The organocatalytic role of L-(+)-tartaric acid in the synthesis of 5-aryl-1,1′- and 5-aryl-3,1′-dimethyl-1H,1′H-spiro[furo[2,3-d]pyrimidine-6,5′-pyrimidine]2,2′,4,4′,6′(3H,3′H,5H)-pentaones

Article abstract of DOI:10.1007/s13738-020-02041-7

The reaction of 1-methylpyrimidine-(1H,3H,5H)-2,4,6-trione (1-MBA 1a’) as an unsymmetrical barbituric acid with cyanogen bromide (BrCN) and various aldehydes in the presence of L-(+)-tartaric acid (L-(+)-TA) as an organocatalyst afforded heterocyclic stab

Full text of DOI:10.1007/s13738-020-02041-7

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-020-02041-7
ORIGINAL PAPER
The organocatalytic role of L‑(+)‑tartaric acid in the synthesis
of 5‑aryl‑1,1′‑ and 5‑aryl‑3,1′‑dimethyl‑1H,1′H‑spiro[furo[2,3‑d]pyrimi
dine‑6,5′‑pyrimidine]2,2′,4,4′,6′(3H,3′H,5H)‑pentaones
Shahla Shahvirdi1 · Hamid Rashidnejad1 · Nader Noroozi Pesyan1
Received: 1 March 2020 / Accepted: 14 August 2020
© Iranian Chemical Society 2020
Abstract
The reaction of 1-methylpyrimidine-(1H,3H,5H)-2,4,6-trione (1-MBA 1a’) as an unsymmetrical barbituric acid with cyano-
gen bromide (BrCN) and various aldehydes in the presence of L-(+)-tartaric acid (L-(+)-TA) as an organocatalyst aforded
heterocyclic stable 5-aryl-1,1′-dimethyl- and 5-aryl-3,1′-dimethyl-1H,1′H-spiro[furo[2,3-d]pyrimidine-6,5′-pyrimidine]2,2′
,4,4′,6′(3H,3′H,5H)-pentaones which had the dimeric form of 1-methyl barbiturate at the range of 0 °C to room temperature.
In this reaction, L-(+)-TA acted as a sieve to reduce the number of diastereomeric products. Knoevenagel condensation and
Michael adduct were the main processes involved in this reaction. The structure of compounds was investigated by 1H and
13C-NMR, and FTIR spectroscopy techniques.
Keywords Diastereomer · 1-Methylbarbituric acid (1-MBA) · L-(+)-tartaric acid (L-(+)-TA) · Spirodihydrofuran ·
Cyanogen bromide (BrCN)
Introduction
π-conjugated systems including BA and 1,3-dimethyl bar-
bituric acid (DMBA) derivatives [21].
The pharmaceutical and biological efects of fused uracils
[1–3], furo[2,3-d]pyrimidines [4–8] and spirobarbituric
acids [9–12] are well established. C-nucleophilic property
of pyrimidine in barbituric acids (BA) and their 2-thio-
analogues, both substituted and unsubstituted at nitrogen,
have been studied. The reaction of these compounds with
aliphatic or aromatic aldehydes yields 5-aryl or 5-alkylmeth-
ylenebarbituric acids [13, 14]. The nucleophilic reaction of
barbituric acids with a variety of electrophiles such as car-
bodiimides, benzophenone derivatives, 2,2′-bipyridil, and
erythrolactol obtains diaminomethylenebarbiturates [15],
triphenylmethylium salt [16], 5,5′-(2-pyrilidine)bisbarbi-
turic acid [17, 18], spirobarbituric deoxyribonucleoside
[19], spiro-linked condensed [1,2-α]quinolones [20], and
Chiral tartaric acid (TA) and its derivatives play a key
role in various chemical processes such as epoxidation
[22–24], unsymmetrical hydrogenation [25, 26] and Sim-
mons–Smith cyclopropanation [27–30]. Additionally, L-(+)-
TA has also been used in the synthesis of pharmaceutical
and natural product compounds such as (+)-pinellic acid
[31], 5,5′-bis(1,3-dioxolan-4-ones) of tartaric acids [32],
and (−)-muricatacin [33]. It participates in critical pro-
cesses including selective conjugate addition of nitrometh-
ane to enoates [34], enantioselective synthesis of (1R)-1-
(hydroxymethyl)-2-acetyl-1,2,3,4-tetrahydro-β-carboline
[35], novel chiral dithioethers [36], etc.
Despite the toxicity of cyanogen bromide (BrCN), it is
commonly used in organic synthesis. It is an apt reagent for
both bromination and cyanation of imidazoles [37], bromi-
nation of alkenes [38], and α-bromination of β-aminoenones
[39]. von Braun is a well-known reaction in which tertiary
amines react with BrCN to yield organocyanamides [40].
A selective synthesis of thiocyanates using BrCN has been
reported by Chambert et al. [41]. This agent is currently used
in the synthesis of various compounds, among which are
(spiro)cyclopropanes [42–45], β-triketones [46], and spiro-
dihydrofuranes [47, 48].
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-020-02041-7) contains
supplementary material, which is available to authorized users.
* Nader Noroozi Pesyan
n.noroozi@urmia.ac.ir; nnp403@gmail.com
1
Department of Organic Chemistry, Faculty of Chemistry,
Urmia University, 57159 Urmia, Iran
Vol.:(0123456789)
1 3

Journal of the Iranian Chemical Society
The reaction of barbituric acid (BA) with BrCN has
been reported in the literature [49–51]. Recently, we
have reported the racemic synthesis of 5-alkyl and/
or 5-aryl-1H,1′H-spiro[furo[2,3-d]pyrimidine-6,5′-
pyrimidine]-2,2′,4,4′,6′(3H,3′H,5H)-pentaones and
their thio-analogues through the reaction of symmetric
(thio)barbituric acids with aldehydes [47] and ketones
[52, 53]. These reactions were conducted in the pres-
ence of BrCN and triethylamine (Et3N) and/or pyridine
as basic media. We have also performed this reaction
with 1-methyl barbituric acid (as an unsymmetric bar-
bituric acid) under the same conditions. The product of
this reaction was diastereomeric mixture of stable stere-
oisomers 1′,3-dimethyl-5-aryl-1H,1′H-spiro[furo[2,3-d]
pyrimidine-6,5′-pyrimidine]-2,2′,4,4′,6′(3H,3′H,5H)-
pentaone [54]. Acidic media can also provide a suitable
environment. For instance, L-(+)-TA was used in similar
reaction including symmetric BA [55]. All these recent
investigations are shown in Fig. 1.
Based on the above-mentioned concepts and in the con-
tinuation of our research line, we studied another route
for similar reactions. In this work, L-(+)-TA was used as
either organocatalyst or acidic media provider in the reac-
tion of 1-methylbarbituric acid (as unsymmetrical BA)
with some selected aldehydes (from our previous works)
[47, 54, 55] in the presence of BrCN. The number of prod-
uct diastereomers was reduced from diastereomeric mix-
ture [54] to one or two diastereomers in which detected by
means of 1H and 13C NMR spectroscopy.
Fig. 1 Our current BA intersection (1: Symmetrical BA, 2: BrCN, Et3N, 3: BrCN, L-(+)-TA, 4: unsymmetrical BA)
1 3

Journal of the Iranian Chemical Society
Results and discussion
This paper describes a new one-pot reaction of 1-methylb-
arbituric acid (1a′ as an unsymmetrical barbituric acid)
with BrCN and various aldehydes (containing electron-
withdrawing and electron-donating substituents) (2a–p)
in the presence of L-(+)-TA (as either a chiral catalyst or
acidic condition) afording reduced diastereomeric mix-
tures of a new class of stable heterocyclic spiro barbitu-
rates 6a–m through 9a–m, respectively (Scheme 1, path
a). Moreover, the reaction of 1a′ with aldehydes 1-naph-
thaldehyde (2n), 9-antharanaldehyde (2o) and furfural
(2p) were also aforded Knoevenagel adducts (a mixture
of Z- and E-isomers) of 4n–4p through 5n–5p (Scheme 1,
path b).
Fig. 2 Structures of symmetrical (thio)barbituric acids (1) and corre-
sponding salts (10) and 11 [47]
The structures of symmetrical (thio)barbituric acids
(1b′–1e′) are shown in Fig. 2. The reaction of 1b′–1e′
with aldehydes (2a–p) and BrCN in the presence of tri-
ethylamine as a basic media have been accomplished [47].
In this reaction, the salts of triethylammonium-5-bromo-
(thio)barbiturates (10b′–10e′) and the racemic mixture of
spiro[furo[2,3-d]pyrimidine-6,5′-pyrimidine]-pentaones
(11b′–11e′) have been obtained since their 1H-NMR spec-
tra show one singlet peak for C5-H. We also performed
the reaction of 1-methylbarbituric acid 1a′ (as an unsym-
metric barbituric acid) with aldehydes 2 in the presence
of BrCN and triethylamine under the same conditions and
obtained the salt of triethylammonium-5-bromo-2,4,6-
trioxohexahydro-1-methylpyrimidin-5-ide (3), diastere-
omeric mixture of four new class of heterocyclic stable
compounds (5S,5′S)- (6), (5R,5′S)-1,1′-dimethyl-5-aryl-
1H,1′H-spiro[furo[2,3-d]pyrimidine-6,5′-pyrimidine]-
2,2′,4,4′,6′(3H,3′H,5H)-pentaone (7), (5S,5′S)- (8) and
(5R,5′S)-1′,3-dimethyl-5-aryl-1H,1′H-spiro[furo[2,3-d]
pyrimidine-6,5′-pyrimidine]-2,2′,4,4′,6′(3H,3′H,5H)-
pentaone (9) in good yields, respectively (Scheme 1, path
a) [54]. The attempt to separate four diastereomers was
failed due to their almost same polarity.
5-Bromo-1-methyl barbituric acid (12) plays a signif-
cant role (either as a nucleophile or electrophile) in the
synthesis of 8 and 9 through the reaction of 1a′ and 2
in the presence of L-(+)-TA. A proposed mechanism for
the formation of 12 is shown in Scheme 2. On the basis
of the well-established chemistry of barbituric acid [56]
Scheme 1 Reaction of unsymmetrical 1-methylbarbituric acid (1a′) with cyanogen bromide and various aldehydes in the presence of Et3N (path
a) and L-(+)-tartaric acid (path b)
1 3

Journal of the Iranian Chemical Society
Scheme 2 Knoevenagel con-
densation and the mechanism
of the formation of 12 (path a)
under acidic condition
and according to the mechanism of the bromination of
symmetric barbituric acids [47, 52, 53] and 1-alkyl imida-
zoles by cyanogen bromide [37], it is reasonable to assume
that the enolic form of 1a′ reacted with cyanogen bromide
forming intermediate (A). The intramolecular rearrange-
ment of A aforded 5-bromo-1-methylbarbituric acid 12
followed by the loss of hydrogen cyanide (HCN). At the
same time, as a competition reaction, Knoevenagel con-
densation between 1a′ and 2 also occurred (Scheme 2,
path b).
The proposed mechanism of the formation of 8a and 9a
as representatives is shown in Scheme 3. First, the Knoeve-
nagel condensation of 2a with 1a′ aforded (Z)- (4a) and (E)-
1-methyl-5-phenylmethylenepyrimidine-2,4,6(1H,3H,5H)-
trione (5a) and then, Michael addition of the enolic form
of 5-bromo-1-methyl barbituric acid 12 (act as a nucleo-
phile) to the β-carbon position of both 4a and 5a as an α,β-
unsaturated carbonyl compound gave intermediates B, C,
B′ and C′. Unfortunately, all attempts failed to separate
and characterize these intermediates. L-(+)-TA as a chiral
HO
HO
O
O
HO
O
O
O
H
H
O
O
O
O
O
H
H
H
H
H
O
Me
O
O
O
O
H
N
N
Me
O
H
O
O
O
H
O
N
N
O
O
Me
O
H
Me
O
H
H
N
N
O
L-(+)-TA
N
N
O
O
O
H
(1)
H
H
O
Br
Ph
O
Br
Me
N
O
H
Ph
Br
O
O
O
Ph
N
H
Ph
Z
-isomer
4a
Me
N
O
Me
Me
N
N
HO
N
H
8a
N
H
N
H
O
H
O
O
12
B
C
HO
HO
O
HO
O
O
O
O
O
O
O
H
H
O
O
O
O
H
H
H
H
Me
H
O
O
O
H
N
N
O
Me
H
O
H
O
N
N
O
O
Me
H
Me
H
H
N
N
O
O
L-(+)-TA
N
N
O
O
H
O
O
(2)
H
H
O
O
Br
Ph
O
O
Br
Me
N
O
H
Ph
H
O
O
Br
O
Ph
N
H
Ph
E
-isomer
5a
Me
O
N
Me
Me
N
N
HO
N
H
9a
N
H
N
H
O
H
O
O
12
B'
C'
Scheme 3 Possible mechanism of diastereoselective controlled reactions between 4a (1) and 5a (2) with 12 for the formation of 8a and 9a in the
presence of L-(+)-TA, respectively
1 3

Journal of the Iranian Chemical Society
catalyst can bind to 4 and/or 5 by intermolecular H-bond and
controlled the Michael addition of 12 (Scheme 3). Finally,
intramolecular nucleophilic attack of hydroxyl group to car-
bon atom to leave bromide ion (as an electrophile) aforded
8a and 9a in good yields (Scheme 3).
are four diferent chemical shifts for N-CH3 in 11kc′ [47]
(Fig. 5a) while there are two diferent environments for
N-CH3 of spiro compound derived from the reaction of
1a′ and 2k in the presence of L-(+)-TA (Fig. 5b). These
observations also indicated the diastereoselective forma-
tion of 6k–9k. The number of diastereoselective reaction
products from some aldehydes is summarized in Table 1.
In comparison, the aromatic aldehydes possessing
electron-withdrawing substituents were more reactive
than those containing electron-donating substituents [50].
Owing to the aromatic nature of 1b′ and 1d′, the nucleo-
philicity of these compounds was less than that of 1c′ and
1e′. Therefore, the reactivity of 1a′ was higher than that
of 1b′ and 1d′ due to amide resonance dominates over the
aromaticity in barbituric acids [41].
There are eight possible spiro stereoisomers (four or less
diastereomers) that were synthesized and derived from the
reaction of 1a′ with 2 in the presence of BrCN and Et3N
(Figs. 3 and 4a). Instead, in the presence of BrCN and L-(+)-
TA aforded only two diastereomers under the same condi-
tions (Fig. 4b). These observations indicated that L-(+)-TA
as a chiral catalyst controlled the progress direction of the
reaction (see later). For instance, 1H and 13C NMR spectra
of the reaction between 1a′ and 2c show exclusively one
product of 6c–9c. 1H NMR spectrum of the product shows
a singlet for C5-H at δ 5.26 ppm, and its 13C NMR spectrum
shows ffteen distinct peaks (two distinct peaks for N-CH3
carbon atoms). These data show the diastereoselectivity of
the reaction in the presence of L-(+)-TA. In contrast, 2c
gives four mixtures of diastereomers (6c–9c) [54]. Four pos-
sible diastereomers were also obtained from the reaction of
1a′ and 2k (as a representative) in the presence of BrCN and
triethylamine (under basic condition) [55]. Representatively,
the existence of six overlapped singlets for C5-H proton of
the diastereomeric mixture of 6k–9k revealed that presum-
ably there was an equilibrium mixture of lactam and lactim
forms (each diastereomer consisting of an equilibrium mix-
ture of lactam and lactim forms). Instead, in the presence of
L-(+)-TA, only two distereomers were obtained and each
diastereomer had both lactam and lactim forms (Scheme 4).
Another evidence for the diastereoselective formation
of 6–9 by the reaction of 1a′ with 2 and BrCN in the pres-
ence of L-(+)-TA is shown in Fig. 5. For instance, there
Reaction yield in the presence of L-(+)-tartaric acid
was higher than that of the presence of triethylamine under
the same conditions. As we previously reported for the
reaction of symmetrical (thio)barbituric acids with BrCN
in the presence of L-(+)-tartaric acid [55], the intermedi-
ate 5-bromo (thio)barbituric acid 12 was formed which
was soluble in methanol and caused the progress of reac-
tion. This intermediate was vital for the formation of spiro
compounds. Instead, in the reactions in the presence of
triethylamine, the salt of triethylammonium 5-bromo-
1-methyl-2,4,6-trioxohexahydropyrimidin-5-ide (3 in
Scheme 1) was formed, and a small portion of this salt was
precipitated which reduced the reaction yield. Likewise,
this salt was an intermediate for the formation of spiro
compounds. In these types of reactions, a small fraction
of triethylammonium hydrobromide salt (Et3NHBr) was
also formed in the presence of BrCN and trimethylamine
that decreased reaction yield [47].
Fig. 3 Four possible diastere-
omers (eight stereoisomers) of
6–9 derived from the reaction
between 1a′ and 2 in the pres-
ence of BrCN and Et3N
O
N
O
N
O
N
O
N
H
H
H
H
N
N
N
N
2
3
4
O
O
O
O
1
H
H
H
H
C
C
C
C
3
3
3
3
5
*
R
O
R
O
R
O
R
O
O
O
O
O
6
*
O
O
O
O
5'
4'
6'
N
3'N
N
N
N
1'
N
N
N
2'
H
H
H
H
3C
3C
H
H
H
H
C
C
3
3
O
O
5R 5'R
,
O
O
5'R
S
,
)
m rror
i
7 5R 5'
5
(
6 5S 5'S
S
)
,
,
(
)
(
)
(
O
O
O
O
H
H
H
H
3C
N
O
3C
3C
N
3C
N
N
21N
N
N
H
3
4
O
O
O
N
H
H
H
5
R
O
R
O
R
O
R
O
O
O
O
O
6
O
O
O
O
5'
2'
N61''
HN
N
HN
4'
3'
NH
N
NH
N
H
H
3C
3C
H
C
H
C
3
3
O
O
O
O
5
S
,
5'R
'
5R 5'R
5R 5'
S
,
( )
8 5S 5 S
9
,
,
(
)
(
)
(
)
1 3

Journal of the Iranian Chemical Society
O
N
H
3C
OH
N
H
3C
N
N
O
O
H
5
R
O
R
O
O
O
O
O
5'
HN
N
HN
N
CH3
form
CH3
O
O
Lactam
,
Lactim
form
,
8[I]
8[II]
O
H
O
3C
OH
H
3C
N
N
N
O
H
N
R
O
R
O
O
O
O
O
HN
N
HN
N
CH3
CH3
O
O
Lactam
form
,
Lactim
form
,
9[I]
9[II]
Scheme 4 Possible equilibrium mixture of lactam (6[I] and 7[I] and/
or 8[I] and 9[I]) and lactim (6[I] and 7[I] and/or 8[II] and 9[II])
forms of two diastereomeric mixtures of 6 and 7 and/or 8 and 9 (8
and 9 are shown as representative)
Fig. 4 Expanded C5-H proton’s peaks of an equilibrium mixture of
lactam and lactim forms of diastereomeric mixture of 6k, 7k, 8k and
9k derived from the one-pot reaction of 1a′ with 2k in the presence
of BrCN and Et3N (a) and diastereoselective formation of 6k and 7k
(and/or 8k and 9k) in the presence of L-(+)-TA (b) in DMSO-d6
Experimental section
Conclusion
General procedures
In conclusion, in the reaction of symmetric barbituric
acids with aromatic aldehydes and cyanogen bromide
in the presence of triethylamine, the racemic mixture of
5-aryl-1H,1′H-spiro[furo[2,3-d]pyrimidine-6,5′-pyrimid
ine]2,2′,4,4′,6′(3H,3′H,5H)-pentaones was aforded. The
reaction of 1-methylbarbituric acid 1a′ as an unsymmet-
ric barbituric acid with the same aldehydes and cyano-
gen bromide in the presence of triethylamine aforded a
mixture of eight stereoisomers (four diastereomers) under
the same conditions. Instead, the reaction of 1a′ with the
same aldehydes and cyanogen bromide in the presence of
L-(+)-tartaric acid reduced the number of stereoisomers.
The drawing and nomenclature of compounds were per-
formed by ChemBioDraw Ultra version 12.0 software. Melt-
ing points were measured with a digital melting point appa-
ratus (Electrothermal) and were uncorrected. IR spectra were
recorded in the region of 4000–400 cm−1 on a NEXUS 670
FT IR spectrometer by preparing KBr pellets (Urmia Univer-
sity, Urmia, Iran). 1H and 13C NMR spectra were recorded
on Bruker 300 FT-NMR at 300 and 75 MHz, respectively
1
(Urmia University, Urmia, Iran). H and 13C NMR spec-
tra were obtained in the solution of DMSO-d6 as solvent
using TMS as internal standard. The data were reported as
s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet
or unresolved, bs=broad singlet, coupling constant(s) in Hz,
1 3

Journal of the Iranian Chemical Society
Table 1 Number of diastereomer(s) obtained in the presence of
L-(+)-TA
Entry
1
Aldehyde
Number
of product
O
1
H
2c
NO2
2
3
4
O
2
1
2
H
2e
Br
O
H
2f
HO
O
MeO
MeO
H
2k
OMe
5
O
1
N
H
2l
(BrCN), 0.15-g (0.96 mmol) 1-methyl barbituric acid, and
0.23-g (0.57 mmol) 2c were dissolved in 10-mL metha-
nol, and then 0.06-g (0.6 mmol) L-(+)-tartaric acid was
added into the solution at 0 °C. The reaction mixture was
stirred for 3 h while heating from 0 °C to room tempera-
ture (Caution! Cyanogen Bromide is highly toxic. Reac-
tions should be carried out under a well-ventilated hood).
Tefon-faced screw cap tube prevented the vaporization of
cyanogen bromide during the reaction. Reaction progress
was monitored by thin layer chromatography (TLC). After
the completion of reaction, the crystalline white solid was
precipitated, fltered of, washed with a few mL methanol
and dried (70% yield).
Fig. 5 Comparison of the expanded 13C NMR spectra of N-CH3 ali-
phatic regions of 11kc′ (a) in CDCl3 and two diastereomeric mixture
of 6k and 7k (and/or 8k and 9k) in the presence of L-(+)-TA (b) in
DMSO-d6
integration. All reactions were monitored by TLC with silica
gel-coated plates (AcOEt:AcOH/80:20/v:v). The compound
1a′ was synthesized and purifed in our laboratory as previ-
ously described in the literature [55, 57]. Cyanogen bromide
was synthesized based on the method reported in Ref. [58].
Triethylamine and used solvents were purchased from Merck
Company and were employed without further purifcation.
1′,3‑Dimethyl‑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)‑pentaone (6c–9c)
White solid; m.p. 261–265 °C (decomps); FT IR (KBr) 3427,
3023, 2813, 1736, 1707, 1655, 1528, 1441, 1355 cm−1; 1H
NMR (DMSO-d6, 300 MHz) δ 2.34, 2.45, 3.14, 3.29 (4 s,
6H, 2Me), 5.26 (s, 1H, CH-aliph), 7.61 (m, 2H, CH-ar.),
8.11 (m, 2H, CH-ar.), 11.18 (s, 1H, NH), 11.96 (s, 1H, NH);
13C NMR (DMSO-d6, 75 MHz) 165.7, 164.8, 164.1, 159.1,
151.0, 149.8, 147.9, 137.6, 136.0, 130.1, 124.0, 123.8, 90.0,
85.9, 54.8, 29.3, 27.4.
General procedures for the preparation of 6–9 (c, d,
e, f, l)
The physical and spectral data of compounds 6c–9c are
described as representatives.
In a 10-mL Tefon-faced screw cap tube equipped with
a magnetic stirrer, 0.06-g (0.48 mmol) cyanogen bromide
1 3

Journal of the Iranian Chemical Society
149.3, 137.2, 123.8, 123.8, 89.4, 85.3, 58.7, 49.0, 31.1, 29.3,
27.4.
5‑(4‑Bromophenyl)‑1′,3‑dimethyl‑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)‑pentaone (6e–9e)
Supporting information
White solid; m.p. 292–296 °C (decomps.); FT IR (KBr)
3422, 3251, 3070, 2925, 2853, 1719, 1659, 1544, 1402,
1
1374 cm−1; H NMR (DMSO-d6, 300 MHz) δ 2.37–3.30
Full characterization and spectral data for compounds 6c–9c,
6e–9e, 6f–9f, 6k–9k and 6l–9l are available.
(6H, 2Me), 4.93 – 5.00 (3 s, 1H, CH-aliph., a mixture of
three diastereomers), 7.05–7.17 (m, 2H, CH ar.), 7.48 (d,
2H, J=8.1 Hz, CH-ar.), 11.1 (s, 1H, NH), 11.9 (s,1H, NH);
13C NMR (DMSO-d6, 75 MHz) 166.1, 166.0, 164.5, 164.1,
159.1, 151.0, 149.9, 149.9, 134.5, 131.4, 131.3, 122.2,
122.2, 90.2, 86.2, 55.6, 29.2, 27.4, 27.2.
Acknowledgements We gratefully acknowledge fnancial support
by the Research Council of Urmia University (Grant Research No.
#9-10523).
References
5‑(4‑Hydroxyphenyl)‑1′,3‑dimethyl‑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)‑pentaone (6f–9f)
1. D.J. Brown, in Comprehensive Heterocyclic Chemistry, vol. 3, ed.
by A.R. Katritzky, C.W. Rees (Pergamon, Oxford, 1984)
2. H. Wamhof, J. Dzenis, K. Hirota, Adv. Heterocycl. Chem. 55,
129 (1992)
White solid; m.p. 234–236 °C (decomps.); FT IR (KBr)
3435, 3213, 2925, 2850, 1720, 1666, 1547, 1520, 1435,
3. S.I. Naya, H. Miyama, K. Yasu, T. Takayasu, M. Nitta, Tetrahe-
dron 59, 1811 (2003)
1
1366 cm−1; H NMR (DMSO-d6, 300 MHz) δ 2.40, 3.29
4. V. Cody, N. Galitsky, J.R. Luft, W. Pangborn, A. Gangjee, R.
Devraj, S.F. Queener, R.L. Blakley, Acta Crystallogr. Sect. D. 53,
638 (1997)
(2 s, 6H, 2Me), overlapped with water of DMSO), 4.78 (s,
1H, CH-aliph.), 6.63 (d, 2H, J=7.5 Hz, CH-ar.), 6.88 (d, 2H,
J = 7.5 Hz, CH-ar.), 9.49 (s, 1H, OH), 11.11 (s, 1H, NH),
11.86 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz) 166.4,
164.4, 164.1, 159.1, 158.0, 151.0, 150.0, 130.1, 124.7,
115.2, 90.6, 86.5, 56.6, 29.2, 27.4.
5. R.G. Melik-Ogandzhanyan, V.E. Khachatryan, A.S. Gapoyan,
Russ. Chem. Rev. 54, 262 (1985)
6. J.D. Figuera-Villar, C.L. Carneiro, E.R. Cruz, Heterocycles 34,
891 (1992)
7. E. Campaigne, R.L. Ellis, M. Bradford, J. Ho, J. Med. Chem. 12,
339 (1969)
8. F. Blume, F. Arndt, R. Ress, Ger. Patent 3712782 (1988)
9. K. Krasnov, V. Kartsev, Russ. J. Org. Chem. 41, 901 (2005)
10. S. Kotha, A.C. Deb, R.V. Kumar, Bioorg. Med. Chem. Lett. 15,
1039 (2005)
1′,3‑Dimethyl‑5‑(3,4,5‑trimethoxyphenyl)‑1,5‑dihyd
ro‑2H,2′H‑spiro[furo[2,3‑d]pyrimidine‑6,5′‑pyrimidi
ne]‑2,2′,4,4′,6′(1′H,3H,3′H)‑pentaone (6k–9k)
11. J.F. Gerkens, Eur. J. Pharmacol. 134, 293 (1987)
12. J. Duan, Z. Lu, US Patent. 6936620B2 (2005)
13. B.S. Jursic, E.D. Stevens, Tetrahedron Lett. 44, 2203 (2003)
14. A.V. Moskvin, N.R. Reznikova, B.A. Ivin, Russ. J. Org. Chem.
38, 463 (2002)
White solid; m.p. 269–271 °C (decamps); FT IR (KBr)
3424, 2927, 2848, 1712, 1686, 1665, 1594, 1511, 1382,
1126, 1038 cm−1; 1H NMR (DMSO-d6, 300 MHz): δ 2.40,
2.49 (2 s, 3H), 3.07, 3,15 (s, 3H, CH-aliph), 3.61–3.76 (m,
9H, CH-aliph.), 3.15 (s, 3H, CH-aliph.), 4.8–4.9 (m, 1H,
CH-aliph) a mixture of two diastereomers, 6.43–6.46 (s, 2H,
CH-ar.), 11.12 (s, 1H, NH), 11.34 (s, 1H, NH); 13C NMR
(DMSO-d6, 75 MHz) 164.3, 163.5, 163.14, 159.14, 152.9,
150.2, 138.1, 130.3, 107.0, 90.6, 60.4, 57.1, 56.4, 28.6, 27.3.
15. B.S. Jursic, F. Douelle, E.D. Stevens, Tetrahedron 59, 3427 (2003)
16. S. Spange, M. Bauer, B. Walfort, H. Lang, J. Org. Chem. 71, 7850
(2006)
17. B.S. Jursic, D.M. Neumann, K.L. Martin, E.D. Stevens, Org. Lett.
4, 811 (2002)
18. B.S. Jursic, D.M. Neumann, Z. Moore, E.D. Stevens, J. Org.
Chem. 67, 2372 (2002)
19. A. Renard, J. Lhomme, M. Kotera, J. Org. Chem. 67, 1302 (2002)
20. I.V. Paramonov, N.A. Belyaev, T.V. Glukhareva, A.S. Volkov,
E.V. Deeva, Y.Y. Morzherin, Chem. Heterocycl. Compd. 42, 127
(2006)
1′,3‑Dimethyl‑5‑(pyridin‑2‑yl)‑1,5‑dihydro‑2H,2′H‑s
piro[furo[2,3‑d]pyrimidine‑6,5′‑pyrimidine]‑2,2′,4,4′
,6′(1′H,3H,3′H)‑pentaone (6l–9l)
21. S.I. Naya, K. Yoda, M. Nitta, Tetrahedron 61, 8616 (2005)
22. C.J. Burns, C.A. Martin, K.B. Sharpless, J. Org. Chem. 54, 2826
(1989)
23. T. Katsuki, A.W.M. Lee, P. Ma, V.S. Martin, S. Masamune, K.B.
Sharpless, D. Tuddenham, F.J. Walker, J. Org. Chem. 47, 1373
(1982)
White solid; m.p. 272 °C (decomps.); FT IR (KBr) 3434,
3186, 2997, 1700, 1620, 1457, 1403, 1354 cm−1; 1H NMR
(DMSO-d6, 300 MHz) δ 2.40 (s, 3H, Me), 3.30 (s, 3H, Me),
4.84 (s, 1H, CH-aliph), 7.20 (m, 1H, Pyr.), 7.30 (m, 1H,
Pyr.), 7.73 (m, 1H, Pyr.), 8.43 (s, 1H, Pyr.), 11.21 (s, 1H,
NH), 11.96 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz)
δ 166.3, 164.7, 164.0, 159.3, 154.8, 151.0, 149.9, 149.3,
24. K. Berijani, A. Morsali, J.T. Hupp, Catal. Sci. Technol. 9, 3388
(2019)
25. A.A. Choliq, R. Nakae, M. Watanabe, T. Misaki, M. Fujita, Y.
Okamoto, T. Sugimura, Bull. Chem. Soc. Japan. 92, 1175 (2019)
26. N. Haruna, D.E. Acosta, S. Nakagawa, K. Yamaguchi, A. Tai, T.
Okuyama, T. Sugimura, Heterocycles 62, 375 (2004)
1 3

Journal of the Iranian Chemical Society
44. N. Noroozi Pesyan, A. Gharib, M. Behroozi, A. Shokr, Arabian J.
Chem. 10, S1558 (2017)
27. I. Arai, A. Mori, H. Yamamoto, J. Am. Chem. Soc. 107, 8254
(1985)
45. N. Noroozi Pesyan, H. Rashidnejad, J. Iran. Chem. Soc. 14, 1365
(2017)
28. A. Mori, I. Arai, H. Yamamoto, H. Nakai, Y. Arai, Tetrahedron
42, 6447 (1986)
46. E. Kashani, N. Noroozi Pesyan, H. Rashidnejad, Synthesis 48,
2079 (2016)
29. E.A. Mash, K.A. Nelson, Tetrahedron 43, 679 (1987)
30. E.A. Mash, K.A. Nelson, Tetrahedron Lett. 27, 1441 (1986)
31. K.R. Prasad, B. Swain, Tetrahedron Asymmetry 19, 1134 (2008)
32. M. Markert, I. Buchem, H. Krüger, R. Mahrwald, Tetrahedron
Asymmetry 15, 803 (2004)
47. M. Jalilzadeh, N. Noroozi Pesyan, F. Rezaee, S. Rastgar, Y. Hos-
seini, E. Şahin, Mol. Divers. 15, 721 (2011)
48. H. Zhian, N. Noroozi Pesyan, M. Alinejad, H. Rashidnejad, B.
Notash, J. Heterocycl. Chem. 55, 2563 (2018)
49. M.-E. Capella-Peiró, S. Carda-Broch, L. Monferrer-Pons, J.
Esteve-Romero, Anal. Chim. Acta 517, 81 (2004)
50. O. Pelletier, J.A. Campbell, J. Pharm. Sci. 51, 594 (1962)
51. O. Pelletier, J.A. Campbell, J. Pharm. Sci. 50, 926 (1961)
52. N. Noroozi Pesyan, S. Rastgar, Y. Hosseini, Acta Cryst. E 65,
O1444 (2009)
33. K.R. Prasad, P. Anbarasan, Tetrahedron Asymmetry 17, 2465
(2006)
34. A.C. Pinto, C.B.L. Freitas, A.G. Dias, V.L.P. Pereira, B. Tinant,
J.-P. Declercq, P.R.R. Costa, Tetrahedron Asymmetry 13, 1025
(2002)
35. Z. Araźny, Z. Czarnocki, K. Wojtasiewicz, J.K. Maurin, Tetrahe-
dron Asymmetry 11, 2793 (2000)
53. Y. Hosseini, S. Rastgar, Z. Heren, O. Büyükgüngör, N. Noroozi
Pesyan, J. Chin. Chem. Soc. 58, 309 (2011)
36. L. Flores-Santos, E. Martin, M. Diéguez, A.M. Masdeu-Bultó, C.
Claver, Tetrahedron Asymmetry 12, 3029 (2001)
37. P.B.W. McCallum, M.R. Grimmett, A.G. Blackman, R.T. Weav-
ers, Aust. J. Chem. 52, 159 (1999)
54. M. Jalilzadeh, N. Noroozi Pesyan, J. Korean Chem. Soc. 55, 940
(2011)
55. M. Jalilzadeh, N. Noroozi Pesyan, Bull. Korean Chem. Soc. 32,
3382 (2011)
38. D.D. Tanner, G. Lycan, N.J. Bunce, Can. J. Chem. 48, 1492 (1970)
39. A. Alberola, C. Andres, A.G. Ortega, R. Pedrosa, M. Vicente,
Synth. Commun. 16, 1161 (1986)
56. D.J. Brown, S.F. Mason, Chemistry of Heterocyclic Compounds,
the Pyrimidines, vol. 16 (Wiley, New York, 1962)
57. A. Vogel, Textbook of Practical Organic Chemistry, 4th edn.
(Longman, New York, 1978)
40. J. von Braun, K. Heider, E. Müler, Chem. Ber. 51, 273 (1918)
41. S. Chambert, F. Thomasson, J.-L. Dĕcout, J. Org. Chem. 67, 1898
(2002)
58. W.W. Hartman, E.E. Dreger, Org. Synth. Coll. 2, 150 (1943)
42. N. Noroozi Pesyan, M. Rezaee, Monatshefte fűr chemie 145, 1165
(2014)
43. E. Kashani, N. Noroozi Pesyan, H. Rashidnejad, A. Poursattar
Marjani, H. Yaghoobnejad Asl, J. Iran. Chem. Soc. 14, 2143
(2017)
1 3