Special Issue "Microwave Assisted Synthesis"

Guest Editor
Dr. Julio A. Seijas Vázquez
Departamento de Química Orgánica, Universidad de Santiago de Compostela, Facultad de Ciencias-Campus de Lugo, Alfonso X el Sabio, 27002 Lugo, Spain
Website: http://www.usc.es/orchemlu/
E-Mail:
Phone: +34 982 285 900
Fax: +34 982 285 872
Interests: synthesis of compounds with biologic activity; synthesis of compounds with interest for agro-food field; solation, estructural determination and synthesis of natural products; microwave organic reactions enhancement

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Manuscript ID: molecules-micrasyn-01-it-Brusotti
Type of Paper: Article
Title: Experimental Design Methodology applied to a Microwave assisted Synthesis of a fragrant Compound: Calone 1951^®
Authors: Gloria Brusotti ^1,*, Sandra Furlanetto ²,Carmela De Risi ³,Marco Carando ⁴,Giorgio Marrubini ¹,Carlo Gandini ¹,Gabriella Massolini¹
Affiliations: ¹Department of Pharmaceutical Chemistry, Pavia University, viale Taramelli12, 27100 Pavia,Italy
²Department of Pharmaceutical Science, Florence University, Via U. Schiff 6, 50019 Sesto F.no (FI), Italy
³ Department of Pharmaceutical Science, Via Fossato di Mortara, 17-19, 44100 Ferrara, Italy
⁴ Osmotech Srl, viale Taramelli12, 27100 Pavia,Italy
^* Author to whom correspondence should be addressed; E-mail: gloria.brusotti@unpv.it
Abstract: The first application of experimental design methodology to the microwave assisted organic synthesis (MAOS) is here described for the synthesis of 7-methyl-benzo[b][1,4]dioxepin-3-one 1, or Calone 1951^®, chosen as target compound. The industrial synthesis involves a three steps sequence: Williamson reaction, Dieckmann condensation and acid hydrolysis/decarboxylation. Starting from an European patent we aimed at synthesising 1 reducing the reaction time and the number of steps: the reaction of 4-methyl catechol with dichloroacetone was investigated using microwave heating instead of conventional heating while a widely applicable multivariate approach of experimental design was applied to maximize the synthesis yield and to reduce the number of experiments.
A 12-run D-optimal asymmetrical screening matrix (2²1⁴//12) allowed us toidentify, among different factors, those which really had an influence on the response. A response surface study, carried out in the experimental domain defined by temperature and time, pointed out the best reaction conditions.
Applying microwave heating the reaction can be carried out in one step reducing the time from 6 h to 18 min. and increasing the yield from 56% to 70.5%.
Calone 1951^® was determined and characterized by gas chromatography-mass spectrometry (GC-MSD), gas chromatography with Flame Ionization Detector (GC-FID) and ¹H-NMR analysis.
Keywords: Experimental design/Fragrances/Microwaves irradiation

Type of Paper: Article
Title: The Effect of Microwave Irradiation on Biodiesel Synthesis Catalyzed by Lipases
Authors: Ingrid C. R. Costa ¹, Selma G. F. Leite ¹,  Leandro S. M. e Miranda ², Rodrigo O. M. A. de Souza ³
Affiliations: ¹ Escola de Química, Universidade Federal do Rio de Janeiro, Cidade Universitária, Bloco E, CEP 21941-909, RJ, Brazil
² Instituto Federal de Educação Ciência e Tecnologia do Rio de Janeiro – Maracanã, Rio de Janeiro CEP 20270-021, RJ, Brazil
³ Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universitária, Bloco A, CEP 21941-909, RJ, Brazil;
E-Mail: souzarod21@gmail.com (R.O.M.A.S.)
Abstract: The lipase-catalyzed biodiesel synthesis has been investigated applying both microwave irradiation and conventional heating in order to evaluate the existence of nonthermal microwave effects. All transformations were conducted at 40 °C in both Monowave 300 and CEM Discover instruments that allowed accurate internal reaction temperature measurements with use of fiber-optic probes. The conventional heating experiment was performed in an EasyMax reactor, Mettler-Toledo, which also allowed accurate measurement of internal temperature. The results revealed no difference on the reaction time or yield.

Type of Paper: Article
Title: Microwave Assisted Organic Synthesis (MAOS) of Small Molecules as Potential HIV-1 Integrase Inhibitors
Authors: Stefania Ferro ¹, Sara De Grazia ¹, Laura De Luca ¹, Rosaria Gitto ¹, Caterina Elisa Faliti ¹, Zeger Debyzer ² and Alba Chimirri ¹
Affiliations: ¹ Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata I-98168 Messina, Italy
² Molecular Medicine, Katholieke Universiteit Leuven and IRC KULAK, Kapucijnenvoer 33, B-3000 Leuven, Flanders
Abstract: Many drugs for the treatment of human immunodeficiency virus type 1 (HIV-1) are currently involved in the highly active anti-retroviral therapy (HAART), which tipically consists of a cocktail of potent drugs including inhibitors of reverse transcriptase, protease and recently, integrase and viral entry. However, the HAART success is often limited by drug-related toxicities, drug–drug/food interactions, and by the emergence of multidrug resistant viral strains. Among numerous attempts to identify new drugs active against HIV-1, the integrase (IN) enzyme has become an attractive target because it has no known human homologue, and thus there is a lower risk of disrupting normal cellular processes. To date the only IN inhibitor approved by FDA is .raltegravir (Isentress), belonging to the family of β-diketo acid analogues (DKAs) which generally display potent antiviral activity. Their IN-binding mechanism is connected to the presence of DKA pharmacophoric motif which could be involved in a functional sequestration of one or both divalent metal ions in the enzyme catalytic site. In recent years our research group has been engaged in the stucture-function study of IN and the development of some tridimensional pharmacophore models led to identify a series of 1-H-benzylindole derivatives as potent Integrase Strand Transfer Inhibitors (INSTIs). ^1-5 In order to expand the SARs of our compounds and to obtain more information about their binding mode at the IN catalytic site, herein we report the synthesis of new derivatives rationally designed by ligand- and structure-based studies. All the obtained compounds have been tested in biological assays. The most innovative eco-friendly methods and technologies have been used for the synthesis of the new compounds. In particular the application of microwave-assisted organic synthesis (MAOS) was adopted in many steps of the synthetic pathway thus shortening the reaction times and the solvent amount as well as increasing the yields and the safety condition.

References:
¹ Barreca ML, Ferro S, De Luca L, Monforte AM, Debyser Z, Witvrouw M, Chimirri A. J. Med. Chem. 2005, 48, 7084-7088.
² De Luca L, Barreca ML, Ferro S, Iraci N, Michiels M, Christ F, Debyser Z, Witvrouw M, Chimirri A. Bioorg. Med. Chem. Lett. 2008, 18, 2891-2895.
³ Ferro S.; De Luca L.; Barreca M.L.; Iraci N.; De Grazia S.; Christ F.; Witvrouw M.; Debyser Z.; Chimirri A. J. Med. Chem. 2009, 52, 569-573.
⁴ Ferro S.; De Luca L.; Barreca M.L.; De Grazia S.; Christ F.; Debyser Z.; Chimirri A. Bioorg Med Chem. 2010 18 5510-5518.
⁵ De Luca L., De Grazia S., Ferro S., Gitto R., Christ F., Debyser Z., Chimirri A. E J Med Chem 2011 46 756-764.

Title: Eco-Friendly Methodology to Prepare N-heterocycles Related to Dihydropyridines: Microwave Assisted Synthesis of Alkyl 4-arylsubstituted-6-chloro-5-formyl-2-methyl-1,4-dihydropyridine-3-carboxylate and 4-arylsubstituted-4,7-dihydrofuro[3,4-b]pyridine-2,5(1H,3H)-dione
Authors: Hortensia Rodríguez ^1,3,  Osnieski Martin ¹, Margarita Suarez ¹,  Nazario Martín ² and Fernando Albericio ^3,4,5
Affiliations: ¹ Laboratorio de Síntesis Orgánica, Facultad de Quimica, Universidad de La Habana, 10400-Ciudad Habana, Cuba
² Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Complutense, 28040-Madrid, Spain
³ Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028-Barcelona, Spain
⁴ CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028-Barcelona, Spain
⁵ Department of Organic Chemistry, University of Barcelona,Martí iFranqué 1-10, 08028-Barcelona, Spain; E-Mail: albericio@pcb.ub.es
Abstract: An efficient synthesis of alkyl 4-arylsubstituted-6-chloro-5-formyl-2-methyl-1,4-dihydropyridine-3-carboxylate (II) and 4-arylsubstituted-4,7-dihydrofuro[3,4-b]pyridine-2,5(1H,3H)-dione (III) via microwave-accelerated reaction of alkyl 4-arylsubstituted-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylate (I) with the adequate reagents is described. This represents an eco-friendly, green approach to these valuable dihydropyridine derivatives that avoids the harsh or highly contaminant conditions involving classical heating and offers a reduction or even elimination of solvent use and recovery, simplification of the work up procedures, facility of scale up and low energy consumption, in addition with moderate to higher yields.