Organometal-Free Arylation and Arylation/Trifluoroacetylation of Quinolines by Their Reaction with CF3-ynones and Base-Induced Rearrangement

Article abstract of DOI:10.1021/acs.joc.0c01277

The reaction of quinolines with CF3-ynones resulted in the formation of 1,3-oxazinoquinolines. Subsequent treatment of the reaction mixture with a base initiated deep structural transformation of primary products. Both steps proceed in very high yield. As a result, unusual rearrangement of 1,3-oxazinoquinolines to form either 2-arylquinolines or 2-aryl-3-trifluoroacetylquinolines was discovered. The decisive role of the base in the reaction direction was shown. Using these reactions, highly efficient pathways to 2-arylquinolines and 2-aryl-3-trifluoroacetylquinolines were elaborated to provide the corresponding compounds in high yields using a simple one-pot procedure. The possible mechanism of rearrangement is discussed.

Full text of DOI:10.1021/acs.joc.0c01277

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Article
Organometalics free arylation and arylation/trifluoroacetylation of quinolines
by their reaction with CF3-ynones and base induced rearrangement
Vasiliy M. Muzalevskiy, Kseniya Belyaeva, Boris A. Trofimov, and Valentine Georgievich Nenajdenko
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01277 • Publication Date (Web): 07 Jul 2020
Downloaded from pubs.acs.org on July 7, 2020
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Organometalics free arylation and arylation/trifluoroacetylation of quinolines by
their reaction with CF3-ynones and base induced rearrangement
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Vasiliy M. Muzalevskiya, Kseniya V. Belyaevab, Boris A. Trofimov*b, Valentine G. Nenajdenko*a
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a M. V. Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory 1, Moscow, 119991 Russia
bA. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., Irkutsk,
664033, Russia; Fax: (395-2)41-93-46
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O
R
1) H2O
2) base
X
N
CF3
R
R
or
X
N
Ar
X
N
Ar
+
O
base = morpholine
base = NaOH
19 examples
up to 91%
Ar
19 examples
up to 88%
CF3
X=CH, N
Abstract The reaction of quinolines with CF3-ynones resulted in formation of 1,3-oxazinoquinolines.
Subsequent treatment of the reaction mixture with a base initiated deep structural transformation of
primary products. Both steps proceed in very high yield. As a result, unusual rearrangement of 1,3-
oxazinoquinolines to form either 2-arylquinolines or 2-aryl-3-trifluoroacetylquinolines was discovered.
The decisive role of base on the reaction direction was shown. Using these reactions, highly efficient
pathways to 2-arylquinolines and 2-aryl-3-trifluoroacetylquinolines were elaborated to provide the
corresponding compounds in high yields using simple one-pot procedure. The possible mechanism of
rearrangement is discussed.
Introduction
Quinoline is one of the very first organic molecules known to organic chemists. It was discovered
almost two centuries ago in 1834 by German chemist Friedlieb Ferdinand Runge in extracts of coal
tar.1 Nevertheless, chemistry of quinoline is a still intensively developing branch of the modern organic
chemistry due to wide applications of quinoline derivatives.2 Thus, this type of heterocycles has found
application as sensors,3 agrochemicals,4 materials for phosphorescent organic light-emitting diodes,5
ligands for transition metal complexes6 and anti-foaming agents in refineries.7 Quinoline scaffolds play
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a significant role in drug discovery showing many types of biological activity such as antifungal,8
anticancer,9 anti-inflammatory,10 and antileishmaniasis actions.11 Almost 300 alkaloids, having
quinoline moiety were listed in “The Dictionary of Alkaloids”.12 Nowadays, quinoline cinchona
alkaloids and their derivatives are widely used in organic synthesis as key catalysts for asymmetric
catalysis and organocatalysis (Figure 1).13 Perhaps, probably the most important application of
quinoline derivatives is their use as drugs. Quinolone antibiotics including the organofluorine
compounds such as ofloxacin (Floxin), norfloxacin (Noroxin), ciprofloxacin (Cipro), and moxifloxacin
(Avelox) are widely used worldwide for treatment a broad range of bacterial infections―such as
pneumonia and tuberculosis (Figure 1).14 In spite of big progress in treatment of tuberculosis, about 10
million people fell ill in 2018, 1.2 million lost their struggle with illness in 2018.15 Quinoline alkaloid
quinine was a first cure for treatment of malaria, known since the 17th century.16 Malaria is the
dangerous infective disease affected 228 million people in 2018, reaping nearly 0.4 million casualities
that year.17 There are a number of modern antimalarial quinoline derived drugs, for example
Chloroquine, Hydroxychloroquine, Mefloquine.18 In addition to the treatment or preventing malaria
above mentioned drugs are currently tested as a possible cure for COVID-19.19
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R
O
N
HO
F
CO2H
HN
N
N
H
N
N
HN
Cl
N
CF3
Chloroquine
R=H
R=OH
Ciprofloxacin
CF3
Mefloquine
antimalarial
Hydroxychloroquine
antimalarial
antibiotic
R
R
H
H
N
N
OH
HO
N
N
Quinine
Quinidine
R=OMe,
R=OMe,
, Cinchonidine
, Cinchonine
R=H
R=H
Figure 1. Selected examples of FDA approved drugs having quinoline moiety and cinchona alkaloids.
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Nowadays, organofluorine compounds are in the focus of intensive investigation due to their unique
physicochemical and biological properties.20 These compounds are widely used as construction
materials, components of liquid crystalline compositions, agrochemicals21 and pharmaceuticals22. By
recent estimation, about 20% (more than 300 compounds) of currently used drugs23 contain at least one
fluorine atom.24 Moreover, last years show even higher shares of fluoropharmaceuticals among new
small-molecule drugs (45% in 2018,25 41% in 201926). Fluorinated heterocycles make a noticeable
contribution into this group. In 2018 and 2019 FDA approved 11 drug bearing fluorinated heterocyclic
motifs. As a result, a great attention has been paid for the development of novel effective
methodologies for the synthesis of fluorinated heterocycles.27
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Recently, we elaborated highly efficient stereoselective synthesis of CF3-oxazinoquinolines using the
reaction of CF3-ynones28 with quinolines (Scheme 1).29 The synthetic utility of the prepared CF3-
oxazinoquinolines was demonstrated.30 In this manuscript we report investigation of two intriguing
rearrangements of 3 under treatment with NaOH in water at 80 С and morpholine in MeCN at 80 С.
The first one leads to 2-phenylquinoline 4 while the second one affords 2-phenyl-3-
trifluoroacetylquinoline 5. The scope of the reactions and their mechanism is also reported.
R
H
O
O
H2O
r. t.
X
N
Ar
X=CH, N
+
R
OH
CF3
X
N
Ar
CF3
1
2
MeCN ot H2O
3
Scheme 1. Synthesis of 3a.
Results and discussion
To start our investigation, optimization of the reaction conditions was performed using CF3-oxazine 3a
as a model substrate (Scheme 2). Both nature of solvent and base were tested (for details see Tables S1
and S2 in SI). The main findings of this screening are following. Strong inorganic bases (t-BuOK,
NaOH) favor formation of only 2-phenylquinoline in THF, MeCN or H2O and aqueous NaOH is the
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reagent of choice. In contrast, formation of trifluoroacetylquinoline 5a is preferable under action of
4
5
milder organic bases to give exclusively 5a in case of morpholine and N-methylpiperidine in MeCN.
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O
H
NaOH/H2O
8
9
CF3
N
O
OH
N
Ph
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N
Ph
Ph
CF3
5a
4a
3a
90%
N-methylpiperidine/MeCN, 87%
morpholine/MeCN, 88%
Scheme 2. Base induced transformation of oxazine 3a into quinolines 4a and 5a.
Having optimal conditions in hand, we investigated the synthetic scope of both reactions. It was found,
that various CF3-oxazinoquinolines 3 can be easily transformed into the corresponding 2-arylquinolines
in up to 91% yield (Scheme 3). One pot version was also used to prepare 2-arylquinolines in up to 83%
yield. The reaction is very general, allowing construction of 2-arylquinolines having different
substituents in the structure. No restrictions were found. As a rule, quinolines 4 bearing electron-
donating and electron-withdrawing groups as well as bulky substituents in both quinoline and aryl
moieties are formed in high yield. Somehow decreased yields were observed for ortho-substituted 4f
and electron rich 4m prepared in 53% and 63% correspondingly (one pot synthesis). It was also found
that the transformation can be used for the synthesis of other heterocyclic derivatives. Thus, 2-(2-
thiophenyl)quinoline 4n and 2-phenyl-1,8-naphtyridine 4s were prepared successfully.
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R
R
H
O
4
5
6
7
8
9
X
N
+
ii
i
R
1
2
X
N
OH
X
N
Ar
NaOH
H2O, 80 °C
2-4h
H2O, r.t.
O
Ar
CF3
3
4
Ar
X=CH, N
CF3
A
B
only step ii
one pot synthesis with both steps i and ii
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N
N
N
75% (B)
N
Ph
N
, 83% (B)
4a
, 90% (A),
75%(B)
O
4d,
4c
4b
, 80% (B)
4e
4j
, 91% (A)
O
Cl
N
N
, 84% (A)
N
, 78% (B)
N
N
S
CF3
Cl
4g
4f
, 57% (B)
4h
, 73% (B)
4i
, 88% (A)
O
O
S
N
83% (B)
N
N
, 75% (B)
CN
N
F
Br
Br
4k
4n,
4l,
38% (B)
4m,
63% (B)
Br
Cl
N
Ph
N
4s,
N
Ph
N
Ph
N
Ph
N
Ph
4r,
80% (B)
85% (A)
4p,
4q,
67% (A)
87% (B)
4o,
79% (B)
Scheme 3. Synthesis of 2-arylquinolines 4.
The investigation of the second rearrangement revealed even better results. The reaction was appeared
to be insensitive to the nature of the substituents in oxazines 3 to form 2-aryl-3-
trifluoroacetylquinolines 5 in up to 88% yields (Scheme 4). High yields were observed for any
derivatives. For example, 2-aryl-3-trifluoroacetylquinolines 5f and 5m were prepared in 87% and 70%
in one pot variation of the synthesis. Thiophenyl- and 1,8-naphtyridine derivatives were also
successfully synthesized. Notably, the yield of 2-thiophenyl derivative 5n was almost twice better
comparing to synthesis of 4n.
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O
R
R
H
O
CF3
X
N
+
ii
i
R
1
2
X
N
OH
X
N
Ar
morpholine
1 equiv. H2O
MeCN, r.t.
O
Ar
CF3
MeCN, 80 °C
4-6h
3
5
Ar
X=CH, N
CF3
A
B
only step ii
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one pot synthesis with both steps i and ii
O
O
O
O
O
CF3
CF3
CF3
CF3
CF3
N
N
N
, 84% (A),
75% (B)
N
Ph
, 88% (A),
81%(B)
N
, 82% (B)
5a
5b
5d
, 80% (B)
O
5e
, 65% (A)
88% (B)
5c
O
O
O
O
O
CF3
CF3
CF3
CF3
CF3
N
N
, 71% (A)
N
N
N
O
S
CF3
Cl
Cl
5g
5h
, 81% (B)
5i
, 71% (A)
5f
, 87% (B)
5j
, 77% (B)
O
O
O
O
CF3
CF3
CF3
CF3
N
O
O
N
S
N
N
F
Br
5l
, 84% (B)
O
5k
, 78% (A)
O
5n,
79% (B)
5m,
70% (B)
O
O
CN
Br
O
Br
CF3
CF3
CF3
CF3
CF3
N
N
Ph
N
Ph
N
Ph
N
Ph
75% (A)
Cl
N
5r,
83% (A)
Ph
5q,
5s,
66% (A)
81% (A)
5p,
5o,
81% (A), 69%(B)
Scheme 4. Synthesis of 2-arylquinolines-3-trifluoroacetylquinoline 5.
We have also carried out syntheses of 2-phenylquinoline 4a and 2-phenyl-3-trifluoroacetylquinoline 5a
in sub gram scale. In both cases one pot procedures were used starting from 6 mmol of CF3-ynone 2a.
As a result, the corresponding quinolines were prepared in high yield (4a, 0.722 g, 60% and 5a, 1.432 g,
82%).
There are plenty methods for the synthesis of 2-arylquinolines or 3-trifluoroacetylquinolines. The most
straightforward literature approaches to 2-arylquinolines are based on application of organometallic
(lithium31, magnesium32, zinc33, bismuth34) or organoelement (boron35, silicon36, tin37) derivatives.
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Effective transformations of o-alkenylarylisonitriles into 2-arylquinolines by radical cascades were also
reported38. 3-Trifluoroacetylquinolines have been prepared using trifluoroacetylating reagents39 or by
condensations of 2-aminobenzaldehyde40 and 2-aminoaceto- and benzophenones41 with carbonyl
compounds. Obviously, these two groups of the methods are not compartible, in terms of starting
materials and the reaction products. By each group of methods, either 2-diarylquinoline or 2-
trifluoromethylquinoline can be obtained. In contrast, the proposed here approach allows preparation of
both quinoline derivatives 4 and 5 using the same starting quinolines. Direction of transformation can
be switched by choosing the base using for the rearrangement. As a result, formal arylation of starting
quinoline at the C-2 position takes place or simultaneous arylation at C-2 and trifluoroacetylation at C-
3 of quinoline. In addition, the proposed approaches are “orthogonal” to other methods. Thus, they are
tolarate the Br substituents to open opportunities for further cross-couplings of the quinonine products
obtained. To the best of our knowledge there are no such flexible methods known in the literature for
modification of quinolines.
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Next, some efforts were undertaken to investigate possible mechanisms of both rearrangements. First,
we proposed possibility of transformation of trifluoroacetylquinoline 5 into quinoline 4 under action of
NaOH in aqueous solution. However, heating of 5a with NaOH led to formation of the corresponding
quinoline-3-carboxylic acid 7 in 64% yield. No decarboxylation was observed under the reaction
conditions. Similarly, formation of acid 7 was observed in MeCN. It was found, that addition of NaOH
to the solution of trifluoroacetylquinoline 5a obtained in situ by the treatment with morpholine afforded
amide 6b in moderate yield. Addition of water to the reaction mixture allowed to switch the reaction
direction to form acid 7. As a result, one pot three step synthesis of acid 7 was elaborated to give
desired compound in 73% yield (Scheme 5). The obtained data permits to exclude transformation of
compounds 5 into 2-arylquinolines 4 under the reaction conditions.
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O
O
O
iii
O
i,ii
CF3
NaOH
N
-
OH
Ph
O
CF3
conditions
N
Ph
N
6b
Ph
N
7
Ph
2a
5a
1a
i: 0.95 equiv. , 1 equiv. H2O, MeCN, r.t.
ii: morpholine, MeCN, 80 °C, 4-6h
A
B
C
D
only step iii, H2O, 2 days, r.t.
i,ii then iii, 80 °C, 4-6h
i,ii then iii, 10 equiv. H2O, 80 °C, 4-6h
64%
traces
46%
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43% strong tarring
11% strong tarring
B, C, D
one pot
i,ii then iii, 55 equiv. H2O, 80 °C, 4-6h traces
73%
Scheme 5. Transformation of 2-arylquinolines-3-trifluoroacetylquinoline 5a under action of NaOH.
Next, additional experiments to study the reaction mechanism were performed. For this aim the
reaction of 3a with NaOH in D2O was investigated. It was found, that no deuterium was incorporated
into the structure of quinoline 4a under these conditions. Next, deuterated oxazine 3a’ was prepared
and their rearrangement to 4a was studied. Treatment of 3a’ with NaOH in D2O and H2O resulted in
transformation to quinoline 4a’ having position 3 deuterated. Small admixture of non-deuterated
quinoline 4a was formed as well. Monodeuterated product 4a’ was major product both in D2O and H2O.
One the base of these results one can conclude, that proton adjacent to the third position of quinoline is
originated from the enamine moiety of oxazine 3a’. No significant exchange between substrate and the
reaction media is observed during the rearrangement (Scheme 6).
H
D
H
O
N
+
OX
N
Ph
N
Ph
Ph
CF3
4a'
4a
X
4a+4a'
4a+4a'
4a+4a'
X=H,
X=D,
X=D,
D2O, NaOH, 80 °C, 4h (
D2O, NaOH, 80 °C, 4h (
H2O, NaOH, 80 °C, 4h (
) 71%, 100
:
:
:
0
94
84
3a
3a'
3a'
) 80%,
) 82%,
6
16
Scheme 6. Experiments with deuterium labeled compounds and in D2O.
Taking into account the obtained results and literature data42, we proposed following mechanism for
the formation of 4a (Scheme 7). Most probably the rearrangement proceeds through ANRORC type
mechanism (Addition of a Nucleophile, followed by the Ring Opening and Ring Closure during the
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substitution)43. It is initiated by deprotonation of hydroxy group of 3a to form intermediate A followed
by elimination of trifluoromethyl fragment to give B. Subsequent NaOH induced ring opening resulted
in formation of intermediate C which has semiaminal fragment and is in equilibrium with opened form
D. This intermediate D has in the structure fragment of Michael acceptor (unsaturated aldehyde). On
the other hand, it has enamine fragment in the structure as well. As a result new C-C bond is formed to
give intermediate E. Finally, aromatization takes place by elimination of acetaldehyde and CO2 to give
target 2-substituted quinoline 4a.
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OH-
NaOH
N
O
N
O
N
O
-CF3-
H
CF3
O-
CF3
OH
Ph
O
Ph
Ph
B
A
3a
O
O
O
N
OH
O
NH
N
Ph
-CH3CHO
N
Ph
4a
Ph
Ph
E
C
D
COOH
COOH
Scheme 7. Possible mechanism of formation of 4a.
The proposed scheme of rearrangement of 3a to 4a can be simply adapted to the synthesis of
trifluoroacetylated derivatives 5. Significantly lower basicity of the reaction media (morpholine-
CH3CN) for this transformation should be taken into account. As a result, no elimination of
trifluoromethyl anion takes place. In contract, base induced ring opening of 3a gives semiaminal
intermediate F which is in equilibrium with its opened form G (Scheme 8). E/Z isomerization of
enaminoketone fragment and subsequent intramolecular Michael type reaction of enaminone H (or its
more nucleophilic hemiaminal form) and unsaturated aldehyde resulted in cyclized intermediate I.
Elimination of acetaldehyde from I ends up the transformation to form quinoline 5a.
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morpholine
O
N
O
NH
N
OH
OH
COCF3
COCF3
Ph
CF3
Ph
Ph
3a
G
F
7
8
9
O
O
O
O
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H
CF3
CF3
Ph
COCF3
Ph
-
OH
CH3C(O)H
N
Ph
N
N
H
5a
I
H
Scheme 8. Possible mechanism of formation of 5a.
These two mechanisms are in perfect agreement with influence of nature of amine on the reaction
(Table S2, SI). It was found, that rearrangement of oxazine 3a under treatment of pyrrolidine in MeCN
led surprisingly to amide 6a after heating at 80 C for 6 hours (Scheme 9). Most favorable explanation
of this fact is a reaction of highly nucleophilic pyrrolidine with formed trifluoroacetylquinoline 5a.
Indeed, heating of 5a with pyrrolidine afforded amide 6a in high yield. We proposed, that various
amines can be involved into the reaction to give efficient route to the corresponding amides. Less
nucleophilic amines demanded to use elevated temperature. Thus, heating of 5a in piperidine and
morpholine at 110 C for 7h afforded amides 6b and 6c in near quantitative yields. Heating of 5a with
primary amines did not lead to formation of the desired amides. However, addition of NaOH to the
reaction mixture led to fast consumption of starting material to give the corresponding amides bearing
cyclopropyl- and n-hexyl moieties 6d, 6e.
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O
3
4
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6
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N
H
ii
N
O
H
O
i
Ph
N
80 °C, 6h
N
6a
Ph
OH
CF3
2a
Ph
CF3
A
B
only step ii, 96%
, i,ii 97%
1a
i: 0.95 equiv. , 1 equiv. H2O, MeCN, r.t.
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O
O
C
D
E
6a,
98%
MeCN, 80 °C, 6h;
neat, 110 °C, 7h
CF3
amine
NR2
neat, NaOH, 110 °C, 2h
conditions
N
Ph
N
Ph
6
5
O
O
O
O
N
N
H
N
N
H
O
N
Ph
N
Ph
N
Ph
N
Ph
D
)
6e
E
, 74%( )
6d
E
, 99%( )
6b
D
, 97%( )
6c
, 99%(
Scheme 9. Synthesis of amides 6.
It should be noted, that NMR investigation of the reaction mixtures revealed the formation of CF3H in
the reaction. Thus, presence of quadruplet at 6.60 ppm having very large H-F coupling constant (79 Hz)
in H NMR spectra as well as doublet at -77.8 (79 Hz) in F NMR confirmed that fact.44 Taking into
account these results, the mechanism of the transformation of ketones 5 to amides can be rationalized
as a two step process. Addition of a nucleophile to carbonyl group of 5 led to intermediate J which
eliminates trifluoromethyl anion to afford final amide (Scheme 10).
1
19
O
O
O
"H -source"
CF3
Nu
Ar
Nu
CF3
Nu
R
R
R
CF3
CF3H
+
N
N
Ar
N
Ar
1H NMR  6.60 (q, 79 Hz)
19F NMR  -77.8 (d, 79 Hz)
J
5
6
Scheme 10.
In conclusion, we developed general and efficient pathways towards to 2-arylquinolines and 2-aryl-3-
trifluoroacetylquinolines based on rearrangement of 1,3-oxazinoquinolines 3. The reaction direction is
orchestrated easily by choosing of the base. Thus, 2-arylquinolines 4 were prepared in high yields
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under treatment of 1,3-oxazinoquinolines with NaOH in water. Alternatively, synthesis of 2-aryl-3-
trifluoroacetylquinolines 5 can be performed using morpholine as a base. One pot versions of both
syntheses were also elaborated starting from quinolines and CF3-ynones. As a result, formal C-2
arylation and C-2 arylation/3-trifluoroacetylation of quinolines were developed. Possible mechanisms
of all transformations are discussed. In addition, 2-aryl-3-trifluoroacetylquinolines 5 can be used as
staring materials for novel efficient approaches to 2-phenylquinoline carboxylic acid and its amides.
Experimental section
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1
General remarks. H, 13C and 19F NMR spectra were recorded on Bruker AVANCE 400 MHz
spectrometer in CD3CN and CDCl3 at 400, 100 and 376 MHz respectively. Chemical shifts (δ) in ppm
1
are reported with the use of the residual CHD2CN and chloroform signals (1.94 and 7.25 for H and
77.0 for 13C) as internal reference. The 19F chemical shifts were referenced to C6F6, (-162.9 ppm). The
coupling constants (J) are given in Hertz (Hz). ESI-MS spectra were measured with an Orbitrap Elite
instrument. TLC analysis was performed on “Merck 60 F254” plates. Column chromatography was
performed on silica gel. All reagents were of reagent grade and were used as such or were distilled
prior to use. CF3-ynones 228,45 and CF3-oxazines 330 were prepared as reported previously. Melting
points were determined on an Electrothermal 9100 apparatus.
Synthesis of CF3-ynones 2 from terminal acetylenes (general procedure): Preheated 500 mL three-
necked round bottom flask equipped with thermometer, dropping funnel (with rubber septum) and
argon inlet was purged with argon and then charged with 200 mL of dry THF and 0.1 mol of
corresponding terminal acetylene. Thus obtained solution was cooled to -60°C and 0.11 mol of n-BuLi
(44 mL, 2.5 M solution in hexane, 0.11 mol) was added dropwise. The reaction mixture was allowed to
warm up to -20 °C and then was cooled to -60 °C. Next, CF3CO2Et was added slowly at temperature
lower than -50 °C. The reaction mixture was allowed to warm up to room temperature (15-20 °C) and
then quenched with ~100 mL of 2M HCl at 0-20 °C. Organic layer was separated and water phase was
extracted with CH2Cl2 (3x30 mL). Combined extracts were washed with water (50 mL), dried over
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Na2SO4 and volatiles were evaporated in vacuo. The residue was purified by vacuum distillation,
recrystallization or by passing through short silica gel pad using appropriate hexane–CH2Cl2 mixtures
as an eluent. Using this procedure CF3-ynones 2a,c,k,m (for structures see SI) were prepared. For
characterization data of CF3-ynones 2a,c,k,m see28.
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4-(3,4-diMethylphenyl)-1,1,1-trifluorobut-3-yn-2-one (2c). Obtained from 4-ethynyl-1,2-
dimethylbenzene (13.0 g, 0.1 mol). Yellow oil, yield 14.74 g (65%).
1H NMR (400.1 MHz, CDCl3): δ 7.43 (s, 1H), 7.41 (dd, 3J = 7.7 Hz, 4J = 1.7 Hz, 1H), 7.19 (d, 3J = 7.7
19
Hz, 1H), 2.32 (s, 3H, Me), 2.28 (s, 3H, Me) ppm. F NMR (376.5 MHz, CDCl3): δ -78.7 (CF3) ppm.
2
13C{1H} NMR (100.6 MHz, CDCl3): δ 167.2 (q, JCF = 42.0 Hz, C=O), 142.7, 137.7, 134.9, 131.7,
1
130.3, 115.2, 114.9 (q, JCF = 288.6 Hz, CF3), 102.0, 83.5, 20.1, 19.4 ppm. HRMS (ESI-TOF): m/z
[M+H]+ Calcd for C12H10F3O +: 227.0678; found: 227.0691.
Synthesis of CF3-ynones 2 from dichloroalkenes (general procedure): Preheated 500 mL three-
necked round bottom flask equipped with thermometer, dropping funnel (with rubber septum) and
argon inlet was purged with argon and then charged with dry THF (125 mL) and corresponding
dichloroalkene (0.1 mol) or dibromoalkene (for 2n). Thus obtained solution was cooled to -90°C and n-
BuLi (0.205 mol, 82 mL, 2.5 M solution in hexane) was added dropwise keeping temperature below -
70 to -60 °C. The reaction mixture was kept at -60 to -45 °C for 1h, cooling bath was removed and the
reaction mixture was allowed to warm up to 0 to 5 °C. Then the reaction mixture was cooled to -90 °C
and CF3CO2Et (15.6 g, 0.11 mol) was quite rapidly added for 1-2 minutes. Cooling bath was removed
and the reaction mixture was allowed to warm up to 0 to 5 °C. Then the reaction mixture was cooled to
-20 °C and HCl (0.25 mol, 125 mL, 2 M aqueous solution) was carefully added for 1 minute. After
warming to room temperature (15-20 °C) organic layer was separated and water phase was extracted
with CH2Cl2 (3x30 mL). Combined extracts were washed with water (50 mL), dried over Na2SO4 and
volatiles were evaporated in vacuo. The residue was purified by vacuum distillation or by passing
through short silica gel pad using hexane and appropriate hexane–CH2Cl2 mixtures as an eluents. Using
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this procedure CF3-ynones 2d,e,f,g,h,i,j,l were prepared (for structures see SI). For characterization
data of CF3-ynones 2d,e,f,g,h,i,j,l see.45
6
7
1,1,1-Trifluoro-4-(thiophen-2-yl)but-3-yn-2-one (2n). Obtained from 2-(2,2-dibromovinyl)thiophene
8
9
1
(20.1 g, 0.075 mol). Yellow oil, yield 3.23 g (21%). H NMR (400.1 MHz, CDCl3): δ 7.68 (pd, 3J ~ 4.4
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Hz, 2H), 7.15 (d, J ~ 4.4 Hz, 1H), ppm. F NMR (376.5 MHz, CDCl3): δ -78.6 (CF3) ppm. C{1H}
NMR (100.6 MHz, CDCl3): δ 166.7 (q, 2JCF = 42.0 Hz, C=O), 139.5, 134.8, 128.3, 117.8, 114.9 (q, 1JCF
= 288.4 Hz, CF3), 94.9, 88.8 ppm. The NMR data are in agreement with those in the literature.46
Synthesis of oxazines 3 by the reaction of CF3-ynones and quinolines in water (general
procedure): A 4 mL vial with a screw cap was charged with water (0.5 mL or D2O for synthesis of
3a’), quinoline 1 (0.475 mmol, 0.95 equiv.) and then CF3-ynone 2 (0.5 mmol, 1 equiv.) was added at
vigorous stirring. The reaction mixture was stirred at room temperature for 1-2 h and left overnight.
Excess water was decanted; the solid residue was dissolved in ethyl acetate (0.5 mL) and dried over
Na2SO4 (directly in the reaction vial). The solution was transferred into a round bottomed flask and the
product crystallized by addition of appropriate amount of heptane (2-3 mL). The mother liquor was
decanted, the crude product was dried under reduced pressure to give pure (3R*,4aR*)-isomer of 3.
Using this procedure oxazines 3a,d,e,g,i,k,o,p,q,r,s were prepared (for structures see SI). For
characterization data of these compounds see.30
3
19
13
Synthesis of 2-arylquinolines (4) (general procedure A). A 4 mL vial with a screw cap was charged
with oxazine 3 (0.1 mmol), water (0.5 mL) and NaOH (0.012 g, 0.3 mmol, 3 equiv.). The reaction
mixture was heated at 80 C at stirring for 2 h using magnetic stirrer with heating. After cooling down
to room temperature, the reaction mixture was extracted with EtOAc (2x0.5 mL), combined organic
phase was passed through a short silica gel pad using hexane followed by hexane-CH2Cl2 (3:1) as
eluents. Evaporation of volatiles afforded pure 2-arylquinoline 4.
One pot synthesis of 2-arylquinolines(4) (procedure B). A 4 mL vial with a screw cap was charged
with water (1 mL), quinoline 1 (0.475 mmol, 0.95 equiv.) and then CF3-ynone 2 (0.5 mmol) was added
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at vigorous stirring. The reaction mixture was stirred at room temperature overnight. After that NaOH
(0.060 g, 1.5 mmol, 3 equiv.) was added and the reaction mixture was heated at 80 C at stirring for 2 h
using magnetic stirrer with heating. After cooling down to room temperature, the reaction mixture was
extracted with CH2Cl2 (2x0.5 mL), combined organic phase was passed through a short silica gel pad
using hexane followed by hexane-CH2Cl2 (3:1) as eluents. Evaporation of volatiles afforded pure 2-
arylquinoline 4.
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2-Phenylquinoline (4a). Obtained from oxazine 3a (0.030 g, 0.087 mmol) by procedure A or from
quinoline 1a (0.061 g, 0.473 mmol) and acetylene 2a (0.099 g, 0.5 mmol) by procedure B Light brown
powder, m.p. 81-83 C (Lit. data47: 82-84 C), yield 0.016 g (90%, A) or 0.073 g (75%, B). Sub gram
scale synthesis was performed using procedure B from quinoline 1a (0.756 g, 5.86 mmol) and
acetylene 2a (1.200 g, 6.061 mmol). Yield 0.722 g, (60%). 1H NMR (400.1 MHz, CDCl3): δ 8.22 (d, 3J
3
3
4
= 8.6 Hz, 1H), 8.19-8.15 (m, 3H), 7.87 (d, J = 8.6 Hz, 1H), 7.83 (dd, J = 8.1 Hz, J = 0.7 Hz, 1H),
13
7.75-7.70 (m, 1H), 7.54-7.51 (m, 3H), 7.48-7.44 (m, 1H) ppm. C{1H} NMR (100.6 MHz, CDCl3): δ
157.3, 148.2, 139.6, 136.7, 129.63, 129.61, 129.3, 128.8, 127.5, 127.4, 127.1, 126.2, 119.0 ppm. The
NMR data are in agreement with those in the literature47.
2-Phenylquinoline-3-d (4a’). Obtained from oxazine 3a’ (0.051 g, 0.147 mmol) by procedure A or
from quinoline 1a (0.129 g, 1 mmol) and acetylene 2a (0.205 g, 1.035 mmol) by procedure B (D2O was
used instead of H2O). Light brown viscous oil, yield 0.025 g (82%, A, 84:16 mixture with 3a) or 0.165
g (80%, B, 94:6 mixture with 3a). 1H NMR (400.1 MHz, CDCl3): δ 8.27 (d, 3J = 8.6 Hz, 1H), 8.23-8.20
(m, 2H), 8.11 (s, 1H), 7.79-7.72 (m, 2H), 7.58-7.47 (m, 4H) ppm. 13C{1H} NMR (100.6 MHz, CDCl3):
δ 157.0, 148.1, 139.4, 136.4, 129.49, 129.43, 129.1, 128.6, 127.4, 127.3, 126.9, 126.0, 118.4 (t, 1JCD
=
24.8 Hz) ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C15H11DN+: 207.1027; found: 207.1020.
2-(p-Tolyl)quinoline (4b). Obtained from quinoline 1a (0.030 g, 0.233 mmol) and acetylene 2b
(0.0556 g, 0.262 mmol) by procedure B. Yellow-orange crystals, m.p. 80-82 C (Lit. data47: 79-81 C),
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yield 0.041 g (80%). 1H NMR (400.1 MHz, CDCl3): δ 8.18 (d, 3J = 8.5 Hz, 2H), 8.08 (d, 3J = 8.1 Hz,
2H), 7.85 (d, 3J = 8.6 Hz, 1H), 7.80 (dd, 3J = 8.2 Hz, 4J = 1.4 Hz, 1H), 7.72 (ptd, 3J = 7.8 Hz, 4J = 1.4
5
6
7
8
9
3
4
3
Hz, 1H), 7.51 (ptd, J = 7.5 Hz, J = 1.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 2.44 (s, 3H, Me) ppm.
13C{1H} NMR (100.6 MHz, CDCl3): δ 157.3, 148.2, 139.3, 136.8, 136.6, 129.6, 129.5, 127.4, 127.0,
126.0, 118.8, 21.3 ppm. The NMR data are in agreement with those in the literature47.
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2-(3,4-diMethylphenyl)quinoline (4c). Obtained from quinoline 1a (0.0313 g, 0.242 mmol) and
acetylene 2a (0.0603 g, 0.267 mmol) by procedure B. Light yellow powder, m.p. 91-93 C (Lit. data48:
89-91 C), yield 0.047 g (83%). 1H NMR (400.1 MHz, CDCl3): δ 8.18 (d, 3J = 8.3 Hz, 1H), 8.17 (d, 3J
= 8.4 Hz, 1H), 7.99 (d, 3J = 8.1 Hz, 1H), 7.87 (dd, 3J = 8.3 Hz, 4J = 1.8 Hz, 1H), 7.85 (d, 3J = 8.6 Hz,
1H), 7.80 (dd, 3J = 8.1 Hz, 4J = 1.1 Hz, 1H), 7.72 (ptd, 3J = 7.8 Hz, 4J = 1.4 Hz, 1H), 7.50 (ptd, 3J = 7.5
Hz, 4J = 1.1 Hz, 1H), 7.29 (d, 3J = 7.8 Hz, 1H), 2.39 (s, 3H, Me), 2.34 (s, 3H, Me) ppm. 13C{1H} NMR
(100.6 MHz, CDCl3): δ 157.5, 148.2, 138.1, 137.2, 137.0, 136.6, 130.1, 129.6, 129.5, 128.6, 127.4,
127.0, 126.0, 124.9, 118.9, 19.9, 19.7 ppm. The NMR data are in agreement with those in the
literature48.
2-(4-(tert-Butyl)phenyl)quinoline (4d). Obtained from quinoline 1a (0.0305 g, 0.236 mmol) and
acetylene 2d (0.068 g, 0.268 mmol) by procedure B. Light brown solid, m.p. 62-64 C (Lit. data49: 84-
3
85 C), yield 0.046 g (75%). 1H NMR (400.1 MHz, CDCl3): δ 8.18 (d, J = 8.6 Hz, 2H), 8.11 (d, 3J =
8.6 Hz, 2H), 7.86 (d, 3J = 8.6 Hz, 1H), 7.81 (dd, 3J = 8.1 Hz, 4J = 1.2 Hz, 1H), 7.72 (ptd, 3J = 7.7 Hz, 4J
3
3
4
= 1.4 Hz, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.51 (ptd, J = 7.5 Hz, J = 1.1 Hz, 1H), 1.39 (s, 9H, t-Bu)
13
ppm. C{1H} (100.6 MHz, CDCl3): δ 157.3, 152.5, 148.3, 136.9, 136.6, 129.6, 129.5, 127.4, 127.2,
127.0, 126.0, 125.8, 118.9, 34.7, 31.3 ppm. The NMR data are in agreement with those in the
literature49.
2-(4-Methoxyphenyl)quinoline (4e). Obtained from oxazine 3e (0.081 g, 0.216 mmol) by procedure A.
Light brown powder, m.p. 124-125 C (Lit. data47: 119-121 C), yield 0.046 g (91%). 1H NMR (400.1
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MHz, CDCl3): δ 8.16-8.11 (m, 4H), 7.82-7.77 (m, 2H), 7.70 (ptd, J = 7.7 Hz, J = 1.4 Hz, 1H), 7.48
3
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5
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8
9
3
4
3
13
(ptd, J = 7.5 Hz, J = 1.0 Hz, 1H), 7.04 (d, J = 8.9 Hz, 2H), 3.87 (s, 3H, MeO) ppm. C{1H} NMR
(100.6 MHz, CDCl3): δ 160.7, 156.9, 148.2, 136.6, 132.2, 129.5, 129.4, 128.8, 127.4, 126.8, 125.9,
118.5, 114.2, 55.3 ppm. The NMR data are in agreement with those in the literature47.
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2-(2-Methoxyphenyl)quinoline (4f). Obtained from quinoline 1a (0.061 g, 0.473 mmol) and acetylene
1
2f (0.114 g, 0.5 mmol) by procedure B. Light yellow oil, yield 0.063 g (57%). H NMR (400.1 MHz,
CDCl3): δ 8.19 (d, 3J = 8.5 Hz, 1H), 8.13 (d, 3J = 8.6 Hz, 1H), 7.89 (d, 3J = 8.6 Hz, 1H), 7.87 (dd, 3J =
4
3
4
3
4
7.6 Hz, J = 1.8 Hz, 1H), 7.82 (dd, J = 8.1 Hz, J = 1.1 Hz, 1H), 7.70 (ptd, J = 7.7 Hz, J = 1.4 Hz,
1H), 7.52 (ptd, 3J = 7.5 Hz, 4J = 1.1 Hz, 1H), 7.42 (ptd, 3J = 7.4 Hz, 4J = 1.8 Hz, 1H), 7.14 (td, 3J = 7.5
Hz, 4J = 1.0 Hz, 1H), 7.02 (d, 3J = 8.3 Hz, 1H), 3.85 (s, 3H, MeO) ppm.
13C{1H} NMR (100.6 MHz, CDCl3): δ 157.1, 157.0, 148.2, 135.0, 131.4, 130.2, 129.6, 129.5, 129.1,
127.3, 126.9, 126.1, 123.4, 121.2, 111.3, 55.5 ppm. The NMR data are in agreement with those in the
literature50.
2-(4-(Methylthio)phenyl)quinoline (4g). Obtained from oxazine 3g (0.0286 g, 0.0731 mmol) by
procedure A. Light yellow powder, m.p. 146-148 C (Lit. data51: 128-130 C), yield 0.0154 g (84%).
1H NMR (400.1 MHz, CDCl3): δ 8.19 (d, 3J = 8.6 Hz, 1H), 8.14 (d, 3J = 8.5 Hz, 1H), 8.09 (d, 3J = 8.5
Hz, 2H), 7.84 (d, 3J = 8.6 Hz, 1H), 7.81 (d, 3J = 8.1 Hz, 1H), 7.71 (ptd, 3J = 7.7 Hz, 4J = 1.3 Hz, 1H),
3
4
3
13
7.51 (ptd, J = 7.5 Hz, J = 1.1 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 2.54 (s, 3H, MeS) ppm. C{1H}
NMR (100.6 MHz, CDCl3): δ 156.6, 148.3, 140.4, 136.8, 136.2, 129.7, 129.6, 127.8, 127.4, 127.1,
126.4, 126.2, 118.6, 15.5 ppm. The NMR data are in agreement with those in the literature51.
2-(4-(Trifluoromethyl)phenyl)quinoline (4h). Obtained from quinoline 1a (0.033 g, 0.256 mmol) and
acetylene 2h (0.070 g, 0.263 mmol) by procedure B. Light brown powder, m.p. 125-126 C (Lit. data50:
122-124 C), yield 0.0545 g (78%). 1H NMR (400.1 MHz, CDCl3): δ 8.26 (d, 3J = 8.1 Hz, 2H), 8.22 (d,
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Hz, J = 1.1 Hz, 1H) ppm. F NMR (376.5 MHz, CDCl3): δ -63.8 (CF3) ppm. C{1H} NMR (100.6
MHz, CDCl3): δ 155.6, 148.2, 142.9 (q, 4JCF = 1.1 Hz), 137.1, 131.0 (q, 2JCF = 32.4 Hz, C-CF3), 130.0,
129.8, 127.8, 127.5, 127.4, 126.8, 125.7 (q, 3JCF = 3.7 Hz), 115.9 (q, 1JCF = 272.2 Hz, CF3), 118.7 ppm.
The NMR data are in agreement with those in the literature50.
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2-(4-Chlorophenyl)quinoline (4i). Obtained from oxazine 3i (0.036 g, 0.0947 mmol) by procedure A.
Light brown powder, m.p. 108-110 C (Lit. data47: 114-116 C), yield 0.020 g (88%). 1H NMR (400.1
MHz, CDCl3): δ 8.21 (d, 3J = 8.6 Hz, 1H), 8.15 (d, 3J = 8.5 Hz, 1H), 8.11 (d, 3J = 8.4 Hz, 2H), 7.82 (d,
3J = 8.6 Hz, 2H), 7.73 (ptd, 3J = 7.7 Hz, 4J = 1.0 Hz, 1H), 7.53 (pt, 3J = 7-8 Hz, 1H), 7.48 (d, 3J = 8.4
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Hz, 2H) ppm. C{1H} NMR (100.6 MHz, CDCl3): δ 156.0, 148.2, 138.0, 137.0, 135.5, 129.8, 129.6,
129.0, 128.8, 127.5, 127.2, 126.5, 118.6 ppm. The NMR data are in agreement with those in the
literature47.
2-(2-Chlorophenyl)quinoline (4j). Obtained from quinoline 1a (0.0313 g, 0.243 mmol) and acetylene
2j (0.0605 g, 0.257 mmol) by procedure B. Light yellow-brown powder, m.p. 77-79 C (Lit. data52: 72-
75 C), yield 0.0428 g (73%). 1H NMR (400.1 MHz, CDCl3): δ 8.21 (d, 3J = 8.7 Hz, 1H), 8.18 (d, 3J =
8.7 Hz, 1H), 7.86 (dd, 3J = 8.1 Hz, 4J = 0.9 Hz, 1H), 7.75 (d, 3J = 8.4 Hz, 1H), 7.74 (ptd, 3J = 7.7 Hz, 4J
= 1.4 Hz, 1H), 7.69 (dd, 3J = 7.4 Hz, 4J = 2.1 Hz, 1H), 7.57 (ptd, 3J = 7.5 Hz, 4J = 1.1 Hz, 1H), 7.50 (dd,
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3J = 7.4 Hz, J = 2.1 Hz, 1H), 7.43-7.35 (m, 2H) ppm. C{1H} NMR (100.6 MHz, CDCl3): δ 157.4,
148.0, 139.6, 135.6, 132.3, 131.7, 130.0, 129.8, 129.7, 129.6, 127.5, 127.14, 127.07, 126.7, 122.7 ppm.
The NMR data are in agreement with those in the literature52.
2-(4-Bromophenyl)quinoline (4k). Obtained from quinoline 1a (0.0305 g, 0.236 mmol) and acetylene
2k (0.069 g, 0.249 mmol) by procedure B. Light brown powder, m.p. 114-115 C (Lit. data47: 120-122
C), yield 0.050 g (75%). 1H NMR (400.1 MHz, CDCl3): δ 8.19-8.14 (m, 2H), 8.03 (d, 3J = 8.5 Hz, 2H),
7.80 (d, 3J = 8.1 Hz, 1H), 7.79 (d, 3J = 8.6 Hz, 1H), 7.73 (ptd, 3J = 7.6 Hz, 4J = 1.3 Hz, 1H), 7.63 (d, 3J
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2-(4-Fluorophenyl)quinoline (4l). Obtained from quinoline 1a (0.0301 g, 0.233 mmol) and acetylene
2l (0.0612 g, 0.5 mmol) by procedure B. Light brown powder, m.p. 92-94 C (Lit. data47: 90-91 C),
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yield 0.043 g (83%). H NMR (400.1 MHz, CDCl3): δ 8.19 (d, J = 8.7 Hz, 1H), 8.18-8.13 (m, 3H),
7.81 (d, 3J = 8.6 Hz, 2H), 7.72 (ptd, 3J = 7.4 Hz, 4J = 1.4 Hz, 1H), 7.52 (ptd, 3J = 7.5 Hz, 4J = 1.0 Hz,
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1H), 7.20 (pt, JHH, JHF = 8.7 Hz, 2H) ppm. F NMR (376.5 MHz, CDCl3): δ -113.67…-113.75 (m,
Ar-F) ppm. C{1H} NMR (100.6 MHz, CDCl3): δ 163.7 (d, JCF = 249.0 Hz), 156.2, 148.2, 136.9,
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135.8 (d, JCF = 3.1 Hz), 129.8, 129.6, 129.4 (d, JCF = 8.5 Hz), 127.4, 127.0, 126.3, 118.4, 115.7 (d,
2JCF = 21.6 Hz) ppm. The NMR data are in agreement with those in the literature47.
2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)quinoline (4m). Obtained from quinoline 1a (0.0314 g,
0.243 mmol) and acetylene 2m (0.063 g, 0.246 mmol) by procedure B. Light yellow powder, m.p. 115-
117 C (Lit. data53: 104 C), yield 0.0405 g (63%). 1H NMR (400.1 MHz, CDCl3): δ 8.14 (pt, 3J = 8.3
Hz, 2H), 7.78 (d, 3J = 8.6 Hz, 2H), 7.74 (d, 4J = 2.1 Hz, 1H), 7.69 (ptd, 3J = 7.7 Hz, 4J = 1.4 Hz, 1H),
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7.68 (dd, J = 8.4 Hz, J = 2.1 Hz, 1H), 7.48 (ptd, J = 7.5 Hz, J = 1.1 Hz, 1H), 7.00 (d, J = 8.4 Hz,
1H), 4.30 (s, 4H, 2CH2) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 156.5, 148.1, 144.9, 143.8, 136.6,
133.2, 129.52, 129.50, 127.4, 126.9, 125.9, 120.8, 118.5, 117.5, 116.5, 64.5, 64.3 ppm. The NMR data
are in agreement with those in the literature53.
2-(Thiophen-2-yl)quinoline (4n). Obtained from quinoline 1a (0.060 g, 0.465 mmol) and acetylene 2n
(0.101 g, 0.495 mmol) by procedure B. Light brown powder, m.p. 129-131 C (Lit. data50: 124-127 C),
yield 0.0374 g (38%). 1H NMR (400.1 MHz, CDCl3): δ 8.12 (d, 3J = 8.8 Hz, 1H), 8.09 (d, 3J = 8.6 Hz,
1H), 7.79-7.75 (m, 2H), 7.72 (dd, 3J = 3.7 Hz, 4J = 1.0 Hz, 1H), 7.69 (ptd, 3J = 7.7 Hz, 4J = 1.4 Hz, 1H),
7.50-7.45 (m, 2H), 7.15 (dd, 3J = 5.0 Hz, 3J = 3.7 Hz, 1H) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ
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152.3, 148.1, 145.3, 136.6, 129.8, 129.2, 128.5, 128.0, 127.4, 127.1, 126.1, 125.8, 117.6 ppm. The
NMR data are in agreement with those in the literature50.
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2-Phenylquinoline-5-carbonitrile (4o). Obtained from quinoline 1b (0.037 g, 0.240 mmol) and
acetylene 2a (0.056 g, 0.281 mmol) by procedure B. Light yellow-green powder, m.p. 142-144 C,
yield 0.0436 g (79%). 1H NMR (400.1 MHz, CDCl3): δ 8.54 (d, 3J = 8.8 Hz, 1H), 8.37 (d, 3J = 8.5 Hz,
1H), 8.18-8.15 (m, 2H), 8.04 (d, 3J = 8.8 Hz, 1H), 7.92 (dd, 3J = 7.3 Hz, 4J = 0.9 Hz, 1H), 7.75 (dd, 3J =
8.5 Hz, 3J = 7.3 Hz, 1H), 7.56-7.48 (m, 3H) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 158.8, 147.4,
138.4, 135.2, 133.9, 132.4, 130.1, 129.0, 128.8, 127.6, 126.8, 121.0, 116.8, 109.9 ppm. HRMS (ESI-
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TOF): m/z [M+H]+ Calcd for C16H11N2 : 231.0917; found: 231.0926.
5-Bromo-2-phenylquinoline (4p). Obtained from quinoline 1c (0.0518 g, 0.249 mmol) and acetylene
2a (0.0518 g, 0.262 mmol) by procedure B. Light brown powder, m.p. 80-82 C, yield 0.0612 g (87%).
1H NMR (400.1 MHz, CDCl3): δ 8.55 (d, 3J = 8.8 Hz, 1H), 8.18-8.12 (m, 3H), 7.93 (d, 3J = 8.8 Hz, 1H),
7.77 (d, 3J = 7.3 Hz, 1H), 7.57-7.48 (m, 4H) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 157.8, 148.9,
138.8, 136.1, 129.9, 129.8, 129.7, 129.6, 128.9, 127.6, 126.5, 121.7, 120.0 ppm. HRMS (ESI-TOF):
m/z [M+H]+ Calcd for C15H1179BrN+: 284.0069; found: 284.0068; Calcd for C15H1181BrN+: 286.0049;
found: 286.0049.
6-Bromo-2-phenylquinoline (4q). Obtained from oxazine 3q (0.0626 g, 0.148 mmol) by procedure A.
Light brown powder, m.p. 123-124 C (Lit. data49: 123-124 C), yield 0.0282 g (67%). 1H NMR (400.1
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MHz, CDCl3): δ 8.15-8.12 (m, 2H), 8.10 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.97 (d, J =
2.2 Hz, 1H), 7.87 (d, 3J = 8.7 Hz, 1H), 7.78 (dd, 3J = 9.0 Hz, 4J = 2.2 Hz, 1H), 7.55-7.45 (m, 3H) ppm.
13C{1H} NMR (100.6 MHz, CDCl3): δ 157.6, 146.8, 139.1, 135.7, 133.1, 131.4, 129.6, 129.5, 128.9,
128.2, 127.4, 120.0, 119.7 ppm. The NMR data are in agreement with those in the literature49.
7-Chloro-2-phenylquinoline (4r). Obtained from quinoline 1e (0.0389 g, 0.239 mmol) and acetylene
2a (0.057 g, 0.288 mmol) by procedure B. White powder, m.p. 114-115 C (Lit. data54: 110-111 C),
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yield 0.046 g (80%). H NMR (400.1 MHz, CDCl3): δ 8.17-8.14 (m, 4H), 7.85 (d, J = 8.5 Hz, 1H),
7.73 (d, 3J = 8.6 Hz, 1H), 7.55-7.44 (m, 4H) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 158.2, 148.6,
139.1, 136.5, 135.4, 129.6, 128.9, 128.63, 128.62, 127.5, 127.2, 125.4, 119.1 ppm. The NMR data are
in agreement with those in the literature54.
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2-Phenyl-1,8-naphthyridine (4s). Obtained from quinoline 1f (0.027 g, 0.208 mmol) and acetylene 2a
(0.056 g, 0.288 mmol) by procedure B. White powder, m.p. 119-120 C (Lit. data55: 120-121 C), yield
0.0365 g (85%). 1H NMR (400.1 MHz, CDCl3): δ 9.09 (dd, 3J = 4.2 Hz, 4J = 2.0 Hz, 1H), 8.30-8.27 (m,
2H), 8.19 (d, 3J = 8.5 Hz, 1H), 8.14 (dd, 3J = 8.1 Hz, 4J = 2.0 Hz, 1H), 7.96 (d, 3J = 8.5 Hz, 1H), 7.52-
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7.43 (m, 3H), 7.42 (dd, J = 8.1 Hz, J = 4.2 Hz, 1H) ppm. C{1H} NMR (100.6 MHz, CDCl3): δ
160.1, 156.0, 153.7, 138.4, 137.7, 136.7, 130.0, 128.7, 127.8, 121.7, 121.6, 119.6 ppm. The NMR data
are in agreement with those in the literature55.
Synthesis of 2,2,2-trifluoro-1-(2-arylquinolin-3-yl)ethanones (5) (procedure A). A 4 mL vial with a
screw cap was charged with oxazine 3a (0.1 mmol), MeCN (0.5 mL) and morpholine (0.0087 g, 0.1
mmol, 1 equiv.). The reaction mixture was heated at 80 C for 4-6 h using magnetic stirrer with heating
and then volatiles were evaporated in vacuo. The residue was passed through a short silica gel pad
using hexane followed by hexane-CH2Cl2 (3:1) as eluents. Evaporation of volatiles afforded pure 5.
One pot synthesis of 2,2,2-trifluoro-1-(2-arylquinolin-3-yl)ethanones (5) (procedure B). A 4 mL
vial with a screw cap was charged with water (0.009 g, 0.5 mmol, 1 equiv.), quinoline 1 (0.475 mmol,
0.95 equiv.), MeCN (1.5 mL) and then CF3-ynone 2 (0.5 mmol, 1 equiv.) was added at stirring. The
clear solution thus obtained was left at room temperature for 24h. Next, morpholine (0.044 g, 0.5 mmol,
1 equiv.) was added and the reaction mixture was heated at 80 C for 6 h using magnetic stirrer with
heating. Volatiles were evaporated in vacuo, the residue was passed through a short silica gel pad using
hexane followed by hexane-CH2Cl2 (3:1) as eluents. Evaporation of volatiles afforded pure 5.
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2,2,2-Trifluoro-1-(2-phenylquinolin-3-yl)ethanone (5a). Obtained from oxazine 3a (0.030 g, 0.087
mmol) by procedure A or from quinoline 1a (0.061 g, 0.475 mmol) and acetylene 2a (0.099 g, 0.5
mmol) by procedure B. Pale yellow powder, m.p. 86-87 C, yield 0.023 g (88%, A) or 0.116 g (81%,
B). Sub gram scale synthesis was performed using procedure B from quinoline 1a (0.751 g, 5.821
mmol) and acetylene 2a (1.167 g, 5.89 mmol). Yield 1.432 g, (82%). 1H NMR (400.1 MHz, CD3CN): δ
8.77 (s, 1H), 8.09 (m, 1H), 8.07 (m, 1H), 7.91 (m, 1H), 7.68 (m, 1H), 7.56 (m, 2H), 7.49 (m, 3H) ppm.
13C{1H} NMR (100.6 MHz, CD3CN): δ 185.4 (q, 2JCF = 36.0 Hz, C=O), 158.4, 149.6, 140.8, 140.7 (q,
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CF3) ppm. 19F NMR (376.5 MHz, CD3CN): δ -72.4 (CF3) ppm. 1H NMR (400.1 MHz, CDCl3): δ 8.58
(s, 1H), 8.22 (d, 3J = 8.5 Hz, 1H), 7.93 (d, 3J = 8.1 Hz, 1H), 7.87 (ptd, 3J = 8 Hz, 4J = 1 Hz, 1H), 7.65-
7.60 (m, 3H), 7.53-7.46 (m, 3H) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 184.5 (q, 2JCF = 36.3 Hz,
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C=O), 157.6, 148.6, 139.3, 138.9 (q, JCF = 2.0 Hz, C-4), 132.9, 129.6, 129.3, 128.9, 128.7, 128.6,
127.8, 125.8, 124.8, 115.9 (q, 1JCF = 292.3 Hz, CF3) ppm. 19F NMR (376.5 MHz, CDCl3): δ -73.7 (CF3)
ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C17H11F3NO+: 302.0793; found: 302.0790.
2,2,2-Trifluoro-1-(2-(p-tolyl)quinolin-3-yl)ethan-1-one (5b). Obtained from quinoline 1a (0.061 g,
0.475 mmol) and acetylene 2b (0.106 g, 0.5 mmol) by procedure B. Pale yellow powder, m.p. 78-80 C,
yield 0.120 g (80%). 1H NMR (400.1 MHz, CDCl3): δ 8.56 (s, 1H), 8.20 (d, 3J = 8.5 Hz, 1H), 7.95 (d,
3J = 8.3 Hz, 1H), 7.88 (ptd, 3J = 7.7 Hz, 4J = 1.4 Hz, 1H), 7.64 (ptd, 3J = 7.5 Hz, 4J = 1.1 Hz, 1H), 7.48
(d, 3J = 8.0 Hz, 2H), 7.30 (d, 3J = 8.0 Hz, 2H), 2.42 (s, 3H, Me) ppm. 19F NMR (376.5 MHz, CDCl3): δ
-73.8 (CF3) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 184.9 (q, 2JCF = 36.1 Hz, C=O), 157.6, 148.8,
139.5, 138.9 (q, 4JCF = 2.0 Hz), 136.5, 132.8, 129.6, 129.5, 128.8, 128.7, 127.7, 126.0, 124.8, 115.9 (q,
1JCF = 292.5 Hz, CF3), 21.4 ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C18H13F3NO,+: 316.0944;
found: 316.0941.
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Hz, 1H), 7.43 (s, 1H), 7.23 (s, 2H), 2.34 (s, 3H, Me), 2.32 (s, 3H, Me) ppm. F NMR (376.5 MHz,
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157.7, 148.8, 138.8 (q, JCF = 2.0 Hz), 138.2, 137.3, 136.9, 132.8, 130.0 (2C), 129.6, 128.6, 127.7,
126.4, 126.2, 124.8, 115.9 (q, 1JCF = 292.5 Hz, CF3), 19.9, 19.7 ppm. HRMS (ESI-TOF): m/z [M+H]+
Calcd for C19H15F3NO+: 330.1100; found: 330.1100.
1-(2-(4-(tert-Butyl)phenyl)quinolin-3-yl)-2,2,2-trifluoroethan-1-one (5d). Obtained from oxazine 3d
(0.060 g, 0.15 mmol) and morpholine (0.013 g, 0.150 mmol) by procedure A or from quinoline 1a
(0.017 g, 0.13 mmol) and acetylene 2d (0.035 g, 0.138 mmol) by procedure B. Pale yellow powder,
m.p. 109-111 C, yield 0.045 g (84%, A) or 0.035 g (75%, B). IR (microlayer): 1615 (C=C), 1727
(C=O) cm-1. 1H NMR (400.1 MHz, CD3CN): δ 8.74 (s, 1H), 8.06 (m, 2H), 7.89 (m, 1H), 7.65 (m, 1H),
7.54-7.48 (m, 4H,), 1.34 (s, 9H, t-Bu) ppm. C{1H} NMR (100.6 MHz, CD3CN): δ 185.4 (q, JCF
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34.7 Hz, C=O), 158.2, 153.4, 149.6, 140.5, 137.7, 134.1, 130.2, 130.1, 129.9, 128.9, 128.0, 126.5,
125.8, 117.1 (q, JCF = 291.6 Hz, CF3), 35.4 (C from t-Bu), 31.5 (3Me from t-Bu) ppm. 19F NMR
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(376.5 MHz, CD3CN): δ -73.0 (CF3) ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C21H19F3NO+:
358.1419; found: 358.1425.
2,2,2-Trifluoro-1-(2-(4-methoxyphenyl)quinolin-3-yl)ethan-1-one (5e). Obtained from oxazine 3e
(0.052 g, 0.138 mmol), morpholine (0.004 g, 0.046 mmol) by procedure A or from quinoline 1a (0.061
g, 0.475 mmol) and acetylene 2a (0.114 g, 0.5 mmol) by procedure B. Pale yellow powder, m.p. 96-98
C, yield 0.029 g (65%, A) or 0.139 g (88%, B). IR (microlayer): 1605 (C=C), 1725 (C=O) cm-1. H
1
NMR (400.1 MHz, CD3CN): δ 8.74 (s, 1H), 8.09 (m, 2H), 7.93 (m, 1H), 7.69 (m, 1H), 7.54 (m, 2H),
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7.05 (m, 2H), 3.86 (s, 3H, OMe) ppm. 13C{1H} NMR (100.6 MHz, CD3CN): δ 185.6 (q, 2JCF = 35.5 Hz,
C=O), 161.8, 157.8, 151.6, 149.7, 140.6, 136.9, 134.1, 133.0, 131.6, 130.1, 128.8, 125.8, 117.5 (q, 1JCF
5
6
7
19
1
= 291.4 Hz, CF3), 115.1, 56.1 (OMe) ppm. F NMR (376.5 MHz, CD3CN): δ -73.2 (CF3) ppm. H
8
9
3
3
NMR (400.1 MHz, CDCl3): δ 8.51 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.85
(ptd, 3J = 7.7 Hz, 4J = 1.5 Hz, 1H), 7.59 (ptd, 3J = 7.5 Hz, 4J = 1.0 Hz, 1H), 7.56 (d, 3J = 8.8 Hz, 2H),
7.02 (d, 3J = 8.8 Hz, 2H), 3.84 (s, 3H, MeO) ppm. 19F NMR (376.5 MHz, CDCl3): δ -73.8 (CF3) ppm.
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13C{1H} NMR (100.6 MHz, CDCl3): δ 185.2 (q, JCF = 36.1 Hz, C=O), 160.6, 156.9, 148.7, 138.8 (q,
2
4JCF = 1.9 Hz), 132.7, 131.7, 130.4, 129.4, 128.6, 127.5, 125.9, 124.6, 115.8 (q, 1JCF = 292.5 Hz, CF3),
+
114.2, 55.2 ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C18H13F3NO2 : 332.0893; found: 332.0901.
2,2,2-Trifluoro-1-(2-(2-methoxyphenyl)quinolin-3-yl)ethan-1-one (5f). Obtained from quinoline 1a
(0.061 g, 0.475 mmol) and acetylene 5f (0.114 g, 0.5 mmol) by procedure B. Light yellow powder, m.p.
1
3
152-154 C, yield 0.136 g (87%). H NMR (400.1 MHz, CDCl3): δ 8.48 (s, 1H), 8.20 (d, J = 8.5 Hz,
1H), 7.91 (d, 3J = 8.1 Hz, 1H), 7.85 (dd, 3J = 7.5 Hz, 4J = 1.7 Hz, 1H), 7.83 (ptd, 3J = 7.7 Hz, 4J = 1.4
Hz, 1H), 7.61 (ptd, 3J = 7.5 Hz, 4J = 0.9 Hz, 1H), 7.45 (ptd, 3J = 7.9 Hz, 4J = 1.7 Hz, 1H), 7.22 (ptd, 3J
= 7.5 Hz, 4J = 0.8 Hz, 1H), 6.90 (d, 3J = 8.2 Hz, 2H), 3.71 (s, 3H, MeO) ppm. 19F NMR (376.5 MHz,
CDCl3): δ -73.5 (CF3) ppm. C{1H} NMR (100.6 MHz, CDCl3): δ 182.2 (q, JCF = 35.6 Hz, C=O),
154.5, 154.4, 149.0, 135.5 (q, 4JCF = 2.4 Hz), 132.2, 130.99, 130.95, 129.6, 128.6, 127.64, 127.6, 126.5,
124.8, 122.0, 116.4 (q, 1JCF = 292.3 Hz, CF3), 110.7, 54.8 ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd
13
2
+
for C18H13F3NO2 : 332.0893; found: 332.0884.
2,2,2-Trifluoro-1-(2-(4-(methylthio)phenyl)quinolin-3-yl)ethan-1-one (5g). Obtained from oxazine
3g (0.054 g, 0.138 mmol) by procedure A. Yellow brown powder, m.p. 105-107 C, yield 0.034 g
1
3
3
(71%). H NMR (400.1 MHz, CDCl3): δ 8.57 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 8.1 Hz,
1H), 7.89 (ptd, 3J = 7.7 Hz, 4J = 1.0 Hz, 1H), 7.65 (pt, 3J = 7.4 Hz, 1H), 7.50 (d, 3J = 8.3 Hz, 2H), 7.34
(d, J = 8.3 Hz, 2H), 2.52 (s, 3H, MeS) ppm. 19F NMR (376.5 MHz, CDCl3): δ -73.7 (CF3) ppm.
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13C{1H} NMR (100.6 MHz, CDCl3): δ 184.6 (q, JCF = 36.1 Hz, C=O), 157.0, 148.8, 140.7, 139.1 (q,
4JCF = 2.2 Hz), 135.8, 133.0, 129.6, 129.3, 128.7, 127.9, 126.2, 125.7, 124.9, 115.9 (q, 1JCF = 292.5 Hz,
CF3), 15.4 ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C18H13F3NOS+: 348.0664; found: 348.0665.
2,2,2-Trifluoro-1-(2-(4-(trifluoromethyl)phenyl)quinolin-3-yl)ethan-1-one (5h). Obtained from
quinoline 1a (0.061 g, 0.475 mmol) and acetylene 2h (0.133 g, 0.5 mmol) by procedure B. White
powder, m.p. 120-122 C, yield 0.142 g (81%). 1H NMR (400.1 MHz, CDCl3): δ 8.70 (s, 1H), 8.19 (d,
3J = 8.5 Hz, 1H), 7.99 (d, 3J = 8.1 Hz, 1H), 7.93 (ptd, 3J = 7.7 Hz, 4J = 1.3 Hz, 1H), 7.76-7.66 (m, 5H)
ppm. 19F NMR (376.5 MHz, CDCl3): δ -63.8 (Ar-CF3), -73.3 (COCF3) ppm. 13C{1H} NMR (100.6
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MHz, CDCl3): δ 183.1 (q, 2JCF = 36.1 Hz, C=O), 156.7, 148.7, 142.9 (q, 4JCF = 1.1 Hz), 139.6 (q, 4JCF
=
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3
2.8 Hz), 133.5, 131.1 (q, JCF = 32.6 Hz), 129.7, 129.2, 128.9, 128.5, 125.6 (q, JCF = 3.7 Hz), 125.1,
1
1
124.8, 124.0 (q, JCF = 272.4 Hz, CF3), 116.0 (q, JCF = 292.1 Hz, CF3) ppm. HRMS (ESI-TOF): m/z
[M+H]+ Calcd for C18H10F6NO+: 370.0661; found: 370.0650.
1-(2-(4-Chlorophenyl)quinolin-3-yl)-2,2,2-trifluoroethan-1-one (5i). Obtained from oxazine 3i
(0.093 g, 0.245 mmol) by procedure A. Light yellow powder, m.p. 115-116 C, yield 0.058 g (71%).
1H NMR (400.1 MHz, CDCl3): δ 8.62 (s, 1H), 8.19 (d, 3J = 8.5 Hz, 1H), 7.97 (d, 3J = 8.2 Hz, 1H), 7.91
(ptd, 3J = 7.7 Hz, 4J = 1.4 Hz, 1H), 7.68 (ptd, 3J = 7.5 Hz, 4J = 1.0 Hz, 1H), 7.51 (d, 3J = 8.6 Hz, 2H),
7.46 (d, J = 8.6 Hz, 2H) ppm. 19F NMR (376.5 MHz, CDCl3): δ -73.6 (CF3) ppm. 13C{1H} NMR
3
2
4
(100.6 MHz, CDCl3): δ 183.9 (q, JCF = 36.1 Hz, C=O), 156.6, 148.7, 139.3 (q, JCF = 2.2 Hz), 137.8,
1
135.6, 133.3, 130.2, 129.7, 129.0, 128.8, 128.2, 125.3, 125.0, 115.9 (q, JCF = 292.3 Hz, CF3) ppm.
HRMS (ESI-TOF): m/z [M+H]+ Calcd for C17H10ClF3NO+: 336.0398; found: 336.0395.
1-(2-(2-Chlorophenyl)quinolin-3-yl)-2,2,2-trifluoroethan-1-one (5j). Obtained from quinoline 1a
(0.061 g, 0.475 mmol) and acetylene 2j (0.116 g, 0.5 mmol) by procedure B. Yellow solid, m.p. 86-88
C, yield 0.122 g (77%). 1H NMR (400.1 MHz, CDCl3): δ 8.75 (s, 1H), 8.21 (d, 3J = 8.5 Hz, 1H), 8.03
(d, 3J = 8.1 Hz, 1H), 7.93 (ptd, 3J = 7.7 Hz, 4J = 1.4 Hz, 1H), 7.72 (ptd, 3J = 7.6 Hz, 4J = 1.0 Hz, 1H),
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7.51 (pd, 3J = 7-8 Hz, 2H), 7.48-7.41 (m, 3H) ppm. 19F NMR (376.5 MHz, CDCl3): δ -72.3 (CF3) ppm.
4
5
2
4
13C{1H} NMR (100.6 MHz, CDCl3): δ 180.7 (q, JCF = 35.4 Hz, C=O), 156.3, 148.9, 138.9 (q, JCF
=
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7
8
9
3.3 Hz), 138.4, 133.4, 131.3, 130.7, 130.2, 129.8, 129.5, 129.2, 128.5, 127.6, 125.3, 124.5, 116.3 (q,
1JCF = 292.5 Hz, CF3) ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C17H10ClF3NO+: 336.0398;
found: 336.0396.
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1-(2-(4-Bromophenyl)quinolin-3-yl)-2,2,2-trifluoroethan-1-one (5k). Obtained from oxazine 3k
1
(0.083 g, 0.196 mmol) by procedure A. Light yellow solid, m.p. 125-127 C, yield 0.058 g (78%). H
3
3
NMR (400.1 MHz, CDCl3): δ 8.63 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.91
(ptd, 3J = 7.7 Hz, 4J = 1.4 Hz, 1H), 7.68 (ptd, 3J = 7.5 Hz, 4J = 1.0 Hz, 1H), 7.62 (d, 3J = 8.6 Hz, 2H),
3
7.44 (d, J = 8.6 Hz, 2H) ppm. 19F NMR (376.5 MHz, CDCl3): δ -73.6 (CF3) ppm. 13C{1H} NMR
2
4
(100.6 MHz, CDCl3): δ 183.8 (q, JCF = 36.3 Hz, C=O), 156.7, 148.7, 139.4 (q, JCF = 2.2 Hz), 138.2,
1
133.3, 131.9, 130.5, 129.7, 128.8, 128.2, 125.2, 125.0, 123.9, 115.9 (q, JCF = 292.5 Hz, CF3) ppm.
HRMS (ESI-TOF): m/z [M+H]+ Calcd for C17H1079BrF3NO+: 379.9892; found: 379.9884; Calcd for
C17H1081BrF3NO+: 381.9873; found: 381.9865.
1-(2-(4-Fluorophenyl)quinolin-3-yl)-2,2,2-trifluoroethan-1-one (5l). Obtained from quinoline 1a
(0.061 g, 0.475 mmol) and acetylene 2l (0.113 g, 0.5 mmol) by procedure B. Light yellow powder, m.p.
94-95 C, yield 0.127 g (84%). 1H NMR (400.1 MHz, CDCl3): δ 8.60 (s, 1H), 8.19 (d, 3J = 8.5 Hz, 1H),
7.95 (d, 3J = 8.2 Hz, 1H), 7.90 (ptd, 3J = 7.7 Hz, 4J = 1.4 Hz, 1H), 7.66 (ptd, 3J = 7.5 Hz, 4J = 1.1 Hz,
3
4
3
3
19
1H), 7.57 (dd, JHH = 8.8 Hz, JHF = 5.2 Hz, 2H), 7.18 (pt, JHH , JHF = 8.7 Hz, 2H) ppm. F NMR
(376.5 MHz, CDCl3): δ -73.6 (s, 3F, CF3), -112.88…-112.96 (m, 1F, Ar-F) ppm. 13C{1H} NMR (100.6
2
1
MHz, CDCl3): δ 184.2 (q, JCF = 36.3 Hz, C=O), 163.5 (d, JCF = 249.5 Hz), 156.6, 148.7, 139.2 (q,
4
3
4JCF = 2.4 Hz), 135.4 (d, JCF = 3.3 Hz), 133.1, 130.8 (d, JCF = 8.5 Hz), 129.6, 128.7, 128.0, 125.5,
124.9, 115.9 (q, 1JCF = 292.3 Hz, CF3), 115.8 (d, 2JCF = 21.9 Hz) ppm. HRMS (ESI-TOF): m/z [M+H]+
Calcd for C17H10F4NO+: 320.0693; found: 320.0685.
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1-(2-(2,3-diHydrobenzo[b][1,4]dioxin-6-yl)quinolin-3-yl)-2,2,2-trifluoroethan-1-one
(5m).
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Obtained from quinoline 1a (0.061 g, 0.475 mmol) and acetylene 2m (0.128 g, 0.5 mmol) by procedure
B. Yellow brown solid, m.p. 84-85 C, yield 0.120 g (70%). 1H NMR (400.1 MHz, CDCl3): δ 8.51 (s,
1H), 8.18 (d, 3J = 8.5 Hz, 1H), 7.93 (d, 3J = 7.9 Hz, 1H), 7.87 (ptd, 3J = 7.7 Hz, 4J = 1.3 Hz, 1H), 7.63
(ptd, 3J = 7.5 Hz, 4J = 1.2 Hz, 1H), 7.21 (d, 4J = 2.1 Hz, 1H), 7.00 (dd, 3J = 8.3 Hz, 4J = 2.1 Hz, 1H),
7.44 (d, 3J = 8.3 Hz, 1H), 4.31-4.29 (m, 4H, 2CH2) ppm. 19F NMR (376.5 MHz, CDCl3): δ -73.8 (CF3)
ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 185.1 (q, 2JCF = 36.7 Hz, C=O), 156.8, 148.7, 145.0, 143.9,
138.8, (q, 4JCF = 1.8 Hz), 132.8, 132.7, 129.6, 128.6, 127.7, 126.0, 124.8, 122.4, 118.0, 117.7, 115.9 (q,
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+
1JCF = 290.3 Hz, CF3), 64.5, 64.3 ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C19H13F3NO3 :
360.0842; found: 360.0849.
2,2,2-Trifluoro-1-(2-(thiophen-2-yl)quinolin-3-yl)ethan-1-one (5n). Obtained from quinoline 1a
(0.061 g, 0.475 mmol) and acetylene 2n (0.102 g, 0.5 mmol) by procedure B. White powder, m.p. 67-
69 C, yield 0.115 g (79%). 1H NMR (400.1 MHz, CDCl3): δ 8.38 (s, 1H), 8.13 (dd, 3J = 8.4 Hz, 4J =
0.6 Hz, 1H), 7.86 (d, 3J = 7.8 Hz, 1H), 7.83 (ptd, 3J = 7.7 Hz, 4J = 1.4 Hz, 1H), 7.58 (ptd, 3J = 7.5 Hz,
4J = 1.1 Hz, 1H), 7.54 (dd, 3J = 5.1 Hz, 4J = 1.0 Hz, 1H), 7.22 (dd, 3J = 3.7 Hz, 4J = 1.0 Hz, 1H), 7.11
3
3
19
13
(dd, J = 5.1 Hz, J = 3.7 Hz, 1H) ppm. F NMR (376.5 MHz, CDCl3): δ -74.5 (CF3) ppm. C{1H}
NMR (100.6 MHz, CDCl3): δ 185.9 (q, 2JCF = 36.5 Hz, C=O), 149.5, 148.6, 142.5, 138.3 (q, 4JCF = 1.5
Hz), 132.7, 129.6, 129.3, 128.8, 128.4, 128.0, 127.7, 125.3, 124.7, 115.8 (q, 1JCF = 292.5 Hz, CF3) ppm.
HRMS (ESI-TOF): m/z [M+H]+ Calcd for C15H9F3NOS+: 308.0351; found: 308.0353.
2-Phenyl-3-(2,2,2-trifluoroacetyl)quinoline-5-carbonitrile (5o). Obtained from oxazine 3a (0.0392 g,
0.106 mmol) by procedure A or from quinoline 1b (0.077 g, 0.5 mmol) and acetylene 2a (0.104 g,
0.525 mmol) by procedure B. White powder, m.p. 107-109 C, yield 0.028 g (81%, A) or 0.113 g (69%,
B). 1H NMR (400.1 MHz, CDCl3): δ 8.84 (s, 1H), 8.46 (d, 3J = 8.5 Hz, 1H), 8.08 (d, 3J = 7.2 Hz, 1H),
7.95 (pt, 3J = 7.9 Hz, 1H), 7.61-7.60 (m, 2H), 7.54-7.52 (m, 3H) ppm. 19F NMR (376.5 MHz, CDCl3): δ
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-74.2 (CF3) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 185.0 (q, 2JCF = 37.3 Hz, C=O), 159.0, 148.1,
4
5
1
138.4, 135.6, 135.1, 134.0, 131.6, 130.1, 129.0 (2C), 128.6, 124.8, 115.8, 115.6 (q, JCF = 292.0 Hz,
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8
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CF3), 111.3 ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C18H10F3N2O+: 327.0740; found:
327.0739.
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1-(5-Bromo-2-phenylquinolin-3-yl)-2,2,2-trifluoroethan-1-one (5p). Obtained from oxazine 3p
1
(0.091 g, 0.215 mmol) by procedure A. Light brown solid, m.p. 125-127 C, yield 0.061 g (75%). H
NMR (400.1 MHz, CDCl3): δ 8.93 (s, 1H), 8.17 (d, 3J = 8.4 Hz, 1H), 7.91 (dd, 3J = 7.5 Hz, 4J = 0.9 Hz,
3
3
19
1H), 7.72 (dd, J = 8.4 Hz, J = 7.5 Hz, 1H), 7.62-7.57 (m, 2H), 7.54-7.49 (m, 3H) ppm. F NMR
(376.5 MHz, CDCl3): δ -73.9 (CF3) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 184.7 (q, 2JCF = 36.7
Hz, C=O), 158.2, 149.4, 138.6, 138.5 (q, 4JCF = 2.2 Hz), 132.9, 131.5, 129.7, 129.5, 129.0, 128.9, 127.1,
1
124.8, 122.8, 115.8 (q, JCF = 292.1 Hz, CF3) ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for
C17H1079BrF3NO+: 379.9892; found: 379.9899; Calcd for C17H1081BrF3NO+: 381.9873; found:
381.9880.
1-(6-Bromo-2-phenylquinolin-3-yl)-2,2,2-trifluoroethan-1-one (5q). Obtained from oxazine 3q
1
(0.070 g, 0.165 mmol) by procedure A. Light yellow solid, m.p. 89-91 C, yield 0.051 g (81%). H
4
3
NMR (400.1 MHz, CDCl3): δ 8.45 (s, 1H), 8.12 (d, J = 1.5 Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.94
(dd, 3J = 8.9 Hz, 4J = 1.5 Hz, 1H), 7.58-7.56 (m, 2H), 7.49-7.48 (m, 3H) ppm. 19F NMR (376.5 MHz,
13
2
CDCl3): δ -74.0 (CF3) ppm. C{1H} NMR (100.6 MHz, CDCl3): δ 184.6 (q, JCF = 36.7 Hz, C=O),
157.9, 147.3, 138.9, 137.6, 136.3, 131.4, 130.5, 129.6, 128.91, 128.85, 126.9, 126.0, 121.9, 115.8 (q,
1JCF = 292.3 Hz, CF3) ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C17H1079BrF3NO+: 379.9892;
found: 379.9887; Calcd for C17H1081BrF3NO+: 381.9873; found: 381.9867.
1-(7-Chloro-2-phenylquinolin-3-yl)-2,2,2-trifluoroethan-1-one (5r). Obtained from oxazine 3r
1
(0.065 g, 0.174 mmol) by procedure A. Light yellow oil, yield 0.048 g (83%). H NMR (400.1 MHz,
CDCl3): δ 8.55 (s, 1H), 8.21 (d, 4J = 1.9 Hz, 1H), 7.89 (d, 3J = 8.7 Hz, 1H), 7.60 (dd, 3J = 8.7 Hz, 4J =
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1.9 Hz, 1H), 7.58-7.55 (m, 2H), 7.52-7.48 (m, 3H) ppm. 19F NMR (376.5 MHz, CDCl3): δ -73.8 (CF3)
ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ 184.4 (q, 2JCF = 36.5 Hz, C=O), 158.7, 149.0, 139.2, 138.9,
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138.7 (q, JCF = 2.0 Hz), 129.8, 129.6, 129.1, 128.88, 128.83, 128.75, 126.1, 123.3, 115.8 (q, JCF
=
8
9
292.3 Hz, CF3) ppm. HRMS (ESI-TOF): m/z [M+H]+ Calcd for C17H10ClF3NO+: 336.0398; found:
336.0395.
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2,2,2-Trifluoro-1-(2-phenyl-1,8-naphthyridin-3-yl)ethan-1-one (5s). Obtained from oxazine 3s
1
(0.066 g, 0.191 mmol) by procedure A. Light brown powder, m.p. 74-76 C, yield 0.038 g (66%). H
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4
3
NMR (400.1 MHz, CDCl3): δ 9.28 (dd, J = 4.2 Hz, J = 2.0 Hz, 1H), 8.59 (s, 1H), 8.36 (dd, J = 8.1
4
3
3
Hz, J = 2.0 Hz, 1H), 7.70-7.68 (m, 2H), 7.63 (dd, J = 8.1 Hz, J = 4.2 Hz, 1H), 7.52-7.48 (m, 3H)
ppm. 19F NMR (376.5 MHz, CDCl3): δ -74.1 (CF3) ppm. 13C{1H} NMR (100.6 MHz, CD3CN): δ 185.3
2
4
(q, JCF = 36.1 Hz, C=O), 161.4, 158.1, 157.0, 142.3 (q, JCF = 2.2 Hz), 140.1, 139.5, 130.6, 130.1,
129.7, 127.2, 124.5, 121.0, 116.8 (q, 1JCF = 291.7 Hz, CF3) ppm.
HRMS (ESI-TOF): m/z [M+H]+ Calcd for C16H10F3N2O+: 303.0740; found: 303.0738.
Synthesis of (2-phenylquinolin-3-yl)(pyrrolidin-1-yl)methanone (6a) (procedure A). A 4 mL vial
with a screw cap was charged with oxazine 3a (0.025 g, 0.0724 mmol), MeCN (0.5 mL) and
pyrrolidine (0.012 g, 0.169 mmol). The reaction mixture was heated at 80 C for 6 h using magnetic
stirrer with heating and then volatiles were evaporated in vacuo. The residue was passed through a
short silica gel pad using hexane-CH2Cl2 (1:1) followed by CH2Cl2 and CH2Cl2 -MeOH (100:1) as
eluents. Evaporation of volatiles afforded 0.021 g (96%) of pure 6a. One pot synthesis of 6a (procedure
B). A 8 mL vial with a screw cap was charged with water (0.0188 g, 1.05 mmol), quinoline 1a (0.1228
g, 0.952 mmol), MeCN (1 mL) and then CF3-ynone 2a (0.2035 g, 1.028 mmol) was added at stirring.
The clear solution thus obtained was left at room temperature for 24h. Next, pyrrolidine (0.177 g, 2.49
mmol) was added and the reaction mixture was heated at 80 C for 6 h. Volatiles were evaporated in
vacuo, the residue was passed through a short silica gel pad using hexane-CH2Cl2 (1:1) followed by
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