A base-controlled chemoselective transfer hydrogenation of α,β-unsaturated ketones catalyzed by [IrCpCl2]2 with 2-propanol

Article abstract of DOI:10.1039/c5ra00484e

A simple homogeneous catalyst system based on commercially available [IrCpCl₂]₂ has been developed for the conjugate reduction of α,β-unsaturated ketones. Under the optimized conditions, a wide range of α,β-unsaturated ketones were reduced to saturated ketones in 83-98% yield. While switching the base from K₂CO₃ to KOH, saturated alcohols was selectively obtained.

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A Baseꢀcontrolled Chemoselective Transfer
Hydrogenation of α,βꢀUnsaturated Ketones Catalyzed
Cite this: DOI: 10.1039/x0xx00000x
*
by [IrCp Cl ] With 2ꢀPropanol
2
2
a
a
a
Shuꢀjie Chen , Guoꢀping Lu , and Chun Cai
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
simple homogeneous catalyst system based on
As part of our continuing interest in homogeneous iridium catalysts
*
14
commercially available [IrCp Cl ] has been developed for for organic transformations, we herein reported the potential of
2
2
*
2 2
the conjugate reduction of α,βꢀunsaturated ketones. Under commercial available catalyst [IrCp Cl ] in transfer hydrogenation of
the optimized conditions, a wide range of α,βꢀunsaturated α,βꢀunsaturated ketones with 2ꢀpropanol as hydrogen source and
ketones was reduced to saturated ketones in 83ꢀ98% yield. solvent.
While switching the base from K CO3 to KOH, saturated
alcohols was selectively obtained.
We began our studies by utilizing chalcone 1a as a model substrate in
2
*
15
the presence of [IrCp Cl
2
]
2
under various conditions (Table 1).
*
Treatment of 1a with catalytic amount of [IrCp Cl
]
2 2
2
and K CO
3
in
The catalytic transfer hydrogenation of unsaturated organic compounds
MeOH at 85 °C for 5 h gave the conjugate reduction product 2a in
1 % yield with none of the double hydrogenation product 3a (Table 1,
1
is an attractive methodology in synthetic organic chemistry.
3
Chemoselective reduction of α,βꢀunsaturated carbonyl compounds is
one of the most important subjects in this field. Since the second half of
the 20th century, a number of protocols have been developed for the
transfer hydrogenation of α,βꢀunsaturated ketones with the aim of
entry 1). A screening on other straightꢀchain fatty alcohols, that is,
EtOH, 1ꢀPrOH, and 1ꢀBuOH, gave 2a in 36%, 70%, and 57% yields,
respectively (entries 2ꢀ4). To our delight, when 2ꢀPrOH was used, the
reaction proceeded smoothly, yielding the 2a in 92% yield with
excellent chemoselectivity (entry 5). To further improve the yield, a
2ꢀ3
avoiding the use of hazardous hydrogen gas and other costly
4
5
6
hydrogen sources (hydrosilanes, NaBH
4
, Hantzsch ester etc.). This
series of bases was then screened and Na
CO (entry 6). Interestingly, in the case of Cs
was further hydrogenated to the saturated alcohol 3a in 64% yield
entry 7). Other strong bases, such as KOH and NaOH, gave 3a in 86 ,
4% yields, respectively (entries 8ꢀ9). Organic base NEt exhibited
inhibitory effect on the reaction and resulted in a low yield (entry 10). It
should be noted that decreasing the amount of K CO to 5 mol% led to
full conversion of 1a and 99 % of the 2a was obtained within 5 h (Table
, entry 11). However, in the absence of K CO , the reaction proceeded
sluggishly (entry 12).
2
CO
3
gave the similar result to
type of transformation has been achieved by the use of transition metals
K
2
3
2
CO , the generated 2a
3
7
ꢀ8
9ꢀ10
11
12
derived from ruthenium, rhodium,
palladium, iridium, and
13
nickel. The use of alcohols, formic acid and its salts is oftentimes
preferred. Among them, 2ꢀpropanol is the most attractive hydrogen
donor due to it’s good solvent properties, less expensive, and easy to
(
8
3
1
c
remove from the reaction system as itself or the generated acetone.
2
3
Despite all these advances, considering the constitution of these
catalyst systems, most of the catalysts required tedious steps of
synthesis or additive ancillary ligands. Only a few processes directly
applied the commercially available catalyst, and most of them also
suffered from drawbacks such as low yields, high temperature, and the
1
2
3
8ꢀ9
use of toxic solvents. In this respect, the search for simple and
practical catalyst system especially consisting of commercially
available catalyst is still in high demand.
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Base on the above findings and the literature data, we inferred that satisfactory results (entries 2ꢀ3); while the chalcones bearing Me and
*
the role of the base was to generate a highly active Cp IrH
2
catalyst MeO groups on the 4 position respectively were easy to reduce cleanly
16
from the dichloride (eqns. (1) and (2)). In addition, an excess of base (entries 10ꢀ11). The transformations of halogenꢀ and trifluoromethylꢀ
resulted in low solubility of the substrate, which ultimately led to low substituted chalcones afforded desired products in 92ꢀ98% yields, and
yield. To validate our assumption, a series of controlled experiments the position of the substituted groups did not significantly affect the
based on the volume of 2ꢀPrOH was carried out under the condition of reactivity (entries 4ꢀ7, 12ꢀ15). A similar result was observed in the case
entry 5, as showed in Figure 1. As expected, the yield of 2a was merely of 4’,2ꢀdisubstituted chalcone (entry 16). We also studied the cases of
2 3
moderate when the concentration of K CO was high. Increasing the heterocyclic αꢀenones. To our delight, it still exhibited high activity and
volume of 2ꢀPrOH improved the yield of 2a. A full conversion of 1a good selectivity, provided the desired products in excellent yields
2
and 99% yield of 2a was achieved when the amount of 2ꢀPrOH was (entries 17ꢀ18). When the R group was occupied by H or alkyl groups,
increasing to 2 mL. Continue increasing the volume of 2ꢀPrOH to 5 mL the reaction also proceeded smoothly in good to excellent yields
did not change the yield of 2a
.
(entries 19ꢀ21). Activated α,βꢀunsaturated ketones 1v and 1w, which
have been proved to be good substrates in the previous reports, were
also reduced in high yields (entries 22ꢀ23). Furthermore, the present
catalytic system also displayed high catalytic efficiency for the
reduction of cyclic enones (entries 24ꢀ25). However, α,β,γ,εꢀ
unsaturated enone 1z was proved to be sluggish substrate and only trace
amount of 2z was observed (entry 26). The transfer hydrogenations of
α,βꢀunsaturated ketones to the corresponding alcohols were also
investigated by applying KOH as the base. As expected, the desired
*
Table 1. Optimization of reaction conditions in transfer hydrogenation of
a
chalcone
b
Entry
Solvent
Base
Yield (%)
2
a
3a
0
0
0
0
0
0
64
86
84
0
1
2
3
4
5
6
7
8
9
MeOH
EtOH
K
K
2
K
2
K
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
31
36
70
57
92
89
16
2
Table 2. [IrCp Cl
2
]
2
catalyzed transfer hydrogenation of α,βꢀunsaturated
a
ketones
1ꢀPrOH
1ꢀBuOH
2ꢀPrOH
2ꢀPrOH
2ꢀPrOH
2ꢀPrOH
2ꢀPrOH
2ꢀPrOH
2ꢀPrOH
2ꢀPrOH
K
2
Na
Cs
2
CO
CO
3
2
3
KOH
NaOH
3
1
2
Entry
1
1
R
R
Yield (%)
2
1
1
1
0
1
2
NEt
CO
3
14
99
66
b
c
c
3
K
2
3
0
0
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
Ph
pꢀMeC
pꢀMeOC
pꢀFC
pꢀClC
pꢀBrC
m-ClC
oꢀMeC
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
97 (2a)
90 (2b)
85 (2c)
92 (2d)
98 (2e)
92 (2f)
94 (2g)
96 (2h)
95 (2i)
94 (2j)
93 (2k)
97 (2l)
96 (2m)
95 (2n)
94 (2o)
93 (2p)
93 (2q)
97 (2r)
87 (2s)
96 (2t)
94 (2u)
95 (2v)
94 (2w)
91 (2x)
88 (82)
83
78
85
91
88
84
90
85
ꢀ
d
2
3
6
H
4
a
*
d
Reactions conditions: 1a (0.2 mmol), [IrCp Cl ]
2
c
2
(1 mol%), base (0.5
CO was used.
6
H
4
o
b
equiv.), solvent (1 mL), 85 C, 5 h. GC yield. 5 mol% K
Cp : 1,2,3,4,5ꢀpentamethylcyclopentadiene.
2
3
4
5
6
7
8
9
6
H
4
*
6
H
4
6
H
4
6
H
4
6
H
4
2ꢀnaphthyl
Ph
pꢀMeC
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Ph
6
H
4
84
85
89
pꢀMeOC
pꢀClC
pꢀCF
mꢀCF
oꢀCF
oꢀCF
Ph
Ph
H
Ph(CH
CH
Ph
furanyl
6
H
4
6
H
4
3
C
6
H
4
3
C
6
H
4
3
C
C
6
H
H
4
pꢀClC
furanyl
thiophenyl
Ph
Ph
Ph
Me
Me
-C H ꢀ
3 6
6
H
4
3
6
4
1t
2
)
2
1u
1v
1w
1x
1y
1z
3
(CH
2
)
5
e
92
c
ꢀ C
Ph
2
H
4
ꢀ
97 (2y)
Figure 1. Effect of the volume of 2ꢀPrOH on the catalytic transfer hydrogenation
PhCH=CH
trace (2z)
*
2 2
of chalcone with [IrCp Cl ] .
a
*
2 2 2 3
Condition A: 1 (0.4 mmol), [IrCp Cl ] (1 mol%), K CO (5 mol%), 2ꢀ
*
o
2 2
PrOH (4 mL), 85 C, 5 h; condition B: 1 (0.4 mmol), [IrCp Cl ] (1 mol%),
c
With the optimized conditions in hands, various α,βꢀunsaturated
o
b
KOH (50 mol%), 2ꢀPrOH (4 mL), 85 C, 5 h. Isolated yield. Yields were
ketones were then subjected to the reaction to establish the scope and determined by GC analysis using nꢀhexadecane as internal standard (yield
d
*
2 2 2 3
in parentheses is the isolated yield). [IrCp Cl ] (2 mol%), K CO (10
generality of this protocol (Table 2). Firstly, a series of substituted
chalcones were investigated (entries 2ꢀ16). The chalcones bearing
electronꢀdonating group Me and MeO on the 4’ position respectively
required a higher catalyst loading and temperature to achieve
o
e
mol%), 100 C, 10 h. 8 h.
2
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saturated alcohols were obtained in 78ꢀ92% yields, which established complete, the solvent was removed under reduced pressure. The crude
our findings on the baseꢀcontrolled chemoselectivity (entries 1ꢀ12, 22). residue was purified by flash column silica gel chromatography
Finally, an α,βꢀunsaturated ketone 1aa bearing a nonꢀpolarized double (petroleum ether/ ethyl acetate: 95:5 to 90:10) to yield the product 2.
bond was subjected to the condition (eqn. (3)). To our delight, the Notes and references
a
present catalytic system selectively reduced the enone and kept the nonꢀ
Chemical Engineering College, Nanjing University of Science &
polarized double bond.
Technology, Nanjing, Jiangsu 210094, P. R. China.
Eꢀmail: c.cai@mail.njust.edu.cn
Electronic Supplementary Information (ESI) available: Experimental
1
13
19
details, HꢀNMR, CꢀNMR, and FꢀNMR spectra of all isolated
products. See DOI: 10.1039/c000000x/
1
Selected reviews: (a) R. A. W. Johnstone, A. H. Wilby, I. D.
Entwistle, Chem. Rev. 1985, 85, 129; (2) R. Noyori, S. Hashiguchi,
Acc. Chem. Res. 1997, 30, 97; (c) J.ꢀi. Ito, H. Nishiyama,
Tetrahedron Lett. 2014, 55, 3133.
A plausible mechanism is proposed in Scheme 1 to explain the
selective transfer hydrogenation of α,βꢀunsaturated ketones to the
1
7
saturated ketones or alcohols. In the initial step, the active catalyst
was generated via the sequences showed in eqns. (1) and (2). The αꢀ
enone 1a then coordinated to , followed by a hydride transfer to give
intermediate , which underwent an enolization to produce . The
resulting Irꢀenolate was protonated by 2ꢀPrOH to give product 2a and
produced the catalytic species , which sequently underwent a
elimination to reproduce the active catalyst . Although detailed
A
2
(a) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wileyꢀ
VCH, Weinheim, 1994; (b) M. Bartók, A. Molnár, Heterogeneous
Catalytical Hydrogenation, WileyꢀVCH, Weinheim, Chapter 16. pp.
843ꢀ908, 1997; (c) S. Nishimura, Handbook of Heterogeneous
A
B
C
C
D
βꢀ
Catalytic Hydrogenation for Organic Synthesis, WileyꢀVCH,
A
Weinheim, 2001; (d) Fine Chenicals through Heterogeneous
Catalysis, Eds: R. A. Sheldon, H. van Bekkum, WileyꢀVCH,
Weinheim, 2001.
mechanism for the secondary hydrogenation of the resulting ketones in
the presence of KOH is not clear. A base promoted Meerweinꢀ
PonndorfꢀVerley type reaction may be responsible for this unexpected
3
4
5
Selected reference see: (a) G. Szöllösi, B. Török, L. Baranyi and M.
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Mori, Y. Miyakawa, E. Ohashi, T. Haga, T. Maegawa, H. Sajiki, Org.
18
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mechanism.
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2
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Conclusions
*
We have demonstrated that [IrCp Cl
]
2 2
was a highly effective and
versatile catalyst for the transfer hydrogenation of α,βꢀunsaturated
ketones with 2ꢀPrOH. The simplicity of this protocol employing
commercially available catalyst makes it attractive for laboratory
8
9
hydrogenations without the need for hazardous H
2
and other costly
hydrogen sources. By changing the base from K
2
CO to KOH, the
3
(a) D. Beaupere, P. Bauer and R. Uzan, Can. J. Chem. 1979, 57, 218;
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(b) Z. Baán, Z. Finta, G. Keglevich, I. Hermecz, Green Chem. 2009,
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1
1
0
1
X. Li, L. Li, Y. Tang, L. Zhong, L. Cun, J. Zhu, J. Liao, J. Deng, J.
Org. Chem. 2010, 75, 2981.
Experimental section
An Ar purged flameꢀdried Schlenk tube (25 mL) containing α,βꢀ
(a) B. Basu, M. H. Bhuiyan, P. Das and I. Hossain, Tetrahedron Lett.
*
unsaturated ketone
1
(0.40 mmol, 1 equiv), [IrCp Cl
]
2 2
(1 mol%), and
2
003, 44, 8931; (b) B. Basu, S. Das, P. Das, A. K. Nanda,
K
2
CO
3
(5 mol%) were added 2ꢀPrOH (4 mL). The reaction mixture was
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Yorimitsu, A. Osuka, Angew. Chem. Int. Ed. 2014, 53, 1127; (d) D. B.
o
stirred at 85 C for 5 h unless stated otherwise. After the reaction was
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*
[IrCp Cl
2
]
2
was an efficient catalyst for the hydrogen autotransfer (or
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8
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4
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