1,3-Dienones and 2H-Pyran-2-ones from Soft α-Vinyl Enolization of β-Chlorovinyl Ketones: Defined Roles of Br?nsted and Lewis Base

Article abstract of DOI:10.1021/acs.orglett.5b03265

The eliminative reaction pathways of (E)-β-chlorovinyl ketones were investigated in the presence of both Br?nsted and Lewis bases. The Br?nsted base, Et₃N, effected the soft α-vinyl enolization of (E)-β-chlorovinyl ketones to [3]cumulenol intermediates; in turn, a catalytic amount of Lewis base, PPh₃, initiated isomerization to provide 1,3-dienones in high yields. The introduction of a carbon-based nucleophile into the reaction mixture provided the highly efficient synthetic route to 2H-pyran-2-ones in one pot, where the carbon-based nucleophile generated by an extra equivalent of Br?nsted base, Et₃N, attacked the electrophilic [3]cumulenol intermediates to initiate cyclization to give 2H-pyran-2-ones.

Full text of DOI:10.1021/acs.orglett.5b03265

Letter
pubs.acs.org/OrgLett
1
,3-Dienones and 2H‑Pyran-2-ones from Soft α‑Vinyl Enolization of
β‑Chlorovinyl Ketones: Defined Roles of Bronsted and Lewis Base
̈
Hun Young Kim and Kyungsoo Oh*
Center for Metareceptome Research, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak, Seoul 156-756,
Republic of Korea
*
S Supporting Information
ABSTRACT: The eliminative reaction pathways of (E)-β-chlorovinyl ketones were investigated in the presence of both
Bronsted and Lewis bases. The Bronsted base, Et N, effected the soft α-vinyl enolization of (E)-β-chlorovinyl ketones to
3]cumulenol intermediates; in turn, a catalytic amount of Lewis base, PPh , initiated isomerization to provide 1,3-dienones in
̈
̈
3
[
3
high yields. The introduction of a carbon-based nucleophile into the reaction mixture provided the highly efficient synthetic route
to 2H-pyran-2-ones in one pot, where the carbon-based nucleophile generated by an extra equivalent of Bronsted base, Et N,
attacked the electrophilic [3]cumulenol intermediates to initiate cyclization to give 2H-pyran-2-ones.
̈
3
he development of a chemical species that displays
Scheme 1. Soft α-Vinyl Enolization-Induced Janus-like
Reactivity of β-Chlorovinyl Ketones
T
multiple reaction pathways remains one of the primary
1
goals in the field of organic chemistry. The recently
demonstrated ambivalent reactivity of β-chlorovinyl ketones
has opened up new divergent reaction pathways of α,β-
unsaturated carbonyl compounds beyond the typical nucleo-
2
philic addition reactions to enones (Scheme 1). The fact that
the ambivalent reactivity of β-chlorovinyl ketones enables facile
access to stereochemically and structurally diverse products
strongly suggests that β-chlorovinyl ketones possess high
synthetic potential in an integral part of new reaction discovery
3
and development. With an aim of utilizing the soft α-vinyl
enolization of β-chlorovinyl ketones, we previously investigated
the use of a Lewis acid to promote the addition of glycinates to
3b
metal [3]cumulenolate intermediate species. Motivated by
the electrophilic nature of metal [3]cumulenolates from the soft
α-vinyl enolization of β-chlorovinyl ketones under Lewis acid
conditions, we became interested in the reaction mode of
[
3]cumulenol intermediates in the absence of a Lewis acid. In
this report, we present strong evidence for the electrophilic
modes of [3]cumulenol intermediates under Lewis base
conditions (or in the presence of a nucleophile).
ment of more direct synthetic methods to 1,3-dienones has
been the subject of intense investigation. Metal-catalyzed cross-
coupling reactions as well as cross-metathesis approaches
8
1
,3-Dienones are versatile synthetic intermediates in
4
5
conjugate addition, cycloaddition, and Diels−Alder reac-
tions. While there are established synthetic methods using the
6
Received: November 12, 2015
7
traditional condensation and Wittig reactions, the develop-
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03265
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Organic Letters
Letter
9
provide an array of diversely substituted 1,3-dienones.
Scheme 2. Scope of the One-Pot Synthesis of 1,3-Dienones
Moreover, phosphine-catalyzed isomerizations of electron-
1
0
poor alkynes to 1,3-dienones have been pioneered by Trost
1
1
and Lu, respectively. While the tandem elimination/isomer-
ization of enol triflates under palladium catalysis has been
12
recently disclosed by Frantz, there are no other examples that
employ α,β-unsaturated ketones as precursors to 1,3-dienones.
Herein, we report a facile one-pot synthesis of 1,3-dienones
from the soft α-vinyl enolization of β-chlorovinyl ketones in the
presence of both Bro
defined roles.
̈
nsted and Lewis bases with distinctively
To evaluate the compatibility of the Lewis base with the soft
α-vinyl enolization conditions of β-chlorovinyl ketones, we
investigated the potential use of phosphines as a Lewis base
(
Table 1). Thus, our previously optimized soft α-vinyl
Table 1. Optimization of 1,3-Dienones from (E)-β-
Chlorovinyl Ketones
a
entry
Et N, x equiv
PR , y mol %
solvent
CH Cl
2a, yield (%)
3
3
b
1
2
3
4
5
6
7
8
1.1
1.5
1.5
1.5
1.5
1.5
1.5
PPh , 10
2a, 73
3
2
2
2
PPh , 10
CH Cl
2a, 87
3
2
b
PPh , 10
THF
2a, 67
3
PPh , 10
CH CN
2a, 79
c
3
3
n‑
P( Bu) , 10
CH Cl
a
b
c
3
2
2
2
2
2
PPh (10 mol %). PPh (50 mol %) at 0 °C for 3 h. Reaction at 83
3
3
PPh , 5
CH Cl
2a, 86
3
2
°C.
d
PPh , 3
CH Cl
2a, 51
3
2
PPh , 10
CH Cl
2a, 0
3
2
a
b
Isolated yield of 2a after column chromatography. Unreacted (E)-1a
reaction to provide 1,3,5-trienone 2n in 74% yield. In addition,
a substrate 1o with an enolizable ester moiety provided a 1:1
mixture of 1,3-dienone and 1,3-dienyl ester in 85% yield. It
should be noted that the current one-pot synthesis of 1,3-
dienones from α,β-unsaturated ketones demonstrates the
c
was recovered. A 1:2 mixture of 3a and 4a was isolated in 90% yield.
d
The remaining molecular mass balance accounts for a 1:2 mixture of
3
a and 4a.
enolization of (E)-β-chlorovinyl ketone 1a was performed in
compatibility between a Bro
̈
nsted base (Et N) and a Lewis
3
the presence of PPh (10 mol %). To our delight, the formation
base (PPh ) during the reaction.
3
3
of 1,3-dienone 2a was obtained in 73% yield with about 80%
̈
The defined roles of Bronsted and Lewis bases in the one-opt
synthesis of 1,3-dienones strongly imply that a nucleophile
could be utilized in the tandem soft α-vinyl enolization and
conjugate addition reaction sequence. Thus, based on the pKa
reaction conversion (entry 1). The use of 1.5 equiv of Et N led
3
to the full consumption of 1a, providing 87% yield of 2a (entry
2). Solvents that are suitable mediums for the soft α-vinyl
enolization were investigated; however, the reaction in THF led
of Et N, we investigated the use of methyl cyanoacetate (pKa
12.8) as a potential nucleophile. Gratifyingly, a simple mixing of
3
to a lower reactivity (entry 3) and the use of CH CN provided
3
a slightly diminished yield of 2a in 79% (entry 4). Interestingly,
(E)-1, methyl cyanoacetate 5, and 2 equiv of Et N in CH CN
3
3
n
the use of P( Bu) under our reaction conditions did not
provided a facile synthetic route to 2H-pyran-2-ones 5a−j in
3
13
14
provide 2a (entry 5). Lowering the amount of PPh to 5 mol
71−85% yields (Scheme 3). At the present time, the one-pot
3
%
did not affect the observed yields of 2a, although the
synthesis of 2H-pyran-2-ones from (E)-β-chlorovinyl ketones is
limited to nonenolizable (E)-1, possibly due to the competing
employment of 3 mol % did result in a mixture of unreacted
propargyl ketone 3a and allenone 4a (entries 6 and 7). The
control experiments also confirmed that (E)-β-chlorovinyl
15
enolization of an alkyl group.
To elucidate the electrophilic species, a mixture of propargyl
ketone 1a did not react with PPh (entry 8).
ketone 3a and allenone 4a was treated with PPh (5 mol %)
3
3
Scheme 2 shows the generality of our one-pot synthesis of
,3-dienones from a soft α-vinyl enolization of β-chlorovinyl
(Scheme 4). A full conversion of the mixture to 1,3-dienone 2a
took 3 h at ambient temperature, while the consumption of 3a
and 4a could be monitored. Next, we monitored the reaction of
(E)-β-chlorovinyl ketone 1a at several intervals; however, the
presence of propargyl ketone 3a and allenone 4a could not be
confirmed. Our experimental observations suggest that the
major pathway to 1,3-dienones from (E)-β-chlorovinyl ketones
1
ketones. The reaction was widely applicable to various
substrates (E)-1 with electronically as well as sterically diverse
substituents (2a−i). The preparation of substituted alkene 2j,
α-alkyl-1,3-dienone 2k, and functionalized 1,3-dienones 2l,m
was achieved under the optimized reaction conditions. (E)-β-
Chlorovinyl ketone 1n with a chlorine atom four carbons away
from the enone moiety smoothly underwent the desired
is likely the result of the PPh -catalyzed isomerization of
3
[3]cumulenol species. More experimental support for the
B
DOI: 10.1021/acs.orglett.5b03265
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Letter
Scheme 3. One-Pot Synthesis of 2H-Pyran-2-ones
Scheme 5. Major Reaction Pathways in a One-Pot Access to
1,3-Dienones and 2H-Pyran-2-ones
Scheme 4. Involvement of [3]Cumulenol Species during
One-Pot Synthesis of 1,3-Dienones and 2H-Pyran-2-ones
In summary, we developed a one-pot synthesis of 1,3-
dienones and 2H-pyran-2-ones from the soft α-vinyl enolization
of β-chlorovinyl ketones in the presence of both Bronsted and
Lewis bases. Complementary to the electrophilic mode of metal
3]cumulenolate species under Lewis acid conditions, the
̈
[
electrophilic reaction pathway of [3]cumulenol species under
Lewis base conditions reinforces the divergent and ambivalent
reaction pathways of β-chlorovinyl ketones, paving the way for
synthetically useful transformations. We are currently exploring
the divergent reaction pathways of β-chlorovinyl ketones using
other electrophiles and nucleophiles, and our results will be
reported in due course.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03265.
Experimental procedures and characterization data for all
new compounds (PDF)
involvement of electrophilic [3]cumulenol species was obtained
upon using methyl cyanoacetate as a nucleophile. Thus, the
treatment of a mixture of propargyl ketone 3a and allenone 4a
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: kyungsoooh@cau.ac.kr.
with Et N and methyl cyanoacetate resulted in the formation of
3
2
H-pyran-2-one 5a in 38% yield. Similarly, the trisubstituted
Notes
allenone 4j failed to undergo the desired cyclization to 2H-
pyran-2-ones even at elevated reaction temperature. The use of
The authors declare no competing financial interest.
(
Z)-1a led to the formation of 1,3-dienone 2a and 2H-pyran-2-
ACKNOWLEDGMENTS
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government
■
one 5a in 20−25% yields within 18 h, corresponding to the
kinetics of the soft α-vinyl enolization of (Z)-1a.
2
While the possibility of stepwise reaction pathways, involving
(
MSIP) (NRF-2015R1A5A1008958).
the PPh -assisted isomerization of allenones 4 to 1,3-dienones
3
or the conjugate addition of methyl cyanoacetate to allenones 4
followed by an intramolecular cyclization to 2H-pyran-2-ones,
could not be completely ruled out, our data suggested that the
major pathways to 1,3-dienones and 2H-pyran-2-ones involved
the electrophilic [3]cumulenol species, as we observed for the
reaction between metal [3]cumulenolates and glycinates
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(
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(
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D
DOI: 10.1021/acs.orglett.5b03265
Org. Lett. XXXX, XXX, XXX−XXX