Hydrogen bond-assisted 6π-azaelectrocyclization of penta-2,4-dienamides: Synthesis of dihydropyridin-2(3 H)-ones

Article abstract of DOI:10.1021/jo4001959

A facile and efficient synthesis of substituted dihydropyridin-2(3H)-ones is developed from penta-2,4-dienamides, in which an intramolecular C-N bond was formed through thermal 6π-azaelectrocyclization. The intramolecular hydrogen bonding-assisted cyclization reaction opens access to a variety of dihydropyridin-2(3H)-ones.

Full text of DOI:10.1021/jo4001959

Article
pubs.acs.org/joc
Hydrogen Bond-Assisted 6π-Azaelectrocyclization of
Penta-2,4-dienamides: Synthesis of Dihydropyridin-2(3H)‑ones
Xu Liu,† Ning Zhang,*,† Jiming Yang,† Yongjiu Liang,† Rui Zhang,†,‡ and Dewen Dong*,†,‡
†Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
‡Changzhou Institute of Energy Storage Materials & Devices, Changzhou, 213000, China
S
* Supporting Information
ABSTRACT: A facile and efficient synthesis of substituted
dihydropyridin-2(3H)-ones is developed from penta-2,4-
dienamides, in which an intramolecular C−N bond was
formed through thermal 6π-azaelectrocyclization. The intra-
molecular hydrogen bonding-assisted cyclization reaction
opens access to a variety of dihydropyridin-2(3H)-ones.
however, would impair the substituent versatility in the
dihydropyridin-2(3H)-one ring.
INTRODUCTION
■
Pyridin-2(1H)-ones and their analogues, a prominent class of
nitrogen heterocyclic compounds, have provoked great interest
in chemical and biological fields.1−9 These structural motifs can
serve as efficient catalysts in a variety of proton-dependent reac-
tions2 and valuable ligands in coordination chemistry.3 Further-
more, pyridin-2(1H)-ones are versatile intermediates in the
synthesis of a wide range of aza-heterocycles such as indoli-
zidine,4 quinolizidine,4 quinoline5 and isoquinoline derivatives.6 On
the other hand, pyridin-2(1H)-one is key unit in a variety of
naturally occurring alkaloids,7 biologically active molecules,8 and
pharmacologically active compounds, such as cerpegin9 and
camptothecin.10 To date, a variety of synthetic approaches have
been well established to access pyridin-2(1H)-ones and their
analogues, which comprise the modification of the preconstruc-
ted heterocyclic ring by pyridinium salt chemistry11 and
N-alkylation,12 and the construction of heterocyclic skeletons
from appropriately substituted open-chain precursors via metal-
catalyzed sp2 C−H bond amination,13 ring closing metathesis,14
and Diels−Alder reaction.15 In spite of the successful pioneering
work, the aforementioned reactions may suffer from either tedious
synthetic procedures or utilization of toxic or expensive metal
catalyst in the synthesis. Thus, the development of efficient and
convenient synthetic approaches for such nitrogen-containing
heterocycles is demanded.16
Recently, we achieved the synthesis of quinolin-2(1H)-ones
and 2,5-dihydrofurans from penta-2,4-dienamides mediated by
concentrated H2SO4 and hypervalent iodine reagent, respec-
tively.24 It should be noted that these penta-2,4-dienamides
exhibit a promising structual feature as a potential oxatriene or
azatriene, which, subjected to suitable electrocyclization
conditions, might lead to the construction of the skeleton of
hetercycles. In light of this, we examined their reaction behavior
under varied conditions and, to the end, developed an efficient,
diastereoselective synthesis of dihydropyridin-2(3H)-ones via
6π-electrocyclization of such penta-2,4-dienamides. Herein, we
wish to report our experimental results and the reaction
mechanism involved.
RESULTS AND DISCUSSION
■
The substrates, penta-2,4-dienamides 1, were prepared by
Knoevenagel condensation of commercially available β-oxo
amides with cinnamaldehydes in the presence of piperidine in
high yields according to the procedure described in literature.24,25
Then, 2-acetyl-5-phenyl-N-(p-tolyl)penta-2,4-dienamide 1a was
selected as a model compound for the investigation. The reaction
of 1a was attempted in toluene under reflux. As indicated by TLC,
the reaction occurred and furnished a product along with some
starting material remaining intact after workup and purification by
column chromatography of the resulting mixture. The product was
characterized as 3-(1-hydroxy ethylidene)-6-phenyl-1-(p-tolyl)-1,6-
dihydro-pyridin-2(3H)-one 2a (Table 1, entry 1a). It was noted
that the reaction conversion was still low even with prolonged
reaction time (Table 1, entry 1b).
6π-Electrocyclization,17 one of the well-known concerted pericyclic
reactions,18 represents an elegant annulation approach for the
synthesis of heterocycles and has gained great interest in the
synthesis of pyridines,19 chromene,20 nicotinamide21 and
pyridinium bisretinoid.22 Recently, Katsumura and co-workers
reported the synthesis of dihydropyridin-2(3H)-ones via a Pd-
catalyzed 6-endo type cyclization of N-sulfonyldienamide.23 Soon
after, they revealed that analogous reactions could successfully
proceed in the absence of transition metal catalysts following a
thermal 6π-azaelectrocyclization mechanism. The presence of N-p-
tosyl and ester groups in the N-sulfonyl-dienamide precursors was
proved essential to ensure and accelerate the cyclic reaction, which,
To optimize the reaction conditions, the thermal cyclic reaction
of 1a was conducted in other solvents. When 1a was subjected
into xylene at 130 °C, the reaction proceeded smoothly to afford
Received: January 31, 2013
© XXXX American Chemical Society
A
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a
reactions of 1b−f bearing varied electron-donating and
electron-withdrawing aryl groups or alkyl group R1 proceeded
smoothly in xylene at 130 °C to afford the corresponding
substituted dihydropyridin-2(1H)-ones 2b−f in high yields
(Table 2, entries 1b−1f). The versatility of this cyclization was
further evaluated by performing the reaction of penta-2,4-
dienamides 1g−p containing a variety of aryl amide or alkyl
amide groups R2 (Table 2, entries 1g−1p). The dihydropyridin-
2(3H)-one synthesis was also proved to be suitable for penta-
2,4-dienamides 1q and 1r with different acyl groups, i.e., COR3
(Table 2, entries 1q and 1r). The dihydropyridin-2(3H)-ones 2
were characterized by means of NMR (1H, 13C) spectra and
elemental analysis. The structure of 2i was further confirmed by
the X-ray single crystal analysis.
It was reported that enantioselective synthesis of dihydropyr-
idin-2(3H)-ones could be realized via a Pd-catalyzed 6-
endocyclization of dienamides induced by chiral ligands.22 In
the present work, we achieved diastereoselective synthesis of
dihydropyridin-2(3H)-ones 2g, 2i, 2k and 2m without any
catalyst or chiral ligands. The configuration of these compounds
was identified by means of NMR spectral and single crystal
analysis (Table 2, entries 1g, 1i, 1k and 1m). The slightly inferior
diastereoselectivity as observed in 2g, 2i, 2k and 2m is very likely
attributed to the steric hindrance of R2 and/or the electronic effect
of the 2-substitution in the phenyl ring.27
Table 1. Reactions of 1a under Different Conditions
b
yield (%)
entry
solvent
toluene
temp (°C)
time (h)
2a 3a
c
1a
1b
1c
1d
1e
1f
reflux
reflux
130
6.0
36
65
91
83
78
0
toluene
12.0
12.0
12.0
12.0
12.0
0
xylene
5
mesitylene
phenyl ether
DMF
140
10
12
130
130
complex mixture
a
b
Reaction conditions: 1a (2.0 mmol), solvent (10.0 mL). Isolated
c
yield. 53% of 1a was recovered.
2a in 91% yield. Meanwhile, 3-acetyl-6-phenyl-1-(p-tolyl)pyridin-
2(1H)-one 3a was isolated as a byproduct, which was most likely
derived from the oxidation of 2a by air (Table 1, entry 1c). The
employment of mesitylene at increased reaction temperature resulted
in much more oxidized product 3a (Table 1, entry 1d). The reaction
of 1a performed in diphenyl ether furnished 2a in 78% yield (Table
1, entry 1e), whereas in DMF it formed a complex mixture (Table 1,
entry 1f). The findings indicated that polar solvents might not be
suitable as reaction media for the eletrocyclizations, which was
consistent with the results reported by Katsumura.26
Under the optimal conditions as for 2a in entry 1c, Table 1, a
range of reactions of substrates 1 were carried out to determine
the scope of the dihydropyridin-2(3H)-one synthesis, and some
of the results are summarized in Table 2. It was found that the
Over the past decades, extensive experimental and theoretical
work had demonstrated that the substituents in the triene
precursors had a distinct effect on facilitating the electro-
cyclization.28,29 This “substituent-driven activation” was clarified
by Katsumura and co-workers on rapid 6π-azaelectrocyclization of
dienamides to substituted pyridines and chiral piperidines
(Scheme 1). The cyclization was realized by the remarkable
Table 2. Synthesis of Substituted Dihydropyridin-2(3H)-
ones 2
Scheme 1. Katsumura’s Work and a Plausible Mechanism for
the 6π-Azaelectrocyclization of Penta-2,4-dienamides 1
a
b
entry
R1
R2
R3
2
yield (%)
1a
1b
1c
1d
1e
1f
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Pr
2a
2b
2c
2d
2e
2f
91
82
87
89
84
86
4-MeOC6H4
2-MeOC6H4
4-MeC6H4
4-ClC6H4
Me
c
1g
1h
1i
4-MeOC6H4
2-MeC6H4
4-ClC6H4
2-ClC6H4
4-MeOC6H4
2-MeC6H4
4-ClC6H4
2-ClC6H4
4-MeOC6H4
Ph
2g
2h
2i
86 (61:39)
4-MeOC6H4
87
c
c
c
4-MeOC6H4
94 (86:14)
1j
4-MeOC6H4
2j
85
1k
1l
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2k
2l
85 (65:35)
82
1m
1n
1o
1p
1q
1r
2m
2n
2o
2p
2q
2r
87 (86:14)
90
91
79
88
83
Bn
substituent effect due to the enhancement of the HOMO−
LUMO interaction in the 6π-electron system, which mainly
derived from the C-4 ester substituent and the additional electron-
withdrawing group at the nitrogen.23,26 In contrast, our present
cyclic reaction of penta-2,4-dienamides, carrying an electron-
withdrawing acyl group at C-3 position and an aryl or alkyl group
Ph
4-MeC6H4
Ph
a
Reagents and conditions: 1 (5.0 mmol), xylene (20 mL), reflux,
b
c
10.0−16.5 h. Isolated yield. The data in parentheses are
diastereomeric ratios (dr) determined by H NMR.
1
B
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Article
Synthesis. Typical Procedure for the Synthesis of Substituted
Penta-2,4-dienamides 1 (1b as an example). To a 100 mL round-
bottomed flask was added 3-oxo-N-(p-tolyl)butanamide (0.955 g,
5.0 mmol), 3-(4-methoxyphenyl)acrylaldehyde (0.811 g, 5.0 mmol),
piperidine (0.1 mmol) and ethanol (30 mL). Then the mixture was
heated under reflux for 3.5 h and cooled to room temperature. The
resulting mixture was slowly poured into saturated aqueous NaCl (100 mL)
and extracted with dichloromethane (3 × 30 mL). The combined
organic phase was washed with water (3 × 30 mL) and dried over
anhydrous Na2SO4. The solvent was removed under reduced pressure,
and the crude product was purified by flash chromatography (silica gel,
petroleum ether: ethyl acetate10:1) to give 92% yield of 1b: 1.543 g,
at the nitrogen, proceeded smoothly without any catalyst. The
results imply that the activation to the electrocyclization of
1-azatrienes might not merely originate from the electronic effect
of the substituents or their position. For further investigation, we
synthesized 2-(1- hydroxyethyl)-N,5-diphenylpenta-2,4-dienamide
1s and N,5-diphenylpenta-2,4-dienamide 1t bearing CH(OH)-
CH3 and H at C-3 position, respectively, and subjected them to
the identical conditions described above. However, no reaction
was observed in both cases, which suggested that the acyl group at
C-3 position might play a special role in the cyclization.
On the basis of the observations above and the work reported
in literature,30 we propose that the intramolecular hydrogen bond
within the imidic acid A,26,31 a tautomer of penta-2,4-dienamide 1,
is the main driving force for the cyclization as shown in Scheme 1.
The hydrogen bond can stabilize the structure of A and keep the
azadiene NCCC in a cis conformation, both favoring the
subsequent 6π-azaelectrocyclization to give the intermediate B.
Furthermore, the acyl group can form hydrogen bonds to stabilize
the product 2, which is generated from B through a 1,5-H
migration.32
It should be mentioned that pyridin-2(1H)-one 3a was
obtained during the screening of the optimal conditions. We
next intended to synthesize this kind of heterocycle under
oxidative conditions. Thus, dihydropyridin-2(3H)-ones 2a and
2i were selected and subjected to toluene in the presence of
SeO2 (1.2 equiv) at 80 °C for 1.5 h. The corresponding pyridin-
2(1H)-ones 3a and 3i were obtained in 86 and 91% yields,
respectively (Scheme 2). Obviously, this transformation can
broaden the choices for the synthesis of 2-pyridone analogues.
1
orange solid; mp 84−85 °C; H NMR (300 MHz, CDCl3) δ 2.33 (s,
3H), 2.52 (s, 3H), 3.85 (s, 3H), 6.89 (d, J = 9.0 Hz, 2H), 7.06−7.16
(m, 3H), 7.53 (d, J = 1.5 Hz, 2H), 7.56 (d, J = 2.4 Hz, 2H), 7.60 (d,
J = 11.7 Hz, 1H), 8.19−8.28 (m, 1H), 10.25 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 20.7, 27.4, 55.2, 114.2, 120.3, 123.1, 128.4, 129.3, 130.0,
133.6, 135.4, 147.4, 151.8, 161.3, 162.8, 199.7. Anal. Calcd for C21H21NO3:
C, 75.20; H, 6.31; N, 4.18. Found: C, 75.49; H, 6.42; N, 4.03.
Substrates 1a, 1f, 1g, 1k, 1l, 1n, 1o, 1q, 1r and 1t are known
compounds. For the spectral and analytical data of 1a, 1g, 1k, 1l, 1n,
1o, 1q, 1r, and 1t, see ref 24a, and for 1f, see ref 33.
1
1c: 1.560 g, yield 93%, orange solid; mp 129−131 °C; H NMR
(300 MHz, CDCl3) δ 2.32 (s, 3H), 2.51 (s, 3H), 3.87 (s, 3H), 6.88 (d,
J = 8.1 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 7.14 (d, J = 8.1 Hz, 2H),
7.53−7.58 (m, 3H), 7.63 (d, J = 11.4 Hz, 1H), 7.71 (d, J = 7.5 Hz,
1H), 8.24−8.33 (dd, J1 = 15.6 Hz, J2 = 11.4 Hz, 1H), 10.14 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 20.8, 27.4, 55.4, 110.9, 120.3, 120.7,
124.5, 125.2, 127.9, 129.3, 130.0, 131.5, 133.6, 135.5, 142.0, 152.0,
157.8, 162.8, 199.8. Anal. Calcd for C21H21NO3: C, 75.20; H, 6.31; N,
4.18. Found: C, 75.63; H, 6.39; N, 4.31.
1d: 1.421 g, yield 89%, white solid; mp 136−137 °C; 1H NMR (300
MHz, CDCl3) δ 2.33 (s, 3H), 2.37 (s, 3H), 2.51(s, 3H), 7.10 (d, J =
15.0 Hz, 1H), 7.14−7.19 (m, 4H), 7.49 (d, J = 7.5 Hz, 2H), 7.54−7.60
(m, 3H), 8.21−8.30 (dd, J1 = 15.0 Hz, J2 = 11.4 Hz, 1H), 10.20 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 20.8, 21.4, 27.5, 120.4, 124.4,
128.3, 129.3, 129.5, 132.9, 133.8, 135.4, 140.7, 147.0, 147.5, 151.6,
162.7, 199.9; IR (KBr, cm−1): 3265, 1670, 1635, 1593, 1570, 1242,
802, 739. Anal. Calcd for C21H21NO2: C, 78.97; H, 6.63; N, 4.39.
Found: C, 79.22; H, 6.49; N, 4.56.
Scheme 2. Synthesis of Substituted Pyridin-2(1H)-ones 3
1
1e: 1.495 g, yield 88%, orange solid; mp 141−144 °C; H NMR
(300 MHz, CDCl3) δ 2.33 (s, 3H), 2.54 (s, 3H), 7.08 (d, J = 15.0 Hz,
1H), 7.16 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 3.3
Hz, 2H), 7.54 (d, J = 15.0 Hz, 1H), 8.27−8.36 (dd, J1 = 15.0 Hz, J2 =
10.4 Hz, 1H), 10.16 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.8,
27.5, 120.4, 125.8, 129.0, 129.3, 129.4, 131.2, 134.0, 134.1, 135.3,
135.9, 145.3, 150.4, 162.4, 199.9. Anal. Calcd for C20H18ClNO2: C,
70.69; H, 5.34; N, 4.12. Found: C, 70.51; H, 5.40; N, 3.97.
CONCLUSION
■
1
In summary, a facile and efficient synthesis of substituted
dihydropyridin-2(3H)-ones is developed from elaborately
designed penta-2,4-dienamides, through which an intramolec-
ular C−N bond was formed via an intramolecular hydrogen
bonding-assisted 6π-azaelectrocyclization. The simple execu-
tion, readily available substrates, good yields, high diaster-
eoselectivity and synthetic potential of the products make this
protocol highly desirable. Expanding the scope of the
methodology and further exploration of the mechanism are
currently under investigation in our laboratory.
1h: 1.619 g, 91%, orange solid; mp 129−131 °C; H NMR (300
MHz, CDCl3) δ 2.55 (s, 3H), 3.86 (s, 3H), 7.15 (d, J = 15.0 Hz, 1H),
7.31 (d, J = 9.0 Hz, 2H), 7.60 (t, J = 3.0 Hz, 3H), 7.64−7.69 (m, 2H),
8.28−8.37 (q, J = 12.0 Hz, 1H), 10.59 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 27.5, 55.3, 114.4, 121.6, 123.2, 128.1, 128.4, 128.8, 128.9,
130.2, 136.7, 148.4, 153.5, 161.6, 162.8. Anal. Calcd for C20H18ClNO3:
C, 67.51; H, 5.10; N, 3.94. Found: C, 67.27; H, 5.23; N, 3.72.
1
1i: 1.672 g, 94%, orange solid; mp 120−121 °C; H NMR (300
MHz, CDCl3) δ 2.57 (s, 3H), 3.86 (s, 3H), 6.92 (d, J = 8.7 Hz, 2H),
7.03−7.09 (m, 1H), 7.16 (d, J = 15.3 Hz, 1H), 7.31 (d, J = 7.5 Hz,
1H), 7.40−7.42 (m, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 11.4
Hz, 1H), 8.24−8.33 (q, J = 4.2 Hz, 1H), 8.53 (d, J = 8.1 Hz, 1H),
10.91 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 27.3, 55.2, 114.3,
122.1, 123.2, 123.7, 124.4, 127.2, 128.1, 128.3, 129.1, 130.1, 135.3,
148.4, 153.6, 161.5, 162.8, 199.9. Anal. Calcd for C20H18ClNO3: C,
67.51; H, 5.10; N, 3.94. Found: C, 67.32; H, 5.01; N, 3.77.
EXPERIMENTAL SECTION
■
Materials and Methods. All reagents were purchased from
commercial sources and used without further treatment, unless
otherwise indicated. The products were purified by column
chromatography over silica gel. 1H NMR and 13C NMR spectra
were recorded at 300 MHz and at 400 and 100 MHz, respectively,
with TMS as internal standard. IR spectra (KBr) were recorded in the
range of 400−4000 cm−1. Petroleum ether (PE) was the fraction
boiling in the range 60−90 °C. All melting points were determined in
open capillary tubes and are uncorrected.
1
1j: 1.599 g, 91%, orange solid; mp 114−115 °C; H NMR (300
MHz, CDCl3) δ 2.55(s, 3H), 3.81(s, 3H), 3.85(s, 3H), 6.89(t, J = 3.0
Hz, 2H), 6.91 (t, J = 3.0 Hz, 2H), 7.12 (d, J = 15.0 Hz, 1H), 7.58(d,
J = 9.0 Hz, 4H), 7.64(d, J = 12.0, 1H), 8.25−8.34(q, J = 12.0 Hz, 1H),
10.28 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 27.6, 55.4, 55.5, 114.1,
114.4, 122.2, 123.6, 128.6, 129.0, 130.2, 131.3, 147.7, 152.8, 156.4,
C
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161.5, 162.6, 200.4. Anal. Calcd for C21H21NO4: C, 71.78; H, 6.02; N,
3.99. Found: C, 71.44; H, 6.15; N, 4.17.
1m: 1.401 g, 86%, yellow solid; mp 114−116 °C; H NMR (300
(m, 3H), 6.99 (d, J = 8.4 Hz, 2H), 7.12−7.17 (m, 1H), 7.30 (d, J = 7.2
Hz, 1H),14.68 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 18.0, 21.0,
55.4, 60.5, 98.5, 110.9, 117.6, 120.5, 121.0, 127.5, 128.3, 129.0, 129.4,
136.9, 137.7, 156.1, 169.5, 169.7. Anal. Calcd for C21H21NO3: C,
75.20; H, 6.31; N, 4.18. Found: C, 75.39; H, 6.36; N, 4.27.
1
MHz, CDCl3) δ 2.58 (s, 3H), 7.07 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 15.6
Hz, 1H), 7.30 (q, J = 4.5 Hz, 2H), 7.41 (t, J = 3.6 Hz, 4H), 7.63 (t, J =
3.6 Hz, 2H), 7.68 (d, J = 11.1 Hz, 1H), 8.30−8.51 (dd, J1 = 15.6 Hz,
J2 = 11.1 Hz, 1H), 8.52 (d, J = 8.1 Hz, 1H), 10.73 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 27.2, 122.0, 124.4, 125.0, 125.5, 127.1, 128.1,
128.6, 128.9, 129.4, 130.0, 135.0, 135.2, 147.7, 152.2, 162.4, 199.8; IR
(KBr, cm−1): 3085, 1673, 1579, 1441, 1377, 977, 745. Anal. Calcd for
C19H16ClNO2: C, 70.05; H, 4.95; N, 4.30. Found: C, 70.29; H, 4.86;
N, 4.18.
2d: 1.421 g, yield 89%, white solid; mp 117−119 °C; 1H NMR (300
MHz, DMSO) δ 2.09 (s, 3H), 2.22 (s, 6H), 5.41 (q, J = 6.0 Hz, 1H),
5.56 (d, J = 3.0 Hz, 1H), 6.45 (d, J = 11.2 Hz, 1H), 6.92 (d, J = 8.4 Hz,
2H), 7.02 (d, J = 8.4 Hz, 2H), 7.04−7.08 (m, 3H), 14.82 (s, 1H); 13C
NMR (100 MHz, DMSO) δ 18.0, 21.0, 21.1, 67.4, 98.2, 118.2, 120.4,
127.4, 127.8, 129.3, 129.7, 137.2, 137.5, 137.8, 168.9, 170.2; IR (KBr,
cm−1): 3128, 1666, 1624, 1609, 1595, 1580, 816, 768, 702. Anal. Calcd for
C21H21NO2: C, 78.97; H, 6.63; N, 4.39. Found: C, 78.64; H, 6.72; N, 4.17.
2e: 1.427 g, yield 84%, white solid; mp 207−208 °C; 1H NMR (300
MHz, CDCl3) δ 2.31 (s, 3H), 2.71 (s, 6H), 6.36 (d, J = 7.5 Hz, 1H),
6.95 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.1 Hz,
2H), 7.19 (d, J = 8.1 Hz, 2H), 8.27 (d, J = 7.5 Hz, 1H); 13C NMR
(100 MHz, DMSO) δ 21.2, 31.1, 107.6, 126.5, 128.3, 128.4, 129.5,
129.8, 130.0, 133.3, 135.3, 138.7, 143.2, 154.0, 162.1, 197.6; IR (KBr,
cm−1): 3421, 3126, 1676, 1655, 1600, 1547, 1491, 810, 744. Anal.
Calcd for C20H18ClNO2: C, 70.69; H, 5.34; N, 4.12. Found: C, 71.02;
H, 5.27; N, 3.99.
1p: 1.298 g, 85%, white solid; mp 75−77 °C; 1H NMR (300 MHz,
CDCl3) δ 2.46 (s, 3H), 4.60 (d, J = 6.0 Hz, 2H), 7.08 (d, J = 16.0 Hz,
1H), 7.26−7.33 (m, 2H), 7.34−7.36 (m, 6H), 7.48−7.53 (m, 3H),
7.99−8.06 (dd, J1 = 20.0 Hz, J2 = 12.0 Hz, 1H), 8.11 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 27.4, 43.4, 125.2, 127.4, 127.7, 128.2,
128.7, 128.9, 130.1, 131.6, 135.7, 138.3, 146.3, 149.4, 164.9, 199.2; IR
(KBr, cm−1): 3481, 3292, 1663, 1634, 1607, 1580, 1539, 731, 692.
Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59. Found: C,
79.02; H, 6.41; N, 4.45.
Typical Procedure for the Synthesis of 1s. To a 100 mL round-
bottomed flask was added 2-acetyl-N,5-diphenylpenta-2,4-dienamide
1o (1.457 g, 5.0 mmol), NaBH4 (0.227 g, 6.0 mmol) and ethanol
(20 mL). Then the mixture was stirred at room temperature for 5 min.
The resulting mixture was slowly poured into saturated aqueous NaCl
(100 mL) and extracted with dichloromethane (3 × 30 mL). The
combined organic phase was washed with water (3 × 30 mL) and
dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure, and the crude product was purified by flash
chromatography (silica gel, petroleum ether: ethyl acetate 9:1) to give
2f: 0.986 g, yield 86%, white solid; mp 228−231 °C; 1H NMR (300
MHz, DMSO) δ 1.07 (d, J = 6.0 Hz, 3H), 2.04 (s, 3H), 4.62 (t, J = 5.1
Hz, 1H), 5.45−5.50 (dd, J1 = 4.2 Hz, J2 = 10.2 Hz, 1H), 6.38−6.42
(dd, J1 = 1.2 Hz, J2 = 10.2 Hz, 1H), 7.28−7.31 (m, 2H), 7.34−7.37 (m,
1H), 7.45 (t, J = 7.5 Hz, 2H), 14.68 (s, 1H); 13C NMR (100 MHz,
DMSO) δ 17.6, 22.2, 58.0, 98.1, 119.0, 120.5, 127.4, 128.0, 129.1,
139.8, 168.7, 169.3. Anal. Calcd for C14H15NO2: C, 73.34; H, 6.59; N,
6.11. Found: C, 73.69; H, 6.67; N, 6.25.
2g: 1.442 g, yield 86%, white solid; mp 127−130 °C; [dr = 61:39];
1H NMR (major isomer) (300 MHz, CDCl3) δ 2.16 (s, 3H), 2.33 (s,
3H), 3.80 (s, 3H), 5.01 (d, J = 4.2 Hz, 1H), 5.44 (t, J = 4.2 Hz, 1H),
6.45 (d, J = 10.2 Hz, 1H), 6.82 (d, J = 8.7 Hz, 2H), 7.01−7.07 (m,
1
76% yield of 1s as white solid (1.113 g): mp 123−125 °C; H NMR
(300 MHz, CDCl3) δ 1.50 (d, J = 6.6 Hz, 1H), 2.89 (s, 1H), 4.62 (q,
J = 6.6 Hz, 1H), 6.52 (d, J = 11.1 Hz, 1H), 6.73 (d, J = 15.6 Hz, 1H),
7.13 (t, J = 7.2 Hz, 1H), 7.23−7.37 (m, 5H), 7.45 (d, J = 7.2 Hz, 2H),
7.58−7.66 (m, 3H), 8.93 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
21.8, 71.9, 120.2, 124.4, 124.6, 127.1, 128.6(1), 128.6(2), 129.0, 136.0,
136.4, 137.7, 139.0, 166.0. Anal. Calcd for C18H19NO: C, 81.47; H,
7.22; N, 5.28. Found: C, 81.25; H, 7.13; N, 5.04.
1
3H), 7.26−7.31 (m, 3H), 14.77 (s, 1H); H NMR (minor isomer)
(300 MHz, CDCl3) δ 1.53 (s, 3H), 2.16 (s, 3H), 3.75 (s, 3H), 5.48 (d,
J = 6.6 Hz, 2H), 6.29 (d, J = 7.8 Hz, 1H), 6.55 (d, J = 8.7 Hz, 1H),
6.72 (d, J = 8.7 Hz, 2H), 6.91−6.96 (m, 3H), 7.15−7.17 (m, 2H),
14.81 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 17.2, 17.6, 17.9, 55.1, 65.7,
67.1, 97.9, 98.1, 100.5, 113.4, 113.8, 117.3, 117.9, 120.5, 121.5, 126.0, 126.5,
126.9, 127.7, 127.9, 129.0, 129.8, 130.0, 130.5, 131.0, 132.8, 134.6, 138.0,
138.4, 138.9, 159.4, 167.2, 168.5, 170.0, 170.3. Anal. Calcd for C21H21NO3:
C, 75.20; H, 6.31; N, 4.18. Found: C, 74.92; H, 6.19; N, 4.35.
Typical Procedure for the Synthesis of Substituted Dihydropyr-
idin-2(3H)-ones 2 (2a as an example). To a 50 mL round bottomed
flask was added 1a (1.527 g, 5.0 mmol) and xylene (10.0 mL). The
mixture was heated to reflux for 13.0 h. The resulting mixture was
slowly poured into saturated aqueous NaCl (100 mL) and extracted
with dichloromethane (3 × 20 mL). The combined organic phase was
washed with water and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure, and the crude product was purified
by flash chromatography (silica gel, petroleum ether: ethyl acetate
12:1) to give 91% yield of 2a (1.389 g): white solid; mp 177−178 °C;
1H NMR (300 MHz, CDCl3) δ 2.15 (s, 3H), 2.28 (s, 3H), 5.36 (d, J =
3.9 Hz, 1H), 5.42−5.46 (dd, J1 = 3.9 Hz, J2 = 9.9 Hz, 1H), 6.40−6.43
(dd, J1 = 0.9 Hz, J2 = 9.9 Hz, 1H), 6.81 (d, J = 8.1 Hz, 2H), 7.06 (d, J =
8.1 Hz, 2H), 7.13−7.16 (m, 2H), 7.25−7.28 (m, 3H), 14.73 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 17.9, 21.0, 67.7, 98.2, 117.9, 120.6,
127.5, 127.8, 128.0, 128.6, 129.7, 137.3, 137.4, 140.8, 168.9, 170.3; IR
(KBr, cm−1): 3126, 1663, 1618, 1593, 1491, 1448, 1285, 816, 768, 706.
Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59. Found: C,
78.91; H, 6.20; N, 4.33.
2h: 1.548 g, yield 87%, white solid; mp 201−204 °C; 1H NMR (300
MHz, CDCl3) δ 2.15 (s, 3H), 3.78 (s, 3H), 5.40−5.45 (q, J = 6.0 Hz,
1H), 6.39−6.43 (dd, J1 = 12.0 Hz, J2 = 3.0 Hz, 1H), 6.77−6.81 (m,
2H), 6.84−6.88 (m, 2H), 7.02−7.04 (m, 2H), 7.23−7.26 (m, 2H),
14.55 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 18.0, 55.2, 67.1, 98.1,
114.0, 118.0, 120.5, 128.8, 129.2, 129.6, 130.2, 132.4, 133.2, 138.7,
159.5, 168.7, 170.7. Anal. Calcd for C20H18ClNO3: C, 67.51; H, 5.10;
N, 3.94. Found: C, 67.22; H, 5.03; N, 4.11.
2i: 1.672 g, yield 94%, light blue solid; mp 123−126 °C; [dr =
1
86:14]; H NMR (major isomer) (300 MHz, CDCl3) δ 2.16 (s, 3H),
3.78 (s, 3H), 5.26 (d, J = 3.9 Hz, 1H), 5.43−5.48 (dd, J1 = 9.9 Hz, J2 =
3.9 Hz, 1H), 6.43−6.45 (dd, J1 = 6.3 Hz, J2 = 0.9 Hz, 1H), 6.46−6.48
(dd, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 2H), 6.99−7.06
(m, 3H), 7.18−7.24 (m, 1H), 7.48−7.51 (dd, J1 = 7.8 Hz, J2 = 0.9 Hz,
1
1H), 14.46 (s, 1H); H NMR (minor isomer) (300 MHz, CDCl3) δ
2b: 1.375 g, yield 82%, white solid; mp 129−130 °C; 1H NMR (300
MHz, CDCl3) δ 2.14 (s, 3H), 2.28 (s, 3H), 3.77 (s, 3H), 5.30 (d, J =
3.9 Hz, 1H), 5.39−5.44 (dd, J1 = 9.9 Hz, J2 = 3.9 Hz, 1H), 6.40 (d, J =
9.9 Hz, 1H), 6.77 (d, J = 3.0 Hz, 2H), 6.80 (d, J = 3.0 Hz, 2H), 7.05 (t,
J = 7.5 Hz, 4H), 14.75 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 17.9,
21.0, 55.2, 67.1, 98.2, 113.9, 118.2, 120.4, 127.9, 128.8, 129.7, 132.9,
137.2, 137.4, 159.3, 168.8, 170.2. Anal. Calcd for C21H21NO3: C,
75.20; H, 6.31; N, 4.18. Found: C, 74.99; H, 6.42; N, 4.03.
2.16 (s, 3H), 3.74 (s, 3H), 5.39 (d, J = 3.9 Hz, 1H), 5.48 (s, 1H), 6.51
(d, J = 1.2 Hz, 1H), 6.71 (d, J = 8.4 Hz, 2H), 6.99−7.06 (m, 2H),
7.18−7.24 (m, 2H), 7.30−7.36 (m, 1H), 7.39−7.41 (m, 1H), 14.50 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 17.9, 55.2, 65.3, 67.2, 97.8,
113.3, 113.5, 113.9, 117.6, 117.9, 120.4, 121.1, 126.9, 127.7, 128.2,
128.8, 129.1, 129.9, 130.0, 130.2, 131.9, 132.2, 132.5, 136.9, 159.5,
168.6, 170.6. Anal. Calcd for C20H18ClNO3: C, 67.51; H, 5.10; N, 3.94.
Found: C, 67.33; H, 5.18; N, 3.82.
Crystal data for 2i: C20H18ClNO3, light blue crystal, M = 355.80,
Monoclinic, P21/c, a = 12.269 (4) Å, b = 12.814 (4) Å, c = 11.380 (3)
Å, α = 90.00°, β = 98.462(5) °, γ = 90.00°, V = 1769.7(9) Å3, Z = 4,
T = 293 K, F000 = 744, Tmin = 0.9667, Tmax =0.9893, R = 0.0797,
2c: 1.459 g, yield 87%, white solid; mp 117−118 °C; 1H NMR (300
MHz, CDCl3) δ 2.06 (s, 3H), 2.20 (s, 3H), 3.51 (s, 3H), 5.36−5.41
(dd, J1 = 4.5 Hz, J2 = 9.9 Hz, 1H), 5.87 (d, J = 3.0 Hz, 1H), 6.28−6.31
(dd, J1 = 1.2 Hz, J2 = 9.9 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.84−6.92
D
dx.doi.org/10.1021/jo4001959 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
wR2 = 0.3123. CCDC deposition number: 910106. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html
or from the Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB21EZ, U.K. (fax (+44)1223-336-033 or deposit@ccdc.
cam.ac.uk).
C20H19NO2: C, 78.66; H, 6.27; N, 4.59. Found: C, 78.47; H, 6.35; N,
4.71.
2q: 1.405 g, yield 88%, white solid; mp 196−198 °C; 1H NMR (300
MHz, DMSO) δ 0.92 (t, J = 9.0 Hz, 3H), 1.54−1.64 (m, 2H), 3.07 (t,
J = 4.0 Hz, 2H), 7.20−7.25 (m, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.59−
7.65 (m, 1H), 7.86 (d, J = 4.0 Hz, 1H), 8.43 (s, 1H), 12.11 (s, 1H);
13C NMR (150 MHz, DMSO) δ 13.7, 17.0, 44.0, 115.0, 118.1, 122.3,
2j: 1.493 g, yield 85%, white solid; mp 110−112 °C; 1H NMR (300
MHz, CDCl3) δ 2.16 (s, 3H), 3.77 (s, 3H), 3.80 (s, 3H), 5.29 (d, J =
3.9 Hz, 1H), 5.41−5.46 (dd, J1 = 10.2 Hz, J2 = 3.9 Hz, 1H), 6.41−6.44
(dd, J1 = 10.2 Hz, J2 = 0.9 Hz, 1H), 6.79−6.85 (m, 6H), 7.05 (d, J =
8.4 Hz, 2H), 14.76 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 17.9,
55.1, 55.2, 67.2, 98.2, 113.8, 114.3, 118.1, 120.4, 128.8, 129.1, 132.7,
132.8, 158.5, 159.3, 168.9, 170.2. Anal. Calcd for C21H21NO4: C,
71.78; H, 6.02; N, 3.99. Found: C, 72.09; H, 6.11; N, 3.80.
2k: 1.298 g, yield 85%, white solid; mp 112−116 °C; [dr = 65:35];
1H NMR (major isomer) (300 MHz, CDCl3): 2.17 (s, 3H), 2.33 (s,
3H), 5.05 (d, J = 3.9 Hz, 1H), 5.44−5.46 (m, 1H), 6.28 (d, J = 7.8 Hz,
1H), 6.46 (d, J = 10.2 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 7.01 (t, J = 7.5
Hz, 2H), 7.13−7.30 (m, 5H), 14.73 (s, 1H); 1H NMR (minor isomer)
(300 MHz, CDCl3): 1.48 (s, 3H), 2.17 (s, 3H), 5.47−5.50 (m, 2H),
6.57 (d, J = 10.2 Hz, 1H), 7.13−7.30 (m, 9H), 14.77 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 19.1, 19.4, 19.7, 68.3, 69.6, 99.8, 99.9,
118.9, 119.6, 122.6, 123.6, 127.9, 128.3, 128.8, 129.6, 129.8, 130.0(1),
130.0(2), 130.1, 130.4, 130.5, 131.7, 132.3, 132.9, 136.5, 140.3, 142.6,
169.2, 170.5, 172.1, 172.3. Anal. Calcd for C20H19NO2: C, 78.66; H,
6.27; N, 4.59. Found: C, 78.50; H, 6.18; N, 4.44.
129.6, 129.9, 132.7, 140.3, 142.7, 160.3, 200.1; IR (KBr, cm−1): 3447, 2968,
1659, 1607, 1587, 1491, 1454, 1283, 768. Anal. Calcd for C21H21NO2: C,
78.97; H, 6.63; N, 4.39. Found: C, 79.31; H, 6.57; N, 4.56.
2r: 1.525 g, yield 83%, white solid; mp 112−114 °C; 1H NMR (300
MHz, DMSO) δ 2.24 (s, 3H), 5.52−5.56 (m, 1H), 5.67 (d, J = 3.0 Hz,
1H), 6.33−6.37 (m, 1H), 6.98 (d, J = 9.0 Hz, 2H), 7.09 (d, J = 6.0 Hz,
2H), 7.23 (t, J = 6.0 Hz, 3H), 7.30 (t, J = 9.0 Hz, 2H), 7.52 (t, J = 3.0
Hz, 3H), 7.55−7.60 (m, 2H), 15.16 (s, 1H); 13C NMR (100 MHz,
DMSO) δ 20.5, 66.5, 98.4, 120.1, 120.3, 127.2, 127.6, 127.8, 128.46, 128.6,
129.2, 130.2, 133.9, 136.5, 137.2, 140.4, 168.0, 168.8; IR (KBr, cm−1):
3447, 1659, 1591, 1570, 1512, 1458, 1283, 816. Anal. Calcd for
C25H21NO2: C, 81.72; H, 5.76; N, 3.81. Found: C, 81.41; H, 5.87; N, 3.94.
Typical Procedure for the Synthesis of Substituted Pyridin-2(1H)-
ones 3 (3a as an example). To a 50 mL round bottomed flask was
added 2a (0.710 g, 2.0 mmol), SeO2 (0.266g, 2.4 mmol), and toluene
(10.0 mL). The mixture was heated to reflux for 1.5 h. The resulting
mixture was slowly poured into saturated aqueous NaCl (100 mL) and
extracted with dichloromethane (3 × 20 mL). The combined organic
phase was washed with water and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure, and the crude product
was purified by flash chromatography (silica gel, petroleum ether: ethyl
acetate 9:1) to give 86% yield of 3a (0.522 g): white solid, mp 187−
2l: 1.336 g, yield 82%, white solid; mp 139−141 °C; 1H NMR (300
MHz, CDCl3) δ 2.15 (s, 3H), 5.35 (d, J = 3.0 Hz, 1H), 5.42−5.46 (m,
1H), 6.40−6.43 (m, 1H), 6.86−6.89 (m, 2H), 7.11−7.14 (m, 2H),
7.21−7.24 (m, 3H), 7.28−7.30 (m, 2H), 14.53 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 17.9, 67.6, 98.0, 117.7, 120.5, 127.4, 128.2, 128.7,
129.1, 129.4, 133.1, 138.6, 140.2, 168.7, 170.7; IR (KBr, cm−1): 3446, 1664,
1614, 1585, 1494, 1443, 1281, 833, 702. Anal. Calcd for C19H16ClNO2: C,
70.05; H, 4.95; N, 4.30. Found: C, 70.31; H, 5.02; N, 4.39.
1
189 °C; H NMR (300 MHz, CDCl3) δ 2.29 (s, 3H), 2.72 (s, 3H),
6.39 (d, J = 7.5 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 7.09−7.13 (m, 4H),
7.18−7.26 (m, 3H), 8.29 (d, J = 7.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 21.1, 31.2, 107.6, 126.1, 128.1, 128.5, 128.7, 129.0, 129.6,
135.0, 135.6, 138.4, 143.3, 155.4, 162.2, 197.8; IR (KBr, cm−1): 3394,
1672, 1653, 1544, 1404, 764. Anal. Calcd for C20H17NO2: C, 79.19; H,
5.65; N, 4.62. Found: C, 78.89; H, 5.60; N, 4.83.
2m: 1.417 g, yield 87%, white solid; mp 152−156 °C; [dr = 86:14];
1H NMR (major isomer) (300 MHz, CDCl3) δ 2.17 (s, 3H), 5.31 (d, J =
3.9 Hz, 1H), 5.45−5.50 (dd, J1 = 10.2 Hz, J2 = 4.2 Hz, 1H), 6.44−6.46
(dd, J1 = 4.5 Hz, J2 = 0.9 Hz, 1H), 6.48 (s, 1H), 6.96−7.02 (m, 1H),
7.10−7.23 (m, 4H), 7.28 (t, J = 2.7 Hz, 2H), 7.48−7.51 (m, 1H), 14.46
(s, 1H); 1H NMR (minor isomer) (300 MHz, CDCl3): 2.17 (s, 3H), 5.42
(d, J = 3.9 Hz, 1H), 5.54 (s, 1H), 6.50 (s, 1H), 6.54 (d, J = 1.2 Hz, 1H),
7.10−7.29 (m, 4H), 7.33−7.36 (m, 2H), 7.42 (d, J = 8.1 Hz, 2H), 14.50
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 17.9, 65.9, 67.8, 97.8, 117.2,
117.6, 120.6, 121.3, 126.8, 127.7, 127.8, 128.0, 128.1, 128.3, 128.6, 128.8,
129.1, 130.0, 130.2, 131.9, 132.0, 136.8, 140.3, 167.4, 168.6, 170.6. Anal.
Calcd for C19H16ClNO2: C, 70.05; H, 4.95; N, 4.30. Found: C, 69.89; H,
5.05; N, 4.42.
3i: 0.644 g, yield 91%, white solid; mp 160−161 °C; 1H NMR (300
MHz, DMSO) δ 2.54 (s, 3H), 3.69 (s, 3H), 6.50 (d, J = 9.0 Hz, 1H),
6.81 (d, J = 9.0 Hz, 1H), 7.18 (d, J = 9.0 Hz, 2H), 7.33−7.37 (m, 2H),
7.48−7.52 (m, 2H), 8.19 (d, J = 6.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 30.4, 54.5, 106.9, 112.8, 125.0, 125.7, 126.9, 129.2, 129.4,
129.5, 130.0, 131.7, 135.9, 143.2, 154.7, 159.7, 160.7, 196.6; IR (KBr,
cm−1): 1678, 1664, 1609, 1545, 1508, 1477, 825, 762, 737. Anal. Calcd
for C20H16ClNO3: C, 67.90; H, 4.56; N, 3.96. Found: C, 67.63; H,
4.49; N, 4.11.
ASSOCIATED CONTENT
1
2n: 1.446 g, yield 90%, white solid; mp 88−89 °C; H NMR (300
■
MHz, CDCl3) δ 2.14 (s, 3H), 3.74 (s, 3H), 5.33 (d, J = 3.0 Hz, 1H),
5.41−5.46 (m, 1H), 6.39−6.43 (m, 1H), 6.75−6.84 (m, 4H), (m, 1H),
7.12−7.15 (m, 2H), 7.25−7.28 (m, 4H), 14.72 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 17.5, 54.8, 67.5, 97.8, 113.9, 117.5, 120.2, 127.2,
127.7, 128.2, 128.7, 132.3, 140.3, 158.1, 168.6, 169.9; IR (KBr, cm−1):
3447, 2968, 1659, 1607, 1587, 1491, 1454, 1283, 768. Anal. Calcd for
C20H19NO3: C, 74.75; H, 5.96; N, 4.36. Found: C, 74.66; H, 5.81; N, 4.28.
2o: 1.326 g, yield 91%, white solid; mp 116−119 °C; 1H NMR (300
MHz, CDCl3) δ 2.15 (s, 3H), 5.38 (d, J = 3.6 Hz, 1H), 5.42−5.47 (dd,
J1 = 1.8 Hz, J2 = 10.2 Hz, 1H), 6.42 (d, J = 10.2 Hz, 1H), 6.93 (d, J =
7.2 Hz, 2H), 7.12−7.14 (m, 2H), 7.21−7.26 (m, 6H), 14.67 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 17.9, 67.7, 98.1, 117.9, 120.6, 127.5,
128.0, 128.6, 128.7, 129.0, 140.1, 140.6, 168.7, 170.5; IR (KBr, cm−1):
3142, 1655, 1647, 1607, 1587, 1491, 168, 696. Anal. Calcd for C19H17NO2:
C, 78.33; H, 5.88; N, 4.81. Found: C, 77.95; H, 5.75; N, 5.03.
S
* Supporting Information
1
ORTEP drawing and crystal data (CIF) of 2i, copies of H
NMR and 13C NMR spectra for new compounds 1, 2, and 3.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ning.zhang@ciac.jl.cn; dwdong@ciac.jl.cn.
Notes
The authors declare no competing financial interest.
2p: 1.206 g, yield 79%, white solid; mp 105−107 °C; 1H NMR (400
MHz, CDCl3) δ 2.11 (s, 3H), 3.47 (d, J = 16.0 Hz, 1H), 4.98 (s, 3H),
5.24−5.27 (m, 1H),5.52 (d, J = 16.0 Hz, 1H), 6.26 (d, J = 8.0 Hz, 1H),
7.23−7.29 (m, 4H), 7.31−7.40 (m, 6H), 14.91 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 17.9, 45.9, 62.6, 97.9, 117.8, 120.1, 127.0, 127.5,
128.1, 128.2, 128.7, 129.1, 136.5, 140.8, 169.0, 169.7; IR (KBr, cm−1):
3443, 1677, 1600, 1583, 1493, 1454, 1258, 719, 696. Anal. Calcd for
ACKNOWLEDGMENTS
■
Financial support of this research by the National Natural
Science Foundation of China (51073150 and 21172211), the
Department of Science and Technology of Jilin Province
(20111802), and “Hundred Talents Program” of the Chinese
Academy of Sciences is greatly acknowledged.
E
dx.doi.org/10.1021/jo4001959 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(19) Marvell, E. N. Thermal Electrocyclic Reactions; Academic Press:
New York, 1980.
(20) Parker, K. A.; Mindt, T. L. Org. Lett. 2001, 3, 3875.
(21) Colabroy, K. L.; Begley, T. P. J. Am. Chem. Soc. 2005, 127, 840.
(22) Parish, C. A.; Hashimoto, M.; Nakanishi, K.; Dillon, J.; Sparrow,
J. Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 14609.
(23) Tsuchikawa, H.; Maekawa, Y.; Katsumura, S. Org. Lett. 2012, 14,
2326.
(24) (a) Liu, X.; Xin, X.; Xiang, D.; Zhang, R.; Kumar, S.; Zhou, F.;
Dong, D. Org. Biomol. Chem. 2012, 10, 5643. (b) Liu, X.; Xin, X.;
Xiang, D.; Liang, Y.; Xin, X.; Li, W.; Dong, D. RSC Adv. 2013, 3, 1456.
(25) Raman, N. J. Indian Chem. Soc. 2007, 84, 29.
REFERENCES
■
(1) (a) Elbein, A. D.; Molyneux, R. J. Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1981;
Vol. 5, pp 1−54. (b) Jones, G. Pyridines and Their Benzo Derivatives:
Synthesis in Comprehensive Heterocyclic Chemistry II; McKillop, A., Ed.;
Pergamon Press: Oxford, U.K., 1996; Vol. 5, p 167. (c) Li, Q.;
Mitscher, L. A.; Shen, L. L. Med. Res. Rev. 2000, 20, 231. (d) Nagarajan,
M.; Xiao, X. S.; Antony, S.; Kohlhagen, G.; Pommier, Y.; Cushman, M.
J. Med. Chem. 2003, 46, 5712.
(2) Fischer, C. B.; Steininger, H.; Stephenson, D. S.; Zipse, H. J. Phys.
Org. Chem. 2005, 18, 901.
(3) Rawson, J. M.; Winpenny, R. E. P. Coord. Chem. Rev. 1995, 139,
313.
(4) Grundon, M. F. Nat. Prod. Rep. 1989, 6, 523.
(5) Fujita, R.; Watanabe, K.; Ikeura, W.; Ohtake, Y. H. Heterocycles
2000, 53, 2607.
(26) Maekawa, Y.; Sakaguchi, T.; Tsuchikawa, H.; Katsumura, S.
Tetrahedron Lett. 2012, 53, 837.
(27) Hatano, B.; Hashimoto, K.; Katagiri, H.; Kijima, T.; Murakami,
S.; Matsuba, S.; Kusakari, M. J. Org. Chem. 2012, 77, 3595.
(28) (a) Tanaka, K.; Mori, H.; Fujii, S.; Itagaki, Y.; Katsumura, S.
Tetrahedron Lett. 1998, 39, 1185. (b) Tanaka, K.; Katsumura, S. Org.
Lett. 2000, 2, 373. (c) Yu, T.; Fu, Y.; Liu, L.; Guo, Q. J. Org. Chem.
2006, 71, 6157.
(29) Bishop, L. M.; Barbarow, J. E.; Bergman, R. G.; Trauner, D.
Angew. Chem., Int. Ed. 2008, 47, 8100.
(30) (a) Malamidou-Xenikaki, E.; Spyroudis, S.; Tsanakopoulou, M.;
Krautscheid, H. J. Org. Chem. 2007, 72, 502. (b) Malamidou-Xenikaki,
E.; Spyroudis, S.; Tsanakopoulou, M.; Hadjipavlou-Litina, D. J. Org.
Chem. 2009, 74, 7315.
(31) (a) Wang, Z.; Bi, X.; Liao, P.; Zhang, R.; Liang, Y.; Dong, D.
́
Chem. Commun. 2012, 48, 7076. (b) Vicente, V.; Martin, J.; Jimenez-
Barbero, J.; Chiara, J. L.; Vicent, C. Chem.Eur. J. 2004, 10, 4240.
(c) Zhang, Y.; Zimmerman, S. C. Beilstein J. Org. Chem. 2012, 8, 486.
(d) Zhang, Y.; Lavin, J. M.; Shimizu, K. D. J. Am. Chem. Soc. 2009, 131,
12062.
́
(6) Casamitjana, N.; Lopez, V.; Jorge, A.; Bosch, J.; Molins, E.; Roig,
A. Tetrahedron 2000, 56, 4027.
(7) (a) Jones, T. H.; Blum, M. S. Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1983; Vol. 1, pp
33−84. (b) Fodor, G. B.; Colasanti, B. Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1985;
Vol. 3, pp 1−90. (c) Strunz, G. M.; Findlay, J. A. The Alkaloids; Brossi,
A., Ed.; Academic Press: Orlando, FL, 1985; Vol. 26, p 89.
(8) (a) Paulvannan, K.; Chen, T. J. Org. Chem. 2000, 65, 6160.
(b) Tasker, S. Z.; Bosscher, M. A.; Shandro, C. A.; Lanni, E. L.; Ryu, K.
A.; Snapper, G. S.; Utter, J. M.; Ellsworth, B. A.; Anderson, C. E. J. Org.
Chem. 2012, 77, 8220.
(9) (a) Adibatti, N. A.; Thirugnanasambantham, P.; Kulothungan, C.;
Viswanathan, S.; Kameswaran, L.; Balakrishna, K.; Sukumar, E.
Phytochemistry 1991, 30, 2449. (b) Kelly, T. R.; Walsh, J. J. J. Org.
Chem. 1992, 57, 6657. (c) Hong, H.; Comins, D. L. J. Org. Chem.
1996, 61, 391.
(32) Bickelhaupt, F.; De Graaf, W. L.; Klumpp, G. W. Chem.
Commun. 1968, 53.
(33) Sengupta, T.; Gayen, K. S.; Pandit, P.; Maiti, D. K. Chem.Eur.
(10) (a) Josien, H.; Ko, S. B.; Bom, D.; Curran, D. P. Chem.Eur. J.
1998, 4, 67. (b) Comins, D. L.; Nolan, J. M. Org. Lett. 2001, 3, 4255.
(c) Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.; Kanai, M.;
Du, W.; Curran, D. P.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123,
9908.
J. 2012, 18, 1905.
(11) (a) Decker, H. Chem. Ber. 1892, 25, 443. (b) Comins, D. L.;
Saha, J. K. J. Org. Chem. 1996, 61, 9623. (c) Du, W. Tetrahedron 2003,
59, 8649.
(12) (a) Comins, D. L.; Gao, J. L. Tetrahedron Lett. 1994, 35, 2819.
(b) Hu, T.; Li, C. Org. Lett. 2005, 7, 2035. (c) Cristau, H. J.; Cellier, P.
P.; Spindler, J. F.; Taillefer, M. Chem.Eur. J. 2004, 10, 5607.
(13) (a) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058.
(b) Inamoto, K.; Saito, T.; Hiroya, K.; Doi, T. J. Org. Chem. 2010, 75,
3900.
(14) (a) Fiorelli, C.; Savoia, D. J. Org. Chem. 2007, 72, 6022. (b) Lee,
J. H.; Shin, S.; Kang, J.; Lee, S. G. J. Org. Chem. 2007, 72, 7443.
(15) (a) Chen, Z.; Lin, L.; Chen, D.; Li, J.; Liu, X.; Feng, X.
Tetrahedron Lett. 2010, 51, 3088. (b) Itoh, J.; Fuchibe, K.; Akiyama, T.
Angew. Chem., Int. Ed. 2006, 45, 4796.
(16) (a) Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9, 1757.
(b) Angibaud, P. R.; Venet, M. G.; Filliers, W.; Broeckx, R.; Ligny, Y.
A.; Muller, P.; Poncelet, V. S.; End, D. W. Eur. J. Org. Chem. 2004, 479.
(c) Litvinov, V. P. Russ. Chem. Rev. 2003, 72, 69.
(17) Beaudry, C. M.; Malerich, J. P.; Trauner, D. Chem. Rev. 2005,
105, 4757.
(18) (a) Marvell, E. N.; Caple, G.; Schatz, B.; Pippin, W. Tetrahedron
1973, 29, 3781. (b) Marvell, E. N.; Caple, G.; Delphey, C.; Platt, J.;
Polston, N.; Tashiro, J. Tetrahedron 1973, 29, 3797. (c) Spangler, C.
W.; Jondahl, T. P.; Spangler, B. J. Org. Chem. 1973, 38, 2478.
(d) Palenzuela, J. A.; Elnagar, H. Y.; Okamura, W. H. J. Am. Chem. Soc.
1989, 111, 1770. (e) Beaudry, C. M.; Malerich, J. P.; Trauner, D.
Chem. Rev. 2005, 105, 4757. (f) Okamura, W. H.; de Lera, A. R. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Paquette, L. A., Vol. Ed.; Pergamon Press: London, 1991; Vol. 5,
Chapter 6.2, pp 699−750.
F
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