Regiospecific N-Arylation of Aliphatic Amines under Mild and Metal-Free Reaction Conditions

Article abstract of DOI:10.1002/anie.201807001

A transition metal-free N-arylation of primary and secondary amines with diaryliodonium salts is presented. Both acyclic and cyclic amines are well tolerated, providing a large set of N-alkyl anilines. The methodology is unprecedented among metal-free methods in terms of amine scope, the ability to transfer both electron-withdrawing and electron-donating aryl groups, and efficient use of resources, as excess substrate or reagents are not required.

Full text of DOI:10.1002/anie.201807001

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Regiospecific N-Arylation of Aliphatic Amines under Mild and
Metal-Free Conditions
Authors: Nibadita Purkait, Gabriella Kervefors, Erika Linde, and Berit
Olofsson
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807001
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10.1002/anie.201807001
Angewandte Chemie International Edition
COMMUNICATION
Regiospecific N-Arylation of Aliphatic Amines under Mild and
Metal-Free Conditions
Nibadita Purkait, Gabriella Kervefors, Erika Linde and Berit Olofsson*[a]
Abstract:
A
transition metal-free N-arylation of primary and
one-pot reactions.[13] Their efficiency in arylations has been
demonstrated with a wide range of nucleophiles under metal-
free conditions.[14] Arylation of certain nitrogen nucleophiles has
been well established with diaryliodonium salts,[15] but reactions
with amines have proven difficult.[16] In 2016, Stuart and
coworkers reported the first synthetically useful, intermolecular
arylation of amines with diaryliodonium salts (Scheme 1b).[17] In
this pioneering paper, a range of electron-deficient aryl groups
could be transferred using excess amounts of cyclic, secondary
amines in halogenated solvent. The limited substrate scope and
environmental aspects of this procedure inspired us to initiate an
investigation towards a general methodology. Herein we present
the efficient arylation of primary amines, as well as acyclic and
cyclic secondary amines. The reactions are high-yielding without
excess reagents, and tolerate diaryliodonium salts with both
electron-withdrawing (EWG) and electron-donating (EDG)
substituents (Scheme 1c).
secondary amines with diaryliodonium salts is presented. Both
acyclic and cyclic amines are well tolerated, providing a large set of
N-alkyl anilines. The methodology is unprecedented among metal-
free methods in terms of amine scope, the ability to transfer both
electron-withdrawing and electron-donating aryl groups, and efficient
use of resources, as excess substrate or reagents are not required.
Arylated amine derivatives are ubiquitous in Nature, as well as in
medicinal applications and material science,[1] which has led to
an intense research focus on development of efficient synthetic
methodology for this compound class. Transition metal-
catalyzed cross couplings have provided a wide range of
arylamines on industrial scale, as intermediates towards
pharmaceutically active compounds.[1b, 2] More recently also C-
H activation has proven efficient for N-arylation of amines.[3]
Still, the drawbacks associated with transition metal
catalysis, including toxicity, cost, need for substrate-dependent
designer ligands, and risk of product contamination has led to an
increased focus on development of metal-free methodology for
C-N bond formation.[4] While nucleophilic aromatic substitution
generally has rather narrow aryl scope,[5] fluoroarenes lacking
highly electron-withdrawing substituents can be utilized in
arylation of secondary amines upon strongly basic conditions at
high temperature (Scheme 1a).[6] Iminomalonates have recently
been introduced as electrophilic aminating reagents with
arylmetal reagents. This strategy has a wide scope, although
requiring extra steps for attachment and cleavage of the
umpolung reagent.[7]
a) Nucleophilic aromatic substitution - Diness
R1
R3
LiHMDS (1.5 equiv)
THF, 100 °C, 3-24 h
R3
+
R1
NH
R2
F
N
R2
(1 equiv)
(1.5 equiv)
b) Arylation of cyclic amines - Stuart
KF (2 equiv)
+
Ar
TFA
I
N
Ar
NH
H2O (5 equiv)
DCE, 70 °C, 24 h
TMP
(1 equiv)
(2 equiv)
Ar: only EWG
c) General arylation of aliphatic amines - This work
Ar1
RNH2
or
Na2CO3 (1 equiv)
Ar1
I
OTf
H/R
+
N
R
Ar2
toluene
110 °C, 4-22 h
R2NH
Other important advances in metal-free C-N bond formation
include organocatalytic radical coupling,[8] reactions with
arynes[9] and hypervalent iodine reagents.[10] Antonchick and
coworkers have demonstrated that (diacetoxyiodo)benzene
(DIB) and related iodine(III) reagents can oxidize the nitrogen
(1 equiv)
acyclic, cyclic
(1 equiv)
EWG, EDG
>60 examples
41-99% yield
Scheme 1. Metal-free N-arylation of amines. HMDS = hexamethyldisilazane;
TFA = trifluoroacetate; Tf = trifluoromethanesulfonyl; DCE = dichloroethane.
and enable nucleophilic attack by
a
variety of arenes.[11]
Organocatalytic N-arylations of amides and anilines, with in situ
formation of iodine(III) from iodoarene precursors, have also
been reported.[11a, 12] While useful in many reactions, both aryne
reactions and DIB oxidations are limited by the moderate
regioselectivity often observed, and DIB cannot be used to
arylate aliphatic amines.
The optimization was performed with primary amine 1a and
nitrophenyliodonium salts 2 in a 1:1 ratio in refluxing toluene
(Table 1).[18][19] The reaction showed poor conversion in the
absence of an external base, also upon increased loading of salt
2a (entries 1-2). To the contrary, excess amine proved efficient,
with the second equivalent of amine likely acting as base (entry
3). To comply with our aim to develop an efficient arylation
procedure, the use of excess substrate was highly unattractive.
We hence investigated the addition of bases, such as
triethylamine, which indeed improved the yield of product 3a
(entry 4). Several inorganic bases could also be employed,
including K3PO4 and carbonates,[18] and sodium carbonate
pleasingly delivered 3a in 81% yield (entry 5). The counterion of
the diaryliodonium salts 2 proved important, as reactions with
Diaryliodonium salts are bench stable iodine(III) reagents
that can be easily synthesized from iodoarenes or arenes via
[a]
Dr. N. Purkait, G. Kervefors, E. Linde, Prof. B. Olofsson
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University, SE-106 91 Stockholm, Sweden
E-mail: Berit.Olofsson@su.se
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201807001
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Selected results from the optimization of reaction conditions.[a]
trimethoxyphenyl (TMP) salts 2e and 2f, as TMP has recently
proven to be an efficient “dummy group” in arylations with
unsymmetric iodonium salts.[20] Indeed, tosylate 2e and
trifluoroacetate 2f could both be employed under our conditions,
albeit with moderate results (entries 9-10). To the contrary, only
decomposition was observed when 1a was reacted with 2f using
Stuart’s recently reported procedure for cyclic amines,[17]
illustrating the large difference between these protocols.
NO2
base
X
+
O2N
I
Ph
NH2
1a (1 equiv)
Ph
N
H
toluene
110 °C
Ar
3a
2a-f (1 equiv)
Entry
Salt 2 (X)
Ar
Base (equiv)
Time
(h)
Isolated
yield (%)
1
2[b]
3[c]
4
2a (OTf)
2a (OTf)
2a (OTf)
2a (OTf)
2a (OTf)
2b (Br)
Ph
Ph
-
1
2
2
2
4
4
4
4
4
4
35
The substrate scope was investigated under the conditions
in entry 5, i.e. without excess of substrate or reagents. To our
satisfaction, a variety of primary amines, cyclic and acyclic
secondary amines proved suitable for the transformation. As
previous protocols were incompatible with primary amines,[16-17]
the scope investigation was focused on that substrate class.
Nitrophenylation of primary amines with iodonium salt 2a could
be performed within 4 h, as depicted in Scheme 2a. Amines with
various hydrocarbon chains were efficiently monoarylated to
provide arylamines 3a-3e in 79-91% yield. Cycloalkyl
substituents were also tolerated, with improved reactivity for
larger ring sizes (3f-3h). Even the highly sterically hindered
adamantyl amine could be arylated to provide 3i in 60% yield
within 24 h reaction time. Furthermore, substrates containing a
variety of functional groups, including methoxy, bromide, pyridyl,
and silicate proved suitable (3j-m). Importantly, the arylation of
(R)-1-phenylethylamine proceeded without erosion of the ee
(3n). Aromatic amines can also be employed, as demonstrated
by the transformation of aniline into diarylamine 3o in 91% yield.
-
25
Ph
-
86
Ph
Et3N (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
74
5
Ph
81
6
Ph
4
7
2c (BF4)
2d (OTs)
2e (OTs)
2f (TFA)
Ph
54
8
Ph
77
9
TMP
TMP
62
10
43
[a] 2 (0.1 mmol), base and 1a (0.1 mmol) in anhydrous, degassed toluene (0.5
mL) under Ar. [b] 2a (2 equiv). [c] 1a (2 equiv). Ts = para-toluenesulfonyl; TMP
= trimethoxyphenyl.
iodonium bromide 2b were severely retarded, whereas
tetrafluoroborate 2c and tosylate 2d were more compatible
(entries 6-8). The reaction was also evaluated with
Na2CO3 (1 equiv)
H
N
Ar1
I
OTf
+
R
NH2
R
Ar1
Ar2
2 (1 equiv)
toluene
110 °C, 4-22 h
1 (1 equiv)
3
a) Nitrophenylations of primary amines (with 2a, Ar2 = Ph, 4 h):
H
N
H
N
H
N
H
N
H
N
H
N
H
N
Ar1
Ar1
Ar1
H
N
Ph
Ar1
Ar1
Ar1
Ar1
Ar1
Ph
3g 54%
3a 81%
3b 88%
3c 91%
3d 79%
3e 84%
3f 50%
Ar1
3h 68%
H
H
N
H
N
H
Ar1
=
H
N
HN
OEt
Ar1
N
MeO
MeO
N
H
N
Ar1
Br
Ar1
Ar1
EtO
Ar1
Si
Ar1
Ph
EtO
N
3i 60%[a]
3j 64%
3n 51%[a]
>99% ee
3o 91%
NO2
3k 55%
3l 72%
3m 41%
b) Phenylations of primary amines (with 2h, Ar2 = Ph, 22 h):
H
H
N
H
Diarylation:
Ph
N
N
MeO
MeO
N
H
H
H
Ph
Ph
Ph
Ph
N
N
N
Ph
Ph
Ph
Ph
3q 82%[b]
n-alkyl
Ph
n
Br
N
3r (pentyl) 37%
3s (hexyl) 43%[b]
3t (nonyl) 61%[b]
3y 50%[b]
3u (n=0) 41%[b]
3v (n=2) 59%
3w (n=3) 58%[b]
4 75%[d]
3x 85%
3p 52%
66%[b]
74%[c]
c) Other arylations of primary amines (4 h):
H
N
H
N
H
N
H
N
H
N
H
N
H
N
Ph
CF3
Ph
N3
Ph
Ph
Ph
Ph
3
Ph
3
3
3
3
Me
Br
t-Bu
CN
CF3
3ac 40%
(Ar2 = anisyl)
3ae 92%[a]
(Ar1 = Ar2)
3af 42%[a]
(Ar1 = Ar2)
3ad 73%
(Ar1 = Ar2)
3z 80%
(Ar2 = Ph)
3aa 81%
(Ar2 = anisyl)
3ab 45%
(Ar2 = Ph)
[e]
F
H
H
H
N
3
H
H
H
N
N
Ph
N
OMe
N
CO2Me
OMe
Ph
Ph
Ph
N
Ph
Ph
3
3
3
OMe
NO2
NO2
3al 88%[a]
(Ar1 = Ar2)
3ah 66%
(Ar2 = anisyl)
3aj 62%
(Ar2 = Ph)
3ag 45%
(Ar1 = Ar2)
3ai 62%
(Ar1 = Ar2)
3ak 75%
(Ar2 = Ph)
[e]
Scheme 2. Arylation of primary amines. [a] Reaction time 22-24 h. [b] Amine 1 (1.5 equiv). [c] Amine 1 (2 equiv). [d] Yield based on 2h. [e] OTs anion.
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10.1002/anie.201807001
Angewandte Chemie International Edition
COMMUNICATION
Diaryliodonium salts lacking EWG groups are generally more
difficult to apply in metal-free arylations, due to decreased
reactivity for ligand coupling and increased propensity to form
byproducts via aryne or radical pathways.[14, 21] We were thus
keen to investigate more challenging arylations, and started by
examining reactions with diphenyliodonium triflate (2h).
Pleasingly, amines with acyclic and cyclic substituents could be
phenylated to products 3p-3w in moderate to high yields upon
increasing the reaction time to 22 h (Scheme 2b). Functional
groups like methoxy and bromide were well tolerated, and
delivered arylamines 3x and 3y in 85% and 50% yield,
respectively. Formation of minor amounts of separable,
diarylated byproduct was observed with some substrates, and
could be avoided by using reagent 2h as limiting reagent.[18] As
illustrated with product 3p (footnotes [b-c]), this increased the
isolated yield at the expense of a less atom efficient reaction.
R
R
Ar1
Na2CO3 (1 equiv)
Ar1
NH
R
I
OTf
N
R
+
Ar2
toluene
110 °C, 4 h
1 (1 equiv)
2 (1 equiv)
5
a) Cyclic secondary amines
Ar1
Ar1
Ar1
Ar1
Ar1
N
N
N
N
N
N
O
S
Ph
Ph
5a 98%
5b 97%
5c 87%
5d 76%
5e 25%
Ar1
Ar1
Ar1
=
N
N
NO2
(Ar2 = Ph)
5f 99%
5g 95%
Ph
Ph
N
Ph
Ph
Ph
N
N
N
N
O
S
Ph
N
5h 90%
(Ar2 = Ph)
5i 83%
(Ar2 = Ph)
5j 86%
(Ar2 = Ph)
5k 83%
(Ar2 = Ph)
5l 64%
(Ar2 = Ph)
Surprisingly, 2-(2-pyridyl)ethylamine
underwent selective
5m 84%[a]
(Ar2 = Ph)
5n 49%[a]
(Ar2 = anisyl)
diarylation under standard conditions, and furnished diarylamine
4 in 75% yield without any sign of monoarylated product.[18]
N
Ph
CF3
t-Bu
The scope investigation was continued using a range of
symmetric and unsymmetric diaryliodonium salts (Scheme 2c).
As expected, electron-deficient aryl groups were easily
transferred, providing products with cyano or CF3 substituents
(3z-3ab) within 4 h. An azido-substituted iodonium salt could be
utilized to reach the azidophenylated product 3ac, which is well
suited for further transformations. Importantly, also electron-
donating diaryliodonium salts could be employed. Alkyl-
substituted aryl groups were easily transferred, and 3ae was
obtained in excellent yield. Even highly electron-rich iodonium
salts proved compatible, as demonstrated by transfer of
methoxy-substituted aryl groups to yield amines 3ag-3ai.
Sterical hindrance was well tolerated also in the aryl groups, as
illustrated by the densely functionalized arylamines 3aj-3al.
N
N
N
N
OMe
5o 70%[b]
(Ar2 = anisyl)
5p 55%
(Ar1 = Ar2)
5q 46%[c]
(Ar2 = anisyl)
b) Acyclic secondary amines
NO2
NO2
CF3
N
N
N
Bn
Bn
5s 79%
(Ar2 = Ph)
5t 68%
(Ar2 = anisyl)
5r 77%
(Ar2 = Ph)
t-Bu
N
N3
N
N
OMe
N
Bn
Bn
Bn
5x 65%[b,c]
(Ar2 = anisyl)
Bn
Arylation of secondary, cyclic amines was expected to be
more facile than primary amines, as such amines were
previously the only suitable substrates.[17] Indeed, cyclic amines
proved highly reactive under our standard conditions without
excess reagents (Scheme 3a). Piperidines, morpholine and
thiomorpholine provided products 5a-5d in good to excellent
yields with nitro salt 2a. While N-phenylpiperazine proved less
suitable (5e), pyrrolidine and tetrahydroisoquinoline were
efficiently arylated, delivering 5f and 5g in excellent yields. The
preferential arylation of secondary, cyclic amines over primary
was illustrated by a competition experiment that delivered 5c
and 3a in 4:1 ratio (see Scheme S5 in the SI).
5u 57%[b,c]
(Ar2 = anisyl)
5v 71%
(Ar1 = Ar2)
5w 58%
(Ar1 = Ar2)
Scheme 3. Arylation of secondary amines. [a] Reaction time 22 h.
[b] Inseparable from Ar2I. [c] OTs anion.
The arylation of acyclic secondary amines was initially
investigated with one symmetric and one unsymmetric
dialkylamine, providing products 5r and 5s in similar, good yields
(Scheme 3b). N-methyl benzylamine was then treated with a
range of symmetric and unsymmetric iodonium salts. To our
satisfaction, both EWG- and EDG-substituted aryl groups could
be transferred, providing products 5t-5x. In all cases, reactions
with unsymmetric diaryliodonium salts proceeded with high
chemoselectivity using the indicated dummy groups. This
approach facilitates the synthesis of the iodonium salts, the
recovery of the resulting iodoarene in large scale applications
and the atom efficiency when transferring complex aryl groups.
Separation of the formed Ar2I from the product proved
challenging in a few cases, and we are currently investigating
other dummy groups for those substrates.
A selection of cyclic amines was subsequently phenylated
with Ph2IOTf (2h) in high yields, including piperidines (5h, 5i)
and morpholine (5j, 86%). The latter compares very well to
literature,[17] where 5j was only obtained in 55%, despite a large
excess of morpholine. Thiomorpholine, pyrrolidine and 2-
methylindoline were also suitable substrates (5k-5m). Arylation
with other iodonium salts was accomplished next, providing the
pyridyl-decorated indoline 5n, as well as piperidines 5o-5q with
EWG- and EDG-substituted aryl moieties.
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10.1002/anie.201807001
Angewandte Chemie International Edition
COMMUNICATION
Control reactions with the radical scavenger 1,1-
diphenylethylene (DPE) and the aryne trap furan were
conducted to understand the mechanism, and found to not alter
the reaction outcome.[18] Furthermore, all products were formed
in a regiospecific manner, and we hence suggest that the
arylation proceeds via the commonly accepted ligand coupling
mechanism depicted in Scheme 5. The amine reacts with the
diaryliodonium salt to give the charged T-shaped intermediate A,
which is then deprotonated in the presence of base (or excess
amine) to give intermediate B. Subsequent ligand coupling
provides the arylated product and ArI. Alternatively, a four-
coordinated intermediate C, where two amines are coordinated
to the iodine, could be a more reactive intermediate for ligand
Olle Engkvist Byggmästare Foundation (2014/645) and
Swedish Research Council (2015-04404) are
the
kindly
acknowledged for financial support.
Keywords: anilines • arylamines • diaryliodonium salts •
hypervalent iodine • metal-free
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Scheme 5. Suggested arylation mechanism.
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In conclusion, we have developed an efficient, metal-free N-
arylation of aliphatic amines with diaryliodonium salts under mild
conditions without excess reagents. The methodology is
applicable to primary amines, as well as secondary cyclic and
acyclic amines, containing a variety of functional groups. Both
electron-deficient and electron-donating aryl groups, as well as
heteroaryl groups can be transferred. Sterical hindrance is well
tolerated in both coupling partners, and no erosion of ee was
observed. Extension of the methodology to amino acid
derivatives, as well as mechanistic studies are currently ongoing,
and will be reported in due course.
[12]
[13]
Experimental Section
General procedure for the synthesis of arylamines 3-5:
Diaryliodonium salt 2 (0.1 mmol) and Na2CO3 (0.1 mmol, 1.0 equiv) were
[14]
[15]
added to an oven-dried microwave vial, which was sealed with
a
microwave vial cap. The vial was kept in vacuum for 15 minutes through
a needle and then flushed with argon. This procedure was repeated for
3-4 times. Amine 1 (0.1 mmol, 1.0 equiv) was added via syringe followed
by anhydrous and degassed toluene (0.5 mL), and the mixture was
stirred at 110 °C for the indicated time. After completion of the reaction, it
was brought down to RT and subjected to purification by silica gel
column chromatography with a pentane/EtOAc or pentane/Et2O gradient
to obtain arylamines 3-5.
[16]
[17]
A. H. Sandtorv, D. R. Stuart, Angew. Chem. Int. Ed. 2016, 55,
15812.
[18]
[19]
See the Supporting Information for details.
Unlike many metal-free arylations with iodonium salts, the use of
anhydrous, degassed solvent proved important.
Acknowledgements
[20]
[21]
a) J. Malmgren, S. Santoro, N. Jalalian, F. Himo, B. Olofsson,
Chem. Eur. J. 2013, 19, 10334; b) D. R. Stuart, Chem. Eur. J.
2017, 23, 15852.
E. Stridfeldt, E. Lindstedt, M. Reitti, J. Blid, P.-O. Norrby, B.
Olofsson, Chem. Eur. J. 2017, 13249.
This article is protected by copyright. All rights reserved.

10.1002/anie.201807001
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Nibadita Purkait, Gabriella Kervefors
and Berit Olofsson*
Page No. – Page No.
Regiospecific N-Arylation of Aliphatic
Amines under Mild and Metal-Free
Conditions
A metal-free N-arylation of primary and secondary amines with diaryliodonium salts
has been developed. The methodology is unprecedented for metal-free reactions in
terms of amine scope and the ability to transfer both electron-withdrawing and
electron-donating aryl groups, and tolerates steric hindrance well.
This article is protected by copyright. All rights reserved.