O-Perhalopyridin-4-yl Hydroxylamines: Amidyl-Radical Generation Scaffolds in Photoinduced Direct Amination of Heterocycles

Article abstract of DOI:10.1021/acs.orglett.1c00064

Reported herein is the design and synthesis of new O-perhalopyridin-4-yl hydroxylamines as shelf-stable and versatile amidyl-radical precursors. The novel amination reagents can be easily prepared via a single synthetic step from inexpensive commercially available starting materials using monoprotected HONH2 as amino source. The synthetic potency of the developed reagents was well demonstrated by direct amination of a series of quinoxalin-2(1H)-ones and their analogues under photocatalytic conditions, even without any additive and photocatalysts.

Full text of DOI:10.1021/acs.orglett.1c00064

pubs.acs.org/OrgLett
Letter
O‑Perhalopyridin-4-yl Hydroxylamines: Amidyl-Radical Generation
Scaffolds in Photoinduced Direct Amination of Heterocycles
Lan Zheng, Yu-En Qian, Yuan-Zhuo Hu, Jun-An Xiao, Zhi-Peng Ye, Kai Chen, Hao-Yue Xiang,*
Xiao-Qing Chen,* and Hua Yang*
Cite This: Org. Lett. 2021, 23, 1643−1647
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ABSTRACT: Reported herein is the design and synthesis of new
O-perhalopyridin-4-yl hydroxylamines as shelf-stable and versatile
amidyl-radical precursors. The novel amination reagents can be
easily prepared via a single synthetic step from inexpensive
commercially available starting materials using monoprotected
HONH2 as amino source. The synthetic potency of the developed
reagents was well demonstrated by direct amination of a series of
quinoxalin-2(1H)-ones and their analogues under photocatalytic
conditions, even without any additive and photocatalysts.
ue to the wide presence of nitrogen-containing natural
products, pharmaceuticals, and functionalized materials,
Scheme 1. Visible-Light-Driven Photocatalytic
Aminationbased on Amidyl Radicals
D
facile accesses to the construction of C−N bond are intensively
pursued.1 In this context, direct amination to forge C−N
bonds through N-centered radicals is progressively emerging as
an efficient and straightforward pathway.2 Notably, amidyl
radicals, as versatile nitrogen-centered radical intermediates,
are playing an important role in the fusion of various C−N
bonds.3 Traditionally, formation of amidyl radicals mainly
relied on the homolysis of difficult-to-construct N−X bonds
under harsh conditions,4 which fundamentally precluded their
wide implementation in synthetic community. Encouragingly,
recent progress on visible-light-induced photocatalysis5
provides fresh opportunities for the generation of various
amidyl radicals under mild conditions. While direct cleavage of
the strong N−H bond of the amide has been sparsely achieved
to assemble various N-containing heterocycles,2a,6 most
present strategies dominantly count on the photoinduced
N−heteroatom bond cleavage6b,7 (Scheme 1a). Recently,
various protected hydroxylamine derivatives have received
particular attention, which have been prepared and applied as
effective amidyl-radical precursors in the domain of visible-
light photochemistry (Scheme 1a).8 To cater for the redox
potential of photocatalyst, a series of electrophores including
dinitrophenylsulfonyl (DNs),8a benzenesulfonyl (Bs),8b O-2,4-
dinitrophenyl,8c and α-amido-oxy acid8d pendents have been
introduced onto the oxygen atom of hydroxylamines to
facilitate the generation of amidyl radicals. Despite these
encouraging advances, their applications are somewhat limited
by the inherent drawbacks, including high cost of amination
reagents, dependence on substrate redox potentials, and
involvement of metal photocatalysts or sacrificial donors. As
such, exploiting new and easily accessible amination reagents
would overcome the present hurdles to extend the boundary of
Received: January 8, 2021
Published: February 15, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00064
Org. Lett. 2021, 23, 1643−1647
© 2021 American Chemical Society
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Letter
the amidyl-radical chemistry, thus offering new synthetic
opportunities for direct amination.
with a range of biological activities.14 To shed more light on
the nature of the present reaction, further control experiments
were launched. As expected, light was necessary to this
transformation. Solvent screening demonstrated that CH2Cl2
was the optimal choice (Table S1, see the Supporting
Information for details). Interestingly, addition of exogenous
photocatalysts such as Ru(bpy)3(PF6)2 or Solvent Red 43
could further improve the reaction efficacy. Simultaneously,
various amination reagents bearing different electrophores
were also investigated. Perfluoropyridin-4-yl reagent 1b gave
similar results, while other commercially available potential
amination reagents 1g−1i were unsuitable for the photo-
catalyst-free process (Figure 1).
At this stage, we preliminarily postulated that the photo-
chemically active EDA complexes between 1a and 2a might be
involved in this process. Subsequently, mixing 1a with 2a
resulted in an obvious red shift in their UV−vis absorption
spectra, which is likely attributed to the association of these
two species (Figure 2a). The 19F NMR signal of 2b shifted
From the viewpoint of green chemistry, photocatalyst-free
process in the visible-light photochemistry is especially
attractive as a more eco-friendly strategy.9 Mostly, electron
donor−acceptor (EDA) complexes were usually observed in
these processes,10 where electron donor and electron acceptor
were actively interacted. Up to now, a series of electron
acceptors,7f,11 including Umemoto’s reagents,11a Katritzky
pyridinium salts,7f phthalimide-derived esters,11e etc., have
been widely used in an impressive range of photocatalyst-free
transformations. Realizing the fact that the amidyl-radical
reagent is still rarely found in the EDA process, we sought to
develop a new amidyl-radical precursor by rationally
modulating the features of its electrophore to facilitate the
exploitation of photocatalyst-free amination protocol. Very
recently, our group identified perfluoropyridin-4-yl moiety as a
novel activation module in the generation of nitrogen-centered
radicals from cycloketone oximes.12 Motivated by this work
and given our long-standing interest in photochemistry,13 we
envisioned that this interesting scaffold might also possess the
potential to serve as an ideal electrophore for facilitating the
generation of amidyl radicals through an EDA process due to
its intrinsic electronic properties. Following this rationale, we
designed a set of O-perhalopyridin-4-yl hydroxylamines as
amidyl-radical precursors, which could be conveniently
prepared from inexpensive commercially available pentahalo-
pyridines and monoprotected HONH2 (Scheme 1b) over a
single step. The structures of these prepared amination
reagents were confirmed by X-ray as well as NMR analysis.
By taking advantage of the newly developed amination
reagents, direct amination of a variety of biologically relevant
heterocycles were expected to realize under photocatalytic
conditions without any additive and photocatalysts (Scheme
1c).
Figure 2. Mechanistic studies: (a) UV/vis absorption spectrometry;
(b) 19F NMR titration experiments.
downfield and upfield respectively, along with changing the
ratio of 1a and 2b (Figure 2b). All the above observations
essentially provide the evidence for the formation of EDA
complex between 1a and 2a. The mass analysis of the reaction
mixture in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT) indi-
cates the formation of amidyl-radical species (see Supporting
Information for details). Electron paramagnetic resonance
(EPR) experiments with DMPO were conducted to detect the
radical species. However, the EPR signals for amidyl adduct
were unable to be precisely identified due to their insufficient
intensity. Instead, the EPR signals clearly indicate the
To verify our design, we first sought to test the direct
amination of 1-methylquinoxalin-2(1H)-one(2a) by utilizing
tert-butyl (perchloropyridin-4-yl)oxycarbamate (1a) (Figure 1,
involvement of carbon-centered radical (aN = 14.33 G, aH
=
20.95 G, g = 2.002) (see Supporting Information for details).
The on−off experiments support the involvement of a radical
chain process (see Supporting Information for details), while
the results of a quantum yield measurement (F = 2.78) cannot
rule out an inefficient chain propagation pathway. Despite the
complication of the mechanism for this transformation (see
Supporting Information for details), a plausible EDA pathway
is proposed in Figure 3. With blue LEDs irradiation, a SET
process occurred within the EDA complex A, delivering the
radical ion pair B. Irreversible fragment of B generated the
radical cation E and amidyl radical D, with the release of
C5Cl4NO− C. Subsequent radical cross coupling of E and D
formed the intermediate F. Final deprotonation of F gave the
corresponding product.
Figure 1. Optimization of the reaction conditions.
see the Supporting Information for details). Gratifyingly, the
target product tert-butyl (4-methyl-3-oxo-3,4-dihydroquinox-
alin-2-yl)carbamate (3a) was obtained in 66% yield under
irradiation of 30 W blue LEDs without adding any photo-
catalyst. Notably, such nitrogen-containing heterocycles are
widely encountered in natural products and pharmaceuticals
Next, the feasibility and reliability of the designed amidyl-
radical precursors as well as the compatibility of the reaction
conditions were comprehensively evaluated (Scheme 2).
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different substituents and protecting groups were proven to
be suitable reaction partners in this photoinduced process,
delivering the desired aminated products 3a−3s smoothly.
Interestingly, unprotected quinoxalin-2(1H)-one also delivered
the desired product 3l in an acceptable yield. This photo-
induced protocol was also amenable to the heterocyclic
analogues such as 2H-benzo[b][1,4]oxazin-2-one and coumar-
ins (3t−3w). However, other heterocyclic substrates including
1H-benzo[d]imidazole, benzo[d]thiazole, and quinolone were
unable to give the desired products (see Supporting
Information for details), presumably because of their
incapacity for the formation of EDA or mismatching redox
properties. Meanwhile, the protecting group on hydroxylamine
could be changed to benzoxycarbonyl (Cbz) and 9-
fluorenylmethyl (Fmoc) groups, albeit with lower reaction
efficiency (3x and 3y).
Figure 3. Proposed mechanism for photocatalyst-free conditions.
Scheme 2. Scope of the Photoinduced Amination Reaction
Ultimately, the scalability and practicality of this photo-
induced process were evaluated (Scheme 3). Pleasingly, a
Scheme 3. Scalability and Practicality of the Photoinduced
Process
scale-up reaction for the direct amination of quinoxalin-2(1H)-
one 2a was performed under both photocatalyst-free
conditions and photocatalyst-assisted conditions, and the
corresponding product 3a was successfully isolated with
mostly comparable yields (62%, Scheme 3a, 67%, Scheme
3b), respectively. The reaction for quinoxalin-2(1H)-one 2l
could also be easily scaled up with lower yield (Scheme 3c).
Furthermore, an alternative four-in-one process by starting
from o-phenylenediamine, ethyl glyoxalate, pentafluoropyr-
idine, and N-Boc-hydroxylamine was also established to deliver
the desired product 3l in 11% yield, rendering this protocol
more adjustable and industry-friendly (Scheme 3d).
To conclude, we have first designed and identified a new
class of highly reactive, practical and easy-to-prepared O-
perhalopyridin-4-yl hydroxylamines as effective amidyl-radical
precursors, allowing the general and direct amination of
various heterocycles under visible-light-driven conditions. It is
noteworthy that this photoinduced transformation is able to
proceed smoothly without adding any photocatalyst, metal
catalyst, or additive. These salient features of this new type of
reagents in photocatalytic transformation would offer intrigu-
ing opportunities for rapid expansion of nitrogen-containing
Generally, there was no obvious difference in the reactivity
between perchloropyridin-4-yl and perfluoropyridin-4-yl re-
agents. In general, the photocatalyst-free process usually gave
slightly lower yields than the photocatalyst-assisted process,
which was possibly attributed to the inferior efficiency of
absorption of photons for EDA complex than the photo-
catalyst. A wide range of quinoxalin-2(1H)-ones bearing
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Notes
molecular complexity. Further efforts are underway in our
laboratory to utilize the newly developed precursors in other
transformations, which will be reported in due course.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00064.
■
We gratefully acknowledge the financial support from National
Natural Science Foundation of China (22078370, 21776318,
22078369, 81703365), Basic Science Center Project for
National Natural Science Foundation of China (No.
72088101,the Theory and Application of Resource and
Environment Management in the Digital Economy Era),
Natural Science Foundation of Hunan Province (2018JJ3868,
2020JJ4682), the Fundamental Research Funds for Central
South University (2020zzts401), and Central South University.
sı
Experimental details, characterization data, and mecha-
nisms for new compounds, including EPR and NMR
spectra, X-ray crystallographic data of 1a, X-ray
crystallographic data of 1d, and X-ray crystallographic
data of 3m (PDF)
Accession Codes
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AUTHOR INFORMATION
Corresponding Authors
■
Hao-Yue Xiang − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, P.
R. China; orcid.org/0000-0002-7404-4247;
Email: xianghaoyue@csu.edu.cn
Xiao-Qing Chen − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, P.
R. China; orcid.org/0000-0002-8768-8965;
Email: xqchen@csu.edu.cn
Hua Yang − College of Chemistry and Chemical Engineering,
Central South University, Changsha 410083, P. R. China;
orcid.org/0000-0002-5518-5255; Email: hyangchem@
csu.edu.cn
Authors
Lan Zheng − College of Chemistry and Chemical Engineering,
Central South University, Changsha 410083, P. R. China
Yu-En Qian − College of Chemistry and Chemical Engineering,
Central South University, Changsha 410083, P. R. China
Yuan-Zhuo Hu − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, P.
R. China
Jun-An Xiao − College of Chemistry and Materials Science,
Nanning Normal University, Nanning 530001, Guangxi, P.
R. China
Zhi-Peng Ye − College of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, P.
R. China
Kai Chen − College of Chemistry and Chemical Engineering,
Central South University, Changsha 410083, P. R. China
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