Palladium-catalyzed direct C-H arylation of cyclic enaminones with aryl iodides

Article abstract of DOI:10.1021/jo400830t

A ligand-free method for the Pd-catalyzed direct arylation of cyclic enaminones using aryl iodides was developed. This method can be applied to a wide range of cyclic enaminones and aryl iodides with excellent C5-regioselectivity. Using widely available aryl iodides, the generality of this transformation provides easy access to a variety of 3-arylpiperidine structural motifs.

Full text of DOI:10.1021/jo400830t

Article
pubs.acs.org/joc
Palladium-Catalyzed Direct C−H Arylation of Cyclic Enaminones with
Aryl Iodides
Yi-Yun Yu, Lei Bi, and Gunda I. Georg*
Department of Chemistry, Department of Medicinal Chemistry, and the Institute for Therapeutics Discovery and Development,
University of Minnesota, 717 Delaware Street SE, Minneapolis, Minnesota 55414, United States
S
* Supporting Information
ABSTRACT: A ligand-free method for the Pd-catalyzed direct arylation
of cyclic enaminones using aryl iodides was developed. This method can
be applied to a wide range of cyclic enaminones and aryl iodides with
excellent C5-regioselectivity. Using widely available aryl iodides, the
generality of this transformation provides easy access to a variety of 3-
arylpiperidine structural motifs.
Among the possible C−H activation mechanisms,7 our past
INTRODUCTION
■
study suggested that an electrophilic palladation pathway was
Cyclic enaminones, also known as 2,3-dihydropyrid-4(1H)-
more likely involved in reactions with the nucleophilic
ones, have displayed a distinctive reactivity profile, including
enaminones (Figure 1, top).1a However, a carbopalladation
notably a strong innate nucleophilicity.1 As piperidine
process is also feasible and would lead to C6-arylation as the
surrogates, these nonaromatic substrates have been exploited
double bond in the nonaromatic enaminone scaffold could be a
Heck donor (Figure 1, bottom).7c,d Therefore, the regiose-
as versatile synthetic intermediates in the syntheses of various
heterocycles and heterocyclic natural products.2 As our
lectivity of the coupling reaction presented another challenge.
laboratory continues to investigate the pharmaceutical
Herein, we disclose the development of a C5 regioselective
applications of phenanthropiperidine alkaloids, the syntheses
of these natural products and analogs entail a regioselective C5-
direct C−H arylation of cyclic enaminones using aryl iodides.
arylation of cyclic enaminones as a key step.3 Our strategy has
RESULTS AND DISCUSSION
■
been employing direct C−H arylation reactions because of their
convenience and efficiency.
We initiated our study by examining a collection of C−H
arylation conditions (catalysts, additives, reagent stoichiometry,
and reaction time)8 and then proceeded with the Jeffery
conditions (a combination of a PdII catalyst, a tetraalkylammo-
nium salt, and an inorganic base)9 for the optimization studies
shown in Table 1. As anticipated, in addition to the desired C5-
arylated 3a, C6-arylated 4a was observed as well. A survey of
seven solvents (entries 1−7) revealed that DMSO favored the
formation of 3a via the presumed electrophilic palladation
pathway (e.g., 50% in DMSO, entry 7 vs 10% in dioxane, entry
2), whereas toluene (entry 1) significantly increased the
formation of 4a. Indeed, DMSO provided the highest yield
and the best regioselectivity (entry 7). The choice of the base
was also proven imperative (entries 8−15). NaHCO3 (entry 7)
and Na2CO3 (entry 9) were more effective in facilitating the
deprotonation process than NaOAc (entry 8). Addition of
pivalic acid (PivOH) with Na2CO3 did not improve the yield
(entry 10). The selection of base cations also showed that the
sodium cation had beneficial effects on direct arylation (entries
11−13). Unsurprisingly, strong bases such as NaOH (entry 14)
or NaO-t-Bu (entry 15) decomposed the enaminones. Thus,
the originally chosen NaHCO3 provided the best outcome
(50%, entry 7). Next, the reaction temperature was tuned from
Direct C−H arylation chemistry has been extensively studied
over the years due to the ubiquity of heterocycle−aryl linkages
in pharmaceuticals.4 Our previous syntheses have demonstrated
that the regioselective C5-arylation of cyclic enaminones can be
achieved through convenient and high-yielding C−H arylation
protocols via oxidative Pd catalysis (Scheme 1, route 1).5 In
these protocols, aryl metal precursors were used (i.e., aryl
boronic acids,5a silanes,5b and trifluoroborates5c). Issues of
limited commercial availability or high cost led us to explore the
widely available aryl iodides as alternative reagents (Scheme 1,
route 2).6
Scheme 1. Direct Arylation of Cyclic Enaminones
Received: April 17, 2013
Published: June 10, 2013
© 2013 American Chemical Society
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Article
Figure 1. Postulated competing pathways for direct C−H arylation.
a
Table 1. Initial Optimization of the Direct C−H Arylation of Cyclic Enaminones
b
b
entry
ligand
additive
base
temp (°C)
solvent
3a (%)
4a (%)
1
2
3
4
5
6
7
8
9
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaOAc
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
20
50
110
140
80
80
80
80
80
80
80
80
toluene
dioxane
t-BuOH
NMP
14
10
8
18
12
12
7
15
29
22
50
36
49
51
29
16
0
DMF
7
DMA
8
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
6
5
Na2CO3
Na2CO3
Li2CO3
8
c
10
8
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
3
K2CO3
0
Cs2CO3
0
NaOH
0
0
NaOtBu
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
0
0
8
2
31
46
35
40
49
35
0
3
9
7
12
3
Bu4NCl
Bu4NI
16
0
PPh3
Bu4NCl
Bu4NCl
Bu4NCl
Bu4NCl
Bu4NCl
P(OPh)3
0
0
P(C6F5)3
0
0
d
26
Boc-Ala-OH
Boc-Phe-OH
52
45
6
d
27
4
a
1a (0.2 M), 2a (1.5 equiv), Pd(OAc)2 (20 mol %), ligand (40 mol %), additive (1.0 equiv), base (3.0 equiv) in DMSO (1 mL). p-Tol = p-tolyl.
NMR yields with Ph3SiMe (1.0 equiv) as the internal standard. With PivOH (40 mol %). 2a (3.0 equiv), Bu4NCl (0.5 equiv), and NaHCO3 (1.0
b
c
d
equiv).
20 to 140 °C in 30-degree intervals (entries 16−19). We found
that 80 °C was the optimal temperature to activate the
transformation without decomposing the heat-sensitive enam-
inones. Moreover, several tetraalkylammonium salts were
assessed as phase-transfer agents in order to enhance yields
and selectivities (entries 20−22).9 The absence of Bu4NBr
indeed resulted in a lower yield of 3a and a reduced
regioselectivity (entry 20). Interestingly, Bu4NCl (entry 21)
provided a better regioselectivity than Bu4NI (entry 22) or
Bu4NBr (entry 7). Lastly, the ligand effect was investigated.
Phosphine ligands (i.e., PPh3, P(OPh)3, and P(C6F5)3),
regardless of their electronic properties, were detrimental to
catalysis (entries 23−25). Amino acids (i.e., Boc-L-alanine and
Boc-L-phenylalanine), supposedly coordinating to the Pd center
through weak ligation,10 showed no improvement in either
yields or regioselectivity (entries 26 and 27).
We also examined eight silver salts as additives (Table 2).
Silver salts are often used to irreversibly abstract halide anions
from Pd complexes, thus rendering them more electrophilic
and preventing the formation of mostly inactive PdI2.11 Indeed,
the regioselectivity was greatly enhanced in the presence of a
silver salt (entries 1−8). We found that AgCl not only
increased the yield of 3a, but also promoted exclusive reaction
at the C5-position (entry 6). Additional extensive fine-tuning8
of reagent stoichiometry and reaction time furnished the
desired C5-arylated 3a in 72% with Bu4NCl (0.5 equiv) and
NaHCO3 (1.0 equiv) in DMSO (0.5 mL) (entry 9).
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chlorine terminus intact, which may be subjected to sequential
cross-coupling reactions.12 It is worth mentioning that phenyl
bromide was tested under the optimized conditions and
afforded an inferior yield (21% with 32% recovered 1a)
compared to phenyl iodide, which afforded 3d in 68%. Neither
4-chlorotoluene nor phenyl triflate functioned as arylating
reagents to afford the desired product.
Given the high coupling efficiency of electron-rich aryl
iodides, a series of cyclic enaminones was subjected to the
optimized conditions with 4-iodoanisole (2f, Table 4).
Consistent with our previous results,1a,5 electron-rich, mono-
cyclic, and bicyclic enaminones were all compatible with the
optimized conditions (3q−v). Compared to N-benzylenami-
none 3q, N-phenylenaminone 3r was formed in a decreased
yield probably due to its attenuated nucleophilicity. Notably,
these mildly basic conditions did not compromise the
stereochemical integrity of the epimerizable enaminone 3v. In
contrast, no reaction took place on either the N-unprotected
enaminone 1w or the E-enaminone 1x to form products 3w or
3x.1a,5 Electron-deficient enaminones also failed to furnish
desired 5-arylated products 3y or 3z.
Table 2. Silver Effect on the Regioselectivity of the Direct
C−H Arylation of Cyclic Enaminones
a
b
b
entry
Ag salt
3a (%)
4a (%)
1
2
3
4
5
6
AgTFA
AgF2
33
14
32
30
30
65
30
49
<1
0
AgNO3
AgOAc
0
<1
<1
0
Ag2CO3
AgCl
c
7
Ag2O + benzoic acid
Ag2O + PivOH
AgCl
0
c,d
8
9
3
e
f
75 (72 )
<1
a
1a (0.2 M), 2a (3.0 equiv), Pd(OAc)2 (20 mol %), Bu4NCl (1.0
equiv), NaHCO3 (3.0 equiv), silver salt (1.2 equiv) in DMSO (1 mL).
b
p-Tol = p-tolyl. NMR yields with Ph3SiMe (1.0 equiv) as the internal
c
d
standard. Ag2O (0.75 equiv), acid (1.5 equiv), no NaHCO3. No
e
Bu4NCl. AgCl (1.2 equiv), Bu4NCl (0.5 equiv), NaHCO3 (1.0 equiv)
Mechanistically, the aforementioned electrophilic palladation
pathway (Figure 1) for direct arylation can account for the
observed C5-regioselectivity, the silver salt effect, the solvent
dependency, and the substituent effects. Presumably, AgCl
abstracts the iodide from the Pd oxidative adduct (i.e., Ar−Pd−
I) to generate a cationic [Ar−Pd]+ complex, whose electro-
philicity matches the innate C5-nucleophilicity of enaminones
to yield C5-arylated enaminones. This unique C5-regioselec-
tivity is enhanced by DMSO because the cationic [Ar−Pd]+
species should be stabilized by this highly polar and
coordinating solvent. In addition, the [Ar−Pd]+ species should
also be stabilized by electron-donating substituents, which
would lead to less catalyst degradation and subsequently higher
yields (e.g., 80% of 3h vs 32% of 3o). It is worth noting that a
concerted metalation−deprotonation (CMD) mechanism
cannot be excluded at this time. However, the lack of reactivity
in DMSO (0.5 mL). (See Table S2 in the Supporting Information for
more details.) Isolated yield.
f
Next, we explored the scope of aryl iodides in this reaction
using the optimized conditions (Table 3) and found that the
electronic properties of the aryl iodides affected reaction yields
significantly. Good yields were generally obtained with
electron-rich aryl iodides (3a−l). Electron-poor aryl iodides
afforded slightly lowered yields (3m−p). Reactions of aryl
iodides with strongly electron-withdrawing substituents, e.g.,
NO2 (3o) and CF3 (3p), resulted in low yields. Steric
hindrance, as expected, impeded the effectiveness of the cross
coupling. For instance, compared to the 4-tolyl derivative (3a),
2-tolyl iodide afforded a lower yield (3b) with 14% recovered
1a. In addition, arylation of bifunctional 4-chlorophenyliodide
(2n) proceeded exclusively at the iodine terminus with the
a
Table 3. Scope of Aryl Iodides for the Direct C−H Arylation
a
1a (0.2 M), 2 (3.0 equiv), Pd(OAc)2 (20 mol %), Bu4NCl (0.5 equiv), NaHCO3 (1.0 equiv), AgCl (1.2 equiv) in DMSO (0.5 mL), 24 h. Isolated
b
yields with full consumption of 1a, unless otherwise noted. 14% recovered 1a.
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a
Table 4. Scope of Cyclic Enaminones for the Direct C−H Arylation
a
1 (0.2 M), 2f (3.0 equiv), Pd(OAc)2 (20 mol %), Bu4NCl (0.5 equiv), NaHCO3 (1.0 equiv), AgCl (1.2 equiv) in DMSO (0.5 mL), 24 h. Isolated
b
c
d
e
yields with full consumption of 1, unless otherwise noted. 60% recovered 1w. 65% recovered 1x. 15% recovered 1y. 27% recovered 1z.
Representative Procedure for Direct C−H Arylation of Cyclic
Enaminones with Aryl Iodides. In a clear 1-dram vial, the cyclic
enaminone (0.1 mmol), aryl iodide (0.3 mmol, 3.0 equiv), Pd(OAc)2
(4.5 mg, 0.02 mmol, 20 mol %), Bu4NCl (13.9 mg, 0.05 mmol, 0.5
equiv), NaHCO3 (8.4 mg, 0.1 mmol, 1.0 equiv), and AgCl (17.2 mg,
0.12 mmol, 1.2 equiv) were mixed in DMSO (0.5 mL). The reaction
vessel was then capped and stirred at 80 °C for 24 h and then cooled
to room temperature. The mixture was filtered through a pad of Celite
(washed with EtOAc). The filtrate was concentrated under reduced
pressure and purified by flash column chromatography.
1-Benzyl-2-(4-methoxyphenyl)-5-p-tolyl-2,3-dihydropyridin-
4(1H)-one (3a). Compound 3a was prepared by the general
procedure described above and purified by flash column chromatog-
raphy (30% EtOAc in hexanes) on silica gel to provide 27.3 mg (72%)
as an orange wax. Analytical data are consistent with those from our
previous report.5a
1-Benzyl-2-(4-methoxyphenyl)-6-p-tolyl-2,3-dihydropyridin-
4(1H)-one (4a). Compound 4a was a side product during the
optimization study and purified by flash column chromatography (25%
EtOAc in hexanes) on silica gel as a yellow wax: 1H NMR (400 MHz,
CDCl3) δ 7.40−7.20 (m, 9H overlapping with CHCl3), 7.15 (d, J = 6.8
Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 5.17 (s, 1H), 4.76 (d, J = 15.7 Hz,
1H), 4.61 (dd, J = 7.3, 4.0 Hz, 1H), 3.99 (d, J = 15.7 Hz, 1H), 3.81 (s,
3H), 2.97 (dd, J = 16.5, 7.4 Hz, 1H), 2.61 (dd, J = 16.7, 3.9 Hz, 1H),
2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.1, 164.9, 159.4,
140.0, 137.8, 133.6, 131.3, 129.6, 129.0, 128.0, 128.0, 127.8, 127.2,
114.4, 102.8, 59.4, 55.5, 53.9, 42.6, 21.5; FTIR (NaCl, cm−1) 3054,
2987, 1639, 1598, 1513, 1442, 1179, 1032, 896; HRMS (ESI+) m/e
calcd for [M + H]+ C26H26NO2 384.1963, found 384.1969.
of the electron-deficient enaminones 1y and 1z indicates a low
possibility for this process, which often works well on electron-
deficient substrates.13 In addition, a PdII/PdIV catalytic cycle,
albeit not ruled out, is also less likely because (1) more than
one catalytic turnover was observed in the absence of silver salts
(e.g., Table 1, entry 7, TON = 2.5), suggesting that silver salts
did not serve to regenerate the Pd catalyst;14 (2) our initial
optimization demonstrated that other Pd0 catalysts (e.g.,
Pd(dba)2 or Pd2(dba)3) would catalyze C5-arylation as well,
albeit in low yields (8−11%).8 Presumably, the ligands in these
Pd0 conditions tempered the electrophilicity of the PdII center
after oxidative addition, hence resulting in the observed low
yields.
CONCLUSION
■
We have developed a straightforward method for the
regioselective C−H arylation of cyclic enaminones with aryl
iodides. In spite of showing reduced but nevertheless good
yields compared to our earlier arylation protocols, the new
method reported herein utilizes aryl iodides with broader
commercial availability. This transformation tolerates a wide
range of substrates and presents an alternative approach to
synthesize 3-arylpiperidine derivatives.
EXPERIMENTAL SECTION
■
1-Benzyl-2-(4-methoxyphenyl)-5-o-tolyl-2,3-dihydropyridin-
4(1H)-one (3b). Compound 3b was prepared by the general
procedure described above and purified by flash column chromatog-
raphy (25% EtOAc in hexanes) on silica gel to provide 16.9 mg (43%)
General Information. All reactions were carried out in clear 1-
dram vials under air. Vials were used without drying. Palladium(II)
acetate, aryl iodides, all other chemicals and solvents were purchased
and were directly used without further purification. Cyclic enaminones
(1a,1a 1q,r,3d,15 1s,5b and 1t−w3d,15) were prepared according to the
reported procedures, and enaminone 1x is commercially available.
Flash column chromatography was carried out on silica gel (230−400
mesh). TLC was conducted on 250 μm, F254 silica gel plates. 1H NMR
spectra were recorded at 400 MHz and 13C NMR spectra at 100 MHz
with complete proton decoupling. Chemical shifts are reported as ppm
relative to chloroform (CHCl3: 7.26 ppm for 1H, 77.16 ppm for 13C).
Data are reported as follows: chemical shift, multiplicity (s = singlet, d
= doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling
constants (Hz), and integration. IR spectra of solids were obtained by
dissolving the sample in CH2Cl2 and letting the solvent evaporate on a
NaCl plate. High-resolution mass spectrometry was performed on an
ESI-TOF instrument. Melting points are uncorrected.
1
as a yellow solid (mp 139−142 °C): H NMR (400 MHz, CDCl3) δ
7.32−7.22 (m, 4H overlapping with CHCl3), 7.18−7.03 (m, 8H), 6.83
(d, J = 8.6 Hz, 2H), 4.48 (t, J = 7.6 Hz, 1H), 4.27 (d, J = 15.1 Hz, 1H),
4.10 (d, J = 15.1 Hz, 1H), 3.75 (s, 3H), 2.85 (dd, J = 16.3, 6.7 Hz, 1H),
2.76 (dd, J = 16.3, 8.7 Hz, 1H), 2.16 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 187.7, 159.7, 154.0, 138.2, 136.2, 136.0, 130.6, 130.2, 129.1,
128.6, 128.5, 128.3, 127.9, 127.2, 125.8, 114.5, 112.6, 60.7, 57.3, 55.5,
44.4, 20.7; FTIR (NaCl, cm−1) 3054, 2987, 1638, 1596, 1551, 1422,
1157, 1029, 896; HRMS (ESI+) m/e calcd for [M + Na]+
C26H25NO2Na 406.1783, found 406.1779.
1-Benzyl-2-(4-methoxyphenyl)-5-m-tolyl-2,3-dihydropyri-
din-4(1H)-one (3c). Compound 3c was prepared by the general
procedure described above and purified by flash column chromatog-
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raphy (30% EtOAc in hexanes) on silica gel to provide 27.2 mg (72%)
as a yellow wax: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.34 (td,
J = 18.5, 15.9, 9.5 Hz, 4H), 7.25−7.14 (m, 6H), 7.07−6.99 (m, 1H),
6.89 (d, J = 8.5 Hz, 2H), 4.52 (t, J = 7.5 Hz, 1H), 4.41 (d, J = 15.1 Hz,
1H), 4.21 (d, J = 15.1 Hz, 1H), 3.82 (s, 3H), 2.95 (dd, J = 16.2, 6.8 Hz,
1H), 2.82 (dd, J = 16.2, 8.3 Hz, 1H), 2.37 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 188.0, 159.7, 153.3, 137.8, 136.1, 130.6, 129.1, 128.6,
128.6, 128.5, 128.3, 128.3, 127.8, 126.7, 124.8, 114.5, 111.4, 60.4, 57.5,
55.5, 44.6, 21.7; FTIR (NaCl, cm−1) 3054, 2987, 1639, 1598, 1513,
1422, 1179, 1035, 896; HRMS (ESI+) m/e calcd for [M + Na]+
C26H25NO2Na 406.1783, found 406.1779.
1-Benzyl-2-(4-methoxyphenyl)-5-phenyl-2,3-dihydropyri-
din-4(1H)-one (3d). Compound 3d was prepared by the general
procedure described above and purified by flash column chromatog-
raphy (30% EtOAc in hexanes) on silica gel to provide 24.8 mg (68%)
as a yellow oil. Analytical data are consistent with those from our
previous report.5a
1635, 1597, 1583, 1511, 1459, 1442, 1377, 1357, 1315, 1298, 1282,
1250, 1178, 1127, 1071, 1036, 834; HRMS (ESI+) m/e calcd for [M +
Na]+ C27H25NO4Na 450.1681, found 450.1684.
1-Benzyl-2-(4-methoxyphenyl)-5-(4-morpholinophenyl)-2,3-
dihydropyridin-4(1H)-one (3j). Compound 3j was prepared by the
general procedure described above and purified by flash column
chromatography (70% EtOAc in hexanes) on silica gel to provide 33.9
1
mg (75%) as a yellow oil: H NMR (400 MHz, CDCl3) δ 7.47 (s,
1H), 7.38−7.30 (m, 5H), 7.23−7.12 (m, 4H), 6.92−6.86 (m, 4H),
4.51 (t, J = 7.6 Hz, 1H), 4.38 (d, J = 15.1 Hz, 1H), 4.18 (d, J = 15.1
Hz, 1H), 3.86 (t, J = 4.6 Hz, 4H), 3.81 (s, 3H), 3.14 (t, J = 4.0 Hz,
4H), 2.93 (dd, J = 16.3, 6.6 Hz, 1H), 2.82 (dd, J = 16.2, 8.7 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 188.3, 159.7, 152.7, 149.6, 136.2,
130.7, 129.1, 128.6, 128.6, 128.3, 127.8, 116.0, 114.5, 114.5, 111.3,
67.1, 60.6, 57.4, 55.4, 49.8, 44.7; FTIR (NaCl, cm−1) 3155, 2967,
2901, 2839, 1794, 1634, 1595, 1514, 1452, 1380, 1307, 1231, 1177,
1121, 1035, 907; HRMS (ESI+) m/e calcd for [M + H]+ C29H31N2O3
455.2329, found 455.2324.
1-Benzyl-5-(4-tert-butylphenyl)-2-(4-methoxyphenyl)-2,3-di-
hydropyridin-4(1H)-one (3e). Compound 3e was prepared by the
general procedure described above and purified by flash column
chromatography (25% EtOAc in hexanes) on silica gel to provide 27.9
1-Benzyl-2-(4-methoxyphenyl)-5-(naphthalen-1-yl)-2,3-di-
hydropyridin-4(1H)-one (3k). Compound 3k was prepared by the
general procedure described above and purified by flash column
chromatography (40% EtOAc in hexanes) on silica gel to provide 33.3
mg (80%) as a red wax: 1H NMR (400 MHz, CDCl3) δ 7.89−7.75 (m,
3H), 7.50−7.28 (m, 10H), 7.19 (d, J = 6.5 Hz, 2H), 6.95 (d, J = 8.5
Hz, 2H), 4.66 (t, J = 7.7 Hz, 1H), 4.38 (d, J = 15.1 Hz, 1H), 4.23 (d, J
= 15.1 Hz, 1H), 3.86 (s, 3H), 3.06 (dd, J = 16.3, 6.5 Hz, 1H), 2.97 (dd,
J = 16.2, 8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 188.3, 159.8,
154.8, 136.1, 134.3, 134.0, 133.2, 130.5, 129.1, 128.6, 128.6, 128.4,
128.0, 128.0, 127.9, 127.7, 126.3, 125.7, 125.7, 114.6, 111.1, 60.7, 57.4,
55.6, 44.5; FTIR (NaCl, cm−1) 3155, 3035, 2936, 2840, 1794, 1637,
1599, 1513, 1464, 1442, 1388, 1376, 1359, 1306, 1253, 1178, 1137,
1096, 1035, 834, 796; HRMS (ESI+) m/e calcd for [M + Na]+
C29H25NO2Na 442.1783, found 442.1783.
5-([1,1′-Biphenyl]-4-yl)-1-benzyl-2-(4-methoxyphenyl)-2,3-
dihydropyridin-4(1H)-one (3l). Compound 3l was prepared by the
general procedure described above and purified by flash column
chromatography (30% EtOAc in hexanes) on silica gel to provide 32.2
mg (73%) as a yellow wax: 1H NMR (400 MHz, CDCl3) δ 7.68−7.51
(m, 7H), 7.46−7.31 (m, 6H), 7.23−7.18 (m, 4H), 6.90 (d, J = 8.6 Hz,
2H), 4.55 (t, J = 7.5 Hz, 1H), 4.44 (d, J = 15.1 Hz, 1H), 4.23 (d, J =
15.1 Hz, 1H), 3.82 (s, 3H), 2.99 (dd, J = 16.2, 6.8 Hz, 1H), 2.86 (dd, J
= 16.2, 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 188.0, 159.8,
153.1, 141.3, 138.6, 136.0, 135.3, 130.5, 129.1, 128.8, 128.5, 128.5,
128.4, 128.0, 127.9, 127.1, 127.1, 114.6, 110.9, 60.5, 57.6, 55.5, 44.6;
FTIR (NaCl, cm−1) 3054, 2087, 1638, 1597, 1513, 1488, 1421, 1357,
1179, 1126, 1035, 896; HRMS (ESI+) m/e calcd for [M + Na]+
C31H27NO2Na 468.1939, found 468.1937.
1
mg (66%) as a yellow wax: H NMR (400 MHz, CDCl3) δ 7.53 (s,
1H), 7.43−7.29 (m, 7H), 7.24−7.14 (m, 4H), 6.88 (d, J = 8.7 Hz,
2H), 4.52 (t, J = 7.5 Hz, 1H), 4.40 (d, J = 15.1 Hz, 1H), 4.20 (d, J =
15.1 Hz, 1H), 3.82 (s, 3H), 2.96 (dd, J = 16.2, 6.8 Hz, 1H), 2.83 (dd, J
= 16.2, 8.4 Hz, 1H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
188.1, 159.7, 153.1, 148.7, 136.1, 133.2, 130.7, 129.1, 128.5, 128.3,
127.9, 127.4, 125.3, 114.5, 111.3, 60.5, 57.5, 55.5, 44.6, 34.5, 31.5;
FTIR (NaCl, cm−1) 3054, 2986, 1637, 1598, 1513, 1422, 1376, 1358,
1306, 1179, 1130, 1034, 896, 837; HRMS (ESI+) m/e calcd for [M +
Na]+ C29H31NO2Na 448.2252, found 448.2259.
1-Benzyl-2,5-bis(4-methoxyphenyl)-2,3-dihydropyridin-
4(1H)-one (3f). Compound 3f was prepared by the general procedure
described above and purified by flash column chromatography (50%
EtOAc in hexanes) on silica gel to provide 29.2 mg (74%) as a yellow
oil. Analytical data are consistent with those from our previous
report.5a
1-Benzyl-5-(3-methoxyphenyl)-2-(4-methoxyphenyl)-2,3-di-
hydropyridin-4(1H)-one (3g). Compound 3g was prepared by the
general procedure described above and purified by flash column
chromatography (35% EtOAc in hexanes) on silica gel to provide 31.2
mg (79%) as a red oil. Analytical data are consistent with those from
our previous report.5a
1-Benzyl-2-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-
2,3-dihydropyridin-4(1H)-one (3h). Compound 3h was prepared
by the general procedure described above and purified by flash column
chromatography (50% EtOAc in hexanes) on silica gel to provide 36.5
1
mg (80%) as a yellow solid (mp 125−128 °C): H NMR (400 MHz,
1-Benzyl-5-(4-(ethoxycarbonyl)phenyl)-2-(4-methoxyphen-
yl)-2,3-dihydropyridin-4(1H)-one (3m). Compound 3m was
prepared by the general procedure described above and purified by
flash column chromatography (30% EtOAc in hexanes) on silica gel to
provide 21.9 mg (50%) as a yellow wax: 1H NMR (400 MHz, CDCl3)
δ 7.99 (d, J = 8.4 Hz, 2H), 7.64 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.37
(q, J = 6.1 Hz, 3H), 7.22−7.14 (m, 4H), 6.88 (d, J = 8.6 Hz, 2H), 4.55
(t, J = 7.3 Hz, 1H), 4.46 (d, J = 15.1 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H),
4.25 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 2.98 (dd, J = 16.2, 6.9 Hz, 1H),
2.82 (dd, J = 16.2, 7.8 Hz, 1H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 13C 187.7, 166.9, 159.9, 153.5, 141.1, 135.7,
130.2, 129.7, 129.2, 128.6, 128.4, 127.89, 127.4, 126.9, 114.6, 110.0,
60.8, 60.3, 57.8, 55.4, 44.5, 14.5; FTIR (NaCl, cm−1) 3054, 2987,
1707, 1642, 1597, 1513, 1422, 1368, 1180, 1127, 1107, 1034, 896;
HRMS (ESI+) m/e calcd for [M + Na]+ C28H27NO4Na 464.1838,
found 464.1832.
CDCl3) δ 7.51 (s, 1H), 7.39−7.31 (m, 3H), 7.23−7.14 (m, 4H), 6.89
(d, J = 8.6 Hz, 2H), 6.67 (s, 2H), 4.52 (t, J = 7.5 Hz, 1H), 4.42 (d, J =
15.1 Hz, 1H), 4.22 (d, J = 15.1 Hz, 1H), 3.87 (s, 6H), 3.83 (s, 3H),
3.81 (s, 3H), 2.95 (dd, J = 16.2, 6.8 Hz, 1H), 2.81 (dd, J = 16.2, 8.2
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 188.0, 159.8, 153.1, 136.5,
136.0, 131.9, 130.5, 129.1, 128.5, 128.5, 128.4, 127.9, 114.6, 111.0,
105.2, 61.0, 60.4, 57.5, 56.3, 55.5, 44.6; FTIR (NaCl, cm−1) 3054,
2987, 2840, 1639, 1598, 1583, 1512, 1422, 1357, 1327, 1129, 1034,
1005, 896; HRMS (ESI+) m/e calcd for [M + H]+ C28H30NO5
460.2118, found 460.2126.
1-Benzyl-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(4-me-
thoxyphenyl)-2,3-dihydropyridin-4(1H)-one (3i). Compound 3i
was prepared by the general procedure described above and purified
by flash column chromatography (40% EtOAc in hexanes) on silica gel
1
to provide 35.4 mg (83%) as an orange wax: H NMR (400 MHz,
CDCl3) δ 7.46 (s, 1H), 7.39−7.30 (m, 3H), 7.20−7.14 (m, 4H),
6.98−6.81 (m, 5H), 4.50 (dd, J = 8.4, 6.8 Hz, 1H), 4.37 (d, J = 15.1
Hz, 1H), 4.24 (s, 4H), 4.17 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 2.92
(dd, J = 16.2, 6.7 Hz, 1H), 2.80 (dd, J = 16.2, 8.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 188.1, 159.7, 152.9, 143.3, 142.0, 136.1, 130.6,
129.7, 129.1, 128.5, 128.3, 127.8, 121.1, 117.0, 116.7, 114.5, 111.0,
108.8, 64.5, 60.5, 57.4, 55.5, 44.6; FTIR (NaCl, cm−1) 3155, 2935,
1-Benzyl-5-(4-chlorophenyl)-2-(4-methoxyphenyl)-2,3-dihy-
dropyridin-4(1H)-one (3n). Compound 3n was prepared by the
general procedure described above and purified by flash column
chromatography (25% EtOAc in hexanes) on silica gel to provide 20.3
mg (51%) as a yellow wax. Analytical data are consistent with those
from our previous report.5a
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Article
1-Benzyl-2-(4-methoxyphenyl)-5-(4-nitrophenyl)-2,3-dihy-
dropyridin-4(1H)-one (3o). Compound 3o was prepared by the
general procedure described above and purified by flash column
chromatography (30% EtOAc in hexanes) on silica gel to provide 13.0
mg (32%) as a bright yellow solid (mp 98−100 °C). Analytical data
are consistent with those from our previous report.5a
1-Benzyl-2-(4-methoxyphenyl)-5-(4-(trifluoromethyl)-
phenyl)-2,3-dihydropyridin-4(1H)-one (3p). Compound 3p was
prepared by the general procedure described above and purified by
flash column chromatography (25% EtOAc in hexanes) on silica gel to
provide 12.8 mg (30%) as a yellow wax. Analytical data are consistent
with those from our previous report.5a
1-Benzyl-5-(4-methoxyphenyl)-2,3-dihydropyridin-4(1H)-
one (3q). Compound 3q was prepared by the general procedure
described above and purified by flash column chromatography (70%
EtOAc in hexanes) on silica gel to provide 22.6 mg (78%) as a yellow
oil. Analytical data are consistent with those from our previous
report.5a
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We greatly appreciate financial support from the National
Institutes of Health (GM081267) and the University of
Minnesota through the Vince and McKnight Endowed Chairs
(to G.I.G.).
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5.6 Hz, 2H), 3.37 (dt, J = 14.6, 7.4 Hz, 1H), 3.23 (dt, J = 13.6, 6.4 Hz,
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report.5a
(4aR,8aR)-3-(4-Methoxyphenyl)-1-methyl-4a,5,6,7,8,8a-hex-
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mg (48%) as a yellow wax. Analytical data are consistent with those
from our previous report.5a
(4aS,8aR)-3-(4-Methoxyphenyl)-1-methyl-4a,5,6,7,8,8a-hex-
ahydroquinolin-4(1H)-one (3v). Compound 3v was prepared by
the general procedure described above and purified by flash column
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mg (60%) as a yellow wax. Analytical data are consistent with those
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: georg@umn.edu.
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