Further 'tethered' Ru(II) catalysts for asymmetric transfer hydrogenation (ATH) of ketones; the use of a benzylic linker and a cyclohexyldiamine ligand

Article abstract of DOI:10.1016/j.jorganchem.2008.08.026

The synthesis and characterisation of two new Ru(II) catalysts for the asymmetric transfer hydrogenation (ATH) of ketones is described. In the case of 4, the novelty lies in the use of a benzyl tethering group between the asymmetric ligand part (TsDPEN) a

Full text of DOI:10.1016/j.jorganchem.2008.08.026

Journal of Organometallic Chemistry 693 (2008) 3527–3532
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Further ‘tethered’ Ru(II) catalysts for asymmetric transfer hydrogenation (ATH)
of ketones; the use of a benzylic linker and a cyclohexyldiamine ligand
*
Jose E.D. Martins, David J. Morris, Bhavana Tripathi, Martin Wills
Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 June 2008
Received in revised form 17 August 2008
Accepted 21 August 2008
Available online 28 August 2008
The synthesis and characterisation of two new Ru(II) catalysts for the asymmetric transfer hydrogenation
(ATH) of ketones is described. In the case of 4, the novelty lies in the use of a benzyl tethering group
between the asymmetric ligand part (TsDPEN) and the
g
6-arene ring, which increases the complex rigid-
ity. For 5, the use of a cyclohexyldiamine as a chiral ligand is described for the first time. In the ATH of
ketones in formic acid/triethylamine, alcohols with ees of up to 97% were formed.
Ó 2008 Elsevier B.V. All rights reserved.
Keywords:
Ruthenium catalyst
Asymmetric
Transfer hydrogenation
Reduction
Ketone
Alcohol
1. Introduction
Asymmetric transfer hydrogenation (ATH) of ketones using
ruthenium(II) complexes has recently developed into an area of
major international research [1–3]. This has largely been the result
of initial breakthroughs by Noyori et al., who demonstrated that
monotosylated diamine complexes of Ru(II), particularly 1, form
highly enantioselective catalysts for ketone reductions [2a–e]. Aro-
matic/alkyl ketones, in particular, are excellent substrates because
their reduction takes place through a six-centre transition state in
which an additional stabilising CH/p interaction favours the ap-
proach of one face of the ketone as shown in Fig. 1 [3]. In our recent
studies in this area, we have reported the closely related catalysts 2
and 3, in which the chiral ligand component is attached by a ‘teth-
ering’ group to the
g
6-arene ring located above the ruthenium
atom [4]. These complexes also reduce ketones in high enantiose-
lectivity and, in the case of 3, exhibit significantly higher reactivi-
ties in this application.
During the development of this area of research, we wished to
investigate the effect of changes to the chiral ligand part and the
tethering group. In this paper we report the synthesis and applica-
tions of the catalyst containing a benzylic tether, i.e. 4, in place of
the aliphatic one, and of the complex 5, in which the diphenyl-
derivatives have been reported to be effective ligands in this appli-
cation when used in the untethered form [5].
2. Results and discussion
substituted diamine ligand is replaced with
a homochiral
R,R-1,2-diaminocyclohexane (R,R-DAC). 1,2-Diaminocyclohexane
Both new catalysts, 4 and 5, were prepared from the R,R-dia-
mine starting material (Scheme 1 and 2, respectively) by a modifi-
cation of the route developed for complex 3. This involved the
reductive amination of the appropriate monotosylated diamine
* Corresponding author. Tel.: +44 24 7652 3260; fax: +44 24 7652 4112.
E-mail address: m.wills@warwick.ac.uk (M. Wills).
0022-328X/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2008.08.026

3528
J.E.D. Martins et al. / Journal of Organometallic Chemistry 693 (2008) 3527–3532
Fig. 1. Orientation of substrate in ATH by catalyst 3.
(both are commercially available) with an aldehyde derivative of a
1,4-cyclohexadiene (i.e. 6 and 7) to give 8 and 9 respectively. Alde-
hyde 7 is a known molecule [4b], but 8 was prepared by a novel
process for this application. Starting from 2-bromobenzaldehyde
diethyl acetal, treatment with nBuLi followed by cyclohexen-2-
one provided alcohol 10 in 92% yield [6]. The hydroxyl elimination
of 10 using 2,4-dinitrosulfenylchloride provided compound 11 in
46% yield [7]. Mild hydrolysis of 11 furnished 6 in 71% yield and
reductive alkylation of R,R-N-tosyl,1,2-diphenyl-1,2-ethyldiamine
(R,R-TsDPEN) using aldehyde 6 generated ligand 8 in 63% yield.
Treatment of 8 with RuCl3 ꢀ H2O in ethanol at 70 °C provided dimer
12 [4b] which was not isolated but converted directly in situ to cat-
alyst R,R-4 by its treatment with triethylamine in ethanol at 70 °C
for 3 h (overall 30% yield). Complexation of 9 with ruthenium tri-
chloride hydrate furnished the dimer 13, which was isolated in this
form. Dimers such as 13 are known to be converted to the Ru(II)
monomers in situ, under the reaction conditions employed for
the ketone reductions by ATH [4].
Scheme 1. Synthesis of catalyst R,R-4.
temperatures (ca. 40 °C). Substituted chloro-derivatives of aceto-
phenone were more reactive, being fully converted to the alcohols
at 28 °C with significant enantiomeric excesses (Table 1). In addi-
tion, two dialkylketones (20 and 21) were reduced with 4, however
the enantiomeric excesses were poor in both cases. The reversed
enantioselectivities for these reductions, relative to acetophenone
derivatives, suggest that (weaker) steric factors are directing the
reaction, rather than electronic ones.
2.1. Applications to ketone reduction
A range of ketones (14–24, the orientation of the diagrams
reflects the relative functional group positions in Table 1) were
reduced to alcohols using catalysts 4 and 5 and formic acid/trieth-
ylamine as both the solvent and the source of hydrogen. Catalyst 4
demonstrated a slower rate of ATH in formic acid/triethylamine
at 28 °C as compared to other tethered catalysts [4b], possibly
due to its bulky tethered structure. However, acetophenone and
a series of further ketones were fully reduced at slightly higher
Using complex 5, acetophenone 14 was fully reduced to 1-phe-
nyl ethanol in 92% enantiomeric excess (ee) within 10–12 h at
28 °C (Table 1) whereas reduction of acetylcyclohexane 20 using
0.5 mol% of this catalyst gives a product of 59% ee (S). Again this re-
flects the lower level of transition state organization when an aryl
ring is absent from the ketone substrate.

J.E.D. Martins et al. / Journal of Organometallic Chemistry 693 (2008) 3527–3532
3529
Table 1
Asymmetric ketone reduction using catalysts R,R-4 and R,R-5a
Catalyst
Ketone
T (°C)
Time (h)
Conversion (%)
ee (%)b
R/S
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
14
14
15
16
17
18
19
19
20
21
14
16
17
18
19
20
21
22
23
24
28
40
28
28
40
28
28
40
40
40
28
28
28
28
28
28
28
28
28
28
66
24
16
24
24
24
24
5
24
24
12
24
24
24
24
24
24
24
24
18
43
97
95
69
88
89
92
93
91
51
33
92
86
86
83
85
59
26
88
51
83
R
R
R
R
R
S
S
S
S
S
R
R
R
S
S
S
100
100
97
100
100
92
99
100
97
100
100
100
100
100
100
25
95
100
100
S
R
R
R
a
Reactions were carried out in a 2 M solution of ketone in a formic acid/trieth-
ylamine (5:2) azeotrope mixture, using catalyst loading = 0.5 mol%, S/C = 200 under
N2 atmosphere.
b
Determined by GC or HPLC: GC; cyclodextrin-b-236M-19, 50 m, HPLC: Chiracel
OD- 250 ꢁ 4.6 mm, mobile phase typically 90% hexane:10% IPA: 0.1% Et2NH; flow
rate: 0.7 mL/min.
time demonstrated that acetophenone has completely converted
to the product 1-phenylethanol (R > S enantiomer) in nearly 10 h.
The highly linear nature of the graph suggests zero-order kinetics
at the early stages of the reaction, i.e. the rate is relatively unsen-
sitive to the concentration of ketone. This suggests that the
rate-limiting step is the regeneration of the ‘Ru–H’ species in
the catalytic cycle, rather than the rate of hydrogen transfer from
the metal hydride to the substrate, as has been observed previously
for this class of tethered catalyst [4c]. The initial slow rate is also
observed when dimer precursors are employed as catalysts, and
reflects the conversion of dimer to monomer prior to reduction,
i.e. an induction period during catalyst formation [4d].
Scheme 2. Synthesis of catalyst R,R-5.
In addition to several of the same acetophenone derivatives as
were used with 4, we examined ketone 23, since its reduction
product is an intermediate in the synthesis of the Merck drug
aprepitant [8], and 24, a building block of the agricultural fungicide
MA-20565 [9]. Whilst both were fully converted to alcohols, 24
was reduced in good ee (but lower than that of similar ketones)
ketone 23 was reduced in rather poor yield. Other substituted ace-
tophenones gave higher enantioselectivities with full conversions.
The reaction of acetophenone 14 using catalyst 5 was studied by 1H
NMR spectroscopy (Fig. 2). A graph of conversion versus reaction
120
100
80
60
40
20
0
0
100
200
300
400
500
600
700
800
900
1000
Time/min
Fig. 2. Reaction/time profile for ATH of acetophenone by catalyst 5 followed by 1H NMR spectroscopy.

3530
J.E.D. Martins et al. / Journal of Organometallic Chemistry 693 (2008) 3527–3532
In conclusion, two new organometallic catalysts have been pre-
organic layer was dried over anhydrous MgSO4 and evaporated,
providing the crude product which was purified by silica gel col-
umn chromatography (0 ? 1% v/v ethyl acetate/pentane) to afford
pared and have demonstrated good activity in ATH of ketones
using formic acid/triethylamine as the solvent and hydrogen
source. Although neither gave an improved performance relative
to catalyst 3, they both represent effective catalysts for the
required application. The results for catalyst 5 suggest that cyclo-
hexyldiamine may be considered a reasonable viable alternative
to the more commonly employed trans-diphenyl (TsDPEN) system.
6 as a light yellow oil (0.47 g, 2.54 mmol, 71%). m :
max(neat)/cmꢂ1
3030, 2931, 2825, 2742, 1686, 1649, 1594, 1254, 1223, 1192,
992, 826, 760, 726, 693; 1H NMR (300 MHz; CDCl3): d 10.17 (s,
1H), 7.94–7.10 (m, 4H), 6.08 (m, 1H), 5.95 (m, 1H), 5.84 (d,
J = 5.7 Hz, 1H), 2.56 (m, 2H), 2.36 (m, 2H); 13C NMR (75 MHz;
CDCl3): d 192.3, 146.9, 133.9, 133.8, 133.4, 128.4, 128.0, 127.9,
127.1, 124.6, 28.3, 22.9; HRMS (ESI) m/z ((M+H)+) Calc. for
C13H13O: 185.0963. Found: 185.0961 (1.0 ppm error).
3. Experimental
3.1. General
3.5. Synthesis of N-[2-(2-cyclohexa-1,5-dienyl-benzylamino)-1R,2R-
diphenyl-ethyl]-4-methyl-benzenesulfonamide (8) [6]
General experimental conditions and instrumentation have
been previously reported [4d].
To a stirred solution of (1R,2R)-TsDPEN (0.55 g, 1.62 mol) and
molecular sieves (1 g) in dry methanol (20 mL), was added alde-
hyde 6 (0.30 g, 1.62 mmol) followed by 3 drops of glacial acetic
acid. The reaction was followed by TLC until the imine was formed
(3 h) and then sodium cyanoborohydride (0.37 g, 5.8 mmol) was
added and the reaction left to stir overnight at r.t. The molecular
sieves were filtered through filter paper and the solution was con-
centrated under reduced pressure. The residue was dissolved in
chloroform (15 mL), washed with saturated NaHCO3 solution
(15 mL) and then dried over anhydrous MgSO4. The solvent was re-
moved to give a crude solid which was purified by silica gel column
chromatography (0 ? 30% v/v ethyl acetate/hexane) to afford the
product 8 as a yellow solid (0.57 g, 1.02 mmol, 63%). m.p. 40–
3.2. Synthesis of 1-(2-diethoxymethyl-phenyl)-cyclohexen-2-ol (10)
[6]
2-Bromobenzaldehyde diethyl acetal (5.0 g, 1.93 mmol) in THF
was cooled to ꢂ78 °C and a solution of nBuLi in hexane (2.5 M,
8.40 mL, 0.021 mol) was added dropwise. After maintaining the
reaction at this temperature for 1 h, a solution of cyclohexen-2-
one (2.0 mL, 0.021 mol) was added dropwise. The reaction was al-
lowed to warm to r.t. and stirred for further 3 h. The reaction was
quenched by the addition of toluene (20 mL) and water (20 mL).
The organic layer was separated and washed with saturated brine
(20 mL) and then dried with anhydrous MgSO4. The solvent was re-
moved to give 10 (5.33 g, 1.78 mmol, 92%) as a light yellow oil.
42 °C; ½a 2D7
ꢃ
¼ ꢂ26 (c 0.97, CHCl3);
m
max(neat)/cmꢂ1: 3262, 3029,
2923, 2820, 1598, 1493, 1453, 1323, 1153, 1091, 925, 812, 756,
700; 1H NMR (300 MHz; CDCl3): d 7.36–6.91 (m, 18H), 6.18 (brs,
1H), 5.92 (m, 1H), 5.75 (m, 1H), 5.60 (d, J = 5.1 Hz, 1H), 4.28 (d,
J = 7.3 Hz, 1H), 3.67 (d, J = 7.3 Hz, 1H), 3.59 (d, J = 12.6 Hz, 1H),
3.40 (d, J = 12.6 Hz, 1H), 2.28 (s, 3H), 2.14 (m, 2H), 2.04 (m, 2H);
13C NMR (75 MHz; CDCl3) d 143.3, 142.6, 138.9, 138.5, 137.7,
137.0, 129.5, 129.1, 128.6, 128.4, 128.0, 127.6, 127.5, 127.4,
127.3, 127.2, 127.0, 136.2, 125.4, 124.8, 123.2, 67.3, 63.1, 49.1,
28.3, 23.0, 21.4; HRMS (ESI) m/z ((M+Na)+) Calc. for C34H34N2Na-
SO2: 557.2225. Found: 557.2238 (2.3 ppm error).
m
max(neat)/cmꢂ1: 3428, 2973, 2930, 2868, 1706, 1444, 1371,
1271, 1055, 1004, 750, 735; 1H NMR (300 MHz; CDCl3): d 7.80–
7.22 (m, 4H), 6.20 (s, 1 H), 5.98 (m, 1 H), 5.83 (d, 1 H, J = 10.0 Hz,
1H), 3.75–3.46 (m, 4H, m), 3.33 (s, 1H), 2.15–1.92 (m, 4H), 1.83
(m, 1H), 1.56 (m, 1H), 1.24 (t, J = 7.0 Hz, 1H), 1.21 (t, J = 7.1 Hz,
3H); 13C NMR (75 MHz; CDCl3) d 144.0, 136.0, 133.0, 128.5,
127.4, 127.1, 126.9, 126.5, 99.1, 61.9, 61.6, 38.3, 24.2, 18.5, 14.6;
HRMS (ESI) m/z ((M+Na)+) Calc. for C17H24NaO3; 299.1616. Found:
299.1611 (1.6 ppm error).
3.3. Synthesis of 1-cyclohexa-1,5-dienyl-2-diethoxymethyl-benzene
(11) [7]
3.6. Synthesis of N-{2-[(Biphenyl-2-ylmethyl)-amino]-1R,2R-
diphenyl-ethyl}-4-methyl-benzenesulfonamide chloro ruthenium
monomer (4) [4b]
2,4-Dinitrosulfenylchloride was added to a cooled solution
(0 °C) of alcohol 10 (2.5 g, 8.4 mmol) and triethylamine (2.9 mL,
36 mmol) in dichloromethane (40 mL). After 10 min, the reaction
was allowed to warm to r.t. and was stirred overnight. After 18 h,
pentane (20 mL) was added and the mixture was filtered and evap-
orated, providing 2.5 g of a black oil which was purified by silica
gel column chromatography (0 ? 2% v/v ethyl acetate/pentane)
to afford 11 as a light yellow oil (1.09 g, 3.87 mmol, 46%).
To a stirred solution of 8 (0.32 g, 0.57 mmol) in dichlorometh-
ane (10 mL) was added a 1 M solution of HCl in diethyl ether
(1.8 mL, 1.8 mmol). After stirring for 30 min, the solvent was re-
moved under vacuum. The resulting precipitate was dissolved in
ethanol (10 mL) and ruthenium trichloride trihydrate (0.12 g,
0.6 mmol) was added. The reaction mixture was heated at 70 °C
overnight to give 12 which was converted in situ in the monomer
4 by the addition of triethylamine (0.17 mL, 1.2 mmol) to the mix-
ture at 70 °C followed stirring at this temperature for a further 3 h.
The solvent was removed under reduced pressure and the residue
was washed with NaHCO3 solution (10 mL). The organic layer was
separated and dried over anhydrous MgSO4 providing the crude
monomer which was purified by fluorisil column chromatography
(1:1 v/v ethyl acetate/hexane and then 0 ? 20% v/v MeOH/dichlo-
romethane) to afford the pure monomer 4 as a black solid (0.107 g,
m
max(neat)/cmꢂ1: 3035, 2973, 2929, 2869, 1708, 1675, 1594,
1529, 1444, 1341, 1052, 760, 693; 1H NMR (300 MHz; CDCl3): d
7.68–7.12 (m, 4H), 6.06 (m, 1H), 5.88 (m, 2H), 5.55 (s, 1H), 3.63
(m, 2H), 3.46 (m, 2H), 2.45 (m, 2H), 2.32 (m, 2H), 1.21 (t,
J = 7.1 Hz, 6H); 13C NMR (75 MHz; CDCl3): d 142.6, 136.9, 136.0,
128.1, 128.0, 126.9, 125.4, 124.8, 123.7, 100.2, 62.0, 28.5, 23.1,
15.2; HRMS (ESI) m/a ((M+Na)+) Calc. for C17H22NaO2: 281.1509.
Found: 281.1512 (1.0 ppm error).
0.169 mmol, 30%). m.p. > 300 °C; ½a D27
¼ ꢂ633 (c 0.0012, CHCl3);
ꢃ
m
max(neat)/cmꢂ1: 3059, 3029, 2926, 2869, 1598, 1493, 1453,
3.4. Synthesis of 2-cyclohexa-1,5-dienyl-benzaldehyde (6)
1441, 1270, 1130, 1083, 1026, 937, 809, 748, 698, 661; 1H NMR
(400 MHz; CDCl3): d 7.65–6.35 (m, 18H), 6.10 (brs, 1H), 6.04 (brs,
1H) 5.16 (brs, 1H), 5.10 (brs, 1H), 4.93 (d, J = 10.8 Hz, 1H), 4.72
(d, J = 13.3 Hz, 1H), 4.08 (d, J = 10.5 Hz, 1H), 3.84 (d, J = 13.4 Hz,
1H), 3.29 (brt, J = 11.4 Hz, 1H), 2.20 (s, 3H); 13C NMR (75 MHz;
Acetal 11 (1.0 g, 3.56 mmol) was dissolved in THF (20 mL), a 1%
HCl solution (10 mL) was added and the reaction was stirred over-
night at r.t. After 18 h, aq. NaHCO3 (10 mL) was added and the or-
ganic phase was extracted with diethylether (3 ꢁ 20 mL). The

J.E.D. Martins et al. / Journal of Organometallic Chemistry 693 (2008) 3527–3532
3531
CDCl3): d 141.6, 139.2, 138.1, 135.0, 133.4, 132.5, 131.4, 129.8,
3.10. Analysis of asymmetric reduction products
129.6, 129.2, 128.5, 128.4, 127.7, 127.0, 126.6, 126.1, 96.6, 78.8,
76.0, 68.7, 53.2, 21.0. HRMS (ESI) m/z ((MꢂCl)+) Calc. for
C34H31N2SO2Ru: 633.1139. Found: 633.1124 (2.3 ppm error).
1-Phenylethanol: Enantiomeric excess was determined by GC
analysis (Chrompac cyclodextrin-b-236M-19, 50 m, T = 115 °C,
P = 15 psi, ketone 9.1 min, R isomer 13.3 min, S isomer 14.1 min);
3.7. Synthesis of N-[(1R,2R)-2-(3-cyclohexa-1,4-
dienyl)propylamino)cyclohexyl]-4-methylbenzenesulfonamide (9)
½
a 2D2
ꢃ
¼ þ49:0 (c 1.0 in CHCl3) 95% ee (R) (cat 4) (lit. [10]
½
a 2D3
ꢃ
¼ þ48:6 (c 1.0 in CH2Cl2); 96% ee (R)); 1H NMR (300 MHz;
CDCl3; Me4Si): d 1.47 (d, J = 6.4 Hz, 3H), 2.04 (brs, 1H), 4.86 (q,
J = 6.4 Hz), 7.33–7.35 (m, 5 H).
To a suspension of 4Å molecular sieves (1.0 g) in dichlorometh-
ane (15 cm3), aldehyde 7 (0.650 g, 4.78 mmol) followed by R,R-
TsDAC (1.41 g, 5.25 mmol) was added. The reaction mixture was
stirred overnight, filtered, concentrated under vacuum and dis-
solved in anhydrous CH3OH (15 mL) to which sodium cyanoboro-
hydride (0.600 g, 9.55 mmol) was added slowly with stirring.
Glacial acetic acid (0.5 mL) was added and the reaction was stir-
red overnight, filtered, and the solvent was removed under re-
duced pressure. The residue was purified by flash column
chromatography to give 9 (0.629 g, 1.61 mmol, 34%) as viscous
pale yellow oil. (Anal. Calc. for C22H32N2O2S: C, 68.0; H, 8.3; N,
1-(20-Chlorophenyl)ethanol: Enantiomeric excess was deter-
mined by GC analysis (Chrompac cyclodextrin-b-236M-19, 50 m,
T = 150 °C, P = 10 psi, ketone 6.4 min, R isomer 11.2 min, S isomer
12.1 min); 69% ee (R) (cat 4) (lit. [11] ½a D20
¼ þ41 (c 1.0 in CHCl3)
ꢃ
67% ee (R); 1H NMR (400 MHz; CDCl3): d 7.56 (dd, J = 7.8 and
1.8 Hz, 1H), 7.32–7.25 (m, 2H), 7.18 (td, J = 7.7 and 1.8 Hz, 1H),
5.26 (dq, J = 6.3 and 2.8 Hz, 1H), 2.33 (brd, J = 3.0 Hz, 1H), 1.46 (d,
J = 6.5 Hz, 3H).
1-(30-Chlorophenyl)ethanol: Enantiomeric excess was deter-
mined by GC analysis (Chrompac cyclodextrin-b-236M-19, 50 m,
T = 150 °C, P = 10 psi, ketone 11.1 min, R isomer 16.4 min, S isomer
7.21. Found: C, 68.5; H, 8.6; N, 6.7%; ½a D20
¼ þ35:9 (c 0.5 in CHCl3);
ꢃ
m
max/cmꢂ1 (viscous solid): 3151, 1329, 1158, 817, 660; 1H NMR
16.9 min); 88% ee (R) (cat 4) (lit. [6] ½a D24
¼ þ38:2 (c 0.9 in CHCl3)
ꢃ
(400 MHz, CDCl3; Me4Si): d 7.85–7.75 (d, J = 12 Hz, 2H), 7.30–
7.25 (d, J = 12 Hz, 2H), 5.70–5.90 (brs, 2H, brs), 5.70 (brs, 2H),
5.35 (brs, 1H), 2.80–3.10 (m, 2H), 3.60–3.50 (m, 2H), 2.40–2.30
(m, 2H), 2.10–1.10 (m, 14H), 2.35 (s, 3H); 13C NMR (100.6 MHz,
CDCl3; Me4Si): d 21.6, 23.5, 24.2, 26.4, 26.7, 28.6, 31.2, 34.1,
44.4, 54.3, 60.9, 77.1, 119.9, 124.0, 126.4, 127.3, 128.6, 130.3,
132.3, 136.3, 144.6. MS m/z (LSIMS): 389 (MH+, 100%), 154 (40%).
HRMS (LSIMS) m/z ((M+H)+) Calc. for C22H33N2O2S 389.22. Found:
389.227.
96% ee (R); 1H NMR (400 MHz; CDCl3): d 7.36 (brs, 1H), 7.30–
7.20 (m, 3H), 4.85 (q, J = 6.4 Hz, 1H), 2.15 (brs, 1H), 1.46 (d,
J = 6.4 Hz, 3H).
1-(40-Chlorophenyl)ethanol: Enantiomeric excess was deter-
mined by GC analysis (Chrompac cyclodextrin-b-236M-19, 50 m,
T = 150 °C, P = 10 psi, ketone 11.5 min, R isomer 16.5 min, S isomer
17.1 min); 89% ee (R) (cat 4) (lit. [6] ½a D29
¼ þ52:6 (c 0.56 in Et2O)
ꢃ
95% ee (R); 1H NMR (400 MHz; CDCl3): d 7.29 (dd, J = 5.3 and
3.0 Hz, 4H), 4.85 (brs, 1H), 7.30–7.20 (m, 3H), 4.85 (q, J = 6.5 Hz,
1H), 2.11 (brs, 1H), 1.5 (d, J = 6.5 Hz, 3H).
3.8. Synthesis of N-[(1R,2R)-2-(3-cyclohexa-1,4-
dienyl)propylamino)cyclohexyl]-4-methylbenzenesulfonamide
ammonium chloride ruthenium dimer (13)
2-Chloro-1-phenylethanol: Enantiomeric excess was determined
by GC analysis (Chrompac cyclodextrin-b-236M-19, 50 m,
T = 140 °C, P = 10 psi, ketone 20.6 min, S isomer 24.9 min, R isomer
25.8 min); 83% ee (S) (cat 5) (lit. [12] ½a D25
¼ ꢂ47:5 (c 1.7 in cyclo-
ꢃ
To a stirred solution of 9 (0.357 g, 0.92 mmol) in dichloro-
methane (10 cm3) was added a 1 M solution of HCl in diethyl
ether (3 cm3, 3.00 mmol). After stirring for 30 min, the solvent
was removed from the resulting precipitate under vacuum,
dissolved in ethanol (20 cm3) and ruthenium trichloride trihydrate
(0.179 g, 0.69 mmol) was added. The reaction mixture was heated
at 70 °C overnight and then cooled to r.t. The precipitate was
collected by filtration and washed with ethanol (5 ꢁ 10 mL) to
give 13 (0.230 g, 0.21 mmol, 45%) as a dark green powder;
hexane); 96% ee (R), >99% yield, 1H NMR (400 MHz; CDCl3): d 7.37–
7.39 (m, 5H), 4.87 (dd, J = 3.5, 8.8 Hz, 1H), 3.72 (dd, J = 3.5, 11.2 Hz,
1H), 3.62 (dd, J = 8.8, 11.2, 1H), 2.77 (brs, 1H).
1-Cyclohexyl-ethanol: Enantiomeric excess was determined by
GC analysis (Chrompac cyclodextrin-b-236M-19, 50 m, T = 92 °C,
P = 9 psi, ketone 25.4 min, R isomer 40.5 min, S isomer 41.1 min);
59% ee (S) (cat 5) (lit. [13,4b] [a]D = +3.51 (c 3.1 in CHCl3) 95% ee
(S)); 1H NMR (400 MHz; CDCl3; Me4Si): d 3.54 (dt, J = 6.5, 6.3 Hz,
1H), 1.63–1.88 (m, 5H), 1.46 (brs, 1H), 1.15 (d, J = 6.3 Hz, 3H),
0.92–1.32 (m, 6H).
decomposition temperature >250 °C. ½a D20
¼ ꢂ134:7 (c 0.0125 in
ꢃ
DMSO);
m
max/cmꢂ1 (solid) 2942, 1448, 1325, 1158, 772, 666; 1H
3,3-Dimethylbutan-2-ol: Enantiomeric excess was determined
by GC analysis (Chrompac cyclodextrin-b-236M-19, 50 m,
T = 80 °C, P = 7 psi, ketone 5.5 min, S isomer 8.7 min, R isomer
NMR (400 MHz, DMSO-d6): d 9.66 (brs, 1H), 9.55 (brs, 1H),
8.66–8.56 (brs, 1H), 7.25–7.92 (m, 4H), 6.04–5.83 (m, 5H), 3.58–
3.43 (m, 2H), 2.52–2.41 (m, 4H), 2.37 (s, 3H), 1.44–1.04 (m, 10H);
13C NMR (100.4 MHz, DMSO-d6): d 21.1, 23.6, 23.0, 30.8, 39.5,
52.8, 83.7, 85.2, 85.4, 85.6, 88.7, 88.9, 106.0, 126.6, 128.4, 128.5,
129.9, 138.4, 138.3, 143.1. MS (LSIMS) m/z 523.07 (monomeric
species formed in situ+, 100%). 102RuC22H29N2O2S35Cl requires
522.07.
8.9 min); 33% ee (S) (cat 4) (lit. [14] [
a
]
29 = ꢂ43.0 (c 1.5 in CCl4)
D
99% ee (R)); 1H NMR (400 MHz; CDCl3; Me4Si): d 3.52–3.44 (m,
1H). 7.37–7.39 (m, 5H), 4.87 (dd, J = 3.5, 8.8 Hz, 1H), 3.72 (dd,
J = 3.5, 11.2 Hz, 1H), 3.62 (dd, J = 8.8, 11.2, 1H), 2.77 (brs, 1H),
1.58–1.82 (brs, 1H), 1.12 (d, J = 6.5 Hz, 3H), 0.89 (s, 9H).
2-Phenoxy-1-phenylethanol: Enantiomeric excess by HPLC was
determined by 1H NMR (Chiracel HPLC OD: 250 x 4.6 mm, mobile
phase = 90% Hexane: 10% IPA: 0.1% Et2NH, Flow rate: 0.7 mL/min,
ketone 29.6 min, S isomer 38.2 min, R isomer 19.9 min) 93% ee
3.9. Reduction of ketones using tethered R,R Ru(II) catalysts 4 and 5
A solution of ruthenium monomer 4 (0.0104 mmol) or dimer 13
(0.0052 mmol) in formic acid: triethylamine 5:2 azeotrope
(2.08 mL) was stirred in a flame dried Schlenk tube at 28 °C for
1 h. Ketone substrate (4.16 mmol; S/C (monomer) = 200) was
added and the reaction mixture was stirred at 28 °C for 24 h. The
reaction mixture was filtered (silica), washed with 40% EtOAc/hex-
ane and concentrated under vacuum to give the reduction product.
The residue was purified by flash column chromatography on silica
gel.
(S) (cat 4) (lit. [15a] ½a D20
¼ ꢂ27:0 (c 2.0, CHCl3) 72% yield. (R), lit.
ꢃ
[15b] a 2D3
ꢃ
¼ þ23:0 (c 0.81, CH2Cl2) 97% ee (S), 1H NMR (400 MHz;
CDCl3): d 7.46–7.25 (m, 7H), 6.99–6.91 (m, 3H), 5.12 (dd, J = 3.2,
8.8 Hz, 1H), 2.77 (brs, 1H).
1-(3-Methoxyphenyl)ethanol: Enantiomeric excess was deter-
mined determined by GC analysis (Chrompac cyclodextrin-b-
236M-19, 50 m, T = 140 °C, P = 15 psi, ketone 13.3 min, R isomer
18.2 min, S isomer 18.9 min); 88% ee (R) (cat 5) ½a D22
¼ þ32:9 (c
ꢃ
0.75 in MeOH) 97% ee (R) (lit. [16] ½a D21
¼ ꢂ34:9 (c 0.849 in MeOH)
ꢃ

3532
J.E.D. Martins et al. / Journal of Organometallic Chemistry 693 (2008) 3527–3532
>99% ee, 90% Conv. (S)); 1 H NMR (400 MHz; CDCl3): d 7.26 (dd,
J = 8.0, 8.0 Hz, 1H), 6.96–6.92 (m, 2H), 6.83–6.79 (m, 1H), 4.86 (q,
J = 6.4, 1H), 3.81 (s, 3H), 1.94 (brs, 1 H), 1.48 (d, J = 6.5 Hz, 3H).
1-(3,5-bis-Trifluoromethylphenyl)ethanol: Enantiomeric excess
was determined determined by GC analysis (Chrompac cyclodex-
trin-b-236M-19, 50 m, T = 110 °C, P = 8 psi, ketone 9.3 min, R iso-
(h) N. Dahlin, A. Bogevig, H. Adolfsson, Adv. Synth. Catal. 346 (2004) 1101;
(i) K. Matsumura, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 119
(1997) 8738;
(j) D.M. Tellers, M. Bio, Z.J. Song, J.C. McWilliams, Y. Sun, Tetrahedron:
Asymmetr. 17 (2006) 550.
[3] (a) M. Yamakawa, I. Yamada, R. Noyori, Angew. Chem., Int. Ed. 40 (2001)
2818;
(b) R. Noyori, M. Yamakawa, S. Hashiguchi, J. Org. Chem. 66 (2001) 7931;
(c) M. Yamakawa, H. Ito, R. Noyori, J. Am. Chem. Soc. 122 (2000) 1466;
(d) D.A. Alonso, P. Brandt, S.J.M. Nordin, P.G. Andersson, J. Am. Chem. Soc. 121
(1999) 9580;
(e) P. Brandt, P. Roth, P.G. Andersson, J. Org. Chem. 69 (2004) 4885;
(f) A. Taskinen, V. Nieminen, E. Tonkonitty, D.Y. Murzin, M. Hottokka,
Tetrahedron 61 (2005) 8109;
mer 27.7 min, S isomer 29.8 min); 51% ee (R) (cat 5) ½a D22
¼ ꢂ24
ꢃ
(c 1.00 in CH3OH), (lit. [8a] ½a D22
¼ þ16 (c 1.204 in CHCl3) 99% ee
ꢃ
(R)).
1-(3-Trifluoromethylphenyl)ethanol: Enantiomeric excess was
determined determined by GC analysis (Chrompac cyclodextrin-
b-236M-19, 50 m, T = 120 °C, P = 10 psi, ketone 10.0 min, R isomer
(g) M. Zanfir, X. Sun, A. Gravriilidis, Chem. Eng. Sci. 62 (2007) 741.
[4] (a) J. Hannedouche, G.J. Clarkson, M. Wills, J. Am. Chem. Soc. 126 (2004)
986;
20.2 min, S isomer 21.5 min); 83% ee (R) (cat 5) ½a D22
¼ þ28:4 (c
ꢃ
1.26 in CH3OH), (lit. [6] ½a D22
¼ þ27:1 (c 1.60 in CH3OH) 96% ee (R)).
ꢃ
(b) A.M. Hayes, D.J. Morris, G.J. Clarkson, M. Wills, J. Am. Chem. Soc. 127 (2005)
7318;
(c) F.K. Cheung, C. Lin, F. Minissi, A. Lorente Crivillé, M.A. Graham, D.J. Fox, M.
Wills, Org. Lett. 9 (2007) 4659;
Acknowledgements
(d) D.J. Morris, A.M. Hayes, M. Wills, J. Org. Chem. 71 (2006) 7035.
[5] (a) K. Püntener, L. Schwink, P. Knochel, Tetrahedron Lett. 37 (1996) 8165;
(b) X. Xu, D. Vinci, T. Ikariya, J. Xiao, Chem. Commun. (2005) 447;
(c) J. Canivet, G. Labat, H. Stoeckli-Evans, G. Suss-Fink, Eur. J. Inorg. Chem.
(2005) 4493;
We thank the EPSRC (postdoctoral funding for DJM and JEDM)
and the Daphne Jackson Trust (Postdoctoral funding for BT) for
generous financial support of this project. We thank the EPSRC
Mass Spectrometry Service (Swansea) for analysis of certain li-
gands and intermediates and the use of the EPSRC Chemical Data-
base Service at Daresbury [17].
(d) X. Li, J. Blacker, I. Houson, X. Wu, J. Xiao, Synlett (2006) 1155;
(e) X. Wu, X. Li, A. Zanotti-Gerosa, A. Pettman, J. Liu, A.J. Mills, J. Xiao, Chem.
Eur. J. 14 (2008) 2209.
[6] D.S. Matharu, D.J. Morris, A.M. Kawamoto, G.J. Clarkson, M. Wills, Org. Lett. 7
(2005) 5489.
[7] H.J. Reich, S. Wollowitz, J. Am. Chem. Soc. 104 (1982) 7051.
[8] (a) R.P. Singh, B. Twamley, L. Fabry-Asztalos, D.S. Matteson, J.M. Shreeve, J.
Org. Chem. 65 (2000) 8123;
References
(b) K.B. Hansen, J.R. Chilenski, R. Desmond, P.N. Devine, E.J.J. Grabowski, R.
Heid, M. Kubryk, D.J. Mathre, R. Versolona, Tetrahedron: Asymmetr. 14 (2003)
3581.
[1] (a) M.J. Palmer, M. Wills, Tetrahedron: Asymmetr. 10 (1999) 2045;
(b) R. Noyori, S. Hashiguchi, Acc. Chem. Res. 30 (1997) 97;
(c) S.E. Clapham, A. Hadzovic, R.H. Morris, Coord. Chem. Rev. 248 (2004) 2201;
(d) S. Gladiali, E. Alberico, Chem. Soc. Rev. 35 (2006) 226;
(e) T. Ikariya, K. Murata, R. Noyori, Org. Biomol. Chem. 4 (2006) 393;
(f) G. Zassinovich, G. Mestroni, S. Gladiali, Chem. Rev. 92 (1992) 1051;
(g) T. Ikariya, A.J. Blacker, Acc. Chem. Res. 40 (2007) 1300.
[2] (a) S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya, R. Noyori, J. Am. Chem. Soc.
117 (1995) 7562;
[9] K. Tanaka, M. Katsurada, F. Ohno, Y. Shiga, M. Oda, M. Miyagi, J. Takehara, K.
Okano, J. Org. Chem. 65 (2000) 432.
[10] T. Hayashi, Y. Matsumoto, Y. Ito, Tetrahedron: Asymmetr. 2 (1991) 601.
[11] E.F.J. De Vries, J. Brussee, C.G. Kruse, A. Van der Gen, Tetrahedron: Asymmetr. 5
(1994) 377.
[12] T. Ohkuma, K. Tsutsumi, N. Utsumi, N. Arai, R. Noyori, K. Murata, Org. Lett. 9
(2007) 255.
[13] G. Li, G.W. Kabalka, J. Organomet. Chem. 581 (1999) 66.
[14] T. Imai, T. Tamura, A. Yamamuro, T. Sato, T.A. Wollmann, R.M. Kennedy, S.
Masamune, J. Am. Chem. Soc. 108 (1986) 7402.
[15] (a) G.C. Franchini, A. Carocci, A. Catalano, M.A. Cavalluzzi, F. Corbo, G. Lentini,
A. Scilimati, P. Tortorella, D.C. Camerino, A. De Luca, J. Med. Chem. 46 (2003)
5238;
(b) J.M. Ready, E.N. Jacobsen, J. Am. Chem. Soc. 123 (2001) 2687.
[16] K. Nakamura, T. Matsuda, J. Org. Chem. 63 (1998) 8957.
[17] D.A. Fletcher, R.F. McMeeking, D. Parkin, J. Chem. Inf. Comput. Sci. 36 (1996)
746.
(b) A. Fujii, S. Hashiguchi, N. Uematsu, T. Ikariya, R. Noyori, J. Am. Chem. Soc.
118 (1996) 2521;
(c) K. Matsumura, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 119
(1997) 8738;
(d) K. Murata, K. Okano, M. Miyagi, H. Iwane, R. Noyori, T. Ikariya, Org. Lett. 1
(1999) 1119;
(e) K.J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya, R. Noyori, Angew. Chem., Int.
Ed. 36 (1997) 285;
(f) S. Hashiguchi, A. Fujii, K.-J. Haack, K. Matsumura, T. Ikariya, R. Noyori,
Angew. Chem., Int. Ed. Engl. 36 (1997) 288;
(g) D. Šterk, M.S. Stephan, B. Mohar, Tetrahedron Lett. 45 (2004) 535;