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substitution and application to asymmetric hydrogenation of ketones. Within the Wills group there have been many studies into the development of

polymer supports for tethered ruthenium catalysts in order to establish a catalytic

system that would allow for improved recovery of the catalyst after reactions and

allow for recycling of the catalyst, as well as the potential to carry out

hydrogenations in water through the use of water-soluble polymers. Previously work

within our group has looked at linking the catalyst to methacrylate based polymer via

a Click coupling with an alkyne substituted TsDPEN ligand.161 With the

development of the aryl substitution process for tethered catalyst preparation it was

thought that the catalysts could be linked to the polymer through the aromatic ring,

again with a Click coupling approach being most appealing due to its robust nature.

Poly(glycidyl methacrylate), as a well studied and readily available polymer, was

selected as a basis for further studies. The epoxide functionality could easily be

converted to an azide group through ring opening of the epoxide with an azide

nucleophile giving a polymeric substrate for Click coupling to a ligand prior to

complexation by aryl substitution.162, 163

A potential ligand with TsDPEN coupled to an aromatic ring with a 3C tether was

prepared, with the aromatic ring containing an alkoxy substituent with a terminal

167

Scheme 96. Preparation of asymmetric ligand 248 as a substrate for Click coupling.

Initial small scale scouting reactions found the ligand to undergo complexation by

aryl substitution to give a tethered complex 249 as shown in Scheme 97.

Scheme 97. Formation of complex 249 by aryl substitution as a model for polymer supported complexation.

The crude complex 249 was found to show some activity for the ATH of

acetophenone giving 21.5% conversion to phenyl ethanol with a high ee. of 97.1%

(R) at a catalyst loading of 1 mol% in formic acid/Et3N at room temperature for 24 hours.

Studies also found ligand 248 to undergo successful Click coupling with benzyl

azide. Further small scale scouting reactions found this product to successfully

168

Scheme 98. Formation of complex 251 by aryl substitution as a model for polymer supported complexation.

The long alkyl chain between the aromatic ring and alkyne should allow the triazole

group to be far enough from the complex after Click coupling to not affect the

activity of the complex. A polymer supported ligand and complex was then prepared

as shown in Scheme 99.

169 Compound 252 was soluble in THF and DMSO allowing characterisation data to be

obtained. However compounds 253 and 254 were found to be insoluble in a range of

solvents tested including THF, DMF, DCM, CHCl3, MeOH, hexane, EtOAc and

DMSO. Full characterisation data therefore could not be obtained for 253 and 234.

These compounds were analysed by Infrared Spectroscopy. The azide in 252 gives a

characteristic absorbance at 2096 cm-1 shown in Figure 68, and reduction of this

signal was taken as an indication of a successful Click coupling having occurred

(Figure 69).

Figure 68. IR spectrum of azide opened polymer 252.

OH

CH

N3

170

Figure 69. IR spectrum of polymer supported triazole-linked ligand 253.

After complexation, the reaction mixture was washed with DCM to remove any

unreacted dimer and this left an orange/brown insoluble solid which was later used

in hydrogenation reactions to test for catalytic activity (Table 35 and 36).

The clicked ligand 253 prior to complexation, and indeed the product obtained after

complexation, were insoluble. In order to reduce the catalyst loading on the polymer

and increase the solubility and flexibility of the polymer, a 10 mol% loading of

ligand 248 was used in an initial click reaction followed by a sequential reaction with

90 mol% hexyne to give complex 256. A second complex (258) was also prepared

using 30 mol% ligand and 70 mol% hexyne. An even distribution of hexyne and

ligand is assumed along the polymer backbone (Scheme 100).

Reduced N3

171

Scheme 100. Synthesis of polymer supported tethered ruthenium catalysts 256 and 258.

The solubility of the polymer supported ligands and complexes was not improved so

again, infrared spectroscopy was used to confirm successful Click coupling of the

ligand and polymer.

Alternative functionalities were explored for ring opening of the epoxide. It was

hoped that the epoxide could be opened with the p-OH derivative of the prepared ligand, however initial attempts to ring open the epoxide with phenol proved

unsuccessful. A further survey of the literature showed that epoxides on analogous

polymer chains had been ring opened with amines.164 This approach was therefore

applied to the preparation of our polymer supported complexes. Hence 90% of the

epoxide was first opened with diethylamine whilst 10% was opened with sodium

azide as before to give 260 which was then converted to polymer supported complex

172 additional 90% of clicked alkane chain will help improve the solubility of the

supported ligands and hence complexes. Diethylamine was chosen as a small and

available secondary amine that would mean there was no NH functionality in the

polymer supported ligand to compete with the TsDPEN for complexation to

ruthenium (Scheme 101).

Scheme 101. Preparation of diethylamine functionalised polymer supported ruthenium tethered catalyst 262.

The addition of diethylamine and reduction in the loading of azide on the polymer

did not improve the solubility of the polymer supported complex. Compounds 260-

262 remained insoluble allowing only minimal characterization data to be obtained

for each. The 10% azide functionality of 259 was confirmed by 1HNMR analysis as

173

Figure 70. 1H NMR analysis of 259 (300 MHz, d8-THF).

Comparison of the 1H NMR of 259 to poly(glycidyl methacrylate) and 252

confirmed the presence of a 10% loading of azide. The major peaks in the spectrum

compare well with the spectrum of poly(glycidyl methacrylate) and the smaller set of

peaks match well with 252. Analysis of the integration of the peaks shows a ratio of

epoxide:azide of 9:1 as expected.

The 1H NMR spectrum confirms the 10% opening of the epoxide with N3 in

compound 259. Comparison to the 1H NMR spectra for the starting material and

fully ring opened product shows a 1:9 ratio of epoxide:azide peaks in compound

259.Infrared spectroscopy also helped confirm the formation of 259 (Figure 71) and

also 260 (Figure 72).

THF

259

252

174

Figure 71. Infrared spectrum of 259.

The small OH and N3 absorbance at 3435 and 2102 cm-1 respectively show the

presence of a small amount of azide opened epoxide in the compound. The weakness

of the absorbances comply with the expected 10% loading of azide.

Figure 72. Infrared spectrum of 260.

OH

CH

N3 C=O

C=O in ring opened epoxide HC=O in DMF

N3

CH OH

175 After ring opening the remainder of the epoxide with diethylamine to give 260 the

size of the OH absorbance relative to that of the N3 has increased suggesting the

presence of more alcohol in 260 than in 259. The CH signals at 2963-2874 cm-1 have

also increased in intensity, presumably due to the presence of the diethylamine.

With a variety of polymer supported tethered ruthenium complexes having been

prepared, a series of hydrogenations of acetophenone were carried out to establish

the activity of the compounds. ATH and APH conditions were investigated and the

results are shown in Table 35.

Table 35. ATH and APH of acetophenone using polymer supported tethered catalysts.

Entry Catalyst H2 source Temp.

(°C) Conv. (%)a Ee. (%) a,b 1 254 Formic acid:Et3N 5:2 28°C 1.3 ND 2 254 IPA/KOH 28°C 0.4 ND 3 254 Water/sodium formate 60°C 6.5 68.3 (R) 4 256 Formic acid:Et3N 5:2 28°C 0.61 ND 5 256 IPA/KOH 28°C 0.71 ND 6 256 Water/sodium formate 60°C 32.0 92.7 (R) 7 Recovered 256 from entry 6 Water/sodium formate 60°C 4.3 Only 1 enantiomer seen by GC 8 256 H2 , MeOH 60°C 13.1 Racemic

176 9 258 Water/sodium formate 60°C 16.2 50.2 (R) 10 258 H2, MeOH 60°C 34.5 Racemic 11 262 Formic acid:Et3N 5:2 28°C 6.9 93.0 (R) 12 262 IPA/KOH 28°C 0.45 ND 13 262 Water/sodium formate 60°C 26.3 37.9 (R) 14 262 H2, MeOH 60°C 79.4 2.7 (R) a

Determined by GC analysis. bFor conversions less than 2% the ee. was not determined.

Use of polymer supported ligand 261 and dimer 197 in place of the catalyst under all

reaction conditions investigated gave no conversion to product. It was also found

that use of formic acid/Et3N as the hydrogen source caused leaching of the

ruthenium from the polymer support in all cases with strong colouration of the

reaction solution occurring. This explains the low activity of all complexes with use

of formic acid as the hydrogen source.

Initial reactions using polymer supported complex 254 showed low conversion.

Improvements to conversion were seen with use of water/sodium formate when

polymer supported catalyst 256 was used giving 32% conversion, and an ee. of 92.7

(R) (Table 35, entry 6). Polymer 256 has only a 10% loading of ruthenium complex and it is thought that the reduced level of complexation leads to a more flexible

polymer and also a reduction in steric hindrance allowing for improved conversion.

The reaction solution was removed from the reaction for Table 35, entry 6 and

further acetophenone and water/sodium formate mixture added in order to determine

177 reaction however, only 4.3% conversion to product was obtained over 24 hours

showing a loss of activity of the catalyst (Table 35, entry 7). Catalyst 256 also

demonstrated activity for APH of acetophenone (Table 35, entry 8) however to a

lesser extent than in ATH with water/sodium formate and with no enantioselectivity.

Polymer supported catalyst 258 was applied to ATH with water/sodium formate and

APH as these conditions seemed most conducive to hydrogenation occurring. The

results obtained showed a reduction in conversion with the water/formic acid system,

but an increase in conversion for APH of acetophenone with hydrogen, although the

product obtained was racemic.

Use of polymer supported catalyst 262 showed conversion to product with ATH in

water/sodium formate and achieved the highest conversion of all at 79.4% with APH

conditions although again the product obtained was racemic.

Further ATH reactions were carried out using formic acid/triethylamine and

IPA/KOH at increased temperatures with those polymer supported catalysts found to

178

Table 36. ATH of acetophenone using polymer supported ruthenium complexes.

Entry Catalyst H2 source Temp.

(°C) Conv. (%)a Ee. (%) a 1 256 Formic acid:Et3N 5:2 60°C 10.8 87.0 (R) 2 256 IPA/KOH 80°C 11.3 2.8 (R) 3 258 Formic acid:Et3N 5:2 60°C 17.9 82.7 (R) 4 258 IPA/KOH 80°C 35.2 Racemic 5 262 Formic acid:Et3N 5:2 60°C 5.6 82.8 (R) 6 262 IPA/KOH 80°C 4.6 14.4 (R) a Determined by GC analysis.

The conversions and enantioselectivities achieved were improved compared to the

equivalent reactions at room temperature reported in Table 35, however the use of

256 with water/sodium formate (Table 35, entry 6) remains the best ATH result

when both conversion and the enantiomeric excess of the product obtained are

considered.

No conversion was achieved with use of only ruthenium dimer 197 or ligand 261

under each of the reaction conditions investigated. This confirms that the polymer

supported catalysts themselves are the source of the hydrogenation taking place and

179 Due to the low solubility of all the prepared polymer supported catalysts,

characterisation was difficult. It therefore cannot be determined whether the desired

complexes were being formed. It may be the case that the desired complexation of

ruthenium to the supported ligand by aryl substitution is not occurring in its entirety.

For example it may be that the nitrogens of the TsDPEN coordinate to the ruthenium

to give a derivative of complex 195 with aryl substitution and displacement of the

ethylbenzoate not occurring to give complexes such as 263 in Figure 73 which may

not be highly active or enantioselective for the hydrogenation of ketones.

Figure 73. Potential polymer supported complex obtained from incomplete aryl substitution process.

Work continues within the Wills group to establish more effective polymer

supported catalysts for ATH and APH applications using aryl substitution

180

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