Multicomponent and one-pot synthesis of trisubstituted pyridines through a Pd-catalyzed cross-coupling/cross-coupling/cycloaddition sequence

Article abstract of DOI:10.1016/j.tet.2007.10.112

Trisubstituted pyridines are regioselectively synthesized through multicomponent and one-pot processes promoted by a bifunctional Pd-catalyst. The process involves formation of an enamine by Pd-catalyzed amination of an alkenyl bromide, formation of a 2-aza-1,3-butadiene by Pd-catalyzed cross-coupling of a trimethylsilylimine with an alkenyl bromide, and Lewis acid catalyzed cycloaddition between the enamine and the azadiene.

Full text of DOI:10.1016/j.tet.2007.10.112

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 778e786
www.elsevier.com/locate/tet
Multicomponent and one-pot synthesis of trisubstituted pyridines through
a Pd-catalyzed cross-coupling/cross-coupling/cycloaddition sequence
*
Jose Barluenga , Agustın Jimenez-Aquino, M. Alejandro Fernandez, Fernando Aznar,
´
´
´
´
*
´
Carlos Valdes
Instituto Universitario de Qu´ımica Organometa´lica ‘Enrique Moles’, Unidad asociada al CSIC, Universidad de Oviedo,
Julia´n Claver´ıa 8, 33006 Oviedo, Spain
Received 12 September 2007; received in revised form 22 October 2007; accepted 26 October 2007
Available online 3 December 2007
Abstract
Trisubstituted pyridines are regioselectively synthesized through multicomponent and one-pot processes promoted by a bifunctional Pd-
catalyst. The process involves formation of an enamine by Pd-catalyzed amination of an alkenyl bromide, formation of a 2-aza-1,3-butadiene
by Pd-catalyzed cross-coupling of a trimethylsilylimine with an alkenyl bromide, and Lewis acid catalyzed cycloaddition between the enamine
and the azadiene.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
elementary reaction (a multifunctional catalyst)5 are particu-
larly appealing, since catalyst economy must be added to the
aforementioned list of advantages of MCRs.
The construction of complex molecules through multicom-
ponent reactions (MCR) constitutes a very attractive strategy
in organic synthesis.1 In a multicomponent reaction three or
more reactants are involved in a cascade of bond-forming in-
dividual steps to provide a complex molecule without isolation
of intermediates or modification of the reaction conditions. At-
tractive features of MCRs are simplicity of operation, reduc-
tion of isolation and purification steps, and minimization of
costs, time, energy, solvents, and waste production. Moreover,
by employing an array of diverse reagents, molecular diversity
is efficiently generated. In fact, MCRs have been extensively
employed in combinatorial and parallel diversity oriented
synthesis.
In recent years we have been investigating the cross-cou-
pling reactions between amines and alkenyl halides.6 This
transformation, which is inspired by the well-known Buch-
waldeHartwig amination of aryl halides,7 gives rise to the cor-
responding enamines and imines with very high yields.8
Moreover, catalytic conditions have been developed that allow
for the preparation of the corresponding coupling products
from alkenyl bromides, chlorides,9 and triflates.10 This method-
ology has been applied for the preparation of simple enamines
and imines, and also of 1- and 2-amino-1,3-butadienes,11 ver-
satile intermediates in organic synthesis through [4þ2] cyclo-
additions (Scheme 1).
Most of the early examples of multicomponent reactions
are based either on condensation2 or isocyanide3 chemistry.
However, in the recent years, new methodologies have ap-
peared, which rely on transition metal catalyzed and in partic-
ular Pd-catalyzed processes.4 In this context, multicomponent
processes in which the same catalyst promotes more than one
R3
N
R4
HN
R3
"Pd(0) / L"
Base
X
R1
R4
+
R1
R2
R2
R4=H
N
X = Br, Cl
R1, R2 = H, alkyl, aryl, alkenyl
R3, R4 = alkyl, aryl
R1
R3
R2
* Corresponding authors. Tel./fax: þ34 985 103450.
E-mail addresses: barluenga@uniovi.es (J. Barluenga), acvg@uniovi.es
Scheme 1. Pd-catalyzed alkenyl amination for the synthesis of enamines and
imines.
´
(C. Valdes).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.112

J. Barluenga et al. / Tetrahedron 64 (2008) 778e786
779
Taking advantage of the versatility and stability of currently
available Pd-catalysts, we have designed various strategies in
which alkenyl amination processes are included in cascade se-
quences leading to indoles.12,13 In these domino processes, the
same Pd-based catalytic system promotes two and even three
independent coupling reactions. For instance, in Scheme 2 is
presented a three-component synthesis of indoles in which
the same Pd-catalyst promotes three independent coupling re-
actions: alkenyl amination, a-arylation of the imine formed,
and intramolecular aryl amination.
a multicomponent fashion, both cross-coupling processesd
promoted by the same Pd-catalystdfollowed by the cycload-
dition reaction (Scheme 4). This process would hopefully
lead to a very convergent, regioselective, and multicomponent
preparation of 2,3,5-trisubstituted pyridine derivatives,16
a type of compounds with interesting biological activity.17 In
this paper we wish to report our progress toward this goal.
R
N
TMS
"Pd(0) / L"
N
Br
+
+
+
HN
R
N
R
R'
R'
2
R3
Br
1
R3
[4+2]
"Pd(0) / L"
Base
Cl
R1
N
R2-NH2
X
R
+
R2
N
R
R1
N
R3
Br
Cl
R'
R1
R3
R1
Scheme 4. Plan for a multicomponent Pd-catalyzed cross-coupling/cross-
coupling/cycloaddition sequence.
N
N
R2
R2
Cl
Scheme 2. Multicomponent synthesis of indoles promoted by a multifunctional
Pd-catalyst.
2. Results and discussion
2.1. Optimization of the cycloaddition reaction
Continuing with our work on Pd-catalyzed CeN bond
forming reactions, we have also introduced N-trimethylsilyl-
aldimines as coupling partners for CeN bond forming cross-
couplings. In this way, the silylimines became a synthetic
equivalent of the unstable NH-aldimines in cross-coupling re-
actions, and can be also employed as an alternative to intro-
duce a protected NH2 group in an aromatic molecule. The
coupling reaction can be conducted with aryl and alkenyl ha-
lides. Noteworthy, the reaction with alkenyl halides furnishes
2-aza-1,3-butadienes, interesting intermediates in [4þ2]
cycloadditions (Scheme 3).
First of all we carried out a study of the proper conditions to
carry out the cycloaddition reaction between the previously syn-
thesized enamine 1a and 2-aza-1,3-butadiene 2a (Scheme 5).18
Ph
O
N
Ph
Ph
Lewis Acid
N
+
N
Ph
Cl
Cl
2a
R2
R2
1a
3a
Si(CH3)3
Pd(0), BINAP
N
N
+
Ph
NaOtBu
Ph
O
N
N
R1
R1
R1
Br
HN
O
N
N
N
Ph
Ph
Si(CH3)3
+
R2
Pd(0), DavePhos
Br
R2
NaOtBu
R1
Scheme 3. Synthesis of aldimines and 2-aza-1,3-butadienes by cross-coupling
reaction of silylimines with aryl and alkenyl halides, respectively.
Cl
5
Cl
4
Scheme 5. Lewis acid catalyzed cycloaddition of enamine 1a with 2-azadiene
2a. Synthesis of pyridine 3a.
It is worth noting that the coupling reactions of alkenyl ha-
lides with secondary amines and N-trialkylsilylimines, which
deliver enamines 1 and 2-aza-1,3-butadienes 2, respectively,
are carried out under very similar reaction conditions and em-
ploying the same catalytic system. Moreover, enamines are
electron-rich olefins, while 2-aza-1,3-butadienes are expected
to react as 4p-components in inverse electron demand het-
ero-DielseAlder reactions.14,15 Therefore, these systems are,
in fact, complementary reagents for [4þ2] cycloadditions.
We wondered whether it might be possible to carry out, in
Although some examples had been described of reactions
of enamines with 2-azadienes substituted with electron-with-
drawing groups,19 to the best of our knowledge, the same
type of reaction with neutral 2-azadienes had not been previ-
ously explored.20 We found that in order to effect the cycload-
dition it was necessary the presence of a catalytic amount of
a Lewis acid, to enhance the reactivity of the otherwise poorly
reactive 2-azadiene.

780
J. Barluenga et al. / Tetrahedron 64 (2008) 778e786
Table 1
Optimization of the reaction conditions for the multicomponent synthesis
of 3a
Several Lewis acids promoted the cycloaddition, and the
best results were obtained employing a 20 mol % loading of
Yb(OTf)3 at 90 ꢀC (Scheme 5). Under these conditions the
corresponding trisubstituted pyridine 3a was obtained with
good yield. The process involves the [4þ2] cycloaddition, fol-
lowed by morpholine elimination, and oxidation to deliver the
aromatic system. In no case could the tetrahydropyridine 4 or
the dihydropyridine 5 be isolated.
TMS
N
Ph
Ph
O
Ph
Pd2(dba)3 / L
+
+
N
Base, Lewis acid
Toluene
N
H
Br
Cl
Cl
Entry
Ligand
Basea (equiv)
Lewis acid
T (ꢀC)
Yield (%)
2.2. Multicomponent reactions
1
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
XPhos
NaOtBu (1.4)
NaOtBu (1.4)
NaOtBu (1.2)
NaOtBu (1.1)
NaOtBu (1.0)
Cs2CO3 (1.1)
CsF (1.1)
NaOtBu (1.1)
NaOtBu (1.1)
NaOtBu (1.1)
NaOtBu (1.1)
NaOtBu (1.1)
NaOtBu (1.1)
Yb(OTf)3
Sc(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Sc(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
90
90
90
90
90
90
90
90
90
110
90
90
90
35
30
40
50
30
d
d
50
50
50
50
31
49
2
Once we had discovered some proper reaction conditions to
effect the cycloaddition reaction, we turned our attention to the
sequential multicomponent process. In a preliminary set of ex-
periments we mixed 1 equiv of b-bromostyrene 6a, 0.5 equiv
of morpholine, and 0.5 equiv of silylimine 7a under the
cross-coupling conditions: NaOtBu as base (1.4 equiv),
Pd2(dba)3 (2 mol %), and a supporting ligand for the metal
(8 mol %) (Scheme 6). We employed DavePhos (2-dicyclo-
hexylphosphino-20-N,N-dimethylamino)biphenyl as ligand be-
cause it had been found as one of the most effective ligands in
both individual cross-coupling reactions. Analysis of the reac-
tion crude at this stage, after 10 h of reaction, showed that
indeed, both coupling reactions had occurred with full conver-
sion. As expected, no cycloaddition product was detected in
the absence of an additional Lewis acid. Nevertheless, addition
of 20 mol % of Yb(OTf)3 to the reaction mixture at this point
promoted the cycloaddition, and after additional 10 h of heat-
ing at 90 ꢀC, the expected pyridine 3a was obtained in a 40%
overall yield.
Encouraged by this promising result, we investigated
whether the transformation could be achieved in a strict mul-
ticomponent fashion, with the addition of all the reagents, in-
cluding the Lewis acid, at the beginning of the reaction. To
this end, a set of experiments with variation of base, reaction
conditions, and amounts of reagents were conducted. Some
selected results are presented in Table 1.
The amount of base has some influence on the reaction
yield, and an excess has a negative effect on the overall yield
(entries 1, 2). Mild bases such as Cs2CO3 or CsF did not pro-
mote the reaction at all (entries 6, 7). Very similar results were
obtained when Sc or Yb triflates were employed as Lewis acid.
Regarding the ligand, DavePhos and XPhos provided nearly
identical yields. The influence of the amine in the enamine
was also explored. Morpholine and N-methylaniline (entries
3
4
5
6
7
8
9
XPhos
10
11b
12c
13d
a
DavePhos
DavePhos
DavePhos
DavePhos
Equivalents referred to bromostyrene.
Silylimine (0.75 equiv).
Silylimine (1 equiv).
b
c
d
N-Methylaniline was employed instead of morpholine.
4 and 13, respectively), which would render enamines with
different electronic properties, were employed in the multi-
component reactions, giving rise to very similar results. Inter-
estingly, under these new experimental conditions, the reaction
time is highly reduced, and the formation of the pyridine
occurs in only 14 h at 90 ꢀC.
With some convenient reaction conditions for the multi-
component reaction, the scope of the process with regard of
the substituents of the starting alkenyl bromide 6 and N-silyl-
imine 7 was studied.
As depicted in Table 2, the trisubstituted pyridines were ob-
tained for a variety of alkenyl bromides and imines. The reac-
tion tolerates electron-neutral and electron-rich substituents in
both aromatic rings. However, the use of a silylimine bearing
an electron-withdrawing group such as the cyano did not lead
to the formation of the desired pyridine, due to the low effi-
ciency of the coupling reaction of that particular silylimine
with the alkenyl bromide. We are currently working on the op-
timization of this reaction, and hopefully, it will enhance the
Ph
TMS
N
then
Yb(OTf)3
90 °C, 20h
Ph
O
O
Ph
Ph
N
Pd2(dba)3 / DavePhos
N
+
+
+
1,4 Eq. tBuONa
Toluene, 90 °, 20 h.
N
H
N
Br
Ph
Cl
Cl
Cl
2a
6a
7a
1a
3a
40%
1 Eq.
0,5 Eq.
0,5 Eq.
Scheme 6. Preliminary experiments on the Pd-catalyzed synthesis of pyridine 3a.

J. Barluenga et al. / Tetrahedron 64 (2008) 778e786
781
scope of this multicomponent process. Despite this, a variety
of trisubstituted pyridines can be obtained through this multi-
component reaction in a reasonable yield, taking into account
all the events that have occurred in the reaction flask: (i)
formation of an enamine by Pd-catalyzed alkenylation of
morpholine; (ii) formation of a 2-aza-1,3-butadiene by cross-
coupling reaction of the silylimine with the alkenyl bromide;
note that both processes are promoted by the same catalytic
system; (iii) Hetero-DielseAlder reaction promoted by
Yb(OTf)3; (iv) elimination of morpholine and aromatization.
Moreover, advantages of the multicomponent process when
compared to a conventional multistep synthesis can be pointed
out: (i) the same Pd-catalyst is employed to promote two inde-
pendent reactions; (ii) no purification of intermediates is re-
quired, which is an important fact in this particular case,
since both enamines and azadienes are sensitive to humidity
and are not suitable for conventional chromatographic
techniques.
Table 2
Pyridines synthesized through the multicomponent reactiona
Ar1
Ar1
Ar2
O
Ar1
TMS
N
Pd2(dba)3 / DavePhos
+
Br
+
1,1 eq. t-BuONa
Yb(OTf)3 (20% mol)
Toluene, 90 ºC
N
N
H
Ar2
7
6
3
Compound
Ar1
Ph
Ar2
Pyridine 3
Yieldb (%)
Ph
Ph
a
48
N
Cl
Cl
Ph
Ph
2.3. One-pot reactions: synthesis of pyridines with three
different substituents
b
c
Ph
Ph
PMP
55
57
N
N
PMP
Ph
Ph
An important limitation of the present strategy is that the
pyridines 3 obtained feature the same substituent Ar1 at posi-
tions 3 and 5, since both are coming from the same alkenyl
bromide 6. To increase the versatility of this multicomponent
reaction we decided to investigate a different approach that
might circumvent this limitation by employing two different
alkenyl halides.
We carried out some preliminary experiments employing
two different alkenyl halides (bromides and chlorides) under
the same conditions presented above, but a mixture of pyri-
dines with scrambled substituents was always obtained. For
this reason we decided to explore a sequential addition of re-
agents, that hopefully would allow for the preparation of the
differently substituted pyridines.
To this end, the right sequence for the addition of reagents
should be found. We observed that after the formation of the
enamine by coupling reaction of an alkenyl halide with mor-
pholine, which takes place very fast, the Pd retains its catalytic
activity, and by addition of a second alkenyl halide and the
silylimine, the second coupling reaction occurs efficiently.
Poor results were obtained when the sequence of coupling pro-
cesses was reversed. These preliminary experiments allowed
us to design a one-pot procedure for the preparation of the tri-
substituted pyridines. First of all, Pd2(dba)3, DavePhos, and
NaOtBu are mixed in toluene and heated at 90 ꢀC. Then, the
first alkenyl halide 6 is added, after 1 min, by the morpholine.
After the proper reaction time (0.5e1 h as monitored by
GC/MS) a solution containing the second alkenyl halide 60
and the silylimine is added. Finally, once the second alkenyl
halide has been consumed as monitored by GC/MS, Yb(OTf)3
is added to the reaction mixture and heating is continued for
additional 14 h (Scheme 7). It is important to wait until the
second alkenyl halide 60 has been consumed before adding
the Lewis acid. If Yb(OTf)3 is added at the same time as the
silylimine 7 and the second alkenyl halide 60, the expected
pyridine 8 is obtained together with a smaller amount of
pyridine 9. The formation of 9 can be explained considering
that during the formation of 8 a molecule of morpholine is
p-Tol
p-Tol
Ph
Ph
d
e
Ph
61
60
N
NMe2
NMe2
Cl
PMP
PMP
PMP
N
Cl
PMP
PMP
PMP
f
PMP
PMP
PMP
55
58
N
N
PMP
PMP
g
p-Tol
p-Tol
PMP
PMP
h
i
PMP
54
54
N
NMe2
NMe2
p-Tol
p-Tol
p-Tol
N
Cl
Cl
p-Tol
p-Tol
j
p-Tol
p-Tol
PMP
53
54
N
N
PMP
p-Tol
p-Tol
k
p-Tol
p-Tol
p-Tol
p-Tol
l
p-Tol
62
N
NMe2
NMe2
a
Reaction conditions: alkenyl halide 6 (1 mmol); morpholine (0.5 mmol);
N-trimethylsilylimine 7 (0.5 mmol); Pd2(dba)3 (1 mol %); DavePhos (2-dicy-
clohexylphosphino-20-(N,N-dimethylamino)biphenyl, 4 mol %); NaOtBu
(1.1 mmol, 1.1 equiv); Yb(OTf)3 (0.1 mmol, 0.2 equiv); toluene (4 mL).
b
Isolated yields after column chromatography or recrystallization. PMP¼
p-MeO-C6H4.

782
J. Barluenga et al. / Tetrahedron 64 (2008) 778e786
TMS
Ar3
+
N
Ar2
7
Br
6'
Ar3
Ar1
Ar2
Ar3
Ar3
Ar2
+
Yb(OTf)3
90 ºC, 20h
N
N
8
9
O
Ar1
Pd2(dba)3 / DavePhos
2,1 Eq. t-BuONa
+
TMS
N
Ar3
+
N
H
Br
Toluene, 90 °, 30min-1h.
6
Ar2
7
Ar3
Ar1
Ar2
Br
then
Yb(OTf)3
6'
90 ºC, 14 h
90 ºC, 2-3h
N
8
Scheme 7. One-pot synthesis of trisubstituted pyridines 8 with three different substituents.
released, which could react with the second alkenyl halide 60,
and participate in an undesired cycloaddition (Scheme 7).
Nevertheless, employing the optimized protocol described
above, the trisubstituted pyridines are obtained with compara-
ble yields than those obtained in the multicomponent reaction
discussed previously (Table 3).
The one-pot reaction features similar characteristics to the
multicomponent process. Electron-neutral and electron-rich
substituents are tolerated on every substituent. Moreover,
o-substitution in the aromatic ring is also compatible with
the reaction. Additionally, the presence of a chlorine atom in
the aromatic ring is particularly interesting, since it could be
easily substituted employing cross-coupling techniques in
order to increase the structural diversity of pyridines. The ex-
amples presented in Table 3 establish the one-pot procedure
presented herein as a viable and efficient route to the prepara-
tion of 2,3,5-trisubstituted pyridines with three different sub-
stituents. Although the scope of the reaction is still limited,
we are currently working on the optimization of the indepen-
dent steps to increase the functional group tolerance of these
reactions.
3. Conclusion
In summary, we have presented herein novel multicompo-
nent and one-pot methodologies for the regioselective
Table 3
Pyridines 8 prepared by the one-pot procedurea
Ar1
Ar2
Ar3
Pyridine 8
p-Tol
Yieldb (%)
Ar1
Ph
Ar2
Ar3
Pyridine 8
Yieldb (%)
PMP
Cl
Ph
N
p-Tol
PMP
51
PMP
52
Cl
N
PMP
Cl
Cl
8d
8a
OMe
Cl
OMe
p-Tol
PMP
OMe
Cl
Cl
N
PMP
p-Tol
56
47
N
MeO
OMe
Cl
Cl
OMe
Cl
8b
8e
OMe
OMe
Ph
Ph
Cl
OMe
Cl
Ph
Cl
49
Ph
51
N
MeO
OMe
N
Cl
OMe
Cl
Cl
8c
8f
a
Reaction conditions: alkenyl halide 6 (1 mmol); morpholine (1 mmol); N-trimethylsilylimine 7 (1.2 mmol); alkenyl halide 60 (1 mmol); Pd2(dba)3 (2 mol %);
DavePhos (2-dicyclohexylphosphino-20-(N,N-dimethylamino)biphenyl, 8 mol %); NaOtBu (2.1 mmol, 2.1 equiv); Yb(OTf)3 (0.2 mmol, 0.2 equiv); toluene (3 mL).
b
Isolated yields after column chromatography or recrystallization. PMP¼p-MeO-C6H4.

J. Barluenga et al. / Tetrahedron 64 (2008) 778e786
783
synthesis of trisubstituted pyridines through processes, which
involve (i) formation of an enamine by cross-coupling of an
alkenyl halide with an amine; (ii) formation of a 2-azadiene
by cross-coupling of a silylimine with an alkenyl halide; (iii)
Lewis acid catalyzed aza-DielseAlder cycloaddition; (iv)
aromatization. These procedures present all the advantages
associated with multicomponent processes, such as easy gen-
eration of molecular diversity, reduction of time, solvents,
and waste, no need for purification of intermediates, and addi-
tionally, catalyst economy, since the same Pd-based catalytic
system is employed to promote two independent
transformations.
1H NMR (CDCl3, 300 MHz): d¼7.26e7.22 (m, 4H), 7.38e
7.32 (m, 5H), 7.53e7.43 (m, 3H), 7.69e7.63 (m, 2H), 7.93 (d,
J¼2.3 Hz, 1H), 8.93 (d, J¼2.3 Hz, 1H). 13C NMR (CDCl3,
75 MHz): d¼127 (2CH), 127.4 (eCH), 128.0 (2CH), 128.2
(CH), 128.5 (2CH), 129.0 (2CH), 129.4 (2CH), 131.1
(2CH), 133.8 (C), 135.1 (C), 135.8 (C), 136.9 (CH), 137.8
(C), 138.1 (C), 139.4 (C), 146.6 (CH), 154.4 (C). MS(EI):
343 (23), 342 (47), 431 (68), 340 (100). HRMS calcd for
C23H15ClN (MꢂH): 341.0893; found: 340.0884.
4.1.1.2. 2-(4-Methoxyphenyl)-3,5-diphenylpyridine 3b. Flash
chromatography in (SiO2, HxH/EtOAc, 9:1); 186 mg of white
solid were obtained (55%), recrystallized from diethyl ether.
4. Experimental section
Mp¼179.6e181.0 ꢀC. IR (KBr): n 1429, 1243, 700 cmꢂ1
.
1H NMR (CDCl3, 300 MHz): d¼3.79 (s, 3H, OCH3), 6.80
(d, J¼8.8 Hz, 2H), 7.44e7.29 (m, 8H), 7.50 (t, J¼7.5 Hz,
2H), 7.69e7.66 (m, 2H), 7.90 (d, J¼2.3 Hz, 1H), 8.92 (d,
J¼2.3 Hz, 1H). 13C NMR (CDCl3, 75 MHz): d¼55.0 (OCH3),
113.2 (2CH), 126.9 (2CH), 127.1 (CH), 127.9 (CH), 128.3
(2CH), 128.9 (2CH), 129.4 (2CH), 131.1 (2CH), 132.0 (C),
134.4 (C), 135.4 (C), 136.8 (CH), 137.7 (C), 140.1 (C), 146.4
(CH), 155.3 (C), 159.3 (C). MS(EI): 337 (82), 336 (100).
HRMS calcd for C24H18NO (MꢂH): 336.1383; found:
336.1382.
4.1. General
All reactions were carried out under nitrogen atmosphere
in a RR98030 12 place Carousel Reaction StationÔ from
Radleys Discovery Technologies, equipped with gas-tight
threaded caps with a valve, cooling reflux head system,
and digital temperature controller. NMR spectra were re-
1
corded at 400 or 300 MHz for H and 100.6 or 75.45 MHz
1
for 13C, with tetramethylsilane as internal standard for H
and the residual solvent signals as standard for 13C. Chemi-
cal shifts are given in parts per million. Mass spectra were
obtained by EI or electrospray ionization (ESI). Pd2(dba)3
was purchased from Strem Chemical co. and used without
further purification. All phosphine ligands used are commer-
cially available from Strem or Aldrich and were used with-
out further purification. Commercial NaOtBu was
lyophilized and stored under nitrogen. Non-commercial N-
trialkylsilylimines were prepared according to literature
procedures.21
4.1.1.3. 3,5-Diphenyl-2-p-tolylpyridine 3c. Flash chromatog-
raphy in (SiO2, HxH/EtOAc, 9:1); 183 mg of pale orange solid
were obtained (57%), recrystallized from diethyl ether.
1
Mp¼187.0e188.2 ꢀC. IR (KBr): n 1425, 780, 698 cmꢂ1. H
NMR (CDCl3, 300 MHz): d¼2.34 (s, 3H, CH3), 7.08 (d,
J¼8 Hz, 2H), 7.27e7.34 (m, 7H), 7.42e7.46 (m, 1H), 7.50e
7.54 (m, 2H), 7.68e7.70 (d, J¼8 Hz, 2H), 7.93 (d, J¼2.2 Hz,
1H), 8.94 (d, J¼2.2 Hz, 1H). 13C NMR (CDCl3, 75 MHz):
d¼21.2 (CH3), 127.1 (2CH), 127.3 (CH), 128.1 (CH), 128.4
(2CH), 128.6 (2CH), 129.1 (2CH), 129.5 (2CH), 129.8 (2CH),
134.7 (C), 135.8 (C), 136.7 (C), 137.0 (CH), 137.4 (C), 137.7
(C), 140.0 (C), 146.4 (CH), 155.7 (C). MS(EI): 321 (62), 320
(100). HRMS calcd for C24H18N (MꢂH): 320.1434; found:
320.1433.
4.1.1. General procedure for the multicomponent synthesis
of pyridines 3
A carousel reaction tube under nitrogen atmosphere was
charged with Pd2(dba)3 (0.01 mmol, 1 mol %), DavePhos
(0.04 mmol, 4 mol %), NaOtBu (1.1 mmol), and toluene
(1 mL). After 1 min of stirring, morpholine (0.5 mmol), the
bromoalkene 6 (1 mmol), the silylimine 7 (0.6 mmol) and
Yb(OTf)3 (0.1 mmol, 20 mol %) were added sequentially
while stirring, separated by 1 min intervals. Finally an addi-
tional 1 mL of toluene was added. The mixture was heated
at 90 ꢀC for 14 h. Once the reaction has been completed, the
mixture is allowed to reach rt, diluted with EtOAc (15 mL),
and washed with saturated NaHCO3 solution. The aqueous
phase is extracted with EtOAc (2ꢁ5 mL) and the combined
organic layers are dried over Na2SO4 and concentrated under
reduced pressure. The pyridines are purified by flash
chromatography.
4.1.1.4. 2-(4-N,N-Dimethylaminophenyl)-3,5-diphenylpyridine
3d. Flash chromatography in (SiO2, HxH/EtOAc, 9:1);
213 mg of yellow solid were obtained (61%), recrystallized
from diethyl ether. Mp¼182.6e184.4 ꢀC. IR (KBr): n 1607,
1426, 699 cmꢂ1
.
1H NMR (CDCl3, 300 MHz): d¼2.98 (s,
6H, N(CH3)2), 6.63 (d, J¼8.7 Hz, 2H), 7.30e7.54 (m, 10H),
7.68 (d, J¼8.7 Hz, 2H), 8.00 (d, J¼2.3 Hz, 1H), 8.96 (d,
J¼2.3 Hz, 1H). 13C NMR (CDCl3, 75 MHz): d¼40.26 (2CH3),
111.7 (CH), 126.9 (2CH), 127.6 (CH), 128.5 (2CH), 128.6
(2CH), 129.2 (2CH), 129.3 (2CH), 129.7 (C), 131.2 (2CH),
132.7 (C), 133.6 (CH), 135.0 (C), 137.0 (C), 144.9 (C), 150.1
(CH), 154.7 (C). MS(EI): 350 (85), 349 (100). HRMS calcd
for C25H21N2 (MꢂH): 349.1699; found: 349.1699.
4.1.1.1. 2-(4-Chlorophenyl)-3,5-diphenylpyridine 3a. Flash
chromatography in (SiO2, HxH/EtOAc, 9:1); 164 mg of white
solid were obtained (48%), recrystallized from diethyl ether.
4.1.1.5. 2-(4-Chlorophenyl)-3,5-bis-(4-methoxyphenyl)-pyri-
dine 3e. Flash chromatography in (SiO2, HxH/EtOAc, 9:1);
241 mg of pale orange solid were obtained (60%),
Mp¼173.3e174.5 ꢀC. IR (KBr): n 1429, 1090, 699 cmꢂ1
.

784
J. Barluenga et al. / Tetrahedron 64 (2008) 778e786
recrystallized from diethyl ether. Mp¼143.5e144.5 ꢀC. IR
(2CH), 128.0 (2CH), 129.7 (C), 130.5 (2CH), 130.8 (2CH),
132.7 (C), 133.6 (CH), 135.0 (C), 137.0 (C), 144.9 (C), 150.1
(CH), 154.7 (C), 158.8 (C), 159.7 (C). MS(EI): 409 (95), 410
(100). HRMS calcd for C27H25N2O2 (MꢂH): 409.1911;
found: 409.1914.
1
(KBr): n 1512, 1245, 823 cmꢂ1. H NMR (CDCl3, 300 MHz):
d¼3.84 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.87 (d,
J¼8.7 Hz, 2H), 7.04 (d, J¼8.7 Hz, 2H), 7.15 (d, J¼8.7 Hz,
2H), 7.25 (d, J¼8.4 Hz, 2H), 7.36 (d, J¼8.4 Hz, 2H), 7.61
(d, J¼8.7 Hz, 2H), 7.86 (d, J¼2.28 Hz, 1H), 8.86 (d,
J¼2.28 Hz, 1H). 13C NMR (CDCl3, 75 MHz): d¼55.2
(OCH3), 55.4 (OCH3), 114.0 (2CH), 114.8 (2CH), 128.1
(2CH), 129.6 (C), 130.6 (2CH), 131.2 (2CH), 131.8 (C),
133.7 (C), 134.9 (C), 135.5 (C), 136.3 (CH), 138.5 (C), 146.0
(CH), 159.1 (C), 159.9 (C). HRMS calcd for C25H19NO2Cl
(MꢂH): 400.1099; found: 400.1101.
4.1.1.9. 2-(4-Chlorophenyl)-3,5-(4-tolyl)pyridine 3i. Flash
chromatography in (SiO2, HxH/EtOAc, 9:1); 200 mg of pale
yellow solid were obtained (54%), recrystallized from diethyl
ether. Mp 135.8e136.6 ꢀC. IR (KBr): n 1437, 1013, 812 cmꢂ1
.
1H NMR (CDCl3, 300 MHz): d¼2.38 (s, 3H), 2.44 (s, 3H),
7.14 (m, 4H), 7.25 (d, J¼8.0 Hz, 2H), 7.32 (d, J¼8.0 Hz,
2H), 7.38 (d, J¼8.0 Hz, 2H), 7.58 (d, J¼8.0 Hz, 2H), 7.90
(d, J¼2.2 Hz, 1H), 8.90 (d, J¼2.2 Hz, 1H). 13C NMR
(CDCl3, 75 MHz): d¼21.2 (2CH3), 126.9 (2CH), 128.1 (2CH),
129.3 (2CH), 129.4 (2CH), 129.9 (2CH), 131.2 (2CH), 133.8
(C), 133.8 (C), 134.2 (C), 135.2 (C), 135.9 (C), 136.5 (C),
136.9 (C), 138.2 (C), 146.2 (CH), 154.0 (C). HRMS calcd
for C25H20ClN: 369.1279; found: 369.1280.
4.1.1.6. 2,3,5-Tris-(4-methoxyphenyl)pyridine 3f. Flash chro-
matography in (SiO2, HxH/EtOAc, 9:1); 217 mg of pale or-
ange solid were obtained (55%), recrystallized from diethyl
ether. Mp¼133.2e135.0. IR (KBr): n 1512, 1243, 812 cmꢂ1
.
1H NMR (CDCl3, 300 MHz): d¼3.78 (s, 3H, OCH3), 3.80
(s, 3H, OeCH3), 3.85 (s, 3H, OCH3), 6.79 (d, J¼8.8 Hz, 2H),
6.83 (d, J¼8.8 Hz, 2H), 7.02 (d, J¼8.8 Hz, 2H), 7.17 (d,
J¼8.8 Hz, 2H), 7.35 (m, 2H), 7.59 (m, 2H), 7.82 (d, J¼
2.3 Hz, 1H), 8.82 (d, J¼2.3 Hz, 1H). 13C NMR (CDCl3,
75 MHz): d¼57.6 (OCH3), 57.6 (OCH3), 57.8 (OCH3),
115.7 (2CH), 116.2 (2CH), 116.9 (2CH), 130.53 (2CH),
132.3 (C), 133.0 (2CH), 133.5 (2CH), 134.8 (C), 134.9
(CH), 136.5 (C), 137.5 (C), 138.7 (CH), 148.2 (C), 157.2 (C),
161.2 (C), 161.6 (C), 162.1 (C). HRMS calcd for C26H22NO3
(MꢂH): 396.1594; found: 396.1593.
4.1.1.10. 2-(4-Methoxyphenyl)-3,5-(4-tolyl)pyridine 3j. Flash
chromatography in (SiO2, HxH/EtOAc, 9:1); 194 mg of pale
yellow solid were obtained (54%), recrystallized from diethyl
ether. Mp¼124.1e125.0 ꢀC. IR (KBr):
n 1437, 1249,
817 cmꢂ1. 1H NMR (CDCl3, 300 MHz): d¼2.38 (s, 3H), 2.43
(s, 3H), 3.81 (s, 3H), 6.81 (d, J¼8.0 Hz, 2H), 7.31 (d, J¼
8.0 Hz, 2H), 7.38 (d, J¼8.0 Hz, 2H), 7.50 (m, 4H), 7.57 (d,
J¼8.0 Hz, 2H), 7.90 (d, J¼2.4 Hz, 1H), 8.89 (d, J¼2.2 Hz,
1H). 13C NMR (CDCl3, 75 MHz): d¼21.2 (2CH3), 55.2
(OCH3), 113.4 (2CH), 126.9 (2CH), 129.2 (2CH), 129.3 (2CH),
129.8 (2CH), 131.2 (2CH), 134.4 (C), 134.5 (C), 135.7 (C),
137.1 (CH), 137.2 (C), 138.1 (C), 145.7 (CH), 154.8 (C),
159.4 (C). HRMS calcd for C26H23NO: 365.1774; found:
365.1771.
4.1.1.7. 3,5-Bis-(4-methoxyphenyl)-2-(4-tolyl)pyridine 3g.
Flash chromatography in (SiO2, HxH/EtOAc, 9:1); 221 mg
of pale orange solid were obtained (58%), recrystallized
from diethyl ether. Mp¼109.3e110.1 ꢀC. IR (KBr): n 1510,
1243, 827 cmꢂ1
.
1H NMR (CDCl3, 300 MHz): d¼2.34 (s,
3H, CH3), 3.83 (s, 3H, OeCH3), 3.89 (s, 3H, OeCH3), 6.85
(d, J¼8.7 Hz, 2H), 7.05 (d, J¼8.7 Hz, 2H), 7.09 (d, J¼
8.0 Hz, 2H), 7.18 (d, J¼8.7 Hz, 2H), 7.33 (d, J¼8.0 Hz, 2H),
7.62 (d, J¼8.7 Hz, 2H), 7.87 (d, J¼2.2 Hz, 1H), 8.87 (d,
J¼2.2 Hz, 1H). 13C NMR (CDCl3, 75 MHz): d¼21.2 (CH3),
55.2 (eOCH3), 55.4 (eOCH3), 113.8 (2CH), 114.6 (2CH),
128.1 (2CH), 128.7 (2CH), 129.7 (2CH), 130.6 (2CH), 132.2
(C), 134.5 (C), 135.5 (C), 136.6 (CH), 137.6 (C), 145.5 (CH),
154.8 (C), 158.9 (C), 159.8 (C). MS(EI): 381 (85), 380 (100).
HRMS calcd for C26H22NO2 (MꢂH): 380.1645; found:
380.1648.
4.1.1.11. 2,3,5-Tris-(4-tolyl)pyridine 3k. Flash chromatogra-
phy in (SiO2, HxH/EtOAc, 9:1); 189 mg of pale yellow solid
were obtained (54%), recrystallized from diethyl ether.
1
Mp¼122.3e123.1 ꢀC. IR (KBr): n 1441, 828, 815 cmꢂ1. H
NMR (CDCl3, 300 MHz): d¼2.38 (s, 3H), 2.39 (s, 3H), 2.45
(s, 3H), 7.10 (d, J¼8.1 Hz, 2H), 7.16 (m, 4H), 7.45 (m, 4H),
7.60 (d, J¼8.1 Hz, 2H), 7.90 (d, J¼2.4 Hz, 1H), 8.93 (d,
J¼2.2 Hz, 1H). 13C NMR (CDCl3, 75 MHz): d¼21.2
(2CH3), 21.3 (CH3), 126.9 (2CH), 128.6 (2CH), 129.1 (2CH),
129.4 (2CH), 129.8 (2CH), 129.9 (2CH), 134.6 (C), 134.7 (C),
135.7 (C), 136.7 (CH), 137.0 (C), 137.1 (C), 137.2 (CH),
137.5 (C), 138.0 (C), 146.2 (CH), 155.5 (C). HRMS calcd
for C26H23N: 349.1825; found: 349.1821.
4.1.1.8. 2-(4-N,N-Dimethylaminophenyl)-3,5-bis-(4-methoxy-
phenyl)pyridine 3h. Flash chromatography in (SiO2, HxH/
EtOAc, 9:1); 221 mg of orange solid were obtained (54%), re-
crystallized from diethyl ether. Mp 115.6e117.2 ꢀC. IR (KBr):
n 1608, 1246, 824 cmꢂ1. 1H NMR (CDCl3, 300 MHz): d¼2.97
(s, 6H, N(CH3)2), 3.84 (s, 3H, OCH3), 3.88 (s, 3H, OCH3),
6.61 (d, J¼8.9 Hz, 2H), 6.88 (d, J¼8.7 Hz, 2H), 7.04 (d,
J¼8.7 Hz, 2H), 7.23 (d, J¼8.7 Hz, 2H), 7.35 (d, J¼8.9 Hz,
2H), 7.61 (d, J¼8.7 Hz, 2H), 7.83 (d, J¼2.2 Hz, 1H), 8.8 (d,
J¼2.2 Hz, 1H). 13C NMR (CDCl3, 75 MHz): d¼40.3 (2CH3),
55.2 (OCH3), 55.4 (OCH3), 111.6 (2CH), 113.9 (2CH), 114.5
4.1.1.12.
2-(4-N,N-Dimethylaminophenyl)-3,5-bis-(4-tolyl)
pyridine 3l. Flash chromatography in (SiO2, HxH/EtOAc,
9:1); 235 mg of orange solid was obtained (62%), recrystal-
lized from diethyl ether. Mp¼194.0e195.6 ꢀC. IR (KBr): n
1
1611, 1439, 1192, 816 cmꢂ1. H NMR (CDCl3, 300 MHz):
d¼2.39 (s, 3H), 2.44 (s, 3H), 2.96 (s, 6H), 6.62 (d,
J¼8 Hz, 2H), 7.19 (m, 4H), 7.33 (m, 4H), 7.58 (d, J¼8 Hz,
2H), 7.85 (s, 1H), 8.88 (s, 1H). 13C NMR (CDCl3, 75 MHz):

J. Barluenga et al. / Tetrahedron 64 (2008) 778e786
785
d¼21.20 (CH3), 21.23 (CH3), 40.3 (2CH3), 111.6 (2CH),
126.8 (2CH), 129.1 (2CH), 129.4 (2CH), 129.8 (2CH),
130.9 (2CH), 133.6 (C), 134.8 (C), 135.1 (C), 136.7 (C),
136.9 (CH), 137.8 (C), 137.9 (C), 146.1 (CH), 150.0
(C), 155.6 (C). HRMS calcd for C27H26N2: 378.2091; found:
378.2098.
4.1.2.3. 2-(2-Chlorophenyl)-5-(4-chlorophenyl)-3-phenylpyri-
dine 8c. Flash chromatography in (SiO2, HxH/EtOAc, 9:1);
1
216 mg of pale yellow solid were obtained (56%). H NMR
(CDCl3, 300 MHz): d¼7.2e7.4 (m, 13H), 7.89 (s, 1H), 8.82
(s, 1H). 13C NMR (CDCl3, 75 MHz): d¼127.3 (CH), 127.6
(CH), 128.2 (CH), 128.6 (CH), 129.6 (CH), 130.3 (CH),
131.3 (CH), 131.4 (CH), 132.8 (C), 133.8 (C), 134.1 (C),
135.4 (C), 136.4 (C), 138.2 (C), 139.3 (C), 139.5 (CH),
148.5 (CH), 154.7 (C). MS(EI): 379 (5), 378 (17), 377 (33),
376 (67), 375 (54), 374 (100). HRMS (ESI) calcd for
C23H16NCl2 (Mþ1): 376.0654; found: 376.0650.
4.1.2. General procedure for the one-pot synthesis of
pyridines 8
A carousel reaction tube under nitrogen atmosphere was
charged with Pd2(dba)3 (0.02 mmol, 2 mol %), DavePhos
(0.08 mmol, 8 mol %), NaOtBu (2.1 mmol), and toluene
(2 mL). After 1 min of stirring, morpholine (1 mmol) and
the first bromoalkene 6 (1 mmol) were added and the mixture
was stirred at 90 ꢀC for 1 h. The silylimine 7 (1.2 mmol) and
the second bromoalkene 60 (1 mmol) were added to the reac-
tion mixture and stirring continued at 90 ꢀC for 6 h or until
complete disappearance of the bromoalkene (GC monitoring).
Then, Yb(OTf)3 (0.2 mmol, 20 mol %) was added while stir-
ring. Finally an additional 1 mL of toluene was added. The
mixture was heated at 90 ꢀC for additional 14 h. The mixture
was allowed to reach rt, diluted with EtOAc (15 mL), and
washed with saturated NaHCO3 solution. The aqueous phase
was extracted with EtOAc (2ꢁ5 mL) and the combined
organic layers dried over Na2SO4 and concentrated under
reduced pressure. The pyridines were purified by flash
chromatography.
4.1.2.4. 5-(4-Chlorophenyl)-2-(4-methoxyphenyl)-3-phenylpyr-
idine 8d. Flash chromatography in (SiO2, HxH/EtOAc, 9:1);
193 mg of pale yellow solid were obtained (52%), recrystal-
lized from diethyl ether. Mp 139.0e139.9 ꢀC. IR (KBr): n
1
1512, 1430, 1251, 785 cmꢂ1. H NMR (CDCl3, 300 MHz):
d¼3.81 (s, 3H), 6.81 (d, J¼8.6 Hz, 2H), 7.25 (m, 7H), 7.37
(d, J¼8.6 Hz, 2H), 7.48 (d, J¼8.6 Hz, 2H), 7.87 (d,
J¼2.4 Hz, 1H), 8.88 (d, J¼2.4 Hz, 1H). 13C NMR (CDCl3,
75 MHz): d¼55.2 (CH3), 113.4 (CH), 127.4 (CH), 128.2
(CH), 128.5 (CH), 129.3 (CH), 129.5 (CH), 131.2 (CH),
132.0 (C), 133.3 (C), 134.3 (C), 135.7 (C), 135.9 (C), 136.9
(CH), 140.0 (C), 155.8 (C), 159.5 (C). MS(EI): 373 (26),
372 (45), 371 (91), 370 (100), 329 (13), 327 (36). HRMS
(ESI) calcd for C24H19NOCl (MþH): 372.1150; found:
372.1143.
4.1.2.1. 2-(4-Chlorophenyl)-5-(4-methoxyphenyl)-3-(4-tolyl)-
pyridine 8a. Flash chromatography in (SiO2, HxH/EtOAc,
9:1); 187 mg of pale orange solid were obtained (51%), recrys-
tallized from diethyl ether. Mp¼129.3e130.8 ꢀC. IR (KBr):
4.1.2.5. 5-(2-Chlorophenyl)-2-(4-chlorophenyl)-3-(3,4,5-trime-
thoxy)pyridine 8e. Flash chromatography in (SiO2, HxH/
EtOAc, 9:1); 219 mg of yellow solid were obtained (47%),
recrystallized from diethyl ether. Mp¼126.4e127.2 ꢀC. IR
(KBr): n 1584, 1409, 1241, 1128 cmꢂ1. H NMR (CDCl3,
1
1
n 1515, 1606, 1243, 831 cmꢂ1. H NMR (CDCl3, 300 MHz):
d¼2.39 (s, 3H), 3.89 (s, 3H), 7.05 (d, J¼8.4 Hz, 2H), 7.15
(m, 4H), 7.26 (d, J¼8.4 Hz, 2H), 7.39 (d, J¼8.4 Hz, 2H),
7.62 (d, J¼8.4 Hz, 2H), 7.88 (d, J¼2.4 Hz, 1H), 8.89 (d,
J¼2.4 Hz, 1H). 13C NMR (CDCl3, 75 MHz): d¼21.2 (CH3),
55.4 (CH3), 114.7 (CH), 120.2 (CH), 128.3 (CH), 129.3 (CH),
129.4 (CH), 129.5 (C), 131.2 (CH), 133.9 (C), 135.0 (C),
136.0 (CH), 136.6 (C), 136.8 (C), 137.4 (C), 138.1 (C), 145.9
(CH), 153.6 (C), 160.0 (C). HRMS calcd for C25H20NOCl:
385.1228; found: 385.1226.
300 MHz): d¼3.68 (s, 6H), 3.87 (s, 3H), 6.42 (s, 2H), 7.27
(d, J¼8.4 Hz, 2H), 7.4e7.5 (m, 5H), 7.53 (dd, J¼6.6 Hz,
J¼1.2 Hz, 1H), 7.89 (d, J¼2.4 Hz, 1H), 8.76 87 (d,
J¼2.4 Hz, 1H). 13C NMR (CDCl3, 75 MHz): d¼56.1 (CH3),
61.0 (CH3), 107.0 (CH), 127.3 (CH), 128.2 (CH), 129.6
(CH), 130.3 (CH), 131.1 (CH), 131.3 (CH), 132.9 (C),
133.9 (C), 134.1 (C), 134.5 (C), 135.2 (C), 136.3 (C), 137.6
(C), 138.3 (C), 139.0 (CH), 148.5 (CH), 153.2 (C), 154.7
(C). MS(EI): 469 (17), 467 (78), 465 (100), 454 (6), 452
(20), 450 (27), 151 (29). HRMS (ESI) calcd for C26H22NO3Cl2
(MþH): 466.0971; found: 466.0967.
4.1.2.2. 2-(4-Chlorophenyl)-3-(4-methoxyphenyl)-5-(4-tolyl)-
pyridine 8b. Flash chromatography in (SiO2, HxH/EtOAc,
9:1); 216 mg of yellow solid were obtained (56%), recrystal-
lized from diethyl ether. Mp¼111.8e113.3 ꢀC. IR (KBr): n
4.1.2.6. 2-(4-Chlorophenyl)-3-(3,4,5-trimethoxy)-5-phenylpyri-
dine 8f. Flash chromatography in (SiO2, HxH/EtOAc, 9:1);
220 mg of yellow solid was obtained (51%), recrystallized
from diethyl ether. Mp¼144.7e146.3 ꢀC. IR (KBr): n 1583,
1
1603, 1510, 1246, 815 cmꢂ1. H NMR (CDCl3, 300 MHz):
d¼2.44 (s, 3H), 3.84 (s, 3H), 6.87 (d, J¼8.4 Hz, 2H), 7.16
(d, J¼8.4 Hz, 2H), 7.25 (d, J¼8.4 Hz, 2H), 7.32 (d,
J¼8.4 Hz, 2H), 7.37 (d, J¼8.4 Hz, 2H), 7.58 (d, J¼8.4 Hz,
2H), 7.90 (s, 1H), 8.89 (s, 1H). 13C NMR (CDCl3, 75 MHz):
d¼21.2 (CH3), 55.3 (CH3), 114.1 (CH), 126.7 (CH), 128.3
CH), 129.9 (CH), 130.6 (CH), 131.3 (CH), 131.7 (C), 133.9
(C), 134.2 (C), 135.4 (C), 135.8 (C), 137.0 (CH), 138.1 (C),
138.4 (C), 145.9 (CH), 153.9 (C), 159.2 (C). HRMS calcd
for C25H20NOCl: 385.1228; found: 385.1222.
1408, 1237, 1127 cmꢂ1
.
1H NMR (CDCl3, 300 MHz):
d¼3.71 (s, 6H), 3.89 (s, 3H), 6.44 (s, 2H), 7.2e7.5 (m, 7H),
7.68 (d, J¼7.5 Hz, 2H), 7.96 (s, 1H), 8.9)s, 1H). 13C NMR
(CDCl3, 75 MHz): d¼56.1 (CH3), 61.0 (CH3), 107.0 (CH),
127.2 (CH), 128.1 (CH), 128.4 (CH), 129.2 (CH), 131.1
(CH), 133.9 (C), 134.8 (C), 135.4 (C), 135.9 (C), 136.5
(CH), 137.2 (C), 137.9 (C), 138.4 (C), 146.8 (CH), 153.2
(C), 154.6 (C). MS(EI): 433 (36), 431 (100), 418 (12), 416

786
J. Barluenga et al. / Tetrahedron 64 (2008) 778e786
´
8. (a) Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valdes, C. Chem. Commun.
2002, 2362; (b) Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valdes, C.
´
(32). HRMS (ESI) calcd for C26H23NO3Cl (MþH): 432.1361;
´
´
found: 432.1354.
Chem.dEur. J. 2004, 10, 494.
´
9. Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valdes, C. Chem. Commun.
´
Acknowledgements
2004, 1400.
10. Willis, M. C.; Brace, G. N. Tetrahedron Lett. 2002, 43, 9085.
´
11. Barluenga, J.; Aznar, F.; Moriel, P.; Valdes, C. Adv. Synth. Catal. 2004,
´
´
This work was generously supported by Fundacion Ramon
Areces and DGI of Spain. A FPI predoctoral fellowship to
A.J.-A. is gratefully acknowledged.
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