Facile N-formylation of amines using Lewis acids as novel catalysts

Article abstract of DOI:10.1016/j.tetlet.2009.10.006

Alky, aryl, and heteroaryl amines were found to react efficiently with formic acid under Lewis acid catalysis giving N-formyl derivatives in high yields. A study of ZnCl₂-catalyzed N-formylation of a variety of amines using formic acid as formylating agent is described.

Full text of DOI:10.1016/j.tetlet.2009.10.006

Tetrahedron Letters 50 (2009) 7099–7101
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Tetrahedron Letters
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Facile N-formylation of amines using Lewis acids as novel catalysts
*
A. Chandra Shekhar, A. Ravi Kumar, G. Sathaiah, V. Luke Paul, Madabhushi Sridhar, P. Shanthan Rao
Fluoroorganics Division, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Alky, aryl, and heteroaryl amines were found to react efficiently with formic acid under Lewis acid catal-
ysis giving N-formyl derivatives in high yields. A study of ZnCl2-catalyzed N-formylation of a variety of
amines using formic acid as formylating agent is described.
Received 1 September 2009
Revised 29 September 2009
Accepted 3 October 2009
Available online 8 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
N-Formylation
Amines
Formic acid
Lewis acid
Formylation of amines is an important reaction in synthetic or-
ganic chemistry. Formamides have wide applications as intermedi-
ates in the preparation of pharmaceuticals1 such as fluoroquinolines
and as important reagents for Vilsmeier formylation.2 They are also
in use as Lewis base catalysts in organic transformations such as
allylation,3 hydrosilylation4 of carbonyl compounds. In addition,
the formyl group is one of the important amino-protecting groups
in peptides synthesis5 and the N-formyl derivatives are useful pre-
cursors in the preparation of N-methyl compounds.6
In recent years, a number of methods have been reported on
N-formylation of amines. Some of the useful formylation reagents
are chloral,7 formic acid-DCC,8 formic acid-EDCI,9 formic acid
esters,10 KF-alumina,11 and other solid-supported reagents,12
ammonium formate,13 CDMT.14 Many of the N-formylation meth-
ods have disadvantages such as expensive reagents, formation of
side products, thermal instability, and difficult accessibility to
reagents. Thus, a mild, convenient, and high yield procedure using
inexpensive catalyst would be valuable.
catalysts. This reaction has proceeded well with other Lewis acids
also such as FeCl3, AlCl3, and NiCl2 giving yields in the range of 80–
90%, but no reaction was observed in the presence of ZnF2 and AlF3.
Among all the catalysts studied in this reaction, the best results
were obtained with ZnCl2, which is not only inexpensive but also
environment friendly. This has encouraged us to further investi-
gate the N-formylation of a variety of alkyl, aryl, and heteroarylam-
ines 1a–q with formic acid under similar conditions using ZnCl2 as
a catalyst16 (Scheme 2). The results are shown in Table 1.
In this study, the arylamines having electron-donating groups
were found to be more active to N-formylation as their reactions
were completed in less than 1.5 h. Primary amines, secondary
amines, and arylamines substituted with electron-withdrawing
groups, that is, 1g, 1h, and 1i were, however, sluggish requiring
3–12 h for completion of the reaction. The plausible mechanism
for N-formylation of amines under Lewis acid catalysis is shown
in Scheme 3.
In continuation of our interest in the development of new syn-
thetic methods using Lewis acids as catalysts,15 we report herein a
convenient and novel approach for activation of formic acid as an
N-formylation agent using Lewis acid as catalyst under solvent-
free condition (Scheme 1).
Lewis Acid
RNHCHO
RNH2 + HCOOH
R= alkyl or aryl
°
neat, 70 C
In our study, no reaction was observed when a mixture of ani-
line and formic acid was heated at 100 °C for 4 h. However, addi-
tion of a catalytic amount of Lewis acid to this mixture has
rapidly induced N-formylation producing formanilide in high
yields. In this reaction, we have obtained formanilide in very high
yields (>90%), when ZnCl2, SnCl2, LaCl3, and La(OTf)3 were used as
Scheme 1. Lewis acid-catalyzed N-formylation of amines with formic acid.
ZnCl2
RNHCHO
2 a-q
RNH2 + HCOOH
°
neat, 70 C
1a-q
60-98%
* Corresponding author. Tel.: +91 040 27193171; fax: +91 040 27193185.
E-mail address: shanthanpp@yahoo.co.in (P. Shanthan Rao).
Scheme 2. ZnCl2-catalyzed N-formylation of amines with formic acid.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.006

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A. Chandra Shekhar et al. / Tetrahedron Letters 50 (2009) 7099–7101
Table 1
ZnCb-catalyzed N-formylation of amines with formic acid
Entry
a
Formamide 2
Time (min)
10
Yielda (%)
96
NHCHO
b
c
NHCHO
30
60
98
80
H3C
NHCHO
COCH3
d
e
90
90
85
80
NHCHO
Br
NHCHO
F
NHCHO
f
80
92
Cl
g
720
720
90
90
O2N
F3C
O2N
NHCHO
h
NHCHO
NHCHO
i
900
30
92
96
95
F3C
N
N
NHCHO
J
CO2Et
k
200
S
NHCHO
CN
1
240
90
92
90
S
NHCHO
m
NHCHO
n
0
240
360
80
60
N
CHO
O
N CHO
NHCHO
NHCHO
p
q
45
60
60
60
a
Isolated yields. All products gave satisfactory 1H NMR, IR and mass spectral data.

A. Chandra Shekhar et al. / Tetrahedron Letters 50 (2009) 7099–7101
7101
LA
LA
OH
O
O
-LA
RNHCHO
OH
HCOOH + LA
-H2O
H2N-R
H
NHR
H
H
Scheme 3. Mechanism of Lewis acid-catalyzed N-formylation of amines with formic acid.
Shen, Z.; Skoumbourdis, A. P.; Barrish, J. C. Tetrahedron Lett. 2000, 41, 5453; (c)
Jackson, A.; Meth-Cohn, O. J. Chem. Soc., Chem. Commun. 1995, 1319.
2. Downie, I. M.; Earle, M. J.; Heaney, H.; Shuhaibar, K. F. Tetrahedron 1993, 49,
4015.
3. Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 56, 6620.
4. Kobayashi, S.; Yasuda, M.; Hachiya, I. Chem. Lett. 1996, 407.
5. Hartinez, J.; Laur, J. Synthesis 1982, 979.
6. (a) Kraus, N. A. Synthesis 1973, 361; (b) Kizuka, H.; Elmaleh, D. R. Nucl. Med. Biol.
1993, 20, 239.
7. Blicke, F. F.; Lu, C.-J. J. Am. Chem. Soc. 1952, 74, 3933.
When compared to formic acid, higher carboxylic acids are
more resistant to amidation. In our study, the reactions of acetic
acid and propionic acid with anilines in the presence of ZnCl2 have
produced the corresponding amides in moderate yields (55% and
50%, respectively) upon heating at 70 °C for 12 h and the long chain
carboxylic acids such as decanoic acid and levulinic acid remained
unreactive with aniline upon heating at 100 °C for 24 h.
The esters of formic acid such as phenyl formate and pentaflu-
orophenyl formate were useful reagents for direct N-formylation
without requiring any catalyst.10 However, these reagents are
expensive and not readily available. Unlike these aryl formats,
ethyl formate is highly sluggish and recently, TiCl3(OTf)17 and sil-
ica-bonded N-propylsulfamic acid18 were reported to be effective
catalysts for N-formylation using ethyl formate. When compared
to these procedures, the present protocol is more advantageous
as the reagents are inexpensive and easily available. This method
is simple and applicable to a variety of amines.
In conclusion, we have developed a novel and efficient method
for N-formylation of an amine using formic acid as a formylating
agent and ZnCl2 as a catalyst. This Letter describes first the obser-
vation of Lewis acid-catalyzed N-formylation of amines using for-
mic acid and it offers a simple, economical, environment friendly
method for N-formylation of amines.
8. Waki, J.; Meinhofer, J. J. Org. Chem. 1977, 42, 2019.
9. Chen, F. M. F.; Benoiton, N. L. Synthesis 1979, 709.
10. (a) Yale, H. L. J. Org. Chem. 1971, 36, 3238; (b) Kisfaludy, L.; Laszlo, O. Synthesis
1987, 510; (c) Duezek, W.; Deutsch, J.; Vieth, S.; Niclas, H. J. Synthesis 1996, 37.
11. Mihara, M.; Ishino, Y.; Minakara, S.; Komatsu, M. Synthesis 2003, 2317.
12. Das, B.; Krishnaiah, M.; Balasubramanyam, P.; Veeranjaneyulu, B.; Nandan
kumar, D. Tetrahedron Lett. 2008, 49, 2225.
13. Reddy, P. G.; Kumar, G. D. K.; Bhaskaran, S. Tetrahedron 2000, 41, 9149.
14. Luca, L. D.; Giacomelli, G.; Porcheddu, A.; Salaris, M. Synlett 2004, 2570.
15. (a) Shanthan Rao, P.; Venkataratnam, R. V. Tetrahedron Lett. 1991, 32, 5821; (b)
Sridhar, M.; Ramanaiah, B. C.; Narsaiah, Ch.; Mahesh, B.; Kumaraswamy, M.;
Kishore Kumar, M.; Vishnu Murthy, A.; Shanthan Rao, P. Tetrahedron Lett. 2009,
50, 3897.
16. General procedure for N-formylation of an amine: 2-Amino-5,6,7,8-terahydro-
4H-cyclohepta[b]thiophene-3-carbonitrile (0.5 g, 2.6 mmol) and anhydrous
ZnCl2 (35 mg, 0.26 mmol) were taken in a 50 ml round bottomed flask fitted
with a calcium chloride guard tube. To the mixture, formic acid (0.3 ml,
7.8 mmol) was added drop-wise with constant stirring for 10 min. This
mixture was heated at 70 °C for 1 h and the progress of the reaction was
monitored by TLC. When the reaction was completed, the mixture was cooled
to room temperature and diluted with ethyl acetate (40 ml). The organic layer
was washed with water (2 Â 10 ml), brine (2 Â 10 ml) and dried over anhyd
Na2SO4. The solvent was removed under reduced pressure and the resulting
crude product was purified by column chromatography (silica gel—100–200
mesh, ethyl acetate/hexane 1:10) to obtain the corresponding N-formyl
derivative, 2l (0.53 g, 92%, mp 194–196 °C), which gave satisfactory spectral
data as follows: 1H NMR (CDCl3, 300 MHz): d ppm 1.45 (m, 3H), 1.7 (m, 5H), 1.9
(m, 2H), 8.45 (s, 1H), 9.2 (s, 1H); 13C NMR (CDCl3, 75 MHz): d ppm 23.1, 28.6,
Acknowledgment
The authors are thankful to Dr. J. S. Yadav, Director, IICT, Hyder-
abad, for his constant encouragement and financial support from
an industry-sponsored project.
29.1, 31.2, 31.6, 67.4, 115.2, 128.8, 135.4, 148.8, 160.4; I.R. (KBr,
m
cmÀ1): 3397,
2210, 1679, 1565, 1450, 1113, 1026, 957; HRMS(ESI) for C11H11N2OS
References and notes
(MÀH+) = 219.059 (observed), 219.060 (calculated).
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18. Niknam, K.; Saberi, D. Tetrahedron Lett. 2009, 50, 5210.
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