Synthesis and antimicrobial activity of thioxopyrimidines and related derivatives

This article was downloaded by: [Memorial University of Newfoundland]

On: 23 November 2014, At: 00:52

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

Phosphorus, Sulfur, and Silicon

and the Related Elements

Publication details, including instructions for

authors and subscription information:

http://ww w .tandfonline.com/loi/gpss20

Synthesis and Antimicrobial

Activity of Thioxopyrimidines

and Related Derivatives

Ahmed M. El-Agrody ^a, Fawzy M. Ali ^a, Fathy A. Eid

^a, Mohammed A. A. El-Nassag ^a, Gamal El-Sherbeny

^b& Ahmed H. Bedair ^a

^aDepartment of Chemistry , Al-Azhar University ,

Nasr City, Cairo, Egypt

^bDepartment of Botany and Microbiology , Al-Azhar

University , Nasr City, Cairo, Egypt

Published online: 15 Aug 2006.

To cite this article: Ahmed M. El-Agrody , Fawzy M. Ali , Fathy A. Eid , Mohammed

A. A. El-Nassag , Gamal El-Sherbeny & Ahmed H. Bedair (2006) Synthesis

and Antimicrobial Activity of Thioxopyrimidines and Related Derivatives,

Phosphorus, Sulfur, and Silicon and the Related Elements, 181:4, 839-864, DOI:

10.1080/10426500500272087

To link to this article: http://dx.doi.org/10.1080/10426500500272087

PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of all the

information (the “Content”) contained in the publications on our platform.

However, Taylor & Francis, our agents, and our licensors make no

representations or warranties whatsoever as to the accuracy, completeness,

or suitability for any purpose of the Content. Any opinions and views

expressed in this publication are the opinions and views of the authors, and

are not the views of or endorsed by Taylor & Francis. The accuracy of the

Content should not be relied upon and should be independently verified with

primary sources of information. Taylor and Francis shall not be liable for any

losses, actions, claims, proceedings, demands, costs, expenses, damages,

and other liabilities whatsoever or howsoever caused arising directly or

indirectly in connection with, in relation to or arising out of the use of the

Content.

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. Terms & Conditions of access and use can be found at

http://www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur, and Silicon, 181:839–864, 2006

ISSN: 1042-6507 print / 1563-5325 online

DOI: 10.1080/10426500500272087

Synthesis and Antimicrobial Activity

of Thioxopyrimidines and Related Derivatives

Ahmed M. El-Agrody

Fawzy M. Ali

Fathy A. Eid

Mohammed A. A. El-Nassag

Department of Chemistry, Al-Azhar University, Nasr City, Cairo, Egypt

Gamal El-Sherbeny

Department of Botany and Microbiology, Al-Azhar University, Nasr City,

Cairo, Egypt

Ahmed H. Bedair

Department of Chemistry, Al-Azhar University, Nasr City, Cairo, Egypt

The interaction of thiourea with activated cyanooleﬁns under different reaction

conditions were studied, in which a variety of thiopyrimidines (8, 9, 12, 18, 20, &

21) and related derivatives (10, 11, 14, 16, & 17) were obtained respectively. Also,

the reactions of thiopyrimidines (8, 9) with different electrophilic and nucleophilic

1

13

reagents were reported. IR, H NMR, C NMR and mass spectra for the newly syn-

thesized compounds were studied. Most of the obtained compounds were screened

against Gram-postive and Gram-negative bacteria and fungi, for which some of

these derivatives gave promising results.

Keywords Activated nitriles; antimicrobial activities; (1H-pyrazol-1-yl)pyrimidine;

[(pyrimidin-2-yl)disulfanyl] pyrimidine; thiourea; thioxopyrimidines

INTRODUCTION

The importance of the pyrimidine nucleus is well established in the ﬁeld

of pharmaceutical chemistry and biochemistry.¹⁻³The pyrimidine-2-

thiol moiety is present in several compounds of biological and medicinal

interest.⁴⁻⁸

Received January 12, 2005; accepted April 7, 2005.

Address correspondence to Ahmed H. Bedair, Al-Azhar University, Department

of Chemistry, Faculty of Science, Nasr City, Cairo 11884, Egypt. E-mail:bedair AH@

yahoo.com

839

840

A. M. El-Agrody et al.

Pyrimidine-5-carboxamides of type (1) are reported to possess an-

ticarcinogenic activity.⁹Antiinﬂammatory,^10,11analgesic, and blood

platelet aggregation inhibitory activity¹²was found in a number

of derivatives. 1,4-Dihydropyrimidines (2) (Scheme 1) is useful as

a platelet-activating factor antagonist.¹³Also, the 1,4-dihydropyri-

midines have many biological activities. For example, they represent

the largest and most studied class of organic calcium channel blockers

widely used in the management of angina pectoris and hypertension as

some 1,4-dihydropyrimidine (e.g., Nifedipine).¹⁴

SCHEME 1

RESULTS AND DISCUSSION

The readily available cyanooleﬁns are a class of important organic syn-

thones having exciting chemistry.¹⁵⁻¹⁷The obvious route to pyrimidine-

5-carbonitriles is primary synthesis followed by the removal or modiﬁ-

cation of unwanted groups, e.g., ethoxymethylenemalononitrile (3) and

thiourea give 4-amino-2-thioxo-1,2-dihydropyrimidine-5-carbonitrile

(4),^18,19(Scheme 2) which can be desulfurized, S-alkylated, N-acety-

lated, or hydrolyzed to 5-cyanocytosine without affecting the cyano

group.

SCHEME 2

So, we felt it would be valuable to investigate the addition of thiourea

to activated nitriles (5–7),^20,21(Scheme 3) which was previously inten-

sively investigated.²²⁻³³

Thus, the piperidine-catalyzed addition of 5 with thiourea in

boiling abs. ethanol gave two reaction products as 4-amino-1,2-

dihydro-2-thioxo-6-(aryl)pyrimidine-5-carbonitrile (8a,b) and 4-amino-

Thioxopyrimidines and Related Derivatives

841

SCHEME 3

2-mercapto-6-(4-methoxyphenyl)pyrimidine-5-carbonitrile (9), respec-

tively (Scheme 4).

SCHEME 4 Synthesis of 8a,b,9, 10a,b & 11 reagents and conditions: (i) piperi-

dine, boiled EtOH, 4 h, 35–57% yield; (ii) Anh. K₂CO₃, boiled EtOH, 4 h 12–14%

yield.

The structures of 8a,b and 9 have been fully characterized by IR, ¹H

NMR, ¹³C NMR, mass and elementary analysis. In ¹H NMR spectra of

8 showed the signals of NH₂at δ (ppm) = 7.909–8.361 (brs), NH as a

singlet signal at δ (ppm) = 12.983–13.091, and ¹³C NMR for 8a showed

1

δ_c(ppm) = CS at 180.464, while for compound 9, H NMR showed a

842

A. M. El-Agrody et al.

singlet signal at δ (ppm) = 3.572 (SH) and NH₂protons at δ (ppm) =

7.987 (brs).

Treatment of 5a with thiourea in the presence of boiled alco-

holic K₂CO₃solution gave a compound as 3,4,7,8-tetrahydro-4,7-bi

(4-methoxyphenyl)pyrimido[4,5-d]pyrimidine-2,5(1H,6H)-dione (10a)

(Scheme 4), while the treatment of 5b with (NH₂)₂CS/K₂CO₃under sim-

ilar reaction conditions gave two reaction products as 3,4,7,8-tetrahy-

dro-4,7-di(p-tolyl)-pyrimido[4,5-d]pyrimidine-2,5(1H,6H)-dione (10b)

(Scheme 4) and 4-amino-6-(p-tolyl)-2-[2-(4-amino-5-cyano-6-(p-tolyl)py-

rimidine-2-yl)disulfanyl]pyrimidine-5-carbonitrile (11) (Scheme 4).

The establishment of structures 10 and 11 were based on its spectral

analysis. The IR for compound 10 showed N-H at 3465–3268 and CONH

at 1636–1634; ¹H NMR (δ ppm). For 10a, 3.726 & 3.755 (2s, 6H, 2CH₃O-

Ar), 4.627 (br, s, 2H, H-4 & H-7) and singlet signals at 7.58, 7.963,

9.032, 9.847, 10.112, 10.964 (NH and enolic OH), the mass spectum

gave molecular ion peak at m/z (%): 380 (M⁺, 10.8) and a base peak

at m/z 121 (100) with other peaks at 259 (14.9), 202 (18.9), 178 (19.8),

1

77 (14.8). For 10b, the H NMR showed absorption signals at 2.233,

2.321 (2s, 6H, 2CH₃-Ar), 6.07 (t, 2H, H-4 & H-7, J = 5.1 Hz); and six

absorption peaks at 7.327, 7.719, 7.972, 9.761, 10.043, 10.884 (NH &

enolic OH); the mass spectrum showed a molecular ion peak at m/z (%):

343 (M⁺, 30.5) and base peak at 105 (100) with other peaks at 288 (14.4),

243 (31.0), 186 (37.3), 262 (39.4). For compound 11, the IR showed NH₂

at 3232.1 and 3144.7 and CN at 2218; ¹H NMR showed δ (ppm) at 2.302

(s, 6H, 2CH₃-Ar) and 6.965 (br, s, 2H, NH₂), and the mass spectrum gave

a molecular ion peak at m/z (%): 482 (25.7) and base peak at 241 (100)

corresponding to M⁺/2 with other peaks at 209 (26.8), 183 (25.6), 141

(7.1), 91 (22.1).

The spectrometric fragmentation of 11 supported the proposed struc-

ture (Scheme 5).

SCHEME 5 Spectrometric fragmentation pattern of compound 11.

Thioxopyrimidines and Related Derivatives

843

The base-catalyzed condensation of 5a with thiourea in the pres-

ence of a methoxide ion under different reaction conditions have

also been investigated, where 4-oxo-6-(4-methoxyphenyl)-2-thioxohexa-

hydropyrimidine-5-carbonitr-ile (12a)³⁴and 2-amino-6-methoxy-4-

(4-methoxyphenyl)pyridine-3,5-dicarbonitrile (15a) were obtained

(Scheme 6).

SCHEME 6 Synthesis of compounds 12–15 reagents and conditions.

(iii) CH₃ONa, boiled MeOH, 4 h, 48–50% and 28–30% yield; (iv) excess CH₃ONa,

boiled MeOH, 4 h 31% yield.

Similar to the behavior of 5a, oleﬁnic nitrile 5c reacted with

thiourea under the same reaction grounds in the presence of a methox-

ide ion and yielded 4-oxo-6-(4-chlorophenyl)-2-thioxohexahydro-

primidine-5-carbonitrile (12b) and 2-amino-4-(4-chlorophenyl)-6-

methoxypyridine-3,5-dicarbonitrile (15b) (Scheme 6).

The reﬂuxing of activated cyanooleﬁn 5a with thiourea in the pres-

ence of an excess methoxide ion afforded 4-amino-5-cyano-2-methoxy-

6-(4-methoxyphenyl)pyrimidine (13).

The treatment of 13 with formic acid under reﬂux afforded the cor-

responding 2-methoxy-4-(4-methoxyphenyl)-6-oxo-1,6-dihydropyrimi-

dine-5-carbonitrile (14) (Scheme 6).

844

A. M. El-Agrody et al.

The structures of 12–15 were established on the basis of spectral

data. Thus, IR for 12 showed CO at 1748–1724; ¹H NMR for 12a showed

δ (ppm) at 5.479 (d, 1H, 5-H, J = 11.6 Hz), (5.746–5.621) (m, 1H, 6-H),

10.952, 10.632 (2s, 1H, 1H) and 12.336 (2s, 1H, 3-H). Compound 12b

showed signals at 5.034 (d, 1H, 5-H, J = 11.719 Hz) and 5.247 (d, 1H, H-

6, J = 11.33 Hz) and four absorption signals at 10.198, 10.468, 11.796,

& 11.907 (NH & enolic OH proton). Also, the mass spectrum for 12a,b

showed a very intense molecular ion peak at m/z (%) 269 (M⁺, 100), &

265 ((M⁺, 100), respectively. The ¹³C NMR for 12a showed δ_c(ppm) at

160.329 (CO) and 178.522 (CS).

For compound 13, the IR showed the absence of υ C O, its ¹H NMR

showed δ (ppm) at 3.834 (s, 3H, H₃CO-pyrimidine) and 3.824 (s, 3H,

H₃CO-Ar), and the mass spectrum showed a molecular ion peak at m/z

(%); 257 (M⁺, 100).

1

Also, for product 15a, the H NMR showed δ (ppm) at 3.828 (s, 3H,

H₃CO-Ar) and 3.953 (s, 3H, H₃CO-py); the ¹³C NMR showed signals at δ_c

(ppm) 55.454 (C-CH₃O-Ar), 56.454 (C-CH₃O-py), 166.71 (C-2), 170.078

(C-6) and the mass spectrum showed a very intense molecular ion peak

1

at m/z (%): 280 (M⁺, 100). For compound 15b, the H NMR showed δ

(ppm) at 3.985 (s, 3H, CH₃-O) and mass spectrum at m/z (%): 284 (100).

The formation of products 8–15 could be explained by the proposed

mechanism (Schemes 4 and 6). The formation products 8–15 (Schemes 4

and 6) could be explained by initial Michael addition of thiourea to the

activated double bond (path a 1,4-addition) followed by the cyclization

to the intermediate [A], which hydrolyzed into the corresponding car-

boxamide (CN → CONH₂) and then reacted with a molecule of free

aldehyde obtained from retro Michael addition³⁵to give the product

10. The previous intermediate may be oxidized into 8 and 9, and two

molecules of 9 joined together with the elimination of one molecule of

hydrogen to give the product 11.

Also, the intermediate [A] hydrolyzed into 12 or underwent the nu-

cleophilic substitution of SH⁻with MeO⁻followed by aromatization to

give 13.

An alternative path b (1,2–addition) of thiourea to the cyano group

was followed by the addition of a malononitrile molecule obtained from a

retro Michael addition³⁵to another molecule of cyano oleﬁn, followed by

a ring closure with the elimination of NH₃, HCN, and the substitution

¯

of SH by MeO⁻to give the product 15.³⁶

The interaction of ethoxymethylenemalononitrile (3) with

(NH₂)₂CS in the presence of boiled alcoholic K₂CO₃solution gave

4-amino-2-[2-(4-amino-5-cyanopyrimidine-2-yl)di-sulfanyl]pyrimidine-

5-carbonitrile (16) (Scheme 7) instead of 4-amino-2-thioxo-1,2-dihydro-

pyrimidine-5-carbonitrile (4) previously obtained.^18,19

Thioxopyrimidines and Related Derivatives

845

SCHEME 7

1

The H NMR for 16 showed δ (ppm) at 8.252 (br, 4H, 2NH₂disap-

peared by D₂O) and 8.499 (s, 2H, H-6 & 6^ꢀ), and the mass spectrum

gave a molecular ion peak as an intense peak at m/z (%) 302 (92).

Oleﬁnic 6a was allowed to react with thiourea in the presence

of methanolic methoxide at r.t., which gave rise to three different

reaction products, one assigned as 4-amino-1,2,5,6-tetrahydro-6-(4-

methoxyphenyl)-2-oxopyrimidine-5-carboxamide (17), 4-(4-methoxy-

benzylidine)amino-1,2,5,6-tetrahydro-6-(4-methoxyphenyl)-2-thioxo-

pyrimidine-5-carboxamide (18), and 3,5-dicyano-2,4-di(4-methoxy-

phenyl)-3,4,5,6-tetrahydro-6-oxopyridine-3-carboxamide (19).

The reaction seemed to proceed by the Michael addition of the

thiourea anion to the activated double bond of 6a followed by the cy-

clization of the adduct to give the nonisolated intermediate (B), which

on hydrolysis gave 17 or when added to second mol of 6a under the

reaction conditions formed a acyclic adduct, which underwent a retro

Michael addition to furnish the product 18. The formation of 19 as

a byproduct resulted from the dimerization of 6a under the previous

reaction conditions; a similar ﬁnding has been reported previously³⁷

(Schemes 8 and 9).

Reﬂuxing a mixture of 6a and thiourea in methanol-methoxide

afforded

4-amino-1,2,5,6-tetrahydro-6-(4-methoxyphenyl)-2-thioxo-

pyrimidine-5-carboxylic acid (20) as a solo product (Scheme 8).

The structures of 17–20 are substantiated by IR, ¹H NMR, and mass

spectra studies. For 18, ¹H NMR showed δ (ppm) at 3.738, 3.767 (2s, 6H,

2OCH₃), 5.205 (s, 1H, 5-H), 5.551 (s, 1H, 6-H), 6.135 (s, 1H, CH-Ar),

9.553 (s, br, 3H, NH + NH₂). Ms for 17 and 18 gave a molecular ion

peak at m/z (%): 262 (M⁺, 88.9), 396 (M⁺, 31.5), respectively. Also, the

¹H NMR for 19 showed absorption signals at δ (ppm) = 3.695, 3.775 (2s,

6H, 2CH₃O-Ar), 4.818, 4.12 (2d, J = 2.734 Hz, 6-H + 5-H), and (8.35–

8.616) (s, br, 2H, CONH₂). Its mass spectrum showed a molecular ion

peak at m/z: 402 (M⁺, 14.7) and a base peak 121 (100) with other peaks

360 (29.3), 294 (13.2), 242 (27.8), 201 (14.1), 162 (26.7), 134 (53.4), 77

(38.8). For 20, IR (υ C O at 1686) with a shoulder at 1704; ¹H NMR δ

(ppm) = 4.296 (d, 1H, H-5, J = 12.89 Hz), 4.861 (d, 1H, H-6, J = 12.89

Hz), 5.217 (s, 1H, NH), 7.545 (s, 2H, NH₂), 8.797 (s, 1H, CO₂H), and mass

846

A. M. El-Agrody et al.

SCHEME 8 Synthesis of compounds 17, 18, and 20 and reagent and condi-

tions, (i) Methanolic CH₃O⁻, r.t. 48h (45 & 20) % yield for 17 and 18; (ii) CH₃OH/

CH₃O⁻, reﬂuxed methanol, 4h, 40% yield for compound 20.

spectrum affords an additional support, which showed a molecular ion

peak at (%) 279 (M⁺, 1.35).

When 7a was stirred with a methanolic methoxide solution

containing thiourea at r.t., it gave 4-oxo-6-(4-methoxyphenyl)-2-

thioxohexahydropyrimidine-5-carbonitrile (12a) previously obtained

from 5a and thiourea (identical IR, ¹H NMR, ¹³C NMR, m.p., and mixed

SCHEME 9 The dimarization of 6a reagent and conditions (i) CH₃OH/CH₃O⁻,

r.t., 48 h, 15% yield.

Thioxopyrimidines and Related Derivatives

847

m.p.), while reﬂuxing 7a with thiourea in a methanolic solution con-

taining sodium methoxide gave 4-oxo-2-thioxo-6-(4-methoxyphenyl)-

1,2,3,4-tetrahydropyrimidine-5-carbonitrile (21) besides 12a.

It is assumed that the reaction involved the addition of an anionic

form of thiourea to 7a and a subsequent intramolecular attack at the

carbonyl group of the ester to form the cyclized product 12a, which

underwent oxidation into 21 under the inﬂuence of oleﬁnic nitrile upon

reﬂux (Scheme 10).

SCHEME 10 (i) NaOMe/MeOH, r.t., 48 h, 50% yield; (ii) NaOMe/MeOH, boiled

MeOH, 4 h, 77% yield.

The structure of 21 is inferred from IR (υ C O:1676.7); the ¹H NMR

showed a signal at 13.099 (s, 1H, enolic OH), and its mass spectra

added further support, which showed a molecular ion peak m/z (%):

259 (M⁺, 100).

Compound 15a reacted with (EtO)₃CH/Ac₂O and gave 2-(E)-etho-

xymethyleneamino-6-methoxy-4-(4-methoxyphenyl)pyridine-3,5-dica-

rbonitrile (22). The IR spectrum showed the disappearance of NH₂

1

bands and the appearance of CH N at 3002.8; the H NMR showed δ

at 8.772 (s, 1H, N CH), and its mass spectrum gave a molecular ion

peak at m/z (%): 336 (M⁺, 100).

When compound 22 was treated with hydrazine hydrate in well-

stirred ethanol at r.t., it lead to the formation of a product, which was

found to be identical in all respects (m.p., mixed m.p., and spectral data)

with 15a (Scheme 11).

The formation of 15a from 22 was assumed to proceed via the addi-

tion of hydrazine as a nucleophile at a N CH site to give the nonisolated

intermediate (C) followed by the elimination of ethyl formatehydrazone

(Scheme 11).

The treatment of 15a with formaline solution in boiling

methanol gave 2-(N-hydroxymethyl)amino-6-methoxy-4-(4-methoxy-

phenyl)pyridine-3,5-dicarbonitrile (23), while the treatment of 15a

with formaline solution in boiling methanol containing an equimo-

lar ratio of ethanolamine gave

a product, which was ana-

lyzed as 2-(N-hydroxymethyl,N-(β-hydroxyethyl))-amino-6-amino-4-(4-

methoxyphenyl)-pyridine-3,5-dicarbonitrile (24) (Scheme 11).

848

A. M. El-Agrody et al.

SCHEME 11

The formation of 24 was assumed by the nucleophilic substitu-

tion of a methoxy group by the β-ethylamino group followed by N-

hydroxymethylation by formaldehyde (Scheme 11).

IR spectrum of 23 showed a broad strong absorption band at 3350

1

(OH, NH), and H NMR δ (ppm) at 3.953 (s, 1H, OH), 4.877 (d, J =

6.4 Hz, CH₂), 8.795 (s, br, 1H, NH); its mass spectrum gave a molecular

ion peak at m/z (%) 310 (M⁺, 12.1).

Also for compound 24, IR [υNH₂as a triplet at 3426, 3334, 3234],¹H

NMR [δ (ppm) at 1.113 (t, J = 7Hz, 2H, HOCH₂CH₂N), 3.543 (q, J =

7Hz, 2H, NCH₂CH₂OH), 3.928 (s, 1H, OH), 4.006 (s, 1H, OH), 4.919 (d.

J = 6Hz, NCH₂OH), 8.772 (s, br, 2H, NH₂)], its mass spectrum gave

a molecular ion peak at m/z (%): 339 (M⁺; 18) and a base peak at 309

(100) with other peaks 393 (80), 280 (72), 59 (42).

The treatment of 9 with boiling formic acid afforded the 4-oxo-2-

thioxo-6-(4-methoxyphenyl)-1,2,3,4-tetrahydroprimidine-5-carbonitrile

(21), (identical IR, ¹H NMR, mass, m.p., and mixed m.p.)

Also, the treatment of 9 with CH(OEt)₃/Ac₂O under reﬂux

gave the corresponding N-(5-cyano-2-thioxo-6-(4-methoxyphenyl)-1,2-

dihydropyrimidin-4-yl)formamide (25) (Scheme 12). IR spectrum for 25

showed [υ CO at 1726.7 ¹H NMR gave δ at 9.255 (d, J = 4.688 Hz, 1H,

HN-CHO), 11.565 (br, s, 2H, NH), and mass spectrum gave a molecular

ion peak at m/z (%): 286 (12.8) together with a base peak at 241 (100).

Also, the condensation of 9 with ethyl chloroacetate and/or phenacyl

bromide afforded the corresponding ethyl 2-(4-amino-5-cyano-6-(4-

methoxyphenyl)pyrimidin-2-yl)thioacetate (26) and 4-amino-2-(2-be-

nzoylmethylthio)-6-(4-methoxyphenyl)pyrimidine-5-carbonitrile (27),

respectively (Scheme 12).

Thioxopyrimidines and Related Derivatives

849

SCHEME 12

Spectral data for compounds 26 and 27 support the proposed struc-

ture, thus IR [υCO at 1742.7, 1690], ¹H NMR [δ (ppm) at 3.629 (s,

2H, CH₂S), 4.781 (s, 2H,CH₂S)], and its mass spectrum [m/z (%): 344

(M⁺, 6.2), 271 (100), 225 (27.4) and 376 (M⁺, 10.3), 343 (10.9), 271 (27.4),

105 (100), 77 (36.7)] respectively.

The condensation of 9 and 8b with hydrazine hydrate gave prod-

ucts that were identiﬁed as 4-amino-6-aryl-2-hydrazinylpyrimidine-

5-carbonitril (28a,b), respectively. Also, the condensation of 28a,b

with an equimolar ratio of aromatic aldehydes in reﬂuxing n-butanol

afforded the corresponding 4-amino-2-((Z)-2-arylidenehydrazinyl)-6-

arylpyrimidine-5-carbonitrile 29a–e (Scheme 12).

The condensation of 2-hydrazinylpyrimidine derivative (28a) with

1,3-dicarbonyl compounds, namely acetylacetone and ethyl acetoac-

etate in boiling ethanol containing a few drops of piperidine, gave 4-

amino-6-(4-methoxyphenyl)-2-[(3,5-dimethyl)-1H-pyrazol-1-yl]pyrimi-

dine-5-carbonitrile (30) and 4-amino-2-(2-ethoxycarbonylisopropy-

lidenehydrazinyl)-6-(4-methoxyphenyl)pyrimidine-5-carbonitrile (31),

respectively (Scheme 13).

1

The H NMR for 30 showed at δ (ppm) = 2.174 (s, 3H, CH₃), 2.603

(s, 3H, CH₃), and 6.137 (s, 1H, 4-H, pyrazole). Its mass spectrum gave

a molecular ion peak as a base peak at m/z (%): 320 (M⁺, 100). Also for

850

A. M. El-Agrody et al.

SCHEME 13

1

compound 31, the IR showed υCO at 1732, H NMR: δ (ppm) = 1.978

(s, 3H, CH₃C ), 3.297 (s, 2H, CH₂C O), 7.4 (s, br, 2H, NH₂cancelled

by D₂O) 9.907 (s, 1H, NH cancelled by D₂O). Its mass spectrum gave

m/z (%) at 368 (M⁺, 5.08) and a base peak at 281 (100).

The condensation of 8 with piperidine afforded 1,6-dihydro-4-(4-

methoxyphenyl)-6-oxo-2-(piperidin-1-yl)pyrimidine-5-carbonitrile (32)

(Scheme 12). The ¹H NMR for 32 showed absorption signals in the form

of a complex pattern at δ (ppm) = (1.506–1.591) (10 H, piperidine–H), its

mass spectrum showed a molecular ion peak at m/z (%): 310 (M⁺, 18.7).

together with a base peak at 280 (M⁺-CH₂O).

IR, ¹H NMR, ¹³C NMR, and mass spectra for the newly synthesized

pyrimidine derivatives were studied (Table I).

ANTIMICROBIAL ACTIVITIES

Some selected compounds were screened for their antimicrobial ac-

tivity using Bacillus subtilis (ATCC 7972) (BS), Staphylococcus au-

rous (NCTC 7447) (SA) (Gram-positive), Escherichia coli (NCTC

10416) (EC), Pseudomonas aeuroginosa (ATCC 10415) (PA), Can-

dida albican (IMRU 3669) (CA) (Gram-negative), and Aspergillus

niger (ATCC 6275) (AN) (fungi) microorganisms. The activities of

these compounds were tested using disc diffusion method.^38,39The

tested compound were dissolved in N,N-dimethylformamide (DMF)

to get a solution of mg mL⁻¹. The inhibition zones were measured

in millimeters at the end of incubation period of 48 h at 28^◦C. N,N-

dimethylformamide showed no inhibition zones. The area of the zone

of inhibition was measured using neomycin (30 mg) as a standard

antibiotic.

Compound 26 showed the highest antibacterial activity (+++,

the inhibition zone was between 12–15 mm), against BS, SA, EC,

Thioxopyrimidines and Related Derivatives

851

TABLE I Spectral Data for the Newly Prepared Compounds

Compound

IR (ν

cm⁻¹

)

¹HNMR/¹³CNMR (δ ppm)/MS (m/z %)

max

8a

3405.8, 3345, 3233.6,

3163.9 (NH₂, NH),

2213.3 (CN), 1639.2

(C N), 1392 (C S)

2.386 (s, 3H, CH₃-Ar), 7.351, 7.570 (2d,

J = 8.203 Hz, 4H, Ar-H), 7.909, 8.361

(2brs, 2H, NH₂), 12.983 (s, 1H, NH)

21.057, 68.275, 115.069, 128.792, 128.967,

142.16, 163.796, 180.464

242 (75.9), 241 (100), 209 (15.7), 184 (32.5),

140 (12.5), 118 (12.6), 91 (13.6), 65 (19.6)

7.599, 7.826 (2d, 4H, Ar-H, J = 8.203 Hz),

8.112 (brs, 2H, NH₂), 13.091 (s, 1H, NH)

262 (85.2), 261 (100), 229 (24), 204 (40),

187 (12), 162 (14.5), 138 (22.4), 111 (14.3),

92 (17.6), 75 (34.4), 67 (29.3), 51 (29.6)

3.572 (s, 1H, SH), 3.831 (s, 3H, CH₃O-Ar),

7.057, 7.840 (2d, J = 8.984 Hz, 4H, Ar-H)

and 7.987 (brs, 2H, NH₂)

8b

3471.3, 3329.8, 3226.3

(NH₂, NH), 2221.5

(CN), 1392 (C S)

9

3434, 3333.4, 3229.5

(NH₂), 2218 (CN)

10a

3465.3, 3268.9 (NH),

1634.3 (CONH)

3.726, 3.755 (2s, 6H, 2CH₃O-Ar), 4.627 (br,

s, 2H, H-4 & H-7), (6.907–6.948) (br, s,

4H, Ar-H), 7.05 & 7.18 (2d, 4H, Ar-H,

J = 8.5 Hz), 7.58, 7.963, 9.032 (hump),

9.847 (broad), 10.112 (broad), 10.964 (NH

and enolic OH protons)

380 (10.8), 121 (100), 259 (14.9), 202 (18.9),

178 (19.8), 77 (14.8)

10b

3460.5, 3404.1, 3326.1

(NH), 2986.2 , 2903.7

(CH), 1636.1 (CONH)

2.233 (s, 3H, CH₃-Ar), 2.321 (s, 3H,

CH₃-Ar), 6.07 (t, 2H, H-4 & H-7, J = 5.1

Hz), 7.019 & 7.171 (2m, 8H, Ar-H), 7.327

& 7.719 & 7.972 & 9.761 & 10.043 &

10.884 (NH and enolic OH protons)

348 (30.5), 105 (100), 288 (14.4), 243 (31.0),

186 (37.3), 162 (39.4)

11

3232.1, 3144.7 (NH₂),

2218.6 (CN)

2.302 (s, 6H, 2CH₃-Ar), 6.965 (br, s, 2H,

NH₂), 7.049 (m, 8H, Ar-H)

482 (25.7), 241 (100), 209 (26.8), 184 (23.4),

183 (25.6), 142 (13.2), 141 (7.1), 140 (16.3),

91 (22.1), 65 (35.1)

12a

3431, 3137.9 (NH),

2267.4, (CN), 1724.1

(CO)

4.262 (s, 3H, OCH₃), 5.479 (d, J = 11.6 Hz,

1H, 5-H), (5.746–5.621) (m, 1H, 6-H),

7.869, 7.498 (2d, J = 8.2 Hz, 4H, Ar-H),

10.952 & 10.632 (2s, 1H, 1-H), 12.337,

12.336 (2s, 1H, 3-H)

39.667 (C-5), 40.669 (C-6), 55.189 (OCH₃),

114.128, 114.280 (C-3^ꢀ, 5^ꢀ), 114.575 (CN),

127.374 (C1^ꢀ), 127.928, 129.096 (C2^ꢀ, 6^ꢀ),

159.806 (C4^ꢀ), 160.329 (CO), 178.522 (CS)

261 (100), 186 (68.1), 178 (75.7), 158 (21.8),

134 (73.9), 121 (33.6), 89 (25.4), 77 (22.3),

51 (22.6)

(Continued on next page)

852

A. M. El-Agrody et al.

TABLE I Spectral Data for the Newly Prepared Compounds

(Continued)

1

Compound

IR (ν

cm⁻¹

)

HNMR/¹³CNMR (δ ppm)/MS (m/z %)

max

12b

3302, 3162 (NH), 2940,

2902 (CH), 2245 (CN),

1748 (CO)

5.034 (d, 1H, H-5; J = 11.719 Hz), 5.247

(d, 1H, H-6; J = 11.328 Hz), 7.456 & 7.536

(2d, 4H, Ar-H, J = 8.594 Hz), 10.198,

10.468, 11.796, 11.907 (NH and enolic

OH)

265 (100), M + 2 (39.37), 182 (55.37), 138

(38.47), 28.1 (36,93), 101 (9.76), 86 (7.14),

75 (16.04), 59 (20.76)

13

14

3.923 (s, 3H, CH₃O-Ar), 4.051 (s, 3H,

CH₃O-pyrimidine), 7.352, 7.546 (2d, 4H,

Ar-H, J = 9.0 Hz), 7.934 (br, s, 2H, NH₂)

3.834 (s, 3H, OCH₃-py), 3.824 (s, 3H,

OCH₃-Ar), 7.100 & 7.625 (2d, 4H, Ar-H),

12.931, 13.081 (s, br, 2H, 2NH).

257 (M⁺, 100), 200 (18.9), 199 (25.2),

134 (20.9), 63 (13.2)

3451.1 (NH), 3062.4 (C-H

arom.), 2964 (C-H

aliph.), 2214.8 (CN),

1673.4 (CO), 1603

(C N)

15a

3424, 3330, 3234 (NH₂),

2942 ( aliph. C-H),

2224, 2210 (CN)

3.828 (s, 3H, CH₃O-Ar), 3.953 (s, 3H,

CH₃O-Py), 7.096 & 7.473 (2d, 4H, Ar-H;

J = 8.985 Hz), 7.936 (s, br, 2H, NH₂)

55.454 (C-CH₃O-Ar), 56.454 (C-CH₃O-Py),

82.811 (C-3, C-5), 113.938 (C-3^ꢀ, C-5^ꢀ),

116.267 (2CN), 127.571 (C-2^ꢀ, C-6^ꢀ),

130.393 (C-1^ꢀ), 161.885 (C-4^ꢀ), 164.107

(C-4), 166.710 (C-2), 170.078 (C-6)

280 (100), 238 (2.8), 157 (2), 127 (2.3),

100 (2.9)

15b

16

3481, 3346, 3227.2 (NH₂),

2955 (aliph. C-H), 2217

(CN)

3.985 (s, 3H, CH₃O ), 7.544 & 7.654 (2d,

4H, Ar-H; J = 6.6 Hz) and at 7.967 (br, s,

2H, NH₂)

284 (100), M + 2 (33.4), 255 (24.2),

249 (42.2), 165 (12.7)

3421.6, 3308, 3205.6

(NH₂), 2224.4 (CN)

8.252 (br, 4H, 2NH₂, disappeared by D₂O),

8.499 (s, 1H, 2H, 2H-6).

302 (92), 94 (100), 270 (8), 238 (45), 185 (20),

152 (64),119 (45), 93 (53), 66 (60)

262 (M⁺, 88.9), 261 (100), 204 (33.2), 134

(19.2), 99 (20.7), 67 (40.4)

3.738, 3.767 (2s, 6H, 2OCH₃), 5.205 (s, 1H,

5-H), 5.551 (s, 1H, 6-H), 6.135 (s, 1H,

=CH-Ar), 6.90, 6.972 (2d, J = 7 Hz, 4H,

Ar-H), 7.237, 7.455 (2d, J = 7 Hz, 4H,

Ar-H), 9.553 (s, br, 3H, NH + NH₂)

396 (31.51), 134 (100), 394 (47.8), 353 (41.3),

287 (90.7), 178 (38.5), 119 (33.1), 77 (57.6)

17

18

3372, 3172 (NH₂), 3075.2

(C-H arom.), 2932 (C-H

aliph.), 1668.3 (CO)

(Continued)

Thioxopyrimidines and Related Derivatives

853

TABLE I Spectral Data for the Newly Prepared Compounds

(Continued)

1

Compound

IR (ν

cm⁻¹

)

HNMR/¹³CNMR (δ ppm)/MS (m/z %)

max

19

3240.5 (NH₂), 2215 (CN),

1663.4 (CO)

3.695 (s, 3H, OCH₃), 3.775 (s, 3H, OCH₃),

4.818, 4.12 (2d, J = 2.734 Hz, 6-H + 5-H),

7.515, 7.122, 6.995, 6.87 (4d, 8H, Ar H),

(8.35–8.616) (s, br, 2H, CONH₂)

402 (M⁺, 14.7), 121 (100), 360 (29.3), 294

(13.2), 242 (27.8), 201 (14.1), 162 (26.7),

134 (53.4), 77 (38.8)

20

3454, 3350 (NH₂), 1704,

1686 (CO)

3.746 (s, 3H, OCH₃), 4.296 (d, 1H, H-5,

J = 12.89 Hz), 4.861 (d, 1H, H-6,

J = 12.89 Hz), 5.217 (s, 1H, NH), three set

of multiples at (6.922–7.424) (m, 4H,

Ar-H), 7.545 (s, 2H, NH₂), 8.797 (s, 1H,

CO₂H)

279 (M⁺, 1.35), 268 (7.7), 211 (24.79), 196

(29.62), 161 (9.16), 149 (12.47), 135 (6.75),

97 (10.08), 85 (15.21), 71 (23.1), 45 (100)

3.843 (s, 3H, OCH₃), 7.103 & 7.651 (2d,

J = 9.0 Hz, 4H, Ar-H), 13.099 (s, 1H, OH)

259 (M⁺, 100), 231 (19.7), 201 (27),

158 (16.2), 134 (63.5), 91 (13.8), 63 (13.8)

1.352 (t, J = 7.0 Hz, 3H, CH₃), 3.848 (s, 3H,

OCH₃), 4.088 (s, 3H, OCH₃); 4.424 (q,

J = 7.0 Hz, 2H, CH₂) 7.147, 7.565 (2d,

J = 8.6 Hz, 4H, Ar-H), 8.772 (s, 1H,

N=CH)

21

22

3470.9 (NH), 2212.1 (CN),

1676.7, (CO)

3002.8 (C-H arom.),

2966.2 (C-H aliph.)

2226.2 (CN)

336 (M⁺, 100), 280 (98.40), 249 (24.9), 195

(12.0), 114 (11.3)

23

24

Strong broad at 3350 (OH

& NH), 2214 (CN )

3.836 (s, 3H, OCH₃-Ar), 3.953 (s, 1H, OH),

4.010 (s, 3H, OCH₃-Py), 4.877 (d,

J = 6.4 Hz, CH₂), 7.112, 7.499 (2d,

J = 8.59, 4H, Ar-H), 8.795 (s, br, 1H, NH).

310 (M⁺, 12.1), 309 (13.2), 292 (100),

280 (83.8), 195 (20), 152 (18.2), 114 (16.2),

63 (13.2)

3426, 3334, 3234 (NH₂),

2944 (CH-aliph.),

2212 (CN)

1.113 (t, J = 7 Hz, 2H, HOCH₂CH₂N), 3.543

(q, J = 7 Hz, 2H, NCH₂CH₂OH), 3.83 (s,

3H, OCH₃), 3.928 (s, 1H, OH), 4.006 (s,

1H, OH), 4.919 (d. J = 6Hz, NCH₂OH),

7.104, 7.484 (2d, J = 8.6 Hz, 4H, Ar-H),

8.772 (s, br, 2H, NH₂)

339 (M⁺; 18), M-1 (68), 309 (100), 293 (80),

280 (72), 59(42)

25

3329, 3228 (NH ), 2219.4

(CN), 1726.7 (CO)

3.826 (s, 3H, OCH₃), 7.089, 7.889 (2d,

J = 9.0 Hz, 4H, Ar-H), 9.255 (d, J = 4.688

Hz, 1H, HN-CHO), 11.565 (br, s, 2H, NH).

(Continued on next page)

854

A. M. El-Agrody et al.

TABLE I Spectral Data for the Newly Prepared Compounds

(Continued)

1

Compound

IR (ν

cm⁻¹

)

HNMR/¹³CNMR (δ ppm)/MS (m/z %)

max

286 (12.8), 241 (100), 257 (64.2), 199 (41.7),

157 (11.2), 92 (11.4), 64 (20)

26

3354.8, 3327, 3150.7

(NH₂), 2217.1 (CN),

1742.7 (CO)

2.074 (s, 3H, CH₃), 3.629 (s, 2H, CH₂S),

3.838 (s, 3H, OCH₃), 4.01 (s, CH₂CH₃)

(7.071–7.893) (m, 6H, Ar-H + NH₂)

344 (M⁺, 6.2), 271 (100), 225 (27.4)

3.777 (s, 3H, OCH₃), 4.781 (s, 2H, CH₂);

6.868, 7.559 (2d, J = 8.5 Hz, 4H-ArH),

(7.634-8.061) (m, 7H, Ar-H + NH₂)

376 (M⁺, 10.3), 343 (10.9), 271 (27.4),

105 (100), 77 (36.7)

27

3354, 3164 (NH₂), 2222

(CN), 1690 (CO), 1666

(C N)

28a

3454.2, 3301.8, 3238.3

(NH₂), 3153.4 (NH),

2193.7 (CN)

3.809 (s, 3H, OCH₃); 4.375 (s, 2H, NH₂),

7.039 (d, J = 8.985, 4H, ArH), 7.834,

8.661 (2s, br, 3H, NH₂+ NH)

256 (M⁺, 100), 227 (26), 225 (30), 184 (10)

260 (M⁺, 100), M + 2 (34.4), 231 (42.2), 230

(16.1), 204 (15.91), 138 (14.4), 67 (16.1)

360 (M⁺, 25.43), 343 (20.15), 241 (100),

240 (61.29), 225 (27.35), 200 (28.39), 199

(28.52), 157 (15.37), 134 (24.02), 119

(42.89), 105 (38), 91 (70.17), 77 (60.34)

2.335 (s, 3H, CH₃), 3.848 (s, 3H, OCH₃),

7.092–7.246 (2d, J = 8.4 Hz, 4H, Ar-H),

7.42 (s, br, 2H, NH₂, cancelled by D₂O)

7.566, 7.867 (2d, J = 8.7 Hz, 4H, Ar-H),

8.167 (s, 1H, N = CH), 11.29 (s, br, 1H,

NH, cancelled by D₂O)

28b

29a

3414, 3342 (NH₂), 3250

(NH), 2214 (CN)

3475, 3372 (NH₂), 3298

(NH), 2200 (CN)

29b

3470, 3350, 3294 (NH₂),

3148 (NH), 2202 (CN)

358 (M⁺, 8), 276 (16), 241 (100) 199 (28),

134 (16), 117 (44), 91 (68), 65 (40)

3.795 (s, 3H, OCH₃), 3.84 (s, 3H, OCH₃),

6.100, 7.083 (2d, J = 8.7 Hz, 4H, Ar-H),

7.394 (s, br, 2H, NH₂cancelled by D₂O),

7.631, 7.856 (2d, J = 8.4 Hz, 4H, Ar-H),

8.14 (s, 1H, N=CH), 11.227 (s, br, 1H, NH,

cancelled by D₂O)

29c

3476, 3290 (NH₂), 3112

(NH), 2196 (CN)

374 (M⁺, 3.36), 241 (100), 199 (27.3),

157 (12.84), 133 (37.4), 91(35), 77 (44.74)

6.881 (m, 4H, Ar-H), 7.244 (hump, 2H,

NH₂), (7.629–7.885) (m, 4H, Ar-H), 8.413

(s, 1H, N=CH), 11.052, (11.702–11.903)

(br signals, OH + NH)

29d

29e

3402 (br), 3254 (NH₂,

NH), 2210 (CN)

3470, 3346, 3292 (NH₂),

3158 (NH), 2206 (CN)

2.32 (s, 3H, CH₃), 7.232, 7.547 (2d,

J = 8.203 Hz, 4H, Ar-H), 7.610, 7.843 (2d,

J = 8.6 Hz, 4H, Ar-H), 8.155 (s, 1H,

N=CH), 7.598 (s, br, 2H, NH₂), 11.434 (s,

br, 1H, NH)

(Continued)

Thioxopyrimidines and Related Derivatives

855

TABLE I Spectral Data for the Newly Prepared Compounds

(Continued)

1

Compound

IR(ν

cm⁻¹

)

HNMR/¹³CNMR (δ ppm)/MS (m/z %)

max

362 (4.89), M + 2 (2.21), 271 (4.4), 245 (100),

229 (2.56), 205 (11), 203 (24.74), 162

(2.12), 138 (4.6), 91 (6.18)

30

3477.4, 3274.1 (NH₂),

3140.9, 2208.7 (CN ),

1649.1 (C N)

2.174 (s, 3H, CH₃), 2.603 (s, 3H, CH₃),

3.842 (s, 3H, OCH₃), 6.137 (s, 1H, 4-H,

pyrazole), 7.117, 7.944 (2d, J = 9 Hz, 4H,

Ar-H), 7.922–7.965 (s, br, 2H, NH₂)

320 (100), 305 (21.4), 278 (11.8), 225 (11.7),

121 (10.2), 95 (11.7)

31

3484, 3294, 3152 (NH₂,

NH), 2202 (CN), 1732

(CO)

1.202 (t, J = 5.1 Hz, 3H, CH₃), 1.978 (s, 3H,

CH₃C=), 3.297 (s, 2H, CH₂C=O), 3.835

(s, 3H, OCH₃), 4.118 (q, J = 5.1 Hz,

CH₂CH₃), 7.008, 7.819 (2d, J = 8.7 Hz,

4H, Ar-H), 7.4 (s, br, 2H, NH₂cancelled by

D₂O) 9.907 (s, 1H, NH cancelled by D₂O)

368 (5.08), 281 (100), 353 (2.51), 322 (12.74),

254 (9.56), 225 (18.91), 183 (10.86),

158 (7.42), 134 (10.11), 77 (5.86), 68 (10)

(1.506–1.591) (complex pattern, 10 H,

piperidine–H), 3.812 (s, 3H, OCH₃),

7.041, 7.816 (2d, J = 8.6 Hz, 4H, Ar-H),

7.131 (s, br, 1H, NH)

32

3258.6 (NH), 2947.9,

28471 (C-H aliph.),

229.8 (CN), 1730.8 (CO)

310 (18.7), 180 (100), 309 (89.2), 294 (30.2),

281 (26.3), 266 (39), 254 (42.8), 226 (37.0),

225 (38.5), 183 (10.7), 84 (81.3)

and PA, while compound 12a showed the same effect against BS,

SA, and PA, and compound 24 gave the same effect against BS

and SA. Compound 26 showed moderate inhibition (++, inhibition

zone ≈ 8–12 mm) against CA and AN, while compounds 17, 18, 27,

29a, and 30 showed moderate inhibition against BS, SA, EC, and

PA, compound 8 gave a moderate effect against BS, and SA, Com-

pound 24 gave a moderate effect against EC, and PA, compound 12a

also gave a moderate effect against EC. The remaining tested com-

pounds showed weak (+) to poor (−) activities against all the tested

microorganisms.

It was observed that the compounds containing pyridine nucleus sub-

stituted by two carbonitriles (3,5-) and two amino groups (2,6-) (com-

pound 24) that contained a pyrimidine moiety with poly functional sub-

stituted groups (compounds 12a, 26) showed a promising effect against

most of the tested microorganisms (Table II).

856

A. M. El-Agrody et al.

TABLE II Antimicrobial Activity of Some Newly

Synthesized Compounds. −ve ( no activity); +ve (when

inhibition zone up to 8 mm); ++ve (when inhibition zone

was between 8–12 mm); +++ve (when inhibition zone was

between 12–15 mm); ++++ve (when inhibition zone was

over 15 mm); −MIC 50 mg/mL.

Gram-positive

Gram-negative

Fungi

AN

Compound

BS SA

EC

−ve

PA

CA

8a

9

12a

15a

15b

17

18

19

21

22

24

26

27

29a

30

−ve

+ve

−ve

+ve

−ve

+ve

−ve

++ve

+ve

−ve

++ve

+++ve

+ve

++ve

+++ve

+ve

−ve

+ve

−ve

++ve

−ve

++ve

+ve

+++ve

+ve

+

+ve

++ve

+ve

++ve

+ve

++ve

+ve

++ve

+ve

+++ve

++ve

++++ve

+++ve

++ve

++++ve

++ve

+++ve

++ve

+++ve

++ve

+++ve

++ve

+++ve

Neomycin

EXPERIMENTAL SECTION

Melting points were measured using the melting point apparatus (Stu-

art Scientiﬁc Co., UK), and remained uncorrected. The IR spectra were

recorded on a Shimadzu IR 440 spectrophotometer (Shimadzu, Japan)

1

in KBr. H and ¹³C NMR spectra were recoded on a Varian Gemini

200 NMR spectrometer at 200 and 50 MHz with a chemical shift calcu-

lated from deuterated solvent residues. Microanalytical data (Table II)

were obtained from the Microanalytical Unit of the Cairo University

(Cairo, Egypt).

4-Amino-1,2-dihydro-2-thioxo-6-arylpyrimidine-5-carbonitrile

(8a, b) 4-Amino-2-mercapto-6-(4-methoxyphenyl)pyrimidine-

5-carbonitrile (9)

A solution of thiourea (760 mg, 10 mmol) in ethanol (15 mL) containing

three drops of piperidine and the corresponding benzylidenemalonon-

itrile (5) (10 mmol) dissolved in ethanol (15 mL), were successively

Thioxopyrimidines and Related Derivatives

857

added, and the reaction mixture was reﬂuxed for 4 h. The reaction mix-

ture was precipitated with dil. HCl; the solid product so formed was

collected by ﬁltration, washed several times by water, and then recrys-

tallized from the appropriate solvent (Table III).

3,4,7,8-Tetrahydro-4,7-bis(4-methoxyphenyl)pyrimido[4,5-d]-

pyrimidine-2,5(1H, 6H)-dione (10a), 3,4,7,8-Tetrahydro-4,7-bi-

(p-tolyl)pyrimido[4,5-d]-pyrimidine-2,5(1H, 6H)-Dione (10b),

4-Amino-6-(p-tolyl)-2-[2-(4-amino-5-cyano-6-(p-tolyl))pyrimid-

in-2-yl)-disulfanyl]pyrimidine-5-carbonitrile (11) and 4-Amino-

2- [2-(4-amino-5-cyanopyrimidin-2-yl) disulfanyl]-pyrimidine-5-

carbonitrile (16)

To a solution of respective benzylidenemalononitrile (5) or ethoxymeth-

ylenemalononitrile (3) (10 mmol) in (10 mL) absolute ethanol and

(760 mg, 10 mmol) of thiourea in ethanol (10 mL) containing anhy-

drous K₂CO₃(1.380 g, 10 mmol) were added. The reaction mixture was

reﬂuxed for 4 h. The potassium salt, which precipitated during the reac-

tion, was collected. The crude salt was stirred in water at 80^◦C; stirring

was continued until a clear solution was obtained. After cooling, the

solution was acidiﬁed with dil. HCl; the solid product so formed was

collected by ﬁltration, washed several times by water, and then recrys-

tallized from the appropriate solvent (Table III). In the case of 5b, the

reaction product was a mixture of 10b and 11 and was separated by

gas–liquid chromatography.

4-Oxo-6-(4-methoxyphenyl)-2-thioxohexahydropyrimidine-5-

carbonitrile (12a), 2-Amino-6-methoxy-4-(4-methoxyphenyl)-

pyridine-3,5-dicarbonitrile (15a), and 4-Oxo-6(4-chlorophenyl)-

2-thioxohexahydroprimidine-5-carbonitrile (12b) and

2-Amino-4-(4-chlorophenyl)-6-methoxypyridine-3,5-

dicarbonitrile (15b)

To a solution of sodium (230 mg, 10 mmol) in methanol (50 mL), thiourea

(760 mg, 10 mmol) was added. When it became dissolved, (10 mmol) of

the corresponding benzylidenemalononitrile (5) dissolved in methanol

was added. The resulting mixture was reﬂuxed for 4 h. The reaction

mixture was poured onto ice water and neutralized by dil. hydrochlo-

ric acid (10%); the solid product so formed was collected by ﬁltration,

washed several times with water, and then recrystallized from the ap-

propriate solvent (Table III).

858

A. M. El-Agrody et al.

TABLE III Physical and Analytical Data for the Newly Prepared

Compounds

Calcd/(found)

M.P.^◦C

(solvent)

Color

(yield %)

M. formula

(m. wt.)

Compound

C

H

N

8a

.265–267

(D)

Colorless

(57)

C₁₂H₁₀N₄S

(242.23)

59.48

4.16

23.12

(59.38) (4.08) (23.03)

50.29 2.69 21.33

(50.18) (2.53) (21.25)

55.80 3.90 21.69

(55.79) (3.74) (21.57)

63.15 5.30 14.73

(62.96) (5.18) (14.56)

68.95 5.79 16.08

(68.84) (5.67) (16.08)

59.73 3.76 23.22

(59.67) (3.63) (23.11)

4.24 16.08

(54.98) (4.28) (15.30)

C₁₁H₈ClN₃OS 49.72 3.03 15.81

(49.28) (2.96) (15.04)

60.93 4.72 21.86

(60.84) (4.61) (21.72)

60.70 4.31 16.33

(60.61) (4.22) (16.22)

64.28 4.32 19.99

(64.17) (4.23) (19.86)

59.06 3.19 19.68

(58.92) (3.02) (19.53)

39.73 2.00 37.06

(39.62) (1.91) (36.93)

54.96 5.38 21.36

(54.82) (5.18) (21.12)

5.08 14.13

(60.42) (4.98) (14.6)

65.66 4.51 13.92

(65.58) (4.43) (13.81)

4.69 15.04

(51.49) (4.53) (14.92)

55.59 3.50 16.21

(55.49) (3.39) (16.15)

64.28 4.79 16.66

(64.18) (4.70) (16.58)

61.93 4.55 18.06

(61.82) (4.47) (17.94)

60.17 5.05 20.64

(60.8) (4.96) (20.58)

3.52 19.57

8b

9

268–270

(D)

258–260

(DMF)

206–208

(Et)

Colorless

(53)

Colorless C₁₂H₁₀N₄OS

(35)

Brown

(12)

Yellow

(14)

Yellow

(14)

Yellow

(50)

Yellow

(48)

Colorless

(31)

Yellow

(92)

Colorless C₁₅H₁₂N₄O₂

(30)

Colorless

(28)

Yellow

(53)

C

₁₁H₇CIN₄S

(262.72)

(258.23)

₂₀H₂₀N₄O₄

(380.40)

₂₀H₂₀N₄O₂

(348.40)

10a

10b

11

C

Mixed 230–234

(Et)

Mixed 230–234

(Et)

C₂₄H₁₈N₈S₂

(482.58)

C₁₂H₁₁N₃O₂S 55.16

(261.30)

12a

12b

13

226–228^∗

(Et)

216–218

(B)

250–252

(E/B)

(265.72)

₁₃H₁₂N₄O₂

(256.26)

₁₃H₁₁N₃O₃

(257.24)

C

14

268–270

(GAA)

15a

15b

16

280–282^∗∗

(D)

(280.28)

₁₄H₉ClN₄O

(284.7)

282–284

(D)

314–316

(DMF)

C

C₁₀H₆N₈S₂

(302.40)

C

17

Mixed 248–252 Colorless

(Et) (45)

Mixed 248–252 Colorless

₁₂H₁₄N₄O₃

(262.26)

18

C₂₀H₂₀N₄O₃S 60.59

(Et)

272–174

(DMF)

252–254

(D)

280–282

(Et)

188–190

(B)

184–186

(Et)

178–180

(Et)

226–228

(D)

(20)

Green

(15)

Colorless

(40)

(396.46)

₂₂H₁₈N₄O₄

(402.40)

19

C

20

C

₁₂H₁₃N₃O₃S 51.60

(279.31)

21

Colorless C₁₂H₉N₃O₂S

(77)

Colorless

(80)

Colorless

(67.7)

Colorless

(69.9)

Colorless

(60)

(259.28)

₁₈H₁₆N₄O₃

(336.12)

₁₆H₁₄N₄O₃

(310.31)

22

C

23

24

₁₇H₁₇N₅O₃

(339.35)

25

C₁₃H₁₀N₄O₂S 54.54

(286.31)

(54.43) (3.51) (19.48)

(Continued on next page)

Thioxopyrimidines and Related Derivatives

859

TABLE III Physical and Analytical Data for the Newly Prepared

Compounds (Continued)

Calcd/(found)

M.P.^◦C

(solvent)

Color

(yield%)

M. formula

(m. wt.)

Compound

C

H

N

26

180–182

(Et)

174–176

(Et)

280–282

(D)

258–260

(D)

216–218

(Et)

218–220

(Et)

234–236

(Et/B)

246–248

(Et)

230–232

(Et)

Yellow

(72)

Colorless

(80)

Colorless

(81)

Colorless

(76)

Colorless

(68)

Colorless

(69)

Yellow

(73)

Colorless

(70)

Colorless

(66)

Colorless

(80)

Yellow

(76)

Colorless

(72)

C₁₆H₁₆N₄O₃S

(344.39)

55.80

(55.69)

63.81

(63.72)

56.24

(56.16)

50.68

(50.79)

63.32

(63.22)

67.02

(66.93)

64.16

(64.8)

59.27

(59.18)

62.90

(62.87)

63.74

(63.66)

58.69

(58.59)

65.79

(65.66)

4.68

(4.56)

4.28

(4.21)

4.72

(4.64)

3.48

(3.41)

4.48

(4.41)

5.06

(4.96)

4.85

(4.78)

3.59

(3.49)

4.17

16.27

(16.18)

14.88

(14.79)

32.79

(32.79)

32.24

(32.17)

23.32

(23.21)

23.45

(23.38)

22.45

(22.35)

23.04

(22.96)

23.16

(23.7)

26.23

(26.13)

22.81

(22.69)

18.05

(17.96)

27

C

₂₀H₁₆N₄O₂S

(376.43)

28a

28b

29a

29b

29c

29d

29e

30

C₁₂H₁₂N₆O

(256.26)

C

₁₁H₉ClN₆

(260.68)

C

₁₉H₁₆N₆O₂

(360.37)

C₂₀H₁₈N₆O

(358.40)

C

₂₀H₁₈N₆O₂

(374.40)

C₁₈H₁₃ClN₆O

(364.79)

C

₁₉H₁₅ClN₆

(362.82)

(4.9)

5.03

(4.96)

5.47

(5.41)

5.85

255–256

(Et/B)

160–161

(Et)

260–262

(Et/B)

C

₁₇H₁₆N₆O

(320.35)

31

C

₁₈H₂₀N₆O₃

(368.39)

₁₇H₁₈N₄O₂

(310.35)

32

(5.78)

^∗(lit.³⁴m.p. 231–232).

^∗∗(lit.³⁷m.p. 279–280).

B, Benzene; D, Dioxan; DMF, Dimethylformamide; Et, Etanol; GAA, Glacial acetic

acid.

2-Methoxy-5-cyano-4-amino-6-(4-methoxyphenyl)-

pyrimidine (13)

To a solution of sodium (230 mg, 10 mmol) in methanol (30 mL),

thiourea (380 mg, 5 mmol) was added. When it became dissolved,

(920 mg, 5 mmol) of p-methoybenzylidenemalononitrile (5a) dissolved

in methanol (10 mL) were added. The resulting mixture was reﬂuxed

for 4 h. The reaction mixture was poured onto ice water and neutral-

ized by dil. hydrochloric acid (15%) up to pH 6; the solid product so

formed was collected by ﬁltration and washed several times by water

(Table III).

860

A. M. El-Agrody et al.

6-Amino-1,2,3,4-tetrahydro-4-(4-methoxyphenyl)-2-thioxopyr-

imidine-5-carboxamide (17), 6-(4-Methoxybenzylidine)

amino-1,2,3,4-tetrahydro-4-(4-methoxyphenyl)-2-thioxopyri-

midine-5-carboxamide (18), and 3,5-Di-cyano-4,6-di(4-methox-

yphenyl)-2,3,4,5-tetrahydropyridine-2-one (19)

Thiourea (760 mg, 10 mmol) and (E)-3-(4-methoxyphenyl)-2-cyanoprop-

enamide (6a) (2.02 g, 10 mmol) were added to a solution of sodium

methoxide (230 mg, 10 mmol) in dry methanol (40 mL). The mixture

was stirred at r.t. for 48 h, and the solvent was removed in vacuo. By

the addition of water (60 mL) and then adiciﬁed with 10% hydrochlo-

ric acid, a precipitate was formed that was collected and washed with

water. The product thus obtained was boiled with ethanol and ﬁltered.

The remaining solid was recrystallized from DMF to give 19. The boiled

ethanol gave a solid, which was separated by gas–liquid chromatogra-

phy into 17 and 18 (Table III).

6-Amino-1,2,3,4-tetrahydro-4-(4-methoxyphenyl)-2-

thioxopyrimidine-5-carboxylic acid (20)

Thiourea (760 mg, 10 mmol) and (E)-3-(4-methoxyphenyl)-2-cyanoprop-

enamide (6a) (2.02 g, 10 mmol) were added to a solution of sodium

methoxide (230 mg, 10 mmol) in dry methanol (40 mL). The mixture

was reﬂuxed for 4 h. The reaction mixture was poured onto ice water

and acidiﬁcation with (10%) hydrochloric acid; a precipitate was formed

that was collected and washed with water (Table III).

5-Cyano-4-oxo-6-(4-methoxyphenyl)-

2-thioxotetrahydro-pyrimidine (21)

Method A

To a solution of sodium (230 mg, 10 mmol) in methanol (50 mL),

thiourea (760 mg, 10 mmol) was added. When it became dissolved, (2.31

g, 10 mmol) of ethyl p-methoybenzylidenecyanoacetate (7a) was added

the resulting mixture was reﬂuxed for 4 h. The reaction mixture was

poured onto ice water and neutralized by dil. hydrochloric acid (10%) the

solid product so formed was collected by ﬁltration and washed several

times by water (Table III).

Method B for Compound 21 and 14

A mixture of 8 or 13 (1 mmol) and formic acid (10 mL) was reﬂuxed

for 3 h; the solvent was evaporated in vacuo, and the solid so obtained

Thioxopyrimidines and Related Derivatives

861

was washed by dil. ethanol; the obtained solid was recrystallized from

a suitable solvent.

(E)-Ethoxymethyleneamino-6-methoxy-4-(4-

methoxyphenyl)pyridine-3,5-dicarbonitrile (22) and

N-(5-Cyano-2-thioxo-6-(4-methoxyphenyl)-1,2-di-

Hydropyrimidin-4-yl)formamide (25)

A mixture of 13a or 8 (1 mmol), triethylorthoformate (148 mg, 1 mmol),

and acetic anhydride (10 mL) was reﬂuxed for 3–5 h then cooled, and

the solid product was collected by ﬁltration, washed by pet. ether, and

recrystallized from an appropriate solvent (Table III).

2-(N-Hydroxymethyl)amino-6-methoxy-4-(4-

methoxyphenylpyridine-3,5-di-carbonitrile (23)

A mixture of 13a (280 mg, 1 mmol) and formaline solution (1 mL) in

ethanol (10 mL) was reﬂuxed for 2 h; the solid product was collected by

ﬁltration and washed by dil. ethanol (Table III).

2-(N-Hydroxymethyl,N-(β-hydroxyethyl))amino-6-amino-4-

(4-methoxyphenyl)pyridine-3,5-dicarbonitrile (24)

A mixture of 13a (560 mg, 2 mmol), formaline solution (1 mL), and

ethanolamine (122 mg, 2 mmol) in ethanol (10 mL) was reﬂuxed for

2 h; the solid product was collected by ﬁltration and washed by dil.

ethanol (Table III).

2-(4-Amino-5-cyano-6-(4-methoxyphenyl)pyrimidin-

2-yl)thioethylacetate (26)

A solution of 4-amino-2-mercapto-6-(4-methoxyphenyl)pyrimidine-5-

carbonitrile (8) (258 mg, 1 mmol), ethyl chloroacetate (122 mg, 1 mmol),

and 2 drops of sodium methoxide were added. The mixture was reﬂuxed

for 3 h in dioxane (30 mL). The reaction mixture was poured onto ice

water and neutralized by dil. hydrochloric acid (10%); the solid product

so formed was collected by ﬁltration and washed several times by water

(Table III).

2-(2-Benzoylmethylthio)-4-amino-6-(4-

methoxyphenyl)pyrimidine-5-carbonitrile (27)

A solution of 4-amino-2-mercapto-6-(4-methoxyphenyl)pyrimidine-5-

carbonitrile (8) (516 mg, 2 mmol) and phenacylbromide (384 mg

862

A. M. El-Agrody et al.

2 mmol). The mixture was reﬂuxed for 1 h in ethanol (30 mL); the

solid product so formed was collected by ﬁltration and washed by dil.

ethanol (Table III).

4-Amino-6-(4-methoxyphenyl)-2-hydrazinylpyrimidine-

5-carbonitrile (28a) and 4-Amino-6-(4-chlorophenyl)-

2-hydrazinylpyrimidine-5-carbonitrile (28b)

A suspension of 8 or 9b (10 mmol) and hydrazine hydrate (320 mg,

10 mmol) in n-butanol (30 mL) was reﬂuxed for 3 h. The solvent was

evaporated in vacuo; the residue was triturated with dil. ethanol and

the solid, which separated, was ﬁltered off (Table III).

2-((Z)-2-Arylidenehydrazinyl)-4-amino-6-(aryl)pyrimidine-

5-carbonitrile 29a–e

A mixture of 28a,b (1 mmol) and aromatic aldehyde (1 mmol) in n-

butanol (10 mL) was reﬂuxed for 30 min. The solvent was evaporated

in vacuo; the solid product was collected by ﬁltration, washed by dil.

ethanol, and recrystallized from an appropriate solvent (Table III).

4-Amino-6-(4-methoxyphenyl)-2-[(3,5-dimethyl)-1H-pyrazol-

1-yl)pyrimidine-5-carbonitrile (30) and 2-(2-

Ethoxycarbonylisopropylidenehydrazinyl)-4-amino-

6-(4-methoxyphenyl)pyrimidine-5-carbonitrile (31)

A

suspension of 4-amino-6-(4-methoxyphenyl)-2-hydrazinylpyri-

midine-5-carbonitril (28a) (256 mg, 1 mmol), acetyl acetone and/or

ethyl aceto-acetate (1 mmol) in ethanol (30 mL) and 2 drops of piperi-

dine was added. The mixture was reﬂuxed for 3 h; the solid obtained

was collected by ﬁltration, washed by dil. ethanol, and recrystallized

from a suitable solvent (Table III).

1,6-Dihydro-4-(4-methoxyphenyl)-6-oxo-2-(piperidin-1-yl)-

pyrimidine-5-carbonitrile (32)

A suspension of 4-amino-2-mercapto-6-(4-methoxyphenyl)-pyrimidine-

5-carbonitrile (8) (516 mg, 2 mmol) and piperidine (168 mg, 2 mmol) was

reﬂuxed in ethanol (30 mL) for 3 h. The solid obtained was collected by

ﬁltration and washed by dil. ethanol (Table III).

REFERENCES

[1] A. R. Katritzky, Advances in Heterocyclic Chemistry (Academic Press, New York,

1966), Vol. 6.

Thioxopyrimidines and Related Derivatives

863

[2] C. R. Criag and E. F. Shidenman, J. Pharmacal. Exp. Ther., 35, 179 (1971); Chem.

Abstr. 74, 62990j (1971).

[3] D. T. Hurst and J. C. Christophides, Heterocycles., 6, 1977 (1999).

[4] A. Mange, V. Martines-Merino, C. Sammartin, F. J. Fernandwz, M. C. Ochoda, C.

Bellver, P. Artigas, and E. Fernandez-Alverez, Eur. J. Med. Chem., 24, 209 (1989).

[5] D. T. Hurst, C. Beaumont, D. T. E. Jones, D. AKingsly, J. D. Partridge, and T. J.

Rutherford, Aut. J. Chem., 41, 1209 (1988).

[6] K. Kikuawa, J. Kato, and A. Iwata, Anal. Biochem., 174, 512 (1988).

[7] J. A. Knight, R. K. Pieper, and L. Meclellan, Clin. Chem., 34, 2433 (1988).

[8] P. W. Albro, J. T. Corbett, and J. L. Schroeder, J. Biochem. Biophs. Methods, 13, 185

(1986).

[9] T. Kata, Japn. Kokai Tokkyo Koho JP., 59, 190, 974 (1984).

[10] Y. S. Sadanandam, M. M. Shetty, and P. V., Diwan, Eur. J. Med. Chem., 27, 87

(1992).

[11] D. Bozing, P. Benko, L. Petocz, M. Szecsey, P. Toempe, G. Gigles, I. Gacsalyi, and

I. Gyertyan, EGIS Gyoyszergyar, Eur. pat. Appl. Ep., 409 233 (1991); Chem. Abstr.,

114, 247, 302z (1991).

[12] M. Ertan, A. Balkan, S. Sarac, S. Uma, K. Ruebseman, and J. F. Renaud, Arzneim-

Forsch., 41, 725 (1991).

[13] G. Siliniece and A. Kimenis, Farmakal. Neirotroprykh Sredstv., 135 (1978); Chem.

Abstr., 92, 69368t (1980).

[14] T. Godfraind, R. Miller, and M. Wibo, Pharmacal. Rev., 38, 321 (1986).

[15] E. Compaigne and S. W. Schneller, Synthesis, 11, 705 (1976).

[16] F. Freeman, Chem. Rev., 31, 224 (1980).

[17] F. Freeman, Synthesis, 12, 825 (1981).

[18] S. K. Chatterjee and N. Anand, J. Sci. Ind, Re., Sect. B., 17, 63 (1958).

[19] G. Cottis and H. Tiecklmann, J. Org. Chem., 26, 79 (1961).

[20] W. S. Emerson and T. M. Patric, J. Org. Chem., 14, 795 (1949).

[21] F. D. Popp and A. Catals, Org. Chem., 62, 2738 (1961).

[22] Z. El-Shahat Kandeel, K. Mohamed Hassan, N. Ahmed Ismail, and M. Hilmy

ElNagdi, J. Prakt. Chemie, 326, 248 (1984).

[23] A. Lorente, Josel. G. Navio, Josec. L. Pesez, and Jose. L. Soto, Communication, 89

(1985).

[24] M. K. A. Ibrahim, M. R. H. El-moghayar, and M. A. F. Sharaf, Indian J. Chem., 26B,

216 (1987).

[25] M. K. A. Ibrahim, Indian J. Chem., 27B, 478 (1988).

[26] R. M. Fikry, J. Indian. Chem. Soc., 73, 698 (1996).

[27] G. W. Kenner and A. R. Todd, In Heterocyclic Compounds, Elderﬁeld, Ed. (John

Wiley & Sons, London, 1957), Vol. 6, p. 234.

[28] D. J. Brown, The Pyrimidine in the Chemistry of Heterocyclic Compounds, Suppl. 1,

A. Weissberger and E. C. Taylor, Eds. (Wiley-Interscince, New York, 1970), Vol. 16,

p. 20.

[29] T. S. Grifﬁn, T. S. Woods, and D. I. Klayman, Avd. Heterocyclic Chem. A. R. Katrizky,

and A. J. Boulton, Eds. (Acadimic Press, New York, London, 1975), Vol. 18, p. 121.

[30] S. M. S. Chauhan and H. Junjappa, Synthesis, 12, 880 (1974).

[31] F. G. Baddar, F. H. Al-Hajjar, and N. R. El-Rayyes, J. Heterocyclic Chem., 15, 105

(1978).

[32] F. H. Al-Hajjar, Y. A. Al-Farkh, and H. S. Hamoud, Can. J. Chem., 57, 2734

(1979).

[33] S. Kambe, K. Saito, H. Kishi, A. Sakurai, and H. Midorikawa, Synthesis, 4, 287

(1979).

864

A. M. El-Agrody et al.

[34] J. L. Garcia Navio, A. Lorente, and J. L. Soto, Heterocycles, 19, 305 (1982).

[35] C. F. Bernaconi, J. P. Fox, and S. Fornaria., J. Am. Chem. Soc., 102, 2810 (1980).

[36] M. Angeles Cabrerizo, Y. Jose, and L. Soto, An. Quim., 70, 951 (1974).

[37] G. Ditz, W. Fiedler, and G. Faust, Chem. Ber., 100, 3127 (1967).

[38] L. P. Carrod and F. D. Grady, Antibiotic and Chemotherapy (Churchil Livingestoner

Edimburgh, 1972), 3rd Ed.

[39] Pcourvalin inter pretive reading Antimicrobial ceptibily testes, Am. Soc. Microbial

News, 25, 368 (1992).

Article Doi

Synthesis and antimicrobial activity of thioxopyrimidines and related derivatives

DOI: 10.1080/10426500500272087

Source and publish data:

Authors:

Article abstract of DOI:10.1080/10426500500272087

Full text of DOI:10.1080/10426500500272087

Products guided by the article

R&D Labs maybe for 926043-76-7

Relevant to this article

Hot Product