MnO₂ catalyzed formylation of amines and transamidation of amides under solvent-free conditions

Abstract

A facile and efficient MnO₂ catalyzed one-pot protocol for formylation of amine and transamidation of primary and secondary amides by amines has been developed. The present methodology is operationally simple, inexpensive and scalable under solvent free conditions. A series of formylated and transamidated products were synthesized in good to excellent yields.

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Introduction

The amide linkage is one of the most prevalent bonds, being found in a wide variety of polymers, dyes, pharmaceuticals and biologically active compounds (Scheme 1).^1–4 It forms the primary backbone of all naturally occurring proteins and peptides (which is the basis of all life-forms), thus making it a ubiquitous functional group. From statistical figures, it is found that nearly one-fourth of all pharmaceutical drugs contain amide bond linkages.⁵

Scheme 1 Examples of molecules containing an amide functional group.

Traditionally, amides are synthesized by reaction of amines with activated carboxylic acids,⁶ acid chlorides,⁷ aldehydes,⁸ esters,⁹ oxidative coupling of alcohols with amines,¹⁰ ketone (aldoxime rearrangement).¹¹ However, these methods are limited by utilization of stoichiometric amount of activating reagents/oxidizing agents/base/acids with poor atom economy.

The transamidation involves the cleavage of an existing C–N bond and formation of a new C–N bond in amide functional groups.¹² In past decade, transamidation has gained great attention of various research groups. Nevertheless, these methods have several disadvantages: (a) the use of expensive, specialized metal complexes and metal oxide catalysts such as Zr(NMe₂)₄,¹³ CeO₂,¹⁴ Cp₂ZrCl₂,¹⁵ Nb₂O₅,¹⁶ Fe(III)¹⁷ and [Ru–NHC]¹⁸ (b) longer reaction time¹⁹ (c) inert reaction conditions²⁰ and (d) the use of different polar and non polar solvents.²¹ Moreover, most of these methods involve tedious workup procedures for the preparation of catalysts.^14,16 In 2014, Fu et al. reported microwave-assisted heteropolyanion-based ionic liquids catalyzed transamidation.²² However, the synthesis of ionic liquid require various organic solvents with inert condition. Williams and co-workers have carried out transamidation using hydroxylamine hydrochloride as an inorganic catalyst.²³ However; they used toluene as an organic solvent.

In the last few years, application of manganese oxide (MnO₂) has gained great attention not only as an oxidant but also as an excellent catalyst in organic transformations.²⁴ Recently, Singh and co-workers have reported a binuclear Mn(II) complex for the transamidation of caboxamides with amines.²⁵ However, this reported method is limited by the use of 2-benzoylpyridine and oxalic acid dihydrazide as ligand, tedious procedure for preparation of catalyst. Moreover, the substrate scope for formylation and transamidation is limited to acetamide. In addition, this protocol is not applicable for the gram-scale synthesis.

In continuation of our ongoing research on the development of facile and efficient protocols for C–N bond formation,²⁴ herein we report a simple and an inexpensive MnO₂ catalyzed formylation of aromatic amines and transamidation of primary and secondary amides with amines. The results of our studies are described herein.

Results and discussion

To optimize the reaction conditions, aniline 1a and formamide 2a were chosen as model substrates for the formylation reaction. A series of experiments were carried out to study the effect of various reaction parameters such as catalyst loading, temperature and time. Initially, various commercially available Mn based catalysts were screened such as MnSO₄·H₂O, MnCl₂·4H₂O, Mn(OAc)₂·4H₂O, MnO₂ and KMnO₄ (Table 1, entries 1–5). It was observed that all Mn based catalysts showed good catalytic activity for the formylation of 1a with 2a to give formanilide 3aa and MnO₂ was found to be the best catalyst as it furnished maximum yield of 3aa (Table 1, entry 4). In the absence of the catalyst, only trace amount of 3aa was observed (Table 1, entry 6). To our delight, increase in temperature has significant effect on the yield of 3aa and it was found that a maximum yield of 97% of the desired product 3aa was formed at 150 °C (Table 1, entry 7). Further increase in the reaction temperature has no effect on the yield of 3aa (Table 1, entry 8). Next, the reaction time was studied (Table 1, entries 9–12), and it revealed that the reaction time could be reduced to 3 h from 12 h (Table 1, entry 11). However, decreasing the reaction time to 2 h resulted in a considerable decrease in the yield of 3aa (Table 1, entry 12). In the next set of experiments, catalyst loading was studied (Table 1, entries 15 and 16). It was found that decreasing the catalyst loading from 10 mol% to 5 mol% resulted in the decrease of yield of 3aa (Table 1, entry 15). However, increasing the catalyst loading from 10 mol% to 20 mol% did not affect the yield of 3aa, even after carrying out the reaction for 12 h (Table 1, entry 16).

Table 1 Optimization of reaction conditions^a

Entry	Catalyst (mol%)	Time (h)	Temp (°C)	Yield^b (%)
a Reaction conditions: aniline 1a (2 mmol), formamide 2a (4 mmol) under solvent-free conditions.b G. C. yields.c Reaction time 12 h.
Catalyst screening
1	MnSO4·H2O (10)	12	140	80
2	MnCl2·4H2O (10)	12	140	74
3	Mn(OAc)2·4H2O (10)	12	140	75
4	MnO2 (10)	12	140	81
5	KMnO4 (10)	12	140	72
6	—	12	140	Trace
Effect of time and temperature
7	MnO2 (10)	12	150	97
8	MnO2 (10)	12	160	97
9	MnO2 (10)	6	150	97
10	MnO2 (10)	4	150	97
11	MnO2 (10)	3	150	97
12	MnO2 (10)	2	150	54
Effect of catalyst loading
15	MnO2 (5)	3	150	82
16	MnO2 (20)	3	150	97, 97^c

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With these optimized reaction conditions in hand, substrate scope of this protocol was studied for the formylation of a wide range of aromatic amines and these results are summarized in Table 2. In general, aniline 1a reacts with formamide 2a to give the corresponding formylated product 3aa in 95% yield. Aniline derivatives with electron-donating groups such as –Me and –OMe at para- and meta-position were employed, and it was observed that, the formylation reaction with electron rich anilines offers excellent yields 3ba–3da. Next, the steric effect was studied and it was found that ortho-methoxy aniline, 2,4,6-trimethyl aniline and 2,6-diethyl aniline provided low yield of 3ea–3ga as compared to 3ba–3da. The para-OCHF₂ substituted aniline also gave an excellent yield of 89% of 3ha. Weakly electron withdrawing groups such as –Br and –F on the aniline, afforded corresponding products 3ia and 3ja in excellent yields.

Table 2 Substrate scope of formylation of aniline derivatives^a,b

a Reaction conditions: aniline derivatives 1a–1j (2 mmol), formamide 2a (4 mmol), MnO₂ (10 mol%) in a sealed tube for 3 h at 150 °C.b Yield of isolated pure product.

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After the study of formylation reaction, the study of transamidation of primary amide with benzylamine was carried out and the corresponding results are shown in Table 3. Firstly, we initiated our work by choosing benzamide 4a and benzylamine 5a as model substrates under the same reaction parameters as that of formylation reaction. This resulted in a 56% yield of 6aa. Encouraged by this result, we increased the catalyst loading and the reaction was run for a longer period of time. To our delight, the yield of 6aa went up to 93% (Table 3, entry 1). Thus, the optimized reaction conditions of transamidation are: 4a (2 mmol), 5a (4 mmol), MnO₂ (20 mol%) at 150 °C for 12 h. Under the optimized reaction conditions, scope of this methodology was explored for various aromatic and aliphatic amides with different amines. As shown in Table 2, all the substrates examined provided excellent to good yields. Effects of electron donating and withdrawing groups were also studied. It was found that electron donating groups on benzamide 4a produced corresponding products 6ba–6fa in excellent yields (Table 3, entries 2–6). Subsequently, the reaction of 4a bearing electron weakly withdrawing groups also furnished corresponding amides 6ag–6aj in good to moderate yields (Table 3, entries 7–10). However, the amide 4k bearing two –NO₂ groups provided only 24% yield of 6ka (Table 1, entry 11). Interestingly, the reaction could also tolerate aliphatic amide 4l thus leading to the formation of products 6la and 6lb respectively (Table 3, entry 12 and 13). In the next set of experiments, we explored the substrate scope of benzylamines. The electron donating groups on benzylamine 5a at para- and ortho-positions provided the products 6ab–6ae in excellent yields (Table 3, entries 14–17). Benzyl amine containing weak electron withdrawing groups reacts smoothly with benzamide afforded corresponding products with good yield 6af–6ag. The benzyl amine containing –CN group at para position furnishes moderate yield of product 6ah.

Table 3 Substrates cope of transamidation of amide by amine

Entry	Primary amides	Amines	Products	Yield^b (%)
a Reaction conditions: primary amide derivatives 4a–4r (2 mmol), amine 5a–5h (4 mmol), MnO2-catalyst (20 mol%) in a sealed tube for 12 h at 150 °C.b Isolated yields.
1				93
2		5a		91
3		5a		90
4		5a		83
5		5a		89
6		5a		86
7		5a		82
8		5a		71
9		5a		77
10		5a		65
11		5a		27
12		5a		81
13	4l			83
14	4a	5b		90
15	4a			93
16	4a			81
17	4a			87
18	4a			82
19	4a			83
20	4a			64

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Finally, we investigated transamidation of phthalimide (secondary amide) with various primary amines (Table 4). Phthalimides are widely used in organic transformations as a precursor for dyestuffs, drugs and in fine chemicals.²⁶ Initially, the reaction parameters were optimized by using phthalimide 7a (2 mmol) and aniline 8a (4 mmol) in the presence of 10 mol% of MnO₂ catalyst at 150 °C for 3 h. Unfortunately, a very low yield of 36% of the desired product 9aa was obtained. However, when the reaction was carried out for 12 h, an excellent yield of 98% of 9aa was obtained. Thus, the optimized reaction conditions of transamidation of phthalimide are: 7a (2 mmol), 8a (4 mmol), MnO₂ (10 mol%), at 150 °C for 12 h.

Table 4 MnO₂ catalysed transamidation of phthalimide with primary amines^a,b

a Reaction conditions: phthalimide 9a (2 mmol), amine derivatives 8a–8o (4 mmol), catalyst (10 mol%) in a sealed tube for 12 h at 150 °C.b Isolated yields.

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Various transamidated products of phthalimide with anilines and benzylamines were synthesised in good to excellent yields (78–98%). Aniline and benzylamine with electron donating substituents at para- and meta-position gave excellent yields whereas sterically hindered ortho-substituted aniline and benzylamine gave corresponding products 9ab–9al in good yields. Benzylamine containing weakly electron withdrawing groups such as –Cl, –F and –CN gave good to excellent yields of products 9am–9ao.

To demonstrate the synthetic utility of this developed protocol, gram scale reactions were carried out by employing 1.02 g (11 mmol) of aniline 1a under the standard reaction condition (Scheme 2, eqn (a)). This transformation proceeded smoothly to give 1.14 g (86%) of formanilide 3aa (eqn (b), Scheme 2). Further, transamidation of both benzamide and phthalimide with benzylamine and aniline were also carried out successfully and provided corresponding products 6aa and 9aa in good isolated yields 1.66 g (79%) and 1.26 g (81%) respectively (Scheme 2, eqn (b) and (c)).

Scheme 2 Gram scale formylation and transamidation reaction.

A plausible reaction mechanism for the MnO₂ catalyzed transamidation reactions is proposed (Scheme 3). Manganese acts as a Lewis acid possessing strong adjacent basic sites. It is believed that the reaction first precedes with the formation of a six-member intermediate¹⁵ I by addition of A and B to MnO₂ This is followed by a proton transfer which takes place from B to MnO₂ resulting in the formation of intermediate II which further isomerises to intermediate III. This intermediate collapses to afford the product along with expulsion of ammonia and simultaneous regeneration of MnO₂. The regenerated MnO₂ is available for the subsequent catalytic cycle.

Scheme 3 Plausible mechanism for MnO₂ catalyzed transamidation reaction.

Conclusions

In conclusion, we have developed a simple and synthetically efficient protocol for the synthesis of N-substituted amides by carrying out formylation and transamidation reactions catalyzed by MnO₂. The present methodology involves the use of relatively inexpensive Mn catalyst as compared to other expensive transition metals reported. Additionally, the protocols do not require inert atmosphere, take place in less reaction time, solvent free (neat) reaction conditions, are scalable and provide good to excellent yield of the products.

General procedure

All reactions were carried out in oven-dried glassware. All derivatives of amine, amide and MnO₂ were purchased from Aldrich, Alfa Aesar, Spectrochem and Thomas Baker. Analytical TLC was performed with 60 F254 silica gel plates (0.25 mm thickness). Column chromatography was performed with silica gel (100–200 mesh). NMR spectra were recorded with an Agilent Technologies (¹H NMR at 500 MHz, ¹³C NMR at 125 MHz) spectrometer. The chemical shifts are reported in ppm relative to tetramethylsilane as internal standard and the coupling constant in Hz. GC yields were obtained with a Perkin Elmer Clarus 400 instrument with an ELITE-1 column. The mass spectrometry was performed with a Shimadzu instrument in Electro Spray Ionization (ESI) mode.

(I) Experimental procedure for MnO₂ catalyzed formylation of aniline using formamide

An oven dried 15 mL glass vial with a magnetic bar was charged with aniline (1a, 2 mmol, 186 mg), formamide (2a, 4 mmol, 180 mg) and MnO₂ (10 mol%, 8.7 mg), the reaction mixture was stirred for 3 h at 150 °C. After completion of reaction, the reaction mixture was cooled to room temperature. All volatiles were removed under vacuum. The product was extracted with 20 mL of ethyl acetate and the organic layer was washed with saturated aq. HCl (20 mL) and dried over Na₂SO₄ and the solvent was removed under vacuum. The formylated amide product was purified by column chromatography (silica gel, 100–200 mesh).

(II) Experimental procedure for MnO₂ catalyzed transamidation of benzamide with benzylamine

An oven dried 15 mL glass vial with a magnetic bar was charged with MnO₂ (20 mol%, 17.4 mg), benzamide (4a, 2 mmol, 242 mg), benzylamine (5a, 4 mmol, 428 mg), the reaction mixture was stirred for 12 h at 150 °C in 15 mL. After completion of reaction, the reaction mixture was cooled to room temperature. All volatiles were removed under vacuum. The product was extracted with 20 mL of ethyl acetate and the organic layer was washed with saturated aq. HCl (20 mL) and dried over Na₂SO₄ and the solvent was then removed under vacuum. The N-benzylbenzamide product was purified by column chromatography (silica gel, 100–200 mesh).

(III) Experimental procedure MnO₂ catalyzed transamidation of phthalimide with aniline

An oven dried 15 mL glass vial with a magnetic bar was charged with MnO₂ (10 mol%, 8.7 mg), phthalamide (7a, 2 mmol, 370 mg), aniline (8a, 4 mmol, 372 mg), the reaction mixture was stirred for 12 h at 150 °C. After completion of reaction, the reaction mixture was cooled to room temperature. All volatiles were removed under vacuum. The product was extracted with 20 mL of ethyl acetate and the organic layer was washed with saturated aq. HCl (20 mL) and dried over Na₂SO₄ and the solvent was then removed under vacuum. The transamidated amide product was purified by column chromatography (silica gel, 100–200 mesh).

Representative analytical data

N-Phenylformamide (3aa)¹⁷

Pale brownish solid ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 8.91 (d, J = 11.0 Hz, 1H), 8.49 (d, J = 11.5 Hz, 1H), 8.43 (s, 1H), 8.23 (d, J = 1.8 Hz, 1H), 7.46–7.40 (m, 2H), 7.08–6.96 (m, 2H), 6.89–6.74 (m, 4H), 3.77 (s, 3H), 3.74 (s, 3H).

N-(4-Methoxyphenyl)formamide (3ba)¹⁸

Yellow oil; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 8.54 (d, J = 11.4 Hz, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 7.80 (s, 1H), 7.31 (dd, J = 33.9, 3.5 Hz, 2H), 6.92 (dd, J = 8.6, 2.3 Hz, 1H), 6.80 (dd, J = 19.0, 8.5 Hz, 2H), 6.66 (dd, J = 8.5, 2.4 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 3.85 (d, J = 10.1 Hz, 12H).

N-(3-Methoxyphenyl)formamide (3ca)^27a

Yellow oil; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 8.69 (s, 2H), 8.35 (d, J = 1.7 Hz, 1H), 7.82 (s, 1H), 7.34–7.16 (m, 3H), 7.09–6.98 (m, 1H), 6.78–6.57 (m, 4H), 4.01–3.67 (m, 6H).

N-(3,4-Dimethoxyphenyl)formamide (3da)^27b

Yellow oil; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 8.53 (d, J = 11.5 Hz, 1H), 8.33 (s, 1H), 7.89 (d, J = 10.0 Hz, 1H), 7.57 (ddd, J = 43.5, 22.4, 1.7 Hz, 1H), 7.39–7.25 (m, 3H), 7.03–6.88 (m, 2H), 6.82 (dd, J = 15.0, 8.5 Hz, 2H), 6.70–6.60 (m, 2H), 3.98 (d, J = 6.3 Hz, 2H), 3.89–3.86 (m, 11H).

N-(2-Methoxyphenyl)formamide (3ea)^27c

Yellow solid; ¹H NMR (400 MHz, CDCl₃) δ_H/ppm 8.67–8.29 (m, 2H), 8.07 (d, J = 83.8 Hz, 1H), 7.13–6.94 (m, 1H), 6.93–6.75 (m, 2H), 3.77 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ_C/ppm 161.89, 159.26, 148.90, 147.98, 126.75, 126.07, 125.34, 124.27, 120.98, 120.86, 120.41, 117.05, 111.31, 110.15, 55.66; GCMS (EI, 70 eV): m/z (%): 151 (72.3, M⁺), 123 (35.3), 108 (100.0), 92 (5.9), 80 (62.6), 65 (16.8), 52 (15.8).

N-Mesitylformamide (3fa)^27d

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 8.40–8.03 (m, 1H), 6.92 (d, J = 15.2 Hz, 3H), 2.26 (dd, J = 22.2, 18.4 Hz, 9H).

N-(2,6-Diethylphenyl)formamide (3ga)^27d

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 8.31 (d, J = 1.5 Hz, 1H), 8.05 (d, J = 11.9 Hz, 1H), 7.82 (d, J = 10.8 Hz, 1H), 7.41 (s, 1H), 7.30–7.20 (m, 2H), 7.13 (dd, J = 19.7, 7.6 Hz, 4H), 2.62 (dd, J = 43.4, 7.6 Hz, 8H), 1.26–1.13 (m, 12H).

N-(4-(Difluoromethoxy)phenyl)formamide (3ha)

Yellow oil; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 8.64 (t, J = 18.8 Hz, 1H), 8.34 (s, 1H), 7.87 (s, 1H), 7.54 (d, J = 8.9 Hz, 2H), 7.11 (dt, J = 17.4, 8.6 Hz, 5H), 6.48 (td, J = 73.7, 10.0 Hz, 2H).

N-(3-Bromophenyl)formamide (3ia)^27a

Yellow solid; ¹H NMR (400 MHz, CDCl₃) δ_H/ppm 9.37–8.62 (m, 2H), 8.30 (s, 1H), 7.78 (s, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.22–6.95 (m, 3H), 3.25 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ_C/ppm 162.99, 160.15, 138.24, 138.17, 131.03, 130.37, 128.19, 127.75, 123.22, 123.13, 122.53, 121.55, 118.71, 117.15; GCMS (EI, 70 eV): m/z (%): 201 (54.1, M⁺), 199 (57.7), 173 (47.6), 171 (49.3), 143 (3.8), 145 (3.6), 92 (99.3), 65 (100.0), 50 (6.9).

N-(2-Fluorophenyl)formamide (3ja)^27d

Yellow oil; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 8.69 (d, J = 11.3 Hz, 1H), 8.47 (s, 2H), 8.32 (t, J = 8.0 Hz, 2H), 7.78 (d, J = 86.1 Hz, 3H), 7.25 (dd, J = 13.2, 3.6 Hz, 1H), 7.19–7.02 (m, 8H).

N-Benzylbenzamide (6aa)¹⁶

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.79 (dd, J = 5.0, 3.9 Hz, 2H), 7.52–7.41 (m, 3H), 7.35 (d, J = 4.4 Hz, 4H), 7.30 (dd, J = 8.8, 4.5 Hz, 1H), 6.61 (br s, 1H), 4.64 (d, J = 5.7 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ_C/ppm 167.43, 138.19, 134.33, 131.55, 128.76, 128.58, 127.89, 127.59, 126.99, 44.10; GCMS (EI, 70 eV): m/z (%): 211 (47.6, M⁺), 105 (100.0), 91 (10.7), 77 (65.1), 51 (20.2).

N-Benzyl-4-methylbenzamide (6ba)¹⁶

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.70 (d, J = 7.8 Hz, 2H), 7.35 (d, J = 4.3 Hz, 3H), 7.30 (dd, J = 8.5, 4.2 Hz, 1H), 7.23 (d, J = 7.8 Hz, 2H), 6.49 (s, 1H), 4.64 (d, J = 5.6 Hz, 2H), 2.39 (s, 3H).

N-Benzyl-3-methylbenzamide (6ca)^28a

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.63 (s, 1H), 7.57 (dd, J = 4.2, 2.8 Hz, 1H), 7.43–7.21 (m, 7H), 4.63 (d, J = 5.7 Hz, 2H), 2.38 (s, 3H).

N-Benzyl-4-methoxybenzamide (6ea)²¹

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.77 (d, J = 8.7 Hz, 2H), 7.39–7.22 (m, 4H), 6.93–6.85 (m, 2H), 6.64 (s, 1H), 4.60 (d, J = 5.5 Hz, 2H), 3.83 (s, 3H).

N-Benzyl-4-chlorobenzamide (6ga)¹⁵

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.72 (dd, J = 8.8, 2.2 Hz, 2H), 7.48–7.24 (m, 7H), 6.61 (s, 1H), 4.61 (d, J = 5.7 Hz, 2H).

N-Benzyl-2-chlorobenzamide (6ha)^28b

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 8.14 (t, J = 7.9 Hz, 1H), 7.54–7.43 (m, 1H), 7.39–7.27 (m, 5H), 7.11 (dd, J = 12.1, 8.3 Hz, 2H), 4.69 (d, J = 5.7 Hz, 2H).

N-Benzyl-2-fluorobenzamide (6ia)^28c

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 8.14 (t, J = 8 Hz, 1H), 7.53–7.44 (m, 1H), 7.41–7.25 (m, 5H), 7.11 (dd, J = 12, 8 Hz, 2H), 4.69 (d, J = 5.7 Hz, 2H).

N-Benzyl-3,5-dinitrobenzamide (6ka)^28d

Yellow solid; ¹H NMR (500 MHz, DMSO) δ_H/ppm 9.08–8.59 (m, 2H), 7.39 (ddd, J = 34.2, 23.6, 7.3 Hz, 2H), 4.08 (s, 1H).

N-Benzylacetamide (6la)¹⁸

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.39–7.13 (m, 5H), 6.38 (s, 1H), 4.36 (t, J = 6.7 Hz, 2H), 2.00–1.91 (m, 3H).

N-(4-Methoxybenzyl)benzamide (6ab)¹⁶

White solid; ¹H NMR (400 MHz, CDCl₃) δ_H/ppm 7.76 (d, J = 6.7 Hz, 2H), 7.41 (dd, J = 26.0, 6.8 Hz, 3H), 7.24 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 6.59 (br s, 1H), 4.52 (d, J = 4.9 Hz, 2H), 3.76 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ_C/ppm 167.28, 159.05, 134.39, 131.45, 130.24, 129.25, 128.52, 126.93, 114.10, 55.28, 43.58; GCMS (EI, 70 eV): m/z (%): 241 (27.5, M⁺), 221 (7.3), 207 (42.9), 191 (6.7), 121 (10.5), 105 (45.3), 91 (20.0), 77 (70.3), 55 (40.2), 39 (100.0).

N-(4-(tert-Butyl)benzyl)benzamide (6ac)^28d

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.80 (dd, J = 4.3, 3.9 Hz, 2H), 7.58–7.47 (m, 1H), 7.44–7.35 (m, 4H), 7.33–7.26 (m, 2H), 6.62 (s, 1H), 4.60 (d, J = 5.5 Hz, 2H), 1.33 (d, J = 1.3 Hz, 9H).

N-(2-Methoxybenzyl)benzamide (6ad)^28e

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.93–7.69 (m, 2H), 7.48 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.5 Hz, 2H), 7.35 (d, J = 7.3 Hz, 1H), 7.28 (dd, J = 13.0, 4.3 Hz, 1H), 7.05–6.86 (m, 2H), 6.76 (s, 1H), 4.64 (d, J = 5.8 Hz, 2H), 3.88 (s, 3H).

N-(Benzo[d][1,3]dioxol-5-ylmethyl)benzamide (6ae)^28f

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.78 (d, J = 6.6 Hz, 2H), 7.54–7.45 (m, 1H), 7.39 (dd, J = 10.0, 5.1 Hz, 2H), 6.84–6.73 (m, 3H), 6.67 (s, 1H), 5.92 (d, J = 2.7 Hz, 2H), 4.51 (dd, J = 4.9, 2.9 Hz, 2H).

N-(3-Chlorobenzyl)benzamide (6ag)^19b

White solid; ¹H NMR (400 MHz, CDCl₃) δ_H/ppm 7.76 (d, J = 7.2 Hz, 2H), 7.43 (d, J = 5.5 Hz, 1H), 7.33 (s, 2H), 7.17 (t, J = 22.8 Hz, 4H), 4.47 (d, J = 3.3 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ_C/ppm 167.70, 140.46, 134.37, 133.99, 131.62, 129.88, 128.52, 127.64, 127.50, 127.09, 127.07, 125.75, 43.29; GCMS (EI, 70 eV): m/z (%): 245 (6.8, M⁺), 135 (5.1), 105 (50.0), 103 (36.0), 91 (3.7), 77 (35.4), 76 (17.5), 51 (15.4), 32 (100.0).

N-(4-Cyanobenzyl)benzamide (6ah)^28g

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.80 (d, J = 7.9 Hz, 2H), 7.58 (d, J = 7.9 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.48–7.22 (m, 4H), 6.94 (s, 1H), 4.66 (d, J = 5.7 Hz, 2H).

2-Phenylisoindoline-1,3-dione (9aa)^21b

White solid; ¹H NMR (400 MHz, CDCl₃) δ_H/ppm 7.94–7.92 (m, 2H), 7.78–7.77 (m, 2H), 7.45 (dt, J = 17.7, 8.1 Hz, 5H); ¹³C NMR (101 MHz, CDCl₃) δ_C/ppm 167.26, 134.37, 131.72, 131.62, 129.09, 128.09, 126.55, 123.73; GCMS (EI, 70 eV): m/z (%): 223 (100.0, M⁺), 207 (18.2), 179 (60.4), 152 (7.5), 111 (6.9), 104 (26.8), 76 (58.6), 50 (15.6).

2-(p-Tolyl)isoindoline-1,3-dione (9ab)^19b

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.96–7.94 (m, 2H), 7.80–7.78 (m, 2H), 7.32–7.27 (m, 4H), 2.42 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ_C/ppm 167.46, 138.21, 134.33, 131.80, 129.80, 128.67, 126.47, 123.70, 21.24; GCMS (EI, 70 eV): m/z (%): (100.0, M⁺), 193 (41.9), 165 (8.1), 117 (10.2), 104 (18.2), 90 (9.5), 76 (43.1), 50 (12.9).

2-(4-Methoxyphenyl)isoindoline-1,3-dione (9ac)^19b

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.95–7.93 (m, 2H), 7.79–7.77 (m, 2H), 7.35–7.33 (m, 2H), 7.04–7.00 (m, 2H), 3.84 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ_C/ppm 167.61, 159.22, 134.33, 134.28, 131.77, 127.96, 124.21, 123.67, 123.54, 114.46, 55.51; GCMS (EI, 70 eV): m/z (%): 253 (100.0, M⁺), 238 (54.8), 210 (17.7), 130 (15.3), 106 (13.8), 76 (25.6).

2-(3-Methoxyphenyl)isoindoline-1,3-dione (9ad)^29a

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 8.01–7.91 (m, 2H), 7.85–7.73 (m, 2H), 7.42 (t, J = 7.9 Hz, 1H), 7.07–6.90 (m, 3H), 3.84 (s, 3H).

2-(2-Methoxyphenyl)isoindoline-1,3-dione (9ae)^29b

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.96–7.77 (m, 4H), 7.46–7.42 (m, 1H), 7.28–7.26 (m, 1H), 7.10–7.05 (m, 2H), 3.80 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ_C/ppm 167.42, 155.39, 134.29, 134.13, 132.23, 130.70, 129.98, 123.67, 123.56, 120.86, 120.20, 112.12, 55.82; GCMS (EI, 70 eV): m/z (%): 253 (100.0, M⁺), 235 (38.7), 224 (16.3), 210 (10.4), 195 (7.3), 179 (32.0), 154 (5.8), 120 (17.9), 104 (43.3), 76 (60.2), 50 (15.2).

2-Mesitylisoindoline-1,3-dione (9af)^29c

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.97 (dd, J = 4.4, 3.3 Hz, 2H), 7.80 (dd, J = 4.4, 3.2 Hz, 2H), 7.01 (s, 2H), 2.34 (s, 3H), 2.13 (s, 6H).

2-(2-Fluorophenyl)isoindoline-1,3-dione (9ag)^29d

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 8.01–7.93 (m, 2H), 7.85–7.76 (m, 2H), 7.46 (ddd, J = 8.2, 7.1, 4.1 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.28 (ddd, J = 9.6, 8.7, 7.6 Hz, 2H).

2-Benzylisoindoline-1,3-dione (9ah)²⁰

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.85 (dd, J = 5.2, 3.1 Hz, 2H), 7.71 (dd, J = 5.3, 3.1 Hz, 2H), 7.44 (d, J = 7.5 Hz, 2H), 7.35–7.24 (m, 3H), 4.85 (s, 2H).

2-(4-(tert-Butyl)benzyl)isoindoline-1,3-dione (9ai)^29e

White solid; ¹H NMR (500 MHz, cdcl₃) δ 7.84 (dd, J = 5.2, 3.1 Hz, 2H), 7.70 (dd, J = 5.3, 3.0 Hz, 2H), 7.36 (dd, J = 23.0, 8.3 Hz, 4H), 4.83 (s, 2H), 1.29 (s, 9H).

2-(4-Methoxybenzyl)isoindoline-1,3-dione (9aj)^29f

White solid; ¹H NMR (400 MHz, CDCl₃) δ_H/ppm 7.74 (d, J = 2.4 Hz, 2H), 7.60 (s, 2H), 7.36–7.26 (m, 2H), 6.78 (dd, J = 4.6, 3.3 Hz, 2H), 4.72 (s, 2H), 3.70 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ_C/ppm 167.99, 159.14, 133.87, 132.08, 130.09, 128.63, 123.20, 113.93, 55.19, 40.99; GCMS (EI, 70 eV): m/z (%): 241 (27.5, M⁺), 221 (7.3), 207 (42.9), 191 (6.7), 121 (10.5), 105 (45.3), 91 (20.0), 77 (70.3), 55 (40.2), 39 (100.0).

2-(2-Methoxybenzyl)isoindoline-1,3-dione (9ak)^29g

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.92–7.81 (m, 2H), 7.76–7.67 (m, 2H), 7.30–7.13 (m, 2H), 6.88 (td, J = 8.6, 5.6 Hz, 2H), 4.92 (s, 2H), 3.85 (s, 3H).

2-(Benzo[d][1,3]dioxol-5-ylmethyl)isoindoline-1,3-dione (9al)^29h

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.84 (dd, J = 5.4, 3.1 Hz, 2H), 7.70 (dd, J = 5.4, 3.0 Hz, 2H), 6.93 (d, J = 7.8 Hz, 2H), 6.74 (d, J = 7.7 Hz, 1H), 5.91 (s, 2H), 4.75 (s, 2H).

2-(4-Fluorobenzyl)isoindoline-1,3-dione (9an)²⁹ⁱ

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm 7.95–7.82 (m, 2H), 7.78–7.70 (m, 2H), 7.64–7.57 (m, 2H), 7.51 (d, J = 8.2 Hz, 2H), 4.88 (s, 2H).

4-((1,3-Dioxoisoindolin-2-yl)methyl)benzonitrile (9ao)^29d

White solid; ¹H NMR (500 MHz, CDCl₃) δ_H/ppm δ 7.87 (dd, J = 5.3, 3.2 Hz, 2H), 7.75 (dd, J = 5.5, 3.0 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 4.89 (s, 2H).

Acknowledgements

SLY is grateful to the Council of Scientific and Industrial Research (CSIR), New Delhi, India for providing Junior Research Fellowship (JRF).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C-NMR. See DOI: 10.1039/c5ra13094h

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