DABCO-mediated [4+2] annulation of but-3-yn-2-one and activated ketones: Facile preparation of 2,3-dihydropyran-4-one

Article abstract of DOI:10.1002/ejoc.201200264

We found that nitrogen-containing Lewis base mediated [4+2] annulation of but-3-yn-2-one with activated ketones could proceed efficiently to give the corresponding 2,3-dihydropyran-4-ones in moderate to good yields under mild conditions. The substrate scope has been carefully examined. Moreover, a plausible reaction mechanism for the [4+2] annulation of but-3-yn-2-one with activated ketones mediated by DABCO has been proposed on the basis of previous literature and our own investigations. Copyright

Full text of DOI:10.1002/ejoc.201200264

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DOI: 10.1002/ejoc.201200264
DABCO-Mediated [4+2] Annulation of But-3-yn-2-one and Activated Ketones:
Facile Preparation of 2,3-Dihydropyran-4-one
Zhong Lian,[a] Qian-Yi Zhao,[a] Yin Wei,[a] and Min Shi*[a]
Keywords: Ketones / Alkynes / Lewis bases / Organocatalysis / Annulation
We found that nitrogen-containing Lewis base mediated
[4+2] annulation of but-3-yn-2-one with activated ketones
could proceed efficiently to give the corresponding 2,3-di-
hydropyran-4-ones in moderate to good yields under mild
conditions. The substrate scope has been carefully examined.
Moreover, a plausible reaction mechanism for the [4+2] an-
nulation of but-3-yn-2-one with activated ketones mediated
by DABCO has been proposed on the basis of previous litera-
ture and our own investigations.
cellent yields under mild reaction conditions (Scheme 1).[11]
In this paper, we wish to disclose a novel nitrogen-contain-
ing Lewis base mediated [4+2] annulation of activated
ketones 4 with but-3-yn-2-one (2) to produce the corre-
sponding 2,3-dihydropyran-4-ones 5 in good yields under
mild conditions (Scheme 1).[11]
Introduction
2,3-Dihydropyran-4-ones are present in many natural
products.[1] Their rich source of functionalities renders them
versatile intermediates in the synthesis of a variety of biolo-
gically important compounds, such as carbohydrates,[2] an-
tibiotics,[3] and toxins.[4] The syntheses of 2,3-dihydropyran-
4-one have been well documented in the literature. A pion-
eering synthetic approach for such heterocycles was estab-
lished through the hetero-Diels–Alder reaction of carbonyl
compounds and activated dienes by Danishefsky and co-
workers.[5] Later, many research papers and excellent re-
views reported variations and improvements to that origi-
nally published synthetic method, which provide the basis
for a number of synthetic strategies.[6] New strategies that
have been recently developed include the tandem aldol reac-
tion/conjugate addition[7] and the oxidative cyclization of α-
hydroxyenones with a palladium(II) catalyst.[8] The ad-
dition of a variety of nucleophiles to unsaturated lactones
that result from the reaction of Brassard’s diene with alde-
hydes has also been employed to synthesize 2,3-dihydropyr-
an-4-ones.[9] In 1999, Ramachandran and co-workers re-
ported that DABCO (1,4-diazabicyclo[2.2.2]octane) cata-
lyzed the self- and cross-condensation of but-3-yn-2-one.[10]
In their report, but-3-yn-2-one was deprotonated by
DABCO to produce the corresponding carbanion, and
intermolecular condensation then took place. Inspired by
those results, we have recently reported that nitrogen-con-
taining Lewis base catalyzed [4+2] annulation of isatins 1
with but-3-yn-2-one (2) could proceed smoothly to give the
corresponding spirocyclohexaneoxindoles 3 in good to ex-
Scheme 1. Nitrogen-containing Lewis base mediated [4+2] annu-
lations.
Results and Discussion
The initial investigation involved the reaction of the acti-
vated ketone ethyl 2-oxo-2-phenylacetate (4a, 1.0 equiv.)
and but-3-yn-2-one (2, 1.5 equiv.) in the presence of
DABCO (20 mol-%) in tetrahydrofuran (THF) at room
temperature (20 °C). We found that oxygen-atom-contain-
ing six-membered cyclic product ethyl 4-oxo-2-phenyl-3,4-
dihydro-2H-pyran-2-carboxylate (5a) was obtained in 15%
yield (Table 1, Entry 1). The structure of product 5a was
assigned on the basis of spectroscopic analyses. Its structure
[a] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032 China
Fax: +86-21-64166128
E-mail: mshi@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200264.
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Z. Lian, Q.-Y. Zhao, Y. Wei, M. Shi
FULL PAPER
was further unambiguously determined by X-ray diffraction
analysis of its analogue compound 5n. The ORTEP drawing
of 5n is shown in Figure 1.[12] Pleasingly, increasing the
amount of DABCO employed to 0.5 equiv. (50 mol-%) and
1.0 equiv. (100 mol-%) afforded product 5a in 37 and 75%
yield, respectively (Table 1, Entries 2 and 3). However, in-
creasing the amount of DABCO further to 1.2 or 1.5 equiv.
did not significantly improve the yield of product 5a
(Table 1, Entries 4 and 5). When the reaction was carried
out by using 4a/2/DABCO = 1:1:1 or 1:2:1 in THF at room
temperature, it was found that corresponding annulation
product 5a was obtained in 62 and 75% yield, respectively
(Table 1, Entries 6 and 7). Using other nitrogen- or phos-
phorus-containing Lewis bases such as 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU), triethylamine, 4-N,N-dimeth-
ylpyridine (DMAP), diisopropylethylamine (DIPEA), tri-
phenylphosphane, methyldiphenylphosphane, and tributyl-
phosphane did not further improve the yield of 5a and no
reactions occurred in most cases (Table 1, Entries 8–14), in-
dicating that DABCO is the best promoter for this reaction.
An examination of solvent effects revealed that THF is the
solvent of choice for this novel [4+2] annulation reaction
(Table 1, Entries 15–18).
Figure 1. ORTEP drawing of 5n.
electron-withdrawing or electron-donating groups were in-
troduced on the benzene rings of the R1 group, suggesting
that the electronic properties of the substituents on the
benzene rings did not have an impact on the outcome of
the reactions (Table 2). It should be also noted that, in the
Table 1. Optimization of the reaction conditions.[a]
Table 2. Substrate scope of the [4+2] annulation.[a]
Entry
4a/2
Catalyst
x [mol-%]
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DMAP
DBU
Et3N
DIPEA
PPh3
PPh2Me
PBu3
DABCO
DABCO
DABCO
DABCO
20
50
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
toluene
DCM
CH3CN
Et2O
15
37
75
74
75
62
75
–
trace
35
–
–
–
100
120
150
100
100
100
100
100
100
100
100
100
100
100
100
100
1:2
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
9
10
11
12
13
14
15
16
17
18
–
55
72
61
50
[a] Compound 4a (0.1 mmol) and catalyst were dissolved in solvent
(0.5 mL), and then compound 2 was added into the reaction solu-
tion. The resulting reaction mixture was stirred for 5 min. [b] Iso-
lated yield.
Having identified the optimal reaction conditions, we
next set out to examine the substrate scope of this [4+2]
annulation mediated by DABCO by using various activated
ketones 4 with different substituents on the R1 and R2
groups. The results are summarized in Table 2. The reac-
tions proceeded efficiently to give the corresponding prod-
[a] Compound 4 (0.1 mmol) and DABCO were dissolved in solvent
(0.5 mL), and then compound 2 was added into the reaction solu-
tion. The resulting reaction mixture was stirred for 5 min. [b] Iso-
ucts 5b–i in moderate to good yields regardless of whether lated yield. [c] N.R. = No reaction.
2
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DABCO-Mediated Annulation of But-3-yn-2-one and Activated Ketones
case of other activated ketones 4j–k bearing alkenyl and
alkyl groups, the reactions also proceeded smoothly to pro-
duce the corresponding 2,3-dihydropyran-4-ones 5j and 5k
in 72 and 70% yield, respectively (Table 2). We also found
that other activated ketones such as phosphonate 4l and
amide 4m did not give the corresponding products under
the standard conditions.
With the optimized reaction conditions in hand, we de-
cided to further explore the substrate scope of this [4+2]
annulation reaction. Activated ketones 4 bearing a trifluoro-
methyl group were treated with but-3-yn-2-one (2) under
the standard conditions, and the results are shown in
Table 3. We found that a wide range of activated ketones 4,
in which R2 is a trifluoromethyl group, were suitable sub-
strates in this reaction, affording desired 2,3-dihydropyran-
4-ones 5n–s in 58–70% yield regardless of the electronic
properties of the aromatic R1 groups on the benzene ring
(Table 3). Extension of the substrate scope was also per-
formed by using an activated ketone having a thiophene
ring, giving desired product 5t in 51% yield (Table 3).
Moreover, increasing the fluorinated alkyl chain of R2 did
not hamper the reaction, giving desired product 5u in 65%
yield (Table 3). Notably, when R2 was a pentyl group, the
reaction did not give desired product 5v (Table 3).
Scheme 2. Enlarging the reaction scale of the [4+2] annulation reac-
tions.
A plausible stepwise mechanism for the formation of 5a
is outlined in Scheme 3. Initially, DABCO deprotonates
but-3-yn-2-one (2) to generate enolate intermediate A,[10,11]
which undergoes nucleophilic addition to the carbonyl
group of activated ketone 4a to give intermediate B. Then,
intermediate B undergoes protonation, and the following
intermolecular Michael addition of DABCO to the alkynyl
group in intermediate C gives intermediate D. This interme-
diate subsequently undergoes 1,5-hydrogen shift to produce
intermediate E. The oxyanion of intermediate E attacks the
alkenyl group to form six-membered cyclic intermediate F,
which is followed by the release of DABCO to produce cor-
responding product 5a. Notably, product 5a may be depro-
tonated by DABCO to form ion pair G.
Table 3. Further examination of the substrate scope of the [4+2]
annulation.[a]
Scheme 3. A plausible stepwise mechanism for the formation of 5a.
[a] Compound 4 (0.1 mmol) and DABCO were dissolved in solvent
(0.5 mL), and then compound 2 was added into the reaction solu-
tion. The resulting reaction mixture was stirred for 5 min. [b] Iso-
lated yield. [c] N.R. = No reaction.
Conclusions
In summary, we have disclosed a facile synthetic protocol
To our delight, by increasing the reaction scale to for the preparation of functionalized 2,3-dihydropyran-4-
2.0 mmol, similar results could be obtained, affording the ones in moderate to good yields by nitrogen-containing
corresponding products 5a and 5n in a yield of 61 and 55%, Lewis base catalyzed annulations of activated ketones 4
respectively (Scheme 2).
with but-3-yn-2-one (2) under mild conditions. Moreover, a
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Z. Lian, Q.-Y. Zhao, Y. Wei, M. Shi
FULL PAPER
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plausible stepwise reaction mechanism for the [4+2] annu-
lation of but-3-yn-2-one with activated ketones mediated by
DABCO has been proposed on the basis of previous litera-
ture and our own investigations. Efforts are underway to
elucidate the mechanistic details of this annulation and to
explore some other interesting annulation reactions by
using nitrogen-containing Lewis bases.
[2] a) S. J. Danishefsky, W. H. Pearson, B. E. Segmuller, J. Am.
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Experimental Section
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General Procedure for the Formation of 5a: Under an argon atmo-
sphere, activated ketone 4a (0.1 mmol), but-3-yn-2-one (2,
0.15 mmol), DABCO (0.1 mmol), and THF (0.5 mL) were added
into a Schlenk tube. The mixture was stirred at room temperature
for 5 min, and the reaction was monitored by TLC. The solvent
was removed under reduced pressure, and the residue was purified
by flash column chromatography (silica gel; PE/EtOAc, 2:1) to af-
ford compound 5a as a white solid in 75% yield.
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Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR and 13C NMR spectroscopic data, charts of the
compounds shown in Table 1–3.
Acknowledgments
We thank the Shanghai Municipal Committee of Science and Tech-
nology (11JC1402600), the National Basic Research Program of
China [(973)-2009CB825300], and the National Natural Science
Foundation of China (21072206, 20472096, 20872162, 20672127,
21121062, and 20732008) for financial support and Mr. Jie Sun for
performing X-ray diffraction studies.
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[11] Z. Lian, M. Shi, Eur. J. Org. Chem. 2012, 581–586.
[12] CCDC-868565 (for 5n) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. Empirical formula:
C12H9F3O2; formula weight: 242.19; crystal color: colorless;
crystal dimensions: 0.341ϫ0.201ϫ0.112 mm; crystal system:
[1] a) D. L. Boger, S. H. Weinreb, Hetero-Diels–Alder Methodology
in Organic Synthesis, Academic Press, New York, 1987; b) H. B.
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monoclinic; lattice parameters:
a = 12.356(2) Å, b =
11.2157(19) Å, c = 8.0006(14) Å, α = 90°, β = 90.451(4)°, γ =
90°, V = 1108.7(3) Å3; space group: Pc; Z = 4; Dcalcd. = 1.451 g/
cm3; F(000) = 496; final R indices [IϾ2σ(I)] R1 = 0.0547, wR2
= 0.1670.
Received: March 5, 2012
Published Online: ᭿
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DABCO-Mediated Annulation of But-3-yn-2-one and Activated Ketones
Organocatalysis
Z. Lian, Q.-Y. Zhao, Y. Wei,
M. Shi* ............................................. 1–5
DABCO-Mediated [4+2] Annulation of
But-3-yn-2-one and Activated Ketones:
Facile Preparation of 2,3-Dihydropyran-4-
one
We found that nitrogen-containing Lewis
base mediated [4+2] annulations of but-3-
yn-2-one with activated ketones could pro-
ceed efficiently to give the corresponding
2,3-dihydropyran-4-ones in moderate to
good yields under mild conditions. The
substrate scope has been carefully exam-
ined. A plausible reaction mechanism for
the [4+2] annulation mediated by DABCO
has been proposed.
Keywords: Ketones
/ Alkynes / Lewis
bases / Organocatalysis / Annulation
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