DESARROLLO Y EVOLUCIÓN DEL CAC.

alkylation of 1,2-diphenylethanone 184. Reaction Conditions:186 (1 eq.), KOtBu (3 eq.), EtI (3 eq.), tetrahydrofuran, 0C → rt, 16 h, 66%.

2.2.2 Catalysis

Hydrogenation of substrates 183and 184was carried out using the original catalyst precursor (R,R)-174, prepared according to the literature.1 Both ketones were reduced quantitatively by catalyst (R,R)-174in 16 h using 40 bar hydrogen pressure at 70C. It was found that while a

high degree of enantioselectivity was maintained in the secondary alcohol products (Table II-2), there was a small but significant decrease from that observed for the hydrogenation product of ketone184(the stereochemical configuration of alcohols187and188was tentatively assigned as (S) akin to that of entries 2,3 and 5 in Table II-1. All products display the same sense of optical rotation and order of elution from the chiral HPLC).

Entry R = PH2 [bar] T [C] Conversion (yield) [%] ee [%] 1 Me 40 70 >99 (79) 84 2 Et 40 70 62 75

Table II-2The hydrogenation of ketones183 and184 using catalyst (R,R)-174. General conditions: ketone (~1 mmol), catalyst (R,R)-174

(0.5 mol%), potassium tert-butoxide (1 mol%), isopropanol (3 mL), molecular H2, 16 h.

The results suggest that as the R substituent of the ketone substrate gets larger than that of ketone183, the preference for the attack of the ruthenium hydride at theSi-face of the ketone is somewhat diminished, perhaps due to enhanced steric repulsion between the ligand and the bulky substrate. Thus, as well as showing that catalyst (R,R)-174is effective in producing useful bulky secondary alcohols with good enantioselectivity, these results give clues to the possible direction of catalyst optimisation, which shall be discussed more extensively in Chapter IV. The reductions of substrates 183 and 184 were also studied in a microwave-assisted transfer hydrogenation protocol, developed in this group,6employing isopropanol as the hydride source. It was gratifying to observe that alcohols 187 and 188 could be furnished with good enantioselectivity (Table II-3). Reaction temperatures had to be tuned to give enantioselectivities approaching that of the H2-hydrogenation system for the hydrogenation of 183but this led to

poor conversions when the temperature was lowered. Good enantioselectivity was also obtained in the transfer hydrogenation of184but the conversion was again poor. It is likely that further optimisation of reaction conditions, in particular increasing the reaction time and base loading, would improve the yield of enantiomerically enriched product. However, this was not considered an important objective given that this has been demonstrated for other substrates by Diaz and Clarke.6We have nevertheless demonstrated that the transfer hydrogenation procedure,

albeit requiring further optimisation, gives an alternative route to chiral secondary alcohol building blocks, without the need for high pressure equipment. This is particularly convenient in the research laboratory which does not always have the facilities for H2-hydrogenation. H2-

hydrogenation however, is normally preferred at a commercial scale and having a catalyst which can operate in both systems is highly beneficial.

The similarly high enantioselectivity observed for substrates 183and 184 in H2-hydrogenation

and transfer hydrogenations also suggests a common pathway in the enantio-determining step in each process, and this shall be discussed further in Chapter III.

Entry R = t [min] T [C] Conversion (yield) [%] ee [%] 1 Me 20 120 55 71 2 Me 40 100 31 75 3 Et 20 120 18 83

Table II-3The transfer hydrogenation of ketone183and184using catalyst (R,R)-174. General conditions: ketone (~1 mmol), catalyst (R,R)-174 (0.5 mol%), potassium tert-butoxide (1 mol%), isopropanol (3 mL).

2.3 Preparation of Chiral Secondary Alcohols with Distinct Electronic Properties In light of the proposed mechanism for ketone hydrogenation with Noyori’s [RuCl2(P^P)(N^N)]

catalyst system, it is conceivable that altering the electronic environment at the substrate carbonyl functionality could impact both activity and enantioselectivity in such reactions. For a catalyst to be synthetically useful it must be shown that it can tolerate a variety of electronically different substrates as well as steric bulk. Studies into the effect of substituents upon catalysis can also shed light upon the mechanism by which the catalytic cycle operates. It was shown for the Noyori system that electron-poor substrates, such as p-trifluoromethylacetophenone, were hydrogenated up to 11 times faster than electron-rich substrates such as p- methoxyacetophenone, although this is a smaller effect than the substituent effect on reduction with sodium borohydride.2 It was also demonstrated by Noyori that the electronic effects of

para substituents on enantioselectivity are relatively small and thus efficient enantioselective hydrogenation with such catalysts can tolerate a range of ring substituents.8Noyori does suggest however, that substrates with an electron donating susbstituent gives rise to high

enantioselectivity due to the greater stabilisation of an NH/π interaction between the diamine

ligand and the aryl component of the substrate.9

In order to investigate this issue for the hydrogenation of bulky ketones with the [RuCl2(P^N^N)L] catalytic system, a range of derivatives of,,-trimethylacetophenone were

prepared, to cover a spectrum of electronic influences on the carbonyl functionality of the substrate (Scheme II-8). The para-methoxy derivative 197was prepared as an example of an relatively electron-rich substrate compared to ,,-trimethylacetophenone 159, while para- chloro andpara-trifluoromethyl derivatives,198and199, were prepared as relatively electron- poor substrates, and their performance in catalysis was compared and contrasted. To investigate whether orthosubstitution can also be tolerated by the [RuCl2(P^N^N)L] system, where steric

influences also becomes a factor, the ortho-methoxy derivative 200 was prepared and its performance in catalysis was explored.

Scheme II-8 Para- and ortho-substituted ,,-trimethylacetophenone derivatives prepared to probe the effect of the electronic environment at the carbonyl group.upon productivity and enantioselectivity.

2.3.1 Synthesis

The syntheses of the tert-butyl ketones 197-200 were carried out in moderate to good yields from commercially available acid chlorides by adaptation of literature procedures (Scheme II- 9).10,11 The tert-butyl cuprate was first generated by reaction of copper(I) bromide dimethylsulfide complex with tert-butyllithium in THF at 0C. Addition of the requisite aroyl chloride and stirring overnight yielded the desired product in each case. Purification by short- path distillation using Kugelrohr apparatus was carried out before each substrate was investigated in catalysis.

Scheme II-9 Preparation of para- and ortho-substituted ,,-