Lithiation of prochiral 2,2′-dichloro-5,5′-dibromo-4,4′- bipyridine as a tool for the synthesis of chiral polyhalogenated 4,4′-bipyridines

Article abstract of DOI:10.1021/jo401255q

Lithiation of the achiral tetrahalogenated 4,4′-bipyridine 1 with alkyllithiums was investigated. n-BuLi was found to induce either the chlorine-directed deprotolithiation reaction alone or with a concomitant halogen-lithium exchange furnishing after iodine trapping chiral 4,4′-bipyridines 2 and 6, respectively. The role of n-BuLi in the deprotolithiation process of 1 was elucidated on the basis of isolated secondary derivatives. After deprotolithiation, the lithiated species could be trapped by different electrophiles such as MeI, TMSCl, MeSSMe, R₃SnCl (R = Me or n-Bu), and PPh₂Cl. Moreover, 4,4′-bipyridine 2 was submitted to cross-coupling reactions (Suzuki and Sonogashira) which occurred selectively at the carbon-iodine bond. All compounds of this new family of atropisomeric 4,4′-bipyridines were separated by chiral HPLC (high-performance liquid chromatography), and the absolute configurations of obtained enantiomers were mainly assigned by XRD (X-ray diffraction) using anomalous dispersion.

Full text of DOI:10.1021/jo401255q

Article
pubs.acs.org/joc
Lithiation of Prochiral 2,2′-Dichloro-5,5′-dibromo-4,4′-bipyridine as a
Tool for the Synthesis of Chiral Polyhalogenated 4,4′-Bipyridines
Victor Mamane,*,† Emmanuel Aubert,‡ Paola Peluso,§ and Sergio Cossu∥
‡
†Laboratoire SRSMC UMR CNRS 7565 and Laboratoire CRM2 UMR CNRS 7036, Universite
Vandoeuvre-les-Nancy, France
́
de Lorraine, 54506
§Istituto di Chimica Biomolecolare ICB CNR, UOS di Sassari, 07100 Sassari, Italy
∥Dipartimento di Scienze Molecolari e Nanosistemi, Universita
̀
Ca’ Foscari di Venezia, 30123 Venezia, Italy
S
* Supporting Information
ABSTRACT: Lithiation of the achiral tetrahalogenated 4,4′-
bipyridine 1 with alkyllithiums was investigated. n-BuLi was
found to induce either the chlorine-directed deprotolithiation
reaction alone or with a concomitant halogen−lithium
exchange furnishing after iodine trapping chiral 4,4′-
bipyridines 2 and 6, respectively. The role of n-BuLi in the
deprotolithiation process of 1 was elucidated on the basis of
isolated secondary derivatives. After deprotolithiation, the
lithiated species could be trapped by different electrophiles such as MeI, TMSCl, MeSSMe, R3SnCl (R = Me or n-Bu), and
PPh2Cl. Moreover, 4,4′-bipyridine 2 was submitted to cross-coupling reactions (Suzuki and Sonogashira) which occurred
selectively at the carbon−iodine bond. All compounds of this new family of atropisomeric 4,4′-bipyridines were separated by
chiral HPLC (high-performance liquid chromatography), and the absolute configurations of obtained enantiomers were mainly
assigned by XRD (X-ray diffraction) using anomalous dispersion.
INTRODUCTION
■
The 4,4′-bipyridine framework represents an important
synthetic intermediate for the preparation of viologens,1 liquid
crystals,2,3 and polyheterocyclic compounds4,5 and can serve as
a target for biological systems.6,7 More importantly, 4,4′-
bipyridine ligands play a key role in the design of metal organic
frameworks (MOFs),8 which represent promising nano- or
microporous materials with various potential applications.9
Specifically, homochiral MOFs have found some applications in
enantioselective separation10 and heterogeneous asymmetric
catalysis.11,12 Among the different routes to prepare homochiral
MOFs, the direct approach based on chiral bridging ligands is
the more promising, and many improvements have still to be
carried out. In this regard, the development of easily accessible
chiral atropisomeric 4,4′-bipyridine ligands represents an
important step toward the design of novel homochiral MOFs.
Atropisomeric 4,4′-bipyridines are very rare in the literature
compared to their biphenyl analogues,13 and two examples have
been only recently described. In 2008, Schalley et al. have
reported the synthesis of 3,3′-dimethyl-5,5′-disubstituted-4,4′-
bipyridines starting from 3,3′,5,5′-tetramethyl-4,4′-bipyridine.14
In 2012, our group widened the family of 3,3′,5,5′-
tetrasubstituted-4,4′-bipyridines by using a chiral tetrahalo-
genated 4,4′-bipyridine as the key starting material (Figure
1).15,16
Figure 1. Atropisomeric 4,4′-bipyridines described in the literature.
liquid chromatography (HPLC) using immobilized polysac-
charide-based chiral stationary phases, and the absolute
configurations were determined by X-ray diffraction (XRD)
and by correlation with the HPLC elution order of similar
enantiomers of known absolute configuration.
Herein, we report new chiral configurationally stable 4,4′-
bipyridines based on the directed deprotolithiation of
tetrahalogenated achiral 4,4′-bipyridine 1 in the presence of
n-BuLi. The enantiomers were separated by high-performance
Received: June 13, 2013
© XXXX American Chemical Society
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RESULTS AND DISCUSSION
Scheme 1. Reactivity of 1 in the Presence of LDA
■
Recently we observed that the presence of halogen atoms of
different nature offers the possibility to selectively tune the
reactivity of the 4,4′-bipyridine system.15 In the case of 3,3′-
diodo-5,5′-dibromo-4,4′-bipyridine, the iodine acts as a
regioselective modulator in cross-coupling processes under
Suzuki and Sonogashira reaction conditions leading to the
corresponding 3,3′-disubstituted-5,5′-dibromo-4,4′-bipyridines.
The substituents surrounding the chiral axis make the chiral
4,4′-bipyridine conformationally stable, and importantly, the
surviving halogen moiety is suitable for further selective
transformations, thus opening the way to more complex and
interesting structures. Aimed at extending the potential of the
4,4′-bipyridine system, a new molecular platform suitable for
access to a new family of chiral polyhalogenated 4,4′-
bipyridines starting from 2,2′-dichloro-5,5′-dibromo-4,4′-bipyr-
idine 1 was envisaged. In this particular case, the presence of a
substituent at the 2-position is worthy of special interest
because it allows steric and electronic control of the nitrogen
sites.
1
both the GC−MS and H NMR analyses revealed that, along
with the desired product 2, several regioisomeric bipyridine
derivatives arising from competitive reaction pathways were
present in the reaction mixture (Figure 3).
The synthetic strategy we conceived is based on the
monofunctionalization at the 3-position of 1 through a
metalation−electrophilic trapping sequence. It is worth noting
that compound 1 containing hydrogen substituents at the 3-
and 3′-positions possesses a low energy barrier to rotation
around the 4,4′ axis; the formation of rotational conformers
(atropisomers) is thus avoided, and the 4,4′ axis does not
represent a chiral axis. In contrast, bulky substituents at the 3-
position induce a higher energy barrier to rotation around the
4,4′ axis leading to molecular chirality (Figure 2).
Figure 3. Other bipyridines observed during the lithiation of 1.
Table 1 compiles the most representative results made in
order to optimize the formation of 2. Importantly, among the
Table 1. Reactivity of 1 in the Presence of Alkyllithium
a
Bases
base (n equiv),
T (°C)
1
5
entry
(%)
2 (%)
27
4 (%)
31
(%)
6 (%)
1
2
3
4
5
6
7
8
t-BuLi (1.2), −78
s-BuLi (1.2), −78
n-BuLi (1.2), −78
n-BuLi (1.2), −95 15
n-BuLi (1.0), −78 15
n-BuLi (1.0), −70
n-BuLi (0.8), −70 29
n-BuLi (0.8),
−60
25
63
6
17
12
38
47
35
33
30
10
0
5
20
0
29
12
15
5
21
12
36
11
3
Figure 2. New family of chiral 4,4′-bipyridines.
3
28
20
16
0
24
17
10
55 (41)
25 (20)
0
The nature of the heteroaromatic aza-rings of 1 suggests an
unpredictable reactivity arising from the presence of
halogenated substituents linked at the 2,2′ and 5,5′ positions,
which can both competitively drive the reactivity of the
aromatic ring due to different mesomeric and inductive effects.
Consequently, for the monofunctionalization of the 3-position,
we first considered in detail the behavior of 1 toward metalation
processes promoted by lithium reagents.17 Taking into account
that lithium diisopropylamide (LDA) is well-known to promote
the directed deprotometalation of halopyridines avoiding
lithium−halogen exchange, the reactivity of 1 toward this
reagent was explored by quenching the lithium derivative with
I2, which leads to the formation of an inseparable mixture of 2
and 3 in a 3:1 ratio as the result of the competitive metalation
involving positions 3 and 6 of 1 (Scheme 1).
Polyhalogenopyridines can also be deprotonated by
alkyllithium compounds,14 even in the presence of bromine
atoms.18,19 Therefore, t-BuLi, s-BuLi, and n-BuLi were tested at
different temperatures and base concentrations in order to carry
out the deprotolithiation of 1. The results of these experiments
were evaluated through the analysis of the crude reaction
mixtures after trapping of the intermediates with I2. In all cases,
9
n-BuLi (0.8), −50
0
64 (15)
28
8
0
10 n-BuLi (1.4),
−60
11
0
0
33 (22)
9
58 (36)
b
n-BuLi (1.6), −60
0
6
0
26
46
10
0
37
12
−78, slow
48 (28)
0
addition
13 PhLi (0.8), −78,
15
56 (40)
22
7
slow addition
a
b
THF was used as the solvent in all experiments. 27% of
nonidentified products.
secondary compounds shown in Figure 3, we were delighted to
observe the formation of dissymmetric 5-bromo-2,2′-dichloro-
3,5′-diiodo-4,4′-bipyridine 6 deciding also to improve its
formation. Starting from 1, compounds 47 and 5a−c arise
from bromine−lithium exchanges, whereas bipyridine 6 is the
result of both a lithiation and bromine−lithium exchange. Such
dual reactivity of organolithium compounds in the same pot
was already observed with 2,4,6-triphenylbromobenzene20 and
4,4′-dibromo-3,3′-bithiophene.21
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Among the three alkyllithium bases which were compared
under the same reaction conditions (−78 °C, 1.2 equiv of
alkyllithium, entries 1−3, Table 1), n-BuLi gave the best
conversion (entry 3). Although the formation of 2 was
comparable by using t-BuLi and n-BuLi (compare entries 1
and 3), the latter was chosen for a further optimization study
and, in addition, in order to evaluate the formation of
bipyridine 6 which was exclusively observed carrying out the
reaction in the presence of this base (entry 3, Table 1). This
product can be almost completely avoided by decreasing the
temperature (entry 4) or by using only 1 equiv of n-BuLi (entry
5). The conversion was, however, lower in these two last cases.
More importantly, decreasing the temperature caused an
increase of the bromine−lithium exchange products 5 (entry
4). Increasing the temperature to −70 °C has the reverse effect,
but the formation of 6 became high (entry 6). Decreasing again
the amount of n-BuLi to 0.8 equiv allowed the complete
disappearance of 6 but with lower conversion (entry 7). Finally,
it was found that 0.8 equiv of n-BuLi at −60 °C were the best
conditions to achieve a good conversion with no formation of 6
(entry 8). In this case, bipyridine 2 could be isolated with 41%
yield. Increasing the temperature to −50 °C caused degradation
as shown by the lower yield of 15% (entry 9). It is worth noting
that under conditions of entry 8, the amount of 4 was the same
independently of the quantity of I2 added at the end of the
reaction. It is probable that this compound is formed during the
lithiation step (vide infra). Bipyridine 6 could be obtained
selectively by increasing the amount of n-BuLi. The best result
was obtained with 1.4 equiv of n-BuLi (entry 10) and higher
amount resulted in the formation of other secondary products
(entry 11). Under conditions of entry 10, the chiral bipyridine
6 was isolated with 36% yield and the amount of 2 was almost
unchanged compared to entry 8. The reaction could be
performed at −78 °C by slow addition (30 min) of 0.8 equiv of
n-BuLi, but the amount of compound 4 increased (entry 12).
Substitution of n-BuLi by PhLi could maintain the formation of
4 at a low level (entry 13), and the yield of 2 was comparable to
entry 8.
bromine−lithium exchange is faster at −60 °C probably
because the steric hindrance around the C4 − C4′ bond is
higher in 1 than in Bipy_Br1Li1. Moreover, the influence of the
negative charge for the second bromine−lithium exchange is
negligible due to the independent nature of the two pyridine
parts. Bipy_Li2 (0.3 equiv) can then react with the remaining
amount of 1 to give Bipy_Br2Li and 4 in a 2:1 ratio.22 This
deprotolithiation step is slow below −78 °C while it is fast
above −60 °C. During the final step of the reaction,
Bipy_Br2Li as well as unreacted Bipy_Li2 (0.1 equiv) can
react with I2 furnishing 2 and 5c, respectively. When 1.4 equiv
of n-BuLi is used, the excess (0.6 equiv) can react with
Bipy_Br2Li to give Bipy_BrLi2 which, after quenching with I2,
generates 6. This result indicates that the sequence 1 to
Bipy_Br2Li through Bipy_Li2 is very fast. According to this
mechanism, 2 and 6 cannot exceed 60% in yield. During the
slow addition of n-BuLi at −78 °C (entry 12), the higher
amount of 4 can be explained taking into account the reaction
between Bipy_Li2 and n-BuBr (formed by lithium−bromine
exchange from 1 and n-BuLi) with concomitant formation of
butene and LiBr. This reaction is not allowed with PhBr formed
after lithium−bromine exchange between Bipy_Li2 and PhLi
(entry 13); therefore, the amount of 4 remains unchanged
compared to entry 8.
Under the best reaction conditions (0.8 equiv of n-BuLi, −60
°C) previously established, a family of chiral compounds was
obtained by the deprotolithiation of 1. It was observed that
different electrophiles reacted smoothly thus providing the way
to the direct access to racemic 3-substituted 5,5′-dibromo-2,2′-
dichloro-4,4′-bipyridines 7 (Table 2). Chiral 4,4′-bipyridines 7
Table 2. Electrophile Scope after Deprotolithiation of 1
On the basis of our observations, a rationalization can be
proposed as follows (Scheme 2). Bipyridine 1 reacts rapidly
with n-BuLi in bromine−metal exchange reiterated process to
produce Bipy_Br1Li1 and, in turn, Bipy_Li2. The second
electrophile
product
yield (%)
MeI
7a (R = Me)
46
32
53
33
45
46
MeSSMe
ClSiMe3
ClSnMe3
ClSnBu3
ClPPh2
7b (R = SMe)
7c (R = SiMe3)
7d (R = SnMe3)
7e (R = SnBu3)
7f (R = POPh2)
Scheme 2. Proposed Mechanism for the Formation of 2 and
6
a
a
The product was oxidized during the purification on silica gel.
bearing alkyl, sulfur, silyl, stannyl, and phosphine functional
groups were isolated in the reported yields. In this context, it is
important to remember that due to the particular reaction
pathway here operative, the process cannot exceed 60% in the
overall yield. In the case of 7f, the phosphine group underwent
spontaneous oxidation during the chromatographic treatment
on silica gel. In all cases, bipyridine 4 was formed with
approximately 20% yield.
Having at disposal chiral compound 2, a different family of
chiral 4,4′-bipyridines derivatives was obtained by cross-
coupling 2 with a series of boronic acids and phenylacetylene
(Scheme 3). The Suzuki reaction was performed under
standard conditions with 1.2 equiv of either phenyl-, 4-
methoxyphenyl-, 4-(methylthio)phenyl-, or 4-pyridylboronic
acid to give the desired bipyridines 8 in 46 to 78% yields
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crystal packing of these two compounds is characterized by
numbers of halogen···Lewis base and halogen···halogen
interactions. For example, in 2 a cyclic I,Br···N motif binds
the two crystallographic independent molecules (Br1···N19 =
3.083 Å; C5Br1···N19 = 175.9°; I2···N7 = 3.070 Å; C15
I2···N7 = 176.0°) with the σ-hole of the halogen atoms
pointing toward the nitrogen atoms of a neighboring molecule
(Figure 4).
Scheme 3. Cross-Coupling Reactions of 2
(Scheme 3). Concerning the Sonogashira coupling, the
overcoupling products have been limited by using 1.3 equiv
of phenylacetylene, thus giving bipyridine 9 in a 52% yield.
All the atropisomeric 3-substituted 5,5′-dibromo-2,2′-di-
chloro-4,4′-bipyridines23 as well as bipyridine 6 were
enantioseparated by HPLC on immobilized polysaccharide-
based chiral stationary phases, namely Chiralpak IA and
Chiralpak IC, which exhibited complementary enantiosepara-
tion properties (Table 3). For instance, 500 mg of racemic
bipyridine 2 was separated on Chiralpak IA, furnishing pure
enantiomers (>99% ee).24
Figure 4. ORTEP plots of the asymmetric unit of 2, showing the cyclic
halogen (I2, Br1)···Lewis base (N7, N19) intermolecular interaction.
Atomic displacement parameter ellipsoids set at 50% probability and
hydrogen atoms shown as sticks.
Table 3. Absolute Configurations of All 4,4′-Bipyridine
The absolute configuration determination for compounds
7a,b,f and 8b,c was not achievable by XRD because these
compounds could not be crystallized. For compounds 8b,c, the
absolute configuration was deduced from the results of the
Suzuki reaction between 4,4′-bipyridine (P)-2 and phenyl, 4-
methoxyphenyl, and 4-(methylthio)phenyl boronic acids.
Indeed, (P)-2 reacted with phenylboronic acid to give (M)-8a
demonstrating that the Suzuki coupling is completely stereo-
conservative, as observed previously in the case of 3,3′-
dibromo-5,5′-diiodo-4,4′-bipyridine.15 Therefore, under the
same conditions, we assume that (P)-2 gave (M)-8b and
(M)-8c (Scheme 4).
Atropisomers
a
absolute configuration (ee, %)
bipyridine
HPLC column
1st eluted peak
2nd eluted peak
2
Chiralpak IA
Chiralpak IA
Chiralpak IC
Chiralpak IC
Chiralpak IC
Chiralpak IC
Chiralpak IA
Chiralpak IC
Chiralpak IC
Chiralpak IC
Chiralpak IA
Chiralpak IA
P (>99)
P (>99)
M (>99)
M (>99)
M (>99)
P (>99)
M (>99)
M (>99)
M (>99)
M (>99)
M (>99)
M (>99)
M (>99)
M (>99)
M (>99)
M (>99)
P (>99)
M (>99)
P (99)
6
7a
7b
7c
7d
7f
8a
8b
8c
8d
9
P (>99)
P (>99)
P (>99)
P (>99)
P (99)
Scheme 4. Stereoconservative Coupling of (P)-2
a
The assignment of the reported absolute configurations were
achieved by XRD for 2, 6, 7c,d, 8a, and 9 and by correlation from
HPLC data for 7a,b,f and 8b,c.
Compared to 3,3′,5,5′-tetrasubstitued-4,4′-bipyridines,15 the
new 4,4′-bipyridines showed much lower signals in electronic
circular dichroism (ECD) rendering the absolute configuration
determination very problematic by this method (coupled with
time-dependent density functional theory calculations). How-
ever, in several cases, single crystals were obtained and the
absolute configuration could be assigned by single-crystal XRD
with the help of anomalous dispersion (Table 3 and Supporting
Information).25 For 4,4′-bipyridines 2 and 6, in addition to the
absolute configuration determination, XRD was helpful in order
to unambiguously assign their structure (Figures S1 and S2 in
Supporting Information). Due to the presence of a high
number of halogen atoms substituent on the bipyridyl rings, the
Finally, for compounds 7a,b,f, the absolute configuration was
determined by correlation with the HPLC elution order of the
similar compounds 2, 6, 7c,d, 8a,d, and 9 of known absolute
configuration (see discussion in the Supporting Information).
CONCLUSION
■
We have developed an efficient way to prepare chiral
polyhalogenated 4,4′-bipyridines through a directed deprotoli-
thiation reaction of a symmetrical prochiral 4,4′-bipyridine and
subsequent reaction with a large set of electrophiles.
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507 (M, 25), 429 (M − Br, 100), 381 (M − I, 23), 302 (M − Br − I,
30); HRMS calcd for C10H4Br2Cl2IN2 (M + H) 506.7157, found
506.7159.
Unexpectedly, n-BuLi can drive either the deprotolithiation
process alone or the simultaneous deprotolithiation and
bromine−lithium exchange. However, a deep analysis of
product distribution has revealed that n-BuLi was not directly
involved in the deprotolithiation process. Probably n-BuLi first
performs bromine−lithium exchange reactions with 1 to
generate a dilithiated species which is proposed to be the key
intermediate in the deprotolithiation reaction. Once the first
lithiated species is formed, further bromine−lithium exchange
can occur. After trapping with iodine, the mono- and dilithiated
species give access to chiral pentahalogenated 4,4′-bipyridines
which represent valuable intermediates for the preparation of
functionalized chiral derivatives through cross-coupling reac-
tions. For instance, bipyridine 2 bearing only one iodine atom
was successfully functionalized through Suzuki and Sonogashira
couplings. All the reported 4,4′-bipyridines could be
enantioseparated by HPLC and the absolute configurations of
the obtained enantiomers were assigned by means of XRD and
comparative HPLC elution. The asymmetric versions of the
reported lithiation reactions and the reactivity of bipyridine 6
are under investigation and will be reported in due course.
1
2,2′-Dichloro-4,4′-bipyridinyl (4): mp 238−240 °C; H NMR
(CDCl3, 200 MHz) δ = 7.43 (dd, J = 5.2, 1.4 Hz, 2H), 7.56 (d, J = 1.4
Hz, 2H), 8.54 (d, J = 5.2 Hz, 2H) ppm; 13C NMR (CDCl3, 50 MHz) δ
= 120.2, 122.1, 147.4, 150.7, 152.8 ppm; MS (ESI) m/z 224 (M,
100%), 189 (M − Cl, 65), 153 (M − Cl2, 50), 302.
Lithiation Procedure of 1 with 0.8 equiv of PhLi (Table 1,
Entry 13). Bipyridine 1 (1 mmol, 383 mg) in THF (4 mL) was cooled
to −78 °C. PhLi (1.8 M in n-Bu2O, 0.8 mmol, 0.45 mL) was added
slowly during 30 min, and the mixture was stirred at −78 °C for 30
min. After the mixture was cooled to −78 °C, I2 (1 mmol, 254 mg) in
THF (1 mL) was added dropwise, and the temperature was raised to
ambient. A saturated aqueous solution of Na2S2O3 (1 mL) was added,
and the mixture was extracted with dichloromethane (2 × 20 mL).
The organic phases were combined, washed with brine, and dried over
MgSO4. After concentration, the mixture was purified by chromatog-
raphy on silica gel (eluent: cyclohexane/ethyl acetate 95/5) to give 2
as a white solid (204 mg, 40%).
Lithiation Procedure of 1 with 1.4 equiv of n-BuLi (Table 1,
Entry 10): Formation of 6. Bipyridine 1 (0.5 mmol, 192.5 mg) in
THF (2 mL) was cooled to −60 °C. n-BuLi (1.3 M in hexanes, 0.7
mmol, 0.54 mL) was added dropwise during 10 min, and the mixture
was stirred at −60 °C for 15 min. After being cooled to −78 °C, I2 (1
mmol, 254 mg) in THF (1 mL) was added dropwise, and the
temperature was raised to ambient. A saturated aqueous solution of
Na2S2O3 (1 mL) was added and the mixture was extracted with
dichloromethane (2 × 15 mL). The organic phases were combined,
washed with brine and dried over MgSO4. After concentration, the
mixture was purified by chromatography on silica gel (eluent:
cyclohexane/ethyl acetate 95/5) to give 6 as a white solid (100 mg,
36%).
EXPERIMENTAL SECTION
■
General Experimental Methods. All reactions were performed
under an atmosphere of argon in oven-dried glassware. Tetrahy-
drofuran (THF) was distilled over sodium/benzophenone and stored
over sodium. All other solvents and reagents were used as received.
TLC was performed on silica gel plates and visualized with a UV lamp
(254 nm). Chromatography was performed on silica gel (70−230
mesh). All melting points were uncorrected. The H and 13C NMR
1
5-Bromo-2,2′-dichloro-3,5′-iodo-4,4′-bipyridinyl (6): mp
spectra were recorded at 200 and 50 MHz, respectively. Chemical
shifts are quoted in parts per million (ppm) downfield of
tetramethylsilane. Coupling constants J are quoted in hertz. Mass
spectra were recorded using EI at 70 eV and high resolution mass
spectra were recorded using APCI.
For chiral HPLC analyses, a high-pressure binary gradient system
equipped with a diode-array detector operating at 254 (220, 280) nm
and a 20 μL sample loop was employed. Chiralpak IA (amylose tris-
3,5-dimethylphenylcarbamate) and Chiralpak IC (cellulose tris-3,5-
dichlorophenylcarbamate) (250 × 4.6 mm) (5 μm) were used as chiral
columns. HPLC-grade solvents were purchased and used as received.
Analyses were performed in isocratic mode. Normal phase was used as
elution mode, at 22 °C.
Crystal structures of bipyridines 2 (first eluted peak), 6 (first eluted
peak), 7c (first eluted peak), 7d (second eluted peak), 8a (first eluted
peak), 8d (first eluted peak), and 9 (first eluted peak) were
determined by single-crystal X-ray diffraction using either Mo or Cu
Kα radiations (Supernova Dual source diffractometer, Agilent
Technologies) at low temperature (T = 110 K).
Lithiation Procedure of 1 with 0.8 equiv of n-BuLi (Table 1,
entry 8): Formation of 2 and 4. Bipyridine 1 (1.38 mmol, 530 mg)
in THF (5.5 mL) was cooled to −60 °C. n-BuLi (1.3 M in hexanes, 1.1
mmol, 0.85 mL) was added dropwise, and the mixture was stirred at
−60 °C for 15 min. After the mixture was cooled to −78 °C, I2 (1.38
mmol, 351 mg) in THF (1.4 mL) was added dropwise and the
temperature was raised to ambient. A saturated aqueous solution of
Na2S2O3 (1 mL) was added, and the mixture was extracted with
dichloromethane (2 × 25 mL). The organic phases were combined,
washed with brine, and dried over MgSO4. After concentration, the
mixture was purified by chromatography on silica gel (eluent:
cyclohexane/ethyl acetate 95/5) to give 2 as a white solid (290 mg,
41%). Increasing gradually the eluent ratio to 1/1 furnished 4 as a
white solid (62 mg, 20%).
1
162−164 °C; H NMR (CDCl3, 200 MHz) δ = 7.10 (d, J = 0.4 Hz,
1H), 8.57 (s, 1H), 8.87 (d, J = 0.4 Hz, 1H) ppm; 13C NMR (CDCl3,
50 MHz) δ = 93.8, 99.7, 117.6, 124.1, 150.6, 152.1, 155.2, 155.3, 156.5,
157.8 ppm; MS (ESI) m/z 555 (M, 30), 429 (M − I, 100), 348 (M −
Br − I, 10), 302 (M − I2, 15); HRMS calcd for C10H4BrCl2I2N2 (M +
H) 554.7019, found 554.7042.
Typical Procedure for the Preparation of 7. Bipyridine 1 (0.5
mmol, 192.5 mg) in THF (2 mL) was cooled to −60 °C. n-BuLi (1.3
M in hexanes, 0.4 mmol, 0.3 mL) was added dropwise, and the mixture
was stirred at −60 °C for 15 min. After being cooled to −78 °C,
electrophile (1 mmol) in THF (0.5 mL) was added dropwise and the
temperature was raised to ambient. Water (1 mL) was added and the
mixture was extracted with dichloromethane (2 × 15 mL). The
organic phases were combined, washed with brine, and dried over
MgSO4. After concentration, the mixture was purified by chromatog-
raphy on silica gel (eluent: cyclohexane/ethyl acetate 9/1 except for
7f: 3/1) to give 7.
5,5′-Dibromo-2,2′-dichloro-3-methyl-4,4′-bipyridinyl (7a):
1
mp 76−78 °C; H NMR (CDCl3, 200 MHz) δ = 2.15 (s, 3H), 7.14
(s, 1H), 8.51 (s, 1H), 8.68 (s, 1H) ppm; 13C NMR (CDCl3, 50 MHz)
δ = 17.9, 119.0, 119.1, 124.6, 132.0, 147.2, 148.7, 149.1, 151.0, 151.3,
152.3 ppm; MS (ESI) m/z 396 (M, 100), 317 (M − Br, 35), 279 (M
− Br − Cl, 16), 236 (M − Br2, 20), 200 (M − Br2 − Cl, 30); HRMS
calcd for C11H7Br2Cl2N2 (M + H) 394.8348, found 394.8356.
5,5′-Dibromo-2,2′-dichloro-3-(methylthio)-4,4′-bipyridinyl
1
(7b): mp 88−90 °C; H NMR (CDCl3, 200 MHz) δ = 2.38 (s, 3H),
7.11 (s, 1H), 8.59 (s, 1H), 8.66 (s, 1H) ppm; 13C NMR (CDCl3, 50
MHz) δ = 18.4, 118.9, 119.0, 124.5, 133.0, 149.7, 150.6, 150.65, 151.9,
152.3, 155.6 ppm; MS (ESI) m/z 349 (M − Br, 100), 334 (M − Br −
CH3, 65); HRMS calcd for C11H7Br2Cl2N2S (M + H) 426.8068, found
426.8056.
5,5′-Dibromo-2,2′-dichloro-3-trimethylsilyl-4,4′-bipyridinyl
(7c): mp 116−118 °C; 1H NMR (CDCl3, 200 MHz) δ = 0.12 (s, 9H),
7.12 (s, 1H), 8.58 (s, 1H), 8.60 (s, 1H) ppm; 13C NMR (CDCl3, 50
MHz) δ = 0.8, 120.35, 120.4, 125.3, 135.1, 150.4, 150.8, 151.6, 151.7,
153.2, 156.7 ppm; MS (ESI) m/z 439 (M − CH3, 75), 403 (M − Cl −
5,5′-Dibromo-2,2′-dichloro-3-iodo-4,4′-bipyridinyl (2): mp
1
164−166 °C; H NMR (CDCl3, 200 MHz) δ = 7.11 (s, 1H), 8.57
(s, 1H), 8.68 (s, 1H) ppm; 13C NMR (CDCl3, 50 MHz) δ = 99.5,
117.5, 118.5, 124.3, 150.5, 152.4, 153.1, 155.0 ppm; MS (ESI) m/z
E
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CH3, 55), 73 (Si(CH3)3, 100); HRMS calcd for C13H13Br2Cl2N2Si (M
+ H) 452.8586, found 452.8618.
cooled to room temperature, the mixture was extracted with ethyl
acetate and dried over MgSO4. After concentration, the residue was
purified by chromatography on silica gel (cyclohexane/ethyl acetate 3/
5,5′-Dibromo-2,2′-dichloro-3-(trimethylstannanyl)-4,4′-bi-
1
1
pyridinyl (7d): mp 100−102 °C; H NMR (CDCl3, 200 MHz) δ =
1) to give bipyridine 8d (42 mg, 46%): mp 218−220 °C; H NMR
0.11 (m, J(1H−119Sn) = 56.8 Hz, J(1H−117Sn) = 54.8 Hz, 9H), 7.13 (s,
1H), 8.52 (s, 1H), 8.62 (s, 1H) ppm; 13C NMR (CDCl3, 50 MHz) δ =
−6.1, 119.8, 120.0, 125.2, 140.1, 150.65, 150.7, 151.6, 152.0, 155.0,
157.8 ppm; MS (ESI) m/z 529 (M − CH3, 100), 164 (Sn(CH3)3, 20),
155 (50); HRMS calcd for C13H13Br2Cl2N2Sn (M + H) 544.7814,
found 544, 7801.
(CDCl3, 200 MHz) δ = 6.98 (s, 1H), 7.18 (m, 2H), 8.47 (s, 1H), 8.62
(broad s, 2H), 8.74 (s, 1H) ppm; 13C NMR (CDCl3, 50 MHz) δ =
119.0, 119.7, 123.6, 124.5, 124.8, 133.6, 143.7, 146.8, 147.7, 148.8,
149.1, 149.3, 150.5, 151.6, 152.0 ppm; MS (ESI) m/z 459 (M, 15),
380 (M − Br, 100), 344 (M − Br − Cl, 25), 302 (M − Br2 − Cl, 45);
HRMS calcd for C15H8Br2Cl2N3 (M + H) 475.8457, found 457.8480.
5,5′-Dibromo-2,2′-dichloro-3-phenylethynyl-4,4′-bipyridin-
yl (9). An oven-dried resealable 10-mL tube equipped with a magnetic
stir bar was charged with PdCl2(PPh3)2 (7 mg, 0.01 mmol), CuI (1.9
mg, 0.01 mmol), and bipyridine 2 (50.9 mg, 0.1 mmol). The tube was
capped, evacuated, and backfilled with argon (with a needle). A
degassed solution of phenylacetylene (13.3 mg, 0.13 mmol) in dry
triethylamine (1 mL) was added, and the mixture was heated at 70 °C
for 12h. The reaction mixture was then allowed to cool to room
temperature, extracted with ethyl acetate, and concentrated.
Purification by column chromatography on silica gel (cyclohexane/
ethyl acetate 9/1) gave bipyridine 9 (25 mg, 52%): mp 119−121 °C;
1H NMR (CDCl3, 200 MHz) δ = 7.16−7.24 (m, 2H), 7.28−7.39 (m,
5,5′-Dibromo-2,2′-dichloro-3-(tributylstannanyl)-4,4′-bipyri-
1
dinyl (7e): H NMR (CDCl3, 200 MHz) δ = 0.70−0.90 (m, 15H),
1.10−1.50 (m, 12H), 7.06 (s, 1H), 8.50 (s, 1H), 8.61 (s, 1H) ppm;
13C NMR (CDCl3, 50 MHz) δ = 12.0, 13.5, 27.0, 28.7, 119.8, 120.1,
125.2, 140.9, 150.7, 151.1, 151.3, 151.8, 155.4, 158.0 ppm; MS (ESI)
m/z 615 (M − C4H9, 35), 429 (M − (C4H9)2, 25), 57 (C4H9, 100);
HRMS calcd for C22H31Br2Cl2IN2Sn (M + H) 670.9224, found
670.9251.
5,5′-Dibromo-2,2′-dichloro-3-(diphenylphosphinoyl)-4,4′-
bipyridinyl (7f): mp 105−107 °C; 1H NMR (CDCl3, 200 MHz) δ =
6.89 (s, 1H), 7.40−7.80 (m, 10H), 8.44 (s, 1H), 8.80 (d, J(1H−31P) =
1.6 Hz, 1H) ppm; 13C NMR (CDCl3, 50 MHz) δ = 119.8, 122.4 (J =
6.5 Hz), 124.3, 128.6 (J = 13.2 Hz), 128.8 (J = 12.8), 129.8, 129.8,
131.0 (J = 80.4 Hz), 131.7 (8.0 Hz), 131.9 (J = 8.4 Hz), 132.5 (J = 2.9
Hz), 132.7 (J = 2.9 Hz), 149.1 (J = 2.9 Hz), 149.8, 151.0, 152.7 (J =
6.4 Hz), 152.7 (J = 6.4 Hz), 153.5 (J = 6.2 Hz), 154.2 (J = 1 Hz) ppm.
31P NMR (CDCl3, 121 MHz) δ = 26.9 ppm; MS (ESI) m/z 503 (M −
4H), 8.58 (s, 1H), 8.71 (s, 1H) ppm; 13C NMR (CDCl3, 50 MHz) δ =
81.9, 102.7, 118.3, 119.1, 121.0, 121.1, 125.0, 128.6, 129.9, 131.7,
148.6, 149.0, 150.5, 151.5, 152.1 ppm; MS (ESI) m/z 483 (M, 15%),
402 (M − Br, 100), 368 (M − Br − Cl, 20), 322 (M − Br2 − Cl, 30),
286 (M − Br2 − Cl2, 75), 252 (60), 225 (50), 99 (50); HRMS calcd
for C18H9Br2Cl2N2 (M + H) 480.8504, found 480.8487.
Crystal data for 2: C10H3Br2Cl2IN2, M = 508.74, triclinic, a =
6.8899(1) Å, b = 9.0638(1) Å, c = 11.7741(2) Å, α = 90.773(1)°, β =
101.424(1)°, γ = 111.340(1)°, V = 668.341(17) Å3, T = 110(2) K,
space group P1, Z = 2, μ(Mo Kα) = 8.750 mm−1, 65157 reflections
measured, 13261 independent reflections (Rint =0.0311). Flack
parameter =0.001(3). The final R1 values were 0.0282 (I > 2σ(I))
and 0.0289 (all data). The final wR(F2) values were 0.0711 (I > 2σ(I))
and 0.0718 (all data). The goodness of fit on F2 was 1.045. CCDC no.
CCDC 942342.
Crystal data for 6: C10H3BrCl2I2N2, M = 555.75, monoclinic, a =
26.6463(3) Å, b = 8.86220(10) Å, c = 13.57710(10) Å, β =
119.9080(10)°, V = 2779.19(5) Å3, T = 110(2) K, space group C2, Z
= 8, μ(Mo Kα) = 7.762 mm−1, 87960 reflections measured, 11433
independent reflections (Rint = 0.0254). Flack parameter = −0.001(4).
The final R1 values were 0.0152 (I > 2σ(I)) and 0.0158 (all data). The
final wR(F2) values were 0.0348 (I > 2σ(I)) and 0.0350 (all data). The
goodness of fit on F2 was 1.080. CCDC no. CCDC 942343.
Crystal data for 7c: C13H12Br2Cl2N2Si, M = 455.06, ortho-
rhombic, a = 9.3313(1) Å, b = 13.9522(1) Å, c = 25.8239(1) Å, V =
3362.07(5) Å3, T = 110(2) K, space group P212121, Z = 8, μ(Cu Kα) =
9.638 mm−1, 117489 reflections measured, 7061 independent
reflections (Rint = 0.0327). Flack parameter = 0.002(10). The final
R1 values were 0.0187 (I > 2σ(I)) and 0.0187 (all data). The final
wR(F2) values were 0.0484 (I > 2σ(I)) and 0.0484 (all data). The
goodness of fit on F2 was 1.124. CCDC no. CCDC 942344.
Crystal data for 7d: C13H12Br2Cl2N2Sn, M = 545.66,
orthorhombic, a = 9.36000(10) Å, b = 14.37080(10) Å, c =
26.1227(2) Å, V = 3513.78(5) Å3, T = 110(2) K, space group
P212121, Z = 8, μ(Cu Kα) = 19.641 mm−1, 33415 reflections measured,
7378 independent reflections (Rint = 0.0359). Flack parameter =
0.002(4). The final R1 values were 0.0302 (I > 2σ(I)) and 0.0303 (all
data). The final wR(F2) values were 0.0795 (I > 2σ(I)) and 0.0796 (all
data). The goodness of fit on F2 was 1.071. CCDC no. CCDC 942345.
Crystal data for 8a: C16H8Br2Cl2N2, M = 458.96, orthorhombic, a
= 8.6743(1) Å, b = 10.3483(1) Å, c = 17.3438(2) Å, V = 1556.85(3)
Å3, T = 110(2) K, space group P212121, Z = 4, μ(Mo Kα) = 5.544
mm−1, 24187 reflections measured, 4866 independent reflections (Rint
= 0.0182). Flack parameter = 0.000(4). The final R1 values were
0.0152 (I > 2σ(I)) and 0.0159 (all data). The final wR(F2) values were
0.0363 (I > 2σ(I)) and 0.0366 (all data). The goodness of fit on F2 was
1.070. CCDC no. CCDC 942346.
Br, 85), 387 (M − Br2 − Cl, 30), 77 (C6H5, 100); HRMS calcd for
C22H13Br2Cl2N2OP (M + H) 580.8583, found 580.8576.
Typical Procedure for the Preparation of 8a−c. To a degassed
toluene solution (1 mL) containing Pd(PPh3)4 (5.8 mg, 0.01 mmol)
and bipyridine 2 (50.9 mg, 0.1 mmol) were successively added
degassed solutions of arylboronic acid (0.12 mmol, 1.2 equiv) in
methanol (0.5 mL) and Na2CO3 (25.5 mg, 0.24 mmol) in water (0.5
mL). After heating for 12h at 100 °C, the reaction mixture was cooled
to room temperature, extracted with ethyl acetate, and dried over
MgSO4. After concentration, the residue was purified by chromatog-
raphy on silica gel to give bipyridine 8a−c.
5,5′-Dibromo-2,2′-dichloro-3-phenyl-4,4′-bipyridinyl (8a):
1
mp 225−227 °C; H NMR (CDCl3, 200 MHz) δ = 6.94 (s, 1H),
7.05−7.40 (m, 6H), 8.43 (s, 1H), 8.67 (s, 1H) ppm; 13C NMR
(CDCl3, 50 MHz) δ = 119.4, 119.5, 125.2, 128.25, 128.3, 128.6, 129.0,
129.2, 134.4, 137.0, 147.4, 148.8, 150.1, 150.4, 150.5, 151.7 ppm; MS
(ESI) m/z 458 (M, 25), 429 (M − Br − Cl, 70), 262 (M − Br2 − Cl,
100), 227 (M − Br2 − Cl2, 40); HRMS calcd for C16H9Br2Cl2N2 (M +
H) 456.8504, found 456.8495.
5,5′-Dibromo-2,2′-dichloro-3-(4-methoxyphenyl)-4,4′-bipyr-
idinyl (8b): 1H NMR (CDCl3, 200 MHz) δ = 3.78 (s, 3H), 6.80 (t, J
= 9.4 Hz, 2H), 6.95 (s, 1H), 7.02 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 8.3
Hz, 1H), 8.44 (s, 1H), 8.64 (s, 1H) ppm; 13C NMR (CDCl3, 50 MHz)
δ = 55.2, 113.8, 113.9, 119.3, 125.2, 126.5, 129.7, 130.6, 136.8, 147.6,
149.0, 150.1, 151.0, 151.7, 159.7 ppm; MS (ESI) m/z 488 (M, 30),
409 (M − Br, 25), 373 (M − Br − Cl, 35), 292 (M − Br2 − Cl, 100);
HRMS calcd for C17H11Br2Cl2N2O (M + H) 486.8610, found
486.8598.
5,5′-Dibromo-2,2′-dichloro-3-(4-(methylthio)phenyl)-4,4′-
bipyridinyl (8c): 1H NMR (CDCl3, 200 MHz) δ = 2.46 (s, 3H), 6.96
(s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.12 (s, 2H), 7.16 (d, J = 8.2 Hz,
1H), 8.45 (s, 1H), 8.66 (s, 1H) ppm; 13C NMR (CDCl3, 50 MHz) δ =
15.0, 119.4, 119.45, 125.2, 125.5, 125.7, 128.8, 129.6, 130.6, 136.5,
140.3, 147.4, 148.8, 150.2, 150.4, 150.7, 151.8 ppm; MS (ESI) m/z
506 (M, 100), 471 (M − Cl, 60), 425 (M − Br, 15), 302 (M − Br −
SCH3, 60); HRMS calcd for C17H11Br2Cl2N2S (M + H) 502.8381,
found 502.8379.
5,5′-Dibromo-2,2′-dichloro-3-(4-pyridyl)-4,4′-bipyridinyl
(8d). Bipyridine 2 (120 mg, 0.2 mmol), 4-pyridineboronic acid (85%
purity, 35 mg, 0.24 mmol), and Pd(PPh3)4 (11.6 mg, 0.01 mmol) were
placed under argon. Dioxane (1.4 mL) was added, and the mixture was
stirred for 10 min. An aqueous solution of Na2CO3 (1M, 0.6 mL) was
added, and the mixture was heated under reflux for 18 h. After being
F
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Crystal data for 8d: C15H7Br2Cl2N3, M = 459.96, orthorhombic, a
= 8.4324(1) Å, b = 10.3748(1) Å, c = 17.2945(2) Å, V = 1513.00(3)
Å3, T = 110(2) K, space group P212121, Z = 4, μ(Cu Kα) = 10.036
mm−1, 15483 reflections measured, 3173 independent reflections (Rint
= 0.0316). Flack parameter = −0.012(13). The final R1 values were
0.0173 (I > 2σ(I)) and 0.0175 (all data). The final wR(F2) values were
0.0467 (I > 2σ(I)) and 0.0467 (all data). The goodness of fit on F2 was
1.092. CCDC no. CCDC 942347.
Crystal data for 9: C18H8Br2Cl2N2, M = 482.98, monoclinic, a =
7.1636(1) Å, b = 29.2923(2) Å, c = 8.4859(1) Å, β = 94.362(1)°, V =
1775.51(3) Å3, T = 110(2) K, space group P21, Z = 4, μ(Cu Kα) =
8.575 mm−1, 34991 reflections measured, 7421 independent
reflections (Rint = 0.0249). Flack parameter = 0.001(11). The final
R1 values were 0.0325 (I > 2σ(I)) and 0.0326 (all data). The final
wR(F2) values were 0.0814 (I > 2σ(I)) and 0.0815 (all data). The
goodness of fit on F2 was 1.064. CCDC no. CCDC 942348.
(16) Peluso, P.; Mamane, V.; Aubert, E.; Cossu, S. J. Chromatogr. A
2012, 1251, 91−100.
́
(17) Mongin, F.; Queguiner, G. Tetrahedron 2001, 57, 4059−5090.
(18) Pierrat, P.; Gros, P. C.; Fort, Y. Synlett 2004, 2319−2322.
(19) Abboud, M.; Mamane, V.; Aubert, E.; Lecomte, C.; Fort, Y. J.
Org. Chem. 2010, 75, 3224−3231.
(20) Jenkins, H. A; Abeysekera, D.; Dickieb, D. A.; Clyburne, J. A. C.
J. Chem. Soc., Dalton Trans. 2002, 3919−3922.
(21) Han, H.; Zhao, W.; Song, J.; Li, C.; Wang, H. J. Org. Chem.
2013, 78, 2726−2730.
(22) Such deprotonation behavior of pyridyllithium species was
already proposed to explain the formation of secondary products
during the reaction of 2,6-dibromopyridine with n-BuLi. See: Cai, D.;
Hughes, D. L.; Verhoeven, T. R. Tetrahedron Lett. 1996, 37, 2537−
2540.
(23) Except for compound 7d.
(24) Chromatographic parameters: Chiralpak IA (250 × 4.6 mm, 5
μm), n-hexane/2-propanol 95:5 as mobile phase, flow rate 0.8 mL/
min, T = 22 °C, α = 1.34, Rs = 4.0. Starting from 500 mg of rac-2
(HPLC chemical purity 85%), the HPLC multimilligram recovery led
to 194 mg of atropisomer (P)-2 (91% recovery) and 185 mg of
atropisomer (M)-2 (87% recovery). To enhance throughput, the
technique of overlapping injections was used.
ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C spectra of all compounds; X-ray structures of (P)-2,
(P)-6, (M)-7c, (M)-7d, (M)-8a, (M)-8d, and (M)-9; discussion
on the absolute configuration assignment of compounds 7a,b ,f.
This material is of charge free of charge via the Internet at
http://pubs.acs.org.
(25) Flack, H. D.; Bernardinelli, G. Chirality 2008, 20, 684−690.
AUTHOR INFORMATION
Corresponding Author
*E-mail: victor.mamane@univ-lorraine.fr.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the CNRS and Universite
Lorraine for financial support. The Service Commun de
■
́
de
́
Diffraction des rayons X-Universite de Lorraine is thanked
for providing access to crystallographic facilities.
REFERENCES
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