Direct catalytic intermolecular α-allylic alkylation of aldehydes by combination of transition-metal and organocatalysis

Article abstract of DOI:10.1002/anie.200504021

(Chemical Equation Presented) All in the same pot together: The direct catalytic α-allylic alkylation of aldehydes and cyclic ketones is achieved by using a simple, unprecedented one-pot procedure. Transition-metal and enamine catalysis are combined so that α-allylic alkylated aldehydes and cyclic ketones are formed in high yield with a direct catalytic chemo- and regioselective method.

Full text of DOI:10.1002/anie.200504021

Communications
Synthetic Methods
DOI: 10.1002/anie.200504021
Direct Catalytic Intermolecular a-Allylic
Alkylation of Aldehydes by Combination of
Transition-Metal and Organocatalysis**
Ismail Ibrahem and Armando Córdova*
The a-alkylation of carbonyl compounds is a fundamental
[
1]
carbon–carbon bond-forming reaction in organic synthesis.
The conventional a-alkylation of carbonyl compounds is
performed by utilizing stoichiometric amounts of metal
enolates for addition to alkyl halides. In this context,the
catalytic direct a-alkylation of nonstabilized aldehydes and
ketones is challenging due to competing side reactions,such
as aldol condensations,Cannizzaro and Tishchenko reactions,
[
2,3]
and N- or O-alkylations.
ods that rely on the stoichiometric use of preactivated
Therefore,metal-catalyzed meth-
[
4]
aldehydes and ketones as their metal enolates, silyl enol
[
5]
[6]
[7]
ethers, enol carbonates, or enamines have been devel-
oped. There are a few methods for the catalytic intermolec-
ular a-alkylation of nonactivated aldehydes and ketones. For
example,Tamaru and co-workers reported that the a-allylic
alkylation of aldehydes is possible in the presence of a
[
8]
catalytic amount of palladium and a slight excess of Et B.
3
Most recently,transition-metal catalysis was employed in the
[
9]
a-alkylation of ketone enolates with alcohols.
Organocatalysis is a fast forward-moving research field.
In this area,phase-transfer catalysis is used in the a-
[
10]
[
11]
alkylations of glycine derivatives. In addition,palladium
catalysis has been combined with chiral phase-transfer
[
11f–g]
catalysis for the a-allylation of glycine imino esters.
Moreover,Koga and co-workers have developed oligo-
amine-mediated a-benzylations of preformed cyclohexanone
[
12]
lithium enolates. Most recently,List and Vignola reported
an elegant amino acid catalyzed intramolecular aldehyde a-
[
13]
alkylation reaction. Well-designed,two-component activa-
tion systems with Pd that combine metal catalysis and the
employment of stoichiometric or catalytic amounts of an
organic catalyst have also been successfully employed in
[
14]
allylic alkylation reactions.
Herein,we report the first
direct intermolecular a-alkylation of aldehydes,which
involves catalytic enamine intermediates. The novel catalytic
reaction assembles the corresponding a-allylic alkylated
[
*] I. Ibrahem, Prof. Dr. A. Córdova
Department of Organic Chemistry
The Arrhenius Laboratory
Stockholm University, 10691 Stockholm (Sweden)
Fax: (+46)8-154-908
E-mail: acordova@organ.su.se, acordova1a@netscape.net
[
**] We gratefully acknowledge the Swedish National Research Council
and Wenner-Gren Foundation for financial support and Prof. Jan E.
Bäckvall for valuable discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
aldehydes and cyclic ketones in high yield and chemoselec-
tivity by combining enamine- and transition-metal-catalysis in
one pot.
In an initial experiment,we treated 3-phenylpropionalde-
[
17]
hyde (1a; 1.5 mmol) with allyl acetate (0.5 mmol) in the
[
18]
presence of a catalytic amount of [Pd(PPh ) ] (5 mol%)
3
4
[
15–16]
As part of our research program on amine catalysis,
and pyrrolidine (10 mol%) in dimethyl sulfoxide (DMSO;
2 mL) at room temperature [Eq. (2)]. To our delight,the
reaction was highly chemoselective,and we were able to
we have made several attempts to alkylate catalytic enamine
intermediates (generated in situ) with allyl or benzyl bro-
mides [Eq. (1)]. However,our initial
attempts into the intermolecular a-
alkylation of aldehydes and cyclohex-
anone failed and the N-alkylation of
the pyrrolidine and proline catalysts
occurred.
Inspired by the work of Trost and
[
5]
Tsuji on allylic alkylations, the use of
isolate the corresponding a-benzylic alcohol 3a in 72% yield
after 16 h by reduction of the a-allylic alkylated aldehyde 2a
in situ with excess NaBH4.
In addition,we found that other cyclic and acyclic
secondary amines catalyzed the direct allylic alkylation
reactions between aldehyde 1a and allyl acetate but with
lower efficiency than pyrrolidine (Table 1).
previously reported two-component catalyst systems with
Encouraged by these initial results,we decided to inves-
tigate the combined transition-metal- and amine-catalyzed
direct allylic alkylation reactions for a set of simple aldehydes
1 (Table 2).
The reactions proceeded smoothly to give the correspond-
ing a-allylic alkylated alcohols 3a–d after reduction in situ of
2a–d,respectively,in high yield with high chemoselectivity. In
addition,the combined palladium- and amine-catalyzed
reactions furnished quaternary carbon centers. For example,
the a-allylic alkylated cyclohexanone carboxaldehyde 2e was
isolated in 65% yield. The direct allylic alkylation of cyclic
ketones was also investigated (Table 3).
[
14]
Pd,
and our experience from initial experiments,we
decided to pursue a different highly challenging strategy for
the a-alkylation of aldehydes and cyclic ketones: the one-pot
combination of transition-metal and enamine catalysis
(
Scheme 1). Thus,the merging of two powerful catalytic
cycles would enable both electrophilic and nucleophilic
activation,which is not possible by one activation mechanism
alone. For example,our reaction design would plausibly
enable CÀC bond formation by allowing catalytic enamine
intermediates generated in situ to attack catalytically gener-
ated electrophilic palladium p-allyl complexes. Reductive
elimination and subsequent hydrolysis of the iminium inter-
The direct catalytic allylic alkylation reactions were
efficient,and the corresponding a-allylic alkylated ketones
5 were isolated in high yield: for example, 5a was recovered in
95% yield. Thus,the one-pot combination of transition-metal
0
mediate would regenerate the Pd and amine catalysts,
respectively,and yield the a-allylic alkylated aldehyde or
ketone.
Scheme 1. Combined transition-metal and enamine catalysis.
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Table 1: Combined palladium- and amine-catalyzed direct a-allylic
alkylation of aldehyde 1a.
Table 3: Combined palladium- and amine-catalyzed direct allylic a-
alkylation of ketones 4.
[
a]
[a]
[
b]
[c]
Entry Ketone
1
Product
16
t [h] d.r.
Yield [%]
Entry
1
Amine catalyst
3a
[
b]
t [h]
Yield [%]
95
16
72
2
3
16
16
45
20
2
3
16
16
1:1 90
4
16
37
1:1 85
[a] See the Experimental Section for the reaction conditions. [b] Yield of
the isolated product after column chromatography on silica gel.
Table 2: Combined palladium- and amine-catalyzed direct a-allylic
[
a]
alkylation of aldehydes 1.
4
16
82
5
6
15
14
2:1 70
[
b]
Entry
1
Aldehyde
Product
t [h]
Yield [%]
72
65
16
[a] See the Experimental Section for the reaction conditions. [b] Deter-
mined by NMR spectroscopic analysis. [c] Yield of the isolated product
after column chromatography on silica gel.
2
3
4
16
17
17
70
76
80
[
c]
5
15
65
[a] See the Experimental Section for the reaction conditions. [b] Yield of
the isolated product of the corresponding alcohol 3 after column
chromatography on silica gel. [c] The yield of the isolated product of
aldehyde 2e.
Scheme 2. Regioselective catalytic a-allylic alkylation of aldehydes and
ketones.
and enamine catalysis is applicable to the synthesis of
functional a-allylic alkylated cyclohexanones. Notably,the
combined palladium- and amine-catalyzed reactions proceed
with excellent regioselectivity when a substituted allylic
acetate or carbonate is used as the electrophile. For example,
the treatment of aldehyde 1a or ketone 4a with cinnamyl
acetate furnished a-alkylated alcohol 3 f in 61% yield and
ketone 5g in 90% yield,respectively,as single regioisomers
lyzed allylic alkylation reaction exhibited excellent regiose-
lectivity with respect to the electrophile.
We also investigated a catalytic asymmetric version of the
allylic alkylation reaction. In preliminary studies,inexpensive
optically active pyrrolidine derivatives or (S)-proline provides
a-allylic alkylated alcohol 3a and ketone 4a with high
(
Scheme 2). Thus,the combined palladium and amine-cata-
1
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Chemie
enantioselectivity but in moderate yields (see the Supporting
Information).
Aggarwal,B. Olofsson, Angew. Chem. 2005, 117,2652; Angew.
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[
[
5] a) J. Tsuji,I. Minami,I. Shimizu,
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In summary,we have developed a simple method for the
direct catalytic allylic alkylation of aldehydes and cyclic
ketones. The direct catalytic highly chemo- and regioselective
intermolecular a-allylic alkylation reaction is mediated by an
unprecedented combination of palladium and enamine catal-
ysis which furnishes a-allylic alkylated aldehydes and cyclic
ketones in high yield. Thus,transition-metal and amine
catalysis can be efficiently merged for the development of
selective reactions. We are currently focusing on the following
topics: 1) expansion of the concept of one-pot combinations
of transition-metal and enamine catalysis to other metals and
electrophiles; 2) the development of catalytic asymmetric
allylic alkylation (AAA) reactions by employing simple and
inexpensive optically active amine catalysts and/or chiral
metal ligands. The initial results will be reported in due
course.
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Typical experimental procedure (Table 1,entry 1): A mixture of allyl
acetate (0.5 mmol) and [Pd(PPh ) ] (5 mol%) in DMSO (2 mL) was
3
4
stirred for 5 min. Aldehyde 1a (1.5 mmol,3 equiv) and amine
10 mol%) were added to the reaction mixture,which was stirred at
(
room temperature for 15–16 h. The reaction was quenched by
reduction of aldehyde 2a in situ with excess NaBH4 to yield the
corresponding alcohol 3a. Aqueous work up and purification by
[
column chromatography (toluene/EtOAc,3:1) furnished alcohol 3a
1
in 72% yield as a clear oil. H NMR (400 MHz,CDCl ): d = 7.32–7.15
3
(m,5H),5.82 (m,1H),5.22 (m,2H),3.59–3.52 (m,2H),2.69–2.63 (m,
1
3
2
H),2.15 (t, J = 6.8 Hz,2H),1.97–1.90 ppm (m,1H);
C NMR: d =
3
5.7,37.5,42.6,64.9,116.8,126.2 1, 28.6,129.4,137.1,140.7 ppm.
Received: November 11,2005
Keywords: aldehydes · allylation · homogeneous catalysis ·
organocatalysis
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1955

Communications
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[
[
17] Allyl carbonates could also be used as electrophiles.
18] The initial palladium complexes were [Pd(PPh ) ] generated
3
4
in situ,commercially available [Pd(PPh 3)4],or [Pd(dppa) 2]
dppa = 1,2-bis(diphenylphosphanyl)acetylene).
(
1
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