Cr-Salen mediated asymmetric epoxidation of alkenes: rational complex design and substrate scope of catalyst

Recent explorations of the structure space of Cr(salen) complexes have led to the rational design of improved catalysts for the asymmetric epoxidation of alkenes. The synthesis of these catalysts is presented and their substrate scope detailed. Catalyst 3a , in combination with triphenylphosphine oxide, gives the highest enantiomeric excesses achieved to date in both stoichiometric and catalytic epoxidation with Cr(salen) complexes.

We have reported detailed studies of the effect on AE of various substituents at all positions on the arene ring of the salen ligand 40 which culminated in complex 1a. 41,42 ecently, an exploration of salen substituent effects led to the discovery of complex 2b, which was also an effective mediator of epoxidation. 43We envisaged that, by incorporating the beneficial substituents from 1a and 2b into a new catalyst 3, we could obtain further improvements in the asymmetric epoxidation of unfunctionalised alkenes.The new catalyst was expected to be a less reactive but more selective epoxidising agent.We now describe the synthesis of 3a,b and their use in the AE of a variety of classes of alkenes

Results and Discussion
Scheme 1 shows the synthetic route adopted for the synthesis of 3a,b.After unsuccessful attempts to introduce the trifluoromethyl group into the benzene ring late in the synthesis, we adopted the methods previously used for the synthesis of 3-trifluoromethylsalicylaldehyde. 41The synthesis of phenol 5 had been described previously by Stokker et al .44The protection, formylation, and deprotection steps proceeded in good yield. 45Contrary to our previous experience, 41 the use of N,N,N′,N′-tetramethylethylenediamine (TMEDA) was found to be essential to achieve a selective formylation -a complicated mixture resulted in its absence.Care had to be taken also to prevent decomposition of the delicate trifluoromethyl phenol derivative 7 which is sensitive to acid and base. 46,47 fter some experimentation, we found that 3% TFA in CH2Cl2 removed the protecting group without causing the product to decompose.With the requisite salicylaldehyde 8 in hand, the synthesis of 3a,b was achieved in good yield using standard methods. 41The paramagnetic complexes were characterised by IR and ES-MS.Elemental analyses were not satisfactory, however this is not unusual for these complexes 26 and epoxidation results were reproducible from batch to batch.
We first tested our new catalysts in the stoichiometric epoxidation of trans-β-methylstyrene (our standard test substrate) by O=Cr(salen) (see Table 1).Gratifyingly, the catalysts lived up to our expectations, exhibiting higher enantioselectivity than any previous Cr(salen) catalyst in the epoxidation of this substrate.The epoxide is stable in the presence of Cr III (salen) + and O=Cr V (salen) + , thus enantioselectivity is not a result of kinetic resolution.The effect of changing counterion was unusually large, nitrate was found to be significantly better than hexafluorophosphate.The addition of Ph 3 PO was found to improve the ees obtained, in line with previous results.The yields in stoichiometric mode were low, however this is not unexpected. 43The most notable result in Table 1 is that obtained in catalytic mode (10 mol% Cr III (salen)) with Ph 3 PO additive, which is the highest ee (88%) obtained thus far under catalytic conditions with Cr(salen) complexes.However it is still slightly lower than in stoichiometric mode, as had been observed previously with 1a. 41Also the yields were unexpectedly low, usually the yield in catalytic mode is significantly higher than in stoichiometric mode (71% vs 45% with 1a).The very low catalytic yield is probably due to disproportionation of PhIO over the extended reaction times necessary for this slower catalyst. 48In line with previous results, 41 the use of NaOCl as terminal oxidant resulted in a poor ee (entry 3), however, the sense of the enantioselectivity was reversed suggesting a different oxidation pathway. 43We have also rationalised the reduction in ee relative to stoichiometric mode in terms of a second oxidation cycle being in operation under catalytic conditions. 41,430][51][52][53] Bryliakov and Talsi 10 have recently reported evidence supporting the presence of two discrete (salen)chromium-oxo species starting from Cr(salen) chloride complexes and iodosylbenzene: a monomeric [(salen)Cr V =O] + and a dimeric mixed valent Cr III Cr V -oxo species.They proposed that only the former species was acting as an oxidant under their conditions, while the latter species acted as a reservoir. 10The nature of the proposed second oxidant and/or oxidation cycle in our system is currently under investigation in our laboratory and will be the focus of a future report.
Having established that 3a was the better catalyst we then examined its substrate scope.Examples of terminal mono-substituted, terminal di-substituted, cis-and trans-1,2-disubstituted alkenes, were all examined.Table 2 shows results for those substrates where epoxide was formed as product.Unfortunately, the excellent selectivity of the catalyst in the case of trans-βmethylstyrene did not extend to other substrates.Only trans-stilbene and cis-β-methylstyrene gave ees greater than 50%, which is a significant improvement for the latter substrate in Cr(salen)-mediated AE.Yields were poor in all cases.The attempted epoxidation of αmethylstyrene resulted in a complicated mixture with no epoxide or starting material present.trans-Methyl cinnamate was recovered unchanged after 48 hours under stoichiometric conditions.

Conclusions
A rationally designed, novel Cr(salen) complex has been synthesised and tested in the epoxidation of a range of alkenes.The highest ever selectivity for the AE of trans-βmethylstyrene by a Cr(salen) complex was achieved but only moderate to poor selectivity with other substrates.The differences in results between catalytic and stoichiometric modes are suggested to be due to the presence of a second oxidation cycle.

Experimental Section
General Procedures.All chemicals were available from Aldrich and used as received unless stated.2-Trifluoromethylphenol was obtained from Fluorochem Ltd. and used as received.trans-Cyclohexane-1,2-diamine was purchased in racemic form and resolved using literature methods. 54Iodosylbenzene was synthesised using literature procedures.

4-tert-Butyl-1-methoxymethoxy-2-trifluoromethylbenzene (6).
Sodium hydride (1.38 g of a 60% dispersion in mineral oil, 34.5 mmol) was washed with hexane and transferred to a 3-neck 100 ml RB flask under an atmosphere of N 2 .After addition of anhydrous DMF (11 ml), the slurry was cooled with stirring to 0°C.To the resulting grey suspension, a solution of 5 (5.00 g, 22.9 mmol) in anhydrous DMF (6 ml) was added dropwise at such a rate that the evolution of hydrogen did not become too vigorous.After complete addition the ice bath was removed and the reaction mixture was stirred for 1 h.Chloromethylmethyl ether (2.6 ml, 34 mmol) was then added dropwise and the resulting solution was stirred overnight.Ice/water (

5-tert-Butyl-2-methoxymethoxy-3-trifluoromethylbenzaldehyde (7).
To a solution of 6 (8.41 g, 32.1 mmol) in dry hexane (75 ml) under an atmosphere of N 2 was added TMEDA (4.9 ml, 32 mmol) via syringe.The solution was then cooled to 0°C and nBuLi (20 ml of a 1.6M solution in hexanes, 32 mmol) was added dropwise via syringe.The resulting thick grey solution was stirred for 2 h at 0°C followed by addition of dry DMF (2.72 ml, 35.1 mmol).The solution was then stirred for 0.5 h at 0°C followed by 1 h at room temperature.Following the addition of 1M HCl (50 ml) the mixture was extracted with Et 2 O (3 × 50 ml).The combined ether extracts were then washed with brine (50 ml), dried over MgSO 4 , and the solvent was removed under reduced pressure to yield a clear liquid, which was distilled under vacuum (7.39 g, 79%): Bp 95-96°C (0.1 mm Hg); , J C-F = 5.0 Hz, ArCH), 123.4 (q, -CF 3 , J C-F = 273 Hz), 121.1, 118.8 (q, J C-F = 31 Hz, ArC 3 ),  General epoxidation procedure.Details of procedures for epoxidations are given in the supplementary information of Daly et al. 41 Daly et al. have described conditions for the analysis of reaction mixtures by chiral GC or HPLC except: α-methylstyrene and styrene oxide which were analysed by chiral GC (Supelco cyclodextrin-β capillary column (betadex 120), 30 m × 0.25 mm i.d., 0.25 µm film.) with column temperatures of 80°C and 100°C, respectively.

Table 2 .
Epoxidation of alkenes using 3a and PhIO in acetonitrile at 0°C a a See Table 1 for general details.Entries 1 & 2 are taken from Table 1.b NR = no reaction.c ND = not determined. 55 44modified version of the procedure ofStokker et al.was used.44To a solution of 2-trifluoromethylphenol (24.0 g, 148 mmol) and tert-butanol (11.5 g, 155 mmol) in trifluoroacetic acid (TFA) (100 ml) was added concentrated sulphuric acid (2 ml).The colourless solution was stirred for 3 days at room temperature, during which time a dark yellow colour developed.The reaction mixture was concentrated under vacuum to yield a dark green oil (26.4 g) which was dissolved in CH 2 Cl 2 (150 ml). Ths solution was then washed with water (150 ml), saturated sodium bicarbonate (3 × 150 ml) and brine (150 ml).After drying over Na 2 SO 4 , the solvent was removed under vacuum to yield a light green coloured oil which solidified on standing.The resulting solid was recrystallised from pet.
50 ml) was added cautiously and the mixture extracted with Et 2 O (3 × 50 ml).The combined Et 2 O extracts were washed with NaOH solution (2M, 50 ml), hydrochloric acid (2M, 50 ml), and brine (50 ml).The solution was dried over MgSO 4 and the solvent was removed in vacuo to yield a colourless liquid (5.57g, 93%) which was used in the next step without further purification: 1 H NMR (300 MHz, Aldehyde 7 (7.07 g, 24.4 mmol) was dissolved in a 3% solution of TFA in CH 2 Cl 2 (180 ml).The solution was stirred and monitored by TLC for the disappearance of starting material.When no starting material remained, the solvent was removed in vacuo to yield a clear solution which, on standing, solidified to yield a low melting solid (5.19 g, 87%).