Organic Syntheses, Vol. 78, 51
Checked by Erik Kuester and Louis S. Hegedus.
1. Procedure
C. 5-Methyl-2,2'-bipyridine (
3). The 4- and
6-methyl-2,2'-bipyridines may also be prepared using the following procedure. A
500-mL,
two-necked, round-bottomed flask (Note
2) with a
Teflon-coated magnetic stirrer is placed in a
dry
ice/acetone bath (−78°C), then
80
mL of tetrahydrofuran (THF) (Note
11) and
tert-butyllithium (tert-BuLi) (1.75
M in pentane, 52 mL, 91.0 mmol)
(Note
12) are added to it, followed by dropwise addition of
2-bromopyridine (7.13 g, 4.3
mL, 45.1 mmol) (Note
13).
The canary yellow THF solution becomes reddish-brown upon addition of the
pyridyl
bromide. After the solution is stirred at −78°C for 30 min,
anhydrous zinc chloride (ZnCl2) (13.3
g, 97.4 mmol) (Note
14) is added,
and the reaction is stirred at 25°C for 2 hr. The
5-methylpyridyl
triflate (2) (8.95 g, 37.1 mmol),
lithium choride (LiCl) (3.18 g, 75.2
mmol) (Note
15), and
tetrakis(triphenylphosphine)
palladium (Pd(PPh3)4) (1.75 g, 1.5
mmol) (Note
16) are then added. The brownish-yellow
reaction mixture is heated at reflux (Note
17) for 18 hr. After
the solution is cooled, an
aqueous solution of ethylenediaminetetraacetic
acid (EDTA) (55 g, 148 mmol in 400
mL) (Note
18) is added and the pH is adjusted
to ≈8 with
saturated aqueous sodium bicarbonate
(NaHCO3). The solution is stirred for 15 min then poured into
a
separatory funnel. The product is extracted with
CH2Cl2 (3 × 200 mL).
The combined organic fractions are dried over
anhydrous Na2SO4,
filtered, and concentrated using a
rotary evaporator. Flash
chromatography on
275 g of deactivated silica
gel (Note
9) (
20%
EtOAc:80% hexanes) affords
5.94 g (
94%)
of
5-methyl-2,2'-bipyridine as a very pale yellow oil (Note
19).
2. Notes
2. Before use, all glassware, needles, and syringes were dried overnight
in a 120°C oven.
4.
Sodium nitrite
was purchased from Aldrich Chemical Company, Inc.
and used as obtained.
6. The following characterization data was obtained:
1H NMR (CDCl
3, 300 MHz) δ:
1.99 (s, 3 H), 6.43 (d, 1 H, J = 8.8), 7.06 (s, 1
H), 7.23 (dd, 1 H, J = 2.2, 9.5), 13.48 (s, 1 H);
13C NMR (CDCl
3,
75 MHz) δ: 17.1, 116.2, 119.8, 132.5,
144.4, 164.9. Anal. Calcd for C
6H
7NO:
C, 66.04; H, 6.46; N, 12.84. Found: C, 66.09; H, 6.31; N, 13.05.
7.
Pyridine (99.9+%
HPLC grade) was purchased from Aldrich Chemical Company, Inc.,
and used without further purification.
8.
Trifluoromethanesulfonic anhydride,
obtained from Aldrich Chemical Company, Inc., was
used as received and weighed in a syringe inside a dry box. The checkers measured
the anhydride volumetrically in a dry syringe, in a hood using a density of 1.68.
Transfer in a dry box proved unnecessary.
9.
Silica gel used for flash chromatography
(particle size 0.035-0.075 mm) was obtained from VWR Scientific Products.
Silica chromatography columns were deactivated by flushing with 10%
triethylamine
(Et
3N) in hexanes and then were washed with hexanes prior to use.
10. The product has the following properties: TLC R
f =
0.54 (20% EtOAc:80% hexanes);
1H
NMR (CDCl
3, 300 MHz) δ: 2.37 (s, 3 H), 7.06 (d,
1 H, J = 8.1), 7.67 (dd, 1 H, J = 2.4, 8.5), 8.17 (s, 1
H);
13C
NMR (CDCl
3, 75 MHz) δ: 17.9, 114.9, 118.8
(q, J
CF = 320.3), 134.7, 141.6, 148.8,
154.2. Anal. Calcd for C
7H
6F
3NO
3S:
C, 34.86; H, 2.51; N, 5.81. Found: C, 34.99; H, 2.19; N, 5.70.
11. THF was dried and purified by passage through
alumina
solvent purification columns
3 or by distillation over
sodium/
benzophenone.
12. A
1.6 M solution of tert-BuLi
in pentane was obtained from Aldrich Chemical Company,
Inc. It is crucial to have at least
2
equiv of tert-BuLi for the
lithium-halogen
exchange. Depressed yields (25-60%) were obtained when less than 2 equiv were used.
The
tert-BuLi is titrated prior to its use in each reaction using
the following procedure.
4
To a
50-mL Schlenk flask is added
N-benzylbenzamide
(274 mg, 1.3 mmol) (as received from Aldrich
Chemical Company, Inc.) and
THF (10
mL) (Note
11). The solution is cooled to
−43°C (
acetonitrile/dry ice) and
tert-BuLi
is added dropwise to the blue endpoint (color persists for >30 s). The molarity
is calculated using a 1:1 stoichiometric ratio of
N-benzylbenzamide
to
tert-BuLi (just greater than 1 equivalent of alkyllithium
needed to reach the endpoint).
13.
2-Bromopyridine
was purchased from Aldrich Chemical Company, Inc.,
and used as received.
14.
Zinc chloride,
obtained from Strem Chemicals Inc., was flame-dried
to remove excess H
2O and stored in a dry box prior to use. Weighing out
flame-dried
zinc chloride on the bench rather than in a dry box
resulted in reduced yields. When a 1M solution of the above flame-dried
zinc
chloride was prepared in THF and transferred by syringe, the published
yields were obtained.
15. Granular
lithium chloride
from Mallinckrodt, Inc. was stored in a dry box prior
to use. The checkers stored the LiCl in a
desiccator before
use.
16. The
Pd(PPh3)4
catalyst can be purchased from Aldrich Chemical Company, Inc.,
or Strem Chemicals Inc. However, it was easily prepared
using the procedure of Coulson
5 for the synthesis
delineated here.
17.
Pentane is removed by distillation (bp 36°C).
A reflux temperature of 70-75 is required for the reaction to proceed to completion.
18.
Ethylenediaminetetraacetic
acid, disodium salt dihydrate, 99+%
was obtained from Aldrich Chemical Company, Inc. and
used as received. The EDTA mixture was heated gently to facilitate dissolution and
was allowed to cool to room temperature prior to use.
19. The analytical data for
5-methyl-2,2'-bipyridine
are as follows: TLC R
f = 0.46 (20% EtOAc:80% hexanes);
1H NMR (CDCl
3, 300 MHz) δ:
2.43 (s, 3 H), 7.35 (dd, 1 H, J = 4.6, 7.7), 7.71
(d, 1 H, J = 7.7), 7.87 (t, 1 H, J = 7.3), 8.39 (d, 1 H,
J = 7.7), 8.48 (d, 1 H, J = 7.3), 8.55 (s, 1 H),
8.70 (d, 1 H, J = 4.6);
13C NMR (CDCl
3, 75 MHz) δ: 17.7,
120.0, 120.2, 122.8, 132.8, 136.2,
136.8, 148.5, 149.1, 153.0, 155.7.
Anal. Calcd for C
11H
10N
2: C, 77.62; H, 5.92; N, 16.46.
Found: C, 77.66; H, 5.98; N, 16.37.
All toxic materials were disposed of in accordance with "Prudent Practices in the
Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
As ligands for metal ions, 2,2'-bipyridines find wide application in chemistry.
They have been used in studies of supramolecular assembly,
6 in bioinorganic contexts,
7 and in polymeric materials,
8 as well
as in discrete small-molecule analogues.
Traditionally, methyl-2,2'-bipyridines (methyl bpys) have been prepared by the
Kröhnke method, which involves reaction of pyridinium salts with α,β-unsaturated
ketones followed by treatment with
ammonium acetate to effect
cyclization.
9 They have also been made by coupling pyridyllithium reagents
with pyridyl sulfoxides,
10 by Ni and other metal-catalyzed
cross-coupling reactions,
11 by the Ullman reaction
9
and by use of α-oxoketene dithioacetals among a variety of other routes.
12 Many methods lead
to mixtures of isomers or they produce dimethyl byproducts. Nearly all of them afford
products in moderate yields at best. The cross-coupling of a pyridyl zinc reagent
and a pyridyl triflate in the presence of a catalytic amount of
palladium
by the Negishi method
13 as described here constitutes an efficient, large scale,
high yield synthesis of 4-, 5-, and
6-methyl-2,2'-bipyridine.
These methyl bpys are readily converted to bromomethyl and chloromethyl analogues,
14 which are valuable starting
materials for further derivatization.
15 Moreover, the halomethyl bipyridines have been used
as ligand initiators in controlled polymerizations.
16
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
2-Hydroxy-5-methylpyridine: 2(1H)-Pyridinone,
5-methyl- (8,9); (1003-68-5)
2-Amino-5-methylpyridine: Aldrich Name: 2-Amino-5-picoline:
HIGHLY TOXIC: 3-Picoline, 6-amino- (8); 2-Pyridinamine,
5-methyl- (9); (1603-41-4)
Sodium nitrite: Nitrous acid, sodium salt
(8,9); (7632-00-0)
5-Methyl-2-(trifluoromethanesulfonyl)oxypyridine: Methanesulfonic
acid, trifluoro-, 5-methyl-2-pyridinyl ester (13); (154447-03-7)
4-Methyl-2-pyridyl triflate: Methanesulfonic
acid, trifluoro-, 4-methyl-2-pyridinyl ester (13); (179260-78-7)
6-Methyl-2-pyridyl triflate: Methanesulfonic
acid, trifluoro-, 6-methyl-2-pyridinyl ester (13); (154447-04-8)
Trifluoromethanesulfonic anhydride: Methanesulfonic
acid, trifluoro-, anhydride (8,9); (358-23-6)
5-Methyl-2,2'-bipyridine: 2,2'-Bipyridine,
5-methyl- (9); (56100-20-0)
4-Methyl-2,2'-bipyridine: 2,2'-Bipyridine,
4-methyl- (9); (56100-19-7)
6-Methyl-2,2'-bipyridine: 2,2'-Bipyridine,
6-methyl- (9); (56100-22-2)
tert-Butyllithium: Lithium, tert-butyl-
(8); Lithium, (1,1-dimethylethyl)- (9); (594-19-4)
2-Bromopyridine: HIGHLY TOXIC: Pyridine,
2-bromo- (8,9); (109-04-6)
Zinc chloride (8,9); (7646-85-7)
Lithium chloride (8,9); (7447-41-8)
Tetrakis(triphenylphosphine)palladium(0): Palladium,
tetrakis(triphenylphosphine)- (8); Palladium, tetrakis(triphenylphosphine)-,
(T-4)- (9); (14221-01-3)
Ethylenediaminetetraacetic acid, disodium salt dihydrate:
Acetic acid (ethylenedinitrilo)tetra-, disodium salt, dihydrate
(8); Glycine, N,N'-1,2-ethanediylbis[N-(carboxymethyl)-, disodium salt,
dihydrate (9); (6381-92-6)
2-Hydroxy-4-methylpyridine: 2(1H)-Pyridinone,
4-methyl- (9); (13466-41-6)
2-Hydroxy-6-methylpyridine: 2(1H)-Pyridinone,
6-methyl- (9); (3279-76-3)
2-Amino-4-methylpyridine: Aldrich Name: 2-Amino-4-picoline:
HIGHLY TOXIC: 4-Picoline, 2-amino- (8); 2-Pyridinamine,
4-methyl- (9); (695-34-1)
2-Amino-6-methylpyridine: Aldrich Name: 2-Amino-6-picoline:
HIGHLY TOXIC: 2-Picoline, 6-amino- (8); 2-Pyridinamine,
6-methyl- (9); (1824-81-3)
N-Benzylbenzamide: Benzamide, N-benzyl-
(8); Benzamide, N-(phenylmethyl)- (9); (1485-70-7)
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