ZnO as a new catalyst for N-formylation of amines under solvent-free conditions

Article abstract of DOI:10.1021/jo060847z

The treatment of amines with formic acid in the presence of ZnO under solvent-free conditions brings about highly and efficient N-formylation to give the corresponding formamides in excellent yields. The N-formylation reaction not only involves mild conditions, simple operation, and high yields but also high chemoselectivity.

Full text of DOI:10.1021/jo060847z

TABLE 1. Formylation of Aniline under Different Reaction
Conditions
ZnO as a New Catalyst for N-Formylation of
Amines under Solvent-Free Conditions
time (h)/ yielda
entry
1
conditions
solvent
none
T (°C)
(%)
Mona Hosseini-Sarvari* and Hashem Sharghi*
aniline (1 mmol)/HCO2H
(excess)/ZnO (1 mmol)
aniline (1 mmol)/HCO2H
(5 mmol)/ZnO (1 mmol)
aniline (1 mmol)/HCO2H
(3 mmol)/ZnO (1 mmol)
aniline (1 mmol)/HCO2H
(1 mmol)/ZnO (1 mmol)
aniline (1 mmol)/HCO2H
(3 mmol)/ZnO (0.5 mmol)
aniline (1 mmol)/HCO2H
(3 mmol)/ZnO (0.25 mmol)
aniline (1 mmol)/HCO2H
(3 mmol)/ZnO (0. 5 mmol)
aniline (1 mmol)/HCO2H
(3 mmol)/ZnO (0.5 mmol)
aniline (1 mmol)/HCO2H
(3 mmol)/ZnO (0.5 mmol)
aniline (1 mmol)/HCO2H
(3 mmol)/ZnO (0.5 mmol)
aniline (1 mmol)/
48/70
trace
Department of Chemistry, Faculty of Science, Shiraz UniVersity,
2
3
none
none
none
none
none
none
DMF
CH2Cl2
3/70
50
90
5
Shiraz 71454, I.R., Iran
3/70
shashem@chem.susc.ac.ir; hossaini@susc.ac.ir
4
3/70
ReceiVed April 23, 2006
5
0.16/70
2/70
99
20
70
0
6
7
0.16/25
48/70
48/70
8
9
0
10
11
12
CH3CN 48/70
0
The treatment of amines with formic acid in the presence of
ZnO under solvent-free conditions brings about highly and
efficient N-formylation to give the corresponding formamides
in excellent yields. The N-formylation reaction not only
involves mild conditions, simple operation, and high yields
but also high chemoselectivity.
none
none
48/70
48/70
50
0
HCO2H (3 mmol)
aniline (1 mmol)/CH3CO2H
(3 mmol)/ZnO (0.5 mmol)
a Isolated yields.
atmospheric moisture and cannot be stored due to decomposition
to acetic acid and carbon monoxide. Many other useful form-
ylation reagents have been reported such as chloral,14 activated
formic acid using DCC,15 or EDCI,16 activated formic acid
esters,17-20 KF-Al2O3,21 ammonium formates,22 CDMT,23 solid-
supported reagents,24 and other reagents. Heating with ethyl or
phenyl formate seems a good procedure, but the method requires
very long times and high-temperature for completion.25 How-
ever, there are several factors in some cases limiting their
applications, for example, thermal instability, formation of by-
products, difficult accessibility to the preparation of the formy-
lating agents.
Formamides are a class of important intermediates in organic
synthesis. They have been widely used in the synthesis of
pharmaceutically important compounds such as fluoroquino-
lines,1 substituted aryl imidazoles,2 1,2-dihydroquinolines,3
nitrogen-bridged heterocycles,4 etc. Formamides are Lewis
bases, which are known to catalyze reactions such as allylation5
and hydrosilylation6 of carbonyl compounds. More recently,
asymmetric allylation of aldehydes has been achieved with chiral
formamides.7 Furthermore, formamides are very useful reagents
in Vilsmeier formylation reactions.8 In addition, and they have
been used in the synthesis of formamidines9 and isocyanides.
More over, the formyl group is a useful amino-protecting group
in peptide synthesis10 and N-formylamino acid esters can, for
example, serve as starting materials for peptide synthesis.11
A number of formylation methods have been reported in
recent years. Acetic formic anhydride12,13 continues to be the
most widely used formylating reagent, but it is sensitive to
In recent years, the use of inorganic solid oxides as catalysts,
reagents, and reaction media has received considerable attention
(11) Floresheimer, A.; Kula, M. R. Monatsh. Chem. 1988, 119, 1323.
(12) (a) Green, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley-Interscience: New York, 1999. (b) Sheehan, J.
C.; Yang, D. D. H. J. Am. Chem. Soc. 1958, 80, 1154.
(13) Strazzolini, P.; Giumanini, A. G.; Cauci, S. Tetrahedron 1990, 46,
1081.
(14) Blicke, F. F.; Lu, C.-J. J. Am. Chem. Soc. 1952, 74, 3933.
(15) Waki, J.; Meienhofer, J. J. Org. Chem. 1977, 42, 2019.
(16) Chen, F. M. F.; Benoiton, N. L. Synthesis 1979, 709.
(17) Yale, H. L. J. Org. Chem. 1971, 36, 3238.
(18) Kisfaludy, L.; Laszlo, O. Synthesis 1987, 510.
(19) Neveux, M.; Bruneaum, C.; Dixneuf, P. H. J. Chem. Soc., Perkin
Trans. 1 1991, 1197.
* To whom correspondence should be addressed. Tel: +98-711-2284822.
Fax: +98-711-2280926.
(1) Jackson, A.; Meth-Cohn, O. J. Chem. Soc., Chem. Commun. 1995,
1319.
(2) Chen, B.-C.; Bednarz, M. S.; Zhao, R.; Sundeen, J. E.; Chen, P.;
Shen, Z.; Skoumbourdis, A. P.; Barrish, J. C. Tetrahedron Lett. 2000, 41,
5453.
(3) Kobayashi, K.; Nagato, S.; Kawakita, M.; Morikawa, O.; Konishi,
H. Chem. Lett. 1995, 575.
(4) Kakehi, A.; Ito, S.; Hayashi, S.; Fujii, T. Bull. Chem. Soc. Jpn. 1995,
68, 3573.
(5) Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620.
(6) Kobayashi, S.; Yasuda, M.; Hachiya, I. Chem. Lett. 1996, 407.
(7) Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y. Tetrahedron 1999,
55, 977.
(20) Duezek, W.; Deutsch, J.; Vieth, S.; Niclas, H.-J. Synthesis 1996,
37.
(21) Mihara, M.; Ishino, Y.; Minakata, S.; Komatsu, M. Synthesis 2003,
15, 2317.
(22) Reddy, P. G.; Kumar, G. D. K.; Baskaran, S. Tetrahedron 2000,
41, 9149.
(8) Downie, I. M.; Earle, m. J.; Heaney, H.; Shuhaibar, K. F. Tetrahedron
1993, 49, 4015.
(9) Han, Y.; Cai, L. Tetrahedron Lett. 1997, 38, 5423.
(10) Martinez, J.; Laur, J. Synthesis 1982, 979.
(23) Luca, L. D.; Giacomelli, g.; Porcheddu, A.; Salaris, M. Synlett 2004,
14, 2570.
(24) Desai, B. Danks, T. N.; Wagner, G. Tetrahedron Lett. 2005, 955.
(25) Schmidhammer, H.; Brossi, A. Can. J. Chem. 1982, 60, 3055.
10.1021/jo060847z CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/28/2006
6652
J. Org. Chem. 2006, 71, 6652-6654

TABLE 2. ZnO-Catalyzed N-Formylation of Amines
a Yields are the isolated compounds. b Reaction was recorded on 100 mmol scale.
because of their high level of chemo selectivity and environ-
mental compatibility as well as simplicity of operation and their
use of availability at low cost. Thus, a number of heterogeneous
reactions using inorganic oxides such as SiO2, Al2O3, clay,
zeolite, etc. have already been reported.26
In particular, zinc oxide (ZnO) as such is an important
material with wide range of applications. This particular catalyst
with high specific surface area make it a potential candidate
especially for a wide range of applications.27 We now report a
practical formylation procedure using formic acid in the presence
of ZnO as a new catalyst. The reaction of amines with formic
acid first appeared in 1955.28 Fieser reported that N-methyla-
niline reacted with formic acid to give N-methylformanilide.
Recently, Choi and co-workers29 have reexamined this method
using aqueous 85% formic acid. However, this method needed
to use a large amount of solvent with a Dean-Stark trap under
reflux conditions and involve longer reaction times. We have
(27) (a) Hosseini Sarvari, M.; Sharghi, H. J. Org. Chem. 2004, 69, 6953.
(b) Sharghi, H.; Hosseini Sarvari, M. Synthesis 2002, 8, 1057. (c) Hosseini
Sarvari, M. Synthesis 2005, 5, 787. (d) Hosseini Sarvari, M. Sharghi, H.
Tetrahedron 2005, 61, 10903. (e) Kim, Y. J.; Varma, R. S.; Tetrahedron
Lett. 2004, 45, 7205.
(28) Fieser, L. F.; Jones, J. E. Organic Syntheses; Wiley: New York,
1955; Collect. Vol. III, p 590.
(26) Mihara, M.; Ishino, Y.; Minakata, S.; Komatsu, M. Synlett 2002,
1526.
(29) Jung, S. H.; Ahn, J. H.; Park, S. K., Choi, J.-K. Bull. Korean Chem.
Soc. 2002, 23, 149.
J. Org. Chem, Vol. 71, No. 17, 2006 6653

TABLE 3. Reuse of ZnO
extended this method as a general procedure which accom-
modates practicality and functionality. The method can also be
carried out under solvent-free conditions, impressing that the
catalyst (ZnO) is reusable.
As shown in Table 1, the reaction of aniline as a model
compound with formic acid was examined under various
reaction conditions. The use of excess formic acid provided only
a trace amount of the desired product (entry 1). When the
amount of formic acid was reduced the yields were dramatically
increased (entries 2 and 3). The effect of solvents was also
studied. No product was detected in any solvents (entries 8-10).
The best results were obtained with 3 mmol of formic acid in
solvent-free conditions using 0.5 mmol of ZnO as catalyst (entry
5). On the basis of these preliminary results, the application of
this procedure to various amines was investigated. The results
are summarized in Table 2.
Aromatic and aliphatic primary and secondary amines can
react with formic acid. For a variety of amines, e.g., hindered
amines (entries 24, 25), heterocyclic amines (entries 22, 23, 27,
and 32), and a diamine (entry 23), the reaction shows good
results without any significant influence of their structures on
the product yields. Reactions of aromatic amines bearing both
electron-donating and -withdrawing groups proceed smoothly
to give the corresponding N-formyl compound in quantitative
yields (entries 1-21). The conversion of aniline into N-form-
ylaniline on a 100 mmol scale (entry 2) proceeds just as well
as the reaction on a 1 mmol scale. In comparison with other
previously methods, 4-nitroaniline (entry 16) was formylated
in 77% isolated yield using the present protocol but according
to the method reported by Choi and co-workers29 but did not
afford the same reaction. Primary amines are easily form-
ylated to provide formamide in short reaction time and high
yields. However, secondary amines need longer reaction times,
and the corresponding formamides are afforded in 60-75%
yields.
It is interesting to note that N-formylamino acid esters could
be obtained in good yields using the procedure outlined in this
report (entry 31). It is notable that the amino acid ester used is
not an optically active substrate. Also, entry 32 can survive in
the present method indicating the mildness of reactions, whereas
2-amino antraquinone (entry 33) remains inert under the
conditions.
O-Formylation of alcohol or phenol derivatives under these
reaction conditions was not successful. No reaction was observed
with phenol and alkyl alcohol (entries 29 and 30). It was found
that this reaction is chemoselective. This justifies that only
N-formylated product was formed with molecules containing
both the hydroxyl and amino groups (entries 10-13 and 28).
According to Table 2, the reaction of secondary amines with
formic acid is slow in comparison to those primary amines.
no. of uses
yield (%)
Recovery of ZnO
1
2
3
90
86
84
96
90
90
Indeed, a mixture of primary and secondary amines furnishes
only the expected formanilide 1 on reaction with 1 mmol of
formic acid (entry 34).
Furthermore, catalytic activity of the recovered catalyst (ZnO)
was examined. As shown in Table 3, the yields of N-form-
ylaniline after two and three reuses of the catalyst were almost
the same as that in the first use. In every case, almost >90% of
the ZnO was easily recovered from reaction mixture by simple
washing with dichloromethane.
In conclusion, we have developed a novel and highly efficient
solvent-free protocol for N-formylation of amines using non-
toxic, inexpensive, and biocompatible ZnO powder. The ad-
vantages of this environmentally benign and safe protocol
include a simple reaction setup, not requiring specialized equip-
ment, very mild reaction conditions, high product yields, short
reaction times, the possibility for reusing the catalyst, chemose-
lectivity, and solvent-free conditions.
Experimental Section
General Procedure. To a mixture of HCO2H (3 mmol, 0.11
mL) and ZnO (0.5 mmol, 0.04 g) was added an amine (1 mmol),
and then the reaction mixture was heated in an oil bath at 70 °C
and stirred with a magnetic stirrer. The progress of the reaction
was monitored by TLC. After the reaction was complete, CH2Cl2
or EtOAc was added to the reaction mixture, and ZnO was removed
by filtration. The organic solvent was then washed with H2O (2 ×
10 mL) and a saturated solution of NaHCO3 and dried over
anhydrous Na2SO4. After removal of the solvent, the pure product
was obtained. This was further purified by recrystallization with
suitable solvent (ether or CHCl3). The structure of the products
1
was confirmed by H NMR, IR, and comparison with authentic
samples obtained commercially or prepared by reported methods.
Acknowledgment. We gratefully acknowledge the support
of this work by the Shiraz University Research Council and
Professor M. H. Ghatee for his helpful comments.
Supporting Information Available: Complete experimental
procedure and relevant spectra (13C and H NMR spectra) for all
1
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO060847Z
6654 J. Org. Chem., Vol. 71, No. 17, 2006