Pd(0)-catalyzed allylic alkylation/Heck coupling in domino sequence

Article abstract of DOI:10.1016/S0040-4039(01)00951-0

A new molecular queuing process has been achieved, in which a single Pd-based catalytic system promotes two unrelated, sequential catalytic cycles in chronologically distinct order. This study demonstrates also that allylic alkylations can be catalyzed by the Herrmann's phosphapalladacycle, a result that further supports the involvement of a Pd(0) species in its mechanism of action.

Full text of DOI:10.1016/S0040-4039(01)00951-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5179–5182
Pd(0)-catalyzed allylic alkylation/Heck coupling in domino
sequence†
Giovanni Poli,a,* Giuliano Giambastianib and Barbara Pacinib,‡
aLaboratoire de Chimie des Organoe´le´ments, UMR 7611 CNRS, Universite´ Pierre et Marie Curie, Tour 44-45, 4, Place Jussieu,
Boˆıte 183, F-75252 Paris Cedex 05, France
bDipartimento di Chimica Organica ‘Ugo Schiff’
and Centro CNR di Studio per la Chimica e la Struttura dei Composti Eterociclici e loro Applicazioni, Via G. Capponi 9,
I-50121 Florence, Italy
Received 17 May 2001; revised 31 May 2001; accepted 5 June 2001
Abstract—A new molecular queuing process has been achieved, in which a single Pd-based catalytic system promotes two
unrelated, sequential catalytic cycles in chronologically distinct order. This study demonstrates also that allylic alkylations can be
catalyzed by the Herrmann’s phosphapalladacycle, a result that further supports the involvement of a Pd(0) species in its
mechanism of action. © 2001 Elsevier Science Ltd. All rights reserved.
studied,3 and their success cannot be taken for granted
owing to possible incompatibilities between the cata-
lytic cycles.4
The research in the field of domino reactions is attract-
ing considerable attention in synthetic organic chem-
istry since it enables the rapid assembly of complex
molecules in one-pot processes.1 In this context, very
elegant examples of palladium-catalyzed cascade pro-
cesses where a single catalytic cycle entails several
sequential bond transformations, have been recently
reported.2 On the other hand, multi-step palladium-cat-
alyzed processes belonging to multiple sequential cata-
lytic cycles, albeit synthetically interesting and
mechanistically intriguing, have been so far scantily
We recently reported that trans-3,4-disubstituted 4-
alkenyl-2-pyrrolidones could be easily and stereoselec-
tively obtained via the palladium-catalyzed cyclization
of a stabilized acetamide anion on a properly tethered
allylic acetate (Scheme 1).5
In this letter, we wish to report that by setting appro-
priate initial reaction conditions the terminal double
bond generated in the allylic alkylation step can further
undergo a Heck arylation process. Thus, the same
catalytic system is able to promote two different, but
sequential catalytic cycles. Preliminary tests of the Heck
reaction on the already cyclized pyrrolidone 2 indicated
that the arylation reaction takes places regioselectively
on the terminal olefinic atom, to give an E-configurated
1,2-disubstituted alkene (Scheme 2).6
Scheme 1. Reagents and conditions: Pd2(dba)3 (0.05 equiv.),
PPh3 (0.5 equiv.), BSA (1.2 equiv.), AcOK (0.1 equiv.), THF,
reflux, 12 h. EWG: CO2Me, COMe, CN, SO2Ph, PO(OEt)2.
Keywords: palladium and compounds; allylations; Heck reactions.
* Corresponding author. Tel.: +33-1-44275572; fax: +33-1-44277567;
e-mail: poli@ccr.jussieu.fr
†
Dedicated to Professor Jean F. Normant in honor of his 65th
birthday.
Scheme 2. Reagents and conditions: (i) NEt3, Pd(dba)2, P(o-
Tol)3, THF reflux, 28 h. R=H: 46%; R=3-OMe: 74% yield.
‡
Present address: IRBM, Biotechnology Dept., Via Pontina km.
30.600, I-00040 Pomezia (Rome), Italy.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00951-0

5180
G. Poli et al. / Tetrahedron Letters 42 (2001) 5179–5182
Initial attempts to react the acyclic precursor 1 with an
equivalent amount of aryl bromide and a base,7 under
otherwise identical conditions, were disappointing, and
produced only the simple cyclization product 2. The
first encouraging result was obtained by adding, in
consecutive fashion, the aryl halide and NEt3 to the
reaction mixture, only after detection of the cyclized
material 2. Six examples are illustrated in Table 1.
Inspection of Table 1 reveals that under these condi-
tions the reaction is always plagued by important
amounts of the undesired intermediate 2. Moreover, the
Heck reaction did not work at all when p-bromoanisole
and m-bromoacetophenone were used.
In order to improve our results we then tested other
catalytic systems for the coupling reaction. After some
experimentation we found that Herrmann’s catalyst,8 a
phosphapalladacycle easily available from Pd(OAc)2
and P(o-Tol)3, fulfilled our expectations.9 This catalyst,
which is known to efficiently catalyze the Heck reaction
with high turnover numbers, has been the object of
several mechanistic studies. Although many results indi-
rectly suggest the involvement of a Pd(0) species, such a
putative complex has been so far elusive,10 and an
alternative Pd(II)/Pd(IV) redox process has also been
considered.11
Table 1. The consecutive approach
Entry
X
R
3 (%)
2 (%)
1
2
3
4
5
6
Br
I
Br
Br
Br
Br
3-MeO
3-MeO
4-MeO
H
3-MeCO
4-MeCO
3a (46)
3a (32)
3b (–)
3c (61)
3d (–)
(23)
(53)
(30)
(5)
(25)
(55)
3e (21)
This catalyst allowed the Heck coupling to take place
with all the aryl halides tested, including those that
failed with the previous catalytic system. On the other
hand, the high reaction temperatures required brought
about demethoxycarbonylation of the arylated adducts
(Table 2).12
Reagents and conditions: (i) NaH, Pd2(dba)3 cat., P(o-Tol)3, THF
reflux; (ii) ArX, NEt3, reflux 19 h.
Table 2. Heck coupling between 2 and aryl bromides
using the Herrmann’s catalyst
Given the positive results obtained in the simple Heck
coupling we were thus intrigued to test the same cata-
lyst also for the preceding intramolecular allylic alkyla-
tion, so as to accomplish
a
global domino
transformation. To our knowledge, phosphapalladacy-
cle-catalyzed allylic alkylations have not been investi-
gated so far.13 Moreover, since the allylic alkylations
under study are known to proceed via oxidative addi-
tion of the allylic acetate to a Pd(0) species, the success
of such an experiment could not be taken for granted at
the outset.
Entry
ArBr
Time (h)
4 (%)
5 (%)
1
2
3
4
5
3-MeO
4-MeO
H
3-MeCO
4-MeCO
31
51
30
24
23
4a (68)
4b (48)
4c (43)
4d (59)
4e (60)
–
(29)
(51)
–
In the light of what stated above, it was gratifying to
observe that Herrmann’s phosphapalladacycle was
capable indeed of catalyzing the reaction between an
active methylene and an allylic acetate, as exemplified
in the model reaction between diethyl malonate and
cinnamyl acetate (Scheme 3). Such a positive result
appears not only to be important from the synthetic
point of view, but it also strongly supports the implica-
tion of a Pd(0) species in its mechanism.
–
Reagents and conditions: (i) Herrmann’s catalyst (0.05 equiv.),
AcONa (1.1 equiv.), Me2NAc, 80“140°C.
Scheme 3. Reagents and conditions: (i) NaH (1.2 equiv.),
NaOAc (1.1 equiv.), Herrmann’s cat. (0.05 equiv.), Me2NAc,
90°C, 2 h (92%).
Such a result led us to investigate next the intramolecu-
lar alkylation of 1. This transformation turned out to
be quite temperature dependent. Thus, at 60°C (Table
3, entry 1) the reaction proceeded very slowly (40% of
conversion after 23 h), whereas heating at 90°C for 1.5
h (Table 3, entry 2) afforded the cyclized product in
72% yield. Total demethoxycarbonylation, to give 5,
was observed by either heating the reaction at 140°C
for 2.5 h (Table 3, entry 3), or at 90°C for a more
prolonged period (Table 3, entry 4).
Table 3. Intramolecular allylic alkylation using the Herr-
mann’s catalyst (1“2 or 5)
Entry
T (°C)
Time (h)
Prod.
Yield (%)
1
2
3
4
60
90
140
90
23
2
2
5
5
Not det.
1.5
2.5
48
72
66
36
The finding that a phosphapalladacycle was able of
catalyzing the allylic alkylation opened the way towards
its use in discrete sequential processes (Table 4). A first
experiment was conducted by performing the allylic
Reagents and conditions: (i) NaH (1.2 equiv.), NaOAc (1.1 equiv.),
Herrmann’s cat. (0.05 equiv.) Me2NAc.

G. Poli et al. / Tetrahedron Letters 42 (2001) 5179–5182
5181
Table 4. Intramolecular allylic alkylation/intermolecular
alkylation at 90°C, followed by in situ addition of
3-bromoanisole at 140°C (entry 1). By following the
course of the reaction it could be inferred that the
demethoxycarbonylation stage precedes the more slug-
gish arylation step. Most importantly, the presence of
the aryl halide at the outset of the cyclization step was
found to be compatible with the global process. In
particular, 4a could be attained at will, either raising
the temperature from 90 to 140°C after the cyclization
step (entry 2), or directly, by setting the temperature at
140°C from the outset (entry 3). This result indicates
that there is no interference between the oxidative
addition of the allylic acetate and that of the aryl
bromide, the former process being much faster than the
latter one.
Heck coupling under consecutive and domino conditions
Entry
4a (%)
5 (%)
1
2
3
44
59
58
38
26
36
The same reaction conditions used in entry 3 of Table
4 were then applied to other aryl bromides. It is inter-
esting to note that in the case of the bromoacetophe-
nones the conversion is now complete (Table 5).
Reagents and conditions: (i) Entry 1: (a) NaH (1.2 equiv.), AcONa
(1.1 equiv.), Herrmann’s cat. (0.05 equiv.), Me2NAc, 90°C, 1.5 h; (b)
3-MeOC6H4Br (1.4 equiv.), 90“140°C, 29 h. Entry 2: (a) NaH (1.2
equiv.), 3-MeOC6H4Br (1.4 equiv.), AcONa (1.1 equiv.), Herrmann’s
cat. (0.05 equiv.), Me2NAc, 90°C, 1.5 h; (b) 90“140°C, 29 h. Entry
3: NaH (1.2 equiv.), 3-MeOC6H4Br (1.4 equiv.), AcONa (1.1 equiv.),
Herrmann’s cat. (0.05 equiv.), Me2NAc, 140°C, 47 h.
In conclusion, we have shown that the appropriate
choice of the reaction conditions allowed to perform an
allylic alkylation/Heck coupling sequence, as a one-pot
procedure using a single catalyst. The catalytic system
P(o-Tol)3/Pd(dba)2 allows to perform the global process
under consecutive conditions, whereas the use of the
Herrmann’s catalyst permits a domino process to take
place. In this way, a single catalytic system is capable of
promoting two sequential but independent catalytic
cycles in the desired chronological order, thereby allow-
ing a new molecular queuing process to take place
(Scheme 4).14,15
Table 5. Domino intramolecular allylic alkylation/inter-
molecular Heck coupling
Last but not least, this study demonstrates that allylic
alkylations can be catalyzed by the Herrmann’s phos-
phapalladacycle, a result that further supports the
involvement of a Pd(0) species in its mechanism of
action.
Entry
ArBr
Time (h)
4a–e (%)
5 (%)
1
2
3
4
5
3-MeO
4-MeO
H
3-MeCO
4-MeCO
47
50
31
22
22
4a (58)
4b (38)
4c (54)
4d (59)
4e (60)
(36)
(42)
(30)
–
Acknowledgements
–
The authors gratefully acknowledge MURST and CNR
(Italy), as well as the University Pierre et Marie Curie
and CNRS (France) for funding of this research.
Reagents and conditions: (i) NaH (1.2 equiv.), ArBr (1.4 equiv.),
AcONa (1.1 equiv.), Herrmann’s cat. (0.05 equiv.), Me2NAc, 140°C,
47 h.
Scheme 4.

5182
G. Poli et al. / Tetrahedron Letters 42 (2001) 5179–5182
were tested as bases. These bases were added with the
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