Deacylative allylation: Allylic alkylation via retro-Claisen activation

Article abstract of DOI:10.1021/ja205717f

A new method for allylic alkylation of a variety of relatively nonstabilized carbon nucleophiles is described herein. In this process of "deacylative allylation", the coupling partners, an allylic alcohol and a ketone pronucleophile, undergo in situ retro-Claisen activation to generate an allylic acetate and a carbanion. In the presence of palladium, these reactive intermediates undergo catalytic coupling to form a new C-C bond. In comparison to unimolecular decarboxylative allylation, a commonly utilized method for allylation of carbon anions, deacylative allylation is an intermolecular process. Moreover, deacylative allylation allows the direct coupling of readily available allylic alcohols. Lastly, the full utility of deacylative allylation is demonstrated by the rapid construction of a variety 1,6-heptadienes via 3-component couplings.

Full text of DOI:10.1021/ja205717f

ARTICLE
pubs.acs.org/JACS
Deacylative Allylation: Allylic Alkylation via Retro-Claisen Activation
Alexander J. Grenning and Jon A. Tunge*
Department of Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045-7528, United States
S Supporting Information
b
ABSTRACT: A new method for allylic alkylation of a variety of relatively
nonstabilized carbon nucleophiles is described herein. In this process of
“deacylative allylation”, the coupling partners, an allylic alcohol and a ketone
pronucleophile, undergo in situ retro-Claisen activation to generate an allylic
acetate and a carbanion. In the presence of palladium, these reactive
intermediates undergo catalytic coupling to form a new CꢀC bond. In
comparison to unimolecular decarboxylative allylation, a commonly utilized
method for allylation of carbon anions, deacylative allylation is an intermo-
lecular process. Moreover, deacylative allylation allows the direct coupling of readily available allylic alcohols. Lastly, the full utility of
deacylative allylation is demonstrated by the rapid construction of a variety 1,6-heptadienes via 3-component couplings.
’ INTRODUCTION
electrophilic reactive intermediates in situ. While the literature
is replete with reactions that proceed by CꢀC bond cleavage via
retro-Claisen condensation, these reactions typically utilize the
acetyl unit only as a readily cleavable activating group.11,12 In
DaA reactions, the transfer of an acyl group has a functional role
in activating the allylic alcohol toward reaction with Pd(0)
catalysts. Thus, our approach is unique since both the nucleo-
phile and the electrophile are activated by a single CꢀC bond
cleavage event.10,12 In addition to facilitating intermolecular
allylations, DaA is attractive since it results in alkylation of
carbanions directly from allylic alcohols.13 Herein, we wish to
report our findings that many ketone pronucleophiles can under-
go intermolecular deacylative allylation (Scheme 2). The utility
of deacylative allylation is further demonstrated by the rapid
construction of 1,6-heptadienes via 3-component bisallylation;
such products have significant utility as precursors for cycloi-
somerizations and cycloadditions.14
Decarboxylative allylation (DcA)1 has emerged as a conveni-
ent method for the generation and allylation of carbon nucleo-
philes including ketone enolates,2a,b nitrile stabilized anions,2c α-
sulfonyl anions,2d,e 2-aza-allyl anions,2f,g and nitronates2h (Scheme1).
In comparison to more classical couplings, DcA reactions are
distinguished by the use of CꢀC bond cleavage (decarboxy-
lation) to generate the nucleophile.3 One hallmark of decarbox-
ylative metalation is that it has been shown to allow the site-
specific generation of a variety of carbon nucleophiles.2c,d,4
A second hallmark of DcA reactions is the ease with which the
reactants are synthesized and derivatized via mild acetoacetic
ester-type substitution.5 As a testament to DcA’s utility, there has
been significant interest in using the reaction for the synthesis of
natural products (Scheme 1).1,6 Despite the demonstrated utility
of DcA in natural product synthesis,6a,b the sensitivity of allyl
esters often necessitates late-stage introduction of the allylic ester
via transesterification using excessive amounts of an allylic
alcohol and Otera’s catalyst (Scheme 1).7,8 Thus, a clear dis-
advantage of DcA is the necessity to covalently link the nucleo-
philic and electrophilic coupling partners through an ester
linkage prior to decarboxylative coupling (e.g., in 1). Ultimately,
it would be advantageous if the same CꢀC bond formation could
occur in an intermolecular fashion. Such a process could obviate
the need for the two-step transesterification/decarboxylative
allylation sequence and facilitate more rapid production of
analogues.9
’ DEVELOPMENT OF DEACYLATIVE ALLYLATION
Our driving hypothesis for deacylative allylation is that an
allylic alkoxide can induce a retro-Claisen condensation of an
appropriately substituted ketone (Scheme 2). The retro-Claisen
reaction should produce a carbanion nucleophile and an allylic
acetate that can be coupled via palladium catalysis. A survey of the
literature showed that there is a plethora of examples of retro-
Claisen cleavage reactions of α,α-disubstistuted nitroacetone de-
rivatives.15 The retro-Claisen condensation of nitroketones is
generally facile because the nitronate leaving group is more
thermodynamically stable than the alkoxide nucleophile.16 Ni-
tronates are also known to undergo facile allylic alkylation under
standard TsujiꢀTrost conditions.17 Thus, α-nitroketones were
ideal substrates for our preliminary investigations, and our desire
We recently communicated the development of “deacylative
allylation” (DaA) of nitroacetone derivatives, where intermole-
cular CꢀC bond formation was facilitated by a retro-Claisen
condensation.10 As shown herein, the DaA process maintains
several hallmarks of decarboxylative allylation. Specifically, it (A)
allows the site-specific generation of carbanions via CꢀC clea-
vage, (B) allows rapid synthesis of precursors via acetoacetic
ester-like chemistries, and (C) forms both nucleophilic and
Received: June 20, 2011
Published: August 10, 2011
r
2011 American Chemical Society
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Scheme 1. Decarboxylative Allylation
Table 1. Deacylative Allylation of Nitroketones and
Derivatives
Scheme 2. Deacylative Allylation
a 2.5 mol % Pd(PPh3)4, 1.2 equiv of allyl alcohol, 1 equiv of Cs2CO3 80
°C, overnight, DCM:DCE (1:1) for nitro compounds, THF for
acetylacetone derivatives. b >20:1 l:b. c 10 mol % Pd(PPh3)4. d 5.6 1:
E:Z, 3.8:1, l:b. e DCE, 7 h.
to pursue efficient synthesis of 1,6-heptadienes led us to utilize α-
allyl nitroacetone (2a) as a model substrate. Initially, it was
observed that 2a underwent the desired deacylative allylation
quantitatively (eq 1). However, the reaction conditions (5 equiv
of K2CO3 and allyl alcohol, 2.5 mol % Pd(PPh3)4) were
unattractive because excessive amounts of alcohol and base were
required and the method was not applicable to coupling of
substituted allylic alcohols.
produced the desired product in just 25% yield (eq 2). This
suggests that deacylative allylation exhibits a steric selectivity for
coupling of primary allylic alcohols.
In addition to nitroacetone derivatives, nitrophenylacetylace-
tone derivatives also underwent smooth coupling with various
allylic alcohols to produce allylated nitroarylketones (Table 1,
4aꢀ4d). However, attempts to allylate the more basic p-acet-
ylarylketone enolate showed that only allyl alcohol gave product
in high yield (4e). Furthermore, an unsubstituted phenylketone
product was allylated in low yield (4f, Table 1). Thus, it was
apparent that relatively high enolate stability (pKa < 20 in
DMSO) was required for CꢀC bond formation under these
conditions.
Fortunately, by simply switching from K2CO3 to Cs2CO3
base, both the base and the alcohol could be used in stoichio-
metric quantities. Moreover, the simple change in base additive
led to facile coupling of many other allylic alcohol derivatives
with α,α-disubstituted nitroacetone substrates (Table 1). For
example, various commercially available allylic alcohols including
cinnamyl (3b), crotyl (3c), and 1-hexenyl (3d) alcohols were
successfully utilized as coupling partners. The cinnamyl and the
hexenyl alcohols both gave exclusively the linear regioisomeric
product as expected for reactions proceeding via π-allyl palla-
dium intermediates.1,2h However, when crotyl alcohol was
utilized, a mixture of linear/branched regioisomers was isolated
(l:b = 3.8:1) and the linear isomer was obtained as a mixture of E
and Z isomers (E:Z = 5.6:1).1,18c The allylic alcohol coupling
partner can also contain substitution at the internal carbon, as
was determined by the successful DaA of β-methylallyl alcohol
(3e). In addition to simple allylic alcohols, the dienyl allylic
alcohol underwent DaA to form product 3f in 78% yield; such
products are potential substrates for the elegant metal-catalyzed
intramolecular [4 + 2] cycloaddition reactions of unactivated
dienes and dienophiles that have been developed by Livinghouse
and others.19 While primary allylic alcohols were compatible reac-
tion partners in DaA, a secondary allylic alcohol (1-hexen-3-ol)
’ DEACYLATIVE ALLYLATION OF KETONE ENOLATES
With the goal of developing a more broadly applicable de-
acylative allylation, we screened reaction conditions to improve
the yield of product 4f (Table 2). A screen of solvents indicated
that, in nonpolar solvents such as toluene, deacylation was
sluggish and the desired CꢀC bond formation was ineffective
(entry 1). The somewhat more polar solvent, tetrahydrofuran
(THF), did promote deacylation but did not lead to substantial
allylation (entry 3). Finally, good yields of the DaA product could
be isolated in various polar aprotic solvents (entries 4ꢀ7), with
the best conversion to 4f occurring in N-methylpyrrolidinone
(entry 7). Subsequently, a brief screening of bases revealed that
strong bases such as potassium tert-butoxide or sodium hydride
gave excellent results (entries 8ꢀ10). Not only is NaH a much
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Table 2. Optimization of Deacylative Allylation
derivatives (Table 3). As expected, aryl ketones that contain an
electron withdrawing group worked quite well in the deacylative
allylation reaction, giving high yields of the desired products
4eꢀ4k. For example, the reaction was compatible with electron
deficient aryl ketones (4e and 4h) and benzonitriles (4g) as well
as with meta-nitro (4i, 4j) and fluoro (4k) substituents. It was
particularly gratifying to find that challenging electron rich
aromatic ketones and dialkyl ketones that lack an α-aryl group
could be allylated cleanly (4m, 4p).
Next, we examined the regioselectivity of deacylation in
unsymmetric 1,3-diketone substrates that have the potential for
reaction at two different carbonyl groups. For indanones and
α- or β-tetralone, DaA was completely regioselective for cleavage
of the exocyclic acetyl over the cyclic ketone (eqs 3 and 4). While
exocyclic acetyl groups can be selectively cleaved, there is little
selectivity for cleavage of an acetyl versus a benzoyl group (eq 5).
Given the lower electrophilicity of esters versus ketones, it is not
surprising that the cleavage of an acetyl group is preferred over
the cleavage of an ethyl ester (eq 6). Nonetheless, this reaction
does illustrate that the retro-Claisen reaction is faster than
transesterification of the ethyl ester to the allyl ester. Finally,
an aryl β-ketoester substrate did not react chemoselectively when
Cs2CO3 was utilized as the base (Scheme 3); the DaA product
(4s) and a decarboxylative allylation product were formed in a
∼1:1 ratio. Interestingly, switching to NaH as the base resulted in
complete selectivity for deacylative allylation.
entry
solvent
base
time (h) temp (°C) conv (4f:prot)
1
Tol
Cs2CO3
Cs2CO3
Cs2CO3
15
15
15
15
15
15
15
3
38
80
80
80
80
80
80
80
60
60
25% (0:100)
0%
2
DCE
THF
3
100% (20:80)
100% (70:30)
100% (75:25)
100% (67:33)
100% (87:13)
100% (82:18)
100% (85:15)
100% (89:11)
4
CH3CN Cs2CO3
5
DMF
Cs2CO3
Cs2CO3
Cs2CO3
tBuOK
NaH
6
DMSO
NMP
NMP
DMSO
THF
7
8
9
3
10
NaH
1
Table 3. DaA of 1,3-Diketones with Allyl Alcohols
a 1.0:1.05 ketone/allyl alcohol, 1.1 equiv of NaH, 2.5 mol % Pd(PPh3)4
60 °C. b DMSO, 3 h. c THF, 60 min. d NMP, Cs2CO3 80 °C, 12 h.
e THF, 12 h. f 2.1 equiv of NaH.
Having identified β-diketones that undergo deacylative allyla-
tion with allyl alcohol, we turned our attention to varying the
allylic alcohol coupling partner (Table 4). In general, these reactions
were as robust as with simple allyl alcohol but often required
longer reaction times for reaction completion. β-Methallyl alcohol
underwent deacylative allylation with similar rates to that of allyl
alcohol (4tꢀ4w, Table 4), while hexenyl alcohol generated good
to high yields of products in 3 h (4aaꢀ4dd). Cinnamyl alcohol
was generally the slowest reacting allylic alcohol, usually requir-
ing 8ꢀ12 h for reaction completion (4xꢀ4z). Prenyl alcohol was
less expensive base than Cs2CO3, but reaction completion using
NaH was realized in a shorter time frame at a lower temperature
of 60 °C. Thus, further studies of reaction scope were done
primarily under conditions similar to that of entry 10.
Next, a variety of α-aryl 1,3-diketones were prepared by facile
copper-catalyzed enolate arylations followed by mild alkylation.20
Subsequent treatment under the reaction conditions for deacy-
lative allylation showed that the optimized reaction conditions
worked well for the DaA of many different α-aryl acetylacetone
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Scheme 3
Scheme 4. DaA of α-Cyanoketones and Esters
Table 5. Deacylative Allylation of Cyanoacetone Derivatives
Table 4. Deacylative Allylation of Acetylacetone Derivatives
a 1:1.05cyanoacetone: allylic alcohol, 1.1 equiv of NaH. b 60 °C, 12 h.
and allylic alkylation (Scheme 4).23 Thus, a deacylative allylation
of cyanoacetones could lead to a broad array of α-quaternary
allylated nitriles.2a,24,25
To begin, we investigated the reaction of an α-phenyl cya-
noacetone derivative under the conditions that were previously
developed for the DaA of 1,3-diketones (eq 7). Under these
conditions, the α-cyanoketone underwent high yielding DaA to
generate 5a rapidly at room temperature.
As Table 5 shows, deacylative allylations of a variety of
phenylacetonitriles with allyl alcohol were successful. As before,
deacylative allylation provides a straightforward route to 1,6-
heptadienes (Table 5, 5aꢀ5c). While these targets were our
focus, DaA of simple alkyl-substituted nitriles was also feasible
(5d, 5h). In addition, a variety of aryl substituents including
heteroaromatic, polyaromatic, and electron rich aromatics were
compatible with the coupling conditions (5eꢀ5g). That said,
longer reaction times were necessary to couple electron-rich aryl
acetonitrile derivatives (5g, 5h).
Following the successful coupling of allyl alcohol via deacyla-
tive allylation, the DaA reactions of quaternary α-aryl cyanoace-
tones with various allyl alcohols were investigated (Table 6).
Cinnamyl and hexenyl alcohol gave good yields of a single
regioisomer (5i, 5j) and β-methallyl alcohol reacted cleanly
(5j). Prenyl alcohol was also a viable coupling partner; however,
it underwent coupling without significant regioselectivity, giving
a 1.0:1.05 ketone:allylic alcohol, 1.1 equiv of NaH, 2.5 mol % Pd(PPh3)4.
b THF. c NMP, Cs2CO3, 80 °C. d DMSO. e MeCN.
also a viable coupling partner, although it gave a noticeably lower
yield than the other allyl alcohols used (4ee). It was particularly
exciting that 3-cyclopropyl allyl alcohol was also an excellent
coupling partner (4ff, 4gg). The inclusion of the vinyl cyclopro-
pane onto these allylated compounds represents an efficient
synthesis of chiral [5 + 2] precursor substrates (Scheme 4).21
In addition to the coupling of ketone enolates via deacylative
allylation, we wished to demonstrate the potential utility of
deacylation for the generation and allylation of other nucleo-
philes. α-Aryl cyanocarbonyl compounds are versatile chemical
building blocks that can be readily elaborated via classic alkyla-
tion (such as K2CO3/MeI), palladium-catalyzed α-arylation22
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Table 6. DaA of α-Arylcyanoacetones with Allylic Alcohols
Scheme 6. Synthesis of a Verapamil Precursor from
Homoveratronitrile
(a) LiH, Ac-lmidazole, DMSO, rt, 94%, (b) 4 equiv of K2CO3 and
2-iodopropane, 5 h, DMSO, 71% yield, (c) 2.5 mol % Pd(PPh3)4,
1 equiv of allyl alcohol, 2 equiv of NaH, THF.
Scheme 7. DaA of Cyanoacetic Ester
a 1:1.05 cyanoacetone:allylic alcohol, 1.1 equiv of NaH, 2.5 mol %
Pd(PPh3)4. b Inseparable mixture.
Scheme 5. Verapamil Intermediate
Table 7. Deacylative Allylation of Ethyl Cyanoactate
Derivatives
a 55:45 mixture of prenylation (5l) and reverse-prenylation
(5m).26 A potential explanation for this regiochemical outcome
involving inner-sphere versus outer-sphere allylation has been
previously discussed.2c
The ability to allylate electron rich α-aryl nitriles via DaA
suggested that we might be able to demonstrate the utility of DaA
via the production of a key intermediate in the synthesis of
verapamil (Scheme 5).25,27,28 The required precursor to 5o was
synthesized in two steps from the commercially available homo-
veratronitrile by acetylation and substitution with isopropyl
iodide (Scheme 6).29 Here the use of an α-cyanoketone provided
significant synthetic advantages. First, the substitution of iso-
propyl iodide with the relatively nonbasic α-cyanoenolate al-
lowed the construction of a sterically hindered quaternary carbon
center. Second, the acetyl group acts as a blocking group, allowing
only a single alkylation. Next, we chose to initiate our pursuit of
5o using the DaA conditions that successfully coupled allyl
alcohol and the para-methoxy substrate corresponding to pro-
duct 5g (Table 5, NaH, DMSO, 60 °C, 12 h). Unfortunately, the
requisite isopropyl containing substrate gave <5% yield of the
desired product 5o. However, use of an additional equivalent of
NaH allowed the synthesis of the verapamil intermediate (5o) in
good yield (Scheme 6). Moreover, the deacylative allylation was
performed on a gram-scale, suggesting that the DaA reaction is
reasonably scalable.30 From this intermediate, verapamil can be
synthesized following Nelson’s three-step protocol.27a
a 1:5 ethyl cyanoacetate:allylic alcohol, 1.1 equiv. NaH, 2.5 mol %
Pd(PPh3)4. b DMSO. c >20:1 l:b.
arene using Hartwig’s arylation method,22 which does not work
well with α-cyanoketones. However, for this process to be a
success, an allylic alcohol would need to induce a retro-Claisen
condensation of an ester carbonyl. This process was expected to
be challenging since ester carbonyls have a reduced electrophi-
licity in comparison to their acetyl analogues (eq 6).
To begin, we investigated the deacylative allylation of several
α-aryl cyanoacetic ester derivatives. We were pleased to find that
ethyl cyanoacetate derivatives (synthesized by Hartwig’s arylation)
could be utilized in deacylative allylation reactions.22 As Table 7
shows, not only could cyanoacetic esters be used to access the
previously synthesized compounds such as 5a, but they also
allowed extension of the methodology to deacylative allylation of
substrates that were prepared by cyanoacetate bisarylation (5p,
5q).22 Related quaternary diarylacetonitrile derivatives often
exhibit interesting biological activity.31
There are two possible pathways for formation of allylated
products from α-cyanoesters. First, a retro-Claisen condensation
could be initiated by the allylic alkoxide, producing a nitrile
stabilized anion and allylic carbonate, which subsequently under-
go Pd-catalyzed coupling (path A, Scheme 8). Second, the allylic
alkoxide could induce transesterification to produce an allyl ester
whichcouldundergodecarboxylativeallylation(pathB, Scheme8).2c
While DaA worked well for the synthesis of 5o, the need to
acylate the substrate prior to deacylation was clearly synthetically
inefficient. To fully realize the synthetic utility of DaA, we thought it
may be possible to construct the same compound beginning with
readily available α-cyanoesters (Scheme 7). We further expected
that α-cyanoester reactants would enable introduction of the
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Scheme 8. Mechanisms of Allylation
Scheme 10. Synthesis of a Verapamil Precursor from Iso-
propyl Cyanoaceate
Scheme 9. Inhibition by Ethoxide
Scheme 11. New Approaches to the Synthesis of 1,6-
Heptadienes
Table 8. Deacylative Allylation of Isopropyl Cyanoacetate
Derivatives
Since we previously showed that 2° alkoxides are ineffective at
inducing retro-Claisen fragmentation (eq 2), we envisioned that
isopropyl cyanoacetates, which would produce isopropoxide,
would obviate the need for excess allyl alcohol. Indeed, a single
equivalent of allylic alkoxide can effectively out-compete the
byproduct isopropoxide in the retro-Claisen activation, allowing
the allylation to occur in good to excellent yields (Table 8).
To demonstrate the synthetic flexibility of cyanoester reac-
tants, the verapamil precursor 5o was synthesized in 91% overall
yield, via palladium-catalyzed nitrile anion arylation,22 alkylation
of the stabilized enolate,5 and DaA (Scheme 10).
To examine which pathway is followed, an α-cyano ethyl ester
was treated under our reaction conditions in the absence of
palladium. After 15 min, the reaction was quenched by the
addition of acid. These conditions led to the formation of the
protonation product in 81% yield (eq 8). Moreover, analysis of
1
the crude reaction mixture by H NMR spectroscopy showed
that ∼80% of the allyl alkoxide converted to allyl ethyl
carbonate.32 The formation of this nitrile in high yield indicates
that the reaction likely proceeds via preferential retro-Claisen
activation (path A).
’ THREE-COMPONENT UNSYMMETRIC BISALLYLATION
As detailed above, a variety of 1,6-heptadienes can be prepared
in good to excellent yields via DaA of α-allyl ketones. Such
ketones were readily prepared by palladium-catalyzed TsujiꢀTrost
allylation of stabilized enolate nucleophiles. Since both of these
processes utilized a palladiumꢀmetal catalyst to effect the
transformation, we hypothesized that the process could be done
in a single tandem operation that would synthesize these important
cycloisomerization substrates via a one-pot, three-component
coupling (Scheme 11).14,19,21,33
Our strategy for three-component bisallylation is highlighted
in Scheme 11. An initial TsujiꢀTrost allylation of the stabilized
enolate should produce a substrate that is poised to undergo
deacylative allylation. For selective three-component bisallyla-
tion to produce chiral products containing two different allyl
groups, it is desirable that the two allylation events are kinetically
distinct. Since the TsujiꢀTrost allylation of nitroketones is usually
complete within minutes at room temperature34 and DaA was
Interestingly, the retro-Claisen allylation reactions of ethyl
esters required an excess of the allylic alcohol. We hypothesized
that higher concentrations of allyl alkoxide were required due to
the build-up of ethoxide as the allylation progresses (via dec-
arboxylation of the byproduct ethyl carbonate). This ethoxide
can perform a competing retro-Claisen fragmentation, which
funnels the reaction down an unproductive pathway toward
diethyl carbonate formation (Scheme 9). Therefore, we posited
that the higher concentration of allyl alcohol was necessary to
more effectively compete with ethoxide for the requisite retro-
Claisen activation.
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Table 9. Three-Component Bisallylation of Nitroacetone
Derivatives
To investigate the three-component coupling, the general
conditions developed for deacylative allylation were utilized;
however, an extra equivalent of base was added to facilitate the
initial TsujiꢀTrost allylation. In the three-component coupling,
nitroacetone derivatives were coupled with allyl tert-butyl carbo-
nates and allylic alcohols in the presence of 2.5 mol % Pd(PPh3)4
and 1 equiv of Cs2CO3; a second equivalent of base is provided
by the tBuCO3ꢀ leaving group (Table 9). As shown in Table 9,
2b was synthesized in one pot from methyl nitroacetone,
cinnamyl carbonate, and allyl alcohol in an 89% yield (Table 9);
the same product can be derived from cinnamyl acetate in 81%
yield. Comparison of products 2b/2b0, 2d/2d0, and 2f/2f0
demonstrates that the allylic carbonate and alcohol coupling
partners can be interchanged with little effect on the transforma-
tion. Aside from coupling, methyl nitroacetone (2bꢀ2f), α-aryl
(2g), α-benzyl (2h), and more functionalized nitroacetone
derivatives (2iꢀ2k) underwent bisallylation in good yield. As
noted vida supra, even potentially base sensitive methyl esters
were compatible with the reaction conditions (2iꢀ2k). In
addition to bisallylation, starting from unsubstituted nitroace-
tone and utilizing 2 equiv of cinnamyl carbonate and 1 equiv of
allyl alcohol, three new CꢀC bonds can be made in single
operation in an 81% yield (eq 9). Finally, cyclic α-nitroketones
can be utilized in our bisallylation and lead to products with a
pendant carboxylic acid (eq 10).
a 1:1:1.2 nitroacetone/allyl carbonate:allyl alcohol, 2.5 mol % Pd-
(PPh3)4, 1 equiv of Cs2CO3, DCM/DCE (1:1), 80 °C, 12h. b 81% yield
using 2 equiv of Cs2CO3 and cinnamyl acetate. c 10 mol % Pd(PPh3)4.
Table 10. Three-Component Bisallylation of Acetylacetones
Next, we turned our attention to developing a three-compo-
nent bisallylation of ketones (Table 10). In this instance, we
investigated the scope of the transformation using commercially
available allylic acetates and allylic alcohols as coupling partners.
In contrast to the nitroacetone substrates, higher yields of three-
component bisallylation of the diketones were obtained if re-
agents were added sequentially and if the alcohol was injected as
its corresponding alkoxide. A lag-time between the addition of
allylic acetate and allylic alcohol of 5ꢀ10 min gave the best
results. Presumably, this is due to the necessity to complete the
TsujiꢀTrost allylation with cinnamyl acetate before a second
allylic acetate is generated via acyl transfer to allyl alkoxide.
Nonetheless, the procedure is operationally simple and the yields
of unsymmetrically bisallylated ketones are good.
Simple α-phenyl acetylacetone was shown to couple in good
yield with cinnamyl acetate and allyl or β-methyl allyl alcohol
(Table 10). α-Aryl acetylacetone derivatives with various elec-
tron-withdrawing substituents were shown to couple nicely in
this three-component reaction, with ketones (4ii), nitriles (4jj),
and nitro groups (4kk, 4t) all providing products in good yield.
Finally, β-tetralone was an excellent substrate for bisallylations
utilizing allyl alcohol or hexenyl alcohol (4z and 4ll).
a 1:1:1.1 ketone, cinnamyl acetate, allylic alcohol, 2.1 equiv of NaH, 2.5
mol % Pd(PPh3)4, 60 °C THF. b DMSO. x MeCNd. d Cs2CO3.
The same protocol that was used to perform bisallylations of
acetylketone derivates was applied to the three-component
bisallylation of α-cyanoacetones (Table 11). Under these conditions,
anticipated to proceed more slowly, unsymmetric bisallylation
should be possible.
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Table 11. Three-Component Bisallylation of Cyanoacetone
Derivatives
activates the allyl alcohol toward formation of palladium-π-allyl
electrophiles. Thus, the retro-Claisen condensation activates
both the nucleophile and electrophile toward Pd-catalyzed CꢀC
coupling. A further benefit of DaA is the use of activated ketone
substrates that are readily functionalized. Thus, one can readily
construct the desired nucleophiles prior to DaA. These features
allow three-component couplings of ketones, allylic acetates, and
allylic alcohols to produce useful 1,6-heptadienes in one pot. It is
anticipated that intermolecular deacylative allylation will be a
powerful complement to intramolecular decarboxylative allylations.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
complete compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
a 1:1:1.1 cyanoacetone/allylic acetate/allylic alcohol, 2.1 equiv of NaH,
’ AUTHOR INFORMATION
2.5 mol % Pd(PPh3)4, DMSO, 60 °C. b THF. c 10:1 l:b in DaA.
Corresponding Author
tunge@ku.edu
α-phenyl cyanoacetone underwent bisallylation with cinnamyl
acetate as well as hexenyl acetate (5b and 5c, respectively). An α-
pyridyl cyanoketone was also bisallylated in good yield (5u and
5v, Table 11); 5v was also synthesized on the gram-scale using
just 0.5 mol % Pd without a substantial drop in yield (eq 11).30
Finally, other α-aryl cyanoacetones, including 2-naphthyl and
ortho-chlorobenzene, reacted cleanly to give bisallylated products
in good yield.
In addition to α-aryl cyanoacetones, substrates that are
derived from the arylation of cyanoacetates were also competent
coupling partners for bisallylation (eq 12). As before, the ethyl
substrate required an excess of the allylic alcohol and the
isopropyl acetate could be used in a near stoichiometric amount.
’ ACKNOWLEDGMENT
We acknowledge the National Institute of General Medical
Sciences (NIGMS 1R01GM079644) for funding.
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We have developed deacylative allylation as a method for the
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