Indium-catalyzed N -formylation of amines under solvent-free conditions

Article abstract of DOI:10.1055/s-0029-1219784

We have developed a simple, mild method for N-formylation of a wide variety of amines in the presence of indium metal 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. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1219784

LETTER
1231
Indium-Catalyzed N-Formylation of Amines under Solvent-Free Conditions
I
ndium-Ca
o
talyzed
N
-
Fo
o
r
mylation of
n
A
mines g-Gon Kim,a Doo Ok Jang*b
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 8 February 2010
Initially, aniline was treated with three equivalents of for-
mic acid in the presence of one equivalent of indium at
70 °C without an organic solvent for 1 h, which resulted
in a 97% yield of formanilide (Table 1, entry 1). The reac-
tion was found to be efficient with a catalytic amount of
In (as little as 0.1 equiv), which afforded the same yield of
the product as with a stoichiometric amount of In (entry
3). Higher reaction temperatures (up to 100 °C) had no ef-
fect on the yield (entry 4), whereas a decrease in the
amount of formic acid gave lower yields of the desired
product (entry 5). The reaction did not reach completion
even after 72 hours at room temperature (entry 6). Reac-
tions performed in acetonitrile afforded lower yields than
those performed under solvent-free conditions (entry 7).
A control experiment without In did not proceed efficient-
ly, affording only a 52% yield of formanilide (entry 8).
We assumed that formic acid reacts with indium metal to
generate In(OC(O)H)3, which plays a role as a Lewis acid
in the reaction.19
Abstract: We have developed a simple, mild method for N-formy-
lation of a wide variety of amines in the presence of indium metal
as a catalyst under solvent-free conditions. This reaction is applica-
ble to the chemoselective N-formylation of amino groups and a-
amino acid esters without epimerization.
Key words: amine, formylation, formic acid, indium, ethanol-
amine, formylamino ester, solvent-free
Formylation of amines is an important method of protect-
ing a wide variety of amines and amino acids.1 The prod-
ucts, formamides, are important intermediates in organic
synthesis and have been widely used in the synthesis of
pharmaceuticals.2 Formamides have been used as re-
agents in the Vilsmeier formylation3 and in the allylation4
and hydrosilylation5 of carbonyl compounds. Due to their
broad range of applications, various reagents for the
formylation of amines have been developed, including
formic acid with activating reagents such as DCC,6
EDCI,7 CDMT,8 PEG-400,9 or Lewis acids,10 formic acid
derivatives (i.e. acetic formic anhydride,11 2,2,2,-trifluo-
roethyl formate,12 pentafluorophenyl formate,13 cyano-
methyl formate,14 and ammonium formate),15 and solid-
supported reagents.16 However, these agents have draw-
backs, including thermal instability, sensitivity to mois-
ture, toxicity, high cost, prolonged reaction times, and
formation of undesirable by-products. Thus, a convenient
and efficient approach to catalytic formylation of amines
is highly desirable.
Table 1 Optimizing Reaction Conditions for N-Formylation of
Anilines
Entry
Aniline HCOOH In
(equiv) (equiv) (equiv) (h)
Time
Temp
(°C)
Yield
(%)
1
1
1
1
1
1
1
1
1
3
3
3
3
2
3
3
3
1.0
0.5
0.1
0.1
0.1
0.1
0.1
0
1
1
70
70
97
96
97
95
92
51
53
52
2
3
2
70
4a
5
2
100
70
Recently, indium-mediated reactions have gained consid-
erable attention because of its high reactivity and unique
properties including non-toxicity and inertness toward air
and water.17 Moreover, pretreatment is unnecessary to ac-
tivate indium metal. As part of our research effort to de-
velop new synthetic methods using indium metal as
catalyst,18 we herein report a simple and convenient ap-
proach to the N-formylation of amines using indium metal
as catalyst under solvent-free conditions (Scheme 1).
2
6
72
2
r.t.
70
7b
8
72
70
a The reaction was carried out at 100 °C (boiling point of formic acid).
b The reaction was performed in MeCN.
In (10 mol%)
R
NH2
+
HCOOH
R
NHCHO
On the basis of these preliminary results, various amines
were subjected to these novel reaction conditions to inves-
tigate the scope and limitations of the reaction. The results
of these experiments are presented in Table 2. The reac-
tion was found to be effective in formylating both elec-
tron-rich and electron-poor anilines in high yields,
although anilines with electron-releasing groups were
more reactive and afforded higher yields of the corre-
70 °C
Scheme 1
SYNLETT 2010, No. 8, pp 1231–1234
Advanced online publication: 23.03.2010
DOI: 10.1055/s-0029-1219784; Art ID: U00810ST
x
x.
x
x.
2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

1232
J.-G. Kim, D. O. Jang
LETTER
Table 2 In-Catalyzed N-Formylation of Various Amines under Sol-
vent-Free Conditions (continued)
sponding products in shorter reaction times than anilines
with electron-withdrawing groups (entries 1–5). Formyla-
tion of a heterocyclic amine was also efficiently achieved,
affording the corresponding formamide in 84% yield (en-
try 6). Secondary aryl amines were also shown to be good
substrates for the reaction (entries 7–12). The reaction
with aliphatic primary and secondary amines also resulted
in high product yields (entries 13–18). Previously, the N-
formylation of aliphatic amines under solvent-free condi-
tions was not efficient.10b
Entry Amine
Product
Time Yield
(h) (%)
14
15
16
n-BuNH2
n-BuNHCHO
2
2
8
92
91
70
NHCHO
NH2
(i-Pr)2NH
(i-Pr)2NCHO
Table 2 In-Catalyzed N-Formylation of Various Amines under Sol-
vent-Free Conditions
CHO
N
H
N
17
6
69
Entry Amine
Product
Time Yield
(h) (%)
O
O
CHO
N
H
N
NHCHO
NH2
1
1.5 98
1.5 97
18
4
75
N
MeO
MeO
N
Me
NH2
NHCHO
NHCHO
NHCHO
Me
2
Cl
Cl
O-Formylation of phenol and benzyl alcohol was exam-
ined using the same reaction conditions. These reactions
did not proceed even with a stoichiometric amount of In
at 70 °C for a prolonged reaction time (72 h). This differ-
ence in reactivity between amines and alcohols under
these conditions allowed us to achieve a highly chemose-
lective formylation of primary or secondary amines in the
presence of unprotected primary or secondary alcohols.
When substrates containing both amino and hydroxyl
groups were subjected to our reaction conditions, the ami-
no group was selectively formylated, which demonstrates
the high chemoselectivity of our novel reaction (Table 3).
For instance, ethanolamine afforded the N-formylated
product in 92% isolated yield after two hours (entry 1).
NH2
3
4
88
Ac
Ac
NH2
4
24 73
10 87
O2N
O2N
NH2
Bz
NHCHO
5
Bz
6
4
6
84
79
N
NH2
N
NHCHO
Me
Me
NH
NCHO
7
Table 3 N-Formylation of Amino Alcohols in the Presence of In
under Solvent-Free Conditions
Me
NH
Me
NCHO
Entry Amino alcohol
Product
Time Yield
(h) (%)
8
5
6
82
81
1
2
2
92
NH2
NHCHO
MeO
MeO
Cl
HO
NH2
HO
Me
Me
NCHO
NHCHO
OH
NH
OH
9
1.5 92
Cl
Me
NH
Me
NCHO
3
4
5
6
71
70
HO
HO
NH
HO
HO
N
CHO
N
10
6
6
80
82
NH
CHO
Me
Me
O
Et
Et
NCHO
NH
11
O
Next, we applied our new method to the synthesis of N-
formylamino acid esters, which serve as starting materials
for peptide synthesis.20 The formylation of a-amino acid
esters was readily achieved by using the present method
without cleavage of either methyl or benzyl ester func-
tional groups, as shown in Table 4. L-Phenylalanine meth-
O
O
12
13
Ph2NH
PhCH2NH2
Ph2NCHO
8
2
80
95
PhCH2NHCHO
Synlett 2010, No. 8, 1231–1234 © Thieme Stuttgart · New York

LETTER
Indium-Catalyzed N-Formylation of Amines
1233
Table 4 N-Formylation of a-Amino Acid Esters
Entry Amino acid ester
Product
Time (h) Yield (%)
[a]D
Measured
Ref
O
O
1
2
2
82
80
+86.1 (c 2, EtOH)
–45.1 (c 1, MeOH)
+85.3 (c 2.3, EtOH)1b
–43.5 (c 1, MeOH)14
OMe
OMe
NH2
NHCHO
O
O
2
OMe
OMe
NH2
NHCHO
O
O
3
4
3
6
77
70
+25.5 (c 2, MeOH)
–46.6 (c 3, MeOH)
+20.7 (c 2, MeOH)19
–42.9 (c 3, MeOH)15
OMe
NHCHO
OMe
NH2
HO
HO
OBn
OBn
N
H
N
O
CHO
O
(3) Downie, I. M.; Earle, M. J.; Heaney, H.; Shuhaibar, K. F.
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yl ester and L-leucine methyl ester were transformed into
the corresponding products in high yields within two
hours (entries 1 and 2). Formylation of L-tyrosine methyl
ester was achieved in high yield without protection of the
hydroxyl group (entry 3). L-Proline benzyl ester reacted
somewhat sluggishly, requiring six hours to complete the
reaction, giving the product with a relatively low yield
(entry 4). We could not detect any signs of epimerization
of the stereogenic centers of products from optically pure
amino acid esters as determined by comparing the optical
rotations of the products with authentic samples.
In conclusion, we have developed a convenient and effi-
cient method for the formylation of a wide variety of
amines, including amines with low nucleophilicity.21
With substrates containing both amino and hydroxyl
groups, our reaction conditions led to exclusive formyla-
tion of the amino group, demonstrating the high chemose-
lectivity of the reaction. The present method has a number
of advantages, including low cost and availability of the
reagents, easy handling and stability of the reagents, and
ease of operation.
(13) Kisfaludy, L.; Ötvös, L. Jr. Synthesis 1987, 510.
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Acknowledgment
This work was supported by the Center for Bioactive Molecular
Hybrids.
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Synlett 2010, No. 8, 1231–1234 © Thieme Stuttgart · New York

1234
J.-G. Kim, D. O. Jang
LETTER
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(21) Typical procedure for the formylation of amines: A mixture
of amine (2 mmol), formic acid (purity = 99%; 226 mL, 6
mmol), and In metal (23 mg, 0.2 mmol) was stirred at 70 °C,
and the reaction was monitored by TLC. After completion of
the reaction, the mixture was diluted with CH2Cl2 and
filtered through Celite. The filtrate was washed with
saturated NaHCO3 and brine, then dried over anhydrous
MgSO4. After filtration and evaporation of the solvent, the
residue was purified by column chromatography on silica
gel to give the formylated product.
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Synlett 2010, No. 8, 1231–1234 © Thieme Stuttgart · New York

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