Molecules. 2016 Jun 22;21(6). pii: E815. doi: 10.3390/molecules21060815.

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

Bosica G1, Abdilla R2.

Author information

  • 1Department of Chemistry, University of Malta, Msida MSD 2080, Malta. giovanna.bosica@um.edu.mt.
  • 2Department of Chemistry, University of Malta, Msida MSD 2080, Malta. roderick.abdilla.12@um.edu.mt.

 

Abstract

Aza-Michael reactions between primary aliphatic and aromatic amines and various Michael acceptors have been performed under environmentally-friendly solventless conditions using acidic alumina as a heterogeneous catalyst to selectively obtain the corresponding mono-adducts in high yields. Ethyl acrylate was the main acceptor used, although others such as acrylonitrile, methyl acrylate and acrylamide were also utilized successfully. Bi-functional amines also gave the mono-adducts in good to excellent yields. Such compounds can serve as intermediates for the synthesis of anti-cancer and antibiotic drugs.

KEYWORDS: Aza-Michael reactions; acidic alumina; mono-addition; primary amines; solvent-free

PMID: 27338336

 

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).

 

 

sch1

Scheme 1 – aza-Michael reaction involving the synthesis of β-aminoacids which can be used in the synthesis of receptor antagonists as degradation-resistant peptides

 

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

 

 

sch2

Scheme 2 – aza-Michael reaction between propargylamine (5) and acrylate (2) to generate secondary propargylamines (6) which can aid in the therapy of neurodegenerative diseases

 

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.

 

 

fig1

Figure 1 –Product obtained by the aza-Michael mono-addition between ethyl acrylate and 2- aminobutan-1-ol whose structure is similar to that of 2-aminoalcohols, a sub-class of β-blockers

 

When acrylonitrile was used as an acceptor, impressive yields (83 – 100 %) were recorded for both aliphatic and aromatic amines such as when the pharmaceutically interesting p-methoxybenzylamine (100%, 90 0C / 4 hours) was utilised. In effect, benzylamine derivatives have a wide range of pharmaceutical applications such as:

  • in the treatment of Alzheimer’s – a neurodegenerative diseases;
  • in the reduction of plasma cholesterol levels;
  • as vasodilators;
  • in the treatment of tumours.12,13

 

Furthermore, β-aminonitriles, the products derived from acrylonitrile acceptor, can be converted to diamines which are extremely important in the synthesis of drugs.14 The last Michael acceptor which was tried was acryloamide and once more good to excellent results were obtained (75 – 95%). Remarkably, the mono-adducts can act as local anaesthetics i.e. compounds which cause reversible decrease in pain sensation in cases involving cough or diarrhoea suppression or to decrease opioid-induced constipation.15

 

All in all, these results were obtained under environmentally benign conditions. This is because acidic alumina proved to be a cheap, safe, easily-recoverable and recyclable catalyst whilst the reactions were performed in neat conditions in the absence of any solvent, stabilizers or additives and in relatively short reaction times. A possible extension of this study could involve the application of the catalyst in the intramolecular version of the reaction.

 

References

  1. Perlmutter, P. Conjugate addition reactions in organic synthesis. Pergamon: Oxford, UK, 1992.
  2. Rulev, A. Y. Aza-Michael reaction: achievements and prospects. Russ. Chem. Rev. 2011, 80, 197-218.
  3. Mather, B. D.; Viswanathan, K.; Miller, K. M.; Long, T. E. Michael addition reactions in macromolecular design for emerging technologies. Prog. Polym. Sci. 2006, 31, 487-531.
  4. Steer, D. L.; Lew, R. A.; Perlmutter, P.; Smith, A. I.; Aguilar, M. β-amino acids: versatile peptidomimetics. Curr. Med. Chem. 2002, 9, 811 – 822.
  5. Abraham, T. W.; Kalman, T. I.; McIntee, E. J.; Wagner, C. R. Synthesis and biological activity of aromatic amino acid phosphoramidates of 5-Fluoro-2′-deoxyuridine and 1-β-arabinofuranosylcytosine: evidence of phosphoramidase activity. J. Med. Chem. 1996, 39, 4569 – 4575.
  6. Winter, H.; Maeda, Y.; Mitsuya, H.; Zemlicka, J. Phosphodiester amidates of allenic nucleoside analogues: anti-HIV activity and possible mechanism of action. J. Med. Chem. 1996, 39, 3300 – 3306.
  7. Bosica, G.; Spiteri, J.; Borg, C. Aza-Michael reaction: Selective mono- versus bis-addition under environmentally friendly conditions. Tetrahedron Lett. 2014, 70, 2449–2454.
  8. Boulton, A. A.; Davis, B. A.; Durden, D. A.; Dyck, L. E.; Juorio, A. V.; Li, X.; Paterson, A.; Yu, P. H. Aliphatic propargylamines: new antiapoptotic drugs. Drug Dev. Res. 1997, 42, 150 – 156.
  9. Kochman, A.; Skolimowski, J.; Gebicka, L.; Metodiewa, D. Antioxidant properties of newly synthesized N-propargylamine derivatives of nitroxyl: a comparison with deprenyl. Pol. J. Phrmacol. 2003, 55, 389 – 400.
  10. Bosica, G.; Gabarretta, J. Unprecedented one-pot multicomponent synthesis of propargylamines using Amberlyst A-21 supported CuI under solvent-free conditions. RSC Adv. 2015, 5, 46074–46087.
  11. Shuvani, B.; Pujala, A. K.; Chakraborti, J. Zinc(II) perchlorate hezahydrate catalyzed opening of epoxide ring by amines: applications to synthesis of (RS)/(R)-propranolols and (RS)/(R)/(S)-naftopidils. J. Org. Chem. 2007, 72, 3713 – 3722.
  12. Yan, T.; Feringa, B. L.; Barta, K. Benzylamines via iron catalyzed direct amination of benzyl alcohols. ACS Catal. 2016, 6, 381 – 388.
  13. Madonna, S.; Beclin, C.; Laras, Y.; Kraus, J. Structure-activity relationships and mechanism of action of antitumour bis 8-hydroxyquinoline. Eur. J. Med. Chem. 2009, 45, 623 – 638.
  14. Yadav, J. S.; Reddy, B. V.; Parimala, G. P.; Reddy, V. Lithium perchlorate catalyzed regioselective ring opening of aziridines with sodium azide and sodium cyanide. Synthesis 2002, 16, 2383 – 2386.
  15. Loew, G.; Lawson, J.; Toll, L.; Frenking, G.; Berzetei-Gurske, I.; Polgar, W. Structure activity studies of two classes of beta-amino-amides: the search for kappa-selective opiodis. NIDA Res. Monogr. 1988, 90, 144 – 151.

 

 

 

Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann