Visible-Light-Induced Remote C(sp3)-H Pyridylation of Sulfonamides and Carboxamides

Article abstract of DOI:10.1021/acs.orglett.9b03879

Visible-light-induced site-selective C(sp³)-H pyridylation of amides has been accomplished using N-amidopyridinium salts. The N-centered radicals generated by the single-electron reduction of N-amidopyridinium substrates undergo 1,5-hydrogen at

Full text of DOI:10.1021/acs.orglett.9b03879

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Induced Remote C(sp3)−H Pyridylation of
Sulfonamides and Carboxamides
Namhoon Kim,†,‡ Changseok Lee,†,‡ Taehwan Kim,†,‡ and Sungwoo Hong*,‡,†
†Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea
‡Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea
S
* Supporting Information
ABSTRACT: Visible-light-induced site-selective C(sp3)−H pyridylation of
amides has been accomplished using N-amidopyridinium salts. The N-
centered radicals generated by the single-electron reduction of N-
amidopyridinium substrates undergo 1,5-hydrogen atom transfer to form
alkyl radical intermediates. Excellent C4-selectivity in radical trapping with
pyridinium salts is observed for the alkyl radicals to provide δ-pyridyl
sulfonamides and γ-pyridyl carboxamides. The utility is demonstrated by
offering a practical approach for the late-stage functionalization of complex
amide derivatives.
he site-selective functionalization of unactivated C(sp3)−
TH bonds in the presence of multiple reaction sites
constitutes a long-standing challenge in synthetic chemistry
and late-stage transformations.1 Due to its ubiquity and
versatility, the amino group is an attractive functionality
capable of directing transformations and for the subsequent
elaboration of amine-containing targets.2 Inspired by the
Scheme 1. Strategy for Remote C−H Pyridylation at the C4-
Position of Pyridine Core
3
4
̈
Hofmann−Loffler−Freytag reaction, photocatalytic remote
C−H functionalization has been widely used by a facile and
selective 1,5-hydrogen atom transfer (HAT) reaction5 where
pendant N-centered radicals cleave inert aliphatic C−H bonds.
This photochemical approach enables C−H functionalization
of previously inaccessible distant C−H bonds in the nitrogen-
containing compounds even in complex molecular settings
under mild and environmentally benign conditions.6 Despite
the great success in HAT catalysis, the remote and
regioselelctive C−H pyridylation in the aliphatic chain of
amides has not been explored.
Pyridine derivatives are extensively found in a large number
of biologically active natural products, pharmaceuticals, and
fine chemicals.7 Consequently, considerable effort has been
directed toward chemical modification of the pyridine core.8,9
Recently, N-alkoxypyridinium salts10 have been used as
versatile pyridine surrogates with increased levels of selectivity
and reactivity.11 However, these approaches have faced limited
success due to the regioselectivity issue regarding two
competing sites (C2 vs C4) on the N-alkoxypyridinium salts
(Scheme 1a). Hiyama and Ong reported bimetallic catalysis for
the C4-selective C−H bond activation of the pyridine core by
employing nickel/Lewis acid cooperative catalysis (Scheme
1b).12 In this innovative system, a bulky AlMe3 Lewis acid
coordinates at the pyridine nitrogen to allow for the C4-
selective synthesis of alkyl or alkenylpyridines.
effect of a bulky Lewis acid to avoid an unfavorable clash at the
C2 position between the N-substituents and the translocated
alkyl radical, as depicted in Scheme 1c. In designing a strategy
to enable remote C−H pyridylation, we speculated that
sulfonamide- and carboxamide-based pyridinium substrates
would offer an opportunity to activate different remote
positions (e.g., amino acids) via a radical relay mechanism.
In the process, the N-centered radicals6 formed from a single-
electron transfer (SET) reduction trigger an intramolecular
Drawing inspiration from these studies, we hypothesized
that N-substituents on pyridinium salts could exhibit a similar
Received: October 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03879
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Letter
1,5-HAT to generate δ-radical sulfonamides or γ-radical
carboxamides, providing impressive synthetic versatility for
subsequent installation of pyridyl moiety. Herein, we report a
photocatalytic remote C(sp3)−H pyridylation that addresses
the regioselectivity issue of the two competing sites (C2 vs C4)
through C4−H activation of the pyridine core to provide
synthetically valuable δ-pyridyl sulfonamides and γ-pyridyl
carboxamides. This approach significantly broadens the
synthetic scope of amide-directed remote C(sp3)−H function-
alization and has the potential to simplify installation of the
pyridyl group across a wide range of complex sulfonamides and
carboxamides under mild, metal-free conditions.
With these very simple reaction conditions, we explored the
scope of N-amidopyridinium substrates to evaluate the utility
and generality of the current cascade reaction. As summarized
in Scheme 2, sulfonamide substrates containing various groups
were successfully employed in the reaction and provided δ-
C(sp3)−H pyridylated products under the optimized reaction
conditions. Remarkably, we observed that radical trapping
a,b
Scheme 2. Exploration of Substrate Scope
To verify the validity of our proposed approach, we
investigated the remote C(sp3)−H pyridylation of sulfona-
mides using N-amidopyridinium salt 1a as a model substrate at
room temperature (Table 1). After an extensive survey of the
a
Table 1. Optimization of the Reaction Conditions
b
entry
variation from the standard conditions
yield (%)
c
1
2
3
4
5
6
7
8
9
none
Q1 (2.5 mol %)
95 (83 )
92
82
36
80
87
NR
NR
NR
Ru(bpy)3Cl2 instead of Q1
Ir(ppy)3 instead of Q1
Eosin Y instead of Q1
addition of NaHCO3 (1.2 equiv)
without visible light irradiation
without Q1
addition of TEMPO (1.0 equiv)
a
Reaction conditions: 1a (0.1 mmol), photocatalyst in DMSO (0.5
mL) under irradiation using 10 W blue LEDs at rt for 30 min under
b
c
N2. Yield was determined by 1H NMR spectroscopy. 1 mmol scale.
Q1 = 3-(diphenylphosphoryl)-6-methoxy-1-methylquinolin-2(1H)-
one, DMSO = dimethyl sulfoxide.
reaction parameters, we were pleased to find that a promising
result was obtained under blue LED irradiation using 3-
10b,11c,g
phosphonated quinolinone Q1
(1 mol %) as the
photoredox catalyst, leading to the remote pyridylation of
the C−H bond at the δ position. Under these conditions, the
desired product 2a was produced in 95% yield as a single
isomer. Increasing the Q1 loading (2.5 mol %) provided a
comparable yield (entry 2, 92%). Among the screened
solvents, DMSO was more effective than any of the others
tested. Of the various photocatalysts tested, Q1 displayed the
best activity. We examined the influence of the light source,
and the blue LED was found to be the best light source. A
series of control experiments carried out in the absence of light
or photocatalyst confirmed that the current reaction is driven
by a photocatalytic process (entries 7 and 8). To examine the
role of a photocatalyst Q1, a series of Stern−Volmer quenching
experiments were performed with N-amidopyridinium salt 1a,
revealing the feasibility of the oxidative quenching cycle (see
the Supporting Information for details). The addition of
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) completely
inhibited the formation of 2a, indicating that a radical process
was involved. To demonstrate the robustness of this method,
the reaction was carried out on the 1 mmol scale, leading to
83% of 2a under the standard conditions.
a
Reaction conditions: 1 (0.1 mmol) and Q1 (1.0 mol %) in DMSO
b
(0.5 mL) using 10 W blue LEDs at rt for 30 min under N2. Yields of
c
isolated products. The ratio was determined by 1H NMR
spectroscopy.
B
DOI: 10.1021/acs.orglett.9b03879
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Letter
a−c
occurs exclusively at the C4 position of the pyridine core in all
investigated cases with primary (2ah−2ai), secondary (2s−
2ag), and tertiary alkyl (2a−2r) C(sp3)−H bonds, highlighting
the advantage of the current strategy over the previous results
obtained from the use of N-alkoxypyridinium salts.9 Variation
at the aliphatic chains has little influence on reaction efficiency,
and substrates with different substitution patterns were suitable
to deliver the corresponding products 2a, 2c, 2s, 2t, and 2u.
The current protocol could also be adapted for the
functionalization of the internal cycloalkyl C−H bond. For
example, C−H bonds in cyclohexane and cycloheptane could
be activated to provide an efficient approach for the decoration
of the cycloalkyl skeleton (2v and 2z). The reaction was
further expanded to an interesting example of a substrate
containing a sterically bulky adamantyl group, effectively
yielding the product 2w. The reaction worked well with
substrates bearing an oxygen atom adjacent to the reaction
position (2i, 2x, 2y, 2ah, and 2ai). Substrates bearing cyclic
motifs, such as cyclobutane, cyclopentane, cyclohexane, N-Boc-
piperidine, and tetrahydropyran, were all tolerated, providing
the products 2d, 2e, 2f, 2g, and 2h. Moreover, the scope could
be expanded to α-branched sulfonamides, which afforded the
corresponding secondary sulfonamide products 2b and 2aa.
The utility of the present method was further broadened by the
reaction with primary C(sp3)−H bonds (2ah and 2ai). With
respect to the scope of pyridyl groups, we were pleased to
observe that substrates possessing methyl, substituted aryl,
alkoxy, or thienyl groups on the pyridine core could be
incorporated into the δ-C(sp3)−H to afford the corresponding
products (2j−2n, 2ab−2ag). Notably, the method accom-
modates sterically bulky groups at the C3 position of pyridine,
affording the C4-selective products (2n, 2o, 2p, 2q, 2ae, 2af,
and 2ag). The reaction is also applicable to the 2,6-
disubstituted pyridinium substrate (2r).
Next, we turned our attention to evaluating the remote C−
H pyridylation of carboxamides. To our delight, the protocol
could be successfully applied to a variety of carboxamide and
pyridinium substrates, leading to the remote functionalization
of the C−H bond at the γ position, and the results are
summarized in Scheme 3. Interestingly, both secondary and
tertiary C−H bonds could also be selectively functionalized at
the C4 position of the pyridine core with modest to good
regioselectivity. Together with the excellent scope of
sulfonamides, the strategy would potentially broaden the
synthetic application of the remote C−H pyridylation strategy.
To further demonstrate the broad synthetic utility of this
method, we investigated the late-stage functionalization of
various complex biomolecules as illustrated in Scheme 4.
Specifically, derivatives of bisacodyl13 and abiraterone14 were
successfully employed to furnish the desired products (2aj,
2ak, and 2am). In addition, the reaction of a pentoxifylline15
derivative was employed under standard reaction conditions to
afford the product 2al in 62% yield with excellent C4-
regioselectivity of the pyridine core. Significantly, the strategy
could be applied to unnatural amino acid derivatives for the
C−H activation of different positions. For instance, site-
specific C−H functionalization offers a significant advantage by
installing a pyridyl group at the δ- or γ-positions of L-
norleucine16 (2an and 4l). This late-stage functionalization
exhibits a wide tolerance for biologically relevant function-
alities and highlights the potential utility of this method in
medicinal chemistry and chemical biology.
Scheme 3. Carboxamide Substrate Scope
a
Reaction conditions: 1 (0.1 mmol) and Q1 (2 mol %) in DMSO (1.0
mL) using 10 W blue LEDs at rt for 16 h under N2. Isolated yields.
The C2/C4 ratio was determined by H NMR spectroscopy.
b
c
1
To better understand the observed excellent C4-regiose-
lectivity, density functional theory (DFT) calculations were
carried out (see the SI for computational details), and the
reaction energy profile is illustrated in Figure 1. Depending on
the reaction sites of the N-amidopyridinium salt (C4 vs C2)
with an alkyl radical intermediate, the generation of two
regioisomeric products is possible, and this radical addition
step is responsible for the regiocontrol. This transition state
TS-C2, leading to the C2-product, is located at 16.4 kcal
mol−1, whereas the pathway leading to the experimentally
observed C4-product traverses transition state TS-C4 at 13.6
kcal mol−1 (Figure 1a).
The computed structures of these two transition states
indicated that the barrier difference of 2.7 kcal mol−1 stems
mainly from the greater steric demand of the N-alkyl tosyl
group. As a consequence, these different radical trapping
barriers have a profound impact on the regioselectivity, and the
C4-substituted regioisomer is predicted to be a major product.
On the other hand, the C4-position is preferred by a barrier of
0.81 kcal mol−1 in the case of amide substrate 3a (Figure 1b),
which again shows good agreement with the modest
regioselectivity experimentally observed.
A possible mechanistic pathway is depicted in Figure 2.
Initially, the photolytic N−N bond cleavage of the N-
amidopyridinium salt A by SET of the Q1* leads to amidyl
radical B and neutral pyridine. A subsequent 1,5-HAT reaction
of N-centered radical B produces an alkyl radical intermediate
C. Nucleophilic alkyl radical C engages in an intermolecular
radical addition to substrate A to give a radical cation D,
leading to the final product and the amidyl radical after
deprotonation and the cleavage of the N−O bond. The
measured quantum yield (Φ = 41.2) of the model reaction
suggests that this radical-chain pathway is quite productive.
Alternatively, SET oxidation of D completes the catalytic cycle
C
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Scheme 4. Late-Stage Functionalization of Complex Molecules
Figure 1. Free-energy profile for the remote C−H pyridylation. Solid black traces represent the p-alkylpyridine formation pathway. Blue and green
traces represent the o-alkylpyridine formation pathway.
In summary, we developed visible-light-induced site-
selective C(sp3)−H pyridylation of sulfonamides and carbox-
amides using N-amidopyridinium salts under metal-free, mild
reaction conditions. In the process, the N-centered radicals
formed from a SET reduction trigger a 1,5-HAT reaction to
produce δ-radical sulfonamides or γ-radical carboxamides for
subsequent installation of the pyridyl moiety. Remarkably,
excellent C4-selectivity in radical trapping with pyridinium
salts was observed for all cases investigated with primary,
secondary, and tertiary alkyl C(sp3)−H bonds, ultimately
providing synthetically valuable δ-pyridyl sulfonamides and γ-
pyridyl carboxamides. The utility of this powerful method was
further demonstrated by offering a practical approach for the
late-stage functionalization of complex amide derivatives.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03879.
Figure 2. Plausible reaction mechanism.
Experimental procedures and characterization of new
compounds (1H and 13C NMR spectra) (PDF)
to provide cation E, which undergoes further SET reduction
from Q1* to form product and B.
D
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hongorg@kaist.ac.kr.
ORCID
Sungwoo Hong: 0000-0001-9371-1730
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported financially by Institute for Basic
Science (IBS-R010-A2). We thank Inyoung Park and Mannkyu
Hong (KAIST) for substrate preparation and discussion.
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