Facile and highly efficient N-formylation of amines using a catalytic amount of iodine under solvent-free conditions

Article abstract of DOI:10.1055/s-0030-1258518

We developed a simple, practical, and catalytic method for the N-formylation of a wide variety of amines in the presence of molecular iodine as a catalyst under solvent-free conditions. This reaction is applicable to the chemoselective N-formylation of amino groups and -amino acid esters without epimerization.

Full text of DOI:10.1055/s-0030-1258518

LETTER
2093
Facile and Highly Efficient N-Formylation of Amines Using a Catalytic
Amount of Iodine under Solvent-Free Conditions
ne ng-Gon Kim, Doo Ok Jang*b
a
N
J
-Formyl
o
ation of
A
mi
o
a
Biotechnology Division, Hanwha Chemical R&D Center, Daejeon 305-345, South Korea
Department of Chemistry, Yonsei University, Wonju 220-710, South Korea
Fax +82(33)7602182; E-mail: dojang@yonsei.ac.kr
b
Received 28 May 2010
aniline was treated with formic acid (3 equiv) at 70 °C in
the presence of stoichiometric levels of iodine under sol-
vent-free conditions. The reaction proceeded smoothly
Abstract: We developed a simple, practical, and catalytic method
for the N-formylation of a wide variety of amines in the presence of
molecular iodine as a catalyst under solvent-free conditions. This
reaction is applicable to the chemoselective N-formylation of amino and was completed in two hours, affording formanilide in
groups and a-amino acid esters without epimerization.
a 93% yield (Table 1, entry 1). To develop a catalytic vari-
ant, the reaction was carried out in the presence of catalyt-
ic amounts of iodine (0.1 equiv). The reaction proceeded
efficiently, affording formanilide in the same yield as that
of the stoichiometric version (entry 2).
Key words: amine, N-formylation, formic acid, iodine catalysis,
solvent-free
Formamides have been widely used as amino acid protect- Further studies to establish the optimal reaction condi-
ing groups in peptide synthesis, as these amino acids are tions determined that 5 mol% iodine and 2 equivalents of
valuable starting materials in pharmaceutical syntheses.1
–3
formic acid were sufficient to efficiently perform the reac-
Formamides have also been involved in Vilsmeier tion (entry 5). A decrease in the amount of formic acid
4
5
6
formylation and in the allylation and hydrosilylation of gave a lower yield of the desired product (entry 6). Higher
carbonyl compounds. As such, a number of formylating reaction temperatures decreased the yield (entry 7), and
methods have been reported. General formylation meth- the reaction did not reach completion after 72 hours at
odologies typically employ the use of mixed anhydrides room temperature (entry 8). The reaction performed in
7
8
including acetic formic anhydride, formic acid/EDAC,
MeCN was less effective than those performed under sol-
vent-free conditions (entry 9).
9
10
formic acid/DCC, and formyl pivaloyl anhydride.
Formylation with formates such as 2,2,2-trifluoroethyl
1
1
12
formate, pentafluorophenyl formate, cyanomethyl for- Table 1 The Optimization of Reaction Conditions for N-Formyla-
1
3
14
tion of Aniline in the Presence of Iodine
mate, and ammonium formate have been reported, al-
though the reactivities of these reactions are low. In
I2
1
5
16
17
Ph NH2
Ph NHCHO
addition, chloral, formic acid/Lewis acids, PEG-400,
HCOOH
KF-alumina, and solid-supported reagents19 have also
been used in formylation reactions. Regardless of the
method, many of these formylation agents have draw-
backs, including thermal instability, sensitivity to mois-
ture, toxicity, high cost, prolonged reaction time, and
formation of undesirable byproducts. Thus, a simple and
efficient method for catalytic formylation of amines is
highly desirable.
18
Entry HCOOH (equiv) I (equiv) Time (h) Temp (°C) Yield (%)
2
1
2
3
4
5
6
7
8
3
3
3
2
2
1
2
2
2
1
2
2
70
70
93
93
93
94
94
35
86
42
71
0.1
0.1
2
70
0.1
2
70
Molecular iodine has emerged as a versatile catalyst for
various organic transformations, affording corresponding
products in high levels of chemical yield and selectivity.20
In addition, molecular iodine provides several advantages
such as low cost, nontoxicity, and easy workup with envi-
ronmentally benign reaction conditions. As part of our ef-
0.05
0.05
0.05
0.05
0.05
2
70
4
70
2
100
r.t.
70
72
4
2
1
fort to develop new catalytic reactions, we report herein 9a
a simple and convenient approach for N-formylation of
amines using molecular iodine as a catalyst under solvent-
free conditions. An initial study was performed in which
a
The reaction was performed in MeCN.
To demonstrate the versatility of the iodine method, we
next investigated the scope of this reaction under the opti-
mized conditions. A wide range of aromatic and aliphatic
amines were subjected to the novel reaction conditions,
SYNLETT 2010, No. 14, pp 2093–2096
Advanced online publication: 22.07.2010
DOI: 10.1055/s-0030-1258518; Art ID: U04610ST
x
x
.x
x
.2
0
1
0
©
Georg Thieme Verlag Stuttgart · New York

2
094
J.-G. Kim, D. O. Jang
LETTER
and the results are summarized in Table 2. All of the Table 2 Iodine-Catalyzed N-Formylation of Amines under Sol-
vent-Free Conditions
amines examined reacted efficiently, affording the corre-
sponding N-formyl products in good to excellent yields.
Anilines containing either electron-donating or electron-
withdrawing groups underwent the conversion smoothly
I2 (5 mol%)
70 °C
R
NH2
+
HCOOH
(2 equiv)
R
NHCHO
(
1 equiv)
(
entries 1–4), although anilines with a strong electron- Entry Amine
withdrawing group required longer reaction times (entry
). Previously, the N-formylation of anilines with elec-
Product
Time Yield
(h) (%)
4
2
2
14
Me
N
NH
3
74
Me
N
N CHO
tron-withdrawing groups was found to be difficult. Sec-
ondary aryl amines were also good substrates for the
reaction, affording high yields of the corresponding for-
mamides (entries 5–7). The reactions with aliphatic pri- Chemoselectivity of the iodine reaction was also investi-
mary and secondary amines resulted in high product gated by performing formylation of amines in bifunction-
yields (entries 8–14).
al compounds (Table 3). Excellent chemoselectivity was
observed for substrates with hydroxy functionalities, pro-
viding N-formyl derivatives as the sole product without
side reactions (entries 1–4). The iodine-catalyzed N-
formylation strategy was also applied to the formylation
of optically pure chiral a-amino acid esters (entries 5–7).
When the a-amino acid esters were treated with formic
acid in the presence of iodine, N-formyl amino acid esters
were obtained in high yield without epimerization at the
stereogenic centers, as determined by comparing the opti-
cal rotations of the products with those of the authentic
samples.
Table 2 Iodine-Catalyzed N-Formylation of Amines under Sol-
vent-Free Conditions
I2 (5 mol%)
R
NH2
+
HCOOH
(2 equiv)
R
NHCHO
7
0 °C
(
1 equiv)
Entry Amine
Product
Time Yield
h) (%)
(
NH2
NHCHO
1
2
2
4
8
96
96
82
86
MeO
MeO
Cl
It is known that iodine reacts with formic acid to afford
NH2
NHCHO
NHCHO
NHCHO
2
3
2
HI. Thus, we assumed that in situ generated HI is the real
active species. Protonation of the carbonyl group of for-
mic acid (I) is followed by an attack of the amine to give
intermediate II, which is transformed into the desired
formylated product, water, and proton, which further cat-
alyzes the reaction (Scheme 1).
Cl
NH2
3
Ac
Ac
NH2
4
I2
O2N
O2N
HCOOH
2 HI
+
CO2
H
Me
NH
Me
NCHO
H
O
5
3
3
82
84
+
O
+
–
H2O
OH2
R
NHCHO
H
– H+
HN
H
OH
2
H N R
R
Me
NH
Me
I
II
NCHO
6
Scheme 1
MeO
MeO
7
8
9
Ph NH
Ph NCHO
3
2
4
85
91
79
In summary, we developed a simple, practical, and cata-
lytic method for amine N-formylation in the presence of
molecular iodine as a catalyst under solvent-free condi-
tions. A wide variety of amines are good substrates for the
reaction. This reaction is applicable to the chemoselective
N-formylation of amino groups and a-amino acid esters
without epimerization.
2
2
BnNH2
BnNHCHO
n-BuNH2
n-BuNHCHO
1
1
0
1
2
3
89
82
NH2
NHCHO
O
O
NH2
NHCHO
Typical Experimental Procedure
1
1
2
3
(i-Pr) NH
(i-Pr) NCHO
4
4
69
71
A mixture of amine (2 mmol), formic acid (99% purity, 151 mL, 4
mmol), and iodine (12.7 mg, 5 mmol%) was stirred at 70 °C. After
completion of the reaction as determined by TLC, the mixture was
diluted with CH Cl (20 mL), washed with sat. Na S O (10 mL),
2
2
O
NH
O
N
CHO
2
2
2
2
3
sat. NaHCO (10 mL), and brine (10 mL), and then dried over anhyd
3
MgSO . After filtration and evaporation of the solvent, the residue
4
Synlett 2010, No. 14, 2093–2096 © Thieme Stuttgart · New York

LETTER
N-Formylation of Amines
2095
Table 3 N-Formylation of Amino Alcohols and a-Amino Acid Esters in the Presence of Iodine under Solvent-Free Conditionsa
Entry
1
Substrate
Product
Time (h)
2
Yield (%)
NH2
NH2
NHCHO
NHCHO
85
HO
HO
2
3
4
2
4
4
90
OH
OH
72
84
HO
NH
OH
HO
N
N
CHO
OH
N
H
CHO
O
O
5
6
2
2
3
82
80
77
OMe
OMe
NH2
O
NHCHO
O
OMe
OMe
NH2
NHCHO
O
O
7
OMe
OMe
NHCHO
NH2
HO
HO
a
Reaction conditions: a mixture of amine (2 mmol), formic acid (4 mmol), and iodine (5 mmol%) was stirred at 70 °C.
was purified by column chromatography on silica gel to give the
formylated product.
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(
This work was supported by the National Research Foundation
1996, 37.
(
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