Diels-Alder Reactions of 1-Alkoxy-1-amino-1,3-butadienes: Direct Synthesis of 6-Substituted and 6,6-Disubstituted 2-Cyclohexenones and 6-Substituted 5,6-Dihydropyran-2-ones

Article abstract of DOI:10.1021/acs.orglett.1c01031

We report the cycloaddition reactions of 1-alkoxy-1-amino-1,3-butadienes. These doubly activated dienes are prepared on a multigram scale from crotonic acid chloride and its derivatives. The dienes undergo Diels-Alder (DA) and hetero-Diels-Alder (HDA) reactions under mild reaction conditions with a variety of electron-deficient dienophiles to afford cycloadducts in good yields with excellent regioselectivities. The hydrolysis of the DA cycloadducts provides 6-substituted and 6,6-disubstituted 2-cylohexenones, which are versatile building blocks for complex molecule synthesis. The corresponding HDA cycloadducts afford 6-substituted 5,6-dihydropyran-2-ones.

Full text of DOI:10.1021/acs.orglett.1c01031

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Letter
Diels−Alder Reactions of 1‑Alkoxy-1-amino-1,3-butadienes: Direct
Synthesis of 6‑Substituted and 6,6-Disubstituted 2‑Cyclohexenones
and 6‑Substituted 5,6-Dihydropyran-2-ones
Pavel K. Elkin,† Nathaniel D. Durfee,† and Viresh H. Rawal*
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ABSTRACT: We report the cycloaddition reactions of 1-alkoxy-1-
amino-1,3-butadienes. These doubly activated dienes are prepared on a
multigram scale from crotonic acid chloride and its derivatives. The
dienes undergo Diels−Alder (DA) and hetero-Diels−Alder (HDA)
reactions under mild reaction conditions with a variety of electron-
deficient dienophiles to afford cycloadducts in good yields with
excellent regioselectivities. The hydrolysis of the DA cycloadducts
provides 6-substituted and 6,6-disubstituted 2-cylohexenones, which
are versatile building blocks for complex molecule synthesis. The
corresponding HDA cycloadducts afford 6-substituted 5,6-dihydropyr-
an-2-ones.
he Diels−Alder (DA) reaction is one of the most
Timportant transformations in organic chemistry, provid-
ing direct access to six-membered cyclic compounds in a regio-
and stereocontrolled manner with up to four chiral centers.1
The power of the DA reaction is evident from its indispensable
role in the synthesis of numerous complex molecules.2 Of
special importance in the development of this reaction has
been the advent of a suite of heteroatom-substituted dienes,
which not only are more reactive but also yield a wide range of
functionalized building blocks for chemical synthesis.3 The
introduction of Danishefsky’s diene (1, Scheme 1a), for
example, enabled the facile synthesis of various 4,4-
disubstituted cyclohexenones (and further substituted deriva-
tives thereof), which paved the way to many intricate natural
products.4 The development of the 1-amino-derivatives of this
diene (i.e., 3, Scheme 1b), which is considerably more reactive,
opened further opportunities in synthesis,5−7 including the
development of enantioselective DA reactions.8 Given the
importance of 6,6-disubstituted cyclohexanone cores (5) as
building blocks for the synthesis of complex molecules9 and
the paucity of methods to access them, we investigated various
additional heteroatom-substituted butadienes and their cyclo-
additions and report here the results of our studies on the
synthesis and DA and hetero-Diels−Alder (HDA) reactions of
1-alkoxy-1-amino-1,3-butadienes.
whereas 1,1-dimethoxybutadiene gave the expected cyclo-
adducts with highly electron-deficient dienophiles such as
dimethyl 2,3-dicyanomaleate, its reactions with common
dienophiles, such as methyl acrylate, acrylonitrile, fumaro-
and maleonitrile, dimethyl fumarate, and dimethyl maleate,
gave no cycloadducts and only polymeric materials.10d Among
the 1,1-dialkoxybutadienes, the most important is Brassard’s
diene (7b, Scheme 1d). Although used widely for HDA and
Mukaiyama aldol reactions, its successful use in DA reactions is
primarily with quinone or doubly activated dienophiles.11
Additionally, the cycloadducts it generates are necessarily more
highly oxygenated, giving 3-alkoxycyclohexenone products, the
masked form of 1,3-cyclohexanediones, rather than 2-
cycohexenones. The related 1-alkoxy-1-aminobutadiene (cf.
8), which is expected to be even more reactive, has seen
limited use for DA reactions. Indeed, the reaction of 8b with
dimethyl acetylenedicarboxylate did not afford the expected
DA adduct, instead giving a product (9) “with a substitution
pattern incompatible with the normal Diels−Alder pathway”.12
We reasoned that the poor DA reactivity of 1-alkoxy-1-
aminobutadienes such as 8 was likely due to steric interactions
that disfavor the s-cis rotamer that is required for DA reactions,
Received: March 31, 2021
Published: June 1, 2021
The synthesis of 6,6-disubstituted cyclohexenones (5) via a
DA cycloaddition requires either vinyl ketene (6) or its formal
equivalent (Scheme 1c). To realize this capability, several 1,1-
dialkoxybutadienes have been developed and examined (7a) in
cycloaddition reactions.10 Notably, Sustmann reported that
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be subjected to a 2 M NaOH/H2O solution with no
degradation. By quenching the reaction with such a solution,
all polar nonvolatiles can be removed by extraction, and the
desired diene can be obtained pure without the need for
distillation. This improved route is shorter and affords the
diene in high yield, requiring no distillation or columns.
Importantly, intermediate 15 is stable for an extended period
of time, even when stored at room temperature. The improved
route was used to prepare over 15 g of salt 15 and 4 g of diene
10 in a single pass.
Scheme 1. Activated Butadienes for Diels−Alder Reactions
The initial studies were aimed at assessing the cycloaddition
capability of the new dienes. Upon heating a solution of diene
10 and methacrolein in toluene to 60 °C for 2 h, the diene was
fully consumed and yielded a 3:1 mixture of two products, as
observed by NMR. The major product was the expected
cycloadduct, and the minor product was tentatively assigned to
be the HDA adduct.15a The major product was unstable to
silica gel but could be hydrolyzed to give the desired 6,6-
disubstituted cyclohexanone 17a (Scheme 3). The analogous
Scheme 3. Diels−Alder Reactions of Diene 10 with
Dienophiles
instead allowing alternate reaction paths (Scheme 1e).13 Given
this background of literature reports, we investigated the
oxazolidine-fused butadiene 10, wherein the N and O atoms
are linked through a two-carbon unit, thereby obviating the
steric issues. The desired diene was synthesized in good yield
through a simple protocol starting with Woollaston’s route to
α,β-unsaturated oxazoline 12a (Scheme 2).14 This oxazoline
Scheme 2. Synthesis of Oxazolidine-Fused Butadienes
a
b
DA reactions run in a sealed tube. Expected cycloadduct not
c
formed. Mixture of keto and enol forms.
reaction with the gem-dimethylated diene 13 gave a cyclo-
adduct (cf. 16, 30%) that was column-stable, allowing the
confirmation of its structure. However, the DA reaction
proceeded significantly more slowly, so diene 13 was not
further investigated.15b
Various parameters were examined to improve the reaction
outcome with diene 10. When carried out in toluene at room
temperature, the reaction required 10 h to go to completion
and gave a similar ratio of the two products. In hydrogen-bond
donor solvents (e.g., t-BuOH), the reaction rate of the HDA
reaction increased, and the reaction gave a lower proportion of
the desired DA cycloadduct. The best outcome, albeit by a
small margin, was obtained when the reaction was performed
in benzene. Upon optimization, the DA reaction and the
hydrolysis could be performed in a single procedure that
afforded ketone 17a in 70% isolated yield.
To evaluate the generality of the protocol, we reacted diene
10 with several common dienophiles (Scheme 3). Ethyl- and
n-butyl-acroleins reacted analogously to methacrolein and
afforded the respective 6,6-disubstituted 2-cyclohexenones in
good yields. We were delighted to find that even tiglic
aldehyde participated in the cycloaddition to give, after
hydrolysis, trisubstituted cyclohexenone 17d. The reactions
was then converted into the desired diene in two steps via the
formation of the oxazolinium salt followed by deprotonation
with NaHMDS. Through this route, we prepared both the base
diene 10 and the gem-dimethyl-substituted diene 13. An
alternate synthesis of the diene was also developed to
overcome the long reaction times and the difficult isolation
procedure, especially the distillation of the thermally unstable
oxazolines 12. Crotonyl chloride was reacted with N-
methylethanolamine, and the resulting amide 14 was treated
with triflic anhydride, which induced the desired cyclization to
give oxazolonium triflate salt 15. Deprotonation of 15 with
NaHMDS then proceeded cleanly to give the desired diene in
71% overall yield from crotonyl chloride. Whereas the diene is
unstable in aqueous solutions of pH <10, we found that it can
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with acrylonitrile and methyl acrylate proceeded well, as did
the reaction with methyl maleate. Unfortunately, the reaction
with methyl vinyl ketone gave no cycloadduct 17e.15c
Scheme 5. Synthesis of Substituted Oxazolidine-Butadienes
The useful reactivity shown by diene 10 in DA reactions
with traditional dienophiles motivated us to examine its
reactions with nitroalkenes (Scheme 4). Whereas nitroethylene
Scheme 4. Diels−Alder Reactions of Diene 10 with
Nitroalkenes
Scheme 6. Diels−Alder Reactions of Substituted
Oxazolidine−Butadienes with Various Dienophiles
a
Yield in parentheses is the NMR yield of the cycloadduct (18).
is reported to react at room temperature with highly active
dienes like cyclopentadiene, the DA reaction of β-arylnitro-
ethylenes generally requires higher temperatures or special
activation modes.16 In light of this limitation, we were
delighted to observe that the oxazolidine-fused butadiene 10
rapidly reacted at room temperature with β-nitrostyrene to give
a cycloadduct (cf. 18), which upon quenching with aqueous
oxalic acid gave the expected 6-nitro-substituted cyclo-
hexenone 19a in 75% yield.17 Several additional β-arylnitro-
ethylenes and two β-alkyl-substituted nitroethylenes were
subjected to the cycloaddition/hydrolysis protocol, and all
gave the cyclohexanone products in good to excellent yields.
Nitroethylenes with aryl units possessing donor groups or
withdrawing groups worked equally well, as did naphthyl- and
heteroaryl-substituted nitroethylenes. The two alkyl-substi-
tuted β-nitroalkene products are also noteworthy, in particular,
the spiro-fused bicyclic compound 19i, which was formed in
78% yield. The present method offers a simple route to various
6-nitrocyclohexenones, the chemistry of which appears to have
been scarcely investigated.18
We next turned our attention to the preparation and DA
reactivity of more substituted analogs of diene 10 (Scheme 5).
Three different dienes were synthesized using the first protocol
described above, starting with the requisite acid chlorides. The
procedures transferred well and enabled the synthesis of gram
quantities of the different dienes, which were isolated as
colorless liquids that were stored under an inert atmosphere.
The dienes reacted with several common dienophiles to afford,
after the in situ hydrolysis of the cycloadducts, the expected
cyclohexanone products in good overall yields (Scheme 6).19
Given the robustness of diene preparation and the generality of
the DA reactions, the present method provides facile access to
various functionalized mono- and bicyclic systems that should
prove to be of value in complex molecule synthesis.
To further expand the scope of the cycloadditions of diene
10, we examined its HDA reaction with aldehydes, which
would provide a simple and direct route to 6-substituted
dihydro-2-pyrones. This subunit is found in many bioactive
natural products and consequently is the subject of much
synthesis work.20 As previously noted, we had observed the
formation of a labile side product that was presumed to be the
HDA adduct. To capitalize on this observation, we carried out
the reaction of 10 with benzaldehyde (PhH, 60 °C) and were
delighted to observe the clean formation of cycloadduct 28, as
confirmed by NMR. As the cycloadduct proved labile to
isolation, the reaction was directly quenched with aqueous
oxalic acid, which promoted its hydrolysis to afford the α,β-
unsaturated δ-lactone product 29a in 70% yield. Given the
simplicity of the procedure, we examined the HDA reaction of
10 with several common aldehydes and found the process to
be useful for both electron-poor and electron-rich aromatic
aldehydes (Scheme 7). Aliphatic aldehydes were unreactive
under the conditions used.
The breadth of facile reactions observed with diene 10 and
its more substituted derivatives motivated us to benchmark its
reactivity against other highly reactive dienes, such as
Danishefsky’s diene (1), 1-amino-3-siloxybutadiene (3), and
its carbamate derivative (30). The kinetic measurements were
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Scheme 7. HDA Reaction of Diene 10 with Aromatic
Aldehydes
Figure 1. Arrhenius plots and activation parameters for the reaction of
dienes 1 and 10 with diethyl fumarate in toluene; [diene]0 = 0.2 M,
[dienophile]0 = 0.6 M. Rate constants for 1 measured at 50, 60, and
70 °C. Rate constants for 10 measured at 40, 50, and 60 °C.
carried out at 60 °C in C6D6, and the product concentrations
1
As expected, the activation energy (Ea) for the reaction with
Danishefsky’s diene was found to be substantially larger than
that with diene 10. Arrhenius plots extrapolated from the
kinetic data indicate a much larger difference in the relative
reactivities of dienes 1 and 10 at room temperature.15b
Interestingly, above 140 °C, diene 1 is predicted to react faster
with diethyl fumarate than diene 10.
were monitored by H NMR. The second-order rate constant
for the reaction between diene 10 and diethyl fumarate in
benzene was determined to be 2.6 × 10−4 M−1 s−1 (Table
1).15b For diene 1 and carbamate diene 30, the rate constants
Table 1. Rate Constants for DA Reactions of Some Reactive
Dienes
As the previously described results demonstrate, 1-amino-1-
oxobutadienes represent an important addition to the family of
reactive, heteroatom-substituted dienes. The parent diene can
be synthesized in one step from a stable triflate salt precursor,
and it and all related dienes can be prepared on a multigram
scale. The new dienes undergo DA reactions with a broad
range of dienophiles to afford, after in situ hydrolysis, a variety
of 6-substituted 2-cyclohexenones, which should prove to be
versatile building blocks for the synthesis of complex
molecules. The HDA reactions of the parent diene with
aldehydes give direct access to 6-substituted 5,6-dihydro-2-
pyrones. Kinetics experiments indicate that the new diene,
despite its added steric interactions, is significantly more
reactive than other highly active dienes such as Danishefsky’s
diene, especially at lower temperatures. Further expansion of
the chemistry of these dienes, especially the development of
enantioselective DA or HDA reactions or reactions with other
heterodienophiles, is expected to greatly enhance their
usefulness in chemical synthesis.
a
b
c
d
Run in C6D6. Values from Kozmin et al.21 Run in CDCl3 Run in
ASSOCIATED CONTENT
* Supporting Information
■
sı
Tol-d8.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01031.
are 4.1 × 10−5 M−1 s−1 and 3.5 × 10−5 M−1 s−1, respectively.
Also listed are the reported rate constants for the reaction
between the 1-amino-3-siloxy diene 3 and diethyl fumarate at
17 °C and with methacrolein at 17 and 60 °C.21 The results
show that whereas Danishefsky’s diene 1 and carbamate diene
30 react with fumarate at approximately the same rate, diene
10 reacts nearly seven times faster. All three dienes reacted two
to three times faster in chloroform. Interestingly, although
dienes 3 and 10 have similar heteroatom substituents, the
latter is considerably less reactive, likely due to the steric
hindrance from the cis-oriented oxygen.
Experimental procedures and spectroscopic data for all
reported compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Viresh H. Rawal − Department of Chemistry, University of
Chicago, Chicago, Illinois 60637, United States;
orcid.org/0000-0003-4606-0239; Email: vrawal@
uchicago.edu
Authors
To get further insight into the relative reactivities of the
dienes, we determined the activation parameters for the DA
reactions of diethyl fumarate with dienes 1 and 10 (Figure 1).
Pavel K. Elkin − Department of Chemistry, University of
Chicago, Chicago, Illinois 60637, United States
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Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Single enantiomers from
a chiral-alcohol catalyst. Nature 2003, 424, 146. (c) Watanabe, Y.;
Washio, T.; Shimada, N.; Anada, M.; Hashimoto. Highly
enantioselective hetero-Diels−Alder reactions between Rawal’s
diene and aldehydes catalyzed by chiral dirhodium(II) carboxami-
dates. Chem. Commun. 2009, 7294−7296. (d) Economou, C.;
Tomanik, M.; Herzon, S. B. Synthesis of myrocin G, the putative
active form of the myrocin antitumor antibiotics. J. Am. Chem. Soc.
2018, 140, 16058−16061. Review on enantioselective DA reactions
of siloxydienes: (e) Harada, S.; Nishida, A. Catalytic and
enantioselective Diels-Alder reaction of siloxydienes. Asian J. Org.
Chem. 2019, 8, 732−745.
Nathaniel D. Durfee − Department of Chemistry, University
of Chicago, Chicago, Illinois 60637, United States;
orcid.org/0000-0002-5265-8328
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01031
Author Contributions
†P.K.E. and N.D.D. contributed equally to the work.
Notes
The authors declare no competing financial interest.
(9) The 6,6-disubstituted cyclohexanone motif, or its further
modified derivative, is found in numerous natural products, including
platencin, welwitindolinones, cyanthiwigin B, acutifolone A, and
lycopoclavamine A.
ACKNOWLEDGMENTS
■
Financial support from the National Science Foundation
(NSF-1566402) is gratefully acknowledged. N.D.D. thanks the
NIH (T32 GM008720) for partial support.
(10) Such dienes have been shown to be effective primarily with
highly activated dienophiles. See: (a) Banville, J.; Grandmaison, J.-L.;
Lang, G.; Brassard, P. Reactions of ketene acetals. Part I. A simple
synthesis of some naturally occurring anthraquinones. Can. J. Chem.
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T. V.; Barton, D. H. R. The synthesis and Diels−Alder reactions of 2-
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(11) (a) Banville, J.; Brassard, P. Reactions of ketene acetals. Part 7.
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(17) NMR analysis of the crude reaction mixture showed a clean and
nearly quantitative formation (>95%) of the DA adducts (18). The
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hydrolysis step.
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NOTE ADDED AFTER ASAP PUBLICATION
A correction was made to structure 10 in Scheme 3 on June 10,
2021.
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Org. Lett. 2021, 23, 5288−5293