Pd-Catalyzed Spirocyclization via C-H Activation and Benzyne Insertion

Article abstract of DOI:10.1021/acs.orglett.6b03213

A palladium-catalyzed spirocyclization forming spirooxindoles and spirodihydrobenzofurans has been achieved. Mechanistic studies suggest that the transformation proceeds through sequential carbopalladation, C-H activation, and benzyne insertion. Both classes of spirocycles have been synthesized in good to excellent yields, and the procedure is readily scalable.

Full text of DOI:10.1021/acs.orglett.6b03213

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Spirocyclization via C−H Activation and Benzyne
Insertion
Hyung Yoon, Alexis Lossouarn, Felicitas Landau, and Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: A palladium-catalyzed spirocyclization forming spirooxindoles and spirodihydrobenzofurans has been achieved.
Mechanistic studies suggest that the transformation proceeds through sequential carbopalladation, C−H activation, and benzyne
insertion. Both classes of spirocycles have been synthesized in good to excellent yields, and the procedure is readily scalable.
alladium-catalyzed C−H functionalization has attracted
considerable interest as it provides an efficient and atom-
Scheme 2. Pd-Catalyzed Cascade Reactions
P
economical process to forge novel bond connections.1 Although
a wide array of intermolecular transformations have been
reported, the utility of this approach in an intramolecular cascade
reaction has been underdeveloped. The combination of C−H
functionalization with the intramolecular Heck reaction has
provided a new venue in generating polyheterocyclic cores.2 In
addition, various groups have expanded the intramolecular
process to the formation of biologically relevant spirocycles
(Scheme 1).3−5 Alternatively, the Pd-catalyzed domino-Heck
Scheme 1. Pd-Catalyzed Intramolecular C−H Activation and
Domino Heck Anion Capture Cascade
spirocyclic palladacycle was reported9b (Scheme 2B). Reductive
elimination yielded the benzocyclobutene derivatives, while in
the presence of alkyl halides, a Catellani-like reaction furnished
benzofurans. Interested in the reactivity of the described
palladacycle (Scheme 2B), we sought to insert highly reactive
benzynes11 into this intermediate to access various classes of
spirocycles.12
In addition to determining the generality of this process, we
provide mechanistic insight on the Pd-catalyzed domino-Heck
spirocyclization via C−H activation and benzyne insertion
sequence. The described transformation showcases the synthesis
anion capture cascade pioneered by Grigg6 has become a
valuable methodology to synthesize useful heterocyclic scaffolds
that map onto pharmaceutical agents and natural products
(Scheme 1).7,8
Recently, our group has made contributions in the fields of
intramolecular C−H functionalization9 and domino-Heck anion
capture cascade.10 In 2014, both methodologies were applied in a
single transformation by intercepting the palladacycle generated
by an intramolecular C−H functionalization with an aryl iodide
to provide polycyclic cores (Scheme 2A).9a
Following this work, a divergent Pd-catalyzed cascade reaction
in which two classes of compounds originate from a single
Received: October 26, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03213
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Letter
of spirooxindoles and spirodihydrobenzofurans in good to
excellent yields (Scheme 2C).
We envisioned the cyclization of 1a and insertion of a benzyne
(generated in situ from precursor 2a) to afford 3a. The desired
spirooxindole 3a was obtained in 48% yield and was
accompanied by triphenylene (TP) (Scheme 3). The spirocyclic
in high yield and did not undergo side reactions with the aryne
(3e, 90% yield). Fluorine and trifluoromethyl substitution
produced the desired products in 79% and 58% yield,
respectively (3f and 3g). Electron-rich substituents also cyclized
to generate 3h in 84% yield. Gratifyingly, substitution of the
tethered aryl group with a fluorine improved the reactivity, giving
3i in 91% yield. N-Benzylated acrylamides also participated in the
reaction in excellent yields (3j and 3k, 85% and 87% yield,
respectively). N-MOM- and N-CH2CO2Et-protected acryla-
mides also cyclized in 92% and 86% yield, respectively (3m and
3n). Electron-poor N-protected acrylamide 1o reacted in slightly
lower yield (66% yield). Electron-rich and -poor substituents on
the tethered aryl group did not negatively impact the cyclization
(3p and 3q, 96% and 92% yield, respectively). An ortho
substituent on the tethered aryl group produced the spiroox-
indole in good yield (3r, 78% yield). Sterically encumbered and
electron-rich benzyne precursors 2a and 2b were reacted with 1a
to produce 3s and 3t in 85% and 82% yield, respectively.
Electron-poor benzyne precursor 2c cyclized to form 3u in 50%
yield. On a gram scale, 3a was isolated in 85% yield. Alkynes and
cyclohexynes did not undergo insertion to form the respective
spirocycles.
Scheme 3. Initial Hit
structure of 3a was confirmed by spectroscopic data and X-ray
crystallography. Encouraged by the initial hit, the reaction
conditions were optimized to yield 3a and minimize the
formation of TP in 96% and 4% yield, respectively (Scheme 4).13
Scheme 4. Optimized Conditions
In addition to the preparation of spirooxindoles, the synthesis
of spirodihydrobenzofurans was also investigated (Scheme 6).
Scheme 6. Pd-Catalyzed Domino Heck Spirocyclization
b
Forming Spirodihydrobenzofurans: Reaction Scope
With the optimized conditions, we investigated the substrate
scope (Scheme 5). Acrylamides bearing halogens and electron-
neutral substituents at the 4- and 5-positions were well-tolerated
(1b−d, 89−95% yield). A methyl ester at the 4-position cyclized
Scheme 5. Pd-Catalyzed Domino Heck Spirocyclization
b
Forming Spirooxindoles: Reaction Scope
a
b
The reaction was run on a 2.97 mmol scale. Isolated yields of
spirodihydrobenzofurans are shown. rr = ratio of regioisomers.
Lowering the catalyst loading to 5 mol % Pd and altering the
solvent ratio to PhMe:MeCN = 2:1 allowed the cyclization to
give 5a in 84% yield. Sterically encumbered aryl iodide 4d also
reacted to give 5d in 67% yield. Electron-poor tethered aryl
groups enhanced the cyclization to give the spirobenzofurans
(5e, 94% yield). It was found that unsymmetrical tethered aryl
groups underwent the C−H activation regioselectively to
minimize steric interaction on the palladacycle (5f and 5g,
6.7:1 rr and 9:1 rr, respectively). In line with the findings on the
a
b
The reaction was run on a 2.75 mmol scale. Isolated yields of the
spirooxindoles are shown.
B
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Letter
spirooxindoles, sterically encumbered and electron-rich ben-
zynes 2b and 2c reacted to generate 5h and 5i in 98% and 84%
yield, respectively. An electron-poor aryne generated 5j in 55%
yield. Interestingly, the unsymmetrical benzyne precursor 2d
reacted with 3.3:1 rr to give 5k. A gram-scale reaction was
performed to examine the scalability, and 5a was generated in
86% yield.
Scheme 9. Mechanistic Experiments
Derivatizations of the spirocycles were explored. A radical
benzylic bromination gave ring expansion and aromatization of
both the spirodihydrobenzofuran and spirooxindole in moderate
yields (6a and 6b, 40% and 41%, respectively; Scheme 7).
Scheme 7. Ring Expansion of Spirocycles
under the standard reaction conditions, the cyclization following
the C−H activation did not occur, and instead, arylation of
acetonitrile proceeded exclusively to generate M2 (52% yield;
Scheme 9).15 The formation of M2 suggests that generation of
the seven-membered palladacycle after insertion of the benzyne
is unfavorable under the reaction conditions. We propose that
the reaction proceeds exclusively through pathway 1.
The spirocyclization product can be explained through the
postulated mechanism in Scheme 8. Aryl iodide 1a undergoes
Scheme 8. Postulated Mechanism for the Spirocyclization
In order to determine whether the intramolecular C−H
activation is the rate-determining step, a kinetic isotope effect was
measured using parallel experiments. The initial rates of
cyclization of acrylamide 1a and the deuterated derivative were
determined, and a kH/kD of 1.04 was determined. This result
provides evidence that C−H activation is not the rate-limiting
step in the catalytic cycle (Scheme 10).16
Scheme 10. Parallel KIE Experiment
Pd-catalyzed oxidative addition followed by carbopalladation to
generate alkylpalladium(II) intermediate B, from which two
divergent pathways are possible. In pathway 1, intramolecular
C−H activation of the pendant aryl group generates palladacycle
C. Insertion of the aryne leads to intermediate E or F,14 which
undergoes reductive elimination to release 3a and regenerate the
catalyst. In constrast, pathway 2 involves intermolecular insertion
of the aryne to form intermediate D followed by C−H activation
to yield intermediate E and reductive elimination to form 3a.
Intrigued by the two pathways and eager to gain insight into
the C−H activation versus addition to the aryne, we performed a
series of mechanistic experiments (Scheme 9). Pathway 1
involves an intramolecular C−H activation forming palladacycle
C. To support its viability in the mechanism, 1a was reacted with
stoichiometric quantities of Pd(PPh3)4 and excess Cs2CO3 to
generate C in 50% yield. The structure was confirmed by
spectroscopic data and X-ray crystallography. Palladacycle C was
then reacted with the in situ-generated benzyne to yield 3a in
83% yield (Scheme 9A). The generation of 3a from C suggests
that C can be an intermediate in the catalytic cycle.
In summary, we have developed a Pd-catalyzed domino Heck
spirocyclization to provide a range of spirooxindoles and
spirodihydrobenzofurans in good to excellent yields. A series of
mechanistic experiments were performed to provide insight into
the reaction, and some derivatization experiments showed the
utility of these spirocycles. We are currently investigating the
enantioselective variant.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03213.
X-ray data for C (CIF)
X-ray data for 3a (CIF)
X-ray data for 5a (CIF)
Experimental procedures, optimization, characterization,
and X-ray data (PDF)
Pathway 2 was investigated by generating intermediate D via
oxidative addition of the corresponding aryl halide M1. However,
C
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Organic Letters
Letter
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mlautens@chem.utoronto.ca.
ORCID
Hyung Yoon: 0000-0003-4573-2160
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Toronto, Alphora Research, Inc., and
the Natural Sciences and Engineering Research Council
(NSERC) for financial support. H.Y. thanks the Ontario
Graduate Scholarship for funding. We thank Dr. J. Ye (Columbia
University) for the synthesis of 4b, 4c, and 4e. We thank Dr. D.
Petrone, Dr. I. Franzoni, and Y. J. Jang (University of Toronto)
and Dr. Z. Qureshi (Simon Fraser University) for insightful
discussions during the project. We thank Dr. Alan Lough
(University of Toronto) for single-crystal X-ray analysis of 3a, 5a,
and C.
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