Synthesis of 2-trifluoromethylated quinolines from CF3-alkenes

Article abstract of DOI:10.1039/d1ob00098e

α-CF3-enamines can be prepared by the reaction of pyrrolidine with the corresponding haloalkenes. The prepared enamines react with 2-nitrobenzaldehydes to give ortho-nitro-substituted α,β-diaryl-CF3-enones highly stereoselectively in up to 88% yield. Subsequent reduction of the nitro-group by an Fe-AcOH system promotes intramolecular cyclization to afford 2-CF3-3-arylquinolines in up to 99% isolated yield. High synthetic utility of all synthetic steps of the sequence was shown. A one-pot procedure was developed to give the target trifluoromethylated quinolines directly from enamines or haloalkenes. This journal is

Full text of DOI:10.1039/d1ob00098e

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Synthesis of 2-trifluoromethylated quinolines from
CF3-alkenes†
Cite this: DOI: 10.1039/d1ob00098e
Vasiliy M. Muzalevskiy, a Zoia A. Sizova,a Vladimir T. Abaev b,c and
a
Valentine G. Nenajdenko
*
α-CF3-enamines can be prepared by the reaction of pyrrolidine with the corresponding haloalkenes. The
prepared enamines react with 2-nitrobenzaldehydes to give ortho-nitro-substituted α,β-diaryl-CF3-
enones highly stereoselectively in up to 88% yield. Subsequent reduction of the nitro-group by an Fe–
AcOH system promotes intramolecular cyclization to afford 2-CF3-3-arylquinolines in up to 99% isolated
yield. High synthetic utility of all synthetic steps of the sequence was shown. A one-pot procedure was
developed to give the target trifluoromethylated quinolines directly from enamines or haloalkenes.
Received 19th January 2021,
Accepted 7th April 2021
DOI: 10.1039/d1ob00098e
rsc.li/obc
example, Chloroquine, Hydroxychloroquine, and Mefloquine,16
are used to treat malaria, which is a dangerous infective disease
Introduction
Quinoline was discovered by F. Runge in 1834.1 Two centuries that affected 228 million people in 2018, leading to nearly
of investigations have afforded many approaches to the syn- 0.4 million casualties that year.17 Proflavine is used as a topical
thesis of the quinoline core. The Skraup,2 Doebner–von antiseptic. Pitavastatin is a representative of statins used for low-
Miller,3 Combes,4 Friedländer,5 Pfitzinger,6 and Conrad– ering lipid levels in the blood. Bosutinib possesses antineoplastic
Limpach7 syntheses have become classics of heterocyclic activity and is used for the treatment of chronic myelogenous leu-
chemistry known to students from textbooks. Modern kemia (Fig. 1).
approaches to quinoline synthesis often employ transition
One of the defining trends of modern science is concern
metal-catalyzed reactions.8 Green and clean syntheses using about the applicability of the obtained results in everyday life.
microwaves, clay, or some other catalyst which could be A lot of attention has been paid to organofluorine chemistry
recycled and reused, one-pot reactions, solvent-free reaction due to organofluorine compounds having unique physico-
conditions, ionic liquids, ultrasound promoted synthesis, and chemical and biological properties.18 As a result these com-
photocatalytic synthesis (UV radiation) have also been devel- pounds have found applications as construction materials,
oped.9 Nevertheless, novel approaches to quinolines are in great components of liquid crystalline compositions, agrochem-
demand because quinoline chemistry is still at the top of the icals19 and pharmaceuticals.20 About 20% (more than 300
modern organic chemistry agenda. The high biological activity of compounds) of currently used drugs21 contain at least one
quinolines makes them very attractive scaffolds in drug discovery. fluorine atom.22 Recent analysis revealed sustainable growth of
For example, antifungal,10 anticancer,11 anti-inflammatory,12 and the fluoropharmaceuticals share among new small-molecule
antileishmanial actions13 have been documented. A number of drugs, which has doubled in the last two years (45% in 2018,23
quinoline derivatives are used as important drugs. Thus, quino- 41% in 201924). Obviously, the combination of fluorine or
lone antibiotics such as ofloxacin (Floxin), norfloxacin (Noroxin), fluorinated substituents with heterocyclic moieties is a fruitful
ciprofloxacin (Cipro), and moxifloxacin (Avelox) are widely used strategy in drug design. Indeed, 11 drugs bearing fluorinated
worldwide for treating a broad range of bacterial infections— heterocyclic motifs and 19 drugs with both fluorine and
such as pneumonia and tuberculosis.14 The quinoline alkaloid heterocyclic moieties in the molecule were approved by the
quinine15 and a number of modern quinoline derived drugs, for FDA in 2018 and 2019. Novel effective methodologies for the
synthesis of fluorinated heterocycles are in great demand.25
It should be pointed out that fluorinated quinolines are hot
aDepartment of Chemistry, Lomonosov Moscow State University, 119899 Moscow,
Russia. E-mail: nenajdenko@org.chem.msu.ru
bNorth Ossetian State University, 44-46 Vatutina St., Vladikavkaz, 362025, Russia
cNorth Caucasus Federal University, 1a Pushkin St., Stavropol 355009, Russia
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data, copies of NMR spectra. See DOI: 10.1039/
d1ob00098e
topic compounds. A lot of effort has been made in this field
due to the high importance of fluoroquinolone antibiotics.
2-CF3-quinolines are highly attractive molecules as well. A lot
of reports devoted to their synthesis have appeared in the lit-
erature during the last 2 decades.25 For example, for only the
last 10 years, more than 9000 hits can be found in the Reaxys
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Fig. 1 Selected examples of drugs with quinoline moieties.
data base. The most popular methods are based on trifluoro-
methylation of quinoline derivatives,26 2-haloquinolines27 or
isocyanides.28 Various cyclizations using anilines29 or isa-
tines30 as precursors have also been reported.
Scheme 1 Synthesis of starting enamines 2.
In this article, we report the synthesis of ortho-nitro-substi-
tuted α,β-diaryl-α′-CF3-enones based on the condensation of
α-CF3-β-aryl enamines with 2-nitrobenzaldehydes. Subsequent
conversion of these ketones into 2-CF3-quinolines can be per-
formed by reduction of the nitro-group followed by intra-
molecular cyclization.
dehyde was performed in acetic acid at 80–90 °C. To our
delight, the reaction gave the desired ketone 4a in 76% yield
after 6 h heating at 80–90 °C (Scheme 2).
Next, the scope of 2-nitrobenzaldehydes 3 was studied
using 2a as a model enamine. It was found that the reaction is
very general. All target ketones 4b–k were prepared in good to
high yields. Further, we varied the enamine moiety and con-
ducted the reaction with 2-nitrobenzaldehyde. Again, a set of
ketones 4l–u was successfully prepared in up to 86% yield. We
Results and discussion
To start our investigation, a set of enamines 2 with both elec- also attempted to involve enamine 2l with a heterocyclic motif
tron-withdrawing and electron-donating groups was prepared in the reaction. As a result, the corresponding ketone 4v
(Scheme 1). Depending on the quantity of pyrrolidine used, bearing a 4-pyridyl substituent was synthesized in good yield.
the reaction of 4-fluoro-substituted styrene 1d afforded To have a heterocyclic ring adjacent to the other side of the
enamine 2d (1.5 equiv.) or enamine 2e with a additional pyrro- double bond of ketone 4, we performed the reaction of
lidine moiety in the para-position of the aryl ring (3 equiv.). enamine 2b with 2-nitro-3-thiophenecarbaldehyde. The reac-
Similarly, styrene 1i can be converted into either enamine 2j or tion afforded the thiophene derived ketone 4w in 61% yield.
enamine 2k by controlling the reaction time. Performing the Summarizing the results obtained, one can point out the high
reaction overnight is enough to create the enamine functional synthetic utility of the reaction, allowing us to prepare the
group to give enamine 2j. Conversion of the ester to the amide desired ketones with various combinations of electron-donat-
can be performed by carrying out the reaction for 7 days to ing and electron-withdrawing groups on both aryl rings.
give enamine 2k. Enamine 2l with a heterocyclic moiety was Aldehydes and enamines with various functional groups, as
also successfully prepared in 94% yield (Scheme 1).
well as bulky substituents and heterocyclic moieties, can be
With a set of trifluromethylated enamines 2 in hand, their involved in the reaction.
reaction with ortho-nitro-substituted benzaldehydes was inves-
Another outstanding feature of the reaction is its very high
tigated. The model reaction of enamine 2a with 2-nitrobenzal- stereoselectivity. Thus, the E-isomer with cis-arranged aryl sub-
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Scheme 2 Scope of the synthesis of o-nitrophenyl-substituted enones.
stituents is the major product of the reaction. As a rule, the target quinoline 5a in 90% yield. An attempt to carry out the
fraction of the minor Z-isomer does not exceed 1–6%. reaction in one pot in acetic acid showed that no reduction
Moreover, in many cases formation of the Z-isomer was not occurs at room temperature. When heated, the reaction pro-
detected at all. Only in the case of 4b, about 14% Z-isomer was ceeds successfully, however, formation of a minor amount of
formed. The stereochemical outcome of the reaction can be impurities decreases the yield of the target quinoline 5a by
explained by the formation of a Zimmerman–Traxler like tran- about 10%.
sition state.31
Thus, the Fe–AcOH system appears to be optimal for this
Next, the possibility of transformation of the ortho-nitro- transformation. Using these conditions, a set of 2-CF3-3-aryl-
substituted ketones 4 into the corresponding CF3-quinolines quinolines 5 with various combinations of substituents was
was studied. It was found that ketone 4a can be converted into prepared from the corresponding enones (Scheme 3, method
the desired quinoline 5a in 95% yield using an Fe–AcOH B). The reaction tolerates both electron-donating and electron-
system. A very clean reduction–heterocyclization sequence withdrawing groups, and cyano, amide and ester functional
takes place when these classical conditions for the reduction groups to give the target quinolines in nearly quantitative
of the nitro-group are used. No formation of any organic by- yields for the 1-step transformation from ketones (5a,g,h,m,s),
products was observed during the reaction (Scheme 3, method or in good to high yields for the one-pot 2-step transformation
A). As a result, the isolation of the target product can be per- from enamines (5a,b–f,i–l,n–t). The reaction is not sensitive to
formed just by separation of the target product from the in- steric demands, allowing us to involve ketones with ortho-sub-
organic products of iron oxidation.
stituents on both aryl rings (5g,i,j,r). When the starting ketone
On the other hand, one can mention that the synthesis of has an additional nitro-group in the structure (enones 4c,s,p),
the starting ketone was carried out in the same solvent (acetic reduction of both NO2 groups takes place to give the corres-
acid). Therefore, we decided to use a more attractive one-pot ponding quinolines 5c,s,p with aminoaryl fragments. This
protocol (Scheme 3, method B). To our delight, quinoline 5a functionality can be used to create a library of 2-CF3-quino-
was obtained in 77% yield using a two-step one-pot procedure lines for subsequent study of their biological activity
without intermediate isolation of ketone 4a. Some other reduc- (Scheme 3).
tive systems were studied as well. However, catalytic reduction
We also found that all 3 steps of this approach can be per-
using hydrogen and palladium on carbon in methanol led to formed in one pot starting from the CF3-alkenes 1. We demon-
the formation of a complex mixture of products. Most prob- strated the synthesis of quinolines directly from styrenes 1,
ably, deeper reduction occurred as well. All our attempts to bypassing the purification of the intermediate enamines 2 and
halt over-reduction to obtain pure quinoline 5a or force the the isolation of ketones 4. In this case, the yields of quinolines
reaction to isolate the corresponding tetrahydroquinoline 5r,u reached a respectable 70%, allowing us to simplify the
failed. An ammonium formate–Pd/C system in methanol at procedure and avoid purification of the intermediate products
room temperature works much more selectively, leading to the (Scheme 3, method C).
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Scheme 3 Synthesis of quinolines 5 from enamines 2.
As a proof of principle, we examined the possibility of shift- (Scheme 4). Cyclization of this intermediate into quinoline 5 is
ing the reduction step to the beginning of the sequence. For not possible due to geometrical reasons. However, isomeriza-
that purpose, 2-nitrobenzaldehyde was treated with Fe powder tion of the double bond of E-aniline A can occur very easily
in AcOH to form 2-aminobenzaldehyde in about
Subsequent addition of enamine 2b followed by heating for merization is typical for CF3-substituted aminoenones.9d It can
several hours afforded quinoline 5l in high yield (method D). be explained by the corresponding resonance form of A
1 h. due to the low rotation barrier for the double bond. Such iso-
We have also shown that this approach is applicable for the (Scheme 4). Cyclization of Z-aniline B thus formed leads to
preparation of quinolines with heterocyclic substituents. Thus, intermediate C, which eliminates water to finally give 5.
the 4-pyridyl derived quinoline 5v was synthesized in 40%
It should be noted that similar isomerization of non-fluori-
yield (method C). In addition, the approach can be expanded nated analogs of 2-aminostyryl ketones does not proceed spon-
to the synthesis of other heterocyclic cores. Starting from taneously in contrast to CF3-derived A. Thus, isomerization of
2-nitrothiophene-3-carbaldehyde,
6-(trifluoromethyl)thieno non-fluorinated 2-aminostyryl ketones requires catalysis by
[2,3-b]pyridine 5w was obtained in good yield. Using 4-amino- phosphoric acid derivatives,32 benzylamine33 or iodide.34
3-pyridinecarbaldehyde, the corresponding trifluoromethyl- Taking into account these data, an alternative explanation for
ated 1,6-naphthyridine 5x was prepared in 84% yield using the isomerization of A can be proposed, using the partici-
method E.
pation of acetate in the reaction. Reversible Michael addition
The possible mechanism of the reaction should be dis- of AcO− to the activated double bond of A leads to intermedi-
cussed due to the fact that the enones are formed exclusively ate D. Subsequent elimination of acetate results in the desired
or preferentially as E-isomers. The transformation can be Z-aniline B. Alternatively, cyclization of D can afford the tetra-
rationalized as follows. In the first step, reduction of the nitro- hydroquinoline intermediate E, which eliminates acetate to
group takes place to form the E-configured aniline
A
give C (Scheme 4).
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Scheme 4 Possible mechanism of the reduction–heterocyclization sequence.
procedures.35 The NMR data of compounds 2a–c and 2g–j are
Conclusions
in agreement with those in the literature.35 2-Nitrothiophene-
In conclusion, we developed a novel approach to 2-CF3-3-aryl- 3-carbaldehyde36 and 4-aminonicotinaldehyde37 were prepared
quinolines 5. The target trifluoromethylated derivatives 5 were as previously reported.
prepared in up to quantitative yield by reduction of nitro-sub-
stituted α,β-diaryl-CF3-enones by an Fe–AcOH system. Key
nitro-substituted α,β-diaryl-CF3-enones can be prepared by
condensation of α-CF3-enamines with 2-nitrobenzaldehydes.
Efficient one-pot 2-step (from enamines) and 3-step (from sty-
(Z)-4-(2-Chloro-3,3,3-trifluoroprop-1-en-1-yl)pyridine (1j)
Obtained from isonicotinaldehyde (16.07 g, 150 mmol) by a
catalytic olefination reaction using the procedure used for ole-
fination of picolinaldehyde.38 Burgundy oil, yield 16.51 g
renes) protocols for the synthesis of the target trifluoromethyl-
(53%). Mixture of Z- and E-isomers: 82 : 18. For the mixture of
ated quinolines were also developed. The high yields and
1
isomers: Z-isomer: H NMR (400.1 MHz, CDCl3): δ 7.23 (s, 1H,
broad scope of all synthetic transformations are distinct
advantages of the method.
CHvC), 7.46–7.54 (m, 2H, Py), 8.64–8.74 (m, 2H, Py). 13C{1H}
1
NMR (100.6 MHz, CDCl3): δ 120.1 (q, JCF = 272.4 Hz, CF3),
2
3
123.3, 123.7 (q, JCF = 37.4 Hz, C
̲–CF3), 128.4 (q, JCF = 4.4 Hz,
C̲
4
1
Experimental
General remarks
−70.4 (d, J = 0.7 Hz, 3F, CF3). E-isomer: H NMR (400.1 MHz,
CDCl3): δ 7.09–7.15 (m, 2H, Py), 7.17 (s, 1H, CHvC), 8.58–8.64
(m, 2H, Py). 13C{1H} NMR (100.6 MHz, CDCl3): δ 119.8 (q, JCF
1
1H, 13C and 19F NMR spectra were recorded on a Bruker
AVANCE 400.1 MHz spectrometer in CDCl3 at 400.1, 100.6 and
376.5 MHz respectively. Chemical shifts (δ) in ppm are
reported with use of the residual chloroform signals (7.25 for
1H and 77.0 for 13C) as internal reference. The 19F chemical
shifts were referenced to C6F6 (−162.9 ppm). The coupling con-
stants (J) are given in Hertz (Hz). The following abbreviations
are used in reporting NMR data: s, singlet; br s, broad singlet;
3
2
= 274.4 Hz, CF3), 122.4 (q, JCF = 2.0 Hz), 124.2 (q, JCF = 38.4
3
Hz, C–̲ CF3), 133.9 (q, JCF = 2.4 Hz, C̲HvCCF3), 140.1, 149.8.
19F NMR (376.5 MHz, CDCl3): δ −62.9. HRMS (ESI-TOF): m/z
[M + H]+ calcd for C8H6ClF3N+: 208.0135; found: 208.0130.
Synthesis of enamines 2 by the reaction of styrenes 1 with
lithium pyrrolidide (method A)
d, doublet; t, triplet; q, quartet; dd, doublet of doublets; ddd, A preheated three neck 250 mL round bottomed flask was
doublet of doublets of doublets; td, triplet of doublets; pt, flushed with argon, charged with dry THF (75 mL) and dry pyr-
pseudo-triplet; ptd, pseudo-triplet of doublets; m, multiplet. rolidine (6.72 mL, 82 mmol), and cooled down to −70 °C.
ESI-MS spectra were recorded with an Orbitrap Elite instru- Next, n-BuLi (32 mL, 80 mmol, 2.5 M solution of n-BuLi in
ment. TLC analysis was performed on “Merck 60 F254” plates. hexane) was added dropwise over 5 min. The cooling bath was
Column chromatography was performed on silica gel. Melting removed and the reaction mixture was allowed to warm to
points were determined on an Electrothermal 9100 apparatus. −5–0 °C. After that the reaction mixture was cooled down to
All reagents were of reagent grade and were used as received or −70 °C and the corresponding styrene 1 (40 mmol) was slowly
distilled prior to use. The starting α-CF3-β-aryl enamines 2 added. The reaction mixture was allowed to warm to room
were synthesized by the reaction of β-halogeno- temperature and quenched with water (80 mL). The organic
β-trifluoromethylstyrenes with 2.2 equivalents of lithium pyrro- phase was separated and the water phase was extracted with
lidide (generated by the reaction of pyrrolidine and n-BuLi, 2a– ether (3 × 20 mL). The combined extracts were washed with
e) in THF (method A) or by the reaction with 10 equivalents of water (50 mL) and brine (50 mL), and dried over Na2SO4.
neat pyrrolidine (2f–k, method B), using previously reported Volatiles were removed in vacuo, and the residue was filtered
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1
through a short silica gel pad using hexane followed by 260.1060. E-isomer: H NMR (400.1 MHz, CDCl3): δ 2.00–2.04
hexane–CH2Cl2 (3 : 1).
(m, 4H, N(CH2CH2̲ )2), 3.16–3.19 (m, 4H, N(CH2̲ CH2)2) 5.59 (s,
1H, CHvC), 6.91–6.96 (m, 2H, Ar). Other signals are over-
(Z)-1-(3,3,3-Trifluoro-1-phenylprop-1-en-2-yl)pyrrolidine (2a)
lapped with those of the major isomer. 13C NMR (100.6 MHz,
4
Obtained
from
(Z)-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl) CDCl3): δ 24.7, 49.4 (q, JCF = 1.9 Hz, N(C
̲
benzene 1a (8.26 g, 40 mmol) by method A. Pale brown oil, signals are overlapped with those of the major isomer or
yield 8.26 g (86%). 1H NMR (400.1 MHz, CDCl3): δ 1.85–1.93 cannot be seen in the spectrum due to the low concentration
(m, 4H, N(CH2CH2̲ )2), 3.11–3.18 (m, 4H, N(CH2̲
CH2)2), 6.24 (s, of the minor isomer. 19F NMR (376.5 MHz, CDCl3): δ −59.5 (s,
1H, CHvC), 7.23–7.29 (m, 1H, Ph), 7.35–7.39 (m, 4H, Ph). 13C 3F, CF3), −117.72, −117.97 (m, 1F, 4-FC6H4).
{1H} NMR (100.6 MHz, CDCl3): δ 25.5, 50.2, 110.0 (q, JCF = 5.9
3
1
2
(Z)-1-(3,3,3-Trifluoro-1-(4-(pyrrolidin-1-yl)phenyl)prop-1-en-2-
yl)pyrrolidine (2e)
Hz, C
28.5 Hz,
(376.5 MHz, CDCl3): δ −65.7.
̲
=
C
̲
Obtained from (Z)-1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-4-
fluorobenzene 1d (5.78 g, 18 mmol), pyrrolidine (4.42 mL,
54 mmol, 3 equiv.) and n-BuLi (22 mL, 55 mmol, 3 equiv.) by
method A. Slightly beige solid, m.p. 57–58 °C, yield 4.035 g
(Z)-1-(3,3,3-Trifluoro-1-(4-methoxyphenyl)prop-1-en-2-yl)
pyrrolidine (2b)
Obtained from (Z)-1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-4- (72%). Mixture of Z- and E-isomers: 97 : 3. For the mixture of
methoxybenzene 1b (9.46 g, 40 mmol) by method A. Slightly isomers: Z-isomer: 1H NMR (400.1 MHz, CDCl3): δ 1.82–1.90
1
brown oil, yield 9.41 g (87%). H NMR (400.1 MHz, CDCl3): δ (m, 4H, N(CH2CH2 2
̲
) ), 1.98–2.06 (m, 4H, N(CH2CH2 2
) ), 3.04–3.11 (m, 4H, 3.07–3.11 (m, 4H, N(CH2CH2)2), 3.31–3.34 (m, 4H,
2CH2)2), 3.84 (s, 3H, OCH3), 6.21 (s, 1H, CHvC), 6.88 (d, N(CH
2CH2)2), 6.29 (s, 1H, CHvC), 6.53 (d, 3J = 8.8 Hz, 2H, Ar),
3J = 8.7 Hz, 2H, Ar), 7.34 (d, J = 8.7 Hz, 2H, Ar). 13C{1H} NMR 7.38 (d, 3J = 8.8 Hz, 2H, Ar). 13C{1H} NMR (100.6 MHz, CDCl3):
̲ ) ),
1.81–1.89 (m, 4H, N(CH2CH2 2
̲
̲
N(CH
̲
̲
3
3
3
(100.6 MHz, CDCl3): δ 25.4, 49.9, 55.1, 112.9 (q, JCF = 5.1 Hz, δ 25.3, 25.5, 47.5, 49.5, 111.0, 117.3 (q, JCF = 6.1 Hz,
HvCCF3), 122.8 (q, 1JCF = 279.6 Hz, CF3), 132.2 (q, 2JCF = 27.8 HvCCF3), 122.0, 123.3 (q, 1JCF = 280.0 Hz, CF3), 129.8 (q, 2JCF
Hz, C
C
̲
C̲
–CF3), 113.4, 127.9, 130.6, 158.6. 19F NMR (376.5 MHz, = 27.5 Hz, C
̲
CDCl3): δ −65.4.
δ −64.7. E-isomer: 1H NMR (400.1 MHz, CDCl3): δ 1.92–1.95
(m, 4H, N(CH2CH2 2
3.28–3.31 (m, 4H, N(CH
= 8.6 Hz, 2H, Ar), 7.11 (d, 3J = 8.6 Hz, 2H, Ar). Other signals are
̲
) ), 3.13–3.16 (m, 4H, N(CH2
̲
̲ CH2)2),
(Z)-1-(1-(4-Chlorophenyl)-3,3,3-trifluoroprop-1-en-2-yl)
pyrrolidine (2c)
2CH2)2), 5.79 (s, 1H, CHvC), 6.51 (d, 3J
Obtained from (Z)-1-chloro-4-(2-chloro-3,3,3-trifluoroprop-1-en- overlapped with those of the major isomer. 13C{1H} NMR
1-yl)benzene 1c (9.64 g, 40 mmol) by method A. Slightly brown (100.6 MHz, CDCl3): δ 24.36, 24.42, 45.0, 49.8, 110.9, 130.5 (q,
oil, yield 7.97 g (72%). 1H NMR (400.1 MHz, CDCl3): δ 2JCF = 29.4 Hz, C
̲
1.76–1.85 (m, 4H, N(CH2CH2 2
̲
N(CH
̲
2CH2)2), 6.06 (s, 1H, CHvC), 7.19 (d, 3J = 8.6 Hz, 2H, Ar), trum due to the low concentration of the minor isomer. 19F
7.25 (d, 3J = 8.6 Hz, 2H, Ar). 13C{1H} NMR (100.6 MHz, CDCl3): NMR (376.5 MHz, CDCl3): δ −59.8. HRMS (ESI-TOF): m/z [M +
+
δ 25.5, 50.2, 108.2 (q, 3JCF = 5.9 Hz, C
̲
=
H]+ calcd for C17H22F3N2 : 311.1730; found: 311.1723.
2
278.8 Hz, CF3), 134.1 (q, JCF = 28.5 Hz, C
̲
Synthesis of α-CF3-β-arylenamines by the reaction with neat
pyrrolidine (general procedure, method B)
131.8, 134.2. 19F NMR (376.5 MHz, CDCl3): δ −64.6.
(Z)-1-(3,3,3-Trifluoro-1-(4-fluorophenyl)prop-1-en-2-yl)
pyrrolidine (2d)
A one neck 25 mL round bottomed flask was charged with dry
pyrrolidine (8.5 mL, 100 mmol) and cooled down to −18 °C,
Obtained from (Z)-1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-4- and the corresponding styrene 1 (10 mmol) was added in one
fluorobenzene 1d (2.240 g, 10 mmol), pyrrolidine (1.23 mL, portion with vigorous stirring. The reaction mixture was stirred
15 mmol, 1.5 equiv.) and n-BuLi (6 mL, 15 mmol, 1.5 equiv.) at room temperature for 1–3 h until all starting styrene was
by method A. Slightly brown oil, yield 1.760 g (68%). Mixture consumed (TLC monitoring). The excess pyrrolidine was evap-
of Z- and E-isomers: 95 : 5. For the mixture of isomers: orated in vacuo, and the viscous residue was dissolved in
Z-isomer: 1H NMR (400.1 MHz, CDCl3): δ 1.76–1.87 (m, 4H, CH2Cl2 (50 mL), washed with water (3 × 50 mL) and dried over
N(CH2CH2̲ )2), 3.02–3.05 (m, 4H, N(CH2̲ CH2)2), 6.11 (s, 1H, Na2SO4. CH2Cl2 was removed in vacuo, and the residue was fil-
CHvC), 6.96–7.03 (m, 2H, Ar), 7.25–7.30 (m, 2H, Ar). 13C{1H} tered through a short silica gel pad using hexane or appropri-
4
NMR (100.6 MHz, CDCl3): δ 25.4, 50.1 (q, JCF = 1.1 Hz, ate mixtures of hexane and CH2Cl2. The Z/E-isomers of enam-
N(C
= 21.4 Hz), 122.4 (q, JCF = 279.0 Hz, CF3), 130.7 (d, JCF = 7.7
̲ ̲
H2CH2)2), 109.5 (q, 3JCF = 5.9 Hz, CHvCCF3), 114.7 (d, 2JCF ines 2 could not be separated by column chromatography.
1
3
4
2
1-[(1Z)-3,3,3-Trifluoro-1-(4-trifluoromethylphenyl)prop-1-en-
Hz), 131.6 (d, JCF = 3.5 Hz), 133.5 (dq, JCF = 26.7 Hz, C
̲
1
2yl]pyrrolidine (2f)
−65.5 (s, 3F, CF3), −115.50, −116.15 (m, 1F, 4-FC6H4). HRMS Obtained from (Z)-1-(2-bromo-3,3,3-trifluoroprop-1-en-1-yl)-4-
(ESI-TOF): m/z [M + H]+ calcd for C13H14F4N+: 260.1057; found: (trifluoromethyl)benzene 1e (3.962 g, 12.420 mmol) by method
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B. Colourless oil, yield 3.257 g (85%). 1H NMR (400.1 MHz, signals are overlapped with those of the major isomer. 19F
CDCl3): δ 1.80–1.87 (m, 4H, N(CH2CH2)2), 3.04–3.08 (m, 4H, NMR (376.5 MHz, CDCl3): δ −59.7.
N(CH
2CH2)2), 6.07 (s, 1H, CHvC), 7.30 (d, 3J = 8.3 Hz, 2H, Ar),
̲
̲
Methyl 4-[(1Z)-3,3,3-trifluoro-2-pyrrolidin-1-ylprop-1-enyl]
benzoate (2j)
7.54 (d, 3J = 8.3 Hz, 2H, Ar). 13C{1H} NMR (100.6 MHz, CDCl3):
4
3
δ 25.5, 50.6 (q, JCF = 1.7 Hz, N(C
̲
1
1
Hz, C
HvCCF3), 122.0 (q, JCF = 278.6 Hz, CF3), 124.2 (q, JCF
=
Obtained from methyl (Z)-4-(2-bromo-3,3,3-trifluoroprop-1-en-
271.6 Hz, CF3), 124.6 (q, 3JCF = 3.7 Hz), 127.8 (q, 2JCF = 32.4 Hz, 1-yl)benzoate 1i (3090 mg, 10 mmol) by method B by perform-
C̲
̲
;
̲
̲
̲
310.1025; found: 310.1020.
CH̲
̲
(Z)-1-(1-(2-Bromophenyl)-3,3,3-trifluoroprop-1-en-2-yl)
pyrrolidine (2g)
̲
̲
̲
̲
Obtained from (Z)-1-bromo-2-(2-bromo-3,3,3-trifluoroprop-1- 127.4, 128.8, 129.0, 140.9 (Ar), 166.9 (C
en-1-yl)benzene 1f (3.3001 g, 10.005 mmol) by method
̲O2CH3).
(Z)-Pyrrolidin-1-yl(4-(3,3,3-trifluoro-2-(pyrrolidin-1-yl)prop-1-
B. Colorless oil, yield 2.402 g (75%). Mixture of Z- and
E-isomers: 90 : 10. For the mixture of isomers: Z-isomer: 1H
en-1-yl)phenyl)methanone (2k)
NMR (400.1 MHz, CDCl3): δ 1.70–1.75 (m, 4H, N(CH2CH2 2
̲
) ), Obtained from methyl (Z)-4-(2-bromo-3,3,3-trifluoroprop-1-en-
2.93–2.97 (m, 4H, N(CH2CH2)2), 5.93 (s, 1H, CH̲vC), 6.98 (td, 1-yl)benzoate 1i (3.092 g, 10 mmol) by method B by perform-
̲
4
3
4
3J = 7.6 Hz, J = 1.6 Hz, 1H, Ar), 7.13 (dd, J = 7.6 Hz, J = 1.4 ing the reaction for 7 days. Yellow oil, yield 2.970 g (88%).
Hz, 1H, Ar), 7.16–7.22 (m, 1H, Ar), 7.47 (dd, 3J = 7.9 Hz, 4J = 0.6 Mixture of Z- and E-isomers: 76 : 24. For the mixture of
Hz, 1H, Ar). 19F NMR (376.5 MHz, CDCl3): δ −65.9. E-isomer: isomers: Z-isomer: 1H NMR (400.1 MHz, CDCl3): δ 1.75–2.02
1H NMR (400.1 MHz, CDCl3):
N(CH2CH2)2), 3.19–3.22 (m, 4H, N(CH2
δ
1.88–1.92 (m, 4H, (m, 8H, 2N(CH2CH2 2
CH2)2), 5.43 (s, 1H, 3.43–3.46 (m, 2H, N(CH
̲
) ), 3.03–3.06 (m, 4H, N(CH2
̲ CH2)2),
̲
̲
2̲ CH2)2), 3.61–3.65 (m, 2H,
CHvC). Other signals are overlapped with those of the major N(CH̲
2CH2)2), 6.07 (s, 1H, CHvC), 7.24 (d, 3J = 8.3 Hz, 2H, Ar),
isomer. 19F NMR (376.5 MHz, CDCl3): δ −60.3.
7.45 (d, 3J = 8.3 Hz, 2H, Ar). 13C{1H} NMR (100.6 MHz, CDCl3):
4
δ 24.2, 25.3, 26.2, 46.02, 49.4, 50.2 (q, JCF = 1.3 Hz), 107.5 (q,
(Z)-1-(3,3,3-Trifluoro-1-(4-nitrophenyl)prop-1-en-2-yl)
pyrrolidine (2h)
Obtained from (Z)-1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-4- 169.2. 19F NMR (376.5 MHz, CDCl3): δ −65.8. E-isomer: 1H
nitrobenzene 1g (2.516 g, 10.000 mmol) by method B. Orange- NMR (400.1 MHz, CDCl3): δ 3.19–3.22 (m, 4H, N(CH2CH2)2),
1
3JCF = 6.1 Hz, C
̲
2
126.50, 128.5, 134.2 (q, JCF = 28.3 Hz, C̲–CF3), 134.5, 137.3,
̲
3
3
yellow crystals, m.p. 74–77 °C, yield 2.576 g (90%). Mixture of 5.59 (s, 1H, CH
Z- and E-isomers: 96 : 4. For the mixture of isomers: Z-isomer: 8.2 Hz, 2H, Ar). Other signals are overlapped with those of the
1H NMR (400.1 MHz, CDCl3): 1.81–1.91 (m, 4H, major isomer. 13C{1H} NMR (100.6 MHz, CDCl3): δ 24.5, 45.98,
N(CH2CH2 2
̲vC), 7.18 (d, J = 8.2 Hz, 2H, Ar), 7.41 (d, J =
δ
̲
) ), 3.07–3.10 (m, 4H, N(CH̲2 ̲HvC), 121.8 (q,
CH2)2), 6.03 (s, 1H, 49.2 (q, 4JCF = 1.9 Hz), 105.6 (q, 3JCF = 3.1 Hz, C
3
3
3
CHvC), 7.26 (d, J = 8.7 Hz, 2H, Ar), 8.14 (d, J = 8.7 Hz, 2H, 1JCF = 277.9 Hz, CF3), 126.47, 128.6 (q, JCF = 2.3 Hz), 134.3,
Ar). 19F NMR (376.5 MHz, CDCl3): δ −65.9. E-isomer: H NMR 135.3 (q, 2JCF = 30.1 Hz, C
̲
1
(400.1 MHz, CDCl3): δ 7.37 (s, 1H, CHvC), 7.86 (d, 3J = 8.8 Hz, overlapped with those of the major isomer or cannot be seen
2H, Ar), 8.29 (d, 3J = 8.8 Hz, 2H, Ar). Other signals are over- in the spectrum due to the low concentration of the minor
lapped with those of the major isomer. 19F NMR (376.5 MHz, isomer. 19F NMR (376.5 MHz, CDCl3):
δ
−59.7. HRMS
(ESI-TOF): m/z [M + H]+ calcd for C18H22F3N2O+: 339.1679;
found: 339.1681; [M
Na]+ calcd for C18H21F3N2NaO+:
361.1498; found: 361.1496.
CDCl3): δ −59.8.
+
(Z)-1-(3,3,3-Trifluoro-1-(3-nitrophenyl)prop-1-en-2-yl)
pyrrolidine (2i)
4-(3,3,3-Trifluoro-2-(pyrrolidin-1-yl)prop-1-en-2-yl)pyridine (2l)
Obtained from (Z)-1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-3-
nitrobenzene 1h (6.780 g, 26.949 mmol) by method B. Yellow Obtained from 4-[2-chloro-3,3,3-trifluoro-1-propenyl]pyridine
oil, yield 6.865 g (89%). Mixture of Z- and E-isomers: 97 : 3. For 1j (1.07 g, 4.8 mmol) by method B. Pale brown oil, yield 1.09 g
the mixture of isomers: Z-isomer: 1H NMR (400.1 MHz, (94%). Mixture of Z- and E-isomers: 74 : 26. For the mixture of
CDCl3): δ 1.81–1.90 (m, 4H, N(CH2CH2 2
N(CH2CH2)2), 6.08 (s, 1H, CHvC), 7.46 (td, J = 15.7 Hz, J = (m, 4H, N(CH2CH2̲ )2), 3.02–3.05 (m, 4H, N(CH̲2CH2)2), 5.87 (s,
̲
) ), 3.05–3.08 (m, 4H, isomers: Z-isomer: 1H NMR (400.1 MHz, CDCl3): δ 1.76–1.84
3
3
̲
3
3
3
7.8 Hz, 2H, Ar), 8.00 (d, J = 8.0 Hz, 1H, Ar), 8.06 (s, 1H, Ar). 1H, CHvC), 6.97 (d, J = 5.9 Hz, 2H, Py), 8.45 (d, J = 4.9 Hz,
19F NMR (376.5 MHz, CDCl3): δ −66.0. E-isomer: 1H NMR 2H, Py). 13C{1H} NMR (100.6 MHz, CDCl3): δ 25.4, 50.9 (q, JCF
4
3
1
(400.1 MHz, CDCl3):
3.22–3.26 (m, 4H, 2NCH
δ
1.94–1.98 (m, 4H, 2NCH2CH2
̲
), = 1.7 Hz), 102.9 (q, JCF = 6.3 Hz, C
̲
=
2
̲
2CH2), 5.50 (s, 1H, CHvC). Other 278.8 Hz, CF3), 123.3, 136.5 (q, JCF = 28.8 Hz, C
̲
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3
149.0. 19F NMR (376.5 MHz, CDCl3): δ −65.9. E-isomer: 1H 7.02–7.05 (m, 2H, Ph), 7.07 (d, J = 8.1 Hz, 1H, Ar), 7.26–7.35
3
4
NMR (400.1 MHz, CDCl3): δ 1.87–1.93 (m, 4H, N(CH2CH̲2)2), (m, 3H, Ph), 7.58 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H, Ar), 8.10 (s,
3.19–3.23 (m, 4H, N(CH̲
2CH2)2), 5.33 (s, 1H, CHvC), 7.01 (d, 3J 1H, CHvC), 8.43 (d, 4J = 1.5 Hz, 1H, Ar). 13C{1H} NMR
3
1
= 5.4 Hz, 2H, Py), 8.40 (d, J = 4.5 Hz, 2H, Py). 13C{1H} NMR (100.6 MHz, CDCl3): δ 113.9, 115.9, 116.3 (q, JCF = 292.0 Hz,
4
(100.6 MHz, CDCl3): δ 24.8, 49.3 (q, JCF = 2.7 Hz), 102.0 (q, CF3), 128.5, 128.8, 129.4, 130.0, 131.2, 132.9, 135.2, 135.9,
3JCF = 3.0 Hz, C
HvCCF3), 121.7 (q, JCF = 277.9 Hz, CF3), 137.9, 140.4 (q, 4JCF = 3.2 Hz, C
vC–CvO), 147.7, 180.8 (q, 2JCF
1
123.9, 136.4 (q, 2JCF = 30.2 Hz, C
̲
–CF3), 144.9. Other signals are = 34.0 Hz, CvO). 19F NMR (376.5 MHz, CDCl3): δ −71.6. For
overlapped with those of the major isomer or cannot be seen the Z-isomer: 1H NMR (400.1 MHz, CDCl3): δ 7.39–7.47 (m, 5H,
3
3
4
in the spectrum due to the low concentration of the minor Ph), 7.53 (d, J = 8.0 Hz, 1H, Ar), 7.92 (dd, J = 8.0 Hz, J = 1.5
isomer. 19F NMR (376.5 MHz, CDCl3):
δ
−59.8. HRMS Hz, 1H, Ar), 8.47 (d, 4J = 1.5 Hz, 1H, Ar). Other signals are over-
+
(ESI-TOF): m/z [M + H]+ calcd for C12H14F3N2 : 243.1104; lapped with those of the major isomer. 13C{1H} NMR
found: 243.1106.
(100.6 MHz, CDCl3): δ 113.8, 115.9, 127.1, 128.7, 129.1, 132.4,
133.26, 134.9, 136.6, 139.4, 147.2. Other signals are overlapped
with those of the major isomer or cannot be seen in the spec-
trum due to the low concentration of the minor isomer. 19F
Synthesis of α,β-diaryl-CF3-enones 4 by the reactions of α-CF3-
β-aryl enamines 2 with aromatic aldehydes 3 (general
procedure)
A one-necked 50 mL round bottom flask (or 12 mL vial) was H]+ calcd for C17H10F3N2O3 : 347.0638; found: 347.0633.
NMR (376.5 MHz, CDCl3): δ −75.9. HRMS (ESI-TOF): m/z [M +
+
charged with enamine 2 (5 mmol), aromatic aldehyde 3
(5.75 mmol) and glacial acetic acid (10 mL or 5 mL for reaction
in a vial). The reaction mixture was kept at 80–90 °C under stir-
(E)-4-(2,4-Dinitrophenyl)-1,1,1-trifluoro-3-phenylbut-3-en-2-one
(4c)
ring for 6–12 hours until the aldehyde was consumed and the Obtained from enamine 2a (1.206 g, 5.0 mmol) and 2,4-dini-
corresponding benzyl ketone formed by hydrolysis of the trobenzaldehyde (1.127 g, 5.75 mmol). Dark orange viscous
1
enamine (monitored by H NMR). Volatiles were evaporated in liquid, yield 1.061 g (58%). Mixture of E- and Z-isomers: 94 : 6.
vacuo, and the residue was dissolved in CH2Cl2 (50 mL), For the E-isomer: 1H NMR (400.1 MHz, CDCl3): δ 7.03–7.08 (m,
washed with water (2 × 20 mL) and dried over Na2SO4. 2H, Ph), 7.17 (d, 3J = 8.6 Hz, 1H, Ar), 7.25–7.35 (m, 3H, Ph),
3
4
Volatiles were evaporated in vacuo, and the residue was puri- 8.13 (s, 1H, CHvC), 8.16 (dd, J = 8.6 Hz, J = 2.3 Hz, 1H, Ar),
fied by column chromatography, using appropriate mixtures of 8.96 (d, 4J = 2.3 Hz, 1H, Ar). 13C{1H} NMR (100.6 MHz, CDCl3):
1
hexane and CH2Cl2 or CH2Cl2 as eluents.
δ 116.3 (q, JCF = 291.9 Hz, CF3), 120.3, 127.3, 128.8, 129.4,
4
130.0, 131.2, 133.3, 136.8, 138.1, 140.1 (q, JCF = 3.2 Hz, C̲vC–
(E)-1,1,1-Trifluoro-4-(2-nitrophenyl)-3-phenylbut-3-en-2-one
(4a)
2
CvO), 147.5, 147.8, 180.8 (q, JCF = 35.2 Hz, CvO). 19F NMR
(376.5 MHz, CDCl3): δ −71.8. For the Z-isomer: 1H NMR
4
Obtained from enamine 2a (1.206 g, 5.0 mmol) and 2-nitro- (400.1 MHz, CDCl3): δ 7.41–7.48 (m, 4H), 7.62 (t, J = 4.0 Hz,
3
4
4
benzaldehyde (0.869 g, 5.75 mmol). Yellow oil, yield 1.225 g 2H, Ph), 8.47 (dd, J = 8.5 Hz, J = 2.3 Hz, 1H, Ar), 8.98 (d, J =
(76%). Mixture of E- and Z-isomers: 97 : 3. For the E-isomer: 1H 2.3 Hz, 1H, Ar). Other signals are overlapped with those of the
NMR (400.1 MHz, CDCl3): δ 6.93 (d, 3J = 7.8 Hz, 1H, major isomer. 13C{1H} NMR (100.6 MHz, CDCl3): δ 115.0 (q,
2-NO2C6H4), 7.02–7.10 (m, 2H, Ph), 7.21–7.30 (m, 3H, Ph), 7.34 1JCF = 292.7 Hz, CF3), 120.5, 120.6, 127.1, 127.9, 128.9, 129.1,
(td, J = 7.8 Hz, J = 1.2 Hz, 1H, 2-NO2C6H4), 7.41 (td, J = 7.8 129.4, 132.3, 132.7, 136.6, 139.7, 147.3, 186.0 (q, 2JCF = 36.8 Hz,
3
4
3
4
3
4
Hz, J = 1.2 Hz, 1H, 2-NO2C6H4), 8.14 (dd, J = 7.8 Hz, J = 1.2
C̲vO). Other signals are overlapped with those of the major
Hz, 1H, 2-NO2C6H4), 8.19 (s, 1H, CHvC). 13C{1H} NMR isomer or cannot be seen in the spectrum due to the low con-
(100.6 MHz, CDCl3): δ 116.5 (q, JCF = 292.1 Hz, CF3), 124.8, centration of the minor isomer. 19F NMR (376.5 MHz, CDCl3):
1
128.4, 128.7, 129.9, 130.1, 130.7, 131.6, 132.1, 133.4, 136.2,
δ
−75.7. HRMS (ESI-TOF): m/z [M
+
H]+ calcd for
C16H10F3N2O5+: 367.0536; found: 367.0523.
4
2
143.3 (q, JCF = 3.3 Hz, C
̲vC–CvO), 147.7, 181.1 (q, JCF =
34.5, CvO). 19F NMR (376.5 MHz, CDCl3): δ −71.3. For the
1
3
(E)-1,1,1-Trifluoro-4-(2-nitro-4-(trifluoromethyl)phenyl)-3-
phenylbut-3-en-2-one (4d)
Z-isomer: H NMR (400.1 MHz, CDCl3): δ 7.55 (td, J = 8.2 Hz,
4J = 1.1 Hz, 1H, 2-NO2C6H4), 7.61–7.67 (m, 2H, 2-NO2C6H4 and
3
4
CHvC), 8.22 (dd, J = 8.2 Hz, J = 1.1 Hz, 2-NO2C6H4). Other Obtained from enamine 2a (0.482 g, 2 mmol) and 2-nitro-4-
signals are overlapped with those of the major isomer. 19F (trifluoromethyl)benzaldehyde (0.460 g, 2.100 mmol). Orange
NMR (376.5 MHz, CDCl3): δ −76.3. HRMS (ESI-TOF): m/z [M + viscous liquid, yield 0.529 g (68%). Mixture of E- and
H]+ calcd for C16H11F3NO3 : 322.0686; found: 322.0679.
Z-isomers: 99 : 1. For the E-isomer: 1H NMR (400.1 MHz,
CDCl3): δ 7.06–7.08 (m, 2H, Ph), 7.12 (d, J = 8.2 Hz, 1H, Ar),
7.24–7.33 (m, 3H, Ph), 7.57–7.62 (m, 1H, Ar), 8.16 (s, 1H,
CHvC), 8.41 (d, 4J = 0.6 Hz, 1H, Ar). 13C{1H} NMR (100.6 MHz,
+
3
(E)-3-Nitro-4-(4,4,4-trifluoro-3-oxo-2-phenylbut-1-en-1-yl)
benzonitrile (4b)
Obtained from enamine 2a (1.206 g, 5.0 mmol) and 4-formyl- CDCl3): δ 116.5 (q, 1JCF = 291.9 Hz, CF3), 122.2 (q, 4JCF = 3.8 Hz,
1
3-nitrobenzonitrile (1.013 g, 5.75 mmol). Dark orange viscous Ar–CF3), 122.4 (q, JCF = 272.9 Hz, Ar–CF3), 128.7, 129.2, 129.8
liquid, yield 1.368 g (79%). Mixture of E- and Z-isomers: (q, 4JCF = 3.2 Hz, Ar–CF3), 130.0, 131.5, 132.1 (q, 2JCF = 34.5 Hz,
4
86 : 14. For the E-isomer: 1H NMR (400.1 MHz, CDCl3): δ Ar–CF3), 132.8, 134.3, 137.5, 141.1 (q, JCF = 3.3 Hz, C
vC–
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2
CvO), 147.7, 181.0 (q, JCF = 34.9 Hz, CvO). 19F NMR (E)-4-(3,5-Dimethyl-2-nitrophenyl)-1,1,1-trifluoro-3-phenylbut-
(376.5 MHz, CDCl3): δ −71.4 (COCF3), −64.2 (Ar–CF3). For the 3-en-2-one (4g)
Z-isomer: 1H NMR (400.1 MHz, CDCl3): δ 7.43–7.48 (m, 5H,
Obtained from enamine 2a (1.222 g, 5.065 mmol) and 3,5-
Ph), 7.54 (d, J = 8.0 Hz, 1H, Ar–CF3), 7.91 (dd, 3J = 8.0 Hz, J =
0.9 Hz, 1H, Ar–CF3), 8.47 (br s, 1H, Ar–CF3). Other signals are
overlapped with those of the major isomer. 13C{1H} NMR
(100.6 MHz, CDCl3): δ 127.2, 129.9, 132.4, 132.70, 132.71.
Other signals are overlapped with those of the major isomer or
cannot be seen in the spectrum due to the low concentration
of the minor isomer. 19F NMR (376.5 MHz, CDCl3): δ −76.0
(COCF3), −64.1 (Ar–CF3). HRMS (ESI-TOF): m/z [M + Na]+ calcd
for C17H9F6NO3Na+: 412.0379; found: 412.0391.
3
4
dimethyl-2-nitrobenzaldehyde (1.043 g, 5.821 mmol). Light beige
solid, m.p. 56–59 °C, yield 1.132 g (64%). H NMR (400.1 MHz,
1
CDCl3): δ 2.04 (s, 3H, CH3), 2.35 (s, 3H, CH3), 6.46 (s, 1H, Ar),
7.00 (s, 1H, Ar), 7.10–7.15 (m, 2H, Ph), 7.27–7.34 (m, 3H, Ph),
7.74 (s, 1H, CHvC). 13C{1H} NMR (100.6 MHz, CDCl3): δ 18.3,
1
20.9, 116.5 (q, JCF = 292.1 Hz, CF3), 127.8, 128.5, 128.8, 129.1,
4
130.0, 131.2, 132.3, 133.3, 137.7, 140.2 (q, JCF = 2.8 Hz, Cv
̲
C–
CvO), 140.9, 148.6, 181.2 (q, JCF = 34.4 Hz, CvO). 19F NMR
2
(376.5 MHz, CDCl3): δ −71.4. HRMS (ESI-TOF): m/z [M + H]+
+
calcd for C18H15F3NO3 : 350.0999; found: 350.1009.
(E)-4-(4-Chloro-2-nitrophenyl)-1,1,1-trifluoro-3-phenylbut-3-en-
2-one (4e)
(E)-1,1,1-Trifluoro-4-(6-nitrobenzo[d][1,3]dioxol-5-yl)-3-
phenylbut-3-en-2-one (4h)
Obtained from enamine 2a (1.205 g, 5 mmol) and 4-chloro-2-
nitrobenzaldehyde (0.978 g, 5.26 mmol). Pale yellow viscous
liquid, yield 1.336 g (75%). Mixture of E- and Z-isomers: 97 : 3.
Obtained from enamine 2a (1.257 g, 5.210 mmol) and 6-nitro-
benzo[d][1,3]dioxole-5-carbaldehyde (1.169 g, 5.992 mmol).
Yellow solid, m.p. 99–101 °C, yield 1.903 g (77%). Mixture of E-
1
3
For the E-isomer: H NMR (400.1 MHz, CDCl3): δ 6.87 (d, J =
8.4 Hz, 1H, Ar), 7.05–7.07 (m, 2H, Ph), 7.24–7.35 (m, 3H, Ph
1
and Z-isomers: 94 : 6. For the E-isomer: H NMR (400.1 MHz,
4
and 1H, Ar), 8.10 (s, 1H, CHvC), 8.13 (d, J = 2.0 Hz, 1H, Ar).
CDCl3): δ 5.97 (s, 2H, CH2), 6.28 (s, 1H, Ar), 7.06–7.14 (m, 2H,
Ph), 7.25–7.33 (m, 3H, Ph), 7.57 (s, 1H, Ar), 8.14 (s, 1H,
CHvC). 13C{1H} NMR (100.6 MHz, CDCl3): δ 103.4, 105.1,
1
13C{1H} NMR (100.6 MHz, CDCl3): δ 116.5 (q, JCF = 291.9 Hz,
CF3), 125.1, 128.7, 129.0, 129.1, 130.1, 131.8, 132.8, 133.5,
4
1
135.9, 136.8, 141.6 (q, JCF = 3.5 Hz, C
̲
109.6, 116.5 (q, JCF = 292.2 Hz, CF3), 127.2, 128.4, 128.7,
(q, JCF = 34.8 Hz, CvO). 19F NMR (376.5 MHz, CDCl3): δ
2
4
130.0, 132.0, 135.2, 142.3, 143.8 (q, JCF = 3.1 Hz, C
̲
−71.4. For the Z-isomer: 1H NMR (400.1 MHz, CDCl3): δ
148.6, 151.8, 180.9 (q, JCF = 34.3 Hz, CvO). 19F NMR
2
(376.5 MHz, CDCl3): δ −71.3. For the Z-isomer: 1H NMR
7.42–7.50 (m, 5H, Ph), 7.56 (s, 1H, CHvC), 7.64 (dd, J = 8.2
Hz, 4J = 2.0 Hz, 1H, Ar), 8.22 (d, 4J = 2.0 Hz, 1H, Ar).
Other signals are overlapped with those of the major isomer.
19F NMR (376.5 MHz, CDCl3): δ −76.1. HRMS (ESI-TOF): m/z
[M + NH4]+ calcd for C16H13ClF3N2O3+: 373.0561; found:
373.0566.
(400.1 MHz, CDCl3): δ 6.03 (s, 2H, 4,5-O2CH2
6.25 (s, 1H, 4,5-O2CH2-2-NO2C6H2-), 7.07–7.10 (m, 2H, Ph),
7.28–7.33 (m, 3H, Ph), 7.61 (s, 1H, 4,5-O2CH2-2-NO2C6H2-),
8.12 (s, 1H, CH
vC). 13C{1H} NMR (100.6 MHz, CDCl3): δ
̲ -2-NO2C6H2-),
̲
̲
1
103.5, 105.8, 109.9, 116.8 (q, JCF = 292.0 Hz, CF3), 127.2,
4
128.4, 128.9, 129.6, 133.4, 134.6, 141.5, 146.2 (q, JCF = 2.8 Hz,
2
Methyl-3-nitro-4-[(1E)-4,4,4-trifluoro-3-oxo-2-phenylbut-1-en-1-
yl]benzoate (4f)
C
̲
NMR (376.5 MHz, CDCl3): δ −76.2. HRMS (ESI-TOF): m/z [M +
+
H]+ calcd for C17H11F3NO5 : 366.0584; found: 366.0595.
Obtained from enamine 2a (1.205 g, 5 mmol) and methyl
4-formyl-3-nitrobenzoate (1.097 g, 2.25 mmol). Yellow viscous
liquid, yield 1.321 g (70%). Mixture of E- and Z-isomers: 96 : 4.
(E)-1,1,1-Trifluoro-4-(3-methoxy-2-nitrophenyl)-3-phenylbut-3-
en-2-one (4i)
1
For the E-isomer: H NMR (400.1 MHz, CDCl3): δ 3.94 (s, 3H,
CH3), 7.02–7.07 (m, 3H, Ar, Ph), 7.24–7.31 (m, 3H, Ph), 7.98 Obtained from enamine 2a (1.206 g, 5.0 mmol) and
3
4
(dd, J = 8.1 Hz, J = 1.3 Hz, 1H, Ar), 8.17 (s, 1H, CHvC), 8.77 3-methoxy-2-nitrobenzaldehyde (1.042 g, 5.75 mmol). Beige
(d, 4J = 1.3 Hz, 1H, Ar). 13C{1H} NMR (100.6 MHz, CDCl3): δ viscous liquid, yield 1.054 g (60%). Mixture of E- and
1
52.9, 116.5 (q, JCF = 291.9 Hz, CF3), 125.9, 128.6, 129.1, 130.1, Z-isomers: 98 : 2. For the E-isomer: 1H NMR (400.1 MHz,
4
3
131.7, 131.8, 132.1, 133.7, 134.8, 137.2, 141.9 (q, JCF = 3.1 Hz, CDCl3): δ 3.88 (s, 3H, CH3), 6.38 (d, J = 8.2 Hz, 1H, Ar), 6.95
2
3
3
C̲
NMR (376.5 MHz, CDCl3): δ −71.5. For the Z-isomer: H NMR (m, 2H, Ph), 7.28–7.35 (m, 3H, Ph), 7.67 (s, 1H, CHvC). 13C
1
(400.1 MHz, CDCl3): δ 7.44–7.49 (m, 5H, Ph), 7.63 (s, 1H, {1H} NMR (100.6 MHz, CDCl3): δ 56.5, 113.6, 116.4 (q, JCF
=
1
3
4
4
CHvC), 8.29 (dd, J = 7.9 Hz, J = 1.4 Hz, 1H, Ar), 8.85 (d, J = 292.1 Hz, CF3), 121.8, 128.2, 128.6, 129.0, 129.9, 130.9, 132.0,
4
1.3 Hz, 1H, Ar). Other signals are overlapped with those of the 138.2 (q, JCF = 2.9 Hz, C̲vC–CvO), 138.9, 141.0, 151.1, 181.1
major isomer. 13C{1H} NMR (100.6 MHz, CDCl3): δ 127.2, (q, JCF = 34.4 Hz, CvO). 19F NMR (376.5 MHz, CDCl3): δ
2
1
129.2, 129.8. Other signals are overlapped with those of the −71.4. For the Z-isomer: H NMR (400.1 MHz, CDCl3): δ 3.89
major isomer or cannot be seen in the spectrum due to the (s, 3H, CH3), 6.85 (d, 3J = 7.7 Hz, 1H, Ar), 7.38–7.44 (m, 3H, Ph
low concentration of the minor isomer. 19F NMR (376.5 MHz, and 1H, CHvC). Other signals are overlapped with those of
CDCl3): δ −76.2. HRMS (ESI-TOF): m/z [M + H]+ calcd for the major isomer. 13C{1H} NMR (100.6 MHz, CDCl3): δ 113.6,
1
C18H13F3NO5+: 380.0740; found: 380.0731.
115.1 (q, JCF = 292.8 Hz, CF3), 121.0, 126.9, 129.1, 129.7,
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131.7, 133.9, 140.0, 140.8, 151.3, 187.5 (q, JCF = 37.0 Hz, m.p. 86–88 °C, yield 1.482 g (88%). Mixture of E- and
CvO). Other signals are overlapped with those of the major Z-isomers: 97 : 3. For the E-isomer: 1H NMR (400.1 MHz,
isomer or cannot be seen in the spectrum due to the low con- CDCl3): δ 3.75 (s, 3H, CH3), 6.77 (d, 3J = 8.8 Hz, 2H,
centration of the minor isomer. 19F NMR (376.5 MHz, CDCl3): 4-MeOC6H4), 6.94–7.01 (m, 2H, 4-MeOC6H4 and 1H,
3
4
δ
−76.0. HRMS (ESI-TOF): m/z [M
+
H]+ calcd for 2-NO2C6H4), 7.37 (td, J = 7.8 Hz, J = 1.5 Hz, 1H, 2-NO2C6H4),
C17H13F3NO4+: 352.0791; found: 352.0791.
7.42 (td, J = 7.8 Hz, J = 1.5 Hz, 1H, 2-NO2C6H4), 8.11 (s, 1H,
3
4
CHvC), 8.14 (dd, J = 7.8 Hz, J = 1.5 Hz, 1H, 2-NO2C6H4). 13C
3
4
(E)-4-(3,6-Dimethoxy-2-nitrophenyl)-1,1,1-trifluoro-3-
phenylbut-3-en-2-one (4j)
1
{1H} NMR (100.6 MHz, CDCl3): δ 55.1, 113.9, 116.6 (q, JCF
=
292.3 Hz, CF3), 124.1, 124.8, 129.7, 131.0, 131.5, 131.7, 133.4,
4
Obtained from enamine 2a (0.455 g, 1.887 mmol) and 3,6- 136.0, 142.4 (q, JCF = 2.6 Hz, C̲vC–CvO), 147.8, 159.8, 181.6
dimethoxy-2-nitrobenzaldehyde (0.458 g, 2.170 mmol). Yellow (q, JCF = 34.3 Hz, CvO). 19F NMR (376.5 MHz, CDCl3): δ
2
solid, m.p. 92–94 °C, yield 0.489 g (68%). Mixture of E- and −70.2. For the Z-isomer: 19F NMR (376.5 MHz, CDCl3): δ −75.2.
+
Z-isomers: 94 : 6. For the E-isomer: 1H NMR (400.1 MHz, CDCl3): HRMS (ESI-TOF): m/z [M + NH4]+ calcd for C17H16F3N2O4 :
δ 3.44 (s, 3H, CH3), 3.81 (s, 3H, CH3), 6.76 (d, 3J = 9.2 Hz, 1H, Ar), 369.1057; found: 369.1052.
6.92 (d, 3J = 9.2 Hz, 1H, Ar), 7.02–7.07 (m, 2H, Ph), 7.19–7.27 (m,
(E)-3-(4-Chlorophenyl)-1,1,1-trifluoro-4-(2-nitrophenyl)but-3-
3H, Ph), 7.58 (s, 1H, CHvC). 13C{1H} NMR (100.6 MHz, CDCl3):
1
en-2-one (4m)
δ 55.7, 56.7, 113.6, 114.2, 116.4 (q, JCF = 292.1 Hz, CF3), 117.9,
127.8, 128.7, 129.2 132.8, 136.2 (q, JCF = 2.9 Hz, Cv
4
̲
C–CvO), Obtained from enamine 2c (1.375 g, 5 mmol) and 2-nitroben-
140.3, 140.4, 144.8, 149.3, 180.8 (q, JCF = 34.7 Hz, CvO). 19F zaldehyde (0.808 g, 5.35 mmol). Pale brown solid,
2
NMR (376.5 MHz, CDCl3): δ −71.3. For the Z-isomer: H NMR m.p. 48–50 °C, yield 1.072 g (60%). 1H NMR (400.1 MHz,
1
(400.1 MHz, CDCl3): δ 6.97 (d, 3J = 7.5 Hz, 1H, Ar), 7.42–7.38 (m, CDCl3): δ 6.93 (d, J = 7.8 Hz, 1H, 2-NO2C6H4), 7.01 (d, J = 8.5
3
3
3
3H, Ph). Other signals are overlapped with those of the major Hz, 2H, 4-ClC6H4), 7.22 (d, J = 8.5 Hz, 2H, 4-ClC6H4), 7.40 (td,
isomer. 13C{1H} NMR (100.6 MHz, CDCl3): δ 113.7, 127.7, 128.8, 3J = 7.7 Hz, 4J = 1.3 Hz, 1H, 2-NO2C6H4), 7.46 (td, 3J = 7.7 Hz, 4J
129.4, 140.3, 144.9. Other signals are overlapped with those of = 1.3 Hz, 1H, 2-NO2C6H4), 8.16 (dd, 3J = 7.7 Hz, 4J = 1.3 Hz, 1H,
the major isomer or cannot be seen in the spectrum due to the 2-NO2C6H4), 8.22 (s, 1H, CHvC). 13C{1H} NMR (100.6 MHz,
low concentration of the minor isomer. 19F NMR (376.5 MHz, CDCl3): δ 116.5 (q, JCF = 291.9 Hz, CF3), 124.9, 128.8, 130.2,
1
CDCl3): δ −74.2. HRMS (ESI-TOF): m/z [M + H]+ calcd for 130.5, 130.6, 131.5, 131.6, 133.7, 134.9, 135.1, 144.0, 147.7,
+
C18H15F3NO5 : 382.0897; found: 382.0897.
180.8 (q, 2JCF = 34.6 Hz, CvO). 19F NMR (376.5 MHz, CDCl3): δ
−70.2. HRMS (ESI-TOF): m/z [M
+
Na]+ calcd for
(E)-1,1,1-Trifluoro-4-(5-fluoro-2-nitrophenyl)-3-phenylbut-3-en-
2-one (4k)
C16H9ClF3NO3Na+: 378.0115; found: 378.0109.
(E)-1,1,1-Trifluoro-3-(4-fluorophenyl)-4-(2-nitrophenyl)-but-3-
en-2-one (4n)
Obtained from enamine 2a (1.206 g, 5.0 mmol) and 5-fluoro-2-
nitrobenzaldehyde (0.972 g, 5.75 mmol). Beige crystals,
m.p. 44–45 °C, yield 1.018 g (60%). Mixture of E- and Obtained from enamine 2d (1.036 g, 4 mmol) and 2-nitroben-
Z-isomers: 99 : 1. For the E-isomer: 1H NMR (400.1 MHz, zaldehyde (0.635 g, 4.205 mmol). Yellow-red viscous oil, yield
3
4
CDCl3): δ 6.64 (dd, J = 8.7 Hz, J = 2.7 Hz, 1H, Ar), 7.07–7.11 1.165 g (86%). Mixture of E- and Z-isomers: 99 : 1. For the
(m, 2H, Ph and 1H, Ar), 7.26–7.33 (m, 3H, Ph), 8.17 (s, 1H, E-isomer: 1H NMR (400.1 MHz, CDCl3): δ 6.90–6.97 (m, 1H,
CHvC), 8.27 (dd, 3J = 9.2 Hz, 3J = 5.0 Hz, 1H, Ar). 13C{1H} 2-NO2C6H4 and 2H, 4-FC6H4), 7.02–7.08 (m, 2H, 4-FC6H4),
1
NMR (100.6 MHz, CDCl3): δ 116.4 (q, JCF = 292.0 Hz, CF3), 7.36–7.48 (m, 2H, 2-NO2C6H4), 8.15 (d, 3J = 8.1 Hz, 1H,
2
2
116.9 (d, JCF = 23.4 Hz, Ar), 118.5 (d, JCF = 25.3 Hz, Ar), 127.7 2-NO2C6H4), 8.21 (s, 1H, CHvC). 13C{1H} NMR (100.6 MHz,
3
3
2
1
(d, JCF = 10.2 Hz, Ar), 128.6, 129.0, 129.9, 131.5, 133.8 (d, JCF CDCl3): δ 115.6 (d, JCF = 21.7 Hz, 4-FC6H4), 116.5 (q, JCF
=
4
4
= 9.8 Hz, Ar), 136.7, 141.9 (q, JCF = 2.8 Hz, C̲vC–CvO), 143.8 292.1 Hz, CF3), 124.9, 128.1 (d, JCF = 3.5 Hz, 4-FC6H4), 130.0,
4
1
3
(d, JCF = 2.8 Hz, Ar), 164.4 (d, JCF = 258.9 Hz, Ar), 181.0 (q, 130.6, 131.5, 132.1 (d, JCF = 8.3 Hz, 4-FC6H4), 133.6, 135.2,
2JCF = 34.7 Hz, CvO). 19F NMR (376.5 MHz, CDCl3): δ −71.6 143.9 (q, JCF = 3.3 Hz, C
̲vC–CvO), 147.7, 162.7 (d, JCF =
4
1
(CF3), −103.04 to −103.11 (Ar–F). For the Z-isomer: 1H NMR 249.3 Hz, C–F), 181.0 (q, JCF = 34.6 Hz, CvO). 19F NMR
(400.1 MHz, CDCl3): δ 7.43 (br s, 5H, Ph), 7.58 (s, 1H, CHvC), (376.5 MHz, CDCl3): δ −71.2 (CF3), −112.67 to −113.15
8.25 (dd, 3J = 9.1 Hz, 3J = 5.0 Hz, 1H, Ar). Other signals are (4-FC6H4). For the Z-isomer: 19F NMR (376.5 MHz, CDCl3): δ
overlapped with those of the major isomer. 19F NMR −76.1 (CF3), −112.10 to −112.24 (4-F-C6H3). HRMS (ESI-TOF):
(376.5 MHz, CDCl3): δ −76.0 (CF3), −102.41, −102.48 (Ar–F). m/z [M + Na]+ calcd for C16H9F4NO3Na+: 362.0411; found:
2
HRMS (ESI-TOF): m/z [M
+ MeOH +
NH4]+ calcd for 362.0414.
C17H17F4N2O4+: 389.1119; found: 389.1113.
(E)-1,1,1-Trifluoro-4-(2-nitrophenyl)-3-(4-
(E)-1,1,1-Trifluoro-3-(4-methoxyphenyl)-4-(2-nitrophenyl)but-3-
trifluoromethylphenyl)but-3-en-2-one (4o)
en-2-one (4l)
Obtained from enamine 2f (0.473 g, 1.53 mmol) and 2-nitro-
Obtained from enamine 2b (1.355 g, 5 mmol) and 2-nitroben- benzaldehyde (0.266 g, 1.759 mmol). Beige viscous liquid,
1
3
zaldehyde (0.801 g, 5.305 mmol). Light yellow solid, yield 0.316 g (53%). H NMR (400.1 MHz, CDCl3): δ 6.89 (d, J
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3
4
= 7.7 Hz, 1H, 2-NO2C6H4), 7.20 (d, J = 8.1 Hz, 2H, 4-CF3C6H4), 3J = 8.0 Hz, J = 1.5 Hz, 1H, Ar), 8.31 (s, 1H, CHvC). 13C{1H}
7.39 (td, 3J = 7.6 Hz, 4J = 1.2 Hz, 1H, 2-NO2C6H4), 7.43–7.50 (m, NMR (100.6 MHz, CDCl3): δ 116.4 (q, JCF = 291.8 Hz, CF3),
1
3
1H, 2-NO2C6H4), 7.52 (d, J = 8.1 Hz, 2H, 4-CF3C6H4), 8.19 (dd, 124.3, 124.8, 127.7, 130.2, 130.3, 130.45, 130.51, 131.8, 132.6,
3J = 8.2 Hz, J = 1.2 Hz, 1H, 2-NO2C6H4), 8.30 (s, 1H, CHvC). 133.7, 134.2, 136.1, 144.0 (q, JCF = 3.1 Hz, C
̲
4
4
13C{1H} NMR (100.6 MHz, CDCl3): δ 116.5 (q, JCF = 291.8 Hz, 180.0 (q, 2JCF = 34.9 Hz, C
vO). 19F NMR (376.5 MHz, CDCl3): δ
1
CF3), 123.7 (q, 1JCF = 272.3 Hz, 4-C
̲
F3C6H4), 125.0, 125.4 (q, 4JCF −71.9. For the Z-isomer: 1H NMR (400.1 MHz, CDCl3): δ
= 3.7 Hz, 4-CF3C6
̲
H4), 130.2, 130.4, 130.68 (q, 2JCF = 32.8 Hz, C
̲
7.19–7.23 (m, 1H), 7.28–7.35 (m, 2H), 7.60–7.65 (m, 1H),
CF3), 130.74, 131.4, 133.8, 134.8, 136.0, 145.1 (q, JCF = 3.2 Hz, 7.65–7.72 (m, 1H), 8.25 (dd, 3J = 8.3 Hz, 4J = 1.1 Hz, 1H,
4
2
C̲
vC–CvO), 147.6, 180.5 (q, JCF = 35.0 Hz, CvO). 19F NMR 2-NO2C6H4). Other signals are overlapped with those of the
(376.5 MHz, CDCl3): δ −71.1 (COCF3), −63.8 (4-CF3C6H4). major isomer. 19F NMR (376.5 MHz, CDCl3): δ −75.3. HRMS
+
HRMS (ESI-TOF): m/z [M + K]+ calcd for C17H9F6NO3K+: (ESI-TOF): m/z [M
+
NH4]+ calcd for C16H13BrF3N2O3 :
428.0118; found: 428.0124.
417.0056, 419.00361; found: 417.0046, 419.0031.
(E)-1,1,1-Trifluoro-3-(4-nitrophenyl)-4-(2-nitrophenyl)but-3-en-
(3E)-1,1,1-Trifluoro-3-(3-nitrophenyl)-4-(2-nitrophenyl)-but-3-
2-one (4p)
en-2-one (4s)
Obtained from enamine 2h (0.286 g, 1.0 mmol) and 2-nitro- Obtained from enamine 2i (0.98 g, 3.423 mmol) and 2-nitro-
benzaldehyde (0.174 g, 1.15 mmol). White crystals, benzaldehyde (0.595 g, 3.936 mmol). Light beige crystals,
m.p. 129–132 °C, yield 0.282 g (77%). 1H NMR (400.1 MHz, m.p. 92–93 °C, yield 0.98 g (78%). 1H NMR (400.1 MHz,
3
3
3
CDCl3): δ 6.88 (d, J = 7.6 Hz, 1H, 2-NO2C6H4), 7.27 (d, J = 8.7 CDCl3): δ 6.92 (d, J = 7.7 Hz, 1H, 2-NO2C6H4), 7.35–7.52 (m,
3
4
Hz, 2H, 4-NO2C6H4), 7.41 (t, J = 7.6 Hz, 1H, 2-NO2C6H4), 7.50 2H, 2-NO2C6H4 and 2H, 3-NO2C6H4), 7.99 (pt, J ∼ 1.9 Hz, 1H,
(t, 3J = 7.8 Hz, 1H, 2-NO2C6H4), 8.12 (d, 3J = 8.7 Hz, 2H, 3-NO2C6H4), 8.14 (ddd, 3J = 8.2 Hz, 4J = 2.1 Hz, 4J = 1.1 Hz, 1H,
3
3
4
4-NO2C6H4), 8.22 (d, J = 8.2 Hz, 1H, 2-NO2C6H4), 8.35 (s, 1H, 3-NO2C6H4), 8.20 (dd, J = 8.1 Hz, J = 1.0 Hz, 1H, 2-NO2C6H4),
CHvC). 13C{1H} NMR (100.6 MHz, CDCl3): δ 116.4 (q, JCF
=
8.37 (s, 1H, CHvC). 13C{1H} NMR (100.6 MHz, CDCl3): δ 116.4
1
1
291.8 Hz, CF3), 123.6, 125.2, 129.9, 130.7, 131.2, 131.4, 133.9, (q, JCF = 291.7 Hz, CF3), 123.7, 125.2, 125.3, 129.6, 129.9,
4
4
134.1, 139.0, 145.8 (q, JCF = 3.4 Hz, C̲vC–CvO), 147.5, 147.8, 130.7, 131.3, 133.7, 133.8, 133.9, 136.4, 145.8 (q, JCF = 3.5 Hz,
180.1 (q, 2JCF = 35.3 Hz, CvO). 19F NMR (376.5 MHz, CDCl3): δ
C̲
vC–CvO), 147.5, 148.0, 180.2 (q, JCF = 35.3 Hz, CvO). 19F
2
−71.2. HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H10F3N2O5
:
NMR (376.5 MHz, CDCl3): δ −71.14. HRMS (ESI-TOF): m/z [M +
+
+
367.0536; found: 367.0547.
H]+ calcd for C16H10F3N2O5 : 367.0536; found: 367.0546.
(3E)-Methyl 4-(4,4,4-trifluoro-1-(2-nitrophenyl)-3-oxobut-1-en-2- (E)-1,1,1-Trifluoro-4-(2-nitrophenyl)-3-(4-(pyrrolidin-1-yl)
yl)benzoate (4q) phenyl)but-3-en-2-one (4t)
Obtained from enamine 2j (0.748 g, 2.5 mmol) and 2-nitroben- Obtained from enamine 2e (1.24 g, 4 mmol) and 2-nitrobenzal-
zaldehyde (0.408 g, 2.702 mmol). Light yellow crystals, dehyde (0.653 g, 4.32 mmol). Dark red viscous oil, yield
m.p. 152–153 °C, yield 0.597 g (63%). Mixture of E- and 1.291 g (83%). Mixture of E- and Z-isomers: 98 : 2. 1H NMR
Z-isomers: 99.6 : 0.4. For the E-isomer: 1H NMR (400.1 MHz, (400.1 MHz, CDCl3):
δ
1.93–2.01 (m, 4H, N(CH2CH2 2
̲ ) ),
CDCl3): δ 3.85 (s, 3H, CH3), 6.89 (d, 3J = 7.7 Hz, 1H, 3.22–3.25 (m, 4H, N(CH
̲
2CH2)2), 6.39 (d, 3J = 8.7 Hz, 2H, Ar),
3
2-NO2C6H4), 7.14 (d, J = 8.3 Hz, 2H, 4-CO2MeC6H4), 7.34 (td, 6.88 (d, 3J = 8.7 Hz, 2H, Ar), 7.02–7.07 (m, 1H, 2-NO2C6H4),
3J = 7.6 Hz, 4J = 1.1 Hz, 1H, 2-NO2C6H4), 7.39–7.45 (m, 1H, 7.34–7.41 (m, 2H, 2-NO2C6H4), 7.93 (s, 1H, CHvC), 8.10–8.15
3
2-NO2C6H4), 7.89 (d, J = 8.3 Hz, 2H, 4-CO2MeC6H4), 8.14 (dd, (m, 1H, 2-NO2C6H4). 13C{1H} NMR (100.6 MHz, CDCl3): δ 25.4,
4
1
3J = 8.2 Hz, J = 1.0 Hz, 1H, 2-NO2C6H4), 8.26 (s, 1H, CHvC). 47.4, 111.3, 116.7 (q, JCF = 292.3 Hz, CF3), 118.2, 124.7, 129.3,
13C{1H} NMR (100.6 MHz, CDCl3): δ 52.1, 116.4 (q, 1JCF = 291.9 131.4, 131.8, 132.0, 133.3, 136.9, 139.7 (q, JCF = 3.5 Hz, C
̲
4
Hz, CF3), 124.9, 129.5, 130.21, 130.25, 130.3, 131.4, 133.6, CvO), 147.9, 148.0, 182.6 (q, JCF = 33.9 Hz, CvO). 19F NMR
2
4
4
135.2, 136.8, 144.5 (q, JCF = 3.3 Hz, C̲vC–CvO), 147.5, 166.3, (376.5 MHz, CDCl3): δ −71.4 (d, J = 0.6 Hz, 3F, CF3). For the
180.5 (q, 2JCF = 34.9 Hz, CvO). 19F NMR (376.5 MHz, CDCl3): δ Z-isomer: 19F NMR (376.5 MHz, CDCl3): δ −76.5. HRMS
+
−71.2 (d, 4J = 0.9 Hz, 3F, CF3). For the Z-isomer: 19F NMR (ESI-TOF): m/z [M + H]+ calcd for C20H18F3N2O3 : 391.1264;
(376.5 MHz, CDCl3): δ −76.2. HRMS (ESI-TOF): m/z [M + H]+ found: 391.1255.
calcd for C18H13F3NO5+: 380.0740; found: 380.0744.
(E)-1,1,1-Trifluoro-4-(2-nitrophenyl)-3-(4-(pyrrolidine-1-
(3E)-3-(2-Bromophenyl)-1,1,1-trifluoro-4-(2-nitrophenyl)but-3-
carbonyl)phenyl)but-3-en-2-one (4u)
en-2-one (4r)
Obtained from enamine 2k (1.698 g, 5 mmol) and 2-nitroben-
Obtained from enamine 2g (2.401 g, 7.5 mmol) and 2-nitro- zaldehyde (0.757 g, 5.01 mmol). Beige viscous liquid, yield
benzaldehyde (1.139 g, 7.537 mmol). Light yellow viscous 1.464 g (70%). 1H NMR (400.1 MHz, CDCl3): δ 1.95–2.14 (m,
liquid, yield 1.861 g (62%). Mixture of E- and Z-isomers: 96 : 4. 4H, 2NCH2CH2
̲
), 3.52 (br s, 2H, N(CH2
̲ CH2)2), 3.74 (br s, 2H,
For the E-isomer: 1H NMR (400.1 MHz, CDCl3): δ 6.92–6.97 (m, N(CH
2̲ CH2)2), 6.88 (d, J = 7.6 Hz, 1H, 2-NO2C6H4), 7.22 (d, J =
1H, Ar), 7.08 (dd, 3J = 7.3 Hz, 4J = 1.2 Hz, 1H, Ar), 7.11–7.18 (m, 8.2 Hz, 2H, Ar), 7.36–7.51 (m, 2H, 2-NO2C6H4 and 2H, Ar), 8.19
2H, Ar), 7.36–7.49 (m, 2H, Ar), 7.50–7.59 (m, 1H, Ar), 8.15 (dd, (dd, J = 8.2 Hz, J = 0.8 Hz, 1H, 2-NO2C6H4), 8.35 (s, 1H,
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CHvC). 13C{1H} NMR (100.6 MHz, CDCl3): δ 24.1, 26.1, 46.0, 80 °C under stirring for 0.5–1 hours until the Fe powder dis-
1
49.3, 116.3 (q, JCF = 292.1 Hz, CF3), 124.6, 127.0, 129.95, solved (after 10–15 min the gas pressure must be released!)
4
129.99, 130.1, 131.3, 133.4, 133.5, 135.1, 137.0, 144.0 (q, JCF
=
and the vigorous reaction finished. Volatiles were evaporated
2
3.0 Hz, C
CvO). 19F NMR (376.5 MHz, CDCl3):
(ESI-TOF): m/z [M + H]+ calcd for C21H18F3N2O4 : 419.1213; ated, washed with water (10 mL) and dried over Na2SO4.
found: 419.1219. Volatiles were evaporated in vacuo, to give pure quinoline 5.
̲
δ
+
(E)-1,1,1-Trifluoro-4-(2-nitrophenyl)-3-(pyridine-4-yl)but-3-en-2- One pot synthesis of quinolines 5 by the reduction of nitro-
one (4v)
substituted CF3-enones 4 starting from enamines 2 (general
procedure B from pure enamine; procedure C from crude
enamine)
Obtained from enamine 2l (1.017 g, 4.2 mmol) and 2-nitroben-
zaldehyde (0.728 g, 4.82 mmol). Dark orange viscous liquid,
yield 0.568 g (42%). The compound is quite unstable and An aliquot of the reaction mixture for the synthesis of ketone 4
forms black tar upon standing for several days. 1H NMR (∼0.5 mmol, 1 mL) was placed into a 12 mL vial with a screw
(400.1 MHz, CDCl3): δ 6.90 (d, 3J = 7.7 Hz, 1H, 2-NO2C6H4), cap, and water (0.1 mL) and Fe powder (0.084 g, 1.5 mmol)
6.97–7.03 (m, 2H, Py), 7.40 (td, 3J = 7.6 Hz, 4J = 1.1 Hz, 1H, were then added. The reaction mixture was kept at 80 °C under
3
4
2-NO2C6H4), 7.49 (td, J = 8.0 Hz, J = 0.9 Hz, 1H, 2-NO2C6H4), stirring for 0.5–1 hours until the Fe powder dissolved (after
3
4
8.21 (dd, J = 8.2 Hz, J = 1.1 Hz, 1H, 2-NO2C6H4), 8.33 (s, 1H, 10–15 min the gas pressure must be released!) and the vigor-
CHvC), 8.47–8.55 (m, 2H, Py). 13C{1H} NMR (100.6 MHz, ous reaction finished. Volatiles were evaporated in vacuo, and
1
CDCl3): δ 116.4 (q, JCF = 291.9 Hz, CF3), 125.0, 125.1, 129.9, the residue was dispersed between CH2Cl2 (5–10 mL) and 6 M
4
130.6, 131.2, 133.7, 133.9, 140.5, 145.5 (q, JCF = 3.3 Hz, C
̲
CvO), 147.5, 150.0, 180.0 (q, JCF = 35.3, CvO). 19F NMR water (10 mL) and dried over Na2SO4. Volatiles were evaporated
2
(376.5 MHz, CDCl3): δ −71.3 (d, 4J = 0.8 Hz, 3F, CF3). HRMS in vacuo, and the residue was purified by column chromato-
(ESI-TOF): m/z [M + H]+ calcd for C15H10F3N2O3 : 323.0638; graphy, using appropriate mixtures of hexane and CH2Cl2 or
+
found: 323.0645.
CH2Cl2 as eluents.
(E)-1,1,1-Trifluoro-3-(4-methoxyphenyl)-4-(2-nitrothiophen-3-yl) 3-Phenyl-2-(trifluoromethyl)quinoline (5a)
but-3-en-2-one (4w)
Obtained from ketone 4a (0.160 g, 0.5 mmol) by procedure A
Obtained from enamine 2b (0.140 g, 0.516 mmol) and or by procedure B (2 mmol). Pale brown solid, m.p. 71–73 °C,
2-nitrothiophene-3-carbaldehyde (0.092 g, 0.59 mmol). Yellow- yield 0.130 g (95%, A) or 0.420 g (77%, B). 1H NMR
brown solid, m.p. 125–127 °C, yield 0.103 g (61%). Mixture of (400.1 MHz, CDCl3): δ 7.40–7.48 (m, 5H), 7.67 (ptd, 3J = 7.6 Hz,
E- and Z-isomers: 87 : 13. For the E-isomer: 1H NMR 4J = 1.0 Hz, 1H), 7.81 (ptd, 3J = 7.7 Hz, 4J = 1.4 Hz, 1H), 7.86 (d,
3
(400.1 MHz, CDCl3): δ 3.82 (s, 3H, CH3), 6.26 (d, J = 5.7 Hz, 3J = 8.2 Hz, 1H), 8.15 (s, 1H), 8.27 (d, 3J = 8.6 Hz, 1H) ppm. 13
C
1H, 2-NO2SC4H2), 6.90 (d, 3J = 8.7 Hz, 2H, 4-MeOC6H4), 7.06 {1H} NMR (100.6 MHz, CDCl3): δ 121.8 (q, JCF = 276.6 Hz,
1
(d, 3J = 8.7 Hz, 2H, 4-MeOC6H4), 7.19 (d, 3J = 5.7 Hz, 1H, CF3), 127.4, 128.0, 128.1, 128.3, 129.0, 129.2 (q, JCF = 1.5 Hz),
4
2-NO2SC4H2), 8.37 (s, 1H). 13C{1H} NMR (100.6 MHz, CDCl3): δ 129.8, 130.6, 133.4, 137.4, 139.7, 145.4 (q, JCF = 32.4 Hz),
2
55.3, 114.4, 116.6 (q, JCF = 292.1 Hz, CF3), 124.5, 128.5, 129.1, 145.6 ppm. 19F NMR (376.5 MHz, CDCl3): δ −62.4 (CF3) ppm.
1
4
129.5, 131.2, 135.3 (q, JCF = 3.1 Hz, C
vC–CvO), 135.8, 138.2, HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H11F3N+: 274.0838;
160.5, 181.7 (q, JCF = 34.5, CvO). 19F NMR (376.5 MHz, found: 274.0836.
2
4
1
CDCl3): δ −71.3 (d, J = 0.7 Hz, 3F, CF3). For the Z-isomer: H
NMR (400.1 MHz, CDCl3): δ 3.85 (s, 3H, CH3), 6.96 (d, J = 8.8
3
3-Phenyl-2-(trifluoromethyl)quinoline-7-carbonitrile (5b)
Hz, 2H, 4-MeOC6H4), 7.34 (d, 3J = 8.8 Hz, 2H, 4-MeOC6H4), Obtained from ketone 4b by procedure B (0.5 mmol). Pale
7.47 (d, 3J = 5.6 Hz, 1H, 2-NO2SC4H2), 7.62 (s, 1H). Other green solid, m.p. 145–147 °C, yield 0.096 g (64%). 1H NMR
signals are overlapped with those of the major isomer. 13C{1H} (400.1 MHz, CDCl3): δ 7.39–7.41 (m, 2H), 7.45–7.50 (m, 3H),
3
4
3
NMR (100.6 MHz, CDCl3): δ 55.4, 114.7, 124.8, 128.7, 130.8, 7.82 (dd, J = 8.4 Hz, J = 1.5 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H),
136.0, 139.8, 150.8, 161.1. Other signals are overlapped with 8.25 (s, 1H), 8.61 (s, 1H) ppm. 13C{1H} NMR (100.6 MHz,
1
those of the major isomer or cannot be seen in the spectrum CDCl3): δ 114.0, 117.8, 121.2 (q, JCF = 277.0 Hz, CF3), 128.2,
due to the low concentration of the minor isomer. 19F NMR 128.7, 128.96 (q, JCF = 1.3 Hz), 129.0, 129.4, 130.1, 135.7,
4
(376.5 MHz, CDCl3): δ −76.0. HRMS (ESI-TOF): m/z [M + MeOH 136.17, 136.25, 139.7, 144.3, 147.4 (q, JCF = 33.2 Hz) ppm. 19F
2
+ NH4]+ calcd for C16H18F3N2O5S+: 407.0883; found: 407.0832.
NMR (376.5 MHz, CDCl3): δ −63.0 (CF3) ppm. HRMS
+
(ESI-TOF): m/z [M + H]+ calcd for C17H10F3N2 : 299.0791;
Synthesis of quinolines 5 by the reduction of nitro-substituted
CF3-enones 4 (general procedure A)
found: 299.0789.
3-Phenyl-2-(trifluoromethyl)quinolin-7-amine (5c)
A 12 mL vial with a screw cap was charged with ketone 4
(0.5 mmol), glacial acetic acid (1 mL), water (0.1 mL) and Fe Obtained from ketone 4c by procedure B (0.5 mmol). Light
1
powder (0.084 g, 1.5 mmol). The reaction mixture was kept at yellow powder, m.p. 174–175 °C, yield 0.087 g (60%). H NMR
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3
(400.1 MHz, CDCl3): δ 4.22 (s, 2H, NH2), 7.09 (dd, J = 8.7 Hz, NMR (376.5 MHz, CDCl3):
δ
−62.4 (CF3) ppm. HRMS
4J = 2.0 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.37–7.46 (m, 5H), (ESI-TOF): m/z [M + H]+ calcd for C18H15F3N+: 302.1151; found:
4
7.65 (d, 3J = 8.7 Hz, 1H), 7.96 (s, 1H) ppm. 13C{1H} NMR 302.1154.
1
(100.6 MHz, CDCl3): δ 108.8, 121.2, 121.9 (q, JCF = 276.6 Hz,
CF3), 122.3, 127.7, 127.9, 128.6, 129.3, 129.8, 137.9, 139.3,
7-Phenyl-6-(trifluoromethyl)-[1,3]dioxolo[4,5-g]quinoline (5h)
2
145.4 (q, JCF = 31.9 Hz), 147.6, 148.7 ppm. 19F NMR
Obtained from ketone 4h (0.183 g, 0.5 mmol) by procedure
A. Yellow-brown solid, m.p. 104–107 °C, yield 0.158 g (>99%).
1H NMR (400.1 MHz, CDCl3): δ 6.17 (s, 2H, CH2), 7.08 (s, 1H),
7.36–7.40 (m, 2H), 7.41–7.45 (m, 3H), 7.50 (s, 1H), 7.94 (s, 1H)
ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 101.9, 102.1, 105.7,
(376.5 MHz, CDCl3): δ −62.5 (CF3) ppm. HRMS (ESI-TOF): m/z
[M + H]+ calcd for C16H12F3N2+: 289.0947; found: 289.0952.
3-Phenyl-2,7-bis(trifluoromethyl)quinoline (5d)
Obtained from ketone 4d by procedure B (0.5 mmol). White
solid, m.p. 88–90 °C, yield 0.133 g (78%). 1H NMR (400.1 MHz,
1
122.0 (q, JCF = 276.2 Hz, CF3), 126.0, 127.9, 129.1, 131.9,
2
137.5, 138.1, 142.8 (q, JCF = 32.4 Hz), 144.0, 149.8, 151.7.
3
CDCl3): δ 7.40–7.44 (m, 2H), 7.47–7.50 (m, 3H), 7.85 (dd, J =
+
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H11F3NO2 :
4
3
8.6 Hz, J = 1.5 Hz, 1H), 8.02 (d, J = 8.6 Hz, 1H), 8.25 (s, 1H),
8.59 (s, 1H) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 121.5 (q,
318.0736; found: 318.0738.
1JCF = 277.0 Hz, CF3), 123.6 (q, JCF = 272.6 Hz, CF3), 124.6 (q,
1
3
8-Methoxy-3-phenyl-2-(trifluoromethyl)quinoline (5i)
3JCF = 3.0 Hz), 127.9 (q, JCF = 4.4 Hz), 128.2, 128.5, 128.8,
4
2
129.1 (q, JCF = 1.5 Hz), 129.7, 132.3 (q, JCF = 33.0 Hz), 135.6, Obtained from ketone 4i by procedure B (0.5 mmol). Yellow-
136.6, 139.7, 144.6, 147.0 (q, JCF = 33.0 Hz) ppm. 19F NMR brown solid, m.p. 93–95 °C, yield 0.117 g (77%). 1H NMR
2
3
(376.5 MHz, CDCl3): δ −62.9 (s, 3F, CF3), −64.1 (s, 3F, CF3) (400.1 MHz, CDCl3): δ 7.12 (d, J = 7.7 Hz, 1H), 7.38–7.45 (m,
ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H10F6N+: 6H), 7.58 (t, J = 7.7 Hz, 1H), 8.12 (s, 1H) ppm. 13C{1H} NMR
3
1
342.0712; found: 342.0722.
(100.6 MHz, CDCl3): δ 56.2, 118.9, 121.7 (q, JCF = 276.6 Hz,
4
CF3), 127.9, 128.1, 129.1 (q, JCF = 1.3 Hz), 129.47, 129.54,
7-Chloro-3-phenyl-2-(trifluoromethyl)quinoline (5e)
134.0, 137.2, 137.5, 139.6, 144.0 (q, 2JCF = 32.8 Hz), 155.7 ppm.
Obtained from ketone 4e by procedure B (0.5 mmol). Brown 19F NMR (376.5 MHz, CDCl3): δ −62.2 (CF3) ppm. HRMS
oil, yield 0.120 g (78%). 1H NMR (400.1 MHz, CDCl3): δ (ESI-TOF): m/z [M + H]+ calcd for C17H13F3NO+: 304.0944;
3
7.38–7.42 (m, 2H), 7.44–7.48 (m, 3H), 7.62 (dd, J = 8.8 Hz, 4J = found: 304.0936.
3
4
1.9 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 8.14 (s, 1H), 8.25 (d, J =
1.9 Hz, 1H) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 121.5 (q,
1JCF = 276.7 Hz, CF3), 126.6, 128.1, 128.3, 128.6, 128.8, 129.1
(q, 4JCF = 1.5 Hz), 130.1, 133.7, 136.5, 136.9, 139.6, 145.8, 146.3
5,8-Dimethoxy-3-phenyl-2-(trifluoromethyl)quinoline (5j)
Obtained from ketone 4j by procedure B (0.189 mmol). Pale
brown solid, m.p. 149–152 °C, yield 0.043 g (68%). 1H NMR
(400.1 MHz, CDCl3): δ 3.94 (s, 3H, MeO), 4.07 (s, 3H, MeO),
6.87 (d, 3J = 8.5 Hz, 1H), 7.02 (d, 3J = 8.5 Hz, 1H), 7.39–7.47 (m,
5H), 8.56 (s, 1H) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ
2
(q, JCF = 32.6 Hz) ppm. 19F NMR (376.5 MHz, CDCl3): δ −62.7
(CF3) ppm. HRMS (ESI-TOF): m/z [M
+
H]+ calcd for
C16H10ClF3N+: 308.0448; found: 308.0450.
1
55.8, 56.4, 106.0, 108.1, 121.8 (q, JCF = 276.4 Hz, CF3),
Methyl 3-phenyl-2-(trifluoromethyl)quinoline-7-carboxylate
(5f)
4
121.9, 127.9, 128.0, 129.3 (q, JCF = 1.3 Hz), 133.3, 135.1,
2
137.6, 137.9, 144.5 (q, JCF = 32.8 Hz), 148.3, 149.6 ppm. 19F
Obtained from ketone 4f by procedure B (1 mmol). Pale brown
solid, m.p. 92–94 °C, yield 0.221 g (67%). 1H NMR (400.1 MHz,
CDCl3): δ 7.40–7.43 (m, 2H), 7.46–7.49 (m, 3H), 7.94 (d, 3J = 8.8
Hz, 1H), 8.21 (s, 1H), 8.28 (dd, 3J = 8.6 Hz, 4J = 1.6 Hz, 1H),
8.99 (s, 1H) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 52.4,
NMR (376.5 MHz, CDCl3):
δ −62.3 (CF3) ppm. HRMS
(ESI-TOF): m/z [M + H]+ calcd for C18H15F3NO2 : 334.1049;
+
found: 334.1049.
1
6-Fluoro-3-phenyl-2-(trifluoromethyl)quinoline (5k)
121.5 (q, JCF = 276.5 Hz, CF3), 127.7, 128.0, 128.27, 128.34,
129.0, 130.4, 131.9, 132.4, 135.2, 136.8, 139.4, 144.8, 146.4 (q, Obtained from ketone 4k by procedure B (0.5 mmol). Pale
1
2JCF = 33.3 Hz), 166.1 ppm. 19F NMR (376.5 MHz, CDCl3): δ beige powder, m.p. 120–123 °C, yield 0.103 g (71%). H NMR
−62.8 (CF3) ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for (400.1 MHz, CDCl3): δ 7.39–7.42 (m, 2H), 7.44–7.49 (m, 4H),
3
3
C18H13F3NO2+: 332.0893; found: 332.0898.
7.56–7.61 (m, 1H), 8.10 (s, 1H), 8.27 (dd, J = 9.3 Hz, J = 5.3
Hz, 1H) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 110.4 (d,
6,8-Dimethyl-3-phenyl-2-(trifluoromethyl)quinoline (5g)
2
1
2JCF = 22.1 Hz), 121.2 (d, JCF = 26.2 Hz), 121.7 (q, JCF = 276.5
4
Obtained from ketone 4g (0.366 g, 1.049 mmol) by procedure Hz, CF3), 128.1, 128.3, 129.1 (q, JCF = 1.5 Hz), 129.2 (dq, JCF
A. White powder, m.p. 70–72 °C, yield 0.302 g (96%). H NMR 10.6 Hz, JCF = 0.6 Hz), 132.7 (d, JCF = 9.6 Hz), 134.3, 137.0,
=
1
2
6
(400.1 MHz, CDCl3): δ 2.55 (s, 3H, Me), 2.89 (s, 3H, Me), 139.0 (d, JCF = 5.7 Hz), 142.7, 145.9 (qd, JCF = 32.6 Hz, JCF
=
7.44–7.54 (m, 7H), 8.01 (s, 1H) ppm. 13C{1H} NMR (100.6 MHz, 3.0 Hz), 161.9 (d, JCF = 252.3 Hz, CF3) ppm. 19F NMR
1
1
CDCl3): δ 17.4, 21.7, 122.1 (q, JCF = 276.2 Hz, CF3), 123.9, (376.5 MHz, CDCl3): δ −62.6 (s, 3F, CF3), −110.15, −110.21 (m,
127.9, 127.9, 128.4, 129.2 (q, 4JCF = 1.5 Hz), 132.8, 133.1, 137.8, 1F, F) ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for
2
137.8, 138.8, 138.9, 143.2 (q, JCF = 32.4 Hz), 143.4 ppm. 19F C16H10F4N+: 292.0744; found: 292.0746.
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3-(4-Methoxyphenyl)-2-(trifluoromethyl)quinoline (5l)
4-(2-(Trifluoromethyl)quinolin-3-yl)aniline (5p)
Obtained from ketone 4l by procedure B (0.5 mmol). Pale Obtained from ketone 4p by procedure B (0.5 mmol). Light
1
1
beige powder, m.p. 127–128 °C, yield 0.135 g (89%). H NMR yellow powder, m.p. 115–117 °C, yield 0.039 g (27%). H NMR
3
3
(400.1 MHz, CDCl3): δ 3.86 (s, 3H, MeO), 6.98 (d, J = 8.6 Hz, (400.1 MHz, CDCl3): δ 3.81 (s, 2H, NH2), 6.76 (d, J = 8.3 Hz,
3
3
3
3
2H), 7.33 (d, J = 8.6 Hz, 2H), 7.66 (pt, J = 7.5 Hz, 1H), 7.80 2H), 7.20 (d, J = 8.3 Hz, 2H), 7.66 (pt, J = 7.5 Hz, 1H), 7.79
(ptd, 3J = 7.7 Hz, 4J = 1.3 Hz, 1H), 7.85 (d, 3J = 8.1 Hz, 1H), 8.13 (ptd, 3J = 7.7 Hz, 4J = 1.3 Hz, 1H), 7.85 (d, 3J = 8.2 Hz, 1H), 8.14
(s, 1H), 8.24 (d, 3J = 8.5 Hz, 1H) ppm. 13C{1H} NMR (s, 1H), 8.24 (d, 3J = 8.5 Hz, 1H) ppm. 13C{1H} NMR
1
1
(100.6 MHz, CDCl3): δ 55.2, 113.4, 121.8 (q, JCF = 276.8 Hz, (100.6 MHz, CDCl3): δ 114.5, 121.9 (q, JCF = 276.8 Hz, CF3),
CF3), 127.3, 128.3, 128.9, 129.6, 129.8, 130.38 (q, 4JCF = 1.5 Hz), 127.3, 127.4, 128.5, 128.8, 129.9, 130.23, 130.25, 133.7,
2
2
130.40, 133.2, 139.8, 145.4, 145.6 (q, JCF
159.5 ppm. 19F NMR (376.5 MHz, CDCl3): δ −62.7 (CF3) ppm. NMR (376.5 MHz, CDCl3):
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H12F3NONa+: (ESI-TOF): m/z [M + H]+ calcd for C16H12F3N2 : 289.0947;
=
32.1 Hz), 139.8, 145.4, 145.8 (q, JCF = 32.3 Hz), 146.4 ppm. 19F
δ
−62.7 (CF3) ppm. HRMS
+
326.0763; found: 326.0753.
found: 289.0952.
3-(4-Chlorophenyl)-2-(trifluoromethyl)quinoline (5m)
Methyl 4-(2-(trifluoromethyl)quinolin-3-yl)benzoate (5q)
Obtained from ketone 4m (0.178 g, 0.5 mmol) by procedure Obtained from ketone 4q by procedure B (0.5 mmol). Bright
1
1
A. Pale brown solid, m.p. 134–136 °C, yield 0.137 g (89%). H yellow crystals, m.p. 136–139 °C, yield 0.098 g (59%). H NMR
NMR (400.1 MHz, CDCl3): δ 7.33 (d, 3J = 8.3 Hz, 2H), 7.43 (d, 3J (400.1 MHz, CDCl3): δ 3.95 (s, 3H, CO2Me), 7.48 (d, 3J = 8.3 Hz,
3
3
3
4
3
= 8.3 Hz, 2H), 7.69 (pt, J = 7.5 Hz, 1H), 7.83 (pt, J = 7.7 Hz, 2H), 7.70 (ptd, J = 7.5 Hz, J = 0.9 Hz, 1H), 7.84 (ptd, J = 7.7
3
3
4
3
3
1H), 7.88 (d, J = 8.1 Hz, 1H), 8.13 (s, 1H), 8.25 (d, J = 8.5 Hz, Hz, J = 1.3 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 8.12 (d, J = 8.5
1H) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 121.7 (q, JCF
=
Hz, 2H), 8.16 (s, 1H), 8.26 (d, 3J = 8.5 Hz, 1H) ppm. 13C{1H}
1
4
1
276.6 Hz, CF3), 127.4, 128.2, 128.3, 129.2, 130.0, 130.6 (q, JCF NMR (100.6 MHz, CDCl3): δ 52.2, 121.6 (q, JCF = 276.6 Hz,
= 1.5 Hz), 130.8, 132.2, 134.4, 135.8, 139.7, 145.2 (q, 2JCF = 32.4 CF3), 127.5, 128.1, 129.2, 129.3, 129.4 (q, JCF = 1.5 Hz), 129.9,
4
Hz), 145.7 ppm. 19F NMR (376.5 MHz, CDCl3): δ −62.5 (CF3) 130.0, 130.9, 132.4, 139.5, 142.0, 145.0 (q, JCF = 32.8 Hz),
2
ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H10ClF3N+: 145.8, 166.7 ppm. 19F NMR (376.5 MHz, CDCl3): δ −62.5 (CF3)
+
308.0448; found: 308.0460.
ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H13F3NO2 :
332.0893; found: 332.0889.
3-(4-Fluorophenyl)-2-(trifluoromethyl)quinoline (5n)
3-(2-Bromophenyl)-2-(trifluoromethyl)quinoline (5r)
Obtained from ketone 4n by procedure B (0.5 mmol). Pale
brown solid, m.p. 103–105 °C, yield 0.124 g (85%). 1H NMR Obtained from ketone 4r by procedure C (2.5 mmol). Pale
3
3
1
(400.1 MHz, CDCl3): δ 7.14 (pt, J = 8.6 Hz, 2H), 7.37 (dd, J = yellow oil, yield 0.403 g (46%). H NMR (400.1 MHz, CDCl3): δ
4
3
3
8.4 Hz, J = 5.4 Hz, 2H), 7.69 (pt, J = 7.5 Hz, 1H), 7.83 (ptd, J 7.29–7.34 (m, 2H), 7.38–7.42 (m, 1H), 7.68–7.71 (m, 2H), 7.85
= 7.7 Hz, 4J = 1.3 Hz, 1H), 7.88 (d, 3J = 8.2 Hz, 1H), 8.15 (s, 1H), (ptd, 3J = 7.7 Hz, 4J = 1.0 Hz, 1H), 7.89 (d, 3J = 8.2 Hz, 1H), 8.14
8.26 (d, 3J = 8.5 Hz, 1H) ppm. 13C{1H} NMR (100.6 MHz, (s, 1H), 8.28 (d, 3J = 8.5 Hz, 1H) ppm. 13C{1H} NMR
2
1
1
CDCl3): δ 115.1 (d, JCF = 21.8 Hz), 121.7 (q, JCF = 276.6 Hz, (100.6 MHz, CDCl3): δ 121.5 (q, JCF = 276.8 Hz, CF3), 123.9,
CF3), 127.4, 128.3, 129.1, 130.0, 130.8, 131.0 (dq, JCF = 8.3 Hz, 126.8, 127.6, 128.1, 129.1, 130.0, 130.9, 131.2 (q, 4JCF = 1.1 Hz),
4
5JCF = 1.5 Hz), 132.4, 133.3 (d, JCF = 3.5 Hz), 139.8, 145.4 (q, 131.9, 132.5, 137.7, 140.1, 145.3 (q, 2JCF = 32.6 Hz), 146.0 ppm.
4
2JCF = 32.6 Hz), 145.7, 162.7 (d, 1JCF = 247.7 Hz) ppm. 19F NMR 19F NMR (376.5 MHz, CDCl3): δ −64.4 (CF3) ppm. HRMS
(376.5 MHz, CDCl3): δ −62.7 (s, 3F, CF3), −114.90, −114.98 (m, (ESI-TOF): m/z [M + H]+ calcd for C16H10BrF3N+: 351.9943,
1F, F) ppm. HRMS (ESI-TOF): m/z [M + H]+ calcd for 353.9923; found: 351.9941, 353.9922.
C16H10F4N+: 292.0744; found: 292.0752.
3-(2-(Trifluoromethyl)quinolin-3-yl)aniline (5s)
2-(Trifluoromethyl)-3-(4-(trifluoromethyl)phenyl)quinoline (5o)
Obtained from ketone 4s (0.195 g, 0.53 mmol) by procedure
1
Obtained from ketone 4o by procedure B (0.5 mmol). White A. Light yellow powder, m.p. 70–72 °C, yield 0.062 g (41%). H
powder, m.p. 135–138 °C, yield 0.116 g (68%). 1H NMR NMR (400.1 MHz, CDCl3): δ 3.77 (s, 2H, NH2), 6.71 (br s, 1H),
3
3
3
(400.1 MHz, CDCl3): δ 7.54 (d, J = 8.2 Hz, 2H), 7.71–7.75 (m, 6.75–6.79 (m, 2H), 7.21 (d, J = 7.8 Hz, 1H), 7.68 (ptd, J = 7.5
3H), 7.87 (ptd, 3J = 7.7 Hz, 4J = 1.4 Hz, 1H), 7.92 (d, 3J = 8.2 Hz, Hz, 4J = 1.0 Hz, 1H), 7.81 (ptd, 3J = 7.7 Hz, 4J = 1.5 Hz, 1H),
3
3
3
1H), 8.18 (s, 1H), 8.28 (d, J = 8.5 Hz, 1H) ppm. 13C{1H} NMR 7.87 (d, J = 8.3 Hz, 1H), 8.16 (s, 1H), 8.25 (d, J = 8.6 Hz, 1H)
1
4
(100.6 MHz, CDCl3): δ 121.6 (q, JCF = 276.6 Hz, CF3), 124.0 (q, ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 114.8, 115.9 (q, JCF
3
4
1
1JCF = 272.2 Hz, CF3), 125.0 (q, JCF = 3.7 Hz), 127.5, 128.1, = 1.1 Hz), 119.7 (q, JCF = 1.5 Hz), 121.8 (q, JCF = 276.8 Hz,
4
2
129.3, 129.7 (q, JCF = 1.1 Hz), 130.0, 130.4 (q, JCF = 32.8 Hz), CF3), 127.4, 128.3, 128.9, 129.0, 129.9, 130.5, 133.7,
131.1, 131.9, 139.7, 141.1, 145.0 (q, 2JCF = 32.6 Hz), 145.9 ppm. 138.5, 139.5, 145.4 (q, JCF = 32.8 Hz), 145.6, 146.0 ppm. 19F
2
19F NMR (376.5 MHz, CDCl3): δ −61.4 (CF3), −62.7 (CF3) ppm. NMR (376.5 MHz, CDCl3):
δ −62.6 (CF3) ppm. HRMS
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H10F6N+: 342.0712; (ESI-TOF): m/z [M + H]+ calcd for C16H12F3N2 : 289.0947;
+
found: 342.0709.
found: 289.0954.
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Paper
3-(4-(Pyrrolidin-1-yl)phenyl)-2-(trifluoromethyl)quinoline (5t)
Synthesis of quinoline 5l by the reaction of enamine 2b with
2-aminobenzaldehyde 3′a generated in situ (procedure D)
Obtained from ketone 4t by procedure B (0.5 mmol). Light
1
brown powder, m.p. 212–214 °C, yield 0.112 g (65%). H NMR A 12 mL vial with a screw cap was charged with 2-nitrobenzal-
(400.1 MHz, CDCl3): δ 2.02–2.07 (m, 4H, CH2), 3.33–3.37 (m, dehyde (0.075 g, 0.5 mmol), glacial acetic acid (2 mL), water
3
3
4H, NCH2), 6.63 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), (0.1 mL) and Fe powder (0.084 g, 1.5 mmol). The reaction
7.65 (pt, J = 7.5 Hz, 1H), 7.78 (ptd, 3J = 7.7 Hz, J = 1.3 Hz, mixture was kept at 80 °C under stirring for 0.5–1 hours until
3
4
3
3
1H), 7.85 (d, J = 8.0 Hz, 1H), 8.14 (s, 1H), 8.23 (d, J = 8.5 Hz, the Fe powder dissolved (after 10–15 min the gas pressure
1H) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 25.5, 47.5, must be released!) and the vigorous reaction finished. Next,
1
111.0, 122.0 (q, JCF = 276.6 Hz, CF3), 123.3, 127.3, 128.6, enamine 2b (0.088 g, 0.325 mmol) was added and the reaction
128.7, 129.8, 130.0, 130.1 (q, 4JCF = 1.5 Hz), 134.2, 139.7, 145.2, mixture was heated at 80–90 °C under stirring for 8 hours.
145.9 (q, JCF = 31.9 Hz), 147.5 ppm. 19F NMR (376.5 MHz, Volatiles were evaporated in vacuo, and the residue was dis-
2
CDCl3): δ −62.7 (CF3) ppm. HRMS (ESI-TOF): m/z [M + H]+ persed between CH2Cl2 (5–10 mL) and 6 M HCl (1 mL).
calcd for C20H18F3N2+: 343.1417; found: 343.1423.
Volatiles were evaporated in vacuo, and the residue was puri-
fied by column chromatography, using a mixture of hexane
and CH2Cl2 (1 : 1) as eluent. Quinoline 5l was obtained as a
pale beige powder, yield 0.084 g (85%). For characterization
date see above.
Pyrrolidin-1-yl(4-(2-(trifluoromethyl)quinolin-3-yl)phenyl)
methanone (5u)
Obtained from ketone 4u by procedure C (0.758 mmol).
1
Yellow-brown solid, m.p. 132–134 °C, yield 0.195 g (70%). H
NMR (400.1 MHz, CDCl3): δ 1.80–1.94 (m, 4H, CH2), 3.42–3.45
Synthesis of 3-(4-methoxyphenyl)-2-(trifluoromethyl)-1,6-
naphthyridine (5x) by the reaction of enamine 2b with
4-aminonicotinaldehyde
3
(m, 2H, NCH2), 3.60–3.63 (m, 2H, NCH2), 7.37 (d, J = 8.2 Hz,
2H), 7.56 (d, 3J = 8.2 Hz, 2H), 7.60 (ptd, 3J = 7.5 Hz, 4J = 1.0 Hz,
1H), 7.74 (ptd, 3J = 7.7 Hz, 4J = 1.4 Hz, 1H), 7.80 (d, 3J = 7.9 Hz,
A 12 mL vial with a screw cap was charged with enamine 2b
(0.086 g, 0.32 mmol), 4-aminonicotinaldehyde (0.039 g,
0.32 mmol) and glacial acetic acid (2 mL). The reaction
mixture was kept at 80–90 °C under stirring for 12 hours
(monitored by 1H NMR). Volatiles were evaporated in vacuo,
and the residue was purified by column chromatography,
using a mixture of CH2Cl2 and MeOH (100 : 1) as eluent. Pale
3
1H), 8.08 (s, 1H), 8.15 (d, J = 8.6 Hz, 1H) ppm. 13C{1H} NMR
1
(100.6 MHz, CDCl3): δ 24.2, 26.2, 46.1, 49.5, 121.5 (q, JCF
=
276.6 Hz, CF3), 126.7, 127.3, 128.0, 129.0, 129.6, 130.6, 132.4,
2
136.6, 138.7, 139.5, 144.8 (q, JCF = 32.6 Hz), 145.4, 169.0 ppm.
19F NMR (376.5 MHz, CDCl3): δ −62.5 (CF3) ppm. HRMS
(ESI-TOF): m/z [M + H]+ calcd for C21H18F3N2O+: 371.1366;
found: 371.1361.
1
brown oil, yield 0.082 g (84%). H NMR (400.1 MHz, CDCl3): δ
3
3
3.85 (s, 3H), 6.98 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H),
3-(Pyridin-4-yl)-2-(trifluoromethyl)quinoline (5v)
3
3
8.04 (d, J = 6.0 Hz, 1H), 8.28 (s, 1H), 8.83 (d, J = 6.0 Hz, 1H),
9.34 (d, 3J = 0.8 Hz, 1H) ppm. 13C{1H} NMR (100.6 MHz,
Obtained from ketone 4v by procedure C (∼0.87 mmol). Pale
1
brown powder, m.p. 137–139 °C, yield 0.096 g (40%). H NMR
1
CDCl3): δ 55.3, 113.7, 121.2 (q, JCF = 277.4 Hz, CF3), 122.1,
3
(400.1 MHz, CDCl3): δ 7.36 (d, J = 6.0 Hz, 2H, Py), 7.69–7.78
123.4, 128.5, 130.3 (q, 4JCF = 1.7 Hz), 135.1, 139.6, 147.5, 147.6,
3
(m, 1H), 7.84–7.90 (m, 1H), 7.92 (d, J = 8.2 Hz, 1H), 8.16 (s,
2
150.0 (q, JCF = 32.8 Hz), 152.7, 159.8 ppm. 19F NMR
1H), 8.28 (d, 3J = 8.5 Hz, 1H), 8.72 (d, 3J = 6.0 Hz, 2H, Py) ppm.
(376.5 MHz, CDCl3): δ −63.2 (CF3) ppm. HRMS (ESI-TOF): m/z
1
13C{1H} NMR (100.6 MHz, CDCl3): δ 121.5 (q, JCF = 276.4 Hz,
[M + H]+ calcd for C16H12F3N2O+: 305.0896; found: 305.0896.
4
CF3), 124.1 (d, JCF = 1.5 Hz), 127.5, 128.0, 129.4, 130.0, 130.5,
131.3, 139.4, 144.6 (q, 2JCF = 33.2 Hz), 145.4, 146.0, 149.6 ppm.
19F NMR (376.5 MHz, CDCl3): δ −62.4 (CF3) ppm. HRMS
(ESI-TOF): m/z [M + H]+ calcd for C15H10F3N2 : 275.0791;
+
Conflicts of interest
found: 275.0802.
There are no conflicts to declare.
5-(4-Methoxyphenyl)-6-(trifluoromethyl)thieno[2,3-b]pyridine (5w)
Obtained from ketone 4w by procedure B (∼0.26 mmol). White
powder, m.p. 81–82 °C, yield 0.063 g (78%). 1H NMR
Acknowledgements
3
(400.1 MHz, CDCl3): δ 3.86 (s, 3H, CH3), 6.97 (d, J = 8.7 Hz,
2H, 4-MeOC6H4), 7.29 (d, 3J = 8.7 Hz, 2H, 4-MeOC6H4), 7.32 (d, This work was supported by the Russian Science Foundation
3J = 6.0 Hz, 1H), 7.74 (d, 3J = 6.0 Hz, 1H), 8.03 (s, 1H) ppm. 13
C
(grant no. 18-13-00136). The authors acknowledge partial
{1H} NMR (100.6 MHz, CDCl3): δ 55.3, 113.5, 121.0, 122.1 (q, support for recording the NMR spectra from M.V. Lomonosov
4
1JCF = 275.7 Hz, CF3), 129.7, 130.4 (q, JCF = 1.5 Hz), 131.3, Moscow State University Program of Development. The
2
132.8, 134.2, 134.8, 142.1 (q, JCF = 32.6 Hz), 159.0, 159.5 ppm. authors acknowledge Thermo Fisher Scientific Inc., MS
19F NMR (376.5 MHz, CDCl3): δ −61.5 (CF3) ppm. HRMS Analytica (Moscow, Russia), and personally acknowledge
(ESI-TOF): m/z [M + H]+ calcd for C15H11F3NOS+: 310.0508; Prof. A. Makarov for providing mass spectrometry equipment
found: 310.0515.
for this work.
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