Palladium-catalyzed alkylation of 1,4-dienes by Ci-H activation

Article abstract of DOI:10.1002/anie.201200601

Activated: The title reaction proceeds with a broad range of nucleophiles and variously substituted 1,4-dienes under mild conditions, and provides direct access to the corresponding 1,3-diene-containing products with high regio- and stereocontrol (see scheme; 2,6-DMBQ=2,6-dimethylbenzoquinone, EWG=electron-withdrawing group). This is the first catalytic allylic Ci-H alkylation that proceeds in the absence of sulfoxide ligands. Copyright

Full text of DOI:10.1002/anie.201200601

Angewandte
Chemie
DOI: 10.1002/anie.201200601
À
C H Activation
À
Palladium-Catalyzed Alkylation of 1,4-Dienes by C H Activation**
Barry M. Trost,* Max M. Hansmann, and David A. Thaisrivongs
À
Transition-metal-catalyzed direct functionalization of C H
bonds is an area of widespread and active research, because of
the potential to dramatically affect the ways in which
molecules are synthesized.[1] Because of such new chemical
methods the need to prepare substrates that bear functional
groups with which transition-metal catalysts engage can be
avoided, thus increasing the efficiency of a synthetic sequence
by rendering prefunctionalization steps unnecessary.[2] Syn-
À
thesis plans that rely upon direct C H bond functionalization
may also benefit significantly in terms of chemoselectivity,
À
because C H bonds can often be carried through a series of
reactions until they are converted into the functional group of
Scheme 1. a) DMSO-promoted allylation of sodium diethyl malonate
with [(h3-C3H5)PdCl]2. b) PPh3-promoted allylation of sodium methyl
2-(methylsulfonyl)acetate with a p-allylpalladium complex. DMSO=
dimethyl sulfoxide.
À
interest. Despite the relative inertness of C H bonds and the
challenges associated with the development of catalysts that
can discriminate between many C H bonds in a given
substrate, this strategy for molecular construction has made
and will continue to make important contributions to the
design and execution of chemical synthesis.[3]
Given the myriad ways in which palladium-catalyzed
allylic substitutions have enabled the synthesis of a broad
range of complex molecules,[4] our and other research groups
have been motivated to evaluate whether the value of this
methodology could be further enhanced by performing these
reactions by allylic C-H activation rather than allylic leaving
group ionization, because the latter approach requires
prefunctionalization of the electrophile.[5] Stoichiometric
À
that phosphorus-based ligands proved advantageous for
promoting the attack by stabilized nucleophiles on such
complexes (Scheme 1b),[10] a discovery that has provided the
basis for chemo-, regio-, and stereocontrol in palladium-
catalyzed allylic alkylation chemistry ever since. Although
these ligands have been reported to be unsuitable under the
[11]
À
oxidative conditions necessary for C H activation,
we
hypothesized that if phosphorus-based ligands could promote
À
palladium-catalyzed allylic C H alkylations, there would be
À
palladium-mediated allylic alkylations that proceed by C H
a similarly great opportunity to expand both the scope and
selectivity of this process.
activation are well known,[6] and the first disclosure of
a nucleophilic addition to a stoichiometrically prepared
p-allylpalladium complex was made in 1965 by Tsuji and co-
workers, who demonstrated that sodium diethyl malonate (2)
could be allylated with [(h3-C3H5)PdCl]2 (1) in the presence of
DMSO (Scheme 1a).[7] Despite nearly half a century of
advances in organometallic chemistry, only recently[8] have
there been reports of methods that reduce this two-step
procedure to a single, palladium-catalyzed process, and all
have similarly employed sulfoxides as ligands.[9]
We began our investigation by studying the ability of
palladium to catalyze the alkylation of tert-butyl 2-cyano-2-
phenylacetate (8) with 1,4-pentadiene (9). We were motivated
to evaluate 1,4-pentadiene in particular as an electrophile for
such a transformation, because palladium activation of a bis-
À
allylic C H bond might prove more facile than the analogous
À
activation of a mono-allylic C H bond, and because uncon-
jugated 1,4-dienes are a class of substrates that have never
been reported to undergo any transition-metal-catalyzed
À
In our early work, we found that such conditions failed
with more substituted allylic substrates. In the course of
studying the alkylation of p-allylpalladium species, we found
C H alkylation. Furthermore, such a transformation would
generate the corresponding 1,3-diene, a functional group with
diverse applications in synthetic chemistry.[12] We were
delighted to discover that in the presence of 1.1 equivalents
Et3N, 1.0 equivalent 2,6-dimethylbenzoquinone (2,6-DMBQ),
5.0 mol% Pd(OAc)2, and 10 mol% PPh3, the desired allylic
[*] Prof. B. M. Trost, M. M. Hansmann, D. A. Thaisrivongs
Department of Chemistry, Stanford University
Stanford CA 94305-5080 (USA)
À
C H alkylation product (10) can be isolated in 73% yield as
E-mail: bmtrost@stanford.edu
Homepage: http://www.stanford.edu/group/bmtrost
a single regio- and stereoisomer (Scheme 2). Control experi-
ments establish that 2,6-DMBQ, Pd(OAc)2, and PPh3 are each
essential to the success of the reaction.[13]
[**] We thank the NSF (CHE 0948222) for their generous support of our
programs. M.M.H. acknowledges support from the Studienstiftung
des deutschen Volkes and the DAAD–PROMOS scholarship; D.A.T.
acknowledges support from a Stanford Graduate Fellowship (The
William K. Bowes, Jr. Foundation).
These reaction conditions can be used for a broad range of
nucleophiles (Scheme 3). Many substituted a-cyano-tert-butyl
esters undergo allylic C H alkylation with 1,4-pentadiene (9),
including those that bear a-phenyl, a-methyl, a-ethyl, a-iso-
propyl, a-benzyl, and a-n-hexyl substituents (10–15). Many
À
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200601.
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a-nitro ketones (20) and a-nitro sulfones (21) also provide the
desired allylated products, as do b-keto esters (22).
Nitro-substituted substrates are sufficiently acidic that
they do not require a second a-electron-withdrawing group to
activate them for nucleophilic attack. For example, (1-nitro-
À
ethyl)benzene gives the desired C H alkylation product (23)
in 86% yield with complete stereoselectivity. Primary alkyl
nitro nucleophiles, such as nitroethane, 1-nitropropane, and
À
Scheme 2. Palladium-catalyzed allylic C H alkylation of cyano ester 8
with 1,4-pentadiene. 2,6-DMBQ=2,6-dimethylbenzoquinone.
À
(nitromethyl)benzene, also undergo C H alkylation (24–26).
This catalyst system shows reactivity that is orthogonal to
cross-coupling chemistry. For example, tert-butyl 2-(4-bromo-
phenyl)-3-oxobutanoate can be allylated (27) without the
significant production of side products that result from
À
oxidative addition into the C(aryl) Br bond by the palla-
dium(0) species, which is presumably generated in the
reaction. The method is not limited to acyclic nucleophiles
either; cyclic substrates, such as 2-nitrocyclohexanone and
3-nitrotetrahydro-2H-pyran-2-one, react to give the desired
products (28 and 29).
À
Notably, allylic C H alkylation proceeds smoothly with
(E)-tert-butyl 2-cyano-6-hydroxyhex-4-enoate (30) to give 31
(Scheme 4), thus demonstrating that an unprotected reactive
functionality, such as a primary alcohol, is well tolerated by
À
the catalyst, and that allylic C H activation is chemoselec-
À
tively effected only at 1,4-dienes. The mono-allylic C H
bonds, even those on a carbon atom that also bears
a heteroatom, are inert to these reaction conditions.
À
Scheme 4. Palladium-catalyzed allylic C H alkylation of tert-butyl
2-cyano-6-hydroxyhex-4-enoate with 1,4-pentadiene.
À
This palladium-catalyzed allylic C H alkylation is also
general for many differently substituted 1,4-dienes
(Scheme 5). When tert-butyl 2-nitropropanoate (32) is treated
with trans-1,4-hexadiene under the optimized conditions,
alkylated product 33, which results from nucleophilic attack
at the less sterically-hindered terminus of the electrophile, can
be isolated in 66% yield as a single stereoisomer. Signifi-
cantly, if a mixture of cis- and trans-1,4-hexadiene is employed
instead, 33 can still be obtained in 62% yield as a single
stereoisomer, evidence that the catalyst is able to isomerize
the alkene geometry of the electrophile to the thermodynami-
cally favored E,E configuration observed in the product.
Replacing the methyl substituent of 1,4-hexadiene with either
a phenyl or benzyldimethylsilyl group gives the corresponding
products (34 and 35) as sole regioisomers and with predom-
inantly E,E configurations.
À
Scheme 3. Palladium-catalyzed allylic C H alkylations of nucleophiles
with 1,4-pentadiene. Reactions were performed on a 0.2 mmol scale in
THF (0.2m) for 24 h at RT with nucleophile (1.0 equiv), 1,4-pentadiene
(1.1 equiv), Et3N (1.1 equiv), 2,6-DMBQ (1.0 equiv), Pd(OAc)2
(5.0 mol%), and PPh3 (10 mol%). All yields are of isolated products;
E:Z ratios were obtained by 1H NMR spectroscopy. [a] Reaction per-
formed on a 0.1 mmol scale. [b] Isolated as mixture with (E)-6-nitro-
hepta-1,3-diene; see the Supporting Information for details.
À
It is not necessary for the bis-allylic C H bond that
À
À
corresponding a-nitro esters also undergo allylic C H
alkylation (16–18), even when they are otherwise unsubsti-
tuted, as in the case of ethyl 2-nitroacetate (19). Similarly,
undergoes activation to be a methylene C H bond; reaction
of 32 with 3-methylpenta-1,4-diene, an electrophile for which
a methine C H bond must be activated, gives alkylation
À
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a crucial role as a ligand for the metal in addition to
regenerating the palladium(II) species that is responsible for
À
C H activation. In the presence of manganese(II) oxide,
a reagent known to oxidize hydroquinones to the correspond-
ing quinones,[15] the quantity of 2,6-DMBQ employed can be
dramatically reduced. As an example, when the amount of
2,6-DMBQ is reduced from 1.0 equivalent to only 10 mol% in
the reaction of (1-nitroethyl)benzene (41) with 1,4-penta-
diene (9), the addition of 1.4 equivalents of manganese(II)
oxide is sufficient for the desired product 23 to be obtained in
68% yield (Scheme 7a). Similarly, when tert-butyl 2-cyano-3-
À
methylbutanoate (42) is reacted with 1,4-pentadiene (9), C H
alkylation product 13 is isolated in 90% yield (Scheme 7b).
À
Scheme 5. Palladium-catalyzed allylic C H alkylation of tert-butyl
2-nitropropanoate with 1,4-dienes. Reactions were performed on
a 0.2 mmol scale in THF (0.2m) for 24 h at RT with tert-butyl
2-nitropropanoate (1.0 equiv), 1,4-diene (1.1 equiv), Et3N (1.1 equiv),
2,6-DMBQ (1.0 equiv), Pd(OAc)2 (5.0 mol%), and PPh3 (10 mol%). All
1
yields are of isolated products; E:Z ratios were obtained by H NMR
spectroscopy. [a] Alkene geometry was determined by NOE measure-
ments; see the Supporting Information for details. [b] Reaction per-
formed at 358C. [c] Reaction performed on a 0.1 mmol scale at 508C.
À
Scheme 7. Palladium-catalyzed allylic C H alkylations with MnO2 as
the terminal oxidant.
product 36. The reaction with the corresponding 3-benzyl-
oxypenta-1,4-diene provides 37, and thus constitutes the
stereoselective formation of a benzyl enol ether. Finally,
reaction with 2-methylpenta-1,4-diene gives predominantly
38, the product of nucleophilic attack on the less sterically
hindered terminus of the diene.
À
We propose that this allylic C H alkylation proceeds
through a catalytic cycle that is mechanistically distinct from
that of a traditional palladium-catalyzed allylic alkylation
(Scheme 8). Rather than beginning with a palladium(0)-
mediated ionization of an allylic leaving group, this process
À
The addition of a base, such as Et3N, is not always
starts with a palladium(II)-mediated allylic C H activation to
À
required, thus indicating that it is not necessary in the C H
generate an electrophilic p-allylpalladium intermediate.
Nucleophilic attack reduces the catalyst and decomplexation
of the alkene releases the allylic alkylation product. Finally,
activation event. For example, when tert-butyl 2-cyano-3-
phenylpropanoate (40), a nucleophile that readily undergoes
keto/enol tautomerization, is reacted with 1,4-pentadiene (9)
in the absence of Et3N,[14] the desired product 14 is obtained in
86% yield (Scheme 6). Remarkably, this yield is significantly
higher than the yield of 14 obtained in the presence of Et3N
(Scheme 3), thus indicating that for certain activated sub-
strates it may be beneficial to conduct the reaction under
base-free conditions.
À
The palladium-catalyzed allylic C H alkylation of 1,4-
pentadiene can be performed with less than one equivalent of
2,6-DMBQ. No desired reaction is observed in the absence of
a quinone, an observation that suggests that the quinone plays
À
Scheme 6. Palladium-catalyzed allylic C H alkylation under neutral
conditions.
Scheme 8. Mechanistic comparison of palladium-catalyzed traditional
À
allylic alkylation and oxidative allylic C H alkylation.
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[5] Palladium-catalyzed asymmetric allylic alkylation reactions with
allene electrophiles proceed by allene hydropalladation rather
than ionization of an allylic leaving group. For examples, see:
a) B. M. Trost, C. Jꢀkel, B. Plietker, J. Am. Chem. Soc. 2003, 125,
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oxidation by 2,6-DMBQ regenerates the palladium(II) spe-
cies necessary for the next catalytic turnover.
By demonstrating that PPh3 promotes palladium-cata-
À
lyzed allylic C H alkylations, this study contains the first
examples of such catalytic transformations that proceed in the
absence of a sulfoxide ligand, an advance that augurs well for
À
further developments in allylic C H alkylation chemistry,
given the chemo-, regio-, and stereocontrol in traditional
palladium-catalyzed allylic substitution processes that have
been enabled by the discovery and development of phospho-
rus-based ligands. We have also demonstrated that a broad
range of nucleophiles undergo reaction with variously sub-
stituted 1,4-dienes under mild conditions, providing direct
access to the corresponding 1,3-diene-containing alkylation
products with high regio- and stereocontrol. Investigations
À
into other palladium-catalyzed allylic C H alkylation reac-
tions with phosphorus-based ligands are ongoing.
Experimental Section
À
General procedure for the palladium-catalyzed allylic C H alkylation
of 1,4-dienes: An oven-dried reaction vial equipped with an oven-
dried stirrer bar was charged with 2,6-DMBQ (27.2 mg, 0.200 mmol),
Pd(OAc)2 (2.20 mg, 0.010 mmol), and PPh3 (5.20 mg, 0.020 mmol).
The vial was sealed with a septum, and then evacuated and filled with
Ar three times. THF (0.6 mL) was added and the mixture was stirred
for ca. 1 min until a yellow solution was obtained. 1,4-pentadiene
(23.0 mL, 0.220 mmol) was then added by syringe, followed by tert-
butyl 2-cyano-2-phenylacetate (43.5 mg, 0.200 mmol), Et3N (30.5 mL,
0.220 mmol), and THF (0.4 mL). The reaction was stirred for 24 h at
room temperature, over which time the solution changed color from
yellow to red. After concentration under reduced pressure, the crude
material was purified by column chromatography on silica gel
(hexanes:EtOAc = 95:5) to give the (E)-tert-butyl 2-cyano-2-phenyl-
hepta-4,6-dienoate (41.4 mg, 73% yield, > 19:1 E:Z) as a colorless oil.
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4387 – 4388.
À
[8] For a singular example of a palladium(0)-catalyzed allylic C H
alkylation of propene and 1-butene under reducing conditions,
see: L. S. Hegedus, T. Hayashi, W. H. Darlington, J. Am. Chem.
Soc. 1987, 109, 7747 – 7748.
[9] a) S. Lin, C.-X. Song, G.-X. Cai, W.-H. Wang, Z.-J. Shi, J. Am.
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Dietsche, J. Am. Chem. Soc. 1978, 100, 3416 – 3426.
À
General procedure for the palladium-catalyzed allylic C H
alkylation of 1,4-dienes with MnO2 as the terminal oxidant: As per
À
the general procedure for the palladium-catalyzed allylic C H
alkylation of 1,4-dienes, except for the initial addition of MnO2
(24.3 mg, 0.280 mmol) and the reduced amount of 2,6-DMBQ
(3.00 mg, 0.020 mmol) that was used.
[11] D. J. Covell, M. C. White, Angew. Chem. 2008, 120, 6548 – 6551;
Angew. Chem. Int. Ed. 2008, 47, 6448 – 6451.
[12] The Chemistry of Dienes and Polyenes, Vol. 2 (Ed.: Z. Z.
Rappoport), Wiley, Chichester, UK, 2000.
Received: January 21, 2012
[13] In the absence of PPh3, palladium black is rapidly formed.
[14] The palladium phenoxide generated in the oxidation of palla-
dium(0) to palladium(II) by 2,6-DMBQ likely serves as a neces-
sary base in the absence of Et3N. See: B. V. Popp, J. L. Thorman,
S. S. Stahl, J. Mol. Catal. A 2006, 251, 2 – 7.
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4619 – 4631.
Published online: && &&, &&&&
À
Keywords: 1,3-dienes · 1,4-dienes · allylic alkylation · C
.
H activation · palladium
À
[1] For recent reviews of transition-metal-catalyzed direct C H
bond functionalization, see: a) L.-C. Campeau, K. Fagnou,
Chem. Commun. 2006, 1253 – 1264; b) O. Daugulis, V. G. Zait-
sev, D. Shabashov, Q.-N. Pham, A. Lazareva, Synlett 2006, 3382 –
3388; c) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007,
4
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Chemie
Communications
À
C H Activation
B. M. Trost,* M. M. Hansmann,
D. A. Thaisrivongs
&&&& — &&&&
Palladium-Catalyzed Alkylation of 1,4-
À
Dienes by C H Activation
Activated: The title reaction proceeds
with a broad range of nucleophiles and
variously substituted 1,4-dienes under
mild conditions, and provides direct
access to the corresponding 1,3-diene-
containing products with high regio- and
stereocontrol (see scheme; 2,6-DMBQ=
2,6-dimethylbenzoquinone, EWG=elec-
tron-withdrawing group). This is the first
À
catalytic allylic C H alkylation that pro-
ceeds in the absence of sulfoxide ligands.
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
These are not the final page numbers!