Direct amidation of aniline derivatives with 1,1-dichloro-2-nitroethene in water

Article abstract of DOI:10.1016/j.tetlet.2015.09.048

A green methodology was established for direct amidation of anilines using 1,1-dichloro-2-nitroethene. The new protocol provides convenient N-nitroacetylation for the anilines. This method was applicable to anilines include anthranilic acids, anthranilami

Full text of DOI:10.1016/j.tetlet.2015.09.048

Tetrahedron Letters 56 (2015) 5945–5949
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct amidation of aniline derivatives with 1,1-dichloro-2-
nitroethene in water
a,b
Fengjuan Zhu a, Xue Tian a, Xusheng Shao a, , Zhong Li
⇑
a Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China
b Shanghai Collaborative Innovation Center for Biomanufacturing Technology, 130 Meilong Road, Shanghai 200237, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A green methodology was established for direct amidation of anilines using 1,1-dichloro-2-nitroethene.
The new protocol provides convenient N-nitroacetylation for the anilines. This method was applicable to
anilines include anthranilic acids, anthranilamides, phenylbenzohydrazides, diphenylamine, and
2-aminobenzenesulfonamide. The amidation process was accomplished in water and the products can
be easily separated by filtration.
Received 17 August 2015
Revised 11 September 2015
Accepted 15 September 2015
Available online 15 September 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Green methodology
Direct amidation
1,1-Dichloro-2-nitroethene
N-nitroacetylation
Introduction
withdrawing nitro group makes it reactive to amines, aryl alcohols
or mercaptans (Fig. 1). Our recent explorations on reaction behav-
Amides are pervasive structural functionality for naturally
occurring and artificial molecules, such as natural products,
proteins, polymers, pharmaceuticals, and agrochemicals.1–4 The
development of efficient procedures for construction of amide
bonds is a long-standing task for chemists.4,5 The oldest and green-
est formation of amides is developed by enzymes from carboxylic
acids and amines.6 Nowadays, the most conventional methods are
coupling of amines with stoichiometrically activated carboxylic
acids,7–9 accounting for 93% of amidation in 128 drugs synthesis.6
However, this method suffered from poor atom economy,10 use of
hazardous reagent11,12 and complicated workup procedures.13,14
Therefore, the greener procedures or novel catalysts for direct ami-
dation have been developed in recent years.15,16 These innovative
strategies included, transamidation of amides under solvent-free
conditions,17 microwave irradiated direct amidation,18 oxidative
amidation of methylarenes,10 metal-salts6,19 or boron-reagents
catalyzed amidation,6,20 oxidative coupling of alcohols with ami-
nes,11,21 mechanochemical synthesis of amides22 and hydroamina-
tion of olefins.23 Despite these progresses, direct amidation in
water is still a challenging task due to its biocompatibility for the
transformation of biologically relevant substrates.
iors of DCNE revealed an efficient procedure for 1,3,4-oxadiazoles
formation from hydrazides in water.24 As an extension of DCNE
research, we reported herein an efficient, catalyst-free and mois-
ture insensitive method for amidation of aniline derivatives using
DCNE.
Results and discussion
Our previous success of high-yielding reactions of DCNE with
hydrazides in water inspired us to screen the reaction conditions
directly using water. Furthermore, the reaction can proceed
smoothly without catalysts. Thus, the only variant for screening
here was the temperature. DCNE and 2-amino-6-chlorobenzoic
acid were selected as the model reaction. The reaction proceeded
well at a wide range of temperatures with the lowest yields of
70% at 10 °C (Table 1). At 50 °C, the reaction reached the highest
yield of 95%. The reaction rate was accelerated when elevating
the temperature, but the yields slightly decreased. Therefore, the
temperature of 50 °C was selected for further exploration. The suc-
cess of using water as solvent can be partly explained by its high
heat capacity to this exothermic reaction. Furthermore, water ser-
ver as a reactant in the hydrolysis of the reaction intermediate.
The substrate scope evaluation commenced with different
anthranilic acids (Scheme 1). Different sets of anthranilic acids
having various substituent patterns underwent a smooth amide
functionalization and delivered the desired products in excellent
1,1-Dichloro-2-nitroethene (DCNE) is a reactive intermediate
used for insecticidal molecules construction. The strong electron-
⇑
Corresponding author. Tel.: +86 21 64253967; fax: +86 21 64252603.
E-mail address: shaoxusheng@ecust.edu.cn (X. Shao).
http://dx.doi.org/10.1016/j.tetlet.2015.09.048
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

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F. Zhu et al. / Tetrahedron Letters 56 (2015) 5945–5949
Figure 1. Reaction of DCNE with amines, aryl alcohols, mercaptans and hydrazides.
Table 1
Screening of the temperature
was applicable to diphenylamine 2p with moderate yields, but
higher reaction temperature is needed to drive this conversion.
The success of amidation of substrate 2p could be attributed to
its steric hindrance for preventing the formation of 1:2 product
as observed in aniline. Actually, trace amounts of amide product
2-nitro-N-phenylacetamide can be separated in the reaction of ani-
line with DCNE, although the major products were 2-nitro-N,N0-
diphenylethene-1,1-diamine. Reaction of 2-aminobenzenesulfon-
amide 2q with DCNE afforded amide product 3q with quite low
yield. An array of unseparated side products formed for substrate
2o–2q, affecting the efficient nitroacetylation transformation.
Reaction of 2-aminophenol with DCNE was also tested in water,
but unfortunately, the cyclization occurred, which is consistent
with the previous Letter (Fig. 1). The water solubility of 2i–2q is
much lower than that of anthranilic acids, this low solubility fea-
ture resulted in the low transformation and impurity of the precip-
itates which needed further purification by silica gel column
chromatography.
Entry
Temp (°C)
Time (h)
Yielda (%)
1
2
3
4
5
10
30
50
70
90
72
20
6
1
0.8
70
81
95
83
81
a
Product was isolated by filtration.
The scope observation suggested the high efficiency of this
methodology to anthranilic acids with more than 90% yields. While
other substrates gave moderate to low yields or complicated reac-
tions this high compatibility to anthranilic acids prompted us to
investigate the role of carboxyl group in the reaction. Several con-
trol experiments were run as depicted in Scheme 2. Splitting
anthranilic acid to two starting materials benzoic acid and aniline
was not feasible, but gave the similar reaction phenomenon with
that of aniline. Changing the substituent position of carboxyl to
meta- or para-one could not benefit the reaction with the produc-
tion of more than four products which were not separated here,
suggesting that the ortho-carboxyl was a preferable component
for obtaining high yield of the desired products. Thus, we infer that
the ortho-carboxyl group may play two roles here, that is, the for-
mation of hydrogen bond with amino and the steric hinderance.
Therefore, the ortho-substituent effects were further evaluated. A
diminished reaction activity of a-nitroaniline implied that the nitro
could stabilized the substrate, but still giving low fields of the pro-
duct (less than 10%). Attempts of using dinitro-substituted amines
2,4-dinitroaniline and 2,6-dinitroaniline were met with no reaction
even the reaction temperature was raised to reflux.
yields (up to 95%). Both electron-withdrawing (trifluoromethyl 3b,
nitro 3e) and electron-donating (methoxyl 3d) groups were well
tolerated. However, the reaction rate can be perturbed by the
patterns of substituents, the substrate with electron-withdrawing
trifluoromethyl (3b) and nitro (3e), long reaction time was needed
for the completion of the amidation. Notably, the products precip-
itated from reaction mixture, which were easily separated through
filtration. This conversion was applicable to anthranilamides
(2i–2l) were also with good yields except substrate 2i, at milder
conditions, probably due to the higher electrophilicity caused by
the hyper-conjugation effect of methyl. Interestingly, the two main
products of the reaction of 2i with DCNE were N-methyl-2-(2-ni-
troacetamido)benzamide 3i and N-(2-(3-methyl-4-oxo-3,4-dihy-
droquinazolin-2-yl)phenyl)-2-nitroacetamide 3I, which formed
by further condensation of 2i and 3I with a 25% separated yield.
However, the similar conversions were not observed on other
anthranilamides.
We then extended the substrate scopes to other aniline deriva-
tives. The phenylbenzohydrazides 2m and 2n were compatible
with this protocol giving the corresponding amides in 74% and
57% yields, respectively. This transformation can also be subjected
to the cyclic hydrazide 2o with a yield of 45%. No reaction was
observed on diarylhydrazide N0-benzoylbenzohydrazide, which
might be caused by the low basicity of nitrogen. This method
Treatment of ethyl 2-aminobenzoate was accomplished with
the formation of an array of products. Substrate with high steric
tert-butyl group can slow down the reaction rate but could not
afford the high yield amide product, indicating that the steric effect

F. Zhu et al. / Tetrahedron Letters 56 (2015) 5945–5949
5947
Scheme 1. Substrate scope investigation.
was not the determinant to the high yield. Excluding the electronic
and steric effect, we proposed here that the ortho-carboxyl group
may involve in the reaction. A plausible reaction pathway was
proposed as shown in Scheme 3. For anthranilic acids, the reaction
was initiated by the nucleophilic substitution of anthranilic acids
to DCNE to give intermediate A, which underwent intramolecular
cyclization affording intermediate B. Then the direct hydrolysis of
B occurred giving intermediate C which tautomerized to the final
product. While for other aniline substrates, direct hydrolysis of
the carbon–chlorine bond occurred after the formation of aniline-
DCNE adducts D to get intermediate E, which tautomerized to final
products.
Conclusion
In summary, an efficient direct amidation protocol for anilines
was established using 1,1-dichloro-2-nitroethene. The reactions
underwent in water and the products were easily separated by fil-
tration. The presence of an ortho-carboxyl group is crucial for the
high yields of the reactions. The electronic and steric effect of the

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F. Zhu et al. / Tetrahedron Letters 56 (2015) 5945–5949
Scheme 2. Substituent effect on the reaction.
Scheme 3. Plausible reaction pathways.

F. Zhu et al. / Tetrahedron Letters 56 (2015) 5945–5949
5949
substituent can also perturb the amidation reaction. This novel
procedure provides an efficient and catalyst-free method for direct
amidation of aniline derivatives using DCNE. The tolerance of the
reaction to water creates the potential for the conversion of
biomolecules.
Technology Research Development Program of China (863 Pro-
gram, 2011AA10A207), Shanghai Pujiang Program (14PJD012)
and the Fundamental Research Funds for the Central Universities
(222201414015), this work was also partly supported by Australia
DC Foundation.
Experimental
Supplementary data
Melting points (mp) were recorded on Büchi B540 apparatus
(Büchi Labortechnik AG, Flawil, Switzerland) and are uncorrected.
1H NMR and 13C NMR spectra were recorded on Bruker AM-400
(1H at 400 MHz, 13C at 100 MHz, 19F at 377 MHz) spectrometer
with DMSO-d6 as the solvent and TMS as the internal standard.
Chemical shifts are reported in d (parts per million) values.
High-resolution electron mass spectra (ESI-TOF) were performed
on a Micromass LC-TOF spectrometer. High Resolution Mass Spec-
trometry (HRMS) were recorded under electron impact (70 eV)
condition using a MicroMass GCT CA 055 instrument. Analytical
thin-layer chromatography (TLC) was carried out on precoated
plates (silica gel 60 F254) and spots were visualized with
ultraviolet (UV) light. The following abbreviations were used to
explain the multiplicities: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, coupling constant (Hz) and integration.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.09.
048.
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This work was financially supported by National Natural
Science Foundation of China (21372079, 21472046), National High