DOPAL+Synthesis


 * Chapter 2: Synthesis of DOPAL**


 * 2.1 Introduction**

Find-A-Drug provided the Bradley group with a library of 218 compounds as potential anti-malarial agents along with the THINK software they used for docking calculations (Bradley 2005). Many of these compounds contained the component 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is not commercially available. We originally set out to synthesize the compound based on a paper by Kim (Kim 1996) that proposed the rearrangement in one step using perchloric acid in glacial acetic acid. Due to the risks associated with perchloric acid (can be explosive when heated), we sought out other means of synthesizing DOPAL. In 1966, Robbins (Robbins 1966) synthesized a sodium bisulfite addition of DOPAL from epinephrine (adrenaline) using a phosphoric acid solution. Robbins based much of his work on a previously published paper by J. H. Fellman for which he proposed a pinacol-pinacolone type mechanism for the rearrangement of epinephrine (14) to DOPAL (15) in phosphoric acid (Fellman 1958) (Scheme 2.1). Using the same procedure (Robbins 1966), we attempted to synthesize DOPAL (15) from commercially available epinephrine (adrenaline) (14).


 * Scheme 2.1**: Pinacol-pinacolone rearrangement of epinephrine to 3,4-dihydroxyphenylacetaldehyde.


 * 2.2 Experimental**

Epinephrine was purchased from Sigma Aldrich Chemical Company (Milwaukee, WI). Phosphoric acid, methanol, and methylene chloride were purchased from Fisher Scientific (Fair Hill, NJ). Uniplate ™ Silica Gel TLC plates with 250 micron pores were purchased from Analtech, Incorporated (Newark, DE).
 * 2.2.1 Materials and Reagents**


 * 2.2.2 Synthesis**
 * This procedure is a modification from Robbins 1996:**

To a 25mL volumetric flask was added adrenaline (26.68mg, 0.15mmol), phosphoric acid (2.5mL, 42.9 mmol) in methanol and heated (116-118C) in a round bottom flask (for 1 hour) in a heating mantle, then removed from heat and allowed to cool. One milliliter samples of the reaction were removed at various times and placed in one dram vials to monitor the reaction via TLC over time**.** Sodium bicarbonate was added to neutralize acid until no further bubbling was observed. Samples were filtered to remove sodium bicarbonate. Using a capillary tube a small amount of sample was placed on a TLC plate and run using a 4:1 methylene chloride/methanol solvent system.


 * 2.2.3 Instrumentation**

All NMR spectra were taken on a Varian Inova 500MHz instrument using standard parameters for proton NMR experiments.
 * 2.2.3.1 Nuclear Magnetic Resonance Spectroscopy**

It was determined that all samples taken over the course of the reaction did not contain any aldehyde. We expected to see a UV active spot appear on the TLC plate as the aldehyde formed, however, this was not observed. My colleague Khalid Mirza (Mirza 2006) was able to obtain eighty milligrams (9.5% yield) of DOPAL in his experiement. He confirmed the formation of DOPAL via TLC and HNMR after discovering that DOPAL could be extracted into ether. The HNMR spectra of Khalid's experiment showed a singlet peak at 9.8 ppm, indicating that an aldehyde was present (Figure 2.1).
 * 2.3 Results and Discussion**


 * Figure 2.1** Evidence of aldehyde peak in DOPAL synthesis.

He then repeated the experiment under a nitrogen atmosphere. This was compared with previous experiments where the reaction was not carried out under nitrogen, resulting in oxidation caused by the CAM stain. (Figure 2.2) seen in his TLC plate (This was not confirmed via instrumentation).




 * Figure 2.2** Comparison of TLC images when run under an inert atmosphere and without.

Based on my experiement, it was determined that DOPAL cannot be synthesized using a 20% phosphoric acid solution in one hour. The concentration of phosphoric acid must be 85% and the reaction must occur in an inert atmosphere to avoid impurities (Khalid 2006). In order to gain a better understanding of DOPAL’s behavior in the Ugi reaction, similar commercially available aldehydes will be used in the initial attempts of the Ugi reaction.
 * 2.4 Conclusion**

Bradley, JC http://usefulchem.blogspot.com/2005/11/anti-malaria-compounds.html 2005
 * 2.5 Reference List**

[|Fellman, J. The rearrangement of epinephrine. Nature 182, 311, 1958]

[|Kim, J. et al. Unusual Rearrangement of 2-amino-1-substituted phenyl-1-alkanol to 1-substituted phenyl-2-alkanone. Bull. Korean Chem. Soc. 17(2), 105, 1996]

Mirza, K. and Cheng, L. www.usefulchem.wikispaces.com/Exp025 2006

[|Robbins, J. Preparation and properties of p-hydroxyphenylacetaldehyde and 3-methoxy-4-hydroxyphenylacetaldehyde. Arch. Biochem and Biophys, 114(3), 576-584, 1966.]

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