Asymmetric hydrogenation of heteroaromatic ketones and cyclic and acyclic enones mediated by Cu(I)-chiral diphosphine catalysts

Article abstract of DOI:10.1055/s-0029-1218347

Copper(I)-catalyzed asymmetric hydrogenation of heteroaromatic ketones, cyclic and acyclic enones is reported. The choice of the chiral diphosphine ligand highly influenced enantiose-lectivity as well as chemoselectivity. Highly enantioselective hydrogenation of ortho-substituted heteroaromatic ketones was achieved using BDPP as the ligand. In the 1,2-selective hydrogenation of acylic enone, SEGPHOS gave higher enantioselectivity than BDPP. On the other hand, the bulky ligand DTBM-SEGPHOS had a 1,4-selective nature, leading to the first highly 1,4-selective and enantioselective hydrogenation of cyclic enones.

Full text of DOI:10.1055/s-0029-1218347

LETTER
3143
Asymmetric Hydrogenation of Heteroaromatic Ketones and Cyclic and
Acyclic Enones Mediated by Cu(I)–Chiral Diphosphine Catalysts
Asymmetric
H
ydro
i
genatio
d
n of Hetero
e
aromatic
K
o
e
tone
s
Shimizu,*a,b Takuto Nagano,b Noboru Sayo,a Takao Saito,a Takashi Ohshima,*b Kazushi Mashima*b
a
Research & Development Division, Takasago International Corporation, 1-4-11 Nishi-yawata, Hiratsuka, Kanagawa, 254-0073, Japan
E-mail: hideo_shimizu@takasago.com
b
Department of Chemistry, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka 560-8531, Japan
E-mail: ohshima@chem.es.osaka-u.ac.jp; E-mail: mashima@chem.es.osaka-u.ac.jp
Received 3 August 2009
ic ketones positively affected enantioselectivity to afford
the desired alcohols in up to 92% ee. In the reaction of
enones, the choice of the chiral diphosphine ligand influ-
enced both enantioselectivity and 1,2- and 1,4-selectivity,
Abstract: Copper(I)-catalyzed asymmetric hydrogenation of het-
eroaromatic ketones, cyclic and acyclic enones is reported. The
choice of the chiral diphosphine ligand highly influenced enantiose-
lectivity as well as chemoselectivity. Highly enantioselective hy-
drogenation of ortho-substituted heteroaromatic ketones was leading to the highly 1,4-selective and enantioselective
achieved using BDPP as the ligand. In the 1,2-selective hydrogena-
hydrogenation of cyclic enones (up to >99% ee).
tion of acylic enone, SEGPHOS gave higher enantioselectivity than
BDPP. On the other hand, the bulky ligand DTBM-SEGPHOS had
We first examined the asymmetric hydrogenation of
heteroaromatic ketones under the optimized conditions
for aromatic ketones ({Cu(NO3)[P(3,5-xylyl)3]2}/(S,S)-
BDPP/P(3,5-xylyl)3, molar ratio of substrate to catalyst
(S/C) = 200, initial H2 pressure of 5.0 MPa, 30 °C,
Table 1).6 Hydrogenation of 5-methyl-2-acetylfuran (1a)
and 2-acetylthiophene (1b) proceeded smoothly, though
enantioselectivities of the corresponding alcohols 2a and
2b were moderate, 40% and 36% ee, respectively (entries
1 and 2). On the other hand, the introduction of a methyl
group at the ortho-position of 1b greatly enhanced enantio-
selectivity to 90% ee (entry 3), consistent with a previous
observation that the hydrogenation of ortho-methyl-sub-
stituted acetophenone derivatives affords the correspond-
ing alcohols with higher enantioselectivty.6
a 1,4-selective nature, leading to the first highly 1,4-selective and
enantioselective hydrogenation of cyclic enones.
Key words: asymmetric catalysis, hydrogenations, copper, het-
eroaromatic ketones, enones
Asymmetric hydrogenations catalyzed by chiral metal
complexes are among the most powerful and environmen-
tally benign processes used to produce optically active
natural and artificial compounds. Since the initial devel-
opment of asymmetric reactions, platinum-group metals
(e.g., Rh, Ru, Ir, and Pt) have been used as the catalytical-
ly active center of various chiral catalysts1 and show
prominent compatibility and wide applicability in many
industrial processes.2 Despite their high performance, re-
cent research has focused on minimizing the use of plati-
num-group metals and replacing them with an abundant
and inexpensive transition metal.3 A pioneering study by
Stryker demonstrating the feasibility of homogeneous
copper-catalyzed hydrogenation4 prompted us to focus
our attention on copper-based catalyst systems, and we
recently found that a Cu(I) complex, {Cu(NO3)[P(3,5-
xylyl)3]2}, together with (S,S)-2,4-bis(diphenylphosphi-
no)pentane (BDPP)5 and NaOt-Bu catalyzed asymmetric
hydrogenation of aryl ketones. Notably, ortho-substituted
acetophenone derivatives were hydrogenated to give the
corresponding alcohols in a highly enantioselective man-
ner (up to 91% ee).6 As a part of our continuing efforts
aimed at developing an efficient asymmetric Cu(I) cataly-
sis, we report on the asymmetric hydrogenation of het-
eroaromatic ketones and acyclic and cyclic enones
catalyzed by a Cu(I) complex, which was prepared from
[Cu(NO3)(PAr3)2] (Ar = Ph or 3,5-xylyl), chiral diphos-
phine, and NaO-t-Bu. ortho-Substitution of heteroaromat-
Regardless of the position of the acetyl group in five-
membered heterocycles, the presence of a methyl group at
the ortho-position to the acetyl group resulted in almost
complete formation of the corresponding alcohols 2 with
much higher enantioselectivity (89–92% ee, entries 4–6).
The present catalysis was also effective for the reaction of
six-membered heteroaromatic ketone 1g with ortho-meth-
oxy substitution to the acetyl group, affording the product
2g in 89% ee (entry 7).
We then examined the asymmetric hydrogenation of cy-
clic and acyclic enones for chemoselective asymmetric
hydrogenation, which potentially provides three kinds of
products, that is, ketones, allylic alcohols, and saturated
alcohols. Only a few previous chemoselective hydrogena-
tions by Cu catalyst systems have been reported: Stryker
reported that the [CuH(PPh3)]6/PhPMe2 system selective-
ly hydrogenated the carbonyl group of enals and enones to
give the corresponding allylic alcohols,4d and we reported
the same carbonyl selective hydrogenation of enals using
a
[Cu(NO3)(PPh3)2]/1,4-bis(diphenylphosphino)butane
(DPPB) system.7 Accordingly, we applied the present
Cu(I) catalyst system, {Cu(NO3)[P(3,5-xylyl)3]2}/(S,S)-
BDPP/NaO-t-Bu,8 to asymmetric hydrogenation of an
acyclic ketone, benzalacetone (3), to give the allylic alco-
SYNLETT 2009, No. 19, pp 3143–3146
x
x
.x
x
.2
0
0
9
Advanced online publication: 03.11.2009
DOI: 10.1055/s-0029-1218347; Art ID: U07909ST
© Georg Thieme Verlag Stuttgart · New York

3144
H. Shimizu et al.
LETTER
Table 1 Asymmetric Hydrogenation of Heteroaromatic Ketones 1a
Compared to 1,2-selective reduction of cyclic enones
where a diamine-modified Ru catalyst achieved high
enantioselectivity and excellent catalytic productivity,10
1,4-selective counterparts are quite limited11 because of
the unfavorable s-trans coordination of the cyclic enone to
transition metals. Thus, although excellent asymmetric
1,4-selective reduction of cyclic enones using Cu-cata-
lyzed hydrosilylation12 and hydroboration13 were report-
ed, asymmetric 1,4-selective reduction of cyclic enones
using Cu-catalyzed hydrogenation has not been reported.
Based on the results shown in Table 2, we examined
asymmetric 1,4-selective hydrogenation of isophorone (7)
using the {Cu(NO3)[P(3,5-xylyl)3]2}/(R)-DTBM-SEG-
PHOS/NaOt-Bu system (Table 3).
H2 (5.0 MPa)
{Cu(NO3)[P(3,5-xylyl)3]2} (S/C = 200)
O
OH
(S,S)-BDPP (1 equiv to Cu)
P(3,5-xylyl)3 (6 equiv to Cu)
NaOt-Bu (10 equiv to Cu)
Me
Me
hetero
aromatic
hetero
aromatic
i-PrOH, 30 °C, 16 h
Ph2P PPh2
1a–g
2a–g
Me
(S,S)-BDPP
Me
O
O
O
O
O
S
S
Me
Me
Me
Me
Me
Me
Me
Me
S
Me
1c
Me
O
1a
1b
1d
Table 2 Asymmetric Hydrogenation of Benzalacetone (3)
O
O
H2 (5.0 MPa)
S
N
[Cu(NO3)(PAr3)2] (S/C = 200)
Me
O
Me
Me
chiral ligand (1 equiv to Cu)
NaOt-Bu (10 equiv to Cu)
O
MeO
N
OMe
Me
Me
Me
EtOH, 30 °C, 16 h
1e
1f
1g
3
OH
Me
O
Entry
Substrate Conv.
(%)b
Isolated yield ee
Configd
(%)c
(%)b
Me
Me
+
+
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
>99
>99
97
79
40
36
90
92
89
90
89
(–), (S)
(–), (S)
(–), (S)
(–), (S)
(–)
4
5
6
OH
82
89
>99
99
93
Entry Ar
Chiral Ligand
Conv. 4/5/6a
ee of 4
80
(%)a
(%)b
>99
77
91
(–)
1
3,5-xylyl (S,S)-BDPP
3,5-xylyl (R)-SEGPHOS
93
97:2:<1 62 (S)
1g
71e
(–)
2
98c 98:2:<1 72 (S)
a The reaction was performed at 3.6 mmol scale.
b Determined by GC analysis.
3
Ph
Ph
(R)-SEGPHOS
99
89:9:2
19 (S)
c Isolated yield by bulb-to-bulb distillation.
4d
(R)-DTBM-SEGPHOS 70
38:61:1
–
d Sign of [a]D27 of each product and absolute configuration of 2a–d.
e Isolated yield by silica gel chromatography.
a Determined by GC analysis.
b Determined by HPLC analysis.
c Isolated yield by bulb-to-bulb distillation was 81%.
hol (S)-4 with excellent chemoselectivity (97%) and mod-
erate enantioselectivity (62% ee, Table 2, entry 1). The
use of the biaryl ligand (R)-SEGPHOS9 instead of (S,S)-
BDPP improved enantioselectivity to 72% ee while main-
taining high 1,2-selectivity (98%, entry 2). Changing
the Cu source from {Cu(NO3)[P(3,5-xylyl)3]2} to
[Cu(NO3)(PPh3)2] resulted in slight decrease of 1,2-selec-
tivity (89%) and significant decrease of enantioselectivity
(19% ee, entry 3). On the other hand, the use of DTBM-
SEGPHOS, a bulkier variant of SEGPHOS, yielded 1,4-
reduction product 5 as a major product (entry 4). These
data clearly indicate that Cu(I)–DTBM-SEGPHOS com-
plex preferentially promoted a 1,4-reduction of enone 3 to
the saturated ketone 5, in sharp contrast to the high 1,2-se-
lectivity promoted by the Cu(I)–SEGPHOS complex. We
thus anticipated that the Cu catalyst system of (R)-DTBM-
SEGPHOS could be applied to an asymmetric 1,4-reduc-
tion of cyclic enones.
d Reaction time was 41 h. Isolated yields of 4 and 5 were 5% and 7%,
respectively, due to the formation of unidentified oligomeric com-
pounds.
O
PAr2
O
(R)-SEGPHOS: Ar = Ph
(R)-DTBM-SEGPHOS: Ar = C6H2-3,5-t-Bu2-4-OMe
O
PAr2
O
As expected, the desired saturated ketone (R)-9 was ob-
tained in a highly 1,4-selective manner (97%) with quite
high enantioselectivity (98% ee), though conversion was
unsatisfactory (entry 1). To compensate for this low con-
version, we switched the catalyst precursor to less bulky
[Cu(NO3)(PPh3)2] and the conversion was improved to
51% while maintaining high 1,4-selectivity (91%) and
high enantioselectivity (99% ee, entry 2).14 The conver-
Synlett 2009, No. 19, 3143–3146 © Thieme Stuttgart · New York

LETTER
Asymmetric Hydrogenation of Heteroaromatic Ketones
3145
sion was further improved by increasing the reaction tem-
perature (50 °C, entry 3) or by increasing catalyst loading
(S/C = 100, entry 4). Under the conditions shown in entry
3, ketone 9 was reduced to saturated alcohol 10 with 69%
conversion whereas the allylic alcohol 8 was not reduced
at all. These results indicated that over-reduction proceed-
ed through a 1,4-selective reduction of enone and subse-
quent C=O bond reduction, and thus the 1,4-selectivity of
the Cu(I)–DTBM-SEGPHOS system would be quite high
(96:4 to >99:1). In the previous [CuH(PPh3)]6-catalyzed
Table 4 Asymmetric Hydrogenation of Piperitenone (11)
H2 (5.0 MPa)
[Cu(NO3)(PPh3)2]
(R)-DTBM-SEGPHOS
(1 equiv to Cu)
NaOt-Bu (10 equiv to Cu)
Me
Me
Me
+
i-PrOH, 50 °C, 18 h
O
O
OH
Me
Me
Me
Me
Me
Me
11
12
13
hydrogenation, the use of excess Ph3P to Cu was essential Entry S/C
Conv.
(%)a
12/13a
ee of 12
ee of 13
(%)a
(%)a,b
to achieve high conversion.4 In contrast, the present
Cu(I)–DTBM-SEGPHOS system proceeded even under
Ph3P-free conditions with comparable selectivity and only
slightly less conversion (entry 5), indicating that mono-
dentate phosphine Ph3P does not participate in the catalyt-
ic cycle. To the best of our knowledge, this is the first
example of a Cu-catalyzed asymmetric 1,4-selective hy-
drogenation of enone.15
1
2
200
100
98
73c:27
31:69d
96 (R)
90 (R)
>99 (1R,5R)
>99 (1R,5R)
>99
a Determined by GC analysis.
b Only cis-isomer was observed on GC (cis/trans = >99:1)
c Isolated yield by silica gel chromatography was 52%.
d Isolated yield by silica gel chromatography was 50%.
Finally, we applied the Cu(I)–DTBM-SEGPHOS catalyst
system to a 1,4-reduction of another attractive substrate,
piperitenone (11), which is a starting compound for the
synthesis of optically active (–)-menthol.16 Hydrogena-
tion of 11 potentially affords 26 products via the satura-
tion of C=C and/or C=O double bonds. Thus, a highly
enantioselective as well as highly chemoselective catalyst
is required to obtain the desired (R)-pulegone (12). The
asymmetric hydrogenation of 11 was conducted with 0.5
mol% loading of the Cu(I) catalyst under the same reac-
tion conditions as entry 3 in Table 3 to give (R)-12 (73%,
96% ee) together with (1R,5R)-pulegol (13, 27%, >99%
ee, Table 4, entry 1). Increasing catalyst loading to 1.0
mol% gave more 13 (69%), which is more advanced inter-
mediate for the synthesis of (–)-menthol, with high enan-
tioselectivity (>99% ee) and high diastereoselectivity (cis/
trans >99:1, entry 2). In contrast to the reported Rh cata-
lyst system where the s-cis C=C double bond was also re-
duced to afford a fully saturated ketone as a major over-
reduced product,16 the present Cu-catalyzed system did
not reduce the s-cis C=C double bond.17
In conclusion, we demonstrated that a Cu(I)-based system
involving chiral chelating diphosphine ligands effectively
catalyzed the asymmetric hydrogenation of several het-
eroaromatic ketones and enones with good to high enanti-
oselectivity (up to 99% ee). The chemoselectivity and
enantioselectivity of acyclic and cyclic enones highly de-
pended on the chiral diphosphine ligands. In contrast to
the general tendency that a Cu(I)-based system prefers a
1,2-selective reduction, this new Cu(I) system bearing the
DTBM-SEGPHOS ligand catalyzed a 1,4-selective re-
duction with high enantioselectivity. Further investigation
of the Cu(I)-based catalyst system for asymmetric hydro-
genation of various functionalized alkenes, ketones, and
imines is ongoing in our laboratory.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Table 3 Asymmetric Hydrogenation of Isophorone (7)
H2 (5.0 MPa), [Cu]
Me
Me
Me
Me
(R)-DTBM-SEGPHOS
(1 equiv to Cu)
NaOt-Bu (10 equiv to Cu)
+
+
Me
Me
i-PrOH, T, 18 h
Me
Me
Me
Me
Me
Me
O
OH
O
OH
7
8
9
10
Entry
[Cu]
Temp (°C)
S/C
Conv. (%)a
8/9/10a
0:97:3
ee of 9 (%)a
98 (R)
1
2
3
4
5
{Cu(NO3)[P(3,5-xylyl)3]2}
[Cu(NO3)(PPh3)2]
[Cu(NO3)(PPh3)2]
[Cu(NO3)(PPh3)2]
CuCl
30
30
50
30
30
200
200
200
100
100
16
51
72
77
59
2:91:7
99 (R)
4:82:14
<1:84:16b
<1:91:9
98 (R)
99 (R)
96 (R)
a Determined by GC analysis.
b Isolated yield of 9 by silica gel chromatography was 51% due to the relatively low boiling point of 9.
Synlett 2009, No. 19, 3143–3146 © Thieme Stuttgart · New York

3146
H. Shimizu et al.
LETTER
(10) (a) Ohkuma, T.; Ikehira, H.; Ikariya, T.; Noyori, R. Synlett
1997, 467. (b) Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham,
T.; Kozawa, M.; Murata, K.; Katayama, E.; Yokozawa, T.;
Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 13529.
(c) Doucet, H.; Ohkuma, T.; Murata, K.; Yokozawa, T.;
Kozawa, M.; Kitayama, E.; England, A. F.; Ikariya, T.;
Noyori, R. Angew. Chem. Int. Ed. 1998, 37, 1703.
(11) (a) Solodar, J. J. Org. Chem. 1978, 43, 1787.
(b) Massonneau, V.; Le Maux, P.; Simonneaux, G.
J. Organomet. Chem. 1987, 327, 269. (c) Ohta, T.; Miyake,
T.; Seido, N.; Kumobayashi, H.; Takaya, H. J. Org. Chem.
1995, 60, 357. (d) Lu, S.-M.; Bolm, C. Chem. Eur. J. 2008,
14, 7513. (e) Lu, S.-M.; Bolm, C. Angew. Chem. Int. Ed.
2008, 47, 8920.
(12) (a) Moritani, Y.; Appella, D. H.; Jurkauskas, V.; Buchwald,
S. L. J. Am. Chem. Soc. 2000, 122, 6797. (b) Lipshutz,
B. H.; Servesko, J. M. Angew. Chem. Int. Ed. 2003, 42,
4789. (c) Lipshutz, B. H.; Servesko, J. M.; Petersen, T. B.;
Papa, P. P.; Lover, A. A. Org. Lett. 2004, 6, 1273.
(13) Lipshutz, B. H.; Papa, P. Angew. Chem. Int. Ed. 2002, 41,
4580.
(14) The reaction using BDPP and SEGPHOS instead of DTBM-
SEGPHOS under the reaction conditions of entry 2 resulted
in low conversion and low chemoselectivity. (S,S)-BDPP:
conv. 25%, 8/9/10 = 53:11:36. R-SEGPHOS: conv. 17%,
8/9/10 = 11:18:70.
(15) Asymmetric hydrogenation of 3-methylcyclohex-2-enone
under the reaction conditions described in Table 3, entry 4
resulted in 51% conversion, allylic alcohol/sat. ketone/sat.
alcohol = 2:61:37, 30% yield of sat. ketone, 92% ee (R) of
sat. ketone (not optimized).
References and Notes
(1) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
Wiley-VCH: New York, 2000, 1–110.
(2) Blaser, H.-U.; Pugin, B.; Spindler, F. Enantioselective
Synthesis, In Applied Homogeneous Catalysis with
Organometallic Compounds, 2nd ed., Vol. 3; Cornils, B.;
Hermann, W. A., Eds.; Wiley-VCH: Weinheim, 2002,
1131–1149.
(3) For reviews on asymmetric reduction using 3d transition
metals. For Fe catalysts, see: (a) Gaillard, S.; Renaud, J.-L.
ChemSusChem 2008, 1, 505. (b) Enthaler, S.; Junge, K.;
Beller, M. Angew. Chem. Int. Ed. 2008, 47, 3317. For Cu
catalysts, see: (c) Render, S.; Oestreich, M. Angew. Chem.
Int. Ed. 2007, 46, 498.
(4) (a) Mahoney, W. S.; Stryker, J. M. J. Am. Chem. Soc. 1989,
111, 8818. (b) Stryker, J. M.; Mahoney, W. S.; Daeuble,
J. F.; Brestensky, D. M. In Catalysis of Organic Reactions;
Pascoe, W. E., Ed.; Marcel Dekker: New York, 1992, 29–
44. (c) Daeuble, J. F.; Stryker, J. M. In Catalysis of Organic
Reactions; Sacros, M. G.; Prunier, M. L., Eds.; Marcel
Dekker: New York, 1995, 235–247. (d) Chen, J.-X.;
Daeuble, J. F.; Brestensky, D. M.; Stryker, J. M.
Tetrahedron 2000, 56, 2153. (e) Chen, J.-X.; Daeuble, J. F.;
Stryker, J. M. Tetrahedron 2000, 56, 2789.
(5) Bakos, J.; Tóth, I.; Markó, L. J. Org. Chem. 1981, 46, 5427.
(6) Shimizu, H.; Igarashi, D.; Kuriyama, W.; Yusa, Y.; Sayo,
N.; Saito, T. Org. Lett. 2007, 9, 1655.
(7) Shimizu, H.; Sayo, N.; Saito, T. Synlett 2009, 1295.
(8) The reaction with additional 3 equiv of P(3,5-xylyl)3 gave an
almost identical result.
(9) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.;
Miura, T.; Kumobayashi, H. Adv. Synth. Catal. 2001, 343,
264.
(16) Ohshima, T.; Tadaoka, H.; Hori, K.; Sayo, N.; Mashima, K.
Chem. Eur. J. 2008, 14, 2060.
(17) Formation of the fully sat. ketone, menthone, was <1%
based on GC analysis.
Synlett 2009, No. 19, 3143–3146 © Thieme Stuttgart · New York