Functionalisation including fluorination of caffeine, guanosine tetraacetate, and uridine triacetate using electrochemical oxidation

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Vol. 35, No. 49, pp. 9231-9238, 1994 Elsevia Science Ltd Printed in Great Britain oo40-4039194 s7.m.oo

Fuuctionalisation Including Fluorination of Caffeine, Guanosine Tetraacetate, and Uridine Triacetate using Electrochemical Oxidation Masakazu Sot@, NaokoToyoda, Yoshiktuu Shizuri, and Motoo Tori

Abstmu:. The title ccsnpoundshave teen subjecredto electrochemicaloxidationwith Exp3HF as an ekctdyte. csffaine atxxdd 8-fluorocstrebw as a sole pduct in 43% yield. Guanosinet&mace- and uridi~ trkcmtn theflluxilWdcompounds in 7.3 and 4.8 % yield, respectively. Similarcbc~icsl oxidationof caffbine~~ metbad, KCIoc KCN yielded&metixyc&eine, 8chlotucaNeinc,ot &cy~dne, respcctidy.

One of the methods for development of new &ugs is the modification of functional groups existing in biologically active compounds. Especially when the fluorine atom is introduced, compounds often show a significant increase in effect and a large change in tffective spe~trum!~ In recent years many fluorinated medicines have appeared on the market. As very few f&mrinated compounds am present in Nature,- the development of synthetic methodology to make fluorinated compounds is very important. Ahhough various electrophylic and nucleophilic fluorinating reagents have heen rqorted recently? these are often difficult to be used owing to thein poisonous nature and difficult handling. Although the electrolysis of nucleic acids have been reported,~only degradation compounds have been produced. We now report our simple and efficient partial ~~~~~on and fu~tio~i~tion of caffeine (I), ~0~~ tetraacetate (2). and uridine triacetate (3) using electrochemical oxidation. Anodic oxidation of heterocyclic compounds (ca 1 mmol) in acetonitrile (20 ml) coutaining Et&+3HF (ca. 1 ml) as supporting electrolyte was carried out in an un~vi~ cell equipped with a platinum wire electrode under constant potential conditions at mom tempesatum. When the starting material was consumed (checked by TLC), the electricity was stopped and the mixture was worked up as usual and purified by silica gel c~a~phy. The results are summarired in Table 1. First of all the xanthine compound, caffeii (l), was oxidized el~~hemically under several conditions. Constant potential oxidation of caffeine (1) in methanol (Entry I) afforded 8-me~oxyc~feine (4)” in 43 96 yield. On the other hand electrolysis of caffeine (1) with KC1 as an electrolyte in acetonitrile gave 8-chl~affeine (5)e in 47 % yield (Enny 2). These two compounds (4 and 5), have been known to have topoisomerasc II inhibitory a~tivity.~ When KCN was used as an electrolyte in acetonitrile, I-cyanoeaffeine (6)” was formed Entry 3). Caffeine (1) was fluotinated by using EqN-3HF as an electrolyte in acetonitile to give 8-fhmrocai?eine (7)‘**)(42 % yield) (Entry 4). When guanosine tetraacetaa (2) was oxidized using Et@-3ISF as an electxolytein acetonitrik;under similar conditions, 8-fluoroguanosine tetraacetate (8)‘” was produced in 7.3 % yield (Entry 5). Uridine triacetate (3) was also oxidized using Et&3HF as an electrolyte in acetonitrile to afford Mhmrouridine triacetate (9)“*‘n in 4.8 % yield (Entry 6). Although the yield of fluorination is not so high, the present method requires only one step and it is therefore advanta~us for the functionalixation of some heterucycles having biological activity, as fluorinated compounds in general are synthesized by not less than two steps. These are the first examples of electrolytic fluorination of this class of compounds, Further investigation from a mechanistic and pharmacological aspect is underway. 9237

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Table 1. Elecrmchemical oxidationofcaffcine

(1)andrclatedctmrxbunds. cI!onditions

Entry

Substrate

Solvent

1 2 3

1 1 1

MeOH

M&N MeCN

electrolyte KF

KU

Potential vs. ) 1.3 v 1.5v

Time 2.5 h 11.5 h 5.0 h

KCN ISV 4 1 M&N Et&3HF 5.0 Vb 17.0h 5 2 M&N Et&3HF 3.0 v 10.0 h 6 3 McCN Et&3HF C.C.E. lOOmA 5.5 h a: Based on consumedstartmgmats-ml. b: C!eJJ voltage (AC 60 Hz) .

Iwducts

Yidd

(4) 43.0 % (5) 42.7 96 (47.2 96). (6) 13.6 % (7)

(8) (9)

40.3 96(42.2 96)’ 6.3 % (7.3 46)’

4.6 96 (4.8 %)

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