Rhodium-catalyzed synthesis of γ-pyrones by three consecutive redoxaldol reactions of allylic alcohols with α, β-unsaturated aldehydes

Article abstract of DOI:10.1002/chem.201001068

(Figure Presented) All together now! A unique Rh^I-catalyzed reaction was developed to produce γ-pyrones, which are 1,3,5-triketone equivalents. This reaction was thought to proceed by three redox reactions of allylic alcohols, two intermolecular aldol reactions of α,β-un- saturated aldehydes, and one intramo lecular aldol reaction to afford 1,3cyclohexanediones, which were then converted into y-pyrones (see scheme TMSOTf= trimethylsilyl trifluoromethanesulfonate).

Full text of DOI:10.1002/chem.201001068

DOI: 10.1002/chem.201001068
Rhodium-Catalyzed Synthesis of g-Pyrones by Three Consecutive Redox–
Aldol Reactions of Allylic Alcohols with a,b-Unsaturated Aldehydes
Akio Mizuno, Hiroyuki Kusama, and Nobuharu Iwasawa*[a]
Consecutive 1,3-dicarbonyl units are an important feature
of compounds[1] as a precursor for a variety of polyketides
with diverse biological activities. Various methods for the
synthesis of 1,3-diketones have been reported, such as the
Claisen-type reaction between ketone enolates and acylating
this process,[8] protonation by the allylic alcohols to give ke-
tones usually occurs and only a few reports deal with appli-
cation to carbon–carbon bond-forming processes, such as
aldol reactions.[9] Herein, we report a RhI-catalyzed reaction
for the unique formation of g-pyrones, a 1,3,5-triketone
equivalent, through three consecutive redox–aldol reac-
tions.[10]
Our basic idea is as follows: By using a,b-unsaturated al-
dehydes as acceptors for the enolates generated from allylic
alcohols by the oxidation–reduction process, the aldol prod-
ucts formed (C) are again allylic alcohols. Then, a further
redox–aldol reaction with another molecule of the aldehyde
would give allylic alcohols E. Repetition of these processes
would give consecutive 1,3-diketones in a single operation
(Scheme 1).
agents,[2] oxidation of aldol compounds,[3] N O bond cleav-
À
age of isoxazoles[4] and others.[5] On the contrary, there are
few reports of a concise method for the preparation of 1,3,5-
triketones or their equivalents.[6]
Secondary allylic alcohols 1 are known to undergo isomer-
ization to saturated ketones 2 with several transition-metal
catalysts, such as Rh and Ru, through b-hydride elimination
to give a,b-unsaturated ketones A followed by hydrometala-
tion of the enones by the generated metal hydride
(Scheme 1).[7] Although metal enolates B are generated in
With these considerations, we first examined the reaction
of allylic alcohol 3 and cinnamaldehyde using various Rh
catalysts. It was found that when allylic alcohol 3 was treat-
ed with cinnamaldehyde (4 equiv) in the presence of
[{RhOHACTHNURTGENNG(U cod)}2] (0.5 equiv; equimolar based on Rh metal,
cod=1,5-cyclooctadiene) and PPh3 (2 equiv) in THF at
room temperature, cyclohexenone 4a was obtained in 76%
yield after treatment with acetyl chloride (Scheme 2). The
proposed mechanism for the formation of this product is as
Scheme 1. Concept of consecutive redox–aldol reactions.
[a] Dr. A. Mizuno, Dr. H. Kusama, Prof. Dr. N. Iwasawa
Department of Chemistry, Tokyo Institute of Technology
O-okayama, Meguro-ku, Tokyo 152-8551 (Japan)
Fax : (+81)3-5734-2931
E-mail: niwasawa@chem.titech.ac.jp
Scheme 2. Consecutive redox–aldol reaction. a) 1) [{Rh(OH)ACHTUNGTRENNUNG(cod)}2]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001068.
(0.5 equiv), PPh3 (2 equiv), THF, RT, 24 h; 2) AcCl, cat. 4-dimethylami-
nopyridine (DMAP), pyridine, 08C to RT.
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Chem. Eur. J. 2010, 16, 8248 – 8250

COMMUNICATION
Table 1. Reactions of several a,b-unsaturated aldehydes with 3.
follows: Twofold consecutive redox–aldol reactions proceed-
ed between 3 and cinnamaldehyde to afford E’. This com-
pound once again underwent a redox reaction to give the
Rh–enolate of triketone F, which finally underwent an intra-
molecular aldol reaction to give the 1,3-cyclohexanedione
G. Since this product was found to be unstable, it was isolat-
ed as acetylated cyclohexenone 4a by treatment with acetyl
chloride.
As three consecutive redox–aldol reactions were found to
proceed as expected, we then examined various reaction
conditions to realize catalytic reactions. The amount of Rh
catalyst could be reduced to 20 mol% based on Rh metal
Entry
R
Product
Yield [%]
1
Ph
5a
5b
74
64
44
68
59
71
69
2[a,b]
3
4-MeOC6H4
4-CF3C6H4
2-furyl
Me
Et
iPr
5c
4
4d[c]
5e
5[a]
6
5 f
by using [{RhCl
N
7
5g[d]
with a stoichiometric amount of BuLi as a base for Li alkox-
ide formation. 1,4-Dioxane also gave a better result than
THF. Furthermore, it was found that treatment of the crude
product with trimethylsilyl trifluoromethanesulfonate
(TMSOTf) instead of an acetylating agent gave g-pyrone 5a
in high yield, which is thought to be produced through an in-
tramolecular O-cyclization of triketone enolate H generated
from cyclic diketone G by a retro-aldol reaction (Scheme 3).
[a] [{RhClACHTUNGRTNEUNG(coe)2}2] (15 mol%) and PPh3 (60 mol%) were used. [b] 23%
of the starting material was recovered. [c] The yield of the acetylated
product. [d] The reaction for step 2 was carried out at 608C for 1 h.
Table 2. Reactions of several allylic alcohols with cinnamaldehyde.
Entry
Alcohol
R1
R2
R3
Product
Yield [%]
1
2
3
4
6a
6b
6c
6d
6e
6 f
6g
4-MeOC6H4
4-CF3C6H4
2-furyl
2-thienyl
Ph
Me
Me
Me
Me
Me
Me
H
H
H
H
H
Me
Ph
Ph
7a
7b
8c[b]
7d
7e
7 f
62
76
80
74
52
55
53
5[a,c]
6[a,d]
7[a]
Ph
Ph
7g
[a] [{RhClACHTUNGRTNEUNG(coe)2}2] (15 mol%) and PPh3 (60 mol%) were used. [b] The
yield of the acetylated product. [c] 28% of the starting material was re-
covered. [d] 26% of the starting material was recovered.
Scheme 3. Rhodium(I)-catalyzed consecutive redox–aldol reaction.
a) 1) nBuLi (1 equiv), [{RhClACHTUNRGTENGNU(coe)2}2] (10 mol%), PPh3 (40 mol%), 1,4-
dioxane, RT; 2) TMSOTf, toluene, 08C to RT.
g-pyrones in good yields (Table 2, entries 1–2). Heteroaro-
matics, such as furan[11] and thiophene, as R1 were applicable
for this RhI-catalyzed consecutive reaction (Table 2, en-
tries 3 and 4). In the case of allylic alcohols 6e and 6 f,
which possess methyl or phenyl groups as substituent R3,
corresponding g-pyrones were obtained in reasonable yields
and 20–30% of the starting materials were recovered
(Table 2, entries 5 and 6). Even allylic alcohol 6g, which has
no a substituent (R2 =H), gave the corresponding g-pyrone
7g in an acceptable yield (Table 2, entry 7).[12,13]
In summary, we have developed a new and simple syn-
thetic approach for the production of g-pyrones[6a,b,13] as a
triketide equivalent by the novel rhodium-catalyzed tandem
redox–aldol reaction of allylic alcohols with a,b-unsaturated
aldehydes. Further studies are currently in progress to
expand the scope and utility of this reaction.
Thus, under the optimized conditions, g-pyrone 5a was ob-
tained in 74% yield by the reaction of the lithium salt of al-
lylic alcohol 3 and cinnamaldehyde with [{RhClACTHNUTRGNE(UNG coe)2}2]
(10 mol%) and PPh3 (40 mol%) in 1,4-dioxane at room
temperature followed by treatment of the crude product
with TMSOTf in toluene at 08C to room temperature.
The reaction of several aldehydes with allylic alcohol 3
was carried out according to the optimized conditions
(Table 1). Unsaturated aldehydes, which possess p-anisyl, 2-
furyl,[11] methyl, ethyl, and isopropyl groups at the b posi-
tion, gave the corresponding g-pyrones in good yields
(Table 1, entries 2 and 4–7). In the case of p-CF3-substituted
cinnamaldehyde, the yield of the product was somewhat
lowered (Table 1, entry 3). Acrolein and b,b-disubstituted
unsaturated aldehyde did not give g-pyrones at all.
Next, we carried out the reaction using several allylic al-
cohols with cinnamaldehyde (Table 2). Allylic alcohols 6a
and 6b, which possess an electron-donating and -withdraw-
ing substituent on the phenyl ring, gave the corresponding
Experimental Section
General procedure: nBuLi (0.13 mL of a 1.57m solution in hexanes,
0.20 mmol) was added to
a
solution of allylic alcohol
3
(30.2 mg,
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N. Iwasawa et al.
0.204 mmol) in 1,4-dioxane (4.0 mL) at 08C and the mixture was warmed
to room temperature, and then [{RhCl(coe)2}2] (14.3 mg, 0.020 mmol,
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[8] For recent reviews of transition metal-catalyzed reductive aldol re-
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279, 105–137; for other representative examples, see: c) A. E. Rus-
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2004, 6, 2309–2312, and references therein.
[9] For representative recent examples, see: a) N. Ahlsten, B. Martꢃn-
Matute, Adv. Synth. Catal. 2009, 351, 2657–2666; b) A. Bartosze-
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Varma, C.-J. Li, J. Mol. Catal. A 2004, 214, 147–154; e) L. J. Gaz-
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[10] The 1,3-diketone synthesis by a similar concept, consecutive reduc-
tion–aldol–oxidation reactions by RuII complex, has been reported,
see: T. Fukuyama, T. Doi, S. Minamino, S. Omura, I. Ryu, Angew.
Chem. 2007, 119, 5655–5657; Angew. Chem. Int. Ed. 2007, 46, 5559–
5561, and references of related works therein.
AHCTUNGTRENNUNG
0.040 mmol based on Rh atom) and PPh3 (21.0 mg, 0.080 mmol) were
added. After the catalyst almost dissolved (ca. 1 min), cinnamaldehyde
(100 mL, 0.79 mmol) was added to the reaction mixture and then the re-
action mixture was kept in a closed system and was stirred for 24 h at
room temperature. The reaction was quenched by addition of pH 7 phos-
phate buffer. The organic layer was extracted with Et2O twice, and the
combined organic layer was washed with brine. After the organic layer
was dried over MgSO4, the solvent was removed under reduced pressure.
The residue was dissolved in toluene (5.0 mL), and TMSOTf (0.15 mL,
0.96 mmol) was added at 08C and the mixture was stirred at 08C for 2 h
and at room temperature for 2 h. The reaction was quenched by addition
of pH 7 phosphate buffer. The organic layer was extracted with AcOEt
twice, and the combined organic layer was washed with H2O and brine.
After the organic layer was dried over MgSO4, the solvent was removed
under reduced pressure. The residue was purified by preparative TLC
(20% ethyl acetate in hexanes) to afford g-pyrone 5a as a colorless oil
(58.0 mg, 0.147 mmol, 74%).
Acknowledgements
This research was partly supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science and
Technology of Japan. A.M. has been granted a Research Fellowship of
the Japan Society for the Promotion of Science for Young Scientists.
[11] In these cases, treatment with TMSOTf gave a complex mixture of
unidentified products. Thus, the crude product of RhI-catalyzed re-
action was treated with Ac2O instead of TMSOTf to afford 4d and
8c, respectively.
Keywords: aldehydes · aldol reaction · allylic compounds ·
homogeneous catalysis
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Received: April 22, 2010
Published online: June 22, 2010
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