Novel N-Substituted Amino-4-methylsulfanyl-2-pyridones and Deazapurine Analogues from Ketene Dithioacetals

Article abstract of DOI:10.1039/a701889d

A novel synthesis of N-substituted amino-4-methylsulfanyl-2-pyridones and deazapurine analogues via the reaction of ketene dithioacetals with substituted semi- and thio-semicarbazide derivatives is reported and the synthetic potential of the method is dem

Full text of DOI:10.1039/a701889d

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164 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 164±165$
Novel N-Substituted Amino-4-methylsulfanyl-2-
pyridones and Deazapurine Analogues from Ketene
Dithioacetals{
Galal H. Elgemeie,*a Ahmed H. Elghandour,b Ali M. Elzanateb and
Wafaa A. Masoudb
aChemistry Department, Faculty of Science, Helwan University, Cairo, Helwan, Egypt
bChemistry Department, Faculty of Science, Cairo University (bani Suef Branch), Bani Suef, Egypt
A novel synthesis of N-substituted amino-4-methylsulfanyl-2-pyridones and deazapurine analogues via the reaction of ketene
dithioacetals with substituted semi- and thio-semicarbazide derivatives is reported and the synthetic potential of the method is
demonstrated.
Synthetic analogues of purines are widely used in the medi-
cal sciences and in clinical medicine. Examples include the
6-sulfanylguanine and 6-sulfanylpurine which are widely
used clinically. The purine analogue 4-hydroxypyrazolo-
pyrimidine (allopurine), used in the treatment of hyper-
uricemia and gout, inhibits de novo purine biosynthesis and
xanthine oxidase. Azathiopurine, which is catabolized to
6-sulfanylpurine, is employed in organ transplantation to
supress events involved in immunologic rejection. As a part
of our program directed towards the development of
new simple and ecient procedures for the synthesis of
antimetabolities,1 we have recently reported di€erent
successful approaches for the synthesis of sulfanylpurine,
5-deazafolic acid and deazapyrimidine nucleosides.2,3
Derivatives of these ring systems are interesting because
they have useful properties as antimetabolites in biochemical
reactions.4 The present research deals with a novel synthesis
of N-substituted amino-4-methylsulfanyl-2-pyridones and
deazapurine analogues using ketene dithioacetals. Thus, it
has been found that compounds 1 reacted with 4-substituted
1-cyanoacetylthiosemicarbazide 3a,b at room temperature
in the presence of pulverized potassium hydroxide in 1,4-
dioxane to give the corresponding N-(4-methylsulfanyl-2-
oxo-1-pyridyl)thiourea derivatives 4. The structures of com-
pounds 4 were established on the basis of their elemental
analysis and spectral data (MS, 1H NMR, 13C NMR and
IR). Thus, structure 4a is supported by its mass spectrum
which showed a molecular ion corresponding to the formula
pyridones 5a,b were obtained in good yield. In related work,
Peseke et al.5 has reported the synthesis of compound 6 by
the reaction of 1 with cyanoacetohydrazide 2 in unreported
conditions. The structures of 5 were established and con-
®rmed on the basis of their elemental analysis and spectral
data (MS, 1H NMR, 13C NMR and IR). The analytical
data for 5a revealed
1
a
molecular formula C8H7N5SO
(M+=221) and H NMR spectroscopy was used to con®rm
SMe
SMe
EtO2C
N
NC
Y
CN
O
RNCS
N
5
N
1,4-dioxane, heat
N
H2N
O
HN
C
NH
R
6
S
4
Y
R
4a NH2 Ph
b
c
d
Ph
COPh
COPh
OH
NH2
OH
O
H
H
in case
of 1b
NC
N
N
N
R
KOH–1,4-dioxane
H
S
3a R = Ph
b R = COPh
O
NC
NH2
N
H
NC
X
1
C15H12N6S2O (M+=356). The H NMR spectrum revealed
2
a band at d 2.78 assignable to the SCH3 group, a multiplet
at d 7.21±7.60 assigned to aromatic protons, a broad singlet
at d 8.78 assignable to an amino group and two broad
singlets at d 9.85 and 10.69 assigned to the NH protons.
The 13C NMR spectrum was characterized by a signal at
d 19.81 attributed to the SCH3 carbon and two signals at
d 113.17 and 115.52 attributed to the two CN carbons.
Moreover, signals appeared at d 124.32, 127.56, 146.34,
149.12 and 161.93 corresponding to C-5, C-3, C-4, C-6 and
C-2, respectively.
KOH–1,4-dioxane
room temp.
MeS
SMe
1a X = CN
b X = CO2Et
O
NC
N
Ar
H
N
H
KOH–1,4-dioxane
room temp.
7
NH
SMe
SMe
N
The formation of 4 from the reaction of 1 with 3 is
assumed to proceed via Michael addition of the active
methylene of 3 to the double bond in 1. The formed
Michael adducts then cyclized smoothly via MeSH elimin-
ation and addition to the cyano group. In a typical exper-
iment, when the ketene dithioacetals 1a,b reacted with
cyanoacetohydrazide 2 at room temperature in the presence
of KOH±1,4-dioxane, the N-amino-4-methylsulfanyl-2-
CN
NC
CN
NC
CN
H2N
NH2NH2
ArCHO
EtOH, heat
1,4-dioxane,
heat
Y
N
N
O
Y
N
O
Y
N
O
CHAr
N
CHAr
NH2
9
8
5a Y = NH2
b Y = OH
Y
R
Y
R
9a NH2 C6H4-4-Cl
b
c
d
NH2 C6H4-4-Me
NH2 C6H4-4-Me
OH
OH
C6H5
C6H4-4-Me
*To receive any correspondence.
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
Scheme 1

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J. CHEM. RESEARCH (S), 1998 165
the structure. Thus, 1H NMR revealed a band at d 2.68
assignable to the SMe group and two broad singlets at
d 5.52 and 8.42 assignable to two amino groups. The 13C
NMR spectrum revealed a signal at d 18.93 assigned to the
SMe group and signals appeared at d 120.32, 122.90, 147.14,
149.17 and 160.96 corresponding to C-5, C-3, C-4, C-6 and
C-2, respectively. The formation of 5 from the reaction of 1
and cyanoacetohydrazide 2 is assumed to proceed via the
intermediacy of Michael adducts, which cyclized to yield the
®nal N-amino-2-pyridones . The reaction of ketene dithio-
acetals with Schi€ bases was also examined. Thus, when
1a,b were reacted with 1-cyanoacetyl-4-arylmethylidene-
semicarbazide 6 in the presence of KOH±1,4-dioxane, the 2-
pyridone-N-Schi€ bases 8 were obtained. The structures of 8
were established on the basis of elemental analysis and spec-
NH) (Found: C, 49.5; H, 3.0; N, 18.4%. C16H11N5S2O3 requires C,
49.9; H, 2.9; N, 18.2%).
N-Amino-4-methylsulfanyl-2-pyridone Derivatives 5a,bÐGeneral
Procedure.ÐA mixture of [bis(methylsulfanyl)methylene]malono-
nitriles 1a or ethyl 2-cyano-3,3-bis(methylsulfanyl)acrylate 1b
(0.01 mol), cyanoacetohydrazide 2 (0.01 mol), and potassium hy-
droxide (0.012 mol) in dry 1,4-dioxane (50 ml) was stirred at room
temperature for 24 h. The reaction mixture was acidi®ed with hydro-
chloric acid and the formed precipitate was collected by ®ltration,
dried and then recrystallized from the appropriate solvent.
1
5a: yield 40%, mp >300 8C (from MeOH), ꢀmax (KBr)/cm
3549, 3292 (NH2), 2216 (CN), 1734 (CO) (Found: C, 43.6; H, 3.3;
N, 31.5%. C8H7N5SO requires C, 43.4; H, 3.2; N, 31.6%).
1
5b: yield 35%; mp 150±151 8C (from MeOH); ꢀmax (KBr)/cm
3609, 3316 (OH, NH2), 2213 (CN), 1734 (CO) (Found: C, 43.4; H,
2.9; N, 25.0%. C8H6N4SO2 requires C, 43.2; H, 2.7; N, 25.5%).
1-(N-Substituted)arylmethylideneamino-4-methylsulfanyl-2-pyridone
Derivatives 8a±f. Method A.ÐA mixture of [bis(methylsulfanyl)-
methylene]malononitriles 1a or ethyl 2-cyano-3,3-bis(methyl-
sulfanyl)acrylate 1b (0.01 mol), 1-cyanoacetyl-4-arylidenesemicarba-
zide (0.01 mol), potassium hydroxide (0.012 mol) and 1,4-dioxane
(50 ml) were stirred at room temperature for 24 h. The reaction
mixture was acidi®ed with hydrochloric acid and the precipitate
formed was collected by ®ltration, dried and then recrystallized
from the appropriate solvent.
1
tral data (MS, H NMR, 13C NMR and IR). The analytical
data for 8c revealed a molecular formula C16H13N5SO
(M+=323). The 13C NMR showed a signal at d 18.15 due
to the SMe carbon and a signal at d 160.17 attributed to
a 2-pyridone carbonyl carbon. Compounds 4 and 8 can
also be prepared by the reaction of the corresponding N-
amino-2-pyridones 5 with substituted isothiocyanates and
aldehydes, respectively, in re¯uxing 1,4-dioxane for 2 h.
Compounds 8 reacted with hydrazine in re¯uxing ethanol to
give the corresponding pyrazolo[3,4-c]pyridines 9. The struc-
tures of each of the compounds 9 were established on the
basis of elemental analysis and spectral data.
In summary, we have achieved a regiospeci®c synthesis
of interesting N-substituted amino-4-methylsulfanyl-2-
pyridones and deazapurine analogues via the reaction of
ketene dithioacetals with semi- and thio-semicarbazide-
derivatives. The products obtained are currently under
biological evaluation studies.
Method B. To a solution of N-amino-2-pyridones 5 (0.01 mol)
in 1,4-dioxane (50 ml), aromatic aldehyde (0.01 mol) was added.
The resulting mixture was re¯uxed for 2 h and the solid product
collected by ®ltration and crystallized from the appropriate solvent.
1
8a: yield 51%; mp >300 8C (from 1,4-dioxane); ꢀmax (KBr)/cm
3425 (NH2), 2211 (CN), 1634 (CO) (Found: C, 52.7; H, 3.1; N,
20.2%. C15H10ClN5SO requires C, 52.4; H, 2.9; N, 20.4%).
8b: yield 83%; mp >300 (from 1,4-dioxane); ꢀmax (KBr)/cm
1
3446 (NH2), 2220 (CN), 1685 (CO) (Found: C, 59.0; H, 4.2; N,
21.5%. C16H13N5SO requires C, 59.4; H, 4.0; N, 21.7%).
1
8c: yield 76%; mp 285±287 8C (from MeOH); ꢀmax(KBr)/cm
3506±3345 (OH), 2209 (CN), 1654 (CO) (Found: C, 58.2; H, 3.3; N,
17.8%. C15H10N4SO2 requires C, 58.0; H, 3.2; N, 18.0%).
1
8d: yield 62%; mp 210±211 8C (from EtOH); ꢀmax/cm 3498,
3381 (NH2), 2206 (CN), 1687 (CO) (Found: C, 59.0; H, 3.9; N,
17.3%. C16H12N4SO2 requires C, 59.3; H, 3.7; N, 17.3%).
6-Amino-3-cyanopyrazolo[3,4-c]pyridin-2(1H)-one Derivatives 9a±d.
General Procedure.ÐA mixture of equivalent amounts of 5b,c,e,f
(0.01 mol) and hydrazine hydrate (0.01 mol) was heated in ethanol
(30 ml) for 4 h. The solid product formed was collected by ®ltration
and crystallized from the appropriate solvent.
Experimental
All melting points are uncorrected. IR spectra were obtained
(KBr) on a Pye Unicam instrument. 1H- and 13C-NMR spectra
were measured on a Varian 400 or Wilmad 270 MHz spectrometer
for (CD3)2SO solutions using SiMe4 as internal standard. Mass
1
9a: yield 53%; mp >300 8C (from DMF); ꢀmax (KBr)/cm 3479,
spectra were recorded on
a Varian MAT 112 spectrometer.
3315 (NH, NH2), 2210 (CN), 1655 (CO); dH (DMSO) 5.68 (s, br, 2
H, NH2), 6.87±7.89 (m, 4 H, C6H4), 8.12 (s, 1 H, ylidic CH), 8.28
(s, br, 2 H, NH2), 11.85 (s, br, 1 H, NH) (Found: C, 51.5; H, 2.9;
N, 30.2%. C14H10ClN7O requires C, 51.3; H, 3.1; N, 29.9%).
Analytical data were obtained from the Microanalytical Data
Centre at Cairo University.
N-(4-Methylsulfanyl-2-oxo-1-pyridyl)thiourea Derivatives 4a,b.
Method A.ÐA mixture of [bis(methylsulfanyl)methylene]malono-
nitriles 1a or ethyl 2-cyano-3,3-bis(methylsulfanyl)acrylate 1b
1
9b: yield 55%; mp >300 8C (from EtOH); ꢀmax (KBr)/cm
3600±3182 (NH, NH2), 2206 (CN), 1639 (CO) (Found: C, 58.2; H,
4.3; N, 32.2%. C15H13N7O requires C, 58.6; H, 4.2; N, 31.9%).
(0.01 mol),
4-substituted
cyanoacetythiosemicarbazide
3a,b
(0.01 mol), potassium hydroxide (0.012 mol) and dry 1,4-dioxane
(50 ml) were stirred at room temperature for 24 h. The reaction
mixture was acidi®ed with hydrochloric acid and the formed precipi-
tate was collected by ®ltration, dried and then crystallized from the
appropriate solvent.
1
9c: yield 54%; mp >300 8C (from 1,4-dioxane); ꢀmax (KBr)/cm
3450, 3350 (OH, NH, NH2), 2205 (CN), 1702 (CO) (Found: C,
57.4; H, 3.5; N, 28.3%. C14H10N6O2 requires C, 57.1; H, 3.4; N,
28.6%).
1
9d: yield 54%; mp >300 8C (from MeOH); ꢀmax (KBr)/cm
Method B.ÐTo a solution of N-amino-2-pyridones 5 (0.01 mol)
in 1,4-dioxane (50 ml), phenyl isothiocyanate or benzoyl isothio-
cyanate (0.01 mol) was added. The resulting mixture was re¯uxed
for 2 h and the solid product collected by ®ltration and crystallized
from the appropriate solvent.
3451, 3352 (OH, NH, NH2), 2205 (CN), 1703 (CO) (Found: C,
58.0; H, 4.0; N, 27.5%. C15H12N6O2 requires C, 58.4; H, 3.9; N,
27.3%).
1
4a: yield 52%, mp 280±282 8C (from EtOH); ꢀmax (KBr)/cm
Received, 18th March 1997; Accepted, 13th August 1997
Paper E/7/01889D
3391 (NH, NH2), 2217 (CN), 1655 (CO) (Found: C, 50.3; H, 3.6;
N, 23.5%. C15H12N6S2O requires C, 50.7; H, 3.4; N, 23.6%).
4b: yield 52%, mp 242±244 8C (from 1,4-dioxane); ꢀmax (KBr)/
1
References
cm 3600, 3380, 3320±3100 (OH, NH), 2212 (CN), 1655 (CO)
(Found: C, 50.7; H, 3.0; N, 19.4%. C15H11N5S2O2 requires C, 50.4;
H, 3.1; N, 19.6%).
4c: yield 53%, mp >300 8C (from EtOH); ꢀmax (KBr)/cm 3312,
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2 G. H. Elgemeie, A. M. Attia, D. S. Farag and S. M. Sherif,
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1
3280 (NH, NH2, 2211 (CN), 1650 (CO); dH (DMSO) 2.69 (s, 3 H,
SMe), 6.92 (m, 2 H, NH2), 7.19±7.77 (m, 5 H, Ph), 9.60 (s, br, 1 H,
NH), 10.53 (s, br, 1 H, NH) (Found: C, 49.7; H, 3.2; N, 21.9%.
C16H13N6S2O2 requires C, 50.0; H, 3.0; N, 21.6%).
4d: yield 55%, mp 290±293 8C (from MeOH); ꢀmax (KBr)/cm
3454, 3350 (OH, NH), 2213 (CN), 1634 (CO). 2.82 (s, 3 H, SMe),
7.18±7.81 (m, 5 H, Ph), 11.35 (s, br, 1 H, NH), 13.50 (s, br, 1 H,
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1