Novel cyanoketene N,S-acetals and pyrazole derivatives using potassium 2-cyanoethylene-1-thiolates

Article abstract of DOI:10.1080/00397910701473317

Novel ketene N,S-acetals 3 were readily prepared by the reaction of cyanoacetamide or cyanothioacetamide with phenylisothiocyanate in the presence of potassium hydroxide, followed by alkylation of the produced salts with methyl iodide. The reaction of compounds 3 with hydrazines afforded different substituted pyrazoles 6. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701473317

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Novel Cyanoketene N,S‐Acetals and
Pyrazole Derivatives using Potassium
2‐Cyanoethylene‐1‐thiolates
Galal H. Elgemeie a , Ahmed H. Elghandour b & Ghada W. Abd Elaziz b
a Faculty of Science, Chemistry Department, Helwan University, Helwan,
Cairo, Egypt
b Faculty of Science, Chemistry Department, Cairo University, Beni‐Suef
Branch, Beni‐Suef, Egypt
Version of record first published: 30 Aug 2007.
To cite this article: Galal H. Elgemeie , Ahmed H. Elghandour & Ghada W. Abd Elaziz (2007): Novel
Cyanoketene N,S‐Acetals and Pyrazole Derivatives using Potassium 2‐Cyanoethylene‐1‐thiolates, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:17,
2827-2834
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Synthetic Communicationsw, 37: 2827–2834, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701473317
Novel Cyanoketene N,S-Acetals and
Pyrazole Derivatives using Potassium
2-Cyanoethylene-1-thiolates
Galal H. Elgemeie
Faculty of Science, Chemistry Department, Helwan University, Helwan,
Cairo, Egypt
Ahmed H. Elghandour and Ghada W. Abd Elaziz
Faculty of Science, Chemistry Department, Cairo University, Beni-Suef
Branch, Beni-Suef, Egypt
Abstract: Novel ketene N,S-acetals 3 were readily prepared by the reaction of cyanoa-
cetamide or cyanothioacetamide with phenylisothiocyanate in the presence of
potassium hydroxide, followed by alkylation of the produced salts with methyl
iodide. The reaction of compounds 3 with hydrazines afforded different substituted
pyrazoles 6.
Keywords: activated nitriles, cyanoacetamide, cyano ketene N,S-acetals, cyanothio-
acetamide, phenylisothiocyanate, pyrazoles
Ketene dithioacetals bearing the cyano, amide, thioamide, or alkoxycarbo-
nyl group at the a-position are extremely interesting electrophilic
reagents for the introduction of three or two carbon units into the ring of
heterocyclic compounds.[1,2] We have recently reported different successful
approaches for synthesis of new classes of novel antimetabolites utilizing
ketene S,S- and N,S-acetals as starting materials.[3] In an extension of this
Received in the USA January 10, 2007
Address correspondence to Galal H. Elgemeie, Faculty of Science, Chemistry
Department, Helwan University, Helwan, Cairo, Egypt. E-mail: elgemeie@lormail.com
2827

2828
G. H. Elgemeie, A. H. Elghandour, and G. W. A. Elaziz
work, we now report a synthesis of some novel ketene N,S-acetals and their
use in the synthesis of functionalized pyrazole derivatives. Thus, it has been
found that reaction of cyanoacetamide 1a and cyanothioacetamide 1b with
phenylisothiocyanate in KOH-EtOH at room temperature gives the corre-
sponding potassium 2-cyanoethylene-1-thiolate derivatives 2 in high yield.
Alkylation of the latter with methyl iodide gives the corresponding novel
ketene N,S-acetals 3. The structures of 3 were established on the basis of
their elemental analysis and spectral data (MS, IR, and 1H NMR).
Reaction of ketene N,S-acetals 3 with aniline afforded the corresponding
ketene N,N-acetals 4. When compounds 3 were treated with substituted
hydrazines 5, the 5-anilinopyrazoles 6 were obtained. The structures of
compounds 6 were established on the basis of their elemental analyses
and spectral data. To investigate the scope of this reaction further, we
studied the reaction of ethyl cyanoacetate 7 with phenylisothiocyanate in
KOH-EtOH at room temperature to give the corresponding potassium salt
of addition product 8. Alkylation of the latter with methyl iodide
afforded the methylated product 9. Compound 9 reacted with thiourea
and hydrazines 5a,b to form the corresponding novel pyrimidine-2-
thiones 12 and 5-aminopyrazols 10, respectively. Reaction of the ketene
N,S-acetal 9 with aniline afforded the corresponding ketene N,N-acetal
11. Phenylthiosemicarbazide 13 reacted with phenylisothiocyanate under
analogous conditions to yield the potassium salt of pyrazole ketene N,S-
acetal 15 and not the expected potassium salt of 2-cyanoethylene-1-
thiolate derivative 14. The formation of 15 is assumed to proceed via
intermediacy of 14, which cyclized via addition to the cyano group to
yield 15. On alkylation with methyl iodide in ethanol, compound 15
afforded the novel pyrazole ketene N,S-acetal 16. The structure of 16 was
established on the basis of its elemental analysis and spectral data (MS,
1
IR, and H NMR) (Schemes 1–3).
In summary, we have achieved a regiospecific synthesis of interesting
ketene N,S- and N,N-acetals and their conversions to several substituted
pyrazole derivatives.
EXPERIMENTAL
All melting points are 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 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.
Analytical data were obtained from the Microanalytical Data Center at
Cairo University.

Cyanoketene N,S-Acetals and Pyrazole Derivatives
2829
Scheme 1.
Ketene N,S-acetals (3,9)
General Procedure
A mixture of cyanoacetamide, cyanothioacetamide 1a,b, or ethyl cyanoacetate
7 (0.01 mol) and phenylisothiocyanate (0.01 mol, 1.19 mL) was stirred at
room temperature for 30 min in the presence of potassium hydroxide
(0.01 mol, 0.56 g) in ethanol (30 mL). Methyl iodide (0.01 mol, 0.62 mL)
was then added to the reaction mixture, and stirring is continued until a

2830
G. H. Elgemeie, A. H. Elghandour, and G. W. A. Elaziz
Scheme 2.
solid product is formed. The precipitated solid product was filtrated off and
recrystallized from the appropriate solvent.
Data
3a: White; mp 1638C; from ethanol; yield 83%; nmax/cm21 (KBr) 3422,
3331 (NH, NH2), 2190 (CN), 1642 (CO); dH[(CD3)2SO]: 2.52 (s, 3H,

Cyanoketene N,S-Acetals and Pyrazole Derivatives
2831
Scheme 3.
SCH3), 6.98 (s, 2H, NH2), 7.25–7.49 (m, 5H, C6H5), 8.67 (s, 1H, NH); m/z
(233); found: C, 56.50; H, 4.62; N, 18.12%; calcd. for C11H11N3OS (233): C,
56.65; H, 4.72; N, 18.03%. 3b: Yellow; mp 2178C; from ethanol; yield, 78%;
nmax/cm21 (KBr) 3447, 3326 (NH, NH2), 2177 (CN); dH[(CD3)2SO]: 2.56
(s, 3H, SCH3), 5.40 (s, 2H, NH2), 7.18–7.45 (m, 5H, C6H5); 10.73 (s, 1H,
NH); m/z (248); found: C, 53.25; H, 4.35; N, 16.98%; calcd. for
C11H11N3S2 (249): C, 53.01; H, 4.42; N, 16.87%. 9: White; mp 828C;
from ethanol; yield 86%; nmax/cm21 (KBr) 3472 (NH), 2204 (CN), 1659
(CO); dH[(CD3)2SO]: 1.33–1.38 (t, 3H, CH3); 2.25 (s, 3H, SCH3); 4.23–
4.30 (q, 2H, CH2); 7.27–7.43 (m, 5H, C6H5); 11.51 (s, 1H, NH); m/z
(262); found: C, 59.71; H, 5.40; N, 10.78%; calcd. for C13H14N2O2S
(262): C, 59.54; H, 5.34; N, 10.69%.
Ketene N,N-Acetals (4,11)
General Procedure
A mixture of compounds 3a,b or 9 (0.01 mol) and aniline (0.02 mol, 1.96 mL
or 0.01 mol, 0.98 mL) was heated for 2–3 h at 2008C in an oil bath, and then
the reaction mixture was diluted with ethanol. The resulting solid product was
filtered off and recrystallized from the appropriate solvent.

2832
G. H. Elgemeie, A. H. Elghandour, and G. W. A. Elaziz
Data
4a: Pale brown; mp 2388C; from ethanol; yield 75%; nmax/cm21 (KBr) 3469
(NH); 1649 (CO); dH[(CD3)2SO]: 6.00 (s, 2H, NH2), 6.95–7.48 (m, 10H,
2C6H5), 8.66 (s, 1H, NH), 9.89 (s, 1H, NH); found: C, 69.30; H, 5.12; N,
19.98%; calcd. for C16H14N4O (278): C, 69.07; H, 5.04; N, 20.14%. 4b:
Pale brown; mp 2408C; from ethanol; yield 75%; nmax/cm21 (KBr) 3290
(NH); found: C, 65.17; H, 4.71; N, 19.25%, calcd. for C16H14N4S (294): C,
65.31; H, 4.76; N, 19.05%. 11: Pale brown; mp 2438C; from ethanol; yield
78%; nmax/cm21 (KBr) 3327, 3196 (NH); 1650 (CO); dH[(CD3)2SO]:
6.93–7.46 (m, 15H, 3C6H5), 8.62 (s, 1H, NH), 9.99 (s, 1H, NH), 10.42
(s, 1H, NH); m/z (343); found: C, 74.41; H, 5.02; N, 15.95%; calcd. for
C22H18N4O (354): C, 74.58; H, 5.09; N, 15.82%.
5-Amino-3-anilino-4-substituted Pyrazoles (6,10)
General Procedure
A mixture of compounds 3a,b or 9 (0.01 mol) and hydrazine derivatives 5a,b
(0.01 mol) was refluxed for 3–4 h in ethanol (30 mL). The solution mixture
was poured over ice water and acidified with drops of dilute hydrochloric
acid. The solid product was collected by filtration and recrystallized from
the appropriate solvent.
Data
6a: White; mp 1788C; from ethanol; yield 76%; nmax/cm21 (KBr) 3423,
3325 (NH, NH2); 1646 (CO); dH[(CD3)2SO]: 5.58 (s, 2H, NH2), 6.70
(s, 2H, NH2), 7.15–7.54 (m, 5H, C6H5), 8.25 (s, 1H, NH), 10.58 (s, 1H,
NH); m/z (219); found: C, 55.43; H, 5.15; N, 32.37%; calcd. for
C10H11N5O (217): C, 55.30; H, 5.07; N, 32.26%. 6b: White; mp 2858C;
from ethanol; yield 72%; nmax/cm21 (KBr) 3453, 3310 (NH, NH2); m/z
(233); found: C, 51.33; H, 4.77; N, 30.21%; calcd. for C10H11N5S (233):
C, 51.50; H, 4.72; N, 30.04%. 6c: White; mp . 3008C; from ethanol;
yield 69%; nmax/cm21 (KBr) 3432, 3315 (NH, NH2), 1659 (CO); found:
C, 65.66; H, 5.20; N, 23.76%; calcd. for C16H15N5O (293): C, 65.53; H,
5.12; N, 23.89%. 6d: White; mp . 3008C; from ethanol; yield 66%;
nmax/cm21 (KBr) 3435, 3354 (NH, NH2); found: C, 61.99; H, 4.76; N,
22.82%; calcd. for C16H15N5S (309): C, 62.14; H, 4.85; N, 22.65%. 10a:
White; mp 1688C; from ethanol; yield 80%; nmax/cm21 (KBr) 3473,
3380 (NH, NH2), 1642 (CO); dH[(CD3)2SO]: 1.29–1.36 (t, 3H, CH3),
4.22–4.32 (q, 2H, CH2), 6.05 (s, 2H, NH2), 6.80–7.59 (m, 5H, C6H5),
8.06 (s, 1N, NH), 11.10 (s, 1H, NH); m/z (246); found: C, 58.43; H,
5.73; N, 22.57%; calcd. for C12H14N4O2 (246): C, 58.54; H, 5.69; N,

Cyanoketene N,S-Acetals and Pyrazole Derivatives
2833
22.76%. 10b: White; mp . 3008C; from ethanol; yield 62%; nmax/cm21
(KBr) 3423, 3353, 3280 (NH, NH2), 1654 (CO); found: C, 67.23; H,
5.54; N, 17.60%; calcd. for C18H18N4O2 (322): C, 67.08; H, 5.59; N,
17.39%.
4-Anilino-5-cyano-6-oxopyrimidine-2-thione (12)
Procedure
A mixture of compound 9 (0.01 mol, 2.62 g) and thiourea (0.01 mol, 0.76 g)
was heated for 3 h in ethanol (25 mL) containing an equivalent amount of
potassium hydroxide (0.01 mol, 0.56 g). The reaction mixture was poured
over ice water and acidified with drops of dilute hydrochloric acid. The
solid product was filtered off and recrystallized from ethanol.
Data
12: White; mp 2768C; from ethanol; yield 75%; nmax/cm21 (KBr) 3420, 3310
(NH); 2212 (CN); 1647 (CO); dH[(CD3)2SO]: 7.27–7.46 (m, 5H, C6H5), 9.42
(s, 1H, NH), 12.51 (s, 1H, SH); m/z (244); found: C, 54.23; H, 5.17; N,
23.07%; calcd. for C11H8N4OS (244): C, 54.10; H, 3.28; N, 22.95%.
(4Z)-4-[Anilino(methylthio)methylene]-5-imino-3-oxo-N-
phenylpyrazolidine-1-carbothioamide (16)
Procedure
A mixture of 1-cyanoacetyl-4-phenylthiosemicarbazide 13 (0.01 mol, 2.34 g)
and phenylisothiocyanate (0.01 mol, 1.19 mL) was heated for 20 min in
ethanol (25 mL) containing potassium hydroxide (0.01 mol, 0.56 g). After
cooling, methyl iodide (0.01 mol, 0.62 mL) was added, and the mixture was
stirred until a solid product was formed. The precipitated solid product was
collected by filtration and recrystallized from 30 ml of ethanol.
Data
16: Yellow; mp 2198C; from ethanol; yield 77%; nmax/cm21 (KBr) 3450,
3375 (NH); 1642 (CO); dH[(CD3)2SO]: 2.10 (s, 3H, SCH3), 7.25–7.58
(m, 10H, 2C6H5), 10.82 (s, 1H, NH), 12.31 (s, 1H, NH), 12.52 (s, 1H, NH),
12.97 (s, 1H, NH), m/z (383); found: C, 56.24; H, 4.52; N, 18.13%; calcd.
for C18H17N5OS2 (383): C, 56.40; H, 4.44; N, 18.28%.

2834
G. H. Elgemeie, A. H. Elghandour, and G. W. A. Elaziz
REFERENCES
1. Elgemeie, G. H.; Elghandour, A. H.; Elzanate, A. M.; Ahmed, S. A. Novel synthesis
of thioguanine and sulfanylpurine analogues: Reaction of heterocyclic ketene
dithioacetals with nucleophiles. J. Chem. Res., Synop. 1998, 162–163.
2. Elgemeie, G. H.; El-Ezbawy, S. R.; El-Aziz, H. A. The design and synthesis of
structurally related mercaptopurine analogues: Reaction of dimethyl N-cyano-
dithioiminocarbonate with 5-aminopyrazoles. Synth. Commun. 2001, 31,
3453–3458.
3. Elgemeie, G. H.; Elghandour, A. H.; Elzanate, A. M.; Ahmed, S. A. Synthesis of
some novel a-cyanoketene S,S-acetals and their use in heterocyclic synthesis.
J. Chem. Soc., Perkin Trans. 1997, 1, 3285–3289.