Cu-catalyzed aerobic oxidative C–CN bond cleavage of benzyl cyanide for the synthesis of primary amides

Abstract

An efficient method via copper-catalyzed aerobic oxidative amidation of benzyl cyanide for primary amides is successfully developed. Using readily available NH₄Cl as a nitrogen source and Cu/O₂ as a catalytic oxidation system offers new opportunities for C–CN bond cleavage and primary amide bond formation.

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Primary amides are prevalent organic motifs in peptide, protein synthesis, intensifiers of perfume, anti-block reagents, color pigments for inks, detergents, and lubricants.¹ Generally, the synthetic procedures for the preparation of primary amides are rely on the reaction of carboxylic acid,² or its derivatives with ammonia or ammonium salt.³ However, toxic and corrosive, materials, low functional groups tolerance and complex operation are generally required in conventional synthetic procedures. To overcome these problems, alternative methods for primary amide synthesis have been developed. The direct amidation of aldehydes,⁴ alcohols,⁵ or methylarenes⁶ to primary amides represents an interesting topic in this area, however, hazardous peroxides (TBHP), the toxic halogens, or an excess amount of molecular sieves were required. Other attractive approaches include the hydration of nitriles,⁷ oxidative amidation of terminal alkynes,⁸ transition-metal-catalyzed C–H activation and amidation⁹ and catalytic oxidation C–C bond cleavage of ketones into benzamides.¹⁰ Although great progress has been achieved in this field, there still remains significant challenges for synthetic organic chemists in reactivity, efficiencies, and high functional group tolerance.

Recently, C–C bond cleavage has become an attractive topic because of its potential usage in new chemical bond formation via inert starting materials.¹¹ Also molecular oxygen has been considered as an ideal oxidant due to its atom-economical, environmentally benign, and abundance.¹² However, few reactions are compatible with aerobic oxidation¹³ and C–C bond cleavage in one transformation.¹⁴ Therefore, the development of an efficient catalytic system towards aerobic oxidative unstrained C–C bonds cleavage is always highly desired. As our continued interest in Cu or Fe-catalyzed aerobic oxidative C–C bond cleavage reaction,¹⁵ we developed a Cu-catalyzed aerobic oxidative C–C bond cleavage of benzyl cyanide for the synthesis of primary amides. Using readily available NH₄Cl as a nitrogen source and a Cu/O₂ catalytic oxidation system offers new opportunities for primary amide bond formation. The developed methodology tolerated a wide range of functional groups and produced high yields for the synthesis of primary amides.

We carried out experiments to test the reactivity of benzyl cyanide 1a with ammonium salts in the presence of a metal catalyst under an oxygen atmosphere and the obtained results are compiled in Table 1. First, our studies started with the reaction between benzyl cyanide 1a and 5.0 equiv. of ammonia (25% aqueous) in CH₃CN at 120 °C (Table 1, entries 1–5). When 5 mol% of CuCl was used as catalyst, the benzamide 2a was obtained in 38% yield along with the hydration of nitrile products 2b (Table 1, entry 1). We then screened the types of catalysts, and discovered that CuCl₂ or Cu₂O produces higher yields (Table 1, entries 4–5). However the products 2b was always by a product. Then, optimization studies were performed to improve the yield of 2a. To our surprise, when ammonia was replaced with NH₄Cl, 2a was obtained in 50% yield, and only trace amounts 2b was observed (Table 1, entry 6). Four bases were tested using Cu₂O as the catalyst in CH₃CN, and NaOH showed the highest yield (Table 1, entries 6–9). Several copper salts and amine salts were screened (Table 1, entries 10–16), and the best result was obtained under Cu₂O/NH₄Cl/NaOH system (Table 1, entry 9). Noteworthily, NaOH is essential for this reaction. In the absence of NaOH, 2a could not be obtained at all (Table 1, entry 17). The reaction did not proceed in the absence of copper catalyst (Table 1, entry 18). The reaction was also dependent on dioxygen; when air was used as the oxidant, only trace of 2a was obtained (Table 1, entry 19). Other solvents such as, toluene and DMF gave lower yields (Table 1, entries 20–21).

Table 1 Optimization of the reaction conditions^a

Entry	Cat	[N] source	Base	2a^b%	2b^b%
a Reaction conditions: 2-benzyl cyanide 1a (0.2 mmol), cat (5 mol%), N source (0.3 mmol), base (0.4 mmol), CH3CN (2 mL), in 25 mL Schlenk tube, 120 °C, O2 (1 atm), 30 h.b Yields were determined by GC using n-hexadecane as an internal standard.c Air was used as oxidant.d Toluene as solvent.e DMF as solvent.
1	CuCl	NH3·H2O	—	35	20
2	Cu(OAc)2	NH3·H2O	—	25	30
3	CuO	NH3·H2O	—	40	41
4	CuCl2	NH3·H2O	—	50	25
5	Cu2O	NH3·H2O		50	31
6	Cu2O	NH4Cl	Ba(OH)2	50	<1
7	Cu2O	NH4Cl	KOH	58	<1
8	Cu2O	NH4Cl	Ca(OH)2	20	<1
9	Cu2O	NH4Cl	NaOH	88	<1
10	CuCl	NH4Cl	NaOH	71	<1
11	CuCl2	NH4Cl	NaOH	65	<1
12	Cu(OAc)2	NH4Cl	NaOH	58	<1
13	Cu2O	NH4OAc	NaOH	63	<1
14	Cu2O	(NH4)2SO4	NaOH	50	<1
15	Cu2O	(NH4)2CO3	NaOH	71	<1
16	Cu2O	Urea	NaOH	<1	<1
17	Cu2O	NH4Cl	—	—	<1
18	—	NH4Cl	NaOH	—	<1
19^c	Cu2O	NH4Cl	NaOH	Trace	Trace
20^d	Cu2O	NH4Cl	NaOH	20	<1
21^e	Cu2O	NH4Cl	NaOH	13	<1

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With the optimal conditions in hand, the scope of copper-catalyzed aerobic oxidative amidation of substituted 2-benzyl cyanides with “NH₂” producing primary amides was investigated, the results were compiled in Table 2. A variety of 2-benzyl cyanide with either an electron-donating or an electron-withdrawing group, were all converted readily to the corresponding primary amides efficiently. Thus, in addition to 2-benzyl cyanide, benzyl cyanide with electron-donating substituents methyl (–CH₃), methoxy (–OCH₃) reacted smoothly with NH₄Cl/NaOH to provide the corresponding primary amides 2a–2c (Table 2, entries 1–3). However, when hydroxyl (–OH) substituted 2-benzyl cyanide was used as a substrate, none of the expected products were detected. This may have been due to the interaction between the hydroxyl and base or oxidizing agent, which would hinder the C–CN bond activation (Table 2, entry 4). Benzyl cyanide with fluoro (–F), chloro (–Cl), bromo (–Br), iodo (–I), trifluoromethyl (–CF₃) or phenyl (–Ph) electron-withdrawing groups served as good substrates to produce the corresponding primary amides 2e–2j in excellent yields (Table 2, entries 5–10), and there is no sharp difference. Interestingly, when nitro (–NO₂) substituted 2-benzyl cyanide were used, the corresponding 4-nitrobenzamide was obtained in high yield and with short time (Table 2, entry 11).

Table 2 Cu-catalysed aerobic oxidative amidation of benzyl cyanide with NH₄Cl producing primary amides^a

Entry	Benzonitriles	Products	Yield^b
a Reaction conditions: substrate 1a–1q (0.2 mmol), Cu2O (5 mol%), NH4Cl (0.3 mmol), NaOH (0.4 mmol), CH3CN (2 mL), O2 in 25 mL Schlenk tube, 120 °C, 24 h.b Isolated yield.c 16 h.d 48 h.
1	1a		2a, 82%
2	1b		2b, 81%
3	1c		2c, 79%
4	1d		2d, trace
5	1e		2e, 81%
6	1f		2f, 78%
7	1g		2g, 83%
8	1h		2h, 69%
9	1i		2i, 78%
10	1j		2j, 73%
11^c	1k		2k, 92%
12	1l		2l, 57%
13	1m		2m, 71%
14	1n		2n, 63%
15	1o		2o, 72%
16	1p		2p, 71%
17^d	1q		2q, 35%

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Even the 1-(naphthalen-2-yl)acetonitrile and 2-(naphthalen-2-yl)acetonitrile furnished the corresponding primary amide 2l and 2m in 57% and 71% yield respectively. The heteroaryl-substituted primary amide 2n and 2o were obtained from the corresponding 2-(thiophen-2-yl)acetonitrile or 2-(pyridin-2-yl)acetonitrile under the present Cu₂O/NH₄Cl/NaOH system. While, the reaction was influenced by the substituent steric effects. For example, the yield of 2q was decreased for ortho-substituted 2-benzyl cyanide contrast to para-substituted and meta-substituted 2-benzyl cyanide (Table 2, entry 2, entries 16–17).

To get more information of the reaction mechanism, a few potential intermediates were subjected to the reaction under standard conditions. As shown below, phenylacetic acid 1r was used as a substrate under the standard reaction conditions, while 2a was not detected at all (eqn (2)). Benzaldehyde 1s was treated under the optimized conditions, 2a was obtained in 15% yield (eqn (3)), indicating that an aldehyde or acid was not the efficient intermediate. The reaction of benzonitrile 1t with NH₄Cl/NaOH under standard conditions was also explored, and the desired benzamide 2a was not detected at all, showing that benzyl cyanide was not converted to benzonitrile via hydration of nitriles to primary amides (eqn (4)). The reaction of benzoyl cyanide 1u and NH₄Cl/NaOH was performed in the absence of Cu₂O, the corresponding primary amide 2a was obtained in 89% yield (eqn (5)). The results indicated that benzoyl cyanide 1u was the efficient intermediate for this transformation, at first benzyl cyanide was converted to benzoyl cyanide via sp³ C–H bond oxygenation. Under dry conditions and in the absence of air, the desired product 2a was also generated in 82% yield under the optimal conditions, thus the oxygen atoms of the product amides should originate from molecular dioxygen (eqn (6)).

*The solvent CH₃CN and 1a were dried, degassed by standard methods before use, and stored under nitrogen using standard Schlenk techniques.

Based on the above results and the reported literature,^15a a possible mechanism for the copper-catalyzed aerobic oxidative amidation of benzyl cyanide to the synthesis of primary amides is suggested in Scheme 1. The catalytic cycle reaction involved sp³ C–H bond oxygenation of benzyl cyanide to the intermediate benzoyl cyanide M and with the Cu catalyst being regenerated, NH₃ was generated from the heating of NH₄Cl and NaOH. Then intermediate benzoyl cyanide M was attacked by NH₃ to generate I, followed by C–CN bond cleavage affording the desired primary amide 2.

Scheme 1 Plausible reaction pathway for the synthesis of primary amides 2.

Conclusions

In summary, we have developed a simple and highly efficient method for the synthesis of primary amides via C–CN bond cleavage under copper-catalyzed aerobic oxidative conditions. Using readily available NH₄Cl as a nitrogen source, conversion of benzyl cyanides to primary amides provides an opportunity to utilize inert starting materials to construct amides bond. The present method is practical and economical, and the starting materials are readily available.

Acknowledgements

Financial supports by National Natural Science Foundation of China (21603068), Science and Technology Innovation Team Project of Hubei Provincial Department of Education (T201419), and research fund for the doctoral program of Hubei University of Science and Technology are gratefully appreciated.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data for the products. See DOI: 10.1039/c7ra02207g

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