Palladium-Catalysed Reductive Aminocarbonylation of Aryl Bromides and Iodides with Nitroarenes

Abstract

Amide functional groups are a structural feature in a vast array of beneficial organic molecules. This has resulted in a surge in new methodologies developed to enable access to this functional group using a broad range of coupling partners. Herein, we report a palladium-catalysed reductive aminocarbonylation of aryl bromides and iodides with nitroarenes to afford the respective amide products. The developed protocol employs Mo(CO)₆ as a carbonyl source and a combination of Zn and TMSCl as co-reducing agents. For most substrates, the anticipated amide products were obtained in modest to high amide product yields.

Key words

amides - reductive aminocarbonylation - palladium - nitro­arenes - C–N bond formation

The amide functional group is present in several interesting compounds, including natural products, peptides and agrochemicals.[1] [2] [3] Furthermore, this functional group is found to be present in two-thirds of drug candidates and in over 25% of commercially available drugs.[4,5] Some of the drugs are highlighted in Figure [1] and these include moclobemide (1), used for the treatment of depression, nevirapine (2), an antiretroviral drug for HIV, valsartan (3), which is known as a treatment for hypertension and cardiovascular diseases, and paracetamol (4), which is a commonly used analgesic.[6] [7] [8] [9]

Figure 1 Commercially available amide-containing drugs

Thus, research and development of new amide synthesis procedures has become a key research area due to the prevalence of amide functional groups in beneficial organic molecules.[10] [11] Traditionally, amides are synthesised from the condensation of carboxylic acids and amines. However, some of these methods are associated with drawbacks, such as using stoichiometric amounts of carboxylic acid activators. These usually generate undesired products in high quantities.[12,13] Furthermore, one of the commonly used activators­, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (hexa­fluorophosphate azabenzotriazole tetramethyl uronium, HATU), has been reported to cause allergies, raising health concerns.[14] Protocols using alternative functional groups instead of carboxylic acids have been established to try to overcome some of these challenges and these include reactions that utilise catalytic activators, esters, aldehydes, alcohols and amides as amine coupling partners.[15] [16] [17] [18] The direct use of nitroarenes as arylamine surrogates has also gained momentum in the amidation reactions as they offer step-economic access to amides.[19,20] Nitroarenes are cheaper and more stable than their amine analogues and are ideal for late-stage transformation in multistep syntheses due to their ‘chemical inertness’. They have been successfully coupled to various functional groups such as esters, carboxylic acids, amides, aldehydes, aryl iodides and alcohols to afford the respective amide products.[21–26] In addition, amides have been obtained from reactions between nitroarenes and aryl halides (or equivalent) in the presence of a carbonyl source, and in most cases, nickel was employed as the catalyst of choice.[27] [28] [29] Although nickel offers a more sustainable option, the general superior robustness of palladium catalysts in cross-coupling reactions prompted us to explore herein an optimisation study for a palladium-catalysed reductive aminocarbonylation of aryl halides with nitroarenes and a subsequent application of the protocol in the synthesis of a variety of amides.[30]

Our optimal reaction conditions revealed that palladium(II) acetate [Pd(OAc)₂] catalyst, 1,3-bis(diphenylphosphino)­propane (dppp) as a supporting ligand for the metal, molybdenum hexacarbonyl [Mo(CO)₆] as a carbonyl source, pyridine as a base and Zn/TMSCl as additives were essential for the successful coupling of the model substrates, 4-bromoanisole (5a) and nitrobenzene (6a), to afford the amide product 7a in 95% yield at 130 °C (Table [1], entry 1). Alternative inorganic and organic bases did not afford better yields in comparison to pyridine (entries 2–7). For example, the use of NaOH, Cs₂CO₃ and K₂CO₃ resulted in lowered product yields (entries 2–4). In comparison to the inorganic bases, Et₃N, quinoline and 2-quinolone afforded slightly improved yields of 50%, 63% and 55%, respectively (entries 5–7). The stronger basicity of pyridine in comparison to its derivatives quinoline and 2-quinolone could be the reason for the observed reactivity trend.[31] [32] Although pyridine has been reported as a suitable ligand in other studies, such as the ­C–H activation reaction, phosphine-free reactions in our case afforded poor yields (entry 8).[33] Monodentate ligand 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (SPhos) and bidentate ligand 1,2-bis(diphenylphosphino)ethane (dppe) were also investigated as suitable alternative ligands. However, these did not outperform dppp as lower amide product yields of 54% and 60% for dppe and SPhos, respectively, were obtained (entries 9 and 10).

Table 1 Optimisation Study for the Reductive Aminocarbonylation Reaction

Entry	Change in reaction conditions	Product yield (%)a
1	none	95
2	NaOH instead of pyridine	25
3	K2CO3 instead of pyridine	11
4	Cs2CO3 instead of pyridine	15
5	Et3N instead of pyridine	50
6	quinoline instead of pyridine	63
7	2-quinolone instead of pyridine	55
8	no ligand	12
9	dppe instead of dppp	54
10	SPhos instead of dppp	60
11	Pd(acac)2 instead of Pd(OAc)2	–
12	PdCl2 instead of Pd(OAc)2	14
13	PdCl2(cod) instead of Pd(OAc)2	16
14	NiCl2 instead of Pd(OAc)2	–
15	CH3CN instead of dioxane	23
16	THF instead of dioxane	43
17	DMF instead of dioxane	32
18	NMP instead of dioxane	–
19	DMSO instead of dioxane	trace

^a Dash (–) indicates no amide product formed.

Other palladium catalysts were also explored and, in our case, Pd(acac)₂, PdCl₂ and PdCl₂(cod) afforded low yields to no product (entries 11–13). A different choice of a metal catalyst, NiCl₂, showed no reactivity as no amide product was formed (entry 14). Furthermore, different solvents were investigated and these included CH₃CN, DMF and THF which all gave diminished product yields of 23%, 32% and 43%, respectively (entries 15–17). The use of NMP afforded no amide product at all while DMSO only gave trace amounts of the amide product (entries 18 and 19). Lastly, reducing the reaction temperature to below 130 °C afforded trace amounts of the amide product.

The substrate scope and limitations of our protocol were then explored by varying the aryl halide and nitroarene (Scheme [1]). Firstly, we investigated the reactivities of variously substituted aryl bromides with nitrobenzene (6a). Substituted aryl bromides containing an electron-­donating group (EDG) afforded products 7b–7d and 7g in good to excellent yields. However, product 7e was obtained in a lower product yield and the anticipated product 7f was not formed due to the possible steric hindrance presented by the ortho-substituted aryl bromide utilised. Aryl bromides with a methylene- or ethylenedioxy substituent afforded products 7i and 7j in 37% and 59% yield, respectively. Aryl bromides possessing an electron-withdrawing group (EWG) were less reactive than those with an EDG, and in some cases completely inactive. This could be due to a reduced inductive stabilisation of the intermediate complexes formed between the metal, carbonyl, halide, ligand and phenyl ring. This further results in reduced rates of carbonylation and thus, the observed poor reactivities.[34] [35] This trend was prominent in para-substituted aryl bromides which did not react to afford the anticipated products 7k and 7l. Amides 7m and 7n bearing an EWG on the para and ortho positions were obtained in 41% and 23% yield, respectively. Reactions between both substituted bromoarenes and nitroarenes afforded products 7s–7w in average to excellent yields. The reactivities of electron-rich nitroarenes and an ortho-substituted bromobenzene resulted in higher product yields compared to yields obtained with neutral nitroarenes (product 7v vs 7e). The product yields of 7w and 7m also revealed a similar trend, whereby the reactivities of an aryl bromide possessing an EWG at the para position were improved when reacted with an electron-rich nitroarene.

Scheme 1 Substrate scope study. ^a Reaction at 90 °C.

Aryl iodides also reacted using the established reaction conditions and, in most cases, were found to be reactive at a lower reaction temperature of 90 °C (Scheme [1]). Product 7q was obtained in 91% yield using iodobenzene as the coupling partner compared to the 51% yield obtained with bromobenzene at 130 °C. A similar trend was observed with the yields of product 7t. However, the use of aryl iodides for the synthesis of products 7p and 7u resulted in unimproved yields. Increasing the reaction temperature from 90 °C to 130 °C resulted in an improved product yield from 35% to 91% for product 7x.

Heterocyclic aryl halides and nitropyridines were also investigated; however, reactions using these substrates did not afford the desired products (Scheme [1]). 3-Bromopyridine was reacted with various nitroarenes resulting in no formation of anticipated products 7z and 7aa. Similarly, coupling reactions with 2-nitropyridine did not afford the anticipated amide products 7ab and 7ac. We also went on to investigate the reductive aminocarbonylation of aryl chlorides and aryl triflates and, unfortunately, these substrates did not afford the anticipated amide products. Increasing the catalyst loading (20 mol%), carbonyl source moles (5 eq) and reaction time (24 h), as well as the reaction temperature (150 °C), did not afford the anticipated product.

Insights into the reductive aminocarbonylation reaction mechanism have been sought.[35] A variety of possible reactive nitroarene intermediates have also been identified. To establish the reaction mechanism, we also undertook a brief study to identify the possible reactive intermediates that are formed under the current protocol. GC analysis of products obtained from the reaction of nitrobenzene (6a) under the optimal conditions, as highlighted in Scheme [2] a, revealed aniline (8) as the reduction intermediate. However, and similarly to reports by Wu and co-workers, the direct use of aniline as a coupling partner under these reaction conditions did not afford the desired product (Scheme [2, b]).[36] Interestingly, when the reaction was repeated in the presence of nitrobenzene 6b, the amide products 7a and 7u were successfully formed in 100% GC yield (Scheme [2, c]). Although specific mechanistic studies are yet to be established, this indicates that the presence of the nitro group plays a vital role in the reductive aminocarbonylation reaction.

Scheme 2 Control experiments. * GC yield.

In addition, coupling aryl bromides with other possible intermediates, such as azobenzene (9a), azoxybenzene (9b), 1,2-diphenylhydrazine (9c) and nitrosobenzene (9d), did not afford the anticipated amide products. However, these intermediates apart from 9d were also successfully coupled to in the presence of nitroarene 6b and afforded the anticipated amide products (Table [2], entries 2–4). This further demonstrates the possible role of the nitro functional group in activating the coupling of the proposed intermediates.

Table 2 Reductive Aminocarbonylation between Nitroarene 6b, Intermediates and Aryl Bromide 5a

Entry	Intermediate	Yield (%)a 7a	Yield (%)a 7u
1		100	100
2		100	100
3		100	100
4		100	100
5		0	0

^a GC yield.

Scheme [3] outlines a general proposed mechanism of the reductive aminocarbonylation reaction. Initially, the Pd(II) species is converted into Pd(0) by the ligand. This is then followed by the oxidative addition of the aryl halide to give the aryl–Pd–halide intermediate ii. CO liberated from Mo(CO)₆ then coordinates to Pd affording the aryl–Pd–CO intermediate iii that undergoes a rearrangement and carbonylation to form the phenacyl–Pd–halide complex iv. Zn or Mo and TMSCl reduce nitroarene v to the possible intermediates of type 8 and 9a–9c. These undergo amidation followed by a base-promoted reductive elimination to afford the target amide product vi and regeneration of the active Pd(0) catalyst.

Scheme 3 Proposed reductive amidation mechanism

In conclusion, we have demonstrated the potential applicability of Pd as a metal catalyst in reductive aminocarbonylation of nitroarenes with aryl bromides and iodides. Overall, products were obtained in modest to excellent yields. Aryl iodides showed better reactivities at lower reaction temperatures. Detailed mechanistic studies to establish the role of nitroarenes in activating the possible reduction intermediates are underway and these will be reported in the future. We will also focus on the development of more active catalysts that will promote the reductive coupling of a broader substrate scope.

Amides 7; General Procedure

Pd(OAc)₂ (18 mg, 10 mol%), dppp (34 mg, 10 mol%) and pyridine (66 μL, 1.0 eq) were added in a pressure tube (10 mL) with dioxane (2.0 mL) as a solvent, followed by the addition of the reacting starting materials, nitroarene (e.g., nitrobenzene, 100 mg, 1.0 eq) and aryl halide (e.g., 4-bromoanisole, 0.12 mL, 1.2 eq). The additives TMSCl (0.011 mL, 10 mol%) and Zn (106 mg, 2.0 eq) were added to the reaction vessel, followed by Mo(CO)₆ (643 mg, 3.0 eq). The reaction was sealed and stirred at 130 °C for 12 h. After the reaction was stopped, water (20 mL) was added and the mixture was extracted with EtOAc (3 × 10 mL). The extracts were combined and dried over anhydrous MgSO₄, filtered and concentrated using a rotary evaporator. The concentrated crude material was then purified using silica gel column chromatography (30% EtOAc/hexane) to afford the desired amide product 7. The following notes apply to the yields below: ^a Aryl halide used was Br. ^b Aryl halide used was I. * Reaction temperature was 90 °C.

4-Methoxy-N-phenylbenzamide (7a)

Isolated yield: 175 mg (95%); mp 173 °C.

IR (neat): 3336 (N-H), 1652 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.83 (d, J = 8.50 Hz, 2 H, Ar), 7.75 (br, 1 H, -NH), 7.62 (d, J = 8.00 Hz, 2 H, Ar), 7.40–7.30 (m, 2 H, Ar), 7.15–7.10 (m, 1 H, Ar), 6.96 (d, J = 8.50 Hz, 2 H, Ar), 3.85 (s, 3 H, -OCH₃).

¹³C NMR (126 MHz, CDCl₃): δ = 165.20 (-C=O), 162.51 (-Ar), 138.14 (-Ar), 129.04 (-Ar), 128.88 (-Ar), 127.22 (-Ar), 124.32 (-Ar), 120.17 (-Ar), 113.99 (-Ar), 55.45 (-OCH₃).

HRMS: m/z [M + H]⁺ calcd: 228.1026; found: 228.1025.

Data in agreement with literature.[37]

4-Methyl-N-phenylbenzamide (7b)[37]

Isolated yield: 145 mg (85%)^a; mp 148 °C.

IR (neat): 3350 (N-H), 1648 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.94 (br, 1 H, -NH), 7.75 (d, J = 8.00 Hz, 2 H, -Ar), 7.63 (d, J = 8.00 Hz, 2 H, -Ar), 7.39–7.20 (m, 4 H, -Ar), 7.14–7.10 (m, 1 H, -Ar), 2.39 (s, 3 H, -CH₃).

¹³C NMR (126 MHz, CDCl₃): δ = 165.70 (-C=O), 142.27 (-Ar), 138.06 (-Ar), 132.10 (-Ar), 129.41 (-Ar), 129.35 (-Ar), 128.99 (-Ar), 124.36 (-Ar), 120.20 (-Ar), 21.42 (-CH₃).

HRMS: m/z [M + H]⁺ calcd: 212.0997; found: 212.1078.

4-Isopropyl-N-phenylbenzamide (7c)[38]

Isolated yield: 130 mg (67%)^a; mp 168 °C.

IR (neat): 3368 (N-H), 1630 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.79 (d, J = 8.00 Hz, 2 H, -Ar), 7.63 (d, J = 8.00 Hz, 2 H, -Ar), 7.40–7.30 (m, 4 H, -Ar), 7.15–7.11 (m, 1 H, -Ar), 3.00–2.90 (m, 1 H, -CH), 1.27 (d, J = 7.00 Hz, 6 H, -CH₃).

¹³C NMR (126 MHz, CDCl₃): δ = 165.63 (-C=O), 153.20 (-Ar), 138.04 (-Ar), 132.52 (-Ar), 129.08 (-Ar), 127.12 (-Ar), 126.87 (-Ar), 124.41 (-Ar), 120.09 (-Ar), 34.12 (-CH), 23.75 (-CH₃).

HRMS: m/z [M + H]⁺ calcd: 240.1390; found: 240.1380.

2-Methyl-N-phenylbenzamide (7d)[38]

Isolated yield: 113 mg (66%)^a; mp 124 °C.

IR (neat): 3307 (N-H), 1643 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.61 (d, J = 7.50 Hz, 2 H, -Ar), 7.51 (br, 1 H, -NH), 7.48–7.32 (m, 1 H, -Ar), 7.32–7.30 (m, 2 H, -Ar), 7.28–7.20 (m, 3 H, -Ar), 7.16–7.10 (m, 1 H, -Ar), 2.48 (s, 3 H, -CH₃).

¹³C NMR (126 MHz, CDCl₃): δ = 168.02 (-C=O), 154.79 (-Ar), 137.99 (-Ar), 136.44 (-Ar), 131.27 (-Ar), 130.27 (-Ar), 129.19 (-Ar), 126.58 (-Ar), 125.90 (-Ar), 124.54 (-Ar), 119.88 (-Ar), 18.78 (-CH₃).

2-Methoxy-N-phenylbenzamide (7e)[39]

Isolated yield: 61 mg (33%)^a; mp 147 °C.

IR (neat): 3336 (N-H), 1728 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 9.78 (br, 1 H, -NH), 8.29 (dd, J = 2.00, 8.00 Hz, 1 H, -Ar), 7.67 (d, J = 8.00 Hz, 2 H, -Ar), 7.50–7.45 (m, 1 H, -Ar), 7.36 (t, J = 7.50 Hz, 2 H, -Ar), 7.16–7.09 (m, 2 H, -Ar), 7.02 (d, J = 8.00 Hz, 1 H, -Ar), 4.04 (s, 3 H, -OCH₃).

¹³C NMR (126 MHz, CDCl₃): δ = 163.19 (-C=O), 157.19 (-Ar), 138.38 (-Ar), 133.20 (-Ar), 132.52 (-Ar), 128.95 (-Ar), 124.12 (-Ar), 121.76 (d, J = 19.2 Hz, -Ar), 120.43 (-Ar), 111.53 (-Ar), 56.21 (-OCH₃).

HRMS: m/z [M + H]⁺ calcd: 228.1026; found: 228.1028.

3-Methyl-N-phenylbenzamide (7g)[38]

Isolated yield: 140 mg (82%)^a; mp 126 °C.

IR (neat): 3350 (N-H), 1647 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.92 (br, 1 H, -NH), 7.69–7.71 (m, 4 H, -Ar), 7.37–7.30 (m, 4 H, -Ar), 7.13–7.10 (m, 1 H, -Ar), 2.39 (s, 3 H, -CH₃).

¹³C NMR (126 MHz, CDCl₃): δ = 165.95 (-C=O), 138.64 (-Ar), 138.00 (-Ar), 134.98 (-Ar), 132.51 (-Ar), 129.02 (-Ar), 128.58 (-Ar), 127.77 (-Ar), 124.45 (-Ar), 123.94 (-Ar), 120.19 (s), 21.33 (-CH₃).

HRMS: m/z [M + H]⁺ calcd: 212.1071; found: 212.1073.

3,5-Dimethyl-N-phenylbenzamide (7h)

Isolated yield: 81 mg (44%)^a; mp 135 °C.

IR (neat): 3367 (N-H), 1650 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.83 (br, 1 H, -NH), 7.64 (d, J = 8.00 Hz, 2 H, -Ar), 7.44 (s, 2 H, -Ar), 7.40–7.30 (m, 2 H, -Ar), 7.18–7.09 (m, 2 H, -Ar), 2.36 (s, 6 H, -CH₃).

¹³C NMR (126 MHz, CDCl₃): δ = 166.09 (-C=O), 138.48 (-Ar), 138.05 (-Ar), 135.01 (-Ar), 133.39 (-Ar), 129.02 (-Ar), 124.76 (-Ar), 124.38 (-Ar), 120.12 (-Ar), 21.23 (-CH₃).

N-Phenylbenzo[d][1,3]dioxole-5-carboxamide (7i)[38]

Isolated yield: 72 mg (37%)^a; mp 139 °C.

IR (neat): 3347 (N-H), 1655 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.77 (br, 1 H, -NH), 7.60 (d, J = 8.00 Hz, 2 H, -Ar), 7.49–7.40 (m, 4 H, -Ar), 7.15–7.10 (m, 1 H, -Ar), 6.84 (d, J = 8.00 Hz, 1 H, -Ar), 6.03 (s, 2 H, -CH₂).

¹³C NMR (126 MHz, CDCl₃): δ = 164.96 (-C=O), 150.66 (-Ar), 148.19 (-Ar), 137.99 (-Ar), 129.19 (-Ar), 129.05 (-Ar), 124.43 (-Ar), 121.64 (-Ar), 120.18 (-Ar), 108.10 (-Ar), 107.74 (-Ar), 101.80 (-CH₂).

N-Phenyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide (7j)

Isolated yield: 122 mg (59%)^a; mp 140 °C.

IR (neat): 3336 (N-H), 1646 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.76 (br, 1 H, -NH), 7.60 (d, J = 7.00 Hz, 2 H, -Ar), 7.40 (d, J = 2.0 Hz, 1 H, -Ar), 7.38–7.33 (m, 3 H, -Ar), 7.13–7.08 (m, 1 H, -Ar), 6.91 (d, J = 8.50 Hz, 1 H, -Ar), 4.29 (dd, J = 5.0, 10.5 Hz, 4 H, -CH₂).

¹³C NMR (126 MHz, CDCl₃): δ = 164.97 (-C=O), 146.78 (-Ar), 143.53 (-Ar), 138.05 (-Ar), 129.02 (-Ar), 128.95 (-Ar), 128.20 (-Ar), 124.35 (-Ar), 120.44 (-Ar), 120.14 (-Ar), 120.08 (-Ar), 117.42 (-Ar), 116.61 (-Ar), 64.55 (-CH₂), 64.20 (-CH₂).

HRMS: m/z [M + H]⁺ calcd: 256.0975; found: 256.0968.

4-Cyano-N-phenylbenzamide (7m)[40]

Isolated yield: 74 mg (41%)^a; mp 180 °C.

IR (neat): 3353 (N-H), 1655 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.96 (d, J = 8.00 Hz, 2 H, -Ar), 7.85 (br, 1 H, -NH), 7.77 (d, J = 8.00 Hz, 2 H, -Ar), 7.62 (d, J = 7.50 Hz, 2 H, -Ar), 7.39 (t, J = 8.00 Hz, 2 H, -Ar), 7.19–7.15 (m, 1 H, -Ar).

¹³C NMR (126 MHz, CDCl₃): δ = 163.89 (-C=O), 138.89 (-Ar), 137.28 (-Ar), 132.61 (-Ar), 129.22 (-Ar), 127.77 (-Ar), 125.25 (-Ar), 120.87 (-Ar), 120.41 (-Ar), 115.43 (-CN).

HRMS: m/z [M + H]⁺ calcd: 223.0873; found: 223.0872.

N-Phenyl-2-(trifluoromethyl)benzamide (7n)

Isolated yield: 50 mg (23%)^a; mp 158 °C.

IR (neat): 3327 (N-H), 1652 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.74 (d, J = 8.00 Hz, 1 H, -NH), 7.64 (d, J = 6.00 Hz, 2 H, -Ar), 7.58 (d, J = 8.00 Hz, 3 H, -Ar), 7.46 (br, 1 H, -Ar), 7.38–7.31 (m, 1 H, -Ar), 7.18–7.11 (m, 2 H, -Ar).

¹³C NMR (126 MHz, CDCl₃): δ = 165.63 (-C=O), 137.42 (-Ar), 132.22 (-Ar), 130.20 (-Ar), 129.16 (-Ar), 128.64 (-Ar), 126.54 (-Ar), 126.50 (-Ar), 125.08 (-Ar), 120.27 (-CF₃).

N-(p-Tolyl)benzamide (7o)[39]

Isolated yield: 132 mg (86%)^a; mp 158 °C.

IR (neat): 3336 (N-H), 1650 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.95 (br, 1 H, -NH), 7.84 (d, J = 7.50 Hz, 2 H, -Ar), 7.52–7.39 (m, 5 H, -Ar), 7.14 (d, J = 8.00 Hz, 2 H, -Ar), 2.32 (s, 3 H, -CH₃).

¹³C NMR (126 MHz, CDCl₃): δ = 165.72 (-C=O), 135.39 (-Ar), 135.07 (-Ar), 134.16 (-Ar), 131.61 (-Ar), 129.49 (-Ar), 128.64 (-Ar), 127.00 (-Ar), 120.40 (-Ar), 20.84 (-CH₃).

HRMS: m/z [M + H]⁺ calcd: 212.1077; found: 212.1075.

N-(o-Tolyl)benzamide (7p)[39]

Isolated yield: 65 mg (42%)^a, 65 mg (42%)^b; mp 146 °C.

IR (neat): 3255 (N-H), 1650 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.92–7.85 (m, 3 H, Ar), 7.72 (br, -NH), 7.56–7.45 (m, 3 H, -Ar), 7.25–7.20 (m, 2 H, -Ar), 7.12–7.08 (m, 1 H, -Ar), 2.32 (s, 3 H, -CH₃).

¹³C NMR (126 MHz, CDCl₃): δ = 165.62 (-C=O), 135.77 (-Ar), 135.01 (-Ar), 131.78 (-Ar), 130.52 (-Ar), 129.32 (-Ar), 128.78 (-Ar), 127.03 (-Ar), 126.85 (-Ar), 125.35 (-Ar), 123.19 (-Ar), 17.77 (-CH₃).

HRMS: m/z [M + H]⁺ calcd: 212.1077; found: 212.1071.

N-Phenylbenzamide (7q)[39]

Isolated yield: 82 mg (51%)^a, 146 mg (91%)^b*; mp 160 °C.

IR (neat): 3344 (N-H), 1655 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.90-7.82 (m, 3 H, NH and -Ar), 7.64 (d, J = 8.00 Hz, 2 H, -Ar), 7.50–7.45 (m, 2 H, -Ar), 7.38–7.33 (m, 3 H, -Ar), 7.16–7.10 (m, 1 H, -Ar).

¹³C NMR (126 MHz, CDCl₃): δ = 165.69 (-C=O), 154.78 (-Ar), 137.93 (-Ar), 137.36 (-Ar), 135.02 (-Ar), 131.82 (-Ar), 129.09 (-Ar), 128.78 (-Ar), 126.99 (-Ar), 124.95 (-Ar), 124.55 (-Ar), 120.19 (-Ar).

HRMS: m/z [M + H]⁺ calcd: 198.0921; found: 198.0917.

N-(Benzo[d][1,3]dioxol-5-yl)-4-methoxybenzamide (7s)[41]

Isolated yield: 89 mg (55%)^a; mp 172 °C.

IR (neat): 3304 (N-H), 1606 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.81 (d, J = 8.50 Hz, 2 H, -Ar), 7.60 (br, 1 H, -NH), 7.33 (d, J = 1.0 Hz, 1 H, -Ar), 6.96 (d, J = 8.50 Hz, 2 H, -Ar), 6.89–6.83 (m, 1 H, -Ar), 6.77 (d, J = 8.00 Hz, 1 H, -Ar), 5.95 (s, 2 H, -CH₂), 3.85 (s, 3 H, -OCH₃).

¹³C NMR (126 MHz, CDCl₃): δ = 162.48 (C=O), 147.93 (-Ar), 144.40 (-Ar), 132.36 (-Ar), 128.81 (-Ar), 127.09 (-Ar), 113.99 (-Ar), 113.39 (-Ar), 108.10 (-Ar), 103.17 (-Ar), 101.30 (-CH₂), 55.47 (-OCH₃).

HRMS: m/z [M + H]⁺ calcd: 272.0925; found: 272.0921.

N-(4-Methoxyphenyl)-4-methylbenzamide (7t)

Isolated yield: 104 mg (62%)^a, 151 mg (90%)^b*.

IR (neat): 3336 (N-H), 1657 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.77 (br, 1 H, -NH), 7.74 (d, J = 8.00 Hz, 2 H, -Ar), 7.52 (d, J = 9.00 Hz, 2 H, -Ar), 7.38–7.32 (m, 2 H, -Ar), 6.88 (d, J = 9.00 Hz, 2 H, -Ar), 3.79 (s, 3 H, -OCH₃), 2.39 (s, 3 H, -CH₃).

¹³C NMR (126 MHz, CDCl₃): δ = 165.55 (-C=O), 156.55 (-Ar), 142.13 (-Ar), 132.17 (-Ar), 131.15 (-Ar), 129.35 (-Ar), 126.97 (-Ar), 122.08 (-Ar), 114.22 (-Ar), 55.48 (-OCH₃), 21.43 (-CH₃).

HRMS: m/z [M + H]⁺ calcd: 242.1183; found: 242.1178.

4-Methoxy-N-(p-tolyl)benzamide (7u)

Isolated yield: 157 mg (89%)^a, 99 mg (56%)^b*; mp 165 °C.

IR (neat): 3339 (N-H), 1650 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.86 (br, 1 H, -NH), 7.81 (d, J = 9.00 Hz, 2 H, -Ar), 7.50 (d, J = 8.00 Hz, 2 H, -Ar), 7.13 (d, J = 8.00 Hz, 2 H, -Ar), 6.91 (d, J = 8.50 Hz, 2 H, -Ar), 3.83 (s, 3 H, -OCH₃), 2.31 (s, 3 H, -CH₃).

¹³C NMR (126 MHz, CDCl₃): δ = 165.19 (-C=O), 162.33 (-Ar), 135.56 (-Ar), 133.89 (-Ar), 132.18 (-Ar), 129.47 (-Ar), 128.85 (-Ar), 127.23 (-Ar), 120.29 (-Ar), 113.85 (-Ar), 113.43 (-Ar), 55.39 (-OCH₃), 20.83 (-CH₃).

HRMS: m/z [M + H]⁺ calcd: 242.1183; found: 242.1175.

2-Methoxy-N-(p-tolyl)benzamide (7v)

Isolated yield: 107 mg (61%)^a, 120 mg (68%)^b, less than 10 mg (trace)^b*; mp 174 °C.

IR (neat): 3356 (N-H), 1652 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 9.71 (br, 1 H, -NH), 8.28 (d, J = 7.00 Hz, 1 H, -Ar), 7.55 (d, J = 8.50 Hz, 2 H, -Ar), 7.48–7.40 (m, 1 H, -Ar), 7.15–7.05 (m, 3 H, -Ar), 7.01 (d, J = 8.50 Hz, 1 H, -Ar), 4.02 (s, 3 H, -OCH₃), 2.32 (s, 3 H, -CH₃).

¹³C NMR (126 MHz, CDCl₃): δ = 163.05 (-C=O), 157.18 (-Ar), 135.86 (-Ar), 133.66 (-Ar), 133.03 (-Ar), 132.47 (-Ar), 129.42 (-Ar), 121.98 (-Ar), 121.61 (-Ar), 120.42 (-Ar), 111.53 (-Ar), 56.18 (-OCH₃), 20.84 (-CH₃).

HRMS: m/z [M + H]⁺ calcd: 242.1183; found: 242.1184.

4-Cyano-N-(p-tolyl)benzamide (7w)

Isolated yield: 86 mg (54%)^a; mp 178 °C.

IR (neat): 3339 (N-H), 1649 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.94 (d, J = 8.00 Hz, 2 H, -Ar), 7.87 (s, 1 H, -NH), 7.75 (d, J = 8.50 Hz, 2 H, -Ar), 7.49 (d, J = 8.00 Hz, 2 H, -Ar), 7.17 (d, J = 8.00 Hz, 2 H, -Ar), 2.33 (s, 3 H, -CH₃).

¹³C NMR (126 MHz, CDCl₃): δ = 163.80 (-C=O), 138.97 (-Ar), 135.02 (-Ar), 134.70 (-Ar), 132.55 (-Ar), 129.70 (-Ar), 127.74 (-Ar), 120.49 (-Ar), 117.89 (-CN), 115.29 (-Ar), 20.91 (-CH₃).

HRMS: m/z [M + H]⁺ calcd: 237.1030; found: 237.1028.

4-Methoxy-N-(o-tolyl)benzamide (7x)

Isolated yield: 62 mg (91%)^b, (35%)^b*; mp 160 °C.

IR (neat): 3279 (N-H), 1641 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.92 (d, J = 8.00 Hz, 1 H, -Ar), 7.84 (d, J = 8.50 Hz, 2 H, -Ar), 7.61 (br, 1 H, -NH), 7.26–7.18 (m, 2 H, -Ar), 7.11–7.04 (m, 1 H, -Ar), 6.97 (d, J = 9.00 Hz, 2 H, -Ar), 3.86 (s, 3 H, -OCH₃), 2.31 (s, 3 H, -CH₃).

¹³C NMR (126 MHz, CDCl₃): δ = 165.12 (-C=O), 162.48 (-Ar), 135.98 (-Ar), 130.49 (-Ar), 129.11 (-Ar), 128.99 (-Ar), 127.22 (-Ar), 126.85 (-Ar), 125.11 (-Ar), 123.09 (-Ar), 114.00 (-Ar), 55.45 (-OCH₃), 17.80 (-CH₃).

HRMS: m/z [M + H]⁺ calcd: 242.1183; found: 242.1174.

N-(Benzo[d][1,3]dioxol-5-yl)benzamide (7y)

Isolated yield: 47 mg (32%)^a; mp 135 °C.

IR (neat): 3329 (N-H), 1648 cm^–1 (C=O).

¹H NMR (500 MHz, CDCl₃): δ = 7.84 (br, 1 H, -NH), 7.82 (d, J = 9.00 Hz, 2 H, -Ar), 7.55–7.40 (m, 3 H, -Ar), 7.32 (s, 1 H, -Ar), 6.88 (d, J = 8.00 Hz, 1 H, -Ar), 6.74 (d, J = 8.00 Hz, 1 H, -Ar), 5.94 (s, 2 H, -CH₂).

¹³C NMR (126 MHz, CDCl₃): δ = 165.67 (-C=O), 147.87 (-Ar), 144.52 (-Ar), 134.87 (-Ar), 132.13 (-Ar), 131.73 (-Ar), 128.71 (-Ar), 126.96 (-Ar), 113.60 (-Ar), 108.07 (-Ar), 103.32 (-Ar), 101.30 (-CH₂).

HRMS: m/z [M + H]⁺ calcd: 242.0739; found: 242.0815.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We extend our sincere gratitude to the University of Johannesburg and the Centre for Synthesis and Catalysis. The National Research Foundation (NRF) is also acknowledged. Mr. Mutshi Nwamadi and the University of Stellenbosch are acknowledged for NMR analyses and HRMS analyses, respectively.

• References

• 1 Mgbeahuruike EE, Yrjönen T, Vuorela H, Holm Y. S. Afr. J. Bot. 2017; 112: 54
• 2 Dong WL, Xu JY, Xiong LX, Li ZM. Molecules 2012; 17: 10414
• 3 Santos Oliveira AJ. d. M, de Castro RD, Pessôa H. dL. F, Wadood A, de Sousa DP. BioMed Res. Int. 2019; 9209676
• 4 Ghose AK, Viswanadhan VN, Wendoloski JJ. J. Comb. Chem. 1999; 1: 55
• 5 Carey JS, Laffan D, Thomson C, Williams MT. Org. Biomol. Chem. 2006; 4: 2337
• 6 Bonnet U. CNS Drug Rev. 2003; 9: 97
• 7 Blough ER, Wu M. Front. Pharmacol. 2011; 2: 1
• 8 Mehta SK, Jindal N. AAPS PharmSciTech 2015; 16: 67
• 9 Black HR, Bailey J, Zappe D, Samuel R. Drugs 2009; 69: 2393
• 10 Constable DJ. C, Dunn PJ, Hayler JD, Humphrey GR, Leazer JL, Linderman RJ, Lorenz K, Manley J, Pearlman BA, Wells A, Zaks A, Zhang TY. Green Chem. 2007; 9: 411
• 11 Bryan MC, Dunn PJ, Entwistle D, Gallou F, Koenig SG, Hayler JD, Hickey MR, Hughes S, Kopach ME, Moine G, Richardson P, Roschangar F, Steven A, Weiberth FJ. Green Chem. 2018; 20: 5082
• 12 Montalbetti CA. G. N, Falque V. Tetrahedron 2005; 61: 10827
• 13 Ghosh AK, Shahabi D. Tetrahedron Lett. 2021; 63: 152719
• 14 McKnelly KJ, Sokol W, Nowick JS. J. Org. Chem. 2020; 85: 1764
• 15 Wu JW, Wu YD, Dai JJ, Xu HJ. Adv. Synth. Catal. 2014; 356: 2429
• 16 Nguyen TB, Sorres J, Tran MQ, Ermolenko L, Al-Mourabit A. Org. Lett. 2012; 14: 3202
• 17 Bantreil X, Kanfar N, Gehin N, Golliard E, Ohlmann P, Martinez J, Lamaty F. Tetrahedron 2014; 70: 5093
• 18 Wilson CR, Gessner RK, Moosa A, Seldon R, Warner DF, Mizrahi V, Soares de Melo C, Simelane SB, Nchinda A, Abay E, Taylor D, Njoroge M, Brunschwig C, Lawrence N, Boshoff HI. M, Barry CE. III, Sirgel FA, van Helden P, Harris CJ, Gordon R, Ghidelli-Disse S, Pflaumer H, Boesche M, Drewes G, Sanz O, Santos G, Rebollo-Lopez MJ, Urones B, Selenski C, Lafuente-Monasterio MJ, Axtman M, Lelièvre J, Ballell L, Mueller K, Street LJ, Ghorpade SR, Chibale K. J. Med. Chem. 2017; 60: 10118
• 19 Barak DS, Batra S. Chem. Rec. 2021; 21: 4059
• 20a Moshapo PT, Simelane SB. ARKIVOC 2020; 190
• 21 Owsley DC, Bloomberg JJ. Synthesis 1977; 118
• 22 Cheung CW, Ploeger ML, Hu X. Nat. Commun. 2017; 8: 1
• 23 Jain SK, Aravinda Kumar KA, Bharate SB, Vishwakarma RA. Org. Biomol. Chem. 2014; 12: 6465
• 24 Xiao F, Liu Y, Tang C, Deng GJ. Org. Lett. 2012; 14: 984
• 25 Ling L, Chen C, Luo M, Zeng X. Org. Lett. 2019; 21: 1912
• 26 Zhao S, Mankad NP. Org. Lett. 2019; 21: 10106
• 27 Peng JB, Li D, Geng HQ, Wu XF. Org. Lett. 2019; 21: 4878
• 28 Shen N, Cheung CW, Ma J.-A. Chem. Commun. 2019; 55: 13709
• 29 Cheung CW, Leendert Ploeger M, Hu X. Chem. Sci. 2018; 9: 655
• 30 Cooper AK, Burton PM, Nelson DJ. Synthesis 2020; 52: 565
• 31 Hosmane RS, Liebman JF. Struct. Chem. 2009; 20: 693
• 32 Lõkov M, Tshepelevitsh S, Heering A, Plieger PG, Vianello R, Leito I. Eur. J. Org. Chem. 2017; 4475
• 33 Khodja W, Leclair A, Rull-Barrull J, Zammattio F, Kutonova KV, Trusova ME, Felpin F, Rodriguez-Zubiri M. New J. Chem. 2016; 40: 8855
• 34 Barnard CF. J. Organometallics 2008; 27: 5402
• 35 Garrou PE, Heck RF. J. Am. Chem. Soc. 1976; 98: 4115
• 36 Peng JB, Geng HQ, Li D, Qi X, Ying J, Wu X. Org. Lett. 2018; 20: 4988
• 37 Wang Y, Zhu D, Tang L, Wang S, Wang Z. Angew. Chemie 2011; 123: 9079
• 38 Wang W, Cong Y, Zhang L, Huang Y, Wang X, Zhang T. Tetrahedron Lett. 2014; 55: 124
• 39 Ling L, Chen C, Luo M, Zeng X. Org. Lett. 2019; 21: 1912
• 40 Sakai N, Takeoka M, Kumaki T, Asano H, Konakahara T, Ogiwara Y. Tetrahedron Lett. 2015; 56: 6448
• 41 Cheung CW, Shen N, Wang S, Ullah A, Hu X, Ma J. Org. Chem. Front. 2019; 6: 756

Publication History

Received: 17 August 2022

Accepted: 19 August 2022

Article published online:
22 September 2022