Pyridyl Radical Cation for C?H Amination of Arenes

Article abstract of DOI:10.1002/anie.201810261

Electron-transfer photocatalysis provides access to the elusive and unprecedented N-pyridyl radical cation from selected N-substituted pyridinium reagents. The resulting C(sp²)?H functionalization of (hetero)arenes furnishes versatile intermediates for the development of valuable aminated aryl scaffolds. Mechanistic studies that include the first spectroscopic evidence of a spin-trapped N-pyridyl radical adduct implicate SET-triggered, pseudo-mesolytic cleavage of the N?X pyridinium reagents mediated by visible light.

Full text of DOI:10.1002/anie.201810261

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Pyridyl Radical Cation for C–H Amination of Arenes
Authors: Erick Moran Carreira, Simon Rössler, Benson Jelier, Pascal
Tripet, Andrej Shemet, Gunnar Jeschke, and Antonio Togni
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810261
Angew. Chem. 10.1002/ange.201810261
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10.1002/anie.201810261
Angewandte Chemie International Edition
Pyridyl Radical Cation for C–H Amination of Arenes
Simon L. Rössler,+ Benson J. Jelier,+ Pascal F. Tripet, Andrej Shemet, Gunnar Jeschke, Antonio
Togni,* and Erick M. Carreira*
Abstract: Electron-transfer photocatalysis provides access to the
elusive and unprecedented N-pyridyl radical cation from selected N-
substituted pyridinium reagents. The resulting C(sp2)–H
functionalization of hetero(arenes) furnishes versatile intermediates
for the development of valuable aminated aryl scaffolds. Mechanistic
studies that include the first spectroscopic evidence of a spin-
trapped N-pyridyl radical adduct implicate SET-triggered, pseudo-
mesolytic cleavage of the N–X pyridinium reagents triggered by
visible light.
nitrogen, and carbon-based radicals generated from such
pyridinium compounds have been leveraged for direct
perfluoroalkylation,[13] trifluoromethoxylation,[14] amination,[5d] and
alkylation,[15] of arenes and hetarenes.
A. Prior Work: Radical C–H Amination
Electrophile
Nucleophile
•
+
+
NR2
R2NX
R2N
hv
R3N
+•
Nitrogen containing motifs are among the most eminent
structural components in discovery programs.[1] Radical
mediated C–H functionalization of (hetero)arenes provides direct
methods for elaborating (hetero)aryl frameworks without
requiring prior manipulation of the structural core.[2] In particular,
nitrogen-centered radicals have long captured the interest of the
synthetic community for late-stage C–H amination of a wide
range of substrates.[3] However, available methods are typically
limited by harsh conditions,[4] the requirements for multiple
equivalents of a valuable arene substrate,[5] or only provide
anilines and their protected derivatives.[6] Herein, we describe
visible light-mediated generation of pyridinium radicals for direct
C–H pyridination of arenes and hetarenes. The method affords
N-aryl pyridinium adducts, enabling divergent access to anilines,
dihydropyridines, and substituted piperidines.
B.
SET Induced Fragmentation N–X Bond Cleavage
X
•
N+
N
e-
e-
•
X
+
X
X = OR, NR2,
O2CCF3, alkyl
homolysis
X = F or OTf
I
heterolysis
pyridyl radical
cation
C. This Work: Direct Access to C(sp2)-N(sp2) Bond Formation
Ar NH2
OTf
N+
*
*
*
OTf
OTf
Ar
CO2R
hv
Ar
N
N
N
[Ru], MeCN
Ar–H
R
Ar
Scheme 1. Visible light-mediated generation of a pyridiyl radical cation for
direct C–H amination of arenes and hetarenes. Tf = trifluoromethylsulfonyl.
Photoredox catalysis has led to powerful strategies for
radical functionalization chemistry and serves as an attractive
approach to forge new disconnections including those applicable
to the amination of arenes. In one approach commonly
employed (Scheme 1A), electrophilic imidyl,[7] amidyl,[8] and
ammonium radicals[9] aminate sufficiently electron-rich arenes.
As an alternative, nucleophilic amines have been reported to
trap aryl radical cations generated by electrochemical or
photoredox processes.[10]
We have been interested in exploring an alternative
fragmentation pathway for pyridiniums, specifically, N–X
cleavage leading to an N-centered pyridyl radical cation
(Scheme 1B). In this respect the selection of X might influence
the fragmentation if the ensuing X anion is energetically favored
over the corresponding radical.[14] In the presence of suitable
arenes, these reactive intermediates could undergo C–H
amination. Ritter and co-workers have utilized Selectfluor® to
generate nitrogen-centered radicals for the introduction of N-
(chloromethyl)triethylenediamine) (TEDA) radical into arenes.[6]
Likewise, we reasoned that N-fluoropyridinium reagents when
triggered by single electron reduction could afford N-centered
pyridyl radical cation with concomitant expulsion of energetically
favored fluoride anion.[16] Similarly, N-sulfonyloxypyridiniums
could provide an alternative source of the pyridyl radical cation
(Scheme 1). Advantages to the latter include convenient
synthesis from inexpensive precursors (pyridine-N-oxide and
triflic anhydride) and opportunities for structural and electronic
variation of the pyridinium fragment.[17]
N-functionalized pyridinium reagents (I) have been explored
as convenient precursors to radicals (X•), following single
electron transfer (SET) reduction and subsequent homolysis
(Scheme 1B).[11] Pioneering work carried out by the Kodak
company focused on N-alkoxypyridinium salts for photoinduced
polymerizations.[12] Recent advances in photoredox processes
have enabled the facile reduction of diverse N-functionalized
pyridinium salts to yield a wide array of radicals. Oxygen-,
[*]
S. L. Rössler, A. Shemet, Prof. Dr. E. M. Carreira
Laboratory of Organic Chemistry
E-mail: erickm.carreira@org.chem.ethz.ch
Dr. B. J. Jelier, P. F. Tripet, Prof. Dr. A. Togni,
Laboratory of Inorganic Chemistry
E-mail: antonio.togni@inorg.chem.ethz.ch
Prof. Dr. G. Jeschke
Laboratory of Physical Chemistry
The C–H amination of arenes with pyridyl radical cations
would enable direct access to
a versatile class of N-
arylpyridinium products. First disclosed over a century ago by
Zincke,[18] pyridiniums have been exploited in a wide range of
synthetic transformations.[19] Contemporary efforts have
showcased the ability of pyridinium substrates to undergo Ni-
catalyzed coupling reactions, deaminative borylation, and
ETH Zürich, Vladimir-Prelog-Weg, 8093 Zürich, Switzerland
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201810261
Angewandte Chemie International Edition
heterocycle functionalization as well as their use in alkaloid
synthesis.[20] An N-centered pyridyl radical cation could provide
straightforward access to such products.[21]
identification of an optimal reaction system consisting of
[Ru(bpy)3](PF6)2 (2 mol%) in anhydrous acetonitrile in
combination with arene as the limiting reactant and a slight
excess of triflyloxypyridinium 1 (entry 1). For comparative
purposes, a threefold excess of arene with 1 as the limiting
reactant was also employed (entry 2). The N-fluoropyridinium
triflate 2 effects the amination reaction in 11% yield with arene
as limiting reactant (entry 4); marginally improved yields were
observed (19-30%) only with excess of arene (entry 5-7),
significantly more expensive Ir-based photocatalyst (entry 8),
and extended reaction times. Control experiments confirmed
that both light and catalyst are crucial for amination; in the
absence of either no product formation is observed (entry 10).
Table 1. Exploration of Reaction Conditions.[a]
1 or 2 (1.3 equiv)
X
OTf
N
Photocat. (2 mol%)
OTf
N
MeCN, blue LEDs, 90 min
X = OTf (1)
F (2)
entry
1
2
3
4
reagent (equiv)
1 (1.3 equiv)
1 (1.0 equiv)
1 (1.0 equiv)
2 (1.3 equiv)
2 (1.3 equiv)
2 (1.0 equiv)
2 (1.0 equiv)
2 (1.0 equiv)
2 (1.3 equiv)
equiv PhH
Photocat.[b]
[Ru]
[Ru]
[Ru
yield (%)[c]
1
3
10
1
1
3
10
10
1
64
86
94
11
19
20
30
22
57
0
[Ir]
[Ir]
[Ir]
[Ir]
[Ru]
[Ru]
5[d]
6[d]
7[d]
8[d]
9
Having established optimal reaction conditions, we explored
the scope of pyridination. A salient feature of this transformation
is that the arene substrate is employed as limiting reactant,
however, for comparative purposes to the state of the art we
include yields of reactions conducted with 3 equivalents of
arenes. The parent N-phenylpyridinium salt 3a was isolated in
good yields under both conditions. Sterically encumbered alkyl
groups were observed to exert little influence on the
regioselectivity (3b-d). Particularly noteworthy is the success of
this transformation with electron-poor arenes, thus providing a
complementary amination approach to current methods, which
are mostly limited to sufficiently electron-rich arenes. For
example, electron deficient PET monomer undergoes
10
no catalyst; or no light; or 80 °C and no light
[a] Reactions were conducted on 0.2 mmol scale. [b] [Ru] = [Ru(bpy)3](PF6)2;
[Ir] = [Ir(dtbbpy)(ppy)2]PF6 (2 mol%) was employed. [c] Determined by 1H NMR
analysis of the unpurified reaction mixture. [d] Reaction run for 20 h. bpy =
2,2'-bipyridine, dtbbpy = 2,2'-di-t-butyl-2,2'-dipyridine, ppy = 2-phenylpyridine
Our investigations commenced by evaluating the reactivity of
pyridinium salts 1 and 2 with benzene in the presence of
photocatalyst under irradiation of the reaction mixture with blue
LEDs (Table 1). Detailed experimentation allowed the
pyridination
to
afford
3h.
Table 2. Scope of the C–H pyridination.
OTf
OTf
OTf
Ar
N
[Ru(bpy)3](PF6)2 (2 mol%)
Ar
+
N
MeCN, blue LEDs, 90 min
X-Ray[c] (1)
1
3
tBu
Me
N
F
p
OTf
OTf
OTf
N
o
N
N
o
m
N
N
Me
N
F
N
m
OTf
p
OTf
o
p
F
TfO
TfO
3a
57%[a], 66%[b]
3b
3c
3d
3e
3f
3g
32%[a], 52%[b]
35%[a], 71%[b]
(1:2.4:4.6)
42%[a], 68%[b]
(1.6:2.3:1)
58%[a], 70%[b]
(1.1:1.5:1)
63%[a], 89%[b]
(2:1:1.2)
76%[a], 79%[b]
OTf
NO2
Cl
O
CN
O
TfO
TfO
TfO
N
O
Cl
OMe
N
F
F
S
OMe
m
A
O
N
Me
N
N
N
N
B
m
N
TfO
OMe
F
OTf
3m
O
56%[a], 59%[b]
(4:1:5)
3h
47%[a], 59%[b]
3i
3j
3k
60%[a], 71%[b]
3l
20%[a], 40%[b]
(8:1)
58%[a], 68%[b]
X-ray[c]
53%[b] (1.2:1)
OMe
O
p
Me
O
Cl
Cl
Me
N
Cl
N
OTf
OTf
N
OTf
OTf
N
N
OMe
N
N
N
N
N
N
o
Me
Me
p
TfO
Cl
Cl
Cl
MeO2C
3r
28%[a], 39%[b]
(2.2:1)
3n
3o
31%[a], 37%[b]
3p
32%[b]
3q
56%[a] (2.1:3:1)
66%[a], 75%[b]
X-ray[c]
[a] Performed with arene (1.0 equiv), reagent (1.3 equiv), [Ru(bpy)3](PF6)2 (2 mol%) in anhydrous MeCN (0.2 M), yield after isolation by column chromatography,
regioisomeric ratio after isolation given in brackets as (ortho/meta/para). [b] Arene (3.0 equiv), reagent (1.0 equiv). [c] Thermal ellipsoids are shown at the 50%
probability level. Counterions in 1 have been omitted for clarity. CCDC codes: 1865356 (1), 1865357 (3a), 1865358 (3h), 1865359 (3k), 1865360 (3o).
This article is protected by copyright. All rights reserved.

10.1002/anie.201810261
Angewandte Chemie International Edition
Electron-rich substrates such as xylene are also suitable,
furnishing product 3g in diminished yield presumably due to
competing radical-mediated homodimerization of xylene.
Functional groups such as nitriles, ethers, nitro, and esters were
tolerated, furnishing the corresponding products (3i, 3j, 3k, 3l).
Hetarenes also underwent amination to yield pyridinylated
pyridine 3n and pyrazine 3o. However, pyrimidine 3p could only
be obtained in low yields since isolation was hampered by
hydrolysis of one of the chlorides. The pyridination of arylated
bicyclopentane proceeded smoothly to 3q, providing a point of
diversification for the recently popularized bicyclopentane
building blocks.[22] Additionally, pyridination of Metalaxyl
furnished derivative 3r of the systemic fungicide.
Table 2. For the production of amide 4m, optimal conditions
necessitated the addition of acid to the pyridination reaction.
Adams demonstrated almost a century ago that pyridines
could be subjected to reduction, following their activation by
conversion to the corresponding pyridinium salts.[23] Accordingly,
we found that N-arylpyridinium products of this study cleanly
underwent hydrogenation in the presence of Adams’ catalyst
(PtO2), furnishing a variety of N-arylated piperidines at room
temperature within 2 hours (Table 4).
Table 4. Scope of the pyridinium salt hydrogenation.[a]
PtO2 (5 mol%)
N
N
Table 3. Scope of the C–H pyridination-aminolysis sequence.
Ar
H2 (1 atm), EtOH, 2 h
Ar
OTf
OTf
N+
[Ru(bpy)3](PF6)2 (2 mol%)
MeCN, blue LEDs, 90 min
OTf
NH2
N
+
Ar
Ar
N
N
then piperidine (10 equiv)
rt, 14 h
N
*
MeO2C
O
NH2
5a
74%
5b
5c
42%
NH2
NH2
46% (2:1)
*
tBu
*
F3C
NH2
N
F
N
F
N
O
4a
58%[a], 60%[b]
4b
4c
4d[c]
MeO
28%[a], 35%[b]
(3:1)
39%[a], 52%[b]
(2:1)
32%[a], 41%[b]
(2:1)
OMe
N
Me
5d
65%
5e
58%
5f
70%
O
Cl
NH2
O2N
NH2
N
Me
OMe
*
*
*
O
Cl
N
O
O
H2N
NH2
4e
40%[a], 52%[b]
(2:1)
Me
O
Me
4h
36%[a], 41%[b]
Me
N
Me
4f
4g
N
N
*
OMe
59%[a], 66%[b]
(8:1)
48%[a], 59%[b]
(1.3:1)
N
Me
Me
Me
*
O
5g
74%
5h
52% (1.3:1)
5i
69% (4:1)
O
O
N
NH2
*
NH2
*
MeO
NH2
[a] Performed with arene (1.0 equiv), PtO2 (0.05 equiv), H2 (1 atm) in
anhydrous EtOH (0.2 M), yield after isolation by column chromatography,
regioisomeric ratio after isolation given in brackets, minor regioisomer denoted
with an asterisk.
MeO
O
OMe
OMe
OMe
4i
4j
4k
59%[a], 74%[b]
28%[a], 29%[b]
(4.3:1)
36%[a], 40%[b]
(8:1)
The pyridinium moiety produced herein constitutes
a
O
OCF3
NH2
versatile handle for a myriad of further transformations, a
selection of which is highlighted in Scheme 2. N-
phenylpyridinium triflate 3a was selectively reduced to the
corresponding 1,2- and 1,4-dihydropyridines with sodium
borohydride or sodium amalgam, respectively.[24] The resulting
diene in 8 readily undergoes Diels-Alder cycloadditon to provide
azabicyclooctane 9 in three steps from benzene. Treatment of
3a with methyl Grignard leads to selective C2 alkylation, and
subsequent methoxycarbonylation affords dihydropiperidine 6.[25]
N
O2N
Me
*
OMe
NH2
Me
O
*
H2N
NH2
4n
28%[a], 29%[b]
4l
4m[d]
30%[a], 40%[b]
59%[a], 69%[b]
(1.5:1:1)
[a] Performed with arene (1.0 equiv), reagent (1.3 equiv), [Ru(bpy)3](PF6)2
(2 mol%), piperidine (10 equiv) in anhydrous MeCN (0.2 M), yield after
isolation by column chromatography, regioisomeric ratio after isolation given in
brackets, minor regioisomer denoted with an asterisk. [b] arene (3.0 equiv),
reagent (1.0 equiv). [c] Isolated as its HCl salt due to volatility. [d] Performed
with TfOH (1 equiv with respect to arene).
In
a
similar fashion, trifluoromethylation followed by
hydrogenation yields derivatized piperidine 10.[26] Deuterated
3a-d5 undergoes hydrogenation furnishing partially deuterated
piperidine 11. Pyridinium 3a efficiently underwent rhodium
catalyzed C–H activation and annulation with diphenylacetylene
to afford quinolinium 12, which has been demonstrated to have
applications as an optoelectronic material.[27]
We next examined the in situ conversion of pyridinium
intermediates to anilines (Table 3). Quenching the pyridination
reaction with piperidine initiates high-yielding Zincke aminolysis
under ambient conditions over the course of 14 hours, enabling
the direct synthesis of anilines. It is important to note that
anilines 4b, 4j, 4l-n in Table 3 represent an expansion of the
substrate scope for the pyridinylation beyond that shown in
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10.1002/anie.201810261
Angewandte Chemie International Edition
O
intense signal with hyperfine couplings consistent with DFT
simulations and those reported by Lagercrantz who documented
a multistep synthesis of the PBN-pyridyl spin adduct from
pyridine.[31] After the light was switched off, a weak signal was
still detectable in the first scan, but not thereafter. The
occurrence of misleading artifacts resulting from inverse-spin
trapping or Forrester-Hepburn mechanism were excluded by
control experiments (see SI).[32]
O
a
NPh
O
N
OMe
Me
d
N
c
6
Ph
9
b
N
N
8
OTf
7
• Mechanistic Proposal
X
N
Ph
N
X
X
N+
3a
Ph
SET
heterolysis
N
•
CF3
e
g
f
N
RuII*
•
1
X = OTf ( )
N
N
Ph
PBN
D
X = F (2)
Ph
OTf
10
 = 0.26
D
RuIII
D
hv
D
D
11
12
pyridyl radical
RuII
HX
cation
Scheme 2. Functionalization of N-phenylpyridinium triflate. Reagents and
conditions: a) MeMgCl (6 equiv), THF, 0 °C, 2h; then TCAA (1.4 equiv),
–78 °C to rt, 63%; NaOMe (1.5 equiv), MeOH/THF, 1 min, 76%. b) Na(Hg)
(5 equiv), water, 14 h, 89%. c) NaBH4 (0.4 equiv), KOH (2 equiv), water, 8 h,
86%. d) N-phenylmaleimide (1.1 equiv), Et2O, rt, 4 h, 73%. e) TMSCF3
(1.2 equiv), CsF (1.1 equiv), DCM, rt, 16 h; then H2 (1 atm), Pd/C (0.1 equiv),
•
H
N
N
EPR
spin trap
X
Ph
H
• Photoinduced EPR studies
EtOH, 8 h, 35%. f) from 3a-d5: H2, PtO2, EtOH,
2 h, 51%. g) 1,2-
diphenylethyne (4 equiv), [Cp*RhCl2]2 (0.05 equiv), Cu(OAc)2 (4 equiv),
NaOAc (4 equiv), DCE, 140 °C, 16 h, 52%. THF = tetrahydrofuran, TCAA =
trichloroacetic acid, TMS = trimethylsilyl, DCM = dichloromethane, Cp =
cyclopentadienyl, DCE = 1,2-dichloroethane.
–– experiment
–– simulatinon
N
•
O
A plausible mechanism for visible light-regulated radical
pyridination is proposed in Scheme 3. After initial excitation of
the photocatalyst under blue light irradiation (446 nm),[28] the
resulting excited Ru(bpy)32+* (Ered = –1.2 V vs. Fc0/+) would
undergo oxidative quenching at a rate of 2.2 x 105 M-1 s-1 with
respect pyridinium reagent 1 (Ered = –0.3 V vs. Fc0/+) to afford
Ru(bpy)33+, as evidenced by Stern-Volmer quenching studies
(see SI). The pyridyl radical resulting from this single electron
transfer rapidly and irreversibly undergoes heterolytic N–X bond
fragmentation to give a pyridyl radical cation and anionic X. For
1 and 2 this process is driven by the extrusion of a triflate or
fluoride anion, respectively. DFT calculations support that
heterolytic fragmentation is preferred by more than 10 kcal mol-1
for both reagents in preference to the homolytic cleavage to
high-energy fluorine and triflyl radicals (see SI). Upon addition of
the pyridyl radical cation to the arene, the subsequent oxidation
and deprotonation of the cyclohexadienyl radical completes the
catalytic cycle. The quantum yield ( = 0.26) indicates that the
reaction is catalytic or conversely, operates under a highly
inefficient radical chain process (see SI).[29] The absence of an
isotope effect in an intramolecular competition experiment
indicates that the final C–H bond cleavage is not rate-
determining (see SI).[30]
Ph
N
tBu
PBN-pyridyl spin adduct
N1
= 1.332 mT
N2 = 0.317 mT
H = 0.224 mT

• Cyclic Voltammetry
OTf
N+
F
N+
Scheme 3. Mechanistic proposal, EPR spectrum of PBN-spin trapped pyridyl
radical cation and cyclic voltammetry measurements of reagents 1 and 2.
EPR = electron paramagnetic resonance, PBN = N-tert-butyl-α-phenylnitrone.
In summary, we have identified N-functionalized pyridinium
reagents which produce the pyridyl radical cation upon single
electron reduction. The pyridinium radical efficiently aminates
arenes and hetereoarenes to furnish pyridinium salts, anilines or
piperidenes and derivatives. The existence of the pyridinium
radical was corroborated by EPR studies, which in combination
with other experiments implicate a tenable mechanism. The
work exploits for the first time the mechanistic duality of the
The intermediacy of the elusive pyridyl radical cation is
further corroborated by photo-induced EPR studies based on
our earlier work on pyridinium reagent fragmentation.[14]
A
solution of 2, Ir-photocatalyst and the spin trap PNB was
monitored by EPR, and no signal was observed in the absence
of light. Upon blue light irradiation, immediate formation of spin-
trapped N-pyridyl radical cation adduct was evidenced by an
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10.1002/anie.201810261
Angewandte Chemie International Edition
[11] a) K. Y. Lee, J. K. Kochi, J. Chem. Soc., Perkin Trans. 2 1992, 0, 1011;
b) T. M. Bockman, K. Y. Lee, J. K. Kochi, J. Chem. Soc., Perkin Trans.
2 1992, 0, 1581.
fragmentation process in pyridinium reagents, a process that
has been largely overlooked.[33]
[12] a) D. P. Specht, C. G. Houle, S. Y. Farid, Photopolymerizable
Compositions Featuring Novel Co-Initiators, 1981, US4289844A. b) I. R.
Gould, D. Shukla, D. Giesen, S. Farid, Helv. Chim. Acta 2001, 84, 2796.
[13] a) J. W. Beatty, J. J. Douglas, K. P. Cole, C. R. J. Stephenson, Nature
Communications 2015, 6, 7919; b) J. W. Beatty, J. J. Douglas, R. Miller,
R. C. McAtee, K. P. Cole, C. R. J. Stephenson, Chem 2016, 1, 456; c)
Y. Ouyang, X.-H. Xu, F.-L. Qing, Angew. Chem. Int. Ed. 2018, 57, 6926.
[14] B. J. Jelier, P. F. Tripet, E. Pietrasiak, I. Franzoni, G. Jeschke, A. Togni,
Angew. Chem. Int. Ed. 2018, 57, 13784.
Acknowledgements
ETH Zürich is acknowledged for financial support. NSERC is
thanked for a postdoctoral fellowship (B.J.). This research was
supported by kind gifts from SpiroChem AG. Dr. Kissner and N.
Kaeffer are thanked for cyclic voltammetry expertise and Dr. E.
Meister for assistance with photospectroscopy. The authors
thank Dr. N. Trapp and M. Solar for X-ray crystallographic
analysis. We thank I. Franzoni and C. Gordon for advice
regarding DFT computations.
[15] a) F. J. R. Klauck, M. J. James, F. Glorius, Angew. Chem. Int. Ed. 2017,
56, 12336; b) A. C. Sun, E. J. McClain, J. W. Beatty, C. R. J.
Stephenson, Org. Lett. 2018, 20, 3487.
[16] T. Umemoto, S. Fukami, G. Tomizawa, K. Harasawa, K. Kawada, K.
Tomita, J. Am. Chem. Soc. 1990, 112, 8563.
[17] C. Zhen-Chu, P. J. Stang, Tetrahedron Letters 1984, 25, 3923.
[18] T. Zincke, Justus Liebigs Annalen der Chemie 1904, 330, 361.
[19] S. Sowmiah, J. M. S. S. Esperança, L. P. N. Rebelo, C. A. M. Afonso,
Org. Chem. Front. 2018, 5, 453.
Keywords: late-stage functionalization • amination • photoredox
• pyridyl radical cation • radical mechanism
[20] a) C. H. Basch, J. Liao, J. Xu, J. J. Piane, M. P. Watson, J. Am. Chem.
Soc. 2017, 139, 5313; b) C. D. Vanderwal, J. Org. Chem. 2011, 76,
9555; c) D. Moser, Y. Duan, F. Wang, Y. Ma, M. J. O’Neill, J. Cornella,
Angew. Chem. Int. Ed. 2018, 57, 11035.; d) J. Wu, L. He, A. Noble, V.
K. Aggarwal, J. Am. Chem. Soc. 2018, 140, 10700.
[1]
[2]
[3]
E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57,
10257.
a) J. Jiao, K. Murakami, K. Itami, ACS Catal. 2016, 6, 610; b) M. D.
Kärkäs, ACS Catal. 2017, 7, 4999.
For selected reviews, see: a) R. S. Neale, Synthesis 1971, 1971, 1; b)
Y. L. Chow, W. C. Danen, S. F. Nelsen, D. H. Rosenblatt, Chem. Rev.
1978, 78, 243; c) S. Z. Zard, Chem. Soc. Rev. 2008, 37, 1603; d) T.
Xiong, Q. Zhang, Chem. Soc. Rev. 2016, 45, 3069; e) L. Stella, in
Radicals in Organic Synthesis (Ed.: P Renaud, M. P. Sibi), Wiley-VCH,
2008, pp. 407.
[21] We recently became aware of Ritter and co-workers having
independently and concurrently developed a similar approach.
[22] K. D. Bunker, N. W. Sach, Q. Huang, P. F. Richardson, Org. Lett. 2011,
13, 4746.
[23] T. S. Hamilton, R. Adams, J. Am. Chem. Soc. 1928, 50, 2260.
[24] M. Saunders, E. H. Gold, J. Org. Chem. 1962, 27, 1439.
[25] M.-L. Bennasar, T. Roca, M. Monerris, C. Juan, J. Bosch, Tetrahedron
2002, 58, 8099.
[4]
[5]
a) F. Minisci, Synthesis 1973, 1973, 1; b) U. Lüning, P. S. Skell,
Tetrahedron 1985, 41, 4289.
For selected examples that employ the unreactive arene as the limiting
reactant, see: a) G. B. Boursalian, M.-Y. Ngai, K. N. Hojczyk, T. Ritter,
J. Am. Chem. Soc. 2013, 135, 13278; b) K. Foo, E. Sella, I. Thomé, M.
D. Eastgate, P. S. Baran, J. Am. Chem. Soc. 2014, 136, 5279; c) T.
Kawakami, K. Murakami, K. Itami, J. Am. Chem. Soc. 2015, 137, 2460;
d) W. Xie, J. H. Yoon, S. Chang, J. Am. Chem. Soc. 2016, 138, 12605;
e) M. P. Paudyal, A. M. Adebesin, S. R. Burt, D. H. Ess, Z. Ma, L. Kürti,
J. R. Falck, Science 2016, 353, 1144; f) L. Legnani, G. Prina Cerai, B.
Morandi, ACS Catal. 2016, 6, 8162.
[26] R. Loska, M. Majcher, M. Makosza, J. Org. Chem. 2007, 72, 5574.
[27] Q. Ge, Y. Hu, B. Li, B. Wang, Org. Lett. 2016, 18, 2483.
[28] a) C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 2013, 113,
5322; b) J. J. Douglas, M. J. Sevrin, C. R. J. Stephenson, Org. Process
Res. Dev. 2016, 20, 1134.
[29] M. A. Cismesia, T. P. Yoon, Chem. Sci. 2015, 6, 5426; b) M. Kärkäs, B.
Matsuura, C. R. J. Stephenson, Science 2015, 349, 1285; c) High
intensity irradiation has been shown to diminish the observed quantum
yield, see: S. Pitre, C. D. McTiernan, W. Vine, R. DiPucchio, M.
Grenier, J. C. Scaiano, Sci. Rep. 2015, 5, 16397.
[6]
[7]
For an exception, see: G. B. Boursalian, W. S. Ham, A. R. Mazzotti, T.
Ritter, Nat. Chem. 2016, 8, 810.
[30] E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51, 3066.
[31] C. Lagercrantz, Acta Chem. Scand. 1993, 47, 734.
a) L. J. Allen, P. J. Cabrera, M. Lee, M. S. Sanford, J. Am. Chem. Soc.
2014, 136, 5607; b) H. Kim, T. Kim, D. G. Lee, S. W. Roh, C. Lee,
Chem. Commun. 2014, 50, 9273; c) L. Song, L. Zhang, S. Luo, J.-P.
Cheng, Chem Eur. J. 2014, 20, 14231; d) T. W. Greulich, C. G. Daniliuc,
A. Studer, Org. Lett. 2015, 17, 254; e) E. Ito, T. Fukushima, T.
Kawakami, K. Murakami, K. Itami, Chem 2017, 2, 383.
[32] A. R. Forrester, S. P. Hepburn, J. Chem. Soc. C 1971, 0, 701.
[33] The EPR results in conjunction with cyclic voltammetry data suggest
that in their role as oxidants N-fluoropyridinium salts may not liberate
fluorine radicals as classically proposed, but rather a highly oxidizing
pyridyl radical cation. Hence, when a SET mechanism is invoked the
exact nature of what is colloquially referred to as “F+ oxidant” may need
revising.
[8]
[9]
a) Q. Qin, S. Yu, Org. Lett. 2014, 16, 3504; b) E. Brachet, T. Ghosh, I.
Ghosh, B. König, Chem. Sci. 2015, 6, 987; c) K. Tong, X. Liu, Y. Zhang,
S. Yu, Chem. Eur. J. 2016, 22, 15669; e) J. Davies, T. D. Svejstrup, D.
Fernandez Reina, N. S. Sheikh, D. Leonori, J. Am. Chem. Soc. 2016,
138, 8092
a) T. D. Svejstrup, A. Ruffoni, F. Juliá, V. M. Aubert, D. Leonori, Angew.
Chem. Int. Ed. 2017, 56, 14948; b) K. A. Margrey, A. Levens, D. A.
Nicewicz, Angew. Chem. Int. Ed. 2017, 56, 15644.
[10] a) T. Morofuji, A. Shimizu, J. Yoshida, J. Am. Chem. Soc. 2013, 135,
5000; b) N. A. Romero, K. A. Margrey, N. E. Tay, D. A. Nicewicz,
Science 2015, 349, 1326; c) S. Möhle, S. Herold, F. Richter, H. Nefzger,
S. R. Waldvogel, ChemElectroChem 2017, 4, 2196; d) A. Magomedov,
E. Kasparavičius, K. Rakstys, S. Paek, N. Gasilova, K. Genevičius, G.
Juška, T. Malinauskas, M. K. Nazeeruddin, V. Getautis, J. Mater. Chem.
C 2018, 6, 8874.
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10.1002/anie.201810261
Angewandte Chemie International Edition
COMMUNICATION
Simon L. Rössler, Benson J. Jelier,
Pascal F. Tripet, Andrej Shemet, Gunnar
Jeschke, Antonio Togni,* and Erick M.
Carreira*
Page No. – Page No.
Pyridyl Radical Cation for C–H
Amination of Arenes
The road less travelled: Select pyridinium reagents undergo an unprecedented,
heterolytic fragmentation upon single electron reduction to afford a synthetically
viable N-pyridyl radical cation. This reactive species was leveraged for the C–H
amination of (hetero)arenes to furnish N-aryl pyridinium products, which enable
access to diverse nitrogen scaffolds.
This article is protected by copyright. All rights reserved.