J. Chem. Soc. Chem. Commun. (18), 1844-1845 (2001)
The Wacker oxidation is a versatile reaction that has found broad application in synthetic chemistry for the functionalisation of alkenes. The sigma-bonded (β-hydroxyalkyl)palladium complex has been determined as the key intermediate in this reaction. However, the factors controlling the regiochemistry of the hydroxypalladation step to form this intermediate remain obscure. Although terminal alkenes nearly always give methyl ketones, suggesting that hydroxypalladation takes place according to Markovnikov's principles, disubstituted alkenes give products that do not always obey these rules. A striking example of this paradox is the dramatically different regioselectivity observed with styrene (Markovnikov) and that of β-methylstyrene (apparent anti-Markovnikov). In this study we have identified that there are two key factors that control the regioselectivity: electronic effects (Markovnikov) and the availability of a hydrogen atom allylic to the double bond.
It is intriguing that the substitution of a methyl group on the terminal carbon atom of styrene (Scheme 1) or 4-methoxystyrene (Table 1) switches the regioselectivity from Markovnikov to anti-Markovnikov. To test whether the availability of an allylic hydrogen is responsible for the change in regioselectivity the oxidation of the β-methyl-4-methoxystyrene 1b was directly compared with that of the β-tert-butylstyrene 1c. The result clearly demonstrates that the removal of the allylic hydrogen switches the regioselectivity back to the Markovnikov product (Table 1).
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a | X = 4-CF3 | 1 |
>19 |
b | X = 4-H | 1 |
7.5 |
c | X = 4-CH3 | 1 |
3.8 |
d | X = 2-OCH3 | 1 |
2.7 |
b | X = 4-OCH3 | 1 |
2.0 |
e | X = 2,4-OCH3 | 1.2 |
1 |
f | X = 2,4,6-OCH3 | 2.3 |
1 |
b It is interesting to note that the temperature of the reaction (compare to the result at 100°C, Table 1) can affect the regioselectivity of the reaction. At higher temperatures the "anti-Markovnikov" product is further favoured. |
A flask containing a suspension of palladium(II)chloride (35.4 mg, 0.2 mmol) and copper(I)chloride (198 mg, 2 mmol) in N,N-dimethylformamide (1 ml) and water (1 ml) was stirred under an oxygen atmosphere for 1 h. Alkene, 1b, (296 mg, 2 mmol) in N,N-dimethylformamide (0.5 ml) and water (0.5 ml) was added and the reaction mixture was stirred at 50°C for 24 h. The crude reaction mixture was applied directly to a pad of silica (ethyl acetate–hexane; 1:4) and the concentrated filtrate was analysed by 1H NMR. Purification by flash silica gel chromatography afforded ketones 2b and 3b (in the ratio 1:2) as a pale yellow oil (195 mg, 59%).