Chiral Hexahalogenated 4,4′-Bipyridines

Article abstract of DOI:10.1021/acs.joc.6b00413

The preparation of 27 isomers of chiral hexahalogeno-4,4′-bipyridines by means of two complementary methods is described. The first one is convergent and based on the LDA-induced 4,4′-dimerization of trihalopyridines, whereas the second method is divergent and achieved through regioselective halogenation reactions of 4,4′-bipyridine-2,2′-diones. Iodine in 2,2′-positions of the 4,4′-bipyridines was introduced by a copper-catalyzed Finkelstein reaction (Buchwald procedure) performed on 2,2′-dibromo derivatives. Selected compounds of this new family of atropisomeric 4,4′-bipyridines were enantioseparated by high performance liquid chromatography on chiral stationary phases, and the absolute configurations of the separated enantiomers were assigned by using X-ray diffraction analysis. The latter revealed that various halogen bond types are responsible for crystal cohesion.

Full text of DOI:10.1021/acs.joc.6b00413

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Article
Chiral Hexahalogenated 4,4’-Bipyridines
Victor Mamane, Paola Peluso, Emmanuel Aubert, Sergio Cossu, and Patrick Pale
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00413 • Publication Date (Web): 05 May 2016
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Chiral Hexahalogenated 4,4’ꢀBipyridines
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V. Mamane†,*, P. Peluso‡, E. Aubert§, S. Cossuǁ and P. Pale†
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†
Institut de Chimie de Strasbourg, UMR 7177, Equipe LASYROC, 1 rue Blaise Pascal, BP 296 R8, 67008
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Strasbourg Cedex, France.
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‡
Istituto di Chimica Biomolecolare ICB CNR ꢀ UOS di Sassari, Traversa La Crucca 3, Regione Baldinca, Iꢀ
07100 Li Punti ꢀ Sassari, Italy.
§
Cristallographie, Résonance Magnétique et Modélisations (CRM2), UMR CNRS 7036, Université de Lorraine,
BP 70239, Bd des Aiguillettes, 54506 VandoeuvreꢀlesꢀNancy, France.
ǁ
Dipartimento di Scienze Molecolari e Nanosistemi, Università Ca' Foscari di Venezia, Iꢀ30172 Mestre Venezia,
Italy.
* Eꢀmail of the corresponding author: vmamane@unistra.fr
Abstract graphic
Abstract:
The preparation of 27 isomers of chiral hexahalogenoꢀ4,4’ꢀbipyridines by means of two
complementary methods is described. The first one is convergent and based on the LDAꢀ
induced 4,4’ꢀdimerization of trihalopyridines, whereas the second method is divergent and
achieved through regioselective halogenation reactions of 4,4’ꢀbipyridineꢀ2,2’ꢀdiones. Iodine
in 2,2’ꢀpositions of the 4,4’ꢀbipyridines was introduced by a copperꢀcatalyzed Finkelstein
reaction (Buchwald procedure) performed on 2,2’ꢀdibromo derivatives. Selected compounds
of this new family of atropisomeric 4,4’ꢀbipyridines were enantioseparated by High
Performance Liquid Chromatography (HPLC) on chiral stationary phases and the absolute
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configurations of the separated enantiomers were assigned by using Xꢀray diffraction (XRD)
analysis. The latter revealed that various halogen bond types are responsible for crystal
cohesion.
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Introduction
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Pyridine derivatives are wellꢀknown ligands for transition metals.1 In contrast, the dimeric
4,4’ꢀbipyridyl system is far less common, although quite used as connector between metal
atoms to build macrocyclic complexes,2 coordination polymers,3 and more recently to
construct metalꢀorganic frameworks (MOFs).4
Functionalized 4,4’ꢀbipyridines, especially polyhalogenated 4,4’ꢀbipyridines, constitute
valuable atropisomeric ligands for the preparation and development of new homochiral
complexes, including MOFs, for applications in asymmetric catalysis,5 and
enantioseparations.6 Indeed, halogen substituents offer the possibility of further
functionalization via palladiumꢀcatalyzed crossꢀcoupling reactions and aromatic nucleophilic
substitutions. Halogens can also form specific intermolecular interactions with Lewis bases,
known as halogen bonds,7 which are recognized in many fields such as biology and medicinal
chemistry,8 crystal engineering,9 and are now leading to new emerging applications. In
particular, our groups have recently shown that halogen bond can drive enantiodiscrimination
processes in HPLC environment.10 Furthermore, the availability of iodineꢀenriched fragment
libraries has been recently recognized as an important tool for lead discovery in medicinal
chemistry.11 In another but related medicinal applications, polyiodoꢀ4,4’ꢀbipyridines could
represent an interesting alternative to the wellꢀknown iodoꢀcontaining molecules used as
contrast media for Xꢀray diagnostics, for which the opacifying ability is related to the iodine
content.12 It is worth noting in this context that polyiodinated biaryl compounds have for
example been developed (Figure 1).13
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Figure 1. 4,4’ꢀBipyridines and Some Applications.
All these applications require convenient access to polyhalogenated 4,4’ꢀbipyridines.
However, such derivatives have been scarcely described in the literature. The reported
procedures for the formation of the 4,4’ꢀbipyridine scaffold from substituted pyridines
supported only fluorine and chlorine substitution,14 whereas bromine and iodine were not
considered. Except our recent reports on chiral tetraꢀ and pentahalogenated 4,4’ꢀbipyridines
(Figure 2a),15 only three examples of chiral polyhalogenated 4,4’ꢀbipyridines containing
bromine or iodine were described (Figure 2b).16
X1 X1
a)
Br X
N
N
N
N
X2 X2
Cl
I
Cl
X1, X2 = Cl, Br, I
(refs 15a-c)
X = Br, I
(refs 15d-e)
Cl
Cl
Cl
Cl
Cl
Cl
N
X
b) Cl
Cl
N
N
N
X
Cl
Cl
I
I
Cl
Cl
(ref. 16a)
X = Br, I (ref. 16b)
Figure 2. Polyhalogenated 4,4’ꢀBipyridines Described in the Literature.
In this paper, we focus on the synthesis of chiral symmetrical hexahaloꢀ4,4’ꢀbipyridines. Two
complementary chemical routes are described for the preparation of these compounds: the
LDAꢀinduced 4,4’ꢀdimerization of trihalopyridines (route 1, 8 derivatives) and the
halogenation of 4,4’ꢀbipyridineꢀ2,2’ꢀdiones (route 2, 10 derivatives). In particular, the
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compounds bearing an iodo substituent at 2ꢀposition were obtained through a copperꢀ
catalyzed Finkelstein Br/I exchange (9 derivatives) (Figure 3).
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Figure 3. Strategies for the Preparation of the 27 Examples of Symmetrical Hexahaloꢀ4,4’ꢀ
bipyridines.
Results and discussion
Route 1: Dimerization of trihalopyridines
The dimerization route is based on a method, which was originally disclosed for the
dimerization of dihalopyridines (Scheme 1, top).17 During this study, we noticed that 2,5ꢀ
dihalopyridines were good substrates whereas 2,3ꢀdihalopyridines were prone to halogen
dance18 in the presence of LDA, thus giving a mixture of 4,4’ꢀ and 3,4’ꢀbipyridines in poor
yields (Scheme 1, bottom right). For some 2,5ꢀ and 2,3ꢀdihalopyridines, arynes19 were formed
leading finally to trihalobipyridines (Scheme 1, bottom left).
Since the 2,3,5ꢀsubstitution pattern represents a mixed situation of the 2,3ꢀ and 2,5ꢀ
substitutions, it was worth trying the LDAꢀmediated dimerization procedure. We decided to
start looking at this reaction with the commercially available 3,5ꢀdibromoꢀ2ꢀchloropyridine 1a
(Table 1).
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Scheme 1. Dimerization Reaction Leading to Polyhalogenated 4,4’ꢀBipyridines:
Mechanism and Side Reactions
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Full conversion was observed upon treatment of 1a with 1 equiv. of LDA at ꢀ40°C followed
by temperature rise to ꢀ5°C during 1h. After quenching at ꢀ78°C through the addition of 1
equiv. of I2 as oxidizing agent, 5 was obtained with a good yield of 70%. Other commercially
available or readily prepared trihalopyridines 1ꢀ4 (See Experimental Section) were dimerized
under these optimized conditions (Table 1). Pyridines bearing chlorine, bromine or iodine
reacted smoothly to give the expected bipyridines 5ꢀ12 with moderate to good yields. With
some pyridine substrates (1a, 2aꢀb, 4a and 4b), the reactions were clean with no noticeable
degradation products (entries 1, 3, 4, 7 and 8). In contrast, for other pyridines (1b, 3a and 3b),
mixtures of products were obtained, thus explaining the lower yields (entries 2, 5 and 6). In
these cases, the degradation products could originate from the variable stability of the lithiated
halopyridine intermediates, which could suffer from aryne formation and/or halogen dance
(Scheme 1).
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Table 1. Synthesis of Bipyridines 5ꢀ12 by LDAꢀInduced Dimerization of
Trihalopyridinesa
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Entry Substrate
1
Product
Yield (%)
72
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70
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a Reaction conditions: i) Pyridine 1ꢀ4 (1 mmol), LDA (1 mmol), THF, ꢀ40°C to ꢀ5°C, 1h. ii) I2 (1 mmol), ꢀ78°C,
10 min then rt.
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Route 2: Halogenation of bipyridones
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Although the preceding dimerization route proved useful, its convergence could be a problem
to obtain series of compounds, as for any convergent strategy, usually designed for a specific
compound. When several compounds of a series are needed, a divergent approach can be
more advantageous. Such reasoning led us to envisage an alternative and divergent strategy to
the required hexahalobipyridines. Furthermore, during our precedent study on the
dimerization of dihalopyridines,17 it has been noted that 3,5ꢀdiodopyridine was a poor
substrate for the dimerization process, which in this case led to the corresponding 3,3’,5,5’ꢀ
tetraiodoꢀ4,4’ꢀbipyridine only with low yield (9%). Therefore, a new methodology was
required to introduce iodine atoms at positions 3,3’ and 5,5’. This observation also led us to
look for a divergent method allowing the access to a library of hexahalobipyridines from the
same starting material.
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A retroꢀsynthetic analysis (Figure 4) suggests to get hexahalobipyridines 16ꢀ25 through a
Vilsmeierꢀtype halogenation of 4,4’ꢀbipyridineꢀ2,2’ꢀdiones 13, by analogy with the synthesis
of 2,3,5ꢀtrihalopyridines.20 Compounds 13 could be available upon electrophilic halogenation
of the corresponding 4,4’ꢀbipyridineꢀ2,2’ꢀdiones 14, which can be obtained through
hydrolysis of the 2,2’ꢀCꢀCl bonds of the readily available tetrahaloꢀ4,4’ꢀbipyridines 15.21
Figure 4. Retroꢀsynthetic Analysis for the Synthesis of Bipyridines 16ꢀ25 (Route 2).
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Indeed, bipyridines 15aꢀd have been already described in our previous works17 and compound
15e was obtained by dimerization of 2ꢀchloroꢀ5ꢀiodopyridine or from 15d by double Br/I
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exchange using n
ꢀBuLi and I2 (See Experimental Section). Although 14a was reported,22 we
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found that the best route to 4,4’ꢀbipyridineꢀ2,2’ꢀdiones 14aꢀe was the exchange of the 2,2’ꢀ
chlorine atoms by a methoxy group in an additionꢀelimination process, followed by hydrolysis
of the soꢀformed imidate using aqueous HBr (Scheme 2).
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Scheme 2. Synthesis of 4,4’ꢀBipyridinꢀ2ꢀones 14aꢀe
Di/Tetrahalogenated 4,4’ꢀbipyridineꢀ2,2’ꢀdiones 14aꢀe were thus obtained in good to
excellent yields, but they need to be further halogenated. The iodination of 14a and 14d was
first considered. NꢀIodosuccinimide (NIS) proved to be the best reagent to efficiently perform
this reaction. Starting from 14a or 14d and various amounts of NIS, the reaction was not
complete at room temperature. With NIS excess (5 eq. for 14a and 3 eq. for 14d) and high
temperature, complete reactions were finally achieved, leading to bipyridone 13a in 57% and
43% yield, respectively. Applied to bipyridones 14bꢀc and 14e, these conditions allowed the
formation of bipyridones 13bꢀc with 65% (91% purity) and 70% yield (85% purity) whereas
13d was not sufficiently pure to go further in the synthesis. Consequently,
Nꢀ
chlorosuccinimide (NCS) was used to obtain pure bipyridone 13d by chlorination of 14d with
35% yield. Analogously, dichlorination of bipyridone 14d allowed the formation of
compound 13e with 68% yield (Scheme 3).
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Scheme 3. Synthesis of Chiral Tetrahaloꢀ4,4’ꢀbipyridineꢀ2,2’ꢀdiones 13aꢀe
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Interestingly, dibromination of 14d with 6 equiv. of Br2 delivered the unexpected
tetrabrominated bipyridone 13f where the iodine atoms were replaced by bromines.
Bipyridone 13f could alternatively be obtained by dibromination of 14c. The desired
bipyridone 13g could be observed in the reaction mixture by reducing the amount of Br2 to
2.5 equiv. Nevertheless, it was obtained as an inseparable mixture with bipyridone 13h where
only one iodine atom was exchanged (Scheme 4).23
It is worth noting that for solubility reasons, compounds 13 could not be purified by
chromatography. In most cases, full conversions were achieved leading to pure 13. When the
1
reactions were not complete, the purity of 13 was determined by H NMR. In these cases,
compounds 13 were used as mixtures in the next 2,2’ꢀhalogenation step.
This last step of the sequence was based on a Vilsmeierꢀtype halogenation of the 4,4’ꢀ
bipyridineꢀ2,2’ꢀdiones 13. For the formation of the 2,2’ꢀchlorinated bipyridines 16ꢀ20, the
classical method using POCl3/DMF was first examined and was found efficient for the
transformation of all bipyridones 13.24 Under these conditions, compounds 16ꢀ20 were
obtained with moderate to good yields from the corresponding bipyridones 13a,b and 13d,e.
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It is worth noting that bipyridone 13c (85% purity) delivered pentahalobipyridine 27a15d along
with the expected bipyridine 20 with 15% and 49% yields, respectively (Scheme 5).
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Scheme 4. Br2ꢀInduced Iodine/Bromine Exchange During Bromination of Bipyridone
14d
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O
O
Br2 (6 eq.)
AcONa (2 eq.)
AcOH, 80°C
H
N
HN
NH
O
77%
I
I
Br
Br
Br
Br
14d
O
O
79%
Br2 (3.5 eq.)
AcONa (2 eq.)
HN
NH
O
N
H
13f
AcOH, 80°C
Br
Br
14c
H
N
H
O
O
N
Br2 (2.5 eq.)
AcONa (2 eq.)
Br
I
Br
Br
I
I
+
14d
Br
Br
AcOH, 80°C
O
N
H
13h
O
N
H
13g
Scheme 5. Synthesis of Hexahalobipyridines 16ꢀ20
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To get the analog 2,2'ꢀbrominated bipyridines from bipyridones 13, a similar reaction but with
PBr3 was attempted. However, this reaction required heating at 180°C and the solubility of the
bipyridones in PBr3 represented an important limitation. Therefore, these conditions resulted
in low to moderate yields of the expected products (Scheme 6). The best results were
achieved for the tetrahalogenated 4,4’ꢀbipyridines 21 and 24 which were isolated with yields
of 53% and 57%, respectively. Similarly, bipyridines 22 and 23 were obtained with 35% and
27% yields from 13b and 13d, respectively. Under the same conditions, bipyridone 13c
delivered the expected bipyridine 25 but the pentahalobipyridine 27b was also formed. The
yield of bipyridine 25 was thus lower (25%).
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Scheme 6. Synthesis of Hexahalobipyridines 21ꢀ25
Despite the harsh conditions required for this Vilsmeierꢀtype 2,2'ꢀbromination, this route
provided better results than the dimerization route. The tetrabrominated bipyridone 13f was
thus transformed to bipyridine 6 in 53% yield, while the dimerization route provided lower
yield (35%; Table 1, entry 2). After dibromination in 3,3’ꢀpositions using Br2, the 5,5'ꢀ
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dichlorobipyridone 14b was transformed to the bipyridone 13i, which after 2,2’ꢀ
dibromination with PBr3 furnished bipyridine 10 in excellent yield (Scheme 7). The latter was
previously obtained in poor yield (23%; Table 1, entry 6).
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Scheme 7. Improved Synthesis of Bipyridines 6 and 10
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For iodination reaction in 2ꢀposition, we first examined the method described by Maloney and
coꢀworkers.25 On this basis, bipyridone 13f was first reacted with triflic anhydride to generate
the bisꢀtriflate intermediate, which was subjected in situ to NaI. Unfortunately, the expected
bipyridine 28 could not be observed in the reaction mixture. Attempts to isolate the bisꢀtriflate
intermediate failed probably because of the very low solubility of the bipyridone starting
material. We then considered the copperꢀcatalyzed Finkelstein reaction described by
Buchwald and Klapars26 for Br/I exchange of aryl, heteroaryl, and vinyl bromides, and
recently employed by Lützen and coꢀworkers with 2ꢀbromopyridines.27 Selected as a model,
the hexabrominated bipyridine 6 was mixed with 4 equiv. of NaI, 20 mol% of CuI and 40
mol% of transꢀN,N’ꢀdimethylcyclohexaneꢀ1,2ꢀdiamine in dioxane at 110°C. Although the
reaction was slow, we observed that the starting material was entirely consumed after 40h.
After purification, bipyridine 28 was isolated with a good 58% yield. Therefore, the
Buchwald method was applied to the synthesis of all the other 2,2’ꢀdiiodoꢀ3,3’,5,5’ꢀtetrahaloꢀ
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4,4’ꢀbipyridines through Br/I exchange of the corresponding hexahaloꢀ4,4’ꢀbipyridines. No
modification of the reaction conditions was necessary and after 40h, bipyridines 29ꢀ36 were
obtained with good to excellent yields (53ꢀ87%) (Table 2). Moreover, the possible
halogen/iodine exchange at other positions (3, 3’, 5 and 5’) was never observed, probably
because of the high steric hindrance around the chiral axis. It is worth noting that the
hexaiodoꢀ4,4’ꢀbipyridine 32 having a very high iodine content is a very stable molecule.28
Table 2. Synthesis of Bipyridines 28ꢀ36 by CopperꢀCatalyzed Finkelstein Reaction
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I
N
Br
N
MeHN
NHMe
X2
X2
X1
X1
X2
X2
X1
X1
(40 mol%)
CuI (20 mol%)
NaI (4 eq.)
Dioxane, 110°C, 40h
I
N
Br
N
Entry Substrate
Product
Yield (%)
58
1
6
2
76
8
3
4
5
68
53
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Enantioseparation of chiral hexahalo-4,4’-bipyridines
Fourteen selected chiral racemic, atropisomeric bipyridines 5ꢀ6, 12, 20ꢀ23, 25, 28, 31ꢀ34 and
36 among the 27 hexahalobipyridine derivatives prepared in this work were enantioseparated
by HPLC on chiral stationary phases (Table 3) and the absolute configurations of the
recovered pure enantiomers (≥95.6% ee) were assigned by Xꢀray diffraction (XRD) using
anomalous dispersion signal (for ORTEP plots, see Fig. S16ꢀ29 in S. I.). Interestingly, the (
enantiomers were recovered with a very high ee (>98.5ꢀ99%) except for two cases (21 and 34,
ee 95.7% and 95.6%, respectively). The ( ) enantiomers were recovered with very high ee,
but overall slightly lower than the ( ) enantiomers (97.2ꢀ99%).
M)
P
M
Table 3. Enantioseparation of Selected Hexahalogenoꢀ4,4’ꢀbipyridinesa
absolute configuration
4,4’ꢀBipy Conditionsb
(e.e.c %)
1st eluted 2nd eluted
A
B
C
D
M
M
M
M
(>99)
(98.9)
(99.0)
(>99)
P
P
P
P
(>99)
(>99)
(98.0)
(>99)
5
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C
D
E
D
F
M (95.7) P (98.2)
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22
23
25
28
31
32
33
34
36
M (>99)
P (98.3)
M (98.5) P (97.7)
M (>99)
M (>99)
P (>99)
P (97.2)
F
M (98.6) P (98.6)
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A
G
E
H
M (>99)
M (>99)
P (>99)
P (>99)
M (95.6) P (>99)
M (>99) P (>99)
a
b
All the compounds were separated on Chiralpak IA except 6 which was separated on Chiralcel ODꢀH.
Conditions of enantioseparation: mobile phase and flow rate (IPA = isopropanol). A: nꢀHeptane/IPA 90:10, 1.0
ml/min; B: nꢀHexane/IPA 90:10, 0.8 ml/min; C: MeOH/IPA 1:1, 0.4 ml/min; D: nꢀHeptane/EtOH/MeOH
90:05:05, 0.8 ml/min; E: nꢀHeptane/IPA 95:05, 1.0 ml/min; F: nꢀHexane /IPA 90:10, 1.0 ml/min; G: nꢀ
Hexane/EtOH 90:10, 1.0 ml/min; H: nꢀHexane/IPA/MeOH 90:05:05, 0.8 ml/min. All other data (retention times,
retention factors and separation factors) as well as HPLC traces can be found in in S. I (Tables S1ꢀS2 and Fig.
S1ꢀS14). c e.e.: Enantiomeric excess.
These fourteen bipyridines crystallize in the same P212121 space group with one molecule in
the asymmetric unit, with similar unit cell parameters and volumes (See S.I., Table S3). They
are thus isostructural, as evidenced in Figure 5. The main difference affects bipyridine 22
which presents a similar structure compared to the others but with a significantly different
orientation of the bipyridine molecules.
Figure 5. Left: superposition of the fourteen bipyridine structures, all converted to (M)
enantiomers. The fitting of the structures was performed by minimizing the N···N distances
between each bipyridine molecule included within one unit cell, with the structure of 6 as
reference. The particular bipyridine 22 which deviates from the general trend is displayed
with its carbon atoms drawn in pink. Right: reference structure 6 displayed together with its
unit cell (color axis scheme: a: red; b: green; c: blue).
The intermolecular interactions common to the thirteen isostructures are depicted in Figure 6,
with interatomic distances reported in Table S4 and corresponding penetration parameters in
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Table 4. When comparing interatomic distances to the sum of the corresponding van der
Waals radii,29 the two halogenꢀLewis base contacts (Hal2…N and Hal3…N) emerge as the
most important interactions, with the largest penetration of the van der Waals atomic spheres
(Table 4). These interactions arise from the polarization of the halogen atom due to the
covalent Csp2ꢀHal bond, creating the soꢀcalled sigma hole30 which points toward the electron
rich nitrogen atom of the bipyridine rings. These interactions lead to almost linear Csp2ꢀ
Hal…N contacts (Table S4). The extent of the penetration follows the known halogen bond
strength,31 decreasing in the order I > Br > Cl (I: from ꢀ11.5% to ꢀ15.1%; Br: from ꢀ3.4% to ꢀ
9.8%; Cl: from ꢀ2.8% to ꢀ4.3%). Beside these interactions, a weak hydrogen bond (Hal2…H,
Table 4) and a typeꢀII halogen bond32 (Hal5…Hal3', Table 4) are also present in most of the
structures, although in some of them the interatomic distances are longer than the
corresponding sum of van der Waals radii (compounds 23, 28 and 33).
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Figure 6. Interaction scheme common to the thirteen isostructural bipyridine structures
(excluding 22).
Table 4. Penetration parameters in interatomic contacts At1…At2 (defined as 100×{
(dAt1…At2)/(rvdWAt1+rvdWAt2) ꢀ1}) where dAt1…At2 is the interatomic distance and rvdWAt1,2
the corresponding Van der Waals radii). Bipyridines are arranged in families of
identical atomic chemical composition.
Bipyridine Hal2 Hal3 Hal5 N…Hal2 Hal2…H Hal3…N Hal5…Hal3' Hal3…Hal5
Cl
Br
Br
ꢀ4.3%
ꢀ7.9%
ꢀ9.3%
ꢀ2.7%
5
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Br
Br
Br
ꢀ9.2%
ꢀ6.9%
ꢀ9.8%
ꢀ8.6%
ꢀ12.4% ꢀ2.5%
ꢀ9.3% 1.2%
ꢀ1.7%
ꢀ2.7%
3
4
5
6
7
8
6
Br
Br
I
Br
I
Br
I
Br
Br
ꢀ6.3%
ꢀ7.3%
ꢀ14.9% ꢀ2.0%
ꢀ8.1%
ꢀ5.1%
12
25
28
9
Cl
Br
I
Cl
Br
I
ꢀ2.8%
ꢀ6.7%
ꢀ5.7%
ꢀ8.3%
ꢀ11.5% ꢀ3.6%
ꢀ4.3% 0.1%
ꢀ2.3%
ꢀ2.7%
20
23
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Br
I
I
I
I
Br
I
Br
I
ꢀ3.4%
ꢀ15.1% 0.2%
ꢀ13.8% ꢀ2.8%
ꢀ8.6%
ꢀ11.7% ꢀ3.6%
ꢀ14.3% ꢀ0.4%
21
36
31
ꢀ8.8%
ꢀ3.0%
I
I
I
ꢀ13.9% ꢀ1.8%
ꢀ14.2% ꢀ4.0%
ꢀ13.2% 7.7%
32
I
I
I
Cl
Cl
I
ꢀ14.1% 1.8%
ꢀ13.5% ꢀ2.9%
33
34
ꢀ2.9%
ꢀ0.4%
In sharp contrast and surprisingly, the structure of the bipyridine 22 does not exhibit such
halogenꢀnitrogen interaction (Hal2,3…N; see S.I. Scheme S15) despite the presence of two
good halogen bond donors (Br, I). Furthermore, Cl atoms in structures of 5, 20, 23 and 34
exhibit such interaction, but none exists in 22. Only two characteristic typeꢀII halogenꢀ
halogen interactions can be observed in that particular structure, namely CꢀBr…I (3.749Å,
157.3°) and CꢀBr…Br (3.565Å, 165.3°).
Conclusion
We have disclosed the synthesis of twenty seven new atropisomeric 2,2’,3,3’,5,5’ꢀhexahaloꢀ
4,4’ꢀbipyridines through two complementary methods by means of convergent and divergent
strategies. Based on LDAꢀmediated 4,4’ꢀdimerization of 2,3,5ꢀtrihalopyridines, the
convergent synthesis delivered the expected bipyridines generally in good yields. Another but
divergent synthesis was developed starting from the readily available 4,4’ꢀbipyridineꢀ2,2’ꢀ
dione scaffold. Eleven hexahalogenated 4,4’ꢀbipyridines were thus obtained, generally in
good yields, by means of successive regioselective halogenation reactions. For the synthesis
of the 2,2’ꢀdiiodo derivatives, a Br/I exchange in the 2,2’ꢀdibromoꢀ3,3’,5,5’ꢀtetrahaloꢀ4,4’ꢀ
bipyridines was achieved through a copperꢀcatalyzed Finkelstein reaction.
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Fourteen of these new atropisomeric 4,4’ꢀbipyridines were enantioseparated by HPLC on
chiral stationary phases and the absolute configuration of the pure enantiomers were assigned
by using XRD. Various halogen bonds (Hal…N and Hal…Hal) were observed in almost all
the hexahalobipyridines studied by XRD.
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These racemic and enantiopure polyhalogenated 4,4’ꢀbipyridines represent valuable synthetic
intermediates, which could be further functionalized at the different Cꢀhalogen bonds towards
a multitude of new structures. Further work is in progress in our groups for such selective
modifications and for various applications, including building MOFs.
Experimental section
General Information. Proton (1H NMR) and Carbon (13C NMR) nuclear magnetic resonance
spectra were recorded on the following 300, 400 or 500 MHz instruments. The chemical shifts
are given in part per million (ppm) on the delta scale. The solvent peak was used as reference
1
values. For H NMR: CDCl3= 7.26 ppm. For 13C NMR: CDCl3= 77.16 ppm. Data are
presented as follow; chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, quint = quintet, m = multiplet, b = broad), integration and coupling constants (J/Hz).
High resolution mass spectra (HRMS) data were recorded on a microTOF spectrometer
equipped with orthogonal electrospray interface (ESI). Xꢀray crystallographic data were
collected at low temperature on CCD diffractometers using Cu(Kα) or Mo(Kα) radiations. In
each case anomalous dispersion effects were strong enough in order to unambiguously
attribute the chirality of the compounds (See S.I.) Analytical thin layer chromatography
(TLC) was carried out on silica gel 60 F254 plates with visualization by ultraviolet light.
Reagents and solvents were purified using standard means. Tetrahydrofuran (THF) was
distilled from sodium metal/benzophenone and stored under an argon atmosphere. Anhydrous
reactions were carried out in flameꢀdried glassware and under an argon atmosphere. All other
chemicals were used as received. 3,5ꢀDibromopyridinꢀ2ꢀamine33 and 3ꢀbromoꢀ5ꢀiodopyridinꢀ
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2ꢀamine34 were prepared according to literature procedures. 3,5ꢀDichloropyridinꢀ2ꢀamine and
3ꢀbromoꢀ5ꢀchloropyridinꢀ2ꢀamine were purchased and used as received.
6
7
8
9
For HPLC analyses, a highꢀpressure binary gradient system equipped with a diodeꢀarray
detector operating at 220 (254, 280) nm and a 20 ꢁL sample loop was employed. Chiralcel
ODꢀH (cellulose trisꢀ3,5ꢀdimethylphenylcarbamate) and Chiralpak IA (amylose trisꢀ3,5ꢀ
dimethylphenylcarbamate) were used as chiral columns (250 × 4.6 mm) (5 ꢁm). HPLCꢀgrade
nꢀhexane (Hex), nꢀheptane, ethanol (EtOH), methanol (MeOH) and 2ꢀpropanol (IPA) were
purchased and used as received.
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General procedure for the synthesis of 2ꢀchloroꢀ3,5ꢀdihalopyridines 1aꢀ4a.35 3,5ꢀDihaloꢀ
2ꢀaminopyridine (2 mmol) was dissolved in conc. HCl (6 mL) and the solution was cooled to
ꢀ20°C. NaNO2 (4 mmol, 276 mg) was added by portions. After the end of the addition, the
temperature was raised to room temperature and the mixture was stirred for 4h. NaOH 10M
was added until pH 11 and the mixture was extracted with ethyl acetate (2x30 mL). The
organic phases were combined, washed with brine (40 mL) and dried over anhydrous MgSO4.
After concentration, the crude was purified by chromatography on silica gel (cyclohexane /
ethyl acetate 95/5).
Analytical data of 3,5-dibromo-2-chloropyridine (1a)36 and 2,3,5-trichloropyridine (2a)37 are
identical to those reported in the literature.
3-Bromo-2,5-dichloropyridine (3a). m = 268 mg; yield = 59 %. M.p.: 42ꢀ44°C. 1H NMR (500
MHz, CDCl3) δ 8.36 (d, J = 2.5 Hz, 1H), 7.93 (d, J = 2.5 Hz, 1H). 13C NMR (126 MHz,
CDCl3) δ 148.4, 148.1, 141.0, 131.4, 118.8. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for
C5H3Cl2BrN 225.8820; Found 225.8811.
1
3-Bromo-2-chloro-5-iodopyridine (4a). m = 401 mg; yield = 63%. M.p.: 66ꢀ68°C. H NMR
(500 MHz, CDCl3) δ 8.50 (d, J = 2 Hz, 1H), 8.21 (d, J = 2 Hz, 1H). 13C NMR (126 MHz,
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CDCl3) δ 153.8, 150.5, 149.3, 121.4, 90.4. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for
C5H3ClBrIN 317.8177; Found 317.8207.
6
7
8
9
General procedure for the synthesis of 2ꢀbromoꢀ3,5ꢀdihalopyridines 1bꢀ4b. These
compounds were prepared in two steps starting from 2ꢀaminoꢀdihalopyridines.
Step 1: Transformation of 2-amino-dihalopyridines to dihalopyrid-2-ones. 3,5ꢀDihaloꢀ2ꢀ
aminopyridine (4 mmol) was added to H2SO4 (20%, 24 mL) at ꢀ5°C. A solution of NaNO2 (8
mmol, 552 mg) in H2O (4 mL) was slowly added and the reaction was stirred at ꢀ5°C for 2h.
The precipitate is filtered, washed with H2O (3x20 mL) and dried under vacuum.
Analytical data of 3,5-Dibromopyridin-2(1H)-one22 and 3,5-Dichloropyridin-2(1H)-one38 are
identical to those reported in the literature.
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3-Bromo-5-chloropyridin-2(1H)-one. m = 359 mg; yield = 43%. M.p.: 152ꢀ154°C. H NMR
(500 MHz, DMSO) δ 8.06 (d, J = 2.5 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H). 13C NMR (126 MHz,
DMSO) δ 157.6, 142.6, 134.1, 115.3, 110.9. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for
C5H4ClBrNO 207.9159; Found 207.9172.
1
3-Bromo-5-iodopyridin-2(1H)-one39. m = 1.14 g; yield = 95%. M.p.: 249ꢀ251°C. H NMR
13
(300 MHz, DMSO) δ 12.31 (broad s, 1H), 8.09 (s, 1H), 7.71 (s, 1H). C NMR (126 MHz,
DMSO) δ 158.0, 149.3, 141.2, 116.9, 64.7.
Step 2: Transformation of dihalopyrid-2-ones to 2-bromo-3,5-dihalopyridines 1b-4b
.
Pyridone (2 mmol) was added to PBr3 (8 mL) and the mixture was heated at 180°C and stirred
for 4h. After cooling to room temperature, the mixture is dropped over iceꢀwater (100 mL),
basified with NaOH 10M and extracted with dichloromethane (2x50 mL). The organic phases
were combined, washed with brine (50 mL) and dried over anhydrous MgSO4. After
concentration, the crude was purified by chromatography on silica gel (cyclohexane / ethyl
acetate 95/5).
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Analytical data of 2,3,5-Tribromopyridine (1b),40 2-Bromo-3,5-dichloropyridine (2b),41 and
2,3-Dibromo-5-chloropyridine (3b)42 are identical to those reported in the literature.
1
2,3-Dibromo-5-iodopyridine (4b). m = 537 mg; yield = 74%. M.p.: 76ꢀ78°C. H NMR (300
9
MHz, CDCl3) δ 8.48 (d, J = 1.2 Hz, 1H), 8.17 (d, J = 1.2 Hz, 1H). 13C NMR (126 MHz,
CDCl3) δ 154.0, 148.8, 143.2, 124.8, 91.2. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for
C5H3Br2IN 361.7671; Found 361.7666.
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General procedure for the dimerization reaction. To a solution of freshly prepared LDA (1
mmol) in THF (4 mL) at ꢀ40°C was added a solution of trihalopyridine 1ꢀ4 (1 mmol) in THF
(6 mL) during 20 min while maintaining the temperature close to ꢀ40°C. After the end of the
addition, the temperature was slowly raised to ꢀ5°C (during 1h). The temperature was lowered
to ꢀ78°C then a solution of I2 (280 mg, 1.1 mmol) in THF (1 mL) was slowly added. After 10
min at ꢀ78°C, the temperature was raised to room temperature and the reaction was quenched
by the addition of aqueous saturated solution of Na2S2O3 (2 mL). Water was added (5 mL)
and the mixture was extracted twice with ethyl acetate (2x10 mL). The organic phases were
combined, washed with brine (10 mL) and dried over anhydrous MgSO4. After concentration,
the crude was purified by chromatography on silica gel (cyclohexane / ethyl acetate 95/5) to
give bipyridines 5ꢀ12.
3,3',5,5'-Tetrabromo-2,2'-dichloro-4,4'-bipyridine (5). m = 390 mg; yield = 72%. M. p.: 83ꢀ
1
85°C. H NMR (500 MHz, CDCl3) δ 8.62 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 151.3,
150.1, 150.05, 121.0, 118.7. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Br4Cl2N2
536.6401; Found 536.6425.
1
2,2',3,3',5,5'-Hexabromo-4,4'-bipyridine (
6
). m = 220 mg; yield = 35%. M.p.: 150ꢀ152°C. H
13
NMR (300 MHz, CDCl3) δ 8.60 (s, 2H). C NMR (75 MHz, CDCl3) δ 150.3, 149.9, 143.9,
124.2, 119.3. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Br6N2 624.5391; Found
624.5405.
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2,2',3,3',5,5'-Hexachloro-4,4'-bipyridine (7). m = 254 mg; yield = 70%. M.p.: 101ꢀ103°C. H
4
5
6
7
8
9
NMR (500 MHz, CDCl3) δ 8.50 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 148.8, 146.9, 142.7,
129.9, 129.8. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Cl6N2 360.8422; Found
360.8457.
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2,2'-Dibromo-,3,3',5,5'-tetrachloro-4,4'-bipyridine (
8
). m = 266 mg; yield = 59%. M.p.: 155ꢀ
1
13
157°C. H NMR (500 MHz, CDCl3) δ 8.49 (s, 2H). C NMR (126 MHz, CDCl3) δ 147.3,
142.4, 140.8, 132.6, 130.3. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Br2Cl4N2
448.7412; Found 448.7371.
3,3'-Dibromo-2,2',5,5'-tetrachloro-4,4'-bipyridine (9). m = 212 mg: yield = 47%. M.p.: 95ꢀ
1
97°C. H NMR (500 MHz, CDCl3) δ 8.51 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 150.6,
147.6, 146.9, 129.3, 120.9. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Br2Cl4N2
448.7412; Found 448.7432.
2,2',3,3'-Tetrabromo-5,5'-dichloro-4,4'-bipyridine (10). m = 124 mg; yield = 23%. M.p.: 132ꢀ
1
13
134°C. H NMR (500 MHz, CDCl3) δ 8.50 (s, 2H). C NMR (126 MHz, CDCl3) δ 147.9,
146.6, 143.0, 129.8, 124.2. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Br4Cl2N2
536.6401; Found 536.6400.
3,3'-Dibromo-2,2'-dichloro-5,5'-diiodo-4,4'-bipyridine (11). m = 463 mg; yield = 73%. M.p.:
1
177ꢀ179°C. H NMR (500 MHz, CDCl3) δ 8.78 (s, 2H). 13C NMR (126 MHz, CDCl3) δ
155.8, 155.4, 152.5, 120.9, 93.9. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Br2Cl2I2N2
632.6124; Found 632.6124.
2,2',3,3'-Tetrabromo-5,5'-diiodo-4,4'-bipyridine (12). m = 535 mg (74% yield). M. p.: 206ꢀ
1
13
208°C. H NMR (300 MHz, CDCl3) δ 8.76 (s, 2H). C NMR (126 MHz, CDCl3) δ 155.8,
155.6, 145.2, 123.8, 94.7. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Br4I2N2 720.5114;
Found 720.5117.
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Improved synthesis of 2,2',5,5'-tetrachloro-4,4'-bipyridine (15b) and 2,2',3,3'-tetrachloro-4,4'-
bipyridine (15e).17 To a solution of freshly prepared LDA (11 mmol) in THF (70 mL) at ꢀ
40°C was added a solution of 2,5ꢀdichloropyridine or 2,3ꢀdichloropyridine (2.9 g, 20 mmol)
in THF (120 mL) during 1h while maintaining the temperature close to ꢀ40°C. After the end
of the addition, the temperature was slowly raised to ꢀ15°C (during 1h). The temperature was
lowered to ꢀ78°C then a solution of preꢀcooled solution of I2 (2.8 g, 11 mmol) in THF (10
mL) was added at once. After 10 min at ꢀ78°C, the temperature was raised to room
temperature and the reaction was quenched by the addition of aqueous saturated solution of
Na2S2O3 (20 mL). Water was added (50 mL) and the mixture was extracted twice with ethyl
acetate (2x100 mL). The organic phases were combined, washed with brine (100 mL) and
dried over anhydrous MgSO4. After concentration, the crude was purified by chromatography
on silica gel (cyclohexane / ethyl acetate 95/5) to give 15b (1.75 g, 61%) or 15e (1.66 g,
57%).
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Improved synthesis of 5,5'-dibromo-2,2'-dichloro-4,4'-bipyridine13
(15c). To a solution of
freshly prepared LDA (11 mmol) in THF (70 mL) at ꢀ40°C was added a solution of 5ꢀbromoꢀ
2ꢀchloropyridine (3.85 g, 20 mmol) in THF (120 mL) during 1h while maintaining the
temperature close to ꢀ40°C. After the end of the addition, the mixture was stirred at ꢀ40°C for
1h. The temperature was lowered to ꢀ78°C then a solution of preꢀcooled solution of I2 (2.8 g,
11 mmol) in THF (10 mL) was added at once. After 10 min at ꢀ78°C, the temperature was
raised to room temperature and the reaction was quenched by the addition of aqueous
saturated solution of Na2S2O3 (20 mL). Water was added (50 mL) and the mixture was
extracted twice with ethyl acetate (2x100 mL). The organic phases were combined, washed
with brine (100 mL) and dried over anhydrous MgSO4. After concentration, the crude was
purified by chromatography on silica gel (cyclohexane / ethyl acetate 95/5) to give 15c (2.5 g,
65%).
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2,2'-Dichloro-5,5'-diiodo-4,4'-bipyridine (15d).
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It was prepared by two different routes:
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From 2ꢀchloroꢀ5ꢀiodopyridine: the same procedure as for 15c was employed. LDA (3.3
mmol), 2ꢀchloroꢀ5ꢀiodopyridine (1.44 g, 6 mmol), I2 (3.3 mmol, 840 mg). 15d was obtained
with 37% yield (530 mg).
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From bipyridine 15c: nꢀBuLi (1.43 M, 6.3 mmol, 4.4 mL) in THF (7.5 mL) was cooled at ꢀ
78°C. A solution of bipyridine 15c (1.15 g, 3 mmol) in THF (30 mL) was slowly added and
the mixture was stirred at ꢀ78°C for 15 min. A preꢀcooled solution of I2 (1.6 g, 6.3 mmol) in
THF (7.5 mL) was added at once then the mixture was stirred for 10 min ꢀ78°C. The
temperature was raised to room temperature and the reaction was quenched by the addition of
aqueous saturated solution of Na2S2O3 (10 mL). Water was added (25 mL) and the mixture
was extracted twice with ethyl acetate (2x500 mL). The organic phases were combined,
washed with brine (50 mL) and dried over anhydrous MgSO4. After concentration, the crude
was purified by chromatography on silica gel (cyclohexane / ethyl acetate 95/5) to give 15d
(1.0 g, 70%). M.p.: 215ꢀ217°C. 1H NMR (300 MHz, CDCl3) δ 8.85 (d, J = 3 Hz, 2H), 7.17 (d,
13
J = 3 Hz, 2H). C NMR (101 MHz, CDCl3) δ 157.7, 154.8, 152.0, 124.6, 94.2. HRMS calcd
for C10H5Cl2I2N2 (M + H) 476.7914, found 476.7952.
General procedure for the preparation of bipyridones 14. Sodium (10 equiv., 20 mmol,
460 mg) was added to MeOH (20 mL) at room temperature. After complete dissolution of Na,
bipyridine 15 (2 mmol) was added and the mixture was heated at 65°C for 10h. After cooling
to room temperature, the mixture is added over a cold aqueous solution of NaHCO3 (5%, 20
mL) and extracted with ethyl acetate (50 mL), dried over anhydrous MgSO4 and concentrated
to give 26 which was used without further purification in the next step. To 26 was added HBr
47% (8 mL) and the mixture was heated at 110°C for 4h. After cooling to room temperature,
the mixture was slowly poured on a saturated aqueous solution of NaHCO3 (300 mL). The
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mixture was filtered and washed with water (20 mL), isopropanol (5 mL) and diethyl ether
(10 mL) to give compounds 14 as white powders.
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5,5'-Dichloro-[4,4'-bipyridine]-2,2'(1H,1'H)-dione (14b). m = 218 mg; yield = 85%. M.p. >
9
1
300°C. H NMR (400 MHz, DMSO) δ 11.93 (broad s, 2H), 7.82 (s, 2H), 6.42 (s, 2H). 13C
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NMR (101 MHz, DMSO) δ 161.2, 147.5, 137.0, 118.1, 111.6. HRMS (ESIꢀTOF) m/z [M +
H]+ Calcd for C10H7Cl2N2O2 256.9879; Found 256.9874.
5,5'-Dibromo-[4,4'-bipyridine]-2,2'(1H,1'H)-dione (14c). m = 335 mg; yield = 97%. M.p. >
1
300°C. H NMR (500 MHz, DMSO) δ 12.00 (broad s, 2H), 7.88 (s, 2H), 6.37 (s, 2H). 13C
NMR (126 MHz, DMSO) δ 161.4, 150.5, 139.1, 118.3, 99.3. HRMS (ESIꢀTOF) m/z [M + H]+
Calcd for C10H7Br2N2O2 344.8869; Found 344.8836.
5,5'-Diiodo-[4,4'-bipyridine]-2,2'(1H,1'H)-dione (14d). m = 326 mg; yield = 74%. M.p. >
1
300°C. H NMR (300 MHz, DMSO) δ 11.86 (broad s, 2H), 7.88 (s, 2H), 6.26 (s, 2H). 13C
NMR (126 MHz, DMSO) δ 161.6, 156.1, 143.3, 118.2, 70.7. HRMS (ESIꢀTOF) m/z [M + H]+
Calcd for C10H7I2N2O2 440.8591; Found 440.8572.
3,3'-Dichloro-[4,4'-bipyridine]-2,2'(1H,1'H)-dione (14e). m = 180 mg; yield = 70%. M.p. >
300°C. 1H NMR (500 MHz, DMSO) δ 12.35 (s, 2H), 7.51 (d, J = 6.7 Hz, 2H), 6.17 (d, J = 6.7
Hz, 2H). 13C NMR (126 MHz, DMSO) δ 158.3, 146.7, 134.2, 121.9, 105.1. HRMS (ESIꢀ
TOF) m/z [M + H]+ Calcd for C10H7Cl2N2O2 256.9879; Found 256.9879.
General procedure for 5,5’ꢀdiiodination of bipyridones 14. To bipyridone 14aꢀc (0.5
mmol) in acetic acid (3 mL) were added NIS (428 mg, 1.5 mmol; 713 mg, 2.5 mmol for
iodination of 14a) and trifluoroacetic acid (0.3 mL) and the mixture was stirred for 10h at
room temperature. More NIS (428 mg, 1.5 mmol; 713 mg, 2.5 mmol for iodination of 14a)
and trifluoroacetic acid (0.3 mL) were added and the reaction mixture was heated to 110°C
and stirred for 5h. After cooling to room temperature, the mixture was poured on H2O (10
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mL) and made basic by addition of NH4OH. After filtration, washing with H2O (2x10 mL)
and acetonitrile (2x5 mL), the solid was dried under vacuum.
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3,3',5,5'-Tetraiodo-[4,4'-bipyridine]-2,2'(1H,1'H)-dione (13a). m = 197 mg; yield = 57%.
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Yellow solid. M.p. > 300°C. H NMR (300 MHz, DMSO) δ 11.08 (Broad s, 2H), 7.94 (s,
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2H). C NMR (126 MHz, DMSO) δ 161.4, 159.7, 142.2, 96.9, 66.9. HRMS (ESIꢀTOF) m/z
[M + H]+ Calcd for C10H5I4N2O2 692.6524; Found 692.6547.
5,5'-Dichloro-3,3'-diiodo-[4,4'-bipyridine]-2,2'(1H,1'H)-dione (13b). m = 165 mg; yield =
1
65%. H NMR (300 MHz, DMSO) δ 12.43 (s, 2H), 7.94 (s, 2H). 13C NMR (126 MHz,
DMSO) δ 159.6, 154.7, 135.5, 108.7, 97.1.
5,5'-Dibromo-3,3'-diiodo-[4,4'-bipyridine]-2,2'(1H,1'H)-dione (13c). m = 209 mg; yield =
70%. 1H NMR (300 MHz, DMSO) δ 12.43 (s, 2H), 7.99 (s, 2H).
5,5’ꢀDichlorination of bipyridones 14. To a suspension of bipyridone 14cꢀd (0.34 mmol) in
acetic acid (1 mL) was added NCS (197.4 mg, 1.02 mmol) and the mixture was heated at
120°C for 2h. After cooling to room temperature, H2O (2 mL) was added then the precipitate
was washed with H2O (2x5 mL), acetonitrile (3x2 mL) and diethyl ether (5 mL). After drying
under vacuum, compounds 13dꢀe were recovered as white powders.
3,3'-Dichloro-5,5'-diiodo-[4,4'-bipyridine]-2,2'(1H,1'H)-dione (13d). m = 61 mg; yield =
1
13
35%. M.p. > 300°C. H NMR (400 MHz, DMSO) δ 12.69 (s, 2H), 7.97 (s, 2H). C NMR
(126 MHz, DMSO) δ 157.5, 151.1, 147.4, 140.9, 122.4. HRMS (ESIꢀTOF) m/z [M + H]+
Calcd for C10H5Cl2I2N2O2 508.7812; Found 508.7788.
3,3'-Dichloro-5,5'-dibromo-[4,4'-bipyridine]-2,2'(1H,1'H)-dione (13e). m = 96 mg; yield =
1
13
68%. M.p. > 300°C. H NMR (400 MHz, DMSO) δ 12.86 (s, 2H), 8.02 (s, 2H). C NMR
(126 MHz, DMSO) δ 157.3, 146.0, 136.6, 123.0, 96.3. HRMS (ESIꢀTOF) m/z [M + H]+
Calcd for C10H5Br2Cl2N2O2 412.8089; Found 412.8125.
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General procedure for 5,5’ꢀdibromination of bipyridones 14. To a suspension of
bipyridone 14a, 14c or 14d (0.289 mmol) in acetic acid (1 mL) was added AcONa (47.4 mg,
0.578 mmol). Bromine (2.5, 3.5 or 6 eq.) was slowly added and the mixture was heated at
80°C for 12h. After cooling to room temperature, the precipitate was filtered, washed with
H2O (3x5 mL), isopropanol (2x2 mL) and diethyl ether (5 mL). The white powder was finally
dried under vacuum.
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3,3',5,5'-Tetrabromo-[4,4'-bipyridine]-2,2'(1H,1'H)-dione (13f). m = 105 mg; yield = 72%.
1
M.p. > 300°C. H NMR (400 MHz, DMSO) δ 12.71 (s, 2H), 8.03 (s, 2H). 13C NMR (126
MHz, DMSO) δ 157.9, 150.1, 137.3, 115.3, 96.4. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for
C10H5Br4N2O2 500.7079; Found 500.7098.
3,3'-Dibromo-5,5'-Dichloro-[4,4'-bipyridine]-2,2'(1H,1'H)-dione (13i). m = 95 mg; yield =
1
13
79%. M.p. > 300°C. H NMR (500 MHz, DMSO) δ 12.75 (s, 2H), 8.00 (s, 2H). C NMR
(126 MHz, DMSO) δ 157.7, 147.5, 135.1, 115.3, 109.3. HRMS (ESIꢀTOF) m/z [M + H]+
Calcd for C10H5Br2Cl2N2O2 412.8089; Found 412.8112.
General procedure for 2,2’ꢀdichlorination of bipyridones 13. Bipyridone 13aꢀe (0.1 mmol)
was dissolved in DMF (1 mL). POCl3 (0.12 mL, 1.2 mmol) was added and the mixture was
heated at 110°C for 1h30. After cooling to room temperature, H2O (2 mL) was added and the
mixture was extracted with ethyl acetate (2x10 mL). The organic phase was washed with
NaHCO3 sat. and dried over MgSO4. After filtration and concentration, the product was
purified by chromatography on silica gel (cyclohexane / ethyl acetate 95/5),
hexahalobipyridines 16ꢀ20 were obtained.
2,2'-Dichloro-3,3',5,5'-tetraiodo-4,4'-bipyridine (16). m = 34 mg; yield = 47%. M.p.: 240ꢀ
242°C. 1H NMR (500 MHz, CDCl3) δ 8.77 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 92.9, 99.1,
156.60, 156.65, 162.2. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Cl2I4N2 728.5847;
Found 728.5844.
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2,2',5,5'-Tetrachloro-3,3'-diiodo-4,4'-bipyridine (17). m = 28.9 mg; yield = 53%. M. p.: 135ꢀ
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137 °C. H NMR (500 MHz, CDCl3) δ 8.49 (s, 2H). C NMR (126 MHz, CDCl3) δ 154.7,
154.0, 148.6, 128.1, 99.3. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Cl4I2N2 544.7134;
Found 544.7160.
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2,2',3,3'-Tetrachloro-5,5'-diiodo-4,4'-bipyridine (18). m = 26.2 mg; yield = 48%. M.p.: 151ꢀ
1
13
153°C. H NMR (500 MHz, CDCl3) δ 8.77 (s, 2H). C NMR (126 MHz, CDCl3) δ 154.7,
152.2, 150.6, 129.4, 94.1. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Cl4I2N2 544.7134;
Found 544.7160.
5,5'-Dibromo-2,2',3,3'-tetrachloro-4,4'-bipyridine (19). m = 27.6 mg; yield = 61%. M.p.: 93ꢀ
1
95°C. H NMR (500 MHz, CDCl3) δ 8.58 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 150.6,
147.6, 146.9, 129.3, 120.9. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Br2Cl4N2
448.7412; Found 448.7371.
5,5'-Dibromo-2,2'-dichloro-3,3'-diiodo-4,4'-bipyridine (20). m = 26 mg; yield = 41%. M.p.:
1
135ꢀ137°C. H NMR (500 MHz, CDCl3) δ 8.59 (s, 2H). 13C NMR (126 MHz, CDCl3) δ
157.0, 155.4, 151.1, 117.6, 99.4. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Br2Cl2I2N2
632.6124; Found 632.6108.
General procedure for 2,2’ꢀdibromination of bipyridones 13. A suspension of bipyridone
13aꢀe (0.2 mmol) in PBr3 (1 mL) was heated at 180°C for 6h. After cooling to room
temperature, the mixture was dropped over iceꢀwater (50 mL) and treated with NaOH 10M
until pH 12. The mixture was extracted with dichloromethane (2x20 mL), dried over MgSO4,
filtered and concentrated. After chromatography on silica gel (cyclohexane / ethyl acetate
95/5), hexahalobipyridines 21ꢀ25 were obtained.
2,2'-Dibromo-3,3',5,5'-tetraiodo-4,4'-bipyridine (21). m = 76.7 mg; yield = 53%. M.p.: 208ꢀ
1
13
210°C. H NMR (300 MHz, CDCl3) δ 8.73 (s, 2H). C NMR (126 MHz, CDCl3) δ 162.0,
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156.6, 150.0, 103.5, 93.6. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Br2I4N2 816.4836;
Found 816.4808.
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2,2'-Dibromo-5,5'-dichloro-3,3'-diiodo-4,4'-bipyridine (22). m = 44.4 mg; yield = 35%. M. p.:
9
1
160ꢀ162°C. H NMR (500 MHz, CDCl3) δ 8.47 (s, 2H). 13C NMR (126 MHz, CDCl3) δ
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154.0, 148.8, 148.0, 128.6, 103.7. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for
C10H3Cl2Br2I2N2 632.6124; Found 632.6125.
2,2'-Dibromo-3,3'-dichloro-5,5'-diiodo-4,4'-bipyridine (23). m = 34.3 mg; yield = 27%. M.p.:
1
152ꢀ154°C. H NMR (500 MHz, CDCl3) δ 8.72 (s, 2H). 13C NMR (126 MHz, CDCl3) δ
155.0, 151.7, 142.8, 131.9, 94.8. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Cl2Br2I2N2
632.6124; Found 632.6162.
2,2',5,5'-Tetrabromo-3,3'-dichloro-4,4'-bipyridine (24). m = 61.6 mg; yield = 57%. M.p.: 168ꢀ
1
13
170°C. H NMR (500 MHz, CDCl3) δ 8.56 (s, 2H). C NMR (126 MHz, CDCl3) δ 149.7,
145.7, 141.6, 132.5, 119.8. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Br4Cl2N2
536.6401; Found 536.6393.
2,2',5,5'-Tetrabromo-3,3'-diiodo-4,4'-bipyridine (25). m = 36.2 mg; yield = 25%. M.p.: 188ꢀ
1
13
190°C. H NMR (500 MHz, CDCl3) δ 8.58 (s, 2H). C NMR (126 MHz, CDCl3) δ 157.0,
151.3, 148.8, 118.2, 103.8. HRMS (ESIꢀTOF) m/z [M + H]+ Calcd for C10H3Br4I2N2
720.5114; Found 720.5116.
2,2',5,5'-Tetrabromo-3-iodo-4,4'-bipyridine (27b). m = 17.9 mg; yield = 15%. M.p.: 170ꢀ
13
172°C. 1H NMR (500 MHz, CDCl3) δ 8.66 (s, 1H), 8.56 (s, 1H), 7.24 (s, 1H). C NMR (126
MHz, CDCl3) δ 153.0, 152.9, 152.85, 150.8, 148.7, 141.1, 128.0, 119.4, 118.3, 104.2. HRMS
(ESIꢀTOF) m/z [M + H]+ Calcd for C10H4Br4IN2 594.6147; Found 594.6144.
General procedure for 2,2’ꢀdiiodination of 2,2’ꢀdibromoꢀ3,3’,5,5’ꢀtetrahaloꢀ4,4’ꢀ
bipyridines: synthesis of bipyridines 28ꢀ36. In a dry Schlenk tube were placed 2,2’ꢀ
dibromoꢀterahaloꢀ4,4’ꢀbipyridine (0.1 mmol), NaI (60 mg, 0.4 mmol), CuI (3.8 mg, 0.02
29
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