Regioselective Radical Arene Amination for the Concise Synthesis ofortho-Phenylenediamines

Article abstract of DOI:10.1021/jacs.1c05531

The formation of arene C-N bonds directly from C-H bonds is of great importance and there has been rapid recent development of methods for achieving this through radical mechanisms, often involving reactiveN-centered radicals. A major challenge associated with these advances is that of regiocontrol, with mixtures of regioisomeric products obtained in most protocols, limiting broader utility. We have designed a system that utilizes attractive noncovalent interactions between an anionic substrate and an incoming radical cation in order to guide the latter to the areneorthoposition. The anionic substrate takes the form of a sulfamate-protected aniline and telescoped cleavage of the sulfamate group after amination leads directly toortho-phenylenediamines, key building blocks for a range of medicinally relevant diazoles. Our method can deliver both free amines and monoalkyl amines allowing access to unsymmetrical, selectively monoalkylated benzimidazoles and benzotriazoles. As well as providing concise access to valuableortho-phenylenediamines, this work demonstrates the potential for utilizing noncovalent interactions to control positional selectivity in radical reactions.

Full text of DOI:10.1021/jacs.1c05531

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Regioselective Radical Arene Amination for the Concise Synthesis of
ortho-Phenylenediamines
James E. Gillespie, Charlotte Morrill, and Robert J. Phipps*
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ABSTRACT: The formation of arene C−N bonds directly from C−H bonds is of great importance and there has been rapid recent
development of methods for achieving this through radical mechanisms, often involving reactive N-centered radicals. A major
challenge associated with these advances is that of regiocontrol, with mixtures of regioisomeric products obtained in most protocols,
limiting broader utility. We have designed a system that utilizes attractive noncovalent interactions between an anionic substrate and
an incoming radical cation in order to guide the latter to the arene ortho position. The anionic substrate takes the form of a
sulfamate-protected aniline and telescoped cleavage of the sulfamate group after amination leads directly to ortho-
phenylenediamines, key building blocks for a range of medicinally relevant diazoles. Our method can deliver both free amines
and monoalkyl amines allowing access to unsymmetrical, selectively monoalkylated benzimidazoles and benzotriazoles. As well as
providing concise access to valuable ortho-phenylenediamines, this work demonstrates the potential for utilizing noncovalent
interactions to control positional selectivity in radical reactions.
romatic amines are ubiquitous in pharmaceuticals,
agrochemicals, and natural products. Specifically, o-
give rise to mixtures of regioisomers when given a choice and
few studies have made headway in tackling this. Notable
exceptions, from Ritter and co-workers17 and Leonori and co-
workers,15b have shown that careful tailoring of the structure of
the aminium radical can result in high levels of para-selectivity
(Figure 1b). A complementary approach to para-selective
amination has been reported by Nicewicz and co-workers
whereby an electron rich arene is oxidized and trapped with a
nitrogen source.19 Strategies for achieving ortho-selective
amination using radical approaches are largely undeveloped.20
In many of the aforementioned reactions, N-centered radical
cations are proposed to be the key reactive species; to us their
charged nature presented an exciting opportunity to utilize ion-
pairing interactions between radical and substrate to exert
control over regioselectivity in the C−N bond forming step.
Furthermore, many aminium radicals bear multiple N−H
bonds, which could feasibly act as hydrogen bond donors to
interact with a suitable acceptor on the substrate. While
noncovalent interactions, including electrostatic interactions,
have been used to control regioselectivity in metal-catalyzed
arene C−H functionalization, most extensively in iridium-
catalyzed borylation,21 this approach remains largely unex-
plored in radical-based arene functionalization.20 We were
drawn to the use of cationic N−O reagents as radical
precursors, as utilized for arene amination independently by
Morandi and co-workers18a and Jiao and co-workers.18b Here
A
phenylenediamines are important intermediates for the
synthesis of a variety of heterocycles such as benzimidazoles,
1,5-benzodiazepines, benzotriazoles, and quinoxalines, as
found in numerous pharmaceuticals (Figure 1a).1 Classically,
amines are installed onto aromatic rings via electrophilic
nitration.2 However, the harsh conditions and formation of
regioisomers limit applicability. Transition-metal-catalyzed
cross-couplings have become the most established modern
methods for arylamine synthesis, but require selective
prefunctionalization of the aromatic substrate, incurring
synthetic cost.3 Many recent advances have been made in
directed transition-metal-catalyzed C−H amination of arenes.4
Several methods for ortho-selective C−H amination of aniline
derivatives have been reported, generating variously N-
substituted o-phenylenediamine derivatives, using Pd,5 Cu,6
Ru,7 Ir,8 and Co9 catalysis. While some protocols permit
subsequent manipulations to obtain the free o-phenylenedi-
amines, in practice there are limited means to obtain these
extremely useful intermediates in a concise manner.
Mechanistically distinct to these methods is electrophilic
amination proceeding via radical intermediates. While it has
long been appreciated that electrophilic aminium radical
cations react with aromatic systems,10 the forcing or
inconvenient conditions traditionally required to produce
them have hampered adoption. Recent advances have
overcome these obstacles and have seen numerous new
methods for arene amination utilizing N-centered radicals.11
Fragments such as imides,12 sulfonamides,13 amides,14 alkyl-
amines,15 pyridiniums,16 1,4-diazabicyclo[2.2.2] octane,17 and
free amines18 have been variously incorporated onto arenes.
The biggest barrier to widespread adoption of these methods is
the challenge of positional selectivity; the majority of examples
Received: May 28, 2021
Published: June 15, 2021
© 2021 The Authors. Published by
American Chemical Society
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a
Table 1. Optimization Studies
entry
solvent (ε)
aminating agent
yield
28
selectivity (o:p)
1
2
3
4
5
6
7
8
CH3CN:H2O, 2:1
TFE:H2O, 2:1
CH3CN (38)
TFE (9)
DMA (38)
EtOAc (6)
MeOH (33)
iPrOH (18)
HFIP (16)
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
4:1
4:1
>20:1
>20:1
7:1
>20:1
9:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
−
−
17:1
35
38
45
16
40
21
13
47
38
40
60 (57)
38
6
<5
68 (61)
9
10
11
12
13
14
b
15
2d
3d
16
Figure 1. Background and hypothesis.
a
Yields and ratios were determined by 1H NMR with internal
b
standard. Yield in parentheses is isolated. No iron catalyst.
an iron catalyst mediates the redox events and the
intermediacy of an unsubstituted aminium radical cation
results in free amine products. We envisaged that facile
conversion of aniline to sulfamate salt I (Figure 1c) would
install an anionic group capable of engaging in attractive
noncovalent interactions with the incoming aminium radical
cation.22 I may undergo ion exchange with the cationic radical
precursor, although this step may not be essential (I−II).
Importantly, once reduction of the N−O bond is accomplished
(II−III), the approaching aminium radical should be directed
to attack the proximal arene ortho position (III−IV) by the
anionic sulfamate group of the substrate through a
combination of electrostatic interactions and hydrogen
bonding. Following oxidation and rearomatization (IV−V),
treatment with acid would cleave the sulfamate resulting in the
ortho-phenylenediamine product VI. A concern at the outset
was that the published protocols utilize very polar solvent
mixtures: MeCN/H2O18a or TFE/H2O.18b A subsequent
detailed study from Ritter and co-workers showed that use
of hexafluoroisopropanol (HFIP) increases reactivity, through
proposed hydrogen bonding with the conjugate anions of
various intermediates.18c We reasoned that if both Coulombic
electrostatic interactions and hydrogen bonding are working in
tandem, these interactions may still be sufficient for useful
levels of selectivity, even in relatively polar solvents.
obtained in modest but encouraging yield and ortho:para
selectivity was 4:1, close to the statistical ratio of 2:1 but
showing a small bias toward the ortho position (Table 1,
entries 1 and 2). In line with our hypothesis, removing the
most polar component from these mixtures greatly improved
selectivity as in both MeCN and TFE only the ortho isomer
was observed (entries 3 and 4).
We then compared several aprotic solvents with MeCN, to
probe selectivity trends. DMA has a similar dielectric constant
to MeCN but exhibited reduced selectivity (7:1), most likely
due to its high proficiency as a hydrogen bond acceptor,
interrupting critical interactions (entry 5). Accordingly,
switching to less polar EtOAc restored excellent selectivity,
in line with our hypothesis (entry 6). For protic solvents,
MeOH, of significantly higher dielectric constant than TFE,
gave reduced selectivity (9:1, entry 7). Switching to less polar
iPrOH returned the selectivity to >20:1, albeit in low yield
(entry 8). Finally, HFIP was found to retain excellent (>20:1)
regioselectivity and give the best product yield thus far (entry
9).23 We next evaluated a series of different aminating agents
(entries 10−14) and found that the NMR yield could be
increased to 60% by tuning the substitution on the aromatic
ring, giving an isolated yield of 57% (entry 12). Product
regioselectivity was unaffected by choice of aminating agent, in
line with the proposed mechanism. In the absence of iron
catalyst, only traces of product were observed (entry 15),
We commenced our studies using the sulfamate salt derived
from aniline (1a), aminating agent 2a and FeBr2 as the catalyst
(Table 1). In both MeCN/H2O and TFE/H2O, product was
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a
Scheme 1. Scope of the ortho-Selective Amination for Transfer of NHMe
a
Main ortho:para ratio quoted is after isolation, crude ratio in parentheses. Yields are isolated. If two ortho positions available, main regioisomeric
b
ratio (r.r.) quoted after isolation, crude ratio shown in parentheses if different. Major regioisomer shown, minor indicated by (*). Product isolated
as corresponding benzimidazole.
although a more electron rich substrate gave some conversion
at higher temperature, in line with observations of Morandi
and co-workers in closely related systems (see SI).15c Of
several iron(II) sources evaluated, FeBr2 was optimal although
several reaction components could feasibly ligate iron, making
identification of the true active iron catalyst challenging. It is
important to remember that while a multitude of ionic species
may be present in solution, in addition to those explicitly
depicted in Figure 1c, as long as the crucial interactions
between substrate and incoming radical occur, then high
selectivity should be achievable. Finally, we questioned
whether an N-methylated aminating agent may enable transfer
of NHMe, allowing access to selectively monoalkylated o-
phenylenediamines.15c Pleasingly, use of 3d in place of 2d gave
the aminomethylated product with an ortho:para selectivity of
17:1 and in good isolated yield (entry 16).
First, the scope of NHMe transfer was evaluated and we
were pleased to see high levels of ortho selectivity for a range of
different aniline substrates (Scheme 1). Substrates with alkyl
groups at the 2-position were well tolerated, giving good yields
and excellent ortho selectivity (5b−5d), as were methyl and
isopropyl at the 3-position (5e, 5f). While ortho vs para
selectivity was excellent, low regioselectivity (2.9:1) between
the two distinct ortho positions was seen for 5e but improved
(5.7:1) with the bulkier isopropyl substituent (5f). An alkyne-
containing substrate (5g), one bearing an alkyl group at the 4-
position (5h) as well as multiple alkyl substituents on the ring
were also well accommodated (5i−5k). Substrates bearing
methoxy groups (5l, 5m) and difluoromethoxy groups (5n)
also worked well. In the cases where two ortho isomers were
obtained, these could be separated on silica (5l, 5n). Halides
including Br, Cl, and F could be incorporated in various
positions (5o−5s). Given that alkenes are known to undergo
aminochlorination with related aminating agents,24 we were
pleased that a substrate bearing an allyl substituent
demonstrated excellent chemoselectivity (5t). Substrates
bearing other arenes did not pose problems and only
amination on the aniline-derived ring was observed (5u−
5w). Finally, using different aminating agents we transferred
several other N-alkyl groups including N-ethyl (5x), N-propyl
(5y), N-propanenitrile (5z), and N-hexyl (5aa). Heterocyclic,
polycyclic, and substrates bearing electron withdrawing groups,
protected amines, and vinyl groups exhibited poor reactivity
(see SI for details).
We next evaluated the scope of NH2 transfer (Scheme 2).
Anilines bearing alkyl groups in the 2-position were well
tolerated (4b, 4c), giving the aminated products with excellent
ortho selectivity (>20:1 in all cases by crude NMR and when
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Scheme 2. Scope of the ortho-Selective Amination for
Transfer of NH2
Scheme 3. Telescoped Transformations to Heterocycles
a
a
Ortho:para ratio is that after isolation. In all cases, crude ortho:para
ratio was >20:1.
isolated). Halogen substituents at the 3-position were readily
incorporated (4d−4g) and the two ortho regioisomers were
separable on silica. Several 2,3-disubstituted substrates were
also effective (4h, 4i). We were pleased to discover that N-
alkylated aniline sulfamate salts also underwent the amination,
delivering mono-N-alkylated o-phenylenediamines, with N-
benzyl (4j), N-isopropyl (4k), and N-methyl (4l) all being
compatible.
Benzimidazoles and benzotriazoles are commonly synthe-
sized from o-phenylenediamines and a great challenge of their
chemistry is selective N-alkylation.25,26 We imagined exploiting
our protocol to enable separate access to each isomer of
nonsymmetrical N-methyl benzimidazoles and benzotriazoles.
Telescoping the NHMe transfer to N−H sulfamate substrate
1k with sulfamate cleavage and benzimidazole formation in
one sequence worked extremely well (Scheme 3a). Conversely,
by starting with N-methyl sulfamate 1ae and performing NH2
transfer, the complementary alkylated regioisomer 6b could be
obtained (Scheme 3b). The same divergent strategy is
applicable to benzotriazoles and either N-1 (6c) or N-3 (6d)
methylated isomers could be selectively obtained (Scheme 3c,
d). Here, direct alkylation would be even more challenging as
N-2 is also liable to alkylation.27 We also telescoped our
amination together with quinoxaline and benzodiazepine
formation (Scheme 3e).
radical cation are responsible for selectivity, we performed a
control reaction with neutral sulfamate ester 7 (Figure 2a),
which demonstrated that the anionic sulfamate is critical. To
probe the effect in our optimal system of systematically
increasing the dielectric constant of the solvent, we added
varying amounts of water (ε = 80) to the HFIP (ε = 16)
solvent. Selectivity quickly dropped off beyond 10% v/v and
was essentially statistical at 50% v/v (Figure 2b). The dielectric
constant of HFIP/H2O mixtures varies approximately linearly
in relation to the volume of added water.28 Our observation
that the relationship between water concentration and
regioselectivity is nonlinear likely reflects that a combination
of hydrogen bonding and electrostatic interactions are at play.
Finally, we evaluated whether our strategy may be viable on a
phenol-derived sulfate salt, to access 2-aminophenols (Figure
2c). While the reactivity of 8 was relatively low, crucially the
selectivity was >20:1 for the ortho position. This provides
further support for our hypothesis on the origin of selectivity.
We anticipate that future developments to increase reactivity
may enable this to become a synthetically useful process.
In conclusion, we have developed an ortho-selective radical
amination of aniline-derived sulfamate salts which allows
To probe our hypothesis that attractive noncovalent
interactions between the anionic substrate and the aminium
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.E.G. is grateful to the Royal Society for a PhD studentship.
We are grateful to the Royal Society for a University Research
Fellowship (R.J.P., URF\R\191003) and an Enhancement
Award (RGF\EA\180005), the EPSRC (EP/S03269X/1) and
the ERC (Starting Grant NonCovRegioSiteCat, 757381). We
are very grateful to Prof. Chris Hunter for useful discussions.
REFERENCES
■
(1) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the
Structural Diversity, Substitution Patterns, and Frequency of Nitrogen
Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med.
Chem. 2014, 57, 10257−10274.
(2) Olah, G. A.; Narang, S. C.; Olah, J. A.; Lammertsma, K. Recent
aspects of nitration: New preparative methods and mechanistic
studies (A Review). Proc. Natl. Acad. Sci. U. S. A. 1982, 79, 4487−
4494.
(3) (a) Hartwig, J. F. Evolution of a Fourth Generation Catalyst for
the Amination and Thioetherification of Aryl Halides. Acc. Chem. Res.
2008, 41, 1534−1544. (b) Ruiz-Castillo, P.; Buchwald, S. L.
Applications of Palladium-Catalyzed C−N Cross-Coupling Reactions.
Chem. Rev. 2016, 116, 12564−12649. (c) Dorel, R.; Grugel, C. P.;
Haydl, A. M. The Buchwald−Hartwig Amination After 25 Years.
Angew. Chem., Int. Ed. 2019, 58, 17118−17129.
(4) (a) Park, Y.; Kim, Y.; Chang, S. Transition Metal-Catalyzed C−
H Amination: Scope, Mechanism, and Applications. Chem. Rev. 2017,
117, 9247−9301. (b) Jiao, J.; Murakami, K.; Itami, K. Catalytic
Methods for Aromatic C−H Amination: An Ideal Strategy for
Nitrogen-Based Functional Molecules. ACS Catal. 2016, 6, 610−633.
(5) (a) Ng, K.-H.; Chan, A. S. C.; Yu, W.-Y. Pd-Catalyzed
Intermolecular ortho-C−H Amidation of Anilides by N-Nosylox-
ycarbamate. J. Am. Chem. Soc. 2010, 132, 12862−12864. (b) Sun, K.;
Li, Y.; Xiong, T.; Zhang, J.; Zhang, Q. Palladium-Catalyzed C−H
Aminations of Anilides with N-Fluorobenzenesulfonimide. J. Am.
Chem. Soc. 2011, 133, 1694−1697.
(6) (a) Li, Q.; Zhang, S.-Y.; He, G.; Ai, Z.; Nack, W. A.; Chen, G.
Copper-Catalyzed Carboxamide-Directed Ortho Amination of Ani-
lines with Alkylamines at Room Temperature. Org. Lett. 2014, 16,
1764−1767. (b) Yang, Q.-L.; Wang, X.-Y.; Lu, J.-Y.; Zhang, L.-P.;
Fang, P.; Mei, T.-S. Copper-Catalyzed Electrochemical C−H
Amination of Arenes with Secondary Amines. J. Am. Chem. Soc.
2018, 140, 11487−11494.
(7) Park, J.; Lee, J.; Chang, S. Iterative C−H Functionalization
Leading to Multiple Amidations of Anilides. Angew. Chem., Int. Ed.
2017, 56, 4256−4260.
(8) Ryu, J.; Kwak, J.; Shin, K.; Lee, D.; Chang, S. Ir(III)-Catalyzed
Mild C−H Amidation of Arenes and Alkenes: An Efficient Usage of
Acyl Azides as the Nitrogen Source. J. Am. Chem. Soc. 2013, 135,
12861−12868.
(9) Park, J.; Chang, S. Comparative Catalytic Activity of Group 9
[Cp*MIII] Complexes: Cobalt-Catalyzed C-H Amidation of Arenes
with Dioxazolones as Amidating Reagents. Angew. Chem., Int. Ed.
2015, 54, 14103−14107.
(10) (a) Minisci, F.; Galli, R.; Cecere, M. Homolytic amination of
aromatic compounds by redox systems. Reactivity and orientation.
Tetrahedron Lett. 1965, 6, 4663−4667. (b) Citterio, A.; Gentile, A.;
Minisci, F.; Navarrini, V.; Serravalle, M.; Ventura, S. Polar effects in
free radical reactions. Homolytic aromatic amination by the amino
radical cation, .+NH3: reactivity and selectivity. J. Org. Chem. 1984,
49, 4479−4482.
(11) Murakami, K.; Perry, G. J. P.; Itami, K. Aromatic C−H
amination: a radical approach for adding new functions into biology-
and materials-oriented aromatics. Org. Biomol. Chem. 2017, 15, 6071−
6075.
Figure 2. Experiments to probe the origin of selectivity and extension
to phenols.
transfer of NH2 and alkylamine groups. Our method allows
rapid conversion of anilines to a variety of diazines and
triazines, and we envisage it will have particular utility where
selective N-alkylation is required. We propose that the origin of
selectivity is attractive noncovalent interactions between the
anionic sulfamate substrate and cationic N-centered radical.
While we anticipate that these results will have practical utility
in heterocyclic chemistry, more broadly they demonstrate the
potential of harnessing noncovalent interactions for controlling
positional selectivity in radical reactions.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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AUTHOR INFORMATION
Corresponding Author
■
Robert J. Phipps − Yusuf Hamied Department of Chemistry,
University of Cambridge, Cambridge CB2 1EW, U.K.;
orcid.org/0000-0002-7383-5469; Email: rjp71@
cam.ac.uk
Authors
James E. Gillespie − Yusuf Hamied Department of Chemistry,
University of Cambridge, Cambridge CB2 1EW, U.K.
Charlotte Morrill − Yusuf Hamied Department of Chemistry,
University of Cambridge, Cambridge CB2 1EW, U.K.
Complete contact information is available at:
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(12) (a) Boursalian, G. B.; Ngai, M.-Y.; Hojczyk, K. N.; Ritter, T.
Pd-Catalyzed Aryl C−H Imidation with Arene as the Limiting
Reagent. J. Am. Chem. Soc. 2013, 135, 13278−13281. (b) Allen, L. J.;
Cabrera, P. J.; Lee, M.; Sanford, M. S. N-Acyloxyphthalimides as
Nitrogen Radical Precursors in the Visible Light Photocatalyzed
Room Temperature C−H Amination of Arenes and Heteroarenes. J.
Am. Chem. Soc. 2014, 136, 5607−5610. (c) Kim, H.; Kim, T.; Lee, D.
G.; Roh, S. W.; Lee, C. Nitrogen-centered radical-mediated C−H
imidation of arenes and heteroarenes via visible light induced
photocatalysis. Chem. Commun. 2014, 50, 9273−9276. (d) Song, L.;
Zhang, L.; Luo, S.; Cheng, J.-P. Visible-Light Promoted Catalyst-Free
Imidation of Arenes and Heteroarenes. Chem. Eur. J. 2014, 20,
14231−14234. (e) Foo, K.; Sella, E.; Thomé, I.; Eastgate, M. D.;
Baran, P. S. A Mild, Ferrocene-Catalyzed C−H Imidation of
(Hetero)Arenes. J. Am. Chem. Soc. 2014, 136, 5279−5282.
(f) Kawakami, T.; Murakami, K.; Itami, K. Catalytic C−H Imidation
of Aromatic Cores of Functional Molecules: Ligand-Accelerated Cu
Catalysis and Application to Materials- and Biology-Oriented
Aromatics. J. Am. Chem. Soc. 2015, 137, 2460−2463. (g) Tripathi,
C. B.; Ohtani, T.; Corbett, M. T.; Ooi, T. Photoredox ketone catalysis
for the direct C−H imidation and acyloxylation of arenes. Chem. Sci.
2017, 8, 5622−5627.
(13) Greulich, T. W.; Daniliuc, C. G.; Studer, A. N-Amino-
pyridinium Salts as Precursors for N-Centered Radicals − Direct
Amidation of Arenes and Heteroarenes. Org. Lett. 2015, 17, 254−257.
(14) Davies, J.; Svejstrup, T. D.; Fernandez Reina, D.; Sheikh, N. S.;
Leonori, D. Visible-Light-Mediated Synthesis of Amidyl Radicals:
Transition-Metal-Free Hydroamination and N-Arylation Reactions. J.
Am. Chem. Soc. 2016, 138, 8092−8095.
(15) (a) Svejstrup, T. D.; Ruffoni, A.; Juliá, F.; Aubert, V. M.;
Leonori, D. Synthesis of Arylamines via Aminium Radicals. Angew.
Chem., Int. Ed. 2017, 56, 14948−14952. (b) Ruffoni, A.; Juliá, F.;
Svejstrup, T. D.; McMillan, A. J.; Douglas, J. J.; Leonori, D. Practical
and regioselective amination of arenes using alkyl amines. Nat. Chem.
2019, 11, 426−433. (c) Falk, E.; Gasser, V. C. M.; Morandi, B.
Synthesis of N-Alkyl Anilines from Arenes via Iron-Promoted
Aromatic C−H Amination. Org. Lett. 2021, 23, 1422−1426.
(16) (a) Ham, W. S.; Hillenbrand, J.; Jacq, J.; Genicot, C.; Ritter, T.
Divergent Late-Stage (Hetero)aryl C−H Amination by the
Pyridinium Radical Cation. Angew. Chem., Int. Ed. 2019, 58, 532−
536. (b) Rössler, S. L.; Jelier, B. J.; Tripet, P. F.; Shemet, A.; Jeschke,
G.; Togni, A.; Carreira, E. M. Pyridyl Radical Cation for C−H
Amination of Arenes. Angew. Chem., Int. Ed. 2019, 58, 526−531.
(17) Boursalian, G. B.; Ham, W. S.; Mazzotti, A. R.; Ritter, T.
Charge-transfer-directed radical substitution enables para-selective
C−H functionalization. Nat. Chem. 2016, 8, 810−815.
Outer-Sphere Direction in Iridium C−H Borylation. J. Am. Chem. Soc.
2012, 134, 11350−11353. (b) Kuninobu, Y.; Ida, H.; Nishi, M.;
Kanai, M. A meta-selective C−H borylation directed by a secondary
interaction between ligand and substrate. Nat. Chem. 2015, 7, 712−
717. (c) Davis, H. J.; Mihai, M. T.; Phipps, R. J. Ion Pair-Directed
Regiocontrol in Transition-Metal Catalysis: A Meta-Selective C−H
Borylation of Aromatic Quaternary Ammonium Salts. J. Am. Chem.
Soc. 2016, 138, 12759−12762. (d) Chattopadhyay, B.; Dannatt, J. E.;
Andujar-De Sanctis, I. L.; Gore, K. A.; Maleczka, R. E.; Singleton, D.
A.; Smith, M. R. Ir-Catalyzed ortho-Borylation of Phenols Directed by
Substrate−Ligand Electrostatic Interactions: A Combined Exper-
imental/in Silico Strategy for Optimizing Weak Interactions. J. Am.
Chem. Soc. 2017, 139, 7864−7871. (e) Davis, H. J.; Genov, G. R.;
Phipps, R. J. meta-Selective C−H Borylation of Benzylamine-,
Phenethylamine-, and Phenylpropylamine-Derived Amides Enabled
by a Single Anionic Ligand. Angew. Chem., Int. Ed. 2017, 56, 13351−
13355. (f) Hoque, M. E.; Bisht, R.; Haldar, C.; Chattopadhyay, B.
Noncovalent Interactions in Ir-Catalyzed C−H Activation: L-Shaped
Ligand for Para-Selective Borylation of Aromatic Esters. J. Am. Chem.
Soc. 2017, 139, 7745−7748.
(22) Mihai, M. T.; Williams, B. D.; Phipps, R. J. Para-Selective C-H
Borylation of Common Arene Building Blocks Enabled by Ion-Pairing
with a Bulky Countercation. J. Am. Chem. Soc. 2019, 141, 15477−
15482.
(23) Colomer, I.; Chamberlain, A. E. R.; Haughey, M. B.; Donohoe,
T. J. Hexafluoroisopropanol as a highly versatile solvent. Nat. Rev.
Chem. 2017, 1, 0088.
(24) Legnani, L.; Prina-Cerai, G.; Delcaillau, T.; Willems, S.;
Morandi, B. Efficient access to unprotected primary amines by iron-
catalyzed aminochlorination of alkenes. Science 2018, 362, 434−439.
(25) Bansal, Y.; Silakari, O. The therapeutic journey of
benzimidazoles: A review. Bioorg. Med. Chem. 2012, 20, 6208−6236.
(26) For representative examples, see: (a) He, Y.; Chen, Y.; Du, H.;
Schmid, L. A.; Lovely, C. J. A convenient synthesis of 1,4-
disubstituted imidazoles. Tetrahedron Lett. 2004, 45, 5529−5532.
(b) Van Den Berge, E.; Robiette, R. Development of a Regioselective
N-Methylation of (Benz)imidazoles Providing the More Sterically
Hindered Isomer. J. Org. Chem. 2013, 78, 12220−12223. (c) Chen,
S.; Graceffa, R. F.; Boezio, A. A. Direct, Regioselective N-Alkylation of
1,3-Azoles. Org. Lett. 2016, 18, 16−19.
(27) (a) Tomas, F.; Abboud, J. L. M.; Laynez, J.; Notario, R.; Santos,
L.; Nilsson, S. O.; Catalan, J.; Claramunt, R. M.; Elguero, J.
Tautomerism and aromaticity in 1,2,3-triazoles: the case of
benzotriazole. J. Am. Chem. Soc. 1989, 111, 7348−7353. (b) Katritzky,
A. R.; Yannakopoulou, K.; Anders, E.; Stevens, J.; Szafran, M. Ab
initio and semiempirical calculations on the tautomeric equilibria of
N-unsubstituted and N-substituted benzotriazoles. J. Org. Chem.
1990, 55, 5683−5687.
(18) (a) Legnani, L.; Prina Cerai, G.; Morandi, B. Direct and
Practical Synthesis of Primary Anilines through Iron-Catalyzed C−H
Bond Amination. ACS Catal. 2016, 6, 8162−8165. (b) Liu, J.; Wu, K.;
Shen, T.; Liang, Y.; Zou, M.; Zhu, Y.; Li, X.; Li, X.; Jiao, N. Fe-
Catalyzed Amination of (Hetero)Arenes with a Redox-Active
Aminating Reagent under Mild Conditions. Chem. Eur. J. 2017, 23,
563−567. (c) D’Amato, E. M.; Börgel, J.; Ritter, T. Aromatic C−H
amination in hexafluoroisopropanol. Chem. Sci. 2019, 10, 2424−2428.
(d) See, Y. Y.; Sanford, M. S. C−H Amination of Arenes with
Hydroxylamine. Org. Lett. 2020, 22, 2931−2934.
(28) Fioroni, M.; Burger, K.; Mark, A. E.; Roccatano, D. Model of
1,1,1,3,3,3-Hexafluoro-propan-2-ol for Molecular Dynamics Simula-
tions. J. Phys. Chem. B 2001, 105, 10967−10975.
(19) (a) Romero, N. A.; Margrey, K. A.; Tay, N. E.; Nicewicz, D. A.
Site-selective arene C−H amination via photoredox catalysis. Science
2015, 349, 1326−1330. (b) Margrey, K. A.; Levens, A.; Nicewicz, D.
A. Direct Aryl C−H Amination with Primary Amines Using Organic
Photoredox Catalysis. Angew. Chem., Int. Ed. 2017, 56, 15644−15648.
(20) For a recent example of ortho-selective amination of anisole
with azoles, in which hydrogen bonding is proposed to play an
important role, see: Wang, J.-H.; Lei, T.; Nan, X.-L.; Wu, H.-L.; Li, X.-
B.; Chen, B.; Tung, C.-H.; Wu, L.-Z. Regioselective Ortho Amination
of an Aromatic C−H Bond by Trifluoroacetic Acid via Electro-
chemistry. Org. Lett. 2019, 21, 5581−5585.
(21) For selected examples, see: (a) Roosen, P. C.; Kallepalli, V. A.;
Chattopadhyay, B.; Singleton, D. A.; Maleczka, R. E.; Smith, M. R.
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