Out of Africa

Published: February 11, 2013

Algeria is an unknown hotbed of chemistry. Andrew Warmington reports from ISCSC in Algeria

Tlemcen, a small, historic town in the west of Algeria, hosted the first International Symposium on Catalysis & Speciality Chemicals (ISCSC) in September 2012. Organised by the University of Tlemcen, ISCSC actually attracted over 500 abstracts, which were ultimately whittled down to four plenary lectures, seven keynotes, 24 oral presentations and 175 posters.

As well as being a seemingly unlikely setting for such an event, ISCSC posed some other surprises. First, Algeria, which is best known for its booming oil and gas sector, is actually something of a research hotbed into catalysis for fine and speciality chemicals, with strengths in areas like nanotechnology and green chemistry.

Secondly, in a country that has just emerged from a long civil war against Islamists opposed to female education at any level - and which Al-Qaeda had just tried to resume by attacking a gas facility in the Sahara just as this article was being drafted - women were in a clear majority of the 200 or so attendees, mostly PhD students from universities across the country. Women also contributed most of the oral presentations.

The keynote addresses and plenary lectures came from professors from the US, Spain, France, Canada and Russia, as well as Algeria itself. Subjects included the green synthesis of organics and nanomaterials, nano-structed supports for catalysts, gold-based bimetallic catalysts supported on oxides, supported vanadia catalysts, catalysis for biofuels, the green synthesis of nanomaterials and even the chemistry and biology of Alzheimer's disease, among many others.

ISCSC was an unusual chemistry conference - most of those attending were women

The posters themselves had a distinctly Algerian flavour. For instance, many focussed on the valorisation of local biomass, such as Ziziphus jujube, or the use of Algerian clays and minerals, including maghnites, montmorillonites and bentonites, in nanocomposites and other applications. There were many posters, too, on the catalytic and photocatalytic degradation of dyes or coloured wastewater from the local dyes and textiles industries.

Among the young Algerian academics present, Louisa Chouguiat of the University Mentouri of Constantine described a one-pot, solvent-free, multi-component synthesis of a variety 3,4-dihydropyrimidone (DHPM)-thione derivatives via Bignelli condensation using potassium tert-butoxide (t-BuOK) as a Brønsted base catalyst (Figure 1).

DHPMs are heterocycles that have been known for over 100 years and have important therapeutic properties as the integral backbone of various calcium channel blockers, anti-hypertensives and α1a-antagonists. Several alkaloids derived from marine sources with interesting biological activity also have the DHPM moiety in their structure.

Ever since the 1890s, DHPMs have been synthesised via Bignelli condensation, by heating a mixture of β-keto ester, aledhyde and urea in ethanol. However, this requires the use of a catalytic amount of HCl and yields are sometimes low. Recent work by Chouguiat's group and others, verified by 1H and 13C NMR, has established t-BuOK as an alternative. Its low cost and environmentally benign character make t-BuOK "a powerful catalyst" in these applications, she said.

From the same university, Amel Zetchi described the screening of new catalysts for use in the Mannich reaction to generate the highly useful compound β-aminoketone. This reaction consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group with formaldehyde and ammonia or any primary or secondary amine, producing a β-amino-carbonyl compound. It is widely used in the synthesis of natural compounds, including peptides and nucleotides.

The Mannich reaction, Zetchi said, is a classic multi-component reaction (MCR), i.e. one in which two or more reactants combine sequentially to give highly selective products that retain most of the starting materials. MCRs, another speaker noted, date all the way back to the Strecker reaction in the 1850s but have now, like one-pot reactions, become "essential ways of creating complex compounds in an atom-efficient way", thus addressing a key principle of Green Chemistry.

Figure 1 - Reaction mechanism for synthesis of 3,4-DHPM-thione derivatives

The catalyst is the key to time- and energy-economy in the Mannich reaction. The screening process done by Zetchi's group on various Lewis acids generated catalysts with encouraging results in preliminary tests. Further optimisation generated a chemical library of Mannich bases with important benefits, such as low catalyst loading, simple operation, ease of preparation and green credentials, despite the presence of antimony in the catalyst.

Assya Taleb and others from the University Es-Senia d'Oran, not far from Tlemcen, have worked alongside teams from the University of Djelfa, also in Algeria, and University Paul Cezanne in Marseille on the efficient synthesis of carbobicycle structures from cyclic β-keto esters based on ring-closing metathesis (RCM) using Grubbs's catalysts. This has become an increasingly popular methodology in recent years.

During this synthesis, the group observed the formation of bicyclic dihydrofuran structures with propargyl-substituted compounds, in good yields of 71-92%. These structures - which Taleb said, are "among the most important heterocycles for the construction of a wide range of naturally occurring substances". They are found in several natural bioactive compounds and are of strong interest as intermediates in organic synthesis.

Whilst several versatile synthetic routes exist for bicyclic dihydrofuran structures, they are all based on metal-mediated synthesis, variously using tungsten, rhodium, ruthenium and cobalt catalysts. Now, Taleb said, a novel method has been developed via a selective ruthenium-catalysed oxacyclisation reaction from 1,4-alkynol. In some cases, this can be diverged to RCM.

In addition, the ruthenium complexes promote the double cyclisation of alkyne diols, affording high yields of tricyclic acetals. These were prepared in good to excellent (81-90%) yields in the presence of Grubbs' catalysts from dihydroxylated derivatives. Work is continuing on studying the cycloisomeration using different heteroatoms.

Another Franco-Algerian collaboration, presented by Dr Hadjira Habib-Zahmani of the University of Oran from work with Aix-Marseilles University, showcased what she said was the first ever MCR for the synthesis of functionalised alkenes. These are highly useful intermediates in organic chemistry, notably olefination reactions, and are found in many natural products with biological activity. The alkenes were in turn used in the stereoselective preparation of 1,3-dienes.

Figure 2 - Multi-component reaction to synthesis of trisubsituted alkenes

Various methods already exist in this field but they suffer from issues like poor selectivity and yield, among others. Habib-Zahmani's group's approach (Figure 2) entailed a base-induced domino sequence, creating multiple compounds in situ. This started with the oxa-Michael addition of alcohols to α,β-unsaturated acceptors, followed by an intra-molecular aldol/dehydration step with aldehyde.

This gives the expected condensation products with stereodefined tri-substituted double bonds. As the experimental conditions are very simple, Habib-Zahmani added that "we hope this methodology could be in some cases a good complement to existing procedures". The method, she added, "is also clean, economical and easy to implement".

Likewise, Zahira Kibou and others at Abou Bekr-Belkaid University in Tlemcen have worked with the University of Caen in France on green synthetic approaches to nitrogen heterocycles, notably the derivation of 4-amino-5H-chromeono[3,4-c]pyridine-5-one. This can subsequently be used as an intermediate or building block for other heterocycles.

Chromenopyridines, Kibou noted, are an important class of compound and are of growing interesting because of their active biological and pharmacological properties. The newly developed route began with the synthesis of coumarin, then 4-methyl-2-oxo-2H-chromene-3-carbonitrile in a solvent-free MCR with ammonium acetate, followed by another MCR to 4-amino-5H-chromeono[3,4-c]pyridine-5-one in good yields. The key advantages of the new route are a short reaction time, excellent yield, mild conditions and easy purification.

Algeria has a strong base in chemistry education

Badji Mokhtar University in Annaba has a group active in bioctalysis and asymmetric synthesis that yielded two presentations at ISCSC. Mounia-Merabet Khelassi and others at described work with the Catholic University of Louvain in Belgium on efficient chemoenzymatic acylation approaches to enantio-enriched 1,2-disubstituted ferrocences that possess only planar chirality.

This work had previously demonstrated the efficiency and high enantioselectivity of lipase-catalysed kinetic resolution catalysed by the enzyme Candida antarctica in the synthesis of 2-hydroxymethyl-1-phenylthioferrocene, a homochiral primary alcohol with planar chirality, affording it in high chemical and optical yield. The group has now applied this approach to other primary ferrocenyl alcols via the creation of C-C bonds on the cyclopentadienyl rings.

Meanwhile, Dr Nassima Bouzemi and others at the same university investigated a resolution by enzymatic hydrolysis of racemic esters corresponding to a series of optically active arylalkylcarbinols in the presence of Candida Antarctica lipase. These alcohols are important intermediates for the preparation of bioactive compounds. The kinetic route has afforded access to these compounds in high purity, but it has poor atom economy, with over 50% of the material being lost.

In a first step, an alcohol enantiomer is formed with the remaining acetate enantiomer. The alcohol enantiomer was then transformed into the acetate enantiomer with the opposite configuration via the Mitsunobu reaction.

This, said Bouzemi, "is one of the most powerful and versatile stereochemical transformations we have and which can be combined with enzymatic kinetic resolution to avoid undesired enantiomers of chiral secondary alcohols". Acetates with configuration (S) were obtained with enantiomeric purity of 92-99% and yields of 76-86% via this deracemisation process. Simple chemical hydrolysis then afforded the corresponding arylalkylcarbinols.

Professor Chewki Ziani-Cherif
Université Abou Bekr Belkaid
E-mail: [email protected]
Website: http://iscsc.univ-tlemcen.dz/zianicherif




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