Regioselective hydrogenation of α,β-unsaturated ketones over wilkinsons catalyst

Article abstract of DOI:10.1055/s-0029-1217117

The reactivity of a variety of α,β-unsaturated acyclic and cyclic ketones towards regioselective hydrogenation in the presence of Wilkinsons catalyst was determined. Hydrogenation of sterically hindered ,-unsaturated ketones proceeded at inefficient rates, if at all. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1217117

PAPER
421
Regioselective Hydrogenation of a,b-Unsaturated Ketones over Wilkinson’s
Catalyst
R
a
egioselec
o
tive
H
ydrog
h
e
nationof
a
,
a
b
-Unsatura
n
ted
K
etonesnes H. van Tonder,a Charlene Marais,a David J. Cole-Hamilton,b Barend C. B. Bezuidenhoudt*a
Department of Chemistry, University of the Free State, PO Box 339, Bloemfontein 9300, South Africa
Fax +27(51)4446384; E-mail: bezuidbc.sci@ufs.ac.za
b
School of Chemistry, University of St Andrews, St Andrews, Fife, KY16 9ST, UK
Received 6 October 2009
identified by GC-MS after completion of the reaction. In
the second and larger reactor,4 sampling of the reaction
mixtures was possible, so reactions could be followed and
products identified by 1H NMR spectroscopy. This setup
was used for the nonvolatile substrates. Due to the differ-
ent diameters (30 mm vs 50 mm for reactor 1 and 2, re-
spectively) and therefore capacities of the two reactors (30
mL vs 50 mL), as well as the cost of chemicals, reactions
were performed under more dilute conditions in reactor 2
and experimental data obtained in one reactor could there-
fore not be linearly extrapolated to the other.
Abstract: The reactivity of a variety of a,b-unsaturated acyclic and
cyclic ketones towards regioselective hydrogenation in the presence
of Wilkinson’s catalyst was determined. Hydrogenation of sterical-
ly hindered a,b-unsaturated ketones proceeded at inefficient rates,
if at all.
Key words: enones, regioselectivity, hydrogenation, Wilkinson’s
catalyst, flavonoids
The availability of a wide range of optically active mono-
meric flavonoids is crucial for the metabolic studies of
such compounds. As current synthetic strategies are te-
dious and renowned for both low yields and enantiomeric
excesses, the development of new strategies towards the
synthesis of these monomers is crucial. Since most a,b-
unsaturated flavonoids, such as flavones, isoflavones and
flavonols, are easily obtainable from readily available
starting materials, the aim of this study was to investigate
the feasibility of the regioselective and future stereoselec-
tive hydrogenation of the 2,3-double bond in model
a,b-unsaturated compounds with Wilkinson’s catalyst
[(Ph3P)3RhCl (1), Figure 1]. Although the application of
Wilkinson’s catalyst (1) in the hydrogenation of a,b-un-
saturated systems is, to the best of our knowledge, unex-
plored, rhodium catalysts are renowned for their high
selectivity towards the hydrogenation of olefinic double
bonds in the presence of carbonyl groups.1 Furthermore,
Wilkinson’s catalyst (1) is reported to catalyze the hydro-
genation of internal alkenes, including stilbenes, in high
yield.2 In order to facilitate stereoselectivity during these
hydrogenation reactions, numerous modifications to the
basic metal system have also been documented.1,3
All hydrogenations were performed in the noncoordinat-
ing solvent, dichloromethane.5 This solvent proved to be
superior to acetone and tetrahydrofuran in the selective
hydrogenation of chromone (2a, Scheme 1) with yields of
46.2%, 7.8% and 14.3%, respectively, being obtained for
the different solvents after a reaction time of 24 hours.
PPh3
(I)
Ph3P Rh Cl
Ph3P
1
Figure 1
O
O
1, H2
O
O
2a
3a
Scheme 1 Hydrogenation of chromone (2a) to chromanone (3a)
The effect of substitution around the double bond was
subsequently investigated. According to the turnover fre-
quency (TOF; product/catalyst molar ratio per hour), the
addition of a substituent to the b-carbon dramatically de-
creased the reaction rate, which is also reflected in the
turnover number (TON; product/catalyst molar ratio) and
the yield (Table 1, entries 1 and 2). This result corre-
sponds to the sluggish (Cy3P)2Ru(CO)(Cl)H catalyzed hy-
drogenation of internal alkenes.6 No hydrogenation was
observed upon the addition of another substituent to either
the a- or b-carbon (Table 1, entries 3 and 4). Aromatic
substitution as in the case of trans-chalcone (4e) had an
even larger negative effect on hydrogenation as is corrob-
orated by TOF, TON and yield values considerably lower
than those of pent-3-en-2-one (4b) (Table 1, entries 2 and
As two types of flavonoids, acyclic and cyclic, occur nat-
urally, initial studies focused on acyclic model com-
pounds 4a–f, where after the focus shifted to the more
relevant cyclic models 2a–c and 6a,b.
In an attempt to gather as much data as possible with the
equipment at hand, two different reactor systems were
used in the investigation. The first reactor system, mainly
used for the volatile substrates 4a–f and 6a,b, allowed the
monitoring of the reaction by hydrogen consumption as a
function of time under isobaric conditions. Products were
SYNTHESIS 2010, No. 3, pp 0421–0424
x
x
.
x
x
.2
0
0
9
Advanced online publication: 13.11.2009
DOI: 10.1055/s-0029-1217117; Art ID: P13709SS
© Georg Thieme Verlag Stuttgart · New York

422
J. H. van Tonder et al.
PAPER
Table 1 Hydrogenation of Linear Substrates 4a–f
R3
R3
1, H2
R1
R2
R1
R2
R4
O
R4
O
4
5
Entrya
Substrate R1
R2
R3
R4
Concn
(M)
Temp
(°C)
P
(bar)
TONb
TOFb
(h–1)
Yieldb
(%)
1
2
4a
4b
4c
4d
4e
4f
Me
Me
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
0.67
0.57
0.49
0.50
0.53
0.67
0.53
0.080
0.16
0.24
0.32
0.48
0.080
80
80
80
80
80
80
80
80
80
80
80
80
80
10
10
10
10
10
10
10
20
20
20
20
20
20
138
29
–
413
88
22
4.8
–
Me
Me
Me
Ph
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3
Me
Me
Ph
H
–
4
–
–
–
5
14
–
42
2.6
–
6
–
7
4e
4e
4e
4e
4e
4e
4e
Ph
Ph
Ph
Ph
Ph
Ph
Ph
141
26
96
113
153
222
42
443
79
19
24
43
34
35
33
38
8
9
286
339
460
666
127
10
11
12
13c
a Entries 1–6 were performed in reactor 1 and entries 7–13 in reactor 2.
b TON, TOF and yield were determined after 20 minutes.
c With additional triphenylphosphine.
5). The bulky and slightly electron-withdrawing phenyl Investigation of the effect of substitution in the cyclic sub-
substituents presumably influence alkene coordination to strate 6a proved once again that the introduction of a sub-
the rhodium complex both sterically and electronically in stituent at the double bond has a significant effect on the
the rate-determining step.7 Aldehydes like crotonalde- TOF (44 h–1 vs 371 h–1 for 6b and 6a, respectively;
hyde (4f) did not react under these conditions (Table 1, Table 2, entries 8 and 2).
entry 6), most probably due to unfavorable electronic ef-
fects on the olefinic bond.
As an increase in hydrogen pressure from 10 bar to 20 bar
proved to have a substantial effect on the TOF (Table 2,
In switching from reactor 1 to 2, improved results were entries 1 and 2) and as no reaction could be obtained for
obtained for chalcone (4e) (Table 1, entries 5 and 7). This flavone (2b) and 4¢,7-dimethoxyisoflavone (2c) (vide in-
result is probably explicable in terms of improved mass fra), the effect of pressure and temperature on the reaction
transfer, including enhanced dissolution of hydrogen in rate was subsequently fully investigated. The TOF of cy-
the solvent due to the larger liquid surface area and/or bet- clohex-2-enone (6a) increased with an increase in pres-
ter mixing in this reactor. For trans-chalcone (4e), both sure up to 30 bar, where after considerable fallout of
the TON and TOF increased with increasing chalcone rhodium black was encountered (Table 2, entries 1–4).
concentration (Table 1, entries 8–12). Interestingly, the The increased reaction rate at higher pressures might be
addition of triphenylphosphine to the reaction mixture in- explained by increased dissolution of hydrogen in the liq-
creased the TON, TOF and yield (Table 1, entries 8 and uid phase, thus favoring the formation and stabilization of
13), possibly due to additional stabilization of the catalyst, the active catalytic complex.8 Subsequent investigation of
thus preventing fallout of rhodium black.
the effect of temperature, by increasing the reaction tem-
perature at 30 bar, revealed that the catalyst was rapidly
deactivated at elevated temperatures as the reactions at
90 °C and 100 °C had stopped within 200 seconds and
150 seconds, respectively (Table 2, entries 5 and 6). The
TONs after 100 seconds at 80 °C and 90 °C were compa-
rable (Table 2, entries 3 and 5), whereas the reaction at
100 °C (Table 2, entry 6) initially proceeded more rapid-
When the hydrogenation was extended to the simple cy-
clic substrate, cyclohex-2-enone (6a), TON, TOF and
yield comparable to that of the b-substituted aliphatic
enone, pent-3-en-2-one (4b), were obtained (Table 2, en-
try 1 and Table 1, entry 2), indicating similar accessibili-
ties of the olefinic bond of these substrates to the catalyst.
Synthesis 2010, No. 3, 421–424 © Thieme Stuttgart · New York

PAPER
Regioselective Hydrogenation of a,b-Unsaturated Ketones
423
Table 2 Hydrogenation of Cyclic Substrates 6a,b and 2a–c
R3
O
R1
R2
R
R3
O
R1
R2
R
1, H2
1, H2
O
O
O
O
6
7
2
3
Entrya
Substrate
R
R1
R2
R3
Concn
(M)
Temp
(°C)
P
(bar)
TONb
TOFb
(h–1)
Yieldb
(%)
4.9
23
1
2
6a
6a
6a
6a
6a
6a
6a
6b
2a
2b
2c
H
H
H
H
H
H
H
Me
–
–
–
–
0.58
0.58
0.58
0.58
0.58
0.58
0.58
0.49
0.080
0.080
0.080
80
80
10
20
30
40
30
30
30
20
20
20
20
26
78
371
–
–
–
124
3
–
–
–
80
139 (43)
418 (1543) 26
4
–
–
–
80
43
(42)
(63)
–
130
(1498)
(2269)
–
8.1
5c
6d
7
–
–
–
90
11
14
–
–
–
–
100
110
80
–
–
–
8
–
–
–
15
1.6
–
44
3.3
9
H
Ph
H
H
H
PMP
H
80
4.9
1.5
–
10
11
–
H
80
–
–
–
OMe
80
–
–
a Entries 1–8 were performed in reactor 1 and entries 9–11 in reactor 2.
b TON, TOF and yield were determined after 20 minutes. The values in brackets were calculated after 100 seconds as the reactions in entries 5
and 6 had stopped within 200 seconds. Final yields are given for entries 5 and 6.
c Reaction had stopped after ca. 200 seconds.
d Reaction had stopped after ca. 150 seconds.
ly, but had stopped after 150 seconds with a yield of only tically active monomeric flavonoids due to steric and elec-
14% compared to 26% at 80 °C (Table 2, entry 3). As tronic factors. Our results also indicate that higher
problems were also experienced with regard to repeatabil- electron density over the double bond seems to enhance
ity at 30 bar, even at 80 °C, ensuing reactions were per- binding of Wilkinson’s catalyst to the olefin and therefore
formed at 80 °C and 20 bar.
the selective hydrogenation of this functional group.
The hydrogenation of chromone (2a) proceeded sluggish-
ly compared to that of trans-chalcone (4e) under similar
conditions (Table 2, entry 9 and Table 1, entry 8). This is
in stark contrast to the behavior of cyclohex-2-enone (6a)
and pent-3-en-2-one (4b) (Table 2, entry 1 and Table 1,
entry 2) and might be ascribed to the presence of the het-
erocyclic oxygen or the conformation of the heterocyclic
ring. The lack of reactivity of flavone (2b) and 4¢,7-
All chemicals were obtained from Sigma-Aldrich and used without
further purification. Solvents were dried by standard methods and
degassed three times with argon using standard Schlenk techniques.
Catalyst solutions were degassed three times with argon and then
flushed three times with H2 prior to injection. The catalyst was pre-
saturated with H2 before the initiation of experiments. NMR spec-
troscopy was performed at 296 K in CDCl3 on a Bruker AM-600 FT
spectrometer. GC-MS analysis was performed on an HP 6890 GC
dimethoxyisoflavone (2c) towards hydrogenation instrument fitted with an HP 5973 mass selective detector (MSD), a
National Institute of Standards and Technology (NIST) 98 library
(Table 2, entries 10 and 11) corresponds with the above,
and a Supelco fused capillary column (30 m, 0.25 mm i.d., 0.25 mm
as well as with the results encountered for 4a–d (Table 1,
film thickness). The temperature program was started at 50 °C (held
entries 1–4) where steric hindrance by a substituent at ei-
for 4 min), ramped to 130 °C at 20 °C/min (held for 2 min) and
ramped to 220 °C at 20 °C/min (held for 15 min) at a carrier gas
flow rate of 1 mL/min.
ther the a- or b-position had a negative effect on the reac-
tion rate.
Thus, although it was established that Wilkinson’s cata-
lyst (1) in fact is able to regioselectively hydrogenate the
olefinic bond of a,b-unsaturated ketones and though
promising results were obtained for the reduction of trans-
chalcone (4e), the regio- and stereoselective hydrogena-
Ketones 5 and 7; General Procedure for Liquid Substrates
4a–d,f and 6a,b in Reactor 1
For experiments in reactor 1 (Table 1, entries 1–6 and Table 2, en-
tries 1–8), a soln of (Ph3P)3RhCl (1; 9 mg, 0.01 mmol) in CH2Cl2 (9
mL) was charged to the reactor and the hydrogen ballast vessel was
tion of flavonoid monomers with Wilkinson’s catalyst pressurized to a value of ca. 70 bar. The substrate, 4a–d,f and 6a,b
(0.5 mL, 4.4–6.0 mmol depending on the substrate), was subse-
does not seem to be a viable option for the synthesis of op-
quently injected into the reactor and the regulator on the ballast ves-
Synthesis 2010, No. 3, 421–424 © Thieme Stuttgart · New York

424
J. H. van Tonder et al.
PAPER
Procedure for Chalcone (4e) in Reactor 2 in the Presence of
sel set to maintain the pressure inside the reactor at the required
constant level by feeding hydrogen from the ballast vessel into the
reactor. Hydrogen gas consumption was recorded electronically as
a function of time and the reaction products were identified by GC-
MS upon completion of the reaction.
Triphenylphosphine
A soln of (Ph3P)3RhCl (1; 20 mg, 0.022 mmol) and Ph3P (3 mg, 0.01
mmol) in CH2Cl2 (5 mL) was injected into a soln of trans-chalcone
(4e; 0.50 g, 2.4 mmol) in CH2Cl2 (25 mL) and the reaction was
executed and followed as described previously.
Procedure for Chalcone (4e) in Reactor 1
A soln of trans-chalcone (4e; 1.10 g, 5.3 mmol) in CH2Cl2 (1 mL)
was injected into a soln of (Ph3P)3RhCl (1; 9 mg, 0.01 mmol) in
CH2Cl2 (9 mL) at 80 °C and 10 bar, and the mixture stirred at that
temperature. As in the case of the liquid substrates, the progress of
the reaction was monitored by hydrogen consumption, whereas the
product was identified by GC-MS.
Acknowledgment
Financial support from Sasol Ltd is gratefully acknowledged.
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H-8), 4.52 (t, J = 6.46 Hz, 2 H, H-2), 2.79 (t, J = 6.46 Hz, 2 H, H-
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Dihydrochalcone (5e)
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Synthesis 2010, No. 3, 421–424 © Thieme Stuttgart · New York