Copper-catalyzed asymmetric hydrogenation of aryl and heteroaryl ketones

Article abstract of DOI:10.1021/ol4021223

High throughput screening enabled the development of a Cu-based catalyst system for the asymmetric hydrogenation of prochiral aryl and heteroaryl ketones that operates at H₂ pressures as low as 5 bar. A ligand combination of (R,S)-N-Me-3,5-xylyl-BoPhoz and tris(3,5-xylyl)phosphine provided benzylic alcohols in good yields and enantioselectivities. The electronic and steric characteristics of the ancillary triarylphosphine were important in determining both reactivity and selectivity.

Full text of DOI:10.1021/ol4021223

ORGANIC
LETTERS
2013
Vol. 15, No. 17
4560–4563
Copper-Catalyzed Asymmetric Hydro-
genation of Aryl and Heteroaryl Ketones
Scott W. Krabbe,† Mark A. Hatcher,*,‡ Roy K. Bowman,‡ Mark B. Mitchell,‡
Michael S. McClure,‡ and Jeffrey S. Johnson*,†
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599, United States, and Product Development, GlaxoSmithKline,
Research Triangle Park, North Carolina 27709, United States
jsj@unc.edu; mark.a.hatcher@gsk.com
Received July 26, 2013
ABSTRACT
High throughput screening enabled the development of a Cu-based catalyst system for the asymmetric hydrogenation of prochiral aryl and
heteroaryl ketones that operates at H2 pressures as low as 5 bar. A ligand combination of (R,S)-N-Me-3,5-xylyl-BoPhoz and tris(3,5-
xylyl)phosphine provided benzylic alcohols in good yields and enantioselectivities. The electronic and steric characteristics of the ancillary
triarylphosphine were important in determining both reactivity and selectivity.
Asymmetric hydrogenation of simple, unactivated pro-
chiral ketones is an important process that provides access
to synthetically useful chiral secondary alcohol building
blocks from inexpensive starting materials. Transition
metals (Ru, Rh, Pd, Ir)1 are generally the catalysts of
choice for these reductions because they provide highly
active and selective catalysts. The high cost, limited supply,
and sometimes significant toxicity of transition metals
have sparked interest in the use of more environmentally
friendly base metals such as iron2 and copper. The purpose
of this communication is to report a new copper-based
catalyst system for the enantioselective hydrogenation of
prochiral ketones.
Racemic reduction using copper hydride complexes has
been known for several decades. Pioneering work by
Stryker and co-workers provided the hexameric copper
hydride species, [{CuH(PPh3)}6], which was particularly
useful in the reduction of R,β-unsaturated carbonyl
compounds.3 Phosphine steric modifications and tethering
provided particularly regioselective catalyst systems.4
With respect to asymmetric reduction, the use of copper
hydride complexes and silanes as the stoichiometric re-
ductant has been reported, with a variety of chiral ligands
providing exceptional reactivity and selectivity.5,6 Most of
these systems require the use of cryogenic temperatures for
optimal selectivity, and the reactions generate superstoi-
chiometric silane byproducts that detract from the overall
mass efficiency. A greener and more scalable alternative
would utilize hydrogen, but significantly less work has
been reported in this area.
† The University of North Carolina at Chapel Hill.
‡ GlaxoSmithKline.
(1) For selected reviews, see: (a) Ohkuma, T.; Noyori, R. Compre-
hensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin-Heidelberg, 1999; Vol. 1, pp 199À246. (b) Ohkuma,
T.; Noyori, R. Transition Metals in Organic Synthesis; Beller, M., Bohm,
K., Eds.; Wiley-VCH: Weinheim, 1998; Vol. 2, pp 29À41. (c) Chi, Y.; Tang,
W.; Zhang, Z. Modern Rhodium Catalyzed Organic Reactions; Evans,
P. A., Ed.; Wiley-VCH: Weinheim, 2005; pp 1À31. (d) Noyori, R.;
Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40. (e) Ohkuma, T. Proc.
Jpn. Acad., Ser. B 2010, 86, 202. (f) Malacea, R.; Poli, R.; Manoury, E.
Coord. Chem. Rev. 2010, 254, 729. (g) Chen, Q.-A.; Ye, Z.-S.; Duan, Y.;
Zhou, Y.-G. Chem. Soc. Rev. 2013, 42, 497.
(3) (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am.
Chem. Soc. 1988, 110, 291. (b) Mahoney, W. S.; Stryker, J. M. J. Am.
Chem. Soc. 1989, 111, 8818. (c) Brestensky, D. M.; Stryker, J. M.
Tetrahedron Lett. 1989, 30, 5677. (d) Koenig, T. M.; Daeuble, J. F.;
Brestensky, D. M.; Stryker, J. M. Tetrahedron Lett. 1990, 31, 3237.
(4) Chen, J.-X.; Daeuble, J. F.; Brestensky, D. M.; Stryker, J. M.
Tetrahedron 2000, 56, 2153.
(2) (a) Sui-Seng, C.; Freutel, F.; Lough, A. J.; Morris, R. H. Angew.
Chem., Int. Ed. 2008, 47, 940. (b) Morris, R. H. Chem. Soc. Rev. 2009, 38,
€
2282. (c) Berkessel, A.; Reichau, S.; von der Hoh, A.; Leconte, N.;
€
Neudorfl, J.-M. Organometallics 2011, 30, 3880.
r
10.1021/ol4021223
Published on Web 08/27/2013
2013 American Chemical Society

Shimizu and co-workers reported the first asymmetric
copper-catalyzed ketone hydrogenation utilizing the chiral
ligand BDPP, but only ortho-substituted aryl and hetero-
aryl ketones provided good enantioselectivities.7 Beller
and co-workers reported a more general catalyst system
using copper acetate and monodentate binaphthopho-
sphepine ligands, but enantioselectivities generally did
not exceed 75%.8 In addition to the moderate enantios-
electivities, both methodologies required hydrogen pres-
sures (50 bar) generally outside the desired range for pro-
cess applications.
We sought to employ high throughput screening of com-
mercially available chiral phosphine ligands to develop a
catalyst system which would provide usable enantioselec-
tivities and operate at lower pressures. By virtue of the
design of our screening procedure (all reagents were mixed
without a catalyst precomplexation time and run at 20 bar
of H2 pressure),9 only those ligands that perform well
under our desired conditions were identified. Screening
of ∼60 chiral phosphine ligands under conditions similar
to those of Shimizu and Beller for hydrogenation of
acetophenone led to the identification of several active
and selective complexes (Figure 1).
Given the precedent for asymmetric ketone reduction
with BIPHEP- and SEGPHOS-ligated copper hydride
species, their activity, and that of closely related ligands,
under the current conditions is not surprising.5d Unfortu-
nately, commercially available variants provided little
Figure 1. Ligands identified by parallel screening.
increase in selectivity. Despite the lower selectivity ob-
served, Me-BoPhoz emerged as an attractive candidate for
development due to its modular synthesis, relatively high
reactivity even at lower base loadings, and excellent sta-
bility.10 Attempts to increase selectivity using the parent ligand
through variation of additives and conditions were unsuc-
cessful.9 Of 33 phosphines tested, tris(3,5-xylyl)phosphine
(5) For examples of Cu-catalyzed hydrosilylation with homogeneous
Cu sources, see: (a) Lipshutz, B. H.; Noson, K.; Chrisman, W. J. Am.
Chem. Soc. 2001, 123, 12917. (b) Sirol, S.; Courmarcel, J.; Mostefai, N.;
Riant, O. Org. Lett. 2001, 3, 4111. (c) Lipshutz, B. H.; Lower, A.; Noson,
K. Org. Lett. 2002, 4, 4045. (d) Lipshutz, B. H.; Noson, K.; Chrisman,
W.; Lower, A. J. Am. Chem. Soc. 2003, 125, 8779. (e) Lee, D.-W.; Yun, J.
Tetrahedron Lett. 2004, 45, 5415. (f) Lipshutz, B. H.; Frieman, B. A.
Angew. Chem., Int. Ed. 2005, 44, 6345. (g) Lipshutz, B. H.; Lower, A.;
Kucejko, R. J.; Noson, K. Org. Lett. 2006, 8, 2969. (h) Issenhuth, J. T.;
Dagorne, S.; Bellemin-Laponnaz, S. Adv. Synth. Catal. 2006, 348, 1991.
(i) Mostefai, N.; Sirol, S.; Courmarcel, J.; Riant, O. Synthesis 2007, 1265.
(j) Lipshutz, B. H. Synlett 2009, 509. (k) Zhang, X.-C.; Wu, Y.; Yu, F.;
Wu, F.-F.; Wu, J.; Chan, A. S. C. Chem.;Eur. J. 2009, 15, 5888. (l)
Junge, K.; Wendt, B.; Addis, D.; Zhou, S.; Das, S.; Beller, M. Chem.;
Eur. J. 2010, 16, 68. (m) Zhang, X.-C.; Wu, F.-F.; Li, S.; Zhou, J.-N.;
Wu, J.; Li, N.; Fang, W.; Lam, K. H.; Chan, A. S. C. Adv. Synth. Catal
2011, 353, 1457.
Table 1. BoPhoz Ligand Screening
(6) For examples of Cu-catalyzed hydrosilylation with heteroge-
neous Cu sources, see: (a) Lipshutz, B. H.; Frieman, B. A.; Tomaso,
A. E., Jr. Angew. Chem., Int. Ed. 2006, 45, 1259. (b) Kantam, M. L.;
Laha, S.; Yadav, J.; Likhar, P. R.; Sreedhar, B.; Choudary, B. M. Adv.
Synth. Catal. 2007, 349, 1797. (c) Kantam, M. L.; Laha, S.; Yadav, J.;
Likhar, P. R.; Sreedhar, B.; Jha, S.; Bhargava, S.; Udayakiran, M.;
Jagadeesh, B. Org. Lett. 2008, 10, 2979. (d) Kantam, M. L.; Yadav, J.;
Laha, S.; Srinivas, P.; Sreedhar, B.; Figueras, F. J. Org. Chem. 2009, 74,
4608.
(7) (a) Shimizu, H.; Igarashi, D.; Kuriyama, W.; Yusa, Y.; Sayo, N.;
Saito, T. Org. Lett. 2007, 9, 1655. (b) Shimizu, H.; Nagano, T.; Sayo, N.;
Saito, T.; Ohshima, T.; Mashima, K. Synlett 2009, 3143.
(8) Junge, K.; Wendt, B.; Addis, D.; Zhou, S.; Das, S.; Fleischer, S.;
Beller, M. Chem.;Eur. J. 2011, 17, 101.
(9) See the Supporting Information
(10) (a) Boaz, N. W.; Debenham, S. D. Phosphino-Aminopho-
sphines, Catalyst Complexes and Enantioselective Hydrogenation.
WO 02/026750 A3, April 4, 2002. (b) Boaz, N. W.; Debenham, S. D.;
Mackenzie, E. B.; Large, S. E. Org. Lett. 2002, 4, 2421. (c) Boaz, N. W.;
Debenham, S. D.; Large, S. E.; Moore, M. K. Tetrahedron: Asymmetry
2003, 14, 3575. (d) Boaz, N. W.; Ponasik, J. A., Jr.; Large, S. E.
Tetrahedron: Asymmetry 2005, 16, 2063. (e) Li, X.; Jia, X.; Xu, L.;
Kok, S. H. L.; Yip, C. W.; Chan, A. S. C. Adv. Synth. Catal. 2005, 347,
1904. (f) Deng, J.; Duan, Z.-C.; Huang, J.-D.; Hu, X.-P.; Wang, D.-Y.;
Yu, S.-B.; Xu, X.-F.; Zheng, Z. Org. Lett. 2007, 9, 4825.
conv
(%)a
er
entry
R
Ar
(R:S)b
1
Me
Et
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
100
98
79:21
72:28
67:33
75:25
67:33
À
2
3
H
16
4
Me
Me
Me
Me
Et
4-CF3C6H4
52
5
4-F-C6H4
76
6
3,5-diCF3-C6H3
4-CH3C6H4
0
7
3g
3h
3i
100
100
100
100
53
79:21
74:26
68:32
91:9
8
4-CH3C6H4
9
Me
Me
H
4-OMe-C6H4
10
11
12
13
14
3,5-diMe-C6H3
3,5-diMe-C6H3
3,5-diMe-C6H3
3,5-diMe-4-OMe-C6H2
3,5-tBu-4-OMe-C6H2
3j
3k
3l
57:43
80:20
67:33
89:11
Et
76
Me
Me
3m
3n
100
43
a Determined by comparison of relative integration by HPLC of
alcohol to ketone. b Determined by HPLC analysis.
Org. Lett., Vol. 15, No. 17, 2013
4561

showed little to no increase in selectivity (entries 7À9).
Gratifyingly, 3,5-dimethyl-substitution resulted in an in-
crease in selectivity while maintaining reactivity (entry 10).
Increasing the steric demand at the 3 and 5 positions from
Me to Bu resulted in a similarly selective catalyst albeit
with diminished reactivity (entry 14).
Table 2. Ancillary Phosphine Screening
t
conv
(%)a
er
(R:S)b
Table 4. Substrate Scope
entry
R
1
3,5-CF3-C6H3
3,5-CF3-C6H3
3,5-F-C6H3
4-F-C6H4
4b
4b
4c
4d
4e
10
31:69
8:92
2c
3
78
37
42:58
41:59
47:53
53:47
51:49
52:48
52:48
53:47
75:25
66:34
91:9
4
>99
>99
17
5
3-F-C6H4
6
no ancillary
Ph
7
4f
>99
24
8
c-hexyl
4g
4h
4i
9
4-Me-C6H4
2-Me-C6H4
3-Me-C6H4
3-Et-C6H4
3,5-Me-C6H3
3,5-Et-C6H3
3,5-Me-4-OMe-C6H2
>99
17
10
11
12
13
14
15
4j
>99
>99
>99
90
4k
4a
4l
87:13
89:11
4m
>99
a Determined by comparison of relative HPLC integration of alcohol
to ketone. b Determined by HPLC analysis. c tBuOH instead of iPrOH.
Table 3. Temperature and Pressure Optimization
temp
pressure
(bar)
entrya
(°C)
t (h)
er (R:S)b
1
2
3
4
5
6
30
25
20
15
10
25
20
20
20
20
20
5
16
24
24
24
24
28
89.5:10.5
90.5:9.5
90.7:9.3
92.1:7.9
92.3:7.7
90.6:9.4
a All reactions proceeded to >97% conversion in the specified time
period. b Determined by HPLC analysis.
was identified as the optimal ancillary ligand. Based on
these unsuccessful attempts to increase selectivity, struc-
tural modification of the BoPhoz ligand was pursued
(Table 1).
Variation of the alkyl-amino group from methyl to ethyl
resulted in diminished reactivity and selectivity (entry 2).
Further decreased reactivity and selectivity was observed
when the free amino group was used (entry 3). Systematic
variation of the aryl substituents on the nonferrocenyl
phosphorus was easily achieved from a single precursor
and a variety of diaryl phosphorus chlorides. Decreased
electron density on this phosphorus resulted in less reactive
systems (entries 4À6). Electron releasing para-substituents
a Time when hydrogen uptake ceased. b Isolated yield. c Determined
by HPLC analysis. d tBuOH instead of iPrOH. e 4b instead of 4a, 30 °C.
f 3.0 mol % Cu(OAc)2, 3.0 mol % 3j, 3.0 mol % 4a, 45 mol % KOtBu.
g 25 °C.
4562
Org. Lett., Vol. 15, No. 17, 2013

Having identified BoPhoz ligand 3j as the most selective
of those examined, we revisited the impact of the ancillary
triarylphosphine (Table 2). As previously observed with
commercial (S,R)-N-Me-BoPhoz, the electronic and steric
characteristics of the aryl substituents played a key role
in determining reactivity and selectivity. In the absence
of added triarylphosphine, poor reactivity and selec-
tivity were observed (entry 6). Relatively electron deficient
phosphines favored the formation of the (S)-alcohol
(entries 1À5), while electron rich phosphines favored for-
mation of the (R)-alcohol (entries 7À15). Remarkably,
complete reversal of enantioselectivity could be achieved
by switching from phosphine 4b to 4a (entries 2 and 13).11
Unfortunately, ancillary phosphine 4b was only effec-
tive when tBuOH was used as the solvent (entry 1 vs 2).
Lower isolated yields of the chiral alcohols were obtained
of 4- and 3-substituted acetophenones, both electron-rich
and -deficient, were effectively reduced under the standard
conditions with good enantioselectivities (entries 3À9).
2-Substituted acetophenones were also reduced, albeit in
slightly decreased enantioselectivities (entries 10À11).
Increasing steric demand by variation of the ketone
R-substitution was well tolerated (entries 13À14). Although
the selectivity remains modest, 4-phenyl-2-butanone was
reduced with higher enantioselectivity than previously
reported with Cu-catalyzed hydrogenation (entry 15).
Several heteroaryl substituted ketones were also viable
substrates (entries 16À20), with some giving the best
enantioselectivities observed with this methodology. The
reduction of acetylferrocene, the first step in the synthesis
of BoPhoz ligands, can also be performed with this catalyst
system providing 2s in excellent yield and good enantio-
selectivity (entry 21).
In summary, high throughput screening enabled the
identification of commerically available (S,R)-N-Me-Bo-
Phoz as a lead ligand in the Cu-catalyzed asymmetric
reduction of prochiral ketones. Systematic structural var-
iation of both the chiral BoPhoz ligand and the ancillary
triarylphosphine provided a catalyst system which operates
at moderate H2 pressures and provides good enantioselec-
tivities for a variety of aryl and heteroaryl ketones. Investi-
gation into the use of this catalyst system in the reduction of
other unsaturated systems is currently underway.
t
i
with BuOH; therefore, PrOH was selected for further
study.
We next turned our attention to the effects of both
temperature and pressure on selectivity (Table 3). Low-
ering the temperature provided a modest increase in
selectivity without greatly increasing the reaction time
(entries 1À5). Gratifyingly, in contrast to the Cu-catalyzed
hydrogenations previously reported, the current system
still operates efficiently at pressures as low as 5 bar, giving
the same selectivity with only a slight increase in reaction
time (entry 6).
With standard conditions realized, we examined the
substrate scope of this hydrogenation (Table 4). A variety
Supporting Information Available. Hydrogenation
screening procedures and additional data not included
in manuscript tables; chiral ligand sources or synthesis;
selectivity determination methods. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(11) (a) Reetz, M. T.; Mehler, G. Tetrahedron Lett. 2003, 44, 4593.
(b) For a reversal in enantioselectivity by changing an achiral counter-
anion, see: Ding, Z.-Y.; Chen, F.; Qin, J.; He, Y.-M.; Fan, Q.-H. Angew.
Chem., Int. Ed. 2012, 51, 5706. (c) For a reversal in enantioselectivity
when the electronic features of the phosphine in a chiral ligand were
changed, see: Wu, H.-C.; Hamid, S. A.; Yu, J.-Q.; Spencer, J. B. J. Am.
Chem. Soc. 2009, 131, 9604.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 17, 2013
4563