Mild regioselective halogenation of activated pyridines with N-bromosuccinimide

Article abstract of DOI:10.1055/s-2001-18070

Regioselective mono and dihalogenations of amino, hydroxy and methoxy pyridines (2-, 3-, and 4-substituted) as well as 2,6-dimethoxy pyridine with N-bromosuccinimide in different solvents have been studied. Reactivity of the substrates decreases in the order amino>hydroxy>methoxy and regioselectivity depends on the position of the substituent (2-substituted > 3-substituted). In most of the cases we obtained monobrominated derivatives regioselectively and in high yields. Hydroxy and amino pyridines can also be dibrominated in almost quantitative yield with 2 equivalents of NBS.

Full text of DOI:10.1055/s-2001-18070

PAPER
2175
Mild Regioselective Halogenation of Activated Pyridines with N-
Bromosuccinimide
M
ild Regioselectiv
i
e
H
alo
c
genation of
t
Activa
o
ted Pyridine
s
with
Nia
succinimide Cañibano,a Justo F. Rodríguez,a Mercedes Santos,a M. Ascensión Sanz-Tejedor,*a M. Carmen Carreño,b
Gema González,b José L. García-Ruano*b
a
Organic Chemistry Department (E.T.S.I.I.), Universidad de Valladolid, Pº del Cauce s/n, 47011-Valladolid, Spain
Fax +34(983)423310; E-mail: atejedor@dali.eis.uva.es
b
Organic Chemistry Department (C-I), Universidad Autónoma, Cantoblanco, 28049-Madrid, Spain
Received 4 July 2001; revised 25 August 2001
droxypyridine to yield exclusively 2-bromo-3-hydroxy-
pyridine but, to our knowledge, the authors have not
extended this study to other pyridine derivatives.
Abstract: Regioselective mono and dihalogenations of amino, hy-
droxy and methoxy pyridines (2-, 3-, and 4-substituted) as well as
2,6-dimethoxy pyridine with N-bromosuccinimide in different sol-
vents have been studied. Reactivity of the substrates decreases in
the order amino>hydroxy>methoxy and regioselectivity depends on
the position of the substituent (2-substituted > 3-substituted). In
most of the cases we obtained monobrominated derivatives regiose-
lectively and in high yields. Hydroxy and amino pyridines can also
be dibrominated in almost quantitative yield with 2 equivalents of
NBS.
N-Halosuccinimides have previously been reported as re-
agents for the nuclear bromination of 8-quinolinol and its
copper (II) chelate14 but they have scarcely been used on
pyridines bearing activating groups.15 By contrast, radical
brominations at lateral chains of alkylpyridines with NBS
in the presence of radical initiators have been widely doc-
umented.16 The good results obtained by our group in the
regioselective bromination of methoxybenzenes and
methoxynaphtalenes,17 as well as phenols and napthols18
under very mild conditions with NBS, prompted us to in-
vestigate the behaviour of activated pyridines. In this pa-
per we report a systematic study of the bromination with
NBS of pyridines bearing OH, NH2, and OMe groups at
different positions and under different conditions.
Key words: halogenation, pyridines, N-bromosuccinimide (NBS),
regioselective bromination, substituent effects
Polyfunctional pyridines are very useful compounds
which have found applications as precursors of pharmaco-
logical compounds,1 in the synthesis of liquid crystals2
and polymers,3 as well as ligands for different transition
metal cations.4 The wide range of halopyridines,5,6 which
are able to undergo metal-halogen exchange with n-BuLi,
nucleophilic substitutions and oxidative additions with
Pd(0) allowing the introduction of many functional
groups to the pyridine ring, means they are of great inter-
est from a synthetic point of view. Moreover, halopy-
ridines are themselves important final products as
herbicides,7 insecticides8 and fungicides.9 As a conse-
quence of these features the regioselective synthesis of ha-
lopyridines is a matter of great interest.
Compounds used in this study were commercially avail-
able. Halogenations were carried out at different tempera-
tures, in solvents of different polarity (CH3CN, CCl4, CS2,
CH3OH), using different molar ratios (NBS:sustrate). The
most relevant results of this study are depicted in the Ta-
ble. Those results, which are interesting from a synthetic
point of view, have been indicated with bold characters. In
these cases we have indicated the isolated yields between
brackets. The structures of bromoderivatives were estab-
lished from their NMR parameters.
Data published in the literature up to 1970 showed that
bromination of activated pyridines must be carried out
with bromine in polar protic solvents, such as water or
ethanol.10 Several years later, it was reported the bromina-
tion of aminopyridines and N-oxides11 with bromine in
mixtures of CH3CN/CH2Cl2, while bromination of
methoxypyridines10,12 was carried out in acetic acid. Also
tetrabromocyclohexa-2,5-dienone10 has been used for the
bromination of 3-aminopyridine. In most of these papers,
the formation of mixtures of monohalo and dihalo deriva-
tives is reported but their relative proportions as well as
Reactivity of the substrates seems to be related to the elec-
tron density of the aromatic rings. Thus, bromination of
amino derivatives is slightly easier than for hydroxy py-
ridines, which in their turn show a higher reactivity than
methoxyderivatives (compare, for example, entries 1, 5
and 8 or 11, 15 and 18 or 19, 23 and 27, all of them corre-
sponding to reactions conducted in acetonitrile). On the
other hand, the formation of polybrominated compounds
does not allow us to state unequivocally the actual influ-
ence of the position of the substituent on the reactivity, but
it seems to be similar for 3- and 4-substituted hydroxy or
amino pyridines, which are lower than the corresponding
to 2-substituted ones. By contrast, reactivity of the less re-
active methoxy derivatives is clearly dependent on the po-
sition, the total bromination of 2-methoxy pyridine (entry
9) and the partial bromination of 4-methoxy pyridine be-
ing possible under stronger conditions (entry 18), whereas
the 3-methoxy pyridine does not react even after long re-
1
their H NMR characterisation is omitted. Recently, Br2/
NaOH has successfully been employed by Schnatterer et
al.13 for the highly regioselective bromination of 3-hy-
Synthesis 2001, No. 14, 26 10 2001. Article Identifier:
1437-210X,E;2001,0,14,2175,2179,ftx,en;Z07701SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

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V. Cañibano et al.
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Table Proportion of Obtained Products in the Bromination of Activated Pyridines with NBSa
Substituent
Substituent
Br
N
NBS
N
Entry Substituent Solvent Equiv T (ºC) t (h)
2-Br
3-Br
5-Br
6-Br
3,5-Br2
2,6-Br2 2,4,6-Br3 s.mb
NBS
1
2
2-NH2
2-NH2
2-NH2
2-NH2
2-OH
CH3CN
CCl4
1
1
1
2
1
1
2
1
1
1
1
1
1
2
1
2
1
1
1
1
1
2
1
1
2
3.3
1
rt
rt
rt
rt
rt
rt
rt
rt
17
20
96
24
48
48
48
72
100 (93)
84
16
6
3
MeOH
CCl4
94
4
100 (91)
5
CH3CN
CCl4
11
3
89 (76)
6
2-OH
29
34
34
60
7
2-OH
CCl4
100 (95)
8
2-OMe
2-OMe
CH3CN
CH3CN
40
9
reflux 20
100 (80)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
2,6-diOMe CH3CN
rt
rt
rt
rt
rt
rt
rt
rt
96
48
100(85)c
80 (65)
20
4-NH2
4-NH2
4-NH2
4-NH2
4-OH
4-OH
4-OH
4-OMe
3-NH2
3-NH2
3-NH2
3-NH2
3-OH
3-OH
3-OH
3-OH
3-OMe
CH3CN
CCl4
10
10
40
50
48
40
MeOH
CCl4
120
24
44
6
100 (95)
44
CH3CN
CCl4
72
12
44
24
100 (95)
32
CCl4
72
35
33
80
14
20
36
CH3CN
CH3CN
MeOH
CS2
reflux 120
20 (15)d
rt
rt
rt
rt
0
24
144
24
40
32
6
14
20
54 (43)
28
36
CCl4
24
100 (92)
19
CH3CN
CCl4
48
15
28
15
51
36
33
rt
rt
rt
48
32
4
CCl4
24
33
33
CCl4
72
100 (96)
CH3CN
reflux 120
100
a Isolated yields are in brackets.
b Recovered starting material.
c The same result was obtained after 10 h at reflux in CH3CN.
d Longer reaction times did not improve the yields.
Synthesis 2001, No. 14, 2175–2179 ISSN 0039-7881 © Thieme Stuttgart · New York

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Mild Regioselective Halogenation of Activated Pyridines with N-Bromosuccinimide
2177
action times (entry 27). Finally, the reactivity is also dif- sive products in almost quantitative yields starting from
ferent depending on the solvent and is usually higher in amino substituted pyridines (entries 4, 14 and 22). 2-Hy-
acetonitrile than in CCl4 or CS2, which is in agreement droxy and 4-hydroxypyridines are also dibrominated un-
with other results.17 The reactivity is the lowest in MeOH der the same conditions (entry 7 and 16), whereas 3-
(see entries 3, 13, and 20), due to its ability to stabilise the hydroxy pyridine yielded mixtures of the 2,4,6-tribromo
reagent by forming hydrogen bonds.
derivative under such conditions (entry 25). The latter is
satisfactorily obtained as a sole compound by using 3
equivalents of NBS in CCl4 (entry 26). In this sense we
must indicate that 3,5-dibromo derivatives were also the
only detected products when 2-hydroxy and 4-hydroxy
pyridines were treated with Br2 in water,10a while all the
methods described in the literature for bromination of
aminopyridines10,11 report lower regioselectivities than
those obtained by us with NBS.
Concerning the regioselectivity, it is affected by both, the
position and the nature of the substituent. Thus, excellent
results were exhibited in the bromination of 2-methoxy
and 2,6-dimethoxypyridine (entries 9 and 10), affording
5-bromo-2-methoxypyridine and 3-bromo-2,6-dimethox-
ypyridine, respectively, with complete regioselectivity
and in almost quantitative isolated yields, thus indicating
the high activation of the para position with respect to the
methoxy group (it had been shown previously for meth- In summary, we have confirmed that the use of NBS in ac-
oxy benzenes17). Kompis12a and Vögtle12c have also re- etonitrile allows the regioselective monobromination of
ported regioselective bromination of 2-methoxypyridine 2- and 4-amino pyridines, as well as 2-hydroxy, 2-meth-
but under harsher conditions (Br2 in glacial acetic acid). oxy and 2,6-dimethoxy pyridines in high yields. More-
Regioselectivity decreases for 2-hydroxy pyridines and over, regioselective dibromination of 2- and 4-hydroxy as
thus, reactions conducted in acetonitrile (entry 5) yield 5- well as 2-, 3-, and 4-amino pyridines has also been
bromo-2-hydroxy pyridine as the major regioisomer, but achieved in quantitative yield. The results herein de-
the 3-bromo derivative is also obtained. The association scribed are clearly better than other previously reported.
of NBS with OH could facilitate the attack on the ortho
position (as has been observed in the bromination of
phenols18) thus explaining the lower regioselectivity of
the hydroxy pyridines. In CCl4 (entry 6), the formation of
3,5-dibromo pyridine prevents the complete regioselec-
tivity of the reactions being established. Nevertheless, as
the hydrogen bonds are more easily formed in CCl4, we
could expect a higher proportion of 3-bromo derivative
than that obtained in acetonitrile, which suggests that the
dibromo derivative could mainly derive from 3-bromo-2-
hydroxy pyridine. Finally 2-aminopyridine, with a lower
tendency than the hydroxy derivative to form hydrogen
bonds with the reagent, shows complete regioselectivity
with the exclusive formation of the 5-bromoderivative19
in all the solvents employed (entries 1–3).
1H and 13C NMR spectra were recorded in CDCl3 or DMSO-d6 at
300 MHz and 80 MHz respectively; chemical shifts (d) are reported
in ppm. Mass spectra were measured on a HP-588-A spectrometer
at 70 eV with a temperature source of 200 °C.
General Procedure for the Nuclear Bromination of Activated
Pyridines with NBS.
To a solution of the corresponding activated pyridine (1 mmol) in 5
mL of solvent, NBS was added and the reaction was stirred at the
desired temperature in darkness (reaction conditions are given in the
Table). The progress of the reaction was followed in all cases by 1H
NMR spectroscopy. After the reaction was complete, the solvent
was evaporated under reduced pressure, to obtain a mixture of suc-
1
cinimide and brominated compounds, as was established by H
NMR. The crude bromoderivative was purified by flash chromatog-
raphy.
The ease of polybromination of 3- and 4-hydroxy py-
ridines and the rather low regioselectivity (even lower
than that of 2-substituted ones) determined that they could
not be monobrominated under satisfactory conditions (en-
tries 15, 17, 23, 24). In this case better results were ob-
tained by Schnatterer,13 in the bromination of 3-
hydroxypyridine with Br2 in NaOH. Aminopyridines are
less prone to polybromination, which made it possible to
find the conditions allowing the synthesis of 4-amino-3-
bromopyridine as the major product (65% isolated yield,
entry 11). As in the case of the hydroxy derivatives, the
worst results were achieved from 3-amino pyridine (en-
tries 19–21). The reactions in MeOH for the preparation
of the 2-bromo derivative are the most interesting from a
synthetic point of view (entry 20). The low reactivity of
the 3- and 4-methoxy pyridines discards their use as start-
ing compounds to prepare their brominated derivatives
despite the fact that the last one evolved into the monobro-
minated compound as the sole product (entry 18).
5-Bromo-2-hydroxypyridine
Flash chromatography with Et2O–hexane, 30:1 gave the titled com-
pound as a yellow solid.
1H NMR (DMSO-d6): d = 6.34 (dd, 1 H, J = 9.6, 0.5 Hz, H-3), 7.53
(dd, 1 H, J = 9.6, 2.8 Hz, H-4), 7.67 (dd, 1 H, J = 2.8, 0.5 Hz, H-6),
11.77 (br s, 1 H, OH).
13C NMR (DMSO-d6): d = 98.5 (C-5), 120.6 (C-3), 137.5 (C-4),
143.6 (C-6), 161.5 (C-2).
MS: m/z (%) 175/173 (75/74.5, M+), 94 (13), 81/79 (62/60, Br+).
Anal. Calcd for C5H4NOBr: C, 34.51; H, 2.32; N, 8.05. Found: C,
34.65; H, 2.31; N, 8.03.
3-Bromo-2-hydroxypyridine
Flash chromatography with Et2O–hexane, 30:1 gave gave the titled
compound as a yellow solid.
1H NMR (DMSO-d6): d = 6.12 (dd, 1 H, J = 7.2, 6.4 Hz, H-5), 7.43
(dd, 1 H, J = 6.4, 1.9 Hz, H-4), 7.90 (dd, 1 H, J = 7.2, 1.9 Hz, H-6),
11.77 (br s, 1 H, -OH).
MS: m/z (%) 175/173 (97/100, M+), 81/79 (17/11, Br+).
The use of 2 equivalents of NBS in CCl4 allows the regi-
oselective synthesis of dibrominated compounds as exclu-
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V. Cañibano et al.
PAPER
Anal Calcd for C5H4NOBr: C, 34.51; H, 2.32; N, 8.05. Found: C,
34.62; H, 2.33; N, 8.08.
3-Amino-6-bromopyridine
Flash chromatography with Et2O–hexane, 4:1 gave the titled com-
pound as a yellow solid.
3,5-Dibromo-2-hydroxypyridine10a
Flash chromatography with Et2O–hexane, 20:1gave the titled com-
pound as a yellow solid.
1H NMR (DMSO-d6): d = 7.74 (d, 1 H, J4,6 =1.6 Hz, H-4), 8.09 (d,
1 H, J = 1.6 Hz, H-6).
13C NMR (DMSO-d6): 96.6 (C-5), 115.9 (C-3), 136.3 and144.7 (C-
4 and C-6), 157.7 (C-2).
1H NMR (CDCl3): d = 3.64 (br s, 2 H, NH2), 6.88 (dd, 1 H, J = 8.5,
3.0 Hz, H-4), 7.22 (d, 1 H, J = 8.5 Hz, H-5), 7.85 (d, 1 H, J = 3.0
Hz, H-2).
13C NMR (CDCl3): d = 124.7 (C-4), 127.7 (C-5), 129.4 (C-6), 137.0
(C-2), 142.1 (C-3).
MS: m/z (%) 174/172 (100/100, M+), 93 (45), 81/79 (16/16, Br+).
Anal Calcd for C5H5N2Br: C, 34.72; H, 2.91; N, 16.19. Found: C,
34.64; H, 2.93; N, 16.12.
MS: m/z (%) 255/253/251 (52/100/49, M+), 81/79 (18/11, Br+).
Anal Calcd for C5H3NOBr2: C, 23.74; H, 1.20; N, 5.54. Found: C,
23.83; H, 1.17; N, 5.51.
3-Amino-2-bromopyridine10a
Flash chromatography in Et2O–hexane, 3:1 gave the titled com-
pound as a yellow solid.
1H NMR (CDCl3): d = 7.02 (dd, 1 H, J = 7.9, 1.9 Hz, H-4), 7.07 (dd,
1 H, J = 7.9, 4.3 Hz, H-5), 7.78 (dd, 1 H, J = 4.3 Hz, 1.9 Hz, H-6).
13C NMR (CDCl3): d = 121.9 and 123.6 (C-4 and C-5), 124.7 (C-2),
138.7 (C-6) 141.2 (C-3).
3-Bromo-2,6-dimethoxypyridine
Flash chromatography with hexane gave the titled compound as a
yellow oil.
1H NMR (CDCl3): d = 3.90 and 3.99 (2 ¥ s, 6 H, 2 ¥ CH3O-), 6.23
(d, 1 H, J = 8.3 Hz, H-5), 7.64 (d, 1 H, J = 8.3 Hz, H-4).
13C NMR (CDCl3): d = 53.8 and 54.2 (2 ¥ CH3O), 95.3 (C-3), 102.6
(C-5), 143.6 (C-4), 158.4 (C-6), 162.0 (C-2).
MS: m/z (%) 174/172 (98/100, M+), 81/79 (17/15, Br+).
Anal Calcd. for C5H5N2Br: C, 34.72; H, 2.91; N, 16.19. Found: C,
34.85; H, 2.92; N, 16.25.
MS: m/z (%) 219/217 (100/98, M+), 190/188 (48/57, M+-OCH3),
159/157 (6/3, M+-2 OCH3), 108 (34), 93 (40).
Anal Calcd for C7H8NO2Br: C, 38.57; H, 3.70; N, 6.42. Found: C,
38.38; H, 3.68; N, 6.41.
3-Amino-2,6-dibromopyridine10a
Flash chromatography with Et2O–hexane, 5:1 gave the titled com-
pound as a yellow solid.
3-Bromo-4-hydroxypyridine
Flash chromatography with acetone–methanol, 10:1 gave the titled
compound as a white solid.
1H NMR (DMSO-d6): d 6.26 (d, 1 H, J = 7.2 Hz, H-5), 7.71 (dd, 1
H, J = 7.2, 1.4 Hz, H-6), 8.21 (d, 1H, J = 1.4 Hz, H-2).
13C NMR (DMSO-d6): d = 113.8 (C-3), 115.3 (C-5), 137.8, 139.1
(C-2 and C-6), 171.9 (C-4).
MS: m/z (%) 175/173 (98/100, M+), 81/79 (17/15, Br+).
1H NMR (CDCl3): d = 4.21 (br s, 2 H, NH2), 6.92 (d, 1 H, J = 8.3
Hz, H-4), 7.20 (d, 1 H, J = 8.3 Hz, H-5).
13C NMR (CDCl3): d = 123.4 and 124.5 (C-2 and C-6), 124.4 and
127.4 (C-4 and C-5), 141.2 (C-3).
MS: m/z (%) 254/252/250 (48/100/51, M+), 81/79 (18/11, Br+).
Anal Calcd for C5H4N2Br2: C, 23.84; H, 1.60; N, 11.12. Found: C,
23.94; H, 1.61; N, 11.17.
Spectroscopic data of 2-amino-5-bromo pyridine,11 2-amino-3,5-di-
bromopyridine,11 5-bromo-2-methoxy pyridine,12c 4-amino-3-bro-
mo pyridine,11 4-amino-3,5-dibromopyridine,11 2-bromo-3-
hydroxypyridine,13 2,6-dibromo-3-hydroxypyridine,13 and 2,4,6-
tribromo-3-hydroxypyridine13 are identical with those reported in
the literature.
Anal Calcd for C5H4NOBr: C, 34.51; H, 2.32; N, 8.05. Found: C,
34.58; H, 2.37; N, 8.03.
3,5-Dibromo-4-hydroxypyridine10a
Flash chromatography with acetone–methanol, 10:1 gave the titled
compound as a yellow solid.
1H NMR (DMSO-d6): d = 8.25 (s, 2 H, H-2 and H-6).
13C NMR (DMSO-d6): d = 111.9 (C-3 and C-5), 138.3 (C-2 and C-
6), 157.5 (C-4).
Acknowledgement
We thank DGYCIT (grant BQU2000-0246) for financial support.
MS: m/z (%) 255/253/251 (51/100/52, M+), 94 (12), 81/79 (10/7,
Br+).
References
Anal Calcd for C5H3NOBr2: C, 23.74; H, 1.20; N, 5.54. Found: C,
23.66; H, 1.19; N, 5.52.
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Flash chromatography with hexane–ethyl acetate, 2:1 gave the titled
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38.39; H, 3.26; N, 7.25.
Synthesis 2001, No. 14, 2175–2179 ISSN 0039-7881 © Thieme Stuttgart · New York

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Mild Regioselective Halogenation of Activated Pyridines with N-Bromosuccinimide
2179
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Synthesis 2001, No. 14, 2175–2179 ISSN 0039-7881 © Thieme Stuttgart · New York