A one-pot domino reaction in constructing isoorotate bases and their nucleosides

Article abstract of DOI:10.1016/j.tetlet.2006.01.057

A novel strategy, involving the coupling of enaminoesters with chlorosulfonyl isocyanate and accelerated by microwave irradiation, enables the straightforward preparation of the biologically important isoorotate bases. Extensions to nucleoside derivatives

Full text of DOI:10.1016/j.tetlet.2006.01.057

Tetrahedron Letters 47 (2006) 1989–1992
A one-pot domino reaction in constructing isoorotate bases
and their nucleosides
a
a
a
b
´
Martın Avalos, Reyes Babiano, Pedro Cintas, Michael B. Hursthouse,
a,
a
b
a
*
´
´
´
Jose L. Jimenez, Encarnacion Lerma, Mark E. Light and Juan C. Palacios
aDepartamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Extremadura, E-06071 Badajoz, Spain
bDepartment of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
Received 12 December 2005; revised 10 January 2006; accepted 13 January 2006
Available online 3 February 2006
Abstract—A novel strategy, involving the coupling of enaminoesters with chlorosulfonyl isocyanate and accelerated by microwave
irradiation, enables the straightforward preparation of the biologically important isoorotate bases. Extensions to nucleoside deriva-
tives are also described.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The biosynthesis of purine and pyrimidine nucleotides is
at the heart of chemical biology. In particular, the meta-
bolic pathway for the de novo synthesis of pyrimidine
bases is a relatively simple multienzymatic process that
ultimately leads to orotate (uracil-6-carboxylate) as a
heterocyclic precursor.1 A large production of orotic
acid results in orotic aciduria, the only genetic deficiency
in pyrimidine nucleotide biosynthesis.2 While orotate
decarboxylase is prevalent in mammals and numerous
bacteria, lower eukaryotes possess isoorotate decarbox-
ylase and, hence isoorotic acid (uracil-5-carboxylic acid)
is the precursor of pyrimidine bases in such organisms.3
Metal derivatives of both orotate and isoorotate offer
promising pharmacological perspectives.4,5 In addition,
uracil nucleosides modified at C-5 exhibit HIV-targeting
antiviral activity,6 and their hydrogen-bonding ability
make them excellent candidates in constructing non-
covalent supramolecular networks.7–9
reaction outcomes depend on the structure of the start-
ing materials leading to several addition or substitution
products. Amino hydrouracils were obtained as high-
temperature by-products from disubstituted tertiary
enamines and isocyanates,13 whereas milder conditions
provided b-amino-b-lactams.14 Primary enamines react
with isocyanates to afford uracil derivatives, although
this transformation arises from the well-known N-acyl-
ation of enamines (i.e., nucleophilic attack of the amino
group to the electrophilic carbon of the heterocumu-
lene), followed by further cyclization of the resultant
intermediates to uracils.15 Recently, this strategy has
been applied to the synthesis of fluorinated (thio)uracils
in solution and on solid phase.16
In our preliminary screening we tested the unprece-
dented condensation of N-substituted aminomethylene
malonates (1 and 2) with excess of phenyl isocyanate
(1:3 molar ratio). Such reactions were certainly disap-
pointing as moderate yields of 3 (68%) or 4 (57%) could
only be obtained after 20 days in refluxing toluene
(Scheme 1). Starting from 2, the enaminoamide 5
(38%) was also isolated as by-product.
The preparation of pyrimidine bases, especially uracils,
represents a current synthetic goal.10,11 Herein, we
describe a novel and efficient route to uracils, exemplified
by the isoorotate nucleus, by reaction of enaminoesters
with isocyanates. Although transformations involving
enamines and iso(thio)cyanates are well documented,12
The above transformations could be improved by non-
conventional techniques such as ultrasonic irradiation
(cleaning bath at 35 kHz; yet these reactions were
incomplete after one week) and especially microwave
irradiation (Milestone reactor, approx. 1 h). Remark-
ably, such an acceleration also avoided the formation
of side products like 5.
Keywords: Enamines; Isocyanates; Isoorotates; Microwaves;
Nucleosides.
*
Corresponding author. Tel.: +34 9242 89380; fax: +34 9242 71149;
e-mail: requejo@unex.es
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.057

1990
M. Avalos et al. / Tetrahedron Letters 47 (2006) 1989–1992
H
Ph
OEt
O
O
N
N
O
EtOOC
EtOOC
Ph
O
O
N
EtO
O
H
C
Toluene
+
∆
H
N
N
N
Ph
Ar
Ar
H3C
CH3
1, Ar = C6H5
2, Ar = 2,6-(CH3)2C6H3
3, Ar = C6H5
4, Ar = 2,6-(CH3)2C6H3
5
Scheme 1.
In the search for milder conditions, attention was paid
to the more reactive electrophile chlorosulfonyl isocya-
nate. With this reagent, coupling of 1 took place in tolu-
ene at reflux within 48 h. To our delight, the labile
chlorosulfonyl group was removed during the work-up
protocol (involving SiO2-based chromatography),17
which provides straightforward access to the isoorotate
nucleus (Table 1). Irradiation with microwaves largely
accelerated this transformation (reactants essentially
disappeared after 1 h). It now could be achieved at a
lower temperature (in refluxing benzene), although the
uracil derivative 9 was isolated in lower yield (44% vs
60% under conventional heating), presumably due to
decomposition. The irradiated reaction of 2 with chloro-
sulfonyl isocyanate occurred within 30 min and the iso-
orotate 10 could be isolated in 77% yield.18 Crystals of
this derivative, well-suited for X-ray diffraction analysis,
could be obtained.19 It is worth noting that the solid-
Table 1. Reactions of enamines with chlorosulfonyl isocyanate
Enamine
Methoda
Time (h)
Yieldb (%)
Product
OEt
O
N
H
EtOOC
EtOOC
O
A
B
48
1
60
44
N
H
N
O
1
9
O
OEt
H
EtOOC
H3C
EtOOC
H3C
N
O
H
N
O
N
B
0.5
77
CH3
CH3
2
10
COOEt
OAc
H
N
COOEt
COOEt
AcO
AcO
O
OAc
O
AcO
AcO
O
N
N
A
B
72
1
70
58
H
OAc
H
OAc
O
6
13
COOEt
O
OBz
H
N
COOEt
COOEt
BzO
BzO
OBz
O
BzO
BzO
O
N
N
H
A
B
48
1
60
46
OBz
H
OBz
O
7
12
COOEt
OAc
H
N
COOEt
COOEt
O
OAc
O
O
AcO
N
N
A
B
48
1
44
30
AcO
H
OAc
AcO
H
AcO
OAc
O
8
13
a Method A: toluene at reflux; Method B: MW, benzene, 80 ꢁC.
b Yields refer to isolated, crystalline materials.

M. Avalos et al. / Tetrahedron Letters 47 (2006) 1989–1992
1991
state structure reveals the orthogonal arrangement
between phenyl and uracil moieties. As expected for
a naked pyrimidine base, the crystal structure also
shows the antiparallel self-assembly of the isoorotate
bases associated by two N–HÁ Á ÁO@C hydrogen bonds
A plausible rationale for the whole transformation is
depicted in Scheme 2. This mechanistic approach is
based on the well-established reactivity pattern between
alkenes and isocyanates. Thus, the zwitterionic inter-
mediate I could be generated either by an initial [2+2]
cycloaddition followed by subsequent opening of the
resulting b-lactam,21 or by direct nucleophilic attack.
That polar intermediate would further evolve into II,
which could lead to formation of isoorotates by intra-
molecular reaction or the acyclic adduct by loss of the
carboxyethyl group. It is often said that mechanisms
can only be disapproved22 and further studies will be
undertaken to test this rationale.
˚
with a length of 2.01 A and an angle NHO of 173.1ꢁ
(Fig. 1).
We reasoned that formation of isoorotates by means of
this protocol would largely be enhanced if one were also
able to obtain the corresponding nucleoside derivatives.
Although sugar fragments are sensitive to harsh reaction
conditions, we tackled this goal in view of the facile
preparation of O-protected carbohydrate-based enam-
ines from readily available raw materials.20 Enamines
6–8 reacted with chlorosulfonyl isocyanate in refluxing
toluene to produce isoorotate nucleosides 10–12 in mod-
erate to good yields within 2–3 days. Substantial
improvement could be achieved under microwave
(1-h irradiation at 80 ꢁC), though lower yields were
invariably obtained, again attributed to partial
decomposition.
The last concern to be addressed is the sensitivity of this
transformation to microwave irradiation. Whilst in
polar media the expected dielectric heating should be
operating, no thermal effect is to be expected in apolar
hydrocarbon solvents, like the present situation. The
observed acceleration thus points to non-thermal effects,
yet controversial, which have been rationalized by
Loupy and associates based on mechanistic consider-
ations.23 Thus, a bimolecular reaction between neutral
reactants should be assisted by microwave irradiation
as the reaction goes through a dipolar transition state.
If stabilization of the transition state is more pro-
nounced than that of the ground state, this should result
in enhancement of reactivity as consequence of a
decrease in the activation energy, because of electro-
static (dipole–dipole type) interactions of polar
molecules (or intermediates) with the electric field.
In conclusion, this communication discloses a one-pot
sequential transformation that converts enamines into
isoorotate derivatives by reaction with chlorosulfonyl
isocyanate. The protocol can also be extended to nucleo-
sides. We believe this novel strategy should stimulate
further pursuits, and such heterocyclic products can find
a niche as antimetabolites and molecular scaffolds for
oligomer construction. These applications are currently
under way.
Figure 1. Solid-state diagram of 10 forming pairs owing to intermole-
cular hydrogen bonds.
O
EtOOC
a
R1
O
N
N
R
OEt
R1
OEt
O
N
O
R1
O
C
N
EtOOC
EtOOC
EtOOC
O
N
O
H
OEt
+
H
N
R
NH
R
N
R
O
R1
b
H
R1
(II)
O
N
(I)
[2+2]
EtO
O
H
N
R
EtOOC
OEt
O
C
O
N
H
N
R
R1
Scheme 2.

1992
M. Avalos et al. / Tetrahedron Letters 47 (2006) 1989–1992
16. Fustero, S.; Piera, J.; Sanz-Cervera, J. F.; Catalan, S.;
´
Acknowledgements
´
Ramırez de Arellano, C. Org. Lett. 2004, 6, 1417–1420.
17. The presence of water or moisture causes removal of the
chlorosulfonyl group: Graf, R. Angew. Chem. Int. Ed.
Engl. 1968, 7, 172–182.
This work was supported by the Ministry of Education
and Science of Spain (Grants BQU2003-05946 and
BQU2005-07676) and the Junta de Extremadura-Fondo
Social Europeo (Grant 2PRI-A016). E.L. thanks the
EU Program Interreg-III (Project LABTRANS/
SP4.E44) for a scholarship.
18. Preparation of compound 10. To a solution of 2 (0.70 g,
2.40 mmol) in benzene (3.5 mL) was added dropwise
chlorosulfonyl isocyanate (0.37 g, 0.23 mL, 2.5 mmol)
and the mixture was then irradiated at 80 ꢁC for 30 min.
The reaction mixture was evaporated and purified by
column chromatography (SiO2, dichloromethane/diethyl
ether, 21:1). The resulting product was crystallized from
methanol (0.57 g, 77%). Mp 225 ꢁC; IR (KBr) m 3072 (N–
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288.30, monoclinic, P21/c, a = 11.4449(3), b = 12.7636(3),
3
˚
˚
c = 11.1048(2) A, b = 114.5070(10)ꢁ, V = 1476.03(6) A ,
Z = 4, Dcalcd = 1.297 g cmÀ3
,
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˚
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