Molecular iodine-catalysed tandem synthesis of oxospirotricyclic furopyrimidines in water

Article abstract of DOI:10.3184/174751916X14568468874639

A simple, efficient and high yielding one-pot protocol for the synthesis of oxospirotricyclic furobarbiturates was developed by pseudo three-component domino coupling of barbituric acids and various benzaldehydes in water, catalysed by molecular iodine.

Full text of DOI:10.3184/174751916X14568468874639

196 RESEARCH PAPER
VOL. 40 APRIL, 196–198
JOURNAL OF CHEMICAL RESEARCH 2016
Molecular iodine-catalysed tandem synthesis of oxospirotricyclic
furopyrimidines in water
Mohammad Bagher Teimouria* and Peyman Akbari-Moghaddamb
aFaculty of Chemistry, Kharazmi University, Mofateh Ave., Tehran, Iran
bChemistry and Chemical Engineering Research Centre of Iran (CCERCI), P.O. Box 14335-186, Tehran, Iran
A simple, efficient and high yielding one-pot protocol for the synthesis of oxospirotricyclic furobarbiturates was developed by pseudo
three-component domino coupling of barbituric acids and various benzaldehydes in water, catalysed by molecular iodine.
Keywords: barbituric acids, benzaldehydes, iodine, spiro compounds
Nowadays organic chemists are required to investigate clean,
economical and environmentally safer methodologies.1 The
need to reduce the amount of toxic waste and by-products arising
from chemical processes requires increasing emphasis on the
use of less toxic and environmentally compatible materials in
the design of new synthetic methods.2 One of the fundamental
challenges and ultimate goals for reactions of organic molecules
is to perform the reaction in water,3 because the application of
water would reduce the use of harmful organic solvents and
lead to the development of environmentally friendly processes.
Molecular iodine has gained importance as an inexpensive,
non-toxic and readily available catalyst for various organic
transformations affording the corresponding products with high
selectivity in excellent yields (see reference4 and references
cited therein). The mild Lewis acidity associated with iodine
enhances its use in organic synthesis to perform several organic
transformations using stoichiometric or catalytic amounts.
Compounds containing a fused pyrimidine ring represent a
broad class of compounds which have received considerable
attention due to their wide range of biological activities.5 A
survey of the literature revealed that furopyrimidines have
been the object of intense investigation in organic synthesis and
medicinal chemistry and several approaches have been reported
for the synthesis of these heterocyclic compounds.6–8 In 2010,
Elinson et al. reported the first synthesis of spiro-derivatives of
{furo[2,3-d]pyrimidine-6,5’-pyrimidine}pentone via a cascade
assembly of 1,3-dialkylbarbituric acids and benzaldehydes
in the presence of molecular bromine.7 Later, they examined
the electrocatalytic transformation of benzylidenebarbituric
acids and 1,3-dialkylbarbituric acids into spirobarbiturates
containing the furo[2,3-d]pyrimidine framework.8 It should be
noted that although synthesis of {furo[2,3-d]pyrimidine-6,5’-
pyrimidine}pentones has been reported in the literature,7,8 no
attempts were made to utilise 2-thiobarbituric acid derivatives
and also unsubstituted barbituric acid to furnish thio-analogues
of the products. Notably, one of the drawbacks of the previously
described method for the synthesis of {furo[2,3-d]pyrimidine-
6,5’-pyrimidine}pentones was the use of molecular bromine as
a volatile, hazardous and strongly corrosive oxidant. Recently
we have reported that the urotropine-bromine complex is a safe
source of active bromine and promotes the reaction between
barbituric acids and benzaldehydes yielding oxospirotricyclic
furobarbiturates.9 To expand and improve this type of domino
process, we have now utilised thio-analogues of barbituric acid
and unsubstituted barbituric acid and also molecular iodine as a
mild oxidant in water to produce spiro{furo[2,3-d]pyrimidine-
6,5’-pyrimidine} derivatives.
In continuation of our efforts to develop one-pot protocols10–13
for the synthesis of biologically important heterocycles in
water, we describe here a straightforward one-pot synthesis
of
5-aryl-1,5-dihydro-2H,2’H-spiro{furo[2,3-d]pyrimidine-
6,5’-pyrimidine} derivatives promoted by molecular iodine
in aqueous media, as an improved and expanded paper that
includes more results compared to another report.7 Our
literature survey at this stage revealed that there is no report
yet available on the synthesis of spiro{furo[2,3-d]pyrimidine-
6,5’-pyrimidine} derivatives in one-pot procedures by pseudo
three-component coupling of aromatic aldehydes and barbituric
acids in water promoted by iodine. In fact, as clearly stated by
Sheldon, it is generally recognised that “the best solvent is no
solvent and when a solvent (diluent) is needed then water is the
preferred choice”.14
Initially, the pseudo three-component coupling reaction
of barbituric acid (1a) and benzaldehyde (2a) in water was
examined without any catalyst at room temperature. It was
found that no desired product 3a was observed by TLC analysis
even after 24 h, while undesired products of Knoevenagel
condensation and also Michael addition adducts were formed
under the above conditions. Subsequently, the addition of
molecular iodine to the above reaction mixture resulted in the
desired product 3a in good yield.
Encouraged by these results obtained with the above
reaction conditions and in order to show the generality
and scope of this new protocol, we used eleven variously
substituted benzaldehydes and four barbituric acid derivatives
(Scheme 1). Four derivatives of barbituric acids (barbituric
acid, 1,3-dimethylbarbituric acid, 2-thiobarbituric acid and
1,3-diethyl-2-thiobarbituric acid) afforded oxospirotricyclic
furobarbiturates in good to excellent isolated yields. Also,
the results showed that substituted benzaldehydes containing
electron-withdrawing groups (o-, m- and p-NO2, p-CN, o-, m-
and p-Cl and p-Br and p-F) and electron-donating groups at the
meta position (m-OH) all tolerate the reaction conditions with
excellent yields.
Scheme 1 clearly demonstrates that molecular iodine is an
excellent catalyst for this one-pot three-component reaction in
water. Notably, the reactions were clean and all the products
were easily isolated simply by filtration and washing with water.
A probable mechanistic rationale portraying the sequence
of events for this domino coupling is postulated in Scheme 2.
The first step is believed to be the Knoevenagel condensation
between a barbituric acid 1 and an aldehyde 2 to generate
adduct 4, which acts as a Michael acceptor. The second
barbituric acid molecule 1 attacks adduct 4 in a Michael-
* Correspondent. E-mail: teimouri@khu.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2016 197
R1
X
CHO
X
R1
R1
N
R1
O
R1
O
O
O
O
N
N
I2, H2O
r.t.
N
N
X
N
R1
2
+
R2
O
R2
1a-d
2a-k
a R2 = H, b R2 = 3-OH
c R2 = 4-Br, d R2= 4-Cl
e R2 = 4-F, f R2 = 2-NO2
g R2 = 3-NO2, h R2 = 2-Cl
i R2 = 3-Cl, j R2 = 4-NO2
k R2 = 4-CN
a R1 = H, X = O
b R1 = H, X = S
c R1 = Me, X = O
d R1 = Et, X = S
3a-v
R1
X
R2
Yield (%) [Ref.]
R1
X
R2
4-NO2
Yield (%) [Ref.]
3a
3b
3c
3d
3e
3f
3g
3h
3i
9
9
9
9
9
-
9
-
9
-
H
H
H
H
H
H
H
H
H
H
H
O
H
90
88
91
90
93
90
85
81
82
79
85
3l
H
S
88
92
87
83
90
81
93
94
77
79
78
9
7
9
7
9
-
7
9
9
9
9
O
O
O
O
O
O
S
S
S
S
3-OH
4-Br
4-Cl
4- F
2-NO2
3-NO2
H
2-Cl
3-Cl
4-Cl
3m Me
3n Me
3o Me
3p Me
3q Me
3r Me
3s Me
3t Et
3u Et
3v Et
O
O
O
O
O
O
O
S
H
4-CN
4-Cl
2-NO2
3-NO2
4-NO2
4-F
H
4-Cl
4-NO2
3j
3k
S
S
9
Scheme 1 The synthesis of oxospirotricyclic furobarbiturates 3.
X
R
O
R
O
N
N
R
R
N
X
R
N
O
Knoevenagel
condensation
O
X
R
R
R
R
O
H
O
O
H
N
N
N
N
1
+
X
X
N
H
N
Ar
H
Michael
addition
O
R
O
2
Ar
I2
O
Ar
O
4
5
1
X
R
R
X
R
N
R
N
R
N
O
O
N
N
_
HI
X
HO
X
N
R
N
O
O
Williamson
cycloetherification
O
N
R
Ar
O
R
I
3
O
Ar
6
Scheme 2 Plausible reaction scenario for the formation of oxospirotricyclic furobarbiturates 3.
type fashion to produce an aryl-bis(barbitur-5-yl)methane
5. Subsequently, iodination of the Michael-adduct 5 gives a
substituted 5-iodo-5-[aryl(barbitur-5-yl)methyl]pyrimidine 6.
Finally, intramolecular Williamson cycloetherification of 6
gives the oxospirotricyclic furobarbiturate 3.
In comparison to another method,7 this protocol has several
advantages such as a clean reaction, easy operation, low cost,
simple purification and improved yields. Furthermore, it can
be considered as environmentally friendly, since it uses water
as the reaction medium and purification is done by simple
filtration and washing, avoiding the use of organic solvents at
any point of the experimental procedure. More importantly
the purification of compounds by a non-chromatographic
method makes this process very significant for academic
research and practical applications. In this experimentally
simple process three new bonds (two C–C and one C–O) and
one stereocentre are generated in a single operation with all
reactants efficiently utilised. From the synthetic perspective,
this reaction represents a major achievement in the synthesis of
new biologically interesting oxospirotricyclic furobarbiturates
containing unsubstituted (thio)barbituric acids or 1,3-diethyl-2-
thiobarbituric acid moieties.
In order to gain an insight into a possible reaction mechanism,
the 5-benzylidenebarbituric acid as
a
representative
Knoevenagel condensation adduct was synthesised separately
by the condensation of benzaldehyde and barbituric acid.15 Then
we examined the reaction of the isolated 5-benzylidenebarbituric
acid with one equivalent of barbituric acid in the presence of
one equivalent of molecular iodine in water at room temperature
and we obtained the product 3a in excellent yield within 4 h.
In summary we have developed a simple one-pot pseudo
three-component synthesis of 5-aryl-1,5-dihydro-2H,2’H-
spiro{furo[2,3-d]pyrimidine-6,5’-pyrimidine} derivatives, by
the coupling of benzaldehydes and barbituric acid derivatives
in water, promoted by molecular iodine as a mild oxidant.

198 JOURNAL OF CHEMICAL RESEARCH 2016
Experimental
The products 3a–e, 3g, 3i, 3k–p and 3r–v are known compounds
which were characterised using IR and H NMR spectroscopy and
trione (3j): Pale yellow powder; yield 0.323 g (79%); m.p. 291–293 °C;
IR (KBr) (νmax cm–1): 3300, 3234, 3140 and 3068 (N–H), 1735, 1706,
1680 and 1648 (C=O); 1H NMR (400.2 MHz, DMSO-d6): δH 5.10 (1 H,
s, CH), 7.17–7.27 (1 H, m, arom), 7.29–7.35 (2 H, m, arom), 7.36–7.48
(1 H, m, arom), 10.94, 11.30, 11.77 and 12.70 (4 H, 4 s, 4 NH); 13C NMR
(100.6 MHz, DMSO-d6): δC 167.4, 165.1, 164.0, 160.1, 151.2, 149.9,
133.8, 132.5, 132.0, 130.7, 129.6, 127.7, 88.4, 86.0, 51.7. Anal. calcd for
1
their melting points were compared with literature values.7,9 The
products 3f, 3h, 3j and 3q are new compounds. Melting points were
measured on a Büchi 535 apparatus and are uncorrected. Elemental
analyses were performed using an Elementar Vario EL III instrument.
FTIR Spectra were recorded on a Bruker Equinox-55 spectrometer. 1H
and 13C NMR spectra were recorded on a Bruker DRX-400 Avance
spectrometer at 400.13 and 100.77 MHz respectively, with CDCl3
or DMSO-d6 as solvents and calibrated using residual undeuterated
solvent as an internal reference. Chemical shifts are reported in
parts per million (ppm) relative to TMS as an internal reference.
Analytical TLC was carried out on pre-coated plates (Merck silica gel
60, F254) and visualised with UV light. All chemical reagents were
obtained from Merck, Fluka or Acros and were used without further
purification.
C15H9ClN4O4S2 (408.84): C, 44.07; H, 2.22; N, 13.70; found: C, 43.88;
H, 2.19; N, 13.71%.
1,1’, 3, 3’-Tetramethyl-5- (3-nitrophenyl) -1, 5- dihydro -
2H,2’H-spiro [furo [2,3- d] pyrimidine- 6,5’-pyrimidine] -
2,2’,4,4’,6’(1’H,3H,3’H)-pentone (3q): Cream powder; yield 0.359 g
(81%); m.p. 275–277 °C; IR (KBr) (νmax cm–1): 1674 and 1667 (C=O);
1H NMR (400.1 MHz, DMSO-d6): δH 2.53, 3.07, 3.20 and 3.36 (12 H,
4 s, 4 NMe), 5.34 (1 H, s, CH), 7.48–7.55 (1 H, m, arom), 7.56–7.59
(1 H, m, arom), 7.64–7.68 (1 H, m, arom), 7.97–7.99 (1 H, m, arom);
13C NMR (100.6 MHz, DMSO-d6): δC 166.6, 164.0, 163.9, 159.1, 152.1,
151.3, 149.6, 134.8, 133.8, 131.5, 129.7, 125.9, 89.6, 87.2, 51.9, 31.0, 30.1,
29.2, 28.9. Anal. calcd for C19H17N5O8 (443.36): C, 51.47; H, 3.86; N,
15.80; found: C, 51.60; H, 3.85; N, 15.81%.
General procedure for the synthesis of 3a–v
A mixture of barbituric acid derivative 1 (2.0 mmol), the appropriate
benzaldehyde 2 (1.0 mmol), molecular iodine (1.0 mmol) and distilled
water (10 mL), was taken in a 50 mL round bottom flask. The mixture
was stirred at room temperature (25 °C) for 4 h. After completion of
the reaction (monitored by TLC using EtOAc–hexane 1:1 as eluent),
the reaction mixture was filtered off and the resulting precipitate was
washed with water to afford the crude products 3. Eventually, the crude
product was purified by recrystallisation from ethanol. The dried
products thus obtained each showed a single spot on TLC and were
pure enough for all analytical purposes.
The authors thank the Kharazmi University Research Council
(Project No. 4/296) for financial support of this research.
Received 2 December 2015; accepted 2 February 2016
Paper 1503752 doi: 10.3184/174751916X14568468874639
Published online: 16 March 2016
5- (2-Nitrophenyl) -1,5-dihydro-2H,2’H-spiro{furo[2,3-d]
pyrimidine-6,5’-pyrimidine}-2,2’,4,4’,6’(1’H,3H,3’H)-pentone
(3f): Cream powder; yield 0.349 g (90%); m.p. 335–337 °C; IR (KBr)
(νmax cm–1): 3204, 3108 and 3080 (N–H), 1774, 1717 and 1648 (C=O);
1H NMR (400.1 MHz, DMSO-d6): δH 5.12 (1 H, s, CH), 7.56–7.64 (2 H,
m, arom), 8.06–8.17 (2 H, m, arom), 10.90, 11.06, 11.64 and 12.80 (4 H,
4 s, 4 NH); 13C NMR (100.6 MHz, DMSO-d6): δC 167.7, 166.1, 165.1,
161.1, 152.2, 150.5, 148.7, 138.8, 137.1, 131.1, 124.9, 124.7, 90.1, 86.6,
55.1. Anal. calcd for C15H9N5O8 (387.26): C, 46.52; H, 2.34; N, 18.08;
found: C, 46.39; H, 2.36; N, 18.11%.
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1
3573, 3460, 3221 and 3150 (N–H), 1714 and 1661 (C=O); H NMR
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2.72; N, 15.00%.
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