Rearomatization of trifluoromethyl sulfonyl dihydropyridines: Thermolysis vs photolysis

Article abstract of DOI:10.1002/poc.3789

In this article, we describe the static gas-phase pyrolysis, microwave-induced pyrolysis, and photolysis reactions of trifluoromethyl sulfonyl dihydropyridines. The goal of this work was to find a methodology that allows obtaining of substituted pyridines-which are known to be difficult to synthesize-to be reused in a new substitution reaction. We demonstrated that it is possible to achieve the rearomatization process by the elimination of the trifluoromethyl sulfonyl moiety through the 3 processes, with the static pyrolysis being the best method to obtain the substituted pyridines. In addition, we propose the 1,4-elimination (CF₃SO₂ + H) as the first step, since it is the less energetic process, as has also been corroborated by calculations. A competitive reaction (CO₂ extrusion) also occurs, yielding undesired products. Copyright

Full text of DOI:10.1002/poc.3789

Received: 5 September 2017
DOI: 10.1002/poc.3789
Accepted: 25 October 2017
S P E C I A L I S S U E A R T I C L E
Rearomatization of trifluoromethyl sulfonyl
dihydropyridines: Thermolysis vs photolysis
Guadalupe Firpo1 | María V. Cooke1 | Walter J. Peláez1
| Guillermo M. Chans2 |
Gustavo A. Argüello1 | Elizabeth Gómez3 | Cecilio Alvarez‐Toledano3
1 INFIQC, Departamento de
Abstract
Fisicoquímica, Facultad de Ciencias
In this article, we describe the static gas‐phase pyrolysis, microwave‐induced
Químicas, Universidad Nacional de
Córdoba, Córdoba, Argentina
pyrolysis, and photolysis reactions of trifluoromethyl sulfonyl dihydropyridines.
The goal of this work was to find a methodology that allows obtaining of
substituted pyridines—which are known to be difficult to synthesize—to be
reused in a new substitution reaction. We demonstrated that it is possible to
achieve the rearomatization process by the elimination of the trifluoromethyl
sulfonyl moiety through the 3 processes, with the static pyrolysis being the best
method to obtain the substituted pyridines. In addition, we propose the 1,4‐
elimination (CF3SO2 + H) as the first step, since it is the less energetic process,
as has also been corroborated by calculations. A competitive reaction (CO2
extrusion) also occurs, yielding undesired products.
2 Facultad de Ingeniería, Universidad
Anáhuac (México Norte), Huixquilucan,
Mexico
3 Instituto de Química, Universidad
Nacional Autónoma de México, México,
DF, Mexico
Correspondence
W. J. Peláez, INFIQC, Departamento de
Fisicoquímica, Facultad de Ciencias
Químicas, Universidad Nacional de
Córdoba, Ciudad Universitaria,
X5000HUA Córdoba, Argentina.
Email: waldemar31@fcq.unc.edu.ar
KEYWORDS
gas‐phase and microwave‐induced pyrolysis, rearomatization reactions, TD‐DFT calculations,
trifluoromethyl sulfonyl dihydropyridines
Funding information
MINCYT‐CONACYT (2013‐2016), Grant/
Award Number: MX/12/07; SECyT‐UNC;
MINCYT; FONCyT; CONACyT 191400
FOINS; CONICET
1 | INTRODUCTION
experimental data for the energy transitions and molar
extinction coefficients of the compounds studied have
As part of our ongoing project on sulfonyl derivatives
as bioactive heterocyclic compounds, our research
has been focused on exploring the consequences of a
N–SO2–R linkage on the stereoelectronic properties of
been obtained and were presented for the first time.[1]
In addition, we recently reported the thermal behavior
of some trifluoromethyl‐1H,3H‐pyrrolo[1,2‐c]thiazole‐2,2‐
dioxides (compounds 5‐8, Figure 1) evaluated by compar-
ing flash vacuum pyrolysis (at 475°C) with the micro-
wave‐induced pyrolysis (MIP at 240°C). In both cases,
the azafulvenium methide intermediate was involved
and claimed to be responsible for the interesting
compounds obtained.[2,3]
some
1‐benzenesulfonyl‐1,2,3,4‐tetrahydroquinolines
(compounds 1‐4, Figure 1). Recently, we reported a
detailed analysis of UV spectra and the molecular orbitals
involved in electronic transitions and a conformational
study of 1‐benzenesulfonyl‐1,2,3,4‐tetrahydroquinoline
derivatives conducted using the time‐dependent density
functional theory (TD‐DFT) (B3LYP/6‐31 + G(d,p))
method. Good correlations between theoretical and
Currently, we are interested in trifluoromethyl sulfo-
nyl dihydropyridines and their benzene‐fused derivatives
(compounds 9 and 10, Figure 1).
J Phys Org Chem. 2017;e3789.
wileyonlinelibrary.com/journal/poc
Copyright © 2017 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/poc.3789

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FIRPO ET AL.
how the trifluoromethanesulfonic moiety can be removed
to afford the aromatic pyridine. The goal of the present
work is to find a good methodology to complete the
sequence of activation, nucleophilic reaction, and
deprotection that will allow having an activated substrate
again to perform new substitutions and thus opening
endless synthetic possibilities. Therefore, a comparison
of 3 methodologies (MIP, static gas‐phase pyrolysis, and
photolysis at 254 nm) aimed at the synthesis of the target
compound is presented.
CO2H
R1
N
S
1: R = H
9: R1 = H
R2
R3
O
O
2: R = NO2
R2/R3 =
: R1 = CN
3
10
: R = NH2
N
S
4: R = NHCOCH3
R2 = R3 = H
O
O
CF3
R
R
5
6
: R = H
N
O
O
: R = CH3
7: R = CH2Ph
: R = Ph
S
8
F3C
FIGURE 1 1‐Benzenesulfonyl‐1,2,3,4‐tetrahydroquinolines (1‐4)
and 2,2‐dioxo‐pyrrolo‐thiazole (5‐8) previously studied, and
trifluoromethyl sulfonyl dihydropyridines (9 and 10) studied in this
work
2 | RESULTS AND DISCUSSION
2.1 | UV characterization
Pyridines emerge as one of the most prevalent
heterocyclic structural units in pharmaceutical and agro-
chemical targets, as well as in material science.[4–6] Pyr-
idine derivatives are widely known as gifted
starting materials for the synthesis of dihydropyridines,
tetrahydropyridines, and piperidines, which have been
used as intermediates in alkaloid synthesis,[7,8] in nico-
tinamide adenine dinucleotide hydrogen models,[9,10]
and as important biologically active structures.[11–15] It
is known that one key aspect about the reactivity of
pyridine and its derivatives is that once activated, they
can react with a large variety of nucleophiles to afford
substituted dihydropyridines,[7,16–23] which, after the
elimination of the trifluoromethyl sulfonyl moiety, can
further be reactivated to undergo secondary nucleo-
philic additions. Following this approach, the activation
of aza‐aromatic compounds can be achieved through
the nitrogen atom by alkyl chloroformates,[24–26] acid
chlorides,[27,28] or triflic anhydride,[29–31] via their
pyridinium salts.[32] Taking advantage of the pyridine
activation versatility, ours and other research groups
have described the direct synthesis of functionalized
polycyclic δ‐ and γ‐lactones[33–36] via a double nucleo-
philic addition of bis(trimethylsilyl)ketene acetals to
previously activated pyridines. Recently, it has been
shown that this reaction can be extended to other aza‐
aromatic substrates such as pyrazine, quinoxaline, and
pyrimidine, where the course of the reaction depends
on the activating agent.[37,38] We also reported that this
method could be applied to pyridine N oxide, affording
tetrahydrofuro[3,2‐b]pyridine‐2(3H)‐ones through a dou-
ble‐activation procedure and an unexpected decarboxyl-
ation step.[36] Monoaddition (dihydropyridines) and
double‐addition products (tetrahydropyridine‐fused lac-
tones) are of interest because of their biological activi-
ties.[16,17,39–42]
The UV/visible characterization was performed in aceto-
nitrile (ACN), methanol (MeOH), ethanol (EtOH), and
water (only for compound 10) with the main objective of
knowing about the nature of the transitions (either
π → π* or n → π*) involved in the main absorption bands.
The experimental absorption maxima were determined
with the aid of the second derivative spectra.
Compound 9 presents 4 absorption bands in ACN: 2
intense broad bands at short wavelengths, 205 nm
(ε = (22.0
0.4) × 103M−1 cm−1) and 226 nm (broad
shoulder, ε = (11.4 0.2) × 103M−1 cm−1), and 2 bands
of very small intensity at longer wavelengths, 269 nm
(ε = (6.70
0.03) × 102M−1 cm−1) and 277 nm
(ε = (5.4 0.02) × 102M−1 cm−1). No clear trend in the
band shifting was observed when the spectra were taken
in different solvents (EtOH, MeOH, see the spectra in
page S3 of the Supporting Information). For that reason,
the determination of the transition that occurs was
performed through TD‐DFT calculations (B3LYP/6‐
31 + G(d,p)) as it was reported in our previous work
on 1‐benzenesulfonyl‐1,2,3,4‐tetrahydroquinoline deriva-
tives.[1] After performing the optimization and analyzing
the symmetry of the molecular orbitals involved in each
transition, we established that all of them are of π → π*
nature.
On the other hand, compound 10 presents 2 well‐
defined absorption regions in ACN with maxima deter-
mined again by the second derivative methodology. The
shorter wavelength band possesses a shoulder at 220 nm
(ε = (7.8 0.3) × 103M−1 cm−1), whereas the other band
appears centered at 270 nm (ε = (5.0
0.2) × 103M
cm−1). Changing the polarity of the solvents (EtOH,
MeOH, and H2O, see the spectra in page S5 in the
Supporting Information) a bathochromic shifting is
observed, allowing us to assess that all transitions are
π → π*. The TD‐DFT calculations (B3LYP/6‐31 + G(d,
p)) corroborate this assumption.
−1
Specifically, we are interested in the reactivity of the
monoactivated trifluoromethyl sulfonyl derivatives and

FIRPO ET AL.
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2.2 | Reactions of 1‐(1‐((trifluoromethyl)
sulfonyl)‐1,4‐dihydroquinolin‐4‐yl)
cyclohexane‐1‐carboxylic acid (9)
The identification of all products obtained from com-
pound 9 under different reaction conditions was per-
formed by a careful analysis of the data, obtained from
gas chromatography (GC)/mass spectrometry (MS) and
nuclear magnetic resonance (NMR) techniques. Under
all reaction conditions, it was possible to obtain the
desired aromatized ring (1‐(quinolin‐4‐yl)cyclohexane‐1‐
carboxylic acid, 11) after the loss of the CF3–SO2 + H;
nevertheless, other competitive processes occurred, which
generated undesired compounds with variable yields
depending on the reaction conditions (Table 1). Photoly-
sis, in turn, was the most unfavorable method, affording
low yields of 11 and almost 50% of an unidentified insolu-
ble solid. Nevertheless, important mechanistic informa-
tion was obtained from this experiment. For example,
the detection of the product of m/z = 345 (4‐cyclohexyl‐
1‐((trifluoromethyl)‐sulfonyl)‐1,4‐dihydro‐quinoline 14)
allows us to postulate that the loss of CO2 is competing
with the fragmentation of the N–S bond.
The analysis of the results obtained by MIP shows that
this method is barely more efficient than photolysis in the
production of the desired aromatized compound. In par-
ticular, the attempts to improve the yield of 11 were
unsuccessful, since the change of 10°C in the reaction
temperature raised the yield of by‐products (the 3 isomers
of (trifluoromethyl)sulfonyl‐quinoline, 15a‐c) by as much
as 45%, while 11 is only increased by less than 10%. The
detection of compound 16 (1‐((trifluoromethyl)sulfonyl)‐
1,4‐dihydroquinoline, m/z = 263) supports the idea of a
competitive reaction where the C–C bond breaks apart,
either directly from 9 or from 14, where the loss of CO2
should have already occurred. Only through gas‐phase
pyrolysis did we find a reasonable balance between the
target compound and the by‐products. Attempts to study
the gas‐phase pyrolysis at temperatures lower than
200°C were ineffective. By increasing the exposure time,
the yield of 11 was doubled; nevertheless, the undesired
products also increased. It is worth mentioning that Fou-
rier transform infrared (FT‐IR) analysis of the gases pro-
duced during pyrolysis assessed the presence of HCF3
and SO2, identified by comparison of pure samples.
By unraveling the by‐products obtained, regardless of
the method used, another interesting outcome is noticed.
The formation of 3 isomers of 15 proves that the S–C bond
is strong enough to allow the migration of the
trifluoromethyl sulfonyl group (–SO2CF3) toward the aro-
matic ring, even though it should suffer its own fragmen-
tation, as confirmed by the detection of HCF3 and SO2
through FT‐IR measurements.

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FIRPO ET AL.
The analysis of all products and reaction conditions
the trifluoromethyl moiety). Nevertheless, it is also unsta-
ble and decomposes into compound 12 (through a
rearomatization reaction by the loss of SO2CF3, way F)
and the intermediate 14I by the breaking of the C–C bond
between the heterocycle and the cyclohexyl moiety
(path G). This unstable radical reorganizes to yield a
complex mixture of compounds (ways H, I, and J;
compounds 15‐17, respectively), which were isolated as a
mixture.
resulted in the reaction mechanism proposed for
compound 9, which is presented in Scheme 1. This
mechanism is proposed mainly on the basis of thermolyses
in gas and solution phases (MIP). The scheme illustrates
both competitive processes: the loss of SO2CF3 (way A)
and the loss of CO2 (way B). Way A involves the reaction
that is of our interest (rearomatization of the pyridine
ring allowing a second possible substitution on the ring
after a new activation of the nitrogen). Unfortunately,
compound 11 proved to be unstable, suffering elimination
of CO2 (way C) under all conditions tested and affording
intermediate (11I). From this radical, compound 12 would
be generated by hydrogen abstraction (way D), while 13
is produced by hydrogen loss (path E).
2.3 | Reactions of 1‐(3‐cyano‐1‐
((trifluoromethyl)sulfonyl)‐1,4‐
dihydropyridin‐4‐yl)cyclohexane‐1‐
carboxylic acid (10)
On the other hand, way B, which is the other compet-
itive process, affords compound 14 (which still possesses
The identification of all products of the reactions of 10
was performed through the analysis of GC/MS and
SCHEME 1 Proposed mechanism for the thermal and photochemical reactions of 9

FIRPO ET AL.
5 of 12
NMR spectra. Once more, as in the case of 9, under all
reaction conditions, the desired compound 18 was
obtained (Table 2).
loss of CO2 (way C). On the other hand, way B would
yield the proposed intermediate 21I. This could afford
the unsaturated hydropyridine 21 (which in turn would
increase the amount of 20) or fragment itself to intermedi-
ate 22I to form the products 22a to 22c (which retain the –
SO2CF3 moiety).
For a deeper understanding on the mechanisms of
reaction of hydropyridines 9 and 10, density functional
theory calculations (B3LYP/6‐31 + G(d,p)) were per-
formed in both gas and solution phases (Table 3). These
calculations provided information about the energy
required for the different processes that occur in the reac-
tions, particularly in the thermolysis (gas phase pyrolysis
and MIP).
As it is possible to see, the energies required to break
the C–C bonds between the cyclohexyl group and the car-
boxylic acid for both hydropyridines are higher than the
ones required to break the N–S bond (between the
hydropyridine and the trifluoromethyl sulfonyl moiety)
or the S–C (between the trifluoromethyl and sulfonyl
group), regardless of the phase.
This would perfectly explain why it is always the low‐
energy path that yields the aromatized compounds (path
A, Schemes 1 and 2, and left part of Figure 2, paths A
and B) in both cases.
Photolysis was again the most unfavorable method
with yields of about 2%. Nevertheless, the partially unsatu-
rated compound 20 (formed from 18 after decarboxylation
and elimination of a radical hydrogen) was obtained in
44% yield. Another interesting result is the generation of
the mixture of 3 trifluoromethyl sulfonyl unsaturated
isomers 22a to 22c (42%). This fact confirms that both
paths involving loss of small moieties (–SO2CF3 and –
CO2) compete, as was proposed for 9. A clear evidence
that this occurs was the detection of the unsaturated
compound 21, which should come from 10 upon loss of CO2.
On the other hand, MIP (230°C, 10 min) was a better
method than photolysis for 18 in terms of yield (26%).
Nevertheless, the reaction that affords 22a to 22c is still
the main mechanism of reaction. Additionally, gas‐phase
pyrolysis was also the best method to produce 18 (74%
yield) and provided the possibility of preparing other
interesting substituted pyridines (19 and 20) just by
adjusting the reaction time.
As was proposed for 9 and mainly for the reactions ini-
tialized by thermic processes, Scheme 2 shows the mech-
anism of formation of all compounds obtained from 10.
The scheme shows both competitive processes (ways A
and B). The desired aromatic compound is obtained
directly from way A. Nevertheless, in any case, it was pos-
sible to avoid the decomposition to secondary products
(19‐22).
In addition, the energy required to break the S–CF3
bond (red line, Figure 2) is higher than the one required
to break the N–S bond in both cases. These facts allow
us to think about the shifting of the SO2CF3 moiety as a
whole and also justify the fact that many trifluoromethyl
sulfonyl isomeric derivatives were obtained.
It is important to note that compounds 19 and 20 were
not the target products, but they are interesting
substituted pyridines, which could be obtained from the
Other studies performed thermogravimetric analysis
and differential thermal analysis (DTA) on 9 and 10 (see
TABLE 2 Pyrolysis (microwave induced and gas phase) vs photolysis reaction of compound 10
Compound
Gas chromatography reaction Time, min
9.2
8.4
6.6
6.3
4.3
5.5, 7.1 and 8.1
238
m/z
364
230
211
209
318
Reaction condition
Photolysis, %
Acetonitrile, 254 nm
1
2
7
44
7
2
1
0
0
0
42
43
1
Microwave pyrolysis, %
Gas‐phase pyrolysis, %
Acetonitrile, 230°C, 10 min 14
26
74
48
36
7
200°C, 5 min
200°C, 10 min
200°C, 20 min
5
2
0
2
8
20
15
28
26
1
2

6 of 12
FIRPO ET AL.
SCHEME 2 Proposed mechanism for the thermal and photochemical reactions of 10
TABLE 3 Calculated relative bond energy dissociation (Δ(ΔE)) for the breaking of different bonds of compounds 9 and 10 in gas phase and
solution (ACN) (B3LYP/6‐31 + G(d,p), kcal mol−1
)
Δ(ΔE N–S)
Δ(ΔE S–CF3)
Δ(ΔE C–C(O)OH)
ACN
Gas Phase
ACN
Gas Phase
ACN
Gas Phase
9
0.0
15.3
30.5
34.0
73.3
84.5
10
11.9
18.9
43.1
45.2
58.5
86.2
the thermograms in pages S5 and S7 in the Supporting
Information). Thermogravimetric analysis of 10 shows a
continuous mass loss, while DTA shows 2 endothermic
bands corresponding to the fusion and the sublimation.
On the contrary, for 9, a more complicated thermogram
is observed, with the thermogravimetric analysis giving
4 different mass losses and the DTA showing both
endothermic and exothermic processes. This suggests that
irrespective of the phase, including the solid state, com-
pound 9 is more unstable, thus affording products.
These facts support the information obtained from
Tables 1 and 2, where it is possible to observe the selectiv-
ity of 10 toward the formation of the desired compound 18
(74%), while
9 affords a widespread amount of

FIRPO ET AL.
7 of 12
FIGURE 2 Reaction coordinates in the gas phase for different breaking bonds of compounds 9 (A) and 10 (B)
compounds. This conclusion would be reached also from
the calculations performed, where all the gas‐phase
energy barriers calculated for compound 9 are lower than
those for compound 10.
with a Bruker Avance II 400‐MHz spectrometer (BBI
probe,
gradient) (1H at 400.16 MHz, 13C at
z
100.56 MHz, and 19F at 376.53 MHz). Chemical shifts
are reported in parts per million downfield from
trimethylsilyl. The spectra were measured at 25°C.
Absorption spectra were recorded with a UV‐1601
Shimadzu spectrophotometer, using a quartz cell with
an optical path length of 1 cm. Infrared spectra were
recorded with an FT‐IR Bruker IFS 28 spectrometer, with
a resolution of 2 cm−1 in the range from 4000 to 400 cm−1
by using KBr disks for solid samples or a quartz cell fitted
with KBr windows. Gas chromatography/mass spectrom-
etry analysis was performed with a Shimadzu GC/MS QP
3 | CONCLUSIONS
Through the use of the 3 methodologies used in the pres-
ent article, it was possible to achieve the desired
substituted pyridines. Nevertheless, this work shows one
more time the usefulness of the gas‐phase pyrolysis, in
this particular case to complete the sequence of activa-
tion‐substitution‐deprotection in the generation of hetero-
cycles that are difficult to prepare by other methods.
Through experimental observations and quantum chemi-
cal calculations, we were able to rationalize the sequence
and the energy requirements of the different processes for
each compound. Moreover, we found that 2 competitive
processes occur in the thermolysis reactions of 9 and 10.
However, the elimination of the CF3SO2 moiety for both
reactants is the predominant mechanism of reaction.
Although the yields are not equally high for both com-
pounds tested, it is particularly important to highlight
the purpose of this contribution in the sense of providing
a “do it again” method. Nevertheless, further work is still
needed to reach a unique and undisputed method.
5050 spectrometer equipped with
a
VF column
(30 m × 0.25 mm × 5 μm) by using helium as an eluent
at a flow rate of 1.1 mL min−1. The injector and the ion
source temperature was 280°C, and the oven heating
ramp was 15°C min−1 from 200°C up to 280°C. The pres-
sure in the MS instrument was 10−5 Torr, precluding ion‐
molecule reactions, and MS recordings were made in the
electron impact (EI) mode at an ionization energy of
70 eV. High‐resolution mass spectra were recorded at
the University of Vigo, Spain.
Thermogravimetric measurements were performed
using a Shimadzu DTG‐60 thermoanalyzer, under an oxi-
dizing atmosphere (air) with a gas flux of 75 mL min−1, a
heating rate of 10°min−1, and 30°C to 600°C temperature
range.
4 | EXPERIMENTAL SECTION
4.1 | Materials and analytical methods
4.2 | Photolysis reactions
Solutions of compounds
9
and 10 in ACN
((6 1) × 10−5M and (22.2 0.4) × 10−5M, respectively)
were photolyzed by using low‐pressure mercury lamps
emitting at 254 nm, and their decomposition was followed
by UV spectroscopy (see Figures SA and SB, page S14 in
the supporting information). Only for compound 10 were
we able to obtain the photodegradation rate, measuring
Pure compounds 9 and 10 were prepared as previously
reported[43] and together with main products were char-
acterized by standard spectroscopic techniques (1H, 13C,
19F, and UV) and mass spectrometry. All data are in
agreement with the proposed structures. Nuclear mag-
netic resonance spectra were recorded in chloroform‐d
the decay at 270 nm (k25 = (3.5 0.2) × 10−3 −1). This
s

8 of 12
FIRPO ET AL.
was determined from the slope in the linear region of a
plot of intensity vs irradiation time. The experiments were
performed at different temperatures (25°C, 35°C, 45°C,
and 55°C) without change in the rate constant values,
which allows us to conclude that this reaction is a purely
photochemical process. Preparative photolysis in ACN
(100 mL, (1.0 0.2) × 10−4M) was performed to identify
the photoproducts, and then the reaction mixtures were
analyzed by GC/MS spectrometry (Tables 1 and 2).
de Córdoba (http://ccad.unc.edu.ar/), in particular the
Mendieta Cluster, which is part of SNCAD, MinCyT,
República Argentina.
4.6 | Characterization
4.6.1 | 1‐(1‐((Trifluoromethyl)sulfonyl)‐
1,4‐dihydroquinolin‐4‐yl)cyclohexane‐1‐car-
boxylic acid (9)
mp: 160°C to 161°C (white amorphous solid). 19F NMR
(376 MHz, CDCl3): δ (ppm) = −75.11. 1H NMR
(400 MHz, CDCl3): δ (ppm) = 7.57 (1H, d, J = 8.4 Hz),
7.31 (1H, td, J1 = 7.92 Hz, J2 = 1.55 Hz), 7.21 (1H, td,
J1 = 7.54 Hz, J2 = 1.04 Hz), 7.14 (1H, dd, J1 = 7.84 Hz,
J2 = 1.50 Hz), 6.77 (1H, d, J = 7.53 Hz), 5.58 (1H, dd,
J1 = 6.40 Hz, J2 = 8.11 Hz), 5.53 (1H, s broad, OH), 3.66
(1H, d, J = 6.40 Hz), 2.18 (1H, d, J = 12.80 Hz), 2.01
(1H, d, J = 8.29 Hz), 1.64 (3H, m), 1.37 (3H, m), 1.19
(1H, m), 1.06 (1H, m). 13C NMR (100 MHz, CDCl3):
δ(ppm) = 179.9, 135.6, 130.8, 127.9, 127.3, 126.9, 126.0,
120.2 (JC‐F = 2.36 Hz), 119.8 (JC‐F = 323.22 Hz), 113.9,
54.5, 46.4, 30.4 (×2), 25.5, 23.4, 23.3. IR (KBr, cm−1):
2952.4, 2926.4, 2973.4, 1697.0, 1495.5, 1487.8, 1462.7,
1454.0, 1402.0, 1388.5, 1287.2, 1250.6, 1234.2, 1227.4,
1196.6, 1191.8, 1154.1, 1149.3, 1123.3, 1078.8, 1072.2,
1052.9, 1010.5, 929.5, 753.0, 739.5, 680.7, 611.3, 600.7,
575.6. GC: 11.795 minutes. MS (EI): m/z (%) = 389 (M+,
8), 265 (4), 264 (31), 263 (7), 262 (72), 256 (3), 228 (6),
213 (4), 212 (17), 211 (3), 210 (15), 200 (3), 198 (5), 186
(6), 185 (5), 184 (15), 182 (5), 170 (4), 168 (5), 167 (4),
158 (3), 157 (3), 156 (11), 154 (5), 146 (6), 144 (6), 143
(5), 142 (3), 132 (6), 131 (13), 130 (100), 129 (31), 128
(12), 127 (4), 126 (7), 118 (8), 117 (6), 115 (5), 110 (20),
109 (3), 106 (3), 103 (8), 102 (6), 91 (7), 89 (3), 83 (4), 82
(3), 81 (16), 79 (6), 78 (3), 77 (15), 69 (9), 67 (9), 65 (3),
55 (7), 53 (4), 51 (3), 41 (9).
4.3 | Gas‐phase pyrolysis reactions
Static pyrolysis reactions were performed in gas phase
(using a vacuum‐sealed tube) to compare the products
and yields obtained with those provided by photolysis
reactions. The goal was to find the method that maxi-
mizes the aromatized pyridines.
The static pyrolysis of 9 and 10 was performed by
using a tube furnace with a temperature controller device.
The substrates (50 mg, 0.128 mmol; 50 mg, 0.137 mmol for
9 and 10, respectively) were each introduced into a reac-
tion tube (1.5 cm × 12 cm Pyrex), sealed under vacuum
(0.06 mbar) and then placed inside the furnace for 5 to
20 minutes at 200°C. The resultant pale yellow reaction
mixtures were then extracted with solvents (ethyl acetate
for GC/MS and acetone‐d6 for NMR analyses), analyzed
through GC/MS, and subjected to purification (prepara-
tive plate chromatography in dichloromethane : ethyl ace-
tate [95:5]) (Tables 1 and 2).
4.4 | Microwave‐induced pyrolysis
Microwave‐induced pyrolysis was performed in a micro-
wave reactor Monowave 300 Anton Paar, using 10‐mL
microwave tubes. The reaction temperatures were mea-
sured by infrared surface detector during the microwave
heating. A suspension of either 9 (20 mg, 0.051 mmol)
or 10 (20 mg, 0.055 mmol) in ACN was irradiated in the
microwave reactor at the temperature and time indicated
in each case. After cooling to room temperature, the mix-
ture was analyzed by GC/MS and then subjected to puri-
4.6.2 | 1‐(3‐Cyano‐1‐((trifluoromethyl)sul-
fonyl)‐1,4‐dihydropyridin‐4‐yl)cyclohexane‐
1‐carboxylic acid (10)
fication
(preparative
plate
chromatography
in
dichloromethane : ethyl acetate [95:5]) (Tables 1 and 2).
mp: 169°C to 170°C (white amorphous solid). 19F NMR
(376 MHz, CDCl3): δ (ppm) = −74.72. 1H NMR
(400 MHz, CDCl3): δ (ppm) = 7.64 (1H, s), 6.82 (1H, d,
J = 8.16 Hz), 5.49 (1H, dd, J1 = 8.23 Hz, J2 = 5.40 Hz),
3.45 (1H, d, J = 5.25 Hz), 2.87 (1H, s broad, OH), 2.14
(2H, m), 1.66 (3H, m), 1.41 (4H, m), 1.19 (1H, m). 13C
NMR (100 MHz, CDCl3): δ (ppm) = 179.8, 136.4, 122.8,
117.6, 109.6, 94.9, 53.7, 42.3, 30.2 (×2), 25.5, 23.2, 23.1.
IR (KBr, cm−1): 2939.9, 2187.7, 1682.5, 1673.9, 1620.8,
1420.3, 1292.0, 1250.6, 1234.2, 1226.5, 1196.6, 1182.1,
1134.9, 1050.0, 670.1, 612.9, 579.5. GC: 9.178 minutes.
4.5 | Calculations
All calculations were performed with the GAUSSIAN09
program.[44] The geometric parameters for all the reac-
tants, transition states, and products of the studied reac-
tions were fully optimized using density functional
theory (density functional theory and TD‐DFT with
B3LYP/6‐31 + G(d,p)) approaches. This work used com-
putational resources from CCAD, Universidad Nacional

FIRPO ET AL.
9 of 12
MS (EI): m/z (%) = 364 (M+, 6), 232 (5), 231 (37), 175 (7),
160 (10), 123 (12), 110 (9), 109 (100), 107 (3), 106 (24), 105
(4), 92 (3), 82 (3), 81 (37), 80 (4), 79 (14), 78 (30), 77 (5), 69
(12), 67 (5), 65 (3), 54 (3), 53 (6), 51 (9), 41 (7). High‐reso-
lution MS (electrospray ionization time of flight): Calcd
185 (3), 184 (3), 183 (4), 182 (9), 181 (5), 180 (10), 176 (3),
171 (4), 170 (10), 169 (8), 168 (28), 167 (18), 165 (3), 158
(5), 157 (4), 156 (11), 155 (9), 154 (12), 153 (4), 152 (5),
145 (3), 144 (16), 143 (10), 142 (13), 141 (3), 140 (4), 139
(3), 134 (3), 132 (6), 131 (11), 130 (100), 129 (9), 128 (10),
127 (8), 118 (20), 117 (19), 116 (6), 115 (13), 114 (3), 107
(6), 106 (8), 103 (5), 102 (4), 101 (3), 95 (20), 94 (4), 93 (5),
91 (12), 90 (8), 89 (6), 81 (12), 79 (14), 78 (5), 77 (12), 69
(8), 67 (11), 65 (6), 63 (3), 55 (3), 54 (3), 50 (3), 41 (9).
for C14H15F3N2O4S [M
found = 387.05 876.
+
Na]+
=
387.05 968,
4.6.3 | 1‐(Quinolin‐4‐yl)cyclohexane‐1‐car-
boxylic acid (11)
4.6.7 | ((Trifluoromethyl)sulfonyl)quino-
line (15a‐c)
GC: 9.326 minutes. MS (EI): m/z (%) = 256 (2), 255 (M+,
13), 254 (19), 253 (100), 227 (5), 226 (9), 225 (53), 224 (35),
213 (3), 211 (4), 210 (16), 209 (3), 208 (5), 199 (8), 198 (22),
197 (47), 196 (39), 195 (3), 185 (4), 184 (14), 183 (39), 182
(69), 181 (4), 180 (9), 171 (7), 170 (19), 169 (14), 168 (18),
167 (17), 166 (8), 165 (3), 159, 156 (6), 155 (6), 154 (22),
153 (6), 152 (7), 151 (3), 146 (3), 145 (5), 143 (7), 142
(12), 141 (16), 140 (12), 139 (8), 132 (3), 131 (3), 130 (22),
129 (63), 128 (20), 127 (18), 126 (7), 118 (3), 117 (8), 116
(7), 115 (29), 114 (16), 113 (10), 110 (3), 105 (4), 104 (3),
103 (4), 102 (13), 101 (7), 100 (3), 91 (5), 90 (4), 89 (10),
88 (8), 87 (6), 86 (3), 81 (3), 79 (5), 78 (4), 77 (18), 76 (8),
75 (7), 74 (4), 67 (5), 65 (4), 64 (4), 63 (10), 62 (4), 55 (4),
53 (4), 52 (3), 51 (8), 50 (4), 41 (9).
a. GC: 3.167 minutes. MS (EI): m/z (%) = 262 (2), 261 (M
+,16), 193 (2), 192 (15), 129 (11), 128 (100), 127 (2),
102 (4), 101 (35), 100 (4), 89 (3), 77 (4), 76 (3), 75
(17), 74 (5), 69 (7), 51 (7), 50 (4).
b. GC: 3.463 minutes. MS (EI): m/z (%) = 262 (2), 261
(M+,14), 193 (4), 192 (37), 176 (2), 148 (2), 129 (13),
128 (100), 127 (6), 116 (2), 102 (11), 101 (30), 100
(4), 89 (2), 77 (10), 76 (4), 75 (13), 74 (7), 51 (9),
50 (5).
c. GC: 4.685 minutes. MS (EI): m/z (%) = 261 (M+,14),
194 (3), 193 (5), 192 (56), 176 (3), 129 (12), 128
(100), 127 (7), 116 (4), 102 (9), 101 (35), 100 (5), 89
(3), 77 (12), 76 (5), 75 (17), 74 (8), 69 (10), 63 (4), 62
(3), 52 (3), 51 (8), 50 (5).
4.6.4 | 4‐Cyclohexylquinoline (12)
GC: 6.79 minutes. MS (EI): m/z (%) = 212 (14), 211 (M+,
100), 210 (29), 196 (4), 183 (7), 182 (19), 180 (11), 170 (8),
169 (9), 168 (46), 167 (35), 166 (15), 157 (7), 156 (387), 155
(33), 154 (54), 152 (6), 144 (7), 143 (56), 142 (17), 140 (4),
139 (5), 130 (10), 129 (12), 128 (9), 127 (15), 126 (5), 116
(4), 115 (19), 102 (6), 101 (7), 89 (5), 77 (7), 76 (4), 75
(6), 41 (10).
4.6.8 | 1‐((Trifluoromethyl)sulfonyl)‐1,4‐
dihydroquinoline (16)
GC: 4.342 minutes. MS (EI): m/z (%) = 264 (2), 263 (M+,6),
262 (38), 236 (4), 198 (6), 178 (5), 169 (5), 147 (4), 142 (9),
140 (4), 130 (9), 129 (100), 128 (15), 116 (5), 115 (5), 103
(5), 102 (15), 101 (6), 89 (6), 77 (5), 76 (7), 75 (4), 73 (7),
69 (12), 67 (3), 63 (4), 52 (3), 51 (7), 50 (3), 43 (3).
4.6.5 | 4‐(Cyclohex‐1‐en‐1‐yl)quinolone
4.6.9 | 8‐((Trifluoromethyl)sulfonyl)‐1,4‐
dihydroquinoline (17a‐c)
(13)
GC: 6.456 minutes. MS (EI): m/z (%) = 210 (12), 209 (M
+,100), 208 (36), 194 (9), 193 (4), 192 (7), 191 (4), 182
(3), 181 (30), 180 (90), 179 (5), 169 (6), 168 (13), 167 (52),
166 (85), 155 (6), 154 (18), 153 (14), 152 (16), 151 (4),
140 (5), 139 (8), 138 (3), 127 (10), 126 (6), 115 (8), 101
(5), 89 (4), 79 (5), 77 (5), 75 (6), 69 (2), 66 (2), 64 (2), 63
(4), 52 (3), 51 (3), 43 (3).
a. GC: 7.552 minutes. MS (EI): m/z (%) = 264 (5), 263 (M
+,10), 262 (96), 214 (11), 213 (3), 198 (9), 185 (5), 178
(3), 130 (15), 129 (100), 128 (11), 103 (4), 102 (12), 81
(15), 79 (6), 77 (4), 76 (3), 69 (5), 67 (4), 53 (3), 51 (5),
41 (4).
b. GC: 7.727 minutes. MS (EI): m/z (%) = 264 (7), 263
(M+, 10), 262 (89), 235 (6), 209 (14), 208 (4), 198
(14), 194 (5), 181 (4), 180 (20), 178 (7), 168 (3),
167 (4), 166 (4), 156 (3), 152 (4), 148 (3), 143 (5),
142 (4), 135 (3), 130 (24), 129 (100), 128 (11), 127
(3), 115 (5), 103 (5), 102 (17), 99 (3), 81 (10), 79 (6),
77 (5), 76 (5), 73 (4), 69 (5), 67 (4), 53 (4), 51 (4),
41 (4).
4.6.6 | 4‐Cyclohexyl‐1‐((trifluoromethyl)
sulfonyl)‐1,4‐dihydroquinoline (14)
GC: 8.966 minutes. MS (EI): m/z (%) = 346 (4), 345 (M+,
14), 262 (3), 239 (3), 225 (9), 214 (6), 213 (7), 212 (49), 211
(14), 210 (28), 209 (3), 208 (5), 198 (11), 197 (4), 196 (9),

10 of 12
FIRPO ET AL.
c. GC: 10.262 minutes. MS (EI): m/z (%) = 263 (M+, 8),
262 (59), 261 (2), 207 (5), 198 (5), 178 (4), 130 (19), 129
(100), 128 (18), 103 (5), 102 (16), 101 (5), 81 (5), 78 (3),
77 (4), 76 (8), 75 (4), 74 (4), 73 (5), 69 (4), 65 (3), 64 (4),
63 (3), 55 (3), 54 (3), 53 (3), 51 (6), 50 (4), 41 (4).
4.6.13 | 4‐(Cyclohex‐1‐en‐1‐yl)‐1‐
((trifluoromethyl)sulfonyl)‐1,4‐
dihydropyridine‐3‐carbonitrile (21)
GC: 4.338 minutes. MS (EI): m/z (%) = 319 (3), 318 (M+,
18), 250 (5), 239 (5), 238 (8), 237 (77), 186 (5), 185 (85), 174
(5), 173 (60), 168 (69), 158 (4), 153 (5), 141 (4), 133 (12),
114 (4), 111 (5), 105 (4), 83 (19), 81 (27), 80 (9), 79 (39),
77 (8), 73 (5), 70 (3), 69 (100), 66 (8), 65 (5), 55 (23), 53
(28), 52 (4), 51 (5), 43 (3), 41 (12).
4.6.10 | 1‐(3‐Cyanopyridin‐4‐yl)cyclohex-
ane‐1‐carboxylic acid (18)
1H NMR (400 MHz, dimethyl sulfoxide‐d6):
δ
(ppm) = 11.51 (1H, s), 9.22 (1H, s), 8.92 (1H, d,
J = 5.65 Hz), 8.06 (1H, d, J = 5.78 Hz), 5.60 (1H, s
broad, OH), 1.94 (5H, m), 1.74 (1H, m), 1.62 (2H, m),
1.44 (1H, m), 1.27 (1H, m). 13C NMR (100 MHz,
dimethyl sulfoxide‐d6): δ(ppm) = 175.0, 162.7, 158.2,
150.7, 146.6, 122.2, 121.8, 45.9, 35.1 (×2), 24.0, 21.4
(×2). GC: 8.390 minutes. MS (EI): m/z (%) = 231 (3),
230 (M+, 20), 176 (10), 175 (100), 162 (8), 158 (5), 157
(22), 131 (3), 130 (5), 129 (14), 103 (3), 102 (4), 89 (3),
78 (4), 77 (5), 76 (4), 75 (3), 65 (3), 63 (3), 51 (5), 50
(3), 41 (4). High‐resolution MS (electrospray ionization
time of flight): Calcd for C13H14N2O2 [M + H]
4.6.14 | 1‐((Trifluoromethyl)sulfonyl)‐1,2‐
dihydropyridine‐3‐carbonitrile (22a)
GC: 5.563 minutes. MS (EI): m/z (%) = 239 (4), 238 (M+,
7), 237 (100), 174 (3), 173 (41), 153 (3), 133 (9), 110 (4), 105
(4), 104 (10), 81 (12), 79 (4), 77 (7), 69 (56), 67 (4), 53 (4),
51 (4), 41 (7).
4.6.15 | 1‐((Trifluoromethyl)sulfonyl)‐1,4‐
dihydropyridine‐3‐carbonitrile (22b)
+
= 231.11 280, found = 231.11 241.
GC: 7.130 minutes. MS (EI): m/z (%) = 239 (3), 238 (M+,
6), 237 (100), 231 (3), 127 (15), 186 (19), 185 (11), 184 (4),
176 (19), 173 (26), 171 (4), 170 (5), 169 (16), 168 (29), 167
(6), 159 (10), 158 (19), 156 (4), 154 (3), 148 (6), 147 (4), 146
(18), 145 (6), 144 (3), 143 (5), 142 (3), 133 (10), 132 (5), 131
(5), 130 (19), 128 (3), 119 (3), 118 (4), 117 (7), 116 (4), 115
(3), 109 (4), 105 (5), 104 (6), 103 (5), 102 (4), 91 (5), 90 (4),
89 (6), 81 (15), 79 (7), 78 (6), 77 (12), 76 (6), 75 (3), 69 (28),
67 (7), 65 (6), 63 (6), 55 (4), 54 (5), 53 (6), 52 (3), 51 (8), 50
(5), 41 (10).
4.6.11 | 4‐Cyclohexylnicotinonitrile (19)
GC: 3.697 minutes. MS (EI): m/z (%) = 187 (12), 186 (M+,
49), 185 (28), 172 (3), 71 (8), 170 (3), 169 (9), 168 (23), 167
(4), 159 (7), 158 (38), 157 (73), 156 (4), 155 (4), 154 (3), 146
(9), 145 (51), 144 (18), 143 (12), 142 (11), 133 (9), 132 (51),
131 (100), 130 (27), 129 (12), 128 (3), 119 (5), 118 (18), 117
(11), 116 (10), 115 (4), 105 (6), 104 (10), 103 (12), 102 (5),
91 (5), 90 (9), 89 (10), 88 (3), 79 (6), 78 (7), 77 (13), 76
(16), 75 (7), 69 (4), 67 (9), 65 (5), 64 (3), 63 (11), 62 (3),
56 (19), 55 (10), 54 (5), 53 (6), 52 (7), 51 (12), 50 (6), 42
(4), 41 (49).
4.6.16 | 1‐((Trifluoromethyl)sulfonyl)‐1,6‐
dihydropyridine‐3‐carbonitrile (22c)
GC: 8.080 minutes. MS (EI): m/z (%) = 239 (5), 238 (M+,
9), 237 (100), 174 (4), 173 (43), 153 (3), 133 (10), 109 (3),
105 (6), 104 (9), 81 (12), 79 (5), 78 (3), 77 (7), 69 (57), 67
(4), 55 (4), 53 (5), 50 (3), 43 (4), 41 (8).
4.6.12 | 4‐(Cyclohex‐1‐en‐1‐yl)
nicotinonitrile (20)
GC: 3.898 minutes. MS (EI): m/z (%) = 185 (13), 184 (M+,
48), 183 (100), 182 (6), 171 (3), 170 (3), 169 (34), 168 (26),
167 (36), 166 (22), 158 (13), 157 (35), 156 (15), 155 (44),
145 (19), 144 (11), 143 (10), 142 (18), 141 (4), 140 (3),
132 (17), 131 (46), 130 (16), 129 (19), 128 (12), 127 (6),
126 (3), 118 (11), 117 (5), 116 (14), 115 (6), 114 (7), 106
(7), 105 (4), 104 (9), 103 (7), 102 (6), 101 (6), 100 (4), 91
(4), 90 (8), 89 (7), 88 (5), 87 (4), 81 (4), 79 (8), 78 (8), 77
(23), 76 (16), 75 (9), 67 (5), 65 (6), 64 (13), 63 (12), 58
(3), 56 (5), 55 (4), 54 (13), 53 (6), 52 (11), 51 (15), 50
(11), 48 (3), 44 (7), 43 (7), 41 (32).
ACKNOWLEDGEMENTS
Thanks are due for the financial support provided by
MINCYT‐CONACYT (MX/12/07), CONICET, CONACyT
191400 FOINS, FONCyT, MINCYT, and SECyT‐UNC.
This work used computational resources from CCAD,
Universidad Nacional de Córdoba (http://ccad.unc.edu.
ar/), in particular the Mendieta Cluster, which is part of
SNCAD, MinCyT, República Argentina. G.F. and M.V.C.
thank CONICET for their doctoral fellowships.

FIRPO ET AL.
11 of 12
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SUPPORTING INFORMATION
Additional Supporting Information may be found online
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How to cite this article: Firpo G, Cooke MV,
Peláez WJ, et al. Rearomatization of trifluoromethyl
sulfonyl dihydropyridines: Thermolysis vs.
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