An efficient method for the N-formylation of amines under catalyst- and additive-free conditions

Article abstract of DOI:10.1016/j.tetlet.2019.03.071

A simple catalyst- and additive-free method for the N-formylation of amines has been developed. The advantages of this protocol include a wide range of functional group tolerance, high efficiency and a lack of required extra promoters under mild conditions. This convenient strategy will provide a facile synthesis towards N-formamide natural products and pharmaceutical derivatives. A mechanism that involves difluorocarbene is proposed for this reaction.

Full text of DOI:10.1016/j.tetlet.2019.03.071

Accepted Manuscript
An efficient method for the N-formylation of amines under catalyst- and addi-
tive-free conditions
Zhuo-Wei Xu, Wen-Yi Xu, Xiao-Jun Pei, Fei Tang, Yi-Si Feng
PII:
S0040-4039(19)30309-0
https://doi.org/10.1016/j.tetlet.2019.03.071
TETL 50712
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
28 February 2019
26 March 2019
29 March 2019
Please cite this article as: Xu, Z-W., Xu, W-Y., Pei, X-J., Tang, F., Feng, Y-S., An efficient method for the N-
formylation of amines under catalyst- and additive-free conditions, Tetrahedron Letters (2019), doi: https://doi.org/
10.1016/j.tetlet.2019.03.071
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Tetrahedron Letters
An efficient method for the N-formylation of amines under catalyst- and additive-free
conditions
Zhuo-Wei Xu a, Wen-Yi Xu a, Xiao-Jun Pei a, Fei Tang a, and Yi-Si Feng a, b, 
a Anhui Province Key Laboratory of Advanced Catalytic Materials and Reaction Engineering, School of Chemistry and Chemical Engineering, Hefei University
of Technology, Hefei 230009, P. R. China
b Anhui Provincial Laboratory of Heterocyclic Chemistry, Maanshan 243110, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple catalyst- and additive-free method for the N-formylation of amines has been
developed. The advantages of this protocol include a wide range of functional group tolerance,
high efficiency and a lack of required extra promoters under mild conditions. This convenient
strategy will provide
a facile synthesis towards N-formamide natural products and
Available online
pharmaceutical derivatives. A mechanism that involves difluorocarbene is proposed for this
reaction.
Keywords:
N-Formylation
2019 Elsevier Ltd. All rights reserved.
Catalyst- and additive-free
Environment-friendly
Organic synthesis
The N-formylation of amines plays a unique role in organic
synthesis because amide frameworks have been extensively
reported in natural products, pharmaceuticals and other
functional materials.1 For amine compounds, formyl is an
important protecting group.2 Moreover, formamides are also
important intermediates used as the precursors to synthesize
corresponding products.3 Generally, conventional synthetic
strategies were carried out by using acid derivatives,4 alcohols,5
N,N-dimethylformamide6 and aldehydes.7 With the development
of biochemistry and organic chemistry, increased concern has
arisen over the protocol for N-formylation of amines. The recent
decades have seen a wealth of methods that utilize transition
metal catalysis.8 In addition, other acylating reagents9 and even
carbon dioxide10 were used in some N-formylation reactions.
However, the previously developed methods suffered from large
consumption of Lewis acid/base, poor functional group tolerance
and long reaction time. Hence, it is essential to further research
more efficient and environmentally friendly N-formylation
reactions. Extra ligands or additives impose restrictions on their
application in synthetic chemistry.
1a).13 Meanwhile, Song’s group developed the N-formylation
through the system of B2pin2 as additive in CH3CN under an N2
atmosphere, in which BrCF2CO2Et participates in the process via
quadruple cleavage. (Scheme 1b).14
On this basis, a general and effective method to achieve the N-
formylation of amines without catalyst, base or additives is
presented.
BrCF2CO2Et is known as a common fluorination reagent
which is inexpensive and easy to handle.11 Our group has studied
the coupling reaction related to ethyl bromodifluoroacetate.12
Recently, several efficient methods for the N-formylation of
amines have been developed through the aniline and N-
methylaniline derivatives with ethyl bromodifluoroacetate. Zhang
and co-workers initially reported a copper-catalysed reaction that
Scheme 1 Use of Ethyl Bromodifluoroacetate in the N-formylation of Amines
mediated the formylation of amines with BrCF2CO2Et (Scheme
———
 Corresponding author. Tel.: + 86-551-62904405; fax: +86-551-62904405; e-mail: fengyisi@hfut.edu.cn

2
Tetrahedron Letters
Table 1.
Optimization of the Reaction Conditionsa
Entry
Solvents
Base (equiv)
Yield (%)b
Temperature (℃)
1
2
CH2Cl2/H2O (v/v=1:1)
Py/H2O (v/v=1:1)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
K2CO3 (2)
KOH (2)
100
100
100
100
100
100
100
100
100
100
100
100
r,t
7
46
3
NMP/ H2O (v/v=1:1)
CH3CN/H2O (v/v=1:1)
DMSO/H2O (v/v=1:1)
DMAC/H2O (v/v=1:1)
DMF/H2O (v/v=1:1)
DMF/H2O (v/v=1:1)
DMF/H2O (v/v=1:1)
DMF/H2O (v/v=1:1)
DMF/H2O (v/v=1:1)
DMF/H2O (v/v=1:1)
DMF/H2O (v/v=1:1)
DMF/H2O (v/v=1:1)
DMF/H2O (v/v=1:1)
DMF/H2O (v/v=1:1)
DMF
13
4
5
5
trace
66.5
79
6
7
8
82
9
74
10
11
12
13
14
15
16
17
18d
19e
NaOH (2)
iPr2NEt (2)
84
72
86
0
60
55
110
150
110
110
110
92(84)c
87
28
DMF/H2O (v/v=1:1)
88
DMF/H2O (v/v=1:1)
0
a Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol) in solvents (2 mL) under air, unless otherwise noted.
b Determined by GC using N-phenylacetamide as internal standard.
c The isolated yield is shown in parentheses.
d Reaction was carried out under an argon atmosphere.
e Reaction was carried out without BrCF2CO2Et.
In preliminary investigations, we commenced with N-
methylaniline (1a) and BrCF2CO2Et (2) as the model substrates
with 2 equivalents of Cs2CO3 in an attempt to obtain N-methyl-
N-phenylformamide (3a). Surprisingly, we obtained the desired
product 3a when CH2Cl2/H2O was used as the solvent, albeit in
7% yield (Table 1, entry 1). After extensive screening of solvents,
a subsequent survey of solvents indicated that DMF/H2O (1:1, 2
mL) was optimal and the desired product 3a was obtained in 79%
yield (Table 1, entries 1-7). Among the bases examined, we
Eventually, we discovered the optimized conditions listed in
Table 1, entry 15.
Having established the available optimized conditions (Table
1, entry 15), we were interested in researching the scope of the
N-formylation of amines and to determine how different
substituents would affect the yield of this reaction. The outcome
was presented in Table 2, and the substrates with different
substituents on the -R position were investigated first. We were
surprised to find that both the electron-withdrawing and -
donating groups generate good yields under the system and that
electron donating groups produce better yields than electron
withdrawing groups (3a-3h). We then discussed the effects of the
meta-substitution and obtained better yields (3i-3l). However,
when we studied the ortho- substituents, the reaction yield was
found to be significantly reduced (3m-3n), especially when
diphenylamine or N-isopropylaniline was used as a substrate, and
no related products were obtained. We speculate that the steric
hindrance effect in this system may play a more important role.
Fortunately, we still obtained fairly good yields of 46-72% for
the 3o-3s substrates. It is worth noting that the fluoride-,
chloride-, bromide-, allylic- and cyano- substituents are
compatible under this system (3e-3g, 3i-3j, 3r, 3s), thus
providing opportunities for additional structural transformations.
Subsequently, we studied the cyclic aniline and found that the
system is highly adaptable to this type (3t-3v). Further
investigation showed that a relatively high yield (3w-3x) can be
obtained. When the N-formylation of aliphatic amine was carried
out, 3y was obtained in 43% yield.
i
found that the organic base Pr2NEt and the inorganic bases
Cs2CO3, K2CO3, NaOH, and KOH did not improve the desired
product yield (Table 1, entries 7-11). Therefore, we removed the
base and found that the yield was 86% without base (Table 1,
entries 12). The temperature had a significant effect on the
reaction and when the temperature dropped to room temperature,
no desired product was observed at all. When the temperature
was lowered to 60 °C, the corresponding yield of product 3a was
reduced to 55%; however, when the temperature was raised to
110 °C, the yield of N-methyl-N-phenylformamide obtained was
92%. Increasing the temperature to 150℃ did not increase the
yield of 3a (Table 1, entry 13-16). We then optimized the
reaction time, and the best result was found in the reaction time
of 6 h (Table S3 in ESI). Subsequently, we found that water plays
a vital role in this system. We further screened the amount of
water used in the system. We found that maximum product was
obtained with 1mL of water (Table 1, entry 17, Table S2 in ESI).
With further experimentation, the reaction still proceeded under
argon atmosphere (Table 1, entry 18) which means that oxygen
in the air did not promote this reaction, and no product was
observed in the absence of BrCF2CO2Et (Table 1, entry 19).

secondary amines under this system, but that comparable yields
were obtained. Methyl-, methoxy-, tert-butyl-, fluorine-,
bromine-, and carbonyl- substituted anilines all have good yields
(5b-5g). Subsequent studies on meta- and para- substituents also
showed good results (5h-5k, 5l-5m). The disubstituted
derivatives bearing electrondonating groups yielded the desired
products in moderate yields (5n). In addition, naphthalen-2-
amine (5o) gave the corresponding products in 47% yield.
Table 2
The substrate scope of secondary aminesa,b
To prove this system application prospect of the N-
formylation of amines, a gram-scale reaction of N-methylaniline
1a and BrCF2CO2Et (2) was performed. When the reaction was
extended to the gram scale， product 3a was obtained in 65%
isolated yield (Scheme 2). This general and efficient method may
provide practical access to N-formylation.
Scheme 2
Gram-Scale Experiment
Scheme 3
Preliminary Mechanistic Studies
a Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol) in solvents (2 mL) at
110℃ under air, unless otherwise noted.
b Yield of the isolated product.
Table 3
The substrate scope of primary aminesa,b
Scheme 4
Proposed mechanism
a Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol) in solvents (2 mL) at
110℃ under air, unless otherwise noted.
bYield of the isolated product.
Given the importance of primary amines, we studied the
suitability of primary amines under this system. It was found that
the suitability of primary amines was not as good as that of
To prove the reaction mechanism, we conducted a series of
control experiments. First, we added TEMPO(2,2,6,6-

4
Tetrahedron Letters
3. (a) Y. Han, L. Cai, Tetrahedron Lett. 38 (1997) 5423; (b) Y. Jo, J. Ju, J.
tetramethyl-1-oxylpiperidine) (6), (1-cyclopropylvinyl)benzene
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(7), and ethene-1,1-diyldibenzene (8) as radical scavenger under
the standard conditions, GC-MS detection then indicated that the
reaction was not suppressed, and we speculated that the reaction
did not involve a radical mechanism (Scheme 3, eq 1, 2, 3). We
then used H2O18 instead of the H2O in the reaction. The product
of the corresponding molecular weight was obtained by GC-MS.
At the same time, we also carried out the study of adding D2O
instead of H2O to the reaction system, and successfully obtained
the corresponding product. This result is consistent with our
finding that water plays a very important role in the reaction
system under optimized conditions. The above two isotopic
labelling experiments show that the oxygen atom in the carbonyl
group and the hydrogen atom in the aldehyde group in the final
amide are derived from H2O. (Scheme 3, eq 4, 5) To verify the
source of C in the N-formylation group, we have performed a
related experiment (Table S4 in ESI) to find that ClCF2CO2Na
and ICF2CO2Et can obtain moderate yield instead of ethyl
bromodifluoroacetate and BrCH(CH3)CO2Et, which did not yield
the corresponding product. To verify the formation of :CF2, we
have found a method of capturing these intermediates in which
benzimidazole (9) is added to standard conditions. We verified
that 9 captures :CF2, and observed 1-(difluoromethyl)-1H-
benzo[d]imidazole (10) by GC-MS. (Scheme 3, eq 6) Therefore,
we speculate that BrCF2CO2Et functions as a C source and that
the :CF2 plays an important role in this system.
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Based on control experiments and related literature,13,14 we
have hypothesized two possible mechanisms. Path A: first
BrCF2CO2Et produces :CF2 in a mixed solvent of DMF/H2O
under heating conditions. The generation of :CF2 from
BrCF2COOEt is activated by dehalogenation. Intermediate A was
then formed by :CF2 combining with an amine. The :CF2 is self-
attacked by a lone pair of electrons from the amine, producing a
reactive intermediate B by a defluorination process. Intermediate
B is soon decomposed into C. Intermediate C emerges with
tautomerism eventually delivering products 3 and 5. Path B:
BrCF2CO2Et undergoes the amination reaction with N-
methylaniline to furnish intermediate D. Subsequently,
defluorinative hydrolysis of intermediate D affords oxoacetate E.
Intermediate E is further hydrolysed to give oxoacetic acid F.
The decarboxylation of intermediate F occurs to produce the N-
formylated final products 3 and 5.
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Conclusions
In conclusion, we have developed a simple and efficient
method for the N-formylation of amines by the use of ethyl
bromodifluoroacetate. A series of amine derivatives were
subjected to the reaction system and furnished the corresponding
products in good yields. In addition, this reliable and simple
reaction protocol, without a base and under ambient coditions,
makes the present work a useful method for further research into
biological and chemical applications.
Acknowledgments
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Cat. 4 (2019) 708.
We gratefully acknowledge financial support from the
National Natural Science Foundation of China (No. 21571047).
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•
the N-formylation of amines with
BrCF2CO2Et.
•
Simple amines produce formylation
products under mild conditions.
•
Clean reaction, the reaction product is easy
to separate and the reaction step is simple.

6
Tetrahedron
Graphical Abstract
An efficient method for the N-Formylation of
amines under catalyst- and additive-free
conditions
Leave this area blank for abstract info.
Zhuo-Wei Xua, Wen-Yi Xua, Xiao-Jun Peia, Fei Tanga and Yi-Si Fenga,b,
a Anhui Province Key Laboratory of Advanced Catalytic Materials and Reaction Engineering, School of
Chemistry and Chemical Engineering, Hefei University of Technology, Hefei 230009, P. R. China
b Anhui Provincial Laboratory of Heterocyclic Chemistry, Maanshan 243110, China.