Synthesis of novel substituted 2-lactosylthiothieno[2,3-d]pyrimidin-4(3H)-one derivatives

Article abstract of DOI:10.1002/jhet.1794

The title compounds substituted 2-lactosylthiothieno[2,3-d]pyrimidin-4-ones 6 were synthesized by the glycosyl reaction and alcoholysis reaction of substituted 2-thioxo-thieno[2,3-d]pyrimidin-4-ones 4,which is formed by the base catalytic and acetic acidify reaction of amino esters 2 with alkyl or arylisothiocyanates and hepta-O-acetyl-lactosyl bromide in good yields. All of the compounds were confirmed by NMR, ESI-MS, and elemental analysis.

Full text of DOI:10.1002/jhet.1794

1390
Synthesis of Novel Substituted 2-Lactosylthiothieno[2,3-d]pyrimidin-4
(3H)-one Derivatives
Vol 51
*
Qiu-hong Dai, Kai Yan, and Ming-guo Liu
Hubei Key Laboratory of Natural Products Research and Development, China Three Gorges University, Yichang
443002, P.R.China
*
E-mail: mgliu0427@yahoo.com
Received April 22, 2012
DOI 10.1002/jhet.1794
Published online 25 March 2014 in Wiley Online Library (wileyonlinelibrary.com).
The title compounds substituted 2-lactosylthiothieno[2,3-d]pyrimidin-4-ones 6 were synthesized by the glycosyl
reaction and alcoholysis reaction of substituted 2-thioxo-thieno[2,3-d]pyrimidin-4-ones 4,which is formed by the
base catalytic and acetic acidify reaction of amino esters 2 with alkyl or arylisothiocyanates and hepta-O-acetyl-
lactosyl bromide in good yields. All of the compounds were confirmed by NMR, ESI-MS, and elemental analysis.
J. Heterocyclic Chem., 51, 1390 (2014).
INTRODUCTION
Compounds 2 were easily converted to thioureas 3 by
treatment with ethyl/phenyl/naphthyl isothiocyanates in dry
triethylamine solution in good yields [14,15].Intermediates
3 were changed to substituted 2-thioxo-thieno[2,3-d]
pyrimidin-4-ones 4 after the base catalytic reaction and acetic
acidify reaction in acetonitrile solution (Scheme 2).
Hepta-O-acetyl-lactosyl bromide was synthesized from
the starting materials lactose according to the reference
[16].We promoted the isolated yield from 52.5% to
87.6% by decreasing the reaction temperature to 0–5ꢀC
and increasing the reaction time.
The thienopyrimidin-4-ones 4 reacted with hepta-O-acetyl-
lactosyl bromide to give the protected glycosyl heterocyclic
compounds 5 (Scheme 3) in acetonitrile solution with the
catalyst of potassium carbonate. As the lager molecular
weight and special space configuration of naphthyl and
hepta-O-acetyl-lactosyl moiety, there were rotamer present
in 5ac and 5fc, but that phenomenon has disappeared when
the acetyl esters were alcoholysis.
The derivatives of heterocycles containing thienopyrimi-
dine system are of great significance as their remarkable
biological activities [1]. For instance, some 2-alkyl/2-
alkoxy/2-methylthio substituted thienopyrimidinones show
important antimicrobial [2,3], antitumor [4], analgesic [5],
antitrichinellosis, and antiprotozoal [6] activities, whereas
others exhibited good anticonvulsant and angiotensin or H1
receptor antagonistic activities [7–9].The new intermediates
substituted 2-thioxo-thieno[2,3-d]pyrimidin-4-ones 4 were
synthesized from easily accessible materials ethyl 2-amino-
3-carboxythiophenes, which were synthesized by the
Gewald reaction [10]. Recently, there are considerable
interest in the preparation of S/N-glycoside analogs [11,12]
as these species are promising building blocks for the
synthesis of glycosyl heterocyclic compounds.
Recent years, our work has been concerned on the discov-
ery and development of the synthesis of new heterocyclic
compounds containing thienopyrimidine moiety in order to
find new pharmacological or biologically active compounds.
Our group has previously reported about the synthesis of
novel tricyclic ring systems, containing the thienopyrimidine
skeleton, with antibacterial and antifungal activity [13].
As a continuation of our study, the synthesis of some
substituted 2-thioxo-thieno[2,3-d]pyrimidin-4-ones and
their S-glycoside analogs was reported here.
When the compounds 5 undergone alcoholysis in methyl
alcohol with equivalent ammonia water [17], the target preci-
pitations 6 appeared. As many hydroxy found in the molecular
1
structure, the splittings of H NMR were not perfect. The
peaks of the hydrogens in sugar ring except the hydroxy were
between 3.0 and 4.0 ppm near the peeks of DMSO-d6 solu-
tion. And we confirmed the accuracy by 13C NMR, ESI-
MS, and elemental analysis. What is more, we choose one
of the compounds 6fb to further verify by HSQC. The syn-
thetic route to target compounds 6 was shown in Scheme 4.
RESULTS AND DISCUSSION
Amino esters 2 were obtained by means of a modified
Gewald method from cyclopentanone or cyclohexanone
1, ethyl 2-cyanoacetate, and sulfur in the presence of
trithylamine (Scheme 1).
EXPERIMENTAL
Measurements.
Melting points were determined with an
uncorrected X-4 Digital melting point apparatus (Beijing Tech
© 2014 HeteroCorporation

September 2014 Synthesis of Novel Substituted 2-Lactosylthiothieno[2,3-d]pyrimidin-4(3H)-one Derivatives
1391
Scheme 1
without further purification. The solvents for the reactions were
dried and distilled immediately before use.
COOEt
NH2
O
Preparation of the thiourea intermediates 3.
General
NCCH2COOEt
n(CH2)
procedure. A mixture of amino ester 2(2mmol) and isothiocyanate
(2mmol) in triethylamine (20mL) was stirred at 70ꢀC for 3 h, and
then cooled to room temperature. The precipitate formed was
collected and washed with ethanol to afford the thiourea
intermediates 3 as an analytically pure crystalline solid.
n(CH2)
S
S
1
2
n=3,4
n=3,4
Ethyl 2-(3-ethylthioureido)-5,6-dihydro-4H-cyclopenta[b]
thiophene-3-carboxylate (3aa). This compound was obtained as
brown crystals, mp 198–200ꢀC;1H NMR (600 MHz, DMSO-d6):d
1.14 (s, 3H, CH3), 1.30 (t, J= 12 Hz, 3H, CH3), 2.28 (t, J=12Hz,
2H, CH2), 2.76 (s, 2H, CH2), 2.82 (s, 2H, CH2), 3.41 (s, 2H, CH2),
4.24–4.28 (m, 2H, CH2), 9.42 (s, 1H, NH), 11.19 (s, 1H, NH); MS
(EI, 70 eV): m/z (%) 299.4 (100), 298.1 (32), 210.7 (37), 165.6
(71), 164.2 (100), 104.2 (10). Anal. Calcd for C13H18N2O2S2: C,
52.32; H, 6.08; N, 9.39. Found C, 52.18; H, 6.10; N, 9.40.
Ethyl 2-(3-phenylthioureido)-5,6-dihydro-4H-cyclopenta[b]
thiophene-3-carboxylate (3ab). This compound was obtained
as light yellow crystals, mp 173–174ꢀC; 1H NMR (600 MHz,
DMSO-d6): d 1.27 (t, J = 18 Hz, 3H, CH3), 2.28–2.33 (m, 2H,
CH2), 2.79 (t, J = 18 Hz, 2H, CH2), 7.22–7.49 (m, 5H, 5CH),
Instrument Co.,LTD. Beijing, China). NMR spectra were
recorded in CDCl3 or DMSO-d6 on Bruker UltrashiedTM
400MHz (Bruker, Germany) or Varian Mercury 600MHz
(Varian, USA) spectrometer, and resonances were given in ppm
(d) relative to TMS, and various 2D techniques and DEPT
experiments were used to establish the structures and assign the
signals. MS were measured on Finnigan Trace MS (EI-MS,
70eV, Finnigan, USA ) or Bruker amaZon X&ETD MS
(ESI-MS, Bruker, Germany) spectrometer. The purity of the
compounds was confirmed by thin layer chromatography on
silica gel HF254 (Merck).Unless otherwise noted, all reagents and
materials were purchased from commercial suppliers and used
Scheme 2
O
COOEt
+
COOEt
S
S
R
S
NEt3
C
N
a,CH3CN/K2CO3
b,CH3COOH
N
n(CH2)
n(CH2)
n(CH2)
R
S
S
NH2
R
N
N
N
H
S
H
H
2
4
3
3aa,n=3,R=ethyl;3ab,n=3,R=phenyl;3ac,n=3,R=naphthyl.
3fa,n=4,R=ethyl;3fb,n=4,R=phenyl;3fc,n=4,R=naphthyl.
4aa,n=3,R=ethyl;4ab,n=3,R=phenyl;4ac,n=3,R=naphthyl.
4fa,n=4,R=ethyl;4fb,n=4,R=phenyl;4fc,n=4,R=naphthyl.
Scheme 3
O
R
N
O
n(CH2)
OAc
OAc
AcO
Br
R
S
AcO
S
N
S
OAc
N
O
OAc
AcO
O
n(CH2)
+
AcO
CH3CN/K2CO3
OAc
O
O
O
S
N
OAc
AcO
O
OAc
H
OAc
OAc
4
5
5aa,n=3,R=ethyl;5ab,n=3,R=phenyl;5ac,n=3,R=naphthyl.
5fa,n=4,R=ethyl;5fb,n=4,R=phenyl;5fc,n=4,R=naphthyl.
Scheme 4
O
R
O
R
N
CH3OH/NH3 H2O
N
n(CH2)
n(CH2)
S
N
S
OH
OH
HO
OH
S
N
S
OAc
O
AcO
OAc
OH
O
O
OAc
O
O
O
OAc
OH
OH
OAc
OAc
5
6
6aa,n=3,R=ethyl;6ab,n=3,R=phenyl;6ac,n=3,R=naphthyl.
6fa,n=4,R=ethyl;6fb,n=4,R=phenyl;6fc,n=4,R=naphthyl.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Q. Dai, K. Yan, and M. Liu
Vol 51
11.01 (s, 1H, NH), 11.57 (s, 1H, NH). Anal. Calcdfor
C17H18N2O2S2: C, 58.93; H, 5.24; N, 8.09. Found C, 59.11; H,
5.22; N, 8.06.
(m, 2H, CH2), 2.70–2.71 (d, J =5.4 Hz, 4H, 2CH2), 7.44–7.61 (m,
5H, 5CH), 7.89–8.01 (m, 2H, 2CH), 13.80 (s, 1H, NH); MS (EI,
70eV): m/z (%) 365.3 (19), 364.2 (100), 179.1 (71), 151.0 (25),
127.1 (12), 77.2 (6). Anal. Calcd for C20H16N2OS2: C, 65.91; H,
4.42; N, 7.69. Found C, 65.78; H, 4.41; N, 7.71.
Ethyl 2-(3-(naphthalen-2-yl)thioureido)-5,6-dihydro-4H-
cyclopenta[b]thio phene-3-carboxylate (3ac).
This compound
1
was obtained as light yellow crystals, mp 181–183ꢀC; H NMR
(600 MHz, DMSO-d6): d 1.16 (m, 3H, CH3), 2.27 (m, 2H, CH2),
2.78–3.29 (m, 4H, 2CH2), 3.35–4.04 (m, 2H, CH2), 7.56–7.61
(m, 4H, 4CH), 7.86–8.02 (m, 3H, 3CH), 11.05 (s, 1H, NH), 11.48
(s, 1H, NH); MS (EI, 70eV): m/z (%) 396.4 (3), 211.2 (33), 185.2
(87), 165.2 (100), 127.2 (54), 77.3(60). Anal. Calcd for
C21H20N2O2S2: C, 63.01; H, 5.08; N, 7.01. Found C, 63.42; H,
5.09; N, 7.08.
Preparation of the substituted 2-hepta-O-acetyl-lactosylthio-
thieno[2,3-d] pyrimidin-4(3H)-ones 5.
General procedure. A
mixture of intermediates 4(2 mmol) and potassium carbonate
(2 mmol) in acetonitrile solution (25 mL) was refluxed at 80ꢀC for
2–3 h until the solid disappeared. If the solid does not disappear, add
2–3 drops of water dropwise. Then, hepta-O-acetyl-lactosyl bromide
(1.54 g, 2.2 mmol) was added to the reaction system; another reflux
of about 2–3 h was needed to complete the reaction. The solvent
was evaporated under reduced pressure at 40ꢀC, and the crude
product was filtered off and washed with distilled water and ethanol
to remove the formed KBr to give the products 5.
3-Ethyl-2-(hepta-O-acetyl-lactosylthio)-2,3,6,7-tetrahydro-1H-
cyclopenta[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (5aa). This
compound was obtained as gray crystals, mp 188–189ꢀC; 1H
NMR (400 MHz, CDCl3): d 1.32 (t, 3H, J = 14 Hz, CH3), 1.97
(s, 3H, CH3), 2.03 (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.07 (s, 3H,
CH3), 2.08 (s, 6H, 2CH3), 2.17 (s, 3H, CH3), 2.41–2.48 (m, 2H,
CH2), 2.94 (t, 2H, J = 13.6 Hz, CH2), 3.04 (t, 2H, J = 13.6 Hz,
CH), 4.04–4.17 (m, 5H), 4.46 (d, 1H, J = 8.4 Hz, CH), 4.48 (d,
1H, J = 4.8 Hz, CH), 4.96 (dd, 1H, J = 7.2 Hz, 13.6 Hz, CH),
5.11–5.20 (m, 2H, 2CH), 5.32–5.38 (m, 2H, 2CH), 5.80 (d, 1H,
J = 10.8 Hz, CH). 13C NMR (100 MHz, CDCl3): d 170.33,
170.12, 170.03, 169.75, 169.59, 169.14 [(CH3)C═O], 166.39
(C═O), 157.90 (C-S), 151.65, 140.13, 137.50, 117.12 (C,
carbons of the thiophene), 101.07, 82.40, 77.13, 75.98, 73.79,
70.94, 70.70, 69.11, 69.00, 66.57 (CH, carbons of the sugar
ring), 62.05, 60.80, 39.61, 29.52, 28.86, 27.87 (CH2), 20.80,
20.73, 20.63, 20.46 [(C═O)CH3], 13.22 (CH3); MS (ESI): m/z
871.2 (M + H)+. Anal. Calcd for C37H46N2O18S2: C, 51.03; H,
5.32; N, 3.22. Found C, 50.86; H, 5.34; N, 3.21.
Ethyl 2-(3-(naphthalen-2-yl)thioureido)-4,5,6,7-tetrahydrobenzo
[b]thiophene-3-carboxylate (3fc). This compound was obtained
as white crystals, mp 197–199ꢀC; 1H NMR (600 MHz, DMSO-d6):
d 1.13 (s, 3H, CH3), 1.66–1.70 (m, 4H, 2CH2), 2.50–2.63 (m, 4H,
2CH2), 4.01 (s, 2H, CH2), 7.54–7.60 (m, 4H, 4CH), 7.86
(t, J= 9.6 Hz, 1H, CH), 7.97–8.02 (m, 2H, 2CH), 11.03 (s, 1H,
NH), 11.73 (s, 1H, NH); MS (EI, 70 eV): m/z (%) 411.4 (8), 410.3
(36), 225.2 (89), 179.2 (100), 151.0 (48), 127.2 (29), 77.2 (17).
Anal. Calcd for C22H22N2O2S2: C, 64.36; H, 5.40; N, 6.82. Found
C, 64.51; H, 5.41; N, 6.80.
Preparation of the substituted 2-thioxo-thieno[2,3-d]
pyrimidin-4-ones 4.
General procedure. A mixture of
thiourea 3(2 mmol) and potassium carbonate (0.28 g,2 mmol) in
methanol solution(25 mL) was refluxed at 70ꢀC for 2–3 h until
the solid disappeared, and then cooled to room temperature.
About 5 mL of acetic acid was added to the reaction mixture to
precipitation completely. The precipitated crystals were filtered
off, washed with water and ethanol, and dried to give
intermediates 4.
3-Ethyl-2-thioxo-2,3,6,7-tetrahydro-1H-cyclopenta[4,5]thieno
[2,3-d]pyrimidin-4-one (4aa). This compound was obtained as
gray crystals, mp 242–243ꢀC; 1H NMR (600 MHz, DMSO-d6): d
1.19 (t, J = 18 Hz, 3H, CH3), 2.36 (d, J = 12 Hz, 2H, CH2), 2.82
(s, 4H, 2CH2), 4.83 (d, J = 12 Hz, 2H, CH2), 13.60 (s, 1H, NH);
MS (EI, 70 eV): m/z (%) 253.3 (8), 252.2 (55), 165.1 (100),
109.2 (18), 104.2 (20). Anal. Calcd for C11H12N2OS2: C, 52.35;
H, 4.79; N, 11.10. Found C, 52.51; H, 4.80; N, 11.08.
3-Phenyl-2-thioxo-2,3,6,7-tetrahydro-1H-cyclopenta[4,5]thieno
[2,3-d]pyrimidin-4-one (4ab). This compound was obtained as
white crystals, mp 241–242ꢀC; 1H NMR (600 MHz, DMSO-d6): d
2.36–2.39 (m, 2H, CH2), 2.80 (t, J= 18 Hz, 2H, CH2), 2.81 (t,
J= 18 Hz, 2H, CH2), 7.21–7.47 (m, 5H, 5CH), 13.70 (s, 1H, NH);
MS (EI, 70 eV): m/z (%) 301.3 (7), 300.0 (49), 165.1 (100), 109.2
(24), 104.2 (21), 77.2 (95). Anal. Calcd for C15H12N2 OS2: C,
59.97; H, 3.95; N, 9.43. Found C, 60.12; H, 3.92; N, 9.40.
3-(Naphthalen-2-yl)-2-thioxo-2,3,6,7-tetrahydro-1H-cyclopenta
3-Phenyl-2-(hepta-O-acetyl-lactosylthio)-2,3,6,7-tetrahydro-1H-
cyclopenta[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (5ab).
This
compound was obtained as white crystals, mp 202–203ꢀC; 1H
NMR (400 MHz, CDCl3):d 1.96 (s, 6H, 2CH3), 2.02 (s, 3H, CH3),
2.04 (s, 3H, CH3), 2.05 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.15
(s, 3H, CH3), 2.41–2.48 (m, 2H, CH2), 2.96 (t, 2H, J= 16.8 Hz,
CH2), 3.00 (t, 2H, J= 15.6 Hz, CH2), 3.74–3.82 (m, 2H, CH2), 3.85
(t, 1H, J= 14 Hz, CH), 4.04–4.14 (m, 3H), 4.44–4.47 (m, 2H,
2CH), 4.92–4.99 (m, 2H, 2CH), 5.10 (dd, 1H, J=2.4Hz, 18Hz,
CH), 5.28 (t, 1H, J= 17.6 Hz, CH), 5.34 (d, 1H, J= 3.6 Hz, CH),
5.67 (d, 1H, J= 10.8 Hz, CH), 7.16–7.19 (m, 1H, CH), 7.29–7.32
(m, 1H, CH), 7.46–7.52 (m, 3H, 3CH), 7.29–7.32 (m, 1H, CH),
7.46–7.52 (m, 3H, 3CH). 13C NMR (100 MHz, CDCl3): d 170.33,
170.31, 170.10, 170.02, 169.63, 169.40, 169.13 [(CH3)C═O],
166.75 (C═O), 158.26 (C-S), 135.07 (C-N), 130.30, 129.80,
129.75, 129.16, 128.65 (CH, carbons of the benzene), 153.15,
140.55, 137.71, 117.40 (C, carbons of the thiophene), 101.04,
82.23, 77.11, 75.89, 73.93, 70.95, 70.68, 69.13, 69.04, 66.59 (CH,
carbons of the sugar ring), 62.06, 60.79, 29.57, 28.82, 27.89,
(CH2), 20.82, 20.71, 20.60, 20.52, 20.45 [(C═O)CH3]; MS (ESI):
m/z 919.2 (M + H)+. Anal. Calcd for C41H46N2O18S2: C, 53.59; H,
5.05; N, 3.05. Found C, 53.48; H, 5.07; N,3.06.
[4,5]thieno[2,3-d]pyrimidin-4-one (4ac).
This compound was
obtained as white crystals, mp 250–252ꢀC; 1H NMR (600 MHz,
DMSO-d6): d 2.38 (t, J= 12 Hz, 2H, CH2), 2.79 (t, J=12Hz, 2H,
CH2), 2.79 (t, J=12Hz, 2H, CH2), 2.87 (t, J=12Hz, 2H, CH2),
7.45–7.61 (m, 5H, 5CH), 8.00 (t, J= 12 Hz, 2H, 2CH), 13.84 (s, 1H,
NH); MS (EI, 70 eV): m/z (%) 351.3 (12), 350.1 (65), 185.2 (15),
165.1 (100), 127.2 (39), 77.2 (17). Anal. Calcd for C19H14N2OS2:
C, 65.12; H, 4.03; N, 7.99. Found C, 64.98; H, 4.04; N, 7.97.
3-(Naphthalen-2-yl)-2-thioxo-2,3,5,6,7,8-hexahydrobenzo[4,5]
3-(Naphthalen-2-yl)-2-(hepta-O-acetyl-lactosylthio)-2,3,6,7-
tetrahydro-1H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4(3H)-
one (5ac). This compound was obtained as white crystals, mp
thieno[2,3-d]pyrimidin-4-one (4fc).
This compound was
obtained as light yellow crystals, mp 258–259ꢀC; 1H NMR
(600 MHz, DMSO-d6): d 1.70 (t, J = 8.4 Hz, 2H, CH2), 1.78–1.80
1
236–237ꢀC; H NMR (400 MHz, CDCl3): d 1.96 (s, 3H, CH3),
Journal of Heterocyclic Chemistry
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September 2014 Synthesis of Novel Substituted 2-Lactosylthiothieno[2,3-d]pyrimidin-4(3H)-one Derivatives
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1.97 (s, 3H, CH3), 2.00 (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.07 (s,
3H, CH3), 2.09 (s, 3H, CH3), 2.15 (s, 3H, CH3), 2.43–2.49 (m,
2H, CH2), 2.98–3.03 (m, 4H, 2CH2), 3.71–3.84 (m, 3H), 4.06–
4.11 (m, 3H), 4.41–4.44 (m, 2H, 2CH), 4.77–4.96 (m, 2H,
2CH), 5.08–5.13 (m, 1H, CH), 5.22–5.29 (m, 1H, CH), 5.33 (t,
1H, J = 2.4 Hz, CH), 5.59–5.69 (m, 1H, CH), 7.38 (d, 1H,
J = 7.6 Hz, CH), 7.34–7.59 (m, 4H, 4CH), 7.93 (d, 1H,
J = 7.6 Hz, CH), 8.02 (d, 1H, J = 8.4 Hz, CH). 13C NMR
(100 MHz, CDCl3): d 170.37, 170.31, 170.24, 170.10, 170.03,
169.65, 169.60, 169.36, 169.18, 169.11 (C═O), 158.15 (C-S),
134.46 (C-N), 131.79, 131.46, 131.10, 131.02, 129.64, 128.78,
128.57, 128.04, 127.95, 127.61, 127.49, 126.86, 126.59,
125.44, 125.31, 121.75, 121.24 (CH, carbons of the
naphthlene), 153.81, 140.68, 137.90, 117.39 (C, carbons of the
thiophene), 101.05, 100.96, 82.71, 75.88, 75.78, 73.86, 73.67,
70.90, 70.63, 69.06, 69.01, 68.84, 66.54 (CH, carbons of the
sugar ring), 61.79, 60.73, 29.60, 28.85, 27.92 (CH2), 20.88,
20.73, 20.64, 20.59, 20.46, 20.04 [(C═O)CH3]; MS (ESI): m/z
969.2 (M + H)+. Anal. Calcd for C45H48N2O18S2: C, 55.78; H,
4.99; N, 2.89. Found C, 56.01; H, 4.98; N, 2.88.
3-(Naphthalen-2-yl)-2-(hepta-O-acetyl-lactosylthio)-2,3,5,6,7,8-
hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (5fc).
This compound was obtained as white crystals, mp 233–234ꢀC;
1H NMR (400 MHz,CDCl3): d 1.81 (t, 2H, J =5.6 Hz, CH2), 1.89
(d, 2H, J = 4 Hz, CH2), 1.96–2.15 (m, 21H, 7CH3), 2.81 (s, 2H,
CH2), 2.93 (s, 2H, CH2), 3.68–3.85 (m, 3CH), 4.03–4.12 (m, 3H),
4.41–4.50 (m, 2H, 2CH), 4.76–4.88 (m, 1H, CH), 4.91–4.95
(m, 1H, CH), 5.08–5.12 (m, 1H, CH), 5.21–5.29 (m, 1H, CH),
5.33 (d, 1H, J = 2 Hz, CH), 5.59–5.69 (m, 1H, CH), 7.38 (d, 1H,
J = 9.2 Hz, CH), 7.43–7.59 (m, 4H, 4CH), 7.93 (d, 1H, J = 7.6Hz,
CH), 8.01 (d, 1H, J = 8.4 Hz ,CH). 13C NMR (100MHz, CDCl3):
d 170.38, 170.34, 170.27, 170.20, 170.15, 170.08, 169.99,
169.61, 169.57, 169.34, 169.13, 169.08, 169.05 [(CH3)C═O],
162.11 (C═O), 158.27 (C-S), 134.45, 134.39 (C-N), 131.89,
131.85, 131.51, 131.03, 130.93, 129.68, 129.61, 128.85, 128.55,
128.07, 127.90, 127.56, 127.52, 126.83, 126.56, 125.44, 125.31,
121.78, 121.26 (CH, carbons of the naphthalene),154.46, 132.63,
131.87, 119.66 (C, carbons of the thiophene), 101.01, 100.93,
82.63, 82.10, 77.08, 76.88, 75.86, 75.75, 73.84, 73.67, 70.92,
70.59, 69.06, 68.97, 68.84, 66.53, 66.07 (CH, carbons of the
sugar ring), 62.06, 61.77, 60.77, 60.73, 25.30, 25.12, 22.90, 22.16
(CH2), 20.88, 20.72, 20.69, 20.67, 20.63, 20.58, 20.45, 20.04
[(C═O)CH3]; MS (ESI): m/z 983.2 (M +H)+. Anal. Calcd for
C46H50N2 O18S2: C, 56.20; H, 5.13; N, 2.85. Found C, 56.42; H,
5.10; N, 2.89.
3-Ethyl-2-(hepta-O-acetyl-lactosylthio)-2,3,5,6,7,8-hexahydro-
benzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (5fa).
This
1
compound was obtained as gray crystals, mp 251–252ꢀC; H
NMR (400 MHz, CDCl3): d 1.30 (t, 3H, J = 14 Hz, CH3),
1.82–1.88 (m, 4H, 2CH2), 1.98 (s, 3H, CH3), 2.05 (s, 6H,
2CH3), 2.07 (s, 3H, CH3), 2.08 (s, 6H, 2CH3), 2.17 (s, 3H,
CH3), 2.75 (s, 2H, CH2), 2.97 (d, 2H, J = 5.6 Hz, CH2), 3.85
(d, 2H, J = 5.2 Hz, CH2), 3.89 (t, 1H, J = 13.6 Hz, CH), 4.04–
4.18 (m, 5H), 4.44–4.49 (m, 2H, 2CH), 4.96 (dd, 1H,
J = 6.8 Hz, 14 Hz, CH), 5.11–5.20 (m, 2H, 2CH), 5.34–5.38
(m, 2H, 2CH), 5.80 (d, 1H, J = 10.4 Hz, CH). 13C NMR
Preparation of the substituted 2-lactosylthiothieno[2,3-d]
pyrimidine-4(3H)-ones 6.
General procedure. Treating
intermediates 5(2 mmol) and a small amount of ammonia water
to a vigorously stirred solution of methanol at room temperature
about 7–8 h to the precipitation is not increased. Then, the
turbid liquid was filtered off and gave the target compounds 6.
3-Ethyl-2-lactosylthio-2,3,6,7-tetrahydro-1H-cyclopenta[4,5]
thieno[2,3-d]pyrimidin-4(3H)-one (6aa). This compound was
(100 MHz, CDCl3):
d 170.37, 170.16, 170.07, 169.79,
169.63, 169.16 [(CH3) C═O], 161.46 (C═O), 158.06 (C-S),
151.97, 132.24, 131.39, 119.51 (C, carbons of the thiophene),
101.10, 82.41, 77.15, 76.01, 73.83, 70.99, 70.74, 69.17,
69.04, 66.62 (CH, carbons of the sugar ring), 62.09, 60.86,
39.51, 25.48, 25.14, 22.94, 22.25 (CH2), 20.86, 20.78, 20.68,
20.52 [(C═O)CH3], 13.28 (CH3); MS (ESI): m/z 885.2
(M + H)+. Anal. Calcd for C38H48N2O18 S2: C, 51.58; H, 5.47;
N, 3.17. Found C, 51.42; H, 5.49; N, 3.18.
1
obtained as white crystals, mp 193–195ꢀC; H NMR (400 MHz,
DMSO-d6): d 1.24 (t, 3H, J= 13.6 Hz, CH3), 2.38 (t, 2H, J=12Hz,
CH2), 2.90 (t, 4H, J= 13.6 Hz, 2CH2), 2.41–2.65 (m, 12H), 4.07
(t, 2H, J=6.4Hz, CH2), 4.24 (d, 1H, J= 6.8 Hz, CH), 4.49–4.52
(m, 2H, 2OH), 4.63 (s, 1H, OH), 4.75 (d, 1H, J= 4.4 Hz, OH), 4.86
(s, 1H, OH), 5.06 (d, 1H, J= 3.2 Hz, OH), 5.46 (d, 1H, J= 10.6 Hz,
CH), 5.66 (d, 1H, J= 6.4 Hz, OH). 13C NMR (100 MHz, DMSO-
d6): d 166.08 (C═O), 156.90 (C-S), 154.00, 139.33, 136.48,
115.97 (C, carbons of the thiophene), 103.74, 85.00, 79.78, 79.55,
76.53, 75.54, 73.16, 71.35, 70.56, 68.14 (CH, carbons of the
sugar ring), 60.42, 59.96, 39.15, 29.03, 28.62, 27.33, (CH2), 12.97
(CH3); MS (ESI): m/z 621.4 (M + 2Na À H)+. Anal. Calcd for
C23H32N2O11S2: C, 47. 91; H, 5.59; N, 4.86. Found C, 48.06;
H, 5.57; N, 4.87.
3-Phenyl-2-(hepta-\O-acetyl-lactosylthio)-2,3,5,6,7,8-hexahy-
drobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (5fb).
This
compound was obtained as white crystals, mp 228–229ꢀC; 1H
NMR (400 MHz, CDCl3): d 1.81 (t, 2H, J = 12.4 Hz, CH2), 1.88
(d, 2H, J = 5.6 Hz, CH2), 1.97 (s, 6H, 2CH3), 2.03 (s, 3H, CH3),
2.06 (s, 6H, 2CH3), 2.08 (s, 3H, CH3), 2.16 (s, 3H, CH3), 2.78
(s, 2H, CH2), 2.93 (d, 2H, J = 5.6 Hz, CH2), 3.75–3.82 (m, 2H,
CH2), 3.87 (t, 1H, J = 14 Hz, CH), 4.05–4.15 (m, 3H), 4.44–4.48
(m, 2H, 2CH), 4.93–4.99 (m, 2H, 2CH), 5.11 (dd, 1H,
J = 2.4 Hz, 18.4 Hz, CH), 5.27–5.31 (m, 1H, CH), 5.35 (d, 1H,
J = 3.2 Hz, CH), 5.69 (d, 1H, J = 10.4 Hz, CH), 7.18–7.19
(m, 1H, CH), 7.28–7.31 (m, 1H, CH), 7.48–7.53 (m, 3H, 3CH).
13C NMR (100 MHz, CDCl3): d 170.38, 170.36, 170.15,
170.06, 169.68, 169.44, 169.16 [(CH3)C═O], 161.86 (C═O),
158.46 (C-S), 135.15 (C-N), 130.29, 129.84, 129.81, 129.23,
128.74 (CH, carbons of the benzene), 153.44, 132.50, 131.79,
119.77 (C, carbons of the thiophene), 101.05, 82.20, 77.28, 75.89,
73.94, 70.97, 70.69, 69.14, 69.04, 66.61 (CH, carbons of the sugar
ring), 62.08, 60.83, 25.35, 25.13, 22.95, 22.23 (CH2), 20.89, 20.77,
20.68, 20.65, 20.58, 20.51 [(C═O)CH3]; MS (ESI): m/z 933.2
(M + H)+. Anal. Calcd for C42H48N2O18S2: C, 54.07; H, 5.19; N,
3.00. Found C, 54.21; H, 5.18; N, 3.01.
3-Phenyl-2-lactosylthio-2,3,6,7-tetrahydro-1H-cyclopenta[4,5]
thieno[2,3-d]pyrimidin-4(3H)-one (6ab).
This compound was
1
obtained as white crystals, mp 235–237ꢀC; H NMR (400MHz,
DMSO-d6): d 2.35–2.42 (m, 2H, CH2), 2.87 (t, 2H, J = 13.2Hz,
CH2), 2.93 (t, 2H, J = 13.2Hz, CH2), 3.11–3.64 (m, 12H), 4.20
(d, 1H, J = 6.8Hz, CH), 4.54–4.57 (m, 2H, 2OH), 4.64–4.67
(m, 1H, OH), 4.81 (d,2H, J = 1.6 Hz, 2OH), 5.10 (d, 1H, J = 4 Hz,
OH), 5.31 (d, 1H, J = 10.4 Hz, CH), 5.58 (d, 1H, J =6.4 Hz, OH),
7.36–7.42 (m, 2H, 2CH), 7.56–7.58 (m, 3H, 3CH). 13C NMR
(100MHz, DMSO-d6): d 166.47 (C═O), 157.28 (C-S), 135.56
(C-N), 130.30, 129.99, 129.66, 129.56, 129.27 (C, carbons of the
benzene), 155.22, 139.62, 136.50, 116.42 (C, carbons of the
thiophene), 103.73, 84.56, 79.76, 79.45, 76.54, 75.52, 73.16,
71.06, 70.55, 68.13 (CH, carbons of the sugar ring), 60.41, 59.93,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1394
Q. Dai, K. Yan, and M. Liu
Vol 51
29.07, 28.63, 27.38 (CH2); MS (ESI): m/z 669.4 (M + 2Na À H)+.
Anal. Calcd for C27H32N2O11S2: C, 51.91; H, 5.16; N, 4.48.
Found C, 51.78; H, 5.18; N, 4.49.
3-(Naphthalen-2-yl)-2-lactosylthio-2,3,5,6,7,8-hexahydro benzo
[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (6fc).
This compound
was obtained as white crystals, mp 213–214ꢀC; 1H NMR
(400 MHz, DMSO-d6): d 1.76–1.84 (m, 4H, 2CH2), 2.79 (d, 4H,
J=5.6Hz, 2CH2), 3.03–3.64 (m, 12H), 4.18 (d, 1H, J=7.2Hz,
CH), 4.36 (t, 1H, J= 11.6 Hz, OH), 4.41 (s, 1H, OH), 4.54 (s, 1H,
OH), 4.66 (s, 1H, OH), 4.73 (s, 1H, OH), 4.98 (s, 1H, OH), 5.32
(d, 1H, J= 10.4 Hz, CH), 5.42 (d, 1H, J= 5.6 Hz, OH), 7.47 (d, 1H,
J=8Hz, CH),7.54–7.69 (m, 4H, 4CH), 8.08 (d, 1H, J=8Hz, CH),
8.14 (d, 1H, J= 8 Hz, CH). 13C NMR (100 MHz, DMSO-d6):
d 161.68 (C═O), 157.44 (C-S), 133.81, 132.14, 130.33, 129.29,
128.37, 128.05, 127.71, 126.65, 125.69, 121.78 (carbons of the
naphthalene), 155.89, 131.45, 130.88, 118.63 (C, carbons of
thiophene), 103.14, 84.57, 79.86, 79.43, 76.45, 75.45, 73.14, 71.08,
70.54, 68.09 (CH, carbons of the sugar ring), 60.35, 60.18, 25.08,
24.42, 22.41, 21.67 (CH2); MS (ESI): m/z 733.4 (M + 2Na À H)+.
Anal. Calcd for C32H36N2O11S2: C, 55.80; H, 5.27; N, 4.07. Found
C, 55.98; H, 5.28; N, 4.08.
3-(Naphthalen-2-yl)-2-lactosylthio-2,3,6,7-tetrahydro-1H-
cyclopenta[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (6ac).
This
1
compound was obtained as white crystals, mp 230–231ꢀC; H
NMR (400 MHz, DMSO-d6): d 2.36–2.43 (m, 2H, CH2), 2.88
(t, 2H, J = 13.6 Hz, CH2), 2.96 (t, 2H, J = 14 Hz, CH2), 3.27–
3.59 (m, 12H), 4.17 (d, 1H, J = 7.2 Hz, CH), 4.47 (t, 1H, J = 11.
Hz, OH), 4.52 (d, 1H, J = 4.4 Hz, OH), 4.63 (t, 1H, J = 9.6 Hz,
OH), 4.79 (d, 2H, J = 4.8 Hz, 2OH), 5.08 (d, 1H, J = 4 Hz, OH),
5.33 (d, 1H, J = 10.4 Hz, CH), 5.53 (d, 1H, J = 6.4 Hz, OH),
7.48 (d, 1H, J = 8.4 Hz, CH), 7.57–7.69 (m, 4H, 4CH), 8.10 (d,
1H, J = 7.6 Hz, CH), 8.16 (dd, 1H, J = 4.8 Hz, 9.2 Hz, CH). 13C
NMR (100 MHz, DMSO-d6): d 166.70 (C═O), 157.26 (C-S),
139.58, 136.68, 133.78, 129.19, 128.41, 128.07, 127.79,
126.71, 125.75, 121.76 (carbons of the naphthalene), 155.58,
132.02, 130.43, 116.30 (C, carbons of the thiophene), 103.64,
84.49, 79.80, 79.36, 76.39, 75.39, 73.04, 70.95, 70.44, 68.01
(CH, carbons of the sugar ring), 60.28, 59.96, 29.01, 28.55,
27.32 (CH2); MS (ESI): m/z 719.4 (M + 2Na À H)+. Anal.
Calcd for C31H34N2O11S2: C, 55.18; H, 5.08; N, 4.15. Found
C, 54.96; H, 5.10; N, 4.16.
Acknowledgments. We gratefully acknowledge the financial support
of this work by the Science Foundation of Hubei Province Education
Department, China (Project No. D20091301), Excellent Fund for
Scientific Research, and Special Projects in China Three Gorges
University, China (Project No. 2011CX088).
3-Ethyl-2-lactosylthio-2,3,5,6,7,8-hexahydrobenzo[4,5]thieno
[2,3-d]pyrimidin-4(3H)-one (6fa).
This compound was
1
obtained as white crystals, mp 183–185ꢀC; H NMR (400 MHz,
DMSO-d6): d 1.23 (t, 3H, J=14Hz, CH3), 1.76–1.81 (m, 4H,
2CH2), 2.72 (s, 2H, CH2), 2.85 (s, 2H, CH2), 3.31–3.64 (m, 12H),
4.02–4.08 (m, 2H, CH2), 4.23 (d, 1H, J = 7.2 Hz, CH), 4.56–
4.60 (m, 2H, 2OH), 4.69 (t, 1H, J = 7.2 Hz, OH), 4.83 (d,
1H, J = 5.2 Hz, OH), 4.89 (d, 1H, J = 1.6 Hz, OH), 5.13 (d, 1H,
J = 4 Hz, OH), 5.45 (d, 1H, J = 10.4 Hz, CH), 5.73 (d, 1H,
J = 6.4 Hz, OH); 13C NMR (100 MHz, DMSO-d6): d 161.04
(C═O), 157.15 (C-S), 154.30, 131.25, 130.62, 118.32 (C,
carbons of the thiophene), 103.76, 84.99, 79.78, 79.57, 76.55,
75.58, 73.20, 71.38, 70.60, 68.18 (CH, carbons of the sugar
ring), 60.47, 59.99, 25.21, 24.46, 22.47, 21.77 (CH2), 13.02
(CH3); MS (ESI): m/z 635.4 (M + 2Na À H)+. Anal. Calcd for
C24H34N2O11S2: C, 48.80; H, 5.80; N, 4.74. Found C, 48.98;
H, 5.78; N, 4.75.
3-Phenyl-2-lactosylthio-2,3,5,6,7,8-hexahydrobenzo[4,5]thieno
[2,3-d]pyrimidin-4(3H)-one (6fb). This compound was obtained
as white crystals, mp 223–225ꢀC; 1H NMR (400 MHz, DMSO-d6):
d 1.78 (t, 4H, J=18Hz, 2CH2), 2.75 (s, 2H, CH2), 2.81 (s, 2H, CH2),
3.09–3.64 (m, 12H), 4.21 (d, 1H, J= 6.4Hz, CH), 4.49 (s, 2H, 2OH),
4.62 (s, 1H, OH), 4.75 (d, 1H, J =3.6Hz, OH), 4.79 (s, 1H, OH),
5.05 (d, 1H, J = 2.4 Hz, OH), 5.31 (d, 1H, J = 10.4 Hz, CH), 5.58
(d, 1H, J= 6 Hz, OH), 7.38 (t, 2H, J= 9.2 Hz, 2CH), 7.57 (t, 3H,
J= 6Hz, 3CH). 13C NMR (100 MHz, DMSO-d6): d 161.33
(C═O), 157.40 (C-S), 135.49 (C-N), 129.85, 129.56, 129.45,
129.21 (CH, carbons of the benzene), 155.37, 131.19, 130.78,
118.61 (C, carbons of the thiophene), 103.62, 84.40, 79.64, 79.34,
76.44, 75.42, 73.06, 70.97, 70.46, 68.04 (CH, carbons of the sugar
ring), 60.32, 59.58, 25.06, 24.34, 22.78, 21.64 (CH2); MS (ESI):
m/z 683.4 (M + 2Na À H)+. Anal. Calcd for C28H34N2O11S2: C,
52.65; H, 5.37; N, 4.39. Found C, 52.78; H, 5.35; N, 4.38.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet