Microwave-Assisted Passerini Reactions under Solvent-Free Conditions

Diversas a-acilóxi carboxamidas foram facilmente obtidas combinando três componentes em uma única etapa: um ácido carboxílico, um aldeído e uma isonitrila (reação de Passerini), usando irradiação de micro-ondas em condições sem solvente. Os produtos foram obtidos em bons rendimentos (61-90%) e em tempos reacionais bastante curtos (≤ 5 min), usando duas diferentes temperaturas (60 e 120 °C). A 120 °C, os rendimentos foram mais altos e as reações mais rápidas (≤ 1 min). Vários dos produtos formados são multifuncionais, possibilitando sua aplicação em reações de Passerini consecutivas.


Introduction
Multicomponent reactions (MCRs) are referred to as one-pot processes, where three or more reactants combine to give a single product which incorporates essentially most of the atoms of the starting materials. 1MCRs constitute an especially attractive synthetic strategy since they offer greater possibilities for molecular diversity per step with a minimum of synthetic effort, time and formation of by-products. 2he development of atom-economic and synthetically effective methodologies is currently an important goal in organic synthesis 3 and in this regard MCRs play a significant role.At the same time, the use of microwave energy to facilitate chemical reactions has become increasingly popular in organic synthesis. 4Microwave-assisted organic synthesis (MAOS) has been demonstrated to be efficient at increasing the rate of MCR reactions with significant improvements in reaction times and yields. 5ombining these two powerful tools is a particularly attractive methodology in modern organic synthesis. 6This combination allows for rapid production of molecular complexity and diversity from simple and readily accessible bioactive molecules.Recently, literature has provided many examples of microwave-promoted multicomponent reaction protocols, for example, Ugi, Biginelli and Hantzsch reactions. 6Nevertheless, to the best of our knowledge, the Passerini three-component reaction had not yet been explored.This reaction, 7 described in 1921, is a multicomponent reaction which provides a-acyloxy carboxyamides by combining three building blocks in one step: a carboxylic acid, an oxo-component (aldehyde or ketone) and an isonitrile. 8n continuation to our research on MCRs, 9 we herein report the results of a systematic study of unprecedented microwave-assisted Passerini reactions under solvent-free conditions (Scheme 1).

Experimental
All reactions were performed on a CEM Co., Discover microwave reactor using sealed vessels, dynamic program, at 60 °C or 120 °C (temperature detection by internal fiber optic probe), with stirring, simultaneous cooling and at a fixed power (40 W).Melting points were recorded on a Thomas Hoover Capillary melting point apparatus and are uncorrected.IR spectra were recorded on a Bomem MB-100 Vol.22, No. 3, 2011   FTIR. 1 H and 13 C NMR spectra were recorded on a Varian Mercury Plus 300 spectrometer, operating at 300 MHz for 1 H NMR and 75 MHz for 13 C NMR.Chemical shifts (d ppm) in CDCl 3 were reported downfield from TMS (= 0) for 1 H NMR. For 13 C NMR, chemical shifts were reported in the scale relative to CDCl 3 (77.00ppm) as an internal reference.Column chromatography was performed on silica gel (Acros Organic 0.035-0.070mm).High resolution mass spectra (electrospray ionization) were obtained using a Micro TOF Ic-Bruker Daltonics instrument.All compounds were analyzed by 1 H NMR, 13 C NMR, IR, melting points (for solid products) and high resolution mass spectra giving data consistent with those proposed.

General procedure for the Passerini reaction
A sealed 10 mL glass tube containing the carboxylic acid (1 equiv.), the aldehyde (1 equiv.)and the isonitrile (1 equiv.) was introduced in the cavity of a microwave reactor (CEM Co., Discover).The flask was irradiated (40 W) while stirring for the time and temperature specified in Table 1.Purification by column chromatography on silica gel eluted with 4:6 (4a-g) or 2:8 (4h-j) ethyl acetate-hexane gave the pure products.

Results and Discussion
In the synthesis of a-acyloxy carboxyamides, aliphatic, aromatic and heteroaromatic aldehydes were reacted with equivalent amounts of isonitriles (methyl isocyanoacetate and tert-butyl isocyanide) and carboxylic acids (benzoic acid and Cbz-glycine).The three components were subjected to MW irradiation for the time specified in Table 1.Aromatic aldehydes substituted with both electron withdrawing and electron donating groups could be used successfully.The temperature was initially set at 60 °C (40 W) and the reactions were completed within 3-5 min as monitored by TLC showing the disappearance of the starting materials.Due to the good results obtained with the initial potency of 40 W, it was kept constant and used in all experiments.The yields of the purified products were generally very good and varied according to the substitution pattern of the aromatic aldehydes.Increasing the temperature to 120 °C, the yields were slightly better in all cases except for benzaldehyde (entry 1) in which the yield of the product was significantly improved.Reaction times in Table 1 correspond to the time at which the temperature was maintained at 60 or 120 °C.Furthermore, in all cases the increase of the temperature caused a decrease in the reaction time.
The results obtained in this study, especially in terms of reaction time (1 min or less at 120 °C), are remarkable as compared with our previous results on the Passerini reaction using ionic liquids (2-14 h) and PEG (0.5-6 h) as alternative solvents. 9Compared to usual organic solvents, such as CH 2 Cl 2 , the difference for similar reactions is even greater (completion usually above 18 h). 10Water has been demonstrated to accelerate these reactions but only in a limited extent (completion in 3-3.5 h). 10 According to a recent report on Passerini reactions, the yields were usually better under solvent-free conditions compared to the same reactions using dichloromethane as solvent. 11or comparison, the reactions of entries 1 and 2 were also performed using acetonitrile as solvent at 60 °C (oil bath) allowed formation of the products after 3 h in moderate yields (65 and 64%, respectively) as compared to 90 and 84% for the MW-assisted, solvent-free method (Table 1).The choice for acetonitrile relies on the fact that the acid component Cbz-glycine is not soluble in solvents commonly used in Passerini reactions such as dichloromethane.These results prove the superiority of our methodology in effectively promoting Passerini reactions.
Spectral analysis of 4a-j supported the success of the MW-mediated triple one-pot condensation.The isolated products were characterized on the basis of their IR, 1 H and 13 C NMR spectroscopy and mass spectra.
The most important characteristic of the 1 H NMR spectra is the presence of a singlet around d 6.00-6.50ppm relative to the hydrogen of the stereogenic center (except for 4b which gives a doublet at d 5.20 ppm).The 13 C NMR spectra corroborated the analysis of the compounds, showing four peaks corresponding to the carbonyl groups (d 155-170 ppm) when Cbz-glycine and methyl isocyanoacetate were used.Accordingly, when benzoic acid and tert-butylisocyanide were used two peaks corresponding to the carbonyl groups were observed at d 165-175 ppm.

Conclusions
A simple and efficient method was achieved for the preparation of a-acyloxy carboxyamides.Compounds 4a-g are versatile multifunctional intermediates that can be further functionalized at the NCbz-moiety.For instance, 4a-g can be easily hydrolyzed to the respective acid components which could be used in a subsequent Passerini reaction opening the possibility for the study of consecutive Passerini reactions.This new methodology is already being developed in our research group.The simplicity of the reaction conditions, its efficacy and the excellent results obtained using two different temperatures, under solvent-free conditions, constitute an attractive contribution among the existing methodologies.

60
°C / 3 min 120 °C / 1 min a Isolated yield of the chromatographically pure products.

Figure S2. 1 H
Figure S2. 1 H NMR (CDCl 3 , 300 MHz) of 4a.Note: The number below each peak refers to the number of integration.

Figure S6. 1 H
Figure S6. 1 H NMR (CDCl 3 , 300 MHz) of 4b.Note: The number below each peak refers to the number of integration.

Figure S10. 1 H
Figure S10. 1 H NMR (CDCl 3 , 300 MHz) of 4c.Note: The number below each peak refers to the number of integration.

Figure S14. 1 H
Figure S14. 1 H NMR (CDCl 3 , 300 MHz) of 4d.Note: The number below each peak refers to the number of integration.

Figure S18. 1 H
Figure S18. 1 H NMR (CDCl 3 , 300 MHz) of 4e.Note: The number below each peak refers to the number of integration.

Figure S22. 1 H
Figure S22. 1 H NMR (CDCl 3 , 300 MHz) of 4f.Note: The number below each peak refers to the number of integration.

Figure S26. 1 H
Figure S26. 1 H NMR (CDCl 3 , 300 MHz) of 4g.Note: The number below each peak refers to the number of integration.

Figure S30. 1 H
Figure S30. 1 H NMR (CDCl 3 , 300 MHz) of 4h.Note: The number below each peak refers to the number of integration.

Figure S34. 1 H
Figure S34. 1 H NMR (CDCl 3 , 300 MHz) of 4i.Note: The number below each peak refers to the number of integration.

Figure S38. 1 H
Figure S38. 1 H NMR (CDCl 3 , 300 MHz) of 4j.Note: The number below each peak refers to the number of integration.