Three-component sequential synthesis of N,N′-disubstituted 5-arylidenedihydropyrimidine-2,4-dione

Article abstract of DOI:10.1016/j.tetlet.2012.06.109

A three-component sequential process consisting in (1) in situ formation of carbodiimides by Staudinger reaction, (2) reaction with 2-(bromomethyl)-3-aryl- 2-propenoic acids, and (3) final cyclization of the resulting N-acylurea intermediates in order to obtain the synthesis of an array of N,N′-disubstituted 5-arylidenedihydropyrimidine-2,4-dione under mild conditions is presented.

Full text of DOI:10.1016/j.tetlet.2012.06.109

Tetrahedron Letters 53 (2012) 4733–4737
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Three-component sequential synthesis of N,N0-disubstituted
5-arylidenedihydropyrimidine-2,4-dione
Maria Cristina Bellucci a, Alessandro Volonterio b,
⇑
a Dipartimento di Scienze Molecolari Agroalimentari, Università degli Studi di Milano, via Celoria 2, 20133 Milano, Italy
b Department of Chemistry, Materials and Chemical Engineer ‘Giulio Natta’, Politecnico di Milano, via Mancinelli 7, 20131 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A three-component sequential process consisting in (1) in situ formation of carbodiimides by Staudinger
reaction, (2) reaction with 2-(bromomethyl)-3-aryl-2-propenoic acids, and (3) final cyclization of the
resulting N-acylurea intermediates in order to obtain the synthesis of an array of N,N0-disubstituted 5-
arylidenedihydropyrimidine-2,4-dione under mild conditions is presented.
Received 23 May 2012
Revised 19 June 2012
Accepted 25 June 2012
Available online 29 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Multi-component
Sequential synthesis
Carbodiimides
Dihydropyrimidine-2,4-dione
N-Acylurea
The development of a new multi-component (MC) coupling
process has attracted intense interest in recent years.1 Such pro-
cesses allow the efficient construction of elaborate molecules from
simple precursors in a minimum numbers of steps, and many are
ideally suited for the generation of structurally diverse libraries
of small molecules. In particular, ‘one-pot’ MC sequential synthesis
features a high degree of reaction mass efficiency, thus playing a
central role in the development of modern synthetic methodology
for pharmaceutical and drug discovery programs.2 This is particu-
larly true for the synthesis of heterocycles. Indeed, many small
synthetic molecules with high medicinal potential contain hetero-
cyclic rings. However, the range of easily accessible and suitably
functionalized heterocyclic building blocks is surprisingly limited
and the construction of even a small array of relevant heterocyclic
compounds is far from trivial.3 Thus, one of the challenges of
medicinal chemistry is the promotion of the structural diversity
of a ligand, which can be achieved by the attachment of pharmaco-
phoric groups to the rigidified molecule. Small, substituted hetero-
cyclic compounds offer a unique possibility of different kinds and
degrees of substitution. In particular, pyrimidine-2,4-diones are a
class of bioactive molecules which have attracted considerable
attention in the pharmaceutical industry as anti-inflammatory
agents,4 dopamine receptor antagonists,5 serotonin uptake inhibi-
tors,6 and antiepileptic agents.7 This moiety is also the core struc-
tural element of some fungicides8 and herbicides.9 The observed
activities usually do not arise from the heterocycle itself, but from
the different ligands that have been attached to it. For this reason
there is a lot of interest in developing new strategies for a straight-
forward synthesis of substituted pyrimidine-2,4-diones, overall if
milder than the most utilized strategies used to prepare such scaf-
folds which rely on the strongly acidic or basic cyclization of b-ure-
idopropionic acids10 or by hydrogenation of the corresponding
11
uracils.
As a part of a project aimed at developing new MC domino pro-
cess for the synthesis of small heterocycles and glyco-conjugates
by using in situ generated carbodiimides and suitable carboxylic
acids,12 we wish to report the straightforward regioselective dom-
ino synthesis of N,N0-disubstituted-5-arylidendihydropyrimidine-
2,4-diones 7 under mild conditions (room temperature, avoiding
the use of strong acids/bases), starting from easily accessible 2-
(bromomethyl)-3-aryl-2-propenoic acids 4 (Scheme 1). The reac-
tion sequence involves the synthesis in situ of the reacting carbo-
diimide
3 through Staudinger reaction starting from the
corresponding azides 1 and isocyanates 2, followed by the addition
of acids 4 into the reaction mixture which leads to the formation of
N-acylurea derivatives 6 through the O?N acyl migration rear-
rangement of the corresponding O-acylisourea intermediates 5. Fi-
nally, in situ addition of a suitable base triggers the cyclization to
the final N,N0-disubstituted-5-arylidendihydropyrimidine-2,4-
diones 7.
The starting 2-(bromomethyl)-3-aryl-2-propenoic acids 4 were
easily synthesized by Baylis–Hillman reaction13 of ethyl acrylate 8
and aromatic aldehydes 9a–c, followed by hydrolysis of the ester
function and bromination with a HBr solution (Scheme 2).14
⇑
Corresponding author. Tel.: +39 02 23993139; fax: +39 02 23993180.
E-mail address: alessandro.volonterio@polimi.it (A. Volonterio).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.109

4734
M. C. Bellucci, A. Volonterio / Tetrahedron Letters 53 (2012) 4733–4737
O
Ar
OH
R1
O
N
H
Br
4
Ar
O
NH
R2
R1-N3 + R2-NCO
R1
N
C
N
R2
1
2
3
Br
5
O
N acyl migration
O
R1
O
O
base
Ar
N
R2
Ar
N
N
H
N
R2
7
O
R1
Br
6
Scheme 1. Synthesis of N,N0-disubstituted-5-arylidendihydropyrimidine-2,4-diones 7.
O
OH
1) KOH, MeOH/H2O
DABCO
COOEt
Ar
OH
COOEt
+
Ar-CHO
Ar
2) HBr/AcOH/H2SO4
CH2Cl2
8
Br
9a-c
4a (64%)
4b (59%)
4c (62%)
10a-c
a: Ph; b: 2-Me-Ph; c: 3-Br-Ph
Scheme 2. Synthesis of 2-(bromomethyl)-3-aryl-2-propenoic acids 4.
With the acids 4 in hand, we began to study their reactivity in
the presence of carbodiimides 3 (Table 1). Acids 4a–c resulted to
be highly reactive and prone to undergo side reactions, such as
decarboxylation and subsequent formation of byproducts, when
the reaction is carried out in the presence of a base, such as
2,4,6-trimethylpyridine (TMP, generally used in this kind of reac-
tions)12 and polar solvents such as dioxane or acetonitrile.15 How-
ever, when dichloromethane (DCM) is used, the process furnished
the clean formation of N-acylurea derivatives 6 in high yields un-
less highly basic carbodiimides were used. Indeed, when acid 4a
was reacted with N,N0-dialkylcarbodiimides, such as commercially
available DIC 3a and DCC 3b, we obtained the formation of a mix-
ture of uncharacterized byproducts which likely arises from decar-
boxylation of the starting acid due to the high basicity of such
carbodiimides (Table 1, entries 1 and 2, respectively). Less basic
‘strongly asymmetric’12b carbodiimides, namely carbodiimides
bearing an aryl and an alkyl substituent, such as N-benzyl, N0-phe-
nyl carbodiimide 3c, reacted smoothly with acid 4a producing the
corresponding N-acyl urea 6a in high yield and, gratifyingly, as the
only regioisomer (Table 1, entry 3). The reaction worked efficiently
also with 2-(bromomethyl)-3-aryl-2-propenoic acids with differ-
ent substitution at the aromatic ring, such as methyl- and bro-
mo-derivatives 4b,c, leading to the regiospecific formation of
compounds 6b,c, respectively, in high yields (Table 1, entries 4
and 5). To our surprise ‘weakly asymmetric’12b N,N0-dialkylcarbo-
diimides, namely carbodiimides bearing two alkyl substituents
very different in terms of bulkiness, such as N-tert-butyl, N0-phen-
ethyl carbodiimide 3d, did not promote the decarboxylation of the
Table 1
Synthesis of N-acylurea derivatives 6
O
O
O
DCM
r.t.
R2
R1
+
N
C
N
R2
Ar
N
N
H
Ar
OH
R1
3
Br
Br
4
6
Entry Ar
Acid
R1
R2
Carbodiimide
Product
/
Yielda (%)
n.r.b
COOH
Br
N
C
N
1
2
Ph
Ph
i-Pr
i-Pr
3a
4a
4a
4a
COOH
Br
N
C
N
N
cyclo-Hex cyclo-Hex
/
n.r.b
88
3b
COOH
Br
O
O
N
C
N
N
H
3c
3
Ph
Ph
Bn
Br
6a

M. C. Bellucci, A. Volonterio / Tetrahedron Letters 53 (2012) 4733–4737
4735
Table 1 (continued)
Entry Ar
Acid
R1
R2
Carbodiimide
Product
Yielda (%)
O
O
N
C
N
N
COOH
Br
N
N
H
3c
4
5
2-Me-Ph
3-Br-Ph
Ph
Bn
95
85
Br
4b
6b
O
Br
COOH
Br
O
N
C
Br
N
N
3c
H
Ph
Bn
4c
Br
6c
O
O
O
COOH
Br
N
N
N
H
N
C N
84c
Br
O
O
6
7
2-Me-Ph
tert-Bu
–(CH2)2-Ph
3d
+
4b
4b
6d
N
N
H
6d'
Br
O
N
C
N
COOH
Br
N
H
3e
Ph
Ph
Ph
92
Br
6e
a
b
c
Isolated yields.
No reaction. The formation of byproducts was detected.
Equimolecular mixture of the two diastereoisomers.
Table 2
One-pot multi-component sequential synthesis of N,N0-disubstituted-5-arylidendihydropyrimidine-2,4-diones 7
O
Ar
OH
R1-N3
O
R1
O
O
O
1
Br
4
PPh3
DCM
tert -BuOK
Ar
N
R2
R1
N
C
N
R2
+
Ar
N
N
H
N
R2
7
R1
3
R2-NCO
2
Br
6
Entry
1
R1N3
R2-NCO
NCO
Carbodiimide
Acid
Product
Yielda (%)
COOH
Br
N3
N3
N3
O
N
N
N
C
N
N
N
N
2a
3c
1a
1a
1a
77
4a
N
O
7a
NCO
O
N
C
COOH
Br
N
2a
3c
2
3
79
73
O
4b
7b
NCO
Br
COOH
Br
O
C
Br
N
2a
3c
4c
N
O
7c
NCO
N3
1b
O
N
C N
COOH
Br
MeO
N
2a
3f
4
68
N
O
4b
MeO
7d
MeO
(continued on next page)

4736
M. C. Bellucci, A. Volonterio / Tetrahedron Letters 53 (2012) 4733–4737
Table 2 (continued)
Entry
R1N3
R2-NCO
Carbodiimide
Acid
Product
Yielda (%)
N3
NCO
OMe
O
N
N
C
N
OMe
COOH
Br
MeO
2b
N
3g
1c
O
4b
4b
5
75
7e
N3
1d
NCO
O
N
N
N
C
N
COOH
Br
N
2a
3e
6
7
64
70
O
7f
N3
1d
NCO
Br
COOH
Br
O
C
N
Br
N
2a
3e
4c
N
O
7g
a
Overall yields.
starting acid 4a. However, the reaction was not regioselective at all,
producing a 1:1 mixture of the two regioisomers 6d, 6d0 although
in high yields (Table 1, entry 6).16 Finally, acid 4b reacted effi-
ciently also with N,N0-diaryl carbodiimide, such as N,N0-diphenyl
carbodiimide 3e, giving the formation of the corresponding N-acyl
urea derivative 6e in high yields (Table 1, entry 7).
In conclusion, we have developed a novel and efficient process
for the synthesis of libraries of N,N0-disubstituted-5-arylidendihy-
dropyrimidine-2,4-diones through a three-component sequential
reaction that occurs in very mild conditions, involving simple
and readily accessible starting materials. The operational simplic-
ity and the good chemical yields, combined with favorable atom-
economy aspects and a small number of synthetic steps, render
this new synthetic strategy attractive and promising for the prep-
aration of the target compounds. The application of this methodol-
ogy to other Baylis–Hillman adducts and the functionalization of
the C@C double bond of the final compounds are currently in pro-
gress in our laboratories and will be reported in a forthcoming full
paper.
Next, we investigated the use of a suitable base to trigger the
cyclization in situ, thus in DCM as solvent, in order to obtain the
target N,N0-disubstituted-5-arylidendihydropyrimidine-2,4-diones
7 with a sequential process. After careful screening of the bases
and conditions,17 the best results were obtained by adding at
0 °C 1.5 equiv of potassium tert-butoxide to the DCM solution once
18
the N-acylurea is formed (see scheme in Table 2).
Thus with these results in hand, we studied the possibility to
obtain the target molecules through a multi-component sequential
process consisting in (1) in situ formation of the reacting carbodii-
mides 3 by Staudinger reaction, performed in DCM, of azides 1 and
isocyanates 2, (2) addition to the resulting solutions of acids 4 once
the carbodiimide is already formed (TLC monitoring), and (3) final
addition of potassium tert-butoxide once the N-acylurea interme-
diates are formed (TLC monitoring). The process and the results
are summarized in Table 2.
Accordingly, Staudinger reaction, performed in DCM, of benzyl
azide 1a and phenyl isocyanate 2a gave the clean formation of
the corresponding carbodiimide 3c along with Ph3PO byproduct.
Without isolating the carbodiimide, acids 1a-c were added and
the resulting N-acylureas cyclized by adding, in situ, potassium
tert-butoxide, leading to the final regiospecific formation of N-
benzyl,N0-phenyl-5-arylidendihydropyrimidine-2,4-diones 7a–c,
respectively, in high yields (Table 2, entries 1–3). Acid 4b reacted
smoothly also with in situ formed carbodiimides 3f,g giving rise
to the formation, after cyclization, of compounds 7d,e, respectively,
as the only regioisomers, confirming that the reaction with
‘strongly asymmetric’ carbodiimides is totally regioselective inde-
pendently from the nature of the N-alkyl and N0-aryl substituents.
Finally, the process worked smoothly also with symmetric N,N0-
diaryl carbodiimides. Indeed, starting from phenyl azide 1d and
phenyl isocyanate 2a, at the end of the MC process performed with
acids 4b,c we could obtain the formation of N,N0-diphenyl-5-ary-
lidendihydropyrimidine-2,4-diones 7f,g in very good overall yields
(Table 1, entries 6 and 7).
Acknowledgments
Mr. Marco Barozzi and Mr. Andrea Bassani are acknowledged
for performing preliminary experiments.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
06.109.
References and notes
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16. The regiochemistry of the two products was assessed by 1H NMR: the NH
signals of 6d appears as a broad singlet, while the same NH of 6d0 appears as a
broad triplet (see Supplementary data).
17. Nucleophilic bases such as NaOH or NaOEt lead to the formation of a mixture of
byproducts as well as performing the cyclization with tert-BuOK at higher
temperatures.
18. It is worth noting that the exocyclic C@C double bond of compounds 7 could
migrate to give rise the formation of the corresponding unsaturated pyrimidine
structures. However, considering the NMR spectra of the final compounds, and
in particular the proton chemical shift of the endocyclic methylene and the
carbon chemical shifts of the C@C (see Supplementary data), this is not the
case.