Superacid-promoted synthesis of quinoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2020.151630

A series of vinylogous imines have been prepared from anilines and cinnamaldehydes. These substrates react in superacidic media to provide quinolines and related compounds. A mechanism for the conversion is proposed which involves the cyclization of dicationic superelectrophilic intermediates. Aromatization of the quinoline ring is thought to occur by superacid-promoted elimination of benzene.

Full text of DOI:10.1016/j.tetlet.2020.151630

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Superacid-promoted synthesis of quinoline derivatives
Hein Vuong, Michael R. Stentzel, Douglas A. Klumpp
PII:
S0040-4039(20)30043-5
DOI:
https://doi.org/10.1016/j.tetlet.2020.151630
TETL 151630
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Tetrahedron Letters
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20 November 2019
8 January 2020
12 January 2020
Please cite this article as: Vuong, H., Stentzel, M.R., Klumpp, D.A., Superacid-promoted synthesis of quinoline
derivatives, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151630
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Superacid-promoted synthesis of quinoline derivatives.
Hein Vuong, Michael R. Stentzel, and Douglas A. Klumpp*
Department of Chemistry and Biochemistry
Northern Illinois University
DeKalb, IL 60115
Abstract: A series of vinylogous imines have been prepared from anilines and cinnamaldehydes.
These substrates react in superacidic media to provide quinolines and related compounds. A
mechanism for the conversion is proposed which involves the cyclization of dicationic
superelectrophilic intermediates. Aromatization of the quinoline ring is thought to occur by
superacid-promoted elimination of benzene.
Keywords:
Heterocycle; Quinoline; Superacid; Superelectrophile
Introduction
Quinolines are an important class of heterocycles.1 This ring system is commonly found
in natural products and biologically active substances.2 This includes medicinal agents such as
quinine and the anti-malaria drug (1). Quinolines are also common structural elements in
material science applications, polymers, and in dyes/pigments. For example, a well-known

pigment is quinolone yellow (2). While a number of synthetic methods have been developed
leading to the quinolone ring system,1,3 there continues to exist the need for new synthetic
methods – especially those utilizing inexpensive reagents or catalysts.
Recently, we described a series of reactions in superacid that provided access to aza-
polycyclic aromatic compounds.4-6 The superacid-promoted chemistry allowed for the synthesis
of a wide-variety of ring systems and substituent patterns. For example, the pyridine derivative
3 reacts in triflic acid to provide the benzo[h]isoquinoline 4 in nearly quantitative yield (eq 1).5
This chemistry is thought to involve double protonation of substrate 3 to generate the
dicationic intermediate 5. Cyclization is then followed by ipso protonation of the phenyl group
(6) followed by elimination of benzene and aromatization of the aza-polycyclic aromatic
compound. As an extension of this methodology leading to condensed arenes, we describe
herein an efficient synthetic route to quinolone derivatives. The methodology formally derives
the quinolone ring system from anilines and cinnamaldehydes.
Results and Discussion

It was hypothesized that vinylogous imines should undergo double protonation and the
resulting superelectrophilic intermediates should provide the condensed aromatic ring system –
in this case the quinoline ring system. The required substrates (7) are prepared readily by
reacting anilines with cinnamaldehydes in ethanol with catalytic acetic acid (eq 2).7 Initial
experiments sought to explore the conditions necessary to promote the cyclization (eq 3). Using
excess trifluoroacetic acid or methanesulfonic acid at 80°C gave no product even with a 24 hr
reaction period. Sulfuric acid does give a trace amount of quinoline product using similar
reaction conditions. Using the Brønsted superacid, triflic acid (CF3SO3H), quinoline (8) can be
isolated in 95% yield. This conversion required 34 equivalents of acid and a reaction
temperature of 80°C. Using a lower reaction temperature (25°C) or less triflic acid leads to a
markedly lower product yield.
Using excess triflic acid to promote the condensation reactions, a series of vinylogous
imines were converted to quinoline derivatives (Table 1).8 The quinoline derivatives are
prepared in generally good yields (70-95%) from this chemistry. By varying the aniline
component, substituents are readily incorporated into the quinoline product. This includes
quinolines with halogen (9-11), ether (12), alkyl (13), and phenolic substituents (14-15).
Likewise, ring-fused products are readily prepared. Thus, 1-aminonaphthalene and

Table 1. Products and yields from the superacid-promoted condensations of vinylogous imines.
cinnamaldehyde provide the vinylogous imine, which upon reaction in superacid, provides
benzo[h]quinoline (16) in excellent yield. With chalcone and aniline, 2-phenylquinoline (17) is
obtained, while aniline and -phenylcinnamaldehyde provides 4-phenylquinoline (18). In an
effort to prepare a halogen-functionalized product, imine 19 was prepared. Upon reaction with
superacid however, 4-chloroquinoline was not formed but instead only the phenyl-substituted
product (18) was obtained (eq 4). The chlorinated substrate (19) was prepared from a published

procedure,9 utilizing the Vilsmeier-Haack reaction (POCl3-DMF) with acetophenone -providing
-chlorocinnamaldehyde – followed by condensation with aniline. Using a similar approach, the
naphthyl- and bromophenyl- derivatives (20 and 21) were obtained in fair yields. These
products were prepared, respectively, from 1-acetylnaphthalene and 4-bromoacetophenone
with aniline.
As with our previous studies, a mechanism is suggested involving dicationic,
electrophilic cyclizations and benzene elimination leading to the condensed aromatic (Scheme
1). Initial protonation of imine 7a provides the monocationic iminium ion 22. In the excess
superacid, ion 22 is likely in equilibrium with the the dicationic, superelectrophilic species 23.10-
12 An isomeric dication (24) is conceivable, however DFT calculations (see Supporting
Information) indicate that ion 23 is about 6 kcal/mol more stable than ion 24.13 There may be
several factors that contribute to the greater stability of dication 23. One factor may be the
separation of the two cationic charge centers by the sp3 carbon in structure 23.14 With

Scheme 1.
formation of the reactive carbocationic center, cyclization provides intermediate 25. Ipso-
protonation leads to ion 26 and loss of benzene, gives the dicationic secies 27 as the precursor
to the quinoline aromatic system. Deprotonation provides quinoline (8).
In the case of the chlorinated systems, a similar mechanism is proposed (eq 5).
Superacid-promoted cyclization leads to intermediate 28, however instead of ionization at the
phenyl group, the chloride is evidently the source of ionization. It is suggested that the
superacid protosolvates the chloride, and with loss of HCl, the carbocation species (29) is
formed. This leads to product 19 from deprotonation steps.

Interestingly, the Doebner-von Miller reaction is a classic synthetic method leading to
quinolines.15 One example of this transformation involves the reactions of anilines with
crotonaldehyde and condensation with heteropolyacids (eq 6).16 The mechanism for this
conversion is thought to involve an initial conjugate addition step followed by subsequent
dehydrative cyclization (SEAr step). In our chemistry, the initial step involves condensation of
the aniline at the carbonyl group of cinnamaldehyde, followed by a Friedel-Crafts cyclization.
This type of reaction sequence has been previously described as a reverse Doebner-von Miller
reaction.15,17 Our chemistry is a unique extension of the reverse Doebner-von Miller reaction, in
that the aromatization occurs by superacid-promoted benzene elimination (or in some cases,
HCl elimination).
In summary, we have found that vinylogous imines provide good access to
functionalized quinolines by reaction in superacid. The proposed mechanism involves formation
of iminium-carbenium dications. Cycilzation of this superelectrophilic species leads to
formation of the new heterocycles, and with protolytic elimination of benzene, the quinoline
product in generated. The chemistry represents a convenient synthetic route to the quinoline
ring system from readily available precursors and it is promoted by a Brønsted acid which may
be quantitatively recycled.18

Acknowledgements. The support of the NIGMS-NIH(1R15GM126498-01) is gratefully
acknowledged. We acknowledge the generous support from the NSF MRI program (award no.
CHE:1726931) for the purchase of the high-resolution mass spectrometer.
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Keywords:
Heterocycle
Quinoline
Superacid
Superelectrophile
Cyclization
Graphical Abstract:

Highlights
Quinolines from simple precursors
Superelectrophilic cyclization with reactive dicationic intermediates
Recyclable Brønsted acid catalyst and transition-metal free synthesis