Trapping σ-Alkyl–Palladium(II) Intermediates with Arynes Encompassing Intramolecular C?H Activation: Spirobiaryls through Pd-Catalyzed Cascade Reactions

Article abstract of DOI:10.1002/anie.201607976

A palladium-catalyzed cascade reaction based on the trapping of transient alkyl–Pd^IIintermediates with arynes encompassing a C?H activation step has been developed. This synthetic pathway gives rise to hetero-spirocyclic scaffolds containing a biaryl motif, and opens up new synthetic strategies in the design of cascade reactions since it gathers several aspects of Pd chemistry, i.e., intra- and intermolecular carbopalladation of unsaturated species, C?H activation and C?C coupling processes.

Full text of DOI:10.1002/anie.201607976

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201607976
German Edition: DOI: 10.1002/ange.201607976
Synthetic Methods
Trapping s-Alkyl–Palladium(II) Intermediates with Arynes
À
Encompassing Intramolecular C H Activation: Spirobiaryls through
Pd-Catalyzed Cascade Reactions
Marta Pꢀrez-Gꢁmez and Josꢀ-Antonio Garcꢂa-Lꢁpez*
Abstract: A palladium-catalyzed cascade reaction based on
the trapping of transient alkyl–PdII intermediates with arynes
À
encompassing a C H activation step has been developed. This
synthetic pathway gives rise to hetero-spirocyclic scaffolds
containing a biaryl motif, and opens up new synthetic strategies
in the design of cascade reactions since it gathers several
aspects of Pd chemistry, i.e., intra- and intermolecular
À
carbopalladation of unsaturated species, C H activation and
À
C C coupling processes.
T
he use of aryl halides or pseudohalides bearing a tethered
alkene in the Heck–Mizoroki reaction[1] has proven partic-
ularly well suited for the synthesis of five- and six-membered
carbo- and heterocyclic scaffolds such as indole, benzofuran
and oxoindole derivatives, among others.[2] Furthermore, the
design of substrates where b-hydride elimination (upon the
initial carbopalladation step) is blocked has promoted the
development of both intra- and intermolecular palladium-
catalyzed cascade reactions, a topic of extraordinary interest
since these reactions allow the construction of complex
molecular structures from simple substrates in a straightfor-
À
ward and efficient manner, especially when they involve C H
Scheme 1. Cascade routes involving intramolecular Heck arylation.
activation processes in some of their steps.[3]
Pioneering work from Grigg in the trapping of transient s-
alkyl PdII intermediates arising from intramolecular Heck
reactions opened up a wide range of organic transformations
according to the terminating step of the cascade.[4] For
instance, the intermediate complex A (Scheme 1) can be
trapped with different nucleophilic coupling partners such as
hydride,[4,5] boron derivatives,[6] organotin reagents,[7] hydra-
zones,[8] or cyanides among others[9,10] (path a, Scheme 1).
The presence of unsaturated molecules like CO,[11]
allenes,[12] and also recently isocyanides[13] in the reaction
mixture can serve to extend the cascade process by their
À
spirocyclic compounds when the C H activation event is
performed intramolecularly.
The reactivity of type
B intermediates (Scheme 1)
remains underexplored. Shi et al. reported recently the
intramolecular carbopalladation of alkenes followed by
À
C H activation/amination sequence using a diaziridinone
reagent to access indoline derivatives.[19] To our knowledge,
the behavior of type B intermediates toward unsaturated
species has not yet been studied.
Inspired by the findings discussed above, and in con-
À
À
insertion into the Pd C bond present in the intermediate A
(path b, Scheme 1).
nection with our interest in the C H activation and carbo-
palladation fields,[20] we envisioned that three basic trans-
formations in palladium chemistry such as the intramolecular
Heck arylation of an olefin, the intermolecular carbopalla-
A different strategy to quench the s-alkyl PdII intermedi-
À
ate relays on the ability of this metal to activate C H bonds
(path c, Scheme 1).[14–18] Noteworthy, the reaction leads to
dation of an unsaturated species and a C H activation step
À
could all be implemented in a single reaction through both the
appropriate design of the substrate and the use of an adequate
unsaturated coupling partner (path d, Scheme 1).
To prove the feasibility of the cascade process under study
we chose the substrate N-(2-phenylallyl)sulfonamide 1a,
a type of structure where selective 5-exo-trig cyclization
under Pd0 catalysis is well documented.[11a–c] Benzyne was
selected as the coupling partner for several reasons: first, it
bears two reactive positions which leads to 1,2-difunctional-
ized arenes,[21,22] and second, it is a highly reactive species that
[*] M. Pꢀrez-Gꢁmez, Dr. J.-A. Garcꢂa-Lꢁpez
Grupo de Quꢂmica Organometꢃlica. Dpto. Quꢂmica Inorgꢃnica,
Universidad de Murcia
Campus de Espinardo, 30100, Murcia (Spain)
E-mail: joangalo@um.es
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201607976.
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could trap the intermediates A or B (Scheme 1) fast enough
to avoid the undesired and well-documented [1,4]-Pd shift-
induced intramolecular termination of the cascade reaction
(see below, Scheme 7).[23] Furthermore, the carbopalladation
À
of benzyne and subsequent C C coupling would lead to
a biaryl scaffold, a structural motif present in a widespread
number of functional materials, natural products, pharma-
ceuticals and ligands used in catalysis.[24]
A small amount of the expected product 3a (Scheme 2)
was formed when the substrate 1a was reacted with the
benzyne precursor 2a (2 equiv) in MeCN at 908C in the
presence of CsF (3 equiv) and a catalytic amount of Pd-
(OAc)2/PPh3. Under these conditions, a substantial quantity
of triphenylene arising from the Pd-catalyzed cyclotrimeriza-
tion of the aryne was generated,[25,26] plus other by-products
(see below). In order to conciliate the generation rates of the
desired s-alkyl PdII intermediate and benzyne, we screened
other solvents to modulate the formation of benzyne, and
found that a 1:1 mixture of toluene and MeCN gave the best
results (Scheme 2). Lower catalyst loadings (5 mol%) or
other phosphine ligands were less effective (see the Support-
ing Information (SI)).
Scheme 3. Scope of the cascade reaction.
Scheme 2. Optimized conditions for the cascade reaction.
We studied the scope of the reaction by varying the nature
and length of the tethering chain bearing the alkene moiety,
the substituents on the aryl or heteroaryl rings, and the aryne
coupling partner (Schemes 3 and 4). The substrates 1a–k,
undergoing an initial 5-exo-trig cyclization, generated selec-
tively the corresponding [4,5]-spirocycles 3a–k in moderate to
À
good yields in spite of the existence of two possible C H
moieties susceptible to be activated and later functionalized.
Interestingly, the substrates 1l and 1m, where the Heck
carbopalladation occurs via 6-exo-trig cyclization, gave mix-
À
tures of isomers arising from the two possible C H activation
sites (3l, 4l and 3m, 4m, respectively). The influence of the
nature of the tethering chain in the regioselectivity of the
cascade process might be related to the relative tension of the
quaternary spiro-carbon in the former palladacycle inter-
mediate, leading to the structures 3 or 4 (see below,
Scheme 7). Other substrates such as N-(2-bromopyridin-3-
yl)-N-(2-phenylallyl)benzenesulfonamide or 2-bromophenyl
2-phenylacrylate were unproductive under the standard
conditions of the cascade reaction.
We performed the cascade reaction of substrate 1d
replacing PPh3 for (R)-BINAP as ligand, obtaining a slightly
enantioenriched product 3d (ratio 54:46) in a 42% yield.
It is widely proven that meta-substituted arynes do not
undergo regioselective attack to their strained triple
bond.[22,28a] We tested the reaction of substrate 1d and the
Scheme 4. Scope of the cascade reaction with different arynes.
m-methyl-substituted substrate 2b. As expected, the reaction
afforded a 1:1 mixture of the spirocycles 3n and 3n’ in good
yield (Scheme 4). The 3-OMe-substituted aryne, however,
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gave a 3:1 mixture of isomers 3o and 3o’, with 3o as the major
component, which arises from the carbopalladation where the
Pd atom occupies the closer position to the OMe group,
resulting from both the higher electrophilicity of the remote
carbon of the aryne and the suitable coordination of the OMe
group to Pd. This is the behavior observed in other transition
metal-catalyzed transformations where this type of aryne has
been used.[27,28] The symmetrically substituted aryne 2d
reacted smoothly to give the compounds 3p and 3q in
moderate yield.
We attempted the cascade reaction with the substrate 1r
bearing an N-substituted indole moiety (Scheme 5). While
only traces of the expected arylated product were detected,
the main component of the mixture was the spirocyclic
compound 6, formerly reported by Grigg et al.[14a]
Scheme 6. Extended cascade reaction from substrate 1s.
Scheme 5. Attempted cascade reaction from the indole derivative 1r.
À
This result indicated that, first, the C H activation event
could take place prior to the aryne carbopalladation step, and
À
second, the final oxidative C C coupling process from the
intermediate 5 could happen fast enough to prevent the aryne
insertion if it leads to unstrained cyclic structures. In the case
of the substrates 1a–k, a similar process would lead to much
more strained [4,3]-spirocycles.
The cascade reactions can be extended by including
a relay moiety (such as a second unsaturation) in the tethering
chain.[10b,29] Hence, when 1s was submitted to the standard
reaction conditions (Scheme 6), we could isolate the biaryl 8
(23%), resulting from the premature quenching of inter-
mediate 7 with benzyne, and the polyspirocycle 10 (36%),
produced when two sequential intramolecular carbopallada-
tion steps occur prior to the insertion of the aryne into the
Scheme 7. Proposed mechanism for the cascade process. “L” repre-
sents a generic ligand or counterion (Br, OAc).
À
À
Pd C bond and final oxidative C C coupling. Interestingly, in
À
this domino process four C C bonds are formed in a diaste-
reoselective way, probably due to a chair-like pre-transition
state of intermediate 7 where the Ph group occupies the
equatorial position.[11a,29,30]
1m, could also give rise to the palladacycle of type C. The
regioselectivity of this step would be determined by the
relative strain of the two possible structures. Related five-
membered palladacycles containing a C(sp3),C(sp2)-chelating
ligand have been isolated and characterized by Cꢀmpora
Two possible mechanisms are compatible with the cascade
process reported herein (Scheme 7). In the first one, the
intramolecular Heck arylation of the tethered alkene leads to
the s-alkyl PdII intermediate A, where the metal performs
et al.[31] The desired cascade reaction can be quenched when
3
À
the intermediate B undergoes a protonolysis of the C(sp ) Pd
À
a C H activation in any of the two nearby aryl rings to afford
bond, which is formally a [1,4]-Pd shift from A, to further
evolve giving 11, which was detected in small amounts during
the optimization of the conditions for the cascade reaction,
and isolated in 60% yield in the absence of the aryne
a five-membered palladacycle. In principle, while the sub-
strates 1a–k would selectively generate the palladacycle of
type B, substrates with longer tethering chain, such as 1l or
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À
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À
À
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In conclusion, we have reported a new synthetic strategy
À
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Acknowledgements
We thank the Spanish Ministerio de Economꢁa y Competiti-
vidad (grant CTQ2015-69568-P) and Fundaciꢂn Sꢃneca
(grant 19890/GERM/15) for financial support. Prof. I.
Saura-Llamas is acknowledged for useful comments and
discussion. Dr. E. Vispe (ISQCH) is acknowledged for the
measurement of chiral-HPLC traces.
Keywords: aryne · carbopalladation · cascade reactions ·
À
C H activation · spirocycles
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2
2
À
[32] C(sp ) C(sp ) bond formation is proposed to occur first since
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[29] The stereochemistry of 10 was established by NOESY experi-
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DFT calculations (see the SI file).
Received: August 17, 2016
Published online: && &&, &&&&
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Communications
Synthetic Methods
From simple to complex: A palladium-
catalyzed cascade Heck carbopallada-
À
M. Pꢁrez-Gꢂmez,
J.-A. Garcꢃa-Lꢂpez*
tion/C H activation/aryne insertion pro-
vides easy access to spirobiaryls. The
process tales advantage of several
&&&& — &&&&
Trapping s-Alkyl–Palladium(II)
Intermediates with Arynes Encompassing
aspects of Pd chemistry, i.e., intra- and
intermolecular carbopalladation of unsa-
À
À
À
Intramolecular C H Activation:
Spirobiaryls through Pd-Catalyzed
Cascade Reactions
turated species, C H activation and C C
coupling processes.
6
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