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1 2 Journal Name RSC 3 4 5 ARTICLE 6 7 8 9 AlCl3-Catalyzed O-Alkylative Passerini Reaction of 10 11 , 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 , cinnamaldehyde and alcohol. Instead of in 21 classical Passerini reaction, alcohols performed both as and substrate nicely to afford 22 -alkoxy- 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, 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 , 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 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). The corresponding -alkoxy-,- b c indicated time. 50 mol% AlCl3 was added in two portion Isolated yield. 58 enamide were obtained in 61-85% yields. However, when the 59 60 2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 2012 Page 3 of 4 Organic Chemistry Frontiers Journal Name ARTICLE

1 To further investigate the substrate scope, a series of 2 Acknowledgements substituted cinnamaldehydes 2b-2l were investigated as shown We gratefully thank the startup fund from South University of 3 in Table 3. The results indicated that electronic effect of Science and Technology of China (SUSTC) for financial 4 cinnamaldehyde 2 make a serious influence on this reaction. support. 5 Cinnamaldehydes with electronic donating group provided the 6 formation of -alkoxy-,-enamides in good yields (entries 1,5- 8). Under the same optimized condition, substrates with weak 7 Notes and references electronic withdrawing group (F, Cl, Br) were also performed 8 a nicely to give corresponding products in moderate yields Department of Chemistry, South University of Science and Technology 9 (entries 2-4). The reactions of cinnamaldehydes with strong of China, Shenzhen, Guangdong, 518055, China. Fax: (+86) 755- 10 electronic withdrawing group (NO2, CN) were sluggish in this 88018304 E-mail: [email protected]. 11 catalyst system. After further optimization, the desired products b School of Chinese Medicine, Hong Kong Baptist University, Hong 12 4aja and 4aka were obtained in moderate yields when 50 mol% Kong. Fax: (+852)-34112929 E-mail: [email protected]. AlCl was added in two portion (entries 9 and 10). In addition, 13 3 2-hydroxy-cinnamaldehyde with no protection at hydroxy 14 Electronic Supplementary Information (ESI) available: [details of any 15 group was also suitable for the reaction, indicating good supplementary information available should be included here]. See 16 substrate toleration for this synthetic methodology (entry 11). DOI: 10.1039/b000000x/

The influence of steric effect was also investigated. We found Manuscript 17 that orth-substitutes in phenyl ring showed no significant 18 effects on the yields of products due to the distance from 1 (a) M. Passerini and L. Simone, Gazz. Chim. Ital., 1921, 51, 126; (b) 19 functional group of aldehyde. Therefore, it was not surprising M. Passerini and G. Ragni, Gazz. Chim. Ital., 1931, 61, 964. 20 that 2-methylcinnamaldehyde 2g and 2- ö 21 methoxycinnamaldehyde 2h with electron-donating group but 2 (a) A. D mling and I. Ugi. Angew. Chem., Int. Ed., 2000, 39, 3168; 22 steric hindrance could still give the desired product 4aga and (b) A. Dömling, Chem. Rev., 2006, 106, 17; (c) L. Banfi and R. Riva, 23 4aha in 80% and 83% yield separately (entries 6-7). Org. React., 2005, 65, 1; (d) C. de Graaff, E. Ruijter and R. V. A. 24 On the basis of the result, a mechanism for the Lewis acid- Orru, Chem. Soc. Rev., 2012, 41, 3969; (e) S. S. van Berkel, B. G. M. 25 catalyzed formation of -alkoxy-,-enamide derivatives via Boegels, M. A. Wijdeven, B. Westermann and F. P. J. T. Rutjes, Eur. direct O-Alkylative Passerini reaction was shown in Scheme 2. J. Org. Chem. 2012, 19, 3543; (f) A. Domling, W. Wang and K. 26 In the presence of Lewis acid AlCl , cinnamaldehyde reacts Accepted 3 Wang, Chem. Rev., 2012, 112, 3083. 27 with alcohol to generate oxocarbenium species A, which was 3 Selected examples for recent Passerini-type reactions in preparation 28 isolated as shown in table 3 (entry 9 and 10) and lost a H2O. 29 Subsequently, A is attacked by isocyanide to give nitrilium polymers, see: (a) O. Kreye, T. Tóth and M. A. R. Meier, J. Am. 30 intermediate B. Then, the hydrolysis of the intermediate B Chem. Soc., 2011, 133, 1790; (b) X. X. Deng, Y. Cui, F. S. Du and Z. 31 result the formation of C which is easy to isomerize to give - C. Li, Polym. Chem., 2014, 5, 3316; (c) O. Kreye, D. Kugele, L. 32 alkoxy-,-enamide 2. Faust and M. A. R. Meier, Macromol. Rapid. Comm., 2014, 35, 317;

1 33 Me Me R (d) W. Lin, T. Sun, M. Zheng, Z. Xie, Y. Huang and X. Jing, RSC O+ O O 34 Cy-NC H2O OH Adv. 2014, 4, 25114; (e) S. C. Solleder and M. A. R. Meier, Angew. N 35 -OMe Chem., Int. Ed., 2014, 53, 711; (f) L. Li, A. Lv, X.-X. Deng, F.-S. Du, Cy N Frontiers B C H Cy 36 A Z.-C. Li, Chem. Commun. 2013, 49, 8549; 37 AlCl3 4 Selected examples for recent Passerini-type reactions in preparation MeOH 38 -H2O peptides, see: (a) M. Paravidino, R. Scheffelaar, R. F. Schmitz, F. J. Me 39 O J. de Kanter, M. B. Groen, E. Ruijter and R. V. A. Orru J. Org. Chem. CHO AlCl , 20 mol % H 3 N 40 Cy Cy-NC, MeOH, 60 oC 2007, 72, 10239; (b) W. Szymanski, M. Zwolinska, S. Klossowski, I. 41 2a O Mlynarczuk-Bialy, L. Bialy, T. Issat, J. Malejczyk and R. 3aaa 42 Ostaszewski, Bioorg. Med. Chem. 2014, 22, 1773; (c) S. Shaaban, R.

43 Scheme 2 Proposed mechanism of the AlCl3-catalyzed O-Alkylative Diestel, B. Hinkelmann, Y. Muthukumar, R. P. Verma, F. Sasse, and 44 Passerini reaction for accessing -alkoxy-,-enamides. C. Jacob, Eur. J. Med. Chem. 2012, 58, 192; (d) S. Faure, T. 45

Hjelmgaard, S. P. Roche and D. J. Aitken, Org. Lett. 2009, 11, 1167. Chemistry 46 Conclusions 5 Selected examples for recent enantioselective Passerini-type reactions, 47 In summary, we developed an efficient and practical O- see: (a) H. Mihara, Y. Xu, N. E. Shepherd, S. Matsunaga and M. 48 Shibasaki, J. Am. Chem. Soc. 2009, 131, 8384; (b) T. Yue, M.-X. 49 alkylative Passerini reaction of isocyanides, cinnamaldehydes and alcohols catalyzed by inexpensive Lewis acid AlCl . This Wang, D.-X. Wang and J.-P. Zhu, Angew. Chem., Int. Ed. 2008, 47, 50 3 method offers a direct synthesis of -alkoxy-,-enamide 9454; (c) S.-X. Wang, M.-X. Wang, D.-X. Wang and J.-P. Zhu, 51 derivatives in one step. A large scope of isocyanides, Angew. Chem., Int. Ed. 2008, 47, 388; (d) S. E. Denmark and Y. Fan, 52 cinnamaldehydes and alcohols were suitable substrates in this J. Org. Chem. 2005, 70, 9667; (e) P. R. Andreana, C. C. Liu and S. L. 53 catalyst system to afford the -alkoxy-,-enamide derivatives Schreiber, Org. Lett. 2004, 6, 4231; (f) U. Kusebauch, B. Beck, K. Organic 54 up to 91% yields. Further investigations on asymmetric Messer, E. Herdtweck and A. Dömling, Org. Lett. 2003, 5, 4021; (g) 55 synthesis methodology of -alkoxy-,-enamide derivatives 56 and their biological activities evaluation are ongoing in our S. E. Denmark and Y. Fan, J. Am. Chem. Soc. 2003, 125, 7825; (h) 57 laboratory. A. M. Deobald, A. G. Corrêa, D. G. Rivera and M. W. Paixão, Org. 58 59 60 This journal is © The Royal Society of Chemistry 2012 J. Name., 2012, 00, 1-3 | 3 Organic Chemistry Frontiers Page 4 of 4 ARTICLE Journal Name

1 2 Biomol. Chem., 2012, 10, 7681; (i) T. Yue, M.-X. Wang, D.-X. Wang, 8 H. Yanai, T. Oguchi and T. Taguchi, J. Org. Chem., 2009, 74, 3927; 3 G. Masson and J.-P. Zhu, J. Org. Chem., 2009, 74, 8396. 9 (a) H. Azuma, R. Takao, H. Niiro, K. Shikata, S. Tamagaki, T. 4 6 (a) L. E. Kaim, M. Gizolme, and L. Grimaud, Org. Lett. 2006, 8, Tachibana and K. Ogino, J. Org. Chem., 2003, 68, 2790; (b) C. 5 5021; (b) L. E. Kaim, M. Gizolme, L. Grimaud and J. Oble, J. Org. Steuer, C. Gege, W. Fischl, K. H. Heinonen, V. Bartenschlager and 6 Chem. 2007, 72, 4169. C. D. Klein, Bioorg. Med. Chem., 2011, 19, 4067. 7 7 T. Soeta, Y. Kojima, Y. Ukaji, and K. Inomata, Org. Lett., 2010, 12, 8 434. 9 10 11 12 13 14 15 16 17 Manuscript 18 19 20 21 22 23 24 25

26 Accepted 27 28 29 30 31 32 33 34 35 Frontiers 36 37 38 39 40 41 42 43 44 45 46 Chemistry 47 48 49 50 51 52 53 54 Organic 55 56 57 58 59 60 4 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 2012