S 391.1475, found 391.1482. 2-(3-Fluorophenyl)-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3i). Yellow solid (49.2 mg, 70% yield); mp 111−112 °C; 1H NMR (400 MHz, CDCl3) 9.12 (dt, J = 7.0, 1.0 Hz, 1H), 7.72 (dt, J = 9.0, 0.9 Hz, 1H), 7.68−7.66 (m, 2H), 7.57 (dt, J = 7.8, 1.2 Hz, 1H), 7.52− 7.42 (m, 4H), 7.38 (t, J = 8.12 Hz, 2H), 7.17 (td, J = 8.5, 2.6 Hz, 1H), 7.08 (td, J = 7.0, 1.2 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 163.0, 161.3, 151.4 (JC−F = 2.1 Hz), 146.7, 141.8, 134.6 (JC−F = 8.2 Hz), 133.5, 129.4 (JC−F = 8.0 Hz), 129.2, 128.8, 126.8, 126.4 (JC−F = 3.0 Hz), 126.3, 118.1, 117.7, 117.6, 117.4, 116.3 (JC−F = 21.0 Hz), 114.9; 19F NMR (376 MHz, CDCl3) δ −113.50; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14FN2O2S 353.0755, found 353.0756. 2-(3-Chlorophenyl)-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3j). Yellow solid (49.2 mg, 67% yield); mp 106−107 °C; 1H NMR (400 MHz, CDCl3) δ 9.1 (dt, J = 7.0, 1.2 Hz, 1H), 7.73−7.66 (m, 5H), 7.53−7.43 (m, 3H), 7.41−7.37 (m, 3H), 7.09 (td, J = 7.0, 1.2 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 151.3, 146.7, 141.7, 134.4, 133.7, 133.6, 130.3, 129.4, 129.2, 129.1, 128.9, 128.8, 126.8, 126.4, 118.1, 117.8, 114.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14ClN2O2S 369.0459, found 369.0468. 2-(3-Bromophenyl)-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3k). Yellow solid (44.0 mg, 53% yield); mp 144−145 °C; 1H NMR (400 MHz, CDCl3) δ 9.12 (dt, J = 7.0, 1.2 Hz, 1H), 7.84−7.77 (m, 1H), 7.74−7.66 (m, 4H), 7.60 (dq, J = 8.0, 1.0 Hz, 1H), 7.53−7.46 (m, 2H), 7.39 (t, J = 8.1 Hz, 2H), 7.34 (t, J = 7.9 Hz, 1H), 7.09 (td, J = 7.0, 1.2 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 151.1, 146.7, 141.7, 138.8, 138.3, 134.6, 133.6, 133.1, 132.3, 129.4, 129.3, 129.2, 128.8, 126.8, 126.4, 121.8, 118.1, 117.8, 115.0. HRMS (ESI343

DOI: 10.1021/acs.joc.7b02734 J. Org. Chem. 2018, 83, 338−349

Article

The Journal of Organic Chemistry

1H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.2, 144.1, 141.6, 133.6, 132.1, 130.7, 129.6, 129.1, 127.8, 127.4, 126.5, 125.5, 123.9, 119.4, 114.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14ClN2O2S 369.0459, found 369.0466. 8-Methoxy-2-phenyl-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3ab). Yellow solid (60.4 mg, 83% yield); mp 178−179 °C; 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 7.7 Hz, 1H), 7.76−7.73 (m, 2H), 7.62−7.59 (m, 2H), 7.47−7.43 (m, 4H), 7.32 (t, J = 8.2 Hz, 2H), 6.95 (d, J = 2.5 Hz, 1H), 6.72 (dd, J = 7.7, 2.6 Hz, 1H), 3.86 (s, 3H); 13 C{1H} NMR (151 MHz, CDCl3) δ 160.5, 153.6, 148.9, 142.3, 133.1, 132.7, 130.5, 129.3, 129.0, 127.8, 127.3, 126.2, 116.2, 109.1, 95.6, 55.8; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H17N2O3S 365.0954, found 365.0960. 8-Methyl-2-phenyl-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3ac). Yellow solid (63.8 mg, 92% yield); mp 120−121 °C; 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J = 6.9 Hz, 1H), 7.73−7.71 (m, 2H), 7.63 (dd, J = 8.2, 1.0 Hz, 2H), 7.47−7.43 (m, 4H), 7.33 (t, J = 8.1 Hz, 2H), 7.23 (dt, J = 7.0, 1.0 Hz, 1H), 6.95 (t, J = 7.0 Hz, 1H), 2.63 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 152.6, 147.0, 142.1, 133.3, 132.9, 130.6, 129.2, 129.0, 128.2, 127.8, 127.4, 126.3, 124.5, 117.7, 114.7, 17.1; HRMS (ESI-TOF) m/z [M + H] + calcd for C20H17N2O2S 349.1005, found 349.1004. 6-Fluoro-3-(phenylsulfonyl)-2-(p-tolyl)imidazo[1,2-a]pyridine (3ad). Yellow solid (45.7 mg, 62% yield); mp 137−138 °C; 1H NMR (400 MHz, CDCl3) δ 9.13 (qd, J = 2.3, 0.4 Hz, 1H), 7.68 (q, J = 4.8 Hz, 1H), 7.64−7.61 (m, 4H), 7.49 (tt, J = 7.5, 1.1 Hz, 1H), 7.39− 7.34 (m, 3H), 7.26 (d, J = 7.9 Hz, 2H), 2.43 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 154.7, 153.9, 153.2, 144.2, 141.8, 139.6, 133.5, 130.3, 129.4, 129.1, 128.6, 126.3, 120.4, 120.2, 118.6, 118.4 (JC−F = 8.7 Hz), 114.5, 114.2, 21.4; 19F NMR (376 MHz, CDCl3) δ −135.42; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H16FN2O2S 367.0911, found 367.0915. 6-Iodo-3-(phenylsulfonyl)-2-(p-tolyl)imidazo[1,2-a]pyridine (3ae). Yellow solid (33.4 mg, 35% yield); mp 171−172 °C; 1H NMR (400 MHz, CDCl3) δ 9.39 (d, J = 0.5 Hz, 1H), 7.63−7.60 (m, 5H), 7.51−7.47 (m, 2H), 7.36 (t, J = 8.0 Hz, 2H), 7.25 (d, J = 7.7 Hz, 2H), 2.43 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.2, 145.2, 141.8, 139.7, 136.6, 133.5, 131.7, 130.4, 129.2, 129.1, 128.6, 126.4, 118.8, 117.4, 76.8, 21.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H16IN2O2S 474.9972, found 474.9979. 3-(Phenylsulfonyl)-2-(p-tolyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (3af). Yellow solid (52.6 mg, 63% yield); mp 155−156 °C; 1 H NMR (400 MHz, CDCl3) δ 9.55 (s, 1H), 7.81 (d, J = 9.4 Hz, 1H), 7.65−7.58 (m, 5H), 7.50 (tt, J = 7.5, 1.0 Hz, 1H), 7.36 (t, J = 8.2 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 2.44 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 154.5, 146.4, 141.5, 140.0, 133.7, 130.4, 129.2, 128.9, 128.7, 126.5, 126.0 (JC−F = 5.4 Hz), 124.3 (JC−F = 1.7 Hz), 123.2 (JC−F = 271.3 Hz), 118.9, 118.8 (JC−F = 34.8 Hz), 118.6, 21.5; 19F NMR (376 MHz, CDCl3) δ −62.01; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H16F3N2O2S 417.0879, found 417.0884. 7-Methoxy-3-(phenylsulfonyl)-2-(p-tolyl)imidazo[1,2-a]pyridine (3ag). Brown solid (56.5 mg, 75% yield); mp 116−117 °C; 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 7.8 Hz, 1H), 7.67−7.61 (m, 4H), 7.45 (tt, J = 7.4, 1.1 Hz, 1H), 7.33 (t, J = 8.1 Hz, 2H), 7.26 (d, J = 7.9 Hz, 2H), 6.95 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 7.7, 2.4 Hz, 1H), 3.85 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 160.4, 153.9, 148.9, 142.4, 139.3, 133.1, 130.4, 129.8, 129.0, 128.5, 127.3, 126.1, 115.9, 108.9, 95.5, 55.8, 21.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H19N2O3S 379.1111, found 379.1114. 2-(4-Methoxyphenyl)-7-methyl-3-(phenylsulfonyl)imidazo[1,2a]pyridine (3ah). Brown oil (41.3 mg, 55% yield); 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J = 7.1 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.54 (dd, J = 8.1, 0.9 Hz, 2H), 7.39−7.36 (m, 2H), 7.25 (t, J = 8.1 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.77 (dd, J = 7.2, 1.7 Hz, 1H), 3.79 (s, 3H), 2.35 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 160.6, 153.3, 147.2, 142.3, 140.1, 133.1, 132.0, 129.0, 126.1, 126.0, 125.1, 117.0, 116.4, 116.1, 113.3, 55.3, 21.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H19N2O3S 379.1111, found 379.1108. 2-(Naphthalen-2-yl)-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3ai). Yellow solid (40 mg, 52% yield); mp 133−134 °C; 1H NMR

154.3, 146.4, 141.4, 133.8, 131.8, 130.5, 129.8, 129.2, 128.0, 126.5, 126.1, 126.0 (JC−F = 6.1 Hz), 124.4 (JC−F = 2.0 Hz), 123.2 (JC−F = 271.7 Hz), 119.3, 119.0 (JC−F = 34.7 Hz), 118.7; 19F NMR (376 MHz, CDCl3) δ −62.02; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H14F3N2O2S 403.0723, found 403.0724. 2-Phenyl-3-(phenylsulfonyl)imidazo[1,2-a]pyridine-6-carbonitrile (3t). White solid (9.8 mg, 14% yield); mp 172−173 °C; 1H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.72 (d, J = 6.6 Hz, 2H), 7.60−7.56 (m, 3H), 7.54−7.45 (m, 4H), 7.37 (t, J = 7.9 Hz, 2H); 13C{1H} NMR (151 MHz, CDCl3) δ 141.2, 134.0, 132.9, 130.5, 130.1, 129.3, 128.3, 128.1, 126.5, 119.1, 115.8, 101.1, 77.2, 77.0, 76.8, 29.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H14N3O2S 360.0801, found 360.0809. 6-Methyl-2-phenyl-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3u). Yellow solid (49.4 mg, 71% yield); mp 128−129 °C; 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 7.72−7.70 (m, 2H), 7.64−7.60 (m, 3H), 7.48−7.42 (m, 4H), 7.36−7.29 (m, 3H), 2.42 (s, 3H); 13 C{1H} NMR (151 MHz, CDCl3) δ 152.9, 145.7, 142.2, 133.2, 132.8, 131.6, 130.5, 129.2, 129.0, 128.8, 127.8, 126.3, 126.1, 124.7, 124.6, 117.2, 117.0, 18.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H17N2O2S 349.1005, found 349.1009. 6-Methoxy-2-phenyl-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3v). Brown solid (28.4 mg, 39% yield); mp 130−131 °C; 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 2.2 Hz, 1H), 7.71−7.69 (m, 2H), 7.61 (t, J = 7.2 Hz, 3H), 7.50−7.41 (m, 4H), 7.34 (t, J = 8.1 Hz, 2H), 7.23 (dd, J = 7.2, 2.4 Hz, 1H), 3.92 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 152.8, 150.5, 143.6, 142.0, 133.3, 132.7, 130.4, 129.2, 129.0, 127.8, 126.3, 123.3, 118.0, 117.9, 109.0, 56.4; HRMS (ESITOF) m/z [M + H]+ calcd for C20H17N2O3S 365.0954, found 365.0954. 7-Chloro-2-phenyl-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3w). Yellow solid (58.2 mg, 80% yield); mp 146−147 °C; 1H NMR (400 MHz, CDCl3) δ 9.09 (dd, J = 7.5, 0.6 Hz, 1H), 7.72−7.69 (m, 3H), 7.59 (dd, J = 8.3, 1.0 Hz, 2H),7.50−7.43 (m, 4H), 7.34 (t, J = 7.7 Hz, 2H), 7.04 (dd, J = 7.5, 2.2 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.8, 146.6, 141.7, 135.5, 133.5, 132.2, 130.5, 129.6, 129.1, 127.9, 127.2, 126.3, 117.9, 116.9, 116.2; HRMS (ESI-TOF) m/ z [M + H]+ calcd for C19H14ClN2O2S 369.0459, found 369.0466. 7-Bromo-2-phenyl-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3x). Yellow solid (40.2 mg, 49% yield); mp 142−143 °C; 1H NMR (400 MHz, CDCl3) δ 9.02 (dd, J = 7.4, 0.6 Hz, 1H), 7.89 (dd, J = 2.0, 0.6 Hz, 1H), 7.71 (dd, J = 7.6, 1.6 Hz, 2H), 7.59 (dd, J = 8.4, 1.1 Hz, 2H), 7.50−7.43 (m, 4H), 7.34 (t, J = 8.2 Hz, 2H), 7.16 (dd, J = 7.4, 2.0 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.6, 146.7, 141.7, 133.5, 132.1, 130.5, 129.6, 129.1, 127.9, 127.1, 126.3, 123.1, 120.3, 118.5, 118.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14BrN2O2S 412.9954, found 412.9959. 7-Methoxy-2-phenyl-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3y). Yellow solid (61.4 mg, 84% yield); mp 173−174 °C; 1H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 7.7 Hz, 1H), 7.75−7.23 (m, 2H), 7.61−7.59 (m, 2H), 7.48−7.44 (m, 4H), 7.33 (t, J = 8.1 Hz, 2H), 6.96 (d, J = 2.6 Hz, 1H), 6.73 (dd, J = 7.7, 2.6 Hz, 1H), 3.88 (s, 3H); 13 C{1H} NMR (151 MHz, CDCl3) δ 160.5, 153.6, 148.9, 142.3, 133.1, 132.7, 130.4, 129.3, 129.0, 127.8, 127.3, 126.2, 116.2, 109.1, 95.5, 55.8; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H17N2O3S 365.0954, found 365.0959. 7-Methyl-2-phenyl-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3z). Brown solid (54.3 mg, 78% yield); mp 156−157 °C; 1H NMR (400 MHz, CDCl3) δ 8.98 (d, J = 7.2 Hz, 1H), 7.74−7.72 (m, 2H), 7.61 (dd, J = 8.3, 1.0 Hz, 2H), 7.47−7.43 (m, 5H), 7.33 (t, J = 8.2 Hz, 2H), 6.88 (dd, J = 7.2, 1.7 Hz, 1H), 2.45 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.3, 147.2, 142.2, 140.2, 133.2, 132.7, 130.5, 129.3, 129.0, 127.8, 126.2, 125.9, 117.2, 116.7, 116.5, 21.4; HRMS (ESITOF) m/z [M + H]+ calcd for C20H17N2O2S 349.1005, found 349.1010. 8-Chloro-2-phenyl-3-(phenylsulfonyl)imidazo[1,2-a]pyridine (3aa). Brown solid (32.1 mg, 44% yield); mp 168−169 °C; 1H NMR (400 MHz, CDCl3) δ 9.11 (dd, J = 7.0, 1.0 Hz, 1H), 7.71 (dd, J = 7.6, 1.5 Hz, 2H), 7.59 (dd, J = 8.2, 1.0 Hz, 2H), 7.52 (dd, J = 7.5, 0.9 Hz, 1H), 7.50−7.42 (m, 4H), 7.34 (t, J = 8.2 Hz, 2H), 7.01 (t, J = 7.2 Hz, 344

DOI: 10.1021/acs.joc.7b02734 J. Org. Chem. 2018, 83, 338−349

Article

The Journal of Organic Chemistry (400 MHz, CDCl3) δ 9.16 (d, J = 7.0 Hz, 1H), 8.28 (s, 1H), 7.94− 7.85 (m, 4H), 7.75 (d, J = 9.0 Hz, 1H), 7.63 (dd, J = 8.2, 0.9 Hz, 2H), 7.57−7.50 (m, 2H), 7.48−7.41(m, 2H), 7.31−7.26 (m, 2H), 7.06 (td, J = 7.0, 1.2 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.0, 146.8, 142.0, 133.7, 133.4, 132.7, 130.6, 130.0, 129.1, 128.73, 128.68, 127.7, 127.4, 126.91, 126.86, 126.33, 126.27, 118.0, 117.7, 114.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for C23H17N2O2S 385.1005, found 385.1003. 3-((4-Fluorophenyl)sulfonyl)-2-phenylimidazo[1,2-a]pyridine (5a). Yellow solid (61.8 mg, 88% yield); mp 132−133 °C; 1H NMR (400 MHz, CDCl3) δ 9.13 (dt, J = 7.0, 1.0 Hz, 1H), 7.74−7.70 (m, 3H), 7.64−7.59 (m, 2H), 7.49−7.44 (m, 4H), 7.07 (td, J = 6.9, 1.2 Hz, 1H), 7.00 (t, J = 8.4 Hz, 2H); 13C{1H} NMR (151 MHz, CDCl3) δ 166.3, 164.6, 153.1, 146.7, 138.1 (JC−F = 2.3 Hz), 132.5, 130.5, 129.5, 129.2 (JC−F = 9.8 Hz), 128.7, 127.9, 126.8, 118.1, 117.4, 116.4, 116.2, 114.8; 19F NMR (376 MHz, CDCl3) δ −103.64; HRMS (ESITOF) m/z [M + H]+ calcd for C19H14FN2O2S 353.0755, found 353.0757. 3-((4-Chlorophenyl)sulfonyl)-2-phenylimidazo[1,2-a]pyridine (5b). Yellow solid (55.7 mg, 76% yield); mp 121−122 °C; 1H NMR (400 MHz, CDCl3) δ 9.12 (dt, J = 7.0, 1.0 Hz, 1H), 7.74−7.70 (m, 3H), 7.52 (d, J = 8.8 Hz, 2H), 7.50−7.44 (m, 4H), 7.29 (d, J = 8.8 Hz, 2H), 7.08 (td, J = 7.0, 1.2 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.3, 146.8, 140.5, 140.0, 132.4, 130.5, 130.0, 129.3, 128.8, 127.9, 127.8, 126.8, 118.1, 117.2, 114.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14ClN2O2S 369.0459, found 369.0464. 2-Phenyl-3-((4-(trifluoromethyl)phenyl)sulfonyl)imidazo[1,2-a]pyridine (5c). Brown solid (44.2 mg, 64% yield); mp 114−115 °C; 1 H NMR (400 MHz, CDCl3) δ 9.08 (dt, J = 7.0, 1.0 Hz, 1H), 7.66 (dt, J = 9.0, 0.9 Hz, 1H), 7.64−7.61 (m, 4H), 7.50 (d, J = 8.4 Hz, 2H), 7.43−7.36 (m, 4H), 7.02 (td, J = 7.0, 1.2 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.9, 147.1, 145.4, 134.9 (JC−F = 32.9 Hz), 132.3, 130.5, 129.7, 129.0, 127.9, 126.8, 126.2 (JC−F = 3.4 Hz), 123.0 (JC−F = 273.0 Hz), 118.2, 116.6, 115.0; 19F NMR (376 MHz, CDCl3) δ −63.27; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H14F3N2O2S 403.0723, found 403.0726. 3-((4-Methoxyphenyl)sulfonyl)-2-phenylimidazo[1,2-a]pyridine (5d). Yellow solid (28.4 mg, 39% yield); mp 131−132 °C; 1H NMR (400 MHz, CDCl3) δ 9.11 (dt, J = 7.0, 1.0 Hz, 1H), 7.74−7.70 (m, 3H), 7.57 (d, J = 9.0 Hz, 2H), 7.47−7.42 (m, 4H), 7.05 (td, J = 7.0, 1.2 Hz, 1H), 6.79 (d, J = 9.0 Hz, 2H), 3.78 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 163.5, 152.4, 146.5, 133.6, 132.7, 130.5, 129.3, 128.7, 128.3, 127.8, 126.8, 118.3, 118.0, 114.5, 114.2, 55.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H17N2O3S 365.0954, found 365.0958. 2-Phenyl-3-tosylimidazo[1,2-a]pyridine (5e). Yellow solid (53.8 mg, 77% yield); mp 132−133 °C; 1H NMR (400 MHz, CDCl3) δ 9.10 (dt, J = 7.0, 1.0 Hz, 1H), 7.76−7.74 (m, 2H), 7.70 (d, J = 9.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.47−7.41 (m, 4H), 7.13 (d, J = 8.1 Hz, 2H), 7.04 (td, J = 7.0, 1.2 Hz, 1H), 2.31 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 152.8, 146.6, 144.4, 139.1, 132.7, 130.5, 129.7, 129.3, 128.5, 127.8, 126.8, 126.4, 118.0, 117.8, 114.6, 21.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H17N2O2S 349.1005, found 349.1007. 3-(Naphthalen-2-ylsulfonyl)-2-phenylimidazo[1,2-a]pyridine (5f). Yellow solid (24.8 mg, 32% yield); mp 137−138 °C; 1H NMR (400 MHz, CDCl3) δ 9.21 (d, J = 7.0 Hz, 1H), 8.23 (d, J = 1.7 Hz, 1H), 7.80 (t, J = 7.0 Hz, 2H), 7.77−7.70 (m, 4H), 7.61−7.53 (m, 2H), 7.50−7.43 (m, 5H), 7.07 (td, J = 7.0, 1.2 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.2, 146.7, 138.7, 135.0, 132.6, 131.9, 130.6, 129.5, 129.41, 129.36, 129.1, 128.6, 127.9, 127.83, 127.79, 127.6, 126.9, 121.4, 118.0, 117.6, 114.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for C23H17N2O2S 385.1005, found 385.1004. 2-(4-Fluorophenyl)-3-((4-fluorophenyl)sulfonyl)imidazo[1,2-a]pyridine (5g). Yellow solid (63.5 mg, 86% yield); mp 139−140 °C; 1 H NMR (400 MHz, CDCl3) δ 9.11 (dt, J = 7.0, 0.9 Hz, 1H), 7.77− 7.71 (m, 3H), 7.65−7.60 (m, 2H), 7.49 (td, J = 7.0, 1.2 Hz, 1H), 7.16 (t, J = 8.7 Hz, 2H), 7.09 (td, J = 7.0, 1.2 Hz, 1H), 7.03 (t, J = 8.5 Hz, 2H); 13C{1H} NMR (151 MHz, CDCl3) δ 166.3, 164.6, 164.5, 162.8, 152.0, 146.7, 138.0 (JC−F = 2.6), 132.5 (JC−F = 8.3 Hz), 129.1 (JC−F =

9.4 Hz), 129.0, 128.5 (JC−F = 3.0 Hz), 126.7, 118.0, 117.3, 116.5, 116.3, 115.0, 114.9 (JC−F = 4.4 Hz); HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H13F2N2O2S 371.0660, found 371.0664. 2-(4-Chlorophenyl)-3-((4-fluorophenyl)sulfonyl)imidazo[1,2-a]pyridine (5h). Yellow solid (63.8 mg, 83% yield); mp 149−150 °C; 1 H NMR (400 MHz, CDCl3) δ 9.10 (dt, J = 7.0, 1.0 Hz, 1H), 7.74− 7.70 (m, 3H), 7.66−7.62 (m, 2H), 7.51−7.43 (m, 3H), 7.09 (td, J = 7.0, 1.2 Hz, 1H), 7.04 (t, J = 8.4 Hz, 2H); 13C{1H} NMR (151 MHz, CDCl3) δ 166.4, 164.7, 151.8, 147.6, 146.8, 138.4, 137.9 (JC−F = 3.3 Hz), 135.8, 131.9, 131.0, 129.1 (JC−F = 9.7 Hz), 129.0, 128.1, 126.7, 119.7, 118.1, 117.4, 116.5, 116.4, 115.0, 114.1; 19F NMR (376 MHz, CDCl3) δ −103.25; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H13ClFN2O2S 387.0365, found 387.0370. 3-((4-Fluorophenyl)sulfonyl)-2-(4-methoxyphenyl)imidazo[1,2a]pyridine (5i). Brown solid (62.4 mg, 82% yield); mp 122−123 °C; 1 H NMR (400 MHz, CDCl3) δ 9.11 (dt, J = 7.0, 1.1 Hz, 1H), 7.74− 7.69 (m, 3H), 7.64−7.61 (m, 2H), 7.45 (td, J = 7.0, 1.2 Hz, 1H), 7.05 (td, J = 7.0, 1.2 Hz, 1H), 7.02−6.98 (m, 4H), 3.88 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 166.2, 164.5, 160.8, 153.1, 146.8, 138.1 (JC−F = 2.6 Hz), 132.0, 129.1 (JC−F = 9.5 Hz), 128.7, 126.8, 124.8, 117.9, 116.8, 116.4, 116.2, 114.6, 113.4, 55.3; 19F NMR (376 MHz, CDCl3) δ −103.81; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H16FN2O3S 383.0860, found 383.0863. 3-((4-Fluorophenyl)sulfonyl)-2-(p-tolyl)imidazo[1,2-a]pyridine (5j). Yellow solid (59.4 mg, 81% yield); mp 178−179 °C; 1H NMR (400 MHz, CDCl3) δ 9.11 (dt, J = 7.0, 1.1 Hz, 1H), 7.71 (dt, J = 9.0, 1.0 Hz, 1H), 7.65−7.61 (m, 4H), 7.47−7.43 (m, 1H), 7.27 (d, J = 7.8 Hz, 2H), 7.05 (td, J = 7.0, 1.2 Hz, 1H), 7.02−6.98 (m, 2H), 2.43 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 166.2, 164.5, 153.3, 146.8, 139.5, 138.1 (JC−F = 2.6 Hz), 130.4, 130.0, 129.2 (JC−F = 9.6 Hz), 128.6 (JC−F = 7.8 Hz), 126.8, 119.6, 118.0, 117.1, 116.3, 116.2, 114.7, 21.4; 19F NMR (376 MHz, CDCl3) δ −103.81; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H16FN2O2S 367.0911, found 367.0916. 3-((4-Fluorophenyl)sulfonyl)-7-methoxy-2-phenylimidazo[1,2a]pyridine (5k). Yellow solid (61.3 mg, 80% yield); mp 144−145 °C; 1 H NMR (400 MHz, CDCl3) δ 8.92 (d, J = 7.7 Hz, 1H), 7.73−7.71 (m, 2H), 7.60−7.57 (m, 2H), 7.47−7.43 (m, 3H), 7.00−6.96 (m, 3H), 6.74 (dd, J = 7.6, 2.6 Hz, 1H), 3.87 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 166.1, 164.4, 160.5, 153.6, 148.9, 138.4 (JC−F = 2.5 Hz), 132.6, 130.4, 129.4, 129.0 (JC−F = 9.4 Hz), 127.8, 127.2, 116.3, 116.2, 109.2, 95.6, 55.8; 19F NMR (376 MHz, CDCl3) δ −104.09; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H16FN2O3S 383.0860, found 383.0865. 3-((4-Fluorophenyl)sulfonyl)-8-methoxy-2-phenylimidazo[1,2a]pyridine (5l). Yellow solid (61.3 mg, 80% yield); mp 143−144 °C; 1 H NMR (400 MHz, CDCl3) δ 8.92 (dd, J = 7.8, 0.3 Hz, 1H), 7.73− 7.71 (m, 2H), 7.60−7.57 (m, 2H), 7.47−7.43 (m, 3H), 7.00−6.96 (m, 3H), 6.74 (dd, J = 7.7, 2.6 Hz, 1H), 3.87 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 166.1, 164.4, 160.5, 153.6, 148.9, 138.4, 132.6, 130.4, 129.4, 129.0 (JC−F = 9.4 Hz), 127.8, 127.2, 116.3, 116.2, 109.2, 95.6, 55.8; 19F NMR (376 MHz, CDCl3) δ −104.09; HRMS (ESITOF) m/z [M + H]+ calcd for C20H16FN2O3S 383.0860, found 383.0863. 6-Phenyl-5-(phenylsulfonyl)-2,3-dihydroimidazo[2,1-b]thiazole (6a). Yellow solid (20.2 mg, 30% yield); mp 155−156 °C; 1H NMR (400 MHz, CDCl3) δ 7.68−7.66 (m, 2H), 7.58 (d, J = 7.5 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.39−7.34 (m, 5H), 4.54 (t, J = 7.4 Hz, 2H), 3.86 (t, J = 7.5 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 154.4, 153.4, 141.9, 133.4, 132.3, 129.6, 129.1, 127.9, 126.6, 124.7, 48.4, 34.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H15N2O2S2 343.0569, found 343.0573. 6-Phenyl-5-(phenylsulfonyl)imidazo[2,1-b]thiazole (6b). Yellow oil (27.9 mg, 41% yield); 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 4.5 Hz, 1H), 7.77−7.74 (m, 2H), 7.60 (dd, J = 8.4, 1.1 Hz, 2H), 7.48 (tt, J = 7.4, 1.2 Hz, 1H), 7.44−7.41 (m, 3H), 7.33 (t, J = 8.2 Hz, 2H), 7.04 (d, J = 4.6 Hz, 1H); 13C NMR (151 MHz, CDCl3) δ 153.3, 152.7, 142.0, 133.4, 132.2, 129.9, 129.4, 129.0, 128.0, 126.4, 120.7, 120.6, 114.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H13N2O2S2 341.0413, found 341.0412. 345

DOI: 10.1021/acs.joc.7b02734 J. Org. Chem. 2018, 83, 338−349

Article

The Journal of Organic Chemistry

6.81 (td, J = 6.8, 1.1 Hz, 1H), 2.36 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 151.6, 147.1, 138.6, 135.3, 130.5, 129.4, 129.2, 128.3, 126.6, 126.0, 125.6, 124.5, 117.6, 113.0, 106.0, 21.4; HRMS (ESITOF) m/z [M + H]+ calcd for C20H17N2S 317.1107, found 317.1110. 2-(4-Ethylphenyl)-3-(phenylthio)imidazo[1,2-a]pyridine (7f). Yellow solid (53.1 mg, 80% yield); mp 111−112 °C; 1H NMR (400 MHz, CDCl3) δ 8.24 (dt, J = 6.8, 1.0 Hz, 1H), 8.14 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 9.0 Hz, 1H), 7.31−7.24 (m, 3H), 7.18 (t, J = 7.2 Hz, 2H), 7.10 (t, J = 7.3 Hz, 1H), 7.00−6.98 (m, 2H), 6.82 (td, J = 6.8, 1.0 Hz, 1H), 2.67 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 151.6, 147.1, 144.9, 135.4, 130.8, 129.4, 128.3, 128.0, 126.6, 126.0, 125.6, 124.5, 117.6, 113.0, 105.9, 28.7, 15.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H19N2S 331.1263, found 331.1268. Methyl 4-(3-(Phenylthio)imidazo[1,2-a]pyridin-2-yl)benzoate (7g). White solid (31.5 mg, 44% yield); mp 165−166 °C; 1H NMR (400 MHz, CDCl3) δ 8.30 (t, J = 8.6 Hz, 3H), 8.10 (d, J = 8.6 Hz, 2H), 7.74 (d, J = 9.0 Hz, 1H), 7.38−7.33 (m, 1H), 7.23−7.19 (m, 2H), 7.14 (t, J = 7.2 Hz, 1H), 7.00−6.97 (m, 2H), 6.89 (td, J = 6.8, 1.1 Hz, 1H), 3.92 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.0, 145.0, 147.2, 137.8, 134.7, 129.9, 129.7, 129.5, 128.2, 127.0, 126.3, 125.7, 124.6, 117.9, 113.4, 107.6, 52.1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H17N2O2S 361.1005, found 361.1009. 2-(3-Chlorophenyl)-3-(phenylthio)imidazo[1,2-a]pyridine (7h). White solid (59.5 mg, 89% yield); mp 127−128 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 6.0 Hz, 2H), 8.03 (m, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.26−7.21 (m, 3H), 7.10 (t, J = 7.1 Hz, 2H), 7.03 (t, J = 7.2 Hz, 1H), 6.90−6.87 (m, 2H), 6.76 (td, J = 6.8, 1.0 Hz, 1H); 13 C{1H} NMR (101 MHz, CDCl3) δ 149.7, 147.1, 135.2, 134.8, 134.4, 129.7, 129.5, 128.6, 128.4, 127.0, 126.4, 126.3, 125.8, 124.5, 117.7, 113.3, 107.1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14ClN2S 337.0561, found 337.0564. 3-(Phenylthio)-2-(m-tolyl)imidazo[1,2-a]pyridine (7i). White solid (53.7 mg, 85% yield); mp 126−127 °C; 1H NMR (400 MHz, CDCl3) δ 8.24 (dt, J = 6.8, 1.1 Hz, 1H), 8.03−8.00 (m, 2H), 7.72 (d, J = 9.0 Hz, 1H), 7.30 (m, 2H), 7.20−7.16 (m, 3H), 7.10 (t, J = 7.3 Hz, 1H), 7.00−6.98 (m, 2H), 6.82 (td, J = 6.8, 1.1 Hz, 1H), 2.39 (s, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 151.6, 147.1, 138.1, 135.3, 133.3, 129.4, 129.1, 128.3, 126.6, 126.1, 125.7, 125.5, 124.5, 117.6, 113.0, 106.4, 21.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H17N2S 317.1107, found 317.1112. 2-(3-Methoxyphenyl)-3-(phenylthio)imidazo[1,2-a]pyridine (7j). White solid (59.0 mg, 89% yield); mp 95−96 °C; 1H NMR (400 MHz, CDCl3) δ 8.27 (dt, J = 6.8, 1.0 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.77 (t, J = 2.5 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.35−7.28 (m, 2H), 7.18 (t, J = 7.2 Hz, 2H), 7.11 (t, J = 7.3 Hz, 1H), 7.00−6.98 (m, 2H), 6.92 (dd, J = 8.2, 2.6 Hz, 1H), 6.84 (td, J = 6.8, 1.1 Hz, 1H), 3.78 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 159.6, 151.2, 147.1, 135.2, 134.7, 129.5, 126.7, 126.1, 125.6, 124.5, 120.9, 117.7, 115.1, 113.2, 113.1, 106.5, 55.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H17N2OS 333.1056, found 333.1062. 2-(2-Fluorophenyl)-3-(phenylthio)imidazo[1,2-a]pyridine (7k). Yellow oil (54.7 mg, 85% yield); 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 6.8, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.60 (td, J = 7.5, 1.7 Hz, 1H), 7.31−7.22 (m, 2H), 7.13−7.06 (m, 4H), 7.02 (t, J = 7.3 Hz, 1H), 6.86 (d, J = 7.4 Hz, 2H), 6.77 (td, J = 6.8, 0.8 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.6, 159.1, 148.0, 147.3, 135.0, 132.0 (JC−F = 2.9 Hz), 130.5 (JC−F = 8.3 Hz), 129.3, 126.6, 126.0, 125.8, 124.6, 124.0 (JC−F = 3.3 Hz), 121.7, 121.6, 118.0, 116.2, 116.0, 113.3, 109.0; 19F NMR (376 MHz, CDCl3) δ −113.33; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14FN2S 321.0856, found 321.0862. 2-(2-Chlorophenyl)-3-(phenylthio)imidazo[1,2-a]pyridine (7l). Yellow solid (47.3 mg, 70% yield); mp 134−135 °C; 1H NMR (400 MHz, CDCl3) δ 8.19 (dt, J = 6.8, 1.1 Hz, 1H), 7.75 (dt, J = 9.0, 0.9 Hz, 1H), 7.51−7.48 (m, 2H), 7.36−7.28 (m, 3H), 7.17 (t, J = 7.1 Hz, 2H), 7.10 (tt, J = 7.3, 1.3 Hz, 1H), 6.94−6.92 (m, 2H), 6.88 (td, J = 6.8, 1.1 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 151.0, 146.9, 134.9, 134.1, 132.8, 132.4, 129.9, 129.8, 129.3, 126.5, 126.4, 126.1, 126.0, 124.7, 118.1, 113.3, 109.2; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14ClN2S 337.0561, found 337.0564.

6-Phenyl-5-((4-(trifluoromethyl)phenyl)sulfonyl)imidazo[2,1-b]thiazole (6c). Yellow solid (30.8 mg, 38% yield); mp 130−131 °C;1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 4.6 Hz, 1H), 7.76−7.73 (m, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.48−7.42 (m, 3H), 7.08 (d, J = 4.6 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 154.1, 153.3, 145.3, 135.0 (JC−F = 32.6 Hz), 131.9, 129.9, 129.7, 128.4, 128.2, 127.5, 126.9, 126.2 (JC−F = 3.6 Hz), 123.0 (JC−F = 272.5 Hz), 120.5, 119.6, 114.9; 19F NMR (376 MHz, CDCl3) δ −63.27; HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H12F3N2O2S2 409.0287, found 409.0288. 2-Phenyl-3-(phenylsulfonyl)benzo[d]imidazo[2,1-b]thiazole (6d). Yellow solid (31.2 mg, 40% yield); mp 179−180 °C; 1H NMR (400 MHz, CDCl3) δ 8.80 (dd, J = 8.5, 0.5 Hz, 1H), 7.73−7.69 (m, 3H), 7.66−7.64 (m, 2H), 7.53−7.45 (m, 2H), 7.44−7.35 (m, 6H); 13 C{1H} NMR (151 MHz, CDCl3) δ 156.0, 152.8, 142.0, 133.29, 133.27, 132.6, 130.5, 129.9, 129.3, 129.1, 127.7, 127.0, 126.7, 125.8, 124.1, 122.4, 117.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H15N2O2S2 391.0569, found 391.0578. 3-(Phenylsulfonyl)-2-(thiophen-2-yl)imidazo[1,2-a]pyridine (6e). Yellow solid (36.7 mg, 54% yield); mp 196−197 °C; 1H NMR (400 MHz, CDCl3) δ 9.13 (dt, J = 7.1, 1.0 Hz, 1H), 8.18 (dd, J = 3.8, 1.1 Hz, 1H), 7.81−7.79 (m, 2H), 7.69 (dt, J = 9.0, 1.1 Hz, 1H), 7.54− 7.49 (m, 2H), 7.46−7.38 (m, 3H), 7.19−7.17 (m, 1H), 7.02 (td, J = 7.0, 1.2 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 146.6, 146.1, 141.9, 134.6, 133.6, 130.9, 129.3, 129.0, 128.9, 128.1, 126.8, 126.0, 117.8, 115.8, 114.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H13N2O2S2 341.0413, found 341.0416. 2-Phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (7a). White solid (53.3 mg, 88% yield); mp 97−98 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 (dt, J = 6.8, 1.0 Hz, 1H), 8.13−8.11 (m, 2H), 7.63 (dt, J = 9.0, 0.8 Hz, 1H), 7.34 (t, J = 7.1 Hz, 2H), 7.29−7.19 (m, 2H), 7.10 (t, J = 7.1 Hz, 2H), 7.02 (tt, J = 7.3, 1.2 Hz, 1H), 6.91−6.89 (m, 2H), 6.74 (td, J = 6.8, 1.0 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 151.4, 147.1, 135.2, 133.4, 129.5, 128.6, 128.5, 128.4, 126.7, 126.1, 125.6, 124.5, 117.7, 113.1, 106.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H15N2S 303.0950, found 303.0953. 2-(4-Chlorophenyl)-3-(phenylthio)imidazo[1,2-a]pyridine (7b). Yellow solid (55.4 mg, 83% yield); mp 114−115 °C; 1H NMR (400 MHz, CDCl3) δ 8.25 (dt, J = 6.8, 1.0 Hz, 1H), 8.17 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 8.7 Hz, 2H), 7.34− 7.30 (m, 1H), 7.21−7.17 (m, 2H), 7.12 (t, J = 7.3 Hz, 1H), 6.98− 6.96 (m, 2H), 6.85 (td, J = 6.8, 1.0 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 150.2, 147.1, 134.9, 134.6, 131.9, 129.6, 129.5, 128.7, 126.9, 126.2, 125.6, 124.52 117.7, 113.3, 106.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14ClN2S 337.0561, found 337.0564. 3-(Phenylthio)-2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine (7c). Yellow solid (60.4 mg, 82% yield); mp 130−131 °C; 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.1 Hz, 2H), 8.28 (dt, J = 6.8, 1.1 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.37−7.33 (m, 1H), 7.23−7.19 (m, 2H), 7.14 (t, J = 7.2 Hz, 1H), 6.99−6.97 (m, 2H), 6.88 (td, J = 6.8, 1.0 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 149.7, 147.2, 136.9, 134.7, 130.2 (JC−F = 32.6 Hz), 129.6, 128.5, 127.1, 126.4, 125.4 (JC−F = 3.7 Hz), 124.6, 122.9, 117.9, 113.5, 107.4; 19F NMR (376 MHz, CDCl3) δ −62.55; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H14F3N2S 371.0824, found 371.0829. 2-(4-Methoxyphenyl)-3-(phenylthio)imidazo[1,2-a]pyridine (7d). Yellow solid (59.2 mg, 89% yield); mp 107−108 °C; 1H NMR (400 MHz, CDCl3) δ 8.23 (dt, J = 6.8, 0.9 Hz, 1H), 8.17 (d, J = 8.9 Hz, 2H), 7.69 (d, J = 9.0 Hz, 1H), 7.31−7.27 (m, 1H), 7.18 (t, J = 7.2 Hz, 2H), 7.11 (t, J = 7.3 Hz, 1H), 7.00−6.95 (m, 4H), 6.81 (td, J = 6.8, 1.0 Hz, 1H), 3.81 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.1, 151.3, 147.1, 135.3, 129.7, 129.5, 126.6, 126.02, 125.97, 125.5, 124.4, 117.4, 113.9, 112.9, 105.4, 55.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H17N2OS 333.1056, found 333.1060. 3-(Phenylthio)-2-(p-tolyl)imidazo[1,2-a]pyridine (7e). Yellow solid (54.8 mg, 87% yield); mp 80−81 °C; 1H NMR (400 MHz, CDCl3) δ 8.23 (dt, J = 6.8, 1.1 Hz, 1H), 8.11 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 9.0 Hz, 1H), 7.31−7.27 (m, 1H), 7.23 (d, J = 8.2 Hz, 2H), 7.20−7.16 (m, 2H), 7.10 (t, J = 7.3 Hz, 1H), 6.99−6.97 (m, 2H), 346

DOI: 10.1021/acs.joc.7b02734 J. Org. Chem. 2018, 83, 338−349

Article

The Journal of Organic Chemistry 2-(2-Methoxyphenyl)-3-(phenylthio)imidazo[1,2-a]pyridine (7m). Yellow solid (39.1 mg, 59% yield); mp 81−82 °C; 1H NMR (400 MHz, CDCl3) δ 8.15 (dt, J = 6.8, 1.1 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.53 (dd, J = 7.5, 1.7 Hz, 1H), 7.37 (td, J = 8.3, 1.8 Hz, 1H), 7.32−7.28 (m, 1H), 7.19−7.16 (m, 2H), 7.09 (t, J = 7.3 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 6.98−6.95 (m, 3H), 6.84 (td, J = 6.8, 1.0 Hz, 1H), 3.63 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 157.5, 150.5, 147.1, 135.7, 132.0, 130.1, 129.1, 126.1, 125.8, 125.6, 124.5, 122.8, 120.4, 117.8, 113.0, 111.0, 108.9, 55.2; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H17N2OS 333.1056, found 333.1063. 6-Fluoro-2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (7n). Yellow solid (56.4 mg, 88% yield); mp 122−123 °C; 1H NMR (400 MHz, CDCl3) δ 8.20−8.18 (m, 3H), 7.68 (qd, J = 4.9, 0.5 Hz, 1H), 7.45−7.41 (m, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.25−7.19 (m, 3H), 7.13 (t, J = 7.3 Hz, 1H), 7.01−6.98 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 155.0, 152.6, 152.5 (JC−F = 2.4 Hz), 144.6, 134.5, 133.1, 129.6, 128.8, 128.5, 128.2, 126.4, 125.8, 118.7, 118.4, 118.2 (JC−F = 8.7 Hz), 111.6, 111.2, 108.0 (JC−F = 1.4 Hz); 19F NMR (376 MHz, CDCl3) δ −138.09; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14FN2S 321.0856, found 321.0861. 6-Chloro-2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (7o). Yellow solid (56.0 mg, 83% yield); mp 151−152 °C; 1H NMR (400 MHz, CDCl3) δ 8.30 (dd, J = 2.0, 0.7 Hz, 1H), 8.20−8.18 (m, 2H), 7.65 (dd, J = 9.4, 0.6 Hz, 1H), 7.45−7.41 (m, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.28−7.19 (m, 3H), 7.14 (t, J = 7.3 Hz, 1H), 7.01−6.98 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 152.2, 145.4, 134.6, 133.0, 129.6, 128.9, 128.5, 128.3, 128.1, 126.4, 125.7, 122.5, 121.6, 118.1, 107.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14ClN2S 337.0561, found 337.0566. 2-Phenyl-3-(phenylthio)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (7p). Yellow solid (54.4 mg, 74% yield); mp 106−107 °C; 1 H NMR (400 MHz, CDCl3) δ 8.64 (t, J = 0.7 Hz, 1H), 8.24−8.22 (m, 2H), 7.80 (d, J = 9.4 Hz, 1H), 7.47−7.37 (m, 4H), 7.25−7.20 (m, 2H), 7.15 (t, J = 7.2 Hz, 1H), 7.03−7.01 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 153.0, 146.9, 134.2, 132.6, 129.7, 129.2, 128.6, 128.4, 126.6, 126.0, 124.8, 123.4 (JC−F = 5.8 Hz), 122.6 (JC−F = 2.5 Hz), 122.1, 118.4, 117.5 (JC−F = 34.5 Hz), 108.6; 19F NMR (376 MHz, CDCl3) δ −61.96; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H14F3N2S 371.0824, found 371.0828. 6-Methyl-2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (7q). Brown solid (50.8 mg, 80% yield); mp 136−137 °C; 1H NMR (400 MHz, CDCl3) δ 8.10−8.08 (m, 2H), 7.96 (s, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.32 (t, J = 7.1 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 7.13− 7.01 (m, 4H), 6.91−6.89 (m, 2H), 2.19 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 151.3, 146.2, 135.6, 133.5, 129.8, 129.4, 128.5, 128.4, 128.3, 126.0, 125.5, 123.0, 122.2, 117.0, 105.7, 18.4; HRMS (ESITOF) m/z [M + H]+ calcd for C20H17N2S 317.1107, found 317.1112. 2-Phenyl-3-(phenylthio)-7-(trifluoromethyl)imidazo[1,2-a]pyridine (7r). White solid (50.1 mg, 68% yield); mp 95−96 °C; 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 7.2 Hz, 1H), 8.22 (d, J = 7.0 Hz, 2H), 8.02 (t, J = 0.6 Hz, 1H), 7.47−7.37 (m, 3H), 7.23−7.19 (m, 2H), 7.15 (t, J = 7.2 Hz, 1H), 7.03−6.98 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 153.0, 145.3, 134.2, 132.7, 130.0, 129.1, 128.6, 128.4, 128.3, 126.5, 125.9, 125.4, 124.6, 121.8, 119.1, 115.6 (JC−F = 4.8 Hz), 108.9 (JC−F = 2.9 Hz), 108.7; 19F NMR (376 MHz, CDCl3) δ −63.57; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H14F3N2S 371.0824, found 371.0830. 7-Methoxy-2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (7s). White solid (51.8 mg, 78% yield); mp 74−75 °C; 1H NMR (400 MHz, CDCl3) δ 8.19−8.17 (m, 2H), 8.04 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.19 (t, J = 7.2 Hz, 2H), 7.11 (t, J = 7.4 Hz, 1H), 7.01−6.99 (m, 3H), 6.54 (dd, J = 7.4, 2.5 Hz, 1H), 3.86 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 159.5, 151.3, 148.6, 135.7, 133.5, 129.4, 128.4, 128.4, 128.1, 126.0, 125.5, 124.9, 107.8, 104.8, 95.2, 55.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H17N2OS 333.1056, found 333.1061. 7-Methyl-2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (7t). White solid (51.7 mg, 82% yield); mp 174−175 °C; 1H NMR (400 MHz, CDCl3) δ 8.19−8.17 (m, 2H), 8.10 (d, J = 7.0 Hz, 1H), 7.47 (s, 1H), 7.41 (t, J = 7.1 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.18 (t, J = 7.2

Hz, 2H), 7.10 (t, J = 7.3 Hz, 1H), 6.99−6.97 (m, 2H), 6.65 (dd, J = 7.0, 1.5 Hz, 1H), 2.40 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 151.3, 147.5, 137.9, 135.6, 133.5, 129.4, 128.5, 128.4, 128.3, 126.0, 125.5, 123.7, 116.2, 115.7, 105.5, 21.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H17N2S 317.1107, found 317.1111. 8-Methyl-2-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (7u). White solid (50.5 mg, 89% yield); mp 130−131 °C; 1H NMR (400 MHz, CDCl3) δ 8.19−8.18 (m, 2H), 8.11 (d, J = 6.7 Hz, 1H), 7.42 (t, J = 7.1 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.18 (t, J = 7.2 Hz, 2H), 7.11−7.08 (m, 2H), 6.98−6.96 (m, 2H), 6.74 (t, J = 6.8 Hz, 1H), 2.70 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 151.1, 147.5, 135.6, 133.7, 129.4, 128.5, 128.4, 128.3, 127.8, 126.0, 125.6, 125.5, 122.3, 113.1, 106.5, 16.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H17N2S 317.1107, found 317.1114. 2-Phenyl-3-(phenylthio)-8-(trifluoromethyl)imidazo[1,2-a]pyridine (7v). Yellow solid (59.1 mg, 80% yield); mp 135−136 °C; 1 H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 6.8 Hz, 1H), 8.26−8.24 (m, 2H), 7.63 (d, J = 7.1 Hz, 1H), 7.44−7.34 (m, 3H), 7.23−7.18 (m, 2H), 7.13 (t, J = 7.2 Hz, 1H), 7.00−6.98 (m, 2H), 6.89 (t, J = 7.0 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 152.3, 142.7, 134.4, 132.8, 129.6, 129.0, 128.7, 128.5, 127.8, 126.4, 125.8, 125.0 (JC−F = 5.05 Hz), 124.1, 121.4, 119.4 (JC−F = 32.2 Hz), 111.4, 108.0; 19F NMR (376 MHz, CDCl3) δ −62.93; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H14F3N2S 371.0824, found 371.0828. Methyl 2-Phenyl-3-(phenylthio)imidazo[1,2-a]pyridine-8-carboxylate (7w). Yellow solid (48.4 mg, 67% yield); mp 152−153 °C; 1H NMR (400 MHz, CDCl3) δ 8.45 (dd, J = 6.8, 1.3 Hz, 1H), 8.31−8.29 (m, 2H), 8.08 (dd, J = 7.2, 1.3 Hz, 1H), 7.45−7.41 (m, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.18 (t, J = 7.0 Hz, 2H), 7.12 (t, J = 7.2 Hz, 1H), 6.98−6.96 (m, 2H), 6.92 (t, J = 7.0 Hz, 1H), 4.08 (s, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 165.0, 152.4, 144.6, 134.6, 133.0, 131.2, 129.5, 128.9, 128.7, 128.4, 126.3, 125.7, 119.9, 112.0, 107.4, 52.9; HRMS (ESI-TOF) m/z [M + H] + calcd for C21H17N2O2S 361.1005, found 361.1007. 6-Fluoro-3-(phenylthio)-2-(p-tolyl)imidazo[1,2-a]pyridine (7x). Yellow solid (59.0 mg, 92% yield); mp 125−126 °C; 1H NMR (400 MHz, CDCl3) δ 8.18 (t, J = 3.0 Hz, 1H), 8.09 (d, J = 8.2 Hz, 2H), 7.68 (q, J = 4.8 Hz, 1H), 7.24−7.18 (m, 5H), 7.13 (tt, J = 7.3, 1.2 Hz, 1H), 7.00−6.98 (m, 2H), 2.37 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 154.9, 152.6 (JC−F = 2.2 Hz), 152.6, 144.6, 138.8, 134.6, 130.3, 130.0, 129.2, 128.1, 126.3, 125.7, 118.5, 118.3, 118.1, 118.0, 111.6, 111.2, 107.6, 21.4; 19F NMR (376 MHz, CDCl3) δ −138.32; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H16FN2S 335.1013, found 335.1017. 6-Chloro-2-(4-methoxyphenyl)-3-(phenylthio)imidazo[1,2-a]pyridine (7y). Brown solid (30.7 mg, 42% yield); mp 70−71 °C; 1H NMR (400 MHz, CDCl3) δ 8.30 (dd, J = 1.9, 0.6 Hz, 1H), 8.15 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 9.4 Hz, 1H), 7.29−7.21 (m, 3H), 7.16 (tt, J = 7.3, 1.2 Hz, 1H), 7.01−6.99 (m, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 160.2, 152.1, 145.4, 134.7, 129.6, 128.0, 126.3, 125.6, 122.4, 121.4, 117.8, 114.0, 55.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H16ClN2OS 367.0666, found 367.0670. 3-(Phenylthio)-2-(p-tolyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (7z). White solid (65.9 mg, 89% yield); mp 108−109 °C; 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.13 (d, J = 8.2 Hz, 2H), 7.79 (q, J = 9.3 Hz, 1H), 7.44 (dd, J = 9.4, 1.8 Hz, 1H), 7.26−7.19 (m, 4H), 7.14 (t, J = 7.2 Hz, 1H), 7.02−7.00 (m, 2H), 2.38 (s, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 153.1, 146.8, 139.2, 134.3, 129.8, 129.6, 129.3, 128.3, 126.5, 125.9, 124.8, 123.4 (JC−F = 5.8 Hz), 122.5 (JC−F = 2.52 Hz), 122.1, 118.2, 117.3 (JC−F = 34.43 Hz), 108.2; 19 F NMR (376 MHz, CDCl3) δ −61.92; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H16F3N2S 385.0981, found 385.0985. 7-Methoxy-3-(phenylthio)-2-(p-tolyl)imidazo[1,2-a]pyridine (7aa). White solid (48.4 mg, 70% yield); mp 130−131 °C; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.2 Hz, 2H), 8.04 (d, J = 7.5 Hz, 1H), 7.23−7.17 (m, 4H), 7.10 (tt, J = 7.3, 1.2 Hz, 1H), 7.01−6.98 (m, 3H), 6.53 (dd, J = 7.4, 2.5 Hz, 1H), 3.86 (s, 3H), 2.36 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 159.5, 151.4, 148.6, 138.3, 135.8, 130.7, 129.4, 129.1, 128.0, 125.9, 125.5, 124.8, 107.7, 104.3, 95.2, 347

DOI: 10.1021/acs.joc.7b02734 J. Org. Chem. 2018, 83, 338−349

Article

The Journal of Organic Chemistry 55.7, 21.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H19N2OS 347.1213, found 347.1216. 2-(Naphthalen-2-yl)-3-(phenylthio)imidazo[1,2-a]pyridine (7ab). White solid (62.9 mg, 89% yield); mp 132−133 °C; 1H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 0.8 Hz, 1H), 8.39 (dd, J = 8.6, 1.7 Hz, 1H), 8.26 (d, J = 6.8 Hz, 1H), 7.87 (d, J = 8.9 Hz, 2H), 7.82−7.80 (m, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.46−7.42 (m, 2H), 7.31−7.27 (m, 1H), 7.19−7.16 (m, 2H), 7.10 (t, J = 7.3 Hz, 1H), 7.04−7.01 (m, 2H), 6.81 (td, J = 6.8, 1.0 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 151.3, 147.2, 135.2, 133.4, 130.9, 129.5, 128.7, 128.0, 127.9, 127.7, 126.8, 126.4, 126.2, 126.1, 126.0, 125.8, 124.5, 117.7, 113.1, 106.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for C23H17N2S 353.1107, found 353.1112. 2-Methyl-3-(phenylthio)imidazo[1,2-a]pyridine (7ac). White solid (39.8 mg, 65% yield); mp 84−85 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 (dt, J = 6.8, 1.0 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.29−7.24 (m, 1H), 7.21−7.17 (m, 2H), 7.13−7.09 (m, 1H), 6.94− 6.92 (m, 2H), 6.81 (td, J = 6.8, 1.0 Hz, 1H), 2.58 (s, 3H); 13C{H} NMR (101 MHz, CDCl3) δ 151.7, 147.0, 135.6, 129.3, 126.0, 125.9, 125.6, 124.3, 117.0, 112.6, 107.4, 14.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C14H13N2S 241.0794, found 241.0798. 3-(Phenylthio)imidazo[1,2-a]pyridine (7ad). Yellow solid (12.7 mg, 21% yield); mp 85−86 °C; 1H NMR (400 MHz, CDCl3) δ 8.21 (dt, J = 6.8, 1.0 Hz, 1H), 8.00 (s, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.33− 7.29 (m, 1H), 7.23−7.19 (m, 2H), 7.15−7.11 (m, 1H), 7.01−7.00 (m, 2H), 6.88 (td, J = 6.8, 0.9 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 148.1, 142.4, 135.2, 129.3, 126.2, 126.2, 126.0, 124.3, 118.2, 113.2, 110.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H11N2S 227.0637, found 227.0643. 3-((4-Fluorophenyl)thio)-2-phenylimidazo[1,2-a]pyridine (7ae). White solid (58.1 mg, 91% yield); mp 128−129 °C; 1H NMR (400 MHz, CDCl3) δ 8.25 (dt, J = 6.8, 1.0 Hz, 1H), 8.22−8.20 (m, 2H), 7.72 (dt, J = 9.0, 0.9 Hz, 1H), 7.46−7.42 (m, 2H), 7.37 (t, J = 7.3 Hz, 1H), 7.33−7.29 (m, 1H), 6.99−6.95 (m, 2H), 6.92−6.83 (m, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 162.8, 160.3, 151.4, 147.1, 133.3, 130.1 (JC−F = 3.2 Hz), 128.7, 128.5, 128.4, 127.7 (JC−F = 8.12 Hz), 126.8, 124.4, 117.7, 116.7, 116.5, 113.2, 106.6; 19F NMR (376 MHz, CDCl3) δ −115.93; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14FN2S 321.0856, found 321.0860. 3-((4-Chlorophenyl)thio)-2-phenylimidazo[1,2-a]pyridine (7af). White solid (63.6 mg, 95% yield); mp 166−167 °C; 1H NMR (400 MHz, CDCl3) δ 8.22 (dt, J = 6.8, 1.0 Hz, 1H), 8.19−8.17 (m, 2H), 7.72 (d, J = 9.0 Hz, 1H), 7.45−7.41 (m, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.34−7.30 (m, 1H), 7.15 (dd, J = 6.6, 2.0 Hz, 2H), 6.90 (dd, J = 6.6 Hz, 2H), 6.85 (td, J = 6.8, 1.0 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 151.6, 147.2, 133.8, 133.2, 132.1,130.2, 129.6, 128.8, 128.5, 128.3, 126.9, 124.3, 117.8, 113.3, 105.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14ClN2S 337.0561, found 337.0565. 2-Phenyl-3-((4-(trifluoromethyl)phenyl)thio)imidazo[1,2-a]pyridine (7ag). White solid (70.5 mg, 95% yield); mp 180−181 °C; 1 H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 6.8 Hz, 1H), 8.17−8.15 (m, 2H), 7.75 (d, J = 9.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 4H), 7.39−7.33 (m, 2H), 7.05 (d, J = 8.2 Hz, 2H), 6.88 (td, J = 6.8, 1.0 Hz, 1H); 13 C{1H} NMR (101 MHz, CDCl3) δ 152.1, 147.5, 140.5, 133.1, 128.9, 128.5, 128.4 (JC−F = 32.6 Hz), 128.3, 127.1, 126.3 (JC−F = 4.0 Hz), 125.3, 124.3, 122.6, 119.9, 117.9, 113.4, 104.6; 19F NMR (376 MHz, CDCl3) δ −62.46; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H14F3N2S 371.0824, found 371.0827. 2-Phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine (7ah). Yellow solid (53.7 mg, 85% yield); mp 141−142 °C; 1H NMR (400 MHz, CDCl3) δ 8.25 (dt, J = 6.8, 1.0 Hz, 1H), 8.22−8.21 (m, 2H), 7.71 (d, J = 9.0 Hz, 1H), 7.45−7.41 (m, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.31− 7.27 (m, 1H), 7.00 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 8.2 Hz, 2H), 6.82 (td, J = 6.8, 1.0 Hz, 1H), 2.24 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 151.2, 147.0, 136.1, 133.5, 131.5, 130.2, 128.6, 128.43, 128.40, 126.6, 125.9, 124.5, 117.6, 113.0, 106.9, 20.9; HRMS (ESITOF) m/z [M + H]+ calcd for C20H17N2S 317.1107, found 317.1111. 3-(Methylthio)-2-phenylimidazo[1,2-a]pyridine (7ai). Yellow oil (16.7 mg, 35% yield); 1H NMR (400 MHz, CDCl3) δ 8.49 (dt, J = 6.9, 1.0 Hz, 1H), 8.30−8.28 (m, 2H), 7.68 (d, J = 9.0 Hz, 1H), 7.49

(t, J = 7.3 Hz, 2H), 7.39 (tt, J = 7.4, 1.2 Hz, 1H), 7.32−7.28 (m, 1H), 6.95 (td, J = 6.8, 1.0 Hz, 1H), 2.26 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 148.8, 146.3, 133.7, 128.4, 128.31, 128.28, 126.0, 124.3, 117.6, 112.8, 111.5, 18.2; HRMS (ESI-TOF) m/z [M + H]+ calcd for C14H13N2S 241.0794, found 241.0792. 2-(4-Chlorophenyl)-3-((4-fluorophenyl)thio)imidazo[1,2-a]pyridine (7aj). White solid (60.7 mg, 75% yield); mp 134−135 °C; 1 H NMR (400 MHz, CDCl3) δ 8.26 (dt, J = 6.8, 1.0 Hz, 1H), 8.18 (dd, J = 6.7, 1.9 Hz, 2H), 7.71 (d, J = 9.0 Hz, 1H), 7.40 (dd, J = 6.8, 2.0 Hz, 2H), 7.36−7.31 (m, 1H), 6.98−6.86 (m, 5H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.8, 160.4, 150.1, 147.1, 134.7, 131.8, 129.8 (JC−F = 3.3 Hz), 129.6, 128.7, 127.7 (JC−F = 8.1 Hz), 127.0, 124.3, 117.8, 116.8, 116.6, 113.4, 106.8; 19F NMR (376 MHz, CDCl3) δ −115.60; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H13ClFN2S 355.0467, found 355.0470. 3-((4-Fluorophenyl)thio)-2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine (7ak). White solid (69.6 mg, 89% yield); mp 114− 115 °C; 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 6.8 Hz, 2H), 8.29 (dt, J = 6.9, 0.9 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.38−7.34 (m, 1H), 6.99−6.89 (m, 5H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.9, 160.4, 149.6, 147.2, 136.8, 130.5 (JC−F = 32.3 Hz), 129.6 (JC−F = 3.2 Hz), 128.5, 127.8 (JC−F = 7.4 Hz), 127.2, 125.4 (JC−F = 3.7 Hz), 124.4, 124.2 (JC−F = 272.8 Hz), 124.4, 117.9, 116.9, 116.6, 113.6, 107.7; 19F NMR (376 MHz, CDCl3) δ −62.58, −115.44; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H13F4N2S 389.0730, found 389.0734. 2-Phenyl-3-(pyridin-3-ylthio)imidazo[1,2-a]pyridine (7al). Yellow oil (60.6 mg, 18% yield); 1H NMR (400 MHz, CDCl3) δ 8.39−8.38 (m, 2H), 8.29 (dt, J = 6.8, 1.0 Hz, 1H), 8.19−8.17 (m, 2H), 7.75 (d, J = 9.0 Hz, 1H), 7.48−7.44 (m, 2H), 7.42−7.35 (m, 2H), 7.21−7.18 (m, 1H), 7.12−7.09 (m, 1H), 6.92 (td, J = 6.8, 1.0 Hz, 1H); 13C{H} NMR (101 MHz, CDCl3) δ 151.9, 147.4, 147.3, 147.1, 133.3, 133.1, 132.6, 128.9, 128.6, 128.3, 127.0, 124.2, 124.1, 117.9, 113.5, 104.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H14N3S [M + H+] 304.0903, found 304.0908.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02734. X-ray data for 3a in CIF format (CIF) Optimization of reaction conditions, control experiments and mechanism, crystallography of product 3a, and NMR spectra of 3a−3ag (PDF) NMR spectra of compounds 3ah−6e (PDF) NMR spectra of compounds 7a−7al (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*X.Z. e-mail: [email protected]. *T.S. e-mail: [email protected]. ORCID

Xin-Qi Hao: 0000-0003-1942-8309 Xinju Zhu: 0000-0003-1966-3480 Mao-Ping Song: 0000-0003-3883-2622 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation of China (Grant Nos. 21528201 and 21672192), the China Postdoctoral Science Foundation (Grant Nos. 2016M602254 and 2016M600582), and the Program for Science & Technology Innovation Talents in Universities of Henan Province (17HASTIT004) is gratefully appreciated. 348

DOI: 10.1021/acs.joc.7b02734 J. Org. Chem. 2018, 83, 338−349

Article

The Journal of Organic Chemistry

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DOI: 10.1021/acs.joc.7b02734 J. Org. Chem. 2018, 83, 338−349