Direct route to a new class of acrylamide thioglycosides and their conversions to pyrazole derivatives

Article abstract of DOI:10.1080/00397910802222605

A new method for preparation of a new class of acrylamide thioglycosides via a one-pot reaction of potassium 2-cyanoethylene-1-thiolate salts with 2,3,4,6-tetra-O-acetyl-α-D-gluco- and galactopyranosyl bromides has been studied. The E-configuration of these thioglycosides were proven by their transformations to the corresponding 5-aminopyrazoles. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802222605

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Direct Route to a New Class of
Acrylamide Thioglycosides and
Their Conversions to Pyrazole
Derivatives
Galal H. Elgemeie a , Shahinaz H. Elsayed a & Ashraf
S. Hassan a
a Chemistry Department , Faculty of Science,
Helwan University , Ain-Helwan, Cairo, Egypt
Published online: 25 Aug 2010.
To cite this article: Galal H. Elgemeie , Shahinaz H. Elsayed & Ashraf S. Hassan (2008)
Direct Route to a New Class of Acrylamide Thioglycosides and Their Conversions
to Pyrazole Derivatives, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 38:16, 2700-2706, DOI:
10.1080/00397910802222605
To link to this article: http://dx.doi.org/10.1080/00397910802222605
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Synthetic Communications1, 38: 2700–2706, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802222605
Direct Route to a New Class of Acrylamide
Thioglycosides and Their Conversions to
Pyrazole Derivatives
Galal H. Elgemeie, Shahinaz H. Elsayed, and Ashraf S. Hassan
Chemistry Department, Faculty of Science, Helwan University,
Ain-Helwan, Cairo, Egypt
Abstract: A new method for preparation of a new class of acrylamide thio-
glycosides via a one-pot reaction of potassium 2-cyanoethylene-1-thiolate salts
with 2,3,4,6-tetra-O-acetyl-a-D-gluco- and galactopyranosyl bromides has been
studied. The E-configuration of these thioglycosides were proven by their
transformations to the corresponding 5-aminopyrazoles.
Keywords: Acrylamide thioglycosides, halosugars, phenyl isothiocyanate,
potassium 2-cyanoethylene-1-thiolates, pyrazoles
In recent year, nucleoside analogs have occupied a significant position in
the search for effective antiviral agents, because a large number of unnatu-
ral nucleoside derivatives have been shown to inhibit infection caused by
viruses.[1] The heterocyclic thioglycosides constitute a class of analogs
with potential biological activity.[2] As a part of our program directed
toward the development of new, simple, and efficient procedures for the
synthesis of antimetabolites,[3,4] we have recently described how pyridine
thioglycosides exerted inhibitory effects on both DNA- and RNA-
containing viruses.[5] On the basis of these findings, it was of interest
to prepare modified cyclic and acyclic thioglycosides to search for
more effective agents. Here we report a novel synthesis of acryl-
amide thioglycoside derivatives as a possible new class of glycosides
and their conversions to pyrazole derivatives. Thus, the potassium
Received in the U.K. August 22, 2006
Address correspondence to Galal H. Elgemeie, Chemistry Department, Faculty
of Science, Helwan University, Ain-Helwan, Cairo, Egypt. Tel: 2-02-5870668;
Fax: 2-010-1510203; E-mail: elgemeie@hotmail.com
2700

Acrylamide Thioglycosides
2701
Scheme 1.
2-cyanoethylene-1-thiolate salts 2a,b were chosen as the key intermediate.
The sequence of reactions followed in the preparation of the designed
compounds is summarized in Scheme 1. Thus, cyanoacetamide or cyano-
thioacetamide 1a,b reacted with phenyl isothiocyanate in KOH–EtOH
with heating to give the corresponding stable potassium 2-cyano-ethyl-
ene-1-thiolate salts 2a,b. The latter react with 2,3,4,6-tetra-O-acetyl-a-
D-gluco- and galacto-pyranosyl bromides 3 in ethanol at room

2702
G. H. Elgemeie, S. H. Elsayed, and A. S. Hassan
temperature to give the corresponding S-glucosides 4a,b and S-galacto-
sides 4c,d, respectively in high yields. The structures of the reaction
products 4a–d were established by their elemental analysis and spectral
1
data (mass spectrum (MS), infrared (IR), ultraviolet (UV), H NMR,
and 13C NMR). As an example, the analytical data for 4a revealed
1
molecular formula C24H27N3SO10 (m=z ¼ 549). The H NMR spectrum
showed the anomeric proton as a doublet at d 5.16. The coupling con-
stant J1 ,2 ¼ 9.8 Hz indicated H-10 to be trans-diaxial to H-20.
Attempted removal of protecting groups in 4a–d by methanolic
ammonia did not result in formation of the corresponding free
glycosides. We suggested that structures 4a–d should be present in the
E form and not in the Z form; this was shown by reacting compounds
4a–d with hydrazine hydrate in refluxing ethanol to give the corre-
sponding 5-aminopyrazole derivatives 5a,b. Alternatively, these
compounds could also be prepared by reaction of the 3-methylthio
acrylamide derivatives 6a,b with hydrazine hydrate. Compounds 6a,b
were prepared by the reaction of acrylamide derivatives 1 with
phenyl isothiocyanate in the presence of potassium hydroxide
followed by the alkylation with methyl iodide to give the ketene
S,N-acetals 6; the latter reacts with hydrazine hydrate to give
compounds 5a,b.
0
0
In summary, we have achieved a novel synthesis of interesting
acrylamide thioglycosides by the reaction of the potassium 2-cya-
noethylene-1-thiolate salts with a-glycosyl halides. These acyclic glyco-
sides can be utilized as excellent starting materials for the synthesis of
other carbohydrate derivatives and for further biological evaluation
studies.
EXPERIMENTAL
All melting points were measured on a Gallenkamp melting-point appa-
ratus and are uncorrected. The IR spectra were recorded (KBr disk) on
1
a Perking-Elmer 1650 FT-IR instrument. The H NMR spectra were
recorded on a Varian 400-MHz spectrometer in (CD3)2SO using
Si(CH3)4 as an internal standard. Mass spectra were recorded on a
Varian MAT 112 high-resolution spectrometer. Elemental analyses were
obtained from the Microanalytical Data Center at Cairo University,
Egypt.
Progress of the reactions was monitored by thin-layer chromotogra-
phy (TLQ) using aluminum sheets coated with silica gel F254 (Merck)
viewing under a short-wavelength UV lamp. All evaporations were
carried out under reduced pressure at 40 ꢀC.

Acrylamide Thioglycosides
2703
(2E)-3-Anilino-2-cyano-3(20,30,40,60-tetra-O-acetyl-b-D-gluco- and
galactopyranosylthio)-acrylamide or -thioacrylamide (4 a–d)
General Procedure
A mixture of cyanoacetamide or cyanothioacetamide 1a–d (0.01 mol) and
phenyl isothiocyanate (0.01mol) was heated for 10–20 min in ethanol
(25ml) containing potassium hydroxide (0.01mol). After cooling, a solution
of 2,3,4,6-tetra-O-acetyl-a-D-gluco- or galacto-pyranosyl bromide 3a,b
(0.01mol) in ethanol (20 ml) was added. The reaction mixture was stirred
at room temperature until completion (TLC) and then evaporated under
reduced pressure, and the residue was washed with distilled water to remove
the formed potassium bromide. The resulting solid product was dried and
crystallized from a mixture of EtOH=dimethyl formamide (DMF).
Data
Compound 4a: white, mp 180–182 ꢀC (from EtOH=DMF), yield (85%).
IR (KBr), Vmax=cmꢁ1 3373 (NH, NH2), 2200 (CN), 1630 (CO), 175l
1
(CO, ester of glucose). H NMR (DMSO) d 1.89–2.07 (4s, 12H, 4 CH3
CO), 3.93–4.02 (m, 3H , 2H-60 and H-50), 4.85–4.95 (m, 2H, H-40 and
H-30), 5.09 (t, 1H, H-20), 5.16 (d, J1 ,2 9.80 Hz, 1H, H-10), 6.60 (s, 2H,
NH2), 7.31–7.40 (m; 5H, C6H5), 7.45–7.61 (s, 1H, NH). 13C NMR
(DMSO) d 20.57–20.78 (4 CH3), 61.87 (C-60), 67.83 (C-40), 70.19 (C-20),
73.04 (C-30), 74.78 (C-50), 82.59 (C-10), 118.48 (CN), 126.03–129.32
(aromatic-C), 138.48 (C-2), 160.77 (C-3), 168.41 (CONH2), 169.39–170.22
(4CO). C24H27N3SO10 (m=z ¼ 549), (calcd.: C, 52.46; H, 4.95; N,
7.64. Found: C, 52.44; H, 4.93; N, 7.61%.
0
0
Compound 4b: yellow, mp 183–185 ꢀC (from EtOH=DMF), yield
(82%). IR (KBr) Vmax=cmꢁ1 3400 (NH, NH2), 2200 (CN), 1749 (CO,
1
ester of glucose). H NMR (DMSO) d 1.88–2.O4 (4s, 12H, 4 CH3CO),
3.97 (d, 2H, 2H-60) 4.78–4.91 (m, 2H, H-50 and H-400); 5.11–5.29 (m,
2H, H-30 and H-20), 5.31 (d, J1 ,2 , 9.66 Hz, 1H, H-1 ); 7.23–7.46 (m,
5H, C6H5), 8.42 (s, br, 2H, NH2); 9.38 (s, br, 1H, NH). 13C NMR
(DMSO) d 20.58–20.81 (4 CH3), 62.03 (C-60), 67.79 (C-40), 70.18 (C-20),
73.02 (C-30), 74.87 (C-50), 84.88 (C-10), 117.88 (CN), 125.46–129.36
(aromatic-C), 138.24 (C-2), 162.20 (C-3), 169.39–170.23 (4 CO), 189.53
(CS). C24H27N3S2O9, calcd.: C, 50.97; H, 4.81; N, 7.42. Found: C,
50.93; H, 4.80; N, 7.41%.
0
0
Compound 4c: white, mp 160–162 ꢀC (from EtOH=DMF), yield
(80%). IR (KBr) Vmax=cmꢁ1 3337 (NH, NH2), 2202 (CN), 1749 (CO,
ester of galactose), 1654 (CO). 1H NMR (DMSO) d 1.85–2.13 (4s,

2704
G. H. Elgemeie, S. H. Elsayed, and A. S. Hassan
12H, 4 CH3CO), 3.80 (s, 2H, 2H-60), 4.05–4.09 (m, H, H-50), 4.80 (t, H,
H-40), 5.00 (m, H, H-30), 5.12 (t, 1H, H-20), 5.20 (d, J1 ,2 9.50 Hz, 1H, H-
10), 7.201–7.41 (m, 5H, C6H5). 13C NMR (DMSO) d 20.00–20.89 (4 CH3),
60.50 (C-60), 67.80 (C-40), 71.00 (C-20), 72.77 (C-30), 74.50 (C-50), 81.43
(C-10), 116.00 (CN), 125.00–129.87 (aromatic-C), 139.00 (C-2), 161.50
(C-3), 167.00 (CONH2), 169.00–171.56 (4CO). C24H27N3SO10
(m=z ¼ 549), calcd.: C, 52.46; H, 4.95; N, 7.64. Found: C, 52.43; H,
4.92; N, 7.63%.
0
0
Compound 4d: white, mp 163–165 ꢀC (from EtOH=DMF), yield
(81%). IR (KBr) Vmax=cmꢁ1 3458 (NH, NH2), 2215 (CN), 1750
(CO, ester of glucose). 1H NMR (DMSO) d 1.66–1.96 (4s, 12H, 4
CH3CO), 3.90 (m, 2H, 2 H-60), 4.80–4.90 (m, 2H, H-50 and H-40),
5.08–5.26 (m, 3H, H-30, H-20 and H-10), 7.11–7.33 (m, 5H, C6H5),
8.66 (s, br, 2H, NH2, 10.09 (s, br, 1H, NH). 13C NMR (DMSO)
d 20.20–20.77 (4 CH3), 61.76 (C-60), 67.50 (C-40), 70.00 (C-20),
73.00 (C-30), 74.74 (C-50), 83.50 (C-10), 115.38 (CN), 124.00–130.22
(aromatic-C), 137.11 (C-2), 161.90 (C-30), 168.69–171.67 (4CO),
186.00 (CS). C24H27N3S2O9, calcd.: C, 50.97; H, 4.81; N, 7.42. Found:
C, 50.95; H, 4,79; N, 7.39%.
3-Anilino-2-cyano-3-(methylthio)acrylamide and -thioacrylamide (6a,b)
General Procedure
A mixture of cyanoacetamide 1a or cyanothioacetamide 1b (0.01 mol) and
phenylisothiocyanate (0.01 mol) was heated for 5–10min in ethanol
(25 ml) containing potassium hydroxide (0.01 mol). After cooling, methyl
iodide (0.01 mol) was added. The reaction mixture was stirred at room
temperature for 2 h and then poured onto ice water. The precipitated
product was filtered off and recrystallized from ethanol to give the title com-
pounds.
Data
Compound 6a: white, mp 161–63 ꢀC (from EtOH), yield (76%). IR (KBr)
1
V
max=cmꢁ1 3423, 3325 (NH, NH2), 219l (CN), 1546 (CO). H NMR
(DMSO) d 2.58 (s, 3H, SCH3), 6.70 (s, 2H, NH2), 7.25–7.15 (m, 5H,
C6 H5), 10.58 (s, 1H, NH). C11H11N3SO (m=z ¼ 233), calcd.: C, 56.64;
H, 4.75; N, 18.01. Found: C, 56.62; H, 4.71; N, 18.00%.
Compund 6b: yellow, mp 216–217 ꢀC (from EtOH), yield (75%). IR
(KBr) vmax=cmꢁ1 3450, 3300 (NH, NH2), 2210 (CN). 1H NMR (DMSO)

Acrylamide Thioglycosides
2705
d 2.60 (s, 3H, SCH3), 6.9l (s, br, 2H, NH2), 7.13–7.41 (m, 5H, C6 H5),
10.03 (s, br, H, NH). 13C NMR (DMSO) d 17.00 (SCH3), 118.48 (CN),
126.18–129.15 (aromatic-C), 139.58 (C-2), 172.79 (C-3), 187.84 (C-l).
C11H11N3S2 (m=z ¼ 249) (calcd.: C, 52.98; H, 4.44; N, 16.84. Found:
C, 52.93; H, 4.41; N, 16.81%.
5-Amino-3-anilino-lH-pyrazole-4-carboxamide and -carbthioamide (5a,b)
Method A
A solution of hydrazine hydrate (0.01 mol) in ethanol (20 ml) was added
to a solution of compounds 4a–d (0.01 mol) in ethanol (30 ml). The reac-
tion mixture was heated at reflux for 2 h and then evaporated under
reduced pressure. The resulting solid product was collected by filtration
and recrystallized from ethanol.
Method
A solution of hydrazine hydrate (0.01 mol) in ethanol (20 ml) was added
to a solution of compounds 6a–d (0.01 mol) in ethanol (30 ml). The reac-
tion mixture was heated at reflux for 2 h and then evaporated under
reduced pressure. The resulting solid product was collected by filtration
and recrystallized from ethanol. These products were found to be ident-
ical with those obtained in method A.
Data
Compound 5a: white, mp 178 180 ꢀC (from EtOH), yield (85%). IR (KBr)
V
max=cmꢁ1 3303 (NH, NH2), 1699 (CO). 1H NMR (DMSO) d5.79 (s, br,
2H, NH2), 6.70 (s, 2H, NH2), 7.13–7.31 (m, 5H, C6H5), 8.92 (s, br, NH),
10.95 (s, br, 1H, NH). C10H11N5O (m=z ¼ 217), calcd.: C, 55.29; H, 5.10;
N, 32.36. Found: C, 55.25; H, 5.09; N, 32.33%.
Compound 5b: buff, mp 283–285 ꢀC (from EtOH), yield (70%).
v
calcd.: C, 51.48; H, 4.74; N, 30.01. Found: C, 51.45; H, 4.71; N, 30.00%.
max=cmꢁ1 (KBr) 3453, 3310 (NH, NH2), C10H11N5S (m=z ¼ 233),
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