Aminohydroxy phosphine oxide ligands in ruthenium-catalysed asymmetric transfer hydrogenation reactions

Article abstract of DOI:10.1016/j.tetasy.2004.04.040

A class of aminohydroxy phosphine oxide ligands was derived from optically active amino alcohols, containing stereogenic centres at phosphorus and at carbon. Their activities and selectivities in the asymmetric transfer hydrogenation reaction were assesse

Full text of DOI:10.1016/j.tetasy.2004.04.040

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2241–2246
Aminohydroxy phosphine oxide ligands in ruthenium-catalysed
asymmetric transfer hydrogenation reactions
Xiaohui Cheng,a, Peter N. Horton,b Michael B. Hursthouseb and King Kuok (Mimi) Hiic,*
aDepartment of Chemistry, King’s College London, Strand WC2R 2LS, UK
bEPSRC National X-Ray Crystallography Service, University of Southampton, Highfield, Southampton SO17 1BJ, UK
cDepartment of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
Received 31 March 2004; accepted 21 April 2004
Abstract—A class of aminohydroxy phosphine oxide ligands was derived from optically active amino alcohols, containing stereo-
genic centres at phosphorus and at carbon. Their activities and selectivities in the asymmetric transfer hydrogenation reaction were
assessed, including match and mismatch of chiralities. Enantioselectivities of more than 92% were achieved in the reduction of
acetophenone and propiophenone under mild reaction conditions.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
and propiophenone, affording products with up to 93%
ee (Scheme 1).3
Previously, we reported the synthesis and coordination
of a class of aminophosphine 1 (PNH) and diphosphine
2 (PNP) ligands to ruthenium complexes (Fig. 1), and
their comparative catalytic activity in transfer hydroge-
nation reactions of aryl ketones.1;2 In subsequent at-
tempts to achieve asymmetric catalysis, we prepared a
range of chiral aminodiphenylphosphine (PNH) ligands
from optically active amines, and established that the
catalyst activity of ruthenium catalysts generated from
these ligands (both phosphines and phosphine oxides)
can be enhanced by the incorporation of an extra
hydroxy group. From this study, the norephedrine-
derived P–N–O ligand 3a was found to induce good
enantioselectivities in the reduction of acetophenone
O
OH
1 mol% [Ru]/L*
i-PrOH, KOH
R
R
2 h, 29 oC
when L* = 3a,
Ph
R = Me, 95%, 93%ee (R)
R = Et, 84%, 80% ee (R)
when L* = 3b,
R = Me, 83%, 79% ee (R)
R = Et, 84%, 75% ee (R)
H
L* =
N
HO
PPh2
Y
3a (Y = O);
3b (Y = lone pair)
Scheme 1. Asymmetric ruthenium-catalysed transfer hydrogenation of
ketones by PNO ligands.
Prior and concurrent to our investigation, Pietrusiewicz
et al. reported the synthesis of b-aminophosphine oxides
of type 4 (Fig. 2) as ligands in ruthenium-catalysed
asymmetric transfer hydrogenation of aryl ketones,
R
N
R
N
Ph2P
Ph2P
PPh2
H
1 (PNH)
2 (PNP)
Figure 1.
O
H
N
H
N
H
N
O
O
Ph
Ph
Ph
P
P
PPh2
Ph
Ph
CH3
CH3
CH3
* Corresponding author. Tel.: +44-20-7594-1142; fax: +44-207-594-
5804; e-mail: mimi.hii@imperial.ac.uk
4a
Figure 2. Pietrusiewicz’s ligands 4a–c.
4b
4c
Present address: Institute of Polymer Chemistry, Nankai University,
Tianjin 300071, PR China.
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.04.040

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X. Cheng et al. / Tetrahedron: Asymmetry 15 (2004) 2241–2246
producing optically active alcohols with up to 84% ee.4;5
The authors observed that the aminophosphine oxides
generally induced much higher rates of turnover than
the corresponding aminophosphines. They also noted an
enhancement in the catalytic activities of the phosphine
oxide ligands by the presence of a bulky alkyl sub-
stituent at the phosphorus 4b and 4c. Interestingly, the
configuration of the hydrogenation product appeared to
be independent of the stereochemistry at the phosphorus
donor atom.
R1
b
a
(Rp)-8
(Sp)-8
NH2
11 and 12
9 and 10
+
HO
R2
O
P
O
O
P
O
Ph
N
N
H
H
Ph
Ph
OH
Ph
OH
CH3
(Rp,2S)-9
(Sp,2S)-9
O
P
O
CH3
O
O
Ph
With the above findings, we initiated a project to
examine the activity of aminophosphine oxide ligands,
combining the bulky stereogenic phosphorus moiety
with an OH donor; two key structural features identified
in earlier systems to promote fast catalytic turnover.
P
Ph
N
N
H
H
OH
OH
(Rp,1S,2R)-10
(Sp,1S,2R)-10
O
O
Ph
P
P
N
H
N
H
Ph
2. Results and discussion
OH
Ph
OH
(Rp,2S)-11
(Sp,2S)-11
2.1. Preparation of P-chirogenic amido and aminophos-
phine ligands
O
CH3
O
CH3
Ph
P
P
Ph
N
N
H
H
Ph
OH
OH
By modifying literature procedures, menthyl(tert-butyl-
phenylphosphinoyl)acetate 7 was obtained by the
nucleophilic substitution of ())-menthyl chloroacetate 5
with the anion generated from tert-butylphenylphos-
phine oxide 6 (Scheme 2). The resultant product was
purified by fractional crystallisation, affording 20% and
26% of the enantiomerically pure (Rp)- and (Sp)-diaste-
reomers of 7, respectively.
(Rp,1S,2R)-12
(Sp,1S,2R)-12
Scheme 3. Amide coupling to give PNO ligands. Reagents and con-
ditions: (a) EDC, DMAP (cat); (b) i. BH3–THF; ii. NaOH, MeOH.
O
O
i
Cl
Cl
Cl
OMen
5
O
O
iii
+
P
OMen
Ph
O
O
ii
7
Ph P H
PhPCl2
Figure 3. Crystal structure of 10, showing the requisite Sp, 1S,2R
stereochemistry (aromatic hydrogens omitted for clarity).
iv
O
6
O
2.2. Catalytic results
P
OH
(R)- and (S)-8
Ph
Using reaction conditions previously optimised for P–
N–O ligands 3a and 3b, the asymmetric transfer
hydrogenation reactions of aryl ketones (acetophenone
and propiophenone) were carried out using isopropanol
as the hydrogen source (Scheme 4).
Scheme 2. Preparation of optically active (tert-butylphenylphosphi-
noyl)acetic acid 8. Reagents and conditions: (i) ())-menthol, N,N-
dimethylaniline, CH2Cl2, 0–30 ꢁC; (ii) tert-BuMgCl (5 equiv), Et2O,
reflux, 40 h; (iii) NaH, THF, 0 ꢁC, fractional crystallisation; (iv) KOH,
MeOH.
OH
OH
O
[Ru] catalyst
R
R
R
+
Following hydrolysis under mild conditions, the resul-
tant phosphinoacetic acids 8 were coupled with (S)-
valinol and ())-norephedrine to furnish diastereomeric
pairs of amido ligands 9 and 10 (Scheme 3) as highly
crystalline solids. Thus, the stereochemistry of
(Sp,1S,2R)-10 can be determined unequivocally by sin-
gle-crystal X-ray crystallography (Fig. 3).6 Finally, using
borane as a reducing agent, amino hydroxyl phosphine
oxides 11 and 12 can be obtained from 9 and 10,
respectively.
(R)-configuration
(S)-configuration
R = CH3 or CH2CH3
Scheme 4. Asymmetric transfer hydrogenation of ketones.
2.2.1. Amido phosphine oxide ligands 9 and 10. The
presence of a lone pair of electrons on the nitrogen was
once again found to be crucial for catalyst activity. The

X. Cheng et al. / Tetrahedron: Asymmetry 15 (2004) 2241–2246
2243
amidophosphine oxide ligands (Rp,2S)-9, (Sp,2S)-9,
(Rp,1S,2R)-10 and (Sp,1S,2R)-10 gave uniformly low
conversions in the reduction of acetophenone (12%,
15%, 6% and 6%, respectively). As a result, these ligands
were not investigated further for this catalytic reaction.
(entry 1 vs 7), and 93% to 80% whilst employing ligand
3a (entries 2 vs 8). In the case of ligand 11, there is a
dramatic reduction in catalytic turnover, falling to just
11%, suggesting a significant steric effect exerted by the
isopropyl substituent.
In light of the above observations, it is rather surprising
to find that the ligand (Rp,1S,2R)-12 does not seem to
suffer any decline in yield or selectivity in the reduction
of the more sterically demanding substrate (entries 5 and
11); a high ee of 92% was achieved for the reduction of
propiophenone under the same catalytic conditions,
making it one of the most selective for this particular
substrate. Once again, changing the chirality at
the phosphorus moiety had a detrimental effect on the
activity and selectivity of the catalyst (entry 12). The
stereoinduction remained unchanged, with the (R)-
alcohol as the major product in both cases.
2.2.2. Amino hydroxy phosphine oxides 11 and 12.
Reduction of the amido functionality to ligands 11
and 12 led to much more impressive turnovers. For the
purpose of comparison, norephedrine and the previ-
ously prepared aminodiphenylphosphine oxide ligand
3a were included in this part of the study.
Without the phosphine moiety, the amino alcohol nor-
ephedrine gave good conversions under these catalytic
conditions, offering an ee of 85% for the reduction of
acetophenone (Table 1, entry 1). The incorporation of a
diphenylphosphine oxide moiety improved the enantio-
selectivity of this process to 93% (entry 2).
3. Conclusions
In comparison, the valinol-derived ligand (Rp,2S)-11
showed fast catalytic turnover, but low enantioselectiv-
ity (entry 3). Its (Sp,2S)-diastereomer displayed a lower
conversion rate and ee (entry 4), suggesting a coopera-
tive effect between the two stereogenic centres on the
reaction outcome. In both cases, the configuration of the
product alcohol was found to be predominantly S.
A class of asymmetric aminohydroxy phosphine oxide
ligands was prepared. The ligands derived from nor-
ephedrine were found to afford high activities and
selectivities in ruthenium-catalysed transfer hydrogena-
tion of aryl ketones. Unusually, high enantioselectivities
of greater than 90% can be achieved with ligand
(Rp,1S,2R)-12 for the reduction of acetophenone and
propiophenone. The studies demonstrate the existence
of highly synergistic effects between the donor groups
and the stereogenic centres, working in concert to
determine the course of these reactions. However, the
optical activity of the product is dictated only by the
chirality of the amino alcohol.
In contrast, both diastereomers of ligand 12 displayed
comparable conversions, but with dramatically different
enantioselectivities (entries 5 and 6). (Rp,1S,2R)-12
facilitated the formation of the alcohol with 93% ee,
whereas the opposite diastereomer afforded only 41% ee.
Once again, the stereogenic centres associated with the
amino alcohol dictated stereoinduction––favouring the
(R)-configuration in both cases.
4. Experimental
The enantioselectivity of the asymmetric hydrogenation
of aryl ketones is often very sensitive to the steric bulk of
the substrate. When the acetophenone is substituted by
propiophenone, a drop in product ee from 85% to 65%
was observed when norephedrine was used as the ligand
4.1. General procedure
All reactions were carried out under an inert atmosphere
of nitrogen using standard Schlenk line techniques.
Solvents were purified by standard procedures.
Table 1. Asymmetric ruthenium-catalysed transfer hydrogenation of ketonesa
Entry
Ligand
Substrate
% Conversionb
% Eec (R/S)
1
Norephedrine
3a
A
A
A
A
A
A
B
B
B
B
B
B
94
91
98
76
95
98
96
84
11
11
99
80
85 (R)
93 (R)
34 (S)
29 (S)
93 (R)
41 (R)
65 (R)
80 (R)
––d
2
3
(Rp,2S)-11
(Sp,2S)-11
(Rp,1S,2R)-12
(Sp,1S,2R)-12
Norephedrine
3a
4
5
6
7
8
9
(Rp,2S)-11
(Sp,2S)-11
(Rp,1S,2R)-12
(Sp,1S,2R)-12
10
11
12
––d
92 (R)
86 (R)
a General reaction conditions: [RuCl2(cymene)]2 (0.5 mol %), ligand (1.0 mol %), KOH (1.3 mol %) and the aryl ketone substrate (1 mmol) in
isopropanol (10 mL) at 29 ꢁC for 2 h. A: acetophenone, B: propiophenone.
b Determined by 1H NMR.
c Determined by chiral HPLC using a Chiralcel OD-H column.
d Not determined.

2244
X. Cheng et al. / Tetrahedron: Asymmetry 15 (2004) 2241–2246
[RuCl2(g6-p-MeC6H4CHMe2)]2 was prepared follow-
ing reported procedures. Unless otherwise stated, all
other reagents were obtained from Avocado, Lancaster
or Aldrich chemical companies and used as received.
31P, 1H and 13C NMR spectra were recorded using
Bruker Avance 360, 400 or 500 MHz instruments with
TMS (1H and 13C) and 85% H3PO4 (31P) as external
standards. Mass spectrometry facilities were performed
at London Metropolitan University. HPLC were per-
formed on a Gilson instrument. Infrared spectra were
recorded on a Perkin–Elmer Paragon 1000 FTIR spec-
trometer.
CDCl3) d: +48.7. 13C NMR (90.5 MHz, CDCl3) d: 23.8
(d, J ¼ 2 Hz), 32.4 (d, J ¼ 69 Hz), 129.0 (d, J ¼ 12 Hz),
130.0 (d, J ¼ 92 Hz), 131.0 (d, J ¼ 10 Hz), 133.0 (d,
J ¼ 3 Hz). IR (cmÀ1, thin film, NaCl discs) m: 3442, 2963,
2307, 1591, 1175.
7
4.2.3. tert-Butylphenylphosphinoyl acetic acid menthyl
ester 7.9 ())-Menthyl chloroacetate 5 (10.1 g, 43.3 mmol)
was added dropwise to a mixture of butylphenylphos-
phine oxide 6 (9.0 g, 43.3 mmol) and NaH (1.4 g,
60.6 mmol) in THF (80 mL) at 0 ꢁC under nitrogen.
After stirring overnight at room temperature, satd
NH4Cl (30 mL) was added, followed by extraction with
hexane (3 · 50 mL). The combined organic layers were
dried over Na2SO4 and evaporated to give a syrup,
which was dissolved in hexane (40 mL). The solution
was kept at 5 ꢁC to give a crystalline solid (12.2 g). The
solid was dissolved in hexane (240 mL) and cooled to
)7 ꢁC, whereupon white crystal needles formed, which
were filtered off and recrystallised in hexane (180 mL) to
give (Rp)-7. The combined mother liquid was concen-
trated and dissolved in hexane (50 mL) and kept at 5 ꢁC
for 3 days, to give a crystalline solid. The mixture was
warmed to 30 ꢁC and filtered. The residue was then
recrystallised from hexane (30 mL) to give (Sp)-7. (Rp)-7:
4.2. Ligand synthesis
4.2.1. ())-Menthyl chloroacetate 5.8 ())-Menthol (40 g,
256 mmol) was slowly added to a cooled (ice bath)
mixture of chloroacetic chloride (20 mL, 256 mmol) and
N,N-dimethylaniline (32.6 mL, 256 mmol) in CH2Cl2
(30 mL) over 20 min, during which the reaction tem-
perature was maintained at <30 ꢁC. The reaction mix-
ture was stirred at room temperature for 1 h, before it
was cooled in an ice-water bath. H2O (3 mL) was added
and the mixture stirred for another 10 min, before it was
extracted using hexane (120 mL). The organic extract
was washed with cold 10% H2SO4 until the aqueous
layer, made alkaline with NaOH, was no longer cloudy.
The organic layer was then washed with brine (20 mL),
saturated aq NaHCO3 (20 mL), brine (10 mL) and dried
over Na2SO4. The solution was filtered and concen-
trated, then fractionally distilled to afford a colourless
Yield 3.8 g, 20%. Mp 75–76 ꢁC (lit.8 75–76 ꢁC).
25
½aŠ ¼ À80:0 (c 1.0, CH3OH) lit.8 )85.7 (c 1.0,
D
1
CH3OH). H NMR (360 MHz, CDCl3) d: 0.65 (d, 3H,
J ¼ 6:9 Hz), 1.16 (d, 9H, J ¼ 15:3 Hz), 0.67–1.18 (m,
15H), 3.18–3.32 (m, 2H), 4.60 (dt, 1H, J ¼ 4:4, 10.9 Hz),
7.45–7.82 (m, 5H). 31P NMR (145 MHz, CDCl3) d:
+44.9. 13C NMR (90.5 MHz, CDCl3) d: 16.1, 21.2, 22.2,
23.2, 24.7, 25.8, 31.6, 33.5 (d, JPC ¼ 51 Hz), 34.1 (d,
JPC ¼ 63 Hz), 34.4, 40.6, 46.8, 75.9, 128.4 (d,
JPC ¼ 12 Hz), 129.7 (d, J ¼ 92 Hz), 132.1 (d, J ¼ 3 Hz),
liquid. Yield: 52.7 g, 81%. Bp 98–99 ꢁC (3 mmHg).
25
D
½aŠ ¼ À84:9 (c 1.24, EtOH) lit.8 )86.2 (c 1.0, EtOH).
1H NMR (360 MHz, CDCl3) d: 0.78 (d, 3H, J ¼ 7:0 Hz),
0.79–1.18 (m, 10H), 1.30–1.61 (m, 2H), 1.65–1.73 (m,
2H), 1.83–1.93 (m, 1H), 4.05 (s, 2H), 4.78 (dt, 1H,
J ¼ 4:4, 10.9 Hz). 13C NMR (90.5 MHz, CDCl3) d: 16.6,
21.1, 22.3, 23.7, 26.5, 31.7, 34.6, 40.9, 41.5, 47.2, 76.9,
167.3. IR (cmÀ1, thin film, NaCl discs) m: 2956, 1758,
1735, 1456, 1188, 983.
132.4 (d, J ¼ 9:0 Hz), 166.7 (d, J ¼ 7 Hz). IR (cmÀ1
,
Nujol, NaCl discs) m: 3053, 2921, 1721, 1464, 1265, 1171,
727. (Sp)-7: Yield 5.1 g, 26%. Mp 116–117 ꢁC (lit.8
25
116.5–117.5 ꢁC). ½aŠ ¼ þ7:8 (c 1.0, CH3OH), lit.8 +9.4
D
(c 1.0, CH3OH). 1H NMR (360 MHz, CDCl3) d: 0.43 (d,
3H, J ¼ 7:0 Hz), 1.16 (d, 9H, J ¼ 15:3 Hz), 0.60–1.80
(m, 15H), 3.10–3.32 (m, 2H), 4.54 (dt, 1H, J ¼ 4:3,
10.9 Hz), 7.46–7.81 (m, 5H). 31P NMR (145 MHz,
CDCl3) d: +44.9. 13C NMR (90.5 MHz, CDCl3) d: 15.9,
21.1, 22.3, 23.2, 24.6, 25.8, 31.6, 33.5 (d, J ¼ 42 Hz), 34.1
(d, J ¼ 61 Hz), 34.4, 40.6, 46.8, 76.1, 128.3 (d,
J ¼ 11 Hz), 128.9 (d, J ¼ 91 Hz), 132.1 (d, J ¼ 3 Hz),
132.5 (d, J ¼ 8 Hz), 166.6 (d, J ¼ 6 Hz). IR (cmÀ1, Nu-
jol, NaCl discs) m: 2924, 1731, 1723, 1462, 1377, 1170.
4.2.2. tert-Butylphenylphosphine oxide 6. A solution of
tert-butyl chloride (60.9 mL, 560 mmol) in Et2O (50 mL)
was added slowly to a suspension of Mg turnings (15.0 g,
625 mmol) in Et2O (280 mL), such that the reaction
mixture was maintained under slow reflux. After the
addition, the reaction mixture was refluxed for 3 h. After
cooling to room temperature, the mixture was filtered by
using a cannula. The filtrate was brought to reflux,
whereupon a solution of phenyl phosphonic dichloride
(20.0 g, 102.6 mmol) in Et2O (40 mL) was added drop-
wise. The reaction mixture was refluxed for another 40 h
during which precipitation of a yellow solid occurred.
After cooling to 0 ꢁC, 10% aq HCl (200 mL) was added
dropwise. The layers were separated, and the aqueous
layer extracted with CHCl3 (3 · 50 mL). The combined
organic layers were dried over Na2SO4, filtered and
fractionally distilled to afford a colourless liquid. Yield
0.86 g, 46%. Bp 100–104 ꢁC (0.1 mmHg). 1H NMR
(360 MHz, CDCl3) d: 1.77 (d, 9H, J ¼ 16:6 Hz), 7.04 (d,
J ¼ 453 Hz), 7.06–7.73 (m, 5H). 31P NMR (145 MHz,
4.2.4. (tert-Butylphenylphosphinoyl)acetic acid 8. The
corresponding ester 7 (3.2 g, 13.3 mmol) and KOH
(1.5 g, 26.8 mmol) were stirred in CH3OH (10 mL) at
room temperature for 48 h. After removal of methanol,
H2O (10 mL) was added. The aqueous layer was washed
with diethyl ether and acidified by the addition of concd
HCl (3 mL). NaCl (2.0 g) was added and the mixture
extracted repeatedly with CHCl3 (6 · 10 mL). The com-
bined organic layers were washed with brine (15 mL),
dried over MgSO4 and filtered. The solvent was removed
to give the product as a white solid. Yield 2.0 g, 99%.

X. Cheng et al. / Tetrahedron: Asymmetry 15 (2004) 2241–2246
2245
Mp 166–168 ꢁC (decompose) (lit.8 166–168 ꢁC). 1H
NMR (360 MHz, CDCl3) d: 1.17 (d, 9H, J ¼ 15:9 Hz),
3.17 (dd, 1H, J ¼ 10:1, 14.6 Hz), 3.31 (dd, 1H, J ¼ 11:8,
14.6 Hz), 7.44–7.71 (m, 5H). 31P NMR (145 MHz,
CDCl3) d: +50.7. 13C NMR (90.5 MHz, CDCl3) d: 24.2,
31.8 (d, J ¼ 52 Hz), 33.8 (d, J ¼ 71 Hz), 128.1 (d,
J ¼ 94 Hz), 128.8 (d, J ¼ 12 Hz), 131.9 (d, J ¼ 8 Hz),
132.8 (d, J ¼ 3 Hz), 167.1 (d, J ¼ 6 Hz). IR (cmÀ1, Nu-
jol, NaCl discs) m: 3418, 2925, 2854, 2576, 1961, 1724,
1463, 1270.
88%. Mp 159–160 ꢁC. Anal. Calcd for C17H28NO3P: C,
62.75; H, 8.67; N, 4.30. Found: C, 62.66; H, 8.69; N,
4.22. 1H NMR (360 MHz, CDCl3) d: 0.91 (d, 3H,
J ¼ 6:8 Hz), 0.92 (d, 3H, J ¼ 6:8 Hz), 1.17 (d, 9H,
J ¼ 15:7 Hz), 1.78–1.89 (m, 1H), 3.04–3.23 (m, 3H, H2),
3.27–3.39 (m, 2H), 3.52–3.60 (m, 1H), 7.06 (br d,
J ¼ 8:6 Hz), 7.48–7.75 (m, 5H). 31P NMR (145 MHz,
CDCl3) d: 50.4. 13C NMR (90.5 MHz, CDCl3) d: 18.2,
18.9, 28.1, 31.0 (d, JPC ¼ 51 Hz), 32.5 (d, JPC ¼ 70 Hz),
57.7, 62.9, 126.9–137.9, 165.3 (d, JPC ¼ 5 Hz). HRMS
(FAB): exact mass calcd for C17H29NO3P (Mþ+1)
25
D
(Sp)-8: ½aŠ ¼ À52:1 (c 1.0, EtOH).
20
326.1885, found 326.1870. IR (cmÀ1, Nujol, NaCl discs):
25
D
m 3273, 2924, 1628, 1561, 1463, 1377, 1165. ½aŠ ¼ À61:8
(Rp)-8: ½aŠ ¼ þ51:9 (c 1.0, EtOH).
(c 1.23, EtOH).
D
4.2.5. General procedure for the synthesis of (Rp,1S,2R)-
2-(tert-butylphenylphosphinoyl)-N-(2-hydroxyl-1-methyl-
2-phenylethyl)acetamide, (Rp,1S,2R)-10. EDC (1.0 g,
5.2 mmol) was added to a solution of (Rp)-8 (0.60 g, 2.5
4.2.8. (Sp,2S)-2-(tert-Butylphenylphosphinoyl)-N-(1-hy-
droxymethyl-2-methylpropyl)acetamide (Sp,2S)-9. From
(Sp)-8 and (S)-(+)-2-amino-3-methyl-1-butanol. Yield:
92%. Mp 106–107 ꢁC. Anal. Calcd for C17H28NO3P: C,
62.75; H, 8.67; N, 4.30. Found: C, 62.67; H, 8.77; N,
4.28. 1H NMR (360 MHz, CDCl3) d: 0.60 (d, 3H,
J ¼ 6:8 Hz), 0.63 (d, 3H, J ¼ 6:8 Hz), 1.10 (d, 9H,
J ¼ 15:5 Hz), 1.59–1.69 (m, 1H), 3.00 (dd, 1H, J ¼ 8:3,
15.1 Hz), 3.19 (dd, 1H, J ¼ 13:5, 15.1 Hz), 3.37–3.41 (br
s, 1H), 3.47–3.64 (m, 3H), 7.39–7.67 (m, 5H). 31P NMR
(145 MHz, CDCl3) d: 49.4. 13C NMR (90.5 MHz,
CDCl3) d: 15.8, 17.2, 21.9, 26.7, 30.5 (d, JPC ¼ 51 Hz),
31.3 (d, JPC ¼ 70 Hz), 55.7, 61.8, 126.1–130.2, 164.0 (d,
JPC ¼ 6 Hz). HRMS (FAB): exact mass calcd for
C17H29NO3P (Mþ+1) 326.1893, found 326.1885. IR
mmol),
L
-())-(1S,2R)-norephedrine (0.42 g, 2.7 mmol)
and DMAP (0.45 g, 3.7 mmol) in CH2Cl2 (12 mL) at
room temperature. The reaction mixture was stirred at
40 ꢁC overnight and then diluted with CHCl3. The
organic layer was washed with 1 M aq HCl (6 mL,
6 mmol), brine (6 mL), saturated sodium carbonate
(3 mL) and brine (6 mL) successively, before it was dried
over MgSO4 and filtered. The filtrate was evaporated in
vacuum to give a white powder. Yield 0.91 g, 93%. Mp
188–189 ꢁC. Anal. Calcd for C21H28NO3P: C, 67.54; H,
1
7.56; N, 3.75. Found: C, 67.66; H, 7.64; N, 3.65. H
NMR (360 MHz, CDCl3) d: 0.83 (d, 3H, J ¼ 6:9 Hz),
1.13 (d, 9H, J ¼ 15:7 Hz), 2.95–3.17 (m, 2H), 3.99–4.09
(m, 1H), 4.43 (d, 1H, J ¼ 3:5 Hz), 7.08–7.67 (m, 10H).
31P NMR (145 Hz, CDCl3) d: 50.0. 13C NMR
(90.5 MHz, CDCl3) d: 13.0, 24.4, 33.2 (d, J ¼ 50 Hz),
33.7 (d, JPC ¼ 70 Hz), 52.1, 74.9, 126.3–141.3, 165.5 (d,
J ¼ 5 Hz). HRMS (FAB): exact mass calcd for
C21H29NO3P (Mþ+1) 374.1874, found 374.1885. IR
(cmÀ1, Nujol, NaCl discs) m: 3291, 3162, 2925, 1654,
25
D
1557, 1463, 1161. ½aŠ ¼ þ19:1 (c 1.62, EtOH).
4.2.9. General procedure for the reduction of amide
ligands and deprotection of borane for the synthesis of
(Rp,1S,2R)-2-[2-(tert-butylphenylphosphinoyl)ethylamino]-
1-phenylpropan-1-ol (Rp,1S,2(R)-12. BH3–THF solution
(1.5 M in THF, 4.0 mL, 6.0 mmol, 4 equiv) was added to
a suspension of (RP)-10 (0.52 g, 1.4 mmol) in THF
(20 mL). The mixture was stirred at room temperature
for 2 h and then at 60 ꢁC overnight. The reaction mix-
ture was then cooled in an ice bath and CH3OH (1 mL)
added. Solvents were removed in vacuum. CH3OH
(20 mL) and 30% aqueous NaOH solution (2 mL) were
added to the residue and the reaction mixture stirred at
40 ꢁC for 1 h. The volatiles were removed in vacuo, H2O
(5 mL) and CH2Cl2 (20 mL) were added. The aqueous
layer was extracted with CH2Cl2 (4 · 10 mL). The com-
bined organic layers were dried over MgSO4, filtered,
concentrated in vacuo and purified by flash chroma-
tography (SiO2, isopropanol/NEt3/chloroform: 2/1/22,
Rf ¼ 0:36) to give a white solid. Yield: 0.32 g, 64%. Mp
164–166 ꢁC. Anal. Calcd for C21H30NO2P: C, 70.17; H,
(cmÀ1, Nujol, NaCl discs): m 3165, 2921, 1636, 1539,
25
D
1463, 1377, 1166. ½aŠ ¼ À36:0 (c 1.05, EtOH).
4.2.6. (Sp,1S,2R)-2-(tert-Butylphenylphosphinoyl)-N-(2-
hydroxyl-1-methyl-2-phenylethyl)acetamide, (Sp,1S,2R)-
10. This was prepared from (Sp)-8 and
L
-())-(1S,2R)-
norephedrine. Yield: 88%. Mp 166–167 ꢁC. Anal. Calcd
for C21H28NO3P: C, 67.54; H, 7.56; N, 3.75. Found: C,
1
67.51; H, 7.66; N, 3.66. H NMR (360 MHz, CDCl3) d:
0.75 (d, 3H, J ¼ 6:8 Hz), 1.14 (d, 9H, J ¼ 15:7 Hz), 3.04
(dd, 1H, J ¼ 9:4, 14.8 Hz), 3.21 (dd, 1H, J ¼ 12:7,
14.8 Hz), 4.06–4.16 (m, 1H), 4.54–4.59 (br s, 1H), 4.91 (t,
1H, J ¼ 3:0 Hz), 7.21–7.72 (m, 10H). 31P NMR
(145 MHz, CDCl3) d: 48.8. 13C NMR (90.5 MHz,
CDCl3) d: 13.1, 24.4, 33.6 (d, JPC ¼ 51 Hz), 33.8 (d,
JPC ¼ 70 Hz), 52.0, 75.1, 126.4–141.8, 165.5 (d,
JPC ¼ 5:0 Hz). HRMS (FAB): exact mass calcd for
C21H29NO3P (Mþ+1) 374.1885, found 374.1900. IR
1
8.41; N, 3.90. Found: C, 70.26; H, 8.45; N, 3.83. H
NMR (360 MHz, CDCl3) d: 0.68 (d, 3H, J ¼ 6:6 Hz),
1.06 (d, 9H, J ¼ 14:7 Hz), 1.60 (br s, 1H), 2.12–2.31 (m,
2H), 2.69–2.77 (m, 1H), 2.81–3.01 (m, 2H), 3.80 (br s,
1H), 4.64 (d, 1H, J ¼ 3:2 Hz), 7.11–7.69 (m, 10H). 31P
NMR (145 MHz, CDCl3) d: 50.9. 13C NMR (90.5 MHz,
CDCl3) d: 14.7, 23.9 (d, JPC ¼ 63 Hz), 24.6, 32.1
(d, JPC ¼ 69 Hz), 40.6 (d, JPC ¼ 3 Hz), 58.7, 72.5,
(cmÀ1, Nujol, NaCl discs) m: 3267, 2917, 1659, 1529,
25
D
1463, 1163, 1103. ½aŠ ¼ þ33:5 (c 1.35, EtOH).
4.2.7. (Rp,2S)-2-(tert-Butylphenylphosphinoyl)-N-(1-hy-
droxymethyl-2-methylpropyl)acetamide, (Rp,2S)-9. From
(Rp)-8 and (S)-(+)-2-amino-3-methyl-1-butanol. Yield:

2246
X. Cheng et al. / Tetrahedron: Asymmetry 15 (2004) 2241–2246
126.3–142.1. HRMS (FAB): exact mass calcd for
C21H31NO2P (Mþ+1) 312.2092, found 312.2084. IR
4.3. General catalytic procedure
(cmÀ1, Nujol, NaCl discs) m: 3265, 2923, 1600, 1462,
Ligand (0.011 mmol) and [RuCl2(g6-p-MeC6H4-
CHMe2)]2 (0.005 mmol, 0.5 mol %) were added to a dry
Schlenk tube, which was subsequently purged and filled
with nitrogen successively. Anhydrous isopropanol
(8 mL) was added and the mixture was left to reflux at
83 ꢁC for 30 min. After cooling to 30 ꢁC, acetophenone
(0.12 mL, 1.0 mmol) was added. The catalytic process
was initiated by the addition of a solution of KOH in
isopropanol (0.013 M, 2.0 mL, 0.026 mmol). After the
appropriate time, the reaction was quenched by the
addition of water (0.5 mL). The solvents were evapo-
25
D
1157, 1000. ½aŠ ¼ À6:5 (c 1.38, EtOH).
4.2.10. (Sp,1S,2R)-2-[2-(tert-Butylphenylphosphinoyl)eth-
ylamino]-1-phenylpropan-1-ol, (Sp,1S,2R)-12 was simi-
larly prepared from (Sp)-10. Yield 51%. Mp 143–144 ꢁC.
Anal. Calcd for C21H30NO2P: C, 70.17; H, 8.41; N, 3.90.
1
Found: C, 70.26; H, 8.45; N, 3.83. H NMR (360 MHz,
CDCl3) d: 0.69 (d, 3H, J ¼ 6:5 Hz), 1.13 (d, 9H,
J ¼ 14:2 Hz), 1.50 (br, s, 1H), 2.45–2.48 (m, 2H), 2.77–
2.85 (m, 1H), 2.86–3.10 (m, 2H), 4.20 (br s, 1H), 4.72 (d,
1H, J ¼ 3:6 Hz), 7.10–7.91 (m, 10H). 31P NMR
(145 MHz, CDCl3) d: 45.1. 13C NMR (90.5 MHz,
CDCl3) d: 14.8, 23.9 (d, JPC ¼ 63 Hz), 24.6, 33.1 (d,
JPC ¼ 69 Hz), 41.1 (d, JPC ¼ 3 Hz), 58.7, 73.1, 126.0–
141.1. HRMS (FAB): exact mass calcd for C21H31NO2P
(Mþ+1) 360.2092, found 360.2083. IR (cmÀ1, Nujol,
1
rated and the residue was examined by H NMR to
determine the percentage conversion. Enantiomeric ex-
cesses were determined by HPLC with a Chiracel OD-H
column: for 1-phenylethanol, 5% isopropanol in hexane,
0.5 mL/min, tR ¼ 15:5 min,
1-phenylpropanol, 2% isopropanol in hexane, 0.3 mL/
tS ¼ 17:7 min;
for
min, tR ¼ 48:7 min, tS ¼ 53:9 min.
NaCl discs) m: 3274, 2922, 1463, 1377, 983, 702.
25
D
½aŠ ¼ þ19:0 (c 1.15, EtOH).
Acknowledgements
4.2.11. (Sp,2S)-2-[2-(tert-Butylphenylphosphinoyl)ethyl-
amino]-3-methylbutan-1-ol, (Sp,2S)-11. From (Sp)-9.
Yield: 48%. Mp 81–82 ꢁC. Anal. Calcd for C17H30NO2P:
C, 65.57; H, 9.71; N, 4.50. Found: C, 65.53; H, 9.73; N,
4.40. 1H NMR (360 MHz, CDCl3) d: 0.78 (d, 3H,
J ¼ 6:9 Hz), 0.83 (d, 3H, J ¼ 6:8 Hz), 1.07 (d, 9H,
J ¼ 20:2 Hz), 1.56–1.66 (m, 1H), 2.12–2.41 (m, 3H),
2.75–3.00 (m, 2H), 3.24 (dd, 1H, J ¼ 7:6, 10.9 Hz), 3.52
(dd, 1H, J ¼ 3:8, 10.9 Hz), 3.80 (br s, 2H), 7.41–7.80 (m,
5H). 31P NMR (145 MHz, CDCl3) d: +52.0. 13C NMR
(90.5 MHz, CDCl3) d: 18.9, 19.7, 23.6 (d, JPC ¼ 64 Hz),
24.6, 29.6, 33.1 (d, JPC ¼ 69 Hz), 41.7 (d, JPC ¼ 5 Hz),
61.4, 65.0, 128.6–132.2. HRMS (FAB): exact mass calcd
for C17H31NO2P (MHþ) 312.2092, found 312.2084. IR
The authors thank the following organisations for
financial support: K. C. Wong Education Foundation,
British Foreign and Commonwealth Office (FCO),
Education Department of PR China and The Nuffield
Foundation.
References and notes
1. Rahman, M. S.; Steed, J. W.; Hii, K. K. Synthesis 2000,
1320–1326.
2. Rahman, M. S.; Prince, P. D.; Steed, J. W.; Hii, K. K.
Organometallics 2002, 21, 4927–4933.
3. Rahman, M. S. Ph.D. thesis, University of London, 2002;
Rahman, M. S.; Oliana, M.; Hii, K. K. Tetrahedron:
Asymmetry 2004, 15, in press.
(cmÀ1, Nujol, NaCl discs) m: 3366, 2922, 1466, 1376,
25
D
1148, 1050. ½aŠ ¼ þ23:9 (c 1.10, EtOH).
4. Maj, A. M.; Pietrusiewicz, K. M.; Suisse, I.; Agbossou, F.;
Mortreux, A. Tetrahedron: Asymmetry 1999, 10, 831–835.
5. Maj, A. M.; Pietrusiewicz, K. M.; Suisse, I.; Agbossou, F.;
Mortreux, A. J. Organometal. Chem. 2001, 626, 157–
160.
6. Crystallographic data (excluding structure factors) for
compound 10 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 234960. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk.
4.2.12. (Rp,2S)-2-[2-(tert-Butylphenylphosphinoyl)ethyl-
amino]-3-methylbutan-1-ol, (Rp,2S)-11. From (RP)-9.
Colourless liquid. Yield: 46%. Anal. Calcd for
C17H30NO2P: C, 65.57; H, 9.71; N, 4.50. Found: C,
1
65.46; H, 9.85; N, 4.39. H NMR (360 MHz, CDCl3) d:
0.73 (d, 3H, J ¼ 6:7 Hz), 0.79 (d, 3H, J ¼ 6:8 Hz), 1.06
(d, 9H, J ¼ 14:7 Hz), 1.40–1.60 (m, 1H), 2.19–2.40 (m,
3H), 2.76–2.92 (m, 2H), 3.21 (dd, 1H, J ¼ 7:5, 11.0 Hz),
3.46 (dd, 1H, J ¼ 3:9, 11.0 Hz), 7.30–7.72 (m). 31P NMR
(145 MHz, CDCl3) d: +51.3. 13C NMR (90.5 MHz,
CDCl3): d 19.1, 19.9, 24.1 (d, JPC ¼ 63 Hz), 24.6, 29.5,
32.7 (d, JPC ¼ 69 Hz), 40.8, 61.0, 65.0, 128.6–132.2.
HRMS (FAB): exact mass calcd for C21H31NO2P
(MHþ) 312.2092, found 312.2100. IR (cmÀ1, thin film,
7. Bennett, M. A.; Smith, A. K. J. Chem. Soc., Dalton Trans.
1974, 233–239.
8. Imamoto, T.; Sato, K.; Johnson, C. R. Tetrahedron Lett.
1985, 26, 783–786.
NaCl discs) m: 3325, 2957, 1655, 1475, 1155.
½aŠ ¼ À19:2 (c 1.08, EtOH).
9. Sisido, K.; Nakanishi, O.; Nozaki, H. J. Org. Chem. 1961,
26, 4878–4881.
25
D