Organic Syntheses, Vol. 78, pp. 82-89
Submitted by Adam P. Smith, Jaydeep J. S. Lamba, and Cassandra L. Fraser
1
.
Checked by Motoki Yamane and Koichi Narasaka.
1. Procedure
A. 4,4'-Bis[(trimethylsilyl)methyl]-2,2'-bipyridine.
A
500-mL, two-necked, round-bottomed flask (Note
1),
equipped with a
nitrogen inlet,
magnetic stirrer,
and
rubber septum is charged with
tetrahydrofuran
(THF) (90 mL) (Note
2) and
diisopropylamine (9.8 mL, 69.7
mmol) (Note
3). The reaction mixture is cooled
to −78°C and a solution of
butyllithium
(n-BuLi) (1.7 M in hexanes, 36.0 mL, 61.4 mmol)
(Note
4) is added. The solution is stirred at −78°C for
10 min, warmed to 0°C and stirred for 10 min, then cooled back to −78°C. A solution
of
4,4'-dimethyl-2,2'-bipyridine
(5.14 g, 27.9 mmol) (Note
5)
in
THF (130 mL) (Note
2),
prepared in a
250-mL, two-necked, round-bottomed flask under
a
nitrogen atmosphere, is added via cannula to the
cold lithium diisopropylamide (LDA)
solution. The resulting maroon-black reaction mixture is stirred at −78°C for
1 hr, then
chlorotrimethylsilane (TMSCl)
(8.85 mL, 69.7 mmol) (Note
6)
is rapidly added via syringe. After the solution becomes pale blue-green (≈10
sec after the TMSCl addition), the reaction is quenched by rapid addition of
absolute ethanol (10 mL).
(Note: the reaction should be quenched regardless of color change after a maximum
of 15 seconds to avoid over silylation). The cold reaction mixture is poured into
a
separatory funnel (1 L) containing aqueous saturated
sodium bicarbonate (NaHCO3, ≈200
mL) and allowed to warm to ≈25°C. The product is extracted
with
dichloromethane (CH2Cl2,
3 × 300 mL); the combined organic fractions are shaken
with
brine (≈200 mL) and
dried over
sodium sulfate
(Na
2SO
4). Filtration and concentration on a
rotary
evaporator affords
8.85 g
(
97%) of
4,4'-bis[(trimethylsilyl)methyl]-2,2'-bipyridine
as a slightly off-white crystalline solid (Note
7).
B. 4,4'-Bis(chloromethyl)-2,2'-bipyridine.
Into a
500-mL, two-necked, round-bottomed flask (Note
1)
equipped with a
magnetic stirring bar are placed
5.22 g (15.9 mmol) of 4,4'-bis[(trimethylsilyl)methyl]-2,2'-bipyridine,
15.1 g (63.6 mmol) of hexachloroethane
(Cl
3CCCl
3, Note
8) and
9.65 g (63.6 mmol) of cesium
fluoride (CsF, Note
9)
at 25°C under a
nitrogen atmosphere.
Acetonitrile
(260 mL) (Note
10) is added and the
heterogeneous reaction mixture is stirred at 60°C for ≈3.5 hr (or until TLC
indicates that all TMS starting material is consumed). After the mixture is cooled
to 25°C, it is poured into a
separatory funnel containing
ethyl
acetate (EtOAc) and water (H
2O, ≈100 mL each). The product
is extracted with
EtOAc (3 × 100 mL);
the combined organic fractions are shaken with
brine (≈200
mL) and dried over Na
2SO
4. Filtration and
concentration on a
rotary evaporator, followed by flash chromatography
using deactivated silica gel (
60% EtOAc: 40% hexanes)
(Note
11), gives
3.67
g (
91%) of the chloride
as a white solid (Note
12).
2. Notes
1. Before use, all glassware, needles, and syringes were dried overnight
in a 120°C oven.
2. THF was dried and purified by passage through alumina solvent
purification columns
2 or by distillation over
sodium/
benzophenone.
4. A
1.7 M solution of n-BuLi in hexanes
was obtained from Aldrich Chemical Company, Inc. The n-BuLi is titrated
prior to its use in each reaction using the following procedure.
3 To a
50-mL, round-bottomed flask
(Note
1), equipped with
nitrogen inlet
and a
magnetic stirrer is added
N-benzylbenzamide
(854 mg, 4.0 mmol) (as received from Aldrich Chemical
Company, Inc.) and
THF (40 mL)
(Note
2). The solution is cooled to −42°C (
acetonitrile/dry
ice) and n-BuLi is added dropwise to the blue endpoint (color persists for >30
sec). The molarity is calculated using a 1:1 stoichiometric ratio of
N-benzylbenzamide
to n-BuLi. (Just greater than 1 equivalent of alkyllithium is needed to reach the
endpoint).
6.
Chlorotrimethylsilane
(TMSCl) was purchased from Aldrich Chemical Company, Inc.,
and used as obtained.
7. The following characterization data was obtained:
mp 90-92°C;
1H
NMR (CDCl
3, 300 MHz) δ: 0.04 (s, 18 H), 2.21 (s,
4 H), 6.94 (d, 2 H, J = 5.01), 8.05 (br s, 2 H),
8.46 (d, 2 H, J = 5.00);
13C NMR (CDCl
3, 75 MHz) δ: −2.2,
27.1, 120.4, 123.0, 148.3, 150.8,
155.5. Anal. Calcd for C
18H
28N
2Si
2:
C, 65.79; H, 8.59; N, 8.53. Found: C, 65.78; H, 8.43; N, 8.76. It has been noted that
desilylation occurs after standing in
deuterochloroform (CDCl
3)
overnight. The resulting methyl derivatives have also been observed in certain purified
TMS bipyridine samples when stored over time. Therefore, it is best to convert these
intermediates to the corresponding halides in a timely fashion.
8.
Hexachloroethane
(Cl3CCCl3), obtained from Aldrich Chemical Company,
Inc., was used as received.
9.
Cesium fluoride
was purchased from Acros Organics, Inc. or Soekawa
Chemicals Co.and stored in a dry box prior to use.
10.
Acetonitrile was distilled over CaH
2
and stored in a
500-mL Kontes flask prior to use.
11.
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 in hexanes and then were washed with hexanes prior to use.
12. Spectral properties are as follows:
mp 98-100°C;
1H
NMR (CDCl
3, 300 MHz) δ: 4.63 (s, 4 H), 7.38 (dd,
2 H, J = 1.9, 5.0), 8.43 (s, 2 H), 8.70 (d, 2 H, J = 4.6);
13C NMR (CDCl
3,
75 MHz) δ: 43.9, 120.1, 122.8, 146.7,
149.4, 155.8. Anal. Calcd for C
12H
10Cl
2N
2:
C, 56.94; H, 3.98; N, 11.07. Found: C, 56.82; H, 4.04; N, 11.01.
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the
Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Halomethylbipyridines, are typically synthesized either by radical
halogenation
4 or
from hydroxymethylbipyridine precursors.
5
Radical methods often give rise to mixtures of halogenated species that are difficult
to separate with flash chromatography. A solution to this problem, involving the selective
reduction of polyhalogenated by-products with diisobutylaluminum hydride (DIBAL-H),
has resulted in slight improvements in overall yields.
6 While the synthesis of halomethyl
compounds from hydroxymethyl precursors is more efficient than radical halogenation,
such procedures involve many steps, each of which give intermediates in moderate to
high yields.
5 Direct trapping of bpy (CH
2Li)
n
with electrophiles has proved unsuccessful for the generation of halide products.
5a The quenching of LDA-generated carbanions with TMSCl
prior to halogenation as described here constitutes an efficient, high yield synthesis
of halomethyl bpys substituted at various positions around the ring system.
7,8
Currently, 2,2'-bipyridine derivatives figure prominently in supramolecular
assembly,
9 in bioinorganic
contexts,
10
in studies of redox electrocatalysis
4a
and in polymeric materials.
11 Halomethyl bpys and their various metal complexes
have also been used as initiators for controlled polymerizations of several different
monomers including styrene and 2-alkyl-2-oxazolines.
12
TABLE II
SYNTHESIS
OF HALOMETHYL-2,2'-BIPYRIDINES
|
|
Product |
R1 |
R2 |
R3 |
R4 |
Yield (%) |
|
4-Chloromethyl-2,2'-bipyridine
|
ClCH2 |
H |
H |
H |
94 |
5-Chloromethyl-2,2'-bipyridine
|
H |
ClCH2 |
H |
H |
98 |
6-Chloromethyl-2,2'-bipyridine
|
H |
H |
ClCH2 |
H |
95 |
4,4'-Bis(chloromethyl)-2,2'-bipyridine
|
ClCH2 |
H |
H |
ClCH2 |
91 |
4-Bromomethyl-2,2'-bipyridine
|
BrCH2 |
H |
H |
H |
92 |
5-Bromomethyl-2,2'-bipyridine
|
H |
BrCH2 |
H |
H |
98 |
6-Bromomethyl-2,2'-bipyridine
|
H |
H |
BrCH2 |
H |
99 |
4,4'-Bis(bromomethyl)-2,2'-bipyridine
|
BrCH2 |
H |
H |
BrCH2 |
97 |
|
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
4,4'-Bis(chloromethyl)-2,2'-bipyridines:
2,2'-Bipyridine, 4,4'-bis(chloromethyl)- (13); (138219-98-4)
4,4'-Bis[(trimethylsilyl)methyl]-2,2'-bipyridine:
2,2'-Bipyridine, 4,4'-bis[(trimethylsilyl)methyl]-
(14); (199282-52-5)
Diisopropylamine (8); 2-Propanamine, N-(1-methylethyl)-
(9); (108-18-9)
Butyllithium: Lithium, butyl-
(8,9); (109-72-8)
4,4'-Dimethyl-2,2'-bipyridine: 2,2'-Bipyridine,
4,4'-dimethyl- (9); (1134-35-6)
Chlorotrimethylsilane: Silane, chlorotrimethyl-
(8,9); (75-77-4)
Hexachloroethane: Ethane, hexachloro-
(8,9); (67-72-1)
Cesium fluoride (8,9); (13400-13-0)
Acetonitrile: TOXIC (8,9); (75-05-8)
N-Benzylbenzamide: Benzamide, N-benzyl-
(8); Benzamide, N-(phenylmethyl)- (9); (1485-70-7)
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