Bis-(cyanoacetamide)alkanes in heterocyclic synthesis: Synthesis of bis-heteryl(carboxymido)alkanes and bis-(heteryl)alkanes of thiophene, pyrrole, thiazole and pyrimidinone series

Article abstract of DOI:10.1080/17415993.2012.683433

Bis-N-substituted cyanoacetamides 3a and b reacted with active methylene-containing compounds 2a-c and elemental sulfur to give bis-thiophene 4a and b and bis-pyrrole 6a and b derivatives. Compounds 4a and b reacted with ethyl cyanoacetate 2a to afford bis-thienopyrimidine derivatives 5a and b; on the other hand, 6a and b reacted with cyanothioacetamide 2c to give the corresponding bis-thioxopyrrolopyrimidine derivatives 7a and b. Compounds 7a and b reacted with methyl iodide to give the corresponding bis-2-S- methylpyrrolopyrimidine derivatives 8a and b, which could be, in turn, cyclized into the bispyrazolopyrrolopyrimidine derivatives 9a and b by refluxing with hydrazine hydrate. On the other hand, 7a and b reacted with ethyl chloroacetate to yield the corresponding bis-thienopyrrolopyrimidine derivatives 10a and b. Finally, compounds 3a and b reacted with phenylisothiocyanate and elemental sulfur to give the corresponding bis-2-thioxoaminothizole derivatives 11a and b.

Full text of DOI:10.1080/17415993.2012.683433

This article was downloaded by: [University of Guelph]
On: 22 July 2012, At: 05:14
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Journal of Sulfur Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gsrp20
Bis-(cyanoacetamide)alkanes in
heterocyclic synthesis: synthesis of bis-
heteryl(carboxymido)alkanes and bis-
(heteryl)alkanes of thiophene, pyrrole,
thiazole and pyrimidinone series
Mohamed A.A. Elneairy a , Ahmed E.M. Mekky a & Ahmed A.M.
Ahmed a
a Faculty of Science, Chemistry Department, Cairo University,
Giza, 2613, Egypt
Version of record first published: 07 Jun 2012
To cite this article: Mohamed A.A. Elneairy, Ahmed E.M. Mekky & Ahmed A.M. Ahmed (2012): Bis-
(cyanoacetamide)alkanes in heterocyclic synthesis: synthesis of bis-heteryl(carboxymido)alkanes
and bis-(heteryl)alkanes of thiophene, pyrrole, thiazole and pyrimidinone series, Journal of Sulfur
Chemistry, 33:3, 373-383
To link to this article: http://dx.doi.org/10.1080/17415993.2012.683433
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Journal of Sulfur Chemistry
Vol. 33, No. 3, June 2012, 373–383
Bis-(cyanoacetamide)alkanes in heterocyclic synthesis: synthesis
of bis-heteryl(carboxymido)alkanes and bis-(heteryl)alkanes of
thiophene, pyrrole, thiazole and pyrimidinone series
Mohamed A.A. Elneairy*, Ahmed E.M. Mekky and Ahmed A.M. Ahmed
Cairo University, Faculty of Science, Chemistry Department, Giza 2613, Egypt
(Received 4 April 2012; final version received 4 April 2012)
Bis-N-substituted cyanoacetamides 3a and b reacted with active methylene-containing compounds 2a–c
and elemental sulfur to give bis-thiophene 4a and b and bis-pyrrole 6a and b derivatives. Compounds 4a
and b reacted with ethyl cyanoacetate 2a to afford bis-thienopyrimidine derivatives 5a and b; on the other
hand, 6a and b reacted with cyanothioacetamide 2c to give the corresponding bis-thioxopyrrolopyrimidine
derivatives 7a and b. Compounds 7a and b reacted with methyl iodide to give the corresponding
bis-2-S-methylpyrrolopyrimidine derivatives 8a and b, which could be, in turn, cyclized into the bis-
pyrazolopyrrolopyrimidine derivatives 9a and b by refluxing with hydrazine hydrate. On the other hand,
7a and b reacted with ethyl chloroacetate to yield the corresponding bis-thienopyrrolopyrimidine deriva-
tives 10a and b. Finally, compounds 3a and b reacted with phenylisothiocyanate and elemental sulfur to
give the corresponding bis-2-thioxoaminothizole derivatives 11a and b.
Keywords: bis-thiophene; bis-pyrrole; bis-thiazole; bis-pyrrolopyrimidine; bis-thienopyrimidine
1. Introduction
N-Substituted cyanoacetamides are versatile and convenient intermediates for the synthesis
of a wide variety of heterocyclic compounds and their corresponding bis-fused derivatives.
Bis-heterocycles, such as thiophene (1–10), pyrrole (11–15), thiazole (16–20), pyrrolopyrimidine
(21, 22) and thienopyrimidine (23), have received a great deal of attention due to their diverse
biological properties. The present study deals with the effective use of bis N-substituted cyanoac-
etamides in the synthesis of a variety of polyfunctionalized bis-heterocyclic compounds of
biological interest.
2. Results and discussion
Bis-N-substituted cyanoacetamide derivatives 3a and b could be prepared via the reaction of
diamines 1a and b with ethyl cyanoacetate (2a) (24). Compounds 3a and b were explored as
*Corresponding author. Email: elneairy65@yahoo.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2012 Taylor & Francis
http://dx.doi.org/10.1080/17415993.2012.683433
http://www.tandfonline.com

374 M.A.A. Elneairy et al.
starting materials for the present study because of their multiple active sites such as the NH,
=
−
−
≡
C O, active CH2 and C N groups (cf. Scheme 1 and Experimental section).
CN
+
H2N
Z
NH2
Y
1a,b
2a
O
O
2 equiv. 2a,b / S8
S
O
O
S
NH2
H2N
N
Z
N
NC
CN
H
H
N
Z
N
EtONa / EtOH
H
H
NH2
X
H2N
X
3a,b
4a,b
2 equiv. 2a
- 2 H2O
2a / S8
4 equiv.
3b
EtONa / EtOH
EtONa / EtOH
O
O
S
S
N
H
O
O
N
NH2
H2N
Z
N
H
- 2 EtOH
NH2
S
S
N
Z
N
H2N
N
OEt
X
EtO
N
X
N
X
X
CN CN
NC
CN
5a,b
i a,b
Z
4,5
2
Y
X
3
Z
a
b
-CH2-
-CH2-CH2-
CN
COOEt
a
b
c
COOEt
CN
CSNH2
a
b
-CH2-
-CH2-CH2-
Scheme 1. Synthesis of bis-thiophene and bis-thieno[3,2-d]pyrimidinone derivatives.
Compounds 3a and b reacted with active methylene-containing compounds and elemental
sulfur to generate several new interesting bis-heterocyclic compounds. Compound 3a reacted
with two equivalents of 2b and elemental sulfur in basic medium to give the corresponding bis-
thiophene derivative 4a via a Gewald reaction. The IR spectrum of 4a showed the absorption bands
for NH and NH2 at 3464 and 3385 cm−1 and at 3323 cm−1, for CN at 2225 cm−1 and for CO at
1688 cm−1. Its 1H-NMR spectrum revealed the signals for NH (s, 2H, 8.24 ppm) and two NH2 (s,
4H, 2.66 ppm and s, 4H, 2.85 ppm). Consistent with these assignments, these three singlets readily
underwent D2O exchange. Moreover, the mass spectrum gave a peak at m/e = 404 (13.6%) as
anticipated for the molecular ion for 4a. According to the above results, the reaction product was
formulated as 1,3-bis[3,5-diamino-4-cyanothiophen-2-carboxamido]propane (4a).
Following the same steps, 3b reacted with 2a and elemental sulfur to give the corresponding
bis-thiophene derivative 4b. The structure of 4b was elucidated based on elemental analysis and
spectral data as described previously for 4a (cf. Scheme 1 and Experimental section).
The presence of amide NH and NH2 groups at position 3 in the thiophene moiety of 4a and b
provided the opportunity to build up other bis-heterocyclic derivatives. Thus, it has been found that
4a reacted with two equivalents of 2a to give the corresponding bis-thienopyrmidinone derivative
5a.Thestructureof 5a wasdeterminedusingelementalanalysisandspectraldata.TheIRspectrum
of 5a showed absorption bands for NH2 at 3382 cm−1, for CN at 2226 and 2221 cm−1 and for
CO at 1682 cm−1. Its 1H-NMR spectrum revealed signals for NH2 (s, 4H, 2.84 ppm) and CH2CN
(s, 4H, 4.51 ppm). The protons at 2.84 ppm were readily exchanged with D2O consistent with its

Journal of Sulfur Chemistry 375
assignment to the NH2 protons (cf. Scheme 1). On the other hand, the 1H-NMR spectrum did not
exhibit signals assignable to amide NH and NH2 at position 3 consistent with their disappearance
during conversion of 4a to 5a.
The formation of 5a is assumed to proceed via loss of two molecules of water and two molecules
of ethanol through the intermediate ia (Scheme 1). In the same manner, compound 4b reacted
with 2a to give the corresponding bis-thienopyrmidinone derivative 5b. On the other hand, an
authentic sample of compound 5b could be prepared via a direct single-step reaction between 3b
and 4 moles of 2a in the presence of elemental sulfur. Compound 5b prepared via this single-step
route was found completely identical in all aspects to that prepared via the first two-step route
(cf. Scheme 1 and Experimental section).
In contrast to the behavior of 3a and b towards 2a and b and elemental sulfur, compounds 3a
and b reacted with 2c and elemental sulfur to afford the corresponding bis-pyrrole-2(1H)-thione
derivatives 6a and b instead of the expected bis-thiophene derivatives 4c and d (Scheme 2). Thus,
compound 3a reacted with 2c and elemental sulfur in ethanolic sodium ethoxide solution to give
the intermediate (ii) via loss of two molecules of hydrogen sulfide, followed by addition of the
amino group to the nitrile function to afford the bis-pyrrole-2(1H)-thione derivative 6a. The IR
spectrum of 6a showed the absorption bands for NH and NH2 at 3463 and 3457 cm−1 and at
3382 cm−1, for CN at 2226 cm−1, for CO at 1689 cm−1 and for CS at 1548 cm−1. Its 1H-NMR
spectrum revealed the signals for NH (s, 2H, 8.11 ppm), pyrrole NH (s, 2H, 3.88 ppm), NH2 (s,
4H, 4.81 ppm) and pyrrole H-4 (s, 2H, 5.35 ppm). The signals for both NH and NH2 protons were
readily exchanged with D2O. Moreover, the mass spectrum gave a peak at m/e = 418 (12.7%),
consistent with the molecular ion for 6a (cf. Scheme 2).
Scheme 2. Action of cyanothioacetamide and sulfur on bis-N-substituted cyanoacetamide
derivatives.

376 M.A.A. Elneairy et al.
In the same manner, compound 3b reacted with 2c and elemental sulfur to afford the bis-
pyrrolethione derivative 6b. The structure of 6b was also established based on elemental analysis
and spectral data as 6a described previously.
Unequivocal support for the structures of 6a and b came from their reactions with 2c to afford
the corresponding bis-pyrrolopyrimidinone derivatives 7a and b, respectively. The IR spectrum
of 7a showed absorption bands for NH at 3326 cm−1, for CN at 2227 and 2222 cm−1 and for the
CO group at 1689 cm−1. Its 1H-NMR spectrum revealed signals for pyrrole NH (s, 2H, 3.78 ppm),
CH2CN (s, 4H, 4.57 ppm) and pyrrole H-4 (s, 2H, 5.53 ppm). Moreover, the mass spectrum gave
a peak at m/e = 502 (15.9%) as anticipated for the molecular ion for 7a. Authentic samples of
compounds 7a and b could also be prepared by reaction of 3a and b with four equivalents of
2c and elemental sulfur. Compounds 7a and b prepared via this single-step route were found
completely identical in all aspects with 7a and b prepared via the two-step route (cf. Scheme 2).
The presence of the thione group adjacent to the nitrile functions in 7a and b gave the opportu-
nity to study their reactions with different reagents. Thus, compounds 7a and b reacted with two
molecules of methyl iodide to give the corresponding bis-S-methylpyrrolopyrimidine derivatives
8a and b which could be, in turn, reacted with hydrazine hydrate to give sulfur-free reaction
products corresponding to the bis-pyrazolopyrrolopyrimidine derivatives 9a and b through the
intermediate iii (Scheme 3). The formation of 9a and b in this reaction is assumed to proceed
initially by displacement of two molecules of methyl mercaptan followed by a nucleophilic addi-
tion of the hydrazino group to the nitrile function at position 5. The IR spectrum of compound 9a
showed an absorption band corresponding to only one nitrile function, which provided evidence
for the involvement of the nitrile function at position 5 in the cyclization step. Its 1H-NMR spec-
trum revealed signals for NH2 (s, 4H, 8.32 ppm) and CH2CN (s, 4H, 4.27 ppm) (cf. Scheme 3 and
Experimental section).
Additional solid evidence for the structures of 7a and b came from their reactions with
ethyl chloroacetate to afford the corresponding bis-thienopyrrolopyrimidine derivatives 10a
and b through the intermediate ix (Scheme 3). The IR spectrum of 10a showed absorp-
tion bands for NH and NH2 at 3466 and 3383 cm−1, for CN at 2224 cm−1 and for CO at
Scheme 3. Synthesis of bis-pyrazolopyrrolopyrimidinone and bis-thienopyrrolopyrimidinone
derivatives.

Journal of Sulfur Chemistry 377
Scheme 4. Synthesis of bis-(4-amino-2-thioxothiazole) derivatives.
1690 and 1685 cm−1. Its 1H-NMR spectrum revealed signals for NH2 (s, 4H, 6.34 ppm),
NH (s, 2H, 3.86 ppm), CH2CN (s, 4H, 4.71 ppm), CH2CH3 (t, 6H, J = 6 Hz, 1.74 ppm) and
CH2CH3 (q, 4H, J = 6 Hz, 4.22 ppm). Moreover, the mass spectrum gave a peak at m/e =
674 (19.7%) as anticipated for the molecular ion of 10a (cf. Scheme 3 and Experimental
section).
The reaction of compounds 3a and b with two equivalents of phenylisothiocyanate and ele-
mental sulfur in the presence of a basic medium afforded the corresponding bis-thiazolethione
derivatives 11a and b (Scheme 4). The IR spectrum of 11a showed absorption bands for NH
and NH2 at 3465 and 3329 cm−1 and for CO at 1687 cm−1. Its 1H-NMR spectrum revealed sig-
nals for NH (s, 2H, 8.18 ppm) and NH2 (s, 4H, 6.76 ppm). Moreover, the mass spectrum gave
a peak at m/e = 542 (15.4%) as anticipated for the molecular ion of 11a (cf. Scheme 4 and
Experimental section).
3. Experimental
All melting points are uncorrected. IR spectra were recorded as KBr discs on a Shimadzu FTIR-
1
8201PC Spectrophotometer. H-NMR spectra were recorded on Varian Mercury 300 MHz and
Varian Gemini 200 MHz NMRs. Data were collected using TMS as an internal standard and
DMSO-d6 as solvent and chemical shifts are expressed as δ ppm units. Mass spectra were
recorded on a Shemadzu GCMS-QP1000EX using an accelerating voltage of 70 eV. Elemen-
tal analyses were carried out at the Microanalytical Center of Cairo University. Compounds
1,3-diaminopropoane (1a) and 1,4-diaminobutane (1b) were used as purchased from Aldrich.
3.1. Synthesis of bis(2-cyanoacetamido) derivatives 3a and b
General procedure. To 1,3-diaminopropane (1a) (0.074 g, 1 mmol) or 1,4-diaminobutane (1b)
(0.088 g, 1 mmol) ethyl cyanoacetate (2a) was added dropwise (0.22 g, 2 mmol). The reaction
mixture was then stirred at room temperature for 1 h. The solid product that formed in each case
was filtered off, washed with water, dried and purified by recrystallization from ethanol to give
the products as colorless crystals.
3.1.1. 1,3-Bis(2-cyanoacetamido)propane (3a)
With the use of the general procedure 1a and 2a gave crude 3a (88%); mp 158–160 ◦C; IR (KBr)
ν (cm−1): 3456 (NH), 2223 (CN), 1686 (CO); 1H NMR (DMSO-d6): δ 1.51 (quintet, J = 6 Hz,
2H, NCH2CH2CH2N), 3.04 (t, J = 6 Hz, 4H, NCH2CH2CH2N), 3.36 (s, 4H, 2 CH2CN), 8.18 (s,
2H, 2 NH, D2O-exchangeable); MS: m/z (%) 208 (M+, 21.7), 174 (10.5), 150 (24.4), 138 (15.7),
121 (100), 78 (41.6), 60 (53.8); C9H12N4O2: Anal. Calcd: C, 51.92; H, 5.81; N, 26.91. Found C,
51.95; H, 5.78; N, 26.87%.

378 M.A.A. Elneairy et al.
3.1.2. 1,4-Bis(2-cyanoacetamido)butane (3b)
With the use of the general procedure 1b and 2a gave crude 3b (83%); mp 148–150◦C; IR
1
(KBr) ν (cm−1): 3450 (NH), 2222 (CN), 1688 (CO); H NMR (DMSO-d6): δ 1.53 (brs, 4H,
NCH2CH2CH2CH2N), 3.14 (brs, 4H, NCH2CH2CH2CH2N), 3.32 (s, 4H, 2 CH2CN), 8.14 (s,
2H, 2 NH, D2O-exchangeable); MS: m/z (%) 222 (M+, 23.1), 178 (12.3), 155 (20.1), 139 (14.7),
125 (100), 77 (32.7), 60 (43.7); C10H14N4O2: Anal. Calcd: C, 54.04; H, 6.35; N, 25.21. Found C,
54.02; H, 6.38; N, 25.17%.
3.2. Synthesis of bis(thiophene) derivatives 4a and b, bis(5-thioxo-1H-pyrrole) derivatives
6a and b and bis(2-thioxo-thiazole) derivatives 11a and b
General procedure. To a solution of compound 3a or 3b (1 mmol) in an ethoxide mix-
ture (ethanol (10 ml)/Na (0.046 g, 2 mmol) were added either malononitrile (2b) (0.132 g,
2 mmol), ethylcyanoacetate (2a) (0.226 g, 2 mmol), cyanoethanethioamide (2c) (0.20 g, 2 mmol)
or phenylisothiocyanate (0.26 g, 2 mmol) together with elemental sulfur (0.064 g, 2 mmol). The
whole reaction mixture was heated under reflux for 4 h, then poured onto an ice/water mixture
and the formed solid product, in each case, was collected by filtration.
3.2.1. 1,3-Bis[3,5-diamino-4-cyanothiophen-2-carboxamido]propane (4a)
With the use of the general procedure 3a and 2b gave crude 4a which crystallized from
DMF/acetic acid mixture as yellow crystals (64%); mp 212–214◦C; IR (KBr) ν (cm−1): 3464,
3385, 3323 (NH, NH2), 2225 (CN), 1688 (CO); 1H NMR (DMSO-d6): δ 1.56 (quintet, J = 6 Hz,
2H, NCH2CH2CH2N), 2.66 (s, 4H, 2 NH2, D2O-exchangeable), 2.85 (s, 4H, 2 NH2, D2O-
exchangeable), 3.16 (t, J = 6 Hz, 4H, NCH2CH2CH2N), 8.24 (s, 2H, 2 NH, D2O-exchangeable);
13C NMR (DMSO-d6): δ 27.81, 42.32, 115.68, 131.15, 140.36, 151.80, 165.60, 170.13; MS: m/z
(%) 404 (M+,13.6), 378 (12.7), 337 (19.1), 214 (13.5), 157 (17.3), 125 (43.2), 64 (100), 55 (42.2);
C15H16N8O2S2: Anal. Calcd: C, 44.54; H, 3.99; N, 27.70; S, 15.86. Found: C, 44.51; H, 4.02; N,
27.72; S, 15.53%.
3.2.2. 1,4-Bis[2,4-diamino-3-ethoxycarbonylthiophen-5-carboxamido]butane (4b)
With the use of the general procedure 3b and 2a gave crude 4b which crystallized
from acetic acid as yellow crystals (55%); mp 230–232◦C; IR (KBr) ν (cm−1): 3464,
3383, 3324 (NH, NH2), 1692, 1686 (CO); 1H NMR (DMSO-d6): δ 1.53 (brs, 4H,
NCH2CH2CH2CH2N), 1.82 (brs, 6H, 2 CH2CH3), 3.23 (brs, 4H, NCH2CH2CH2CH2N),
3.57 (brs, 4H, 2 NH2, D2O-exchangeable), 4.33 (brs, 4H, 2 CH2CH3), 7.37 (brs, 4H, 2
NH2, D2O-exchangeable), 7.84 (s, 2H, 2 NH, D2O-exchangeable); 13C NMR (DMSO-d6):
δ 13.98, 27.83, 42.33, 59.24, 105.31, 130.47, 141.96, 159.70, 165.66, 169.05; MS: m/z (%) 512
(M+,16.3), 487 (17.9), 417 (15.3), 294 (14.4), 244 (16.7), 188 (20.2), 178 (21.5), 125 (29.1),
119 (36.5), 97 (43.5), 74 (30.2), 64 (100); C20H28N6O6S2: Anal. Calcd: C, 46.86; H, 5.51; N,
16.39; S, 12.51. Found: C, 46.83; H, 5.47; N, 16.42; S, 12.48%.
3.2.3. 1,3-Bis[2-amino-4-cyano-5-thioxo-4,5-dihydro-1H-pyrrol-3-carboxamido]propane (6a)
With the use of the general procedure, 3a and 2c gave crude 6a which crystallized from acetic
acid as yellow crystals (55%); mp 202–204◦C; IR (KBr) ν (cm−1): 3463, 3457, 3382 (NH,
NH2), 2226 (CN), 1689 (CO), 1548 (CS); 1H NMR (DMSO-d6): δ 1.67 (quintet, J = 6 Hz, 2H,

Journal of Sulfur Chemistry 379
NCH2CH2CH2N), 3.28 (t, J = 6 Hz, 4H, NCH2CH2CH2N), 3.96 (s, 2H, 2 pyrrole NH, D2O-
exchangeable), 4.73 (s, 4H, 2 NH2, D2O-exchangeable), 5.64 (s, 2H, 2 pyrrole H-4,), 8.02 (s, 2H,
2 NH, D2O-exchangeable); 13C NMR (DMSO-d6): δ 27.80, 42.31, 45.23, 86.76, 115.69, 163.26,
167.89, 193.51; MS: m/z (%) 404 (M+,17.3), 388 (14.2), 362 (17.0), 245 (12.7), 227 (16.6),
167 (15.1), 121 (76.8), 97 (28.5), 77 (42.0), 70 (50.2), 64 (100); C15H16N8O2S2: Anal. Calcd: C,
44.54; H, 3.99; N, 27.70; S, 15.86. Found: C, 44.51; H, 4.03; N, 27.66; S, 15.88%.
3.2.4. 1,4-Bis[2-amino-4-cyano-5-thioxo-4,5-dihydro-1H-pyrrol-3-carboxamido]butane (6b)
With the use of the general procedure 3b and 2c gave crude 6b which crystallized from acetic acid
as yellow crystals (59%); mp 224–226◦C; IR (KBr) ν (cm−1): 3464, 3457, 3384 (NH, NH2), 2223
(CN), 1687 (CO), 1541 (CS); 1H NMR (DMSO-d6): δ 1.57 (brs, 4H, NCH2CH2CH2CH2N), 3.19
(brs, 4H, NCH2CH2CH2CH2N), 3.88 (s, 2H, 2 pyrrole NH, D2O-exchangeable), 4.81 (s, 4H, 2
NH2, D2O-exchangeable), 5.35 (s, 2H, 2 pyrrole H-4,), 8.11 (s, 2H, 2 NH, D2O-exchangeable);
13C NMR (DMSO-d6): δ 26.15, 42.35, 45.22, 86.76, 115.68, 163.32, 167.87, 193.63; MS: m/z
(%) 418 (M+,12.7), 391 (12.4), 360 (14.5), 247 (18.7), 227 (15.9), 169 (13.1), 125 (46.3), 97
(24.5), 77 (32.6), 70 (40.2), 64 (67.7), 55 (100); C16H18N8O2S2: Anal. Calcd: C, 45.92; H, 4.34;
N, 26.78; S, 15.32. Found: C, 45.88; H, 4.36; N, 26.80; S, 15.28%.
3.2.5. 1,3-Bis[4-amino-3-phenyl-2-thioxo-2,3-dihydrothiazol-5-carboxamido]propane (11a)
With the use of the general procedure, 3a and phenylisothiocyanate gave crude 11a which crystal-
lized from acetic acid as yellow crystals (55%); mp 312–314◦C; IR (KBr) ν (cm−1): 3465, 3329
(NH2, NH), 1687 (CO); 1H NMR (DMSO-d6): δ 1.60 (quintet, J = 6 Hz, 2H, NCH2CH2CH2N),
3.08 (t, J = 6 Hz, 4H, NCH2CH2CH2N), 6.76 (s, 4H, 2 NH2, D2O-exchangeable), 7.07–7.70 (m,
10H, ArH), 8.18 (s, 2H, 2 NH, D2O-exchangeable); MS: m/z (%) 542 (M+,15.4), 436 (11.4), 395
(16.4), 245 (12.1), 188 (21.3), 178 (24.1), 125 (32.2), 117 (26.7), 97 (32.7), 77 (31.5), 64 (100),
55 (76.5); C23H22N6O2S4: Anal. Calcd: C, 50.90; H, 4.09; N, 15.49; S, 23.63. Found: C, 50.94;
H, 4.13; N, 15.46; S, 23.61%.
3.2.6. 1,4-Bis[4-amino-3-phenyl-2-thioxo-2,3-dihydrothiazol-5-carboxamido]butane (11b)
With the use of the general procedure, 3b and phenylisothiocyanate gave crude 11b
which crystallized from acetic acid as yellow crystals (58%); mp 306–308◦C; IR (KBr)
ν (cm−1): 3463, 3326 (NH2, NH), 1689 (CO);1H NMR (DMSO-d6): δ 1.48 (brs, 4H,
NCH2CH2CH2CH2N), 3.21 (brs, 4H, NCH2CH2CH2CH2N), 6.64 (s, 4H, 2 NH2, D2O-
exchangeable), 7.11–7.74 (m, 10H, ArH), 8.11 (s, 2H, 2 NH, D2O-exchangeable); MS:
m/z (%) 556 (M+,12.1), 485 (15.3), 443 (18.4), 397 (18.4), 244 (15.1), 187 (24.3), 177
(23.1), 121 (32.7), 119 (24.7), 97 (32.7), 77 (31.5), 60 (100), 55 (56.5); C24H24N6O2S4:
Anal. Calcd: C, 51.78; H, 4.34; N, 15.09; S, 23.04. Found: C, 51.74; H, 4.31; N, 15.06;
S, 23.07%.
3.3. Synthesis of bis(thieno[3,2-d]pyrimidine) derivatives 5a and b and bis(pyrrolo[2,3-d]-
pyrimidine) derivatives 7a and b
General procedure: Method (A): To a solution of compounds 4a (1 mmol) or 4b (1 mmol) and
6a (1 mmol) and 6b (1 mmol) in an ethoxide mixture (ethanol (10 ml)/Na (0.046 g, 2 mmol),
ethylcyanoacetate (2a) (0.226 g, 2 mmol) or cyanoethanethioamide (2c) (0.20 g, 2 mmol) was

380 M.A.A. Elneairy et al.
added. The whole reaction mixture was heated under reflux for 4 h, then poured onto an ice/water
mixture and the formed solid product, in each case, was collected by filtration.
Method (B): To a solution of 3a or 3b (1 mmol) in an ethoxide mixture (ethanol (10 ml)/Na
(0.046 g, 2 mmol), ethyl cyanoacetate (2a) (0.45 g, 4 mmol) or cyanoethane-thioamide (2c)
(0.40 g, 4 mmol) together with elemental sulfur (0.064 g, 2 mmol) was added. The reaction mix-
ture was heated under reflux for 5 h, then poured onto ice/water and the solid product, in each
case, was collected by filtration.
3.3.1. 1,3-Bis[6-amino-7-cyano-2-(cyanomethyl)-4-oxo-3,4-dihydrothieno[3,2-d]-
pyrimidin-3-yl]propane (5a)
With the use of the general procedure, 4a and 2a gave crude 5a which crystallized from acetic
acid as white crystals (50%); mp above 320◦C; IR (KBr) ν (cm−1): 3382 (NH2), 2226, 2221 (CN),
1682 (CO);1H NMR (DMSO-d6): δ 1.55 (quintet, J = 6 Hz, 2H, NCH2CH2CH2N), 2.84 (s, 4H,
2 NH2, D2O-exchangeable), 3.13 (t, J = 6 Hz, 4H, NCH2CH2CH2N), 4.51 (s, 4H, 2 CH2CN);
MS: m/z (%) 502 (M+,11.3), 244 (13.2), 222 (14.5), 147 (100), 125 (21.4), 117 (14.3), 65 (41.3),
60 (63.7); C21H14N10O2S2: Anal. Calcd: C, 50.19; H, 2.81; N, 27.87; S, 12.76. Found: C, 50.16;
H, 2.77; N, 27.89; S, 12.73%.
3.3.2. 1,4-Bis[6-amino-2-(cyanomethyl)-7-ethoxycarbonyl-4-oxo-3,4-dihydrothieno-
[3,2-d]pyrimidin-3-yl]butane (5b)
With the use of the general procedure, 4b and 2a (MethodA) or 3b and 2a (Method B) gave crude
5b which crystallized from DMF/acetic acid mixture as yellow crystals (53%); mp above 320◦C;
IR (KBr) ν (cm−1): 3387 (NH2), 2223 (CN), 1691, 1689 (CO);1H NMR (DMSO-d6): δ 1.52 (brs,
4H, NCH2CH2CH2CH2N), 1.87 (brs, 6H, 2 CH2CH3), 3.24 (brs, 4H, NCH2CH2CH2CH2N), 3.51
(brs, 4H, 2 NH2, D2O-exchangeable), 4.28 (brs, 4H, 2 CH2CH3), 4.76 (s, 4H, 2 CH2CN); MS:
m/z (%) 610 (M+,14.3), 563 (28.3), 207 (39.1), 175 (41.5), 133 (42.1), 119 (39.7), 92 (41.6), 77
(33.2), 54 (100); C26H26N8O6S2: Anal. Calcd: C, 51.14; H, 4.29; N, 18.35; S, 10.50. Found: C,
51.11; H, 4.31; N, 18.39; S, 10.47%.
3.3.3. 1,3-Bis[5-cyano-2-(cyanomethyl)-4-oxo-6-thioxo-4,5,6,7-tetrahydro-3H-pyrrolo-
[2,3-d]pyrimidin-3-yl]propane (7a)
With the use of the general procedure, 6a and 2c (Method A) or 3a and 2c (Method B) gave crude
7a which crystallized from DMF/acetic acid mixture as yellow crystals (50%); mp 302–304◦C;
1
IR (KBr) ν (cm−1): 3326 (NH), 2227, 2222 (CN), 1689 (CO); H NMR (DMSO-d6): δ 1.63
(quintet, J = 6 Hz, 2H, NCH2CH2CH2N), 3.24 (t, J = 6 Hz, 4H, NCH2CH2CH2N), 3.78 (s, 2H,
2 pyrrole NH, D2O-exchangeable), 4.57 (s, 4H, 2 CH2CN), 5.53 (s, 2H, 2 pyrrole H-4); 13C
NMR (DMSO-d6): δ 21.82, 30.72, 41.50, 45.82, 103.71, 115.84, 116.19, 156.01, 156.86, 163.11,
194.05; MS: m/z (%) 502 (M+,15.9), 448 (13.6), 382 (11.3), 154 (21.0), 143 (18.2), 135 (40.3),
120 (42.6), 119 (58.7), 107 (25.2), 91 (31.2), 77 (43.5), 64 (45.6), 54 (100); C21H14N10O2S2:Anal.
Calcd: C, 50.19; H, 2.81; N, 27.87; S, 12.76. Found: C, 50.21; H, 2.79; N, 27.84; S, 12.80%.
3.3.4. 1,4-Bis[5-cyano-2-(cyanomethyl)-4-oxo-6-thioxo-4,5,6,7-tetrahydro-3H-pyrrolo-
[2,3-d]pyrimidin-3-yl]butane (7b)
With the use of the general procedure, 6b and 2c (MethodA) or 3b and 2c (Method B) gave crude
7b which crystallized from DMF/acetic acid mixture as yellow crystals (53%); mp 266–268◦C;

Journal of Sulfur Chemistry 381
1
IR (KBr) ν (cm−1): 3324 (NH), 2226, 2222 (CN), 1686 (CO); H NMR (DMSO-d6): δ 1.56
(brs, 4H, NCH2CH2CH2CH2N), 3.11 (brs, 4H, NCH2CH2CH2CH2N), 3.88 (s, 2H, 2 pyrrole NH,
D2O-exchangeable), 4.51 (s, 4H, 2 CH2CN), 5.46 (s, 2H, 2 pyrrole H-4); 13C NMR (DMSO-d6):
δ 21.24, 27.83, 42.31, 46.23, 101.56, 115.79, 116.10, 156.12, 156.94, 161.87, 193.41; MS: m/z
(%) 516 (M+,13.2), 446 (11.2), 377 (14.3), 156 (11.8), 144 (13.5), 135 (23.4), 123 (32.4), 119
(38.4), 103 (22.5), 91 (41.2), 77 (42.1), 64 (100); C22H16N10O2S2:Anal. Calcd: C, 51.15; H, 3.12;
N, 27.12; S, 12.41. Found: C, 51.11; H, 3.09; N, 27.14; S, 12.44%.
3.4. Synthesis of bis(6-methylthiopyrrolo[2,3-d]pyrimidine) derivatives 8a and b and
bis(thieno-[2ꢀ,3ꢀ:5,4]pyrrolo[2,3-d]pyrimidine) derivatives 10a and b
General procedure. To a solution of 7a or 7b (1 mmol) in an ethoxide mixture (ethanol (10 ml)/Na
(0.046 g, 2 mmol) was added methyl iodide (0.28 g, 2 mmol) or ethyl chloroacetate (0.24 g,
2 mmol). The reaction mixture was heated under reflux for 6 h, then poured onto an ice/water
mixture and the solid product, in each case, was collected by filtration.
3.4.1. 1,3-Bis[5-cyano-2-(cyanomethyl)-4-oxo-6-(methylthio)-4,5-dihydro-3H-pyrrolo-
[2,3-d]pyrimidin-3-yl]propane (8a)
With the use of the general procedure, 7a and methyl iodide gave crude 8a which crystallized
from acetic acid as yellow crystals (53%); mp above 320◦C; IR (KBr) ν (cm−1): 3327 (NH), 2228,
2222 (CN), 1692 (CO); 1H NMR (DMSO-d6): δ 1.53 (quintet, J = 6 Hz, 2H, NCH2CH2CH2N),
2.64 (s, 6H, 2 SCH3), 3.21 (t, J = 6 Hz, 4H, NCH2CH2CH2N), 3.88 (s, 2H, 2 pyrrole NH,
D2O-exchangeable),4.62 (s, 4H, 2 CH2CN); MS: m/z (%) 530 (M+,14.2), 433 (21.5), 157
(23.2), 143 (17.2), 137 (41.7), 125 (72.4), 119 (62.4), 105 (23,6), 91 (34.2), 77 (100), 64 (47.5);
C23H18N10O2S2: Anal. Calcd: C, 52.06; H, 3.42; N, 26.40; S, 12.09. Found: C, 52.03; H, 3.44;
N, 26.42; S, 12.06%.
3.4.2. 1,4-Bis[5-cyano-2-(cyanomethyl)-4-oxo-6-(methylthio)-4,5-dihydro-3H-pyrrolo-
[2,3-d]pyrimidin-3-yl]butane (8b)
With the use of the general procedure, 7b and methyl iodide gave crude 8b which crystallized from
acetic acid as yellow crystals (56%); mp above 320◦C; IR (KBr) ν (cm−1): 3324 (NH), 2227, 2223
(CN), 1690 (CO); 1H NMR (DMSO-d6): δ 1.51 (brs, 4H, NCH2CH2CH2CH2N), 2.72 (s, 6H, 2
SCH3), 3.17 (brs, 4H, NCH2CH2CH2CH2N), 3.72 (s, 2H, 2 pyrrole NH, D2O-exchangeable),4.54
(s, 4H, 2 CH2CN); MS: m/z (%) 544 (M+,16.9), 435 (26.5), 154 (27.2), 141 (19.2), 137 (31.3),
126 (42.5), 118 (52.1), 101 (24,2), 95 (31.2), 77 (100), 64 (37.2); C24H20N10O2S2: Anal. Calcd:
C, 52.93; H, 3.70; N, 25.72; S, 11.78. Found: C, 52.89; H, 3.74; N, 25.69; S, 11.76%.
3.4.3. 1,3-Bis[5-amino-2-(cyanomethyl)-6-ethoxycarbonyl-4-oxo-4H-thieno[2ꢀ, 3ꢀ:5,4]-
pyrrolo[2,3-d]pyrimidin-3-yl]propane (10a)
Withtheuseofthegeneralprocedure, 7a andethylchloroacetategavecrude 10a whichcrystallized
from acetic acid as yellow crystals (54%); mp 294–296◦C; IR (KBr) ν (cm−1): 3466, 3383
(NH, NH2), 2224 (CN), 1690, 1685 (CO); 1H NMR (DMSO-d6): δ 1.61 (quintet, J = 6 Hz, 2H,
NCH2CH2CH2N), 1.74 (t, 6H, J = 6 Hz, 2 CH2CH3), 3.23 (t, J = 6 Hz, 4H, NCH2CH2CH2N),
3.86 (s, 2H, 2 pyrrole NH, D2O-exchangeable), 4.22 (q, J = 6 Hz, 4H, 2 CH2CH3), 4.71 (s, 4H,
2 CH2CN), 6.34 (s, 4H, 2 NH2, D2O-exchangeable); MS: m/z (%) 674 (M+,19.7), 642 (12.6),
567 (14.3), 154 (24.7), 143 (13.2), 135 (41.3), 125 (64.5), 119 (61.3), 107 (25.4), 97 (41.4), 77

382 M.A.A. Elneairy et al.
(52.4), 64 (100); C29H26N10O6S2: Anal. Calcd: C, 51.62; H, 3.88; N, 20.76; S, 9.50. Found: C,
51.58; H, 3.85; N, 20.74; S, 9.53%.
3.4.4. 1,4-Bis[5-amino-2-(cyanomethyl)-6-ethoxycarbonyl-4-oxo-4H-thieno[2ꢀ, 3ꢀ:5,4]-
pyrrolo[2,3-d]pyrimidin-3-yl]butane (10b)
Withtheuseofthegeneralprocedure, 7bandethylchloroacetategavecrude 10bwhichcrystallized
from acetic acid as yellow crystals (51%); mp 278–280◦C; IR (KBr) ν (cm−1): 3464, 3383 (NH,
NH2), 2223(CN), 1690, 1687(CO);1H NMR(DMSO-d6):δ 1.48(brs, 4H, NCH2CH2CH2CH2N),
1.83 (brs, 6H, 2 CH2CH3), 3.08 (brs, 4H, NCH2CH2CH2CH2N), 3.68 (s, 2H, 2 pyrrole NH,
D2O-exchangeable), 4.14 (brs, 4H, 2 CH2CH3), 4.78 (s, 4H, 2 CH2CN), 6.43 (s, 4H, 2 NH2,
D2O-exchangeable); MS: m/z (%) 688 (M+,13.6), 644 (13.7), 567 (15.3), 154 (24.7), 147 (16.2),
137 (31.2), 125 (55.3), 119 (58.2), 101 (23.4), 97 (31.2), 77 (42.4), 64 (100); C30H28N10O6S2:
Anal. Calcd: C, 52.32; H, 4.10; N, 20.34; S, 9.31. Found: C, 52.28; H, 4.13; N, 20.31; S, 9.33%.
3.5. Bis(pyrazolo[3,4-d]pyrrolo[2,3-d]pyrimidine) derivatives 9a and b
General procedure.A solution of compounds 8a and b (1 mmol) in hydrazine 80% (5 ml)/ethanol
(5 ml) mixture was heated under reflux for 4 h, then poured onto ice/water and the solid products
were collected by filtration.
3.5.1. 1,3-Bis[5-amino-2-(cyanomethyl)-4-oxo-4H-pyrazolo[3ꢀ, 4ꢀ:5,4]pyrrolo[2,3-d]-
pyrimidin-3-yl]propane (9a)
With the use of the general procedure, 8a gave crude 9a which crystallized from acetic acid as
yellow crystals (58%); mp 142–144◦C; IR (KBr) ν (cm−1): 3466 (NH2), 2222 (CN), 1684(CO);
1H NMR (DMSO-d6): δ 1.54 (quintet, J = 6 Hz, 2H, NCH2CH2CH2N), 3.14 (t, J = 6 Hz, 4H,
NCH2CH2CH2N), 4.27 (s, 4H, 2 CH2CN), 8.32 (s, 4H, 2 NH2, D2O-exchangeable); MS: m/z (%)
494 (M+,17.5), 452 (16.9), 437 (16.6), 337 (23.5), 281 (22.7), 177 (21.5), 152 (27.5), 140 (21.3),
125 (32.1), 121 (43.9), 90 (15.2), 88 (31.7), 64 (32.5), 55 (100); C21H14N14O2: Anal. Calcd: C,
51.01; H, 2.85 ; N, 39.66. Found:. C, 50.99; H, 2.82; N, 39.63%.
3.5.2. 1,4-Bis[5-amino-2-(cyanomethyl)-4-oxo-4H-pyrazolo[3ꢀ, 4ꢀ:5,4]pyrrolo[2,3-d]-
pyrimidin-3-yl]butane (9b)
With the use of the general procedure, 8b gave crude 9b which crystallized from acetic acid as
yellowcrystals(64%);mp166–168◦C;IR(KBr)ν (cm−1):3464(NH2), 2222(CN), 1686(CO);1H
NMR (DMSO-d6): δ 1.55 (brs, 4H, NCH2CH2CH2CH2N), 3.12 (brs, 4H, NCH2CH2CH2CH2N),
4.23 (s, 4H, 2 CH2CN), 8.18 (s, 4H, 2 NH2, D2O-exchangeable); MS: m/z (%) 508 (M+,13.3),
487 (16.9), 455 (14.5), 437 (12.7), 335 (21.5), 283 (20.3), 177 (23.4), 155 (24.5), 143 (22.3), 125
(35.1), 121 (43.9), 94 (12.1), 86 (29.6), 64 (100), 55 (33.6); C22H16N14O2: Anal. Calcd: C, 51.97;
H, 3.17 ; N, 38.57. Found:. C, 52.01; H, 3.14; N, 38.53%.
References
(1) Molvi, K.I.; Vasu, K.K.; Yerande, S.G.; Sudarsanam, V.; Haque, N. Eur. J. Med. Chem. 2007, 42, 1049–1058.
(2) Asthalatha, B.V.; Narayana, B.; Vijaya Raj, K.K.; Kumari, N.S. Eur. J. Med.Chem. 2007, 42, 719–728.
(3) Rai, N.S.; Kalluraya, B.; Lingappa, B.; Shenoy, S.; Puranic, V.G. Eur. J. Med.Chem. 2008, 43, 1715–1720.
(4) Arroyo, S.; Salas-Puig, J. Rev. Neurol. 2001, 32, 1041–1043.

Journal of Sulfur Chemistry 383
(5) Noguchi, H.; Kitazumi, K.; Mori, M.; Shiba, T. J. Pharm. Sci. 2004, 94, 246–251.
(6) Lankau, H.J.; Unverferth, K.; Grunwald, C.; Hartenhauer, H.; Heinecke, K.; Bernoster, K.; Dost, R.; Egerland, U.;
Rundfeldt, C. Eur. J. Med. Chem. 2006, 41, 1–6.
(7) Ragavendran, J.V.; Sriram, D.; Patil, S.; Reddy, I.V.; Bharathwajan, N.; Stables, J.;Yogeeswari, P. Eur. J. Med. Chem.
2007, 42, 146–151.
(8) Yogeeswari, P.; Thirumurugan, R.; Kavya, R.; Samuel, J.S.; Stables, J.; Sriram, D. Eur. J. Med. Chem. 2004, 39,
729–734.
(9) Gunizkuculguzel, S.; Mazi, A.; Sahin, F.; Qzturk, S.; Stables, J. Eur. J. Med. Chem. 2003, 38, 1005–1013.
(10) Thirumurugan, R.; Sriram, D.; Saxena, A.; Stables, J.; Yogeeswari, P. Bioorg. Med.Chem. 2006, 14, 3106–3112.
(11) El-Gaby, M. S. A.; Gaber, A. M.; Atalla, A. A.; Abd Al-Wahab, K. A. Farmaco. 2002, 55, 613.
(12) Raimondi, M. V.; Cascioferro, S.; Schillaci, D.; Petruso, S. Eur. J. Med. Chem. 2006, 41, 1439–1445.
(13) Rochais, C.; Lisowski, V.; Dallemagne, P.; Rault, S. Bioorg. Med. Chem. 2006, 14, 8162–8175.
(14) Bijev, A. Lett. Drug Des. Discovery 2008, 5, 15–24.
(15) Zakharova, O. D.; Baranova, S.; Parissi, V.; Ryabinin, V.A.; Sinyakov, A.N.; Litvak, S.; Litvak, L.T.; Nevinsky, G.A.
J. Pept. Res. 2005, 66 (Suppl. 1), 138–145.
(16) Quiroga, J.; Hernandez, P.; Insuassty, B.R.; Abonia, R.; Cobo, J.; Sanchez, A.; Nogueras, M.; Low, J.N. J. Chem.
Soc., Perkin Trans. 2002, 1, 555–559.
(17) Hutchinson, I.; Jennings, S.A.; Vishnuvajjala, B.R.; Westwell, A.D.; Stevens, M.F.G. J. Med. Chem. 2002, 45,
744–747.
(18) Abdel-latif, E.; Bondock, S. Heteroatom Chem. 2006, 17, 299–305.
(19) El-desoky, S.I.; Bondock, S.B.; Etman, H.A.; Fadda, A.A.; Metwally, M.A. Sulfur Lett. 2003, 26, 127–135.
(20) El-desoky, S.I.; Etman, H.A.; Bondock, S.B.; Fadda, A.A.; Metwally, M.A. Sulfur Lett. 2002, 25, 199–205.
(21) Dang, Q.; Gomez-Galeno, J.E. J. Org. Chem. 2002, 67, 8703–8705.
(22) Gangjee, A.; Lin, X.; Queener, S.F. J. Med. Chem. 2004, 47, 3689–3692.
(23) El-Gaby, M.S.A.E.-A.; Abdel-Hamide, S.G.; Ghorab, M.M.; El-Sayed, S.M. Acta Pharm. 1999, 49, 149–158.
(24) Wang, K.; Nguyen, K.; Huang, Y.; Dömling, A. J. Comb. Chem. 2009, 11, 920–927.