Deprotometalation of substituted pyridines and regioselectivity-computed CH acidity relationships

Article abstract of DOI:10.1016/j.tet.2016.03.022

A series of methoxy- and fluoro-pyridines have been deprotometalated in tetrahydrofuran at room temperature by using a mixed lithium-zinc combination obtained from ZnCl₂·TMEDA (TMEDA=N,N,N′,N′-tetramethylethylenediamine) and LiTMP (TMP=2,2,6,6-tetramethylpiperidino) in a 1:3 ratio, and the metalated species intercepted by iodine. Efficient functionalization at the 3 position was observed from 4-methoxy, 2-methoxy, 2,6-dimethoxy, 2-fluoro and 2,6-difluoropyridine, and at the 4 position from 3-methoxy and 2,3-dimethoxypyridine. Interestingly, clean dideprotonation was noted from 3-fluoropyridine (at C2 and C4) and 2,6-difluoropyridine (at C3 and C5). The obtained regioselectivities have been discussed in light of the CH acidities of the substrates, determined both in the gas phase (DFT B3LYP and G3MP2B3 levels) and in THF solution. In the case of methoxypyridines, the pK_a values have also been calculated for complexes with LiCl and LiTMP.

Full text of DOI:10.1016/j.tet.2016.03.022

Tetrahedron xxx (2016) 1e10
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Deprotometalation of substituted pyridines and regioselectivity-
computed CH acidity relationships
,
,
b
c,
Madani Hedidi a b, Ghenia Bentabed-Ababsa b , Aïcha Derdour , Yury S. Halauko
,
*
*
Oleg A. Ivashkevich c, Vadim E. Matulis d, Floris Chevallier a, Thierry Roisnel e,
Vincent Dorcet e, Florence Mongin a
,
*
a
ꢀ
ꢀ
^
Chimie et Photonique Moleculaires, Institut des Sciences Chimiques de Rennes, UMR 6226, Universite de Rennes 1-CNRS, Batiment 10A, Case 1003,
Campus de Beaulieu, 35042 Rennes, France
b
ꢁ
ꢀ
ꢀ
ꢀ
Laboratoire de Synthese Organique Appliquee, Faculte des Sciences, Universite d’Oran 1 Ahmed Ben Bella, BP 1524 El M’Naouer, 31000 Oran, Algeria
c UNESCO Chair of Belarusian State University, 14 Leningradskaya Str., Minsk 220030, Belarus
d Research Institute for Physico-Chemical Problems of Belarusian State University, 14 Leningradskaya Str., Minsk 220030, Belarus
e
ꢀ
ꢀ
^
Centre de Diffractometrie X, Institut des Sciences Chimiques de Rennes, UMR 6226, Universite de Rennes 1-CNRS, Batiment 10B, Campus de Beaulieu,
35042 Rennes, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of methoxy- and fluoro-pyridines have been deprotometalated in tetrahydrofuran at room
Received 2 February 2016
Received in revised form 3 March 2016
Accepted 7 March 2016
Available online xxx
temperature by using
a
mixed lithiumezinc combination obtained from ZnCl2$TMEDA
(TMEDA¼N,N,N0,N0-tetramethylethylenediamine) and LiTMP (TMP¼2,2,6,6-tetramethylpiperidino) in
a 1:3 ratio, and the metalated species intercepted by iodine. Efficient functionalization at the 3 position
was observed from 4-methoxy, 2-methoxy, 2,6-dimethoxy, 2-fluoro and 2,6-difluoropyridine, and at the
4 position from 3-methoxy and 2,3-dimethoxypyridine. Interestingly, clean dideprotonation was noted
from 3-fluoropyridine (at C2 and C4) and 2,6-difluoropyridine (at C3 and C5).
Keywords:
CH acidity
Pyridine
Mixed lithiumezinc base
Substituent effect
The obtained regioselectivities have been discussed in light of the CH acidities of the substrates, de-
termined both in the gas phase (DFT B3LYP and G3MP2B3 levels) and in THF solution. In the case of
methoxypyridines, the pKa values have also been calculated for complexes with LiCl and LiTMP.
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
Alternative deprotometalation methods have since emerged
with the use of metal additives allowing chemoselective reactions to
Pyridines are present in numerous biological key positions, with
derivatives such as nicotine, nicotinamide (niacin), nicotinamide
adenine dinucleotide phosphate (NADP) and pyridoxine (vitamin
B6). In addition to occurring in pharmaceuticals and agrochemi-
cals,1 pyridines are important part of organic materials.2
be performed.5 In the pyridine series, pioneering reagents combin-
ing alkyllithiums with LiDMAE (DMAE¼2-dimethylaminoethoxide)
proved to direct the deprotonation to the 2 position.6 In addition,
0
0
(R)n(R )n MLi-type reagents, in which M is a nonalkali metal
(e.g., Cu,7 Zn,8 Cd9), have been reported for their ability to depro-
tometalate sensitive aromatics including pyridines.
To functionalize regioselectively these heterocycles, depro-
tonative lithiation3 appears as a valuable tool; alkyllithiums and
hindered lithium dialkylamides have been largely used for this
In this context, we have developed a lithiumezinc combination,
prepared from ZnCl2$TMEDA (TMEDA¼N,N,N0,N0-tetramethylethy-
lenediamine) and LiTMP (TMP¼2,2,6,6-tetramethylpiperidino) in
a 1:3 ratio, capable of accomplishing room-temperature depro-
tometalation of a large range of substrates.10 Probably in relation
with high steric hindrance, this base proved by NMR and DFT
studies to be a 1:1 mixture of the homometallic amides rather than
a lithium zincate,10a a result confirmed by DOSY NMR spectros-
copy.11 The idea of a deprotolithiation through LiTMP occurring
first, followed by Zn(TMP)2-mediated transmetalation, was pro-
posed in 2008 to rationalize its synergic behavior,10a and supported
by others who pinpointed LiTMP$2LiClꢀTMEDA as the possible
purpose.4 Nevertheless, the low compatibility between
p-deficient
heteroaromatics on the one hand, and either the alkyllithiums used
as base or the heteroaryllithiums generated by deprotonation on
the other hand, implies very low reaction temperatures and limits
the scope of the method.
* Corresponding authors. E-mail addresses: badri_sofi@yahoo.fr (G. Bentabe-
d-Ababsa), hys@tut.by (Y.S. Halauko), florence.mongin@univ-rennes1.fr (F. Mongin).
http://dx.doi.org/10.1016/j.tet.2016.03.022
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Hedidi, M.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.03.022

2
M. Hedidi et al. / Tetrahedron xxx (2016) 1e10
active lithiating base.11 This ‘trans-metal trapping’12 has since been
extended to other pairs behaving synergically such as mixtures of
LiTMP on the one hand, and ZnCl2$2LiCl, MgCl2 or CuCN$2LiCl on
the other hand.13
We here describe the use of this lithiumezinc combination for
the deprotonative metalation of pyridines substrates and comment
on the results, and notably on the regioselectivities observed, on
the basis of the CH acidities in THF (THF¼tetrahydrofuran).
OMe
383.7
383.1
374.0
373.9
375.8
375.7
OMe
386.2
385.8
383.8
383.4
384.5
383.9
394.0
393.1
391.1
390.4
391.9
391.0
390.6
389.7
N
OMe
N
N
384.6
383.6
375.3
375.0
386.0
OMe
OMe
385.8
385.0
385.4
392.7
391.9
N
MeO
N
OMe
2. Results and discussion
2.1. Computational aspects
369.4
370.6
376.0
376.5
369.5
370.6
368.8
370.3
379.2
379.8
F
377.6
378.1
374.3
375.0
The literature data on CH acidity of pyridines are scanty.14 The
main reasons are the necessity of using very strong bases at low
temperatures and the side reactions of the azine carbanions gen-
erated.4 A brief review of the papers devoted to experimental and
theoretical investigation of azine CH acidities is presented in our
previous publications.10e,10h In the present work we report the
values of CH acidity of pyridines both in gas-phase (DacidG) and in
THF solution (pKa), which were calculated by means of quantum
chemistry.
Data on gas-phase acidity are important for the development of
an acidity scale not depending on the basicity of the solvent in
which the ionization takes place. Its recommended measure is the
Gibbs energy (DacidG) of deprotonation of the substance:
384.8
385.1
381.1
381.6
387.5
387.8
F
N
F
N
F
N
Scheme 1. Calculated DacidG values for the studied methoxypyridines and fluoropyr-
idines (upper straight values obtained at DFT B3LYP level, and lower italic values at
G3MP2B3 level).
where PyꢁH is bare pyridine, whose pKa value in THF (40.2, for
position 4 of the ring) is known experimentally.
The homodesmic reaction Gibbs energy was calculated using
the following equation:
X
X
DrGs
¼
Gs ꢁ
Gs:
reactants
product
Further, it can be proved that:
ReHðgÞ/RꢁðgÞ þ HþðgÞ
DrGs
1
pKaðReHÞ ¼ 40:2 þ
$
:
All the calculations were performed by using the Gaussian 03
software. Two different approaches, namely (i) the DFT B3LYP level
of theory and (ii) the hybrid G3MP2B3 method,15 were used as
described below.
RT ln 10
The CH acidity values for fluoro- and methoxy-pyridines in THF
solution can be compared with those previously determined for
chloro- and bromo-pyridines (Table 1).10e
While the values of pKa(THF) of methoxypyridines are rather
high and are of magnitude of monosubstituted benzenes,16 the
insertion of halogen makes the compounds much more acidic.
When present at the 2 position, fluorine exerts a short range effect
similar to that of chlorine; in contrast, positions remote from
fluorine are less acidified (than with chlorine and, above all, bro-
mine), in agreement with the electronic effects of the sub-
stituents.17 The influence of the methoxy group is not quite that
prominent. For molecules containing a methoxy group at the 2-, 4-
and even 3-position, only adjacent sites are acidified. That the
strongest acidifying effect is observed at both 2- and 4-sites,
neighboring to the substituent, is a general trend for 3-substituted
pyridines. In addition, this effect is stronger at the 4-position, which
is far from the nitrogen lone pair, and also more affected because of
concordant halogen/methoxy and nitrogen effects. In the case of
2,6-dihalogenated pyridines, the strongest acidifying effect is ob-
served at the 3- and 5-positions of the ring. In addition, the 4-
position also becomes much more acidic, notably compared to 2-
monohalogenated substances, because of the cooperative long
range electron-withdrawing effects of both halogens. With 2,6-
dimethoxypyridine, the short range ꢁI effects exhibited at the 3-
and 5-position of the cycle by the methoxy groups are concealed by
their stronger long range ‘para’ electron-donating (þM) effects.
From 2,3-dimethoxypyridine, the ‘meta’ electron-donating effect
exhibited by the methoxy group at C2 does not offset the short
range inductive acidifying effect exerted at C4 by the methoxy
group at C3; as a result, the 4 position is more acidified for 2,3-
dimethoxypyridine than for 2,6-dimethoxypyridine.
2.1.1. DFT B3LYP level of theory. The geometries were fully opti-
mized by using the 6-31G(d) basis set. No symmetry constraints
were implied and minima were found by the potential energy
surface scans. In order to perform stationary point characterization
and to calculate zero-point vibrational energies and thermal cor-
rections, vibrational frequencies were calculated at the same level
of theory. The single point energies were obtained using the 6-
311þG(d,p) basis set and tight convergence criteria.
2.1.2. Hybrid G3MP2B3 method. G3MP2B3 is a modified version of
Gaussian-3 (G3) theory for calculating energies of molecules with
high accuracy. G3MP2B3 uses MP2 instead of MP4 for the basis set
extension corrections and geometries and zero point vibrational
energies calculated at the B3LYP/6-31G(d) level of theory.
The DacidG values were calculated from the calculated values of
Gibbs energy of species in gas phase by the following equation:
ꢀ
ꢁ
ꢀ
ꢁ
DacidG ¼ G0298 Rꢁ þ G2098 Hþ ꢁ G2098ðReHÞ
As shown in Scheme 1, the values of the gas-phase acidity cal-
culated at DFT B3LYP and G3MP2B3 levels are in excellent agree-
ment (maximum deviation: 1.5 kcal molꢁ1), and are typical of those
for very weak acids.
The solvent effects were treated by using the IEF formalism of
polarized continuum model (PCM) with the default parameters for
THF. The PCM energies were calculated at the B3LYP/6-311þG(d,p)
level using geometries optimized for isolated structures.
The pKa values were further calculated by means of the fol-
lowing homodesmic reaction:
By using the computational approach described above, we also
investigated the influence of substrate coordination to lithium
species on the pKa(THF) values (Fig. 1). It is worth noting that, be-
sides impacting the pKa(THF) values, complexation to lithium can
ReHðsÞþPyꢁ /RðꢁsÞ þ PyeH
;
ðsÞ
ðsÞ
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M. Hedidi et al. / Tetrahedron xxx (2016) 1e10
3
Table 1
and oxygendwere investigated, and several trends can be noted
here. As expected, coordination of methoxypyridine to LiCl by ni-
trogen is more effective than by oxygen (with the corresponding
isomeric complexes up to 8 kcal molꢁ1 more stable). In the case of
O-Li complexation, the anions formed under deprotonation at po-
sitions adjacent to the methoxy group benefit from additional cyclic
stabilization (values with asterisk on Fig. 1). Finally, coordination of
the metal by the ring nitrogen lone pair drastically increases CH
acidity of the adjacent positions, making them competitive in
deprotometalation processes.
Pyridine pKa(THF) changes caused by substituent effects
X
DpKa(THF)
C2
C3
C4
C5
C6
Cl
Br
F
d
d
d
d
ꢁ6.9
ꢁ7.4
ꢁ6.9
ꢁ0.7
ꢁ4.5
ꢁ5.2
ꢁ3.3
þ0.5
ꢁ3.1
ꢁ3.5
ꢁ2.2
þ1.2
ꢁ3.9
ꢁ4.4
ꢁ3.4
þ0.5
2.2. Synthetic aspects
OMe
We first focused on the deprotometalation of 3-methoxypyridine
(1a). 1a can be deprotolithiated regioselectively at its 2 position by
using BuLi$TMEDA in THF at ꢁ40 ꢂC, as evidenced by trapping with
acetaldehyde to afford the expected alcohol in 49% yield.19 A favored
coordination of the metal of the base by the ring nitrogen (when
compared to the methoxy substituent) is advanced to rationalize this
result. By increasing the deprotometalation temperature to ꢁ23 ꢂC,
which proves possible by using less nucleophilic mesityllithium, 2-
substituted 3-methoxypyridines are formed in higher yields.20 Us-
ing LiDA (DA¼diisopropylamino) in THF at ꢁ42 ꢂC only proves effi-
cient in the presence of chlorotrimethylsilane as an in situ trap, but
mainly gives rise to a mixture of the 2- and 4-substituted derivatives
(assumed to be the kinetic and thermodynamic products,
respectively).20
Cl
Br
OMe
ꢁ3.7
ꢁ4.3
þ0.4
ꢁ7.9
ꢁ8.8
ꢁ3.8
d
d
d
ꢁ7.9
ꢁ8.8
ꢁ3.8
ꢁ3.7
ꢁ4.3
þ0.4
Cl
Br
F
ꢁ6.2
ꢁ6.3
ꢁ7.1
ꢁ1.3
d
d
d
d
ꢁ8.1
ꢁ8.8
ꢁ8.7
ꢁ3.8
ꢁ4.1
ꢁ4.5
ꢁ3.4
ꢁ0.1
ꢁ2.5
ꢁ3.0
ꢁ1.7
þ1.3
OMe
Cl
Br
F
d
d
d
d
ꢁ9.3
ꢁ9.9
ꢁ9.0
þ0.7
ꢁ8.4
ꢁ9.7
ꢁ6.4
þ1.2
ꢁ9.3
ꢁ9.9
ꢁ9.0
þ0.7
d
d
d
d
OMe
Magnesation of 3-methoxypyridine (1a) can be achieved selec-
tively at its 4 position by using a dipotassium tetra(alkyl)magnesate
including a polydentate N-donor, (PMDETA)2K2Mg(CH2SiMe3)4
(PMDETA¼N,N,N0,N00,N00-pentamethyldiethylenetriamine), in hex-
ane at 0 ꢂC.21 Similarly, 1a can be 4-zincated by using Kondo and
Uchiyama’s TMP-zincate, Li(TMP)Zn(tBu)2,22 in THF at 25 ꢂC.23
The 1:1 mixture of LiTMP and Zn(TMP)2, obtained from
ZnCl2$TMEDA and LiTMP,10a,11 was involved in the reaction with 1a
in order to better understand the behavior of this combination
(Table 2). Upon treatment by the base (0.5 equiv of each metal
amide) in THF for 2 h at room temperature (or 0 ꢂC) and subsequent
Cl
Br
OMe
d
d
d
d
d
d
ꢁ11.3
ꢁ12.2
ꢁ3.0
ꢁ6.4
ꢁ7.0
þ1.4
ꢁ6.2
ꢁ6.8
þ1.6
favor the deprotonation at a neighboring site through complex-
induced proximity effect.18 To this purpose, we considered 1:1
complexes of 3-, 4- and 2-methoxypyridine with LiCl and LiTMP.
With LiCl, two types of coordinationdnamely through nitrogen
Cl
Li
32.6
35.1
36.4
OMe
OMe
OMe
36.7
35.0
38.0
37.7
40.8
45.4
24.9*
OMe
40.1
42.7
32.5
35.3
42.8
N
Li
N
Li
N
28.6*
N
N
1a
Cl
Cl
Li
OMe
OMe
OMe
OMe
33.0
34.4
34.1
37.1
44.5
36.6
26.3*
N
Li
N
Li
N
45.2
N
N
3a
Cl
39.1
36.2
36.3
40.7
26.1*
35.6
33.4
40.1
42.7
40.2
36.8
37.8
35.0
42.1
44.6
30.6*
N
OMe
Li
N
Li
OMe
N
Li
OMe
N
OMe
N
4a
Cl
Cl
Fig. 1. Calculated pKa(THF) values for 3-, 4- and 2-methoxypyridine, as well as their complexes with LiCl or/and LiTMP.
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4
M. Hedidi et al. / Tetrahedron xxx (2016) 1e10
Table 2
Calculated pKa(THF) values for 3-methoxypyridine (1a), deprotometalation using in situ prepared 1:1 LiTMP-Zn(TMP)2 followed by iodolysis and ORTEP diagram (30%
probability) of 1d
Entry
n (equiv)
Temperature (ꢂC)
Reaction time
Products, yields (%)
1
2
3
4
5
6
0.5
0.5
0.5
1
2
2
20a
ꢁ40
20
20
20
2 h
2 h
10 min
2 h
2 h
1b, 10b
d
1b, 50b
1b, 11b
d
1c, 85b
d
1c, 25b
1c, 50b
1c, 58b
1c, 45c
d
d
d
1d, 30b
1d, 35b
1d, 55c
20
20 h
d
a
A similar result was obtained at 0 ꢂC and using Et2O as solvent at room temperature.
Yield after purification by column chromatography.
b
c
Ratio determined from the 1H NMR spectrum of the crude.
trapping with iodine, 1a was converted to a mixture of the 2- and 4-
iodo derivatives (1b and 1c), both purified, isolated in 10 and 85%
yield, respectively (entry 1). In order to see if this ratio could be
modified, reactions were performed at a lower temperature or
using a shorter reaction time. Whereas no reaction was noted at
ꢁ40 ꢂC (entry 2), shortening the reaction time to 10 min led to
a mixture of 1b (50% yield) and 1c (25% yield) (entry 3). By keeping
a 2 h contact at room temperature with the base, extending the
base amount to 1 equiv of each metal amide led to the competitive
formation of the 2,4-diiodo derivative 1d (30% yield, entry 4). With
2 equiv of each metal amide, 1c (58% yield) and 1d (35% yield) were
the only products isolated (entry 5); in spite of caking of the re-
action mixture, the formation of 1d proved favored by extending
the contact time between base and substrate to 20 h (entry 6).10h By
using LiTMP (2 equiv) under similar reaction conditions, the 4-iodo
derivative 1c was obtained in 6% yield together with traces of 1b
and the 4,4ʹ-dimer24 (25% yield). Upon a similar treatment but in
the presence of TMEDA (2 equiv), 1c and the 4,4ʹ-dimer formed in 5
and 11% yield, respectively, together with traces of 1b.
products, respectively. The kinetic products are observed by using
organolithiated (alkyl/aryl) bases, and coordination of the ring ni-
trogen to lithium favors reaction at C2 by both proximity effect18a
and strongly decreasing of the corresponding pKa values (Fig. 1).
Results also evidence formation of transient 2-metalated 3-
methoxypyridines by using amido-containing bases such as LiDA,
LiTMP and 1:1 LiTMP-Zn(TMP)2. If chlorotrimethylsilane is not
present to intercept the 2-metalated species, they change to pre-
sumably more stable 4-metalated derivatives (reversible reactions).
Such an isomerization could also take place by using TMP-zincate,
with lithium coordination by the pyridine nitrogen first giving rise
to a 2-metalated species,25 provided that this conversion is faster
than the consumption of generated H-TMP by the tert-butyl
ligands.26
The formation of 2,4-dimetalated species is only observed by
using 1:1 LiTMP-Zn(TMP)2 (1 or 2 equiv) for which ‘trans-metal
trapping’12 can take place. If lithium is coordinated by the pyridine
nitrogen in the 2-metalated 3-methoxypyridine, methoxy could be
still available to stabilize a 4-metalated species. Similarly, if lithium
is coordinated by the methoxy group in the 4-metalated 3-
methoxypyridine, pyridine nitrogen could be free to play a role in
the formation of a 2-metalated derivative (Scheme 2).
Some conclusions can be drawn from these data. The different
results above confirm that the 2- and 4-metalated 3-
methoxypyridines correspond to kinetic and thermodynamic
R = TMP or 3-methoxy-2/4-pyridyl
N
R
Li
Zn
O
OMe
O
at C2
at C4
R
Zn
N
N
R
Zn
N
Li
Li
N
1st metalation
2nd metalation
N
at C4
at C2
N
R
Li
O
Zn
N
Scheme 2. Proposed pathways to the 2,4-dimetalated 3-methoxypyridine.
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M. Hedidi et al. / Tetrahedron xxx (2016) 1e10
5
presence of chlorotrimethylsilane leads to the 3-silylated derivative
(61% yield) together with the 3,5-disilylated (16%).20 Depro-
tolithiation can be carried out at the 3 position more efficiently by
using either mesityllithium in THF at ꢁ23 ꢂC20 or phenyllithium in
THF at 0 ꢂC.31
X
R
N
R
Zn
N
Li
Zn
N
Li
N
O
Due to lower LUMO levels, 2-methoxypyridine (4a) is more
prone to nucleophilic attacks than 3- and 4-methoxypyridines (1a
and 3a).32 Using BuLi in THF with 4a at temperatures between
0 and 20 ꢂC leads to both deprotolithiation and nucleophilic addi-
tion.33 Conducting the reaction by using LiDA and chloro-
trimethylsilane as an in situ trap quantitatively furnishes the 3-
trimethylsilyl derivative.32 To make efficient this LiDA-promoted
deprotometalation, and extend it to other kinds of electrophilic
trapping, it is possible to consume the diisopropylamine formed by
reaction either with MeLi32 or with PhLi.34 As for 3-
methoxypyridine (1a), mesityllithium can be used in THF at room
temperature.20 Bimetallic combinations such as 1:1 LiTMP-Al(iBu)3
(‘trans-metal trapping’12 in THF at ꢁ78 ꢂC),35 putative LiCo(TMP)3
(in THF at room temperature),36 LiCu(TMP)2 (in THF at room tem-
perature)37 and putative LiFe(TMP)3 (in THF at room tempera-
ture),38 can be employed for the same purpose. The regioselectivity
of the reaction can be switched from the more acidic 3 to the less
acidic 6 position by recourse to BuLieLiDMAE in hexane at 0 ꢂC,
conditions that favor coordination-over acidity-driven reaction.39
As previously for 3-methoxypyridine (1a), 4- and 2-
methoxypyridines (3a and 4a) can be converted to the 3-iodo de-
rivatives either in 58 and 70% yield, respectively, by using (PMDE-
TA)2K2Mg(CH2SiMe3)4 in hexane at 0 ꢂC,21 or in 92 and 70% yield by
using TMP-zincate in THF at room temperature.23
Upon treatment by the 1:1 mixture of LiTMP and Zn(TMP)2
(0.5 equiv of each metal amide) in THF for 2 h at room temperature
followed by quenching with iodine, 4-methoxypyridine (3a)
cleanly provided the 3-iodo derivative 3b, which was isolated in
89% yield (Table 4, entry 1). When the amount of base was in-
creased to 1 equiv of each metal amide, no more starting material
was detected but 3,5-diiodo-4-methoxypyridine 3c (7% yield), 2,3-
diiodo-4-methoxypyridine 3d (2% yield) and 2,5-diiodo-4-
methoxypyridine 3e (traces) concomitantly formed with the
monoiodide 3b (88% yield) (Table 4, entry 2). It is worth mentioning
that, by using LiTMP (1.5 equiv) without Zn(TMP)2 in THF at 0 ꢂC for
2 h, the yield of 3b dropped to 38% again demonstrating the value of
the ‘trans-metal trapping’12 approach.
R = TMP or
3-methoxy-4-pyridyl
X = Cl, Br; R = TMP or
3-substituted 2-pyridyl
Fig. 2. Proposed metalated species for 3-methoxy, 3-chloro and 3-bromopyridine.
By contrast with 1a, for which deprotometalation is observed at
C4 by using 1:1 LiTMP-Zn(TMP)2 in THF at room temperature for
2 h, 3-chloro and 3-bromopyridine are attacked at C2 under similar
conditions.10e Such a difference could be in relation with a higher
ability to coordinate lithium in the case of the methoxy group,
contributing to a greater stabilization of the corresponding 4-
metalated derivative, as shown in Fig 2.
This difference led us to study the behavior of 3-fluoropyridine
(2a). 2a reacts with BuLi$TMEDA at ꢁ40 ꢂC to afford either the 2-
(kinetic) or the 4- (thermodynamic) lithio species, depending on if
Et2O or more polar THF is, respectively, employed as solvent; the
isomerization was supposed to occur through the formation of the
2,4-dilithio species.27 The use of BuLi$DABCO (DABCO¼1,4-
diazabicyclo[2.2.2]octane) in Et2O at ꢁ75 ꢂC allows 2a to be se-
lectively attacked next to nitrogen.27b In contrast, 2a gives 4-
substituted products by using LiDA in THF at ꢁ75 ꢂC.28,27b A simi-
lar regioselectivity can be reached by using BuLi$tBuOK in THF at
ꢁ75 ꢂ
C
29 and LiMgBu3 in THF at ꢁ10 ꢂC.30
Thus, 3-fluoropyridine (2a) was involved in the reaction with the
1:1 mixture of LiTMP and Zn(TMP)2 (Table 3). After 2 h contact with
the base (0.5 equiv of each metal amide) inTHFat room temperature,
iodolysis furnished a mixture of the 2- and 4-iodo derivatives (2b and
2c) in 57 and 37% yield, respectively (entry 1). Compared with
methoxy (see above) and the other halogens (chlorine, bromine),10e
fluorine at C3 is less capable than the former and more than the
latter of contributing to the stabilization of a 4-metalated species;
thus, its ability to coordinate and stabilize a 4-metalated derivative
seems to be intermediate between methoxy and the other halogens.
Increasing the base amount (to 1 equiv of each metal amide)
allowed the diiodide 2d to be obtained in 46% yield together with
the 4-iodo 2c (45% yield) and the 2-iodo 2b (9% yield). The experi-
ment carried out by using 2 equiv of each metal amide quantitatively
provided the diiodo 2d (entry 3); this result is different to what is
observed from 1a, and can be in relation with lower pKa values.
We next focused on 4- and 2-methoxypyridines (3a and 4a).
Concerning 4-methoxypyridine (3a), using LiDA in THF in the
Under the same reaction conditions, 1:1 LiTMPeZn(TMP)2
(0.5 equiv of each metal amide) converted 2-methoxypyridine (4a)
into the 3-iodo derivative 4b but in a moderate 31% yield (Table 5,
entry 1), a result that could be due to higher pKa values at the 3
position. A quantitative yield was reached by doubling the amount
of base (Table 5, entry 2). Such a result could not be reproduced by
using LiTMP, even in the presence of LiCl.
Table 3
Calculated pKa(THF) values for 3-fluoropyridine (2a), and deprotometalation using in situ prepared 1:1 LiTMP-Zn(TMP)2 followed by iodolysis and ORTEP diagram (30%
probability) of 2d
Entry
n (equiv)
Products, yieldsa (%)
1
2
3
0.5
1
2
2b, 57
2b, 9
2b, e
2c, 37
2c, 45
2c, 6
2d, 1
2d, 46
2d, 94
a
Yield after purification by column chromatography.
Please cite this article in press as: Hedidi, M.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.03.022

6
M. Hedidi et al. / Tetrahedron xxx (2016) 1e10
Table 4
Calculated pKa(THF) values for 4-methoxypyridine (3a), and deprotometalation using in situ prepared 1:1 LiTMPeZn(TMP)2 followed by iodolysis
Entry
n (equiv)
Products, yieldsa (%)
1
2
0.5
1
3b, 89
3b, 88
3c, e
3c, 7
3d, e
3d, 2
3e, e
3e, traces
a
Yield after purification by column chromatography.
Table 5
Compared with 2-methoxypyridine (4a), 2-fluoropyridine (5a)
is more reactive. Alkyllithiums already add nucleophilically to the
latter at low temperatures, e.g., BuLi$TMEDA in Et2O at ꢁ40 ꢂC and,
to a lesser extent, BuLi in Et2O at ꢁ60 ꢂC.40 In contrast, using more
protophilic LiDA40,41 or BuLi$tBuOK,29 both in THF at ꢁ75 ꢂC, favors
proton abstraction (which occurs next to fluorine). Turning to
Calculated pKa(THF) values for 2-methoxypyridine (4a), and deprotometalation
using in situ prepared 1:1 LiTMPeZn(TMP)2 followed by iodolysis
30
37
Li2(TMP)MgBu3 and LiCu(TMP)2 in THF allows 5a to be depro-
tometalated at ꢁ10 ꢂC and rt, respectively.
Thishigherreactivityof2-fluoropyridine(5a)over4a, probablyin
relation with lower pKa values, was here evidenced by reaction with
1:1 LiTMPeZn(TMP)2 to give under the same reaction conditions 2-
fluoro-3-iodopyridine (5b) as the main product together with 15% of
2-fluoro-3,6-diiodopyridine (5c) (Table 6). Once again, the behavior
of fluorine is intermediate between those of the methoxy group and
the other halogens (chlorine, bromine). Indeed, for the latter, not
only 2-halo-3-iodo and 2-halo-3,6-diiodo derivatives are formed,
but also 2-halo-6-iodo and 2-halo-4-iodo derivatives.10e
Entry
n (equiv)
Yielda (%)
31b
98
1
2
0.5
1
a
Yield after purification by column chromatography.
The rest is starting material.
b
Table 6
Compared
with
2-methoxypyridine
(4a),
2,6-
Calculated pKa(THF) values for 2-fluoropyridine (5a), and deprotometalation using
in situ prepared 1:1 LiTMP-Zn(TMP)2 followed by iodolysis
dimethoxypyridine (6a) is less prone to nucleophilic attacks. BuLi
can thus be employed to functionalize efficiently the 3 position.42
The bimetallic base LiCo(TMP)3 can also be used in THF at room
temperature for the same purpose.36 In the case of 2,3-
dimethoxypyridine (7a), 2 equiv of BuLi are required to perform
an efficient functionalization at the 4 position.43
Both compounds 6a and 7a could be quantitatively depro-
tometalated next to the methoxy group by using 1:1
LiTMPeZn(TMP)2 (1 equiv of each metal amide), a result evidenced
by subsequent iodolysis. From 6a, dimetalation was only observed
when the amount of base was doubled and the reaction time ex-
tended to 20 h. Reducing the amount of base in the case of 7a led to
a lower 20% yield (Scheme 3).
Entry
n (equiv)
Products, yieldsa (%)
1
2
0.5
1
5b, 66
5b, 82
5c, 15
5c, 15
a
Yield after purification by column chromatography.
1) ZnCl2.TMEDA
41.4
(x equiv)
I
I
I
41.6
+ LiTMP (3x equiv)
THF, rt, y h
2) I2
MeO
N
OMe
MeO
N
OMe
MeO
N
OMe
6a
6b (x = 1, y = 2): 98%
6c (x = 1, y = 2): 0%
6b (x = 2, y = 20): 70% 6c (x = 2, y = 20): 30%
I
1) ZnCl2.TMEDA
(x equiv)
+ LiTMP (3x equiv)
37.2
OMe
OMe
OMe
OMe
42.3
45.7
THF, rt, 2 h
2) I2
N
N
7a
7b (x = 1): 98%
7b (x = 0.5): 20%
Scheme 3. Calculated pKa(THF) values for 2,6-dimethoxypyridine (6a) and 2,3-dimethoxypyridine (7a), deprotometalation using in situ prepared 1:1 LiTMPeZn(TMP)2 followed by
iodolysis and ORTEP diagram (30% probability) of 6c and 7b.
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M. Hedidi et al. / Tetrahedron xxx (2016) 1e10
7
We finally studied the behavior of 2,6-difluoropyridine (8a). 8a
can be cleanly deprotolithiated at its 3 position upon treatment
with LiDA in THF at ꢁ75 ꢂC.44,41b,c A similar reaction is also possible
by using Li2(TMP)MgBu3 in THF at ꢁ10 ꢂC.30 In contrast to what can
be observed by employing LiDA, using 1:1 LiTMP-Zn(TMP)2 in THF
at room temperature led either to mono or to dideprotonation (0.5
or 1 equiv of each metal amide, respectively) of 2,6-difluoropyridine
(8a), as demonstrated by subsequent interception with iodine to
furnish either the monoiodide 8b (66% yield) or the diiodide 8c (85%
yield) (Table 7).
accordance with a ‘trans-metal trapping’12 allowing the pyr-
idyllithiums to be trapped by zinc species as they are formed.
4. Experimental
4.1. General
All the reactions were performed in Schlenk tubes under an
argon atmosphere. THF was distilled over sodium/benzophenone.
Liquid chromatography separations were achieved on silica gel
Merck-Geduran Si 60 (63e200 mm). Melting points were measured
on a Kofler apparatus. IR spectra were taken on a PerkineElmer
Spectrum 100 spectrometer. 1H and 13C Nuclear Magnetic Reso-
nance (NMR) spectra were recorded on a Bruker Avance III spec-
Table 7
Calculated pKa(THF) values for 2,6-difluoropyridine (8a), and deprotometalation
using in situ prepared 1:1 LiTMP-Zn(TMP)2 followed by iodolysis
trometer at 300 and 75 MHz, respectively. 1H chemical shifts (
d) are
given in ppm relative to the solvent residual peak, and 13C chemical
shifts are relative to the central peak of the solvent signal.47
4.1.1. Crystallography. The sample was studied with graphite
ꢂ
monochromatized Mo-K
a
radiation (
l
¼0.71073 A). The X-ray dif-
fraction data were collected by using either APEXII, Bruker-AXS
diffractometer (compounds 1d, 2d and 5d) or D8 VENTURE
Bruker AXS diffractometer (compounds 6c and 7b). The structure
was solved by direct methods using the SIR97 program,48 and then
refined with full-matrix least-square methods based on F2 (SHELX-
97)49 with the aid of the WINGX program.50 All non-hydrogen
atoms were refined with anisotropic atomic displacement param-
eters. H atoms were finally included in their calculated positions.
Molecular diagrams were generated by ORTEP-3 (version 2.02).50
Entry
n (equiv)
Products, yieldsa (%)
1
2
0.5
1
8b, 66
8b, e
8c, e
8c, 85
a
Yield after purification by column chromatography.
Compared with 2,6-dimethoxypyridine (6a), 8a is more prone to
dimetalation, probably in relation with lower pKa values. Compared
with 8a, pyridines bearing heavier halogens (chlorine, bromine)
give under similar reaction conditions more than one product,10e
a result probably resulting from both steric and longer range
acidifying effects.45
Finally, we have shown that it is possible to associate
deprotometalation-iodination of pyridines with N-arylation of
azoles for the generation of C,Nʹ-linked bis-heterocycles. To this
purpose, after hydrolysis and work-up, we involved the crude
containing the iodide 5b in the reaction with pyrazole (2 equiv)
using metal copper (0.2 equiv) as transition metal, cesium car-
bonate (2 equiv) as base, and acetonitrile as solvent at its reflux
temperature for 24 h.46 Under these conditions, both substitution
of fluorine and N-arylation were noted, as evidenced with the
formation of 5d in 70% yield (Scheme 4).
4.2. General procedure 1
To
a
stirred, cooled (0 ꢂC) solution of 2,2,6,6-
tetramethylpiperidine (0.25 mL, 1.5 mmol) in THF (2e3 mL) were
successively added BuLi (about 1.6 M hexanes solution, 1.5 mmol)
and, 5 min later, ZnCl2$TMEDA51 (0.13 g, 0.50 mmol). The mixture
was stirred for 15 min at 0 ꢂC before introduction of the substrate
(1.0 mmol) at 0e10 ꢂC. After 2 h at room temperature, a solution of
I2 (0.38 g, 1.5 mmol) in THF (4 mL) was added. The mixture was
stirred overnight before addition of an aqueous saturated solution
of Na2S2O3 (4 mL) and extraction with AcOEt (3ꢃ20 mL). The
combined organic layers were dried over MgSO4, filtered and
concentrated under reduced pressure. Purification by chromatog-
raphy on silica gel (the eluent is given in the product description)
led to the compounds described below.
3. Conclusion
In summary, the basic mixture prepared from 1:3 ZnCl2$TME-
DAeLiTMP, and supposed to be a 1:1 mixture of LiTMP and
Zn(TMP)2, allows reactions that are not reached by its lithium
precursor. Besides more efficient monodeprotonations, for exam-
ple, from 2-methoxypyridine, dideprotonation can be efficiently
achieved for substrates benefiting from lower pKa values such as 3-
fluoropyridine and 2,6-difluoropyridine. Such results are in
4.2.1. 2-Iodo-3-methoxypyridine (1b). The general procedure 1, but
with a 10 min contact time between the base and the substrate
instead of 2 h, using 3-methoxypyridine (0.10 mL) gave 1b (eluent:
heptane-AcOEt 20:80) in 50% yield as a yellow oil: 1H NMR (CDCl3)
d
3.86 (s, 3H), 6.97 (dd, 1H, J¼8.1 and 1.5 Hz), 7.17 (dd, 1H, J¼8.1 and
4.5 Hz), 7.95 (dd, 1H, J¼4.5 and 1.5 Hz); 13C NMR (CDCl3)
d 56.4
1) ZnCl2.TMEDA (0.5 equiv)
+ LiTMP (1.5 equiv)
THF, rt, 2 h
N
N
2) I2
I
3) hydrolysis and work-up
N
N
4) pyrazole (1.5 equiv)
Cs2CO3 (2 equiv)
Cu (0.2 equiv)
N
F
N
5b
5d
CH3CN, reflux, 24 h
(70% yield)
Scheme 4. Deprotometalation-iodination of 5a followed by N-arylation of pyrazole with the crude iodide 5b and ORTEP diagram (30% probability) of 5d.
Please cite this article in press as: Hedidi, M.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.03.022

8
M. Hedidi et al. / Tetrahedron xxx (2016) 1e10
(CH3), 111.6 (C), 116.9 (CH), 123.6 (CH), 142.5 (CH), 155.3 (C). These
data are in accordance with those previously described.52
1d (CCDC 1450720, room temperature): C6H5I2NO, M¼360.91, or-
ꢂ
thorhombic, P b c a, a¼13.2964(7), b¼8.6329(3), c¼15.5558(7) A,
3
ꢁ3
ꢂ
V¼1785.60(14) A , Z¼8, d¼2.685 g cm
,
m
¼6.982 mmꢁ1. A final
4.2.2. 4-Iodo-3-methoxypyridine (1c). The general procedure 1 us-
ing 3-methoxypyridine (0.10 mL) gave 1c (eluent: heptane-AcOEt
20:80) in 85% yield as a pale yellow powder: mp 88e90 ꢂC; IR
refinement on F2 with 2035 unique intensities and 93 parameters
converged at
u
R(F2)¼0.0730 (R(F)¼0.0311) for 1679 observed re-
flections with I>2
s
(I).
(ATR): 720, 815, 1015, 1065, 1196, 1250, 1281, 1403, 1473, 1558 cmꢁ1
;
1H NMR (CDCl3)
d
3.98 (s, 3H), 7.72 (d, 1H, J¼5.1 Hz), 7.87 (d, 1H,
4.3.2. 3-Fluoro-2,4-diiodopyridine (2d). The general procedure 2
using 3-fluoropyridine (43 L) gave 2d (eluent: heptane-AcOEt
90:10) in 94% yield as a yellow powder: mp 102 ꢂC (lit.54 102 ꢂC);
1H NMR (CDCl3)
7.63 (dd, 1H, J¼4.8 and 4.2 Hz), 7.82 (dd, 1H, J¼5.1
and 0.9 Hz); 13C NMR (CDCl3)
J¼5.1 Hz), 8.10 (s, 1H). The 1H NMR data are in accordance with
m
those previously described.23 13C NMR (CDCl3)
132.9 (CH), 134.4 (CH), 143.0 (CH), 155.2 (C).
d 57.1 (CH3), 97.4 (C),
d
d
91.1 (d, C, J¼17 Hz), 105.4 (d, C,
4.2.3. 3-Fluoro-2-iodopyridine (2b). The general procedure 1 using
3-fluoropyridine (86 L) gave 2b (eluent: CH2Cl2) in 57% yield as
J¼32 Hz), 134.0 (d, CH, J¼1.1 Hz), 146.9 (d, CH, J¼6.2 Hz), 158.6 (d, C,
J¼254 Hz). Crystal data for 2d (CCDC 1450721, T¼150 K): C5H2FI2N,
m
a yellow oil: 1H NMR (CDCl3)
d
7.29e7.42 (m, 2H), 8.25 (dt, 1H, J¼4.5
M¼348.88, triclinic, P -1, a¼7.1039(4), b¼7.8955(5), c¼7.9442(5) A,
ꢂ
and 1.5 Hz). The 1H NMR data are in accordance with those pre-
viously described.53
a
¼109.945(2),
b
¼105.973(2),
g
¼102.495(2) , V¼378.21(4) A , Z¼2,
3
ꢂ
ꢂ
d¼3.063 g cmꢁ3
,
m
¼8.244 mmꢁ1. A final refinement on F2 with 1737
unique intensities and 83 parameters converged at
u
s(I).
R(F2)¼0.1171
4.2.4. 3-Iodo-4-methoxypyridine (3b). The general procedure 1
using 4-methoxypyridine (0.10 mL) gave 3b (eluent: heptane-
AcOEt 20:80) in 89% yield as a pale yellow powder: mp 62e64 ꢂC
(R(F)¼0.0389) for 1639 observed reflections with I>2
4.3.3. 3,5-Diiodo-2,6-dimethoxypyridine (6c). The general pro-
cedure 2, but with a contact time of 20 h with the base, using 2,6-
(lit.10h 64 ꢂC); 1H NMR (CDCl3)
d
3.95 (s, 3H), 6.78 (d, 1H, J¼5.7 Hz),
8.40 (d, 1H, J¼5.4 Hz), 8.75 (s, 1H). The 1H NMR data are in accor-
dimethoxypyridine (66 mL) gave 6c (eluent: heptane-CH2Cl2 60:40)
dance with those previously reported.10h 13C NMR (CDCl3)
(CH3), 84.6 (C), 106.5 (CH), 150.1 (CH), 156.8 (CH), 163.2 (C).
d
55.7
in 30% yield as a pale yellow powder: mp 126 ꢂC; IR (ATR): 708, 736,
908, 999, 1038, 1235, 1247, 1288, 1315, 1385, 1361, 1459, 1552,
2948 cmꢁ1
(CDCl3)
for 6c (CCDC 1450723, T¼150 K): C7H7I2NO2, M¼390.94, mono-
; d
1H NMR (CDCl3) 3.96 (s, 6H), 8.16 (s, 1H); 13C NMR
4.2.5. 2-Fluoro-3,6-diiodopyridine (5c). The general procedure 1
d 54.9 (2CH3), 66.8 (2C), 156.8 (CH), 161.3 (2C). Crystal data
using 2-fluoropyridine (86
mL) gave 5c (eluent: heptane-AcOEt
10:90) in 15% yield as a pale yellow powder: mp 88 ꢂC (lit.10d
89 ꢂC); IR (ATR): 671, 727, 823, 871, 1010, 1114, 1135, 1226, 1257,
clinic,
b
P
21/c, a¼8.2579(3), b¼8.6432(3), c¼14.7789(6) A,
3
ꢂ
ꢂ
¼104.7150(10)ꢂ, V¼1020.24(7) A , Z¼4, d¼2.545
g ,
cmꢁ3
1368, 1416, 1531, 1548, 3508 cmꢁ1; 1H NMR (CDCl3)
d
7.38 (dd, 1H,
m
¼6.128 mmꢁ1. A final refinement on F2 with 2337 unique in-
J¼7.8 Hz), 7.75 (t, 1H, J¼8.0 Hz). These 1H NMR data are in accor-
tensities and 112 parameters converged at
0.0174) for 2190 observed reflections with I>2s(I).
u
R(F2)¼0.0433 (R(F)¼
dance with those previously described.10d
4.2.6. 2,6-Difluoro-3-iodopyridine (8b). The general procedure 1
4.4. General procedure 3
using 2,6-difluoropyridine (91
10:90) in 66% yield as a white powder: mp<50 ꢂC; 1H NMR (CDCl3)
6.69 (ddd, 1H, J¼8.4, 3.0 and 0.9 Hz), 8.19 (td, 1H, J¼8.1 and
7.8 Hz); 13C NMR (CDCl3)
CH, J¼35 and 5.9 Hz), 153.6 (dd, CH, J¼7.4 Hz), 160.3 (dd, C, J¼241
and 14 Hz), 162.0 (dd, C, J¼247 and 13 Hz). These data are in ac-
cordance with those previously reported.30
mL) gave 8b (eluent: heptane-AcOEt
To
a
stirred, cooled (0 ꢂC) solution of 2,2,6,6-
d
tetramethylpiperidine (0.25 mL, 1.5 mmol) in THF (2e3 mL) were
successively added BuLi (about 1.6 M hexanes solution, 1.5 mmol)
and, 5 min later, ZnCl2$TMEDA51 (0.13 g, 0.50 mmol). The mixture
was stirred for 15 min at 0 ꢂC before introduction of the substrate
(0.5 mmol) at 0e10 ꢂC. After 2 h at room temperature, a solution of
I2 (0.38 g, 1.5 mmol) in THF (4 mL) was added. The mixture was
stirred overnight before addition of an aqueous saturated solution
of Na2S2O3 (4 mL) and extraction with AcOEt (3ꢃ20 mL). The
combined organic layers were dried over MgSO4, filtered and
concentrated under reduced pressure. Purification by chromatog-
raphy on silica gel (the eluent is given in the product description)
led to the compounds described below.
d
69.3 (dd, C, J¼40 and 5.9 Hz), 108.4 (dd,
4.3. General procedure 2
To
a
stirred, cooled (0 ꢂC) solution of 2,2,6,6-
tetramethylpiperidine (0.50 mL, 3.0 mmol) in THF (5 mL) were
successively added BuLi (about 1.6 M hexanes solution, 3.0 mmol)
and, 5 min later, ZnCl2$TMEDA51 (0.26 g, 1.0 mmol). The mixture
was stirred for 15 min at 0 ꢂC before introduction of the substrate
(0.5 mmol) at 0e10 ꢂC. After 2 h at room temperature, a solution of
I2 (0.76 g, 3.0 mmol) in THF (8 mL) was added. The mixture was
stirred overnight before addition of an aqueous saturated solution
of Na2S2O3 (8 mL) and extraction with AcOEt (3ꢃ30 mL). The
combined organic layers were dried over MgSO4, filtered and
concentrated under reduced pressure. Purification by chromatog-
raphy on silica gel (the eluent is given in the product description)
led to the compounds described below.
4.4.1. 3-Fluoro-4-iodopyridine (2c). The general procedure 3 using
3-fluoropyridine (43
mL) gave 2c (eluent: hexane-CH2Cl2 80:20) in
45% yield as a yellow powder: mp 94 ꢂC (lit.53 96 ꢂC); IR (ATR): 1415,
1475, 1550, 1570, 3060 cmꢁ1 1H NMR (CDCl3)
; d 7.75 (t, 1H,
J¼5.1 Hz), 8.10 (d, 1H, J¼5.1 Hz), 8.35 (s, 1H); 13C NMR (CDCl3)
d 92.4
(d, C, J¼23 Hz), 133.7 (s, CH), 137.1 (d, CH, J¼26 Hz), 145.6 (d, CH,
J¼5.1 Hz), 159.1 (d, C, J¼256 Hz).
4.4.2. 3,5-Diiodo-4-methoxypyridine (3c). The general procedure 3
4.3.1. 2,4-Diiodo-3-methoxypyridine (1d).10h The general procedure
using 4-methoxypyridine (51
20:80) in an estimated 7% yield. It was identified by NMR: 1H
NMR (CDCl3) 3.91 (s, 3H), 8.72 (s, 2H).
mL) gave 3c (eluent: heptane-AcOEt
2 using 3-methoxypyridine (50 mL) gave 1d (eluent: heptane-AcOEt
20:80) in 35% yield as a pale yellow powder: mp 146e148 ꢂC; IR
d
(ATR): 698, 810, 840, 919, 978, 1012, 1185, 1247, 1358, 1452, 1523,
1540, 1717, 2931, 3345 cmꢁ1; 1H NMR (CDCl3)
d
3.92 (s, 3H), 7.66 (d,
4.4.3. 2,3-Diiodo-4-methoxypyridine (3d). The general procedure 3
using 4-methoxypyridine (51 L) gave 3d (eluent: heptane-AcOEt
20:80) in an estimated 2% yield. It was identified by NMR: 1H
1H, J¼5.1 Hz), 7.74 (d, 1H, J¼5.1 Hz); 13C NMR (CDCl3)
d
61.2 (CH3),
m
100.9 (C), 115.2 (C), 134.3 (CH), 146.8 (CH), 157.1 (C). Crystal data for
Please cite this article in press as: Hedidi, M.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.03.022

M. Hedidi et al. / Tetrahedron xxx (2016) 1e10
9
NMR (CDCl3)
J¼5.4 Hz).
d
3.93 (s, 3H), 6.68 (d, 1H, J¼5.4 Hz), 8.20 (d, 1H,
concentrated under reduced pressure. To the crude iodide were
added Cs2CO3 (0.65 g, 2.0 mmol), Cu powder (13 mg, 0.20 mmol),
the azole (1.5 mmol) and MeCN (5 mL) and the resulting mixture
was heated under reflux for 24 h. Filtration over CeliteÒ, washing
with AcOEt, removal of the solvent and purification by chroma-
tography on silica gel (the eluent is given in the product de-
scription) led to the compound described below.
4.4.4. 2,5-Diiodo-4-methoxypyridine (3e). The general procedure 3
using 4-methoxypyridine (51 mL) gave 3e (eluent: heptane-AcOEt
20:80) as traces. It was identified by NMR: 1H NMR (CDCl3)
d 3.91
(s, 3H), 7.11 (s, 1H), 8.44 (s, 1H).
4.4.5. 3-Iodo-2-methoxypyridine (4b). The general procedure 3
using 2-methoxypyridine (53 L) gave 4b (eluent: heptane-AcOEt
80:20) in 98% yield as a yellow oil: 1H NMR (CDCl3)
3.95 (s, 3H),
4.5.1. 2,3-Bis(1H-1-pyrazolyl)pyridine (5d). The general procedure
4 using 2-fluoropyridine (86 mL) and pyrazole (0.10 mL) gave 5d
m
d
(eluent: heptane-AcOEt 90:10) in 70% yield as a yellow powder: mp
6.60 (dd, 1H, J¼7.5 and 4.8 Hz), 7.98 (dd, 1H, J¼7.5 and 1.8 Hz), 8.08
98 ꢂC; IR (ATR): 757, 808, 937, 1018, 1036, 1050, 1262, 1297, 1393,
(dd, 1H, J¼5.1 and 1.8 Hz); 13C NMR (CDCl3)
d
54.7 (CH3), 79.9 (C),
1458, 1479, 1521, 1584, 3090, 3122 cmꢁ1; 1H NMR (CDCl3)
d 6.29 (t,
118.3 (CH), 146.5 (CH), 148.0 (CH), 161.9 (C). These NMR data are in
1H, J¼2.3 Hz), 6.34 (t, 1H, J¼2.3 Hz), 7.06 (d, 1H, J¼2.4 Hz), 7.40 (dd,
accordance with those previously described.36
1H, J¼8.1 and 4.8 Hz), 7.61e7.67 (m, 3H), 8.05 (dd, 1H, J¼7.8 and
1.5 Hz), 8.50 (dd, 1H, J¼4.8 and 1.8 Hz); 13C NMR (CDCl3)
d 107.6
4.4.6. 2-Fluoro-3-iodopyridine (5b). The general procedure 3 using
(CH), 107.7 (CH), 123.6 (CH), 129.8 (CH), 130.2 (C), 130.6 (CH), 136.2
(CH), 141.5 (CH), 142.0 (CH), 144.9 (C), 147.8 (CH). Crystal data for
5d (CCDC 1450722, T¼150 K): C11H9N5, M¼211.23, orthorhombic, P
2-fluoropyridine (43 mL) gave 5b (eluent: heptane-AcOEt 10:90) in
82% yield as a white powder: mp<50 ꢂC; IR (ATR): 737, 794, 843,
1018, 1065, 1137, 1253, 1370, 1407, 1424, 1557, 1576, 3383 cmꢁ1; 1H
21 21 21, a¼8.7934(9), b¼8.9384(7), c¼13.0819(14) A,
ꢂ
3
ꢁ3
NMR (CDCl3)
d
6.93 (ddd, 1H, J¼7.5, 5.1 and 2.1 Hz), 8.09e8.16 (m,
V¼1028.22(17) A , Z¼4, d¼1.365 g cm
, m
¼0.090 mmꢁ1. A final
ꢂ
2H). These data are in accordance with those described
previously.10d
refinement on F2 with 1369 unique intensities and 145 parameters
converged at
u
R(F2)¼0.0937 (R(F)¼0.0392) for 1211 observed re-
flections with I>2
s
(I).
4.4.7. 3-Iodo-2,6-dimethoxypyridine (6b). The general procedure 3
using 3-methoxypyridine (50 mL) gave 6b (eluent: heptane-AcOEt
Acknowledgements
This work was supported by the Ministere de l’Enseignement
10:90) in 98% yield as a yellow oil: IR (ATR): 670, 807, 950, 1002,
1020,1050,1112,1191,1234,1265,1309,1372,1411,1462,1567, 2948,
ꢁ
2985 cmꢁ1; 1H NMR (CDCl3)
d 3.89 (s, 3H), 3.96 (s, 3H), 6.15 (d, 1H,
ꢀ
ꢀ
superieur et de la Recherche scientifique Algerien (M.H.). F.M.
thanks the Institut Universitaire de France and also Thermo Fisher
for the generous gift of 2,2,6,6-tetramethylpiperidine. T.R. and V.D.
thank FEDER founds (D8 VENTURE Bruker AXS diffractometer).
J¼8.1 Hz), 7.80 (d, 1H, J¼8.1 Hz); 13C NMR (CDCl3)
d 53.5 (CH3), 54.3
(CH3), 65.5 (C), 103.4 (CH), 149.3 (CH), 160.5 (C), 163.1 (C). These
data are in accordance with those previously described.36
4.4.8. 4-Iodo-2,3-dimethoxypyridine (7b). The general procedure 3
Supplementary data
using 3-methoxypyridine (50 mL) gave 7b (eluent: heptane-AcOEt
10:90) in 98% yield as a pale yellow powder: mp<50 ꢂC; IR (ATR):
659, 769, 819, 855, 986, 1020, 1157, 1215, 1383, 1460, 1562,
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2016.03.022.
2938 cmꢁ1; 1H NMR (CDCl3)
d 3.83 (s, 3H), 3.96 (s, 3H), 7.22 (d, 1H,
J¼5.4 Hz), 7.51 (d, 1H, J¼5.4 Hz); 13C NMR (CDCl3)
d 53.7 (CH3), 60.0
References and notes
(CH3), 101.7 (C), 126.6 (CH), 141.4 (CH), 144.3 (C), 156.8 (C). Crystal
data for 7b (CCDC 1450724, T¼150 K): C7H8INO2, M¼265.04, or-
1. Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of Heterocycles, 2nd ed.;
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Chem. A 2013, 1, 1770e1777.
ꢂ
thorhombic, P b c a, a¼8.0585(4), b¼13.4414(6), c¼15.7058(7) A,
3
ꢂ
ꢁ3
, m
V¼1701.21(14) A , Z¼8, d¼2.070 g cm
¼3.715 mmꢁ1. A final
refinement on F2 with 1957 unique intensities and 102 parameters
R(F2)¼0.0408 (R(F)¼0.0177) for 1730 observed re-
3. (a) Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 1e360; (b) Beak, P.;
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converged at
flections with I>2
u
s
(I).
4.4.9. 2,6-Difluoro-3,5-diiodopyridine (8c). The general procedure 3
using 2,6-difluoropyridine (45 L) gave 8c (eluent: heptane-AcOEt
10:90) in 85% yield as a pale yellow powder: mp 102 ꢂC; IR (ATR):
m
666, 728, 811, 1047, 1268, 1363, 1423, 1567, 2922 cmꢁ1
;
1H NMR
(CDCl3)
d
8.50 (t, 1H, J¼7.7 Hz); 13C NMR (CDCl3)
d 70.7e71.3 (m,
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To
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stirred, cooled (0 ꢂC) solution of 2,2,6,6-
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Please cite this article in press as: Hedidi, M.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.03.022