One Pot Synthesis of Methyl Aminoacetylcyanoacetates

Article abstract of DOI:10.1081/SCC-120026861

The C-acylation reactions of the methyl cyanoacetate with N-protected glycines by simultaneous activation of the amino acid carbonyl group and the methyl cyanoacetate methylene group using carbonyl diimidazole (CDI) have been here performed. The correspon

Full text of DOI:10.1081/SCC-120026861

This article was downloaded by: [Lulea University of Technology]
On: 07 August 2013, At: 11:59
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
One Pot Synthesis of Methyl Aminoacetylcyanoacetates
Stylianos Hamilakis a & Assistant Professor Athanase Tsolomitis a
a The Laboratory of Organic Chemistry, The School of Chemical Engineering, The National
Technical University of Athens, Athens, Greece
Published online: 21 Aug 2006.
To cite this article: Stylianos Hamilakis & Assistant Professor Athanase Tsolomitis (2003) One Pot Synthesis of Methyl
Aminoacetylcyanoacetates, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 33:24, 4313-4319, DOI: 10.1081/SCC-120026861
To link to this article: http://dx.doi.org/10.1081/SCC-120026861
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 24, pp. 4313–4319, 2003
One Pot Synthesis of Methyl
Aminoacetylcyanoacetates
*
Stylianos Hamilakis and Athanase Tsolomitis
The Laboratory of Organic Chemistry, The School of
Chemical Engineering, The National Technical
University of Athens, Athens, Greece
ABSTRACT
The C-acylation reactions of the methyl cyanoacetate with
N-protected glycines by simultaneous activation of the amino acid
carbonyl group and the methyl cyanoacetate methylene group
using carbonyl diimidazole (CDI) have been here performed.
The corresponding aminoacetylcyanoacetates were isolated
(devoided of any impurities) as enols 4 in high yields, with a simple
experimental, one pot, procedure.
Key Words: Aminoacetylcyanoacetates; Imidazolides; CDI; Enol-
imidazolinium salt; C-Aminoacetylation.
*Correspondence: Athanase Tsolomitis, Assistant Professor, The Laboratory of
Organic Chemistry, The School of Chemical Engineering, The National Technical
University of Athens, 9, Heroon Polytechniou Str., Zografou Campus, Athens
15780, Greece; E-mail: tsolom@chemeng.ntua.gr.
4313
DOI: 10.1081/SCC-120026861
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
4314
Hamilakis and Tsolomitis
Aminoacetyl derivatives of active methylene compounds (such as
cyanoacetates) have been used as useful intermediates in synthesis of
tetramic acids[1–3] and statines.[4,5] Therefore these compounds must be
considered to be of interest as potential prodrugs.
The C-acylaion of methyl cyanoacetate with N-protected a-amino
acids has been reported using hippuric acid chlorides,[6] hippuric acid
esters,[7–9] mixed anhydrides[10] of hippuric acid or the hippuric acid
azlactone, (2-phenyl-5(4H )-oxazolone), and salts of methyl cyanoacetate.
In that process, the N-protected amino acids were activated with a
separate reaction and with a second reaction, followed the cyanoacetate
anion formation by bases such as t-BuOK, NaH, or non nucleophilic
bases e.g., triethylamine and 4-N,N-dimethylaminopyridine.
In a previous communication[11] we have reported the C-acylation of
Meldrum’s acid with N-protected glycines (via their imidazolides), using
1,10-carbonyl diimidazole (CDI). We now report an investigation into
the C-acylation reactions of methyl cyanoacetate, also using N-protected
glycines as the acylating reagents and describe the procedure of
formation of the intermediates imidazolides 2 and of the imidazolinium
enol salts 3 we observed (see Sch. 1 and Table 1). In this process
obviously the CDI is the amino acid activation reagent. Simultaneously
the presence of imidazole (ImH), which is liberated during the formation
of the amino acid imidazolide, is sufficient to create the basic medium
required for the cyanoacetate anion formation. Actually, 1H NMR
spectroscopy revealed that amino acid 1 is rapidly and quantitatively
converted to its imidazolide 2 and that addition of methyl cyanoacetate
in the imidazolide solution results in a rather fast but remarkably clean
1
reaction, to the imidazolinium enol salt 3. The H NMR of a sample of
the reaction mixture withdrawn after 60 min at room temperature
disclosed the disappearance of amino acid and the exclusive formation
of the corresponding imidazolide 2. After 24 h the transformation of
imidazolide 2 to imidazolium salt 3 through a smooth and clean reaction
was revealed with the same procedure. It is reasonable to assume that the
upfield shift of signals for compounds 3 (relatively to the corresponding
of compounds 4) were assigned to the enol anion formed.
The samples (usually 1 mL) were withdrawn from the reaction flask
mixture and concentrated in vacuo (at room temperature). Their solids or
retinous mass residues showed clean 1H NMR spectra (see Table 1) which
were only indicative, without correspondence to the precise chemical
shifts, because the samples contained some impurities (e.g., imidazole
in the aromatic region). Attempts for purification (e.g., by recrystalli-
zation) of these intermediates were ineffective probably because of their
thermal instability in the solvent.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Methyl Aminoacetylcyanoacetates
4315

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
4316
Hamilakis and Tsolomitis

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Methyl Aminoacetylcyanoacetates
4317
The acylation compounds 4 were isolated, after acidification of
the reaction mixture, in high yields, 85–87.5% after recrystallization. It
must be pointed out that the crude compounds 4 showed clean 1H NMR
spectra, devoid of any impurities, such as the by-products which were
observed when N-protected amino acids were acylated under different
activation conditionst.[7,8,10]
The 1H NMR spectra of compounds 4 (see Experimental) are
consistent with the enolic (and not the keto tautomer 5) structure of
the acylated cyanoacetates, as shown by the presence of a broad singlet
at low field, ꢀ 11.30–13.30 ppm; this signal is assigned to the enol-OH
proton which participates in an intramolecular hydrogen bond.[11] In
agreement with their enolic structure, compounds 4a–d give an intense
orange color with an aqueous solution of ferric chloride.
In conclusion, the C-acylation of methyl cyanoacetate with
N-protected glycines has been performed by a simple experimental
procedure using the imidazolide activation method. The 1H NMR spectra
of aminoacetylcyanoacetates, are consistent with their enolic structure.
The progress of formation and the purity of intermediates (imidazolides
and enol-imidazolinium salts) has been examined. The application of the
imidazolide activation to acylation reactions with chiral N-protected
amino acids is currently being investigated.
EXPERIMENTAL
Melting points were determined in capillary tubes and are
1
uncorrected. The H NMR spectra were recorded on a Varian EM-360
60 MHz spectrometer, chemical shifts are given in ppm (ꢀ) downfield
from TMS (internal standard). The IR spectra were obtained with a
Nicolet Magna 560 spectrometer; as nujol mulls and were calibrated
against the polystyrene 1601 cmꢀ1 band, and given in reciprocal
centimetres.
General Procedure for the Aminoacetylation Reaction
To a solution or suspension of the acid 1 (10 mmol) in dichloro-
methane (40 mL), 1,l0-carbonyldiimidazole (10.1 mmol) was added. The
reaction flask was protected with a calcium chloride drying tube and the
mixture stirred for 60 min, until the gas (CO2) evolution ceased and a
solution was obtained. Methyl cyanoacetate (10 mmol) was then added
and the solution was stirred at room temperature for an additional 20 h.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
4318
Hamilakis and Tsolomitis
The solution (or suspension), was cooled with ice-water and 20 mL of
10% hydrochloric acid were added dropwise under vigorous stirring. If a
suspension was formed additional dichloromethane was added until a
solution was obtained. The organic phase was separated and the aqueous
layer was extracted thrice with 10 mL of dichloromethane, the combined
organic layers were dried (magnesium sulfate) and concentrated to a solid
which proved to be almost pure (1H NMR) compound 4.
2-Hippuryl-2-cyano-methylacetate (4a). Yield, 86.5%, m.p.
145–146ꢁC, Lit. m.p. 146–147ꢁC.[7] IR (Nujol mull): 1530, 1640, 2222,
1
3270. H NMR (CDCl3): ꢀ 3.88 (s, 3H, -CH3,), 4.56 (d, J ¼ 6 Hz, 2H,
ꢀ
-CH2 ), 6.80 (br m, 1H, NH), 7.28–7.98 (m, 5H, Ph-), 11.80 (br s, 1H,
enolic -OH).
Methyl 4-acetylamino-2-cyano-3-hydroxybut-2-enoate (4b). Yield,
85%, m.p. 149–151ꢁC, Lit. m.p. 151–152ꢁC.[8] IR (Nujol mull): 1550,
1
1665, 2221, 3290. H NMR (CDCl3): ꢀ 2.05 (s, 3H, -COMe), 3.89 (s,
ꢀ
3H, OMe), 4.28 (d, J ¼ 6 Hz, 2H, ꢀCH2 ), 7.66 (br m, 1H, NH), 11.30
(br s, 1H, enolic -OH).
2-(N-Z-Glycyl)-2-cyano-methylacetate (4c). Yield, 86%, m.p.
101–102ꢁC, Lit. m.p. 104–105ꢁC.[9] IR (Nujol mull): 1535, 1660, 1694,
2225, 3320. 1H NMR (CDCl3): ꢀ 3.88 (s, 3H, -CH3), 4.27 (d, J ¼ 6 Hz, 2H,
ꢀ
-CH2 ), 5.12 (s, 2H, OCH2Ph), 5.35 (br m, 1H, NH), 13.30 (br s, lH,
enolic -OH).
2-(N-Boc-glycyl)-2-cyano-methylacetate (4d). Yield, 87.5%, m.p.
104–106ꢁC, Lit. m.p. 105–107ꢁC.[9] IR (Nujol mull): 1515, 1660, 1690,
1
2230, 3365. H NMR (CDCl3): ꢀ 1.46 (s, 9H, CMe3), 3.90 (s, 3H, OMe),
ꢀ
4.23 (d, J ¼ 6 Hz, 2H, -CH2 ), 5.16 (br m, 1H, NH), 12.90 (br s, 1H,
enolic -OH).
REFERENCES
1. Poncet, J.; Jouin, P.; Castro, B.; Nicolas, L.; Boutar, M.;
Gandemer, A. Tetramic acid chemistry. Part 1. Reinvestigation of
racemization during the synthesis of tetramic acids via Dieckmann
cyclization. J. Chem. Soc. Perkin Trans. 1 1990, 611.
2. Williard, P.G.; de Laszlo, S.E. Total synthesis of (ꢂ)-dysidin, a
marine metabolite containing an N-acyl-O-methyltetramic acid. J.
Org. Chem. 1984, 49, 3489.
3. Jouin, P.; Castro, B.; Nisato, D. Stereospecific synthesis of N-
protected statine and its analogs via chiral tetramic acid. J. Chem.
Soc. Perkin Trans. 1, 1987, 1177.
4. Maibaum, J.; Rich, D.H. A facile synthesis of statine and analogs by
reduction of b-keto esters derived from Boc-protected amino acids.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Methyl Aminoacetylcyanoacetates
4319
HPLC analyses of their enantiomeric purity. J. Org. Chem. 1988, 53,
869.
5. Schuda, P.F.; Greenlee, W.J.; Chakravarty, P.K.; Eskola, P. A short
and efficient synthesis of (3S,4S)-4[(tert-butyloxycarbonyl) amino]-
5-cyclohexyl-3-hydroxypentanoic acid. J. Org. Chem. 1988, 53, 873.
6. Scheiber, J.; Reckleben, Transformations with succinylglycyl
chloride and hippurgh chlorideH. Ber. 1913, 46, 2412.
7. Igglessi-Markopoulou, O.; Sandris, C. Acylaminoacetyl derivatives
of active methylene compounds. 1. The cyclization of the benzo-
ylaminoacetyl derivatives to a-substituted tetramic acids. (1). J.
Heterocycl. Chem. 1982, 19, 883.
8. Igglessi-Markopoulou, O.; Sandris, C. Acylaminoacetyl derivatives
of active methylene compounds. 2. The cyclization of the acetyl-
aminoacetyl derivatives to a-substituted tetramic acids and the
formation of N-acetyl-a-substituted tetramic acids. J. Heterocycl.
Chem. 1985, 22, 1599.
9. Detsi, A.; Micha, M.; Igglessi-Markopoulou, O. Synthesis of N-
alkoxycarbonyl-3-substituted tetramic acids and functionalized
enols via C-acylation reactions of active methylene compounds
with N-hydroxysuccinimide esters of N-alkoxycarbonyl-a-amino
acids. J. Chem. Soc. Perkin Trans. 1 1998, 15, 2443.
10. Hamilakis, S.; Kontonassios, D.; Sandris, C. Acylaminoacetyl deri-
vatives of active methylene compounds 3[1]. C-acylation reactions
via the hippuric acid azlactone. J. Heterocycl. Chem. 1994, 31, 1145.
11. Hamilakis, S.; Kontonassios, D.; Sandris, C. Acylaminoacetyl
derivatives of active methylene compounds. 4[1]. Synthesis of N-
protected tetramic acids via the C-acylation reaction of Meldrum’s
acid with the imidazolides of N-protected glycines. J. Heterocycl.
Chem. 1996, 33, 825.
Received in the UK June 19, 2003

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.