Catalyst and Additive-Free Direct Amidation/Halogenation of Tertiary Arylamines with N-haloimide/amides

Article abstract of DOI:10.1002/adsc.202000796

An approach has been developed for the amidation (halogenation) of tertiary arylamines by electrophilic activation using N-haloimide/amides. Several control experiments have been performed, and the coupling reaction outcomes indicated that the N-haloimide/amide brings three major functions, including electrophilic activation, aromatic halogenation and nucleophilic nitrogen sources. This cascade reaction features simple manipulation, requires no additional catalyst, oxidant or additives, and is performed under mild conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.202000796

Title: Catalyst and Additive-Free Direct Amidation/ Halogenation of
Tertiary Arylamines with N-haloimide/amides
Authors: Xiu Juan Xu, Adila Amuti, and Abudureheman Wusiman
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000796
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10.1002/adsc.202000796
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Catalyst and Additive-Free Direct Amidation/ Halogenation of
Tertiary Arylamines with N-haloimide/amides
Xiu Juan Xu, a Adila Amuti, a Abudureheman Wusimana, b*
a
School of Chemistry and Chemical Engineering, Xinjiang Normal University, Urumqi 830054, China
E-mail: arahman@xjnu.edu.cn
Xinjiang Key Laboratory of Energy Storage and Photoelectrocatalytic Materials, Urumqi 830054, China
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An approach has been developed for the
amidation (halogenation) of tertiary arylamines by
electrophilic activation using N-haloimide/amides. Several
control experiments have been performed, and the coupling
reaction outcomes indicated that the N-haloimide/amide
brings three major functions, including electrophilic
activation, aromatic halogenation and nucleophilic nitrogen
sources. This cascade reaction features simple
manipulation, requires no additional catalyst, oxidant or
additives, and is performed under mild conditions.
N-iodosuccinimide (NIS)–promoted methods have
been successfully applied for cross-dehydrogenative
coupling (CDC) or oxidative C–N cross-coupling
reactions.[13] Recently, 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU)–activated N-bromosuccinimide (NBS)
has been utilized in C–N bond formation.[14]
Amides are one of the most-important
functional groups in life and are present in many
biologically
active
compounds.[15]
Selective
functionalization of C−H bonds adjacent to a nitrogen
atom in tertiary amines for the construction of amide
containing compounds has been vastly studied,
including extensive pioneering work with transition-
metal-catalysts and iodine-based reagents. For
example, Cu[16] and Fe[17] catalytic oxidative
amidation has been performed for the direct C(sp3)-H
amidation of tertiary amines (Scheme 1, a). Minakata
and co-workers[18] have reported direct oxidative
amidation of the C(sp3)–H bond of N,N-
Keywords: catalyst-free; C-H activation; tertiary amines;
amidation; N-haloimide
Nitrogen-containing organic structures with C–
N bonds are some of the most abundant, versatile and
important fundamental fragments in nature,[1] and
they are widely presented in bioactive natural
products,[2] synthetic drugs[3] and material sciences.[4]
In addition, they can constitute the main backbone of
biomolecules such as peptides and proteins.[5]
Therefore, construction of C–N bonds has great
synthetic importance in organic chemistry.[6]
dimethylanilines
with
a
phthalimidate-based
hypervalent iodine (III) reagent (Scheme 1, b). Zheng
and
co-workers[19]
have
developed
for the
an
1,3-
of
NIS/succinimide
difunctionalization
condition
(imidation/iodination)
Direct C–N bond formation through C–H
cyclopropylamines by an electrophilic ring opening
pathway (Scheme 1, c). Du and co-workers[20]
successfully developed an efficient intramolecular
activation represents an extremely attractive and
efficient route because it is straightforward and more
atom economical and environmentally friendly than
traditional methods.[7] Over the past several years,
significant progress has been made establishing a
transition-metal catalyzed oxidative cross-coupling
strategy for the activation of C(sp2)–H[8] and C(sp3)–
H[9] bonds to construct C–N bonds. The development
of environmentally benign methods[10] for C–N-bond
construction is hugely significant,[11] and, more
recently, metal-free approaches have received
considerable attention for this reason.[12] N-
haloimides can be generally used as a convenient
source of both cationic halogens and halogen radicals.
oxidative
amidation
method
of
N-aryl
tetrahydroisoquinolines with the use of phenyliodine
(III) diacetate (PIDA) and NaN3 (Scheme 1, d). An
electrochemical approach has also been developed by
the Ley group.[21]
Although significant achievements have been
made in this field, some limitations still exist such as
the use of metal catalysts and excess external
oxidants, tedious workup procedures and harsh
reaction conditions. Therefore, the development of
cheaper, milder and more environmentally friendly
metal-free methods for the construction of C–N
1
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10.1002/adsc.202000796
Advanced Synthesis & Catalysis
bonds through sp3 carbon-hydrogen bond activation
is still a challenging task.
Based on our previous work on the oxidative
functionalization of tertiary amines,[17b, 22] herein we
report a simple catalyst and additive-free direct
amidation (halogenation) of tertiary arylamines
through
electrophilic
activation
with
N-
haloimide/amide under ambient conditions without
using external oxidants (Scheme 1, e).
Initial studies focused on investigating the
coupling reaction of N,N-dimethyl-p-toluidin 1a and
NIS in methanol at room temperature under air. The
expected coupling product 3a was isolated in 65%
yield after 3 h with 1.5 equiv of NIS (Table 1, entry
1), and the reaction led to I2 generation, which was
confirmed by an iodine-starch test.[23] Subsequently,
we examined this transformation with different
solvents (Table 1, entries 2–9) and the best result was
obtained in ethyl acetate (EtOAc), in which 3a was
isolated with 71% yield (Table 1, entry 8). Hence,
EtOAc was chosen as the best solvent for this
transformation. Then, as the NIS loading was
increased from 1.5 equiv to 1.8 equiv, the yield also
increased from 71% to 75% (Table 1, entry 10).
Scheme 1. Direct amidation of a tertiary amine through
activation of the C–H bond adjacent to a nitrogen
Table 1. Optimization of the reaction conditions[a]
Entry
1
2
3
4
5
6
7
2 (equiv)
NIS (1.5)
NIS (1.5)
NIS (1.5)
NIS (1.5)
NIS (1.5)
NIS (1.5)
NIS (1.5)
NIS (1.5)
NIS (1.5)
NIS (1.8)
NIS (1.8)
NIS (1.8)
NIS (1.8)
NIS (1.8)
NIS (1.8)
NIS (1.8)
NIS (1.8)
NIS (2.0)
NIS (2.2)
NIS (2.0)
NIS (2.0)
NHS (2.0)
Solvent
CH3OH
CH3CN
THF
Acetone
DCM
Additive
Time/h
Yield (%)[b]
65
-
-
-
-
-
-
-
-
3
3
12
6
6
6
6
6
6
1.5
6
6
6
6
6
6
6
64
30
52
50
66
65
71
64
75
75
73
65
55
57
72
34
DCE
CHCl3
EtOAc
CCl4
8
9
-
-
10
11
12
13
14
15
16
17
18
19
20[c]
21[d]
22
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
NaHCO3
Na2CO3
NaOH
KOH
Cs2CO3
2,6-Lutidine
DBU
-
-
-
-
-
1.5
1.5
1.5
1.5
12
81
81
80
78
NR[e]
[a] Reaction conditions: 1a (0.4 mmol) with additive (0.4 mmol) in solvent (2.0 mL) under air atmosphere at room
temperature in a 5-mL vial.
[b] Isolated yield.
[c] Under an argon atmosphere.
[d] The reaction was carried out in darkness.
[e] No reaction.
2
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10.1002/adsc.202000796
Advanced Synthesis & Catalysis
Table 2. The amidation of tertiary arylamines with N-
Because bases may promote the deprotonation of
methyl hydrogen,[24] various inorganic and organic
bases were tested (Table 1, entries 11–17). However,
no obvious improvement to the reaction outcome was
found, and moderate-to-good yields were achieved in
most bases. Surprisingly, the addition of DBU
resulted in a dramatic decrease in the yield of 3a to
34% (Table 1, entry 17). Probably, NIS was reacted
with DBU and hampered the transformation.[25] When
the NIS loading was gradually increased to 2.0 equiv,
the yield reached 81% (Table 1, entry 18). However,
with more NIS, the yield was no longer improved
(Table 1, entry 19). Furthermore, the reaction also
proceeded smoothly with 80% yield under an argon
atmosphere (Table 1, entry 20). It should be noted
that when the reaction was conducted in darkness, 3a
was isolated with 78% yield (Table 1, entry 21). The
reaction of 1a and succinimide (NHS) does not occur
under same conditions (Table 1, entry 22). Therefore,
the best reaction was performed using 2 equiv NIS at
room temperature in EtOAc.
iodoimides[a,b]
With the optimal conditions in hand, we next
evaluated the synthetic scope of the coupling reaction.
As depicted on Table 2, NIS and para-substituted
N,N-dimethylaniline derivatives were first applied in
this transformation. A wide range of electron-
donating and halide substituents were well tolerated
and furnished the corresponding desired products in
good to high yields (3a–3e). Moreover, N,N-
dimethylanilines bearing both para- and meta-
dimethyl groups were also used as reaction partners,
yielding corresponding coupling products 3f in 75%
yield. Unfortunately, when strongly electron-
withdrawing groups such as nitro and cyano were
present, no product was observed (3g and 3h). The
decrease in the electron density on the nitrogen of
aniline may attenuate their reactivity toward NIS.
Then, various N-iodoimide/amides, including N-iodo-
4-nitrophthalimide (INPT), N-iodophthalimide (IPT),
N-iodohexahydrophthalimide, N-iodobutyrolactam
and N-iodobenzamide, were also subjected to the
coupling reaction and proved to be reliable reaction
partners with tertiary aryl amines, delivering good to
excellent yields (3i-3m). The highest yield (93%) was
generated using IPT (3i). Unfortunately, this
methodology did not work with N-iodosaccharin
(NISac) (3n). Next, we investigated the reactivity of
ortho-, meta- and unsubstituted anilines and,
interestingly, found that when the para position of the
benzene ring is vacant, both para iodination and N-
methyl amidation reactions occurred on the same
molecule, giving corresponding products 4a-4e with
moderate yields. In contrast, ortho-iodination analogs
were not observed. This result can be attributed to the
fact that the bulky iodine atom at the ortho position
may cause steric hindrance in the molecule. The
structure of compound 4b was confirmed by X-ray
[a] Reactions were conducted using 1 (0.4 mmol) and 2 (0.8
mmol) in EtOAc (2.0 mL) under air atmosphere at room
temperature.
[b] Isolated yield.
[c] Gram scale reaction in 5h.
[d]
N-benzyl-4-iodo-N-methylaniline was isolated in 34%
yield.
[e]
N,N-diethyl-4-iodoaniline and N-ethyl-4-iodoaniline
were obtained in 42% and 18% yield, respectevily.
[f] No reaction.
crystallographic analysis.[26] Notably, 2-bromo-N,N-
dimethylaniline was used as a reaction partner. After
13 h of reaction, a mixture of 3o/4e (nearly 2:3 ratio)
was obtained with 45% total yield. When the reaction
time was extended to 70 h, the 3o/4e ratio changed to
1
1:5 (the products ratio was determined by H NMR),
which means that 3o may gradually convert to 4e.
Furthermore, the reactions were also attempted with
other anilines such as N-methyl-N-benzylaniline and
N,N-diethylaniline, and it was found that substitution
on the nitrogen had a significant impact on the
reaction. With N-methyl-N-benzylaniline, only 24%
yield of desired 4f and 34 % of the para-iodinated
aniline by-product were isolated after a prolonged
reaction time (46 h). However, with N,N-
3
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10.1002/adsc.202000796
Advanced Synthesis & Catalysis
diethylaniline the corresponding amidated product
could not be obtained under the optimized conditions.
It is noteworthy that, these reactions are accompanied
by a certain amount of iodinated aniline by-products.
And then, N,N-dimethylalkylamine and N,N-
dimethylamide were also applied to examine the
crystallographic analysis.[26] Thus, the reactions were
conducted with 2 equiv. of N-bromoimides at room
temperature (Table 3). The N,N-dimethylanilines
bearing electron withdrawing groups (Br, F, CO2Me,
CO2H, CN and NO2,) gave monobrominated
amidation products (5a–5f) with 44–63% yields,
together with corresponding brominated aniline by-
products. In contrast, the anilines with electron
donating substituents afforded monobrominated and
dibrominated products (5g/5g’–5j/5j’) with lower
yields under the established conditions. Unsubstituted
aniline was tested in the presence of 3.0 equiv NBS
and the dibrominated product 5a was obtained (44%
reactivity.
Anfortunatly,
when
N,N-
dimethylbutylamine was used, the reaction turned a
complex mixture, and the reaction did not occurr with
N,N-dimethlybenzamide under standard conditions.
After the use of N-iodoimides/amides in this
reaction was examined, we turned our attention to
using other commercially available N-haloimides.
The reaction of 4-bromo-N,N-dimethylaniline and
NBS was optimized. DCM was identified as the best
solvent (for details, see ESI S2) and the ortho-
brominated amidation product 5a was isolated. The
structure of 5a was further determined by X-ray
yield). With
a
N,N-dimethyl-m-toluidine, the
bromination occurred at both the para and ortho
positions of the aniline, affording a 7:1 mixture of 5i
and 5i’ with 41% yield (the product ratio was
determined by 1H NMR). When N-bromophthalimide
(NBP) was used, the reaction proceeded smoothly
and delivered the desired products (5j and 5j’ ) with
40% yield. Unfortunately, only traces of the coupling
product could be detected when the same reaction
was conducted with N-chlorosuccinimide (NCS).
To probe the reaction pathway, in situ NMR
monitoring experiments were initially performed.
Table 3. The amidation of tertiary aromatic amines with N-
bromoimides[a,b]
1
From a crude H NMR spectrum of the reaction
mixture of 1a and NIS (1.2 equiv) in CDCl3,
chemical shifts associated with coupling product 3a
and succinimide were observed, as well as another
component related to 1a. Interestingly, the chemical
shifts related to 1a shifted to low field, which could
be attributed to the adjacent electropositive nitrogen
atom in the ArN+(Me)2-I complex.[27] Next, a HRMS
experiment of the reaction mixture was investigated
and to our delight, the signal at m/z 262.0094 (calcd
for C9H13IN+, 262.0087) was detected. (for details,
see ESI S6). In addition, the reaction occurred in
darkness under standard conditions with the same
efficiency. Since homolysis of N–I bonds generally
requires light or heat, the dark condition suggests that
the reaction did not involve homolysis of NIS (N–I
bond). Furthermore, upon the addition of radical
inhibitor 2,2,6,6-tetramethylpiperidinyloxy (TEMPO,
1.0 equiv) under standard conditions, no negative
influence on the reaction was observed and,
interestingly, mono- and bis-amidated products were
generated (for details, see ESI S10). These results
suggesting that the reaction proceeds via an ionic
pathway.
[a]
Reactions were conducted using 1 (0.4 mmol) and 2’
(0.8 mmol) in DCM (2.0 mL) under air atmosphere at
room temperature.
[b] Isolated yield.
[c] 3-Bromo-4-(dimethylamino)benzoic acid was isolated in
28% yield yield.
[d] 3-Bromo-4-(dimethylamino)benzonitrile was isolated in
To further clarify the details of this reaction,
several control experiments were conducted (Scheme
2). First, the reaction of 1a and NHS was performed
in the presence of hypervalent iodine (III) reagents
s u c h a s PIDA or phenyl iodine (III) bis-
trifluoroacetate (PIFA) and the desired 3a was
delivered with 32% and 28% yield, respectively
(Scheme 2, a). This result attributes that an ionic
34% yield.
[e] 2-Bromo-N,N-dimethyl-4-nitroaniline was isolated in 33%
yieid
[f] 3.0 Equiv of NBS was used.
[g]
2,4-Dibromo-N,N-dimethylaniline was isolated in 15%
yield.
[h]
2-Bromo-N,N,4-trimethylaniline was isolated in 12%
yield.
4
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10.1002/adsc.202000796
Advanced Synthesis & Catalysis
effect (KIE)[31] experiments were conducted by
deuterium-labeling (for details, see ESI S8) and they
showed that the intramolecular and intermolecular
KIE (KH/KD) were 1.7 and 3.3 respectively (Scheme
2, d and e). These results suggest that the cleavage of
the C(sp3)−H bond may actively participate in the
reaction, but it is not the rate determining step.
Combined with the experimental results and the
related literature, a plausible mechanism for this
coupling reaction is proposed in Scheme 3.
According to the reaction order, there are two
possible pathways that can be suggested. In path a,
NXS initially provides a cationic halogen to tertiary
aryl amine to form N-haloaminium complex A-X
through ionic interactions. Since the reaction
conditions are base free, the succinimide ion might
abstract a proton from the methyl group to give the
N-aryl iminium intermediate B. In these cases,
succinimide (NHS) would be liberated as a by-
product. Subsequently, B would be prone to reacting
with nucleophilic NHS to generate product 3 and
eliminate HX. The HX can be further converted to
halogen molecules in the presence of NXS,
rereleasing NHS.[32] This may explain the excess
amount of NXS required for this transformation. In
path b, the initial step begins with an electrophilic
halogenation reaction of an aromatic ring with NXS
(X+) [24, 33] or molecular halogen (X2)[34] to form para-
/ortho-halogenated aniline XA, which is followed by
a similar reaction as pathway (a) to sequentially form
the iminium ion XB. Then, nucleophilic substitution
with NHS occurs to generate halogenative amidation
products 4 or 5. In addition, if the substrate structure
is appropriate, 3 can be gradually changed to 4 or 5
with the use of NXS.
Scheme 2. Control experiments and KIE studies.
[20, 28]
pathway might be involved in the reaction.
Next, the reaction of 1a and phtalimide (PhthNH2)
was treated in the presence of 1 equiv NIS under
standard conditions, wherein a mixture of 3a and 3i
was obtained in 38% and 44% yield, respectively
(Scheme 2, b). This indicates that imides are released
during the reaction[29] and react with the active
iminium cation[30] to form the final product. Another
control experiment was conducted with amidative
N,N-dimethylaniline 3o and NIS under standard
conditions and the para-iodination product 4a was
isolated in 72% yield after 60 h, which suggests that
slow halogenation can occur after the amidation
process (Scheme 2, c). After that the kinetic isotope
Scheme 3. Tentative mechanistic pathway
5
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10.1002/adsc.202000796
Advanced Synthesis & Catalysis
284-287; b) A. Ricci, Amino Group Chemistry: From
Synthesis to the Life Sciences; 1st ed.; Wiley-VCH:
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Scheme 4. Further elaboration of compounds 3 and 4
At last, to illustrate the synthetic utilities of this
method, we investigated further transformations of
amidated anilines (Scheme 4), because amido acids
are a useful functional group that have been reported
to exhibit broad spectrum of biological and
pharmaceutical activities.[35] After treatment of 3a, 3e
or 4b with NaOH in water at room temperature, the
succinimide ring smoothly opened and afforded the
corresponding amido acid derivatives (6a–6c) with
high yield.
In conclusion, a simple, novel and efficient one-
pot amidation (halogenation) of N,N-dimethyl
anilines has been developed using N-haloimide/
amides by the electrophilic activation strategy. This
protocol proceeds under mild conditions without the
need for any catalysts or external oxidants and
tolerates a wide range of substrates bearing broad
functional groups. Further development and the
catalytic application of N-haloimide in other reactions
are currently underway in our laboratory.
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Experimental Section
General procedure for the amidation of
tertiary arylamines
In a 5-mL screw cap vial with a stir bar, tertiary
arylamines 1 (0.4 mmol) was dissolved in ethyl
acetate or DCM (2.0 mL) and the N-
haloimide/amides (0.8 mmol) was added under air
atmosphere and stirred at room temperature for the
indicated reaction time. The reaction mixture washed
with cold saturated sodium thiosulfate, and then
extracted with ethyl acetate or DCM (3 x 10 mL).
The combined organic layer was dried over sodium
carbonate. Organic solvents were removed under
reduced pressure and the crude reaction mixture was
purified by column chromatography on a silica gel
column (ethyl acetate /petroleum ether /triethylamine)
to afford the desired product.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China No: 21762044.
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10.1002/adsc.202000796
Advanced Synthesis & Catalysis
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10.1002/adsc.202000796
Advanced Synthesis & Catalysis
COMMUNICATION
Catalyst and Additive-Free Direct Amidation/
Halogenation of Tertiary Arylamines with N-
haloimide/amides
Adv. Synth. Catal. Year, Volume, Page – Page
Xiu Juan Xu, a Adila Amuti, a Abudureheman
Wusimana, b*
8
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