A new, simple procedure for the synthesis of formyl amides

Article abstract of DOI:10.1055/s-2004-834788

A simple and mild method for the N-formylation of amines and α-amino esters is described via reaction with 2-chloro-4,6-dimethoxy[1,3,5]triazine and formic acid. The reaction can be accelerated under microwave irradiation and yields the N-formyl species in high yields and without racemization in the case of optically active α-amino esters.

Full text of DOI:10.1055/s-2004-834788

LETTER
A
A New, Simple Procedure for the Synthesis of Formyl Amides
P
rocedure for th
i
e
Synt
d
hesis of Form
i
yl
A
m
a
ides De Luca, Giampaolo Giacomelli,* Andrea Porcheddu, Margherita Salaris
Dipartimento di Chimica, Università degli Studi di Sassari, Via Vienna 2, 07100 Sassari, Italy
Fax +39(079)229559; E-mail: ggp@ uniss.it
Received 30 July 2004
flux of the solvent (CH2Cl2) or under microwave irradia-
tion,20 using a self-tunable microwave synthesizer.
Abstract: A simple and mild method for the N-formylation of
amines and a-amino esters is described via reaction with 2-chloro-
4,6-dimethoxy[1,3,5]triazine and formic acid. The reaction can be
accelerated under microwave irradiation and yields the N-formyl
species in high yields and without racemization in the case of opti-
cally active a-amino esters.
The method allows the preparation of formyl amides in a
single step reaction. Thus, dry formic acid (1.0 equiv) and
the amine derivative (1.0 equiv) are treated with CDMT
(1.1 equiv), and dimethylamino pyridine (DMAP) as cat-
alyst (0.1 equiv), in CH2Cl2, followed by N-methylmor-
pholine (NMM, 1.1 equiv) in dichloromethane (method
A). Stirring is continued at reflux of the solvent until com-
plete conversion of the carboxylic acid (monitored by
TLC). The reaction mixture is then diluted with CH2Cl2
and then washed with aqueous HCl, water, aqueous
NaHCO3, and brine. The desired product is recovered in
pure form, simply by concentration of the organic extracts
at reduced pressure. The triazine by-product is easily re-
moved by this simple aqueous work-up. The reaction is
not fast and requires from five to 20 hours for completion
in most of the cases examined.
Key words: amines, formyl amides, cyanuric acid, formylamino
esters, microwave
The formylation of amines and alcohols is an important
reaction that is used in organic synthesis. Formamides are
a class of important intermediates that have been widely
used in synthesis of pharmaceutically important com-
pounds such as fluoroquinolones,1 substituted aryl imida-
zoles,2 1,2-dihydroquinolines,3 and nitrogen bridged
heterocycles.4 Moreover, the formyl group is a useful ami-
no-protecting group in peptide synthesis5 and N-formyl-
amino acid esters can, for example, serve as starting
materials for peptide synthesis6 and for conversion to iso-
cyano acids that are requested for the four-component
condensation methods7 or especially in enzymatic synthe-
sis in aqueous media.6
A number of formylating methods and formylating agents
have been reported even in recent years. N-Formyl amines
and in particular N-formyl amino acid esters can be ob-
tained from the corresponding amino derivatives by reac-
tion with formic acid and acetic anhydride,8 in situ formed
formic anhydride,9 chloral followed by elimination,10 am-
monium formate11 and other reagents.12–15 Heating with
ethyl or phenyl formate seems a good procedure, but the
method requires very long times and high temperature for
completion.16 However, there are several factors in some
cases limiting their applications, for example thermal in-
stability, formation of by-products, difficult accessibility
to the preparation of the formylating agents.
Scheme 1
With the goal of reducing the reaction times, we have
therefore checked the possibility to carry out the reactions
under microwave irradiation, using a self-tunable micro-
wave synthesizer. The MW experiments were performed
in a self-tuning single mode CEM DiscoverTM Focused
Synthesizer apparatus. The instrument continuously ad-
justs the applied wattage to maintain the desired tempera-
ture.
Reactions were performed using a flask equipped with a
reflux condenser mounted outside the apparatus. The
formylation was successfully carried out in CH2Cl2 under
microwave irradiation that gave high yields of the desired
formyl amides after 3–6 minutes (Scheme 1).
Recently, there was reported a synthesis of N-formyl ami-
no acid esters under mild conditions.17 The procedure, al-
though simple, required the use of cyanomethyl formate
that has to be prepared. Following our interest in the use
of [1,3,5]triazine derivatives in organic synthesis,18 we
report here a new simple and high yielding synthesis of
formyl amides from amines and amino acid esters that
uses 2-chloro-4,6-dimethoxy[1,3,5]triazine (CDMT)19 as
the coupling agent. The reaction can be conducted at re-
The procedure could be used directly on hydrochlorides of
amino acid methyl esters. In these cases, the hydrochlo-
ride has to be added with 1.1 equivalents of TEA, in order
to free the amino acid ester. Both the reactions carried out
according method A and that under microwave irradiation
(method B) furnished the formyl compounds in practical-
ly quantitative yields and conversions depending on the
structure of the starting amino compound (Table 1).
SYNLETT 2004, No. x, pp 000A–000C
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Advanced online publication: xx.xx.2004
DOI: 10.1055/s-2004-834788; Art ID: G30004ST
© Georg Thieme Verlag Stuttgart · New York

B
L. De Luca et al.
LETTER
Table 1 N-Formylation of Amines and a-Amino Acid Esters (Scheme 1)
Run
1
Compound
Pyrrolidine
Method
Conditions
Yield (%)
A
B
35 °C, 4 h
MW, 3 min
88
95
2
3
4
Heptylamine
A
B
35 °C, 8 h
MW, 3 min
98
90
Cyclohexylamine
Benzylamine
A
B
35 °C, 13 h
MW, 6 min
87
85
A
B
35 °C, 5 h
MW, 6 min
95
99
5
6
7
8
4-Methoxyaniline
B
B
B
MW, 6 min
MW, 3 min
MW, 3 min
86
92
91
4-(Trifluoromethyl)aniline
4-Methoxybenzylamine
3-Phenylpropan-1-amine
A
B
35 °C, 5 h
MW, 3 min
90
99
9
2-(3,4-Dimethoxyphenyl)ethanamine
A
B
35 °C, 5 h
MW, 3 min
95
98
10
11
Furan-2-ylmethanamine
B
MW, 6 min
95
(S)-Alanine methyl ester
A
B
35 °C, 10 h
MW, 6 min
93
99
12
(S)-Valine methyl ester
A
B
35 °C, 9 h
MW, 6 min
90
95
13
14
(S)-Phenylalanine methyl ester
(S)-Leucine methyl ester
B
B
MW, 6 min
MW, 6 min
92
95
Optical rotations compared well with the literature data, In conclusion, we think that the one-flask method de-
indicating that the chiral center is not involved during the scribed here is simple and convenient, particularly using
reaction. Thus, (S)-methyl 2-formamido-3-methyl- the procedure under microwave irradiation, for the prepa-
butanoate, [a]D25 –27.5 (c 1.7, EtOH)13,14 was recovered, ration of formyl amides even in large scale, as it uses
without significant racemization of the chiral center, from friendly reaction conditions and cheap reagents.22 The
(S)-valine methyl ester.
method can be used as a valid alternative to other ones,
however, as it avoids any tedious subsequent purification
of the final product.
The results obtained may be consistent with the mecha-
nism depicted in Scheme 2. As other carboxylic acids,
formic acid should form an active formate ester with
CDMT21 that reacts with the amine compound to form the
formyl derivative.
Acknowledgment
The University of Sassari (Fondi ex-60%) has financially supported
this work.
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Scheme 2
Synlett 2004, No. x, A–C © Thieme Stuttgart · New York

LETTER
Procedure for the Synthesis of Formyl Amides
C
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(22) A. Conventional Procedure: Formic acid (0.35 g, 7.62
mmol), benzylamine (0.71 g, 7.62 mmol), 2-chloro-4,6-
dimethoxy[1,3,5] triazine (CDMT, 1.47 g, 8.30 mmol), 4-
dimethylaminopyridine (DMAP, 0.03 g, 0.2 mmol) and N-
methylmorpholine (NMM, 0.92 mL, 8.30 mmol) were
placed in this order in a flask containing CH2Cl2 (20 mL) and
maintained at r.t. The mixture was stirred at reflux (6 h),
monitored by TLC in order to control the end of the
conversion, then diluted with CH2Cl2, washed twice with aq
HCl (15 mL), aq NaHCO3 (15 mL), and brine (10 mL). The
organic layer was dried (Na2SO4). Removal of the solvent in
vacuo gave 0.98 g of chemically pure N-benzylformamide,
(95%), mp 57 °C.12
B. Microwave Procedure: TEA (1.2 mL, 8.38 mmol) and
L-valine methyl ester hydrochloride (1.27 g, 7.62 mmol)
were placed in a flask equipped with a reflux condenser,
containing CH2Cl2 (20.0 mL). Then formic acid (0.35 g, 7.62
mmol), CDMT (1.47 g, 8.30 mmol), DMAP (0.03 g, 0.20
mmol) and N-methylmorpholine (NMM, 0.92 mL, 8.30
mmol) were added in this order. The open flask was
irradiated at 35 °C (by modulation of the power) for 6 min in
a self-tuning single mode CEM DiscoverTM Focused
Synthesizer. The solution was cooled rapidly at r.t. by
passing compressed air through the 25 microwave cavity for
1 min, then diluted with CH2Cl2 and worked up as above. 1H
NMR (300 MHz, CDCl3): d = 8.27 (s, 1 H), 6.23 (br s, 1 H),
4.67 (dd, 1 H, J = 9.0, 4.8 Hz), 3.76 (s, 3 H), 2.24–2.17 (m,
1 H), 0.97 (d, 3 H, J = 6.8 Hz), 0.92 (d, 3 H, J = 6.6 Hz).
(S)-Methyl 2-formamido-3-methylbutanoate from method A
had [a]D25 –27.2 (c 2.0, EtOH). Similarly, (S)-methyl 2-
formamidobutanoate, (S)-methyl 2-formamido-3-phenyl-
propanoate, and (S)-methyl 2-formamido-4-methyl-
pentanoate were recovered and had [a]D25 values of –36.1
(c 3.5, EtOH),13 +85.3 (c 2.3, EtOH),14 and –43.2 (c 1.2,
EtOH), respectively.13
(k) Giacomelli, G.; Porcheddu, A.; Salaris, M. Org. Lett.
2003, 5, 2715.
(19) Kaminski, Z. J. Tetrahedron Lett. 1985, 26, 2901.
Synlett 2004, No. x, A–C © Thieme Stuttgart · New York