A study on the BF3 directed lithiation of 3-chloro- and 3-bromopyridine

Article abstract of DOI:10.1016/j.tet.2013.10.026

The BF₃-directed lithiation of 3-chloro- and 3-bromopyridine (1a and 1b, respectively) has been investigated. The reactions of 3-chloro- or 3-bromopyridine-BF₃ adduct with LDA (1.3/1.1 equiv) followed by quenching with benzaldehyde or iodine exclusively gave the C-2 substituted products. However, when 2.2 equiv of LDA and dimethyl disulfide was used, a C-6 substituted product was obtained. Dilithiation of 1a and 1b has been studied with and without the involvement of BF₃ complexation. The role of Lia?F(BF₃) interactions has been investigated by experimental and DFT calculations.

Full text of DOI:10.1016/j.tet.2013.10.026

Tetrahedron 69 (2013) 10284e10291
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A study on the BF3 directed lithiation of 3-chloro- and
3-bromopyridine
, ,
Jaspreet S. Dhau a y, Amritpal Singh a, Yoganjaneyulu Kasetti b, Sonam Bhatia b,
*
,
c
d
e
Parsad V. Bharatam b , Paula Brandao , Vítor Felix , Kamal N. Singh
*
~
ꢀ
a Department of Chemistry, Punjabi University, Patiala 147002, India
b Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S. A. S. Nagar,
160 062 Punjab, India
c Departamento de Química, CICECO, Universidade de Aveiro, Aveiro 3810-193, Portugal
d
~
ꢀ
^
ꢀ
Departamento de Química, CICECO, and Secc¸ ao Autonoma de Ciencias da Saude, Universidade de Aveiro, Aveiro 3810-193, Portugal
e Department of Chemistry and Centre of Advanced Studies, Panjab University, Chandigarh 160014, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 June 2013
Received in revised form 26 September 2013
Accepted 10 October 2013
Available online 17 October 2013
The BF3-directed lithiation of 3-chloro- and 3-bromopyridine (1a and 1b, respectively) has been in-
vestigated. The reactions of 3-chloro- or 3-bromopyridineeBF3 adduct with LDA (1.3/1.1 equiv) followed
by quenching with benzaldehyde or iodine exclusively gave the C-2 substituted products. However, when
2.2 equiv of LDA and dimethyl disulfide was used, a C-6 substituted product was obtained. Dilithiation of
1a and 1b has been studied with and without the involvement of BF3 complexation. The role of Li/F(BF3)
interactions has been investigated by experimental and DFT calculations.
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
3-Chloropyridine
3-Bromopyridine
Lithiation
Density functional calculation
1. Introduction
The methodologies involving BF3 prompted pyridine ring lith-
iation are an efficient route for the functionalization of various
The lithiation of halopyridines with the retention of halogen
atom offers many advantages in organic synthesis as it allows an
easy route for the introduction of new functionalities.1,2 Treatment
of 3-chloro- and 3-bromopyridine (1a and 1b, respectively) with
lithium diisopropylamide (LDA)3,4 or tBuLi5 in THF at ꢀ78 ꢁC affords
the C-4 substituted product.6 A small amount of the C-2 substituted
product has also been detected in the reactions involving LDA as the
lithiating reagent. In case a complexing lithiating reagent (nBu-
LieTMEDA, nBuLieLDMAE or TMSCH2LieLDMAE) is used, a shift in
the site of lithiation from C-4 to C-2 is noticed.7e9 The later
methods suffer from certain disadvantages, which include isolation
of a product corresponding to addition to the azomethine bond7
and use of excessive amount of the base.8,9
pyridine moieties.10ꢀ15 The BF3-controlled metalation of 1a and 1b
has been studied with highly expensive bimetallic tetramethylpi-
peridine (TMP) bases like, TMPMgCl$LiCl, (TMP)4Zr$4MgCl2$6LiCl
and [tBu2Zn(TMP)Li] in THF.16,17 The metalation of BF3-complexed
1a and 1b with these bases occurs at the C-4 position whereas, it
proceeds at the C-2 position without the BF3$Et2O precomplex-
ation. Contrary to this, the metalation of uncomplexed 1a with
Bu2(TMP)MgLi or (TMP)3MgLi in THF gives the C-4 substituted
product along with the dimers of 1a.18 Also, the treatment of 1b
with a mixture of ZnCl2$TMEDA and [(TMP)Li] provides a mixture
of C-2 and C-4 substituted product.19 Clearly, different methodol-
ogies afford different products depending upon the reaction con-
ditions and the type of the reagents used. A survey of the literature
reveals no report on the BF3-directed lithiation of 3-chloro- and 3-
bromopyridine with LDA and lithium tetramethylpiperidide (LTMP)
as the lithiating reagent. In continuation of our study concerning
lithiation of substituted pyridyl derivatives,12ꢀ15 we report herein,
a study on the BF3-controlled mono and dilithiation of 3-chloro-
and 3-bromopyridine with LDA and LTMP. The role of Li/F(BF3)
and Li/X(PyeCl/Br) interactions in these reaction has been in-
vestigated by experimental and DFT calculations.
* Corresponding authors. E-mail addresses: jassiv02@yahoo.co.in (J.S. Dhau),
pvbharatam@niper.ac.in (P.V. Bharatam).
y
Present address: University of South Florida, Department of Electrical Engi-
neering, Tampa, FL 33620, USA. Tel.: þ1 813 974 4787; fax: þ1 813974 6438.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.026

J.S. Dhau et al. / Tetrahedron 69 (2013) 10284e10291
10285
Table 1
2. Results and discussion
BF3-controlled lithiation of 1a and 1b
Complexation of 1a or 1b with BF3 not only increases the acidity
of the aromatic protons but also increases the number of potential
lithiation sites from two (C-2 and C-4) in uncomplexed 1a and 1b to
three (C-2, C-4, and C-6). Initially, our main objective was to ex-
amine the preferred lithiation site in these moieties.
Entry Substrate Base
Electrophile
E (product, yield)
1.
2.
3.
4.
5.
6.
7.
8.
1a
1a
1b
1b
1a
1b
1a
1b
1a
1a
1a
1a
1b
LDA (1.3 equiv) PhCHO (1.3 equiv) PhC(OH)H (4a, 77%)
LDA (1.1 equiv) PhCHO (1.1 equiv) PhC(OH)H (4a, 81%)
LTMP (1.3 equiv) PhCHO (1.3 equiv) PhC(OH)H (4b, 68%)
LTMP (1.1 equiv) PhCHO (1.1 equiv) PhC(OH)H (4b, 65%)
LDA (1.3 equiv) I2 (1.3 equiv)
LDA (1.3 equiv) I2 (1.3 equiv)
LDA (0.95 equiv) I2 (0.95 equiv)
LDA (0.95 equiv) I2 (0.95 equiv)
LDA (0.95 equiv) Br2 (0.95 equiv)
LDA (0.55 equiv) I2 (0.55 equiv)
LDA (1.3 equiv) 1a (1.3 equiv)
LDA (1.3 equiv) 2a (1.3 equiv)
LDA (1.3 equiv) 1b (1.3 equiv)
I (5a, 77% and 6a, 10%)
I (5b, 60% and 6b, 12%)
I (5a, 74%)
2.1. Use of benzaldehyde, iodine, and bromine as the
electrophiles
I (5b, 67%)
9.
Br (7a, 70%)
10.
11.
12.
13.
5a (93%)a
Treatment of 1a/1b with BF3$Et2O gives the adduct 2a/2b20 in
dry diethyl ether at 0 ꢁC (Scheme 1a). The reaction of 2a/2b with
LDA or LTMP (1.3/1.1 equiv) at ꢀ78 ꢁC gives 3a/3b, which upon
quenching with benzaldehyde followed by hydrolysis affords 4a/4b
in excellent yield (Table 1, entries 1e4). The use of iodine instead of
benzaldehyde affords 3-chloro-/3-bromo-2-iodopyridine (5a/5b)
in a major quantity along with a small quantity of 3-chloro-/3-
bromo-2,6-diiodopyridine (6a/6b, Table 1, entries 5 and 6).21 The
formation of 6a/6b in the later reaction could be due to; 1) the
existence of a dilithiated species, DL-2a/DL-2b (Scheme 1b), as
excess amount of LDA is used in the reaction or 2) the lithiation of
the in situ formed BF3-complexed iodo-species (5a-BF3 or 5b-BF3)
with the unreacted LDA followed by quenching with superfluous
iodine (Scheme 1b).
8a (25%) and 9a, (49%)
8a (21%) and 9a (27%)
9b (60%)
a
Based on the amount of LDA and iodine used.
2.2. Use of dimethyl disulfide as the electrophile
Contrary to the above mentioned electrophiles, different prod-
ucts were obtained when dimethyl disulfide (DMDS) was used as
the electrophile. The reaction of the lithiated species of 2a with
DMDS gave the dimers of 1a, namely 3,50-dichloro-2,20-bipyridine
(8a) and 5,50-dichloro-2,20-bipyridine (9a, Scheme 2a). In case of
1b, 5,50-dibromo-2,20-bipyridine (9b) was the only product ob-
tained in 68% yield.22 Carrying out these reactions with LTMP and at
greater dilution also gave the coupled product. It appears that
DMDS is a weaker electrophile than iodine or benzaldehyde.
Therefore, the lithiated/dilithiated species react preferentially with
each other or with unreacted 1a/1b or 2a/2b to form the dimers
instead of reacting with DMDS.
Scheme 1. a: Lithiation of BF3-controlled 1a and 1b. b: Route to 6a and 6b.
To accomplish the exclusive formation of the monoiodo product,
we used 0.95 equiv of LDA and iodine. The later reaction afforded
5a/5b (Table 1, entries 7 and 8) as the only product in good yield.
The same behavior was noticed when bromine was used as the
electrophile (Table 1, entry 9). No product corresponding to C-6 or
C-4 lithiation was detected in any of the above-mentioned re-
actions. This suggests that BF3-directed lithiation of 1a and 1b takes
place preferably at the C-2 position. This is contrary to the results
obtained with the bimetallic TMP bases.16,17
Scheme 2. a: Formation of dimers of 1a and 1b. b: Formation of 5-chloro- and 5-
bromo-2-(methylsulfanyl)pyridine (10a and 10b).
To confirm the above findings, we reacted 2a with 0.55 equiv of
LDA so that both 2a and 3a exist simultaneously in the reaction
mixture. The reaction mixture was then treated with iodine
(0.55 equiv), which gave 5a as the only product (Table 1, entry 10).

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J.S. Dhau et al. / Tetrahedron 69 (2013) 10284e10291
The later result establishes that whole of the lithiated species reacts
preferentially with iodine instead of reacting with itself or with
unreacted 2a, which is not the case when DMDS is used as the
electrophile. We also examined a series of reaction where 1a/1b
and 2a were used as electrophiles. These reactions gave different
proportion of the dimers (8a and 9a/9b, Table 1, entries 11e13).
Surprisingly, no 3,30-dichloro- or 3,30-dibromo-2,20-bipyridine was
noticed, which suggests a definitive role of the dilithiated species in
the nature of the dimers formed.
atom into the C(6)-Li bond of DL-2a/DL-2b activates the pyridine
ring for the second electrophilic addition of the selenium atom into
the C(2)-Li bond. To verify this posit, 2a was treated with 2.2 equiv
of LDA and quenched with 1.0 equiv of the selenium and iodo-
methane. Hydrolysis of the reaction mixture afforded 12a in 79%
yield (based on the amount of selenium used).
2.4. Dilithiation of 1a/1b with and without BF3 complexation
and iodine as the electrophile
The dilithiation of 2a/2b with 2.2 equiv of LDA and DMDS was
investigated in the hope that both the
lithiated, which could prevent the formation of the dimers. In-
terestingly, C-6 substituted product, 5-chloro-/5-bromo-2-
a-carbon positions would be
We also examined the BF3 aided and unaided dilithiation re-
action of 1a and 1b with iodine as the electrophile. In the presence
of BF3 complexation the dilithiation reaction yielded 6a and 6b in
58% and 60% yield, respectively, along with a small fraction of the
monosubstituted product. However, without BF3 complexation
a
(methylsulfanyl)pyridine (10a/10b), was obtained in a good yield
with no sign of the formation of the dimers (Scheme 2b). To the
best of our knowledge, the C-6 substitution of 1a and 1b has never
been achieved with a lithiating reagent. The formation of 10a/10b
could be possible by two different routes. One route would
involve the existence of 3-chloro-/3-bromopyridine-BF3 adduct
lithiated at C-6 (LC-6a/LC-6b), however, the non-isolation of a C-6
substituted product in any of the monolithiation reaction does not
support this possibility. Another route involves the preferential
attack of DMDS at the C-6 position of DL-2a/DL-2b. The isolation of
11a/11b in this reaction partly supports the later route (Scheme 2b).
These results were corroborated by carrying out thermodynamic
theoretical analysis on the monosubstituted DL-2b (Fig. 1), which
shows that the structure I (with eSCH3 moiety attached to the C-6
position) is 9.22 kcal/mol more stable than the isomeric species II
(eSCH3 moiety at the C-2 position).
a
different disubstituted product, 3-chloro-2,4-diiodopyridine
(13a), along with 5a was obtained (Scheme 4). These results in-
dicate that the complexation of BF3 with 3-halopyridines com-
pletely alters the precedence of the lithiation sites (mentioned
below).
ꢂ C-4>C-2 for 1a and 1b
ꢂ C-2>C-6>C-4 for 2a and 2b
The DoM, which has a major role in directing the lithiation in the
uncomplexed halopyridines via lithium/halogen (PyeX) in-
teraction, does not wield the same influence in the BF3-controlled
reactions. Instead, chelating effect of the lithium/fluoride (BF3)
ꢁ
Fig. 1. 3D optimized structures of I and II in gas phase with the bond distances given in A.
2.3. Use of selenium as the electrophile
interaction appears to be playing a major role in the stabilizing the
carbanion, which subsequently directs the lithiation process. The
Li/F interaction, an example of Complex Induced Proximity Effect
(CIPE), has been reported as a factor responsible for the BF3-aided
lithiation of picolines, lutidines, and anilines.12,23
To check the dominance of the Li/F interaction over the DoM of
the chloride group, we carried out the reaction of 1a with LDA,
which afforded 3-chloropyrid-4-yllithium (LC-4).3 LC-4 was then
added to an RBF containing 2a at ꢀ78 ꢁC. The quenching of the
resulting lithiated species with benzaldehyde afforded 4a as the
only product (Scheme 4). The isolation of 4a and non-detection of
any product corresponding to the C-4 lithiation suggests efficient
conversion of LC-4 to 3a.
The monolithiation of 2b with LDA (1.3 equiv) and subsequent
quenching with elemental selenium (1.3 equiv) and iodomethane
(1.3 equiv) gave 9b as the only product in 64% yield. It appears that
selenium is also a weak electrophile and the lithiated species un-
dergoes self-quenching to give the dimer. The dilithiation route was
again examined to check this hypothesis. Treatment of 2a and 2b
with LDA (2.2 equiv) followed by the addition of 2.2 equiv of ele-
mental selenium and iodomethane afforded 3-chloro- and 2-
bromo-2,6-bis(methylselenenyl)pyridine (12a and 12b), re-
spectively (Scheme 3). The formation of the disubstituted product
in substantial yield suggests that the insertion of the first selenium
Scheme 3. Synthesis of 3-chloro- and 3-bromo-2,6-bis(methylselenenyl)pyridine (12a and 12b).

J.S. Dhau et al. / Tetrahedron 69 (2013) 10284e10291
10287
Scheme 4. Lithiation of 1a with LDA and its quenching with iodine.
2.5. Lithiation of 1a and 1b with BCl3 and BH3 complexation
with lithiation at C-2, C-4, and C-6 (Table 3). The product stabilities
also indicate that the lithiation at C-4 is strongly preferred in
uncomplexed 1b. This is supported by the reported observation on
1b.3 In case of 2b, C-2 and C-4 are equally the preferred sites of
deprotonation (Table 2). However, a comparison of pKa values
clearly establishes that the C-2 hydrogen is more acidic compared
to the C-4 hydrogen. This indicates that there is a switch in the
observed preferences of lithiation in 1b before and after com-
plexation with BF3. The relative energies of 3b with Li at C-2, C-4,
and C-6 positions indicate that the C-2 lithiated 3b is much more
stable than the other alternatives. This extra stability can be at-
tributed to the Li/F interaction (Fig. 2), which originates from the
CPIE. Taken together, it can be expected that C-2 center gets
lithiated much easily than the C-4 centre. This is in agreement with
our experimental observation when 1.1 equiv of LDA or LTMP is
used.
In order to remove the disparity in comparing the Li/F(BF3) and
Li/Cl (DoM) interaction, we investigated the BCl3-controlled lith-
iation of 1a and 1b. The lithiation of 3-chloro-/3-
bromopyridineeBCl3 adduct (BC-2a/BC-2b) with LDA (1.1 equiv)
and subsequent quenching with benzaldehyde afforded 4a/4b in
yields similar to that obtained with BF3 complexation (Scheme 5).
Contrary to this, the lithiation of 3-chloro- or 3-bromopyridine-BH3
adduct did not afford any product corresponding to either the C-2
or C-6 lithiation. Thus, it can be inferred that the CIPE via Li/F/Cl
(BF3/BCl3) interaction is a dominant factor in the BF3/BCl3 con-
trolled lithiation of halogen substituted pyridines. Interestingly, the
internal lithium chelating effect (Pyridino directed metalation)
have also been shown to dominate the DoM in the lithiation of
anisylpyridines and phenylchloropyridines.24,25
Scheme 5. Lithiation of 1a/1b aided by BCl3 complexation.
Table 3
2.6. Computational studies
Relative stability (in kcal/mol) of 1b-L and 3b, in diethyl ether as solvent using IEF-
PCM solvent model
The mechanism of the BF3 aided lithiation process was studied
by performing quantum chemical analysis on the neutral 1b and its
boron trifluoride adduct, 2b. Computational calculations on 1b
indicate that the most favorable site for deprotonation is C-4 (Table
2). Similarly, the pKa values at C-2 (1.28), and C-4 (1.22) indicate
that C-4 hydrogen is more acidic in 1b and is more prone to attack
by LDA. The relative stabilities of the lithiated 1b were compared
Lithiation site
1b-L
3ba
0.00
7.79
11.62
5.87
C-2
C-4
C-5
C-6
3.91
0.00
6.03
9.36
a
3b is a species with lithiation at C-2 position. Other isomers are 3b(C-4), 3b(C-5),
and (LC-6b).
Table 2
Deprotonation energy (DPE) in kcal/mol and pKa values of 1b and 2b in diethyl ether
as solvent using IEF-PCM solvent model
A perusal of the data in Table 3 also reveals that the lithiation at
C-6 gives a more stable species than one obtained by the lithiation
at C-4, which is supported by the dilithiation experimental results.
The formation of the doubly lithiated species, DL-2b, was also in-
vestigated by quantum calculations. The DFT structure of DL-2b
Site of deprotonation
DPE of 1b
pKa
DPE of 2b
pKa
C-2
C-4
C-5
C-6
346.16
336.79
342.64
349.811
1.28
1.22
1.33
1.35
325.14
325.10
330.70
329.39
0.98
1.10
1.18
1.07
ꢁ
(Fig. 2) has Li/F bond slightly longer (1.94 A) than that in 3b
ꢁ
(1.90 A). The pKa value of C-6 proton in 3b is 1.25 and that of C-2

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J.S. Dhau et al. / Tetrahedron 69 (2013) 10284e10291
Fig. 2. 3D structures of 3-bromopyridine (with numbering scheme) and its BF3-lithiated complex (2b-L) (showing the lithium fluoride contacts).
proton in LC-6b is 1.15; in both the cases, the acidity increased with
reference to pKa values of 1b. This facilitates double lithiation either
originating from 3b or from LC-6b.
pKa ¼
D
GR=2:303RT
(1)
4.3. General procedure 1: lithiation of 3-chloro- and 3-
bromopyridine (1a and 1b)
3. Conclusions
A solution of 1a (1.70 g, 1.40 mL, 15.0 mmol) or 1b (2.37 g,
1.44 mL, 15.0 mmol) in dry diethyl ether (60 mL) was cooled to 0 ꢁC
and boron trifluoride etherate (BF3$Et2O) in diethyl ether (2.34 g,
2.07 mL, 16.5 mmol) was added to it. The resulting white suspen-
sion of 3-chloro-/3-bromopyridine-BF3 adduct (2a/2b) was cooled
to ꢀ78 ꢁC and LDA/LTMP (16.5 mmol) was added to it. The reddish
brown solution, indicating the formation of carbanion 3a/3b, was
stirred for 5e10 min at ꢀ78 ꢁC.
In summary, we have discussed BF3-aided lithiation of 3-
halopyridines with different electrophiles, which provides in-
sight into the mechanism of the reaction involved. It has been
established that the mere acidifying inductive effect of the Lewis
acid in the 3-halopyridine adduct is not enough and the presence
of the lithium/halogen (BX3) interaction is essential for
obtaining the desired
a-lithiation. The methodology discussed
here provides a single step incorporation of one or more elec-
trophiles in 3-halopyridines. The present protocol is an efficient
way of synthesizing 2,6-diiodo and 2,6-diseleno derivatives of 1a
and 1b.
4.3.1. (3-Chloropyridine-2-yl)phenylmethanol (4a). Benzaldehyde
(1.75 g, 1.67 mL, 16.5 mmol) was added drop wise to a solution of
3a (15.0 mmol) at ꢀ78 ꢁC. The reaction mixture was slowly
brought to room temperature and hydrolyzed with cold water.
The organic layer was extracted with diethyl ether, washed with
water, brine solution, and then again with water. The combined
organic layer was dried over anhydrous sodium sulfate and the
solvent was removed in vacuo to give the crude product. The
crude product was purified by column chromatography (60e120
mesh silica gel and 20% EtOAc/hexane) to give the title com-
pound 4a (2.53 g, 77%) as a white solid; mp 72e75 ꢁC; [Found: C,
65.51, H, 4.53, N, 6.27. C12H10NOCl requires C, 65.61, H, 4.58, N,
6.37%]; Rf (15% EtOAc/hexane) 0.61; 1H NMR (400 MHz CDCl3)
4. Experimental section
4.1. General
All experiments were carried out in dry oxygen-free nitrogen
atmosphere. All the solvents were dried before use. LDA and LTMP
were prepared by adding nBuLi to a solution of diisopropylamine
and N,N,N0,N0-tetramethylpiperidine, respectively, in dry diethyl
ether.13 1H NMR and 13C NMR spectra were recorded on Bruker
400 MHz spectrophotometer in CDCl3 using tetramethylsilane
(TMS) as an internal standard. EI mass spectra were taken by using
GC-Mass Spectrometer [GCeMS QP-2010 plus] with Rtx-1MS
d
8.53e8.55 (dd, J¼1.32, 4.82 Hz, 1H), 7.65e7.67 (dd, J¼1.40,
8.06 Hz, 1H), 7.21e7.36 (m, 6H), 6.00 (s, 1H), 5.31 (s, 1H). 13C NMR
(100 MHz CDCl3)
d 157.4, 146.1, 141.6, 137.8, 130.0, 128.4, 127.8,
127.5, 123.7, 72.0; MS m/z 219 (Mþ, 100), 201 (7), 184 (13), 166
(17), 154 (8), 142 (55), 127 (6), 113 (63), 100 (6), 91 (12), 77 (58),
51 (36%).
(30 mꢃ0.25 mm IDꢃ0.25
mm) capillary column. Microanalysis
was carried out on Vario MICRO Elemantar analyzer at Department
of Chemistry, Punjabi University, Patiala. All the reported yields of
the products are the isolated yield obtained after column chro-
matography procedure.
4.3.2. (3-Bromopyridine-2-yl)phenylmethanol33 (4b). The lithiated
species, 3b (15.0 mmol) and benzaldehyde (1.75 g, 1.67 mL,
16.5 mmol) were used to provide the title compound 4b (2.69 g,
68%) as white solid; mp 58e60 ꢁC; [Found: C, 54.47, H, 3.71, N, 5.25.
4.2. Methodology for theoretical studies
C
12H10NOBr requires C, 54.57, H, 3.81, N, 5.30%]; 1H NMR (400 MHz
CDCl3)
d
8.47e8.48 (dd, J¼1.32, 4.70 Hz, 1H), 7.72e7.74 (dd, J¼1.40,
Density Functional Theory (DFT) studies were carried out using
the GAUSSIAN09 suite of programs to comprehend the role of BF3 as
a promoter and the BF3 assisted (through the coordination bonds)
lithiation process in pyridine derivatives.26 B3LYP (Becke3, Lee,
Yang, Parr) level of theory with the 6-31þG(d) basis set was
employed for geometry optimizations and frequency calculations
throughout this study,27,28 a scaling factor29 of 0.9806 was used for
thermal corrections to Gibbs free energy. Solvent level optimization
studies have been performed using the IEF-PCM solvent model for
diethyl ether as a solvent.30 For pKa calculations the ab initio ge-
ometries were employed in calculating the solvation free energies
carried out using at the B3LYP/6-31G(d) level. pKa is calculated by
using Eq. 1.31,32
8.02 Hz, 1H), 7.21 (m, 5H), 7.03e7.06 (dd, J¼4.68, 8.00 Hz, 1H), 5.90
(s, 1H), 5.18 (s, 1H); 13C NMR (100 MHz CDCl3)
d 158.6, 146.7, 141.6,
141.1, 128.4, 127.8, 127.7, 124.1, 119.9, 73.5; MS m/z 263 (Mþ, 66), 246
(4), 234 (5), 186 (44), 157 (54), 127 (11), 105 (26), 91 (22), 77 (100),
63 (11), 51 (67%).
4.3.3. 3-Chloro-2-iodopyridine8 (5a). The lithiated species, 3a
(15.0 mmol) and iodine (4.19 g, 16.5 mmol) were used. Purification
by column chromatography (60e120 mesh silica gel and 10%
EtOAc/hexane) gave the title compound 5a (2.76 g, 77%) as a white
solid; mp 54e56 ꢁC; [Found: C, 24.93, H, 1.13, N, 5.76. C5H3NICl
requires C, 25.08, H, 1.26, N, 5.84%]; 1H NMR (400 MHz CDCl3)

J.S. Dhau et al. / Tetrahedron 69 (2013) 10284e10291
10289
d
8.19e8.20 (dd, J¼1.72, 4.60 Hz, 1H), 7.58e7.60 (dd, J¼1.72, 7.94 Hz,
4.6. 5-Chloro-2-(methylsulfanyl)pyridine (10a)
1H), 7.14e7.16 (dd, J¼4.64, 7.96 Hz, 1H); 13C NMR (100 MHz CDCl3)
d
146.9, 137.2, 135.2, 122.5, 120.5; MS m/z 239 (Mþ, 79), 127 (14), 112
LDA (33.0 mmol) was added slowly to a suspension of 2a
(15.0 mmol) in diethyl ether at ꢀ78 ꢁC. A reddish brown solution
containing the dilithiated species (DL-2a) was formed. DMDS
(3.10 g, 33.0 mmol) was added to it at ꢀ78 ꢁC. The reaction mixture
was slowly brought to the room temperature, hydrolyzed and pu-
rified by column chromatography (60e120 mesh silica gel and 2%
EtOAc/hexane) to provide the title compound 10a (1.50 g, 63%) as
a yellowish liquid; [Found: C, 45.22, H, 3.88, N, 8.65, S, 20.29.
C6H6NClS requires C, 45.16, H, 3.78, N, 8.77, S, 20.05%]; Rf (5% EtOAc/
(100), 85 (14), 76 (70), 62 (5), 50 (26%).
4.3.4. 3-Bromo-2-iodopyridine33 (5b). The lithiated species, 3b
(15.0 mmol) and iodine (4.19 g, 16.5 mmol) were used to provide
the title compound 5b (2.54 g, 60%) as white solid; mp 52e54 ꢁC;
[Found C, 21.19, H, 1.08, N, 4.91. C5H3NIBr requires C, 21.15, H, 1.06,
N, 4.93%]; 1H NMR (400 MHz CDCl3)
d
8.23e8.24 (dd, J¼1.64,
4.60 Hz, 1H), 7.73e7.76 (dd, J¼1.68, 7.92 Hz, 1H), 7.07e7.10 (dd,
J¼4.60, 7.96 Hz, 1H); 13C NMR (100 MHz CDCl3)
d
147.2, 138.6, 128.8,
hexane) 0.80; 1H NMR (400 MHz CDCl3)
1H), 7.35e7.38 (dd, J¼2.52, 8.64 Hz, 1H), 7.02e7.04 (dd, J¼0.60,
d
8.30e8.31 (d, J¼2.48 Hz,
123.0, 122.6; MS m/z 283 (Mþ, 57), 156 (79), 127 (25), 106 (4), 76
(100), 50 (58%).
8.50 Hz, 1H), 2.46 (s, 3H); 13C NMR (100 MHz CDCl3)
d 158.1, 148.0,
135.6, 127.4, 122.1, 14.3. MS m/z 159 (Mþ, 100), 144 (2), 126 (36), 113
4.3.5. 2-Bromo-3-chloropyridine (7a). The lithiated species, 3a
(14.25 mmol) and bromine (2.28 g, 14.25 mmol) were used to
provide the title compound 7a (1.95 g, 70%) as a white solid; mp
50e53 ꢁC; [Found C, 31.53, H, 1.72, N, 7.46. C5H3NClBr requires C,
31.20, H, 1.57, N, 7.27%]; Rf (hexane) 0.89; 1H NMR (400 MHz CDCl3)
(51), 107 (13), 90 (6), 78 (54%).
4.6.1. 3-Chloro-2,6-bis(methylsulfanyl)pyridine (11a). The com-
pound 11a (0.12 g, 4%) was obtained from the above reaction as
a yellowish liquid; [Found: C, 40.96, H, 3.89, N, 6.79, S, 31.10.
C7H8NClS2 requires C, 40.86, H, 3.91, N, 6.80, S, 31.16%]; Rf (hexane)
d
8.29e8.30 (dd, J¼1.64, 4.64 Hz, 1H), 7.74e7.76 (dd, J¼1.76, 6.04 Hz,
1H), 7.23e7.26 (dd, J¼4.68, 7.96 Hz, 1H); 13C NMR (100 MHz CDCl3)
0.95; 1H NMR (400 MHz CDCl3)
d
7.30e7.32 (d, J¼8.16 Hz, 1H),
d
147.8, 138.7, 136.1, 123.1, 117.5; MS m/z 195 (Mþ, 40), 193 (58), 191
6.82e6.84 (d, J¼8.12 Hz,1H), 2.58 (s, 6H); 13C NMR (100 MHz CDCl3)
(63), 156 (31), 76 (100%).
d
157.1, 157.0, 135.4, 124.2, 117.0, 14.3; MS m/z 205 (Mþ, 99), 190 (11),
173 (37), 171 (100), 159 (14), 136 (25), 124 (39), 112 (4), 83 (39), 64
(41%).
4.4. Synthesis of 3,50-dichloro-2,20-bipyridine (8a) and 5,50-
dichloro-2,20-bipyridine (9a)
4.7. 5-Bromo-2-(methylsulfanyl)pyridine36 (10b)
LDA (16.5 mmol) was added to a suspension of 2a (15.0 mmol) in
diethyl ether at ꢀ78 ꢁC. Compound 1a (1.87 g, 1.56 mL, 16.5 mmol)
was added to it at ꢀ78 ꢁC. Purification by column chromatography
(60e120 mesh silica gel and 20% EtOAc/hexane) gave 8a (0.84 g,
25%) and 9a (1.65 g, 49%) as white solids.
LDA (33.0 mmol) was added slowly to a suspension of 2b
(15.0 mmol) in diethyl ether at ꢀ78 ꢁC. A reddish brown solution
containing the dilithiated species (DL-2b) was formed. DMDS
(3.10 g, 33.0 mmol) was added to it at ꢀ78 ꢁC. The reaction mixture
was hydrolyzed and purified by column chromatography (60e120
mesh silica gel and 2% EtOAc/hexane) to provide the title com-
pound 10b (1.72 g, 56%) as a white solid; mp 34e36 ꢁC; [Found: C,
35.42, H, 2.94, N, 6.84, S, 15.97. C6H6NBrS requires C, 35.31, H, 2.96,
N, 6.86, S, 15.70%]; Rf (5% EtOAc/hexane) 0.88; 1H NMR (400 MHz
4.4.1. 3,50-Dichloro-2,20-bipyridine (8a). Mp 115e117 ꢁC; [Found: C,
52.08, H, 2.91, N, 12.11. C10H6N2Cl2 requires C, 52.36, H, 2.68, N,
12.44%]; Rf (15% EtOAc/hexane) 0.63; 1H NMR (400 MHz CDCl3)
d
8.71e8.72 (dd, J¼0.64, 2.28 Hz, 1H), 8.62e8.63 (dd, J¼1.4, 4.68 Hz,
CDCl3)
d
8.47e8.48 (d, J¼2.52 Hz, 1H), 7.55e7.58 (dd, J¼2.40,
1H), 7.77e7.86 (m, J¼2.4, 1.4, 0.6 Hz, 3H), 7.30e7.33 (dd, J¼4.68,
8.56 Hz, 1H), 7.05e7.07 (dd, J¼0.60, 8.72 Hz, 1H), 2.53 (s, 3H); 13C
8.16 Hz, 1H); 13C NMR (100 MHz CDCl3)
d 148.1, 147.6, 138.6, 136.7,
NMR (100 MHz CDCl3) d 158.7, 150.2, 138.2, 122.6, 115.7, 13.4; MS m/
136.1, 132.1, 125.3, 124.3, 121.8; MS m/z 224 (Mþ, 100), 189 (65), 162
z 205 (Mþ, 69), 170 (19), 157 (31), 78 (100), 50 (52%).
(78), 139 (3), 126 (10), 112 (32), 99 (10), 76 (42), 62 (9), 50 (35%).
4.7.1. 3-Bromo-2,6-bis(methylsulfanyl)pyridine (11b). The com-
pound 11b (0.3 g, 8%) was obtained from the above reaction as
4.4.2. 5,50-Dichloro-2,20-bipyridine34 (9a). Mp 195e197 ꢁC; [Found:
C, 53.27, H, 2.84, N, 12.39. C10H6N2Cl2 requires C, 53.36, H, 2.68, N,
12.44%]; Rf (3% EtOAc/hexane) 0.85; 1H NMR (400 MHz CDCl3)
a
yellowish liquid; [Found: C, 33.63, H, 3.21, N, 5.61, S,
25.91.C7H8NBrS2 requires C, 33.60, H, 3.22, N, 5.59, S, 25.63%]; Rf
d
8.52e8.53 (d, J¼2.28 Hz, 2H), 8.26e8.28 (d, J¼8.36 Hz, 2H),
(100% hexane) 0.96; 1H NMR (400 MHz CDCl3)
d 7.37e7.39 (d,
7.70e7.72 (dd, J¼2.48, 8.52 Hz, 2H). 13C NMR (100 MHz CDCl3)
J¼8.20 Hz, 1H), 6.69e6.71 (d, J¼8.20 Hz, 1H), 2.50 (s, 6H); 13C NMR
d
152.2, 147.0, 135.7, 131.4, 120.7; MS m/z 224 (Mþ, 73), 189 (100),
(100 MHz CDCl3) d 158.4, 157.8, 138.6, 117.4, 113.5, 14.3, 13.5; MS m/z
162 (42), 153 (11), 126 (15), 112 (25), 99 (12), 85 (12), 76 (46), 62
(10), 51 (41%).
251 (Mþ, 100), 236 (7), 217 (68), 170 (71), 155 (36), 136 (69), 124
(43), 109 (28), 96 (29), 78 (12%).
4.5. 5,50-Dibromo-2,20-bipyridine35 (9b)
4.8. 3-Chloro-2,6-bis(methylselenenyl)pyridine (12a)
LDA (16.5 mmol) was added to a suspension of 2b (15.0 mmol) in
diethyl ether at ꢀ78 ꢁC. Compound 1b (2.60 g, 1.58 mL, 16.5 mmol)
was added to it. Purification by column chromatography (60e120
mesh silica gel and 3% EtOAc/hexane) gave 9b (2.8 g, 60%) as a white
solid; mp 190e192 ꢁC; [Found: C, 38.32, H, 1.81, N, 8.43. C10H6N2Br2
requires C, 38.25, H, 1.92, N, 8.92%]; Rf (3% EtOAc/hexane) 0.92; 1H
Elemental selenium (2.60 g, 33.0 mmol) was added to a solution
containing DL-2a (15.0 mmol) at ꢀ78 ꢁC. The temperature was
slowly raised to ambience temperature and stirring was continued
till all the selenium got dissolved. The reddish brown solution was
recooled to ꢀ78 ꢁC and iodomethane (4.68 g, 2.05 mL, 33.0 mmol)
was added to it. The reaction mixture was slowly brought to the
room temperature, hydrolyzed and purified by column chroma-
tography (60e120 mesh silica gel and 2% EtOAc/hexane) to provide
the title compound 12a (2.38 g, 53%) as a orange viscous liquid;
[Found: C, 28.11, H, 2.56, N, 4.61.C7H8NClSe2 requires C, 28.07, H,
2.69, N, 4.67%]; Rf (100% hexane) 0.98; 1H NMR (400 MHz CDCl3)
NMR (400 MHz CDCl3)
d
8.70e8.71 (d, J¼2.08 Hz, 2H), 8.28e8.30 (d,
J¼8.20 Hz, 2H), 7.92e7.95 (dd, J¼2.35, 8.50 Hz, 2H); 13C NMR
(100 MHz CDCl3) d
153.5, 150.2, 139.6, 122.2, 121.4; MS m/z 314 (Mþ,
92), 233 (100), 206 (20),154 (43),127 (24),103 (12), 76 (37), 63 (7), 50
(36%).

10290
J.S. Dhau et al. / Tetrahedron 69 (2013) 10284e10291
d
7.13e7.15 (d, J¼8.12 Hz, 1H), 6.89e6.91 (d, J¼8.16 Hz, 1H), 2.40 (s,
added to it. The resulting white suspension was slowly brought to
3H), 2.39 (s, 3H); 13C NMR (100 MHz CDCl3)
d
154.7, 153.1, 134.8,
room temperature and stirred for 20 min to obtain a clear solution
of pyridine-BCl3 adduct in diethyl ether. The solution was cooled to
ꢀ78 ꢁC and LDA (3.3 mmol) was added to it. The reddish brown
solution, indicating the formation of carbanion, was stirred for
5e10 min at ꢀ78 ꢁC. Benzaldehyde (0.35 g, 0.33 mL, 3.3 mmol) was
then added to it at ꢀ78 ꢁC. The reaction mixture was slowly brought
to room temperature, hydrolyzed, and purified by column chro-
matography to provide 4a (0.512 g, 78%) and 4b (0.544 g, 69%),
respectively.
128.1, 120.9, 6.2, 6.0; MS m/z 301 (Mþ, 60), 221 (79), 206 (28), 185
(16), 170 (13), 156 (21), 140 (100), 114 (15), 95 (61), 76 (36), 64 (28),
50 (14%).
4.9. 3-Bromo-2,6-bis(methylselenenyl)pyridine (12b)
Elemental selenium (2.60 g, 33.0 mmol), DL-2b (15.0 mmol), and
iodomethane (4.68 g, 2.05 mL, 33.0 mmol) was used to provide the
title compound 12b (2.32 g, 45%) as a white solid; mp 63e65 ꢁC;
[Found: C, 24.38, H, 2.36, N, 4.04. C7H8NBrSe2 requires C, 24.49, H,
2.34, N, 4.07%]; Rf (100% hexane) 0.99; 1H NMR (400 MHz CDCl3)
Acknowledgements
d
7.34e7.36 (d, J¼8.20 Hz, 1H), 6.91e6.93 (d, J¼8.12 Hz, 1H), 2.48 (s,
We are thankful to the CSIR, New Delhi, India, for financial
support. Additional support from SAP by UGC, New Delhi, is also
acknowledged. We are also thankful to Mr. Avtar Singh, CIL, Punjab
University, Chandigarh, for NMR spectra.
3H), 2.46 (s, 3H); 13C NMR (100 MHz CDCl3)
d 156.6, 153.8, 138.1,
121.3, 118.1, 7.3, 5.9; MS m/z 345 (Mþ, 100), 266 (88), 251 (43), 185
(63),171 (52),156 (36),144 (13),130 (19),117 (13), 95 (59), 76 (47), 64
(62), 50 (22%).
Supplementary data
4.10. 3-Chloro-2,6-diiodopyridine (6a)
The computational data, X-ray single crystal structures of 5b, 6a,
8a, and 9a including the ORTEP diagrams, data collection, and re-
finement details are presented in the Supplementary data. Sup-
plementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.10.026.
A solution of iodine (8.40 g, 33.0 mmol) in dry diethyl ether was
slowly cannulated to the RBF containing a solution of DL-2a
(15 mmol) at ꢀ78 ꢁC. The temperature was raised to room tem-
perature and stirring was continued for 30 min. The reaction
mixture was then hydrolyzed and purified by column chromatog-
raphy (60e120 mesh silica gel and 1% EtOAc/hexane) to provide the
title compound 6a (3.17 g, 58%), as a white solid; mp 79e81 ꢁC;
[Found: C, 16.05, H, 0.57, N, 3.61. C5H2NI2Cl: requires C, 16.43, H,
0.55, N, 3.83%]; Rf (100% hexane) 0.87; 1H NMR (400 MHz CDCl3)
References and notes
ꢀ
ꢀ
ꢀ
1. Marsais, F.; Trecourt, F.; Breant, P.; Queguiner, G. J. Heterocycl. Chem. 1988, 25,
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d
7.59e7.61 (d, J¼8.40 Hz, 1H), 7.26e7.28 (d, J¼7.01 Hz, 1H); 13C
2. Sammakia, T.; Stangeland, E. L.; Whitcomb, M. C. Org. Lett. 2002, 4, 2385.
3. Gribble, G. W.; Saulnier, M. G. Tetrahedron Lett. 1980, 21, 4137.
NMR (100 MHz CDCl3) d 138.9, 137.1, 134.7, 120.5, 112.2; MS m/z 365
ꢀ
4. Mongin, F.; Queguiner, G. Tetrahedron 2001, 57, 4059.
(Mþ, 100), 238 (84), 202 (5), 182 (5), 152 (3), 127 (23), 111 (61), 76
(48), 50 (14%).
5. Pierrat, P.; Gros, P.; Fort, Y. Synlett 2004, 13, 2319.
6. Schlosser, M.; Mongin, F. Chem. Soc. Rev. 2007, 36, 1161.
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7. Marsais,F.;Breant,P.;Ginguene, A.;Queguiner, G.J. Organomet.Chem.1981, 216,139.
8. Choppin, S.; Gros, P.; Fort, Y. Eur. J. Org. Chem. 2001, 603.
4.11. 3-Bromo-2,6-diiodopyridine (6b)
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10. Kessar, S. V.; Singh, P.; Singh, K. N.; Dutt, M. J. Chem. Soc., Chem. Commun.1991, 570.
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13. Dhau, J. S.; Singh, A.; Dhir, R. J. Organomet. Chem. 2011, 696, 2008.
A solution of DL-2b (15.0 mmol) and iodine (8.40 g, 33.0 mmol)
in dry diethyl ether were used to provide the title compound 6b
(3.68 g, 60%) as a white solid; mp 61e63 ꢁC; [Found: C, 14.81, H,
0.70, N, 3.17. C5H2NI2Br requires C, 14.65, H, 0.49, N, 3.41%]; Rf (100%
~
~
ꢀ
ꢀ
14. Dhau, J. S.; Singh, A.; Sooch, B.; Brandao, P.; Felix, V. Inorg. Chim. Acta 2012, 392, 335.
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Ed. 2010, 49, 5451.
hexane) 0.92; 1H NMR (400 MHz CDCl3)
d
7.52e7.54 (d, J¼8.08 Hz,
1H), 7.39e7.41 (d, J¼8.12 Hz,1H); 13C NMR (100 MHz CDCl3)
d 140.4,
134.8, 130.4, 122.5, 112.9; MS m/z 409 (Mþ, 55), 282 (53), 155 (31),
ꢀ
ꢀ
18. Awad, H.; Mongin, F.; Trecourt, F.; Queguiner, G.; Marsais, F. Tetrahedron Lett.
2004, 45, 7873.
127 (37), 104 (3), 76 (100), 50 (27%).
ꢀ
19. Snegaroff, K.; Nguyen, T. T.; Marquise, N.; Halauko, Y. S.; Harford, P. J.; Roisnel,
T.; Matulis, V. E.; Ivashkevich, O. A.; Chevallier, F.; Wheatley, A. E. H.; Gros, P. C.;
Mongin, F. Chem.dEur. J. 2011, 17, 13284.
20. Martin, D. R.; Mondal, J. U.; Williams, R. D.; Iwamoto, J. B.; Massey, N. C.; Nuss,
4.12. 3-Chloro-2,4-diiodopyridine19 (13a)
D. M.; Scott, P. L. Inorg. Chim. Acta 1983, 70, 47.
LDA (33.0 mmol) was added slowly to a solution of 1a (1.70 g,
1.40 mL, 15.0 mmol) in diethyl ether at ꢀ78 ꢁC. A solution of iodine
(8.40 g, 33.0 mmol) in dry diethyl ether was slowly cannulated in it.
The reaction mixture was hydrolyzed and purified by column
chromatography (60e120 mesh silica gel and 10% EtOAc/hexane) to
provide the title compound 13a (1.47 g, 27%), as a white solid; mp
105e107 ꢁC; [Found: C, 16.25, H, 0.60, N, 3.55. C5H2NI2Cl requires C,
21. If one considers the excess of the LDAused (0.3 equiv) and the equivalent amount of
thedicarbanionformed(0.3equiv), theyieldof6a and 6b comesout be 40% and 32%,
respectively, and based on 0.7 equiv of 3-halopyridine left, the yield of 5a and 5b is
approximately 86%. However, for uniformity purpose, the yields of the reactions
have been calculated according to the total amount of the 3-halopyridine used.
22. The structures of 8a, 9a and 9b were established by COSY NMR and X-ray single
crystal diffraction studies as presented in the Supplementary data.
23. Kessar, S. V.; Singh, P.; Singh, K. N.; Bharatam, P. V.; Sharma, A. K.; Lata, S.; Kaur,
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16.43, H, 0.55, N, 3.83%]; 1H NMR (400 MHz CDCl3)
d 7.80e7.81 (d,
24. Parmentier, M.; Gros, P.; Fort, Y. Tetrahedron 2005, 61, 3261.
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J¼5.00 Hz, 1H), 7.13e7.15 (d, J¼5.28 Hz, 1H); 13C NMR (100 MHz
26. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Na-
katsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng,
G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery,
J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K.
N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J.
M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
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CDCl3) d
147.6, 142.0, 134.9, 119.4, 107.6; MS m/z 365 (Mþ, 100), 238
(84), 202 (5), 182 (5), 152 (3), 127 (23), 111 (61), 76 (48), 50 (14%).
4.13. General procedure 2: lithiation of 1a and 1b aided by
BCl3 complexation
A solution of 1a (0.34 g, 0.29 mL, 3.0 mmol) or 1b (0.474 g,
0.29 mL, 3.0 mmol) in dry diethyl ether (30 mL) was cooled to 0 ꢁC
and boron trichloride (3.3 mL, 1.0 M in hexane, 3.3 mmol) was

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