Poly(N-bromo-N-ethyl-benzene-1,3-disulfonamide) and N,N,N′,N′-tetrabromobenzene-1,3-disulfonamide as new efficient reagents for one-pot synthesis of furano and pyrano pyrimidinones (thiones)

Article abstract of DOI:10.1039/c5ra16646b

In this study, a one-pot diastereoselective three-component reaction of urea/thiourea, 2,3-dihydrofuran/3,4-dihydro-2H-pyran with aromatic aldehydes has been developed for synthesis of furano and pyrano pyrimidinones (thiones) using poly(N-bromo-N-ethyl-b

Full text of DOI:10.1039/c5ra16646b

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Poly(N-bromo-N-ethyl-benzene-1,3-disulfonamide)
and
N,N,N',N'-
tetrabromobenzene-1,3-disulfonamide as new efficient reagents for one-
pot synthesis of furano and pyrano pyrimidinones (thiones)
Ramin Ghorbani-Vaghei,* Yaser Maghbooli, Jafar Mahmoodi and Azadeh Shahriari
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Recently, Wu
and
coworkers reported
a
novel
In this study, oneꢀpot diastereoselective threeꢀcomponent reaction
of urea/thiourea, 2,3ꢀdihydrofuran/3,4ꢀdihydroꢀ2Hꢀpyran with
aromatic aldehydes have been developed for synthesis of
furano and pyrano pyrimidinones (thiones) using poly(Nꢀ 10
bromoꢀNꢀethylꢀbenzeneꢀ1,3ꢀdisulfonamide) [PBBS] and
N,N,N',N'ꢀtetrabromobenzeneꢀ1,3ꢀdisulfonamide [TBBDA].
diastereoselective oneꢀpot threeꢀcomponent reaction 50
containing urea/thiourea, various aldehydes and alkenes
for the synthesis of pyrimidinone (thione) derivatives
using TMSꢀCl.14 Then, these compounds have been
synthesized in the presence of Lꢀproline/TFA,15 pꢀTSA,16
antimony trichloride17 and [Hnmp]HSO4.18
55
Although several methods are available for the preparation of
furano and pyrano pyrimidinones (thiones), some of them
suffer from disadvantages such as long reaction time, low
yields of products, the use of toxic metal reagents and
Introduction
Multiꢀcomponent reactions (MCRs) are important tools for the
rapid and effective synthesis of a wide variety of organic 15
molecules.1 These reactions convert more than two
starting materials directly into their products by oneꢀpot
reactions. Further, they are performed without need to
isolate any intermediate during their processes; this
strongly acidic conditions. Therefore, to avoid these 60
limitations, the discovery of a new, easily available
reagent for the preparation of these compounds is still
desirable.
reduces time and saves both energy and raw material.2
In recent years, fused ring pyrimidinones (thiones) have
attracted intense interest due to their useful biological and
pharmacological properties, such as being antitumor,
antiallergic, antibacterial, antihypertensive, cardiotonic,
20
Poly(NꢀbromoꢀNꢀethylꢀbenzeneꢀ1,3ꢀdisulfonamide) [PBBS]
and
N,N,N',N'ꢀtetrabromobenzeneꢀ1,3ꢀdisulfonamide 65
[TBBDA] are effective reagents19 for several organic
transformations.20ꢀ26 They react under heterogeneous
conditions, are conveniently handled and after completion
of the reaction, the sulfonamide was recovered,
rebrominated and used for several times (Scheme 2).
vasodilator, bronchiodilator and hepatoprotective agents. 25
They have antimalarial, antifungal, analgesics, antiꢀHIV
and herbicidal properties in some cases.3ꢀ9
70
For example, some pyrimidine sulfonamide derivatives of the
general structure 1 (Scheme 1) have been developed as
powerful
herbicides.10
Several
4,5,6ꢀtrisubstituted 30
furo[2,3ꢀd]pyrimidinꢀ4ꢀamines 2 (Scheme 1) have been
detected as ACK1 (Activated Cdc42ꢀassociated tyrosine
Kinase 1) inhibitors. Some findings suggest that ACK1 is
a potential target for developing antiꢀcancer therapeutics.11
Furthermore, the results revealed that 5ꢀaminoꢀ2,4ꢀdi(2ꢀ 35
thienyl)ꢀ4,6ꢀdihydroꢀ6ꢀphenylpyrano[2,3ꢀd]pyrimidinꢀ7ꢀ
thione compounds of the general structure 3 (Scheme 1)
containing thione and dithienyl moieties showed
antibacterial activity equal to that of gentamycin.12
Biginelli reactions are ranked as one of the most powerful 40
tools for the facile synthesis of complex heterocyclic
scaffolds such as fused ring pyrimidinones (thiones).13
Scheme 2. The structure of TBBDA and PBBS.
In continuation of our studies in the application of poly(Nꢀ 75
bromoꢀNꢀethylꢀbenzeneꢀ1,3ꢀdisulfonamide) [PBBS] and
N,N,N',N'ꢀtetrabromobenzeneꢀ1,3ꢀdisulfonamide
[TBBDA], in organic synthesis,19ꢀ26 herein we report a
simple and efficient method for the preparation of pyrano
and furano pyrimidinone (thione) derivatives from oneꢀpot 80
threeꢀcomponent reactions of cyclic enol ethers with
urea/thiourea−aldehyde mixtures (Scheme 3).
45
Scheme 3. Diastereoselective threeꢀcomponent reactions of cyclic enol ethers 85
Scheme 1. Some examples of fused ring pyrimidinones (thiones).
with urea/thiourea−aldehyde mixtures.
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Results and discussion
d]pyrimidinꢀ2ꢀone failed in the absence of reagent, the
Initially, we decided to explore the role of TBBDA and PBBS
as reagents for the threeꢀcomponent reaction of 4ꢀ
chlorobenzaldehyde (1a, 1 mmol), urea (2, 1 mmol) and
3,4ꢀdihydroꢀ2Hꢀpyran (3, 1 mmol) (Table 1). In the
absence of reagent, no desired product was observed, even
after prolonged reaction time (Table 1, entry 1). Since the
synthesis of 4ꢀ(4ꢀchlorophenyl)octahydroꢀ2Hꢀpyrano[2,3ꢀ
effect of the reagent was also investigated in various 10
conditions, and the results are presented in Table 1, entries
2ꢀ10. The best results were achieved when the reaction
was carried out in CH3CN (5 mL) in the presence of
TBBDA (0.1 g, 0.18 mmol) or PBBS (0.1 g) at 82 oC
5
(Table 1, entry 3).
15
Table 1. Optimization of reaction conditions for the synthesis of pyrano pyrimidinone 4aa
TBBDA (mol%)/
Yield (%)b
Entry
Solvent
Temp (˚C)
Time (h)
PBBS (g)
TBBDA/PBBS
1
2
CH3CN
CH3CN
0
82
82
12
6
c
9 /0.05
18 /0.1
30 /0.15
18 /0.1
18 /0.1
18 /0.1
18 /0.1
18 /0.1
18 /0.1
88/78
92/90
92/90
36/23
29/15
75/72
72/68
58/47
91/90
3
CH3CN
82
2
4
CH3CN
82
3
5
CHCl3
62
8
6
Toluene
EtOH
110
78
8
7
8
8
CH3OH
65
8
9
EtOH/H2O
CH3CN/DMF
Reflux
Reflux
8
10
8
a
b
c
Reaction conditions: 4ꢀchlorobenzaldehyde (1.0 mmol), urea (1.0 mmol), 3,4ꢀdihydroꢀ2Hꢀpyran (1.0 mmol) in solvent (5 mL).
Isolated yield.
Desired product not formed.
After optimization of the reaction conditions, in order to study 20
the generality of the procedure, various aromatic
aldehydes, urea/thiourea and 3,4ꢀdihydroꢀ2Hꢀpyran were
submitted to these reaction conditions and provide
Table 2. Synthesis of pyrano pyrimidinones (thiones)a
corresponding
4ꢀaryloctahydroꢀ2Hꢀpyrano[2,3ꢀ
d]pyrimidinꢀ2ꢀones or 4ꢀaryloctahydroꢀ2Hꢀpyrano[2,3ꢀ 25
d]pyrimidinꢀ2ꢀthiones in good to high yields (Table 2).
30
Time(h)/Yield(%)b
Entry
Aldehyde
X
Product
TBBDA
2/92
PBBS
2/90
1
2
3
4
5
6
7
4ꢀChlorobenzaldehyde
4ꢀChlorobenzaldehyde
4ꢀBiphenylcarbaldehyde
4ꢀBiphenylcarbaldehyde
2ꢀNaphthaldehyde
O
S
4a
4b
4c
4d
4e
4f
3/89
2/89
3/85
2/90
2/82
2/95
3/81
3/82
5/80
3/83
3/79
2/90
O
S
O
S
2ꢀNaphthaldehyde
4ꢀNitrobenzaldehyde
O
4gc
a
Reaction conditions: aryl aldehyde (1.0 mmol), urea or thiourea (1.0 mmol), reagent (0.18 mmol) and 3,4ꢀdihydroꢀ2Hꢀpyran (1.0 mmol) in CH3CN (5 mL).
b
c
Isolated yield.
35
1:1 Diastereomeric mixture obtained.
It was shown that the aromatic aldehydes with electronꢀ
withdrawing groups reacted faster than the electronꢀ
donating groups (Table 2, entries 1, 2 and 7). Replacing
urea with thiourea produced the corresponding thioꢀ 40
2
|
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derivatives in good yields (Table 2, entries 2, 4 and 6).
Comparatively, thiourea shows lower reactivity than urea.
The reason for low yields in producing the desired
products with thiourea is probably due to the strong
coordinating ability of sulfur often leads to the belief that
sulfur will hinder reagent activity.27
To test this type of MCR, the scope of the reaction was
investigated with series of aromatic aldehydes,
a
urea/thiourea and 2,3ꢀdihydrofuran in an effort to build up
similar 4ꢀarylhexahydrofuro[2,3ꢀd]pyrimidinꢀ2(1H)ꢀones 10
5
or
4ꢀarylhexahydrofuro[2,3ꢀd]pyrimidinꢀ2(1H)ꢀthiones
(Table 3).
Table 3. Synthesis of furano pyrimidinones (thiones)a
15
Time(h)/Yield(%)b
Entry
Aldehyde
X
Product
TBBDA
2/92
PBBS
3/85
3/80
3/84
3/82
2/84
3/85
1
2
3
4
5
6
4ꢀMethylbenzaldehyde
4ꢀMethylbenzaldehyde
O
S
5a
5b
5c
5d
5e
5f
3/90
2ꢀHydroxyꢀ3ꢀmethoxybenzaldehyde
2ꢀHydroxyꢀ3ꢀmethoxybenzaldehyde
2ꢀChlorobenzaldehyde
O
S
2/91
3/89
O
S
2/94
2ꢀChlorobenzaldehyde
3/90
a
Reaction conditions: aryl aldehyde (1.0 mmol), urea or thiourea (1.0 mmol), reagent (0.18 mmol) and 2,3ꢀdihydrofuran (1.0 mmol) ) in CH3CN (5 mL).
Isolated yield.
20
b
We obtained the desierd products in good to high yields under
this condition reaction (Table 3). Comparison of yield and
time for the reaction was shown that aromatic aldehydes
carrying either electron donating (Table 3, entries 1ꢀ4) or 25
electronꢀwithdrawing substituents (Table 3, entries 5 and
6) reacted in good to high yields.
We have proposed a possible mechanism for this Biginelli
type reaction which is based on the mechanism suggested
by Overman and Wolfe (Scheme 4).28 Since PBBS and 30
TBBDA contain bromine atoms which are attached to
nitrogen atoms, it is probable that they release Br+ in situ
which can act an electrophilic specie.19ꢀ26 It accelerates the
formation of the Nꢀacyliminium ion intermediate A from
an aldehyde and urea in presence of these reagents. The 35
nucleophilic attack of cyclic enol ether 3 on intermediate
as only the cisꢀisomer was observed. In previous 45
reports,14ꢀ18 the NOE and NOESY experiments and by the
Xꢀray crystallographic analysis of this compounds
provided a straight evidence of the cis fused ring juncture.
But aromatic aldehydes containing a nitro group led to
diastereomeric mixtures (Table 2, entry 7). The portion of 50
1
isomers was determined from their H NMR spectrum. In
case of 4ꢀchlorobenzaldehyde (1a) no diastereomeric
mixture was formed (Table 2, entry 1). So it was
concluded that the electronic nature and position of the
substituents on the aromatic ring is very important on 55
these reaction (Scheme 4).17
To investigate the role of HOBr in activating the reaction,
hydrogen bromide was added to a solution of sodium
hypochlorite in water.29 When the reaction was carried out
in this condition only a trace amount of corresponding 60
products was observed. Also, using a catalytic amount of
aqueous 48% HBr instead of TBBDA gave lower yields
(15%). This result indicates that the generation of the
protic acids HOBr or HBr may not be the only factor
responsible for the reagent activity of TBBDA. It is 65
possible that the positive bromonium moiety also has
some role in facilitating the process.
A
generates an oxonium ion intermediate B, which
undergoes cyclization either in an exo and/or endo fashion
as shown in Scheme 4, leading to exo and/or endo
intermediate. The severe steric interaction between the 40
tetrahydropyrylium or dihydrofuranium cycle and urea or
thiourea group disfavors the reaction by endo intermediate
and the cyclization occurs by attack of the NH2 group in
an exo fashion. The reaction is diastereoselective in nature
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Scheme 4. Suggested mechanism for the synthesis of pyrano and furano pyrimidinones (thiones)
To demonstrate the efficiency of the described method in
comparison with formerly reported procedures in the
furano and pyrano pyrimidinones (thiones) by a threeꢀ
component condensation of aromatic aldehydes,
literature, we compared the results obtained in the
preparation of 4ꢀ(4ꢀchlorophenyl)octahydroꢀ2Hꢀ
5
urea/thiourea with 2,3ꢀdihydrofuran (DHF)/3,4ꢀdihydroꢀ 20
2Hꢀpyran (DHP) using poly(NꢀbromoꢀNꢀethylꢀbenzeneꢀ
pyrano[2,3ꢀd]pyrimidinꢀ2ꢀone with those of other methods
(Table 4). The results clearly indicate that use of TBBDA
is an efficient method for the synthesis of furano and
pyrano pyrimidinones (thiones). We observed significant 10
decrease of reaction time, product purity and thus cost
efficiency.
1,3ꢀdisulfonamide)
[PBBS]
and
N,N,N',N'ꢀ
tetrabromobenzeneꢀ1,3ꢀdisulfonamide [TBBDA] in a oneꢀ
pot manner was developed. This method offers several
significant advantages, such as being inexpensive 25
reagents, high yield, high atom economy, ease of product
isolation, environmental friendliness (nonꢀcorrosive
reagent) which make it a useful and attractive process for
the rapid synthesis of furano and pyrano pyrimidinones
Table 4. Compared performance of various methods for the synthesis of
pyrano pyrimidinone 4a
(thiones).
30
Entry
Catalyst/(mol%)
TMSCl/100
Time (h) Yield (%)
Ref.
Experimental
1
2
3
4
10
7
92
85
91
92
14
15
Mass spectra were recorded on a Shimadzu QP 1100 BX Mass
Spectrometer (University of Tehran, Iran). 1H and 13Cꢀ
NMR spectra were recorded on Bruker Advance 400 FT
Lꢀproline/15
TFA/6
NMR spectrometers (undertaken at University of 35
Mazandaran, Iran) at 400MHz and 100MHz in DMSOꢀd6,
respectively. Chemical shifts are reported in ppm (δ),
relative to the internal standard of tetramethylsilane
(TMS). Chemical shift values are reported in parts per
million relative to TMS as internal reference, unless 40
SbCl3/10
3.5ꢀ7
2
17
TBBDA/18
This work
15
Conclusions
In conclusion, a simple and highly efficient synthesis of
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otherwise stated; s (singlet), d (doublet), t (triplet), m
(multiplet); J in Hertz (Hz). Infrared (IR) spectroscopy
was performed on a Perkin Elmer GX FTꢀIR spectrometer
in KBr pellets. All starting materials were obtained from
commercial sources and used without purification.
°C; IR (KBr): υ 3154, 3079, 2942, 2857, 1655, 1603,
1570, 1536, 1203, 1068, 1034, 769 cmꢀ1; 1H NMR (400 60
MHz, DMSOꢀd6): δ 1.27–1.38 (m, 2H), 1.54–1.65 (m,
1H), 1.74–1.91 (m, 2H), 3.43–3.49 (m, 1H), 3.86 (d, J =
10.8 Hz, 1H), 4.41 (s, 1H), 4.52–4.59 (m, 1H), 7.35–7.47
(m, 5H), 7.66 (d, J = 7.2 Hz, 4H), 8.43 (s, 1H), 8.84 (s,
1H); 13C NMR (100 MHz, DMSOꢀd6): δ 20.4, 22.6, 36.0, 65
53.6, 65.6, 78.3, 126.6, 127.5, 128.1, 128.9, 130.2, 130.7,
139.6, 139.7, 176.5; MS: m/z = 324 (M+, 92%), 265
(40%), 249 (53%), 181 (100%), 165 (42%), 152 (53%),
113 (23%), 76 (90%), 59 (40%), 43 (62%).
5
General procedure for the synthesis of furano and pyrano
pyrimidinones (thiones):
TBBDA (0.1 g, 0.18 mmol ) or PBBS (0.1 g) was added to a
solution of aromatic aldehyde 1 (1 mmol), urea or thiourea
2 (1 mmol), 2,3ꢀdihydrofuran or 3,4ꢀdihydroꢀ(2H)ꢀpyran 3 10
(1 mmol) in CH3CN (5 mL) and the reaction mixture was
magnetically stirred and refluxed till the reaction was
completed (monitored by thinꢀlayer chromatography TLC
(3:2, nꢀhexane/acetone)). The products were precipitated
directly. The crude product was isolated by filtration 15
through a Buechner funnel. Then, CH2Cl2 (5 mL) was
added, and the precipitated sulfonamide was removed by
filtration. The residue so obtained was purified by simple
crystallization using ethanol to give pure product.
4-(Naphthalen-2-yl)octahydro-2H-pyrano[2,3-
70
d]pyrimidine-2-one (4e): White solid; Mp: 258ꢀ259 °C;
IR (KBr): υ 3311, 3200, 3079, 2943, 2894, 1671, 1603,
1
1494, 1374, 1076, 745 cmꢀ1; H NMR (400 MHz, DMSOꢀ
d6): δ 1.22–1.25 (m, 2H), 1.51–1.57 (m, 1H), 1.78–1.95
(m, 2H), 3.38–3.48 (m, 1H), 3.91 (d, J = 9.2 Hz, 1H), 4.44 75
(d, J = 8.8 Hz, 1H), 4.71 (d, J = 10.8 Hz, 1H), 6.72 (m,
1H), 7.33 (s, 1H), 7.43–7.51 (m, 3H), 7.85–7.91 (m, 4H);
13C NMR (100 MHz, DMSOꢀd6): δ 22.0, 24.5, 39.2, 54.4,
67.4, 81.9, 125.7, 126.4, 126.7, 127.0, 128.0, 128.2, 128.5,
133.1, 133.2, 139.4, 155.3; MS: m/z = 282 (M+, 22%), 279 80
(100%), 164 (20%), 159 (45%), 149 (25%), 131 (28%), 92
(15%), 63 (7%), 43 (5%).
Spectral data:
20
4-(4-Chlorophenyl)octahydro-2H-pyrano[2,3-d]pyrimidin-
2-one (4a): White solid; Mp: 235ꢀ236 (Lit.15 239ꢀ241 °C);
IR (KBr): υ 3307, 3212, 3097, 2945, 2863, 1701, 1595,
1490, 1298, 1087, 1029, 762 cmꢀ1; 1H NMR (400 MHz,
DMSOꢀd6): δ 1.19–1.24 (m, 2H), 1.52–1.59 (m, 1H), 25 4-(Naphthalen-2-yl)octahydro-2H-pyrano[2,3-
1.69–1.80 (m, 2H), 3.44 (dd, J = 10, 11.6 Hz, 1H), 3.88 (d,
J = 8 Hz, 1H), 4.42 (dd, J = 2.4, 4.4 Hz, 1H), 4.56 (d, J =
10.8 Hz, 1H), 6.68 (s, 1H), 7.30 (d, J = 3.2 Hz, 1H), 7.34
(d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H); 13C NMR
(100 MHz, DMSOꢀd6): δ 20.7, 23.3, 38.1, 52.4, 66.2, 80.7, 30
128.8, 129.9, 132.5, 141.0, 155.1.
d]pyrimidine-2-thione (4f): White solid; Mp: 275ꢀ277
°C; IR (KBr): υ 3358, 3262, 3177, 2925, 2855, 1619, 85
1
1537, 1211, 1034, 748 cmꢀ1; H NMR (400 MHz, DMSOꢀ
d6): δ 1.32 (m, 5H), 2.49–2.53 (m, 1H), 3.29–3.34 (m,
1H), 3.39–3.43 (m, 1H), 4.38–4.51 (m, 1H), 7.40–7.56 (m,
3H), 7.78–7.82 (m, 1H), 7.87–7.89 (d, J = 7.6 Hz, 3H),
8.30–8.33 (m, 1H), 8.64 (s, 1H); 13C NMR (100 MHz, 90
DMSOꢀd6): δ 19.0, 25.0, 30.2, 60.7, 66.4, 97.7, 124.5,
125.2, 125.8, 126.1, 127.5, 127.9, 128.0, 132.3, 132.4,
132.8, 176.1; MS: m/z = 298 (M+, 100%), 239 (42%), 194
(9%), 179 (15%), 165 (17%), 155 (63%), 128 (18%), 76
4-(4-Chlorophenyl)octahydro-2H-pyrano[2,3-
d]pyrimidine-2-thione (4b): White solid; Mp: 268ꢀ270
(Lit.15 260ꢀ263 °C); IR (KBr): υ 3186, 3042, 2962, 2835,
1
1670, 1572, 1534, 1490, 1203, 1035, 1029, 746 cmꢀ1; H 35
NMR (400 MHz, DMSOꢀd6): δ 1.23 (d, J = 14.8 Hz, 2H),
1.59–1.65 (m, 1H), 1.69–1.75 (m, 1H), 1.86 (t, J = 4.4 Hz,
1H), 3.46 (t, J = 10.2 Hz, 1H), 3.86 (d, J = 11.2 Hz, 1H),
3.96 (dd, J = 2.4, 4 Hz, 1H), 4.53 (d, J = 10.4 Hz, 1H),
7.34 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 8.47 (s, 40
1H), 8.87 (d, J = 2.8 Hz, 1H); 13C NMR (100 MHz,
DMSOꢀd6): δ 20.8, 22.9, 36.4, 53.6, 66.1, 78.7, 128.8,
130.0, 132.8, 139.6, 176.9.
(20%), 59 (20%), 43 (23%).
95
4-(4-Nitrophenyl)octahydro-2H-pyrano[2,3-d]pyrimidin-2-
one (4g): White solid (1:1 diastereomeric mixture) ; Mp:
267ꢀ268 (Lit.15 260ꢀ265 °C); IR (KBr): υ 3315, 3219,
3086, 2939, 2860, 1696, 1606, 1520, 1348, 1273, 1033,
755 cmꢀ1; 1H NMR (400 MHz, DMSOꢀd6): δ 0.60–0.62 100
(m, 1H), 1.23 (m, 2H), 1.44–1.47 (m, 1H), 1.55–1.62 (m,
2H), 1.78–1.91 (m, 4H), 3.14 (t, J = 11.2 Hz, 1H), 3.46 (t,
J = 11.2 Hz, 1H), 3.74 (d, J = 11.6 Hz, 1H), 3.90 (d, J =
9.2 Hz, 1H), 4.00 (d, J = 9.2 Hz, 1H), 4.44 (s, 1H), 4.51
(s, 1H), 4.72 (d, J = 10.8 Hz, 1H), 6.83 (s, 1H), 7.13 (s, 105
1H), 7.15 (s, 1H), 7.40 (s, 1H), 7.41 (d, J = 8.8 Hz, 2H),
7.65 (d, J = 8.8 Hz, 2H), 8.24 (t, J = 8.8 Hz, 4H); 13C
NMR (100 MHz, DMSOꢀd6): δ 20.7, 23.2, 24.9, 25.7,
39.3, 40.2, 52.7, 55.1, 65.4, 66.2, 80.6, 81.7, 123.8, 124.0,
4-([1,1'-Biphenyl]-4-yl)octahydro-2H-pyrano[2,3-
d]pyrimidin-2-one (4c): White solid; Mp: 220ꢀ223 °C; IR 45
(KBr): υ 3329, 3276, 3077, 2946, 2870, 1677, 1649, 1508,
1
1384, 1082, 1034, 766 cmꢀ1; H NMR (400 MHz, DMSOꢀ
d6): δ 1.21–1.32 (m, 2H), 1.53–1.60 (m, 1H), 1.75–1.85
(m, 2H), 3.90 (d, J = 10.4 Hz, 1H), 4.44 (s, 1H), 4.59 (d, J
= 9.2 Hz, 1H), 6.61 (s, 1H), 7.29 (s, 1H), 7.34 (d, J = 7.2 50
Hz, 1H), 7.41–7.47 (m, 5H), 7.66 (d, J = 6.4 Hz, 4H); 13C
NMR (100 MHz, DMSOꢀd6): δ 20.3, 22.9, 37.7, 52.3,
65.8, 80.3, 126.5, 126.6, 127.4, 128.1, 128.9, 139.5, 139.8,
140.8, 154.6; MS: m/z = 308 (M+, 17%), 249 (54%), 208
(25%), 182 (48%), 152 (37%), 107 (30%), 84 (50%), 69 55
(65%), 55 (62%), 43 (100%).
128.8, 129.4, 147.2, 147.4, 149.6, 150.0, 154.9, 155.0.
4-(p-Tolyl)hexahydrofuro[2,3-d]pyrimidin-2(1H)-one (5a):
White solid; Mp: 211ꢀ214 °C; IR (KBr): υ 3294, 3218,
3091, 2933, 2900, 1695, 1661, 1502, 1371, 1284, 1035,
110
1
768 cmꢀ1; H NMR (400 MHz, DMSOꢀd6): δ 1.61 (m, 1H),
4-([1,1'-Biphenyl]-4-yl)octahydro-2H-pyrano[2,3-
d]pyrimidine-2-thione (4d): White solid; Mp: 244ꢀ246
1.89 (m, 1H), 2.62 (m, 4H), 3.63 (m, 1H), 3.89 (m, 1H), 115
4.03 (m, 1H), 4.77 (m, 1H), 6.73 (s, 1H), 7.15 (m, 3H),
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7.21 (m, 2H); 13C NMR (100 MHz, DMSOꢀd6): δ 22.3,
28.6, 42.7, 55.6, 64.9, 84.6, 128.8, 130.5, 138.2, 140.2,
156.9; MS: m/z = 232 (M+, 33%), 187 (52%), 146 (13%),
120 (100%), 118 (32%), 91 (32%), 70 (78%), 56 (10%),
42 (37%).
(100 MHz, DMSOꢀd6): δ 27.2, 40.1, 51.6, 64.6, 80.8,
127.7, 128.1, 129.6, 130.7, 135.8, 137.8, 177.1; MS: m/z = 60
268 (M+, 18%), 222 (12%), 193 (10%), 163 (100%), 139
(100%), 112 (31%), 102 (36%), 76 (87%), 60 (62%), 43
(89%).
5
4-(p-Tolyl)hexahydrofuro[2,3-d]pyrimidin-2(1H)-thione
(5b): White solid; Mp: 227ꢀ229 °C; IR (KBr): υ 3207,
2950, 2881, 1612, 1543, 1518, 1313, 1203, 1050, 811, 633
cmꢀ1; 1H NMR (400 MHz, DMSOꢀd6): δ 1.64 (m, 1H),
Acknowledgements
We acknowledge with thanks the financial support received 65
from BuꢀAli Sina University, Center of Excellence and
Development of Chemical Methods (CEDCM).
2.04 (m, 1H), 2.27 (s, 3H), 2.37 (m, 1H), 3.70 (d, J = 5.6 10
Hz, 1H), 3.89 (d, J = 6 Hz, 1H), 4.09 (m, 1H), 4.69 (m,
1H), 7.16 (m, 4H), 8.57 (s, 1H), 8.63 (s, 1H); 13C NMR
(100 MHz, DMSOꢀd6): δ 21.1, 27.6, 42.7, 55.0, 64.5, 81.5,
127.4, 129.5, 137.3, 138.1, 177.3; MS: m/z = 248 (M+,
100%), 203 (14%), 173 (14%), 145 (28%), 118 (73%), 91 15
(37%), 76 (40%), 60 (23%), 43 (53%).
Notes and references
Faculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838683,
Iran
70
75
*Corresponding Author: Fax: +98(81)38257407
E-mail: rgvaghei@yahoo.com.
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
4-(2-Hydroxy-3-methoxyphenyl)hexahydrofuro[2,3-
d]pyrimidin-2(1H)-one (5c): White solid; Mp: 229ꢀ231
°C; IR (KBr): υ 3419, 3324, 3218, 2935, 1667, 1591,
1505, 1269, 1201, 1077, 766 cmꢀ1; 1H NMR (400 MHz, 20
DMSOꢀd6): δ 1.54–1.55 (m, 1H), 2.18 (m, 1H), 3.54 (m,
2H), 3.70 (s, 3H), 4.03 (m, 1H), 4.62 (m, 1H), 5.22 (m,
1H), 6.69 (m, 1H), 6.78–6.85 (m, 3H), 7.12 (s, 1H), 7.41
(s, 1H); 13C NMR (100 MHz, DMSOꢀd6): δ 30.5, 40.0,
46.7, 55.4, 58.1, 79.0, 111.5, 120.0, 120.6, 127.5, 139.5, 25
148.3, 154.2; MS: m/z = 264 (M+, 78%), 233 (37%), 219
(100%), 204 (95%), 176 (60%), 150 (48%), 106 (43%), 91
(78%), 77 (40%), 56 (38%).
4-(2-Hydroxy-3-methoxyphenyl)hexahydrofuro[2,3-
d]pyrimidin-2(1H)-thione (5d): White solid; Mp: 274ꢀ 30
276 °C; IR (KBr): υ 3405, 3195, 2930, 1588, 1556, 1504,
1485, 1268, 1181, 1079, 980 cmꢀ1; 1H NMR (400 MHz,
DMSOꢀd6): δ 1.34–1.48 (m, 1H), 2.20 (m, 1H), 3.52–3.53
(m, 2H), 3.72 (s, 3H), 4.18 (m, 1H), 4.66 (m, 1H), 5.20
(m, 1H), 6.70–6.72 (m, 1H), 6.83–6.90 (m, 3H), 9.01 (s, 35
1H), 9.12 (s, 1H); 13C NMR (100 MHz, DMSOꢀd6): δ
20.7, 29.0, 47.2, 55.6, 59.7, 76.9, 101.7, 111.8, 120.7,
125.3, 139.3, 148.2, 175.5; MS: m/z = 280 (M+, 100%),
249 (15%), 235 (37%), 205 (17%), 190 (17%), 176 (15%),
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4-(2-Chlorophenyl)hexahydrofuro[2,3-d]pyrimidin-2(1H)-
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756 cmꢀ1; H NMR (400 MHz, DMSOꢀd6): δ 1.53 (m, 1H),
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1.75–1.82 (m, 1H), 1.92–2.07 (m, 1H), 3.59–3.68 (m, 2H), 45
5.36–5.42 (m, 1H), 5.54–5.61 (m, 1H), 6.36–6.50 (m, 1H),
6.58–6.78 (m, 1H), 7.31–7.63 (m, 4H); 13C NMR (100
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128.5, 129.4, 129.7, 130.7, 135.8, 159.7; MS: m/z = 252
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4-(2-Chlorophenyl)hexahydrofuro[2,3-d]pyrimidin-2(1H)-
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3219, 2949, 2887, 1617, 1542, 1521, 1477, 1316, 1204,
1034, 757 cmꢀ1; 1H NMR (400 MHz, DMSOꢀd6): δ 1.70 55
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