Solvent- and catalyst-free aza-Michael addition of imidazoles and related heterocycles

This work demonstrates the scope and limitations of the aza-Michael addition of imidazoles and related heterocycles with electron deficient olefins under solventand catalyst-free conditions. The reaction proceeds at 80°C within hours towards completion as long as the azole derivative is sufficiently soluble in the Michael acceptor, which has been used in small excess. Workup only comprises evaporation of surplus Michael-acceptor and no additional solvents are necessary for purifying the products.

Introduction. The ideal chemical reaction proceeds fast at ambient temperature and quantitatively yields a single product without the need of a catalyst. This means no side-but also no byproducts are formed, resulting in perfect atom economy 1 and full consumption of educts. In this case, no purification or any other workup is necessary. In reality, the situation is in most cases different. Conversions are not complete, catalysts are needed to speed up the reaction or to provide alternative reaction pathways and/or selectivity, by-and side products form and often solvents have to be employed. Solvent use in organic chemistry is in many cases inevitable for providing high reaction rates, for obtaining the desired selectivity or for facilitating the heat management of a reaction. Moreover, many purification techniques heavily rely on the use of solvents. Accordingly, solvent use is in many cases accountable for a huge part of the synthesis' negative impact on the environment. Consequently, research striving for solvent-free and at the same time catalyst-free reactions evolved as a branch of green chemistry. 2 However, many examples termed solvent-free in literature are using solvents during isolation and purification to meet the stringent requirements in terms of purity in preparative organic chemistry. Taking into account, that usually much more solvent is needed during purification than during preparation, the impact of performing a reaction without solvent (and catalyst) in saving resources is rather limited as soon as a solvent-based purification is necessary. 3 In other words, solvent-and catalyst-free reactions should ideally proceed to completeness without forming side-or byproducts that have to be separated with the help of solvent-based methods in order to provide a significant advantage in terms of sustainability.
Among the many classes of different reactions, in particular addition reactions qualify for designing side-and byproduct free transformations without the need of catalysts and solvents at any stage of the preparation. Some selected examples comprise the cycloaddition of aziridines and carbon dioxide, 4 hydrophosphanation of alkenes, 5 Diels-Alder reactions, 6 Knoevenagel reaction of aldehydes (which is a condensation type reaction) 7 or the aza-Michael reactions. 8 The aza-Michael reaction involves a nucleophilic amine (the Michael donor) and an electron deficient alkene (the Michael acceptor). Generally, it is performed with the aid of a catalyst under mild reaction conditions leading to high conversions with an atom economy of 100%. Side-products are usually not observed. The works of Desmet et al. 9 and Bláha, et al. 8c describe the mechanistic understanding of the (uncatalyzed) reaction in detail. In essence, the aza-Michael addition is a third-order reaction (first order in the acceptor and second order in the donor). The third-order kinetics are rationalized by the formation of a rate-determining zwitterionic transition state in which a second amine is needed to facilitate the proton transfer from the attacking amine to the α-carbon of the electron deficient olefin (Scheme 1). The mechanism implies that the aza-Michael reaction should ideally proceed with amines of high nucleophilicity (to facilitate the formation of the zwitter-ion) and bearing loosely bound protons (facilitating the hydrogen transfer). Preferably, reactions should be performed with the highest possible concentration of the reactants and not too high temperature (because the reaction is of third-order). Accordingly, the aza-Michael reaction is perfectly suitable for being performed in an uncatalyzed solvent-free manner. Surprisingly, to the best of our knowledge, only three publications on solvent-and catalyst-free aza-Michael addition are available and only aliphatic amines have been investigated so far. 8 Herein, we wish to elucidate the reactivity of azoles with Michael acceptors under solvent and catalyst free conditions. Using azoles, like imidazoles or pyrazoles is an attractive target, because they show rich Michael chemistry with outreach into material, medicinal and biological chemistry. A recent review nicely summarizes the state of the art in aza-Michael additions of imidazoles. 10 Interestingly it has been stated in that work, that only a few reports on reactions that satisfyingly proceed only in solvent without catalysis are known. The question whether this lack of reactivity is due to the use of unfavorable reaction conditions or the electronic features of azoles remains. The nucleophilicities and the acidities of imidazoles and related heterocycles suggest them to be poorer aza-Michael donors then aliphatic amines. Their nucleophilicity is comparable to the one of secondary aliphatic amines as judged by the methyl cation affinity (imidazole 531.7 kJ/mol vs. dimethylamine 523.1 kJ/mol) 11 or less pronounced considering the nucleophilicity parameter N (imidazole N = 11.47 12 vs. dimethylamine N = 15.10 13 ). Moreover, the acidity of the proton residing at the second nitrogen atom is about 3-4 orders of magnitude lower than in aliphatic amines (e.g. imidazole pKa = 13.9 vs. pKa = 10.73 for diethylamine). 14 The investigations presented here are intentionally restricted to Michael-acceptors, which can be separated upon evaporation in order to avoid a work-up involving any solvent.   -23). 15 The reaction of 2-methyl imidazole (2) with A-D was somewhat slower than with 1. This might be explained by the lower pKa-value calculated for 2 when compared to 1 (Fig. 1), since the nucleophilicity of 2 is slightly higher (N = 11.74 vs. 1: N = 11.47 12 ).

Results and
To further examine the impact of the acidity of the heterocycles' protons, a selection of different Michel donors covering a range of different acidities was made (Fig. 2, left). Their  Fig. 2 (right). In all cases, heterocycles dissolved more slowly contributing to the distinctly longer reaction times.
This was confirmed by using a higher excess of E (5 equiv.) which allowed for shortening the reaction time giving a conversion of 97% towards 2E in 24 h. Accordingly, in these cases, a solvent and catalyst free protocol is lacking merit.  Weaker Michael acceptors being at the same time poorer solvents for the azole derivatives require reaction times of more than 24 h to reach completeness. In such cases, the use of solvents and catalysts is advisable. The findings contain a caveat for all researching catalysis in aza-Michael additions, namely that the concentration of the reaction partners is of crucial importance for determining the speed of the reaction, just as expected for a third-order reaction. Finally, the statement issued in a recent review, that only few reports on reactions that satisfyingly proceed only in solvent without catalysis are known, has been demystified.
Experimental. All reactions were performed under ambient conditions. Chemicals were purchased from TCI, Acros or Sigma-Aldrich and were used as received (stabilizers present in the Michael acceptors were not removed). 1 H and 13 C-NMR spectra were recorded at 23°C on a Bruker Ultrashield 300 spectrometer operating at 300.36 MHz ( 1 H) and 75.53 MHz ( 13 C).
Deuterated solvents were purchased from Cambridge Isotope Laboratories.
A general procedure is given by the example of the preparation of 2B. Methyl acrylate