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In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. http://rsc.li/frontiers-organic Page 1 of 4 Organic Chemistry Frontiers 1 2 Journal Name RSC 3 4 5 ARTICLE 6 7 8 9 AlCl3-Catalyzed O-Alkylative Passerini Reaction of 10 11 Isocyanides, Cinnamaldehydes and Various Aliphatic 12 Alcohols for Accessing -Alkoxy--Enamides 13 14 15 Long-yun Lyu,a,b Han Xie,a Huaixue Mu,b Qijie He,a Zhaoxiang Bian＊b and 16 ＊a 17 Jun Wang Manuscript 18 19 The inexpensive Lewis acid AlCl3 was found to be an efficient catalyst for O-alkylative 20 Passerini reaction of isocyanide, cinnamaldehyde and alcohol. Instead of carboxylic acid in 21 classical Passerini reaction, alcohols performed both as solvent and substrate nicely to afford 22 -alkoxy-amide product in good yield (up to 91%). This method provide a practical accessing 23 for functional -alkoxy- -enamide derivatives. 24 25 26 The Passerini three-component reaction (P-3CR), discovered in Accepted O 3 1 R 1921, is the known isocyanide-based multiconponent reactions 3 R NC 3 O 27 R3 O R -CO2H R -OH + NHR1 to give -acyloxy amide with isocyanide, aldehyde and 1 2 28 NHR 2 R 1 R2 R CHO carboxylic acid. The Passerini three-component reaction (3CR) O 29 O play important roles in combinatorial chemistry, for drug R3= Aryl O-arylative Passerini reaction 30 2 Classical Passerini reaction discovery as well as natural product synthesis. Besides, the Alky O-alkylative Passerini reaction 31 application of Passerini reaction in the preparation of polymers Scheme 1 Passerini reaction. 32 and peptides have also been reported.3,4 Recently, several 33 examples of enantioselective versions for Passerini reactions Table 1 Optimization of the reaction conditions of O-Alkylative Passerini a 34 have been developed. 5 Although various modifications of this reaction of Cy-NC 1a, cinnamaldehyde 2a and MeOH 3a. 35 reaction have been already developed, the direct Passerini O Frontiers H 36 reaction use a phenol or an aliphatic alcohol instead of a CHO Catalyst N carboxylic acid are still less developed. Only three examples 37 NC O using other components instead of carboxylic acid have been MeOH 3a 38 reported so far. In 2006, El Kaim and Grimaud reported the O- 1a 2a 4aaa 39 arylative Passerini-type reaction using nitrophenol derivatives, Entry 1a (eq) 2a (eq) Catalyst Yield (%)b 40 which have a more acidic proton compared to aliphatic 1 1 1.2 None trace 41 alcohols.6 In 2010, Soeta and Inomata used silanol instead of 2 1 1.2 Zn(OTf) 2/ 0.2 trace 3 1 1.2 AgOTf/ 0.2 trace 42 carboxylic acid component, giving the corresponding - 7 4 1 1.2 In(OTf)3/ 0.2 65 43 siloxyamides in moderate to good yields. The only report 5 1 1.2 ZnCl / 0.2 trace 8 2 44 using aliphatic alcohol was developed by Taguchi. Catalyzed 6 1 1.2 AlCl3/ 0.2 73 45 by In(OTf)3 with HC(OMe)3 as an additive, isocyanides, 7 1 1.2 FeCl3/ 0.2 43 46 aldehydes and aliphatic alcohols afforded -alkoxy amide 8 1 1.2 CuCl2/ 0.2 trace Chemistry derivatives in good yield, but there was only one example of 9 1 1.2 CH3COOH/ 0.2 trace 47 unsubstituted cinnamaldehyde and one isocyanide were 10 1 1 AlCl3/ 0.2 76 48 reported. Herein, we developed an inexpensive Lewis acid 11 1.2 1 AlCl3/ 0.2 79 49 12 1.5 1 AlCl3/ 0.2 85 AlCl3 catalyzed direct Passerini reaction for accessing - 13 1.8 1 AlCl / 0.2 80 50 3 alkoxy-,-enamide derivatives. A large scope of commonly 14 1.5 1 AlCl3/0.1 63 51 available alcohols, isocyanides, cinnamaldehydes are suitable a Reaction conditions: To a solution of catalyst (0.2 eq) in MeOH (1 mL) in a 52 substrates in this catalyst system. By this synthetic strategy, a sealed vial were added cinnamaldehyde (0.2 mmol) and isocyanides (0.3 53 polyfunctional molecular scafford, -alkoxy-,-enamides mmol) in sequence. The reaction mixtures were stirred at 60 oC for 12 h. b 54 could be prepared in one step. -Alkoxy-,-enamides is the Isolated yield. Organic core part in many natural compounds, such as symbioramide, a 55 We initially started to optimize the reaction conditions using 56 type of bioactive ceramide with antileukemic activities and as inhibitors of the Dengue and West Nile virus proteases.9 cyclohexyl isocyanide (Cy-NC) 1a and cinnamaldehyde 2a as 57 the model substrates, MeOH 3a as reagent as well as solvent. 58 Selected results of Lewis acids are summarized in table 1. To 59 60 This journal is © The Royal Society of Chemistry 2013 J. Name., 2013, 00, 1-3 | 1 Organic Chemistry Frontiers Page 2 of 4 ARTICLE Journal Name 1 our delight, moderate to good yields were obtained catalyzed by sterically hindered tert-butyl alcohol was used as substrate as 2 several Lewis acids. Among them, AlCl3 was the most efficient well as solvent, only 53% yield was obtained even in presence o 3 catalyst which gave the expected P-3CR product in 73% yield of 100 mol% AlCl3 stirring at 80 C for 36 h (entry 5). The 4 (entry 6, Table 1). The other two Lewis acid In(OTf)3 and steric effect of isocyanides showed no obvious influence on the 5 FeCl3 were also effective in the reaction, while lower yields yields of products. 81% and 82% yields were obtained for n- 6 were resulted. The ratio of isocyanide 1a and cinnamaldehyde butyl isocyanide and tert-butyl isocyanide separately (entries 6 7 2a were also investigated (entries 10-13), leaded to and 7). Aromatic isocyanides 1e also suitable substrate in this 8 improvement of the yield from 73% to 85% (entry 12). 10 rection condition, affording corresponding product 4eaa in 72% mol% AlCl3 can make the reaction work, but relatively lower yield, but a longer reaction time (24h) was needed (entry 9). 9 yield (63%) was obtained (entry 14). 10 Table 3 O-Alkylative Passerini reaction of substituted cinnamaldehyde 2 11 Table 2 O-Alkylative Passerini reaction of various isocyanides 1 and with cyclohexyl isocyanide 1a and methol 3a.a 12 alcohols 3 with cinnamaldehyde 2a.a O H 3 CHO 13 R NC R2 AlCl3, 20 mol % 2 N O R CHO AlCl , 20 mol % H o 14 3 N 2b-2l MeOH, 3a, 60 C O R1 NC R1 1a 15 o 3a-3e, 60 C O 1.5 equiv 1 equiv 4aba-4ala 16 1a-1e 2a 4aaa-4eaa Yield Entry Cinnamaldehyde Time(h) Products d Manuscript 17 Entry Isocyanides Alcohols Products Yield (%)d (%) 18 19 MeOH 1 12 85 1 85 20 1a 3a 2b 4aaa 4aba 21 22 EtOH 2 63 2 24 64 23 1a 3b 2c 4aab 4aca 24 25 3 64 3 24 76 26 Accepted 1a 3c 2d 27 4aac 4ada 28 29 4 61 4 24 73 1a 3d 2e 30 4aad 4aea 31 32 b 5 12 91 5 53 1a 2f 33 3e 4afa 34 4aae 35 MeOH 6 18 80 Frontiers 6 81 36 3a 2g 1b 4aga 37 4baa 38 MeOH 7 82 7 24 83 39 1c 3a 2h 40 4caa 4aha 41 MeOH 42 8 75 1d 3a 8 24 75 43 4daa 2i 44 4aia c MeOH 9 72 O 45 3a O2N CHO H 1e O2N N Chemistry 4eaa 9 b 48 58 46 O a To a solution of AlCl (0.1 mmol, 0.20eq) in indicated alcohols (1 mL) in a 47 3 2j 4aja sealed vial were added cinnamaldehyde 2a (1mmol) and isocyanides 1 (1.5 48 mmol, 1.5 eq) in sequence. The reaction mixtures were stirred at 60 oC for 49 12h. b The reaction was carried out in t-BuOH in presence of 100 mol% 10 b 48 56 o c d 50 AlCl3, stirred at 80 C for 36 h. The reaction was carried out for 24 h. 2k 4aka 51 Isolated yield. 52 With the optimized reaction conditions in hand, various - 53 11 24 70 alkoxy-,-enamides were successfully synthesized via O- 2l Organic 54 4ala alkylative Passerini reaction of various isocyanide 1 and a 55 alcohols 3 with cinnamaldehyde 2a. As shown in table 2, the To a solution of AlCl3 (0.1 mmol, 0.20eq) in indicated alcohols (1 mL) in a sealed vial were added cinnamaldehyde 2a (1mmol) and isocyanides 1 (1.5 56 reaction proceeded smoothly in many primary and secondary o mmol, 1.5 eq) in sequence. The reaction mixtures were stirred at 60 C for 57 alcohols (entries 1-4).