Solvent- and catalyst-free N-formylations of amines at ambient condition: Exploring the usability of aromatic formates as N-formylating agents

Article abstract of DOI:10.1080/00397911.2016.1255334

A solvent- and catalyst-free N-formylation protocol has been developed for amines (1s–21s) where aromatic formates (1r–6r) were used as the N-formylating agents. The amine substrates include both primary and secondary aromatic amines (1s–19s) as well as aliphatic amine (20s) and a primary amide (21s). Structures of both the aromatic formate and amine components strongly influenced the rate of the reaction and yield of the N-formamide products. The reaction condition is mild and easy to operate. This protocol can be done smoothly under ambient conditions and gives high yield of formamide products. Furthermore, the present method cannot be applied for the formylation of thiol group (22s). This signifies its possible use for the chemoselective N-formylation of amine in the presence of thiol functionality.

Full text of DOI:10.1080/00397911.2016.1255334

Solvent and catalyst free N-formylations of amines at ambient condition: Exploring
the usability of aromatic formates as N-formylating agents
1
1,
Shaikh Batuta , Naznin Ara Begum
Department of Chemistry, Visva-Bharati (Central University), Santiniketan, India
1
Corresponding author Naznin Ara Begum. E-mail: naznin.begum@visva-bharati.ac.in
Abstract
A solvent and catalyst free N-formylation protocol has been developed for amines (1s-
2
1s) where aromatic formates (1r-6r) were used as the N-formylating agents. The amine
substrates include both primary and secondary aromatic amines (1s-19s) as well as
aliphatic amine (20s) and a primary amide (21s). Structures of both the aromatic formate
and amine components strongly influenced the rate of the reaction and yield of the N-
formamide products. The reaction condition is mild and easy to operate. This protocol
can be done smoothly under ambient condition and gives high yield of formamide
products. Furthermore, the present method can not be applied for the formylation of thiol
group (22s). This signifies its possible use for the chemoselective N-formylation of amine
in presence of thiol functionality.
KEYWORDS: N-formylation, Aromatic formates, Amines.
INTRODUCTION
1

N-formylation reaction is often regarded as the key step in the synthesis of plethora of
[1-6]
important organic precursors, intermediates, reagents and bioactive compounds.
Various amines undergo N-formylations leading to different types of formamide
derivatives and structure of these compounds controls their usefulness in a specific
organic reaction. Formamides are used as the precursors in the synthesis of formamidines
[
1-2, 6-8]
and isocyanides.
for the preparation of bioactive heterocyclic compounds.
nature, formamides find application as catalyst in the allylation
of carbonyl compounds. Moreover, chiral formamides are being used in the asymmetric
These compounds are being used as the synthetic intermediates
[2, 9, 10]
Being Lewis basic in
[11]
[12]
and hydrosilylation
[
13]
allylation of aldehyde functionalities.
in the organic synthesis (e.g. in the peptide synthesis) to protect the amino group.
Apart from these, one of the most well known applications of formamides is their use as
N-formylation reaction is also extensively used
[
14]
[
15]
the reagent in the Vilsmeir formylation reaction. Furthermore, formamides are
[
16]
extensively used as solvents in various cases.
So the development of easy, environment friendly and cost effective synthetic methods
for the synthesis of task-specific formamides is a highly cherished goal for the synthetic
organic chemists and over the years, researchers have developed a number of N-
[
17]
formylation methods. Mixed anhydrides (e.g. acetic formic anhydride ) are the most
extensively used formylating agents. But these types of reagents are moisture sensitive
[
2]
and decomposed to acetic acid and carbon monoxide on storage. Besides this, use of
[
18, 19]
[20]
activated formic acid/DCC or EDCI, .
chloral
and various solid-supported
[
21]
reagents
are quite common as N-formylation reagents. However, these reagents are
2

not free from the drawbacks like high hygroscopic nature, toxicity and high cost. On the
[
20]
[22]
other hand, various formates e.g. ammonium formates , cyanomethyl formate
,
[
23]
2
,2,2-trifluoroethyl formate
and other aliphatic formates are often used as the source
of formyl group in N-formylation reactions. In addition to these, ethyl or phenyl formate
often serves as a promising alternative but longer reaction time and heating at high
[2, 24]
temperature are necessary for the completion of the N-formylation reactions.
H.L.
Yale reported the use of phenyl formate as the N-formylation agent at very low
[
25]
[25]
temperature.
But in that reported work , phenyl formate used was not be separated
from the starting phenol substrate and other impurities were also present in it.
Certainly, each of these methods have some merits but they are also not free from the
drawbacks like complicated synthesis of the N-formylating reagents and thermal
instability of these N-formylating reagents, formation of undesired by-products, prolong
[
1-3,5-6]
reaction time and high temperature.
often the control the outcome of the N-formylation reaction.
In the present work, we have synthesized and isolated in pure form a series of aromatic
Moreover, the nature of the catalyst and solvent
[
5-6]
[26]
formates (1r-6r) (fig.1) according to the method previously developed by us
explored their efficacy in the N-formylation of a series of primary and secondary amines
both aromatic and aliphatic) and also a primary amide type of compound under solvent
and
(
and catalyst free condition at ambient temperature.
These formylating agents are easy to synthesize (scheme 1) and they are not thermally
unstable or hygroscopic which made them suitable as N-formylating agents. However,
3

best result (in terms of yield and reaction time) was obtained with p-chlorophenyl
formate (3r) as the N-formylating agent (scheme 2). We have also studied the role of
solvent on the reaction time/rate and yield of the N-formylated products synthesized by
the present protocol.
RESULT AND DISCUSSION
Several combinations of aromatic formates (1r-6r) and aromatic amines (1s-21s) were
tried to optimize the reaction condition. However, to test the efficacy of the six aromatic
formates (1r-6r) towards N-formylation reaction, we have used p-methoxy aniline (3s) as
the model substrate. Results are displayed in Table 1. Best result (in terms of reaction
time and yield) was obtained when p-chlorophenyl formate (3r) was used as the N-
formylating reagent and the substrate was p-methoxy aniline (3s) (scheme 2) (Table 1).
The plausible mechanistic pathway is very simple as shown in scheme 3.
Apart from 3r, p-bromophenyl formate (4r) was also found to be effective for the N-
formylation of the substrate, 3s (table 1). It is evident from scheme 3 that the carbonyl
group of aromatic formates behaves as the electrophilic centre whereas amines act as the
nucleophilic centre. The electrophilicity of the carbonyl C-centre of aromatic formates is
high when it has an electron withdrawing substituents like Cl/Br. On the other hand,
electron donating group on the aromatic nucleus enhances the nucleophilicity of amine
functionality. This ultimately facilitates the N-formylation reaction as observed under the
present protocol. Cl/Br has weak resonance dipole but the electronegativity dipole
(electron withdrawing effect) for Cl is higher than that of Br. In the present case, this
4

phenomenon may be responsible for the better efficacy of p-chlorophenyl formate (3r)
as N-formylating agent than p-bromophenyl formate (4r). However, besides the presence
of electron withdrawing group on the aromatic nucleus, steric hindrance can be another
controlling factor towards the reactivity of aromatic formates (as in the case 5r and 6r)
and comparatively low yield and longer reaction time were observed in these cases (table
1
).
To further optimize the reaction condition regarding the effect of solvent on the yield and
reaction completion time, we have performed the same reaction [using p-Methoxy aniline
(3s) (1 mmol) and p-chlorophenyl formate (3r) (1 mmol) as model substrate and reagent
respectively] in the presence of different polar and non-polar solvents and the results are
shown in table 2.
Present protocol was found to be most suitable under solvent-free condition with respect
to the maximum % yield of 3p and minimum reaction completion time. However, better
%
yield and shorter reaction time was observed in case of non-polar solvents in
comparison to the polar solvent systems (table 2). Later, we have extended this
standardized and optimized procedure towards the other combination of substrates and p-
chlorophenyl formate (3r) as the N-formylating reagent and same trend was observed.
It is note-worthy that p-chlorophenyl formate (3r) showed considerably good yield with
other aromatic amines as shown in table 3 under the same reaction condition. Total 21
formamide derivatives (1p-21p) were synthesized and isolated in pure form under the
5

present work (table 3). The synthesized products were characterized with the help of
spectroscopic and other analytical data (detail is given in the supplementary information).
Results shown in the above table point out that the present N-formylation protocol is
effective for wide varieties of amines ranging from aromatic amines (both primary and
secondary) (1s-19s) as well as aliphatic amine (20s) to a primary amide type of
functionality (21s). Moreover, to study the structural effect of the substrates on the rate of
the reaction, we have selected aromatic amine substrates having electron donating and
electron withdrawing substituents at o,m and p positions of its aromatic ring.
A detailed scrutiny of the results (table 3) points towards some interesting facts as
discussed here. Present protocol was found to be more effective (in terms of % yield and
reaction completion time) for both the primary and secondary aromatic amines (1s-19s)
than the aliphatic amine (20s) or the amide (21s) substrates. Aromatic amines having both
the electron donating or electron withdrawing substituent can be N-formylated by the
present method. However, slight difference in their reactivity was observed. Presence of
electron donating substituent on the aromatic ring of the amine was found to be a
favorable factor as it increases the nucleophilicity of the amine group which ultimately
facilitates the reaction rate. This effect was found to be maximum when there is a -OMe
group at p-position of the aromatic ring with respect to the -NH group as it is observed
2
in the case of 3s. Longer reaction time was noticed in the case of substrates having
electron withdrawing group at o- or p-positions as in the cases of 11s, 13s, 14s and 15s
(table 3). However, presence of electron withdrawing group at m-position do not show
6

that much influence on the reaction pathway as it is evidenced in the case of 12s. Electron
withdrawing substituents can deactivate the amine substrate by decreasing its
nucleophilicity and slower reaction rate was observed. Fused ring primary aromatic
amine (17s, 18s) and heterocyclic aromatic primary amine (16s) also showed good
response towards the present protocol. Primary amide group like that present in 21s was
also N-formylated by p-chlorophenyl formate (3r) under the present reaction condition
but as the amine part is deactivated due to the electron withdrawing effect of amide
carbonyl group, a very long reaction completion time was observed. Halogen substituted
aromatic amines (5s and 6s) can also be N-formylated by the present method and we have
been able to get crystal structure of the product, N-(4-bromophenyl)formamide (6p) as
shown in fig.2.
Present method was not found to be effective in the formylation of thiol group as in the
case of (22s). This further opens up the possibility of the application of this method in the
chemoselective N-formylation in presence of thiol group.
CONCLUSION
We have developed a solvent and catalyst free N-formylation protocol for amine type of
compounds (1s-21s) using aromatic formates (1r-6r) as the N-formylating agents. The
reaction condition is mild, easy to operate and it occurs smoothly under ambient
condition giving high yield of formamide derivatives of the corresponding amine
substrate. The present method is applicable to wide varieties of amine substrates ranging
from aromatic amines (both primary and secondary) (1s-19s) as well as aliphatic amine
7

(20s) to a primary amide type of functionality (21s). Aromatic amines having electron
donating or electron withdrawing substituent can be N-formylated by the present method.
However in all the cases, p-chlorophenyl formate (3r) was found to most suitable N-
formylating agent in terms of minimum reaction completion time and maximum yield of
the N-formamide product and best result was obtained when p-methoxy aniline (3s) (1
mmol) (model substrate) and p-chlorophenyl formate (3r) (1 mmol) (model reagent)
were reacted under neat and catalyst free conditions. Furthermore, the present method
could not be applied for the formylation of thiol group (22s) which signifies the
possibility of chemoselective N-formylation of amine in presence of thiol group by the
present method. All the N-formamide products were characterized on the basis of
physico-chemical and spectroscopic data. The structure of product N-(4-bromophenyl)
[
27]
formamide (6p) was further confirmed by X-ray crystallography study (Fig. 2).
EXPERIMENTAL
[27,
Analytical Data For Selected Compounds: N-(4-Methoxyphenyl) Formamide (3p)
2
8]
o
+
1
Yield-99 %,( 149.6 mg), M.P. ( C) 78-82, LCMS (M+H )-152. H NMR (400 MHz,
CDCl ): δ (ppm) 8.25 (s, 1H), 7.36 (d, 1H, J =8.8 Hz), 6.95 (d, 1H, J =8.8 Hz), 6.78-6.83
3
1
3
(
m, 2H, J =8.8 Hz), 3.73(s, 3H); C NMR (100 MHz, CDCl ): δ (ppm) 55.55, 114.22,
3
1
2
14.91, 121.70, 121.81, 130.21, 158.91, 163.25. IR (KBr): 3262, 3058, 2893, 2834, 2544,
-1
313, 2047, 1885, 1687, 1609, 1534, 1403, 1306, 1237, 1168 cm . Elemental analysis
(
%), Calcd for C H NO : C, 63.56; H, 6.00; N, 9.27. Found. C, 63.76; H, 5.89; N, 9.39.
8 9 2
8

[27, 28]
N-(4-Bromophenyl) Formamide (6p)
o
+
1
Yield-98%, (196 mg), M.P.( C) 117-121, LCMS (M-H )-198. H NMR (400 MHz,
1
3
CDCl ): δ (ppm) 8.40 (s, 1H), 8.39 (s, 1H), 7.41-7.51 (m, 2H), 6.98-6.02 (m, 2H); C
3
NMR (75 MHz, CDCl ): δ (ppm) 118.21, 120.27, 121.56, 132.03, 132.73, 135.89 162.48.
3
-1
IR (KBr): 3288, 3050, 2872, 2681, 2363, 1894, 1673, 1595, 1534, 1393, 1248, 1181 cm .
Elemental analysis (%), Calcd for C H BrNO: C, 42.03; H, 3.02; N, 7.00. Found. C,
7
6
4
2.29; H, 2.98; N, 7.21.
Single crystal X-ray crystallography for (6p): Empirical formula= C H BrNO, Fw =
7
6
2
00.03, T = 296 K, Orthorhombic, space group =P b c a, Hall group = ‐ P 2ac 2ab ,a
0
0
0
=
10.789(2)A , b = 9.8239(18) A , c = 13.878(3) A , α = 90, β = 90 γ = 90, V =
-
3
0
-1
1
7
1
470.9(5), Z = 8, Dx = 1.807 g/cm , λ (MoKa) = 0.71073 A , µ = 5.513 mm , F000 =
84.0, F000' = 782.10. θmax =25.00 , R = 0.0574( 849) , wR2 = 0.1575( 1298), S =
0
.098, Bond precision: C‐ C = 0.0088 A , h,k,l =12,11,16 . N =1299, N = 91.
max
ref
par
Crystallographic data for the structures of 6p reported in the present work have been
deposited at the Cambridge Crystallographic Data Centre with CCDC No.1035596.
[28, 29]
N,N-Diphenylformamide (19p)
o
+
1
Yield-98%, (193.3 mg), M.P. ( C) 66-68, LCMS (M+H )-198. H NMR (400 MHz,
CDCl ): δ (ppm) 8.60 (s, 1H), 7.30-7.35 (m, 4H), 7.18-7.24 (m, 4H), 7.09-7.11 (m, 2H);
3
1
3
C NMR (100 MHz, CDCl ): δ (ppm) 126.13, 126.89, 127.06, 129.20, 161.77. . IR
3
-1
(
KBr): 3313, 3059, 2852, 2355, 1686, 1535, 1593, 1490, 1337, 1264, 1134 cm .
9

Elemental analysis (%), Calcd for C H NO: C, 79.16; H, 5.62; N, 7.10. Found. C,
1
3
11
7
9.31; H, 5.64; N, 7.23.
[27]
N-Benzylformamide (20p)
o
+
1
Yield-90 %, ( 121.6 mg), M.P. ( C) 46-48, LCMS (M+H )-136. H NMR (400 MHz,
13
CDCl ): δ (ppm) 8.27 (s, 1H), 7.25-7.39 (m, 6H), 4.48 (d, 2H, J =6.0 Hz); C NMR
3
(
100 MHz, CDCl ): δ (ppm) 55.73, 110.04, 121.07, 121.11, 124.29, 147.88, 158.78. IR
3
(KBr): 3293, 3045, 2866, 2758, 2353, 1960, 1676, 1535, 1525, 1546, 1397, 1233, 1081
-1
cm . Elemental analysis (%), Calcd for C H NO: C, 71.09; H, 6.71; N, 10.36. Found. C,
8
9
7
1.21; H, 6.64; N, 10.46.
[30]
N-Formylbenzamide (21p)
o
+
1
Yield-90%, (134.2 mg), M.P. ( C) 108-110, LCMS (M+H )-150. H NMR (300 MHz,
CDCl ): δ (ppm) 10.39 (s, 1H), 9.44 (d, 1H, J =9.6 Hz), 8.05 (d, 1H, J =7.5 Hz), 7.69 (t,
3
1
3
1
1
1
H, J =7.2 Hz),), 7.58(t, 2H, J =7.5 Hz); C NMR (75 MHz, CDCl ): δ (ppm) 128.15,
3
28.98, 129.06, 131.07, 133.95, 164.93, 166.77. IR (KBr): 3313, 3059, 2852, 2355,
-1
686, 1535, 1593, 1490, 1337, 1264, 1134 cm . Elemental analysis (%), Calcd for
C H NO : C, 64.42; H, 4.73; N, 9.39. Found. C, 64.39; H, 4.64; N, 9.53.
8
7
2
SUPPLEMENTAL MATERIAL
General experimental, characterization data of N-formylated products and related
1
13
references, H and C NMR, LC-MS and IR Spectra of N-formylated products can be
accessed on the publisher’s website.
1
0

FUNDING
We acknowledge SERB-DST [sanction order no. SR/SO/BB-0007/2011 dated
2
1.08.2012 to N. A. B.] and CSIR, India [Sanction No. 01 (2504)/11/EMR-II) to N.A.B.]
for their financial support. S.B. is thankful to MANF-UGC his fellowship. We thank the
Dept. of Chemistry, Siksha Bhavana, Visva-Bharati (Central University) and its DST-
FIST programme for necessary infrastructural and instrumental facilities.
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1
2

Table 1: Optimization towards the selection of aromatic formates as the N-formylating
a
reagent for p-methoxy aniline (3s), selected as model the substrate .
b
Entry Reagent Time
Yield (%)
1
2
3
4
5
1r
2r
3r
4r
5r
6r
1 hr
99
99
99
99
94
93
2 hr
30 min
40min
8 hr
6
24 hr
a
Reaction condition: p-Methoxy aniline (3s) (1 mmol) (model substrate) and various
aromatic formates (1 mmol) under neat condition.
b
Isolated yields.
1
3

a
Table 2: Optimization of reaction condition (neat/solvent) .
b
Entry No.
Solvent
Neat
Time
Yield (%)
1
2
3
4
5
6
7
8
9
30 min 99
Hexane
1.5 hr
97
97
97
96
94
93
88
83
81
p-Xylene 1.5 hr
Toluene
DCM
1.5 hr
1.5 hr
3.5 hr
Ethanol
Methanol 3.5 hr
DMF
6.0 hr
6.5 hr
4.0 hr
DMSO
Water
1
0
a
Reaction condition: p-Methoxy aniline (3s) (1 mmol) (model substrate) and p-
chlorophenyl formate (3r) (1 mmol) (model reagent) were reacted under neat condition as
well as in presence of solvent (3 ml) to get the product, N-(4-methoxyphenyl)formamide
(3p).
b
Isolated yields.
1
4

Table 3. Synthesis of N-formyl amine derivatives using p-chlorophenyl formate (3r) as
a
the N-formylating reagent under solvent and catalyst free condition.
Entry Substrate
Product
Time
Yield
M.P.
b
o
(%)
( C)
1
2
3 hr
95
99
47-49
80-82
1 hr
3
4
30 min 99
78-82
45-48
2 hr
2 hr
97
98
5
6
7
100-
1
02
117-
21
104-
06
2.5 hr 98
2.5 hr 97
1
1
8
3 hr
95
132-
36
1
1
5

9
1
1
2 hr
98
98
90
156-
58
154-
56
120-
24
126-
28
1
0
1
2 hr
1
10 hr
1
1
1
1
1
2
3
4
5
4 hr
93
92
93
90
1
12 hr
14 hr
16 hr
186-
88
1
164-
66
1
75-78
1
1
1
6
7
8
3 hr
5 hr
6 hr
97
97
97
78-80
136-
1
38
202-
06
2
1
6

1
2
2
9
0
1
2
2 hr
98
66-68
46-48
108-
3.5 hr 90
24 hr
24 hr
90
0
1
-
10
2
a
Reaction condition: Amine substrates (1s-21s) or thiophenol (22s) (1 mmol) and p-
chlorophenyl formate (3r) (1 mmol) (model N-formylating reagent) were reacted under
neat condition.
b
Isolated yields.
1
7

Figure 1: Aromatic formates used as N-formylating agents
1
8

Figure 2. Single crystal X-ray diffraction structure of N-(4-bromophenyl) formamide (6p)
[
27]
1
9

[
26]
Scheme 1. Synthesis of aromatic formates used as N-formylating agents
.
2
0

Scheme 2. N-formylation of 4-methoxyaniline (3s) using 4-chlorophenyl formate (3r) as
N-formylating agent at ambient temperature and under solvent and catalyst free
condition.
2
1

Scheme 3: Plausible mechanistic pathway of the N-formylations of amines by aromatic
formates.
2
2