Copper(0)-catalyzed aerobic oxidative synthesis of imines from amines under solvent-free conditions

Abstract

A copper(0)-catalyzed direct synthesis of imines from amines under solvent-free aerobic conditions is described. The method is applicable for the synthesis of various imines from corresponding amines such as benzylic, aliphatic, cyclic secondary and heteroaromatic amines. Being solvent free, using air as a benign oxidant, and the easy separation and easy availability of the catalyst (copper powder) are the vital advantages of present protocol.

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Imines are building blocks for the synthesis of nitrogen-heterocycles, fine chemicals and pharmaceuticals.¹ Significant progress has been made in recent years in the synthesis of imines, including direct synthesis of imines from amines and condensation of amines with alcohols,² self-condensation of primary amines with oxidants³ and oxidation of secondary amines.⁴ Most of these reactions are performed in solvent media. Solvents are perhaps the most active area for green chemistry research;⁵ they represent an important challenge because solvents often account for the vast majority of mass wasted in syntheses and processes.⁶ Recently, much attention has been paid to organic reactions carried out under solvent-free conditions⁷ or the use of greener solvents such as water,⁸ supercritical fluids⁹ (SCF) and ionic liquids.¹⁰ However, the ideal situation would be not to use any solvent because the decision to include an auxiliary always implies effort and energy to remove or regenerate it from a designated system.

In continuation of our development of copper(I)-catalyzed synthetic methodologies^11,12 and to overcome the drawbacks of by-product (aldehyde) formation during the imine synthesis,¹² we have developed a novel strategy for the selective synthesis of imines under solvent-free conditions.¹³ Initially, the reaction of benzylamine 1 was subjected to oxidative imination using copper powder (0.5 mol%) as a heterogeneous catalyst under neat conditions at 90 °C in an open atmosphere and provided the corresponding benzylimine 2 in high yield (>99% GC yield) with 100% conversion (Table 1, entry 1). Attempts were made to use other copper catalysts including Cu supported on alumina¹⁴ (Cu/Al₂O₃) (Table 1, entries 2–9). The reaction does not proceed without catalyst (Table 1, entry 10). When the reaction was performed under argon and nitrogen (Table 1, entries 11 and 12) atmosphere, low conversions were observed. However, under an oxygen (balloon) atmosphere 33% imine 2a was observed along with undesired products (Table 1, entry 13). To understand the role of moisture in air, we carried out an experiment with a trace amount of water (without copper catalyst), it showed only 45% conversion (Table 1, entry 14). However, when the reaction was carried out under controlled conditions [copper powder, water, and oxygen (balloon)], 76% imine was observed (Table 1, entry 15). Notably, the presence of water increases the yield of imine and helps to avoid overoxidation of the amine (as seen in Table 1, entry 13). The selective conversion of benzylamine to imine with time was also monitored by GC-MS (see Table S1, ESI†). Therefore, the rest of the amines were subjected to this procedure (Table 1, entry 1) to synthesize various imines under solvent-free conditions using inexpensive and commercially available copper powder as a catalyst and in an open atmosphere (Table 2). As is evident from Table 2, the present catalytic system has a high degree of functional-group tolerance. Both electron-rich (para, meta, and ortho substituted) and electron-deficient substrates were well-tolerated, and produced good to excellent yields of imines (Table 2, entries 2–4). Similar yields were obtained from halo (F and Cl)-substituted benzylamines (Table 2, entries 5–9). These halo substituted imines are useful synthons for the synthesis of chiral amines.¹⁵ The chloro imine (Table 2, entry 7) was obtained in better yield (84%) compared to the literature method.¹⁶ The successful transformation of benzylamines into corresponding imines under neat conditions with as low a catalyst loading (0.5 mol%) prompted us to extend the generality of this method for the synthesis of other imines with different amine substrates. To our delight, we found the general applicability of this transformation for a wide range of amines such as the heteroaromatic amine pyridin-2-ylmethanamine (Table 2, entry 10), a secondary amine (Table 2, entry 11) and cyclic secondary amines (Table 2, entries 12 and 13). Alkyl primary amine substrates also produced corresponding imine in moderate yield (Table 2, entry 14). By using the newly established protocol, oxidative dimerization of para-methoxyaniline was unsuccessful due to the lack of α-H hydrogen (Table 2, entry 15). However, oxidative coupling of different amines such as para-methoxyaniline and benzyl aniline resulted in a good yield of un-symmetrical imine (Table 2, entry 16). To check the copper contamination in the product, we carried out an ICP-OES analysis, and the results showed a very low amount of copper in the product.¹⁷

Table 1 Optimization of conditions for the copper-catalyzed oxidation of 1^a

Entry	Catalyst (mol%)	Time/h	Conv. (%)	Yield^b (%)	Select. (%)
a Reaction conditions unless otherwise stated, benzylamine 1 (9.3 mmol), catalyst, T = 90 °C, open atmosphere. b Yield based on GC-area %. c Reactions performed under argon, nitrogen and oxygen atmosphere in entries 11, 12 and 13 respectively. d Rest constitutes unidentified oxidized product.
1	Cu powder (0.5)	20	100	>99	100
2	Cu wire (0.5)	20	89	89	100
3	Cu/Al2O3 (0.5)	20	29	29	100
4	CuCl (0.5)	20	96	96	100
5	CuCl2 (0.5)	20	94	94	100
6	CuI (0.5)	18	100	89	89
7	CuBr (0.5)	18	78	73	94
8	CuBr2(0.5)	18	88	83	94
9	CuO (0.5)	20	09	09	100
10	No catalyst	20	—	—	—
11^c	Cu powder (0.5)	20	26	26	100
12^c	Cu powder (0.5)	20	22	22	100
13^c	Cu powder (0.5)	20	100	33^d	33
14	H2O (50 μL)	20	45	36	81
15	Cu powder/H2O(50 μL)/O2(balloon)	20	76	76	100

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Table 2 Copper-catalyzed aerobic oxidation of benzylamines to imines^a

Entry	Amine	Time/h	Imine	Yield^b (%)	Ref.
a Conditions: Amine (9.3 mmol), Cu (0.05 mmol), 90 °C, open atmosphere. b Isolated products. c GC yield. d 19% picolinamide and 49% remaining starting amine.
1		20		88	3a
2		20		76	3d
3		18		88	3d
4		22		90	3a
5		21		90	3a
6		22		86	3a
7		18		84	3d
8		22		62	12
9		24		6	3a
				0
10		20		20^c^,^d	3c
11		12		82	3a
12		19		65	4d
13		19		58	4d
14		18		34^c	12
15		15	NR	—	—
16	a	18		82	12

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After completion of the reaction, copper powder (catalyst) was recovered through filtration and washed with diethyl ether, dried and its morphological changes studied using scanning electron microscopy (SEM) before and after the reaction (Fig. 1). The SEM image of copper-powder recovered after the reaction in an open atmosphere [Fig. 1(b)] clearly shows the formation of pits (indicated by arrow) on the copper surface due to oxidative corrosion (i.e. oxidation of copper by aerial oxygen) and it is easily understandable why it acts as an efficient oxidizing system for imine synthesis.

Fig. 1 SEM images of copper powder (a) fresh; and after the reaction (b) in an open atmosphere.

This study clearly explains the crucial role of atmospheric oxygen in the selective synthesis of imines with the present catalytic system. In the present study, copper powder is a more effective catalyst than its bulk metal (copper wire) counterpart (Table 1, entry 2). Therefore copper powder has been employed as a catalyst in the present work. The catalytic activities of Cu(0) in the forms of powder, turnings, or nanoparticles are useful in an aqueous environment.¹⁸ The surface area of the copper catalyst was determined by the BET method and found to be 0.9713 m² g⁻¹. Mechanistic investigations of copper-catalyzed aerobic oxidative reactions are well studied in the literature.¹⁹ Although we do not isolate the intermediates, we propose a plausible reaction mechanism for this transformation as outlined in Scheme 1. The different copper catalysts (Cu powder, Cu wire, Cu supported on alumina, CuCl and CuCl₂) gave only desired product, even though Cu supported on alumina gave lower conversion (Table 1, entries 1–5). These results imply that the reaction rate varies with the copper catalyst. Copper halides act as efficient catalysts, but the selectivity varies with the halide (Table 1 entries 4–8). In addition, the selectivity was not dependent on the valence state of copper. These results suggest that copper ions generated from copper powder might be active species for oxidative coupling reactions through the catalytic cycle consisting of copper(I) and copper(II) ions. Based on our observation and literature reports, we propose that the first step is the formation of complexes A and B with oxidative addition of copper to amine. Further oxidation of complexes A and B provides intermediate methanimine C.^3k,12,16 In addition, it is also possible that water may form hydrogen bonds with amino groups which may lead to a peroxide intermediate,^3m also subsequently leading to intermediate C. Finally the reaction of C with another molecule of amine provides imine (path 1)^3n,3o,16 or partial hydrolysis of C (to aldehyde^3l,16) followed by condensation with amine gives imine product (path 2). Since we have monitored the reaction with time and did not observe aldehyde (GC-MS), therefore we hypothesize that path 1 is likely to be more probable in the present study. A linear plot was obtained for the conversion of substrate with time, showing a slightly negative intercept (ESI†). This zero-order plot fits with the data better than a first order plot; suggesting that the observed reaction order does not depend upon substrate concentration. The rate limiting step is probably one of the following: (1) the transport of oxygen into the reaction liquid; (2) the activation of dioxygen into surface-bound oxygen atoms; or (3) the oxidation of the copper from a lower to a higher oxidation state. These results are consistent with a redox mechanism and it is known that copper is a redox catalyst.

Scheme 1 Probable mechanism for the copper-catalyzed aerobic oxidation of primary amines to imines.

In conclusion, we have developed a novel copper-catalyzed protocol for the synthesis of imines, through oxidative imination. Particularly, the present protocol is highly useful for benzyl imine synthesis. Both symmetrical and cyclic imines can be conveniently prepared by this route. Notably, nominal catalyst loading, use of atmospheric air as an environmentally-friendly oxidant and mild reaction conditions are added advantages of the methodology.

Acknowledgements

We thank Mr. Hitesh, Mr. A.K. Das/Mr. H. Bramhabhatt, Mr. V. Agrawal, Mr. Rajesh Patidar and Mr. Jayesh Analytical Division of this institute for supporting NMR, LC/GC-MS, IR, ICP and BET and SEM analyses respectively. R.D.P. is thankful to CSIR, New Delhi, India, for the award of SRF. We are also thankful to the reviewers of this manuscript for their valuable and constructive comments.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedure and NMR spectra of compounds. See DOI: 10.1039/c2ra20339a/

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