Deproto-metallation using mixed lithium-zinc and lithium-copper bases and computed CH acidity of 2-substituted quinolines

Article abstract of DOI:10.1039/c4ra02583k

2-Substituted quinolines were synthesized, and their deproto-metallation using the bases prepared by mixing LiTMP with either ZnCl₂TMEDA (1/3 equiv.) or CuCl (1/2 equiv.) was studied. With phenyl and 2-naphthyl substituents, the reaction occurred at the 8 position of the quinoline ring, affording the corresponding iodo derivatives or 2-chlorophenyl ketones using the lithium-zinc or the lithium-copper combination, respectively. With a 4-anisyl substituent, a dideprotonation at the 8 and 3′ position was noted using the lithium-zinc base. With 3-pyridyl, 2-furyl and 2-thienyl substituents, the reaction took place on the substituent, at a position adjacent to its heteroatom. 2-Chlorophenyl-2-phenyl-8-quinolyl ketone could be cyclized under palladium catalysis. The experimental results were analyzed with the help of the CH acidities of the substrates, determined in THF solution using the DFT B3LYP method.

Full text of DOI:10.1039/c4ra02583k

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Deproto-metallation using mixed lithium–zinc and
lithium–copper bases and computed CH acidity of
2-substituted quinolines†
Cite this: RSC Adv., 2014, 4, 19602
a
a
a
a
*
Nada Marquise, Guillaume Bretel, Frederic Lassagne, Floris Chevallier,
´ ´
b
b
c
Thierry Roisnel, Vincent Dorcet, Yury S. Halauko, Oleg A. Ivashkevich,c
*
d
e
a
*
Vadim E. Matulis, Philippe C. Gros and Florence Mongin
2-Substituted quinolines were synthesized, and their deproto-metallation using the bases prepared by
mixing LiTMP with either ZnCl2$TMEDA (1/3 equiv.) or CuCl (1/2 equiv.) was studied. With phenyl and
2-naphthyl substituents, the reaction occurred at the 8 position of the quinoline ring, affording the
corresponding iodo derivatives or 2-chlorophenyl ketones using the lithium–zinc or the lithium–copper
combination, respectively. With a 4-anisyl substituent, a dideprotonation at the 8 and 30 position was
noted using the lithium–zinc base. With 3-pyridyl, 2-furyl and 2-thienyl substituents, the reaction took
place on the substituent, at a position adjacent to its heteroatom. 2-Chlorophenyl-2-phenyl-8-quinolyl
ketone could be cyclized under palladium catalysis. The experimental results were analyzed with the
help of the CH acidities of the substrates, determined in THF solution using the DFT B3LYP method.
Received 24th March 2014
Accepted 14th April 2014
DOI: 10.1039/c4ra02583k
www.rsc.org/advances
effects. Due to the low LUMO level of such substrates, very low
temperatures are oen required in the protocoles employed.
Introduction
Efficient tools for the deproto-metallation of sensitive
aromatic compounds have recently emerged. In particular,
synergic combinations of lithium reagents and soer metal
compounds such as bimetal ate compounds, salt-activated
metal amides, and pairs of metal amides have appeared as
promising alternatives to lithium bases,5 and notably in the
quinoline series.6
Quinolines are key heterocycles present in numerous natural
products and biologically active compounds.1 In addition,
derivatives are widely used in different elds, e.g. as biocides,
dyes, rubber chemicals and corrosion inhibitors.2 Depro-
tonative lithiation3 has been developed in the quinoline series,4
in general with recourse to substituents capable of directing the
reaction to specic sites through acidifying and/or coordinating
In the search of new bimetal ate bases, our group developed
(TMP)2CuLi(ꢀLiCl) (TMP ¼ 2,2,6,6-tetramethylpiperidido),7
a
lithiocuprate prepared in situ from CuCl and LiTMP. Besides its
possible use at room temperature, one main advantage of using
the base is the possible trapping of the formed arylmetal species
by aroyl chlorides to directly afford ketones.
a
´
Chimie et Photonique Moleculaires, Institut des Sciences Chimiques de Rennes, UMR
´
ˆ
6226 Universite de Rennes 1, CNRS, Batiment 10A, Case 1003, Campus Scientique de
Beaulieu, 35042 Rennes, France. E-mail: oris.chevallier@univ-rennes1.fr; orence.
mongin@univ-rennes1.fr; Fax: +33-2-2323-6955
Our group also developed the use of the TMP-based pair of
metal amides, in situ prepared by mixing ZnCl2$TMEDA
(TMEDA ¼ N,N,N',N'-tetramethylethylenediamine) with LiTMP
(3 equiv.),8 and supposed to be a 1 : 1 LiTMP$2LiCl(ꢀTMEDA)–
Zn(TMP)2 mixture.9 By complementing each other in deproto-
metallation reactions, this mixture of lithium and zinc amides
allows sensitive substrates to be mono- or di- deproto-metal-
lated, as evidenced by subsequent iodolysis.7c,8,10 In addition,
compared with both heteroleptic amido-organo lithium zinca-
tes10d and salt-activated hindered zinc amides,5d the above
combination allows the conversion of less activated substrates.
Synthesis of 2-substituted quinolines, e.g. 2-arylquinolines,
b
´
Centre de DIFfractometrie X, Institut des Sciences Chimiques de Rennes, UMR 6226
´
ˆ
Universite de Rennes 1, CNRS, Batiment 10B, Campus de Beaulieu, 35042 Rennes,
France
cUNESCO Chair of Belarusian State University, 14 Leningradskaya Str., Minsk,
220030, Belarus. E-mail: hys@tut.by
dResearch Institute for Physico-Chemical Problems of Belarusian State University, 14
Leningradskaya Str., Minsk, 220030, Belarus. Fax: +375-17-2264696
e
´
HECRIN, SRSMC, Universite de Lorraine-CNRS, Boulevard des Aiguillettes, 54506,
`
Vandoeuvre-Les-Nancy, France
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra,
calculated values of the Gibbs energies DacidG [kcal molꢁ1] for deprotonation at
the corresponding positions of the investigated quinolines, and cartesian
coordinates of molecular geometry for the most stable rotamer form of selected
quinolines (on example of 1f, 1h) (neutral molecule, gas phase) optimized at
B3LYP/6-31G(d) level of theory. CCDC 981282–981288. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ra02583k
¨
was recently simplied with the one-pot Friedlander access
from 2-nitroarylcarbaldehydes.11 We thus decided to study the
deprotonative metallation of the substrates 1 (Scheme 1) using
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Table 1 Synthesis of the quinoline substrates 1
Entry
Ketone
Product (R1, R2)
Yielda (%)
1
2
3
PhCOMe
2-NaphthylCOMe
4-MeOC6H4COMe
1a (Ph, H)
1b (2-naphthyl, H)
1c (4-MeOC6H4, H)
99
90
95
Scheme
studied.
1 Quinolines 1 for which the deproto-metallation was
both the lithium–zinc and the lithium–copper base in order to
prepare iodo derivatives and ketones, respectively, aer direct
trapping. We earlier showed that the regioselectivity of the
reactions for related substrates is partly determined by the
acidity of the different hydrogens in their molecules.7c,10j Simi-
larly, here we tried to rationalize the outcome of reactions by
using the CH acidities in THF of the quinoline-based substrates
calculated by means of the isodesmic reaction approach within
the density functional theory (DFT) framework.
4
1d (C6H4-2-CH2)
87
5
1e ((CH2)2C(t-Bu)CH2)
91
6
7
8
3-PyridylCOMe
2-FurylCOMe
2-ThienylCOMe
1f (3-pyridyl, H)
1g (2-furyl, H)
1h (2-thienyl, H)
89
100
80
a
Aer purication.
Results and discussions
Synthetic aspects
To reach the target quinolines 1, the conditions reported by Li,
Mulvihill and co-workers were employed.11 Thus, 2-nitro-
benzaldehyde was reduced using iron in the presence of cata-
lytic aqueous HCl, and the obtained 2-aminobenzaldehyde was
condensed in situ with ketones to form either 2-substituted or
2,3-disubstituted quinolines in high yields (Table 1). The
structure of 1e was conrmed by X-ray diffraction analysis
(Fig. 1, le).‡
Fig. 1 ORTEP diagram (50% probability) of 1e and 2a.
The lithium–zinc TMP-based mixture of amides, prepared
in situ from ZnCl2$TMEDA (0.5 equiv.) and LiTMP (1.5 equiv.),
was rst attempted for the deproto-metallation of the quino-
lines 1. Previous studies aimed at optimizing the reaction on
different substrates showed that THF is the most suitable
solvent, and 2 h a sufficient reaction time for a reaction per-
formed at room temperature.7c,10a,b In addition, iodolysis was
similarly identied as an efficient quenching mode for the
arylmetal compounds thus generated.10d
Upon treatment under these conditions, 2-phenyl and
2-naphthylquinoline 1a,b were converted to the corresponding
8-iodo derivatives 2a,b in 74 and 54% yield, respectively
(Scheme 2). The product 2a was identied unequivocally by
X-ray diffraction (Fig. 1, right).‡ Functionalization at the 8
position had previously been observed by deproto-lithiation4 or
-magnesiation6f,12 of quinolines, but in general either in the
presence of a directing group at the 7 position or in the absence
of free/accessible position on the quinoline ring. For bare
quinoline, deproto-metallation using the Kondo's TMP-zincate
LiZn(TMP)(t-Bu)2 followed by iodolysis was reported, and
showed the formation of both the 2- and 8-iodo regioisomers in
Scheme 2 Deproto-metallation of 1a,b followed by iodination.
a 3 : 7 ratio.13 A substituted 2 position together with the absence
of directing group on the pyridine ring leads to a reaction at the
8 position in the case of 1a,b.
Anisole being easily ortho-deprotonated under similar reac-
tion conditions,10d it was interesting to involve in the deproto-
nation–iodination sequence 2-(4-methoxyphenyl)quinoline (1c).
Under the same reaction conditions, the diiodide 3c was
obtained in 61% yield (Scheme 3). Such
a
double
‡ CIF les available in the ESI: CIF les of 1e (CCDC 981282), 2a (981283), 2h
(981284), 3h (981285), 4a (981286), 4b (981287), and 5a (981288).
Scheme 3 Deproto-metallation of 1c followed by iodination.
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functionalization generally does not take place using mono-
metal lithium bases, but is a reaction commonly observed using
the present lithium–zinc base.10e,g,j
In the case of 11H-indeno[1,2-b]quinoline (1d), no more ring
deprotonation was noted due to the presence of more acidic
benzylic hydrogens. Under the same reactions conditions, the
mono and diiodide 2d and 3d were isolated in 4 and 51% yield,
respectively (Scheme 4). From 2-tert-butyl-1,2,3,4-tetrahy-
droacridine (1e), a complex mixture of iodides was formed, a
result probably due to a larger number of deprotonation sites in
this case.
Scheme 7 Deproto-metallation of 1h followed by iodination.
By switching from 2-phenylquinoline (1a) to 2-(3-pyridyl)-
quinoline (1f), the regioselectivity of the reaction was
completely modied. The deproto-metallation no more took
place on the quinoline ring but on its pyridine substituent. In
addition, the two sites next to the pyridine ring were unregio-
selectively attacked, with a preference for the less hindered 6
position (product 2f, 47% yield) over the 2 position (product 2f0,
20% yield) (Scheme 5).
Fig. 2 ORTEP diagrams (50% probability) of 2h and 3h.
When submitted to the same reaction conditions, 2-(2-furyl)
quinoline (1g) was attacked at the furan ring, next to oxygen, to
afford the iodo derivative 2g in 71% yield (Scheme 6).
2-(2-Thienyl)quinoline (1h) had previously been deproto-
lithiated using butyllithium in ethereal solvents, either to give a
mixture resulting from a reaction at the 30 or 50 position at 0 ꢂC
(trapping with chlorotrimethylsilane),3a or to furnish the
product functionalized at the 50 position at ꢁ78 ꢂC (interception
by DMF).14
monoiodide 2h and diiodide 3h were isolated in 52 and 12%
yield, respectively (Scheme 7 and Fig. 2).
In order to reach other kinds of functionalization by direct
trapping aer deproto-metallation, we turned to another base.
It was decided to attempt the use of the lithiocuprate prepared
in situ from CuCl and LiTMP (2 equiv.) on some of the quinoline
substrates in order to prepare ketone derivatives by interception
with an aroyl chloride.7
Previous studies established THF containing TMEDA
(1 equiv.) as the most suitable solvent, and 2 h as a sufficient
reaction time for a reaction performed at room temperature.7
First, the TMP-based lithiocuprate, prepared in situ from CuCl
(1 equiv.) and LiTMP (2 equiv.), was evaluated for the deproto-
metallation of 2-phenyl and 2-naphthylquinoline 1a,b. Both
substrates were functionalized at their 8 position, affording
aer trapping with 2-chlorobenzoyl chloride the ketones 4a,b in
58 and 30% yield, respectively (for the latter, recovery of
starting material was also noted) (Scheme 8 and Fig. 3). Simi-
larly, 2-(2-thienyl)quinoline (1h) was converted to the ketone 4h,
isolated in 62% yield (Scheme 9).
By using the lithium–zinc base as before, the bis(heterocycle)
1h was functionalized at the thienyl ring. The corresponding
Scheme 4 Deproto-metallation of 1d followed by iodination.
It is possible to involve the generated heterocyclic iodides in
different transition metal-catalyzed coupling reactions,15 and
the chloro ketones in intramolecular direct arylation through
palladium-catalysed C–H bond activation.16 To attempt the
conversion of 8-(2-chlorobenzoyl)-2-phenylquinoline (4a) to the
Scheme 5 Deproto-metallation of 1f followed by iodination.
Scheme 6 Deproto-metallation of 1g followed by iodination.
19604 | RSC Adv., 2014, 4, 19602–19612
Scheme 8 Deproto-metallation of 1a,b followed by aroylation.
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pKa values experimentally found for 4-methylquinoline and
several alkylpyridines in THF,18 and for substituted arenes and
uorenes in CH3CN.19 Some experimental gas-phase acidities of
condensed heteroaromatics including bare quinoline were also
reported.20 To the long-standing semi-empirical studies of the
deprotonation energies of nitrogen heterocycles,21 DFT calcu-
lations of pKa values of benzo-azines22 and -quinuclidines23 were
recently added.
Fig. 3 ORTEP diagrams (50% probability) of 4a and 4b.
In the present paper, the DFT calculations of CH acidity of
the different quinolines, both in gas phase (see ESI†) and in
THF solution (Scheme 11), are presented. The gas phase acidi-
ties DacidG and pKa values in THF solution of all the substrates
were calculated using the theoretical protocol thoroughly
described previously.24 This approach already proved to be
worthy for substituted azines7c and biaryl compounds.10j
All the calculations were performed by using the DFT B3LYP
method. The geometries were fully optimized using the
6-31G(d) basis set. No symmetry constraints were implied. In
order to perform stationary points assessment and to calculate
zero-point vibrational energies (ZPVE) and thermal corrections,
the Hessian matrix eigenvalues were calculated at the same level
of theory. The single point energies were found using the
6-311+G(d,p) basis set and tight convergence criteria. The gas
phase Gibbs energies (G0298) were calculated for each isolated
species using the following equation:
Scheme 9 Deproto-metallation of 1h followed by aroylation.
uorenone 5a, we proceeded as reported for the cyclization of
2-chloro diaryl aniline to carbazole.17 Using catalytic amounts of
Pd(OAc)2, Cy3P (Cy ¼ cyclohexyl) as an electron-rich and bulky
trialkyl phosphine, K2CO3 as a base and DMF as solvent at
130 ꢂC afforded the tetracycle 5a in a moderate 45% yield due to
the competitive formation of 8-benzoyl-2-phenylquinoline in
30% yield (Scheme 10 and Fig. 4).
G0298 ¼ E + ZPVE + H0/298 ꢁ TS2098
.
The gas phase acidities DacidG were determined as the Gibbs
Computational aspects
energies of deprotonation of the substrates R–H (R–H(g) / Rꢁ
(g)
Unfortunately, both experimental and computational data on
CH acidity for quinoline and its derivatives are scanty. The main
reasons are the necessity of using very strong bases at low
temperatures, the possible side reactions of the generated
carbanions and also the acidity closeness between different C–
H bonds in such condensed aromatics. A brief review of papers,
devoted to experimental and theoretical investigation of CH
acidity in azines, is presented in our previous publication.7c For
such aromatic substrates, one should especially mention the
+ H+(g)) by the following formula:
Scheme 10 Cyclization to 5a.
Fig. 4 ORTEP diagrams (50% probability) of 5a.
Scheme 11 Calculated values of pKa (THF) of the quinoline substrates.
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D
acidG ¼ G2098(Rꢁ) + G0298(H+) ꢁ G2098(RH).
Discussion
The calculations of the CH acidities in THF of 1a–d and 1f–h
(Scheme 11) allowed us to comment on the regioselectivities
observed in the course of the reactions involving these
substrates.
The solvent effects were treated by using the polarized
continuum model (PCM) with the default parameters for THF.25
The PCM energies EPCM were also calculated at the B3LYP/6-
311+G(d,p) level using geometries optimized for isolated
structures. The Gibbs energies in solution Gs were calculated for
each species by the formula:
The calculations performed on the quinoline derivatives 1a,b
show that the hydrogens at the two free positions of the pyrido
ring are more acidic than those of the benzo and aryl rings.
Nevertheless, reactions did not lead to any 3- and 4-substituted
quinolines but to the 8-iodo and 8-(2-chlorobenzoyl) derivatives
2a,b and 4a,b, respectively using the lithium–zinc (Scheme 2)
and lithium–copper (Scheme 8) bases. Such reactions at the
8 position could be due to the presence of a nitrogen able to
coordinate a metal, either favouring the approach of the base
and/or stabilizing the arylmetal compound formed. Recently,
C–H borylation of quinoline derivatives was similarly observed
at the C8 position.26
Using the lithium–zinc base under the same reaction condi-
tions with the substrate 1c led to the formation of the diiodide 3c
(Scheme 3). When a methoxy group is present on the phenyl
ring, the ortho sites are acidied by its inductive effect and their
pKa values become similar to those of the quinoline pyrido
hydrogens. This could explain the formation of a heteroaryl
compound metallated both at the 8 position peri to the quino-
line nitrogen and at the 30 position ortho to the methoxy group.
From the substrate 1d and the lithium–zinc base, the diio-
dide 3d was predominately formed (Scheme 4). This can be
rationalized in terms of a huge pKa values difference in favour of
benzylic hydrogens. pKa (THF) values less than 20 are typical of
those for uorenes with acceptor substituents.19 The same
effect, enhanced by a larger number of potential deprotonation
sites, was noted in the case of 1e, leading to a mixture of
iodides.
In the case of the substrate 1f, with a 3-pyridyl group con-
nected to the 2 position of the quinoline ring, deproto-metal-
lation was only observed on the pyridine group in spite of higher
acidities at the quinoline pyrido ring (Scheme 5). Such a result
could be rationalized by a coordination exerted by the pyridine
nitrogen toward a metal, either intermolecularly (approach of
the metallic base) or intramolecularly (internal stabilization of
the metallated species). The result suggests a more unlikely
coordination by the quinoline nitrogen, maybe for steric
reasons.
Upon treatment by the lithium–zinc and lithium–copper
base, the quinolines 2-substituted by a 2-furyl and 2-thienyl
group 1g,h were functionalized on the ve-membered ring, and
mainly at the 50 position (Schemes 6, 7 and 9). The reason why
there is no functionalization at the 8 position of the quinoline
ring could be in relation with the presence of a clearly more
acidic site at the position adjacent to the furan and thiophene
heteroatom.
Gs ¼ G0298 + EPCM ꢁ E.
To cancel the majority of calculation errors, the pKa values
were calculated by means of the following isodesmic reaction:
R–H(s) + Hetꢁ(s) / Rꢁ + Het–H(s)
,
(s)
where Het–H is an appropriate heterocycle with experimentally
determined pKa values. In the present study, pyridine was
chosen as the reference compound owing to its structural
similarity and expected pKa proximity.
It could be shown easily that the Gibbs energies of the iso-
desmic reactions (DrGs) and the corresponding pKa values are
linked together by the following equation:
DrGs
1
pKaðR ꢁ HÞ ¼ 40:2 þ
:
RT ln 10
The CH acidity of the methoxy group for the substrate 1c was
not considered here since it was expected to be signicantly
lower and there was no sign of its deprotonation in the exper-
iment. The calculations on 1e were also skipped due to the
obvious prevalence of benzylic acidity in deprotonation.
It is obvious that, with the exception of 1a and 1d, all the
investigated arylquinolines exist in form of several rotamers. So,
the data on Scheme 11 (and ESI†) refer to the most stable ones.
Among these molecules with several rotamers, the naphthyl
derivative 1b is likely to exist in the stretched form, 1f and 1g
with remote heteroatoms, while for the sulfur-containing
compound 1h the syn-form should prevail. These ndings are in
agreement with those for arylated azoles.10k
There are several potential deprotonation sites in the inves-
tigated substrates. When comparing the CH acidity in gas-phase
(see ESI†) and in THF solution (Scheme 11), the correlation can
be easily seen. The analysis of the obtained results shows that
CH acidity increases logically with the introduction of electron-
withdrawing groups, and decreases for electron-donating ones.
The calculated values of gas-phase acidity of the investigated
quinolines mostly lie within the range of 375 to 390 kcal molꢁ1
(see ESI†). Such DacidG values are typical of very weak acids and
correspond to those found previously in experiment for bare
quinoline20 (exp. 376.9 kcal molꢁ1 vs. calc. 377.3 kcal molꢁ1
,
position 4) as well as for computed ones.22 When analyzing the
pKa values distribution for a common quinolinic part of the
molecules, one can see some general trends. The most acidic
hydrogen is at the position 4, while the least acidic is at the 8.
These results, together with earlier ndings for azines7c and
biaryls,10j lead us to the following conclusions. The pKa values
obtained by our theoretical protocol are useful for the reaction
outcome prediction. When using amido-based bimetallic bases
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ꢂ
in THF solution, it seems that there is a boundary corre- mL, 0.5 mmol). The mixture was then stirred at 95 C for 1 h.
sponding to a pKa value of ca. 36. Consequently, the substrates The required ketone (10 mmol) was then added. KOH (0.67 g,
with C–H bonds of enough acidity are deprotonated at the most 12 mmol) was introduced portionwise (Caution! Potential exo-
acidic site in THF at moderate temperatures. The other option therm) before stirring at 95 ꢂC for 30 min. The mixture was
implies a substitution at a position adjacent to the ring nitrogen cooled to room temperature, diluted with CH2Cl2 (300 mL) and
through metal complexation for weak CH acids (this course of ltered over silica. The ltrate was dried over MgSO4, and the
the reaction could be enhanced by using less polar solvents at solvents were removed under vacuum. The crude product was
low temperatures).
puried by chromatography over silica gel (eluent: 4 : 1
heptane–AcOEt).
2-Phenylquinoline (1a). 2-Phenylquinoline (1a) was prepared
from acetophenone (1.2 mL) using the general procedure 1, and
was isolated in 99% yield (2.0 g) as a white solid: mp 85 ꢂC; 1H
NMR (CDCl3, 300 MHz) 7.46–7.56 (m, 4H), 7.73 (m, 1H), 7.84
(dd, 1H, J ¼ 1.2 and 8.1 Hz), 7.89 (d, 1H, J ¼ 8.6 Hz), 8.15–8.18
(m, 3H), 8.23 (d, 1H, J ¼ 8.6 Hz); 13C NMR (CDCl3, 75 MHz)
119.1, 126.4, 127.3, 127.6, 127.7 (2C), 129.0 (2C), 129.4, 129.8,
129.9, 136.9, 139.8, 148.4, 157.5. These data are analogous to
those obtained from a commercial sample.
2-(2-Naphthyl)quinoline (1b). 2-(2-Naphthyl)quinoline (1b)
was prepared from 2-acetonaphthone (1.7 g) using the general
procedure 1, and was isolated in 90% yield (2.3 g) as a white
solid: mp 160 ꢂC (lit.28 162–163 ꢂC); 1H NMR (CDCl3, 300 MHz)
7.54 (m, 3H), 7.76 (m, 1H), 7.78–7.93 (m, 2H), 8.02 (m, 3H), 8.24
(m, 2H), 8.3 (m, 1H), 8.63 (d, 1H, J ¼ 1.2 Hz); 13C NMR (CDCl3,
75 MHz) 119.2, 125.2, 126.4, 126.8, 127.2, 127.3, 127.6, 127.8,
128.3, 128.7, 128.9, 129.8, 129.9, 133.6, 134.0, 136.9, 137.0,
148.5, 157.2. The NMR data are analogous to those previously
described.28
Conclusions
Upon treatment with the lithium–zinc base prepared in situ from
ZnCl2$TMEDA (0.5 equiv.) and LiTMP (1.5 equiv.), different
2-arylquinolines were deproto-metallated, as evidenced by
subsequent interception by iodine. In the presence of unsub-
stituted phenyl and naphthyl substituents, a single reaction at
the 8 position was noted; in contrast, with a 4-anisyl group
bearing a substituent able to acidify the neighbouring hydro-
gens, a double functionalization took place at both the 8 and 30
position. When a 3-pyridyl, a 2-furyl or a 2-thienyl was connected
to the 2 position of the quinoline ring, the reaction occurred on
this heteroaryl substituent, next to nitrogen, oxygen or sulfur,
respectively. The iodo derivatives could be elaborated, for
example by Suzuki cross-coupling as shown recently in the pyr-
azole series.10e
Using the corresponding lithiocuprate generated from CuCl
(1 equiv.) and LiTMP (2 equiv.), a similar regioselectivity was
observed. 2-Chlorophenyl ketones could be prepared, and a
subsequent palladium-catalysed cyclization to polycycle
demonstrated.
The CH acidities of the substrates in THF solution, which
were calculated using a continuum solvation model, were used
to rationalize the outcome of the reactions. The related
substances could be preliminary functionalized to enhance the
regioselectivity of deproto-metallation.
2-(4-Methoxyphenyl)quinoline (1c). 2-(4-Methoxyphenyl)-
quinoline (1c) was prepared from 4-methoxyacetophenone
(1.5 g) using the general procedure 1, and was isolated in 95%
1
yield (2.2 g) as a yellow solid: mp 124 C (lit.29 123–125 C); H
NMR (CDCl3, 300 MHz) 3.89 (s, 3H), 7.05 (d, 2H, J ¼ 8.9 Hz), 7.50
(m, 1H), 7.71 (m, 1H), 7.81 (m, 1H), 7.84 (d, 1H, J ¼ 8.7 Hz), 8.13
(m, 1H), 8.14 (d, 2H, J ¼ 8.9 Hz), 8.18 (d, 1H, J ¼ 8.7 Hz); 13C
NMR (CDCl3, 75 MHz) 55.5, 114.3 (2C), 118.7, 126.0, 127.0,
127.6, 129.0 (2C), 129.6, 129.7, 132.4, 136.7, 148.4, 157.0, 160.9.
The NMR data are analogous to those previously described.29
11H-Indeno[1,2-b]quinoline (1d). 11H-Indeno[1,2-b]quino-
line (1d) was prepared from 1-indanone (1.3 g) using the general
procedure 1, and was isolated in 87% yield (1.9 g) as a yellow
solid: mp 166 ꢂC (lit.30 164–166 ꢂC); 1H NMR (CDCl3, 300 MHz)
4.01 (s, 2H), 7.49 (m, 3H), 7.59 (m, 1H), 7.70 (m, 1H), 7.80
ꢂ
ꢂ
Experimental
General methods
Metallation reactions were performed under an argon atmosphere.
THF was distilled over sodium/benzophenone. Column chroma-
tography separations were achieved on silica gel (40–63 mm).
Melting points were measured on a Koer apparatus. IR spectra
were taken on a Perkin-Elmer Spectrum 100 spectrometer. 1H and
13C Nuclear Magnetic Resonance (NMR) spectra were recorded on
a Bruker Avance III spectrometer at 300 and 75 MHz, respectively.
1H chemical shis (d) are given in ppm relative to the solvent
residual peak, 13C chemical shis are relative to the central peak of
the solvent signal.27 Mass spectra (HRMS) measurements were
(m, 1H), 8.15 (s, 1H), 8.21 (d, 1H, J ¼ 8.5 Hz), 8.30 (m, 1H); 13
C
NMR (CDCl3, 75 MHz) 34.1, 122.1, 125.6, 125.8, 127.5, 127.6,
127.9, 128.9, 129.2, 130.1, 131.2, 134.7, 140.5, 145.2, 148.2,
161.8. These data are analogous to those previously described.30
2-tert-Butyl-1,2,3,4-tetrahydroacridine (1e). 2-tert-Butyl-
1,2,3,4-tetrahydroacridine (1e)31 was prepared from 4-tert-
butylcyclohexanone (1.5 g) using the general procedure 1, and
´
performed at the CRMPO (Centre Regional de Mesures Physiques
de l'Ouest) of Rennes using a Waters Q-TOF 2 instrument.
ꢂ
was isolated in 88% yield (2.1 g) as a white solid: mp 91 C; IR
(ATR): 3870, 3753, 3620, 3194, 2945, 2923, 2548, 2313, 2051,
1618, 1601, 1494, 1428, 1416, 1365, 1234, 1159, 955, 931, 782,
General procedure 1 for the synthesis of the substituted
quinolines 1a–h11
765, 752 cmꢁ1 1H NMR (CDCl3, 300 MHz) 0.99 (s, 9H), 1.57
;
(m, 2H), 2.15 (m, 1H), 2.70 (m, 1H), 3.03 (m, 2H), 3.25 (m, 1H),
To 2-nitrobenzaldehyde (1.5 g, 10 mmol) in EtOH (20 mL) was 7.41 (dd, 1H, J ¼ 7.0 and 8.0 Hz), 7.59 (dd, 1H, J ¼ 7.0 and 8.1
added iron powder (2.2 g, 40 mmol) and 0.1 N aqueous HCl (5 Hz), 7.67 (d, 1H, J ¼ 8.1 Hz), 7.79 (s, 1H), 7.97 (d, 1H, J ¼ 8.0 Hz);
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13C NMR (CDCl3, 75 MHz) 24.6, 27.3 (3C), 30.8, 32.6, 34.4, 44.6, 1.3 and 8.0 Hz), 7.95 (d, 1H, J ¼ 8.6 Hz), 8.13 (d, 1H, J ¼ 8.6 Hz),
125.5, 126.9, 127.2, 128.3, 128.5, 131.2, 135.2, 146.6, 159.4.
8.33–8.38 (m, 3H); 13C NMR (CDCl3, 75 MHz) 104.7, 119.2,
2-(3-Pyridyl)quinoline (1f). 2-(3-Pyridyl)quinoline (1f) was 127.5, 127.7, 127.8, 128.4, 128.9, 129.0, 129.1, 129.9, 137.5,
prepared from 3-acetylpyridine (1.1 g) using the general proce- 138.7, 140.1, 146.7, 157.7.
dure 1, and was isolated in 89% yield (1.8 g) as a yellow solid:
8-Iodo-2-(2-naphthyl)quinoline (2b). 8-Iodo-2-(2-naphthyl)-
mp 68 ꢂC (lit.29 69–72 ꢂC); 1H NMR (CDCl3, 300 MHz) 7.45 (ddd, quinoline (2b) was obtained from 2-(2-naphthyl)quinoline (1b,
1H, J ¼ 0.8, 4.8 and 8.0 Hz), 7.55 (ddd, 1H, J ¼ 1.1, 6.9 and 8.1 0.26 g) using the general procedure 2 (eluent: 1 : 1 heptane–
1
ꢂ
Hz), 7.75 (ddd, 1H, J ¼ 1.3, 6.9 and 8.4 Hz), 7.84 (br dd, 1H, J ¼ CH2Cl2) in 54% yield (0.21 g) as a yellow solid: mp 210 C; H
1.3 and 8.1 Hz), 7.87 (d, 1H, J ¼ 8.6 Hz), 8.17 (br d, 1H, J ¼ 8.4 NMR (CDCl3, 300 MHz) 7.19 (dd, 1H, J ¼ 7.5 and 8.0 Hz), 7.53
Hz), 8.25 (br d, 1H, J ¼ 8.6 Hz), 8.50 (ddd, 1H, J ¼ 1.8, 2.3 and 8.0 (m, 2H), 7.74 (dd, 1H, J ¼ 1.2 and 8.0 Hz), 7.88–8.09 (m, 5H),
Hz), 8.70 (dd, 1H, J ¼ 1.8 and 4.8 Hz), 9.35 (dd, 1H, J ¼ 0.8 and 8.34 (dd, 1H, J ¼ 1.2 and 7.5 Hz), 8.60 (dd, 1H, J ¼ 1.7 and 8.6
2.3 Hz); 13C NMR (CDCl3, 75 MHz) 118.6, 123.7, 126.9, 127.4, Hz), 8.68 (br s, 1H); 13C NMR (CDCl3, 75 MHz) 104.8, 119.3,
127.6, 129.8, 130.1, 135.0, 135.2, 137.2, 148.5, 148.9, 150.3, 125.2, 126.4, 127.0, 127.3, 127.5, 127.7, 127.8, 128.4, 128.7,
154.7. The NMR data are analogous to those previously 129.0, 133.5, 134.2, 136.0, 137.5, 140.1, 146.8, 157.5; HRMS
described.29
2-(2-Furyl)quinoline (1g). 2-(2-Furyl)quinoline (1g) was
(ESI): calcd for C19H12IN [M + H]+ 381.0014, found 381.0012.
8-Iodo-2-(3-iodo-4-methoxyphenyl)quinoline (3c). 8-Iodo-2-
prepared from 2-acetylfuran (1.1 g) using the general procedure (3-iodo-4-methoxyphenyl)quinoline (3c) was obtained from 2-(4-
1, and was isolated in 100% yield (2.0 g) as a yellow solid: mp 94 methoxyphenyl)quinoline (1c, 0.24 g) using the general proce-
ꢂC (lit.32 94 ꢂC); 1H NMR (CDCl3, 300 MHz) 6.59 (dd, 1H, J ¼ 1.8 dure 2 (eluent: 4 : 1 heptane–AcOEt) in 61% yield (0.30 g) as a
and 3.4 Hz), 7.24 (br d, 1H, J ¼ 3.4 Hz), 7.49 (ddd, 1H, J ¼ 1.1, 6.9 yellow solid: mp 158 ꢂC; 1H NMR (CDCl3, 300 MHz) 3.97 (s, 3H),
and 8.1 Hz), 7.63 (dd, 1H, J ¼ 0.7 and 1.8 Hz), 7.70 (ddd, 1H, J ¼ 6.98 (d, 1H, J ¼ 8.7 Hz), 7.22 (dd, 1H, J ¼ 7.5 and 8.0 Hz), 7.78
1.3, 6.9 and 8.4 Hz), 7.77 (br dd, 1H, J ¼ 1.3 and 8.1 Hz), 7.82 (dd, 1H, J ¼ 1.2 and 8.0 Hz), 7.86 (d, 1H, J ¼ 8.6 Hz), 8.1 (d, 1H, J
(d, 1H, J ¼ 8.5 Hz), 8.15 (br d, 1H, J ¼ 8.4 Hz), 8.16 (br d, 1H, J ¼ ¼ 8.6 Hz), 8.33 (dd, 1H, J ¼ 1.2 and 7.5 Hz), 8.37 (dd, 1H, J ¼ 2.2
8.5 Hz); 13C NMR (CDCl3, 75 MHz) 110.2, 112.3, 117.5, 126.3, and 8.7 Hz), 8.74 (d, 1H, J ¼ 2.2 Hz); 13C NMR (CDCl3, 75 MHz)
127.2, 127.6, 129.4, 129.9, 136.7, 144.2, 148.1, 149.1, 153.7. 56.7, 86.5, 104.5, 111.0, 118.6, 127.5, 127.6, 128.4, 129.3, 133.2,
These data are analogous to those previously described.32
2-(2-Thienyl)quinoline (1h). 2-(2-Thienyl)quinoline (1h) was
prepared from acetyl thiophene (1.3 g) using the general
137.7, 138.9, 140.3, 146.7, 155.9, 159.7; HRMS (ESI): calcd for
C
16H11I2NO [M + H]+ 486.8930, found 486.8927.
11-Iodo-11H-indeno[1,2-b]quinoline (2d). 11-Iodo-11H-
procedure 1, and was isolated in 80% yield (1.7 g) as a yellow indeno[1,2-b]quinoline (2d) was obtained from 11H-indeno[1,2-
solid: mp 129 ꢂC (lit.30 130–132 ꢂC); 1H NMR (CDCl3, 300 MHz) b]quinoline (1d, 0.22 g) using the general procedure 2 (eluent:
7.16 (m, 1H), 7.17 (m, 2H), 7.73–7.80 (m, 4H), 8.11 (m, 2H); 13
NMR (CDCl3, 75 MHz) 117.7, 125.9, 126.2, 127.3, 127.6, 128.2, 211 C (rapidly decomposes by loss of iodine); IR (ATR): 3742,
C
4 : 1ꢂheptane–AcOEt) in 4% yield (14 mg) as a yellow solid: mp
128.7, 129.3, 129.9, 136.7, 145.5, 148.2, 152.4. These data are 3417, 3238, 2925, 2329, 1717, 1621, 1459, 1380, 1257, 1175,
1
analogous to those previously described.30
1138, 856, 735 cmꢁ1; H NMR (CDCl3, 300 MHz) 5.51 (s, 1H),
7.48–7.55 (m, 3H), 7.71 (ddd, 1H, J ¼ 1.4, 6.9 and 8.4), 7.81
(m, 1H), 7.88 (dd, 1H, J ¼ 1.2 and 8.1), 8.23 (br d, 1H, J ¼ 8.4),
8.33 (m, 2H).
General procedure 2 for the deprotonative metallation using
the lithium–zinc base followed by iodination
11,11-Diiodo-11H-indeno[1,2-b]quinoline (3d). 11,11-Diiodo-
ꢂ
To a stirred, cooled (0 C) solution of 2,2,6,6-tetramethylpiper- 11H-indeno[1,2-b]quinoline (3d) was obtained from 11H-indeno-
idine (0.26 mL, 1.5 mmol) in THF (3 mL) was added BuLi (about [1,2-b]quinoline (1d, 0.22 g) using the general procedure 2
1.6 M hexanes solution, 1.5 mmol). Aer 15 min at 0 ꢂC, (eluent: 4 : 1 heptane–AcOEt) in 51% yield (0.24 g) as an orange
ZnCl2$TMEDA (0.13 g, 0.50 mmol) was added, and the mixture liquid: IR (ATR): 3333, 2933, 2345, 1713, 1621, 1604, 1578, 1387,
was stirred for 15 min at this temperature before introduction of 1039, 924, 864, 766 cmꢁ1; 1H NMR (CDCl3, 300 MHz) 7.52–7.91
the substrate (1.0 mmol). Aer 2 h at room temperature, a (m, 6H), 8.12 (m, 1H), 8.39 (m, 2H); 13C NMR (CDCl3, 75 MHz)
solution of I2 (0.38 g, 1.5 mmol) in THF (5 mL) was added. The 26.2, 122.0, 124.3, 126.6, 127.4, 128.3, 130.0, 130.4, 130.7, 131.8,
mixture was stirred overnight before addition of an aqueous 132.3, 132.7, 135.8, 137.6, 144.0, 150.8; HRMS (ESI): calcd for
saturated solution of Na2S2O3 (10 mL) and extraction with
C
16H9I2N [M + H]+ 468.8824, found 468.8820.
CH2Cl2 (3 ꢃ 20 mL). The combined organic layers were dried
2-(6-Iodo-3-pyridyl)quinoline (2f). 2-(6-Iodo-3-pyridyl)quino-
over Na2SO4 and concentrated under reduced pressure before line (2f) was obtained from 2-(3-pyridyl)quinoline (1f, 0.21 g)
purication by ash chromatography on silica gel (the eluent is using the general procedure 2 (eluent: 4 : 1 heptane–AcOEt) in
given in the product description).
8-Iodo-2-phenylquinoline (2a). 8-Iodo-2-phenylquinoline 1737, 1420, 1380, 1015, 793, 757 cmꢁ1
47% yield (0.16 g) as a yellow solid: mp 151 ꢂC; IR (ATR): 2925,
1H NMR (CDCl3, 300
;
(2a) was obtained from 2-phenylquinoline (1a, 0.21 g) using the MHz) 7.57 (ddd, 1H, J ¼ 0.9, 7.0 and 7.9 Hz), 7.76 (ddd, 1H, J ¼
general procedure 2 (eluent: 9 : 1 heptane–AcOEt) in 74% yield 1.3, 7.0 and 8.4 Hz), 7.85 (m, 3H), 8.16 (m, 2H), 8.26 (d, 1H, J ¼
(0.25 g) as a yellow solid: mp 89 ꢂC; IR (ATR): 2349, 1596, 1483, 8.6 Hz), 9.07 (d, 1H, J ¼ 2.5 Hz); 13C NMR (CDCl3, 75 MHz) 118.3,
1284, 954, 835, 760, 689 cmꢁ1; 1H NMR (CDCl3, 300 MHz) 7.23 119.2, 127.3, 127.6, 127.7, 129.6, 130.5, 134.5, 135.2, 136.8,
(dd, 1H, J ¼ 7.4 and 8.0 Hz), 7.48–7.58 (m, 3H), 7.80 (dd, 1H, J ¼
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137.8, 148.2, 149.7, 153.5; HRMS (ESI): calcd for C14H9IN2 [M + treated with TMEDA (0.15 mL, 1.0 mmol) and CuCl (99 mg, 1.0
H]+ 331.9810, found 331.9804.
mmol). The mixture was stirred for 15 min at 0 ꢂC before
2-(2-Iodo-3-pyridyl)quinoline (2f0). 2-(2-Iodo-3-pyridyl)quino- introduction of the required substrate (1.0 mmol). Aer 2 h at rt,
line (2f0) was obtained from 2-(3-pyridyl)quinoline (1f, 0.21 g) a solution of 2-chlorobenzoyl chloride (0.25 mL, 2.0 mmol) in
ꢂ
using the general procedure 2 (eluent: 4 : 1 heptane–AcOEt) in THF (3 mL) was added. The mixture was stirred at 60 C over-
20% yield (66 mg) as a yellow solid: mp 108 ꢂC; IR (ATR): 3039, night before addition of a 1 M aqueous solution of NaOH
2922, 2849, 1740, 1594, 1570, 1555, 1548, 1501, 1421, 1380, (10 mL) and extraction with Et2O (2 ꢃ 20 mL). Aer washing the
1046, 1025, 834, 802, 728 cmꢁ1; 1H NMR (CDCl3, 300 MHz) 7.40 organic phase with an aqueous saturated solution of NH4Cl
(dd, 1H, J ¼ 4.7 and 7.6 Hz), 7.62 (ddd, 1H, J ¼ 1.2, 6.9 and 8.1 (10 mL) and drying over anhydrous Na2SO4, the solvent was
Hz), 7.70 (d, 1H, J ¼ 8.5 Hz), 7.78 (ddd, 1H, J ¼ 1.5, 6.9 and 8.3 evaporated under reduced pressure, and the product was iso-
Hz), 7.80 (dd, 1H, J ¼ 2.0 and 7.6 Hz), 7.90 (dd, 1H, J ¼ 1.2 and lated aer purication by ash chromatography on silica gel
8.1 Hz), 8.16 (br d, 1H, J ¼ 8.3 Hz), 8.27 (br d, 1H, J ¼ 8.5 Hz), (the eluent is given in the product description).
8.43 (dd, 1H, J ¼ 2.0 and 4.7 Hz); 13C NMR (CDCl3, 75 MHz)
8-(2-Chlorobenzoyl)-2-phenylquinoline (4a). 8-(2-Chlor-
120.3, 122.4, 123.1, 127.3, 127.4, 127.8, 129.7, 130.3, 136.4, obenzoyl)-2-phenylquinoline (4a) was obtained from 2-phenyl-
137.8, 143.1, 147.9, 150.3, 158.6; HRMS (ESI): calcd for C14H9IN2 quinoline (1a, 0.21 g) using the general procedure 3 (eluent:
[M + H]+ 331.9810, found 331.9802.
19 : 1 heptane–AcOEt) in 58% yield (0.20 g) as a yellow powder;
2-(5-Iodo-2-furyl)quinoline (2g). 2-(5-Iodo-2-furyl)quinoline mp 126 ꢂC; IR (ATR): 3627, 3496, 3056, 2607, 1665, 1584, 1544,
(2g) was obtained from 2-(2-furyl)quinoline (1g, 0.20 g) using 1437, 1344, 1288, 1239, 1074, 1033, 817, 751, 700, 688 cmꢁ1; 1H
the general procedure 2 (eluent: 9 : 1 heptane–AcOEt) in 71% NMR (CDCl3, 300 MHz) 7.15–7.32 (m, 6H), 7.42 (dd, 2H, J ¼ 1.5
yield (0.23 g) as a brown solid: mp 159 ꢂC; IR (ATR): 1595, 1500, and 8.2 Hz), 7.52 (dd, 1H, J ¼ 7.3 and 8.0 Hz), 7.57–7.60 (m, 1H),
1066, 1013, 780 cmꢁ1; 1H NMR (CDCl3, 300 MHz) 6.75 (d, 1H, J 7.76 (d, 1H, J ¼ 8.7 Hz), 7.88 (dd, 1H, J ¼ 1.4 and 8.1 Hz), 8.07
¼ 3.4 Hz), 7.17 (d, 1H, J ¼ 3.4 Hz), 7.50 (ddd, 1H, J ¼ 1.2, 6.9 and (dd, 1H, J ¼ 1.5 and 7.2 Hz) 8.08 (d, 1H, J ¼ 8.7 Hz); 13C NMR
8.1 Hz), 7.70 (ddd, 1H, J ¼ 1.3, 6.9 and 8.7 Hz), 7.78 (dd, 1H, J ¼ (CDCl3, 75 MHz) 118.6 (CH), 126.1 (CH), 126.8 (CH), 127.0 (C),
1.3 and 8.1 Hz), 7.82 (d, 1H, J ¼ 8.6 Hz), 8.09 (br d, 1H, J ¼ 8.7 127.4 (2CH), 128.5 (2CH), 129.7 (CH), 130.4 (CH), 130.7 (CH),
Hz), 8.16 (br d, 1H, J ¼ 8.6 Hz); 13C NMR (CDCl3, 75 MHz) 90.5, 131.3 (CH), 131.8 (CH), 131.9 (CH), 132.1 (C), 136.9 (CH), 138.3
112.8, 117.3, 123.2, 126.6, 127.4, 127.7, 129.2, 130.2, 137.1, (C), 138.5 (C), 141.5 (C), 145.9 (C), 156.4 (C), 197.2 (C); HRMS
147.8, 147.9, 159.0; HRMS (ESI): calcd for C13H8INO [M + H]+ (ASAP): calcd for C22H1535ClNO [M + H]+ 344.0842, found
320.9651, found 320.9652.
344.0842.
8-(2-Chlorobenzoyl)-2-(2-naphthyl)quinoline
2-(5-Iodo-2-thienyl)quinoline (2h). 2-(5-Iodo-2-thienyl)quin-
(4b).
8-(2-
oline (2h) was obtained from 2-(2-thienyl)quinoline (1h, 0.21 g) Chlorobenzoyl)-2-(2-naphthyl)quinoline (4b) was obtained from
using the general procedure 2 (eluent: 3 : 2 heptane–CH2Cl2) in 2-(2-naphthyl)quinoline (1b, 0.26 g) using the general procedure
52% yield (0.18 g) as a yellow solid: mp 156 ꢂC; IR (ATR): 1595, 3 (eluent: 4 : 1 heptane–AcOEt) in 30% yield (0.12 g) as a yellow
1499, 1418, 819, 782 cmꢁ1
;
1H NMR (CDCl3, 300 MHz) 7.31 powder: mp 192 ꢂC; IR (ATR): 3050, 2345, 1673, 1590, 1558,
(d, 1H, J ¼ 3.9 Hz), 7.38 (d, 1H, J ¼ 3.9 Hz), 7.50 (ddd, 1H, J ¼ 1.2, 1284, 1265, 1036, 933, 827, 809, 755, 744, 727 cmꢁ1; H NMR
6.9 and 8.1 Hz), 7.71 (ddd, 1H, J ¼ 1.5, 6.9 and 8.4 Hz), 7.72 (CDCl3, 300 MHz) 7.40–7.53 (m, 5H), 7.60–7.75 (m, 4H), 7.81–
(d, 1H, J ¼ 8.6 Hz), 7.78 (br d, 1H, J ¼ 8.1 Hz), 8.07 (br d, 1H, J ¼ 7.87 (m, 2H), 8.02–8.06 (m, 2H), 8.14 (s, 1H), 8.67 (dd, 1H, J ¼ 1.5
8.4 Hz), 8.15 (br d, 1H, J ¼ 8.6 Hz); 13C NMR (CDCl3, 75 MHz) and 7.2 Hz), 8.26 (d, 1H, J ¼ 8.7 Hz); 13C NMR (CDCl3, 75 MHz)
78.3, 117.0, 126.4, 126.9, 127.3, 127.6, 129.2, 130.1, 136.9, 138.1, 118.9 (CH), 124.8 (CH), 126.2 (CH), 126.3 (CH), 126.8 (CH), 126.9
1
148.0, 151.3, 151.3.
(CH), 127.0 (CH), 127.7 (CH), 128.1 (CH), 128.9 (CH), 130.5 (CH),
2-(3,5-Diiodo-2-thienyl)quinoline
(3h).
2-(3,5-Diiodo-2- 130.8 (CH), 131.5 (CH), 131.8 (CH), 131.9 (CH), 132.2 (C), 133.4
thienyl)quinoline (3h) was obtained from 2-(2-thienyl)quinoline (C), 134.1 (C), 136.0 (C), 136.9 (CH), 137.9 (C), 138.4 (C), 141.5
(1h, 0.21 g) using the general procedure 2 (eluent: 3 : 2 heptane– (C), 146.1 (C), 156.3 (C), 197.3 (C); HRMS (ESI): calcd for
CH2Cl2) in 12% yield (56 mg) as a yellow solid: mp 156 C; IR
(ATR): 1590, 1493, 1422, 1321, 949, 785, 757 cmꢁ1 1H NMR
C
26H1735ClNO [M + H]+ 394.0999, found 394.1009.
ꢂ
;
2-(5-(2-Chlorobenzoyl)-2-thienyl)quinoline (4h). 2-(5-(2-
(CDCl3, 300 MHz) 7.35 (s, 1H), 7.55 (ddd, 1H, J ¼ 1.2, 6.9 and 8.1 Chlorobenzoyl)-2-thienyl)quinoline (4h) was obtained from 2-(2-
Hz), 7.73 (ddd, 1H, J ¼ 1.3, 6.9 and 8.5 Hz), 7.82 (dd, 1H, J ¼ 1.3 thienyl)quinoline (1h, 0.21 g) using the general procedure 3
and 8.1 Hz), 8.10 (br d, 1H, J ¼ 8.5 Hz), 8.23 (br d, 1H, J ¼ 8.7 (eluent: 9 : 1 heptane–AcOEt) in 62% yield as a yellow powder:
Hz), 8.29 (d, 1H, J ¼ 8.7 Hz); 13C NMR (CDCl3, 75 MHz) 79.6, mp 160 ꢂC; IR (ATR): 3750, 3060, 2329, 1646, 1592, 1471, 1426,
1
103.5, 117.5, 127.2, 127.5, 127.7, 128.4, 137.6, 138.1, 140.5, 1300, 1263, 1237, 1049, 854, 820, 761, 749, 739, 696 cmꢁ1; H
146.7, 151.1, 152.1.
NMR (CDCl3, 300 MHz) 7.25–7.45 (m, 6H), 7.59–7.71 (m, 4H),
7.8 (d, 1H, J ¼ 8.4 Hz), 8.1 (d, 1H, J ¼ 8.5 Hz); 13C NMR (CDCl3,
75 MHz) 117.8 (CH), 126.3 (CH), 126.7 (CH), 127.1 (CH), 127.7
(CH), 127.8 (C), 129.0 (CH), 129.6 (CH), 130.3 (CH), 130.4 (C),
131.3 (CH), 131.4 (CH), 136.4 (CH), 137.1 (CH), 138.4 (C), 144.5
General procedure 3 for the deprotonative metallation using
the lithium–copper base followed by aroylation
A stirred cooled (0 ꢂC) solution of LiTMP prepared at 0 ꢂC in (C), 148.1 (C), 151.0 (C), 154.5 (C), 187.3 (C); HRMS (ESI): calcd
THF (3 mL) from 2,2,6,6-tetramethylpiperidine (0.34 mL, for C20H1235ClNOS [M + H]+ 350.0406, found 350.0411.
2.0 mmol) and BuLi (1.6 M hexanes solution, 2.0 mmol) was
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2-Phenyl-11H-indeno[1,2-h]quinolin-11-one (5a). A degassed
Crystal data for 4a. C22H14ClNO, M ¼ 343.79, monoclinic,
˚
mixture of K2CO3 (0.28 g, 2.0 mmol), Pd(OAc)2 (11 mg, 5 mol%, P21/c, a ¼ 7.6161(4), b ¼ 10.4578(4), c ¼ 20.7837(8) A, b ¼
50 mmol), Cy3P$HBF4 (37 mg, 10 mol%, 0.10 mmol), 8-(2- 98.336(2) , V ¼ 1637.88(12) A , Z ¼ 4, d ¼ 1.394 g cmꢁ3, m ¼
chlorobenzoyl)-2-phenylquinoline (4a, 0.34 g, 1.0 mmol) in 0.242 mmꢁ1. A nal renement on F2 with 3738 unique inten-
DMF (4 mL) was heated at 130 ꢂC for 24 h. Aer ltration over a sities and 226 parameters converged at uR(F2) ¼ 0.0924 (R(F) ¼
celite pad, washing using CH2Cl2 (3 ꢃ 10 mL), and removal of 0.0402) for 2991 observed reections with I > 2s(I).
3
ꢂ
˚
the solvents under reduced pressure, the product was isolated
Crystal data for 4b. C26H16ClNO, M ¼ 393.85, monoclinic,
˚
aer purication by ash chromatography on silica gel P21/c, a ¼ 12.2577(4), b ¼ 7.6576(2), c ¼ 20.6631(7) A, b ¼
(eluent: 9 : 1 heptane–AcOEt) in 45% yield (0.14 g) as a yellow 102.2370(10) , V ¼ 1895.46(10) A , Z ¼ 4, d ¼ 1.38 g cmꢁ3, m ¼
3
ꢂ
˚
powder; mp 164 ꢂC; IR (ATR): 3623, 2921, 2345, 1704, 1601, 0.219 mmꢁ1. A nal renement on F2 with 4335 unique inten-
1547, 1462, 1312, 1278, 1175, 1152, 844, 758, 697 cmꢁ1
;
1H sities and 262 parameters converged at uR(F2) ¼ 0.1087 (R(F) ¼
NMR (CDCl3, 300 MHz) 7.34 (1H, dt, J ¼ 0.9 and 7.3 Hz), 7.45– 0.043) for 3362 observed reections with I > 2s(I).
7.59 (m, 5H), 7.69–7.73 (m, 2H), 7.89 (d, 1H, J ¼ 8.7 Hz), 7.98
Crystal data for 5a. C22H13NO, M ¼ 307.33, monoclinic,
˚
(d, 1H, J ¼ 8.1 Hz), 8.15 (d, 1H, J ¼ 8.7 Hz), 8.36–8.39 (m, 2H); P21/n, a ¼ 11.9851(4), b ¼ 8.0059(3), c ¼ 16.6683(8) A, b ¼
13C NMR (CDCl3, 75 MHz) 118.5 (CH), 118.7 (CH), 120.4 (CH), 110.6260(10) , V ¼ 1496.83(10) A , Z ¼ 4, d ¼ 1.364 g cmꢁ3, m ¼
124.1 (CH), 127.1 (C), 127.9 (2CH), 128.5 (C), 129.0 (2CH), 0.084 mmꢁ1. A nal renement on F2 with 3420 unique inten-
130.0 (CH), 130.3 (CH), 134.1 (CH), 134.7 (C), 135.5 (CH), 137.3 sities and 218 parameters converged at uR(F2) ¼ 0.107 (R(F) ¼
(CH), 138.8 (C), 143.1 (C), 144.9 (C), 149.7 (C), 159.9 (C), 192.8 0.0422) for 2679 observed reections with I > 2s(I).
(C); HRMS (ASAP): calcd for C22H14NO [M + H]+ 308.1075,
3
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˚
found 308.1074.
Acknowledgements
We are grateful to the Agence Nationale de la Recherche for
nancial support to NM and GB. FM thanks the Institut Uni-
Crystallography
´
The samples were studied with graphite monochromatized Mo-
versitaire de France and Rennes Metropole for nancial
˚
Ka radiation (l ¼ 0.71073 A). X-ray diffraction data were
support. We also thank Thermo Fischer for generous gi of
collected at T ¼ 150(2) K using APEXII Bruker-AXS diffractom-
eter. The structure was solved by direct methods using the
SIR97 program,33 and then rened with full-matrix least-square
methods based on F2 (SHELX-97)34 with the aid of the WINGX
program.35 All non-hydrogen atoms were rened with aniso-
tropic atomic displacement parameters. H atoms were nally
included in their calculated positions. Molecular diagrams were
generated by ORTEP-3 (version 2.02).
2,2,6,6-tetramethylpiperidine.
Notes and references
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Crystal data for 1e. C17H21N, M ¼ 239.35, monoclinic, P21/a,
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ꢂ
˚
a ¼ 12.2168(5), b ¼ 8.6679(3), c ¼ 12.9252(5) A, b ¼ 98.611(2) , V
3
¼ 1353.27(9) A , Z ¼ 4, d ¼ 1.175 g cmꢁ3, m ¼ 0.067 mmꢁ1. A
˚
nal renement on F2 with 3090 unique intensities and 166
parameters converged at uR(F2) ¼ 0.107 (R(F) ¼ 0.0406) for 2454
observed reections with I > 2s(I).
Crystal data for 2a. C15H10IN, M ¼ 331.14, orthorhombic,
˚
Pbcn, a ¼ 11.1278(3), b ¼ 12.2969(4), c ¼ 18.3090(6) A, V ¼
3
2505.36(13) A , Z ¼ 8, d ¼ 1.756 g cmꢁ3, m ¼ 2.532 mmꢁ1. A nal
˚
renement on F2 with 2861 unique intensities and 154 param-
eters converged at uR(F2) ¼ 0.0607 (R(F) ¼ 0.0295) for 2261
observed reections with I > 2s(I).
Crystal data for 2h. C13H8INS, M ¼ 337.16, monoclinic,
˚
P21/n, a ¼ 6.0678(2), b ¼ 9.6385(3), c ¼ 19.7538(5) A, b ¼
3
94.1170(10) , V ¼ 1152.31(6) A , Z ¼ 4, d ¼ 1.943 g cmꢁ3, m ¼
2.928 mmꢁ1. A nal renement on F2 with 2632 unique inten-
sities and 145 parameters converged at uR(F2) ¼ 0.0457 (R(F) ¼
0.0207) for 2393 observed reections with I > 2s(I).
ꢂ
˚
Crystal data for 3h. C13H7I2NS, M ¼ 463.06, monoclinic,
˚
P21/c, a ¼ 4.1495(2), b ¼ 12.4526(5), c ¼ 25.0266(9) A, b ¼
3
90.217(2) , V ¼ 1293.17(9) A , Z ¼ 4, d ¼ 2.378 g cmꢁ3, m ¼ 5.000
mmꢁ1. A nal renement on F2 with 2962 unique intensities
and 154 parameters converged at uR(F2) ¼ 0.0698 (R(F) ¼
0.0259) for 2662 observed reections with I > 2s(I).
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19612 | RSC Adv., 2014, 4, 19602–19612
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