Longyun
Lyu
ab,
Han
Xie
a,
Huaixue
Mu
b,
Qijie
He
a,
Zhaoxiang
Bian
*b and
Jun
Wang
*a
aDepartment of Chemistry, South University of Science and Technology of China, Shenzhen, Guangdong 518055, China. E-mail: wang.j@sustc.edu.cn; Fax: (+86) 755-88018304
bSchool of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China. E-mail: bzxiang@hkbu.edu.hk; Fax: (+852)-34112929
First published on 30th April 2015
The inexpensive Lewis acid AlCl3 was found to be an efficient catalyst for the O-alkylative Passerini reaction of isocyanides, cinnamaldehydes and alcohols. Instead of carboxylic acid in the classical Passerini reaction, alcohols performed both as the solvent and substrate nicely to afford α-alkoxy-amide products in good yield (up to 91%). This method provides practical access for functional α-alkoxy-β,γ-enamide derivatives.
We initially started to optimize the reaction conditions using cyclohexyl isocyanide (Cy-NC) 1a and cinnamaldehyde 2a as the model substrates, MeOH 3a as the reagent as well as the solvent. Selected results of Lewis acids are summarized in Table 1. To our delight, moderate to good yields were obtained, catalyzed by several Lewis acids. Among them, AlCl3 was the most efficient catalyst which gave the expected P-3CR product in 73% yield (entry 6, Table 1). The other two Lewis acids In(OTf)3 and FeCl3 were also effective in the reaction, but resulted in lower yields. The ratios of isocyanide 1a and cinnamaldehyde 2a were also investigated (entries 10–13), leading to improvement of the yield from 73% to 85% (entry 12). 10 mol% AlCl3 can make the reaction work, but relatively lower yield (63%) was obtained (entry 14).
Entry | 1a (eq.) | 2a (eq.) | Catalyst | Yieldb (%) |
---|---|---|---|---|
a Reaction conditions: to a solution of the catalyst (0.2 eq.) in MeOH (1 mL) in a sealed vial were added cinnamaldehydes (0.2 mmol) and isocyanides (0.3 mmol) in sequence. The reaction mixtures were stirred at 60 °C for 12 h. b Isolated yield. | ||||
1 | 1 | 1.2 | None | Trace |
2 | 1 | 1.2 | Zn(OTf)2/0.2 | Trace |
3 | 1 | 1.2 | AgOTf/0.2 | Trace |
4 | 1 | 1.2 | In(OTf)3/0.2 | 65 |
5 | 1 | 1.2 | ZnCl2/0.2 | Trace |
6 | 1 | 1.2 | AlCl3/0.2 | 73 |
7 | 1 | 1.2 | FeCl3/0.2 | 43 |
8 | 1 | 1.2 | CuCl2/0.2 | Trace |
9 | 1 | 1.2 | CH3COOH/0.2 | Trace |
10 | 1 | 1 | AlCl3/0.2 | 76 |
11 | 1.2 | 1 | AlCl3/0.2 | 79 |
12 | 1.5 | 1 | AlCl3/0.2 | 85 |
13 | 1.8 | 1 | AlCl3/0.2 | 80 |
14 | 1.5 | 1 | AlCl3/0.1 | 63 |
With the optimized reaction conditions in hand, various α-alkoxy-β,γ-enamides were successfully synthesized via the O-alkylative Passerini reaction of various isocyanides 1 and alcohols 3 with cinnamaldehyde 2a. As shown in Table 2, the reaction proceeded smoothly in many primary and secondary alcohols (entries 1–4). The corresponding α-alkoxy-β,γ-enamides were obtained in 61–85% yields. However, when the sterically hindered tert-butyl alcohol was used as the substrate as well as the solvent, only 53% yield was obtained even in the presence of 100 mol% AlCl3 with stirring at 80 °C for 36 h (entry 5). The steric effect of isocyanides showed no obvious influence on the yields of products. 81% and 82% yields were obtained for n-butyl isocyanide and tert-butyl isocyanide separately (entries 6 and 7). Aromatic isocyanides 1e, also suitable substrates under these reaction conditions, afforded the corresponding product 4eaa in 72% yield, but a longer reaction time (24 h) was needed (entry 9).
Entry | Isocyanides | Alcohols | Products | Yieldd (%) |
---|---|---|---|---|
a To a solution of AlCl3 (0.2 mmol, 0.20 eq.) in indicated alcohols (1 mL) in a sealed vial were added cinnamaldehyde 2a (1 mmol) and isocyanides 1 (1.5 mmol, 1.5 eq.) in sequence. The reaction mixtures were stirred at 60 °C for 12 h. b The reaction was carried out in t-BuOH in the presence of 100 mol% AlCl3, stirred at 80 °C for 36 h. c The reaction was carried out for 24 h. d Isolated yield. | ||||
1 |
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MeOH 3a |
![]() |
85 |
2 |
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EtOH 3b |
![]() |
63 |
3 |
![]() |
![]() |
![]() |
64 |
4 |
![]() |
![]() |
![]() |
61 |
5b |
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![]() |
53 |
6 |
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MeOH 3a |
![]() |
81 |
7 |
![]() |
MeOH 3a |
![]() |
82 |
8 |
![]() |
MeOH 3a |
![]() |
75 |
9c |
![]() |
MeOH 3a |
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72 |
To further investigate the substrate scope, a series of substituted cinnamaldehydes 2b–2l were investigated as shown in Table 3. The results indicated that the electronic effect of cinnamaldehyde 2 has a serious influence on this reaction. Cinnamaldehydes with electron donating groups provided the formation of α-alkoxy-β,γ-enamides in good yields (entries 1, 5–8). Under the same optimized conditions, substrates with weak electron withdrawing groups (F, Cl, Br) also performed nicely to give the corresponding products in moderate yields (entries 2–4). The reactions of cinnamaldehydes with strong electron withdrawing groups (NO2, CN) were sluggish in this catalyst system. After further optimization, the desired products 4aja and 4aka were obtained in moderate yields when 50 mol% AlCl3 was added in two portions (entries 9 and 10). In addition, 2-hydroxy-cinnamaldehyde with no protection at the hydroxy group was also suitable for the reaction, indicating good substrate tolerance for this synthetic methodology (entry 11). The influence of the steric effect was also investigated. We found that ortho-substitutes in the phenyl ring showed no significant effects on the yields of products due to the distance from the functional group of aldehyde. Therefore, it was not surprising that 2-methylcinnamaldehyde 2g and 2-methoxycinnamaldehyde 2h with electron-donating groups but with steric hindrance could still give the desired products 4aga and 4aha in 80% and 83% yield separately (entries 6 and 7).
Entry | Cinnamaldehyde | Time (h) | Products | Yieldc (%) |
---|---|---|---|---|
a To a solution of AlCl3 (0.2 mmol, 0.20 eq.) in indicated alcohols (1 mL) in a sealed vial were added cinnamaldehyde 2a (1 mmol) and isocyanide 1 (1.5 mmol, 1.5 eq.) in sequence. The reaction mixtures were stirred at 60 °C for the indicated time. b 50 mol% AlCl3 was added in two portions. c Isolated yield. | ||||
1 |
![]() |
12 |
![]() |
85 |
2 |
![]() |
24 |
![]() |
64 |
3 |
![]() |
24 |
![]() |
76 |
4 |
![]() |
24 |
![]() |
73 |
5 |
![]() |
12 |
![]() |
91 |
6 |
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18 |
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80 |
7 |
![]() |
24 |
![]() |
83 |
8 |
![]() |
24 |
![]() |
75 |
9b |
![]() |
48 |
![]() |
58 |
10b |
![]() |
48 |
![]() |
56 |
11 |
![]() |
24 |
![]() |
70 |
On the basis of the result, a mechanism for the Lewis acid-catalyzed formation of α-alkoxy-β,γ-enamide derivatives via the direct O-alkylative Passerini reaction is shown in Scheme 2. In the presence of the Lewis acid AlCl3, cinnamaldehydes react with alcohols to generate oxocarbenium species A, and lost a H2O molecule. Subsequently, A is attacked by an isocyanide to give nitrilium intermediate B. Then, the hydrolysis of the intermediate B results in the formation of C which easily isomerizes to give α-alkoxy-β,γ-enamide 2.
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Scheme 2 Proposed mechanism of the AlCl3-catalyzed O-alkylative Passerini reaction for accessing α-alkoxy-β,γ-enamides. |
Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5qo00106d |
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