MICROWAVE ASSISTED CHEMISTRY USING SUPPORTED FORMATES AS REAGENTS IN ORGANIC CHEMISTRY.

Timothy N. Danks* and Bimisar Desai

Department of Chemistry, University of Surrey, Guildford, Surrey GU2 7XH, UK.
Tel. + 44(0) 1483 686829, Fax. +44 (0) 1483 686851, E-mail T.Danks@surrey.ac.uk
 

Keywords: polymer-supported, alumina, formate, reduction, formamides.

INTRODUCTION

Transfer hydrogenation of alkenes using ammonium formate as a source of hydrogen has been well established as a synthetic procedure for the reduction of alkenes and for the removal of O- and N-Benzyl groups for many years¹. When cinnamic acid, for example, is treated with ammonium formate and Wilkinson’s catalyst in a solvent such as DMF at 70 ^oC for 3 h high yields of the saturated acid are produced.

The application of microwave irradiation to these reactions results in a significantly reduced reaction times and solvent volumes which are environmentally attractive².

In a recent paper we demonstrated the use of the diformate salt of TMEDA as a hydrogen source for transfer hydrogenation of a-methyl cinnamic acid using Wilkinson’s catalyst under both microwave and thermal conditions. In that paper we also compared the relative rates of the reaction under microwave and thermal conditions³. At 50 and 100 ^oC the reaction achieved 80 % yield after 1.5 and 1 h respectively. Under microwave conditions an 80 % yield was obtained after only 1 minute of irradiation.

TEMDA / 2HCOOH

Recent environmental constraints have resulted in the development of clean and easily recycled reagents for use in synthetic chemistry. This need has led to the development and use of reagents that are supported on a solid matrix⁴. Also, because of the development of robotic systems for chemical synthesis in many industrial sectors, the need for solid-supported reagents has increased considerably.

In view of this we set out to develop a polymer-supported version of formate that is suitable for use as a transfer hydrogenation source. It was anticipated that the support would not only facilitate the purification of the reaction but also would remove the problems often observed due to sublimation of ammonium formate.

RESULTS AND DISCUSSION

Synthesis of Polymer Supported Formates

For this work the commercially available (aminomethyl)polystyrene and Amberlite^®-938 were used as polymers to support formate.

Activation of (aminomethyl)polystyrene was achieved by washing the resin with a 20 % solution of formic acid in dichloromethane, followed by drying under reduce pressure. The loading of formate was determined as 0.6 mmol g^-1.

Activation of Amberlite^®-983 was achieved by anion exchange. The resin was washed with 98 % formic acid and water until no further chloride was eluted. The solid was collected and then dried over P₂O₅. The loading of formate was determined as 2.5 mmol g^-1.

Hydrogenation Reactions

Polymer-Supported Formates⁵

Initially the reduction of cinnamic acid and its methyl and ethyl esters, using Wilkinsons’s catalyst and formate (aminomethyl)polystyrene was studied. The reactants and catalyst were mixed in a minimum quantity of DMSO (ca. 0.5 ml) and irradiated at 100 Watts for 30 s. Isolation of the reaction product was achieved by filtration and removal of the solvent under reduced pressure. These reactions lead to no more than 50 % of the desired products. Attempts to improve the yield by either increasing irradiation time or microwave power led to degradation of the product and catalyst.

For the reduction of alkenes using Amberlite^®-938 supported formate a procedure identical to that described previously was used and led to excellent yields of the fully saturated product.

In each case thermal comparisons were performed to illustrate the influence of the microwave irradiation on the reaction. The results from these investigations are shown in table 1.

After separation of the Amberlite^® at the end of the reaction, and by washing it with formic acid, the formate salt could be regenerated. In total at least 5 reduction/regeneration cycles have been used before there was an appreciable reduction in the reaction yield.

  1-8                                                        9-16
 

Entry	Alkene	R	R'	Producta	Yield (%)b Microwave8	Yield (%)c Thermal
1	1	Ph	CO2H	9	95	80
2	2	Ph	CO2Me	10	90	75
3	3	Ph	CO2Et	11	80	62
4	4	Ph	CHO	12	95	70
5	5	Ph	COCH3	13	95	88
6	6	Et	CO2H	14	95	50
7	7	Ph	CN	15	95	95
8	8	Ph	CON(CH3)2	16	95	70

a All products gave satisfactory spectroscopic data.
b All microwave irradiations were carried out at 100 W for 30 s.
c All thermal reactions were performed at 70 ^oC for 3 h in DMSO
Table 1 Hydrogenation of Alkenes using Polymer Supported Formate and Wilkinson's Catalyst under Microwave and Thermal Reaction Conditions.

Alumina Supported Formates⁶

In addition to our work on the polymer supported formate we also considered basic alumina as a support for formate.

Alumina supported formate was prepared by eluting a chromatography column packed with basic alumina (Brockmann grade 1) five times with a 20 % solution of formic acid in dichloromethane. The alumina was collected and dried under vacuum for 24 h until a free flowing solid was obtained. The loading of formate on the polymer was determined as 2 mmol g^-1 by potentiometric titration.

For the reduction of alkenes a mixture of alumina/HCOOH, Wilkinson's catalyst and an alkene in DMSO were irradiated at 100 Watts for 30 s. After the reaction, filtration of the product mixture and removal of the solvent the reaction product was obtained. Serendipitously the alumina also acts as a scavenger and results in partial removal of the Wilkinson's catalyst and other reaction residues.

The results from these experiments are illustrated in table 2.

In all cases, the microwave route demonstrates an enhanced reaction yield and also, as expected, a significantly reduced reaction time and solvent volume.

In this section we have demonstrated that formate supported on alumina and/or polymers acts as an efficient transfer hydrogenation source under both thermal and microwave conditions. Additionally, in the case of the alumina-based reagent also acts as a scavenger for Wilkinson's catalyst and therefore aids in the purification process.

1 - 8                                                     9 - 16

Entry	Alkene	R	R’	Producta	Yield (%)b Microwave	Yield (%)c Thermal
1	1	Ph	CO2H	9	95	80
2	2	Ph	CO2Me	10	88	75
3	3	Ph	CO2Et	11	70	62
4	4	Ph	CHO	12	60	50
5	5	Ph	COCH3	13	95	88
6	6	Et	CO2H	14	73	50
7	7	Ph	CN	15	95	95
8	8	Ph	CON(CH3)2	16	95	70

a All products gave satisfactory spectroscopic data.
b All microwave irradiations were conducted at 100 W for 30 seconds.
c All thermal reactions were performed at 70° C for 4 h in DMSO.
Table 2, Hydrogenation of alkenes using alumina supported formate and Wilkinson’s catalyst under Microwave and Thermal conditions

N-Formylation Reactions

In addition to our work on the use of solid-supported formate as transfer hydrogenation sources we have recently turned our attention to the use of these reagents in N-formylation reactions. N-formamides are an important class of compounds frequently used during the synthesis of biologically active compounds⁷, cancer chemotherapeutic agents⁸ and antibacterials.⁹ New routes to the synthesis of formamides is therefore an important area of organic chemistry.

In our approach to the synthesis of these compounds primary and secondary amines were reacted with solid-supported formate under microwave conditions at 100 Watts for 30 s After filtration and removal of the solvent formamides were isolated in good yield.

The results from our experiments are shown in table 3.

We have demonstrated that solid supported formate may be used as an ideal clean transfer hydrogenation source in conjunction with Wilkinson's catalyst for the reduction of alkenes. Similar results are observed when alumina is used as a support and in this case the solid also acts as a partial scavenger for the reaction impurities and catalyst.

When the reagents are heated with primary and secondary amines smooth formation of formamides is observed.

ACKNOWLEDGEMENTS

We thank Personal Chemistry AB for financial support and provision of a Microwell-10 microwave reactor.

References

1. P. N. Rylander, Hydrogenation Methods: Academic Press: Orlando, FL, 1985; James, B. R. Homogenous Hydrogenation, Wiley: New York, 1973.
2. B. K. Banik, K. J. Barakat, D. R. Wagle, M. S. Manhar and Bose, J. Org. Chem. 1999, 64, 5746.
3. M. H. Al-Qahtani, N. Cleator, T. N. Danks, R. N. Garman, J. R Jones, S. Stefaniak, A. D. Morgan and A. J. Simmonds, J. Chem. Res. 1998, 26, 400.
4. S. V. Ley, I. R. Baxendale, R. N. Bream, P. S Jackson, A. G Leach, D. A. Longbottom, M. Nesi, J. S Scott, R. I. Store and S. J Taylor, J. Chem. Soc., Perkin Trans. 1, 2000, 3815; A. Kirschning; H. Monenschein and R. Wittenberg, Angew. Chem., Int. Ed. Engl. 2001, 40, 650.
5. T. N. Danks and B. Desai, Tetrahedron Lett., 2001, 42, 5963.
6. T. N. Danks, and B. Desai, Manuscript in preparation.
7. K. Kobayashi, S. Nagato, M. Kawakitu, M. Morikawa and H. Konishi, Chem. Lett., 1995, 575.
8. G. R. petit, M. V. Kalnins, T. M. H. Liu, E. G. Thomas and K. Parent, J. Org. Chem., 1961, 26, 2563
9. A. Jackson and O. Meth-Cohen, J. Chem. Soc., Perkin Trans. 1,1995, 1319.