Anionic Diels-Alder Chemistry of Cyclic Sodium Dien-1-olates Delivering Highly Stereoselective and Functionalized Polycyclic Adducts

Article abstract of DOI:10.1021/acs.orglett.1c01807

Anionic Diels-Alder chemistry of electron-deficient cross-conjugated vinylogous alkenones, providing highly stable sodium dienolate ion pairs as electron-rich dienes in the presence of a weak sodium base in THF, has been newly developed, leading to a single Diels-Alder adduct, in racemic form, in moderate to high yields (up to 97%, 37 examples).

Full text of DOI:10.1021/acs.orglett.1c01807

pubs.acs.org/OrgLett
Letter
Anionic Diels−Alder Chemistry of Cyclic Sodium Dien-1-olates
Delivering Highly Stereoselective and Functionalized Polycyclic
Adducts
Jing-Kai Huang and Kak-Shan Shia*
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ABSTRACT: Anionic Diels−Alder chemistry of electron-deficient
cross-conjugated vinylogous alkenones, providing highly stable
sodium dienolate ion pairs as electron-rich dienes in the presence
of a weak sodium base in THF, has been newly developed, leading to
a single Diels−Alder adduct, in racemic form, in moderate to high
yields (up to 97%, 37 examples).
iels−Alder cycloaddition reactions remain and continue
for unexpected anionic Diels−Alder reactions when EWG is an
aldehyde group (the present work, Figure 2d).
D
to be of extreme utility in synthetic organic chemistry
particularly in terms of their extraordinary capacity to construct,
in one step, fused polycyclic skeletons in a highly regio- and
stereoselective manner.1 As shown in Figure 1, 2-cyclohexenone
Regularly, dienes in Diels−Alder chemistry are referred to as
1,3-butadienes, usually installed with an electron-rich functional
group(s) as represented by various classical reagents (Figure
2a).6 Though some Nazarov reagents, as typified by 1 in Figure
2b, could undergo a base-catalyzed Diels−Alder reaction with a
conjugated olefin, mechanistically many turned out to proceed
with a tandem double-Michael addition rather than a concerted
cycloaddition.7 Several dienolate salts of 2 (Figure 2c),
generated in situ through transmetalation, also have been
reported to undergo Diels−Alder reactions effectively, but they
must be prepared and operated at low temperature (−78 to −20
°C) because of thermal instability.8 Herein, we wish to report
that a novel series of dienolate salts (Figure 2d), derived in situ
from the cross-conjugated vinylogous alkenones 3 with base, are
found to be highly thermally stable, allowing reaction with a
broad diversity of dienophiles to afford a variety of highly
oxygenated Diels−Alder adducts in moderate to high yields.
Details of these studies are presented in the following.
According to Scheme 1, using 1,3-dioxin 4 as starting
material,9 cyclohexenone 7 was readily prepared as a model
compound via a three-step synthetic sequence, involving
repeated α-methylation, Stork−Danheiser methylation,10 and
Dess−Martin oxidation,11 in an overall yield of ca. 60%. Not
unexpectedly, different from α-activated 2-cyclohexenones (II)
serving as versatile dienophiles, α-aldehyde 7 with a β
substituent is a rather poor dienophile for Diels−Alder reactions
under either thermal or Lewis acid-catalyzed conditions.
Figure 1. α-Activated 2-cyclohexenones are efficient dienophiles and
Michael acceptors.
(I) and its α-activated analogue (II) have been well studied in
their Diels−Alder chemistry as dienophiles, and several vital
conclusions can be derived: (1) Diels−Alder cycloaddition of 2-
cycloalkenone (I) is a rather poor process; (2) employing Lewis
acid as catalyst and/or introducing an additional electron-
withdrawing group at its α to ketone position can significantly
enhance the dienophilicity of the carbon−carbon double bond;
(3) introducing a second double bond into the ring can enhance
the secondary effect; (4) C-4 substituent can control the facial
selectivity by steric hindrance.2,3
In our long-lasting interest in Diels−Alder chemistry of 2-
cycloalkenones, β-substituted α-activated 2-cyclohexenones
(III) are further designed to evaluate whether they are as
synthetically useful as their enone counterparts (II). Unfortu-
nately, they have experimentally proved to be rather poor
dienophiles for Diels−Alder reactions, most likely because of
steric hindrance imposed on the β substituent as indicated by
many historic cases bearing a similar structure.4 Instead, they are
found to be desirable donors for Michael-type [4 + 2] anionic
annulation when EWG is an ester group5 and excellent dienes
Received: June 2, 2021
Published: July 21, 2021
© 2021 The Authors. Published by
American Chemical Society
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Table 1. Screening of Optimal Conditions for Anionic [4 + 2]
Annulation
reagent
isolated yield (%)
entry
(1.2 equiv)
solvent
THF
THF
THF
T (°C)/t
9/10
b
1
2
3
4
Li2CO3
LiOtBu
LiHMDS
LiHMDS
66/48 h
0
b
0−66/24 h
0−66/24 h
0−66/15 h
0
c
0
c
HMPA/
THF
0
5
6
7
8
Li2CO3
DMF
THF
THF
THF
THF
MeCN
DMF
THF
CH2Cl2
THF
MeCN
DMF
CH2Cl2
CH2Cl2
100/4 h
66/20 h
rt/16 h
66/30min
66/20 h
rt/12 h
70/15
e
NaHCO3
Na2CO3
Na2CO3
cat. Na2CO3
Na2CO3
Na2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NEt3
89/
91/
e
e
97/
d
e
9
88/
10
11
12
13
14
15
16
17
18
88/6
62/30
85/5
rt/1 h
rt/4 h
rt/30 min
rt/15 min
rt/10 min
rt/<5 min
rt/48 h
71/10
70/16
43/35
20/65
Figure 2. (a) Neutral electron-rich dienes. (b) Nazarov 1,3-dien-2-
olates as dienes. (c) 1,3-Dien-1-olates as dienes. (d) 2′-Oxo-1,3-dien-1-
olates as dienes.
b
0
MgBr2·OEt2/
NEt3
rt/15 h
81/trace
Scheme 1. Preparation of Cyclohexenone 7 as a Model
Compound
19
20
DBU
DBU
THF
DMF
rt/30 min
rt/<5 min
22/30
9/72
a
All reactions were performed in solvent (0.2 M) as indicated above
b
c
under N2. Reactants 7 and 8 were recovered intact. A complex
d
unidentified mixture was observed on TLC. 20 mol % of sodium
e
carbonate was used as base. Product 10 was not detected in crude 1H
f
NMR. The relative configuration was unambiguously determined by
Instead, its γ protons can be easily deprotonated and isomerized
to form 1,3-dien-1-olates to serve as an electron-rich diene.
In principle, a cycloaddition product obtained from reacting
the 1,3-dien-1-olate of 7 with an electron-deficient olefin 8 can
be explained by either a sequential double-Michael addition or a
Diels−Alder concerted cycloaddition. Preliminary results of this
study are listed in Table 1 and discussed below. As seen in
entries 1−3, all tested reactions using a strong, medium or weak
lithium base in a less polar solvent THF turned out to be fruitless
at either ambient or elevated temperature. To further activate
the lithium−enolate ion pair, solvation of lithium cation by
HMPA in THF (V/V = 1/4) was then examined;12 however,
reactions resulted in a complex unidentified mixture as observed
on TLC (entry 4). Interestingly, when lithium carbonate was
applied in the more polar solvent DMF at higher temperature
(entry 5, 100 °C), products 9 and 10 were obtained in 70% and
15%, respectively, of which the relative configuration is
unambiguously determined by a single-crystal X-ray analysis.13
Encouraged by these results, attention was then paid to using
other alkali-metal carbonates. When reactions were tested with
sodium base, such as Na2CO3 and NaHCO3, they all proceeded
efficiently in THF to afford a single diastereomer 9 in high yields
(entries 6 and 7). More importantly, when the reaction was
performed in refluxing THF, the reaction rate could be
significantly accelerated and completed in ca. 30 min (entry
8), affording product 9 in quantitative yield (97%). Thus, the
reaction system (Na2CO3 (1.2 equiv)/THF/66 °C) is
a single-crystal X-ray analysis.
tentatively considered to be optimal for this newly developed
[4 + 2] annulation process. When the quantity of Na2CO3 was
further reduced to a catalytic amount (20 mol %; entry 9),
product 9 was also produced in high yield (88%), but reaction
time should be prolonged overnight (20 h), indicating that the
annulation process can proceed with a cost-effective catalytic
cycle. Also noticed is that as reactions are carried out using
Na2CO3 as base at room temperature (entries 7, 10, and 11),
rate acceleration is reflected by the increase of solvent polarity
(THF, 16 h; CH3CN, 12 h; DMF, 1 h). Interestingly, the
formation of 10 is also significantly increased when more polar
solvents (CH3CN, 6%; DMF, 30%) are employed, which is
totally not detected in a less polar solvent (THF, 0%) by the
crude 1H NMR spectrum.
Similarly, when Cs2CO3 is used as base at room temperature,
product 10 is formed increasingly with the increase of solvent
polarity, culminating in a maximal yield of 65% in DMF (entries
13−16). As well, reaction rates are dramatically enhanced and
completed within 5−30 min whether in less or more polar
solvents. The size of the cation counterion appears to affect both
product distribution and reaction rate, as seen in entries 7, 12,
and 14. The Hunig base, trimethylamine, is apparently too weak
̈
to deprotonate γ acidic protons in CH2Cl2. As a result, no
reaction occurred, and reactants 7 and 8 were recovered intact
(entry 17). However, when an extra Lewis acid was added (entry
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18), the reaction was triggered and proceeded smoothly to
afford 9 in 81% along with a trace of 10, as detected by the crude
1H NMR. In sharp contrast, when a strong base DBU was used, a
high selectivity for product 10 over 9 was observed, particularly
in a more polar solvent DMF (entry 19 vs 20). According to
Table 1, not only was the trans isomerism of dienophile 8
constantly preserved in products, but also no Michael-addition
intermediates were detected in all cases examined.14 To
elucidate these outcomes, a plausible mechanism is proposed
as follows. Obtaining merely a pair of products 9 and 10 is
actually hard to be justified by simply applying an exo or endo
addition rule to a single dienolate (Z)-7a or (E)-7a because they
are basically in equilibrium (Figure 3). Instead, they are thought
Lewis acid MgBr2 (entry 18) appears to be an effective catalyst
to intensify the formation of (Z)-7a isomer through bidentate
chelation, leading to product 9 predominantly. When DBU was
applied (entry 20), the reaction rate was dramatically enhanced,
suggesting that the conjugate acid DBUH+ could behave like a
bulky cation Cs+ (entry 16) to shift the equilibrium to isomer
(E)-7a. The standard protocol depicted in entry 8 is then
employed to explore the scope and limitation of the method-
ology. Results are listed in Table 2, wherein Diels−Alder adducts
highlighted in blue are dienolate parts generated in situ from the
corresponding α-aldehyde cycloalkenones, including 5−8
membered ring, verbenones, cumarins, and cinnamates, and
those parts in green belong to structurally different dienophiles,
individually comprising a cyclic maleimide, cumarin, p-quinone,
Table 2. Diels−Alder Adducts Derived from Aldehyde-
dienolates
Figure 3. A proposed endo approach for Diels−Alder products 9 and/or
10.
to be formed by a concerted addition of dienophile 8 to both
dienolates following the endo approach A and B, respectively.
Because product distribution and reaction rate are highly
dependent on the base and solvent used, conformers (Z)-7a and
(E)-7a are assumed to be interconvertible with a small energy
barrier.
In addition, (Z)-7a is assigned to have a lower ground-state
energy than (E)-7a because of forming the more stable six-
membered ring ion pairs. The reaction-energy profile is
conceptually drawn in Figure S1 to interpret their relative
relationships along the reaction course. Lithium cation (Li+),
because of its exceptional oxophilicity,15 might reduce electron
density on the oxy anion significantly and thus stop enriching
dienolates in sufficient electron density from activating the
cycloaddition process (entries 1−4). However, this high degree
of cation coordination appears to be loosened/disrupted under
harsh reaction conditions in a polar solvent (entry 5). Analogous
to the anionic oxy-Cope rearrangement,16 we believe the
negative charge on the oxygen of dienolates should play a crucial
role to promote the observed Diels−Alder chemistry. Sodium
carbonate in a noncoordinating solvent like THF allows Na+ to
form a stable chelated bridge with two oxygen atoms of the (Z)-
dienolate, leading to product 9 exclusively in high yields.
However, the well-coordinating solvent DMF can solvate Na+
such that Na+ is free and two partially negative charged oxygen
atoms tend to be as far apart as possible, as in (E)-dienolate.
Collectively, it is concluded that anionic Diels−Alder reactions
proceed primarily through the endo approach A in a less polar
solvent with a small countercation Li+ or Na+ but shift
significantly toward the endo approach B in a more polar solvent
with a bulky countercation K+ or Cs+. The reactivity trend of
base and solvent is found to be in descending order of cation size
and polarity, namely, Cs+ > K+ > Na+ > Li+ and DMF > CH3CN
> THF > CH2Cl2. Thus, a maximum synergistic effect on
reaction rate (ca. 5 min) was observed when the reaction was
carried out in combination with Cs2CO3 and DMF (entry 16).
a
b
Reaction was carried out in a sealed tube. A mixture of (E)- and
c
(Z)-cinnamate ester was used. Product 31a (8%) and 35a (10%) was
individually isolated. The relative configuration was determined by
an X-ray analysis.
d
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acylic α-substituted acrolein, fumarate, or isobutylidene
malonate unit. Expected products were commonly obtained in
moderate to excellent yields as a single diastereomer, indicating
that the methodology is synthetically practicable.
Table 3. Diels−Alder Adducts Derived from Ketone-
dienolates
More importantly, many are structurally unambiguously
identified by X-ray analysis, lending substantial evidence to
Diels−Alder chemistry claimed for this novel [4 + 2] annulation.
For example, products 15 (89%) and 25 (90%),13 formed
exclusively in high yields as a single stereoisomer, are considered
to be typically governed by the ortho and endo addition rule with
complete face selectivity via effectively shielding the gem-
dimethyl side of verbenone. Product 30 (84%),13 containing
four contiguous stereogenic centers precisely predicted by the
ortho and endo rule, also provides strong support for a concerted
Diels−Alder approach. Encouragingly, when starting α-
aldehyde β-methyl alkenones allow both γ and γ′ sites to
undergo deprotonation, the desired aldehyde-dienolate prod-
ucts are still constantly formed in good to excellent yields (77−
96%) as seen in 12−14, 17, 18, 23, 26, 27, 29−33, and 35−37,
with the exception of 18 (53%) in a moderate yield, presumably
because of the obstruction of the transannular strain in medium
rings. Nevertheless, when products 31 (85%) and 35 (79%)
were isolated, the corresponding ketone-dienolate adducts 31a
and 35a (see the Supporting Information) were also individually
identified in 8% and 10% yield, indicating that cisoid dienolates
through enolization of γ′ protons could also be formed and
captured by certain active dienophiles such as N-phenylmaleic
imide. A single diastereomer 21 (84%) obtained exclusively also
supports that a concerted approach should be adopted as both
cisoid and transoid dienolates were generated during the
reaction. Indeed, the highly conserved configuration of the
dienophile during the transformation into the corresponding
product is hard to explain if a two-step Michael−Aldol addition
is thought to be a preferred pathway.
a
Reactions were performed in THF (0.2 M) with Na2CO3 (1.2 equiv)
b
c
under N2. Reaction was carried out in a sealed tube. 2.0 equiv of
dienophile was used instead. The relative configuration was
determined by a single-crystal X-ray analysis.
d
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01807.
Experimental procedures and spectroscopic data for all
new compounds (PDF)
Accession Codes
To further confirm whether ketone-dienolate D−A adducts
are synthetically useful and general, a series of α-aldehyde
cycloalkenones, containing only γ′ protons, or α-ester cyclo-
alkenones, containing γ and/or γ′ protons, were designed in
order to generate merely the ketone-type cisoid dienolate.
Results are listed in Table 3. As predicted by a concerted endo-
addition approach, all products 38−46 were obtained with high
regio- and stereoselectivity in good to high yields (71∼95%).17
Products 38−41, produced at higher temperature (100 °C) than
their α-aldehyde counterparts 42−46 (66 °C), are somewhat
contradictory because dienolates containing a weaker electron-
withdrawing ester group should be more reactive in terms of
inductive effects. These reverse outcomes might result from the
steric hindrance caused by the ester group during cycloaddition.
In conclusion, unprecedented anionic Diels−Alder chemistry
of highly electron-deficient cross-conjugated vinylogous systems
has been newly developed, in which the cyclic sodium dienolate
ion pairs, generated in situ in the presence of a weak sodium base
in THF, are highly thermally stable and operationally simple to
play the role of electron-rich dienes during reactions. Products
thus obtained contain multiple contiguous chiral centers, whose
stereochemical arrangements could be accurately predicted by
the ortho and endo rule, thus strongly supporting a concerted [4
+ 2] cycloaddition rather than a consecutive Michael−Aldol
type annulation.
CCDC 2007692−2007693, 2074040, 2074048−2074049,
2074053, 2074055, 2074071−2074076, and 2074078 contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.uk,
or by contacting The Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033.
AUTHOR INFORMATION
Corresponding Author
■
Kak-Shan Shia − Institute of Biotechnology and Pharmaceutical
Research, National Health Research Institutes, 35053 Taiwan,
R.O.C.; orcid.org/0000-0001-9560-2466;
Email: ksshia@nhri.edu.tw
Author
Jing-Kai Huang − Institute of Biotechnology and
Pharmaceutical Research, National Health Research
Institutes, 35053 Taiwan, R.O.C.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01807
Notes
The authors declare no competing financial interest.
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Deslongchamps, P. Synthesis of cis-Decalin via Diels-alder and Double
michael Cycloaddition with Substituted Nazarov Reagent. Tetrahedron
Lett. 1988, 29, 5117.
ACKNOWLEDGMENTS
■
We are grateful to the Ministry of Science and Technology
(MOST 106-2113-M-400-004-MY2, MOST 108-2113-M-400-
005, and MOST 110-2731-M-007-001/MS005300) and Na-
tional Health Research Institutes of the Republic of China for
financial support.
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D−A products, including compounds 9 (CCDC 2074048), 10 (CCDC
2074049), 15 (CCDC 2007692), 22 (CCDC 2074040), 24 (CCDC
2074071), 25 (CCDC 2007693), 26 (CCDC 2074072), 27 (CCDC
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from The Crystallographic Data Centre.
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