Ruthenium hydride catalyzed regioselective addition of aldehydes to enones to give 1,3-diketones

Article abstract of DOI:10.1002/anie.200701005

(Chemical Equation Presented) It all adds up: Straightforward access to 2-alkyl-substituted 1,3-diketones is provided by a regioselective addition of aldehydes to enones catalyzed by the ruthenium hydride catalyst [RuHCl(CO)(PPh₃)₃]

Full text of DOI:10.1002/anie.200701005

Angewandte
Chemie
DOI: 10.1002/anie.200701005
Homogeneous Catalysis
Ruthenium Hydride Catalyzed Regioselective Addition of Aldehydes
to Enones To Give 1,3-Diketones**
Takahide Fukuyama, Takashi Doi, Satoshi Minamino, Sohei Omura, and Ilhyong Ryu*
In memory of Yoshihiko Ito
Despite the rapid progress in the development of metal-
catalyzed cross-coupling reactions,[1] many challenges remain
À
for the as yet unrealized classes of metal-catalyzed C C bond-
forming reactions. 1,3-Diketones are important basic building
blocks, which are traditionally prepared by the acylation of
ketone enolates, or by an aldol reaction of enolates with
aldehydes followed by oxidation.[2,3] A transition-metal-based
hydroacylation approach would give a short and atom-
economic method to generate 1,3-diketones from readily
available enones and aldehydes (Scheme 1, bottom). How-
Scheme 1. Two regiochemical pathways for the catalytic hydroacylation
of aldehydes to enones.
ever, known examples of the hydroacylation of enones show
Table 1: Effect of the Ru catalyst source on the reaction.[a]
that a reaction pathway that leads to 1,4-diketones is
preferred (Scheme 1, top).[4] In principle, if the catalyst can
support the three consecutive unit reaction processes of:
1) hydrometalation of enones to form metal enolates, 2) a
cross-aldol reaction to form an alkoxymetal species, and 3) a
Yield[b]
1d
b-metal hydride elimination of the resulting alkoxymetal
species, it would give the desired 1,3-diketones with regen-
eration of the metal hydride. Herein we report an efficient
method for the synthesis of 2-alkyl-substituted 1,3-diketones
from readily available enones and aldehydes by using
[RuHCl(CO)(PPh3)3] as a catalyst.[5]
Entry Catalyst
Quantity Solvent
[mol%]
T [8C] 3 f
[%]
[%]
1
2
3
4
5
6
7
8
9
[RuH2(PPh3)4]
[RuHCl(PPh3)3]
[RuH2(CO)(PPh3)3] 10
[RuHCl(CO)(PPh3)3] 10
[RuHCl(CO)(PPh3)3]
[RuHCl(CO)(PPh3)3] 10
[RuHCl(CO)(PPh3)3] 10
[R 3(COu)12]
[R 3(COu)12]/
Et2MeN·HI
PPh3
10
10
C6H6
C6H6
C6H6
C6H6
C6H6
80
80
80
80
80
0
87
94
65
0
35
0
9[c]
75[d]
49
83
10
0
We surveyed a variety of ruthenium hydride complexes
using the reaction of 2-cyclohexenone (1d) and p-fluoroben-
zaldehyde (2c) as a model system (Table 1). We thereby
found that [RuHCl(CO)(PPh3)3] catalyzed the required
reaction of 1d and 2c effectively to give 2-(p-phenacyl)cy-
clohexanone 3 f. Thus, the reaction of 1d with 2c in the
presence of 10 mol% [RuHCl(CO)(PPh3)3] in benzene under
reflux for 5 h gave 3 f in 75% yield after isolation by
chromatography on silica gel (Table 1, entry 4). A phos-
phine-free ruthenium hydride system was unsuccessful as the
catalyst (Table 1, entry 9).[6] Since PPh3 is known to catalyze
the Morita–Baylis–Hillman reaction,[7,8] we performed an
experiment using 30 mol% PPh3 under similar conditions
(benzene, reflux, 5 h); the experiment gave neither 3 f nor the
Morita–Baylis–Hillman product (Table 1, entry 10).[9]
5
(ClCH2)2 80
tBuOCH3 55
40
75
10
10
C6H6
C6H6
80
80
n.d.[e]
n.d.
0
10
30
C6H6
80
0
n.d.
[a] All reactions were performed using 1d (0.4 mmol), 2c (0.52 mmol),
catalyst (5 or 10 mol%), and solvent (1.5 mL) for 5 h at reflux. [b] Yield
based on GC analysis relative to dodecane as an internal standard.
[c] Yield based on 1H NMRanalysis relative to Cl 2CHCHCl2 as an internal
standard. [d] Yield of isolated product. [e] Not determined.
We then examined the generality of the reaction by using
a variety of unsaturated ketones and aldehydes (Table 2). The
reaction of ethyl vinyl ketone (1a) with aldehydes 2a and 2b
gave the corresponding 1,3-diketones 3a and 3b in good
yields (Table 2, entries 1 and 2). The reaction was also
effective for b-mono- and dialkyl-substituted enones such as
1b, 1c, and 1d (Table 2, entries 3–6). On the other hand, the
reaction of enone 1e, which has an a-methyl substituent,
failed to give the 2-ethyl-2-methyl-1,3-diketone (Table 2,
entry 7); in this case, 1e was recovered. Since the ruthenium
hydride catalyst employed affects the isomerization of double
[*] Dr. T. Fukuyama, Dr. T. Doi, S. Minamino, S. Omura, Prof. Dr. I. Ryu
Department of Chemistry, Graduate School of Science
Osaka Prefecture University
Sakai, Osaka 599-8531 (Japan)
Fax: (+81)72-254-9695
E-mail: ryu@c.s.osakafu-u.ac.jp
[**] I.R. acknowledges a Grant-in-Aid for Scientific Research from MEXT
Japan and JSPS.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
bonds,[5a,10] we then tested enones with a remote C C double
À
Angew. Chem. Int. Ed. 2007, 46, 5559 –5561
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
Table 2: Synthesis of b-diketones by a RuH-catalyzed regioselective addition of aldehydes to enones.[a]
Entry
1
Enones 1
Aldehydes 2
1,3-Diketones 3
Yield [%][b]
76
1a
1a
1b
1c
1d
2a
2b
2a
2a
2a
3a
3b
3c
3d
3e
2
3
4
5
72
64
73
75[c]
6
1d
2c
3 f
75[c]
7
8
1e
1 f
2a
2a
n.r.[f]
3g
3h
3i
92
83
85
91
9
1 f
1 f
1 f
2c
2d
2e
10
11
3j
12
1 f
2 f
3k
95
13
1 f
1 f
1 f
1a
2g
2h
2i
3l
66[c]
69[d]
91
14
3m
3n
3o
15
16[e]
2j
77[c],[d]
[a] General conditions: enone 1 (1 mmol), aldehyde 2 (1.3 mmol), [RuHCl(CO)(PPh3)3] (0.1 mmol), C6H6 (3.75 mL), reflux, 5 h. [b] Yields of isolated
products after column chromatography on silica gel. [c] Obtained as a mixture of keto and enol forms. For details, see the Supporting Information.
[d] d.r.=ca. 1:1 (13C NMR). [e] 2.3 equivalents of 1a and 20 mol% of catalyst were used. [f] No reaction.
bond, such as 1 f, in the hope that migration of the double
bond would be followed by a coupling reaction to give 1,3-
diketones. Indeed we were able to obtain good yields of 1,3-
diketones by an alkene isomerization/dehydrogenative aldol
reaction sequence (Table 2, entries 8–12). Aliphatic alde-
hydes 2g and 2h as well as a,b-unsaturated aldehyde 2i were
effective for the synthesis of 1,3-diketones (Table 2,
entries 13–15). We examined the reaction of 2.3 equivalents
of 1a with dialdehyde 2j in the hope of obtaining a three-
component coupling product (Table 2, entry 16). As hoped,
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Angewandte
Chemie
Keywords: addition · aldehydes · enones ·
.
homogeneous catalysis · ruthenium
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Li, C. J. Li, J.Am.Chem.Soc. 2006, 128, 56; b) X. Yao, C. J. Li, J.
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[4] For examples of transition-metal-catalyzed hydroacylation of
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Chem.Commun. 2001, 2558; b) E.-A. Jo, C.-H. Jun, Eur.J.Org.
Chem. 2006, 2504.
[5] For our previous work on the use of the ruthenium hydride
catalyst, see a) T. Doi, T. Fukuyama, S. Minamino, G. Husson, I.
Ryu, Chem.Commun. 2006, 1875; b) T. Doi, T. Fukuyama, J.
Horiguchi, T. Okamura, I. Ryu, Synlett 2006, 721; c) T. Doi, T.
Fukuyama, S. Minamino, I. Ryu, Synlett 2006, 3013.
Scheme 2. Possible reaction mechanism.
the envisaged tetracarbonyl compound 3o was obtained
(77% yield).
To get some insight into the mechanism, we carried out a
separate experiment using [D]benzaldehyde (2a’). Deute-
rium was introduced mainly at the b-carbon atom of the
enone (65%), which lends support for the proposed mech-
anism, however, deuterium incorporation at the a-carbon
atom was also observed (35%). This finding may suggest that
a hydroruthenation step leading to b-Ru ketones also exists in
rapid equilibrium, which allows for the introduction of
deuterium into the a-position of 1a by a back b-hydride
elimination (Scheme 2). Thus, the hydroruthenation of
enones gives two types of ruthenium enolates, A and
A’,[11,12] which then undergo an aldol reaction with the
aldehydes to give b-keto alkoxyruthenium complexes B and
B’. A b-elimination then takes place to give the 1,3-diketones
C and C’, with regeneration of the ruthenium hydride catalyst
for use in further reactions.
[6] T. Fukuyama, Y. Higashibeppu, R. Yamaura, I. Ryu, Org.Lett.
2007, 9, 587.
[7] Using a similar system comprising a,b-unsaturated ketones,
aldehydes, and [RuH2(PPh3)4] under neat conditions, a Morita–
Baylis—Hillman-type reaction was reported to take place, with
PPh3 playing a role, see S. Sato, I. Matsuda, M. Shibata, J.
Organomet.Chem. 1989, 377, 347.
[8] For a system using PPh3 and p-nitrophenol, see M. Shi, Y.-H. Liu,
Org.Biomol.Chem. 2006, 4, 1468.
[9] We thank one of the referees for calling our attention to the
mechanistic possibility in our system.
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Krompiec, T. Bieg, S. Baj, K. Skutil, A. Chrobok, J.Organomet.
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In summary, we have reported a novel regioselective
addition reaction of aldehydes to enones, which provides an
atom-economic and straightforward access to a wide variety
of 2-alkyl-substituted 1,3-diketones. Synthetic applications of
the present reaction as well as detailed mechanistic studies
are currently underway.
[11] For examples of catalytic transformations based on ruthenium
enolates, see a) S.-I. Murahashi, T. Naota, H. Taki, M. Mizuno,
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Uma, M. Davies, C. CrØvisy. R. GrØe, Tetrahedron Lett. 2001, 42,
Experimental Section
General procedure for the synthesis of 2-substituted 1,3-diketones
catalyzed by [RuHCl(CO)(PPh3)3]: A mixture of ethyl vinyl ketone
(1a; 86 mg, 1.03 mmol), benzaldehyde (2a; 138 mg, 1.3 mmol), and
[RuHCl(CO)(PPh3)3] (96.0 mg, 0.1 mmol) in benzene (3.75 mL) was
stirred at reflux for 5 h under nitrogen. Purification by column
chromatography on silica gel using 2% AcOEt in hexane as the
eluent gave 2-propanoylpropiophenone (3a) (149 mg, 76%).
3069; c) B. M. Trost A. B. Pinkerton, J.Am.Chem.Soc.
2000,
122, 8081; d) S. Chang, Y. Na, E. Choi, S. Kim, Org.Lett. 2001, 3,
2089; e) H. Wang, M. Watanabe, T. Ikariya, Tetrahedron Lett.
2005, 46, 963.
[12] For isolated ruthenium enolate complexes, see a) J. F. Hartwig,
R. A. Andersen, G. B. Bergman, J.Am.Chem.Soc. 1990, 112,
5670; b) J. F. Hartwig, R. G. Bergman, R. A. Andersen, Organo-
metallics 1991, 10, 3326; c) B. T. Tasley, M. Rapta, R. J. Kulawiec,
Organometallics 1996, 15, 2852.
Received: March 7, 2007
Published online: June 20, 2007
Angew. Chem. Int. Ed. 2007, 46, 5559 –5561
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5561