7th International Electronic Conference on Synthetic Organic Chemistry (ECSOC-7), http://www.mdpi.net/ecsoc-7, 1-30 November 2003

[E011]

Microwave - Assisted Synthesis of Substituted Pyridines and Furans

Yousef M. Hijji*  and  Achelle A. Edwards

Chemistry Department, Morgan State University, Baltimore MD 21251

[email protected]

ABSTRACT:

Substituted Pyridines and Furans were synthesized from 2,4,5-Trimethyloxazole (diene), and olefinic and acetylenic dienophiles by a microwave-assisted Diels-Alder reaction. The reaction with olefinic dienophiles gave the adducts that underwent dehydration under the microwave conditions to give substituted pyridines in good yields within minutes.  While the reaction with acetylenic dienophiles provided substituted furan in excellent yield by Diels-Alder –retro Diels-Alder reaction.

Key Words: Microwave, Oxazole, pyridine, Furan, Dies-Alder reaction, retro Diels-Alder, olefinic dienophiles, acetylenic dienophiles.

INTRODUCTION:

            The introduction of microwave energy into conventional organic reactions, can decrease reaction times over 1000 fold and thereby save both time and money. Another advantage of the reactions studied in this paper is that they were carried out under neat conditions, in that no solvent was used. Since these microwave driven reactions can work in a solvent-less environment, this leads to less waste and improved synthetic processing. The microwave has been used to carry out organometallic cross-coupling reactions, heterocycles synthesis, nucleophilic additions and substitutions, condensations, as well as cycloadditions.¹ For the purposes of this paper, we would focus on the cycloaddition reactions in the microwave.

The Diels-Alder reaction has proven to be a very useful and easy method for the carbon-carbon synthesis of cyclic and bicyclic organic compounds. It provides an efficient way to synthesize six-membered carbon skeletons that maintain diverse stereochemistry.

Oxazoles have been used as dienes in the Diels Alder reaction.^2,3,4  The cycloaddition occurs at high temperature.  The reaction with bis trimethylsilyl acetylene gave the 3,4-disilylfuran by the Diels-Alder retro Diels Alder reaction and loss of hydrogen cyanide.  The process is very useful in providing substituted furans.⁵  as the synthesis of 3,4-substituted is tricky and challenging. A recent synthesis of furan dicarboxylate required few steps.⁶ With the developments of microwave application in organic synthesis,  the Diels-Alder reaction of oxazoles is a suitable example for the study of cyclo-addition with acetylenic and olefinic dienophiles

2,4,5-Trimethyloxazole was the diene used in our study along with six different dienophiles. In this study the reaction conditions were investigated and products identified to explore it as a possible efficient method for the synthesis of furans and pyridines.

EXPERIMENTAL:

All of the reactions were carried out in a conventional microwave.  The reactants were placed into a 4mL glass vial in the absence of solvents, using a 1:1 mole ratio and the vial and its contents were allowed to react in the microwave for a pre-selected amount of time. Also because one of the aims of this experiment is to show a decrease in the reaction time using the microwave, all of the reactions had to be performed using the reflux in toluene, to serve as a comparison. Then using thin layer chromatography (TLC), silica gel column chromatography and the Gas chromatography-mass spectrometer (GC-MS), the products were separated, purified and identified.

RESULTS:

Table1:  Diels-Alder reaction of 2,4,5-trimethyl oxazoles with acetylenic and olefinic olefinic dienophiles under microwave irradiation to give furans and pyridines respectively.

Table2:   Diels-Alder reaction of 2,4,5-trimethyl oxazoles with acetylenic and olefinic olefinic dienophiles under reflux in toluene to give furans and pyridines respectively

DISCUSSION:

 The reaction of 2,4,5-trimethyloxazole with acetylenic dienophile tends to produce the adduct.  This adduct proceed to lose acetonitrile giving tri and tetra substituted furan in excellent yields more than 90%, within minutes of microwave irradiation.  The adduct and the furan can be observed in the products too.  This provides an efficient method for the synthesis 3,- and 3,4- furan dicarboxylate. The synthesis of these compounds requires many steps.  The synthesis of 3,4-furan in general is a challenge and tricky.  The compounds can be produced in low after reflux in toluene for overnight.

The more interesting is the reaction of 2,4,5-trimethyloxazole with acetylenic dienophiles as shown in table 1 is the formation of the adducts that tends to dehydrate under the reaction condition to give tetra and penta substituted pyridine.  Such compounds are versatile intermediates for the synthesis pyridine based alkaloids.            The yields were good, and the method is efficient as one pot synthesis of pyridine within 10 minutes.  Table 2 depicts the reaction of 2,4,5-trimethyloxazole with variety of dienophiles. The reactivity with maleic anhydride was high due to the high reactivity of the dienophile and it was accomplished in seconds. Similar products were obtained upon long heating under reflux, but in lower yields.  Diethylfumarate was unreactive for both microwave irradiated or refluxed reactions while dibenzolyethylene was effective under the microwave conditions while no product was obtained under reflux.

The mechanism for the reactions is presented in schemes 1 and 2.

Scheme 1

Scheme 2

In conclusion this work demonstrate that substituted furans and pyridines can be synthesized efficiently from oxazoles under microwave conditions within minutes.

Acknowledgement:

We would like to thank the NIH for support through Research Infrastructure in Minority Institution (RIMI) grant # 5P20RR011606-02 and  NSF for Grant # HBCU-Rise- 0236753

References:

1. For recent books on microwaves:
   1. Hayes, B. L.; Microwave synthesis, Chemistry at the speed of light, CEM publishing, 2002.
   2. Loupy, A. Microwaves in organic synthesis, Wiley VCH, Weinheim, 2003.
   3. Kingston, H. M., Haswell, Stephen J.” Microwave –Enhanced Chemistry, Fundamentals, sample preparation and applications, American Chemical society, Washington D. C., 1997.

2. Keay, B. A.; Chem. Soc. Rev. 209-215 and references therein. 

3. Hou, X.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H. N. C.; Tetrahedron, 1998, 54, 1955-2020 and references therein.

4. Wong, M. K.; Leung, C. Y.; and Wong, H. N. C.; Tetrahedron, 1997, 53, 3497-351.

5. Hijji, Y. M.; Wanene J.; Obot, E.;  Fuller, J.; The fifth electronic conference in synthetic organic chemistry, E0023.  September 1-30, 2001. www.mdpi.net/ecsoc-5.
6. Deshpande, A. M.; Natu, A. A.; Argade, N. P.; Synthesis, 2002, 8, 1010-1014.