Three-component, one-pot sequential synthesis of N-Aryl, N′-alkyl barbiturates

Article abstract of DOI:10.1021/ol063074+

(Chemical Equation Presented) Condensation between N-alkyl, N′-aryl carbodiimides and malonic acid monoesters leads to a high-yield formation of N-acyl urea derivatives that could be cyclized to C-monosubstituted barbiturates by addition of a suitable bas

Full text of DOI:10.1021/ol063074+

ORGANIC
LETTERS
2007
Vol. 9, No. 5
841-844
Three-Component, One-Pot Sequential
Synthesis of N-Aryl, N′-Alkyl
Barbiturates§
Alessandro Volonterio*,† and Matteo Zanda*,‡
Dipartimento di Chimica, Materiali ed Ingegneria Chimica “G. Natta” del Politecnico
di Milano, C.N.R-Istituto di Chimica del Riconoscimento Molecolare, Sezione “A.
Quilico”, Via Mancinelli 7, I-20131 Milano, Italy
alessandro.Volonterio@polimi.it
Received December 20, 2006
ABSTRACT
Condensation between N-alkyl, N′-aryl carbodiimides and malonic acid monoesters leads to a high-yield formation of N-acyl urea derivatives
that could be cyclized to C-monosubstituted barbiturates by addition of a suitable base in a one-pot sequential fashion. In the presence of an
electrophile, the last step gives rise to a one-pot, three-component sequential synthesis of fully substituted barbiturates.
The main emphasis of the pharmaceutical industry’s im-
proved performance in the reaction synthesis of targets was
the demonstration of considerable waste reduction by reduc-
ing the number of isolations of intermediates along a given
pathway by concatenating one reaction into the next.1
Efficiency is also being currently pursued, when possible,
by implementation of classical multicomponent reactions
(MCRs) as well as by the invention of new ones.2 In this
context, one-pot MC sequential synthesis features a high
degree of reaction mass efficiency3 and is especially suited
for applications in combinatorial chemistry and diversity-
oriented synthesis.
used in the manufacturing of plastics,5 textiles,6 and poly-
mers7 and as useful building blocks in assembling supramo-
lecular structures via noncovalent interactions.8 The fact that
barbituric acid derivatives have been employed in medicinal
practice for a long time by no means implies that all of the
problems related to their synthesis are solved. The general
route for their preparation is through the condensation of
urea and malonic ester derivatives with sodium alcolate in
dry ethanol or DMSO at high temperature.9 However, the
yields of this reaction are often low due to the presence of
side reactions such as hydrolysis of the malonate, decar-
Barbiturates are a well-known class of compounds with
(4) (a) Jovanovic, M. V.; Biel, E. R. J. Org. Chem. 1987, 24, 191-204.
(b) Grams, F.; Brandstetter, H.; D’Alo`, S.; Gepperd, D.; Krell, H.-W.;
Leinert, H.; Livi, V.; Menta, E.; Oliva, A.; Zimmermann, G. Biol. Chem.
2001, 382, 1277-1285. (c) Maquoi, E.; Sounni, N. E.; Devy, L.; Oliver,
F.; Frankenne, F.; Krell, H.-W.; Grams, F.; Foidart, J.-M.; Noe¨l, A. Clin.
Cancer Res. 2004, 10, 4038-4047.
various pharmacological activities4 and have been widely
§ This communication is dedicated to Prof. Pierfrancesco Bravo on the
occasion of his retirement.
† Dipartimento di Chimica, Materiali ed Ingegneria Chimica “G. Natta”
del Politecnico di Milano.
(5) Thetford, D.; Chorlton, A. P.; Hardman Dyes Pigm. 2003, 59, 185-
‡ C.N.R. Istituto di Chimica del Riconoscimento Molecolare.
(1) Andersonn, N. G. Pratical Process Research and DeVelopment;
Academic Press: San Diego, 2000.
191.
(6) Bartzatt, R. J. Pharm. Biomed. Anal. 2002, 29, 909-915.
(7) (a) Andreu, R.; Garin, J.; Orduna, J.; Alcala, R.; Villacumpa, B. Org.
Lett. 2003, 5, 3143. (b) McClenaghan, N. D.; Absalon, C.; Bassani, D. M.
J. Am. Chem. Soc. 2003, 125, 13004.
(8) (a) Prins, L. J.; Jolliffe, K. A.; Hulst, R.; Timmerman, P.; Reinhoudt,
D. N. J. Am. Chem. Soc. 2000, 122, 3617-3627. (b) Timmerman, P.; Prins,
L. J. Eur. J. Org. Chem. 2001, 3191-3205.
(2) For an overview of multicomponent reactions, see: (a) Multicom-
ponent Reactions; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH: Weinheim,
Germany, 2005. (b) Multicomponent reactions. Marek, I., Ed.; Tetrahedron
Symposium-in-Print No. 114. Tetrahedron 2005, 61, 11309-11519.
(3) Andraos, J. Org. Process Res. DeV. 2005, 9, 149-163.
10.1021/ol063074+ CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/07/2007

Table 1. Three-Component Sequential Synthesis of Barbiturates 1a,e Using the NaOH\Dioxane Protocol
boxylation, transesterification, and urea degradation.10 With
this in mind, we aimed at developing a new synthesis of
barbiturates that was practical, experimentally simple, and
efficient for the one-pot generation of several new chemical
bonds.
Carbodiimides12 when reacted with carboxylic acids
rapidly form O-acyl isourea intermediates that in the absence
Recently, we demonstrated that the reaction of activated
R,â-unsaturated carboxylic acids with carbodiimides that
occurs through a novel one-pot multistep reaction represents
a viable entry to hydantoines.11 Now we show that the
reaction of N-alkyl, N′-aryl carbodiimides 4 (Figure 1) with
malonic acid monoesters 3 in the presence of alkyl halides
that takes place through a three-component, one-pot sequen-
tial process involving N-acyl ureas 2 as intermediates affords
a wide array of structurally diverse barbiturates 1.
The starting malonic acid monoesters 3a-c were prepared
either by alkylation of the commercially available benzyl
ethylmalonate 5 promoted by NaH in DMF followed by
hydro-debenzylation or by carboxylation of the corresponding
metalated ethyl ester 6 with CO2 (Scheme 1).
Figure 1. Retrosynthetic analysis.
of a nucleophile undergo a rearrangement, the so-called O
f N acyl migration, to give N-acyl ureas.13 Because it was
known that treatment of N-acyl ureas of type 2 with aqueous
NaOH in dioxane promotes ring closure affording barbitu-
rates in good yields,14 we decided to use these conditions to
perform our MC reaction in a sequential fashion. Accord-
(9) Weygand/Hilgetag PreparatiVe Organic Chemistry; Wiley: New
York, 1972; p 493. For a recent improvement of this reaction by microwave
irradiation, see: Devi, I.; Bhuyan, P. J. Tetrahedron Lett. 2005, 46, 5727-
5729.
(10) Beres, J. A.; Pearson, D. E.; Bush, M. T. J. Med. Chem. 1967, 10,
1078-1080.
(11) Volonterio, A.; Ramirez de Arellano, C.; Zanda, M. J. Org. Chem.
2005, 70, 2161-2170 and references therein.
842
Org. Lett., Vol. 9, No. 5, 2007

Table 2. Three-Component Sequential Synthesis of Barbiturates 1f,o Using the K2CO3\CH3CN Protocol
ingly, the condensation between carboxylic acid 3a (Table
1, entry 1) and carbodiimide 4a in dioxane (rt, overnight)
followed by one-pot addition of a 2 N NaOH aqueous
solution gave the barbituric acid 1a in a few minutes and in
very good yields.
Unfortunately, the addition of the electrophile after the
cyclization step gave satisfactory yields only with highly
reactive benzyl bromides (Table 1, entries 2-5). Other
halides, such as alkyl and even allyl halides, gave very poor
yields or did not react at all.15 Moreover, only barbiturates
that were N-aromatic “neutral” (Table 1, entry 2) or electron
rich (Table 1, entries 3-5) gave the desired products,
whereas electron-poor N-aryl barbiturates and C-aryl-
Scheme 1. Synthesis of the Starting Malonic Acid Monoesters
3
Org. Lett., Vol. 9, No. 5, 2007
843

substituted malonic acid monoester 3c did not react with any
benzyl halide affording only monosubstituted barbiturates.
Surprisingly, in the literature, we could not find any simple
general procedure for the C-alkylation of barbituric acids.
Thus, after screening several combinations of solvents and
bases for sequential cyclization and alkylation of N-acyl ureas
2, we were able to find a suitable procedure consisting of
the use of a suspension of anhydrous K2CO3 in acetonitrile
in a sealed tube at 120 °C (Table 2). 2-Octyl malonic acid
monoesters 3a underwent a three-component reaction with
electron-rich carbodiimide 4a and n-propyl iodide 7e (Table
2, entry 1) or n-octyl bromide 7f (Table 2, entry 2) producing
C-disubstituted barbiturates 1f and 1g, respectively, in very
good yields.
Even when 3a was reacted with the electron-poor carbo-
diimide 4c, the final products 1h-j were obtained in
excellent to good yields depending on the reactivity of the
alkyl halide used in the third step of the sequential pathway
(Table 2, entries 3-5, respectively). 2-Phenylmalonic acid
monoethyl ester 3c reacted with electron-rich carbodiimide
4a giving rise to the formation of C-disubstituted barbiturates
1k,l in very good yield with highly reactive benzyl bromide
7a and allyl bromide 7g, respectively (Table 2, entries 6 and
7), whereas with the less reactive n-propyl iodide 7e, the
final product 1m was obtained in acceptable yield (Table 2,
entry 8). 3c reacted also with phenyl-substituted carbodiimide
4b in the presence of n-hexyl iodide 7i giving rise to the
formation of barbiturate 1n in acceptable yield (Table 2, entry
9). Finally, alkylation of the barbiturate obtained by con-
densation of electron-poor carbodiimide 4c with 3c occurred
only with highly reactive alkyl halides such as allyl bromide
7g (Table 2, entry 10), whereas no reaction was detected
with less reactive 3-phenylethyl bromide 7h (Table 2, entry
11).
In conclusion, we have developed a novel and efficient
process for the synthesis of a wide range of structurally
diverse N-alkyl, N′-aryl barbiturates by a three-component
sequential reaction involving malonic acid monoesters,
carbodiimides, and alkyl halides. This process generates
compounds with a high level of diversity from simple and
readily accessible starting materials. Furthermore, the op-
erational simplicity and good chemical yield, combined with
favorable atom-economy aspects and a small number of
steps, make this new synthetic strategy highly attractive and
promising for the preparation of barbiturate compounds with
potential synthetic and biological uses.
Acknowledgment. Politecnico di Milano and CNR are
gratefully acknowledged for economic support.
(12) For a review on carbodiimide chemistry, see: Williams, A.; Ibrahim,
I. T. Chem. ReV. 1981, 81, 589-636. For a pioneering work on the synthesis
of barbituric acids from malonic acids and carbodiimides, see: Bose, K.
A.; Garratt, S.; Pelosi, J. J. J. Org. Chem. 1963, 28, 730-733.
(13) (a) Rebek, J.; Fitler, D. J. Am. Chem. Soc. 1973, 95, 4052-4053.
(b) Rebek, J.; Feitler, D. J. Am. Chem. Soc. 1974, 96, 1606-1607. (c) Rebek,
J.; Feitler, D Int. J. Pept. Protein Res. 1975, 7, 167.
(14) Graziano, M. L.; Cimminiello, G. Synthesis 1989, 1, 54-56.
(15) Increasing the temperature during the last step resulted in the
formation of complex mixtures.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL063074+
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