Regioselective rhodium-catalyzed intermolecular [2+2+2] cycloaddition of alkynes and isocyanates to form pyridones

Article abstract of DOI:10.1016/j.tet.2009.02.021

A highly regioselective rhodium-catalyzed intermolecular [2+2+2] cycloaddition of terminal alkynes with a variety of isocyanates to provide 2- and 4-pyridones has been developed. This reaction proceeds in good to excellent yields and overcomes the problem of dimerization and trimerization through the use of phosphoramidite ligands. A CO migration in the metallacycle is proposed to account for the formation of 4-pyridone.

Full text of DOI:10.1016/j.tet.2009.02.021

Tetrahedron 65 (2009) 5056–5061
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Tetrahedron
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Regioselective rhodium-catalyzed intermolecular [2þ2þ2] cycloaddition
of alkynes and isocyanates to form pyridones
*
Kevin M. Oberg, Ernest E. Lee, Tomislav Rovis
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly regioselective rhodium-catalyzed intermolecular [2þ2þ2] cycloaddition of terminal alkynes
with a variety of isocyanates to provide 2- and 4-pyridones has been developed. This reaction proceeds in
good to excellent yields and overcomes the problem of dimerization and trimerization through the use of
phosphoramidite ligands. A CO migration in the metallacycle is proposed to account for the formation of
4-pyridone.
Received 23 December 2008
Received in revised form 9 February 2009
Accepted 11 February 2009
Available online 20 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
methodology was applied toward the synthesis of the natural
product camptothecin. Flynn initially demonstrated rhodium’s abil-
Pyridones display a variety of interesting biological properties
including anticancer, antiviral, and antibacterial activity.1 Pyridones
can be synthesized in a variety of ways; the most common strate-
gies are transformations from other heterocycles, often pyridines,
and condensation reactions.1b Most of these strategies allow for
regiocontrolled syntheses of pyridones, but often require multiple
transformations to reach the desired product. Cycloadditions using
ity to catalyze pyridone formation, but substituted benzenes6 were
the major product.7 Terminal alkynes present another issue when
attempting metal-catalyzed cycloadditions, because they are known
to undergo metal-catalyzed dimerization to produce enynes.8
Several researchers have expanded on these initial results by
examining different metals and tethered substrates. Itoh has
demonstrated ruthenium’s ability as an efficient cycloaddition
three
p
-components are a rapid and efficient route to heterocycles.
catalyst of a,u-diynes and exogenous isocyanates to afford
This reaction manifold has been applied to the synthesis of
pyridones (Scheme 1).9 Louie has shown that nickel complexes
modified with a carbene or phosphorous ligand provide catalysts
that are selective for either pyrimidine-diones or pyridones.10
Kondo improved on Flynn’s initial work with rhodium to form both
pyridones and pyrimidine-diones using symmetrical alkynes.11 In
pyridones and a variety of other heterocycles.2
Yamazaki and Hoberg pioneered metal-catalyzed pyridone for-
mation from 2 equiv of alkyne and 1 equiv of isocyanate. Yamazaki
used cobalt to catalyze the [2þ2þ2] cycloaddition of methyl phe-
nylpropiolate and methyl isocyanate to form a mixture of pyridone
isomers.3 Use of methyl propiolate, a terminal alkyne, in the reaction
provided hydantoin products instead of pyridones. Hoberg used
a nickel catalyst to synthesize pyridones from symmetrical and
unsymmetrical alkynes and isocyanates (Scheme 1).4 Using stoi-
chiometric nickel, these workers were able to isolate metallacycles
presumably involved in the catalytic cycle. In addition to these
studies, it was demonstrated that pyrimidine-diones could be
synthesized from 2 equiv of isocyanate and 1 equiv of alkyne.4
an effort to incorporate three different
p-components, Takahashi
developed a highly regioselective method to synthesize pyridones
and other heterocycles that overcame the problem with
regioisomers and allowed for the incorporation of three
p-com-
ponents, but uses stoichiometric amounts of zirconium and
nickel.12
Recently, Tanaka has used cationic rhodium modified by
enantioenriched ligands to synthesize pyridones containing axial
chirality from tethered diynes (Scheme 1).13 Tanaka is also one of
the few who reports metal-catalyzed cycloadditions with terminal
alkynes and isocyanates.4a,13a,14 These researchers observed for-
mation of multiple regioisomers when 1-dodecyne and benzyl
isocyanate were subjected to their reaction conditions using cat-
ionic rhodium (Scheme 2). Better selectivity was observed with
different alkynes: cyclohexenylacetylene furnished primarily 4,5-
subsitituted pyridone and trimethylsilylacetylene furnished only
3,5-substituted pyridone (Scheme 2).
Vollhardt developed
a regioselective partially intermolecular
cobalt-catalyzed cycloaddition by tethering an alkyne to either an-
other alkyne or an isocyanate (Scheme 1).5 This strategy surmounts
the problem associated with multiple regioisomers and this
* Corresponding author. Tel.: þ1 970 491 7208; fax: þ1 970 491 1801.
E-mail address: rovis@lamar.colostate.edu (T. Rovis).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.021

K.M. Oberg et al. / Tetrahedron 65 (2009) 5056–5061
5057
Hoberg (ref. 4a):
in good to excellent yields in a regioselective manner using phos-
phoramidite ligands.
O
Ph
O
Me
Ph
Ph
Ph
N
Ni(COD)2, PCy3
PhMe, 23 °C
C
N
+
2. Results and discussion
2.1. Ligand screen
Ph
Me
Me
76%
Vollhardt (ref. 5a):
TMS
We initially found that [Rh(C2H4)2Cl]2 (2.5 mol %) and triphe-
nylphosphine (5 mol %) catalyze the reaction between phenyl
acetylene 1a and benzyl isocyanate 2a to yield 2-pyridone 3aa in
poor yield along with an undesired enynamide 4aa (Table 1, entry
1).16 An attempt to optimize reaction conditions using different
ligands was undertaken. Use of electron-deficient and electron-rich
triaryl phosphine ligands gives marginally better yields of both 3aa
and 4aa, but yields of the desired product remain low (entries 2 and
3). We observe an increase in desired product and a decrease in
undesired product by using MonoPhos, rac-L1, as a ligand (entry 4).
Excited by this dramatic improvement, additional phosphor-
amidites were screened; these ligands prove better than the triaryl
phosphine ligands in both yield and selectivity for the desired
product with rac-L2 being the optimal (entry 5).
TMS
TMS
CpCo(CO)2
N
+
N
m-xylene, hν, 139 °C
C
O
TMS
O
72%
Itoh (ref. 9a):
Ph
Ph
N
N
C
O
CpRu(COD)Cl
Ts
N
+
Ts
N
DCE, 90 °C
O
82%
Tanaka (ref. 13a):
MeO2C
CO2Me
MeO2C CO2Me
Cl
[Rh(COD)2]BF4
(R)-DTBM-Segphos
Cl
2.2. Alkyne scope
CH2Cl2, -20 °C
N
The alkyne scope was examined using benzyl isocyanate 2a and
is summarized in Table 2. Use of the electron-deficient alkyne 1b
gives a moderate yield, while the electron-rich alkyne 1c affords an
excellent yield of 3 (entries 2 and 3). Methoxy substitution on
various positions on the aromatic ring affords the corresponding
2-pyridones smoothly (entries 4 and 5). A slightly lower yield at the
meta position can be attributed to methoxy being electron-with-
drawing at this position and a lower yield at the ortho position can
be attributed to sterics. Other conjugated alkynes, 1f and 1g, pro-
vide excellent yields (entries 6 and 7). Alkyl alkynes show a lower
overall reactivity, while benzyl alkyne 1i promotes the formation of
4ia (entries 8 and 9). Ethynyl ethers are tolerated in the reaction,
but produce a yield similar to alkyl alkynes (entry 10). The use of
diynes in the reaction does not provide pyridone product; dipro-
pargyl ether produces the arene dimer and 1,6-heptadiyne affords
a mixture of inseparable products. The electron-deficient alkyne
Bn
O
O
C
N
89%, 92% ee
Bn
Scheme 1. Precedent for metal-catalyzed [2þ2þ2] pyridone forming cycloadditions.
Our interest in pyridone synthesis was piqued by its errant
formation in our studies on enantioselective rhodium-catalyzed
[2þ2þ2] cycloadditions of alkynes with an isocyanate tethered to
an alkene.15 We investigated this reaction further to determine its
scope, and were pleased to find this [2þ2þ2] cycloaddition pro-
ceeds smoothly with terminal alkynes without issues of
dimerization or trimerization. More importantly, this reaction
proves highly regioselective furnishing exclusively 4,6-substituted
pyridones despite a range of electronically and sterically different
alkynes (Scheme 2). During the course of our investigation, we
were surprised to isolate 4-pyridones generated from an apparent
CO migration, the formation of which is unprecedented in [2þ2þ2]
cycloadditions of alkynes and isocyanates (Scheme 2). Herein, we
describe the rhodium-catalyzed [2þ2þ2] cycloaddition of terminal
alkynes with various isocyanates to afford novel 2- and 4-pyridones
Table 1
Ligand screena
Bn
O
NH
O
C
N
[Rh(C2H4)2Cl]2 (2.5 mol%)
L (5.0 mol%)
Bn
+
N
O
Tanaka (ref. 13a):
O
O
PhMe,110 °C
Ph
O
Bn
O
C
N
Ph
Ph Ph
[Rh(COD)2]BF4
H8-BINAP
R2
R1
R1
R2
R2
N
N
+
Ph
N
1a
2a
3aa
4aa
CH Cl , 23 °C
R1
R1
2
2
R2
R1
Entry
L
2-Pyridoneb
Enynamideb
R1
R1
1
2
3
4
5
PPh3
5%
11%
22%
39%
13%
18%
12%
d
R1
R2
yield
P(4-MeO-C6H4)3
P(4-CF3-C6H4)3
rac-L1
Bn
n-Dec
31%
47%
-
30%
1%
-
<5%
-
Bn
rac-L2
68%
6%
Me
t-Bu
TMS
n-Bu
65%
This work:
Me
Me
Me
Me
O
O
P
O
O
Me
Me
O
P N
O
C
N
N
O
R2
R1
RhLn
+
N
R1
R1
N
R2
minor
R1
t-Bu
rac-L2
R2
Me
R1
rac-L1
major
a
Conditions: 1 (3 equiv), 2, Rh catalyst (2.5 mol %), L (5 mol %) in PhMe reflux for
Scheme 2. Rhodium-catalyzed [2þ2þ2] pyridone forming cycloadditions with ter-
12 h.
b
minal alkynes.
Isolated yield.

5058
K.M. Oberg et al. / Tetrahedron 65 (2009) 5056–5061
Table 2
Table 3
Terminal alkyne scopea
Isocyanate scopea
O
O
O
[Rh(C2H4)2Cl]2 (2.5 mol%)
rac-L2 (5.0 mol%)
O
C
O
C
N
[Rh(C2H4)2Cl]2 (2.5 mol%)
Bn
R
R
rac-L2 (5.0 mol%)
+
N
N
+
PhMe, 110 °C
Ar
N
R
PhMe, 110 °C
Ar
R
Bn
N
R
Ar
5
Ar Ar
R
1
2a
3
1c
2
3
Ar = p-MeO-C6H4
Entry
R
Product
Yieldb
1
2
3
4
5
Ph, 1a
3aa
3ba
3ca
3da
3ea
68%
46%
88%
73%
54%
Entry
R
Product
Yield 3b
Yield 5b
m-F-C6H4, 1b
p-MeO-C6H4, 1c
m-MeO-C6H4, 1d
o-MeO-C6H4, 1e
1
2
3
4
5
6
7
Bn, 2a
PMB, 2b
Ph, 2c
p-MeO-C6H4, 2d
p-CF3-C6H4, 2e
n-Hex, 2f
Cy, 2g
ca
cb
cc
cd
ce
cf
88%
79%
37%
43%
34%
52%
55%
4%
4%
20%
19%
30%
18%
12%
S
, 1f
6
3fa
80%
cg
a
7
3ga
92%
See Table 1.
See Table 1.
, 1g
b
8
9
10
n-Hex, 1h
Bn, 1i
OEt, 1j
3ha
3ia
3ja
38%
19%c
38%
carbon–nitrogen bond formation occurs first. Addition of a second
equivalent of alkyne and reductive elimination of the rhodium cata-
lyst would provide 2-pyridone 3. CO migration in metallacycle A to
furnish metallacycle B and subsequent alkyne addition followed by
reductive elimination would afford 4-pyridone 5. This pathway is
consistent with our previous results using alkenyl isocyanates and
alkynes.15 Theformationof5 ismost pronounced when R2 iselectron-
deficient (see Table 3). Although this pathway accounts for both
products, an alternate route to 2-pyridones cannot be ruled out.
Formation of metallacycle C, where carbon–carbon bond formation is
the first step, can be followed by alkyne insertion and reductive
elimination to afford 2-pyridone.19 This metallacycle would not be
able to furnish 4-pyridone and thus suggests that metallacycle A from
carbon–nitrogen bond formation occurring first is more probable.
a
See Table 1.
See Table 1.
Isolated 16% of enynamide 4ia.
b
c
methyl propiolate fails to yield any pyridone product. It is signifi-
cant to note that all terminal alkynes provide the same single
regioisomer and products from trimerization and dimerization of
either isocyanates or alkynes are not observed.17,18
Efforts to incorporate internal alkynes such as diphenyl acety-
lene, 5-decyne, and dimethyl acetylenedicarboxylate were
unsuccessful. Despite screening a variety of ligands, these alkynes
do not yield pyridone products under these conditions. One
internal alkyne that affords pyridone is methyl phenylpropiolate 1k
with rac-L1 as a ligand (Eq. 1). The more sterically hindered ligand,
rac-L2, does not provide product. We assigned the regioisomer
through comparison to a similar pyridone in the literature.3a
Saponification of the ester groups and subsequent decarboxylation
of the resulting acids produced pyridone 3aa confirming our orig-
inal assignment.
Ln
Rh
O
O
C
N
CO
R2
O
RhLn
R2
migration
N
N
RhLn
+
R1
R2
B
A
R1
R1
R1
R1
RhLn
O
RhLn
RhLn
COOMe
+
[Rh(C2H4)2Cl]2 (2.5 mol %)
rac-L1 (5.0 mol %)
PhMe, 110 °C
O
C
N
MeOOC
Ph
Bn
Ph
O
N
O
O
(1)
R2
N
R2
Bn
N
Ph
COOMe
3ka
RhLn
C
N
R2
R1
R1
1k
2a
R1
R1
RhLn
R1
42%
2-pyridone 3
4-pyridone 5
R1
2.3. Isocyanate scope
Scheme 3. Proposed mechanism.
We found that reacting 4-methoxyphenyl acetylene 1c and
benzyl isocyanate 2a provides an excellent yield of pyridone; this
alkyne was chosen to explore the scope of isocyanates that could be
used in this system (Table 3). During the exploration with different
isocyanates, it was found that a CO migration could occur giving 4-
pyridone 5 in addition to 2-pyridone 3. Benzyl isocyanate and PMB-
isocyanate both give excellent yields of 2-pyridone with only trace
amounts of 4-pyridone (entries 1 and 2). Aryl isocyanates afford
good combined yields of pyridone (entries 3–5). As the electron-
withdrawing ability of the aryl isocyanates increases, an increase in
the amount of 4-pyridone is observed. Despite this trend, para-
trifluoromethyl phenyl isocyanate only provides a w1:1 ratio of 2-
pyridone/4-pyridone. Alkyl isocyanates afford good combined
yields (entries 6 and 7).
2.4. PMB deprotection
As seen in Table 3, pyridone 3cb was synthesized in good yield.
The PMB-protected amide of this pyridone can be cleaved in neat
TFA to afford free pyridone 6 (Eq. 2).20 Free pyridones have been
reacted with triflic anhydride to make triflated pyridines, which
have been successfully subjected to a variety of coupling reactions
and reduced to the pyridine.21
O
O
TFA (neat)
110 °C
PMB
Ar
N
NH
Ar
(2)
Ar
Ar
3cb
6
The proposed mechanism for pyridone formation is shown in
Scheme 3. Both products can be formed from metallacycle A where
78%
Ar = p-MeO-C6H4

K.M. Oberg et al. / Tetrahedron 65 (2009) 5056–5061
5059
3. Conclusion
isolated salt was dissolved in concd aq NaOH solution and extracted
three times with EtOAc. The resulting solution was dried and
concentrated in vacuo to afford 6 (78%).
In conclusion, we have shown that 2- and 4-pyridones can be
accessed in a highly regioselective manner in good to excellent
yields using a rhodium-catalyzed [2þ2þ2] cycloaddition. These
catalytic conditions do not promote dimerization or trimerization
of terminal alkynes. A variety of isocyanates and alkynes participate
in this reaction and conjugated alkynes provide the best yields. This
catalytic system provides a regioselective method to synthesize
4,6-substituted 2-pyridones from readily available precursors.
4.4. Characterization of 2-pyridones
4.4.1. 1-Benzyl-4,6-diphenyl-2-pyridone (3aa)
1H NMR
d 7.62 (m, 2H), 7.43 (m, 4H), 7.34 (m, 2H), 7.19 (m, 5H),
6.94 (m, 3H), 6.40 (d, J¼2.1 Hz, 1H), 5.22 (s, 2H). 13C NMR
d 163.5,
150.6,149.8,137.2,137.1,135.2,129.4,129.1,128.8,128.6,128.2,127.0,
126.8, 126.7, 115.6, 107.8, 48.4. Rf¼0.24 (2:1 hex/EtOAc). IR (NaCl,
CHCl3) 3053, 3027, 2996,1650,1603,1583,1532,1486, 748, 723, 697.
HRMS (ESI) [C24H20NO]þ calcd 338.15002, found 338.15438.
4. Experimental
4.1. General
4.4.2. 1-Benzyl-4,6-bis(3-fluorophenyl)-2-pyridone (3ba)
All reactions were carried out under an atmosphere of argon in
oven-dried glassware with magnetic stirring. Toluene was degassed
with argon and passed through one column of neutral alumina and
one column of Q5 reactant. Column chromatography was performed
on Silicycle Inc. silica gel 60 (230–400 mesh). Thin layer chroma-
tography was performed on Silicycle Inc. 0.25 mm silica gel 60-F
plates. Visualization was accomplished with UV light (254 nm),
potassium permanganate, and/or ceric ammonium nitrate.
1H NMR
d
7.41 (m, 2H), 7.31 (m, 2H), 7.21 (m, 3H), 7.13 (m, 2H),
6.96 (m, 1H), 6.91 (m, 3H), 6.86 (m, 1H), 6.33 (d, J¼2.1 Hz, 1H), 5.20
(s, 2H). 13C NMR
164.2,163.4,163.3,161.8,160.9,149.4,148.7,139.4,
d
139.4, 136.9, 136.8, 130.6, 130.5, 130.1, 130.0, 128.4, 127.2, 126.8,
124.5, 122.4, 116.5, 116.3, 116.2, 116.0, 113.9, 113.6, 107.5, 48.5.
Rf¼0.24 (2:1 hex/EtOAc). IR (NaCl, CHCl3) 3063, 3027, 3001, 2955,
1660, 1588, 1537, 1475, 1265, 784, 692. HRMS (ESI) [C24H18F2NO]þ
calcd 374.13118, found 374.13546.
1H NMR and 13C NMR spectra were obtained in CDCl3 at ambient
temperature and chemical shifts are expressed in parts per million
4.4.3. 1-Benzyl-4,6-bis(4-methoxyphenyl)-2-pyridone (3ca)
(d
, ppm). Proton chemical shifts are referenced to 7.26 ppm (CHCl3)
1H NMR
d
7.58 (m, 2H), 7.21 (m, 3H), 7.10 (m, 2H), 6.96 (m, 4H),
6.87 (d, J¼2.1 Hz, 1H), 6.85 (m, 2H), 6.38 (d, J¼2.1 Hz, 1H), 5.21 (s,
2H), 3.84 (s, 3H), 3.82 (s, 3H). 13C NMR
163.7, 160.7, 160.0, 150.0,
and carbon chemical shifts are referenced to 77.0 ppm (CDCl3). Data
reporting uses the following abbreviations: s, singlet; br s, broad
singlet; d, doublet; dd, doublet of doublets; t, triplet; m, multiplet;
and J, coupling constant in hertz.
d
149.6, 137.3, 130.0, 129.4, 128.2, 128.0, 127.7,126.9, 126.7,114.2, 114.1,
113.6, 107.8, 55.2, 48.4. Rf¼0.23 (1:1 hex/EtOAc). IR (NaCl, CHCl3)
3063, 3032, 2960, 2838, 1650, 1608, 1511, 1250, 1030, 830, 728.
HRMS (ESI) [C26H24NO3]þ calcd 398.17115, found 398.17577.
Alkynes 1a–1j, isocyanates 2a, 2c–2g, triphenylphosphine,
tris(4-methoxyphenyl)phosphine, and TFA were purchased from
Aldrich Chemicals Co. and used without further purification.
[Rh(C2H4)2Cl]2 and tris(4-trifluoromethylphenyl)phosphine were
purchased from Strem Chemical, Inc. and used without further
purification. Isocyanate 2b was synthesized by converting 4-
methoxyphenylacetic acid to the acyl azide with diphenylphos-
phoryl azide and gentle heating of the acyl azide neat to afford the
isocyanate as described in previous work.15c rac-L2 was synthesized
as described in the literature.22
4.4.4. 1-Benzyl-4,6-bis(3-methoxyphenyl)-2-pyridone (3da)
1H NMR
d
7.36 (t, J¼8.0 Hz, 1H), 7.29–7.14 (m, 6H), 6.96 (m, 4H),
6.92 (d, J¼2.1 Hz, 1H), 6.81 (m, 1H), 6.60 (m, 1H), 6.40 (d, J¼2.1 Hz,
1H), 5.20 (s, 2H), 3.85 (s, 3H), 3.56 (s, 3H). 13C NMR
163.6, 160.0,
d
159.1, 150.6, 149.8, 138.8, 137.4, 136.4, 130.0, 129.5, 128.4, 127.0,
126.8, 120.8, 119.1, 115.8, 115.7, 115.1, 113.6, 112.1, 107.6, 55.3, 55.0,
48.7. Rf¼0.26 (95:5 CH2Cl2/EtOAc). IR (NaCl, CHCl3) 3063, 3027,
3001, 2955, 2827, 1654, 1588, 1532, 1491, 1286, 1030, 733, 702.
HRMS (ESI) [C26H24NO3]þ calcd 398.17115, found 398.17625.
4.2. Typical pyridone reaction
To an oven-dried round bottom flask, [Rh(C2H4)2Cl]2 (2.3 mg,
0.006 mmol) and rac-L2 (5.1 mg, 0.012 mmol) were added and an
oven-dried reflux condenser was fitted in an inert atmosphere (N2)
glove box. After removal from the glove box, 1 ml of toluene was
added via syringe and allowed to stir for 15 min at 23 ꢀC under Ar
flow. To this solution, a solution of alkyne 1 (0.720 mmol) and
isocyanate 2 (0.240 mmol) in 1 ml toluene was added via syringe.
After rinsing the condenser with additional 6 ml toluene, the so-
lution was heated to 110 ꢀC in an oil bath and maintained at reflux
for 12 h. The reaction mixture was allowed to cool to 23 ꢀC, con-
centrated in vacuo, and purified by flash chromatography (gradient
elution typically 1:1 hex/EtOAc, difficult separations used 95:5
CH2Cl2/EtOAc, and 4-pyridones required elution with 10:1 EtOAc/
MeOH). Evaporation of solvent afforded the analytically pure
compounds.
4.4.5. 1-Benzyl-4,6-bis(2-methoxyphenyl)-2-pyridone (3ea)
1H NMR
d
7.33 (m, 3H), 7.10 (m, 3H), 6.95 (m, 3H), 6.86 (m, 5H),
6.29 (d, J¼2.0 Hz, 1H), 5.44 (d, J¼14.8 Hz, 1H), 4.71 (d, J¼14.8 Hz,
1H), 3.78 (s, 3H), 3.60 (s, 3H). 13C NMR
163.7, 156.6, 156.4, 149.0,
d
145.5, 137.4, 131.0, 130.8, 130.2, 130.1, 127.9, 127.5, 127.0, 126.7, 124.5,
120.7, 120.3, 118.7, 111.2, 110.5, 55.5, 55.1, 48.2. Rf¼0.28 (1:1 hex/
EtOAc). IR (NaCl, CHCl3) 3063, 3006, 2966, 2827, 1650, 1603, 1573,
1245, 1020. HRMS (ESI) [C26H24NO3]þ calcd 398.17115, found
398.17582.
4.4.6. 1-Benzyl-4,6-di(thiophen-3-yl)-2-pyridone (3fa)
1H NMR
d
7.61 (dd, J¼2.7, 1.6 Hz, 1H), 7.39 (m, 2H), 7.32 (dd,
J¼5.0, 3.0 Hz, 1H), 7.22 (m, 3H), 7.16 (dd, J¼3.0, 1.3 Hz, 1H), 6.98 (m,
2H), 6.91 (dd, J¼5.0, 1.3 Hz, 1H), 6.89 (d, J¼2.0 Hz, 1H), 6.45 (d,
J¼2.1 Hz, 1H), 5.22 (s, 2H). 13C NMR
d 163.7, 145.1, 144.6, 138.6, 137.2,
135.4, 128.4, 127.8, 127.0, 126.9, 126.5, 126.2, 125.9, 125.6, 123.9,
114.6, 107.6, 48.5. Rf¼0.13 (2:1 hex/EtOAc). IR (NaCl, CHCl3) 3104,
3083, 3022, 3001, 2950, 1660, 1578, 1552, 851, 789, 728. HRMS (ESI)
[C20H15NOS2]þ calcd 350.06286, found 350.06775.
4.3. Deprotection of PMB-protected pyridone
Compound 3cb (19.6 mg, 0.046 mmol) was dissolved in neat TFA
and added to an oven-dried pressure tube. The reaction vessel was
sealed and heated to 110 ꢀC for 12 h. The resulting solution was
allowed to cool to 23 ꢀC, concentrated in vacuo, and purified with
flash chromatography (gradient elution 10:1 EtOAc/MeOH). The
4.4.7. 1-Benzyl-4,6-dicyclohexenyl-2-pyridone (3ga)
1H NMR
d
7.21 (m, 2H), 7.14 (m, 1H), 7.07 (m, 2H), 6.44 (d,
J¼2.0 Hz, 1H), 6.33 (m, 1H), 6.07 (d, J¼2.1 Hz, 1H), 5.54 (m, 1H), 5.15

5060
K.M. Oberg et al. / Tetrahedron 65 (2009) 5056–5061
(s, 2H), 2.26 (m, 2H), 2.16 (m, 2H),1.98 (m, 2H),1.89 (m, 2H),1.69 (m,
2H), 1.57 (m, 6H). 13C NMR
164.1, 151.4, 150.8, 137.9, 133.9, 133.6,
130.5, 129.4, 128.2, 126.8, 126.6, 112.6, 103.7, 47.9, 29.6, 26.0, 25.9,
24.9, 22.6, 22.3, 21.8, 21.4. Rf¼0.17 (2:1 hex/EtOAc). IR (NaCl, CHCl3)
3068, 3022, 2930, 2853, 2827, 1644, 1568, 1521, 1429, 748, 687.
HRMS (ESI) [C24H28NO]þ calcd 346.21262, found 346.21702.
1H), 3.86 (s, 3H), 3.75 (s, 3H), 3.74 (s, 3H). 13C NMR
d 164.0, 160.7,
d
159.3,158.6,150.5,149.4,131.3,130.3,129.9,129.7,128.3,128.0,114.4,
114.3, 114.0, 113.3, 107.1, 55.3, 55.2, 55.1. Rf¼0.40 (EtOAc). IR (NaCl,
CHCl3) 3037, 2996, 2960, 2838, 1650, 1608, 1506, 1250, 1030, 825,
723. HRMS (ESI) [C26H24NO4]þ calcd 414.16606, found 414.17046.
4.4.15. 4,6-Bis(4-methoxyphenyl)-1-(4-(trifluoromethyl)phenyl)-2-
4.4.8. 1-Benzyl-4,6-dihexyl-2-pyridone (3ha)
pyridone (3ce)
1H NMR
d
7.28 (m, 2H), 7.21 (m, 1H), 7.10 (m, 2H), 6.38 (s, 1H),
1H NMR
d
7.62 (m, 2H), 7.55 (m, 2H), 7.25 (m, 2H), 7.01 (m, 4H),
6.84 (d, J¼1.9 Hz, 1H), 6.71 (m, 2H), 6.54 (d, J¼1.9 Hz, 1H), 3.86 (s,
3H), 3.75 (s, 3H). 13C NMR
163.8, 161.2, 159.9, 151.4, 148.8, 142.1,
5.91 (d, J¼1.7 Hz, 1H), 5.32 (s, 2H), 2.47 (t, J¼7.8 Hz, 2H), 2.41 (t,
J¼7.6 Hz, 2H), 1.58 (m, 2H), 1.51 (m, 2H), 1.27 (m, 12H), 0.88 (t,
d
J¼6.8 Hz, 3H), 0.86 (t, J¼6.9 Hz, 3H). 13C NMR
d
164.0, 155.0, 149.3,
130.5,130.2,129.9,129.6,128.4,127.8,126.1,126.0,114.7,114.6,113.8,
108.0, 55.6, 55.4. Rf¼0.19 (2:1 hex/EtOAc). IR (NaCl, CHCl3) 3063,
3001, 2955, 2832, 1660, 1598, 1501, 1250, 1117, 825, 723. HRMS (ESI)
[C26H21F3NO3]þ calcd 452.14288, found 452.14608.
136.9, 128.6, 127.1, 126.2, 115.4,107.8, 46.2, 35.3, 32.8, 31.5, 31.4, 29.1,
28.8, 28.5, 22.5, 22.4, 14.0, 13.9. Rf¼0.22 (4:1 hex/EtOAc). IR (NaCl,
CHCl3) 3063, 3027, 2960, 2930, 2853, 1665, 1588, 1547, 1450, 728.
HRMS (ESI) [C24H36NO]þ calcd 354.27522, found 354.27904.
4.4.16. 1-Hexyl-4,6-bis(4-methoxyphenyl)-2-pyridone (3cf)
4.4.9. 1,4,6-Tribenzyl-2-pyridone (3ia)
1H NMR
d 7.53 (m, 2H), 7.29 (m, 2H), 6.95 (m, 4H), 6.74 (d,
1H NMR
d
7.35–7.20 (m, 11H), 7.11 (m, 2H), 7.04 (m, 2H), 6.42 (s,
J¼2.0 Hz, 1H), 6.29 (d, J¼2.0 Hz, 1H), 3.88 (t, J¼7.9 Hz, 2H), 3.86 (s,
1H), 5.87 (d, J¼1.8 Hz, 1H), 5.18 (s, 2H), 3.78 (s, 2H), 3.77 (s, 2H). 13C
3H), 3.82 (s, 3H), 1.56 (m, 2H), 1.14 (m, 6H), 0.79 (t, J¼7.0 Hz, 3H). 13C
NMR
d
164.1, 153.0, 147.1, 137.9, 136.7, 136.2, 129.1, 129.0, 128.8,
NMR d 163.5, 160.6, 160.0, 149.5, 149.2, 129.9, 129.7, 128.1, 127.9,
128.7, 128.1, 127.2, 127.1, 126.7, 126.1, 117.1, 110.1, 46.2, 41.3, 39.2.
Rf¼0.12 (95:5 CH2Cl2/EtOAc). IR (NaCl, CHCl3) 3058, 3022, 2996,
1660, 1588, 1542, 1486, 723, 692. HRMS (ESI) [C26H24NO]þ calcd
366.18132, found 366.18559.
114.2, 113.8, 107.4, 55.3, 55.2, 45.4, 31.0, 28.6, 26.3, 22.3, 13.9.
Rf¼0.12 (2:1 hex/EtOAc). IR (NaCl, CHCl3) 3037, 3001, 2955, 2925,
2853, 2827, 1660, 1614, 1592, 1511, 1301, 1245, 1178, 1030, 825, 723.
HRMS (ESI) [C25H30NO3]þ calcd 392.21810, found 392.22287.
4.4.10. 1-Benzyl-4,6-diethoxy-2-pyridone (3ja)
4.4.17. 1-Cyclohexyl-4,6-bis(4-methoxyphenyl)-2-pyridone (3cg)
1H NMR
d
7.26 (m, 5H), 5.69 (d, J¼2.0 Hz,1H), 5.21 (br s, 3H), 3.97
1H NMR
d 7.52 (m, 2H), 7.27 (m, 2H), 6.97 (m, 2H), 6.93 (m, 2H),
(m, 4H), 1.36 (m, 6H). 13C NMR
d
168.3, 163.6, 156.8, 137.5, 128.2,
6.65 (d, J¼2.2 Hz, 1H), 6.23 (d, J¼2.2 Hz, 1H), 3.87 (s, 3H), 3.82 (s,
128.0, 127.1, 89.9, 79.6, 65.3, 63.9, 43.8, 14.3, 14.0. Rf¼0.24 (1:1 hex/
EtOAc). IR (NaCl, CHCl3) 3063, 3032, 2976, 2935, 2894, 1660, 1593,
1547, 1255, 1189, 1112, 738. HRMS (ESI) [C16H20NO3]þ calcd
274.13985, found 274.14439.
3H), 3.80 (m, 1H), 2.79 (m, 2H), 1.74 (m, 2H), 1.61 (m, 2H), 1.50 (m,
1H), 1.22 (m, 1H), 0.96 (m, 2H). 13C NMR
d 164.4, 160.5, 159.9, 149.8,
148.8, 129.6, 129.4, 129.2, 127.9, 116.1, 114.2, 113.8, 107.6, 61.8, 55.3,
28.6, 26.1, 24.9. Rf¼0.22 (2:1 hex/EtOAc). IR (NaCl, CHCl3) 3042,
2996, 2925, 2848, 1650, 1603, 1511, 1245, 1168, 1025, 820, 743.
HRMS (ESI) [C25H28NO3]þ calcd 390.20245, found 390.20656.
4.4.11. Dimethyl 1-benzyl-2-oxo-4,6-diphenyl-1,2-dihydropyridine-
3,5-dicarboxylate (3ka)
1H NMR
d
7.44–7.31 (m, 8H), 7.21 (m, 3H), 7.11 (m, 2H), 6.90 (m,
4.4.18. 4,6-Bis(4-methoxyphenyl)-2-pyridone (6)
2H), 5.15 (s, 2H), 3.64 (s, 3H), 3.05 (s, 3H). 13C NMR
d
166.1, 165.9,
1HNMR
d
7.69(m, 2H), 7.60(m, 2H), 7.01(m, 4H), 6.66(m, 2H), 3.88
159.3, 149.4, 148.4, 136.0, 135.5, 132.0, 129.8, 128.8, 128.8, 128.3,
128.2, 128.1, 127.4, 127.3, 127.2, 124.3, 116.0, 52.3, 51.8, 49.3. Rf¼0.38
(2:1 hex/EtOAc). IR (NaCl, CHCl3) 3063, 3032, 2950, 1736, 1644,
1532, 1486, 1429, 1250, 1214, 1132, 764, 697. HRMS (ESI)
[C28H24NO5]þ calcd 454.16098, found 454.16491.
(s, 3H), 3.87 (s, 3H). 13C NMR
d
165.1, 161.1, 160.8, 153.2, 146.1, 130.4,
128.2, 127.9, 126.2, 114.6,114.4,103.6, 55.5, 55.4. Rf¼0.51 (10:1 EtOAc/
MeOH). IR(NaCl,CHCl3)3078, 2955, 2904,1639,1603,1234,1024,809.
HRMS (ESI) [C19H18NO3]þ calcd 308.12420, found 308.12806.
4.5. Characterization of enynamides
4.4.12. 1-(4-Methoxybenzyl)-4,6-(4-methoxyphenyl)-2-
pyridone (3cb)
4.5.1. (Z)-N-Benzyl-3,5-diphenylpent-2-en-4-ynamide (4aa)
1H NMR
d
7.57 (m, 2H), 7.11 (m, 2H), 6.96 (m, 2H), 6.88 (m, 4H),
6.83 (d, J¼2.1 Hz, 1H), 6.74 (m, 2H), 6.34 (d, J¼2.1 Hz, 1H), 5.14 (s,
2H), 3.84 (s, 6H), 3.75 (s, 3H). 13C NMR
163.7, 160.6, 160.0, 158.4,
1H NMR
d 7.73 (m, 2H), 7.64 (s, 1H), 7.44–7.24 (m, 11H), 7.13 (m,
2H), 6.69 (s,1H), 4.64 (d, J¼5.3 Hz, 2H). 13C NMR
d 165.0,137.8,137.0,
d
131.6, 129.5, 129.0, 128.8, 128.7, 128.5, 128.3, 128.1, 127.6, 126.9,
121.2, 101.6, 85.8, 44.1. Rf¼0.31 (95:5 CH2Cl2/EtOAc). IR (NaCl,
CHCl3) 3247, 3058, 3022, 2914, 1639, 1526, 1230, 989. HRMS (ESI)
[C24H20NO]þ calcd 338.15002, found 338.15405.
149.8, 149.5, 130.0, 129.5, 128.3, 127.9, 127.8, 114.2, 113.5, 107.6, 55.2,
55.0, 47.7. Rf¼0.18 (1:1 hex/EtOAc). IR (NaCl, CHCl3) 3063, 3001,
2955, 2832, 1650, 1608, 1506, 1245, 1030, 820, 748. HRMS (ESI)
[C27H26NO4]þ calcd 428.18171, found 428.18407.
4.5.2. (Z)-N,3-Dibenzyl-6-phenylhex-2-en-4-ynamide (4ia)
4.4.13. 4,6-Bis(4-methoxyphenyl)-1-phenyl-2-pyridone (3cc)
1H NMR
d 7.40 (s,1H), 7.37–7.14 (m,13H), 7.05 (m, 2H), 6.09 (s,1H),
1H NMR
d
7.62 (m, 2H), 7.26 (m, 3H), 7.11 (m, 2H), 7.05 (m, 2H),
6.99 (m, 2H), 6.85 (d, J¼2.0 Hz, 1H), 6.69 (m, 2H), 6.50 (d, J¼2.0 Hz,
1H), 3.86 (s, 3H), 3.73 (s, 3H). 13C NMR
163.8, 160.8, 159.4, 150.7,
4.42 (d, J¼5.5 Hz, 2H), 3.57 (s, 2H), 3.53 (s, 2H). 13C NMR
d 164.8,
138.0,137.0,135.2,130.4,129.6,129.2,128.7,128.6,128.5,127.8,127.4,
126.9, 100.5, 80.3, 44.9, 43.6, 25.7. Rf¼0.28 (95:5 CH2Cl2/EtOAc). IR
(NaCl, CHCl3) 3283, 3058, 3022, 2996, 2914, 1644, 1485, 1450, 697.
HRMS (ESI) [C26H24NO]þ calcd 366.18132, found 366.18552.
d
149.1, 138.7, 130.3, 129.7, 129.0, 128.7, 128.2, 128.1, 127.8, 114.6, 114.4,
113.3, 107.2, 55.4, 55.1. Rf¼0.68 (2:1 hex/EtOAc). IR (NaCl, CHCl3)
3063, 3037, 2960, 2935, 2838, 1655, 1603, 1506, 1250, 1025, 820,
728. HRMS (ESI) [C25H22NO3]þ calcd 384.15550, found 384.16035.
4.6. Characterization of 4-pyridones
4.4.14. 1,4,6-Tris(4-methoxyphenyl)-2-pyridone (3cd)
4.6.1. 1-Benzyl-2,6-bis(4-methoxyphenyl)-4-pyridone (5ca)
1H NMR
d
7.62 (m, 2H), 7.07 (m, 2H), 7.02 (m, 2H), 6.98 (m, 2H),
1H NMR
d
7.17 (m, 4H), 7.11 (m, 3H), 6.85 (m, 4H), 6.49 (m, 2H), 6.41
6.84 (d, J¼2.0 Hz, 1H), 6.79 (m, 2H), 6.71 (m, 2H), 6.48 (d, J¼2.0 Hz,
(s, 2H), 4.93 (s, 2H), 3.81 (s, 6H). 13C NMR
d
179.0, 160.3, 153.7, 137.0,

K.M. Oberg et al. / Tetrahedron 65 (2009) 5056–5061
5061
130.0, 128.4, 127.5, 125.7, 120.6, 113.9, 55.3, 53.8. Rf¼0.12 (10:1 EtOAc/
MeOH). IR (NaCl, CHCl3) 3068, 3001, 2925, 2838,1619,1496,1250,1173,
1020, 830. HRMS (ESI) [C26H24NO3]þ calcd 398.17115, found 398.17478.
P. Sloan Foundation and thanks the Monfort Family Foundation for
a Monfort Professorship. We thank Professor Abarbri (Tours) for
sharing spectral data for 4aa.
4.6.2. 1-(4-Methoxybenzyl)-2,6-bis(4-methoxyphenyl)-4-
References and notes
pyridone (5cb)
1H NMR
d
7.18 (m, 4H), 6.86 (m, 4H), 6.62 (m, 2H), 6.41 (s, 2H),
1. (a) Mitscher, L. A. Chem. Rev. 2005, 105, 559–592; (b) Torres, M.; Gil, S.; Parra, M.
Curr. Org. Chem. 2005, 9, 1757–1779.
2. (a) Varela, J. A.; Saa´, C. Chem. Rev. 2003, 103, 3787–3801; (b) Heller, B.; Hapke,
M. Chem. Soc. Rev. 2007, 36, 1085–1094.
3. (a) Hong, P.; Yamazaki, H. Synthesis 1977, 1, 50–52; (b) Hong, P.; Yamazaki, H.
Tetrahedron Lett. 1977, 15, 1333–1336.
4. (a) Hoberg, H.; Oster, B. W. Synthesis 1982, 324–325; (b) Hoberg, H.; Oster, B. W.
J. Organomet. Chem. 1982, 234, C35–C38; (c) Hoberg, H.; Oster, B. W. J. Orga-
nomet. Chem. 1983, 252, 359–364.
6.38 (m, 2H), 4.87 (s, 2H), 3.81 (s, 6H), 3.72 (s, 3H). 13C NMR
d
178.9,
160.3, 158.8, 153.8, 130.0, 128.8, 127.5, 127.0, 120.5, 113.9, 113.8, 55.3,
55.2, 53.4. Rf¼0.33 (10:1 EtOAc/MeOH). IR (NaCl, CHCl3) 3006, 2925,
2832, 1619, 1496, 1245, 1173, 1020, 835. HRMS (ESI) [C27H26NO4]þ
calcd 428.18171, found 428.18501.
4.6.3. 2,6-Bis(4-methoxyphenyl)-1-phenyl-4-pyridone (5cc)
5. (a) Earl, R. A.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1983, 105, 6991–6993; (b) Earl,
R. A.; Vollhardt, K. P. C. J. Org. Chem. 1984, 49, 4786–4800.
6. Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901–2915.
7. Flynn, S. T.; Hasso-Henderson, S. E.; Parkins, A. W. J. Mol. Catal. 1985, 32,
101–105.
8. (a) Albano, P.; Aresta, M. J. Organomet. Chem. 1980, 190, 243–246; (b) Scha¨fer, H.;
Marcy, R.; Ru¨ping, T.; Singer, H. J. Organomet. Chem. 1982, 240, 17–25; (c)
Ohshita, J.; Furumori, K.; Matsuguchi, A.; Ishikawa, M. J. Org. Chem. 1990, 55,
3277–3280.
1H NMR
d
7.03 (m, 3H), 6.98 (m, 4H), 6.80 (m, 2H), 6.66 (m, 4H),
6.49 (s, 2H), 3.72 (s, 6H). 13C NMR
d
179.0, 159.4, 152.4, 139.9, 130.5,
129.8, 128.4, 127.9, 127.7, 119.6, 113.3, 55.1. Rf¼0.14 (10:1 EtOAc/
MeOH). IR (NaCl, CHCl3) 3058, 3001, 2925, 2832, 1629, 1501, 1296,
1250, 1173, 1025, 830, 728. HRMS (ESI) [C25H22NO3]þ calcd
384.15550, found 384.16090.
9. (a) Yamamoto, Y.; Takagishi, H.; Itoh, K. Org. Lett. 2001, 3, 2117–2119; (b)
Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.; Okuda, S.; Nishiyama, H.;
Itoh, K. J. Am. Chem. Soc. 2005, 127, 605–613.
10. (a) Duong, H. A.; Cross, M. J.; Louie, J. J. Am. Chem. Soc. 2004, 126, 11438–11439;
(b) Duong, H. A.; Louie, J. J. Organomet. Chem. 2005, 690, 5098–5104; (c) Duong,
H. A.; Louie, J. Tetrahedron 2006, 62, 7552–7559.
11. Kondo, T.; Nomura, M.; Ura, Y.; Wada, K.; Mitsudo, T. Tetrahedron Lett. 2006, 47,
7107–7111.
12. Takahashi, T.; Tsai, F.; Li, Y.; Wang, H.; Kondo, Y.; Yamanaka, M.; Nakajima, K.;
Kotora, M. J. Am. Chem. Soc. 2002, 124, 5059–5067.
13. (a) Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett. 2005, 7, 4737–4739; (b) Tanaka, K.
Synlett 2007, 1977–1993; (c) Tanaka, K.; Takahashi, Y.; Suda, T.; Hirano, M.
Synlett 2008, 1724–1728.
14. Diversi, P.; Ingrosso, G.; Lucherini, A.; Malquori, S. J. Mol. Catal. 1987, 40,
267–280.
15. (a) Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2782–2783; (b) Yu, R. T.; Rovis,
T. J. Am. Chem. Soc. 2006, 128, 12370–12371; (c) Lee, E. E.; Rovis, T. Org. Lett.
2008, 10, 1231–1234; (d) Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2008, 130,
3262–3263.
16. Cherry, K.; Thibonnet, J.; Ducheˆne, A.; Parrain, J.; Abarbri, M. Tetrahedron Lett.
2004, 45, 2063–2066.
4.6.4. 1,2,6-Tris(4-methoxyphenyl)-4-pyridone (5cd)
1H NMR
d
6.98 (m, 4H), 6.68 (m, 6H), 6.51 (m, 2H), 6.48 (s, 2H),
3.74 (s, 6H), 3.65 (s, 3H). 13C NMR
d
178.9, 169.7, 159.4, 158.5, 152.7,
132.7, 130.6, 130.5, 127.9, 119.5, 113.4, 113.3, 55.2, 55.2. Rf¼0.11 (10:1
EtOAc/MeOH). IR (NaCl, CHCl3) 3053, 3001, 2930, 2832, 1624, 1501,
1557, 1434, 1255, 1030, 825, 733. HRMS (ESI) [C26H24NO4]þ calcd
414.16606, found 414.17067.
4.6.5. 2,6-Bis(4-methoxyphenyl)-1-(4-(trifluoromethyl)phenyl)-4-
pyridone (5ce)
1H NMR
d
7.30 (m, 2H), 6.94 (m, 6H), 6.67 (m, 4H), 6.52 (s, 2H),
3.72 (s, 6H). 13C NMR
d
179.1, 160.0, 152.3, 143.2, 130.7, 130.5, 127.2,
125.8,125.7,120.0,113.8, 55.4. Rf¼0.28 (10:1 EtOAc/MeOH). IR (NaCl,
CHCl3) 3058, 3001, 2935, 2832,1629,1501,1245,1178,1020, 835, 723.
HRMS (ESI) [C26H21F3NO3]þ calcd 452.14288, found 452.14620.
17. Regioisomers were determined unambiguously by comparison to reported
NMR data. 2-Pyridones: (a) Overman, L. E.; Tsuboi, S.; Roos, J. P.; Taylor, G. F.
J. Am. Chem. Soc. 1980, 102, 747–754; (b) Kaneko, C.; Uchiyama, K.; Sato, M.;
Katagiri, N. Chem. Pharm. Bull. 1986, 34, 3658–3671; (c) Yamamoto, K.; Yama-
zaki, S.; Murata, I.; Fukazawa, Y. J. Org. Chem. 1987, 52, 5239–5243; (d) Rozen, S.;
Hebel, D. Heterocycles 1989, 28, 249–258; (e) Brun, E. M.; Gil, S.; Mestres, R.;
Parra, M. Synthesis 2000, 2, 273–280; (f) Carles, L.; Narkunan, K.; Penlou, S.;
Rousset, L.; Bouchu, D.; Ciufolini, M. A. J. Org. Chem. 2002, 67, 4304–4308; (g)
Sutherland, A.; Gallagher, T. J. Org. Chem. 2003, 68, 3352–3355; 4-Pyridones: (h)
Beak, P.; Bonham, J. J. Am. Chem. Soc. 1965, 87, 3365–3371; (i) Lim, S. H.; Curtis,
M. D.; Beak, P. Org. Lett. 2001, 3, 711–714; (j) Blouin, M.; Frenette, R. J. Org. Chem.
2001, 66, 9043–9045.
4.6.6. 1-Hexyl-2,6-bis(4-methoxyphenyl)-4-pyridone (5cf)
1H NMR
d 7.33 (m, 4H), 6.98 (m, 4H), 6.34 (s, 2H), 3.86 (s, 6H),
3.70 (t, J¼7.8 Hz, 2H), 1.13 (m, 2H), 0.98 (m, 2H), 0.77 (m, 4H), 0.68
(t, J¼7.3 Hz, 3H). 13C NMR
d 178.7, 160.3, 153.0, 130.0, 127.8, 120.5,
114.0, 55.4, 50.2, 30.6, 29.8, 25.5, 22.0, 13.7. Rf¼0.16 (10:1 EtOAc/
MeOH). IR (NaCl, CHCl3) 3001, 2955, 2935, 2853, 1619, 1552, 1501,
1250, 1178, 1035, 830. HRMS (ESI) [C25H30NO3]þ calcd 392.21810,
found 392.22238.
18. 1H NMR’s of unpurified terminal aryl alkyne reactions show only starting
material and product.
4.6.7. 1-Cyclohexyl-2,6-bis(4-methoxyphenyl)-4-pyridone (5cg)
19. The failure of diynes to participate in this chemistry under these conditions
1H NMR
d
7.33 (m, 4H), 6.95 (m, 4H), 6.27 (s, 2H), 3.87 (s, 6H),
3.85 (m, 1H), 1.67 (m, 2H), 1.50 (m, 2H), 1.29 (m, 3H), 0.74 (m, 2H),
0.58 (m, 1H). 13C NMR
178.4, 160.2, 154.2, 130.4, 129.1, 121.6, 113.6,
also argues against the intermediacy of
C with the caveat that oxidative
cyclization of the diyne in preference to alkyne/isocyanate may occur. The
observation that arene dimer is formed from dipropargyl ether under these
conditions supports this latter argument.
d
66.1, 55.3, 33.9, 26.6, 24.8. Rf¼0.09 (10:1 EtOAc/MeOH). IR (NaCl,
CHCl3) 3001, 2930, 2858, 1624, 1501, 1245, 1025, 830, 733. HRMS
(ESI) [C25H28NO3]þ calcd 390.20245, found 390.20633.
20. Furuta, T.; Kitamura, Y.; Hashimoto, A.; Fujii, S.; Tanaka, K.; Kan, T. Org. Lett.
2007, 9, 183–186.
21. (a) Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4623–4633; (b) Nagata, T.; Koide,
Y.; Nara, K.; Itoh, E.; Arisawa, M.; Naruto, S.; Torisawa, Y.; Hino, T.; Nakagawa, M.
Chem. Pharm. Bull. 1996, 44, 451–453; (c) Nishihara, Y.; Ikegashira, K.; Hir-
abayashi, K.; Ando, J.; Mori, A.; Hiyama, T. J. Org. Chem. 2000, 65, 1780–1787; (d)
Mello, J. V.; Finney, N. S. Org. Lett. 2001, 3, 4263–4265; (e) Shin, C.; Saito, H.;
Yonezawa, Y. Heterocycles 2003, 61, 45–50.
Acknowledgements
We thank NIGMS (GM080442), Eli Lilly, Boehringer Ingelheim,
and Johnson & Johnson for support. T.R. is a fellow of the Alfred
22. Giacomina, F.; Meetsma, A.; Panella, L.; Lefort, L.; de Vries, A. H. M.; de Vries,
J. G. Angew. Chem., Int. Ed. 2007, 46, 1497–1500.