Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-6,5'-pyrimidine]2, 2',4,4',6'(3H,3'H,5H)-pentaones derived from one-pot reaction of (thio)barbituric acids with aromatic dialdehydes and BrCN in the presence of Et3N

Article abstract of DOI:10.3906/kim-1201-27

Reaction of pyrimidine-(1H,3H,5H) -2,4,6-trione (barbituric acid), 1,3-dimethyl pyrimidine-(1H,3H,5H)- 2,4,6-trione (1,3-dimethyl barbituric acid), and 1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (1,3-diethyl thiobarbituric acid) with cyanogen bromide and aromatic dialdehydes in the presence of triethylamine leads to the selective and efficient formation of a novel class of bifunctionalized stable heterocyclic bisspiro[ furo[2,3-d]pyrimidine-6,5'-pyrimidine]2,2',4,4',6'(3H,3'H,5H)pentaones and their sulfur analogues, which are dimeric forms of barbiturate linked by a phenyl ring. A proposed mechanism was suggested for the formation of the products. The reaction of phthalaldehyde with BrCN and (thio)barbituric acids resulted in only monofunctionalized spiro[furo[2,3-d]pyrimidine-6,5'-pyrimidine]2,2',4,4',6'(3H, 3'H,5H)pentaones, while isophthalaldehyde and terphthalaldehyde resulted in the bifunctionalized form. TUeBITAK.

Full text of DOI:10.3906/kim-1201-27

Turk J Chem
36 (2012) , 788 – 804.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1201-27
Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-
6,5ꢀ -pyrimidine]2,2ꢀ,4,4ꢀ ,6ꢀ(3H,3ꢀH,5H)-pentaones
derived from one-pot reaction of (thio)barbituric acids
with aromatic dialdehydes and BrCN in the presence
of Et3N
Nader NOROOZI PESYAN∗, Mohammad JALILZADEH
Department of Chemistry, Faculty of Science, Urmia University, 57159, Urmia-IRAN
e-mails: n.noroozi@urmia.ac.ir, pesyan@gmail.com
Received: 16.01.2012
Reaction of pyrimidine-(1H,3H,5H)-2,4,6-trione (barbituric acid), 1,3-dimethyl pyrimidine-(1H,3H,5H)-
2,4,6-trione (1,3-dimethyl barbituric acid), and 1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H ,5H)-dione
(1,3-diethyl thiobarbituric acid) with cyanogen bromide and aromatic dialdehydes in the presence of triethy-
lamine leads to the selective and efficient formation of a novel class of bifunctionalized stable heterocyclic bis-
spiro[furo[2,3-d]pyrimidine-6,5ꢀ -pyrimidine]2,2ꢀ ,4,4ꢀ ,6ꢀ (3H,3ꢀ H,5H)pentaones and their sulfur analogues,
which are dimeric forms of barbiturate linked by a phenyl ring. A proposed mechanism was suggested for the
formation of the products. The reaction of phthalaldehyde with BrCN and (thio)barbituric acids resulted in
only monofunctionalized spiro[furo[2,3-d]pyrimidine-6,5ꢀ -pyrimidine]2,2ꢀ ,4,4ꢀ ,6ꢀ (3H ,3ꢀ H,5H)pentaones,
while isophthalaldehyde and terphthalaldehyde resulted in the bifunctionalized form.
Key Words: Barbituric acid, bis-spiro[furo[2,3-d]pyrimidine-6,5ꢀ -pyrimidine], diastereomer, rotamer, cyanogen
bromide
Introduction
The heterocyclic structures furo[2,3-d]pyrimidines,1−4 spirobarbituric acids,5,6 and fused uracils7,8 are well
known due to their wide varieties of pharmaceutical and biological effects.
∗Corresponding author
788

Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-6,5ꢀ..., N. NOROOZI PESYAN, M. JALILZADEH
Barbituric acid (BA) reacts with cyanogen bromide in the presence of pyridine derivatives through a
Ko¨nig-form reaction in which the pyridine derivative reacts with cyanogen bromide and is then coupled with
an active methylene to give polymethine dye.9 For instance, determination of niketamide10 and niacinamide11
through the reaction of BA and cyanogen bromide has been used.
BA derivatives can act as nucleophiles and react with different electrophiles such as carbodiimides,12 ben-
zophenone derivatives,13 and 2,2ꢀ -bipyridil to form 5,5ꢀ -(2-pyrilidine)bisbarbituric acid,14,15 C60 molecules,16
and erythrolactol to obtain spiro-barbituric deoxyribonucleoside,17 spiro-linked condensed [1,2-a]quinolines,18 π -
conjugated systems containing BA, and 1,3-dimethyl barbituric acid (DMBA) derivatives.19
More recently, a new class of stable heterocyclic 5-alkyl and/or 5-aryl-1H ,1ꢀ H-spiro[furo[2,3-d]pyrimidine-
6,5ꢀ -pyrimidine]2,2ꢀ ,4,4ꢀ ,6ꢀ (3H ,3ꢀ H,5H) pentaones has been reported by our group from one-pot reactions
between (thio)barbituric acids and aromatic and aliphatic mono-aldehydes20,21 and ketones22 in the presence of
cyanogen bromide and triethylamine. Previously, we have also reported the crystal structure of spiro[furo[2,3-
d]pyrimidine-6,5ꢀ-pyrimidine]2,2ꢀ ,4,4ꢀ ,6ꢀ (3H ,3ꢀ H ’5H)pentaone derivative from the reaction of DMBA and
acetone in the presence of cyanogen bromide and Et3 N.23 Elinson et al. have also reported the reaction of
DMBA with aldehydes in the presence of bromine under basic conditions (EtONa/EtOH).24 Based on these
concepts, here we report a one-pot reaction of BA and thiobarbituric acid (TBA) derivatives with aromatic
dialdehydes (phthalaldehyde, isophthalaldehyde and terphthalaldehyde) and cyanogen bromide in the presence
of triethylamine.
Experimental
General procedures
Melting points were measured using a digital melting point apparatus (Electrothermal) and were uncorrected.
IR spectra were recorded in the 4000–400 cm−1 region on a NEXUS 670 FT-IR spectrometer through preparing
KBr pellets. The 1 H- and 13 C-NMR spectra were recorded on a Bruker 300 FT-NMR at 300 and 75 MHz,
respectively (Urmia University, Urmia, Iran). 1 H- and 13 C-NMR spectra were obtained using CDCl3 and
DMSO-d6 as solvents and TMS as an internal standard. All reactions were monitored by TLC with silica
gel-coated plates (AcOEt:AcOH/80:20/v:v). Mass analysis of compounds 3a and 4b was performed using a
mass spectrometer (Agilent Technology (HP) type, MS Model: 5973 network mass selective detector, electron
impact (EI) 70 eV); ion source temperature was 230 ◦ C (Tehran University, Tehran, Iran). Compounds 2a–d
were synthesized and purified in our laboratory as described previously in the literature.25 Cyanogen bromide
was synthesized based on a reported reference.26 Compounds 1a–c, triethylamine, and solvents were purchased
from Merck and were used without further purification.
Representative physical and spectral data of compounds 3a–4c are given below.
General procedures for the preparation of 3a, 3b, 3c, 3e, 3f, 3h, 4a, 4b, 4c, and 11c
In a 10 mL tube with Teflon-faced screw cap equipped with a magnetic stirrer was dissolved 0.06 g (0.48 mmol)
of cyanogen bromide (BrCN), 0.15 g (0.96 mmol) of barbituric acid, and 0.06 g (0.48 mmol) of phthalaldehyde in
10 mL of methanol, and then 0.06 g (0.6 mmol, 0.8 mL) of triethylamine was added to the solution at 0 ◦ C. The
789

Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-6,5ꢀ..., N. NOROOZI PESYAN, M. JALILZADEH
reaction mixture was stirred for 3 h at 0 ◦ C to room temperature. (Caution! The cyanogen bromide is highly
toxic. Reactions should be carried out in a well-ventilated hood). The Teflon-faced screw cap tube prevents
the vaporization of cyanogen bromide during the reaction. The progression of the reaction was monitored by
thin layer chromatography (TLC). After the completion of the reaction, a crystalline white solid precipitate
appeared, which was filtered off, washed with a few milliliters of methanol, and dried (0.12 g, 70% yield, 4a).
1,3-bis{[1H,1ꢀH -Spiro[furo[2,3-d]pyrimidine-6,5ꢀ-pyrimidine]2,2ꢀ ,4,4ꢀ ,6ꢀ (3H,3ꢀH,5H )pentaone]-
5-yl}benzene (3a)
White solid (85% Yield); mp 320 ◦ C (decomps.); FT-IR (KBr) 3470 (NH), 3047 (CH-ar.), 2825 (CH-aliph.),
1706 (C=O), 1441, 1378 cm−1 1 H-NMR (DMSO-d6 , 300 MHz) δ 4.64, 4.67, 4.70 (s, 2H, 3CH-aliph.), 6.94
;
(s, 1H, Ph), 7.03 (m, 2H, Ph), 7.17 (m, 1H, Ph), 10.31 (bs, 1H, NH (a shoulder at the peak’s left side)), 10.76,
10.80, 10.84 (1H, NH), 11.56, 11.59 (1H, NH), 12.66 (bs, 1H, NH) (an equilibrium mixture of 3 rotamers);
13 C-NMR (DMSO-d6 , 75 MHz) δ: 167.2 (CO), 165.0 (CO), 164.8 (CO), 163.7 (CO), 160.7 (CO), 160.6 (CO),
160.3 (CO), 151.2 (Ph), 151.1 (Ph), 149.2 (Ph), 135.4 (Ph), 129.8 (Ph), 129.7 (Ph), 128.4 (Ph), 89.5 (C6 and
C6ꢀꢀ ), 86.6 (Cα -C4=O), 55.8 (C5 and C5ꢀꢀ , minor product), 55.5 (C5 and C5ꢀꢀ , major product); MS (m/z,
%) 606 (M+ , 1), 493 (6), 438 (12), 294 (6), 279 (10), 246 (15), 203 (50), 190 (18), 177 (20), 164 (12), 149 (24),
85 (16), 71 (32), 57 (66), 43 (100, base peak).
1,3-bis{[1,1ꢀ ,3,3ꢀ -Tetramethyl-1H,1ꢀH -spiro[furo[2,3-d]pyrimidine-6,5ꢀ-pyrimidine]2,2ꢀ ,4,4ꢀ ,6ꢀ
(3H,3ꢀH,5H )pentaone]-5-yl}benzene (3b)
White solid (90% Yield); mp 251 ◦ C (decomps.); FT-IR (KBr) 3050 (CH-ar.), 2954 (CH-aliph.), 2926 (CH-
aliph.), 2856 (CH-aliph.), 1691 (C=O), 1515 (C=C), 1440, 1378, 1041, 753 cm−1 1 H-NMR (CDCl3 , 300 MHz)
;
δ 2.72 (s, 3H, N-CH3), 3.32 (s, 3H, N-CH3), 3.38 (s, 3H, N-CH3), 3.52 (s, 3H, N-CH3), 4.77 (s, 1H, CH-aliph.),
4.85 (s, 1H, CH-aliph.), 6.84 (s, 1H, Ph), 7.10 (d, 2H, J = 7.5 Hz, Ph), 7.32 (t, 1H, J = 7.5 Hz, Ph); 13 C-NMR
(CDCl3 , 75 MHz) δ: 165.4 (CO), 162.9 (CO), 162.6 (CO), 158.2 (CO), 151.2 (CO), 149.2 (CO), 134.6 (Ph),
134.3 (Ph), 129.8 (Ph), 129.3 (Ph), 129.0 (Ph), 128.6 (Ph), 128.2 (Ph), 89.9 (C6 and C6ꢀꢀ ), 85.9 (Cα -C4=O),
58.5 (C5 and C5ꢀꢀ , major product), 30.1 (N-CH3 , minor product), 30.0 (N-CH3 , major product), 29.5 (N-CH3 ,
major product), 28.9 (N-CH3 , major product), 28.8 (N-CH3 , minor product), 28.2 (N-CH3 , major product).
1,3-bis{[1,1ꢀ,3,3ꢀ-Tetraethyl-2,2ꢀ-dithioxo-2,2ꢀ,3,3ꢀ-tetrahydro-1H,1ꢀH -spiro[furo[2,3-d]pyrimidine-
6,5ꢀ -pyrimidine]-4,4ꢀ ,6ꢀ (5H )trione]-5-yl}benzene (3c)
White solid (24% Yield); mp 342 ◦ C; FT-IR (KBr) 2980 (CH-aliph.), 1741 (C=O), 1698 (C=O), 1620 (C=C),
1491, 1437, 1385 cm−1
;
1 H-NMR (CDCl3 , 300 MHz) δ 1.19–1.50 (m, 12H, 4 CH3), 4.54–4.71 (m, 8H, 4
CH2), 4.83 (s, 1H, CH-aliph.), 6.85 (s, 1H, CH-aliph.), 7.12 (d, 2H, J = 7.8 Hz, Ph), 7.29 (t, 1H, J = 7.8
Hz, Ph); 13 C-NMR (CDCl3 , 75 MHz) δ: 177.5 (CS), 174.6 (CS), 163.7 (CO), 162.1 (CO), 162.0 (CO), 161.0
(CO), 132.3 (Ph), 129.3 (Ph), 127.7 (Ph), 126.7 (Ph), 126.6 (C6 and C6ꢀꢀ ), 124.3 (Cα -C4=O), 59.0 (C5 and
C5ꢀꢀ ), 44.6 (N-CH2 CH3), 44.0 (N-CH2 CH3), 43.9 (N-CH2 CH3), 43.6 (N-CH2 CH3), 12.5 (N-CH2 CH3),
12.4 (N-CH2 CH3), 11.8 (N-CH2 CH3), 11.5 (N-CH2 CH3).
790

Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-6,5ꢀ..., N. NOROOZI PESYAN, M. JALILZADEH
1,4-bis{[1H,1ꢀH -Spiro[furo[2,3-d]pyrimidine-6,5ꢀ-pyrimidine]2,2ꢀ ,4,4ꢀ ,6ꢀ (3H,3ꢀH,5H )pentaone]-5-
yl}benzene (3e)
White solid (93% Yield); mp 386 ◦ C (decomps.); FT-IR (KBr) 3448, 3209 (NH), 3064 (CH-ar.), 2833 (CH-
;
aliph.), 1719 (C=O), 1674 (C=O), 1411, 1357 cm−1 1 H-NMR (DMSO-d6 , 300 MHz) δ 4.68, 4.71, 4.74 (3s,
2H), 6.95, 6.99, 7.01 (3s, 4H), 10.54 (bs, 2H), 10.74, 10.77, 10.80 (3s, 2H), 11.58 (s, 2H), 12.58 (bs, 2H); 13 C-
NMR (DMSO-d6 , 75 MHz) δ: 167.3 (CO), 164.8 (CO), 163.7 (CO), 160.2 (CO), 151.2 (CO), 149.6 (CO), 135.4
(Ph), 128.9 (Ph), 89.4 (C6 and C6ꢀꢀ ), 86.2 (Cα -C4=O), 55.4 (C5 and C5ꢀꢀ ).
1,4-bis{[1,1ꢀ ,3,3ꢀ -Tetramethyl-1H,1ꢀH -spiro[furo[2,3-d]pyrimidine-6,5ꢀ-pyrimidine]2,2ꢀ ,4,4ꢀ ,6ꢀ
(3H,3ꢀH,5H )pentaone]-5-yl}benzene (3f)
White solid (87% Yield); mp 364 ◦ C (decomps.); FT-IR (KBr) 3050 (CH-ar.), 2965 (CH-aliph.), 1712 (C=O),
;
1691 (C=O), 1662 (C=O), 1517, 1437, 1374 cm−1 1 H-NMR (CDCl3 , 300 MHz) δ 2.59 (s, 3H), 2.66 (s, 3H),
3.29 (s, 3H), 3.30 (s, 3H), 3.41 (s, 3H), 3.52 (s, 3H), 4.87 (s, 1H), 4.90 (s, 1H), 7.045 (s, 2H), 7.054 (s, 2H)
(mixture of 2 rotamers 3fA and 3fB); 13 C-NMR (CDCl3 , 75 MHz) δ: 165.4 (CO), 162.8 (CO), 158.3 (CO),
151.2 (CO), 149.5 (CO), 134.6 (Ph), 128.8 (Ph), 89.9 (C6 and C6ꢀꢀ ), 85.1 (Cα -C4=O), 58.5 (C5 and C5ꢀꢀ ),
30.0 (N-CH3), 29.5 (N-CH3), 28.7 (N-CH3), 28.5 (N-CH3).
5-(4-(1ꢀ ,3-Dimethyl-2,2ꢀ ,4,4ꢀ ,6ꢀ -pentaoxo-2,2ꢀ ,3,3ꢀ ,4,4ꢀ ,5,6ꢀ -octahydro-1H,1ꢀH -spiro[furo[2,3-d]
pyrimidine-6,5ꢀ -pyrimidin]-5-yl)phenyl)-1,1ꢀ-dimethyl-1H,1ꢀH -spiro[furo[2,3-d]pyrimidine-6,5ꢀ-
pyrimidine]-2,2ꢀ ,4,4ꢀ ,6ꢀ (3H,3ꢀH,5H )pentaone (3h)
White solid (80% Yield); mp 232 ◦ C (decomps.); FT-IR (KBr) 3470 (NH), 3047 (CH-ar.), 2825 (CH-aliph.),
;
1706 (C=O), 1650 (C=O), 1550, 1513, 1441, 1378, 1022, 757, 567 cm−1 1 H-NMR (DMSO-d6 , 300 MHz) δ
2.32 (s, 3H), 3.03 (s, 3H), 3.05 (s, 3H), 3.29 (s, 3H), 4.84, 4.89, 4.93 (s, 2H, mixture of at least 3 diastereomers
and equilibrium mixtures of tautomers), 7.00 (m, 4H), 10.76, 11.43 (bs, 1H), 11.13 (s, 1H), 11.82 (bs, 1H), 12.98
(bs, 1H); 13 C-NMR (DMSO-d6 , 75 MHz) δ: 167.2 (CO), 165.1 (CO), 164.4 (CO), 163.3 (CO), 159.6 (CO),
159.1 (CO), 151.4 (CO), 151.0 (CO), 150.0 (CO), 136.0 (Ph), 135.03 (Ph), 135.0 (Ph), 129.0 (Ph), 128.8 (Ph),
90.05 (C6 and C6ꢀꢀ ), 90.00 (Cα -C4=O), 49.0 (C5 and C5ꢀꢀ ), 46.1 (N-CH2 CH3 , triethyl ammonium salt), 29.2
(N-CH3), 28.7 (N-CH3), 27.27 (N-CH3), 27.26 (N-CH3), 9.0 (N-CH2 CH3 , triethyl ammonium salt).
5-(2-Formylphenyl)-1H,1ꢀH -spiro[furo[2,3-d]pyrimidine-6,5ꢀ-pyrimidine]2,2ꢀ ,4,4ꢀ ,6ꢀ (3H,3ꢀH,5H )
pentaone (4a)
White solid (70% Yield); mp 287 ◦ C (decomps.); FT-IR (KBr) 3224 (NH), 2991 (CH-aliph.), 2787 (COH),
;
2687 (COH), 1736 (C=O), 1688 (C=O), 1587 (C=C) cm−1 1 H-NMR (DMSO-d6 , 300 MHz) δ 5.88 (s, 1H,
CH-aliph.), 7.31 (d, 1H, J = 5.7 Hz, Ph), 7.59 (m, 2H, Ph), 7.95 (d, 1H, J = 6.3 Hz, Ph), 10.06 (s, 1H, COH),
10.88 (s, 1H, NH), 11.10 (s, 1H, NH), 11.74 (s, 1H, NH), 12.66 (bs, 1H, NH); 13 C-NMR (DMSO-d6 , 75 MHz)
δ: 191.5 (CO), 171.8 (CO), 164.5 (CO), 163.0 (CO), 157.6 (CO), 151.2 (CO), 149.8 (CO), 139.8 (Ph), 134.4
(Ph), 134.2 (Ph), 133.6 (Ph), 131.5 (Ph), 129.4 (Ph), 90.5 (C6), 86.6 (Cα -C4=O), 51.5 (C5).
791

Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-6,5ꢀ..., N. NOROOZI PESYAN, M. JALILZADEH
5-(2-Formylphenyl)-1,1ꢀ,3,3ꢀ -tetramethyl-1H,1ꢀH -spiro[furo[2,3-d]pyrimidine-6,5ꢀ-pyrimidine]2,2ꢀ ,
4,4ꢀ ,6ꢀ (3H,3ꢀH,5H )pentaone (4b)
White solid (90% Yield); mp 388 ◦ C (decomps.); FT-IR (KBr) 3050 (CH-ar.), 2926 (CH-aliph.), 2854 (CH-
;
aliph.), 2738 (CH-aliph.), 1691 (C=O), 1518 (C=C), 1438, 1382 cm−1 1 H-NMR (CDCl3 , 300 MHz) δ 2.64 (s,
3H, N-CH3), 3.31 (s, 3H, N-CH3), 3.46 (s, 3H, N-CH3), 3.50 (s, 3H, N-CH3), 6.10 (s, 1H, CH-aliph.), 7.39 (d,
1H, J = 7.2 Hz, Ph), 7.60 (m, 2H, Ph), 7.77 (d, 1H, J = 6.9 Hz, Ph), 9.94 (s, 1H, COH); 13 C-NMR (CDCl3 ,
75 MHz) δ: 194.4 (CH=O), 165.6 (CO), 163.4 (CO), 162.6 (CO), 158.6 (CO), 151.2 (CO), 149.8 (CO), 136.0
(Ph), 134.4 (Ph), 134.2 (Ph), 133.6 (Ph), 131.5 (Ph), 129.4 (Ph), 88.6 (C6), 86.8 (Cα -C4=O), 52.3 (C5), 29.9
(N-CH3), 29.5 (N-CH3), 28.2 (N-CH3), 28.2 (N-CH3); MS (m/z, %) 426 (M+ , 6), 397 (4), 310 (90), 280 (6),
253 (65), 222 (100, base peak), 197 (30), 183 (50), 156 (15), 138 (16), 111 (10), 83 (18), 69 (80), 58 (60), 53
(28), 43 (28).
2-(1,1ꢀ ,3,3ꢀ -Tetraethyl-4,4ꢀ ,6ꢀ -trioxo-2,2ꢀ -dithioxo-2,2ꢀ ,3,3ꢀ ,4,4ꢀ ,5,6ꢀ -octahydro-1H,1ꢀH -spiro[furo
[2,3-d]pyrimidine-6,5ꢀ -pyrimidine]-5-yl)benzaldehyde (4c)
White solid (85% Yield); mp 212 ◦ C (decomps.); FT-IR (KBr) 3050 (CH-ar.), 2979 (CH-aliph.), 2930 (CH-
;
aliph.), 2856 (CH-aliph.), 2748 (COH), 1738 (C=O), 1696 (C=O), 1666 (C=C), 1493, 1401, 1111 cm−1 1 H-
NMR (CDCl3 , 300 MHz) δ 0.68 (t, 3H, J = 6.9 Hz, N-CH2 CH3), 1.27 (t, 3H, J = 6.9 Hz, N-CH2 CH3),
1.37 (t, 3H, J = 6.9 Hz, N-CH2 CH3), 1.47 (t, 3H, J = 6.9 Hz, N-CH2 CH3), 3.49 (m, 1H, N-CH2 CH3),
3.85 (sextet, 1H, J = 6.9 Hz, N-CH2 CH3), 4.43-4.67 (m, 6H, 2 N-CH2 CH3), 6.34 (s, 1H, CH-aliph.), 7.36
(d, 1H, J = 7.2 Hz, Ph), 7.55-7.64 (m, 2H, Ph), 7.73 (d, 1H, J = 6.6 Hz, Ph), 9.92 (s, 1H, COH); 13 C-NMR
(CDCl3 , 75 MHz) δ: 193.7 (CH=O), 177.2 (CS), 175.8 (CS), 163.8 (CO), 162.0 (CO), 161.6 (CO), 157.0 (CO),
136.2 (Ph), 134.1 (Ph), 133.8 (Ph), 133.6 (Ph), 131.4 (Ph), 129.4 (Ph), 91.5 (C6), 88.5 (Cα -C4=O), 51.9 (C5),
45.1 (N-CH2 CH3), 44.8 (N-CH2 CH3), 43.7 (N-CH2 CH3), 43.6 (N-CH2 CH3), 12.5 (N-CH2 CH3), 12.1
(N-CH2 CH3), 11.7 (N-CH2 CH3), 11.5 (N-CH2 CH3).
2-(bis(2,4,6-Trioxohexahydropyrimidin-5-yl)methyl)benzaldehyde (10a)
White solid (75% Yield); mp 260 ◦ C (decomps.); FT-IR (KBr) 3224 (NH), 3100 (CH-ar.), 2990 (CH-aliph.),
;
1738 (C=O), 1687 (C=O), 1586, 1460, 1377, 1048, 775, 533 cm−1 1 H-NMR (DMSO-d6 , 300 MHz) δ 4.82, 4.98
(2s, 1H), 5.17, 5.32 (2s, 1H), 6.78-7.10 (m, 4H, Ph), 9.17 (s, 1H, COH), 10.54, 10.83 (2 bs, 4H, NH); 13 C-NMR
(DMSO-d6 , 75 MHz) δ: 191.0 (CHO), 165.1 (CO), 151.5 (CO), 145.2 (Ph), 142.6 (Ph), 127.1 (Ph), 125.6 (Ph),
124.2 (Ph), 122.6 (Ph), 52.8 (CH-aliph.), 48.9 (OC-CH-CO).
5,5ꢀ 5ꢀꢀ 5ꢀꢀꢀ -(1,3-Phenylenebis(methanetriyl))tetrakis(1,3-diethyl-6-hydroxy-2-thioxo-2,3-dihyd-
ropyrimidin-4(1H)one) (11c)
◦
White solid (76% Yield); mp 197–198 C (decomps.); FT-IR (KBr) 3437 (OH), 3100 (CH-ar.), 2980 (CH-aliph.),
1741 (C=O), 1698 (C=O), 1620, 1437, 1385, 1267, 1111 cm−1
;
1 H-NMR (CDCl3 , 300 MHz) δ 1.36 (t, 8 ×
3H, J = 6.9 Hz), 4.51 (q, 8 × 2H, J = 6.9 Hz), 5.51 (s, 1H), 5.70 (s, 2H), 6.75 (s, 1H), 7.05 (d, 2H, J = 7.5
Hz), 7.29 (t, 1H, J = 7.8 Hz), 9.0 (bs, 2H), 14.0 (bs, 2H); 13 C-NMR (CDCl3 , 75 MHz) δ: 174.3 (CS), 163.6
792

Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-6,5ꢀ..., N. NOROOZI PESYAN, M. JALILZADEH
(CO), 162.2 (CO), 136.8 (Ph), 136.0 (Ph), 128.6 (Ph), 125.0 (Ph), 97.3 (HO-C=C-C=O), 45.1 (Ph-CH-aliph.),
44.4 (N-CH2 CH3), 35.0 (N-CH2 CH3), 12.1 (N-CH2 CH3), 12.0 (N-CH2 CH3).
Results and discussion
This article describes the reaction of aromatic dialdehydes such as isophthalaldehyde (1b) and terphthalaldehyde
(1c) with BAs such as BA (2a), DMBA (2b), and DETBA (2c) as representative symmetric BAs and 1-
methyl barbituric acid (1-MBA, 2d) as an unsymmetric BA in the presence of cyanogen bromide and Et3 N
affording a new class of stable heterocyclic bis-spiro[furo[2,3-d]pyrimidine barbiturate derivatives (3a–3h) as
major products. In contrast, the reaction of phthalaldehyde (1a) with 2a–d and cyanogen bromide afforded
mono-functionalized spiro[furo[2,3-d]pyrimidine barbiturate (4a–d) that reacted with only one aldehyde group
under the same conditions (Scheme 1).
Scheme 1. Reaction of aromatic dialdehydes (1a–c) with (thio)barbituric acids (2a–d) and cyanogen bromide in the
presence of Et3 N in methanol.
More recently, we have reported the reaction mechanism for the formation of stable mono-functionalized
heterocyclic 5-alkyl and/or 5-aryl-1H,1ꢀ H -spiro[furo[2,3-d]pyrimidine-6,5ꢀ-pyrimidine]2,2ꢀ,4,4ꢀ ,6ꢀ (3H,3ꢀH,5
H)pentaones (8a, 8b) and their sulfur analogues from the reaction of aldehydes20,21 and ketones22 with 2a
and 2b in the presence of cyanogen bromide and triethylamine (Figure 1). Another mechanism has also been
proposed for the formation of triethylammonium-5-bromo-barbiturate salts (5a and 5b).20−22 These salts play
a major role in the synthesis of 3a–h through 4a–d as major products and 4e–l as minor products (Scheme
1).
793

Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-6,5ꢀ..., N. NOROOZI PESYAN, M. JALILZADEH
Y
X
X
G = Alkyl or aryl
O
O
X-Y-X =
O
HN-CO-NH (a),
CH3N-CO-NCH3 (b)
G
O
8
X
Y
X
Figure 1. The structures of (8a, b)20−23
.
Representatively, the reaction of 2b with cyanogen bromide and 1a afforded 4b in 90% yield in the
presence of triethylamine in methanol. Owing to the hindrance effect in 1a, only one aldehyde functional group
reacted with 2b and cyanogen bromide (Scheme 1). The reaction of 2b and 1b with cyanogen bromide afforded
3b as major product (96%) and 4f as minor product (4%) (Figures 2a and 3). The reaction of 2b with 1c also
afforded 3f as major product (92%) and 4j as minor product (8%) (Figure 2b). Representatively, a proposed
Scheme 2. Proposed mechanism for the formation of 3e as representative.
794

Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-6,5ꢀ..., N. NOROOZI PESYAN, M. JALILZADEH
Figure 2. Expanded 1 H-NMR spectra and the percentage of each structure in the equilibrium mixture of 3b and 4f
(a) and mixture of 3f and 4j (b).
Figure 3. 13 C-NMR spectrum of the mixture of 3b (major) and 4f (minor) (a) and expanded N-CH3 aliphatic region
(b) in CDCl3 .
795

Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-6,5ꢀ..., N. NOROOZI PESYAN, M. JALILZADEH
mechanism for the formation of 3e is shown in Scheme 2. The IR spectrum of 3e shows frequencies at 3448
and 3209 cm−1 that correspond to NH groups and at 3064 and 2833 cm−1 that are of CH frequencies of the
aromatic phenyl ring and aliphatic groups. Frequencies at 1719 and 1674 cm−1 correspond to carbonyl groups.
The 1 H-NMR spectrum of this compound shows 3 peaks at δ 4.74, 4.71, and 4.68 ppm related to C5 -H and/or
ꢀꢀ
C5 -H aliphatic protons. The phenyl protons also show 3 peaks at δ 7.01, 6.99, and 6.95 ppm. There are
4 broadened peaks at δ 12.58, 11.58, 10.77, and 10.57 ppm (see Experimental). These data demonstrate the
formation of the mixture of 3e diastereomers (similar to 3f in Figure 6).
Bifunctionalized products (9a–c) were not observed in the reaction of 1a and 2a–c in the presence of
BrCN and triethylamine. In this reaction, the compounds 10a–c were obtained in the absence of BrCN under
the same conditions (Scheme 3). In contrast, new compounds 4a–c were obtained in excellent yields due to the
hindrance effect at the ortho-position on the phenyl ring (Schemes 1 and 3).
Scheme 3. Reaction between phthalaldehyde (1a) and (thio)barbituric acids (2a–c) in the presence (path a) and in
the absence of BrCN (path c) in methanol, respectively.
On the other hand, in the reaction of 1b or 1c with 2a–d and BrCN, the compounds 3a–d and 3e–h
were obtained as major products (more than 85%), while the minor products 4e–h and 4i–l were afforded under
15%. These observations about 1b and 1c are attributed to the lower hindrance effect between 2 neighboring
aldehyde groups on the phenyl ring.
796

Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-6,5ꢀ..., N. NOROOZI PESYAN, M. JALILZADEH
In the reaction of 1b and 2c, compound 11c was afforded as major product (76%) and 3c as minor
product (24%) (Scheme 4). This compound 11c shows 2 intramolecular H-bonds between the carbonyl group
of thiobarbituric acid ring moiety with the hydroxyl group of the enolic form of the other thiobarbituric acid
ring moiety (these protons were assigned as Hb) (Schemes 4 and 5a). The formation of 11c was attributed to
the strong nucleophilicity of 2c rather than 5c. Therefore, the nucleophilic attack of 2c is faster than 5c on the
Michael adduct of 7c and it has a competitive reaction with 5c for the formation of corresponding compounds
(11c and 3c, respectively).
The 1 H-NMR spectrum of this compound shows 2 broad singlets at δ 9.0 and 14.0 ppm that correspond
to 2 types of exchangeable protons (the exchangeability was examined by adding 2 drops of D2 O). The peak at δ
14.0 ppm corresponds to the 8-membered intramolecular H-bond (Hb and Hf were assigned as intramolecular
H-bonded and H-free, respectively, in Schemes 4 and 5). Similarly, 2 mono-functionalized compounds 12b
and 13c also showed the same structures including an intramolecular H-bond (Scheme 5b). The chemical
shifts of the H-bonded and H-free of compounds 11c, 12b, and 13c are summarized in the Table. These
types of barbiturates having amidic (-CO-NH-) and/or thioamidic protons (-CS-NH-) do not show 8-membered
intramolecular H-bonds, and so only N -alkylated barbiturates show this behavior (Scheme 5c). It seems that
this phenomenon arose from tautomerization of (thio)barbituric acids (lactam-thiolactam ꢀ lactim-thiolactim
forms) that occurred prior to formation of the intramolecular H-bond. Another compound consisting of 8-
membered intramolecular H-bonds has also been reported.27
Scheme 4. Reaction of 1b with 2c for the formation of the mixture of 3c and 11c in the presence of BrCN and Et3 N
in methanol.
797

Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-6,5ꢀ..., N. NOROOZI PESYAN, M. JALILZADEH
Scheme 5. Tautomeric forms and intramolecular H-bonding in 11c (Hb : H-bonding and Hf : H-free).
An interesting situation occurred in the molecules 3a, 3b and 3c, and 3e–h, which have C-H protons on
the phenyl ring. For instance, the 1 H-NMR spectrum of crude 3b shows 4 distinct methyl groups at δ 2.72,
3.31, 3.38, and 3.52 ppm. Another 4 methyl peaks were also observed in the 1 H-NMR spectrum of 3b at δ 2.68,
ꢀꢀ
3.32, 3.42, and 3.55 ppm. Two singlets also appeared at δ 4.77 and 4.85 ppm for C5 -H and/or C5 -H with
integration ratio of 1.01:0.61 in the 1 H-NMR spectrum of 3b assigned as 3bA and 3bB, respectively (Figure
2a). These observations indicated that the equilibrium mixture of 2 diastereomers and/or rotamers 3bA and
798

Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-6,5ꢀ..., N. NOROOZI PESYAN, M. JALILZADEH
3bB existed with the exact ratio of ≈60%:≈36%, (Figure 2a). In contrast, obviously, the 1 H- and 13 C-NMR
spectra of pure 3a were complicated and showed the equilibrium mixtures of at least 3 distinct diastereomers
and/or rotamers (Figures 4 and 5). For example, the expanded 1 H-NMR spectrum of 3a showed 3 singlets at
ꢀꢀ
δ 4.64, 4.67, and 4.70 ppm for C5 -H and/or C5 -H, respectively. This observation agrees with the existence of
more than 13 distinct peaks for 3a in its 13 C-NMR spectrum. Representatively, possible diastereomers and/or
rotamers that existed for 3a are shown in Figure 5.
Table. The chemical shifts of the exchangeable protons of Hb (H-bonded) and Hf (H-free) in compounds 11c, 12b,
and 13c.
Compd.
11c
Hb
Hf
14.00 9.00
13.46 10.13
13.90 8.50
12b
13c
Figure 4. Expanded 1 H-NMR spectrum of 3a at aliphatic (a) and aromatic regions (b) that confirms the mixture of
at least 3 diastereomers and/or rotamers in 3a.
On the other hand, the 1 H-NMR spectrum of 3f shows 2 singlets at δ 7.045 and 7.054 ppm for the
ꢀꢀ
phenyl ring protons and 2 singlets at δ 4.87 and 4.90 ppm for C5 -H and C5 -H protons, respectively. The Ha ,
Hb , and Hc protons on the phenyl ring in each diastereomer and/or rotamer have equivalent chemical shift
because of a plane of symmetry (σ ) (in 3fA form) and an axis of symmetry (C2) (in 3fB form) and also the
ꢀꢀ
free rotation about the single bond between C5 -C1 and C5 -C4 (on phenyl ring) (Figures 2b and 6). The
experimental results (1 H- and 13 C-NMR data) confirm the structures of 3fA and 3fB diastereomers and/or
rotamers in equilibrium mixture, because 2 singlets were observed in the aromatic region (a singlet for each of
799

Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-6,5ꢀ..., N. NOROOZI PESYAN, M. JALILZADEH
3fA and 3fB phenyl ring). The 1 H-NMR spectrum of 3f shows 4 methyl groups at δ 2.61, 3.29, 3.41, and 3.52
ppm and also other peaks at δ 2.66, 3.00, 3.41, and 3.52 ppm for methyl groups. Two singlets at δ 4.87 and
ꢀꢀ
4.90 ppm for C5 -H and/or C5 -H (with integration ratio of 50%:50%) and at δ 7.045 and 7.054 ppm for C-H
on the phenyl ring (46%:46%) corresponded to the mixture of equal amounts of 3fA and 3fB forms. According
to Figure 6, 2 rotamers 3fA (R,S or S ,R) and 3fB (R,R or S ,S) are diastereomers.
O
O
R
N
R
O
R
N
R
O
R
N
R
R
N
N
N
O
N
N
R
O
O
H
O
O
O
O
O
O
O
O
R
R
O
O
N
N
R
H
O
N
H
O
H
O
O
N
N
N
R
N
R
A (R,R)
N
R
O
O
R
R
C2
C2
O
O
O
N
O
R R
O
R
N
R
R
N
R
O
R
N
R
N
N
N
N
O
O
O
O
O
O
O
O
O
O
R
R
O
N
N
R
R
O
N
N
H
H
H
O
H
O
O
O
N
R
N
O
O
O
N
R
N
R
R
Plane of symmetry
Plane of symmetry
B (R,S)
O
R
N
R
R
O
N
N
O
N
R
H
O
O
O
O
R = H, X = O (
3a)
O
O
R
= Me, X = O (3b)
= Et, X = S (3c)
H
O
N
N
N
R
N
R
O
C2
R
O
A' (R,S)
Figure 5. Possible plane of symmetry σ (B) and axis of symmetry C2 (A and A’) in 3a–c.
Representatively, the reaction of 1c with an unsymmetric barbituric acid, 2d, afforded a diastereomeric
mixture of spiro adducts (3h) (Figure 7). One of the most interesting situations in these compounds is the
800

Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-6,5ꢀ..., N. NOROOZI PESYAN, M. JALILZADEH
binding of triethylammonium hydrobromide salt to one of the diastereomers among 3h diastereomers in the ratio
of 1:1. First, one can unambiguously think that the salt of triethylammonium hydrobromide is an impurity in
the spiro compound. Therefore, it was washed several times with methanol and then with water. The remaining
liquid did not show the salt of triethylammonium hydrobromide. These experiments indicated the binding of
triethylammonium hydrobromide salt to the molecule (Figure 7).
O
O
O
O
R
R
R
R
R
R
R
R
N
N
N
N
N
N
N
N
Hc
O
O
O
N
O
N
O
O
O
O
O
O
O
O
R
R
R
R
H
H
H
H
N
N
O
O
O
O
Hb
Ha
N
N
R
N
N
O
O
O
O
R
R
R
Plane of symmetry
Plane of symmetry
A (R,S or S,R)
O
O
R
R
R
R
R
R
N
N
O
O
N
N
N
N
Hc
O
O
N
N
O
O
Hc
Hb
H
H
H
R
R
O
O
O
O
O
R
O
R
R
O
O
H
Ha
H
N
N
O
O
O
O
Ha
N
N
O
O
N
N
N
N
R
R
C2
C2
R
R
R
B (R,R or S,S)
O
O
R = H, X = O (3e)
= Me, X = O (3f )
= Et, X = S (3g)
Figure 6. Possible plane of symmetry σ (A) and axis of symmetry C2 (B) in 3e–g.
801

Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-6,5ꢀ..., N. NOROOZI PESYAN, M. JALILZADEH
Figure 7. 1 H-NMR (a) and 13 C-NMR spectra of diastereomeric mixture of 3h (b) and the binding of Et3 NHBr salt
(in DMSO-d6).
802

Bifunctionalized linked bis-spiro[furo[2,3-d]pyrimidine-6,5ꢀ..., N. NOROOZI PESYAN, M. JALILZADEH
Conclusion
In summary, the reaction of symmetrical (thio)barbituric acids (BA, DMBA, TBA, and DETBA) with cyanogen
bromide and phthalaldehyde afforded mono-functionalized spiro compound derivatives. This reaction with
isophthalaldehyde or terphthalaldehyde afforded bifunctionalized spiro compound derivatives and their sulfur
analogues as major products and mono-functionalized spiro compound as minor product. In the reaction of
1,3-diethylthiobarbituric acid with isophthalaldehyde and terphthalaldehyde the Michael product as major and
spiro adduct as minor products were obtained. The later Michael product showed an 8-membered intramolecular
H-bond.
Supporting information
Full characterization data for compounds 3a, 3b, 3c, 3e, 3f, 3h, 4a, 4b, 4c, 5a, 11c, and 11g are available.
Acknowledgements
We gratefully acknowledge financial support from the Research Council of Urmia University.
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804

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