Bronsted acid catalyzed cycloisomerizations of 5,2-enyne-1-ones: Highly regioselective synthesis of 2,3-dihydro-4H-pyran-4-ones

Article abstract of DOI:10.1002/chem.201103771

Dual-action catalyst: A Bronsted acid catalyzed regioselective cycloisomerization was found to be highly effective for the preparation of structurally diverse 2,3-dihydro-4H-pyran-4-ones in a 6-exo-trig manner from the corresponding 5,2-enyne-1-ones. In t

Full text of DOI:10.1002/chem.201103771

COMMUNICATION
DOI: 10.1002/chem.201103771
Brønsted Acid Catalyzed Cycloisomerizations of 5,2-Enyne-1-ones: Highly
Regioselective Synthesis of 2,3-Dihydro-4H-pyran-4-ones
Fang Yang, Ke-Gong Ji, Shu-Chun Zhao, Shaukat Ali, Yu-Ying Ye, Xue-Yuan Liu, and
Yong-Min Liang*[a]
Dihydropyranones occur widely as key structural subunits
in numerous natural products, such as obolactone,[1] cyclo-
curcumin[2] and a competitive inhibitor in cholesterol biosyn-
thesis.[3] Various conventional methods are used for prepar-
ing the dihydropyranone skeleton because of their interest-
ing pharmacological and bioactive properties.[4] However,
most of these syntheses often met drawbacks, such as unsta-
ble substrates,[5a–c] harsh reaction conditions,[5d,e] limited sub-
strate scope,[5f,h] and expensive catalytic reagents.[5i–k] Re-
cently, many extremely efficient strategies have been devel-
oped for the synthesis of a variety of dihydropyranones by
using acid-catalyzed cyclization of 1,3-diketones.[6] But it re-
mains difficult to prepare all kinds of diketones as well as
suitable substituted dihydropyranones by these methodolo-
gies. Therefore, more facile and effective protocols involving
atom economic, environmentally benign and mild reaction
conditions from readily available substrates still need to be
actively pursued.
Scheme 1. Design of the reaction.
lysts could be replaced by cheaper and easily handled
Brønsted acids. Also note that for this procedure, the mode
of activation of Brønsted acids is different from that of tra-
ditional transition metals, which generally activate the
carbon–carbon triple bond and facilitate regio- and stereose-
lective nucleophilic addition,[7] whereas the Brønsted acid
activates the carbonyl group, which favors Michael addition
(Scheme 4).
In contrast with transition-metal-catalyzed and stoichio-
metric Brønsted acid mediated reactions, examples of the
cyclization or cycloisomerization reactions of enynes cata-
lyzed by Brønsted acids[11] have rarely been reported. Addi-
tionally, Brønsted acid induced nucleophilic addition to al-
kynes, especially with aliphatic alcohols, are particularly
rare. Herein, we report a Brønsted acid catalyzed regioselec-
tive cycloisomerization of 5,2-enyne-1-ones 1, providing
a metal-free methodology for the synthesis of highly substi-
tuted dihydropyranone derivatives by 6-exo-trig cyclization.
Crucial to the success of this reaction is the dual role of
Brønsted acids as the catalyst to activate both the carbonyl
and alkene moieties in a cascade manner.
Initial attempts to promote the cascade reaction were per-
formed with the model 5,2-enyne-1-one 1a as a starting ma-
terial. To our delight, compound 1a with 5 mol% of
HAuCl4·4H2O and 1.0 equivalent of H2O in methanol at
608C gave the desired product 2,2-dimethyl-6-phenyl-2H-
pyran-4(3H)-one (2a) in 78% yield after 10 h (Table 1,
entry 1). Upon increasing the temperature to 758C, a 90%
yield of 2a was isolated after 5 h (Table 1, entry 2). Using
these reaction conditions, other gold catalysts and the influ-
ence of reaction additives were screened but no higher
yields were obtained (Table 1, entries 3–9). Considering the
fact that these gold salts can easily hydrolyze and give
In recent years, the cycloisomerization of alkynes is
known as an efficient synthetic route to a variety of carbo-
and/or heterocycles.[7] Previously, we have described a gold-
catalyzed tandem cyclization/ACTHNUTRGENUGN[1,2]-alkyl migration reaction
of epoxy alkynes for the synthesis of spiropyranones.[8] En-
couraged by this, we envisioned that the treatment of 5,2-
enyne-1-one 1[9] with a gold catalyst in the presence of meth-
anol would first give the corresponding vinyl gold ether spe-
cies A (Scheme 1),[10] which would subsequently cycloiso-
merize in a 6-exo-trig or 7-endo-trig manner resulting in a di-
hydropyranone 2 or dihydrooxepinone derivative 3. Howev-
er, after an extensive and thorough study, the actual catalyst
for the reaction was found to be a Brønsted acid and not
gold. The Brønsted acid was produced in the reaction mix-
ture by hydrolysis of the gold catalyst and then acted as the
catalytic agent. Thus, we thought that we could surpass this
problem by developing a new tandem reaction promoted by
a single Brønsted acid catalyst. If successful, the gold cata-
[a] Dr. F. Yang, K.-G. Ji, S.-C. Zhao, S. Ali, Y.-Y. Ye, X.-Y. Liu,
Prof. Dr. Y.-M. Liang
State Key Laboratory of Applied Organic Chemistry
Lanzhou University
Lanzhou 730000 (P.R. China)
Fax : (+86)931-8912582
E-mail: liangym@lzu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103771.
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Table 1. Optimization of reaction conditions for the cyclization of 1a.[a]
Table 2. Cascade Brønsted acid catalyzed synthesis of 2,3-dihydro-4H-
pyran-4-ones 2 from 5,2-enyne-1-ones 1.[a]
Entry Catalyst [mol%]
Additive [equiv] t [h] Yield [%][b]
1
2
3
HAuCl4·4H2O (5)
HAuCl4·4H2O (5)
NaAuCl4·2H2O (5)
H2O (1.0)
H2O (1.0)
H2O (1.0)
10
5
2
78[c]
90
73
4
G
5
88
5
6
7
8
U
2
5
5
2
4
3
4
4
63
73
60
81
71
85
84
78
2a (90%[b], 4 h)
2d (80%, 5 h)
2g (65%, 5 h)
2b (83%, 6.5 h)
2e (76%, 2 h)
2h (78%, 6 h)
2c (76%, 6 h)
2 f (70%, 6.5 h)
2i (81%, 3 h)
H2O (0)
H2O (2.0)
F3CSO3H (0.1)
p-TsOH (0.1)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
–
–
–
–
–
–
–
–
–
–
–
–
–
4
42
5.5 60
3
8
12
7
8
5
4
90
45[e]
63
69
trace
60
78
72[c]
79[g]
[a] Conditions: 1a (0.2 mmol), MeOH (3.0 mL) at 758C in the presence
of catalyst/mediator. [b] Isolated yield. [c] At 658C. [d] TFA=trifluoro-
acetic acid. [e] 50% of starting material was re-isolated. [f] Polymer-sup-
ported p-toluenesulfonic acid, 4.0–4.5 mmolgÀ1 on polystyrene. [g] At
858C.
2j (80%, 6 h)
2k (74%, 5.5 h)
2l (65%, 5.5 h)
2m (89%, 5 h)
2p (68%, 4 h)
2s (57%, 7 h)
2n (66%, 6.5 h)
2q (78%, 5 h)
2t ( 40%, 6 h)
2o (60%, 6.5 h)
2r (68%, 6 h)
Brønsted acids, we also used 100 mol% of TfOH and p-
TsOH without gold catalysts under these experimental con-
ditions. Surprisingly, we still afforded the product in 85%
and 84% yields (Table 1, entries 10 and 11). Moreover, we
observed that the reaction could also be carried out under
truly Brønsted acid catalytic conditions (Table 1, entry 12).
Then a number of Brønsted acids were screened, p-TsOH
was proven to be the most efficient catalyst (Table 1, en-
tries 13–18). We also investigated p-TsOH immobilized on
polystyrene (PS-p-TsOH, Table 1, entry 19) as the catalyst,
however, the result showed that PS-p-TsOH provided
a lower reactivity profile than that exhibited by the non-sup-
ported acid. Furthermore, neither changing the p-TsOH
loading nor the temperature could give better results
(Table 1, entries 20–22). In view of the fact that Brønsted
acids are much cheaper than gold catalysts, we finally used
p-TsOH (10 mol%) in methanol at 758C as the standard
conditions.
[a] All reactions were carried out under the following conditions:
1 (0.2 mmol) with p-TsOH (10 mol%) in MeOH (3.0 mL) at 758C.
[b] Isolated yield.
To investigate the scope of the metal-free cascade cyclo-
isomerization, various representative 5,2-enyne-1-ones 1a–t
were submitted to the above standard reaction conditions,
as depicted in Table 2. Thus, a tandem carbon–oxygen bond
formation of 5,2-enyne-1-ones 1a–t proceeded smoothly to
afford the corresponding products 2a–t in moderate to ex-
cellent yields. The structure of product 2h was also con-
firmed by X-ray crystal structure analysis (Figure 1). When
Figure 1. X-ray structure of 2h.[12]
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Brønsted Acid-Catalyzed Cycloisomerizations
COMMUNICATION
R2 is a methyl group, the reaction was found to tolerate var-
ious substituents on the aromatic R1 groups 2b–m. Electron-
donating aryl groups showed a slightly better result than
those with an electron-withdrawing group for 5,2-enyne-1-
one derivatives. Substrates with a heteroaromatic R1 moiety,
such as furan group, also afforded the desired product 2n in
a moderate yield (66%). To our delight, when substrates
with an aliphatic R1 group were subjected to this transfor-
it was found that by increasing the catalyst loading to
20 mol%, the corresponding product 2v was smoothly ob-
tained in 80% yield (Scheme 2). Thus, our developed meth-
odology provides a new approach to the synthesis of these
polycyclic products.
To probe the mechanism of this cycloisomerization, inter-
mediate 3a was isolated and a deuterium-labeling experi-
ment was performed. As shown in Scheme 3, when substrate
mation,
the
corresponding
products 2o–q, which are
known precursors to natural
products,[13] were separated in
yields of 60–78%. We also in-
vestigated substrates with dif-
ferently substituted R2 groups
under the standard reaction
conditions, the corresponding
products 2r–t were obtained in
moderate yields of 68, 57, and
40%, respectively (Table 2).
Additionally, when substrate
Scheme 3. Isolation of intermediate 3a and deuterium-labeling experiments.
1u with styrene R1 group and
two olefin groups was subjected
to the optimal reaction conditions, it was found that the sty-
rene group was selectively retained in this reaction and the
corresponding product 2u, which appears as a subunit in
many natural products,[1,2] was obtained in moderate yield
(Scheme 2).
1a was subjected to the standard conditions, intermediate
3a was isolated in 30% yield after 2 h. The intermediate 3a
when subjected to the same reaction conditions was found
to convert to the product 2a in 40% yield after 5 h. The
deuterium-labeling experiments showed that the deuterium
in MeOD incorporated into the product after the reaction.
When 2a was further treated with p-TsOH in MeOD, a tri-
deuterated product [D]-2aa was obtained, revealing the fact
that both hydrogen atoms alpha to the carbonyl are activat-
ed. The formation of product [D]-2a was also confirmed by
both high-resolution mass spectrometry and nuclear magnet-
ic resonance spectroscopy (see the Supporting Information).
On the basis of the above observations, we propose the
following plausible mechanisms (path a and path b) for this
transformation (Scheme 4). Path a: Initial interaction of the
proton from the Brønsted acid with the carbonyl oxygen
atom of 1 gives complex A. Methanol acts as a nucleophile
and attacks the carbon–carbon triple bond to form B.[14] The
release of a proton followed by a keto–enol tautomerization
would lead to the formation of intermediate C and regener-
ate the acid catalyst. Owing to the steric hindrance, upon
To exploit the synthetic utility of this reaction, we also
prepared the symmetrical 5,2-enyne-1-one substrate 1v, and
Scheme 2. Synthesis of (E)-2,2-dimethyl-6-styryl-2H-pyran-4(3H)-one
(2u) and 6,6’-(1,4-phenylene)bis(2,2-dimethyl-2H-pyran-4(3H)-one) (2v).
Scheme 4. Proposed mechanism.
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Y.-M. Liang et al.
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highly regioselective cycloisomerization of 5,2-enyne-1-ones
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lyst was used to activate both the carbonyl and alkene moi-
eties in a cascade manner. Further exploration of novel
Brønsted acid catalyzed cycloisomerizations to synthesize
important scaffolds are currently in progress.
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Acknowledgements
We thank the NSF (NSF-21072080, NSF-20732002) for financial support.
We acknowledge the National Basic Research Program of China (973
program), 2010CB833203 and also the support by the 111 Project.
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Keywords: Brønsted acid · cyclization · dihydropyranones ·
dual catalyst · enynes
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Brønsted Acid-Catalyzed Cycloisomerizations
COMMUNICATION
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Received: December 1, 2011
Revised: March 8, 2012
Published online: && &&, 0000
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Y.-M. Liang et al.
Isomerization
F. Yang, K.-G. Ji, S.-C. Zhao, S. Ali,
Y.-Y. Ye, X.-Y. Liu,
Y.-M. Liang* .................. &&&& — &&&&
Dual-action catalyst: A Brønsted acid
catalyzed regioselective cycloisomeri-
zation was found to be highly effective
for the preparation of structurally
diverse 2,3-dihydro-4H-pyran-4-ones in
a 6-exo-trig manner from the corre-
sponding 5,2-enyne-1-ones. In this
Brønsted Acid Catalyzed Cycloisome-
rizations of 5,2-Enyne-1-ones: Highly
Regioselective Synthesis of 2,3-
Dihydro-4H-pyran-4-ones
reaction, the Brønsted acid acts as
a dual catalyst activating both the car-
bonyl and alkene moieties in a cascade
manner (see scheme).
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These are not the final page numbers!