Gang
Hong
,
Dan
Mao
,
Xiaoyan
Zhu
,
Shengying
Wu
* and
Limin
Wang
*
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. China. E-mail: wanglimin@ecust.edu.cn; wsy1986wsy@126.com; Fax: +86-21-64253881; Tel: +86-21-64253881
First published on 16th June 2015
A direct amidation of aldehydes or benzylamines with azobenzenes through TBHP-mediated NN 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 NN double bond cleavage of azobenzenes used in synthesizing amide compounds.
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 NN 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 NN 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).
Entry | Oxidant | Additive (equiv.) | Solvent | T (°C) | Yieldb (%) |
---|---|---|---|---|---|
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 |
20c | TBHP | KOH (1.0) | DCE | 120 | 60 |
21d | TBHP | KOH (1.0) | DCE | 120 | 62 |
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).
Entry | 1, R = | 2, R1 = | Product 4 | Yieldb (%) |
---|---|---|---|---|
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 |
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).
Entry | 1, R = | 3, R2 = | Product 4 | Yieldb (%) |
---|---|---|---|---|
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′ | 37c |
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 NN double bond of azobenzenes and the acyl radical can attack the different positions of the NN double bond when unsymmetrically substituted azobenzene is used.
On the basis of the previous reports12,16–19 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 NN 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†).
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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