Regioselectivity in free radical bromination of unsymmetrical dimethylated pyridines

Article abstract of DOI:10.1016/j.tetlet.2014.08.069

During a literature review some curious inconsistencies in the free radical bromination of picolines were noted. To achieve a better understanding of the mechanisms and regioselectivity we reran these reactions, extending our work to unsymmetrical lutidin

Full text of DOI:10.1016/j.tetlet.2014.08.069

Accepted Manuscript
Regioselectivity in free radical bromination of unsymmetrical dimethylated
pyridines
Rajesh Thapa, Jordon Brown, Thomas Balestri, Jordon Brown, Richard T.
Taylor
PII:
S0040-4039(14)01412-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.08.069
TETL 45036
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 July 2014
15 August 2014
18 August 2014
Please cite this article as: Thapa, R., Brown, J., Balestri, T., Brown, J., Taylor, R.T., Regioselectivity in free radical
bromination of unsymmetrical dimethylated pyridines, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/
j.tetlet.2014.08.069
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Regioselectivity in free radical bromination of
unsymmetrical dimethylated pyridines
Rajesh Thapa1a,, Jordon Browna, Thomas Balestria and Richard T. Taylora,*

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Regioselectivity in free radical bromination of unsymmetrical dimethylated pyridines
Rajesh Thapaa,1 , Jordon Browna , Thomas Balestria and Jordon Browna Richard T. Taylora,*
aDeparment of Chemistry and Biochemistry, Miami University, Oxford, Ohio, 45056, USA
1Department of Chemistry, University of Louisville, Louisville, Kentucky, 40292, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
During a literature review some curious inconsistencies in the free radical bromination of
picolines were noted. To achieve a better understanding of the mechanisms and regioselectivity
we reran these reactions, extending our work to unsymmetrical lutidines using N-
bromosuccinimide in limiting amount. Characterization of the products was done with GC/MS
and H NMR. The regioselectivity of bromination in unsymmetrical dimethylpyridines shows
that nitrogen in the ring is deactivating inductively. The competition between 2,3, 2,4 and 2,5
dimethyl pyridine towards bromination results with bromination in the methyl group farthest
from the N in the ring. 3,4-Lutidine shows only the 4,4- dibrominated product.
2009 Elsevier Ltd. All rights reserved.
Received in revised form
Accepted
Available online
Keywords:
N-bromosuccinimide
Free radical bromination
Unsymmetrical Lutidine
Picolines
Regioselectivity
Introduction
catalyzed by silica-supported sodium bicarbonate under free
radical conditions. 3
N-Bromosuccinimide (NBS) is one of the important
brominating agents in organic synthetic chemistry. NBS is a
convenient source of bromine for both free radical substitution1
and electrophilic addition reactions.2 NBS is economical, easy to
handle and easily available. The major advantage of the use to
the NBS is that the reaction byproduct succinimide can be easily
recovered.3 NBS is a highly selective free radical brominating
agent. NBS is widely used in radical bromination at allylic
position of alkenes, known as Wohl-Ziegler bromination
reaction3. Allylic bromination4 can be obtained by refluxing the
alkene solution and NBS in anhydrous carbon tetrachloride
(CCl4) using free radical initiator azobisisobutyronitrile (AIBN)
or benzoyl peroxide (BPO). The formation of allylic bromides as
the major product is due to the allylic radical intermediates
formed during the course of the reaction are much more stable
than other carbon radicals.4 When the same conditions as allylic
bromination are applied to the benzylic bromination of aromatic
compounds, NBS effects the bromination of benzylic positions.5
Bromine can also be used for benzylic bromination6 but many
functional groups are sensitive to the generation of HBr during
the reaction which competes with acid catalyzed bromination.
This makes NBS the reagent of choice for bromination of
polyfunctional aromatic compounds.
NBS is used as oxidant for an efficient enantioselective oxidation
of secondary alcohols catalyzed by Mn(III)-salen complex.8 NBS
is also used as efficient catalyst in one pot synthesis of xanthane
derivatives under solvent free condition9 and polycyclic [2,3-
β]quinolone derivative under ambient conditions.10
The reaction between methyl substituted anisole and NBS
shows the competition between free radical bromination and
electrophilic bromination. The competition can be under
condition which favor the radical process, such as irradiation.11
Competition between electrophilic aromatic and radical
substitution depend on the structures of electron-rich aromatic
rings and the solvents used in the reactions.12 The presence of
methoxy group activates p-position of the aromatic ring and
enhances nuclear bromination.11 Electron donating groups in the
benzene ring such as methoxy and acetanilide group facilitate
electrophilic ring substitution reaction.13 The side chain
bromination follows
a radical pathway, while aromatic
bromination is an electrophilic substitution reaction. Nuclear
bromination is favored by low temperature and polar solvent
such as acetonitrile and dimethylformamide14 while free radical
bromination is favored by high temperature and non-polar
solvent such as carbon tetrachloride and benzene.
NBS is increasingly used for α-bromination of carbonyl
compounds including indanone and cyclopentenone.7 Various
ketones and β−ketoesters are selectively α-brominated with NBS
NBS bromination indicated that the bromine atom is the
hydrogen abstracting species in all reaction.15 Trace of bromine
present in commercially available NBS may influence the
———
1
Tel.: +1-502-291-8651, Fax: 502-852-8149
E-mail addresses: r0thap01@louisville.edu

2
Tetrahedron
stability of NBS.16 The small amount of bromine radical
Free radical bromination of toluene with different brominating
agents was carried out. The rates relative to toluene for hydrogen
abstraction from substituted toluene by various brominating
agents were accumulated and average ρ value of -1.42 was
obtained with nearly independent of the brominating agents. In
all cases, an excellent fit of the points to the Hammett correlation
was obtained when σ+ values were used.29
produced by NBS with radical initiator BPO initiates the main
propagation steps. NBS is a source of bromine, in low, steady
state concentration and it consumes the liberated hydrogen
bromide (HBr) by an ionic process.17 The consumption of HBr
avoids the inhibition of bromination.18
Free radical bromination with NBS was conventionally carried
out using CCl4 as solvent with various radical initiatiors.19 CCl4
solvent is restricted due to its high toxicity, possible
carcinogenicity and ozone layer depleting effect.20 Free radical
benzylic brominations for several aromatic compounds are
carried out in non-chlorinated solvents such as methyl formate
and methyl acetate.21 Free radical side chain bromination in
supercritical carbon dioxide has shown similar selectivity to the
conventional organic solvents.22 Free radical bromination by
NBS in pure water at ambient temperature and with visible light
as initiator was conducted effectively. The aqueous phase permits
easy isolation of the insoluble brominated product from water
soluble succinimide byproduct. Aqueous NBS system is reported
for selective benzylic bromination in presence of ketone
functionality.13 However, water as solvent is limited for
hydrophobic substrates only due to the poor solubility of most of
organic compounds in water.23 Benzylic bromination was
achieved using (trifluoromethyl) benzene as solvent.
(trifluoromethyl) benzene is chemically inert and less toxic than
conventional solvent CCl4.24
Extending this work to picolines, the substituents effects i.e.;
σ values of 2-picoline and 4-picoline show that the reactivities of
2-picoline and 4-picoline should be similar whereas the reactivity
of 3-picoline seems higher compared to 2 and 4-picolines owing
to the higher σvalue.29 The order of reactivity of picoline
comparing its σ value can be given as 3-methyl > 2-methyl > 4-
methyl.
The published σ values for methyl pyridines are as follows:
Figure 1: σ−value of picolines
The reaction 2-picoline with NBS to give mixture of mono and
di-substituted products was reported. Similarly 4-picoline was
reacted with NBS and the product was isolated as the
hydrobromide salt and was analyzed as fully brominated i.e.; 4-
tribromomethyl-pyridine. Kutney group reported that no
brominated product obtained with 3-methylpyridine under same
conditons. Their results conclude that in the methylpyridine
series, the rate of reactivity towards NBS is 4-methyl > 2-methyl
> 3-methyl.30 The classical approach to explain reactivity in
relation to σ value seems inadequate.
The goal of our research work is to determine the reactive site
and products of unsymmetrical dimethylpyridine and to achieve
better understanding of the regioselectivity of the compound
towards free radical NBS bromination (10%) and with
stoichiometric amounts. NBS bromination of the unsymmetrical
dimethyl pyridine was carried out with limiting NBS. Mono
brominated product was initially obtained by using 10% of the
reagent to find the reactive site of the compound. Reaction is
further carried out in1:1 equivalent to obtain a sufficient amount
of monobrominated product so that it can be isolated and
1
analyzed with the help of GC/MS, H NMR and NOE. Namely
Result and Discussion
2,3-, 2,5-, 2,4- and 3,4 dimethyl pyridine were reacted with NBS
with standard methods mention in the experimental section and
the data were obtained and discussed. Our research focus is to
accomplish the understanding of regioselectivity towards NBS
bromintion of unsymmetrical dimethyl pyridine so no effort was
done to isolate and analyze the polybrominated products.
Bromination of picoline and other aromatic compounds with
Br2/SiO2 was reported after Smith and Bye31 have reported the
use of NBS/SiO2 for aromatic bromination. Silica gel effects on
the rate and the mechanism of bromination of aromatic
compounds. Bromination of 2-methyl pyridine and 3-
methylpyridine was carried out in 1:1 stoichiometry for 24 hours.
The bromination at the methyl branch to give 2-
Bromomethylpyridine and 3-methylpyridine was reported.
However the yield is low. 3-bromomethylpyridine is a known
compound. It was prepared from 3-aminomethylpyridine. 2-
bromomethyl pyridine is also a known compound. It is prepared
either directly from 2-picoline by NBS bromination or from
pyridin-2-ylmethanol.
An Unusual Orienting effect in the Bromination of Alkyl
Bromides
The directive influence of polar substituents in free radical
halogenation reaction has been studied by several groups. 25 The
results agree with theory that the electronegative attacking
radicals prefer position of higher electron density. The
halogenation of several alkyl and cycloalkyl halides is through
photo- bromination of alkyl bromides is quite different from the
bromination of other alkyl halides and from alkyl halide
halogenations in general.26 The chlorination of alkyl bromides is
reported to produce the expected isomer distribution; preferential
attack occurring at positions remote from the bromine
substituent.
Scheme 1. Free radical bromination of picolines
Electronic effect in selectivity σ+ values for different position
of pyridine.
The application of the Hammett equation for the prediction of
the effects of substituents on the heterocyclic compounds was
reported.27 The derived σ+ values have proven useful in
correlating on electrophilic aromatic substitution and
electrophilic side-chain reaction.28
The classical approach to predict the substituent effect on the
reactivity of the free radical bromination of picolines by NBS is
not adequate. Hence, we revisited in this article the reactions to
investigate the reactivities of 2, 3 and 4-picolines towards the free

3
radical bromination by NBS and extended the work to
symmetrical and unsymmetrical lutidines as well (Scheme 2).
methylpyridne and 5-(bromomethyl)-2-methyl pyridine as
shown in the Table 2 respectively.
Free radical bromination of 4-methylpyridine gives only
dibrominated product that can be explained as in case of 3,4-
dimethylpyridine as above. In the case of 3-methylpyridine
bromination at methyl group does not takes place instead ring
substituted product was obtained as shown in the table 2 (entry
6b) probably by non radical mechanism. It is not clear why 3-
methyl group in 3-methylpyridine is not brominated. The
unsuccessful attempt of metalation of 3-methylpyridine was
reported.32 The unusual nuclear bromination in presence of side
In case of 3,4-dimethyl pyridine monobrominated product was
not obtained even when only 10% NBS was used. It is surprising
that a monobrominated product was formed in case of 2,3- and
2,4-dimethyl pyridine but monobromination does not takes place
in case of 3,4-methylpyridine. 3,4-dimethylpyridine produce 4-
(dibromomethyl)-3-methylpyridine as shown in the table 2
(entry7b). This may be because 4-methyl group is most reactive
site as it has highest electron density comparing 2-methyl and 3-
methyl group as it lies farthest from the inductively deactivating
nitrogen in the pyridine ring. The dibrominated product was well
characterized by mass spectrum, proton NMR and nuclear
overhauser effect (NOE) difference spectroscopy.
chain in aromatic compounds under apparent radical conditions
were reported in the literature.11a,
33
The reaction of 3,5-
dimethylanisole with NBS under irradiation did not yield
expected side chain substituted product instead nuclear
Table 2: Reactants and Products of NBS bromination of
unsymmetrical dimethylpyridines
brominated
product i.e.; 4-bromo-3-(bromomethyl)-5-
methylanisole was obtained.11a The reaction of 3-methyl pyridine
with NBS under free radical reaction conditions belong to this
category.
Reactant
Product
Remarks
Scheme 2. Free radical bromination of unsymmetrical dimethyl
pyridine
Br
Reported in the
literature.33
4a.
5a.
4b.
N
N
Br
5b.
6b.
We report
We report
N
N
N
6a.
7a.
Br
N
Br
Br
In the case of 2-bromomethylpyridine our result is consistently
low yield in keeping with the literature.31 Only dibrominated
product (Table 1, 3b) is obtained in case of 4-methylpyridine.
N
N
We report
7b.
Table 1: Reactants and Products of NBS bromination of
monomethylpyridines
In case of case of 3,4-dimethylpyridne, the monobromination
may causes the C-H bond to be more polar and highly reactive so
that dibromination takes place rapidly; no monobrominated
product was observed. For 2,4-dimethylpyridine is similar, but in
this case monobrominated product can be observed. The methyl
group is an electron releasing group. The methyl group in 3-
position is in closer proximity in 3,4-dimethylpyridine than 2-
methyl group in 2,4-dimethyl- pyridine; this may be the cause
that the electron density in 4-methyl in 3,4-dimethylpyridine is
higher comparing 4-methyl group in 2,4-dimethylpyridine that
may cause the 4-methyl group in 3,4-dimethylpyridine more
reactive. Several examples of side-chain free-radical
halogenation of N-heterocyles have been reported in literature.21,
Reactant
Product
Remarks
Literature report low
yield 25%
monobrominated
substantial amount of
diborominated product
obtained.
1a.
1b.
Br
N
N
Br
2a.
3a.
Literature report, no
reaction.33
2b.
3b.
N
N
31
2, 3- and 3,4-dimethylpyridine with NBS in CCl4 under
photobromination condition was carried out to obtain tetrabromo
substituted products.36
Br
Br
N
Only dibrominated
product obtained.
N
The major product by the radical bromination reaction of 2,3-
dimethyl pyridine with NBS obtained was 3-(bromomethyl)-2-
pyridine reported in the literature.32 The preferential bromination
of the C-3 methyl group of 2, 3-lutidine was unexpected because
2-picoline was found to be much more reactive than 3-picoline
towards NBS bromination.30 several attempts were made to
established the location of the bromine by independent synthesis
of 3-(bromomethyl)-2-methylpyridine from ethyl-2-methyl-3-
nicotinate following the literature procedure. However, the
Bromination at the farthest methyl group from nitrogen was
obtained during selective free radical bromination of
unsymmetrical dimethyl pyridines. The free radical bromination
of 2,3-, 2,4- and 2,5-dimethyl pyridine by NBS generate 3-
(bromomethyl)-2-methylpyridine,
4-(bromomethyl)-2-

4
Tetrahedron
15. (a) Maiti, S.; Sengupta, S.; Giri, C.; Achari, B.; Banerjee, A.K.
Tetrahedron Letters, 2001, 42, 2389; (b) Oberhauser, T. J. Org.
Chem. 1997, 62, 4504; (c) Fujikawa, N;. Ohta, T.; Yamaguchi, T.;
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16. Russell, G. A.; DeBoer, C.; Desmond, K. M. J. Am. Chem. Soc.
1963, 85, 365
reaction does not proceed with the given procedure in the
literature.31
Side chain bromination of aromatic and heteroaromatic methyl
groups by microwave-assisted solid phase NBS without radical
initiator was reported. 2, 6 – Lutidine by single step solid phase
NBS reaction without radical initiator by Microwave irradiation
give 2-(bromomethyl)-6-pyridine was reported. Simple methyl
substituted aromatic and heterocyclic ring like pyridine, pyrizine
and phenanthroline prevents ring bromination but mostly
favorsside chain bromination due to lesser electron density on the
ring due to presence of nitrogen heteroatom.34
17. Jereb, M.; Zupan, M.; Stavber, S. Helv. Chim. Acta 2009, 92, 555
18. (a) Bedel, S.; Ulrich, G.; and Picard, C.; Tetrahedron Lett., 2002,
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1953, 171, 704
19. Walling, C.; Rieger, A. L.; Tanner, D. D. J. Am. Chem. Soc. 1963,
85, 3129
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21. Material Safety Data Sheet.
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23. Tanko, J. M.; Blackert, J. F. Science, 1994, 263, 203
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7447
The competition between 2, 3-, 2, 4- and 2, 5-dimethyl pyridine
towards bromination results with bromination in the methyl
group farthest from the N in the ring. The results are consistent
with theory that the electronegative attacking radicals prefer
positions of high electron density and abstract hydrogens from
carbon atoms, which are farthest from the electron-withdrawing
substituents. Regioselectivity of bromination in unsymmetrical
dimethyl Pyridine shows that Nitrogen in ring is deactivating
inductively. The unusual bromination occurred in case of 3-
picoline; which does not brominates on methyl branch instead
brominates on the aromatic ring while 2,3 and 2,5-dimethyl
pyridine brominates in the side chain. Surprisingly, 3,4-dimethyl
pyridine dibrominates but 2,4-dimethyl pyridine doesnot.
25. Suarez, D.; Laval, G.; Tu, S-M.; Jiang D.; Robinson, C. L.; Scott,
R.; Golding, B.T. Synthesis, 2009, 11, 1807
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personal thanks to Celsus laboratories, Cincinnati, Ohio.
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