A direct, copper-catalyzed functionalization of pyridines with alkynes

Article abstract of DOI:10.1055/s-0029-1218632

A one-pot, copper-catalyzed method to construct 2-alk-ynylpyridines is presented. This provides a route to access these products directly from terminal alkynes and the parent pyridine, and without prefunctionalization of the pyridine core. In addition, (Z)-alk-2-enylpyridines can be prepared via a related procedure. These reactions are used to synthesize a number of new alkynyl-and alkenyl-substituted pyridines in one pot.

Full text of DOI:10.1055/s-0029-1218632

1000
PAPER
A Direct, Copper-Catalyzed Functionalization of Pyridines with Alkynes
C
opper-Catalyze
a
m
lization of Pyridine
s
s
w
ith
A
lk
a
ynes y E. Beveridge,a,b Bruce A. Arndtsen*a
a
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, QC, H3A 2K6, Canada
Fax +1(514)3982382; E-mail: bruce.arndtsen@mcgill.ca
Pfizer Global Research and Development, Groton, CT 06340, USA
E-mail: ramsay.beveridge@pfizer.com
b
Received 6 November 2009
We have recently reported a regioselective copper-cata-
lyzed alkynylation of pyridine in the presence of an acid
chloride or chloroformate activator.17–20 This reaction
yields the partially reduced pyridine derivatives 1 in ca. 20
Abstract: A one-pot, copper-catalyzed method to construct 2-alk-
ynylpyridines is presented. This provides a route to access these
products directly from terminal alkynes and the parent pyridine, and
without prefunctionalization of the pyridine core. In addition, (Z)-
alk-2-enylpyridines can be prepared via a related procedure. These minutes with a variety of terminal alkynes at ambient tem-
reactions are used to synthesize a number of new alkynyl- and
alkenyl-substituted pyridines in one pot.
perature (Equation 1). Since dihydropyridines can serve
as precursors to pyridines, we considered the potential of
Key words: pyridine, copper, catalytic, alkyne, alkene
applying this catalytic coupling to the one-pot synthesis of
substituted aromatic pyridines. This would provide a
method to directly derivatize the parent pyridine with sim-
ple alkynes, and without the need for additional steps to
activate the pyridine (e.g., ortho-halogenation for Sono-
gashira couplings), or the use of reactive (and stoichio-
metric) organometallic reagents. Our progress towards
this goal is described herein.
The pyridine core is found in a variety of natural prod-
ucts,1 ligands,2 dendrimers,3 polymers,4 and synthetic bio-
logically active compounds.5 For example, pyridine
containing alkaloids have been found to exhibit potent cy-
totoxic, antimicrobial, and antiviral activities,1 while sim-
ple substituted pyridines can behave as antagonists of
human metabotropic glutamate receptors (mGluR5), and
cytotoxic agents to human cancer cells.5 Due to their
broad utility, the construction of substituted pyridines re-
mains an active area of research.6,7 Currently, the most
common approach to functionalize pyridines under mild
conditions involves transition-metal catalyzed cross-cou-
pling reactions with halogenated (or metallated) pyridines
(e.g., Suzuki,8 Heck,9 Sonogashira,10 or Stille11 cou-
plings), or more recently with pyridine N-oxides12,13 or N-
iminopyridinium ylides.14 While useful, the initial gener-
ation of the correctly positioned halogenated or metallated
pyridine precursor (or N-oxide or N-iminopyridinium
ylide) prior to functionalization is required for this chem-
istry. Alternatively, pyridines can be reductively function-
alized via the addition of organometallic nucleophiles to
in situ formed N-acylpyridinium salts, yielding 1,2- or
1,4-dihydropyridines.15,16 However, this approach typi-
cally employs stoichiometric amounts of a preformed re-
active organometallic reagent, which can be incompatible
with common functional groups.
Initial efforts towards the synthesis of 2-phenylalkynylpy-
ridine 2 probed coupling of the copper-catalyzed alkyn-
ylation of pyridine with subsequent in situ oxidation
(Table 1). As shown in entries 1–4, no oxidized products
were formed with oxygen or peroxide sources, or even
with the known dihydropyridine oxidant, elemental sul-
fur.15f,16 While these early attempts led to almost complete
recovery of 1 or decomposition, a moderate yield of 2 was
obtained when the crude reaction mixture was treated with
a stoichiometric amount of Cu(OTf)2 (entry 5).21 Alterna-
tively, we were pleased to find that treatment of the in situ
generated 1 with DDQ (2,3-dichloro-5,6-dicyano-1,4-
quinone) or the related quinone o-chloranil (3,4,5,6-tetra-
chloro-1,2-quinone), resulted in the high yield, one-pot
formation of 2-alkynylpyridine 2 (Table 1, entries 6, 7).
Interestingly, this copper-mediated coupling/oxidation
can also be performed in a single step, provided a stoi-
chiometric amount of CuI is employed (entry 8). While
more copper is required for this protocol, the product is
isolated in similarly high yield.
CuI (10 mol%)
O
i-Pr2NEt (1.4 equiv)
R2
+
+
H
N
MeCN
r.t., 20 min
R1
Cl
R2
N
R1
O
R1 = Ph, OEt, OPh, Troc, Fmoc
R2 = Ph, CO2Et, n-Bu, TMS, CH2Cl
1
62–88%
Equation 1 Copper-catalyzed multicomponent coupling of pyridines, acyl chlorides and alkynes
SYNTHESIS 2010, No. 6, pp 1000–1008
x
x
.
x
x
.2
0
1
0
Advanced online publication: 04.01.2010
DOI: 10.1055/s-0029-1218632; Art ID: M05809SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Copper-Catalyzed Functionalization of Pyridines with Alkynes
1001
Table 1 Towards a Direct Copper-Catalyzed Alkynylation of
Table 2 Alkyne Diversity in the Tandem Alkyne Coupling and
Pyridinea
Oxidation Route to Alkynylpyridinesa
CuI (10 mol%)
1) CuI (10 mol%)
i-Pr2NEt
MeCN, r.t., 20 min
i-Pr2NEt (1.4 equiv)
O
DDQ (1 equiv)
O
R2
+
+
H
Cl
+
+
N
MeCN, 45 °C, 1 h
H
Ph
R1
N
N
2) [O] conditions
EtO
Cl
N
R2
Ph
2
Entry R1
R2
Ph
Product
Yield
(%)c
Entry
[O]
air
Time (h) Temp (°C) Yield (%)b
1
2
3
4
5
6
7
8
48
46
16
40
16
1
45
r.t.
65
45
65
45
45
45
–
1
2
3
4
OEt
81
45
55
54
O2
–
N
N
N
N
Ph
Ph
Ph
H2O2
S8
–
–
Ph
Ph
Cu(OTf)2
DDQ
33
81
83
81c
Trocb Ph
o-chloranil
DDQ
1
1
a Reaction conditions: pyridine (0.5 mmol), chloroformate (0.6
mmol), and alkyne (0.5 mmol) in MeCN (2 mL) were added to a vial
containing CuI (0.05 mmol) and i-Pr2NEt (0.7 mmol) in MeCN (1
mL) in a glove box, stirred for 20–30 min, followed by the addition of
oxidant.
OPh
OPh
CO2Et
CO2Et
b Yield of isolated product.
S
c CuI used: 1 equiv; DDQ added last after ~30 seconds stirring.
5d
52
N
N
S
As shown in Tables 2 and 3, this protocol can be used to
construct a range of 2-alkynylpyridines directly from the
parent heterocycle. For example, a number of alkynes can
be employed in this reaction, including phenyl-, substitut-
ed aryl-, heteroaryl- and ester-substituted alkynes, each
providing the corresponding 2-substituted pyridine in
good overall yield. More electron-rich alkynes, however,
are not compatible with these reaction conditions, and
yielded a complex mixture of products (Table 2, entries 8,
9). Of particular interest is the use of bromo-substituted
alkynes (Table 2 entries 6; Table 3, entries 12, 13) and
ethyl propriolate (Table 2 entry 4; Table 3 entries 9, 11),
since these alkynes can be problematic reagents in
Sonogashira couplings. This reaction can also be per-
formed in air, obviating the requirement for inert reaction
conditions (Table 2, entries 5–7; Table 3, entries 4, 7, 9–13).
6d
OPh
OEt
54
66
Br
Br
7d
Ph
N
Ph
e
8
9
OEt
OEt
TMS
–
–
–
e
n-Bu
–
a Reaction conditions: pyridine (0.5 mmol), chloroformate (0.6
mmol), and alkyne (0.5 mmol) in MeCN (2 mL) were added to CuI
(0.05 mmol) and i-Pr2NEt (0.7 mmol) in MeCN (1 mL), stirred for
20–30 min, then DDQ (1 equiv) added and warmed to 45 °C, 1 h.
b 2,2,2-Trichloroethyl.
In addition to pyridine, a number of substituted pyridines
also undergo catalytic functionalization under these con-
ditions (Table 3). Aryl-, alkyl-, halo-, and even sensitive
aldehyde and ketone pyridine functionalities are all toler-
ated, leading to the formation of alkynylpyridine struc-
tures. While exclusive a-alkyne substitution is observed
for all aromatic products, regioisomeric mixtures of the
1,2- and 1,6-dihydropyridine intermediates are observed
when 3-methyl, 3-formyl, and 3-acetyl substituted py-
ridines were employed (Table 3, entries 2, 3, 4, 10, 13).
However, in each case only one of the dihydropyridine re-
gioisomers is found to be reactive towards oxidation.22 In
the case of entries 2, 4, and 13, the 2-alkynyl-3-picoline
c Yield of isolated product.
d Performed open to air.
e Less than 10% of the alkynylpyridine product was observed by LC-
MS and NMR analyses of the crude reaction mixture.
product isolated are interesting regioisomers of the known
highly selective human mGlu5 receptor antagonists.5a,b
While probing the potential use of bases to deprotect the
propargyl carbamate intermediates and facilitate oxida-
tion,23 it was found that treatment of crude in situ generat-
ed 1 with base and overnight heating yielded instead the
alkenylpyridine product 3 (Table 4). N-Acyl-2-ethynyl-
Synthesis 2010, No. 6, 1000–1008 © Thieme Stuttgart · New York

1002
R. E. Beveridge, B. A. Arndtsen
PAPER
1,2-dihydropyridines have been previously reported to in a 1:1 E/Z mixture (Table 4, entry 6). Conversely, when
undergo base-mediated isomerization to alkenylpyridines, DABCO was employed, the more hindered cis-isomer
presumably via allene intermediates, though in low yield was the only product isolated in moderate yield (Table 4,
and E/Z stereoselectivity.24 Our preliminary results show entry 5). The latter likely arises via selective re-protona-
this rearrangement to be base dependent. Use of K2CO3 in tion of the central carbon of the allene from the less hin-
methanol provided the highest overall conversion, though dered face by bulky, protonated DABCO.
Table 3 Pyridine Diversity in the Tandem Alkyne Coupling and Oxidation Route to Alkynylpyridinesa
CuI (10 mol%)
R
i-Pr2NEt (1.4 equiv)
DDQ (1 equiv)
R
O
R2
+
+
H
MeCN, 45 °C, 1 h
N
R1
Cl
N
R2
Entry
1
Pyridine
R1
R2
Product
Yield (%)b
73
Br
Br
OEt
OEt
Ph
Ph
N
N
Ph
2
3
69
33
N
N
O
Ph
O
OEt
Ph
N
N
Ph
O
4c
OPh
OEt
OEt
51
39
43
N
N
O
5
Ph
Ph
N
N
Ph
Ph
N
Ph
6
N
Ph
Br
Br
S
7c
OPh
54
N
N
S
8
OEt
OEt
Ph
40
82
N
N
Ph
Br
Br
9c
CO2Et
N
N
CO2Et
Synthesis 2010, No. 6, 1000–1008 © Thieme Stuttgart · New York

PAPER
Copper-Catalyzed Functionalization of Pyridines with Alkynes
1003
Table 3 Pyridine Diversity in the Tandem Alkyne Coupling and Oxidation Route to Alkynylpyridinesa (continued)
CuI (10 mol%)
R
i-Pr2NEt (1.4 equiv)
DDQ (1 equiv)
R
O
R2
+
+
H
MeCN, 45 °C, 1 h
N
R1
Cl
N
R2
Entry
10c
Pyridine
R1
R2
Product
Yield (%)b
O
O
OPh
OPh
OPh
53
F
N
N
F
Ph
Ph
11c
CO2Et
60
53
N
N
CO2Et
Ph
N
Ph
N
12c
Br
Br
Br
13c
OPh
60
N
Br
N
a Reaction conditions as in Table 2.
b Yield of isolated product.
c Reaction performed open to air.
As shown in Table 5, this DABCO-mediated rearrange- available alkynes and pyridines into more highly func-
ment can be applied to the synthesis of a number of alke- tionalized derivatives in one pot.
nyl-substituted pyridines in moderate yields with good
cis-stereoselectivity. In particular, haloaryl-, aldehyde-,
Unless otherwise noted, all manipulations were performed under an
ester-, and heteroaryl-substituted alkynes can be em-
ployed, with some leading to only a single observable iso-
meric product. As with the alkynylation above, these
functionalized substrates would be challenging to gener-
ate via more classic Heck couplings (e.g., those requiring
halo-substituted alkynes) or alkynyl Grignard reagents
(e.g., aldehyde- or ester-substituted reagents).
inert atmosphere in a Vacuum Atmospheres 553-2 dry box. All re-
agents were purchased from Aldrich and used as received. MeCN
was distilled from CaH2 under N2. CDCl3 was dried over 3 Å mo-
1
lecular sieves. H and 13C NMR spectra were recorded on Varian
Mercury 200 MHz, 300 MHz, Mercury 400 MHz, Unity 500 MHz,
and JEOL 270 MHz spectrometers. 1D NOE spectra were recorded
on a Varian Mercury 400 MHz spectrometer. All compounds were
1
characterized by H and 13C NMR, HRMS, and by comparison to
literature data.24,25 Regioisomer assignments for all compounds
were determined by 1H NMR and 1D NOESY and by comparison
to literature data.25,26 Stereoisomer assignments for the alkenylpy-
ridines were determined by 1H NMR, comparison to literature da-
In conclusion, a one-pot tandem copper-catalyzed cou-
pling and oxidation protocol has been developed to regio-
selectively prepare o-propargyl-substituted pyridines
directly from the parent heterocycles and terminal
alkynes. This provides a mild alternative to more tradi-
tional Sonogashira couplings to generate these products,
without the need to initially construct halogenated py-
ridines. In addition, a number of 2-alkenylpyridines can
be prepared in a related procedure by coupling the copper-
catalyzed reaction with a base-mediated rearrangement.
Both reactions allow the efficient conversion of readily
3
ta,26 and by magnitude of the alkenyl JH,H coupling constant.27
Mass spectra were obtained from the McGill University and Pfizer
Discovery Research mass spectral facilities.
Copper-Catalyzed Synthesis of o-Alkynylpyridines; General
Procedure
Pyridine (0.5 mmol), chloroformate (0.62 mmol), and alkyne (0.5
mmol) were mixed in MeCN (2 mL) and added to a vial containing
a stirred mixture of CuI (9 mg, 0.05 mmol) and i-Pr2NEt (105 mL,
0.7 mmol) in MeCN (1 mL) in an inert atmosphere glove box. The
Synthesis 2010, No. 6, 1000–1008 © Thieme Stuttgart · New York

1004
R. E. Beveridge, B. A. Arndtsen
PAPER
Table 4 Base Influence of o-Alkenylpyridine Formationa
Table 5 Copper-Catalyzed o-Alkenylpyridine Synthesisa
CuI (10 mol%)
i-Pr2NEt (1.4 equiv)
DABCO (5 equiv)
CuI (10 mol%)
R
R
i-Pr2NEt (1.4 equiv)
R2
O
O
base
+
+
H
+
Cl
R2
+
H
Ph
N
Ph
MeCN, 65 °C, 16 h
MeCN, 65 °C, 16 h
R1
EtO
Cl
N
N
N
3
Entry Product
Yield (%)b
Ratio (E/Z)c
Entry
Base
3, Yield (%)b Ratio (E/Z)c
Br
1d
69
30
0:100
Ph
1
2
3
4
5
6
Pyridine (5 equiv)
i-Pr2NEt (10 equiv)
K3PO4 (5 equiv)d
t-BuOK (2.2 equiv)
DABCOe
–
–
N
–
–
CO2Et
2d
3d
1:2.5
–
–
N
5
100:0
0:100
1:1
Ph
49
80
29
45
0:100
Ph
Br
K2CO3/MeOHf
N
a Reaction conditions: pyridine (0.5 mmol), chloroformate (0.6
mmol), and alkyne (0.5 mmol) in MeCN (2 mL) were added to CuI
(0.05 mmol) and i-Pr2NEt (0.7 mmol) in MeCN (1 mL) and the solu-
tion stirred for 20–30 min, then base added and warmed to 65 °C for
16 h.
Ph
4d,e
0:100
b Isolated yield of both isomers.
N
c Ratio of isolated stereoisomers.
F
d 18-Crown-6-ether (1 equiv) was added to solubilize the K3PO4.
e 1,4-Diazabicyclo[2.2.2]octane.
5e,f
6e,f
7e,f
63
64
55
1:3.5
1:3.5
1:3
f Aq sat. K2CO3 (2 mL) and MeOH (2 mL) were added.
Br
Br
reaction mixture was stirred at r.t. for 20–30 min. The vial was re-
moved from the glove box, exposed to air, and DDQ (114 mg, 0.5
mmol) was added. The resulting black solution was placed in a 45
°C bath for 1 h. The product was isolated by column chromatogra-
phy on silica gel using EtOAc–hexanes as eluent (Tables 2 and 3 ).
N
S
N
Copper-Catalyzed Synthesis of o-Alkenylpyridines with
DABCO; General Procedure
Me
Pyridine (0.5 mmol), chloroformate (0.62 mmol), and alkyne (0.5
mmol) were mixed in MeCN (2 mL) and added to a vial containing
a stirred mixture of CuI (9 mg, 0.05 mmol) and i-Pr2NEt (105 mL,
0.7 mmol) in MeCN (1 mL) in an inert atmosphere glove box. The
reaction mixture was stirred at r.t. for 20–30 min, then DABCO
(280 mg, 2.5 mmol) was added, the vial removed from the glove
box, and placed in a 65 °C oil bath for 16 h. The product was isolat-
ed by column chromatography on silica gel using EtOAc–hexanes
as eluent (Table 5).
NC
N
O
8e,f
59
1:1
Ph
2-(Phenylethynyl)pyridine (2)25a,b
N
Yield: 81%.
a Table 4, entry 5 procedure was used.
b Isolated yield of both isomers.
1H NMR (300 MHz, CDCl3): d = 8.60 (d, J = 6 Hz, 1 H), 7.72 (t,
J = 9 Hz, 1 H), 7.58–7.52 (m, 3 H), 7.38–7.22 (m, 4 H).
13C NMR (68.0 MHz, CDCl3): d = 149.9, 143.4, 136.7, 132.2,
129.3, 128.6, 127.5, 123.0, 122.3, 90.0, 88.4.
c Ratio of isolated stereoisomers.
d Ethyl chloroformate was used.
e Reaction performed open to air on the bench.
f Phenyl chloroformate was used.
HRMS: m/z calcd for C13H9N (M + H): 180.0815; found: 180.0807.
Pyridin-2-ylpropynoic Acid Ethyl Ester (Table 2, Entry 4)25e
Yield: 54%.
HRMS: m/z calcd for C10H9NO2 (M + H): 176.0713; found:
176.0704.
1H NMR (300 MHz, CDCl3): d = 8.62 (d, J = 6 Hz, 1 H), 7.72 (t,
J = 6 Hz, 1 H), 7.58 (d, J = 9 Hz, 1 H), 7.35–7.32 (m, 1 H), 4.28 (q,
J = 7 Hz, 2 H), 1.37 (t, J = 7 Hz, 3 H).
13C NMR (68.0 MHz, CDCl3): d = 153.9, 150.8, 140.6, 136.6,
128.7, 125.0, 84.0, 79.6, 62.7, 14.4.
2-[2-(Thiophen-3-yl)ethynyl]pyridine (Table 2, Entry 5)25h
Yield: 52%.
1H NMR (400 MHz, CDCl3): d = 7.18–7.26 (m, 2 H), 7.26–7.32 (m,
1 H), 7.48 (d, J = 7.81 Hz, 1 H), 7.58–7.70 (m, 2 H), 8.59 (d,
J = 4.49 Hz, 1 H).
Synthesis 2010, No. 6, 1000–1008 © Thieme Stuttgart · New York

PAPER
Copper-Catalyzed Functionalization of Pyridines with Alkynes
1005
13C NMR (101 MHz, CDCl3): d = 84.69, 88.47, 99.99, 121.59,
122.88, 125.71, 127.18, 130.37, 136.35, 143.68, 150.28.
13C NMR (67.9 MHz, CDCl3): d = 148.0, 140.3, 137.7, 132.7,
131.9, 128.8, 128.6, 128.4, 122.8, 92.4, 87.6, 19.4, 18.4.
HRMS: m/z calcd for C11H7NS (M + H): 186.0371; found:
HRMS: m/z calcd for C15H13N (M + H): 208.1058; found:
186.0377.
208.1118.
2-[2-(4-Bromophenyl)ethynyl]pyridine (Table 2, Entry 6)
Yield: 54%.
4-Phenyl-2-(phenylethynyl)pyridine (Table 3, Entry 6)
Yield: 43%.
1H NMR (400 MHz, CDCl3): d = 7.28–7.21 (m, 1 H), 7.46–7.41 (m,
2 H), 7.54–7.46 (m, 3 H), 7.67 (td, J = 7.71, 1.76 Hz, 1 H), 8.61 (d,
J = 4.29 Hz, 1 H).
13C NMR (101 MHz, CDCl3): d = 88.26, 89.82, 121.44, 123.16,
123.59, 127.37, 131.92, 133.62, 136.41, 143.39, 150.35.
1H NMR (500 MHz, CDCl3): d = 8.67 (d, J = 7.5 Hz, 1 H), 7.79 (s,
1 H), 7.67–7.60 (m, 4 H), 7.53–7.44 (m, 4 H), 7.39–7.36 (m, 3 H).
13C NMR (68.0 MHz, CDCl3): d = 150.7, 149.0, 144.2, 137.7,
132.3, 129.6, 129.4, 129.2, 128.6, 127.2, 125.4, 122.5, 121.0, 89.5,
89.0.
HRMS: m/z calcd for C13H8BrN (M + H): 257.9912; found:
HRMS: m/z calcd for C19H13N (M + H): 256.1128, found: 256.1118.
257.9922.
5-Bromo-2-[2-(thiophen-3-yl)ethynyl]pyridine (Table 3, Entry
7)
5-Bromo-2-phenylethynylpyridine (Table 3, Entry 1)25f,g
Yield: 73%.
Yield: 54%.
1H NMR (500 MHz, CDCl3): d = 8.56 (d, J = 5 Hz, 1 H), 7.92 (d,
J = 5 Hz, 1 H), 7.64–7.62 (m, 2 H), 7.39–7.35 (m, 3 H), 7.14–7.11
(m, 1 H).
1H NMR (500 MHz, CDCl3): d = 7.14 (dd, J = 8.05, 4.64 Hz, 1 H),
7.29–7.33 (m, 1 H), 7.33–7.37 (m, 1 H), 7.72 (d, J = 1.95 Hz, 1 H),
7.94 (d, J = 8.29 Hz, 1 H), 8.56 (s, 1 H).
13C NMR (68.0 MHz, CDCl3): d = 148.5, 144.0, 140.1, 132.4,
129.6, 128.7, 124.1, 123.8, 122.2, 94.3, 87.7.
13C NMR (126 MHz, CDCl3): d = 87.36, 89.55, 121.33, 123.69,
125.86, 129.95, 130.25, 131.07, 140.06, 144.03, 148.51.
HRMS: m/z calcd for C13H8BrN (M + H): 257.9920; found:
HRMS: m/z calcd for C11H6BrNS (M + H): 263.9477; found:
257.9911.
263.9485.
3-Methyl-2-phenylethynylpyridine (Table 3, Entry 2)25c
Yield: 69%.
4-tert-Butyl-2-(phenylethynyl)pyridine (Table 3, Entry 8)
Yield: 40%.
1H NMR (300 MHz, CDCl3): d = 8.43 (d, J = 6 Hz, 1 H), 7.62–7.56
(m, 3 H), 7.38–7.35 (m, 3 H), 7.17–7.12 (m, 1 H), 2.52 (s, 3 H), 2.37
(s, 0.15 H, minor regioisomer).
13C NMR (68.0 MHz, CDCl3): d = 147.6, 143.4, 137.2, 136.2,
132.2, 129.1, 128.6, 123.0, 122.8, 93.3, 87.7, 19.7.
1HNMR (500 MHz, CDCl3): d = 8.51 (d, J = 10 Hz, 1 H), 7.62–7.58
(m, 1 H), 7.55 (s, 1 H), 7.39–7.36 (m, 3 H), 7.28–7.21 (m, 2 H).
13C NMR (68.0 MHz, CDCl3): d = 160.6, 150.2, 143.5, 132.3,
129.1, 128.6, 124.6, 122.6, 120.3, 89.3, 88.8, 35.0, 30.7.
HRMS: m/z calcd for C17H17N (M + H): 236.1441; found:
HRMS: m/z calcd for C14H11N (M + H): 194.0871; found:
236.1432.
194.0962.
Ethyl 3-(5-Bromopyridin-2-yl)propiolate (Table 3, Entry 9)
Yield: 82%.
6-Phenylethynylpyridine-3-carbaldehyde (Table 3, Entry 3)25f,g
Yield: 33%.
1H NMR (500 MHz, CDCl3): d = 1.37 (t, J = 7.20 Hz, 3 H), 4.34 (q,
J = 7.07 Hz, 2 H), 7.25 (dd, J = 8.29, 4.64 Hz, 1 H), 7.96 (d,
J = 8.29 Hz, 1 H), 8.60 (d, J = 4.39 Hz, 1 H).
1H NMR (500 MHz, CDCl3): d = 10.14 (s, 1 H), 9.07 (s, 1 H), 8.18
(d, J = 10 Hz, 1 H), 7.68–7.61 (m, 3 H), 7.40–7.36 (m, 3 H).
13C NMR (68.0 MHz, CDCl3): d = 190.1, 152.6, 148.6, 136.1,
132.6, 130.0, 128.7, 128.8, 127.6, 121.7, 93.8, 88.6.
13C NMR (126 MHz, CDCl3): d = 14.27, 62.73, 82.14, 83.18,
125.02, 125.54, 140.32, 141.46, 148.87, 155.93.
HRMS: m/z calcd for C14H9NO (M + H + MeOH): 240.1026; found:
HRMS: m/z calcd for C10H8BrNO2 (M + H): 253.9811; found:
240.1017.
253.9814.
4-[2-(3-Methylpyridin-2-yl)ethynyl]benzaldehyde (Table 3,
Entry 4)
1-{6-[2-(4-Fluorophenyl)ethynyl]pyridin-3-yl}ethanone (Table
3, Entry 10)
Yield: 51%.
Yield: 53%.
1H NMR (500 MHz, CDCl3): d = 2.56 (s, 3 H), 7.22 (dd, J = 7.68,
4.76 Hz, 6 H), 7.59 (d, J = 7.81 Hz, 1 H), 7.77 (d, J = 8.29 Hz, 2 H),
7.90 (d, J = 8.05 Hz, 2 H), 8.50 (d, J = 4.15 Hz, 1 H), 10.05 (s, 1 H).
13C NMR (126 MHz, CDCl3): d = 19.68, 91.28, 91.88, 123.54,
128.97, 129.82, 132.70, 136.14, 136.62, 137.42, 142.68, 147.87,
191.59.
1H NMR (400 MHz, CDCl3): d = 2.64 (s, 3 H), 6.97–7.14 (m, 2 H),
7.52–7.66 (m, 3 H), 8.21 (dd, J = 8.20, 2.34 Hz, 1 H), 9.13 (s, 1 H).
13C NMR (101 MHz, CDCl3): d = 26.96, 88.28, 91.73, 116.05,
127.05, 130.91, 134.55, 135.88, 147.22, 150.45, 162.22, 164.73,
196.15.
HRMS: m/z calcd for C15H10FNO (M + H): 240.0819; found:
HRMS: m/z calcd for C15H11NO (M + H): 222.0913; found:
240.0826.
222.0919.
Ethyl 3-(5-Phenylpyridin-2-yl)propiolate (Table 3, Entry 11)
Yield: 60%.
3,5-Dimethyl-2-phenylethynylpyridine (Table 3, Entry 5)
Yield: 39%.
1H NMR (500 MHz, CDCl3): d = 1.38 (t, J = 7.07 Hz, 3 H), 4.34 (q,
J = 7.07 Hz, 2 H), 7.43–7.49 (m, 1 H), 7.50–7.55 (m, 2 H), 7.58–
7.65 (m, 2 H), 7.68 (d, J = 8.05 Hz, 1 H), 7.93 (dd, J = 8.05, 2.20
Hz, 1 H), 8.91 (d, J = 1.71 Hz, 1 H).
1H NMR (300 MHz, CDCl3): d = 8.29 (s, 1 H), 7.64–7.56 (m, 2 H),
7.38–7.33 (m, 4 H), 2.48 (s, 3 H), 2.34 (s, 3 H).
Synthesis 2010, No. 6, 1000–1008 © Thieme Stuttgart · New York

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R. E. Beveridge, B. A. Arndtsen
PAPER
13C NMR (126 MHz, CDCl3): d = 14.28, 62.58, 79.99, 84.13,
127.43, 128.74, 129.10, 129.52, 134.62, 136.88, 137.74, 139.27,
149.29, 153.80.
CH=CHCO2Et), 6.15–6.12 (d, J = 12 Hz, 1 H, CH=CHCO2Et), 4.21
(q, J = 7 Hz, 2 H), 1.26 (t, J = 7 Hz, 3 H).
13C NMR (67.9 MHz, CDCl3): d = 166.9, 153.8, 149.4, 139.9,
136.2, 124.6, 123.3, 123.2, 60.8, 14.3.
HRMS: m/z calcd for C16H13NO2 (M + H): 252.1019; found:
252.1028.
HRMS: m/z calcd for C10H11NO2 (M + H): 178.0880; found:
178.0862.
2-[2-(4-Bromophenyl)ethynyl]-4-phenylpyridine (Table 3,
Entry 12)
Yield: 53%.
Ethyl (E)-3-(Pyridin-2-yl)acrylate (Table 5, Entry 2)26b
Yield: 9%.
1H NMR (500 MHz, CDCl3): d = 8.65 (d, J = 8 Hz, 1 H), 7.73–7.67
(m, 2 H), 7.72–7.70 (d, J = 15 Hz, 1 H, CH=CHCO2Et), 7.44–7.42
(d, J = 10 Hz, 1 H, ArH), 7.27 (t, J = 10 Hz, 1 H), 6.90 (d, J = 15
Hz, 1 H, CH=CHCO2Et), 4.26 (q, J = 7 Hz, 2 H), 1.37 (t, J = 7 Hz,
3 H).
1H NMR (400 MHz, CDCl3): d = 7.43–7.53 (m, 8 H), 7.61–7.67 (m,
2 H), 7.75 (dd, J = 1.76, 0.78 Hz, 1 H), 8.64 (d, J = 8.00 Hz, 1 H).
13C NMR (101 MHz, CDCl3): d = 88.32, 90.03, 121.18, 121.44,
123.63, 125.36, 127.20, 129.41, 129.62, 131.95, 133.66, 137.59,
143.80, 149.05, 150.74.
HRMS: m/z calcd for C19H12BrN (M + H): 334.0225; found:
334.0230.
13C NMR (68.0 MHz, CDCl3): d = 167.0, 153.3, 150.4, 143.5,
136.9, 124.4, 124.3, 122.7, 60.9, 14.5.
HRMS: m/z calcd for C10H11NO2 (M + H): 178.0880; found:
178.0862.
2-[2-(4-Bromophenyl)ethynyl)]-3-methylpyridine (Table 3,
Entry 13)
Yield: 54%.
4-Phenyl-2-[(Z)-2-phenylethenyl]pyridine (Table 5, Entry 3)26c
Yield: 29%.
1H NMR (300 MHz, CDCl3): d = 8.63 (d, J = 6 Hz, 1 H), 7.39–7.26
(m, 12 H), 6.89 (d, J = 12 Hz, 1 H), 6.78 (d, J = 12 Hz, 1 H).
13C NMR (125.7 MHz, CDCl3): d = 157.0, 150.2, 148.0, 138.4,
137.1, 133.8, 130.9, 129.2, 129.1, 129.0, 128.6, 127.9, 127.1, 122.3,
120.0.
1H NMR (400 MHz, CDCl3): d = 2.49 (s, 3 H), 7.16 (dd, J = 7.81,
4.68 Hz, 1 H), 7.41–7.51 (m, 4 H), 7.53 (d, J = 6.64 Hz, 1 H), 8.44
(d, J = 3.51 Hz, 1 H).
13C NMR (101 MHz, CDCl3): d = 19.65, 88.72, 92.03, 121.69,
123.12, 123.48, 131.92, 133.53, 136.20, 137.28, 143.03, 147.69.
HRMS: m/z calcd for C14H10BrN (M + H): 272.0069; found:
272.0074.
HRMS: m/z calcd for C19H15N (M + H): 258.1275; found:
258.1277.
2-[(E)-2-Phenylethenyl]pyridine [(E)-3] (Table 4, Entry 6)26a
Yield: 40%.
(Z)-2-(4-Bromostyryl)-4-phenylpyridine (Table 5, Entry 4)
Yield: 45%.
1H NMR (400 MHz, CDCl3): d = 6.77 (s, 2 H), 7.19 (d, J = 8.59 Hz,
2 H), 7.29–7.34 (m, 2 H), 7.34–7.43 (m, 7 H), 8.60 (d, J = 6.25 Hz,
1 H).
1H NMR (300 MHz, CDCl3): d = 8.62 (d, J = 6 Hz, 1 H), 7.68–7.57
(m, 4 H), 7.40–7.25 (m, 4 H), 7.20–7.12 (m, 2 H).
13C NMR (67.9 MHz, CDCl3): d = 155.7, 149.7, 136.7, 136.6,
132.8, 128.8, 128.4, 128.0, 127.2, 122.2, 122.1.
HRMS: m/z calcd for C13H11N (M + H): 182.0967; found:
182.0964.
13C NMR (101 MHz, CDCl3): d = 120.20, 121.83, 122.23, 127.05,
129.21, 129.29, 130.88, 131.43, 131.71, 132.44, 135.95, 138.19,
148.34, 150.26, 156.56.
2-[(Z)-2-Phenylethenyl]pyridine [(Z)-3] (Table 4, Entry 6)26a
Yield: 40%.
1H NMR (300 MHz, CDCl3): d = 8.59 (d, J = 6 Hz, 1 H), 7.45 (t,
J = 10 Hz, 1 H), 7.27–7.22 (m, 5 H), 7.17 (d, J = 9 Hz, 1 H), 7.10–
7.06 (m, 1 H), 6.81 (d, J = 12 Hz, 1 H), 6.71 (d, J = 12 Hz, 1 H).
13C NMR (67.9 MHz, CDCl3): d = 156.4, 149.6, 136.8, 135.7,
133.3, 130.6, 128.9, 128.3, 127.6, 123.9, 121.8.
HRMS: m/z calcd for C19H14BrN (M + H): 336.0382; found:
336.0388.
(Z)-2-(4-Fluorostyryl)-5-bromopyridine (Table 5, Entry 5)
Yield: 63% of a 3.5:1 mixture of Z/E isomers; only the Z-isomer
was fully characterized.
1H NMR (400 MHz, CDCl3): d = 6.70 (d, J = 12.00 Hz, 1 H), 6.75
(d, J = 12.00 Hz, 1 H), 6.81–6.90 (m, 2 H), 7.05 (dd, J = 8.20, 4.49
Hz, 1 H), 7.08–7.16 (m, 2 H), 7.86 (dd, J = 8.00, 1.56 Hz, 1 H), 8.43
(dd, J = 4.68, 1.37 Hz, 1 H).
HRMS: m/z calcd for C13H11N (M + H): 182.0967; found:
182.0964.
3-Bromo-6-[(Z)-6-phenylethenyl]pyridine (Table 5, Entry 1)
Yield: 69%.
13C NMR (101 MHz, CDCl3): d = 115.27, 121.37, 123.73, 127.75,
131.08, 132.33, 133.59, 140.60, 148.11, 155.50, 161.18, 163.64.
1H NMR (300 MHz, CDCl3): d = 8.46 (d, J = 6 Hz, 1 H), 7.88 (d,
J = 9 Hz, 1 H), 7.19–7.05 (m, 6 H), 6.81 (d, J = 12 Hz, 1 H), 6.76
(d, J = 12 Hz, 1 H).
HRMS: m/z calcd for C13H9BrFN (M + H): 277.9975; found:
277.9981.
(Z)-5-Bromo-2-[2-(thiophen-3-yl)vinyl]pyridine (Table 5, Entry
13C NMR (68.0 MHz, CDCl3): d = 155.9, 148.2, 140.5, 136.2,
6)
134.8, 129.4, 128.2, 128.0, 127.9, 123.6, 121.3.
Yield: 64% of a 3.5:1 mixture of Z/E isomers; only the Z-isomer
HRMS: m/z calcd for C13H10BrN (M + H): 260.0069; found:
260.0068.
was fully characterized.
1H NMR (400 MHz, CDCl3): d = 6.65 (d, J = 12.00 Hz, 1 H), 6.77
(d, J = 12.00 Hz, 1 H), 6.83 (dd, J = 5.08, 0.98 Hz, 1 H), 7.03–7.13
(m, 2 H), 7.37 (d, J = 2.73 Hz, 1 H), 7.88 (dd, J = 8.00, 1.56 Hz, 1
H), 8.53 (dd, J = 4.59, 1.46 Hz, 1 H).
Ethyl (Z)-3-(Pyridin-2-yl)acrylate (Table 5, Entry 2)26b
Yield: 22%.
1H NMR (400 MHz, CDCl3): d = 8.60 (d, J = 8 Hz, 1 H), 7.67–7.65
(m, 2 H), 7.23–7.19 (m, 1 H), 6.96–6.93 (d, J = 12 Hz, 1 H,
Synthesis 2010, No. 6, 1000–1008 © Thieme Stuttgart · New York

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Copper-Catalyzed Functionalization of Pyridines with Alkynes
1007
13C NMR (101 MHz, CDCl3): d = 121.55, 123.66, 124.98, 126.20,
H.; Takaishi, Y.; Momota, H.; Ohmoto, Y.; Taki, T.; Jia, Y.;
126.73, 128.40, 128.74, 137.66, 140.57, 147.96, 155.64.
Li, D. J. Nat. Prod. 2001, 64, 582. (e) Tsukamoto, S.;
Takahashi, M.; Matsunaga, S.; Fusetami, N.; van Soet, R.
W. M. J. Nat. Prod. 2000, 63, 682. (f) Chang, F.-R.;
Hayashi, K.-I.; Chen, I.-H.; Liaw, C.-C.; Bastow, K. F.;
Nakanishi, Y.; Nozaki, H.; Cragg, G. M.; Wu, Y.-C.; Lee, K.
H. J. Nat. Prod. 2003, 66, 1416. (g) Horiuch, M.;
Murakami, C.; Fukami, N.; Yu, D.; Chen, T.-H.; Bastow, K.
F.; Zhang, D.-C.; Takaishi, Y.; Imakura, Y.; Lee, K.-H.
J. Nat. Prod. 2006, 69, 1271.
HRMS: m/z calcd for C11H8BrNS (M + H): 265.9633; found:
265.9629.
6-[(Z)-2-p-Tolylvinyl)]nicotinonitrile (Table 5, Entry 7)
Yield: 55% of a 3:1 mixture of Z/E isomers; only the Z-isomer was
fully characterized.
1H NMR (400 MHz, CDCl3): d = 2.29 (s, 3 H), 6.75 (d, J = 12.10
Hz, 1 H), 6.96 (d, J = 12.10 Hz, 1 H), 6.99–7.05 (m, 2 H), 7.06–7.12
(m, 2 H), 7.21–7.24 (m, 1 H), 7.88 (dd, J = 7.81, 1.95 Hz, 1 H), 8.71
(dd, J = 4.69, 1.95 Hz, 1 H).
13C NMR (101 MHz, CDCl3): d = 21.53, 109.43, 116.63, 121.67,
124.58, 129.11, 129.43, 132.94, 137.97, 138.60, 140.68, 152.58,
159.86.
(2) Pyridines are used extensively as ligands, for reviews in this
area, see: (a) Dumur, F.; Dumas, E.; Mayer, C. R. Targ.
Heterocycl. Syst. 2007, 11, 70. (b) von Zelewsky, A. Coord.
Chem. Rev. 1999, 190-192, 811. (c) van Koten, G.;
Albrecht, M. Angew. Chem. Int. Ed. 2001, 40, 3750.
(d) Belda, O.; Moberg, C. Coord. Chem. Rev. 2005, 249,
727. (e) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev.
2003, 103, 3119. (f) Chelucci, G.; Thummel, R. Chem. Rev.
2002, 102, 3129.
HRMS: m/z calcd for C15H12N2 (M + H): 221.1073; found:
221.1082.
(3) (a) Shifrina, Z. B.; Rajadurai, M. S.; Firsova, N. V.;
Bronstein, L. M.; Huang, X.; Rusanov, A. L.; Muellen, K.
Macromolecules 2005, 38, 9920. (b) Rauckhorst, M. R.;
Wilson, P. J.; Hatcher, S. A.; Hada, C. M.; Parquette, J. R.
Tetrahedron 2003, 59, 3917.
(4) (a) Zheng, J. Y.; Feng, X. M.; Bai, W. B.; Qin, J. G.; Zhan,
C. M. Eur. Polym. J. 2005, 41, 2770. (b) duBois, C. J.;
Abboud, K. A.; Reynolds, J. R. J. Phys. Chem. B 2004, 108,
8550. (c) Yamamoto, T.; Yamaguchi, I.; Yasuda, T. Adv.
Polym. Sci. 2005, 177, 181.
(5) (a) Alagille, D.; Baldwin, R. M.; Roth, B. L.; Wroblewski, J.
T.; Grajkowska, E.; Tamagnan, G. D. Bioorg. Med. Chem.
2005, 13, 197. (b) Yu, M.; Tueckmantel, W.; Wang, X.;
Zhu, A.; Kozikowski, A. P.; Brownell, A.-L. Nucl. Med.
Biol. 2005, 32, 631. (c) Jakopec, S.; Dubravcic, K.; Polanc,
S.; Kosmrlj, J.; Osmak, M. Toxicol. in Vitro 2006, 20, 217.
(d) Jacguemard, U.; Routier, S.; Dias, N.; Lansiaux, A.;
Goossens, J.-F.; Bailly, C.; Merour, J.-Y. Eur. J. Med. Chem.
2005, 40, 1087. (e) Zhou, X.-F.; Yang, X.; Wang, Q.;
Coburn, R. A.; Morris, M. E. Drug Metab. Dispos. 2005, 33,
1220.
(6) Recent reviews on the construction and functionalization of
pyridines: (a) Schlosser, M.; Mongin, F. Chem. Soc. Rev.
2007, 36, 1161. (b) Varela, J. A.; Saa, C. Synlett 2008,
2571. (c) Henry, G. Tetrahedron 2004, 60, 6043.
(7) Selected recent examples of new methods: (a) Dash, J.;
Lechel, T.; Reissig, H.-U. Org. Lett. 2007, 9, 5541.
(b) Sasada, T.; Sakai, N.; Korakahara, T. J. Org. Chem.
2008, 73, 6905. (c) Eidamshaus, C.; Reissig, H.-U. Adv.
Synth. Catal. 2009, 351, 1162. (d) Kobayashi, T.; Hatano,
S.; Tsuchikawa, H.; Katsumura, S. Tetrahedron Lett. 2008,
49, 4349. (e) Kiss, L. E.; Ferreira, H. S.; Learmonth, D. A.
Org. Lett. 2008, 10, 1835. (f) Donohoe, T. J.; Fishlock, L.
P.; Procopiou, P. A. Synthesis 2008, 2665.
(Z)-4-[2-(5-Phenylpyridin-2-yl)vinyl]benzaldehyde (Table 5,
Entry 8)
Yield: 30%.
1H NMR (400 MHz, CDCl3): d = 6.85 (s, 2 H), 7.19 (d, J = 8.20 Hz,
1 H), 7.39 (d, J = 7.03 Hz, 1 H), 7.43–7.51 (m, 4 H), 7.57 (d,
J = 7.03 Hz, 2 H), 7.68 (dd, J = 8.20, 2.34 Hz, 1 H), 7.78 (d,
J = 8.59 Hz, 2 H), 8.82 (d, J = 2.73 Hz, 1 H), 9.97 (s, 1 H).
13C NMR (101 MHz, CDCl3): d = 124.10, 127.16, 128.42, 129.32,
129.85, 129.93, 132.19, 132.57, 134.36, 135.26, 135.57, 137.56,
143.42, 148.25, 154.44, 191.93.
HRMS: m/z calcd for C20H15NO (M + H): 286.1226; found:
286.1236.
(E)-4-[2-(5-Phenylpyridin-2-yl)vinyl]benzaldehyde (Table 5,
Entry 8)
Yield: 29%.
1H NMR (400 MHz, CDCl3): d = 6.63 (d, J = 12.00 Hz, 1 H), 6.72
(d, J = 12.00 Hz, 1 H), 7.19 (d, J = 8.20 Hz, 2 H), 7.22–7.26 (m, 2
H), 7.26–7.30 (m, 1 H), 7.29–7.34 (m, 3 H), 7.57–7.69 (m, 3 H),
8.51 (dd, J = 4.88, 1.76 Hz, 1 H), 9.92 (s, 1 H).
13C NMR (101 MHz, CDCl3): d = 122.99, 127.87, 128.46, 129.41,
129.57, 129.68, 131.98, 132.36, 135.15, 137.22, 137.86, 138.80,
143.20, 148.48, 153.71, 192.06.
HRMS: m/z calcd for C20H15NO (M + H): 286.1226; found:
286.1228.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
(8) (a) A review: Schröter, S.; Stock, C.; Bach, T. Tetrahedron
2005, 61, 2245. (b) Blachut, D.; Czarnocki, Z.;
Wojtasiewicz, K. Synthesis 2006, 2855. (c) Cailly, T.;
Fabis, F.; Bouillon, A.; Lemaitre, S.;
Sopkova de Oliveira Santos, J.; Rault, S. Synlett 2006, 53.
(d) Couve-Bonnaire, S.; Carpentier, J.-F.; Mortreux, A.;
Castanet, Y. Tetrahedron 2003, 59, 2793.
The authors would like to thank CFI and NSERC for financial sup-
port, and R. E. Beveridge would like to thank McGill University for
a graduate student fellowship. R. E. Beveridge would also like to
thank Pfizer Global Research and Development for the use of their
equipment and resources towards the completion of this work.
(9) (a) Joubert, N.; Pohl, R.; Klepetarova, B.; Hocek, M. J. Org.
Chem. 2007, 72, 6797. (b) Mei, K.; Wang, J.; Hu, X. Synth.
Commun. 2006, 36, 2525. (c) Masselot, D.; Charmant, J. P.
H.; Gallagher, T. J. Am.Chem. Soc. 2006, 128, 694.
(d) Lachance, N.; April, M.; Joly, M.-A. Synthesis 2005,
2571. (e) Zhao, J.; Yang, X.; Jia, X.; Luo, S.; Zhai, H.
Tetrahedron 2003, 59, 9379.
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Synthesis 2010, No. 6, 1000–1008 © Thieme Stuttgart · New York

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R. E. Beveridge, B. A. Arndtsen
PAPER
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2002, 1009. (d) See also ref. 15.
(24) (a) Agaw a, T.; Miller, S. I. J. Am. Chem. Soc. 1961, 83, 449.
(b) Chen, C.; Wang, B.; Munoz, B. Synlett 2003, 2404.
(25) References for known 2-alkynylpyridine compounds: (a) 2-
Phenylethynylpyridine (2): Wang, B.; Bonin, M.; Micouin,
L. Org. Lett. 2004, 6, 3481. (b) See also: Shirakawa, E.;
Kitabata, T.; Otsuka, H.; Tsuchimoto, T. Tetrahedron 2006,
61, 9878. (c) Table 3, entry 2: Alagille, D.; Baldwin, R. M.;
Roth, B. L.; Wroblewski, J. T.; Grajkowska, E.; Tamagnon,
G. D. Bioorg. Med. Chem. 2005, 13, 197. (d) Table 3, entry
1: Tilley, J. W.; Zawoiski, S. J. Org. Chem. 1988, 53, 386.
(e) Table 2, entry 4: Sakamoto, T.; Shiga, F.; Yasuhara, A.;
Uchiyama, D.; Kondo, Y.; Yamanaka, H. Synthesis 1992,
746. (f) Table 3, entry 3 has not been reported, however, the
other o-phenylalkynyl regioisomer has been reported: Yue,
D.; Larock, R. C. Org. Lett. 2004, 6, 1581. (g) See also:
Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002, 67, 86.
(h) Table 2, entry 5: Novak, I.; Ng, S.-C.; Mok, C.-Y.;
Huang, H.-H.; Fang, J.; Wang, K. K.-T. J. Chem. Soc.,
Perkin Trans. 2 1994, 1771.
(26) References for known 2-alkenylpyridine compounds: (a) 2-
phenylethenylpyridine (3): Chen, C.; Wang, B.; Munoz, B.
Synlett 2003, 2404. (b) Table 5, entry 2: Heimgärtner, G.;
Raatz, D.; Reiser, O. Tetrahedron 2005, 61, 643. (c) Table
5, entry 3: Ciutolini, M. A.; Byrne, N. E. J. Chem. Soc.,
Chem. Commun. 1988, 1230.
(27) The coupling constant J for trans-isomers is always larger
(>10 Hz) than cis-isomers and is typically ~15 Hz for E-
alkenylpyridines (see ref. 25).
(14) Larivée, A.; Mousseau, J. J.; Charette, A. B. J. Am. Chem.
Soc. 2008, 130, 52.
(15) Reviews on this topic: (a) Eicher, T.; Hauptmann, S. The
Chemistry of Heterocycles; Wiley-VCH: Weinheim, 2003.
(b) Joule, J. A.; Mills, K. Heterocyclic Chemistry; Blackwell
Science: Oxford, 2000. (c) Lavilla, R. J. Chem. Soc., Perkin
Trans. 1 2002, 1141. (d) Meyers, A. I.; Stout, D. Chem. Rev.
1982, 82, 223. (e) Eisner, U.; Kuthan, J. Chem. Rev. 1972,
72, 1. (f) Comins, D. L.; O’Connor, S. Adv. Heterocycl.
Chem. 1988, 44, 199. (g) Comins, D. L.; Joseph, S. Adv.
Nitrogen Heterocycl. 1996, 2, 251.
(16) Specific examples: (a) Lyle, R. E.; Comins, D. L. J. Org.
Chem. 1976, 41, 3250. (b) Comins, D. L.; Abdullah, A. H.
J. Org. Chem. 1982, 47, 4315. (c) Comins, D. L.; Brown, J.
Tetrahedron Lett. 1984, 25, 3297.
(17) (a) Black, D. A.; Beveridge, R. E.; Arndtsen, B. A. J. Org.
Chem. 2008, 73, 1906. (b) Black, D. A.; Arndtsen, B. A.
Org. Lett. 2004, 6, 1107.
(18) Additional report of copper-catalyzed enantioselective
addition of activated terminal alkynes to N-acylpyridinium
salts: Sun, Z.; Yu, S.; Ding, Z.; Ma, D. J. Am. Chem. Soc.
2007, 129, 9300.
(19) Recent reports where the isolated N-acyl-2-alkynyl-1,2-
dihydropyridine precursor was generated via in situ
stoichiometric copper-acetylide formation: (a) Yadav, J. S.;
Reddy, B. V. S.; Sreenivas, M.; Sathaiah, K. Tetrahedron
Lett. 2005, 46, 8905. (b) Yamada, S.; Toshimitsu, A.;
Takahashi, Y. Tetrahedron 2009, 65, 2329.
Synthesis 2010, No. 6, 1000–1008 © Thieme Stuttgart · New York