A feasibility study on the synthesis of phenylephrine via ruthenium-catalyzed homogeneous asymmetric hydrogenation

Article abstract of DOI:10.1016/j.tetasy.2010.09.013

We report a feasibility study on a new route to (R)-phenylephrine, based on the ruthenium-catalyzed asymmetric hydrogenation of an aminoketone precursor. The direct and fast asymmetric reduction of aminoketones or their hydrochloride salts is achievable at low catalyst loadings (molar substrate to catalyst ratio, S/C, >25,000/1, TOF up to 25,000 h^-1) with high enantioselectivity (>95% ee), without the need for N-protection nor isolation of the free base prior to reaction.

Full text of DOI:10.1016/j.tetasy.2010.09.013

Tetrahedron: Asymmetry 21 (2010) 2479–2486
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A feasibility study on the synthesis of phenylephrine via
ruthenium-catalyzed homogeneous asymmetric hydrogenation
John F. McGarrity a, Antonio Zanotti-Gerosa b,
⇑
a Lonza AG, CH-3930, Visp, Switzerland
b Johnson Matthey, Catalysis and Chiral Technologies, Cambridge Science Park, Unit 28, Cambridge CB1 2PY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a feasibility study on a new route to (R)-phenylephrine, based on the ruthenium-catalyzed
asymmetric hydrogenation of an aminoketone precursor. The direct and fast asymmetric reduction of
aminoketones or their hydrochloride salts is achievable at low catalyst loadings (molar substrate to cat-
alyst ratio, S/C, >25,000/1, TOF up to 25,000 hꢀ1) with high enantioselectivity (>95% ee), without the need
for N-protection nor isolation of the free base prior to reaction.
Received 20 August 2010
Accepted 29 September 2010
Available online 26 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
scope of the reaction by introducing catalysts of the type [(diphos-
phine) RuCl2 (diamine)], which performed the hydrogenation of
(R)-Phenylephrine (Fig. 1) is an
a
1-adrenergic receptor agonist
acetophenone derivatives with excellent enantioselectivity and
activity.10 [(Diphosphine) RuCl2 (diamine)] catalysts operate under
basic conditions (usually with sub-stoichiometric amounts of
t-BuOK in i-PrOH), a fact that has been conveniently exploited to
achieve the asymmetric reduction of some aminoketones via
dynamic kinetic resolution (DKR).11 The catalysts, however, are
sensitive to the presence of any acidic functionality in the sub-
strate, which can shut down the catalysis. The published examples
of hydrogenation with Noyori-type catalysts required the protec-
tion of nitrogen as N-dimethyl or N-alkyl/N-carbamate.12
In view of the recent advances in the field of ruthenium cataly-
sis, in 2006 Lonza and Johnson Matthey initiated a feasibility study
of a catalytic hydrogenation process to produce (R)-phenylephrine
using new-generation [(diphosphine) RuCl2 (diamine)] catalysts.
Three possible substrates, aminoketones 1ꢁHCl, 2 and 3ꢁHCl, were
investigated (Fig. 1). All substrates 1, 2, and 3 had a mildly acidic
phenol group. Substrate 1 had a free NH group and substrates 1
and 3 were available as the hydrochloride salts. The free base of
aminoketone 1 could also be expected to have limited stability,
giving rise to self-condensation by-products. Ruthenium catalysts
bearing PPhos phosphine ligands were selected for catalyst test-
ing.13 PPhos-catalysts, developed by Chan et al. had already been
successfully applied to ketone reduction in combination with var-
ious 1,2-diamines, 1,3-diamines, and 1,4-diamines (Fig. 2).14,15
Johnson Matthey had previous experience on the application of
PPhos-ruthenium catalysts to the hydrogenation of phenol-con-
taining aromatic ketones.16 Good catalytic efficiency was achieved
at low catalyst loadings by using more than 1 equiv of base and by
introducing water as the reaction’s co-solvent. We also found that
10 M aq KOH could be used instead of the more usual t-BuOK/t-
BuOH solution. The applicability of such a procedure was, however,
used as a decongestant and in a number of other medical applica-
tions.1 Various asymmetric syntheses of (R)-phenylephrine have
been reported2 but only a few are of industrial value. Homoge-
neous asymmetric hydrogenation is widely accepted in industry
as an efficient way to produce enantiomerically enriched mole-
cules3 and, in principle, offers a particularly attractive route to
(R)-phenylephrine.4 Asymmetric hydrogenation processes, how-
ever, must operate at catalyst loadings as low as possible in order
to be cost-effective, while retaining high stereoselectivity, volume,
and time efficiency. A homogeneous asymmetric route to (R)-
phenylephrine and related aminoalcohols is available through the
use of rhodium catalysts bearing pyrrolidine-based diphosphines,
which were introduced by Achiwa5 and developed by Boheringer
Ingelheim researchers into an efficient process.6 High enantioselec-
tivity (92% ee) has been achieved at molar substrate to catalyst ra-
tio (S/C) as low as 40,000/1 in THF using the N-benzyl protected
phenylephrone. Asymmetric transfer hydrogenation of aminoke-
tones has been applied to the reduction of N-alkyl or N-acyl pro-
tected aminoketones with good enantioselectivity and moderate
catalyst activity (S/C 100–400/1).8 The ruthenium-catalyzed asym-
metric hydrogenation of functionalised ketones, such as b-ketoest-
ers and amino and hydroxyketones,7 was first introduced by
Noyori in the 1980s and has found numerous applications in indus-
trial transformations. These catalysts have also been used for the
highly enantioselective hydrogenation of dialkylamino ketones at
relatively high catalyst loading (S/C 1000/1) and high hydrogen
pressure.9 In the mid 1990s, Noyori further expanded upon the
⇑
Corresponding author. Tel.: +44 1223 225800; fax: +44 1223 438037.
E-mail address: antonio.zanotti-gerosa@matthey.com (A. Zanotti-Gerosa).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.09.013

2480
J. F. McGarrity, A. Zanotti-Gerosa / Tetrahedron: Asymmetry 21 (2010) 2479–2486
OH
H
N
HO
(R)-Phenylephrine
Ph
O
Ac
O
O
H
N
HO
N
HO
N
HO
2
1
3
Figure 1.
NH2
NH2
NH2
NH2
OMe
N
MeO
MeO
PAr2
PAr2
OMe
(R,R)-DCEN
(R,R)-DPEN
MeO
N
NH2
OMe
NH2
NH2
NH2
Ar = Ph:
(R)-PPhos
(R)-Tol-PPhos
Ar = 3,5-diMe-Ph: (R)-Xyl-PPhos
NH2
r
A = 4-Me-Ph:
NH2
(R,R)-DACH
(R)-DAIPEN
(S,S)-DPPN
Figure 2.
substrate-specific and, in some cases, side-reactions caused by the
presence of excess base were detected.17
consistently gave >97% ee when the catalyst loadings were gradu-
ally reduced from S/C 1000/1 to S/C 10,000/1 using both anhydrous
and aqueous experimental procedures (t-BuOK in i-PrOH and KOH
in i-PrOH/water) (entries 14–24). At low catalyst loadings the reac-
tions with KOH were always faster, although some by-products
were detected by HPLC, which were tentatively assigned as
de-acetylation products. The reactions at S/C 5000/1 (entries 16
and 17) went to completion (as judged by hydrogen uptake curves)
in 1–2 h. Finally, the catalyst loadings with [(S)-DAIPEN RuCl2 (S)-
Xyl-PPhos] were reduced to 4 at S/C 10,000/1 with full conversion
and 97% ee (S). At this stage the use of the i-PrOH/KOH 10 M mix-
ture was clearly better in comparison to the use of t-BuOK in
t-BuOH/i-PrOH mixture, which gave full conversion at S/C 7500/1
(entries 18 and 19) but not at S/C 10,000/1 (entries 20 and 21).
We successfully repeated the reactions at S/C 10,000/1 (entries
20–24) using different amounts of KOH (5 equiv in the reactions
reported in entry 23, 2.5 equiv in entry 22 and 1.5 equiv in entry
21). The use of t-BuOK in i-PrOH and some added water led to only
limited conversion (entry 20). The starting material was also sub-
jected to the standard hydrogenation conditions in the absence
of catalyst (entry 25) and found to be sufficiently stable over the
reaction time (96% purity by HPLC analysis after 3.5 h).
2. Results and discussion
2.1. Hydrogenation of substrate 2
We began our catalyst screening and small-scale development
using substrate 2, which was available as the free base (Table 1).
Three bases were compared using catalyst [(S,S)-DPEN RuCl2
(S)-Xyl-PPhos] and i-PrOH as the reaction solvent: 1.05–1.1 equiv
of t-BuOK 1 M in t-BuOH (entry 1); excess KOH 10 M (5–10 equiv)
(entry 2); 0.2 equiv of t-BuOK 1 M in t-BuOH (entry 3). The results
of entries 1–3 indicated that more than 1 equiv of base was re-
quired for the reaction to proceed to completion (most likely the
base neutralized the phenol group). At higher temperatures and
shorter reaction times, both procedures using excess base worked
equally well (see also entries 4 and 5).
A set of PPhos-based catalysts were tested at S/C 100/1. The re-
sults obtained at S/C 100/1 allowed us to discard the use of ‘mis-
matching’ catalysts (entry 6) and catalysts bearing the diamines
DPPN (entry 7) and DACH (entry 8). Other catalysts bearing phos-
phines PPhos, Tol-PPhos, Xyl-PPhos and diamines DCEN, DPEN, and
DAIPEN (entries 9–14) gave relatively similar results at high cata-
lyst loadings. Thus, [DAIPEN RuCl2 Xyl-PPhos] (entry 9) was chosen
as the catalyst for further development. The use of this catalyst
The reaction with [(S)-DAIPEN RuCl2 (S)-Xyl-PPhos] in i-PrOH/
KOH 10 M was repeated on a 2 g scale in a standalone Parr
autoclave at S/C 10,000/1, 63 °C, 30 bar hydrogen, for 3 h to give
full conversion, 82% isolated yield, 97.6% ee (S), 95% purity by 1H

J. F. McGarrity, A. Zanotti-Gerosa / Tetrahedron: Asymmetry 21 (2010) 2479–2486
2481
Table 1
Small-scale hydrogenation of substrate 2
Entry
1
Catalyst
S/C
Reaction conditions
Temp./press.
Time (h)
3.5
Conv.a
>99%
eeb
91% (S)
[(S,S)-DPEN RuCl2 (S)-Xyl-PPhos]
100/1
1.05 equiv t-BuOK,
i-PrOH, 0.2 M
30 °C (1.5 h), 45 °C
(2 h)/25 bar
2
3
[(S,S)-DPEN RuCl2 (S)-Xyl-PPhos]
[(S,S)-DPEN RuCl2 (S)-Xyl-PPhos]
[(S,S)-DPEN RuCl2 (S)-Xyl-PPhos]
[(S,S)-DPEN RuCl2 (S)-Xyl-PPhos]
[(S)-DAIPEN RuCl2 (R)-Xyl-PPhos]
[(S,S)-DPPN RuCl2 (R)-PPhos]
100/1
5 equiv KOH 10 M,
i-PrOH, 0.2 M
0.2 equiv t-BuOK,
i-PrOH, 0.2 M
5 equiv KOH 10 M,
i-PrOH, 0.2 M
1.05 equiv t-BuOK,
i-PrOH, 0.2 M
1.05 equiv t-BuOK,
i-PrOH, 0.2 M
1.05 equiv t-BuOK,
i-PrOH, 0.2 M
1.05 equiv t-BuOK,
i-PrOH, 0.2 M
1.05 equiv t-BuOK,
i-PrOH, 0.2 M
1.05 equiv t-BuOK,
i-PrOH, 0.2 M
1.05 equiv t-BuOK,
i-PrOH, 0.2 M
1.05 equiv t-BuOK,
i-PrOH, 0.2 M
1.05 equiv t-BuOK,
i-PrOH, 0.2 M
1.1 equiv. t-BuOK,
i-PrOH, 0.2 M
10 equiv KOH 10 M,
i-PrOH, 0.2 M
1.05 equiv. t-BuOK,
i-PrOH, 0.5 M
4 equiv KOH 10 M,
i-PrOH, 0.5 M
1.05 equiv. t-BuOK,
i-PrOH, 0.4 M
5 equiv KOH 10 M,
i-PrOH, 0.4 M
1.05 equiv. t-BuOK,
i-PrOH, 0.4 M
1.5 equiv KOH 10 M,
i-PrOH, 0.5 M
2.5 equiv KOH 10 M,
i-PrOH, 0.5 M
5 equiv KOH 10 M,
i-PrOH, 0.4 M
1.05 t-BuOK 1 M,
i-PrOH + 10% water, 0.5 M
5 equiv KOH 10 M,
i-PrOH, 0.5 M
30 °C (1.5 h), 45 °C
(2 h)/25 bar
30 °C (1.5 h), 45 °C
(2 h)/25 bar
3.5
3.5
1.5
1.5
2
90–100%
<30%
>99%
>99%
>99%
>99%
>99%
>99%
>99%
>99%
>99%
>99%
>99%
>99%
>99%
>99%
98%
95% (S)
n.d.
100/1
4
100/1
65 °C/25 bar
91% (S)
92% (S)
ꢂ45% (S)
rac
5
100/1
65 °C/25 bar
60 °C/25 bar
60 °C/25 bar
60 °C/25 bar
60 °C/25 bar
60 °C/25 bar
60 °C/25 bar
60 °C/25 bar
60 °C/25 bar
65 °C/28 bar
65 °C/28 bar
65 °C/28 bar
65 °C/28 bar
65 °C/28 bar
65 °C/28 bar
65 °C/28 bar
65 °C/28 bar
65 °C/28 bar
65 °C/28 bar
65 °C/28 bar
65 °C/28 bar
6
100/1
7
100/1
2
8
[(R,R)-DACH RuCl2 (R)-Xyl-PPhos]
[(S)-DAIPEN RuCl2 (S)-Xyl-PPhos]
[(R,R)-DPEN RuCl2 (R)-PPhos]
[(R)-DAIPEN RuCl2 (R)-PPhos]
[(S,S)-DPEN RuCl2 (S)-Tol-PPhos]
[(R,R)-DCEN RuCl2 (R)-Xyl-PPhos]
[(R)-DAIPEN RuCl2 (R)-Xyl-PPhos]
[(R)-DAIPEN RuCl2 (R)-Xyl-PPhos]
[(S)-DAIPEN RuCl2 (S)-Xyl-PPhos]
[(S)-DAIPEN RuCl2 (S)-Xyl-PPhos]
[(S)-DAIPEN RuCl2 (S)-Xyl-PPhos]
[(S)-DAIPEN RuCl2 (S)-Xyl-PPhos]
[(S)-DAIPEN RuCl2 (S)-Xyl-PPhos]
[(S)-DAIPEN Ru Cl2 (S)-Xyl-PPhos]
[(S)-DAIPEN Ru Cl2 (S)-Xyl-PPhos]
[(S)-DAIPEN RuCl2 (S)-Xyl-PPhos]
[(S)-DAIPEN Ru Cl2 (S)-Xyl-PPhos]
No catalyst
100/1
2
ꢂ50% (R)
92% (S)
ꢂ82% (R)
94% (R)
91% (S)
ꢂ90% (R)
>97% (R)
>97% (R)
>97% (S)
>97% (S)
>97% (S)
>97% (S)
—
9
100/1
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
100/1
2
100/1
2
100/1
2
100/1
2
1000/1
1000/1
5000/1
5000/1
7500/1
7500/1
10,000/1
10,000/1
10,000/1
10,000/1
10,000/1
—
1.5
1.5
1.5
1.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
>99%
84%
>99%
>99%
>99%
18%
>97% (S)
—
>97% (S)
—
—
>96% purity s.m.
a
By HPLC, Method A, see Section 4.
By HPLC, Method B, see Section 4.
b
NMR (Scheme 1). The isolated yield of 4 was only limited by the
formation of some de-acetylated product, which would be in any
case an intermediate en-route phenylephrine. The reaction was
deemed to be complete in less than 1 h judging by hydrogen
uptake. Under the same conditions, a reaction at S/C 25,000/1
gave ꢂ80% conversion (of which 10% was de-acetylated product)
over 3 h.
2.2. Hydrogenation of substrate 1ꢁHCl
The reaction conditions previously developed for substrate 2
were suitable for substrate 1ꢁHCl, provided that a minimum of
3 equiv of base were used to neutralize the hydrochloride salt,
the phenol and the amino group. The starting material 1ꢁHCl was
found to be reasonably stable under the reaction conditions used
O
Ac
N
S/C 10,000/1, 63ºC,
30 bar H2, 3 hours
OH
Ac
N
HO
HO
[(S)-Xyl-PPhos RuCl2 (S)-DAIPEN]
KOH 10 M, i-PrOH
4
2
82% yield, 97% ee (S)
Scheme 1.

2482
J. F. McGarrity, A. Zanotti-Gerosa / Tetrahedron: Asymmetry 21 (2010) 2479–2486
Table 2
Small-scale hydrogenation of substrate 1ꢁHCl
a
c
Entry Catalyst
S/C
Reaction conditions
Temp./Press. Time (h) Conv.
NMR purityb
ee
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
No catalyst
[(S)-DAIPEN RuCl2 (S)-Xyl-PPhos]
[(R)-DAIPEN RuCl2 (R)-PPhos]
—
5 equiv KOH 10 M, i-PrOH, 0.4 M
65 °C/28 bar
65 °C/28 bar
65 °C/28 bar
65 °C/28 bar
65 °C/28 bar
65 °C/28 bar
65 °C/28 bar
65 °C/28 bar <1
65 °C/28 bar <1
40 °C/28 bar
1
1
1
2.5
2
<2%
98%
>99%
95%
78%
15%
<5%
99%
>99%
>99%
<2%
98% (s.m.)
90%
90%
53%
85%
50%
—
92%
>90%
>90%
—
95%
77%
—
2500/1 5 equiv KOH 10 M, i-PrOH, 0.4 M
2500/1 5 equiv KOH 10 M, i-PrOH, 0.4 M
2500/1 3.2 equiv KOH 10 M, i-PrOH, 0.5 M
2500/1 5 equiv KOH 10 M, EtOH, 0.4 M
2500/1 5 equiv KOH 10 M, MeOH, 0.4 M
2500/1 2 equiv. KOH 10 M, i-PrOH, 0.5 M
2500/1 6 equiv KOH 10 M, i-PrOH, 0.5 M
2500/1 3.2 equiv KOH 10 M, i-PrOH, 0.5 M
2500/1 3.2 equiv KOH 10 M, i-PrOH, 0.5 M
>95% (S)
70% (R)
80% (R)
—
[(R,R)-DPEN RuCl2 (R)-Xyl-PPhos]
[(S)-DAIPEN RuCl2 (S)-Xyl-PPhos]
[(S)-DAIPEN RuCl2 (S)-Xyl-PPhos]
[(R)-DAIPEN RuCl2 (R)-Xyl-P-Phos]
[(R)-DAIPEN RuCl2 (R)-Xyl-P-Phos]
[(R)-DAIPEN RuCl2 (R)-Xyl-P-Phos]
[(R)-DAIPEN RuCl2 (R)-Xyl-P-Phos]
[(R)-DAIPEN RuCl2 (R)-Xyl-PPhos]
[(R)-DAIPEN RuCl2 (R)-Xyl-PPhos]
[(R)-DAIPEN RuCl2 (R)-Xyl-PPhos]
[(R)-DAIPEN RuCl2 (R)-Xyl-PPhos]
[(R)-DAIPEN RuCl2 (R)-Xyl-PPhos]
[(S)-DAIPEN RuCl2 (S)-Xyl-PPhos]
[(R)-DAIPEN RuCl2 (R)-Xyl-PPhos]
[(R)-DAIPEN RuCl2 (R)-Xyl-PPhos]
[(R)-DAIPEN RuCl2 (R)-Xyl-PPhos]
[(R)-DAIPEN RuCl2 (R)-Xyl-PPhos]
[(R)-DAIPEN RuCl2 (R)-Xyl-PPhos]
[(R)-DAIPEN RuCl2 (R)-Xyl-PPhos]
2
4
—
—
97% (R)
97% (R)
97% (R)
—
97% (R)
97% (R)
97% (R)
—
>95% (S)
96% (R)
97% (R)
—
97% (R)
96% (R)
96% (R)
4
2.5
2500/1 3.2 equiv KOH 25 M, i-PrOH, 0.55 M 65 °C/28 bar
2500/1 3.2 equiv NaOH 10 M, i-PrOH, 0.5 M 65 °C/28 bar <1
2500/1 3.2 equiv KOH 10 M, 2-BuOH, 0.5 M 65 °C/28 bar <1
99%
>99%
>99%
2500/1 3.2 equiv KOH 10 M, 1-BuOH, 0.5 M 65 °C/28 bar
2
2
1.5
95%
2500/1 3.2 equiv KOH 10 M, water, 1 M
5000/1 5 equiv KOH 10 M, i-PrOH, 0.4 M
20,000/1 5 equiv KOH 10 M, i-PrOH, 0.5 M
40,000/1 5 equiv KOH 10 M, i-PrOH, 0.5 M
40,000/1 5 equiv KOH 10 M, i-PrOH, 0.3 M
40,000/1 5 equiv KOH 10 M, i-PrOH, 0.8 M
50,000/1 5 equiv KOH 10 M, i-PrOH, 0.5 M
50,000/1 5 equiv KOH 10 M, i-PrOH, 0.4 M
65 °C/28 bar
65 °C/28 bar
No H2 uptake by-products only
>99%
>97%
>97%
ꢂ90%
>97%
>97%
>97%
93%
90%
81%
50%
78%
>85%
74%
75 °C/32 bar 16
75 °C/32 bar 16
75 °C/32 bar 16
75 °C/32 bar 16
75 °C/25 bar 16
85 °C/32 bar 16
a
b
c
By HPLC, Method A, see Section 4.
1H NMR (DMSO-d6) product purity in brackets.
By HPLC, Method B, see Section 4.
Table 3
Hydrogenation of 1ꢁHCl on a gram scale with [DAIPEN RuCl2 Xyl-PPhos]
a
d
Entry Catalyst Substrate
S/C
Reaction conditions
Time (h) Conv. (%) NMR purityb (%) Yieldc (%) ee
1
2
3
4
5
6
(S),(S) 2.01 g, 10 mmol 10,000/1 3.5 mL KOH 10 M, 11.5 mL i-PrOH, 80 °C, 29–33 bar, [S] = 0.60 M 2.5
>99
>99
>99
>99
90
—
>90
93
92.5
86
74
80
83
82.5
74
—
96.5% (S)
97% (S)
97.5% (R)
95.5% (R)
96.5% (R)
95% (R)
(S),(S) 6.03 g, 30 mmol 15,000/1 10 mL KOH 10 M, 40 mL i-PrOH, 80 °C, 29–33 bar, [S] = 0.60 M
1.5e
(R),(R) 4.02 g, 20 mmol 20,000/1 6.5 mL KOH 10 M, 23.5 mL i-PrOH, 67 °C, 29–33 bar, [S] = 0.67 M 2.5e
(R),(R) 4.02 g, 20 mmol 25,000/1 6.5 mL KOH 10 M, 23.5 mL i-PrOH, 67 °C, 29–33 bar, [S] = 0.67 M 2.5e
(R),(R) 2.01 g, 10 mmol 40,000/1 3.5 mL KOH 10 M, 10.5 mL i-PrOH, 70 °C, 29–33 bar, [S] = 0.7 M 2.5
(R),(R) 2.01 g, 10 mmol 50,000/1 3.5 mL KOH 10 M, 12 mL i-PrOH, 80 °C, 29–33 bar, [S] = 0.67 M
3
70
—
a
b
c
By HPLC, Method A, see Section 4.
1H NMR (DMSO-d6) purity determined after work up of the crude mixture.
The reaction was worked up according to the different procedures described in the text. In all cases the isolated hydrochloride salt of the product had >95% 1H NMR
(DMSO-d6) purity
d
By HPLC, Method B, see Section 4.
Hydrogen uptake took place in less than 1 h.
e
for the hydrogenation at S/C 2500/1 (Table 2, entry 1). In addition,
Catalyst loadings were reduced to S/C 5000/1 (entry 16) with-
out any need for further adjustment of the reaction conditions,
while the reaction at S/C 20,000/1 (entry 17, 65 °C, 28 bar) gave full
conversion at a slightly higher temperature and pressure (75 °C,
32 bar). The enantioselectivity remained higher than 95% ee.
The reactions at S/C 40,000/1 (entries 18–20, 75 °C, 32 bar) re-
vealed that substrate concentration (and the linked parameter of
base concentration) played an important role, with an optimal con-
centration of 0.5 M (entry 18). Under otherwise equal reaction con-
ditions, incomplete conversion was obtained at 0.3 M (entry 19)
and an erosion of product purity occurred at 0.8 M (entry 20).
The lowest catalyst loading was finally demonstrated at S/C
50,000/1, 75 °C (entry 21) with full conversion. Increasing the
reaction temperature to 85 °C only reduced the product purity
(entry 22).
having already conducted
a broader screen of catalysts on
substrate 2, only a limited selection of catalysts were tested on
1ꢁHCl at S/C 2500/1, 65 °C, 28 bar, i-PrOH/KOH 10 M, for 2 h. [DAI-
PEN RuCl2 Xyl-PPhos] gave high enantioselectivity (entry 2), while
the use of the PPhos ligand (entry 3) or the diamine DPEN (entry 4)
significantly reduced the enantioselectivity.
The reaction with [DAIPEN RuCl2 Xyl-PPhos] was studied at S/C
2500/1, 65 °C, 30 bar for 2–4 h, giving some insights on the optimal
conditions for; (1) the choice of solvent, (2) the amount of base,
and (3) reaction temperature.
(1) The best activity was obtained in the system alcohol/KOH
10 M. The use of MeOH and EtOH gave low conversion (entries
5 and 6). The use of 1-BuOH also reduced the reaction rate
(entry 14). The use of i-PrOH and 2-BuOH (entry 13) gave fast
reactions with full conversion in less than 30–40 min.
(2) At least 3 equiv of base (KOH) were required. Low conver-
sions and significant decomposition were obtained with
2 equiv of KOH (entry 7). NaOH could be used instead of
KOH (entry 12). The use of KOH 25 M (entry 11) or KOH in
water without alcoholic co-solvent (entry 15) gave only
extensive decomposition.
2.3. Hydrogenation of the substrate 1ꢁHCl on a gram scale
The best reaction conditions developed on a small scale in the
Biotage Endeavour were reproduced in standalone Parr autoclaves
(Table 3, Scheme 2).
In the first instance, the reaction with [(S)-DAIPEN RuCl2 (S)-
Xyl-PPhos] was reproduced at conservative catalyst loadings of
S/C 10,000/1 (2 g scale) and S/C 15,000/1 (6 g scale) (Scheme 2,
Table 3, entries 1 and 2) with full conversion, 80–83% isolated yield
(3) A reaction at 40 °C (entry 10) instead of 65 °C gave the same
impurity profile but at a much lower reaction rate.

J. F. McGarrity, A. Zanotti-Gerosa / Tetrahedron: Asymmetry 21 (2010) 2479–2486
2483
O
H
N
OH
H
N
.HCl
HO
1. 70-80ºC, 29-33 bar H2
HO
[Xyl-PPhos RuCl2 DAIPEN]
KOH 10 M, i-PrOH
1.HCl
Phenylephrine
Scheme 2.
of the hydrochloride salt with 96–97% ee and >97% purity by 1H
NMR after precipitation from MeOH/MTBE as described below.
The hydrogenation with [(R)-DAIPEN RuCl2 (R)-Xyl-PPhos] was
then demonstrated at S/C 20,000/1 (entry 3) and at S/C 25,000/1
(entry 4) on 4 g scale at 67 °C, 30 bar hydrogen. The reactions gave,
respectively, 82% isolated yield (97% ee) and 74% isolated yield
(95.5% ee). In all these cases the reaction took place in less than
1 h, which was equivalent to an average turnover frequency
Xyl-PPhos] two reactions went to completion at S/C 5000/1 within
3.5 h (entries 2 and 3) regardless of the fact that the hydrochloride
salt or the free base was used. The reaction was repeated on 3ꢁHCl
at S/C 10,000/1 and gave 74% conversion to product. The reaction
was stopped after 2.5 h to obtain data comparable to the best re-
sults obtained using 1ꢁHCl (Tables 2 and 3). This confirmed that
the hydrogenation of 3ꢁHCl was generally slower than the hydroge-
nation of 1ꢁHCl. Taking into account the fact that an additional
debenzylation step would have been required, this route was
abandoned.
(TOF) of 10,000–25,000 hꢀ1
.
The reactions at S/C 40,000/1 (entry 5) and 50,000/1 (entry 6)
gave only partial conversion (50–77% by 1H NMR) over 3 h. While
further optimization would be likely to fully reproduce the most
successful small-scale experiments of Table 2, these experiments
also confirmed that reactions at loadings lower than 25,000/1 were
generally compromising product purity, therefore, potentially off-
setting any advantage associated with the use of reduced amounts
of catalysts.
The use of strongly basic conditions and of a water/alcohol sol-
vent mixture appeared to produce fast hydrogenation and limited
decomposition, and, as long as sufficiently high catalyst loadings
were used, hydrogenation remained faster than decomposition.
The drawback of this approach was the requirement for a relatively
complex work up to recover the product from the strongly basic
reaction mixture.
The preferred work-up method for the larger scale reactions in
Table 3 consisted of quenching the basic reaction mixture with HCl
in EtOH or MeOH and to repeatedly evaporate the solvent until a
solid residue was obtained. The product was extracted with i-PrOH
and the salts (KCl) were removed by filtration. Evaporation to dry-
ness, re-dissolution in MeOH, and slow addition of such solution to
MTBE allowed the precipitation of the hydrochloride salt of the
product as an off-white solid. As an alternative, the pH of the crude
reaction mixture was adjusted to pH 11–12, the aqueous phase ex-
tracted with 2-BuOH. The combined organic phases were acidified
with alcoholic HCl, evaporated, and the hydrochloride salt of the
target product was isolated by precipitation from MeOH/MTBE as
described above. In view of the limited scope of the project, the iso-
lation procedures were not optimized further.
3. Conclusions
We have established that catalyst [(R)-Xyl-P-Phos RuCl2 (R)-DAI-
PEN] can be used for the fast and enantioselective hydrogenation of
aminoketone 1ꢁHCl to prepare (R)-phenylephrine, thus circumvent-
ing the need for a protection/deprotection strategy. We have proven
that low catalyst loadings could be achieved while maintaining high
conversion and minimizing the formation of side-products. Reac-
tions with full conversion, >95% ee and >80% isolated yield of pure
product were demonstrated on multi-gram scale at catalyst loadings
as low as S/C 20,000/1 and 25,000/1 (estimated average
TOF = 20,000–25,000 hꢀ1). In addition, small-scale experiments
suggested that further optimizationmight lead to achieving full con-
version at even lower catalyst loadings.
4. Experimental section
Compounds 1ꢁHCl [94240-17-2],18 3ꢁHCl [71786-67-9], [56917-
44-3],6 5 [1159977-09-9], [286426-31-1],6 4 [58952-80-0],19 have
been previously reported in the literature. A reference sample of
(R)-phenylephrine was purchased from a commercial supplier
(Aldrich).
4.1. N-[2-(3-Hydroxyphenyl)-2-oxo-ethyl]-N-methyl-acetamide
(N-acetyl phenylephrone), 2
Phenylephrone hydrochloride 1ꢁHCl (10 g, 0.05 mol) and Ac2O
(14.1 mL, 0.15 mol) were heated to 110 °C under stirring for 4 h.
Next, Ac2O was evaporated under reduced pressure to give a brown
oil that was purified by silica gel chromatography (eluent: AcOEt)
to afford O-acetyl, N-acetyl phenylephrone. 1H NMR (400 MHz,
DMSO-d6), (two rotamers are visible): d 2.18 (3H, s, CH3CO, 1.97
2.4. Hydrogenation of substrate 3ꢁHCl
The reaction conditions developed for substrates 1ꢁHCl and 2
were applied directly to the asymmetric hydrogenation of 3ꢁHCl
(Table 4, Scheme 3). In the presence of [(S)-DAIPEN RuCl2 (S)-
Table 4
Small-scale hydrogenation of substrate 3ꢁHCl
Entry
Substrate
S/C
—
5000/1
5000/1
Conv.a
eeb
1
2
3
4
3ꢁHCl
3ꢁHCl
3c
3ꢁHCl
87% recovery, >90% purity by 1H NMR
>99%
>99%
74%
>95% (S)
>95% (S)
—
10,000/1
Experimental conditions: [(R)-DAIPEN RuCl2 (R)-Xyl-PPhos], 3.2 equiv KOH 10 M i-PrOH, 0.5 M, 65 °C, 28 bar, 3.5 h (2.5 h entry 4).
a
By HPLC, Method A, see Section 4.
By HPLC, Method B, see Section 4, after debenzylation on Pd/C, hydrogen.
The free base was prepared by neutralization of 3ꢁHCl with sodium bicarbonate solution and extraction with AcOEt.
b
c

2484
J. F. McGarrity, A. Zanotti-Gerosa / Tetrahedron: Asymmetry 21 (2010) 2479–2486
Ph
.HCl
Ph
O
OH
65ºC, 28 bar H2
HO
N
HO
N
[Xyl-PPhos RuCl2 DAIPEN]
KOH 10 M, i-PrOH
3.HCl
5
Scheme 3.
minor rotamer), 2.31 (3H, s, CH3CO, 2.33 minor), 3.08 (3H, s, CH3N,
2.97 minor), 4.80 (2H, s, C(O)CH2–N, 4.73 minor), 7.30 (1H, dd,
CHAr, 7.32 minor), 7.48 (1H, t, CHAr, 7.50 minor), 7.66 (1H, m,
CHAr), 7.80 (1H, dd, CHAr). 13C NMR (two rotamers are visible):
193.5 (195.5 minor), 171.3, 169.2, 151.1 (150.9 minor), 136.5
(136.0 minor), 129.8 (130.1 minor), 126.9 (127.5 minor), 125.4
(125.1 minor), 121.1, 54.0 (57.1 minor), 35.1 (37.3 minor), 21.3,
21.0. The compound was used for the next step without further
characterization. The O-acetyl, N-acetyl phenylephrone was added
into a 100 mL aqueous solution of K2CO3 (3.45 g, 25 mmol). The
mixture was warmed to 50 °C and maintained for 1 h. After cooling
to room temperature the solution was acidified to pH ꢂ6 with HCl,
then extracted with AcOEt (50 mL ꢃ 3). The organic layers were
combined, dried over sodium sulfate, and concentrated under vac-
uum to afford 7.84 g of 2 as a white solid (75% over two steps). 1H
NMR (400 MHz, DMSO-d6), (two rotamers are visible): d 2.06 (3H,
s, CH3CO, 1.84 minor rotamer), 3.02 (3H, s, CH3N, 2.80 minor), 4.77
(2H, s, C(O)CH2–N, 4.97 minor), 7.06 (1H, ddd, J1 = 8 Hz, J2 = 2.4 Hz,
J3 = 0.8 Hz, CHAr, 7.09 minor), 7.30 (1H, broad t, J = ꢂ2 Hz, CHAr,
minor ꢂ7.35), 7.35–7.40 (1H, m, CHAr), 7.43 (1H, dt, J1 = 8 Hz,
J2 = ꢂ2 Hz, CHAr, 7.46 minor). 13C NMR (400 MHz, DMSO-d6),
(two rotamers are visible): d 194.7 (195.2 minor), 170.3 (170.7
minor), 157.7, 136.4 (136.1 minor), 129.8 (130.1 minor), 126.9
(127.5 minor), 125.4 (13C NMR (two rotamers are visible): 194.6
(195.2 minor), 170.3 (170.7 minor), 157.6, 136.4 (136.1 minor),
129.9, 120.9 (120.6 minor), 118.7 (118.8 minor), 113.8 (114.1 min-
or), 54.0 (–CH2–, 56.9 minor), 37.0 (N–Me, 34.3 minor), 21.1 (Ac,
20.9 minor). MS (CI): 208 (M+H)+.
acetylated enantiomers were eluted at 25 min (S) and at
19 min (R).
4.4. General procedure for hydrogenation in a Biotage
Endeavour (Tables 1, 2 and 4)
Substrates 1ꢁHCl, 2 or 3ꢁHCl (1–2.5 mmol) and the catalyst were
weighed in a glass vial and placed under an inert atmosphere in a
Biotage Endeavour. Base (KOH aq solution or t-BuOK 1 M in t-
BuOH) was added, followed by solvent. At low catalyst loadings,
the catalyst was added to a stock solution in i-PrOH. The reactions
were purged by pressurizing under stirring at least five times with
nitrogen (3 bar) and hydrogen (25–32 bar), then heated and pres-
surized to the set values. HPLC Method A (C-18) was used to ana-
lyze the crude reaction mixtures for conversion. The crude reaction
mixture was then evaporated under reduced pressure, after which
a sample reacted with excess pyridine and Ac2O, evaporated, fil-
tered over silica gel. The acetylated derivative was analyzed for
the ee determination using HPLC Method B (Chiracel OJ). The prod-
uct derived from substrate 3 was debenzylated by hydrogenation
in the presence of Pd/C prior to derivatization.
4.5. Work-up of hydrogenations of Table 2
Most reactions reported in Table 2 were run in 2 mmol of 1ꢁHCl
salt with 1 mL KOH 10 M and 4 mL i-PrOH. Upon completion of the
reaction, at room temperature, the aqueous phase separated out.
The i-PrOH layer was separated and NaCl was added to saturate
the aqueous phase, which was extracted twice with i-PrOH. The
combined organic phases were filtered over Celite to give a clear
solution. This was adjusted to pH 1–2 by the addition of HCl 1 M
in Et2O. The mixtures were filtered and the solution was evapo-
rated to give the hydrochloride salt of the target product. Alterna-
tively, an ammonium chloride saturated solution (1 mL) and a
more solid ammonium chloride were added to the crude reaction
mixture, which was extracted with AcOEt (2 ꢃ 3 mL) and dried
over sodium sulfate. The solvent was evaporated to give the free
base of the product. All the materials isolated according to the
above procedures were analyzed by 1H NMR (DMSO-d6) and the
purity of the product was estimated by integration of the protons
of the side-products arising from self-condensation of the
aminoketone.
4.2. Analytical Method A
This method allowed the analysis of crude reaction mixtures
from substrates 1, 2 and 3. Column: EC 250/4 Nucleodur 100–5
C18 EC (Macherey-Nagel), water/acetonitrile 90:10 + 0.1% TFA for
10 min, then to 50:50, 40 °C, 0.6 mL/min (unless the analysis was
run at 40 °C significant broadening and splitting of the peaks oc-
curred). A sample of the crude reaction mixture was diluted in
water/acetonitrile/TFA for analysis. Both 254 and 220 nm wave-
lengths were monitored. In general, by-products had a response
factor 3–4 times higher than the starting material and products
(as qualitatively assessed by comparison with 1H NMR spectra of
the crude products). Substrate 1ꢁHCl: starting material: 6.4 min;
product: 5.2 min. Substrate 2: starting material: 18.5 min; prod-
uct: 16.2 min. Substrate 3ꢁHCl: starting material: 12.9 min; prod-
uct: 12.4 min.
4.6. Hydrogenation of 2 in a 25 mL Parr autoclave
Substrate 2 (2.07 g, 10 mmol) and [(S)-DAIPEN RuCl2 (S)-Xyl-
PPhos] (1.2 mg, 0.001 mmol, S/C 10,000/1) were weighed and
placed in 25 mL Parr autoclave with an overhead stirrer and heat-
ing jacket under a nitrogen atmosphere. Next, i-PrOH (8.5 mL,
[S] = 0.6 M) and KOH 10 M (1.5 mL, 15 mmol KOH) were added
through the injection port and the reaction was purged five times
by pressurizing to 30 bar hydrogen and releasing the pressure un-
der stirring. The reaction was then pressurized to 30 bar hydrogen,
stirred at around 1000 rpm, and heated to 63 °C over 30 min. The
reaction was stirred for 2.5 h while the hydrogen pressure was
4.3. Analytical Method B
This method was used to determine the enantioselectivity of
the reactions on substrates 1 and 2 after derivatization to the ace-
tate derivative. The product derived from substrate 3 was debenzy-
lated by hydrogenation in the presence of Pd/C prior to
derivatization. Column: Chiracel OJ 25 ꢃ 0.4 cm, hexane/2-propa-
nol 80:20, 1 mL/min, 25 °C (wavelength: 220 nm). Retention times:
(S)-enantiomer: 10 min; (R)-enantiomer: 13 min. The partially

J. F. McGarrity, A. Zanotti-Gerosa / Tetrahedron: Asymmetry 21 (2010) 2479–2486
2485
maintained between 30 and 31 bars. The hydrogen uptake took
place within the first hour. The reaction was then allowed to cool
to room temperature over 1 h, after which the pressure released.
HPLC analysis (Method A) of the crude reaction mixture indicated
that 78% product (254 nm), 2% starting material, and 20% of a side-
product were present. The side-product was identified as phenyl-
ephrine by co-injection of an authentic sample. The solvent was
evaporated under reduced pressure and a saturated solution of
ammonium chloride (100 mL) was added. The pH was then ad-
justed to pH 1 by addition of HCl 2 N. The aqueous phase was ex-
tracted twice with AcOEt (2 ꢃ 150 mL). The organic layer was dried
over sodium sulfate, filtered, and evaporated to give 1.3 g of an off
white residue. The aqueous solution was saturated with sodium
chloride and extracted again with AcOEt (2 ꢃ 150 mL). The organic
layer was dried over sodium sulfate, filtered, and evaporated to
give 0.40 g of an off white residue that was combined with the first
crop: 1.70 g (82% yield), off white solid; 95% pure by 1H NMR anal-
ysis (DMSO-d6); 97.6% ee [(S)-enantiomer] by HPLC (Method B) on
the acetylated derivative.
aminoalcohol with 7% aromatic by-products. The aqueous solu-
tion was treated with more HCl 2 M to obtain pH 7/8 and it
was extracted again with i-PrOH (50 mL). The 1H NMR analysis
indicated that the i-PrOH solution contained the hydrochloric salt
of the product in >95% purity. The i-PrOH solutions were com-
bined and acidified by the addition of 100 mL of HCl 1 M in EtOH.
The mixture was heated at reflux for 5 min and then filtered over
Celite in order to remove solid impurities (salts). A clear yellow
solution was obtained, which was then evaporated to dryness.
The solid residue was dissolved in methanol (10 mL) and added
dropwise to MTBE (150 mL). The resulting suspension was stirred
overnight and the product was recovered by filtration to give
3.35 g (82.5% isolated yield, off-white solid). >97% purity by 1H
NMR in DMSO-d6, 98% ee [(R)-enantiomer] by HPLC (Method B
on acetylated derivative).
4.9. Hydrogenation of 1ꢁHCl in 100 mL Parr autoclave, S/C
25,000/1
The reaction at S/C 20,000/1 was repeated under the same condi-
tions but at S/C 25,000/1, 67 °C, 29–33 bar hydrogen, 2.5 total reac-
4.7. Hydrogenation of 1ꢁHCl in a Biotage Endeavour
tion time. The hydrogen uptake took place in less than 1 h. The 1
H
NMR analysis of the crude reaction mixture showed full conversion
and 7.5% aromatic by-product. The crude reaction mixture was di-
luted with brine (100 mL) and 2-BuOH (100 mL). The pH of the aque-
ous phase was adjusted to pH 10/11 by addition of HCl 2 M. A solid
precipitated out of the aqueous phase, to which NaCl was added be-
fore being extracted three times with 100 mL of 2-BuOH until color-
less and clear. The combined 2-BuOH solutions were dried over
sodium sulfate, filtered over Celite, and the residue was washed with
more 2-BuOH (100 mL). The resulting orange solution was evapo-
rated. Next, HCl 1.5 M in MeOH (25 mL) and MeOH (30 mL) were
added and the resulting solution was evaporated. The oily residue
was treated with MeOH (10 mL) and MTBE (ꢂ100 mL) to obtain a
suspension. The hydrochloride salt of (R)-phenylephrine was recov-
ered by filtration (3.0 g, 74% isolated yield; pale yellow solid, >97%
purity by 1H NMR in DMSO-d6, 97.5% ee [(R)-enantiomer] by HPLC
(Method B on acetylated derivative).
Substrate 1ꢁHCl (405 mg, 2 mmol) was weighed in a glass liner,
placed in the Endeavour, and put under a nitrogen atmosphere. The
catalyst solution, [(S)-DAIPEN RuCl2 (S)-Xyl-PPhos], 0.8 mL of
0.0005 M in i-PrOH, S/C 5000/1), the base (1 mL KOH 10 M), and
solvent (3.2 mL i-PrOH) were injected into the reaction. The reac-
tion was purged by pressurizing to 28 bar hydrogen and releasing
pressure five times, then was heated to 65 °C and was pressurized
to 28 bar hydrogen. After 1 h, the pressure was released and a sam-
ple of the reaction crude was quenched with water/TFA/acetoni-
trile and analyzed by HPLC (Method A) for conversion (sampling
of the i-PrOH or KOH phases gave the same results). The i-PrOH
layer was separated, then NaCl was added to saturate the aqueous
phase that was extracted with i-PrOH (2 ꢃ 5 mL). The combined
organic phases were filtered over Celite, quenched with HCl 1 M
in Et2O, (6 mL were required to reach pH 1) and the solvent was
evaporated to give a wet, beige solid residue (yield not calculated).
The isolated product was analyzed by 1H NMR (DMSO-d6 + D2O,
93% purity) and HPLC (Method A). A sample was dissolved in pyr-
idine and acetic anhydride, stirred at room temperature until a
clear solution was obtained. The sample was evaporated, dried un-
der vacuum and filtered over a silica gel plug (eluent THF and
MeOH). An aliquot of the solution was diluted in hexane/i-PrOH.
>95% ee, [(S)-enantiomer] by HPLC analysis (Method B).
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