Catalytic conjugate addition of allyl groups to styryl-activated enones

Article abstract of DOI:10.1021/ja067878w

Conjugate addition of pinacolato(allyl)boron to benzylidenealkylidene ketones is remarkably facile when catalyzed by Ni(0) and Pd(0) complexes. Simple enones are inert to the reaction conditions, suggesting a significant activating effect by the auxiliary benzylidene unit. A comparison of different catalysts and substrates is provided, as is a mechanistic rationale, and an example of asymmetric catalysis. Copyright

Full text of DOI:10.1021/ja067878w

Published on Web 02/01/2007
Catalytic Conjugate Addition of Allyl Groups to Styryl-Activated Enones
Joshua D. Sieber,† Shubin Liu,‡ and James P. Morken*,†
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, and
DiVision of Research Computing, Information Technology SerVices, UniVersity of North Carolina,
Chapel Hill, North Carolina 27599
Received November 3, 2006; E-mail: morken@bc.edu
Table 1. Catalyst Survey for Conjugate Allylation
Transition-metal-catalyzed conjugate addition of organometallics
to activated alkenes is an important process.1 Intense research has
focused on the utility of copper2 and rhodium catalysts for asym-
metric additions,3 and recent efforts have led to the introduction of
effective palladium4 catalysts. Each catalyst system exhibits a unique
reactivity profile. The rhodium-catalyzed asymmetric conjugate
addition, first introduced by Hayashi and Miyaura,5 is effective with
many activated alkenes, and it may employ boronic acids in addition
to a variety of other organometallic reagents (i.e., silanes,6 stan-
nanes,7 titanates,8 and zincates9). However, the reaction is limited
by the requirement that the organic fragment must be an aryl or
vinyl group. Copper catalysis enables the asymmetric conjugate
addition of alkyl-derived organometallics, although air-sensitive
organozinc and magnesium reagents are generally required.2,10
Significantly, neither rhodium, copper, nor palladium catalysis has
been extended to the enantioselective addition of allyl nucleo-
philes.11 In this report, we describe the catalytic conjugate allylation
of enones with the pinacol ester of allylboronic acid [allylB(pin)].
This is an unprecedented reactivity mode for allylboron compounds,
reagents that typically react by 1,2-addition to carbonyls.
During our studies on the Pd-catalyzed asymmetric diboration
of allenes, we made the surprising observation that the allylboron
product undergoes conjugate addition to dibenzylidene acetone, the
ligand on the Pd2(dba)3 precatalyst.12 Examination of this side
reaction was conducted with commercially available air-stable
allylB(pin) and a variety of activated alkenes, in the presence of
Pd2(dba)3 and PCy3. Whereas simple unsaturated ketones, esters,
amides, imides, and nitriles afford little addition product, the
reaction with dibenzylidene acetone is remarkably efficient. The
experiments summarized in Scheme 1 illustrate the rapidity with
which the reaction occurs, so long as an appropriate catalyst is
employed and the enone is activated by an auxiliary styryl unit; in
the absence of either, no reaction occurs.
metal
ligand
time (h)
â
:
â′ a
% yieldb
2.5% Pd2(dba)3
2.5% Pd2(dba)3
2.5% Pd2(dba)3
2.5% Pd2(dba)3
2.5% Pd2(dba)3
10% Ni(cod)2
10% Ni(cod)2
10% Ni(cod)2
10% Ni(cod)2
6% PCy3
6% PCy3
2
16
2
2
2
4
4
4
4
n/a
<5
67
76
18
17
82
81
55
49
73:27
50:50
50:50
36:64
88:12
71:29
52:48
70:30
6% P(NMe2)3
6% PPh3
6% P(OPh)3
20% PCy3
20% P(NMe2)3
20% PPh3
20% P(OPh)3
a Regioselectivity determined by 1H NMR analysis of unpurified reaction
mixture. b Yield of conjugate addition product after silica gel chromatog-
raphy. Value is an average of two experiments in each case.
electron-rich phosphine ligands such as PCy3 and P(NMe2)3.13
However, the reactions with these catalysts generally provide low
regioselectivity. Alternatively, when Ni(cod)2 and PCy3 were used,
the addition occurred with good selectivity for the alkylidene site,
and the reaction product was isolated in 82% yield after only 4 h
at room temperature.
A number of enones bearing the styryl activating group
participate in the catalytic conjugate allylation (Table 2). With the
exception of the allylic ether in entry 5, all substrates reacted with
good to excellent regioselectivity. Notably, the trisubstituted alkenes
in entries 8 and 9 undergo conjugate addition exclusively at the
more hindered site and provide the desired products in good yield.
It is notable that the allyl ether in entry 5 delivered the conjugate
addition product in good yield even though the allyl ether
functionality is known to participate in allylic substitution reactions
with boronic acids under Ni(0) catalysis.14
Scheme 1
Strategies for manipulation and cleavage of the styryl auxiliary
have been examined. As depicted in Scheme 2, the styryl unit
Table 2. Ni-Catalyzed Conjugate Allylation of Styryl Ketones
entry
R1
R2
R3
time (h)
â:
â′ a
% yieldb
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
CH3
H
C5H11
CH3
Cy
t-Bu
CH2OTBS
(CH2)2OTBS
Ph
CH3
CH3
H
H
H
H
H
H
H
H
4
24
4
4
24
7
4
24
24
88:12
95:5
83:17
>95:5
61:39
85:15
n/a
82
75
83
74
66
82
Refinement of the catalytic conjugate allylation for use in a broad
array of synthesis settings requires an efficient reaction that applies
to nonsymmetric dialkylidene ketones and is highly site-selective.
As depicted in Table 1, the palladium-catalyzed addition of allylB-
(pin) to nonsymmetric ketone 1 proceeds in good yields with
74
>95:5
>95:5
80c
76c,d
CH3
a Determined by 1H NMR analysis of unpurified reaction mixture. b Yield
of conjugate addition product after silica gel chromatography. Value is an
average of two experiments in each case. c Reaction at 65 °C. d Product
consists of a 1.4:1 diastereomer mixture.
† Boston College.
‡ University of North Carolina.
9
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J. AM. CHEM. SOC. 2007, 129, 2214-2215
10.1021/ja067878w CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
On the basis of the hypothesis that donor ligands are intimately
involved in the reductive elimination step, the conjugate allylation
of dibenzylidene acetone was examined in the presence of chiral
ligands. As depicted in Scheme 4, this preliminary survey revealed
that appreciable levels of asymmetric induction can be observed
in the catalytic conjugate allylation. Further experiments along these
lines will be reported in due course.
Acknowledgment. Support by the NIGMS (GM-59417) and
Merck Research Laboratories. J.D.S. acknowledges an ACS Nelson
J. Leonard/Organic Syntheses fellowship.
Supporting Information Available: Characterization and proce-
dures. This material is available free of charge via the Internet at http://
pubs.acs.org.
provides a convenient handle for alkene metathesis, and a ring-
closing version was readily accomplished with the NHC-derived
Hoveyda-Grubbs catalyst to give cyclohexenone 2, a compound
which is not readily available from other catalytic methods.15
Alternatively, regioselective Baeyer-Villiger oxidation can be
accomplished by treatment of the conjugate allylation product with
trimethylsilylperoxide in the presence of Lewis acid.16 This
transformation selectively provides enol ester 3 which can be readily
converted to a variety of functional groups, including the derived
carboxylic acid (see Scheme 2).
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Pd(trifluoroacetate)2 and Ni(acac)2 are ineffective catalysts for
the conjugate addition of allylB(pin) (<5% conversion). This
observation suggests that the reaction is not initiated by transmeta-
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Scheme 3
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Scheme 4
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