Ruthenium-catalyzed asymmetric hydrogenation of β-keto- enamines: An efficient approach to chiral γ-amino alcohols

Article abstract of DOI:10.1002/adsc.201100305

A highly efficient and enantioselective hydrogenation of unprotected β-ketoenamines catalyzed with ruthenium(II) dichloro{(S)-(-)-2,2′- bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl}[(2S)-(+)-1, 1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine] {Ru[(S)-xylbinap][(S)-daipen] Cl₂} has been successfully developed. This methodology provides a straightforward access to free γ-secondary amino alcohols, which are key building blocks for a variety of pharmaceuticals and natural products, with high yields (>99%) and excellent enantioselectivities (up to 99% ee) in all cases. Copyright

Full text of DOI:10.1002/adsc.201100305

UPDATES
DOI: 10.1002/adsc.201100305
Ruthenium-Catalyzed Asymmetric Hydrogenation of b-Keto-
enamines: An Efficient Approach to Chiral g-Amino Alcohols
Huiling Geng,a,b,c Xiaowei Zhang,b,c Mingxin Chang,b Le Zhou,a Wenjun Wu,a,*
and Xumu Zhangb,*
a
College of Science, Northwest Agriculture & Forestry University, Yangling, Shaanxi 712100, Peopleꢀs Republic of China
Fax : (+86)-29-8709-3987; e-mail: wenjun_wu@263.com
Department of Chemistry and Chemical Biology & Department of Medicinal Chemistry, Rutgers, the State University of
b
New Jersey, Piscataway, New Jersey 08854, USA
Fax : (+1)-732-445-6312; e-mail: xumu@rci.rutgers.edu
Huiling Geng and Xiaowei Zhang contributed equally to this work.
c
Received: April 21, 2011; Revised: July 12, 2011; Published online: October 20, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100305.
Abstract: A highly efficient and enantioselective
hydrogenation of unprotected b-ketoenamines cata-
lyzed with ruthenium(II) dichloro{(S)-(À)-2,2’-
bis[di(3,5-xylyl)phosphino]-1,1’-binaphthyl}[(2S)-
(+)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butane-
b-tertiary amino ketones.[6] However, the hydrogena-
tion products need further tedious and complex trans-
formations to afford the desired product 2. Shimizu
reported an elegant and succinct method to prepare
chiral alcohols with high enantioselectivity and che-
moselectivity by Cu(I)-catalyzed asymmetric hydroge-
nation of several heteroaromatic ketones and
enones.[7] It is highly desired to develop an economic
and efficient protocol for the synthesis of 2 based on
direct asymmetric hydrogenation. Our group has al-
ready reported a direct hydrogenation of protected b-
ACHTUNGTRENNUNGdiamine] {Ru[(S)-xylbinap][(S)-daipen]Cl2} has
been successfully developed. This methodology pro-
vides a straightforward access to free g-secondary
amino alcohols, which are key building blocks for a
variety of pharmaceuticals and natural products,
with high yields (>99%) and excellent enantiose-
lectivities (up to 99% ee) in all cases.
secondary amino ketones to prepare
2
with
[Rh(DuanPhos)
N
ACHTUNGTNER(NUNG NBD)]SbF6 as catalyst, obtaining
Keywords: asymmetric catalysis; enamines; enantio-
selectivity; hydrogenation; ruthenium
Enantiomerically pure amino alcohols and their deriv- ric hydrogenation of b-ketoenamines with ee values of
atives are of great importance in synthetic and phar- >99% and turnover numbers (TON)=1000 under
maceutical chemistry.[1] Especially, g-secondary amino mild reaction condition, which provides an alternative
alcohols 2 have drawn extensive attention as they are and efficient approach to chiral g-amino alcohols 2
key intermediates for the synthesis of an important and the related pharmaceuticals.
family of norepinephrine reuptake inhibitors, 1a–d.[2]
The b-ketoenamine derivatives were synthesized di-
Enantiomerically active compounds 1a–d are widely rectly from readily available methyl aryl ketones 4
used as antidepressants in clinic medicine. Thus, a cat- through crossed Claisen condensation with ethyl for-
alytic access to enantiomerically enriched amino alco- mate, followed by amination with methylamine hy-
hols 2 is of great significance and necessity for the drochloride in a one-pot reaction (Scheme 1 and
pharmaceutical industry. The early synthesis of 2 Table 1).[10] With our optimized procedure, substrates
mainly relied on chiral epoxide compounds[3] or 3a–3j were prepared in moderate yields as stable crys-
enzyme catalysis[4]. Along with the development of talline solids. Due to the intramolecular hydrogen
catalytic asymmetric hydrogenation, several enantio- bonding, only the Z configuration of the products was
selective syntheses of 2, as well as 1, have been re- observed in most cases. It is worthy to note that the
ported based on hydrogenation of b-keto esters[5] or reaction afforded Z/E mixture products, 3b and 3f
Adv. Synth. Catal. 2011, 353, 3039 – 3043
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3039

Huiling Geng et al.
UPDATES
Scheme 1. A retrosynthesis of the family of Fluoxetine by asymmetric hydrogenation.
Table 1. Synthesis of b-ketoenamine 3.[a]
using 2-propanol as solvent (entry 6) could dramati-
cally enhance the enantioselectivity (98.7% ee) and
reactivity (>99%) of 2a. With 2-propanol as the opti-
mal solvent, the effect of the hydrogen pressure was
then investigated. Lowering the pressure to 1 bar can
slightly increase the enantioselectivity to 99.5% ee
(Table 2, entries 6, 9–11). Potassium tert-butoxide was
found to be the base of choice and another inorganic
base, potassium carbonate, also provided comparable
reactivity and enantioselectivity, while an organic
base, triethylamine, cannot promote the reaction at
all (Table 2, entries 6, 12 and 13). The reaction time
was tested as well, and set it to 24 h.
Encouraged by the above promising results, we fur-
ther explored the asymmetric hydrogenation of a
series of b-ketoenamine substrates, 3b–j, under the
optimized conditions with Ru[(S)-xylbinap][(S)-dai-
pen]Cl2 as the catalyst precursor. As shown in
Table 3, entries 1–10, all the hydrogenation reactions
smoothly proceeded to completion and provided g-
amino alcohols 2 in high yields (>99%) with very
high enantioselectivities (99.0–99.7% ee). No obvious
difference was observed between the reactivities and
enantioselectivities of pure (Z)-b-ketoenamines and
their Z/E mixtures (Table 3, entries 1, 2, 5 and 6). The
hydrogenation reactions also showed a high tolerance
to the electronic properties of the para-substituent on
Entry Ar
Ketoenamine Isomer[b] Yield [%][c]
1
2
C6H4
C6H4
3a
3b
3c
Z
52
Z/E=1/5 34
3
p-Me-C6H4
Z
Z
Z
35
66
46
4
p-MeO-C6H4 3d
5
6
7
8
p-F-C6H4
p-F-C6H4
p-Cl-C6H4
p-Br-C6H4
2-thienyl
3e
3f
3g
3h
3i
Z/E=3/2 23
Z
Z
Z
Z
44
56
25
39
9
10
2-naphthyl
3j
[a]
All reactions were carried out in a one-pot reaction with-
out separation of the intermediates, sodium enolates (see
Supporting Information for the detailed procedure).
Z/E ratios were determined by H NMR spectroscopy.
Yield of the isolated product.
[b]
[c]
1
(Table 1, entries 2 and 6), at lower reaction tempera- the phenyl ring regarding to both reactivity and enan-
tures. tioselectivity (Table 3, entries 3–8). b-Ketoenamine 3i,
Inspired by the success of [Rh(DuanPhos)- with a heteroaromatic ring function, was hydrogenat-
(NBD)]SbF6 catalyst in the asymmetric hydrogenation ed to 2i with high yield (>99%) and ee value (99.3%)
of protected b-secondary amino ketones, 3a was ini- as well (Table 3, entry 9).
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
tially examined as the standard substrate in a series of
In conclusion, we have reported that a variety of
rhodium-catalyzed hydrogenation reactions. However, enantiomerically active g-secondary amino alcohols,
neither [Rh
ACHTUNGTRENNUNG(DuanPhos)ACHTUNGTNER(NUGN COD)]BF4 nor [Rh(Tang- which are important pharmaceutical intermediates,
A
ACHTUNGTRENNUNG
catalytic systems could efficiently afford the desired tion of b-ketoenamines with Ru[(S)-xylbinap][(S)-dai-
amino alcohol product.[11] We have to turn our eyes to pen]Cl2 as catalyst. The very high reactivity and enan-
Ru-phosphine catalysts which are one of the most tioselectivity suggest that this protocol provides one
successful catalytic systems for asymmetric hydroge- of the shortest and most practical accesses to the anti-
nation of ketones.[12] Although Ru[(S)-C3-TunePhos- depressant, Fluoxetine, and related drugs. Studies
ACHTUNGTRENNUNG(p-cymene)]Cl2 and Ru[(S)-C3-TunePhosHCAUTNTGREN(NUGN DMF)n]Cl2 aimed at further expanding the substrate scope for
cannot provide the target product, Ru[(S)-xylbinap] the synthesis of various chiral amino alcohols are in
[(S)-daipen]Cl2,[13] L, gave the product 2a with 19.3% progress.
ee and 30.8% yield in methanol under 20 bar of hy-
drogen with 10 equivalents of potassium tert-butoxide.
Solvent screening (Table 2, entries 1–8) indicated that
3040
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 3039 – 3043

Ruthenium-Catalyzed Asymmetric Hydrogenation of b-Ketoenamines
Table 2. Ru[(S)-xylbinap][(S)-daipen]Cl2-catalyzed asymmetric hydrogenation of 3a under various conditions.[a]
Entry
PH [bar]
Solvent
Base
Yield [%][b]
ee [%][c]
2
1
2
3
4
5
6
7
8
20
20
20
20
20
20
20
20
1
MeOH
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
K2CO3
31
19.3
N.A.
N.A.
N.A.
98.0
98.7
99.3
98.1
99.5
99.4
99.3
98.1
N.A.
CF3CH2OH
toluene
EtOAc
CH2Cl2
i-PrOH
1,4-dioxane
THF
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
N.R.
N.R.
N.R.
60
>99
53
49
9
>99
>99
>99
92
10
11
12
13
5
10
20
20
TEA
N.R.
[a]
The hydrogenation reactions were carried out under the described conditions for each entry with 1.0 mol% of L as the
catalyst precursor (see Supporting Information for the general procedure).
Yields were determined by H NMR spectroscopy of the crude products.
The ee values of 2a were determined by chiral HPLC (with a Chiralpak OD-H column) analysis of its N-acyl derivative
[b]
[c]
1
(see Supporting Information).
Table 3. Ru-catalyzed asymmetric hydrogenation of b-ketoenamines 3a–j.[a]
Entry
Substrate
Ar
Isomer
Product
Yield [%][b]
ee [%] (Configuration)[c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5
C6H5
Z
2a
2b
2c
2d
2e
2f
2g
2h
2i
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
99.5 (R)
99.0 (R)
99.4 (R)
99.5 (R)
99.6 (R)
99.7 (R)
99.4 (R)
99.3 (R)
99.3 (R)
99.5 (R)
99.1(R)
Z/E=1:5
Z
Z
Z
Z/E=3:2
Z
Z
Z
p-Me-C6H4
p-MeO-C6H4
p-F-C6H4
p-F-C6H4
p-Cl-C6H4
p-Br-C6H4
2-thienyl
2-naphthyl
C6H5
9
10
3j
3k
Z
2j
2b
11[e]
Z/E=1:5
[a]
The hydrogenations were carried out in 2-propanol with 1.0 mol% of Ru[(S)-xylbinap] [(S)-daipen]Cl2, 10 equivalents of
KO-t-Bu under 1 bar H2 at room temperature for 24 h (see Supporting Information for the general procedure).
Yields were determined by H NMR spectroscopy of the crude products.
The ee values of 2a–2j were determined by chiral HPLC (with a Chiralpak OD-H column) analysis of their N-acyl deriva-
tives 5 (see Supporting Information). The absolute configurations of 2a and 2j were determined by comparing the sign of
the optical rotations with reported data, while the absolute configurations of other products were assumed to be the same
as 2a and 2j.
[b]
[c]
1
[e]
The hydrogenation was carried out in 2-propanol with 0.1 mol% of Ru[(S)-xylbinap] [(S)-daipen]Cl2, 10 equivalents of
KO-t-Bu under 100 bar H2 at 608C for 48 h.
Adv. Synth. Catal. 2011, 353, 3039 – 3043
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3041

Huiling Geng et al.
UPDATES
[2] a) D. T. Wong, J. S. Horong, F. P. Bymaster, K. L.
Hauser, B. B. Molloy, Life Sci. 1974, 15, 471; b) D. T.
Wong, F. P. Bymaster, J. S. Horong, B. B. Molloy, J.
Pharmacol. Exp. Ther. 1975, 193, 804; c) B. J. Foster,
E. R. Lavagnino, Drugs Future 1986, 11, 134; d) S. I.
Ankier, Prog. Med. Chem. 1986, 26, 121; e) D. W. Rob-
ertson, J. H. Krushinski, R. W. Fuller, J. D. Leander, J.
Med. Chem. 1988, 31, 1412; f) D. T. Wong, D. W. Rob-
ertson, F. P. Bymaster, J. H. Krushinski, L. R. Reid,
Life Sci. 1988, 43, 2049; g) Z. X. Wang, R. M. Abdul,
W. Gamini, G. B. Reddy, U.S. Pat. Appl. Publ. US
20070010678, 2007; h) T. Yokozawa, K. Yagi, T. Saito,
Eur. Pat. Appl. EP 1411045A1, 2004.
[3] a) D. Mitchell, T. M. Koenig, Synth. Commun. 1995, 25,
1231; b) Y. Gao, K. B. Sharpless, J. Org. Chem. 1988,
53, 4081; c) H. Kakei, T. Nemoto, T. Ohshima, M. Shi-
basaki, Angew. Chem. 2004, 116, 321; Angew. Chem.
Int. Ed. 2004, 43, 317.
[4] a) C. Xu, C. Yuan, Tetrahedron 2005, 61, 2169; b) A.
Kamal, G. B. R. Khanna, R. Ramu, Tetrahedron: Asym-
metry 2002, 13, 2039; c) C. Savile, J. M. Gruber, E.
Mundoref, G. W. Huisman, S. J. Collier, Patent WO
2010/025287A2, 2010.
[5] a) L. Chai, H. Chen, Z. Li, Q. Wang, F. Tao, Synlett
2006, 15, 2395; b) Y. Li, Z. Li, F. Li, Q. Wang, F. Tao,
Org. Biomol. Chem. 2005, 3, 2513; c) V. Ratovelomana-
na-Vidal, C. Girard, R. Touati, J. P. Tranchier, B. Ben
Hassine, J. P. GenÞt, Adv. Synth. Catal. 2003, 345, 261.
[6] a) T. Ohkuma, D. Ishii, H. Takeno, R. Noyori, J. Am.
Chem. Soc. 2000, 122, 6510; b) T. Ohkuma, M. Koizu-
mi, M. Yoshida, R. Noyori, Org. Lett. 2000, 2, 1749;
c) T. Ohkuma, M. Koizumi, K. Muniz, G. Hilt, C.
Kabuto, R. Noyori, J. Am. Chem. Soc. 2002, 124, 6508.
[7] H. Shimizu, T. Nagano, N. Sayo, T. Saito, T. Ohshima,
K. Mashima, Synlett 2009, 3143.
[8] D. Liu, W. Gao, C. Wang, X. Zhang, Angew. Chem.
2005, 117, 1715; Angew. Chem. Int. Ed. 2005, 44, 1687.
[9] K. Iwakura, T. Higashii, S. Bando, (Sumitomo Seika
Chemicals Co.), Patent WO 2004/103990A1, 2004.
[10] a) S. K. Chatterjee, W. Rudorf, Phosphorus, Sulfur Sili-
con Related Elements 1998, 133, 251; b) A. Zelenin,
U.S. Pat. Appl. Publ. US 20040102651, 2004; c) B.
Chen, J. Yeh, W. Wong, U.S. Pat. Appl. Publ. US
20090112001, 2009; d) K. Kogami, N. Hayashizaka, S.
Satake, I. Fuseya, H. Kagano, (Sumitomo Seika Chemi-
cals Co.), Patent WO 2004/016603A1, 2004; e) S.
Satake, N. Hayashizaka, I. Fuseya, M. Yanaka, H.
Kagano, (Sumitomo Seika Chemicals Co.), Patent WO
2007/020797A1, 2007.
Experimental Section
General Remarks
All reactions and manipulations were performed in a nitro-
gen-filled glovebox or under nitrogen using standard
Schlenk techniques unless otherwise noted. Column chroma-
tography was performed using Sorbent silica gel 60 ꢂ (230–
450 mesh). 13C NMR and 1H NMR spectral data were re-
corded on Bruker 400 MHz spectrometer. Chemical shifts
are reported in ppm. Enantiomeric excess values were deter-
mined by chiral HPLC on Agilent 1200 Series equipment.
Substrate Preparation
To a suspension of sodium ethoxide (100 mmol, 6.81 g) in
anhydrous THF (100 mL) was added ethyl formate
(75 mmol) dropwise at 08C, followed by the addition of
methyl aryl ketones (50 mmol). The resulting mixture was
refluxed overnight, cooled to 08C, treated with 38.5 wt%
methylamine hydrochloride solution (50 mmol) slowly,
warmed up to 308C for 3 h, cooled to room temperature,
and quenched with 0.2 wt% NaOH solution (20 mL) fol-
lowed by removal of the solvent under vacuum. The residue
was extracted with ethyl acetate (3ꢃ100 mL), combined the
organic layer, washed with brine, dried with MgSO4, and
concentrated under vacuum. The mixture was subjected to
column chromatography on silica gel using hexane and ethyl
acetate as the eluent to afford the substrates as stable crys-
talline solids.
General Procedure for Asymmetric Hydrogenation
A stock solution was made by mixing solid trans-RuCl2{(S)-
xylbinap}-{(S)-daipen} and anhydrous KO-t-Bu at a 1:10
molar ratio in 2-propanol at room temperature for 30 min in
a nitrogen-filled glovebox. A specified amount of catalyst
solution (0.1 mL, 0.001 mmol) was then transferred by sy-
ringe into the vials charged with different substrates
(0.1 mmol for each) in 2-propanol (2.9 mL). All the vials
were placed in a steel autoclave into which 1 bar of hydro-
gen gas was charged. After stirring at room temperature for
24 h, the hydrogen was carefully released and the solution
was concentrated and subjected to a short column of silica
gel to afford the desired products 2. The enantiomeric
excess of 2 was determined by chiral HPLC using an OD-H
column after being converted to its respective N-acyl derti-
vative 5.
[11] Rh-C3-TunePhos, Rh-f-binaphane, Rh-bianpine, Rh-Et-
DuPhos, Rh-(R)-BINAP as catalytic systems were also
examined.
Acknowledgements
[12] a) M. Kitamura, T. Ohkuma, S. Inoue, N. Sayo, H. Ku-
mobayashi, S. Akutagawa, T. Ohta, H. Takaya, R.
Noyori, J. Am. Chem. Soc. 1988, 110, 629; b) K. Mashi-
ma, K. Kusano, H. Sato, Y. Matsumura, K. Nazaki, H.
Kumobayashi, N. Sayo, Y. Hori, T. Ishizaki, S. Akutaga-
wa, H. Takaya, J. Org. Chem. 1994, 59, 3064; c) T. Ikar-
iya, K. Murate, R. Noyori, Org. Biomol. Chem. 2006, 4,
393; d) R. Noyori, T. Ohkuma, Angew. Chem. 2001,
113, 40; Angew. Chem. Int. Ed. 2001, 40, 40; e) R.
Noyori, Angew. Chem. 2002, 114, 2108; Angew. Chem.
We gratefully thank the National Institutes of Health
(GM58832) and Northwest Agriculture & Forestry University
for the financial support.
References
[1] M. Nogradi, Stereoselective Synthesis, VCH, Weinheim,
1987.
3042
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 3039 – 3043

Ruthenium-Catalyzed Asymmetric Hydrogenation of b-Ketoenamines
Int. Ed. 2002, 41, 2008; f) T. Ohkuma, M. Koizumi, H.
Doucet, T. Pham, M. Kozawa, K. Murata, E. Kataya-
ma, T. Yokozawa, T. Ikariya, R. Noyori, J. Am. Chem.
Soc. 1998, 120, 13529; g) T. Ohkuma, M. Koizumi, M.
Ohkuma, M. Koizumi, H. Ikehira, T. Yokozawa, R.
Noyori, Org. Lett. 2000, 2, 1749.
[13] Ruthenium(II)
dichloro{(S)-(À)-2,2’-bis[di(3,5-xylyl)-
phosphino]-1,1’-binaphthyl}[(2S)-(+)-1,1-bis(4-meth-
A
a
Yoshida, R. Noyori, Org. Lett. 2000, 2, 1749; h) T.
Adv. Synth. Catal. 2011, 353, 3039 – 3043
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3043