Deproto-metallation of N-arylated pyrroles and indoles using a mixed lithium-zinc base and regioselectivity-computed CH acidity relationship

Article abstract of DOI:10.3762/bjoc.11.160

The synthesis of N-arylated pyrroles and indoles is documented, as well as their functionalization by deprotonative metallation using the base in situ prepared from LiTMP and ZnCl₂·TMEDA (1/3 equiv). With N-phenylpyrrole and -indole, the reactions were carried out in hexane containing TMEDA which regioselectively afforded the 2-iodo derivatives after subsequent iodolysis. With pyrroles and indoles bearing N-substituents such as 2-thienyl, 3-pyridyl, 4-methoxyphenyl and 4-bromophenyl, the reactions all took place on the substituent, at the position either adjacent to the heteroatom (S, N) or ortho to the heteroatom-containing substituent (OMe, Br). The CH acidities of the substrates were determined in THF solution using the DFT B3LYP method in order to rationalize the experimental results.

Full text of DOI:10.3762/bjoc.11.160

Deproto-metallation of N-arylated pyrroles and indoles using a
mixed lithium–zinc base and regioselectivity-computed CH
acidity relationship
Mohamed Yacine Ameur Messaoud1,2, Ghenia Bentabed-Ababsa*2, Madani Hedidi1,2,
Aïcha Derdour2, Floris Chevallier1, Yury S. Halauko*3, Oleg A. Ivashkevich3,
Vadim E. Matulis4, Laurent Picot*5, Valérie Thiéry*5, Thierry Roisnel6, Vincent Dorcet6
and Florence Mongin*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 1475–1485.
1Equipe Chimie et Photonique Moléculaires, Institut des Sciences
Chimiques de Rennes, UMR 6226, CNRS-Université de Rennes 1,
Bâtiment 10A, Case 1003, Campus de Beaulieu, 35042 Rennes,
France, 2Laboratoire de Synthèse Organique Appliquée, Faculté des
Sciences, Université d’Oran 1 Ahmed Ben Bella, BP 1524 El
M’Naouer, 31000 Oran, Algeria, 3UNESCO Chair of Belarusian State
University, 14 Leningradskaya Str., Minsk, 220030, Belarus,
4Research Institute for Physico-Chemical Problems of Belarusian
State University, 14 Leningradskaya Str., Minsk, 220030, Belarus,
5Laboratoire Littoral Environnement et Sociétés, UMRi CNRS 7266,
Université de La Rochelle, 17042 La Rochelle, France, and 6Centre
de Diffractométrie X, Institut des Sciences Chimiques de Rennes,
UMR 6226, CNRS-Université de Rennes 1, Bâtiment 10B, Campus
de Beaulieu, 35042 Rennes, France
doi:10.3762/bjoc.11.160
Received: 21 June 2015
Accepted: 31 July 2015
Published: 24 August 2015
Associate Editor: K. Itami
© 2015 Messaoud et al; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Ghenia Bentabed-Ababsa* - badri_sofi@yahoo.fr; Yury S. Halauko* -
hys@tut.by; Laurent Picot* - laurent.picot@univ-lr.fr; Valérie Thiéry* -
valerie.thiery@univ-lr.fr; Florence Mongin* -
Florence.mongin@univ-rennes1.fr
* Corresponding author
Keywords:
CH acidity; indoles; iodolysis; mixed lithium–zinc bases; pyrroles
Abstract
The synthesis of N-arylated pyrroles and indoles is documented, as well as their functionalization by deprotonative metallation
using the base in situ prepared from LiTMP and ZnCl2·TMEDA (1/3 equiv). With N-phenylpyrrole and -indole, the reactions were
carried out in hexane containing TMEDA which regioselectively afforded the 2-iodo derivatives after subsequent iodolysis. With
pyrroles and indoles bearing N-substituents such as 2-thienyl, 3-pyridyl, 4-methoxyphenyl and 4-bromophenyl, the reactions all
took place on the substituent, at the position either adjacent to the heteroatom (S, N) or ortho to the heteroatom-containing
substituent (OMe, Br). The CH acidities of the substrates were determined in THF solution using the DFT B3LYP method in order
to rationalize the experimental results.
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Introduction
Pyrrole occurs in very important natural products such as than that of the separate LiTMP and Zn(TMP)2) when used to
tetrapyrrolic (linear) bilirubinoids, and (cyclic) porphyrins and functionalize sensitive aromatic compounds such as hetero-
corrins, as well as in pharmaceuticals (e.g., pyrrolnitrin, cycles [31,33-41].
zomepirac) and polymers (e.g., photovoltaic cells). Indole is
similarly present in numerous natural products (e.g., tryptophan, Herein, we report our efforts to functionalize N-arylated
melanin, bufotenin, psilocin, indican) including bioactive prod- pyrroles and indoles through deproto-metallation using this
ucts (e.g., strychnine, brucine, yohimbine, reserpine, vincamine, mixed lithium–zinc base (Figure 1). We showed earlier, for
ergotamine, lysergic acid), as well as in pharmaceuticals (e.g., related substrates, the impact of the different hydrogen acidities
indomethacin, iprindole), agrochemicals (e.g., auxins, pyro- on the regioselectivity of the reaction [37,38,40,42,43]. Based
quilon), and dyes and pigments (e.g., indigo, indocyanines) on these results, we here use CH acidities of the aromatic
[1,2].
substrates in THF (calculated using the homodesmic reaction
approach within the density functional theory (DFT) frame-
The deprotonative metallation [3-7] is a valuable tool for the work) to attempt a rationalization of the practical results.
regioselective functionalization of aromatic heterocycles such
as pyrroles [8] and indoles [9]. A few examples concern the
reaction of N-arylpyrroles and -indoles.
Studies show that, depending on the reaction conditions, two
protons of N-phenylpyrrole (at the 2 and 2’ position) can be
abstracted by a base. Kinetic conditions employing butyl-
lithium activated by N,N,N’,N’-tetramethylethylenediamine
Figure 1: Substrates involved in deproto-metallation reaction.
(TMEDA) in diethyl ether lead to the 2,2’-dilithiated product
[10,11]. In contrast, monolithiation at the 2 position is noted by
Results
using (i) the same base in diethyl ether at room temperature and
long reaction times or in refluxing hexane (thermodynamic Synthetic aspects
conditions) [11,12] or (ii) with butyllithium activated by potas- In order to prepare the different pyrrole and indole substrates 1
sium tert-butoxide (LICKOR) in tetrahydrofuran (THF) at and 2, the unsubstituted azoles were reacted with aryl and
−75 °C [11,13]. N-Arylpyrroles substituted on their six- heteroaryl iodides under copper catalysis. As far as the deriva-
membered ring by methoxy [14], halogen [15,16], alkyl [17,18], tives 1a,b, 1d,e and 2a–e are concerned, the reactions were
or trifluoromethyl [19,20] groups have been the topic of more carried out by using 1.5 equiv of the azole, 0.2 equiv of copper,
recent studies. The reactions are in general performed at low 2 equiv of caesium carbonate as the base, in acetonitrile at
temperatures (between −75 and 0 °C) and do not tolerate the reflux [44] (Table 1, Figure 2, Supporting Information File 2).
presence of reactive functional groups.
Varying yields were obtained, with aryl iodides substituted by
electron-withdrawing groups in general favouring the reaction.
Mono- and dilithiation of N-phenylindole takes place by using In contrast, much lower yields were noted when using aryl bro-
TMEDA-activated butyllithium, respectively in toluene at mides. For the synthesis of derivatives 1f and 2f, we rather
100 °C (1 equiv of base) [21] and in diethyl ether at −70 °C employed 1.2 equiv of the aryl halide, 0.05 equiv of copper(I)
(2 equiv) [22].
iodide, 0.10 equiv of N,N’-dimethylethylenediamine
(DMEDA), 2 equiv of tripotassium phosphate in dimethylform-
In the course of the last fifteen years, combinations of lithium amide as the solvent at 120 °C [45]. Under these conditions, the
reagents and softer metal compounds have established them- N-(4-(trifluoromethyl)phenyl)-substituted azoles were isolated
selves as appropriate tools to deproto-metallate sensitive in high yields (Scheme 1).
aromatic compounds [23-30]. In the search of bases usable
at room temperature, we developed pairs of metal In a previous study [33], we have shown that hexane containing
amides able to behave synergically in such reactions. In N,N,N’,N’-tetramethylethylenediamine (TMEDA) is a suitable
particular, the lithium–zinc basic mixture obtained in situ solvent to perform the C2 deproto-metallation with the TMP-
by mixing ZnCl2·TMEDA and LiTMP (TMP = 2,2,6,6-tetra- based lithium–zinc as the base of commercially available
methylpiperidino) in a 1 to 3 ratio [31], and for which the 1:1 N-phenylpyrrole (1c). The result has been evidenced by subse-
LiTMP·2LiCl(±TMEDA)–Zn(TMP)2 composition was given quent iodolysis (Scheme 2). Nevertheless, for numerous
[32], proved to be a ‘superbase’. Indeed, its reactivity is higher substrates, THF is an alternative solvent that allows the reac-
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Table 1: Synthesis of the azole substrates 1a,b, 1d,e and 2a–e.
Scheme 2: Deproto-metallation of 1c followed by iodolysis [33].
Entry Ar
Azole
Time Product, yield (%)a
tions to be finished after 2 h contact at room temperature
[33,34,36].
1
2
3
4
5
6
7
8
9
2-thienyl
3-pyridyl
pyrrole
pyrrole
16 h 1a, 75 (20)b
32 h 1b, 65 (26)c
72 h 1d, 46
72 h 1e, 81
48 h 2a, 50
48 h 2b, 70
24 h 2c, 30
72 h 2d, 15
56 h 2e, 60
4-MeOC6H4 pyrrole
4-BrC6H4
2-thienyl
3-pyridyl
Ph
pyrrole
indole
indole
indole
Among the different methods of trapping that can be employed
after deproto-zincation (interception with aldehydes, phenyl
disulfide and allyl bromide, or palladium-catalyzed cross-
coupling with aryl halides) [35], we chose the iodolysis, which
is the most efficient quench. In addition, it offers the possibility
of a subsequent functionalization of the formed aryl iodides by
recourse to transition metal-catalyzed coupling reactions [37].
4-MeOC6H4 indole
4-BrC6H4 indole
aAfter purification. bUsing 2-bromothiophene. cUsing 3-bromopyridine.
When bis-heterocyclic compound 1a was reacted in THF for 2 h
at room temperature with the lithium–zinc base, in situ prepared
from ZnCl2·TMEDA (0.5 equiv) and LiTMP (1.5 equiv), a
selective deprotonation at the thiophene ring took place. After
subsequent interception with iodine, N-(5-iodo-2-
thienyl)pyrrole (3a) was isolated in nearly quantitative yield.
Under the same reaction conditions, the corresponding indole
substrate 2a was similarly converted into N-(5-iodo-2-
thienyl)indole (4a) (Scheme 3).
Scheme 3: Deproto-metallation of 1a and 2a followed by iodolysis.
Figure 2: ORTEP diagram (30% probability) of 2e.
Starting from the bis-heterocycles 1b and 2b, better results were
obtained by doubling the amount of base (using 1 equiv of
ZnCl2·TMEDA and 3 equiv of LiTMP). Under the reaction
conditions employed above, the deprotonation occurred on the
pyridine ring, at the 2 position adjacent to the azole substituent.
The corresponding monoiodides 3b and 4b were isolated in 59
and 71% yield, respectively along with unreacted starting ma-
terial in both cases (Scheme 4).
As previously observed for N-phenylpyrrole (1c) [33], the best
solvent for the deprotonation of N-phenylindole (2c) is hexane
Scheme 1: Synthesis of the azole substrates 1f and 2f.
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iodolysis. Increasing the amount of base to 1 equiv of zinc in
the case of 2d (in order to reduce the amount of recovered
starting material at the end of the reaction) led to the isolation of
the diiodide 4d’, resulting from a two-fold deprotonation at both
the 2 and 3’ position (the rest being the monoiodide 4d)
(Scheme 6). The iodide 3d was identified by X-ray diffraction
from suitable crystals (Figure 3, middle, see Supporting Infor-
mation File 2).
Scheme 4: Deproto-metallation of 1b and 2b followed by iodolysis.
containing TMEDA (5 equiv). Optimization of the base amount
led to employ ZnCl2·TMEDA (0.75 equiv) and LiTMP
(2.25 equiv). After 2 h contact at room temperature and subse-
quent iodolysis, the N-phenylated 2-iodopyrrole 3c and
2-iodoindole 4c were produced in 86 and 92% yield, respective-
ly (Scheme 5). The structure of 4c was unambiguously identi-
fied by X-ray diffraction (Figure 3, left, see Supporting Infor-
mation File 2).
Scheme 5: Deproto-metallation of 1c and 2c followed by iodolysis.
Scheme 6: Deproto-metallation of 1d and 2d followed by iodolysis.
It is known that anisole can be ortho-deprotonated using the Whereas various attempts to deprotonate bromobenzene using
lithium–zinc base in THF [35]. It was thus of interest to involve the lithium–zinc base failed, a result probably due to degrad-
N-(4-methoxyphenyl)-substituted azole substrates in the depro- ation of the deproto-metallated compound through benzyne for-
tonation–iodination sequence. Under similar conditions, depro- mation [46], it proved possible to accumulate at room tempera-
tonation of 1d and 2d takes place next to the methoxy group, ture the arylmetal compounds formed from the N-(4-
affording the monoiodides 3d and 4d in satisfying yields after bromophenyl)azoles 1e and 2e, as demonstrated by trapping
Figure 3: ORTEP diagrams (30% probability) of 4c, 3d and 3e.
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with iodine. The best results (minimum of degradation) were
observed by using ZnCl2·TMEDA (1 equiv) and LiTMP
(3 equiv). Under these conditions the iodides 3e and 4e were
obtained in 58 and 57% yield, respectively (Scheme 7). The
structure of product 3e was unequivocally identified by X-ray
diffraction (Figure 3, right, see Supporting Information File 2).
Scheme 8: N-arylation of the iodides 3b, 3d and 4d.
Scheme 7: Deproto-metallation of 1e and 2e followed by iodolysis.
The reactions starting from 1a–e and 2a–e led to predominant
products. In contrast, in the case of 1f and 2f, complex mixtures
containing two monoiodides and one diiodide (unidentified
regioselectivity) were obtained together with recovered starting
material.
In order to test the functionalization of the above synthesized
aryl iodides through a subsequent transition-metal-catalyzed
coupling reaction we subjected three of them to a copper-
catalyzed N-arylation reaction. Thus, the iodides 3b, 3d and 4d
were reacted with 2 equiv of imidazole in the presence of
0.1 equiv of copper(I) oxide, 2 equiv of caesium carbonate as
the base in dimethylsulfoxide (DMSO) at 110 °C [47]. Under
these conditions, the imidazole-substituted compounds 5b, 5d
and 6d were generated in 85, 67 and 40% yield, respectively
(Scheme 8, Figure 4, see Supporting Information File 2).
Figure 4: ORTEP diagram (30% probability) of 5d.
Computational aspects
There is a lack of data on the acidity of N-substituted pyrroles A potential acidity of the methoxy groups in substrates 1d and
and indoles in the literature. NH acidity of unsubstituted pyrrole 2d was ignored here since there was no sign of their deprotona-
and indole in DMSO was measured by Bordwell [48] and tion under the experimental conditions and as a consequence
computed by means of semi-empirical AM1 [49] and ab their acidity was expected to be substantially lower. The data in
initio methods [50]. The pKa values for N-methylindole, Figure 5 refer to the most stable rotamer of the compounds.
N-methylpyrrole and N-(dimethylamino)pyrrole as CH acids in Thus, potential energy surface (PES) scans allowed us to state
THF were experimentally determined by Fraser et al [51]. The that both 2a and 2b are likely to adopt a form in which the
latter are more related to our goals and were found to be in good heteroatoms are far away from the benzo-fragment.
agreement with those computed within the DFT framework
recently [42,52]. The results of quantum chemical calculations The calculated values of gas-phase acidity of the investigated
on CH acidity of the different N-arylated pyrroles 1 and indoles compounds (see Supporting Information File 1) lie within the
2, obtained both for THF solution (Figure 5) and gas phase (see range of 364.4–394.3 kcal mol−1 which is typical for weak CH
Supporting Information File 1), are presented in the current acidic compounds while the pKa values in THF solution
paper.
(Figure 5) covered a 28.8–45.0 span. These data allow the
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both pyrroles and indoles the most acidic hydrogen is at the
2 position of the azole part, while for an aryl substituent it
depends on its nature.
Discussion
The results observed in the course of these deproto-metallation
reactions complete previously reported studies using alkali
metal bases with similar substrates [36-41]. The calculations of
the CH acidities in THF (Figure 5) allow us to comment on the
regioselectivities observed in the different studies.
To our knowledge, the N-(2-thienyl) azoles 1a and 2a
(Scheme 3 and Figure 5) have never been subjected to deproto-
metallation before. If we only consider the reaction of 1a, it is
conceivable that the regioselectivity only results from an attack
of the lithium–zinc base at the most acidic site. In contrast, the
regioselectivity observed in case of substrate 2a cannot be
explained by the pKa values as the only reason. Otherwise,
deprotonation would have been also observed at the 2 position
of the indole ring. Whereas the azole nitrogen in 2a cannot co-
ordinate a metal through its electron lone pair (it is delocalized
within the aromatic π-electron ring system), a coordination by
the sulfur atom of the thiophene substituent could take place
with a possible decrease of neighbouring pKa values.
As for 1a and 2a, deproto-metallation has not yet been reported
for 1b and 2b (Scheme 4 and Figure 5). In the case of these
substrates, it is clear that deprotonation takes place after coordi-
nation of the pyridine nitrogen to a metal; otherwise, the reac-
tions would have been observed at the 2 position of the azole
ring. Among both positions adjacent to the pyridine nitrogen,
the most acidic is attacked.
N-Phenylpyrrole (1c, Scheme 5 and Figure 5) does not have any
atom capable of coordinating a metal. Thus, under thermody-
namic conditions (using TMEDA-activated butyllithium either
in diethyl ether at room temperature after long reaction times or
in refluxing hexane [11,12]; using LICKOR in THF at −75 °C
[11,13]), the most acidic site next to the azole nitrogen is
affected. Using TMEDA-activated butyllithium in diethyl ether
under kinetic conditions leads to 2,2’-dilithiation [10,11]. In this
case, the intermediate 2-lithiated compound can be involved in
aggregates favouring deprotonation at a neighbouring site to
afford the 2,2’-dilithiated derivative. The 2,2’-dimetallated
derivative of 1c has also been noted using the lithium–zinc
base, for example when the reaction is performed in THF
Figure 5: Calculated values of pKa(THF) of the compounds 1 and 2,
and bromobenzene.
assignment of potential deprotonation sites in the investigated (favoured at reflux temperature) [33]. In this case, the dimetal-
substrates. Also the correlation between gas-phase ΔGacid and lated compound does not correspond to a kinetic but to a ther-
the pKa(THF) values can be tracked. In all cases, the CH acidity modynamic compound. This could be due to the formation of a
increases when changing from electron-donating groups to stable zinc metallacycle, as suggested in an earlier paper [37].
more electron-withdrawing ones. One can easily see that for As previously reported [33], dideprotonation can be suppressed
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by using hexane containing TMEDA instead of THF and both lithium–zinc base and the N-(4-(trifluoromethyl)phenyl)azole 1f
compounds 1c and 2c are functionalized at their most acidic or 2f (Figure 5) could be in relation with a reaction temperature
position (Scheme 5 and Figure 5).
(too high) not suitable to discriminate between similarly acidi-
fied positions.
The deprotolithiation of N-(4-methoxyphenyl)pyrrole (1d,
Antiproliferative activity in A2058 melanoma
Scheme 6 and Figure 5) by using chelates of butyllithium in
THF at −75 °C for 1 h was documented by Faigl and cells
co-workers in 1997 [14]. Whereas N,N,N’,N”,N”- The N-arylated pyrroles and indoles exerted low to moderate
pentamethyldiethylenetriamine (PMDETA) employed as ligand antiproliferative activity in A2058 melanoma cells (Figure 6).
leads to reaction at the (maybe less hindered) 2 position (46% The best result was obtained with 1f at 10−5 M, which induced
yield after conversion to the corresponding carboxylic acid), the 31.9 ± 0.1% growth inhibition in cells treated for 72 h. The
most acidic position 3’ is attacked in the presence of TMEDA linear N-arylated pyrroles 1b and 1e were poorly active. Aryl-
(18% yield after similar conversion) [14]. Using the ation by a thiophene moiety (1a and 2a) moderately increased
lithium–zinc base also gives the 3’-metallated derivative, but the antiproliferative activity, with no significant difference
more efficiently. N-(4-Methoxyphenyl)indole (2d, Scheme 6 between the pyrrole and indole derivatives.
and Figure 5) has two similarly acidified sites at C2 and C3’.
The regioselective reaction at C3’ could result from a coordina-
tion of the methoxy group to a metal prior to deprotonation.
Nevertheless, when the amount of base is increased, competi-
tive dideprotonation takes place to furnish diiodides as previ-
ously noted with other azoles [37,38].
Compared with a methoxy group, the bromo substituent
exhibits a stronger acidifying effect. By itself, this effect is not
sufficient to enable the accumulation of a 2-metallated
bromobenzene. However, when this ortho-bromine effect is
combined with the meta-effect of a pyrrolyl group, the corres-
ponding CH acidities are increased (see Figure 5), and things
become different. Thus, whereas the direct deproto-lithiation of
bromobenzene leads to highly unstable 2-bromophenyllithium,
that of N-(4-bromophenyl)pyrrole (1e, Scheme 7 and Figure 5)
is possible. By using LiTMP in THF at −75 °C for 1 h, Faigl
and co-workers evidenced deprotonation next to the bromo
group (21% yield after conversion to the corresponding
Figure 6: Antiproliferative activity (growth inhibition) of the tested com-
pounds 1a,b,e,f, 2a,b and 5d at concentration 10−5 M and 72 h in
A2058 human melanoma cells.
carboxylic acid), i.e. at the most acidic position [16]. With the Conclusion
lithium–zinc base, the reactions from the N-(4-bromophenyl)- Unlike other azoles such as pyrazole and triazoles [37,38,40],
azoles 1e and 2e (Scheme 7 and Figure 5) occurred with the pyrrole and indole do not possess any atom capable of coordi-
same regioselectivity, and proved possible with acceptable nating metals. As a consequence, the corresponding CH acidi-
yields at room temperature.
ties in THF solution, which were calculated using a continuum
solvation model, better help in rationalizing the outcome of the
The deprotolithiation of N-(4-(trifluoromethyl)phenyl)pyrrole deproto-metallation reactions.
(1f, Figure 5) was reported by Faigl and co-workers in 1999
[19]. By employing TMEDA-activated butyllithium in THF at In addition, whereas N-(4-substituted phenyl)pyrazoles and
−75 °C, the authors mainly noted proton abstraction next to the -triazoles (e.g., with methoxy as substituent, Figure 7) can be
trifluoromethyl group. A competitive minor reaction at the deprotonated at C2’ for the same reason [37,38,40], the corres-
2 position of the pyrrole group can be rationalized by similar ponding N-(4-substituted phenyl)pyrroles and -indoles are
pKa values at C2 and C3’ [19]. Indeed, when compared with a rather functionalized at C3’, next to the substituent.
bromo substituent, the trifluoromethyl group similarly (and
maybe more strongly) exhibits a long range acidifying effect, Experimental
but less acidifies the ortho positions [53,54]. The lack of regios- General methods. All the reactions were performed under
electivity observed in the course of the reaction between the argon atmosphere. THF was distilled over sodium/benzophe-
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(12 mmol) in DMF (5 mL) were successively added CuI
(95 mg, 0.50 mmol), K3PO4 (4.2 g, 20 mmol) and DMEDA
(0.11 mL, 1.0 mmol). The mixture was stirred under argon at
120 °C (the reaction time is given in the product description)
before dilution with AcOEt (40 mL) and filtration. Concentra-
tion under reduced pressure and purification by chromatog-
raphy on silica gel (the eluent is given in the product descrip-
tion) led to the compounds described below.
General procedure 3 for the deprotonative metallation fol-
lowed by iodination (analogous to that described in [60]). To a
stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperidine
(0.25 mL, 1.5 mmol) in THF (2–3 mL) were successively added
Figure 7: Iodides previously formed as major products from the
corresponding N-(4-methoxyphenyl)azoles using the lithium–zinc base.
none. ZnCl2·TMEDA was prepared as described previously BuLi (about 1.6 M hexanes solution, 1.5 mmol) and, 5 min
[35]. Column chromatography was performed on silica gel later, ZnCl2·TMEDA (0.13 g, 0.50 mmol). The mixture was
(40–63 μm). Melting points were measured on a Kofler appa- stirred for 15 min at 0 °C before introduction of the substrate
ratus. IR spectra were taken on a Perkin-Elmer Spectrum 100 (1.0 mmol) at 0–10 °C. After 2 h at room temperature, a solu-
spectrometer. 1H and 13C nuclear magnetic resonance (NMR) tion of I2 (0.38 g, 1.5 mmol) in THF (4 mL) was added. The
spectra were recorded on a Bruker Avance III spectrometer at mixture was stirred overnight before addition of an aqueous
300 and 75 MHz, respectively. 1H chemical shifts (δ) are given saturated solution of Na2S2O3 (4 mL) and extraction with
in ppm relative to the solvent residual peak, 13C chemical AcOEt (3 × 20 mL). The combined organic layers were dried
shifts are relative to the central peak of the solvent signal [55]. over MgSO4, filtered and concentrated under reduced pressure.
Mass spectra measurements were performed using a HP 6890 Purification by chromatography on silica gel (the eluent is given
instrument.
in the product description) led to the compounds 3a and 4a.
Crystallography. The single crystals were studied with General procedure 4 for the deprotonative metallation fol-
graphite monochromatized MoKα radiation (λ = 0.71073 Å). lowed by iodination (analogous to that described in [60]). To a
X-ray diffraction data were collected at T = 150(2) K using an stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperidine
APEXII Bruker-AXS diffractometer. The structure was solved (0.25 mL, 1.5 mmol) in THF (2-3 mL) were successively added
by direct methods using the SIR97 program [56], and then BuLi (about 1.6 M hexanes solution, 1.5 mmol) and, 5 min
refined with full-matrix least-square methods based on F2 later, ZnCl2·TMEDA (0.13 g, 0.50 mmol). The mixture was
(SHELX-97) [57] with the aid of the WINGX program [58]. All stirred for 15 min at 0 °C before introduction of the substrate
non-hydrogen atoms were refined with anisotropic atomic dis- (0.5 mmol) at 0–10 °C. After 2 h at room temperature, a solu-
placement parameters. Hydrogen atoms were finally included in tion of I2 (0.38 g, 1.5 mmol) in THF (4 mL) was added. The
their calculated positions. Molecular diagrams were generated mixture was stirred overnight before addition of an aqueous
by ORTEP-3 (version 2.02) [59].
saturated solution of Na2S2O3 (4 mL) and extraction with
AcOEt (3 × 20 mL). The combined organic layers were dried
Procedure 1 for the synthesis of the N-arylated pyrroles and over MgSO4, filtered and concentrated under reduced pressure.
indoles 1a,b,d,e and 2a–e [44]. To azole (6.0 mmol) and aryl Purification by chromatography on silica gel (the eluent is given
halide (4.0 mmol) in acetonitrile (20 mL) were successively in the product description) led to the compounds 3b,e and
added Cu (50 mg, 0.80 mmol), Cs2CO3 (2.6 g, 8.0 mmol) and, 4b,d',e.
in the case of aryl bromides, KI (99 mg, 6.0 mmol). The mix-
ture was stirred under argon at acetonitrile reflux temperature General procedure 5 for the deprotonative metallation fol-
(the reaction time is given in the product description) before lowed by iodination (analogous to that described in [60]). To a
dilution with AcOEt (40 mL) and filtration. Concentration stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperidine
under reduced pressure and purification by chromatography on (0.25 mL, 1.5 mmol) in hexane (2–3 mL) containing TMEDA
silica gel (the eluent is given in the product description) led to (0.50 mL, 3.3 mmol) were successively added BuLi (about
the expected compounds.
1.6 M hexanes solution, 1.5 mmol) and, 5 min later,
ZnCl2·TMEDA (0.13 g, 0.50 mmol). The mixture was stirred
Procedure 2 for the synthesis of the N-arylated pyrroles and for 15 min at 0 °C before introduction of the substrate
indoles 1f and 2f [45]. To azole (10 mmol) and aryl halide (0.67 mmol) at 0–10 °C. After 2 h at room temperature, a solu-
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Beilstein J. Org. Chem. 2015, 11, 1475–1485.
tion of I2 (0.38 g, 1.5 mmol) in THF (4 mL) was added. The ΔGacid = G0298(R−) + G0298(H+) − G0298(R–H).
mixture was stirred overnight before addition of an aqueous
saturated solution of Na2S2O3 (4 mL) and extraction with The solvent influence was simulated within the polarized
AcOEt (3 × 20 mL). The combined organic layers were dried continuum model (PCM) with the default parameters for THF.
over MgSO4, filtered and concentrated under reduced pressure. The cavity was built up using atomic radii from the UFF force
Purification by chromatography on silica gel (the eluent is given field. The PCM energies EPCM were calculated at the B3LYP/6-
in the product description) led to the compounds 3c and 4c.
311+G(d,p) level using geometries optimized for isolated struc-
tures. The Gibbs energy in solution Gsol was calculated for each
General procedure 6 for the deprotonative metallation fol- species by the formula:
lowed by iodination (analogous to that described in [60]). To a
stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperidine Gsol = G0298 + EPCM − E.
(0.25 mL, 1.5 mmol) in THF (2–3 mL) were successively added
BuLi (about 1.6 M hexanes solution, 1.5 mmol) and, 5 min The following homodesmic reaction was composed for the pKa
later, ZnCl2·TMEDA (0.13 g, 0.50 mmol). The mixture was values calculation:
stirred for 15 min at 0 °C before introduction of the substrate
(0.67 mmol) at 0–10 °C. After 2 h at room temperature, a solu- R–H(s) + Het−(s) → R−(s) + Het–H(s),
tion of I2 (0.38 g, 1.5 mmol) in THF (4 mL) was added. The
mixture was stirred overnight before addition of an aqueous where Het–H is N-methylindole. The latter was chosen as refer-
saturated solution of Na2S2O3 (4 mL) and extraction with ence compound due to its structural similarity and since its
AcOEt (3 × 20 mL). The combined organic layers were dried pKa(THF) = 38.1 found by Fraser et al [51] was expected to be
over MgSO4, filtered and concentrated under reduced pressure. close to those for our substrates. Consequently, the Gibbs
Purification by chromatography on silica gel (the eluent is given energy of the homodesmic reaction (ΔGr,sol) and the pKa value
in the product description) led to the compounds 3d and 4d.
are related by the following equation:
Procedure 7 for the N-arylation of imidazole [47]. A mixture
of the prepared iodide (1.0 mmol), Cu2O (0.10 g, 0.10 mmol),
Cs2CO3 (0.65 g, 2.0 mmol), imidazole (0.14 g, 2.0 mmol) and
DMSO (0.5 mL) was stirred for 24 h at 110 °C under argon. Biological evaluation. The antiproliferative activity of
After cooling to room temperature, the mixture was diluted with N-arylated pyrrole and indole derivatives was studied in the
AcOEt (10 mL) and filtered over celite®. Washing with AcOEt, A2058 (ATCC® CRL-11147) cell line as described previously
removal of the solvent and purification by chromatography on [60]. A2058 cells are highly invasive human epithelial adherent
silica gel (the eluent is given in the product description) led to melanoma cells, derived from lymph nodes metastatic cells
the compounds 5b,d and 6d.
obtained from a 43 year old male patient. They are tumorigenic
at 100% frequency in nude mice, and considered as very resis-
Computational procedure. The DFT calculations were tant to anticancer drugs. All cell culture experiments were
performed using GAUSSIAN 03W package [61]. The B3LYP performed at 37 °C. Cells were grown to confluence in 75 cm²
formalism was employed. All optimized geometries were flasks in DMEM supplemented with 10% fetal calf serum
obtained using the 6-31G(d) basis set without any symmetry (FCS) and 1% penicillin–streptomycin (Dominique Dutscher,
constraints implied. Vibrational frequencies were calculated at France), in a 5% CO2 humidified atmosphere. Molecules were
the same level of theory in order to characterize stationary solubilized in DMSO at 10−3 M and diluted in the cell culture
points and to calculate zero-point vibrational energies (ZPVE) medium to obtain 2·10−5 M solutions. Confluent cells were
and thermal corrections. The total energy of species was found trypsinized and centrifuged in FCS at 1500g for 5 min. The
using the 6-311+G(d,p) basis set and tight convergence criteria. supernatant containing trypsin was discarded and the cell pellet
Further, the gas-phase Gibbs energies (G0298) were calculated was resuspended in cell culture medium to obtain a
using the following equation:
4·104 cell·mL−1 suspension. At t0, 50 µL of the 2·10−5 M test
solutions were deposited in a 96-wells flat bottom microplate,
and 50 µL of the cell suspension were added. The 2000 cells
were then grown for 72 h in the cell culture medium containing
G0298 = E + ZPVE + H00→298 – TS0298
The gas-phase acidity ΔGacid was defined as the Gibbs energy 10−5 M molecules. At t72, 20 µL of a 5 g·L−1 MTT solution
of deprotonation of the particular substrate R–H (R–H(g) → were added to each well of the microplate, allowing living cells
R−(g) + H+(g)):
containing a functional mitochondrial succinate dehydrogenase
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Beilstein J. Org. Chem. 2015, 11, 1475–1485.
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40.Nagaradja, E.; Chevallier, F.; Roisnel, T.; Dorcet, V.; Halauko, Y. S.;
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Dorcet, V.; Halauko, Y. S.; Ivashkevich, O. A.; Matulis, V. E.;
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Gaponik, P. N. Tetrahedron 2010, 66, 3415–3420.
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