English

• 1.   Introduction

  Amides are one of the most versatile and significant motifs in biologically natural products and synthetic drugs.^[1] Therefore, the assembly of amides from the nature-abundant and low-cost starting materials has been an important objective in organic chemistry.^[2] A number of synthetic strategies have been developed for their synthesis during the past decades.^[3] Owing to the abundant and readily available carboxylic acids with ubiquitous functional groups, the construction of amides through dehydrative condensation reactions of carboxylic acids with amines has been dominantly employed in recent years (Scheme 1a).^{[2a~2c, 4]} However, most current amide coupling reactions are still carried out in the presence of superstoichiometric amounts of expensive and often dangerous coupling reagents to facilitate the reaction, which leads to not only high-cost but also environmental issues.

  Scheme 1

  

  Scheme 1.  Synthesis of sterically hindered amides

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  Among the multifarious amides, sterically-hindered and electron-deficient amides are of particular interest, given diverse biological activities of these compounds.^[5] However, to the best of our knowledge, only few examples of synthesizing sterically-hindered and electron-deficient amides have been reported. Bode et al.^[6] first treated carboxylic acids with Grignard reagents to form sterically-hindered and electron-deficient secondary amides (Scheme 1b). However, the applicability and efficiency of this process is compromised by the use of air- and moisture sensitive Grignard reagent, which has limited commercial availability for alkyl- or aryl-variants as well as high cost. Zhang and coworkers^[7] have pioneered the copper(I) catalyzed amidation reaction of organoboronic esters with isocyanates, but only arylamides were formed. Moreover, the difficult preparation step of the noncommercially available organoboronate ester, high temperature, long reaction time and inevitable residual metal in the final products have imposed limitations on the applicability of this method. Maes and coworkers^[8] reported the Fe(acac)₃-catalyzed amidation of carboxylic acids by using N-tert-butyl-S- methyl-N'-arylisothiourea as amino sources (Scheme 1d). However, the efficiency and atom economy of this protocol is compromised by the required pre-synthesis of N-tert-butyl-S-methyl-N'-arylisothiourea from moisture- sensitive reagents and unstable starting materials (tert- butyl isocyanide and S-phenyl benzenethiosulfonate)^[9] that require tedious synthetic operations. In addition, the difficulties to remove the trace transition-metal contamination from the final products, particularly for the late-stage modification of medicine restrict their applications. It is therefore highly desired to develop an efficient and practical metal-free methodology that can achieve sterically-hin- dered and electron-deficient secondary amides using abundant and readily available materials under mild reaction conditions.^[10]

  In 2013, Yu and Houghten^[11] first reported a traceless strategy for the synthesis of amides through coupling of thioacids and dithiocarbamates, the later of which served as the activated amino source. Although this modified process is found to be an improvement over previous methods, the inaccessible raw materials have prompted our to develop a straightforward approach for amides synthesis. Given that the isothiocyanate backbone is analogous to dithiocarbamate, we envisioned that the cheap and commercially available isothiocyanates could be used instead of dithiocarbamates. In light of the unique pharmacological activities of sterically-hindered and electron-deficient amides, and also in continuation of our efforts in mild organic synthesis, ^[12] herein, we report a metal-free, base-mediated amidation of carboxylic acids and isothiocyanates at ambient temperature (Scheme 1f). This approach offers a valuable alternative compared to the above-mentioned methods: (a) abundant and readily available raw materials are employed instead of air- and moisture sensitive Grignard reagents, expensive organoboronate esters and inaccessible N-tert-butyl-S-methyl-N'-arylisothiourea; (b) a broad range of amides, which include sterically-encumbered and electron-deficient secondary amides were formed under mild reaction reactions.

  2.   Results and discussion

  Our preliminary investigation focused on the reaction between benzoic acid 1a and phenyl isothiocyanate 2a with Et₃N as the promoter in N, N-dimethylformamide (DMF) at room temperature, which resulted in 11% yield of N-phenylbenzamide 3aa based on 13% conversion of the 2a (Table 1, Entry 1). Fortunately, the first breakthrough was achieved when we replaced Et₃N with 1, 8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base (Entry 2). Next, various bases were examined (Entries 3~6, 8), and 1, 5-diazabicyclo[4.3.0]non-5-ene (DBN) was found to be the most efficient base for this reaction (Entry 3). The investigation on the optimal amount of DBN (Entries 7, 9~8, 11) indicated that 2 equiv. DBN (Entries 7, 9) was an appropriate amount. The amidation did not take place without a base (Entries 9, 12). Further screening of the solvents showed that DMF was the best choice among those tested solvents (Entries 7, 9 vs 10, 13~16, 18). No improvement in the transformation was observed when ultrasonic radiation or microwave radiation was used instead of conventional heating (Entires 19, 20).

  Table 1

  

  Table 1.  Screening the optimized reaction conditions^a

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  Entry	Catalyst (equiv.)	Solvent	Yieldb/%
  1	Et3N (1.5)	DMF	11
  2	DBU (1.5)	DMF	68
  3	DBN (1.5)	DMF	90
  4	i-Pr2NEt (1.5)	DMF	Trace
  5	Na2CO3 (1.5)	DMF	6
  6	Cs2CO3 (1.5)	DMF	9
  7	KF-Celite (1.5)	DMF	Trace
  8c	Amberlite IRA-4200 (10 wt%)	DMF	N.R.
  9	DBN (2)	DMF	97
  10	DBN (1.2)	DMF	78
  11	DBN (0.2)	DMF	12
  12	—	DMF	N.R.
  13	DBN (2)	DCM	8
  14	DBN (2)	THF	15
  15	DBN (2)	MeCN	72
  16	DBN (2)	Toluene	Trace
  17	DBN (2)	DMSO	Trace
  18	DBN (2)	MeOH	Trace
  19d	DBN (2)	DMF	91
  20e	DBN (2)	DMF	94
  a Unless otherwise specified, the reactions were carried out in a vial in the presence of 1a (0.15 mmol), 2a (0.1 mmol), base, solvent (1 mL). b Estimated by 1H NMR spectroscopy using diethyl phthalate as an internal reference. c The quantity of Amberlite IRA-4200 was 0.1 g. d The reaction was conducted under 40 kHz/30 W ultrasonic radiation for 1 h. e The reaction was conducted under 150 W microwave radiation of 20 min. N.R.: no reaction.

  With the optimal system in hand, we examined the scope of carboxylic acid substrates with phenyl isothiocyanate 2a as illustrated in Table 2. To our delight, the current reaction system was suitable for a wide range of aliphatic carboxylic acids (3ba~3pa). Carboxylic acids with various chain lengths and isomeric structures did not significantly affect the product yields. High functional group compatibility was exhibited, such as tolerating alkyl (3ba~3ea), chlorine (3fa), acetyl (3ga), alkynyl (3ha), trifluoromethyl (3ia) and alkenyl (3ja) moieties. Remarkably, the steric effect of the substituted formic acids did not affect the yield of the reaction. For instance, carboxylic acids bearing bulky groups, such as iso-propyl-(3ka), tert-butyl (3la), cyclopropyl (3ma), 1-phenylcyclopropyl (3na), cyclohexyl (3oa) and 1-adamantyl (3pa), could be successfully transformed to the corresponding products in excellent yields. No matter whether the benzene ring of aryl carboxylic acid is substituted with either sterically hindered, electron-donating or electron-withdrawing group, all of them delivered the desired products in good to excellent yields (3aa, 3qa~3va). Polycyclic and heteroaromatic substituted carboxylic acids could also be transformed into the corresponding products in good to excellent yields (3wa~3ya). Interestingly, the reaction of the ferrocenecarboxylic acid gave the corresponding amide in good yield (3za), which highlighted the mild conditions of this reaction and potential applications of it in organocmetallic synthesis.

  Table 2

  

  Table 2.  Reaction scope of carboxylic acids^a

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  a All reactions were carried out in a vail in the presence of 1 (0.45 mmol), 2 (0.3 mmol), DBN (0.6 mmol) and DMF (3 mL); isolated yields are reported.

  We next turned our attention to the scope of isothiocyanate substrates (Table 3). The amidation reaction was compatible with various sensitive functional groups, such as F-, Cl-, Br-, CF₃-, CN- and NO₂-substituted isothiocyanates. For instance, electron-donating groups, such as Me-, tert-Bu-, and MeO-promoted this transformation smoothly, yielding the desired amide products 3cb~3cd in excellent yields. Phenyl isothiocyanates with halogen groups (F, Cl, Br and I) are also suitable reaction partners (3ce~3ch). Less-reactive electron-withdrawing groups, such as CF₃-, CN- and NO₂-substituted isothiocyanates 1i~1k also successfully participated in the current reaction. Switching to meta-substituted phenyl isothiocyanates from para-substi- tuted substrates did not affect the outcome of the reaction (3cl~3cm), and sterically demanding ortho-substituted phenyl isothiocyanate also produced the expected product in moderate yields (3cn). 3, 5-Disubstituted phenyl isothiocyanate containing strong electron- withdrawing functionalities was also sucessfully applied to the reaction (3co). However, heteroaromatic and aliphatic isothiocyanates were ineffective, and only a trace amount of the desired products were detected.

  Table 3

  

  Table 3.  Reaction scope of isothiocyanates^a

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  a All reactions were carried out in a vail in the presence of 1 (0.45 mmol), 2 (0.3 mmol), DBN (0.6 mmol) and DMF (3 mL); isolated yields are reported.

  Amides are not only valuable building blocks in synthetic chemistry but also important structure motifs in numerous biologically and pharmacologically active compounds. Moreover, late-stage structural modification is a highly valuable strategy for drug research and development. Therefore, several complex natural product derivatives were submitted to the standard reaction conditions (Table 4). Biologically active carboxylic acid derivatives, such as dehydroabietic acid, mycophenolic acid, norbornene acid and isoxepac, worked well in the current transformation, generating the corresponding amides in excellent yields (4ca~4cd).

  Table 4

  

  Table 4.  Reaction scope of late-stage modification^a

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  a All reactions were carried out in a vail in the presence of 1 (0.45 mmol), 2 (0.3 mmol), DBN (0.6 mmol) and DMF (3 mL); isolated yields are reported.

  For the small-scale reaction, 1.5 equiv. of benzoic acid 1a were required, and the decrease in 1a loading would reduce the yield. Delightedly, the use of 1.3 equiv. of 1a could afford the desired product in 91% yield (1.07 g) with increase of the scale of the reaction by 20-fold (Eq. 1), demonstrating the synthetic utility of this protocol from a practical point of view.

  (2)

  The amidation reaction may follow a similar mechanism to that of the reaction of thioacids and dithiocarbamateas reported by Yu and Houghten, with the major difference being isothiocyanates as the amino source instead of dithiocarbamate and carboxylic acids instead of thioacid.^[11] First, the abstraction of proton from carboxylic acid by DBN generates the carboxylate anion, which attacks the sp-carbon of isothiocyanate 2 to yield the intermediate A. The intermediate A then proceeds via an intramolecular rearrangement reaction to afford product 3 (Scheme 2).

  Scheme 2

  

  Scheme 2.  Proposed mechanism

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  3.   Conclusions

  In summary, we have presented a simple and direct C(O)—N coupling method for the efficient preparation of amides starting with readily available unactivated carboxylic acid and isothiocyanates using common and cheap DBN as a mild base. Reactions occur readily at ambient temperature with good functional-group tolerance and can be easily scaled-up. Importantly, these transformations occur without the help of any transition metal, and a wide array of amides can be readily obtained in good to excellent yields. This protocol provides an alternative route to access sterically hindered and electron-deficient secondary amides which are difficult to synthesize through a conventional carboxyl-amine coupling reaction. This new method would be of significant use in the amide preparation for pharmaceuticals, natural products, and functional materials.

  4.   Experimental section

  4.2   General procedure for the synthesis of 3

  In a vial was placed carboxylic acids 1 (0.45 mmol), DMF (3 mL), DBN (0.6 mmol, 74 mg) and isothiocyanate 2 (0.3 mmol), then the contents were stirred at room temperature. After completion of the reaction (monitored by TLC), the reaction was quenched with water (5 mL), extracted with CH₂Cl₂ (5 mL×3), and the organic extracts were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexanes/ethyl acetate) to afford 3.

  4.3   Large scale synthesis of N-phenylbenzamide 3aa

  Method A (purify by column chromatography): In a round-bottom flask was placed benzoic acid 1a (7.8 mol, 0.73 g), DMF (60 mL), DBN (12 mmol, 1.49 g) and phenyl isothiocyanate (2a) (6 mmol, 0.81 g), then the contents were stirred at room temperature. After completion of the reaction (monitored by TLC), the reaction was quenched with water (5mL), extracted with CH₂Cl₂ (30 mL×3), and the organic extracts were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate) to afford 1.07 g of 3aa in 91% yield.

  Method B (purify by recrystallization): In a round-bot- tom flask was placed benzoic acid (1a) (7.8 mol, 0.73 g), DMF (60 mL), DBN (12 mmol, 1.49 g) and phenyl isothiocyanate (2a) (6 mmol, 0.81 g), then the contents were stirred at room temperature. After completion of the reaction (monitored by TLC), the reaction was quenched with water (5ml), extracted with CH₂Cl₂ (30 mL×3), and the organic extracts were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by recrystallization with a mixed solvent of ethyl acetate/petrol ether (30 mL, V:V＝1:8) to give 0.99 g of 3aa in 84% yield.

  N-Phenylbenzamide (3aa):^[131] H NMR (400 MHz, DMSO-d₆) δ: 10.27 (s, 1H), 7.96~7.94 (m, 2H), 7.78 (d, J＝8.4 Hz, 2H), 7.60~7.51 (m, 3H), 7.35 (t, J＝8.4 Hz, 2H), 7.10 (t, J＝7.2 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.1, 139.7, 135.5, 132.1, 129.2, 128.9, 128.2, 124.2, 120.9.

  N-Phenylacetamide (3ba):^[14]1H NMR (400 MHz, DMSO-d₆) δ: 9.93 (s, 1H), 7.57 (d, J＝7.6 Hz, 2H), 7.28 (t, J＝7.6 Hz, 2H), 7.01 (t, J＝7.6 Hz, 1H), 2.04 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.4, 139.5, 128.8, 123.1, 119.1, 24.1.

  N-Phenylpropionamide (3ca):^[15]1H NMR (400 MHz, DMSO-d₆) δ: 9.86 (s, 1H), 7.59 (d, J＝8.4 Hz, 2H), 7.28 (t, J＝7.6 Hz, 2H), 7.01(t, J＝6.8 Hz, 1H), 2.34~2.81 (m, 2H), 1.07 (t, J＝7.6 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 172.5, 139.9, 129.2, 123.4, 119.5, 30.0, 10.2.

  N-Phenyloctanamide (3da):^[16]1H NMR (400 MHz, DMSO-d₆) δ: 9.86 (s, 1H), 7.59 (d, J＝7.6 Hz, 2H), 7.27 (t, J＝7.2 Hz, 2H), 7.00 (t, J＝7.2 Hz, 1H), 2.82 (t, J＝7.2 Hz, 2H), 1, 57 (s, 2H), 1.26 (d, J＝9.6 Hz, 8H), 0.87~0.84 (m, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.8, 139.9, 129.1, 123.4, 119.5, 36.9, 31.7, 29.1, 29.0, 25.7, 22.6, 14.5.

  N, 3-Diphenylpropanamide (3ea):^[17]1H NMR (400 MHz, DMSO-d₆) δ: 9.93 (s, 1H), 7.60~7.58 (m, 2H), 7.30~7.26 (m, 6H), 7.20~7.16 (m, 1H), 7.02 (t, J＝7.6 Hz, 1H), 2.91 (d, J＝8.0 Hz, 2H), 2.65~2.61 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.9, 141.7, 139.8, 129.1, 128.9, 128.8, 126.5, 123.5, 119.6, 38.5, 31.4.

  5-Chloro-N-phenylpentanamide (3fa): ¹H NMR (400 MHz, DMSO-d₆) δ: 9.90 (s, 1H), 7.58 (d, J＝7.6 Hz, 2H), 7.28 (t, J＝7.6 Hz, 2H), 7.02 (t, J＝7.6 Hz, 1H), 3.66 (t, J＝6.4 Hz, 2H), 2.34 (t, J＝7.2 Hz, 2H), 1.78~1.68 (m, 4 H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.0, 139.4, 128.8, 123.1, 119.1, 45.2, 35.5, 31.7, 22.6; IR (KBr) ν: 3302, 2946, 1684, 1600, 1500, 1442, 754 cm^－1; HRMS (ESI) calcd for C₁₁H₁₅ClNO [M+H]⁺ 212.0837, found 212.0833.

  6-oxo-N-Phenylheptanamide (3ga): ¹H NMR (400 MHz, DMSO-d₆) δ: 9.94 (s, 1H), 7.64 (d, J＝7.8 Hz, 2H), 7.34 (t, J＝7.8 Hz, 2H), 7.07 (t, J＝7.8 Hz, 1H), 2.52 (t, J＝7.8 Hz, 2H), 2.35 (t, J＝7.2 Hz, 2H), 2.13 (s, 3H), 1.64~1.50 (m, 4 H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 208.9, 171.6, 139.8, 129.2, 123.5, 119.5, 43.0, 36.8, 30.2, 25.2, 23.4; IR (KBr) ν: 3307, 2942, 1682, 1598, 1500, 1441, 755 cm^－1; HRMS (ESI) calcd for C₁₃H₁₈NO₂ [M+H]⁺ 220.1332, found 220.1329.

  N-Phenylhept-6-ynamide (3ha): ¹H NMR (400 MHz, DMSO-d₆) δ: 9.89 (s, 1H), 7.59 (d, J＝8.8 Hz, 2H), 7.28 (t, J＝8.4 Hz, 2H), 7.01 (t, J＝6.4 Hz, 1H), 2.76 (t, J＝2.8 Hz, 1H), 2.31 ((t, J＝7.6 Hz, 2H), 2.21~2.17 (m, 2H), 1.71~1.64 (m, 2H), 1.52~1.44 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ: 171.6, 139.8, 129.2, 123.5, 119.6, 84.9, 71.8, 36.3, 28.1, 24.8, 18.0; IR (KBr) ν: 3310, 2114, 1662, 1600, 1496, 1441, 754 cm^－1; HRMS (ESI) calcd for C₁₃H₁₆NO [M+H]⁺ 202.1226, found 202.1230.

  4, 4, 4-Trifluoro-N-phenylbutanamide (3ia): ¹H NMR (400 MHz, DMSO-d₆) δ: 10.09 (s, 1H), 7.58 (d, J＝8.0 Hz, 2H), 7.30 (t, J＝7.6 Hz, 2H), 7.04 (t, J＝7.6 Hz, 1H), 2.63~2.55 (m, 4 H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.9, 139.6, 129.3, 128.1 (q, J＝274.8 Hz), 123.8, 119.6, 29.2 (q, J＝2.9 Hz), 29.0 (q, J＝28.4 Hz); ¹⁹F NMR (376 MHz, DMSO-d₆) δ: －65.2; IR (KBr) ν: 3314, 2947, 1665, 1599, 1494, 1442, 755 cm^－1; HRMS (ESI) [M+H]⁺ calcd for C₁₀H₁₁F₃NO: 218.0787, found 218.0781.

  N-Phenylmethacrylamide (3ja):^[18]1H NMR (400 MHz, DMSO-d₆) δ: 9.78 (s, 1H), 7.69~7.66 (m, 2H), 7.32~7.28 (m, 2H), 7.07 (t, J＝7.2 Hz, 1H), 5.79 (s, 1H), 5.51 (t, J＝1.2 Hz, 1H), 1.94 (d, J＝0.8 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 167.3, 140.9, 139.6, 129.0, 124.0, 120.7, 120.4, 19.3.

  N-Phenylisobutyramide (3ka):^[19]1H NMR (400 MHz, DMSO-d₆) δ: 9.74 (s, 1H), 7.52 (d, J＝7.6 Hz, 2H), 7.19 (t, J＝7.6 Hz, 2H), 6.93(t, J＝7.6 Hz, 1H), 2.43~2.41 (m, 1H), 1.01 (d, J＝6.8 Hz, 6H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 175.7, 140.0, 129.1, 123.4, 119.6, 35.4, 20.0.

  N-Phenylpivalamide (3la):^[20]1H NMR (400 MHz, DMSO-d₆) δ: 9.25 (s, 1H), 7.69 (d, J＝8.0 Hz, 2H), 7.34 (t, J＝8.0 Hz, 2H), 7.09 (t, J＝7.2 Hz, 1H), 1.28 (s, 9H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 176.8, 139.8, 128.9, 123.6, 120.7, 39.6, 27.7.

  N-Phenylcyclopropanecarboxamide (3ma):^[21]1H NMR (400 MHz, DMSO-d₆) δ: 10.09 (s, 1H), 7.55 (d, J＝8.4 Hz, 2H), 7.22 (t, J＝8.0 Hz, 2H), 6.97 (t, J＝8.0 Hz, 1H), 1.78~1.72 (m, 1H), 0.83~0.79 (m, 2H), 0.76~0.71 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 172.1, 139.8, 128.9, 123.2, 119.4, 14.9, 7.5.

  N, 1-Diphenylcyclopropanecarboxamide (3na): ¹H NMR (400 MHz, DMSO-d₆) δ: 9.04 (s, 1H), 7.55~7.52 (m, 2H), 7.41~7.34 (m, 4H), 7.30~7.24 (m, 3H), 7.04~7.01 (m, 1H), 1.46~1.43 (m, 2H), 1.12~1.10 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.5, 140.8, 139.4, 129.4, 129.1, 129.0, 127.6, 124.0, 120.6, 32.3, 15.3; IR (KBr) ν: 3312, 3050, 2942, 1664, 1597, 1498, 1440, 753 cm^－1; HRMS (ESI) calcd for C₁₆H₁₆NO [M+H]⁺ 238.1226, found 238.1225.

  N-Phenylcyclohexanecarboxamide (3oa):^[22]1H NMR (400 MHz, DMSO-d₆) δ: 9.80 (s, 1H), 7.60(d, J＝7.2 Hz, 2H), 7.29~7.25(m, 2H), 7.00 (t, J＝7.6 Hz, 1H), 2.34~2.29 (m, 1H), 1.80~1.73 (m, 4H), 1.45~1.15 (m, 6H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 174.8, 140.0, 129.1, 123.3, 119.5, 45.4, 29.7, 25.9, 25.8.

  N-Phenyladamantane-1-carboxamide (3pa):^[23]1H NMR (400 MHz, DMSO-d₆) δ: 9.11 (s, 1H), 7.66 (t, J＝1.6 Hz, 2H), 7.29~7.26 (m, 2H), 7.02 (t, J＝7.6 Hz, 1H), 2.01~1.69 (m, 15H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 176.4, 139.9, 128.9, 123.6, 120.7, 41.4, 38.8, 36.5, 28.2.

  4-Methyl-N-phenylbenzamide (3qa):^[13]1H NMR (400 MHz, DMSO-d₆) δ: 10.17 (s, 1H), 7.89~7.77 (m, 4H), 7.36~7.32 (m, 4H), 7.13 (d, J＝7.2 Hz, 1H), 2.38 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 165.9, 142.1, 139.8, 132.6, 129.4, 129.1, 128.2, 124.1, 120.8, 21.5.

  4-Methoxy-N-phenylbenzamide (3ra):^[24]1H NMR (400 MHz, DMSO-d₆) δ: 10.09 (s, 1H), 7.95 (d, J＝8.8 Hz, 2H), 7.76 (d, J＝8.0 Hz, 2H), 7.34 (t, J＝8.0 Hz, 2H), 7.10~7.05 (m, 3H), 3.84 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 165.5, 162.4, 139.9, 130.1, 129.1, 127.4, 123.9, 120.8, 114.1, 55.9.

  4-Bromo-N-phenylbenzamide (3sa):^[25]1H NMR (400 MHz, DMSO-d₆) δ: 10.33 (s, 1H), 7.91 (d, J＝8.4 Hz, 2H), 7.77~7.74 (m, 4 H), 7.36 (t, J＝7.6 Hz, 2H), 7.11 (t, J＝7.2 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 165.1, 139.5, 134.5, 131.9, 130.3, 129.2, 125.9, 124.4, 120.9.

  Methyl 4-(phenylcarbamoyl)benzoate (3ta):^[26]1H NMR (400 MHz, DMSO-d₆) δ: 10.45 (s, 1H), 8.11~8.06 (m, 4H), 7.78 (d, J＝8.8 Hz 2H), 7.37 (t, J＝8.4 Hz, 2H), 7.12 (t, J_＝8.4 Hz, 1H), 3.90 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 166.2, 165.2, 139.6, 139.4, 132.5, 129.7, 129.2, 128.6, 124.5, 120.9, 53.0.

  3-Methyl-N-phenylbenzamide (3ua):^[25]1H NMR (400 MHz, DMSO-d₆) δ: 10.22 (s, 1H), 7.79~7.77 (m, 4H), 7.44~7.40 (m, 4H), 7.12~7.07 (m, 1H), 2.40 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 166.2, 139.7, 138.2, 135.5, 132.6, 129.1, 128.8, 128.6, 125.3, 124.1, 120.8, 21.5.

  2-Methyl-N-phenylbenzamide (3va):^[25]1H NMR (400 MHz, DMSO-d₆) δ: 10.31 (s, 1H), 7.75 (d, J＝8.0 Hz, 2H), 7.46~7.30 (m, 6 H), 7.09 (t, J＝7.2 Hz, 1H), 2.38 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.4, 139.8, 137.8, 135.7, 131.0, 130.1, 129.2, 127.7, 126.2, 124.0, 120.1, 19.8.

  N-Phenyl-2-naphthamide (3wa):^[27]1H NMR (400 MHz, DMSO-d₆) δ: 10.45 (s, 1H), 8.59 (s, 1H), 8.11~8.01 (m, 4H), 7.83 (dd, J＝8.8 Hz, 1.2 Hz, 2H), 7.67~7.61 (m, 2H), 7.38 (t, J＝7.2 Hz, 2H), 7.14~7.10 (m, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 166.1, 139.8, 134.8, 132.8, 132.6, 129.5, 129.2, 128.6, 128.5, 128.4, 128.2, 127.4, 125.0, 124.2, 120.9.

  N-Phenyl-2, 3-dihydrobenzo[b]^{[1, 4]}dioxine-2-carboxamide (3xa): ¹H NMR (400 MHz, DMSO-d₆) δ: 10.16 (s, 1H), 7.65 (d, J＝7.6 Hz, 2H), 7.33 (t, J＝7.6 Hz, 2H), 7.11~7.03 (m, 2H), 6.91~6.87 (m, 3H), 4.99~4.97 (m, 1H), 4.48-4.33 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 166.1, 143.5, 143.0, 138.7, 129.3, 124.6, 122.2, 122.1, 120.5, 117.9, 117.6, 73.2, 65.3; IR (KBr) ν: 3310, 2945, 1665, 1594, 1497, 1441, 754 cm^－1; HRMS (ESI) [M+H]⁺calcd for C₁₅H₁₄NO₃: 256.0968, found 256.0959.

  N-Phenylpicolinamide (3ya):^[25]1H NMR (400 MHz, DMSO-d₆) δ: 10.65 (s, 1H), 8.75~8.71 (m, 1H), 8.18~8.15 (m, 1H), 8.09~8.05 (m, 1H), 7.93 (d, J＝1.2 Hz, 1H), 7.91~7.90 (d, J＝0.8 Hz, 1H), 7.69~7.66 (m, 1H), 7.38~7.34 (m, 2H), 7.14~7.10 (m, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 163.0, 149.1, 149.0, 138.7, 129.2, 127.5, 124.5, 122.9, 120.8.

  N-Phenylferrocenylamide (3za):^[28]1H NMR (400 MHz, DMSO-d₆) δ: 9.44 (s, 1H), 7.70 (s, 2H), 7.33 (t, J＝7.6 Hz, 2H), 7.06 (t, J＝7.2 Hz, 1H), 5.01 (t, J＝2.0 Hz, 2H), 4.45 (t, J＝2.0 Hz, 2H), 4.21 (t, J＝5.2 Hz, 5H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.6, 139.7, 129.0, 123.6, 120.8, 76.9, 71.0, 70.0, 69.1.

  N-(p-Tolyl)acetamide (3cb):^[14]1H NMR (400 MHz, DMSO-d₆) δ: 9.84 (s, 1H), 7.45 (d, J＝8.4 Hz, 2H), 7.09 (d, J＝8.4 Hz, 2H), 2.23 (s, 3H), 2.01 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.5, 137.4, 132.3, 129.5, 119.5, 24.5, 20.9.

  N-(4-(tert-Butyl)phenyl)acetamide (3cc):^[29]1H NMR (400 MHz, DMSO-d₆) δ: 9.86 (s, 1H), 7.48 (d, J＝8.8 Hz, 2H), 7.29 (d, J＝8.8 Hz, 2H), 2.01(s, 3H), 1.25 (s, 9 H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.5, 145.7, 137.3, 125.8, 119.3, 34.5, 31.7, 24.4.

  N-(4-Methoxyphenyl)acetamide (3cd):^[30]1H NMR (400 MHz, DMSO-d₆) δ: 9.78 (s, 1H), 7.47 (d, J＝8.8 Hz, 2H), 6.85 (d, J＝8.8 Hz, 2H), 3.70 (s, 3H), 1.99 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.3, 155.5, 133.0, 121.0, 114.3, 55.6, 24.3.

  N-(4-Fluorophenyl)acetamide (3ce):^[31]1H NMR (400 MHz, DMSO-d₆) δ: 10.00 (s, 1H), 7.60~7.57(m, 2H), 7.13 (t, J＝8.8 Hz, 2H), 2.03 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.7, 158.3 (J＝237.7 Hz), 136.3 (J＝2.2 Hz), 121.2 (J＝8 Hz), 115.7 (J＝21.9 Hz), 24.4; ¹⁹F NMR (376 MHz, DMSO-d₆) δ: －119.8.

  N-(4-Chlorophenyl)acetamide (3cf):^[32]1H NMR (400 MHz, DMSO-d₆) δ: 10.07 (s, 1H), 7.60 (d, J＝8.8 Hz, 2H), 7.33 (d, J＝8.8 Hz, 2H), 2.04 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.5, 138.4, 128.7, 126.5, 120.5, 24.1.

  N-(4-Bromophenyl)acetamide (3cg):^[33]1H NMR (400 MHz, DMSO-d₆) δ: 10.07 (s, 1H), 7.55 (d, J＝8.8 Hz, 2H), 7.46 (d, J＝8.8 Hz, 2H), 2.03 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.6, 138.8, 131.6, 121.0, 114.6, 24.1.

  N-(4-Iodophenyl)acetamide (3ch):^[34]1H NMR (400 MHz, DMSO-d₆) δ: 10.05 (s, 1H), 7.60 (d, J＝8.8 Hz, 2H), 7.41 (d, J＝8.8 Hz, 2H), 2.03 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 169.1, 139.7, 137.9, 121.7, 86.9, 24.6.

  N-(4-(Trifluoromethyl)phenyl)acetamide (3ci):^[35]1H NMR (400 MHz, DMSO-d₆) δ: 10.31 (s, 1H), 7.78 (d, J＝8.4 Hz, 2H), 7.33 (d, J＝8.4 Hz, 2H), 2.08 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 169.5, 143.4, 125.8 (q, J＝32.0 Hz), 124.0 (q, J＝270 Hz) 126.3, 121.0, 24.5; ¹⁹F NMR (376 MHz, DMSO-d₆) δ: －60.4.

  N-(4-Cyanophenyl)acetamide (3cj):^[36]1H NMR (400 MHz, DMSO-d₆) δ: 10.38 (s, 1H), 7.75~7.74 (m, 4 H), 2.09 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 169.3, 143.6, 133.4, 119.2, 119.0, 104.8, 24.3.

  N-(4-Nitrophenyl)acetamide (3ck):^[31]1H NMR (400 MHz, DMSO-d₆) δ: 10.56 (s, 1H), 8.19 (d, J＝8.8 Hz, 2H), 7.80 (d, J＝8.8 Hz, 2H), 2.11 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 169.9, 146.0, 142.5, 125.5, 119.0, 24.8.

  N-(m-Tolyl)acetamide (3cl):^[37]1H NMR (400 MHz, DMSO-d₆) δ: 9.85 (s, 1H), 7.41 (s, 1H), 7.35 (d, J＝8.0 Hz, 1H), 7.15 (t, J＝7.6 Hz, 1H), 6.84 (d, J＝7.6 Hz, 1H), 2.26 (s, 3H), 2.02 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.7, 139.8, 138.3, 129.0, 124.2, 120.0, 116.7, 24.5, 21.7

  N-(3-Fluorophenyl)acetamide (3cm):^[38]1H NMR (400 MHz, DMSO-d₆) δ: 10.16 (s, 1H), 7.61~7.57 (m, 1H), 7.34~7.24 (m, 2H), 6.86~6.81 (m, 1H), 2.05 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 169.3, 162.7 (d, J＝239.2 Hz), 141.6 (d, J＝10.9 Hz), 130.9 (d, J＝9.5 Hz), 115.2 (d, J＝2.9 Hz), 110.0 (d, J＝20.4 Hz), 106.3 (d, J＝26.2 Hz), 24.6; ¹⁹F NMR (376 MHz, DMSO-d₆) δ: －112.2.

  N-(o-Tolyl)acetamide (3cn):^[39]1H NMR (400 MHz, DMSO-d₆) δ: 9.29 (s, 1H), 7.38 (d, J＝7.6 Hz, 1H), 7.20~7.04 (m, 3H), 2.19 (s, 3H), 2.05 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 168.7, 137.0, 132.0, 130.8, 126.4, 125.5, 125.5, 23.8, 18.4.

  N-(3, 5-Bis(trifluoromethyl)phenyl)acetamide (3co): ¹H NMR (400 MHz, DMSO-d₆) δ: 10.56 (s, 1H), 8.20 (s, 2H), 7.58 (s, 1H), 2.08 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 169.9, 141.7, 131.3 (q, J＝32.1 Hz), 122.4 (q, J＝270.6 Hz), 118.9 (d, J＝3.7 Hz), 116.0, 24.5; ¹⁹F NMR (376 MHz, DMSO-d₆) δ: －62.3; IR (KBr) ν: 3312, 2944, 1665, 1597, 1498, 1440, 753 cm^－1; HRMS (ESI) calcd for C₁₀H₈F₆NO [M+H]⁺ 272.0505, found 272.0512.

  (1S, 4aS, 10aR)-7-Isopropyl-1, 4a-dimethyl-N-phenyl-1, 2, 3, 4, 4a, 9, 10, 10a-octahydrophenanthrene-1-carboxamide (4ca): ¹H NMR (400 MHz, DMSO-d₆) δ: 9.31 (s, 1H), 7.60 (d, J＝8.4 Hz, 2H), 7.28 (t, J＝8.0 Hz, 2H), 7.19 (d, J＝8.0 Hz, 1H), 7.05~6.97 (m, 2H), 6.84 (d, J＝1.6 Hz, 1H), 2.82~2.73 (m, 3H), 2.31~2.22 (m, 2H), 1.86~1.68 (m, 4 H), 1.58~1.52 (m, 2H), 1.25~1.23 (m, 4H), 1.17~1.14 (m, 9H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 177.2, 147.7, 145.7, 140.0, 134.9, 129.0, 127.0, 124.7, 124.3, 123.8, 121.2, 48.1, 44.9, 37.8, 37.4, 36.4, 33.5, 30.1, 25.6, 24.6, 24.5, 21.3, 19.1, 17.0; IR (KBr) ν: 3316, 2925, 1664, 1598, 1500, 1442, 752 cm^－1; HRMS (ESI) calcd for C₂₆H₃₄NO [M+H]⁺ 376.2635, found 376.2624.

  6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1, 3-dihydroisobenzofuran-5-yl)-4-methyl-N-phenylhex-4-enamide (4cb): ¹H NMR (400 MHz, DMSO-d₆) δ: 9.84 (s, 1H), 9.35 (s, 1H), 7.54~7.52 (m, 2H), 7.23 (t, J＝7.6 Hz, 2H), 6.98 (t, J＝7.2 Hz, 1H), 3.65 (s, 3H), 3.49 (s, 3H), 3.31 (d, J＝6.8 Hz, 2H), 2.38 (t, J＝6.0 Hz, 2H), 2.26 (t, J＝8.0 Hz, 2H), 2.03 (s, 3H), 1.79 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 171.4, 170.9, 163.1, 153.4, 146.3, 139.9, 134.4, 129.1, 123.4, 123.4, 123.0, 119.6, 116.5, 107.5, 69.2, 61.1, 35.8, 35.4, 23.0, 16.6, 11.4; IR (KBr) ν: 3318, 2945, 1662, 1598, 1498, 1443, 754 cm^－1; HRMS (ESI) calcd for C₂₃H₂₆NO₅ [M+H]⁺ 396.1805, found 396.1811.

  N-Phenylbicyclo[2.2.1]hept-5-ene-2-carboxamide (4cc): ¹H NMR (400 MHz, DMSO-d₆) δ: 9.75 (s, 1H), 7.55 (t, J＝7.2 Hz, 2H), 7.28~7.24 (m, 2H), 6.99 (t, J＝7.6 Hz, 1H), 6.17~6.15 (m, 1H), 5.85~5.83 (m, 1H), 3.28 (s, 1H), 3.05~3.00 (m, 1H), 2.87 (s, 1H), 1.83~1.77 (m, 1H), 1.42~1.30 (m, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 172.4, 140.1, 137.7, 132.2, 129.1, 123.2, 119.6, 50.1, 46.7, 44.7, 42.8, 28.8; IR (KBr) ν: 3320, 2927, 1660, 1598, 1500, 1442, 755 cm^－1; HRMS (ESI) calcd for C₁₄H₁₆NO [M+H]⁺ 214.1226, found 214.1222.

  2-(11-oxo-6, 11-Dihydrodibenzo[b, e]oxepin-2-yl)-N-phenylacetamide (4cd): ¹H NMR (400 MHz, DMSO-d₆) δ: 10.23 (s, 1H), 8.07 (d, J＝2.4 Hz, 1H), 7.95 (s, 2H), 7.78 (d, J＝8 Hz, 1H), 7.67~7.54 (m, 4 H), 7.30 (t, J＝7.6 Hz, 2H), 7.05 (m, 2H), 5.28 (s, 2H), 3.68 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 190.3, 169.1, 160.0, 140.1, 139.3, 136.8, 136.1, 133.2, 131.6, 129.9, 129.3, 128.9, 128.8, 128.4, 124.7, 123.4, 120.8, 119.2, 72.9, 42.3; IR (KBr) ν: 3317, 2948, 1663, 1599, 1498, 1440, 753 cm^－1; HRMS (ESI) calcd for C₂₂H₁₈NO₃ [M+H]⁺ 344.1281, found 344.1278.

  Supporting Information  ¹H NMR, ¹³C NMR and HRMS spectra of products. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.

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• 

  Scheme 1  Synthesis of sterically hindered amides

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  Scheme 2  Proposed mechanism

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  Table 1.  Screening the optimized reaction conditions^a

  Entry	Catalyst (equiv.)	Solvent	Yieldb/%
  1	Et3N (1.5)	DMF	11
  2	DBU (1.5)	DMF	68
  3	DBN (1.5)	DMF	90
  4	i-Pr2NEt (1.5)	DMF	Trace
  5	Na2CO3 (1.5)	DMF	6
  6	Cs2CO3 (1.5)	DMF	9
  7	KF-Celite (1.5)	DMF	Trace
  8c	Amberlite IRA-4200 (10 wt%)	DMF	N.R.
  9	DBN (2)	DMF	97
  10	DBN (1.2)	DMF	78
  11	DBN (0.2)	DMF	12
  12	—	DMF	N.R.
  13	DBN (2)	DCM	8
  14	DBN (2)	THF	15
  15	DBN (2)	MeCN	72
  16	DBN (2)	Toluene	Trace
  17	DBN (2)	DMSO	Trace
  18	DBN (2)	MeOH	Trace
  19d	DBN (2)	DMF	91
  20e	DBN (2)	DMF	94
  a Unless otherwise specified, the reactions were carried out in a vial in the presence of 1a (0.15 mmol), 2a (0.1 mmol), base, solvent (1 mL). b Estimated by 1H NMR spectroscopy using diethyl phthalate as an internal reference. c The quantity of Amberlite IRA-4200 was 0.1 g. d The reaction was conducted under 40 kHz/30 W ultrasonic radiation for 1 h. e The reaction was conducted under 150 W microwave radiation of 20 min. N.R.: no reaction.

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  Table 2.  Reaction scope of carboxylic acids^a

  a All reactions were carried out in a vail in the presence of 1 (0.45 mmol), 2 (0.3 mmol), DBN (0.6 mmol) and DMF (3 mL); isolated yields are reported.

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  Table 3.  Reaction scope of isothiocyanates^a

  a All reactions were carried out in a vail in the presence of 1 (0.45 mmol), 2 (0.3 mmol), DBN (0.6 mmol) and DMF (3 mL); isolated yields are reported.

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  Table 4.  Reaction scope of late-stage modification^a

  a All reactions were carried out in a vail in the presence of 1 (0.45 mmol), 2 (0.3 mmol), DBN (0.6 mmol) and DMF (3 mL); isolated yields are reported.

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•