Formylation of amines through catalyst- and solvent-free transamidation reaction

Article abstract of DOI:10.1016/j.tetlet.2013.11.029

The transamidation between formamide and various amines proceeds under heating, without any catalyst nor solvent, providing thus green and neutral conditions for the formylation of primary and secondary amines. The resulting amide product can be directly transformed, in a one pot sequence, into monomethylamine.

Full text of DOI:10.1016/j.tetlet.2013.11.029

Accepted Manuscript
Formylation of Amines through Catalyst- and Solvent-free Transamidation Re-
action
Thomas Lebleu, Hiyoshizo Kotsuki, Jacques Maddaluno, Julien Legros
PII:
S0040-4039(13)01965-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.11.029
TETL 43824
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 October 2013
5 November 2013
8 November 2013
Please cite this article as: Lebleu, T., Kotsuki, H., Maddaluno, J., Legros, J., Formylationof Aminesthrough Catalyst-
and Solvent-free Transamidation Reaction, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.
2013.11.029
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Formylation of Amines through Catalyst-
and Solvent-free Transamidation Reaction
Leave this area blank for abstract info.
Thomas Lebleu, Hiyoshizo Kotsuki, Jacques Maddaluno and Julien Legros
D
NO CATALYST
NO SOLVENT
- aliphatic, benzylic, aromatic
- primary, secondary

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Formylation of Amines through Catalyst- and Solvent-free Transamidation Reaction
Thomas Lebleua, Hiyoshizo Kotsukib, Jacques Maddalunoa and Julien Legrosa,
a Normandie Univ, COBRA UMR 6014; Univ Rouen, INSA Rouen and CNRS, 1 rue Lucien Tesnière, 76821 Mont-Saint‐ Aignan, France
b Laboratory of Natural Products Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi, 780-8520, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The transamidation between formamide and various amines proceeds under heating, without any
catalyst nor solvent, providing thus green and neutral conditions for the formylation of primary
and secondary amines. The resulting amide product can be directly transformed, in a one pot
sequence, into monomethylamine.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Amide
Neat conditions
Green chemistry
High pressure
Monomethylation
The formyl moiety (-CHO) is one of the simplest group that
can be used to protect an amine function,1 and the resulting
formamides may serve as isocyanate precursors.2 Among all the
methods available for this purpose, reaction between amines and
the inexpensive formamide HC(O)NH2 offers, in theory, a very
interesting way since ammonia is the only effluent produced.
Unfortunately in practice transamidation processes remained
exhibits interesting H-bonding properties, the yield in
transamidation product dropped to 30% (entry 3). Surprisingly,
performing the reaction in water at 80 °C under ambient
atmosphere gave a very good 82% yield (entry 4), while the
conversion was still low under the same conditions in ethanol
(30%, entry 5), showing thus the unique role of water in this
reaction. However, the best result was obtained by performing
the reaction without any solvent at 80 °C, allowing thus almost
full conversion into the target product (97%, entry 6).
unattractive for
a long time due to the harsh conditions
systematically required.3,4 However, some friendlier protocols
have recently emerged to promote these reactions by mean of
catalysts under heating (30-150 °C) for several hours (5-36 h):
Cp2ZrCl2,5 L-proline,6 B(OCH2CF3)3,7 boric acid with water8 and
hydroxylamine hydrochloride.9,10 In these two latter cases,
authors suggested that an hydrogen bonding activation of the
starting amide by the catalysts B(OH)3 and HO-NH2HCl was a
key point of the reaction success.8,9 In this line, water is a
molecule that exhibits both excellent H-bonding donation and
acceptance ability, and could thus be used as solvent to promote
formyl transfer from formamide (1.3 eq) to benzylamine (Table
1). At room temperature, the reaction proceeded very slowly to
afford, after 4 days, 1a as single product in only 37% yield (entry
1). Encouraged by this result and by previous works on the
beneficial effects of hyperbaric conditions on the kinetics of
organic reactions in water,11,12 this transamidation reaction was
assessed under ultra-high pressure conditions. Thus, by
increasing the pressure to 5 kbars, the reaction was significantly
accelerated and 1a was obtained in 66% yield within only 24 h,
still at room temperature (entry 2). However, when the same
reaction was performed in ethanol (20 °C, 5 kbars), which also
———
Table 1
Transamidation between benzylamine and formamidea
Entry
Solvent
H2O
P (bars)
T (°C)
20
t (h)
96
24
24
24
24
24
Yield (%)b
1
2
3
4
5
6
1
37
66
30
82
33
97
5000
20
EtOH
H2O
5000
20
1
1
1
80
EtOH
neat
80
80
a Conditions: benzylamine (1 mmol), formamide (1.3 mmol), solvent (0.7
mL).
b 1H NMR yield
 Corresponding author. Tel.: +33-2-35-52-29-06; e-mail: julien.legros@univ-rouen.fr

2
Tetrahedron
These preliminary experiments show that water is a very
monomethylamines in a one-pot fashion.
Table 2
good solvent for the formylation of benzylamine with a slight
excess of HC(O)NH2 (1.3 eq) under pressure or thermal
activation, but best results were obtained just by performing this
transformation neat at 80 °C. The scope of the reaction was then
studied with various amines at 80 °C, without any solvent, and
with an improved amount of formamide (1.0 eq). Results are
presented in Table 2.
Formylation of amines under solvent-free conditionsa
Yield
(%)b
Entry RR’NH
T (°C) t (h) Product
Under these conditions, N-formyl benzylamine 1a was isolated
in 82% yield after 24 h (entry 1).13 The reaction was also
performed under microwave irradiation in a shorter reaction time
(3 h), but 1a was afforded in a lower yield (68%, entry 2). The
transformation was also successfully extended to 2-
(aminomethyl)-naphthalene (62% yield for 1b; entry 3) and 2-
(aminomethyl)-pyridine (96% yield for 1c; entry 4). The
formylation of ±-α-methylbenzylamine was more difficult with
72 h at 120 °C (66% yield for 1d; entry 5). Moreover, aliphatic
amines cyclohexylamine and dodecylamine also underwent
effective formyl transfer (80% for 1e and 70% yield for 1f;
entries 6 and 7). The reaction of secondary amines is also
effective: morpholine and N-methylbenzylamine yielded the
desired products in good yields (72% for both 1g and 1h, entries
8 and 9). However, when starting from the bulky dibenzylamine,
several days were required to obtain 1i in 60% yield (entry 10).
Aromatic amine indoline was also successfuly transformed after
48 h at 80 °C (71% yield for 1j). Interestingly, with tryptamine as
substrate, the formyl moiety was exclusively transferred onto the
–NH2 without any formylation of the –NH (87% for 1k). As last
example, enantiopure L-valine ethyl ester gave the corresponding
N-formyl valinate 1l in excellent 92% yield with full preservation
of the optical purity (entry 13).14
1
80
80
24
3
82
68
BnNH2
2c
1a
3
4
2-(C10H7)CH2NH2
80
24
24
62
96
1b
3-(C5H4N)CH2NH2 80
1c
5
6
7
PhCH(Me)NH2
C6H11NH2
120 72
66
80
70
1d
80
80
36
31
1e
n-C12H25NH2
1f
Besides protection purpose, the transfer of a formyl moiety
onto an amine is also one of the surest way to selectively access
to the corresponding monomethylamine, since the secondary
formamide product can be fully reduced into monomethylamine
by mean of a hydride reactant.15 Since we have been able to
perform transamidation between simple formamide and amine in
stoichiometric amounts without solvent, we imagined that the
corresponding monomethylamine could be obtained in a one-pot
fashion without isolating the intermediate amide product. Thus,
benzylamine was reacted with formamide as reported in Table 1
(80 °C, 24 h), and the crude product 1a was dissolved in THF at
8
Morpholine
BnNHMe
Bn2NH
80
80
24
24
72
72
60
1g
9
1h
10
120 263
1i
0
°C and LiAlH4 was added to afford the expected
11
Indoline
80
80
48
71
monomethylamine 2a in 81% yield (Scheme 1).
1j
12
13
Tryptamine
24
24
87
91
1k
Scheme 1. One pot monomethylation of benzylamine
L-Valine ethyl ester 80
In conclusion, we have been able to implement simple
conditions for uncatalyzed transamidation reaction between
inexpensive formamide and amines: whereas a good conversion
was obtained with water as solvent under 5 kbars, best results
were attained under thermal heating without any solvent. By this
mean various primary and secondary amines (aliphatic, benzylic,
aromatic) have been succesfully formylated. Moreover, these
1l
a Starting from amine (3 mmol) and formamide (3 mmol).
b Isolated yields.
c Performed under microwave irradiation (200 W).
neutral
conditions
offers
a
convenient
access
to

3
Acknowledgments
Anne-Lise Dubois (undergraduate student ENS-Cachan/Univ.
Paris South) is gratefully acknowledged for her help. This project
was funded by the European INTERREG IV A France (Channel)
– England Cross-border Cooperation Programme AI-Chem, co-
financed by ERDF. The authors wish to thank the CNRS and
JSPS for financial support (2012-2013).
Supplementary Material
Supplementary data associated with this article can be found,
inthe online version, at
References and notes
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3 (a) Zaragoza-Dörwald, F.; von Kiedrowski, G. Synthesis 1988, 917-918; (b)
Miller, I. K. J. Polym. Sci. Part A 1976, 14, 1403-1417; (c) Beste, L. F.;
Houtz, R. C. J. Polym. Sci. 1952, 8, 395-407; (d) Smith, M. E.; Adkins,
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2013, DOI 10.1002/ejoc.201300573.
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J. M. J. Chem. Commun. 2012, 48, 11626–11628.
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13 Typical procedure: L-Valine ethyl ester hydrochloride (545 mg, 3mmol)
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extracted with dichloromethane, dried and the solvent evaporated under
vacuum. To the resulting L-valine ethyl ester was added the formamide
(120 µl, 3 mmol. The solution was stirred for 24 h at 80 ºC. The crude
product was washed with aq. HCl (2 M), extracted with dichloromethane,
dried and the solvent evaporated under vacuum to obtain a yellow oil
(91% yield), [α]D= −50º (20 ºC, c=2.0, H2O).
14 For a specific formylation of amino acid esters with DMF/imidazole, see:
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3952–3955.
15 Blicke, F. F.; Lu, C.-J. J. Am. Chem. Soc. 1952, 74, 3933–3934.

Formylation of Amines through Catalyst-
and Solvent-free Transamidation Reaction
Leave this area blank for abstract info.
Thomas Lebleu, Hiyoshizo Kotsuki, Jacques Maddaluno and Julien Legros