Merging Visible Light with Cross-Coupling: The Photochemical Direct C-H Difluoroalkylation of Imidazopyridines

Article abstract of DOI:10.1021/acs.orglett.9b02487

A transition-metal-free protocol for the difluoroalkylation of imidazopyridines with bromodifluoroaryl ketones promoted by visible light irradiation is presented. This protocol is distinguished by simple, mild, and catalyst-free reaction conditions with a

Full text of DOI:10.1021/acs.orglett.9b02487

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Merging Visible Light with Cross-Coupling: The Photochemical
Direct C−H Difluoroalkylation of Imidazopyridines
Chuan-Hua Qu,† Gui-Ting Song,
,∥
†,§,∥
Jia Xu, Wei Yan, Cheng-He Zhou, Hong-Yu Li,*,‡
†
‡
§
,
†
,†
Zhong-Zhu Chen,* and Zhi-Gang Xu*
†International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, 319 Honghe Avenue,
Yongchuan, Chongqing 402160, China
‡
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas
7
§
2205, United States
Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of
Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
*
S Supporting Information
ABSTRACT: A transition-metal-free protocol for the di-
fluoroalkylation of imidazopyridines with bromodifluoroaryl
ketones promoted by visible light irradiation is presented. This
protocol is distinguished by simple, mild, and catalyst-free
reaction conditions with a wide reaction scope, which is
complementary to existing difluoroalkylation strategies by
photoredox scenarios. Additionally, this protocol potentially
offers a new way for streamlining the synthesis of compounds
containing the difluoro moiety.
he difluoromethylene group (CF ), which represents an
isosteric analogue of the oxygen atom, is an architectur-
Scheme 1. Difluoroalkylation Technology
2
1
T
ally important motif in numerous bioactive molecules and
2
pharmaceuticals. The introduction of C−F bonds into small
molecules has been widely accepted in drug design to solve
3
drug metabolism problems. Direct C−H difluoroalkylation of
arenes is an efficient tool to construct pivotal C−CF bonds,
2
for which tremendous efforts have been committed; however,
these mainstream developments are limited to the transition-
4
5
6
metal-mediated methods (Scheme 1a). Although Ir, Ru,
7
8
9
10
Cu, Pd, Ni, and Fe -catalyzed difluoroalkylation reactions
were reported extensively, there still remains an urgent need
for the synthesis of such a pivotal structural moiety with
environmentally friendly conditions. The transition-metal-free
strategy, undoubtedly, emerged as a novel promising area for
chemical synthesis. In the past two years, visible light-
promoted transition-metal-free protocol involving a distinct
photocatalyst-free, visible light-mediated, radical generation
event is particularly appealing in organic synthesis but was only
minimally explored. To the best of our knowledge, no
example using visible light-promoted transition-metal-free
method in the direct difluoroalkylation of arenes has been
reported.
11
12
of architecturally complex bond constructions that are usually
impossible via classical photoredox pathways in the absence of
photosensitizer. Despite the impressive progress, the radical
precursors are only limited to alkyl iodides, while a rare
precedent has been realized with alkyl bromides. This lack of
development stems from the difficulty in the homolysis of the
C−Br bond compared to the C−I bond when using visible
The seminal work on visible light-induced transition-metal-
12b−g
12a
free protocol from Studer et al.
and Aggarwal et al.
demonstrated the peculiar photochemical behavior of alkyl
iodides in radical chemistry (Scheme 1b). In such cases, alkyl
radicals generated upon the light-induced C−I bond homolysis
can be converted into products over one or several steps. This
strategy allows for the direct and economical transformations
Received: July 17, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02487
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
light as the energy source; however, the C−Br bond homolysis
is necessarily required as a radical initiation step to drive the
desired transition-metal-free mediated cycle.
Table 1. Optimization of Reaction Conditions
Recently, we found that alkyl bromides, such as α-bromo
difluoroacylarenes, exhibit specific photochemical properties,
which can deliver difluoroalkyl radicals upon irradiation to
achieve difluorocarbonylation and radical cyclization of
13
b
oxazoline olefins via transition-metal-free protocol. Alkyl
bromides have several advantages for photoinduced transition-
metal-free protocol compared with alkyl iodides as radical
source: (1) most alkyl bromides are readily commercially
available and more affordable; (2) alkyl bromides are easier to
handle than the severe lachrymatory alkyl iodides; (3) most
alkyl bromides are abundant and structurally diverse synthons.
However, the mechanistic understanding of photochemical
transition-metal-free strategy induced by alkyl bromides is
currently far less clear than the alkyl iodides. The experimental
influencing factors and the structural effect for alkyl bromide-
mediated transition-metal-free strategy are still insufficiently
investigated. For example, when phenacyl iodides and phenacyl
bromides were, respectively, applied to the photochemical
alkylation of the vinyl boronate complexes, alkyl iodides
entry
variation from standard conditions
none
8 h
21 h
without base
yield
1
2
3
4
5
6
7
8
77
31
63
/
2,6-lutidine instead of TMEDA
40
63
65
45
<10
44
37
65
12
/
Et N instead of TMEDA
3
DIPEA instead of TMEDA
Cs CO instead of TMEDA
2
3
9
K CO instead of TMEDA
2 3
10
11
12
13
14
15
16
DMA instead of MeCN
DCM instead of MeCN
MTBE instead of MeCN
5 W blue LEDs instead of 33 W CFL
reaction in the dark
12a
worked well, but alkyl bromides performed poorly.
80 °C without irradiation
under air
/
Fused bicyclic five- to six-membered heterocycles (e.g.,
imidazo[1,2-α]pyridine) are prominent scaffolds due to their
Mess
a
Reactions were performed on a 0.2 mmol scale using 1.5 equiv of 2a
and 2.0 equiv of base, [1a] = 0.1 M, and a 33 W CFL bulb to
illuminate the reaction vessel. Yields are those of products isolated
by column chormatography. DMA = N,N-dimethylacetamide, MTBE
1
4
prevalence in many biologically active drugs, such as
1
5
b
zolpidem, alpidem, saripidem, and necopidem. Indeed,
tremendous progress has been reported in the C-3
functionalization of imidazoheterocycles over the past
=
methyl tert-butyl ether, Et N = triethylamine, DIPEA = N,N-di-
3
1
6
isopropylethylamine, TMEDA = tetramethylethylenediamine.
decade; however, the majority of current methods in this
area require the use of transition metals, stoichiometric
oxidants, and harsh reaction conditions. Developing an
efficient and green synthetic method to functionalize the
imidazoheterocycle skeletons such as the C-3 difluoroalkylated
imidazo[1,2-α]pyridines is therefore highly desirable. In this
paper, we describe a simple and efficient difluoroalkylation
protocol of various imidazopyridines with α-bromo difluor-
oacylarenes through transition-metal-free photoelectron catal-
ysis (Scheme 1c), which distinguishes from the traditional
methods for the modification of imidazo[1,2-α] pyridines. This
transformation should be of fundamental interest, especially for
the area of medicinal chemistry, because the metabolically
important difluoroalkyl moiety and a structurally prominent
heteroarene are fused together in this protocol.
absence of base (entry 4). Using 2,6-lutidine gave a lower yield
of 40% (entry 5). More basic tertiary amines, such as
triethylamine (Et N) and N,N-di-isopropylethylamine
3
(DIPEA), still exhibited inferior reactivity to that of TMEDA
(entries 6 and 7). Interestingly, the difluoroalkylation of
imidazopyridines could also proceed by using an inorganic
base such as Cs CO in the replacement of TMEDA (entry 8),
2
3
since Cs CO has been proven to be an excellent base and
2
3
1
8
electron transfer agent. However, K CO significantly
2
3
reduced the efficiency of the reaction (entry 9). Further
screening demonstrated that solvents, such as dimethylaceta-
mide (DMA), dichloromethane (DCM), and methyl tert-butyl
ether (MTBE), are less effective (entries 10−12). Intriguingly,
the use of 5 W blue light-emitting diodes (LEDs) with a
wavelength of only ∼460 nm instead of 33 W CFL bulb, led to
a significant drop in yield (entry 13). We speculate that the
residual near-ultraviolet light from fluorescent light source
influences the degree of homolysis of 2a and its subsequent
reactivity on the photoinduced transition-metal-free method.
Notably, the essential role of visible light irradiation was
confirmed in the next control experiments (entries 14 and 15):
no detectable product was observed when the reaction was
conducted in dark or even heated conventionally at 80 °C,
excluding the possibility of thermal induction. Moreover, the
exposure of the reaction to air completely prevented the
reaction to occur for the desired product (entry 16).
13,17
Guided by our exploration in difluoroalkylation,
we
decided to utilize bromodifluoroaryl ketones as radical
precursors, since they have been proven to be readily single-
electron transfer (SET)-reduced. Reactions conducted with 2-
phenylimidazo[1,2-α]pyridine (1a) as the C-radical acceptor
and 2-bromo-2, 2-difluoro-1-phenylethan-1-one (2a) as the C-
radical precursor are shown in Table 1. Under the optimal
reaction conditions with a mild organic base (tetramethyle-
thylenediamine, TMEDA), a solvent (acetonitrile, MeCN),
and irradiation by 33 W compact fluorescent light (CFL) bulb
at room temperature, we obtained an exclusively C3-selective
cross-coupled product 3ha in 77% yield (entry 1). Performing
the reaction using TMEDA as an organic base in MeCN for a
series of different reaction time revealed that the longer
reaction time had a more positive influence on the reactivity
To explore the reaction scope, various imidazo[1,2-α]
pyridines were investigated. As shown in Scheme 2, a broad
range of imidazopyridines 1 with diverse substituents on the
arene moiety (Ar) and/or the pyridine ring underwent efficient
cross-coupling. These included methyl- and methoxyl-sub-
stituted substrates, which afforded cross-coupled products in
(
entries 1−3). It was found that TMEDA played a pivotal role
in this reaction. It not only captured the bromine anion but
also unplugged the proton of intermediate II to give a radical
anion III (vide infra). The reaction did not occur at all in the
B
DOI: 10.1021/acs.orglett.9b02487
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of the C−H Difluoroalkylation in the
reaction also worked with benzo[d]-imidazo[2,1-b]thiazoles
bearing various functional groups such as methoxy, chloro, and
fluoro moieties via transition-medal-free strategy (3ga−3gd).
More substituted α-bromodifluoroacylarene-coupling partners
were explored next. α-Bromodifluoroacylarenes 2 bearing
diverse electronic and steric substituents at the para-position
of the aryl ring gave the cross-coupled imidazo[1,2-α]
pyridines 3ha−3he in moderate to excellent yields (73−
,
a b
Transition-Metal-Free Protocol
87%). It was worth noting that difluoroacylarenes derived from
polycyclic arenes 3hf and 3hh were also well-tolerated. Besides
arene substrates, heteroaromatic ring, such as thiophene ring,
was also compatible with the reaction, leading to coupling
product in 79% yield (3hg). The mild reaction conditions
enable the imidazo[2,1-b]thiazoles to react well with t-Bu- and
OMe-substituted difluoroacylarenes, producing desired prod-
ucts in 87% and 83% yields, respectively (3ia and 3ib).
After the substrates scope was evaluated, several control and
comparative experiments were performed to shed light on the
reaction mechanism (see Supporting Information). In initial
experiments, the photoinduced transition-metal-free cross-
coupling reaction of 1a with 2-bromoacetophenone 4 or α-
monofluoroacetophenone 6 could not occur under standard
conditions (Scheme S1). These results suggested that the CF2
group of α-bromo, α-difluoroaryl ketones plays a crucial role in
this transformation. Subsequently, two radical trapping experi-
ments were conducted. When a radical inhibitor, 1,1-
diphenylethylene 8, was introduced into the reaction solution
of 1a, α-bromodifluoroacylarene 2c, and TMEDA in MeCN,
the reaction was partly suppressed; that is, only 25% yield of
the desired product was obtained, accompanied by 68% of
starting material recovery. Meanwhile, the CF COAr-trapped
2
compound 9 was isolated in 70% yield (Scheme S2).
Comparatively, this reaction was completely suppressed in
the presence of 2.0 equiv of (2,2,6,6-tetramethylpiperidin-1-
yl)oxyl (TEMPO) as a radical scavenger, and the CF COAr-
2
trapped product 10 was detected by high-resolution mass
spectrometry (HRMS; Scheme S3). Thus, these results suggest
that a free-radical process is involved in the reaction.
a
Reaction conditions unless otherwise specified: 1 (0.2 mmol), 2 (0.3
On the basis of the experiment results described above and
mmol), TMEDA (0.4 mmol), MeCN (2.0 mL), room temperature,
under Ar atmosphere, for 36−72 h. Yields are reported for the
isolated products.
13
in our previous reports, a postulated mechanism is depicted
b
2
in Scheme 3. We assume that the visible light irradiation of the
photosensitive 2a may induce an energy transfer, affording the
excited intermediate 2a, which undergoes a rapid C−Br bond
homolysis to generate the difluoroacyl radical species I (path
a). Alternatively, the report of tertiary amines to form electron
donor−acceptor complexes (EDACs) with electron-accepting
good yield (3aa and 3ab, 80% and 73% yield, respectively).
Imidazopyridines possessing various halogens, such as fluorine,
chlorine, and bromine, which were useful modules for further
functionalization, were well-compatible, and the desired
products could be obtained in moderate to good yields (3ac,
20
molecules of high electron affinity suggests that the lone-pair
electrons of TMEDA could engage in such a molecular
aggregation with 2a (path b); however, the optical absorption
spectrum did not demonstrate a bathochromic displacement in
the visible spectral region (see Supporting Information),
affirming that path a is the only possible mechanic path. The
difluoroacyl radical I then regioselectively attaches to the C3
position of 1a to afford radical intermediate II. II will be
deprotonated by TMEDA to give the key heteroaryl radical
3
ba−3bd, 3c, 3d, and 3ea−3eb). Remarkably, the CN
substituent, which was a strong electron-withdrawing group,
proceeded well to produce the target molecule 3bc in good
yield. Notably, the 2-ester-substituted imidazopyridine could
also be reacted smoothly to obtain the target product 3c, albeit
with 46% yield. To expand the potential utility of this protocol
for medicinal chemistry, we then turned our attention to
examine the tolerance of other imidazoheterocycles, such as
imidazo[2,1-b]thiazole and benzo[d]-imidazo[2,1-b]thiazole
derivatives, which were pivotal building skeletons in medicinal
21
anion III, which then reduces 2a by SET to eventually afford
the target product 3ha and difluoroacyl radical I.
In summary, we have developed a direct C−H difluor-
oalkylation of heteroarenes. The photosensitizer-free, visible-
1
9
chemistry. Neutral imidazo[2,1-b]thiazoles furnished the
desired products 3fa and 3fd with fair yields. Reaction with
either electron-donating (methoxy) or electron-withdrawing
light-mediated C−CF cross coupling comprises two highly
2
important partners, namely, structurally privileged imidazopyr-
idines and the metabolically pivotal difluoroalkyl moiety, by
transition-metal-free strategy. Notably, transition-metal-free
(
cyano) substrates proceeded successfully to give 3fb and 3fc
in 75% and 87% yields, respectively. The cross-coupling
C
DOI: 10.1021/acs.orglett.9b02487
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Proposed Mechanism
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the Science and Technology Research
Program of Chongqing Municipal Education Commission
■
(
KJZH17129, KJQN201801321, KJZD-M201801301), the
Natural Science Foundation Project of CQ CSTSC
CSTC2015ZDCY-ZTZX120003, cstc2018jszx-cyzd0110,
(
and cstc2018jszx-cyzdX0023), and the Scientific Research
Foundation of the Chongqing Univ. of Arts and Sciences
(
Z2016BX02). We also thank Ms. H. Z. Liu of Chongqing
Univ. of Arts and Sciences for obtaining the LC/MS, HRMS,
and NMR data.
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Organic Letters
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DOI: 10.1021/acs.orglett.9b02487
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