Nickel-Catalyzed Decarboxylative Cross-Coupling of Bicyclo[1.1.1]pentyl Radicals Enabled by Electron Donor-Acceptor Complex Photoactivation

Article abstract of DOI:10.1021/acs.orglett.1c01558

The use of bicyclo[1.1.1]pentanes (BCPs) as para-disubstituted aryl bioisosteres has gained considerable momentum in drug development programs. Carbon-carbon bond formation via transition-metal-mediated cross-coupling represents an attractive strategy to generate BCP-aryl compounds for late-stage functionalization, but these typically require reactive organometallics to prepare BCP nucleophiles on demand from [1.1.1]propellane. In this study, the synthesis and Ni-catalyzed functionalization of BCP redox-active esters with (hetero)aryl bromides via the action of a photoactive electron donor-acceptor complex are reported.

Full text of DOI:10.1021/acs.orglett.1c01558

pubs.acs.org/OrgLett
Letter
Nickel-Catalyzed Decarboxylative Cross-Coupling of
Bicyclo[1.1.1]pentyl Radicals Enabled by Electron Donor−Acceptor
Complex Photoactivation
Viktor C. Polites, Shorouk O. Badir, Sebastian Keess, Anais Jolit,* and Gary A. Molander*
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ABSTRACT: The use of bicyclo[1.1.1]pentanes (BCPs) as para-disubstituted aryl bioisosteres has gained considerable momentum
in drug development programs. Carbon−carbon bond formation via transition-metal-mediated cross-coupling represents an
attractive strategy to generate BCP−aryl compounds for late-stage functionalization, but these typically require reactive
organometallics to prepare BCP nucleophiles on demand from [1.1.1]propellane. In this study, the synthesis and Ni-catalyzed
functionalization of BCP redox-active esters with (hetero)aryl bromides via the action of a photoactive electron donor−acceptor
complex are reported.
with scientists at Merck,11 disclosed the use of 1,3-difunctional
he operational ease of Pd-catalyzed C(sp2)−C(sp2)
Tcoupling reactions along with the availability of coupling benzylamine BCP boronates in Suzuki couplings (Figure 1B).
Leveraging a radical-based mechanism, Baran and co-
workers12 reported the cross-coupling of a single BCP redox-
active ester (RAE) with Ph2Zn. Anderson and co-workers, in
collaboration with Pfizer,13 then reported the iron-catalyzed
Kumada coupling of various BCP iodides with aryl Grignard
reagents (Figure 1C). In 2020, VanHeyst, Qi, and co-workers
from Merck and WuXi engaged BCP trifluoroborate salts in
Ni/photoredox dual cross-coupling and achieved modest to
acceptable yields (Figure 1D).14 Of note and particular
pertinence to the results reported herein, the BCP trifluor-
oborate salts required preparation through a continuous flow
photoborylation method from the corresponding N-(acyloxy)-
phthalimide redox active esters (RAEs).14,15
partners (in particular, arylboronates and aryl halides) has
resulted in a bias toward biaryl-containing molecules in drug
development programs.1 These cross-coupling platforms have
enabled the synthesis of diverse biaryl-containing drugs
targeting a wide swath of therapeutic areas. However,
considerable interest has developed in recent years to
investigate sp3-rich aryl isosteres in drug development
programs.2
Of particular interest is the bicyclo[1.1.1]pentane (BCP)
motif, which has been reported most commonly as a p-
disubstituted aryl bioisostere but also as a tert-butyl or alkyne
bioisostere, often imparting favorable pharmacokinetic proper-
ties, including improved aqueous solubility and membrane
permeability.3
Although considerable advancements have been made in the
synthesis of BCP-containing targets,4−6 the methods available
to forge BCP−aryl products via direct cross-coupling are
somewhat limited. Szeimies and co-workers,7 de Meijere and
co-workers,8 and Knochel and co-workers9 have reported
Kumada- and Negishi-type couplings between aryl halides and
the corresponding BCP organometallic reagents (Figure 1A).
Additionally, Kanazawa, Uchiyama, and co-workers10 reported
a Suzuki-type coupling using 1,3-difunctional silyl BCP
boronates. Shortly after, the Walsh group, in collaboration
Although BCP organometallic reagents perform well as
cross-coupling partners, their applicability in late-stage
functionalization is limited because of their functional group
incompatibility and short-term stability. To address these
Received: May 6, 2021
Published: June 8, 2021
https://doi.org/10.1021/acs.orglett.1c01558
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4828−4833
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Subsequently, we successfully adapted our previously
reported conditions to the cross-coupling of a BCP RAE
(1,3-dioxoisoindolin-2-yl bicyclo[1.1.1]pentane-1-carboxylate)
with 4-((4-bromophenyl)sulfonyl)morpholine in modest yield
(Table S1 of the Supporting Information). The addition of a
mild base, such as NaHCO3 or K2HPO4, improved the cross-
coupling yield by diminishing the loss of the BCP radical to
Minisci-type addition (SI-21) to Hantzsch pyridine, which is
generated upon photoaromatization.
With suitable conditions established (see the Supporting
Information for full optimization details), we proceeded to
investigate the scope of aryl bromides amenable to the cross-
coupling protocol (1−16, Scheme 1). In general, the best
yields were obtained using aryl bromides bearing electron-
withdrawing groups. Modest product formation was observed
with electron-rich and electron-neutral aryl bromides because
of competitive proto-debromination. Electrophilic and protic
functional groups were well-tolerated (in contrast with cross-
coupling methods based on organometallic reagents), includ-
ing several synthetic handles found in substrates such as
boronate 4, chloride 5, ester 7, and amide 15. Selected
heteroaromatic bromides were accommodated and did not
engage in Minisci-type side reactivity, giving modest to
synthetically acceptable cross-coupling yields (17−23). Of
particular note, pyridine 20 bears a 2-Cl handle for
diversification via SNAr, and the successful preparation of
furan 23 was made possible by this net-reductive cross-
electrophile platform. Importantly, these reductively and
oxidatively sensitive systems are traditionally challenging
structures in cross-couplings mediated by external photoredox
catalysts, further underscoring the selectivity using the EDA
paradigm. Finally, comparable reactivity was observed for
product 16 using 3.3 mmol (1.0 g) of aryl bromide instead of
0.5 mmol.
In further investigations using 4-((4-bromophenyl)sulfonyl)-
morpholine as a standard aryl bromide, the method was
demonstrated to be amenable to a wide range of BCP RAEs
with varying bridgehead substitutions (24−31). In particular,
very few BCP−aryl compounds with amino-(27),26−29 Cl-
(28),8 CF3-(29),30 CN-(30),28 and F-(33)31 bridgehead
substitutions have been reported, and to our knowledge,
none have been prepared via direct cross-coupling. Further-
more, the current method is proven to be more versatile than
that of VanHeyst, Qi, and co-workers,14 who were unsuccessful
in employing NHBoc-, CF3-, and CN-BCP trifluoroborates in
Ni/photoredox cross-coupling. Finally, we underscored the
utility of the method by engaging the BCP radical with several
bromides bearing functionally dense, medicinally relevant
structures (37−44). Under the developed conditions, late-
stage functionalization of diverse scaffolds can be accom-
plished, including aryl chloride 37, imidazole 38, quinoline 42,
quinazoline 43, and urea 44. Notably, tertiary amines (40 and
42), often present in biologically active substances to modulate
pharmacokinetic properties but typically susceptible to SET
oxidation with traditional photoredox catalysts, can be
accessed, albeit in low yields.34
Figure 1. Comparison of two- and one-electron strategies to forge
BCP−aryl cross-coupling products.
shortcomings, we envisioned employing bench stable,
commercially available BCP carboxylic acid feedstocks under
mild, Ni-catalyzed photochemical conditions.16
The initial goal was to use carboxylic acids directly in Ni/
photoredox dual cross-coupling. Encouragingly, we established
suitable conditions for the decarboxylation of a BCP
carboxylate and verified that the resultant BCP radical engages
in defluorinative alkylation with a trifluoromethyl-substituted
alkene (Scheme S1A of the Supporting Information).
However, adapting these conditions to Ni-catalyzed C−C
bond formation with 4-bromobenzonitrile failed to generate
the desired arylated BCP product.
Under dilute reaction conditions (0.025 M instead of 0.1
M), the corresponding BCP aryl ester was observed exclusively
(Scheme S1B of the Supporting Information). This result can
be rationalized by the high s character of the BCP−carboxylate
bond (∼sp2.1),6 resulting in a slower rate of decarboxylation,
thus favoring an energy-transfer-dependent C−O coupling.17,18
These results motivated us to investigate the activation of
BCP−N-(acyloxy)phthalimide RAEs, bench-stable solids that
are readily prepared from the corresponding carboxylic acids
via a quantitative Steglich esterification. These derivatives
undergo decarboxylative radical fragmentation upon single-
electron reduction19 through photochemical strategies that are
unavailable to the parent carboxylic acids.20 In this vein, our
group recently reported the nickel-catalyzed cross-coupling of
primary- and secondary alkyl RAEs with (hetero)aryl halides
using Hantzsch ester (HE) as a potent organic photo-
reductant.20 The intermediacy of a photoactive electron
donor−acceptor (EDA) complex21−25 was envisioned to
facilitate the generation and subsequent functionalization of
BCP radicals in a Ni-catalyzed cross-electrophile paradigm,
bypassing the need for preformed carbon nucleophiles as well
as electron transfer events from exogenous photoredox
catalysts. In addition, the developed protocol would provide
a low barrier for practical implementation in medicinal
chemistry settings.
To lend evidence for the intermediacy of an EDA complex,
we measured ultraviolet/visible (UV/vis) absorption spectra
for individual reaction components and mixtures thereof
(Figure 2B). Although the RAE (violet line) and HE (golden
line) absorb in the visible light region, they undergo a
bathochromic shift (blue line) when combined, indicating the
presence of charge-transfer aggregates. Indeed, the color
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a
Scheme 1. Cross-Coupling Scope: Evaluation of BCP RAEs and (Hetero)aryl Bromides
a
Values refer to isolated yields. Unless otherwise noted, reactions were performed using ArBr (1 equiv, 0.5 mmol), RAE (1.5 equiv, 0.75 mmol),
HE (2 equiv, 1.0 mmol), Ni(dtbbpy)Br2 (20 mol %, 0.10 mmol), NaHCO3 (4 equiv, 2.0 mmol), and dry, degassed DMA (5.0 mL). Irradiation was
performed at room temperature using a 390 nm Kessil lamp with fan cooling. For Med-Chem Informer Bromides: ArBr (1 equiv, 0.25 mmol), RAE
(1.5 equiv, 0.38 mmol), HE (2 equiv, 0.5 mmol), Ni(dtbbpy)Br2 (20 mol %, 0.05 mmol), NaHCO3 (4 equiv, 1.0 mmol), and dry degassed DMA
b
(2.5 mL). The reaction was performed using 3.3 mmol of ArBr (1.0 g).
change is apparent to the naked eye (Figure 2A). The
association constant of the EDA complex and analysis via Job’s
method demonstrated a 1:1 molar stoichiometry (panels C and
D of Figure 2).
furnish the cross-coupled product. Finally, photoexcited
Hantzsch ester reduces NiI to the catalytically active Ni0
species to close the cycle (Figure 3).
In conclusion, we have established a general route toward
the synthesis of functionalized bicyclo[1.1.1]pentanes through
Ni-catalyzed C(sp3)−C(sp2) bond formation enabled by
photoactive EDA complex activation. The developed cross-
electrophile protocol evades the need for expensive transition-
metal-based photoredox catalysts, preformed organometallics
or boronate partners, and stoichiometric metal reductants.
Under this photochemical paradigm, the generation of BCP
radicals through direct visible-light excitation followed by
subsequent cross-coupling with diverse (hetero)aryl halides is
feasible. The commercial availability of carboxylic acids,
With these results and with insight from our previous
report,20 we propose the following mechanism. Visible light
excitation of the EDA complex triggers a single-electron
transfer (SET) event from HE to the RAE, which fragments to
generate phthalimidate, CO2, and BCP radical III. This BCP
radical is then captured by NiII oxidative addition complex II.
Alternatively, the low-valent Ni0 complex I could intercept
BCP radical III and then undergo subsequent oxidative
addition with the aryl bromide. Both pathways lead to NiIII
intermediate IV, which undergoes reductive elimination to
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Figure 2. (A) Visual appearance of individual reaction components and mixtures thereof. (B) UV/vis absorption spectra measured in DMA (0.1
M). Aryl bromide, 4-((4-bromophenyl)sulfonyl)morpholine; RAE, 1,3-dioxoisoindolin-2-yl bicyclo[1.1.1]pentane-1-carboxylate; Ni complex,
Ni(dtbbpy)Br2; and HE, diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. (C) Benesi−Hildebrand plot.32 (D) Job plot33 for a mixture
of RAE and HE (0.2 M).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01558.
Preparation of starting materials, optimization of cross-
coupling and control studies, characterization data for
products [nuclear magnetic resonance (NMR), infrared
(IR), and mass spectrometry (MS)], mechanistic
studies, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Anais Jolit − Medicinal Chemistry Department, Neuroscience
Discovery Research, AbbVie Deutschland GmbH & Co. KG,
67061 Ludwigshafen, Germany; orcid.org/0000-0001-
9810-9474; Email: anais.jolit@abbvie.com
Gary A. Molander − Roy and Diana Vagelos Laboratories,
Department of Chemistry, University of Pennsylvania,
Figure 3. Proposed cross-coupling mechanism.
Philadelphia, Pennsylvania 19104-6323, United States;
orcid.org/0000-0002-9114-5584; Email: gmolandr@
sas.upenn.edu
Authors
(hetero)aryl bromides, and HE enables the rapid assembly of
diverse scaffolds. In addition, the mild reaction conditions
facilitate late-stage modification of drug-like molecules with
high functional group tolerance. Key spectroscopic studies
highlight the necessity for EDA photoactivation for efficient
BCP radical generation and subsequent functionalization.
Viktor C. Polites − Roy and Diana Vagelos Laboratories,
Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323, United States
Shorouk O. Badir − Roy and Diana Vagelos Laboratories,
Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323, United States
Sebastian Keess − Medicinal Chemistry Department,
Neuroscience Discovery Research, AbbVie Deutschland
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GmbH & Co. KG, 67061 Ludwigshafen, Germany;
orcid.org/0000-0002-0791-6877
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01558
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support provided by
NIGMS (R35 GM 131680 to Gary A. Molander). Shorouk O.
Badir is supported by the Bristol-Myers Squibb Graduate
Fellowship for Synthetic Organic Chemistry. The National
Science Foundation (NSF) Major Research Instrumentation
Program (Award NSF CHE-1827457), the National Institutes
of Health (NIH) Supplement Awards 3R01GM118510-03S1
and 3R01GM087605-06S1, and the Vagelos Institute for
Energy Science and Technology supported the purchase of the
NMRs used in this study. The authors thank Dr. Charles W.
Ross, III (UPenn) for mass spectral data. Access to a UV/vis
spectrophotometer was provided by the Petersson laboratory
(UPenn). The authors thank Kessil for the donation of lamps.
AbbVie provided the BCP building blocks and contributed to
the design, experiments, and financial support for this research.
AbbVie participated in the interpretation of data, writing,
reviewing, and approving the publication. The authors thank
the following AbbVie employees for their assistance: Dr.
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