Intermolecular Aryl C?H Amination through Sequential Iron and Copper Catalysis

Article abstract of DOI:10.1002/chem.201605671

A mild, efficient and regioselective method for para-amination of activated arenes has been developed through a combination of iron and copper catalysis. A diverse range of products were obtained from an operationally simple one-pot, two-step procedure involving bromination of the aryl substrate with the powerful Lewis acid iron(III) triflimide, followed by a copper(I)-catalysed N-arylation reaction. This two-step dehydrogenative process for the regioselective coupling of aromatic C?H bonds with non-activated amines was applicable to anisole-, phenol-, aniline- and acetanilide-type aryl compounds. Importantly, the arene substrates were used as the limiting reagent and required no protecting-group manipulations during the transformation.

Full text of DOI:10.1002/chem.201605671

A Journal of
Accepted Article
Title: Intermolecular Aryl C-H Amination Using Sequential Iron and
Copper Catalysis
Authors: Mohamed Mostafa, Ewen Calder, Daugirdas Racys, and
Andrew Sutherland
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Chemistry - A European Journal
10.1002/chem.201605671
COMMUNICATION
Intermolecular Aryl C-H Amination Using Sequential Iron and
Copper Catalysis
Mohamed A. B. Mostafa, Ewen D. D. Calder, Daugirdas T. Racys and Andrew Sutherland*
Abstract: A mild, efficient and regioselective method for para-
amination of activated arenes has been developed using
intermediates that are then subjected to a Cu(I)-catalyzed
amination (Figure 1b).[11] We were interested in developing a
catalytic method for amination of aryl C-H bonds that utilized
only readily available, inexpensive, nontoxic first row transition
metals. Herein, we now report a one-pot, two-step method for
the coupling of aryl C-H bonds with N-H bonds using a
combination of iron(III)- and copper(I)-catalysis (Figure 1c). This
para-directed process is complementary to ortho-directed
methods and is applicable for the general coupling of aryl
compounds with N-heterocycles, amides and sulfonamides.
a
combination of iron and copper catalysis. A diverse range of
products were obtained from an operationally simple one-pot, two-
step procedure involving bromination of the aryl substrate using the
powerful Lewis acid iron(III) triflimide, followed by a copper(I)-
catalyzed N-arylation reaction. This two-step dehydrogenative
process for the regioselective coupling of aromatic C-H bonds with
nonactivated amines was applicable to anisole-, phenol-, aniline-
and acetanilide-type aryl compounds. Importantly, the arene
substrates are used as the limiting reagent and require no protecting
group manipulations during the transformation.
a) ortho-Directed C-H amination
DG
Ni, Cu, Ru
Rh, Pd, Ir
DG
1
2
H
1
2
NR R
+
H NR R
The ability to efficiently and selectively form aryl C-N bonds is an
important challenge in organic chemistry due to the widespread
occurrence of this key linkage in natural products,
pharmaceuticals, agrochemicals and organic materials.[1]
Historically, aryl amination was conducted by nitration of the
aromatic ring, followed by reduction but the use of strongly
acidic conditions has limited the general application of this
method.[2] Another approach is the copper or palladium-
catalyzed amination of aryl (pseudo)halides using Ullmann-
Goldberg, Chan-Evans-Lam or Buchwald-Hartwig protocols.[3,4]
While this method typically produces a single regioisomer,
prefunctionalization of the aromatic ring is required.
oxidant
3
b) para-Directed C-H amination via unsymmetrical l -iodanes
OH
OTs
Ar
NR R2
1
H
Ar
I
I
H
NR R
1
2
OTs
TfOH or
TsOH
Cu(MeCN) BF
4
4
DG
DG
DG
DIPEA
c) This work
Br
N
O
O
NR1R2
H
Br
1
2
H
NR R
FeCl3
BMIM]NTf2
CuI, DMEDA
Cs CO
DG
DG
DG
[
2
3
To circumvent prefunctionalization or preoxidation of either
partner, new methods for direct intermolecular dehydrogenative
coupling of aryl C-H bonds with nonactivated amines have
recently been reported.[5] For example, highly regioselective
intermolecular ortho-amination using transition-metal-catalyzed
chelation-directed aryl C-H activation under oxidative conditions
has been developed for efficient C-N bond formation (Figure
Figure 1. Strategies for regioselective aryl C-H amination.
Before developing the one-pot para-amination process, the
scope, efficiency and regioselectivity of the iron(III)-catalyzed
aryl bromination reaction was initially assessed. We recently
demonstrated that metal triflimide catalysis could be used to
activate N-iodosuccinimide (NIS) for regioselective iodination of
arenes and so a similar procedure was used to investigate
bromination (Scheme 1).[12,13] A mixture of iron(III) chloride (5
mol%) with the inexpensive ionic liquid 1-butyl-3-
2
1
a).[6,7] Procedures for directed aryl C-H and N-H bond coupling
at more distal positions are less well established. Only recently
has a directed meta-amination process been reported[8] and only
a few examples are known for directed para-amination utilizing
transition-metal-, organo- or photo-catalysis, as well as non-
catalytic oxidative methods.[9] Many of these tend to use the aryl
compound as the solvent and/or generate mixtures of
regioisomers. Exceptions that overcome these issues are
known[10] and include work by Suna and co-workers who have
used the electrophilic reaction of arenes with hypervalent
methylimidazolium bis(trifluoromethylsulfonyl)imide ([BMIM]NTf ),
[14]
that forms the powerful Lewis acid Fe(NTf ) in situ, was found
2
3
to activate N-bromosuccinimide (NBS) for the rapid and efficient
bromination of a wide range of anisoles, phenols, anilines and
acetanilides under mild conditions.[15] Arenes with strongly
deactivating groups (e.g. 1l and 1m), naphthalenes (1q and 1r)
and 2,3-benzodihydrofuran (1s) were all tolerated as substrates
for effective bromination. Apart from anisole (1a), which gave a
3
iodonium reagents to form unsymmetrical diaryl- -iodane
[
*]
M. A. B. Mostafa, Dr. E. D. D. Calder, Dr. D. T. Racys, Dr. A.
Sutherland
9
5:5 ratio of p- and o-isomers, the transformation was found to
generate the aryl bromides as single regioisomers.
dibromination reaction was also investigated with cyanophenol
1t). Using two equivalents of NBS resulted in clean
A
WestCHEM, School of Chemistry, The Joseph Black Building,
University of Glasgow
University Avenue, Glasgow, G12 8QQ (UK)
E-mail: Andrew.Sutherland@glasgow.ac.uk
(
dibromination and the efficient synthesis of bromoxynil (2t), a
commercially used nitrile herbicide.[
16]
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
Table 1. Optimization of the one-pot amination process.[a]
Entry
FeCl
mol%]
3
[BMIM]NTf
[mol%]
2
Solvent
3a
Conv. [%][
b]
[
1
2
3
4
5
6
5
10
5
---
30
15
15
15
7.5
[BMIM]NTf
toluene
DMF
2
0
14
39
5
toluene
toluene[c]
toluene[c]
45
5
>95
>95
2.5
[
a] Copper(I) iodide (10 mol%) and DMEDA (20 mol%) were used in the
1
amination reactions. [b] Determined by H NMR analysis of the crude reaction
mixtures. [c] Water (40% of reaction volume) was added to the second step.
Following optimization studies, the scope of the one-pot
amination process of anisole (1a) with various N-nucleophiles
was explored (Scheme 2). Using a range of N-heterocycles such
as indole, pyrazole, imidazole, pyrrole and pyrrolidin-2-one as
well as amides and sulfonamides, the one-pot process was
found to generate the coupled products cleanly and in good
yields as single regioisomers. The use of this procedure for
multigram synthesis of aminated aryl compounds was also
demonstrated with the large-scale synthesis of pyrazole 3b in
essentially quantitative yield.
Scheme 1. Scope of iron(III)-catalyzed bromination.
2 3
Having shown the generality of the Fe(NTf ) -catalyzed aryl
bromination, conditions for the one-pot, two-step amination
process were then investigated (Table 1). Initially, the standard
3
method for the bromination reaction, using FeCl (5 mol%) and
the ionic liquid as the solvent was then followed with a copper(I)
iodide catalyzed amination with indole as the nucleophile and
cesium carbonate as the base (entry 1). While bromination was
successful, no amination was observed. To allow better
compatibility between the two steps, a bromination protocol
using catalytic amounts of both FeCl
was developed. Using this strategy and under typical conditions
40 ºC, 4 h), complete bromination was observed and, when
3 2
and [BMIM]NTf in toluene
(
combined with the Cu(I)-catalyzed amination, conversion to the
coupled product 3a was observed (14%, entry 2). A further
reduction of the catalyst loading in either DMF or toluene
resulted in improved overall conversions (entries 3 and 4).
However, a significant breakthrough was achieved when water
was added as a co-solvent to the second step. This allowed
dissolution of the base and better mixing of reagents, with the
result being nearly quantitative conversion to 3a (entry 5).
Further optimization studies showed that the catalyst loading of
Scheme 2. Scope of the one-pot amination process using anisole (1a). [a]
Amination was performed at 150 ºC for 24 h. [b] Amination was performed at
150 ºC for 36 h.
3 2
both FeCl (2.5 mol%) and [BMIM]NTf (7.5 mol%) could be
lowered further without affecting the rate or overall conversion of
the one-pot process (entry 6).
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Using pyrazole and benzamide as nucleophiles, the scope
of the aryl coupling partner was then explored (Scheme 3). The
one-pot process was found to give para-aminated products in
good yields using various anisole, phenol, aniline and
acetanilide based coupling partners, in the presence of either
activating or deactivating substituents. In addition, despite using
aryl compounds containing nucleophilic functional groups (e.g.
phenols, anilines), the one-pot transformation gave the N-
coupled products cleanly.
reported. Correa and Bolm reported an iron-catalyzed N-
arylation reaction that was later found to be catalyzed by copper
contaminants,[19] while Taillefer and co-workers described an
iron-copper co-catalyzed process.[
20]
To investigate the
individual role of each metal catalyst during the amination step
of this current process, a series of experiments were performed
to mimic the second step of the one-pot process (Table 2). As
expected, these results confirmed that copper iodide is essential
for efficient conversion to the N-coupled product. While this does
not rule out an iron-copper co-catalyzed amination, the Taillefer
study does emphasise that pre-complexation of iron(III) with the
acetylacetonate ligand was critical for effective co-catalysis (use
As part of this research programme,
a preliminary
investigation into ortho-N-arylation using substrates with the
para-position blocked has also been conducted. The one-pot
bromination and amination of p-chloroanisole (1c) with pyrazole
required more forcing conditions but gave 4m cleanly in 53%
yield (Scheme 3). However, a limitation of this approach was
demonstrated with a similar one-pot process with p-nitroaniline
of FeCl
3
as a co-catalyst gave low yields).[20]
Table 2. Role of iron and copper catalysts during the amination step.[a]
(
1l), which gave an inseparable mixture of 1l and the coupled
product 4n.[
17]
In this case, slower copper-catalyzed ortho-
amination results in a competing pathway involving reduction of
the organocopper intermediate, as evidenced by the
regeneration of 1I from the bromide intermediate.[18]
Entry
Cat.
Yield [%]
1
2
3
FeCl
CuI
3
<5
92
87
3
FeCl /CuI
[
a] Standard catalyst loadings were used (FeCl
3
: 2.5 mol%; CuI: 10 mol%).
In conclusion, a general and efficient approach for the
regioselective bromination of aryl compounds has been
demonstrated using iron(III) triflimide activation of NBS.
Combination of a modified version of this transformation that
utilizes catalytic amounts of both FeCl
Cu(I)-catalyzed amination has allowed the development of a
one-pot, two-step dehydrogenative process for the
3 2
and [BMIM]NTf with a
regioselective coupling of aromatic C-H bonds with nonactivated
amines. This process was found to be general for the para-
amination of a range of aromatic compounds in combination with
various nitrogen nucleophiles such as N-heterocycles, amides
and sulfonamides. This study provides a conceptually novel,
one-pot approach for the preparation of valuable synthetic
building blocks that is complementary to ortho-C-H amination
methods and overcomes the limitations of the multistep and
harsh conditions of more traditional chemistries.
Acknowledgements
Financial support from the Ministry of Higher Education and
Scientific Research, Omar Al-Mukhtar University, Libya
Scheme 3. Scope and limitations of the aryl coupling partner. [a] Brominations
(
studentship to M.A.B.M.), EPSRC (EP/P505534/1 and
3 2
were performed at 70 ºC using FeCl (5 mol%) and [BMIM]NTf (15 mol%).
EP/K503903/1) and the University of Glasgow is gratefully
acknowledged.
Methods for the one-step amination of aromatic halides
involving iron and copper catalysis have been previously
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Entry for the Table of Contents
COMMUNICATION
Mohamed A. B. Mostafa, Dr. Ewen D. D.
Calder, Dr. Daugirdas T. Racys, Dr.
Andrew Sutherland*
Page No. – Page No.
Intermolecular Aryl C-H Amination
Using Sequential Iron and Copper
Catalysis
A one-pot, two-step procedure involving iron- and then copper-catalysis has been
developed for para-selective coupling of aryl C-H bonds with N-H bonds. The
general process was used to activate anisole-, phenol-, aniline- and acetanilide-
type aryl compounds for coupling with N-heterocycles, amides and sulfonamides.
This article is protected by copyright. All rights reserved.