Allylic alkylation and ring-closing metathesis in sequence: A successful cohabitation of Pd and Ru

Article abstract of DOI:10.1021/ol702694v

An allylic alkylation/ring-closing metathesis domino catalytic process, wherein a palladium and a ruthenium catalyst are concomitantly present in the reaction mixture from the outset of the reaction, is developed. Evidence for Grubbs' catalysts activity in allylic alkylation is also reported.

Full text of DOI:10.1021/ol702694v

ORGANIC
LETTERS
2008
Vol. 10, No. 3
405-408
Allylic Alkylation and Ring-Closing
Metathesis in Sequence: A Successful
Cohabitation of Pd and Ru
Claire Kammerer, Guillaume Prestat,* Thomas Gaillard, David Madec, and
Giovanni Poli*
UPMC UniV Paris 06, UMR CNRS 7611 Laboratoire de Chimie Organique,
FR2769 Institut de Chimie Mole´culaire, case183, F-75005, Paris, France
guillaume.prestat@upmc.fr; gioVanni.poli@upmc.fr
Received November 6, 2007
ABSTRACT
An allylic alkylation/ring-closing metathesis domino catalytic process, wherein a palladium and a ruthenium catalyst are concomitantly present
in the reaction mixture from the outset of the reaction, is developed. Evidence for Grubbs’ catalysts activity in allylic alkylation is also
reported.
Sustainable chemistry processes appear to be a real challenge
for 21st century chemists. In this respect, transition-metal
catalysis and multistep one-pot processing are, among others,
two powerful tools to reach such a goal. Indeed, transition-
metal catalysis has proven to be of paramount importance,
allowing more atom-economical transformations as compared
to stoichiometric organometallic conditions.1 On the other
hand, domino reactions2 allow the preparation of complex
molecules in a single, step-economical, synthetic operation,
thereby limiting the amount of solvent used as well as the
time-consuming and costly workup and purification proce-
dures. Therefore, combination of the two concepts would
enable a big step toward a more sustainable chemistry.
Despite this evidence, the domain of transition-metal cata-
lyzed domino reactions is still in its infancy. We recently
proposed a classification to distinguish the various condi-
tions covering this concept.3 While pure-domino sequences
(TM-DOM) involve a single catalytic cycle, pseudo-domino
ones (TM-PDOM) involve the succession of two or more
catalytic cycles. In this latter case, a simple multitasking
catalytic system may drive the cycles (TM-PDOM type I)
or different and mutually compatible catalysts may be
responsible for different cycles (TM-PDOM type II).
According to this classification most of the known transi-
tion-metal catalyzed domino processes are TM-DOM,4
while TM-PDOM type I5 have been scarcely studied. The
conceptually intriguing and powerful potential of PDOM type
II6,7 has been explored thus far only by very few scientists.8
Among the transition-metal-catalyzed processes the Tsuji-
Trost allylic alkylation9 (AA) and the ring-closing metathesis
(RCM)10 have proven to be powerful tools for the construc-
tion of complex molecules. Accordingly, we decided to study
the feasibility of an AA/RCM PDOM sequence.11,12
(4) For a review on Pd-DOM, see: Poli, G.; Giambastiani, G.; Heumann,
A. Tetrahedron 2000, 56, 5959-5989.
(5) For examples of PDOM type I, see: (a) Poli, G.; Giambastiani, G.;
Pacini, B. Tetrahedron Lett. 2001, 42, 5179-5182. (b) Lemaire, S.; Prestat,
G.; Giambastiani, G.; Madec, D.; Pacini, B.; Poli, G. J. Organomet. Chem.
2003, 687, 291-300. (c) Maitro, G.; Vogel, S.; Prestat, G.; Madec, D.;
Poli, G. Org. Lett. 2006, 8, 5951-5954. (d) Tietze, L. F.; Nordmann, G.
Eur. J. Org. Chem. 2001, 3247-3253. (e) Evans, P. A.; Robinson, J. E. J.
Am. Chem. Soc. 2001, 123, 4609-4610. (f) Battistuzzi, G.; Bernini, R.;
Cacchi, S.; De Salve, I.; Fabrizi, G. AdV. Synth. Catal. 2007, 349, 297-
302.
(1) (a) Tsuji, J. Transition Metal Reagents and Catalysts; Wiley &
Sons: Sussex, UK, 2000. (b) Hegedus, L. S. Transition Metals in the
Synthesis of Complex Organic Molecules; University Science Books:
Sausalito, CA, 1999.
(2) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115-136. (b) Tietze, L. F.;
Brasche, G.; Gericke K. Domino Reactions in Organic Synthesis; Wiley-
VCH: Weinheim, 2006.
(6) For reviews, see: (a) Walsike, J.-C.; Obrey, J. O.; Baker, R. T.; Bazan,
G. C. Chem. ReV. 2005, 105, 1001-1020. (b) Fogg, D. E.; dos Santos, E.
N. Coord. Chem. ReV. 2004, 248, 2365-2379. (c) Lee, J. M.; Na, Y.; Han,
H.; Chang, S. Chem. Soc. ReV. 2004, 33, 302-312.
(3) Poli, G.; Giambastiani, G. J. Org. Chem. 2002, 67, 9456-9459.
10.1021/ol702694v CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/10/2008

For a model reaction we chose to test the AA/RCM
sequence using dimethyl allylmalonate 1a and allyl acetate
as substrates. After a number of optimization experiments,
success was finally encountered when the sodium enolate
of dimethyl allylmalonate was added to a mixture of
Pd(PPh3)4 (2.5 mol %), allyl acetate (1.05 equiv), and
Grubbs’ catalyst second generation (G2, 7.5 mol %) in
methylene chloride at reflux for 1 h. These conditions
allowed the formation of the Pd/Ru PDOM cyclopentenyl
product 2a in 74% isolated yield (Scheme 1). It should be
of Pd(PPh3)4 with Pd(OAc)2 in the presence of a phosphine
such as dppe (2.5 mol %) or PPh3 (5 mol %) did not affect
the conversion of the reaction (entries 1-3). Conversely, the
use of PCy3 with Pd(OAc)2 afforded, after complete con-
sumption of the starting malonate 1a, a mixture of the allylic
alkylation product 3 and the domino product 2a in a 43:57
1
ratio, as observed in H NMR (entry 4). Suppressing the
phosphine or raising its concentration decreased the yield
of the domino product 2a (entries 5-6 vs entry 2). Decreas-
ing the amount of G2 to 5 or 2.5 mol % still afforded a
reasonable amount of domino product (95 and 79% convn,
entries 7-8). As opposed to G2, Grubbs’ catalyst first
generation (G1), bearing two PCy3 and no N-heterocyclic
carbene ligand, did not allow the domino process (entry 9),
while the AA step was quantitative. Dimeric allylpalladium
chloride and Pd2dba3 without phosphine added were found
less efficient than Pd(OAc)2 with or without phosphine
(entries 11-12 vs entries 2 and 6).
Scheme 1. AA/RCM PDOM Sequence
The N-heterocyclic carbene-liganded Pd catalyst [Pd(C3H5)-
(IPr)Cl]13 showed a good activity (entry 13). Changing
solvent from CH2Cl2 to toluene induced a minor decrease
in the domino yield (entry 14), while THF almost completely
inhibited the RCM step (entry 15). Influence of the nature
of the base was also studied. DBU, K2CO3, Cs2CO3, and
BSA/AcOK induced a dramatic decrease of the domino
product yield (entries 16-19).
Control experiments were next performed. As expected,
when a Grubbs’ catalyst was not added to the reaction
mixture, no RCM product was observed (entry 20). Further-
more, when both Ru and Pd catalysts were omitted, neither
3 nor 2a was observed. Surprisingly, when the reaction was
run in the absence of a Pd source, but in the presence of
G2, the partial formation of 3 was still observed (entry 21).
These two experiments clearly indicate that G2 was able to
promote the allylic alkylation step. Although numerous
nonmetathetic reactions have been reported using ruthenium
metathesis catalysts,14 to the best of our knowledge, this is
the first example showing the activity of one of them in
allylic alkylation.15
The influence of a more polar solvent was next tested.
When 1a and allyl acetate were treated with G2 (7.5 mol
%) in THF at reflux for 24 h, a 55% conversion to 3 was
observed (entry 22). Similarly, replacing the latter catalyst
with G1 still allowed a 39% conversion to 3 (entry 23). The
ruthenium-catalyzed allylic alkylation of the sodium enolate
of the unsubstituted dimethyl malonate 4 was next tested.
In this case, use of G1 allowed isolation of an 89:11 mixture
of mono- and diallylated products 1a and 3a in 37% yield
(Scheme 2).
pointed out that both catalysts are present in the reaction
medium from the outset of the reaction. These conditions
also allowed access to cyclohexenyl 2b and cycloheptenyl
2c PDOM products in, respectively, 67 and 74% isolated
yields running the reaction with malonates 1b and 1c,
respectively.
Representative optimization experiments are reported in
Table 1 using dimethyl allylmalonate 1a. First, replacement
(7) For a selection of significant contributions to this field see: (a) Lebel,
H.; Paquet, V. J. Am. Chem. Soc. 2004, 126, 1152-1153. (b) Son, S. U.;
Park, K. H.; Chung, Y. K. J. Am. Chem. Soc. 2002, 124, 6838-6839. (c)
Park, K. H.; Seung, U. S.; Chung, Y. K. Org. Lett. 2002, 4, 4361-4363.
(d) Jeong, N.; Seo, S. D.; Shin, J. Y. J. Am. Chem. Soc. 2000, 122, 10220-
10221. (e) Grigg, R.; Sridharan, V.; York, M. Tetrahedron Lett. 1998, 39,
4139-4142. (f) Barnhart, R. W.; Bazan, G. C. J. Am. Chem. Soc. 1998,
120, 1082-1083. (g) Cossy, J.; Barigiggia, F.; BouzBouz, S. Org. Lett.
2003, 5, 459-462. (h) Morken, J. P.; Didiuk, M. T.; Visser, M. S.; Hoveyda,
A. H. J. Am. Chem. Soc. 1994, 116, 3123-3124.
(8) This process has also been alternatively described as concurrent
tandem catalysis (ref 6a), tandem orthogonal catalysis (ref 6b), or
cooperatiVe sequential multicatalysis (ref 6c).
(9) (a) Tsuji, J. The Tsuji-Trost reaction and related carbon-carbon
formation reaction. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-I., Ed.; John Wiley & Sons: NY, 2002; pp 1669-
1844. (b) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395-
422.
(10) Handbook of Metathesis; Grubbs, R. H., Ed.; John Wiley & Sons:
New York, 2003.
(11) The only related work has been reported by Braddock et al. who
studied the in situ Pd-catalyzed isomerisation of allylic acetates and Ru-
catalyzed RCM of dienic substrates. These authors demonstrate that the
critical point was the slippage of ligands from one metal center to the other
which inhibits the activity of the catalysts. Optimal conditions were found
using 5 mol % Pd2(dba)3‚dba, 20 mol % PPh3, and 5 mol % of Grubbs’
catalyst second generation or Hoveyda-Grubbs’ catalyst. These conditions
allow a limited (57%) conversion of the tandem isomerization/RCM. See:
(a) Braddock, D. C.; Wildsmith, A. J. Tetrahedron Lett. 2001, 42, 3239-
3242. (b) Braddock, D. C.; Matsuno, A. Tetrahedron Lett. 2002, 43, 3305-
3308.
(12) A reverse one-pot sequence, Ru-catalyzed cross metathesis/Pd-
catalyzed allylic carbonate reduction has been recently reported by Comins
et al. In this sequence, the second catalytic system is added after completion
of the first step, yielding a product in 65-85% yield. Comins, D. L.;
Dinsmore, J. M.; Marks, L. R. Chem. Commun. 2007, 4170-4171.
It is noteworthy that throughout the experiments no RCM
product 2a was ever detected. We therefore suspected that
in the reaction medium the Grubbs’ catalyst gave rise to a
(13) Viciu, M. S.; Germaneau, R. F.; Navarro-Fernandez, O.; Stevens,
E. D.; Nolan, S. P. Organometallics 2002, 21, 5470-5472.
(14) (a) Alcaide, B.; Almendros, P. Chem. Eur. J. 2003, 9, 1259-1262.
(b) Mukherjee, A. Synlett 2006, 1128-1129.
(15) Ruthenium-catalyzed allylic alkylation is a well-known process see:
Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV. 2001, 101, 2067-
2096.
406
Org. Lett., Vol. 10, No. 3, 2008

Table 1. AA/RCM PDOM Sequence
entry
[Pd]
ligand (mol %)
[Ru] (mol %)
base
NaH
solvent
convn (%)a
3:2aa
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2dba3
[Pd(C3H5)Cl]2
[Pd(C3H5)(IPr)Cl]
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
-
-
-
G2b
7.5
7.5
7.5
7.5
7.5
7.5
5
2.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
-
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
100
100
100
100
83
100
100
100
100
100
70
100
100
92
62
17
0:100
0:100
0:100
43:57
12:88
44:56
5:95
21:79
98:2
80:20
57:43
12:88
7:93
dppe
PPh3
PCy3
dppe
-
dppe
dppe
dppe
-
2.5
5
5
G2
G2
G2
G2
G2
G2
G2
G1c
G2
G2
G2
G2
G2
G2
G2
G2
G2
-
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
DBU
K2CO3
5
-
2.5
2.5
2.5
-
-
-
5
9
11
12
13
14
15
16
17
18
19
20
21
22f
23f
-
-
PPh3
PPh3
-
5
91:9
100:0
94:6
-
-
-
-
5
-
-
-
d
-
-
-
d
Cs2CO3
BSA/AcOKe
NaH
76
67
100
35
55
96:4
48:52
100:0
100:0
100:0
100:0
PPh3
-
G2
G2
G1
7.5
7.5
7.5
NaH
NaH
NaH
-
-
-
-
THF
39
a Consumption of 1a and 3:2a ratios as determined by 1H NMR. b G2: Grubbs’ catalyst second generation, [(H2IMes)RuCl2(dCHPh)(PCy3)]. c G1:
Grubbs’ catalyst first generation, [RuCl2(dCHPh)(PCy3)2]. d 2 equiv were used and Bu4NBr (10 mol %) was added. e BSA (1.1 equiv), AcOK (10 mol %).
f Reaction time: 24 h.
non-carbenic Ru species able to catalyze allylic alkylation.
On the basis of this hypothesis, a H NMR study was
undertaken. The carbenic proton of G1 appears as a singlet
at 20.17 ppm in d8-THF (NMR 1, Figure 1). Addition of
sodium malonate (1 equiv) to the reaction mixture did not
affect the carbenic region of the spectrum.
metathesis between allyl acetate and G1. Based on integration
of the NMR spectra a 4:82:14 ratio of G1/5/6 was obtained.
Addition of sodium malonate (10 mol %) to this mixture
induced, in 5 min, the complete disappearance of any
1
In an other experiment, allyl acetate was added to G1 (10
mol %) in d8-THF. After 30 min at room temperature the
appearance of two new signals in the carbenic region was
observed (NMR 2). The triplet (19.00 ppm, J ) 4 Hz) was
attributed to 5, whereas the singlet (19.03 ppm) was attributed
to 6. These two compounds were evidently formed by olefin
Scheme 2. Grubbs-Catalyzed Allylic Alkylation
Figure 1. 1H NMR spectra.
Org. Lett., Vol. 10, No. 3, 2008
407

between G1 and 5 is most likely slow compared to the Pd-
catalyzed allylic alkylation step.
Table 2. Double AA/RCM Sequencea
We finally tackled a more ambitious sequence wherein
2a would be obtained directly from the unsubstituted
dimethyl malonate 4 Via a double allylic alkylation followed
by a ring-closing metathesis step in a one-pot sequence. To
our delight, when dimethyl malonate was submitted to the
action of allyl acetate (2.1 equiv) using our optimized
AA/RCM conditions, cyclopentene 2a was isolated in 45%
yield. This yield could be improved to 71% by simply adding
the Grubbs’ catalyst G2 after complete conversion of
dimethyl malonate to 3 (Table 2, entry 1). In this single
synthetic step three new C-C bonds are formed. Similarly,
acetylacetone 7, methyl acetylacetate 8, and ethyl nitroacetate
9 led to the desired products 13, 14, and 15 in 78%, 89%,
and 81% yield, respectively (Table 2, entries 2-4). Cyclic
precursors gave also quite satisfactory results. Indeed,
Meldrum’s acid 10, cyclohexan-1,3-dione 11, and 1,3-
dimethyl barbituric acid 12 reacted smoothly affording the
expected bicyclic products 16, 17, and 18 in 89%, 68%, and
92%, respectively (Table 2, entries 5-7).
In conclusion, we have developed the first allylic alkyla-
tion/ring-closing metathesis domino sequence concomitantly
catalyzed by Pd and Ru. This study demonstrates the
compatibility of the two catalytic systems. We also observed
for the first time that Grubbs’ catalysts can act as precatalysts
for allylic alkylation.
Acknowledgment. This paper is dedicated to Dr.
Genevie`ve Balme on the occasion of her 60th birthday. We
thank Leslie Levas for her contribution in preliminary
experiments. CNRS and UPMC are acknowledged for
financial support. The sponsorship of COST Action D40
“Innovative Catalysis: New Processes and Selectivities” is
kindly acknowledged.
a All reactions were carried out on a 1 mmol scale. b Isolated yields.
carbenic signal (NMR 3). We thus assume that activation of
Grubbs’ catalyst requires both sodium malonate and allyl
acetate. First, allyl acetate reacts with G1 to generate the
corresponding carbenic complex 5. The latter then interacts
with sodium malonate to generate a new allylic alkylation
active non-carbenic ruthenium complex. While this pathway
formally precludes the PDOM process, metathetic reactivity
can still be observed since thermodynamic equilibration
Supporting Information Available: General procedures
and spectroscopic data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL702694V
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Org. Lett., Vol. 10, No. 3, 2008