Versatile synthesis of malonamic acid derivatives from a β-ketothioester

Article abstract of DOI:10.1016/S0040-4039(01)00760-2

An efficient synthetic route is described that allows the preparation under mild conditions of several types of malonamic acid derivatives. The S-tert-butyl acetothioacetate monoanion reacted with aryl or alkyl isocyanates to give β-amidothioesters in one step and 73-87% yield, after spontaneous deacetylation of tricarbonyl intermediates. Treatment of these thioesters with several aliphatic or aromatic alcohols and amines at room temperature in THF or DME and in the presence of silver trifluoroacetate provided, respectively, the corresponding malonamic acid esters and malonamides in 80-100% yield.

Full text of DOI:10.1016/S0040-4039(01)00760-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4479–4482
Versatile synthesis of malonamic acid derivatives from a
b-ketothioester
Pilar Lo´pez-Alvarado, Carmen Avendan˜o* and J. Carlos Mene´ndez*
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Received 20 February 2001; revised 4 May 2001; accepted 9 May 2001
Abstract—An efficient synthetic route is described that allows the preparation under mild conditions of several types of
malonamic acid derivatives. The S-tert-butyl acetothioacetate monoanion reacted with aryl or alkyl isocyanates to give
b-amidothioesters in one step and 73–87% yield, after spontaneous deacetylation of tricarbonyl intermediates. Treatment of these
thioesters with several aliphatic or aromatic alcohols and amines at room temperature in THF or DME and in the presence of
silver trifluoroacetate provided, respectively, the corresponding malonamic acid esters and malonamides in 80–100% yield. © 2001
Elsevier Science Ltd. All rights reserved.
b-Dicarbonyl derivatives belonging to the malonamic
acid family are very important compounds. More spe-
cifically, a wide variety of malonamides and malonamic
acid esters have interesting pharmacological properties,
including antihypertensive,1 sedative and anticonvul-
sant,2 antiinflammatory,3 analgesic,1b,4 and central ner-
vous system-stimulating activities.5 Their interaction
with several important biomolecules, including the M1
muscarinic6 and cholecystokinin A7 receptors, the
gramicidin channel8 and DNA9 has been also described.
Also, the introduction of malonamide substructures is a
technique for the design of peptidomimetics.10,11 Some
malonamides are useful as X-ray contrast agents12 and
as non-linear optical materials.13 Furthermore, the
unique chelating properties of b-diamides make them
ideal reagents for the extraction and chemical fixation
of heavy metal ions,14 including trivalent lanthanides15
and actinides,16 and have thus interesting potential
applications in environmental decontamination proce-
dures. These chelating properties are also the basis for
a large number of analytical applications as compo-
nents of chromatographic phases17 or as metal-selective
ionophoric speciating reagents.18 Finally, several b-ami-
doesters are used as intermediates in the synthesis of
numerous pharmacologically relevant compounds19–21
or as chiral auxiliaries.22
densation of diethyl malonate derivatives with
amines.3b Other methods for the preparation of malon-
amides and malonamic acid esters start from Mel-
drum’s acid23 or from malonic acid derivatives such as
malonyl chloride,21 malonyl monoacyl chloride24 or
malonic acid monoethyl ester, which is activated
through its conversion into the corresponding acyl
chloride (in solution7 or on a solid support25), or via its
reaction with DCC,2 carbonyldiheterocycles2 or BOP.11
In most cases, these methods lack generality and give
low or moderate yields.
We propose here a new, flexible route to malonamic
acid esters and malondiamides that exploits the well-
known regioselective reaction of b-ketothioesters with
electrophiles at C-2, the easy retro-Claisen degradation
of tricarbonyl compounds26 and the high reactivity of
the thioester group towards alcohols and amines in the
presence of thiophilic metals.27 Our route is shown in
Scheme 1, and starts by the preparation of b-amidoth-
ioesters 3 by treatment of commercially available tert-
butyl acetothioacetate 1 with sodium hydride and an
aryl or alkyl isocyanate in dry dimethoxyethane.
Although the intermediate tricarbonyl derivatives 2
could be detected in the crude reaction products, they
were deacetylated during workup and purification, a
process that was accelerated by the presence of silica-
gel. Compounds 3 were treated with several amines
(including aminoacids), at room temperature in the
presence of silver trifluoroacetate,27 yielding diamides 4
in 80–100% yields. Similar treatment of compounds 3
with alcohols or phenols afforded malonamic acid
esters 5, also in excellent yields.28
The classical preparation of N-symmetrically substi-
tuted malonamides involves the high-temperature con-
* Corresponding authors. E-mail: josecm@eucmax.sim.ucm.es
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00760-2

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Scheme 1.
We also briefly examined the acylation of bifunctional
substrates by compounds 3. Treatment of aminophenol
6 with 2 equiv. of amidothioester 3b gave compound 7
in 96% yield. If only 1 equiv. of the thioester was
employed, the reaction could be made chemoselective, as
shown by the preparation of 8 from 6 and 3c (Scheme 2).
Scheme 2.

P. Lo´pez-Al6arado et al. / Tetrahedron Letters 42 (2001) 4479–4482
4481
All new compounds were characterized by spectral
Mariet, C.; Carrier, M.; Page, J. J. Chim.-Phys. et Phys-
Chim.-Biol. 1998, 95, 1315–1318; (c) Kannan, S.; Fergu-
son, G. Inorg. Chem. 1997, 36, 1724–1725.
1
analysis (IR, H, 13C NMR), and also by other relevant
analytical data (mp and [h], in the case of compounds
4f and 5b). They all gave satisfactory ( 0.30%) combus-
tion microanalyses for CHN.
17. Mohapatra, P.; Sriram, S.; Manchanda, V.; Badheka, L.
Separ. Sci. Technol. 1999, 35, 39.
18. (a) Chen, H. J.; Xu, J. F.; Li, Z. L.; Huang, B. J. Chem.
Res. (S) 1998, 444–445; (b) Zhang, W.; Jenny, L.;
Spichiger, U. E. Anal. Sci. 2000, 16, 11–18.
19. Saalfrank, R. W.; Lutz, T.; Ho¨rner, B.; Gu¨ndel, J.;
Peters, K.; von Schnering, H. G. Chem. Ber. 1991, 2289–
2295.
20. (a) Taylor, E. C.; Liu, B. Tetrahedron Lett. 1999, 40,
5291–5294; (b) Galeazzi, R.; Mobbili, G.; Orena, M.
Tetrahedron 1999, 55, 261–270.
Acknowledgements
Financial support from CICYT (project SAF-2000-
0130) is gratefully acknowledged.
21. Barrett, A. G. M.; Boys, M. L.; Boehm, T. L. J. Org.
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28. Representative experimental procedure. To a slurry of
petroleum ether-washed (2×10 mL) sodium hydride (0.25
g of a 60% dispersion in mineral oil, 6.04 mmol, 1.05
equiv.) in dry 1,2-dimethoxyethane (DME) (40 mL)
under an argon atmosphere at −20°C, was added drop-
wise, via cannula, a solution of S-tert-butyl 3-oxothiobu-
tanoate 1 (1.0 g, 5.75 mmol) in dry DME (10 mL). The
solution was left to warm to 0°C for 5–10 min, and
freshly distilled cyclohexyl isocyanate (0.75 g, 6.04 mmol)
was added. After 14 h at room temperature, the reaction
mixture was quenched with saturated aqueous NH4Cl (50
mL), extracted with diethyl ether (2×100 mL) and washed
again with aqueous NH4Cl (50 mL) and brine (2×50 mL),
dried (Na2SO4), and evaporated under reduced pressure
to give an orange oil. Chromatography on silica-gel
(gradient from 50% petroleum ether/Cl2CH2 to neat
Cl2CH2) yielded 1.29 g (87%) of S-tert-butyl cyclohexyl-
carbamoylthioacetate (3b), as white needles. Mp: 59–
61°C. IR (KBr): 3289 (NH), 1682 (tBuS-CꢀO), 1644
8. Decker, E. R.; Levitt, D. G. Biophys. J. 1988, 53, 25–32.
9. Van der Klein de Gunst, F. J.; van Boom, J. H.;
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Muller, S.; Guillet, J.-G.; Choppin, J.; Briand, J.-P. J.
Med. Chem. 1996, 39, 2030–2039.
12. Mart´ın Jime´nez, J. L.; Carretero Colo´n, J. M.; Bohle, F.;
Alonso Silva, I.; Harto Mart´ınez, J. R.; Gonza´lez
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673922 A1 27 Sep 1995 [Chem. Abstr. 1997, 124, 86597].
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14. (a) Angus, P. M.; Jackson, W. G. Inorg. Chim. Acta 1998,
268, 85–91; (b) Jezierska, J.; Trochimczuk, A. W.;
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1
(NH-CꢀO) cm−1. H NMR (CDCl3, 250 MHz): l 6.66 (d,
1H, J=7.0 Hz, NH), 3.65 (m, 1H, H-1%), 3.29 (s, 2H,
H-2), 1.80–1.75, 1.63–1.44 and 1.28–1.02 (3 m, 10H,
t
H-2%,3%,4%,5%,6%), 1.36 (s, 9H, Bu). 13C NMR (CDCl3, 63
15. (a) Nakamura, T.; Miyake, C. J. Alloys Compd. 1996,
233, 1–14; (b) Spjuth, L.; Liljenzin, J. O.; Hudson, M. J.;
Drew, M. G. B.; Iveson, P. B.; Madic, C. Solvent Extr.
Ion Exch. 2000, 18, 1–23.
MHz): l 195.6 (C-1), 163.5 (CO-NH), 50.9 (C-2), 48.7
(C(CH3)3), 48.1 (C-1%), 32.6 (C-2%,6%), 29.4 (C(CH3)3), 25.3
(C-4%), 24.5 (C-3%,5%). Anal. calcd for C13H23NO2S: C,
60.66; H, 9.01; N, 5.44. Found: C, 60.94; H, 9.23; N,
5.63.
16. (a) Mahajan, G. R.; Prabhu, D. R.; Manchanda, V. K.;
Badheka, L. P. Waste Manag. 1998, 18, 125–133; (b)

4482
P. Lo´pez-Al6arado et al. / Tetrahedron Letters 42 (2001) 4479–4482
To a solution of b-carbamoylthioester 3b (100 mg, 039
1H NMR (CDCl3, 300 MHz): l 9.44 (br. s, 1H, NH%),
8.00 (d, 1H, J=2.9 Hz, H-6%), 7.11 (d, 1H, J=6.8 Hz,
NH%%), 6.79 (d, 1H, J=8.9 Hz, H-3%), 6.59 (dd, 1H, J=8.9
and 2.9 Hz, H-4%), 3.84 and 3.76 (2 s, 2×3H, 2×OMe),
3.76 (m, 1H, H-1%%), 3.39 (s, 2H, H-2), 2.00–1.88, 1.74–
1.58 and 1.47–1.09 (3 m, 10H, H-2%%,3%%,4%%,5%%,6%%). 13C
NMR (CDCl3, 75.5 MHz): l 166.4 and 165.6 (C-1 and
C-3), 153.6 (C-5%), 142.9 (C-2%), 127.8 (C-1%), 110.9 (C-3%),
108.7 (C-4%), 106.9 (C-6%), 56.3 and 55.7 (2 OMe), 48.7
(C-1%%), 44.2 (C-2), 32.7 (C-2%%,6%%), 25.4 (C-4%%), 24.7 (C-
3%%,5%%). Anal. calcd for C17H24N2O4: C, 63.73; H, 7.55; N,
8.74. Found: C, 63.50; H, 7.67; N, 8.65.
mmol) and 2,5-dimethoxyaniline (65 mg, 0.43 mmol) in
dry 1,2-dimethoxyethane (3 mL) was added silver trifl-
uroacetate (94 mg, 0.43 mmol). The reaction mixture was
stirred overnight at room temperature. The resulting sus-
pension was poured onto water (25 mL) and extracted
with CHCl3 (3×25 mL). The combined organic phases
were evaporated under reduced pressure and the residue
was chromatographed on silica-gel, eluting with a gradi-
ent from neat CH2Cl2 to neat Et2O to yield 114 mg (92%)
of compound 4c, as a white solid. Mp: 97–98°C. IR
(KBr): 3337 and 3257 (2 NH), 1662 (2×NH-CꢀO) cm−1
.
.