Highly chemo- And enantioselective hydrogenation of linear α,β-unsaturated ketones

Article abstract of DOI:10.1002/chem.200801096

A study was conducted to report the synthesis of sulfoximine-derived P,N-ligands and their applications in indium-catalyzed asymmetric hydrogenation reactions. Investigations were conducted using linear β,β- disubstituted 1,3-diphenyl-2-butenone as model substrate and iridium, having a ketonic phenyl group and two alkyl substituents at the olefinic β-positions. Methyl ketone with β-methyl and β-phenyl substituent was also applied in the investigations.

Full text of DOI:10.1002/chem.200801096

COMMUNICATION
DOI: 10.1002/chem.200801096
Highly Chemo- and Enantioselective Hydrogenation of Linear
a,b-Unsaturated Ketones
Sheng-Mei Lu and Carsten Bolm*[a]
Asymmetric hydrogenation of olefins is one of the most
powerful transformations in asymmetric catalysis. In reduc-
tions of unfunctionalized substrates, chiral iridium com-
plexes with N-heterocyclic carbene ligands or P,N-ligands
have revealed high activities and excellent enantioselectivi-
ties under relatively mild reaction conditions.[1] Catalytic
asymmetric hydrogenations of functionalized olefins such as
a-(acylamino) acrylic acids, enamides, a,b-unsaturated car-
boxylic acids and esters, allylic and homoallylic alcohols
have also been widely investigated, and they can most suc-
cessfully be performed with chirally modified ruthenium,
rhodium and iridium complexes.[2] In contrast, enone-to-
ketone hydrogenations are less studied, which is surprising
considering the synthetic importance of compounds with ste-
reogenic centers at the a- or b-position to a carbonyl
group.[3]
Generally, the chemoselectivity is a key issue in the hy-
drogenation of a,b-unsaturated ketones, since both double
bonds can react. Commonly, in catalytic hydrogenations C=
C double bonds are more reactive than C=O ones.[4] Impor-
tant exceptions are Noyoriꢀs RuII–diamine–diphosphine[5a–c]
and Takayaꢀs IrI–BINAP[5d] catalyst systems, which preferen-
tially reduce carbonyl groups faster than C=C double bonds.
Effective catalysts for enantioselective C=C bond hydroge-
nations of unsaturated ketones, especially those applicable
for linear substrates, are still rare.[6] The following examples
shall illustrate the current status.
plex as the catalyst,[8] but only 2% ee were achieved in
asymmetric hydrogenations of linear a,b-unsaturated ke-
tones. In 1995, Takaya and co-workers employed RuII–
BINAP complexes as catalysts to hydrogenate exo-cyclic
enones, and they obtained 2-alkyl-substituted cyclic ketones
with up to 98% ee.[9] However, the conversion of a 2-aryl-
substituted substrate provided a product with only 9% ee,
and furthermore, to achieve full conversion, it was necessary
to employ both high pressure (100 bar) and elevated tem-
perature (508C). A few selected examples of hydrogenations
of endo-cyclic enones were reported by Consiglio[10] and
Genet.[11] The former obtained (two) products with up to
76% ee and the latter focused on a synthesis of (+)-cis-
methyl dihydrojasmonate, which was finally prepared with
88% ee. In 2005, Hilgraf and Pfaltz investigated the hydro-
genation of 3-methyl cyclohexenone using iridium/P,N-
ligand complexes as catalysts, and a moderate enantioselec-
tivity (58% ee) was obtained under high pressure (100 bar)
using a 4 mol% catalyst loading.[12] Subsequently, MacMil-
lan[13] and List[14] found organocatalytic transfer hydrogena-
tion of enones using Hantzsch esters as hydrogen sources.
Excellent enantioselectivities (up to 98% ee) were obtained
in the conjugate reduction of endo-cyclic enones. However,
linear enones were less suitable and an eemax of only 70%
was obtained.[14] The most recent developments stem from
Mashima and co-workers, who used a cationic RhI/DTBM-
SegPhos/(CH2CH2PPh3Br)2 catalyst system to hydrogenate
endo-cyclic enones providing products with up to 98% ee.[15]
Heterogeneous hydrogenations of exo-cyclic enones have
also been investigated,[16] but only moderate enantioselectiv-
ities were achieved.
As early as 1983, Maux and Simonneaux investigated
asymmetric hydrogenations of a,b-unsaturated ketones cata-
lyzed by chiral [Co2(CO)8]/phosphine complexes giving satu-
rated ketones with 1–16% ee.[7] Later, the enantioselectivity
was improved to 62% ee by using a chiral ruthenium com-
Recently, we reported the synthesis of sulfoximine-de-
rived P,N-ligands and their applications in iridium-catalyzed
asymmetric hydrogenation reactions.[17,18] As part of our
continued interest in the area and with the goal to explore
the general reactivity pattern of this catalyst family (see
below, complexes 1 and 2), we focused our efforts now on
the hydrogenation of a,b-unsaturated ketones.
[a] Dr. S.-M. Lu, Prof. Dr. C. Bolm
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52056 Aachen (Germany)
Fax : (+49)-241-8092-391
E-mail: Carsten.Bolm@oc.rwth-aachen.de
We began the study using linear b,b-disubstituted 1,3-di-
phenyl-2-butenone [(E)-4a] as model substrate and iridium
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801096.
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Complete conversion and for-
mation of ketone 5a with 76%
ee were found when the reac-
tion was carried out in di-
chloromethane
(Table 1,
entry 4). In THF the conver-
sion was low (35%; entry 5).
By using toluene as solvent,
hydrogenations of (E)-4a cata-
lyzed by complexes 1b–i pro-
ceeded well as indicated by the
results shown in Table 1, en-
tries 6–13. All complexes were
complex 1a as catalyst (1mol%). To our delight, full con-
version and excellent chemoselectivity resulted at 60 bar hy-
drogen pressure in a reaction performed at room tempera-
ture in toluene for 18 h. The major product (ꢀ95%) was sa-
turated ketone 5a (1,3-diphenyl-butan-1-one) with 76% ee,
and only traces of the corresponding saturated alcohol 6a
(ꢁ5%) could be detected (Table 1, entry 1). No allylic alco-
hol was formed. These results were surprising and indicated
the discovery of a complementary catalysts system to that of
Noyori, whose RuII–diamine–diphosphine complexes provid-
ed unsaturated alcohols from a,b-unsaturated ketones.[5]
When the reaction was carried out with complex 2, incom-
plete conversion of enone (E)-4a (75%) resulted, and
larger quantities (15%) of saturated alcohol 6a were
formed (Table 1, entry 2). Although the conversion of the
reaction with complex 3 was complete, the enantioselectivity
was low giving 5a with 26% ee. Furthermore, a significant
amount of 6a was found (entry 3).
highly effective leading to full conversion and the predomi-
nate formation of ketone 5a (>95%). The alkyl substituents
of the sulfoximidoyl moiety and the substitution pattern of
the phenyl group at the phosphorus atom had no obvious
effect on the performance of the resulting catalysts. All
(complexes 1a–h) provided 5a with similar enantioselectivi-
ty (in the range of 71–81% ee, Table 1, entries 1 and 6–12),
and only complex 1i led to 5a with a significantly lower ee
(54%; entry 13). The best result (>95% conversion, 81%
ee) was obtained, when complex 1c was used as catalyst.
Encouraged by the results achieved in the asymmetric hy-
drogenation of (E)-4a catalyzed by complexes 1, various
other b,b-disubstituted enones were applied (Table 2). Gen-
erally, the substrate conversions were high. The reactions
with enones (E)-4a–d revealed that increasing the size of
the alkyl group at the b-position of the carbonyl group had
a positive effect on the enantioselectivity. Thus, methyl sub-
stituted (E)-4a was hydrogenated with 1c as catalyst to give
a product with 81% ee (Table 2, entry 1). Under the same
conditions, the ethyl-, isopropyl, and cyclohexyl-substituted
analogues [(E)-4b, (E)-4c, and (E)-4d] gave the corre-
sponding ketones (5b–d) with 89, 97 and 97% ee, respec-
tively (Table 2, entries 5, 10, and 17).
In order to improve the catalyst system, the effect of the
solvent and the structural details of complex 1 were studied.
Table 1. Enantioselective hydrogenation of 1,3-diphenyl-2-butenone
[(E)-4a].[a]
For the hydrogenation of enone (Z)-4c, which differed
from (E)-4c by its altered olefin geometry, both conversion
and enantioselectivity were slightly lower (compared with
the analogous reaction of its diastereomeric counterpart).
The absolute configuration of the product (ketone 5c) was
reversed (entries 14–16), which indicated that the catalyst
approached the olefin from the same face. Consequently,
the ratio of the (Z)- and (E)-isomers will greatly affect the
enantioselectivity of the product. From a practical point of
view, this offers a convenient access to both enantiomers of
a ketone by using the same catalyst if isomerically pure sub-
strates are available.
Changing the substitution pattern on the ketonic phenyl
group affected both conversion and enantioselectivity only
to a small degree. Thus, hydrogenations of chloro- and me-
thoxy-substituted enones (E)-4e and (E)-4 f with 1d as cata-
lyst led to almost identical results (>95% conversion in
both cases; 96% ee for 5e and 97% ee for 5 f) as conver-
sions of (E)-4c.
Entry
Solvent
Complex
Conversion [%][b]
ee of 5a [%][c]
1toluene
2
3
4
5
6
7
8
1a
2
3
>95
75 (60)[d]
>95 (69)[d]
>95
76
n.d.
26
76
n.d.
75
81
80
78
75
toluene
toluene
CH2Cl2
THF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1a
1a
1b
1c
1d
1e
1 f
1g
1h
1i
35
>95
>95
>95
>95
>95
>95
>95
9
10
11
12
13
75
71
54
>95
[a] Reactions conditions: (E)-4a (0.5 mmol), catalyst 1 (1mol%), sol-
vent (1.5 mL), 18 h reaction time, under argon at room temperature.
[b]Measured by 1H NMR. [c]Enantiomer ratios were determined by
HPLC by using a Chiralcel OJ column. The S enantiomer of the product
was formed in excess; n.d.=not determined. [d]The values in parenthe-
ses refer to the detected amount of saturated ketone 5a.
In order to test if the aryl groups of the substrates were
essential for efficient asymmetric hydrogenations, enone
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Chemo- and Enantioselective Hydrogenation
COMMUNICATION
Table 2. Enantioselective hydrogenations of linear a,b-unsaturated keto-
(E)-4h with a b-methyl and b-phenyl substituent was ap-
plied (Table 2, entries 29–32). For both substrates the con-
versions were complete and the enantioselectivities in the
formation of the corresponding saturated ketones (5g and
5h, respectively) were comparable to the one observed in
the reaction with enone (E)-4a. Noteworthy is that the hy-
drogenation of (E)-4h also generated a significant amount
of saturated alcohol (fully reduced product; not shown),
which was formed with moderate ee (57–66%). These re-
sults allow the conclusion that the aryl groups were not re-
quired for conversion and enantioselectivity, but that the
presence of a ketonic aryl group positively affected the che-
moselectivity of the reaction.
nes.[a]
Entry
Substrates
Catalyst Yield [%][b]
ee [%][c]
configuration[d]
1
2
3
1c
1d
1 f
89
94
9175 (
81( S)
80 (S)
S)
4
5
6
7
8
1a
1c
1d
1 f
1h
92
94
88
92
92
86 (S)
89 (S)
87 (S)
88 (S)
85 (S)
In summary, we discovered and developed catalysts for
the enantioselective hydrogenation of linear enones provid-
ing saturated ketones with up to 97% ee. The application of
the catalyst system to other substrates is currently under in-
vestigation.
9
1a
1c
1d
1 f
1g
90
94
93
93
90
96 (+)
97 (+)
97 (+)
96 (+)
96 (+)
10
11
12
13
Experimental Section
14
15
16
1c
1d
1g
86
80[e]
93
92 (À)
87 (À)
93 (À)
General procedure for hydrogenation: Complex 1a (4.1mg,
0.0025 mmol) and substrate 4 (0.25 mmol) were placed in a 5 mL vial
equipped with a stirrer bar. This vial was then put into an argon-filled
steel autoclave. To the mixture was added toluene (1.0 mL) under an
argon atmosphere. The autoclave was then closed, purged three times
with hydrogen (less than the pressure needed) and finally pressurized to
the value needed. The reaction mixture was stirred for the indicated
period of time, and then the hydrogen gas slowly released. The conver-
sion of the substrate was determined by 1H NMR spectroscopy of the
crude reaction mixture, and the product was purified by chromatography
with pentane/ethyl acetate 10:1. Enantiomeric ratios were analyzed with
HPLC by using a Chiralcel column. The synthetic procedures for the sub-
strate preparations, HPLC conditions, and the spectral data of new com-
pounds are provided in Supporting Information.
17
18
19
1c
1d
1g
88
89
9197 (
97 (+)
97 (+)
+)
20
21
22
1c
1d
1g
9195 (
93
93
À)
96 (À)
94 (À)
23
24
25
1c
1d
1g
93
9197 (
90
97 (À)
À)
97 (À)
Acknowledgements
26
27
28
1c
1d
1h
93
94
89
81( +)
80 (+)
77 (+)
We are grateful to the Fonds der Chemischen Industrie for the financial
support, and S.-M.L. thanks the Alexander von Humboldt Foundation
for a postdoctoral fellowship.
29
30
31
32
1a
1c
1d
1g
65[f]
70[f]
74[f]
75[f]
80 (S)
79 (S)
81( S)
79 (S)
Keywords: enantioselectivity · hydrogenation · iridium ·
ketones · sulfoximines
[a] Reactions conditions: substrate (0.25 mmol), catalyst 1 (1mol%), tol-
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porting Information. [d]Absolute configurations assigned by comparison
of optical rotations with literature values. For unknown compounds, the
sign of optical rotation is noted. [e]Only 80% conversion in this reaction.
[f]The value in parentheses indicates the amount of saturated ketone.
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Received: June 5, 2008
Published online: July 30, 2008
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