Nitrogen-centered radical-mediated C-H imidation of arenes and heteroarenes via visible light induced photocatalysis

Article abstract of DOI:10.1039/c4cc03905j

The C-H imidation of arenes and heteroarenes has been achieved via visible light induced photocatalysis. In the presence of an iridium(iii) photoredox catalyst, the reaction of aromatic substrates with N-chlorophthalimide furnishes the N-aryl products at room temperature through a nitrogen-centered radical mediated aromatic substitution.

Full text of DOI:10.1039/c4cc03905j

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Nitrogen-centered radical-mediated C–H
imidation of arenes and heteroarenes via
visible light induced photocatalysis†
Cite this: Chem. Commun., 2014,
50, 9273
Received 21st May 2014,
Accepted 1st July 2014
Hyejin Kim, Taehoon Kim, Dong Gil Lee, Sang Weon Roh and Chulbom Lee*
DOI: 10.1039/c4cc03905j
www.rsc.org/chemcomm
The C–H imidation of arenes and heteroarenes has been achieved via to be established, an intriguing effect of a palladium catalyst on the
visible light induced photocatalysis. In the presence of an iridium(III) regioselectivity of the oxidative imidation5 and a related process
photoredox catalyst, the reaction of aromatic substrates with N-chloro- utilizing a bimetallic catalyst system with an elaborate scaffold have
phthalimide furnishes the N-aryl products at room temperature been reported to achieve an expanded substrate scope.6
through a nitrogen-centered radical mediated aromatic substitution.
Given the feasibility of arene C–H amination by engaging
oxidatively generated nitrogen species, most likely electrophilic
The direct C–H amination of arenes is a valuable transformation, in nature, with the arene p system, a general strategy could
as the aromatic amine moiety prevalent in pharmaceuticals, be formulated for N-aryl bond formation using a nitrogen-
agrochemicals and organic materials can be constructed from centered radical (N-radical) intermediate.7 More specifically,
aryl substrates without prefunctionalization.1 Not surprisingly, N-radicals derived from N–X bonds may be rendered amenable
formation of N-aryl bonds via selective C–H functionalization to undergo arene addition and in turn lead to C–H amination
has been a subject of intensive investigations, largely making use (Scheme 1).8,9 However, except for a few limiting cases, inter-
of transition metal mediated catalysis. Particularly notable are molecular amination of this type is complicated by hydrogen
the advances in the protocols enabling N-aryl bond formation in abstraction, rearrangement and redox processes of N-radicals.10
intermolecular settings.2 Mechanistically, these processes rely In addition, competing formation of aryl C–X bonds may arise
on metalation of the arene followed by conversion of the aryl- when the N-radical intermediate is produced via homolysis of
metal s bond to a C–N bond. The amination using this strategy N–X bonds.8c,10d,e In connection with our studies on the reduc-
is highly efficient with substrates possessing directing groups tive transformations of organohalides via visible light induced
that can facilitate the metalation step. Without such directing photocatalysis,11 we questioned whether the efficiency and
groups, however, the use of large quantities of arene substrates is mildness noted in the C-radical mediated reductive reactions
typically required in order for the reaction to proceed under could be translated to redox-neutral, N-radical mediated arene
catalysis.3 Distinct from these approaches is the amination amination processes.12 Taking guidance from the findings of
exploiting the arene p system, instead of targeting the aryl-metal electrochemical studies, we anticipated that reductive scission
s complex as a key intermediate. Based on this mechanistic of the N–X bond might be controlled to generate R2Nꢀ and XÀ
modality, intermolecular oxidative amination has been achieved rather than R2NÀ and Xꢀ by tuning the X group.13 Furthermore, it
that gives N-aryl compounds from non-prefunctionalized arenes,4 was envisioned that facile oxidation of the C-radical emanated from
thus obviating the harsh reaction conditions of nitration and the the N-radical arene addition could bring about efficient aromatic
subsequent reduction step as required in the early aniline synthesis substitution while suppressing potentially intervening radical
en route from nitroarenes. These metal-free protocols, though chain processes.10e,14 Reported here is a visible light photocatalytic
performed with a large excess of arene substrates and expensive
oxidants, have provided important examples of the direct formation
of aryl C–N bonds via tandem C–H and N–H functionalization.
While the nitrogen intermediate involved in these reactions remains
Department of Chemistry, Seoul National University, Seoul 151-747,
Republic of Korea. E-mail: chulbom@snu.ac.kr
† Electronic supplementary information (ESI) available: Details of experimental
Scheme 1 Nitrogen radical mediated C–H amination of arenes.
Chem. Commun., 2014, 50, 9273--9276 | 9273
procedures and accompanying spectroscopic data. See DOI: 10.1039/c4cc03905j
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Table 1 Photocatalytic imidation of benzene with phthalimide derivativesa
Entry
X
Cat.
Additive
Yieldb (%)
1
2
3
4
5
6
7
8
OAc, 1a
OMs, 1b
OTs, 1c
OTf, 1d
I, 1e
2a
2a
2a
2a
2a
2a
2a
2b
2c
2b
2b
2b
2b
2b
2b
—
—
—
—
—
—
—
—
NR
20
22
13
0
Br, 1f
4
Cl, 1g
Cl, 1g
Cl, 1g
Cl, 1g
Cl, 1g
Cl, 1g
Cl, 1g
H, 1h
H, 1h
43
55
24
65
46
36
52
50
47
9
—
10
11
12
13c
14c
15c
CH3CO2H
t-BuCO2H
CF3CO2H
CH3CO2H
t-BuOCl/t-BuOH
aq. NaOCl/t-BuOH/AcOH
Scheme 2 Proposed approach for N-radical mediated C–H imidation.
method for C–H imidation of arenes that can be performed on
preparative scales with commercially available, inexpensive
reagents under mild and operationally simple conditions.
Our approach to C–H amination was examined based on the
strategy depicted in Scheme 2, in which the iridium complex was
envisioned to facilitate the N-radical mediated aromatic substitu-
tion process through a photoredox catalytic mechanism. The
catalytic cycle begins with irradiation of IrIII that would generate
photoexcited *IrIII capable of undergoing oxidation or reduction.
With a substrate containing a reduction susceptible N–X bond,
the single electron transfer (SET) from *IrIII to the substrate could
induce reductive fragmentation of the N–X bond to form the
requisite N-radical intermediate. Subsequent to arene addition,
the resulting C-radical undergoes an electron-recycling SET with
IrIV to regenerate photocatalyst IrIII while entering a carbocation
a
Reaction conditions (unless otherwise specified): N–X reagent
(0.5 mmol), benzene (1.0 mmol, 2 equiv.), catalyst (0.5 mol%), K2CO3
(1.5 mmol), MeCN (5.0 mL). Yield determined by 1H NMR analysis.
b
c
For entries 13–15, N–X reagent (1.0 mmol, 2 equiv.) and benzene
(0.5 mmol) were used.
(Wheland intermediate) pathway en route to aromatization. Thus, derivatives 1b–d produced the desired N-phenylphthalimide (3)
the overall scheme harnesses the energy of visible light for in 13–22% yield along with largely unreacted starting materials
metathesis of N–X and C–H bonds into C–N and H–X bonds. (entries 2–4). In light of low conversion, further screening experi-
For implementing the plan, the phthalimidyl system was chosen ments were performed with more reactive N-halogenated phthal-
for several reasons. First, phthalimide derivatives to be probed for imides. When N-iodo and N-bromophthalimides (1e and 1f) were
N-radical generation are commercially available or can be easily used, rapid reactions took place, where reduction to phthalimide
prepared often via a one-pot procedure.15 Second, the nitrogen (1h, 480%) was a dominant pathway (entries 5 and 6). In contrast,
flanked by two carbonyl groups lacks a-amino hydrogen, thus it is N-phenyl product 3 was generated in 43% yield from the reaction of
devoid of potentially problematic b-elimination of the N–X bond N-chlorophthalimide (1g) (entry 7). These results are in congruence
and disproportionation of the N-radical species.16 Third, the ring with previous observations in related studies, indicating that
opening process associated with cyclic imidyl radicals is less prob- dissociative one-electron reduction leading to formation of an
able in the phthalimidyl framework.10b–g Finally, phthalimidation N-radical and expulsion of a halide ion is more efficient with
would constitute effective amination since a phthalimido group can N–Cl bonds than with N–Br or N–I bonds.17 Given the interconnec-
not only be readily converted to an amino group via straightforward tion of the catalyst redox with both N-radical generation and
deprotection but also avoid the issue of polyamination.
C-radical removal (two SET processes in Scheme 2), we turned
Our initial investigations were focused on the identification our attention to examining the photocatalyst (entries 7–9). A brief
of a suitable N–X bond capable of engaging in arene C–H survey revealed that catalyst 2b with a more strongly oxidizing
imidation (Table 1). We first examined a series of phthalimide potential (E1/2 [IrIV/IrIII] = +1.23 V vs. SCE),18 relative to catalyst 2a
derivatives 1 possessing differential N-substituents in their (E1/2 [IrIV/IrIII] = +0.77 V vs. SCE),18 indeed proved more effective,
reaction with benzene (2 equiv.) at room temperature in the giving rise to 3 in 55% yield (entries 7 and 8). Interestingly,
presence of K2CO3 (3 equiv.) and 0.5 mol% fac-Ir(ppy)3 (2a) however, cationic complex 2c also possessing a higher oxidizing
using a 20 W household fluorescent light bulb as the source of potential (E1/2 [IrIV/IrIII] = +1.17 V vs. SCE)11a,19 displayed poor
visible light. Whereas N-acetoxy substrate 1a did not react at all performance (entry 9). Additional improvement came from running
under these conditions (entry 1), the reactions of N-sulfonyloxy the reaction in the presence of acetic acid (20 mol%), which
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Table 2 Substrate scope of iridium-catalysed C–H imidation of arenes and heteroarenesa
a
Reaction conditions (unless otherwise specified): N-chlorophthalimide (1 g, 0.5 mmol), arene (1.0 mmol), catalyst 2b (0.5 mol%), AcOH
b
(20 mol%), K2CO3 (1.5 mmol), MeCN (5 mL, 0.1 M), 20 W CFL, room temperature, 24 h. Isolated yield. 1g (1.0 mmol) and arene (0.5 mmol) were
used. Phthalimide (1.0 mmol), t-BuOCl (1.0 mmol), t-BuOH (1.0 mmol), then arene (0.5 mmol). Phthalimide (1.25 mmol), NaOCl(aq.)
(1.0 mmol), AcOH (1.0 mmol), t-BuOH (1.0 mmol), then arene (0.5 mmol). Along with 4 and 11, ipso-substitution products were formed in
4% and 10% yields, respectively. A 20 mmol scale reaction.
c
d
e
f
increased the yield of 3 to 65% (entries 10–12).20 It was found
that the optimized conditions were applicable to a reaction
employing benzene as the limiting agent, where imidation
product 3 was obtained in 52% yield (entry 13). Finally, the
C–H imidation was successfully carried out directly starting from
phthalimide (1h) through a one-pot N-chlorination/C–H imida-
Scheme 3 Gram scale one-pot C–H amination of mesitylene.
tion procedure (entries 14 and 15).
With the standard conditions in hand, the scope of the
reaction was examined with an assortment of substrates pos-
sessing varied electronic and steric properties. As summarized with highly electron-rich 1,3,5-trimethoxy-benzene, which under-
in Table 2, a wide range of arenes with mono- (4–10), di- (11–18) went chlorination,25 and was often accompanied by ipso-
and tri- (19–21) substitution as well as pyridines (22–26) parti- phthalimidation when certain methoxy-arenes (e.g. 4 and 11)
cipated well in this C–H imidation process. The observed were employed, thus posing a limitation.
pattern of regioselectivity was similar to that of electrophilic
In order to demonstrate the practicality of the reaction, a
aromatic substitution reactions, as expected for a reaction one-pot N-chlorination/C–H imidation/deprotection sequence
mediated by a radical intermediate.21 However, the reaction was applied to mesitylene (Scheme 3). After in situ preparation
proceeded well with both electron-rich and electron-poor of N-chlorophthalimide from phthalimide, a gram scale imida-
arenes,22 including substrates (e.g. 17) that would not exhibit tion was uneventfully performed under the standard condi-
comparable reactivity in classical electrophilic aromatic sub- tions. In this preparative scale experiment, it was found that
stitution processes.23 A variety of functional groups such as the reaction rate could be significantly accelerated, while
halides, esters, ethers and carbamates were tolerated in this maintaining a low catalyst loading, by simply increasing the
reaction, as exemplified well by the formation of L-tyrosine intensity of light.26 Upon completion of the imidation step,
derivatives 18. In line with the findings in the initial studies, hydrazinolysis of the resulting phthalimido product 20
the products arising from multiple imidation were not detected afforded aminomesitylene (27) in 39% overall yield. These
or were produced only in small amounts (o5%). Neither did results serve to illustrate the potential utility of the process as
benzylic C–H bonds interfere with the reaction.24 It is also an efficient C–H amination method.
noteworthy that the process could be conducted employing
In summary, we report a mild and convenient photocatalytic
either the imidating reagent (1g or 1h) or the arene substrate as method for C–H imidation of arenes. The process allows for the
a limiting agent, providing similar results. Although the reac- formation of N-aryl bonds by introducing a phthalimido group
tions carried out in an inert atmosphere gave more consistent to unfunctionalized arenes via a nitrogen radical mediated
results, rigorous removal of air and moisture was unnecessary, aromatic substitution mechanism, accomplishing a Minisci-
as manifested by the comparable yields of 6 and 7 obtained type C–H functionalization. An important feature of this imida-
through the one-pot chlorination/imidation procedure starting tion is mild generation of the phthalimidyl radical intermediate
with phthalimide (1h). The process, however, was ineffective from N-chlorophthalimide at room temperature via reductive
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This research was supported by the Basic Science Research
(2013R1A1A2018730), the Basic Research Laboratory (2010-
0019766) and the GPF (2011–0006901 for HK) Programs of the
National Research Foundation (NRF) funded by the Ministry of
Science, ICT and Future Planning of Korea.
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