Efficient synthesis of 4-, 5-, and 6-methyl-2,2'-bipyridine by a Negishi cross-coupling strategy followed by high-yield conversion to bromo- and chloromethyl-2,2'-bipyridines

Full text of DOI:10.1021/jo981505z

1
0048
6
J . Org. Chem. 1998, 63, 10048-10051
Efficien t Syn th esis of 4-, 5-, a n d
-Meth yl-2,2′-bip yr id in e by a Negish i
2 2 3 3
TMS derivative with BrF CCF Br or Cl CCCl in the
presence of CsF provided the bromide or chloride cleanly
and in high yield. These 4,4′-bis(halomethyl)-2,2′-bipy-
ridines and their metal complexes were utilized by us as
Cr oss-Cou p lin g Str a tegy F ollow ed by
High -Yield Con ver sion to Br om o- a n d
Ch lor om eth yl-2,2′-bip yr id in es
9
initiators for living polymerization reactions. To further
explore the use of metal complexes as templates for
polymerization initiators, it was also of interest to
prepare monofunctional halomethyl bipyridines. More-
over, we wanted to determine the generality of the TMS
methodology for methyl bpys with different substitution
patterns.10 Anions of 4- and 6-methyl bpy possess reso-
nance structures with formal negative charges on elec-
tronegative nitrogen atoms on the same ring. For the
anion of 5-methyl bpy, similar stabilization is achieved
only through delocalization onto the adjacent heteroaro-
matic ring. We were curious to see whether this differ-
ence might correlate with differences in reactivity for the
methyl bpy derivatives.
Scott A. Savage, Adam P. Smith, and
Cassandra L. Fraser*
Department of Chemistry, University of Virginia,
Charlottesville, Virginia 22901
Received J uly 29, 1998
In tr od u ction
Bipyridine ligands and their many complexes find wide
1
application in chemistry. These nitrogen heterocycles are
common in studies of electron transfer in proteins and
2
3
small molecules, in supramolecular assembly, and in
4
sensing and recognition. They also play a central role
Monofunctional bipyridine reagents may be accessed
from monomethyl bpy starting materials. As the vast
literature documenting many alternative routes to these
compounds attests, efficient synthesis of these unsym-
metrical bipyridines represents a long-standing challenge
in the field.11 Traditionally, methyl bpys have been
prepared by the Kr o¨ nke method which involves reaction
of pyridinium salts with R,â-unsaturated ketones fol-
lowed by treatment with ammonium acetate to effect
as ligands for copper catalysts in new living radical
5
polymerization methodologies. Despite their prevalence,
many desirable bipyridine (bpy) derivatives have long
proven elusive. Until recently many of the halomethyl
bipyridines were only obtainable in low to moderate
yields. Common approaches to these compounds include
radical halogenation which can give rise to mixtures of
6
products that are difficult to separate or preparation via
cyclization.12 They have also been made by coupling of
alcohol precursors which are accessed by a multistep
synthesis from the methyl precursors.6 Recently we
introduced a new and highly efficient approach to the
halogenation of dimethyl bipyridines.8 Specifically, 4,4′-
dimethyl-2,2′-bipyridine was deprotonated with lithium
diisopropylamide (LDA) followed by trapping with trim-
ethylsilyl chloride (TMSCl). Reaction of the resulting bis-
,7
6b,13
pyridyllithium reagents with pyridyl sulfoxides,
by Ni
1
4
and other metal-catalyzed cross-coupling reactions, by
the Ullman reaction, and, more recently, by use of
,9a
12
R-oxoketene dithioacetals among a variety of other
routes.15 Many methods lead to mixtures of isomers or
they also produce dimethyl byproducts. Some approaches
require rather involved multistep syntheses and harsh
conditions, few methods are general for different substi-
tution patterns, and nearly all of them produce products
in moderate yields, at best. Though modern palladium-
catalyzed cross-coupling strategies require an expensive
(
1) See the following and references therein: (a) J uris, A.; Balzani,
V.; Barigelletti, F.; Campagna, S.; Belser, P.; von Zelewsky, A. Coord.
Chem. Rev. 1988, 84, 85. (b) Sauvage, J .-P.; Collin, J .-P.; Chambron,
J .-C.; Guillerez, S.; Coudret, C.; Balzani, V.; Barigelletti, F.; De Cola,
L.; Flamigni, L. Chem. Rev. 1994, 94, 993. (c) Balzani, V.; J uris, A.;
Venturi, M.; Campagna, S.; Serroni, S. Chem. Rev. 1996, 96, 759.
(
2) (a) Benniston, A. C.; Mackie, P. R.; Harriman, A. Angew. Chem.,
(10) During the course of our investigations, it was demonstrated
that the TMS to halide methodology extends to 6,6′-dimethyl-2,2′-
bipyridine which was used to generate 6,6′-bis(bromomethyl)-2,2′-
bipyridine in good yield. Hochwimmer, G.; Nuyken, O.; Schubert, U.
S. Macromol. Rapid Commun. 1998, 19, 309.
8
Int. Ed. Engl. 1998, 37, 354 (b) Skov, L. K.; Pascher, T.; Winkler, J .
R.; Gray, H. B. J . Am. Chem. Soc. 1998, 120, 1102. (c) Gray, H. B.;
Winkler, J . R. Annu. Rev. Biochem. 1996, 65, 537. (b) Dandliker, P.
J .; Holmlin, R. E.; Barton, J . K. Science 1997, 275, 1465.
(
3) (a) Boulas, P. L.; Gomez-Kaifer, M.; Echegoyen, L. Angew. Chem.,
(11) Another common route to monofunctional bipyridines involves
monosubstitution of dimethyl bipyridine reagents. This approach is
often complicated by over- or underfunctionalization and separation
of desirable products from starting material and byproducts can be
Int. Ed. Engl. 1998, 37, 216. (b) Mamula, O.; von Zelewsky, A.;
Bernardinelli, G. Angew. Chem., Int. Ed. Engl. 1998, 37, 290. (c) Kaes,
C.; Hosseini, M. W.; Rickard, C. E. F.; Skelton, B. W.; White, A. H.
Angew. Chem., Int. Ed. Engl. 1998, 37, 920.
6
a
troublesome. Our attempts to access monofunctional bpy derivatives
(
4) (a) Beer, P. D. Acc. Chem. Res. 1998, 31, 71. (b) Chin, T.; Gao,
in this manner involved reaction of commercially available 4,4′-
6
a
Z.; Lelouche, I.; Shin, Y.-G. K.; Purandare, A.; Knapp, S.; Isied, S. S.
J . Am. Chem. Soc. 1997, 119, 12849.
dimethyl-2,2′-bipyridine with 0.95 equiv of LDA followed by quench-
ing with TMSCl. After varying reaction conditions and reagent
loadings, in all cases mixtures of the desired product, the difunctional
TMS compound, and the dimethyl starting material were obtained.
These species proved difficult to separate by either chromatography
or recrystallization (Krause, B.; Fraser, C. L. Unpublished results).
Monolithiation followed by reaction with electrophiles has been suc-
cessful in some cases (e.g., with aldehydes). See: Beer, P. D.; Kocian,
R. J .; Mortimer, R. J .; Ridgway, C. J . Chem. Soc., Dalton Trans. 1993,
2629. Other approaches take advantage of the limited solubility of
(5) For a recent review see: Matyjaszewski, K., Ed. Controlled
Radical Polymerizations; American Chemical Society: Washington, DC,
1
998.
(6) (a) Chiana, L. D.; Hamachi, I.; Meyer, T. J . J . Org. Chem. 1989,
5
4, 4, 1731. (b) Uenishi, J .; Tanaka, T.; Nishiwaki, K.; Wakabayashi,
S.; Oae, S.; Tsukube, H. J . Org. Chem 1993, 58, 4382.
7) (a) Newkome, G. R.; Puckett, W. E.; Kiefer, G. E.; Gupta, V. K.;
(
Xia, Y.; Coreil, M.; Hackney, M. A. J . Org. Chem. 1982, 47, 4116. (b)
Newkome, G. R.; Kiefer, G. E.; Kohli, D. K.; Xia, Y.-J .; Fronczek, F.
R.; Baker, G. R. J . Org. Chem. 1989, 54, 5105. (c) Imperiali, B.; Prins,
T. J .; Fisher, S. L. J . Org. Chem. 1993, 58, 1613.
1
5b
monofunctionalized intermediates.
(12) Kr o¨ hnke, F. Synthesis 1976, 1.
(13) Kawai, T.; Furukawa, N.; Oae, S. Tetrahedron Lett. 1984, 25,
(
8) Fraser, C. L.; Anastasi, N. R.; Lamba, J . J . S. J . Org. Chem. 1997,
2549.
6
2, 9314.
(14) Tiecco, M.; Testaferri, L.; Tingoli, M.; Chianelli, D.; Montanucci,
M. Synthesis 1984, 736 and references therein.
(9) (a) Lamba, J . J . S.; Fraser, C. L. J . Am. Chem. Soc. 1997, 119,
1
801. (b) Lamba, J . J . S.; McAlvin, J . E.; Peters, B. P.; Fraser, C. L
(15) (a) Potts, K. T.; Winslow, P. A. J . Org. Chem. 1985, 50, 5405
and references therein. (b) For other approaches to unsymmetrical bpys
see: Newkome, G. R.; Gross, J .; Patri, A. K. J . Org. Chem. 1997, 62,
3013 and references therein.
Polym. Prepr. 1997, 38(1), 193. (c) Collins, J . E.; Lamba, J . J . S.; Love,
J . C.; McAlvin, J . E.; Peters, B. P.; Fraser, C. L. Manuscript submitted.
(d) Collins, J . E.; Fraser, C. L. Macromolecules 1998, 31, 6715.
1
0.1021/jo981505z CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/10/1998

Notes
J . Org. Chem., Vol. 63, No. 26, 1998 10049
transition metal reagent or, in the case of Stille coupling,
tin compounds that are toxic, they are an attractive
alternative nonetheless since both yields and selectivities
are considerably higher than those observed by other
routes.16
Ta ble 1. Syn th esis of 2-P yr id yl Tr ifla tes
This account describes our efforts to develop a more
efficient preparation of methyl 2,2′-bipyridine ligands,
and the achievement of this goal via cross-coupling of an
P yOTf
R1
R2
R3
yield (%)
1
7
aryl Zn reagent and an aryl triflate in the presence of
a catalytic amount of Pd by the Negishi method.18 This
method is general; the 4-, 5-, and 6-methyl-2,2′-bipy-
ridines are all attainable in unprecedented yields. Despite
potential differences in the acidities of the methyl protons
in the 5- vs 4- and 6-methyl bpys, all three regioisomers
are readily converted to the respective (trimethylsilyl)-
methyl analogues and are obtained in high yield. It is
further demonstrated that these reagents serve as pre-
cursors to the useful bromomethyl and chloromethyl bpy
derivatives.
1
2
3
Me
H
H
H
Me
H
H
H
Me
94
90
95
Ta ble 2. Syn th esis of Meth yl-2,2′-bip yr id in es
R1
R2
R3
Mebp y
P yOTf
yield (%)
Resu lts a n d Discu ssion
4
5
6
1
2
3
Me
H
H
Me
H
H
98
94
93
H
After attempting several different Pd-catalyzed meth-
odologies,19 it was discovered that the Negishi cross-
coupling reaction between a pyridyl triflate, P yOTf, and
a pyridyl zinc reagent was consistently the most effective.
This reaction also benefits from the fact that it is
conveniently carried out in a single pot. The 4-, 5-, and
H
Me
Ta ble 3. Syn th esis of
(Tr im eth ylsilyl)m eth yl-2,2′-bip yr id in es
6
-methyl-2-(trifluoromethylsulfonyl)oxypyridines (1-3)
20
were prepared from the respective 2-hydroxypyridines
2
by reaction with triflic anhydride, Tf O, and were ob-
tained in high yield after purification by flash chroma-
tography on silica gel21 (Table 1). Lithium-halogen
exchange was effected by reaction of tert-butyllithium
with 2-bromopyridine at -78 °C. After transmetalation
TMSCH2bp y Mebp y
R1
R2
R3
yield (%)
7
8
9
4
5
6
TMSCH2
H
H
H
93
99
97
H
H
TMSCH2
H
TMSCH2
3 4
to Zn, a THF solution of Pd(PPh ) (generated in situ from
Pd
2
(dba)
3
and PPh ) (dba ) dibenzylideneacetone) and
3
(16) For some other examples of metal-catalyzed cross-coupling of
pyridyl reagents see the following. Cu: (a) Thompson, W. J .; Gaudino,
J . J . Org. Chem. 1984, 49, 5237. Pd: (b) Fernando, S. R. L.; Maharoof,
U. S. M.; Deshayes, K. D.; Kinstle, T. H.; Ogawa, M. Y. J . Am. Chem.
Soc. 1996, 118, 5783. (c) Ishikura, M.; Kamada, M.; Terashima, M.
Synthesis 1984, 936. (d) Bell, A. S.; Roberts, D. A.; Ruddock, K. S.
Tetrahedron Lett. 1988, 29, 5013.
the appropriate triflate were added, and the reactions
were refluxed for 15 h. After aqueous workup in the
presence of ethylenediaminetetraacetic acid (EDTA) to
chelate Zn(II)22 and purification by column chromatog-
raphy, the desired methyl-2,2′-bipyridines, Mebp y, were
all obtained in high yield (Table 2).
(
17) For a review of the use of aryl triflates in Pd-catalyzed Stille
coupling see: Ritter, K. Synthesis 1993, 735.
18) (a) Negishi, E. J . Org. Chem. 1977, 42, 1821. (b) Negishi, E.;
(
The methyl bipyridines, 4-6, were readily converted
to the respective (trimethylsilyl)methyl derivatives,
Takahashi, T.; King, A. O. Org. Synth. 1988, 66, 67. (c) Larsen, M.;
J orgensen, M. J . Org. Chem. 1997, 62, 4171.
1
6c
2
TMSCH bp y (7-9), by deprotonation with 1 equiv of
(
19) Palladium-catalyzed Suzuki coupling of both aryl borates or
aryl boric acid reagents and variously substituted aryl bromides was
attempted. In most cases, large amounts of dimethyl byproducts were
formed in these preparations. The pyridyl bromides were prepared from
the respective amino pyridines by the Craig reaction (Craig, L. C. J .
Am. Chem. Soc. 1934, 56, 231). Negishi coupling of 2-pyridyl zinc
chloride with the methyl-substituted pyridyl bromides generated some
of the desired Mebpy products but in low yield as compared with the
triflates (e.g., bromides, ∼15%; triflates, ∼60% when no EDTA was
used in the workup).
LDA followed by trapping with TMSCl as previously
8
described (Table 3). Products were obtained in nearly
quantitative yield after purification by chromatography
8
on silica gel. As for 4,4-bis(TMSCH
TMSCH
materials for the preparation of chloro- and bromomethyl
derivatives, XCH bpy (Table 4). Reaction of the TMSCH
bpy compounds with either hexachloroethane in CH CN
2
)-2,2′-bipyridine, the
2
bpy compounds, 7-9, serve as useful starting
2
2
-
(20) 2-Hydroxy-4-methylpyridine and 2-hydroxy-6-methylpyridine
3
are commercially available; however they and the 5-methyl analogue
are all conveniently prepared from the appropriate 2-aminopyridine
derivatives by reaction with H SO and NaNO as previously reported
2 4 2
by Barash and modified by Adger. (a) Barash, M.; Osbond, J . M.;
Wickens, J . C. J . Chem. Soc. 1959, 3530. (b) Adger, B. M.; Ayrey, P.;
Bannister, R.; Forth, M. A.; Hajikarimian, Y.; Lewis, N. J .; O’Farrell,
or dibromotetrafluoroethane in DMF in the presence of
dry CsF yielded the chlorides and bromides respectively,
in very high yield.23
C.; Owens, N.; Shamji, A. J . Chem. Soc., Perkin Trans. 1 1988, 2791.
Con clu sion
1
2
-Hydroxy-5-methylpyridine: H NMR (CDCl
3
, 300 MHz) δ 1.99 (s, 3
H), 6.43 (d, J ) 8.8 Hz, 1 H), 7.06 (s, 1 H), 7.23 (dd, J ) 2.2, 9.5 Hz,
This account describes both a new route to 4-, 5-, and
3
1
1
1
H), 13.48 (s, 1 H); 1 C NMR (CDCl
31.9, 143.8, 164.2. Anal. Calcd for C
2.84. Found: C, 66.09; H, 6.31; N, 13.05.
21) 4-Methyltriflate, 1: (a) Yuan, J .; Thurkauf, A. Patent WO 96
6, 058 (US 344,397,23). 5-Methyltriflate, 2: (b) Fey, P.; et al. Bayer
3
, 75 MHz) δ 16.5, 115.5, 119.2,
NO: C, 66.04; H, 6.46; N,
6
-methyl bipyridines and the successful conversion of
6
H
7
(
(22) When EDTA was omitted, Zn complexes of the products were
1
observed (white solids) and the yields were considerably depressed.
(23) The chlorides may also be prepared in DMF solution at 25 °C
as described for the bromides. It has been the experience of some
investigators in our group that large scale chloride reactions are cleaner
AG.; EP 0624583 A1; May 2, 1994. 6-Methyltriflate, 3: (c) Zhu, J .;
Bigot, A.; Elise, M.; Dau, T. H. Tetrahedron Lett. 1997, 38, 1181. (d)
Yoneda, N.; Fukuhara, T.; Mitsubishi Chem Ind, J pn. Kokai Tokkyo
Koho; J P 05,255,251 (93,255,251); Oct 5, 1993.
3
in CH CN than in DMF.

1
0050 J . Org. Chem., Vol. 63, No. 26, 1998
Ta ble 4. Syn th esis of Ha lom eth yl-2,2′-bip yr id in es
Notes
yield
(%)
XCH2bp y
TMSCH2bp y
C2X6
R1
R2
R3
1
1
1
1
1
1
0
1
2
3
4
5
7
8
9
7
8
9
Cl3CCCl3
Cl3CCCl3
Cl3CCCl3
BrF2CCF2Br
BrF2CCF2Br
BrF2CCF2Br
ClCH2
H
H
BrCH2
H
H
H
H
H
94
98
95
92
98
99
ClCH2
H
H
BrCH2
H
ClCH2
H
H
BrCH2
1 H); 13C NMR (CDCl
20.3 Hz), 123.4, 140.6, 154.8, 158.6.
, 75 MHz) δ 23.3, 111.3, 118.3 (q, J CF )
these reagents to the widely used bromo- and chlorom-
ethyl derivatives by way of (trimethylsilyl)methyl bipy-
ridine intermediates. Bipyridine derivatization schemes
that were previously difficult due to the challenges
associated with accessing these unsymmetrical reagents
should now be considerably more practical as a result of
these vast improvements in reaction efficiency and
product yields.
3
3
4
-Meth yl-2,2′-bip yr id in e (4). To THF (20 mL) at -78 °C was
added t-BuLi (1.75 M in pentane, 7.5 mL, 13 mmol) followed by
dropwise addition of 2-bromopyridine (1.05 g, 6.64 mmol). After
stirring at -78 °C for 30 min, ZnCl (2.00 g, 14.6 mmol) was
2
added, and the reaction was stirred for 2 h at 25 °C. The triflate,
1 (1.31 g, 5.43 mmol), LiCl (0.5 g, 12 mmol), and a THF solution
of Pd(PPh
3
)
4
(prepared in situ by stirring Pd
2 3
(dba) (0.17 g, 0.19
mmol) and PPh
3
(0.40 g, 1.5 mmol) in THF (5 mL) for 1 h) were
then added. The reddish-brown reaction mixture was heated at
reflux for 15 h. After cooling, an aqueous solution of EDTA (18
g, 48 mmol in 150 mL) was added and the reaction mixture was
stirred for 5 min. The reaction was poured into a separatory
funnel, the pH was adjusted to 8 with saturated aqueous
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All chemicals were obtained from
Aldrich and were used as received unless otherwise indicated.
Silica gel used for flash chromatography (particle size 0.040-
.063 mm) was obtained from Merck. THF was dried and
purified by passage through alumina solvent purification col-
umns. Acetonitrile and diisopropylamine were distilled over
CaH prior to use. Dry DMF and pyridine were obtained from
Aldrich in Sureseal bottles. All reactions were run under a
nitrogen atmosphere and were monitored by TLC on SiO
detection). Silica plates were deactivated with 10% Et
hexanes prior to use, and plates were heated or dried under
vacuum to evaporate DMF prior to developing. Silica chroma-
tography columns were deactivated with 10% Et
0
NaHCO
3
, and the basic mixture was extracted with CH
2
Cl
2
(3
×
75 mL). Combined organic fractions were dried over Na
2
SO
4
,
2
4
were filtered, and then were concentrated in vacuo. Pure 2 was
isolated as a white solid after purification by flash chromatog-
raphy using deactivated silica gel (30% EtOAc:70% hexanes):
2
2
(UV
N in
0
.90 g (98%); mp 62.5-64 °C, lit. mp 62-64 °C;
15 1
H NMR
3
coincident with data reported by Potts et al.
15
5
-Meth yl-2,2′-bip yr id in e (5). The methyl bpy 5 was obtained
as a very pale yellow oil after preparation from 2-bromopyridine
3
N in hexanes
and the triflate 2 by the method described above for 4: 1.31 g
and then were washed with hexanes prior to use for product
1
15
(
94%); H NMR coincident with data reported by Potts et al.
1
13
purification. H and C NMR spectra were recorded on a GE
6
-Meth yl-2,2′-bip yr id in e (6). The methyl bpy 6 was isolated
QE 300 spectrometer in the solvents specified.
as a white solid after preparation from 2-bromopyridine and the
1a
4
-Meth yl-2-(tr iflu or om eth an esu lfon yl)oxypyr idin e (1).2
triflate 3 by the method described above for 4: 1.05 g (93%);
To 2-hydroxy-4-methylpyridine (2.49 g, 22.8 mmol) in dry
pyridine (90 mL) at 0 °C was rapidly added trifluoromethane-
sulfonic anhydride (7.91 g, 28.0 mmol). The solution was stirred
at 0 °C for 20 min and then was poured into a separatory funnel
6b
recrystallized from hexanes; mp 37-38 °C, lit. mp 50-51 °C;
1
15
H NMR coincident with data reported by Potts et al.
25
4
-(Tr im eth ylsilyl)m eth yl-2,2′-bip yr id in e (7). To diiso-
propylamine (0.72 mL, 5.1 mmol) in THF (35 mL) at -78 °C
was added n-BuLi (1.7 M in hexanes, 2.7 mL, 4.6 mmol). The
solution was stirred at -78 °C for 10 min, was warmed to 0 °C
for 10 min, and then was cooled back down to -78 °C. 4-Methyl-
containing H
Cl
(3 × 60 mL); then combined organic fractions were dried
over Na SO . Filtration and concentration in vacuo, followed by
2 2
O (80 mL). The mixture was extracted with CH -
2
2
4
flash chromatography on deactivated silica gel (20% EtOAc:80%
hexanes), gave pure 1 as a colorless oil: 5.20 g (94%); H NMR
2
,2′-bipyridine (4) (0.695 g, 4.1 mmol) in THF (5 mL) was added
1
dropwise to the cold LDA solution. The resulting maroon-black
reaction mixture was stirred at -78 °C for 1 h; then TMSCl (0.65
mL, 5.1 mmol) was added. After the solution became pale blue-
green in color (∼10 s after TMSCl addition), the reaction was
quenched by rapid addition of absolute EtOH (2.5 mL). The cold
reaction mixture was poured into a separatory funnel containing
(
CDCl
Hz, 1 H), 8.25 (d, J ) 5.1 Hz, 1 H); C NMR (CDCl
δ 21.4, 116.0, 119.2 (q, J CF ) 321.0 Hz), 125.8, 148.5, 153.9,
56.7.
-Meth yl-2-(tr iflu or om eth an esu lfon yl)oxypyr idin e (2).2
3
, 300 MHz) δ 2.45 (s, 3 H), 6.99 (s, 1 H), 7.19 (d, J ) 5.1
13
3
, 75 MHz)
1
1b
5
2
0
The triflate 2 was prepared from 2-hydroxy-5-methylpyridine
by the method described above for 1 and was obtained as a
saturated aqueous NaHCO
to ∼25 °C. The product was extracted with CH
then the combined organic fractions were dried over Na
3
(40 mL) and was allowed to warm
Cl
(3 × 40 mL);
SO
2
2
1
colorless oil: 6.3 g (90%); H NMR (CDCl
3
, 300 MHz) δ 2.37 (s,
2
4
.
3
8
J
H), 7.06 (d, J ) 8.1 Hz, 1 H), 7.67 (dd, J ) 2.4, 8.5 Hz, 1 H),
Filtration and concentration in vacuo, followed by flash chro-
matography using deactivated silica gel (30% EtOAc:70% hex-
1
3
.17 (s, 1 H); C NMR (CDCl
CF ) 320.3 Hz), 134.1, 141.0, 148.1, 153.6. Anal. Calcd for C
SF : C, 34.86; H, 2.51; N, 5.81. Found: C, 34.99; H, 2.19;
N, 5.70.
-Meth yl-2-(tr iflu or om eth an esu lfon yl)oxypyr idin e (3).21c,d
3
, 75 MHz) δ 17.2, 114.2, 118.1 (q,
7
H
6
-
25 1
anes), gave pure 7 as a clear, colorless oil: 0.92 g (93%);
NMR (CDCl
H
NO
3
3
3
, 300 MHz) δ 0.04 (s, 9 H), 2.21 (s, 2 H), 6.95 (dd,
J ) 1.5, 5.0 Hz, 1 H), 7.29 (m, 1 H), 7.8 (td, J ) 1.9, 8.1 Hz, 1
6
H), 8.06 (s, 1 H), 8.38 (d, J ) 8.1 Hz, 1 H), 8.47 (d, J ) 5.0 Hz,
The triflate 3 was prepared from 2-hydroxy-6-methylpyridine
by the method used for 1 and was obtained as a colorless oil:
13
1
3
H), 8.68 (d, J ) 5.1 Hz, 1 H); C NMR (CDCl , 75 MHz) δ
-
2.3, 27.2, 120.3, 120.8, 123.1, 123.2, 136.4, 148.3, 148.7, 150.9,
1
3
.71 g (95%); H NMR (CDCl
J ) 8.1 Hz, 1 H), 7.21 (d, J ) 7.7 Hz, 1 H), 7.74 (t, J ) 7.7 Hz,
3
, 300 MHz) δ 2.52 (s, 3 H), 6.95 (d,
(
25) Generally the TMS compounds are stable when stored at room
temperature under N . It should be noted however that slow decom-
position to the parent methyl compound has been observed for
4-TMSCH bpy and more rarely for 4,4′-bis(TMSCH )bpy.
2
(
24) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J . Organometallics 1996, 15, 1518.
2
2

Notes
J . Org. Chem., Vol. 63, No. 26, 1998 10051
1
1
55.2, 156.1. Anal. Calcd for C14
1.56. Found: C, 69.39; H, 7.73; N, 11.88.
-(Tr im eth ylsilyl)m eth yl-2,2′-bipyr idin e (8). The TMSCH
H
18
N
2
Si: C, 69.37; H, 7.48; N,
4-Br om om eth yl-2,2′-bip yr id in e (13).26 4-(Trimethylsilyl)-
methyl-2,2′-bipyridine, 7 (0.39 g, 1.6 mmol), BrF CCF Br (0.49
2 2
g, 3.2 mmol), CsF (0.84 g, 3.2 mmol), and DMF (15 mL) were
combined and stirred at 25 °C for ∼3 h (or until TLC indicated
absence of all TMS starting material). The reaction mixture was
5
2
-
bpy 8 was prepared from the methyl bpy 5 according to the
method described above for 7 and was obtained as a white
1
solid: 0.708 g (99%); mp 50-52 °C; H NMR (CDCl
3
, 300 MHz)
poured into a separatory funnel containing H
the product was extracted with EtOAc (3 × 40 mL). The
combined organic fractions were washed with H O (100 mL),
were shaken with brine (100 mL), and then were dried over Na
SO . Filtration and concentration in vacuo, followed by flash
2
O (∼50 mL), and
δ 0.04 (s, 9 H), 2.13 (s, 2 H), 7.27 (td, J ) 1.9, 8.0 Hz, 1 H), 7.45
(d, J ) 8.1 Hz, 1 H), 7.79 (td, J ) 1.9, 8.1 Hz, 1 H), 8.25 (d, J )
2
8
8
2
1
.1 Hz, 1 H), 8.34 (d, J ) 7.6 Hz, 1 H), 8.36 (d, J ) 2.4 Hz, 1 H),
.66 (d, J ) 4.6 Hz, 1 H); 13C NMR (CDCl
, 75 MHz) δ -1.5,
4.5, 30.2, 121.1, 123.6, 136.5, 137.2, 137.3, 149.0, 149.6, 152.8,
56.9. Anal. Calcd for C14 Si: C, 69.37; H, 7.48; N, 11.56.
2
-
3
4
chromatography on deactivated silica gel (30% EtOAc:70%
hexanes), yielded the bromide 13 as a clear, colorless oil: 0.45
H
18
N
2
g (92%);2 H NMR (CDCl
6 1
, 300 MHz) δ 4.49 (s, 2 H), 7.33 (m, 2
Found: C, 69.29; H, 7.60; N, 11.43.
-(Tr im eth ylsilyl)m eth yl-2,2′-bipyr idin e (9). The TMSCH
bpy 9 was obtained as a clear, colorless oil after preparation from
the methyl bpy 6 by the method described above for 7 (15%
3
6
2
-
H), 7.83 (td, J ) 1.5, 7.7 Hz, 1 H), 8.40 (d, J ) 7.5 Hz, 1 H), 8.43
13
(s, 1 H), 8.67 (d, J ) 4.8 Hz, 1 H), 8.70 (d, J ) 4.8 Hz, 1 H);
NMR (CDCl
C
3
, 75 MHz) δ 30.4, 120.4, 120.9, 123.2, 123.6, 136.6,
2
5 1
EtOAc:85% hexanes): 0.56 g (97%); H NMR (CDCl
3
, 300 MHz)
146.8, 148.8, 149.3, 155.1, 156.4.
δ 0.07 (s, 9 H), 2.41 (s, 2 H), 6.98 (d, J ) 7.8 Hz, 1 H), 7.27 (m,
5-Br om om eth yl-2,2′-bip yr id in e (14). The bromide 14 was
1
8
5
1
H), 7.63 (t, J ) 7.8 Hz, 1 H), 7.79 (td, J ) 1.8, 7.8 Hz, 1 H),
synthesized from the TMSCH bpy compound 8 by the method
2
.09 (d, J ) 7.2 Hz, 1 H), 8.41 (d, J ) 8.1 Hz, 1 H), 8.66 (d, J )
described for 13, thus producing a white solid: 0.198 g (98%);
1
3
6b 1
.1 Hz, 1 H); C NMR (CDCl
3
, 75 MHz) δ -1.9, 29.8, 116.1,
mp 71-73 °C, lit. mp 72-73 °C; H NMR coincident with data
20.7, 122.0, 122.9, 136.36, 136.41, 148.6, 154.8, 156.5, 160.4.
Si: C, 69.37; H, 7.48; N, 11.56. Found:
C, 69.02; H, 7.52; N, 11.86.
-Ch lor om eth yl-2,2′-bip yr id in e (10). To 4-(trimethylsilyl)-
methyl-2,2′-bipyridine (7) (0.58 g, 2.4 mmol) and Cl CCCl (1.13
CN (15 mL) at 25 °C was added dry CsF
0.72 g, 4.8 mmol). The heterogeneous reaction mixture was
reported by Imperiali7c and Uenishi.6b
Anal. Calcd for C14
18 2
H N
6
-Br om om eth yl-2,2′-bip yr id in e (15). The bromide 15 was
prepared from the TMSCH bpy compound 9 according to the
2
4
method described above for 13 and was obtained as a white
3
3
6b 1
solid: 0.49 g (99%); mp 66-68 °C, lit. mp 65.5-67 °C; H NMR
2
3
g, 4.8 mmol) in CH
3
6b
coincident with data reported by Uenishi.
(
stirred at 60 °C for ∼4 h (or until TLC indicated that all TMS
starting material was consumed). After cooling to ∼25 °C, the
mixture was poured into a separatory funnel containing EtOAc
Ack n ow led gm en t. This work was supported by
grants from the National Science Foundation (CAREER
Award), the Petroleum Research Fund, and the J effress
Foundation. We thank J . Christopher Love for prelimi-
nary investigations that set the stage for the experi-
ments described herein and Dr. Brian J ohns for helpful
discussions.
and H
3 × 30 mL); then the combined organic fractions were shaken
with brine (100 mL) and dried over Na SO . Filtration and
2
O (∼30 mL each). The product was extracted with EtOAc
(
2
4
concentration in vacuo, followed by flash chromatography using
deactivated silica gel (60% EtOAc:40% hexanes), gave pure 10
1
as a clear, colorless oil: 0.46 g (94%); H NMR (CDCl
3
, 300 MHz)
δ 4.64 (s, 2 H), 7.34 (m, 2 H), 7.83 (td, J ) 1.5, 7.7 Hz, 1 H), 8.41
1
1
3
Su p p or tin g In for m a tion Ava ila ble: 300 MHz H and 75
(
m, 2 H), 8.69 (m, 2 H); C NMR (CDCl
20.8, 122.5, 123.6, 136.6, 146.5, 148.8, 149.3, 155.2, 156.3. Anal.
Calcd for C11 Cl: C, 64.56; H, 4.43; N, 13.69. Found: C,
4.25; H, 4.44; N, 13.60.
-Ch lor om eth yl-2,2′-bip yr id in e (11). Chloride 11 was pre-
pared from the TMSCH bpy 8 as described above for 10 and was
obtained as a white solid after purification with deactivated silica
3
, 75 MHz) δ 43.9, 119.8,
MHz 13C NMR spectra for compounds 1, 3, and 13 (6 pages).
Ordering information is given on any current masthead page.
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
1
9 2
H N
6
5
2
1
gel (CH
MHz) δ 4.66 (s, 2 H), 7.33 (t, J ) 6.6 Hz, 1 H), 7.84 (qd, J ) 1.5,
.5, 1.9, 2.3 Hz, 2 H), 8.40 (d, J ) 4.4 Hz, 1 H), 8.43 (d, J ) 7.4
2
Cl
2
): 0.166 g (98%); mp 59-61 °C; H NMR (CDCl
3
, 300
J O981505Z
1
1
3
Hz, 1 H), 8.69 (bs, 2 H); C NMR (CDCl
21.7, 124.4, 133.6, 137.4, 137.6, 149.5, 149.7, 156.1, 156.7. Anal.
Calcd for C11 Cl: C, 64.56; H, 4.43; N, 13.69. Found: C,
4.56; H, 4.57; N, 13.53.
-Ch lor om eth yl-2,2′-bip yr id in e (12). The chloride 12 was
isolated as a clear, colorless oil after synthesis from the TMSCH
3
, 75 MHz) δ 43.6, 121.5,
(
26) Unlike the 5- and 6-bromomethyl bpys (14 and 15), 13 is very
reactive and develops a brown color when solutions are concentrated,
when in CDCl solution as NMR samples, and even when stored in
the freezer under nitrogen. The major impurity gives rise to peaks at
1
H
9
N
2
3
6
1
5
.4 and 5.6 ppm in the H NMR spectrum and may correspond to the
6
dimer formed by nucleophilic attack of the bpy nitrogen at the benzylic
bromide position. Many colored and poorly soluble impurities may be
removed by filtering a 30% EtOAc:70% hexanes solution of the sample
through a plug of deactivated silica gel.
2
-
bpy compound 9 and purification with deactivated silica gel (15%
EtOAc:85% hexanes) as described above for 10: 0.12 g (95%);
1
7a
H NMR coincident with data reported by Newkome et al.