Reduced Phenalenyl in Catalytic Dehalogenative Deuteration and Hydrodehalogenation of Aryl Halides

Article abstract of DOI:10.1021/acs.joc.1c00573

Dehalogenative deuteration reactions are generally performed through metal-mediated processes. This report demonstrates a mild protocol for hydrodehalogenation and dehalogenative deuteration of aryl/heteroaryl halides (39 examples) using a reduced odd alternant hydrocarbon phenalenyl under transition metal-free conditions and has been employed successfully for the incorporation of deuterium in various biologically active compounds. The combined approach of experimental and theoretical studies revealed a single electron transfer-based mechanism.

Full text of DOI:10.1021/acs.joc.1c00573

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Reduced Phenalenyl in Catalytic Dehalogenative Deuteration and
Hydrodehalogenation of Aryl Halides
Bhagat Singh, Jasimuddin Ahmed, Amit Biswas, Rupankar Paira,* and Swadhin K. Mandal*
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ABSTRACT: Dehalogenative deuteration reactions are generally
performed through metal-mediated processes. This report demonstrates
a mild protocol for hydrodehalogenation and dehalogenative deuteration
of aryl/heteroaryl halides (39 examples) using a reduced odd alternant
hydrocarbon phenalenyl under transition metal-free conditions and has
been employed successfully for the incorporation of deuterium in various
biologically active compounds. The combined approach of experimental
and theoretical studies revealed a single electron transfer-based
mechanism.
by Studer and co-workers30 utilized 1,10-phenanthroline/NaH
for radical-mediated catalytic hydrodehalogenation (Scheme
1a), which operates at high temperature (140−160 °C) and
requires high catalyst loading (20 mol %), leaving ample scope
to establish a milder and more effective hydrodehalogenation
methodology.
INTRODUCTION
■
Hydrodehalogenation of aryl/heteroaryl halides is a crucial
reductive reaction,1 which can be accessed by several metal-
catalyzed reductions,2−6 metal−halogen exchange,1,7,8 reduc-
tion by hydride,9 solid-supported metal catalysis,10 etc. This
process is well-known as a remediation strategy to convert
toxic organic halides into benign chemicals in industry.11−13
However, metal-based hydrodehalogenation suffers from toxic
waste, low substrate scope, and high-temperature reaction
conditions. These drawbacks led to the evolution of an
alternative radical dehalogenation method,14−21 which func-
tions under relatively mild conditions. For example,
Stephenson and co-workers successfully described a single
electron transfer (SET)-based method employing an iridium-
based photocatalysft fac-Ir(ppy)3 in the presence of visible light
at ambient temperature.22 However, this method uses the rare
metal-based catalyst. To avoid expensive metals in such
transformation, recent reports appeared on the use of a Na-
alcoholate, solvent-mediated process in the presence of a base
that worked either at high temperature or under light
stimulation in a noncatalytic fashion to perform a hydro-
dehalogenation reaction.23−25 Murphy and co-workers ex-
plored a protocol using an organic electron donor (tetra-
(iminophosphorano)-substituted bispyridinylidene) under
noncatalytic conditions.26,27 Such an approach conceptually
indicates the capability of an organic electron donor to
function as a dehalogenative agent under a mild condition.
Furthermore, the deuterated version of this transformation,
namely, dehalogenative deuteration, is of significant impor-
tance if it can be accomplished under mild and expensive
transition-metal free catalytic conditions. The field of
dehalogenative deuteration has drawn significant attention
due to its tremendous potential in the preparation of different
drug molecules with a longer lifespan in plasma, which
prevents off-target site interactions and/or leads to accom-
plishing higher efficacy.31−34 As a result, incorporation of
deuterium in a molecule appeared as clinically highly
significant. Deuterium-labeled analogues of the drug are
utilized in absorption, distribution, metabolism, and excretion
studies and have the potential to facilitate the discovery of new
pharmacophores.35−40 However, dehalogenative deuteration
reactions1,3,41−44 mainly involved precious transition metal
catalysts/ligands and costly deuterium sources or noncatalytic
methodologies using sodium amalgam45 and lithium-halogen
exchange,46−48 which suffer from harsh conditions and require
highly sensitive alkyl-lithium reagents. In 2011, Mutsumi et
al.49 demonstrated the deuterated version of this hydro-
Received: March 10, 2021
Published: May 5, 2021
̈
In this regard, Konig and co-workers demonstrated the first
metal-free catalytic hydrodehalogenation using the perylene
diimide (PDI)/Et3N combination, which requires light
irradiation (Scheme 1a).28 Later on, de Alaniz et al. developed
a photocatalyzed hydrodehalogenation in the presence of 10-
phenylphenothiazine (PTH) (Scheme 1a).29 A recent report
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Scheme 1. Hydrodehalogenation/Dehalogenative Deuteration of Aryl Halide: (a) Previous Reports on Catalytic
Organocatalytic Hydrodehalogenation; (b) Strategy of This Work; and (c) Our Catalytic Protocol
dehalogenation reaction, namely, catalytic dehalogenative
deuteration of aromatic nuclei utilizing 2,2′-azobis(2,4-
dimethylvaleronitrile) (V-65) in combination with an organo-
tin reagent and THF-d8 as deuterium sources, but the necessity
of toxic Bu3SnH, high temperature, and expensive deuterium
sources (≈$630 for 10 g of THF-d8, Sigma-Aldrich Cat. No.
184314-10G)50 are considered to be the major drawbacks of
this method. Recently, Liu and co-workers51 utilized
hexamethyldisilane in combination with potassium methoxide
and CD3CN as a deuterium source for dehalogenative
deuteration in a noncatalytic fashion. However, this protocol
also suffers from the use of an excess amount of reagents and
expensive deuterium sources52 (≈$787 for 100 g of CD3CN,
Sigma-Aldrich Cat. No. 151807-100G). Therefore, a catalytic
reaction protocol using transition metal-free catalysts and
cheaper deuterium sources functioning at room temperature is
highly desirable for dehalogenative deuteration.
scaffold for designing transition metal-free catalysts to
accomplish dehalogenative deuteration and hydrodehalogena-
tion processes. The capability of a PLY-based moiety as an
organic electron carrier in various organic transformations,
without substantial perturbation of aromaticity of the
phenalenyl core, is very well documented in recent
studies.57−59 The presence of an empty nonbonding molecular
orbital of PLY cations having 12π e− can lead to successive
reduction by two electrons, transforming it into an odd 13π e−-
based neutral radical and an anionic species (14π e−).55,60
Recently, Zeng and co-workers calculated the nuclear
independent chemical shift values in pristine phenalenyl
systems and found the values to be negative, which indicates
that reduced PLY can retain their aromaticity upon electron
acceptance.61 Earlier, the 13π e− radicals of PLY species have
been used extensively in designing spintronics62,63 as well as
bistable materials.64 In addition, it was also recently employed
for the catalytic C−H functionalization of unactivated arenes
as well as heteroarenes with aryl halides at 130 °C.65,66 To
avoid high-temperature activation of aryl halides, we recently
focused on the utilization of the more reactive doubly reduced
14π e− species.67 It may be recalled that the 14π e− species of
Herein, we aimed at developing a catalytic reaction protocol
for dehalogenation (both hydrodehalogenation and dehaloge-
native deuteration) under transition metal-free conditions
adopting a cost-effective approach. In this regard, we introduce
an odd alternant hydrocarbon phenalenyl (PLY)53−56 as a
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a
Table 1. Optimization and Control Experiments on the Hydrodehalogenation/Dehalogenative Deuteration Reaction
b
entry
catalyst (mol %)
base (equiv)
time (h)
K (mol %)
solvent (mL)
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
yield (%)
1
2
3
4
5
6
7
L1 (5)
KOtBu (1.4)
KOtBu (1.4)
KOtBu (1.5)
KOtBu (1.6)
KOtBu (1.5)
KOtBu (1.3)
KOtBu (1.7)
Cs2CO3 (1.3)
CsF (1.3)
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.5)
KOtBu (1.3)
KOtBu (1.3)
24
24
24
24
24
24
24
24
24
24
24
12
24
24
24
24
24
7
47
64
77
L1 (7.5)
L1 (10)
L1 (15)
L2 (10)
L3 (10)
L4 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
L1 (10)
10
13
20
13
25
25
13
13
13
13
13
d
83
62
74
71
39
53
50
c
8
9
c
DMSO (1)
dioxane (1)
10
11
12
13
14
d
DMSO:dioxane (1.4)
DMSO:dioxane (1.4)
DMSO:dioxane (1.4)
DMSO:dioxane (1.4)
DMSO:dioxane (1.4)
DMSO:dioxane (1.4)
93
63
15
17
11
36
13
13
c
15
L1 (10)
L1 (10)
L1 (10)
16
17
KOtBu (1.5)
KOtBu (1.5)
d
13
DMSO-d6 (1.3)
74
a
b
1
Reactions were performed under nitrogen atmosphere in a pressure tube with 0.15 mmol of 4-iodobiphenyl at rt. Determined by H NMR
c
d
spectroscopy. KOtBu, 0.2 mmol. Isolated yield.
PLY, although anticipated six decades back,55 remained
practically unexplored in terms of their applications except
for the recent report by us.67 With the help of preliminary DFT
calculations, we anticipated that the doubly reduced anionic
state of PLY would accumulate sufficient energy to facilitate a
single electron transfer to the LUMO of aryl halide (Scheme
1b), generating reactive aryl radical species that can
subsequently accept hydrogen/deuterium atoms. In this
work, we report the utilization of such reduced PLY species
as a catalyst in combination with potassium tert-butoxide to
execute the hydrodehalogenation and dehalogenative deutera-
tion of aryl halides using DMSO-d6 as a deuterium source
(≈$195 for 100 g of DMSO-d6, Sigma-Aldrich Cat. No.
151874-100G)68 at room temperature (Scheme 1c).
Results and Discussion. To start with, we considered 4-
iodobiphenyl (1a) as a model substrate for the proposed
hydrodehalogenation/dehalogenative deuteration chemistry.
Initially, the hydrodehalogenation of 1a was attempted with
9-methylamino-phenalen-1-one (L1, 5 mol %) as a precatalyst,
metallic potassium (7 mol %), potassium tert-butoxide (1.4
equiv), and DMSO (1 mL) in a pressure tube for 24 h at rt.
(Table 1, entry 1), which produced the hydrodehalogenation
product biphenyl (2a) with a moderate yield of 47%. The yield
improved to 64% when 7.5 mol % precatalyst (L1) was loaded
(Table 1, entry 2) and further raised to 77% (Table 1, entry 3)
with 10 mol % precatalyst loading in DMSO. A further increase
in precatalyst loading, however, did not improve the product
yield (Table 1, entry 4).
Next, we evaluated different phenalenyl ligands L2−L4
(Table 1) for their catalytic efficacy, but none of them could
exhibit improved results (Table 1, entries 5−7), and L1 turned
out to be the best choice. Even screening of different bases,
such as Cs2CO3 and CsF, as well as different solvents could not
improve the yield further (Table 1, entries 8−10). However, a
mixture of DMSO and dioxane in a 1:1 ratio resulted in 93%
isolated yield of the desired hydrodehalogenated product (2a,
Table 1, entry 11) under ambient conditions. The optimum
reaction time was found to be 24 h, as reducing the reaction
time to 12 h (Table 1, entry 12) led to a decreased yield of 2a
to 63%. Finally, in a control experiment, without using both
the phenalenyl ligand and potassium metal and in another
control, excluding the phenalenyl ligand only, afforded 2a in
<20% yield (Table 1, entries 13 and 14). Another control
reaction with the exclusion of base resulted in only 11% yield
of 2a under optimized conditions (Table 1, entry 15). Further
control reaction with PLY and potassium tert-butoxide yielded
36% of the product (Table 1, entry 16). All these results clearly
indicated the essentiality of combining the PLY ligand, a
catalytic amount of metallic potassium, and potassium tert-
butoxide as a productive recipe to execute the hydro-
dehalogenation reaction successfully. Also, under these
optimized reaction parameters, we employed DMSO-d6, as a
relatively cheap deuterium source (≈$195 for 100 g of DMSO-
d6), to perform the dehalogenative deuteration reaction. The
desired product, 4-deuterobiphenyl (2a′) in this case, was
successfully isolated in 74% yield (Table 1, entry 17). More
importantly, the deuterated product was obtained with
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Figure 1. Longevity test of the present catalyst during the hydrodehalogenation reaction. The designated yields are NMR conversion, and the result
was reproduced twice.
a
Scheme 2. Substrate Scope for the Hydrodehalogenation Reaction
a
Reactions were performed under nitrogen atmosphere in a pressure tube with 0.15 mmol of the substrate, 0.015 mmol of catalyst, 0.02 mmol of K,
0.225 mmol of KOtBu, and 1.4 mL of solvent. Yields reported are isolated and an average yield of two catalytic runs.
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exclusive deuterium integration in this transition metal-free
approach under the ambient condition. The deuterium
incorporation was confirmed by comparing the 1H NMR
spectra of both the deuterated product and the corresponding
hydrodehalogenated product, and it was found that the
corresponding proton peak was absent.69 Next, it became
obvious from our longevity experiment (see Figure 1) that the
active catalyst sustains over several consecutive catalytic cycles
under the optimized reaction conditions. In such an experi-
ment, the catalyst (L1) was incorporated at 10 mol % loading
once and executed five successive catalytic cycles with 4-
iodobiphenyl (2a), and the catalytic efficiency was studied over
several runs successively. After each catalytic run, a fresh batch
of 4-iodobiphenyl (1 equiv) and potassium tert-butoxide (1.3
equiv) was added in the same reaction pot, but no further
catalyst (L1) or potassium was loaded into the reaction
mixture (see the Experimental Section for details). To our
delight, the catalyst was found to have sustained activity even
up to the fifth catalytic run. Although its efficiency declined
gradually over successive catalytic cycles to a moderate yield of
60% after the fifth cycle, nevertheless, this observation clearly
indicates the sustained stability of the active catalyst over
consecutive catalytic runs.
With these initial results in hand, this study further advanced
with the exploration of potential substrate scope. A diverse
range of aryl/heteroaryl halides under the optimized reaction
conditions was subjected to such hydrodehalogenation,
yielding good to excellent yields of the hydrodehalogenated
products. For example, 2-iodobiphenyl was efficiently reduced
to biphenyl (2a) with an excellent yield (91%, Scheme 2).
Also, 1-iodonaphthalene produced naphthalene (2c) with a
moderate yield (61%, Scheme 2). The alkoxy and alkylamino-
arenes under the optimized reaction conditions resulted in the
respective hydro-deiodinated arenes, such as hexyloxy (2d)
and dialkyl amino (2f and 2g) benzenes in 53−80% yields
(Scheme 2). Furthermore, diiodoarenes took part in two
consecutive hydrodeiodination cycles, producing doubly
reduced products (2h and 2a) in good isolated yield (67−
70%, Scheme 2). Moreover, 2-methoxy- and 2,7-dimethoxy-
substituted iodonaphthalenes were effectively reduced under
optimized conditions, and the corresponding naphthalenes (2j
and 2k) were isolated in excellent yields (93−94%, Scheme 2).
Interestingly, 2-methoxynaphthalene (2j) is a crucial inter-
mediate70 for the synthesis of nonsteroidal anti-inflammatory
drugs such as nabumetone and naproxen.71 Even iodo-
substituted polycyclic hydrocarbons such as iodophenanthar-
ene and iodoanthracene efficiently took part in the reaction,
and the corresponding arenes (2l and 2m) were isolated in
excellent yields (83−85%, Scheme 2). In addition, several
iodo-heteroarenes (pyrroles and pyrrolidines) were success-
fully reduced to the corresponding hydrodeiodinated products
(2n and 2o), with 56−77% isolated yield (Scheme 2).
report based on PDI catalysts by light irradiation at a higher
temperature (as reported with 54% yield).28 The hydro-
debromination of 1-bromo-2-methoxy-naphthalene (1s) was
rather slow, producing 2-methoxynaphthalene (2j) with only
34% yield (Scheme 2). Interestingly, 9,10-dibromoanthracene
smoothly proceeded through two successive debromination
cycles to yield anthracene (2m) in 65% yield (Scheme 2). Also,
the hydrodehalogenation protocol was successfully employed
for the chloroarene precursor, 9,10-dichloroanthracene, which
was reduced to anthracene (2m) with 46% yield (Scheme 2).
However, the substrates with functional groups such as esters,
nitro, cyano, unprotected alcohols, and amines did not
undergo such hydrodehalogenation processes under our
reaction conditions.
Furthermore, this methodology was successfully applied in
hydrodehalogenation of a number of imidazopyridine deriva-
tives that exhibit distinct biological activities. For example, 3-
iodo-2-(aryl)imidazo[1,2-a]pyridine derivatives produced the
corresponding deiodinated heteroarenes under the optimized
reaction conditions and yielded 2v−2y with excellent yields
(84−94%, Scheme 2), many of which were reported to exhibit
antibacterial activity against Gram-negative and Gram-positive
bacteria.72 Also, the reaction proceeded with a preferential
deiodination process, instead of dechlorination/debromination
at other possible sites. Finally, another important application of
this protocol was found when 2-isobutoxynaphthalene (2z)
was afforded with 87% yield (Scheme 2), which is used in
perfumery as a soap perfume.73,74 It is important to note that
the present study is the first to report hydrodehalogenation of
various halo-arene/heteroarene derivatives such as 1,6-bis(4-
iodophenoxy)hexane, 2,7-dimethoxy-1-iodonaphthalene, 9-io-
doanthracene, 9,10-dibromoanthracene, 9,10-dichloroanthra-
cene, imidazopyridine derivatives, and 1-iodo-2-isobutoxy-
naphthalene into their corresponding arenes under such
transition metal-free and under ambient temperature. Next,
to show the scalability of this protocol, 4-iodobiphenyl was
employed under the optimized reaction conditions with a 10-
fold scale-up (1.5 mmol), which was well tolerated with the
current process, producing 2a in 83% isolated yield.
Furthermore, an increase in the loading of 2-(4-chlorophen-
yl)-3-iodoimidazo[1,2-a]pyridine (1w) by 25-fold (3.75
mmol) was also well tolerated and effectively reduced to 2w
in 76% yield.
Moreover, to demonstrate the potential application of this
protocol, a range of aryl and heteroaryl halides was investigated
for dehalogenative deuteration. It is worth mentioning that an
alternative approach for deuterium labeling is a C−H/C−D
exchange protocol,75 which enables direct incorporation of
deuterium by the addition of a deuterium source without the
requirement of the starting material prefunctionalization or any
significant structural modification of the chemical entity.
However, this approach suffers from various limitations, such
as difficulty to directly activate the C−H bonds,76 low
functional group acceptance, requirement of high temperature,
etc.77 Recently, the direct hydrogen isotope exchange (HIE)
protocol was explored utilizing D2 by Kerr78 and Chirik79
groups, and they successfully employed iridium and iron
catalysis, respectively. Also, the Macmillan80 group utilized
iridium photoredox catalysts for the HIE protocol and D2O as
a deuterium source. In spite of the efficiency of these methods,
these protocols are limited by the use of transition metal
catalysts, the requirement of directing groups, light irradiation,
low deuterium content in the product, high cost, and poor site
To extend the study further, more challenging substrates
were next considered, such as the reduction of aryl bromides
and aryl chlorides. To our delight, the present methodology
worked smoothly by activating aryl chlorides and aryl bromides
under ambient conditions. We successfully performed the
hydrodebromination and hydrodechlorination of bromo/
chloro-arenes. For example, both 9-bromophenanthrene and
9-bromoanthracene were successfully hydrodebrominated to
phenanthrene (79%, 2l) and anthracene (78%, 2m),
respectively, with very good isolated yields (Scheme 2). The
yield of anthracene was notably higher than the preceding
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a
Scheme 3. Substrate Scope for the Dehalogenative Deuteration Reaction
a
Reactions were performed under nitrogen atmosphere in a pressure tube with 0.15 mmol of substrate, 0.015 mmol of catalyst, 0.02 mmol of K,
0.225 mmol of KOtBu, and 1.3 mL of DMSO-d6. Yields are isolated yield. *0.037 mmol of catalyst, 0.049 mmol of K, and 0.232 mmol of KOtBu.
Deuterium incorporation is given in the parentheses.
selectivity. On the contrary, the present method consists of a
transition metal-free dehalogenative protocol under ambient
temperature with DMSO-d6 as a cheap deuterium source,68
and the reactions were found to proceed with the excellent
deuterium incorporation. For example, 4-iodobiphenyl (1a)
led to the desired deuterated product (2a′) in 74% isolated
yield (Scheme 3) and the reduction of 1-iodonaphthalene (1c)
afforded the deuterated naphthalene (2c′) with 50% yield
(Scheme 3) under the optimized reaction conditions of
dehalogenative deuteration. Excellent yields were observed in
the cases of 1-iodo-2-methoxynaphthalene and 1-iodo-2,7-
dimethoxynaphthalene, which were efficiently reduced to 2-
methoxynaphthalene-1-d (2j′, 95%) and 2,7-dimethoxynaph-
thalene-1-d (2k′, 92%), respectively, with this protocol
(Scheme 3). Phenanthrene-9-d (2l′), on the other hand, was
obtained from 9-iodophenantharene with 53% yield (Scheme
3), and anthracene-9-d (2m′) was obtained from 9-
iodoanthracene in 83% yield (Scheme 3). Interestingly, the
yields of debrominative deuteration of their bromo analogues
were only marginally diminished from those of the iodo
compounds. For example, 9-bromophenantharene was deha-
logenatively deuterated to phenanthrene-9-d (2l′) with 51%
yield and 9-bromoanthracene to anthracene-9-d (2m′) with
74% isolated yield (Scheme 3). Moreover, when we shifted
toward the deuteration of pharmaceutically important
heterocyclic moieties, such as imidazopyridine derivatives,
clean deuterodeiodination at room temperature was observed.
As demonstrated in Scheme 3, 2-(4-chlorophenyl)-3-iodo-7-
methylimidazo[1,2-a]pyridine (1v) effectively produced the
deuterated product (2v′) in 71% yield. Also, the deuterated
versions (2w′−2y′) of the antibacterial imidazopyridine
derivatives (2w−2y) were afforded from the corresponding
iodo-imidazopyridines with excellent yields (84−93%, Scheme
3) under this deuterodeiodination protocol. It is noteworthy
that, similar to hydrodehalogenation, chloride and bromide
substituents in imidazopyridine derivatives are also well
tolerated during the course of the catalytic deuteration.
Furthermore, we reduced 1-iodo-2-isobutoxynaphthalene to a
deuterated version of 2-isobutoxynaphthalene (2z′), with 89%
yield (Scheme 3), which is used in the perfumery/flavoring
industry. It is worth mentioning that, in the case of
hydrodehalogenation, the productivity of this mild reaction
protocol at room temperature runs parallel to the existing
transition metal-free methodologies that uses either stoichio-
metric reactants23 and/or harsh reaction parameters24 (such as
high temperature30). For dehalogenative deuteration, the
existing literature is enriched in metal-catalyzed reactions,
except one report, catalyzed by an organotin reagent and
operates at high temperature, utilizing an expensive deuterium
source (THF-d8).49 However, in this study, we utilized the
catalyst under transition metal-free methodology, which runs at
room temperature using a cheap deuterium source (DMSO-
d6) and produces the corresponding arenes and deuterated
arenes in good yield. To the best of our knowledge, this work
reports the first catalytic hydrodehalogenation and dehaloge-
native deuteration protocol of aryl/heteroaryl halides together
using a transition metal-free approach without the assistance of
any external stimuli such as heat or light.
Next, to gain an insight into the underlying mechanism of
the catalytic process, we resorted to a series of control
experiments along with DFT calculations. Keeping in mind the
idea of utilizing the reduced 14π e− anionic state of a
phenalenyl moiety, we hypothesized that such species would
accumulate sufficiently high energy to accomplish a SET
process to the LUMO of aryl halides, splitting it into a reactive
aryl radical and halide and generating the radical species having
13π e−. To confirm the involvement of radical species, we
performed the radical quenching studies, where a radical
scavenger, galvinoxyl, was utilized under the optimized
conditions, and the catalysis was efficiently shut down with
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Scheme 4. Plausible Reaction Mechanism
Figure 2. Energy profile diagram for aryl halide dehalogenation, considering DMSO as one of the reactants.
established in previous studies.57,59,65 A SET from OtBu to I
generates a monoreduced phenalenyl radical-K complex II
(13π electron species) along with a tert-butoxy radical. Such a
monoreduced phenalenyl radical has been trapped and
characterized earlier.81 A further reduction of this mono-
reduced PLY-K complex II by metallic potassium produced a
doubly reduced PLY-K complex III (the anionic 14π electron
species). Such doubly reduced species, upon reduction by
−
no detectable hydrodehalogenative product, even after 24 h
(Scheme S1, Supporting Information). Based on this finding
and on the basis of theoretical calculations and previous
observations67 on the generation of doubly reduced PLY
species upon reaction with K, a mechanistic cycle was
proposed, as illustrated in Scheme 4 and Figure 2. Initially, a
PLY-K complex I was formed by the interaction of the
phenalenyl ligand and KOtBu and such observation was
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Figure 3. Parabolic PESs for reactants (blue) and products (red) in an electron self-exchange process as a function of the reaction coordinate along
with the theoretically calculated reorganization energies λ1 and λ2, which represent the reorganization energies of forward and backward reactions,
respectively. ΔG≠λ1 and ΔG≠λ2 represent the activation energy barriers of forward and backward reactions, respectively. (a) Electron transfer from
the doubly reduced PLY moiety to aryl halides. (b) Catalyst regeneration at the final step of product formation. (c) Radical chain propagation
process.
metallic potassium, has also been trapped and characterized
very recently.67 The doubly reduced PLY-K complex III having
high HOMO energy (−1.68 eV) transfers an electron through
SET to the LUMO of aryl/heteroaryl halide (−1.69 eV for 9-
bromophenanthrene) at room temperature and leads to the
formation of aryl halide radical anion V, oxidizing itself to the
monoreduced PLY-K complex II.
This electron transfer step was supported by theoretical
calculations (considering bromophenanthrene as the sub-
strate), showing a free-energy change of −10.3 kcal/mol
(ΔG), which indicates a thermodynamically favorable process.
It is important to note that the formation of aryl radicals has
been successfully demonstrated by trapping it with galvinoxyl
and characterized by mass spectroscopic measurements
(Scheme S2, Supporting Information).
The aryl radical next accepts a hydrogen atom from DMSO
through a transition state TS1 (Figure 2). The transition state
calculations for this hydrogen atom transfer (HAT) process
show that the transition state TS1 with an energy barrier ΔG⧧
= 17.0 kcal/mol is achievable at room temperature to yield the
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atmosphere prior to use. KOtBu, potassium metal, aryl/heteroaryl
halides, and all other chemicals were acquired from Sigma Aldrich or
other commercial sources and used without further purification.
Deuterated solvents were acquired from Cambridge Isotope
Laboratories. CDCl3 (99.8 atom% D), (CD3)2SO (99.9 atom% D),
and CD3OD (99.8 atom% D) were stored inside a glovebox and used
desired product VIII and DMSO-based radical intermediate IX
(Figure 2). In this case (Figure 2), the Gibbs free-energy
change for the electron transfer from IX (DMSO rad) to
produce the doubly reduced active catalyst was calculated as
83.4 kcal/mol, which is thermodynamically unfavorable
defying its direct electron transfer to regenerate the catalyst.
Alternatively, IX may undergo an additive interaction with a
tert-butoxide anion via a radical anionic transition state TS2,
resulting in a radical anionic intermediate X with an energy
barrier of 19.7 kcal/mol. This intermediate X has a favorable
SOMO energy (−1.66 eV) and can transfer an electron to the
SOMO (−1.76 eV) of the monoreduced PLY-K complex II to
regenerate the doubly reduced active catalyst along with the
formation of XI. Such solvent−potassium tert-butoxide adduct
has been reported in the literature.24 The radical anionic
intermediate X can also directly transfer one electron to the
aryl halide IV and promote another set of reactions to deliver
the desired product through a radical chain propagation
process. Furthermore, to understand electron transfer ener-
getics for all the single electron transfer process, Nelsen’s four-
point calculation based on the Marcus−Hush theory was
carried out (Figure 3).
The energy barriers of the forward reaction for substrate
activation (SET1) and catalyst regeneration considering the
radical anionic DMSO−OtBu adduct, X (SET2), are 1.3 and
24.1 kcal/mol, respectively, for both the reactions, which can
be easily accessible at room temperature (Figure 3a,b). We
explored the possibility of a radical chain propagation process,
where a SET takes place from X to another aryl halide
molecule directly (9-bromophenanthrene, SET3). The activa-
tion energy barrier is 17.1 kcal/mol for the forward reaction,
which indicates that the chain propagation runs parallel to the
catalyst regeneration step (Figure 3c). However, a sequence of
control reactions was carried out in the absence of the ligand
(L1) using only metallic potassium (13 mol %) and potassium
tert-butoxide (1.5 equiv), which produced the hydrodehalo-
genated products [2a, 2j, (X = I, Br); see page S2 in the
Supporting Information] only up to 33% yield. This
observation shows the inefficacy of the chain propagation
step to obtain the satisfactory yield of the hydrodehalogenated
products, whereas the addition of the PLY ligand (10 mol %)
could afford the yield up to 94%. From these experiments, it
can be concluded that although the chain propagation for such
a process is thermodynamically favorable along with the
catalyst regeneration, the chain propagation process alone
cannot offer our observed yield (94%).
1
as received. H and 13C NMR spectra were recorded on a JEOL 400
MHz or a BRUKER 500 MHz NMR spectrometer using CDCl3 or
(CD3)2SO or CD3OD as a solvent. Chemical shifts were reported in
the ppm downfield to tetramethylsilane. The residual undeuterated
1
solvent peaks were used as references for 13C NMR and H NMR
spectra (CDCl3: δC = 77.1 ppm, δH = 7.26 ppm; (CD3)2SO: δC = 39.5
ppm, δH = 2.50 ppm; CD3OD: δC = 49.0 ppm, δH = 3.31 ppm).
HRMS measurements were carried out on a Bruker maXis impact.
Thin-layer chromatography (TLC) was carried out using precoated
aluminum baked silica gel plates and visualized by UV absorbance
(254 nm). Column chromatography was performed using a Merck
silica gel (particle size, 230−400 mesh) and neutral alumina.
Preparation of the Substrates. 1-Hexyloxy-4-iodobenzene,82 1-
hexyloxy-2-iodobenzene,83 N,N-diethyl-4-iodoaniline,84 N,N-dibutyl-
4-iodoaniline,85 1,6-bis(4-iodophenoxy)hexane,86 1-iodo-2-7-dime-
thoxynaphthalene,87 iodophenantharene,88 idooanthracene,89 1-(4-
iodophenyl)-1H-pyrrole,24 1-(4-iodophenyl)-pyrrolidine,90 1-(2-iodo-
phenyl)-pyrrolidine,91 2-(4-chlorophenyl)-3-iodo-7-methylimidazo-
[1,2-a]pyridine,92 2-(4-chlorophenyl)-3-iodoimidazo[1,2-a]-
pyridine,92 6-chloro-2-(4-chlorophenyl)-3-iodoimidazo[1,2-a]-
pyridine,93 2-(4-bromophenyl)-6-chloro-3-iodoimidazo[1,2-
a]pyridine,93 1-iodo-2-isobutoxynaphthalene,94 9-hydroxy-1H-phena-
lenone,65 9-(methylamino)-1H-phenalenone,65 (E)-ethyl(9-(methyl-
amino)-1H-phenalen-1-ylidene)oxonium tetrafluoroborate salt,95 and
9,9′-(ethane-1,2-diylbis(azanediyl))bis(1H-phenalenone)66 were syn-
thesized according to the reported literature.
General Procedure for the Catalytic Hydrodehalogenation
Reaction. Inside a nitrogen-filled glovebox, precatalyst L1 (3.1 mg,
0.015 mmol), KOtBu (3.4 mg, 0.03 mmol), metallic potassium (0.76
mg, 0.02 mmol), DMSO (0.7 mL), and dioxane (0.7 mL) were
charged in a 25 mL pressure tube. Subsequently, aryl/heteroaryl
halide (0.15 mmol) and KOtBu (22 mg, 0.195 mmol) were added to
the reaction mixture. The resulting reaction mixture was allowed to
stir at room temperature for 24 h. After completion of the reaction,
the reaction mixture was extracted with diethyl ether. The organic
phase was dried over anhydrous sodium sulfate. The solvent was
concentrated under reduced pressure to obtain the crude product,
which was purified by column chromatography using hexane or a
hexane/EtOAc mixture to afford the desired products.
General Procedure for the Catalytic Dehalogenative
Deuteration Reaction. Inside a nitrogen-filled glovebox, precatalyst
L1 (3.1 mg, 0.015 mmol), KOtBu (3.4 mg, 0.03 mmol), metallic
potassium (0.76 mg, 0.02 mmol), and DMSO-d6 (1.3 mL) were
charged in a 25 mL pressure tube. Subsequently, aryl/heteroaryl
halide (0.15 mmol) and KOtBu (22 mg, 0.195 mmol) were added to
the reaction mixture. The resulting reaction mixture was allowed to
stir at room temperature (25−30 °C) for 24 h. After completion of
the reaction, the reaction mixture was extracted with diethyl ether.
The organic phase was dried over anhydrous sodium sulfate. The
solvent was concentrated under reduced pressure to obtain the crude
product, which was purified by column chromatography using hexane
or a hexane/EtOAc mixture to afford the desired deuterated products.
Procedure for the Longevity Experiment. Inside a nitrogen-
filled glovebox, precatalyst L1 (3.1 mg, 0.015 mmol), KOtBu (3.4 mg,
0.03 mmol), metallic potassium (0.76 mg, 0.02 mmol), DMSO (0.7
mL), and dioxane (0.7 mL) were charged in a 25 mL pressure tube.
Subsequently, 4-iodobiphenyl (42 mg, 0.15 mmol) and KOtBu (22
mg, 0.195 mmol) were added to the reaction mixture. The resulting
reaction mixture was allowed to stir at room temperature (25−30 °C)
for 24 h. After completion of the reaction, the yield was calculated by
1H NMR spectroscopy. Next, the aliquots of 4-iodobiphenyl (40.2
In summary, we have developed a dehalogenative deutera-
tion/reductive hydrodehalogenation methodology catalyzed by
the reduced (14π e−) state of a phenalenyl system. The
reduced PLY species having sufficiently high energy undergoes
a SET process activating the aryl/heteroaryl halides at room
temperature under mild conditions. The protocol is compatible
with various aryl/heteroaryl halides to access various bio-
logically active molecules under transition metal-free catalytic
conditions at room temperature. The deuterated analogues
were obtained with good yields by employing DMSO-d6 as a
deuterium source.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise stated, all reactions were
performed inside a nitrogen filled glovebox, with the concentration of
H2O and O2 maintained below 0.1 ppm. All solvents were distilled
from calcium hydride or Na/benzophenone under an inert
mg, 0.143 mmol, maintaining the catalyst substrate ratio) and KOtBu
(20.8 mg, 0.186 mmol) were charged in the reaction mixture, and it
was allowed to stir at room temperature (25−30 °C) for 24 h. The
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conversion was calculated by 1H NMR spectroscopy. Maintaining the
catalyst to substrate ratio, the procedure was replicated up to the fifth
catalytic cycle, and after each run, the conversion was calculated by 1H
NMR spectroscopy.
sodium sulfate. The solvent was concentrated under reduced pressure
to obtain the crude product, and the yield was calculated by 1H NMR
spectroscopy.
Spectral Characterization Data of the Hydrodehalogen-
ated/Dehalogenative Deuterated Products. Biphenyl (2a).96
White solid, yield 21 mg (93%); purified by column chromatography
Procedure for the Large-Scale Catalytic Hydrodehalogena-
tion Reaction of Aryl Halide. Inside a nitrogen-filled glovebox,
catalyst L1 (31.3 mg, 0.15 mmol), KOtBu (33.6 mg, 0.30 mmol),
metallic potassium (7.8 mg, 0.20 mmol), DMSO (5 mL), and dioxane
(5 mL) were charged in a 25 mL pressure tube. Subsequently, 4-
iodobiphenyl (420 mg, 1.50 mmol) and KOtBu (218 mg, 1.95 mmol)
were added to the reaction mixture. The resulting reaction mixture
was allowed to stir at room temperature (25−30 °C) for 24 h. After
completion of the reaction, the reaction mixture was extracted with
diethyl ether. The organic phase was dried over anhydrous sodium
sulfate. The solvent was concentrated under reduced pressure to
obtain the crude product, which was purified by column
chromatography using hexane, and 192 mg of biphenyl was isolated
with 83% yield.
Procedure for the Large-Scale Catalytic Hydrodehalogena-
tion Reaction for the Synthesis of Biologically Active
Compounds. Inside a nitrogen-filled glovebox, catalyst L1 (78 mg,
0.375 mmol), KOtBu (84 mg, 0.75 mmol), metallic potassium (19
mg, 0.487 mmol), DMSO (15 mL), and dioxane (15 mL) were
charged in a 70 mL sealed tube. Subsequently, 2-(4-chlorophenyl)-3-
iodoimidazo[1,2-a]pyridine (1329 mg, 3.75 mmol) and KOtBu (546
mg, 4.87 mmol) were added to the reaction mixture. The resulting
reaction mixture was allowed to stir at room temperature (25−30 °C)
for 24 h. After completion of the reaction, the reaction mixture was
extracted with diethyl ether. The organic phase was dried over
anhydrous sodium sulfate. The solvent was concentrated under
reduced pressure to obtain the crude product, which was purified by
column chromatography using a hexane/EtOAc mixture, and 652 mg
of 2-(4-chlorophenyl)imidazo[1,2-a]pyridine was isolated with 76%
yield.
Procedure for Inhibition of the Hydrodehalogenation
Reaction in the Presence of the Radical Scavenger. Inside a
nitrogen-filled glovebox, precatalyst L1 (3.1 mg, 0.015 mmol), KOtBu
(3.4 mg, 0.03 mmol), metallic potassium (0.76 mg, 0.02 mmol),
DMSO (0.7 mL), and dioxane (0.7 mL) were charged in a 25 mL
pressure tube. Subsequently, 4-iodobiphenyl (42 mg, 0.15 mmol),
KOtBu (22 mg, 0.195 mmol), and galvinoxyl (63 mg, 0.15 mmol)
were added to the reaction mixture. The resulting reaction mixture
was allowed to stir at room temperature (25−30 °C) for 24 h. After
completion of the reaction, the reaction mixture was extracted with
diethyl ether. The organic phase was dried over anhydrous sodium
sulfate. The solvent was concentrated under reduced pressure to
obtain the crude product, which was purified by column
chromatography using hexane to obtain a mixture of less than 8%
biphenyl with remaining unreacted 4-iodobiphenyl.
Mass Spectroscopy Analysis of the Galvinoxyl Adduct.
Inside a nitrogen-filled glovebox, catalyst L1 (11.7 mg, 0.056 mmol),
KOtBu (12.5 mg, 0.112 mmol), metallic potassium (2.83 mg, 0.073
mmol), DMSO (0.5 mL), and dioxane (0.5 mL) were charged in a 25
mL pressure tube. Subsequently, 4-iodobiphenyl (15.6 mg, 0.056
mmol), KOtBu (7 mg, 0.062 mmol), and galvinoxyl (20 mg, 0.048
mmol) were added to the reaction mixture. The resulting reaction
mixture was allowed to stir at room temperature (25−30 °C) for 24 h.
After completion of the reaction, the reaction mixture was
characterized by mass spectroscopy. The mass spectra showed exact
molecular ion peaks, which correspond to the proposed galvinoxyl−
biphenyl and galvinoxyl−DMSO trapped product.
1
using hexane; H NMR (400 MHz, CDCl3): δ 7.77−7.80 (m, 4H),
7.59−7.64 (m, 4H), 7.51−7.55 (m, 2H). 13C{1H} NMR (100 MHz,
CDCl3): δ 141.2, 128.8, 127.2, 127.2.
Naphthalene (2c).96 White solid, yield 12 mg (61%); purified by
column chromatography using hexane; 1H NMR (400 MHz, CDCl3):
δ 8.02−8.04 (m, 4H), 7.65−7.67 (m, 4H). 13C{1H} NMR (100 MHz,
CDCl3): δ 133.5, 127.9, 125.8.
(Hexyloxy)benzene (2d).97,98 Colorless oil, yield 15 mg (80%);
1
purified by column chromatography using 3% EtOAc in hexane; H
NMR (400 MHz, CDCl3): δ 7.29−7.33 (m, 2H), 6.93−6.98 (m, 3H),
3.99 (t, J = 6.7 Hz, 2H), 1.78−1.85 (m, 2H), 1.47−1.54 (m, 2H),
1.36−1.40 (m, 4H), 0.95 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 159.2, 129.4, 120.4, 114.5, 67.9, 31.7, 29.3, 25.8,
22.7, 14.1.
N,N-Diethylaniline (2f).23 Colorless liquid, yield 14 mg (62%);
1
purified by column chromatography using 3% EtOAc in hexane; H
NMR (400 MHz, CDCl3): δ 7.24−7.28 (m, 2H), 6.68−6.75 (m, 3H),
3.40 (q, J = 14.6, 7.3 Hz, 4H), 1.21 (t, J = 7.3 Hz, 6H). 13C{1H}
NMR (100 MHz, CDCl3): δ 147.8, 129.3, 115.4, 111.9, 44.3, 12.6.
N,N-Dibutylaniline (2g).99 Colorless liquid, yield 18 mg (58%);
1
purified by column chromatography using 3% EtOAc in hexane; H
NMR (400 MHz, CDCl3): δ 7.20 (t, J = 7.3 Hz, 2H), 6.61−6.66 (m,
3H), 3.26 (t, J = 7.9 Hz, 4H), 1.54−1.61 (m, 4H), 1.31−1.41 (m,
4H), 0.96 (t, J = 7.3 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ
148.3, 129.2, 115.1, 111.7, 50.8, 29.5, 20.4, 14.1.
1,6-Diphenoxyhexane (2h).100 Colorless solid, yield 20 mg (67%);
1
purified by column chromatography using 3% EtOAc in hexane; H
NMR (400 MHz, CDCl3): δ 7.28−7.32 (m, 4H), 6.91−6.97 (m, 6H),
3.99 (t, J = 6.1 Hz, 4H), 1.83−1.86 (m, 4H), 1.55−1.59 (m, 4H).
13C{1H} NMR (100 MHz, CDCl3): δ 159.1, 129.4, 120.5, 114.5, 67.7,
29.3, 25.9.
2-Methoxynaphthalene (2j).96 White solid, yield 22 mg (94%);
1
purified by column chromatography using 3% EtOAc in hexane; H
NMR (400 MHz, CDCl3): δ 7.74−7.79 (m, 3H), 7.45 (t, J = 7.9 Hz,
1H), 7.35 (t, J = 7.9 Hz, 1H), 7.15−7.18 (m, 2H), 3.93 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 157.6, 134.6, 129.4, 129.0,
127.7, 126.8, 126.4, 123.6, 118.8, 105.8, 55.3.
2,7-Dimethoxynaphthalene (2k).101 White solid, yield 26 mg
(93%); purified by column chromatography using 5% EtOAc in
1
hexane; H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 9.1 Hz, 2H),
7.06 (d, J = 2.4 Hz, 2H), 6.99 (dd, J = 2.4, 9.1 Hz, 2H), 3.91 (s, 6H).
13C{1H} NMR (100 MHz, CDCl3): δ 158.2, 135.9, 129.1, 124.3,
116.0, 105.3, 55.2.
Phenanthrene (2l).23 White solid, yield 22 mg (83%); purified by
column chromatography using hexane; 1H NMR (400 MHz, CDCl3):
δ 8.71 (d, J = 7.9 Hz, 2H), 7.92 (d, J = 7.9 Hz, 2H), 7.76 (s, 2H),
7.60−7.70 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ 132.1,
130.3, 128.6, 127.0, 126.6, 122.7.
Anthracene (2m).26 White solid, yield 23 mg (85%); purified by
column chromatography using hexane; 1H NMR (400 MHz, CDCl3):
δ 8.44 (s, 2H), 8.02 (dd, J = 6.7, 3 Hz, 4H), 7.48 (dd, J = 6.7, 3 Hz,
4H). 13C{1H} NMR (100 MHz, CDCl3): δ 131.7, 128.2, 126.2, 125.4.
N-Phenylpyrrole (2n).23 Light brown solid, yield 15 mg (71%);
1
purified by column chromatography using 3% EtOAc in hexane; H
NMR (400 MHz, CDCl3): δ 6.86 (t, J = 2.4 Hz, 2H), 7.49 (t, J = 2.4
Hz, 2H), 7.54−7.58 (m, 1H), 7.71−7.72 (m, 4H). 13C{1H} NMR
(100 MHz, CDCl3): δ 110.4, 118.9, 119.9, 125.1, 129.2, 140.4.
1-Phenylpyrrolidine (2o).102 Colorless oil, yield 12 mg (56%);
Hydrodehalogenation Reactions in the Absence of Cata-
lysts. Inside a nitrogen-filled glovebox, KOtBu (3.4 mg, 0.03 mmol),
metallic potassium (0.76 mg, 0.02 mmol), DMSO (0.7 mL), and
dioxane (0.7 mL) were charged in a 25 mL pressure tube.
Subsequently, aryl/heteroaryl halide (0.15 mmol) and KOtBu (22
mg, 0.195 mmol) were added to the reaction mixture. The resulting
reaction mixture was allowed to stir at room temperature for 24 h.
After completion of the reaction, the reaction mixture was extracted
with diethyl ether. The organic phase was dried over anhydrous
1
purified by column chromatography using 5% EtOAc in hexane; H
NMR (400 MHz, CDCl3): δ 7.33−7.37 (m, 2H), 6.79 (t, J = 7.3 Hz,
1H), 6.69 (d, J = 7.9 Hz, 2H), 3.39 (t, J = 6.7 Hz, 4H), 2.09−2.12 (m,
4H). 13C{1H} NMR (100 MHz, CDCl3): δ 147.9, 129.1, 115.3, 111.6,
47.5, 25.4.
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2-(4-Chlorophenyl)-7-methylimidazo[1,2-a]pyridine (2v).103
Light brown solid, yield 34 mg (94%); purified by column
chromatography using 25% EtOAc in hexane; H NMR (400 MHz,
2-(4-Chlorophenyl)-7-methy-d3-limidazo[1,2-a]pyridine-3,5-d2
(2v′). Light brown solid, yield 26 mg (71%); purified by column
1
1
chromatography using 25% EtOAc in hexane; H NMR (400 MHz,
CDCl3): δ 7.79−7.83 (m, 2H), 7.66 (s, 0.08H), 7.33−7.36 (m, 3H),
6.55 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 145.9, 144.0,
143.8, 135.8, 133.2, 132.2, 128.6, 127.0, 124.4 (t, J = 29.2 Hz), 115.5,
114.9, 107.4, 107.2 (t, J = 27.6 Hz), 20.4 (m). HRMS (ESI-TOF) m/
z: [M] Calcd for C14H6D5ClN2 247.0919; found 247.0911.
CDCl3): δ 7.96 (d, J = 6.7 Hz, 1H), 7.83−7.87 (m, 2H), 7.72 (s, 1H),
7.36−7.39 (m, 3H), 6.60 (dd, J = 6.7, 1.2 Hz, 1H), 2.39 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 146.1, 144.3, 136.1, 133.5,
132.4, 128.9, 127.2, 124.8, 115.9, 115.3, 107.6, 21.4.
2-(4-Chlorophenyl)imidazo[1,2-a]pyridine (2w).103,104 Colorless
needles, yield 32 mg (92%); purified by column chromatography
using 25% EtOAc in hexane; 1H NMR (400 MHz, CDCl3): δ 8.07 (d,
J = 6.7 Hz, 1H), 7.85−7.88 (m, 2H), 7.80 (s, 1H), 7.61 (dd, J = 9.1,
1.2 Hz, 1H), 7.36−7.40 (m, 2H), 7.14−7.18 (m, 1H), 6.76(td, J = 6.7,
1.2 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 145.7, 144.6,
133.7, 132.3, 128.9, 127.2, 125.6, 124.9, 117.5, 112.6, 108.2.
6-Chloro-2-(4-chlorophenyl)-imidazo[1,2-a]pyridine (2x).105,106
White solid, yield 34 mg (87%); purified by column chromatography
using 25% EtOAc in hexane; 1H NMR (400 MHz, CDCl3): δ 8.14 (d,
J = 1.8 Hz, 1H), 7.83−7.86 (m, 2H), 7.78 (s, 1H), 7.56 (d, J = 9.7 Hz,
1H), 7.37−7.41 (m, 2H), 7.14 (dd, J = 9.7, 2.4 Hz, 1H). 13C{1H}
NMR (100 MHz, CDCl3): δ 145.5, 144.0, 134.1, 131.7, 129.0, 127.3,
126.5, 123.4, 120.9, 117.8, 108.5.
2-(4-Chlorophenyl)imidazo[1,2-a]pyridine-3,5-d2 (2w′). Colorless
needles, yield 29 mg (84%); purified by column chromatography
1
using 25% EtOAc in hexane; H NMR (400 MHz, CDCl3): δ 7.87−
7.90 (m, 2H), 7.83 (s, 0.12H), 7.64 (dd, J = 9.1, 1.2 Hz, 1H), 7.38−
7.41 (m, 2H), 7.19 (dd, J = 9.1, 6.7 Hz, 1H), 6.80 (d, J = 6.7 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ 145.6, 144.4, 133.8, 132.1,
129.0, 127.3, 125.4 (t, J = 29.2 Hz), 125.1, 117.5, 112.6, 107.9 (t, J =
29.2 Hz). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H8D2ClN2
[M + H]+ 231.0653; found 231.0653.
6-Chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3,5-d2 (2x′).
White solid, yield 37 mg (93%); purified by column chromatography
1
using 25% EtOAc in hexane; H NMR (400 MHz, CDCl3): δ 7.83−
7.86 (m, 2H), 7.56 (d, J = 9.1 Hz 1H), 7.38−7.41 (m, 2H), 7.14 (d, J
= 9.7 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 145.5, 144.0,
134.1, 131.7, 129.0, 127.3, 126.4, 123.1 (t, J = 27.6 Hz), 120.7, 117.8,
108.3 (t, J = 23 Hz). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C13H7D2Cl2N2 [M + H]+ 265.0263; found 265.0258.
6-Chloro-2-(4-bromophenyl)-imidazo[1,2-a]pyridine (2y).105,107
White solid, yield 39 mg (84%); purified by column chromatography
1
1
using 25% EtOAc in hexane; H NMR (400 MHz, CDCl3): δ H
NMR (400 MHz, CDCl3): δ 8.15−8.16 (m, 1H), 7.78 (s, 1H), 7.77−
7.81 (m, 3H), 7.54−7.59 (m, 3H), 7.16 (dd, J = 9.7, 1.8 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ 145.5, 144.0, 132.0, 127.6,
126.6, 123.4, 122.4, 121.0, 117.8, 108.6.
6-Chloro-2-(4-bromophenyl)imidazo[1,2-a]pyridine-3,5-d2 (2y′).
White solid, yield 40 mg (86%); purified by column chromatography
using 25% EtOAc in hexane; 1H NMR (400 MHz, CDCl3): δ 7.8 (d, J
= 7.9 Hz 2H), 7.55−7.59 (m, 3H), 7.16 (d, J = 8.5 Hz, 1H). 13C{1H}
NMR (100 MHz, CDCl3): δ 145.0, 143.7, 131.9, 131.6, 127.6, 126.8,
123.2 (t, J = 26.1 Hz), 122.5, 121.0, 117.6, 108.5. HRMS (ESI-TOF)
m/z: [M] Calcd for C13H6D2BrClN2 [M] 307.9679; found 307.9687.
2-Isobutoxynaphthalene-1-d (2z′). Yellowish liquid, yield 27 mg
2-Isobutoxynaphthalene (2z). Yellowish liquid, yield 26 mg
1
(87%); purified by column chromatography using hexane; H NMR
(400 MHz, CDCl3): δ 7.77−7.84 (m, 3H), 7.51 (t, J = 7.9 Hz, 1H),
7.40 (t, J = 7.9 Hz, 1H), 7.18−7.26 (m, 2H), 3.91 (d, J = 6.7 Hz, 2H),
2.21−2.27 (m, 1H), 1.16 (d, J = 6.7 Hz, 6H). 13C{1H} NMR (100
MHz, CDCl3): δ 157.2, 134.7, 129.3, 128.9, 127.7, 126.7, 126.3,
123.4, 119.1, 106.6, 74.4, 28.3, 19.4. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C14H17O 201.1274; Found 201.1271.
1
(89%); purified by column chromatography using hexane; H NMR
(400 MHz, CDCl3): δ 7.79−7.84 (m, 3H), 7.50 (t, J = 7.9 Hz, 1H),
7.40 (t, J = 7.9 Hz, 1H), 7.25 (d, J = 9.1 Hz, 1H), 3.90 (d, J = 6.7 Hz,
2H), 2.20−2.27 (m, 1H), 1.15 (d, J = 6.7 Hz, 6H). 13C{1H} NMR
(100 MHz, CDCl3): δ 157.2, 134.6, 129.3, 128.9, 127.6, 126.6, 126.3,
123.4, 119.1, 106.3 (t, J = 24.6 Hz), 74.4, 28.3, 19.4. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C14H16DO 202.1337; found
202.1345.
Biphenyl-4-d (2a′).69,108 White solid, yield 17 mg (74%); purified
by column chromatography using hexane; 1H NMR (500 MHz,
CDCl3): δ 7.61 (d, J = 7.7 Hz, 4H), 7.44−7.47 (m, 4H), 7.34−7.37
(m, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ 141.3, 128.8, 128.7,
127.3, 127.2.
Naphthalene-1-d (2c′).41 Colorless solid, yield 10 mg (50%);
ASSOCIATED CONTENT
* Supporting Information
1
■
purified by column chromatography using hexane; H NMR (400
MHz, CDCl3): δ 7.84−7.88 (m, 3H), 7.47−7.51 (m, 4H). 13C{1H}
NMR (100 MHz, CDCl3): δ 133.5, 133.4, 127.9, 125.9, 125.7.
2-Methoxynaphthalene-1-d (2j′).51 White solid, yield 23 mg
(95%); purified by column chromatography using 3% EtOAc in
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00573.
Experimental procedures; NMR, HRMS spectral data;
and DFT calculation data (PDF)
1
hexane; H NMR (400 MHz, CDCl3): δ 7.77−7.82 (m, 3H), 7.46−
7.49 (m, 1H), 7.36−7.40 (m, 1H), 7.20 (d, J = 8.5 Hz, 1H), 3.95 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 157.6, 134.5, 129.4, 129.0,
127.7, 126.7, 126.4, 123.6, 118.7, 105.5 (t, J = 24.6 Hz), 55.3.
2,7-Dimethoxynaphthalene-1-d (2k′). White solid, yield 26 mg
(92%); purified by column chromatography using 5% EtOAc in
AUTHOR INFORMATION
Corresponding Authors
■
1
Rupankar Paira − Department of Chemistry, Maharaja
Manindra Chandra College, Kolkata 700003, India;
Email: rupankarpaira85@gmail.com
hexane; H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 9.1 Hz, 2H),
7.09 (d, J = 2.4 Hz, 1H), 7.02−7.04 (m, 2H), 3.93 (s, 6H). 13C{1H}
NMR (100 MHz, CDCl3): δ 158.2, 135.9, 129.1, 124.3, 116.0, 105.2,
105.0 (t, J = 24.6 Hz), 55.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C12H12DO2 190.0973; found 190.0977.
Swadhin K. Mandal − Department of Chemical Sciences,
Indian Institute of Science Education and Research, Kolkata
741246, India; orcid.org/0000-0003-3471-7053;
Email: swadhin.mandal@iiserkol.ac.in
Phenanthrene-9-d (2l′).41 White color solid, yield 14 mg (53%);
1
purified by column chromatography using hexane; H NMR (400
MHz, CDCl3): δ 8.71 (d, J = 8.5 Hz, 2H), 7.91 (dd, J = 7.3, 1.2 Hz,
2H), 7.76 (s, 1H), 7.60−7.69 (m, 4H). 13C{1H} NMR (100 MHz,
CDCl3): δ 132.1, 132.0, 130.3, 128.6, 128.6, 126.9, 126.8, 126.6,
122.7.
Authors
Bhagat Singh − Department of Chemical Sciences, Indian
Institute of Science Education and Research, Kolkata 741246,
India
Jasimuddin Ahmed − Department of Chemical Sciences,
Indian Institute of Science Education and Research, Kolkata
741246, India
Anthracene-9-d (2m′).41 White color solid, yield 22 mg (83%);
1
purified by column chromatography using hexane; H NMR (400
MHz, CDCl3): δ 8.44 (s, 1H), 8.01−8.04 (m, 4H), 7.46−7.50 (m,
4H). 13C{1H} NMR (100 MHz, CDCl3): δ 131.7, 131.6, 128.2, 128.1,
126.2, 125.9 (t, J = 26.1 Hz), 125.4.
7252
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pubs.acs.org/joc
Article
̈
(17) Ghosh, I.; Knig, B. Chromoselective Photocatalysis: Controlled
Bond Activation through Light-Color Regulation of Redox Potentials.
Angew. Chem., Int. Ed. 2016, 55, 7676−7679.
Amit Biswas − Department of Chemical Sciences, Indian
Institute of Science Education and Research, Kolkata 741246,
India
(18) Cowper, N. G. W.; Chernowsky, C. P.; Williams, O. P.;
Wickens, Z. K. Potent Reductants via Electron-Primed Photoredox
Catalysis: Unlocking Aryl Chlorides for Radical Coupling. J. Am.
Chem. Soc. 2020, 142, 2093−2099.
(19) Kim, H.; Kim, H.; Lambert, T. H.; Lin, S. Reductive
Electrophotocatalysis: Merging Electricity and Light To Achieve
Extreme Reduction Potentials. J. Am. Chem. Soc. 2020, 142, 2087−
2092.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00573
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
(20) Neumeier, M.; Sampedro, D.; Mjek, M.; de la Pena O’Shea, V.
̃
S.K.M. thanks SERB-DIA, India (grant no. DIA/2018/
000034) and R.P. thanks SERB (DST), India (grant no.
YSS/2014/000877) for financial support. B.S. and J.A. are
thankful to IISER-Kolkata for fellowships. A.B. thanks CSIR for
the fellowship.
A.; von Wangelin, A. J.; Pérez-Ruiz, R. Dichromatic Photocatalytic
Substitutions of Aryl Halides with a Small Organic Dye. Chem. − Eur.
J. 2018, 24, 105−108.
(21) Constantin, T.; Zanini, M.; Regni, A.; Sheikh, N. S.; Julí, F.;
Leonori, D. Aminoalkyl Radicals as Halogen-Atom Transfer Agents
for Activation of Alkyl and Aryl Halides. Science 2020, 367, 1021−
1026.
REFERENCES
■
(22) Nguyen, J. D.; D’Amato, E. M.; Narayanam, J. M. R.;
Stephenson, C. R. J. Engaging Unactivated Alkyl, Alkenyl and Aryl
Iodides in Visible-Light-Mediated Free Radical Reactions. Nat. Chem.
2012, 4, 854−859.
(1) Alonso, F.; Beletskaya, I. P.; Yus, M. Metal-Mediated Reductive
Hydrodehalogenation of Organic Halides. Chem. Rev. 2002, 102,
4009−4092.
(2) Chen, J.; Zhang, Y.; Yang, L.; Zhang, X.; Liu, J.; Li, L.; Zhang, H.
A Practical Palladium Catalyzed Dehalogenation of Aryl Halides and
α-Haloketones. Tetrahedron 2007, 63, 4266−4270.
(23) Dewanji, A.; Muck-Lichtenfeld, C.; Studer, A. Radical
̈
Hydrodeiodination of Aryl, Alkenyl, Alkynyl, and Alkyl Iodides with
an Alcoholate as Organic Chain Reductant through Electron
Catalysis. Angew. Chem., Int. Ed. 2016, 55, 6749−6752.
(3) Desmarets, C.; Kuhl, S.; Schneider, R.; Fort, Y. Nickel(0)/
Imidazolium Chloride Catalyzed Reduction of Aryl Halides. Organo-
metallics 2002, 21, 1554−1559.
(24) Zheng, H.-X.; Shan, X.-H.; Qu, J.-P.; Kang, Y.-B. Transition-
Metal-Free Hydrogenation of Aryl Halides: From Alcohol to
Aldehyde. Org. Lett. 2017, 19, 5114−5117.
(4) Fujita, K.-i.; Owaki, M.; Yamaguchi, R. Chemoselective Transfer
Hydrodechlorination of Aryl Chlorides Catalyzed by Cp*Rh
Complexes. Chem. Commun. 2002, 2964−2965.
(25) Ding, T.-H.; Qu, J.-P.; Kang, Y.-B. Visible-Light-Induced, Base-
Promoted Transition-Metal-Free Dehalogenation of Aryl Fluorides,
Chlorides, Bromides, and Iodides. Org. Lett. 2020, 22, 3084−3088.
(26) Murphy, J. A.; Zhou, S.-z.; Thomson, D. W.; Schoenebeck, F.;
Mahesh, M.; Park, S. R.; Tuttle, T.; Berlouis, L. E. A. The Generation
of Aryl Anions by Double Electron Transfer to Aryl Iodides from a
Neutral Ground-State Organic Super-Electron Donor. Angew. Chem.,
Int. Ed. 2007, 46, 5178−5183.
(5) Guo, H.; Kanno, K.-i.; Takahashi, T. Iron-Catalyzed Dechlori-
nation of Aryl Chlorides. Chem. Lett. 2004, 33, 1356−1357.
(6) Szostak, M.; Spain, M.; Procter, D. J. Recent Advances in the
Chemoselective Reduction of Functional Groups Mediated by
Samarium(II) Iodide: a Single Electron Transfer Approach. Chem.
Soc. Rev. 2013, 42, 9155−9183.
(7) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Highly Functionalized
Organomagnesium Reagents Prepared through Halogen-Metal
Exchange. Angew. Chem., Int. Ed. 2003, 42, 4302−4320.
(8) Bailey, W. F.; Patricia, J. J. The Mechanism of the Lithium -
Halogen Interchange Reaction : a Review of the Literature. J.
Organomet. Chem. 1988, 352, 1−46.
(9) Yoon, N. M. Selective Reduction of Organic Compounds with
Aluminum and Boron Hydrides. Pure Appl. Chem. 1996, 68, 843−
848.
(10) Keane, M. A. Supported Transition Metal Catalysts for
Hydrodechlorination Reactions. ChemCatChem 2011, 3, 800−821.
(11) Mitoma, Y.; Nagashima, S.; Simion, C.; Simion, A. M.; Yamada,
T.; Mimura, K.; Ishimoto, K.; Tashiro, M. Dehalogenation of
Aromatic Halides Using Metallic Calcium in Ethanol. Environ. Sci.
Technol. 2001, 35, 4145−4148.
(12) Vincent, T.; Spinelli, S.; Guibal, E. Chitosan-Supported
Palladium Catalyst. II. Chlorophenol Dehalogenation. Ind. Eng.
Chem. Res. 2003, 42, 5968−5976.
(27) Hanson, S. S.; Doni, E.; Traboulsee, K. T.; Coulthard, G.;
Murphy, J. A.; Dyker, C. A. Pushing the Limits of Neutral Organic
Electron Donors: A Tetra(iminophosphorano)-Substituted Bispyr-
idinylidene. Angew. Chem., Int. Ed. 2015, 54, 11236−11239.
(28) Ghosh, I.; Ghosh, T.; Bardagi, J. I.; König, B. Reduction of Aryl
Halides by Consecutive Visible Light-Induced Electron Transfer
Processes. Science 2014, 346, 725−728.
(29) Discekici, E. H.; Treat, N. J.; Poelma, S. O.; Mattson, K. M.;
Hudson, Z. M.; Luo, Y.; Hawker, C. J.; de Alaniz, J. R. A Highly
Reducing Metal-Free Photoredox Catalyst: Design and Application in
Radical Dehalogenations. Chem. Commun. 2015, 51, 11705−11708.
(30) Hokamp, T.; Dewanji, A.; Lu
C.; Wurthwein, E. U.; Studer, A. Radical Hydrodehalogenation of Aryl
bbesmeyer, M.; Muck-Lichtenfeld,
̈ ̈
̈
Bromides and Chlorides with Sodium Hydride and 1,4-Dioxane.
Angew. Chem., Int. Ed. 2017, 56, 13275−13278.
(31) DeWitt, S. H.; Maryanoff, B. E. Deuterated Drug Molecules:
Focus on FDA-Approved Deutetrabenazine. Biochemistry 2018, 57,
472−473.
(13) Sajiki, H.; Kume, A.; Hattori, K.; Nagase, H.; Hirota, K.
Complete and Truly Catalytic Degradation Method of PCBs Using
Pd/C-Et3N System Under Ambient Pressure and Temperature.
Tetrahedron Lett. 2002, 43, 7251−7254.
(32) Elmore, C. S.; Bragg, R. A. Isotope Chemistry; a Useful Tool in
the Drug Discovery Arsenal. Bioorg. Med. Chem. Lett. 2015, 25, 167−
171.
(33) Helfenbein, J.; Lartigue, C.; Noirault, E.; Azim, E.; Legailliard,
J.; Galmier, M. J.; Madelmont, J. C. Isotopic Effect Study of Propofol
Deuteration on the Metabolism, Activity, and Toxicity of the
Anesthetic. J. Med. Chem. 2002, 45, 5806−5808.
(34) Shao, L.; Hewitt, M. C. The Kinetic Isotope Effect in the
Search for Deuterated Drugs. Drug News & Perspectives 2010, 23,
398−404.
(35) Gant, T. G. Using Deuterium in Drug Discovery: Leaving the
Label in the Drug. J. Med. Chem. 2014, 57, 3595−3611.
(14) Chatgilialoglu, C. (Me3Si)3SiH: Twenty Years After Its
Discovery as a Radical-Based Reducing Agent. Chem.−Eur.J. 2008,
14, 2310−2320.
̂
(15) Leca, D.; Fensterbank, L.; Lacote, E.; Malacria, M. Recent
Advances in the Use of Phosphorus-Centered Radicals in Organic
Chemistry. Chem. Soc. Rev. 2005, 34, 858−865.
(16) Studer, A.; Amrein, S. Silylated Cyclohexadienes: New
Alternatives to Tributyltin Hydride in Free Radical Chemistry.
Angew. Chem., Int. Ed. 2000, 39, 3080−3082.
7253
https://doi.org/10.1021/acs.joc.1c00573
J. Org. Chem. 2021, 86, 7242−7255

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(36) Harbeson, S. L.; Tung, R. D. Deuterium in Drug Discovery and
Development. Annu. Rep. Med. Chem. 2011, 46, 403−417.
(37) Mullard, A. Deuterated Drugs Draw Heavier Backing. Nat. Rev.
Drug Discov. 2016, 15, 219−221.
(60) Haddon, R. C. Design of Organic Metals and Superconductors.
Nature 1975, 256, 394−396.
(61) Wei, H.; Liu, Y.; Gopalakrishna, T. Y.; Phan, H.; Huang, X.;
Bao, L.; Guo, J.; Zhou, J.; Luo, S.; Wu, J.; Zeng, Z. B-N-B Bond
Embedded Phenalenyl and Its Anions. J. Am. Chem. Soc. 2017, 139,
15760−15767.
(38) Timmins, G. S. Deuterated Drugs: Where are We Now? Expert
Opin. Ther. Pat. 2014, 24, 1067−1075.
(39) Belleau, B.; Burba, J.; Pindell, M.; Reiffenstein, J. Effect of
Deuterium Substitution in Sympathomimetic Amines on Adrenergic
Responses. Science 1961, 133, 102−104.
(40) Schmidt, C. First Deuterated Drug Approved. Nat. Biotechnol.
2017, 35, 493−494.
(62) Raman, K. V.; Kamerbeek, A. M.; Mukherjee, A.; Atodiresei,
́
N.; Sen, T. K.; Lazic, P.; Caciuc, V.; Michel, R.; Stalke, D.; Mandal, S.
̈
̈
K.; Blgel, S.; Mnzenberg, M.; Moodera, J. S. Interface-Engineered
Templates for Molecular Spin Memory Devices. Nature 2013, 493,
509−513.
(41) Janni, M.; Peruncheralathan, S. Catalytic Selective Deuteration
of Halo(Hetero)Arenes. Org. Biomol. Chem. 2016, 14, 3091−3097.
(42) Kuriyama, M.; Hamaguchi, N.; Yano, G.; Tsukuda, K.; Sato, K.;
Onomura, O. Deuterodechlorination of Aryl/Heteroaryl Chlorides
Catalyzed by a Palladium/Unsymmetrical NHC System. J. Org. Chem.
2016, 81, 8934−8946.
(43) Donald, C. S.; Moss, T. A.; Noonan, G. M.; Roberts, B.;
Durham, E. C. Deuterodehalogenation-a Mild Method for Synthesis-
ing Deuterated Heterocycles. Tetrahedron Lett. 2014, 55, 3305−3307.
(44) Johansen, S. K.; Sørensen, L.; Martiny, L. Fast and Efficient
Tritium Labelling of the Nonsteroidal Anti-Inflammatory Drugs
Naproxen, Tolmetin, and Zomepirac. J. Labelled Compd. Radiopharm.
2005, 48, 569−576.
(45) Miura, Y.; Oka, H.; Yamano, E.; Morita, M. Convenient
Deuteration of Bromo Aromatic Compounds by Reductive
Debromination with Sodium Amalgam in CH3OD. J. Org. Chem.
1997, 62, 1188−1190.
(46) Neugebauer, W.; Clark, T.; von Ragué Schleyer, P.
Regioselektive Metallierung von Aromaten, II. Zweitmetallierung
von 1-Lithionaphthalin und 9-Lithioanthracen. Chem. Ber. 1983, 116,
3283−3292.
(47) Yus, M. Arene-Catalysed Lithiation Reactions. Chem. Soc. Rev.
1996, 25, 155−161.
(48) Yus, M. From Arene-Catalyzed Lithiation to Other Synthetic
Adventures. Synlett 2001, 2001, 1197−1205.
(49) Mutsumi, T.; Iwata, H.; Maruhashi, K.; Monguchi, Y.; Sajiki, H.
Halogen-Deuterium Exchange Reaction Mediated by Tributyltin
Hydride Using THF-d8 as the Deuterium Source. Tetrahedron 2011,
67, 1158−1165.
(50) Tetrahydrofuran-d8. https://www.sigmaaldrich.com/catalog/
product/aldrich/184314?lang=en&region=IN.
(63) Morita, Y.; Nishida, S.; Murata, T.; Moriguchi, M.; Ueda, A.;
Satoh, M.; Arifuku, K.; Sato, K.; Takui, T. Organic Tailored Batteries
Materials Using Stable Open-Shell Molecules with Degenerate
Frontier Orbitals. Nat. Mater. 2011, 10, 947−951.
(64) Itkis, M. E.; Chi, X.; Cordes, A. W.; Haddon, R. C. Magneto-
Opto-Electronic Bistability in a Phenalenyl-Based Neutral Radical.
Science 2002, 296, 1443−1445.
(65) Paira, R.; Singh, B.; Hota, P. K.; Ahmed, J.; Sau, S. C.;
Johnpeter, J. P.; Mandal, S. K. Open-Shell Phenalenyl in Transition
Metal-Free Catalytic C-H Functionalization. J. Org. Chem. 2016, 81,
2432−2441.
(66) Banik, A.; Paira, R.; Shaw, B. K.; Vijaykumar, G.; Mandal, S. K.
Accessing Heterobiaryls through Transition-Metal-Free C-H Func-
tionalization. J. Org. Chem. 2018, 83, 3236−3244.
(67) Ahmed, J.; Datta, P.; Das, A.; Jomy, S.; Mandal, S. K. Switching
between Mono and Doubly Reduced Odd Alternant Hydrocarbon:
Designing a Redox Catalyst. Chem. Sci. 2021, 12, 3039−3049.
(68) Dimethyl sulfoxide-d6. https://www.sigmaaldrich.com/catalog/
product/aldrich/151874?lang=en&region=IN.
(69) Liu, C.; Chen, Z.; Su, C.; Zhao, X.; Gao, Q.; Ning, G.-H.; Zhu,
H.; Tang, W.; Leng, K.; Fu, W.; Tian, B.; Peng, X.; Li, J.; Xu, Q.-H.;
Zhou, W.; Loh, K. P. Controllable Deuteration of Halogenated
Compounds by Photocatalytic D2O Splitting. Nat. Commun. 2018, 9,
80.
(70) Murai, M.; Origuchi, K.; Takai, K. Bismuth(III)-Catalyzed
Dehydrative Etherification and Thioetherification of Phenolic
Hydroxy Groups. Org. Lett. 2014, 16, 3828−3831.
(71) Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Roszkowski,
A.; Tomolonis, A.; Fried, J. H. Nonsteroidal Antiinflammatory Agents.
I. 6-Substituted 2-Naphthylacetic Acids. J. Med. Chem. 1970, 13, 203−
205.
(51) Wang, X.; Zhu, M.-H.; Schuman, D. P.; Zhong, D.; Wang, W.-
Y.; Wu, L.-Y.; Liu, W.; Stoltz, B. M.; Liu, W.-B. General and Practical
Potassium Methoxide/Disilane-Mediated Dehalogenative Deuteration
of (Hetero)Arylhalides. J. Am. Chem. Soc. 2018, 140, 10970−10974.
(52) Acetonitrile-d3. https://www.sigmaaldrich.com/catalog/
product/aldrich/151807?lang=en&region=IN.
(53) Morita, Y.; Suzuki, S.; Sato, K.; Takui, T. Synthetic Organic
Spin Chemistry for Structurally Well-Defined Open-Shell Graphene
Fragments. Nat. Chem. 2011, 3, 197−204.
(54) Kubo, T. Phenalenyl-Based Open-Shell Polycyclic Aromatic
Hydrocarbons. The Chemical Record 2015, 15, 218−232.
(55) Reid, D. H. The Chemistry of the Phenalenes. Q. Rev., Chem.
Soc. 1965, 19, 274−302.
(56) Kubo, T. Synthesis, Physical Properties, and Reactivity of
Stable, π-Conjugated, Carbon-Centered Radicals. Molecules 2019, 24,
665.
(57) Mukherjee, A.; Sau, S. C.; Mandal, S. K. Exploring Closed-Shell
Cationic Phenalenyl: From Catalysis to Spin Electronics. Acc. Chem.
Res. 2017, 50, 1679−1691.
(58) Bhunia, M.; Sahoo, S. R.; Shaw, B. K.; Vaidya, S.; Pariyar, A.;
Vijaykumar, G.; Adhikari, D.; Mandal, S. K. Storing Redox Equivalent
in the Phenalenyl Backbone Towards Catalytic Multi-Electron
Reduction. Chem. Sci. 2019, 10, 7433−7441.
(59) Singh, B.; Paira, R.; Biswas, G.; Shaw, B. K.; Mandal, S. K.
Graphene Oxide-Phenalenyl Composite: Transition Metal-Free
Recyclable and Catalytic C-H Functionalization. Chem. Commun.
2018, 54, 13220−13223.
(72) Bhargava, S.; Choudhary, A. Ionic Liquid Promoted Synthesis
of 2-Phenylimidazo [1,2-a]pyridine Derivatives and Their Antibacte-
rial Screening. Int. J. Pharm. Pharm. Sci. 2014, 6, 553−557.
(73) Yadav, G. D.; Krishnan, M. S. Etherification of β-Naphthol with
Alkanols Using Modified Clays and Sulfated Zirconia. Ind. Eng. Chem.
Res. 1998, 37, 3358−3365.
(74) Kim, J. W.; Kim, D. J.; Han, J. U.; Kang, M.; Kim, J. M.; Yie, J.
E. Preparation and Characterization of Zeolite Catalysts for
Etherification Reaction. Catal. Today 2003, 87, 195−203.
(75) Atzrodt, J.; Derdau, V.; Fey, T.; Zimmermann, J. The
Renaissance of H/D Exchange. Angew. Chem., Int. Ed. 2007, 46,
7744−7765.
́
(76) Taglang, C.; Martnez-Prieto, L. M.; del Rosal, I.; Maron, L.;
Poteau, R.; Philippot, K.; Chaudret, B.; Perato, S.; Sam Lone, A.;
Puente, C.; Dugave, C.; Rousseau, B.; Pieters, G. Enantiospecific C-H
Activation Using Ruthenium Nanocatalysts. Angew. Chem., Int. Ed.
2015, 54, 10474−10477.
(77) Chatterjee, B.; Krishnakumar, V.; Gunanathan, C. Selective α-
Deuteration of Amines and Amino Acids Using D2O. Org. Lett. 2016,
18, 5892−5895.
(78) Brown, J. A.; Cochrane, A. R.; Irvine, S.; Kerr, W. J.; Mondal,
B.; Parkinson, J. A.; Paterson, L. C.; Reid, M.; Tuttle, T.; Andersson,
S.; Nilsson, G. N. The Synthesis of Highly Active Iridium(I)
Complexes and their Application in Catalytic Hydrogen Isotope
Exchange. Adv. Synth. Catal. 2014, 356, 3551−3562.
(79) Pony Yu, R.; Hesk, D.; Rivera, N.; Pelczer, I.; Chirik, P. J. Iron-
Catalysed Tritiation of Pharmaceuticals. Nature 2016, 529, 195−199.
7254
https://doi.org/10.1021/acs.joc.1c00573
J. Org. Chem. 2021, 86, 7242−7255

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(80) Loh, Y. Y.; Nagao, K.; Hoover, A. J.; Hesk, D.; Rivera, N. R.;
Colletti, S. L.; Davies, I. W.; MacMillan, D. W. C. Photoredox-
Catalyzed Deuteration and Tritiation of Pharmaceutical Compounds.
Science 2017, 358, 1182−1187.
(81) Ahmed, J.; Sreejyothi, P.; Vijaykumar, G.; Jose, A.; Raj, M.;
Mandal, S. K. A New Face of Phenalenyl-Based Radicals in the
Transition Metal-Free C-H Arylation of Heteroarenes at Room
Temperature: Trapping the Radical Initiator via C-C σ-bond
Formation. Chem. Sci. 2017, 8, 7798−7806.
(82) Liu, B.; Dang, F.; Tian, Z.; Feng, Z.; Jin, D.; Dang, W.; Yang,
X.; Zhou, G.; Wu, Z. High Triplet Energy Level Achieved by Tuning
the Arrangement of Building Blocks in Phosphorescent Polymer
Backbones for Furnishing High Electroluminescent Performances in
Both Blue and White Organic Light-Emitting Devices. ACS Appl.
Mater. Interfaces 2017, 9, 16360−16374.
(83) Hwang, J. Y.; Arnold, L. A.; Zhu, F.; Kosinski, A.; Mangano, T.
J.; Setola, V.; Roth, B. L.; Guy, R. K. Improvement of Pharmacological
Properties of Irreversible Thyroid Receptor Coactivator Binding
Inhibitors. J. Med. Chem. 2009, 52, 3892−3901.
(98) El-Deeb, I. Y.; Tian, M.; Funakoshi, T.; Matsubara, R.; Hayashi,
M. Conversion of Cyclohexanones to Alkyl Aryl Ethers by Using a
Pd/C−Ethylene System. Eur. J. Org. Chem. 2017, 2017, 409−413.
(99) Barker, T. J.; Jarvo, E. R. Umpolung Amination: Nickel-
Catalyzed Coupling Reactions of N,N-Dialkyl-N-Chloroamines with
Diorganozinc Reagents. J. Am. Chem. Soc. 2009, 131, 15598−15599.
(100) Goldup, S. M.; Leigh, D. A.; McBurney, R. T.; McGonigal, P.
R.; Plant, A. Ligand-Assisted Nickel-Catalysed sp3-sp3 Homocoupling
of Unactivated Alkyl Bromides and its Application to the Active
Template Synthesis of Rotaxanes. Chem. Sci. 2010, 1, 383−386.
(101) Boas, U.; Christensen, J. B.; Jensen, K. J. Two Dialkoxynaph-
thalene Aldehydes as Backbone Amide Linkers for Solid-Phase
Synthesis. J. Comb. Chem. 2004, 6, 497−503.
(102) Zhao, Y.; Zhang, S.; Yamamoto, Y.; Bao, M.; Jin, T.; Terada,
M. Heterogeneous Catalytic Reduction of Tertiary Amides with
Hydrosilanes Using Unsupported Nanoporous Gold Catalyst. Adv.
Synth. Catal. 2019, 361, 4817−4824.
(103) Donthiri, R. R.; Pappula, V.; Reddy, N. N. K.; Bairagi, D.;
Adimurthy, S. Copper-Catalyzed C-H Functionalization of Pyridines
and Isoquinolines with Vinyl Azides: Synthesis of Imidazo Hetero-
cycles. J. Org. Chem. 2014, 79, 11277−11284.
(104) Katritzky, A. R.; Qiu, G.; Long, Q.-H.; He, H.-Y.; Steel, P. J.
Efficient Syntheses of Imidazolo[1,2-a]pyridines and -[2,1-a]-
isoquinolines. J. Org. Chem. 2000, 65, 9201−9205.
(105) Patil, S. V.; Gaikwad, N. D.; Bobade, V. D. A Simple and
Efficient Synthesis of Imidazolo[1,2-a]pyridines using MgO in
Aqueous Medium. Arabian J. Chem. 2016, 9, S1649−S1653.
(106) Su, H.; Wang, L.; Rao, H.; Xu, H. Iron-Catalyzed
Dehydrogenative sp3-sp2Coupling via Direct Oxidative C−H
Activation of Acetonitrile. Org. Lett. 2017, 19, 2226−2229.
(107) Ganiek, M. A.; Ivanova, M. V.; Martin, B.; Knochel, P. Mild
Homologation of Esters through Continuous Flow Chloroacetate
Claisen Reactions. Angew. Chem., Int. Ed. 2018, 57, 17249−17253.
(108) Lang, Y.; Peng, X.; Li, C.-J.; Zeng, H. Photoinduced Catalyst-
Free Deborylation-Deuteration of Arylboronic Acids with D2O. Green
Chem. 2020, 22, 6323−6327.
(84) Tancini, F.; Wu, Y.-L.; Schweizer, W. B.; Gisselbrecht, J.-P.;
Boudon, C.; Jarowski, P. D.; Beels, M. T.; Biaggio, I.; Diederich, F.
1,1-Dicyano-4-[4-(diethylamino)phenyl]buta-1,3-dienes: Structure−
Property Relationships. Eur. J. Org. Chem. 2012, 2012, 2756−2765.
(85) Sharber, S. A.; Shih, K.-C.; Mann, A.; Frausto, F.; Haas, T. E.;
Nieh, M.-P.; Thomas, S. W. Reversible Mechanofluorochromism of
Aniline-Terminated Phenylene Ethynylenes. Chem. Sci. 2018, 9,
5415−5426.
(86) Fong, D.; Adronov, A. Investigation of Hybrid Conjugated/
Nonconjugated Polymers for Sorting of Single-Walled Carbon
Nanotubes. Macromolecules 2017, 50, 8002−8009.
́
(87) Carreno, M. C.; Garca Ruano, J.; Sanz, G.; Toledo, M. A.;
̃
Urbano, A. Mild and Regiospecific Nuclear Iodination of Methox-
ybenzenes and Naphthalenes with N-iodosuccinimide in Acetonitrile.
Tetrahedron Lett. 1996, 37, 4081−4084.
̈
(88) Stark, T.; Suhartono, M.; Gbel, M.; Lautens, M. A Palladium-
Catalyzed Domino Reaction as Key Step for the Synthesis of
Functionalized Aromatic Amino Acids. Synlett 2013, 24, 2730−2734.
(89) Nesterov, E. E.; Zhu, Z.; Swager, T. M. Conjugation
Enhancement of Intramolecular Exciton Migration in Poly(p-
phenylene ethynylene)s. J. Am. Chem. Soc. 2005, 127, 10083−10088.
(90) Goldsmith, R. H.; Vura-Weis, J.; Scott, A. M.; Borkar, S.; Sen,
A.; Ratner, M. A.; Wasielewski, M. R. Unexpectedly Similar Charge
Transfer Rates through Benzo-Annulated Bicyclo[2.2.2]octanes. J.
Am. Chem. Soc. 2008, 130, 7659−7669.
(91) Hao, W.; Geng, W.; Zhang, W.-X.; Xi, Z. Palladium-Catalyzed
One-Pot Three- or Four-Component Coupling of Aryl Iodides,
Alkynes, and Amines through C-N Bond Cleavage: Efficient Synthesis
of Indole Derivatives. Chem.−Eur.J. 2014, 20, 2605−2612.
(92) Katrun, P.; Kuhakarn, C. K2S2O8-Mediated Halogenation of 2-
Arylimidazo[1,2-a]pyridines using Sodium Halides as the Halogen
Sources. Tetrahedron Lett. 2019, 60, 989−993.
(93) Semwal, R.; Ravi, C.; Kumar, R.; Meena, R.; Adimurthy, S.
Sodium Salts (NaI/NaBr/NaCl) for the Halogenation of Imidazo-
Fused Heterocycles. J. Org. Chem. 2019, 84, 792−805.
(94) Reddy, K. R.; Sana, S.; Uppalaiah, K.; Rajanna, K. C.;
Veerasomaiah, P. Environmentally Benign Electrophilic Halogenation
of Naphthalenes by H2O2-Alkali Metal Halides in An Aqueous
Cationic Micellar Media. Int. J. Org. Chem. 2012, 02, 254−261.
(95) Roy, S. R.; Nijamudheen, A.; Pariyar, A.; Ghosh, A.;
Vardhanapu, P. K.; Mandal, P. K.; Datta, A.; Mandal, S. K. Phenalenyl
in a Different Role: Catalytic Activation through the Nonbonding
Molecular Orbital. ACS Catal. 2014, 4, 4307−4319.
(96) Yue, H.; Guo, L.; Lee, S.-C.; Liu, X.; Rueping, M. Selective
Reductive Removal of Ester and Amide Groups from Arenes and
Heteroarenes through Nickel-Catalyzed C-O and C-N Bond
Activation. Angew. Chem., Int. Ed. 2017, 56, 3972−3976.
(97) Vechorkin, O.; Hu, X. Nickel-Catalyzed Cross-Coupling of
Non-activated and Functionalized Alkyl Halides with Alkyl Grignard
Reagents. Angew. Chem., Int. Ed. Engl. 2009, 48, 2937−2940.
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