Synthesis of some new pyrazolo[1,5-a] pyrimidine, pyrazolo[5,1-c]triazine, 1,3,4-thiadiazole and pyridine derivatives containing 1,2,3-triazole moiety

Pyrazolo[1,5-a]pyrimidines are purine analogues. They have benefcial properties as antimetabolites in purine biochemical reactions. This division compounds have attracted wide pharmaceutical interest because of their antitrypanosomal activity.

Abdelriheem et al Chemistry Central Journal (2017) 11:53

DOI 10.1186/s13065-017-0282-4

RESEARCH ARTICLE

Synthesis of some new pyrazolo[1,5-a]

pyrimidine, pyrazolo[5,1-c]triazine,

1,3,4-thiadiazole and pyridine derivatives

containing 1,2,3-triazole moiety

Nadia A Abdelriheem1, Yasser H Zaki2,3* and Abdou O Abdelhamid1

Abstract

Background: Pyrazolo[1,5-a]pyrimidines are purine analogues They have beneficial properties as antimetabolites in

purine biochemical reactions This division compounds have attracted wide pharmaceutical interest because of their antitrypanosomal activity

Results: The present work depicts an effective synthesis convention of pyrazolo[1,5-a]pyrimidines, pyrazolo[5,1-c]

triazines, thieno[2,3-b]pyridines and polysubstituted pyridines containing 1,2,3,-triazole moiety from the reaction of sodium 3-(5-methyl-1-(p-toly)-1H-1,2,3-triazol-4-yl)-3-oxoprop-1-en-1-olate with the fitting heterocyclic amines and

its diazonium salt, and active methylene compounds, individually Likewise, thiazoles and, 1,3,4-thiadiazoles were

obtained from 2-bromo-1-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethanone and some reagent such as hydrazonoyl

chlorides and halo ketones The newly synthesized compounds were established by elemental analysis, spectral data, and alternative synthetic route whenever possible

Conclusions: New series of pyrazolo[1,5-a]pyrimidines, pyrazolo[5,1-c]triazines, thieno[2,3-b]pyridines and

polysub-stituted pyridines containing the 1,2,3,-triazole moiety were synthesized via reactions of sodium 3-(5-methyl-1-(p-toly)-1H-1,2,3-triazol-4-yl)-3-oxoprop-1-en-1-olate with the appropriate heterocyclic amines and its diazonium salt In

addition, 1,3,4-thiadiazoles and, 1,3-thiazoles were acquired in a decent yield via the reaction of substituted thiourea with the appropriate hydrazonoyl chlorides and halogenated ketenes

Keywords: 1,2,3-Triazole, Pyrazolo[1,5-a]pyrimidines, Pyrazolo[5,1-c]triazines, Thieno[2,3-b]pyridines,

1,3,4-Thiadiazoles, Hyrazonoyl chlorides, Thiazoles, Pyridines

© The Author(s) 2017 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/ publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated.

Background

Pyrazolo[1,5-a]pyrimidines are purine analogs and

therefore have valuable properties as antimetabolites in

purine biochemical activity This class of compounds has

attracted wide pharmaceutical interest because of their

antitrypanosomal activity [1], antischistosomal

activ-ity [2], and other activities such as HMG-CoA reductase

inhibitors [3], COX-2 selective inhibitors [4], AMP

phos-phodiesterase inhibitors [5], KDR kinase inhibitors [6],

selective peripheral benzodiazepine receptor ligaments [7], antimicrobial agents [8], and as antianxiety agents [9] Recently other pharmaceutical activities have been reported, for example, as an agent for the treatment of sleep disorders [10] and as an oncological agent [6] Also,

pyrazolo[5,1-c][1,2,4]triazines are known to exhibit a

broad range of biological activities [11–15] Due to their

structural similarities to nucleic bases, pyrazolo[5,1-c]

[1,2,4]triazines may act as metabolites and therefore they can be useful as antiviral and antitumor agents [11] Pyrazolotriazines have indicated a remarkable cytotoxic activity against colon, breast, and lung carcinoma cells [16] Some derivatives showed selective cytotoxicity in

Open Access

*Correspondence: yzaki2002@yahoo.com

2 Department of Chemistry, Faculty of Science, Beni-Suef University,

Beni-Suef 62514, Egypt

Full list of author information is available at the end of the article

hypoxic and normoxic conditions [17] The

1,3,4-thiadia-zole derivatives have attracted considerable interest due

to their wide spectra of biological activities such as

anti-bacterial, antifungal, antituberculosis, anti-hepatitis B

viral, antileishmanial, anti-inflammatory, analgesic, CNS

depressant, anticancer, antioxidant, antidiabetic,

mollus-cicidal, antihypertensive, diuretic, analgesic,

antimicro-bial, antitubercular, and anticonvulsant activities [18–27]

Results and discussion

Chemistry

The reaction of

1-(5-methyl-1-(p-tolyl)-1H-1,2,3-tria-zol-4-yl)ethan-1-one (1) with ethyl formate in diethyl

ether in the presence of sodium methoxide has afforded

sodium

3-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)-3-oxoprop-1-en-1-olate (2) Likewise, compound (1)

reacted with N,N-dimethylformamide-dimethylacetal

in boiling xylene to afford

3-(dimethylamino)-1-(5-

methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)prop-2-en-1-one (6) The reactivity of compound (2) and compound

(6) towards heterocyclic amines was inspected In this

manner, reaction of compound (2) or compound (6)

with each of 5-phenylpyrazole (3a),

3-amino-4-phenylpyrazole (3b), 3-amino-4-cyanopyrazole (3c),

3-amino-1,2,4-triazole (3d), 2-aminobenzimidazole (3e)

and 4,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-3-amine

(3f) in refluxing piperidinium acetate, in each case, only

one isolable product as evidenced by TLC The isolated

products (5a–f) (Scheme 1) were identified, on the base

of their elemental analysis, spectral data and according to

similar data obtained before [28–30]

The reaction of compound (2) or compound (6) with

each of diazotized 3-amino-5-phenylpyrazole (8a) and

diazotized 3-amino-4-phenylpyrazole (8b) in ethanol

containing sodium acetate at 0–5  °C yielded products

that were distinguished as

(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)(7-phenylpyrazolo[5,1-c][1,2,4]

triazin-3-yl)-methanone (10a) and

(5-methy-1-(p-tolyl)-

1H-1,2,3-triazol-4-yl)(8-phenylpyrazolo[5,1-c][1,2,4]tria-zin-3-yl)-methanone (10b), respectively (Scheme 2) The

structures of the products (10a) and (10b) were

consist-ent with their elemconsist-ental and spectral (Ms, IR, 1H NMR,

and the 13C NMR) analysis (see “Experimental section”)

To account for the formation of the products 10a and

10b, it is suggested as depicted in (Scheme 2) that the

reaction start with electrophilic substitution to yield the

corresponding azo derivative, which undergoes in  situ

dehydrative cyclization, gave the corresponding 10 as a

final product

Treatment of compound (2) with each of

ben-zenediazonium chloride (11a) or p-toluidine

diazonium chloride (11b) in ethanol containing sodium

acetate as a buffer solution yielded 3-(5-methyl-1-

(p-tolyl)-1H-1,2,3-triazol-4-yl)-3-oxo-2-(2-phenylhydra-zono)propanal (12a),

3-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)-3-oxo-2-(2-(p-tolyl)hydrazono)propanal

(12b), respectively (Scheme 3) The structures of

com-pound (12a) and comcom-pound (12b) were affirmed by

ele-mental analysis, spectral data, and alternative synthetic route In this way,

3-(dimethylamino)-1-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)prop-2-en-1-one (6) was

coupled with benzenediazonium chloride or

p-toluidine-diazonium chloride to give a product indistinguishable in all aspects (m.p., mixed m.p and spectra) with compound

(12a) and compound (12b), respectively The 1H NMR

spectrum of compound (12a) showed signals at δ = 2.06

(s, 3H, CH3), 2.34 (s, 3H, 4-CH3C6H4), 7.26–8.20 (m, 9H, ArH’s), 9.75 (s, 1H, CHO) and 14.39 (s, br., NH)

Reaction of compound (2) with cyanothioacetamide (13) in piperdinium acetate gave

2-mercapto-6-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)nicotinonitrile

(14) The Structure of compound (14) was elucidated

by elemental analysis, spectral data, and alternative syn-thetic route or chemical transformation Thus,

treat-ment of compound (6) with cyanothioacetamide in

ethanol containing a catalytic amount of piperidine under reflux gave a product identical in all aspects (m.p.,

mixed m.p and spectra) with compound (14) The prod-uct formulated from treatment of compound (14) with

ethyl chloroacetate, in N,N-dimethylformamide

con-taining potassium hydroxide was ethyl

3-amino-6-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)thieno[2,3-b]

pyridine-2-carboxylate (15a) corresponding to the

addi-tion, dehydrochlorinaaddi-tion, and cyclization reactions (Scheme 4) IR spectrum of compound (15a) showed a

band at 3460, 3355 (NH2 group) and no band of the CN function between 2100 and 2300  cm−1 The 1H NMR

spectrum of compound (15a) revealed signals at 1.26 (t,

3H, J  =  7  Hz, CH2CH3), 2.34 (s, 3H, 4-CH3C6H4), 2.64 (s, 3H, CH3), 4.23 (q, 2H, J = 7 Hz, CH2CH3), 6.8 (s, br., 2H, NH2), 7.32–7.63 (m, 5H, ArH’s) and 8.81–8.83 (d, 1H, ArH) and absence of signals of the –SCH2– group These results proved that the CN and the –SCH2– groups were both involved in the cyclization step leading to

com-pound (15a).

Also, compound (14) was reacted with each of

chlo-roacetone and ω-bromoacetophenone in

N,N-dimeth-ylformamide containing potassium hydroxide to afford

1-(3-amino-6-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)thieno[2,3-b]pyridin-2-yl)ethan-1-one (15b) and

6-(3-amino-6-(5-methyl-1-(p-tolyl)-1H-1,2,3-tria-

zol-4-yl)thieno[2,3-b]pyridin-2-yl)(phenyl)metha-none (15c) respectively Similarly, compound (14) was

reacted with chloroacetonitrile afforded

3-amino-6-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)thieno[2,3-b]

pyridine-2-carbonitrile (16), in a good yield (Scheme 4)

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Abdelriheem et al Chemistry Central Journal (2017) 11:53

The structures of compounds (15a–c) and (16) were

confirmed by elemental analysis and spectral data

Treatment of compound (6) with each of ethyl

ace-toacetate, acetylacetone, ethyl cyanoacetate,

malon-onitrile or benzoylacetmalon-onitrile in boiling acetic acid

containing ammonium acetate under reflux gave ethyl

2-methyl-6-(5-methyl-1-p-tolyl-1H-1,2,3-triazol-4-yl)pyridine-3-carboxylate (17),

1-(2-methyl-6-(5-methyl-1-p-tolyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)

ethanone (18),

1,2-dihydro-6-(5-methyl-1-p-tolyl-1H-1,2,3-triazol-4-yl)-2-oxopyridine-3-carbonitrile (20),

2-amino-6-(5-methyl-1-p-tolyl-1H-1,2,3-triazol-4-yl)

pyridine-3-carbonitrile (21),

6-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)pyridin-3-phenyl-2-carbonitrile (22),

respectively (Scheme 5) Structures (17), (18), and (20– 22) were confirmed based on elemental analysis and

spectral data (cf “Experimental section”)

Next, 4-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)

thiazol-2-amine (25) was prepared from the reaction of

2-bromo-1-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)

ethanone (23) [31] with thiourea The structure of

compound (25) was established based on

elemen-tal analysis, spectral data, and chemical

transfor-mation Thus, compound (25) was coupled with

Scheme 1 Synthesis of pyrazolo[1,5-a]pyrimidines (5a–c), 1,2,4-triazolo[1,5-a]pyrimidine (5d), benzo [4,5]imidazo[1,2-a]pyrimidine (5e), and

pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine (5f)

arenediazonium chlorides in ethanol contained sodium

acetate to afford

4-(5-methyl-1-(p-tolyl)-1H-1,2,3-tria-zol-4-yl)-5-(phenyldiazenyl)thiazol-2-amine (26a) and

5-((4-chlorophenyl)diazenyl)-4-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)thiazol-2-amine (26b), respectively

(Scheme 6) More evidence on the correct structure

of compound (26a) was obtained via reaction of

thio-urea with

2-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)-2-oxo-N-phenylacetohydrazonoyl bromide (28) in

boiling ethanol (cf “Experimental section”)

1-(4-(5-Methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)thia-zol-2-yl)-3-phenylthiourea (27) was prepared via reac-tion of compound (25) with phenyl isothiocyanate in

N,N-dimethylformamide containing potassium

hydrox-ide, followed by acidification with hydrochloric acid The

structure of compound (27) was confirmed by elemental

Scheme 2 Synthesis of pyrazolo[5,1-c]triazines (10)

R = 5-methyl-1-(p-tolyl)-1H-1,2,3

-triazol-4-yl

Scheme 3 Synthesis of 3-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)-3-oxo-2-(2-(aryl)hydrazono)propanal (12a) and (12b)

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Abdelriheem et al Chemistry Central Journal (2017) 11:53

Scheme 4 Synthesis of thieno[2,3-b]pyridines (15a–c) and (16)

Scheme 5 Synthesis of pyridine derivatives (17), (18), and (20–22)

analysis, spectral data, and chemical transformation

Thus, the appropriate hydrazonoyl chloride (30a–d) were

reacted with thioanilide (27) in N,N-dimethylformamide

in presence of triethylamine or potassium hydroxide to

give one isolable product according to TLC The structure

of the product may be one from the structure of

com-pound (31), (31A) or (31B) The obtained spectral data,

however, compatible only with the structures of (31a–d)

and formulated as:

N-(3-aryl-5-substituted-1,3,4-thiadia-

zol-2(3H)-ylidene)-4-(5-methyl-1-(p-tolyl)-1H-1,2,3-tria-zol-4-yl)thiazol-2-amine (31a–d) (Scheme 7)

Treatment of thiourea derivative (27) with

ω-bromoacetophenone or ethyl chloroacetate in

reflux-ing ethanol in the presence of triethylamine gave

N-(3,4-diphenylthiazol-2(3H)-ylidene)-4-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)thiazol-2-amine (32) and

2-((4-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)-thiazol-2-yl)imino)-3-phenylthiazolidin-4-one (33), respectively

(Scheme 8)

Experimental section

General methods

All melting points were determined on an electro

ther-mal Gallen Kamp melting point apparatus (lain George,

Calgary, Canda) and are uncorrected IR (cm−1) spectra were recorded on KBr disk on a FTIR-8201 spectropho-tometer (Shimadzu, Tokyo, Japan) 1H NMR and 13C NMR spectra were measured in deuterated dimethyl

sulfoxide (DMSO-d6) using a Mercury VX-300 NMR

spectrometer (Varian, Inc., Palo Alto, California 94304 USA) Mass spectra were recorded on a Shimadzu GCMS-QP1000 EX mass spectrometer (Tokyo, Japan)

at 70 eV Measurements of the elemental analysis were carried out at the Microanalytical Centre of Cairo Uni-versity, Giza, Egypt All reactions were followed by TLC (Silica gel, Merck, Kenilworth, NJ, USA) Hydrazonoyl halides were prepared as previously reported [32, 33]

Synthesis of sodium salt of 3‑hydroxy‑1‑(5‑methyl‑1‑(p‑tolyl)‑ 1H‑1,2,3‑triazol‑yl)prop‑2‑en‑1‑one (2)

A solution of

1-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethan-1-one (1) [34], (5.4  g, 25  mmol) in ether (25  ml) was added to a mixture of sodium methoxide (1.4 g, 25 mmol) and ethyl formate (1.9 ml, 25 mmol) in dry ether (25 ml) while stirring in ice-bath at 0–5 °C for

2  h The resulting solid was collected and washed with

diethyl ether which afforded compound (2) that was used

without crystallization, yield (76%)

Scheme 6 Synthesis of thiazoles (25), (26), and (27)

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Abdelriheem et al Chemistry Central Journal (2017) 11:53

Scheme 7 Synthesis of 1,3,4-thiadiazoles (31a–d)

Scheme 8 Synthesis of thiazole (32) and thiazolone (33)

Synthesis of 3‑(dimethylamino)‑1‑(5‑methyl‑1‑(p‑tolyl)‑1H‑1,

2,3‑triazol‑4‑yl)prop‑2‑en‑1‑one (6)

A mixture of

1-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl)ethane-1-one (1) (2.3 g, 0.1 mol) and

N,N-dimethyl-formamide-dimethylacetal (11.9 g, 14 ml, 0.1 mol) in dry

xylene (30 ml) was heated under reflux for 4 h The hot

solution evaporated to its half volume and then cooled

The resulting solid was collected and recrystallized from

benzene to give the compound (6) as orange crystals

Yield: (83%); m.p b135 °C FT-IR (KBr, cm−1): 3041, 2965

(CH), 1688 (CO), 1645 (C=N), 1589 (C=C); 1H NMR

(300 MHz, DMSO-d6): δ = 2.31 (s, 3H, CH3), 2.42 (s, 3H,

CH3), 2.48 (s, 3H, CH3), 3.15 (s, 3H, CH3), 6.15 (d, 1H,

J = 12 Hz, CH=), 7.76 (d, 1H, J = 12 Hz, CH=); 7.40–

7.50 (m, 4H, ArH’s) Anal Calcd for C15H18N4O (270.34),

C, 66.64; H, 6.71; N, 20.73 Found: C, 66.67; H, 6.69; N,

20.80

Synthesis of pyrazolo[1,5‑a]pyrimidines (5a–c), [1,2,4]

triazolo[1,5‑a]pyrimidine (5d), benzo [4,5]imidazo[1,2‑a]

pyrimidine (5e) and pyrido[2′,3′:3,4]pyrazolo[1,5‑a]pyrimi‑

dine (5f)

Method A A mixture of sodium salt (2) (1.32 g, 10 mmol)

and the appropriate heterocyclic amines (3a–f) (10 mmol)

in a solution of piperidinium acetate [piperidine (2.5 ml),

water (5  ml) and acetic acid (2  ml)] was heated under

reflux for 15 min, acetic acid (1.5 ml) was added to the

reaction mixture while boiling, then the mixture was

cooled and the resulting solid was collected and

crystal-lized from the proper solvent gave (5a–f).

Method B A mixture of compound (6) (1.35 g, 10 mmol),

the appropriate heterocyclic amines (3a–f) (10 mmol) and

ammonium acetate (0.77 g, 10 mmol) in acetic acid (20 ml)

was heated under reflux for 4 h The reaction mixture was

cooled, after that, the resulting solid was collected and

crystallized from the proper solvent and gave product

identical in all aspects (m.p., mixed m.p., spectra) with the

corresponding (5a–f), which was obtained in method A.

7‑(5‑Methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑triazol‑4‑yl)‑2‑phenylpyrazol

o[1,5‑a]pyrimidine (5a)

Yellow crystals from ethanol, yield (75%); m.p 195–

197 °C FT-IR (KBr, cm−1): 2981 (CH); 1635 (C=N); 1566

(C=C) 1H NMR (300  MHz, CDCl3): δ  =  2.50 (s, 3H,

CH3) 2.65 (s, 3H, CH3), 6.82 (s, 1H, pyrazol H-4), 7.13 (d,

1H, J = 4 Hz, pyrimide H-5), 7.32–7.35 (m, 2H, ArH’s),

7.45–7.62 (m, 5H, ArH’s), 7.77–7.82 (m, 2H, ArH’s),

8.57 (d, 1H, J = 4 Hz, pyrimide H-6) 13C NMR (CHCl3)

δ  =  10.4, 20.6, 98.8, 111.2, 122.5, 127.4, 128.4, 128.8,

130.1, 131.8, 132.2, 133.4, 139.7, 141.2, 144.5, 146.4,

148.2, 152.3 Anal Calcd for C22H18N6 (366.43): C, 72.11;

H, 4.95; N, 22.94 Found: C, 72.20; H, 4.80; N, 22.89

7‑(5‑Methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑triazol‑4‑yl)‑3‑phenylpyrazol o[1,5‑a]pyrimidine (5b)

Yellow crystals from ethanol, yield (75%); m.p 230  °C FT-IR (KBr, cm−1): 3028 (CH); 1635 (C=N); 1573(C=C)

1H NMR (300  MHz, CDCl3): 2.49 (s, 3H, CH3) 2.59 (s, 3H, CH3), 6.90–6.92 (d, 2H, J  =  8  Hz, ArH’s), 7.10 (d, 1H, J = 8 Hz, pyrimidine H-5), 7.32–7.35 (m, 2H, ArH’s),

7.45–762 (m, 5H, ArH’s), 8.32 (s, 1H, pyrazole H-3),

and 8.68 (d, 1H, J = 4 Hz, pyrimidine) Anal Calcd for

C22H18N6 (366.43): C, 72.11; H, 4.95; N, 22.94 Found: C, 72.20; H, 4.80; N, 22.89

7‑(5‑Methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑tria‑

zol‑4‑yl)‑pyrazolo[1,5‑a]pyrimidin‑3‑carbonitrile (5c)

Orange crystals from ethanol, yield (70%); m.p 235–

237 °C FT-IR (KBr, cm−1): 3039, 2970 (CH); 2225 (CN);

1635 (C=N); 1573 (C=C) 1H NMR (300 MHz, CDCl3):

δ  =  2.49 (s, 3H, CH3) 2.54 (s, 3H, CH3), 7.26–7.59 (m, 5H, ArH’s), 8.95 (s, 1H, pyrazol H-3), and 8.84 (d, 1H,

J = 4 Hz, pyrimidine H-6) 13C NMR in CHCl3 δ = 10.4, 20.6, 98.8, 52.4 (CN), 111.2, 11.3.1, 122.4, 128.4, 133.4, 135.1, 139.7, 141.2, 144.5, 146.4, 148.2, 155.3 Anal Calcd for C17H13N7 (315.39): C, 64.75; H, 4.16; N, 31.09 Found:

C, 64.65; H, 4.26; N, 31.12

5‑(5‑Methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑triazol‑4‑yl) [1,2,4]

triazolo[1,5‑a]pyrimidine (5d)

White crystals from acetic acid, yield (65%); m.p 302 °C FT-IR (KBr, cm−1): 3047, 2993 (CH); 1620 (C=N), 1577 (C=C) 1H NMR (300  MHz, DMSO-d6): δ  =  2.07 (s, 3H, CH3) 2.49 (s, 3H, CH3), 6.62–6.63 (d, J = 4 Hz, 1H,

pyrimidine H-5), 7.14–7.67(m, 4H, ArH,s), 8.27 (s, 1H,

triazole), 9.27–9.28 (d, 1H, J  =  4  Hz, pyrimidine H-6)

Anal Calcd for C15H13N7 (291.32): C, 61.84; H, 4.50; N, 33.66 Found: C, 61.75; H, 4.40; N, 33.60

4‑(5‑Methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑triazol‑4‑yl)benzo [4,5] imidazo[1,2‑a]pyrimidine (5e)

Yellow crystals from ethanol, yield (65%); m.p 200–

202 °C FT-IR (KBr, cm−1): 3047, 2981 (CH); 1635 (C=N);

1600 (C=C) 1H NMR (300  MHz, CDCl3): δ  =  2.49 (s, 3H, CH3) 2.79 (s, 3H, CH3), 7.26–7.43 (m, 7H, ArH’s)

8.43–8.45(d, 1H, ArH), 8.80–8.82 (d 1H, J = 8 Hz, ArH), 9.65–9.66 (d, 1H, J = 8 Hz, pyrimidine H-6) MS (El), m/z

(%): 338 (M-2,65), 323 (35), 304 (50), 275 (90), 262 (70),

249 (20), 221 (30), 132 (100), 91 (90), 77 (20), 65 (40) Anal Calcd for C20H16N6 (340.39), C, 70.57; H, 4.74; N, 24.69 Found: C, 70.64; H, 4.48; N, 24.58

8,10‑Dimethyl‑4‑(5‑methyl‑1‑(p‑tolyl)‑1H‑1,2,3,‑triazol‑4‑yl) pyrido[2′,3′:3,4]pyrazolo[1,5‑a]pyrimidine (5f)

Yellow crystals from ethanol, yield (75%); m.p 278–

281 °C FT-IR (KBr, cm−1): 3064, 2951, 2851 (CH); 1624

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Abdelriheem et al Chemistry Central Journal (2017) 11:53

(C=N); 1597 (C=C) 1H NMR (300  MHz, DMSO-d6):

δ  =  2.44 (s, 3H, CH3), 2.51 (s, 3H, CH3), 2.60 (s, 3H,

CH3), 2.88 (s, 3H, CH3), 6.98–7.00 (s, 1H, J = 8 Hz,

pyri-dine H-3), 7.47–7.84 (m, 5H, ArH’s) and 8.89–8.87 (d,

1H, J  =  8  Hz, pyrimidine H-6) 13C NMR (DMSO-d6)

δ = 10.4, 19.6, 20.6, 21.4, 101.2, 112.4, 114.8, 122.4, 125.7,

128.6, 130.4, 131.6, 139.4, 141.3, 145.5, 151.3, 153.2,

164.7 Anal Calcd for C21H19N7 (369.43), C, 68.28; H,

5.18; N, 26.54 Found: C, 68.20; H, 5.15; N, 26.45

Synthesis of 5‑methly‑1‑(p‑tolyl)‑1H‑1,2,3‑triazol‑4‑yl)

(7‑phenylpyrazolo[5,1‑c]‑[1,2,4]‑triazin‑3‑yl)methanone

(10a) and 5‑methly‑1‑(p‑tolyl)‑1H‑1,2,3‑triazolo‑4‑yl)(8‑phe‑

nyl pyrazolo[5.1‑c][1,2,4]‑triazin‑3‑yl)methanone (10b)

Method A Dropwise addition of a solution of the

appro-priate diazonium salt of heterocyclic amines (8a) and (8b)

(5 mmol) to a stirred mixture of sodium salt of (2) (1.25 g,

5  mmol), sodium acetate (0.65  g, 5  mmol) in ethanol

(30 ml) at 0–5 °C The solid so formed after 3 h and was

collected, washed with water and recrystallized to give

compound (10a) and, compound (10b), respectively.

Method B A solution of the appropriate diazonium salt

of heterocyclic amines (8a) or (8b) (5 mmol) were added

dropwise while stirring a mixture of compound (6) (1.35 g,

5  mmol), sodium acetate (0.65  g, 5  mmol) in ethanol

(30 ml) at 0–5 °C The resulting solid so formed after 3 h

and was collected, washed with water, and recrystallized

to give product identical in all aspects (m.p., mixed m.p

and spectra) with the corresponding compound (10a) and

compound (10b), which was obtained in method A.

4‑(5‑Methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑triazol‑4‑yl)‑7‑phenylpyrazol

o[5,1‑c][1,2,4]triazine (10a)

Brown crystals from ethanol, yield (75%); m.p 215–

217 °C FT-IR (KBr, cm−1): 3058, 2969, 2922 (CH); 1681

(CO); 1639 (C=N); 1544 (C=C) 1H NMR (300  MHz,

DMSO-d6): δ = 2.44 (s, 3H, CH3), 2.64 (s, 3H, CH3), 6.33

(s, 1H, pyrazole H-4), 7.32–7.34 (d, 2H, J = 8 Hz, ArH’s),

7.49–7.61 (m, 5H, ArH’s), 7.87–7.89 (d, 2H, J  =  8  Hz,

ArH’s) and 9.8 (s, 1H, triazine H-4) 13C NMR in

DMSO-d6 δ = 10.4, 20.6, 101.1, 120.3, 121.4, 127.4, 128.5, 129.5,

130.2, 134.2, 134.6, 139.6, 142.4, 146.7, 153.1, 154.2 Anal

Calcd for C22H17N7O (395.43): C, 66.82; H, 4.33; N,

24.80 Found: C, 66.89; H, 4.40; N, 24.75

4‑(5‑Methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑triazol‑4‑yl)‑8‑phenylpyrazol

o[5,1‑c][1,2,4]triazine (10b)

Pale brown crystals from ethanol, yield (70%); m.p 258–

260 °C FT-IR (KBr, cm−1): 3046,2919 (CH); 1675 (CO);

1646 (C=N); 1609 (C=C) 1H NMR (300 MHz,

DMSO-d6): δ = 2.46 (s, 3H, CH3), 2.64 (s, 3H, CH3), 7.42–7.61

(m, 7H, ArH’s), 8.34–8.37 (d, 2H, J = 8 Hz, ArH,s), 9.24

(s, 1H, pyrazole H-3) and 10.19 (s, 1H, triazine H-4)

13C-NMR (DMSO-d6) δ = 10.4, 20.6, 102.3, 120.6, 121.3, 125.6, 126.8, 126.2,1 29.4, 130.2, 133.4, 134.8, 139.6, 142.5, 1146.7, 151.7, 154.8 Anal Calcd for C22H17N7O (395.43): C, 66.82; H, 4.33; N, 24.80 Found: C, 66.90; H, 4.37; N, 24.75

Synthesis of 3‑(5‑methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑tria‑

zol‑4‑y1)‑3‑oxo‑2‑(2‑phenylhydrazono)propanal (12a) and 3‑(5‑methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑tria‑

zol‑4‑y1)‑3‑oxo‑2‑(2‑p‑tolylhydrazono)propanal (12b)

Method A Dropwise addition of a solution of the

appro-priate arenediazonium chloride (aniline and

p-methylani-line) (5 mmol) to a stirred mixture of (2) (1.25 g, 5 mmol),

sodium acetate (0.65  g, 5  mmol) in ethanol (30  ml) at 0–5 °C the solid so formed after 3 h and was collected and

crystallized from ethanol to afford (12a) and (12b).

Method B Dropwise addition of a solution of the

appro-priate arenediazonium chloride (aniline and

p-methylani-line) (5 mmol) to a stirred mixture of (6) (1.35 g, 5 mmol),

sodium acetate (0.65  g, 5  mmol) in ethanol (30  ml) at 0–5 °C The solid so formed after 3 h then it was collected and crystallized from ethanol to give products identical in all aspects (m.p., mixed m.p., spectra) with corresponding compounds obtained from method A

3‑(5‑Methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑triazol‑4‑y1)‑3‑oxo‑2‑(2‑phe‑ nylhydrazono)propanal (12a)

Brown crystals from ethanol, yield (85%); m.p 215–

217 °C FT-IR (KBr, cm−1): 3435 (NH); 2924 (CH); 1644 (C=N), 1H NMR (300 MHz, DMSO-d6): δ = 2.06 (s, 3H,

CH3), 2.34 (s, 3H, CH3), 7.26–8.20 (m, 9H, ArH’s), 9.75 (s, 1H CHO) and 14.39 (s, br.,1H, NH) Anal Calcd for

C19H17N5O2 (347.38): C, 65.69; H, 4.93; N, 20.16 Found:

C, 65.73; H, 4.84; N, 20.12

3‑(5‑Methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑tria‑

zol‑4‑y1)‑3‑oxo‑2‑(2‑p‑tolyl)‑hydrazono)propanal (12b)

Dark pink crystals from ethanol, yield (85%); m.p 210–

212 °C FT-IR (KBr, cm−1): 3438 (NH); 2922 (CH), 1643 (C=C), 1H NMR (300 MHz, DMSO-d6): δ = 2.43 (s, 3H,

CH3), 2.53 (s, 3H, CH3), 2.66 (s, 3H, CH3), 7.30–7.72 (m, 8H, ArH’s), 10.80 (s, 1H, CHO) and 13.9 (s, br., 1H, NH) Anal Calcd for C20H19N5O2 (361.41): C, 66.4; H, 5.30; N, 19.38 Found: C, 66.52; H, 5.38; N, 19.46

Synthesis of 2‑mercapto‑6‑(5‑methyl‑1‑(p‑tolyl)‑1H‑1,2,3

‑triazol‑4‑yl)nicotinonitrile (14)

Method A A mixture of sodium salt (2) (1.25 g, 5 mmol)

and 2-cyanothioacetamide (0.5 g, 5 mmol) in piperidine acetate [piperidine (2.5 ml), water (5 ml) and acetic acid (2  ml)] was heated under reflux for 15  min, acetic acid

(1.5 ml) was added to the reaction mixture while boiling

then the mixture was cooled and the resulting solid was

collected and recrystallized from the proper solvent to

give compound (14).

Method B A mixture of (6) (1.35 g, 5 mmol) and

cyan-othioacetamide (0.5 g, 5 mmol) in ethanol (20 ml) and a

catalytic amount of piperidine (10 ml) was heated under

reflux for 4 h After cooling, the resulting solid was

col-lected and recrystallized from ethanol to afford

com-pound 14 as brown crystals from ethanol, yield (65%);

m.p 262–265  °C FT-IR (KBr, cm−1): 3074, 2962 (CH);

2218 (CN); 1573 (C=C) 1H NMR (300  MHz,

DMSO-d6): δ = 2.43 (s, 3H, CH3), 2.61 (s, 3H, CH3), 5.87 (s, 1H,

SH), 7.34–7.36 (d, 2H, J  =  8  Hz, ArH’s), 7.52–7.54 (d,

2H, J = 8 Hz, ArH’s), 7.72–7.74 (d, 1H, J = 8 Hz, ArH’s),

8.39–8.41 (d, 1H, J = 8 Hz, ArH’s) 13C NMR (DMSO-d6)

δ  =  10.4, 20.6, 104.6, 116.5, 123.4, 125.8, 128.4, 139.7,

140.9, 143.8, 144.2, 147.2, 170.8, 173.8 MS (El, m/z (%):

308 (M + 1, 20), 294 (80), 278 (9), 264 (50), 237 (20), 219

(5), 177 (10), 144 (40), 132 (20), 91 (45), 80 (30), 64 (100)

Anal Calcd for C16H13N5O (307.38), C, 62.52; H, 4.26; N,

22.78 Found: C, 62.57; H, 4.23; N, 22.85

Synthesis of ethyl 3‑amino‑6‑(5‑methyl‑1‑(p‑tolyl)‑1H‑1,2,

3,‑triazol‑4‑yl)thieno[2,3‑b]pyridine‑2‑carboxylate (15a),

1‑(3‑amino‑6‑(5‑methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑triazol‑4‑y1)

thino[2,3‑b]pyridin‑2‑yl)‑ethan‑1‑one (15b), 6‑(3‑amino–

6‑(5‑methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑triazal‑4‑yl)thieno[2,3‑b]

pyridin‑2‑yl)‑(phenyl)methanone (15c), and 3‑amino‑6‑(5‑

methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑triazol‑4‑yl)thieno[2,3,‑b]‑pyri‑

dine‑2‑carbonitrile (16)

A mixture of compound (14) (2.1 g, 5 mmol), potassium

hydroxide (0.28  g, 5  mmol) in N,N-dimethylformamide

(10 ml) was stirred for 2 h then, the appropriate of ethyl

chloroacetate, chloroacetone, ω-bromoacetophenone

and chloroacetonitrile (5 mmol) was added while stirring

Stirring was continued for 2 h, the resulting solid was

col-lected and crystallized from the proper solvent to afford

compounds (15a–c), and (16) respectively.

Ethyl 3‑amino‑6‑(5‑methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑triazol‑4‑yl)

thieno[2,3‑b]pyridine‑2‑carboxylate (15a)

Gray crystals from acetic acid, yield (65%); m.p >300 °C

FT-IR (KBr, cm−1): 3460, 3355 (NH2); 3062, 2970 (CH),

1666 (CO); 1604 (C=C) 1H NMR (300 MHz, DMSO-d6):

δ = 1.26 (t, 3H, J = 7 Hz, CH2CH3), 2.34 (s, 3H, CH3), 2.64

(s, 3H, CH3), 4.23 (q, 2H, J = 7 Hz, CH2CH3), 6.80 (s, br.,

2H, NH2), 7.32–7.34 (d, 2H, J = 8 Hz, ArH’s), 7.52–7.54 (d,

2H, J = 8 Hz, ArH’s), 7.61–7.62 (d, 1H, J = 8 Hz, ArH’s),and

8.81–8.83 (d, 1H, J  =  8  Hz, ArH); 13C NMR (DMSO-d6)

δ = 10.4, 14.7, 20.6, 59.5, 105.7, 121.2, 123.2, 128.6, 133.8, 139.8, 140.7, 143.8, 44.2, 144.3, 149.7, 155.4, 166.1 Anal Calcd for C20H19N5O2S (393.47): C, 61.05; H, 4.87; N, 17.80

S, 8.1 Found: C, 61.15; H, 4.81; N, 17.76; S, 8.09

1‑(3‑Amino‑6‑(5‑methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑triazol‑4‑yl) thieno[2,3‑b]pyridin‑2‑yl)ethanone (15b)

Brown crystals from acetic acid, yield (65%); m.p 278–

280 °C FT-IR (KBr, cm−1): 3419, 3321 (NH2); 3092, 2920 (CH); 1675 (CO); 1593 (C=C) 1H NMR (300  MHz, DMSO-d6), δ  =  2.35 (s, 3H, CH3), 2.49 (s, 3H, CH3), 2.62 (s, 3H, CH3), 5.79 (s, br., 2H, NH2), 7.32–7.34 (d,

2H, J = 8 Hz, ArH’s), 7.52–7.54 (d, 2H, J = 8 Hz, ArH’s), 7.70–7.72 (d, 1H, J = 8 Hz, ArH’s) and 8.71–8.73 (d, 1H,

J  =  8  Hz, ArH); 13C NMR (DMSO-d6) δ  =  10.4, 20.6, 128.8, 120.4, 122.7, 123.6, 134.0, 139.8, 140.7, 143.5, 144.2, 149.4, 156.1, 190.9 Anal Calcd for C19H17N5OS (363.45): C, 62.79; H, 4.71; N, 19.27 S, 8.83 Found: C, 62.81; H, 4.71; N, 19.17; S, 8.75

(3‑Amino‑6‑(5‑methyl‑1‑(p‑tolyl)‑1H‑1,2,3‑triazol‑4‑yl) thieno[2,3‑b]pyridin‑2‑yl)(phenyl)methanone (15c)

Brown crystals from acetic acid, yield (65%); m.p 220 °C FT-IR (KBr, cm−1): 3402, 3286 (NH2); 3066, 2920 (CH);

1665 (CO); 1608 (C=C) 1H NMR (300  MHz, DMSO-d6): δ = 2.43 (s, 3H, CH3), 2.57 (s, 3H, CH3), 5.82 (s, br., 2H, NH2), 7.10–7.87 (m, 11H, ArH’s) Anal Calcd for

C24H19N5OS (425.52), C, 67.74; H, 4.56; N, 16.46; S, 7.54 Found: C, 67.81; H, 4.60; N, 16.53; S, 7.62

3‑Amino‑6‑(5‑methyl‑1‑(p‑tolyl)‑1H‑1,2,3,‑triazol‑4‑yl) thieno[2,3,‑b]pyridine‑2‑carbonitrile (16)

Brown crystals from acetic acid, yield (60%); m.p

245 °C FT-IR (KBr, cm−1): 3344, 3236 (NH2); 3058, 2923 (CH); 2194 (CN); 1639 (C=N); 1581 (C=C) 1H NMR (300  MHz, DMSO-d6): δ  =  2.43 (s, 3H, CH3), 2.57 (s, 3H, CH3), 7.10–7.87 (m, 7H, ArH’s and NH2), 9.21–9.23

(d, 1H, J = 8 Hz, ArH) 13C NMR (DMSO-d6) δ = 10.4, 20.6, 93.8, 115.9, 118.6, 121.7, 125.1, 126.3, 126.7, 130.2, 133.2, 133.9, 138.7, 142.9, 147.9, 156.6 Anal Calcd for

C18H14N6S (346.42), C, 62.41; H, 4.07; N, 24.26 S, 9.26 Found: C, 62.50; H, 4.17; N, 24.30; S, 9.36

Synthesis of pyridine derivatives (17), (18) and (20–22)

A mixture of the appropriate ethyl acetoacetate, acety-lacetone, ethyl cyanoacetate, benzoylacetonitrile,

malon-onitrile (5 mmol), (6) (1.35 g, 5 mmol) and ammonium

acetate (0.37  g, 5  mmol) in acetic acid (30  ml) was refluxed for 4  h, the resulting solid was collected and

recrystallized from the proper solvent to give (17), (18), and (20–22), respectively.