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Jun 5, 2017 - Xin HuangYongqi ChenShan ZhenLijuan SongMingqi GaoPanke ZhangHeng LiBingxin YuanGuanyu Yang. The Journal of Organic Chemistry ...
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Rhodium-Catalyzed Direct Bis-cyanation of Arylimidazo[1,2α]pyridine via Double C−H Activation Xinju Zhu, Xiao-Jing Shen, Zi-Yao Tian, Shuai Lu, Lu-Lu Tian, Wen-Bo Liu, Bing Song,* and Xin-Qi Hao* 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: An efficient Cp*Rh(III)-catalyzed selective bis-cyanation of arylimidazo[1,2-α]pyridines with N-cyano-N-phenylp-methylbenzenesulfonamide via N-directed ortho double C−H activation has been developed. The reaction proceeds with broad functional group tolerance to furnish various cyanated imidazopyridines in high yields. The current methodology exhibits unique characteristics, including high bis-cyanation selectivity, operational convenience, and gram-scale production.

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electrophilic cyanating agent.12 In the Rh series,13 Fu13a and Anbarasan13b independently described Cp*RhIII-catalyzed C− H cyanation with NCTS assisted by oxime, pyridine, and pyrazole directing groups. Other chelating groups, such as phosphate,13c ketone or amide,13e and pyrimidine,13e have also been developed to achieve Rh(III)-catalyzed C−H cyanation. Moreover, cyanation of alkenyl C−H bond and C−H cyanation/cyclization cascades were employed to access to vinyl nitriles14 and 3-iminoisoindolinones,15 respectively. Despite the fact that significant advances have been achieved, it remains highly desirable to develop a versatile and efficient methodology for rhodium-catalyzed cyanation of the C−H bond. On the other hand, the imidazopyridine scaffold is an important building block in synthetic chemistry, medicinal chemistry, and material chemistry.16 Numerous strategies have been applied to construct and functionalize imidazo[1,2α]pyridine derivatives.17 In this context, we have been interested in C−H functionalizations of 2-arylimidazo[1,2α]pyridine with different coupling partners.18 However, to date, most of the methodology focused on functionalizations on the C3 position (Scheme 1a),17,19 and imidazopyridines-directed selective C−H functionalizations was rarely reported (Scheme 1b).20 Recently, the Sakhuja group reported Ru-catalyzed orthoamidation of imidazo heterocycles with isocyanates (Scheme 1c).20c On the basis of our previous report and recent

INTRODUCTION The efficient syntheses of aryl nitriles have gained much attention because of their synthetic potential for a variety of useful functionalities and great importance in natural products.1,2 In the past decades, extensive investigation has been made into cyanation reactions.3 Traditional synthetic approaches involve Sandmeyer reaction of aryldiazonium salts4a and Rosenmund−von Braun reaction of aryl halides4b with a stoichiometric amount of CuCN salt. Alternatively, transitionmetal-catalyzed cyanation of aryl halides or arylboronic acids with toxic cyanide sources provided a mild and direct route with increased functional-group compatibility.5 To overcome the hazardous handling of traditional CN sources, less toxic cyanating agents, such as K4[Fe(CN)6], benzyl cyanide, malononitrile, acetonitrile, and dimethylmalononitrile, have been developed.6 Other CN-free cyano sources nitromethane,7a formamide,7b and DMF,7c as well as combined cyano sources DMF/NH4I,8a and DMF/NH4HCO3,8b were also identified to realize the cyanation of functionalized (hetero)aromatics. Despite tremendous progress achieved, the aforementioned methodologies usually required prefunctionalized starting materials, which is not atom-economic and environmentally benign. Recently, transition-metal-catalyzed direct cyanation of aryl C−H bonds has emerged as a promising alternative. Pd,9 Cu,10 and other transition metals11 have been proved to be effective catalysts with both metallic and organic CN surrogates. NCyano-N-phenyl-p-methylbenzenesulfonamide (NCTS) is a bench-stable, environmentally benign, and readily available © 2017 American Chemical Society

Received: December 20, 2016 Published: June 5, 2017 6022

DOI: 10.1021/acs.joc.6b03036 J. Org. Chem. 2017, 82, 6022−6031

Article

The Journal of Organic Chemistry Scheme 1. Strategies for Transition-Metal-Catalyzed C−H Functionalizations of Imidazo[1,2-α]pyridines

Table 1. Optimization of Reaction Conditionsa

entry

X

Y

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

5 5 5 5 2.5 5 5 5 5 5 5

30 40 20 50 20 40 40 40 40 40 40

additive

yieldb

Na2CO3 t-BuONa NaHCO3 NaHCO3 NaHCO3 NaHCO3

44 60 15 53 50 75 80 84 89 18 62

a Reaction conditions: 1a (0.1 mmol), NCTS (0.25 mmol), [RhCp*Cl2]2 (X mol %), AgSbF6 (Y mol %), additive, DCE, 120 °C, 24 h. bIsolated yield. cAdditive (1 equiv). dNaHCO3 (0.5 equiv). eNCTS (0.1 mmol), NaHCO3 (0.5 equiv). fNCTS (0.3 mmol), NaHCO3 (0.5 equiv),

progress,18a,20 N1 in the imidazopyridine moiety could provide sufficient chelation assistance for C−H activation. In continuation of our current work, we herein report the first example of Rh-catalyzed C−H cyanation assisted by the imidazopyridine group (Scheme 1d).

was isolated when the silver complex was reduced to 20 mol % (Table 1, entries 2 and 3). Further increasing the ratio of AgSbF6 to [RhCp*Cl2]2 did not give a positive effect in reaction conversion (Table 1, entry 4). Meanwhile, a decrease in the amount of both [RhCp*Cl2]2 and AgSbF6 led to a lowered yield (Table 1, entry 5). Subsequently, the effects of solvent, temperature, and time were screened, which reveals that the best transformation was achieved in DCE at 120 °C for 24 h (see the Supporting Information). Additives played an important role in determining catalytic efficiency (Table 1, entries 6−8). When 1 equiv of NaHCO3 was added, a dramatic increased yield of 84% was obtained. Finally, the desired product 2a was isolated in 89% when 0.5 equiv of NaHCO3 was applied (Table 1, entry 9). Interestingly, no mono-cyanated

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RESULTS AND DISCUSSION The coupling of 2-phenylimidazo[1,2-α]pyridine 1a with NCTS was employed as the model reaction to optimize the reaction parameters (Table 1). To our delight, bis-cyanated product 2a was obtained in 44% yield in the presence of 5 mol % [RhCp*Cl2]2 and 30 mol % AgSbF6 (Table 1, entry 1). Increasing the ratio of AgSbF6 to [RhCp*Cl2]2 by applying 40 mol % silver salt provided 2a in 60% yield, while only 15% of 2a 6023

DOI: 10.1021/acs.joc.6b03036 J. Org. Chem. 2017, 82, 6022−6031

Article

The Journal of Organic Chemistry Scheme 2. Substrate Scope of Cyanation of 2-Arylimidazo[1,2-α]pyridinesa

a Reaction conditions: 1 (0.1 mmol), NCTS (0.25 mmol), [RhCp*Cl2]2 (5 mol %), AgSbF6 (40 mol %), NaHCO3 (0.5 equiv), DCE (1 mL), 120 °C, 24 h. bGram-scale production: 1 (5.2 mmol), NCTS (13 mmol), [RhCp*Cl2]2 (0.26 mmol), AgSbF6 (2.08 mmol), NaHCO3 (2.6 mmol), DCE (52 mL). cNaHCO3 (1.0 equiv), 36 h. dConversion of 1.

deliver the desired bis-cyanated product 2n in 75% yield. Moreover, a gram-scale reaction was conducted in the presence of substrate 1a and NCTS to provide the bis-cyanated product 2a in 61% yield. Encouraged by the preliminary results, we next extended the optimized conditions to substituted imidazo[1,2-α]pyridine derivatives (Scheme 3). A wide range of substrates bearing substitutents at the C5 and C6 positions of the imidazo[1,2α]pyridine ring, including F, Cl, Br, I, CF3, COOEt, Me, and OMe, were found to be ideal coupling partners for successful bis-cyanation (2o−2w). For 8-methoxyl-substituted substrate 1x, only 25% of bis-cyanated product 2x was obtained due to the steric hindrance, which could be detrimental for the imidazo[1,2-α]pyridine-assisted C−H activation. Variation of substitutents at the both pyridine and benzene rings was also attempted, which afforded the desired products 2y−2ag in moderate to high yields. Moreover, the substrates were explored toward imidazocontaining heterocycles 1ah−1al, which reacted with NCTS smoothly to furnish the bis-cyanated products 2ah−2al in 46− 73% yield (Scheme 4). Heterocycles incorporated with pyridine, thiophene, indole, and quinoline moieties, unfortunately, yielded no cyanation products. Also, the attempt to access other heterocycles bearing oxazole and pyrazole subunits was proved to be unsuccessful.

product 2a′ was detected when 1 equiv of NCTS was employed (Table 1, entry 10). To explain the preferential formation of bis-cyanated product, theoretical calculations using the density functional theory (DFT) were performed, which indicate that 2a was more stable from the thermodynamic perspective (see the Supporting Information). The structure of bis-cyanated compound 2a was further confirmed by X-ray diffraction (see the Supporting Information). With the optimal reaction conditions in hand, the scope of 2arylimidazo[1,2-α]pyridine substrates was investigated as shown in Scheme 2. The substitutents at the para-, meta-, and ortho-positions were tolerated to provide the bis-cyanated products 2a−2m in moderate to good yields. Para-substituted substrates 1b−1i bearing both electron-donating and electronwithdrawing groups proceeded smoothly under the optimized positions without the formation of mono-cyanated products. For meta- and ortho-substituted substrates 1j−1m, only electron-donating groups at the benzene ring are favorable for the C−H cyanation, while low yields were detected for substrates containing electron-withdrawing groups. Interestingly, only bis-cyanated products 2j−2k were isolated for metasubstituted substrates, which is rather rare in C−H activations since it often affords a mixture of both mono- and bisfunctionalized products considering steric hindrance.21 2Naphthalenyl-substituted substrate 1n was also compatible to 6024

DOI: 10.1021/acs.joc.6b03036 J. Org. Chem. 2017, 82, 6022−6031

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The Journal of Organic Chemistry Scheme 3. Substrate Scope of Cyanation of Imidazo[1,2-α]pyridine Derivativesa

a Reaction conditions: 1 (0.1 mmol), NCTS (0.25 mmol), [RhCp*Cl2]2 (5 mol %), AgSbF6 (40 mol %), NaHCO3 (0.5 equiv), DCE (1 mL), 120 °C, 24 h. bGram-scale production: 1 (5.2 mmol), NCTS (13 mmol), [RhCp*Cl2]2 (0.26 mmol), AgSbF6 (2.08 mmol), NaHCO3 (2.6 mmol), DCE (52 mL). cConversion of 1.

the presence of AgSbF6 and NaHCO3. Chelation of N1 at the imidazo[1,2-α]pyridine ring with in situ generated Rh(III) active complex A would form a five-membered rhodacycle B via a reversible C−H rhodation of 2-phenylimidazo[1,2-α]pyridine 1a.20c Coordination and subsequent migratory insertion of the CN group of NCTS into the C−Rh bond afforded intermediate C, which underwent β-amine elimination, proto-demetalation, and roll-over activation to provide mono-cyanated intermediate D. Next, another molecule of NCTS coupled with intermediate D to generate intermediate E, which would release the desired bis-cyanated product 2a and regenerate the active Rh(III) species A to fulfill the catalytic cycle.

To illustrate the mechanism of the cyanation reaction, several control experiments were conducted.22 The H/D exchange experiment was first conducted when an excess amount of D2O was added instead of NCTS under the optimized conditions. It was observed that about 75% deuterium was incorporated at the ortho-position of the benzene ring after 4 h, which suggests that a reversible cleavage of the C−H bond could be involved in the C−H cyanation (Scheme 5, eq 1). Also, a kinetic isotope effect (KIE) value of 1.2 was observed in the parallel coupling of 1a or 1a-d5 with NCTS, respectively (Scheme 5, eq 2). When an equimolar mixture of 1a and 1a-d5 was applied in the catalytic system, a KIE value of 1.1 was found after 2.5 h, indicating that Rh-catalyzed C−H bond cleavage is not involved in the rate-limiting step (Scheme 5, eq 3). In the intermolecular competition experiments between 1b and 1i, no significant electronic effect was observed (Scheme 5, eq 4). On the basis of the above mechanistic studies, a plausible catalytic cycle was proposed (Scheme 6). Initially, the active cationic Rh(III) species A was generated from [RhCp*Cl2]2 in

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CONCLUSION In conclusion, we have successfully developed an efficient and regioselective Rh(III)-catalyzed double C−H activation to access bis-cyanated 2-arylimidazo[1,2-α]pyridines via the employment of environmentally benign and readily available cyanating agent NCTS. The protocol exhibited wide functional 6025

DOI: 10.1021/acs.joc.6b03036 J. Org. Chem. 2017, 82, 6022−6031

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The Journal of Organic Chemistry Scheme 4. Substrate Scope of Cyanation of Imidazo-Containing Heterocyclesa

a Reaction conditions: 1 (0.1 mmol), NCTS (0.25 mmol), [RhCp*Cl2]2 (5 mol %), AgSbF6 (40 mol %), NaHCO3 (0.5 equiv), DCE (1 mL), 120 °C, 24 h. bConversion of 1.

Scheme 5. Control Experiments

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groups tolerance and allowed the synthesis of valuable biscyanated products in high yields. Additionally, the imidazo[1,2α]pyridine moiety was proved to be an effective chelating group to facilitate the cyanation transformations. The present orthocyanation could further be scaled up in a gram-scale synthesis, which provides easy access to valuable synthetic intermediates and pharmaceutical precursors. Further investigation of biological activities of aryl nitriles is currently in progress in our lab.

EXPERIMENTAL SECTION

General Information. All reactions were carried out in oven-dried sealed tubes under an air atmosphere unless otherwise mentioned. Solvents were dried with standard methods and freshly distilled prior to use if needed. Imidazo[1,2-α]pyridines23 and NCTS12 were prepared according to previous references, respectively. 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 6026

DOI: 10.1021/acs.joc.6b03036 J. Org. Chem. 2017, 82, 6022−6031

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The Journal of Organic Chemistry Scheme 6. Proposed Reaction Mechanism

GF254 were used to monitor the reactions and purify products. 1H NMR 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 2a (CCDC file number 1521415) was further confirmed by X-ray diffraction collected on a diffractometer with graphite-monochromated Cu Kα radiation. General Procedure for Bis-cyanation. To an oven-dried 15 mL sealed tube were added imidazo[1,2-α]pyridine 1 (0.1 mmol), NCTS (68.1 mg, 0.25 mmol), [RhCp*Cl2]2 (3.1 mg, 5 mol %), AgSbF6 (14 mg, 40 mol %), and NaHCO3 (4.2 mg, 50 mol %) in DCE (1 mL) under an air atmosphere. The sealed tube was capped and heated at 120 °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 thin-layer chromatography (petroleum ether/ethyl acetate = 1/1) to give the desired product 2. 2-(Imidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2a). White solid (21.7 mg, 89% yield); mp 208−209 °C; 1H NMR (400 MHz, CDCl3) δ 8.21−8.18 (m, 2H), 7.99 (d, J = 7.9 Hz, 2H), 7.74−7.71 (m, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.30−7.25 (m, 1H), 6.89 (td, J = 6.8, 1.0 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 145.3, 140.6, 138.2, 137.8, 128.4, 126.1, 125.9, 118.5, 117.4, 113.8, 113.6, 112.9; HRMS (ESI, m/ z) calcd for C15H9N4 [M + H+] 245.0822, found 245.0821. 2-(Imidazo[1,2-α]pyridin-2-yl)-5-methoxyisophthalonitrile (2b). White solid (18.4 mg, 67% yield); mp 234−235 °C; 1H NMR (400 MHz, CDCl3) δ 8.18 (dt, J = 6.8, 1.1 Hz, 1H), 8.08 (s, 1H), 7.74−7.70 (m, 1H), 7.49 (s, 2H), 7.29−7.24 (m, 1H), 6.88 (td, J = 6.8, 1.1 Hz, 1H), 3.93 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 158.6, 145.3, 138.2, 133.0, 126.0, 125.7, 123.3, 118.4, 117.2, 114.8, 113.4, 112.3, 56.3; HRMS (ESI, m/z) calcd for C16H11N4O [M + H+] 275.0927, found 275.0939. 5-(tert-Butyl)-2-(imidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2c). White solid (21.0 mg, 70% yield); mp 229−230 °C; 1H NMR (600 MHz, CDCl3) δ 8.20 (d, J = 6.8 Hz, 1H), 8.17 (s, 1H), 7.98 (s, 2H),

7.72 (d, J = 9.1 Hz, 1H), 7.28−7.25 (m, 1H), 6.88 (t, J = 6.7 Hz, 1H), 1.39 (s, 9H); 13C{1H} NMR (151 MHz, CDCl3) δ 152.4, 145.3, 138.3, 137.7, 135.2, 126.0, 125.7, 118.5, 117.9, 113.5, 113.4, 112.6, 35.1, 30.8; HRMS (ESI, m/z) calcd for C19H17N4 [M + H+] 301.1448, found 301.1449. 5-Ethyl-2-(imidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2d). Brown solid (23.4 mg, 86% yield); mp 176−177 °C; 1H NMR (400 MHz, CDCl3) δ 8.19 (dt, J = 6.8, 1.1 Hz, 1H), 8.15 (s, 1H), 7.81 (s, 2H), 7.72 (d, J = 9.2 Hz, 1H), 7.29−7.23 (m, 1H), 6.88 (td, J = 6.8, 1.0 Hz, 1H), 2.77 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 145.3, 145.2, 138.3, 138.0, 137.2, 126.0, 125.7, 118.4, 117.6, 113.7, 113.4, 112.6, 27.9, 14.7; HRMS (ESI, m/z) calcd for C17H13N4 [M + H+] 273.1135, found 273.1136. 2-(Imidazo[1,2-α]pyridin-2-yl)-5-methylisophthalonitrile (2e). White solid (18.1 mg, 70% yield); mp 205−206 °C; 1H NMR (600 MHz, CDCl3) δ 8.19 (d, J = 6.8 Hz, 1H), 8.15 (s, 1H), 7.79 (s, 2H), 7.72 (d, J = 9.1 Hz, 1H), 7.29−7.24 (m, 1H), 6.88 (t, J = 6.7 Hz, 1H), 2.48 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 145.3, 139.2, 138.3, 138.2, 137.8, 126.0, 125.8, 118.4, 117.5, 113.6, 113.5, 112.7, 20.7; HRMS (ESI, m/z) calcd for C16H11N4 [M + H+] 259.0978, found 259.0978. 5-Fluoro-2-(imidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2f). Yellow solid (8.2 mg, 31% yield); mp 216−217 °C; 1H NMR (400 MHz, CDCl3) δ 8.21 (dt, J = 6.9, 1.1 Hz, 1H), 8.14 (s, 1H), 7.75−7.71 (m, 3H), 7.32−7.27 (m, 1H), 6.92 (td, J = 6.8, 1.0 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 162.6, 161.8, 159.2, 145.4, 137.3, 126.1, 125.2(JC‑F = 24.2 Hz), 118.5, 116.2 (JC‑F = 2.0 Hz), 115.4 (JC‑F = 9.1 Hz), 113.7, 112.8; 19F NMR (376 MHz, CDCl3) δ −109.1; HRMS (ESI, m/z) calcd for C15H8FN4 [M + H+] 263.0728, found 263.0732. 5-Chloro-2-(imidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2g). Yellow solid (21.5 mg, 77% yield); mp 183−185 °C; 1H NMR (600 MHz, CDCl3) δ 8.21−8.18 (m, 2H), 7.96 (s, 2H), 7.72 (d, J = 9.2 Hz, 1H), 7.31−7.25 (m, 1H), 6.90 (t, J = 6.7 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 145.4, 138.9, 137.5, 137.3, 134.3, 126.1, 126.0, 118.5, 116.3, 115.0, 113.8, 113.0; HRMS (ESI, m/z) calcd for C15H8ClN4 [M + H+] 279.0432, found 279.0445. 6027

DOI: 10.1021/acs.joc.6b03036 J. Org. Chem. 2017, 82, 6022−6031

Article

The Journal of Organic Chemistry

2-(6-Chloroimidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2p). White solid (17.6 mg, 63% yield); mp 236−237 °C; 1H NMR (600 MHz, CDCl3) δ 8.28 (d, J = 1.1 Hz, 1H), 8.18 (s, 1H), 8.02 (s, 1H), 8.00 (s, 1H), 7.70 (d, J = 9.6 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.28− 7.25 (m, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 143.7, 140.1, 139.1, 137.8, 128.7, 127.6, 123.9, 122.0, 118.8, 117.2, 113.8, 113.2; HRMS (ESI, m/z) calcd for C15H8ClN4 [M + H+] 279.0432, found 279.0440. 2-(6-Bromoimidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2q). Yellow solid (12.9 mg, 40% yield); mp: 250−251 °C. 1H NMR (600 MHz, CDCl3) δ 8.38 (d, J = 0.9 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 8.00 (s, 1H), 7.64 (d, J = 9.6 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.35 (dd, J = 9.6, 1.7 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 143.8, 140.0, 138.9, 137.8, 129.6, 128.7, 126.1, 119.1, 117.2, 113.9, 113.0, 108.4; HRMS (ESI, m/z) calcd for C15H8BrN4 [M + H+] 322.9927, found 322.9934. 2-(6-Iodoimidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2r). Brown solid (14.8 mg, 40% yield); mp 245−246 °C; 1H NMR (600 MHz, CDCl3) δ 8.50−8.48 (m, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.99 (s, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.54 (d, J = 9.5 Hz, 1H), 7.47−7.43 (m, 1H); 13 C{1H} NMR (151 MHz, CDCl3) δ 143.9, 140.0, 138.6, 137.8, 134.0, 130.9, 128.7, 119.4, 117.2, 113.9, 112.5; HRMS (ESI, m/z) calcd for C15H8IN4 [M + H+] 370.9788, found 370.9797. 2-(6-(Trifluoromethyl)imidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2s). Yellow solid (26.5 mg, 85% yield); mp 206−207 °C; 1H NMR (400 MHz, CDCl3) δ 8.62−8.61 (m, 1H), 8.30 (s, 1H), 8.03 (s, 1H), 8.01 (s, 1H), 7.84 (d, J = 9.5 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.44− 7.41 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 144.9, 140.1, 139.7, 137.8, 129.0, 125.3 (JC‑F = 5.1 Hz), 124.6, 121.9 (JC‑F = 2.0 Hz), 119.2, 118.2 (JC‑F = 34.3 Hz), 117.0, 114.2, 114.0; 19F NMR (376 MHz, CDCl3) δ −62.4; HRMS (ESI, m/z) calcd for C16H8F3N4 [M + H+] 313.0696, found 313.0719. Ethyl 2-(2,6-Dicyanophenyl)imidazo[1,2-a]pyridine-6-carboxylate (2t). Yellow solid (22.5 mg, 71% yield); mp 244−245 °C; 1H NMR (400 MHz, CDCl3) δ 9.00 (t, J = 1.2 Hz, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 8.01 (s, 1H), 7.85 (dd, J = 9.5, 1.6 Hz, 1H), 7.76−7.73 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.4, 145.7, 139.91, 139.86, 137.7, 130.2, 128.8, 125.7, 118.1, 117.7, 117.2, 113.9, 61.8, 14.3; HRMS (ESI, m/z) calcd for C18H13N4O2 [M + H+] 317.1033, found 317.1040. 2-(7-Methoxyimidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2u). Yellow solid (18.1 mg, 66% yield); mp 239−240 °C; 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 8.02−7.97 (m, 3H), 7.54 (t, J = 7.9 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.63 (dd, J = 7.4, 2.5 Hz, 1H), 3.90 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 158.6, 146.9, 140.7, 137.93, 137.87, 128.1, 126.3, 117.6, 113.5, 111.9, 109.2, 95.1, 55.7; HRMS (ESI, m/z) calcd for C16H11N4O [M + H+] 275.0927, found 275.0935. 2-(7-Methylimidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2v). Yellow solid (20.7 mg, 80% yield); mp 205−206 °C; 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 8.06 (d, J = 7.0 Hz, 1H), 7.98 (s, 1H), 7.96 (s, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.47 (s, 1H), 6.71 (dd, J = 7.0, 1.5 Hz, 1H), 2.42 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 145.8, 140.8, 138.0, 137.7, 137.0, 128.2, 125.2, 117.4, 116.6, 116.3, 113.8, 112.4, 21.4; HRMS (ESI, m/z) calcd for C16H11N4 [M + H+] 259.0978, found 259.0988. 2-(7-(Trifluoromethyl)imidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2w). Yellow solid (20.9 mg, 67% yield); mp 187−188 °C; 1H NMR (600 MHz, CDCl3) δ 8.34 (d, J = 7.1 Hz, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 8.03 (s, 1H), 8.02 (s, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.08 (dd, J = 7.1, 1.3 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 143.4, 140.2, 139.7, 137.8, 128.3 (JC‑F = 34.3 Hz), 127.5, 127.0, 123.0 (JC−F = 272.7 Hz), 117.1, 116.6 (JC‑F = 5.1 Hz), 114.1, 114.0, 109.5 (JC‑F = 3.0 Hz); 19 F NMR (376 MHz, CDCl3) δ −63.9; HRMS (ESI, m/z) calcd for C16H8F3N4 [M + H+] 313.0696, found 313.0705. 2-(8-Methoxyimidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2x). Brown solid (6.9 mg, 25% yield); mp 243−245 °C; 1H NMR (600 MHz, CDCl3) δ 8.04 (s, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.99 (s, 1H), 7.97 (s, 1H), 7.54 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 2.1 Hz, 1H), 6.62 (dd, J = 7.4, 2.4 Hz, 1H), 3.89 (s, 3H); 13C{1H} NMR (151 MHz,

2-(Imidazo[1,2-α]pyridin-2-yl)-5-iodoisophthalonitrile (2h). Brown solid (20.0 mg, 54% yield); mp 167−169 °C; 1H NMR (600 MHz, CDCl3) δ 8.27 (s, 2H), 8.21−8.18 (m, 2H), 7.72 (d, J = 9.2 Hz, 1H), 7.30−7.26 (m, 1H), 6.90 (t, J = 6.7 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 146.0, 145.4, 139.7, 137.5, 126.11, 126.08, 118.5, 116.0, 114.9, 113.7, 113.0, 91.3; HRMS (ESI, m/z) calcd for C15H8IN4 [M + H+] 370.9788, found 370.9792. 2-(Imidazo[1,2-α]pyridin-2-yl)-5-(trifluoromethyl)isophthalonitrile (2i). Yellow solid (16.3 mg, 52% yield); mp 208−209 °C; 1H NMR (600 MHz, CDCl3) δ 8.31 (s, 1H), 8.24−8.21 (m, 3H), 7.75 (d, J = 9.2 Hz, 1H), 7.34−7.30 (m, 1H), 6.94 (t, J = 6.7 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 145.5, 143.4, 137.0, 134.5 (JC‑F = 3.0 Hz), 131.0 (JC‑F = 35.4 Hz), 126.4, 126.2, 122.0 (JC‑F = 273.7 Hz), 118.7, 116.4, 114.5, 114.0, 113.7; 19F NMR (376 MHz, CDCl3) δ −63.2; HRMS (ESI, m/z) calcd for C16H8F3N4 [M + H+] 313.0696, found 313.0704. 2-(Imidazo[1,2-α]pyridin-2-yl)-4-methoxyisophthalonitrile (2j). Yellow solid (15.9 mg, 58% yield); mp 239−240 °C; 1H NMR (600 MHz, CDCl3) δ 8.20−8.17 (m, 1H), 8.15 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.28−7.23 (m, 1H), 7.05 (d, J = 8.9 Hz, 1H), 6.90−6.85 (m, 1H), 4.05 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 164.7, 145.2, 142.9, 139.4, 138.3, 126.0, 125.8, 118.5, 117.7, 114.5, 113.5, 113.1, 110.8, 105.3, 103.2, 56.9; HRMS (ESI, m/z) calcd for C16H11N4O [M + H+] 275.0927, found 275.0933. 2-(Imidazo[1,2-α]pyridin-2-yl)-4-methylisophthalonitrile (2k). White solid (11.7 mg, 50% yield); mp 225−227 °C; 1H NMR (400 MHz, CDCl3) δ 8.20 (dt, J = 6.9, 1.1 Hz, 1H), 8.13 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.72 (dd, J = 9.2, 0.6 Hz, 1H), 7.45−7.42 (m, 1H), 7.29−7.24 (m, 1H), 6.89 (td, J = 6.8, 1.0 Hz, 1H), 2.70 (s, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 148.34, 145.28, 141.2, 138.6, 136.9, 129.8, 126.0, 125.8, 118.5, 117.6, 116.2, 114. 5, 113.5, 112.8, 111.2, 21.7; HRMS (ESI, m/z) calcd for C16H11N4 [M + H+] 259.0978, found 259.0985. 2-(Imidazo[1,2-α]pyridin-2-yl)-3-methoxybenzonitrile (2l). Yellow solid (12.2 mg, 49% yield); mp 175−176 °C; 1H NMR (600 MHz, CDCl3) δ 8.14 (d, J = 6.8 Hz, 1H), 7.95 (s, 1H), 7.70 (d, J = 9.1 Hz, 1H), 7.41−7.39 (m, 2H), 7.22−7.17 (m, 2H), 6.80 (t, J = 6.7 Hz, 1H), 3.90 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 157.4, 144.7, 138.2, 129.3, 126.6, 126.3, 125.6, 124.7, 119.0, 118.2, 115.2, 113.8, 113.3, 112.7, 56.1; HRMS (ESI, m/z) calcd for C15H12N3O [M + H+] 250.0975, found 250.0979. 2-(Imidazo[1,2-α]pyridin-2-yl)-3-methylbenzonitrile (2m). Yellow solid (17.0 mg, 73% yield); mp 111−112 °C; 1H NMR (400 MHz, CDCl3) δ 8.18 (dt, J = 6.8, 1.0 Hz, 1H), 7.78 (s, 1H), 7.65 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.26−7.20 (m, 1H), 6.85 (td, J = 6.8, 1.0 Hz, 1H), 2.42 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 145.1, 141.7, 139.5, 137.3, 134.8, 130.8, 128.3, 125.9, 125.0, 119.0, 117.9, 113.5, 112.7, 112.0, 20.8; HRMS (ESI, m/z) calcd for C15H12N3 [M + H+] 234.1026, found 234.1034. 2-(Imidazo[1,2-α]pyridin-2-yl)naphthalene-1,3-dicarbonitrile (2n). Yellow solid (22.1 mg, 75% yield); mp 234−235 °C; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.43−8.40 (m, 1H), 8.25−8.22 (m, 2H), 8.02 (d, J = 8.2 Hz, 1H), 7.92−7.87 (m, 1H), 7.79−7.73 (m, 2H), 7.32−7.27 (m, 1H), 6.90 (td, J = 6.8, 1.1 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 145.4, 140.1, 137.9, 134.2, 132.0, 131.1, 129.1, 129.0, 126.0, 125.8, 118.53 117.6, 116.3, 113.5, 113.2, 111.1, 110.7; HRMS (ESI, m/z) calcd for C19H11N4 [M + H+] 295.0978, found 295.0991. 2-(6-Fluoroimidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2o). Yellow solid (13.1 mg, 50% yield); mp 262−263 °C; 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 8.16−8.14 (m, 1H), 8.01 (s, 1H), 7.99 (s, 1H), 7.75−7.70 (m, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.26−7.19 (m, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 153.8 (JC‑F = 238.6 Hz), 143.1, 140.2, 139.3 (JC‑F = 1.51 Hz), 137.8, 128.6, 119.1 (JC‑F = 9.1 Hz), 118.4 (JC‑F = 27.2 Hz), 117.3, 114.1 (JC‑F = 1.51 Hz), 113.8, 112.67 (JC−F = 40.8 Hz); 19F NMR (376 MHz, CDCl3) δ −138.4; HRMS (ESI, m/z) calcd for C15H8FN4 [M + H+] 263.0728, found 263.0737. 6028

DOI: 10.1021/acs.joc.6b03036 J. Org. Chem. 2017, 82, 6022−6031

Article

The Journal of Organic Chemistry CDCl3) δ 158.6, 146.9, 140.7, 137.9, 137.8, 128.1, 126. 3, 117.5, 113.5, 111.9, 109.2, 95.1, 55.7; HRMS (ESI, m/z) calcd for C16H11N4O [M + H+] 275.0927, found 275.0935. 2-(6-Fluoroimidazo[1,2-α]pyridin-2-yl)-5-methoxyisophthalonitrile (2y). Yellow solid (9.9 mg, 34% yield); mp 256−257 °C; 1H NMR (600 MHz, CDCl3) δ 8.14−8.12 (m, 1H), 8.09 (s, 1H), 7.72− 7.69 (m, 1H), 7.49 (s, 2H), 7.23−7.18 (m, 1H), 3.93 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 158.8, 153.7(J C‑F = 238.6 Hz), 143.0, 139.4, 132.5, 123.4, 118.9 (JC‑F = 9.1 Hz), 118.1 (JC‑F = 25.7 Hz), 117.2, 114.7, 113.5 (JC‑F = 1.5 Hz), 112.6 (JC‑F = 40.8 Hz), 56.3; 19F NMR (376 MHz, CDCl3) δ −138.8; HRMS (ESI, m/z) calcd for C16H10FN4O [M + H+] 293.0833, found 293.0843. 2-(6-Fluoroimidazo[1,2-α]pyridin-2-yl)-5-methylisophthalonitrile (2z). White solid (23.8 mg, 86% yield); mp 220−221 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 8.15−8.12 (m, 1H), 7.79 (d, J = 0.4 Hz, 2H), 7.72−7.67 (m, 1H), 7.23−7.17 (m, 1H), 2.48 (s, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 153.7 (J C‑F = 240.4 Hz), 143.0, 139.4 (JC‑F = 2.0 Hz), 139.4, 138.3, 137.4, 119.0, 118.6 (JC‑F = 63.6 Hz), 117.7 (JC‑F = 66.7 Hz), 113.9 (JC‑F = 2.0 Hz), 113.6, 112.6 (JC‑F = 41.4 Hz), 20.6; 19F NMR (376 MHz, CDCl3) δ −138.7; HRMS (ESI, m/z) calcd for C16H10FN4 [M + H+] 277.0884, found 277.0896. 2-(6-Chloroimidazo[1,2-α]pyridin-2-yl)-5-methylisophthalonitrile (2aa). White solid (18.7 mg, 64% yield); mp 244−245 °C; 1H NMR (400 MHz, CDCl3) δ 8.26−8.25 (m, 1H), 8.13 (s, 1H), 7.80 (d, J = 0.6 Hz, 2H), 7.70−7.66 (m, 1H), 7.26−7.22 (m, 1H), 2.48 (s, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ 143.6, 139.5, 139.2, 138.3, 137.3, 127.4, 123.8, 121.8, 118.8, 117.4, 113.6, 112.9, 20.7; HRMS (ESI, m/z) calcd for C16H10ClN4 [M + H+] 293.0589, found 293.0596. 2-(6-Iodoimidazo[1,2-α]pyridin-2-yl)-5-methylisophthalonitrile (2ab). Brown solid (13.4 mg, 35% yield); mp 220−222 °C; 1H NMR (600 MHz, CDCl3) δ 8.47 (s, 1H), 8.09 (s, 1H), 7.79 (s, 2H), 7.52 (d, J = 9.5 Hz, 1H), 7.44−7.42 (m, 1H), 2.48 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 143.8, 139.5, 138.6, 138.3, 137.2, 133.9, 130.9, 119.3, 117.4, 113.6, 112.2, 20.7; HRMS (ESI, m/z) calcd for C16H10IN4 [M + H+] 384.9945, found 384.9959. 5-Methyl-2-(6-(trifluoromethyl)imidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2ac). White solid (22.5 mg, 69% yield); mp 201−202 °C; 1H NMR (600 MHz, CDCl3) δ 8.60 (s, 1H), 8.25 (s, 1H), 7.85 (d, J = 9.5 Hz, 1H), 7.82 (s, 2H), 7.44−7.41 (m, 1H), 2.50 (s, 3H); 13 C{1H} NMR (151 MHz, CDCl3) δ 144.9, 140.2, 139.9, 138.4, 136.9, 125.2 (JC‑F = 4.5 Hz), 123.3 (JC‑F = 270.3 Hz), 121.7 (JC‑F = 1.5 Hz), 119.2, 118.1 (JC‑F = 33.2 Hz), 117.2, 113.9, 113.7, 20.7; 19F NMR (376 MHz, CDCl3) δ −62.4; HRMS (ESI, m/z) calcd for C17H10F3N4 [M + H+] 327.0852, found 327.0866. 2-(7-Methoxyimidazo[1,2-α]pyridin-2-yl)-5-methylisophthalonitrile (2ad). Yellow solid (17.3 mg, 60% yield); mp 200−201 °C; 1H NMR (600 MHz, CDCl3) δ 8.00 (s, 1H), 7.99 (d, J = 7.4 Hz, 1H), 7.77 (s, 2H), 6.96 (d, J = 1.9 Hz, 1H), 6.61−6.58 (m, 1H), 3.88 (s, 3H), 2.47 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 158.5, 146.8, 138.7, 138.4, 138.0, 137.9, 126.2, 117.7, 113.3, 111.6, 109.0, 95.1, 55.7, 20.6; HRMS (ESI, m/z) calcd for C17H13N4O [M + H+] 289.1084, found 289.1094. 5-Methoxy-2-(7-methylimidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2ae). Yellow solid (18.7 mg, 65% yield); mp 213-215 °C; 1H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 6.9 Hz, 1H), 7.99 (s, 1H), 7.47−7.45 (m, 3H), 6.71−6.69 (m, 1H), 3.91 (s, 3H), 2.41 (s, 3H); 13 C{1H} NMR (151 MHz, CDCl3) δ 158.5, 145.7, 137.9, 136.7, 133.2, 125.1, 123.3, 117.3, 116.5, 116.0, 114.7, 111.7, 56.2, 21.4; HRMS (ESI, m/z) calcd for C17H13N4O [M + H+] 289.1084, found 289.1094. 5-Methyl-2-(7-methylimidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2af). Yellow solid (11.4 mg, 42% yield); mp 214−216 °C; 1H NMR (600 MHz, CDCl3) δ 8.06−8.04 (m, 2H), 7.77 (s, 2H), 7.46 (s, 1H), 6.71−6.69 (m, 1H), 2.47 (s, 3H), 2.41 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 145.7, 138.9, 138.3, 138.1, 138.0, 136.8, 125.1, 117.6, 116.6, 116.2, 113.5, 112.1, 21.4, 20.6; HRMS (ESI, m/z) calcd for C17H13N4 [M + H+] 273.1135, found 273.1141. 5-Methyl-2-(7-(trifluoromethyl)imidazo[1,2-α]pyridin-2-yl)isophthalonitrile (2ag). White solid (28.4 mg, 87% yield); mp 211−213 °C; 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 7.2 Hz, 1H), 8.26 (s, 1H), 8.06 (d, J = 0.7 Hz, 1H), 7.81 (d, J = 0.6 Hz, 2H), 7.08−7.05 (m,

1H), 2.50 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 143.3, 140.3, 139.8, 138.4, 136.9, 127.8 (JC‑F = 34.3 Hz), 126.9, 123.0 (JC‑F = 273.7 Hz), 117.3, 116.6 (JC‑F = 5.1 Hz), 113.8, 113.7, 109.4 (JC‑F = 3.0 Hz), 20.7; 19F NMR (376 MHz, CDCl3) δ −63.9; HRMS (ESI, m/z) calcd for C17H10F3N4 [M + H+] 327.0852, found 327.0861. 2-(Imidazo[1,2-b]pyridazin-2-yl)isophthalonitrile (2ah). Brown solid (17.9 mg, 73% yield); mp 196−198 °C; 1H NMR (600 MHz, CDCl3) δ 8.21 (s, 1H), 8.15 (d, J = 6.8 Hz, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.26−7.23 (m, 1H), 6.87 (t, J = 6.7 Hz, 1H), 6.69 (d, J = 1.8 Hz, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 156.2, 145.7, 142.6, 134.4, 126.1, 126.0, 118.2, 114.5, 113.6, 112.5, 111.2; HRMS (ESI, m/z) calcd for C14H8N5 [M + H+] 246.0774, found 246.0780. 2-(Imidazo[1,2-b]pyridazin-2-yl)isophthalonitrile (2ai). Yellow solid (13.8 mg, 47% yield); mp 228−230 °C; 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.02−8.00 (m, 3H), 7.84 (dd, J = 7.9, 1.0 Hz, 1H), 7.71−7.59 (m, 3H), 7.59−7.50 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 144.1, 140.6, 137.9, 137.3, 132.5, 129.4, 129.3, 128.2, 127.7, 125.6, 123.6, 117.5, 117.3, 115.5, 113.6, 111.9; HRMS (ESI, m/ z) calcd for C19H11N4 [M + H+] 295.0978, found 295.0986. 2-(Imidazo[1,2-b]pyridazin-2-yl)isophthalonitrile (2aj). Yellow solid (13.8 mg, 46% yield); mp 238−240 °C; 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.99 (s, 1H), 7.97 (s, 1H), 7.76−7.70 (m, 2H), 7.56−7.46 (m, 2H), 7.43−7.38 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 148.6, 140.0, 139.6, 138.0, 131.6, 130.7, 128.0, 126.5, 125.9, 124.5, 117.5, 113.4, 113.1, 112.6; HRMS (ESI, m/z) calcd for C17H9N4S [M + H+] 301.0542, found 301.0555. 2-(Imidazo[1,2-a]pyridin-2-yl)furan-3-carbonitrile (2ak). White solid (11.1 mg, 60% yield); mp: 220−222 °C; 1H NMR (600 MHz, CDCl3) δ 8.58 (s, 1H), 8.41 (dd, J = 4.3, 1.3 Hz, 1H), 8.08 (d, J = 9.2 Hz, 1H), 8.03 (s, 1H), 8.02 (s, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.18− 7.15 (m, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 144.3, 140.1, 139.2, 138.0, 137.8, 128.8, 126.3, 118.4, 117.4, 117.1, 113.9; HRMS (ESI, m/z) calcd for C12H8N3O [M + H+] 210.0662, found 210.0667. 2-(Imidazo[1,2-a]pyridin-2-yl)-1-methyl-1H-pyrrole-3-carbonitrile (2al). White solid (13.6 mg, 61% yield); mp: 112−114 °C; 1H NMR (400 MHz, CDCl3) δ 8.15−8.13 (m, 2H), 7.58 (d, J = 9.1 Hz, 1H), 7.22−7.17 (m, 1H), 6.82 (t, J = 6.7 Hz, 1H), 6.65 (d, J = 2.9 Hz, 1H), 6.46 (d, J = 2.9 Hz, 1H), 4.05 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 145.0, 135.9, 133.9, 125.9, 125.2, 124.7, 118.1, 117.6, 112.9, 111.8, 91.6, 36.9; HRMS (ESI, m/z) calcd for C13H11N4 [M + H+] 223.0978, found 223.0978. Mechanistic Experiments. Procedure for Preparation of 1a-d5. To a 50 mL sealed tube were added 2-aminopyridine (1.13g, 12 mmol), acetophenone-2′,3′,4′,5′,6′-D5 (1.17 mL, 10 mmol), Cu(OAc)2·H2O (200 mg, 1 mmol), 1,10-phenanthroline (200 mg, 1 mmol), and ZnI2 (320 mg, 1 mmol) in 1,2-dichlorobenzene (20 mL) under an air atmosphere. The sealed tube was capped and heated at 120 °C for 36 h. Next, the reaction was cooled down to room temperature and directly concentrated. The organic residue was purified by column chromatography on silica gel (petroleum ether/ ethyl acetate = 3/1) to deliver the 1a-d5 in 19% yield (379 mg). 1H NMR (600 MHz, CDCl3) δ 8.12 (d, J = 6.7 Hz, 1H), 7.86 (s, 1H), 7.64 (d, J = 9.1 Hz, 1H), 7.19−7.15 (m, 1H), 6.79−6.76 (t, J = 6.7 Hz, 1H). H/D Exchange Experiment. To an oven-dried 15 mL sealed tube were added 2-phenylimidazo[1,2-α]pyridine 1a (19.4 mg, 0.1 mmol), D2O (40.0 mg, 2.0 mmol), [RhCp*Cl2]2 (3.1 mg, 5 mol %), AgSbF6 (14 mg, 40 mol %), and NaHCO3 (4.2 mg, 50 mol %) in DCE (1 mL) under an air atmosphere. The sealed tube was capped and heated at 120 °C for 4 h. Next, the reaction mixture was stopped and cooled down to room temperature. The reaction mixture was directly concentrated under vacuo and purified by preparative thin-layer chromatography (petroleum ether/ethyl acetate = 1/1) to recover the starting material. The deuterium content of 75% at the o-position was determined by the 1 H NMR analyses (see the Supporting Information). Parallel Experiment between 1a and 1a-d5. To an oven-dried 15 mL sealed tube was added 2-phenylimidazo[1,2-α]pyridine 1a (19.4 mg, 0.1 mmol) or 1a-d (19.4 mg, 0.1 mmol) under the optimized 6029

DOI: 10.1021/acs.joc.6b03036 J. Org. Chem. 2017, 82, 6022−6031

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The Journal of Organic Chemistry conditions. The sealed tube was capped and heated at 120 °C for 60, 75, 90, 105, and 120 min, and immediately quenched with ethyl acetate, separately. Next, the reaction mixture was filtered and concentrated under vacuo. Anisole (32.4 mg, 0.3 mmol) was added as the internal standard, and the conversion percentage was determined by 1H NMR analysis. The KIE was calculated as KH/KD = 0.193/0.16 ≈ 1.2 (see the Supporting Information). Competitive Experiment between 1a and 1a-d5. To an oven-dried 15 mL sealed tube were added an equimolar mixture of 2phenylimidazo[1,2-α]pyridine 1a (19.4 mg, 0.1 mmol) and 1a-d5 (19.4 mg, 0.1 mmol) under the optimized conditions. The sealed tube was capped and heated at 120 °C for 2.5 h. The reaction mixture was stopped and cooled down to room temperature. The reaction mixture was directly concentrated under vacuo and purified by preparative thin-layer chromatography (petroleum ether/ethyl acetate = 1/1) to afford the target products of 2a and 2a-d3 in 31% yield. The ratio of 2a and 2a-d3 was determined by 1H NMR analysis. The KIE was calculated as KH/KD = 0.534/0.466 ≈ 1.1 based on the integration resonances (see the Supporting Information). Intermolecular Competition Experiments between 1b and 1i. To an oven-dried 15 mL sealed tube was added an equimolar mixture of 1b (19.4 mg, 0.1 mmol) and 1i (19.4 mg, 0.1 mmol) under the optimized conditions. The sealed tube was capped and heated at 120 °C for 24 h. The reaction mixture was stopped and cooled down to room temperature. The reaction mixture was directly concentrated under vacuo and purified by preparative thin-layer chromatography (petroleum ether/ethyl acetate = 1/1) to afford the target products of 2b and 2i in 72% and 76% yield, respectively.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.6b03036. Experimental procedures, crystallography of 2a, theoretical calculations, and spectra copies of 2a−2al (PDF) X-ray data for 2a (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (B.S.). *E-mail: [email protected] (X.-Q.H.). ORCID

Xin-Qi Hao: 0000-0003-1942-8309 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 Outstanding Young Talent Research Fund of Zhengzhou University (1421316036), and the Program for Science & Technology Innovation Talents in Universities of Henan Province (17HASTIT004) is gratefully appreciated.

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