Sterically Congested 2,6-Disubstituted Anilines from Direct C?N Bond Formation at an Iodine(III) Center

Article abstract of DOI:10.1002/anie.201606599

2,6-Disubstituted anilines are readily prepared from the direct reaction between amides and diaryliodonium salts. As demonstrated for 24 different examples, the reaction is of unusually broad scope with respect to the sterically congested arene and the nitrogen source, occurs without the requirement for any additional promoter, and proceeds through a direct reductive elimination at the iodine(III) center. The efficiency of the coupling procedure is further demonstrated within the short synthesis of a chemerin binding inhibitor.

Full text of DOI:10.1002/anie.201606599

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201606599
German Edition: DOI: 10.1002/ange.201606599
Synthetic Methods
À
Sterically Congested 2,6-Disubstituted Anilines from Direct C N Bond
Formation at an Iodine(III) Center
Nicola Lucchetti, Michelangelo Scalone, Serena Fantasia, and Kilian MuÇiz*
Abstract: 2,6-Disubstituted anilines are readily prepared from
the direct reaction between amides and diaryliodonium salts.
As demonstrated for 24 different examples, the reaction is of
unusually broad scope with respect to the sterically congested
arene and the nitrogen source, occurs without the requirement
for any additional promoter, and proceeds through a direct
reductive elimination at the iodine(III) center. The efficiency of
the coupling procedure is further demonstrated within the short
synthesis of a chemerin binding inhibitor.
C
arbon–nitrogen bond formation is a synthetic endeavor of
paramount importance. Processes that enable direct amina-
tion reactions decidedly streamline organic synthesis, and can
be of special significance in cases that have no biosynthetic
precedence.[1] A particularly prominent example of innova-
Figure 1. Examples of pharmaceuticals and herbicides containing
a 2,6-dialkylaniline core.
tive C N bond installment is the synthesis of anilines by
ity,[7] we observed that there is little synthetic prospect for
À
À
transition-metal-catalyzed coupling between amine sources
and aryl halides or related arene sources. In this area,
palladium[2] and copper[3] have traditionally received major
attention. A complementary approach consists of carbon–
nitrogen bond formation through the application of activated
diaryliodonium derivatives,[4] which serve as suitable partners
in transition-metal coupling processes.[5] Alternatively, they
C N bond formation in the particular case of 2,6-disubsti-
tuted aniline derivatives.[8] This scaffold is of significant
interest, since it is incorporated in a series of relevant
compounds of pharmaceutical and herbicidal interest.
Selected examples are depicted in Figure 1.
We demonstrate here that iodine(III) compounds of the
general formula Ar2I-NPhth (HNPhth = phthalimide), which
can be accessed in situ by anion exchange of common
À
may engage in direct C N coupling reactions, even in the
absence of a metal promoter, an aspect which has attracted
considerable attention from biomedical sciences. Examples
include aniline syntheses by the arylation of amides,[6a,b]
aromatic amines,[6c,d] methoxyamines,[6e] ammonia,[6f] hetero-
cycles,[6g,h] and radical rearrangements.[6i] Although aniline
syntheses have thus far reached a significant level of general-
diaryliodonium salts[4b,c] with potassium phthalimide, effi-
2
À
ciently promote a direct reductive C(sp ) N bond formation,
with a particularly broad scope for the coupling of sterically
congested arene groups. In contrast to common methods in
the area, no transition-metal promoters are required for this
process.
[*] N. Lucchetti, Prof. Dr. K. MuÇiz
À
Table 1: Metal-free C N bond formation from diphenyliodonium salts:
reaction optimization.
Institute of Chemical Research of Catalonia (ICIQ)
The Barcelona Institute of Science and Technology
Av. Paꢀsos Catalans 16, 43007 Tarragona (Spain)
E-mail: kmuniz@iciq.es
Dr. M. Scalone, Dr. S. Fantasia
F. Hoffmann-La Roche Ltd, Process Research & Development
Grenzacherstrasse 124, 4070 Basel (Switzerland)
Entry Amide (equiv)
Solvent
t [h] T [8C] Yield [%][a]
Prof. Dr. K. MuÇiz
ICREA
Pg. Lluꢁs Companys 23, 08010 Barcelona (Spain)
1
2
3
4
5
6
7
8
phthalimide (5.0)
phthalimide (4.0)
phthalimide (3.0)
phthalimide (3.0)
phthalimide (2.0)
phthalimide (2.0)
phthalimide (2.0)
CH2Cl2
toluene
toluene
toluene
toluene/PhCl 24 100
toluene/PhCl 24 110
toluene/PhCl 24 120
44
24
24
40
84
84
9
60
54
67
23
50
50
75
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201606599.
24 100
ꢂ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial NoDerivs License, which
permits use and distribution in any medium, provided the original
work is properly cited, the use is non-commercial, and no
modifications or adaptations are made.
4Fphthalimide (3.0)[b] toluene
24 100
[a] Yield of isolated product after purification. [b] 4FPhthalimide =
tetrafluorophthalimide. The product is N-phenyl tetrafluorophthalimide
3a.
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The reaction was initially developed for the diphenyl-
iodonium salt 1a and phthalimide as the nucleophilic nitrogen
source (Table 1).[9] Treatment of 1a with 5 equivalents of
potassium phthalimide in dichloromethane at reflux led to
a low yield of the desired product 2a (entry 1). A change in
the solvent allowed optimization of the reaction, and yields of
60% and 54% were obtained in toluene with 4 and
3 equivalents of phthalimide, respectively (entries 2 and 3).
Alternative solvents such as dichloroethane, dioxane, or DMF
resulted in little to no conversion.[10] Increasing the reaction
temperature to 1008C led to the yield rising to 67% (entry 4),
while the addition of chlorobenzene led to higher solubiliza-
tion of potassium phthalimide, albeit at the expense of the
yields (entries 5–7). Finally, tetrafluorophthalimide was
tested (entry 8). Under the former best conditions for
phthalimide, its tetrafluoro derivative led to formation of 3a
in an improved 75% yield of the isolated product.
although this approach has not yet been employed for the
synthesis of 2,6-disubstituted aniline derivatives.
Based on this observation, the aryl amination reaction was
investigated for additional sterically congested aryl substitu-
tents (Scheme 1). As a consequence of the successful
formation of 3b, preference was directly given to the
challenging 2,6-disubstitution motif. For this particular class
of compounds, the present transformation indeed provided
excellent conditions. Investigation of [Mes2I]OTf revealed an
identical outcome for the synthesis of 3b. As a result of their
more economic synthesis,[4] mixed aryl(phenyl)iodonium salts
were employed in the following. In this way, purification is
eased because, with PhI as the by-product, compounds 3 can
usually be obtained by simple crystallization. In addition to
the examples of 3a and 3b, several 2,6-dimethylated deriv-
atives could be aminated cleanly to give the corresponding
derivatives 3c–f in yields of 70–80%. Aniline derivative 3c
was synthesized readily on a 4.6 mmol scale. Larger ortho
substituents, such as ethyl or even 2-propyl, were likewise
tolerated (3g and 3h; 90 and 70% yield, respectively).
Halogen substitution is readily compatible, as demonstrated
for product 3i, which would be difficult to synthesize through
common transition-metal catalysis.[2] The 2,6-dichloro motif
and higher-substituted derivatives thereof were explored by
using 3j–3n (51–75% yields). Finally, the mixed 2-nitro-6-
methyl derivative 3o demonstrated that even the stereo-
electronically demanding nitro substituent can be employed
(87% yield). In all these reactions, exclusive transfer of the
higher substituted arene was observed, and the alternative
product 3a was not detected in any of these cases. The
attractiveness of tetrafluorophthalimide as the ammonia
surrogate was demonstrated through the deprotection of 3c
by convenient aminolysis to provide 2,6-dimethylaniline 3cꢀ
quantitatively.
Replacement of the diphenyliodonium salt 1a by the
mixed reagent [MesIPh]OTs (1b) led to exclusive formation
À
of a C N bond involving the mesityl group, and N-mesityl
tetrafluorophthalimide 3b was obtained in 68% yield. A
related preferential behavior for mesitylene transfer was
reported for related studies on aniline syntheses with diaryl-
iodonium reagents, including an amination with acetami-
de.[6c,11] These processes are complemented by electrophilic
amination of arenes initiated by hypervalent iodine,[12]
The successful synthesis of compounds 3b–o significantly
broadens the availability of 2,6-disubstituted anilines and
higher-substituted derivatives thereof.
The present amination is not limited to phthalimide and
tetrafluorophthalimide. By employing dimesityliodonium-
Scheme 1. Amination of 2,6-disubstituted arenes: scope. [a] Reaction
with [Mes2I]OTf (4a). [b] Reaction on a 4.6 mmol scale.
Scheme 2. Amination of [Mes2I]OTf (4a) with different nitrogen
sources: scope.
2
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(III) triflate as the aryl component, other phthalimides such
as 4-nitrophthalimide and 4-bromophthalimide provide sim-
ilarly good results (Scheme 2, products 5a,b). Additional
successful nitrogen sources include succinimide (product 5c),
saccharin (product 5d), and 1,8-naphthalimide (product 5e),
which led to products in 43–72% yield. Moreover, the
pharmaceutically important class of oxazolidinones and
lactams also undergo arylation, as demonstrated for the
three products 5 f–h (77–95% yield). While common carbox-
amides display low reactivity, tosylimide underwent a clean
arylation reaction to 5i (56% yield).
The synthetic utility of the present coupling was further
demonstrated within a short synthesis of the N,N’-diarylated
pyrrolidinone carboxamide 9 (Scheme 3). This compound is
Scheme 4. Synthesis of diaryliodonium(III) amidato complexes 11a,b
and solid-state structures (ellipsoids at 50% probability).[14] Selected
bond lengths [ꢃ] and angles [8]: 11a: N1–I1 2.874(1); N1-I1-C1
170.09(5), N1-I1-C7 79.57(5). 11b: N1–I1 2.758(2); N1-I1-C1
174.95(9), N1-I1-C7 86.29(8).
tetrafluorophthalimide from 11a or 1a, respectively. The
latter synthesis successfully demonstrates the viability of
common anion exchange for phthalimide in complexes 1a–o.
According to X-ray analysis, both species 11a,b display the
expected T-shape constitution at the iodine center, with only
a small deviation of the N-I-C bond angles from linearity.[14]
The respective iodine–nitrogen bond lengths of 2.874(1) and
À
2.758(2) ꢀ are comparable. They are longer than the N I
bond in
a
related phthalimidato iodine(III) derivative
Scheme 3. Synthesis of N,N’-diarylated pyrrolidinone carboxamide 9
and solid-state structures of 7 and 9 (ellipsoids at 50% probability).
reported by Minakata and co-workers, which generates
a nucleophilic phthalimide source under oxidation condi-
tions.[18] The present reactivity scenario corroborates an
anionic character of the tetrafluorophthalimide in 11b,
which excludes involvement of electrophilic amination path-
ways commonly encountered in hypervalent iodine chemis-
try.[12,19]
representative of a family of binding inhibitors of the
chemoattractant peptide chemerin to the G-protein coupled
receptor ChemR23. Its reported preparation comprises
a linear synthesis based on preformed anilines.[13] By employ-
À
ing our new C N coupling method as the key transformation,
More instructively, 11a and 11b display significantly
different chemical performances. As a consequence of its
highly stabilized bistosylimide group as the nitrogen source,
iodine(III) compound 11a is stable against any observable
reductive carbon–nitrogen bond formation.[10] Even upon
prolonged heating in toluene solution, only starting material
was recovered. In contrast, isolated 11b readily undergoes
a convenient protecting-group-free two-step synthesis starts
with selective N-arylation at the lactam of commercially
available pyrrolidinone carboxamide 6. The second N-aryla-
tion at the free amide group in 7 yields inhibitor 9, which is
obtained in an overall 45% yield from 6.[14,15] Depending on
the chosen aryl groups, rapid structural diversification should
be possible, thereby creating new pharmaceutical space
À
thermally induced quantitative formation of the C N cou-
À
through advanced C N coupling.
pling product 3a with a clear first order dependence and the
expected temperature dependence.[10] The reaction could thus
be monitored by 19F NMR spectroscopy at different temper-
atures between 80 and 1108C by employing a toluene/DMF
solution to guarantee homogeneous conditions.[20] An Arrhe-
nius plot[10] provides a value for the activation energy of
Mechanistically, the reaction should proceed by anion
exchange at the iodine center, where the tetrafluorophthal-
imidato ligand is incorporated prior to aniline formation. To
À
investigate this direct C N bond formation from diaryliodo-
nium compounds containing defined imidato groups, we
synthesized two derivatives with different nitrogen entities
(Scheme 4). Compound 11a contains the bistosylimide
moiety, which represents the standard nitrogen source in
our recent iodine(III)-mediated amination chemistry.[16,17] It
was conveniently accessed from the known iodine(III)
derivative 10[16a] by electrophilic activation of benzene.
Compound 11b contains the tetrafluorophthalimide anion
and was generated through amide exchange with potassium
34.8 kcalmolÀ1 for C N bond formation from 11b, which is in
À
agreement with the high reaction temperature required
experimentally. The corresponding Eyring plot reveals an
activation enthalpy DDH° of 34.1 kcalmolÀ1 and an entropy
of DDS° = 105.5 JKÀ1. This scenario supports the assumption
À
of an ordered transition state A, in which the original N I
bond has dissociated and in which product formation
proceeds through
a
three-center-four-electron transition
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À
Figure 2. Mechanism of the C N bond formation.
state (Figure 2).[2,21,22] This pathway is reminiscent of related
mechanisms in transition-metal chemistry. It is further aided
by the 2,6-disubstitution motif, which adds steric bulk to
transition state A, thus promoting reductive elimination
within a completely predictable regioselective manner.[23]
Reductive elimination on diaryliodonium(III) derivatives
through a transition state analogous to A was invoked
previously by Ochiai and co-workers.[24]
In summary, we have developed a new procedure for the
rapid and productive synthesis of 2,6-disubstituted anilines
and their higher-substituted derivatives. It proceeds through
À
a direct reductive C N bond formation, which constitutes
a
transition-metal-like performance of the iodine(III)
reagent. This approach is applicable for a wide range of aryl
groups and nitrogen sources. It significantly streamlines the
synthetic path to this class of compounds and should enable
a larger structural diversification of these aniline cores in the
screening of molecular structures of pharmaceutical interest.
[7] The Chemistry of Anilines, Vol. 1,2 (Ed.: Z. Rappoport), Wiley,
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[8] For a nonrelated approach using triarylbismuth derivatives, see
A. Fedorov, S. Combes, J.-P. Finet, Tetrahedron 1999, 55, 1341 –
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[9] For nonrelated metal-free amination of arenes with phthalimide,
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Acknowledgments
We thank F. Hoffmann-La Roche Ltd., the Spanish Ministry
for Economy and Competitiveness, and FEDER (CTQ2014-
56474R grant to K.M., Severo Ochoa Excellence Accredita-
tion 2014–2018 to ICIQ, SEV-2013-0319) for financial sup-
port, as well as E. Escudero-Adꢁn for the X-ray analyses.
[10] See the Supporting Information for details.
[11] a) T. B. Petersen, R. Khan, B. Olofsson, Org. Lett. 2011, 13,
3462 – 3465; b) B. Wang, J. W. Graskemper, L. Qin, S. G.
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[12] Reviews: a) R. Narayan, S. Manna, A. P. Antonchick, Synlett
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Keywords: amination · anilines · arylation · hypervalent iodine ·
phthalimide
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[14] CCDC 1491279 (11a), 1491280 (11b), 1491282 (9), and 1491281
(7) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
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À
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Received: July 7, 2016
Published online: && &&, &&&&
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Synthetic Methods
N. Lucchetti, M. Scalone, S. Fantasia,
K. MuÇiz*
&&&& — &&&&
Sterically Congested 2,6-Disubstituted
À
Anilines from Direct C N Bond
Formation at an Iodine(III) Center
The bulkier, the better: A metal-free
coupling of diaryliodonium salts with
potassium tetrafluorophthalimide and
related nitrogen sources enables a gen-
eral and synthetically productive access
to N-arylated amides with 2,6-disubstitu-
tion patterns on the arene ring. 2,6-
Disubstituted anilines—which are
important building blocks in pharma-
ceutically relevant structures—are also
accessible.
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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