Mixed donor aminophosphine oxide ligands in ruthenium-catalysed asymmetric transfer hydrogenation reactions

Article abstract of DOI:10.1016/j.tetasy.2004.05.001

A number of mixed-donor aminophosphine ligands have been prepared and their activity and selectivity in asymmetric transfer hydrogenation reactions assessed. Enantioselectivities up to 93% and 80% were achieved for the reduction of acetophenone and propiophenone, respectively.

Full text of DOI:10.1016/j.tetasy.2004.05.001

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1835–1840
Mixed donor aminophosphine oxide ligands in ruthenium-catalysed
asymmetric transfer hydrogenation reactions
Mohammed S. Rahman, Marco Oliana and King Kuok (Mimi) Hii*
Department of Chemistry, King’s College London, Strand, London WC2R 2LS, UK
Received 22 February 2004; revised 13 May 2004; accepted 13 May 2004
Available online 4 June 2004
Abstract—A number of mixed-donor aminophosphine ligands have been prepared and their activity and selectivity in asymmetric
transfer hydrogenation reactions assessed. Enantioselectivities up to 93% and 80% were achieved for the reduction of acetophenone
and propiophenone, respectively.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
rality. The resultant aminophosphine hybrid (PNH)
ligands were subsequently assessed as ligands in ruthe-
nium-catalysed transfer hydrogenation of unsymmetri-
cal alkyl aryl ketones.
Over the last few years, we have been actively engaged in
developing novel nitrogen–phosphorus ligands for
catalytic processes.1–6 Previously, we reported the syn-
thesis and coordination chemistry of a class of amino-
phosphine (PNH) 1 and diphosphine (PNP) 2 ligands
to ruthenium complexes.3;7 In the ensuing catalytic
reduction of ketones, we observed that the PNH ligands
1 promoted higher catalytic activity than the PNP
ligands 2, and the activity of both classes of ligands is
dependent on the nature of the nitrogen substituent (R)
(Fig. 1).
2. Preparation of ligands
Six optically active primary amines were chosen for this
part of our investigation: (R)-sec-butylamine, (S)-1-
phenylethylamine, (S)-1-indan-amine, (R)-1,2,3,4-tetra-
hydronaphthylamine, (1R,2R)-cyclohexane diamine (to
give a PNNP ligand) and, guided by the success of
aminoalcohol ligands in this class of reactions, (1R,2S)-
norephedrine.
Herein, we report a class of optically active PNH com-
pounds, employing chiral amines as the source of chi-
The addition of optically active 1-phenylethylamine to
vinyldiphenylphosphine was previously achieved by
prolonged heating in toluene (48 h).8 However,
employing a procedure developed in our laboratory,
the ligands were prepared in a comparative short period
of time.7 By heating a slight excess of the Michael
acceptor (vinyldiphenylphosphine oxide) with the req-
uisite amine in methanol, aminophosphine oxides may
be obtained in typically 3–6 h. Subsequent acid/base
work-up, followed by recrystallisation from methylcy-
clohexane, furnished the aminophosphine oxides 3a–f in
good to excellent yields (>80%). These aminophosphine
oxides were then reduced in a basic trichlorosilane
solution to give the phosphorus(III) analogues 4a–f
(Scheme 1).
Figure 1.
* Corresponding author at present address: Department of Chemistry,
Imperial College London, South Kensington, London SW7 2AZ,
UK. Tel.: +44-20-7594-1142; fax: +44-20-7594-5804; e-mail: mimi.hii@
imperial.ac.uk
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.05.001

1836
M. S. Rahman et al. / Tetrahedron: Asymmetry 15 (2004) 1835–1840
Table 1. Effect of substrate and base concentration and reaction
temperaturea
Entry
S:Cb
B:Cc
T/°C
%Conversiond %Ee (R/S)e
1
2
3
4
5
6
7
8
9
250:1
250:1
250:1
250:1
100:1
100:1
100:1
100:1
100:1
15:1
15:1
15:1
15:1
15:1
8.5:1
5:1
60
50
40
29
29
29
29
29
29
89
83
80
70
89
73
62
10
0
26 (R)
26 (R)
28 (R)
28 (R)
30 (R)
32 (R)
33 (R)
32 (R)
— (ꢀ)
2.5:1
0:1
a Typical catalytic run carried out with 0.18M of acetophenone with
1:1 metal-to-ligand ratio for 2 h.
b Substrate:catalyst ratio.
c Base:catalyst ratio.
d Monitored by 1H NMR.
e Determined by chiral HPLC.
3.2. Substrate concentration and metal-to-ligand ratio
Dilution effects have been reported to be important as it
affects the ketone–alcohol equilibrium.11 Thus, the
reaction was repeated at different dilutions, from 180 to
25 mM (Fig. 2). The optimal concentration (90 mM of
acetophenone in isopropanol) was accompanied by a
concomitant improvement of the enantioselectivity to
36%. Further dilutions led to erosion of both these
values.
Scheme 1. Preparation of chiral PNH ligands.
3. Optimisation of catalytic conditions
3.1. Reaction temperature and catalyst/base ratios
Guided by our previous work,9 the catalytic precursor
was generated by heating to reflux a mixture of [RuCl2
(p-cymene)]2 and the required ligand in isopropanol for
30 min (Scheme 2).
100
80
60
40
20
Scheme 2. Reaction condition optimisation.
0
0.025 0.05 0.07 0.09 0.11 0.18
[Acetophenone]/M
In order to establish optimal catalytic protocols, several
reaction conditions known to affect the outcome of
hydrogenation reactions were examined using ligand 4b,
including: temperature, catalytic loading, catalyst/ligand
ratios and concentration effects (Table 1).10
%ee %conversion
Figure 2. Effect of dilution on conversion and enantioselectivity.
Lowering the temperature from 60 to 29 °C led to a
decrease in catalyst activity with no significant change in
enantioselectivity (Table 1, entries 1–4). At temperatures
lower than 25 °C, the conversions were dramatically
reduced (less than 50%).
Containing potentially hemilabile donor groups, it is
possible that more than one ligand may coordinate to
the metal centre, generating different catalytic active
species.5 The effect of metal-to-ligand ratio was thus
investigated (Table 2).12
Increasing the catalytic loading from 0.4 to 1 mol % led to
an expected increased conversion and a slight improve-
ment in the selectivity (entry 5). Meanwhile, lowering the
amount of KOH led to a slight improvement of the ee
value at the expense of conversion (entries 5–8). In the
absence of the base co-catalyst, the reaction showed no
conversion (entry 9). The optimal base-to-catalyst ratio
(for the highest ee) was thus found to be 5:1.
Between 0.5 and 4 equiv of ligand were employed in this
study. Sub-stoichiometric amounts of ligand led to a
dramatic decrease in activity and selectivity of the
reaction (entry 1). When the ratio was increased to 2:1,
the conversion decreased, although there was no change
in enantioselectivity (entry 3). This implies that the
catalytic active species involves the binding of just one
ligand per metal. Rather interestingly, the ee increased

M. S. Rahman et al. / Tetrahedron: Asymmetry 15 (2004) 1835–1840
1837
Table 2. Catalytic reaction optimisationa
89%) than the corresponding b-aminophosphine oxides
3 (7–62%) but the enantioselectivities were better with
the latter. Interestingly, the stereoinduction remained
the same, regardless of the oxidation state of the phos-
phorus donor.
Entry
Ligand-to-metal
ratio
%Conversionb
%Eec
1
2
3
4
0.5/1
1/1
26
66
29
24
26
36
36
41
2/1
4/1
By incorporation of an added donor group (OH), nor-
ephedrine-derived ligands 3f and 4f proved to be unique
in this study, affording superior conversions and ee
values (entries 11, 12, 23 and 24). The aminophosphine
oxide 3f afforded comparable, if not better conversions
than the aminophosphine 4f. The reduction of aceto-
phenone employing ligand 3f achieved excellent con-
version and ee (95% and 93% ee, respectively, entry 11),
compared to using the phosphorus(III) analogue (83%
conversion, 79% ee, entry 23). Equally, propiophenone
was reduced with higher enantiomeric excess in the
presence of the phosphorus(V) compound 3f (80% ee,
entry 12) compared to 4f (75% ee, entry 24), although
conversions were the same in these cases.
a Reaction runs were carried out with 0.5 mol % of the catalyst, 5 mol %
of KOH and 90 mM of acetophenone at 29 °C for1 h.
b Monitored by 1H NMR.
c Determined by chiral HPLC, the (R)-configuration predominated in
all cases.
to 41% when 4 equiv of ligand was employed, but the
corresponding conversion was low (entry 4).
4. Catalytic activity of ligands 3 and 4
Using the optimal conditions established in the above
studies, both aminophosphines and their oxides 3 and 4
were evaluated in the asymmetric reduction of ace-
tophenone and propiophenone (Scheme 2, Table 3).
It will perhaps be reasonable to postulate, at this junc-
ture, that the phosphorus moiety is not involved in the
catalytic process, since amino alcohols are known to be
excellent ligands in these reductions.13 However, this
appears not to be the case, as (ꢀ)-norephedrine induced
only 55% ee under these reaction conditions (entry 25),
that is, the phosphorus moiety played an important role
in the degree of enantioselection.
Table 3. Catalytic asymmetric transfer hydrogenation reactionsa
Entry
R
Ligand
%Conversionb %Eec (R/S)
1
CH3
CH2CH3
CH3
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
3f
20
15
62
59
13
13
48
29
7
8 (S)
0 (ꢀ)
2
3
32 (R)
43 (R)
22 (R)
15 (R)
26 (R)
45 (R)
19 (R)
18 (R)
93 (R)
80 (R)
Previously, Pietrusiewicz and co-workers reported that
b-amino diphenylphosphine oxides induced low con-
versions and enantioselectivities in transfer hydrogena-
tion of ketones and the activity and selectivity of these
ligands may be improved by increasing the steric bulk
(and introducing an extra stereogenic element) at the
phosphorus donor.14
4
CH2CH3
CH3
5
6
CH2CH3
CH3
7
8
CH2CH3
CH3
9
10
11
12
CH2CH3
CH3
CH2CH3
7
95
84
3f
In the present work, we have demonstrated that the
performance of b-amino diphenylphosphine oxide
ligands in these reactions may also be improved dra-
matically by the introduction of an additional OH group
and an extra carbon centred chirality. Since amino
alcohols are much more available than chirogenic
phosphorus compounds, structural variations will be
much easier to introduce. Further development of these
PNO ligands, involving the introduction of chirogenic
phosphorus donor groups, suggests that the phosphine
oxide moiety is intimately involved in the catalyst
activity and stereoselectivity. This work will be reported
in due course.
13
14
15
16
17
18
19
20
21
22
23
24
25
CH3
CH2CH3
CH3
4a
4a
30
10
89
63
60
51
95
87
24
7
3 (S)
0 (ꢀ)
4b
4b
36 (R)
43 (R)
16 (R)
5 (R)
CH2CH3
CH3
4c
4c
CH2CH3
CH3
4d
4d
9 (R)
CH2CH3
CH3
21 (R)
16 (R)
19 (R)
79 (R)
75 (R)
55 (R)
4e
4e
CH2CH3
CH3
4f
4f
83
84
95
CH2CH3
CH3
(ꢀ)-Ephedrine
a Reaction conditions: [RuCl2(p-cymene)]2 (0.5 mol %), ligand
(1 mol %), 0.09 M of the appropriate ketone in isopropanol, KOH
(5 mol %) at 29 °C for 2 h.
5. Experimental
b Determined by 1H NMR.
c Determined by chiral HPLC.
5.1. General procedure
Overall, ligands derived from chiral amines exhibited
low enantioselectivity in the reduction of unsymmetrical
ketones (entries 1–10, 13–22), with values no more than
36% for the reduction of acetophenone (with ligand 3b,
entry 15) and 45% (with ligand 3d, entry 8). Generally,
the b-aminophosphines 4 induce higher conversions (24–
The apparatus and general techniques were the same as
in other recent papers from this laboratory.3 (SP)-(tert-
butylphenylphosphinoyl)acetic acid (SP)-4.19, (RP)-
(tert-butylphenylphosphinoyl)acetic acid (RP)-4.1915
and [RuCl2(g6-p-MeC6H4CHMe2)]2
following reported procedures. Unless otherwise stated,
were prepared
16

1838
M. S. Rahman et al. / Tetrahedron: Asymmetry 15 (2004) 1835–1840
all other reagents were procured from Avocado, Lan-
caster or Aldrich chemical companies and used as re-
ceived. A Gilson system equipped with a manual
injector was used for HPLC analysis. Detection was
made by UV absorption at 254 nm.
2H), 2.66–2.69 (m, 1H), 2.84–2.86 (m, 1H), 2.94–3.17
(m, 2H), 4.11 (t, 1H, J ¼ 6:6 Hz), 6.97–7.69 (m, 14H).
31P NMR (161 MHz, CDCl3) d: þ34.1. 13C NMR
(125 MHz, CDCl3) d: þ30.7 (d, JPC ¼ 71 Hz), 31.4, 33.7,
40.9 (d, JPC ¼ 2 Hz) 63.5, 124.5–145.0 (aromatic). IR
(cmꢀ1, KBr disc) m: 1185 (P@O), 3270 (N–H). HRMS
(FAB): exact mass calcd for C23H25NOP (MHþ)
362.1674. Found 362.1684.
5.2. Ligand synthesis
5.2.1. General procedure for the preparation of chiral
aminophosphine oxides 3. The appropriate chiral amine
(2.1 mmol) was added to a slight excess of vinyldiphenyl-
phosphine oxide (0.5 g, 2.2 mmol) in methanol (1 mL)
and the reaction mixture was heated at 65 °C in a sealed
tube. After the appropriate reaction time (31P NMR) the
solvent was removed under reduced pressure. The resi-
due was dissolved in diethyl ether and acidified using
2 N HCl (pH ꢁ 2). The aqueous layer was washed with
diethyl ether (50 mL). The aminophosphine oxides were
recovered by cooling the aqueous layer to 0 °C and
basifying it to ꢁpH 10 by the addition of NaOH pellets.
The compound was extracted into dichloromethane
(3 ꢂ 50 mL). The combined organic extracts were dried
over MgSO4, filtered and the filtrate evaporated in
vacuo to leave the required compound as a white solid,
which was recrystallised from methylcyclohexane to
yield analytically pure samples.
5.2.1.4.
[2-(Diphenylphosphinoyl)-ethyl]-(R)-1,2,3,4-
20
tetrahydronaphthylamine 3d. Yield: 91%. ½aꢃ þ 2:3 (c 1,
D
CHCl3). Mp: 105–107 °C. Anal. Calcd for C24H26NOP:
C, 76.78; H, 6.98; N, 3.73%. Found C, 77.05; H, 7.10; N,
3.92%. 1H NMR (500 MHz, CDCl3) d: 1.58–1.81 (m, 5H),
2.44–2.48 (m, 2H), 2.61–2.68 (m, 2H), 2.92–3.05 (m, 2H),
4.63 (t, 1H, J ¼ 4:9 Hz), 6.95–7.65 (m, 14H). 31P NMR
(161 MHz, CDCl3) d: þ32.3. 13C NMR (125 MHz,
CDCl3) d: 19.3, 28.6, 29.7, 31.3 (d, JPC ¼ 71 Hz), 40.7 (d,
JPC ¼ 2 Hz), 55.8, 126.1–139.2 (aromatic). IR (cmꢀ1, KBr
disc): 1185 cmꢀ1 (P@O); 3280 (N–H). HRMS (FAB):
exact mass calcd for C24H27NOP (MHþ) 376.1830.
Found 376.1839.
5.2.1.5. N,N-Bis-[(2-diphenylphosphinoyl)-ethyl]-(1R,
2R)-cyclohexane-diamine 3e. Prepared with 4.4 mmol of
vinyldiphenylphosphine
oxide.
Yield:
80%.
20
D
1
½aꢃ ¼ þ38:3 (c 1, CHCl3). Mp: 140–143 °C. H NMR
(400 MHz, CDCl3) d: 0.89–0.92 (m, 2H), 1.11–1.16 (m,
2H), 1.31–1.42 (m, 2H) 1.64–1.66 (m, 2H), 1.95–2.19 (m,
4H) 2.48–2.59 (m, 4H), 2.74–2.82 (m, 2H), 3.02–3.11 (m,
2H), 7.25–7.99 (m, 20H). 31P NMR (161.9 MHz, CDCl3)
d: þ32.1. 13C NMR (100.6 MHz, CDCl3) d: 25.2, 31.3 (d,
JPC ¼ 71 Hz), 31.7, 40.3 (d, JPC ¼ 2 Hz), 61.6, 128.8–
134.1 (aromatic). IR (cmꢀ1, KBr disc) m: 1185 (P@O),
3275 (N–H). HRMS (FAB): exact mass calcd for
C34H41N2O2P2 (MHþ) 571.2643. Found 571.2652.
5.2.1.1. [2-(Diphenylphosphinoyl)-ethyl]-(R)-sec-butyl-
20
D
amine 3a. Yield: 98%. ½aꢃ ¼ þ5:3 (c 1, CHCl3). Mp:
70–71 °C. Anal. Calcd for C18H24NOP: C, 71.75; H, 8.0;
N, 4.65%. Found C, 71.25; H, 7.9; N, 4.50%. H NMR
1
(400 MHz, CDCl3) d: 0.81 (t, 3H, J ¼ 7 Hz), 0.95 (d, 3H,
J ¼ 7 Hz), 1.18–1.46 (dm, 2H), 1.64 (br s, 1H), 2.46–2.55
(m, 3H), 2.85–2.99 (m, 2H), 7.24–7.95 (m, 10H). 31P
NMR (145 MHz, CDCl3) d: þ32.4. 13C NMR
(90.5 MHz, CDCl3) d: 10.5, 19.9, 29.8, 30.9 (d, JPC
71 Hz), 40.5 (d, JPC ¼ 2 Hz), 54.7, 129.0 (d, JPC
¼
¼
5.2.1.6. [2-(Diphenylphosphinoyl)-ethyl]-(1R,2S)-nor-
20
D
11:7 Hz), 131.0 (d, JPC ¼ 11:0 Hz), 131.1, 131.6 (d,
JPC ¼ 91 Hz). IR (cmꢀ1, KBr disc) m: 1180 (P@O), 3288
(N–H).
ephedrine 3f. Yield: 82%. ½aꢃ ¼ þ2:3 (c 1, CHCl3).
Mp: 144–146 °C. Anal. Calcd for C23H26NO2P: C, 72.81;
H, 6.91; N, 3.69%. Found: C, 73.08; H, 6.92; N, 3.95%.
1H NMR (400 MHz, CDCl3) d: 0.88 (d, 3H, J ¼ 7 Hz),
2.43–2.47 (m, 2H), 2.75–2.79 (m, 1H), 2.96–3.01 (m,
2H), 4.63 (d, 1H, J ¼ 4 Hz), 7.11–7.70 (m, 15H). 31P
NMR (145.7 MHz, CDCl3) d: þ32.7. 13C NMR
(90.5 MHz, CDCl3) d: 14.9, 31.0 (d, JPC ¼ 71 Hz), 40.7
(d, JPC ¼ 3 Hz), 58.7, 73.3, 124.5–139.8 (aromatic). IR
(cmꢀ1, KBr disc) m: 1181 (P@O), 3273 (N–H).
5.2.1.2. [2-(Diphenylphosphinoyl)-ethyl]-(S)-1-phenyl-
ethyl-amine 3b. White solid, yield 95%. Mp: 175–
20
177 °C (lit.8 176–177 °C). ½aꢃ ¼ þ40:0 (c 1.0, CHCl3).
D
1H NMR (360 MHz, CDCl3): 1.21 (3H, d, J ¼ 6:8 Hz),
1.97 (1H, br s), 2.32–2.46 (2H, m), 2.66–2.85 (2H, m),
3.62 (1H, q, J ¼ 6:8 Hz), 7.08–7.26 (5H, m), 7.30–7.50
(6H, m), 7.55–7.74 (4H, m). 31P NMR (145.8 MHz,
CDCl3) d: þ32.9. 13C NMR (90.6 MHz, CDCl3) d: 23.3,
29.3 (d, JPC ¼ 71 Hz), 39.8 (d, JPC ¼ 3 Hz), 57.0, 125.5,
125.8, 127.4, 127.6 (d, JPC ¼ 12 Hz), 129.6 (d,
JPC ¼ 9 Hz), 130.7 (d, s, JPC ¼ 3 Hz), 132.0 (d,
JPC ¼ 99 Hz), 144.2. IR (cmꢀ1, KBr disc) m: 3316 (NH),
1173 (P@O). HRMS (FAB): exact mass calcd for
C22H25NOP (Mþ) 350.1674. Found 350.1678.
5.2.2. General procedure for the reduction of aminophos-
phine oxides. Triethylamine (6 mL) was added to a stir-
red suspension of the aminophosphine oxide (0.22 mol)
in toluene (25 mL) at 0 °C. After 10 min, trichlorosilane
(0.84 mL, 1.12 mol, 5 equiv) was added dropwise, and
the mixture refluxed for 3.5 h. After cooling to room
temperature, the solution was diluted with ether
(100 mL) and a few drops of Na2CO3 were added to
destroy the excess reducing agent. The reaction mixture
was filtered under argon and evaporated to leave the
product as a colourless residue, which was purified by
distillation or recrystallisation as appropriate.
5.2.1.3. [2-(Diphenylphosphinoyl)-ethyl]-(S)-1-indan-
20
D
amine 3c. Yield: 92%. ½aꢃ ¼ ꢀ9:3 (c 1, CHCl3). Mp:
1
90–95 °C. H NMR (500 MHz, CDCl3) d: 1.66–1.68 (m,
1H), 1.89 (br s, 1H), 2.12–2.30 (m, 1H), 2.42–2.50 (m,

M. S. Rahman et al. / Tetrahedron: Asymmetry 15 (2004) 1835–1840
1839
5.2.2.1.
[2-(Diphenylphosphino)ethyl]-(R)-sec-butyl-
5.2.2.6. [2-(Diphenylphosphino)ethyl]-(1R,2S)-norephe-
20
D
20
D
amine 4a. Yield: 90%. ½aꢃ ¼ þ4:0 (c 1, CHCl3). Bp:
drine 4f. Yield: 75%. ½aꢃ ¼ þ5:5 (c 1, CHCl3). Mp: 105–
1
218–220 °C/0.04 mmHg. Anal. Calcd for C18H24 NP: C,
75.76; H, 8.48; N, 4.91. Found C, 75.75; H, 8.33; N,
4.78. 1H NMR (360 MHz, CDCl3) d: 0.78 (t, 3H,
J ¼ 7 Hz), 1.19 (d, 3H, J ¼ 6:5 Hz), 1.48 (m, 1H), 1.8
(m, 1H), 2.75 (m, 2H), 2.78–2.90 (m, 4H), 7.20–7.80 (m,
10H). 31P NMR (145.7 MHz; CDCl3) d: ꢀ19.2. 13C
NMR (90.5 MHz, CDCl3) d: 9.2, 18.7, 28.1 (d,
JPC ¼ 12 Hz), 28.4, 42.9 (d, JPC ¼ 21 Hz), 53.3, 127.4 (d,
JPC ¼ 7 Hz), 127.5, 131.6 (d, JPC ¼ 17 Hz), 137.3 (d,
JPC ¼ 12 Hz). IR (cmꢀ1, thin film, NaCl discs) m: 3412
(N–H).
110 °C. H NMR (400.1 MHz; CDCl3) d: d 0.71 (d, 3H,
J ¼ 7 Hz, CH3), 2.23–2.29 (m, 2H, CH2P), 2.71–2.80 (m,
3H, CHN, CH2N), 4.67 (d, 1H, J ¼ 3 Hz, CHOH) 7.06–
7.94 (m, 15H, Ph), 31P NMR (145.7 MHz; CDCl3) d:
ꢀ19.0. 13C NMR (100.6 MHz; CDCl3) d: 13.0 (s, CH3),
1
2
27.7 (d, JPC ¼ 13 Hz, CH2P), 42.9 (d, JPC ¼ 21 Hz,
CH2N), 57.43 (s, CHN), 71.89 (s, CHOH), 115.3–140.1
(aromatic). IR (cmꢀ1, KBr disc) 3412 (N–H). HRMS:
exact mass calcd for C23H27NOP (MHþ) 364.1830.
Found 364.1833.
5.3. Typical catalytic procedure
5.2.2.2. [2-(Diphenylphosphino)ethyl]-(S)-1-phenylethyl-
20
D
1
amine 4b. Yield: 80%. ½aꢃ ¼ ꢀ56:4 (c 2, CHCl3). H
The catalytic reactions were carried out in parallel using
a Radley’s reaction carousel. [RuCl2(g6-p-cymene)]2 and
the appropriate ketone substrate was dissolved in
anhydrous isopropanol under argon to create the stock
solution. To each carousel tube was added an appro-
priate amount of the stock solution and further amounts
of isopropanol. The appropriate ligand was then added
to each tube and the contents were refluxed at 83 °C for
30 min, then cooled to 29 °C. A solution of KOH in
isopropanol was added to initiate the reaction. The
progress of the reaction was monitored by 1H NMR and
the enantioselectivity was determined by chiral HPLC
(Chiralcel OD-H column).
NMR (360 MHz, CDCl3) d: 1.23 (3H, d, J ¼ 6:8 Hz),
1.41 (1H, br s), 2.09–2.23 (2H, m), 2.48–2.63 (2H, m),
3.66 (1H, q, J ¼ 6:8 Hz), 7.14–7.33 (15H, m). 31 P NMR
(145.8 MHz, CDCl3) d: ꢀ19.6. 13C NMR (90.6 MHz,
CDCl3): d: 24.3, 29.2 (d, JPC ¼ 12 Hz), 44.3 (d,
JPC ¼ 20 Hz), 57.9, 126.5, 126.8, 128.3, 128.4 (d,
JPC ¼ 4 Hz), 128.6, 132.7, 138.4 (d, JPC ¼ 14 Hz), 145.4.
IR (cmꢀ1, thin film, NaCl discs) m: 3382 (NH). HRMS
(FAB): exact mass calcd for C22H25NP (MHþ) 334.1725.
Found 334.1709.
5.2.2.3.
[2-(Diphenylphosphino)ethyl]-(S)-1-indan-
20
amine 4c. Yield: 82%. ½aꢃ ¼ ꢀ4:7 (c 1, CHCl3).
D
Bp: 240–245 °C/0.04 mmHg. Anal. Calcd for C23H24NP:
C, 79.97; H, 7.0; N, 4.06%. Found C, 80.05; H, 6.92; N,
1
5.3.1. 1-Phenylethanol. H NMR (400 MHz, CDCl3) d:
1
3.95%. H NMR (500 MHz, CDCl3) d: 1.59–1.71 (m,
1.42 (d, 3H, J ¼ 6:4 Hz, CH3), 1.96 (br s, 1H, OH), 4.8
(q, 1H, J ¼ 6:4 Hz, CH), 7.25–7.35 (m, 5H, Ph). Chiral
HPLC (hexane/isopropanol ¼ 95/5, flow rate ¼ 0.5 mL/
min, k ¼ 254 nm): tR ¼ 15:5 min, tS ¼ 17:7 min.
2H), 2.19 (m, 2H), 2.05–2.72 (m, 1H), 2.77–2.82 (m, 2H),
2.86–2.94 (m, 1H), 4.13 (t, 1H, J ¼ 6:5 Hz), 7.10–8.3 (m,
14H). 31 P NMR (161 MHz, CDCl3) d: ꢀ19.1. 13C NMR
(125 MHz, CDCl3) d: 29.6 (d, JPC ¼ 12 Hz), 30.8, 33.9,
44.5 (d, JPC ¼ 21 Hz) 53.4, 124.6–145.3 (aromatic). IR
(cmꢀ1, thin film, NaCl discs): 3312 (N–H).
5.3.2. 1-Phenyl-1-propanol. 1H NMR (400 MHz, CDCl3)
d: 0.76 (t, 3H, J ¼ 7:5 Hz, CH3), 1.40 (m, 2H, CH2) 2.96
(br s, 1H, OH), 4.35 (t, 1H, J ¼ 6:5 Hz, CH), 7.07–7.23
(m, 5H, Ph). Chiral HPLC (hexane/isopropanol ¼ 98/2,
flow rate ¼ 0.3 mL/min, k ¼ 254 nm): tR ¼ 48:7 min,
tS ¼ 53:9 min.
5.2.2.4. [2-(Diphenylphosphino)-ethyl]-(R)-1,2,3,4-tet-
20
rahydro-naphthylamine 4d. Yield: 95%. ½aꢃ ¼ þ5:0 (c
D
1, CHCl3). Bp: 225–230 °C/0.04 mmHg. 1H NMR
(500 MHz, CDCl3) d: 1.56–1.97 (m, 5H), 2.30–2.34 (m,
2H), 2.56–2.90 (m, 4H), 3.78–3.85 (t, 1H, J ¼ 4:9 Hz),
6.97–7.65 (m, 14H). 31P NMR (161 MHz, CDCl3) d:
13
ꢀ19.3.
C NMR (100.6 MHz, CDCl3) d: 19.4, 28.1,
Acknowledgements
28.6 (d, JPC ¼ 12 Hz), 29.5, 43.6 (d, JPC ¼ 22 Hz) 55.6,
126.3–138.0 (aromatic). IR (cmꢀ1, thin film, NaCl discs)
m: 1185 (P@O), 3280 (N–H). HRMS (FAB): exact mass
calcd for C24H27NP (MHþ) 360.1881. Found 360.1884.
The authors thank King’s College London (M.S.R.) and
Synetix Chiral Technology (M.O.) for studentship sup-
port.
5.2.2.5. N,N-Bis-[(2-diphenylphosphino)ethyl]-(1R,2R)-
20
cyclohexane-diamine 4e.17 Yield: 80%. ½aꢃ ¼ þ33:4 (c 1,
D
CHCl3). Bp: 285–28 °C/0.04 mmHg. 1H NMR
(360 MHz, CDCl3) d: 0.80–1.17 (m, 4H), 1.75–2.02 (m,
8H), 2.14–2.27 (m, 4H), 2.45–2.58 (m, 2H), 2.73–2.83
(m, 2H), 7.25–7.99 (m, 20H). 31P NMR (161 MHz,
CDCl3) d: ꢀ20.1. 13C NMR (100.6 MHz, CDCl3) d:
25.7, 29.4 (d, JPC ¼ 12 Hz), 31.7, 43.4 (d, JPC ¼ 21 Hz),
59.6, 129.0–135.2 (aromatic). IR (thin film, NaCl discs)
3275 m (N–H). HRMS (FAB): exact mass calcd for
C34H41N2P2 (MHþ) 539.2745. Found 539.2749.
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