Pd-catalyzed sequential C-C bond formation and cleavage: Evidence for an unexpected generation of arylpalladium(II) species

Article abstract of DOI:10.1021/ja304616q

A Pd(II)-catalyzed reaction engaging alkenyl β-keto esters is reported that leads to the formation of 1-naphthols and an unexpected generation of arylpalladium(II) species. Interception of the in situ generated arylpalladium(II) species in a Mizoroki-Heck reaction, together with additional mechanistic studies, provided strong evidence in support of the first aromatization-driven β-carbon elimination process. A single Pd catalyst served to promote a series of both C-C bond forming and cleavage events in an unprecedented manner.

Full text of DOI:10.1021/ja304616q

Communication
pubs.acs.org/JACS
Pd-Catalyzed Sequential C−C Bond Formation and Cleavage:
Evidence for an Unexpected Generation of Arylpalladium(II) Species
So Won Youn,* Byung Seok Kim, and Arun R. Jagdale
Department of Chemistry and Research Institute for Natural Sciences, Hanyang University, Seoul 133-791, Korea
S
* Supporting Information
Scheme 1. Transition-Metal-Mediated Cyclization of 2-
Alkenylphenyl Carbonyl Compounds
ABSTRACT: A Pd(II)-catalyzed reaction engaging alken-
yl β-keto esters is reported that leads to the formation of 1-
naphthols and an unexpected generation of arylpalladium-
(II) species. Interception of the in situ generated
arylpalladium(II) species in a Mizoroki−Heck reaction,
together with additional mechanistic studies, provided
strong evidence in support of the first aromatization-driven
β-carbon elimination process. A single Pd catalyst served
to promote a series of both C−C bond forming and
cleavage events in an unprecedented manner.
ransition-metal-catalyzed transformations involving the
T
cleavage of chemically inert C−H1 and C−C2,3 bonds
have received widespread recent attention from the synthetic
community. The latter transformations, generally more
challenging, have been achieved primarily through oxidative
insertion of a transition metal into the C−C bond or β-carbon
elimination3 of a carbon−metal (i.e., M-C-C-C) or heter-
oatom−metal species (e.g., M-O-C-C). β-Hydride elimination
is often a preferred competing pathway over β-carbon
elimination, where the driving force to facilitate the latter
process usually invokes the release of ring strain or the
formation of a relatively more stable intermediate (such as a π-
allylmetal intermediate). As such, programmed β-carbon
elimination and its potential in organic synthesis remain a
challenging area yet to be explored.
of either one of these reagents.8 The use of base or ligand as
additives did not improve the production of 2a, and the
addition of BHT or ascorbic acid had no deleterious effect on
the reaction, which excludes the presence of propagating radical
species. Ultimately, the use of 5 mol % Pd(O2CCF3)2 and 2
equiv of Cu(OAc)2 in ClCH2CH2Cl (or dioxane) at 100 °C
was identified as the optimal reaction protocol, and the reaction
could be performed without strict exclusion of moisture and air.
The established reaction parameters proved generally effective
for a wide variety of substrates, as shown in Table 1. Substrates
bearing substituted phenyl rings at R5 were well-tolerated, with
little electronic dependence, whereas R5 = alkyl afforded only
trace amount of the 1-naphthol product (entries 1−10). β-Keto
esters bearing alkoxy substituents (entries 12−15) and 1,3-
diketones (entries 16 and 17) were all competent substrates,
apart from diaryl 1,3-diketone 1ha. Allylic substrates 1lb and
1ma also cyclized smoothly to afford 1-naphthols 2l and 2m,
respectively (entries 24 and 25), but trisubstituted stilbene 1la
was unsuccessful in this reaction (entry 23).
As part of our continued interest in transition-metal-
mediated C−C bond-forming processes, we recently disclosed
a Au(I)-catalyzed cyclization of 2-alkenylphenyl carbonyl
compounds to afford a variety of indenes, indenols, indanones,
and naphthalenes (Scheme 1a).4 Early on, we systematically
examined various transition metals, and much to our surprise,
an unexpected formation of 1-naphthol 2a was observed when
2-alkenylphenyl β-keto ester 1aa was exposed to a catalytic
amount of Pd(II) under oxidative conditions (Scheme 1b).5−7
Indeed, on cursory inspection of the skeletal framework of the
substrate (1aa) and the observed 1-naphthol product (2a), we
realized the pendent phenyl group of the stilbene starting
material had been cleaved during this process. Recognizing the
novelty of this process in generating 1-naphthol derivatives, and
more intriguingly, the origin of the unexpected C−C bond
scission, here we report the findings of our methodological and
mechanistic investigations.
Having established a workable condition for the conversion
of 2-alkenylphenyl β-keto esters (and 1,3-diketones) to the 1-
naphthol products, we next pursued in earnest the investigation
of the unexpected C−C bond cleavage. As an entry point to
this study, and because the conversion from 1 to 2 was
generally modest, we set out to account for the mass balance
1
through a series of detailed H NMR and GC-MS analyses,
together with the isolation of side products. We identified
We began using 1aa as the test substrate and soon identified
Pd(O2CCF3)2−Cu(OAc)2 as the most effective Pd(II)−
oxidant combination; no reaction was observed in the absence
Received: February 17, 2012
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
compounds 1aa′, 3aa, 3aa′, and 4aa as the principal byproducts
in the reaction of 1aa (Figure 1). 1aa′ and 3aa′ (and 4aa, vide
infra) were of particular interest due to the incorporation of an
additional phenyl group (similar results were obtained for
reactions with 1ae, 1af, and 1ag8).
Table 1. Pd-Catalyzed Synthesis of Various 1-Naphthols 2
from Alkenyl 1,3-Dicarbonyl Compounds 1
a
Figure 1. Major side products observed in the reaction of 1aa.
While a clear mechanistic picture was elusive at this juncture,
we hypothesized the incorporation of an additional phenyl
group could invoke the participation of an Ar−M species
generated in the reaction mixture. We further questioned if this
Ar−M species could be intercepted with the introduction of a
suitable electrophile. To our delight, when methyl acrylate was
introduced to our standard reaction conditions using 1aa as the
substrate, cinnamate 5aa was obtained in 58% yield, alongside
the previously described 2aa (63%, Table 2, entry 1).
Depending on the 2-alkenylphenyl β-keto ester substrate,
different substituted methyl cinnamates could be obtained in
respectable yields (entries 1−12). Methyl acrylate could also be
replaced with a diverse array of activated olefins (entries 13−
21) and styrenes (entries 22−27).
With the successful identification of cinnamate and stilbene
derivatives 5, the involvement of an Ar−M species seems highly
plausible. The presence of an Ar−M species (M = Pd) was
deemed most likely, since its participation in the Mizoroki−
Heck-type cross-coupling9 with various activated and non-
activated olefins is well-precedented. A plausible mechanistic
proposal is presented in Scheme 2. We speculate that the O,O′-
bound complex A, formed initially upon treatment of 1 with
Pd(II), first undergoes rearrangement to afford the alkene-
coordinated C-bound tautomer B,10 which then engages in a
syn carbopalladation across the stilbene olefin to generate
transient intermediate C with concomitant C−C bond
formation (B→C). At this point, intermediate C, with syn-
orientated Pd and Ar substituents, is poised to undergo β-
carbon elimination, leading to the generation of arylpalladium
species D. We also speculate that, further to the prerequisite syn
stereochemical arrangement of the Pd and Ar substituents in C,
the formation of 1-naphthol (2) through aromatization provides
an additional and essential driving force to facilitate the β-carbon
elimination.11 Carbopalladation of the external olefin with the
newly generated arylpalladium species D in a Mizoroki−Heck
manner affords the cross-coupling product 5, where the so-
liberated Pd(0) is reoxidized to Pd(II) with the aid of
Cu(OAc)2.
Several additional experiments and analysis provided further
support for this mechanistic proposal. First, with the speculated
arylpalladium species D in mind, several attempts to intercept
and subsequently isolate the arylpalladium complex by the
addition of amino or phosphino ligands proved unrewarding.
Reaction of (Z)-1aa under the same reaction conditions failed
to deliver any product 2a. Although 2a′ could be speculated as
the possible product resulting from the alternative β-hydride
elimination pathway, we believe there is a significant energy
barrier that prevents the cis-stilbene olefin from being in close
enough proximity for the reaction to take place (B′, Scheme
a
Reaction conditions: 1 (1 equiv), Pd(O2CCF3)2 (5 mol %), and
b
Cu(OAc)2 (2 equiv) in ClCH2CH2Cl or dioxane at 100 °C. Isolated
yields. In ClCH2CH2Cl (0.025 M). In dioxane (0.1 M).
c
d
B
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Journal of the American Chemical Society
Communication
Table 2. Pd-Catalyzed Reactions of Aryl-Substituted Alkenyl
β-Keto Esters 1 with Olefins
Scheme 2. Proposed Mechanism
a
Scheme 3. Reactions of (Z)-1aa and 1aa in the Presence of
CuCl2
As alluded to earlier, reaction of 1aa afforded 1aa′ and 3aa′ as
the primary side products in addition to 1-naphthol 2a.
Mechanistically, the formation of 1aa′ and 3aa′ can now be
easily rationalized through a Mizoroki−Heck reaction engaging
arylpalladium species D and 1aa and subsequent decarbox-
ylation (or through decarboxylated 3aa and its Mizoroki−Heck
reaction with D), respectively (Scheme 4a). Crossover
experiments between 1aa and 1ae afforded the byproduct
mixture containing all the possible combinations, which further
supports the generation of Ar−Pd (D, and Ar′−Pd) during the
reaction (Scheme 4b). Pd-mediated oxidative cleavage of
substituted stilbene (i.e., 1aa′ or 3aa′) has also been reported,12
and has been validated by us experimentally (4aa, Scheme 4a).
Finally, in the competition experiments between alkenyl β-
keto esters with varying substituents on the departing aryl ring
(1aa, 1ac, 1af, 1ag), electron-rich substrates generally
proceeded significantly faster than their electron-deficient
Scheme 4. Formation of Side Products and Crossover
Experiments
a
Reaction conditions: 1 (1 equiv), olefin (2 equiv), Pd(O2CCF3)2 (5
mol %), and Cu(OAc)2 (2 equiv) in ClCH2CH2Cl (0.05 M) at 100
°C. Isolated yields. 3 equiv of olefin. 1.5 equiv of olefin. 10 mol %
Pd(O2CCF3)2. 5 equiv of olefin. Internal olefin and the
corresponding exo olefin isomer were obtained in 28% and 17%
yields, respectively. The inseparable mixture of internal olefin and the
b
c
d
e
f
g
h
corresponding exo olefin isomer was obtained in 48% yield and a ratio
i
1
of 42:58, determined by H NMR. 2a and 5cc were not separable;
therefore, each yield was calculated from both the weight of the
purified mixture of 2a and 5cc and their ratio, determined by 1H
NMR.
3a). The same steric argument could also account for the failure
of substrate 1la in this reaction. Interestingly, reaction of 1aa in
the presence of CuCl2 instead of Cu(OAc)2 gave a 3-phenyl-
substituted 1-naphthol (2a′) as a sole product, which suggests a
contrasting outer-sphere anti carbopalladation pathway through
the in situ generated PdCl2 (Scheme 3b).5c,6a,b
C
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Journal of the American Chemical Society
Communication
counterparts (Table 3). This electronic dependence is in
agreement with the migratory aptitude of the aryl group during
Seoul National University) for helpful discussions and valuable
suggestions as well as editorial assistance.
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In summary, we have developed a novel and concurrent
preparation of 1-naphthols and cinnamate/stilbene derivatives
through a Pd(II)-catalyzed reaction of 2-alkenylphenyl β-keto
esters and 1,3-diketones with olefins. More significantly, we
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operates through a unique mode of C−C bond activation. A
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bond cleavage via a novel aromatization-driven syn β-carbon
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catalyzed (cascade) transformations. Further investigations to
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are currently underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
(8) For details, see the Supporting Information.
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(b) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
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Full experimental details and characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
sowony73@hanyang.ac.kr
■
Notes
(11) Related examples of aromatization-driven C−C bond cleavage:
(a) Crabtree, R. H.; Dion, R. P.; Gibboni, D. J.; McGrath, D. V.; Holt,
E. M. J. Am. Chem. Soc. 1986, 108, 7222. (b) Halcrow, M. A.; Urbanos,
F.; Chaudret, B. Organometallics 1993, 12, 955.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science and Technology
(Nos. 2011-0003705 and 2012-0002223). We sincerely thank
Professor David Yu-Kai Chen (Department of Chemistry,
(12) Wang, A.; Jiang, H. J. Org. Chem. 2010, 75, 2321.
D
dx.doi.org/10.1021/ja304616q | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX