2,3-dihalo-1-propenes as building blocks in Cu(I)-catalyzed domino reactions: Efficient and selective synthesis of furans

Article abstract of DOI:10.1021/ol502371j

The Cu(I)-catalyzed reaction of 2,3-dibromo-1-propenes with β-ketoesters and 1,3-diketones, respectively, in DMF at 120 °C using Cs₂CO₃ as a base and hydroquinone as an additive exclusively delivers 2,3,5-trisubstituted furans and related compounds with yields up to 96%. The highly regioselective domino process is based on an intermolecular C-allylation followed by an intramolecular Ullmann type O-vinylation and a double bond isomerization.

Full text of DOI:10.1021/ol502371j

Letter
pubs.acs.org/OrgLett
2,3-Dihalo-1-propenes as Building Blocks in Cu(I)-Catalyzed Domino
Reactions: Efficient and Selective Synthesis of Furans
Dietmar Schmidt, Chandi C. Malakar, and Uwe Beifuss*
Bioorganische Chemie, Institut fur Chemie, Universitat Hohenheim, Garbenstraße 30, D-70599 Stuttgart, Germany
̈
̈
S
* Supporting Information
ABSTRACT: The Cu(I)-catalyzed reaction of 2,3-dibromo-1-
propenes with β-ketoesters and 1,3-diketones, respectively, in
DMF at 120 °C using Cs2CO3 as a base and hydroquinone as
an additive exclusively delivers 2,3,5-trisubstituted furans and
related compounds with yields up to 96%. The highly
regioselective domino process is based on an intermolecular
C-allylation followed by an intramolecular Ullmann type O-vinylation and a double bond isomerization.
ignificant progress has been made in the field of Cu(I)-
are also important building blocks and intermediates in organic
S
catalyzed cross-couplings in recent years.1 This holds
synthesis.15 This is why substantial effort has been devoted to the
development of methods for the preparation of furans.16 Apart
from classical methods such as the Paal−Knorr and the Feist−
Benary synthesis, several transition-metal-catalyzed methods
have been developed. Many of them are based on cyclo-
isomerizations and formal [4 + 1], [3 + 2], and [2 + 2 + 1]
cycloadditions.17 Despite considerable achievements, the
selective and efficient synthesis of highly substituted furans
from easily available substrates using reasonably priced reagents,
catalysts, and ligands still remains a major challenge in furan
synthesis.
especially true for the arylations of C-, N-, O-, and S-nucleophiles
with aryl halides.2 The corresponding vinylations are known but
have been much less studied than the arylations.3 The Cu(I)-
catalyzed vinylation of heteronucleophiles has great potential in
synthetic chemistry since it allows direct access to enamines and
enamides,3,4 enol ethers,3,5 and vinyl sulfides.3,6 The synthetic
value of Cu(I)-catalyzed cross-couplings can be extended
considerably by combining them with other reactions to new
domino processes.7 This approach has proven particularly
valuable for the synthesis of heterocycles.8 A prerequisite for
the application of domino reactions is the use of bisfunctional-
ized substrates, such as biselectrophiles or bisnucleophiles.
So far, in most cases bishalides of types A−D (Figure 1) have
been employed as biselectrophiles.9 As part of our studies on
It was envisioned that the synthesis of 2,3,5-trisubstituted
furans V could be achieved by reaction between a 2,3-dihalo-1-
propene I acting as a biselectrophile and a 1,3-dicarbonyl II as a
bisnucleophile by means of a Cu(I)-catalyzed domino
intermolecular C-allylation (I + II → III)/intramolecular O-
vinylation (III → IV)/isomerization (IV → V) (Scheme 1).
Here, we introduce 2,3-dihalo-1-propenes as a new class of
biselectrophilic substrates in transition-metal-catalyzed domino
processes. The novel and efficient Cu(I)-catalyzed domino
reaction between readily available 2,3-dibromo-1-propenes and
Figure 1. Biselectrophiles as substrates for transition-metal-catalyzed
domino reactions.
Scheme 1. Proposed Route for the Cu(I)-Catalyzed Synthesis
of Furans
Cu(I)-catalyzed domino reactions for the synthesis of hetero-
cycles,10 we assumed that 2,3-dihalo-1-propenes E should be
outstanding substrates for transition-metal-catalyzed domino
reactions. 2,3-Dihalo-1-propenes E can easily be obtained from a
number of substrates, such as α-haloacrylates, α-haloacroleins,
and α-haloallylic alcohols, by convenient synthetic procedures.11
2,3-Dihalo-1-propenes have found use as substrates in a number
of transformations,12 but so far they have not been employed as
reaction partners in transition-metal-catalyzed domino reactions.
The furan core is a frequently occurring structural motif in
natural products and pharmaceuticals.13 2,3,5-Trisubstituted
furans with an ester group at C-3, e.g., are found in
furanocembranoids and pseudopteranes.14 Substituted furans
Received: August 10, 2014
© XXXX American Chemical Society
A
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Letter
a
1,3-dicarbonyls, such as β-ketoesters and 1,3-diketones, allows
for the straightforward and selective synthesis of 2,3,5-
trisubstituted furans and related skeletons.
Table 2. Influence of Solvents and Reagent Concentrations
The reaction between 2,3-dibromo-1-phenyl-1-propene (1a)
and ethyl acetoacetate (2a) to 3a was chosen as a model reaction.
The required 2,3-dibromo-1-propene 1a could be obtained in
gram quantities by reduction of α-bromo cinnamic aldehyde (4a)
(1 equiv of NaBH4, MeOH/CH2Cl2 rt, 30 min)18 followed by
bromination of the resulting alcohol 5a (1.1 equiv of Br2, 1.2
equiv of PPh3, 0 °C → rt, 2 h).19 In a first attempt, 1 equiv of 1a
and 2 equiv of 2a were reacted with 10 mol % CuI and 3 equiv of
Cs2CO3 in DMF at 120 °C for 2.5 h in the presence of an additive
(Table 1). With 20 mol % of an additive such as 3,4,7,8-
2a
Cs2CO3
(equiv)
hydroquinone
(equiv)
yield
entry (equiv)
solvent
(%)
1
2
3
4
5
6
7
8
2
2
2
2
2
2
4
6
DMSO
dioxane
NMP
3
3
3
3
3
3
3
4
0.2
0.2
0.2
0.2
0.2
none
1
37
36
39
50
15
34
75
76
DMF
CH3CN
DMF
a
Table 1. Initial Experiments
DMF
DMF
1
a
1 equiv of 1a was reacted.
Then, the 1,3-dicarbonyl scope of the transformation was
studied. In a first set of experiments, 1a was reacted with a
number of β-ketoesters 2 (Scheme 2). The method is not
entry
additive
yield (%)
1
2
3
4
5
6
7
3,4,7,8-tetramethyl-1,10-phenanthroline
26
25
28
31
37
27
50
b
pivalic acid
Scheme 2. Reaction of 1a−c with β-Ketoesters and Related
Compounds 2a−f
N,N-dimethylethylenediamine
picolinic acid
ethyl nicotinate
catechol
hydroquinone
a
1 equiv of 1a was reacted with 2 equiv of 2a in the presence of 20 mol
b
% of an additive. The reaction was performed with 2.4 equiv of the
additive.
tetramethyl-1,10-phenanthroline, pivalic acid, N,N-dimethyl-
ethylenediamine, picolinic acid, ethyl nicotinate, or catechol,
the 2-methyl-5-(phenylmethyl)-3-furancarboxylic acid ethyl
ester (3a) was isolated as the main product in all cases (Table
1, entries 1−6). The yields were in the range between 25% and
37%. The yield could be substantially improved to 50% by
running the reaction in the presence of 0.2 equiv of hydro-
quinone (Table 1, entry 7). Therefore, all further experiments
were performed using hydroquinone as the additive.
In addition to DMF, the reaction could be carried out in a
number of other solvents, including DMSO, dioxane, NMP, and
acetonitrile. However, in all cases the yields were inferior
compared to DMF (Table 2, entries 1−5).
a
Yield refers to reaction of 1 mmol of 1 with 6 mmol of 2 and 4 mmol
of Cs2CO3. b Yield refers to reaction of 1 mmol of 1 with 4 mmol of 2
and 3 mmol of Cs2CO3.
To facilitate the first step of the transformation, i.e. the C-
allylation, it was considered to increase the amount of the β-
ketoester. In order to avoid partial decomposition of the
dibromide 1a observed with the initial experiments (Table 1,
entries 1−6), it was decided to increase the amount of
hydroquinone. In a control experiment that was carried out in
the absence of any hydroquinone the yield of 3a amounted to
only 34% (Table 2, entry 6). This outcome highlights the role of
this additive for the transformation. It is assumed that
hydroquinone inhibits the polymerization/decomposition of
the 2,3-dihalo-1-propene 1a and/or the furan 3a.20As expected,
the yield of 3a could be substantially improved by simultaneously
increasing the amount of β-ketoester 2a and that of hydro-
quinone. With 4 equiv of 2a and 1 equiv of the additive, the furan
3a could be isolated in 75% yield (Table 2, entry 7). With 6 equiv
of 2a and 4 equiv of Cs2CO3 a similar result was observed (Table
2, entry 8).
restricted to acetoacetates, such as tert-butyl acetoacetate (2b)
and benzyl acetoacetate (2c), but can also be performed with
other β-ketoesters, such as ethyl-3-oxo-pentanoate (2d) and
methyl-4-methyl-3-oxo-pentanoate (2e), to deliver the corre-
sponding furans 3d,e. Yields were in the range between 63% and
78%. Remarkably, the reaction was also feasible with 6-methyl-4-
hydroxy-2H-pyran-2-one (2f). Using this substrate, the bicyclic
heterocycle 3f was isolated in 54% yield. The reactions were
performed under the conditions of Table 2, entry 8, i.e. with 6
equiv of the respective β-ketoester 2 and 4 equiv of Cs2CO3.
Running the reactions under the conditions of Table 2, entry 7,
caused yield losses in some cases; see, for example, the formation
of 3d and 3e (Scheme 2).
To establish that the new domino process is not restricted to
2,3-dibromo-1-phenyl-1-propene (1a), (Z)-2,3-dibromo-1-(4-
methoxyphenyl)-1-propene (1b) and (Z)-2,3-dibromo-1-(4-
B
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Letter
fluorophenyl)-1-propene (1c) were selected as substrates. The
two 1-aryl-2,3-dibromo-1-propenes 1b,c were prepared from the
corresponding cinnamic aldehydes in three steps using standard
procedures: First, the respective cinnamic aldehydes were
transformed into the corresponding α-bromo cinnamic
aldehydes 4b,c by bromination/dehydrobromination (1.1
equiv of Br2, pyridine, 0 °C → rt, 2 h).21 This was followed by
reduction to the allylic alcohols 5b,c with NaBH4 (1 equiv of
NaBH4, MeOH/CH2Cl2, rt, 30 min).18 The resulting alcohols
5b,c were treated with Br2/PPh3 to deliver the 2,3-dibromo-1-
propenes 1b,c (1.1 equiv of Br2/1.2 equiv of PPh3, CH2Cl2, 0 °C
→ rt, 2 h).19 Subsequently, 1b and 1c were reacted with ethyl
acetoacetate (2a) under standard conditions to deliver the
corresponding furans 3g,h with yields up to 96% (Scheme 2).
This clearly demonstrates that the domino reaction can be
achieved with different 1-aryl substituted 2,3-dibromo-1-
propenes as starting materials.
Scheme 4. Synthesis and Cyclization of 2-Acetyl-4-bromo-5-
methyl-4-hexenoic Acid Ethyl Ester (9)
to achieve the synthesis of 10 in one step from 1,2-dibromo-3-
methyl 2-butene (8) and ethyl acetoacetate (2a) under the
conditions of the Cu(I)-catalyzed domino reaction were not met
with success.
To prove that the reaction proceeds as a domino C-allylation/
O-vinylation/isomerization, the presumed intermediate 11 was
prepared by a reaction between 2,3-dibromo-1-phenyl-1-
propene (1a) and ethyl acetoacetate (2a) and subjected to the
conditions of the Cu(I)-catalyzed reaction (Scheme 5). The
In a second set of experiments it was shown that 2,3-dibromo-
1-phenyl-1-propene (1a) can also be reacted with 1,3-diketones
to deliver the corresponding furans (Scheme 3). With
Scheme 5. Synthesis and Cyclization of 2-Acetyl-4-bromo-5-
phenyl-4-pentenoic Acid Ethyl Ester (11)
Scheme 3. Reaction of 1a−c with 1,3-Diketones 6a−d
reaction of 1 equiv of 11 in the presence of 5 equiv of 2a, 10 mol
% CuI, 4 equiv of Cs2CO3, and 1 equiv of hydroquinone
delivered 93% of the furan 3a as the product of an intramolecular
O-vinylation/isomerization.6,22 The finding that despite a 5-fold
excess of 2a the furan 3a was formed exclusively and not a trace of
the product of an intermolecular C-vinylation could be observed
provides strong support for the reaction mechanism assumed.
In summary, it has been shown that 2,3,5-trisubstituted furans
and related skeletons can be synthesized in an efficient and
selective one-pot process by reacting 1-substituted 2,3-dibromo-
1-propenes with 1,3-dicarbonyls, such as β-ketoesters and 1,3-
diketones. Future studies will address the potential of 2,3-dihalo-
1-propenes in other transition-metal-catalyzed reactions for the
preparation of carbo- and heterocyclic systems.
a
Yield refers to reaction of 1 mmol of 1 with 6 mmol of 6 and 4 mmol
of Cs2CO3. b Yield refers to reaction of 1 mmol of 1 with 4 mmol of 6
and 3 mmol of Cs2CO3.
acetylacetone (6a) and 3,5-heptanedione (6b) the 2,3,5-
trisubstituted furans 7a and 7b were formed exclusively in 82%
and 84% yield, respectively. Cyclic 1,3-diketones could also serve
as substrates for the domino reaction. Reaction of 1a with 1,3-
cyclohexanedione (6c) and 5,5-dimethyl-1,3-cyclohexanedione
(6d) delivered the benzofurans 7c and 7d as single products with
88% and 83% yield, respectively. Again, it was advantageous to
carry out the reactions under the conditions of Table 2, entry 8.
Attempts to reduce the amount of the 1,3-diketone did not pay
off (see the formation of 7a). Acetylacetone (6a) could also be
reacted with the 1-aryl substituted 2,3-dibromo-1-propenes 1b
and 1c as starting materials. The corresponding furans 7e,f were
isolated as single products in 55% and 72% yield, respectively.
It was expected that 1-alkyl-substituted 2,3-dihalo-1-propenes
could also serve as substrates for the synthesis of furans. This
view was supported by the fact that the Cu(I)-catalyzed reaction
of 2-acetyl-4-bromo-5-methylhex-4-enoic acid ethyl ester (9),
which was obtained by allylation of ethyl acetoacetate (2a) with
1,2-dibromo-3-methyl 2-butene (8), exclusively yields 4,5-
dihydro-2-methyl-5-(1-methylethylidene)-3-furancarboxylic
acid ethyl ester (10) as the product of an intramolecular O-
vinylation in 83% yield (Scheme 4). However, so far all attempts
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, and H−13C
1
NMR spectra for 3a−h, 7a−f, 9, 10, and 11. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ubeifuss@uni-hohenheim.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. J. Conrad and Mr. M. Wolf for NMR spectra and
Dr. A. Baskakova and Dipl.-Chem. H.-G. Imrich (all affiliated
with the University of Hohenheim) for mass spectra.
C
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Letter
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