Furans versus 4H-pyrans: Catalyst-controlled regiodivergent tandem Michael addition-cyclization reaction of 2-(1-alkynyl)-2-alken-1-ones with 1,3-dicarbonyl compounds

Article abstract of DOI:10.1039/b905267d

The DBU-catalyzed reaction of 1-(1-alkynyl)-2-alken-1-ones with 1,3-dicarbonyl compounds produces 4H-pyrans in moderate to excellent yield, whereas the cationic Pd(ii)-catalyzed reaction affords furans regioselectively.

Full text of DOI:10.1039/b905267d

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Furans versus 4H-pyrans: catalyst-controlled regiodivergent tandem
Michael addition–cyclization reaction of 2-(1-alkynyl)-2-alken-1-ones
with 1,3-dicarbonyl compoundsw
Yuanjing Xiaoa and Junliang Zhang*ab
Received (in Cambridge, UK) 16th March 2009, Accepted 15th April 2009
First published as an Advance Article on the web 11th May 2009
DOI: 10.1039/b905267d
The DBU-catalyzed reaction of 1-(1-alkynyl)-2-alken-1-ones
with 1,3-dicarbonyl compounds produces 4H-pyrans in moderate
to excellent yield, whereas the cationic Pd(II)-catalyzed reaction
affords furans regioselectively.
Furans and 4H-pyrans are two types of very important and
widespread groups of five and six-membered oxygen containing
heterocycles. The furan rings are common structural units in
many natural biologically active products, pharmaceuticals,1,2
Scheme 1 The design of direct synthesis of furan or pyran derivatives
and versatile building blocks in synthetic organic chemistry.3,4
by a controlled tandem reaction from the same starting materials.
4H-Pyrans have been identified as potential and specific IKCa
channel blockers5 that were proposed as potential therapeutic
Michael addition–cyclization of 2-(1-alkynyl)-2-alken-1-ones 1
with 1,3-dicarbonyl compounds 2 to give furans or 4H-pyrans,
respectively. To the best of our knowledge, the selective
synthesis of furans or pyrans from the same starting materials
by a simple subtle catalyst selection has rarely been reported.12
In the course of our current studies focused on the chemistry
of electron-deficient 1,3-conjugated enynes, we recently disclosed
that DBU (1,8-diazabicyclo[5.4.0]undecen-7-ene) was found to
be an efficient base catalyst in the reaction of 2-(1-alkynyl)-
2-alken-1-esters with 1,3-dicarbonyl compounds to give
4H-pyrans.11a This new synthetic methodology to the preparation
of novel pyrans can be successfully extended to a variety of
2-(1-alkynyl)-2-alken-1-ones 1 with 1,3-diketones and their
analogues. The results are summarized in Tables 1–2. Some
points are noteworthy: (1) all atoms of both reactants are
incorporated into the desired 4H-pyrans, that is, this reaction
is 100% atom-economic; (2) the transformation is quite
general, and structurally diverse pentasubstituted 4H-pyrans
could be easily synthesized in moderate to excellent yields via
this transformation (Table 1, entries 1–5, method A; Table 2,
entries 1–9, method (A); (3) it is not only 1,3-diketones such as
acetylacetone and dibenzoylmethane but also b-keto esters
that can be used as nucleophiles to afford the corresponding
highly substituted 4H-pyrans (Table 1, entries 1–5, method
(A); (4) alkynes bearing aliphatic groups afford relatively
higher yields than those bearing aryl groups (Table 2, compare
entries 6, 9 to entries 1–5).
agents for several diseases such as sickle cell anaemia,
secretory diarrhea, cystic fibrosis, autoimmune diseases and
restenosis.6 Thus, it is not surprising that various new
synthetic methods have been developed for the assembly of
furans7 or pyrans,8 and the search for new methodologies
proceeding more efficiently from readily available starting
materials still remains an active area of research.
On the other hand, one of the challenges of modern synthesis
is to create distinct types of complex molecules from identical
starting materials based solely on catalyst selection.9
As a continuation of our interest in exploration of novel
regiodivergent reactions,10 and the chemistry of 2-(1-alkynyl)-
2-alken-1-ones,11 we envisaged that the direct synthesis of
4H-pyran 3 or furan 4 might be realized by a one-pot reaction
of 2-(1-alkynyl)-2-alken-1-ones 1 with 1,3-dicarbonyl compounds
2 through controlling sequential C–C and C–O bond formation
under the proper conditions (Scheme 1). First, the inter-
molecular Michael addition of the nucleophile 2 and ketone
1
produce intermediate allenyl ketone 5. There is an
obvious regioselectivity issue in further transformations of
intermediate 5, that is, two kinds of C–O bond formation
patterns occur via the interaction of the allenyl group with two
different carbonyl groups (a carbonyl and g0 carbonyl group)
leading to functionalized 4H-pyrans 3 (Scheme 1, Path a)
or furan 4 (Scheme 1, Path b). Herein we present our
recent results on the catalyst-controlled regiodivergent tandem
a Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal University,
3663 N, Zhongshan Road, Shanghai 200062, P. R. China.
E-mail: jlzhang@chem.ecnu.edu.cn; Fax: (+86) 21-6223-5039
b State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, China
w Electronic supplementary information (ESI) available: Representative
experimental procedure and characterization of reaction products.
CCDC 717871. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b905267d
Having realized path a from reaction intermediate 5 to
produce pyrans 3 using a basic catalyst, we next examined
another envisioned reaction pathway associated with tuning
the regioselectivity of reaction intermediate 5 for furan
synthesis (Path b) by using a metal catalyst. To identify the
optimal reaction conditions for the reaction, a number of
metal catalysts, including AuCl3,13 PdCl2(CH3CN)2,11b,c
cationic Pd(II),14 and several different organic solvents and
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Table 1 Catalyst-controllable selective synthesis of 4H-pyrans 3 or
furans 4 from 1a and 1,3-dicabonyl compounds 2a
compounds undergo Michael reactions, aldol-type reactions
and Mannich-type reactions;14 the present results showed
that cationic Pd(II) catalysts can also efficiently catalyze the
reaction of 1,3-dicarbonyl compounds with ketones 1 to give
furans.
With the optimized reaction conditions in hand, we
next studied the reaction of 1a with various 1,3-dicarbonyl
compounds 2 to determine the scope of this transformation,
and the results are listed in Table 1, method B. Several points
are noteworthy: (1) the reaction is also 100% atom-economic;
(2) when the reaction was examined with b-keto esters, the
desired furans were obtained as an inseparable mixture of two
diastereomers in excellent yields with moderate diastereo-
selectivity (Table 1, method B, entries 3–5); (3) the reaction
Substrate 2
R4/R5
Method A
3 (time, yield)
Method B
4 (time, yield, d.r.)b
Entry
1
2
3
4
5
Me/Me(2a)
Ph/Ph(2b)
Me/OMe(2c)
Ph/OEt(2d)
3aa (4 h, 83%) 4aa (7 h, 99%, —)
3ab (4 h, 51%) 4ab (20 h, 51%, —)c
3ac (4 h, 78%) 4ac (15 h, 96%, 1.6/1)
3ad (4 h, 62%) 4ad (16 h, 82%, 1.8/1)
isopropyl/OMe(2e) 3ae (4 h, 72%) 4ae (10 h, 94%, 1.2/1)
of 1a with low reactive dibenzoylmethane 2b gives
a
a
Method A: The reaction was carried out by using 1 (0.25 mmol) and
2 (0.375 mmol, 1.5 equivalents), DBU (5 mol%) in 1 mL of DMF
at 100 1C. Method B: unless, otherwise specified, The reaction
was carried out by using 1 (0.25 mmol) and 2a (0.375 mmol,
1.5 equivalents), [Pd(dppp)(H2O)2](OTf)2 (5% mol) in 1 mL of
relatively lower yield and requires an elevated temperature
(Table 1, entry 2).
The generality of the method for furan synthesis can be
successfully extended to a variety of ketones 1 leading to the
corresponding trisubstituted functionalized furans in 43–99%
yield (Table 2, method B, entries 1–9). This procedure displays
toleration of the presence of aryl and alkyl substituents at both
the carbonylic carbon (R1) and the triple bond position (R3)
(Table 2, method B, entries 1–3, 6, 8–9). The substituents
attached to the double bond (R2) have a major impact on the
yield of the reaction. For example, the reaction of 1h with
acetylacetone 2a gives a relatively lower yield (43%) and
requires more nucleophile loading (Table 2, method B,
entry 7). The structure of furan 4ca was further confirmed
by single-crystal X-ray diffraction analysis (for details
see the ESIw).
b
c
ClCH2CH2Cl at rt. d.r. = diasteroisomer ratio. The reation was
run at 40 1C.
ligands were examined in the reaction of (E)-3-benzylidene-5-
phenylpent-4-yn-2-one 1a with acetylacetone 2a (for details
see the ESIw). Optimization of the reaction conditions
revealed that the reaction proceeded efficiently when
[Pd(dppp)(H2O)2](OTf)2 and 1,2-dichloroethane were used as
catalyst and solvent, respectively, the desired furan 4aa
was obtained in quantitative yield (99%). The screening of
different solvents showed that the solvent has a significant
influence on the reaction, 1,2-dichloroethane (DCE) was
found to be quite successful for present transformation. The
screening of different catalysts showed that a cationic Pd(II)
catalyst with stronger Lewis acidity generally gave superior
results when compared to AuCl3, PdCl2(CH3CN)2 and
Pd(m-OH)dppp catalysts with weaker Lewis acidity in
terms of conversion and yield. It is well documented that
cationic Pd(II) catalysts that efficiently catalyze 1,3-dicarbonyl
In order to determine our envisioned reaction pathway
proceeding through allenyl ketone 5, some further control
experiments were performed using 1a and dimethyl malonate
2f as representative substrates (Scheme 2).
Allenyl ketone 5af was synthesized according to our
previously reported method11a which could undergo cyclo-
isomerization readily to afford furan 4af in 85% isolated yield
Table 2 Selective synthesis of 4H-pyrans 3 or furans 4 from various 2-(1-alkynyl)-2-alken-1-ones 1 and acetylacetone 2a
Substrate 1
R1/R2/R3
Method A
3 (time, yield)
Method B
4 (time, yield)
Entry
1
2
3
4
5
6
7
8
9
Me/4-MeOC6H4/Ph (1b)
Me/Ph/4-MeOC6H4 (1c)
Me/4-MeOC6H4/4-MeOC6H4 (1d)
Me/Ph/1-Naphthyl(1e)
Me/4-MeOC6H4/1-Naphthyl(1f)
Me/Ph/n-C4H9(1g)
Me/n-C4H9/Ph (1h)
Ph/Ph/Ph (1i)
Ph/Ph/n-C4H9(1j)
3ba (5 h, 50%)
3ca (5 h, 51%)
3da (6 h, 56%)
3ea (5 h, 46%)
3fa (5 h, 56%)
3ga (4 h, 98%)
3ha (5 h, 55%)
3ia (5 h, 83%)
3ja (4 h, 98%)
4ba (7 h, 99%)
4ca (5 h, 96%)
4da (5 h, 85%)
4ea (40 h, 61%)a
4fa (48 h, 68%)a
4ga (4 h, 99%)
4ha (4 h, 43%)b
4ia (3 h, 99%)
4ja (5 h, 99%)
a
b
Additional 5 mol% of catalyst was added after the reaction was stirred for 24 h. 3.0 equivalents of acetylacetone 2a was used.
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 3594–3596 | 3595

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Financial support from the National Natural Science
Foundation of China (20702015) and Science and Technology
Commission of Shanghai Municipality (07DZ22937),
Shanghai Shuguang Program (07SG27), Shanghai Pujiang
Program (07pj14039) and Shanghai Leading Academic
Discipline Project (B409) are greatly appreciated.
Notes and references
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Scheme 2 Cationic Pd(II) catalyzes the reaction of 1a and dimethyl
malonate 2f.
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7 For recent reviews, accounts, and highlights dealing with the
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Chem., Int. Ed., 2005, 44, 850; (b) S. F. Kirsch, Org. Biomol. Chem.,
2006, 4, 2076; (c) D. M. D’Souza and T. J. J. Muller, Chem. Soc.
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vol. 19, p. 176; (g) S. F. Kirsch, Synthesis, 2008, 3183.
8 For recent literature and patents dealing with the synthesis of
pyrans, see: (a) A. John, P. J. P. Yadav and S. Palaniappan, J. Mol.
Catal. A: Chem., 2006, 248, 121; (b) G. I. Shakibaei, P. Mirzaei and
A. Bazgir, Appl. Catal., A, 2007, 325, 188; (c) B. Das,
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9 For selected recent examples, see: (a) S. Kamijo, C. Kanazawa and
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P. Almendros and T. Martınez del Campo, Angew. Chem., Int. Ed.,
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13 For furan formation from 2-(1-alkynyl)-2-alken-1-ones catalyzed
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Soc., 2004, 126, 11164.
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Scheme 3 Proposed catalytic cycle for direct furan syntheses.
catalyzed by 5 mol% cationic Pd(II) at 65 1C. Indeed, the
reaction of 1a with dimethyl malonate 2f under the same
conditions directly affords furan 4af in 92% isolated yield.
On the basis of the above results, a plausible mechanism for
direct synthesis of furan catalyzed by cationic Pd(II) is outlined
in Scheme 3. The initial reaction of cationic Pd(II) catalyst A
with 1,3-dicarbonyl compound 2 gives the palladium enolate
B,15a a strong protic acid (TfOH) and two molecules of water
(2H2O). The water contributes to complete the catalytic
cycle, because no furan is obtained when molecular sieves
(1.5 equiv.) are added to the reaction mixture. The palladium
enolate B could undergo Michael reaction with the aid of
TfOH15b to furnish the addition product C, which upon
hydrolysis affords allenyl ketone 5 and regenerates cationic
Pd(II) catalyst A. Allenyl ketone 5 is ready to undergo
cycloisomerization to final furan 4.
In summary, the chemistry described herein provides an
efficient catalyst-controlled regiodivergent synthesis of furans
and 4H-pyrans from two simple, readily available starting
materials. The regioselective introduction of substituents to
the furans or pyrans arises from the appropriate choice of
2-(1-alkynyl)-2-alken-1-ones or b-keto compounds. Further
studies on the asymmetric version of these reactions are
underway in our laboratory.
15 (a) N. Sasamoto, C. Dubs, Y. Hamashima and M. Sodeoka, J. Am.
Chem. Soc., 2006, 128, 14010; (b) TfOH cooperatively activates the
enone see: Y. Hamashima, D. Hotta, N. Umebayashi, Y. Tsuchiya,
T. Suzuki and M. Sodeoka, Adv. Synth. Catal., 2005, 347, 1576.
ꢀc
This journal is The Royal Society of Chemistry 2009
3596 | Chem. Commun., 2009, 3594–3596