A versatile hexadiene synthesis by decarboxylative sp3-sp 3 coupling/cope rearrangement

Article abstract of DOI:10.1002/anie.200600721

Have it both ways: The palladium-catalyzed decarboxylative coupling of esters with two allyl groups results in kinetic allylation at a position α to electron-withdrawing groups. Tandem allylation/Cope rearrangement provides access to γ-coupling products (

Full text of DOI:10.1002/anie.200600721

Angewandte
Chemie
Recently, our group developed an sp3–sp coupling of allyl
electrophiles with acetylide nucleophiles (Scheme 1).[6] In
doing so, it was demonstrated that decarboxylative metalation
can be used to access organometallic intermediates, and is
Scheme 1. Decarboxylative sp3–sp coupling of allyl electrophiles with
acetylide nucleophiles.
thus an alternative to transmetalation. Such decarboxylative
coupling reactions are advantageous because they allow the
use of readily available carboxylic acids or esters (as opposed
to organometallic reagents), occur under neutral conditions,
and produce CO2 as the only by-product.[7,8]
Allylation
DOI: 10.1002/anie.200600721
As decarboxylative metalation can potentially be used to
circumvent transmetalation, it is desirable to determine what
other types of organometallic intermediates can be accessed
by decarboxylation. With the goal of developing an alter-
native to the Stille-type allyl–allyl coupling, we became
curious as to whether the loss of CO2 from 3-butenoates could
be used to produce bis(allyl) palladium complexes, thus
allowing the coupling of two allyl species (Scheme 2).
AVersatile Hexadiene Synthesis by
Decarboxylative sp3–sp3 Coupling/Cope
Rearrangement
Shelli R. Waetzig, Dinesh K. Rayabarapu,
Jimmie D. Weaver, and Jon A. Tunge*
The sp3–sp3 coupling of two allyl fragments is a potentially
powerful way of generating 1,5-dienes, which are found in a
host of biologically active natural products.[1] However, there
are surprisingly few catalytic transformations that couple two
different allyl groups with high selectivity.[2–4] Seminal studies
by Schwartz showed that electrophilic p-allyl palladium
complexes, which are conveniently accessed by oxidative
addition of allylic acetates, underwent stoichiometric cou-
pling with nucleophilic magnesium allyl reagents.[4] Presum-
ably this reaction proceeds by transmetalation from Mg to
give bis(allyl) palladium complexes which reductively elim-
inate the hexadiene.[5] Transmetalation from tin was also
possible, and allowed the catalytic Stille-type coupling of
allylic bromides with allyl stannanes.[4] However, this method
is clearly nonideal because it suffers from poor yields and
requires the synthesis and use of stoichiometric quantities of
toxic allyl stannanes.
Scheme 2. Decarboxylative sp3–sp3 coupling. EWG=electron-withdraw-
ing group.
Our research in this area has led us to believe that the rate
of decarboxylation correlates with the pKb of the anion
generated following loss of CO2.[7] Therefore, the develop-
ment of a decarboxylative sp3–sp3 coupling was initiated using
substrates 1, where the allyl anion generated by decarbox-
ylation is potentially stabilized by an electron-withdrawing
carbonyl group such as a ketone.[9] Such substrates are readily
prepared by the In(OTf)3-catalyzed vinylation (TfO = tri-
fluoromethanesulfonate) of b-keto esters with acetylenes.[10]
Decarboxylation of these substrates could lead to two
possible unsaturated ketones: one derived from alkylation
of the a position of the dienolate generated upon decarbox-
ylation (2), and the other generated from g alkylation of the
[*] S. R. Waetzig, D. K. Rayabarapu, J. D. Weaver, Prof. J. A. Tunge
Department of Chemistry
University of Kansas
1251 Wescoe Hall Drive, Lawrence, KS 66045-7582 (USA)
Fax : (+1)785-864-5396
E-mail: tunge@ku.edu
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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dienolate (3, Scheme 2).[11] It was gratifying to find that
treatment of 1a with 10 mol% [Pd(PPh3)4] in CH2Cl2 resulted
in the formation of a-allylated product 2a in 84% yield of
isolated product (Scheme 3).
capable of facilitating decarboxylative metalation. Addition-
ally, we were curious as to whether electron-withdrawing
groups could initially be integrated at the olefinic position of
the nucleophilic allyl fragment rather than at the position a to
the ester group. As nitrile groups are expected to stabilize the
incipient charge during decarboxylation and can be further
manipulated by reduction or hydrolysis, alkylidene malono-
nitriles 4 were chosen as promising substrates. Moreover, the
starting materials are easily prepared by a simple Knoevena-
gel condensation of malononitrile[12] with readily available
allylic b-keto esters.[13] To test the feasibility of the proposed
reaction, 4a was allowed to react with 5 mol% [Pd(PPh3)4] in
CH2Cl2 (Scheme 4). After 1.5 h at ambient temperature, the
Scheme 3. Decarboxylative dienolate allylation.
A variety of vinyl-substituted b-keto esters likewise
provided the a-alkylation product as the only isolated
product. As shown in Table 1, the reaction allows coupling
of a variety of substituted allyl fragments with an unsubsti-
tuted allyl group. In fact, the chemistry was only limited by the
variety of substrates that could be prepared by the vinylation
of b-keto esters.[10]
Scheme 4. Decarboxylative dicyanoallyl allylation.
As a consequence of the success of the catalytic decar-
boxylation of vinylic b-keto esters, our focus shifted to other
compounds that incorporate electron-withdrawing groups
reaction was complete and the product was isolated as a single
regioisomer in good yield. Importantly, the analogous control
reaction of 4a, which was run in the absence of catalyst at
1508C for 30 min, showed no degradation or product
formation. Thus, the reaction is palladium-catalyzed, and
the predominance of a alkylation indicates that the regiose-
lectivity is the result of kinetic control.
Table 1: Decarboxylative allyl–dienolate coupling.[a]
Substrate
Product
Yield [%]
65
We further examined the reactivity of other alkylidene
malononitriles in the presence of a catalytic amount of
[Pd(PPh3)4] and found that the reaction was tolerant of a
variety of electrophilic allyl fragments (Table 2). Primary,
substituted, cyclic, and acyclic allylic esters were all used, and
the substitution pattern had no substantial effect on yields or
reaction rates. Esters of disubstituted allylic alcohols exhibit
excellent regioselectivity in favor of a alkylation, while those
of terminally unsubstituted allylic alcohols give rise to
mixtures of a- and g-alkylated products.[14] These results
suggest that the a position is sterically less hindered and
g alkylation can be avoided if one employs a sufficiently large
allylic alcohol fragment. Additionally, as might be expected
for a reaction involving p-allyl palladium intermediates, ester
4i of a monosubstituted allylic alcohol undergoes highly
regioselective alkylation at the less substituted allyl terminus.
Thus, decarboxylative coupling results in regioselective
a coupling at the cyanoallyl fragment and coupling at the
electrophilic allyl fragment occurs at the less hindered site.
77
86
61
79
80
69
82
À
In addition to the regioselectivity of C C bond formation,
the utility of decarboxylative coupling lies in the ability to
kinetically and regiospecifically generate allyl anion equiv-
alents (Scheme 5). In contrast, generation of the equivalent
anions by metalation with a strong base would produce
mixtures of regioisomers (Scheme 5).[2a] By utilizing decar-
boxylative metalation, a variety of cyclic and acyclic dicya-
noallyl anion equivalents are generated regiospecifically at
the site that carries the carboxy group. One current limitation
of this chemistry is that substitution at the a position of the
[a] Yields of isolated products for reactions carried out using [Pd(PPh3)4]
(0.05 mmol) and allyl b-keto esters (0.50 mmol) in CH2Cl2 (3.0 mL) at
room temperature under N2 for 0.5–1 h.
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Table 2: Decarboxylative coupling of alkylidene malononitriles.[a]
The PdII-catalyzed Cope rear-
rangement occurs under mild con-
ditions with substrates such as 2i,
but the rearrangement is limited
to substrates that are substituted
at the 2- or 5-position as outlined
by Overman and Renaldo.[17] For
substrates that do not meet the
criteria necessary for PdII-cata-
lyzed rearrangement (that is, 2a),
the Cope rearrangement was
effected in excellent yield by heat-
ing at 1808C in a microwave
reactor.[18]
The a-alkylated isomers of
alkylidene malononitriles likewise
underwent thermal Cope rear-
rangement to give the g-alkylated
isomers in a microwave reactor at
1508C in essentially quantitative
yields (Scheme 6). Moreover, the
Cope rearrangements occurred
Substrate
a/g
Yield [%]
Substrate
a/g
Yield [%]
58[d]
78:22
80[d]
79:21
>97:3
97
84
62:38
86:14
76[d]
97[d]
93:7
>95:5[b]
>95:5[c]
84
92
84:16
91[d]
93
>95:5
[a] Yields of isolated products for reactions carried out using [Pd(PPh3)4] (0.05 mmol) and b-alkylidene
malononitrile (1.0 mmol) in CH2Cl2 (5 mL) at room temperature under N2 for 1–2 h. [b] E/Z=15:1.
[c] E/Z=8.3:1. [d] Combined yield of two isomers.
Scheme 6. Microwave-assisted Cope rearrangement.
with the expected stereochemical control to provide sub-
strates with contiguous stereocenters in good diastereoselec-
tivity.
Scheme 5. Regiospecific generation of allyl anion equivalents.
B=base.
In addition to more standard thermal and PdII-catalyzed
Cope rearrangements, Yamamoto and co-workers have
demonstrated that it is possible to catalyze a Cope-like
rearrangement of a-alkylation products resembling 5 by using
Pd0.[2a] As our decarboxylative coupling method allows the
synthesis of a wide variety of a-allylated products, we are able
to subject these substrates to modified conditions for Pd0-
catalyzed Cope rearrangements. For example, the a-allylation
product 5j underwent rearrangement to the g-allylation
product 6j upon treatment with [Pd(PPh3)4] in toluene at
708C (Scheme 7).
substrates is necessary to prevent decomposition of the
starting materials. However, Table 2 shows that compounds
that are a-substituted undergo coupling in good to excellent
yields. Furthermore, NOE measurements indicate that the
resulting olefinic products are preferentially formed as the
E isomers.
The a-selective decarboxylative allyl–allyl coupling is an
efficient route to 1,5-dienes, whereas the development of an
analogous g-selective transformation would provide a versa-
tile synthetic method for the synthesis of 1,5-hexadienes. In
this regard, it was expected that Cope rearrangements could
be used to access the thermodynamically favored g-allylation
products directly from the a-allylation products. The resulting
a,b-unsaturated nitriles and ketones are expected to be
versatile synthetic intermediates as a result of the electronic
differentiation of the two olefinic double bonds. With this in
mind, the optimal conditions for Cope rearrangement of the
a-alkylation products to produce g-alkylation products were
briefly investigated. Specifically, a number of the products
were treated to either thermal conditions in a microwave
reactor or conditions for PdII catalysis as described by
Overman and Renaldo,[15] to afford the a,b-unsaturated 1,5-
dienes.[16]
Scheme 7. Pd0-catalyzed tandem allylation/Cope rearrangement.
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Communications
silica gel pad. The filtrate was concentrated and the residue was
purified on a column of silica gel using hexane/dichloromethane
(85:15) as eluent to afford the decarboxylative coupling products 2.
General procedure for the palladium-catalyzed decarboxylation
of alkylidene malononitriles: In a dried Schlenk flask under argon,
[Pd(PPh3)4] (0.025 mmol) was added to substrates 4 (0.5 mmol)
dissolved in dichloromethane (5 mL). The reaction mixture was
stirred at room temperature for 1–2 h, then concentrated and directly
purified by flash chromatography (SiO2, 5% EtOAc/hexane).
The control reaction without [Pd(PPh3)4] resulted in
< 5% rearrangement under identical conditions. The fact
that the decarboxylative coupling and the Cope-like rear-
rangement are both Pd0-catalyzed suggested that a one-pot
tandem decarboxylative allylation/Cope rearrangement was
feasible. Indeed, reaction of the alkylidene malononitrile 4j
with [Pd(PPh3)4] in toluene at 708C provided the g-allylation
product 6j as the exclusive regioisomer (Scheme 7).
Finally, the ability to perform a tandem decarboxylative
coupling/Cope rearrangement suggested that an asymmetric
rearrangement might be possible through appropriate choice
of a chiral ligand. To test the feasibility of this approach, the
rearrangement of rac-4e was performed using Pd0 modified
with the Trost ligand, which led to product formation in good
yield with high diastereoselectivity and modest enantioselec-
tivity (Scheme 8). While the enantioselectivity is not optimal,
Received: February 23, 2006
Revised: April 9, 2006
Published online: July 3, 2006
Keywords: allylation · decarboxylation · hexadienes · palladium ·
.
rearrangement
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[10] a) M. Nakamura, K. Endo, E. Nakamura, J. Am. Chem. Soc.
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Scheme 8. Asymmetric tandem allylation/Cope rearrangement. dba=
trans,trans-dibenzylideneacetone.
this reaction represents the first asymmetric rearrangement of
this type. Moreover, the ability to set contiguous stereocen-
ters by Pd0-catalyzed allylation is rare, and thus tandem
allylation/Cope rearrangements will potentially allow exten-
sion of allylation strategies to new substrates. Current efforts
are directed toward maximizing the enantioselectivity of the
allyl–allyl coupling while maintaining high diastereoselectiv-
ities.
In summary, we have shown that Pd0-catalyzed decarbox-
ylation is a simple and convenient way to trigger the
formation of nucleophilic allyl species in the presence of
electrophilic p-allyl palladium complexes. The resulting sp3–
sp3 coupling reaction favors kinetic allylation at a position a
to electron-withdrawing groups, and the analogous g-allyla-
tion products can be obtained by conversion to the thermo-
dynamic product under conditions of microwave irradiation
or PdII catalysis. With sufficiently stabilized allyl nucleophiles,
the Cope rearrangement can be catalyzed by Pd0, which leads
to the development of a tandem allylation/Cope rearrange-
ment. Thus, either a- or g-coupling products are available in
high yield from methylene malononitrile nucleophiles, and
the desired regioisomer is obtained simply by controlling the
temperature of the reaction mixture.
[13] a) I. Collado, C. Pedregal, A. Mazon, J. F. Espinosa, J. Blanco-
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Experimental Section
[14] The isomers were readily separated by column chromatography.
[15] L. E. Overman, A. F. Renaldo, Tetrahedron Lett. 1982, 23, 3757.
[16] See the Supporting Information for details of the Cope
rearrangements.
[17] L. E. Overman, A. F. Renaldo, J. Am. Chem. Soc. 1990, 112,
3945.
General procedure for the palladium-catalyzed decarboxylation of
vinylic b-keto esters:
A round-bottom side-arm flask (25 mL)
containing [Pd(PPh3)4] (0.050 mmol, 10.0 mol%) was evacuated and
purged with argon gas. An allylic b-keto ester (0.50 mmol) and
dichloromethane were added to the system and the reaction mixture
was stirred at room temperature for 0.5–1.5 h. Next, the mixture was
diluted with dichloromethane and filtered through a short Celite and
[18] C. O. Kappe, Angew. Chem. 2004, 116, 6408; Angew. Chem. Int.
Ed. 2004, 43, 6250.
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