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org/OrgLett Letter

Rapid Assembly of Unsymmetrically Linked Bis-heterocycles via

Palladium Domino Catalysis
Ramon Arora,† Jonathan Bajohr,† and Mark Lautens*
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ABSTRACT: A palladium-catalyzed domino reaction of alkene-

tethered oxime esters is reported. This transformation uses an air-
stable palladium precatalyst that initiates a Narasaka−Heck
reaction, that is interrupted with a Pd(II)-promoted cyclization.
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Through this methodology, a novel class of unsymmetrical alkyl-

linked bis-heterocycles were synthesized in yields up to 99%. The
reaction is scalable up to 1.0 mmol, with simplified purification
steps. This transformation expands the scope of accessible bis-
heterocycles available through Narasaka−Heck reactions beyond
C−H activation and direct anionic capture termination steps.

A pplying tandem catalysis provides an attractive route for

accessing complex polycyclic target molecules. Intercept-
Table 1. Optimization of Conditions

Scheme 1. Precedented and Proposed Work

entry deviation from the standard conditions yield of 3a (%)a

b
1 10 mol % catalyst in MeCN 78
2 Toluene instead of THF 87
3 Dioxane instead of THF 88
4 DMF instead of THF 70
5 1.2 equiv of 2a 83
6 2.0 equiv of 2a 90
7 90 °C 92
a
Yields were determined by 1H NMR analysis of the crude reaction
mixtures with 1,3,5-trimethoxybenzene as an internal standard. bRun
at 100 °C. All reactions were run on a 0.1 mmol scale.

domino reactions.2−6 One catalytic system of particular

interest utilizes palladium, as both Pd(0) and Pd(II) oxidation
states can be leveraged to promote unique reactivity.7−11
An electron-rich Pd(0) complex is typically required for
oxidative addition, whereas higher-valent Pd(II) has been
utilized in Lewis acid-mediated transformations.7 In 1998, the
Lewis acidity of Pd(II) was key in a report by Cacchi, wherein

Received: November 13, 2023

Revised: December 5, 2023
ing reactive intermediates has proven to be a promising Accepted: December 8, 2023
approach in this regard.1 By careful design and pairing of Published: December 12, 2023
substrates, sequential bond-forming steps can occur in a single
reaction under constant conditions, commonly referred to as

© 2023 American Chemical Society https://doi.org/10.1021/acs.orglett.3c03825

9053 Org. Lett. 2023, 25, 9053−9057
Organic Letters
Scheme 2. Reaction Scopea
a
All reactions were run on a 0.1 mmol scale unless indicated otherwise. Isolated yields are reported.
an alkyne-tethered aniline underwent a cycloisomerization to
forge an indole.12 The Cacchi reaction13−15 was subsequently
explored for a variety of terminations. Zhu synthesized
atropoisomerically enriched bis-heterocycles through a Cac-
chi/Suzuki reaction cascade.16 Our group has reported the
interception of both alkyl- and vinyl-Pd(II) species to enantio-
pubs.acs.org/OrgLett Letter
and stereoselectively synthesize linked bis-heterocycles
(Scheme 1A). 17,18 With the goal of accessing novel
heterocyclic scaffolds, we sought to merge Pd(0) and Pd(II)
catalysis.
Hydroxylamine/oxime benzoyl esters readily undergo
oxidative addition in palladium-catalyzed reactions.19,20 When
9054 https://doi.org/10.1021/acs.orglett.3c03825
Org. Lett. 2023, 25, 9053−9057
Organic Letters pubs.acs.org/OrgLett
Scheme 3. Scale-Up and Proposed Mechanism
tethered to a π-system, cyclization to the corresponding
pyrroline derivatives is commonly referred to as the Narasaka−
Heck reaction (Scheme 1B).21,22 This transformation gen-
erates a similar alkyl-Pd(II) intermediate as the Mizoroki−
Heck reaction. Bower, Zhu and Liang have demonstrated the
reactivity of this intermediate via direct anionic capture or a
C−H activation pathway.23−28 However, leveraging this Pd(II)
intermediate to generate a second heterocycle in an
intermolecular fashion has not been explored.
We used alkene-tethered oxime esters in a Pd(0)-catalyzed
iminopalladation, where the transient alkyl-Pd(II) intermediate
would facilitate a Cacchi reaction with o-alkynyl anilines
(Scheme 1C). Access to unsymmetrical alkyl-linked hetero-
cycles has been achieved. The products of this reaction could
be of interest in a medicinal context, as bis-heterocyclic
scaffolds are a common motif in the development of novel
therapeutics.29 The scope was demonstrated with 21 examples
in yields of up to 99% (1.0 mmol scale).
We began our investigation by subjecting compounds 1a
and 2a (1.5 equiv) under similar reaction conditions to those
in previous reports.17,18 Pd(PPh3)4 (10 mol %) and K2CO3
(2.0 equiv) in MeCN at 100 °C led to the desired product 3a
in 78% yield (Table 1, entry 1). Screening solvents revealed
that THF was optimal for product yield and minimized the
amount of 2-arylindole, arising from protodemetalation of 2a
(entries 2−4). Lowering the catalyst loading to 5 mol %
provided the optimal conditions, giving product 3a in 94%
9055
Letter
yield. Other variations of conditions such as the number of
equivalents of 2a and the temperature did not improve the
yield. (Table 1, entries 5−7).
Varying steric and electronic parameters on the parent
scaffold were investigated (Scheme 2). Modification of R1 with
diverse substituted aryl groups led to excellent yields (3a−3e).
Other reactive functional groups such as aryl chlorides were
also tolerated, showing minimal protodehalogenation. Replace-
ment of the gem-dimethyl group by a cyclohexane ring
provided 3f in a high yield of the spirocycle (95%). Variation at
R3 gave 3g−3n with a minimal impact arising from changes in
electronic parameters. However, the presence of increased
steric bulk, such as an o-methyl group, gave diminished yields
and inseparable impurities (see the Supporting Information for
details). The reaction was also tolerant of changes on the
alkyne substituent, providing 3q, 3s, 3t, and 3u.
Increasing the scale to 1.0 mmol scale (Scheme 3A) gave the
product in higher yield, and it was easily purified using a short
silica plug followed by trituration with pentanes.
The reaction pathway of the Narasaka−Heck cyclization has
been postulated to occur either via a one-electron 5-exo-trig
cyclization or a two-electron migratory insertion, depending on
the reaction conditions.27,30 We employed the monodeuter-
ated substrate 1a′31,32 to explore the diastereoselectivity of the
reaction. If the reaction were to occur via a one-electron
process, scrambling at the carbon bearing the deuterium would
occur and should produce a 1:1 mixture of diastereomers. This
outcome differs from a stereospecific two-electron migratory
insertion, which would result in a single diastereomer. When
we subjected 1a′ to the catalytic conditions (Scheme 3B), we
observed a single diastereomer, supporting a mechanism
involving a two-electron migratory insertion.
Based on the stereochemical results, the following
mechanistic scenario is proposed (Scheme 3C). Initial
oxidative addition of the oxime ester 1 generates the imino-
Pd(II) species I. This intermediate undergoes a migratory
insertion to generate intermediate II. Due to the presence of a
non-hydrogen substituent such as R3, the competitive β-
hydride elimination pathway is not possible. As a result, the
neopentyl-Pd(II) intermediate can then coordinate to the
alkyne of coupling partner 2 to yield III. The resulting
cyclization gives intermediate IV, which undergoes a reductive
elimination to give the desired product 3.
In conclusion, we have reported the highly efficient synthesis
of unsymmetrical bis-heterocyclcles via palladium domino
catalysis. Through the use of alkene-tethered oxime esters, we
have expanded the scope of this Narasaka−Heck reaction
beyond C−H activation or direct anionic capture. The reaction
was used to generate a library of compounds bearing both
pyrroline and indole heterocycles in yields of up to 99%.
■ ASSOCIATED CONTENT
Data Availability Statement
The data underlying this study are available in the published
article and its Supporting Information.
*
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.3c03825.
Compound characterization, NMR spectra, and mech-
anistic studies (PDF)
https://doi.org/10.1021/acs.orglett.3c03825
Org. Lett. 2023, 25, 9053−9057
Organic Letters
■ AUTHOR INFORMATION
Corresponding Author
Mark Lautens − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto,
Ontario, Canada M5S 3H6; orcid.org/0000-0002-0179-
2914; Email: mark.lautens@utoronto.ca
Authors
Ramon Arora − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto,
Ontario, Canada M5S 3H6; orcid.org/0000-0003-4585-
4328
Jonathan Bajohr − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto,
Ontario, Canada M5S 3H6; orcid.org/0000-0003-1948-
9320
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.3c03825
Author Contributions
† C−C Bond Activation/cacchi Reaction Between Cyclobutanones and
R.A. and J.B. contributed equally on the project.
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
We thank the University of Toronto and the Natural Science
and Engineering Research Council (NSERC) for financial
support. R.A. thanks OGS, NSERC-CGSD, and the Walter C.
Sumner Memorial Fellowship for funding. J.B. thanks NSERC
for funding. We thank Dr. Darcy Burns and Dr. Jack Sheng,
(University of Toronto) for their assistance with NMR
experiments, Dr. Matthew Forbes for the HRMS data, and
Dr. Alan Lough for the X-ray data.
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