Synthesis of substituted 2,2′-bipyridines from 2-bromo- or 2-chloropyridines using tetrakis(triphenylphosphine)palladium(0) as a catalyst in a modified Negishi cross-coupling reaction

Article abstract of DOI:10.1055/s-2007-965952

A protocol for an efficient, modified Negishi cross-coupling strategy for substituted 2,2′-bipyridines employing tetrakis(triphenylphosphine) palladium(0) as a simple, commercially available, and relatively inexpensive catalyst for both 2-bromo- and 2-chl

Full text of DOI:10.1055/s-2007-965952

PAPER
1061
Synthesis of Substituted 2,2¢-Bipyridines from 2-Bromo- or 2-Chloropyridines
Using Tetrakis(triphenylphosphine)palladium(0) as a Catalyst in a Modified
Negishi Cross-Coupling Reaction
S
ynthesis of 2,2
¢
-B
.
ipyridines fr
K
om 2-Bromo- and
i
2-Chlo
e
ropyridineshne, J. Bunzen, H. Staats, A. Lützen*
University of Bonn, Kekulé-Institute of Organic Chemistry and Biochemistry, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
Fax +49(228)739608; E-mail: arne.luetzen@uni-bonn.de
Received 4 January 2007
bled supramolecular aggregates,11 the synthesis of substi-
Abstract: A protocol for an efficient, modified Negishi cross-
tuted 2,2¢-bipyridines as ligand units was essential.
coupling strategy for substituted 2,2¢-bipyridines employing tet-
Therefore, we developed a general method for the synthe-
rakis(triphenylphosphine)palladium(0) as a simple, commercially
sis of 5-monosubstituted, as well as variously disubstitut-
available, and relatively inexpensive catalyst for both 2-bromo- and
2-chloropyridines has been developed. Further transformations ed 2,2¢-bipyridines, in a one-pot procedure from an
were carried out yielding some new valuable functionalized 2,2¢-bi-
organozinc pyridyl reagent and chloropyridines by a pal-
ladium-catalyzed, modified Negishi cross-coupling strat-
egy using bis(tri-tert-butylphosphine)palladium(0) as a
catalyst.12 This catalyst is commercially available, but rel-
atively expensive, and can also be synthesized,13 or
prepared in situ, from tris(dibenzylideneacetone)dipalla-
pyridines.
Key words: Negishi reaction, 2,2¢-bipyridines, cross-coupling re-
actions, organozinc compounds, palladium
The 2,2¢-bipyridine moiety is among the most widely used dium(0)–chloroform adduct; this synthesis involves the
ligand structure motifs in metal coordination chemistry use of tri-tert-butylphosphine (t-Bu3P), which is also ex-
and its complexes with various transition metal ions have pensive and not easily handled. Since we often perform
been extensively studied.1 Ligands containing two or the Negishi reaction on a large-scale basis, due to our in-
more 2,2¢-bipyridine units can serve as precursors for su- creased demand for starting materials for the design of
pramolecular self-assembled helicates,2 macromolecular 2,2¢-bipyridine-based ligands, we were looking for an in-
devices3 or can be used in asymmetric homogenous catal- expensive and simple, but equally efficient, catalytic sys-
ysis.4 Several methods have been applied to the synthesis tem. In 2003, Hanan reported the synthesis of some,
of mono- and disubstituted bipyridines. Among them are mostly methyl-substituted, 2,2¢-bipyridines from 1.5
the homocoupling of halogenated pyridine precursors, equivalents of 2-pyridylzinc bromide using tetrakis(tri-
which gives access to symmetrically substituted bipy- phenylphosphine)palladium(0) as the catalyst.14 We now
ridines,5 the Kröhnke reaction,6 or the modification of an wish to report a general procedure for the synthesis of var-
existing bipyridine core, which often involves multistep ious mono- and disubstituted 2,2¢-bipyridines using a
procedures and/or requires harsh reaction conditions.7 modified Negishi cross-coupling strategy starting from
With the advance of cross-coupling reactions over the last both 2-bromo- and 2-chloropyridines that is catalyzed by
thirty years, an increasing number of methods has been es- the relatively inexpensive, commercially available cata-
tablished for the formation of aryl–aryl, and also heteroar- lyst tetrakis(triphenylphosphine)palladium(0) (Scheme 1).
yl–heteroaryl, bonds.8 The coupling of two different
R2
pyridine components using palladium-catalyzed cross-
coupling procedures such as the Stille, Suzuki, or Negishi
reactions has proved to be very efficient and it has been
applied to the synthesis of a variety of mono- and disub-
stituted 2,2¢-bipyridines. However, the use of organozinc
compounds provides better transmetalation activity than
that obtained by the use of organotin and organoboron re-
agents and with good chemoselectivity, as most common
functional groups are not attacked by organozinc species.9
One example of a very powerful catalyst in Negishi cross-
coupling reactions is bis(tri-tert-butylphosphine)palladi-
um(0), established by Fu and co-workers.10 During the
course of our studies toward the formation of self-assem-
R2
1. t-BuLi, THF, –78 °C
2. ZnCl2, r.t.
R1
N
ZnCl
R1
N
Br
3. Pd(PPh3)4, THF,
r.t. (X = Br)
X
N
R3
R4
or ∆ (X = Cl)
R2
R1
R5
X = Br, Cl
N
R3
R4
N
R5
Scheme 1 Synthesis of various mono- and disubstituted 2,2¢-bipyri-
dines.
SYNTHESIS 2007, No. 7, pp 1061–1069
x
x
.
x
x
.2
0
0
7
Advanced online publication: 28.02.2007
DOI: 10.1055/s-2007-965952; Art ID: Z00207SS
© Georg Thieme Verlag Stuttgart · New York

1062
U. Kiehne et al.
PAPER
Table 1 Mono- and Disubstituted 2,2¢-Bipyridines Synthesized from Variously Substituted 2-Bromopyridinesa
Entry
Product
R1
R2
R3
R4
R5
Yield (%)
1
2
3
4
5
6
7
1
2
3
4
5
6
7
H
H
H
Me
H
quant.
98
H
H
H
OMe
H
H
H
H
2,5-dimethylpyrrol-1-yl
H
73
H
Me
H
C≡CTMS
H
84
H
n-heptyl
H
Br
H
H
85
2,5-dimethylpyrrol-1-yl
2,5-dimethylpyrrol-1-yl
H
H
CO2Me
H
H
50
H
CO2Me
55
a Pd(PPh3)4 (1.5–3 mol%) was used.
The bromine–lithium exchange of 2-bromopyridine or These results encouraged us to also use the inexpensive
substituted 2-bromopyridines was achieved with tert-bu- and more easily available chloropyridines in the same
tyllithium at –78 °C in tetrahydrofuran according to our way. Due to the fact, that chloropyridines are relatively in-
previously published procedure.12 The preparation of the active compared to the corresponding bromopyridines, no
organozinc species in situ proved to be more efficient than reaction occurred after addition of the solution of the chlo-
using commercially available 2-pyridylzinc bromide solu- ropyridine to the 2-pyridylzinc species and stirring the re-
tion in our hands and it is necessary for the synthesis of sulting mixture at room temperature. However, refluxing
disubstituted bipyridines. Various ratios of 2-pyridylzinc this mixture yielded the desired 2,2¢-bipyridines in good
bromide/halo-substituted pyridine (from 1.5 to 1.1 equiv) to excellent yields. It should be noted that this method is
were used and it could be shown that this variation ap- also successful for the notoriously difficult-to-synthesize
pears to have no effect on the yield of the corresponding bipyridines bearing ester functions. This is also the case
2,2¢-bipyridines. Bromo-substituted pyridines are by far when the organozinc species is generated from a pyridine
more reactive in cross-coupling reactions than chloro- moiety bearing a labile (trimethylsilyl)ethynyl function,
substituted pyridines15 and for this reason they were ini- which is robust enough to overcome lithiation (Table 2,
tially used as substrates. A variety of 2,2¢-bipyridines entry 5).
were synthesized in this manner and the reaction occurred
smoothly at room temperature (Table 1).
Table 2 Mono- and Disubstituted 2,2¢-Bipyridines Synthesized from Variously Substituted 2-Chloropyridinesa
Entry
Product
8
R1
R2
R3
H
H
H
H
H
H
H
H
H
H
R4
R5
H
Yield (%)
1
2
H
H
CO2Me
4-MeOC6H4
C≡CTMS
CO2Me
CO2Me
4-MeOC6H4
H
80
76
90
51
70
66
84
71
9
H
H
H
3
10
11
12
13
14
15
16
17
H
H
H
4
H
n-heptyl
H
5
H
C≡CTMS
H
6
H
Me
H
H
7
Me
Me
OMe
8
OMe
H
H
9
OMe
H
H
2,5-dimethylpyrrol-1-yl 88
OMe 74
10
2,5-dimethylpyrrol-1-yl
H
H
a Pd(PPh3)4 (1.5–3 mol%) was used.
Synthesis 2007, No. 7, 1061–1069 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,2¢-Bipyridines from 2-Bromo- or 2-Chloropyridines
1063
(a)
(b)
(c)
X
O
N
O
N
N
N
N
N
5 (R = Me, X = H)
18 (R = Me, X = n-heptyl)
13
12
OR
O
TMS
MeOH, THF, KF, r.t.
1. BBr3, CH2Cl2, –78 °C
yielding 19 (R = X = H)
and 20 (R = H, X = n-heptyl)
1. LDA, THF,
–78 °C to 0 °C
2. 1-iodohexane
0 °C to r.t.
2. Tf2O, CH2Cl2, Et3N, –10 °C
H15C7
O
X
N
O
N
N
N
N
N
18
24
21 (X = H)
22 (X = n-heptyl)
O
OTf
Pd(dppf)Cl2, bis(pinacolato)diboron,
KOAc, 1,4-dioxane, ∆
X
N
N
23 (X = n-heptyl)
O
B
O
Scheme 2 Further transformations: (a) elongation of the alkyl chain of 13; (b) demethylation of 9 and 18, triflation of 21 and 22, and boryl-
ation of 22; (c) deprotection of 12.
All reactions except the synthesis of 24 were performed under an ar-
Some of the 2,2¢-bipyridines were further functionalized,
gon atmosphere using standard Schlenk techniques and oven-dried
glassware prior to use. TLC was performed on aluminum TLC
plates silica gel 60 F254 from Merck; detection: UV light (254 and
for example an n-heptyl chain was generated from the
methyl-substituted derivative 13 to yield 18 (Scheme 2).
Bipyridines 9 and 18 were transformed via two steps into
366 nm). Products were purified by column chromatography (silica
valuable triflates 21 and 22, which are precursors for fur-
ther cross-coupling reactions as well as the boronic acid
ester derivative 23, which was synthesized from 22 via
palladium-catalyzed borylation. Finally, the (trimethyl-
silyl)ethynyl group of 12 could be deprotected to yield 24,
which is a building block for Sonogashira reactions. We
are currently using all these substituted 2,2¢-bipyridines to
construct larger ligand structures.
1
gel 60, 70–230 mesh, Merck). H and 13C NMR spectra were re-
corded on a Bruker DRX 500 spectrometer at 300 K at 500.1 and
125.8 MHz, a Bruker AM 400 at 298 K at 400.1 MHz and 100.6
MHz, or an Bruker DPX 300 at 298 K at 300.1 MHz and 75.5 MHz,
respectively. 19F NMR spectra were recorded on a Bruker DPX 300
spectrometer at 300 K at 282.4 MHz. NMR chemical shifts are re-
1
ported relative to the following standards: H NMR, residual non-
deuterated solvent, internal standard; 13C NMR, deuterated solvent,
internal standard; 19F NMR: CFCl3, external standard. Signals were
assigned on the basis of 1H, 13C, H,H-COSY, HMQC, and HMBC
NMR experiments. Numbering of the 1H and 13C nuclei is according
to Figure 1.
In conclusion, we have demonstrated that simple tetra-
kis(triphenylphosphine)palladium(0) is a powerful cata-
lyst in the Negishi cross coupling of different mono-
substituted and unsymmetrically disubstituted 2,2¢-bipyr-
idines 1–17 starting from both 2-bromo- and 2-chloropyr-
idines. Furthermore we showed that some of the cross-
coupling products could be used for further transforma-
tions involving, for example, the formation of valuable tri-
flates 21 and 22.
4'
5'
R
3'
2'
6'
2
N
R
R
R
N
6
8
3
4
9
5
R
R
3
4
7
5
8'
10
R
6
2
9'
N
Br
Figure 1 Numbering of the pyridine and bipyridine core for NMR
peak assignments.
Synthesis 2007, No. 7, 1061–1069 © Thieme Stuttgart · New York

1064
U. Kiehne et al.
PAPER
MS spectra were taken on a Finnigan MAT 212 with data system
MMS–ICIS (EI, CI, isobutane, NH3), a Finnigan MAT 95 with data
system DEC-Station 5000 (CI, isobutane or NH3; HiRes-CI, isobu-
tane or NH3; FD), or an A.E.I. MS-50 (EI; HiRes-EI). Melting
points were measured with a hot-stage microscope SM-Lux from
Leitz or a SMP-20 from Büchi and are not corrected. Elemental
analyses were carried out with a Fisons Instrument EA1108 or a
Heraeus Vario EL.
2-Bromo-5-heptylpyridine
Yield: 200 mg (38%).
1H NMR (500.1 MHz, CDCl3): d = 0.88 (t, 3J = 6.8 Hz, 3 H, CH3),
1.20–1.37 (m, 8 H, 4 × CH2), 1.54–1.66 (m, 2 H, CH2), 2.65 (t, 3J =
7.7 Hz, 2 H, CH2), 7.33–7.39 (m, 2H, H3, H4), 7.91 (s, 1 H, H6).
13C NMR (125.8 MHz, CDCl3): d = 14.2 (CH3), 22.7, 29.1, 31.1,
31.8, 32.4 (6 × CH2), 127.7 (C3), 137.5 (C5), 138.7 (C4), 139.4
(C2), 150.3 (C6).
Most solvents were dried, distilled, and stored under argon accord-
ing to standard procedures. t-BuLi solutions were purchased from
Aldrich and were titrated prior to use against N-pivaloyl-o-tolui-
dine.16 All chemicals were used as received from commercial sourc-
es. Pd(PPh3)4 was purchased from ABCR.
MS (CI, isobutane): m/z = 255.9 ([C12H1879BrN]+ = [M]+, 100),
257.9 ([C12H1881BrN]+ = [M]+, 95).
HRMS (EI): m/z [M – H]+ calcd for C12H17BrN: 254.0550; found:
254.0545.
2-Bromo-5-methoxypyridine,17 2-bromo-5-[(trimethylsilyl)ethy-
Anal. Calcd for C12H18BrN: C, 56.26; H, 7.08; N, 5.47. Found: C,
56.98; H, 7.06; N, 5.54.
nyl]pyridine,18
2-chloro-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyri-
dine,12b 2-chloro-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine,12a 2-
chloro-5-(4-methoxyphenyl)pyridine,12b 2-chloro-5-[(trimethylsi-
lyl)ethynyl]pyridine19 were prepared according to published proce-
dures.
2-Bromo-3-heptylpyridine
Yield: 40 mg (8%).
1H NMR (500.1 MHz, CDCl3): d = 0.88 (t, 3J = 6.8 Hz, 3 H, CH3),
1.21–1.41 (m, 8 H, 4 × CH2), 1.57–1.66 (m, 2 H, CH2), 2.69 (t, 3J =
7.9 Hz, 2 H, CH2), 7.16 (dd, 3J = 7.4 Hz, 3J = 7.5 Hz, 1 H, H5), 7.47
(dd, 3J = 7.4 Hz, 4J = 1.6 Hz, 1 H, H4), 8.18 (dd, 3J = 7.5 Hz, 4J =
1.6 Hz, 1 H, H6).
13C NMR (125.8 MHz, CDCl3): d = 14.2 (CH3), 22.8, 29.2, 29.4,
29.5, 31.9, 35.4 (6 × CH2), 122.9 (C5), 138.2 (C4), 139.4 (C3),
144.5 (C2), 147.6 (C6).
MS (EI): m/z = 255.0 ([C12H1879BrN]+ = [M]+, 28), 257.0
([C12H1881BrN]+ = [M]+, 26), 171.0 ([M(79Br) – C6H12]+, 100), 173.0
([M(81Br) – C6H12]+, 95).
HRMS (EI): m/z [M]+ calcd for C12H18BrN: 255.0623; found:
255.0622.
3-Heptylpyridine
A soln of i-Pr2NH (1.66 mL, 11.8 mmol, 1.05 equiv) and THF (60
mL) was cooled to –78 °C. 1.6 M n-BuLi in hexanes (7.36 mL, 11.8
mmol, 1.05 equiv) and 3-methylpyridine (1.09 mL, 11.2 mmol, 1
equiv) were subsequently added via syringe. The acetone–N2 cool-
ing bath was replaced by an ice-water bath. After 5 min, 1-iodohex-
ane (1.75 mL, 11.8 mmol, 1.05 equiv) was added via syringe. The
soln was stirred at this temperature for 5 min, then it was allowed to
warm to r.t., stirred for a further 36 h, and concentrated. The crude
product was dissolved in CH2Cl2 and washed with H2O. The aque-
ous layer was extracted with CH2Cl2 (4 × 25 mL) and the combined
organic layers were dried (Na2SO4). Purification by flash column
chromatography (silica gel, n-hexane–EtOAc, 1:1 + 0.5% Et3N,
Rf = 0.65) gave the product a yellow oil; yield: 1.516 g (76%).
1H NMR (500.1 MHz, CDCl3): d = 0.88 (t, 3J = 6.9 Hz, 3 H, CH3),
1.22–1.36 (m, 8 H, 4 × CH2), 1.57–1.65 (m, 2 H, CH2), 2.59 (t, 3J =
7.7 Hz, 2 H, CH2), 7.17 (m, 1 H, H5), 7.69 (ddd, 3J = 7.69 Hz, 2 ×
4J not resolved, 1 H, H4), 8.40–8.45 (m, 2 H, H2, H6).
13C NMR (125.8 MHz, CDCl3): d = 14.0 (CH3), 22.6, 29.04, 29.09,
31.1, 31.7, 33.0 (6 × CH2), 123.2 (C5), 135.7 (C4), 137.9 (C3),
147.2 (C6), 150.0 (C2).
Anal. Calcd for C12H18BrN: C, 56.26; H, 7.08; N, 5.47. Found: C,
56.41; H, 7.02; N, 5.34.
2-Bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine
2-Amino-6-bromopyridine (5 g, 28.90 mmol, 1 equiv), hexane-2,5-
dione (4.1 mL, 34.68 mmol, 1.2 equiv), and PTSA (50 mg, 0.28
mmol, 1 mol%) were dissolved in toluene (30 mL) and heated in a
Dean–Stark apparatus for 2 h. After cooling to r.t., the mixture was
washed with sat. aq NaHCO3, H2O (5 × 25 mL), and brine (25 mL).
The organic layer was dried (MgSO4). Purification of the crude
product by column chromatography (n-hexane–EtOAc, 5:1 + 0.5%
Et3N, Rf = 0.5) gave the product as a pale yellow solid; yield: 6.83
g (94%); mp 104 °C.
MS (EI): m/z = 177.1 ([C12H19N]+ = [M]+, 14), 93.0 ([M – C6H12]+,
100).
HRMS (EI): m/z (M – H]+ calcd for C12H18N: 176.1445; found:
176.1442.
1H NMR (500.1 MHz, CDCl3): d = 2.15 (s, 6 H, CH3), 5.88 (s, 2 H,
CH-pyrrole), 7.16 (d, 3J = 8.2 Hz, 1 H, H5), 7.47 (d, 3J = 8.2 Hz, 1
H, H3), 7.60 (dd, 3J = 8.2 Hz, 3J = 8.2 Hz, 1 H, H4).
Anal. Calcd for C12H19N: C, 81.30; H, 10.80; N, 7.90. Found: C,
79.54; H, 10.33; N, 7.60.
13C NMR (125.8 MHz, CDCl3): d = 13.3 (CH3), 107.7 (2 C, CH-
pyrrole), 120.2 (C5), 126.4 (C3), 128.7 (2 C, CMe-pyrrole), 139.8
(C4), 140.6 (C2), 151.8 (C6).
2-Bromo-5-heptylpyridine
A soln of 2-(dimethylamino)ethanol (0.63 mL, 6 mmol, 3 equiv) in
n-hexane (2.6 mL) was cooled to 0 °C. At this temperature 1.6 M n-
BuLi in n-hexane (7.5 mL, 12 mmol, 6 equiv) was added. The soln
was stirred at 0 °C for 30 min. 3-Heptylpyridine (363 mg, 2.04
mmol, 1 equiv) dissolved in n-hexane (2.61 mL) was added via sy-
ringe and the soln was stirred at 0 °C for 1 h and then quenched by
the addition of CBr4 (2.436 g, 7.344 mmol, 3.6 equiv) in THF (10
mL). The soln was stirred at r.t. for 72 h, hydrolyzed and then
CH2Cl2 (25 mL) was added and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (5 × 25 mL) and the com-
bined organic layers were dried (Na2SO4). Purification of the crude
product by flash column chromatography (silica gel, n-hexane–
EtOAc, 20:1, Rf = 0.48) gave the product as a yellow oil. The regio-
isomer 2-bromo-3-heptylpyridine could also be isolated as a yellow
oil (n-hexane–EtOAc 20:1, Rf = 0.35).
MS (EI): m/z = 251.1 ([C11H12N2Br79]+ = [M]+, 100), 253.1
([C11H12N2Br81]+ = [M]+, 96), 173.1 ([C11H12N2]+, 15).
HRMS (EI): m/z M – H]+ calcd for C11H10BrN2: 249.0022; found:
249.0023.
Anal. Calcd for C11H11BrN2: C, 52.61; H, 4.42; N, 11.16. Found: C,
52.65; H, 4.45; N, 11.05.
2,2¢-Bipyridines from Substituted 2-Bromopyridines: General
Procedure 1
A two-necked, 250-mL round-bottomed flask equipped with a stir-
ring bar, an argon inlet, and a rubber septum was charged with THF
(50 mL) and cooled to –78 °C. 1.6 M t-BuLi in n-pentane (8.01 mL,
12.82 mmol) was added via syringe resulting in a pale-yellow soln.
Synthesis 2007, No. 7, 1061–1069 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,2¢-Bipyridines from 2-Bromo- or 2-Chloropyridines
5-Bromo-5¢-heptyl-2,2¢-bipyridine (5)
1065
To this mixture the first 2-bromopyridine (8.25 mmol, 1.5 equiv)
was slowly added via syringe [solid pyridines were dissolved in
THF (6 mL)] and stirred at the same temperature for 30 min. After
that time a soln of ZnCl2 (2.68 g, 19.68 mmol, 3.6 equiv) in THF
(40 mL) was added. The resulting soln was allowed to warm to r.t.
and stirred for 2.5 h (soln 1).
Treatment of 2-bromo-5-heptylpyridine (336 mg, 1.31 mmol, 1.2
equiv), 1.6 M t-BuLi in n-pentane (1.65 mL, 2.64 mmol, 2.4 equiv),
ZnCl2 (540 mg, 3.96 mmol, 3.6 equiv), 2,5-dibromopyridine (258
mg, 1.1 mmol, 1 equiv), and Pd(PPh3)4 (38 mg, 33 mmol, 3 mol%)
according to general procedure 1 gave 5 as a yellow solid after flash
column chromatography (n-hexane–EtOAc, 10:1 + 0.5% Et3N, Rf =
0.5); yield: 310 mg (85%); mp 42–46 °C.
1H NMR (400.1 MHz, CDCl3): d = 0.88 (t, 3J = 6.9 Hz, 3 H, CH3),
1.20–1.38 (m, 8 H, 4 × CH2), 1.60–1.69 (m, 2 H, CH2), 2.65 (t, 3J =
7.6 Hz, 2 H, CH2), 7.62 (dd, 3J = 8.1 Hz, 4J = 2.3 Hz, 1 H, H4¢), 7.91
(dd, 3J = 8.5 Hz, 4J = 2.4 Hz, 1 H, H4), 8.27 (m, 2 H, H3, H3¢), 8.48
(d, 4J = 2.3 Hz, 1 H, H6¢), 8.69 (d, 4J = 2.4 Hz, 1 H, H6).
13C NMR (100.6 MHz, CDCl3): d = 14.1 (CH3), 22.7, 29.11, 29.13,
31.1, 31.8, 32.9 (6 × CH2), 120.65 (C3¢), 120.73 (C5), 122.1 (C3),
136.9 (C4¢), 138.8 (C5¢), 139.5 (C4), 149.4 (C6¢), 150.1 (C6), 152.9
(C2¢), 154.8 (C2).
MS (EI): m/z = 332.1 ([C17H2179BrN2]+ = [M]+, 8), 334.1
([C17H2181BrN2]+ = [M]+, 7), 170.9 ([M(79Br) – C11H15N]+, 98),
172.9 ([M(81Br) – C11H15N]+, 100).
A two-necked, 25-mL round-bottomed flask equipped with an ar-
gon inlet, and a rubber septum was charged with the second 2-bro-
mopyridine (5.5 mmol, 1 equiv) and Pd(PPh3)4 (127 mg,
0.11 mmol, 2 mol%). The mixture was evacuated and flushed with
argon (2 ×) and dissolved in THF (10 mL) (soln 2).
Soln 2 was slowly added to soln 1 and the resulting mixture was
stirred at r.t. for 18 h. When TLC monitoring revealed complete
consumption of the starting material the mixture was quenched with
sat. aq EDTA soln (60 mL) and stirred at r.t. for 15 min. After that
time sat. aq Na2CO3 soln was added until pH 8. The product was ex-
tracted with CH2Cl2 (3 × 25 mL) and the combined organic layers
were dried (Na2SO4), concentrated in vacuo, and purified by flash
chromatography (silica gel).
5-Methyl-2,2¢-bipyridine (1)20
HRMS (EI): m/z [M]+ calcd for C17H21BrN2: 332.0888; found:
332.0891.
2-Bromopyridine (648 mg, 4.1 mmol, 1.5 equiv), 1.6 M t-BuLi in
n-pentane (4.13 mL, 6.6 mmol, 2.4 equiv), ZnCl2 (1.35 g, 9.9 mmol,
3.6 equiv), 2-bromo-5-methylpyridine (473 mg, 2.75 mmol, 1
equiv), and Pd(PPh3)4 (95 mg, 82.5 mmol, 3 mol%) were reacted ac-
cording to general procedure 1 to give 1 as a pale yellow oil after
flash column chromatography (n-hexane–EtOAc, 5:1 + 0.5% Et3N,
Rf = 0.20); yield: 467 mg (quant.).
Anal. Calcd for C17H21BrN2·0.25 EtOAc: C, 60.85; H, 6.52; N, 7.88.
Found: C, 62.06; H, 6.67; N, 7.88.
Methyl 6¢-(2,5-Dimethyl-1H-pyrrol-1-yl)-2,2¢-bipyridine-6-car-
boxylate (6)
2-Bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (767 mg, 3.05
mmol, 1.2 equiv), 1.5 M t-BuLi in n-pentane (3.65 mL, 5.47 mmol,
2.15 equiv), ZnCl2 (954 mg, 7.00 mmol, 2.75 equiv), methyl 8-bro-
mopyridine-2-carboxylate (550 mg, 2.55 mmol, 1 equiv), and
Pd(PPh3)4 (88 mg, 76.5 mmol, 3 mol%) were used. Purification by
flash column chromatography (n-hexane–EtOAc, 5:1 + 5% Et3N,
Rf = 0.6) gave 6 as a yellow solid; yield: 394 mg (50%); mp 102 °C.
Analytical data were in accordance with those previously pub-
lished.20
5-Methoxy-2,2¢-bipyridine (2)12a
Treatment of 2-bromopyridine (1.66 g, 10.56 mmol, 1.5 equiv), 1.6
M t-BuLi in n-pentane (10.56 mL, 16.9 mmol, 2.4 equiv), ZnCl2
(3.45 g, 25.34 mmol, 3.6 equiv), 2-bromo-5-methoxypyridine (1.32
g, 7.04 mmol, 1 equiv), and Pd(PPh3)4 (244 mg, 211.2 mmol, 3
mol%) according to general procedure 1 gave 2 as an amorphous
solid after flash column chromatography (EtOAc + 5% Et3N, Rf =
0.20); yield: 1.28 g (98%).
1H NMR (400.1 MHz, CDCl3): d = 2.19 (s, 6 H, CH3), 4.04 (s, 3 H,
OCH3), 5.94 (s, 2 H, CH-pyrrole), 7.26 (dd, 3J = 7.8 Hz, 4J = 0.9 Hz,
3
3
1 H, H5¢), 7.94 (dd, J = 7.9 Hz, J = 7.8 Hz, 1 H, H4), 7.97 (dd,
3J = 7.8 Hz, 3J = 7.8 Hz, 1 H, H4¢), 8.13 (dd, 3J = 7.7 Hz, 4J = 1.0
Hz, 1 H, H5), 8.56 (dd, 3J = 7.8 Hz, 4J = 0.9 Hz, 1 H, H3¢), 8.59 (dd,
3J = 7.9 Hz, 4J = 1.0 Hz, 1 H, H3).
Analytical data were in accordance with those previously pub-
lished.12a
13C NMR (100.6 MHz, CDCl3): d = 13.4 (2 C, CH3), 52.9 (OCH3),
107.1 (2 C, CH-pyrrole), 119.1 (C3¢), 122.1 (C5¢), 124.6 (C3), 125.3
(C5), 128.7 (2 C, CMe-pyrrole), 138.0 (C4), 139.1 (C4¢), 147.6
(C6), 151.4 (C6¢), 155.1 (C2), 155.8 (C2¢), 165.8 (COO).
MS (EI): m/z = 307.1 ([C18H17N3O2]+ = [M]+, 100).
HRMS (EI): m/z [M – H]+ calcd for C18H16N3O2: 306.1237; found:
5-(2,5-Dimethyl-1H-pyrrol-1-yl)-2,2¢-bipyridine (3)12b
Treatment of 2-bromopyridine (1.6 g, 10.16 mmol, 1.5 equiv), 1.6
M t-BuLi in n-pentane (10.16 mL, 16.25 mmol, 2.4 equiv), ZnCl2
(3.32 g, 24.37 mmol, 3.6 equiv), 2-bromo-5-(2,5-dimethyl-1H-pyr-
rol-1-yl)pyridine (1.7 g, 6.77 mmol, 1 equiv), and Pd(PPh3)4 (157
mg, 135.4 mmol, 2 mol%) according to general procedure 1 gave 3
as a brown solid after flash column chromatography (n-hexane–
EtOAc, 1:1 + 0.5% Et3N, Rf = 0.67); yield: 1.23 g (73%).
306.1244.
Anal. Calcd for C18H17N3O2·0.2 EtOAc·0.2 CH2Cl2: C, 66.74; H,
5.60; N, 12.29. Found: C, 66.67; H, 5.77; N, 11.82.
Analytical data were in accordance with those previously pub-
lished.12a
Methyl 6¢-(2,5-Dimethyl-1H-pyrrol-1-yl)-2,2¢-bipyridine-4-car-
boxylate (7)
5-Methyl-5¢-[(trimethylsilyl)ethynyl]-2,2¢-bipyridine (4)12b
Treatment of 2-bromo-5-methylpyridine (1.13 g, 6.56 mmol, 1.12
equiv), 1.65 M t-BuLi in n-pentane (8.35 mL, 13.78 mmol, 2.36
equiv), ZnCl2 (2.24 g, 16.44 mmol, 2.8 equiv), 2-bromo-5-[(tri-
methylsilyl)ethynyl]pyridine (1.485 g, 5.84 mmol, 1 equiv), and
Pd(PPh3)4 (135 mg, 117 mmol, 2 mol%) according to general proce-
dure 1 gave 4 as a yellow solid after flash column chromatography
(n-hexane–EtOAc, 5:1 + 5% Et3N, Rf = 0.62); yield: 1.304 g (84%).
2-Bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (1.00 g, 4.00
mmol, 1.2 equiv), 1.55 M t-BuLi in n-pentane (4.62 mL, 7.17 mmol,
2.15 equiv), ZnCl2 (1.25 g, 9.16 mmol, 2.75 equiv), methyl 2-bro-
mopyridine-6-carboxylate (720 mg, 3.33 mmol, 1 equiv), and
Pd(PPh3)4 (116 mg, 100 mmol, 3 mol%) were used. Purification by
flash column chromatography (n-hexane–EtOAc, 5:1 + 5% Et3N,
Rf = 0.5) gave 7 as a yellow solid; yield: 564 mg (55%); mp 113 °C.
1H NMR (400.1 MHz, CDCl3): d = 2.22 (s, 6 H, CH3), 3.97 (s, 3 H,
Analytical data were in accordance with those previously pub-
lished.12b
OCH3), 5.96 (s, 2 H, CH-pyrrole), 7.26 (dd, 3J = 7.8 Hz, 4J = 0.9 Hz,
3
4
1 H, H5¢), 7.88 (dd, J = 5.0 Hz, J = 1.6 Hz, 1 H, H5), 7.96 (dd,
3J = 7.8, 3J = 7.8 Hz, 1 H, H4¢), 8.46 (dd, 3J = 7.8 Hz, 4J = 0.9 Hz, 1
Synthesis 2007, No. 7, 1061–1069 © Thieme Stuttgart · New York

1066
U. Kiehne et al.
PAPER
H, H3¢), 8.82 (dd, 3J = 5.0 Hz, 5J = 0.9 Hz, 1 H, H6), 8.94 (dd, 4J =
1.6 Hz, 5J = 0.9 Hz, 1 H, H3).
Analytical data were in accordance with those previously pub-
lished.23
13C NMR (100.6 MHz, CDCl3): d = 13.5 (2 C, CH3), 52.8 (OCH3),
107.1 (2 C, CH-pyrrole), 119.4 (C3¢), 120.7 (C3), 122.1 (C5¢), 123.2
(C5), 128.8 (2 C, CMe-pyrrole), 138.6 (C4), 139.0 (C4¢), 150.0
(C6), 151.5 (C6¢), 155.1 (C2), 156.6 (C2¢), 165.7 (COO).
MS (EI): m/z = 307.1 ([C18H17N3O2]+ = [M]+, 100).
HRMS (EI): m/z [M – H]+ calcd for C18H16N3O2: 307.1321; found:
Methyl 5¢-Heptyl-2,2¢-bipyridine-5-carboxylate (11)
Treatment of 2-bromo-5-heptylpyridine (200 mg, 0.78 mmol, 1.2
equiv), 1.5 M t-BuLi in n-pentane (0.929 mL, 1.4 mmol, 2.15
equiv), ZnCl2 (244 mg, 1.79 mmol, 2.75 equiv), methyl 6-chloro-
nicotinate (112 mg, 0.65 mmol, 1 equiv), and Pd(PPh3)4 (15 mg,
13.1 mmol, 2 mol%) according to general procedure 2 gave 11 as a
yellow solid after flash column chromatography (n-hexane–EtOAc,
5:1 + 5% Et3N, Rf = 0.58); yield: 103 mg (51%); mp 76–80 °C.
307.1317.
Anal Calcd for C18H17N3O2·0.33 EtOAc: C, 68.96; H, 5.89; N,
12.48. Found: C, 68.71; H, 5.47; N, 12.74.
1H NMR (400.1 MHz, CDCl3): d = 0.87 (t, 3J = 6.9 Hz, 3 H, CH3),
1.20–1.38 (m, 8 H, 4 × CH2), 1.59–1.68 (m, 2 H, CH2), 2.66 (t, 3J =
3
7.7 Hz, 2 H, CH2), 3.96 (s, 3 H, CO2CH3), 7.64 (dd, J = 8.1 Hz,
2,2¢-Bipyridines from Substituted 2-Chloropyridines; General
Procedure 2
The same procedure was used as applied for the substituted 2-bro-
mopyridines except for the fact that a 2-chloropyridine was used to
prepare soln 2 and that the resulting mixture obtained upon adding
soln 2 to soln 1 was refluxed instead of stirred at r.t.
4J = 2.2 Hz, 1 H, H4¢), 8.37 (m, 2 H, H3¢, H4), 8.46 (dd, 3J = 8.3 Hz,
5J = 0.8 Hz, 1 H, H3), 8.51 (d, 4J = 2.2 Hz, 1 H, H6¢), 9.23 (dd, 4J =
2.1 Hz, 5J = 0.8 Hz, 1 H, H6).
13C NMR (100.6 MHz, CDCl3): d = 14.1 (CH3), 22.7, 29.10, 29.12,
31.1, 31.8, 32.9 (6 × CH2), 52.4 (OCH3), 120.2 (C3), 121.6 (C3¢),
125.3 (C5), 136.9 (C4¢), 138.0 (C4), 139.3 (C5¢), 149.6 (C6¢), 150.5
(C6), 152.8 (C2¢), 159.7 (C2), 165.9 (CO2Me).
Methyl 2,2¢-Bipyridine-5-carboxylate (8)21
Treatment of 2-bromopyridine (1.81 g, 11.45 mmol, 1.2 equiv), 1.5
M t-BuLi in n-pentane (13.67 mL, 20.51 mmol, 2.15 equiv), ZnCl2
(3.58 g, 26.24 mmol, 2.75 equiv), methyl 6-chloronicotinate (1.64
g, 9.54 mmol, 1 equiv), and Pd(PPh3)4 (331 mg, 287 mmol, 3 mol%)
according to general procedure 2 gave 8 as a white solid after flash
column chromatography (n-hexane–EtOAc, 3:1 + 5% Et3N, Rf =
0.48); yield: 1.626 g (80%).
MS (EI): m/z (%) = 312.8 ([C19H24N2O2 (M)]+, 56), 227.1 ([M –
C6H13]+,100).
HRMS (EI): m/z [M]+ calcd for C19H24N2O2: 312.1838; found:
312.1836.
Anal. Calcd for C19H24N2O2·0.5 EtOAc: C, 71.05; H, 8.04; N, 7.71.
Found: C, 70.39; H, 8.04; N, 7.76.
Analytical data were in accordance with those previously pub-
lished.21
Methyl 5¢-[(Trimethylsilyl)ethynyl]-2,2¢-bipyridine-5-carboxy-
late (12)
5-(4-Methoxyphenyl)-2,2¢-bipyridine (9)22
Treatment of 2-bromo-5-[(trimethylsilyl)ethynyl]pyridine (400 mg,
1.57 mmol, 1.2 equiv), 1.6 M t-BuLi in n-pentane (1.97 mL, 3.14
mmol, 2.4 equiv, lithiation time reduced to 5 min), ZnCl2 (500 mg,
3.67 mmol, 2.8 equiv), methyl 6-chloronicotinate (225 mg, 1.31
mmol, 1 equiv), and Pd(PPh3)4 (46 mg, 40 mmol, 3 mol%) according
to general procedure 2 gave 12 as a yellow solid after flash column
chromatography (n-hexane–EtOAc, 5:1 + 5% Et3N, Rf = 0.58);
yield: 284 mg (70%); mp 152–154 °C.
Treatment of 2-bromopyridine (216 mg, 1.37 mmol, 1.5 equiv), 1.6
M t-BuLi in n-pentane (1.37 mL, 2.18 mmol, 2.4 equiv), ZnCl2 (447
mg, 3.28 mmol, 3.6 equiv), 2-chloro-5-(4-methoxyphenyl)pyridine
(200 mg, 0.91 mmol, 1 equiv), and Pd(PPh3)4 (21 mg, 18.2 mmol, 2
mol%) according to general procedure 2 gave 9 as a yellow solid af-
ter flash column chromatography (n-hexane–EtOAc, 1:1 + 0.5%
Et3N, Rf = 0.38); yield: 181 mg (76%); mp 131–133 °C.
1H NMR (500.1 MHz, CDCl3): d = 3.87 (s, 3 H, OCH3), 7.03 (d, 3J =
8.7 Hz, 2 H, H9, H9¢), 7.33 (ddd, 3J = 4.5 Hz, 4J = 1.6 Hz, 1 H, H5¢,
3J = 6.6 Hz), 7.60 (d ,3J = 8.7 Hz, 2 H, H8, H8¢), 7.85 (ddd, 3J = 7.7
Hz, 3J = 6.6 Hz, 4J = 1.6 Hz, 1 H, H4¢), 8.00 (dd, 3J = 8.5 Hz, 4J =
2.2 Hz, 1 H, H4), 8.48 (dd, 3J = 8.5 Hz, 3J = 7.7 Hz, 2 H, H3, H3¢),
8.70 (d, 3J = 4.5 Hz, 1 H, H6¢), 8.90 (d, 4J = 2.2 Hz, 1 H, H6).
13C NMR (125.8 MHz, CDCl3): d = 55.4 (C11), 114.6 (2 C, C9,
C9¢), 121.3 (2 C, C3, C3¢), 123.7 (C5¢), 128.2 (2 C, C8, C8¢), 129.7
(C7), 135.0 (C4), 136.4 (C5), 137.3 (C4¢), 146.9 (C6), 148.9
(C6¢),153.6 (C2), 155.4 (C2¢), 160.0 (C10).
1H NMR (400.1 MHz, CDCl3): d = 0.27 [s, 9 H, Si(CH3)3], 3.95 (s,
3 H, OCH3), 7.86 (dd, 3J = 8.2 Hz, 4J = 2.1 Hz, 1 H, H4¢), 8.36 (dd,
3J = 8.3 Hz, 4J = 2.2 Hz, 1 H, H4), 8.40 (dd, 3J = 8.2 Hz, 5J = 0.8 Hz,
1 H, H3¢), 8.46 (dd, 3J = 8.3 Hz, 5J = 0.8 Hz, 1 H, H3), 8.72 (dd, 4J =
2.1 Hz, 5J = 0.8 Hz, 1 H, H6¢), 9.22 (dd, 4J = 2.1 Hz, 5J = 0.8 Hz, 1
H, H6).
13C NMR (100.6 MHz, CDCl3): d = –0.3 [Si(CH3)3], 52.6 (OCH3),
100.1 (C≡CTMS), 101.8 (C≡CTMS), 121.0 (C3), 121.1 (C3¢),
125.9 (C5), 138.2 (C4), 140.0 (C4¢), 150.7 (C6), 152.3 (C6¢), 153.9
(C2¢), 158.9 (C2), 165.9 (CO2Me); (C5¢) not found.
MS (EI): m/z = 262.1 ([C17H14N2O]+ = [M]+, 100).
HRMS (EI): m/z [M]+ calcd for C17H14N2O: 262.1106; found:
MS (EI): m/z (%) = 310.1 ([C17H18N2O2Si]+ = [M]+, 44), 295.1 ([M
– CH3]+, 100).
262.1105.
HRMS (EI): m/z [M]+ calcd for C17H18N2O2Si: 310.1138; found:
310.1138.
Anal. Calcd for C17H14N2O·0.2 THF: C, 77.26; H, 5.68; N, 10.12.
Found: C, 77.07; H, 5.52; N, 9.92.
Anal. Calcd for C17H18N2O2Si·0.2 EtOAc·.02 C6H14: C, 66.09; H,
6.54; N, 8.11. Found: C, 65.35; H, 6.65; N, 8.08.
5-[(Trimethylsilyl)ethynyl]-2,2¢-bipyridine (10)23
Treatment of 2-bromopyridine (567 mg, 3.59 mmol, 1.5 equiv), 1.6
M t-BuLi in n-pentane (4.63 mL, 7.41 mmol, 3.1 equiv), ZnCl2
(1.08 g, 7.89 mmol, 3.3 equiv), 2-chloro-5-[(trimethylsilyl)ethy-
nyl]pyridine (500 mg, 2.39 mmol, 1 equiv), and Pd(PPh3)4 (55 mg,
48 mmol, 2 mol%) according to general procedure 2 gave 10 as a
yellow solid after flash column chromatography (n-hexane–EtOAc
5:1, + 5% Et3N, Rf = 0.75); yield: 540 mg (90%).
5-(4-Methoxyphenyl)-5¢-methyl-2,2¢-bipyridine (13)12b
Treatment of 2-bromo-5-methylpyridine (1.40 g, 8.16 mmol, 1.5
equiv), 1.6 M t-BuLi in n-pentane (10.54 mL, 16.86 mmol, 3.1
equiv), ZnCl2 (2.7 g, 19.58 mmol, 3.6 equiv), 2-chloro-5-(4-meth-
oxyphenyl)pyridine (1.2 g, 5.44 mmol, 1 equiv), and Pd(PPh3)4 (189
mg, 163.2 mmol, 3 mol%) according to general procedure 2 gave 13
as a yellow solid after flash column chromatography (n-hexane–
EtOAc, 3:1 + 5% Et3N, Rf = 0.45); yield: 990 mg (66%).
Synthesis 2007, No. 7, 1061–1069 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,2¢-Bipyridines from 2-Bromo- or 2-Chloropyridines
1067
Analytical data were in accordance with those previously pub-
lished.12b
(C5¢), 128.5 (2 C, C8, C8¢), 139.5 (C4), 147.5 (C4¢), 149.8 (C6),
152.2 (C2), 157.5 (C2¢), 163.6 (C6¢).
MS (EI): m/z (%) = 279.2 ([C17H17N3O]+ = [M]+, 100), 186.1
4,6¢-Dimethyl-2,2¢-bipyridine (14)24
([C11H10N2O]+, 42).
2-Bromo-6-methylpyridine (2.5 g, 14.53 mmol, 1.2 equiv), 1.5 M t-
BuLi in n-pentane (17.36 mL, 26.04 mmol, 2.15 equiv), ZnCl2 (4.54
g, 33.31 mmol, 2.75 equiv), 2-chloro-4-methylpyridine (1.55 g,
12.11 mmol, 1 equiv), and Pd(PPh3)4 (420 mg, 363 mmol, 3 mol%)
were used. Purification by flash column chromatography (n-
hexane–EtOAc, 5:1 + 5% Et3N, Rf = 0.6) gave 14 as a colorless oil;
yield: 1.88 g (84%).
1H NMR (500.1 MHz, CDCl3): d = 2.42 (s, 3 H, 4-CH3), 2.63 (s, 3
H, 6¢-CH3), 7.10 (d, 3J = 4.9 Hz, 1 H, H5), 7.14 (d, 3J = 7.7 Hz, 1 H,
H5¢), 7.67 (dd, 3J = 7.7 Hz, 3J = 7.7 Hz, 1 H, H4¢), 8.15 (d, 3J = 7.7
Hz, 1 H, H3¢), 8.22 (s, 1 H, H3), 8.51 (d, 3J = 4.9 Hz, 1 H, H6).
13C NMR (125.8 MHz, CDCl3): d = 21.2 (4-CH3), 24.6 (6¢-CH3),
118.2 (C3¢), 121.9 (C3), 123.1 (C5¢), 124.5 (C5), 137.0 (C4¢), 148.0
(C4), 148.9 (C6), 155.7 (C2), 156.2 (C2¢), 157.8 (C6¢).
MS (EI): m/z (%) = 184.1 ([C12H12N2]+ = [M]+, 100).
HRMS (EI): m/z [M – H]+ calcd for C12H11N2: 183.0917; found:
HRMS (EI): m/z [M – H]+ calcd for C18H16N3O: 278.1288; found:
278.1298.
Anal. Calcd for C17H17N3O: C, 73.10; H, 6.13; N, 15.04. Found: C,
72.52; H, 6.32; N, 14.64.
6¢-(2,5-Dimethyl-1H-pyrrol-1-yl)-4-methoxy-2,2¢-bipyridine
(17)
2-Bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (1.09 g, 4.34
mmol, 1.2 equiv), 1.5 M t-BuLi in n-pentane (5.02 mL, 7.78 mmol,
2.15 equiv), ZnCl2 (1.36 g, 9.96 mmol, 2.75 equiv), 2-chloro-4-
methoxypyridine (520 mg, 3.62 mmol, 1 equiv), and Pd(PPh3)4 (126
mg, 108.6 mmol, 3 mol%) were used. Purification by flash column
chromatography (n-hexane–EtOAc, 5:1 + 5% Et3N, Rf = 0.43) gave
17 as a yellow oil; yield: 684 mg (68%).
1H NMR (400.1 MHz, CDCl3): d = 2.21 (s, 6 H, CH3), 3.91 (s, 3 H,
OCH3), 5.95 (s, 2 H, CH-pyrrole), 6.85 (dd, 3J = 5.7 Hz, 4J = 2.7 Hz,
3
4
183.0923.
1 H, H5), 7.22 (dd, J = 7.8 Hz, J = 0.9 Hz, 1 H, H5¢), 7.93 (dd,
3J = 7.8, 3J = 7.8 Hz, 1 H, H4¢), 7.99 (d, 4J = 2.7 Hz, 1 H, H5), 8.43
(dd, 3J = 7.8 Hz, 4J = 0.9 Hz, 1 H, H3¢), 8.49 (d, 3J = 5.7 Hz, 1 H,
H6).
Anal. Calcd for C12H12N2: C, 78.23; H, 6.57; N, 15.21. Found: C,
77.13; H, 7.13; N, 14.64.
4,6¢-Dimethoxy-2,2¢-bipyridine (15)
13C NMR (100.6 MHz, CDCl3): d = 13.5 (2 C, CH3), 55.4 (OCH3),
106.5 (C3), 107.0 (2 C, CH-pyrrole), 111.1 (C5), 119.4 (C3¢), 121.7
(C5¢), 128.8 (2 C, CMe-pyrrole), 138.8 (C4¢), 150.3 (C6), 151.2
(C6¢), 155.7 (C2¢), 157.3 (C2), 166.8 (C4).
MS (EI): m/z (%) = 279.1 ([C17H17N3O]+ = [M]+, 100).
HRMS (EI): m/z [M – H]+ calcd for C17H16N3O: 278.1288; found:
2-Bromo-6-methoxypyridine (1.09 g, 5.8 mmol, 1.2 equiv), 1.5 M
t-BuLi in n-pentane (7.57 mL, 11.36 mmol, 2.15 equiv), ZnCl2
(1.98 g, 14.53 mmol, 2.75 equiv), 2-chloro-4-methoxypyridine (759
mg, 5.28 mmol, 1 equiv), and Pd(PPh3)4 (184 mg, 159 mmol, 3
mol%) were used. Purification by flash column chromatography (n-
hexane–EtOAc, 2:1 + 5% Et3N, Rf = 0.58) gave 15 as a colorless oil;
yield: 811 mg (71%).
278.1295.
1H NMR (500.1 MHz, CDCl3): d = 3.92 (s, 3 H, 4-OCH3), 4.03 (s,
3 H, 6¢-OCH3), 6.76 (d, 3J = 7.7 Hz, 1 H, H5¢), 6.81 (dd, 3J = 5.5 Hz,
4J = 2.2 Hz, 1 H, H5), 7.68 (dd, 3J = 7.7 Hz, 3J = 7.7 Hz, 1 H, H4¢),
7.95 (d, 3J = 2.2 Hz, 1 H, H3), 8.00 (d, 3J = 7.7 Hz, 1 H, H3¢), 8.48
(d, 3J = 5.5 Hz, 1 H, H6).
13C NMR (125.8 MHz, CDCl3): d = 53.2 (4-OCH3), 55.2 (6¢-OCH3),
106.9 (C3), 109.6 (C5), 111.2 (C5¢), 114.0 (C3¢), 139.4 (C4¢), 150.2
(C6), 153.0 (C2¢), 157.7 (C2), 163.5 (C6¢), 166.7 (C4).
Anal. Calcd for C17H16N3O·0.166 CH2Cl2: C, 70.25; H, 5.95; N,
14.32. Found: C, 70.87; H, 6.07; N, 14.42.
5-Heptyl-5¢-(4-methoxyphenyl)-2,2¢-bipyridine (18)
i-Pr2NH (0.610 mL, 4.31 mmol, 1.05 equiv) and anhyd THF (38
mL) were cooled to –78 °C and 1.6 M n-BuLi in n-hexane (2.70
mL, 4.31 mmol, 1.05 equiv) was added. A soln of 13 (1.125 g, 4.08
mmol, 1 equiv) in anhyd THF (10 mL) was added via syringe. The
soln became dark red immediately. The acetone–nitrogen cooling
bath was replaced by an ice-water bath. After 5 min, 1-iodohexane
(0.633 mL, 4.31 mmol, 1.05 equiv) was added via syringe. The soln
was allowed to warm to r.t., stirred for 3 h, concentrated, and the
crude product was dissolved in CH2Cl2 (25 mL) and washed with
H2O (25 mL). After extraction of the aqueous layer with CH2Cl2 (3
× 25 mL) the combined organic layers were dried (Na2SO4) and the
solvent was removed. Purification by flash column chromatography
(n-hexane–EtOAc, 2:1 + 5% Et3N, Rf = 0.3–0.65) gave 18 as a yel-
low solid; yield: 1.059 g (72%); mp 75–76 °C.
MS (EI): m/z (%)
=
215.1 ([C12H11N2O2]+, 100), 216.1
([C12H12N2O2]+ = [M]+, 96), 186.1 ([C11H10N2O]+, 52).
HRMS (EI): m/z [M – H]+ calcd for C12H11N2O2: 215.0815; found:
215.0820.
Anal. Calcd for C12H12N2O2: C, 66.65; H, 5.59; N, 12.96. Found: C,
65.65; H, 5.73; N, 12.32.
4-(2,5-Dimethyl-1H-pyrrol-1-yl)-6¢-methoxy-2,2¢-bipyridine
(16)
1H NMR (500.1 MHz, CDCl3): d = 0.81 (t, 3J = 6.9 Hz, 3 H, CH3),
1.20–1.28 (m, 8 H, 4 × CH2), 1.59 (m, 2 H, CH2), 2.58 (t, 3J = 7.7
Hz, 2 H, CH2), 3.79 (s, 3 H, OCH3), 6.95 (m, 2 H, H9), 7.52 (m, 2
H, H8), 7.57 (dd, 3J = 8.1 Hz, 4J = 2.0 Hz, 1 H, H4¢), 7.89 (dd, 3J =
8.3 Hz, 4J = 2.2 Hz, 1 H, H4), 8.27 (d, 3J = 8.1 Hz, 1 H, H3¢), 8.35
2-Bromo-6-methoxypyridine (1.00 g, 5.32 mmol, 1.2 equiv), 1.5 M
t-BuLi in n-pentane (6.37 mL, 9.56 mmol, 2.15 equiv), ZnCl2 (1.67
g, 12.22 mmol, 2.75 equiv), 2-chloro-4-(2,5-dimethyl-1H-pyrrol-1-
yl)pyridine (916 mg, 4.45 mmol, 1 equiv), and Pd(PPh3)4 (154 mg,
133 mmol, 3 mol%) were used. Purification by flash column chro-
matography (n-hexane–EtOAc, 5:1 + 5% Et3N, Rf = 0.6) gave 16 as
a colorless solid; yield: 1.094 g (88%); mp 84 °C.
1H NMR (400.1 MHz, CDCl3): d = 2.15 (s, 6 H, CH3), 3.99 (s, 3 H,
OCH3), 5.98 (s, 2 H, H7, H7¢), 6.81 (d, 3J = 8.2 Hz, 1 H, H5), 7.16
(dd, 3J = 5.5 Hz, 4J = 1.7 Hz, 1 H, H5¢), 7.73 (dd, 3J = 7.7 Hz, 3J =
8.2 Hz, 1 H, H4), 8.10 (d, 3J = 7.7 Hz, 1 H, H3), 8.31 (d, 3J = 1.7 Hz,
1 H, H3¢), 8.75 (d, 3J = 5.5 Hz, 1 H, H6¢).
4
(d, 3J = 8.3 Hz, 1 H, H3), 8.44 (d, J = 2.0 Hz, 1 H, H6¢), 8.80 (d,
4J = 2.2 Hz, 1 H, H6).
13C NMR (125.8 MHz, CDCl3): d = 14.0 (CH3), 22.6, 29.0, 29.1,
31.1, 31.7, 32.9 (6 × CH2), 55.4 (OCH3), 114.6 (C9), 120.6 (C3¢),
120.7 (C3), 128.1 (C8), 130.0 (C7), 134.7 (C4), 135.8 (C5), 136.9
(C4¢), 138.2 (C5¢), 147.1 (C6), 149.2 (C6¢), 153.5 (C2¢), 154.3 (C2),
159.8 (C10).
MS (CI, isobutane): m/z (%) = 361.3 ([C24H29N2O]+ = [M]+, 100).
13C NMR (100.6 MHz, CDCl3): d = 13.2 (2 C, CH3), 53.3 (OCH3),
107.4 (2 C, C7, C7¢), 112.0 (C5), 114.1 (C3), 120.0 (C3¢), 122.2
Synthesis 2007, No. 7, 1061–1069 © Thieme Stuttgart · New York

1068
U. Kiehne et al.
PAPER
HRMS (CI, isobutane): m/z [M + H]+ calcd for C24H29N2O:
361.2279; found: 361.2274.
Anal. Calcd for C23H26N2O·0.33 CH2Cl2: C, 74.78; H, 7.17; N, 7.47.
Found: C, 74.78; H, 7.49; N, 7.40.
Anal. Calcd for C24H28N2O: C, 79.96; H, 7.83; N, 7.77. Found: C,
80.75; H, 8.00; N, 7.64.
5-[4-(Trifluoromethylsulfonyl)phenyl]-2,2¢-bipyridine (21)
Bipyridine 19 (300 mg, 1.21 mmol, 1 equiv) was dissolved in Et3N
(2 mL) and CH2Cl2 (30 mL) and the soln was cooled to –30 °C. At
this temperature, Tf2O (0.41 mL, 682 mg, 2.42 mmol, 2 equiv) in
CH2Cl2 (10 mL) was slowly added to the mixture. The cooling bath
was removed and the soln was stirred at r.t. for 13 h. The mixture
was then poured into cold H2O (50 mL) and extracted with CH2Cl2
(5 × 25 mL). The combined organic layers were washed with sat. aq
NaHCO3 (50 mL) and with brine (50 mL). The organic layer was
dried (Na2SO4) and the solvents were removed. Purification by flash
column chromatography (n-hexane–EtOAc, 1:1 + 0.5% Et3N, Rf =
0.66) gave 21 as a yellow solid; yield: 184 mg (40%); mp 109–
111 °C.
1H NMR (500.1 MHz, CDCl3): d = 7.36 (ddd, 3J = 6.3 Hz, 3J = 3.9
Hz, 4J = 1.1 Hz, 1 H, H5¢), 7.41 (d, 3J = 8.6 Hz, 2 H, H9, H9¢), 7.72
(d, 3J = 8.6 Hz, 2 H, H8, H8¢), 7.87 (ddd, 3J = 7.7 Hz, 3J = 6.3 Hz,
4J = 1.6 Hz, 1 H, H4¢), 8.01 (dd, 3J = 8.2 Hz, 4J = 2.2 Hz, 1 H, H4),
8.47 (d, 3J = 7.7 Hz, 1 H, H3¢), 8.54 (d, 3J = 8.2 Hz, 1 H, H3), 8.72
(d, 3J = 3.9 Hz, 1 H, H6¢), 8.90 (d, 4J = 2.2 Hz, 1 H, H6).
5-(4-Hydroxyphenyl)-2,2¢-bipyridine (19)
5-(4-Methoxyphenyl)-2,2¢-bipyridine (9, 600 mg, 2.29 mmol, 1
equiv) was dissolved in CH2Cl2 (15 mL) and cooled to –78 °C. 1 M
BBr3 in CH2Cl2 (6.78 mL, 6.78 mmol) was slowly added. The mix-
ture was allowed to warm up to r.t. and stirred for 7 h. After a short
time an orange-brown precipitate formed. H2O (50 mL) was care-
fully added in order to hydrolyze excessive BBr3. EtOAc (50 mL)
was added and the soln was neutralized with 6 M aq NaOH. The or-
ange precipitate was filtered off and dried in vacuo. The neutralized
soln was extracted with EtOAc (5 × 25 mL) and dried (Na2SO4).
The solvents were removed and then, the product fractions were
combined and 19 was obtained as an orange-brown solid; yield: 506
mg (89%); mp 146–148 °C.
1H NMR (500.1 MHz, DMSO-d6): d = 6.91 (d, H9¢, 3J = 8.8 Hz, 2
H, H9), 7.44 (ddd, 3J = 6.9 Hz, 3J = 4.9 Hz, 4J = 1.1 Hz, 1 H, H5¢),
7.64 (d, 3J = 8.8 Hz, 2 H, H8, H8¢), 7.95 (ddd, 3J = 7.7 Hz, 3J = 6.9
Hz, 4J = 1.6 Hz, 1 H, H4¢), 8.14 (dd, 3J = 8.2 Hz, 4J = 2.2 Hz, 1 H,
H4), 8.40 (dd, 3J = 7.7 Hz, 3J = 8.2 Hz, 2 H, H3, H3¢), 8.68 (dd, 3J =
4.9 Hz, 4J = 1.6 Hz, 1 H, H6¢), 8.93 (d, 4J = 2.2 Hz, 1 H, H6), 9.79
(s, 1 H, OH).
13C NMR (125.8 MHz, DMSO-d6): d = 116.1 (2 C, C9, C9¢), 120.4,
120.6 (C3, C3¢), 124.1 (C5¢), 127.3 (C7), 128.1 (2 C, C8, C8¢), 134.3
(C4), 135.8 (C5), 137.5 (C4¢), 146.6 (C6), 149.3 (C6¢), 153.1 (C2),
155.0 (C2¢), 158.0 (C10).
1
13C NMR (125.8 MHz, CDCl3): d = 118.8 (CF3, JC-F = 321 Hz),
121.2 (C3), 121.3 (C3¢), 122.1 (2 C, C9, C9¢), 124.0 (C5¢), 128.9 (2
C, C8, C8¢), 134.7 (C5), 135.4 (C4), 137.3 (C4¢), 138.1 (C7), 147.5
(C6), 149.1 (C6¢), 149.5 (C10), 155.3, 155.4 (C2, C2¢).
19F NMR (282.4 MHz, CDCl3): d = –72.7 (CF3).
MS (EI): m/z (%) = 380.0 ([C17H11F3N2O3S]+ = [M]+, 100).
HRMS (EI): m/z calcd for C17H11F3N2O3S: 380.0442; found:
380.0447.
MS (EI): m/z (%) = 248.0 ([C16H12N2O]+ = [M]+, 100).
HRMS (EI): m/z [M]+ calcd for C16H12N2O: 248.0950; found:
Anal. Calcd for C17H11F3N2O3S·0.33 C6H5CH3: C, 56.49; H, 3.35;
N, 6.82. Found: C, 56.92; H, 2.92; N, 6.52.
248.0950.
Anal. Calcd for C16H12N2O·0.166 EtOAc: C, 76.12; H, 5.11; N,
10.65. Found: C, 76.71; H, 5.18; N, 10.42.
5-Heptyl-5¢-[4-(trifluoromethylsulfonyl)phenyl]-2,2¢-bipyri-
dine (22)
5-Heptyl-5¢-(4-hydroxyphenyl)-2,2¢-bipyridine (20)
Bipyridine 20 (150 mg, 0.43 mmol, 1 equiv) was dissolved in Et3N
(0.2 mL) and CH2Cl2 (10 mL) and the soln was cooled to –30 °C.
At this temperature Tf2O (110 mL, 182 mg, 0.65 mmol, 1.5 equiv)
was slowly added to the mixture. The cooling bath was removed and
the mixture was stirred at r.t. for 15 h. TLC monitoring still revealed
some starting material, hence additional Tf2O (20 mL) was added at
r.t. and the mixture was stirred for an additional 3 h. The mixture
was then poured into cold H2O (25 mL) and extracted with CH2Cl2
(5 × 15 mL). The combined organic layers were washed with sat. aq
NaHCO3 (25 mL) and with brine (25 mL). The organic layer was
dried (Na2SO4) and the solvents were removed. Purification by flash
column chromatography (n-hexane–EtOAc, 5:1 + 5% Et3N, Rf =
0.6) gave 22 as a yellow solid; yield: 152 mg (74%); mp 112–
114 °C.
1H NMR (500.1 MHz, CDCl3): d = 0.88 (t, 3J = 6.9 Hz, 3 H, CH3),
1.25–1.39 (m, 8 H, 4 × CH2), 1.67 (m, 2 H, CH2), 2.69 (t, 3J = 7.7
Hz, 2 H, CH2), 7.40 (m, 2 H, H9), 7.70 (m, 3 H, H4¢, H8), 7.99 (dd,
3J = 8.3 Hz, 4J = 2.2 Hz, 1 H, H4), 8.38 (d, 3J = 7.9 Hz, 1 H, H3¢),
8.52 (m, 2 H, H3, H6¢), 8.87 (s, 1 H, H6).
13C NMR (125.8 MHz, CDCl3): d = 14.0 (CH3), 22.6, 29.0, 29.1,
31.0, 31.7, 32.9 (6 × CH2), 118.8 (CF3, 1JC-F = 321 Hz), 121.1 (C3,
C3¢), 122.1 (C9), 128.9 (C8), 134.5 (C5), 135.4 (C4), 137.4 (C4¢),
138.1 (C7), 139.0 (C5¢), 147.5 (C6), 148.8 (C6¢), 149.5 (C10), 152.6
(C2¢), 155.3 (C2).
Bipyridine 18 (180 mg, 0.49 mmol, 1 equiv) was dissolved in
CH2Cl2 (5 mL) and the soln was cooled to –78 °C. 1 M BBr3 in
CH2Cl2 (2.2 mL, 2.2 mmol, 4.4 equiv) was slowly added. The mix-
ture was allowed to warm up to r.t. and stirred for 10 h. Aq 2 M
NaOH was carefully added in order to hydrolyze excessive BBr3.
EtOAc (25 mL) was added and the soln was neutralized with aq 6
M HCl. The orange precipitate was filtered off and dried in vacuo.
The neutralized soln was extracted with EtOAc (5 × 25 mL) and
dried (Na2SO4). Solvent was removed and the product fractions
were combined to give 20 as an orange-brown solid; yield: 171 mg
(quant); mp 90–92 °C.
Rf = 0.05 (n-hexane–EtOAc, 2:1 + 5% Et3N).
1H NMR (500.1 MHz, CDCl3): d = 0.86 (t, 3J = 6.9 Hz, 3 H, CH3),
1.23–1.34 (m, 8 H, 4 × CH2), 1.64 (m, 2 H, CH2), 2.65 (t, 3J = 7.3
Hz, 2 H, CH2), 6.93 (m, 2 H, H9), 7.44 (m, 2 H, H8), 7.66 (d, 3J =
7.6 Hz, 1 H, H4¢), 7.91 (d, 3J = 7.9 Hz, 1 H, H4), 8.29 (d, 3J = 7.6
Hz, 1 H, H3¢), 8.34 (d, 3J = 7.9 Hz, 1 H, H3), 8.51 (s, 1 H, H6¢), 8.81
(s, 1 H, H6); OH not found.
13C NMR (125.8 MHz, CDCl3): d = 14.0 (CH3), 22.6, 29.0, 29.1,
31.0, 31.7, 32.8 (6 × CH2), 116.3 (C9), 121.1 (C3/C3¢), 128.2 (C8),
129.2 (C7), 134.9 (C4), 136.2 (C5), 137.4 (C4¢), 138.6 (C5¢), 146.9
(C6), 149.0 (C6¢), 153.2 (C2¢), 153.7 (C2), 157.0 (C10).
MS (CI, isobutane): m/z& nbsp;(%) = 347.3 ([C23H27N2O]+ = [M +
19F NMR (282.4 MHz, CDCl3): d = –72.73 (CF3).
MS (CI, NH3): m/z (%) = 479.2 ([C24H26F3N2O3S]+ = [M + H]+,
H]+, 100).
HRMS (CI, isobutane): m/z [M + H]+ calcd for C23H27N2O:
347.2123; found: 347.2122.
100).
Synthesis 2007, No. 7, 1061–1069 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,2¢-Bipyridines from 2-Bromo- or 2-Chloropyridines
1069
HRMS (CI, NH3): m/z [M + H]+ calcd for C24H26F3N2O3S:
479.1616; found: 479.1622.
Acknowledgment
Financial support from the DFG (SFB 624 and SPP 1118) is grate-
fully acknowledged.
Anal. Calcd for C24H25F3N2O3S: C, 60.24; H, 5.27; N, 5.85; S 6.70.
Found: C, 60.96; H, 5.57; N, 5.81; S 6.23.
5-Heptyl-5¢-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]-2,2¢-bipyridine (23)
References
(1) (a) Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000,
100, 3553. (b) Newkome, G. R.; Patri, A. K.; Holder, E.;
Schubert, U. S. Eur. J. Org. Chem. 2002, 235.
(2) Piguet, C.; Bernadinelli, G.; Hopfgartner, G. Chem. Rev.
1997, 97, 2005.
(3) Juris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.; Belser,
P.; von Zelewsky, A. Coord. Chem. Rev. 1998, 84, 85.
(4) (a) Chelucci, G.; Thummel, R. P. Chem. Rev. 2002, 102,
3129. (b) Fletcher, N. C. J. Chem. Soc., Perkin Trans. 1
2002, 1831.
KOAc (246 mg, 2.508 mmol, 3 equiv), 22 (400 mg, 0.84 mmol, 1
equiv), bis(pinacolato)diboron (255 mg, 1.003 mmol, 1.2 equiv),
[PdCl2(dppf)] (61 mg, 84 mmol, 10 mol% Pd), and 1,1¢-bis(diphe-
nylphosphino)ferrocene (dppf) (47 mg, 84 mmol, 10 mol%) were
dissolved in 1,4-dioxane (12 mL) and the resulting soln was heated
to 120 °C and stirred at this temperature for 18 h. When TLC mon-
itoring revealed complete consumption of the starting material H2O
(25 mL) and CH2Cl2 (25 mL) were added. The layers were separat-
ed and the aqueous layer was extracted with CH2Cl2 (3 × 15 mL).
The combined organic layers were dried (Na2SO4) and the solvents
were removed. Purification by flash column chromatography (n-
hexane–EtOAc, 5:1, Rf = 0.6) gave 23 as a brown solid; yield: 343
mg (90%); mp 158–162 °C.
(5) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359.
(6) Kröhnke, F. Synthesis 1976, 1.
(7) Some examples, see: (a) Romero, F.; Ziessel, R.
Tetrahedron Lett. 1995, 36, 6471. (b) Newkome, G. R.;
Gross, J.; Patri, A. K. J. Org. Chem. 1997, 62, 3013.
(8) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de
Meijere, A.; Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004. (c) Cross-Coupling Reactions; Miyaura, N., Ed.;
Springer: Berlin, 2002. Recent special issue on cross-
coupling reactions, see: (d) J. Organomet. Chem. 2002,
653, 1–303.
(9) Tsuji, J. Palladium Reagents and Catalysts; John Wiley &
Sons: Chichester, 1995.
(10) (a) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719.
(b) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41,
4176; Angew. Chem., 2002, 114, 4350.
(11) (a) Lützen, A.; Hapke, M.; Griep-Raming, J.; Haase, D.;
Saak, W. Angew. Chem. Int. Ed. 2002, 41, 2086; Angew.
Chem., 2002, 114, 2190. (b) Schalley, C. A.; Lützen, A.;
Albrecht, M. Chem. Eur. J. 2004, 10, 1072.
(12) (a) Lützen, A.; Hapke, M. Eur. J. Org. Chem. 2002, 2292.
(b) Lützen, A.; Hapke, M.; Staats, H.; Bunzen, J. Eur. J. Org.
Chem. 2003, 3948.
1H NMR (400.1 MHz, CDCl3): d = 0.88 (t, 3J = 6.9 Hz, 3 H, CH3),
1.22–1.41 (m, 8 H, 4 × CH2), 1.37 (s, 12 H, 4 × CH3), 1.61–1.71 (m,
2 H, CH2), 2.67 (t, 3J = 7.7 Hz, 2 H, CH2), 7.62–7.68 (m, 3 H, H4¢,
H8), 7.93 (d, 3J = 8.3 Hz, 2 H, H9), 8.03 (dd, 3J = 8.3 Hz, 4J = 2.4
Hz, 1 H, H4), 8.34 (dd, 3J = 8.1 Hz, 5J = 0.7 Hz, 1 H, H3¢), 8.44 (dd,
3J = 8.3 Hz, 5J = 0.8 Hz, 1 H, H3), 8.51 (dd, 4J = 2.2 Hz, 5J = 0.7 Hz,
1 H, H6¢), 8.92 (dd, 4J = 2.4 Hz, 5J = 0.8 Hz, 1 H, H6).
13C NMR (100.6 MHz, CDCl3): d = 14.1 (CH3), 22.7 (CH2), 24.9 (4
× CH3), 29.13, 29.15, 31.1, 31.8, 32.9 (5 × CH2), 84.0 (2 C, CMe2),
120.71 (C3)*, 120.76 (C3¢)*, 126.3 (2 C, C8), 135.3 (C4), 135.6 (2
C, C9), 136.0 (C5), 136.8 (C4¢), 138.4 (C5¢), 140.4 (C7), 147.7
(C6), 149.4 (C6¢), 153.6 (C2¢), 155.4 (C2), C10 not found; * inter-
changeable assignments.
MS (EI): m/z (%) = 456.3 ([C29H37BN2O2]+ = [M]+, 100).
HRMS (EI): m/z [M]+ calcd for C29H3710BN2O2: 455.2984; found:
455.2977.
Anal. Calcd for C29H37BN2O2·0.2 EtOAc: C, 75.50; H, 8.21; N,
5.91. Found: C, 76.31; H, 8.06; N, 5.89.
Methyl 5¢-Ethynyl-2,2¢-bipyridine-5-carboxylate (24)
Bipyridine 12 (284 mg, 0.91 mmol, 1 equiv) was dissolved in THF
(25 mL) and MeOH (25 mL). KF (64 mg, 1.10 mmol, 1.2 equiv)
was added and the resulting mixture stirred for 24 h. The solvents
were removed and the resulting crude product subjected to flash
column chromatography (n-hexane–EtOAc, 5:1 + 5% Et3N, Rf =
0.69) to give 24 as a yellow solid; yield: 155 mg (71%); mp 180–
182 °C.
(13) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020.
(14) Fang, Y.-Q.; Hanan, G. S. Synlett 2003, 852.
(15) Grushin, V.; Alper, H. Chem. Rev. 1994, 94, 1047.
(16) Suffert, J. J. Org. Chem. 1989, 54, 509.
(17) Leeson, P. D.; Emmett, J. C. J. Chem. Soc., Perkin Trans. 1
1988, 3085.
(18) Grave, C.; Lentz, D.; Schaefer, A.; Samori, P.; Rabe, J. P.;
Franke, P.; Schlueter, A. D. J. Am. Chem. Soc. 2003, 125,
6907.
(19) Baxter, P. N. W. J. Org. Chem. 2000, 65, 1257.
(20) Potts, K. T. J. Org. Chem. 1985, 50, 5405.
(21) Fletcher, N. C.; Nieuwenhuyzen, M.; Rainey, S. J. Chem.
Soc., Dalton Trans. 2001, 2641.
(22) This compound has been described before using a different
synthetic approach; however, no NMR or MS data were
provided: Kozhevnikov, V. N.; Kozhevnikov, D. N.;
Shabunina, O. V.; Rusinov, V. L.; Chupakhin, O. N.
Tetrahedron Lett. 2005, 46, 1791.
1H NMR (400.1 MHz, CDCl3): d = 3.32 (s, 1 H, C≡CH), 3.97 (s, 3
H, OCH3), 7.91 (dd, 3J = 8.3 Hz, 4J = 2.0 Hz, 1 H, H4¢), 8.38 (dd,
3J = 8.4 Hz, 4J = 2.1 Hz, 1 H, H4), 8.40 (m, 3J = 8.2 Hz, 1 H, H3¢),
8.46 (m, 3J = 8.4 Hz, 1 H, H3), 8.72 (dd, 4J = 2.0 Hz, 5J = 0.9 Hz, 1
H, H6¢), 9.22 (dd, 4J = 2.1 Hz, 5J = 0.9 Hz, 1 H, H6).
13C NMR (100.6 MHz, CDCl3): d = 52.5 (OCH3), 80.5 (C≡CH),
82.0 (C≡CH), 120.0 (C5¢), 120.9 (C3), 121.1 (C3¢), 125.9 (C5),
138.1 (C4), 140.1 (C4¢), 150.6 (C6), 152.4 (C6¢), 154.3 (C2¢), 158.6
(C2), 165.7 (C7).
MS (EI): m/z (%) = 238.0 ([C14H10N2O2]+ = [M]+, 100).
HRMS (EI): m/z [M]+ calcd for C14H10N2O2: 238.0742; found:
(23) Grosshenny, V.; Romero, F. M.; Ziessel, R. J. Org. Chem.
238.0746.
1997, 62, 1491.
(24) This compound has been described before using a different
synthetic approach; however, no NMR or MS data were
provided: Schubert, U. S.; Eschbaumer, C.; Heller, M. Org.
Lett. 2000, 2, 3373.
Anal. Calcd for C14H10N2O2·0.25 EtOAc·0.25 C6H14: C, 70.32; H,
5.54; N, 9.94. Found: C, 69.71; H, 5.55; N, 9.78.
Synthesis 2007, No. 7, 1061–1069 © Thieme Stuttgart · New York