Deproto-metallation using a mixed lithium-zinc base and computed CH acidity of 1-aryl 1H-benzotriazoles and 1-aryl 1H-indazoles

Article abstract of DOI:10.1039/c3ob42380h

1-Aryl-1H-benzotriazoles and -1H-indazoles were synthesized, and their deproto-metallation using the base prepared by mixing LiTMP with ZnCl ₂·TMEDA (1/3 equiv.) was studied. In the indazole series, reactions occurring at the 3 position were fo

Full text of DOI:10.1039/c3ob42380h

Organic &
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Deproto-metallation using a mixed lithium–zinc
base and computed CH acidity of 1-aryl
1H-benzotriazoles and 1-aryl 1H-indazoles†
Cite this: Org. Biomol. Chem., 2014,
12, 1475
Elisabeth Nagaradja,a Floris Chevallier,*a Thierry Roisnel,b Vincent Dorcet,b
Yury S. Halauko,*c Oleg A. Ivashkevich,c Vadim E. Matulisd and Florence Mongin*a
1-Aryl-1H-benzotriazoles and -1H-indazoles were synthesized, and their deproto-metallation using the
base prepared by mixing LiTMP with ZnCl2·TMEDA (1/3 equiv.) was studied. In the indazole series, reac-
tions occurring at the 3 position were followed by ring opening, and functionalization of the substrate was
only found possible (on the sulfur ring) using 2-thienyl as aryl group. In the benzotriazole series, either
mono- or bis-deprotonation (depending on the amount of base employed) was achieved with phenyl,
4-methoxyphenyl and 2-thienyl as aryl group, and bis-deprotonation in the case of 4-chlorophenyl
and 4-trifluoromethylphenyl. 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 27th November 2013,
Accepted 20th December 2013
DOI: 10.1039/c3ob42380h
www.rsc.org/obc
benzotriazole can behave like a directing group for deproto-
lithiation of a substituent connected to its N1 nitrogen,14
Introduction
Di- and triazoles and their benzo analogues are key elements further benzotriazole ring deprotonation is far less efficient
present in compounds of biological interest,1 or in materials (<20% yield).15 After studies on the lateral dilithiation of N-Boc
for a large range of applications.1a,b,2
1-amino-7-methylbenzotriazole,16 Knight’s group reported the
Deprotonative lithiation3 is an efficient tool to functionalize double deproto-metallation of N-Boc 1-aminobenzotriazole
regioselectively aromatic heterocycles such as pyrroles,4 using butyllithium in THF containing tetraglyme at −78 °C,
indoles,5 polyazoles,6 furans,7 thiophenes,8 oxazoles,9 thia- affording after electrophilic trapping 7-substituted deriva-
zoles,10 azines11 and polyazines.12
tives.17 Katritzky and co-workers described in 1998 a few ring
Few examples concern the direct lithiation of benzotri- deproto-lithiation reactions followed by methylation starting
azoles.13 In 1995, Katritzky’s team showed that, whereas from complexes between borane and 1-alkyl benzotriazoles
(reaction at the 4 position).18 One year later, Johnson and co-
workers reported similar metallation at the 4 position, but this
time from borane-free 1-(alkoxymethyl)benzotriazoles using
lithium diisopropylamide at low temperature.19 Katritzky and
co-workers documented in 2003 dianion formations (metalla-
tion at both the 7 position and the lateral chain) from benzo-
triazoles bearing a vinyl chain using butyllithium in THF at
−78 °C.20
In the indazole series, deproto-lithiation only proved possi-
ble in the case of 2-substituted 2H-indazoles for which ring
opening of 3-lithio derivatives is unlikely.6b
aEquipe Chimie et Photonique Moléculaires, Institut des Sciences Chimiques de
Rennes, UMR 6226 CNRS-Université de Rennes 1, Bâtiment 10A, Case 1003,
Campus Scientifique de Beaulieu, 35042 Rennes, France.
E-mail: floris.chevallier@univ-rennes1.fr, florence.mongin@univ-rennes1.fr;
Fax: +33-2-2323-6955
bCentre de Diffractométrie X, Institut des Sciences Chimiques de Rennes, UMR 6226
CNRS-Université de Rennes 1, Bâtiment 10B, Campus de Beaulieu, 35042 Rennes,
France
cDepartment of Chemistry 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,
For the functionalization of such substrates, monometal
lithium bases are employed at very low temperatures and do
not tolerate the presence of reactive functional groups.
Combinations of lithium reagents and softer metal com-
pounds have recently emerged as efficient tools to deproto-
metallate sensitive aromatic compounds.21 In the framework
of these studies, our group developed efficient pairs of metal
amides which complement each other in deproto-metallation
14 Leningradskaya Str., Minsk, 220030, Belarus. Fax: +375-17-2264696
†Electronic supplementary information (ESI) available: 1H, 13C and 19F NMR
spectra, crystal data, calculated values of the Gibbs energies ΔacidG [kcal mo1−1
]
for deprotonation at the corresponding positions of the investigated
heteroaromatic compounds, and selected Cartesian coordinates of molecular
geometry for the most stable rotamer forms of the investigated heteroaromatics
(on example of 1e, 2e) (neutral molecule, gas phase) optimized at B3LYP/6-31G(d)
level of theory. CCDC 962368–962380. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c3ob42380h
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Scheme 1 Substrates for which the deproto-metallation was studied.
reactions. In particular, the TMP-based (TMP = 2,2,6,6-tetra-
methylpiperidino) lithium–zinc mixture, prepared by mixing
Fig. 1 ORTEP diagrams (50% probability) of 1f and 2g.
ZnCl2·TMEDA (TMEDA
=
N,N,N′,N′-tetramethylethylenedi-
amine) with LiTMP (3 equiv.), and supposed to be a 1 : 1 LiTM-
P·2LiCl( TMEDA)–Zn(TMP)2 mixture,22 was identified as a
synergic reagent (more efficient than separate LiTMP and
Zn(TMP)2) to functionalize sensitive aromatic compounds
including heterocycles.22a,23
We herein describe our attempts to use such a lithium–zinc
combination for the deproto-metallation of the azole sub-
strates shown in Scheme 1. We earlier showed that the regio-
selectivity of the reaction for related substrates is partly
determined by the acidity of the different hydrogens in their
molecules.23f,h,24 Similarly, we here tried to rationalize the
reaction results using the CH acidities in THF of the heteroaro-
matic substrates calculated using the homodesmic reaction
approach within the density functional theory (DFT)
framework.
noted, with aryl iodides substituted by electron-withdrawing
groups in general favouring the reaction. In the benzotriazole
series, the isomeric 2-aryl derivatives 1′, also formed in low
yields, were discarded by column chromatography. The N-aryl-
ation site was confirmed for the derivatives 1f and 2g by X-ray
diffraction analysis (Fig. 1).‡
As indicated by Buchwald and co-workers, the method is
not suitable for N-arylation using aromatic bromides. Indeed,
it failed to give efficiently N-heteroarylated products when
3-bromopyridine and 4-bromoisoquinoline were employed,
even by trying to generate in situ the corresponding iodides.26
Concerning the deproto-metallation reaction using the
TMP-based lithium–zinc mixture, optimization studies per-
formed on different substrates showed that THF is the most
suitable solvent, and 2 h a sufficient reaction time for a reac-
tion performed at room temperature.23a,b,e Even if other kinds
of trapping can be employed (interception with aldehydes,
phenyl disulfide and allyl bromide, and palladium-catalyzed
cross-coupling with aryl halides),23d we chose iodolysis
because of its efficiency and since it is possible to involve the
generated heterocyclic iodides in different transition metal-
catalyzed coupling reactions.23f
Results and discussion
Synthetic aspects
To reach the target substrates 1 and 2, the unsubstituted
azoles were treated with aryl and heteroaryl iodides under
copper catalysis using the conditions reported by Buchwald
and co-workers (Table 1).25 Moderate to excellent yields were
Except for 1b and 1f from which complex mixtures were
obtained, they led to interpretable results.
Upon treatment 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.), and subsequent interception
with iodine, 1-phenyl-1H-benzotriazole (1a) was converted to a
mixture containing the 4-iodo (3b, 53% yield), 2′-iodo (3b′,
11% yield) and 4,2′-diiodo (4b, 20% yield) derivatives in
addition to the starting material (13% yield). The diiodide 4b
was isolated in 99% yield when 1 equiv. of ZnCl2·TMEDA and
3 equiv. of LiTMP were employed (Scheme 2). All the products
were identified unequivocally by X-ray diffraction (Fig. 2).‡
Starting from 1-(4-chlorophenyl)-1H-benzotriazole (1c), the
use of 0.5 equiv. of ZnCl2·TMEDA and 1.5 equiv. of LiTMP led
to a complex mixture together with the starting material. The
presence of the halogen, which is capable of acidifying the
neighbouring hydrogens,27 could be at the origin of a larger
number of deprotonation sites. By increasing the amount of
Table 1 Synthesis of the azole substrates 1 and 2
Entry
X
(Het)Ar
Product(s), Yield(s)a (%)
1
2
3
4
5
6
7
8
N
N
N
N
N
N
N
CH
CH
CH
CH
Ph
1a, 57
4-FC6H4
4-ClC6H4
4-F3CC6H4
4-MeOC6H4
3-Pyridyl
2-Thienyl
Ph
4-F3CC6H4
4-MeOC6H4
2-Thienyl
1b, 80 (1b′, 5)b
1c, 78 (1c′, 9)b
1d, 71
1e, 43 (1e′, 3)b
1f, 69
1g, 41 (1g′, 5)b
2a, 98
9
10
11
2d, 99
2e, 79
2g, 83
‡CIF files available in the ESI:† CIF files of 1f (CCDC 962368), 2g (962369),
3b (962370), 3b′ (962371), 3e (962372), 3g (962373), 4b (962374), 4c (962375),
4c′ (962376), 4d (962377), 4e (962378), 4e′ (962379), and 4g (962380).
a After purification. b The isomeric 2-aryl derivatives 1′ were isolated by
column chromatography.
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Fig. 3 ORTEP diagrams (50% probability) of 4c, 4c’ and 4d.
Scheme 2 Deproto-metallation of 1a followed by iodination.
Fig. 2 ORTEP diagrams (50% probability) of 3b, 3b’ and 4b.
Scheme 4 Deproto-metallation of 1d followed by iodination.
mixture in addition to the starting material upon treatment
with a low amount of base. However, increasing the amount of
base in this case only afforded the diiodide 4d, isolated in
91% yield (Scheme 4 and Fig. 3).‡ The size of the trifluoro-
methyl group, together with its long range acidifying effect,27
are both important factors that could explain why there is no
metallation at its adjacent position.
Anisole being easily ortho-deprotonated under similar reac-
tion conditions,23d it was interesting to involve in the
deprotonation–iodination sequence 1-(4-methoxyphenyl)-1H-
benzotriazole (1e). The monoiodide 3e was obtained in 74%
yield using 0.5 equiv. of ZnCl2·TMEDA and 1.5 equiv. of LiTMP
(together with the starting material). This reaction on the
benzotriazole ring, similar to that observed using the benzotri-
azole 1a, could be due to the lack of a long range acidifying
effect of the methoxy group when compared with a chloro or a
trifluoromethyl. As expected, doubling the amount of base
resulted in the formation of the diiodides 4e and 4e′. All the
Scheme 3 Deproto-metallation of 1c followed by iodination.
base (1 equiv. of ZnCl2·TMEDA and 3 equiv. of LiTMP), the iodides obtained were identified by X-ray diffraction from suit-
diiodides 4c and 4c′ were obtained in 68 and 22% yield, able crystals (Scheme 5, Fig. 4).‡
respectively (Scheme 3), and their structure was identified
unambiguously by X-ray diffraction (Fig. 3).‡
Finally,28 the deproto-metallation of 1-(2-thienyl)-1H-benzo-
triazole (1g) was similarly performed to afford either the
Using 1-(4-trifluoromethylphenyl)-1H-benzotriazole (1d) as monoiodide 3g resulting from a reaction next to sulfur, or the
the substrate similarly led to the formation of a complex diiodide 4g (minor other iodides were also noted) coming
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Fig. 5 ORTEP diagrams (50% probability) of 3g and 4g.
Scheme 5 Deproto-metallation of 1e followed by iodination.
Scheme 7 Deproto-metallation of 2a followed by iodination.
The deproto-metallation of the 1-substituted 1H-indazoles 2
was next attempted. To our knowledge, only diisopropylzinc in
the presence of catalytic lithium acetylacetonate29 and
Zn(TMP)2 30 are capable of deprotonating 1-substituted 1H-inda-
zoles at their 3 position. Using soft Li(TMP)Zn(tBu)2, deproto-
nation of 2a in THF at temperatures between −78 and −40 °C
for 1–2 h leads to the corresponding N-(2-cyanophenyl)anilide,
coming from ring opening of the 3-metallated derivative.31
Upon treatment with 0.5 equiv. of each metal amide
(LiTMP and Zn(TMP)2), the substrates 2a, 2d and 2e did not
lead to efficient functionalization, and the starting material
was the main compound recovered. Using 1 equiv. of each
metal amide in the case of 1-phenyl-1H-indazole (2a) allowed
us to obtain the expected 3-iodo derivative 5a, but in a moder-
ate 27% yield due to ring opening of the metallated species
before quenching. Indeed, the formation of the nitrile 6a (22%
yield) was also observed (Scheme 7).
Fig. 4 ORTEP diagrams (50% probability) of 3e, 4e and 4e’.
In the case of 1-(4-trifluoromethylphenyl)-1H-indazole (2d),
using 1 equiv. of each metal amide (LiTMP and Zn(TMP)2) led
to the formation of a monoiodide (20% yield) coming from
the deprotonation of the aryl group at the position meta to the
trifluoromethyl. This monoiodide and the substrate 2d (7%
yield) were the only products obtained after reaction work-up.
With 1-(4-methoxyphenyl)-1H-indazole (2e), metallation at the
position adjacent to the nitrogen followed by ring opening
took place under the same reaction conditions, as shown
by the absence of hydrogen at the 3 position for some of the
products contained in the complex mixture obtained.
Scheme 6 Deproto-metallation of 1g followed by iodination.
From 1-(2-thienyl)-1H-indazole (2g), a reaction at the 5 posi-
tion of the thienyl ring was observed using 0.5 equiv. of each
from an attack of both the 4 and 5′ positions (Scheme 6). The metal amide, and the iodide 5g was isolated in 66% yield
(Scheme 8). Increasing the base amount in this case led to
small quantities of diiodides together with ring opening.
structures of the derivatives 3g and 4g were confirmed by X-ray
analysis (Fig. 5).‡
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Scheme 8 Deproto-metallation of 2g followed by iodination.
Computational aspects
CH acidity of substances related to the investigated substrates
has been the subject of few studies. A brief review of papers
devoted to experimental and theoretical investigations of CH
acidity of azoles is presented in our previous publication.24a
One should especially mention pKa values in THF experi-
mentally found for benzofuran, benzothiophene, benzoxazole,
benzothiazole, N-methylindole and alkylazoles.32 The values
obtained were correlated with semi-empirical AM1 gas-phase
deprotonation energies,33 and also with those estimated by
means of DFT calculations recently.34 Some experimental35
and semi-empirical36 gas-phase acidities of condensed hetero-
aromatics were also reported. In the present paper, the DFT
calculations of CH acidity of the different N-aryl benzazoles,
both in gas phase (see ESI†) and in THF solution (Scheme 9),
are presented.
The gas phase acidities ΔacidG and pKa values in THF solu-
tion of all the substrates were calculated using the theoretical
protocol described previously.24
Scheme 9 Calculated values of pKa(THF) of the investigated
compounds.
All the calculations were performed by using the DFT
B3LYP method. The geometries were optimized using the
6-31G(d) basis set. No symmetry constraints were applied.
In order to perform stationary point characterization and to
calculate zero-point vibrational energies (ZPVE) and thermal
corrections, vibrational frequencies were calculated at the
same level of theory. The single point energy calculations
were performed 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:
THF.37 The cavity was built up using a united atom (UA)
model, applied to atomic radii of the UFF force field. The PCM
energies EPCM were 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:
Gs ¼ G0298 þ EPCM ꢀ E:
G0298 ¼ E þ ZPVE þ H0!298 ꢀ TS2098
:
To cancel effectively unavoidable errors, the pKa values were
calculated by means of the following homodesmic reaction:
The gas phase acidities
ΔacidG were determined as
R ꢀ HðsÞ þ Hetꢀ ! RꢀðsÞ þ Het ꢀ H
;
ðsÞ
ðsÞ
the Gibbs energies of deprotonation of the substrates R − H
(R − H(g) → R−(g) + H+(g)) by the following formula:
where Het − H is an appropriate heterocycle with the experi-
mentally known pKa value. In this study, 1-propylpyrazole was
chosen as a reference compound owing to its structural simi-
larity and since its pKa value in THF found by Fraser et al.,32
Δ
acidG ¼ G2098ðRꢀÞ þ G0298ðHþÞ ꢀ G2098ðRHÞ:
The solvent influence was accounted for by using the polar- 35.9, was supposed to be close to those for the investigated
ized continuum model (PCM) with the default parameters for substrates.
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It could be shown by a little algebra that the Gibbs energies
of the homodesmic reactions (ΔrGs) and the pKa values are
linked together by the following equations:
X
X
ΔrGs ¼
Gs ꢀ
Gs
Scheme 10 Possible side-reaction under equilibrium conditions.
reactants
products
ΔrGs
RT ln 10
1
pKaðR ꢀ HÞ ¼ pKaðHet ꢀ HÞ þ
:
One distinct peculiarity for deprotonation at C3 of
The CH acidity of the methoxy groups for the substrates 1e indazoles should be mentioned. Our calculations predict
and 2e was not considered here since it was expected to be sig- that these particular carbanions represent local shallow
nificantly lower and also because there was no sign of their minima. Hence, under appropriate conditions, N–N bond clea-
deprotonation in the experiments.
vage can take place, leading to more stable 2-cyanoanilides
It is obvious that some of the investigated compounds exist (Scheme 10).
in the form of several rotamers due to sterical interaction with
It is strongly desirable to evaluate the impact of the
adjacent hydrogens and/or heteroatom lone pairs. In such nature of the substituents (through their electronic effects)
cases, the data on Scheme 9 refer to the most stable ones. on the CH acidity (hence on their reactivity) in a series
Moreover, among the molecules with several rotamers, the of related substrates. This could be achieved using the
pyridyl benzotriazole 1f is likely to exist in a form with remote Hammett equation (or a similar approach), which is well-
heteroatoms (nitrogens) while for the sulfur-containing com- known as a powerful tool for the prediction of many important
pounds 1g and 2g it is vice versa.
physico-chemical characteristics of substances.38 The linear
There are several potential deprotonation sites in the inves- free energy relationship (LFER) methodology can also be used
tigated substrates. When comparing the CH acidity in gas- to study the electronic effects of the substituents on the CH
phase (see ESI†) and in THF solution (Scheme 9), the corre- acidity.
lation can be easily seen. The analysis of the obtained results
We chose 1-substituted 1H-benzotriazoles for this purpose.
shows that CH acidity increases logically with the introduction The influence of the substituent on the reaction centre was
of electron-withdrawing groups, and decreases for electron- tracked in relation to two aspects: (a) the influence of the X
donating ones.
substituent nature of the heterocycle on the pKa at the 4 posi-
When analyzing the CH acidities distribution for
a
tion of the condensed system, which is rather acidic but free of
common structural motif, namely the benzocondensed part steric hindrance (Table 2, entries 1–5), and (b) the influence of
of the molecules, one can see some general trends. The the Y substituent nature of the N-(4-substituted phenyl)benzo-
most acidic hydrogen is at the 7 position followed by the triazole on the pKa at the 2′ position (Table 2, entries 6–10).
4 position.
The data obtained show that there is a correlation between the
For the benzotriazoles and indazoles bearing a 4-substi- (electron-donating or electron-withdrawing) nature of the X or
tuted phenyl group on N1, there is almost no difference in Y substituent and the pKa change.
C–H acidity between the C2′ and C6′ sites, as well as between
Unfortunately, this study was also restricted by lack of data
the C3′ and C5′ sites, a result in contrast with what was on some LFER constants. As pure ortho-, meta- and para-
noticed earlier for N-arylpyrazoles.23f This difference between positions cannot be found neither for five-membered rings
both series could be explained in terms of electronic and steric nor for annelated systems, it is logical to use Jaffe’s approach
influence of the benzo part of the molecule.
to describe the substituent effects in these ‘unconventional’
Table 2 Calculated pKa(THF) values for the heterocycles and substituent constants38
Entry
Compound, X or Y
pKa (THF)
σm
σp
F
R
1
2
3
4
5
6
7
8
9
1a, Ph
39.0
38.7
38.5
39.6
38.1
38.3
34.9
34.3
34.3
38.0
0.06
0.12
0.15
0.05
0.23
0.00
0.34
0.37
0.43
0.12
−0.01
0.06
0.12
−0.08
0.25
0.00
0.06
0.23
0.54
0.12
0.17
0.18
0.13
0.24
0.00
0.45
0.42
0.38
0.29
−0.13
−0.11
−0.06
−0.21
0.01
1b, 4-FC6H4
1c, 4-ClC6H4
1e, 4-MeOC6H4
1f, 3-Pyridyl
1a, H
1b, F
1c, Cl
0.00
−0.39
−0.19
0.16
1d, CF3
1e, OMe
10
−0.27
−0.56
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rings according to:
mind that the rationalization of the second deproto-metalla-
tion site using the substrate pKa values is a rather oversimple
approach since the first reaction (giving a lithium–zinc aryl-
metal species) will lead to a different distribution of acidities.
In the case of the substrates 1g and 2g, with a 2-thienyl
group connected to the azole nitrogen, deproto-metallation at
the 5 position of the thienyl substituent is the first reaction
observed using the base prepared from ZnCl2·TMEDA (0.5
equiv.) and LiTMP (1.5 equiv.) (Schemes 6 and 8). This result,
evidenced by subsequent trapping with iodine, corresponds to
a reaction at the most acidic site.
Upon treatment with 1 equiv. of each metal amide (LiTMP
and Zn(TMP)2), the phenyl-substituted indazole 2a (and to a
lesser extent its methoxy-substituted derivative 2e) is similarly
attacked at its most acidic site, at the indazole 3 position
(Scheme 7). If an electron-withdrawing group such as a
trifluoromethyl is connected to the 4 position of the phenyl
substituent (substrate 2d), competitive reaction on the
benzene ring, at a position meta to the trifluoromethyl (which
is a long range acidifying group)27 and ortho to the 1H-1-inda-
zolyl, is observed.
The calculations performed on the benzotriazole derivatives
1 show that the hydrogen at the 7 position is always more
acidic than that at the 4 position. Nevertheless, reactions of
the 1-substituted 1H-benzotriazoles 1a, 1d, 1e and 1g do not
lead to any 7-iodo derivative, a result that could be due either
to steric hindrance disfavouring a reaction at C7 or more prob-
ably to the presence of a nitrogen able to coordinate a metal
favouring a reaction at C4. In the absence of an electron-with-
drawing substituent on the phenyl ring 1-connected to 1H-
benzotriazole, deprotonation first takes place at the 4 position
of the heterocycle, as shown using 0.5 equiv. of each metal
amide in the case of 1-phenyl-1H-benzotriazole (1a) and its
methoxy derivative 1e (Schemes 2 and 5). For the latter, such a
result is surprising since there are more acidic sites on the
phenyl ring, in particular ortho to the alkoxy group. Using the
same reaction conditions with the substrates 1c and 1d,
respectively bearing electron-withdrawing chloro and trifluoro-
methyl groups, leads to the formation of complex mixtures
(Schemes 3 and 4).
Property ¼ a1 þ a2σm þ a3σp ðwhere ai – fitted constantsÞ:
The best equation within this approach for the position 4 of
compounds (Table 2, entries 1–5) is as follows:
pKaðTHFÞ ¼ 38:3 þ 9:3 σm ꢀ 9:7 σp
ðN ¼ 5; r2 ¼ 0:975; rmse ¼ 0:079Þ
According to Swain and Lupton, the electronic effects of a
substituent can be split into a field/inductive component (F)
and a resonance component (R).38 The best equation for the
same compounds within this approach is:
pKaðTHFÞ ¼ 38:0 þ 0:50 F ꢀ 7:0 R
ðN ¼ 5; r2 ¼ 0:975; rmse ¼ 0:079Þ
Thereby, both approaches give the equations for CH acidity
prediction of comparable quality. The influence of a substitu-
ent on the forming carbanion center could be described in
terms of a combination of inputs of both meta- and para-
groups in the benzene ring while the resonance effects predo-
minate over the inductive.
Concerning the CH acidity at the 2′ position of the com-
pounds (Table 2, entries 6–10), the benzotriazole was treated
as an ordinary substituent. This led to a good correlation even
under one-parametric formalism:
pKaðTHFÞ ¼ 38:7 ꢀ 10:8 σm ðN ¼ 5; r 2 ¼ 0:954; rmse ¼ 0:22Þ
The best equations within the Swain’s and Jaffe’s
approaches proved to be respectively:
pKaðTHFÞ ¼ 38:5 ꢀ 10:7 F ꢀ 3:8 R
ðN ¼ 5; r 2 ¼ 0:954; rmse ¼ 0:27Þ
and
pKaðTHFÞ ¼ 38:5 ꢀ 9:8 σm ꢀ 0:8 σp
ðN ¼ 5; r 2 ¼ 0:960; rmse ¼ 0:25Þ
Reacting the benzotriazole derivatives 1 with 1 equiv. of
each metal amide furnishes diiodides, as previously noted
with other azoles.23f,h From 1-phenyl-1H-benzotriazole (1a), the
1H-1-benzotriazolyl activates the neighboring site, and the
second reaction occurs at the phenyl ring, affording after inter-
ception with iodine the 4,2′-diiodide 4b (Scheme 2). Things are
similar in the presence of a trifluoromethyl group at the 4 posi-
tion of the phenyl ring (substrate 1d, Scheme 4). When a
methoxy group is introduced at the 4 position of the phenyl
ring (substrate 1e), the ortho sites are acidified by its inductive
So, the correlation between calculated and predicted pKa
values of investigated compounds using LFER equations gives
the opportunity to predict their reactivity semi-quantitatively at
low computational cost.
Discussion
The calculations of the CH acidities in THF (Scheme 9) effect. As a consequence, not only the 4,2′-diiodide 4e but also
allowed us to comment on the regioselectivities observed in the 4,3′-diiodide 4e′ are produced (Scheme 5). As trifluoro-
the course of the reactions. However, it is worth noting that methyl, the chloro group exhibits a strong acidifying effect,27
coordination of substrate heteroatoms (e.g. nitrogen, oxygen, leading in this case to the major formation of the 4,3′-diiodide
etc.) to metals (e.g. of the base) can impact (reduce) the neigh- 4c. Curiously, the 7,2′-diiodo isomer 4c′ also forms from the
bouring pKa values. In addition, it is important to keep in substrate 1c (Scheme 3). Finally, the role of the N3 heteroatom
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in favouring the reaction at the 4 position is also evidenced in
1-Phenyl-1H-benzotriazole (1a) was prepared from benzo-
the case of 1g, which is converted to the 4,5′-diiodide 4g triazole (1.2 g) and iodobenzene (1.4 mL) using the general
(Scheme 6).
procedure 1, and was isolated (eluent: 4 : 1 heptane–AcOEt) in
57% yield (1.1 g) as an orange powder: mp 86 °C; 1H NMR
(CDCl3, 300 MHz) 7.45 (dt, 1H, J = 8.2, 6.9 and 1.0 Hz),
7.49–7.65 (m, 4H), 7.75–7.82 (m, 3H), 8.16 (dt, 1H, J = 8.1 and
0.9 Hz); 13C{1H} NMR (CDCl3, 75 MHz) 110.5 (CH), 120.5 (CH),
123.1 (2CH), 124.5 (CH), 128.4 (CH), 128.8 (CH), 130.0 (2CH),
132.5 (C), 137.2 (C), 146.7 (C). The NMR data are analogous to
those previously described.41
Conclusions
Unlike 2-aryl 2H-1,2,3-triazoles for which ring opening is also
possible after deproto-metallation, 1-aryl 1H-indazoles could
not be functionalized efficiently at the position α to nitrogen
by using the lithium–zinc base in situ prepared from
ZnCl2·TMEDA and LiTMP (3 equiv.) due to further easy ring
opening.
The deproto-metallation of several 1-aryl 1H-benzotriazoles
was also studied using this base. Interception of the metal-
lated species by iodine led to mono- or di-iodides, depending
on the amount of base employed. The CH acidities of the sub-
strates in THF solution, which were calculated using a conti-
nuum solvation model, were used to rationalize the outcome
of the reactions.
The iodo derivatives thus generated could be elaborated.
For example, the monoiodides could be involved in Suzuki
cross-coupling reactions, as shown recently in the pyrazole
series.23f Concerning the diiodides, regioselective metal–
halogen exchange39 could be performed in order to functiona-
lize, one after another, both iodinated sites.
1-(4-Fluorophenyl)-1H-benzotriazole (1b) was prepared
from benzotriazole (1.2 g) and 1-fluoro-4-iodobenzene (2.7 g)
using the general procedure 1, and was isolated (eluent:
4 : 1 heptane–AcOEt) in 80% yield (1.7 g) as a yellow powder:
mp 119 °C; 1H NMR (CDCl3, 300 MHz) 7.27–7.33 (m, 2H), 7.43
(ddd, 1H, J = 8.3, 7.0 and 1.0 Hz), 7.55 (ddd, 1H, J = 8.3, 6.9
and 1.1 Hz), 7.68 (dt, 1H, J = 8.4 and 0.9 Hz), 7.72–7.77 (m,
2H), 8.14 (ddd, 1H, J = 8.3, 1.0 and 0.9 Hz); 13C{1H} NMR
(CDCl3, 75 MHz) 110.0 (CH), 116.9 (d, 2CH, J = 23 Hz), 120.3
(CH), 124.5 (CH), 124.8 (d, 2CH, J = 9 Hz), 128.4 (CH), 132.3
(C), 133.1 (d, C, J = 3 Hz), 146.4 (C), 162.3 (d, C, J = 249 Hz); 19
F
{1H} NMR (CDCl3, 282 MHz) −112. The NMR data are analo-
gous to those previously described.41 2-(4-Fluorophenyl)-2H-
benzotriazole (1b′) was also isolated (eluent: 4 : 1 heptane–
1
AcOEt) in 5% yield (0.11 g) as a green powder: mp 92 °C; H
NMR (CDCl3, 300 MHz) 7.21–7.24 (m, 2H), 7.41–7.44 (m, 2H),
7.91–7.94 (m, 2H), 8.32–8.37 (m, 2H); 13C{1H} NMR (CDCl3,
75 MHz) 116.5 (d, 2CH, J = 23 Hz), 118.4 (2CH), 122.5 (d, 2CH,
J = 9 Hz), 127.4 (2CH), 136.7 (d, C, J = 3 Hz), 145.2 (2C), 162.9
(d, C, J = 249 Hz); 19F{1H} NMR (CDCl3, 282 MHz) −112.
Experimental
General methods
1-(4-Chlorophenyl)-1H-benzotriazole (1c) was prepared
from benzotriazole (1.2 g) and 1-chloro-4-iodobenzene (2.9 g)
using the general procedure 1, and was isolated (eluent:
4 : 1 heptane–AcOEt) in 78% yield (1.8 g) as a yellow powder:
Metallation reactions were performed under an argon atmos-
phere. THF was distilled over sodium/benzophenone. Column
chromatography separations were achieved on silica gel
(40–63 μm). Melting points were measured on a Kofler appar-
atus. IR spectra were taken on a Perkin-Elmer Spectrum 100
1
mp 159 °C; H NMR (CDCl3, 300 MHz) 7.46 (ddd, 1H, J = 8.4,
6.9 and 1.0 Hz), 7.55–7.62 (m, 3H), 7.74 (ddd, 1H, J = 8.4, 1.0
and 0.9 Hz), 7.74–7.77 (m, 2H), 8.16 (ddd, 1H, J = 8.4, 1.0 and
0.9 Hz); 13C{1H} NMR (CDCl3, 75 MHz) 110.2 (CH), 120.5 (CH),
124.0 (2CH), 124.7 (CH), 128.6 (CH), 130.1 (2CH), 132.2 (C),
134.5 (C), 135.6 (C), 146.6 (C). The NMR data are analogous to
those previously described.41 2-(4-Chlorophenyl)-2H-benzotria-
zole (1c′) was also isolated (eluent: 4 : 1 heptane–AcOEt) in 9%
yield (0.21 g) as an orange powder: mp 175 °C; 1H NMR
(CDCl3, 300 MHz) 7.39–7.45 (m, 2H), 7.48–7.54 (m, 2H),
7.89–7.93 (m, 2H), 8.28–8.32 (m, 2H); 13C{1H} NMR (CDCl3,
75 MHz) 118.5 (2CH), 121.9 (2CH), 127.6 (2CH), 129.7 (2CH),
134.9 (C), 139.0 (C), 145.2 (2C).
spectrometer. H and 13C Nuclear Magnetic Resonance (NMR)
spectra were recorded on a Bruker Avance III spectrometer at
1
1
300 and 75 MHz, respectively. H chemical shifts (δ) are given
in ppm relative to the solvent residual peak, and 13C chemical
shifts are relative to the central peak of the solvent signal.40
Mass spectra (HRMS) measurements were performed at the
CRMPO (Centre Régional de Mesures Physiques de l’Ouest) of
Rennes using a Waters Q-TOF 2 instrument in positive electro-
spray CI mode.
General procedure 1 for the synthesis of the 1-aryl 1H-
benzotriazoles 1a–g and 2a,d,e,g25
1-(4-Trifluoromethylphenyl)-1H-benzotriazole (1d) was pre-
A mixture of CuI (0.10 g, 0.50 mmol), the required azole pared from benzotriazole (1.2 g) and 1-iodo-4-(trifluoromethyl)-
(10 mmol), K3PO4 (4.4 g, 20 mmol), the required halide benzene (1.8 mL) using the general procedure 1, and was iso-
(12 mmol) and N,N′-dimethylethylenediamine (0.11 mL, lated (eluent: 4 : 1 heptane–AcOEt) in 71% yield (1.9 g) as a
1.0 mmol) in DMF (5 mL) was degased and heated under white powder: mp 168 °C; 1H NMR (CDCl3, 300 MHz) 7.49
argon at 110 °C for 72 h. After filtration over celite (washing (ddd, 1H, J = 8.4, 7.0 and 0.9 Hz), 7.64 (ddd, 1H, J = 8.4, 7.0
using AcOEt) and removal of the solvents, the crude product and 1.0 Hz), 7.80 (dt, 1H, J = 8.4 and 0.9 Hz), 7.90 (d, 2H, J =
was purified by chromatography over silica gel (the eluent is 8.4 Hz), 7.99 (d, 2H, J = 8.4 Hz), 8.19 (ddd, 1H, J = 8.4, 1.0 and
given in the product description).
0.9 Hz); 13C{1H} NMR (CDCl3, 75 MHz) 110.2 (CH), 120.7 (CH),
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122.6 (2CH), 123.8 (q, CF3, J = 272 Hz), 124.9 (CH), 127.3 (q, 118.6 (CH), 123.4 (CH), 126.9 (CH), 127.6 (2CH), 143.1 (C),
2CH, J = 4 Hz), 129.0 (CH), 130.5 (C, J = 33 Hz), 132.0 (C), 140.0 145.1 (2C).
(C), 146.8 (C); 19F{1H} NMR (CDCl3, 282 MHz) −63. The NMR
1-Phenyl-1H-indazole (2a) was prepared from indazole
(1.2 g) and iodobenzene (1.4 mL) using the general procedure
data are analogous to those previously described.41
1-(4-Methoxyphenyl)-1H-benzotriazole (1e) was prepared 1, and was isolated (eluent: 4 : 1 heptane–AcOEt) in 98% yield
from benzotriazole (1.2 g) and 4-iodoanisole (2.8 g) using the (1.9 g) as a green powder: mp 83 °C (lit.43 77–78 °C); IR (ATR):
general procedure 1 but using CuI (0.20 g, 1.0 mmol) and N,N′- 3062, 1614, 1598, 1501, 1467, 1417, 1379, 1356, 1198, 1089,
1
dimethylethylenediamine (0.22 mL, 2.0 mmol), and was iso- 1063, 978, 905, 838, 771, 741, 709, 693 cm−1; H NMR (CDCl3,
lated (eluent: 4 : 1 heptane–AcOEt) in 43% yield (0.97 g) as a 300 MHz) 7.24 (ddd, 1H, J = 8.1, 6.9 and 0.9 Hz), 7.35 (tt, 1H,
1
yellow powder: mp 98 °C; H NMR (CDCl3, 300 MHz) 3.89 (s, J = 7.5 and 1.2 Hz), 7.44 (ddd, 1H, J = 8.4, 6.9 and 1.2 Hz),
3H), 7.08–7.13 (m, 2H), 7.40 (ddd, 1H, J = 8.2, 6.9 and 1.0 Hz), 7.52–7.58 (m, 2H), 7.72–7.76 (m, 3H), 7.78–7.83 (m, 1H), 8.22
7.52 (ddd, 1H, J = 8.2, 6.9 and 1.0 Hz), 7.63–7.68 (m, 3H), 8.12 (d, 1H, J = 0.9 Hz); 13C{1H} NMR (CDCl3, 75 MHz) 110.5 (CH),
(dt, 1H, J = 8.1 and 0.9 Hz); 13C{1H} NMR (CDCl3, 75 MHz) 121.4 (CH), 121.6 (CH), 122.8 (2CH), 125.4 (C), 126.7 (CH),
55.8 (OMe), 110.4 (CH), 115.1 (2CH), 120.3 (CH), 124.3 (CH), 127.3 (CH), 129.6 (2CH), 135.5 (CH), 138.8 (C), 140.3 (C). The
124.7 (2CH), 128.1 (CH), 130.1 (C), 132.7 (C), 146.4 (C), 159.9 NMR data are in accordance with the literature.43
(C). The NMR data are analogous to those previously
1-(4-Trifluoromethylphenyl)-1H-indazole (2d) was prepared
described.41 2-(4-Methoxyphenyl)-2H-benzotriazole (1e′) was from indazole (1.2 g) and 1-iodo-4-trifluoromethylbenzene
also isolated (eluent: 4 : 1 heptane–AcOEt) in 3% yield (68 mg) (1.8 mL) using the general procedure 1, and was isolated
as a yellow powder: mp 102 °C; 1H NMR (CDCl3, 300 MHz) (eluent: 4 : 1 heptane–AcOEt) in 99% yield (2.6 g) as a yellow
1
3.90 (s, 3H), 7.04–7.07 (m, 2H), 7.39–7.43 (m, 2H), 7.91–7.94 powder: mp 68 °C; H NMR (CDCl3, 300 MHz) 7.28 (ddd, 1H,
(m, 2H), 8.26–8.29 (m, 2H). The 1H NMR data are analogous to J = 7.8, 7.0 and 1.0 Hz), 7.49 (ddd, 1H, J = 8.4, 6.9 and 1.2 Hz),
those previously described.42 13C{1H} NMR (CDCl3, 75 MHz) 7.82 (m, 4H), 7.91 (d, 2H, J = 8.4 Hz), 8.25 (d, 1H, J = 0.9 Hz);
55.8 (OMe), 114.6 (2CH), 118.3 (2CH), 122.2 (2CH), 127.0 13C{1H} NMR (CDCl3, 75 MHz) 110.1 (CH), 121.7 (CH), 122.0
(2CH), 134.1 (C), 145.0 (2C), 160.3 (C).
(2CH), 122.2 (CH), 124.1 (q, CF3, J = 272 Hz), 126.7 (q, 2CH, J =
1-(3-Pyridyl)-1H-benzotriazole (1f) was prepared from benzo- 4 Hz), 127.8 (CH), 128.1 (q, C, J = 33 Hz), 136.6 (CH), 138.6 (C),
triazole (1.2 g) and 3-iodopyridine (2.5 g) using the general 143.1 (C), 143.2 (C); 19F{1H} NMR (CDCl3, 282 MHz) −62.3.
procedure 1, and was isolated (eluent: 9 : 1 CH2Cl2–AcOEt) in The mp and 1H NMR data are in accordance with the
69% yield (1.4 g) as a white powder: mp 142 °C; IR (ATR): literature.43
3087, 3053, 3024, 1579, 1495, 1457, 1427, 1287, 1265,
1-(4-Methoxyphenyl)-1H-indazole (2e) was prepared from
1192, 1065, 810, 731, 702 cm−1 1H NMR (CDCl3, 300 MHz) indazole (1.2 g) and 4-iodoanisole (2.8 g) using the general pro-
;
7.47 (ddd, 1H, J = 8.2, 7.0 and 1.0 Hz), 7.56–7.63 (m, 2H), cedure 1, and was isolated (eluent: 4 : 1 heptane–CH2Cl2) in
7.76 (dt, 1H, J = 8.3 and 0.9 Hz), 8.14–8.18 (m, 2H), 8.76 (d, 79% yield (1.8 g) as a yellow oil; 1H NMR (CDCl3, 300 MHz)
1H, J = 4.2 Hz), 9.12 (s, 1H); 13C{1H} NMR (CDCl3, 75 MHz) 3.87 (s, 3H), 7.03–7.06 (m, 2H), 7.20 (ddd, 1H, J = 7.8, 6.9 and
110.0 (CH), 120.7 (CH), 124.6 (CH), 124.9 (CH), 129.0 (CH), 0.9 Hz), 7.39 (ddd, 1H, J = 8.1, 6.9 and 0.9 Hz), 7.58–7.65 (m,
130.3 (CH), 132.2 (C), 134.0 (C), 143.6 (CH), 146.7 (C), 149.8 3H), 7.78 (dt, 1H, J = 8.1 and 1.0 Hz), 8.16 (d, 1H, J = 0.9 Hz);
(CH).
13C{1H} NMR (CDCl3, 75 MHz) 55.4 (OMe), 110.1 (CH), 114.5
1-(2-Thienyl)-1H-benzotriazole (1g) was prepared from benzo- (2CH), 121.1 (CH), 121.2 (CH), 124.3 (2CH), 124.9 (C), 126.8
1
triazole (1.2 g) and 2-iodothiophene (2.5 g) using the general (CH), 133.2 (C), 134.7 (CH), 138.8 (C), 156.2 (C). The H NMR
procedure 1, and was isolated (eluent: 9 : 1 to 4 : 1 heptane– data are in accordance with the literature.43
AcOEt) in 41% yield (0.83 g) as a yellow powder: mp 76 °C;
1-(2-Thienyl)-1H-indazole (2g) was prepared from indazole
IR (ATR): 3109, 1610, 1551, 1490, 1459, 1444, 1283, 1229, 1177, (1.2 g) and 2-iodothiophene (2.5 g) using the general procedure
1055, 962, 845, 782, 742, 696 cm−1; 1H NMR (CDCl3, 300 MHz) 1, and was isolated (eluent: 4 : 1 heptane–AcOEt) in 83% yield
7.15 (dd, 1H, J = 5.4 and 3.6 Hz), 7.34 (dd, 1H, J = 5.7 and (1.7 g) as a yellow powder: mp 86 °C; IR (ATR): 3104, 3079,
1.5 Hz), 7.39 (dd, 1H, J = 3.6 and 1.2 Hz,), 7.45 (ddd, 1H, J = 1613, 1549, 1497, 1468, 1417, 1369, 1358, 1350, 1185, 1086,
1
8.1, 6.9 and 0.9 Hz), 7.58 (ddd, 1H, J = 7.8, 6.9 and 0.9 Hz), 935, 842, 768, 740, 688 cm−1; H NMR (CDCl3, 300 MHz) 7.07
7.75 (dt, 1H, J = 8.4 and 0.9 Hz), 8.13 (dt, 1H, J = 8.4 and (dd, 1H, J = 5.5 and 3.7 Hz), 7.17 (dd, 1H, J = 5.5 and 1.4 Hz),
1.0 Hz); 13C{1H} NMR (CDCl3, 75 MHz) 110.4 (CH), 120.0 (CH), 7.24 (dd, 1H, J = 3.7 and 1.4 Hz), 7.24–7.28 (m, 1H), 7.48 (ddd,
120.5 (CH), 123.5 (CH), 124.8 (CH), 126.5 (CH), 128.9 (CH), 1H, J = 8.1, 6.9 and 1.2 Hz), 7.74–7.81 (m, 2H), 8.18 (d, 1H, J =
132.9 (C), 137.6 (C), 146.2 (C). HRMS (ESI/ASAP): calcd 0.9 Hz); 13C{1H} NMR (CDCl3, 75 MHz) 110.6 (CH), 117.0 (CH),
for C10H8N3S [M + H]+ 202.0439, found 202.0437. 2-(2-Thienyl)- 121.1 (CH), 121.5 (CH), 122.1 (CH), 125.3 (C), 126.1 (CH), 127.9
2H-benzotriazole (1g′) was also isolated (eluent: 9 : 1 to (CH), 136.1 (CH), 139.5 (C), 142.7 (C).
4 : 1 heptane–AcOEt) in 5% yield (0.10 g) as a yellow powder:
General procedure 2 for the deprotonative metallation
followed by iodination
mp 114 °C; 1H NMR (CDCl3, 300 MHz) 7.08 (dd, 1H, J = 5.4
and 3.9), 7.24 (dd, 1H, J = 5.4 and 1.5 Hz), 7.42 (dd, 2H, J = 6.6
and 3.1 Hz), 7.77 (dd, 1H, J = 3.9 and 1.5 Hz), 7.89 (dd, 2H, J = To a stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperi-
6.6 and 3.1 Hz); 13C{1H} NMR (CDCl3, 75 MHz) 118.1 (2CH), dine (0.50 mL, 3.0 mmol) in THF (5 mL) was added BuLi
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(about 1.6 M hexanes solution, 3.0 mmol). After 15 min at
1-(5-Iodo-2-thienyl)-1H-indazole (5g) was prepared from
0 °C, ZnCl2·TMEDA (0.25 g, 1.0 mmol) was added, and the 1-(2-thienyl)-1H-indazole (2g, 0.40 g) using the general pro-
mixture was stirred for 15 min at this temperature before intro- cedure 2 and was isolated (eluent: 4 : 1 heptane–AcOEt) in 66%
duction of the substrate (2.0 mmol). After 2 h at room temp- yield (0.43 g) as a yellow oil: IR (ATR): 3045, 1612, 1552, 1497,
erature, a solution of I2 (0.74 g, 3.0 mmol) in THF (5 mL) was 1467, 1417, 1361, 1263, 1183, 1075, 950, 921, 767, 732,
1
added. The mixture was stirred overnight before addition of an 702 cm−1; H NMR (CDCl3, 300 MHz) 6.91 (d, 1H, J = 4.0 Hz),
aqueous saturated solution of Na2S2O3 (10 mL) and extraction 7.23 (d, 1H, J = 4.0 Hz), 7.26 (ddd, 1H, J = 7.9, 7.0 and 0.8 Hz),
with CH2Cl2 (3 × 20 mL). The combined organic layers were 7.48 (ddd, 1H, J = 8.5, 7.0 and 1.1 Hz), 7.69 (dd, 1H, J = 8.5 and
dried over Na2SO4 and concentrated under reduced pressure 0.8 Hz), 7.78 (dt, 1H, J = 8.1 and 1.0 Hz), 8.16 (d, 1H, J =
before purification by flash chromatography on silica gel.
0.9 Hz); 13C{1H} NMR (CDCl3, 75 MHz) 68.2 (C), 110.2 (CH),
4-Iodo-1-phenyl-1H-benzotriazole (3b) was obtained from 117.3 (CH), 121.4 (CH), 122.2 (CH), 125.1 (C), 127.9 (CH), 135.7
1-phenyl-1H-benzotriazole (1a, 0.39 g) using the general pro- (CH), 136.3 (CH), 138.7 (C), 147.0 (C). HRMS (ESI): calcd for
cedure 2 (eluent: 9 : 1 heptane–AcOEt) in 53% estimated yield. C11H8N2IS [M + H]+ 326.9453, found 326.9456.
The analyses were obtained from a pure fraction: orange
General procedure 3 for the deprotonative metallation
followed by iodination
powder; mp 155 °C; IR (ATR): 3063, 2923, 2853, 1722, 1598,
1500, 1417, 1253, 1181, 1088, 1058, 930, 826, 779, 750,
693 cm−1 1H NMR (CDCl3, 300 MHz) 7.21–7.26 (m, 1H), To a stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperi-
;
7.47–7.71 (m, 6H), 7.80 (d, 1H, J = 7.2 Hz); 13C{1H} NMR dine (0.50 mL, 3.0 mmol) in THF (5 mL) was added BuLi
(CDCl3, 75 MHz) 85.9 (C), 110.5 (CH), 123.3 (2CH), 129.2 (about 1.6 M hexanes solution, 3.0 mmol). After 15 min at
(CH), 129.5 (CH), 130.1 (2CH), 132.2 (C), 134.1 (CH), 137.0 (C), 0 °C, ZnCl2·TMEDA (0.25 g, 1.0 mmol) was added, and the
148.1 (C).
mixture was stirred for 15 min at this temperature before intro-
1-(2-Iodophenyl)-1H-benzotriazole (3b′) was obtained from duction of the substrate (1.0 mmol). After 2 h at room temp-
1-phenyl-1H-benzotriazole (1a, 0.39 g) using the general pro- erature, a solution of I2 (0.74 g, 3.0 mmol) in THF (5 mL) was
cedure 2 (eluent: 9 : 1 heptane–AcOEt) in 11% estimated yield. added. The mixture was stirred overnight before addition of an
The analyses were obtained from a pure fraction: white aqueous saturated solution of Na2S2O3 (10 mL) and extraction
powder, mp 168 °C (lit.44 148–150 °C); IR (ATR): 3056, 1495, with CH2Cl2 (3 × 20 mL). The combined organic layers were
1477, 1265, 1065, 894, 785, 733, 703 cm−1
300 MHz) 7.29–7.36 (m, 2H), 7.42–7.62 (m, 4H), 8.10 (dd, 1H, before purification by flash chromatography on silica gel.
J = 8.0 and 1.3 Hz), 8.17 (dt, 1H, J = 8.3 and 1.0 Hz); 13C{1H}
4-Iodo-1-(2-iodophenyl)-1H-benzotriazole (4b) was prepared
;
1H NMR (CDCl3, dried over Na2SO4 and concentrated under reduced pressure
NMR (CDCl3, 75 MHz) 95.8 (C), 110.6 (CH), 120.4 (CH), 124.4 from 1-phenyl-1H-benzotriazole (1a, 0.20 g) using the general
(CH), 128.3 (CH), 129.1 (CH), 129.6 (CH), 131.8 (CH), 133.6 (C), procedure 3 and was isolated (eluent: 4 : 1 heptane–AcOEt) in
139.3 (C), 140.6 (CH), 145.8 (C).
99% yield (0.44 g) as an orange powder: mp 149 °C; IR (ATR):
4-Iodo-1-(4-methoxyphenyl)-1H-benzotriazole
(3e)
was 3060, 1599, 1576, 1489, 1442, 1264, 1180, 1069, 1056, 928, 827,
obtained from 1-(4-methoxyphenyl)-1H-benzotriazole (1e, 779, 749, 734 cm−1; H NMR (CD3COCD3, 300 MHz) 7.41 (dd,
0.45 g) using the general procedure 2 (eluent: 95 : 5 CH2Cl2– 1H, J = 8.3 and 7.0 Hz), 7.45–7.54 (m, 2H), 7.70–7.79 (m, 2H),
MeOH) in 74% estimated yield. The analyses were obtained 7.96 (dd, 1H, J = 6.9 and 1.2 Hz), 8.22 (ddd, 1H, J = 7.8, 1.2 and
from a pure fraction: yellow powder; mp 120 °C; IR (ATR): 0.6 Hz); 13C{1H} NMR (CDCl3, 75 MHz) 85.8 (C), 95.7 (C), 110.7
3053, 1591, 1516, 1264, 1181, 1072, 1033, 929, 834, 780, 732, (CH), 129.1 (CH), 129.6 (CH), 129.6 (CH), 132.1 (CH), 133.4 (C),
1
703, 667 cm−1 1H NMR (CDCl3, 300 MHz) 3.91 (s, 3H), 134.0 (CH), 139.1 (C), 140.6 (CH), 147.5 (C); MS (ESI): calcd for
;
7.10–7.13 (m, 2H), 7.29 (dd, 1H, J = 7.2 Hz), 7.61–7.65 (m, 3H), C12H7I2N3 [M]+ 447, found 447.
7.85 (dd, 1H, J = 7.3 and 0.7 Hz); 13C{1H} NMR (CDCl3,
4-Iodo-1-(3-iodo-4-chlorophenyl)-1H-benzotriazole (4c) was
75 MHz) 55.8 (OMe), 85.7 (C), 110.4 (CH), 115.1 (2CH), 124.9 obtained from 1-(4-chlorophenyl)-1H-benzotriazole (1c, 0.23 g)
(2CH), 129.3 (CH), 129.8 (C), 132.4 (C), 133.8 (CH), 147.8 (C), using the general procedure 3 (eluent for preliminary purifi-
160.1 (C).
cation: 4 : 1 heptane–AcOEt, eluent for final purification:
1-(5-Iodo-2-thienyl)-1H-benzotriazole (3g) was prepared 7 : 2 : 1 heptane–AcOEt–CH2Cl2) in 68% estimated yield. The
from 1-(2-thienyl)-1H-benzotriazole (1g, 0.40 g) using the analyses were obtained from a pure fraction: orange powder;
general procedure 2 and was isolated (eluent: 4 : 1 heptane– IR (ATR): 3052, 2923, 2853, 1599, 1576, 1488, 1417, 1366, 1264,
1
AcOEt) in 68% yield (0.44 g) as a beige powder: mp 79 °C; 1180, 1096, 1069, 1036, 928, 827, 778, 733, 702 cm−1; H NMR
IR (ATR): 3059, 1553, 1374, 1281, 1264, 1175, 1038, 1004, 964, (CDCl3, 300 MHz) 7.26–7.28 (m, 2H), 7.38 (d, 1H, J = 8.4 Hz),
781, 764, 732, 702 cm−1 1H NMR (CDCl3, 300 MHz) 7.04 (d, 7.56 (dd, 1H, J = 8.4 and 2.2 Hz), 7.86 (t, 1H, J = 4.0 Hz), 8.07
;
1H, J = 4.0 Hz), 7.30 (d, 1H, J = 4.0 Hz), 7.43 (ddd, 1H, J = 8.4, (d, 1H, J = 2.2 Hz); 13C{1H} NMR (CDCl3, 75 MHz) 85.9 (C),
7.0 and 1.1 Hz), 7.57 (ddd, 1H, J = 8.4, 6.9 and 1.0 Hz), 7.69 96.1 (C), 110.5 (CH), 129.5 (CH), 129.8 (CH), 129.9 (CH), 133.3
(ddd, 1H, J = 8.4, 1.0 and 0.9 Hz), 8.10 (ddd, 1H, J = 8.4, 1.0 (C), 134.2 (CH), 137.4 (C), 137.8 (C), 140.0 (CH), 147.0 (C).
and 0.9 Hz); 13C{1H} NMR (CDCl3, 75 MHz) 71.5 (C), 110.1
7-Iodo-1-(2-iodo-4-chlorophenyl)-1H-benzotriazole (4c′) was
(CH), 120.5 (CH), 120.9 (CH), 125.0 (CH), 129.1 (CH), 132.4 (C), obtained from 1-(4-chlorophenyl)-1H-benzotriazole (1c, 0.23 g)
136.1 (CH), 141.9 (C), 146.1 (C).
using the general procedure 3 (eluent for preliminary
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purification: 4 : 1 heptane–AcOEt, eluent for final purification: (CH), 130.2 (CH), 132.5 (C), 134.6 (CH), 136.3 (CH), 141.6 (C),
7 : 2 : 1 heptane–AcOEt–CH2Cl2) in 22% estimated yield. The 147.8 (C).
analyses were obtained from a pure fraction: orange powder;
IR (ATR): 3084, 1599, 1575, 1488, 1416, 1366, 1264, 1180, 1096, 1-phenyl-1H-indazole (2a, 0.19 g) using the general procedure
1069, 1050, 1036, 997, 928, 873, 827, 777, 733, 702 cm−1 1H 3 (eluent: 9 : 1 to 8 : 2 heptane–AcOEt) in 27% estimated yield:
3-Iodo-1-phenyl-1H-indazole (5a) was obtained from
;
NMR (CDCl3, 300 MHz) 7.18 (dd, 1H, J = 8.3 and 7.5 Hz), 7.45 1H NMR (CDCl3, 300 MHz) 6.97–7.03 (m, 3H), 7.20–7.31 (m,
(d, 1H, J = 8.4 Hz), 7.57 (dd, 1H, J = 8.4 and 2.1 Hz), 7.97 (dd, 3H), 7.47 (ddd, 1H, J = 8.3, 1.3 and 0.44 Hz), 7.53–7.57 (m, 1H),
1H, J = 7.4 and 0.7 Hz), 8.03 (d, 1H, J = 2.2 Hz), 8.17 (dd, 1H, 7.66 (ddd, 1H, J = 7.7, 1.6 and 0.41 Hz); 13C{1H} NMR (CDCl3,
J = 8.3 and 0.7 Hz); 13C{1H} NMR (CDCl3, 75 MHz) 71.7 (C), 75 MHz) 113.5 (C), 117.7 (C), 122.2 (2CH), 122.7 (CH), 126.0
100.9 (C), 120.7 (CH), 126.1 (CH), 129.2 (CH), 131.5 (CH), 137.7 (CH), 129.1 (2CH), 130.2 (CH), 133.9 (CH), 134.0 (CH), 147.0
(C), 138.8 (CH), 139.5 (CH), 3C not seen.
(C), 149.4 (C).
4-Iodo-1-(2-iodo-4-trifluoromethylphenyl)-1H-benzotriazole
2-(Phenylamino)benzonitrile (6a) was obtained from
(4d) was prepared from 1-(4-trifluoromethylphenyl)-1H-benzo- 1-phenyl-1H-indazole (2a, 0.19 g) using the general procedure
triazole (1d, 0.26 g) using the general procedure 3 and was iso- 3 (eluent: 9 : 1 to 8 : 2 heptane–AcOEt) in 22% estimated yield.
lated (eluent: 4 : 1 heptane–AcOEt) in 91% yield (0.47 g) as a The analyses were obtained from a pure fraction: yellow oil;
yellow powder: mp 162 °C; IR (ATR): 3058, 1599, 1500, 1421, IR (ATR): 3343, 2929, 2217, 1726, 1594, 1575, 1515, 1497, 1473,
1
1387, 1317, 1264, 1174, 1132, 1075, 1051, 1035, 929, 828, 738, 1457, 1318, 1292, 1163, 909, 732, 695 cm−1; H NMR (CDCl3,
1
715 cm−1; H{19F} NMR (CDCl3, 300 MHz) 7.29–7.31 (m, 2H), 300 MHz) 6.32 (br s, 1H), 6.81–6.87 (m, 1H), 7.13 (tt, 1H, J =
7.59 (d, 1H, J = 8.2 Hz), 7.84–7.91 (m, 2H), 8.33 (br s, 1H); 13C 7.2 and 1.0 Hz), 7.15–7.21 (m, 3H), 7.34–7.40 (m, 3H), 7.50 (dd,
{1H} NMR (CDCl3, 75 MHz) 86.0 (C), 95.7 (C), 110.5 (CH), 1H, J = 7.8 and 1.5 Hz); 13C{1H} NMR (CDCl3, 75 MHz) 98.6
122.4 (q, CF3, J = 273 Hz), 126.8 (q, CH, J = 4 Hz), 129.3 (CH), (C), 114.2 (CH), 117.7 (C), 119.4 (CH), 121.9 (2CH), 124.4 (CH),
130.0 (CH), 133.0 (C), 133.9 (q, C, J = 33 Hz), 134.3 (CH), 137.8 129.8 (2CH), 133.2 (CH), 134.0 (CH), 140.0 (C), 147.4 (C). The
(q, CH, J = 4 Hz), 142.4 (C), 147.6 (C); 19F{1H} NMR (CDCl3, NMR data are analogous to those previously described.45
282 MHz) −63; MS (ESI): calcd for C13H6F3I2N3 [M]+ 515,
found 515.
1-(2-Iodo-4-trifluoromethylphenyl)-1H-indazole was ob-
tained from 1-(4-trifluoromethylphenyl)-1H-indazole (2d,
4-Iodo-1-(2-iodo-4-methoxyphenyl)-1H-benzotriazole
(4e) 0.26 g) using the general procedure 3 (eluent: 4 : 1 heptane–
was obtained from 1-(4-methoxyphenyl)-1H-benzotriazole (1e, AcOEt) in 20% estimated yield: 1H NMR (CDCl3, 300 MHz)
0.23 g) using the general procedure 3 (eluent: 95 : 5 CH2Cl2– 7.22–7.26 (m, 1H), 7.27 (ddd, 1H, J = 7.9, 7.0 and 0.9 Hz), 7.43
MeOH) in 59% estimated yield. The analyses were obtained (ddd, 1H, J = 8.3, 7.0 and 1.1 Hz), 7.54 (dd, 1H, J = 8.2 and
from a pure fraction: yellow powder; mp 178 °C; IR (ATR): 0.5 Hz), 7.75–7.80 (m, 1H), 7.84 (dt, 1H, J = 8.1 and 1.0 Hz),
3079, 2933, 1722, 1593, 1498, 1296, 1270, 1236, 1181, 1071, 8.27 (d, 1H, J = 1.0 Hz), 8.30 (d, J = 1.1 Hz, 1H); 13C{1H} NMR
1
1031, 750, 736 cm−1; H NMR (CDCl3, 300 MHz) 3.90 (s, 3H), (CDCl3, 75 MHz) 96.1 (C), 110.4 (CH), 120.4 (q, C, J = 275 Hz),
7.07 (dd, 1H, J = 8.7 and 2.8 Hz), 7.24–7.27 (m, 2H), 7.34 (d, 121.5 (CH), 122.0 (CH), 124.7 (C), 126.3 (q, CH, J = 4 Hz), 127.5
1H, J = 8.7 Hz), 7.55 (d, 1H, J = 2.7 Hz), 7.85 (dd, 1H, J = 5.8 (CH), 129.4 (CH), 132.2 (q, C, J = 33 Hz), 136.2 (CH), 137.6 (q,
and 2.4 Hz); 13C{1H} NMR (CDCl3, 75 MHz) 56.1 (OMe), 85.7 (C), CH, J = 4 Hz), 139.9 (C), 145.3 (C); 19F{1H} NMR (CDCl3,
96.4 (C), 110.7 (CH), 115.2 (CH), 125.3 (CH), 129.5 (2CH), 282 MHz) −63.
132.0 (C), 133.8 (C), 133.9 (CH), 147.4 (C), 161.3 (C).
4-Iodo-1-(3-iodo-4-methoxyphenyl)-1H-benzotriazole
(4e′)
Acknowledgements
was obtained from 1-(4-methoxyphenyl)-1H-benzotriazole (1e,
0.23 g) using the general procedure 3 (eluent: 95 : 5 CH2Cl2–
MeOH) in 23% estimated yield: 1H NMR (CDCl3, 300 MHz)
3.97 (s, 3H), 7.00 (d, 1H, J = 8.7 Hz), 7.27 (dd, 1H, J = 8.1 and
7.5 Hz), 7.60 (dd, 1H, J = 8.3 and 0.7 Hz), 7.67 (dd, 1H, J = 8.7
and 2.4 Hz), 7.84 (dd, 1H, J = 7.4 and 0.7 Hz), 8.11 (d, 1H, J =
2.7 Hz); 13C{1H} NMR (CDCl3, 75 MHz) 56.9 (OMe), 85.9 (C),
86.5 (C), 110.2 (CH), 111.2 (CH), 124.8 (CH), 129.6 (CH), 130.8
(C), 132.3 (C), 134.1 (CH), 134.3 (CH), 147.9 (C), 158.9 (C).
4-Iodo-1-(5-iodo-2-thienyl)-1H-benzotriazole (4g) was pre-
pared from 1-(2-thienyl)-1H-benzotriazole (1g, 0.20 g) using the
general procedure 3 and was isolated (eluent: 9 : 1 heptane–
AcOEt) in 54% yield (0.24 g) as a beige powder: mp 176 °C;
We are grateful to Région Bretagne and the Agence Nationale
de la Recherche for financial support to E.N. E.N. and F.M.
also thank the Institut Universitaire de France and Rennes
Métropole for financial support. We gratefully acknowledge
Thermo Fisher for generous gift of 2,2,6,6-tetramethylpiperidine.
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1H NMR (CDCl3, 300 MHz) 7.07 (d, 1H, J = 4.0 Hz), 7.33 (dd,
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