Hydroarylation of Arenes via Reductive Radical-Polar Crossover

Article abstract of DOI:10.1021/jacs.0c03926

A photocatalytic system for the dearomative hydroarylation of benzene derivatives has been developed. Using a combination of an organic photoredox catalyst and an amine reductant, this process operates through a reductive radical-polar crossover mechanism where aryl halide reduction triggers a regioselective radical cyclization event, followed by anion formation and quenching to produce a range of complex spirocyclic cyclohexadienes. This light-driven protocol functions at room temperature in a green solvent system (aq. MeCN) without the need for precious metal-based catalysts or reagents or the generation of stoichiometric metal byproducts.

Full text of DOI:10.1021/jacs.0c03926

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Hydroarylation of Arenes via Reductive Radical-Polar Crossover
Autumn R. Flynn, Kelly McDaniel, Meredith Hughes, David Vogt, and Nathan T. Jui
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c03926 • Publication Date (Web): 07 May 2020
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Hydroarylation of Arenes via Reductive Radical-Polar Crossover
Autumn R. Flynn,‡ Kelly A. McDaniel,‡ Meredith E. Hughes, David B. Vogt, Nathan T. Jui*
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Department of Chemistry and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, United States
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ABSTRACT: A photocatalytic system for the dearomative hydroarylation of benzene derivatives has been developed. Using a
combination of an organic photoredox catalyst and an amine reductant, this process operates through a reductive radical-polar
crossover mechanism where aryl halide reduction triggers a regioselective radical cyclization event, followed by anion formation and
quenching to produce a range of complex spirocyclic cyclohexadienes. This light-driven protocol functions at room temperature in a
green solvent system (aq. MeCN) without the need for precious metal-based catalysts or reagents or the generation of stoichiometric
metal byproducts.
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Aromatic petroleum resources (i.e. benzene, toluene,
xylenes) serve as crucial elementary synthetic precursors, and
the manipulation of petrochemical derivatives, such as aryl
halides in cross-coupling reactions, is essential to the
production of agrichemicals and pharmaceuticals.1–4 Given the
three-dimensional nature of enzymatic architecture, methods
that deliver stereochemically-dense scaffolds from readily
available arenes are highly attractive,5,6 but overcoming
thermodynamic aromatic stabilization energy7 (ASE) remains a
critical challenge. High-pressure hydrogenation,8 Birch
reduction/alkylation,9,10 and enzymatic oxidation11,12 have
emerged as powerful tools for dearomatization, as have an array
of reactions that utilize phenols,13,14 photochemical arene
cycloaddition,15,16 or other catalytic methods17,18 (these general
strategies are depicted in Figure 1). Here, we describe a
complementary photochemical approach to dearomative
functionalization that operates through a highly-selective
radical hydroarylation pathway.
Our group has developed a series of photocatalytic
hydroarylation systems that selectively engage a diverse series
of olefinic substrates.19 A key element of this program arises
from the understanding that catalytic single electron reduction
can be generally employed to deliver highly reactive aryl
radicals from the corresponding halides. Chemoselective olefin
addition followed by reductive radical-polar crossover gives
rise to the hydroarylation products with excellent regiocontrol,
a hallmark characteristic of Giese-type processes.20 We
questioned whether this mechanistic paradigm could be applied
to aromatic substrates, where unactivated arenes would
generally react to afford aryl cyclohexadiene derivatives.
Because a vast array of olefin functionalization protocols has
been developed,21 this strategy would be attractive for the
synthesis of highly-complex cyclohexane derivatives.
Although aromatic systems experience significant
thermodynamic stabilization, aromaticity is routinely broken
(in a transient sense) in aromatic substitution pathways that
operate through anionic,23 cationic,24 and radical
intermediates.25 Indeed, following arene functionalization (the
bond-forming event) within each of these mechanisms,
aromaticity is rapidly restored. Within the radical pathway (i.e.
Minisci radical arylation), this event typically involves an
oxidation/deprotonation sequence. To circumvent this
thermodynamic well, we envisioned a reductive radical-polar
crossover mechanism where rapid interception of transient
radical species would irreversibly deliver the corresponding
anions. To evaluate the feasibility of this proposal, we
considered the dearomative cyclization of linear diaryl
compounds. If successful, this approach would afford
This proposal is supported by early work by Crich and
Tanaka that implicates aryl radicals as potentially valuable
intermediates for dearomatization.22 However, the dependence
of classical methods on toxic reagents (i.e. Bu3SnH/RSeOH or
SmI2/HMPA) coupled with the requirement that the arene
acceptor be used in solvent quantities and/or unpredictable
reaction outcomes severely limits the utility of these processes.
Accordingly, a catalytic system that reliably and predictably
performs dearomatization of unactivated aromatics would be
valuable, particularly if it was safe (no hazardous or toxic
reagents), economical (e.g. no precious metals), and sustainable
(e.g. no stoichiometric metal waste, green solvent). Most
importantly, the ideal strategy would reliably act on a range of
aromatics, regardless of the substitution pattern,
nucleophilicity, or ASE of a given substrate.
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Figure 1. Dearomative radical hydroarylation strategy
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2
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A. Mechanistic blueprint for dearomative hydroarylation
O
O
O
5-exo
cyclization
protonation
O
I
O
e–
– I–
e–
•
H2O
•
5
H
6
7
aryl iodide 1
aryl radical 2
3
4
desired 1,4-diene 5
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B. Generation of reductant via reductive quenching of organic photoredox catalyst with Hünig’s base as stoichiometric reductant
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Ph
Ph
i-Pr
i-Pr
Ph
Ph
N
N
N
F
intersystem
crossing
NC
N
CN
Et
NC
N
CN
S1
T1
Ph
Ph
Ph
Ph
N
photo-
reductive
N
Ph
F
Ph
Ph
Ph
excitation
quenching
e–
E1/2(P1/P1•–) = – 1.59 V vs SCE
P1 (Adachi-type dye)
C. Potential pathways for aryl radical intermediate 2
D. Reaction outcomes under reductive conditions
O
OR
c
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b
8
O
a
d
O
H
O
•
6
5
aryl radical 2
Figure 2. Design of dearomative spirocyclization reaction and support for each component. (A) Proposed arene hydroarylation
through radical-polar crossover (B) Generation of a catalytic reductant through reductive quenching with Hünig’s base. (C)
Demonstrated reaction pathways for aryl radical 2. (D) Comparison of previously demonstrated reaction conditions with those
described here.
spirocyclic cyclohexadienes, a molecular scaffold that is
present in small molecules with diverse biological activities.
For example, the spiro-fused dihydro-benzofuran, -indoline,
and -oxindoles (Figure 1) are critical structural elements in
modulators of cancer and obesity-associated targets.26–29
and facile reductive quenching with i-Pr2NEt. Stern-Volmer
quenching studies revealed that this quenching mechanism is
fast under these conditions (KSV = ~1700), giving rise to the
ground state reductant (P1•–, E1/2° = –1.59 V vs. SCE). This
protocol for catalytic reductant generation is appealing, in part,
because it utilizes inexpensive and readily accessible
components to perform challenging substrate reductions under
mild conditions.
We envisioned the catalytic blueprint shown in Figure 2A,
where reduction of aryl iodide 1 would deliver aryl radical 2 via
rapid mesolytic cleavage. Cyclization through the 5-exo-trig
mode would generate cyclohexadienyl radical 3 which, after
reduction (E1/2° = –1.34 V vs. SCE, see SI for details), would
give rise to dienyl anion 4. Finally, a protonation event would
deliver the desired dearomatized spirocycle 5. Crucial to this
design would be the identification of an effective system where
constant generation of reductant would allow for this two-
electron sequential reduction pathway. We found that in
aqueous acetonitrile, several photocatalyst/stoichiometric
reductant pairs produced the desired product (see SI for details).
The most generally effective system involves the Adachi-
type30,31 donor-acceptor cyanoarene 3DPAFIPN (P1, 5 mol%),
i-Pr2NEt (Hünig’s base, 3 equiv), and commercial 15 W blue
LEDs. As shown in Figure 2B, this proposal involves
photoexcitation of P1, which undergoes intersystem crossing
While radical intermediate 2 has been accessed before, these
systems are known to fall down a number of competing reaction
pathways (a–d, illustrated in Figure 2C). For example,
reduction of aryl iodide 1 by SmI2/HMPA afforded a small
amount of the desired product, but hydrodehalogenation was
the predominant pathway (pathway a, giving rise to 6), and
reaction outcome was largely dictated by arene substitution
patterns.22 Formation of 2 by tributyl tin radical led to a mixture
of arylation products 7 and 8, which result from rearrangement
(pathway b) and fragmentation (pathway c), respectively.32 In
contrast, treating 1 with the photochemical conditions described
here afforded the desired dearomatization product with
excellent selectivity (via pathway d). We attribute the high
selectivity under these conditions to the controlled generation
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of reductant, such that electron transfer to the aryl halide
substrates can be performed by a catalytic species with a tunable
concentration. This effectively suppresses undesired
hydrodehalogenation
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Table 1. Photocatalytic Radical Hydroarylation of Aromatics: Scope of Spirocyclic Productsa
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aReaction conditions: (het)arylhalide–arene (1 equiv), P1 (5 mol%), i-Pr2NEt (3 equiv), MeCN:H2O (1:1 v/v, 15 mL/mmol), blue LEDs, 23
°C, 16 h. Isolated yields shown. bReaction conducted with 10 equiv i-Pr2NEt. c4:1 d.r., isolated yield of major diastereomer shown. d1.8:1
d.r., isolated yield of combined diastereomers shown; para-chlorobenzene dearomatization was followed by chloride solvolysis.
through pathway a as well as eliminating undesired byproducts
from inefficient trapping of radical intermediate 3 (pathways b
and c) through rapid radical-polar crossover.
membered spirocycles (14, 46%). Alteration of the electronic
properties of the aryl radical precursor was also tolerated;
substrates containing either electron donating substituents (15,
16) or withdrawing substituents (17, 18) reacted to afford the
corresponding products (54–84%). Radicals formed at the 3-
position of pyridines also cyclized, yielding hydropyridylation
products 19 and 20 in 77% and 89% yield, respectively.
As illustrated in Table 1, this light-driven reaction effectively
transforms a range of (hetero)aryl radical precursors with
tethered aromatic radical acceptors to undergo dearomative
spirocyclization. For example, the tether can be varied to give
indoline derivatives
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and 10 (65% and 79% yield,
The acceptor arene is also tolerant of substitution–donating
substituents at the ortho, meta, or para positions dearomatize to
give spirocycles 21–24 in 62–87% yield. A multi-substituted
arene smoothly dearomatized to give 1,4-cyclohexadiene 25,
which possesses two differentially reactive alkenes, in 68%
respectively). In addition, N-alkylated amide tethers (11, 55%)
and ether linkers (12, 72%) are good substrates under these
conditions. This allows for further elaboration to give tethers
that are either substituted (13, 50%) or extended to give 6-
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isolated yield. Interestingly, a quinoline substrate reacted to
Page 4 of 7
To illustrate the value of this dearomative hydroarylation, we
applied it to the preparation of the spirocyclic cyclohexane 35
that was developed by Merck as an NPY Y5 receptor
antagonist. While attempted dearomatization of methyl
benzoate or benzonitrile substrates resulted in linker
fragmentation (arising from preferential reduction of the arene
acceptor, rather than aryl radical formation, see SI for details),
reaction of benzoic acid substrate 33 was very efficient. Here,
formation of the corresponding ammonium benzoate ensured
chemoselective reduction of the iodoaniline moiety, which
ultimately delivered spirocyclic diene 34 in excellent yield
(95%), as a 1:1 mixture of diastereomers. As indicated in Figure
4, the resulting acid was subjected to sequential hydrogenation
1
2
3
4
5
6
7
8
give a 5,8-dihydroquinoline in excellent yield (26, 94%). This
is noteworthy because quinoline systems undergo dearomative
functionalization preferentially in the pyridyl subunit, here we
have disrupted the aromaticity of the canonically more stable
aryl ring of the system (ASE = 36 kcal/mol for benzene, 27
kcal/mol for pyridine).10 Halogenation was tolerated at the ortho
(27, 70%; 30, 83%) and meta positions (28, 57%; 31, 83%)
without any competitive dehalogenation observed, where the
resulting vinylic halogens are effective handles for further
reactivity. When acceptor arenes with para-halogens were
subjected to these conditions, they underwent the dearomative
spirocyclization as expected; however, the product obtained
from the para-chlorotoluene derivative was alcohol 29 (85%),
which presumably arises from solvolysis of the doubly allylic
halide products. This reactivity provides a direct alternative to
phenol dearomatization and reduction to give allylic alcohols.
A 3,5-difluorinated arene dearomatized under these conditions
to spirocyclic product 32 (64%) without competitive observable
defluorination. While the standard conditions were generally
effective across a range of substrates, conversion of a few
substrates (corresponding to products 13, 18, and 24) was
slower. In these cases, low conversion could be easily addressed
by increasing equivalents of base (10 equiv amine).
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and
amidation
with
4-aminobiphenyl
(using
propanephosphonic acid cyclic anhydride, T3P) to deliver the
diastereomeric corresponding cyclohexane carboxamides target
35 in 82% yield (ca. 41% of the more active cis-isomer). Studies
to further evaluate the utility of this mechanistic system are
underway.
O
SO2Me
N
standard
MeO2S
OH
N
conditions
33
95% yield, 1:1 dr
34
I
CO2H
This catalytic dearomatization approach is unique, in part,
because it has the ability to execute discrete electron transfer
events with precision that is not possible under alternative
reduction paradigms. In addition to the approaches that were
described above, bulk electrolysis represents a classical method
for performing net-reductive (or net-oxidative) transformations.
However, because further reduction of aryl radicals to the
corresponding anions is rapid near the surface of the cathode
(and more facile than aryl halide reduction),33 radical reactivity
is difficult to harness under electrochemical conditions. Indeed,
a brief survey of conditions (see SI for details) revealed
hydrodehalogenation, rather than dearomatization, as the
primary pathway for the substrates of this study, further
illustrating the power of the described photoredox protocol.34
(2-steps from commercial)
H2, Pd/C
EtOH, quant.
NPY Y5 antagonist 35
SO2Me
Ph
N
SO2Me
N
Ph
H2N
T3P, i-Pr2NEt
N
82% yield
H
O
OH
(ca. 41% cis-isomer)
O
Figure 4. Direct dearomative approach to spiroindoline 35.
In summary, this spirocyclization operates under a distinctive
reductive manifold where a photocatalyst (fueled by light and a
stoichiometric amine reductant) delivers reducing electrons that
deliver highly reactive aryl radicals. Following dearomative C–
C bond formation, the resulting spirocyclic radical species is
effectively intercepted via reductive radical-polar crossover,
prohibiting undesired radical pathways. Finally, protonation
occurs with high regioselectivity to afford the observed 1,4-
diene systems. This mild and selective protocol for dearomative
hydroarylation delivers highly substituted, complex molecules
from aromatic precursors in a single step.
Selectivity for the 1,4-cyclohexadienyl product in our
photochemical system is in accord with both previous studies
on this type of anionic intermediate35 and calculations using
density functional theory (DFT). In more specific terms, the
calculated natural bond orbital (NBO), depicted in Figure 3, that
houses the lone pair suggests that the diallyl anion is the
dominant resonance contributor (see SI for details).
Replacement of water in our system with deuterium oxide
resulted in complete (>95% by NMR) deuterium incorporation
at the indicated position (1,3-diene product was not observed),
further supporting our proposed radical-polar crossover
mechanism.
ASSOCIATED CONTENT
Supporting Information
O
The Supporting Information is available free of charge on the ACS
Publications website.
O
D2O
N
N
Experimental and computational procedures, characterization data,
and spectra (PDF).
D
DFT-
dienyl anion
HOMO
>19:1 (D:H)
AUTHOR INFORMATION
Corresponding Author
Figure 3. Computational structure of anion orbitals as a
rationale for observed regioselectivity.
* njui@emory.edu
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‡A. R. Flynn and K. A. McDaniel contributed equally to this
work; the order was assigned alphabetically.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support for this work was provided, in part, by Emory
University and the National Institutes of Health (GM129495), and
NMR data were collected under support of the National Science
Foundation (CHE-1531620). We thank Colin Swenson for his
help in collecting high resolution mass data.
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