NH4I-promoted N-acylation of amines via the transamidation of DMF and DMA under metal-free conditions

Article abstract of DOI:10.1016/j.tetlet.2019.04.040

An unprecedented NH₄I-promoted N-formylation and N-acetylization of various amines with dimethylformamide (DMF)and dimethylacetamide (DMA)has been developed. This protocol shows broad substrate scope for aromatic, aliphatic, and heterocyclic amines, which provides a metal-free strategy for N-acylation featuring mild reaction conditions, as well as inexpensive and readily available starting materials.

Full text of DOI:10.1016/j.tetlet.2019.04.040

Accepted Manuscript
NH4I-Promoted N-acylation of amines via the transamidation of DMF and DMA
under metal-free conditions
Jiahui Chen, Jing Jia, Ziyi Guo, Jitan Zhang, Meihua Xie
PII:
S0040-4039(19)30389-2
https://doi.org/10.1016/j.tetlet.2019.04.040
TETL 50755
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 March 2019
12 April 2019
24 April 2019
Please cite this article as: Chen, J., Jia, J., Guo, Z., Zhang, J., Xie, M., NH4I-Promoted N-acylation of amines via
the transamidation of DMF and DMA under metal-free conditions, Tetrahedron Letters (2019), doi: https://doi.org/
10.1016/j.tetlet.2019.04.040
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Tetrahedron Letters
NH4I-Promoted N-acylation of amines via the transamidation of DMF and DMA
under metal-free conditions
Jiahui Chen, Jing Jia, Ziyi Guo, Jitan Zhang,* and Meihua Xie*
Key Laboratory of Functional Molecular Solids (Ministry of Education), Anhui Key Laboratory of Molecular Based Materials, College of Chemistry and
Materials Science, Anhui Normal University, Wuhu 241002, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An unprecedented NH4I-promoted N-formylation and N-acetylization of various amines
with dimethylformamide (DMF) and dimethylacetamide (DMA) has been developed.
This protocol shows broad substrate scope for aromatic, aliphatic, and heterocyclic
amines, which provides a metal-free strategy for N-acylation featuring mild reaction
conditions, as well as inexpensive and readily available starting materials.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
transamidation
amines
N-acylation
NH4I
Fe(NO3)3·9H2O,7 Pd/NHC (N-Heterocyclic Carbene) complexes,8
and many others,9 to promote the transamidation. Recently,
Introduction
Amides are an important class of compound with extensive
applications in both the industrial and academic communities.
They have been frequently used in the synthesis of natural
products, pharmaceuticals, biologically active compounds and
functional materials.1 Representative drugs such as paracetamol,
lacosamide, and formoterol contain the formamide or acetamide
structural units (Fig. 1). Therefore, the N-acylation of amines is a
useful reaction in synthetic chemistry for which there is
considerable interest to develop new protocols and reagents.2
metal-free transamidation has emerged as an alternative strategy,
in which hydroxylamine hydrochloride,10 boronic acid,2c
H2SO4˗SiO2,11 K2S2O8,12 and graphene oxide13 were utilized as
catalysts. Despite remarkable progress, the development of novel
transamidation protocols using readily available starting
materials without the use of toxic and/or precious metal catalysts
under mild reaction conditions is still highly desirable.
DMF has been widely used as an inexpensive and excellent
solvent for various reactions as well as a multipurpose precursor
which is widely used in organic synthesis to generate various
intermediates, including Me, CO, CHO, NMe2 groups.14
Generally, the transamidation of DMF to generate formamides
employs metal catalysts, such as Pd, Ni, Ce, Cu, Co or boronic
acids.15
Therefore, we herein describe a simple and cost-effective
protocol for the N-formylation and N-acetylation of amines using
NH4I as an inexpensive, efficient, and environmentally friendly
promoter using DMF and DMA as readily available carbonyl
sources.
Figure 1. Representative drugs containing amide bonds.
The most common approaches to N-acylation are the
condensation of amines with carboxylic acids and activated
carboxylic acid derivatives, such as acyl chlorides and
anhydrides.3 However, these methods generally suffer from harsh
reaction conditions or the use of moisture-sensitive reagents. The
transamidation of amides is a convenient method to generate new
amides from existing ones and has emerged as an attractive
protocol for amide bond formation (Scheme 1). Nevertheless, due
to resonance stabilization of the amide bond, the amide carbonyl
group shows poor electrophilic character and often requires
transition-metal catalysts, such as CeO2,4 Ni(quin)2,5 Pd(OAc)2,6

2
Tetrahedron Letters
a Reagents and conditions: 4-methoxyaniline 1a (0.5 mmol), promoter,
solvent (2 mL), 125 °C, air. b Isolated yield based on 1a. DMF (10
equiv.) was added. d 110 °C. e 46.5% w/w aq. solution. f DMF (1.0 mL). g
145 °C.
c
Further increasing the amount of NH4I to 2.0 equiv. had no
significant effect on the yield of 2a (Entry 6). Other iodides and
other ammonium halides, such as KI, CuI, NH4F, NH4Cl and
NH4Br were examined and NH4I was found to be the best
candidate (Entries 7-11). When the reactions were carried out in
DMSO and o-xylene to investigate the solvent effect, 2a was
formed in trace amount and 33% yield, respectively (Entries 12
and 13). A lower yield of 2a was observed when the reaction
temperature was decreased to 110 °C (Entry 14). The utilization
of 1.0 equiv. of HI (46.5% w/w aq. solution) instead of NH4I
gave 2a in 43% yield (Entry 15), which suggested that HI may be
the actual promoter for this transamidation. NH4I decomposes to
HI which activates the carbonyl of DMF via protonation. The use
of NH4I also helps to avoid the use of volatile and corrosive
acids. The reaction was also efficient in 1.0 mL DMF, giving 2a
in 94% yield (Entry 16). A similar yield of 2a was observed
when the reaction was conducted at 145 °C (Entry 17). Thus, 1.0
equiv. NH4I in 1.0 mL of DMF at 125 °C was defined as the
optimal reaction conditions.
With the optimized reaction conditions in hand, the scope of
NH4I-promoted transamidation reaction was explored with
various amines (Table 2).16 The protocol was compatible with
differently substituted aromatic and aliphatic amines. Primary
aromatic amines with both electron-donating and electron-
withdrawing groups at the para-, meta-, and ortho-positions
underwent transamidation to give the corresponding formamides.
Anilines containing electron-donating groups, such as MeO, Me,
tBu, and OH, gave the corresponding compounds (2a-j) in good
to excellent yields. The formylation of anilines containing
deactivating groups, such as F, Cl, or Br, required higher
temperature (145 °C) and the formylated products (2k-q) were
obtained in lower yields. Notably, N-(pyridin-2-yl)formamide
(2r) can be synthesized in 42% yield using this protocol and the
N-formylation of 2,6-dimethylaniline and 2,6-difluoroaniline also
gave the corresponding formamides 2g and 2q in 84% and 54%
yield, respectively. Unfortunately, this method was not successful
for the N-formylation of 4-nitroaniline and N-methylaniline. This
may be due to the poor nucleophilicity of 4-nitroaniline and the
steric effect of N-methylaniline. Subsequently, various aliphatic
amines were also evaluated. Primary and secondary aliphatic
amines such as benzylamine (1s, 1t), 1-(pyridin-2-yl)ethanamine
(1u), N-methylbenzylamine (1v), n-propyl amine (1w),
dibutylamine (1x), and the cyclic amine morpholine (1y) were all
tolerated, giving the desired products (2s-y) in moderate to good
yields.
Scheme 1. N-acylation of amines via transamidation.
Results and Discussion
Initially, the N-formylation of 4-methoxyaniline (1a) was
selected as the model reaction to optimize the reaction conditions
(Table 1). No reaction occurred when the solution of 0.5 mmol 4-
methoxyaniline in 2.0 mL DMF was stirred at 125 °C for 30 h
(Entry 1). Interestingly, the N-formylation product N-(4-
methoxyphenyl)formamide (2a) was isolated in 69% yield when
0.1 equiv. NH4I was added (Entry 2). An improvement in the
yield was observed by increasing the loading of NH4I and the
reaction was optimal with 1.0 equiv. of NH4I to afford the desired
product in 94% yield (Entries 3-5).
Table 1. Optimization of the reaction conditions. a
Entry
Promoter
(equiv.)b
-
Solvent
t (h)
Yield 2a (%)c
1
2
3
DMF
DMF
30
30
0
69
NH4I (0.1)
NH4I (0.5)
NH4I (0.75)
NH4I (1.0)
NH4I (2.0)
KI (1.0)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
24
20
15
15
30
30
30
15
15
82
89
4
5
94
95
6
7
trace
trace
trace
57
8
CuI (1.0)
Encouraged by the N-formylation of various amines, the N-
acetylation of amines using DMA as the acylating reagent under
similar reaction conditions was investigated. It was found that
2.0 equiv. NH4I was necessary to achieve N-acetylation.
Aromatic primary amines, such as aniline, 4-chloro, 4-methyl, 4-
methoxy-substituted anilines underwent N-acetylation to give the
corresponding N-aryl acetamides 3a-d in 33-52% yield. Notably,
the antipyretic drug paracetamol 3e was also obtained in 29%
yield via the reaction of DMA with p-hydroxyaniline.
Unfortunately, the reactions of DMA and aliphatic amines
9
NH4F (1.0)
NH4Cl (1.0)
NH4Br (1.0)
10
11
12c
13c
14d
15
63
NH4I (1.0)
DMSO
15
trace
NH4I (1.0)
NH4I (1.0)
HI (1.0)e
NH4I (1.0)
NH4I (1.0)
o-xylene
15
15
33
83
DMF
DMF
DMF
DMF
15
11
9
43
94
95
16f
17f ,g

resulted in complex mixtures and the desired products could not
be isolated.
Table 2. Substrate scope of the NH4I-promoted N-formylation of
amines with DMF.
Scheme 2. Gram-scale experiment
Conclusion
A simple and convenient protocol using NH4I as a promoter
was developed for the synthesis of amides via the transamidation
of amines with DMF and DMA. Aromatic, aliphatic, and
heterocyclic amines are all compatible with this transformation.
The advantages of the present protocol are being metal-free, mild
reaction conditions, and using inexpensive and readily available
starting materials.
Acknowledgments
We gratefully acknowledge the National Natural Science
Foundation of China (Nos. 21272004, and 21702237) for
financial support.
Appendix A. Supplementary data
Supplementary
data
(experimental
procedures,
1
characterization data, and copies of H and 13C NMR spectra for
all compounds 2 and 3) to this article can be found online at
https://doi.org/10.1016/j.tetlet.xxxxxx
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as acylation reagents
Highlights:
 Broad substrate scope and gram-scaled
synthesis demonstrate the potential
applications of the transamination reaction
 Inexpensive NH4I-promoted convenient and
metal free N-acylation of various amines is
developed
Graphical Abstract
 Readily available DMF and DMA are used
NH4I-Promoted N-acylation of amines by
transamidation of DMF and DMA under
metal-free conditions
Leave this area blank for abstract info.
Jiahui Chen, Jing Jia, Ziyi Guo, Jitan Zhang,* Meihua Xie*
Key Laboratory of Functional Molecular Solids (Ministry of Education), Anhui Key Laboratory of Molecular
Based Materials, College of Chemistry and Materials Science, Anhui Normal University, Wuhu 241002, China