Nickel-Catalyzed Photoredox-Mediated Cross-Coupling of Aryl Electrophiles and Aryl Azides

Article abstract of DOI:10.1021/acscatal.8b02954

Medicinally relevant diarylamines are prepared through a photoredox-mediated dual catalytic nickel/ruthenium system from aryl azides and aryl electrophiles. Photoreduction of the aryl azide is proposed to proceed through an arylnickel-azide complex, which upon reduction and loss of nitrogen, generates a nickel(III) species capable of facile reductive elimination to afford the desired C-N bond formation. A variety of functionalized (hetero)aryl electrophiles are shown to participate in the coupling, including iodides, bromides, chlorides, and triflates. The reactions are simple to set up and are performed under ambient conditions, without the exclusion of oxygen or moisture.

Full text of DOI:10.1021/acscatal.8b02954

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Letter
Nickel-Catalyzed Photoredox-Mediated Cross-
Coupling of Aryl Electrophiles and Aryl Azides
Mikhail O. Konev, T. Andrew McTeague, and Jeffrey W. Johannes
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02954 • Publication Date (Web): 30 Aug 2018
Downloaded from http://pubs.acs.org on August 30, 2018
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ACS Catalysis
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Nickel-Catalyzed Photoredox-Mediated Cross-Coupling of Aryl Elec-
trophiles and Aryl Azides
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Mikhail O. Konev*, T. Andrew McTeague, Jeffrey W. Johannes*
Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Boston, Massachusetts 02451, US
KEYWORDS. Photoredox catalysis, nickel catalysis, cross-coupling, C–N bond formation, synthetic methods
ABSTRACT: Medicinally-relevant diarylamines are prepared through a photoredox-mediated dual catalytic nick-
el/ruthenium system from aryl azides and aryl electrophiles. Photoreduction of the aryl azide is proposed to proceed
through an arylnickel-azide complex, which upon reduction and loss of nitrogen, generates a nickel(III) species capable of
facile reductive elimination to afford the desired C–N bond formation. A variety of functionalized (hetero)aryl electrophiles
are shown to participate in the coupling, including iodides, bromides, chlorides, and triflates. The reactions are simple to set
up
and
are
run
under
ambient
conditions
without
exclusion
of
oxygen
or
moisture.
Diarylamines are a ubiquitous and privileged scaffold in
functional materials, agrochemicals, and pharmaceuticals.1
For example, they act as a prominent hinge binding motif
in the context of kinase inhibition.2 While a variety of
methods to access these manifolds exist,3 many tend to be
capricious, particularly when applied to complex sub-
strates.4 In an effort to improve the reliability of these
transformations, recent interest in this area has focused on
the development of alternative reaction manifolds which
employ photoredox/transition metal dual catalysis for the
generation and utilization of anilino radicals to achieve N-
arylation of anilines.5,6 While these methods provide good
yields for a variety of substrates and are tolerant of various
functionality, significant substrate dependence on coupling
efficiency has been observed. For example, in our previ-
ously published protocol, m-toluidine coupled with 5-
iodopyrimidine in high yields but the corresponding reac-
tion using p-toluidine did not afford the desired product.7
Additionally, employing more complex heterocycles re-
sults in either diminished yields or no formation of the
desired product. Owing to the limitations of the currently
available protocols, we sought to develop a mild, functional
group tolerant, and mechanistically distinct method for the
synthesis of diarylamines to expand the scope of these
reactions to include complex substrates. Herein we report
a nickel/photoredox dual catalytic system for the synthesis
of diarylamines using aryl azides.
subsequent reductive elimination would yield the desired
diarylamine (Scheme 1, b). In contrast to our previously
published work, the hypothesized pathway relies on an
initial reductive, rather than an oxidative, quenching
mechanism to generate the anilino radical. As such, a less
strongly oxidizing photocatalyst can be utilized, potentially
further expanding the functional group and substrate
compatibility of the reaction and allowing for selective N-
arylation of azides over free anilines.
Scheme 1. a) Photoredox-mediated reduction of az-
ides. b) Initial hypothesis of radical trapping by a nick-
el-oxidative addition complex. c) Current mechanistic
hypothesis of photoredox aminations of aryl electro-
philes with aryl azides or anilines.
Inspired by recent work from the Liu group (Scheme 1,
a),8 we envisioned the generation of anilino radicals
through a photoredox-mediated reduction of aryl azides
could be utilized for our desired coupling. The proposed
pathway begins with an initial photoexcitation of
a
RuII(bpy)3Cl2 catalyst which is subsequently reduced by a
sacrificial amine additive to generate a highly reducing
RuI(bpy)3Cl2 intermediate. This species can in turn reduce
an aryl azide to the corresponding radical anion which
upon protonation and loss of N2 affords anilino radical 2.
Trapping of 2 by a nickel-oxidative addition complex and
With the envisioned pathway in mind, we began our in-
vestigation by employing reaction conditions analogous to
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cluding pyrazine 13, and both 2- and 5-substituted pyrim-
Page 2 of 6
those reported by Liu. Gratifyingly, when using
Ru(bpy)3Cl2 as photocatalyst, diisopropylethylamine
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a
idines (entries 11 and 12). More electron-rich azole- and
thiazole-derived electrophiles were competent coupling
partners, including carbazole 17, indazole 18, imidaz-
opyridine 19, thiophene 14, and benzothiazole 20. Halides
bearing synthetically useful functional groups such as ke-
tone, ether, ester, cyano, trifluoromethyl, and boronate
ester were all well tolerated. Gratifyingly, unprotected N-H
groups remained unreactive towards N-arylation, tolerat-
ing free carbazole 17 and unprotected primary aniline 22.
In addition to aryl iodides as electrophiles, aryl bromides,
chlorides, and triflates all participate well in the reaction.
Aryl iodides served as the preferential site of oxidative
addition in substrates which possess multiple sites of reac-
tivity (entry 9), allowing for site selective couplings to be
carried out on functionally dense substrates.
(DIPEA) as a stoichiometric reductant, NiBr2•glyme as the
nickel source, bathophenanthroline (Bphen) as a ligand,
and Hantzsch ester, we observed complete conversion of
the azide to the desired diarylamine product in near quan-
titative yield without the need of an inert environment or
degassing of the reaction mixture (Table 1, entry 1).
Table 1. Control experiments for the desired coupling.
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Table 2. Scope of aryl electrophile coupling partner.
aReaction mixture sparged with N2 for 5 minutes. Yields determined by 1H NMR
using PhTMS as an external standard.
As demonstrated by several control experiments, both
light and nickel catalyst are essential for product formation
(Table 1, entries 2 and 3). Interestingly, trace amount of
product was observed in the absence of Ru(bpy)3Cl2 (entry
4), suggesting that the nickel complex itself can also serve
as a photocatalyst,9 albeit to a much lower extent. Although
Hantzsch ester can act as a reducing agent for the catalyst,
leading to small quantities of product (entry 5), the yield of
the reaction is greatly improved in the presence of DIPEA
as a sacrificial electron donor (entry 6). Hantzsch ester,
however, was shown to be beneficial to the reaction, re-
sulting in both higher yields and a cleaner reaction profile
overall. Through extensive optimization, BPhen and DMF
were determined to provide optimal yields, although sev-
eral additional solvents and ligands are also well tolerated
under the reaction conditions.10 Similar to previous re-
ports, in the absence of ligand, the reaction affords product
in slightly diminished yield (entry 7).5,6 A Ni(0) precatalyst
proved to be competent in the reaction, suggesting the
intermediacy of Ni(0) in the catalytic cycle (entry 8). Grati-
fyingly, good yields of product can also be obtained with a
lower photocatalyst loading (entry 9), and with one equiv-
alent of aryl electrophile for scenarios when it is a precious
coupling partner (entry 10).
The reaction is similarly tolerant of a wide array of
arenes and substitution patterns on the azide coupling
partner. Both electron-neutral and electron-rich azides
participate in the coupling, affording simple phenyl-
derived diarylamines in good yields (entries 25-27). Steric
hinderance around the azide was not detrimental to the
reaction, affording mesityl-derived product 25 in high
yield. Delightfully, a range of azido-substituted heterocy-
cles are also competent coupling partners. Both N-alkyl
and N-aryl azidopyrazoles are efficiently coupled (entries
28 and 29),11 and related 5-azidoindazole reacted well to
afforded product 38 in high yield. Azine substrates includ-
Upon identifying suitable reaction conditions for the
parent system, we investigated the scope of aryl electro-
philes for this transformation (Table 2). In addition to
simple arene systems, a variety of polyfunctional heteroar-
yl electrophiles perform well under the developed condi-
tions. Pyridines bearing the electrophile in any position
afforded coupling products in good yields (entries 8, 9, 21,
22). Various diazines participated well in the coupling in-
ing
3-azidopyridine,
8-azidoquinoline,
and
4-
azidoisoquinoline also afforded the desired products in
good yields (entries 34, 31, 33). Distal heterocycles includ-
ing pyridine-containing 31, thiazole 35, and triazole and
oxazolidinone 36 did not diminish yields of the coupling.
Furthermore, substrates containing synthetically useful
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functional groups including sulfonamide, aryl fluoride, aryl
chloride, aryl ether, and amides, were well tolerated. Addi-
tionally, a phenylalanine derived azide performed well in
the reaction affording product 39 in high yield, potentially
providing a new straightforward method for the function-
alization of peptides.
substrate, however, product could arise from either sub-
strate presuming the in situ formed aniline is able to be
oxidized by the photocatalyst as is observed in the compe-
tition experiments. Although selectivity in this example is
moderate, enhanced azide coupling selectivity would be
expected for electronically differentiated substrates in
which the competitive aniline is unable to be oxidized by
the photocatalyst.
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Table 3. Scope of aryl azide coupling partner.
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Scheme 2. Competition study.
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Yields determined by 1H NMR using 1,3,5-trimethoxybenzene as an external
standard. Dotted curves indicate product arising from ethylated starting mate-
rial.
In the envisioned pathway (Scheme 1, b), initial azide
reduction and subsequent fragmentation must occur to
generate the desired anilino radical which must be of suffi-
cient lifetime to be trapped by a Ni(II) oxidative addition
complex. Particularly electron deficient azides, such as 44,
are rapidly reduced and the resulting highly unstable ani-
lino radical is quickly quenched by an H-atom donor lead-
ing to formation of the corresponding aniline which does
not undergo further reaction (Scheme 3, a).12 Consistent
with this hypothesis, when a stoichiometric quantity of a
preformed Ni(II) oxidative addition complex was utilized,13
thereby increasing the effective molarity of the catalyst
species, the desired product was formed in modest yield
(Scheme 3, b), suggesting direct reaction of the azide with
complex 47 is necessary for product formation.
Under the developed conditions, both aryl electrophiles
and azides exhibit broad functional group tolerance. In
particular, functional groups amenable for orthogonal
functionalization performed well. An additional hallmark
of the reaction is the range of heterocycle containing sub-
strates which provide synthetically useful yields of a di-
verse array of complex diarylamines. Indeed, when directly
compared with previous methods, the developed condi-
tions provided superior yields, displaying the increased
tolerability of the developed reaction.
Furthermore, we performed preliminary studies to elu-
cidate the reaction mechanism and rule out alternative
pathways. One alternative to the proposed mechanism
involves full reduction of the aryl azide to the correspond-
ing aniline and subsequent oxidation/deprotonation to the
anilino radical intermediate. In order to investigate this
possibility further, a direct competition study was per-
formed to compare the relative reactivities of azides and
anilines. Interestingly, when equimolar amounts of 4-
azidotoluene and p-ethylaniline are used in the reaction,
the azide coupling product is formed preferentially
(Scheme 2). When employing the switched substrates (1-
azido-4-ethylbenzene 41 and p-methylaniline 42), 41 re-
acted slightly faster than 42, although yields of the prod-
ucts were similar. While it appears that p-methylaniline
reacts faster than p-ethylaniline, the obtained data sug-
gests that direct coupling of the azide is more efficient than
the coupling of the analogous aniline. For an individual
Scheme 3. Reactions with electron deficient azide.
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Based on previous reports, another mechanism involv-
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In conclusion, we have developed an efficient method for
the cross-coupling of aryl azides and aryl electrophiles for
the synthesis of functionally diverse diarylamines, enabled
by a dual catalytic Ni/Ru photoredox system. Benefits of
the reaction include an operationally simple protocol, mild
reaction conditions, and a significant improvement of sub-
strate and functional group tolerance compared to previ-
ously published methods. Finally, this protocol appears to
proceed through an alternative reaction manifold which
allows for selective N-arylation of azides over free N-H
bonds.
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4
5
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ing energy transfer to generate an aryl nitrene can also be
envisoned.14 If such a mechanism were operative, subjec-
tion of substrate 48 to the reaction conditions would be
expected to form product 50 through initial nitrene for-
mation and subsequent C=C insertion (Scheme 4). Moreo-
ver, if an anilino radical of sufficient lifetime to combine
with a nickel species was generated, products originating
from a radical 5-exo-trig cyclization would be expected
(e.g. 51).15 Surprisingly, however, only the corresponding
diarylamine product 49 was observed. Furthermore, when
subjecting the corresponding aniline to the standard con-
ditions, a complex mixture of products were observed with
only a trace amount of the desired diarylamine (see SI for
details). Although further studies are necessary to eluci-
date additional mechanistic details, these results, in con-
cert with the competition and stoichiometric experiments,
suggest a mechanism in which the azide is coordinated to
the nickel oxidative addition complex as the key interme-
diate.16 Subsequent single electron reduction and loss of N2
generates a nickel (III) intermediate poised for reductive
elimination as shown in the proposed mechanism outlined
above (Scheme 1, c).
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ASSOCIATED CONTENT
Supporting Information. General experimental details, pro-
cedures, and characterization data for all products are includ-
ed. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
* mikhail.konev@astrazeneca.com
* jeffrey.johannes@astrazeneca.com
Scheme 4. Experiment to rule out nitrene and radical
pathway.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Professor Tehshik Yoon (UW-Madison) for helpful
discussions and Sharon Tentarelli (AstraZeneca) for HRMS
analysis.
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10. A variety of alternative solvents and ligands were tolerated
under the reaction conditions, albeit with lower yields of product.
Other competent solvents include: DCM, MeOH, DMA, and MeCN.
Preformed Ni(II) catalysts including NiCl2dppf, NiCl2(PCy3)2,
NiCl2dppe, NiCl2dppp afforded modest yields of product. Addi-
tionally, a variety of aromatic nitrogen-containing ligands includ-
ing bipyridyl and phenanthroline derivatives were tolerated.
11. While pyrazole derived product 28 is formed in good yields
from the 4-azido-1-benzylpyrazole starting material, switching of
coupling partners (using 4-iodo-1-benzylpyrazole and 4-
azidotoluene) did not yield any of the desired product (see SI for
details).
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