Superelectrophilic Diels–Alder reactions and oxidations leading to heterocyclic biaryl compounds

Article abstract of DOI:10.1080/00397911.2018.1554149

Heterocyclic imines provide biaryl products by a two-step transformation. The first transformation involves a Diels–Alder reaction with a multiply protonated imine to give a tetrahydroquinoline product, whereas the second step involves oxidation with elem

Full text of DOI:10.1080/00397911.2018.1554149

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Superelectrophilic Diels–Alder reactions
and oxidations leading to heterocyclic biaryl
compounds
Hien Vuong & Douglas A. Klumpp
To cite this article: Hien Vuong & Douglas A. Klumpp (2019): Superelectrophilic Diels–Alder
reactions and oxidations leading to heterocyclic biaryl compounds, Synthetic Communications, DOI:
10.1080/00397911.2018.1554149
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https://doi.org/10.1080/00397911.2018.1554149
Superelectrophilic Diels–Alder reactions and oxidations
leading to heterocyclic biaryl compounds
Hien Vuong and Douglas A. Klumpp
Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL, USA
ABSTRACT
ARTICLE HISTORY
Received 26 April 2018
Heterocyclic imines provide biaryl products by a two-step transform-
ation. The first transformation involves a Diels–Alder reaction with a
multiply protonated imine to give a tetrahydroquinoline product,
whereas the second step involves oxidation with elemental sulfur at
260ꢀC.
KEYWORDS
Biaryl; heterocycle;
superacid; oxidation
GRAPHICAL ABSTRACT
Introduction
The synthesis of biaryl compounds has been an active area of research for many deca-
des.[1–3] This class of compounds has been of great interest for their use in pharmaceut-
ical agents[4] and natural products,[5] as well as for material science applications.[6] Many
of these synthetic methods utilize expensive transition metal catalysts and functionalized
arenes in coupling reactions.[7–10] Some efforts have been made to develop biaryl cou-
pling reactions without the use of transition metal catalysts, such as through the use of
radical substitution chemistry.[11,12] Recently, we reported the first example of a cyclo-
addition reaction involving superelectrophilic species (Scheme 1).[13] The synthetic trans-
formations utilize ethylene as a 2-carbon component in the Diels–Alder reaction with
multiply-protonated imines (i.e., 1). This chemistry represents a convenient method for
preparing tetrahydroquinolines having heterocyclic substituents, such as compound 2.
We hypothesized that these products could themselves be converted to heterocyclic biaryl
compounds by oxidative chemistry. This would provide access to biaryl scaffolds from
inexpensive and readily available reagents: an aldehyde, aniline, and ethylene. In the fol-
lowing communication, we report an extension of the Diels–Alder methodology—a com-
bined cycloaddition/oxidation to provide a series of aromatized biaryl compounds.
CONTACT Douglas A. Klumpp
dklumpp@niu.edu
Department of Chemistry and Biochemistry, Northern Illinois
University, DeKalb, IL, 60115, USA.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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H. VUONG AND D. A. KLUMPP
Scheme 1. Superelectrophilic cycloaddition with ethylene.
Results and discussion
The synthetic methodology began with the synthesis of a series of heterocyclic imines—
prepared by routine condensations of anilines and heterocyclic aldehydes (Table 1).
This includes a series of 2-pyridyl derivatives (3, 6–7, 9, 11–13, 15) from 2-pyridinecar-
boxaldehyde. Additionally, the 3- and 4-pyridinecarboxaldehyde and 6-bromo-2-pyridi-
necarboxaldehyde provide the respective imines (4–5, 8). Other heterocyclic aldehydes
provide imine products such as quinoline derivatives (10 and 16) and the quinoxaline
14. Among the anilines, this included halogenated, alkylated, ether, and hydroxyl deriva-
tives to give the respective imines. A bis(aniline) derivative also provides compound 17.
These imine derivatives were all prepared in ethanol solution with catalytic acetic acid
at 25 ꢀC. The conversions were monitored using TLC, and the crude yields of the
imines were all quantitative although the isolated yields were found to be somewhat
lower. In the optimized synthetic procedure (below), the crude imines were found to be
sufficient for the subsequent reactions.
As described previously, heterocyclic imines undergo [4 þ 2] cycloaddition with ethyl-
ene in the presence of the Brønsted superacid, CF3SO3H.[13] With a series of heterocyc-
lic imines, good yields of the tetrahydroquinolines were obtained (vide infra). We
reasoned that subsequent oxidation of the tetrahydroquinoline products should provide
an efficient route to heterocyclic biaryl products. To test this hypothesis, imine 3 was
reacted with ethylene (160 psi) in excess CF3SO3H (7 equivalents) for 5 h to provide the
tetrahydroquinoline 2. Initially, oxidation was attempted by simply adding DDQ to the
acidic solution. This gave a complex mixture of products. When tetrahydroquinoline 2
was isolated and reacted with DDQ in dioxane, however, the desired (2-pyridyl)-2-quin-
oline (18) was obtained in 67% yield. Other attempts at ring oxidation were made with
MnO2 and KMnO4, providing compound (18) 41% and 86% yields, respectively. The
tetrahydroquinoline 2 also oxidizes slowly in air to the quinoline 18. Using a published
method for aromatizing ring systems,[14] the desired biaryl compound 18 was prepared
in 85% yield by heating at 260 ꢀC (15 min) with elemental sulfur (Table 2). Other het-
erocyclic imines were subjected to these reactions and a series of heterocyclic biaryl
compounds were prepared. Although the yields were somewhat variable, a wide array of
structures was prepared. This includes the isomeric pyridyl-2-quinolines 19 and 20,
halogenated derivatives 21–23, and alkyl and aryl-substituted derivatives 27–28 were
prepared with reasonably good efficiencies. Compound 26 has been reported in several
recent synthetic and structural studies, as it is a useful tridentate ligand for organomet-
allic complexes.[15,16] The superelectrophilic chemistry prepared this biaryl compound
in just two steps and in 65% yield. Heterocyclic biaryl ethers are likewise synthesized,
including the benzocrown derivative 24 and the phenyl ether 30. Beyond the pyridyl-
systems, other heterocyclic imines provided the expected biaryl products, for example,

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Table 1. Imines prepared for biaryl synthesis.

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H. VUONG AND D. A. KLUMPP
Table 2. Products and yields from the reactions of imines 9–23 with ethylene and
triflic acid followed oxidation.

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Scheme 2. Isolated yields prior to oxidation.
Scheme 3. Proposed superelectrophilic intermediates.
the quinoxaline and quinoline derivative gave 29 and 25 and 31, respectively. A double
cycloaddition-oxidation reaction was also accomplished with this chemistry. Imine 17
provides the bis(quinoline) ether 32.
For comparison purposes, the isolated yields are given for the intermediate cycloaddition
products 33–36 (Scheme 2).[16] The yields of the tetrahydroquinolines 33–36 parallel the
overall yields of the respective biaryl oxidation products (21, 26, 23, and 28), though some
loss occurs during the oxidation. Similarly, tetrahydroquinoline 2 was isolated in 90% yield
and the oxidation product, (2-pyridyl)-2-quinoline (18), is obtained in 85% yield. Although
the low yields for the biaryl products 24, 25, 31, and 32, may be the result of poor cyclo-
addition efficiencies, these compounds were also found to be very difficult to purify using
column chromatography as they were retained strongly by the silica gel stationary phase.
As described in our initial report,[13] the cycloaddition chemistry is thought to
involve highly ionized aza-dienes. For example, the benzocrown imine (9) should be
ionized to superelectrophile 37 in the excess superacid—also with possible protonation
within the crown ether group (Scheme 3). Other systems are likely to produce both the
tricationic and tetracationic intermediates (38–39). It may not be necessary for diamine
17 to be fully protonated (i.e., 39) to initiate the Diels–Alder chemistry, as an equilib-
rium with di- or triprotonated species could also promote the cycloaddition. Highly ion-
ized aza-dienes—such as 37–39—are expected to have low lying LUMOs.[13,17] As
superelectrophilic species,[18] this facilitates the cycloaddition reaction with ethylene in
the reverse-electron demand Diels–Alder chemistry. The subsequent oxidation of the
tetrahydroquinolines is done at high temperature with elemental sulfur—a well-known
aromatization method, occurring through radical hydrogen atom abstractions.

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H. VUONG AND D. A. KLUMPP
Conclusion
In summary, it has been shown that heterocyclic biaryl products may be prepared by a
two-step sequence involving a Diels–Alder reaction with superelelctrophilic iminium
ions and ethylene, followed by an oxidation with elemental sulfur. The synthetic chem-
istry provides the heterocyclic biaryl products in fair to good yields (25–87%, 15 exam-
ples). This synthetic methodology is notable in that heterocyclic biaryl products are
prepared without the need for a transition metal catalyst, and moreover, the superacid
catalyst used may be recycled quantitatively.[19]
Experimental
General
The reagents and solvents were obtained from commercial suppliers and used as
received. The triflic acid was distilled from an Ar atmosphere prior to its use [Caution:
highly corrosive. Use in an efficient fume hood and wear appropriate safety gear]. The
reactions with ethylene were done in a glass-lined, Parr autoclave reactor fitted with a
high-pressure rupture disk. Within the reactor, a magnet stir bar is placed to ensure
good mixing.
Imine synthesis sample procedure, preparation of (E)-4-fluoro-N-(pyridin-2-
ylmethylene)aniline (6)
The 4-fluoroaniline (0.94 mL, 10 mmol) was combined with 2-pyridine carboxaldehyde
(0.95 mL, 10 mmol) in 20 mL of absolute ethanol. To this solution was added glacial
acetic acid (ca. 0.1 mL), and the mixture was stirred at room temperature for 12 h. The
solvent was then removed and the crude product (colorless solid, quantitative yield)
dried under high vacuum for 24 h. Analysis using NMR, TLC, and GCMS confirms its
identity and the data were in accord with published data.[20] The crude imine 6 was
used without further purification.
Diels–Alder reaction with subsequent oxidation, preparation of 6-fluoro-2-
(pyridin-2-yl)quinolone (21)
The heterocyclic imine 6 (0.3 g, 1.5 mmol) was dissolved in 10 mL of chloroform and
placed in the glass-lined pressure reactor. A magnetic stir bar was placed in the reactor
to ensure good mixing and the reactor was flushed with argon. Prior to sealing the ves-
sel, triflic acid (0.75 mL, 8.5 mmol) was added to the solution. The reactor was sealed,
pressurized with 160 psi of ethylene gas, and the solution was stirred with an external
stir plate. After stirring the mixture for 5 h at 25 ꢀC, the reactor was opened and the
product mixture was poured over ice. To this solution was added 20 mL of chloroform,
and the aqueous phase was made basic with the addition of saturated NaHCO3 solution.
Following extraction of the organic products, the organic extracts were washed with
water and then (2ꢁ) with brine solution. The organic solution was then dried with
sodium sulfate and filtered. To a solution of the crude cycloaddition product was added

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elemental sulfur (1.0 g). The solvent was removed under reduced pressure and the
residual material heated to 260 ꢀC for 3 h. After cooling, the remaining material was
taken up in chloroform (30 mL). This solution was washed with brine, dried over
sodium sulfate, and concentrated. The crude biaryl product was then subjected to col-
umn chromatography on silica gel and eluted with increasing concentrations of ether in
1
hexanes to provide 6-fluoro-2-(pyridin-2-yl)quinolone 21 (0.185 g, 0.83 mmol, 55%). H
NMR (CDCl3, 500 MHz): d, 8.75 (1 H, d, J ¼ 4 Hz), 8.61 (2 H, dd, J ¼ 8, J ¼ 20 Hz), 8.22
(1 H, d, J ¼ 9 Hz), 8.18 (1 H, dd, J ¼ 5.5, J ¼ 9 Hz), 7.88 (1 H, td, J ¼ 1.5, J ¼ 7.5,
J ¼ 1.5 Hz), 7.51 (1 H, td, J ¼ 3, J ¼ 9, J ¼ 2.5 Hz), 7.46 (1 H, dd, J ¼ 3, J ¼ 6 Hz), 7.37
(1 H, dt, J ¼ 5.8, J ¼ 1.5 Hz). 13C NMR (CDCl3, 500 MHz): d, 160.6 (d, J ¼ 247.5 Hz),
156.0, 155.6, 149.2, 145.0, 137.0, 136.1 (d, J ¼ 5 Hz), 132.3 (d, J ¼ 10 Hz), 128.9
(d, J ¼ 10 Hz), 124.1, 121.7, 119.9, 119.7, 110.7 (d, J ¼ 21.3 Hz). Low resolution MS (elec-
tron impact) 224 [Mþ], 196, 146, 112, 78, 51. High resolution MS (electron impact)
Calcd for C14H9FN2 (Mþ), 224.07498. Found, 224.07501.
Funding
This work was supported by the U.S. National Science Foundation (grant number 1300878).
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