High yield synthesis of 5,5'-dimethyl-2,2'-bipyridine and 5,5-dimethyl- 2,2':6',2-terpyridine and some bisfunctionalization reactions using N- bromosuccinimide

Article abstract of DOI:10.1055/s-1999-3465

5,5'-Dimethyl-2,2'-bipyridine and 5,5_-dimethyl-2,2':6',2_-terpyridine were synthesized in multigram quantities in high yields utilizing organotin intermediates and Stille coupling procedures. The obtained ligands were dibrominated using N-bromosuccinimide.

Full text of DOI:10.1055/s-1999-3465

PAPER
779
High Yield Synthesis of 5,5’-Dimethyl-2,2’-bipyridine and 5,5’’-Dimethyl-
2,2’:6’,2’’-terpyridine and Some Bisfunctionalization Reactions Using
N-Bromosuccinimide
Ulrich S. Schubert,* Christian Eschbaumer, Georg Hochwimmer
Lehrstuhl für Makromolekulare Stoffe, Technische Universität München, Lichtenbergstr. 4, D-85747 Garching, Germany
Fax +49(89)28913562; E-Mail: schubert@makroserv.tech.chemie.tu-muenchen.de
Received 12 October 1998
Dedicated to Professor Dr. Dieter Schubert on the occasion of his 60th birthday
In contrast to the well established chemistry of the 6,6’-
disubstituted bipyridines (synthesis of the 6,6’-dimethyl-
2,2’-bipyridine on 100 g scale5 and the functionalization
Abstract: 5,5'-Dimethyl-2,2'-bipyridine and 5,5''-dimethyl-
2,2':6',2''-terpyridine were synthesized in multigram quantities in
high yields utilizing organotin intermediates and Stille coupling
procedures. The obtained ligands were dibrominated using N-bro-
mosuccinimide.
via the N-oxide route and Boekelheide rearrangement5a,6
)
and the commercially available 4,4’-dimethyl-2,2’-bipy-
ridine,7 high yield synthetic routes towards the corre-
sponding 5,5’-dimethyl compound are not described up to
now. (However, a very elegant monofunctionalization
was reported recently8). This is also the case for the corre-
sponding 5,5’-dimethylterpyridine ligands. We describe
here a new large scale approach towards 5,5'-disubstituted
bipyridine and 5,5''-disubstituted terpyridine building
blocks as well as the corresponding dibromination by rad-
ical bromination developed during our research in the di-
rection of new metallo-supramolecular initiators for the
living polymerization of oxazolines and related mono-
mers.9,10
Key words: 2,2’-bipyridines, 2,2':6',2''-terpyridines, Stille cou-
pling, organotin intermediates, radical bromination
Since 1980, many highly ordered metallo-supramolecular
architectures were obtained using the self-assembly of
heterocyclic ligands with transition metal ions.1 However,
only a few heterocyclic systems fulfill the requirements
for practical applications, such as formation of special ar-
chitectures using recognition-directed self-assembly fea-
tures, availability of the components in usable quantities,
and possessing end groups which can be covalently incor-
porated into networks, assemblies or polymers. Some of
the most prominent examples are the 5,5’-disubstituted
oligo(2,2’-bipyridine) nickel(II) or iron(II) complexes
with ethylene linkers between the bipyridine units2,3 and
the 5,5’’-disubstituted-2,2’:6’,2’’-terpyridine nickel(II) or
iron(II) complexes with ethylene or methyleneoxymethyl-
ene linkers between the terpyidine units4 due to their abil-
ity to spontaneously form well-defined double, triple or
circular helical architectures (”helicates”). However, the
multistep preparation of the basic unfunctionalized
5,5'-dimethyl-2,2'-bipyridine or 5,5''-dimethyl-2,2':6',2''-
terpyridine ligands or its functionalized derivatives has al-
ways been the major drawback in the synthetic strategies
towards these supramolecular building blocks.
The synthesis of 5,5'-dimethyl-2,2'-bipyridine has been
reported previously using classical coupling procedures
starting from 3-picoline or 2-bromo-5-methylpyridine.11
However, the yields obtained are rather low (0.5–36%)
and the purification is sometimes very critical. We devel-
oped therefore a directed strategy using organotin inter-
mediates and Stille coupling procedures.12 Starting from
the commercially available 2-amino-5-methylpyridine (1)
the well-described 2-bromo-5-methylpyridine (2) could
be synthesized in a 140 gram scale in 85% yield using a
modified literature procedure13 in a special 2 L glass reac-
tor.
2-Bromo-5-methylpyridine (2) was then reacted with bu-
tyllithium at -78°C and the corresponding lithio com-
pound 3 formed was directly treated with tributyltin
chloride to yield 98% of 5-methyl-2-tributylstannyl pyri-
dine (4). The reaction was carried out in a 70 gram scale
using Kugelrohr distillation for purification (for earlier
preparations of 4 using the same strategy, see References
12,14). Stille-type coupling of 4 with 2-bromo-5-meth-
ylpyridine (2) yielded 86% of the 5,5'-dimethyl-2,2'-bipy-
ridine (5) (72% overall yield starting from the
commercially available 1) (Scheme 1).
Using the same 5-methyl-2-tributylstannyl pyridine (4)
the 5,5''-dimethyl-2,2':6',2''-terpyridine (7) can be ob-
tained by cross-coupling with 2,6-dibromopyridine (6)
(Scheme 2). A 2.5 times excess of 4 yielded 90% of the
Synthesis 1999, No. 5, 779– 782 ISSN 0039-7881 © Thieme Stuttgart · New York

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U. S. Schubert et al.
PAPER
low. Studies in this direction to develop new functional-
ization procedures are currently in progress (cf. Referenc-
es 9b, 9c).
Scheme 3
Reagents were obtained from commercial suppliers and used with-
out further purification. THF was distilled under N2 from potassium
immediately prior to use in lithiation reactions. CH2Cl2 was dried
over CaH2. Organic extracts were dried over MgSO4 or Na2SO4.
Chromatography was carried out on Merck 60 silica gel (0.040–
1
0.063 mm), Merck, activity II–III, alumina (0.063–0.200 mm). H
Scheme 1
and 13C NMR spectra were recorded at 300 and 75 MHz, respective-
ly, on a Bruker AC 300 spectrometer in CDCl3. The chemical shifts
were calibrated to the residual solvent peak or TMS. Melting points
were measured on a digital Mettler FP-5/FP-51 apparatus. Electron-
ic absorption spectra were measured on a Varian Cary 3 spectrom-
eter with λ in nm and ε ( î 104) in M–1cm–1.
corresponding terpyridine 7 (75% overall yield starting
from the commercially available 1). The isolation of 7
could be performed without column chromatography by
separation of the starting materials and the organotin
byproducts by acidification of the reaction mixture and
subsequent extraction with organic solvents. Stannylpyri-
dine 4, 2,6-dibromopyridine (6), and tributyltin bromide
are extracted into the organic phase of a 6 M HCl/CH2Cl2
mixture, whereas the terpyridine 7 remains in the aqueous
phase. After neutralization (pH 9) the crude terpyridine 7
was filtered off and recrystallized. This reaction sequence
2-Bromo-5-methylpyridine (2)
To a stirred aq HBr (48%, 500 mL) was added 2-amino-5-meth-
ylpyridine (1; 100 g, 0.926 mol) at 20–30°C. As soon as 1 had dis-
solved completely, the mixture was cooled to –20°C. The
suspension was stirred and Br2 cooled to -5°C (133 mL, 2.59 mol)
was added dropwise. After stirring for 90 min at –20°C solution of
NaNO2 [170 g (2.46 mol) in H2O (250 mL)] was added dropwise.
The mixture was allowed to warm to r.t. and stirred for 1 h. The
mixture was cooled to –20°C and NaOH [667 g (16.68 mol) in H2O
and the separation can also be performed in one step from (1000 mL)] was added dropwise. The mixture was warmed to r.t.
and extracted 6 times with Et2O. The combined organic layers were
2.
dried (Na2SO4) and the solvent was evaporated in vacuo. The solid
was purified by sublimation resulting in 135 g (85%) of 2; mp 39–
40°C.
1H NMR (CDCl3): δ = 2.28 (3 H, s, H-7), 7.35 (2 H, m, H-3,4), 8.19
(1 H, s, H-6).
13C NMR (CDCl3): δ = 17.64 (C-7), 127.39 (C-3), 132.38 (C-5),
138.88 (C-2), 139.20 (C-4), 150.32 (C-6).
MS (EI, 70 eV): m/z (%) = 171 (44) [M+], 92 (100) [M+ – 79].
Anal. C6H6BrN (172.0): calcd C, 41.86; H, 3.49, Br, 46.45, N, 8.14;
found: C, 41.76; H, 3.50; Br, 46.55; N, 8.19.
Scheme 2
5-Methyl-2-tributylstannyl pyridine (4)
A solution of 2 (32.14 g, 0.187 mol) in THF (300 mL) was cooled
to –78°C and BuLi (122 mL, 1.6 M in hexane, 0.195 mol) was add-
The dimethyl-substituted ligands 5 and 7 can then be eas-
ily reacted with N-bromosuccinimide (NBS) to obtain the
corresponding interesting building blocks 5,5’-bis(bro-
momethyl)-2,2’-bipyridine (8) and 5,5’’-bis(bromo-
methyl)-2,2’:6’,2’’-terpyridine (9) as shown in Scheme 3
(surprisingly we could not find full synthetic procedures,
characterization data or information concerning the yields
in the literature, even though the compounds have been
used in several cases15). However, the yields are rather
ed dropwise during 30 min. After stirring for further 90 min,
Bu3SnCl (60.5 mL, 0.224 mol) was added. The mixture was stirred
for another 8 h at –78°C and was then allowed to warm to r.t. After
adding H2O (100 mL) the aqueous layer was extracted 4 times with
Et2O. The combined organic fractions were dried (Na2SO4) and the
solvent was evaporated in vacuo. The resulting liquid product was
purrified by Kugelrohr distillation to yield 70.59 g (98%) of 4; bp
130°C/0.0038 Torr.
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High Yield Synthesis of 5,5’-Dimethyl-2,2’-bipyridine and 5,5’’-Dimethyl-2,2’:6’,2’’-terpyridine
781
1H NMR (CDCl3): δ = 0.88 (9 H, t, J = 7.3 Hz, H-4’), 1.11 (6 H, t, J
= 8.0 Hz, H-1’), 1.32 (6 H, tq, J = 7.25 Hz, H-3’), 1.56 (6 H, m, H-
2’), 2.28 (3 H, s, H-7), 7.30 (2 H, m, H-3,4), 8.59 (1 H, s, H-6).
13C NMR (CDCl3): δ = 9.71 (C-1’), 13.63 (C-4’), 18.46 (C-7), 27.30
(C-3’), 29.06 (C-2’), 131.19 (C-5), 131.78 (C-3), 133.92 (C-4),
151.27 (C-6), 169.57 (C-2).
maining solid was dissolved in CH2Cl2 (100 mL) and extracted with
0.5 M Na2S2O3 solution (2 î150 mL). The combined Na2S2O3 frac-
tions were extracted with CH2Cl2 (50 î mL)and the combined
CH2Cl2 layers were dried (Na2SO4). The crude product was recrys-
tallized from CH2Cl2 yielding 0.293 g (28%) of a white powder.
Further purification using column chromatography (silica gel,
EtOAc/hexane, 1:4) yielded 0.26 g (25%) of very pure 8; mp 193–
194°C.
1H NMR (CDCl3): δ = 4.56 (4 H, s, H-7,7'), 7.96 (2 H, dd, 8.20 Hz,
J = 2.29 Hz, H-4,4'), 8.55 (2 H, d, J = 8.39 Hz, H-3,3'), 8.74 (2 H, s,
H-6,6').
MS (EI, 70 eV): m/z (%) = 326 (50) [M+ – 56], 268 (45) [M+ – 114],
212 (100) [M+ – 170].
Anal. C18H33NSn (382.2): calcd C, 56.56; H, 8.64; N, 3.67; Sn,
31.08; found: C, 56.29; H, 8.84; N, 3.78; Sn, 31.09.
13C NMR (CDCl3): δ = 29.46 (C-7,7'), 121.24 (C-3,3'), 133.97 (C-
5,5'), 137.71 (C-4,4'), 149.27 (C-6,6'), 155.21 (C-2,2').
5,5’-Dimethyl-2,2’-bipyridine (5)
A mixture of 5-methyl-2-tributylstannyl pyridine (4; 12.13 g, 31.7
mmol), 2-bromo-5-methylpyridine (2; 4.64 g, 27.0 mmol) and
(Ph3P)4Pd (1.11 g, 0.96 mmol) in toluene was refluxed under N2 for
3 d. The resulting brown mixture was evaporated in vacuo and the
dark solid was dissolved in CH2Cl2. The organic phase was extract-
ed 3 times with aq 6 M HCl. To recover the product from aq HCl,
the combined aqueous layers were added dropwise to aq NH3 (10%)
under cooling. The solid formed was filtered, washed with aq NH3,
H2O and purified by chromatography on silica gel with CH2Cl2 as
eluent resulting in 4.27 g (86%) of a white solid; mp 114–115°C.
1H NMR (CDCl3): δ = 2.37 (6 H, s, H-7,7'), 7.60 (2 H, d, J = 8.2 Hz,
H-4,4'), 8.24 (2 H, d, J = 8.0 Hz, H-3,3'), 8.48 (2 H, s, H-6,6').
13C NMR (CDCl3): δ = 18.29 (C-7,7'), 120.31 (C-3,3'), 133.01 (C-
5,5'), 137.41 (C-4,4'), 149.48 (C-6,6'), 153.70 (C-2,2').
MS (EI, 70 eV): m/z (%): 184 (100) [M+].
MS (EI, 70 eV), m/z (%) = 341 (24) [M+].
Anal. C12H10Br2N2 (342.0): Calc. C, 42.14; H, 2.95; N, 8.19; found:
C, 42.39; H, 3.14; N, 8.07.
5,5’’-Bis(bromomethyl)-2,2’:6’,2’’-terpyridine (9)
A mixture of 7 (2.27 g, 8.69 mmol), NBS (7.75 g, 43.5 mmol) and
AIBN (221 mg, 1.35 mmol) in CCl4 (120 mL) was refluxed under
N2 for 32 min and the precipitated succinimide was removed imme-
diately from the hot mixture by filtration. The precipitate was
washed with CCl4, the combined CCl4 phases were reduced to 50
mL in vacuo and the precipitate was removed by filtration. The solid
was dissolved in CH2Cl2 (100 mL) and extracted with 0.5 M
Na2S2O3 solution (2 î 150 mL). The combined Na2S2O3 fractions
were extracted with CH2Cl2 (50 mL) and the combined CH2Cl2 lay-
ers were dried (Na2SO4) yielding 870 mg (24%) of 9 after recrystal-
lization from CHCl3; mp 195–196°C.
1H NMR (CDCl3): δ = 4.56 (4 H, s, H-7,7''), 7.92 (2 H, dd, J = 8.39,
2.29 Hz, H-4,4''), 7.97 (1 H, t, J = 8.01 Hz, H-4'), 8.47 (2 H, d, J =
8.02 Hz, H-3',5'), 8.61 (2 H, d, J = 8.01 Hz, H-3,3''), 8.72 (2 H, d, J
= 2.29 Hz, H-6,6'').
13C NMR (CDCl3): δ = 29.54 (C-7,7''), 121.24 (C-3,3''), 121.55 (C-
3',5'), 133.87 (C-5,5''), 137.79 (C-4,4''), 138.08 (C-4'), 149.06 (C-
6,6''), 154.61 (C-2,2''), 155.78 (C-2',6').
Anal. C12H12N2 (184.1): calcd C, 78.23; H, 6.56; N, 15.20; found: C,
78.02; H, 6.54; N, 15.16.
5,5’’-Dimethyl-2,2’:6’,2’’-terpyridine (7)
A mixture of 4 (70.59 g, 0.185 mol), 2,6-dibromopyridine (6; 17.54
g, 0.074 mol) and (Ph3P)4Pd (5.18 g, 4.48 mmol) in toluene
(500 mL) were heated under reflux for 120 h. The solvent was re-
moved in vacuo and the brown residue was treated with 6 M HCl
(300 mL). The suspension was extraced with CH2Cl2 (1 × 500 mL,
4 × 200 mL) and the organic layers were washed with 6 M HCl (3
× 150 mL). The combined HCl solutions were treated with aq NH3
(25%) and the pH adjusted to 9. The precipitate was separated, dis-
solved in CH2Cl2 and dried (Na2SO4). After removal of the solvent
in vacuo the light yellow solid was recrystallized from EtOAc to af-
ford 7 as a white solid; yield: 17.38 g (90%); mp 174–175°C.
MS (EI, 70 eV), m/z (%) = 419 (20) [M+].
Anal. C17H13Br2N3 (419.1): calcd C, 48.72; H, 3.13; N, 10.03;
found: C, 48.63; H, 2.68; N, 10.05.
Acknowledgement
IR (KBr): n = 2916 w, 1591 w, 1557 s, 1484 m, 1443 m, 1375 w,
1257 w, 1132 m, 1024 m, 812 s, 754 m cm–1.
This study was supported by the Bayerisches Staatsministerium für
Unterricht, Kultus, Wissenschaft und Kunst, the Deutsche For-
schungsgemeinschaft (DFG) and the Fonds der Chemischen Indu-
strie. We thank Reilly Tar & Chem. Corp. for contributing 1 and
Prof. Dr.-Ing. Oskar Nuyken for his support.
UV/VIS (MeCN): λmax (ε) = 245 (1.89), 286 (2.17).
1H NMR (CDCl3): δ = 2.39 (6 H, s, H-7,7’’,), 7.63 (2 H, d, J = 8.01
Hz, H-4,4’’), 7.91 (1 H, t, J = 7.82 Hz, H-4’), 8.38 (2 H, d, J = 7.62
Hz, H-3’,5’), 8.49 (2 H, d, J = 8.40 Hz, H-3,3’’), 8.50 (2 H, s, H-6,6’’).
13C NMR (CDCl3): δ = 18.34 (C-7,7’’), 120.32 (C-3,3’’), 120.64 (C-
3’,5’), 133.32 (C-5,5’’), 137.32 (C-4,4’’), 137.70 (C-4’), 149.46 (C-
6,6’’), 153.75 (C-2,2’’), 155.33 (C-2’,6’).
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Article Identifier:
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Synthesis 1999, No. 5, 779–782 ISSN 0039-7881 © Thieme Stuttgart · New York