Visible-light promoted catalyst-free imidation of arenes and heteroarenes

Article abstract of DOI:10.1002/chem.201404479

We described herein a catalyst-free visible-light photolytic protocol for the imidation of arenes and heteroarenes. N-Bromosaccharin was identified as a viable and chemoselective nitrogen radical precursor that undergoes controllable homolytic cleavage under ambient light irradiation. The reaction can be applied to a number of arenes and heteroarenes with good chemo- and regioselectivity. Mechanistic studies revealed that radical chain termination by electron transfer-proton transfer (ET-PT) is the leading productive pathway for the reaction.

Full text of DOI:10.1002/chem.201404479

DOI: 10.1002/chem.201404479
Communication
&
CÀH Imidation
Visible-Light Promoted Catalyst-Free Imidation of Arenes and
Heteroarenes
Lu Song,[a] Long Zhang,[a] Sanzhong Luo,*[a, b] and Jin-Pei Cheng[a]
Abstract: We described herein a catalyst-free visible-light
photolytic protocol for the imidation of arenes and heter-
oarenes. N-Bromosaccharin was identified as a viable and
chemoselective nitrogen radical precursor that undergoes
controllable homolytic cleavage under ambient light irra-
diation. The reaction can be applied to a number of
arenes and heteroarenes with good chemo- and regiose-
lectivity. Mechanistic studies revealed that radical chain
termination by electron transfer-proton transfer (ET-PT) is
the leading productive pathway for the reaction.
The construction of aromatic Csp2ÀN bonds in arene and het-
eroarene systems are fundamental organic transformations be-
cause of the universal existence of arylamine moieties in phar-
maceuticals, agrochemicals, and organic functional materials.[1]
Echoing the trend in pursuing CÀH functionalization reac-
tions,[2] the direct CÀH amination of arenes, which could avoid
the pre-functionalization of the substrates, has become
a recent research focus for CÀN bond-forming reactions.[3] Cur-
rent Csp2ÀH amination strategies include transition-metal-cata-
lyzed oxidative cross-coupling[4] and the typical electrophilic[5]/
nucleophilic[6] aromatic substitution with proper nitrogen re-
agents. It is still an attractive goal to develop direct CÀH ami-
nation methods to address the remaining issues, such as harsh
reaction conditions, unsatisfied chemoselectivity as well as the
requirements for site-directing groups and the demands for
stoichiometric amounts of oxidants.
Figure 1. A) CÀH imidation by homolytic aromatic substitution; B) Visible-
light photolytic imidation with N-bromosaccharin (NBSA).
1970s when Skell and co-workers reported the C-H imidation
reactions of arenes using NBS as nitrogen source.[9] In this pro-
cess, UV photolysis or high temperatures were always needed
to generate the imidyl radicals and unavoidable CÀH bromina-
tion or benzyl CÀH abstraction was observed in several cases
(Figure 1). Besides, a massive overdose of the arenes were de-
manded to get reasonable yields and the substrate scope was
hence quite limited. On this basis, methods on mild and che-
moselective imidyl-radical amination have been actively pur-
sued recently. Baran and Sanford independently reported the
CÀH imidation of arenes with elegantly designed imidyl pre-
cursors under mild conditions by ferrocene catalysis and pho-
tocatalysis, respectively.[8] Herein, we reported a distinctive cat-
alyst-free CÀH imidation of arenes enabled by visible-light pho-
tolysis of N-bromosaccharin.
Recently, homolytic aromatic substitution (HAS) by radical
species has been found to be a viable approach for CÀH direct
functionalization of arenes and heteroarenes.[7] In this regard,
Csp2ÀH amination with imidyl radicals has gained a renaissance
recently (Figure 1).[8] Such a process can be traced back to
[a] L. Song,+ Dr. L. Zhang,+ Prof. S. Luo, Prof.Dr. J.-P. Cheng
Beijing National Laboratory for Molecular Sciences (BNLMS)
CAS Key Laboratory for Molecular Recognition and Function
Institute of Chemistry, the Chinese Academy of Sciences Beijing
100190 (China)
[b] Prof. S. Luo
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Tianjin, 300071 (China)
Fax: (+86)10-62554449
E-mail: luosz@iccas.ac.cn
Homepage: http://luosz.iccas.ac.cn
Inspired by Skell’s work,[9c–e] we sought to develop visible-
light photolytic imidation to address the chemoselectivity
issues by simply adjusting the innate NÀX bond of N-halogen
imides.[9] In this regard, a quick probe of the NÀX bond
energy[10] shed a new light and the readily available N-bromo-
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404479.
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saccharin (NBSA) was found to possess a significantly weaker
NÀBr bond (48 vs. 62 kcalmolÀ1 in NBS, Figure 1B), which
would be more amenable to visible-light photolysis (400–
700 nm, 40–70 kcalmolÀ1). Indeed, when a solution of NBSA
and benzene (1.5 equiv) in CH2Cl2 was exposed to ambient
light[11] under ambient temperature, an imidation reaction oc-
curred smoothly and the expected adduct was isolated in 73%
yield. In sharp contrast, no reaction was observed with other
N-halogen imides, such as N-bromosuccimide (NBS) and N-bro-
mobenzosuccimide (PNBS) (Figure 1B). The photolytic nature
of the reaction can be verified by the following experimental
observations: 1) no reaction in the dark, 2) the reaction was
stopped by protection from light and restarted by exposure to
light (Figure 2, and Schemes S1–S2 in the Supporting Informa-
was sufficient to deliver a decent yield of imidation adduct
(61%). The use of 1.5 equivalents of benzene was found to
give better yield (73%). A gram-scale reaction with 1.5 equiva-
lents of benzene worked equally well to give a 69% yield. A
plethora of substituted arenes were explored (Scheme 1).
Mono- and disubstituted benzenes, either electron-withdraw-
ing or -donating, can be applied to give the imidated adducts
(3b–m). The observed regioselectivity is generally para- and
ortho- directing, consistent with substitute effect typically ob-
served in radical aromatic substitution reactions (Figure 3).[12]
The steric effect would also contribute in the regioselective
control as reflected by the generally favored para-selectivity. In
the cases with tert-butylbenzenes, the sterically controlled pro-
cess becomes dominant with the major imidation site remote
to the bulky tert-butyl group (3 f and 3j). In an extreme con-
text, the regioselectivity is even reversed with 1-bromo-4-tert-
butylbenzene compared with that of 1-bromo-4-methylben-
zene (3j vs. 3i). Polyarenes, such as naphthalene, anthracene,
and phenanthrene, are also workable to give single imidation
adducts (3n–p). Notably, the reactions with biphenyls occurred
exclusively para to the phenyl moiety (the substituted one)
(3q and 3r) and no other regioisomers were detected. It
should also be noted that the current reaction didn’t work well
with highly electron-rich arenes/heteroarenes, such as phenols
and anilines.[13]
The catalyst-free imidation reaction has also been tested
with heteroarenes. In this regard, N-Boc-pyrrole (tert-butoxycar-
bonyl) and N-Boc-indoles worked well in the reactions to give
the desired adducts in high yields (Scheme 1, 4a–4e), al-
though their N-methylated derivatives worked poorly. Pyridine,
(benzo)thiophene, and benzofuran are also applicable to the
present conditions to furnish imidated adducts in moderate to
high yields (4 f, g).
Figure 2. Light-responsive behaviors by in-situ monitoring the consumption
of NBSA at 1228 cmÀ1
.
tion), 3) the addition of a typical radical species, such as
2,2,6,6-tetramethylpiperidine N-oxide (TEMPO), shut down the
reaction, which indicated the radical nature of the reaction,
and 4) indeed, a radical species was detected in a solution of
NBSA only or in the reaction mixture under ambient light irra-
diation (see Scheme S3 in the Supporting Information). Consis-
tent with their inertness in the reactions, no radical species
was detected with NBS and PNBS under visible-light irradiation
(see Scheme S3 in the Supporting Information). The UV/Vis
spectroscopy of NBSA has also been examined in CH2Cl2 either
alone or in the presence of benzene (1.0 equiv), showing peak
absorption at 288 nm, which tails above 400 nm (e400 =30,
e450 =12) (see Scheme S4 in the Supporting Information). No
change of absorption in the visible light range was observed
in the presence of benzene. A 405 nm laser light resource has
also been examined in the reactions, which shows comparable
results with that by ambient light or LED blue-light irradiation
(see Scheme S2 in the Supporting Information). It seems weak
absorption in the visible-light range may ensure a steady and
controllable generation of the active radical species, and thus
facilitate a chemoseletive reaction. Similarly, the known UV
photolytic imidation with NBS has also been performed at the
weak-absorption range of NBS (e300 =13).[9f]
In all the examined cases in Scheme 1, no brominated
arenes/heteroarenes byproducts have been identified. In the
reactions with toluenes, benzyl bromides can be isolated from
the reaction mixture, and the benzyl bromination with bromo
radical by the Goldfinger or Bloomfield mechanism may com-
pete with the imidyl radical addition pathway in these cases.[14]
Fortunately, the benzyl bromide byproducts can be easily sepa-
rated from the major imidation adducts (e.g. 3e, 3g, and 3h).
On the basis of previous knowledge as well as our own ex-
perimental observations, the homolytic radical substitution
pathway can be proposed. Accordingly, the reaction is initiated
by visible-light photolysis of NBSA to generate saccharin N rad-
ical and Br radical (Scheme 2, step 1). The critical N radical ad-
dition to arene leads to a cyclohexadienyl-type radical inter-
mediate Int-1 (Scheme 2, step 2), which undergoes rearomati-
zation to give the imidation adduct (Scheme 2, step 3). Mecha-
nistically, three rearomatization pathways can be conceived
(Scheme 2). The first one is the radical propagation route
(Scheme 2, pathway I), in which the cyclohexadienyl-type radi-
cal reacts with N-bromo saccharine to generate the final prod-
uct together with a new N radical and HBr. In the radical
quenching route II (Scheme 2, pathway II), Br radical recom-
bines with Int-1 to give intermediate Int-2, and the following
HBr elimination affords the final product; the third one is the
The scope of this mild imidation protocol was next investi-
gated. In the reaction of benzene, a 1:1 arene/NBSA mixture
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Scheme 1. Substrate scope of visible-light promoted imidation with NBSA. General conditions: arene (1.5 or 3.0 equiv), N-bromosaccharin (NBSA, 0.2 mmol),
CH2Cl2 (1.0 mL), RT, ambient light under argon. Major product shown. Yields and selectivities are of isolated products based on the limiting NBSA.
outer sphere radical quenching route (Scheme 2, pathway III),
in which a consecutive electron/proton transfer (ET–PT) occurs,
leading to the final adduct together with a neutral HBr.
We further studied the light effect by in situ monitoring the
reaction by IR (Figure 2). The observed on–off photoresponsive
behaviors in in situ monitor as well as in control experiments
(see Schemes S1–S2 in the Supporting Information) indicate
that the radical propagation is unlikely as the major productive
process and is in strong support of a productive radical
quenching process (Figure 2). ET–PT termination, mostly the
out-sphere process, is generally considered as the productive
pathway in homolytic aromatic substitutions.[15] A similar ET–PT
productive pathway has also been proposed in recent catalytic
radical imidation reactions.[8] At this point, we have been
unable to differentiate pathways II and III either experimentally
or theoretically (see Scheme S5 in the Supporting Information),
and both pathways are plausible to account for the photolytic
process.
ed. Our calculations show that the ac45tivation free energy for
the radical addition onto the para- and ortho-position is similar,
To gain further information, the reaction free-energy profile
of saccharine N radical with benzene was probed by DFT calcu-
C
lations. The addition of saccharin nitrogen radical (SA ) is
indeed quite facile with a free energy of 9.5 kcalmolÀ1. The
radical quenching processes lay deeply downhill towards the
ground states (see Scheme S5 in the Supporting Informa-
tion).The regioselectivity of this amidation reaction was also in-
vestigated by DFT (Figure 3). The reaction of toluene with N-
bromo saccharine gave a mixture of para- and ortho-amidation
product in a ratio of 1:1, no meta-selective product was isolat-
Scheme 2. Possible reaction pathways.
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In summary, we have developed a mild catalyst-free visible-
light photolytic approach for CÀH imidation of arenes and het-
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cation of N-bromosaccharin as the imidation reagent, amena-
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Acknowledgements
We thank the Natural Science Foundation of China (21390400,
21025208, and 21202171) and the National Basic Research Pro-
gram of China (2011CB808600) for financial support.
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Keywords: CÀH imidation · N-bromosaccharin · photolysis ·
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Received: July 20, 2014
Published online on September 11, 2014
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