Formylation of amines catalysed by protic ionic liquids under solvent-free condition

Article abstract of DOI:10.1016/j.tetlet.2012.11.017

A fast, efficient and simple route for the N-formylation of amines has been developed by treating amines with 85% formic acid at 70°C in the presence of 5 mol % of protic ionic liquid as catalyst under solvent-free condition. This method provides a green and much improved protocol over the existing methods.

Full text of DOI:10.1016/j.tetlet.2012.11.017

Tetrahedron Letters 54 (2013) 262–266
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Formylation of amines catalysed by protic ionic liquids under
solvent-free condition
a,
⇑
a
a
b
Swapan Majumdar , Jhinuk De , Jewel Hossain , Ajoy Basak
a
Department of Chemistry, Tripura University, Suryamaninagar 799 022, India
Chronic Disease Program, Regional Protein Chemistry Center, OHRI, 725 Parkdale Avenue, Ottawa, ON, Canada K1Y 4E9
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A fast, efficient and simple route for the N-formylation of amines has been developed by treating amines
with 85% formic acid at 70 °C in the presence of 5 mol % of protic ionic liquid as catalyst under solvent-
free condition. This method provides a green and much improved protocol over the existing methods.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 23 August 2012
Revised 1 November 2012
Accepted 3 November 2012
Available online xxxx
Keywords:
Amine
Protic ionic liquid
N-formylation
Formamides
Catalysis
Formic acid
Formyl group is the one of the most useful and versatile protect-
ing group for the protection of amine functionality in organic
molecules. Formamides are important intermediates in the prep-
reagents and generation of hazardous bi-products. Thus pursuit
of more convenient, mild, high yielding, inexpensive catalysts
which have no or minimal harmful effect on our environment still
remains an active area of research. In this context, much attention
has been focused on organic reactions promoted by room temper-
ature ionic liquids as a useful alternative to conventional organic
solvents or catalysts due to their particular properties, such as neg-
ligible vapour pressure, chemical stability, excellent solvation and
1
aration of amine derivatives and have been widely used in the syn-
thesis of many fine chemicals and pharmaceutically valuable
2
compounds. They are also important precursors for isocyanide
preparation, formamidine synthesis,5 catalyst for allylation and
3,4
6
hydrosilylation of carbonyls. In addition, formyl group is used
7
22
for the protection of the amino group during peptide synthesis.
coordination power for organic and inorganic compounds.
In view of these potential applications of N-formyl derivative of
Formylation of N-methyl aniline by formic acid was first reported
2
3
amines, a large number of formylating methods have been re-
by Fieser in 1955. Recently, other research groups have re-exam-
ined this method using formic acid/toluene with Dean–Stark trap
8
ported which include chloral, formic acid with activating agents
3
9
10
11
18
such as DCC or EDCI, activated formic esters, ethyl formate,
under reflux conditions and heated under closed (sealed) condi-
1
2
13
21
ammonium formate, acetic formic anhydride, formic acid with
activated zinc or ZnO, [TMG] , solid supported reagents and
recently by formic acid under azeotropic removal of water with
toluene. Polyethylene glycol has also been reported as a medium
for formylation of aniline derivatives with formic acid. Very
recently the formylation using ZnCl , FeCl , AlCl and NiCl has
been reported. Direct formylations using formic acid in sealed
tube without any additional solvent and catalyst have also been
reported. Despite the usefulness of these methods, many of them
suffer from serious drawbacks such as a longer reaction time, use
of high temperature, moisture sensitive, expensive and toxic
tions. As a part of our ongoing research programme towards the
1
4
15
+ 16
17
development of new synthetic methodology, we have extended
this method as a solvent-less general procedure promoted by imi-
dazolium based protic ionic liquid which adopted operational
simplicity.
1
8
19
2
3
3
2
Protic ionic liquids (pILs) are a class of ionic liquids that are
formed by mixing strictly equimolar amounts (1:1) of Brønsted
acids and bases. The strength of the acid/base combination deter-
mines the degree to which the acidic proton is transferred to the
proton activity. This tuneable parameter has been used previously
to probe the suitability of pILs to carry out organic transforma-
2
0
2
1
2
4
tions. Amongst the various protic ionic liquids, we were particu-
larly interested in N-substituted imidazolium trifluoroacetate
based ionic liquids because of their easy accessibility, stability
and low viscosity. Thus, five structurally related imidazolium and
⇑
Corresponding author. Fax: +91 3812374802.
E-mail address: smajumdar@tripurauniv.in (S. Majumdar).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.017

S. Majumdar et al. / Tetrahedron Letters 54 (2013) 262–266
263
H
H
H
H
H
-
CF COO-
N
CF COO-
p-TsO-
N
CF COO-
N
N
CF COO
N
3
3
3
3
+
+
+
+
+
N
N
N
N
N
I
II
III
IV
V
Me
Bu
Bu
Me
Bu
Figure 1. Structurally related imidazolium based protic ionic liquids.
Table 1
Optimization of reaction conditions for the N-formylation of benzyl amine catalysed by protic ionic liquid under solvent free condition
8
5% HCOOH
NH2
NHCHO
PIL, 70°C, time
Entry
Benzyl amine (mmol)
HCOOH (equiv)
Ionic liquid
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
10
1.0
100
1.4
7.0
14
1.4
1.4
1.4
1.4
1.4
1.4
1.4
I, 10 mmol
I, 10 mmol
I, 10 mmol
I, 10 mol %
I, 5 mol %
II, 5 mol %
III, 5 mol %
IV, 5 mol %
V, 5 mol %
III, 5 mol %
20
90
360
60
60
60
60
60
120
60
92
76
52
89
92
93
95
94
56
96
1
0
Table 2
Solvent less formylation of amines with 85% formic acid in the presence of 5 mol % of protic ionic liquid III
Entry
Substrate
Time (h)
Product
Yield (%) Ref.
9619
1
1
NH2
1 NHCHO
NH2
NHCHO
9719
9220
2
3
1
2
2
NH2
NH2
3 NHCHO
NHCHO
4
4
2
9619
NH2
NHCHO
9719
9634
5
6
2
2
5
Ph
N
H
Ph
N
6
CHO
Ph
Ph
Ph
Ph
7
8
NH
NH2
1.5
2
N
CHO
9327
9828
7
NHCHO
8
NH2
NH2
N
9
1
9229
N
H
9
N
N
1
0
2.5
5016
8030
N
N
CHO
1
0
H
HO C
NH2
HO C
NHCHO
1
1
1
1
2
2
3
2
2
1
8431
N
NH2
N
NHCHO
1
2
(
continued on next page)

2
64
S. Majumdar et al. / Tetrahedron Letters 54 (2013) 262–266
Table 2 (continued)
Entry
Substrate
Time (h)
4
Product
Yield (%) Ref.
7919
O N
2
NH2
O N
2
NHCHO
1
1
3
4
1
3
Ph
N
Ph
Ph
N
H
2
3
CHO
8219
Ph 14
N
1
5
6
No reaction
—
N
H
1
3
No reaction
No reaction
—
N
H
1
1
7
8
OH
OH
3
1
—
OCHO
9132
15
(
)10 OH
CHO
( )1
0 O
1
9
0
1
2
9633
—
16
OH
2
A complex mixture was formed
No reaction
O
Ph
2
2
1
2
3
1
—
Ph
OH
CO Me
CO Me
2
2
9526
NH2
NHCHO
17
OBn
OBn
N
N
CHO
2
3
1
7318
H
O
O
1
8
benzimidazolium based ionic liquids (Fig. 1; I–V) were prepared
with or without ionic liquid catalyst. On the basis of these preli-
minary results, application of this procedure to the formylation
of other amines was investigated. The results are summarized in
Table 2.
Aliphatic and aromatic primary or secondary amines react with
formic acid under this protocol. For a variety of amines, for exam-
ple, hindered amines, heterocyclic amines or diamines the reaction
shows good results without any significant influence of their struc-
tures on the yields (Table 2, entries 1–10). Interestingly, aromatic
diamine, o-phenylene diamine did not produce mono or di-formy-
lated products; instead it gave benzimidazole in 92% yield (Table 2,
according to the procedure described in the literature25 for the
2
activation of formic acid (HCO H) and allowed for the formylation
of amino compounds. In order to determine the optimum reaction
conditions, N-formylation of benzyl amine with formic acid was
chosen as model reaction (Table 1). Thus, benzyl amine was al-
lowed to react with 85% formic acid (1.4 equiv) and equimolar
amount of ionic liquid IL-I at 70 °C, the reaction was completed
(
as judged by TLC) within 20 min and the corresponding N-formyl
benzyl amine was isolated in 92% yield (Table 1, entry 1). It was
also found that the stoichiometry of the formic acid used is critical.
The use of excess formic acid under the same reaction condition re-
quires a longer time to complete and yield of the product also falls
down dramatically (Table 1, entries 2 and 3). Almost similar yield
of the formylation product was obtained when catalytic amount of
IL-1 was employed but it required a longer time (20 vs 60 min) (Ta-
ble 1, entries 4 and 5). Finally, we found that the use of 5 mol % of
ionic liquids (I–IV) gives marginal differences in yield (Table 1, en-
tries 5–8), amongst them IL-III has been found to give the best re-
sults (Table 1, entry 7). The ionic liquid prepared from the reaction
between substituted imidazole and p-toluene sulfonic acid2 (IL-V)
gives only 56% of the desired formylated product (Table 1, entry 9).
Again, 96% yield of the formylated product of benzyl amine was
also accomplished when the reaction was carried out in 100 mmol
scale under the same condition (Table 1, entry 10). It is worthy to
mention that the reaction was unsuccessful at room temperature
HCOOH
RNHCHO
IL
IL
H2O
IL
O
-
δ
O
+
δ
OH
H
H
OH2
NHR
5
IL
O
RNH2
H
OH
NH2R
Figure 2. Catalytic cycle of protic ionic liquid promoted formylation of amines.

S. Majumdar et al. / Tetrahedron Letters 54 (2013) 262–266
265
Table 3
Protic ionic liquid promoted acetylation of amines by acetic acid
Entry
Substrate
Acylating agent
Time (h)
Product
Yield (%)
1
2
3
4
Aniline
1.2 equiv AcOH
1.2 equiv AcOH
1.2 equiv AcOH
1.2 equiv AcOH
6
8
4
8
N-Acetyl aniline
92
92
92
80
p-Toluidine
Benzylamine
4-Aminophenol
N-Acetyl p-toluidine
N-Acetyl benzylamine
4-N-Acetylaminophenol
entry 9). The addition of excess amount of formic acid did not
change the mode of the reaction. Indeed this has been proven by
carrying out a separate reaction with benzimidazole and formic
acid under the same protocol (Table 2, entry 15). Aromatic amines
bearing electron releasing group provided better results than the
aromatics containing electron withdrawing groups (Table 2, en-
tries 11–13). We also observed that the electronic factor plays an
important role on the outcome of the reaction than the steric fac-
tor. Probably, this is the reason why 4-amino benzoic acid or 4-ni-
tro aniline took a longer reaction time whereas, benzimidazole or
carbazole is completely inert (Table 2, entries 15 and 16). O-formy-
lation of phenol (Table 2, entry 17) under this reaction conditions
was not successful. Primary alcohols, for example, benzyl alcohol
and lauryl alcohol smoothly gave the corresponding O-formylated
product in 91% and 96% yields respectively (Table 2, entries 18 and
ious functional groups are the advantages of the present procedure.
To the best of our knowledge, this is the first report of N-formyla-
tion using formic acid with very low loading (as low as 5 mol %) of
protic ionic liquid as catalyst.
Acknowledgments
S.M. is thankful to the Department of Science and Technology
(
2
DST), Govt. of India for financial support (Grant No.SR/S1/OC-49/
010). S.M. and A.B. are also thankful to the Canadian Institute
for Health Research, Canada for partial financial support under
CANADA-HOPE fellowship programme. Thanks are also due to
Mr. S. Chowdhury, IICB, Kolkata for mass spectral data and CAS,
University of Calcutta for NMR analysis.
1
9). Cinnamyl alcohol or benzoin failed to produce O-formylated
References and notes
products (Table 2, entries 20 and 21). In the case of cinnamyl alco-
hol an unidentified complex mixture was formed which was diffi-
cult to purify. We have also applied our method to the synthesis of
N-formyl amino acid esters, which serve as starting materials for
peptide synthesis. It is interesting to note that the formylation of
1.
(a) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; Wiley
Inter-Science: New York, 1999; (b) Sheehan, J. C.; Yang, D. D. H. J. Am. Chem. Soc.
1958, 80, 1154.
2.
(a) Chen, B.-C.; Bendarz, M. S.; Zhao, R.; Sundeen, J. E.; Chen, P.; Shen, Z.;
Skoum-bourdis, A. P.; Barrish, J. C. Tetrahedron Lett. 2000, 41, 5453; (b)
Kobayashi, K.; Nagato, S.; Kawakita, M.; Morikawa, O.; Konishi, H. Org. Synth.
Coll. 1995, 575; (c) Jackson, A.; Meth-Cohn, O. J. Chem. Soc., Chem. Commun.
a
-amino acid esters was readily achieved using the present meth-
od without cleavage of the methyl or benzyl ester functional
groups (Table 2, entries 22 and 23). We could not detect any sign
of epimerization because of optical rotations compared well with
the literature data indicating that chiral centre is not affected dur-
1995, 1, 1319.
3.
(a) Waki, J.; Meienhofer, J. J. Org. Chem. 1977, 42, 2019; (b) Ugi, I. Angew. Chem.,
Int. Ed. Engl. 1982, 21, 810.
4. Schollkopf, U. Angew. Chem., Int. Ed. Engl. 1977, 16, 339.
5
6
.
.
Han, Y.; Cai, L. Tetrahedron Lett. 1997, 38, 5423.
ing the reaction. Thus L-leucine methyl ester was formylated to
(a) Iseki, K.; Mizuno, S.; Kuroki, Y.; Kobayashi, Y. Tetrahedron 1999, 55, 977; (b)
Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620; (c) Kobayashi, S.; Yasuda,
M.; Hachiya, I. Org. Synth. Coll. 1996, 407.
give N-formyl compound without racemization in 95% yield {½ ꢀ
a
D
ꢁ
41.65 (c 1.2, EtOH), lit26 ꢁ43.2 (c 1.2, EtOH)}. Similarly,
L-proline
7.
(a) Martinez, J.; Laur, J. Synthesis 1982, 979; (b) Floresheimer, A.; Kula, M. R.
Monatsh. Chem. 1988, 119, 1323.
benzyl ester was also formylated to give N-formyl L-proline benzyl
18
ester in 73% yield {½ ꢀ ꢁ47.0 (c 3, MeOH), lit ꢁ47.3 (c 3, MeOH)}.
a
D
8. Blicke, F. F.; Lu, C.-J. J. Am. Chem. Soc. 1952, 74, 3933.
9. Chen, F. M. F.; Benoiton, N. L. Synthesis 1979, 709.
A plausible mechanism for the reaction is shown in Figure 2.
First step is the activation of carbonyl of formic acid by the coordi-
nation of ionic liquid which acts as Lewis acid followed by the
nucleophilic attack by amine on the carbonyl carbon. The proton-
ation and subsequent dehydration produce formamide and regen-
erate catalyst. The role of IL as powerful activator was confirmed
by the fact that the relatively less reactive primary alcohols partic-
ipated in the nucleophilic addition reaction (Table 2, entries 18 and
10. (a) Yale, H. L. J. Org. Chem. 1971, 36, 3238; (b) Kisfaludy, L.; Laszlo, O. Synthesis
1
1
987, 510; (c) Neveux, M.; Bruneau, C.; Dixneuf, P. H. J. Chem. Soc., Perkin Trans. 1
991, 1197; (d) Duczek, W.; Deutsch, J.; Vieth, S.; Niclas, H.-J. Synthesis 1996, 37.
11. Schmidhammer, H.; Brossi, A. Can. J. Chem. 1982, 60, 3055.
12. Reddy, P. G.; Kumar, G. D. K.; Baskaran, S. Tetrahedron Lett. 2000, 41, 9149.
13. Strazzolini, P.; Giumanini, A. G.; Cauci, S. Tetrahedron 1990, 46, 1081.
14. Kim, J.-G.; Jang, D. O. Bull. Korean Chem. Soc. 2010, 31, 2989.
15. Hosseni-Sarvari, M.; Sharghi, H. J. Org. Chem. 2006, 71, 6652.
1
1
1
6. Akbari, J.; Hekmati, M.; Sheykhan, M.; Heydari, A. ARKIVOC 2009, xi, 123.
7. Desai, B.; Danks, T. N.; Wagner, G. Tetrahedron Lett. 2005, 955.
8. Jung, S. H.; Ahn, J. H.; Park, S. K.; Choi, J. K. Bull. Korean Chem. Soc. 2002, 23, 149.
1
9). The activation of acid carbonyl by the protic ionic liquid is fur-
ther attributed to the fact that the primary amines- aromatic or ali-
phatic undergo smooth acetylation under the same condition using
acetic acid as acylating agent. Aniline, p-toluidine and benzylamine
gave 92% yield after crystallization (Table 3, entries 1 and 3)
whereas 4-amino phenol gave 70% of the corresponding N-acetyl
derivative in 80% yield, (Table 3, entry 4). The reason for the inert-
ness of benzimidazole, carbazole, phenol and benzoin (intramolec-
ular hydrogen bonded) towards this formylation reaction is not
clear at this moment but we speculate that due to the strong polar-
ization of N–H or O–H bonds, protic ionic liquid may act as mask-
ing agent which makes amines/phenols or strong H-bonded
alcohol non-nucleophilic.
19. Das, B.; Krishnaiah, M.; Balasubramanyam, P.; Veeranjaneyulu, B.;
Nandakumar, D. Tetrahedron Lett. 2008, 49, 2225.
20. Chandra Shekhar, A.; Ravi Kumar, A.; Sathaiah, G.; Luke Paul, V.; Sridhar, M.;
Shanthan Rao, P. Tetrahedron Lett. 2009, 50, 7099.
21. Rahman, M.; Kundu, D.; Hajra, A.; Majee, A. Tetrahedron Lett. 2010, 51, 2896.
22. (a) Welton, T. Chem. Rev. 1999, 99, 2071; (b) Wasserscheid, P.; Keim, W. Angew.
Chem., Int. Ed. 2000, 39, 3772; (c) Wilkes, J. S. Green Chem. 2002, 4, 73; (d)
Parvulescu, V. I.; Hardacre, C. Chem. Rev. 2007, 107, 2615.
2
3. Fieser, L. F.; Jones, J. E. Org. Synth. Coll. 1955, III, 590.
24. (a) Jain, N.; Kumar, A.; Chauhan, S.; Chauhan, S. M. S. Tetrahedron 2005, 61,
015; (b) Park, S.; Kazlauskas, J. Curr. Opin. Biotechnol. 2003, 14, 432.
5. (a) Zhao, G.; Jiang, T.; Gao, H.; Han, B.; Huang, J.; Sun, D. Green Chem. 2004, 6,
5; (b) Chen, S.-H.; Zhao, Q.; Xu, X.-W. J. Chem. Sci. 2008, 120, 481.
26. Chancellor, T.; Morton, C. Synthesis 1994, 1023.
1
2
7
2
2
7. Henbest, H. B.; Thomas, A. J. Chem. Soc. 1967, 3032.
8. Ugi, I.; Fetzer, U.; Eholzer, U.; Knupfer, H.; Offermann, K. Angew. Chem., Int. Ed.
Engl. 1965, 4, 472–484.
In conclusion, we believe that the present method is a simple,
novel and highly efficient protocol for the N-formylation of amines.
Operational simplicity, solvent-free media, mild reaction condi-
tions, eco-friendly reaction media and the compatibility with var-
29. Wagner, E. C.; Millet, W. H. Org. Synth. Coll. 1943, 2, 65.
3
3
0. Rho, K. Y.; Cho, Y. J.; Yoon, C. M.; Nakamura, H. Tetrahedron Lett. 1999, 40, 4821.
1. Comins, D.; Meyers, A. Synthesis 1978, 403.

2
3
66
S. Majumdar et al. / Tetrahedron Letters 54 (2013) 262–266
2. Shirini, F.; Zolfigol, M. A.; Abedini, M.; Salehi, P. Bull. Korean Chem. Soc. 2003, 24,
683.
in the product) by elution with diethyl ether. The evaporation of the solvent
under reduced pressure, dried under high vacuum afforded light yellowish
sticky solid. The identity of the products was confirmed by IR, 1H, C NMR and
1
13
3
3
3. Park, H. J.; Lee, J. C. Bull. Korean Chem. Soc. 2008, 29, 856.
4. General experimental procedure: To a magnetically stirred mixture of HCO
2
H
mass spectroscopy. Compound 6: IR (neat)
1261 cm ; H NMR (CDCl
3
m
2965, 1639, 1552, 1413,
, 300 MHz) d 8.20 and 8.09 (two s, 1H, –CHO),
7.22–7.07 (m, 5H, aromatic H), 5.70–5.50 (m, 1H, –CH@), 5.15–5.02 (m, 2H,
CH @), 4.40 and 4.25 (two s, 2H, –CH –Ph), 3.73 (d, 1H, J = 6.0 Hz) and 3.60 (d,
1H, J = 5.7 Hz); C NMR (CDCl , 75 MHz) d 163.0 and 162.3, 136.2 and 135.8,
132.9 and 131.8, 129.2, 128.9, 128.7, 128.4, 127.6, 118.8 and 118.4, 50.4 and
ꢁ
1
1
(
0.76 g, 14 mmol, 85%) and IL-III (126 mg, 0.5 mmol) was added N-allyl-N-
benzyl amine (1.470 g, 10 mmol, Table 2, entry 6) and then the reaction
mixture was heated in an oil bath at 70 °C. The progress of the reaction was
monitored by TLC. After completion of reaction, the mixture was diluted with
water (10 ml) and extracted with ether (10 ml ꢂ3). The combined organic layer
2
2
13
3
+
+
was washed with brine, dried over anhydrous Na
2
SO
4
and evaporated to give
50.1, 44.9 and 44.0; EI MS (m/z) 175 (M ), 134 (M ꢁ41); 106, 91, 79; HRMS
Calcd for C11 13NO 175.0997. Found 175.0980.
residue under reduced pressure. The crude product was passed through a short
pad silica-gel column (in order to remove any trace amount of ionic liquid left
H