Direct C3-alkenylation of pyridin-4(1H)-one via oxidative Heck coupling

Article abstract of DOI:10.1016/j.tet.2012.11.061

Oxidative Heck coupling of pyridin-4(1H)-one via palladium(II)-catalyzed C-H bond activation has been achieved in moderate to good yields. The coupling occurred selectively at C3 position. Pivalic acid was found to be an effective additive to promote this

Full text of DOI:10.1016/j.tet.2012.11.061

Tetrahedron 69 (2013) 1115e1119
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Direct C3-alkenylation of pyridin-4(1H)-one via oxidative
Heck coupling
*
Guangling Zhang, Ziyuan Li, Yue Huang, Jinyi Xu, Xiaoming Wu, Hequan Yao
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 August 2012
Received in revised form 15 November 2012
Accepted 16 November 2012
Available online 23 November 2012
Oxidative Heck coupling of pyridin-4(1H)-one via palladium(II)-catalyzed CeH bond activation has been
achieved in moderate to good yields. The coupling occurred selectively at C3 position. Pivalic acid was
found to be an effective additive to promote this alkenylation.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Pyridin-4(1H)-one
Oxidative Heck coupling
Alkenylation
Catalysis
CeH activation
1. Introduction
chromones via a palladium(II)-catalyzed CeH functionalization
reaction.9 As a continuation of our research on nitrogen-containing
During the last few decades, major progress has been achieved
in transition metal catalyzed carbon(sp2)ecarbon(sp2) bond-for-
mation.1 Among them, Heck reaction between halogenated arenes
with alkenes is recognized as one of the most powerful methods to
construct alkenylated arenes.2 More recently, the more economical
and straightforward CeC bond formation via palladium(II)-
catalyzed CeH bond cleavage between unpreactivated arenes or
heteroarenes and olefins, known as oxidative Heck coupling, has
been becoming an exceedingly valuable process in contemporary
organic synthesis since this methodology generally avoids the need
of the preactivation of arene species.3 Up to date, lots of efforts have
been devoted to the direct alkenylation of various heteroaromatic
scaffolds through the oxidative Heck coupling to build diverse
molecular library.4
Pyridin-4(1H)-one is a common motif found in a variety of
bioactive natural products and versatile synthetic molecules.5
Typically, the compounds bearing 2-hydroxymethyl-5-hydroxyl
pyridin-4(1H)-one scaffold are demonstrated to show some in-
teresting bioactivities (Fig. 1),6 which has attracted much attention
in the synthetic community during the past several years. For ex-
ample, Ge et al. reported an efficient alkenylation of quinolones7
and enaminones8 via an oxidative Heck reaction. Very recently,
Hong and co-workers also disclosed a direct alkenylation of various
heteroarenes,10 we wish to utilize an oxidative Heck coupling re-
action to realize the C3-alkenylation of 2,5-disubstituted pyridin-
4(1H)-one, leading to diverse chemical libraries for biological
screening. We herein report our results.
O
O
O
H
O
OH
X
HO
N
O
O
H
N
Me
N
Me
(X = O or CH2)
O
H3CS
O
O
H
O
N
N
Cl
N
H
O
N
O
O
Me
S
Lodop ridone
N
H
Cl
y
Fig. 1. Representative examples of bioactive compounds bearing 2,5-disubstituted
pyridin-4(1H)-one.
2. Results and discussion
Our initial investigation focused on the coupling of 5-methoxy-
2-(methoxymethyl)-1-methylpyridin-4(1H)-one 1a with n-butyl
acrylate 2a as summarized in Table 1.11 1a could be readily achieved
from Kojic acid through double methylation of hydroxyl groups
* Corresponding author. Tel.: þ86 25 83271042; fax: þ86 25 83301606; e-mail
address: hyao@cpu.edu.cn (H. Yao).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.061

1116
G. Zhang et al. / Tetrahedron 69 (2013) 1115e1119
Table 2
,b
Olefin scopea
Table 1
Screening of reaction conditionsa,11
Entry
Oxidant
(2 equiv)
Solvent
(2 mL)
Additive
(equiv)
Yield (%)b
1
2
3
4
5
6
7
8
AgOAc
Cu(OAc)2
Ag2CO3
BQ
DMF
DMF
DMF
DMF
DMF
DMA
CH3CN
AcOH
d
27
Trace
19
Trace
Trace
25
20
17
Trace
54
0
d
d
d
K2S2O8
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAcf
d
d
d
d
9
DMSO
d
10
11
12
13
14
15
16d
17e
18
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
d
Cs2CO3 (2)
K2CO3 (2)
TEA (2)
PivOH (2)
PivOH (10)
PivOH (10)
PivOH (10)
PivOH (10)
Trace
0
63
79c
75
64
85c
a
Reaction conditions: 1a (0.5 mmol), n-butyl acrylate (2a, 1 mmol), Pd(OAc)2
(0.05 mmol), oxidant (1 mmol), and additive in solvent (2 mL) at 120 ꢀC for 16 h.
b
1H NMR yields using dibromomethane (
d
¼4.80) as an internal standard.
c
d
e
f
Isolated yields.
a
Reaction conditions: 1a ( 0.5 mmol), olefin (2a-2k. 1 mmol), Pd(OAc)2 (0.05
mmol), AgOAc (1.5 mmol) and PivOH (5 mmol) in 1,4-dioxane (2 mL) at 120 ꢀC for
16 h.
100 ꢀC.
110 ꢀC.
AgOAc (1.5 mmol) was used.
b
Isolated yields.
with Me2SO4, followed by amination with MeNH2.12 Initial
screening revealed that the use of AgOAc as an oxidant provided the
desired alkenylated product 3a in higher yield than other oxidants
(entries 1e5). NOESY spectrum of 3a proved that the alkenylation
selectively occurred at the C3 position.13 Subsequent screening on
solvent suggested that the yield could be promoted to 54% when
1,4-dioxane was used (entries 6e10). The screening on additive
effect indicated basic additives were detrimental to this alkenyla-
tion (entry 11e13), while PivOH could dramatically increased the
coupling efficiency, resulting in the yield of 3a to 79% (entry 14e15).
This could be explained by the fact that palladiumePivOH combi-
nations could lower the energy of C(sp2)eH bond cleavage, leading
to excellent reactivity in CeH activation reactions.14 Replacing
Pd(OAc)2 with other commonly used Pd(II) catalysts or changing
the reaction temperature gave no further improved results (entries
16e17). Finally, we were pleased to find that the yield of 3a could be
increased to 85% by increasing the loading of AgOAc (entry 18).
With the established condition in hand, we examined various
olefins to demonstrate the reaction scope as shown in Table 2.
Generally, all olefins could react smoothly to provide the desired
cross-coupling products in moderate to good yields. For example,
the good yields of the corresponding products (3aee) maintained
when the substrate 1a was coupled with acrylates, while the yields
of the alkenylation with acrylamides slightly dropped (3f, 3g). More
Beside methyl, small alkyl groups like ethyl, n-propyl or i-propyl did
not influence the effectiveness of this reaction, affording the de-
sired product in good yields (4aec), while n-butyl substitution
slightly declined the yields (4deg). Very interestingly, benzyl
substitution at N1-position dramatically decreased the coupling
yield (4h). TBS and Bn groups on C2 position, or removal of the
methoxyl group were found to be well tolerated under the opti-
mized conditions, providing the desired products in good yields
(4iek).
Finally, we proposed a plausible mechanism for the C3-alkeny-
lation of pyridin-4(1H)-one as illustrated in Fig. 2. The reaction is
initiated by the nucleophilic attack of pyridin-4(1H)-one at C3
position. Such regioselectivity is controlled by the inherent elec-
tronic bias of the pyridin-4(1H)-one substrate itself,7,15 rather than
by the oxygen atom at the 2-methoxymethyl group since 2-methyl
substrate still showed good regioselectivity (4k, Table 3). Depro-
tonation by the pivalate ligand gave C3-palladated intermediate A,
which smoothly inserts into the olefin to produce intermediate B.
Finally, B undergoes a reductive elimination to provide the desired
coupled product and Pd(0), which is reoxidized to Pd(II) by AgOAc
to complete the catalytic cycle.
sterically hindered
a
-methyl acrylates afforded the desired prod-
3. Conclusion
ucts in relatively low yields (3h, 3i). In addition, the coupling with
other olefins, such as acrylonitrile, styrene, could also provide the
corresponding products (3j, 3k) in moderate yields.
Next, the effective conditions were extended to a variety of
substrates bearing N1- and C2-substutions and the results were
shown in Table 3. We observed that steric hindrance at the N1-
position has some impact on the yield of the alkenylated product.
In conclusion, we have developed a general protocol for the
direct C3-alkenylation of 2,5-disubstituted pyridin-4(1H)-one in
moderate to good yields via Pd(II)-catalyzed CeH bond activation.
The coupling reaction selectively occurred at C3 position. Further-
more, PivOH could dramatically improve the coupling efficiency.
Further application of this methodology to the functionalization of

G. Zhang et al. / Tetrahedron 69 (2013) 1115e1119
1117
Table 3
,b
Substrate scopea
Fig. 2. Proposed reaction mechanism.
was vigorously stirred at 120 ꢀC (oil temperature). After stirring for
16 h, the mixture was cooled to room temperature, diluted with
ethyl acetate, and filtered. The filtrate was concentrated in vacuo to
give dark yellow residue, which was purified by flash chromatog-
raphy on silica gel to afford the cross-coupling product.
4.3. Characterization data of products
a
4.3.1. n-Butyl 3-(5-methoxy-2-(methoxymethyl)-1-methyl-4-oxo-1,4-
Reaction conditions: 1b-1h (0.5 mmol), olefin (2a-2d, 1 mmol), Pd(OAc)2 (0.05
mmol), AgOAc (1.5 mmol) and PivOH (5 mmol) in 1,4-dioxane (2 mL) at 120 oC for
16 h.
dihydropyridin-3-yl)acrylate (3a). Yellowish solid, mp 96e98 ꢀC; 1H
NMR (300 MHz, CDCl3)
d
0.95 (t, J¼7.3 Hz, 3H), 1.36e1.49 (m, 2H),
b
Isolated yields.
1.63e1.72 (m, 2H), 3.44 (s, 3H), 3.79 (s, 3H), 3.80 (s, 3H), 4.18 (t,
J¼6.6 Hz, 2H), 4.50 (s, 2H), 6.91 (s, 1H), 7.28 (d, J¼15.6 Hz, 1H), 7.75
(d, J¼15.6 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d 169.8, 167.2,
pyridin-4(1H)-one, as well as the study on their biological activities,
are ongoing in our laboratory, which will be reported in due course.
148.2, 142.7, 135.8, 122.1, 121.3, 120.7, 65.4, 63.1, 57.4, 55.3, 41.1, 29.7,
18.1,12.6 ppm; IR (KBr) 2958,1701,1627,1561,1301,1268,1135,1097,
956, 865 cmꢁ1; HRMS (ESI) calcd for [C16H23NO5þH]þ 310.1649,
found 310.1654.
4. Experimental section
4.1. General information
4.3.2. Methyl
1,4-dihydropyridin-3-yl)acrylate (3b). Yellow solid, mp 180e182 ꢀC;
1H NMR (300 MHz, CDCl3)
3.43 (s, 3H), 3.75 (s, 3H), 3.77 (s, 3H), 3.79
3-(5-methoxy-2-(methoxymethyl)-1-methyl-4-oxo-
Melting point (mp) was measured on a microscopic melting
point apparatus. 1H and 13C NMR spectra were collected on BRUKER
AV-300 (300 MHz) spectrometer using CDCl3 as solvent. Chemical
d
(s, 3H), 4.46 (s, 2H), 6.98 (s, 1H), 7.24 (d, J¼15.6 Hz, 1H), 7.72 (d,
J¼15.6 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d 170.8 168.5, 149.2,
143.8,137.2,123.0,121.8,121.6, 66.4, 58.4, 56.3, 51.4, 42.1 ppm;IR (KBr)
shifts of 1H NMR were recorded in parts per million (ppm,
d
) rel-
¼0.00 ppm) with the solvent resonance
as an internal standard (CDCl3:
¼7.26 ppm). Data are reported as
follows: chemical shift in ppm
3128, 1715, 1625, 1570, 1396, 1307, 1167, 1090, 1041, 981, 870 cmꢁ1
;
ative to tetramethylsilane (
d
HRMS (ESI) calcd for [C13H17NO5þH]þ 268.1179, found 268.1180.
d
(
d
), multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet), coupling constant
(Hertz), and integration. Chemical shifts of 13C NMR were reported
in ppm with the solvent as the internal standard (CDCl3:
4.3.3. Ethyl 3-(5-methoxy-2-(methoxymethyl)-1-methyl-4-oxo-1,4-
dihydropyridin-3-yl)acrylate (3c). Yellow solid, mp 162e164 ꢀC;
1H NMR (300 MHz, CDCl3)
d
1.31 (t, J¼7.0 Hz, 3H), 3.43 (s, 3H), 3.76
d
¼77.0 ppm). Infrared spectra (IR) were recorded on a Thermo
(s, 3H), 3.79 (s, 3H), 4.23 (q, J¼7.0 Hz, 2H), 4.46 (s, 2H), 6.97 (s, 1H),
7.23 (d, J¼15.6 Hz, 1H), 7.72 (d, J¼15.6 Hz, 1H) ppm; 13C NMR
Scientific iS10 FT/IR spectrometer; absorptions are reported in re-
ciprocal centimeters. High Resolution Mass measurement was
performed on Agilent QTOF 6520 mass spectrometer with electron
spray ionization (ESI) as the ion source.
(75 MHz, CDCl3) d 170.8,168.0,149.2,143.7,136.9,123.1,122.4,121.8,
66.4, 60.2, 58.4, 56.3, 42.1, 14.3 ppm; IR (KBr) 2985, 2932, 1710,
1628, 1565, 1298, 1276, 1250, 1099, 1043, 980, 956, 868 cmꢁ1; HRMS
(ESI) calcd for [C14H19NO5þH]þ 282.1336, found 282.1341.
4.2. General experimental procedure
4.3.4. tert-Butyl 3-(5-methoxy-2-(methoxymethyl)-1-methyl-4-
A reaction tube was charged with 5-methoxypyridin-4(1H)-one
substrate (0.5 mmol, 1.0 equiv), olefin (1.0 mmol, 2 equiv), Pd(OAc)2
(11 mg, 0.05 mmol, 10 mol %), AgOAc (250 mg, 1.5 mmol, 3.0 equiv),
pivalic acid (5 mmol,10 equiv), and 1,4-dioxane (2 mL). The mixture
oxo-1,4-dihydropyridin-3-yl)acrylate (3d). Yellowish solid, mp
146e148 ꢀC; 1H NMR (300 MHz, CDCl3)
d 1.51 (s, 9H), 3.43 (s, 3H),
3.77 (s, 3H), 3.78 (s, 3H), 4.47 (s, 2H), 6.95 (s, 1H), 7.15 (d, J¼15.6 Hz,
1H), 7.63 (d, J¼15.6 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d 171.0,

1118
G. Zhang et al. / Tetrahedron 69 (2013) 1115e1119
167.4, 149.2, 143.5, 135.7, 124.7, 123.5, 122.2, 80.0, 66.4, 58.4, 56.5,
42.1, 28.2 ppm; IR (KBr) 2920, 1693, 1628, 1563, 1300, 1273, 1151,
1135, 1099, 956 cmꢁ1; HRMS (ESI) calcd for [C16H23NO5þH]þ
310.1649, found 310.1654.
1H), 7.10e7.35 (m, 5H), 7.47 (s, 1H), 7.50 (s, 1H) ppm; 13C NMR
(75 MHz, CDCl3) 170.2, 147.5, 139.7, 136.8, 133.0, 127.5, 126.5, 126.1,
125.6, 123.0, 121.2, 66.9, 57.2, 55.6, 40.7 ppm; IR (KBr) 3133, 1626,
1544, 1399, 1301, 1147, 1087, 744, 690, cmꢁ1; HRMS (ESI) calcd for
[C17H19NO3þH]þ 286.1439, found 286.1438.
d
4.3.5. 5-Methoxy-2-(methoxymethyl)-1-methyl-3-((2-oxodihydrofur-
an-3(2H)-ylidene)methyl)pyridin-4(1H)-one (3e). Yellow solid, mp
4.3.12. tert-Butyl 3-(1-ethyl-5-methoxy-2-(methoxymethyl)-4-oxo-
146e148 ꢀC; 1H NMR (300 MHz, CDCl3)
d
3.44 (s, 3H), 3.69 (s, 2H),
3.78 (s, 3H), 3.80 (s, 3H), 4.63 (s, 2H), 4.71 (s, 2H), 7.02 (s, 1H), 7.48 (s,
1H) ppm; 13C NMR (75 MHz, CDCl3)
174.5, 170.9, 148.5, 147.5, 141.7,
1,4-dihydropyridin-3-yl)acrylate (4a). Sepia oil; 1H NMR (300 MHz,
CDCl3)
d
1.46 (t, J¼6.2 Hz, 3H), 1.51 (s, 9H), 3.45 (s, 3H), 3.80 (s, 3H),
d
4.07 (q, J¼6.2 Hz, 2H), 4.48 (s, 2H), 7.05 (s, 1H), 7.14 (d, J¼15.6 Hz,
131.5, 125.5, 124.4, 70.4, 67.1, 58.5, 56.5, 41.8, 21.7 ppm; IR (KBr)
2920, 1747, 1630, 1555, 1297, 1136, 1081, 1049, 949, 850 cmꢁ1; HRMS
(ESI) calcd for [C14H17NO5þH]þ 280.1179, found 280.1181.
1H), 7.65 (d, J¼15.6 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d 170.9,
167.4, 149.7, 142.9, 135.9, 124.5, 122.3, 121.6, 79.9, 66.1, 58.4, 56.5,
49.5, 28.1, 16.3 ppm; IR (KBr) 2978, 2926, 1699, 1627, 1567, 1310,
1275, 1152, 1095, 768, 760, 744 cmꢁ1; HRMS (ESI) calcd for
[C17H25NO5þH]þ 324.1805, found 324.1806.
4.3.6. 3-(5-Methoxy-2-(methoxymethyl)-1-methyl-4-oxo-1,4-
dihydropyridin-3-yl)-N,N-dimethylacrylamide (3f). Yellow solid, mp
152e154 ꢀC; 1H NMR (300 MHz, CDCl3)
d
3.05 (s, 3H), 3.17 (s, 3H),
4.3.13. tert-Butyl 3-(5-methoxy-2-(methoxymethyl)-4-oxo-1-propyl-
1,4-dihydropyridin-3-yl)acrylate (4b). Yellow solid, mp 114e116 ꢀC;
3.43 (s, 3H), 3.79 (s, 3H), 3.79 (s, 3H), 4.54 (s, 2H), 6.94 (s, 1H), 7.65
(d, J¼14.8 Hz, 1H), 8.21 (d, J¼14.8 Hz, 1H) ppm; 13C NMR (75 MHz,
1H NMR (300 MHz, CDCl3)
d
1.00 (t, J¼7.4 Hz, 3H), 1.51 (s, 9H),
CDCl3)
d
171.1, 168.1, 149.3, 143.6, 133.4, 122.9, 122.2, 122.0, 66.0,
1.78e1.91 (m, J¼7.6 Hz, 2H), 3.44 (s, 3H), 3.79 (s, 3H), 3.94 (t,
58.5, 56.4, 42.1, 37.3, 35.7 ppm; IR (KBr) 2920, 1649, 1624, 1553,
1403, 1298, 1158, 1091, 1050, 953 cmꢁ1; HRMS (ESI) calcd for
[C14H20N2O4þH]þ 281.1496, found 281.1499.
J¼7.7 Hz, 2H), 4.47 (s, 2H), 7.01 (s, 1H), 7.15 (d, J¼15.6 Hz, 1H), 7.65
(d, J¼15.6 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d 170.9, 167.4,
149.4, 143.0, 135.9, 124.6, 122.3, 122.1, 79.9, 66.1, 58.4, 56.5, 55.9,
28.2, 24.5, 10.9 ppm; IR (KBr) 2976, 2931, 1699, 1626, 1567, 1368,
1310, 1275, 1260, 1152, 1095, 956, 753, 748 cmꢁ1; HRMS (ESI) calcd
for [C18H27NO5þH]þ 338.1962, found 338.1959.
4.3.7. N,N-Diethyl-3-(5-methoxy-2-(methoxymethyl)-1-methyl-4-
oxo-1,4-dihydropyridin-3-yl)acrylamide (3g). Yellow oil; 1H NMR
(300 MHz, CDCl3)
d
1.18 (t, J¼7.2 Hz, 3H), 1.26 (t, J¼7.2 Hz, 3H), 3.43
(s, 3H), 3.49 (q, J¼7.2 Hz, 4H), 3.78 (s, 6H), 4.54 (s, 2H), 6.94 (s, 1H),
4.3.14. tert-Butyl 3-(1-isopropyl-5-methoxy-2-(methoxymethyl)-4-
oxo-1,4-dihydropyridin-3-yl)acrylate (4c). Yellow solid, mp
7.68 (d, J¼14.8 Hz, 1H), 8.18 (d, J¼14.8 Hz, 1H) ppm; 13C NMR
(75 MHz, CDCl3)
d
171.0, 167.1, 149.2, 143.5, 133.3, 122.7, 122.5, 121.9,
104e106 ꢀC; 1H NMR (300 MHz, CDCl3)
d
1.49 (d, J¼6.8 Hz, 6H),
66.0, 58.5, 56.3, 42.3, 42.1, 40.9, 14.9, 13.2 ppm; IR (KBr) 2917, 1634,
1594, 1556, 1461, 1299, 1274, 1091, 1049, 749, 599 cmꢁ1; HRMS (ESI)
calcd for [C16H24N2O4þH]þ 309.1809, found 309.1812.
1.51 (s, 9H), 3.44 (s, 3H), 3.84 (s, 3H), 4.53 (s, 2H), 4.72e4.81 (m,
J¼6.8 Hz, 1H), 7.03 (d, J¼15.6 Hz, 1H), 7.14 (s, 1H), 7.68 (d,
J¼15.6 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d 170.9, 167.4, 149.4,
143.0, 135.9, 124.5, 122.3, 122.1, 79.9, 66.1, 58.4, 56.5, 55.9, 28.2,
24.5, 10.9 ppm; IR (KBr) 2983, 1628, 1574, 1276, 1261, 1150, 768,
760, 756, 741 cmꢁ1; HRMS (ESI) calcd for [C18H27NO5þH]þ
338.1962, found 338.1968.
4.3.8. Ethyl 3-(5-methoxy-2-(methoxymethyl)-1-methyl-4-oxo-1,4-
dihydropyridin-3-yl)but-2-enoate (3h). Yellow solid, mp 96e98 ꢀC;
1H NMR (300 MHz, CDCl3)
d
1.33 (t, J¼7.5 Hz, 3H), 1.75 (s, 3H), 3.34
(s, 3H), 3.79 (s, 3H), 3.81 (s, 3H), 4.24 (q, J¼7.0 Hz, 2H), 4.34 (s, 2H),
7.13 (s, 1H), 7.49 (s, 1H) ppm; 13C NMR (75 MHz, CDCl3)
169.6,
d
4.3.15. tert-Butyl 3-(1-butyl-5-methoxy-2-(methoxymethyl)-4-oxo-
167.5, 148.9, 140.9, 133.2, 133.2, 124.6, 124.4, 67.8, 60.7, 58.3, 56.4,
41.5, 14.4, 14.2 ppm; IR (KBr) 2922, 1704, 1627, 1554, 1400, 1300,
1,4-dihydropyridin-3-yl)acrylate (4d). Yellow solid, mp 94e96 ꢀC;
1H NMR (300 MHz, CDCl3)
d
0.99 (t, J¼7.3 Hz, 3H), 1.37e1.44 (m,
1261, 1146, 1050, 1035, 753 cmꢁ1
;
HRMS (ESI) calcd for
J¼7.3 Hz, 2H), 1.51 (s, 9H), 1.74e1.84 (m, J¼7.3 Hz, 2H), 3.44 (s, 3H),
3.80 (s, 3H), 3.96 (t, J¼7.8 Hz, 2H), 4.47 (s, 2H), 7.00 (s, 1H), 7.16 (d,
J¼15.6 Hz, 1H), 7.65 (d, J¼15.6 Hz, 1H) ppm; 13C NMR (75 MHz,
[C15H21NO5þH]þ 296.1492, found 296.1494.
4.3.9. n-Butyl
3-(5-methoxy-2-(methoxymethyl)-1-methyl-4-oxo-
CDCl3) d 170.9, 167.4, 149.4, 143.0, 135.9, 124.6, 122.4, 122.1, 79.9,
1,4-dihydropyridin-3-yl)but-2-enoate (3i). Yellow oil; 1H NMR
66.2, 58.4, 56.6, 54.3, 33.2, 28.2, 19.8, 13.6 ppm; IR (KBr) 2924, 1632,
1275, 1261, 1151, 768, 760, 744 cmꢁ1; HRMS (ESI) calcd for
[C19H29NO5þH]þ 352.2118, found 352.2124.
(300 MHz, CDCl3)
d
0.95 (t, J¼6.6 Hz, 3H), 1.40e1.47 (m, 2H),
1.66e1.71 (m, 2H), 1.75 (s, 3H), 3.33 (s, 3H), 3.79 (s, 3H), 3.80 (s, 3H),
4.18 (t, J¼5.7 Hz, 2H), 4.34 (s, 2H), 7.08 (s, 1H), 7.48 (s, 1H) ppm; 13
C
NMR (75 MHz, CDCl3)
d
169.6, 167.6, 149.0, 140.9, 133.3, 133.1, 124.7,
4.3.16. Methyl 3-(1-butyl-5-methoxy-2-(methoxymethyl)-4-oxo-1,4-
124.4, 67.8, 64.7, 58.3, 56.5, 41.6, 30.6, 19.2, 14.5, 13.7 ppm; IR (KBr)
dihydropyridin-3-yl)acrylate (4e). Yellow solid, mp 98e100 ꢀC;
2959, 2931,1708,1626,1564,1297,1253,1143,1119,1096, 750 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
0.99 (t, J¼7.2 Hz, 3H), 1.36e1.46 (m,
HRMS (ESI) calcd for [C17H25NO5þH]þ 324.1805, found 324.1810.
J¼7.4 Hz, 2H), 1.75e1.82 (m, J¼7.5 Hz, 2H), 3.44 (s, 3H), 3.77 (s,
3H), 3.80 (s, 3H), 3.96 (t, J¼7.7 Hz, 2H), 4.48 (s, 2H), 7.00 (s, 1H),
7.25 (d, J¼15.6 Hz, 1H), 7.76 (d, J¼15.6 Hz, 1H) ppm; 13C NMR
4.3.10. 3-(5-Methoxy-2-(methoxymethyl)-1-methyl-4-oxo-1,4-
dihydropyridin-3-yl)acrylonitrile (3j). Light yellow solid, mp
(75 MHz, CDCl3) d 171.0, 168.6, 149.6, 143.2, 137.3, 122.2, 121.9,
212e214 ꢀC; 1H NMR (300 MHz, CDCl3)
d
3.47 (s, 3H), 3.80 (s, 3H),
3.81 (s, 3H), 4.45 (s, 2H), 6.92 (s, 1H), 7.35 (s, 2H) ppm; 13C NMR
(75 MHz, CDCl3) 171.1, 149.8, 144.0, 142.2, 122.7, 120.1, 119.8, 100.9,
66.2, 58.5, 56.5, 54.3, 51.4, 33.2, 19.8, 13.6 ppm; IR (KBr) 2954,
2924, 1686, 1628, 1567, 1401, 1266, 1127, 1093, 1053, 764,
750 cmꢁ1; HRMS (ESI) calcd for [C16H23NO5þH]þ 310.1649, found
310.1650.
d
66.0, 58.8, 56.5, 42.4 ppm; IR (KBr) 3185, 2207, 1625, 1609, 1560,
1400, 1290, 1137, 1097, 961, 858 cmꢁ1; HRMS (ESI) calcd for
[C12H14N2O3þH]þ 235.1076, found 235.1077.
4.3.17. Ethyl 3-(1-butyl-5-methoxy-2-(methoxymethyl)-4-oxo-1,4-
dihydropyridin-3-yl)acrylate (4f). Yellow oil; 1H NMR (300 MHz,
4.3.11. 5-Methoxy-2-(methoxymethyl)-1-methyl-3-styrylpyridin-
CDCl3)
d
0.98 (t, J¼7.2 Hz, 3H), 1.31 (t, J¼7.0 Hz, 3H), 1.38e1.44 (m,
4(1H)-one (3k). Brown solid, mp 138e140 ꢀC; 1H NMR (300 MHz,
J¼7.3 Hz, 2H), 1.75e1.85 (m, J¼7.3 Hz, 2H), 3.45 (s, 3H), 3.79 (s, 3H),
3.98 (t, J¼7.8 Hz, 2H), 4.24 (q, J¼7.2 Hz, 2H), 4.47 (s, 2H), 7.02 (s, 1H),
CDCl3)
d 3.41 (s, 3H), 3.76 (s, 3H), 3.76(s, 3H), 4.43 (s, 2H), 7.00 (s,

G. Zhang et al. / Tetrahedron 69 (2013) 1115e1119
1119
7.21 (d, J¼15.6 Hz, 1H), 7.64 (d, J¼15.6 Hz, 1H) ppm; 13C NMR
Supplementary data
(75 MHz, CDCl3) d 170.8, 168.1, 149.4, 143.2, 137.1, 122.4, 122.0, 121.9,
66.1, 60.1, 58.4, 56.4, 54.3, 33.1, 19.7, 14.2, 13.5 ppm; IR (KBr) 2987,
1699, 1627, 1567, 1275, 1260, 1094, 770, 741 cmꢁ1; HRMS (ESI) calcd
for [C17H25NO5þH]þ 324.1805, found 324.1810.
Supplementary data including detailed results of reaction con-
dition screening and reaction scope investigation, along with 1H
NMR and 13C NMR spectra of 3aek, 4aej, and NOESY spectrum of
3a. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2012.11.061.
4.3.18. n-Butyl 3-(1-butyl-5-methoxy-2-(methoxymethyl)-4-oxo-1,4-
dihydropyridin-3-yl)acrylate (4g). Yellow oil; 1H NMR (300 MHz,
CDCl3)
d 0.92e1.01 (m, 6H), 1.39e1.43 (m, 4H), 1.62e1.69 (m,
References and notes
J¼7.1 Hz, 2H), 1.77e1.82 (m, J¼6.8 Hz, 2H), 3.45 (s, 3H), 3.79 (s, 3H),
3.97 (t, J¼7.7 Hz, 2H), 4.18 (t, J¼6.6 Hz, 2H), 4.47 (s, 2H), 7.00 (s, 1H),
7.25 (d, J¼15.6 Hz, 1H), 7.74 (d, J¼15.6 Hz, 1H) ppm; 13C NMR
1. For recent reviews and examples on transition metal catalyzed CeC bond for-
mation, see: (a) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed.
2009, 48, 9792; (b) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2009, 48, 5094; (c) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174; (d) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147; (e)
McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885.
2. (a) Heck, R. F. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 4; (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457; (c) Luh, T. Y.; Leung, M. K.; Wong, K. T. Chem. Rev. 2000, 100, 3187; (d)
Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921; (e) Nicolaou, K. C.;
Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442; (f) Surry, D. S.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338; (g) Xu, L.-M.; Li, B.-J.; Yang,
Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712.
(75 MHz, CDCl3)
d 170.9, 168.2, 149.5, 143.2, 137.0, 122.5, 122.0,
121.9, 66.1, 64.1, 58.4, 56.5, 54.3, 33.2, 30.7, 19.8, 19.1, 13.6, 13.6 ppm;
IR (KBr) 2960, 1704, 1627, 1568, 1275, 1261, 1129, 767, 760,
744 cmꢁ1; HRMS (ESI) calcd for [C19H29NO5þH]þ 352.2118, found
352.2123.
4.3.19. tert-Butyl 3-(1-benzyl-5-methoxy-2-(methoxymethyl)-4-oxo-
1,4-dihydropyridin-3-yl)acrylate (4h). Yellow oil; 1H NMR (300 MHz,
CDCl3)
d 1.51 (s, 9H), 3.40 (s, 3H), 3.75 (s, 3H), 4.42 (s, 2H), 5.26 (s,
3. For reviews and examples on palladium-catalyzed double CeH activation, see:
(a) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215; (b) You, S. L.; Xia, J. B. Top.
Curr. Chem. 2010, 292, 165; (c) Ashenhurst, J. A. Chem. Soc. Rev. 2010, 39, 540; (d)
McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447; (e) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624; (f) Su, Y.; Jiao, N. Curr.
Org. Chem. 2011, 15, 3362; (g) Kyung, S. Y.; Cheol, H. Y.; Kyung, W. J. J. Am. Chem.
2H), 6.98 (s, 1H), 7.05 (d, J¼6.5 Hz, 2H), 7.17 (d, J¼15.6 Hz, 1H),
7.28e7.39 (m, 3H), 7.69 (d, J¼15.6 Hz, 1H) ppm; 13C NMR (75 MHz,
CDCl3)
d 171.3, 167.3, 149.5, 143.5, 135.5, 129.3, 129.1, 128.4, 126.4,
125.9, 125.3, 122.9, 80.1, 66.3, 58.5, 57.2, 56.6, 28.2 ppm; IR (KBr)
2980, 1697, 1627, 1570, 1275, 1151, 752, 748, 739 cmꢁ1; HRMS (ESI)
calcd for [C22H27NO5þH]þ 386.1962, found 386.1968.
€
Soc. 2006, 128, 16384; (h) Crowley, J. D.; Hanni, K. D.; Lee, A.-L.; Leigh, D. A. J.
Am. Chem. Soc. 2007, 129, 12092; (i) Xiong, D.-C.; Zhang, L.-H.; Ye, X.-S. Org. Lett.
2009, 11, 1709; (j) Su, Y.; Jiao, N. Org. Lett. 2009, 11, 2980; (k) Pan, D.; Yu, M.;
Chen, W.; Jiao, N. Chem.dAsian J. 2010, 5, 1090.
4. For selected examples of bioactive alkenylated heterocycles, see: (a) Xu, Q.;
Huang, L.; Liu, J.; Ma, L.; Chen, T.; Chen, J.; Peng, F.; Cao, D.; Yang, Z.; Qiu, N.; Qiu, J.;
Wang, G.; Liang, X.; Peng, A.; Xiang, M.; Wei, Y.; Chen, L. Eur. J. Med. Chem. 2012, 52,
70; (b) Hasmann, M.; Schemainda, I. Cancer Res. 2003, 63, 7436; (c) Caroff, E.;
Hilpert, K.; Hubler, F.; Lehmann, D.; Meyer, E.; Renneberg, D. WO 2010/122504A1,
2010. (d) Baell, J. B.; Bui, C. T.; Colman, P.; Dubley, D. A.; Fairbrother, W. J.; Flygare, J.
A.; Lassene, G. L.; Ndubaku, C.; Nicolakopoulos, G.; Rye, C. S.; Sleebs, B. E.; Smith, B.
J.; Watson, K. G.; Elmore, S. W.; Petros, A. M.; Souers, A. J. WO 2010/080478A1,
2010. (e) Adamczewski, M.; Arnold, C.; Becker, A.; Carles, L.; Dahmen, P.; Dunkel,
R.; Franken, E.; Gorgens, U.; Grosjean-Cournoyer, M.; Helmke, H.; Hillebrand, S.;
Hiroyuki, H.; Kluth, J.; Knobloch, T.; Losel, P.; Nennstiel, D.; Rieck, H.; Rama, R.;
Suelmann, R.; Voerste, A.; Wachendorff-Neumann, U. WO 2010/012793A1, 2010.
(f) Martin, S.; Bergstrom, C. P.; Gentles, R. G.; Yeung, K. S. WO 2009/029384A2,
2009.
4.3.20. tert-Butyl 3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5-
methoxy-1-methyl-4-oxo-1,4-dihydropyridin-3-yl)acrylate (4i). Light
yellow solid, mp 186e189 ꢀC; 1H NMR (300 MHz, CDCl3)
d 0.14 (s,
6H), 0.90 (s, 9H), 1.49 (s, 9H), 3.76 (s, 3H), 3.83 (s, 3H), 4.69 (s, 2H),
6.97 (s, 1H), 7.00 (d, J¼15.7 Hz, 1H), 7.61 (d, J¼15.7 Hz, 1H) ppm; 13
C
NMR (75 MHz, CDCl3) d 171.1, 166.8, 149.0, 145.5, 136.0, 124.8, 123.4,
121.5, 79.9, 58.3, 56.4, 41.9, 28.2, 25.7, 18.1, ꢁ5.4 ppm; IR (KBr) 3102,
2957, 2931, 2858, 1709, 1628, 1561, 1293, 1261, 1154, 840, 765,
750 cmꢁ1; HRMS (ESI) calcd for [C21H35NO5SiþH]þ 410.2357, found
410.2361.
5. For selected examples of pyridin-4(1H)-one based bioactive compounds, see:
(a) Barral, K.; Balzarini, J.; Neyts, J.; De Clercq, E.; Hider, R. C.; Camplo, M. J. Med.
4.3.21. tert-Butyl 3-(2-((benzyloxy)methyl)-5-methoxy-1-methyl-4-
oxo-1,4-dihydropyridin-3-yl)acrylate (4j). Yellow oil; 1H NMR
€
€
Chem. 2006, 49, 43; (b) Ozturk, G.; Erol, D. D.; Aytemir, M. D.; Uzbay, T. Eur. J.
Med. Chem. 2002, 37, 829; (c) Bebbington, D.; Monck, N. J. T.; Gaur, S.; Palmer,
A. M.; Benwell, K.; Harvey, V.; Malcolm, C. S.; Porter, R. H. P. J. Med. Chem. 2000,
43, 2779; (d) Liu, G.; Bruenger, F. W.; Miller, S. C.; Arif, A. M. Bioorg. Med. Chem.
Lett. 1998, 8, 3077; (e) Matulic-Adamic, J.; Gonzalez, C.; Usman, N.; Beigelman,
L. Bioorg. Med. Chem. Lett. 1996, 6, 373.
6. For selected examples of bioactive compounds bearing 2-hydroxymethyl-5-hy-
droxyl pyridin-4(1H)-one scaffold, see: (a) Dehkordi, L. S.; Liu, Z. D.; Hider, R. C.
Eur. J. Med. Chem. 2008, 43,1035; (b) Pirrung, M. C.; Deng, L.; Lin, B.; Webster, N. J.
ChemBioChem 2008, 9, 360; (c) Chen, Y.-L.; Chen, P.-H.; Chung, C.-H.; Li, K.-C.;
Jeng, H.-Y.; Tzeng, C.-C. Helv. Chim. Acta 2003, 86, 778; (d) Shin, K. J.; Roh, E. J.;
Chung, M. K.; Cha, H. J.; Seo, S. H. WO 2011/014008A2, 2011. (e) Maloney, K. N.;
MacMillan, J. B.; Kauffman, C. A.; Jensen, P. R.; DiPasquale, A. G.; Rheingold, A. L.;
Fenical, W. Org. Lett. 2009, 11, 5422.
(300 MHz, CDCl3)
d 1.52 (s, 9H), 3.71 (s, 3H), 3.77 (s, 3H), 4.55 (s,
2H), 4.59 (s, 2H), 6.90 (s, 1H), 7.13 (d, J¼15.6 Hz, 1H), 7.31e7.35 (m,
5H), 7.65 (d, J¼15.6 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3)
d 170.9,
167.2, 149.2, 143.5, 136.6, 136.0, 128.6, 128.3, 128.2, 124.6, 123.4,
122.3, 80.0, 73.1, 64.4, 56.4, 42.1, 28.2 ppm; IR (KBr) 2982, 1699,
1628, 1558, 1276, 1261, 1152, 771, 759, 740, 701 cmꢁ1; HRMS (ESI)
calcd for [C22H27NO5þH]þ 386.1962, found 386.1969.
4.3.22. tert-Butyl 3-(5-methoxy-1,2-dimethyl-4-oxo-1,4-dihydro-
pyridin-3-yl)acrylate (4k). Light yellow solid, mp 218e220 ꢀC; 1H
7. Li, M.; Li, L.; Ge, H. Adv. Synth. Catal. 2010, 352, 2445.
8. Ge, H.; Niphakis, M. J.; Georg, G. I. J. Am. Chem. Soc. 2008, 130, 3708.
9. Kim, D.; Hong, S. Org. Lett. 2011, 13, 4466.
NMR (300 MHz, CDCl3)
3H), 6.86 (s, 1H), 7.34 (d, J¼15.6 Hz, 1H), 7.53 (d, J¼15.6 Hz, 1H) ppm;
13C NMR (75 MHz, CDCl3)
170.9, 168.2, 148.6, 146.6, 136.4, 123.1,
d 1.51 (s, 9H), 2.39 (s, 3H), 3.66 (s, 3H), 3.75 (s,
10. For our previous works on N-containing heteroarenes, see: (a) Li, Z.; Ma, L.; Xu, J.;
Kong, L.; Wu, X.; Yao, H. Chem. Commun. 2012, 3763; (b) Zhao, L.; Li, Z.; Chang, L.;
Xu, J.; Yao, H.; Wu, X. Org. Lett. 2012, 14, 2066; (c) Li, Z.; Ma, L.; Tang, C.; Xu, J.; Wu,
X.; Yao, H. Tetrahedron Lett. 2011, 52, 5643; (d) Li, Z.; Wang, Y.; Huang, Y.; Tang, C.;
Xu, J.; Wu, X.; Yao, H. Tetrahedron 2011, 67, 5550; (e) Wang, Y.; Li, Z.; Huang, Y.;
Tang, C.; Wu, X.; Xu, J.; Yao, H. Tetrahedron 2011, 67, 7406; (f) Huang, Y.; Ni, L.; Gan,
H.; He, Y.; Xu, J.; Wu, X.; Yao, H. Tetrahedron 2011, 67, 2066; (g) Huang, Y.; Gan, H.;
Li, S.; Xu, J.; Wu, X.; Yao, H. Tetrahedron Lett. 2010, 51, 1751.
d
122.6, 119.8, 79.9, 56.5, 43.0, 28.2, 16.2 ppm; IR (KBr) 2979, 1686,
1638, 1611, 1558, 1301, 1266, 1133, 962, 759, 863 cmꢁ1; HRMS (ESI)
calcd for [C15H21NO4þH]þ 280.1549, found 280.1551.
11. Please see Supplementary data for the detailed results of reaction condition
Acknowledgements
screening.
12. Please see Supplementary data for the preparation of pyridin-4(1H)-one
substrates.
Financial support from by NSFC-21272276, 20902111,
PSCIRT1193, and Fok Ying Tong Foundation (121040) by the Min-
istry of Education of China and SKLNM (JKGZ201110) is highly ap-
preciated. We thank Haipin Zhou in this group for reproducing the
results of 3d in Table 2 and 4i in Table 3.
13. Please see Supplementary data for the copy of the NOESY spectrum of 3a.
14. The addition of PivOH into the reaction system produced Pd(OPiv)2, which was
proposed to enable efficient CeH palladation. See recent reviews: (a) Ackermann,
L. Chem. Rev. 2011, 111,1315; (b) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118.
15. Roger, J.; Gottumukkala, A. L.; Doucet, H. ChemCatChem 2010, 2, 20.