Complex-induced proximity effect in the regioselective lithiation of pyridine derivatives

Article abstract of DOI:10.1002/ejoc.201101592

The regioselective ring lithiation of BF₃-complexed 3-picoline (1a), 3,4-lutidine (1b), and 3,5-lutidine (1c) was studied. The dilithiation of 1a, 1b, and 1c was also investigated to experimentally explore the relative preference of the sites on the substituted pyridine ring for lithiation. The role of the complex-induced proximity effect (CIPE) for inducing lithiation in these moieties was investigated using both experimental and computational studies.

Full text of DOI:10.1002/ejoc.201101592

FULL PAPER
DOI: 10.1002/ejoc.201101592
Complex-Induced Proximity Effect in the Regioselective Lithiation of Pyridine
Derivatives
Jaspreet S. Dhau,*[a] Amritpal Singh,[a] Yoganjaneyulu Kasetti,[b] and P. V. Bharatam*[b]
Keywords: Nitrogen heterocycles / Lithiation / Lithium / Regioselectivity / Density functional calculations
The regioselective ring lithiation of BF3-complexed 3-picol-
ine (1a), 3,4-lutidine (1b), and 3,5-lutidine (1c) was studied.
The dilithiation of 1a, 1b, and 1c was also investigated to
experimentally explore the relative preference of the sites on
the substituted pyridine ring for lithiation. The role of the
complex-induced proximity effect (CIPE) for inducing lith-
iation in these moieties was investigated using both experi-
mental and computational studies.
idine (1b), and 3,5-lutidine (1c) aided by complexation with
BF3 is presented. The origin of the regioselectivity in the
BF3-controlled lithiation of pyridine has not been studied
in detail. Up until now, the electrostatic effect was consid-
ered the only factor responsible for the observed regioselec-
tivity.[3c] The role of the complex-induced proximity effect
(CIPE), which is the ability of the heteroatom (N, O, F, etc.)
to coordinate with the metal (lithium) to bring about the
directed deprotonation of the substrate, has not been ex-
plored as a possible contributor to the regioselectivity
achieved in these reactions. In this paper, we report experi-
mental and computational studies on the role of CIPE in
directing lithiation at various sites of 3-methyl-substituted
pyridyl derivatives.
Introduction
The lithiation of substituted and unsubstituted pyridine
rings has attracted the attention of chemists worldwide, as
it is a convenient route to many functional group manipula-
tions leading to molecules that are of material[1] and bio-
logical interest.[2] The direct lithiation of picolines and lut-
idines invariably leads to the functionalization of the acidic
methyl group(s), showing no preference for the ring pro-
tons.[3] One of the methods for preferential ring lithiation
in these derivatives involves the reaction of lithiating rea-
gents with halopyridines and halopicolines under cryo-
genic[4] and noncryogenic conditions.[5] The direct ring lithi-
ation of picolines and lutidines has only been achieved with
the aid of complexing reagents. For example, the α-lithia-
tion of substituted pyridines by using 3–8 equiv. of BuLi–
LDMAE (lithium dimethylethanolamine) complex (6– Results and Discussion
16 equiv. BuLi) has been reported.[6] A large excess amount
Compound 1a has two nonequivalent α-protons, whose
of base was used in these reactions which necessitated the
exorbitant consumption of the electrophiles and a tedious
purification procedure. This drawback limits the scope of
these reactions, particularly for large-scale synthesis. The
complexation of boron trifluoride with pyridine,[7] 4-pico-
line,[8] and 4-(N,N-dimethylamino)pyridine[9] was also ex-
plored for abstracting the α-proton with lithium tetrameth-
ylpiperidide (LTMP). All of the BF3-aided lithiations were
studied on pyridyl substrates possessing two equivalent α-
protons, whereas there are no reports of studies on sub-
strates with two nonequivalent α-protons. Herein, the re-
gioselective ring lithiation of 3-picoline (1a), 3,4-lut-
acidity is likely to increase when 1a is complexed with
BF3·Et2O. The primary objective of this reaction was to
determine which of the two α-protons would undergo lithi-
ation with LDA (lithium diisopropylamide). Treatment of
1a with BF3·Et2O in dry ether at 0 °C gave adduct 2a
(Scheme 1). This adduct upon reaction with LDA at –78 °C
gave a dark orange solution containing the carbanion. Ad-
dition of an electrophile followed by hydrolysis afforded
products 4a–9a (see Table 1), indicating exclusive lithiation
at C-6. No product arising from C-2 lithiation was detected
in these reactions. Under similar conditions, 1b also gave
monosubstituted products 4b–8b, corresponding to lith-
iation at C-6 (see Table 1). The lithiation of BF3-complexed
3,5-lutidine (2c) yielded a carbanion corresponding to the
selective lithiation of one of the two α-protons. When
quenched with an electrophile, this anion exclusively af-
forded the C-2 lithiated products 4c–8c in excellent yields.
The results obtained from the lithiation of 1c followed by
reaction with elemental selenium as the electrophile were
[a] Department of Chemistry, Punjabi University,
Patiala 147002, India
Fax: +91-175-2286682
E-mail: jassiv02@yahoo.co.in
[b] Department of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research (NIPER), Sector-67,
S. A. S.,
Nagar 160062, Punjab, India
1746
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1746–1752

The Regioselective Lithiation of Pyridine Derivatives
reported in an earlier communication of ours.[10] When ence between this reaction and the one where the picoline–
benzophenone was used as the electrophile, we only ob- BCl3 adduct is generated in situ is that the isolated adduct
tained the dimer of 1c.
forms a clear solution with diethyl ether at all temperatures
(room temperature to –78 °C) instead of suspension as in
the former reaction. When LDA (2 equiv.) was used in place
of LTMP, we obtained 5a in 38% yield.
Scheme 2. Lithiation of 3-picoline (1a), 3,4-lutidine (1b), and 3,5-
lutidine (1c) aided by complexation with: i) BCl3 and (ii) BH3.
To compare the roles of the CIPE and the electrostatic
effect in the above reactions, we examined the lithiation of
1a, 1b, and 1c with LDA/LTMP through the complexation
with BH3 instead of BF3 or BCl3. The lithiation of the in
situ generated 3-picoline– and 3,5-lutidine–BH3 adducts
with LDA or LTMP did not result in any ring or side-chain
lithiation. However, when the in situ generated 3,4-lutidine–
BH3 adduct was treated with 1.3 equiv. of LTMP and di-
methyl disulfide, 3-methyl-4-[(methylsulfanyl)methyl]pyr-
idine (10b) was isolated in low yield (20%), corresponding
to lithiation at the methyl carbon at C-4 (Scheme 2, B). No
product resulting from ring lithiation was noticed in this
reaction. In addition, we attempted the lithiation of a pyr-
idine–BH3 adduct with LDA, and no product resulting
from ring lithiation was noticed. In consideration of these
results, it appears that the interaction of lithium with a
halogen atom is essential for achieving the ring lithiation in
the pyridine moieties.
The mechanism of the aforementioned lithiation process
was then studied by performing quantum chemical analysis
on neutral 1a and 1c along with their boron trifluoride ad-
ducts. As a representative example, the numbering scheme
for 1c is shown in Figure 1. 3-Picoline, in principle, can un-
dergo ionization (deprotonation) at five different sites, in
other words, at α-carbons (C-2 and C-6), C-4, C-5, and C-
7 (methyl carbon). Computational analysis indicates that
Scheme 1. Lithiation of 3-picoline (1a), 3,4-lutidine (1b), and 3,5-
lutidine (1c) aided by complexation with BF3.
Table 1. Reaction involving monolithiation of 1a, 1b, and 1c.
Entry
*R[a] Base
[1.3 equiv.]
Electrophile
[1.3 equiv.]
E
Product Yield
[%]
1
2
3
4
5
1a
1a
1a
1a
1a
LDA
I2
I
4a
5a
5a
6a
7a
78
67
71
69
62
LDA
LTMP
LDA
LDA
PhCHO
PhCHO
(CH3S)2
(i) Se
CH(OH)Ph
CH(OH)Ph
SCH3
SeCH3
(ii) CH3I
Ph2CO
Br2
6
7
8
9
10
11
1a
1a
1b
1b
1b
1b
LDA
LDA
LDA
LDA
LDA
LDA
Ph2COH
Br
I
CH(OH)Ph
SCH3
SeCH3
8a
9a
4b
5b
6b
7b
59
68
63
57
72
67
I2
PhCHO
(CH3S)2
(i) Se
(ii) CH3I
Ph2CO
I2
PhCHO
(CH3S)2
(i) Se
12
13
14
15
16
1b
1c
1c
1c
1c
LDA
LDA
LDA
LDA
LDA
Ph2COH
I
CH(OH)Ph
SCH3
8b
4c
5c
6c
7c
64
86
70
74
70[10]
SeCH3
(ii) CH3I
Br2
17
1c
LDA
Br
8c
80
[a] *R = reactant.
Next, we investigated the lithiation of 3-picoline aided by the most favorable site for deprotonation is C-7 (see
complexation with BCl3. Treatment of the 3-picoline–BCl3 Table 2). This is supported by a reported observation on
adduct generated in situ with 1.3 equiv. of LDA followed uncomplexed 3-picoline.[3a,3b] In the case of BF3-complexed
by reaction with various electrophiles did not result in any 3-picoline (2a), C-7 is also the preferred site for deproton-
ring or side-chain lithiation. Instead, the stable picoline– ation (Table 2), which is contrary to experimental observa-
BCl3 adduct was isolated in good yield. Identical results tion. This implies that the information with respect to the
were achieved by replacing LDA with LTMP (2 equiv.). ionization energies of the pyridine derivatives does not pro-
However, when the isolated 3-picoline–BCl3 adduct was vide any clues regarding the product formation. This
treated with LTMP (2 equiv.) followed by reaction with prompted us to study the relative stabilities of the lithiated
benzaldehyde, (5-methylpyridin-2-yl)phenyl methanol (5a) species of 1a, 2a, 1c, and 2c under explicit solvent condi-
was isolated in 50% yield (Scheme 2, A). The major differ- tions. The results indicate that the species with lithiation at
Eur. J. Org. Chem. 2012, 1746–1752
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J. S. Dhau, A. Singh, Y. Kasetti, P. V. Bharatam
FULL PAPER
the methyl carbon (1a-L) is the most stable species (Table 3, Table 3. Relative energy stabilities of lithiated molecules of 3-pic-
oline (1a-L), 3,5-lutidine (1c-L), and their coordinated complexes
with BF3, 2a and 2c, respectively.
Column 2), again confirming the experimental observation.
However, when the relative stabilities of 2a were compared,
Site of
Relative
Relative
Relative
Relative
it became clear that C-6 is the most preferred site for lithi-
ation (Table 3, Column 3). This indicates that there is a
switch in the observed preferences of the sites for lithiation
of 3-picoline before and after complexation with BF3.
Strong coordination between the lithium (on the α-carbon)
and the fluoride of BF3, leading to the formation of a five-
membered chelating ring (Figure 2), is the major contrib-
utor to the seesaw change in the lithiation site preference.
This type of coordinating effect in lithiation processes is
commonly known as the complex-induced proximity effect
(CIPE), recently reported by Kessar et al. in the BF3-con-
trolled lithiation of aniline with sBuLi.[11] In addition, the
data in Table 3 reveals that lithiation at C-6 gave a more
stable species than the one obtained by lithiation at C-2,
which further substantiates the aforementioned experimen-
tal results for 1a (Scheme 1). In the light of the small contri-
bution from the inductive effect, the steric factor at C-2,
from the adjacent methyl group, appears to play a critical
role in determining the site of lithiation.
lithiation stability of stability of stability of stability of
1a-L
[kcal/mol]
2a
1c-L
[kcal/mol]
2c
[kcal/mol]
[kcal/mol]
C-2
C-4
C-5
C-6
C-7
3.90
3.35
3.06
2.77
0.00
0.46
10.78
10.04
0.00
3.93
3.87
–
–
0.00
0.00
11.19
–
–
8.89
8.92
Figure 2. 3D structures of 3a and 3c (showing the Li···F contacts).
The important interatomic distances leading to CIPE are given in
Å units.
Figure 1. 3D structure of 1c (with the numbering scheme presented
in the article).
As a conclusion to the theoretical studies, the complexation
of BF3 with 3-picoline and 3,5-lutidine decreases the depro-
tonation energy of the ring protons to a greater extent than
compared to the methyl protons, however, this decrease is
not enough to promote lithiation at the ring protons. It is
the CIPE which renders the α-carbons more prone to attack
by the lithiating reagents in comparison to the methyl car-
bons.
To further substantiate the theoretical findings, we at-
tempted the dilithiation of 2a with 2.2 equiv. of LDA. Inser-
tion of elemental selenium (2.2 equiv.) to the dicarbanion-
like species followed by reaction with iodomethane
(2.2 equiv.) gave 3-methyl-2,6-bis (methylselenenyl)pyridine
Table 2. Deprotonation energy studies on 3-picoline (1a), 3,5-luti-
dine (1c), and their coordinated complexes with BF3, 2a and 2c,
respectively.
Site of
DPE[a] of 1a DPE of 2a DPE of 1c DPE of 2c
deprotonation
[kcal/mol]
[kcal/mol]
[kcal/mol]
[kcal/mol]
C-2
C-4
C-5
C-6
C-7
355.34
349.19
350.00
355.10
339.40
334.69
336.42
336.99
334.54
326.38
355.91
350.03
–
335.46
337.18
–
–
–
340.01
326.87
[a] DPE = deprotonation energy.
3,5-Lutidine (1c) has three possible deprotonation sites, (11a) in a moderate yield. The result for 1a (Scheme 3, A,
that is to say, C-2, C-4, and C-7. The deprotonation energy Table 4) along with our earlier reported result for the di-
studies on 1c as well as on its BF3 adduct (2c) show that the lithiation of 1c giving 3,5-dimethyl-2,6-bis(methylselenenyl)-
methyl carbon is the most favorable site for deprotonation pyridine (11c)[10] suggests that effective deprotonation
(Table 2, Columns 4 and 5). However, the stabilities of the occurs at the two α-positions with no sign of side-chain
lithiated complexes of 1c and 2c indicate that there is a metallation. To check whether the preceding reaction segues
change in the preference for the site of lithiation (Table 3, through an intermediate dianion formation or proceeds
columns 4 and 5). Also in this case, the intramolecular che- through the intermediate formation of a monocarbanion
lation of lithium (on the α-carbon) with the fluoride of BF3 followed by electrophlic quenching and then a second de-
is responsible for increasing the stability of 3c in compari- protonation and electrophilic quenching sequence, we car-
son to the other BF3-complexed lithiated species (Figure 2). ried out the dimetallation reaction in two steps. The first
1748
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The Regioselective Lithiation of Pyridine Derivatives
step involved the quenching in situ of carbanion 3c with
Interestingly, the dilithiation of 1b behaved differently
elemental selenium. The second step involved the treatment from that of 1a and 1c. In case of selenium and iodo-
of the resulting selenolate anion with LDA (1.3 equiv.) at methane as the electrophiles, 2-(selenomethyl)-4,5-lutidine
–78 °C. The ensuing species was again quenched with ele- (7b), corresponding to monolithiation at C-6, was the major
mental selenium (1.3 equiv.) and iodomethane (2.6 equiv.). product. The dilithiated product 3,4-dimethyl-2,6-bis-
Upon purification of the crude product, 7c was obtained as (methylselenenyl)pyridine (11b) was isolated in a very min-
the major product (48%), whereas 11c was only obtained ute quantity (Table 4, Column 3). When iodine was used as
in 7% yield (Scheme 3B). This is contrary to our earlier the electrophile, monolithiated product 2-iodo-4,5-lutidine
observation for the single-step dilithiation reaction (4b, 55%) was formed in a major quantity. However, two
(Scheme 3A), where 11c was the main product (64%). In different disubstituted products (i.e., 12b and 13b) were iso-
this case, 7c was never isolated, but noticed only as a very lated as well, one corresponding to a second lithiation at C-
minute quantity in the GC–MS chromatogram. The rever- 8 (i.e., 12b) in 12% yield and the other from a second lithi-
sal of the yields for the two products through the two dif- ation at C-2 (i.e., 13b) in 4% yield (Scheme 4, Table 4). This
ferent routes suggests that the single-step dilithiation reac- implies that after complexation with BF3, C-8 is more prone
tion segues through the intermediate formation of the di- to lithiation than C-2. Therefore, it appears that the CIPE,
carbanion.
which plays a detrimental role in directing the first lithiation
at C-6, does not exert the same effect at C-2 in 1b.
Scheme 4. Dilithiation of 3,4-lutidine with iodine as the electro-
phile.
On the basis of the experimental findings, the order of
preference of the sites for BF3-aided lithiation of 1a, 1b, and
1c is: (i) C-6 Ͼ C-2 Ͼ C-7 (methyl carbon) for 1a; (ii) C-6
Ͼ C-8 (methyl carbon) Ͼ C-2 Ͼ C-7 (methyl carbon) for
1b; and (iii) C-6 = C-2 Ͼ C-7 = C-8 (methyl carbon) for 1c.
Scheme 3. (A) Dilithiation of 2a and 2c in a single-step reaction
and (B) dilithiation of 2c in a two-step reaction.
Table 4. Multilithiation of 1a, 1b, and 1c.
Conclusions
In conclusion, we have: (i) demonstrated the regioselec-
tive ring lithiation of 3-picoline, 3,4-lutidine, and 3,5-lut-
idine and (ii) established the relative preference of each of
the positions on the picoline and lutidine ring for lithiation.
The greater role of the complex-induced proximity effect in
comparison to the electrostatic effect for determining the
regioselective lithiation of 1a, 1b, and 1c has also been es-
tablished. The present methodology offers advantages over
those previously reported, as it negates the use of an excess
amount of base in affecting the selective ring lithiation and
dilithiation of picolines and lutidines along with the benefit
of completing the reaction in a single step.
Experimental Section
General Comments: All the apparatus was flame dried, and all the
solvents were dried and distilled before use. BuLi was prepared in
the lab by the reaction of BuBr with lithium metal in dry hexane.
1H NMR and 13C NMR spectroscopic data were recorded with a
Eur. J. Org. Chem. 2012, 1746–1752
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1749

J. S. Dhau, A. Singh, Y. Kasetti, P. V. Bharatam
FULL PAPER
400 MHz spectrometer in CDCl3 using TMS as an internal stan-
dard.
143.4, 137.5, 131.95, 128.5, 127.7, 127.0, 120.8, 74.8, 18.1 ppm. MS
(EI): m/z (%) = 199 (77) [M]+·, 182 (5), 122 (60), 93 (100), 77 (60).
C13H13NO (199.25): calcd. C 78.36, H 6.58, N 7.03; found C 78.43,
H 6.60, N 7.01.
GC–MS Conditions: The GC–MS analyses were carried out with a
GC–Mass Spectrometer. A capillary column used for the GC was
Rtx-1MS (30 mϫ0.25 mm, inner diameter 0.25 μm). The mass
spectrometry conditions used had the electron ionization source set
at 70 eV, the MS source temperature at 200 °C, and the solvent cut
time was 3.5 min.
5-Methyl-2-(methylsulfanyl)pyridine (6a):[6a] Yellow viscous oil
1
(0.86 g, 69%). H NMR (400 MHz, CDCl3): δ = 8.18 (s, 1 H, Ar),
7.20–7.22 (d, J = 8.0 Hz, 1 H, Ar) 6.97–6.99 (d, J = 8.1 Hz, 1 H,
Ar), 2.45 (s, 3 H, SCH3), 2.16 (s, 3 H, CH3) ppm. 13C NMR
(400 MHz, CDCl3): δ = 156.5, 149.6, 136.8, 128.5, 120.9, 17.8,
13.4 ppm. MS (EI): m/z (%) = 139 (100) [M]+·, 124 (4), 106 (25),
93 (73), 79 (11).
Methodology for Theoretical Studies: Ab initio density functional
theory (DFT) studies were carried out using the Gaussian 03 soft-
ware package.[12] The quantum chemical study was carried out to
understand the role of BF3 as a promoter and the BF3-assisted
(through the coordination bonds) lithiation process in the pyridine
derivatives. The B3LYP (Becke3, Lee, Yang, Parr) method with the
6-31+G(d,p) basis set was employed for geometry optimizations,
transition-state searches, and frequency calculations throughout
this study,[13,14] and a scaling factor of 0.9806 was used for the
zero-point energy (ZPE) corrections. The explicit solvent effect was
studied using two units of the model solvent dimethyl ether, and
the complexes were optimized under the implicit solvent conditions
using the conductor-like polarizable continuum model (CPCM)
with diethyl ether as the solvent (RMIN = 0.5, OFAC = 0.8; ε =
4.24).[15] All the reported transition states in the present study have
only one imaginary frequency.
5-Methyl-2-(methylselenenyl)pyridine (7a):[16] Elemental selenium
(0.78 g, 9.9 mmol) was added to the solution containing 3a at
–78 °C. The temperature was slowly raised until all of the selenium
dissolved. The reddish brown solution was again cooled to –78 °C,
and iodomethane (1.40 g, 0.6 mL, 9.9 mmol) was added. The reac-
tion mixture was slowly warmed to the room temperature and hy-
drolyzed, and the workup above was followed to yield a viscous oil
1
(1.0 g, 62%). H NMR: (400 MHz, CDCl3): δ = 8.15 (s, 1 H, Ar),
7.13–7.15 (d, J = 8.0 Hz, 1 H, Ar), 6.99–7.01 (d, J = 8.1 Hz, 1 H,
Ar), 2.35 (s, 3 H, SeCH3), 2.10 (s, 3 H, CH3) ppm. 13C NMR
(400 MHz, CDCl3): δ = 151.6, 149.8, 136.5, 129.0, 123.6, 17.6,
5.2 ppm. MS (EI): m/z (%) = 187 (19) [M]+·, 172 (1), 117 (3), 107
(100), 92 (25), 77 (7).
General Procedure 1. Monolithiation of 3-Picoline, 3,4-Lutidine, and
3,5-Lutidine: 3-Picoline, 3,4-lutidine, or 3,5-lutidine (9.0 mmol) was
added to a three-necked 100-mL round-bottom flask (RBF) con-
taining dry diethyl ether (30 mL) under an inert atmosphere. Boron
trifluoride–diethyl ether (BF3·Et2O; Spectrochem, Mumbai, India,
45–50%; 1.38 g, 1.23 mL, 9.9 mmol) was added to the reaction
mixture at 0 °C. The resulting curdy white suspension was stirred
for 10 min. In another three-necked 100-mL RBF, nBuLi (1.3 n
solution, 7.6 mL, 9.9 mmol) was added slowly to a solution of di-
isopropylamine (0.99 g, 1.4 mL, 9.9 mmol) or tetramethylpiperi-
dine (1.35 g, 1.6 mL, 9.9 mmol) in diethyl ether (20 mL) at –10 °C
to form LDA or LTMP, respectively. The temperature of the RBF
containing the BF3-complexed picoline/lutidine was lowered to
–78 °C and LDA/LTMP was added slowly by cannula. The color
of the suspension changed from white to orange brown in about
10 min. The orange brown solution (i.e., 3a, 3b, or 3c) was stirred
for 15 min at –78 °C.
(5-Methylpyridin-2-yl)diphenylmethanol (8a): Light brown viscous
liquid (1.46 g, 59%). 1H NMR (400 MHz, CDCl3): δ = 8.37 (s, 1
H, Ar), 7.40–7.42 (d, J = 7.7 Hz, 2 H, Ar), 7.26–7.28 (d, J = 7.2 Hz,
1 H, Ar), 7.16–7.24 (m, 9 H, Ar and OH), 7.11–7.12 (d, J = 7.9 Hz,
1 H, Ar), 2.26 (s, 3 H, CH3) ppm. 13C NMR (400 MHz, CDCl3):
δ = 150.2, 147.9, 146.3, 136.6, 128.5, 127.9, 126.5, 123.2, 122.3,
86.1, 18.5 ppm. MS (EI): m/z (%) = 275 (100) [M]+·, 257 (13), 198
(60), 183 (10), 105 (90), 92 (95), 77 (99). C19H17NO (275.35): calcd.
C 82.88, H 6.22, N 5.08; found C 82.63, H 6.49, N 5.35.
2-Bromo-5-methylpyridine (9a):[4d] Yield: 1.05 g (68%); m.p. 50–
1
52 °C. H NMR (400 MHz, CDCl3): δ = 8.17 (s, 1 H, Ar), 7.35 (s,
2 H, Ar), 2.28 (s, 3 H, CH3) ppm. 13C NMR (400 MHz, CDCl3):
δ = 150.4, 139.1, 138.6, 132.2, 127.5, 17.6 ppm. MS (EI): m/z (%)
= 171 (25) [M]+·, 92 (100).
4,5-Dimethyl-2-iodopyridine (4b): Yield: 1.32 g (63%); m.p. 60–
1
62 °C. H NMR (400 MHz, CDCl3): δ = 8.06 (s, 1 H, Ar), 7.48 (s,
2-Iodo-5-methylpyridine (4a):[6a] Iodine (2.51 g, 9.9 mmol) was
added to the solution containing 3a at –78 °C. The temperature
was slowly raised to room temperature. The reaction mixture was
hydrolyzed, and the resulting mixture was extracted with diethyl
ether. The organic layer was washed with sodium thiosulfate, water,
and a brine solution. The organic layer was then dried with anhy-
drous sodium sulfate. The solvent was removed, and the crude resi-
due was purified by column chromatography using 60–120 mesh
silica gel with hexane/ethyl acetate (5:1) as the eluent to yield 4a
(1.54 g, 78%); m.p. 52–54 °C. 1H NMR (400 MHz, CDCl3): δ =
8.20–8.21 (d, J = 2.2 Hz, 1 H, Ar), 7.58–7.60 (d, J = 8.0 Hz, 1 H,
Ar), 7.14–7.16 (dd, J = 2.4, 8.1 Hz, 1 H, Ar) 2.27 (s, 3 H,
CH3) ppm. 13C NMR (400 MHz, CDCl3): δ = 151.2, 138.6, 134.2,
132.9, 114.0, 17.8 ppm. MS (EI): m/z (%) = 219 (38) [M]+·, 127 (6),
92 (100). C6H6IN (219.02): calcd. C 32.90, H 2.76, N 6.39; found
C 32.63, H 2.68, N 6.22.
1 H, Ar), 2.23 (s, 3 H, CH3), 2.19 (s, 3 H, CH3) ppm. 13C NMR
(400 MHz, CDCl3): δ = 150.6, 148.1, 135.0, 132.1, 115.0, 18.7,
15.9 ppm. MS (EI): m/z (%) = 233 (32) [M]+·, 106 (100), 127 (7),
77 (65). C7H8IN (233.05): calcd. C 36.08, H 3.46, N 6.01; found C
36.19, H 3.26, N 5.74.
(4,5-Dimethylpyridin-2-yl)phenylmethanol (5b): Yield: 1.1 g (57%);
m.p. 81–82 °C. 1H NMR (400 MHz, CDCl3): δ = 8.16 (s, 1 H, Ar),
7.15–7.30 (m, 5 H, Ar), 6.83 (s, 1 H, Ar), 5.61 (s, 1 H, CH), 4.70
(s, 1 H, OH), 2.14 (s, 3 H, CH3), 2.10 (s, 3 H, CH3) ppm. 13C NMR
(400 MHz, CDCl3): δ = 157.5, 146.7, 145.7, 142.6, 130.0, 127.4,
126.5, 125.9, 120.8, 73.6, 18.3, 15.0 ppm. MS (EI): m/z (%) = 213
(100) [M]+·, 194 (15), 136 (93), 106 (66), 77 (50). C14H15NO
(213.28): calcd. C 78.84, H 7.09, N 6.57; found C 78.64, H 6.92, N
6.69.
4,5-Dimethyl-2-(methylsulfanyl)pyridine (6b):[6e] Yellow viscous oil
1
(5-Methylpyridin-2-yl)phenylmethanol (5a): Yield: 1.12 g (67%, with
(1.0 g, 72%). H NMR (400 MHz, CDCl3): δ = 8.07 (s, 1 H, Ar),
1
LDA), (71% with LTMP); m.p. 174–176 °C. H NMR (400 MHz,
6.87 (s, 1 H, Ar), 2.45 (s, 3 H, SCH3), 2.11 (s, 3 H, CH3), 2.08 (s,
3 H, CH3) ppm. 13C NMR (400 MHz, CDCl3): δ = 155.7, 148.3,
144.9, 127.0, 120.9, 18.1, 14.8, 12.3 ppm. MS (EI): m/z (%) = 153
(100) [M]+·, 138 (3), 121 (4), 106 (38), 91 (4), 77 (21). C8H11NS
CDCl3): δ = 8.35 (s, 1 H, Ar), 7.23–7.41 (m, 6 H, Ar), 7.02–7.04
(d, J = 8.0 Hz, 1 H, Ar), 5.71 (s, 1 H, CH), 5.34 (s, 1 H, OH) 2.29
(s, 3 H, CH3) ppm. 13C NMR (400 MHz, CDCl3): δ = 158.2, 148.0,
1750
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1746–1752

The Regioselective Lithiation of Pyridine Derivatives
(153.24): calcd. C 62.7, H 7.23, N 9.14; found C 62.59, H 7.30, N
9.18.
= 6.8 Hz, 2 H, Ar), 8.10–8.12 (d, J = 7.8 Hz, 1 H, Ar), 7.73–7.76
(dd, J = 6.7, 7.1 Hz, 1 H, Ar), 2.59 (s, 3 H, CH3) ppm. 13C NMR
(400 MHz, CDCl3): δ = 144.5, 142.1, 137.1, 125.6, 18.9 ppm.
C6H7BCl3N (210.30): calcd. C 34.26, H 3.35, N 6.66; found C
34.14, H 3.19, N 6.55.
4,5-Dimethyl-2-(methylselenenyl)pyridine (7b): Viscous oil (1.2 g,
67%). 1H NMR: (400 MHz, CDCl3): δ = 8.14 (s, 1 H, Ar), 7.05 (s,
1 H, Ar), 2.38 (s, 3 H, SeCH3), 2.16 (s, 3 H, CH3), 2.11 (s, 3 H,
CH3) ppm. 13C NMR (400 MHz, CDCl3): δ = 152.0, 149.2, 146.9,
129.3, 125.4, 19.2, 15.9, 5.8 ppm. MS (EI): m/z (%) = 201 (35)
[M]+·, 186 (1), 121 (100), 106 (27), 91 (7), 77 (24). C8H11NSe
(200.14): calcd. C 48.02, H 5.54, N 7.00; found C 47.94, H 5.63, N
7.13.
Lithiation of 3-Picoline–BCl3 Adduct: The 3-picoline–BCl3 adduct
(0.35 g, 1.63 mmol) obtained from the above reaction was added to
a three-necked 100-mL RBF containing dry diethyl ether (30 mL)
under an inert atmosphere. The resulting clear solution was cooled
to –78 °C, and LTMP/LDA (3.26 mmol), prepared as above, was
added slowly by cannula. Initially, the solution turned from yellow
to brown in color. This solution was stirred for 30 min at this tem-
perature. Benzaldehyde (0.35 g, 0.33 mL, 3.26 mmol) was added
dropwise, and after the complete addition, the reaction mixture was
slowly warmed to room temperature, and the workup was followed
as in the case of BF3. Compound 5a was isolated in 50% yield
(0.162 g) in the case of LTMP and 38% yield (0.12 g) in the case
of LDA.
(4,5-Dimethylpyridin-2-yl)diphenylmethanol (8b): Yield: 1.76 g
(64%); m.p. 208–210 °C. 1H NMR (400 MHz, CDCl3): δ = 8.21 (s,
1 H, Ar), 7.31–7.33 (d, J = 7.9 Hz, 2 H, Ar), 7.13–7.26 (m, 9 H,
Ar and OH), 6.99 (s, 1 H, Ar), 2.19 (s, 3 H, CH3), 2.16 (s, 3 H,
CH3) ppm. 13C NMR (400 MHz, CDCl3): δ = 149.3, 146.7, 146.2,
132.4, 128.0, 127.8, 127.1, 126.2, 124.7, 80.5, 19.2, 16.4 ppm. MS
(EI): m/z (%) = 289 (93) [M]+·, 271 (13), 254 (3), 212 (69), 194 (2),
184 (13), 167 (11), 152 (4), 134 (17), 134 (17), 106 (100), 92 (4), 77
(97). C20H19NO (289.38): calcd. C 83.01, H 6.61, N 4.84; found C
83.13, H 6.54, N 4.68.
Procedure for the Lithiation of 3,4-Lutidine Aided by BH3-Complex-
ation: 3,4-Lutidine (0.642 g, 0.673 mL, 6.0 mmol) was added to a
three-necked 100-mL RBF containing dry diethyl ether (30 mL)
under an inert atmosphere. Borane (BH3) in diethyl ether (1.0 m
solution, 6.6 mL, 6.6 mmol) was added to the reaction mixture at
0 °C. The resulting curdy white suspension was cooled to –78 °C,
and LDA (6.6 mmol), as prepared above, was added slowly by can-
nula. The color of the suspension changed from white to yellowish
orange in about 10 min. The yellowish orange solution was stirred
for 20–25 min at –78 °C. Dimethyl disulfide (0.621 g, 0.594 mL,
6.6 mmol) was added dropwise, and after the complete addition,
the reaction mixture was slowly warmed to room temperature with
the same workup as above. The crude product was purified by col-
umn chromatography using 60–120 mesh silica gel and hexane/ethyl
acetate as the eluent.
3,5-Dimethyl-2-iodopyridine (4c):[6b] Yield: 1.8 g (86%); m.p. 51–
1
53 °C. H NMR (400 MHz, CDCl3): δ = 8.0 (s, 1 H, Ar), 7.26 (s,
1 H, Ar), 2.34 (s, 3 H, CH3), 2.24 (s, 3 H, CH3) ppm. 13C NMR
(400 MHz, CDCl3): δ = 148.2, 138.4, 137.8, 132.8, 121.4, 25.9,
17.5 ppm. MS (EI): m/z (%) = 233 (48) [M]+·, 106 (100), 77 (72),
76 (4). C7H8IN (233.05): calcd. C 36.08, H 3.46, N 6.01; found C
35.83, H 3.42, N 5.77.
(3,5-Dimethylpyridin-2-yl)phenylmethanol (5c): Yield: 1.34 g (70%);
m.p. 61–62 °C. 1H NMR (400 MHz, CDCl3): δ = 8.19 (s, 1 H, Ar),
7.20–7.11 (m, 6 H, Ar), 5.86 (s, 1 H, OH), 5.61 (s, 1 H, CH), 2.21
(s, 3 H, CH3), 1.94 (s, 3 H, CH3) ppm. 13C NMR (400 MHz,
CDCl3): δ = 155.1, 145.1, 142.6, 139.4, 134.5, 129.7, 128.5, 127.6,
126.9, 72.4, 17.9, 17.7 ppm. MS (EI): m/z (%) = 213 (79) [M]+·, 194
(28), 136 (90), 107 (100), 77 (76). C14H15NO (213.28): calcd. C
78.84, H 7.09, N 6.57; found C 78.58, H 7.13, N 6.83.
3-Methyl-4-[(methylsulfanyl)methyl]pyridine (10b):[6e] Light brown-
ish yellow oil (0.18 g, 20%). 1H NMR (400 MHz, CDCl3): δ = 8.30
(s, 1 H, Ar), 8.29 (s, 1 H, Ar), 7.02–7.03 (d, J = 4.9 Hz, 1 H, Ar),
3.54 (s, 2 H, CH2), 2.27 (s, 3 H, CH3), 1.94 (s, 3 H, SCH3) ppm.
13C NMR (400 MHz, CDCl3): δ = 151.0, 147.3, 144.8, 131.9, 123.9,
35.0, 15.8, 15.1 ppm. MS (EI): m/z (%) = 153 (69) [M]+·, 138 (1),
106 (34), 105 (100), 91 (4), 77 (29).
3,5-Dimethyl-2-(methylsulfanyl)pyridine (6c):[10] Viscous oil (1.0 g,
1
74%). H NMR (400 MHz, CDCl3): δ = 8.03 (s, 1 H, Ar), 7.07 (s,
1 H, Ar), 2.55 (s, 3 H), 2.15 (s, 3 H), 2.12 (s, 3 H) ppm. 13C NMR
(400 MHz, CDCl3): δ = 155.0, 146.4, 137.5, 130.3, 128.2, 18.3, 17.6,
13.0 ppm. MS (EI): m/z (%) = 153 (82) [M]+·, 138 (16), 120 (100),
106 (40), 92 (26), 77 (38).
General Procedure 2. Dilithiation of 3-Picoline, 3,4-Lutidine, and
3,5-Lutidine: LDA (26.4 mmol) was added slowly to the BF3-com-
plexed 3-picoline, 3,4-lutidine, or 3,5-lutidine (12 mmol) by can-
nula. The color of suspension changed from white to orange brown
in about 10 min. The orange brown solution was stirred for 15 min
at –78 °C.
3,5-Dimethyl-2-(methylselenenyl)pyridine (7c):[10] Viscous oil
(1.26 g, 70%). 1H NMR: (400 MHz, CDCl3): δ = 8.05 (s, 1 H, Ar),
7.05 (s, 1 H, Ar), 2.36 (s, 3 H, SeCH3), 2.11 (s, 6 H, CH3) ppm.
13C NMR (400 MHz, CDCl3): δ = 152.0, 147.3, 137.0, 132.5, 129.0,
19.3, 17.6, 5.2 ppm. MS (EI): m/z (%) = 201 (100) [M]+·, 186 (64),
121 (99), 106 (75), 92 (25), 77 (61).
3-Methyl-2,6-bis(methylselenenyl)pyridine (11a): Elemental sele-
nium (2.08 g, 26.4 mmol) was added to the solution containing di-
lithiated BF3-complexed 1a at –78 °C. The temperature was raised
slowly until complete dissolution of the selenium took place. The
blackish brown solution was again cooled to –78 °C, and iodo-
methane (3.74 g, 1.64 mL, 26.4 mmol) was added. The reaction
mixture was slowly warmed to the room temperature, hydrolyzed,
and purified to yield a yellow viscous oil (1.1 g, 44%). 1H NMR
(400 MHz, CDCl3): δ = 6.94–6.95 (d, J = 7.6 Hz, 1 H, Ar), 6.86–
6.88 (d, J = 7.7 Hz, 1 H, Ar), 2.40 (s, 3 H, SeCH3), 2.38 (s, 3 H,
SeCH3), 2.08 (s, 3 H, CH3) ppm. 13C NMR (400 MHz, CDCl3): δ
= 155.6, 151.3, 136.0, 129.2, 120.3, 18.7, 5.58, 5.51 ppm. MS (EI):
m/z (%) = 281 (47) [M]+· for 80Se, 266 (8), 200 (100), 186 (26), 106
(47), 91 (67), 77 (14). C8H11NSe2 (279.10): calcd. C 34.40, H 3.95,
N 5.01; found C 34.15, H 3.94, N 4.87.
2-Bromo-3,5-dimethylpyridine (8c):[6b] Liquid (1.32 g, 80%). 1H
NMR (400 MHz, CDCl3): δ = 8.09 (s, 1 H, Ar), 7.42 (s, 2 H, Ar),
2.35 (s, 3 H, CH3), 2.28 (s, 3 H, CH3) ppm. 13C NMR (400 MHz,
CDCl3): δ = 147.0, 140.3, 140.2, 134.7, 133.1, 20.7 ppm. MS (EI):
m/z (%) = 185 (35) [M]+·, 106 (100), 91 (3), 79 (91).
3-Picoline–BCl3 Adduct: 3-Picoline (0.84 g, 9.0 mmol) was added to
a three-necked 100-mL RBF containing dry diethyl ether (30 mL)
under an inert atmosphere. Boron trichloride (1.0 m in hexane,
9.9 mL, 9.9 mmol) was added to the reaction mixture at 0 °C. The
resulting dark curdy white suspension was stirred for 10 min. The
solvent was removed on a rotary evaporator, and the white solid
was used without purification for future reactions. M.p. 101–
102 °C. 1H NMR (400 MHz, CDCl3): δ = 9.12–9.16 (br. d and s, J
Eur. J. Org. Chem. 2012, 1746–1752
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1751

J. S. Dhau, A. Singh, Y. Kasetti, P. V. Bharatam
FULL PAPER
87–90; d) M. L. Davis, B. J. Wakefield, J. A. Wardell, Tetrahe-
dron 1992, 48, 939–52.
3,4-Dimethyl-2,6-bis(methylselenenyl)pyridine (11b): Yield: 0.13 g
(5%); m.p. 72–75 °C. H NMR (400 MHz, CDCl3): δ = 6.87 (s, 1
1
[4] a) B. J. Wakefield in The Chemistry of Organolithium Com-
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Sharma, S. Lata, A. Kaur, Angew. Chem. 2008, 120, 4781; An-
gew. Chem. Int. Ed. 2008, 47, 4703–4706.
[12] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery, T. Vreven Jr,
K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tom-
asi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega,
G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota,
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, L. X. M. Klene, J. E. Knox, H. P. Hratch-
ian, J. B. Cross, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli,
J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Sal-
vador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D.
Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck,
K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Ba-
boul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Lia-
shenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T.
Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M.
Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W.
Wong, C. Gonzalez, J. A. Pople, Gaussian 03, rev. E.01,
Gaussian, Inc., Pittsburgh, PA, 2003.
H, Ar), 2.46 (s, 6 H, SeCH3), 2.18 (s 3 H, CH3), 2.13 (s, 3 H,
CH3) ppm. 13C NMR (400 MHz, CDCl3): δ = 155.1, 150.7, 144.7,
128.0, 122.2, 19.5, 15.2, 6.1, 5.4 ppm. MS (EI): m/z (%) = 295 (40)
[M]+· for 80Se, 280 (8), 214 (100), 200 (20), 185 (4), 120 (23), 105
(24), 90 (8), 77 (35). C9H13NSe2 (293.13): calcd. C 36.89, H 4.47,
N 4.78; found C 37.05, H 4.32, N 4.91.
3,5-Dimethyl-2,6-bis(methylselenenyl)pyridine (11c):[16] Yield: 2.6 g
1
(64%); m.p. 79–80 °C. H NMR (400 MHz, CDCl3): δ = 6.94 (s, 1
H, Ar), 2.50 (s, 6 H, SeCH3), 2.16 (s, 6 H, CH3) ppm. 13C NMR
(400 MHz, CDCl3): δ = 151.3, 136.9, 128.6, 18.4, 5.4 ppm. MS
(EI): m/z (%) = 295 (35) [M]+· for 80Se, 280 (7), 214 (100), 200 (23),
185 (8), 120 (36), 105 (30), 90 (8), 77 (81).
2-Iodo-4-(iodomethyl)-5-methylpyridine (12b): Yield: 0.38 g (12%);
m.p. 98–101 °C. 1H NMR (400 MHz, CDCl3): δ = 8.13 (s, 1 H,
Ar), 7.60 (s, 1 H, Ar), 4.19 (s, 2 H, CH2), 2.23 (s, 3 H, CH3) ppm.
13C NMR (400 MHz, CDCl3): δ = 153.9, 149.8, 135.5, 132.9, 116.6,
16.9, 0.0 ppm. MS (EI): m/z (%) = 359 (4) [M]+·, 358 (86), 232
(100), 191 (5), 127 (12), 105 (63), 90 (2), 78 (38), 77 (27). C7H7I2N
(358.95): calcd. C 23.42, H 1.96, N 3.90; found C 23.48, H 1.90, N
3.86.
2,6-Diodo-3,4-dimethylpyridine (13b): Yield: 0.12 g (4%); m.p. 74–
1
78 °C. H NMR (400 MHz, CDCl3): δ = 7.43 (s, 1 H, Ar), 2.31 (s,
3 H, CH3), 2.26 (s, 3 H, CH3) ppm. 13C NMR (400 MHz, CDCl3):
δ = 146.8, 136.4, 134.4, 123.3, 111.4, 21.7, 19.7 ppm. MS (EI): m/z
(%) = 359 (39) [M]+·, 232 (100), 127 (11), 105 (65), 77 (21).
C7H7I2N (358.95): calcd. C 23.42, H 1.96, N 3.90; found C 23.85,
H 1.99, N 3.94.
Acknowledgments
We are thankful to the Council of Scientific and Industrial Re-
search (CSIR), New Delhi, for financial support. Additional sup-
port from SAP by the University Grants Commission (UGC), New
Delhi, is also acknowledged. We are also thankful to Mr. Avtar
Singh, CIL, Punjab University, Chandigarh, for the NMR spectra.
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Received: November 1, 2011
Published Online: February 3, 2012
1752
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1746–1752