In 2004, Wills and co-workers reported the synthesis and application of a new class
of half-sandwich ruthenium complex to the hydrogenation of ketones incorporating a
45
Scheme 32. Synthesis of tethered ruthenium complex 88.
Ruthenium complexes 87 and 88 were applied to the ATH of acetophenone as shown
in Scheme 33.
Scheme 33. Application of tethered ruthenium monomer 88 and dimer 87 to ATH of acetophenone.
The dimeric (87) and monomeric (88) forms of the catalyst were found to be highly
active for the ATH of acetophenone and a series of aromatic ketones.96 Recently
Mohar has reported the preparation of a similar tethered catalyst and found excellent
activity and enantioselectivity for the ATH of 1-napthyl ketones (Scheme 34).97
46 Wills and co-workers have reported an alternative synthesis for catalysts of type 88
which avoids the hazardous Birch reduction for formation of the diene via a [4+2] cycloaddition.98 The synthesis of the analogous complexes (92a-d) is shown in
Scheme 35.
Scheme 35. Synthesis of tethered ruthenium catalysts 92a-d by an initial [4+2] cyclisation.
The catalysts prepared were subjected to the ATH of acetophenone however each
was less active than catalyst 88, with the best being 92a achieving 88% conversion,
63% ee. in 96 hours with 0.25 mol% dimer in formic acid/Et3N 5/2 at 40°C.98
Further investigations into the position of the tether within the complex by the Wills
group found that tethering the aryl ligand to the amino rather than sulfonamide
nitrogen gave a significantly more active catalyst as shown in Scheme 36.99.
47 Catalyst 97 was found to show high activity for ATH of ketones allowing the
formation of (S)-phenyl ethanol with 100% conversion and 96% ee. in 3 hours at 28°C with 0.5 mol% catalyst.
Further tethered catalysts, including the use of cyclochexadiamine (98) and the
incorporation of a benzene ring into the tether (99) as shown in Figure 17, were
found to be less active than 97.100
Figure 17. Further derivatives of tethered catalysts.
At 28°C with a catalyst loading of 0.5 mol% catalyst 98 gave only 43% conversion
to (R)-phenyl ethanol in 66 hours however the ee. was high at 97%. Catalyst 99 was more active giving 100% conversion in 12 hours however the ee. was reduced
slightly to 92% under the same conditions. The activity of catalyst 98 was improved
with an increase in temperature to 40°C giving (R)-phenyl ethanol in 100% conversion and 95% ee.100
The incorporation of a tether within the aryl/diamine half sandwich ruthenium
complexes has been found to give a more stable structure. Catalyst 88 gave full
conversion of acetophenone to phenyl ethanol within 24 hours, upon which more
acetophenone and formic acid/Et3N 5/2 was added and full conversion was achieved
in 73 hours and upon further addition again full conversion was reached in 176 hours
48
1.3.2.1 Structural and mechanistic insights for application of tethered
ruthenium catalysts to ATH of ketones.
The preparation of a range of catalysts with different tether lengths and a range of
aryl substituent groups allowed for further insights into the structure and mechanism
of action of the catalysts.101,102 The catalysts prepared are shown in Figure 18 and
results of their application to the ATH of acetophenone are given in Table 9.
Figure 18. Structures of tethered catalysts with a variety of tether lengths and aryl substituents.
Table 9. Application of catalysts 97 and 100-104 to the APH of acetophenone.
Entry Catalyst Time
(hours) Conv. (%) Ee.
a (%) 1 100 15 19 92 (R) 2 97 2 100 96 (R) 3 101 1.25 100 96 (R) 4 102 6 38 94 (R) 5 103 4 100 96 (R) 6 104 5 100 93 (R) a Determined by GC.
Complex 101 was the most active of the catalysts both as the monomer shown above
and also in its dimeric form. Kinetic studies revealed this increase in activity to be
49 the other catalysts tested, the overall rate of the reaction was limited by their rate of
hydride formation.
Andersson has reported that the H-Ru-NH angle in Noyori-type catalysts is
important for the catalytic process with a smaller angle giving an increase in reaction
rate.103 It is thought that the smaller angle gives a catalyst that is better pre-organised
for efficient hydrogen transfer. In catalyst 101 with a four-carbon tether, although an
X-ray structure of the ruthenium-hydride complex has not been reported, inspection
of the X-ray for the chloride complexes shows 101 to have the smallest Cl-Ru-N-H
angle of 3.04° compared to 4.59° in the parent three carbon tethered catalyst 97. If
this pattern is retained upon formation of the ruthenium hydride complexes then this
would explain the high reactivity of catalyst 101.
In addition to providing a more stable structure for the catalysts, the tether also
prevents rotation of the aromatic ring. The addition of substituent groups to the
aromatic ring could therefore be used to affect the selectivity or activity of the
catalyst as their position within the catalyst would be fixed rather than existing in an
equilibrium environment as in Noyori’s untethered catalysts due to rapid rotation of the aromatic ring. Reaction of the complexes with cyclohexyl methyl ketone showed
complex 104 to give the highest ee. of 90%.101 It is believed that the additional
methyl groups on the aromatic ring, fixed in position with the addition of the tether
to the catalyst enhance the preference for the substrate to adopt the favoured
transition state shown in Figure 19, in order to minimise steric clash between the
50
Figure 19. Cyclic transition states for ATH of cyclohexylmethyl ketone with catalyst 104.
1.3.2.2
O-Tethered ruthenium catalysts.In late 2011 and early 2012 both Ikariya 104 and Wills105 independently reported the
synthesis and use of four atom ether tethered catalysts 105-107 as shown in Scheme
37. The catalyst showed improved activity for ATH of ketones over the conventional
carbon tethered catalysts. Another benefit offered by this catalyst is that its
preparation is achieved by use of a [4+2] cycloaddition to afford the required diene
as reported by Wills98 rather than the hazardous Birch reduction.
Scheme 37. Application of ether tethered ruthenium catalysts to the APH of acetophenone.
1.3.2.3 Tethered rhodium catalysts.
In 2004, Wills and co-workers reported the use of a tethered rhodium catalyst for the
ATH of ketones.106 Initially asymmetric amino alcohol ligands were used however
later reports showed the use of asymmetric N-(p-tosyl)-1,2-cyclohexanediamine or TsDPEN as ligands gave improved enantioselectivity for product formation.107, 108
51
Table 10. ATH of acetophenone with tethered rhodium catalysts 108, 109a and 109b.
Entry Catalyst Base Solvent Time
(hours)
Conv.a
(%)
Ee.b
(%) 1 108 (5 mol%) KOtBu 2-propanol 10 min. 95 68 (R)
2 109a (0.5 mol%) - Formic
acid/Et3N 5/2 2 100 96 (R)
3 109a (0.5 mol%) - Water/sodium
formate 3 100 96 (R)
4 109b (0.5 mol%) - Formic
acid/Et3N 5/2 10 100 98 (R)
a
Determined by 1H NMR. bDetermined by chiral HPLC.
1.3.2.4 APH with tethered catalysts.
Although Noyori-type untethered ruthenium catalysts have successfully been applied
to the APH of ketones, there is little precedent in the literature for the application of
tethered ruthenium catalysts to the APH of ketones. In 2007 Wills and Morris
reported the application of the three carbon tethered catalyst 97 to the APH of α-
chloro acetophenone as shown in Scheme 38.109
Scheme 38. Application of catalyst 76 to APH of α-chloroacetophenone.
In the more recent publication, Ikariya reported the application of the O-tethered catalyst 105 and the 4C tethered catalyst 106 to the APH of a range of ketones,
52 revealing 105 to be highly active for this application.104 Compared to O-tethered catalyst 105, the four carbon tethered catalyst 106 was found to be less active for
APH at very low loadings. The results are summarised in Table 11.
Table 11. Application of catalysts 105, 106 and 108 to APH of ketones.
Entry R1 R2 Catalyst S/C Time
(hours) Yield (%) Ee.a (%) 1 Ph CH3 (R,R)-105 500/1 20 58 90 (R) 2 Ph CH3 (R,R)-107 500/1 20 99 95 (R) 3 Ph CH2OH (R,R)-105 5000/1 18 99 93 (S) 4 Ph CH2OH (S,S)-106 5000/1 18 35 89 (R) Substrate 5 4-Chromanone (R,R)-105 1000/1 20 99 99 (R) 6 4-Chromanone (R,R)-107 1000/1 20 99 97 (R) 7 1-Indanone (R,R)-105 1000/1 18 59 98 (R) 8 1-Indanone (R,R)-107 1000/1 18 97 98 (R) 9 1-Tetralone (R,R)-105 1000/1 18 52 >99 (R) 10 1-Tetralone (R,R)-107 1000/1 18 85 >99 (R) a Determined by GC or HPLC.