Reaction of Corey ylide with α,β-Unsaturated Ketones: Tuning of Chemoselectivity toward Dihydrofuran Synthesis

Article abstract of DOI:10.1021/ol500877c

A straightforward, efficient, and reliable approach to synthetically valuable 2,3-dihydrofurans via a reaction between Corey ylide and α,β-unsaturated ketones has been developed. The use of simple and widely spread starting materials as well as mild reaction conditions and scalability provide a broad scope of 2,3-dihydrofurans.

Full text of DOI:10.1021/ol500877c

Letter
pubs.acs.org/OrgLett
Reaction of Corey Ylide with α,β-Unsaturated Ketones: Tuning of
Chemoselectivity toward Dihydrofuran Synthesis
Alexey O. Chagarovsky,†,‡ Ekaterina M. Budynina,*,†,‡ Olga A. Ivanova,† Elena V. Villemson,†
Victor B. Rybakov,† Igor V. Trushkov,†,‡ and Mikhail Ya. Melnikov†
†Department of Chemistry, M.V. Lomonosov Moscow State University, Leninskie gory 1-3, Moscow 119991, Russia
‡Laboratory of Chemical Synthesis, Federal Research Center of Pediatric Hematology, Oncology and Immunology, Samory Mashela.
1, Moscow 117997, Russia
S
* Supporting Information
ABSTRACT: A straightforward, efficient, and reliable approach to synthetically valuable
2,3-dihydrofurans via a reaction between Corey ylide and α,β-unsaturated ketones has
been developed. The use of simple and widely spread starting materials as well as mild
reaction conditions and scalability provide a broad scope of 2,3-dihydrofurans.
Scheme 1
he evolution of synthetic organic chemistry is mostly due
Tto the design of new reagents which allow development of
original synthetic methods. Meanwhile, the unexplored
potential of seemingly well-known reagents allows for
unexpected processes to be revealed that lead to a significantly
different outcome in comparison with established reactivity.
In our research, dimethylsulfoxonium methylide was found
to be such a reagent. It is widely known as Corey ylide, the
reactions of which with carbonyl and thiocarbonyl compounds,
imines, or electrophilic alkenes (Corey−Chaykovsky reaction)
constitute a powerful approach to three-membered carbo- and
heterocycles.1 In recent years, this ylide is intensively used for
the synthesis of a representative subclass of donor−acceptor
(DA) cyclopropanes, namely 2-substituted cyclopropane-1,1-
diesters, whose usefulness is mainly defined by their reactivity
in various ring-opening reactions, (3+n)-cycloadditions, and
annulations to unsaturated compounds.2 Synthesis of such
cyclopropanes, among which there is a great variety of 2-alkyl-,
aryl-, heteroaryl-, alkenylcyclopropane-1,1-diesters, is based on
the well-proven, highly efficient, and easily scalable sequence of
Knoevenagel/Corey−Chaykovsky reactions starting from
commercially or synthetically accessible aldehydes and malonic
esters (path a in Scheme 1). By contrast, the reactivity of Corey
ylide toward alkenes derived from other readily available and
commonly used active methylene compounds, such as 1,3-
diketones, β-ketoesters, nitroacetates, and malononitrile, still
remains essentially unknown. Currently, there are only a few
examples of DA cyclopropane synthesis via a Corey ylide
reaction with some vinylidene ketoesters.3 Meanwhile,
introduction of other types of electrophilic alkenes derived
from different active methylene compounds into a reaction with
Corey ylide could significantly enhance the method variability
and facilitate a high diversity of DA cyclopropanes.
different result, namely chemoselective 2,3-dihydrofuran
formation (path b in Scheme 1).4
In our opinion, this reactivity tuning is mainly provided by
the electron-withdrawing ability of α-substituent EWG, the
increase of which enhances anion delocalization in intermediate
A and favors (4 + 1)-annulation through O-attack (path a)
rather than (2 + 1)-annulation via C-attack (path b). Based on
this hypothesis, we designed the general route to 3,4,5-
trisubstituted 2,3-dihydrofurans and developed a very simple
practical method for the synthesis of representatives of these
synthetically useful and biologically important heterocycles5
from various 1,3-diketones and β-ketoesters. This new
However, our initial experiment with a product of acetyl-
acetone-to-benzaldehyde condensation led to a conceptually
Received: March 24, 2014
Published: May 12, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
approach based on the discussed (4 + 1)-annulation provides
broad substituent variability and can serve as a viable and low-
cost alternative to existing methods for the preparation of the
similar dihydrofurans.6 A proposed approach to 3,4,5-
trisubstituted 2,3-dihydrofurans can be considered to be
complementary to the well-known synthesis of 2,4,5-trisub-
stituted 2,3-dihydrofurans via the corresponding cyclopropane
isomerization7 (path c in Scheme 1). Here we report the results
of our research.
To study the scope of the disclosed reaction, we used a broad
series of 2-ylidene-1,3-diketones 1 which were synthesized from
commonly used alkyl, alkenyl, aryl, hetaryl aldehydes and
acetylacetone or other common 1,3-diketones. In all cases,
reaction between equimolar amounts of alkenes 1 and Corey
ylide proceeded as a (4 + 1)-annulation affording exclusively
3,4,5-trisubstituted 2,3-dihydrofurans 2 in good isolated yields
(Table 1). No traces of the corresponding cyclopropanes or
15, 18 and 9, 17, 19). The yield loss mainly arose during
product isolation by column chromatography due to the
moderate stability of 2 on silica. Scaling up the loading and
isolating the product more completely by distillation provided a
gain in reaction outcome (entry 1).
For diketones 1t,u which contain two different acyl groups (4
+ 1)-annulations via both carbonyl O-atoms were equally
probable processes that afforded two isomeric dihydrofurans
2t,t′ and 2u,u′ in an equimolar ratio (Scheme 2).
Scheme 2
a
Table 1. Synthesis of Dihydrofurans 2 from 1,3-Diketones 1
Our further efforts were directed toward extension of this
reaction to other α,β-unsaturated ketones bearing a strong
acceptor at the α-position. Thus, we focused on α-acyl acrylates
3 that can be easily synthesized from various commercially or
synthetically available β-ketoesters. The series 3a−o was
studied in reactions with Corey ylide, revealing mainly
chemoselective formation of dihydrofurans 4a−o (Table 2).
The same tendency as in the case of diketones 1 was observed
for the reaction efficiency of ketoesters 3 depending on
substituents at the carbonyl group or β-position. A decrease in
chemoselectivity was found only for the reaction of β-alkyl or
b
entry
1,2
R
R′
t (h)
yield, %
c
1
a
b
c
d
e
f
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
2
2
2
2
2
2
2
1
1
1
0.3
2
2
1
2
2
2
2
2
89 (95)
82
2
4-MeOC6H4
4-Me2NC6H4
3,4,5-(MeO)3C6H4
2,4,6-(MeO)3C6H4
biphenyl-4-yl
4-O2NC6H4
2-Fu
3
77
4
68
5
72
6
80
Table 2. Synthesis of Dihydrofurans 4 from 1,3-Ketoesters
7
g
h
i
70
a
3
8
57
9
2-Th
62
10
11
12
13
14
15
16
17
18
19
j
2-pyridyl
53
k
l
1-Bn-3-Ind
PhCHC(Me)
4-MeOC6H4CHCH
Me
61
70
m
n
75
b
64
entry
3,4
R
R′
t (h)
yield, %
d
c
o
Ph
82
1
a
b
c
d
e
f
Ph
Me
Me
Me
Me
Me
Me
Me
Ph
2
75 (92)
91
p
q
r
4-Me2NC6H4
2-Th
Ph
77
2
4-MeOC6H4
2
Ph
71
3
4-Me2NC6H4
1
74
Ph
Et
64
4
4-FC6H4
2
83
s
2-Th
Et
68
5
3-O2NC6H4
2
76
a
Reaction conditions: 1 (1.0 mmol), ylide (1.05 mmol), DMSO (9
mL), rt. Isolated yield after column chromatography. Yield of 2a
after distillation when reaction was performed in 7.0 g (37.2 mmol)
scale. Structure of 2o was unambiguously proved by X-ray analysis
6
2-Th
1
69
b
c
d
7
g
1-Bn-3-Ind
0.3
1
52
8
h
i
Ph
81
d
9
4-Me2NC6H4
Ph
1
84
(CCDC no. 924444).
10
11
12
13
14
15
j
2-Th
Ph
2
63
k
l
Ph
2-Th
2-Th
Me
Me
i-Pr
2
70
2-Th
1
59
products of their isomerization, namely 2,4,5-trisubstituted 2,3-
dihydrofurans, were formed. Depending on 1 lability, the
reaction time was varied between 2 h and 20 min. Substituents
with different electronic effects in the benzene ring had no
significant influence on the reaction efficiency (entries 1−7),
while diketones 1h−k containing heteroaromatic groups at the
β-position as well as alkyl-substituted diketone 1n gave
dihydrofurans 2h−k,n in slightly lower yields (entries 8−11,
14). Dienes 1l,m were also applicable for this transformation
allowing for further potential structural modifications. Variation
of substituents at the 1,3-dicarbonyl moiety of 1 did not lead to
noticeable changes in the yields of dihydrofurans 2 (entries 1,
e
m
n
o
Me
1.5
2
57
e
4-MeOC6H4CHCH
42
Ph
2
80
a
Reaction conditions: 3 (1.0 mmol), ylide (1.05 mmol), DMSO (9
b
c
mL), rt. Isolated yields after column chromatography. Yield of 4a
after distillation when reaction was performed in 6.0 g (27.5 mmol)
d
scale. Structure of 4g was unambiguously proved by X-ray analysis
e
(CCDC no. 917373). 4m,n were formed together with isomeric
cyclopropanes, ethyl 1-acetyl-2-methylcyclopropanecarboxylate and 1-
acetyl-2-[(E)-2-(4-methoxyphenyl)ethenyl]cyclopropanecarboxylate,
in 75:25 and 85:15 ratio, respectively.
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Letter
alkenyl-substituted α-acyl acrylates 3m,n where the correspond-
ing cyclopropanes were formed as side products (entries 13,
14).
Scheme 5. Sequential and One-Pot Double Corey−
Chaykovsky Reaction in Synthesis of Donor−Acceptor
Cyclopropane 11
2,3-Dihydrofurans are synthetically significant precursors for
the construction of more complex structures with useful
properties, including synthetic and natural bioactive com-
pounds. Among the evident applications of dihydrofurans, their
role as key intermediates for the straightforward synthesis of
such ubiquitous compounds as furans and tetrahydrofurans can
be named. Thereto, the presence of a donor−acceptor
substituted C−C double bond in structures of types 2 and 4
provides an especial opportunity for simple modifications via
both electrophilic and nucleophilic, cycloaddition, etc.
The synthetic utility of obtained dihydrofurans was primarily
demonstrated via the development of a dihydrofuran-to-furan
oxidation procedure. For this purpose, we tried several well-
known methods of aromatization, such as Pd-catalyzed
dehydrogenation8 and oxidation with DDQ9 or MnO2,10 for
the model compounds 4a,d,f,m under various reaction
conditions. The best yields of the corresponding furan-3-
carboxylates 5a−d were achieved when 4 were heated with
activated MnO2 at 130 °C under microwave irradiation
(Scheme 3). The developed procedure can be successfully
synthesis in a one-pot procedure allowing for cyclopropa[b]-
tetrahydrofuran 11 construction directly from alkene 3a.
In regard to the synthesis of natural compounds,
dihydrofuran 4m derived from acetaldehyde and ethyl
acetoacetate can be easily reduced to alcohol 12 which was
previously transformed to xyloketals A, B, H15 (Scheme 6),
originating from mangrove fungus Xylaria sp.16 and exhibiting a
broad range of biological activities.15b,16b,17
Scheme 6. Formal Synthesis of Xyloketals
Scheme 3
applied in the synthesis of 2,4-dimethylfuran-3-carboxylic acid
(6)11 whose α-L-rhamnopyranoside isolated from culture broth
of Streptomyces sp. was shown to inhibit α-hydroxysteroid
dehydrogenase.12
Moreover, involvement of furan-2,5-dicarbaldehyde (7) and
2,2′-difuran-5,5′-dicarbaldehyde (8) into an assembly of
Knoevenagel/Corey−Chaykovsky/dihydrofuran-to-furan oxi-
dation reactions was successfully applied for the synthesis of
oligofurans 9 and 10 connected via 2,2′ and 2,3′ C−C bonds in
three- and four-ring sequences (Scheme 4). Currently,
In conclusion, we have disclosed a new reactivity of Corey
ylide toward α,β-unsaturated ketones providing chemoselective
synthesis of 2,3-dihydrofurans via (4 + 1)-annulation in
contrast to common (2 + 1)-annulation leading to cyclo-
propane derivatives. An electron-withdrawing group at the α-
position of the used ketones was found to be responsible for
this chemoselectivity switch. Easy availability and variability of
the reagents as well as mild reaction conditions and scalability
allowed us to develop an efficient straightforward method for
the synthesis of a wide range of 3,4,5-trisubstituted 2,3-
dihydrofurans. Easy modifiability of the central dihydrofuran
ring, the C−C double bond, and side substituents makes the
resulting 2,3-dihydrofurans relevant reagents for producing
potentially useful structures, including natural and pharmaco-
logically valuable compounds. Further investigations on the
scope of the described (4 + 1)-annulation as well as the
synthetic application of dihydrofurans are in progress now.
Scheme 4. Oligofurans Synthesis
oligofurans with 2,3′ bonding are novel unique compounds;
however, the related oligofurans with 2,2′ connections were
considered as promising materials for solar cells, OLEDs,
OFETs, etc.13
An elegant approach to 2-oxycyclopropanecarboxylates, one
of the subclasses of DA cyclopropanes,14 was designed on the
basis of the Corey−Chaykovsky reaction with participation of
obtained dihydrofurans. Thus, a model experiment with 4a led
to cyclopropa[b]tetrahydrofuran 11 (Scheme 5). Evidently, this
cyclopropanation can be combined with dihydrofuran 4a
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures as well as NMR, IR, MS spectra,
elemental analyses, and X-ray data. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ekatbud@kinet.chem.msu.ru.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Russian Scientific Foundation for support of this
work. The NMR measurements were carried out in the
Laboratory of Magnetic Tomography and Spectroscopy,
Faculty of Fundamental Medicine of Moscow State University.
G.; Krohn, K.; Steingrover, K.; Zsila, F. J. Org. Chem. 2001, 66, 6252−
̈
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