INTRAMOLECULAR RADICAL CYCLIZATION REACTIONS - SCOPE AND LIMITATIONS FOR ELECTROCHEMICAL PROCESSES
James GRIMSHAW, Jadwiga T. GRIMSHAW, Mandy GIBSON and Marylene DIAS
School of Chemistry, Queen's University, Belfast BT9 SJP, Northern Ireland, UK
Radical-anions formed by one electron attachment to aryl halides undergo cleavage of the carbon-halogen bond in a unimolecular process to give an aryl a-radical and halide ion. Aryl a-radicals are highly reactive intermediates and the objective of our work is to find conditions under which they can be trapped in an intramolecular reaction by an adjacent phenyl or alkene substituent. Further steps lead to a stable cyclised product and the process is of interest in synthesis. The corresponding intermolecular reactions between phenyl radicals and either benzene or an alkene have been shown to have bimolecular rate constants1 in the range 105 to 108 M"1s-1 so that the related intramolecular and unimolecular processes are expected to be very fast. Alternative reactions for the aryl a-radical intermediates include abstraction of a hydrogen atom from the solvent and further electron transfer at the electrode surface to form a carbanion which undergoes protonation.
All the processes described here were carried out under conditions of constant current density in acetonitrile containing tetraethylammonium tetrafluoroborate in order to simulate a potential industrial process. When we propose the electrochemical method for general synthesis it is absolutely necessary to point out the limitations imposed through the relative kinetics of competing reactions.
Cyclization onto an arene ring
In previous publications2 we have given many examples of the intramolecular reaction of aryl a- radicals with an aromatic ring. Reduction of ( 1) in acetonitrile illustrate this process. Reaction can lead to two products (2) and (3) as a consequence of the competing reactions of the a-radical intermediates. Reduction of ( 1, R = H) at a mercury cathode in a divided cell leads to a mixture of (2, R = H) and (3, R = H). This type of reaction can also be carried out at a carbon-steel or a stainless- steel cathode in an undivided cell with a sacrificial magnesium anode3 Under these conditions the yield of(2) is essentially quantitative. Using the substrate (1, R =F) we can only detect one product (2, R = F) by 1~-nrnr spectroscopy on the crude reaction mixture. This presents a striking demonstration of
267
S. Torii (ed.), Novel Trends in Electroorganic Synthesis
© Springer Japan 1998
268
our previous findings that exploration of different electrode materials can point towards improved conditions for the cyclization process.
(!~~
R R=HorF R
(1) (2) (3)
Cyclization onto an alkene
The conversion of(4) to (5) by cyclization ofthe derived a-radical is a useful dihydroindole synthesis.
Other groups4'5 have investigated the generation of the required intermediate a-radical by reaction between the appropriate bromo-compound and tributyltin hydride. This reaction requires a radical initiator to generate the tributyltin radical which will abstract a bromine atom from the substrate. Our objective was to carry out the conversion of chloro-compounds to dihydroindoles in a more environmentally friendly manner. For the process to be useful it must tolerate substituents R1 and R2 as both electron withdrawing and electron donating groups, including also hydrogen. The presence of electron donating groups increases the rate of carbon-halogen bond cleavage from the first formed radical-anion so that the a-radical intermediate is formed closer to the electrode surface and may undergo further electron transfer before cyclization.
(4)
-
CH:JCN +e(5) (6)
Reduction of two substrates with electron withdrawing nitrile substituents (4, R1 = CN, Rz = H or vice versa) at a mercury cathode in a divided cell gave the corresponding cyclised product (5)
269
together with some of the acetanilide (6). Samples of (5) were isolated by chromatography and the structures confirmed by 1H-nmr spectroscopy. The CH3CH arrangement is easily recognised.
Reduction ofN-allyl-2-chloroacetanilide (4, R1 = R2 =H) yielded only N-allylacetanilide and none of the dihydroindole (5, R1 = R2 = H). This illustrates how substituents can influence the course of competing reactions. The half-life of the initially formed radical-anion is critical to successful cyclization. If this half-life (t1) is very short then a high concentration of the intermediate a-radical is formed close to the electrode surface. This intermediate can diffuse back to the electrode and be reduced further when the half-life for cyclization is longer than t1.
The technique of indirect electron transfer was used to achieve cyclization of(4, R1 = R2 =H).
Reduction was carried out with the addition of trans-stilbene at a mercury cathode. Under these conditions, trans-stilbene radical-anion is formed by electron transfer at the cathode. This radical-anion migrate from the cathode and transfers an electron to the substrate. Carbon-halogen bond cleavage then leads to a a-radical which undergoes intramolecular cyclization faster than addition of a second electron ion a bimolecular reaction with more stilbene radical-anion. The product can be isolated by chromatography. Other transfer reagents have also been used.
0
+a-~ ~H cYC..CH,
~ + e t+e+2H+
Reduction of 2-chloro-N-cinnamanylacetanilide (7) lead to an unexpected result. Again the reaction was carried out with the addition of trans-stilbene at a mercury cathode. The major product was acetanilide with only a low yield of the cyclised product (8). The latter was recognised by its 1H- nmr spectrum. These products arise because the radical-anion of (7) can fragment by two competing
270
reactions. Conversion of the bromo-compound related to (7) into(8) has been effected5 by reaction with tributyltin hydride where the phenyl a-radical is formed by abstraction of an atom of bromine and not via the radical-anion.
Conclusions
The scope and limitations for intramolecular cyclization of phenyl a-radicals generated by the electrochemical reduction of aryl halides has been explored. The process is very effective for aryl halides with an electron withdrawing substituent present. In cases where reduction of the intermediate a-radical competes with cyclization, the desired reaction can be promoted through indirect homogeneous electron transfer to the substrate from a stable and electrochemically generated radical- aruon.
References
1) J. C Scaiano and L. C Stewart, J. Am. Chem. Soc, 105,3609 (1983).
2) S. Donnelly, J. Grimshaw and J. Trocha-Grimshaw, .! Chem. Soc., Perkin Trans., 1557 ( 1993 ).
3) S. Donnelly, J. Grimshaw and J. Trocha-Grimshaw, Electrochim. Acta, 41, 489 (!996).
4) K. Jones and J. M.D. Storey, J. Chem. Soc. Chem. Commun, 1766 (1992); K. Jones and J. M.D. Storey, Tetrahedron, 49, 4801 (1993).
5) J. T. Dittami and H. Ramanathan, Tetrahedron !,etters, 29,45 (1988).
