A convenient procedure for N-formylation of amines

Article abstract of DOI:10.1016/j.tetlet.2012.12.009

A simple and convenient method for the N-formylation of primary and secondary amines including amino acids has been developed utilizing formamide and sodium methoxide in moderate to excellent yield. This reagent is also utilized for one pot conversion of compounds having amino esters to N-formyl amides.

Full text of DOI:10.1016/j.tetlet.2012.12.009

Tetrahedron Letters 54 (2013) 929–931
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A convenient procedure for N-formylation of amines
⇑
Sony Joseph, Prasenjit Das, Bindu Srivastava, Hashim Nizar , Mohan Prasad
Chemical Research Division, Ranbaxy Research Laboratories, Gurgaon, Haryana 122001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and convenient method for the N-formylation of primary and secondary amines including
amino acids has been developed utilizing formamide and sodium methoxide in moderate to excellent
yield. This reagent is also utilized for one pot conversion of compounds having amino esters to N-formyl
amides.
Received 14 September 2012
Revised 3 December 2012
Accepted 5 December 2012
Available online 14 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
N-formylation
Amines
Amino acids
Amino esters
Formamide
Sodium methoxide
Amidation
R2
CHO
R1
N-formylation of amines has utmost importance in organic syn-
thesis and medicinal chemistry. A variety of medicinally active
compounds have formamides as their intermediates.1 N-Formyl
protection gained popularity in peptide synthesis2–4 since N-for-
myl deprotection can easily be achieved without affecting peptide
bond and also it may serve as a precursor for isocyanide5 and form-
amidine6 synthesis.
R2
R1
Formamide,NaOMe
N
NH
R1 = alkyl, aryl
R2 = H,alkyl
Scheme 1.
Reported literature methods for N-formylation1,3,7 use reagents
such as chloral, formic acid–DCC, formic acid–EDCI, formic acid–
ZnCl2, formic acid–PEG 400, formic acid esters, CMT, DMF–NaOMe,
formic acid–thiamine hydrochloride, and imidazole–DMF. Most
of these methods suffer from disadvantages such as harsh
condition, low yield, very high reaction temperature, expensive
reagent etc.
In this Letter we report a simple and efficient method for
N-formylation of amines using formamide and sodium methoxide.
The amidation of carboxylic esters and N-Boc amino esters using
formamide and sodium methoxide is a widely used method for
the synthesis of carboxamide.8–10 We explored the synthetic utility
of this method for N-formylation of amino group. The reaction can
be carried out using formamide as solvent or as reactant in THF.
N-formylation of various primary and secondary aliphatic, aro-
matic amines, and amino acids was studied using this method
(Scheme 1). Primary and secondary amines undergo reaction at
room temperature11 in 2–6 h in very good yield except entry 4
(Table 1) which requires higher temperature of 60–70 °C. The
results are summarized in Table 1. Both aliphatic and aromatic
amines with ester functionality resulted in one pot conversion to
N-formylated amide derivatives in good yield Table 1 (entries
5–7) (Scheme 2).
The reported methods of N-formylation of amino acid require
inert atmosphere, expensive reagents, and harsh reaction condi-
tions resulting in tedious purification and in certain cases protec-
tion and deprotection of carboxylic group.1,3,4 We explored this
method for the N-formylation of amino acids and studied the reac-
tion with phenyl alanine, phenyl glycine, and proline.12 The reac-
tion was carried out in THF under reflux condition (8–12 h) and
the corresponding N-formyl product was isolated in 61–92% yield
(Table 1 entries 8–10) (Scheme 2).
In conclusion we have developed a simple, convenient, and
commercially viable method for N-formylation of amines and
amino ester to N-formyl amides using inexpensive formamide
and sodium methoxide.
⇑
Corresponding author. Tel./fax: +91 124 4011832.
E-mail address: hashim.nizar@ranbaxy.com (H. Nizar).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.009

930
S. Joseph et al. / Tetrahedron Letters 54 (2013) 929–931
Table 1
N-formylation of amines
Entry
Starting material
Reaction temp (°C)
Product
Yield (%)
88
NH2
CH3
NHCHO
CH3
1
rt
NH2
CH3
NHCHO
2
3
4
rt
85
92
76
CH3
Cl
NH
NHCHO
Cl
N
N
Cl
Cl
rt
Ph
Ph
60–70
N
H
N
CHO
Ph
Ph
.HCl
H3C
O
H3C
O
CH3
CH3
O
O
O
O
5
6
7
8
9
rt
63
86
68
92
87
OtBu
CH3
NH2
H2N
H2N
OHCHN
OHCHN
NH2
O
O
O
rt
O
O
O
O
H3C
H3C
H3C
CH3
60–70
60–70
60–70
O
NH2
H3C
H N
HN
.HCl
O
2
CHO
O
OH
OH
NHCHO
NHCHO
OH
NH2
NH2
OH
O
O
O
O
OH
10
11
60–70
rt
61
44
OH
N
H
N
CHO
NH
NH
CHO
2
COOR2
COY
R1
R1
Formamide,NaOMe
THF
Acknowledgments
We are grateful to Dr. Apoorva Bhattacharya for his valuable
discussions and suggestions. We are also grateful to the Analytical
Division of Ranbaxy Research Laboratories for their analytical and
spectral support.
NH2
NHCHO
R1 = alkyl, aryl
R2 = H,alkyl
Y= OH, NH2
Scheme 2.

S. Joseph et al. / Tetrahedron Letters 54 (2013) 929–931
931
methoxide (30% solution in methanol, 9.7 g, 0.054 mol) and stirred at room
temperature for 6 h. The solvent was evaporated and the reaction mixture was
diluted with water and extracted with dichloromethane (50 mL Â 2). The
dichloromethane layer was washed with 25 mL of dilute HCl and concentrated
under reduced pressure to give the product (5.1 g, 92%). 1H NMR (400 MHz,
CDCl3): d 2.99–3.056 (m, 4H), 3.55–3.57 (t, 2H), 3.73 (t, 2H), 6.91–6.96 (d, 1H),
7.14–7.21 (m, 2H), 8.09 (s, 1H); MS: (m/z) 259.2.
References and notes
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12. General procedure for N-formylation of amino acids: To a stirred solution of
phenyl alanine (entry 8) (5 g, 0.03 mol) in THF (25 mL) was added formamide
(3.4 g, 0.075 mol). To the above mixture was added sodium methoxide (30%
solution in methanol, 13.6 g, 0.09 mol) and stirred at 60–70 °C for 12 h. The
solvent was evaporated and the reaction mixture was diluted with water
(25 mL) and pH was adjusted to ꢀ3 using aq HCl (ꢀ1 N). The precipitated
product was filtered and washed with water and dried under vacuum to give
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3.20–3.25 (dd, 1H), 4.76–4.79 (dd, 1H), 7.20–7.33 (m, 5H), 8.02 (s, 1H); MS:
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dichlorophenyl) piperazine (entry 3) (5 g, 0.022 mol) in THF (25 mL) was added
formamide (2.4 g, 0.054 mol).To the above mixture was added sodium