N -aminopyridinium salts as precursors for N-centered radicals - Direct amidation of arenes and heteroarenes

Article abstract of DOI:10.1021/ol503338b

Readily prepared N-aminopyridinium salts are valuable precursors for the generation of N-centered radicals. Reduction of these salts by single electron transfer allows for clean generation of amidyl radicals. It is shown that direct radical C-H amination of heteroarenes and arenes can be achieved with N-aminopyridinium salts under mild conditions by using photoredox catalysis.

Full text of DOI:10.1021/ol503338b

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Letter
pubs.acs.org/OrgLett
N‑Aminopyridinium Salts as Precursors for N‑Centered Radicals −
Direct Amidation of Arenes and Heteroarenes
Tobias W. Greulich, Constantin G. Daniliuc, and Armido Studer*
Fachbereich Chemie, Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat, Corrensstraße 40, 48149 Munster, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: Readily prepared N-aminopyridinium salts are
valuable precursors for the generation of N-centered radicals.
Reduction of these salts by single electron transfer allows for
clean generation of amidyl radicals. It is shown that direct
radical C−H amination of heteroarenes and arenes can be
achieved with N-aminopyridinium salts under mild conditions
by using photoredox catalysis.
n contrast to C-centered radicals, N-centered radicals have
and pyridine resonance energy.5 Encouraged by these results
we assumed that intermediates 2 can also be generated from
pyridinium salts 3 upon single electron reduction. Whereas N-
radical generation from 1 occurs via a H-transfer and
subsequent fragmentation, reagents 3 will offer a comple-
mentary approach to N-radicals via an initial electron transfer
process. Compounds 1 are radical hydroamination reagents
where chains are reductively sustained and 3 should be good
amination reagents which can be used in redox processes,
therefore offering as compared to 1 a broader application range
(chains can be sustained by oxidation of arene amidyl radical
adducts).
Reagents of type 3 are readily accessed in one step according
to a literature procedure6 by reacting commercially available7
pyrylium salts 4 with a hydrazine derivative to give the N-
aminopyridinium salts 3a−f in good to excellent yields
(Scheme 2). All salts 3a−f can be stored for months, and
phthaloyl derivatives 3a,b and d8d were previously described.8
N-Aminopyridinium salts have been shown to react with
nucleophiles at the pyridinium moiety,9 with dipolarophiles in
[3 + 2] cyloadditions10 and as electrophilic amination
1
Inot received that much attention in synthesis. This is likely
due to their higher reactivity and to the fact that there are fewer
methods for their clean generation. Mostly, N-centered radicals
are formed via cleavage of a reactive N−X bond, where X can
be a halogen atom, a N-substituent, an O-group, or a S-
substituent.1 Due to the rather strong C−N bond, cleavage of
N−C bonds for generation of the corresponding N-centered
radicals is not efficient.2 There are a few examples of oxidation
of N−H bonds in amides to directly generate amidyl radicals.3
Since most reactive N-radical precursors of the type R1R2N−X
are generally not stable1i and have to be prepared in situ,
development of novel, stable, readily prepared, cheap, and
efficient N-radical precursors is of importance. We report
herein that N-aminopyridinium salts readily prepared in large
scale are highly efficient N-radical precursors and document
their potential for direct radical C−H amidation of arenes and
heteroarenes.
Previously, we reported radical hydroamination of alkenes by
using aminated dihydropyridines 1 as N-radical precursors
(Scheme 1).4 It was shown that reagents 1 are good H-donors
for reduction of reactive C- and S-radicals to give stabilized
proaromatic radicals of type 2. These readily fragment to
amidyl radicals and the corresponding pyridines. The driving
force for the release of N-radicals from 2 is the gain in entropy
Scheme 2. Preparation of N-Aminopyridinium Salts 3a−f
Scheme 1. N-Radical Precursors 1 and 3
Received: November 18, 2014
Published: December 26, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
reagents.11 Moreover, photolysis leads to reactive nitrenium
ions12 and also the electrochemistry of some aminopyridinium
salts was investigated.13 However, these salts have not been
used as precursors for N-centered radicals in organic synthesis
to date. For compound 3b we obtained an X-ray structure
revealing that the pyridinium plane and the amide plane are
perpendicular to each other (Figure 1).
these reactions, since the released pyridine derivative will buffer
the system.
With 3a the amidation product 5a was isolated in 49% yield
(Scheme 3), and a similar result was obtained with 3c (39%).
Scheme 3. Amidation of Arenes and Heteroarenes with 3a
Figure 1. X-ray structure of 3b (thermal ellipsoids are shown with 50%
probability).
Cyclovoltammetry for 3a and 3e (see Supporting Informa-
tion) showed irreversible reduction at −0.75 V and −0.70 V vs
Ag/Ag+, respectively (Figure 2).
a
Conducted with the corresponding heteroarene.
For 3b, we observed significant amounts of amidation of the
phenyl groups of the released 2,4,6-triphenylpyridine (5a: 40%,
see Supporting Information). No amidation product was
identified by using 3d, 3e, and 3f (see Supporting Information).
The following experiments were therefore conducted with 3a.
Due to the electrophilicity of the phthalamidyl radical, direct
amidation worked more efficiently for electron-rich arenes and
yields between 63% and 89% were obtained for 5b−f. As
expected, for monosubstituted arenes a mixture of regioisomers
was formed (see 5b and 5e). para-Disubstituted arenes bearing
an electron-donating and -withdrawing group reacted regiose-
lectively ortho to the electron-donating substituent with
complete regiocontrol (5g,h). Heteroarenes were investigated,
and the α-amidation products 5i−k were regioselectively
formed for the indole, furan, and pyrrole substrates (46−
68%). However, thiophene provided 5l as a mixture of
regioisomers.
Figure 2. CV of 3a.
We also recorded UV/vis spectra of the N-aminopyridinium
salts. As expected, there is no significant absorption above 400
nm for these compounds (see Supporting Information).
Considering the physical data of compounds 3 with the goal
of amidyl radical generation, we were searching for an SET
reducing reagent with a reduction potential of < −0.75 V vs
Ag/Ag+. Moreover, if photochemistry is used to induce the
SET process, irradiation has to occur above 400 nm in order to
suppress excitation of 3 which will lead to unwanted nitrenium
ion formation. Therefore, we decided to use photoredox
catalysis applying blue light and Ru(bpy)3Cl2 as a catalyst.14,15
As a test reaction, direct amidation16 of benzene15a,b was
investigated first. Reactions were conducted in MeCN at 40 °C
with N-aminopyridinium salts 3a−f by using an excess of
benzene (10 equiv) for 5 h. Note that a base is not necessary in
We found that amidation of N-methylindole15c works even
better with reagent 3e where the highest yield was achieved by
using a 2-fold excess of 3e to give regioselectively α-amidation
product 6a (86%, Scheme 4). Therefore, other experiments
with heteroarenes were mainly conducted with 3e.
To test scope and limitations, various indole derivatives were
reacted under optimized conditions. Substituents at the 5-
position of the indole core showed small electronic effects. The
electron poorer Br-, F-derivatives and also the electron richer
Me-substituted indole delivered good yields (see 6b−d, 63−
75%). The congener with the MeO-substituent at the 4-
position also provided an excellent yield (6e, 95%).
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Organic Letters
Letter
Scheme 4. Amidation of Indoles and Pyrrols with Reagent 3e
or 3f
Scheme 5. Suggested Mechanism
species reduces pyridinium salt 3e by SET. Fragmentation of
the thus generated radical leads to the sulfonamidyl radical A
and pyridine B. The amidyl radical A regioselectively adds to
the α-position of N-methylindole to generate radical C.
3+
Oxidation of C by Ru(bpy)3 affords the cationic species D
thereby regenerating Ru(bpy)32+. Pyridine B formed in the
fragmentation acts as a base to deprotonate D to eventually
provide amidated indole 6a.
In summary, we have successfully introduced pyridinium salts
3a, 3e, and 3f as efficient N-radical precursors which are easily
accessible from cheap starting materials. N-radicals are readily
generated upon single electron reduction of these salts. It has
been shown that these novel N-radical precursors can be used
for regioselective radical amidation of heteroarenes and
substituted arenes upon applying photoredox catalysis with
Ru(bpy)3Cl2 as the catalyst. Reactions proceed in the absence
of any additive by irradiating a mixture of the arene/
heteroarene, N-aminopyridinium reagent and the photoredox
catalyst. The reagent design allows for simple variation of the
substituents at the amidyl radical. Therefore, the reactivity of a
reagent can be readily adjusted to the radical acceptor. It has
been shown that arene amidation works best with reagent 3a
and direct radical amidation of the more electron-rich
heteroarenes is best conducted with N-aminopyridinium salt
3e. Notably, in contrast to the recently reported photoredox
catalyzed radical amidations which have to be conducted with
expensive iridium-based photocatalysts,15 the reagents intro-
duced herein allow reactions to be performed with the
significantly cheaper Ru(bpy)3Cl2 catalyst.
a
b
Conducted with 2-methyl-N-methylindole. Conducted with 3f.
Substituents at the 6- and 7-position are tolerated as
demonstrated by the successful preparation of 6f (71%) and
6g (82%). We also showed that 3-substituted N-methylindoles
are readily α-amidated in good to excellent yields (6h−k, 76−
96%). Varying the N-substituent revealed that the free N−H-
indole and its alkyl and aryl derivatives delivered good yields
(6l−o, 59−70%). However, electron poorer indoles bearing an
acetyl- or a Boc-protecting group were not substrates for the
direct α-amidation with the electrophilic sulfamidyl radical and
the targeted products 6p and 6q were not formed. Substrates
where the 2-position is blocked reacted slowly to provide the
corresponding 3-amidated indoles (6r and 6s). Pleasingly,
regioselective radical α-amidation also works on N-substituted
pyrrols as shown by the successful preparation of 6t (71%) and
6u (84%). Amidation of N-methylindole with the Boc-
protected reagent 3f afforded the α-product 6v regioselectively
in 61% yield.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, characterization data for the products,
supplementary crystallographic data (CCDC 1031875−CCDC
103187), CV, and UV/vis data. This material is available free of
charge via the Internet at http://pubs.acs.org.
The suggested mechanism for indole amidation with 3e
exemplified for preparation of 6a is shown in Scheme 5
(amidation of (hetero)arenes with 3a and pyrrols with 3e work
in analogy). In the first step excited Ru(bpy)32+* is generated
AUTHOR INFORMATION
Corresponding Author
■
2+
from Ru(bpy)3 by absorption of blue light. This excited
*E-mail: studer@uni-muenster.de.
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Letter
2014, 50, 9273−9276. (c) Qin, Q.; Yu, S. Org. Lett. 2014, 16, 3504−
3507.
Notes
The authors declare no competing financial interest.
(16) Arene amidation with amidyl radicals: (a) Lidgett, R. A.; Lynch,
E. R.; McCall, E. B. J. Chem. Soc. 1965, 3754−3759. (b) Cadogan, J. I.
G.; Rowley, A. G. J. Chem. Soc., Perkin Trans. 1 1975, 1069−1071.
(c) Day, J. C.; Katsaros, M. G.; Kocher, W. D.; Scott, A. E.; Skell, P. S.
J. Am. Chem. Soc. 1978, 100, 1950−1951. (d) Lu, F.-L.; Naguib, Y. M.
A.; Kitadani, M.; Chow, Y. L. Can. J. Chem. 1979, 57, 1967−1976.
ACKNOWLEDGMENTS
This work was financially supported by the Deutsche
Forschungsgemeinschaft (IRTG Munster/Nagoya).
■
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(e) Lunig, U.; Skell, P. S. Tetrahedron 1985, 41, 4289−4302. (f) Day, J.
̈
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