Towards Uniform Iodine Catalysis: Intramolecular C?H Amination of Arenes under Visible Light

Article abstract of DOI:10.1002/chem.201602138

A photochemical catalytic amination of arenes is presented. The reaction proceeds under benign iodine catalysis in the presence of visible light as the initiator and provides access to a range of differently substituted arylamines. A total of 29 examples demonstrate the broad applicability of this mild oxidation method. The scope of the reaction could further be expanded to silyl-tethered derivatives, which undergo intramolecular amination upon formation of seven-membered heterocycles. Cleavage of the silicon tether provides access to the corresponding 3-substituted anilines.

Full text of DOI:10.1002/chem.201602138

DOI: 10.1002/chem.201602138
Communication
&
CÀH Amination
Towards Uniform Iodine Catalysis:
Intramolecular CÀH Amination of Arenes under Visible Light
Claudio Martꢀnez,[a] Alexandra E. Bosnidou,[a] Simon Allmendinger,[a] and Kilian MuÇiz*[a, b]
ously been addressed under conditions of overstoichiometric
Abstract: A photochemical catalytic amination of arenes
reagent combinations, which in several cases led to undesired
is presented. The reaction proceeds under benign iodine
side-product formation upon overoxidation.[8] One may antici-
catalysis in the presence of visible light as the initiator
pate that catalysis should avoid such problems because it can
and provides access to a range of differently substituted
operate under more defined oxidation conditions. Despite the
arylamines. A total of 29 examples demonstrate the broad
general interest in the field, reliable iodine catalyses remain
applicability of this mild oxidation method. The scope of
largely unexplored for the intramolecular oxidative synthesis of
the reaction could further be expanded to silyl-tethered
aniline derivatives.[5,9]
derivatives, which undergo intramolecular amination upon
We recently reported on the iodine-catalyzed Hofmann–Lçf-
formation of seven-membered heterocycles. Cleavage of
fler reaction, which includes the visible-light-induced amina-
the silicon tether provides access to the corresponding 3-
tion of a sp3-hybridized carbon as the key step (Scheme 1,
substituted anilines.
[Eq. (1)]).[10] Within this context, we became interested in the
application of this amination concept[11] for the related light-in-
Approaches toward the direct CÀH amination of arenes are of
significant interest because they provide a straightforward and
economic access to anilines and higher-functionalized aryl
amine derivatives.[1] Entities of this type are present in a large
number of functional molecules of pharmaceutical and biologi-
cal interest.[1,2] Common approaches toward CÀH amination
rely on the use of transition-metal catalysts and an impressive
body of recent work has demonstrated the usefulness of palla-
dium, rhodium, iridium, and other metals for the aforemen-
tioned transformation.[3]
High oxidation state iodine reagents have been identified as
useful alternatives to common transition metals.[4] Their partic-
ular appeal stems from their broad scope in general oxidation
chemistry combined with the fact that their use is not ham-
pered by the occurrence of residual metal contamination. Con-
Scheme 1. Uniform reaction conditions for light-initiated iodine-catalyzed
alkyl and aryl amination (Equations (1) and (2), respectively). Ar=3-Cl-C6H4,
DCE=1,2-dichloroethane.
sequently, iodine(III)-mediated and catalyzed amination of aro-
matic CÀH bonds has recently been explored.[5–7] In another
area of iodine(III)-mediated reactions, several reports on the
combined use of stoichiometric amounts of molecular iodine
in combination with excess equivalents of compounds of the
general structure ArI(O2CR)2 have become available for intra-
molecular CÀH amination reactions. Such reactions have previ-
duced functionalization of arenes (Scheme 1, [Eq. (2)]).[12] Usual-
ly, conditions for either alkyl or aryl CÀH amination are not
transferable from one case to the other because the operating
reaction mechanisms are profoundly different in nature. From
this perspective, the exploration of nitrogen radical intermedi-
ates from iodine catalysis could result in a useful uniform reac-
tivity comprising both cases.
[a] Dr. C. Martꢀnez, A. E. Bosnidou, Dr. S. Allmendinger, Prof. Dr. K. MuÇiz
Institute of Chemical Research of Catalonia (ICIQ)
The Barcelona Institute of Science and Technology
Av. Pa¨ısos Catalans 16, 43007 Tarragona (Spain)
E-mail: kmuniz@iciq.es
We here report that this assumption indeed leads to a feasi-
ble approach toward a new direct catalytic arene amination
using visible-light initiation.[13] The reaction was initially devel-
oped for biaryl derivatives, and was explored for the phenyl
derivative 1a (Scheme 2). Suitable conditions were obtained al-
ready at the outset of a short screening and consist of the ap-
plication of comparable catalysis from alkyl amination. A cata-
[b] Prof. Dr. K. MuÇiz
Catalan Institution for Research and Advanced Studies (ICREA)
Pg. Lluꢀs Companys 23, 08010 Barcelona (Spain)
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under
http://dx.doi.org/10.1002/chem.201602138.
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Scheme 3. Scope of intramolecular CÀH amination of ethylenylarenes. Yields
refer to isolated yields after purification.
ity also led to a protocol with related efficiency (Scheme 3).
Representative substrates 3a–l include common arene substi-
tution patterns and were investigated for different N-alkyl sul-
fonamides. As in the case of related biaryl derivatives 2, the
formation of compounds 4 proceeds in high isolated yields
(51–99%) and with complete selectivity.
Deprotection of these heterocycles is readily accomplished
through hydrogenolysis of the benzyl derivatives, as demon-
strated for the representative case of product 4b (H2, Pd/C,
EtOH, 91%).[14]
The reaction scope could be extended to silicon-tethered
arenes 5.[16] The subsequent intramolecular CÀH amination
proceeds upon seven-membered ring formation. It requires
a slightly higher catalyst loading of 10 mol%, but proceeds
with the expected complete selectivity in favor of CÀH amina-
tion (Scheme 4). For the parent derivative 6a, the product con-
stitution was secured from X-ray analysis.[15] Arenes 5b–e with
electronically different substitution undergo the CÀH amina-
tion within this protocol (40–78% yield), and a 2-naphthalene
derivative 5 f forms the two regioisomeric amination products
6 f/f’ in combined 80% yield. Advantageously, as demonstrat-
ed for products 6a,d, the silyl tether can be removed upon
mild exposure to tetrabutylammonium fluoride to give the
phenylsulfonyl-substituted anilines 7a,d quantitatively. Conver-
sion of these compounds into the free anilines 8a,d is possible
following a modified literature procedure.[17] This sequence
starting from 5 thus provides access to the corresponding 3-
substituted anilines with complete selectivity. Such a substitu-
tion pattern would be synthetically difficult via a direct CÀH
amination or would not be accessible from standard electro-
philic aromatic substitution.
Scheme 2. Scope of intramolecular CÀH amination of biaryls. Yields refer to
isolated yields after purification. [a] Reaction at 4.1 mmol scale.
lyst loading of 5 mol% elemental iodine was optimum, in com-
bination with a hypervalent iodine reagent as terminal oxi-
dant.[14] The formation of 2a proceeds in quantitative yield and
can be carried out conveniently at 4.1 mmol scale (1.06 g). The
reaction is general for a series of these derivatives and pro-
ceeds in high yields and with complete selectivity. For exam-
ple, para-substituted arenes of different electronic parameters
were all tolerated in the amination (compounds 2b–k, 80–
99%). The constitution of the products was unambiguously as-
sured from X-ray analysis of the 4-phenoxy derivative 2 f.[15]
1,2,3-Trisubstituted compound 2l demonstrates the compat-
ibility of an ortho-disubstituted arene, and the successful ami-
nations of 1m and 1n expand the scope to heteroarenes such
as benzothiophene and indole. Higher-substituted arenes also
undergo the intramolecular amination, although they form re-
gioisomeric mixtures (products 2o/2o’ to 2q/2q’, 1.4:1 to
4.5:1 regioisomeric ratio).
Control experiments demonstrate that no conversion is ob-
tained either in the absence of molecular iodine or in the dark
lab.[12] The reaction appears to involve the expected NÀI bond
as in the related catalytic alkane Csp3-amination.[10] The isolat-
ed tetrabutylammonium iodinane 9[10] was employed to dem-
onstrate the nature of an electrophilic iodine(I) catalyst state at
the outset of the reaction. In line with this anticipation, re-
agent 9 promoted clean aryl amination with standard com-
A rigid preorganization of the coupling entities within
a biaryl scaffold is not a requirement as related alkyl-connectiv-
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pound 1a upon acid activation[18] (Scheme 5, [Eq. (3)]). A com-
petition experiment between 1a and its pentadeuterated de-
rivative [D5]1a revealed no difference regarding the individual
rates (kinetic isotope effect kH/kD =1, see Scheme 5, [Eq. (4)]).
Finally, an internal electronic competition experiment with pre-
cursor 3m showed exclusive amination at the more electron-
rich anisole ring forming 4m in 50% yield (Scheme 5, [Eq. (5)],
99% based on recovered starting material). A related outcome
was observed for two intermolecular competition experiments
between 3a and 3j, and 3a and 3h, respectively. In both
cases, a significant preference for amination of the more elec-
tron-rich arene was encountered, favoring formation of 4j over
4a, and 4a over 4h, respectively (Scheme 5, [Eq. (6)]).
The reaction starts from the established I(O2CAr) catalyst 10
that promotes N-iodination of the sulfonamide starting materi-
als to intermediate A (Figure 1, the structure of 3 is shown ar-
Scheme 4. Scope of intramolecular CÀH amination using a silyl tether. Yields
refer to isolated yields after purification.
Figure 1. Mechanistic context.
bitrarily). As demonstrated by the control experiment using
the isolated reagent 9, a potential alternative pathway pro-
ceeding via aryl radical cations generated from the hypervalent
iodine reagent itself can be ruled out.[19] Photolytically assisted
homolysis of the NÀI bond in A provides access to N-centered
radical B. This electrophilic nitrogen radical directly adds to the
aromatic ring to generate a delocalized cyclohexadienyl radical
C. Subsequent oxidation by the terminal hypervalent iodine
leads to the cationic intermediate D and directly regenerates
the iodine(I) catalyst 10. Although less probable, oxidation
may occur already at stage B to generate a positively charged
nitrogen atom, which engages in electrophilic aromatic substi-
tution[20] toward D. Both of the two potential CÀN bond forma-
tion events should be influenced by the electronic situation of
the arene as corroborated by the control experiments from
Equations (5) and (6). From D, the reaction terminates by final
proton loss upon re-aromatization to the CÀN coupling prod-
uct 4. This final step is rapid as demonstrated by the kinetic
isotope experiment from Equation (4).
Scheme 5. Control experiments.
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In summary, we have developed an iodine catalysis protocol
that provides conditions for a mild and selective intramolecular
aryl amination reaction. This chemistry demonstrates that pho-
tochemical iodine catalysis can provide general oxidative ami-
nation conditions for the cases of aliphatic and aromatic hy-
drocarbons alike. This broad scope is unprecedented in the
area and should stimulate the development of additional reac-
tivity.
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Acknowledgements
Financial support for this project was provided from the Span-
ish Ministry for Economy and Competitiveness and FEDER
(CTQ2014-56474R grant to K.M., Severo Ochoa Excellence Ac-
creditation 2014–2018 to ICIQ, SEV-2013-0319 and FPI Fellow-
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The authors thank E. Escudero-Adꢂn for the X-ray structural
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Received: May 6, 2016
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COMMUNICATION
&
CÀH Amination
C. Martꢀnez, A. E. Bosnidou,
S. Allmendinger, K. MuÇiz*
&& – &&
Iodine catalysis aminates arenes!
Iodine in catalyst loadings of 5–10
mol% provides access to intramolecular
Csp2ÀN bond formation. Sulfonamides
are employed as nitrogen sources, lead-
ing to excellent yields. In some cases,
introduction of a traceless linker pro-
vides ready access to aniline derivatives.
Towards Uniform Iodine Catalysis:
Intramolecular CÀH Amination of
Arenes under Visible Light
Chem. Eur. J. 2016, 22, 1 – 5
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