Metal-free direct oxidative intermolecular diarylation of anilides at ambient temperature assisted by cascade selective formation of C-C and C-N bonds

Article abstract of DOI:10.1039/c2cc30324h

A new atom-economical process of direct oxidative intermolecular functionalization of aniline derivatives by simple arenes was developed. The products were formed in a highly regioselective manner under metal-free conditions at ambient temperature. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc30324h

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COMMUNICATION
Metal-free direct oxidative intermolecular diarylation of anilides at
ambient temperature assisted by cascade selective formation of
C–C and C–N bondsw
a
ab
Rajarshi Samanta,z Jonas Lategahnz and Andrey P. Antonchick*a
Received 5th December 2011, Accepted 25th January 2012
DOI: 10.1039/c2cc30324h
A new atom-economical process of direct oxidative intermolecular
functionalization of aniline derivatives by simple arenes was
developed. The products were formed in a highly regioselective
manner under metal-free conditions at ambient temperature.
Carbon–carbon and carbon–heteroatom intermolecular bond
formation reactions are easily reasoned from broad applica-
Scheme 1 Resonance structures of the aryl nitrenium ion.
tions of these transformations and represent a fundamental
and challenging topic in organic chemistry.1 The development
of effective methods for the formation of cross-coupled products
is an intensively investigated area of great significance. Direct
oxidative cross-coupling between two unfunctionalized
compounds through cleavage of C–H bonds represents an
environmentally benign and economically attractive synthetic
strategy.2 Recently, hypervalent iodine(III) compounds found
application for direct oxidative, metal-free cross-coupling of
unfunctionalized arenes in a regioselective manner under
environmental friendly reaction conditions.3 However, these
methods are limited to electron rich arenes. The development
of new efficient, direct oxidative cross-coupling methods which
could provide access to new scaffolds and/or are based on new
reaction mechanisms is highly demanded.
atom-economical, regioselective, environmentally benign method
of diarylation of derivatives of aniline with non-prefunctionalized
arenes via cascade formation of C–C and C–N bonds at ambient
temperature under metal-free reaction conditions.
To test our hypothesis, we employed derivatives of aniline
and mesitylene (2a) in the presence of PhI(OAc)2 in 1,1,1,3,3,3-
hexafluoro-2-propanol (HFIP) (Table 1, entries 1–6).8 To our
delight, we observed formation of product 3 of the diarylation.
The best result was obtained using N-phenylacetamide which
resulted in a yield of 63% for the product of the cascade
formation of C–C and C–N bonds (Table 1, entry 5). It is
notable that the diarylation could be carried out without usage
of a large excess of arenes at ambient temperature. Interestingly,
the formation of typical by-products of transition-metal-
catalyzed reactions such as homodimers was not observed in
any reaction. Furthermore, all transformations resulted in
regioselective C–C bond formation and products of ortho-
arylation of aniline derivatives were not detected in the
reaction mixtures.6,7 Only a trace amount of the mono-N-
arylated product with mesitylene (2a) was detected. However,
decrease in the loading of mesitylene led to increase of the
mono-N-arylated product. Additionally, an N-iodophenylation
product of 1e was detected as a result of mono-arylation with
iodobenzene.6a Afterwards, various solvents were tested in
order to improve the yield of the product (Table 1, entries 7–12).
However, only in 2,2,2-trifluoroethanol (TFE) the desired
product was obtained in moderate yield. Other sources of
hypervalent iodine(III) oxidants were tested. Besides para-
tolyliodonium diacetate which gave a little increase in the
yield of the diarylated product (Table 1, entry 13), the
application of different oxidants was unsuccessful (Table 1,
entries 14–16). Importantly, the usage of para-tolyliodonium
diacetate instead of PhI(OAc)2 as the oxidation reagent
prevents formation of the product of the N-iodophenylation.
During studies on the direct functionalization of unactivated
C–H bonds, we developed an intermolecular, metal-free, direct
oxidative method of C–N bond formation via cross-coupling
with non-prefunctionalized arenes.4,5 The mechanistic studies
indicated the formation of a nitrenium ion (A) which under-
goes an electrophilic aromatic substitution leading to the
desired products of the C–H bond amination (Scheme 1).4
Based on this study, we considered possibilities for stabilization
of the cation (A) by charge delocalization to a carbenium ion
(C) via an ion (B). Ion C can be trapped by non-prefunctionalized
arenes leading to biphen-4-yl acetamides via formation of a
new C–C bond in para-position to the acetamide group under
metal-free conditions.6,7 We herein report our results on an
a Max-Planck Institute of Molecular Physiology,
Otto-Hahn Strasse 11, Dortmund 44227, Germany.
E-mail: andrey.antonchick@mpi-dortmund.mpg.de
b TU Dortmund, Faculty of Chemistry, Otto-Hahn-Strasse 6,
Dortmund 44227, Germany
w Electronic supplementary information (ESI) available: Detailed proce-
dures and compound characterization. See DOI: 10.1039/c2cc30324h
z These authors contributed equally.
c
3194 Chem. Commun., 2012, 48, 3194–3196
This journal is The Royal Society of Chemistry 2012

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Table 1 Screening of reaction conditionsa
Table 2 Cascade diarylation of acetanildes with mesitylenea
Entry PG
Solvent Oxidant
Time/h Yieldb [%]
1
2
3
4
5
6
7
8
H (1a)
Bz (1b)
p-Tos (1c)
HFIP
HFIP
HFIP
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
40
29
20
29
16
48
16
20
16
16
16
16
o5 (3aa)
38 (3ba)
36 (3ca)
24 (3da)
63 (3ea)
o5
CF3CO (1d) HFIP
Ac (1e)
Me3CCO
Ac (1e)
Ac (1e)
Ac (1e)
Ac (1e)
Ac (1e)
Ac (1e)
Ac (1e)
Ac (1e)
Ac (1e)
Ac (1e)
Ac (1e)
Ac (1e)
Ac (1e)
HFIP
HFIP
TFE
MeNO2 PhI(OAc)2
MeOH PhI(OAc)2
CH2Cl2 PhI(OAc)2
40 (3ea)
4 (3ea)
o5
9
10
11
12
13
14
15
16
17c
18d
19e
o5
DMF
none
PhI(OAc)2
PhI(OAc)2
4-MeC6H4I(OAc)2 23
PhI(OCOCF3)2
PhI(OH)OTos
Ph2IOTf
4-MeC6H4I(OAc)2 21
4-MeC6H4I(OAc)2 21
4-MeC6H4I(OAc)2 21
4-MeC6H4I(OAc)2 21
o5
o5
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
65 (3ea)
o5
16
16
16
o5
o5
60 (3ea)
62 (3ea)
68 (3ea)
68 (3ea)
a
20e,f Ac (1e)
Reaction conditions: aniline derivative 1 (0.2 mmol, 1 equiv.), 2a
(0.6 mmol), 4-MeC6H4I(OAc)2 (0.44 mmol) in HFIP (0.2 M).
a
Conditions: derivative of aniline 1 (0.1 mmol, 1 equiv.), 2a (0.3 mmol),
b
oxidant (0.22 mmol, 2.2 equiv.) in solvent (0.1 M). Isolated yields after
c
column chromatography. 10 equiv. of 2a. 0.03 M solution. 0.2 M
f
solution. Using 3 equiv. of 4-MeC6H4I(OAc)2. PG = protection
group.
d
e
in the absence of the non-prefunctionalized arene undergo an
intramolecular amination to carbazoles. To our delight, we
found that the developed method allows suppression of the
formation of intramolecular reaction products and led to the
selective formation of C–C and C–N bonds in 73–94% yield
(Table 2, products 3ma–3oa).
The yield of 3ea slightly depended on the concentration of the
reaction mixture (Table 1, entries 17–20). However, increase of
the yield of the mono-N-arylated product was detected. The
best yield of 68% for cascade formation of C–C and C–N
bonds was obtained using a 0.2 M solution of 1e.
Subsequently, a variety of non-prefunctionalized arenes
were tested in the developed intermolecular cascade process.
We were pleased to find out that different electron rich
benzene derivatives undergo the oxidative cascade diarylation
process giving products in moderate to good yields (Table 3).
The application of complex or sterically congested derivatives
is tolerated. However, our attempts to employ two structurally
different non-prefunctionalized arenes in diarylation led to the
formation of an inseparable mixture of products. Further-
more, a difference in behaviour of carbenium and nitrenium
ions was found in diarylation with 1-tert-butyl-3,5-dimethyl-
benzene (2i) (Table 3, products 3ei, 3fi, 3hi). The nitrenium ion
is attacked by the most nucleophilic and sterically congested
position of 2i, while the carbenium ion is attacked by the less
nucleophilic and less sterically bulky position of 2i. This result
is exceedingly significant due to the achievement of highly
chemoselective new bond formation. A mixture of regioisomers
was obtained when a tert-butyl group was changed to iso-propyl
(Table 3, product 3ej). The application of less nucleophilic
arenes such as ortho- or para-xylene resulted in the selective
formation of mono-N-arylation products. Furthermore, the
products of arylation were not detected if benzene or its
electron poor derivatives were employed. In general,
the obtained N-arylbiphenyl-4-amines (3) represent a key
scaffold of numerous biological probes and electroluminescent
With optimized conditions in hand, we focused on the
exploration of the scope and generality of the method. We
first examined the effect of substitutions in the aniline derivatives
(Table 2). In general, we found that the presence of a sub-
stituent with different electronic and steric properties in the
ortho-position did not have any negative effects on the
formation of the desired products (Table 2, products 3fa–3ia).
Unfortunately, when using cyclic aniline derivatives such as
2H-1,4-benzoxazin-3(4H)-one and 2-oxindole, formation of
mono-N-arylation products was observed and the desired
products of diarylation were obtained in yields of o10% under
optimized conditions. Afterwards, we examined substitutions in
the meta-position (Table 2, products 3ja–3la). Unfortunately,
the products of cascade diarylation were obtained only in
moderate yields. Gratifyingly, the developed method allows
the formation of the sterically congested product 3la bearing
four methyl groups around the newly formed C–C bond which
is challenging for metal catalyzed reactions. As expected, the
para-substituted derivatives led to the selective formation of
the mono-N-arylation product under identical reaction
conditions (see ESIw). Afterwards, we drew our attention to
2-acetaminobiphenyls which under similar reaction conditions
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3194–3196 3195

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Table
prefunctionalized arenes
3
Cascade diarylation of N-phenylacetamides with non-
In conclusion, we developed a new highly efficient atom-
economical, cascade, oxidative intermolecular process
of introduction of two aryl groups in aniline derivatives. The
desired products were formed in a highly regioselective
manner under metal-free conditions at ambient temperature.
The developed transformation was realized by using a
single environmental friendly reagent—para-tolyliodonium
diacetate.
We gratefully acknowledge Prof. Dr Herbert Waldmann for
his generous support
Notes and references
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Chem., Int. Ed., 2005, 44, 674; (f) S. V. Ley and A. W. Thomas,
Angew. Chem., Int. Ed., 2003, 42, 5400.
2 For selected reviews on C–H activation, see: (a) C. S. Yeung and
V. M. Dong, Chem. Rev., 2011, 111, 1215; (b) S. H. Cho, J. Y. Kim,
J. Kwak and S. Chang, Chem. Soc. Rev., 2011, 40, 5068;
(c) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147;
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(h) X. Chen, K. M. Engle, D. H. Wang and J. Q. Yu, Angew. Chem.,
Reaction conditions: aniline derivative 1 (0.2 mmol, 1 equiv.), arene
(1.0 mmol), 4-MeC6H4I(OAc)2 (0.54 mmol) in HFIP (0.2 M). a Using
Int. Ed., 2009, 48, 5094; (i) J. Wencel-Delord, T. Droge, F. Liu and
F. Glorius, Chem. Soc. Rev., 2011, 40, 4740.
¨
b
arene (2.0 mmol), 4-MeC6H4I(OAc)2 (0.8 mmol). In the mixture
c
DCM/HFIP (1/1) 0.1 M. Regioisomer ratio is 1 : 1.2.
3 (a) K. Morimoto, N. Yamaoka, C. Ogawa, T. Nakae, H. Fujioka,
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materials and can be aminated under metal free conditions
(see ESIw, Scheme S1).
Mechanistically, we assume that the oxidation of N-phenyl-
acetamides (1) led to the formation of the nitrenium ion (A)
which is stabilized by charge delocalization to the carbenium
ion (C) (see ESIw, Scheme S2). Both ions A and C may react
with nucleophilic arenes giving products of arylation. The
electron-deficient ion C is attacked by the nucleophilic arene
giving N-(biphenyl-4-yl)acetamides (4), while arylation of
intermediate (A) leads to formation of a mono-N-arylation
product (5). We assume that under optimized reaction condi-
tions, the extensively charge delocalized intermediate C is
preferred although this depends on the structure of derivatives
1. Product 4 is oxidized by the second equivalent of iodine(III)
reagent to give nitrenium ion (D), which is involved in the
electrophilic aromatic substitution with the arene to yield
product 3. We found that in the presence of radical scavenger,
the yield of product 3 was not decreased. This finding indicates
that radical species do not take part in the diarylation process.
In a control experiment, anilide (5) did not lead to product 3
under identical oxidative reaction conditions. Furthermore,
application of para-substituted aniline derivatives led to
mono-N-arylation products. This result indicates that the
developed process is implemented via a conserved reaction
sequence where the first step is the formation of the C–C bond
and the second step is N-arylation.
4 A. P. Antonchick, R. Samanta, K. Kulikov and J. Lategahn, Angew.
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Y. Kikugawa, J. Org. Chem., 2002, 67, 7424; (b) H. Liu, X. Wang
and Y. Gu, Org. Biomol. Chem., 2011, 9, 1614; (c) H.-L. Wei,
T. Piou, J. Dufour, L. Neuville and J. Zhu, Org. Lett., 2011,
13, 2244; (d) H. Liu, Y. Z. Xie and Y. H. Gu, Tetrahedron Lett.,
2011, 52, 4324.
7 For metal catalysed para-selective arylation, see: C. L. Ciana,
R. J. Phipps, J. R. Brandt, F. M. Meyer and M. J. Gaunt, Angew.
Chem., Int. Ed., 2011, 50, 458.
8 For reviews on hypervalent iodine(III), see: (a) T. Wirth, Angew.
Chem., Int. Ed., 2005, 44, 3656; (b) V. V. Zhdankin and P. J. Stang,
Chem. Rev., 2008, 108, 5299; (c) T. Dohi and Y. Kita, Chem.
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c
3196 Chem. Commun., 2012, 48, 3194–3196
This journal is The Royal Society of Chemistry 2012