A significant substituent effect on the regioselectivity in addition of alkynes to 3-substituted pyridines

Article abstract of DOI:10.1016/j.tet.2009.01.022

A substituent at the 3-position on a pyridine ring significantly affects the regioselectivity during the addition of alkynes to pyridinium salts. When the substituent is an electron-withdrawing group, 1,6-adducts are predominantly produced, whereas, 1,2-a

Full text of DOI:10.1016/j.tet.2009.01.022

Tetrahedron 65 (2009) 2329–2333
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A significant substituent effect on the regioselectivity in addition
of alkynes to 3-substituted pyridines
*
Shinji Yamada , Aya Toshimitsu, Yasuko Takahashi
Department of Chemistry, Faculty of Science, Ochanomizu University, Bunkyo-ku, Tokyo 112-8610, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A substituent at the 3-position on a pyridine ring significantly affects the regioselectivity during the
addition of alkynes to pyridinium salts. When the substituent is an electron-withdrawing group, 1,6-
adducts are predominantly produced, whereas, 1,2-adducts become the major products when the sub-
stituent is an electron-donating group. The changes in the regioselectivity depending on the substituent
can be explained by the difference in the product stabilities. The produced dihydropyridines are easily
aromatized into disubstituted pyridines with chloranil in quantitative yields.
Received 30 October 2008
Received in revised form 26 December 2008
Accepted 6 January 2009
Available online 14 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
The regioselective addition of nucleophiles to the pyridinium
ring is a powerful method for the synthesis of substituted dihy-
dropyridines.1 In particular, the nucleophilic addition to 3-
substituted pyridinium salts has received considerable attention
because the produced dihydropyridines are key intermediates for
the synthesis of disubstituted piperidines,2,3 pyridines,4,5 and var-
ious heterocyclic compounds.6 In general, the regioselectivity sig-
nificantly depends on both the properties of the nucleophiles and
the substituent on the pyridine ring.4b Therefore, elucidation of
substituent effects on the product distribution would provide in-
sight into controlling the regioselectivity.
Scheme 1.
2. Results and discussion
Continuing our research program on the regio- and stereo-
selective addition reaction to pyridinium salts,7 we were interested
in the addition of activated alkynes to 3-substituted pyridinium
compounds because the produced ethynyldihydropyridines and
corresponding pyridines are an important class of compounds as
various synthetic intermediates3,8 and biologically active com-
pounds.9 Among the reported alkynylation methods using various
metallo alkynyl reagents,3a,10 we focused on the copper-mediated
addition reaction due to its potential applicability to organic syn-
thesis.3a,10a We now report that the substituent at the 3-position of
the pyridine ring significantly affects the preferred formation of the
1,2- and 1,6-adducts during the copper-mediated addition of al-
kynes to pyridinium salts (Scheme 1), and the product stabilities
reflect the 1,2- and 1,6-selectivities. Moreover, the reported pref-
erence for the addition to methyl nicotinate10a was revised from the
1,2- to the 1,6-addition.
We attempted to follow the reported 1,2-addition reaction of
phenylacetylene to methyl nicotinate according to the literature;10a
a mixture of the 1,2-, 1,4-, and 1,6-adducts were obtained in 42%
yield with the ratio of 21:14:65 as shown in Table 1 (entry 1). The
yield was significantly improved to 99% using 2 equiv of phenyl-
acetylene and reagents (entry 2). A surprising feature in this re-
action is that the 1,6-adduct 5a was the major product, although it
was assigned to the 1,2-dihydropyridine in the literature.10a The
structure of the 1,6-adduct 5a was confirmed after aromatization to
the known methyl 6-phenylethynylnicotinate (8a)9a as described
later. Various types of substituted terminal alkynes also served as
nucleophiles. The addition of 2b and 2c gave 5ab and 5ac as the
major products, respectively, similar to the case of 2a (entries 3 and
4), suggesting the generality of the formation of the 1,6-adducts
during the addition of alkynes to methyl nicotinate. On the other
hand, the addition of 2d required a longer reaction time for com-
pletion of the reaction, which resulted in a lower regioselectivity
(entry 5). A remarkable feature is that the substituent at the
* Corresponding author. Tel./fax: þ81 3 5978 5349.
E-mail address: yamada.shinji@ocha.ac.jp (S. Yamada).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.022

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S. Yamada et al. / Tetrahedron 65 (2009) 2329–2333
Table 1
Addition of terminal alkynes 2a–2d to 1a–1ea
Entry
Compound
2(R2)
Time/h
Product
Yield/%b
Ratioc 3:4:5
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1c
1d
1e
2a(Ph)d
2a(Ph)
2b(p-MeOC6H4)
2c(p-MeC6H4)
2d(C6H5(CH)2CH2)
2a(Ph)
2a(Ph)
2a(Ph)
2a(Ph)
5
5
5
3a–5a
3a–5a
3ab–5ab
3ac–5ac
3ad–5ad
3b–5b
3c–5c
42
99
82
75
81
99
99
99
97
21:14:65
25:15:60
28:17:55
25:17:58
40:11:49
32:18:50
70:8:22
5
27
25
25
24
27
3d–5d
3e
56:16:28
100:0:0
a
Two equiv of alkyne 2, CuI, diisopropylethylamine (DIEA), and ethyl chloroformate were used unless otherwise noted.
b
c
Isolated yield.
Determined by 1H NMR spectra.
d
One equiv of 2a, CuI, DIEA, and ethyl chloroformate were used.
3-position significantly influenced the regioselectivity (entries 1
dihydropyridine was much more reactive toward oxidation than
and 6–9). The addition to acetylpyridine 1b gave a 1,6-adduct 5b as
the major product similar to the case of 1a (entry 6). On the other
hand, 1,2-adducts 3c and 3d were the major products for the addi-
tion to 1c and 1d having a phenyl and a methyl group at the 3-po-
sition, respectively. Surprisingly, the addition to 1e possessing a MeO
group exclusively afforded the 1,2-adduct 3e. These results suggest
that the electronic properties of the substituents are significantly
responsible for the preference during the 1,2- and 1,6-additions.
The structures of these dihydropyridines were determined
after conversion to the corresponding pyridine derivatives due to
the difficulty in the separation of the isomers by column chro-
matography. Among the various examined oxidizing agents,
chloranil was the most effective for the aromatization of the
the 1,2- and 1,6-dihydropyridines. The assignment of 7a was
based on the disappearance of the H4 peak of 4a at
d 4.44 in the
1H NMR spectrum. When the reaction was conducted at reflux
temperature with 3 equiv of chloranil 6a, 7a, and 8a9a were
produced with recovery of the 1,2-dihydropyridine (3a) (entry
2). Comparison of the 1H NMR data for the major product 8a
with that reported suggested that the structure of 8a was methyl
6-phenylethynylnicotinate as described above. During the oxi-
dation of a mixture of 3b–5b, 4b is also readily aromatized with
chloranil even at rt (entry 3). The further oxidation at the reflux
temperature resulted in 8b with a small amount of 6b (entry 4),
the structures of which were determined by comparison of the
1H NMR data with those already reported.11 Aromatization of the
other dihydropyridines was also performed under the same re-
action conditions. The oxidation of a mixture of 3c, 4c, and 5c
gave 6c, 7c, and 8c12 in 52, 100, and 100% NMR yields, re-
spectively (entry 5). An electron-donating substituent
dihydropyridines.1b,1d,4b The treatment of
a mixture of the
dihydropyridines 3a–5a with 1 equiv of chloranil at rt provided
only the methyl 4-phenylethynylnicotinate (7a) along with the
recovery of 3a and 5a as shown in Table 2 (entry 1); the 1,4-
Table 2
Aromatization of dihydropyridines to disubstituted pyridines
Entry
Compoundsa
Chloranil (equiv)
Temp
Time/h
Conv./%b
3/6
4/7
5/8
1
2
3
4
5
6
7
3a–5a
3a–5a
3b–5b
3b–5b
3c–5c
3d–5d
3e
1
3
1
3
3
3
3
rt
Reflux
rt
Reflux
Reflux
Reflux
Reflux
1
24
1
24
24
24
24
0
28
0
12
52
100
100
100
100
100
100
d
0
100
0
100
100
100
d
100
100
a
A mixture of 3–5 was used except for 3e.
b
Determined by 1H NMR spectra.

S. Yamada et al. / Tetrahedron 65 (2009) 2329–2333
2331
Table 3
significantly affected the regioselectivity; when an electron-with-
drawing group is attached to the pyridine ring, the 1,2-adducts
were the major products, whereas, the 1,6-adducts became the
major products when the substituent is an electron-donating
group. The changes in the regioselectivity depending on the sub-
stituent can be explained by the difference in the product
stabilities.
The electrostatic charges and LUMO coefficients for 1a–1e
Substrate
Chargea
LUMO coefficientb
2-Position
2-Position
6-Position
6-Position
1a
1b
1c
1d
1e
0.206
0.177
0.060
0.001
ꢁ0.152
0.140
0.131
0.117
0.108
0.022
0.380
0.396
0.439
0.359
0.486
0.461
0.485
0.461
0.370
0.424
4. Experimental section
4.1. General information
a
The electrostatic charges were obtained by AM1 calculations.
The 2py component of the LUMO coefficients were indicated.
b
accelerated the aromatization; the 3-methyl and 3-methoxy
substituted 1,2-dihydropyridines 3d and 3e, and 3-methyl 1,6-
dihydropyridine 5d were readily oxidized to give 6d,9b 6e, and
8d9b in quantitative yields, respectively.
Column chromatography and TLC were carried out using silica
gel. IR spectra were taken on a Fourier transform infrared spec-
trophotometer as neat films between NaCl plates or as KBr pellets.
1H NMR spectra were obtained at 400 MHz as dilute solutions in
CDCl3, C6D6 or DMSO-d6 and the chemical shifts were reported
relative to internal TMS. High- and low-resolution mass spectra
were recorded at an ionizing voltage of 70 eV by electron impact.
Semi-empirical and ab initio calculations were conducted with
SPARTAN PC Pro ’06.
It is well documented that the regioselectivity for the nucleo-
philic addition to a pyridinium ion is often explained by the
HSAB rule.10c,13 In particular, it has been known that soft nu-
cleophiles effectively attack the 4-position to give 1,4-dihy-
dropyridines selectively. If the HSAB rule governs the selectivity
in this reaction, the charge density or pyridinium LUMO co-
efficients has to affect the selectivity. Table 3 listed the electro-
static charges and the LUMO coefficients, in which only 2py
components were listed because of the negligible values of 2px
and 2pz. As can be seen from Table 3, neither the electron
density nor the LUMO coefficient accounts for the substituent
effects. Sundberg and his co-workers have suggested the im-
portance of the product stabilities in determining the preference
for 1,2-addition or 1,6-addition during the reduction of pyr-
idinium into dihydropyridines with hydride reagents.14 This hy-
pothesis prompted us to study the relationship between the
product energies and regioselectivities.
4.2. General procedure for the addition of alkynes 2 to 3-
substituted pyridines 1
To a solution of a pyridine derivative (1.0 mmol) in dry
dichloromethane (6.0 ml) was added dropwise ethyl chloroformate
(286
solution was stirred for about 20 min at 0 ꢀC, phenylacetylene
(220 1, 2.0 mmol) and copper(I) iodide (0.382 g, 2.0 mmol) were
added to the solution, and then diisopropylethylamine (340 1,
m
1, 3.0 mmol) at 0 ꢀC under nitrogen atmosphere. After the
m
m
2.0 mmol) was added dropwise to the solution. The mixture was
stirred at rt for 5 h. The reaction was quenched with water and the
precipitate was filtered. The filtrate was extracted with CH2Cl2 at
pH 8–9. The organic layer was washed with water and brine, and
was dried over anhydrous magnesium sulfate. The evaporation of
the solvent gave a crude product, which was purified by column
chromatography on silica gel with a 1:2 mixture of AcOEt and
hexane to afford a mixture of the isomeric dihydropyridines 3, 4,
and 5 (75–99%).
Table 4 lists the energies of the 1,2- and 1,6-adducts and their
differences,
D
E, obtained by the DFT calculations at the B3LYP/6-
31G* level. It is clear that
D
E is significantly dependent on the
substituent. The 1,6-adducts 5a and 5b having an electron-
withdrawing group are more stable than the corresponding 1,2-
adducts 3a and 3b. In contrast, the 1,2-adducts 3d and 3e having
an electron-donating group are more stable than the corre-
sponding 1,6-adducts 5d and 5e. The opposite tendency for the
phenyl-substituted 3c would be due to a resonance effect; the
conjugate system of 3c is more effective for the resonance sta-
bilization than cross-conjugate system of 5c. The comparison of
4.2.1. A mixture of 3a–5a
The product ratio of a mixture of 3a–5a is determined to be
24:14:56 by 1H NMR spectrum. 1H NMR for 3a (400 MHz, CDCl3,
DE with the regioselectivity clearly showed a relationship be-
50 ꢀC)
d
7.38–7.35 (2H, m), 7.33–7.23 (3H, m), 7.12 (2H, d, J¼5.9 Hz),
tween them. These results lead to the conclusion that the
regioselectivity during the addition of alkynes to the pyridinium
would be closely related to the product stabilities.
6.28 (1H, br), 5.57–5.28 (1H, m), 4.41–4.28 (2H, m), 3.82 (1H, s),
1.38–1.34 (3H, m). H NMR for 4a (400 MHz, CDCl3, 50 ꢀC)
1
d 7.98
(1H, s), 7.38–7.35 (2H, m), 7.27–7.10 (3H, m), 6.87 (1H, d, J¼7.8 Hz),
5.23 (1H, dd, J¼8.3, 4.4 Hz), 4.44 (1H, d, J¼4.4 Hz), 4.41–4.30 (2H,
m), 3.81 (1H, s), 1.39–1.33 (3H, m). 1H NMR for 5a (400 MHz, CDCl3,
50 ꢀC)
d 7.90 (1H, s), 7.38–7.35 (2H, m), 7.27–7.10 (3H, m), 6.50 (1H,
3. Conclusion
In summary, the regioselective addition of terminal alkynes to
3-substituted pyridines was performed. The substituents
d, J¼9.8 Hz), 5.78 (1H, d, J¼5.4 Hz), 5.66 (1H, dd, J¼9.8, 5.9 Hz),
4.41–4.30 (2H, m), 3.78 (3H, s), 1.39–1.33 (3H, m).
Table 4
The energies for 3 and 5, and their differences
D
E with the isomer ratioa
E (kcal/mol)
4.2.2. A mixture of 3ab–5ab
The product ratio of a mixture of 3ab–5ab is determined to be
Isomers
Substituent
CO2Me
Ea (kcal/mol)
D
Ratio (3:5)
28:17:55 by 1H NMR spectrum. 1H NMR for 3ab (400 MHz, CDCl3,
3a
5a
3b
5b
3c
5c
3d
5d
3e
5e
ꢁ659 981.64
ꢁ659 981.98
ꢁ612772.38
ꢁ612773.29
ꢁ661974.18
ꢁ661973.75
ꢁ541656.85
ꢁ541655.42
ꢁ588 848.52
ꢁ588 844.59
ꢁ0.34
ꢁ0.91
0.43
24:76
50 ꢀC)
d
7.32–7.29 (2H, m), 7.11 (2H, d, J¼5.9 Hz), 6.80–6.76 (3H, m),
6.25 (1H, br), 5.56–5.52 (1H, m), 4.41–4.29 (2H, m), 3.77 (3H, s),
1.39–1.34 (3H, m). 1H NMR for 4ab (400 MHz, CDCl3, 50 ꢀC)
7.97
COMe
Ph
39:61
76:24
67:33
100:0
d
(1H, s), 7.32–7.29 (2H, m), 6.87 (1H, d, J¼7.8 Hz), 6.80–6.76 (3H, m),
5.23 (1H, dd, J¼8.3, 4.4 Hz), 4.42 (1H, d, J¼4.9 Hz), 4.41–4.29 (2H,
m), 3.81 (3H, s), 1.39–1.34 (3H, m). 1H NMR for 5ab (400 MHz,
Me
1.43
CDCl3, 50 ꢀC)
d 7.90 (1H, s), 7.32–7.29 (2H, m), 6.80–6.76 (3H, m),
OMe
3.93
6.49 (1H, d, J¼9.8 Hz), 5.76 (1H, d, J¼5.9 Hz), 5.65 (1H, dd, J¼9.3,
a
The energies were obtained by DFT calculations at the B3LYP/6-31G* level.
5.4 Hz), 4.41–4.29 (2H, m), 3.78 (3H, s), 1.39–1.34 (3H, m).

2332
S. Yamada et al. / Tetrahedron 65 (2009) 2329–2333
4.2.3. A mixture of 3ac–5ac
d, J¼9.3 Hz), 5.73–5.61 (2H, m), 4.34–4.24 (2H, m), 1.81 (3H, s),
1.37–1.14 (3H, m).
The product ratio of a mixture of 3ac–5ac is determined to be
25:17:58 by 1H NMR spectrum. 1H NMR for 3ac (400 MHz, CDCl3,
50 ꢀC)
d
7.28–7.24 (2H, m), 7.11 (1H, d, J¼5.9 Hz), 7.08–7.04 (3H,
4.2.8. Ethyl 3-methoxy-2-(phenylethynyl)pyridine-1(2H)-
carboxylate (3e)
m), 6.26 (1H, br), 5.56–5.52 (1H, m), 4.41–4.27 (2H, m), 3.81 (3H,
s), 1.94 (6H, s), 1.39–1.34 (3H, m). 1H NMR for 4ac (400 MHz,
Yellow oil; IR (neat) 2980, 2220, 1714, 1662, 1601, 1409, 1377,
CDCl3, 50 ꢀC)
d
7.97 (1H, s), 7.28–7.24 (2H, m), 7.08–7.04 (2H, m),
1324, 1264, 1223, 1111, 1024, 893, 758, 732, 692 cmꢁ1 1H NMR
;
6.87 (1H, d, J¼7.8 Hz), 6.23 (1H, dd, J¼7.8, 4.4 Hz), 4.42 (1H, d,
(400 MHz, CDCl3) d 7.51–7.40 (2H, m), 7.34–7.25 (3H, m), 6.60 (1H,
J¼4.4 Hz), 4.41–4.27 (2H, m), 3.80 (6H, s), 1.39–1.34 (3H, m). 1H
d, J¼7.8 Hz), 6.48 (1H, d, J¼7.3 Hz), 5.72 (1H, s), 5.59 (1H, s), 5.44–
5.37 (1H, m), 5.07 (1H, d, J¼4.4 Hz), 4.34–4.17 (2H, m), 3.67 (3H, s),
1.35–1.29 (3H, m); MS (EI) m/z: 283 (Mþ, 100%), 252 (38), 210 (63),
195 (77), 180 (55), 167 (49), 139 (41); HRMS calcd for C15H12O2N:
283.1208, found: 283.1181.
NMR for 5ac (400 MHz, CDCl3, 50 ꢀC)
d 7.90 (1H, s), 7.28–7.24 (2H,
m), 7.08–7.04 (2H, m), 6.49 (1H, d, J¼9.8 Hz), 5.76 (1H, d,
J¼5.9 Hz), 5.65 (1H, dd, J¼9.8, 4.9 Hz), 4.41–4.27 (2H, m), 3.78 (6H,
s), 1.39–1.34 (3H, m).
4.2.4. A mixture of 3ad–5ad
4.3. General procedure for the oxidation of a mixture of the
isomeric dihydropyridines 3–5
The product ratio of a mixture of 3ad–5ad is determined to be
40:11:49 by 1H NMR spectrum. 1H NMR for 3ad (400 MHz, CDCl3,
50 ꢀC)
d
7.26–7.18 (2H, m), 7.17–7.11 (3H, m), 7.06 (2H, d, J¼6.9 Hz),
A mixture of the isomeric dihydropyridines 3, 4, and 5
6.05 (1H, br), 5.52–5.49 (1H, m), 4.37–4.32 (2H, m), 3.79 (3H, s),
(0.209 mmol) and chloranil (0.628 mmol) in dry benzene (3 ml)
was refluxed for 24 h under nitrogen atmosphere. The reaction
mixture was cooled at rt and the precipitate was filtered. The fil-
trate was extracted with ether and the extract was washed with 5%
NaHCO3. The ether solution was dried over anhydrous magnesium
sulfate and was evaporated in vacuo to give an oily product, which
was purified by column chromatography on silica gel and TLC with
a 1:2 mixture of AcOEt and hexane to afford a mixture of 6, 7, and 8.
2.65–2.62 (2H, m), 2.17–2.11 (2H, m), 1.81–1.71 (2H, m), 1.36–1.32
1
(3H, m). H NMR for 4ad (400 MHz, CDCl3, 50 ꢀC)
d 7.92 (1H, s),
7.26–7.18 (2H, m), 7.17–7.11 (3H, m), 6.86 (1H, d, J¼7.8 Hz), 5.15 (1H,
dd, J¼7.8, 4.4 Hz), 4.37–4.32 (2H, m), 4.30 (1H, d, J¼4.4 Hz), 3.78
(3H, s), 2.65–2.62 (2H, m), 2.17–2.11 (2H, m), 1.81–1.71 (2H, m),
1.36–1.32 (3H, m). 1H NMR for 5ad (400 MHz, CDCl3, 50 ꢀC)
d 7.87
(1H, s), 7.26–7.18 (2H, m), 7.17–7.11 (3H, m), 6.44 (1H, d, J¼9.8 Hz),
5.58 (1H, dd, J¼9.8, 5.9 Hz), 5.53 (1H, d, J¼6.3 Hz), 4.37–4.32 (2H,
m), 2.65–2.62 (2H, m), 2.17–2.11 (2H, m), 1.81–1.71 (2H, m), 1.36–
1.32 (3H, m).
4.3.1. Methyl 2-phenylethynylnicotinate (6a)
Yellow crystal; mp 97.5–99.0 ꢀC (recrystallization from ether–
hexane); IR (KBr) 1729, 1593, 1434, 1281, 1112, 1023, 914, 860, 768,
4.2.5. A mixture of 3b–5b
738, 715, 693 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 9.10 (1H, d,
The product ratio of a mixture of 3b–5b is determined to be
J¼1.6 Hz), 7.95 (1H, dd, J¼8.4, 2.4 Hz), 7.42–7.32 (5H, m), 6.83 (1H, d,
J¼8.0 Hz), 3.91 (3H, s); MS (EI) m/z: 274 (36, Mþþ2), 272 (Mþ,100%),
238 (14), 212 (13), 178 (13), 152 (9), 151 (8), 102 (6); HRMS calcd for
C15H12O2N: 238.0868, found: 238.0852.
32:18:50 by 1H NMR spectrum. 1H NMR for 3b (400 MHz, CDCl3,
50 ꢀC)
d
7.40–7.33 (2H, m), 7.31–7.20 (3H, m), 7.00 (2H, d, J¼5.9 Hz),
6.41 (1H, br), 5.60–5.56 (1H, br), 4.46–4.27 (2H, m), 2.35 (3H, s),
1.41–1.34 (3H, m). H NMR for 4b (400 MHz, CDCl3, 50 ꢀC)
1
d 7.93
(1H, s), 7.40–7.33 (2H, m), 7.31–7.20 (3H, m), 6.89 (1H, d, J¼8.3 Hz),
5.29 (1H, dd, J¼8.3, 4.4 Hz), 4.51 (1H, d, J¼4.4 Hz), 4.46–4.27 (2H,
m), 2.37 (3H, s), 1.41–1.34 (3H, m). 1H NMR for 5b (400 MHz, CDCl3,
4.3.2. 3-Phenyl-2-phenylethynylpyridine (6c)
Yellow oil; IR (neat) 3056, 2221, 1954, 1887, 1598, 1579, 1558,
1490, 1443, 1415, 1242, 1213, 1114, 1006, 916, 776, 755, 700,
50 ꢀC)
d
7.85 (1H, s), 7.40–7.33 (2H, m), 7.31–7.20 (3H, m), 6.64 (1H,
691 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
8.61 (1H, dd, J¼4.9, 1.5 Hz),
7.72 (1H, dd, J¼7.8, 2.0 Hz), 7.66 (2H, d, J¼6.8 Hz), 7.51–7.25 (9H,
m); (400 MHz, benzene)
8.45 (1H, dd, J¼4.3, 1.5 Hz), 7.50–7.48
d, J¼9.8 Hz), 5.77 (1H, d, J¼5.4 Hz), 5.70 (1H, dd, J¼9.8, 5.4 Hz),
4.46–4.27 (2H, m), 2.31 (3H, s), 1.41–1.34 (3H, m).
d
(2H, m), 7.31–7.28 (2H, m), 7.21–7.12 (4H, m), 6.88–6.86 (3H, m),
4.2.6. A mixture of 3c–5c
6.61 (1H, dd, J¼7.8, 4.4 Hz); 13C NMR (67.5 Hz, CDCl3)
d 148.54,
The product ratio of a mixture of 3c–5c is determined to be
141.23, 139.80, 138.12, 136.72, 131.75, 129.22, 128.74, 128.18,
128.08, 128.07, 122.71, 122.33, 91.81, 88.61; MS (EI) m/z: 255 (Mþ,
100%), 254 (83), 226 (16), 200 (9), 150 (15), 127 (30), 102 (24), 878
(15), 77 (25), 63 (30), 51 (43); HRMS calcd for C19H12N: 254.0970,
found: 254.1031.
70:8:22 by 1H NMR spectrum. 1H NMR for 3c (400 MHz, CDCl3)
d
7.61 (2H, d, J¼7.8 Hz), 7.38–7.25 (3H, m), 6.96 (1H, d, J¼7.3 Hz),
6.85 (1H, d, J¼7.3 Hz), 6.48 (1H, J¼5.9 Hz), 6.31 (1H, s), 6.14 (1H,
s), 5.69–5.61 (1H, m), 4.42–4.29 (2H, m), 1.44–1.33 (3H, m). 1H
NMR for 4c (400 MHz, CDCl3)
d
7.61 (2H, d, J¼7.8 Hz), 7.51–7.20
(9H, m), 7.01 (1H, s), 6.30–5.10 (1H, m), 4.57 (1H, d, J¼4.4 Hz),
4.3.3. 3-Methoxy-2-phenylethynylpyridine (6e)
4.32–4.24 (2H, m), 1.35–1.18 (3H, m). 1H NMR for 5c (400 MHz,
Yellow crystal; mp 57.0–59.0 ꢀC (recrystallization from ether–
hexane); IR (KBr) 2217, 1575, 1494, 1464, 1440, 1430, 1275, 1251,
CDCl3)
d
7.61 (2H, d, J¼7.8 Hz), 7.51–7.20 (9H, m), 6.46 (1H,
d, J¼6.3 Hz), 5.90–5.76 (2H, m), 4.32–4.24 (2H, m), 1.35–1.18
1212, 1117, 1012, 798, 756, 695 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
(3H, m).
d
8.23 (1H, dd, J¼3.9, 2.0 Hz), 7.64–7.61 (2H, m), 7.36–7.35 (3H, m),
7.26–7.20 (2H, m), 3.93 (3H, s); (400 MHz, DMSO-d6) 8.18 (1H, d,
J¼4.4 Hz), 7.59–7.56 (3H, m), 7.47–7.40 (4H, m), 3.90 (3H, s);
(400 MHz, C6D6)
d
4.2.7. A mixture of 3d–5d
The product ratio of a mixture of 3d–5d is determined to be
d
8.18 (1H, dd, J¼4.9, 1.6 Hz), 7.55–7.53 (2H, m),
56:16:28 by 1H NMR spectrum. 1H NMR for 3d (400 MHz, CDCl3)
6.92–6.89 (3H, m), 6.58–6.54 (1H, m), 6.34 (1H, dd, J¼8.3, 1.5 Hz),
3.12 (3H, s); MS (EI) m/z: 209 (Mþ, 100%), 208 (57), 180 (76), 166
(46), 139 (26), 127 (27), 69 (25); HRMS calcd for C14H11ON:
209.0841, found: 209.0883.
d
7.56–7.39 (2H, m), 7.34–7.26 (3H, m), 6.76 (1H, d, J¼6.8 Hz), 6.64
(1H, d, J¼7.3 Hz), 6.73 (1H, d, J¼5.4 Hz), 5.61 (1H, s), 5.48 (1H, s),
5.34–6.28 (1H, m), 4.34–4.24 (2H, m), 1.94 (3H, s), 1.37–1.14 (3H,
m). 1H NMR for 4d (400 MHz, CDCl3)
d 7.56–7.39 (3H, m), 7.34–
7.26 (3H, m), 6.51 (1H, s), 5.83–5.79 (1H, m), 4.97 (1H, br), 4.34–
4.3.4. Methyl 4-phenylethynylnicotinate (7a)
4.24 (2H, m), 1.86 (3H, s), 1.37–1.14 (3H, m). 1H NMR for 5d
Yellow crystal; mp 64–66 ꢀC; IR (KBr) 1720, 1591, 1296, 1280,
(400 MHz, CDCl3)
d
7.56–7.39 (3H, m), 7.34–7.26 (3H, m), 5.91 (1H,
1134, 1124, 1021, 779, 762, 696, 689 cmꢁ1 1H NMR (400 MHz,
;

S. Yamada et al. / Tetrahedron 65 (2009) 2329–2333
2333
CDCl3)
d
9.18 (1H, s), 8.69 (1H, d, J¼4.8 Hz), 7.62–7.59 (2H, m), 7.49
References and notes
(1H, d, J¼5.2 Hz), 7.41–7.39 (3H, m), 4.00 (3H, s); MS (EI) m/z: 237
(Mþ, 76%), 212 (35), 206 (57), 178 (63), 151 (100), 126 (36), 102
(43), 77 (42); HRMS calcd for C15H11O2N: 237.0790, found:
237.0728.
1. For reviews, see: (a) Lavilla, R. J. Chem. Soc., Perkin Trans. 1 2002, 1141; (b)
Sausins, A.; Duburs, G. Heterocycles 1988, 27, 291; (c) Stout, D. M.; Meyers, A. I.
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4.3.5. 3-Acetyl-4-phenylethynylpyridine (7b)
Yellow oil; IR (neat) 2218,1684,1576,1528,1496,1358,1264, 962,
840, 758, 690 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 8.99 (1H, s), 8.68
(1H, d, J¼4.8 Hz), 7.60–7.57 (2H, m), 7.48 (1H, d, J¼5.2 Hz), 7.45–7.38
(3H, m), 2.80 (3H, s); MS (EI) m/z: 221 (Mþ,100%), 206 (87),178 (33),
151 (50), 150 (45); HRMS calcd for C15H11ON: 221.0840, found:
221.0800.
5. (a) Comins, D. L.; Smith, E. D. Tetrahedron Lett. 2006, 47, 1449; (b) Comins, D. L.;
´
King, L. S.; Smith, E. D.; Fevrier, F. C. Org. Lett. 2005, 7, 5059; (c) Smith, E. D.;
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4.3.6. 3-Phenyl-4-phenylethynylpyridine (7c)
Yellow oil; IR (neat) 2218, 1955, 1891, 1717, 1623, 1579, 1492,
1446, 1415, 1007, 932, 756, 699 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
8. For recent reports, see: (a) Roschangar, F.; Liu, J.; Estanove, E.; Dufour, M.;
Rodriguez, S.; Farina, V.; Hickey, E.; Hossain, A.; Jones, P.-J.; Lee, H.; Lu, B. Z.;
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Org. Lett. 2007, 9, 1395; (e) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am.
Chem. Soc. 2001, 123, 2074.
9. (a) Vanejevs, M.; Jatzke, C.; Renner, S.; Mueller, S.; Hechenberger, M.; Bauer, T.;
Klochkova, A.; Pyatkin, I.; Kazyulkin, D.; Aksenova, E.; Shulepin, S.; Timonina, O.;
Haasis, A.; Gutcaits, A.; Parsons, C. G.; Kauss, V.; Weil, T. J. Med. Chem. 2008, 51,
634; (b) Alagelle, D.; Baldwin, R. M.; Roth, B. L.; Wroblewski, J. T.; Grajkowska, E.;
Tamagnan, G. D. Bioorg. Med. Chem. 2005, 13, 197; (c) Rodriguez, A. L.; Nong, Y.;
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d
8.73 (1H, dd, J¼4.4, 1.2 Hz), 7.72 (1H, dd, J¼1.6, 8.0 Hz), 7.59–7.56
(2H, m), 7.43–7.33 (9H, m), 7.03 (1H, s); MS (EI) m/z: 256 ((Mþ1)þ,
97%), 254 ((Mꢁ1)þ, 81), 226 (29),102 (62), 77 (100); HRMS calcd for
C19H14N: 256.1127, found: 256.1082.
4.3.7. 3-Methyl-4-phenylethynylpyridine (7d)
Yellow oil; IR (neat) 2215, 1623, 1582, 1445, 1244, 1166, 1108,
930, 859, 767, 693 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 8.45 (1H, s),
7.60–7.58 (2H, m), 7.48 (1H, d, J¼8.0 Hz), 7.43 (1H, d, J¼8.0 Hz),
7.37–7.26 (3H, m), 2.08 (3H, s); MS (EI) m/z: 193 (Mþ, 80%), 165 (41),
139 (29), 102 (51), 63 (66); HRMS calcd for C14H12N: 194.0970,
found: 194.0966.
10. (a) Yadav, J. S.; Reddy, B. V. S.; Sreenivas, M.; Safhaiah, K. TetrahedronLett. 2005, 46,
8905; (b) Yamaguchi, R.; Hata, E.; Utimito, K. Tetrahedron Lett. 1988, 29, 1788; (c)
Yamaguchi, R.; Nakazono, Y.; Kawanisi, M. Tetrahedron Lett. 1983, 24, 1801.
11. Nishiwaki, N.; Minakata, S.; Komatsu, M.; Ohshiro, Y. Chem. Lett. 1989, 773.
12. Kagabu, S.; Mizoguchi, S. Synthesis 1996, 372.
Acknowledgements
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This work was financially supported by a Grant-in-Aid for Sci-
entific Research (B) (No.13650901) from the Japan Society for the
Promotion of Science.
14. Sundberg, R. J.; Hamilton, G.; Trindle, C. J. Org. Chem. 1986, 51, 3672.