Convenient synthesis of 2-pyridyl thioglycosides

Article abstract of DOI:10.3184/030823408X340816

A reported method for preparation of a new class of pyridine thioglycosides via reaction of pyridine-2(1H)-thiones with 2,3,4-tri-O-acetyl-α-D-xylo- and -β-D-arabinopyranosyl bromides has been studied.

Full text of DOI:10.3184/030823408X340816

JOURNAL OF CHEMICAL RESEARCH 2008
AUGUST, 473–475
RESEARCH PAPER 473
Convenient synthesis of 2-pyridyl thioglycosides
Galal Elgemeiea*, Elsayed Eltamnyb, Ibraheim Elgawadc and Nashwa Mahmoudc
aDepartment of Chemistry, Faculty of Science, Helwan University, Ain-Helwan, Cairo, Egypt
bChemistry Department, Faculty of Science, Suez Canal University, Ismaelia, Egypt
cChemistry Department, Faculty of Science in Suez, Suez Canal University, Suez, Egypt
A reported method for preparation of a new class of pyridine thioglycosides via reaction of pyridine-2(1H)-thiones
with 2,3,4-tri-O-acetyl-D-D-xylo- and -E-D-arabinopyranosyl bromides has been studied.
Keywords: 2-pyridinethioglycosides, pyridinethiones, deazanucleosides
were measured on a Varian 400 MHz spectrometer for solution
(CD3)2SO using Si(CH3)4 as an internal standard. Mass spectra were
recorded on a Varian MAT 112 spectrometer. Elemental analyses
were obtained from The Microanalytical Data Centre at Cairo
University, Egypt.
Recently deazanucleoside analogues have been shown to
exhibit antitumour activity.1 During our studies of nucleoside
analogues with novel H-bonding patterns a route for the
synthesis of N- or S-nucleosides bearing a substituted pyridine
ring as the heterocyclic aglycone was desired.2,3 Such a route
could provide access to a variety of analogues of pyrimidine
nucleosides with novel H-bonding patterns.4 Such molecules
might serve as components of an expanded genetic “alphabet”
or display pharmaceutically useful antimetabolite activity.5 We
report here the results of an investigation into the utility of the
reaction of our previously reported pyridine-2(1H)-thiones 4a–
d6 with 2,3,4-tri-O-acetyl-Į-D-xylo- and -E-arabinopyranosyl
bromide for the synthesis of S-xylopyranosylthio- and S-
arabinopyranosylthiopyridine glycosides, compounds 4a–d
ZHUHꢀ SUHSDUHGꢀ E\ꢀ WKHꢀ UHDFWLRQꢀ RIꢀ ĮꢁDON\ODWHGꢀ E-diketones
3 with cyanothioacetamide in boiling sodium ethoxide for
2 h. Compounds 4a–c reacted with 2,3,4-tri-O-acetyl-Į-D-
xylo- and -E-arabinopyranosyl bromide in aqueous potassium
hydroxide to give the corresponding S-xylosides 6a–d and
S-arabinosides 6e–h (Scheme 1). The structure of the reaction
products 6a-hꢀZHUHꢀHVWDEOLVKHGꢀDQGꢀFRQ¿UPHGꢀIRUꢀWKHꢀUHDFWLRQꢀ
products on the basis of their elemental analysis and spectral
data (MS, IR, UV, 1H NMR, 13C NMR). Thus, the analytical
data for 6d revealed a molecular formula (C26H28N2SO7).
4-Methyl-2-(2',3',4'-tri-O-acetyl-E-D-xylo- and -arabinopyranosyl-
thio)pyridine-3-carbonitriles (6a–h): general procedure
To a solution of the pyridine-2(1H)-thiones 4a–d (0.01 mol) in
aqueous potassium hydroxide [0.56 g (0.01 mol) in 6 ml distilled
water],
a solution of 2,3,4-tri-O-acetyl-Į-D-xyloso- or -E-D-
arabinopyranosyl bromide (0.01 mol) in acetone (30 ml) was added.
The reaction mixture was stirred overnight at room temperature,
WKHQꢀZDVꢀSRXUHGꢀRQꢀLFHꢀFROGꢀZDWHUꢎꢀWKHꢀUHVXOWLQJꢀSURGXFWꢀZDVꢀ¿OWHUHGꢎꢀ
collected, dried and recrystallised from ethanol.
6a:ꢀ <HOORZꢎꢀ PꢃSꢃꢀ ꢊꢊꢈꢀƒ&ꢎꢀ \LHOGꢀ ꢏꢄꢈꢐꢑꢃꢀ ,5ꢎꢀ Ȟmax/cm-1 (KBr) 2218
(CN); 1761 (CO). 1H NMR: G 2.01–2.11 (t, 9H, 3H3CO); 2.13 (s, 3H,
CH3), 2.22 (s, 3H, CH3); 2.30 (s, 3H, CH3); 3.55–5.40 (m, 5H, 2H-5',
H-4', H-3', H-2'); 6.11 (d, 1H, H-1'). C20H24N2O7S, Calcd: C, 55.03%;
H, 5.54%; N, 6.41%. Found: C, 55.09%; H, 5.57%; N, 6.52%.
6b:ꢀ<HOORZꢎꢀPꢃSꢃꢀꢊꢈꢂꢀƒ&ꢎꢀ\LHOGꢀꢏꢉꢍꢐꢑꢃꢀ,5ꢎꢀȞmax/cm-1 (KBr) 2217
1
(CN); 1758 (CO). H NMR: G 1.42 (t, 3H, CH3); 2.00–2.04 (t, 9H,
3H3CO); 2.10 (s, 3H, CH3); 2.34 (s, 3H, CH3); 2.50 (q, 2H, CH2);
3.60–5.40 (m, 5H, 2H-5', H-4', H-3', H-2'); 6.13 (d, 1H, H-1').
C21H26N2O7S, Calcd: C, 55.98%; H, 5.81%; N, 6.21%. Found: C,
56.20%; H, 5.82%; N, 6.22%.
6c:ꢀ<HOORZꢎꢀPꢃSꢃꢀꢇꢉꢂꢀƒ&ꢎꢀ\LHOGꢀꢏꢄꢊꢐꢑꢃꢀ,5ꢎꢀȞmax/cm-1 (KBr) 2219 (CN);
1753 (CO). 1H NMR: G 2.00–2.03 (t, 9H, 3 H3CO); 2.27 (s, 3H, CH3);
2.45 (s, 3H, CH3); 3.56–5.34 (m, 5H, 2H-5', H-4', H-3', H-2'); 6.03 (d,
1H, H-1'); 7.41–7.64 (m, 5H, C6H5). C25H26N2O7S, Calcd: C, 60.22%;
H, 5.25%; N, 5.62%. Found: C, 60.24%; H, 5.64%; N, 5.62%.
6d:ꢀ<HOORZꢎꢀPꢃSꢃꢀꢇꢉꢈꢀƒ&ꢎꢀ\LHOGꢀꢏꢄꢉꢃꢉꢐꢑꢃꢀ,5ꢎꢀȞmax/cm-1 (KBr) 2218
(CN); 1749 (CO). 1H NMR: G 1.25 (t, 3H, 3CH3); 2.02–2.12 (m, 9H,
3H3CO); 2.25 (t, 3H, CH3); 2.35 (s, 3H, CH3); 2.47 (m, 2H, CH2);
4.10–6.15 (m, 5H, 2H-5', H-4', H-3', H-2'); 6.38 (d, 1H, H-1'); 7.45–
8.25 (m, 5H, C6H5). 13C NMR: 14.82 (CH3); 18.37–19.203 (CH3);
20.52–21.42 (3CH3CO); 23.28 (CH2); 64.73–71.62 (C-4', C-2', C-
3', C-5'), 81.12 (C-1'); 114.55 (C-3); 117.25 (CN); 122.70–133.74
(C6H5); 136.75 (C-5); 153.85 (C-4); 156.65 (C-6); 158.28 (C-S);
169.63–169.94 (3CO). C26H28N2SO7, Calcd: C, 60.92%; H, 5.50%;
N, 5.46%. Found: C, 60.94%; H, 5.52%; N, 5.48%.
1
The H NMR spectrum showed the anomeric proton as a
GRXEOHWꢀDWꢀįꢀꢂꢃꢄꢅꢀSSPꢃꢀ7KHꢀRWKHUꢀ¿YHꢀ[\ORVHꢀSURWRQVꢀUHVRQDWHGꢀ
DWꢀįꢀꢆꢃꢇꢈ±ꢂꢃꢇꢉꢀSSPꢀDQGꢀWKHꢀWKUHHꢀDFHW\OꢀJURXSVꢀDSSHDUHGꢀDVꢀ
WKUHHꢀ VLQJOHWVꢀ DWꢀ įꢀ ꢊꢃꢈꢊ±ꢊꢃꢇꢊꢀ SSPꢃꢀ7KHꢀ 13C NMR spectrum
of 6d FRQWDLQHGꢀDꢀVLJQDOꢀDWꢀįꢀꢅꢇꢃꢇꢊꢀSSPꢀFRUUHVSRQGLQJꢀWRꢀWKHꢀ
&ꢁꢇꢋꢀDWRPꢀDQGꢀIRXUꢀVLJQDOVꢀDSSHDULQJꢀDWꢀįꢀꢂꢆꢃꢌꢄ±ꢌꢇꢃꢂꢊꢀSSPꢀ
that were assigned to (C-4', C-2', C-3', C-5') respectively.
The formation of S-glycosides 6 and not the corresponding
N-glycosides were proved using 13C NMR spectroscopy which
UHYHDOHGꢀWKHꢀDEVHQFHꢀRIꢀWKHꢀWKLRQHꢀFDUERQꢀDWꢀįꢀꢇꢌꢅꢀSSPꢀDQGꢀWKHꢀ
DSSHDUDQFHꢀRIꢀDꢀVLJQDOꢀDWꢀįꢀꢇꢉꢅꢀSSPꢀFRUUHVSRQGLQJꢀWRꢀWKHꢀ&ꢁ6ꢀ
carbon7 and also with the same value of the corresponding
S-methyl derivative.6 When compounds 6a–h were treated
with methanolic ammonia at 0°C, the free glycoside
derivatives 7a–h were obtained, the structures of those
compounds were established on the basis of elemental analysis
and spectral data. Thus, the 1H NMR spectrum of 7c showed
WKHꢀDQRPHULFꢀSURWRQꢀDVꢀDꢀGRXEOHWꢀDWꢀįꢀꢉꢃꢉꢍꢀSSPꢃꢀ7KHꢀRWKHUꢀ¿YHꢀ
[\ORVHꢀSURWRQVꢀUHVRQDWHGꢀDWꢀįꢀꢄꢃꢈꢌ±ꢄꢃꢅꢌꢀSSPꢀZKLOHꢀWKHꢀWKUHHꢀ
K\GUR[\OꢀJURXSVꢀRIꢀWKHꢀ[\ORVHꢀDSSHDUHGꢀDWꢀįꢀꢉꢃꢈꢂ±ꢉꢃꢆꢅꢀSSPꢃ
These pyridine thioglycosides can be utilised as an excellent
starting material for the synthesis of other carbohydrate
derivatives and for further biological evaluation studies.
6e:ꢀ <HOORZꢎꢀ PꢃSꢃꢀ ꢇꢂꢈꢀƒ&ꢎꢀ \LHOGꢀ ꢏꢌꢅꢐꢑꢃꢀ ,5ꢎꢀ Ȟmax/cm-1 (KBr) 2219
(CN); 1744 (CO). 1H NMR: G 2.09–2.13 (t, 9H, 3 H3CO); 2.21(s, 3H,
CH3); 2.45 (s, 3H, CH3); 2.56 (s, 3H, CH3); 3.75–6.31 (m, 5H, 2H-5',
H-4', H-3', H-2'); 6.87 (s, 1H, H-1'). C20H24N2O7S, Calcd: C, 55.03%;
H, 5.54%; N, 6.41%. Found: C, 55.05%; H, 5.55%; N, 6.55%.
6f:ꢀ<HOORZꢎꢀPꢃSꢃꢀꢇꢇꢈƒ&ꢎꢀ\LHOGꢀꢏꢄꢌꢃꢉꢐꢑꢃꢀ,5ꢎꢀȞmax/cm-1 (KBr) 2181
(CN); 1751 (CO). 1H NMR: G 1.21 (t, 3H, CH3); 1.97–2.08 (m, 12H,
3H3CO, CH3); 2.48 (q, 2H, CH2); 3.93–5.22 (m, 5H, 2H-5', H-4',
H-3', H-2'); 5.97 (s, 1H, H-1'). C21H26N2O7S, Calcd: C, 55.98%; H,
5.81%; N, 6.21%. Found: C, 56.16%; H, 5.82%; N, 6.21%.
6g:ꢀ<HOORZꢎꢀPꢃSꢃꢀꢇꢍꢅꢀƒ&ꢎꢀ\LHOGꢀꢏꢄꢂꢐꢑꢃꢀ,5ꢎꢀȞmax/cm1 (KBr) 2221 (CN);
1752 (CO). 1H NMR: G 2.07–2.13 (t, 9H, 3H3CO); 2.27 (s, 3H, CH3);
2.53 (s, 3H, CH3); 3.61–5.38 (m, 5H, 2H-5', H-4', H-3', H-2'); 6.21 (d,
1H, H-1'); 7.26–7.48 (m, 5H, C6H5). C25H26N2O7S, Calcd: C, 60.22%;
H, 5.25%; N, 5.62%. Found: C, 60.25%; H, 5.26%; N, 5.62%.
6h:ꢀ <HOORZꢎꢀ PꢃSꢃꢀ ꢇꢌꢆƒ&ꢎꢀ \LHOGꢀ ꢏꢆꢊꢃꢂꢌꢐꢑꢃꢀ ,5ꢎꢀ Ȟmax/cm-1(KBr)
Experimental
All melting points were uncorrected on a Gallenkamp melting
point apparatus. The IR spectra were recorded (KBr disk) on
a Perkin Elmer 1650 FT-IR instrument. The 1H NMR spectra
1
2221.3 (CN); 1745 (CO). H NMR: G 1.77 (t, 3H, CH3); 2.00–2.10
(t, 9H, 3H3CO); 2.38 (s, 3H, CH3); 3.66 (q, 2H, CH2), 3.89–5.56
(m, 5H, 2H-5', H-4', H-3', H-2'); 6.10 (d, 1H, H-1'); 7.12–7.54 (m,
5H, C6H5). C26H28N2O7S, Calcd: C, 60.92%; H, 5.50%; N, 5.46%.
Found: C, 60.93%; H, 5.52%; N, 5.47%.
* Correspondent. E-mail: elgemeie@hotmail.com

474 JOURNAL OF CHEMICAL RESEARCH 2008
O
O
O
O
K2CO3
/
acetone
R5I
2a,b
CH3
+
R6
CH3
R6
R5
1a,b
3a–d
CH3
S
R5
R6
CN
S
NC
NH2
N
H
EtOH/EtONa
4a–d
R1
R 3
O
acetone
aq.KOH
OAc
R2
R 4
OAc
5
CH3
CH3
CN
CN
R
R5
R6
5
NH3/CH3OH
N
R
S
N
S
6
R1
R2
O
R1
R2
O
OAc
OH
OAc
OH
6a–h
7a–h
R6
CH3
C6H5
1,2
R5
R3
H
Br
5,
a,
b,
R4
Br
H
CH3
a,
b,
C2H5
6
R1
R2
R5
R6
a
b
c
d
e
f
H
OAc
OAc
OAc
OAc
H
CH3
CH3CH2
CH3
CH3CH2
CH3
CH3CH2
CH3
CH3CH2
CH3
H
CH3
H
H
OAc
OAc
OAc
OAc
C6H5
C6H5
CH3
CH3
C6H5
C6H5
H
g
h
H
H
Scheme 1
R2
7
R1
R5
R6
a
b
c
d
e
f
H
OH
OH
OH
OH
H
CH3
CH3CH2
CH3
CH3CH2
CH3
CH3CH2
CH3
CH3CH2
CH3
H
CH3
H
H
OH
OH
OH
OH
C6H5
C6H5
CH3
CH3
C6H5
C6H5
H
g
h
H
H
Scheme 2
4-Methyl-2-(E-D-xylo- and arabinopyranosylthio)pyridine-3-carbo-
nitriles (7a–h): general procedures
7a:ꢀ<HOORZꢎꢀPꢃSꢃꢀꢇꢄꢈꢀƒ&ꢎꢀ\LHOGꢀꢏꢂꢈꢐꢑꢃꢀ,5ꢎꢀȞmax/cm-1 (KBr) 3384–3470
1
(OH); 2220 (CN). H NMR: G 2.00 (s, 3H, CH3); 2.22 (s, 3H, CH3);
Dry gaseous ammonia was passed through
a
solution of
2.50 (s, 3H, CH3); 3.12–3.79 (m, 5H, 2H-5', H-4', H-3', H-2'); 5.00–5.55
(m, 3H, 3OH); 5.60 (d, 1H, H-1'). C14H18 N2O4S, Calcd: C, 54.17%;
H, 5.84%; N, 9.02%. Found: C, 54.18%; H, 5.84%; N, 9.31%.
protected glycosides 6 (0.5 g) in dry methanol (20 ml) at room
temperature for 10 min. The reaction mixture was stirred 24 h
(Followed by TLC). The resulting mixture was then evaporated under
reduced pressure to afford a solid residue that was crystallised from
ether.
7b:ꢀ<HOORZꢎꢀPꢃSꢃꢀꢇꢈꢍꢀƒ&ꢎꢀ\LHOGꢀꢏꢉꢂꢐꢑꢃꢀ,5ꢎꢀȞmax/cm-1 (KBr) 3404–
1
3480 (OH); 2220 (CN). H NMR: G 1.89 (t, 3H, CH3); 2.20 (s, 3H,
CH3); 2.44 (s, 3H, CH3); 2.58 (q, 2H, CH2); 3.41–3.90 (m, 5H, 2H-

JOURNAL OF CHEMICAL RESEARCH 2008 475
5', H-4', H-3', H-2'); 4.78–5.60 (m, 3H, 3OH); 5.72 (d, 1H, H-1').
C15H20N2O4S, Calcd: C, 55.53%; H, 6.21%; N, 8.63%. Found:
C, 55.54%; H, 6.22%; N, 8.64%.
CH3); 3.39–3.83 (m, 5H, 2H-5', H-4', H-3', H-2'); 4.71–5.57 (3 s, 3H,
2'-OH, 3'-OH, 4'-OH); 6.19 (s, 1H, H-1'); 7.36–7.55 (m, 5H, C6H5).
C19H20N2O4S, Calcd: C, 61.26%; H, 5.41%; N, 7.52%. Found: C,
61.29%; H, 5.43%; N, 7.61%.
7c:ꢀ<HOORZꢎꢀPꢃSꢃꢀꢇꢇꢍꢀƒ&ꢎꢀ\LHOGꢀꢏꢉꢈꢐꢑꢃꢀ,5ꢎꢀȞmax/cm-1 (KBr) 3411–3480
7h:ꢀ<HOORZꢎꢀ PꢃSꢃꢀ ꢍꢍꢀƒ&ꢎꢀ \LHOGꢀ ꢏꢌꢈꢐꢑꢃꢀ ,5ꢎꢀ Ȟmax/cm-1(KBr) 3360–
3420 (OH); 2220 (CN). 1H NMR: G 1.56 (t, 3H, CH3); 2.11 (s, 3H,
CH3); 2.76 (q, 2H, CH2); 3.23–3.89 (m, 5H, 2H-5', H-4', H-3', H-
2'); 5.09–5.76 (m, 3H, 3OH); 5.90 (d, 1H, H-1'); 7.12–7.87 (m, 5H,
C6H5). C20H22N2O4S, Calcd: C, 62.15%; H, 5.73%; N, 7.25%. Found:
C, 62.15%; H, 5.74%; N, 7.29%.
1
(OH); 2218 (CN). H NMR: G 2.24 (s, 3H, CH3); 2.54 (s, 3H, CH3);
3.07–3.87 (m, 5H, 2H-5', H-4', H-3', H-2'); 5.06–5.48 (m, 3H, 3OH);
5.59 (d, 1H, H-1'); 7.41–7.54 (m, 5H, C6H5). C19H20N2O4S, Calcd: C,
61.27%; H, 5.41%; N, 7.52%. Found: C, 61.30%; H, 5.44%; N, 7.54%.
7d:ꢀ<HOORZꢎꢀPꢃSꢃꢀꢇꢉꢉꢀƒ&ꢎꢀ\LHOGꢀꢏꢌꢉꢐꢑꢃꢀ,5ꢎꢀȞmax/cm-1 (KBr) 3380–
1
3470 (OH); 2214 (CN). H NMR: G 1.76 (t, 3H, CH3); 2.24 (s, 3H,
CH3); 2.84 (q, 2H, CH2); 3.07–3.87 (m, 5H, 2H-5', H-4', H-3', H-
2'); 5.11–5.78 (m, 3H, 3OH); 5.99 (d, 1H, H-1'); 7.20–7.76 (m, 5H,
C6H5). C20H22N2O4S, Calcd: C, 62.15%; H, 5.73%; N, 7.25%. Found:
C, 62.15%; H, 5.74%; N, 7.27%.
Received 24 March 2008; accepted 8 July 2008
Paper 08/5179 doi: 10.3184/030823408X340816
Published online: 21 August 2008
7e:ꢀ %URZQꢎꢀ PꢃSꢃꢀ ꢅꢊꢀƒ&ꢎꢀ \LHOGꢀ ꢏꢌꢅꢐꢑꢃꢀ ,5ꢎꢀ Ȟmax/cm-1 (KBr) 3368–
1
3440(OH); 2220 (CN). H NMR: G 2.02 (t, 3H, CH3); 2.11 (s, 3H,
References
CH3), 2.33 (s, 3H, CH3); 3.45–3.79 (m, 5H, 2H-5', H-4', H-3', H-2');
5.20–5.84 (m, 3H, 3OH); 6.00 (d, 1H, H-1'). C14H18N2O4S, Calcd:
C, 54.17%; H, 5.84%; N, 9.02%. Found: C, 54.19%; H, 5.85%; N,
9.30%.
1
2
3
4
5
N. Kojima, K. Inoue, R. Shibata, S. Kawahara and E. Ohtsuka, Nucl.
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7f:ꢀ<HOORZꢎꢀ PꢃSꢃꢀ ꢍꢈꢀƒ&ꢎꢀ \LHOGꢀ ꢏꢂꢌꢐꢑꢃꢀ ,5ꢎꢀ Ȟmax/cm-1 (KBr) 3344–
G.H. Elgemeie, M.M. Hussein and P.G. Jones, Acta Crystallogr., 2002,
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1
3400 (OH); 2179 (CN). H NMR: G 1.48 (t, 3H, CH3); 2.09 (s, 3H,
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CH3); 2.56 (s, 3H, CH3); 2.99 (q, 2H, CH2); 3.51–3.97 (m, 5H, 2H-
5', H-4', H-3', H-2'); 4.88–5.67 (m, 3H, 3OH); 5.92 (d, 1H, H-1').
C15H20N2O4S, Calcd: C, 55.53%; H, 6.21%; N, 8.63%. Found: C,
55.50%; H, 6.25%; N, 8.66%.
S. Scala., N. Akhmed, U.S. Rao, K. Paull, L. Lan, B. Dickstein, J. Lee,
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7g:ꢀ<HOORZꢎꢀ PꢃSꢃꢀ ꢅꢆꢀƒ&ꢎꢀ \LHOGꢀ ꢏꢌꢅꢐꢑꢃꢀ ,5ꢎꢀ Ȟmax/cm-1 (KBr) 3362–
6
7
G.H. Elgemeie, H.A. Ali and M.M. Eid, J. Chem. Res. (S), 1993, 256.
I. Stefaniak, Org. Magn. Reson., 1979, 12, 379.
1
3400 (OH); 2217 (CN). H NMR: G 2.25 (s, 3H, CH3); 2.50 (s, 3H,