Pd-catalyzed regioselective hydroarylation of α-(2-aminoaryl)-α,β-ynones with organoboron derivatives as a tool for the synthesis of quinolines: experimental evidence and quantum-chemical calculations

Article abstract of DOI:10.1016/j.tet.2008.03.015

The Pd-catalyzed hydroarylation of β-(2-aminoaryl)-α,β-ynones with organoboron derivatives, leading to 2,4-diarylquinolines in good to excellent yields through sequential cycloamination, has been investigated. The reaction is catalyzed by both Pd(II) and

Full text of DOI:10.1016/j.tet.2008.03.015

Tetrahedron 64 (2008) 5354–5361
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Tetrahedron
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Pd-catalyzed regioselective hydroarylation of a-(2-aminoaryl)-a,b-ynones with
organoboron derivatives as a tool for the synthesis of quinolines: experimental
evidence and quantum-chemical calculations
*
Antonio Arcadi, Massimiliano Aschi, Fabio Marinelli , Mirella Verdecchia
`
Dipartimento di Chimica, Ingegneria Chimica e Materiali, Universita degli Studi dell’Aquila, via Vetoio, 67010 L’Aquila, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The Pd-catalyzed hydroarylation of b-(2-aminoaryl)-a,b-ynones with organoboron derivatives, leading to
2,4-diarylquinolines in good to excellent yields through sequential cycloamination, has been investi-
gated. The reaction is catalyzed by both Pd(II) and Pd(0) precatalysts, and can be carried out even under
neutral conditions. The regiochemical outcome is inverted with respect to the Pd-catalyzed hydroary-
lation of b-(2-aminoaryl)-a,b-ynones with aryl iodides. This aspect has been rationalized using quan-
tum-chemical calculations, which show significant differences between the energy barriers of the
regioisomeric transition states for the migratory insertion (hydropalladation) step, and are consistent
with the charge density of the p complex that undergoes such insertion.
Received 11 December 2007
Received in revised form 19 February 2008
Accepted 6 March 2008
Available online 18 March 2008
Keywords:
Hydroarylation
Boronic acids
Alkynones
Ó 2008 Elsevier Ltd. All rights reserved.
Palladium
Quinolines
DFT calculations
1. Introduction
with organoboron derivatives/cycloamination represents a useful
entry to 4-substituted quinoline derivatives 4.14 On the other
The quinoline scaffold is prevalent in a variety of pharmacolog-
ically active compounds as well as in naturally occurring prod-
ucts.1 Quinoline-containing drugs are widely used in the
treatment of malaria2 and current reports concerning the study
of novel quinoline derivatives include selective melanin concen-
trating hormone antagonists for treating obesity,3 HIV-1 replica-
tion inhibitors,4 antimicrobial and anti-tuberculosis drugs,5
antihelmintic properties,6 inhibitors of VEGF receptors7 and liver
X receptor modulators.8 In particular, 4-arylquinolines show anti
West Nile Virus activity,9 and are promising positron emission to-
mography (PET) tracers for the in vivo monitoring of neurodegen-
erative processes.10 Besides pharmacological activity, compounds
containing the 4-arylquinoline substructure have found applica-
tions, for example, as chemosensors for fluoride ion,11 and as
fluorescent sensors for metal ions in aqueous solution.12 As
a consequence of the great importance of the quinoline ring sys-
tem, new cyclization processes leading to these heterocycles are
being investigated.13
hand, the Pd-catalyzed hydroarylation of alkynes with arylboronic
acids has been reported,15 and a sequential Pd-catalyzed hydroary-
lation/cyclization process has been applied to the synthesis of
butenolides.16 Our previous investigations of Pd-catalyzed hydroar-
ylation of alkynes with organic halides and triflates as a versatile
tool for the synthesis of heterocycles17 prompted us to study the se-
quential Pd-catalyzed hydroarylation/cycloamination of ynones 1
with organoboron derivatives (Scheme 1) as an alternative route
to quinolines 4. Moreover, since this process was very regioselec-
tive (in contrast with the palladium-catalyzed hydroarylation of
O
Ar
ArB(OH)2 2 or
ArBF3-K+
R
R1
R2
O
R1
R2
3
Pd cat.
R
NH2
NH2
R3
R3
1
Ar
In this context, we have recently reported that the sequential
R1
R2
Rh-catalyzed hydroarylation of b-(2-aminoaryl)-a,b-ynones
1
-H2O
N
4
R
R3
* Corresponding author. Tel.: þ39 0862 433752; fax: þ39 0862 433753.
E-mail address: fmarinel@univaq.it (F. Marinelli).
Scheme 1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.015

A. Arcadi et al. / Tetrahedron 64 (2008) 5354–5361
5355
1 with aryl iodides18), we attempted to rationalize the observed
regioselectivity through quantum-chemical calculations by Density
Functional Theory and continuum solvation model. Herein, we
report our results.
2–4) and best results were obtained in the presence of 3 equiv of
2a (entry 4). A further increase in the amount of boronic acid did
not produce better results (entry 5). When Pd(OAc)2 alone (entries
6 and 7) or a combination of Pd(OAc)2/t-Bu3P (entry 8) were tested
in place of Pd(OAc)2/dppe, we observed a dramatic loss of efficiency
together with a less pronounced decrease in the selectivity. Con-
versely, the Pd(OAc)2/tricyclohexylphosphine catalytic system
gave good results (entry 9), showing that the use of a bidentate li-
gand is not compulsory. The hydroarylation can be catalyzed also
by Pd(0) precatalysts (entries 10–12). The catalytic system
Pd2(dba)3/dppe gave nearly the same yield of Pd(OAc)2/dppe (com-
pare entries 3 and 11), while Pd(PPh3)4 was much less effective (en-
try 10). Finally, we tested the use of Pd2(dba)3 without phosphine
ligands in EtOAc as solvent (entry 12). As reported before, this cata-
lyst/solvent combination favoured the formation of 5a in the
hydroarylation with 4-iodotoluene.18 In the present process, its
use resulted in the regioselective formation of 4a, although in
low yield (entry 11). This observation suggests a sharp difference
in the nature of the pathways involved in the Pd-catalyzed reac-
tions of the alkyne 1a with aryl boron derivatives and aryl iodides,
respectively.
2. Results and discussion
The hydroarylation of 1a with 4-tolylboronic acid 2a (Scheme 2)
was chosen as a model for the present study, and the results are
reported in Table 1.
4-tolylboronic
O
acid 2a
Pd cat.
AcOH
OMe
solvent, 80 °C
NH2
1a
CH3
CH3
Interestingly, the environmentally benign ethanol can be a suit-
able reaction medium (compare entries 3 and 4) and this solvent
was used when the process was extended to the reaction of various
ynones and boron derivatives. The results obtained are reported in
Table 2. The sequential Pd-cataltzed hydroarylation/cycloamina-
tion afforded quinolines 4a–o in good to excellent yields, with
high regioisomeric purity (>95%, as judged by GC/MS analysis).
Various substituents are allowed both on the boron derivative
and on the alkynone. Although 0.05 equiv of dppe (Pd/P¼1:2) has
been generally used, slightly better yields have been observed in
some cases by increasing the amount of dppe to 0.1 equiv (Table
2, compare entries 13 and 14); however, no systematic investiga-
tion was carried out on this aspect. Aryltrifluoroborate salts19
gave results comparable with arylboronic acids (Table 2, entries 1,
3 and 18). To the best of our knowledge, these salts have not
been previously used in the Pd-catalyzed hydroarylation of alkynes.
Moreover, the reaction of 1a with the aryltrifluoroborate 3a and 3b
proceeds also without adding acetic acid (Table 2, entries 2 and 4).
Although these reaction conditions resulted less effective than the
standard protocol (that requires 0.15 equiv of AcOH) and further
optimization is necessary, the possibility of carrying out the Pd-cat-
alyzed hydroarylation under neutral conditions is undoubtedly
worth of interest.
+
N
N
4a
5a
OMe
OMe
Scheme 2.
As stated before, the previously reported sequential Pd-cata-
lyzed hydroarylation/cycloamination of 1a with 4-iodotoluene in
the presence of formate salts gave
a mixture of the two
regioisomers 4a and 5a in low yield.18 In this example, a moderate
regioselectivity towards the formation of 5a was observed only us-
ing Pd2(dba)3 as catalyst in ethyl acetate as solvent. By contrast, the
present process led to the regioselective formation of the quinoline
4a under all reaction conditions tested. The structural assignments
of 4a and 5a were confirmed by comparison with authentic samples
prepared as described.14,18
We were unable to obtain the quinoline 4a in satisfactory yield
(entry 1) under the reaction conditions (1.2 equiv of 2a, Pd(OAc)2,
dppe, acetic acid, dioxane, 80 ꢀC) reported by Oh and co-workers
for the regioselective sequential hydroarylation/cyclization of 4-
hydroxyalkynoates.16 According to our previous findings concern-
ing the Rh-catalyzed process,14 we isolated 4a in higher yield and
good selectivity in the presence of a larger excess of 2a (entries
According to the previous studies of Oh and co-workers,15a
a plausible catalytic cycle for the hydroarylation is depicted in
Scheme 3. The active Pd(0) catalyst can be generated in situ
from Pd(II) species in several ways, including oxidation of dppe20
and homocoupling of arylboronic acid.21, 22 The oxidative addition
of Pd(0) to AcOH affords the hydride complex 6 (it is likely that
under neutral conditions this step can take place through the
insertion of Pd(0) into the O–H bond of ethanol).23 Then, 6 coordi-
nates the ynone 1 to give the p-complex 7. Subsequent hydropal-
ladation followed by trans-metallation with arylboronic acid 2 (or
potassiom trifluoroborate 3) generates the species 9, from which
the hydroarylation product 10 is obtained through reductive elim-
ination of Pd(0). Sequential cycloamination (that could take place
also from intermediates 8–9) results in the formation of quinoline
ring. A similar catalytic cycle has been probed by ESI-FTMS in the
related hydroarylation of allenes with ArB(OH)2 in the presence of
AcOH.24
Table 1
Pd-catalyzed hydroarylation of 1a with 4-tolylboronic acid 2aa
Entry Solvent
Catalystb
Equiv of 2a Time (h) Yield of 4a:5ac
4aþ5a
1
2
3
4
5
6
7
8
Dioxane Pd(OAc)2/dppe
Dioxane Pd(OAc)2/dppe
Dioxane Pd(OAc)2/dppe
Pd(OAc)2/dppe
Dioxane Pd(OAc)2/dppe
Dioxane Pd(OAc)2
1.2
2
3
3
5
5
3
5
5
3
3
2
7
9
7
7.5
7
18
66
90
92
92
24
27
36
78
21
84
32
92:8
94:6
94:6
97:3
91:9
83:17
85:15
75:25
95:5
97:3
98:2
97:3
Ethanol
24
Ethanol
Pd(OAc)2
20
16
5
22
6
Dioxane Pd(OAc)2/t-Bu3P
Dioxane Pd(OAc)2/Cy3P
Dioxane Pd(PPh3)4
9
10
11
12
Dioxane Pd2(dba)3/dppe
An alternative pathway for the hydroarylation could also be
EtOAc
Pd2(dba)3
22
considered (Scheme 4). Initial trans-metallation25 of Pd(OAc)2 with
a
Reactions were carried out on a 0.25 mmol scale in 1 mL of solvent at 80 ꢀ
C
boron derivatives
2 or 3 generates an Ar–PdOAc complex;
under N2 atmosphere, using the following molar ratios: 1a/AcOH/Pd¼1:0.15:0.05.
b
carbopalladation of 1 by this species gives the intermediate 12,
and protonolysis of 12 affords the alkene 10 and regenerates the
P/Pd ratio: 2:1, if phosphines were added.
c
Determined by HPLC analysis (RP-18, MeOH/H2O 85:15 v/v).

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A. Arcadi et al. / Tetrahedron 64 (2008) 5354–5361
Table 2
Pd-catalyzed synthesis of 4-arylquinolines 4 from a,b-ynones 1 and boron derivatives 2–3a
Entry
a,b-ynone 1
–R
–R1
–R2
–R3
ArB(OH)2 2 or
ArBFꢁ3 Kþ 3, –Ar
Time (h)
Quinoline 4
Yieldb (%)
O
Ar
N
R1
R
R1
R2
R
R3
R2
NH2
R3
CH3
1
1a
–H
–H
–H
8
4a
90
OCH3
3a
3a
2
3
1a
1a
24
8
4a
4b
68c
76
–Ph 3b
4
5
1a
1a
3b
24
8
4b
4c
61c
93
2c
6
7
1b
1b
–H
–H
–H
–Ph 2b
7.5
7
4d
4e
78
70
SCH3
F
2d
CH3
8
9
1c
–H
–F
–H
–H
–H
–F
16
20
4f
90
CH3
2e
1d
2b
4g
66d
CH3O
COCH3
10
11
1d
1e
20
4h
4i
60d
2f
OCH3
–H
–CF3
–H
3
70d
CN
2g
CH3
12
13
1e
1f
3
4j
92d
68
2a
–H
–H
–H
–H
–H
–H
2f
24
4k
Cl
14
15
1f
1f
2f
24
24
4k
4l
76d
77d
2e
16
1g
2c
24
4m
70d
COCH3

A. Arcadi et al. / Tetrahedron 64 (2008) 5354–5361
5357
Table 2 (continued )
Entry a,b-ynone 1
–R
–R1
–R2
–R3
ArB(OH)2 2 or
ArBFꢁ3 Kþ 3, –Ar
Time (h)
Quinoline 4
Yieldb (%)
O
Ar
N
R1
R
R1
R2
R2
R
R3
NH2
R3
17
1h
1h
–H
–H
–H
–H
–H
–H
2d
3b
24
30
4n
4o
74
60
t-Bu
18
a
Reactions were carried out in EtOH at 80 ꢀC under N2 atmosphere using the following molar ratios: 1/2(3): AcOH/Pd(OAc):dppe¼1:3:0.15:0.05:0.05.
b
c
Yields refer to single runs and are for pure isolated products.
Without AcOH.
dppe (0.1 equiv).
d
H
R
Assuming therefore that the catalytic cycle depicted in Scheme 3
is operating in the present reaction, in order to shed some light on
the observed regioselectivity, we carried out quantum-chemical
calculations in the framework of Density Functional Theory.29 In
this respect, we decided to focus our computational efforts on the
reaction between HPdOAc (the postulated active species under
our conditions) and the a,b-ynone 1a. In particular, we compared
the height of the free-energy barriers for the two possible migra-
tory insertions of triple bond into Pd–H bond, that result in the H
addition on a or b sp-carbon with respect to the carbonyl group.
Our computational strategy was designed trying to simplify as
much as possible the system without the loss of its chemical pecu-
liarities. Following this concept, dppe was not included in the
model: although the efficiency of the process appears to be influ-
enced by the presence and the nature of added ligand, regioselective
hydroarylation can be achieved also with monophosphines (Table 1,
entries 9 and 10) or without phosphine ligands (Table 1, entries 6
and 7). However, in order to realistically mimic the valence shell
of the Pd, a coordinated solvent molecule was considered. Although
the reaction was carried out in ethanol, an explicit methanol mole-
cule was added. This choice can be justified by the fact that metha-
nol should provide an effect on the Pd valence shell essentially
indistinguishable from ethanol, but at the same time it is conforma-
tionally more confined. For the same reasons, the acetate ligand was
replaced by a formyl group. We hereafter term this adduct as
HPdX(MeOH) (13), where X¼–OCOH. The choice of the environ-
mental effects is another crucial aspect. Reactions in solutions do
represent a tremendously complicated task,30 which, for a system
like the present one, require a drastic simplification. The continuum
solvation model, which basically mimic the presence of the solvent
inserting the molecule into a dielectric cavity, is one of the most
popular methods.31 Obviously the related results may be affected
by large systematic errors, which, however, can be minimized in
cases like the present one where relative values are concerned.
Therefore the two processes under investigation were:
O
-H2O
4
R1
Pd0
NH2
AcOH
10
HPdOAc
6
H
RPd
O
R1
1
NH2
9
HPdOAc
O
H
AcOPd
R1
R-B(OH)2
O
NH2
7
R1
NH2
8
(ligands omitted
for simplicity)
Scheme 3.
catalyst. This cycle can however be ruled out when the reaction is
carried out using a Pd(0) precatalyst (Table 1, entries 10–12). The
regiochemical outcome of the present reaction also suggests that
the formation of the product via Ar–PdOAc is unlikely. Indeed, on
the basis of experimental26 and theoretical27 results concerning the
insertion of a,b-alkynones and alkynals into the Ar–Pd bond, the
isolation of 3-aryl quinolines 5 as the main product should be
expected in this case.
A third possibility, involving the initial oxidative addition of
Ar–B(OH)2 to Pd(0) to give an Ar–Pd–B(OH)2 species that carbopal-
ladates the triple bond,15b seems to be in contrast with recent
results28 showing that such an oxidative addition does not take
place.
13 þ 1aethanol/HPdXðMeOHÞ=1aethanol/TSa
13 þ 1aethanol/HPdXðMeOHÞ=1aethanol/TSb
PdOAc
O
Ar
2 or 3
1
Pd(OAc)2
ArPdOAc
R1
According to this picture, HPdX–MeOH 13 and 1a form an inter-
mediate p-complex, termed HPdX(MeOH)/1aethanol (14) (showed in
Fig. 1), which eventually evolves through the two alternative TSs to
the related products.
The HF/BS1 optimized structure of the intermediate 14 shows
the migrating hydrogen perpendicular to the plane defined by Pd
and the two sp-carbon atoms, in a somewhat symmetrical position
NH2
12
H+
10 + Pd(II)
Scheme 4.

5358
A. Arcadi et al. / Tetrahedron 64 (2008) 5354–5361
Figure 3. Atomic point charges of 14 calculated at HF/BS1//Becke3LYP/BS2þPCM level
Figure 1. Schematic view of HF/BS1 optimized 14.
of theory.
with respect to the two target atoms. Interestingly, NH2 group
forms a hydrogen bond with OH group of the coordinated methanol
molecule. However, this structure does not show any geometrical
implication suggesting the observed regioselectivity. Considering
the same thermodynamic stability of the reactants and intermedi-
ates (being the same in the two processes under investigation), the
problem to tackle is the different stability of the transition struc-
tures, i.e., the estimation of the free-energy barriers. The reaction
energies, determined as described in the Supplementary data, are
shown in Figure 2.
The above results clearly indicate that migration of the hydride
to Ca is energetically favourable in ethanol solution, in nice agree-
ment with experimental observations. Moreover, the difference in
the activation free energies, accounting for about 2 kcal/mol, does
definitely explain the observed large selectivity at 298 K.32 Never-
theless, any simple rationalization of such a result is frustrated by
the fact that both TS geometries do not show any relevant geomet-
rical feature (e.g., strained conformations) or sterical effects justify-
ing their free-energy difference.
result, reported in Figure 3, shows a negative charge density on
the Pd, whereas hydrogen possess some ‘protic’ character. This cal-
culated charge distribution suggests that electronic factors could
provide the main explanation for the observed regioselectivity,
since the more electrophilic b-carbon atom conceivably shows
larger affinity for the palladium.
3. Conclusions
In summary, we have demonstrated that the Pd-catalyzed
hydroarylation of readily available ynones 1 with organoboron de-
rivatives is highly regioselective, takes place using arylboronic acids
as well as potassium aryltrifluoroborates, and could be carried out
under neutral conditions. The sequential Pd-catalyzed hydroaryla-
tion/cycloamination can provide an alternative route for the regio-
selective synthesis of 4-arylquinolines, with respect to the
previously reported procedure,14 because it can be efficiently car-
ried out in a more environmentally benign solvent such as ethanol,
and the molar excess of boron derivatives has been reduced. The
observed regioselectivity is in accord with the difference in calcu-
lated energy barriers for the two alternative migratory insertion
paths of the alkyne moiety into the Pd–H bond of the p-complex
14. An attempt to rationalize such calculated difference showed
that the charge distribution in 14 is in accord with the observed
products distribution.
For this reason, we have further analyzed the charge distribu-
tion in the chemically relevant portions of the intermediate p-com-
plex 14, i.e., Pd, migrating hydrogen and the two sp carbons. The
4. Experimental
4.1. General methods
Temperatures are reported as bath temperature. Compounds
were visualized on analytical thin-layer chromatograms (TLC) by
UV light (254 nm). The products, after usual work-up, were purified
by flash chromatography on silica gel (230–400 mesh) eluting with
n-hexane/ethyl acetate mixtures. 1H NMR and 13C NMR spectra
were recorded at 200 MHz with a Bruker AC 200 E spectrometers.
IR were recorded with Perkin–Elmer 683 spectrometer. Only the
most significant IR absorptions are given. Mass spectra were
recorded with a Saturn 2000 T GC/MS apparatus. CHN analyses
were recorded with an Eager 200 analyser. All starting materials,
catalysts, and solvents, if not otherwise stated, are commercially
available and were used as purchased, without further purification.
The synthesis of b-(2-aminoaryl)-a,b-ynones 1 from 2-trimethylsi-
lanyl-ethynylaniline was previously described.33 The synthesis of 1
Figure 2. Free-energy diagram calculated at the HF/BS1//Becke3LYP/BS2þPCM level of
theory at 298 K.

A. Arcadi et al. / Tetrahedron 64 (2008) 5354–5361
5359
has been also carried out from 2-ethynylanilines,34 as described
4.3. Representative procedure for the sequential
hydroarylation/cycloamination of 1 with arylboronic acids.
Synthesis of 2-(4-methoxyphenyl)-4-(1-naphthyl) quinoline 4c
below. Compounds 1a, 1b, 1f and 1g33 and quinolines 4a, 4b, 4d,
4f and 4g14 were previously characterized.
To a solution of 3-(2-aminophenyl)-1-(4-methoxyphenyl) prop-
2-yn-1-one 1a (0.128 g, 0.51 mmol) in ethanol (4 mL) were added
1-naphtaleneboronic acid 2c (0.263 g, 1.53 mmol), acetic acid
(4.5 mL, 0.075 mmol), Pd(OAc)2 (0.006 g, 0.027 mmol) and 1,2-bis
(diphenylphosphino)ethane (0.011 g, 0.027 mmol). The mixture
was stirred at 80 ꢀC for 8 h under nitrogen atmosphere. After cool-
ing, the mixture was purified by column chromatography (silica
gel; hexane–ethyl acetate 97:3 v/v) to give 4c as pale brown solid
(0.171 g, 93% yield). Mp 123–124 ꢀC. 1H NMR (200 MHz, CDCl3):
d 8.24 (d, J¼8.5 Hz, 1H), 8.16 (d, J¼8.8 Hz, 2H), 7.91 (t, J¼7.2 Hz,
2H), 7.85 (s, 1H), 7.71–7.01 (m, 8H), 7.00 (d, J¼8.8 Hz, 2H), 3.83 (s,
3H). 13C NMR (50.3 MHz, CDCl3): 160.9, 156.4, 148.6, 147.8, 136.1,
133.5, 132.14, 132.05, 129.9, 129.5, 128.9, 128.7, 128.3, 127.8, 127.4,
126.8, 126.4, 126.1, 125.9, 125.7, 125.3, 119.9, 114.2, 55.3. IR (KBr):
4.2. General procedure for the synthesis of b-(2-aminoaryl)-
a,b-ynones 1 from 2-ethynylanilines
To a solution of 2-ethynylaniline (0.70 mmol) in anhydrous THF
(15 mL) were added the aryl halide or the vinyl triflate (1.05 mmol),
triethylamine (3.50 mmol), PdCl2 (0.014 mmol) and dppf
(0.014 mmol). The resulting mixture was stirred at room tempera-
ture overnight under CO atmosphere (PCO¼10 bar35), then
extracted with 0.05 M HCl (75 mL) and ethyl acetate (3ꢂ75 mL).
The combined organic layers were dried (Na2SO4) and evaporated.
The residue was purified by chromatography (hexane/EtOAc mix-
tures) to give 1.
4.2.1. 3-(2-Aminophenyl)-1-(2,4-dimethylphenyl)prop-2-yn-
1-one 1c
3020, 1600, 1580, 1530 cmꢁ1
. IR (KBr): 3010, 1600, 1580,
1530 cmꢁ1. MS (EI) m/z: 361 (Mþ, 100). Anal. Calcd for C26H19NO:
Bright yellow solid (146 mg) was obtained (84% yield). Mp 98–
100 ꢀC. 1H NMR (200 MHz, CDCl3): d 8.16 (d, J¼7.9 Hz, 1H), 7.40
(dd, J1¼7.6 Hz, J2¼1.3 Hz, 1H), 7.23–7.09 (m, 2H), 7.04 (s, 1H),
6.72–6.63 (m, 2H), 4.59 (br s, 2H), 2.62 (s, 3H), 2.35 (s, 3H). 13C
NMR (50.3 MHz, CDCl3): d 179.3, 140.4, 143.7, 140.4, 133.5, 133.4,
133.0, 132.3, 126.6, 117.7, 114.7, 104.0, 94.8, 89.5, 21.9, 21.5. IR
(KBr): 3480, 3390, 2150, 1620 cmꢁ1. MS (EI) m/z: 249 (Mþ, 60),
232 (100). Anal. Calcd for C17H15NO: C, 81.90; H, 6.06; N, 5.62.
Found: C, 81.70; H, 6.05; N, 5.62.
C, 86.40; H, 5.30; N, 3.88. Found: C, 86.71; H, 5.28; N, 3.86.
4.3.1. 4-[4-(Methylthio)phenyl]-2-(1-naphthyl)quinoline 4e
Pale yellow solid (137 mg) was obtained from 140 mg of 1b and
260 mg of 2d (70% yield). Mp 140–142 ꢀC. 1H NMR (200 MHz,
CDCl3): d 8.29 (d, J¼8.3 Hz, 1H), 8.23–8.19 (m, 1H), 8.02 (d,
J¼8.3 Hz, 1H), 7.94–7.88 (m, 2H), 7.73 (d, J¼6.7 Hz, 2H), 7.63 (s,
1H), 7.59–7.44 (m, 6H), 7.36 (d, J¼8.4 Hz, 2H), 2.51 (s, 3H). 13C
NMR (50.3 MHz, CDCl3): 159.1, 148.8, 148.1, 139.5, 138.7, 134.6,
134.1, 131.3, 130.2, 130.0, 129.6, 129.1, 128.4, 127.8, 126.6, 126.4,
4.2.2. 3-(2-Amino-3,5-difluorophenyl)-1-(2-methoxyphenyl) prop-2-
yn-1-one 1d
125.9, 125.7, 125.6, 125.3, 123.2, 15.6. IR (KBr): 3020, 1580 cmꢁ1
.
MS (EI) m/z: 377 (Mþ, 98), 362 (100). Anal. Calcd for C26H19NS: C,
Bright yellow solid (153 mg) was obtained (76% yield). Mp 95–
97 ꢀC. 1H NMR (200 MHz, CDCl3): d 8.00 (dd, J1¼7.8 Hz, J2¼1.7 Hz,
1H), 7.61–7.52 (m, 1H), 7.10–6.89 (m, 4H), 4.50 (br s, 2H), 3.98 (s,
82.72; H, 5.07; N, 3.71. Found: C, 82.98; H, 5.08; N, 3.70.
4.3.2. 1-{3-[6,8-Difluoro-2-(2-methoxyphenyl)quinolin-4-yl]
phenyl}ethanone 4h
3H). 13C NMR (50.3 MHz, CDCl3):
d 175.7, 159.7, 153.3 (dd,
J1¼238 Hz, J2¼11.9 Hz, C–F), 150.3 (dd, J1¼243 Hz, J2¼12.2 Hz, C–F),
135.3, 131.9, 126.7, 120.8, 114.3 (dd, J1¼23.0 Hz, J2¼3.9 Hz), 112.5,
107.4 (d, J¼22.4 Hz), 106.9 (d, J¼22.6 Hz), 96.5, 86.4, 56.1. IR (KBr):
3490, 3390, 2160, 1610 cmꢁ1. MS (EI) m/z: 287 (Mþ, 100), 269
(44). Anal. Calcd for C16H11F2NO2: C, 66.90; H, 3.86; N, 4.88. Found:
C, 67.05; H, 3.84; N, 4.87.
Light yellow solid (75 mg) was obtained from 92 mg of 1d and
158 mg of 2f (60% yield). Mp 145–146 ꢀC. 1H NMR (200 MHz,
CDCl3): d 8.08–8.06 (m, 2H), 7.99–7.93 (m, 2H), 7.77–7.61 (m, 1H),
7.71 (s, 1H), 7.42 (dd, J1¼7.4 Hz, J2¼1.8 Hz, 1H), 7.27 (s, 1H), 7.22
(d, J¼1 Hz, 1H), 7.19–7.08 (m, 1H), 7.01(d, J¼8.5 Hz, 1H), 3.85 (s,
3H), 2.66 (s, 3H). 13C NMR (50.3 MHz, CDCl3): 197.5, 159.5 (dd,
J1¼247 Hz, J2¼11.8 Hz), 158.9 (dd, J1¼260 Hz, J2¼13.2 Hz), 157.3,
156.1, 145.7, 138.3, 137.7, 133.8, 131.7, 130.9, 129.16, 129.13, 128.5,
125.5, 121.4, 111.6, 105.2 (d, J¼22.8 Hz), 104.5 (d, J¼22.8 Hz), 55.7,
26.7. IR (KBr): 3010, 1680, 1630, 1600, 1550 cmꢁ1. MS (EI) m/z:
389 (Mþ, 100). Anal. Calcd for C24H17 F2NO2: C, 74.03; H, 4.40; N,
3.60. Found: C, 73.85; H, 4.42; N, 3.60.
4.2.3. 4-{3-[2-Amino-4-(trifluoromethyl)phenyl]prop-2-ynoyl}
benzonitrile 1e
Yellow-orange solid (132 mg) was obtained (60% yield). Mp
162–163 ꢀC. 1H NMR (200 MHz, DMSO-d6): d 8.33 (d, J¼7.8 Hz,
2H), 8.10 (d, J¼7.8 Hz, 2H), 7.69 (d, J¼8.1 Hz, 1H), 7.13 (s, 1H), 6.87
(d, J¼8.3 Hz, 1H), 6.42 (br s, 2H), 3.37 (s, 3H). 13C NMR (50.3 MHz,
DMSO-d6): d 175.6, 152.2, 139.0, 135.1(q, J¼7 Hz), 132.9, 132.5 (q,
J¼31.5 Hz), 129.8, 123.8 (q, J¼273 Hz, CF3), 118.0, 116.2, 111.6, 111.0,
104.4, 92.8, 91.6. IR (KBr): 3440, 3350, 2200, 2150, 1640 cmꢁ1. MS
(EI) m/z: 314 (Mþ, 100). Anal. Calcd for C17H9F3N2O: C, 64.97; H,
2.89; N, 8.91. Found: C, 65.09; H, 2.89; N, 8.93.
4.3.3. 4-[4-(3-Methoxyphenyl)-7-(trifluoromethyl)quinolin-2-
yl]benzonitrile 4i
Yellow solid (126 mg) was obtained from 140 mg of 1e and
203 mg of 2g (70% yield). Mp 178–180 ꢀC. 1H NMR (200 MHz,
CDCl3): d 8.54 (s, 1H), 8.34 (d, J¼8.3 Hz, 2H), 8.09 (d, J¼8.8 Hz, 1H),
7.94 (s, 1H), 7.82 (d, J¼8.3 Hz, 2H), 7.69 (d, J¼8.8 Hz, 1H), 7.51 (t,
J¼7.6 Hz, 1H), 7.13–7.07 (m, 3H), 3.90 (s, 3H). 13C NMR (50.3 MHz,
CDCl3): 159.9, 155.7, 149.8, 147.8, 142.9, 138.5, 132.7, 130.1, 128.1,
127.9, 127.2, 123.9 (q, J¼272 Hz), 122.65, 122.60, 122.1, 120.4, 118.7,
4.2.4. 3-(2-Aminophenyl)-1-(4-tert-butylcyclohex-1-en-1-yl)prop-2-
yn-1-one 1h
Bright yellow solid (137 mg) was obtained (70% yield). Mp 140–
142 ꢀC. 1H NMR (200 MHz, CDCl3): d 7.42–7.43 (m, 2H), 7.19 (t,
J¼7.5 Hz, 1H), 6.72–6.63 (m, 2H), 4.52 (br s, 2H), 2.68–2.58 (m,
1H), 2.45–2.36 (m, 1H), 2.15–1.90 (m, 3H), 1.31–1.06 (m, 2H), 0.90
(s, 9H). 13C NMR (50.3 MHz, CDCl3): 179.2, 150.1, 147.5, 140.4,
133.4, 132.0, 117.7, 114.6, 104.2, 92.3, 88.7, 43.5, 32.1, 28.3, 27.1,
23.9, 23.2. IR (KBr): 3450, 3350, 2180, 2150, 1640 cmꢁ1. MS (EI)
m/z: 281 (Mþ, 100). Anal. Calcd for C19H23NO: C, 81.10; H, 8.24; N,
4.98. Found: C, 80.87; H, 8.22; N, 4.99.
115.3, 114.3, 113.3, 55.5. IR (KBr): 3020, 2200, 1600, 1580, 1560 cmꢁ1
.
MS (EI) m/z: 404 (Mþ, 100), 374 (39). Anal. Calcd for C24H15F3N2O:
C, 71.28; H, 3.74; N, 6.93. Found: C, 71.47; H, 3.75; N, 6.95.
4.3.4. 4-[4-(4-Methylphenyl)-7-(trifluoromethyl)quinolin-2-
yl]benzonitrile 4j
Yellow solid (161 mg) was obtained from 142 mg of 1e and
185 mg of 2a (92% yield). Mp 163–164 ꢀC. 1H NMR (200 MHz,

5360
A. Arcadi et al. / Tetrahedron 64 (2008) 5354–5361
CDCl3): d 8.53 (s, 1H), 8.33 (d, J¼8.4 Hz, 2H), 8.08 (d, J¼8.7 Hz, 1H),
7.91 (s, 1H), 7.81 (d, J¼8.4 Hz, 2H), 7.66 (dd, J1¼8.8 Hz, J2¼1.6 Hz,
9H). 13C NMR (50.3 MHz, CDCl3): 158.4, 148.3, 148.1, 138.7, 137.6,
130.7, 129.8, 129.5, 129.1, 128.5, 128.2, 125.7, 125.6, 125.4, 118.3,
43.8, 32.2, 27.8, 27.5, 27.2, 24.2. IR (KBr): 3020, 2890, 1600,
1540 cmꢁ1. MS (EI) m/z: 341 (Mþ, 40), 327 (16), 285 (100). Anal.
Calcd for C25H27N: C, 87.93; H, 7.97; N, 4.10. Found: C, 87.67; H,
7.99; N, 4.12.
1H), 7.45 (d, J¼8.4 Hz, 2H), 7.40 (d, J¼8.4 Hz, 2H), 2.50 (s, 3H). 13
C
NMR (50.3 MHz, CDCl3): 155.8, 150.1, 148.0, 143.0, 139.2, 134.3,
132.7, 129.7, 129.4, 128.1, 127.3, 123.9 (q, J¼272 Hz), 122.5 (q,
J¼2.7 Hz), 120.4, 118.6, 116.2, 113.4, 30.2. IR (KBr): 3010, 2200,
1580 cmꢁ1. MS (EI) m/z: 388 (Mþ, 100), 374 (31). Anal. Calcd for
C
7.22.
24H15 F3N2: C, 74.22; H, 3.89; N, 7.21. Found: C, 73.99; H, 3.90; N,
4.4. Representative procedure for the sequential
hydroarylation/cycloamination of 1 with aryltrifluoroborate
salts. Synthesis of 2-(4-methoxyphenyl)-4-(4-methyl-
phenyl)quinoline 4a
4.3.5. 1-{3-[2-(4-Chlorophenyl)quinolin-4-yl]phenyl}ethanone 4k
Off-white solid (127 mg) was obtained from 120 mg of 1f and
230 mg of 2f (76% yield). Mp 117–119 ꢀC. 1H NMR (200 MHz,
CDCl3): d 8.23 (d, J¼8.4 Hz, 1H), 8.12 (d, J¼8.5 Hz, 2H), 8.16–8.08
(m, 2H), 7.82–7.61 (m, 4H), 7.77 (s, 1H), 7.47 (d, J¼8.5 Hz, 2H),
7.51–7.45 (m, 1H), 2.66 (s, 3H). 13C NMR (50.3 MHz, CDCl3): 197.7,
155.5, 148.7, 148.2, 138.7, 137.7, 137.5, 135.7, 134.0, 130.2, 129.9,
129.2, 129.0, 128.8, 128.4, 126.9, 125.5, 125.2, 118.9, 26.8. IR (KBr):
3020, 1680, 1590 cmꢁ1. MS (EI) m/z: 359 (Mþþ2, 35), 357 (Mþ,
100), 317 (24), 315 (65). Anal. Calcd for C23H16 ClNO: C, 77.20; H,
4.51; N, 3.91. Found: C, 76.94; H, 4.50; N, 3.92.
To a solution of 3-(2-aminophenyl)-1-(4-methoxyphenyl) prop-
2-yn-1-one 1a (0.128 g, 0.51 mmol) in ethanol (4 mL) were added
potassium 4-methylphenyltrifluoroborate 3a (0.303 g, 1.53 mmol),
acetic acid (4.5 mL, 0.075 mmol), Pd(OAc)2 (0.006 g, 0.027 mmol)
and 1,2-bis(diphenylphosphino)ethane (0.011 g, 0.027 mmol). The
mixture was stirred at 80 ꢀC for 8 h under nitrogen atmosphere. Af-
ter cooling, the mixture was purified by column chromatography
(silica gel; hexane–ethyl acetate 97:3 v/v) to give 4a (0.149 g, 90%
yield).
4.3.6. 2-(4-Chlorophenyl)-4-(4-fluorophenyl)quinoline 4l
Acknowledgements
White solid (121 mg) was obtained from 120 mg of 1f and
197 mg of 2e (77% yield). Mp 92–94 ꢀC. 1H NMR (200 MHz,
CDCl3): d 8.21 (d, J¼8.4 Hz, 1H), 8.11 (d, J¼8.5 Hz, 2H), 7.83 (d,
J¼8.4 Hz, 1H), 7.70 (s, 1H), 7.76–7.69 (m, 1H), 7.46 (d, J¼8.5 Hz,
2H), 7.53–7.45 (m, 3H), 7.22 (m, 2H). 13C NMR (50.3 MHz, CDCl3):
162.9 (d, J¼248 Hz), 155.4, 148.5 (d, J¼23 Hz), 137.8, 135.6, 134.1,
131.3, 130.1, 129.8, 129.0, 128.8, 128.5, 126.7, 125.7, 125.4, 118.9,
115.7 (d, J¼22 Hz). IR (KBr): 3020, 1600, 1540 cmꢁ1. MS (EI) m/z:
335 (Mþþ2, 36), 333 (Mþ, 100). Anal. Calcd for C21H13ClFN: C,
75.56; H, 3.93; N, 4.20. Found: C, 75.40; H, 3.95; N, 4.21.
`
This work was financed by the Ministero dell’Universita e della
Ricerca, Rome, and by the University of L’Aquila.
Supplementary data
Details of the computational study. Supplementary data associ-
ated with this article can be found in the online version, at
doi:10.1016/j.tet.2008.03.015.
4.3.7. 1-{4-[4-(1-Naphthyl)quinolin-2-yl]phenyl}ethanone 4m
Pale brown solid (129 mg) was obtained from 130 mg of 1g and
255 mg of 2c (70% yield). Mp 158–160 ꢀC. 1H NMR (200 MHz,
CDCl3): d 8.30 (d, J¼8.3 Hz, 2H), 8.32–8.25 (m, 1H), 8.07 (d,
J¼8.3 Hz, 2H), 8.02–7.92 (m, 2H), 7.93 (s, 1H), 7.75–7.25 (m, 8H),
2.63 (s, 3H). 13C NMR (50.3 MHz, CDCl3): 197.8, 155.4, 148.5, 148.3,
143.6, 137.4, 135.7, 133.5, 131.9, 130.1, 129.9, 128.9, 128.8, 128.4,
127.7, 127.4, 127.3, 126.9, 126.6, 126.2, 125.9, 125.3, 120.4, 26.8. IR
(KBr): 3020, 1680, 1600 cmꢁ1. MS (EI) m/z: 373 (Mþ, 100), 359
(35). Anal. Calcd for C27H19NO: C, 86.84; H, 5.13; N, 3.75. Found:
C, 87.05; H, 5.11; N, 3.75.
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quinoline 4n
Orange solid (86 mg) was obtained from 84 mg of 1h and
150 mg of 2d (74% yield). Mp 60–62 ꢀC. 1H NMR (200 MHz,
CDCl3): d 8.11 (d, J¼8.4 Hz, 1H), 7.83 (d, J¼8.3 Hz, 1H), 7.65 (t,
J¼7.1 Hz, 1H), 7.47 (s, 1H), 7.45–7.35 (m, 5H), 6.79 (t, J¼2.5 Hz,
1H), 3.05–2.90 (m, 1H), 2.55 (s, 3H), 2.55–2.00 (m, 4H), 1.45–1.25
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147.5, 139.0, 137.6, 135.3, 130.6, 129.9, 129.1, 126.3, 125.7, 125.5,
125.3, 118.2, 43.9, 32.2, 27.8, 27.5, 27.2, 24.2, 15.7. IR (KBr): 3020,
2970, 1600, 1590 cmꢁ1. MS (EI) m/z: 388 (Mþ, 51), 373 (15), 331
(100). Anal. Calcd for C26H29NS: C, 80.57; H, 7.54; N, 3.61. Found:
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35. The reaction can be carried out also under a balloon of CO, with a slight
decrease (z10%) of yields.