Multicomponent, one-pot sequential synthesis of 1,3,5- and 1,3,5,5-substituted barbiturates

Article abstract of DOI:10.1021/jo801288s

(Chemical Equation Presented) Carbodiimides and malonic acid monoethylesters readily react to afford N-acylurea derivatives that could be cyclized in situ by addition of a suitable base. This process represents a general and straightforward one-pot sequential synthesis of 1,3,5-trisubstituted barbiturates in very mild conditions (organic solvent/2 N NaOH aqueous solution, 20°C). Performing the reaction in the presence of an electrophile resulted in the formation of fully substituted (namely, 1,3,5,5- tetrasubstituted) barbiturates through a three-component one-pot sequential process. The latter, however, occurred only with highly reactive electrophiles, such as benzyl and, in some instances, allyl halides. In order to expand the scope of the process, we sought to develop a general method for the C-alkylation of 1,3,5-trisubstituted barbiturates. We found that C-alkylation occurred upon treatment of 1,3,5-trisubstituted barbiturates with an alkyl halide in CH ₃CN at 120°C in the presence of anhydrous K₂CO ₃ affording the target 1,3,5,5-tetrasubstituted barbiturates in good yields. The multicomponent process was accomplished by combining the three steps in a one-pot sequential fashion, i.e., the condensation of carbodiimides with malonic acid monoethylesters, the cyclization of the resulting N-acylureas, and the C-alkylation of the resulting 1,3,5-substituted barbiturates. A detailed study of the influence of the structure of the reactants on the reaction outcome and mechanism is presented. By selective N′-deprotection of 1,3,5,5-tetrasubstituted barbiturates, the corresponding 1,5,5-trisubstituted barbiturates were also prepared.

Full text of DOI:10.1021/jo801288s

Multicomponent, One-Pot Sequential Synthesis of 1,3,5- and
1,3,5,5-Substituted Barbiturates†
Alessandro Volonterio*,‡,§ and Matteo Zanda*,§
Dipartimento di Chimica, Materiali e Ingegneria Chimica “G. Natta” del Politecnico di Milano and
C.N.R.-Istituto di Chimica del Riconoscimento Molecolare, Sezione “A. Quilico”, Via Mancinelli 7,
I-20131 Milano, Italy
alessandro.Volonterio@polimi.it
ReceiVed June 17, 2008
Carbodiimides and malonic acid monoethylesters readily react to afford N-acylurea derivatives that could
be cyclized in situ by addition of a suitable base. This process represents a general and straightforward
one-pot sequential synthesis of 1,3,5-trisubstituted barbiturates in very mild conditions (organic solvent/2
N NaOH aqueous solution, 20 °C). Performing the reaction in the presence of an electrophile resulted in
the formation of fully substituted (namely, 1,3,5,5-tetrasubstituted) barbiturates through a three-component
one-pot sequential process. The latter, however, occurred only with highly reactive electrophiles, such as
benzyl and, in some instances, allyl halides. In order to expand the scope of the process, we sought to
develop a general method for the C-alkylation of 1,3,5-trisubstituted barbiturates. We found that
C-alkylation occurred upon treatment of 1,3,5-trisubstituted barbiturates with an alkyl halide in CH3CN
at 120 °C in the presence of anhydrous K2CO3 affording the target 1,3,5,5-tetrasubstituted barbiturates
in good yields. The multicomponent process was accomplished by combining the three steps in a one-
pot sequential fashion, i.e., the condensation of carbodiimides with malonic acid monoethylesters, the
cyclization of the resulting N-acylureas, and the C-alkylation of the resulting 1,3,5-substituted barbiturates.
A detailed study of the influence of the structure of the reactants on the reaction outcome and mechanism
is presented. By selective N′-deprotection of 1,3,5,5-tetrasubstituted barbiturates, the corresponding 1,5,5-
trisubstituted barbiturates were also prepared.
Introduction
thereby producing a sequential reaction process. One-pot
processes involving sequential steps are subdivided into two
main families, i.e., domino reactions and consecutive reactions,
independently of the reaction mechanism.2 In domino (often
referred to as tandem or cascade) reactions, reagents and
catalysts are mixed together and experimental conditions are
Although the past 50 years have witnessed extraordinary
progress in the discovery of new reagents, reactions, and
synthetic strategies,1 the tools of synthetic organic chemistry
are often found inadequate when confronted with the challenge
of preparing even modestly elaborate molecules in practical
fashion. One powerful approach toward this goal is to combine
two or more distinct reactions into a single transformation,
(2) For recent reviews, see: (a) Tietze, L. F. Chem. ReV. 1996, 96, 115–136.
(b) Denmark, S. E.; Thorarensen, A. Chem. ReV. 1996, 96, 137–165. (c) Winkler,
J. D. Chem. ReV. 1996, 96, 167–176. (d) Ryu, I.; Sonoda, N.; Curran, D. P.
Chem. ReV. 1996, 96, 177–194. (e) Parsons, P. J.; Penkett, C. S.; Shell, A. J.
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Malacria, M. Chem. ReV. 1996, 96, 289–306. (i) Molander, G. A.; Harris, C. R.
Chem. ReV. 1996, 96, 307–338. (j) Tietze, L. F.; Beifuss, U. Angew. Chem., Int.
Ed. Engl. 1993, 32, 131–163. (k) Ho, T.-L. Tandem Organic Reactions; Wiley
& Sons: New York, 1992.
† In memory of Prof. Ombretta Porta.
‡ Politecnico di Milano.
§ Istituto di Chimica del Riconoscimento Molecolare.
(1) (a) ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vols. 1-9. (b) Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley & Sons: New York, 1995; Vols.
1-8.
7486 J. Org. Chem. 2008, 73, 7486–7497
10.1021/jo801288s CCC: $40.75 2008 American Chemical Society
Published on Web 08/28/2008

Synthesis of 1,3,5- and 1,3,5,5-Substituted Barbiturates
FIGURE 1. Three-component one-pot synthesis of N-alkyl,N′-aryl barbiturates.
set up in such a way to promote the reaction cascade: each bond-
forming step results as a consequence of the functionality left
by the previous reaction. In consecutive reactions the first step
does not promote the second one and external reagents or
changes in reaction conditions are required to favor propagation.
Both processes allow the efficient construction of complex
molecules from simple precursors in a minimum number of steps
and are ideally suited for the generation of structurally diverse
libraries of small molecules. One-pot processes involving
sequential steps are further divided into unicomponent, in which
a single starting molecule undergoes a sequence of intramo-
lecular processes, and multicomponent (MC) processes.3 Ef-
ficiency is also being pursued, when possible, by implementation
of classical MC reactions, as well as by the invention of new
ones. In this context “one-pot” MC sequential syntheses in which
a number (g2) of synthetic steps involving two or more
reactants are carried out in the same flask without isolation of
any intermediate feature a high degree of reaction mass
efficiency4 and are especially suitable in combinatorial chemistry
and diversity-oriented synthesis programs.
Many small synthetic organic molecules with high medicinal
potential contain heterocyclic rings. The range of easily acces-
sible and suitably functionalized heterocyclic building blocks
is, however, surprisingly limited, and the construction of even
a small array of relevant heterocyclic compounds is far from
trivial. Heterocyclic chemistry therefore continues to attract the
attention of medicinal and synthetic chemists,5 and the develop-
ment of novel methodologies allowing for efficient access to
heterocycles is still highly beneficial. Traditionally, methods
based on MC reactions have proved quite efficient for the
construction of many different types of heterocycles.6 Barbi-
turates are a popular class of heterocycles with a number of
pharmacological activities7 and have been widely used also in
the manufacturing of plastics,8 textiles,9 polymers10 and as useful
building blocks in assembling supramolecular structures via
noncovalent interactions.11 In medicinal chemistry, further to
their very well-established use as hypnotics, derivatives of
barbituric acid have been reported to exhibit anticancer, ana-
leptic, immunomodulating, and anti-AIDS activity, while others
are reported to be selective matrix metalloproteinase (MMP)
inhibitors.12 The fact that barbituric acid derivatives have been
employed in medicinal practice for a long time by no means
implies that all or at least some of the problems related to their
synthesis are solved. The use of combinatorial approaches to
the synthesis of the barbiturate scaffold would be a powerful
advance in helping to speed up drug discovery. The general
route for the synthesis of barbiturates is the condensation of
urea and malonic ester derivatives with sodium alcolate in
ethanol or DMSO.13 The yields of this reaction are often modest
due to the presence of side reactions such as hydrolysis of the
malonate, decarbethoxylation, transesterification, and urea deg-
radation. Moreover, the need for dry solvents and high tem-
perature and the use of inert atmosphere and metallic sodium
hamper the use of the classical synthesis of barbiturates for
combinatorial purposes and diversity-oriented synthesis pro-
grams. Another way to prepare barbiturates could be the
alkylation of unsubstitued barbituric acid. However, to the best
of our knowledge, there was no simple general synthetic
procedure for the preparation of 5-monoalkylated barbiturates
until quite recently, when Juric et al. described an effective
reductive alkylation protocol in the presence of platinum and
palladium catalysts.14 With this in mind, we envisioned
developing a new synthesis of barbiturates that was practical
yet experimentally simple, chemically efficient by generating
multiple bonds in one pot, and tolerant of multiple functional
groups, allowing for the preparation of N-mono- and N,N′-
disubstituted 5-mono- and 5,5-disubstituted barbiturates.
Very recently, we reported a new three-component, one-pot
sequential process for the synthesis of a large array of fully
substituted structurally diverse N-alkyl,N′-aryl barbiturates.15 By
reacting N-alkyl,N′-aryl carbodiimides 2 with malonic acid
monoesters 1 we obtained the formation of N-acyl urea
derivatives 3 that underwent one-pot cyclization and alkylation
in the presence of a base and an alkylating agent affording the
desired N-alkyl,N′-aryl 5,5-disubstituted barbiturates 4 in high
yields (Figure 1).
In this paper, we provide a full account on the scope and
limits of this methodology, which has been studied in detail by
performing the reaction with other carbodiimides, namely, N,N′-
dialkyl and N,N′-diaryl carbodiimides. Moreover, we disclose
herein a practical procedure for the C-alkylation of barbituric
acids that, surprisingly, was missing in the literature. The new
results remarkably expand the scope of the process, allowing
(3) For an overview of multicomponent reactions, see: (a) Multicomponent
Reactions; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005.
(b) Marek, I. Multicomponent Reactions. Tetrahedron Symposium-in-Print No.
114. Tetrahedron 2005, 61, 11309–11519.
(4) Andraos, J. Org. Process Res. DeV. 2005, 9, 149–163.
(5) For a recent issue completely devoted to heterocycles, see: Katritzky, A.
Ed.;. Chem. ReV. 2004, 104, 2125–2812.
(6) For recent reviews, see: (a) Orru, R. V. A.; de Greef, M. Synthesis 2003,
1471–1499. (b) Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem. 2003,
34, 4101–4111. (c) Do¨mling, A. Chem. ReV. 2006, 106, 17–89.
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191.
(9) Bartzatt, R. J. Pharm. Biomed. Anal. 2002, 29, 909–915.
(10) (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.
(12) (a) Naguib, F. N. M.; Levesque, D. L.; Wang, E. -C.; Panzica, P. P.; El
Kouni, M. H. Biochem. Pharmacol. 1993, 46, 1273–1281. (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.
(13) 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.
(11) (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.
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J. Org. Chem. Vol. 73, No. 19, 2008 7487

Volonterio and Zanda
CHART 1. Synthesis of Starting Malonic Acid Monoethylesteres 1
CHART 2. Synthesis of Carbodiimides 2
for the preparation of a large array of structurally diverse 1,3,5-
and 1,3,5,5-substituted barbiturates.
groups to nucleophilic substitutions and coupling reactions.18
The mechanism and kinetics of the reaction of carbodiimides
with carboxylic acids have been extensively investigated.19
Recently carbodiimides have been also used for the synthesis
of small heterocycles containing the key N-acylurea moiety.20
In this context, we undertook a study on the synthesis of
barbiturates 11, a class of “N-acylurea-heterocycles”, through
reaction of monoesters 1 with carbodiimides 2, followed by one-
pot cyclization of the resulting N-acylurea 3 promoted by in
situ addition of a suitable base. Since treatment of N-acylureas
3 with aqueous NaOH in dioxane is known to promote ring
closure affording barbiturates in good yields,21 we decided to
study the process using dioxane and other solvents that can be
mixed with water, in order to perform the process in a “one-
pot” sequential fashion. Accordingly, malonate 1a reacted with
carbodiimides 2a,f in THF (entries 1 and 11, Table 1), dioxane
(entries 2 and 12), and acetonitrile (entries 3 and 13) affording
N-acylureas 3a and 3j as the only regioisomers, in good yields.
The best results were obtained in dioxane, and thus we selected
this solvent to perform the reaction in sequential manner. First,
we investigated the reaction of malonates 1 with N-alkyl,N′-
aryl carbodiimides 2a-e.
Results
Synthesis of Starting Materials. The starting C-aryl malonic
acid monoesters 1a,b were obtained in almost quantitative yields
directly by carboxylation of the corresponding metalated ethyl
esters 5a,b with solid CO2 (Chart 1, eq 1). While malonic acid
monoethylester HO2CCH2CO2Et (1e) is commercially available,
C-monoalkyl derivatives 1c,d were prepared by alkylation of
the commercially available benzyl ethylmalonate 6 promoted
by NaH in dry DMF followed by O-debenzylation (Chart 1, eq
2). Finally, C-dialkyl malonic acid monoster 1f was prepared
by sequential alkylations of 6 followed by O-debenzylation
(Chart 1, eq 3).
Carbodiimides 2,16 when not commercially available like bis-
p-tolyl carbodiimide (2f) and DIC (2i), were all prepared in good
yields by dehydration with freshly prepared bromotriphenylphos-
phorane of the corresponding ureas 10,17 which were prepared
by reaction of isocyanates 8 with amines 9 in toluene and
purified by short-path flash chromatography (Chart 2).
Synthesis of 1,3,5-Substitued Barbiturates. Carbodiimides
are very popular reagents often used to activate carboxylic acid
(18) Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77, 1067–1068.
(19) (a) Rebek, J.; Feitler, 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. Peptide Protein Res. 1975, 7, 167.
(20) Volonterio, A.; Ramirez de Arellano, C.; Zanda, M. J. Org. Chem. 2005,
70, 2161–2170.
(16) For a review on the carbodiimide chemistry, see: Williams, A.; Ibrahim,
I. T. Chem. ReV. 1981, 81, 589–636. For a pioneer 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.
(17) Palomo, C.; Mestres, R. Synthesis 1981, 373–374.
(21) Graziano, M. L.; Cimminiello, G. Synthesis 1989, 1, 54–56.
7488 J. Org. Chem. Vol. 73, No. 19, 2008

Synthesis of 1,3,5- and 1,3,5,5-Substituted Barbiturates
TABLE 1. One-Pot Sequential Synthesis of Barbituric Acids 11
entry
malonic acid
R1
carbodiimide
R2
R3
solvent
product
yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1c
1c
1c
1c
1a
1a
1a
1a
1a
1a
1c
1c
1c
1d
1a
1a
1a
1a
1d
1c
1a
1a
1a
1d
1d
Ph
Ph
Ph
Ph
Ph
Ph
2a
2a
2a
2a
2b
2c
2b
2a
2c
2b
2e
2f
2f
2f
2f
2f
2g
2f
2g
2h
2f
2i
2i
Ph
Ph
Ph
Ph
Ph
PMP
Ph
Ph
c-hexyl
c-hexyl
c-hexyl
c-hexyl
PMB
PMB
PMB
c-hexyl
PMB
PMB
Me
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
PMP
p-Tol
PMP
PMP
p-Tol
i-Pr
THF
3a
3a
3a
70a
75a
73a
68
73
85
76
75
83
75
dioxane
CH3CN
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
dioxane
CH3CN
dioxane
CH3CN
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
CH3CN
DCM
11a
11b
11c
11d
11e
11f
11g
11h
3j
4-diphenyl
n-octyl
n-octyl
n-octyl
n-octyl
Ph
Ph
Ph
Ph
Ph
9
PMP
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
p-CF3-Ph
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
PMP
p-Tol
PMP
4-NO2-Ph
p-Tol
i-Pr
80
65a
75a
70a
75
3j
3j
11j
11j
11k
11l
11m
11n
11o
3p
3p
3p
11p
3q
3r
50
82
77
71
79
74
Ph
n-octyl
n-octyl
n-octyl
ethyl
Ph
Ph
Ph
Ph
ethyl
n-octyl
Ph
Ph
Ph
0a,b
0a,b
67a,d
67a,d,e
n.d.a,c
68a,d
71a
68
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
2i
2i
2i
2i
2j
2j
2k
2k
2k
DCM
dioxane
DCM
dioxane
dioxane
dioxane
dioxane
dioxane
i-Pr
i-Pr
PMB
PMB
Bn
Bn
Bn
trityl
trityl
trityl
trityl
trityl
3s
11s
11t
3u
67
ethyl
ethyl
65a
62
11u
a Reactions stopped after formation of intermediates 3. b Only dercarboxylation occurred. c Not determined because decarboxylation occurred in much
higher yields. d Performed with 1 equiv of TMP. e The cyclization step was complete in 12 h.
Both C-aryl malonates 1a,b (entries 4-7, Table 1) and
C-monoalkyl malonate 1c (entries 8-11, Table 1) gave barbi-
turates 11a-h in good yields upon overnight reaction at room
temperature with the N-alkyl,N′-aryl carbodiimides 2a-e,
followed by in situ addition of a 2 N aqueous solution of NaOH.
This process represents a general entry to 1,3,5-substituted
barbiturates 11 because it worked well in all cases, namely, when
the aryl group R2 of the carbodiimide was “neutral” (entries 5,
7, 8, 10), electron-rich (entries 6, 9), or electron-poor (entry
11). Next, we investigated the behavior of N,N′-diaryl carbo-
diimides 2f-h. As expected, barbituric acid 11j was formed in
good yield when the two-step process was performed in dioxane
(entry 15), whereas in acetonitrile we obtained the formation
of 11j in only moderate yield (entry 16), confirming that dioxane
is the best solvent for this reaction. It is worth noting that the
reaction worked well in all cases, namely, with C-aryl malonates
1a (entries 15 and 17) and C-monoalkyl malonates 1c,d (entries
18-21) and with symmetric (entries 15-19 and 21) and
asymmetric (entry 20) carbodiimides.
major outcome (entry 26). Moreover, it was shown that
carboxylic acids possessing a strong electron-withdrawing group
in the R-position, such as malonic acids, undergo facile
dehydration upon reaction with carbodiimides to form the
corresponding highly reactive substituted ketenes.22 In order to
overcome these problems, we though to perform the reaction
using a less polar solvent, such as DCM, and in the presence
of a base, namely, sym-collidine (TMP), which should facilitate
the OfN acyl migration process leading to the formation of
the N-acylurea derivatives 3. Gratifyingly, using these conditions
we were able to suppress almost completely the above-
mentioned side reactions, obtaining N-acylureas 3p and 3r as
the major products in good yields (entries 24 and 27),
respectively from C-aryl and C-alkyl malonates 1a and 1c.
Moreover, we found that in situ addition of a 2 N aqueous NaOH
solution promoted the cyclization step under Schotten-Baumann
condition leading to the formation of barbiturates 11p in good
yield (entry 25, Table 1).23 Dialkylcarbodiimides bearing an
electron-withdrawing N-trityl substituent, such as 2j,k, reacted
smoothly in dioxane both with C-aryl malonate 1a (entry 28)
and C-monoalkyl malonate 1d (entry 31) leading to the
Unexpectedly, dialkylcarbodiimides such as DIC 2i produced
only decarboxylation of the starting malonate 1a (entries 22
and 23). Only with 2-ethyl malonate 1d, which is less acidic
than 1a, we observed the formation of the target N-acylurea
3q, albeit in very low yields since decarboxylation was still the
(22) Shelkov, R.; Nahmany, M.; Melman, A. J. Org. Chem. 2002, 67, 8975–
8982.
J. Org. Chem. Vol. 73, No. 19, 2008 7489

Volonterio and Zanda
SCHEME 1. Reaction with C-Disubstituted Malonic Acid Monoethylester 1f
formation of N-acylureas 3s and 3u, respectively, in good yields.
As expected, cyclization occurred in almost quantitative yields
(data not shown) giving rise to the formation of barbiturates
11s,t,u (entries 29, 30, 32) under the sequential reaction
conditions. Disappointingly, the reaction of C,C-dialkyl malonic
acid monoester 1f with carbodiimide 2b (Scheme 1), followed
by treatment with NaOH, did not afford the desired barbiturate
4d but the carboxylic acid 13.
In this case, the N-acylurea intermediate 12 is probably too
sterically hindered to undergo cyclization before hydrolysis of
the ethyl ester occurs. In fact, by performing only the first step
of the process we could recover the N-acylurea 12, which was
subsequently cyclized by treatment with NaH in dry DMF
affording the target barbiturate 4d.
Three-Component Sequential Synthesis of 1,3,5,5-Substi-
tuted Barbiturates Using the NaOH/Dioxane Protocol. Ac-
cording to the above-described two-step sequential process, the
cyclization step produces a barbituric carbanion that can be
quenched either by protic acids, affording the corresponding
C-monosubstituted barbiturates 11a-t, or by alkylating agents,
producing fully substituted barbiturates through a three-
component sequential process. The results obtained in the latter
process are outlined in Table 2.
Unfortunately, the addition of electrophiles after the cycliza-
tion step did not prove to be a general entry to the target 1,3,5,5-
tetrasubstituted barbiturates 4. In fact, the carbanions of
barbiturates derived from addition of N-alkyl,N′-aryl carbodi-
imide 2c to C-aryl malonate 1a resulted to be very stable and
failed to react even with benzyl bromide (14a) (entry 1, Table
2), affording the corresponding intermediate C-monosubstitued
barbiturate 11c. However, C-monoalkyl or unsubstituted mal-
onates and N-alkyl,N′-aryl carbodiimides bearing N-“neutral”
or N-electron-rich aromatic substituents reacted in the presence
of benzyl bromides affording satisfactory yields of 1,3,5,5-
tetrasubstituted barbiturates, like the 5-benzyl barbiturates 4a,b,d
(entries 2, 3, 9, respectively) or the 5,5-dibenzyl barbiturate 4g
(entry 12). The sequential process worked well also with other
benzyl bromides such as p-CF3 benzyl bromide 14b (entry 4),
p-Br benzyl bromide 14e (entry 10), and fluorenyl bromide 14f
(entry 11). Other rather reactive halides, such as allyl bromide
14c and methyl iodide 14d, did not react even with quite
nucleophilic 5-alkyl barbituric carbanions (entries 5 and 6
respectively).24 Barbiturates derived from the electron-poor
N-aryl carbodiimide 2e or from the N,N′-diaryl carbodiimide
2f failed to react even with 14a probably because the resulting
carbanions are too stabilized (entries 7 and 8, respectively).
Finally, N,N′-dialkyl barbiturates resulted to be much more
reactive than barbiturates bearing one or two aromatic rings. In
fact, N,N′-dialkyl barbiturates derived from both C-aryl malonate
1a (entries 13 and 15) and C-alkyl malonate 1d (entry 17)
reacted with 14a affording fully substituted barbiturates 4 h,j,l
in good overall yields. Surprisingly, the reaction worked
smoothly even with 14c (entries 14, 16, 18) which did not react
with any of the other barbiturates shown above.
Three-Component Sequential Synthesis of 1,3,5,5-Substi-
tuted Barbiturates Using the K2CO3/CH3CN Protocol. Al-
though the protocol above allows for the preparation of different
fully substituted barbiturates, it presents some limitations. In
order to expand the scope of the process we decided to
investigate a new, more flexible protocol for the one-pot
cyclization/alkylation steps in order to prepare a larger array of
barbiturates. First of all, we sought to find a more general
method for the C-alkylation of barbiturates that would work
not only with highly electrophilic benzyl halides. Surprisingly,
in literature we could not find any simple general procedure.
Thus, after screening several combinations of solvents and bases
we were able to find a suitable procedure consisting in the use
of a suspension of anhydrous K2CO3 in acetonitrile in a sealed
tube at 120 °C (Table 3).
Following this procedure, N-alkyl,C,N′-diaryl trisubstituted
barbiturates such as 11b,d, which were unreactive even with
14a under the NaOH/dioxane protocol, afforded the fully
substituted barbiturates 4aa and 4ab, respectively, in good yields
(entries 1 and 2, Table 3) upon alkylation with ethyl iodide 14g.
As expected, even the more nucleophilic barbiturate 11g reacted
(23) It should be noted that in this case the cyclization step resulted to be
much slower (overnight compared to 10 min). However, this should be ascribed
not only to the different conditions but also to the fact that in such reaction the
rate-determining step is the deprotonation step, which is less favored when the
two nitrogens are substituted with two electron-donating groups such as alkyl
groups: Xin, Z.; Pei, Z.; von Geldem, T.; Jirousek, M. Tetrahedron Lett. 2000,
41, 1147–1150.
(24) Increasing the temperature during the last step resulted in the formation
of complex mixtures.
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Synthesis of 1,3,5- and 1,3,5,5-Substituted Barbiturates
TABLE 2. Three-Component Sequential Synthesis of 1,3,5,5-Substituted Barbiturates 4 Using the NaOH/Dioxane Protocol
J. Org. Chem. Vol. 73, No. 19, 2008 7491

Volonterio and Zanda
TABLE 2. Continued
a The alkylation step did not occurr.
smoothly with alkyl halides, such as octyl bromide 14h,
effectively leading to the formation of the barbiturate 4ac (entry
3). The versatility of the K2CO3/CH3CN alkylation protocol is
further demonstrated by the fact that even N,N′-diaryl barbitu-
rates 11l and 11n reacted with 14g affording the desired
barbiturates 4ae and 4af in good yields (entries 5 and 6). As
the only exception, C,N,N′-triaryl barbiturates such as 11j, did
not react in these conditions. However, the alkylated barbiturate
4ad was obtained in good yield (entry 4, Table 3) performing
the reaction in DMF at 80 °C. The three components one-pot
sequential process for the synthesis of fully substituted barbi-
turates (see Table 2) was therefore adapted to the optimized
alkylation conditions with K2CO3/CH3CN (Table 4).
The malonate 1a underwent three-component reaction with
the electron-rich carbodiimide 2c and benzyl bromide 14a (entry
1, Table 4), allyl bromide 14c (entry 2), and even with the less
reactive propyl iodide 14g (entry 3, Table 4) producing the
C-disubstituted barbiturates 4ag-ai, respectively, in very good
yields. The process worked well even when malonates 1a and
1b were reacted with the “neutral” carbodiimide 2b and 1-iodo-
hexane 14i (entries 4 and 5), producing the barbiturates 4aj and
4ak, respectively, in reasonable yields. However, 1a and the
7492 J. Org. Chem. Vol. 73, No. 19, 2008

Synthesis of 1,3,5- and 1,3,5,5-Substituted Barbiturates
TABLE 3. Alkylation of Barbituric Acids 11
entry
barbituric acid
R1
R2
R3
R4
product
yield (%)
1
2
3
4
5
6
11b
11d
11g
11j
11l
Ph
Ph
Ph
Ph
p-Tol
p-Tol
PMB
PMB
PMB
p-Tol
p-Tol
PMP
CH3CH2I, 14g
CH3CH2I, 14g
CH3(CH2)7Br, 14h
CH3(CH2)5I, 14i
CH3CH2I, 14g
CH3CH2I, 14g
4aa
4ab
4ac
4ad
4ae
4af
73
65
78
68a
94
75
biphenyl
n-octyl
Ph
n-octyl
n-octyl
11n
4-NO2-Ph
a Reaction performed in DMF at 80 °C.
electron-poor carbodiimide 2e underwent reaction only with 14c,
affording the fully substituted barbiturate 4al (entry 6), whereas
with 14g (entry 7) we did not observe the formation of the
desired barbiturate. The more reactive 2-octyl malonate 1c,
instead, gave the desired 5,5-dialkylated barbiturates in all cases
when reacted with N-alkyl,N′-aryl carbodiimides. Thus, 1c
reacted smoothly with the electron-rich carbodiimide 2c and
alkyl halides 14g and 14j, affording the barbiturates 4am and
4an, respectively, in excellent yields (entries 8 and 9). Even
the electron-poor carbodiimide 2e, which failed in the three-
component process with C-aryl malonates such as 1a, reacted
successfully with 1c and allyl bromide 14c, iodo propane 14g
and 3-phenethyl bromide 14k affording the C,C-disubstituted
barbiturates 4ao, 4ap, and 4aq, respectively, in good yields,
(entries 10-12). Unsubstituted malonate 1e underwent four-
component one-pot sequential process when reacted with
carbodiimides 2b,c and alkyl bromides 14j affording C-
disubstituted barbiturates 4ac (entry 14) and 4an (entry 13),
respectively, in acceptable yields. Unfortunately, the three-
component process did not work when performed with N,N′-
diaryl carbodiimides, such as 2f and 2h (entries 15-17, Table
4). It should be noted, however, that C-alkyl and C-aryl-N,N′-
diaryl barbiturates can be successfully reacted with alkyl halides
giving 5,5-substituted barbiturates in very good yields (see
Table 3).25
The sequence involves a first proton transfer from the
carboxylic acids 1 to the basic nitrogen of the carbodiimide 2
followed by reversible addition of the carboxylate to form the
O-acyl-isourea intermediate 15. The latter is a reactive species
that, in the absence of a nucleophile, can undergo a rearrange-
ment, the so-called OfN acyl migration, to give N-acylurea
derivatives 3. To obtain the formation of 3 in good yield, one
should suppress two side processes that could arise when
malonic acids such as 1 are used. In fact, it is known that, once
formed, malonic carboxylates easily undergo decarboxylation.
C-Alkyl and, even more, C-aryl malonic acid monoethylesteres
are prone to decarboxylation when treated with dialkyl carbo-
diimides such as DIC (see entries 22, 23, 26, Table 1), because
these carbodiimides are less electrophilic and the equilibrium
leading to 15 is less shifted to the right, thus favoring the loss
of CO2 leading to 16. In fact when the reaction was carried out
with more electrophilic N-alkyl,N′-aryl or N,N′-diaryl and even
N-alkyl,N′-trityl carbodiimides, the corresponding N-acylureas
3 were formed in good yields. Moreover, the intermediate
O-acyl-isourea 15 can undergo elimination of urea leading to
the formation of the highly reactive ketene 17 that, in the
absence of a nucleophile, could react with a molecule of
carbodiimide leading to the formation of a [4 + 2] cycloadduct
18. Again, we observed the formation of 18 as a byproduct only
when the reaction was carried out with basic DIC and C-
monoalkyl malonic acid monoethylesters. However, performing
the condensation between DIC and malonic acid monoethyl-
esters in low polarity solvents, such DCM, and in the presence
of an equivalent of a base, i.e., TMP, which facilitated the OfN
acyl migration process, we were able to suppress almost entirely
the formation of 18, leading to the formation of the N-acylureas
3 in good yields (see entries 24, 27, Table 1). N-Acylureas 3
could be cyclized and alkylated upon in situ treatment with a
base (that should be compatible with the solvent used for their
generation), followed by an electrophile, producing a one-pot
three-component sequential process leading to the target sub-
stituted barbiturates. Two different protocols were explored,
namely, a “soft” protocol consisting in the treatment with
aqueous 2 N NaOH in dioxane at room temperature and a “hard”
protocol consisting in the use of anhydrous K2CO3 in CH3CN
at high temperature. The choice of the most appropriate protocol
depends on the reactivity of the electrophile and of the resulting
carbanion 20, which is strongly stabilized by the two adjacent
carbonyl groups. Moreover, the nucleophilicity of 20 depends
on (1) the substituents on the nitrogen atoms and (2) the
substituent R1. When such substituents are electron-withdrawing
Moreover, starting from carbodiimides with cleavable N-
substituents, we could synthesize the corresponding N-mono-
substituted barbiturates 24. For instance, the trityl group and
the p-methoxy benzyl group could be easily cleaved forming
N-alkyl or N-aryl monosubstituted barbiturates 24, respectively
(Table 5).
Discussion
The full reaction sequence of the MC one-pot process leading
to 1,3,5,5-substituted barbiturates 4 or 1,3,5-trisubstituted
barbiturates 11 is portrayed in Scheme 2.
(25) Because alkylation of C,N,N-triaryl barbituric acids occurred only in
DMF at 80 °C (see entry 4, Table 3), we tried to perform the three-component
process in such conditions. However, the condensation between carbodiimide
2f and acid 1a in DMF afforded exclusively the decarboxylation product, which
subsequently underwent alkylation by iodopropane 14g.
J. Org. Chem. Vol. 73, No. 19, 2008 7493

Volonterio and Zanda
TABLE 4. Three-Component Sequential Synthesis of 1,3,5,5-Substituted Barbiturates 4 with the K2CO3/CH3CN Protocol
7494 J. Org. Chem. Vol. 73, No. 19, 2008

Synthesis of 1,3,5- and 1,3,5,5-Substituted Barbiturates
TABLE 4. Continued
a Alkylation did not occur. b Degradation of the starting material occurred during the alkylation step. c The cyclization step failed.
TABLE 5. Synthesis of N-Monosubstituted Barbiturates 24
entry
barbiturate
R1
R4
Ar or Alk
method
product
yield (%)
1
2
3
4
5
6
4a
4aa
4ak
4j
4k
4l
n-octyl
Ph
biphenyl
Ph
Ph
ethyl
benzyl
ethyl
n-hexyl
benzyl
allyl
Ph
Ph
Ph
benzyl
benzyl
benzyl
A
A
A
B
B
B
24a
24b
24c
24d
24e
24f
76
85
82
92
89
93
benzyl
aromatic rings, the negative charge is further stabilized rendering
dialkyl carbodiimides are more nucleophilic than those derived
20 even less nucleophilic. Thus, barbiturates derived from N,N′-
from N-alkyl,N′-aryl carbodiimides, which in turn are more
J. Org. Chem. Vol. 73, No. 19, 2008 7495

Volonterio and Zanda
SCHEME 2. Mechanism of the Three-Component Sequential Process
nucleophilic than N,N′-diaryl barbiturates. Accordingly, 5-alkyl
barbiturate carbanions having at least one N-alkyl group were
able to react only with highly electrophilic benzyl halides using
the “soft” protocol, whereas more stabilized 5-aryl derivatives
were unreactive. It is worth nothing that N,N′-dialkyl barbitu-
rates, independently of the nature of the R1 substituent, could
be alkylated with both benzyl and allyl bromides following the
“soft” protocol (see entries 13-18, Table 2). Barbiturates
derived from N,N′-diaryl carbodiimides could not be alkylated
by means of the “soft” protocol. However, all of the barbiturate
carbanions could be C-alkylated using the “hard” protocol,
regardless of the N-substituents, with a wide range of alkyl
halides providing a general method for the synthesis of fully
substituted barbiturates (see Table 3). Unfortunately, when the
one-pot sequential process was carried out according to the
“hard” protocol, we discovered that the cyclization step failed
with N,N′-diaryl substrates (see Table 4). In these cases the anion
of 1,3,5-trisubstituted barbiturates, using mild conditions ex-
ploiting a one-pot sequential process starting from easily
accessible starting materials such as carbodiimides and C-
monosubstituted malonic acids monoethylesteres. We have also
studied in detail the reactivity of the target barbiturates toward
alkyl halides, which was found to be strongly dependent on the
stabilization of the barbituric carbanion intermediates and
therefore on the malonic acids substituent R1 as well as on the
N-substituents R2 and R3. By combining the two processes,
namely, the cyclization and the C-alkylation, we have finally
developed two different protocols for the combinatorial synthesis
of 1,3,5,5-tetrasubstituted barbiturates through a three-compo-
nent one-pot sequential process. A large array of structurally
diverse barbiturates can be synthesized through this method,
which appears particularly suitable for solid phase/combinatorial
chemistry.
19 (Scheme 2) is likely to be too stable to undergo sufficiently
rapid cyclization, and therefore elimination of the corresponding
isocyanate becomes competitive, leading to the formation of
the amide 23. However, this is not a big limitation because the
corresponding N,N′-diaryl barbiturates could be easily synthe-
tizated through a stepwise process, namely, the synthesis of the
C-monosubstituted barbiturate through the “soft” NaOH pro-
tocol, and chromatographic isolation followed by alkylation,
using the “hard” protocol (K2CO3 in CH3CN, 120 °C, or DMF
at 80 °C for N,N′-diaryl-C-aryl barbiturates) (see Table 3). In
all other cases, the three-component one pot sequential process
produced the desired fully substituted barbiturates in good yields.
Experimental Section
General Procedure for the Synthesis of 1,3,5-Substituted
Barbiturates 11. To a stirred solution of malonic acid monoesters
1 (1 equiv) in dioxane (0.1 M solution) was added carbodiimide 2
(1.1 equiv), and the mixture was stirred at room temperature
overnight. A 2 N aqueous NaOH solution was added, and when
the cyclization was complete (typically 10 min, TLC monitoring),
a 1 N aqueous HCl solution was added until acidic pH was reached.
The mixture was extracted with AcOEt; the combined organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated under
vacuum; and the crude was purified by flash chromatography
affording 11.
When DIC was used as the carbodiimide component, the reaction
was carried out in DCM in the presence of 1 equiv of TMP, and
the cyclization step was run overnight.
Conclusions
In summary, we have developed a general, straightforward,
and high-yielding method for the preparation of a large array
1-Cyclohexyl-3,5-diphenylpyrimidine-2,4,6(1H,3H,5H)-tri-
one 11a. Rf ) 0.48 (hexane/AcOEt ) 70:30); FTIR (nujol) ν 1711,
7496 J. Org. Chem. Vol. 73, No. 19, 2008

Synthesis of 1,3,5- and 1,3,5,5-Substituted Barbiturates
1695 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.31 (m, 8H), 7.16 (m,
2H), 4.76 (s, 1H), 4.66 (m, 1H), 2.31 (m, 1H), 2.26 (m, 1H), 1.81
(m, 2H), 1.65 (m, 3H), 1.33 (m, 2H), 1.18 (m, 1H); 13C NMR (100.6
MHz, CDCl3) δ 167.3, 166.9, 151.2, 134.4, 133.5, 129.6, 129.4,
129.1, 128.9, 128.3, 127.3, 56.8, 56.0, 29.6, 28.5, 26.3, 26.1, 25.0;
ESI (m/z) 385.1 [M+ + Na, (48)], 363.2 [M+ + 1, (100)]; HRMS
calcd for [C22H22N2O3] 362.1625, found 362.1629.
General Procedure for the Synthesis of 1,3,5,5-Substituted
Barbiturates 4 under NaOH\Dioxane Protocol. To a stirred
solution of malonic acid monoesters 1 (1 equiv) in dioxane (0.1 M
solution) was added carbodiimide 2 (1.1 equiv), and the mixture
was stirred at room temperature overnight. A 2 N aqueous NaOH
solution was added, followed by neat benzyl halide 14 (4 equiv)
upon completion of the cyclization (typically 10 min, TLC
monitoring). After 1 h the solution was acidified with a 1 N aqueous
HCl solution and extracted with AcOEt; the combined organic
layers were dried over anhydrous Na2SO4, filtered, and concentrated
under vacuum; and the crude was purified by flash chromatography
affording 4.
1-(4-Methoxybenzyl)-3-(4-methoxyphenyl)-5-octyl-5-propyl-
pyrimidine-2,4,6-trione 4am. Rf ) 0.60 (hexane/AcOEt ) 80:
20); FTIR (nujol) ν 1699, 1688 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.41 (d, J ) 8.9 Hz, 2H), 7.05 (d, J ) 8.9 Hz, 2H), 6.99 (d, J )
8.9 Hz, 2H), 6.84 (d, J ) 8.9 Hz, 2H), 5.07 (s, 2H), 3.84 (s, 3H),
3.79 (s, 3H), 2.02 (m, 2H), 1.18 (m, 14H), 0.89 (t, J ) 7.0 Hz,
3H), 0.86 (t, J ) 7.5 Hz, 3H); 13C NMR (125.7 MHz, CDCl3) δ
172.1, 172.0, 159.8, 159.3, 151.0, 130.8, 129.3, 128.6, 127.2, 114.7,
113.8, 57.0, 55.5, 55.2, 44.7, 42.3, 40.6, 31.7, 29.4, 29.1, 29.0, 25.0,
22.6, 18.5, 14.0, 13.9; ESI (m/z) 531.3 [M+ + Na, (100)], 509.3
[M+ + 1, (98)]; HRMS calcd for [C30H40N2O5] 508.2927, found
508.2032.
General Procedure for the N-PMB Deprotection of 4 to 24.
To a solution of the barbiturate 4 (1 equiv) in CH3CN (0.1 M
solution) was added a solution of CAN (4 equiv) in water (0.8 M
solution) dropwise at 0 °C. The temperature was raised to room
temperature, and when the starting material disappeared (TLC
monitoring) the mixture was diluted with water and extracted with
AcOEt. The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated under vacuum, and the crude
was purified by flash chromatography to give 24.
5-Benzyl-5-ethyl-1-(4-methoxybenzyl)-3-phenyl-pyrimidine-
2,4,6-trione 4d. Rf ) 0.45 (hexane/AcOEt ) 80:20); FTIR (nujol)
1
ν 1698, 1687 cm-1; H NMR (400 MHz, CDCl3) δ 7.40 (m, 4H),
5-Benzyl-5-octyl-1-phenylpyrimidine-2,4,6(1H,3H,5H)-tri-
one 24a. Rf ) 0.43 (hexane/AcOEt ) 80:20); FTIR (nujol) ν 3250,
7.33 (d, J ) 7.6 Hz, 2H), 7.22 (m, 1H), 7.11 (m, 2H), 6.95 (d, J )
7.9 Hz, 2H), 6.83 (d, J ) 7.6 Hz, 2H), 6.81 (m, 1H), 4.98 (d, J )
13.7 Hz, 1H), 4.86 (d, J ) 13.7 Hz, 1H), 3.81 (s, 3H), 3.38 (d, J
) 12.7 Hz, 1H), 3.24 (d, J ) 12.7 Hz, 1H), 2.28 (m, 2H), 0.89 (t,
J ) 7.6 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 171.5, 171.0,
159.3, 135.0, 134.5, 131.0, 129.5, 129.3, 129.0, 128.6, 128.3, 128.2,
127.6, 113.8, 59.7, 55.3, 46.1, 44.8, 33.3, 9.7; ESI (m/z) 465.2 [M+
+ Na, (100)], 443.1 [M+ + 1, (87)]; HRMS calcd for [C27H26N2O4]
442.1886, found 442.1883.
1
1707, 1694 cm-1; H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H),
7.42 (m, 3H), 7.32 (m, 3H), 7.16 (m, 2H), 6.85 (m, 2H), 3.37 (d,
J ) 13.0 Hz, 1H), 3.29 (d, J ) 13.0 Hz, 1H), 2.30 (m, 2H), 1.28
(m, 12H), 0.90 (t, J ) 7.2 Hz, 3H); 13C NMR (400 MHz, CDCl3)
δ 171.8, 171.3, 148.7, 134.8, 133.6, 129.6, 129.4, 129.2, 128.8,
128.2, 128.0, 59.3, 45.8, 39.5, 31.8, 29.5, 29.2, 29.1, 25.5, 22.6,
14.1; ESI (m/z) 429.2 [M+ + Na, (100)], 407.2 [M+ + 1, (48)].
General Procedure for the N-Trityl Deprotection of 4 to 24.
To a solution of barbiturate 4 (1 equiv) in DCM (0.025 M solution)
was added Et3SiH (4 equiv) at room temperature followed by TFA
(0.25% in volume). When the starting material disappeared (TLC
monitoring) a 5% NaHCO3 aqueous solution was added until basic
pH was reached. The mixture was extracted with DCM; the
combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated under vacuum; and the crude was purified
by flash chromatography affording 24.
General Procedure for the Alkylation of Barbiturates 11 to
4. A suspension of barbituric acid 11 (1 equiv), anhydrous K2CO3
(1.2 equiv), and alkyl halide 14 (2.1 equiv) in CH3CN (0.1 M
solution respect to the acid) was charged in a sealed tube and heated
at 120 °C. When the starting material disappeared (TLC monitoring)
the temperature was lowered to room temperature, water was added,
and the mixture was extracted with AcOEt. The combined organic
layers were dried over anhydrous Na2SO4, filtered, and concentrated
under vacuum, and the crude purified by flash chromatography
affording 4.
1,5-Dibenzyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione 24d.
Rf ) 0.25 (hexane/AcOEt ) 80:20); FTIR (nujol) ν 3124, 1715,
In the case of C-aryl barbituric acids 11 bearing two aromatics
at the nitrogen atoms, the reaction was carried out in DMF at
80 °C.
1
1696 cm-1; H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.34 (m,
5H), 7.26-7.10 (m, 10H), 4.95 (s, 2H), 3.80 (s, 2H); 13C NMR
(400 MHz, CDCl3) δ 170.7, 169.9, 149.4, 137.9, 135.9, 135.2,
130.6, 129.6, 129.1, 128.9, 128.8, 128.2, 127.8, 126.8, 62.7, 45.2,
42.6; ESI (m/z) 407.5 [M+ + Na, (21)], 385.2 [M+ + 1, (100)].
General Procedure for the Synthesis of 1,3,5,5-Substituted
Barbiturates 4 under the K2CO3/CH3CN Protocol. In a sealed
tube, carbodiimide 2 (1.1 equiv) was added to a stirred solution of
malonic acid monoester 1 (1 equiv) in CH3CN (0.1 M solution),
and the mixture was stirred at room temperature overnight. Solid
anhydrous K2CO3 (2.1 equiv) followed by alkyl halide 14 (4 equiv)
was added, and the mixture was heated at 120 °C. After the reaction
was complete (typically 30 min for highly reactive benzyl or allyl
halides and 12 h for less reactive alkyl halides, TLC monitoring),
the mixture was cooled to room temperature, and water was added.
The mixture was extracted with AcOEt; the combined organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated under
vacuum; and the crude was purified by flash chromatography
affording 4.
Acknowledgment. Politecnico di Milano and CNR are
gratefully acknowledged for economic support.
1
Supporting Information Available: Copies of the H and
13C NMR spectra for compounds 1, 2, 3, 4, 11, and 24.
Characterization data for compounds 1a-f, 2a-k, 3a,j,p,r,s,u,
4a-c,e-m,aa-al,an-ar, 11b-u, and 24a-c,e-f. This mate-
rialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO801288S
J. Org. Chem. Vol. 73, No. 19, 2008 7497