Synergistic effect of palladium and copper catalysts: Catalytic cyclizative dimerization of ortho-(1-alkynyl)benzamides leading to axially chiral 1,3-butadienes

Article abstract of DOI:10.1002/chem.201200215

Two is better than one: In the presence of Pd(OAc)₂ and Cu(OAc)₂, o-(1-alkynyl)benzamides 1 were converted into bis-iminobenzoisofurans with an axially chiral 1,3-diene 2 unit. The coexistence of both Pd and Cu catalysts was found to be essential for both the cyclizative dimerization process and for the observed unusual cyclization mode. Copyright

Full text of DOI:10.1002/chem.201200215

DOI: 10.1002/chem.201200215
Synergistic Effect of Palladium and Copper Catalysts: Catalytic Cyclizative
Dimerization of ortho-(1-Alkynyl)benzamides Leading to Axially Chiral
1,3-Butadienes
Bo Yao, Carole Jaccoud, Qian Wang, and Jieping Zhu*[a]
The synergistic effect of two metals in catalytic transfor-
mations[1] is well known and is the key to the success of the
Sonogashira reaction (reaction (1) in Scheme 1)[2] and of the
pling discovered by Alexakis[9] and Liebeskind,[10] respec-
tively, provided the foundation of our working hypothesis.
The development of such a dimerization process is of inter-
est as a number of dimeric natural products having an axial-
ly chiral 1,3-diene unit exist in nature.[11] The propensity of
o-(1-alkynyl)benzamides 1 to undergo Lewis acid or metal-
catalyzed cyclization made them ideal candidates to evalu-
ate the feasibility of our concept.[12] We report herein that
the combined use of PdACHTNUGTRENN(UG OAc)2 and CuACHTUGNTNER(NUGN OAc)2 indeed
changed profoundly the reaction outcome. The synergistic
effect of these two metals led to the formation of the till
now unknown axially chiral dimeric imino benzoisofurans 2
from o-(1-alkynyl)benzamides 1 by way of a cyclizative di-
merization process (Scheme 2).
Scheme 1. Hypothesized synergistic effect of palladium and copper salts
in catalytic transformations.
Wacker oxidation.[3] In connection with our ongoing project
on the development of Pd- and Cu-catalyzed domino[4] and
multicomponent reactions,[5] we were interested in develop-
ing a novel dimerization strategy by combining the use of
Pd and Cu catalysts. The underline principle is shown in re-
action (2) in Scheme 1. We hypothesized that the introduc-
tion of both PdII and CuII salts into a solution of alkyne in
the presence of a suitable nucleophile could afford concur-
rently both the vinylpalladium (A) and the vinylcopper (B)
species. While both of them could further evolve to products
independently, we thought that transmetalation between A
and B could be kinetically competent relative to other possi-
ble pathways to afford divinylpalladium intermediate C,
which upon reductive elimination would provide the 1,3-
diene.[6–8] The palladium-catalyzed coupling of vinyl cuprate
with vinyl halide and the CuI-accelerated Stille cross-cou-
Scheme 2. Cyclizative dimerization of o-(1-alkynyl)benzamides leading to
axially chiral bis-iminobenzoisofurans.
Keeping in mind the synergistic effect of the two metals,
the conditions for the cyclizative dimerization was surveyed
using N-benzyl-2-(phenylethynyl)benzamide 1a as a test
substrate. After having varied the Pd and the Cu sources,
the bases, and the solvents (for details, see the Supporting
Information), the optimum conditions found consisted of
performing the reaction in MeCN under air atmosphere at
1008C for 2 h in the presence of Pd
ACHTUNGRTEN(NUGN OAc)2 (0.1 equiv), Cu-
AHCTUNGTRENNG(UN OAc)2 (1.0 equiv), and K2CO3 (1.0 equiv). Under these con-
ditions, cyclizative dimerization took place smoothly to
afford the dimer 2a with an interesting 1,3-diene unit in
72% isolated yield as a single stereoisomer. The diene ge-
ometry was assigned to be E,E, while that of imine Z by X-
ray diffraction analysis (Figure 2 and the Supporting Infor-
mation). It is worth noting that the reaction worked in the
[a] Dr. B. Yao, C. Jaccoud, Dr. Q. Wang, Prof. Dr. J. Zhu
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
Fax : (+41)21-6939740
presence of a catalytic amount of CuACTHNUTRGENUG(N OAc)2 (0.2 equiv)
E-mail: jieping.zhu@epfl.ch
under otherwise identical conditions to provide 2a albeit
with a slightly lower isolated yield (60%).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200215.
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Chem. Eur. J. 2012, 18, 5864 – 5868

COMMUNICATION
Table 2. Substrate scope.[a]
The synergistic effect of Pd and Cu is evidenced from the
results of our control experiments. As it is shown in Table 1,
monomeric isoindolinone 3 (Figure 1) was isolated as the
Table 1. Control experiments.[a]
Entry
Pd
A
(OAc)2
Cu
A
(OAc)2
K2CO3
[equiv]
Yield 2a
[%]
N
[b]
1
2
3
4
5
6
7
8
–
–
0.1
–
0.1
0.2
0.1
0.1
–
1.0
–
1.0
–
1.0
1.0
1.0
1.0
1.0
–
–
–
–
<10[c]
<10[d]
12[e]
11[f]
48
Entry
1
R1
R2
R
Yield [%][b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
4-MeC6H5
Ph
Ph
Ph
Bn
Ph
Ph
H
H
H
H
H
H
H
H
H
H
6-Me
4-OMe
3-Me
72
79
65
76
55
42
70
46
61
72
52
52
4-MeC6H5
4-ClC6H5
3-ClC6H5
4-OMeC6H5
4-OMeC6H5
4-OMeC6H5
4-OMeC6H5
4-OMeC6H5
4-OMeC6H5
Ph
1.0
1.0
72
[g]
–
10[h]
Ph
Ph
[a] Reaction conditions: 1a (0.1 mmol) in CH3CN (2.0 mL) was heated at
1008C under air atmosphere for 2 h. [b] 3 was isolated in 92% yield. [c] 3
was isolated in 53% yield. [d] 3 was isolated in 63% yield. [e] 4 was iso-
lated in 43% yield. [f] 4 was isolated in 35% yield. [g] 1.0 equiv of benzo-
4-OMeC6H5
4-MeC6H5
4-FC6H5
4-FC6H5
4-FC6H5
Ph
9
10
11
12
13
1j
1k
1l
quinone was used instead of CuACTHNUTRGNE(NUG OAc)2. [h] 3 was isolated in 64% yield.
[c]
1o
–
[a] Reaction conditions:
A
mixture of
1
(0.1 mmol), PdACHTUNGTRENNUNG(OAc)2
(0.01 mmol, 10 mol%), CuACTHNUGRTNE(NUG OAc)2 (0.1 mmol, 1.0 equiv), and K2CO3
(0.1 mmol, 1.0 equiv) in CH3CN (2.0 mL) was heated at 1008C (sealed
tube, air atmosphere) for 2 h. [b] Yield of isolated product. [c] No corre-
sponding dimer was isolated.
Figure 1. Isoindolinone (3) and imino-isocoumarin (4) formed in initial
survey of reaction conditions.
substituents (R, R1, and R2) whether electron-donating or
electron-withdrawing in o-(1-alkynyl)benzamides 1 were tol-
erated. As expected, the chlorine atom was survived under
these reaction conditions providing therefore a handle for
further functionalization. However, incorporation of
a methyl group at the C3 position of the benzamide 1 inhibit-
ed the cyclization completely presumably due to the steric
hindrance (Table 2, entry 13). Finally, while o-(1-alkynyl)-
benzoic ester was inactive towards the cyclization under our
conditions,[18] the o-(1-alkynyl)benzoic acid 5 underwent the
cyclizative dimerization smoothly to furnish the dimer 6 in
52% yield (Scheme 3).[19] The structure of 6 was determined
only product in 92% yield in the presence of K2CO3 alone
(Table 1, entry 1).[13] Treatment of 1a with K2CO3/Cu
ACHTUNGTRENNUNG
or with K2CO3/PdACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
K2CO3 provided iminoisocoumarins 4 as a major product re-
sulting from the 6-endo-dig cyclization with amide oxygen as
nucleophile (Table 1, entries 4 and 5).[15] Only when both
CuACHTUNGTRENNUNG(OAc)2 and PdACHTUNGTRENNUNG(OAc)2 were introduced together with
K2CO3, the cyclizative dimerization took place as a major
pathway to afford diene 2a (Table 1, entries 6 and 7). When
benzoquinone instead of CuACHTNUGRTENUNG(OAc)2 was used as oxidant
under otherwise identical conditions, the dimer 2a was iso-
lated in only 10% yield together with 64% yield of isoindo-
linone 3 (Table 1, entry 8). It is noteworthy that the tandem
catalytic system not only allowed the occurrence of the di-
merization pathway, but also diverted the cyclization mode.
In fact, under the optimized conditions, the amide oxygen
instead of the amide nitrogen was implicated in the 5-exo-
dig cyclization leading to iminobenzoisofuran subunit at the
expense of the isoindolinone and iminoisocoumarin. This
cyclization mode has been rarely reported with o-(1-alky-
nyl)benzamides[16] and only few alternative methods existed
in the literature for the synthesis of iminobenzoisofuran.[17]
With optimum conditions in hand, the scope of this cycli-
zative dimerization was evaluated (Table 2). A variety of
Scheme 3. Cyclizative dimerization of o-(1-alkynyl)benzoic acid 5.
by X-ray analysis (see the Supporting Information). We
were also able to convert the bis-iminobenzoisofuran 2a
into bisbenzolactone 6 under acidic conditions (1N HCl),
thus confirming the dimeric nature and the E,E-stereochem-
istry of the 1,3-diene unit of compound 2a.
Chem. Eur. J. 2012, 18, 5864 – 5868
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5865

J. Zhu et al.
A plausible reaction scenario that could account for the
formation of cyclic dimer is illustrated in Scheme 4. It is
known that both nucleopalladation and nucleocupration of
1a can take place under appropriate conditions in line with
earlier reports.[12–15] and our own observations (Table 1). We
therefore hypothesized that under our reaction conditions,
both oxypalladation and oxycupration could occur concur-
rently to provide vinylpalladium (8a) and vinylcopper (8b)
intermediates, via alkyne–metal complexes 7a and 7b, re-
spectively. While disproportionation of 8a could provide
bis-vinylpalladium species 9, it was considered as a thermo-
dynamically unfavorable process.[20] On the other hand,
transmetalation between 8a and 8b should be kinetically
more viable to afford 9, which upon reductive elimination
would afford the cyclizative dimer 2 and Pd0 (route a in
Scheme 4). Oxidation of Pd0 by CuII would regenerate PdII,
therefore closing the catalytic cycle. According to this mech-
anism, CuII has two distinct roles: as catalyst participating in
would lead to the formation of by-products, hence side reac-
tions should be expected. Indeed, Pd-catalyzed cyclization
of alkynamides followed by trapping of the resulting vinyl-
palladium by an external double bond is known.[22] Howev-
er, detailed studies will be required to determine the exact
mechanism and the role of CuACHTNUTRGENNG(U OAc)2 in this reaction. None-
theless, the spectacular modification of the reaction pathway
catalyzed by the PdII/CuII couple versus that catalyzed by
a single metal (Pd, or Cu) is truly remarkable. With bulky
substituents, 1,3-butadienes show properties of axial chirality
À
due to the hindered rotation around the central C2 C3
s bond.[23] We obtained a single crystal of 2j suitable for X-
ray diffraction analysis (Figure 2). The crystal structure re-
vealed that the torsion angle between the two planes of the
double bonds was 75.088 and two enantiomers were seen in
the crystal. Separation of the two enantiomers by SFC and
HPLC with different enantio-discriminating columns turned
out to be challenging presumably due to the low energy bar-
rier of the racemization. After a number of trials, the two
enantiomers of 2a were finally separated using analytical
Chiralcel OJ-RH column (eluent: acetonitrile/H2O=4:1, see
the Supporting Information) indicating the existence of the
atropisomerism for this series of compounds.
À
À
the processes that form C O and C C bonds and as oxidant
to regenerate the PdII species.[21]
Figure 2. X-ray structure of compound 2j. Thermal ellipsoids are drawn
at 30% probability.
In summary, we developed a PdACHTNUTRGENNUG(OAc)2/CuACHTUNTGRENN(UGN OAc)2 co-cata-
lyzed cyclizative dimerization of o-(1-alkynyl)benzamides
leading to axially chiral E,E-1,3-diene. The concurrent for-
mation of vinylpalladium and vinylcopper species followed
by transmetalation is key to our reaction design. Experimen-
tal evidences have been gathered demonstrating that Cu-
Scheme 4. Plausible reaction pathways.
An alternative pathway from 8a to 9 would involve the
coordination of vinylpalladium (8a) to the alkyne function
of the remaining starting material followed by a second oxy-
palladation via intermediate 10 (route b in Scheme 4). To
gain mechanistic information, the following control experi-
ments were carried out. Cyclization of 1a in the presence of
an excess of dimethyl acetylenedicarboxylate (DMAD) or
1,2-diphenylacetylene under otherwise identical conditions
provided cleanly 2a in a yield comparable to the standard
conditions. If route b was the major reaction pathway, the
competitive coordination of 8a to these additional alkynes
ACHTUNGRTEN(NUNG OAc)2 was not simply acting as an oxidant. It might also
À
À
participate in the process forming C C and C O bonds in
concert with the Pd catalyst.[24] Further studies on the asym-
metric synthesis of axially chiral E,E-1,3-diene of type 2 are
ongoing.
Experimental Section
General procedure: A mixture of N-benzyl-2-(phenylethynyl)benzamide
1a (31.1 mg, 0.1 mmol), PdACHTUNRTGENNUG(OAc)2 (2.24 mg, 0.1 equiv), CuACHTUNGTRENNUNG(OAc)2
5866
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Chem. Eur. J. 2012, 18, 5864 – 5868

Synergistic Effect of Palladium and Copper Catalysts
COMMUNICATION
(18.1 mg, 1 equiv), and K2CO3 (13.8 mg, 1 equiv) in CH3CN (2.0 mL) was
heated at 1008C for 2 h. The reaction mixture was diluted with water and
the aqueous phase was extracted with EtOAc. The combined organic ex-
tracts were washed with brine, dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The crude product was purified by
flash column chromatography on silica gel (petroleum ether/ethyl ace-
tate=4:1) to give the product 2a (22.3 mg, 72%). 1H NMR (400 MHz,
CDCl3): d=7.91–7.82 (m, 6H), 7.57–7.48 (m, 6H), 7.44–7.29 (m, 12H),
7.29–7.22 (m, 4H), 5.00 ppm (s, 4H); 13C NMR (101 MHz, CDCl3): d=
155.5, 148.6, 140.3, 136.5, 135.7, 132.4, 130.6, 130.0, 129.5, 128.7, 128.6,
128.1, 128.1, 128.0, 127.0, 123.6, 123.3, 114.0, 52.4 ppm; FTIR: n˜ =2987,
1770, 1697, 1616, 1494, 1247, 1094, 1022, 989, 761, 729, 687 cmÀ1; HRMS
(ESI): m/z calcd for C44H33N2O2: 621.2542, [M+H]+; found: 621.2538.
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Acknowledgements
We thank EPFL, the Swiss National Centres of Competence in Research
(NCCR) and the Swiss National Science Foundation (SNSF) for financial
supports. We are most grateful to Chiral Technologies Europe for the
HPLC separation of the two enantiomers of 2a.
Keywords: atropisomerism · copper · palladium · synergistic
effects · tandem catalysis
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Received: January 19, 2012
Revised: February 27, 2012
Published online: April 4, 2012
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