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Aza-Michael Mono-addition Using Acidic Alumina under Solventless Conditions.

 

Supplementary information

The aza-Michael reaction involves the formation of a C-N bond following nucleophilic attack by nitrogen-donor compounds (aliphatic and aromatic amines, amides, carbamates, azides and indoles) onto α,β-unsaturated compounds (enones, acrylates, acrylonitriles, acrylamides and nitro alkenes amongst others).^1,2,3

The primary noteworthy application of this conjugate reaction is the synthesis of β-amino acids which have been incorporated in peptidomimetics i.e. compounds which function like polypeptides.4 Scheme 1 specifically shows the aza-Michael reaction between an amine (1) and an α,β-unsaturated acrylate (2) to generate the mono-adduct, a β-aminoester, (3) which when hydrolysed generates a β-amino acid (4).

Interestingly, this family of biologically-active compounds are not susceptible to proteolytic degradation in the body apart from having a wide range of capabilities because they can act as both receptor agonists and antagonists.4 Consequently they can perform their function successfully without ending up broken down before they have actually reached their target site. Of note is the application of these amino acids in bombesin receptor antagonist synthesis. Bombesin is a 14-amino acid peptide which activates particular receptors in the body that elicit:

• smooth muscle contraction – muscles which are not under voluntary control and which are found lining the gut or other internal organs;
• gastrin release – a peptide hormone which stimulates secretion of gastric acid from the pancreas into the duodenum of the small intestine;
• mitogenesis of lung and gastrointestinal tissue – encourages the start of cell division so that new cells are produced.

Meanwhile, bombesin receptor antagonists are molecules which cause opposing effects to receptor agonists. To date, they have been synthesized by replacing some of the α-amino acids in the peptide chain by β-ones (E.g. β-Leucine, β-D-Phenylalanine). Most importantly such compounds have been found to be potent cancer therapeutics.⁴

Apart from being successfully used without modification in β-peptide synthesis, derivatives of amino acids are also of incredible relevance. For example, β-amino acids which have their amino group linked to a chain with a terminal phosphorus moiety are of great interest because they can have anti-tumour, anti-viral or anti-bacterial properties.^5,6

In our study, acidic alumina was chosen as a suitable catalyst for selective formation of mono-adducts between a wide range of primary amines and Michael acceptors. All reactions were performed under green, heterogeneous and solventless conditions in the presence of 200 mol% of catalyst. The molar ratio of the Michael donor and acceptor was always kept at 1.5 : 1. With the above information in context, ethyl acrylate and methyl acrylate were chosen as the main Michael acceptors to generate β-aminoesters that can be hydrolysed to generate β-amino acids. Consequently, our study ensured an environmentally benign method to possibly generate compounds of pharmaceutical relevance. The reaction is completely 100% atom economic because all starting materials get incorporated in the final product and the reaction times were relatively short (3 – 5 h). In addition, the catalyst is easily recoverable and reusable. Lastly, in a separate study it has also been shown that this catalyst can be used to obtain the bis-adduct whilst changing the molar ratio of the Michael donor : acceptor to 1 : 2 and keeping all other conditions the same.⁷ Studies by other research groups have rarely ventured into trying to obtain the mono- and bis- products separately and yet in our study we have managed to do so without varying the conditions (except for the molar ratio).

Turning onto some interesting aspects for the mono-addition, the highest yield for aliphatic amines was obtained when ethyl acrylate was reacted with c-pentylamine (90% / 3 h). Excellent yields were also obtained for aromatic amines including a 98% value when p-methoxyaniline was refluxed with the acceptor for 3 hours. In addition, bifunctional amines such as propargyl (5) and allylamine were also used to generate β-propargylamino/allylamino esters. Without doubt, these products have massive pharmaceutical potential and specifically, compounds derived from 5, act as key intermediates in the synthesis of β-lactams and as neural rescue agents that can help in the therapy of Parkinson’s, Alzheimer’s and other neuro-degenerative diseases.^8-10

Another interesting bifunctional amine which was used, 2-aminobutan-1-ol,  albeit yielding the mono-adduct (7) at a yield of 66% (4 h), has a free terminal OH group which can be potentially involved in nucleophilic substitution reactions or ester formations amongst other reactions. At this stage it is also imperative to mention a subclass of β-blockers, 2-aminoalcohols which have a similar structure to 7 and which are used in the treatment of hypertension and anginapectoris.¹¹ Classical synthesis of 2-aminoalcohols usually involves treating epoxides with an amine but epoxides may be sensitive and can rearrange or polymerize during the reaction. Yet, this method worked quite well and gave the resulting product under environmentally benign conditions.