Visible-Light-Driven C4-Selective Alkylation of Pyridinium Derivatives with Alkyl Bromides

Article abstract of DOI:10.1021/jacs.0c04499

Reported herein is a general strategy for the photochemical cross-coupling between N-amidopyridinium salts and various alkyl bromides under photocatalyst-free conditions, granting facile access to various C4-alkylated pyridines. This approach exploits the intriguing photochemical activity of electron donor-acceptor (EDA) complexes between N-amidopyridinium salts and bromide, which provides a photoactive handle capable of generating silyl radicals and driving the alkylation process. The robustness of this protocol was further demonstrated by the late-stage functionalization of complex compounds under mild and metal-free conditions.

Full text of DOI:10.1021/jacs.0c04499

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Communication
Visible Light-Driven C4-Selective Alkylation
of Pyridinium Derivatives with Alkyl Bromides
Sungwoo Jung, Sanghoon Shin, Seongjin Park, and Sungwoo Hong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c04499 • Publication Date (Web): 12 Jun 2020
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Journal of the American Chemical Society
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Visible Light-Driven C4-Selective Alkylation of Pyridinium Derivatives
with Alkyl Bromides
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Sungwoo Jung,a,b Sanghoon Shin,a,b Seongjin Park,a,b and Sungwoo Hong*,b,a
aDepartment of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
bCenter for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea
Supporting Information Placeholder
radical species.10 This study reveals the intriguing photochemical
ability of the pyridinium salt-bromide complex upon light
absorption, as it effectively undergoes SET to drive a new pattern
of reactivity.
ABSTRACT: Reported herein is a general strategy for the
photochemical cross-coupling between N-amidopyridinium salts
and various alkyl bromides under photocatalyst-free conditions,
granting facile access to various C4-alkylated pyridines. This
approach exploits the intriguing photochemical activity of
electron donor-acceptor (EDA) complexes between N-
amidopyridinium salts and bromide, which provides a photoactive
handle capable of generating silyl radicals and driving the
alkylation process. The robustness of this protocol was further
demonstrated by the late-stage functionalization of complex
compounds under mild and metal-free conditions.
Based on the ability of silyl radicals to generate alkyl radicals
through a silyl radical bromine abstraction from alkyl bromides,11
we envisioned that the photon-absorbing EDA complex between
pyridinium salt and bromide would activate (TMS)3SiH, thus
converting a variety of alkyl bromides into open-shell coupling
partners. Notably, our finding that this EDA complex serving as
an initiator of the chain pathway is key to the successful
implementation of this process to maximize the efficiency of the
desired cross-coupling. At the same time, sterically bulky N-
substituent on the pyridinium salts provides regiochemical
induction, favoring the C4-position.7 Herein, we disclose the C4-
selective alkylation of pyridine moieties with various alkyl
bromides triggered by the photochemical activity of the
pyridinium salt-bromide EDA complexes (Scheme 1c). The
reaction proceeds with primary, secondary and tertiary alkyl
bromides to provide facile access to valuable C4 alkylated
pyridine-containing building blocks under mild and metal-free
conditions.
Pyridine is a valuable motif found in a wide range of natural
products,1 biologically active molecules,2 and functional
materials.3 Along these lines, there is a growing demand for the
regioselective introduction of alkyl groups to the privileged
pyridine scaffolds.4 Among synthetic strategies, direct C–H
alkylation using readily available alkyl halides has emerged as an
increasingly popular approach. For example, the tremendous
efforts have led to various Minisci-type reactions with alkyl
halides for the C−H alkylation of N-heteroarenes.5 Despite these
advances, however, the addition of alkyl radicals to the pyridines
faces site selectivity issues involving two competitive pathways
(C2 vs. C4) or/and overalkylation, which highlights the challenges
for controlling the site-selective alkylation of pyridines (Scheme
1a). The Fu group successfully realized a palladium-catalyzed
alkylation of pyridine N-oxides6 using 2° and 3° alkyl bromides to
afford C2-alkylated pyridine N-oxides (Scheme 1b).6a In addition,
Zhou et al. applied a palladium-catalyzed alkylation to various
heteroarenes.6b On the other hand, the introduction of alkyl groups
at the C4-position of unbiased pyridines with alkyl halides
remains a long-standing challenge in the field of synthetic
chemistry.
Scheme 1. Alkylation of Pyridine Scaffolds with Alkyl
Bromides
a) Acid-promoted Minisci-type alkylation
Challenges
regioselectivity
overalkylation
harsh conditions
[O] or [Red]
+
R
Br
R
or photocatalysis
N
N
H
b) Pd-catalyzed C2-alkylation of pyridine-N-oxide
[Pd]
100 o
Zn
+
R
Br
Me
N
O
C
Me
N
O
R
Me
N
R
Previously, our group reported a photocatalytic strategy for site-
selective radical trapping with a pyridinium salt.7 As with other
photocatalyzed reactions, the photoactivation of the pyridinium
salts relies on an external photocatalyst to trigger a single-electron
transfer (SET) reduction for the generation of the reactive
radical.8 Recently, elegant synthetic strategies involving photon-
absorbing electron donor-acceptor (EDA) complexes have been
developed to promote photochemical transformations under
photocatalyst-free conditions.9 Drawing inspiration from the
utility of this strategy, we imagined a new activation mode for
pyridinium salts that would bypass the external photocatalyst,
opens up novel reactivity to further expand the synthetic potential
of pyridinium salts. On this basis, we questioned whether a
pyridinium salt could be associated with a suitable electron-rich
donor to generate the EDA complex and trigger the formation of
C2-selective
c) This work:
photocatalyst-free C4-alkylation
R
N
R3SiH
+
R
Br
N
blue LEDs, rt
NR'21
C4-selective
*
initiation
Br
Br
R3SiH
SET
BET
1
R
HAT
N
N
R3Si
NR'2
radical ion pair
NR'2
EDA complex
R
Br
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Page 2 of 8
We first screened a variety of anions and amines for their
1
2
3
4
5
6
7
8
abilities to induce the formation of an EDA complex with N-
amidopyridinium salt 1a, analyzed by UV/Vis absorption
spectroscopy. Our initial investigations revealed the formation of
colored EDA complexes upon the treatment with several electron
donors, such as TEA, hydroxide, and bromide (see the Supporting
Information for details). Importantly, mixing 1a and
tetrabutylammonium bromide (TBAB) as a source of bromide
caused a shift in the intensity of the peak corresponding to blue
light irradiation, suggesting the formation of a photoactive EDA
complex between 1a and bromide anion. We then performed a
series of Stern−Volmer experiments, which revealed that the
photoexcited pyridinium salt 1a is effectively quenched and
linearly correlated with the concentration of bromide, supporting
the notion that a reductive-quenching of 1a could generate a
bromine radical.
Considering the proposed chain mechanism, we surmised that
only a small amount of bromine radical is needed for the initiation
of this radical-mediated reaction. Indeed, a central factor in our
strategy is the use of a suitable anion to engage fast back-electron
transfer (BET)9c,12 because a rapid intermolecular SET reduction
would lead to significant consumption of starting substrate 1a
prior to coupling reactions. Notably, it was found that the
photolysis of 1a with the bromide generated a small amount of
production of the photolytic product (see Scheme 2c). In contrast,
replacing the bromide with other electron donors, such as TEA
and hydroxide, led to substantial decomposition of 1a (see
Scheme S5 for detail). Together, these observations indicate that
bromide is a suitable electron donor for inducing the formation of
the EDA complex with 1a and promoting the desired reactivity
with only minimal sacrifice of 1a.
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With this knowledge, we next evaluated the feasibility of the
proposed reactions between 1a and bromocyclohexane (2a) as
model substrates in the presence of (TMS)3SiH and NaOAc
(Table 1, see the SI for details). To our delight, we observed a
promising result under irradiation with blue LED strips at room
temperature, indicating that only trace amounts of the bromide
anion formed from in situ 2a under irradiation5c,11a-11d can
effectively initiate a radical chain reaction. Under these conditions,
C4-alkylated product 3a was produced in 83% yield as a single
n
isomer. The addition of Bu4NBr as a bromide source decreased
the product yield (entry 4), as the presence of bromide at a higher
concentration with (TMS)3SiH caused accelerated decomposition
of 1a. MeCN was the most effective of the solvents tested (entries
2 and 3). The employment of other silane sources that have higher
Si–H bond dissociation energy than that of (TMS)3SiH, failed to
afford the desired product 3a (entries 5 and 6).13 Of the various
bases tested, NaOAc displayed the best activity, and the reactivity
was significantly decreased in the absence of the base (entry 7).
Control experiments confirmed that visible light and (TMS)3SiH
are critical for this transformation (entries 8 and 9). When the
radical
scavenger
(2,2,6,6-tetramethylpiperidin-1-yl)oxyl
Table 1. Optimization of the reaction conditionsa
(TEMPO) was added to the standard reaction conditions,
complete inhibition of the reaction was observed (entry 10).
(TMS)3SiH (2.0 equiv)
NaOAc (2.0 equiv)
With the optimized reaction conditions, a variety of alkyl
bromides were subjected to the optimized reaction conditions to
demonstrate the generality of this method (Table 2). This
exploration exhibited that sterically encumbered substrates, such
as cycloalkyl, linear alkyl, adamantyl, tetrahydropyranyl,
piperidinyl, and azetidine bromides were shown to be competent
coupling partners (3a-3n). Notably, for the dibromo substrate
bearing both primary and secondary bromide groups, the reaction
selectively takes place at the secondary aliphatic position, leaving
the primary bromide intact (3f). Moreover, primary alkyl
bromides bearing common functionalities, such as (silyl)ether,
tosyl, fluoride, chloride, bromide, cyano, phenyl, vinyl, acetylenyl,
amide, ester, ketone, carbamate, and phthalimide groups were
well tolerated and afforded the desired alkylated products (3o-
3ag), reflecting the mildness and high efficiency of the method.
The functional groups that are active in cross-coupling reactions,
such as chloro, bromo, tosyl, and ester groups, remained intact,
potentially allowing for post-transformation modification. In
addition, exclusive chemoselectivity for alkyl bromide was
observed in the presence of aryl bromide, resulting in selective
formation of a single mono-pyridylation product 3y with aryl
bromide untouched. Remarkably, in all cases, complete C4
regioselectivity was achieved, regardless of whether the alkyl
bromides are primary, secondary, or tertiary, and none of the C2-
alkyl pyridines were detected. Next, we explored the scope of the
pyridine core. A broad range of pyridinium substrates bearing
various functional groups, such as methyl, ester and substituted
aryl groups at the C2-position, were selectively alkylated at the
C4-position of the pyridines to afford the desired products (4a-4f).
In addition, pyridinium salts bearing other heteroarenes, such as
thiophene and pyridine can be employed (4g and 4h). Notably,
neither the efficiency of the reaction nor the selectivity were
Br
+
-BF4
Ts
Ph
N
N
MeCN (0.1 M), rt, N2
blue LED, 24 h
2a
(2.0 equiv)
N
Ph
1a
3a
entry
variations from standard conditions
none
yield (%)b
83
1
2
acetone instead of MeCN
1,2-DCE instead of MeCN
addition of nBu4NBr (0.5 equiv)
Et3SiH instead of (TMS)3SiH
(EtO)3SiH instead of (TMS)3SiH
without NaOAc
80
3
49
4
44
5
NR
NR
7
6
7
without (TMS)3SiH
8
NR
NR
NR
without visible light irradiation
addition of TEMPO (2.0 equiv)
9
10
aReactions were performed by using 1a (0.1 mmol), 2a (2.0 equiv),
NaOAc (2.0 equiv), (TMS)3SiH (2.0 equiv) in solvent (1.0 mL) under
light irradiation using blue LED strips at rt under N2 for 24 h. bYields were
determined by 1H NMR analysis.
 Absorption spectra and Stern-Volmer quenching of 1a
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hampered by C3 substituents (methyl and methoxy) under the
1
2
3
4
5
6
7
8
current system, and the corresponding C4-alkylated products were
obtained (4i-4k). Furthermore, this method could be extended to
the alkylation of quinoline scaffold (4l).
To further demonstrate the versatility of this activation mode,
the current transformation was applied to the late-stage
functionalization
of
biorelevant
targets.
Specifically,
dehydroepiandrosterone, hecogenin, oxaprozin, and proxyphylline
could be selectively installed at the C4 position of pyridine
scaffold (5a-5e).14 Additionally, the site-selective alkylation
proceeded well when substrates derived from pyridine-based drug,
such as abiraterone acetate and vismodegib were employed (5f
and 5g). Given its generality, we expect this light-promoted
protocol to be useful for fragment couplings leading toward a
broad range of medicinal agents and complex targets.
9
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Table 2. Substrate Scope of the C4-Selective Alkylationa
1
R
NaOAc (2.0 equiv)
2
3
4
5
R'
-BF4
(TMS)3SiH (2.0 equiv)
N
+
R
Br
R'
MeCN, blue LEDs, N2, rt
N
1
2
N
Ts
3 5
-
secondary & tertiary alkyl bromides
6
7
8
9
tBu
N
Br
Ph
N
Ph
N
Ph
N
Ph
N
Ph
N
Ph
b
3g
, 81%
N
3a
Ph
, 82%
3f
, 67%
3e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
, 81%
3d
3c
, 40%
, 66%
3b
, 80%
Boc
N
Ts
N
Boc
N
O
N
Ph
, 75%
N
Ph
N
Ph
N
Ph
N
Ph
N
3m
Ph
, 58%
N
Ph
3k
3h
3l
3n
, 58%
, 75%
, 71%
3j
, 85%
3i
, 80%
primary alkyl bromidesb
R
Cl
3
OPh
OTBS
4
OTs
2
F
2
Br
O
2
N
Ph
N
Ph
N
Ph
N
Ph
N
Ph
, 60%
N
Ph
, 54%
N
3t
Ph
, 61%
3o
3p
, R = C5H11, 62%
, R = C12H25, 62%
3q
3r
3s
3u
, 60%
, 65%
3v
, 52%
H
N
NHBoc
Ph
Br
CN
Ph
O
N
Ph
N
Ph
N
Ph
N
Ph
N
Ph
N
Ph
N
3x
Ph
, 71%
N
3ad
Ph
, 55%
3w
3z
3aa
3ab
3ac
, 60%
, 52%
, 52%
, 50%
, 62%
3y
, 62%
scope of pyridine core
O
N
O
O
OEt
N
O
O
N
Ph
N
Ph
N
Ph
N
3ae
, 58%
3ag
N
CO2Me
, 56%
, 60%
N
N
Me
b
3af
, 67%
b
4c
4d
, 81%
CF3
4a
4b
, 67%
, 70%
OMe
Me
S
N
N
N
N
N
N
4k
N
Ph
N
b
b
N
b
b
4j
, 65%
4i
, 80%
4l
4h
, 67%
, 71%
,61%
4g
, 60%
4e
4f
Br
, 91%
, 74%
OMe
late-stage functionalizations
dehydroepiandrosterone
from
O
O
O
H
from D-galactopyranose
hecogenin
from
OAc
H
O
H
H
AcO
O
H
H

H
H
*
*
Ph
AcO
5a'
OMe
H
N
OAc
5c
N
N
5b 5b'
66%, (
:
= 1.3:1, d.r.)
b
5a 5a'
= 1.1:1, d.r.)
63%, (
:
, 52%
Ph
Ph
from oxaprozin
vismodegib
from
abiraterone acetate
from
proxyphilline
from
N
Ph
Cl
O
O
N
N
N
O
N
H
N
N
O
H
O
N
N
O
S
O
Cl
H
H
N
b
5g
, 79%
5d
, 51%
5f
5e
, 60%
, 50%
O
aReactions were performed with 1 (0.1 mmol), 2 (2.0 equiv), NaOAc (2.0 equiv), (TMS)3SiH (2.0 equiv) in MeCN (1.0 mL) under light irradiation using
blue LED strips (465 nm) at rt under N2 for 24 h. Yields of isolated products. bUsing Kessil blue LED (440 nm).
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To elucidate the reaction mechanism, we carried out a series of
amidopyridinium salt, and the regioselectivity is controlled by the
N-substituent.7 Next, the reaction is expected to proceed via
deprotonation of cationic radical species II and C–N bond
cleavage to deliver the desired product and amidyl radical. The
photochemically generated amidyl radical initiates a new chain
propagation manifold via a HAT event with (TMS)3SiH. Indeed,
this EDA complex serves as an effective initiator of the chain
pathway, which explains the high value of quantum yield (Φ =
19.0).
1
2
3
4
5
6
7
8
control experiments. When cyclopropylmethyl bromide was
employed as the substrate, ring-opened linear product 6 was
observed, which implies a radical ring-opening is involved
(Scheme 2a). To determine whether the pyridine species
generated by a single-electron reduction could act as a substrate,
mixtures of 1a and pyridine 1ea were subjected to the standard
reaction conditions, and alkylation occurred only at the
pyridinium salt 1a (Scheme 2b). Next, we investigated the
feasibility of the photolysis of the pyridinium salt (Scheme 2c).
Under blue LED irradiation, the photolysis of 1a did not occur.
On the other hand, upon addition of TBAB to the reaction mixture,
we detected the formation of photolytic product 1aa, which could
be accelerated in the presence of (TMS)3SiH. These results
revealed that the photoinduced SET occurred between 1a and
bromide to generate bromine radicals. Finally, to showcase the
synthetic utility of this transformation, we ventured to explore the
sequential pyridylation reactions of the dibromo substrate by
employing two different pyridyl sources 1a and 8. Gratifyingly,
the pyridyl group and vismodegib were consecutively installed
through two sequential processes to afford 9 (Scheme 2d).
NaOAc
9
*
Br
R3Si-H
initiation
R3Si
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SET
BET
Br
Br
N
X
N
X
N
X
HBr
1
I
R
R
Br
NHTs(Me)
R3Si-H
EDA complex
X = NTs(Me)
R3SiBr
chain process
NTs(Me)
R
R
1
- H+
N
N
II
Scheme 2. Control Experiments and Sequential Pyridylation
product
NTs(Me)
standard
Figure 1. Proposed reaction mechanism.
conditions
+
-BF4
Ts
Ph
N
N
1a
a)
Br
61%
In summary, we report a general strategy for the C4 selective
alkylation of N-amidopyridinium salts with alkyl bromides
without requiring an external photoredox catalyst. A photoexcited
pyridinium salt-bromide complex is key to the success of this
process, as it enables the generation of silyl radicals from
(TMS)3SiH. In the process, a variety of alkyl bromides can be
converted to the corresponding alkyl radical coupling partners,
allowing facile access to privileged C4-alkylated pyridine
building blocks that would be difficult to prepare with
conventional approaches. The utility of this protocol is further
demonstrated by the late-stage functionalization of biorelevant
compounds. This study demonstrates the potential of N-
amidopyridinium salts to promote new photochemical reactions in
synthetic chemistry.
(2.0 equiv)
N
Ph
6
Cy
N
Cy
standard
conditions
+
1a
1a
b)
c)
+
cyclohexyl Br
(2.0 equiv)
N
PMP
Ph
N
PMP
1ea
3a
, 82%
N/D
additive
+
1a
CD3CN (0.1 M), rt, N2
blue LEDs, 12 h
N
1aa
Ph
additive (1.0 equiv)
none
1aa
N/D
N/D
3%
1a
>99%
>99%
97%
NaOAc
ASSOCIATED CONTENT
Supporting Information
TBAB
TBAB + TTMSSa
9%
75%
aC4-Silylated product 7 was observed in 14%
Experimental procedure and characterization of new compounds
(1H and 13C NMR spectra). This material is available free of
charge via the Internet at http://pubs.acs.org.
d)
Cl
O
Cl
standard conditions
N
1a,
i) with
67%
H
O
N
Br
AUTHOR INFORMATION
S
O
8,
ii) with 58%
Br
9
Ph
N
Corresponding Author
* hongorg@kaist.ac.kr.
Cl
O
Cl
N
H
Ph
N
-BF4
ORCID
O
S
N
-BF4
Ts
N
N
Ts
Sungwoo Hong: 0000-0001-9371-1730
O
1a
8
ACKNOWLEDGMENT
Based on these observations, we propose a reaction mechanism
involving the initial formation of a photoactive pyridinium-
bromide complex (Figure 1). Photoexcited EDA complex I
undergoes an intramolecular SET to trigger the formation of a
bromine radical that subsequently abstracts a hydrogen atom from
(TMS)3SiH, thus interrupting the BET.9c This process leads to the
formation of a silyl radical that in turn, abstracts bromine from an
alkyl bromide to produce the corresponding alkyl radical. The
alkyl radical is then trapped at the C4 position of the N-
This research was supported financially by Institute for Basic
Science (IBS-R010-A2). We thank Dr. Dongwook Kim (IBS) for
XRD analysis.
REFERENCES
(1) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Heterocycles
in Life and Society: An Introduction to Heterocyclic Chemistry,
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Biochemistry, and Applications, 2nd Edition; John Wiley & Sons:
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(14) CCDC 1994429 (5a’) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
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Journal of the American Chemical Society
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