Synthetic Methodologies

1. Synthesis of aminoalcohol from its respective amino acids using sodium borohydride in methanol

2. Reduction of aromatic and heteroaromatic esters using sodium borohydride in methanol

a) Tetrahedron Lett. 45, 6021, 2004; b) Synth. Commun. 35, 3187, 2005; c) Arkivoc, 1, 128, 2006; d) Applied Organometallic Chem. 29, 798, 2006.

3. Solvent-free Hantzsch reaction in the formation of 2-aminothiazole and 2-aminoselenazole

Synthesis 48(3), 437-440, 2016

4. Rearrangement using DCC (dicyclohexylcarbodiimide) and HOBt (hydroxybenzotriazole)

Using DCC (dicyclohexylcarbodiimide) as the coupling agent and HOBt (hydroxybenzotriazole) as the catalyst under mild conditions, coupling products were not obtained. Instead, an intermediate product resulting from the coupling of the aromatic with the DCC, which was shown to be quite stable, was obtained. After analysis of this product by X-ray diffraction, it was discovered that a rearrangement occurs, resulting in the formation of a dicyclohexyl urea derivative, as described in the scheme. Due to this unexpected reaction we decided to check the relative stability of homologous substances containing the nitrogen atom at different positions of the aromatic ring. With the results obtained we conclude that the reaction using aromatic and heteroaromatic acids also gives the N-acyl-N, N’-dicyclohexylureas via a rearrangement reaction.

 

Journal of Chemical Research, v. 5, p. 468-472, 2008. DCC (1,3eq.), HOBt, THF, t.a., 24 horas.

 

5. Cyclization reactions to obtain tricyclic systems

Journal of Sulfur Chemistry 27(3); 193-202, 2006; Journal of Chemical Research 2; 93-97, 2006

 

 6. Acceleration of chemical reactions using ultrasonic waves

Sonoceistry is a method of synthesis that allows preparing a great variety of materials, including nanostructured, from the radiation of the ultrasound. Ultrasonic waves are located in the sound spectrum at frequencies higher than those that the human ear can detect, that is, above 20KHz. The mechanism causing sonochemistry effects in liquids is the phenomenon of acoustic cavitation.

A. Large-scale reaction of epichlorohydrin

B. Formation of the key intermediate nitroimine used in the synthesis of several camphor derivatives

 
 

Scientia Pharmaceutica  (in press), 2016

 

 

Work done in collaboration with other research groups

Green Chemistry: Obtaining compounds of high structural complexity from furfural

This work was carried out in collaboration with the laboratory of Professor Emannuel Gras (Laboratoire de Chimie de Coordination – Université de Toulouse – France)

Following a line of research that aimed at the planning and synthesis of new compounds of high complexity based on the principles of Green Chemistry, a study based on furfural, one of the products of major commercial importance obtained from biomass, objected the synthesis of bicyclic dihydroisobenzofuran and dihydroisoindolic derivatives.

Objective bicyclic derivatives.

Few methodologies are described in the literature to obtain these bicyclic rings from amines or propargyl alcohols, since furan rings have limited reactivity to Diels-Alder reactions. All methodologies found in the literature are based on the use of 5-10 equivalents of potassium tert-butoxide (t-BuOK) in tert-butanol under heating (40-85°C).(HAYAKAMA et al., 1985; LEE et al., 1994; WU et al., 1998)

Retrosynthetic analysis for the synthesis of bicyclic derivatives.

 

Therefore, the study aimed to develop alternative synthetic methodologies for obtaining these bicyclic derivatives using Green Chemistry principles such as the use of renewable raw materials sources, carbon and energy savings and waste prevention. This methodology would represent a synthesis of rapid conversion of five-membered rings into six-membered rings, and could be used in the synthesis of compounds of greater importance and chemical complexity such as cannabinoid derivatives.

The synthesis of five bicyclic derivatives (A, B, C, D, E) (Figure below) was concluded from the methodologies developed for IMDA reactions employing Green Chemistry principles, four (A, B, C, D) being From furfuraldehyde and derivatives, including two previously unpublished derivatives (A and D).

Structure of derivatives developed from IMDA reactions.

The methodologies developed presented advantages over the methodologies already described in the literature (HAYAKAMA et al., 1985; LEE et al., 1994; WU et al., 1998), using some principles of Green Chemistry. Renewable source, the use of liquid solvent at room temperature which allowed the reactions to be maintained at room temperature and the use of fewer equivalents of potassium tert-butoxide.

In order to continue the studies of the transformation of furfural to isoindolic derivatives performed by the Gras group (CAILLOT et al., 2013) using the Ugi/Diels-Alder reaction sequence, the synthesis of new derivatives was proposed with the objective of comparing A methodology developed by the Gras group (Scheme below) with the use of microwave irradiation to obtain these derivatives, since this proved to be a methodology of fast and efficient access to bicyclic systems fused with total stereochemical control.

Thus, the methodology developed also allowed the use of Green Chemistry principles, such as the use of renewable raw material sources, carbon economy and waste prevention, in the access to isoindolinonic derivatives through a posterior ring opening reaction and rearomatization by dehydration

Synthetic methodology for obtaining isoindolinonic derivatives developed by Gras et al.

Through this study, it was possible to confirm that the use of microwave irradiation was able to significantly reduce the reaction time of these reactions, which demonstrated that this methodology is more efficient in terms of energy savings than previously used. However, it was possible to verify that depending on the aldehyde used, more drastic reaction conditions such as the reaction solvent exchange and the increase in temperature are necessary for the Diels-Alder reaction to occur.

In addition to the Ugi 8 reaction adduct from aldehyde 2, two other derivatives (6 and 7) were also unpublished in the literature (Scheme and Figure below).

 

Reaction conditions: For 6: (a) MeOH, 50 ° C, 72 hours or (b) MeOH, MO at 50 ° C for 1 hour and at 120 ° C for 1.5 hour, 95%; For 7: (a) MeOH, 50 ° C, 72 hours or (b) MeOH, MO at 50 ° C for 1 hour and at 120 ° C for 1.5 hour, 95%; (C) DMF, 120 ° C, 72 hours, 78%.

Ugi-DA reaction sequence used for the synthesis of derivatives 6 and 7.

Structure of the derivatives obtained from the Ugi / Diels-Alder reactions.

 

 

REFERENCES

CAILLOT, G.; HEGDE, S.; GRAS, E. A mild entry to isoindolinones from furfural as renewable resource. New Journal of Chemistry, Cambridge, v.37, n.4, p.1195-1200, 2013.

HAYAKAMA, K.; YAMAGUCHI, Y.; KANEMATSU, K. Novel ring transfer reaction of furans via intramolecular Diels-Alder reaction of allene intermediate: a new double annulation reaction. Tetrahedron Letters, Oxford, v.26, n.22, p.2689-2692, 1985.

LEE, M.; MORITOMO, H.; KANEMATSU, K. A new route to the isoindole nucleus via Furan–pyrrole ring-exchange. Journal of the Chemical Society, Chemical Communication, London, v.1994, n.13, p.1535-1535, 1994.

WU, H. J.; YEN, C. H.; CHUANG, C. T. Intramolecular Diels-Alder Reaction of Furans with Allenyl Ethers Followed by Sulfur and Silicon Atom-Containing Group Rearrangement. The Journal of the Organic Chemistry, Easton, v.63, n.15, p.5064-5070, 1998