Direct synthesis of 1,3-diketones by Rh-catalyzed reductive α-acylation of enones

Article abstract of DOI:10.1021/ol800660y

(Chemical Equation Presented) 1,3-Diketones were synthesized from α,β-unsaturated ketones by treatment with acid chlorides and Et ₂Zn in the presence of RhCl(PPh₃)₃. This is a very simple and extremely chemoselective reaction to give the adduct at the α-position of α,β-unsaturated ketones.

Full text of DOI:10.1021/ol800660y

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2405-2408
Direct Synthesis of 1,3-Diketones by
Rh-Catalyzed Reductive r-Acylation of
Enones
Kazuyuki Sato, Satoshi Yamazoe, Rie Yamamoto, Shizuka Ohata, Atsushi Tarui,
Masaaki Omote, Itsumaro Kumadaki, and Akira Ando*
Faculty of Pharmaceutical Sciences, Setsunan UniVersity, 45-1, Nagaotoge-cho,
Hirakata, Osaka 573-0101, Japan
aando@pharm.setsunan.ac.jp
Received March 21, 2008
ABSTRACT
1,3-Diketones were synthesized from r,ꢀ-unsaturated ketones by treatment with acid chlorides and Et2Zn in the presence of RhCl(PPh3)3. This
is a very simple and extremely chemoselective reaction to give the adduct at the r-position of r,ꢀ-unsaturated ketones.
1,3-Diketones are very important compounds in organic
chemistry, because they exhibit some biological activities
Scheme 1. Rh-Catalyzed R-Fluoroalkylation Reaction
themselves, such as antioxidants, antitumors, and antibacterial
activities,1 and are also key intermediates to various hetero-
cyclic compounds.2 To date, there are many reports for the
synthesis of 1,3-diketones by oxidation of aldol-type com-
pounds, hydroxylation of alkynones, oxidative cleavege of
1,4-dienes, and so on. However, surprisingly, only a limited
number of procedures for a direct synthesis of 1,3-diketones
from ketones has been reported,3 because 1,3-diketones
synthesized from acid chlorides or esters with various metal
enolates of ketones have a problem in their chemoselectivity
owing to the higher acidity of the R-hydrogen of 1,3-
diketones than that of starting ketones. In addition, the
regioselectivity also became a problem, when metal enolates
of aliphatic ketones were used as starting materials which
have R-hydrogens at both sides of the carbonyl group.
Although, recently, some chemists reported new methods to
solve this difficulty, the direct synthesis of 1,3-diketones has
not been satisfactory and is still strongly desired.4,5
Herein, we would like to report a simple and novel
synthesis of 1,3-diketones using an Rh catalyst.
(1) (a) Kel’in, A. V. Curr. Org. Chem. 2003, 7, 1691–1711. (b) Kel’in,
A. V.; Maioli, A. Curr. Org. Chem. 2003, 7, 1855–1886.
(2) (a) Baumstark, A. L.; Choudhary, A.; Vasquez, P. C.; Dotrong, M.
J. Heterocyclic Chem. 1990, 27, 291–294. (b) West, A. P., Jr.; Van Engen,
D.; Pascal, R. A., Jr J. Org. Chem. 1992, 57, 784–786. (c) Felix, C. P.;
Khatimi, N.; Laurent, A. J. J. Org. Chem. 1995, 60, 3907–3909. (d) Martins,
M. A. P.; Brondani, S.; Leidens, V. L.; Flores, D. C.; Moura, S.; Zanatta,
N.; Horner, M.; Flores, A. F. C. Can. J. Chem. 2005, 83, 1171–1177.
(3) For the synthesis of 1,3-diketones using metal enolates: (a) Wiles,
C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E Tetrahedron Lett. 2002, 43,
2945–2948. (b) Nishimura, Y.; Miyake, Y.; Amemiya, R.; Yamaguchi, M.
Org. Lett. 2006, 8, 5077–5080. (c) Lim, D.; Fang, F.; Zhou, G.; Coltart,
D. M. Org. Lett. 2007, 9, 4139–4142.
(4) For the synthesis of 1,3-diketones using transition metals: (a) Ikeda,
Z.; Hirayama, T.; Matsubara, S. Angew. Chem., Int. Ed. 2006, 45, 8200–
8203. (b) Fukuyama, T.; Dai, T.; Minamino, S.; Omura, S.; Ryu, I. Angew.
Chem., Int. Ed. 2007, 46, 5559–5561
.
(5) For the synthesis of 1,3-diketones from benzotriazoles or acyl
cyanides: (a) Katritzky, A. R.; Pastor, A J. Org. Chem. 2000, 65, 3679–
3682. (b) Wiles, C.; Watts, P.; Haswell, S. J.; Pombo-Villar, E. Chem.
Commun. 2002, 10, 1034–1035. (c) Katritzky, A. R.; Meher, N. K.; Singh,
S. K. J. Org. Chem. 2005, 70, 7792–7794. (d) Shen, Z.; Li, B.; Wang, L.;
Zhang, Y. Tetrahedron Lett. 2005, 46, 8785–8788. (e) Lim, D.; Fang, F.;
Zhou, G.; Coltart, D. M. Org. Lett. 2007, 9, 4139–4142
.
10.1021/ol800660y CCC: $40.75
Published on Web 05/14/2008
2008 American Chemical Society

Table 1. Optimization of R-Acylation Reaction
entry
2a (equiv)
Rh cat (mol%)
Et2Zn (equiv)
solv
THF
THF
THF
THF
THF
Et2O
1,4-dioxane
DME
time (h)
yield of 5aa (%)
yield of 6aa (%)
1
2
3
4
5
6
7
8
1.5
1.5
1.5
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
RhCl(PPh3)3 (1)
RhCl(PPh3)3 (2)
RhCl(PPh3)3 (5)
none
RhCl(PPh3)3 (2)
RhCl(PPh3)3 (2)
RhCl(PPh3)3 (2)
RhCl(PPh3)3 (2)
RhCl(PPh3)3 (2)
RhCl(PPh3)3 (2)
RhCl(PPh3)3 (2)
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
26.5
5
5
27
45
44
0
62
trace
29
17
0
0
62
0
35
15
trace
25
23
20
2
24
24
24
24
24
24
24
43
9
10
11
CH2Cl2
toluene
CH3CN
trace
trace
trace
a Isolated yield.
Recently, we have reported a novel trifluoromethylation
at the R-position of R,ꢀ-unsaturated ketones (2) by treating
it with CF3-I (1a) and Et2Zn in the presence of RhCl(P-
Ph3)3.6 This reaction proceeded smoothly, and it could be
applied to other halofluoroalkyl compounds (1; Rf-X)
instead of CF3-I to give R-Rf ketones (Scheme 1).7
In the Rh-catalyzed R-fluoroalkylation, we found that
a rhodium hydride complex, which formed from RhCl(P-
Ph3)3 with Et2Zn, played an important role, and clarified
the reaction mechanism by using a deuterated Zn reagent.7
was used (entries 1-3). In entry 4, only the byproduct (6a)
was obtained in the absence of Rh catalyst. It means that
the Rh catalyst is involved in the formation of 5a. So, we
examined other rhodium catalysts instead of RhCl(PPh3)3,
but the yield and/or the selectivity could not be improved.
Next, we examined the effect of solvents as shown in entries
6-11. The ethereal solvents such as 1,4-dioxane or DME
gave the product, whereas the other solvents did not improve
the yield, unfortunately.
Then, using the optimum reaction condition (entry 5 in
Table 1), we attempted to synthesize a variety of 1,3-
diketones (5) to establish the scope of this method. The
results are summarized in Table 2.8
Scheme 2
.
Rh-Catalyzed Reductive R-Acylation of
R,ꢀ-Unsaturated Ketones
The reaction of methyl vinyl ketone (2a) with benzoyl
chloride (4a) gave the desired 1,3-diketone (5a) without a
decrease of the yield even at 0 °C (entry 2). As shown in
entries 1-8, most enones gave the corresponding 1,3-
diketones (5) in good yields, regardless of whether they were
cyclic or acyclic. However, enones that have two substituents
on the ꢀ-carbon or have a bulky substituent (tBu) next to
the carbonyl group did not give the products (entries 3 or 7)
but propiophenone was obtained in a considerable yield.
Based on this result, we expected if the reaction would
proceed by using acid chlorides (4) instead of Rf-X (1),
the acyl group could be introduced at the R-position of
R,ꢀ-unsaturated ketones to give the 1,3-diketones (5)
reductively (Scheme 2).
Furthermore, the reaction using various acid chlorides gave
the products as shown in entries 9-15. Electronic effects of
acid chlorides affected the yields and the reaction rate.
Electron donating groups decreased the yields and prolonged
the reaction time (entries 9 and 10). On the other hand,
electron withdrawing groups on the acid chlorides improved
the yields and the rate, although the o-substituent on the
aromatic ring decreased the yield probably due to the steric
hindrance (entries 11-13). Also, the heteroaromatic acid
chlorides gave the desired 1,3-diketones in good yields as
shown in entries 14 and 15.
Using the previous condition,6,7 we examined the reaction
of methyl vinyl ketone (2a) with benzoyl chloride (4a) as
shown in entry 2 of Table 1. As expected, the reaction
proceeded and gave the desired product (5a) in a moderate
yield. Decreasing the amount of Rh catalyst (1 mol %) led
to a low yield along with a side product (6a). However, the
yield did not improve even if 5 mol % of the Rh catalyst
(6) (a) Sato, K.; Omote, M.; Ando, A.; Kumadaki, I. Org. Lett. 2004,
6, 4359–4361. (b) Sato, K.; Omote, M.; Ando, A.; Kumadaki, I. Org. Synth.
2006, 83, 177–183.
We think that the mechanism of this reaction is similar to
the previous R-fluoroalkylation of R,ꢀ-unsaturated ketones
(Figure 1).7 More specifically, RhCl(PPh3)3 reacted with
Et2Zn to give a rhodium hydride complex (8) through an
(7) Sato, K.; Ishida, Y.; Murata, E.; Oida, Y.; Mori, Y.; Okawa, M.;
Iwase, K.; Tarui, A.; Omote, M.; Kumadaki, I.; Ando, A. Tetrahedron 2007,
63, 12735–12739.
2406
Org. Lett., Vol. 10, No. 12, 2008

Table 2. Synthesis of Various 1,3-Diketones by Using
Rh-Catalyzed R-Acylation
Figure 1. Reaction mechanism for Rh-catalyzed reductive R-acy-
lation of enones.
Aiming the further application of this reaction, we at-
tempted a one-pot rhodium catalyzed R-acylation using a
carboxylic acid. Thus, benzoic acid was treated with SOCl2
to form benzoyl chloride (4a) followed by the reductive
R-acylation with 2a to give the 1,3-diketone (5a) without a
significant decrease of the yield (eq 1 in Scheme 3). This
result suggests that carboxylic acids could be used instead
of unstable acid chlorides.
Scheme 3
.
Application for One-Pot Synthesis of a 1,3-Diketone
or a Pyrazole
Furthermore, 1,3-diketones are one of the useful key-
intermediates to give various heterocyclic compounds
which are involved in natural compounds and/or medi-
cines. Especially, the most prevalent method of obtaining
pyrazoles is by the reaction of 1,3-diketones with hydra-
zine or its derivatives.9 So, we applied the reaction to one-
pot synthesis of a pyrazole. That is, the 1,3-diketone (5a)
derived from 4a and 2a was subjected to the cyclization
by treatment with hydrazine. This reaction proceeded
a Isolated yield. b Propiophenone was obtained in a considerable yield.
c Mixture yield of the tautomer.
ethyl rhodium complex (7) along with the elimination of
ethylene. The 1,4-reduction of enone (2) by 8 to form
rhodium enolate (9) is followed by oxidative addition of acid
chlorides (4) to give another rhodium complex (10). The
reductive elimination generated the desired R-acylation
product (5) and regenerated a rhodium catalyst.
In entries 3 and 7 of Table 2, the desired 1,3-diketone (5)
was not obtained at all. We think that the enone in entry 3
would be prevented from the 1,4-reduction with the rhodium
hydride (8) by the two substituents at the ꢀ-position. On the
other hand, the reason why the reaction did not give the
product in entry 7 would be that the oxidative addition of
acid chloride could not proceed easily.
(8) General procedure for reductive R-acylation: R,ꢀ-Unsaturated ketone
(2; 4 mmol) and acid chloride (4; 2 mmol) were added to a solution of
RhCl(PPh3)3 (2 mol %) in THF (5 mL) at 0 °C. Then, 1.0 M Et2Zn in
hexane (3 mmol) was gradually added to the mixture at 0 °C and was stirred
at same temperature for the reaction time shown in Table 2. The mixture
was quenched with 10% HCl and extracted with AcOEt. The AcOEt layer
was washed with sat. NaCl and dried over MgSO4. The solvent was removed
in Vacuo, and the residue was purified by column chromatography to give
the corresponding 1,3-diketone (5).
(9) (a) Kost, A. N.; Grandberg, I. I. AdV. Heterocycl. Chem. 1966, 6,
347–429. (b) Heller, S. T.; Natarajan, S. R. Org. Lett. 2006, 8, 2675–2678.
Org. Lett., Vol. 10, No. 12, 2008
2407

smoothly to give a pyrazole (11) in a good yield, as
expected (eq 2 in Scheme 3).
compounds. In particular, this regioselective synthesis has
never been reported to the best of our knowledge. Therefore,
we believe that this reaction would become an important
method for synthesis of such compounds.
In conclusion, we synthesized various 1,3-diketones from
R,ꢀ-unsaturated ketones and acid chlorides in good yields.
The reaction proceeded smoothly, and gave the products
regioselectively at the R-position of enones. Furthermore, it
could be applied to the one-pot synthesis of a 1,3-diketone
or a pyrazole. There are a few reports for the direct synthesis
of 1,3-diketones which can lead to various heterocyclic
Supporting Information Available: Experimental details
and characterization of the compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL800660Y
2408
Org. Lett., Vol. 10, No. 12, 2008