Pd-catalyzed domino carbonylative-decarboxylative allylation: An easy and selective monoallylation of ketones

Article abstract of DOI:10.1039/c2cc32391e

In the presence of an allyl alcohol, α-chloroacetophenones undergo an allyloxycarbonylation reaction followed by in situ decarboxylative allylation to selectively afford the corresponding monoallylated ketones via a Pd-catalyzed domino sequence. The scope of the reaction was extended to substituted α-chloroacetophenones as well as various allyl alcohols.

Full text of DOI:10.1039/c2cc32391e

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COMMUNICATION
Pd-catalyzed domino carbonylative–decarboxylative allylation: an easy
and selective monoallylation of ketonesw
a
a
a
b
b
´
´
Steven Giboulot, Frederic Liron,* Guillaume Prestat,z Benoit Wahl, Mathieu Sauthier,
b
b
a
´
Yves Castanet, Andre Mortreux and Giovanni Poli*
Received 2nd April 2012, Accepted 17th April 2012
DOI: 10.1039/c2cc32391e
In the presence of an allyl alcohol, a-chloroacetophenones undergo
an allyloxycarbonylation reaction followed by in situ decarboxylative
allylation to selectively afford the corresponding monoallylated
ketones via a Pd-catalyzed domino sequence. The scope of the
reaction was extended to substituted a-chloroacetophenones as
well as various allyl alcohols.
the two components of the reaction (step 8). Furthermore,
premature protonation of the palladium complex deriving
from oxidative addition of the halide may also take place, directly,
or via its palladium enolate8 (step 9). Finally, competitive oxidative
addition of the alcohol to Pd(0) may, after b-elimination, generate
acrolein, thereby consuming the alcohol (step 12).9
We first studied both steps separately. On the one hand, in
MeOH and under a CO atmosphere (10 bar), a-chloroaceto-
phenone 1a provided the expected methyl b-ketoester 2.
Unfortunately, the reaction did not proceed at atmospheric
pressure.4f,g
Monoallylation of ketones remains challenging in organic
synthesis. Direct allylation of enolates is not selective and
normally results in mixtures of mono- and diallylated ketones.1
The Stork enamine strategy is highly efficient, but requires the
stoichiometric formation of an enamine, which may not be
stable.2 Pd-catalyzed allylation reactions have recently emerged,
but the need for a special ferrocene-based ligand3 makes these
multi-step syntheses tedious.
On the other hand, treatment of allyl b-ketoester 3 with
catalytic Pd(dba)2/4PPh3 at 90 1C in allyl alcohol gave readily
the allylated acetophenone 4a in high yield (Scheme 2).
We next focused on the pseudo-domino process. Accordingly,
we investigated the reactivity of 1a in the presence of allyl
alcohol, a base, a catalytic amount of a palladium complex, and
under a CO atmosphere (Table 1).
To the best of our knowledge, palladium-catalyzed alkoxy-
carbonylation of a-chloroketones has been so far limited to the
preparation of simple, saturated esters, using the required
alcohol as the solvent.4 We anticipated that, in the presence of
an allyl alcohol, the resulting allyl b-ketoester could undergo
in situ Pd-catalyzed decarboxylative allylation.5 In such a case, a
Pd(0) complex would catalyze the carbonylation step as well as
the decarboxylative allylation in a pseudo-domino type I manner,6
thereby selectively generating the desired monoallylated ketone
via a doubly catalytic one-pot process. Scheme 1 shows the
prospective overall mechanism of this new pseudo-domino
sequence.7 The desired path follows elementary steps from
1 to 7 incorporated in the two consecutive catalytic cycles
sharing Pd(0). However, an accurate perusal at the possible
undesired reactivities (Scheme 1, dotted paths) unveils the caveat
that makes such a sequence challenging. First, an undesired
nucleophilic substitution between allyl alcohol and the halide might
generate the corresponding ether, thereby directly subtracting
Under the conditions suitable for the methoxycarbonyl-
ation reaction, neither allylated acetophenone 4a, nor allyl
b-ketoester 3 was observed (entry 1). Raising the temperature
to 130 1C led to 11% isolated yield of allylated acetophenone
4a (entry 2).
Use of a combination of Pd(OAc)2 and PPh3 (1 : 4) resulted
in a slightly better yield (20%, entry 3). Raising CO pressure to
20 bar gave the desired product in 27% yield (entry 4).
Although an increase in the catalyst loading to 5 mol%
showed no improvement (25%, entry 5), further increase to
10 mol% Pd resulted in a doubled isolated yield (52%, entry 6).
So far, allyl alcohol was used as the solvent (30 equiv.). Next,
we reduced the amount of allyl alcohol to 15 equivalents, in the
presence of an additional solvent, so as to keep the molarity
constant. THF and DMF were less efficient, affording 39% and
3% yield of 4a, respectively (entries 7 and 8), whereas toluene
was suitable (57%, entry 9). Tributylamine as the base was as
efficient as 1,8-bis(dimethylamino)naphthalene (DMAN) (54%,
entry 10), yet, allowing an easier workup. A decrease in the
amount of allyl alcohol to 6 equiv. led to the exclusive
formation of acetophenone (entry 11). A ligand screening
revealed that tri(2-furyl) phosphine (TFP) was the best one
(76%, entry 12). Finally, the reaction proceeded with equal
efficiency reducing the reaction time to 2 h (73%, entry 13).
All electron-rich phosphines studied, but Xantphos, led to
a UPMC, IPCM, UMR CNRS 7201, 4 place Jussieu, case 183,
F-75252 Paris Cedex 05, France. E-mail: giovanni.poli@upmc.fr
b
´
Unite de Catalyse et de Chimie du Solide, UCCS, UMR CNRS
8181, Baˆt. C7, Cite Scientifique, B. P. 90108, 59652 Villeneuve
´
d’Ascq Cedex, France. E-mail: andre.mortreux@ensc-lille.fr
w Electronic supplementary information (ESI) available: Full optimization
details and full spectroscopic characterization of all new compounds.
See DOI: 10.1039/c2cc32391e
´
z Present address: Universite Paris Descartes, UMR 8601 CNRS,
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques,
45 rue des Saints-Peres, 75006 Paris, France.
c
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Chem. Commun., 2012, 48, 5889–5891 5889

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Scheme 1 Mechanism of the Pd-catalyzed carbonylative–decarboxylative allylation pseudo-domino sequence, and the possible side reactions.
unsatisfactory results.10 Triethyl phosphite led to disappointing
results, too (entry 14). Generating CO from methyl formate11
was also not efficient.y
With these optimized conditions in hand (Table 1, entry 13),
substituted acetophenones 1b–n were tested as substrates
(Scheme 3).
In the case of crotyl alcohol, mixtures of regioisomeric
allylated acetophenones 4p and 4q were obtained. Worthy of
note, in the case of methallyl alcohol, Xantphos revealed to be
the ligand of choice.
In conclusion, we have developed a synthetic protocol for
the selective generation of g,d-unsaturated aromatic ketones
Monoallylated aryl ketones bearing an electron-withdrawing
group at the para position were isolated in moderate to
acceptable yields (4b–e, 31–65%). The reaction was equally
successful for ketones bearing electron-donating groups at the
para position (4f–h, 44–77%). An EWG or EDG group at the
meta position was also well tolerated (4i–j, 37%). However,
our procedure proved to be sensitive to steric hindrance.
Allylated acetophenone 4k, bearing chlorine atoms at para
and ortho positions was obtained in a lower yield than
allylated acetophenone 4c bearing only the para chlorine atom
(36% vs. 57%, respectively). Desyl chloride also furnished
the desired monoallylated ketone, albeit in moderate yield
(4l, 33%). a-Chloro cycloalkanones and a-chloroketones bearing
b-hydrogen atoms led to mixtures of b-hydride elimination
and/or reduction products. Finally, a-chloroacetophenone 1a
was reacted with substituted allyl alcohols. These alcohols
were used as the solvent. Indeed, use of 15 equiv. of the desired
alcohol in toluene led to unsatisfactory results. Monosubstitu-
tion at either the 2- or 3-position of the allylic motif was
tolerated, affording the desired allylated ketones 4p–r in good
yields (51%, Scheme 4).
Table 1 Optimization of the reaction conditions for the domino
sequence
T/ PCO/ Yieldc
1C bar (%)
Entry [Pd]a
Ligand Base
Solventb
1
2
3
4
5
PdCl2(PPh3)2
—
DMAN
100 10
130 10
130 10
130 20
130 20
0
11
20
27
25
PdCl2(PPh3)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
—
DMAN
DMAN
DMAN
DMAN
DMAN
DMAN THF
DMAN DMF
DMAN Toluene
Bu3N
Bu3N
Bu3N
Bu3N
PPh3
PPh3
PPh3
6
7
8
9
10
11d
12
13f
14
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
TFPe
TFP
130 20
130 20
130 20
130 20
130 20
130 20
130 20
130 20
130 20
52
39
3
57
54
0
76
73
0
Toluene
Toluene
Toluene
Toluene
Toluene
P(OEt)3 Bu3N
a
Entries 1–4: 0.5 mol%; entry 5: 5 mol%; entries 6–14: 10 mol%; in all
b
cases, 4 equiv. of ligand with respect to [Pd] were used. For allyl
alcohol: 30 equiv. allyl alcohol. For other solvents: 15 equiv. allyl alcohol
c
unless otherwise noted. Isolated yields. The mass balance to 100% was
essentially acetophenone. Traces of aldehydes were sometimes noticed.
d
e
6 equiv. of allyl alcohol. Tri(2-furyl)phosphine. 2 h.
f
Scheme 2 Pd-catalyzed methoxycarbonylation and decarboxylative
allylation, separately.
c
5890 Chem. Commun., 2012, 48, 5889–5891
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Notes and references
y Representative experimental procedure: an autoclave was charged
with Pd(OAc)2 (10 mol%), P(2-furyl)3 (40 mol%), Bu3N (1.5 equiv.),
a-chloroketone (1.0 mmol), allyl alcohol (1 mL) and toluene (1.5 mL).
The autoclave was purged with CO, sealed and pressurized to 20 bar
and heated at 130 1C for 2 h. After cooling to r.t., pressure was
released. The reaction mixture was diluted with ether (10 mL) and
water (20 mL) was added. After extraction with Et2O (3 ꢀ 20 mL),
drying over MgSO4 and concentration in vacuo, the residue was
purified by column chromatography, affording the desired product.
1 H. O. House and V. Kramar, J. Org. Chem., 1963, 28, 3362.
2 See for example: (a) G. Stork, R. Terrell and J. Szmuszkovicz,
J. Am. Chem. Soc., 1954, 76, 2029; (b) G. Stork, A. Brizzolara,
H. Landesman, J. Szmuszkovicz and R. Terrell, J. Am. Chem. Soc.,
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3 See for example: J. P. Chen, C. H. Ding, W. Liu, X. L. Hou and
L. X. Dai, J. Am. Chem. Soc., 2010, 132, 15493.
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Soc., 1940, 704; (b) M. F. Carroll, J. Chem. Soc., 1940, 1266;
(c) M. F. Carroll, J. Chem. Soc., 1941, 507. For the first examples
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T. Yamada and J. Tsuji, Tetrahedron Lett., 1980, 21, 3199;
(e) T. Tsuda, Y. Chujo, S. Nishi, K. Tawara and T. Saegusa,
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J. Am. Chem. Soc., 2010, 132, 8915; (g) D. C. Behenna, J. T. Mohr,
N. H. Sherden, S. C. Marinescu, A. M. Harned, K. Tani, M. Seto,
Scheme 3 Scope and limitations of the pseudo-domino sequence.12
starting from readily accessible a-chloroacetophenones. The
method, which is based on a Pd-catalyzed carbonylative–
decarboxylative allylation pseudo-domino process, was insen-
sitive to the electronic properties of the substituents on the
aromatic ring. As this new concept could be extended to
substituted a-chloroacetophenones, further synthetic appli-
cations involving g,d-unsaturated aromatic ketones can be
foreseen.
S. Ma, Z. Novak, M. R. Krout, R. M. McFadden, J. L. Roizen,
´
J. A. Enquist, Jr., D. E. White, S. R. Levine, K. V. Petrova,
A. Iwashita, S. C. Virgil and B. M. Stoltz, Chem.–Eur. J., 2011,
17, 14199. For a recent review see: (h) J. D. Weaver, A. Recio III,
A. J. Grenning and J. A. Tunge, Chem. Rev., 2011, 111, 1846.
6 G. Poli and G. Giambastiani, J. Org. Chem., 2002, 67, 9456.
7 For a recent example from our laboratories, see: B. Wahl,
S. Giboulot, A. Mortreux, Y. Castanet, M. Sauthier, F. Liron
and G. Poli, Adv. Synth. Catal., 2012, 354, 1077.
We are grateful to ANR CP2D programme (‘Domino-CO’
project), the CNRS and the Ministry of Research and
Technology (UPMC and Lille University) for their financial
support.
8 D. A. Culkin and J. F. Hartwig, Acc. Chem. Res., 2003, 36,
234–245.
9 S.-I. Murahashi and N. Komiya, in Handbook of Organopalladium
Chemistry for Organic Synthesis, ed. E.-I. Negishi, John Wiley &
Sons, Inc, 2002, ch. VIII.3.2, pp. 2881–2894.
10 More optimization details can be found in the available ESIw.
´
11 (a) F. Ramirez Vega, J.-C. Clement and H. des Abbayes,
Tetrahedron Lett., 1993, 34, 9117; (b) S. Pellegrini, Y. Castanet
and A. Mortreux, J. Mol. Catal. A: Chem., 1999, 138, 103;
(c) C. Legrand, Y. Castanet, A. Mortreux and F. Petit, Tetrahedron
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12 Under these reaction conditions, a-chloropropiophenone and
cyclopentanone gave the corresponding a,b-unsaturated carbonyl
compound. See for example: Y. Ito, T. Hirao and T. Saegusa,
J. Org. Chem., 1978, 43, 1011.
Scheme 4 Influence of the substitution pattern of the allyl alcohol.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5889–5891 5891