Unsymmetrical biaryls by palladium-catalyzed coupling of aryl halides with internal reduction

Article abstract of DOI:10.1002/ejoc.200800724

Aryl bromides containing a (1,4,5,6-tetrahydro-6-oxopyridin-3-yl)methyl substituent can be coupled with aryl halides yielding unsummetrical biaryls. In the course of this process, the cyclic enamide is oxidized to the 2(1H)-pyridinone. The reaction procee

Full text of DOI:10.1002/ejoc.200800724

FULL PAPER
DOI: 10.1002/ejoc.200800724
Unsymmetrical Biaryls by Palladium-Catalyzed Coupling of Aryl Halides with
Internal Reduction
Gedu Satyanarayana[a] and Martin E. Maier*[a]
Keywords: Palladacycles / Biaryls / Cross-coupling / Domino reactions / Pyridinones
Aryl bromides containing a (1,4,5,6-tetrahydro-6-oxopyridin-
3-yl)methyl substituent can be coupled with aryl halides
yielding unsummetrical biaryls. In the course of this process,
the cyclic enamide is oxidized to the 2(1H)-pyridinone. The
reaction proceeds by a six-membered palladacycle resulting
from allylic C–H bond activation of the cyclic enamide, lead-
ing to a six-membered palladacycle. A subsequent transmet-
alation reaction with an aryl-Pd-X intermediate eventually
dride elimination. The best yields were obtained with 2
equiv. of aryl halide. The required substrates were prepared
from bromoiodobenzenes by a sequence consisting of a Heck
reaction with allyl alcohol, enamine formation, Michael ad-
dition to ethyl acrylate, and heterocycle formation with ben-
zylamine.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
leads to mixed biaryls by reductive elimination and β-hy- Germany, 2008)
served. We reasoned that a more efficient process might be
Introduction
possible if the reducing agent were contained in one of the
aryl halide substrates. This concept is illustrated in Figure 1.
Thus, if a Y–H bond were in proximity to the halide, then
the initial C–X insertion of Pd0 might be followed by acti-
vation of the neighboring Y–H bond, leading to palladacy-
cle C. This would allow for the formation of palladacycle
D, which then would react with the second aryl halide E,
leading to palladacycle F. A reductive elimination would
form the desired biaryl bond, generating a Heck-type inter-
mediate G. A final β-elimination should then regenerate the
Biaryl compounds are important in many fields of chem-
istry.[1] For example, chiral biaryls function as efficient li-
gands in asymmetric synthesis.[2] Furthermore, the biaryl
subunit can be found in many natural products such as al-
kaloids or certain unusual peptide-based natural prod-
ucts.[3] Finally, biaryl compounds are very common in ma-
terial science.[4,5] Classical methods for aryl–aryl bond for-
mation include reductive methods such as the Ullmann
coupling, which employs an aryl halide and copper.[1] In
addition, catalytic cross-coupling reactions belong to the
standard repertoire in biaryl synthesis.[1,6] A useful varia-
tion in this regard is the decarboxylative biaryl coupling.[7]
Newer methods for the formation of such bonds are based
on direct arylation. In this case, an arylmetal species reacts
selectively with the C–H bond of another arene.[8,9]
From a practical point of view, the unsymmetrical coup-
ling of two aryl halides would also be very useful. In fact,
some processes are known in which two different aryl ha-
lides are coupled in the presence of a palladium catalyst. In
these methods, regeneration of Pd0 is achieved by adding
an organic reducing agent, like formate, 2-propanol, or an
amine. For example, 4-nitrobiphenyl was produced in 32%
from iodobenzene and 4-nitrobromobenzene (4 equiv.) in
the presence of Pd(OAc)2, nBu4NBr, and iPr2NEt.[10] In ad-
dition, some homocoupling of iodobenzene (21%) was ob-
[a] Institut für Organische Chemie, Universität Tübingen,
Auf der Morgenstelle 18, 72076 Tübingen
Fax: +49-7071-295137
Figure 1. Novel strategy for achieving unsymmetrical biaryl coup-
ling from two different aryl halides. Ligands are omitted for sim-
plicity. Y = C or heteroatom, n = 1–3 (to achieve palladacycles of
ring size 5–7).
E-mail: martin.e.maier@uni-tuebingen.de
URL: http://www.uni-tuebingen.de/uni/com/welcome.htm
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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G. Satyanarayana, M. E. Maier
FULL PAPER
Pd0. However, this plan would collapse if the palladium during this process. The formation of biaryl 8a can only
would leave palladacycle C, as is often the case.[11] In this be explained by C–H bond activation of the initial aryl-
paper, we demonstrate the realization of this novel concept palladium species, leading to a palladacycle such as D (Fig-
with piperidin-2-one-substituted aryl bromides.
ure 1). This intermediate must then react with a second aryl
bromide to form the biaryl bond.
Results and Discussion
The required substrates were prepared from bromoiodo-
benzenes[12–14] 1a–d (Scheme 1 and Table 1) by a Jeffery–
Heck coupling[15] with allyl alcohol, yielding 3-(2-bromo)-
phenylpropanals 2a–d. Aldehydes 2a–d were then converted
into the corresponding enamines with pyrrolidine in the
presence of K2CO3. Treatment of the crude enamines with
ethyl acrylate followed by acidic work-up furnished 4-for-
myl esters 4a–d.[16] As shown in previous work,[17] the 4-
formyl esters provide piperidinones by reductive amination
with benzylamine and sodium cyanoborohydride. If the re-
ducing agent was omitted and the formyl esters were simply
reacted with benzylamine in refluxing dichloroethane, cyclic
enamides 5a–d were the sole products. The yields for the
individual steps of the sequence shown in Scheme 1 are
listed in Table 1.
Figure 2. Formation of homobiaryl 8a from cyclic enamide 5a.
We became interested in seeing whether or not unsym-
metrical biaryls would form between 5-(2-bromobenzyl)-
substituted 3,4-dihydro-2(1H)-pyridinones 5 and an added
aryl halide by a palladium-catalyzed C–H activation/aryl-
aryl-bond-forming domino process,[19] as indicated in Fig-
ure 3. Initially, the parent dihydro-2(1H)-pyridinone 5a was
treated with varying amounts of a phenyl halide. We used
the same reaction conditions [Pd(OAc)2 (10 mol-%), Ph3P
(20 mol-%), Cs2CO3 (4 equiv.), DMF, 120 °C] as used pre-
viously for the formation of biaryl compounds like 8a.[18]
We needed to determine how many equiv. of phenyl halide
would give the best yield of the corresponding unsymmetri-
cal biaryl compound 9a. These results are shown in Table 2.
Scheme 1. Synthesis of cyclic enamides 5a–d by Heck coupling,
Michael addition of the enamines 3a–d to ethyl acrylate, and cycli-
zation of 4-formyl esters 4a–d with benzylamine.
Table 1. Yields for the transformations leading to piperidinones
5a–d.
Figure 3. Possible formation of unsymmetrical biaryls from cyclic
enamides 5 and an added aryl halide.
Entry R1
R2
Coupling
step
(%)
Michael
addition
(%)
Cyclization
to the enamide
(%)
Table 2. Reaction of piperidinone 5a with various halobenzenes
and in various amounts in the presence of Pd(OAc)2, base, and
Ph3P. [a]
1
2
3
4
H
H
OMe
H
H
Me
H
2a (80)
2b (70)
2c (70)
2d (74)
4a (75)
4b (72)
4c (73)
4d (64)
5a (85)
5b (78)
5c (83)
5d (89)
Entry
X in aryl
halide
Equiv. of
aryl halide
% Yield of 6a % Yield of 9a[b]
OMe
1
2
3
4
5
6
I
I
I
I
Br
Cl
1.1[c]
8
–
–
8
7
–
32
41
53
In related work, we recently discovered that 5-(2-bro-
5
3
2
2
2
mobenzyl)-substituted piperidin-2-ones form the corre-
sponding homobiaryls in the presence of Pd(OAc)2, Ph3P,
and Cs2CO3 at elevated temperatures.[18] As an example, the
transformation of 5a to biaryl 8a is shown in Figure 2. Be-
sides the desired biaryl compound, we also observed the
formation of debromo derivative 6a and pyridinone 7a. As
shown in Figure 2, one of the 3,4-dihydro-2(1H)-pyrid-
62
65
trace[d]
[a] All reactions were carried out with Pd(OAc)2 (0.1 equiv.), Ph3P
(0.2 equiv.), and Cs2CO3 (4 equiv.) at 120 °C for 72 h. [b] Isolated
yields of 9a. [c] Under these conditions, 7a (16%) and 8a (30%)
were also isolated. [d] 8a (43%), 7a (18%), and 6a (12%) were iso-
inones was oxidized to the fully unsaturated ring system lated.
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Unsymmetrical Biaryls by Palladium-Catalyzed Coupling Reactions
If a slight excess (1.1 equiv.) of iodobenzene was used, 3). It seems that too much halobenzene interferes with the
biaryl 9a was formed in 32% yield (Table 2, Entry 1). How- efficiency of the catalytic cycle. In fact, with 2 equiv. of
ever, debrominated 6a (8%), pyridinone 7a (16%), and a iodobenzene, the yield of 9a improved to 62% (Table 2, En-
substantial amount of homo coupling product 8a (30%) try 4). Now small amounts of debrominated piperidinone
were also observed. Accordingly, the amount of the halide 6a (8%) were also formed. Replacing iodobenzene with bro-
was increased. Indeed, 5 equiv. of iodobenzene led to a 41% mobenzene (2 equiv.) turned out to be optimal with regard
yield of biaryl 9a. Under these conditions, the formation to the yield of 9a (65%) (Table 2, Entry 5). On the other
of the other possible products could be suppressed. Using hand, with chlorobenzene, only a trace of biaryl 9a could
3 equiv. of iodobenzene produced 53% of 9a (Table 2, Entry be detected. Instead, some of dimer 8a (43%), 7a (18%),
Table 3. Reaction of 3,4-dihydro-2(1H)-pyridinones 5a–d with various halobenzenes in the presence of Pd(OAc)2, base, and Ph3P.
[a] The first number is the yield with the aryl bromide, and the second number is the yield with the corresponding iodide. [b] In all the
reactions, 5–8% of debrominated 6 were also observed.
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G. Satyanarayana, M. E. Maier
FULL PAPER
and 6a (12%) were isolated. Ultimately, the conditions
found in Entry 5 of Table 2 provided the best yield of biaryl
9a.
Conclusions
In summary, we demonstrated the facile synthesis of 5-
substituted 3,4-dihydro-1H-pyridin-2-ones from easily ac-
cessible 4-formyl esters with a 2-bromophenyl group at the
terminus. These enamides entered into a novel domino reac-
tion pathway in the presence of a palladium catalyst. Thus,
with the 2-bromobenzyl substituent, the aryl-palladium
species underwent a C–H bond activation to form a palla-
dium intermediate, which reacted with another aryl bro-
mide to form unsymmetrical biaryl compounds such as 9a.
These transformations are unprecedented and further illus-
trate the power of transition-metal-catalyzed transforma-
tions.
Therefore, these conditions were applied to the other en-
amides 5b–d from Scheme 1. The enamides were reacted in
the presence of Pd(OAc)2 (0.1 equiv.), Ph3P (0.2 equiv.), and
Cs2CO3 (4 equiv.) in DMF at 120 °C for 72 h with several
bromo- or iodobenzenes. As shown in Table 3, biaryl deriv-
atives 9 were formed in yields ranging from 46–70%. In
every case where both the bromide and the iodide were
studied, slightly higher yields were obtained with the bro-
mobenzene derivative. However, the reason for this differ-
ence can not be given at the moment. The newly formed
pyridinone part of biaryl derivatives 9 shows a characteris-
tic doublet (H-3, J = 9.4 Hz), doublet of doublets (H-4, J
= 9.4 and 2.5 Hz), and doublet (H-6, J = 2.5 Hz) at around
6.5, 6.9, and 6.5 ppm, respectively. Initial attempts at the Experimental Section
cross-coupling of alkyl bromides (e.g. 1-bromohexane) were
not successful.
General: 1H and 13C NMR spectra were recorded at 295 K in
CDCl3 with a Bruker Avance 400 spectrometer. Chemical shifts are
calibrated to the residual proton and carbon resonance of the sol-
vent, CDCl3 (δH = 7.25 and δC = 77.0 ppm). HRMS (FT-ICR)
was performed with a Bruker Daltonic APEX 2 spectrometer with
electron spray ionization (ESI). Analytical LC-MS was performed
with an HP 1100 Series system connected with an Agilent G1946C
ESI MS detector operating in the positive mode with a fragmenter
voltage of 40 eV; column: Nucleosil 100–5, C-18 HD, 5 µm,
70ϫ3 mm, Macherey–Nagel; eluent: 5 mM NaCl/acetonitrile, gra-
dient: 0–10–15–17–20 min with 20–80–80–99–99% acetonitrile,
flowrate of 0.5 mLmin–1. Flash chromatography was performed on
J. T. Baker silica gel (43–60 µm). Thin-layer chromatography was
performed on Machery–Nagel Polygram Sil G/UV254 plates. Sol-
vents were distilled prior to use. Petroleum ether with a boiling
range of 40–60 °C was used. Reactions were generally run under
nitrogen atmosphere.
In this domino process, the formation of pyridin-2(1H)-
one 7a and the biphenyl-substituted pyridinone 9a can only
be explained by allylic C–H bond activation by base-in-
duced cyclopalladation of aryl-palladium species I, re-
sulting in palladacycle J (Scheme 2).[20] This palladacycle
most likely undergoes a transmetalation-type exchange of
aryl ligands[21] to give bis-organopalladium species L. From
there, a β-hydride elimination and a reductive elimination
will lead to biaryl 9a. The formation of 2(1H)-pyridinone
7a can be explained as well by β-hydride elimination and
reductive elimination from palladacycle J. The transmet-
alation process (K + J Ǟ L) avoids the intermediacy of
PdIV intermediates[22] such as M, which seem like less prob-
able structures.
Typical Procedure. 1-Benzyl-5-(1,1Ј-biphenyl-2-ylmethyl)pyridin-
2(1H)-one (9a): In an oven-dried Schlenk tube fitted with a rubber
septum, to a solution of bromoenamide 5a (100 mg, 0.28 mmol)
and bromobenzene (88.2 mg, 0.56 mmol) in anhydrous DMF
(2 mL) were added together Ph3P (14.7 mg, 20 mol-%), Cs2CO3
(366 mg, 1.12 mmol), and Pd(OAc)2 (6.3 mg, 10 mol-%) at room
temperature in a purging nitrogen atmosphere. The magnetically
stirred reaction mixture was then heated in an oil bath at 120 °C
for 72 h. The reaction was cooled to room temperature and washed
with aqueous HCl (3 ). After separation of the layers, the aqueous
layer was extracted with ethyl acetate (3ϫ10 mL). The combined
organic layers were washed with brine, dried (Na2SO4), and fil-
tered. Concentration of the filtrate and purification of the crude
material by flash chromatography (ethyl acetate/hexane, 1:4 to 3:2)
furnished biarylpyridinone 9a (64 mg, 65%) as a brown viscous oil.
IR (neat): ν = 3059, 3030, 2924, 1668, 1597, 1538, 1496, 1477, 1454,
˜
1352, 1260, 1141, 1073, 1030, 836, 751, 701 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.38–7.05 (m, 14 H, Ar-H), 6.96 (dd, J =
9.4, 2.5 Hz, 1 H, H-4), 6.50 (d, J = 2.5 Hz, 1 H, H-6), 6.46 (d, J =
9.4 Hz, 1 H, H-3), 4.96 (s, 2 H, NCH2Ph), 3.62 (s, 2 H, CH2Ar)
ppm. 13C NMR (100 MHz, CDCl3): δ = 161.8 (OC=O), 142.2 (C-
2Ј), 141.2 (C-1ЈЈ), 140.9 (C-6), 136.6 (C), 136.5 (C), 135.1 (C-4),
130.3 (CH), 129.7 (CH), 128.9 (2 C, CH), 128.7 (2 C, CH), 128.1
(2 C, CH), 127.9 (2 C, CH), 127.8 (CH), 127.6 (C, CH), 127.0
(CH), 126.7 (CH), 120.7 (C-3), 118.7 (C-5), 51.6 (NCH2Ph), 35.3
(CH2Ar) ppm. HRMS (ESI): calcd. for C25H22NO [M + H]+
352.1696; found 352.1696.
Scheme 2. Proposed mechanism explaining the formation of 9a.
For simplicity, phosphane ligands are omitted.
The mechanism suggested in Scheme 2 is somewhat remi-
niscent of the classical Catellani process, where an initial
aryl-palladium species inserts norbornene, which allows a
subsequent formal C–H insertion to produce a five-mem-
bered palladacycle (PdII) that is ready for further coupling
reactions.[23–27]
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Unsymmetrical Biaryls by Palladium-Catalyzed Coupling Reactions
1-Benzyl-5-[(4Ј-methyl-1,1Ј-biphenyl-2-yl)methyl]pyridin-2(1H)-one
(9b): The reaction was performed with enamide 5a (100 mg,
0.27 mmol) and 4-bromotoluene (96 mg, 0.56 mmol) in anhydrous
DMF (2 mL) with Ph3P (14.7 mg, 20 mol-%), Cs2CO3 (366 mg,
1.12 mmol), and Pd(OAc)2 (6.3 mg, 10 mol-%). After combining
the reagents at room temperature, the mixture was heated to
120 °C, as described for 5a. Purification of the crude product by
flash chromatography (ethyl acetate/hexane, 1:4 to 3:2) furnished
biarylpyridinone 9b (72 mg, 70%) as a brown viscous oil. Rf = 0.45
126.7 (CH), 125.0 (2 C, CH), 120.7 (C-3), 119.0 (C-5), 51.7
(NCH2Ph), 35.2 (CH2Ar), 34.5 (C), 31.4 [C(CH3)] ppm. HRMS
(ESI): calcd. for C29H30NO [M + H]+ 408.2322; found 408.2321.
1-Benzyl-5-[(3Ј-methoxy-1,1Ј-biphenyl-2-yl)methyl]pyridin-2(1H)-
one (9e): The reaction was performed with enamide 5a (100 mg,
0.28 mmol) and 3-bromoanisole (105 mg, 0.56 mmol) in anhydrous
DMF (2 mL) with Ph3P (14.7 mg, 20 mol-%), Cs2CO3 (366 mg,
1.12 mmol), and Pd(OAc)2 (6.3 mg, 10 mol-%). After combining
the reagents at room temperature, the mixture was heated to
120 °C, as described for 5a. Purification of the crude product by
flash chromatography (ethyl acetate/hexane, 1:4 to 7:3) furnished
biarylpyridinone 9e (75 mg, 70%) as a brown viscous oil. Rf = 0.35
(ethyl acetate/hexane, 4:1). IR (neat): ν = 3025, 2922, 1666, 1598,
˜
1537, 1496, 1481, 1445, 1388, 1352, 1263, 1141, 1074, 1030, 826,
1
761, 698 cm–1. H NMR (400 MHz, CDCl3): δ = 7.38–7.10 (m, 9
H, Ar-H), 7.12 (d, 2 H) and 7.02 (d, J = 7.9 Hz, 2 H, Ar-H), 6.99
(dd, J = 9.4, 2.5 Hz, 1 H, H-4), 6.54 (d, J = 2.5 Hz, 1 H, H-6), 6.48
(d, J = 9.4 Hz, 1 H, H-3), 4.97 (s, 2 H, NCH2Ph), 3.62 (s, 2 H,
CH2Ar), 2.38 (s, 3 H, ArCH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 161.9 (C=O), 142.2 (C-2Ј), 141.1 (C-6), 138.3 (C-1ЈЈ), 136.7 (2
C, C), 136.5 (C), 135.2 (C-4), 130.4 (CH), 129.7 (CH), 128.9 (2 C,
CH), 128.8 (2 C, CH), 128.7 (2 C, CH), 127.9 (2 C, CH), 127.8
(CH), 127.5 (CH), 126.7 (CH), 120.7 (C-3), 119.0 (C-5), 51.7
(NCH2Ph), 35.3 (CH2Ar), 21.1 (ArCH3) ppm. HRMS (ESI): calcd.
for C26H24NO [M + H]+ 366.1852; found 366.1852.
(ethyl acetate/hexane, 4:1). IR (neat): ν = 3061, 2935, 1667, 1598,
˜
1537, 1495, 1476, 1454, 1352, 1263, 1220, 1176, 1043, 1020, 834,
1
761, 698 cm–1. H NMR (400 MHz, CDCl3): δ = 7.38–7.12 (m, 10
H, Ar-H), 6.97 (dd, J = 9.4, 2.5 Hz, 1 H, H-4), 6.86 (dd, J = 8.1,
1.8 Hz, 1 H, H-4ЈЈ), 6.71 (d, J = 8.1 Hz, 1 H, H-6ЈЈ), 6.70 (d, J =
1.8 Hz, 1 H, H-2ЈЈ), 6.57 (d, J = 2.5 Hz, 1 H, H-6), 6.48 (d, J =
9.4 Hz, 1 H, H-3), 4.97 (s, 2 H, NCH2Ph), 3.74 (s, 3 H, OCH3),
3.62 (s, 2 H, CH2Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.8
(C=O), 159.3 (C-3ЈЈ), 142.6 (C-2Ј), 142.1 (C-1ЈЈ), 141.0 (C-6), 136.6
(C), 136.5 (C), 135.2 (C-4), 130.1 (CH), 129.7 (CH), 129.1 (CH),
128.7 (2 C, CH), 127.9 (2 C, CH), 127.8 (CH), 127.7 (CH), 126.7
(CH), 121.4 (CH), 120.7 (C-3), 118.8 (C-5), 114.5 (CH), 112.6
(CH), 55.1 (OCH3), 51.6 (NCH2Ph), 35.3 (CH2Ar) ppm. HRMS
(ESI): calcd. for C26H24NO2 [M + H]+ 382.1802; found 382.1803.
1-Benzyl-5-[(3Ј,5Ј-dimethyl-1,1Ј-biphenyl-2-yl)methyl]pyridin-2(1H)-
one (9c): The reaction was performed with enamide 5a (100 mg,
0.28 mmol) and bromoxylene (104 mg, 0.56 mmol) in anhydrous
DMF (2 mL) with Ph3P (14.7 mg, 20 mol-%), Cs2CO3 (366 mg,
1.12 mmol), and Pd(OAc)2 (6.3 mg, 10 mol-%). After combining
the reagents at room temperature, the mixture was heated to
120 °C, as described for 5a. Purification of the crude product by
flash chromatography (ethyl acetate/hexane, 1:4 to 1:1) furnished
the biarylpyridinone 9c (76 mg, 71%) as a brown viscous oil. Rf =
1-Benzyl-5-[(4Ј-methoxy-1,1Ј-biphenyl-2-yl)methyl]pyridin-2(1H)-
one (9f): The reaction was performed with enamide 5a (100 mg,
0.28 mmol) and 4-bromoanisole (105 mg, 0.56 mmol) in anhydrous
DMF (2 mL) with Ph3P (14.7 mg, 20 mol-%), Cs2CO3 (366 mg,
1.12 mmol), and Pd(OAc)2 (6.3 mg, 10 mol-%). After combining
the reagents at room temperature, the mixture was heated to
120 °C, as described for 5a. Purification of the crude product by
flash chromatography (ethyl acetate/hexane, 1:4 to 7:3) furnished
biarylpyridinone 9f (64 mg, 60%) as a brown viscous oil. Rf = 0.35
0.48 (ethyl acetate/hexane, 4:1). IR (neat): ν = 3028, 2918, 1667,
˜
1601, 1536, 1495, 1453, 1352, 1260, 1140, 1074, 1030, 852, 834,
1
762, 698 cm–1. H NMR (400 MHz, CDCl3): δ = 7.38–7.10 (m, 9
H, Ar-H), 6.98 (s, 1 H, H-4ЈЈ), 6.97 (dd, J = 9.4, 2.5 Hz, 1 H, H-
4), 6.77 (s, 2 H, H-2ЈЈ, H-6ЈЈ), 6.58 (d, J = 2.5 Hz, 1 H, H-6), 6.49
(d, J = 9.4 Hz, 1 H, H-3), 4.99 (s, 2 H, NCH2Ph), 3.62 (s, 2 H,
CH2Ar), 2.30 (s, 6 H, 2 ArCH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 161.8 (C=O), 142.4 (C-2Ј), 141.2 (2 C, C-1ЈЈ, C-6),
137.6 (2 C, C), 136.6 (C), 136.5 (C), 135.2 (C-4), 130.2 (CH), 129.6
(CH), 128.7 (2 C, CH), 128.5 (CH), 127.9 (2 C, CH), 127.8 (CH),
127.4 (CH), 126.8 (2 C, CH), 126.6 (CH), 120.6 (C-3), 119.1 (C-5),
51.6 (NCH2Ph), 35.3 (CH2Ar), 21.2 (2 C, 2 ArCH3) ppm. HRMS
(ESI): calcd. for C27H26NO [M + H]+ 380.2009; found 380.2008.
(ethyl acetate/hexane, 4:1). IR (neat): ν = 3061, 3029, 2934, 2836,
˜
1667, 1598, 1537, 1496, 1454, 1353, 1295, 1244, 1177, 1141, 1106,
1074, 1035, 1002, 834, 765, 698 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.38–7.23 (m, 5 H, Ar-H), 7.23–7.12 (m, 4 H, Ar-H), 7.04 (d,
2 H) and 6.84 (d, J = 8.7 Hz, 2 H, Ar-H], 6.99 (dd, J = 9.4, 2.5 Hz,
1 H, H-4), 6.54 (d, J = 2.5 Hz, 1 H, H-6), 6.48 (d, J = 9.4 Hz, 1
H, H-3), 4.98 (s, 2 H, NCH2Ph), 3.83 (s, 3 H, OCH3), 3.61 (s, 2 H,
CH2Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.8 (C=O),
158.7 (C-4ЈЈ), 141.9 (C-2Ј), 141.0 (C-6), 136.8 (C), 136.5 (C), 135.1
(C-4), 133.6 (C-1ЈЈ), 130.5 (CH), 130.1 (2 C, CH), 129.7 (CH),
128.7 (2 C, CH), 127.9 (2 C, CH), 127.8 (CH), 127.4 (CH), 126.7
(CH), 120.7 (C-3), 118.9 (C-5), 113.5 (2 C, CH), 55.2 (OCH3), 51.6
(NCH2Ph), 35.4 (CH2Ar) ppm. HRMS (ESI): calcd. for
C26H24NO2 [M + H]+ 382.1802; found 382.1801.
1-Benzyl-5-[(4Ј-tert-butyl-1,1Ј-biphenyl-2-yl)methyl]pyridin-2(1H)-
one (9d): The reaction was performed with enamide 5a (100 mg,
0.28 mmol) and 4-tert-butylbromobenzene (119.7 mg, 0.56 mmol)
in anhydrous DMF (2 mL) with Ph3P (14.7 mg, 20 mol-%), Cs2CO3
(366 mg, 1.12 mmol), and Pd(OAc)2 (6.3 mg, 10 mol-%). After
combining the reagents at room temperature, the mixture was
heated to 120 °C, as described for 5a. Purification of the crude
product by flash chromatography (ethyl acetate/hexane, 1:4 to 1:1)
furnished biarylpyridinone 9d (77 mg, 67%) as a brown viscous oil.
1-Benzyl-5-[(5-methyl-1,1Ј-biphenyl-2-yl)methyl]pyridin-2(1H)-one
(9g): The reaction was performed with enamide 5b (100 mg,
0.27 mmol) and bromobenzene (85 mg, 0.55 mmol) in anhydrous
DMF (2 mL) with Ph3P (14 mg, 20 mol-%), Cs2CO3 (352 mg,
1.1 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). After combining the
R = 0.5 (ethyl acetate/hexane, 4:1). IR (neat): ν = 3027, 2962, 2867,
˜
f
1668, 1599, 1537, 1496, 1482, 1454, 1397, 1362, 1266, 1141, 1029,
1
1005, 836, 766, 697 cm–1. H NMR (400 MHz, CDCl3): δ = 7.35 reagents at room temperature, the mixture was heated to 120 °C,
(d, 2 H) and 7.10 (d, J = 8.1 Hz, 2 H, Ar-H), 7.38–7.10 (m, 9 H,
Ar-H), 6.99 (dd, J = 9.4, 2.5 Hz, 1 H, H-4), 6.61 (d, J = 2.5 Hz, 1
H, H-6), 6.49 (d, J = 9.4 Hz, 1 H, H-3), 4.99 (s, 2 H, NCH2Ph), 3.65
(s, 2 H, CH2Ar), 1.36 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz,
as described for 5a. Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 1:4 to 3:2) furnished biaryl-
pyridinone 9g (62 mg, 63%) as a brown viscous oil. Rf = 0.45 (ethyl
acetate/hexane, 4:1). IR (neat): ν = 3028, 2923, 2853, 1667, 1600,
˜
CDCl3): δ = 161.8 (C=O), 149.9 (C-4ЈЈ), 142.1 (C-2Ј), 141.2 (C-6), 1496, 1487, 1454, 1443, 1388, 1352, 1260, 1142, 1073, 1029, 825,
138.2 (C-1ЈЈ), 136.8 (C), 136.4 (C), 135.2 (C-4), 130.4 (CH), 129.6
757, 734, 701 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.22
(CH), 128.7 (4 C, CH), 127.8 (CH), 127.7 (2 C, CH), 127.4 (CH), (m, 6 H, Ar-H), 7.22–7.05 (m, 6 H, Ar-H), 7.02 (s, 1 H, H-6Ј), 6.97
Eur. J. Org. Chem. 2008, 5543–5552
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5547

G. Satyanarayana, M. E. Maier
FULL PAPER
(dd, J = 9.4, 2.5 Hz, 1 H, H-4), 6.49 (d, J = 2.5 Hz, 1 H, H-6), 6.45
product by flash chromatography (ethyl acetate/hexane, 1:4 to 1:1)
(d, J = 9.4 Hz, 1 H, H-3), 4.95 (s, 2 H, NCH2Ph), 3.57 (s, 2 H, furnished biarylpyridinone 9j (80 mg, 70%) as a brown viscous oil.
CH2Ar), 2.35 (s, 3 H, ArCH3) ppm. 13C NMR (100 MHz, CDCl3):
R = 0.5 (ethyl acetate/hexane, 4:1). IR (neat): ν = 3029, 2961, 1668,
˜
f
δ = 161.9 (C=O), 142.1 (C-2Ј), 141.4 (C-1ЈЈ), 141.0 (C-6), 136.5 (C),
1601, 1537, 1495, 1454, 1392, 1362, 1260, 1142, 1074, 1030, 836,
136.4 (C), 135.0 (C-4), 133.6 (C), 131.1 (CH), 129.7 (CH), 129.0 (2 729, 697 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.34 (d, 2 H) and
C, CH), 128.7 (2 C, CH), 128.3 (CH), 128.1 (2 C, CH), 127.9 (2 7.09 (d, J = 8.1 Hz, 2 H, Ar-H), 7.38–7.12 (m, 5 H, Ar-H), 7.14–
C, CH), 127.8 (CH), 126.9 (CH), 120.7 (C-3), 119.0 (C-5), 51.7
(NCH2Ph), 35.0 (CH2Ar), 20.9 (ArCH3) ppm. HRMS (ESI): calcd.
for C26H24NO [M + H]+ 366.1852; found 366.1854.
7.05 (m, 2 H, Ar-H), 7.05 (s, 1 H, H-6Ј), 6.99 (dd, J = 9.4, 2.5 Hz,
1 H, H-4), 6.61 (d, J = 2.5 Hz, 1 H, H-6), 6.49 (d, J = 9.4 Hz, 1
H, H-3), 4.99 (s, 2 H, NCH2Ph), 3.61 (s, 2 H, CH2Ar), 2.35 (s, 3
H, ArCH3), 1.35 [s, 9 H, C(CH3)3] ppm. 13C NMR (100 MHz,
CDCl3): δ = 161.9 (C=O), 149.9 (C-4ЈЈ), 142.0 (C-2Ј), 141.2 (C-6),
138.3 (C-1ЈЈ), 136.5 (C), 136.2 (C), 135.1 (C-4), 133.7 (C), 131.2
(CH), 129.5 (CH), 128.7 (4 C, CH), 128.1 (CH), 127.7 (3 C, CH),
125.0 (2 C, CH), 120.7 (C-3), 119.3 (C-5), 51.8 (NCH2Ph), 34.8
(CH2Ar), 34.5 (C), 31.4 [3 C, C(CH3)3], 20.9 (ArCH3) ppm. HRMS
(ESI): calcd. for C30H32NO [M + H]+ 422.2480; found 422.2478.
1-Benzyl-5-[(4Ј,5-dimethyl-1,1Ј-biphenyl-2-yl)methyl]pyridin-2(1H)-
one (9h): The reaction was performed with enamide 5b (100 mg,
0.27 mmol) and 4-bromotoluene (92.4 mg, 0.54 mmol) in anhy-
drous DMF (2 mL) with Ph3P (14 mg, 20 mol-%), Cs2CO3
(352 mg, 1.1 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). After com-
bining the reagents at room temperature, the mixture was heated
to 120 °C, as described for 5a. Purification of the crude product by
flash chromatography (ethyl acetate/hexane, 1:4 to 3:2) furnished
biarylpyridinone 9h (67 mg, 65%) as a brown viscous oil. Rf = 0.45
1-Benzyl-5-[(3Ј-methoxy-5-methyl-1,1Ј-biphenyl-2-yl)methyl]pyridin-
2(1H)-one (9k): The reaction was performed with enamide 5b
(100 mg, 0.27 mmol) and 3-bromoanisole (101 mg, 0.54 mmol) in
anhydrous DMF (2 mL) with Ph3P (14 mg, 20 mol-%), Cs2CO3
(352 mg, 1.1 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). After com-
bining the reagents at room temperature, the mixture was heated
to 120 °C, as described for 5a. Purification of the crude product by
flash chromatography (ethyl acetate/hexane, 1:4 to 7:3) furnished
biarylpyridinone 9k (69 mg, 64%) as a brown viscous oil. Rf = 0.35
(ethyl acetate/hexane, 4:1). IR (neat): ν = 3029, 2921, 1667, 1599,
˜
1537, 1515, 1495, 1454, 1352, 1262, 1176, 1142, 1074, 1030, 908,
824, 736, 698 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.38–6.95
(m, 12 H, Ar-H), 6.99 (dd, J = 9.4, 2.5 Hz, 1 H, H-4), 6.54 (d, J =
2.5 Hz, 1 H, H-6), 6.49 (d, J = 9.4 Hz, 1 H, H-3), 4.97 (s, 2 H,
NCH2Ph), 3.58 (s, 2 H, CH2Ar), 2.38 (s, 3 H) and 2.34 (s, 3 H, 2
ArCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.9 (C=O),
142.0 (C-2Ј), 141.1 (C-6), 138.5 (C-1ЈЈ), 136.5 (2 C, C), 136.3 (C),
135.1 (C-4), 133.6 (C), 131.1 (CH), 129.6 (CH), 128.9 (2 C, CH),
128.8 (2 C, CH), 128.7 (2 C, CH), 128.2 (CH), 127.9 (2 C, CH),
127.8 (CH), 120.7 (C-3), 119.2 (C-5), 51.7 (NCH2Ph), 34.9
(CH2Ar), 21.1 (CH3) and 20.9 (CH3, 2 ArCH3) ppm. HRMS (ESI):
calcd. for C27H26NO [M + H]+ 380.2009; found 380.2011.
(ethyl acetate/hexane, 4:1). IR (neat): ν = 3030, 2924, 1667, 1599,
˜
1536, 1481, 1454, 1352, 1262, 1223, 1165, 1036, 822, 792, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.15 (m, 6 H, Ar-H), 7.11
(1 H, H-4Ј) and 7.07 (2d, J = 7.9 Hz, 1 H, H-3Ј), 7.04 (s, 1 H, H-
6Ј), 6.97 (dd, J = 9.4, 2.5 Hz, 1 H, H-4), 6.86 (dd, J = 8.1, 1.8 Hz,
1 H, H-4ЈЈ), 6.71 (d, J = 8.1 Hz, 1 H, H-6ЈЈ), 6.69 (d, J = 1.8 Hz,
1 H, H-2ЈЈ), 6.56 (d, J = 2.5 Hz, 1 H, H-6), 6.47 (d, J = 9.4 Hz, 1
H, H-3), 4.97 (s, 2 H, NCH2Ph), 3.74 (s, 3 H, OCH3), 3.58 (s, 2 H,
CH2Ar), 2.35 (s, 3 H, ArCH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 161.9 (C=O), 159.3 (C-3ЈЈ), 142.8 (C-2Ј), 141.9 (C-1ЈЈ), 141.1
(C-6), 136.5 (C), 136.3 (C), 135.1 (C-4), 133.5 (C), 130.9 (CH),
129.6 (CH), 129.1 (CH), 128.7 (2 C, CH), 128.4 (CH), 127.9 (2 C,
CH), 127.8 (CH), 121.4 (CH), 120.7 (C-3), 119.2 (C-5), 114.5 (CH),
112.5 (CH), 55.2 (OCH3), 51.7 (NCH2Ph), 34.9 (CH2Ar), 20.9
(ArCH3) ppm. HRMS (ESI): calcd. for C27H26NO2 [M + H]+
396.1958; found 396.1959.
1-Benzyl-5-[(3Ј,5,5Ј-trimethyl-1,1Ј-biphenyl-2-yl)methyl]pyridin-
2(1H)-one (9i): The reaction was performed with enamide 5b
(100 mg, 0.27 mmol) and bromoxylene (100 mg, 0.54 mmol) in an-
hydrous DMF (2 mL) with Ph3P (14 mg, 20 mol-%), Cs2CO3
(352 mg, 1.1 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). After com-
bining the reagents at room temperature, the mixture was heated
to 120 °C, as described for 5a. Purification of the crude product by
flash chromatography (ethyl acetate/hexane, 1:4 to 1:1) furnished
biarylpyridinone 9i (73 mg, 68%) as a brown viscous oil. Rf = 0.48
(ethyl acetate/hexane, 4:1). IR (neat): ν = 3029, 2918, 1668, 1597,
˜
1-Benzyl-5-[(4Ј-methoxy-5-methyl-1,1Ј-biphenyl-2-yl)methyl]pyridin-
2(1H)-one (9l): The reaction was performed with enamide 5b
(100 mg, 0.27 mmol) and 4-bromoanisole (101 mg, 0.54 mmol) in
anhydrous DMF (2 mL) with Ph3P (14 mg, 20 mol-%), Cs2CO3
(352 mg, 1.1 mmol), and Pd(OAc)2 (6 mg, 10 mol-%). After com-
bining the reagents at room temperature, the mixture was heated
to 120 °C, as described for 5a. Purification of the crude product by
flash chromatography (ethyl acetate/hexane, 1:4 to 7:3) furnished
biarylpyridinone 9l (57 mg, 53%) as a brown viscous oil. Rf = 0.35
1537, 1496, 1454, 1351, 1258, 1140, 1073, 1031, 852, 825, 795, 736,
698 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.15 (m, 5 H, Ar-
H), 7.09 (1 H, H-4Ј) and 7.05 (2 d, J = 7.9 Hz, 1 H, H-3Ј), 7.03 (s,
1 H, H-6Ј), 6.97 (s, 1 H, H-4ЈЈ), 6.97 (dd, J = 9.4, 2.5 Hz, 1 H, H-
4), 6.77 (s, 2 H, H-2ЈЈ, H-6ЈЈ), 6.58 (d, J = 2.5 Hz, 1 H, H-6), 6.48
(d, J = 9.4 Hz, 1 H, H-3), 4.98 (s, 2 H, NCH2Ph), 3.58 (s, 2 H,
CH2Ar), 2.35 (s, 3 H) and 2.30 (s, 6 H, 3 ArCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 161.8 (C=O), 142.3 (C-2Ј), 141.4 (C-1ЈЈ),
141.2 (C-6), 137.5 (2 C, C), 136.5 (C), 136.2 (C), 135.1 (C-4), 133.6
(C), 130.9 (CH), 129.5 (CH), 128.7 (2 C, CH), 128.4 (CH), 128.1
(CH), 127.9 (2 C, CH), 127.8 (CH), 126.8 (2 C, CH), 120.6 (C-3),
119.3 (C-5), 51.6 (NCH2Ph), 34.9 (CH2Ar), 21.2 (2 C) and 20.9
(C, 3 ArCH3) ppm. HRMS (ESI): calcd. for C28H28NO [M + H]+
394.2165; found 394.2166.
(ethyl acetate/hexane, 4:1). IR (neat): ν = 3031, 2930, 1667, 1600,
˜
1
1537, 1495, 1454, 1292, 1245, 1176, 1073, 1029, 834, 696 cm–1. H
NMR (400 MHz, CDCl3): δ = 7.38–7.22 (m, 3 H, Ar-H), 7.19 (d,
J = 7.9 Hz, 2 H, Ar-H), 7.09 (1 H, H-4Ј) and 7.06 (2d, J = 7.9 Hz,
1 H, H-3Ј), 7.04 (d, 2 H) and 6.84 (d, J = 8.7 Hz, 2 H, Ar-H), 7.01
(s, 1 H, H-6Ј), 6.99 (dd, J = 9.4, 2.5 Hz, 1 H, H-4), 6.54 (d, J =
1-Benzyl-5-[(4Ј-tert-butyl-5-methyl-1,1Ј-biphenyl-2-yl)methyl]- 2.5 Hz, 1 H, H-6), 6.48 (d, J = 9.4 Hz, 1 H, H-3), 4.98 (s, 2 H,
pyridin-2(1H)-one (9j): The reaction was performed with enamide
5b (100 mg, 0.27 mmol) and 4-tert-butyl-bromobenzene (113 mg,
0.54 mmol) in anhydrous DMF (2 mL) with Ph3P (14 mg, 20 mol-
%), Cs2CO3 (352 mg, 1.1 mmol), and Pd(OAc)2 (6 mg, 10 mol-%).
After combining the reagents at room temperature, the mixture was
heated to 120 °C, as described for 5a. Purification of the crude
NCH2Ph), 3.82 (s, 3 H, OCH3), 3.58 (s, 2 H, CH2Ar), 2.34 (s, 3 H,
ArCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.9 (C=O),
158.6 (C-4ЈЈ), 141.7 (C-2Ј), 141.1 (C-6), 136.5 (C), 136.3 (C), 135.0
(C-4), 133.8 (2 C, C), 131.3 (CH), 130.0 (2 C, CH), 129.6 (CH),
128.7 (2 C, CH), 128.1 (CH), 127.9 (2 C, CH), 127.8 (CH), 120.7
(C-3), 119.2 (C-5), 113.5 (2 C, CH), 55.2 (OCH3), 51.6 (NCH2Ph),
5548
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5543–5552

Unsymmetrical Biaryls by Palladium-Catalyzed Coupling Reactions
34.9 (CH2Ar), 20.9 (ArCH3) ppm. HRMS (ESI): calcd. for
C27H26NO2 [M + H]+ 396.1958; found 396.1958.
2.5 Hz, 1 H, H-4), 6.95 (s, 1 H, H-4ЈЈ), 6.81 (dd, J = 8.4, 2.5 Hz, 1
H, H-5Ј), 6.76 (s, 2 H, H-2ЈЈ, H-6ЈЈ), 6.69 (d, J = 2.5 Hz, 1 H, H-
3Ј), 6.62 (d, J = 2.5 Hz, 1 H, H-6), 6.51 (d, J = 9.4 Hz, 1 H, H-3),
5.00 (s, 2 H, NCH2Ph), 3.78 (s, 3 H, OCH3), 3.59 (s, 2 H, CH2Ar),
2.29 (s, 6 H, 2 ArCH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
161.9 (C=O), 158.8 (C-4Ј), 141.2 (C-6), 140.9 (C), 138.0 (C), 137.6
(2 C, C), 136.5 (C), 135.2 (CH, C-4), 135.0 (C), 131.2 (CH), 128.7
(2 C, CH), 128.3 (CH), 127.9 (2 C, CH), 127.8 (CH), 127.1 (2 C,
CH), 120.7 (C-3), 119.0 (C-5), 115.2 (CH), 111.6 (CH), 55.2
(OCH3), 51.6 (NCH2Ph), 35.5 (CH2Ar), 21.2 (2 C, 2 ArCH3) ppm.
HRMS (ESI): calcd. for C28H28NO2 [M + H]+ 410.2115; found
410.2111.
1-Benzyl-5-[(4-methoxy-1,1Ј-biphenyl-2-yl)methyl]pyridin-2(1H)-one
(9m): The reaction was performed with enamide 5c (100 mg,
0.26 mmol) and bromobenzene (81 mg, 0.52 mmol) in anhydrous
DMF (2 mL) with Ph3P (13.6 mg, 20 mol-%), Cs2CO3 (337.7 mg,
1.0 mmol), and Pd(OAc)2 (5.8 mg, 10 mol-%). After combining the
reagents at room temperature, the mixture was heated to 120 °C,
as described for 5a. Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 1:4 to 3:2) furnished biaryl-
pyridinone 9m (62 mg, 63%) as a brown viscous oil. Rf = 0.38
(ethyl acetate/hexane, 4:1). IR (neat): ν = 3029, 2924, 1666, 1599,
˜
1
1537, 1483, 1443, 1234, 1157, 1049, 832, 766, 700 cm–1. H NMR
1-Benzyl-5-[(4Ј-tert-butyl-4-methoxy-1,1Ј-biphenyl-2-yl)methyl]-
pyridin-2(1H)-one (9p): The reaction was performed with enamide
5c (100 mg, 0.26 mmol) and 4-tert-butyl-bromobenzene (110 mg,
0.52 mmol) in anhydrous DMF (2 mL) with Ph3P (13.6 mg,
20 mol-%), Cs2CO3 (337.7 mg, 1.0 mmol), and Pd(OAc)2 (5.8 mg,
10 mol-%). After combining the reagents at room temperature, the
mixture was heated to 120 °C, as described for 5a. Purification of
the crude product by flash chromatography (ethyl acetate/hexane,
1:4 to 3:2) furnished biarylpyridinone 9p (77 mg, 68%) as a brown
(400 MHz, CDCl3): δ = 7.38–7.23 (m, 6 H, Ar-H), 7.23–7.06 (m, 4
H, Ar-H), 7.13 (d, J = 8.4 Hz, 1 H, H-6Ј), 6.98 (dd, J = 9.4,
2.54 Hz, 1 H, H-4), 6.83 (dd, J = 8.4, 2.8 Hz, 1 H, H-5Ј), 6.70 (d,
J = 2.8 Hz, 1 H, H-3Ј), 6.53 (d, J = 2.5 Hz, 1 H, H-6), 6.47 (d, J
= 9.4 Hz, 1 H, H-3), 4.97 (s, 2 H, NCH2Ph), 3.79 (s, 3 H, OCH3),
3.59 (s, 2 H, CH2Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.9
(C=O), 158.9 (C-4Ј), 141.0 (2 C, C and CH, C-6), 138.0 (C), 136.5
(C), 135.1 (C-4), 134.8 (C), 131.4 (CH), 129.3 (2 C, CH), 128.7 (2
C, CH), 128.1 (2 C, CH), 127.9 (2 C, CH), 127.8 (CH), 126.8 (CH),
120.8 (C-3), 118.6 (C-5), 115.4 (CH), 111.7 (CH), 55.2 (OCH3),
51.6 (NCH2Ph), 35.5 (CH2Ar) ppm. HRMS (ESI): calcd. for
C26H24NO2 [M + H]+ 382.1802; found 382.1802.
viscous oil. R = 0.45 (ethyl acetate/hexane, 4:1). IR (neat): ν =
˜
f
3029, 2868, 1667, 1604, 1537, 1492, 1462, 1454, 1362, 1268, 1235,
1158, 1115, 1050, 1003, 834, 779, 733, 699 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 7.32 (d, 2 H) and 7.07 (d, J = 8.5 Hz, 2 H,
Ar-H), 7.38–7.13 (m, 5 H, Ar-H), 7.14 (d, J = 8.4 Hz, 1 H, H-6Ј),
7.00 (dd, J = 9.4, 2.8 Hz, 1 H, H-4), 6.82 (dd, J = 8.4, 2.5 Hz, 1
H, H-5Ј), 6.69 (d, J = 2.5 Hz, 1 H, H-3Ј), 6.63 (d, J = 2.5 Hz, 1 H,
H-6), 6.50 (d, J = 9.4 Hz, 1 H, H-3), 4.99 (s, 2 H, NCH2Ph), 3.78
(s, 3 H, OCH3), 3.61 (s, 2 H, CH2Ar), 1.34 [s, 9 H, C(CH3)3] ppm.
13C NMR (100 MHz, CDCl3): δ = 161.9 (C=O), 158.8 (C-4Ј), 149.7
(C-4ЈЈ), 141.2 (C-6), 138.1 (C), 137.9 (C), 136.5 (C), 135.3 (C-4),
134.7 (C), 131.4 (CH), 129.0 (2 C, CH), 128.7 (2 C, CH), 127.8 (3
C, CH), 125.0 (2 C, CH), 120.8 (C-3), 118.9 (C-5), 115.2 (CH),
111.7 (CH), 55.2 (OCH3), 51.7 (NCH2Ph), 35.4 (CH2Ar), 34.5 (C),
31.4 [3 C, C(CH3)3] ppm. HRMS (ESI): calcd. for C30H32NO2 [M
+ H]+ 438.2428; found 438.2427.
1-Benzyl-5-[(4-methoxy-4Ј-methyl-1,1Ј-biphenyl-2-yl)methyl]pyridin-
2(1H)-one (9n): The reaction was performed with enamide 5c
(100 mg, 0.26 mmol) and 4-bromotoluene (88.6 mg, 0.52 mmol) in
anhydrous DMF (2 mL) with Ph3P (13.6 mg, 20 mol-%), Cs2CO3
(337.7 mg, 1.0 mmol), and Pd(OAc)2 (5.8 mg, 10 mol-%). After
combining the reagents at room temperature, the mixture was
heated to 120 °C, as described for 5a. Purification of the crude
product by flash chromatography (ethyl acetate/hexane, 1:4 to 3:2)
furnished biarylpyridinone 9n (70 mg, 68%) as a brown viscous oil.
R = 0.38 (ethyl acetate/hexane, 4:1). IR (neat): ν = 3028, 2924,
˜
f
1667, 1601, 1537, 1491, 1454, 1352, 1266, 1234, 1158, 1111, 1049,
1
1004, 830, 728, 697 cm–1. H NMR (400 MHz, CDCl3): δ = 7.38–
1-Benzyl-5-[(3Ј,4-dimethoxy-1,1Ј-biphenyl-2-yl)methyl]pyridin-
2(1H)-one (9q): The reaction was performed with enamide 5c
(100 mg, 0.26 mmol) and 3-bromoanisole (97 mg, 0.52 mmol) in
anhydrous DMF (2 mL) with Ph3P (13.6 mg, 20 mol-%), Cs2CO3
(337.7 mg, 1.0 mmol), and Pd(OAc)2 (5.8 mg, 10 mol-%). After
combining the reagents at room temperature, the mixture was
heated to 120 °C, as described for 5a. Purification of the crude
product by flash chromatography (ethyl acetate/hexane, 1:4 to 7:3)
first furnished biarylpyridinone 9q (70 mg, 66%) as a brown vis-
7.15 (m, 5 H, Ar-H), 7.12 (d, J = 8.4 Hz, 1 H, H-6Ј), 7.10 (d, 2 H)
and 7.00 (d, J = 7.9 Hz, 2 H, Ar-H), 6.99 (dd, J = 9.4, 2.5 Hz, 1
H, H-4), 6.81 (dd, J = 8.4, 2.5 Hz, 1 H, H-5Ј), 6.70 (d, J = 2.5 Hz,
1 H, H-3Ј), 6.56 (d, J = 2.5 Hz, 1 H, H-6), 6.50 (d, J = 9.4 Hz, 1
H, H-3), 4.98 (s, 2 H, NCH2Ph), 3.78 (s, 3 H, OCH3), 3.59 (s, 2 H,
CH2Ar), 2.37 (s, 3 H, ArCH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 161.9 (C=O), 158.8 (C-4Ј), 141.1 (C-6), 138.0 (2 C, C), 136.5
(C), 136.4 (C), 135.2 (C-4), 134.8 (C), 131.4 (CH), 129.2 (2 C, CH),
128.8 (4 C, CH), 127.9 (2 C, CH), 127.8 (CH), 120.8 (C-3), 118.9
(C-5), 115.3 (CH), 111.7 (CH), 55.2 (OCH3), 51.7 (NCH2Ph), 35.5
(CH2Ar), 21.1 (ArCH3) ppm. HRMS (ESI): calcd. for C27H26NO2
[M + H]+ 396.1958; found 396.1957.
cous oil. R = 0.32 (ethyl acetate/hexane, 4:1). IR (neat): ν = 3029,
˜
f
2935, 1667, 1599, 1537, 1505, 1496, 1479, 1454, 1389, 1352, 1317,
1292, 1235, 1222, 1159, 1115, 1075, 1052, 1017, 832, 731, 699 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.14 (m, 6 H, Ar-H), 7.14
(d, J = 8.4 Hz, 1 H, H-6Ј), 6.99 (dd, J = 9.4, 2.5 Hz, 1 H, H-4),
6.85 (dd, J = 8.4, 1.8 Hz, 1 H, H-4ЈЈ), 6.82 (dd, J = 8.4, 2.5 Hz, 1
1-Benzyl-5-[(4-methoxy-3Ј,5Ј-dimethyl-1,1Ј-biphenyl-2-yl)methyl]-
pyridin-2(1H)-one (9o): The reaction was performed with enamide
5c (100 mg, 0.26 mmol) and bromoxylene (96 mg, 0.52 mmol) in H, H-5Ј), 6.70 (d, J = 2.5 Hz, 1 H, H-3Ј), 6.69 (d, J = 8.4 Hz, 1 H,
anhydrous DMF (2 mL) with Ph3P (13.6 mg, 20 mol-%), Cs2CO3 H-6ЈЈ), 6.68 (d, J = 1.8 Hz, 1 H, H-2Ј), 6.60 (d, J = 2.5 Hz, 1 H,
(337.7 mg, 1.0 mmol), and Pd(OAc)2 (5.8 mg, 10 mol-%). After H-6), 6.48 (d, J = 9.4 Hz, 1 H, H-3), 4.98 (s, 2 H, NCH2Ph), 3.78
combining the reagents at room temperature, the mixture was
heated to 120 °C, as described for 5a. Purification of the crude
product by flash chromatography (ethyl acetate/hexane, 1:4 to 3:2)
furnished biarylpyridinone 9o (68 mg, 64%) as a brown viscous oil.
(s, 3 H) and 3.74 (s, 3 H, 2 OCH3), 3.59 (s, 2 H, CH2Ar) ppm. 13C
NMR (100 MHz, CDCl3): δ = 161.8 (C=O), 159.3 (C-3ЈЈ), 159.0
(C-4Ј), 142.4 (C), 141.0 (C-6), 138.0 (C), 136.5 (C), 135.2 (C-4),
134.6 (C), 131.2 (CH), 129.1 (CH), 128.7 (2 C, CH), 127.9 (2 C,
CH), 127.8 (CH), 121.8 (CH), 120.8 (C-3), 118.7 (C-5), 115.4 (CH),
114.9 (CH), 112.3 (CH), 111.7 (CH), 55.2, 55.1 (2 OCH3), 51.6
R = 0.42 (ethyl acetate/hexane, 4:1). IR (neat): ν = 3028, 2915,
˜
f
1667, 1602, 1537, 1497, 1454, 1352, 1295, 1234, 1157, 1077, 1038,
854, 832, 698 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.16 (NCH2Ph), 35.5 (CH2Ar) ppm. HRMS (ESI): calcd. for
(m, 5 H, Ar-H), 7.13 (d, J = 8.4 Hz, 1 H, H-6Ј), 6.99 (dd, J = 9.4,
C27H26NO3 [M + H]+ 412.1907; found 412.1907.
Eur. J. Org. Chem. 2008, 5543–5552
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5549

G. Satyanarayana, M. E. Maier
FULL PAPER
1-Benzyl-5-[(4,4Ј-dimethoxy-1,1Ј-biphenyl-2-yl)methyl]pyridin-
2(1H)-one (9r): The reaction was performed with enamide 5c
(100 mg, 0.26 mmol) and 4-bromoanisole (97 mg, 0.52 mmol) in
9.4 Hz, 1 H, H-3), 4.97 (s, 2 H, NCH2Ph), 3.79 (s, 3 H, OCH3),
3.54 (s, 2 H, CH2Ar), 2.38 (s, 3 H, ArCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 161.9 (C=O), 158.1 (C-5Ј), 143.3 (C-1Ј),
anhydrous DMF (2 mL) with Ph3P (13.6 mg, 20 mol-%), Cs2CO3 141.1 (C-6), 138.3 (C), 136.7 (C), 136.5 (C), 135.0 (C-4), 130.7
(337.7 mg, 1.0 mmol), and Pd(OAc)2 (5.8 mg, 10 mol-%). After (CH), 128.8 (5 C, C-2Ј, 4 CH), 128.7 (2 C, CH), 127.9 (2 C, CH),
combining the reagents at room temperature, the mixture was
heated to 120 °C, as described for 5a. Purification of the crude
product by flash chromatography (ethyl acetate/hexane, 1:4 to 7:3)
first furnished biarylpyridinone 9r (56 mg, 53%) as a brown viscous
127.8 (CH), 120.7 (C-3), 119.5 (C-5), 115.6 (CH), 113.1 (CH), 55.2
(OCH3), 51.7 (NCH2Ph), 34.5 (CH2Ar), 21.1 (ArCH3) ppm.
HRMS (ESI): calcd. for C27H26NO2 [M + H]+ 396.1958; found
396.1958.
oil. R = 0.32 (ethyl acetate/hexane, 4:1). IR (neat): ν = 3029, 2936,
˜
f
1-Benzyl-5-[(5-methoxy-3Ј,5Ј-dimethyl-1,1Ј-biphenyl-2-yl)methyl]-
pyridin-2(1H)-one (9u): The reaction was performed with enamide
5d (100 mg, 0.26 mmol) and bromoxylene (96 mg, 0.52 mmol) in
anhydrous DMF (2 mL) with Ph3P (13.6 mg, 20 mol-%), Cs2CO3
(337.7 mg, 1.0 mmol), and Pd(OAc)2 (5.8 mg, 10 mol-%). After
combining the reagents at room temperature, the mixture was
heated to 120 °C, as described for 5a. Purification of the crude
product by flash chromatography (ethyl acetate/hexane, 1:4 to 3:2)
furnished biarylpyridinone 9u (72 mg, 68%) as a brown viscous oil.
2834, 1666, 1605, 1537, 1490, 1454, 1352, 1244, 1177, 1107, 1049,
1
1000, 834, 731, 698 cm–1. H NMR (400 MHz, CDCl3): δ = 7.38–
7.14 (m, 5 H, Ar-H), 7.11 (d, J = 8.4 Hz, 1 H, H-6Ј), 7.02 (d, 2 H)
and 6.83 (d, J = 8.7 Hz, 2 H, Ar-H), 6.99 (dd, J = 9.4, 2.5 Hz, 1
H, H-4), 6.81 (dd, J = 8.4, 2.5 Hz, 1 H, H-5Ј), 6.70 (d, J = 2.5 Hz,
1 H, H-3Ј), 6.56 (d, J = 2.5 Hz, 1 H, H-6), 6.47 (d, J = 9.4 Hz, 1
H, H-3), 4.98 (s, 2 H, NCH2Ph), 3.82 (s, 3 H) and 3.78 (s, 3 H, 2
OCH3), 3.58 (s, 2 H, CH2Ar) ppm. 13C NMR (100 MHz, CDCl3):
δ = 161.8 (C=O), 158.8 (C-4Ј), 158.5 (C-4ЈЈ), 141.0 (C-6), 138.2 (C),
136.5 (C), 135.1 (C-4), 134.4 (C), 133.3 (C), 131.5 (CH), 130.4 (2
C, CH), 128.7 (2 C, CH), 127.9 (2 C, CH), 127.8 (CH), 120.8 (C-
3), 118.7 (C-5), 115.4 (CH), 113.5 (2 C, CH), 111.7 (CH), 55.2 (2
OCH3), 51.6 (NCH2Ph), 35.6 (CH2Ar) ppm. HRMS (ESI): calcd.
for C27H26NO3 [M + H]+ 412.1907; found 412.1909.
R = 0.42 (ethyl acetate/hexane, 4:1). IR (neat): ν = 3028, 2917,
˜
f
2834, 1667, 1601, 1537, 1495, 1454, 1443, 1351, 1281, 1238, 1196,
1171, 1141, 1072, 1038, 852, 836, 796, 773, 735, 699 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.38–7.16 (m, 5 H, Ar-H), 7.07 (d, J =
8.4 Hz, 1 H, H-3Ј), 6.97 (s, 1 H, H-4ЈЈ), 6.96 (dd, J = 9.4, 2.5 Hz,
1 H, H-4), 6.82 (dd, J = 8.4, 2.5 Hz, 1 H, H-4Ј), 6.77 (s, 2 H, H-
2ЈЈ, H-6ЈЈ), 6.76 (d, J = 2.5 Hz, 1 H, H-6Ј), 6.56 (d, J = 2.5 Hz, 1
H, H-6), 6.49 (d, J = 9.4 Hz, 1 H, H-3), 4.98 (s, 2 H, NCH2Ph),
3.79 (s, 3 H, OCH3), 3.54 (s, 2 H, CH2Ar), 2.29 (s, 6 H, 2 ArCH3)
ppm. 13C NMR (100 MHz, CDCl3): δ = 161.9 (C=O), 158.0 (C-
5Ј), 143.5 (C-1Ј), 141.2 (2 C, C-1 and CH, C-6), 137.6 (2 C, C),
136.5 (C), 135.0 (C-4), 130.6 (CH), 128.7 (3 C, C-2 and 2 CH),
128.6 (CH), 127.9 (2 C, CH), 127.8 (CH), 126.7 (2 C, CH), 120.6
(C-3), 119.6 (C-5), 115.4 (CH), 113.1 (CH), 55.2 (OCH3), 51.7
(NCH2Ph), 34.5 (CH2Ar), 21.2 (2 C, 2 ArCH3) ppm. HRMS (ESI):
calcd. for C28H28NO2 [M + H]+ 410.2115; found 410.2113.
1-Benzyl-5-[(5-methoxy-1,1Ј-biphenyl-2-yl)methyl]pyridin-2(1H)-one
(9s): The reaction was performed with enamide 5d (100 mg,
0.26 mmol) and bromobenzene (81 mg, 0.52 mmol) in anhydrous
DMF (2 mL) with Ph3P (13.6 mg, 20 mol-%), Cs2CO3 (337.7 mg,
1.0 mmol), and Pd(OAc)2 (5.8 mg, 10 mol-%). After combining the
reagents at room temperature, the mixture was heated to 120 °C,
as described for 5a. Purification of the crude product by flash
chromatography (ethyl acetate/hexane, 1:4 to 3:2) furnished biaryl-
pyridinone 9s (63 mg, 64%) as a brown viscous oil. Rf = 0.38 (ethyl
acetate/hexane, 4:1). IR (neat): ν = 3028, 2935, 1667, 1601, 1537,
˜
1485, 1443, 1352, 1297, 1264, 1220, 1175, 1143, 1073, 1037, 876,
757, 735, 702 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.23
(m, 6 H, Ar-H), 7.23–7.06 (m, 5 H, Ar-H), 6.95 (dd, J = 9.4, 2.5 Hz,
1 H, H-4), 6.83 (dd, J = 8.4, 2.8 Hz, 1 H, H-4Ј), 6.75 (d, J = 2.8 Hz,
1 H, H-6Ј), 6.48 (d, J = 2.5 Hz, 1 H, H-6), 6.46 (d, J = 9.4 Hz, 1
H, H-3), 4.95 (s, 2 H, NCH2Ph), 3.80 (s, 3 H, OCH3), 3.54 (s, 2 H,
CH2Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.9 (C=O),
158.2 (C-5Ј), 143.4 (C-1Ј), 141.3 (C-1ЈЈ), 141.0 (C-6), 136.5 (C),
134.9 (C-4), 130.8 (CH), 128.9 (2 C, CH), 128.8 (C-2Ј), 128.7 (2 C,
CH), 128.1 (2 C, CH), 127.9 (2 C, CH), 127.8 (CH), 127.1 (CH),
120.7 (C-3), 119.3 (C-5), 115.6 (CH), 113.2 (CH), 55.3 (OCH3),
51.7 (NCH2Ph), 34.6 (CH2Ar) ppm. HRMS (ESI): calcd. for
C26H24NO2 [M + H]+ 382.1802; found 382.1803.
1-Benzyl-5-[(4Ј-tert-butyl-5-methoxy-1,1Ј-biphenyl-2-yl)methyl]-
pyridin-2(1H)-one (9v): The reaction was performed with enamide
5d (100 mg, 0.26 mmol) and 4-tert-butyl-bromobenzene (110 mg,
0.52 mmol) in anhydrous DMF (2 mL) with Ph3P (13.6 mg,
20 mol-%), Cs2CO3 (337.7 mg, 1.0 mmol), and Pd(OAc)2 (5.8 mg,
10 mol-%). After combining the reagents at room temperature, the
mixture was heated to 120 °C, as described for 5a. Purification of
the crude product by flash chromatography (ethyl acetate/hexane,
1:4 to 3:2) furnished biarylpyridinone 9v (75 mg, 66%) as a brown
viscous oil. R = 0.45 (ethyl acetate/hexane, 4:1). IR (neat): ν =
˜
f
3029, 2962, 2867, 1667, 1602, 1537, 1494, 1454, 1393, 1362, 1298,
1
1267, 1176, 1140, 1107, 1093, 1039, 1013, 836, 731, 698 cm–1. H
NMR (400 MHz, CDCl3): δ = 7.33 (d, 2 H) and 7.08 (d, J = 8.4 Hz,
2 H, Ar-H), 7.38–7.12 (m, 5 H, Ar-H), 7.07 (d, J = 8.4 Hz, 1 H,
H-3Ј), 6.99 (dd, J = 9.4, 2.8 Hz, 1 H, H-4), 6.83 (dd, J = 8.4, 2.5 Hz,
1 H, H-4Ј), 6.77 (d, J = 2.8 Hz, 1 H, H-6Ј), 6.58 (d, J = 2.5 Hz, 1
H, H-6), 6.48 (d, J = 9.4 Hz, 1 H, H-3), 4.98 (s, 2 H, NCH2Ph),
3.79 (s, 3 H, OCH3), 3.56 (s, 2 H, CH2Ar), 1.34 [s, 9 H, C(CH3)3]
ppm. 13C NMR (100 MHz, CDCl3): δ = 161.9 (C=O), 158.1 (C-
5Ј), 150.1 (C-4ЈЈ), 143.3 (C-1Ј), 141.2 (C-6), 138.2 (C), 136.5 (C),
135.1 (C-4), 130.7 (CH), 128.9 (C-2Ј), 128.7 (2 C, CH), 128.6 (2 C,
CH), 127.8 (3 C, CH), 125.0 (2 C, CH), 120.7 (C-3), 119.6 (C-5),
115.6 (CH), 113.2 (CH), 55.3 (OCH3), 51.8 (NCH2Ph), 34.5 (C),
34.4 (CH2Ar), 31.4 [3 C, C(CH3)3] ppm. HRMS (ESI): calcd. for
C30H32NO2 [M + H]+ 438.2428; found 438.2426.
1-Benzyl-5-[(5-methoxy-4Ј-methyl-1,1Ј-biphenyl-2-yl)methyl]pyridin-
2(1H)-one (9t): The reaction was performed with enamide 5d
(100 mg, 0.26 mmol) and 4-bromotoluene (88.6 mg, 0.52 mmol) in
anhydrous DMF (2 mL) with Ph3P (13.6 mg, 20 mol-%), Cs2CO3
(337.7 mg, 1.0 mmol), and Pd(OAc)2 (5.8 mg, 10 mol-%). After
combining the reagents at room temperature, the mixture was
heated to 120 °C, as described for 5a. Purification of the crude
product by flash chromatography (ethyl acetate/hexane, 1:4 to 3:2)
furnished biarylpyridinone 9t (67 mg, 65%) as a brown viscous oil.
R = 0.38 (ethyl acetate/hexane, 4:1). IR (neat): ν = 3028, 2936,
˜
f
1667, 1603, 1537, 1495, 1454, 1443, 1352, 1297, 1221, 1175, 1142,
1073, 1039, 877, 825, 736, 698 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.38–7.14 (m, 5 H, Ar-H), 7.11 (d, 2 H) and 7.02 (d, J = 7.9 Hz,
2 H, Ar-H), 7.09 (d, J = 8.4 Hz, 1 H, H-3Ј), 6.99 (dd, J = 9.4,
2.5 Hz, 1 H, H-4), 6.83 (dd, J = 8.4, 2.5 Hz, 1 H, H-4Ј), 6.75 (d, J
1-Benzyl-5-[(3Ј,5-dimethoxy-1,1Ј-biphenyl-2-yl)methyl]pyridin-
2(1H)-one (9w): The reaction was performed with enamide 5d
= 2.5 Hz, 1 H, H-6Ј), 6.52 (d, J = 2.5 Hz, 1 H, H-6), 6.48 (d, J = (100 mg, 0.26 mmol) and 3-bromoanisole (97 mg, 0.52 mmol) in
5550
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5543–5552

Unsymmetrical Biaryls by Palladium-Catalyzed Coupling Reactions
[3] L. Feliu, M. Planas, Int. J. Pept. Res. Ther. 2005, 11, 53–97.
[4] S. Laschat, A. Baro, N. Steinke, F. Giesselmann, C. Hägele, G.
Scalia, R. Judele, E. Kapatsina, S. Sauer, A. Schreivogel, M.
Tosoni, Angew. Chem. 2007, 119, 4916–4973; Angew. Chem.
Int. Ed. 2007, 46, 4832–4887.
[5] R. Kandre, K. Feldman, H. E. H. Meijer, P. Smith, A. D.
Schlüter, Angew. Chem. 2007, 119, 5044–5047; Angew. Chem.
Int. Ed. 2007, 46, 4956–4959, and references cited therein.
anhydrous DMF (2 mL) with Ph3P (13.6 mg, 20 mol-%), Cs2CO3
(337.7 mg, 1.0 mmol), and Pd(OAc)2 (5.8 mg, 10 mol-%). After
combining the reagents at room temperature, the mixture was
heated to 120 °C, as described for 5a. Purification of the crude
product by flash chromatography (ethyl acetate/hexane, 1:4 to 7:3)
furnished biarylpyridinone 9w (72 mg, 67%) as a brown viscous
oil. R = 0.32 (ethyl acetate/hexane, 4:1). IR (neat): ν = 3029, 2936,
˜
f
2834, 1667, 1600, 1537, 1496, 1482, 1454, 1352, 1266, 1235, 1205,
[6]
[7]
S. P. Stanforth, Tetrahedron 1998, 54, 263–303.
O. Baudoin, Angew. Chem. 2007, 119, 1395–1397; Angew.
Chem. Int. Ed. 2007, 46, 1373–1375.
1
1170, 1141, 1074, 1030, 821, 735, 700 cm–1. H NMR (400 MHz,
CDCl3): δ = 7.38–7.14 (m, 6 H, Ar-H), 7.09 (d, J = 8.4 Hz, 1 H,
H-3Ј), 6.98 (dd, J = 9.4, 2.5 Hz, 1 H, H-4), 6.87 (dd, J = 8.4, 1.8 Hz,
1 H, H-4ЈЈ), 6.84 (dd, J = 8.4, 2.5 Hz, 1 H, H-4Ј), 6.77 (d, J =
2.5 Hz, 1 H, H-6Ј), 6.70 (d, J = 8.4 Hz, 1 H, H-6ЈЈ), 6.69 (d, J =
1.8 Hz, 1 H, H-2ЈЈ), 6.55 (d, J = 2.5 Hz, 1 H, H-6), 6.46 (d, J =
9.4 Hz, 1 H, H-3), 4.97 (s, 2 H, NCH2Ph), 3.79 (s, 3 H) and 3.74
(s, 3 H, 2 OCH3), 3.55 (s, 2 H, CH2Ar) ppm. 13C NMR (100 MHz,
CDCl3): δ = 161.8 (C=O), 159.3 (C-3ЈЈ), 158.1 (C-6Ј), 143.2 (C-1Ј),
142.6 (C-1ЈЈ), 141.0 (C-6), 136.5 (C), 135.0 (C-4), 130.8 (CH), 129.1
(CH), 128.7 (3 C, C-2Ј and 2 CH), 127.9 (2 C, CH), 127.8 (CH),
121.3 (CH), 120.7 (C-3), 119.3 (C-5), 115.4 (CH), 114.4 (CH), 113.3
(CH), 112.7 (CH), 55.3, 55.2 (2 OCH3), 51.7 (NCH2Ph), 34.5
(CH2Ar) ppm. HRMS (ESI): calcd. for C27H26NO3 [M + H]+
412.1907; found 412.1908.
[8]
For some reviews, see: a) K. Godula, D. Sames, Science 2006,
312, 67–72; b) L.-C. Campeau, K. Fagnou, Chem. Commun.
2006, 1253–1264; c) O. Daugulis, V. G. Zaitsev, D. Shabashov,
Q.-N. Pham, A. Lazareva, Synlett 2006, 3382–3388; d) I. J. S.
Fairlamb, Annu. Rep. Prog. Chem. Sect. B: Org. Chem. 2007,
103, 68–89; e) D. Alberico, M. E. Scott, M. Lautens, Chem.
Rev. 2007, 107, 174–238.
[9]
For recent examples, see: a) G. Cuny, M. Bois-Choussy, J. Zhu,
Angew. Chem. 2003, 115, 4922–4925; Angew. Chem. Int. Ed.
2003, 42, 4774–4777; b) G. Cuny, M. Bois-Choussy, J. Zhu, J.
Am. Chem. Soc. 2004, 126, 14475–14484; c) S. Hernández, R.
SanMartin, I. Tellitu, E. Domínguez, Org. Lett. 2003, 5, 1095–
1098.
[10]
[11]
J. Hassan, C. Hathroubi, C. Gozzi, M. Lemaire, Tetrahedron
2001, 57, 7845–7855.
1-Benzyl-5-[(4Ј,5-dimethoxy-1,1Ј-biphenyl-2-yl)methyl]pyridin-
2(1H)-one (9x): The reaction was performed with enamide 5d
(100 mg, 0.26 mmol) and 4-bromoanisole (97 mg, 0.52 mmol) in
anhydrous DMF (2 mL) with Ph3P (13.6 mg, 20 mol-%), Cs2CO3
(337.7 mg, 1.0 mmol), and Pd(OAc)2 (5.8 mg, 10 mol-%). After
combining the reagents at room temperature, the mixture was
heated to 120 °C, as described for 5a. Purification of the crude
product by flash chromatography (ethyl acetate/hexane, 1:4 to 7:3)
furnished biarylpyridinone 9x (53 mg, 50%) as a brown viscous oil.
For some reviews, see: a) J. F. Hartwig, Angew. Chem. 1998,
110, 2154–2177; Angew. Chem. Int. Ed. 1998, 37, 2046–2067;
b) G. Zeni, R. C. Larock, Chem. Rev. 2006, 106, 4644–4680; c)
C. Mauger, G. A. Mignani, Aldrichimica Acta 2006, 39, 17–24.
Compound 1b: a) R. R. Bard, J. F. Bunnett, R. P. Traber, J.
Org. Chem. 1979, 44, 4918–4924; b) G. P. M. van Klink,
H. J. R. de Boer, G. Schat, O. S. Akkerman, F. Bickelhaupt,
A. L. Spek, Organometallics 2002, 21, 2119–2135.
Compound 1c: S.-i. Kuwabe, K. E. Torraca, S. L. Buchwald, J.
Am. Chem. Soc. 2001, 123, 12202–12206.
Compound 1d: K. Orito, T. Hatakeyama, M. Takeo, H. Sugin-
ome, Synthesis 1995, 1273–1277.
a) T. Jeffery, Tetrahedron Lett. 1991, 32, 2121–2124; b) J. P.
Wolfe, R. A. Rennels, S. L. Buchwald, Tetrahedron 1996, 52,
7525–7546; c) L. F. Tietze, K. Kahle, T. Raschke, Chem. Eur.
J. 2002, 8, 401–407; d) D. Bruyère, D. Bouyssi, G. Balme, Tetra-
hedron 2004, 60, 4007–4017.
[12]
[13]
[14]
[15]
R = 0.32 (ethyl acetate/hexane, 4:1). IR (neat): ν = 3030, 2934,
˜
f
2835, 1667, 1603, 1537, 1494, 1454, 1441, 1352, 1292, 1246, 1220,
1175, 1142, 1108, 1073, 1039, 1024, 877, 834, 776, 734, 697 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.23 (m, 3 H, Ar-H), 7.18
(d, J = 7.9 Hz, 2 H, Ar-H), 7.08 (d, J = 8.4 Hz, 1 H, H-3Ј), 7.04
(d, 2 H) and 6.83 (d, J = 8.7 Hz, 2 H, Ar-H), 6.98 (dd, J = 9.4,
2.5 Hz, 1 H, H-4), 6.82 (dd, J = 8.4, 2.5 Hz, 1 H, H-4Ј), 6.74 (d, J
= 2.5 Hz, 1 H, H-6Ј), 6.52 (d, J = 2.5 Hz, 1 H, H-6), 6.46 (d, J =
9.4 Hz, 1 H, H-3), 4.97 (s, 2 H, NCH2Ph), 3.82 (s, 3 H) and 3.79
(s, 3 H, 2 OCH3), 3.54 (s, 2 H, CH2Ar) ppm. 13C NMR (100 MHz,
CDCl3): δ = 161.9 (C=O), 158.7 (C-4ЈЈ), 158.1 (C-5Ј), 143.0 (C),
141.0 (C-6), 136.5 (C), 134.9 (C-4), 133.6 (C), 130.8 (CH), 130.0 (2
C, CH), 129.0 (C-2Ј), 128.7 (2 C, CH), 127.9 (2 C, CH), 127.8
(CH), 120.7 (C-3), 119.4 (C-5), 115.8 (CH), 113.5 (2 C, CH), 113.0
(CH), 55.3 (2 OCH3), 51.6 (NCH2Ph), 34.5 (CH2Ar) ppm. HRMS
(ESI): calcd. for C27H26NO3 [M + H]+ 412.1907; found 412.1908.
[16]
A. Padwa, M. A. Brodney, J. P. Marino Jr., S. M. Sheehan, J.
Org. Chem. 1997, 62, 78–87.
[17]
[18]
G. Satyanarayana, M. E. Maier, Tetrahedron 2008, 64, 356–363.
G. Satyanarayana, M. E. Maier, Org. Lett. 2008, 10, 2361–
2364.
[19]
For some reviews of domino processes, see: a) L. F. Tietze,
Chem. Rev. 1996, 96, 115–136; b) G. Poli, G. Giambastiani, A.
Heumann, Tetrahedron 2000, 56, 5959–5989; c) K. C. Nico-
laou, D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006, 118,
7292–7344; Angew. Chem. Int. Ed. 2006, 45, 7134–7186.
For reviews of the chemistry of palladacycles, see: a) G. Dyker,
Chem. Ber./Recueil 1997, 130, 1567–1578; b) G. Dyker, Angew.
Chem. 1999, 111, 1808–1822; Angew. Chem. Int. Ed. 1999, 38,
1699–1712.
[20]
Supporting Information (see also the footnote on the first page of
this article): Copies of NMR spectra for all new compounds.
[21]
[22]
D. J. Cardenas, B. Martin-Matute, A. M. Echavarren, J. Am.
Chem. Soc. 2006, 128, 5033–5040.
For the chemistry of Pd complexes, see: a) A. J. Canty, Acc.
Acknowledgments
IV
Financial support by the Deutsche Forschungsgemeinschaft
(DFG) and the Fonds der Chemischen Industrie is gratefully ac-
knowledged. We thank Graeme Nicholson (Institute of Organic
Chemistry) for measuring the HRMS spectra. G. S. thanks the Al-
exander von Humboldt Foundation for a postdoctoral fellowship.
Chem. Res. 1992, 25, 83–90; b) A. J. Canty, J. L. Hoare, N. W.
Davies, P. R. Traill, Organometallics 1998, 17, 2046–2051.
a) M. Catellani, F. Frignani, A. Rangoni, Angew. Chem. 1997,
109, 142–145; Angew. Chem. Int. Ed. Engl. 1997, 36, 119–122;
b) M. Catellani, F. Cugini, Tetrahedron 1999, 55, 6595–6602;
c) M. Catellani, E. Motti, M. Minari, Chem. Commun. 2000,
157–158; d) F. Faccini, E. Motti, M. Catellani, J. Am. Chem.
Soc. 2004, 126, 78–79.
[23]
[1] J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, M. Lemaire,
Chem. Rev. 2002, 102, 1359–1469.
[2] J. M. Brunel, Chem. Rev. 2005, 105, 857–897.
[24]
For reviews, see: a) M. Catellani, Synlett 2003, 298–313; b) M.
Catellani, E. Motti, N. Della Ca, R. Ferraccioli, Eur. J. Org.
Eur. J. Org. Chem. 2008, 5543–5552
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5551

G. Satyanarayana, M. E. Maier
FULL PAPER
Chem. 2007, 4153–4165; c) J. B. Johnson, T. Rovis, Angew.
Chem. 2008, 120, 852–884; Angew. Chem. Int. Ed. 2008, 47,
840–871.
[27]
For further illustrative examples, see: a) G. Dyker, Angew.
Chem. 1992, 104, 1079–1081; Angew. Chem. Int. Ed. Engl. 1992,
31, 1023–1025; b) G. Dyker, Angew. Chem. 1994, 106, 117–119;
Angew. Chem. Int. Ed. Engl. 1994, 33, 103–105; c) O. Baudoin,
A. Herrbach, F. Gueritte, Angew. Chem. 2003, 115, 5914–5918;
Angew. Chem. Int. Ed. 2003, 42, 5736–5740; d) J. Hitce, P. Re-
tailleau, O. Baudoin, Chem. Eur. J. 2007, 13, 792–799; e) J.
Hitce, O. Baudoin, Adv. Synth. Catal. 2007, 349, 2054–2060.
Received: July 21, 2008
[25] a) C. Bressy, D. Alberico, M. Lautens, J. Am. Chem. Soc. 2005,
127, 13148–13149; b) B. Mariampillai, D. Alberico, V. Bidau,
M. Lautens, J. Am. Chem. Soc. 2006, 128, 14436–14437; c) P.
Thansandote, M. Raemy, A. Rudolph, M. Lautens, Org. Lett.
2007, 9, 5255–5258; d) A. Rudolph, N. Rackelmann, M. Laut-
ens, Angew. Chem. 2007, 119, 1507–1510; Angew. Chem. Int.
Ed. 2007, 46, 1485–1488.
Published Online: October 10, 2008
[26] G. Karig, M.-T. Moon, N. Thasana, T. Gallagher, Org. Lett.
2002, 4, 3115–3118.
5552
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5543–5552