SIKA FUME

3.3. Palladium as a Lewis acid and its’ Use in Asymmetric Fluorination

Palladium is known for its ability to cross couple various organic substituents in transmetallation reactions, including alkynes with vinyl or aryl halides in a Sonagashira reaction and organoboronic acids to halides in a Suzuki coupling. There

are comparatively few examples of palladium acting as a Lewis acid, and asymmetric variants are rarer.[15] Palladium is relatively electron rich and as a result is a poorer Lewis acid than other metals such as aluminium and titanium. There are however some reasons for using it over other metals. The ene reaction is one example in which palladium has been successfully used as a Lewis acid (Scheme 2.5).

One of the first examples of asymmetric fluorination using palladium based catalytic systems[13a] uses BINAP to give an 88% e.e.(Scheme 3.5). The system was further optimised for this reaction with tert-butoxycarbonyl lactones and lactams in ethanol to give up to 99% e.e.[13h] The bridged palladium catalyst 81 can also be used to catalyse the fluorination of oxindole in high enantioselectivity (Scheme 3.6)

Scheme 3.5 [Pd((R)-BINAP)(OH2)2](OTf) 2 catalysed fluorination of beta-ketosesters

+ + 2 2 2 2 - 2 2

Scheme 3.6 Fluorination of oxindole

The bite angle of the ligand used can be varied such that the coordination sphere of the complex favours a particular reaction. For bidentate ligands the bite

angle is often used as a descriptor, and is taken from the angle of the P-M-P bonds. The bite angle can be measured crystallographically or predicted using computational methods in which case it is called the natural bite angle.[16] The bite angle can be varied such that for small ligands such as diphenylphosphinoethane the angle is 78º[17] whereas the larger diphenylphosphinobutane has a bite angle of 99º[17]. Four coordinate palladium complexes are usually square planar, and so chiral bidentate ligands can be used to bind to the palladium so only two labile ligands are required to stabilise the metal complex used for catalysis, which can then be displaced by the substrate. In fluorination this property is particularly useful since as there are many chiral bidentate ligands that can be screened and also the problem of chlorination seen in reactions with titanium complexes can potentially be avoided. Four coordinate nickel complexes have also been shown to catalyse asymmetric fluorinations.[13i] _{In Lewis acid catalysis the metal acts as a Lewis acid and the chiral}

ligand and the substrates acts as Lewis bases.

3.4. Aims and Objectives

There has as yet been no comparison of the effect of changing the ligands in the asymmetric fluorination reaction. In other metal catalysed reactions such as the rhodium catalysed hydroformylation of styrene[17-18] and the Lewis acid catalysed Diels-Alder reaction[19] electronic effects and bite angles of the ligand have been shown to have a significant effect on the activity of the catalyst.

It was decided to see how varying the ligand on the palladium catalyst changes the reactivity of the system and to either use a known ligand complex which has not been used in the reaction before, or synthesise a new one which could give high activity and also enantiomeric excess.

3.5. Fluorination of ketoesters

The ketones required for the fluorination reaction are not commercially available but are readily accessible by the aldol reaction between benzaldehyde and

the corresponding alkyl propionate (Scheme 3.7). The substrate could also be easily changed by using two different starting materials, i.e. another aldehyde or ester, in order to study the limits of the catalysts developed. Oxidising the aldol product using Jones reagent gave a significantly higher yield than using Dess-Martin periodane and so this method was used.

t

Scheme 3.7 Synthesis of ketone substrate

Having synthesised the ketone, the palladium complexes to be used in catalytic tests were then prepared. A method of producing dichloropalladium salts of the ligands from sodium tetrachloropalladate in acetonitrile quickly and in high conversion using microwave heating was utilised (Scheme 3.8, Table 3.1, Table 3.2).[20] The dichloropalladium complexes of dppf and dippf (Figure 3.2) had previously been synthesised within our group. The ligands chosen were selected because of their range of bite angles and steric properties.

It is thought microwave heating is more efficient in this case since the solvent reaches temperature quickly and the reaction is consequently faster. It also has the advantage of using the relatively cheap palladium salt Na2PdCl4. The product can be

purified by separation between dichloromethane and water to extract sodium chloride and any excess ligand can be removed by filtration through a small plug of alumina. The dichloropalladium complexes are stable enough to be handled briefly in solution in air.

Scheme 3.8 Synthesis of palladium dichloride complexes and their transformation into palladium

Figure 3.2 Structures of dppf and dippf dichloropalladium complexes

Ligand Structure Yield (%)

[PdLCl2] 84 dppe 92 85 dppp 94 86 dppb 92 87 dcpe 79 88 dfppe 86 89 (R, R)-Ph-BPE 92 90 (S, S)-Me-BPE quant. 92 (S)-BINAP 2 2 76

Ligand Structure Yield (%) [PdLCl2] 93 (R)-phanephos 90 94 (S)-xylylphanephos 93 95 (1R,2R,4R,5R)-4,5-dimethyl-N1_,N2_- bis((S)-1-phenylethyl)cyclohexane- 1,2-diamine 74

Table 3.2 Synthesised palladium complexes and isolated yields

The formation of the cationic palladium salt is triggered by the precipitation of silver chloride after treatment of the dichloride with two equivalents silver triflate (Scheme 3.9, Table 3.3). Monitoring by 31_{P NMR spectroscopy shows clearly the}

formation of a new complex with a new phosphorus peak formed downfield from the starting material. AgBF4 was initially used to precipitate the chloride, however

AgOTf was found to produce the cationic salt more efficiently.

2 2 2+ -