A multi-task palladium catalyst involved in heck-reduction-cyclization sequences for the preparation of 4-benzyl-1,2-dihydroisoquinolin-3-ones: An unusual homogeneous-heterogeneous sustainable approach

Article abstract of DOI:10.1055/s-0029-1219926

A mixed homogeneous-heterogeneous catalysis that exploits a multi-task palladium catalyst has been developed for one-pot sequential Heck-reduction-cyclization (HRC) reactions leading to novel 4-benzyl-1,2- dihydroisoquinolin-3-ones. The HRC sequence requires mild conditions and allows the separation of the palladium residues under the form of an in situ generated Pd(0)/C catalyst by simple filtration. The homemade and recovered catalyst can be efficiently reused for Suzuki-Miyaura reactions and reductive processes making it useful for sustainable chemistry. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219926

LETTER
1539
A Multi-Task Palladium Catalyst Involved in Heck–Reduction–Cyclization
Sequences for the Preparation of 4-Benzyl-1,2-dihydroisoquinolin-3-ones:
An Unusual Homogeneous–Heterogeneous Sustainable Approach
M
ixe
d
Ho
u
mogeneous–
l
H
etero
i
geneou
a
s
Catalysis Laudien,a Eric Fouquet,a Cécile Zakri,b François-Xavier Felpin*a
a
Université de Bordeaux, UMR CNRS 5255, Institut des Sciences Moléculaires, 351 Cours de la Libération, Talence 33405, France
Fax +33(5)40006286; E-mail: fx.felpin@ism.u-bordeaux1.fr
Université de Bordeaux, CNRS, Centre de Recherche Paul Pascal, Avenue Schweitzer, 33600 Pessac, France
b
Received 16 March 2010
erocycles could be a useful backbone for the preparation
of selective phosphatase inhibitors.5 The general HRC
strategy for the preparation of 4-benzyl-1,2-dihydroiso-
quinolin-3-ones, outlined in the Scheme 2, was inspired
Abstract: A mixed homogeneous–heterogeneous catalysis that ex-
ploits a multi-task palladium catalyst has been developed for one-
pot sequential Heck–reduction–cyclization (HRC) reactions lead-
ing to novel 4-benzyl-1,2-dihydroisoquinolin-3-ones. The HRC se-
quence requires mild conditions and allows the separation of the by our recent work on the synthesis of oxindoles3 and 2-
quinolones.4 First, it features a palladium-catalyzed Heck
palladium residues under the form of an in situ generated Pd(0)/C
catalyst by simple filtration. The homemade and recovered catalyst
coupling of a 2-(2-cyanoaryl)acrylate A with a diazonium
can be efficiently reused for Suzuki–Miyaura reactions and reduc-
salt B. Then, the palladium catalyst operates a double re-
tive processes making it useful for sustainable chemistry.
duction (i.e. alkene and cyano groups) under a hydrogen
Key words: heterogeneous catalysis, heterocycles, palladium,
Heck reaction, hydrogenation
atmosphere to give intermediate D which cyclize into the
4-benzyl-1,2-dihydroisoquinolin-3-one E.
R2
N2BF4
The development of modern sustainable chemistry will be
a key factor in stimulating the creation of new technolo-
gies and efficient processes to solve many environmental
HRC
CO2Me
+
O
ref. 3
NO2
R1
R2
issues that we must face. In this context, the concept of
heterogeneous transition-metal-based multi-task catalysts
has been recently introduced for one-pot sequential reac-
tions.1,2 There are many advantages in elaborating one-pot
processes under heterogeneous catalysis in terms of
waste, time and energy economy. We recently reported
our own contribution in this area by designing original
one-pot Heck–reduction–cyclization (HRC) sequences
for the preparation of oxindoles3 and 2-quinolones.4 The
HRC sequences make an efficient use of diazonium salts
as electrophiles and an original in situ generated Pd/C cat-
alyst (Scheme 1, equations 1–3). Our approach features a
simple and environment friendly experimental protocol
under base-free, ligand-free and additive-free conditions.
In this paper, we wish to present a further development of
the HRC strategy in heterocyclic chemistry for the prepa-
ration of novel 4-benzyl-1,2-dihydroisoquinolin-3-ones
(Scheme 1, equation 4). The HRC sequence developed in
this study features an unusual mixed homogeneous–
heterogeneous catalysis starting from a single source of
palladium.
N
R1
H
(1)
R2
N2BF4
HRC
ref. 4
+
CO2Me
NO2
R2
R1
O
N
H
R1
(2)
R2
N2BF4
NO2
R2
HRC
ref. 4
+
CO2Me
N
O
R1
R1
H
(3)
R2
N2BF4
HRC
CO2Me
O
+
this work
CN
NH
R2
R1
R1
(4)
Scheme 1 Variations in the HRC strategy
1,2-Dihydroisoquinolin-3-ones represent a class of het-
erocycles that have been considerably less studied than
parent isomers such as, for instance, 3,4-dihydroquinolin-
2-ones. However, a recent report suggested that these het-
Optimization of this HRC sequence on a reaction model
provided a protocol that provides the desired 1,2-dihy-
droisoquinolin-3-one 5a in good yield and under mild
conditions (Table 1). Although we gained experience
from previous studies, this HRC sequence required a fine
adjustment of the reaction parameters. The protocol re-
quired 5 mol% of palladium acetate, while under lower
SYNLETT 2010, No. 10, pp 1539–1543
x
x
.x
x
.2
0
1
0
Advanced online publication: 10.05.2010
DOI: 10.1055/s-0029-1219926; Art ID: G07710ST
© Georg Thieme Verlag Stuttgart · New York

1540
J. Laudien et al.
LETTER
lyzed esterification in MeOH followed by a cyanation
using copper cyanide7 furnished compounds 8a,b in ex-
cellent yields over the two steps. The methylenation8 of
ester 8a,b proved to be more difficult to achieve than ex-
pected due to the sensitivity of acrylates 1a,b toward po-
lymerization. Consequently, the reaction temperature
must be accurately controlled to 50 °C, since extensive
degradation occurred above 55–60 °C. However, when
stored in the freezer, acrylates 1a,b are stable for months
allowing the preparation of large quantities.
N2BF4
R2
CO2Me
CN
Heck
'Pd'
+
CO2Me
R2
R1
A
B
CN
C
R1
R2
R2
reduction
H2, 'Pd'
cyclization
O
CO2Me
NH3BF4
Table 1 Optimization Studies
NH
MeO2C
R1
E
R1
D
N2BF4
Pd(OAc)2
Scheme 2 General strategy for the preparation of 4-benzyl-1,2-di-
hydroisoquinolin-3-one
(5 mol%)
CO2Me
+
CO2Me
MeOH,
40 °C, 2 h
CN
1a
CO2Me
CN
palladium loading a complex mixture was obtained due to
incomplete Heck coupling and cyano group reduction (en-
try 2). The reduced intermediate 4, obtained as its tetrafluo-
roborate salt, required a base such as K2CO3 to complete
the intramolecular cyclization (entry 3). In the absence of
any base, no cyclization was observed and only the tet-
rafluoroborate salt 4 was isolated. Most intriguingly, the
nature of the catalysis profoundly impacts the reaction
outcome. Indeed, a fully homogeneous catalysis, i.e. with-
out charcoal, allows the Heck coupling but the following
reduction steps are completely inhibited (entry 4). On the
other hand, a fully heterogeneous catalysis was unsuc-
cessful for the Heck reaction, leading to a quantitative
recovery of the starting material 1a (entry 5). These obser-
vations clearly indicated that the coupling stage requires a
homogeneous palladium catalyst while the reduction
steps are only successful under heterogeneous catalysis.
As a consequence, charcoal was added after the Heck cou-
pling was finished in order to generate in situ a Pd/C cat-
alyst, highly active for the reduction steps. This mixed
homogeneous–heterogeneous catalysis is rather unusual
and could provide more general inspiration for transition
metal catalysis. We also observed that the hydrogenation
(step 2) was temperature dependant (entry 6) and acid co-
catalyzed (entry 7). Indeed, the reduction when carried out
on purified 3 left the cyano group intact whilst fully reduc-
ing the double bond. This surprising reaction outcome
was attributed to HBF4, liberated during the Heck cou-
pling and not trapped with an external base, which acts
likely as a co-catalyst activating the cyano group. Our as-
sumption was definitely proved by the complete reduction
of purified 3 in the presence of one equivalent of HBF4.
This interesting behavior, where a by-product acts as a co-
catalyst, has already been observed in our previous studies
and a related concept has been recently reported for a
domino imine formation–Diels–Alder reaction.6
step 1
3
2
MeO2C
MeO2C
K2CO3
H2, charcoal
O
CO2Me
NH3BF4
25 °C, 1 h
step 3
40 °C, 24 h
step 2
NH
5a
4
"standard" conditions – one pot
Entry Variation from the standard conditions Product Yield (%)a
1
2
3
4
5
6
7
none
5a
89
–
b
1 mol% Pd(OAc)2 instead of 5 mol%
K2CO3 was omitted
–
4
84
95
98
82
71
charcoal was omitted
3
charcoal was added in step 1
step 2 was carried out at 25 °C
step 2 was carried out on purified 3
1a
3
c
–
a Isolated yield.
b Complex mixture.
c Only the double bond was reduced.
R
R
R
R
BF3⋅OEt2
CuCN
CO2H
CO2Me
DMF, 4 h
130 °C
MeOH
60 °C, 2 h
I
I
6a: R = H
6b: R = OMe
7a: 98% yield, R = H
7b: 82% yield, R = OMe
R
R
R
HCHO, K2CO3
CO2Me
CO2Me
n-Bu4NI, toluene
50 °C, 9 h
R
CN
CN
The substituted 2-(2-cyanophenyl)acrylates 1a,b used in
this study were prepared by a straightforward procedure
from the corresponding commercially available 2-iodo-
phenylacetic acids 6a,b (Scheme 3). A BF3·Et2O-cata-
8a: 82% yield, R = H
1a: 77% yield, R = H
8b: 83% yield, R = OMe
1b: 66% yield, R = OMe
Scheme 3 Preparation of 2-(2-cyanophenyl)acrylates
Synlett 2010, No. 10, 1539–1543 © Thieme Stuttgart · New York

LETTER
Mixed Homogeneous–Heterogeneous Catalysis
1541
With the optimized conditions in hands we examined the tistep methodology required two different sources of
scope of this HRC sequence with respect to the diazonium palladium, a silica-supported catalyst (heterogeneous)
salt and the acrylate (Scheme 4).9 It is worth noting that all and PdCl2 (homogeneous), which were added sequential-
arenediazonium tetrafluoroborate salts were easily ac- ly to the reaction mixture. In our HRC sequence, a single
cessed by reaction of the corresponding anilines with so- source of palladium [i.e. Pd(OAc)2] initially homoge-
dium nitrite and tetrafluoroboric acid.10 Importantly, the neous for the Heck coupling, is heterogenized by the ad-
prepared arenediazonium tetrafluoroborate salts showed dition of charcoal (Scheme 5). This unusual way to form
excellent stability for years when stored at –20 °C. The a palladium on activated charcoal catalyst in situ from ho-
presence of electron-rich methoxy groups on acrylate 1b mogeneous Pd(OAc)2 has many advantages : (1) it allows
did not deactivate the Heck coupling since comparable re- the Heck reaction, which is unattainable under heteroge-
action rates were observed with 1a and 1b. The protocol neous conditions, (2) it allows the hydrogenation step that
tolerates both electron-withdrawing and electron-donat- requires a heterogeneous catalysis, (3) the Pd(0)/C formed
ing group at the ortho, meta and para positions in the aryl in situ can be readily recovered from the reaction mixture
diazonium salt fragment. However, in some cases, the avoiding contamination with metal residues. Indeed, ICP–
Heck coupling was found to be sensitive to the steric hin- MS analysis of the methanolic solution after a single fil-
drance on the diazonium salt. For instance, isoquinolone tration showed very low amount of palladium (<12 ppb).
5h was isolated with only 46% yield due to an incomplete This observation indicates that almost 100% of the palla-
Heck reaction (ca. 55% conversion), with the following dium initially introduced under the form of Pd(OAc)2 was
steps (i.e., reduction–cyclization) working perfectly.
transformed into Pd(0)/C during the hydrogenation step.
Moreover, TEM analysis of the filtered catalyst showed a
high dispersion of palladium nanoparticles uniformly dis-
tributed on the support and with an average size of 25–30
nm.
R2
N2BF4
1. Pd(OAc)2
40 °C, 2 h
CO2Me
O
+
2. H2, charcoal
CN
NH
40 °C, 24 h
R2
R1
3. K2CO3
25 °C, 1 h
R1
1a–b
MeO2C
5a–h
F3C
MeO
O
O
O
NH
5a, 89% yield
NH
5b, 51% yield
NH
5c, 71% yield
MeO2C
Me
F3C
MeO
O
O
NH
MeO
MeO
O
NH
5e, 84% yield
NH
MeO
5f, 85% yield
5d, 86% yield
Scheme 5 Schematic representation of the mixed homogeneous–
heterogeneous catalysis
MeO
MeO
O
MeO
MeO
O
We wondered whether the filtered Pd(0)/C catalyst could
be recycled for a variety of reactions (Scheme 6). As al-
ready observed during the optimization studies (see
Table 1), the Heck coupling of diazonium salt 2 with the
2-(2-cyanophenyl)acrylate 1a is unsuccessful under heter-
ogeneous catalysis (Scheme 6, equation 1).12 However,
to our delight, the Pd(0)/C catalyst is highly active for
Suzuki–Miyaura cross-coupling reactions of boronic ac-
ids with diazonium salts under mild, ligand-free and base-
free conditions (Scheme 6, equations 2 and 3).13 It is
worth noting that, for the Suzuki–Miyaura reaction, the
catalyst is selective to the diazonium function in the pres-
ence of chlorine and bromine atoms. The Pd(0)/C catalyst
NH
5g, 89% yield
NH
5h, 46% yield
Scheme 4 Preparation of variously substituted isoquinolones using
the HRC strategy
The HRC sequence developed herein required a mixed
homogeneous–heterogeneous palladium catalysis from
the same palladium source. Tsutsumi and co-workers re-
cently reported the combination of heterogeneous and
homogeneous systems for Sonogashira–cyclization se-
quences devoted to the preparation of indoles.11 This mul-
Synlett 2010, No. 10, 1539–1543 © Thieme Stuttgart · New York

1542
J. Laudien et al.
LETTER
prepared during a HRC sequence is not only active for variety of reactions, giving it a ‘second life’. We antici-
cross-coupling reactions but also for reductive processes pate that such a simple and environmentally friendly
such as hydrogenation (Scheme 6, equation 4) and deben- methodology could be useful for both synthetic and me-
zylation (Scheme 6, equation 5) even on quite elaborated dicinal chemists in the context of sustainable chemistry.
and sensitive substrates. These results clearly showed that An asymmetric variant of this strategy is currently under
our homemade Pd(0)/C catalyst could be as active as the investigation and will be reported in due course.
usual commercially available catalysts. We also demon-
strated that a catalyst formed during a process (i.e. HRC)
can find a ‘second life’ for mechanistically different reac-
Acknowledgment
This work was supported by the Université de Bordeaux and the
Centre National de la Recherche Scientifique (CNRS). We also ack-
nowledge Dr Jürgen Schultz (ISM, Université de Bordeaux 1) for
the gift of nucleoside 15 and Mrs Claire Mouche (CESAMO, Uni-
versité de Bordeaux 1) for HRMS analyses. Dr. Marc Lamblin
(IECB, Université de Bordeaux 1) is gratefully acknowledged for
fruitful discussions.
tions. This concept of reusing a catalyst for an application
different from the one for which the catalyst was initially
developed has almost no precedent14 and would be prom-
ising in the context of sustainable chemistry.
MeO2C
N2BF4
reused
Pd(0)/C
CO2Me
References and Notes
+
CO2Me
MeOH, 40 °C
0% yield
CN
(1) For a review, see: Felpin, F.-X.; Fouquet, E. ChemSusChem
2008, 1, 718.
CO2Me
N2BF4
CN
2
3
1a
(1)
(2) (a) Lipshutz, B. H.; Nihan, D. M.; Vinogradova, E.; Taft, B.
R.; Bošković, V. Ž. Org. Lett. 2008, 10, 4279. (b) Kantam,
L. K.; Chakravarti, R.; Chintareddy, V. R.; Sreedhar, B.;
Bhargava, S. Adv. Synth. Catal. 2008, 350, 2544.
(c) Cusati, G.; Wedig, A.; Djakovitch, L. Lett. Org. Chem.
2009, 6, 77. (d) Jansat, S.; Durand, J.; Favier, I.; Malbosc,
F.; Pradel, C.; Teuma, E.; Gómez, M. ChemCatChem 2009,
1, 244. (e) Climent, M. J.; Corma, A.; Iborra, S.; Mifsud, M.;
Velty, A. Green Chem. 2010, 12, 99.
(3) (a) Felpin, F.-X.; Ibarguren, O.; Nassar-Hardy, L.; Fouquet,
E. J. Org. Chem. 2009, 74, 1349. (b) Ibarguren, O.; Zakri,
C.; Fouquet, E.; Felpin, F.-X. Tetrahedron Lett. 2009, 50,
5071.
Br
reused
Pd(0)/C
B(OH)2
+
MeOH, 25 °C
95% yield
(2)
Br
9
10
11
NO2
B(OH)2
N2BF4
reused
Pd(0)/C
OMe
+
MeOH, 25 °C
98% yield
O2N
O
OMe
(3)
Cl
Cl
14
12
13
(4) Felpin, F.-X.; Coste, J.; Zakri, C.; Fouquet, E. Chem. Eur. J.
2009, 15, 7238.
(5) Wipf, P.; Hopkins, C. R.; Phillips, E. O.; Lazo, J. S.
O
NH
Tetrahedron 2002, 58, 6367.
NH
(6) Alaimo, P. J.; O’Brien, R. III.; Johnson, A. W.; Slauson, S.
R.; O’Brien, J. M.; Tyson, E. L.; Marshall, A.-L.; Ottinger,
E. C.; Chacon, J. G.; Wallace, L.; Paulino, C. Y.; Connell, S.
Org. Lett. 2008, 10, 5111.
HO
reused
HO
N
O
N
O
Pd(0)/C
O
O
H2, MeOH, 25 °C
98% yield
O
(7) General Procedure for the Cyanation of Iodoaryls 7a,b:
To a solution of iodoaryl 7a,b (7.00 mmol, 1 equiv) in DMF
(7 mL) was added CuCN (689 mg, 7.7 mmol). The resulting
mixture was stirred for 4–5 h at 130 °C and then filtered. The
solution was diluted with CH2Cl2 (21 mL) and hydrolyzed
with 5% aq NH4OH solution. After being stirred for 30 min,
the aqueous layer was extracted with CH2Cl2 (3 ×). The
collected organic extracts were dried (MgSO4) and
concentrated under reduced pressure. Purification by flash
chromatography gave the expected products 8a,b.
(8) General Procedure for the Preparation of Acrylates 1a,b:
To a solution of ester 8a,b (10 mmol, 1 equiv) in toluene (13
mL) were added HCHO (28 mmol, 2.8 equiv), Bu4NI (0.2
mmol, 0.04 equiv) and K2CO3 (30 mmol, 3 equiv) at r.t. The
resulting mixture was stirred for 5 h at 50 °C. After cooling
to r.t., H2O (10 mL) was added and the aqueous phase was
extracted with toluene (2 × 20 mL). The collected organic
extracts were dried (MgSO4), filtered and concentrated
under reduced pressure to give the corresponding products
1a,b which were purified by flash chromatography.
(9) General Procedure for the Preparation of 4-Benzyl-1,2-
dihydroisoquinolin-3-ones 5a–h: Acrylate 1a,b (1 mmol)
and Pd(OAc)2 (5 mol%) were added to a solution of
diazonium salt (1.2 mmol) in MeOH (5 mL). The reaction
O
16
15
(4)
O
O
reused
Pd(0)/C
H
H
MeOH–THF
H2, 25 °C
99% yield HO
H
H
H
H
BnO
(5)
17
18
Scheme 6 Recycling studies
In summary, we have reported a novel preparation of 4-
benzyl-1,2-dihydroisoquinolin-3-ones by the mean of our
recently outlined HRC sequence. Several optimizations
were required to develop a one-pot process. Central to this
goal, we developed a mixed homogeneous–heteroge-
neous catalysis with the same palladium source. We also
demonstrated that the in situ generated Pd(0)/C catalyst
could be recovered by simple filtration and reused for a
Synlett 2010, No. 10, 1539–1543 © Thieme Stuttgart · New York

LETTER
was stirred for 12 h at 40 °C, charcoal (110 mg) was added
Mixed Homogeneous–Heterogeneous Catalysis
1543
(11) Sakai, H.; Tsutsumi, K.; Morimoto, T.; Kakiuchi, K. Adv.
Synth. Catal. 2008, 350, 2498.
and the resulting mixture was stirred under H2 (balloon, 1
atm) for 24 h at 50 °C. After cooling to r.t., K2CO3 (2 mmol)
was added in one portion and the heterogeneous mixture was
stirred for 2 h, filtered, and purified by flash chromatography
to give the corresponding 4-benzyl-1,2-dihydroisoquinolin-
3-ones 5a–h.
(12) Heck couplings of aryl diazonium salts have been described
with a Pd(II)/C catalyst, see: Felpin, F.-X.; Fouquet, E.;
Zakri, C. Adv. Synth. Catal. 2008, 350, 2559.
(13) (a) Taylor, R. H.; Felpin, F.-X. Org. Lett. 2007, 9, 2911.
(b) Felpin, F.-X.; Fouquet, E.; Zakri, C. Adv. Synth. Catal.
2009, 351, 649.
(10) (a) Hanson, P.; Rowell, S. C.; Taylor, A. B.; Walton, P. H.;
Timms, A. W. J. Chem. Soc., Perkin Trans. 2 2002, 1126.
(b) Hanson, P.; Jones, J. R.; Taylor, A. B.; Walton, P. H.;
Timms, A. W. J. Chem. Soc., Perkin Trans. 2 2002, 1135.
(14) Zulauf, A.; Mellah, M.; Schulz, E. Chem. Commun. 2009,
6574.
Synlett 2010, No. 10, 1539–1543 © Thieme Stuttgart · New York

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