I2-Catalyzed Oxidative Amidation of Benzylamines and Benzyl

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I2‑Catalyzed Oxidative Amidation of Benzylamines and Benzyl Cyanides under Mild Conditions Sadu Nageswara Rao, N. Naresh Kumar Reddy, Supravat Samanta, and Subbarayappa Adimurthy* Academy of Scientific & Innovative Research, CSIR−Central Salt & Marine Chemicals Research Institute, G.B. Marg, Bhavnagar 364 002, Gujarat, India S Supporting Information *

ABSTRACT: We report a novel and efficient method for the oxidation of benzylic carbons (amines and cyanides) into corresponding benzamides using a catalytic amount of I2 and TBHP as the green oxidant via the C−H bond cleavage of the benzylic carbon under mild reaction conditions. According to the literature survey, this is the first report for the oxidative amidation of benzylamines and decyanation of benzyl cyanides in one pot under metal-free conditions. I2−TBHP. The present transformation proceeds via the C−H bond cleavage of benzylic carbon under mild reaction conditions. To the best of our knowledge, this is the first convenient procedure for oxidative amidation of benzylamines and decyanation11 of arylacetonitriles under metal-free conditions (Scheme 1). Initially, we focused on the optimization of conditions for the oxidative amidation of N-methylbenzylamine using iodine catalyst. To test our initial hypothesis, first we examined the oxidation of N-methylbenzylamine 1a to N-methylbenzamide 2a with 20 mol % of iodine and 4.0 equiv of TBHP (aq) in acetonitrile at 70 °C in a closed tube; under these reaction conditions, the desired amide 2a was isolated in 42% yield (Table 1, entry 1). On the basis of the above observation, we increased the amount of the oxidant (TBHP) from 4.0 to 8.0 equiv; the desired amide 2a was increased to 56% yield (Table 1, entry 2). After a further increase of the oxidant to 10.0 equiv, significant improvement in the yield of the product 2a was observed (entry 3). Use of 10.0 equiv of aq TBHP, lowering the reaction temperature to 60 °C, and performing the reaction at room temperature also decreased the yield (Table 1, entries 4 and 5). When the catalyst loading was decreased to 10 mol %, the yield of 2a was declined to 66% (Table 1, entry 6). However, the yield was suddenly dropped to 40% when the reaction temperature increased to 100 °C (Table 1, entry 7). At higher temperature,

A

mide linkages are not only key chemical connections of proteins and peptides1 but also versatile intermediates used in the preparation of pharmaceuticals, agrochemicals, and polymers.2 Furthermore, the favorable properties of amides, such as high polarity, stability, and conformational diversity, make it one of the most popular and reliable functional groups in all branches of organic chemistry. Given the prevalence of amides in both natural and unnatural materials, several synthetic routes have been developed.3 Traditionally, amides have been prepared by the reaction of amines with carbonyl derivatives,4 hydroamination of alkynes,5 and hydration of nitriles.6 Despite these advancements,3−6 current trends on amide syntheses are being focused on the direct oxidation of benzylamines to benzamides.7 Recently, Beller8 and Mountford9 independently reported an efficient oxidation of benzylamines to benzamides. More recently, Chen10 and Song11 demonstrated the oxidative decyanation of arylacetonitriles to primary benzamides using copper and iron catalysis. Although the reported methods are efficient, they require the use of transition-metal catalysts to promote the transformation efficiently.8−11To replace the transition-metal catalysts, the development of metal-free and sustainable processes for amide synthesis is desirable and deserves investigation. Due to our continuous efforts on the developments of sustainable methods for amide synthesis,12 and based on previous reports on the replacement of transition-metal catalysts by iodine in organic transformations,13 we disclose herein an efficient and practical approach for the oxidative amidation of benzylamines and benzyl cyanides into the corresponding benzamides using © 2017 American Chemical Society

Received: September 13, 2017 Published: December 5, 2017 13632

DOI: 10.1021/acs.joc.7b02211 J. Org. Chem. 2017, 82, 13632−13642

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The Journal of Organic Chemistry Scheme 1. Oxidative Amidation of Benzylic Carbons Adjacent to the “Amine” and “Cyanide” Group

Table 1. Optimization of Reaction Conditionsa

under these conditions a side product formation was observed.14 We then screened the other iodine sources like NIS, TBAI (tetrabutylammonium iodide), and KI for the present transformation; in these cases, moderate yield (40−43%) of the desired amide 2a was isolated (Table 1, entries 8−10). In the absence of the catalyst no product formation was identified (Table 1, entry 11). The effect of other catalysts like TBAB, TBAC, AIBN, and NHPI (N-hydroxyphthalimide), were also checked for the present reaction; no product formation was observed (Table 1, entries 12−15). In contrast, the reaction failed to yield the desired product with other oxidants like H2O2 and DTBP ((di-tert-butyl peroxide) (Table 1, entries 16 and 17). The reaction with TBHP in decane instead of aqueous TBHP and also under inert atmosphere showed no improvement in yield (Table 1, entries 18 and 19). Having identified the effective conditions for oxidative amidation of N-methylbenzylamine 1a to N-methylbenzamide 2a (Table 1, entry 3), we studied the scope of substituted N-methylbenzylamines; the results are illustrated in Table 2. There is no apparent effect of substituent groups in this system. The presence of both electron-donating groups (methyl, methoxy, and tert-butyl) and electron-withdrawing groups (bromo, chloro, fluoro, nitro, cyano, and phenyl) at the para position of 1a could react smoothly and afford the corresponding benzamides 2b−j in good yields (51−77%). The oxidative amidation of 1-(3-fluorophenyl)-N-methylmethanamine and N-methyl-1-(naphthalen-1-yl)methanamine also gave the corresponding amides 2k and 2l in 65% and 44% yield, respectively. In the case of N,N-dimethyl-1-phenylmethanamine and N-benzylethanamine, the corresponding amides 2m (traces) and 2n were isolated in 63% yield. With N-benzyl-2-methylpropan-2-amine,

entry

additive (mol %)

oxidant (equiv)

temp (°C)

yield(%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 b 18 c 19

I2 (20) I2 (20) I2 (20) I2 (20) I2 (20) I2 (10) I2 (10) NIS (20) TBAI (20) KI (20)

TBHP (4) TBHP (8) TBHP (10) TBHP (10) TBHP (10) TBHP (10) TBHP (10) TBHP (10) TBHP (10) TBHP (10) TBHP (10) TBHP (10) TBHP (10) TBHP (10) TBHP (10) H2O2 (10) DTBP (10) TBHP (10) TBHP (10)

70 70 70 60 rt 70 100 70 70 70 70 70 70 70 70 70 70 70 70

42 56 82 74 40 66 40 41 43 40 nd nd nd trace nd nd nd 44 46

TBAB(20) TBAC(20) AIBN (20) NHPI (20) I2 (20) I2 (20) I2 (20) I2 (20)

a Conditions: 1a (1.0 mmol), additive, oxidant, solvent in an oil bath, sealed tube, 18 h, isolated yield. bTBHP in decane. cTBHP under argon atmosphere.

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The Journal of Organic Chemistry Table 2. Substrate Scope of Various Benzylaminesa

a

Conditions: 1 (1.0 mmol), iodine (20 mol %), TBHP (10 equiv), CH3CN (2 mL) in an oil bath in a sealed tube, 70 °C, 18 h, isolated yield.

no reaction was observed (2o). However, the oxidation of N-benzylaniline gave the desired N-phenylbenzamide 2p in 48% yield. The oxidation methodology has been extended to a variety of primary benzylamines. Benzylamine and other benzylamine substituents with electronrich (methyl and methoxy) and electron-deficient (F and Cl) groups at the para/meta position reacted smoothly under these conditions and gave good yields (54−88%) of the desired primary benzamides 2q−v. However, hetero primary amines like 3-pyridylmethylamine, furfurylamine, and 2-thiophene methyl amines provided the corresponding heteroamides 2w−y in low yields (40−30%). While the yields of these products are lower, they exemplify the ability to expand the method toward different heteroamides. We then evaluated the amidation of benzyl cyanides through decyanation under the above optimized conditions using aqueous ammonia and other amines (Table 3). However, the optimization of reaction time (36 h) was evaluated to achieve the complete

conversion of benzyl cyanide 3 to primary benzamide 5 which was obtained in 75% isolated yield with aqueous ammonia (Table 3, 5a). Under the same conditions, benzyl cyanides having electron-donating (methyl, tert-butyl) groups at ortho/ para/meta position gave the corresponding products 5b−e in 52−70% yields. 3,4-Dimethoxybenzyl cyanide also gave 53% yield of the desired amide 5f. Interestingly, the halo (Br, Cl, and F)-substituted benzyl cyanides afford good product yields (5b−i). Further, the strong electron-withdrawing 4-nitrobenzyl cyanide provided the best yield (84%) of desired amide 5j under the optimized conditions. For heteroaromatics such as 3-pyridyl and 2-pyridyl acetonitriles, lower yields of 49% and 33% of products 5k and 5l were obtained, respectively. Furthermore, we extended scope of the present system to secondary and tertiary amines under the same conditions. The reaction of benzyl cyanide with benzylamine and 2-(4-bromophenyl)ethan-1-amine produced 13634

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The Journal of Organic Chemistry Table 3. Broad Scope of Different Benzyl Cyanides with Aminesa

a

Conditions: 3 (0.5 mmol), 4 (aq NH3, 1.5 mL, or other amine, 1.5 mmol), iodine (20 mol %), aq TBHP (8.0 equiv), CH3CN (1.5 mL) in an oil bath in a sealed tube, 70 °C, 36 h, isolated yield.

Scheme 2. Additional Experiments

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DOI: 10.1021/acs.joc.7b02211 J. Org. Chem. 2017, 82, 13632−13642

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The Journal of Organic Chemistry Scheme 3. Control Experiments for Oxidative Amidation

Scheme 4. Control Experiments for Amidation of Benzyl Cyanides

the corresponding secondary amides N-benzylbenzamide 5m and N-(4-bromophenethyl)benzamide 5n in 54% and 50% yield. To amplify the scope of the process, representative nitriles and different amines such as 4-chlorobenzylamine, phenylethylamine, and morpholine were subjected to the present procedure, secondary (5o and 5p) and tertiary 5q amides were

obtained in 50%, 60%, and 43% yields, respectively. However, N-methylbenzylamine does not give the oxidative amidation product 5r under the present conditions. We have not extensively evaluated the scope of this amidation process; a brief study indicates that a range of primary, secondary, and tertiary amide derivatives would be accessible using the 13636

DOI: 10.1021/acs.joc.7b02211 J. Org. Chem. 2017, 82, 13632−13642

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The Journal of Organic Chemistry Scheme 5. Plausible Mechanism

α- methyl benzyl cyanide 17 with aqueous ammonia under the conditions of Scheme 3, led to no formation of the desired amide. The reactions of substrates 11 and 17 suggest that the free benzylic carbon only undergoes oxidation to yield desired amide. The reaction of 3a with TEMPO (3.0equiv) and aqueous ammonia led to 35% yield of desired amide 2q (along with 18 and 19 were observed by GC−MS), but no TEMPO adduct formation was observed. When the reaction of benzoyl cyanide 20 was subjected to the above conditions, 92% of 2q was isolated in 18 h of reaction time. This reaction clearly indicates that, it goes through benzoyl cyanide formation (Scheme 4). Further, benzaldehyde 21 was subjected to the above reaction conditions, and 99% of benzonitrile 22 formation was observed (GC−MS). On the basis of the above control experiments (Schemes 3 and 4), a probable reaction mechanism was proposed (Scheme 5). Initially, the reaction of benzylamine with iodine and TBHP generated the benzyl radical intermediate I, which readily underwent oxidation to yield imine intermediate II. The imine intermediate II may proceed through path A or B via the intermediate III or IV, and their subsequent oxidation yields the desired amide. On the other hand, reaction of benzyl cyanide with iodine and TBHP generates benzyl cyanide radical I′, and its reaction with tert-butyl peroxy radical may generate tetrahedral intermediate II′ upon elimination of tert-butyl alcohol give the stable aroyl cyanide III′. Nucleophilic addition of amine to the intermediate III′ may generate another tetrahedral intermediate IV′. Finally, decyanation through the oxidation yield the desired amide. In conclusion, we have developed a metal- and base-free oxidative amidation of arylmethylamines as well as aryl acetonitriles into the corresponding primary benzamides under mild reaction conditions. To the best of our knowledge, this is the first report on benzylic oxidation of amines and cyanides to amides under metal-free conditions. The present I2−TBHP system is accessible

present protocol. The mild reaction conditions, transition metalfree and base-free conditions, good functional-group tolerance, and accessibility of broad range of amides make this protocol applicable for the practical synthesis of desired amides. The optimized conditions were applied for the oxidation of dibenzyl amine 6; selectively mono-oxidation product 7 was isolated in 47% yield (Scheme 2). When 2-(p-tolyl)isoindoline 8 was subjected to the optimized conditions only traces of product 9 formation was observed. Further, to check the decarboxylative amidation of amino acid 10, under the same conditions but at 100 °C, no decarboxylative amidation was observed. These studies indicate that, present conditions are applicable for selective monobenzylic oxidation only, but does not affect dibenzylic, cyclic, or amino acid moieties (Scheme 2). To understand the reaction mechanism, we performed some control experiments using benzylamines and benzyl cyanides. First, we performed the reaction of α-methyl benzyl amine 11 (Scheme 3) under the optimal reaction conditions; we did not observe the formation of amide 2q product. To gain insight into the reaction mechanism under the optimized conditions, the reaction of 4-methylbenzylamine 12 along with TEMPO (3.0 equiv) was performed, and the TEMPO adduct 13 formation was observed by HRMS (see the Supporting Information), which indicates the reaction may proceed by a radical mechanism. Further, to learn the reaction path, 4-methylbenzonitrile 14 and 4-methylbenzaldehyde 15 were subjected under the optimized conditions, no reaction was observed with nitrile, and 52% of amide 2r was observed in the latter case with aqueous ammonia. With 4-methylbenzylimine 16, the desired amide 2r was obtained in 40% yield with the optimized conditions (Scheme 3). It gives an idea that the reaction goes through the imine intermediate. In order to establish the reaction route for the amidation of benzyl cyanide via decyanation, some control experiments were conducted (Scheme 4). The reaction of 13637

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The Journal of Organic Chemistry

4-Methoxy-N-methylbenzamide (2c). Eluent: 40% EtOAc/ hexane. 71% yield (116.0 mg). White solid. Observed mp 96−99 °C. 1 H NMR (500 MHz,CDCl3): δ 7.74 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 6.21 (br, NH, 1H), 3.84 (s, 3H),2.99 (d, J = 4.0 Hz, 3H). 13 CNMR (125 MHz, CDCl3): δ 167.8, 162.0, 132.1, 128.7, 128.6, 126.9, 113.8, 113.7, 55.3, 26.7. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C9H12NO2 166.0868, found 166.0869.

for a range of primary, secondary, and tertiary amide derivatives in good to excellent yields.

■

EXPERIMENTAL SECTION

General Methods. All commercially available chemicals and reagents were used without any further purification unless otherwise indicated. 1 H and 13C NMR spectra were recorded at 500, 600, and 125 MHz and 150 MHz, respectively. The spectra were recorded in CDCl3 as solvent. Multiplicity is indicated as follows: s (singlet); d (doublet); t (triplet); m (multiplet); dd (doublet of doublets), etc., and coupling constants (J) are given in Hz. Chemical shifts are reported in ppm relative to TMS as an internal standard. The peaks around δ values of 1H NMR (7.2) and 13 C NMR (77.0) correspond to deuterated solvent chloroform, respectively. Mass spectra were obtained using an electron-impact (EI) ionization method. Progress of the reactions was monitored by thin-layer chromatography (TLC). All products were purified through column chromatography using silica gel 100−200 mesh size using hexane/ethyl acetate as eluent unless otherwise indicated. General Procedure for the Synthesis of N-Methylbenzamide (2a). To a reaction tube equipped with a magnetic stir bar were added N-methylbenzylamine 1a (121.0 mg, 1.0 mmol), iodine (50.6 mg, 0.2 mmol), and aq TBHP (10.0 mmol) in 2.0 mL of acetonitrile. The mixture was heated in an oil bath at 70 °C for 18 h in a sealed tube. The reaction was monitored by TLC; after completion of the reaction, it was allowed to attain room temperature. The reaction mixture was quenched by saturated Na2SO3 solution, extracted with ethyl acetate (15 mL × 3), and dried with anhydrous K2SO4. Removal of the solvent under reduced pressure left a residue which was purified by column chromatography using silica gel (40% EtOAc/hexane) to afford 2a (111.2 mg; 82% yield). General Procedure for the Synthesis of Benzamide from Benzyl Cyanide (5). A mixture of benzyl cyanide (58.5 mg, 0.5 mmol), 25% aq NH3 (1.5 mL), and 20 mol % of I2 (25.3 mg, 0.1 mmol and aq TBHP (8.0 mmol) in 1.5 mL of acetonitrile was taken in an oven-dried reaction tube. The reaction mixture was stirred at 70 °C for 36 h. This reaction was monitored by TLC. After completion of the reaction, the solvent was removed on a rotary evaporator. The reaction mixture was quenched by saturated Na2SO3 solution and extracted by ethyl acetate. The organic extract was dried over K2SO4, and the final residue was purified by column chromatography using 40% EtOAc in hexane to afford 5a (45.6 mg; 75%yield).

4-tert-Butyl-N-methylbenzamide (2d). Eluent: 30% EtOAc/ hexane. 77% yield (148.0 mg). White solid. Observed mp 101−103 °C. 1 H NMR (500 MHz, CDCl3): δ 7.70 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 7.5 Hz, 2H), 6.18 (br, NH, 1H), 3.01 (d, J = 3.5 Hz,3H), 1.32 (s, 9H). 13 C NMR (125 MHz, CDCl3): δ 168.1, 154.8, 131.7, 130.0, 126.6, 125.4, 34.8, 31.1, 26.7. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C12H17NONa 214.1208, found 214.1204.

4-Fluoro-N-methylbenzamide (2e). Eluent: 35% EtOAc/hexane. 68% yield (104.2 mg). White solid. Observed mp 121−124 °C. 1 H NMR (500 MHz, CDCl3): δ 7.77 (d, J = 5.5 Hz, 2H), 7.09 (t, J = 8.5 Hz, 2H), 6.20 (br, NH, 1H), 3.01 (t, J = 5.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 167.2, 165.6, (d, J = 250.25 Hz) 163.6, 130.8, 129.17, (d, J = 10.2 Hz), 129.10, 115.6, (d, J = 21.62 Hz), 115.5, 26.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C8H9NOF 154.0668, found 154.0662.

4-Chloro-N-methylbenzamide (2f). Eluent: 35% EtOAc/hexane. 62% yield (105.1 mg). White solid. Observed mp 171−174 °C. 1H NMR (600 MHz,CDCl3): δ 7.70 (d, J = 6.5 Hz, 2H), 7.40 (d, J = 7.5 Hz, 2H), 6.27 (br, NH, 1H), 3.00 (d, J = 3.5 Hz, 3H). 13CNMR (150 MHz, CDCl3): δ 167.2, 137.6, 132.0, 128.8, 128.3, 26.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C8H9NOCl 170.0373, found 170.0368.

N-Methylbenzamide (2a).8 Eluent: 30% EtOAc/hexane. 82% yield (111.2 mg). White solid. 1H NMR (500 MHz, CDCl3): δ 7.77 (d, J = 7.0 Hz, 2H), 7.48 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.0 Hz, 2H), 6.36 (br, NH, 1H), 3.00 (d, (t, J = 5.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 168.2, 134.6, 131.3, 128.5, 126.8, 26.8.

4-Bromo-N-methylbenzamide (2g). Eluent: 35% EtOAc/hexane. 52% yield (111.4 mg). White solid. Observed mp 170−172 °C. 1H NMR (600 MHz, CDCl3): δ 7.61 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 6.23 (br, NH, 1H), 2.98 (d, J = 4.9 Hz, 3H). 13CNMR (151 MHz, CDCl3): δ 167.3, 133.5, 131.8, 128.5, 126.1, 26.9. HRMS (ESITOF) m/z: [M + Na]+ calcd for C8H8NONaBr 235.9687, found 235.9689.

N,4-Dimethylbenzamide (2b). Eluent: 35% EtOAc/hexane. 51% yield (89 mg). White solid. 1H NMR (500 MHz, CDCl3): δ 7.66 (d, J = 7.5 Hz, 2H), 7.22 (d, J = 7.5 Hz, 2H), 6.17 (br, NH, 1H), 3.17 (d, J = 3.5 Hz, 3H), 2.38 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 168.1, 141.7, 131.7, 130.1, 129.2, 127.4, 126.8, 26.8, 21.4. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C9H12NO 150.0919, found 150.0916.

N-Methyl-3-nitrobenzamide (2h). Eluent: 30% EtOAc/hexane. 68% yield (123 mg). Observed mp 162−166 °C. 1H NMR (500 MHz, CDCl3): δ 8.58 (s, 1H), 8.37−8.35 (m, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 6.34 (br, NH, 1H), 3.07 (d, J = 5.0 Hz, 3H). 13638

DOI: 10.1021/acs.joc.7b02211 J. Org. Chem. 2017, 82, 13632−13642

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The Journal of Organic Chemistry C NMR (125 MHz, CDCl3): δ 164.3, 148.1, 136.1, 133.1, 129.8, 126.0, 121.6, 27.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C8H9N2O3 181.0613, found 181.0611.

(125 MHz, CDCl3): δ 167.5, 134.7, 133.4, 131.3, 130.1, 128.5, 128.4, 126.8, 34.9, 14.8.

13

N-Phenylbenzamide (2p).12b Eluent: 20% EtOAc/hexane. 48% yield (94.6 mg). 1H NMR (600 MHz, CDCl3): δ 7.90 (s, 1H), 7.85 (d, J = 6.7 Hz, 2H), 7.63 (d, J = 7.1 Hz, 2H), 7.53 (s, 1H), 7.47 (d, J = 6.2 Hz, 2H), 7.36 (s, 2H), 7.14 (s, 1H). 13C NMR (150 MHz, CDCl3): δ 165.8, 138.0, 131.9, 129.1, 128.8, 127.1, 124.6, 120.3.

4-Cyano-N-methylbenzamide (2i). Eluent: 30% EtOAc/hexane. 55% yield (87.4 mg). Observed mp 203−205 °C. 1H NMR (500 MHz, CDCl3): δ 7.87 (d, J = 7.5 Hz, 2H), 7.74 (d, J = 7.5 Hz, 2H), 6.23 (br, NH, 1H), 3.04 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 166.3, 138.5, 132.4, 127.5, 117.9, 115.0, 27.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C9H9N2O 161.0715, found161.0723.

Benzamide (2q).15d Eluent: 40% EtOAc/hexane. 58% yield (70.5 mg). White solid. 1H NMR (500 MHz, CDCl3): δ 7.82 (t, J = 7.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 6.12 (br, NH, 2H). 13C NMR (125 MHz, CDCl3) δ 169.5, 133.3, 132.0, 128.6, 127.3. N-Methyl-(1,1′-biphenyl)-4-carboxamide (2j). Eluent: 35% EtOAc/hexane. 57% yield (121.2 mg). White solid. Observed mp 167−168 °C. 1H NMR (600 MHz,CDCl3): δ 7.84 (d, J = 6.5 Hz, 2H), 7.65 (q, J = 7.0 Hz, 4H), 7.47 (t, J = 6.5 Hz, 2H), 7.39 (t, J = 5.0 Hz, 1H), 6.31 (br, NH, 1H), 3.04 (d, J = 4.0 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ 168.0, 144.2, 140.0, 133.3, 128.9, 128.0, 127.4, 127.2, 127.2, 26.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H14NO 212.1075, found 212.1069.

4-Methylbenzamide (2r).15d Eluent: 35% EtOAc/hexane. 54% yield (73.3 mg). White solid. 1H NMR (500 MHz, CDCl3): δ 7.72 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.06 (br, NH, 2H), 2.40 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 169.4, 142.5, 130.4, 129.2, 129.0, 127.3, 21.4.

3-Fluoro-N-methylbenzamide (2k). Eluent: 30% EtOAc/hexane. 65% yield (98.9 mg). White solid. 1H NMR (600 MHz, CDCl3): δ 7.52 (q, J = 8.0 Hz, 2H), 7.37 (q, J = 10.0, 7.8 Hz, 1H), 7.20−7.15 (m, 1H), 6.65 (br, NH, 1H), 2.99 (d, J = 4.6 Hz, 3H). 13C NMR (150 MHz, CDCl3): δ 167.1, 163.6, 161.96 (d, J = 246 Hz), 136.93 (d, J = 7.5 Hz), 136.88, 130.27 (J = 7.5 Hz), 130.22 122.4, 118.46 (J = 21.0 Hz), 118.32, 114.4, 26.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C8H9NOF 154.0668, found 154.0665.

3-Methylbenzamide (2s).15d Eluent: 30% EtOAc/hexane. 88% yield (119 mg). White solid. 1H NMR (600 MHz, CDCl3): δ 7.54 (s, 1H), 7.49 (d, J = 5.5 Hz, 1H), 7.23 (d, J = 5.5 Hz, 2H), 6.19 (br, NH, 2H), 2.29 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.1, 138.5, 132.8, 128.5, 128.1, 124.3, 21.4.

3-Methoxybenzamide (2t).15e Eluent: 40% EtOAc/hexane. 55% yield (82.4 mg). White solid. 1H NMR (500 MHz, CDCl3): δ 7.40 (m, 1H), 7.34 (m, 2H), 6.10 (br, NH, 2H), 3.85 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 169.1, 159.9, 134.8, 129.7, 119.2, 118.4, 112.6, 55.5.

N-Methyl-1-naphthamide (2l). Eluent: 30% EtOAc/hexane. 44% yield (81.2 mg). White solid. Observed mp 152−154 °C. 1H NMR (600 MHz, CDCl3): δ 8.26 (d, J = 6.5 Hz, 1H), 7.87 (q, J = 7.0 Hz, 2H), 7.51 (m, 3H), 7.39 (t, J = 6.0 Hz, 1H), 6.25 (br, NH, 1H), 3.01 (s, 3H).13C NMR (150 MHz, CDCl3): δ 170.4, 130.5, 128.3, 127.0,126.4, 125.5, 124.9, 124.7, 26.8. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H12NO 186.0919 found 186.0926.

4-Chlorobenzamide (2u).15e Eluent: 40% EtOAc/hexane. 60% yield (93.7 mg). White solid. 1H NMR (500 MHz, CDCl3): δ 7.75 (d, J = 7.5 Hz, 2H), 7.43 (d, J = 7.0 Hz, 2H), 6.08 (br, NH, 2H). 13C NMR (125 MHz, CDCl3): δ 168.3, 138.4, 131.7, 128.9, 128.8.

N-Ethylbenzamide (2n).15b Eluent: 30% EtOAc/hexane. 63% yield (94.5 mg). White solid. 1H NMR (500 MHz, CDCl3): δ 7.77 (d, J = 7.0 Hz, 2H), 7.48 (m, 1H), 7.43 (q, J = 7.0 Hz, 2H), 6.22 (br, NH, 1H), 3.50 (pent, J = 7.0 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H). 13C NMR

4-Fluorobenzamide (2v).15d Eluent: 40% EtOAc/hexane. 55% yield (76.7 mg). White solid. 1H NMR (500 MHz, CDCl3): δ 7.84 13639

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3-Methoxylbenzamide (5d).15e Eluent: 40% EtOAc/hexane. 63% yield (47.3 mg). White solid. 1H NMR (600 MHz, CDCl3): δ 7.40 (m, 1H), 7.36−7.32 (m, 2H), 7.07 (m, 1H), 6.16 (br, NH, 2H), 3.85 (s, 3H). 13 C NMR (150 MHz, CDCl3): δ 169.4, 159.9, 134.8, 129.7, 119.2, 118.3, 112.6, 55.5.

(m, 2H), 7.12 (t, J = 7.0 Hz, 2H), 6.74 (br, NH, 2H). 13C NMR (125 MHz, CDCl3): δ 168.7, 166.1 (d, J = 251.2 Hz), 164.0, 132.5, 129.82, (d, J = 8.8 Hz), 129.75, 115.82 (d, J = 21.87 Hz), 115.65.

Nicotinamide (2w).15e Eluent: 1:1 EtOAc/hexane. 40% yield (48.8 mg). White solid. 1H NMR (600 MHz, CDCl3): δ 9.04 (s, 1H), 8.75 (d, J = 3.5 Hz, 1H), 8.18 (d, J = 5.5 Hz, 1H), 7.43 (q, J = 4.0 Hz, 1H),6.45 (br, NH, 2H). 13C NMR (150 MHz, CDCl3): δ 167.6, 152.7, 148.3, 130.6, 129.2, 123.6.

4-tert-Butylbenzamide (5e).15d Eluent: 30% EtOAc/hexane. 52% yield (45.6 mg). White solid. 1H NMR (600 MHz, CDCl3): δ 7.73 (d, J = 7.0 Hz, 2H), 7.43 (d, J = 7.0 Hz, 2H), 6.15 (br, NH, 2H), 1.30 (s, 9H). 13 C NMR (150 MHz, CDCl3): δ 169.7, 155.6, 130.5, 127.3, 125.6, 35.0, 31.2.

Furan-2-carboxamide (2x).15e Eluent: 40% EtOAc/hexane. 36% yield (17.6 mg). White solid. 1H NMR (600 MHz, CDCl3): δ 7.39 (s, 1H), 7.09 (d, J = 3.5 Hz, 1H), 6.48−6.41 (m, 1H), 6.32−5.88 (m, 2H). 13C NMR (150 MHz, CDCl3): δ 160.3, 147.4, 144.5, 115.3, 112.40.

3, 4-Dimethoxybenzamide (5f).15f Eluent: 40% EtOAc/hexane. 53% yield (47.6 mg). White solid. 1H NMR (600 MHz, CDCl3): δ 7.42 (d, J = 1.5 Hz, 1H), 7.31 (dd, J = 8.1, 2.0 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.07 (s, 2H), 3.89 (s, 6H). 13C NMR (151 MHz, CDCl3): δ 169.2, 152.2, 149.0, 126.0, 120.2, 110.8, 110.3, 56.1.

Thiophene-2-carboxamide (2y).15e Eluent: 40% EtOAc/hexane. 30% yield (18.9 mg). White solid. 1H NMR (600 MHz, CDCl3): δ 7.51 (dd, J = 7.9, 4.4 Hz, 2H), 7.12−7.04 (m, 1H), 5.84 (s, 2H). 13 C NMR (150 MHz, CDCl3): δ 163.8, 137.8, 131.0, 129.3, 127.8. 4-Bromobenzamide (5g).15d Eluent: 40% EtOAc/hexane. 79% yield (79.2 mg). White solid. 1H NMR (500 MHz, CDCl3): δ 7.69 (d, J = 7.5 Hz, 2H), 7.60 (d, J = 7.0 Hz, 2H), 6.51 (br, NH, 2H). 13C NMR (125 MHz, CDCl3): δ 169.2, 132.0, 129.0, 127.0.

Benzamide (5a).15d Eluent: 40% EtOAc/hexane. 75% yield (45.6 mg). White solid. 1H NMR (500 MHz, CDCl3): δ 7.82 (t, J = 7.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 6.12 (br, NH, 2H). 13C NMR (125 MHz, CDCl3): δ 169.5, 133.3, 132.0, 128.6, 127.3.

4-Chlorobenzamide (5h).15d Eluent: 40% EtOAc/hexane. 72% yield (55.6 mg). White solid. 1H NMR (500 MHz, CDCl3): δ 7.75 (d, J = 7.5 Hz, 2H), 7.43 (d, J = 7.0 Hz, 2H), 6.08 (br, NH, 2H). 13 C NMR (125 MHz,CDCl3): δ 168.3, 138.4, 131.7, 128.9, 128.8.

2-Methylbenzamide (5b).15d Eluent: 40% EtOAc/hexane. 70% yield (47.3 mg). White solid. 1H NMR (500 MHz, CDCl3):δ 7.46 (d, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.23 (pent, J = 8.5 Hz, 2H), 5.94 (br, NH,2H), 2.50 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 172.0, 136.3, 135.1, 131.2, 130.3, 126.9,125.7, 19.9.

4-Fluorobenzamide (5i).15d Eluent: 40% EtOAc/hexane. 56% yield (38.9 mg). White solid. 1H NMR (500 MHz, CDCl3): δ 7.84 (q, J = 5.5 Hz, 2H), 7.13 (t, J = 8.5 Hz, 2H), 6.22 (br, NH, 2H). 13CNMR (125 MHz, CDCl3): δ 168.7, 166.1, (d, J = 251.2 Hz), 164.0, 132.5, 129.82, (d, J = 8.8 Hz), 129.75, 115.82 (d, J = 21.87 Hz), 115.65.

3-Methylbenzamide (5c).15d Eluent: 40% EtOAc/hexane. 66% yield (44.8 mg). White solid. 1H NMR (600 MHz, CDCl3): δ 7.54 (s, 1H), 7.49 (d, J = 5.5 Hz, 1H), 7.23 (d, J = 5.5 Hz, 2H), 6.19 (br, NH, 2H), 2.29 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.1, 138.5, 132.8, 128.5, 128.1, 124.3, 21.4.

4-Nitrobenzamide (5j).15d Eluent: 40% EtOAc/hexane. 84% yield (69.5 mg). White solid. 1H NMR (500 MHz, CDCl3): δ 8.32 (d, J = 7.5 Hz, 2H), 7.99 (d, J = 6.5 Hz, 2H), 6.14 (br, NH, 2H). 13C NMR (125 MHz,CDCl3): δ 165.1, 150.1, 128.6, 123.9. 13640

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The Journal of Organic Chemistry

Nicotinamide (5k).15e Eluent: 1:1 EtOAc/hexane. 49% yield (29.8 mg). White solid. 1H NMR (600 MHz, CDCl3): δ 9.04 (s, 1H), 8.75 (d, J = 3.5 Hz, 1H), 8.18 (d, J = 5.5 Hz, 1H), 7.43 (q, J = 4.0 Hz, 1H), 6.45 (br, NH, 2H). 13C NMR (150 MHz, CDCl3): δ 167.6, 152.7, 148.3, 130.6, 129.2, 123.6.

(4-Chlorophenyl)(morpholino)methanone (5q).12b Eluent: 30% EtOAc/hexane. 43% yield (48.3 mg). White solid. Observed mp 72−75 °C. 1H NMR (500 MHz, CDCl3): δ 7.40−7.35 (m, 4H), 3.75− 3.65 (m, 3H), 3.44 (s, 2H), 1.30 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 168.3, 134.9, 132.5, 127.8, 127.6, 65.7, 47.2, 41.5.

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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.7b02211. Effective solvents for the reaction, 1H and 13C NMR spectra for all compounds, and HRMS spectra for new products (PDF)

Picolinamide (5l).15e Eluent: 1:1 EtOAc/hexane. 33% yield (20.4 mg). White solid. 1H NMR (500 MHz, CDCl3) δ 8.59 (d, J = 4.5 Hz, 1H), 8.22 (t, J = 8.0 Hz, 1H), 7.86 (m, 2H), 5.87 (br, NH, 2H). 13 C NMR (125 MHz, CDCl3): δ 166.8, 149.5, 148.3, 137.3, 126.4, 122.4, 133.4, 131.3, 130.1, 128.5,128.4, 126.8, 34.9, 14.8.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Subbarayappa Adimurthy: 0000-0001-5320-4961

N-Benzylbenzamide (5m). Eluent: 30% EtOAc/hexane. 54% yield (57.4 mg). 1H NMR (500 MHz, CDCl3): δ 7.79 (s, 2H), 7.48−7.28 (m, 8H), 6.67 (br, NH, 1H), 4.61 (s, 2H). 13C NMR (125 MHz, CDCl3): δ 166.9, 137.7, 133.8, 131.0, 128.2, 128.0, 127.3, 127.0, 126.5, 43.5. 12b

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS CSIR-CSMCRI Communication No. 115/2017. S.N.R., N.N.K.R., and S.S. are thankful to AcSIR for their Ph.D. enrollment and the “Analytical Discipline and Centralized Instrumental Facilities” for providing instrumentation facilities. S.N.R. and S.S. are thankful to CSIR, New Delhi, for their fellowships. We thank DST, Government of India (EMR/2016/ 000010), and CSIR-CSMCRI (OLP-087 and OLP-088) for financial support.

N-(4-Bromophenethyl)benzamide (5n).12b Eluent: 30% EtOAc/ hexane. 54% yield (81.5 mg). Observed mp 151−153 °C. 1H NMR (500 MHz, CDCl3): δ 7.70 (d, 2H), 7.50 (m, 1H), 7.44−7.39 (m, 4H), 7.11 (d, 2H), 6.27 (br, NH, 1H), 3.69 (m, 2H), 2.90 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 166.5, 136.8, 133.4, 130.7, 129.5, 127.5, 125.7, 119.4, 39.9, 34.1.

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REFERENCES

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N-(4-Chlorobenzyl)benzamide (5o).12b Eluent: 20% EtOAc/ hexane. 50% yield (61.8 mg). White solid. Observed mp 141−143 °C. 1 H NMR (600 MHz, CDCl3): δ 7.79 (d, J = 7.5 Hz, 2H), 7.50 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.31−7.26 (m, 4H), 6.52 (br, NH, 1H), 4.60 (d, J = 5.5 Hz, 2H). 13C NMR (150 MHz, CDCl3): δ 166.9, 136.2, 133.6, 132.9, 131.2, 128.7, 128.3, 128.1, 126.4, 42.8.

4-Nitro-N-phenethylbenzamide (5p).15g Eluent: 20% EtOAc/ hexane). 60% yield (81.6 mg). White solid. 1H NMR (600 MHz, CDCl3): δ 8.17 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.26 (t, J = 7.4 Hz, 2H), 7.20−7.15 (m,3H), 6.25 (s, 1H), 3.67 (dd, J = 12.9, 6.6 Hz, 2H), 2.88 (t, J = 6.9 Hz, 2H). 13C NMR (151 MHz, CDCl3): δ 165.5, 149.6, 140.2, 138.5, 128.9, 128.8, 128.1, 126.8, 123.8, 41.4, 35.5. 13641

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