Metal free access to amide compounds via peroxide-mediated N=N double bond cleavage of azobenzenes

Abstract

A direct amidation of aldehydes or benzylamines with azobenzenes through TBHP-mediated N=N double bond cleavage of azobenzenes has been developed. A series of amide compounds with a wide range of functionalities were obtained with moderate to good yields. To the best of our knowledge, this is the first example of the N=N double bond cleavage of azobenzenes used in synthesizing amide compounds.

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Introduction

Recently the synthesis of amide compounds has attracted wide attention for their extensive applications in pharmaceuticals, agrochemicals and biomolecules.¹ Some pharmaceutical compounds containing the amide moiety are depicted in Fig. 1. One of the most traditional methods for the synthesis of amides is the condensation of activated carboxylic acids with amines. Many classical name reactions such as Beckmann,² Staudinger,³ Ritter reactions⁴ have been developed to form amide compounds. Furthermore, research during the past decade led to significant progress in the field of direct amidation of aldehydes,⁵ yet for most of which a transition metal was a must. As a result, it is highly necessary to further develop a new method to synthesize amide compounds under mild conditions from other starting materials.

Fig. 1 Structure of pharmaceutical compounds with an amide bond.

Aromatic azo compounds are important materials and have been extensively applied in fields such as indicators, dyes, nonlinear optics and pharmaceuticals due to their unique properties.⁶ Due to the extensive applications, substantial quantities of toxic and carcinogenic azo compounds are dumped into the environment as industrial waste. Thus, it is vital to develop methods for the elimination of these compounds for environmental concerns. The cleavage of the N=N double bond in azo compounds can be achieved through either electrolytic reduction⁷ or chemical reduction using reducing agents such as metal iron⁸ and sulfides.⁹ Complementary to hydrogenations are transfer hydrogenations (CTH),¹⁰ where typically alcohols especially isopropanol or formic acid–amine mixtures are usually used as hydrogen donors.¹¹

Recently, the reaction of azobenzenes with aldehydes has been studied by the research groups of Wang¹² and J. A. Ellman,¹³ respectively. In Wang's work, the acylation of azobenzenes by Pd-catalyzed oxidative coupling of azobenzenes with aldehydes using tert-butyl hydroperoxide (TBHP) as an oxidant via chelation-assisted ortho C–H bond activation was developed (Scheme 1a), while the J. A. Ellman group has succeeded in synthesizing 2-aryl indazoles by co-catalyzed reaction of azobenzenes with aldehydes (Scheme 1b). To the best of our knowledge, the N=N double bond cleavage of aromatic azo compounds under oxidative conditions is rarely reported.¹⁴ To further explore this reaction as well as continue our research in aromatic azo compounds,¹⁵ we would like to report the first example of accessing amide compounds via TBHP-mediated reaction of azobenzenes with aldehydes or benzylamines (Scheme 1c).

Scheme 1 Reaction of azobenzenes with aldehydes studied by different groups.

Results and discussion

Our study started from the model reaction of azobenzene (1a) with benzaldehyde (2a) to optimize the reaction conditions. The results are summarized in Table 1. The reaction was carried out in DCE at 120 °C with tert-butyl hydroperoxide (TBHP) (4.0 equiv., 70% solution in water) as an oxidant. Gratifyingly the product was obtained in 50% yield after 24 h (Table 1, entry 1). Inspired by this result, various oxidants including di-tert-butyl peroxide (DTBP), DDQ, PhI(OAc)₂, and tert-butyl peroxybenzoate (TBPB) were employed with no improvement in yield (Table 1, entries 2–5). Additives were next examined (Table 1, entries 6–11). To our delight, the desired product 4a was obtained in 81% yield in the presence of TBHP and KOH. Efforts to enhance yield by replacing DCE with other solvents such as PhCl, dioxane, DMF, CH₃CN, and DMSO (Table 1, entries 12–16) proved fruitless. Additional screening revealed that the yield decreased gradually upon increasing or decreasing the temperature (Table 1, entries 17–19). A decrease in the amount of TBHP led to a decrease of the yield of the product (Table 1, entry 20). There was a slight decrease in yield when the reaction was conducted under argon (Table 1, entry 21).

Table 1 The optimization of the reaction conditions^a

Entry	Oxidant	Additive (equiv.)	Solvent	T (°C)	Yield^b (%)
a Reaction conditions: 1a (0.25 mmol), 2a (0.25 mmol), oxidant (4.0 equiv.), additive, solvent (1.0 mL), 24 h, air. b Isolated yield. c TBHP (3.0 equiv.) was used. d Under argon.
1	TBHP	—	DCE	120	50
2	DTBP	—	DCE	120	N.P.
3	DDQ	—	DCE	120	N.P.
4	PhI(OAc)2	—	DCE	120	N.P.
5	TBPB	—	DCE	120	46
6	TBHP	TBAB (1.0)	DCE	120	75
7	TBHP	I2 (0.2)	DCE	120	8
8	TBHP	KI (0.2)	DCE	120	N.P.
9	TBHP	FeCl2 (0.1)	DCE	120	Trace
10	TBHP	KOH (1.0)	DCE	120	81
11	TBHP	PivOH (2.0)	DCE	120	54
12	TBHP	KOH (1.0)	PhCl	120	61
13	TBHP	KOH (1.0)	CH3CN	120	43
14	TBHP	KOH (1.0)	Dioxane	120	63
15	TBHP	KOH (1.0)	DMF	120	Trace
16	TBHP	KOH (1.0)	DMSO	120	33
17	TBHP	KOH (1.0)	DCE	110	56
18	TBHP	KOH (1.0)	DCE	rt	N.P.
19	TBHP	KOH (1.0)	DCE	140	77
20^c	TBHP	KOH (1.0)	DCE	120	60
21^d	TBHP	KOH (1.0)	DCE	120	62

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With the optimized conditions in hand, we explored the scope of this novel TBHP-mediated reaction of aldehydes with azobenzenes, and the results are summarized in Table 2. Generally, electron-poor azobenzenes are more reactive than electron-rich aromatic azo compounds. Azobenzenes with electron-withdrawing groups (such as 4-F, 4-Cl, 4-Br, 3-Cl, 3-Br, 4-COOEt, and 4-OCF₃) on the aromatic ring worked well with benzaldehyde giving the corresponding products in good to excellent yields (Table 2, entries 6–12), while electron-donating groups (such as 4-OMe, 2-Me, 3-Me, and 4-Me) on the aromatic ring had a slightly negative effect on the yield of the reaction (Table 2, entries 2–5). The fact that the ortho-substituted and 2,4-disubstituted azobenzenes afforded a relatively lower yield than para- or meta-substituted azobenzenes showed that steric hindrance largely affected the efficiency of this reaction (Table 2, entries 2 and 13). Next, the scope of aldehydes was explored. Contrary to the electronic effect observed in substituted azobenzenes, the aromatic aldehydes with electron-donating groups at ortho, meta and para positions of the aromatic ring afforded the corresponding products in 43–72% yields (Table 2, entries 14–20), while electron-withdrawing groups (such as 4-F, 4-Cl, 4-Br, 3-F, 4-NO₂, 4-CN, 4-CF₃, and 2-CF₃) on the aromatic ring gave slightly lower yields (Table 2, entries 21–28). Notably, meta-F benzaldehyde worked well with azobenzene affording the corresponding product 4x in 79% yield (Table 2, entry 24). To our delight, aliphatic aldehydes such as cyclohexanecarbaldehyde, butyraldehyde could also be transformed into the corresponding amide compounds (Table 2, entries 29 and 31). When azobenzene was treated with furaldehyde, product 4ad was isolated in 38% yield (Table 2, entry 30).

Table 2 The direct amidation of aldehydes with azobenzenes^a

Entry	1, R =	2, R^1 =	Product 4	Yield^b (%)
a Reaction conditions: azobenzenes 1 (0.25 mmol), aldehydes 2 (0.25 mmol), TBHP (4.0 equiv.), KOH (1.0 equiv.), DCE (1.0 mL), 120 °C, 24 h, air. b Isolated yield.
1	H	Ph	4a	81
2	2-Me	Ph	4b	47
3	3-Me	Ph	4c	70
4	4-Me	Ph	4d	72
5	4-OMe	Ph	4e	41
6	4-F	Ph	4f	64
7	4-Cl	Ph	4g	75
8	4-Br	Ph	4h	91
9	3-Cl	Ph	4i	57
10	3-Br	Ph	4j	58
11	4-COOEt	Ph	4k	82
12	4-OCF3	Ph	4l	70
13	2,4-Me, Me	Ph	4m	29
14	H	2-MeC6H4	4n	57
15	H	3-MeC6H4	4o	72
16	H	4-MeC6H4	4p	68
17	H	2-OMeC6H4	4q	46
18	H	3-OMeC6H4	4r	64
19	H	4-OMeC6H4	4s	66
20	H	4-Dimethylamino C6H4	4t	43
21	H	4-FC6H4	4u	41
22	H	4-ClC6H4	4v	53
23	H	4-BrC6H4	4w	39
24	H	3-FC6H4	4x	79
25	H	4-NO2C6H4	4y	40
26	H	4-CF3C6H4	4z	43
27	H	4-CNC6H4	4aa	38
28	H	2-CF3C6H4	4ab	43
29	H	Cyclohexyl	4ac	34
30	H	Furan-2-yl	4ad	38
31	H	n-Propyl	4ae	47

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Proceeding further toward the substrate exploration of this protocol, a broad range of readily available benzylamines were also screened for this reaction protocol, which are summarized in Table 3. The optimized reaction parameters were azobenzene (0.25 mmol), benzylamines (0.5 mmol), TBHP (4.0 equiv.), and DCE as a solvent, at 120 °C for 24 h (see the ESI† for the optimization table). It was found that no obvious decrease in yield was observed when aldehydes were replaced with the corresponding benzylamines, and the electronic effect of benzylamine observed was similar with substituted aldehydes. The reaction of azobenzene with benzylamines with substituents such as Me, OMe, F, Cl, and Br on different positions of the phenyl ring delivered the corresponding products in 47–80% yields (Table 3, entries 2–10). Furthermore, when benzylamine hydrochloride was employed, the corresponding product was also formed as long as KOH was added as an additive (Table 3, entry 11).

Table 3 The direct amidation of benzylamines with azobenzenes^a

Entry	1, R =	3, R^2 =	Product 4	Yield^b (%)
a Reaction conditions: azobenzene 1a (0.25 mmol), benzylamines 3 (0.5 mmol), TBHP (4.0 equiv.), DCE (1.0 mL), 120 °C, 24 h, air. b Isolated yield. c p-Nitrobenzylamine hydrochloride was used; KOH (1.0 equiv.) was added.
1	H	Ph	4a′	72
2	H	2-MeC6H4	4n′	54
3	H	3-MeC6H4	4o′	74
4	H	4-MeC6H4	4p′	66
5	H	4-OMeC6H4	4s′	61
6	H	4-FC6H4	4u′	53
7	H	4-ClC6H4	4v′	56
8	H	4-BrC6H4	4w′	47
9	H	3-FC6H4	4x′	80
10	H	2-FC6H4	4af	57
11	H	4-NO2C6H4	4y′	37^c

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To probe the mechanism of this reaction, several control experiments were performed (Scheme 2). When a typical radical scavenger tetramethylpiperidine N-oxide (TEMPO) was added to the reaction of azobenzene (1a) with benzaldehyde (2a) under the optimized conditions, no corresponding product was detected, which indicates that a radical process may be involved in this reaction (Scheme 2a). Subsequently, benzoic acid was employed to react with aniline under standard conditions, and no product was observed either, which excludes the possibility that formal disproportionation reaction between azobenzene and benzaldehyde was involved (Scheme 2b). As for the unsymmetrically substituted azobenzene, two amidation products, 4a and 4k, were isolated in 38% and 22% yields, respectively (Scheme 2c). On the other hand, there was only a trace of the corresponding product detected when aniline reacted with benzaldehyde (Scheme 2d) and no corresponding product was furnished for ethyl 4-aminobenzoate under standard conditions (Scheme 2e). Moreover, more than 90% of azobenzene survived in the absence of aldehyde (Scheme 2f). These results indicate that amines may not be the intermediates in the transformation, and the amidation reaction may start from the attack of aldehydes to the N=N double bond of azobenzenes and the acyl radical can attack the different positions of the N=N double bond when unsymmetrically substituted azobenzene is used.

Scheme 2 Control experiments for investigation of the mechanism.

On the basis of the previous reports^12,16–19 and the above results, a tentative mechanism for TBHP-mediated reaction of aldehydes or benzylamines with aromatic azo compounds is depicted in Scheme 3. Benzylamine (3a) first underwent oxidation, hydrolysis and the second radical oxidation with a solution of TBHP in water to form the acyl radical.^12,17 Then, the N=N double bond of azobenzene (1a) was attacked by this acyl radical to form the intermediate 5.^14,16 This intermediate 5 may then abstract one H from ^tBuOH to provide 6.¹⁹ Finally, intermediate 6 could afford the product 4a and nitrosobenzene via the hydrolysis process.¹⁸ At the same time, the decomposition of the unstable nitrosobenzene led to the formation of traces of aniline and azoxybenzene (detected by HRMS, see ESI for Fig. S1†), and nitrobenzene (determined by GC-MS, see ESI for Fig. S2 and S3†).

Scheme 3 Tentative mechanism for the amidation of aldehydes or benzylamines.

Conclusions

In conclusion, we have developed a novel method for the synthesis of amide compounds by reaction of aldehydes or benzylamines with aromatic azo compounds using TBHP as an oxidant. Appreciable aldehydes including aliphatic aldehydes can be used in this reaction allowing a direct preparation of the corresponding amide compounds in 29–91% yields. Based on the extensive experimental data, we propose a plausible mechanism. Further studies to refine the mechanism and to extend the application of azobenzenes as synthons are currently underway in our laboratory.

Acknowledgements

This research was financially supported by the National Nature Science Foundation of China (21272069, 20672035) and the Fundamental Research Funds for the Central Universities and Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.

Notes and references

1. (a) E. Valeur and M. Bradley, Chem. Soc. Rev., 2009, 38, 606–631; (b) C. L. Allen and J. M. J. Williams, Chem. Soc. Rev., 2011, 40, 3405–3415; (c) D. W. Zhang, X. Zhao, J. L. Hou and Z. T. Li, Chem. Rev., 2012, 112, 5271–5316; (d) R. Garcia-Alvarez, P. Crochet and V. Cadierno, Green Chem., 2013, 15, 46–66; (e) T. Cupido, J. Tulla-Puche, J. Spengler and F. Albericio, Curr. Opin. Drug Discovery Dev., 2007, 10, 768–783; (f) V. Onnis, M. T. Cocco and R. Fadda, Bioorg. Med. Chem., 2009, 17, 6158–6165.
2. (a) N. A. Owston, A. J. Parker and J. M. J. Williams, Org. Lett., 2007, 9, 3599–3601; (b) M. Hashimoto, Y. Obora, S. Sakaguchi and Y. Ishii, J. Org. Chem., 2008, 73, 2894–2897.
3. (a) E. Saxon and C. R. Bertozzi, Science, 2000, 287, 2007–2010; (b) F. Damkaci and P. DeShong, J. Am. Chem. Soc., 2003, 125, 4408–4409.
4. J. J. Ritter and P. P. Minieri, J. Am. Chem. Soc., 1948, 70, 4045–4048.
5. (a) W. J. Yoo and C. J. Li, J. Am. Chem. Soc., 2006, 128, 13064–13065; (b) S. C. Ghosh, J. S. Y. Ngiam, A. M. Seayad, D. T. Tuan, C. L. L. Chai and A. Q. Chen, J. Org. Chem., 2012, 77, 8007–8015; (c) S. C. Ghosh, J. S. Y. Ngiam, C. L. L. Chai, A. M. Seayad, T. T. Dang and A. Q. Chen, Adv. Synth. Catal., 2012, 354, 1407–1412; (d) M. Zhang and X. F. Wu, Tetrahedron Lett., 2013, 54, 1059–1062; (e) Y. Suto, N. Yamagiwa and Y. Torisawa, Tetrahedron Lett., 2008, 49, 5732–5735; (f) Y. Z. Ding, X. Zhang, D. Y. Zhang, Y. T. Chen, Z. B. Wu and S. Yang, Tetrahedron Lett., 2015, 56, 831–833; (g) K. E. Kovi and C. Wolf, Org. Lett., 2007, 9, 3429–3432.
6. (a) A. Bafana, S. S. Devi and T. Chakrabarti, Environ. Rev., 2011, 19, 350; (b) G. J. Gainsford, M. D. H. Bhuiyan, I. Asselberghs and K. Clays, Dyes Pigm., 2012, 95, 455; (c) D. H. Qu and H. Tian, Adv. Mater., 2006, 18, 2035; (d) A. J. Harvey and A. D. Abell, Tetrahedron, 2000, 56, 9763; (e) M. R. Banghart, A. Mourot, D. L. Fortin, J. Z. Yao, R. H. Kramer and D. Trauner, Angew. Chem., Int. Ed., 2009, 48, 9097; (f) F. Puntoriero, P. Ceroni, V. Balzani, G. Bergamini and F. Voegtle, J. Am. Chem. Soc., 2007, 129, 10714; (g) Y. Zhou, D. S. Wang, S. L. Huang, G. Auernhammer, Y. J. He, H. J. Butt and S. W, Chem. Commun., 2015, 51, 2725–2727.
7. R. Jain, M. Bhargava and N. Sharma, J. Sci. Ind. Res., 2003, 62, 813–819.
8. C. Cao, L. P. Wei, Q. G. Huang, L. S. Wang and S. K. Han, Chemosphere, 1999, 38, 565–571.
9. F. P. van der Zee, G. Lettinga and J. A. Field, Water Sci. Technol., 2000, 42, 301–308.
10. For reviews on transfer hydrogenations, see: (a) S. Gladiali and E. Alberico, Chem. Soc. Rev., 2006, 35, 226–236; (b) J. S. M. Samec, J. E. Backvall, P. G. Andersson and P. Brandt, Chem. Soc. Rev., 2006, 35, 237–248.
11. (a) S. Gowda, K. Abraj and D. C. Gowda, Tetrahedron Lett., 2002, 43, 1329–1331; (b) F. K. Khan, J. Dash, C. Sudheer and R. K. Gupta, Tetrahedron Lett., 2003, 44, 7783–7787.
12. H. J. Li, P. H. Li and L. Wang, Org. Lett., 2013, 15, 629.
13. J. R. Hummel and J. A. Ellman, J. Am. Chem. Soc., 2015, 137, 490–498.
14. (a) A. S. Ozen and V. Aviyente, J. Phys. Chem. A, 2004, 108, 5990–6000; (b) A. S. Ozen and V. Aviyente, J. Phys. Chem. A, 2003, 107, 4898–4907.
15. G. Hong, D. Mao, S. Y. Wu and L. M. Wang, J. Org. Chem., 2014, 79, 10629–10635.
16. K. Selvam, S. Balachandran, R. Velmurugan and M. Swaminathan, Appl. Catal., A., 2012, 413–414, 213–222.
17. For literatures on the generation of the acyl radical, see: (a) Q. Zhang, F. Yang and Y. J. Wu, Chem. Commun., 2013, 49, 6837; (b) A. B. Khemnar and B. M. Bhanage, Org. Biomol. Chem., 2014, 12, 9631–9637; (c) O. Basle, J. Bidange, Q. Shuai and C. J. Li, Adv. Synth. Catal., 2010, 352, 1145–1149; (d) C. L. Li, L. Wang, P. H. Li and W. Zhou, Chem. – Eur. J., 2011, 17, 10208; (e) Y. N. Wu, B. Z. Li, F. Mao, X. S. Li and F. Y. Kwong, Org. Lett., 2011, 13, 3258.
18. G. W. Rong, D. F. Liu, Y. Hong, J. Chen, Y. Zheng, G. Q. Zhang and J. C. Mao, Adv. Synth. Catal., 2015, 357, 71–76.
19. H. B. Peng, J. T. Yu, Y. Jiang, H. T. Yang and J. Cheng, J. Org. Chem., 2014, 79, 9847–9853.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, optimization of reaction conditions, analytical data and NMR spectra for products. See DOI: 10.1039/c5qo00125k

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