Dual palladium-and proline-catalyzed allylic alkylation of enolizable ketones and aldehydes with allylic alcohols

Article abstract of DOI:10.1021/ol9001812

The dual Pd/proline-catalyzed α-allylation reaction of a variety of enolizable ketones and aldehydes with allylic alcohols is described. In this reaction, the choice of a large-bite angle ligand Xantphos and proline as the organocatalyst was essential for generation of the crucial π-allyl Pd intermediate from allylic alcohol, followed by nucleophilic attack of the enamine formed in situ from the corresponding enolizable carbonyl substrate and proline.

Full text of DOI:10.1021/ol9001812

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1453-1456
Dual Palladium- and Proline-Catalyzed
Allylic Alkylation of Enolizable Ketones
and Aldehydes with Allylic Alcohols
Ippei Usui, Stefan Schmidt, and Bernhard Breit*
Institut fu¨r Organische Chemie and Biochemie, Freiburg Institute for AdVanced Studies
(FRIAS), Albert-Ludwigs-UniVersita¨t Freiburg, Albertstrasse 21, 79104 Freiburg,
Germany
bernhard.breit@chemie.uni-freiburg.de
Received January 28, 2009
ABSTRACT
The dual Pd/proline-catalyzed r-allylation reaction of a variety of enolizable ketones and aldehydes with allylic alcohols is described. In this
reaction, the choice of a large-bite angle ligand Xantphos and proline as the organocatalyst was essential for generation of the crucial π-allyl
Pd intermediate from allylic alcohol, followed by nucleophilic attack of the enamine formed in situ from the corresponding enolizable carbonyl
substrate and proline.
During the last two decades, palladium-catalyzed allylic
alkylation has become an attractive and mature synthetic
method.1 Typical substrates are acetates and carbonates
derived from allylic alcohols and acetic acid, and alcohols
are formed as the concomitant byproduct stoichiometrically.
In this respect, the use of allylic alcohols as substrates would
be highly attractive since the extra step for allylic eletrophile
preparation could be circumvented with water being the only
byproduct (Figure 1).2 An interesting synthetic application
is the R-allylic alkylation of enolizable ketones and alde-
hydes. Such a transformation has been realized previously
by employing preformed allylic enol carbonates or allylic
ꢀ-ketoester substrates.3 The alternative intermolecular direct
ketone allylation is more difficult but has been achieved
recently, combining enamine organocatalysis with palladium
catalysis.4 The role of the secondary amine catalyst is to in
situ generate the enamine nucleophile which undergoes
nucleophilic attack at an in situ generated π-allyl palladium
complex. In these cases, allylic acetates were employed as
substrates. A related study employed a dual Brønsted acid
and palladium catalyst for the enantioselective allylic alky-
lation of simple aldehydes. In this case, allylic amines had
to be used as substrates.4b Furthermore, allylic alkylation in
high yield and high enantiomeric excess has been achieved
without a transition-metal catalyst based on organo-SOMO
catalysis.5
(1) (a) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395. (b)
Trost, B. M.; Crawly, M. L. Chem. ReV. 2003, 103, 2921.
(2) (a) Ozawa, F.; Okamoto, H; Kawaguchi, S; Yamamoto, S; Mianami,
T; Yoshifuji, M. J. Am. Chem. Soc. 2002, 124, 10968. (b) Ozawa, F.;
Ishiyama, T.; Yamamoto, S.; Kawagishi, S.; Murakami, H.; Yoshifuji, M.
Organometallics 2004, 23, 1698. (c) Kayaki, Y.; Koda, T.; Ikariya, T. J.
Org. Chem. 2004, 69, 2595. (d) Kinoshita, H.; Shinokubo, H.; Oshima, K.
Org. Lett. 2004, 6, 4085. (e) Utsunomiya, M.; Miyamoto, Y.; Ipposhi, J.;
Ohshima, T.; Mashima, K. Org. Lett. 2007, 9, 3371. (f) Muzart, J. Eur. J.
Org. Chem. 2007, 3077. (g) Bricourt, H.; Carpentier, J. F.; Mortreux, A. J.
Mol. Catal. A 1998, 136, 243. (h) Thoumazet, C.; Gru¨tzmacher, H.;
Deschamps, B.; Ricard, L.; Le Floch, P. J. Inorg. Chem. 2006, 3911.
(3) (a) Tunge, J. A.; Burger, E. C. Eur. J. Org. Chem. 2005, 1715. (b)
Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113. (c) Behenna, D. C.;
Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044. (d) Trost, B. M.; Xu, J.
J. Am. Chem. Soc. 2005, 127, 17180. (e) Trost, B. M.; Xu, J.; Reichle, M.
J. Am. Chem. Soc. 2007, 129, 282.
(4) (a) Ibrahem, I.; Co´rdova, A. Angew. Chem., Int. Ed. 2006, 45, 1952.
Ibrahem, I.; Co´rdova, A. Angew. Chem. 2006, 118, 1986. (b) Mukherjee,
S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336. (c) Bihelovic, F.; Matovic,
R.; Vulovic, B.; Saicic, R. N. Org. Lett. 2007, 9, 5063.
10.1021/ol9001812 CCC: $40.75
Published on Web 02/25/2009
2009 American Chemical Society

Table 2. Screening for the Optimal Organocatalyst
Figure 1. Allylic alkylation with allylic alcohol.
We recently achieved the allylic substitution by employing
allylic alcohols in the presence of a palladium catalyst with
self-assembling ligands developed in our laboratory6 and
made attempts to access R-alkylation of ketones and alde-
hydes with these systems as well. In the course of a catalyst
screening, we discovered the Pd-Xantphos system as an
effective catalyst for this transformation. In this paper, we
report on a dual palladium- and proline-catalyzed allylic
alkylation that allows for a direct R-allylation of enolizable
ketones and aldehydes employing allylic alcohols as elec-
trophiles.
entrya
catalyst
yieldb (%)
1
2
3
4
5
L-4
5
6
7
50c
0
0
20c
89d
(DL)-4
a The solution of ketone (1.5 mmol) and cinnamyl alcohol (0.5 mmol)
in DMSO (2 mL) was stirred in the presence of 2.5 mol % of [(η3-allyl)Pd
Cl]2, 5 mol % of xantphos, and 30 mol % of organocatalyst at 27 °C for
20 h. b Isolated yield. c Racemic 3a was obtained when enantiomerically
pure organocatalyst was used. d At 70 °C. Isolated yield.
chloride dimer was employed as the palladium source, and
a screening of monodentate and bidentate phosphine ligands
with differing bite angles was undertaken. While triph-
enylphosphine and dppe were not effective at all, when dppf
or DPEphos was used a moderate conversion toward the
desired allylation product 3a was observed (Table 1, entries
2-5). Best results were obtained with the large bite angle
diphosphine Xantphos (entry 1). Hence, this reaction shows
a correlation between catalyst activity and the size of the
natural bite angle of the diphosphine ligand employed, with
larger bite angle diphosphines furnishing the more active
catalyst.8 Interestingly, when the catalyst precursor was
switched to [(η3-allyl)Pd(cod)]BF4, which was the most
effective catalyst precursor in the case of Pd/self-assembling
ligands, no reaction took place.5
Next, we examined the combination of organocatalyst and
Pd/Xantphos. Thus, the most active organocatalyst was
proline, which allowed for 50% conversion at 27 °C and
gave a synthetically useful yield of 89% at 70 °C (Table 2,
entries 1 and 5). Unfortunately, employing enantiomerically
pure L-proline 4 (Table 2, entry 1) furnished essentially
racemic allylation product 3a. On the other hand, when
pyrrolidine 5 was used as a potential enamine-forming
organocatalyst, the desired allylation product could not be
observed at all (entry 2). In order to probe the need for the
presence of a carboxylic acid function pyrrolidinium acetate
was employed. However, no reaction was observed (entry
3). Conversely, when proline-derived tetrazole 7 was used,
a 20% yield of product was obtained.
Table 1. Ligand Effects on Cyclohexanone Allylation with
Cinnamyl Alcohol
entry
ligand
convnb (%)
bite anglec (°)
1
2
3
4
5
6e
Xantphos
PPh3
Dppe
Dppf
DPEphos
Xantphos
50
0
0
4
27
111
d
86
101
102
111
0
a The solution of ketone (1.5 mmol) and cinnamyl alcohol (0.5 mmol)
in DMSO (2 mL) was stirred in the presence of 2.5 mol % of [(η3-
allyl)PdCl]2, 5 mol % of ligand, and 30 mol % of (DL)-proline at 70 °C for
20 h. b dppe: bis(diphenylphosphanyl)ethane. dppf: 1,1′-bis(diphenylphos-
phino)ferrocene. DPEphos: bis(2-diphenylphosphinophenyl) ether. Xantphos:
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. c Conversion estimated
f
by 1H NMR. d Reference 6. e 10 mol %. [(η3-allyl)Pd (cod)]BF4 was
employed.
We began our investigations by looking at the R-allylation
of cyclohexanone with cinnamyl alcohol (Table 1). As the
organocatalyst we selected proline since its potential for
reversible enamine/immonium ion formation on reaction with
an enolizable ketone or aldehyde in polar aprotic solvents
such as DMSO is well established.7 π-Allyl palladium
Obviously, the presence of both a secondary amine
function and an acidic function with a pKa in the range of a
carboxylic acid within the same organocatalyst molecule are
essential prerequisites for the title reaction to proceed.
(5) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan,
D. W. C. Science 2007, 316, 582.
(6) Usui, I.; Schmidt, S.; Keller, M.; Breit, B. Org. Lett. 2008, 10, 1207.
(7) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007,
107, 5471.
(8) Van Haaren, R. J.; Goubitz, K.; Fraanje, J.; van Strijdonck, G. P. F.;
Coussens, B.; Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
Inorg. Chem. 2001, 40, 3363.
1454
Org. Lett., Vol. 11, No. 6, 2009

Table 3. Scope of Ketonea
a The solution of ketone (1.5 mmol) and cinnamyl alcohol (0.5 mmol) in DMSO (2 mL) was stirred in the presence of 2.5 mol % of [(η3-allyl)PdCl]2,
5 mol % of xantphos, and 30 mol % of (DL)-proline at 70 °C for 20 h. b Isolated yield.
The allylation reaction with cinnamyl alcohol proceeds
well with unsubstituted cyclic ketones to furnish the corre-
sponding allylation products 3a-c (Table 3, entries 1-3).
When 2-methylcyclohexanone 1dwas used, no reaction took
Table 4. Scope of Allylic Alcohol
place (Table 3, entry 4). Such a lack of reactivity for 1d has
been observed before in the case of organocatalytic attempts
for R-oxygenation of this ketone.9 3-Substituted methylcy-
clohexanone 1e gave a mixture of the two regioisomers 3d
and 3e (Table 3, entry 5). 4-Substituted cyclohexanones 1f
also furnished the allylation product in excellent yield (Table
3, entries 6 and 7) as well as oxygen-containing heterocyclic
ketones (Table 3, entries 8 and 9). Acyclic ketones were
considerably less reactive than cyclic substrates. Only with
acetone could the corresponding allylation product be
obtained in acceptable yield (Table 3, entry 10), though a
considerable amount of the bis(cinammyl) ether was formed
as a byproduct.
The reaction is not restricted to the use of cinnamyl alcohol
but can be transferred to a range of simple allylic alcohols.
Thus, allylation of cyclohexanone employing the parent
allylic alcohol 2b furnished 3k in excellent yield (Table 4,
entry 1). Using either 3-buten-2-ol (2c) or the isomeric crotyl
alcohol (2d) gave a mixture of the R- and γ-allylation product
in similar ratios and good yields. Also, starting either from
cinnamyl alcohol (2a) or 1-phenyl 2-propenol (2e), the same
allylation product 3a was obtained in similar yields. These
observations are in accord with a π-allyl intermediate
involved in the reaction mechanism. In addition, excellent
yields of the corresponding allylation product 3n could be
a The solution of cyclohexanone (1.5 mmol) and allylic alcohol (0.5
mmol) in DMSO (2 mL) was stirred in the presence of 2.5 mol % of [(η3-
allyl) PdCl]2, 5 mol % of xantphos, and 30 mol % of proline at 70 °C for
20 h. b Isolated yield. c At 80 °C.
(9) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Hibino, K.; Shoji, M. J.
Org. Chem. 2004, 69, 5966.
Org. Lett., Vol. 11, No. 6, 2009
1455

obtained with ꢀ-methallyl alcohol (2f). On the other hand,
with R,R- and γ,γ-dimethylallyl alcohol, the allylation
reaction did not proceed at all. In this case, the common
π-allyl Pd intermediate might be sterically to hindered to
allow for reaction with the enamine. Further, using (Z)-4-
(benzyloxy)but-2-en-1-ol (2g) led to formation of 3o. Inter-
estingly, the linear product was formed exclusively as an
E/Z mixture of 1:2, which implies that σ-π-σ isomerization
is faster than nucleophilic attack to the Pd intermediate.
alcohol through hydrogen bonding and protonation of the
hydroxy leaving group. This would result in the formation
of a tight ion pair between enamine nucleophile and π-allyl
palladium electrophile which should allow for a rapid
allylation. An external carboxylic acid would preclude the
formation of such an ion pair, which may be the reason for
its failure (Table 2, entry 3).
Scheme 2. Proposed Mechanism
Table 5. Scope of Aldehyde
In conclusion, a dual transition metal and organocatalytic
R-allylation of enolizable ketones and aldehydes employing
simple allylic alcohols as electrophiles has been developed.
The combination of a palladium wide bite angle diphosphine
ligand (Xantphos) and proline as the organocatalyst proved
essential for the title reaction to proceed. Control experiments
show the importance of the presence of a carboxylic acid
function in the secondary amine catalyst. Unfortunately,
employing enantiomerically pure proline did not allow thus
far for efficient enantioinduction during this allylation
reaction. Hence, future studies will address the problem of
enantioselectivity control.
a The solution of aldehyde (1.5 mmol) and cinnamyl alcohol (0.5 mmol)
in DMSO (2 mL) was stirred in the presence of 2.5 mol % of [(η3-allyl)Pd
Cl]2, 5 mol % of xantphos, and 30 mol % of (DL)-proline at 70 °C for 20 h.
b Isolated yield. c Isolated yield after reduction with NaBH4 as alcohol.
We also briefly looked into enolizable aldehydes, which
turned out to be excellent substrates for the title reaction
(Table 5). Thus, starting from R-disubstituted aldehydes
1j-m the efficient construction of quaternary carbon centers
could be achieved through allylation (Table 5, entries 1-4).
Also an R-monosubstituted aldehyde was employed which
gave the corresponding monoallylation product selectively
(entry 5). Due to stability problems with this aldehyde it was
isolated as the corresponding alcohol after reduction with
sodium borohydride.
Acknowledgment. This work was supported by the Fonds
der Chemischen Industrie, the DFG via the International
Research Training Group “Catalysts and Catalytic Reactions
for Organic Synthesis” (GRK 1038), and the Alfried Krupp
Award for young university teachers of the Krupp foundation
(to B.B.).
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
A mechanistic rationale taking into account all experi-
mental observations is given in Scheme 2. Thus, the
carboxylic acid function of proline may be involved in the
ionization step of the palladium olefin complex of allylic
OL9001812
1456
Org. Lett., Vol. 11, No. 6, 2009