Environmentally benign process for the synthesis of N-formyl amino acid esters

Article abstract of DOI:10.1016/j.tetlet.2004.08.129

Several amino acid ester hydrochlorides were reacted with ammonium formate to give N-formyl amino acid esters in good yields.

Full text of DOI:10.1016/j.tetlet.2004.08.129

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7589–7590
Environmentally benign process for the synthesis of N-formyl
amino acid esters
Sambasivarao Kotha,* Manoranjan Behera and Priti Khedkar
Department of Chemistry, Indian Institute of Technology––Bombay, Powai, Mumbai 400076, India
Received 21 October 2003; revised 11 August 2004; accepted 20 August 2004
Abstract—Several amino acid ester hydrochlorides were reacted with ammonium formate to give N-formyl amino acid esters in
good yields.
Ó 2004 Elsevier Ltd. All rights reserved.
A potentially useful protecting group, which can be
introduced on the amine functionality is the formyl
group.1 N-Formyl amino acid derivatives are useful in
peptide chemistry.2 Moreover, dehydration of forma-
mides can give isocyano derivatives, which are useful
glycine equivalents.3 The formyl group in combination
with a tert-butyl ester group is useful in preparing highly
functionalized peptide derivatives.4 Generally, N-formyl
amino acid esters are prepared from the corresponding
amino esters using orthoformates5 and various other
formylating agents.6 However, many of these methods
involve reagents that are either toxic or expensive.
Although orthoformates are commercially available,
they are prepared from chloroform, which is not a fav-
orable starting material from an environmental point
of view. Herein, we report ammonium formate as an effi-
cient formylating agent for the synthesis of N-formyl
amino acid esters (Scheme 1).
The reaction of amino acid ester hydrochlorides with
ammonium formate in dry acetonitrile at reflux gave
the N-formyl derivatives in good yields. Generally, the
formylation reaction requires 8–12h for completion.
The results are summarized in Table 1.
Moreover, we found that optically pure amino acid ester
hydrochlorides react to give the corresponding N-formyl
derivatives without racemization. The specific rotation
values for these samples are comparable to the literature
values5 as given in Table 2.
It is noteworthy to mention that standard N-formyl-
ation by other methods is incompatible with tert-butyl
groups,8 although DCC was used in combination with
formic acid to formylate glycine tert-butyl ester hydro-
chloride.9 However, the use of ammonium formate gave
N-formyl glycine tert-butyl ester in good yield. In the lit-
erature, it was reported that primary amines did not give
formylation using ammonium formate.10 Surprisingly,
in our hands all the amino acid esters gave the formyl-
ated products in good yields.
O
O
3
3
HCO NH
R
2
4
R
2
2
OR
1
OR
NHCHO
CH CN, Reflux
3
In conclusion, we have developed a simple and useful
methodology for the preparation of N-formyl amino
acid esters using the inexpensive, readily available, and
NH .R
2
1
R = HCl, PTSA
2
R = Et, Me, tert-Bu, CH Ph
environmentally
formate.
acceptable
reagent
ammonium
2
3
R = H, Me, i-Pr, i-Bu, Allyl
Scheme 1.
Typical experimental procedure for the N-formylation:
To a stirred solution of glycine ethyl ester hydrochloride
salt (5g, 35mmol) in dry acetonitrile (35mL) was added
anhydrous ammonium formate (4.6g, 73mmol). The
resultant heterogeneous reaction mixture was refluxed
Keywords: Ammonium formate; N-formylation; Amino acids.
*
Corresponding author. Tel.: +91 22 2576 7160; fax: +91 22 2572
3480; e-mail: srk@chem.iitb.ac.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.129

7590
S. Kotha et al. / Tetrahedron Letters 45 (2004) 7589–7590
20
Table 2. List of ½aꢁ values for the optically active N-formyl
Table 1. The N-formylated derivatives prepared
D
derivatives prepared
Starting material
N-Formyl derivatives
Yield (%)
N-Formyl
derivatives
Observed value
20
½aꢁD
Literature value5
20
O
O
½aꢁD
10
12
13
ꢀ36.6 (c 0.6, EtOAc)
ꢀ23.73 (c 1.98, EtOH)
ꢀ44.28 (c 2.1, EtOH)
ꢀ34.6 (c 0.6, EtOAc)
ꢀ23.24 (c 1.98, EtOH)
ꢀ43.8 (c 2.1, EtOH)
91
OEt
OEt
NHCHO
8
NH2.HCl
1
O
O
Acknowledgements
O tBu
O tBu
86
81
66
84
88
63
NH2.HCl
We thank DST, New Delhi, for financial support. M.B.
and P.K. thank CSIR, New Delhi, for the award of
research fellowships.
NHCHO
9
2
O
O
Me
Me
OMe
OMe
L -
L -
References and notes
NH2.HCl
NHCHO
10
3
O
O
1. Olah, G. A.; Ohannesian, L.; Arvanaghi, M. Chem. Rev.
1987, 87, 671; Robertson, J. Protecting Group Chemistry;
Oxford Science Publication, Oxford University Press:
London, 2000; p 18.
2. Sheehan, J. C.; Yang, D. H. J. Am. Chem. Soc. 1958, 80,
1154; Geiger, R.; Siedel, W. Chem. Ber. 1969, 102,
2487.
3. Ugi, I.; Fetzer, U.; Eholzer, U.; Knupfer, H.; Offerman, K.
Angew. Chem., Int. Ed. Engl. 1965, 4, 472.
4. Giard, T.; Benard, D.; Plaquevent, J. C. Synthesis 1998,
297.
5. Chancellor, T.; Morton, C. Synthesis 1994, 1023.
6. Duczek, W.; Deutsch, J.; Vieth, S.; Niclas, H. J. Synthesis
1996, 37; Chen, F. M. F.; Benoiton, N. L. Synthesis 1979,
709; Kashima, C.; Arao, H.; Hibi, S.; Omote, Y. Tetra-
hedron Lett. 1989, 30, 1561; Duhamel, P.; Benard, D.;
Plaquevent, J. C. Tetrahedron Lett. 1985, 26, 6065;
Kisfalundy, L.; Otvos, L., Jr. Synthesis 1987, 510; Aki-
kusa, N.; Mitsui, K.; Sakamoto, T.; Kikugawa, Y.
Synthesis 1992, 1058.
OMe
OMe
NHCHO
NH2.HCl
O
11
4
O
i-Pr
i-Pr
OMe
OMe
L -
L -
NH2.HCl
NHCHO
12
5
O
O
i-Bu
i-Bu
OMe
OMe
L -
L -
NHCHO
NH2.HCl
13
6
O
O
OCH2Ph
OCH2Ph
7. Spectral data for compound 11:
1H NMR (400MHz, CDCl3): d = 8.21 (s, 1H), 6.23 (br s,
1H), 5.68–5.63 (m, 1H), 5.20–5.12 (m, 2H), 4.80 (m, 1H),
3.78 (s, 3H), 2.66–2.60 (m, 2H).
NHCHO
14
NH2.PTSA
7
13C NMR (100MHz, CDCl3): d = 171.8, 160.6, 131.9,
119.7, 52.7, 50.4, 36.5.
All the compounds except 11 are known and physical properties agree
with literature. The spectral data for 11 is given in Ref. 7. Compound 4
is a racemic mixture.
IR (neat): mmax = 3440 (NH), 1745 (ester), 1658 (formyl)
cmꢀ1. HRMS (QTOF): m/z for C7H11NO3Na (M+Na),
calcd: 180.0637. Found: 180.0640.
for 12h. The solvent was evaporated and the reaction
mixture was diluted with water, extracted with ethyl ace-
tate, and dried over MgSO4. The solvent was removed
under reduced pressure and the crude product was chro-
matographed on a silica gel column. Elution of the col-
umn with 50% ethyl acetate/petroleum ether gave the
pure N-formyl glycine ethyl ester (4.16g, 91% yield) as
a colorless liquid.
8. Ugi, I.; Betz, W.; Fetzer, U.; Offermann, K. Chem. Ber.
1961, 94, 2814; Anderson, G. W.; Callahan, F. M. J. Am.
Chem. Soc. 1960, 82, 3359; Sheehan, J. C.; Yang, D. D. H.
J. Am. Chem. Soc. 1958, 80, 1154; Thomas, J. O.
Tetrahedron Lett. 1967, 8, 335.
9. Waki, M.; Meienhofe, J. J. Org. Chem. 1977, 42, 2019.
10. Reddy, P. G.; Kishore Kumar, G. D.; Baskaran, S.
Tetrahedron Lett. 2000, 41, 9149.