Palladium-Catalyzed Annulations of Strained Cyclic Allenes

Article abstract of DOI:10.1021/jacs.1c04896

We report Pd-catalyzed annulations of in situ generated strained cyclic allenes. This methodology employs aryl halides and cyclic allene precursors as the reaction partners in order to generate fused heterocyclic products. The annulation proceeds via the formation of two new bonds and an sp3 center. Moreover, both diastereo-and enantioselective variants of this methodology are validated, with the latter ultimately enabling the rapid enantioselective synthesis of a complex hexacyclic product. Studies leveraging transition metal catalysis to intercept cyclic allenes represent a departure from the more common, historical modes of cyclic allene trapping that rely on nucleophiles or cycloaddition partners. As such, this study is expected to fuel the development of reactions that strategically merge transition metal catalysis and transient strained intermediate chemistry for the synthesis of complex scaffolds.

Full text of DOI:10.1021/jacs.1c04896

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Palladium-Catalyzed Annulations of Strained Cyclic Allenes
Andrew V. Kelleghan, Dominick C. Witkowski, Matthew S. McVeigh, and Neil K. Garg*
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ABSTRACT: We report Pd-catalyzed annulations of in situ generated strained cyclic allenes. This methodology employs aryl
halides and cyclic allene precursors as the reaction partners in order to generate fused heterocyclic products. The annulation
proceeds via the formation of two new bonds and an sp3 center. Moreover, both diastereo- and enantioselective variants of this
methodology are validated, with the latter ultimately enabling the rapid enantioselective synthesis of a complex hexacyclic product.
Studies leveraging transition metal catalysis to intercept cyclic allenes represent a departure from the more common, historical
modes of cyclic allene trapping that rely on nucleophiles or cycloaddition partners. As such, this study is expected to fuel the
development of reactions that strategically merge transition metal catalysis and transient strained intermediate chemistry for the
synthesis of complex scaffolds.
ince the early 1900s, transient strained cyclic intermedi-
ates, exemplified by benzyne (1, Figure 1A), have
Whereas strained cyclic alkynes have received significant
attention from the synthetic community, reactions of a related
class of fleeting intermediates, strained cyclic allenes (e.g., 1,2-
cyclohexadiene (5)), are relatively less developed.16,17 This is
notable as cyclic allenes and alkynes were both discovered
around the same time and share similar strain-promoted
reactivity.18 Moreover, cyclic allenes are advantageous for the
synthesis of sp3-rich and stereochemically complex targets,
which are becoming increasingly more valuable.19 However, to
date, only three major intermolecular reaction classes have
been reported for these intermediates (Figure 1B), the most
frequently studied being nucleophilic trappings (e.g., 7 + KOt-
Bu → 6) and cycloadditions (e.g., 7 + 8 → 9).16 More than 50
studies detailing such reactions have been reported, including
S
20,21
more recent studies by Guitian,
West,22−25 Okano and
́
Mori,26,27 Schreiber,28 and our laboratory.29−32 A comple-
mentary, albeit rarely studied, approach utilizes transition
metal catalysis to intercept the cyclic allene (e.g., 7 + 10 →
11).20,33 However, this strategy poses an inherent kinetic
challenge due to the requirement for reaction between a
catalytically generated intermediate and an in situ generated
fleeting cyclic allene, both of which are present in low
concentration.
Figure 1. Selected in situ generated strained cyclic intermediates and
overview of strained cyclic allene reactivity.
Previous efforts to intercept strained cyclic allenes
intermolecularly with transition metal catalysis have been
limited, with only two examples known in the literature. The
first was a single example wherein an in situ generated cyclic
allene was intercepted in a Pd-catalyzed [2 + 2 + 2] reaction to
stimulated interest in the chemical community.1 Although
the proposal of benzyne (1) as a reactive intermediate led to
significant controversy in the early 20th century, pioneering
experiments by Roberts2 and Wittig3,4 in the 1950s validated
its existence, despite the high degree of ring strain. Indeed, this
ring strain gives rise to unique and synthetically useful
reactivity, which in turn has motivated the development of
heterocyclic arynes, such as 25 and 3,6 and more highly
saturated analogs of benzyne (1), such as cyclohexyne (4).7,8
These in situ generated intermediates have become increas-
ingly prominent in the modern synthetic toolbox, finding
applications in the construction of heterocycles,9 ligands for
catalysis,10 natural products,11−13 agrochemicals,14 and organic
materials.15
generate a mixture of tetralin products, as demonstrated by
20
́
Guitian and co-workers in 2009.
Subsequently, our
Received: May 11, 2021
Published: June 18, 2021
https://doi.org/10.1021/jacs.1c04896
J. Am. Chem. Soc. 2021, 143, 9338−9342
© 2021 American Chemical Society
9338

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Communication
laboratory developed a Ni-catalyzed annulation of cyclic
allenes with benzotriazinones, including an asymmetric
variant.33 These studies demonstrate that the combination of
transition metal catalysis and cyclic allenes provides an exciting
new avenue in strained intermediate chemistry.
Table 1. Reaction Optimization
With the aim of developing a modular new method for the
metal-catalyzed interception of strained cyclic allenes, we
designed the transformation depicted in Scheme 1.34 We
Scheme 1. Envisioned Reaction Design
a
Reaction conditions: 17 (1.0 equiv), 18 (1.0 equiv), catalyst (10 mol
%), ligand (20 mol %), CsF (as shown), Na2CO3 (3 equiv), solvent
b
1
(0.1 M), 3 h. Yield determined by H NMR analysis using 1,3,5-
c
d
trimethoxybenzene as an external standard. 24 h. 18 (1.5 equiv),
Bu4NOTf (5.0 equiv), 1 h.
optimization led to the use of DMF as solvent, Bu4NOTf37 as
an additive, and a slight excess of silyl triflate 18. Employing
these conditions delivered 19a in nearly quantitative yield after
1 h at 80 °C (entry 6).
To assess the generality of this reaction, we tested a range of
o-iodoaniline derivatives 20 and silyl triflates 13 (Figure 2).
envisioned that bifunctional annulation partners 12 containing
an aryl iodide and a pendant pronucleophile (XH) would first
react with a transition metal catalyst, generating oxidative
addition intermediates 15. Concurrently, silyl triflates 13
would be converted to strained cyclic allenes 7 via fluoride-
mediated desilylation. Cyclic allenes 7 would then undergo
migratory insertion into the Ar−M bond of 15, ultimately
giving rise to η3-coordinated complexes 16. Cyclization of the
pendant pronucleophile would deliver tricycles 14 with
regeneration of the catalyst. Herein, we demonstrate the
successful implementation of this approach to annulate in situ
generated cyclic allenes using Pd catalysis. An array of fused
polycyclic products are obtained in synthetically useful yields
by varying the cyclic allene precursor and the aryl halide
substrate. Stereoselective examples are also demonstrated.
These results highlight the value of merging transition metal
catalysis with strained cyclic allene chemistry and should
enable future reaction development in this emerging area.
To validate our proposed reaction design, we studied the
reaction of o-iodoaniline derivative 17 with silyl triflate 18
using fluoride-based conditions (Table 1). The conditions we
had identified previously for the aforementioned Ni-catalyzed
reaction of benzotriazinones with cyclic allenes33 were deemed
a suitable starting point for reaction discovery. Unfortunately,
no desired product was observed with a Ni(cod)2/dppf catalyst
system, even at increased temperature (entries 1 and 2). Given
the widespread use of palladium in academic and industrial
settings, along with its well-established competency in
heteroannulation reactions,34 we turned to Pd catalysis. We
were gratified to observe that the use of a Pd catalyst enabled
the desired reactivity, leading to tetrahydrocarbazole 19a,
albeit only in 8% yield (entry 3). Because unreacted silyl triflate
18 was observed under these conditions, we increased the
loading of CsF. This led to a significant improvement in the
yield, as shown in entry 4.35 After evaluating other ligands (see
Supporting Information (SI) for details), we found that
employing the bulky monophosphine DavePhos was most
effective,36 generating 19a in 71% yield (entry 5). Further
Figure 2. Scope of the annulation reaction with iodoaniline
derivatives 20. Reactions performed with 20 (1.0 equiv) and 13
(1.5 equiv). a Reaction was performed using 2-(N,N-dimethylamino-
methyl)-1-diphenylphosphanylferrocene as ligand in MeCN at 60 °C
for 3 h. b ArX = 2-halo-6-methyl-3-N-tosylaminopyridine. c Reaction
was performed using 2-(N,N-dimethylaminomethyl)-1-diphenylphos-
phanylferrocene as ligand with CsF (2.5 equiv) in MeCN at 60 °C for
24 h; performed in the absence of Bu4NOTf. d A silyl tosylate was
used as the allene precursor (see ref 38).
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Although our conditions shown in Table 1, entry 6 were
generally useful, some modifications were made to obtain
optimal yields based on empirical observations. Three different
N-substituents were examined, namely tosyl (Ts), tert-
butyloxycarbonyl (Boc), and acetyl (Ac), with Ts providing
the highest yield (90% of 19a). Electronic and steric
perturbations of the annulation partner were also tolerated,
as evidenced by the formation of tetrahydrocarbazoles 22−30.
Of note, the annulation exhibits good functional group
compatibility, leading to products bearing nitriles or esters
(26 and 27), as well as aryl bromides, chlorides, or fluorides
(28−30).39 Given the importance of heterocycles in medicinal
chemistry, we also assessed the compatibility of the reaction
with heterocyclic annulation partners and heterocyclic allenes.
Gratifyingly, an iodopyridyl annulation partner underwent the
desired reaction to afford product 31 in excellent yield. The
corresponding bromopyridine substrate could also be
employed to give 31, albeit in slightly diminished yield
(78%).40 Lastly, we varied silyl triflate 13 to enable further
modulation of the product structure. Oxa- and aza-derivatives
of 13, readily available through known routes,30,31 were
employed to furnish heterocycles 32 and 33, respectively.
This highlights the value of heterocyclic allenes in our
methodology for the modular assembly of more complex
heterocyclic products. Likewise, substituting a 7-membered
cyclic allene precursor in place of a 6-membered cyclic allene
precursor gave straightforward access to the 6−5−7 ring
system seen in 34.
6−5−6 ring systems bearing ethers, lactones, amides, or all-
carbon frameworks.
The feasibility of diastereo- and enantioselective variants of
the methodology was established as shown in Figure 4. In both
Figure 4. Stereocontrolled annulations and synthetic elaboration of
an annulation product.
We also questioned whether other pronucleophiles, beyond
iodoaniline derivatives, could be employed in Pd-catalyzed
reactions of strained cyclic allenes (Figure 3). With regard to
cases, heterocyclic substrates were utilized to evaluate the
strengths and limitations of the metholodogy, while providing
access to polycyclic scaffolds. Regarding the diastereoselective
annulation, it should be noted that diastereoselective reactions
of strained cyclic allenes have been reported in the context of
cycloadditions,16 but there are no prior examples involving
transition metal catalysis. Given our success in employing a
benzylic alcohol (i.e., 35, Figure 3), we prepared tertiary
benzylic alcohol 43. This substrate, rapidly accessed from a
commercially available isatin precursor, was treated with 1,2-
cyclohexadiene precursor 18 under standard annulation
conditions. Tetracycle 44 was obtained as the major product,
with d.r. = 5.6:1, thus providing the first example of substrate-
guided stereocontrol in a metal-catalyzed reaction of cyclic
allenes.41
To probe the feasibility of an enantioselective variant, we
tested the reaction of iodopyridine 45 with silyl triflate 46
(Figure 4). Evaluation of chiral ligands led to the identification
of Pd2(dba)3/Mandyphos as the optimal catalyst system.
Moreover, with CH2Cl2 as solvent at decreased temperature (3
°C) (see SI for extended optimization details), tricycle (−)-47
was generated in 90% ee.42 As catalytic asymmetric reactions of
in situ generated strained cyclic intermediates (i.e., arynes,
cyclohexynes, cyclic allenes, etc.) are rare, we hope this result
will promote further efforts in this area.
Finally, with unique polyheterocyclic product (−)-47 in
hand, we questioned if the styrenyl olefin present in the
annulation products could be leveraged as a handle for further
elaboration. (−)-47 was subjected to oxacyclic allene precursor
48 in the presence of CsF to furnish (+)-49 via a highly
diastereoselective [2 + 2] cycloaddition. The olefin in (+)-49,
newly introduced in the cyclic allene [2 + 2] reaction, then
underwent diastereoselective epoxidation to furnish (+)-50.
This short sequence leverages the asymmetric Pd-catalyzed
Figure 3. Variation of the pronucleophile to furnish structurally
diverse products.
oxygen nucleophiles, we found that benzyl alcohol 35 and
benzoic acid 37 were successful in delivering 36 and 38,
respectively, under our standard reaction conditions. Using
modified conditions with Xantphos as the ligand, we found
that amide 39 was a suitable N-pronucleophile, delivering 40 in
71% yield. Lastly, we tested the viability of a C-based
pronucleophile by employing diester 41. Using our standard
reaction conditions, we obtained tetrahydrofluorene 42, which
bears a newly formed quaternary carbon. These examples
underscore that the union of strained cyclic allenes and Pd
catalysis provides a rapid entryway to the synthesis of
structurally diverse polycyclic products, including 6−6−6 and
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Communication
annulation of an azacyclic allene to ultimately generate an
enantioenriched hexacyclic compound (i.e., (+)-50) bearing
five different fused heterocycles, a highly substituted cyclo-
butane, and six contiguous stereocenters, one of which is
quaternary.
ACKNOWLEDGMENTS
■
The authors thank the NIH-NIGMS (R01-GM123299, R01-
GM132432, and R35-GM139593 for N.K.G. and T32-
GM136614 for M.S.M.), the National Science Foundation
(DGE-1650604 for A.V.K.), the Foote Family (for M.S.M. and
A.V.K.), and the Trueblood Family (for N.K.G.) for financial
support. We thank Professor Hosea Nelson (UCLA),
Benjamin Wigman (UCLA), Chloe Williams (UCLA), and
Sepand Nistanaki (UCLA) for HPLC analysis of 47 and Dr.
Saeed Khan (UCLA) for X-ray analysis. These studies were
supported by shared instrumentation grants from the NSF
(CHE-1048804) and the National Center for Research
Resources (S10RR025631).
In summary, we have developed Pd-catalyzed annulations of
in situ generated strained cyclic allenes. The methodology
employs aryl halides and cyclic allene precursors as the
reaction partners, ultimately forming two new bonds and
generating an array of fused heterocyclic products. Moreover,
through the syntheses of 44 and (−)-47 (see Figure 4), we
demonstrate stereoselective variants of this methodology. The
catalytic asymmetric annulation and resulting swift access to
hexacycle (+)-50 highlight some of the opportunities afforded
by the combination of strained intermediates and Pd catalysis.
As this strategy represents a departure from the more common,
historical modes of cyclic allene trapping using nucleophiles or
cycloaddition partners, we hope this study will stimulate the
future development of reactions that strategically merge
transition metal catalysis and transient strained intermediate
chemistry for the synthesis of complex scaffolds.43
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* Supporting Information
The Supporting Information is available free of charge at
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CCDC 2065022 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Neil K. Garg − Department of Chemistry and Biochemistry,
University of California, Los Angeles, California 90095,
United States; orcid.org/0000-0002-7793-2629;
Email: neilgarg@chem.ucla.edu
Authors
Andrew V. Kelleghan − Department of Chemistry and
Biochemistry, University of California, Los Angeles,
California 90095, United States
Dominick C. Witkowski − Department of Chemistry and
Biochemistry, University of California, Los Angeles,
California 90095, United States
Matthew S. McVeigh − Department of Chemistry and
Biochemistry, University of California, Los Angeles,
California 90095, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04896
́
Christl, Balci and Jones, Elliot, Guitian, West, and many others. For a
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Weinheim, 2004; pp 243−357.
Notes
The authors declare no competing financial interest.
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Communication
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(35) When the experiment shown in entry 4 was performed in the
absence of exogenous ligand, product 19a was obtained in 17% yield.
(36) 2-(N,N-Dimethylaminomethyl)-1-diphenylphosphinoferrocene
was found to provide similar results to DavePhos, but the latter was
chosen for further study given its widespread commercial availability.
9342
https://doi.org/10.1021/jacs.1c04896
J. Am. Chem. Soc. 2021, 143, 9338−9342