Diels-Alder Reactions with Ethylene and Superelectrophiles

Article abstract of DOI:10.1021/acs.orglett.8b00367

Diels-Alder reactions have been accomplished with ethylene as the dienophile through the use of inverse-electron demand Diels-Alder chemistry. As a key aspect of the chemistry, the dienes are part of tri- or dicationic superelectrophilic systems. Theoreti

Full text of DOI:10.1021/acs.orglett.8b00367

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Diels−Alder Reactions with Ethylene and Superelectrophiles
Hien Vuong,† Barada P. Dash,† Sten O. Nilsson Lill,‡ and Douglas A. Klumpp*,†
†Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, Illinois 60115, United States
‡Early Product Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, S-431 83 Molndal, Sweden
̈
S
* Supporting Information
ABSTRACT: Diels−Alder reactions have been accomplished
with ethylene as the dienophile through the use of inverse-
electron demand Diels−Alder chemistry. As a key aspect of the
chemistry, the dienes are part of tri- or dicationic super-
electrophilic systems. Theoretical calculations reveal that the
highly charged superelectrophiles possess exceptionally low
lying LUMOs, and this facilitates the cycloaddition chemistry
with ethylene. The chemistry has been used to prepare a series
of tetrahydroquinoline products. This represents the first
application of superelectrophilic activation in a cycloaddition
reaction, and a new method of utilizing ethylene as a C2 building block.
the system lowered the activation energy for the pericyclic
reaction. It was suggested that the dicationic system benefitted
from enhanced π-electron delocalization, and this facilitated the
pericyclic reaction. A similar type of electrocyclization was also
reported for aza-Nazarov cyclizations.4 At this point, it is not
known if highly charged organic cations may enable other types
of pericyclic reactions. While numerous examples are known of
superelectrophilic reactions forming single C−X and C−C
bonds, no such reactions are known to form two bonds in
concert. In this Letter, we wish to report an example of a series
of cycloaddition reactions involving superelectrophilic inter-
mediates.
The high cationic charge densities on superelectrophiles
often lead to unusually low energy LUMOs and large orbital
coefficients within π-systems.5 Moreover, superelectrophiles
have a strong tendency to separate cationic charge during the
course of their reactions, providing a potential driving force for
pericyclic reactions. These considerations suggest that super-
electrophiles may be useful in cycloadditions, such as the
Diels−Alder reaction. In order to evaluate the possibility of
using superelectrophiles in Diels−Alder reactions, we sought to
use aromatic imines/iminium ions and ethylene in the [4 + 2]
cycloadditions. Aromatic imines are known to react with
electron-rich dienophiles, a transformation known as the
Povarov reaction.6 Dienophiles commonly used in the Povarov
reaction include ethyl vinyl ether, cyclopentadiene, 3,4-dihydro-
2H-pyran, indene, ethyl vinyl sulfide, styrene, and allyltrime-
thylsilane.7 The measured ionization energies for these systems
range from 8.14 eV (indene) to 8.98 eV (ethyl vinyl ether).8
The relatively low energies of ionization are consistent with
high energy HOMOs, a necessary condition for reverse
electron demand Diels−Alder reactions. On the other hand,
he concept of superelectrophilic reactivity was proposed
Tby Olah and co-workers to explain the heightened
reactivities of electrophiles in superacidic media.1 Experimental
studies revealed astonishing levels of reactivity for di- and
tricationic superelectrophiles, including reactions with very
weak nucleophiles, such as alkanes and deactivated arenes.2
Despite several decades of work on superelectrophile chemistry,
almost no work has been done to examine the chemistry of
these highly charged organic structures in pericyclic reactions. A
notable exception is the work of Shudo and co-workers who
reported the chemistry of a superelectrophilic Nazarov reaction
(Scheme 1).3 They found evidence for the involvement of
dicationic species in a series of 4π-electrocyclizations.
Theoretical calculations showed that increasing the charge on
Scheme 1. Superelectrophilic Pericyclic Reactions
Received: January 31, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.8b00367
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Letter
ethylene has a measured ionization potential of 10.51 eV, which
suggests it should be considerably less reactive as a dienophile
in reverse electron demand Diels−Alder reactions.9 Never-
theless with aryl imines as the diene component, utilization of
N-heterocyclic groups allow for an increasing charge on the
system. We reasoned that increasing charge on the aryl group
should lead to lowering of the diene LUMOs and,
consequently, increased reactivities in the cycloaddition
chemistry.
were obtained by cyclizations with the phenyl ring, 1-naphthyl
ring, and the substituted aryl rings. Although imine 6 has
several potential diene or aza-diene sites, cycloaddition was
only observed at the Povarov reaction site. The chemistry is
amenable to biaryl synthesis, as cycloaddition may be
accomplished with subsequent S8 oxidation (Scheme 3). The
Scheme 3. Biaryl Synthesis
Our initial experimentation involved the reaction of pyridyl
imine 1, prepared from 4-fluoroaniline and 2-pyridine-
carboxaldehyde (Scheme 2).
cycloaddition reactions are carried out in excess superacid, and
therefore, it is likely the reactions involve dicationic and
tricationic species. For example, imine 3 should provide
dication 19, while the pyrazine and quinoxaline derivatives (9
and 17) are expected to provide the trications 20 and 21
(Figure 1). It is conceivable that other ionizations may occur
Scheme 2. Ethylene Cycloaddition
In no acid or weak acid (CF3CO2H, 52 equiv), little or no
cycloaddition product (2) could be obtained. Stronger acids,
such as H2SO4 (75 equiv) or CH3SO3H (60 equiv), provided
acceptable yields of the tetrahydroquinoline 2, 57% and 50%,
respectively. Good yields of product 2 are obtained with
inclusion of the Brønsted superacid, CF3SO3H (triflic acid).
The optimized conditions utilize 7 equiv of CF3SO3H and 160
psi ethylene to give product 2 in 81% yield (5 h reaction).
There was no evidence for ethylene oligomerization or
polymerization in the superacid.
A series of aryl imines were then prepared and reacted with
ethylene in the presence of acid (Table 1). Using the optimized
conditions, the imines (3−9) provided the cycloaddition
products (10−16) in good yields. The Diels−Alder products
Figure 1. Superelectrophiles generated from heterocyclic imines.
with imine 6 in the superacid, as the azo group possesses good
basicity. In the original hypothesis, it was suggested that the
more highly ionized dienes would have greater reactivities with
ethylene, compared to monocationic or neutral dienes. This
was confirmed by the reaction of benzylidene imine 22 with
triflic acid and ethylene, as no cycloaddition product is obtained
(Scheme 4). Evidently, the monocationic species 23 is not
Scheme 4. Attempted Reaction with a Monocationic System
Table 1. Reactants, Products, and Isolated Yields from
Cycloaddition Reactions with Ethylene (160 psi) and
CF3SO3H (7 equiv) at 25 °C
sufficiently reactive to undergo cycloaddition. As expected for
the neutral diene, no cycloaddition products were observed
from the same reaction conditions with stilbene.
In order to further explore the observed [4 + 2]
cycloaddition, density functional theory (DFT) calculations
were done (Figure 2). The series of isoelectronic structures
(stilbene 24, iminium ion 23, iminium ion 19, and iminium ion
20) were studied. Geometry optimizations were completed at
the M06-2X/6-31+G(d,p) level of theory in the gas phase.10
Gibbs’ free energy corrections (ΔG) were calculated, and the
structures were verified to be minima or transition states by
inspection of the number of imaginary frequencies. In a final
step, solvent phase single-point calculations at the same level of
theory were performed using a Poisson−Boltzmann solver (v.
4.10), as implemented in Jaguar.11 Solvation effects from the
surroundings were calculated using the SCRF method with
CF3SO3H as the solvent (dielectric constant = 77.4, probe
radius = 2.5985274 Å).12 The free energy correction terms
(ΔG) were added to the solution-phase energy to get a final
solution free energy value. From the localized transition states,
the connecting reactant and product states were determined
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the activation energy decreases. Thus, the average bond
distance (C2−C3 and C4−C5 bonds) in the monocationic
transition state (23ts) is 2.19 Å while the average bond distance
in the tricationic transition state (20ts) increases to 2.37 Å. The
activation energy is also significantly different between the
systems, as it decreases more than 7.0 kcal/mol for the
reactions of the dicationic or tricationic iminium ions (19ts and
20ts), compared to the monocationic iminium ion (23ts). The
lowered activation energies for the superelectrophilic reactions
enable the [4 + 2] cycloadditions to be carried out at ambient
conditions. The activation energies for the superelectrophilic
systems, 19ts and 20ts, are comparable with other Diels−Alder
reactions (ca. 12−30 kcal/mol).13 Cycloaddition with ethylene
leads to structures 24b, 23b, 19b, and 20b as reactive
intermediates from the reactions. With increasing charge on
the system, the conversion is increasingly exergonic. For
example, the neutral system 24b is endergonic by 8.4 kcal/mol,
while the monocationic system 23b is exergonic by −6.0 kcal/
mol. The superelectrophilic systems are significantly exergonic,
−18.2 kcal/mol for dication 19b and −23.1 kcal/mol for
trication 20b. Among the charged systems, this trend can be
understood to be a consequence of the increasing charge on the
aryl group. The cycloaddition leads to charge separation
between the iminium ion and the substituent heteroaryl group.
Thus, the tricationic system benefits most from the reaction
because it provides relief from the electrostatic effects of three
neighboring cationic charge centers. Charge−charge repulsive
effects are known to be a driving force in the reactions of
superelectrophiles.2,14 This also appears to be an important
factor in the Diels−Alder reactions of superelectrophiles.
A previous DFT study of the Povarov reaction found
evidence for highly asynchronous bond formation in the
reactions of N-aryl iminium ions with electron-rich dienophi-
les.6b In some cases, reaction of the iminium ion with an
electron-rich olefin gives the cyclization product by a two-step
process: the iminium ion reacts with the olefin to give
carbocationic or carboxonium ion intermediates, followed by a
Friedel−Crafts reaction to provide the new ring. For example,
the BF3-catalyzed reaction of imine 22 with methyl vinyl ether
is found to have the zwitterionic structure 25 at an energy
minimum (Scheme 5). Interestingly, the above superelectro-
Figure 2. M06-2X/6-31+G(d,p) calculated structures and reactions
energies in solution phase (CF3SO3H).
Scheme 5. Zwitterionic Povarov Reaction
using the QRC approach, employing Chemcraft, to visualize the
reaction mode.
The starting iminium ions (23, 19, and 20) and stilbene (24)
and their reactions with ethylene were calculated. Analysis of
the gas-phase optimized structures reveals a dramatic lowering
of the LUMO, as charge is added to the diene. Thus, stilbene is
found to have a LUMO at −0.803 eV, while the dicationic and
tricationic imines have LUMOs at −10.648 and −15.319 eV,
respectively. In accord with the frontier molecular orbital
theory, lowering of the diene LUMO is essential for the reverse
electron demand Diels−Alder reaction with ethylene (and its
low-lying HOMO).
In all cases, an association complex between ethylene and the
diene is located as a shallow minimum on the potential energy
surface, preceding the transition state (see Supporting
Information). Examination of the calculated transition state
structures reveals that increasing charge has a significant effect
on the structures and energies. With progression from neutral
to monocationic to dicationic to tricationic diene, the transition
state moves earlier, based on the average new bond lengths, and
philic Povarov reactions do show a delay in forming the C4−
C5 bond, compared to the C2−C3 bond. However, bond
formation appears to be more concerted with increasing charge
on the iminium ion. The tricationic transition state structure
(20ts) possesses C2−C3 and C4−C5 bond lengths that differ
by only 0.018 Å. This is consistent with the ethylene Povarov
reaction exhibiting the characteristics of a Diels−Alder type
cycloaddition rather than a stepwise domino process.
Finally, it should be noted that ethylene is a desirable C2
building block, and there has been significant recent interest in
its use as a dienophile in Diels−Alder reactions.15 Many of
these transformations have sought to use biorenewable furan
derivatives and other substrates in Diels−Alder reactions with
C
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ethylene. These conversions utilize solid acid,15a transition
metal,15b or zeolite catalysts15c and require high pressures of
ethylene (200 to 6200 psi) and high temperatures (100−300
°C). In general, Diels−Alder reactions with ethylene often
require forcing conditions. Exceptions to this are known,
however. Diels−Alder reactions with ethylene may be
conducted under mild conditions if the diene is destabilized
by electronic effects. This usually involves chemistry with
reactive species, such as cyclobutadienes, cyclopentadienones,
or tetrazines.16−18 In the present study, we show that
superelectrophiles may also participate in Diels−Alder reactions
with ethylene under mild conditions.
In summary, we have found that superelectrophilic iminium
ions may undergo [4 + 2] cycloadditions with ethylene. The
chemistry provides good yields of heteroaryl-substituted
tetrahydroquinolines and, with oxidation, a good yield of a
biaryl product. DFT calculations reveal that increasing the
charge lowers the LUMO on the diene component and
significantly lowers the activation energy for the cycloaddition.
Formation of the cycloaddition product also becomes
thermodynamically more favorable. To date, the paradigm of
Olah’s superelectrophilic chemistry has largely involved single
C−X or C−C bond formations by reaction of bonding or lone-
pair electrons.2 The present study shows that superelectrophilic
chemistry also includes pericyclic types of reactions, in which
more than one C−X or C−C bond can form during the
process.
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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.8b00367.
(16) Inagaki, Y.; Nakamoto, M.; Sekiguchi, A. Nat. Commun. 2014, 5,
3018.
(17) Szilagyi, S.; Ross, J. A.; Lemal, D. M. J. Am. Chem. Soc. 1975, 97,
5586.
(18) Avram, M. Chem. Ber. 1962, 95, 2248.
Experimental procedures, characterization data, and
NMR spectra of new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: dklumpp@niu.edu. Phone: 1-815-761-3153.
ORCID
Barada P. Dash: 0000-0001-8855-0813
Sten O. Nilsson Lill: 0000-0003-4818-8084
Douglas A. Klumpp: 0000-0001-5271-699X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by the U.S. National Science Foundation
(Grant No. 1300878), and their support is gratefully acknowl-
edged. This paper is dedicated to the fond memory of Professor
George A. Olah (1927−2017).
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DOI: 10.1021/acs.orglett.8b00367
Org. Lett. XXXX, XXX, XXX−XXX