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Pyrimidine Derivatives and Related Compounds, III

Synthesis of Some New Pyrazolo[l,5-a]pyrimidines and Pyrazolo [3,4-d] pyrimidine Derivatives

M O H A M E D H I L M Y E L N A G D I * , S H E R I E F M A H M O U D F A H M Y , E Z Z A T M O H A M E D Z A Y E D ,

a n d M O H A M E D A J M A L M O H A M E D I L I A S

Department of Chemistry, Faculty of Science, Cairo University, Giza, A. R. Egypt

(Z. Naturforsch. 31 b, 795-800 [1976]; received December 5, 1975)

/S-Cyanoethylhydrazine, Enaminonitriles, Cyanoethylation, IR

Whereas /3-cyanoethylhydrazine (1) reacts with the /?-ethoxy-a, /3-unsaturated nitriles (2 a -c) to yield the 5-amino-l-/?-cyanoethylpyrazoles (3 a-c), 1 reacts with anilino-methylenemalononitrile (2d) to yield 3-amino-l-/S-cyanoethyl-4-cyanopyrazole (4; R = H ; X = CN). 3 a readily cyclised into the 5-amino-6,7-dihydropyrazolo[l,5-a]pyrimidine derivative (6) by the action of ethanolic guanidine. 6 was readily converted into the oxo derivative (7) by the action of acetic acid. 7 was also obtained by the action of 1 % NaOH on 3a . On the other hand, 3b afforded a mixture of the pyrazolo[l,5-a]pyrimidine derivative (8) and the carboxylic acid (9) when treated with 1 % NaOH solution.

3-Aminocrotononitrile (2e) reacted with 1 to yield the hydrazone derivative (12). The latter derivative was converted into the pyrazolo[l,5-a]pyrimidine derivative (14) by the action of acetic acid. On the other hand, the hydrochloride (15) was formed on treatment of 12 with acetic acid hydrochloric acid mixture.

Compounds 3a,b reacted with carbon disulphide to yield the pyrazolo[3,4-d]-6(7H)-w-thiazinethione derivatives (16 a, b). The latter were readily converted into the pyrazolo-[3,4-d]pyrimidine derivatives (17 a, b) by the action of aqueous NaOH solution.

Pyrazolopyrimidines are purine analogues and as such have useful properties as antimetabolites in purine biochemical reactions1-4. Moreover, many compounds of this type also have marked anti-tumour and anti-leukamic activity5-10. In previous work11-12 we described the reaction of ß-cyanoethyl-hydrazine (1) with malononitrile, phenylazomalo-nitrile and benzoylacetonitriles to give 5-amino-/?-cyanoethylpyrazole derivatives. The latter com-pounds were cyclized into 4,5,6,7-tetrahydro-pyiazolo[l,5-a]pyrimidin-5-ones with acid or aque-ous alkali11-13.

We have been particularly interested to see if reactions of this type might be extended to include more general synthesis of differently substituted 4,5,6,7 - tetrahy drapyrazolo [ 1,5 -a] pyrimidin es. It has been found that 1 reacts with the 3-ethoxy-2,3-

Requests for reprints should be sent to Dr. M. H. ELNAGDI, Chemistry Department, Faculty of Sciences, Cairo University, Giza, A. R., Egypt.

unsaturated nitriles (2a-c), in refluxing ethanol, to yield the 5-aminopyrazole derivatives (3 a-c) or possible isomeric 4 a-c. Structure 4 was readily eliminated since the reaction products of 1 and 2 a-c could be obtained by the action of acrylo-nitrile on the 5-aminipyrazole derivatives (5 a-c). That cyanoethylation of 5a,b has involved ring N-l and not ring N-2 or the excocychc amino group was assumed by analogy to the well established behav-iour of 5-aminopyrazoles on cyanoethylation11-16.

R CN \ /

H 2 N • N H C H 2 C H 2 C N c = c 1 / \

R ' X 2 a : R = O C 2 H 5 ; R ' - C H 3 ; X = C N 2b: R = OC2H5;R'=C6H5;X=CN 2 c : R = OC2H5 ; R ' = C H 3 : X = C 0 2 C 2 H 5

2 d : R = N H C 6 H 5 ; R / = H ; X = C N 2 e : R = N H 2 ; R ' = C H 3 ; X = H 2 f : R = OC 2 H 5 ;R / = H ; X = C N

796 M. H. ELNAGDI ET AL. • SYNTHESIS OF SOME NEW P Y R A Z O L O P Y R I M I D I N E DERIVATIVES

la-c

X NH2 XJ I CH2CH2CN

X NH2 Irf A . .N.CH2CH2CN FT ^ N '

mixture of the pyrazolo[l ,5-a]pyrimidine derivative (8) and the carboxylic acid (9) was formed com-pound 9 could be converted into 8 by reflux in acetic acid. Compound 8 could also be synthesised by the action of ethyl acrylate on 5 b.

3a

NH II N,N-C-NH,

X NH2

I f CH2=CHCN JL NH

5 3, 5a: R = CH3; X = C N 3, 5b: R = C6H5; X = CN 3 ,5c : R = CH3; X=C0 2 C 2 H 5

In contrast to the behaviour of 2 a-c toward the action of 1, treatment of 2d with the same reagent under the same experimental conditions has afforded the previously reported 3 - amino -l-ß-cyanoethyl-4-cyanopyrazole (4; R = H ; X=CN).

It has been previously shown that the vinyl ether moiety in 2 a-c is the most electrophilic center in the molecule17-18. Now, although the substituted nitrogen atom in 1 might be considered the better nucleophile in the reaction under consideration11-19, it is also the more hindered nitrogen atom and reports have appeared in which the reaction products of alkylhydrazines with electrophiles seem to be diverted exclusively from initial neucleophilic attack by the unsubstituted nitrogen of the hydrazine 2°-22. Since the reaction site in compounds 2 a-c is also more hindered than that in 2d and in ethoxy-methylenemalononitrile (2f) (cf. the reported be-haviour of 2f toward the action of 1 in ref. 11), the difference in behaviour between 2 a-c on one side and 2d, f on the other side might be justified.

Compound 3 a was cyclized by the action of guanidine in ethanol solution to yield 5-amino-3 - cyano - 2 - methyl - 6,7 - dihydropyrazolo [ 1,5 - a] pyri -midine (6). The latter when boiled in acetic acid for a short period was converted into the corresponding keto derivative (7). Compound 7 could be also obtained either directly from 3 a by the action of 1 % NaOH or from reaction of 5 a with ethyl acrylate.

In contrast to the behaviour of 3 a, attempted cyclization of 3 b with guanidine was unsuccessful. Moreover, when 3 b was treated with 1% NaOH a

nc\/VNH2

j = [ I AcOH

6

IC NH 0 J = | J 1 % NAOH

CH,-CHC0,C,H,

5a

3b

N C . NH , 0 NC NH2

5b CH,-CHC0,C,H,

CH2CH2C02H

2-Methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]-pyri-midine-3-carboxylate (10) was obtained on treat-ment of 3c with 1% NaOH under the experimental conditions used for cyclization of 2a,b.

3a 1% NaOH

" C H 3 V O 10

The behaviour of 2e toward the action of 1 was also investigated. Similar to its behaviour toward hydrazine hydrate23, 2e reacted with 1 to yield a product for which structure 12 or isomeric 13 seemed possible. Structure 13 was readily ruled out since the reaction product could be readily cyclised into the pyrazolo[l,5-a]pyrimidine derivative (14). The latter when refluxed with acetic acid-hydro-chloric acid mixture afforded 5-aminopyrazoline hydrochloride (15). This product, 15, could also be directly obtained from the reaction of 12 with acetic acid-hydrochloric acid mixture.

The reaction of 3 a, b with CS2 was investigated as a route for the synthesis of l-/?-cyanoethylpyrazolo-[3,4-d]pyrimidine derivatives. In accordance with T A Y L O R ' S reported behaviour of cyclic-enamino-nitriles24-25, compounds 3a,b reacted with CS2 in pyrimidine-DMF solution to yield the ra-thiazine derivatives (16 a, b). The latter could be readily rearranged into the pyrazolo[3,4-d]pyrimidine de-

797 M. H. ELNAGDI ET AL. • SYNTHESIS OF SOME NEW PYRAZOLOPYRIMIDINE DERIVATIVES

2a

CH3

NC^ >N-NHCH;CH2CN

CH, NC

CH3

> = N - N - C H 2 C H 2 C N

NH (

NH, _ „ AcOH-HCI / CH3 f = f

C H , ' ^ C N l NH . HCl N H

14 15

rivatives (17a,b) with 0.05 N NaOH solution. On the other hand, treatment of 16 a, b with 1 N NaOH at 100 °C has resulted in the formation of the amides (18 a, b). Compounds 18 a, b were also obtained on treatment of 17 a, b with 1 N NaOH solution or by the action of concentrated sulphuric acid on 17 a, b. When compounds 17 a, b or 18 a, b were refluxed with acetic acid-hydrochloric acid mixture the carboxy lie acid derivatives (19 a, b) were formed. The rearrangement of the m-thiazineimine ring in 16 a, b into the corresponding pyrimidine thione derivatives by the action of sodium hydroxide solution is similar to the previously reported re-arrangement of rw-thiazine into the corresponding pyrimidine-thiones24 -25.

\ A I -N N H C - S H . N T Q )

CHJCHJCN

\Xa « A

- U.A. N N

I2NOCCH2CHJ H

N N S I H

NCCH2CH2

N N S

H02CCH2CH2 H

18

-19a: R = CH3

- 1 9 b : R = C6H5

17 19

Experimental All melting points were determined on a micto

hot stage and are uncorrected. The IR spectra were recorded with a Hitachi grating infrared spectro-photometer Model EPI-G27.

5-Amino-4-cyano-l-ß-cyanoethyl-3-substituted-pyrazoles (3 a-c)

1) From reaction of 1 with 2a-c : To a suspension of each of 2 a-c (10.0 g) in ethanol (80 ml), 10 ml of 1 were added. The reaction mixture was refluxed for three hours. The solvent was then removed under vacuo and the resulting sohd products were tri-turated with water collected by filtration and crystallized from the proper solvent.

3a: colourless crystals from water, m.p. 173 °C; yield 12 g. IR: 3400, 3325 cm-1 (NH2 vibration); 2960, 2950, 2900 cm"1 (CH2 and CH3; 2250 cm-1

(unconjugated CN); 2200 cm - 1 (conjugated CN) and 1650 cm"1 (NH2 deformation). C8H9N5

Found C 54.66 H 5.16 N 39.97, Calcd C 54.84 H 5.18 N 39.98. 3b: colourless crystals from ethanol-water mix-

ture; m.p. 175 °C; yield 15.0 g. IR : 3420, 3320, 3225 cm-1 (NH2 vibration); 3010, 2990 em"1 (2 CH2); 2250cm-1 (unconjugated CN); 2200cm"1 (conju-gated CN) and 1640 cm - 1 (NH2 deformation). C13H11N5

Found C 65.68 H 4.93 N 29.85, Calcd C 65.81 H 4.67 N 29.52. 3c: colourless crystals from water; m.p. 155 °C,

yield 12.0 h; IR : 3450, 3350 cm-1 (NH2 vibrations), 2250cm-1 (conjugated CN); 1695cm-1 (ester CO) and 1620 cm -1 (NH2 deformation). Ci0H14O2N4

Found C 54.07 H 6.25 N 25.21, Calcd C 54.04 H 6.36 N 25.24. 2) From 5 a-c and acrylonitrile: A solution of each

of 5 a-c (2.0 g) in pyridine (80 ml) and water (20 ml) was treated with acrylonitrile (1.0ml) and the mixture was refluxed for four hours. The solvent was then removed in vacus and the remaining residue was disolved in hot water. The sohd prod-ucts, obtained on standing, were collected by filtration and identified (m.p. and mixed m.p. and by IR) as 3 a-c, respectively. Yields were 80, 80 and 70% respectively.

Reaction of 2d and 1: The reaction conditions described above for the reaction of 2 a-c with 1 were adopted. The reaction product was identified (m.p. and mixed m.p.) as 3 - amino -1 - - cy anoethy 1 - 4 -cyano-pyrazole11 (4; R = H ; X=CN) .

5-Amino-3-cyano-2-methyl-6,7-dihydropyrazolo-[1,5-a]pyrimidine (6)

To a solution of 3 a (2.0 g) in ethanol (50 ml) one equivalent of guanidine was added. The reaction

798 M. H. ELNAGDI ET AL. • SYNTHESIS OF SOME NEW PYRAZOLOPYRIMIDINE DERIVATIVES

was then left at room temperature for 60 hours. The crystalline product, so formed, was coUected by filtration and crystalhsed from dimethylformamide 10 yield 1.2 g of compound 6; colourless crystals m.p. >300 °C; IR : 3350, 3320, 3100 cm -1 (NH vibrations); 2200cm-1 (conjugated CN) and 1660cm-1

(NH2 deformation). C8H9N5

Found C 54.64 H 5.18 N 39.97, Calcd C 54.84 H5.18 N 39.98.

3-Cyano-2-methyl-4,5,6,7-tetrahydropyrazolo[ 1,5-a]-pyrimidine-5-one (7)

1) From 6 and acetic acid: A solution of 6 (0.5 g) in acetic acid (10 ml) was refluxed for four hours. The solvent was then removed in vacuo and the remaining solid product was crystalhsed from water to yield 0.15 g of compound 7; m.p. 256 °C; IR: 2200 cm - 1 (conjugated CN) and 1690 cm - 1 (ring CO). C8H8ON4

Found C 54.51 H 4.55 N 31.80, Calcd C 54.54 H 4.58 N 31.80. 2) From 3 a and 1% NaOH: A suspension of 3 a

(2.0 g) was treated with NaOH solution (50 ml; 1 %). The reaction mixture was refluxed for five minutes and the resulting solution was kept at room temperature for three hours. The reaction mixture was then neutralised with hydrochloric acid and the solvent was removed under vacuo. The remaining sohd product was dissolved in little hot water and left to cool. The crystals, so formed were collected by filtration and identified (m.p. and mixed m.p. and by IR) as 7, yield 0.9 g.

3) From, 5 and ethyl acrylate: To a solution of 5 a (2.0 g) in pyridine (30 ml) and water (10 ml) ethyl acrylate (2.0 ml) was added. The reaction mixture was then refluxed for three hours. The solvent was then removed in vacuo and the remaining solid product was identified (m.p. and mixed m.p. and by IR) as 7, yield 1.0 g.

Reaction of 3 b with 1 % NaOH solution: Compound 3 b (2.0 g) was treated with 1% NaOH solution using the experimental conditions described pre-viously for reaction of 3 a with 1% NaOH. The resulting reaction solution was evaporated in vacuo and the remaining solid product was triturated with water and left to cool. The crystals so formed, were collected by filtration and crystalhsed from water to yield 1.0 g of compound 8; m.p. 271 °C; IR: 2200 cm - 1 (conjugated CN) and 1690 cm - 1 (ring CO). C 1 3 H 1 0 O N 4

Found C 65.41 H 4.28 N 23.45, Calcd C 65.53 H 4.23 N 23.52. Acidification of the filtrate offered 0.3 g of com-

pound 9; m.p. 145 °C; IR : 3450, 3380 cm - 1 (NH2 vibrations), 2800-2400 cm - 1 (OHdimer), 2200 cm"1

(conjugated CN); 1700cm -1 (carboxyl CO) and 1650 cm -1 (NH2 deformation).

Ci3Hi202N4 Found C 60.55 H 4.72 N 21.72, Calcd C 60.93 H 4.74 N 21.87. Compound 9 was converted into 8 in a 80% yield

when refluxed with acetic acid for five hours. Compound 8 could be also prepared in 60% yield

by the action of ethyl acrylate on 5 b using the experimental conditions previously used for reaction of 5 a with ethyl acrylate.

2-Methyl-4,5,6,7-tetrahydropyrazolo[ 1,5-a] -pyrimidin-5-one - 4 - carboxylate (10)

A suspension of 3c (2.0 g) in NaOH (50 ml; 1%) was heated to boiling and then left to cool to room temperature. The reaction product was then neutrahsed with hydrochloric acid and evaporated in vacuo. The resulting solid product was dissolved in little hot water and left to cool. The crystals, separated on standing, were collected by filtration and recrystalhsed from water.

Compound 10 formed colourless crystals m.p. 277 °C; yield 1.0 g; I R : 3100 cm - 1 (NH vibration); 2700-2400 cm - 1 (OH dimer); 1720 cm - 1 (carboxvl CO) and 1700 cm - 1 (ring CO). C8H9O3N3

Found C 49.48 H 4.42 N 21.38, Calcd C 49.23 H 4.65 N 21.53. Reaction of2e with 1: The experimental conditions

previously described for reaction of 2 a-d with 1 were adopted. The resulting reaction solution was evaporated in vacuo and the remaining product was triturated with little dilute hydrochloric acid. The solid product, so formed, was collected by filtration and crystallised from water.

12: grey crystals, m.p. 225 °C, yield 40%; IR: 2260 cm -1 (unconjugated CN), 2200 cm - 1 (conju-gated CN). C 1 1 H 1 3 N 5

Found C 61.00 H 5.79 N 32.40, Calcd C 61.37 H 6.09 N 32.54.

Action of AcOH on 12 A solution of compound 12 (2.0 g) in acetic acid

(20 ml) was refluxed for thirty minutes. The solvent was then removed in vacuo and the remaining sohd product was triturated with little water and collected 10 g filtration.

Compound 14 formed colourless crystals from water, m.p. >300 °C; yield 70%. IR : 2200 cm -1

(conjugated CN) and 1650 cm - 1 (ring CO). C 1 1 H 1 2 O N 4

Found C 60.80 H 5.60 N 26.10, Calcd C 61.09 H 5.59 N 25.91.

5-Amino-2-pyrazolin hydrochloride (15) A solution of compound 14 (10.0 g) in acetic acid

(100 ml) was treated with concentrated hydrochloric acid (20 ml: 37.5%). The reaction mixture was

799 M. H. ELNAGDI ET AL. • SYNTHESIS OF SOME NEW PYRAZOLOPYRIMIDINE DERIVATIVES

refluxed for one hour and then evaporated in vacuo. The remaining sohd was triturated with ethanol collected by filtration and identified (by m.p. and mixed m.p. and by IR) as 15.

Compound 15 was also formed when 12 was treated with acetic hydrochloric acid mixture under similar conditions.

Reaction of 3a,b with C82: A mixture of each of 3a,b (5.0 g) pyridine (50 ml). CS2 (20 ml) and DMF (20 ml) was heated under reflux for 10 h. The solution was then evaporated in vacuo and the remaining sohd product was triturated with dilute hydro-chloric acid. The reaction product was then collected by filtration and crystallised by dissolution in DMF and gradual addition of water.

1 -ß- Cyanoethy 1 - 4 - imino - 3 - methyl - 6 (7 H) - pyra -zolo[3,4-dl-m-thiazinethione (16 a) formed pale yellow crystals m.p. >300°C; yield 4.5g. IR : 3310-3280 cm-1 (NH vibrations). C 9 H 9 N 5 S 2

Found C 42.85 H 3.52 N 28.00 S 25.19, Calcd C 43.03 H 3.61 N 27.88 S 25.48. l-/9-Cyanoethyl-4-imino-3-phenyl-6(7H)-pyrazolo-

[3,4-d]-m-thiazinethione (16 b) formed pale yellow crystals m. p. 300 °C; yield 3.0 g; IR: 3320 -3280 cm"1

(NH). C 1 4 H 1 1 N 5 S 2

Found C 53.41 H 3.67 N 22.22 S 20.21, Calcd C 53.67 H 3.54 N 22.36 S 20.43.

Rearrangement of 16 a, b by sodium hydroxide A solution of each of 16 a, b (5.0 g) in 25 ml of

NaOH (0.05 N) was heated at 80 °C for 30 minutes. The reaction mixture was then cooled to room temperature and acidified with glacial acetic acid. The reaction solution was then evaporated in vacuo and the resulting sohd product was dissolved in little water and left to cool. The sohd product, so formed, was collected by filtration and crystallised from water.

Compound 17a formed pale yellow crystals m.p. >300 °C; yield 4.0 g; IR : 3390 -3300 cm"1 (NH vibrations). 2260 cm - 1 (unconjugated CN). C 9 H 9 N 5 S 2

Found C 43.10 H 3.56 N 27.80 S 25.10. Calcd C 43.03 H 3.61 N 27.88 S 25.48. Compound 17b formed pale yellow crystals m.p.

>300 °C; yield 4.2 g; IR : 3400-3320 cm"1 (NH vibrations); 2260 cm - 1 (unconjugated CN). C 1 4 H 1 1 N 5 S 2

Found C 53.53 H 3.60 N 22.31 S 20.36, Calcd C 53.67 H 3.54 N 22.36 S 20.43.

When compounds 16 a, b were treated with 1 N NaOH using the experimental conditions described by T A Y L O R et al. to affect rearrangement of pyrazolo-[3,4-d]-m-(7 H)-thiazine-thiones into corresponding pyrazolo[3,4-d]pyrimidinethione has afforded the amides 18 a, b.

Compound 18a, yellow crystals, m.p. 285 °C; IR: 3450, 3350 cm-1 (NH2 vibrations), 3200, 3150 cm-1 (NH vibrations); 1650 cm-1 (amide CO) and 1625 (NH2 deformation). C9HnON5S2

Found C 40.35 H 4.39 N 25.76 S 23.88, Calcd C 40.13 H4.12 N 25.81 S 23.76. Compound 18b, yellow crystals m.p. >300°C;

IR: 3450, 3350 cm-1 (NH2 vibration), 3200, 3150cm-1 NH vibrations); 1654cm-1 (amide CO) and 1620 cm - 1 (NH2 deformation). Ci4H13ON5S2

Found C 50.80 H 3.86 N 20.80 S 16.18, Calcd C 50.75 H 3.64 N 21.14 S 16.05. Compounds 18 a, b were also obtained in 75 and

80% yields when 17 a, b were treated with 1 N NaOH under the same experimental conditions used above.

l-ß-Carboxyethyl-3-substituted-4,5,6,7-tetrahydro-pyrazolo[3,4-d]pyrimidine-4,6-dithiones (19 a, b)

To a solution of each of 17 a,b (2.0 g) in acetic acid (20 ml), 3 ml of HCl (37.5%) were added. The reaction mixture was heated under reflux for 1.5 hours and then evaporated in vacuo. The remaining sohd product was triturated with little water and left to cool. The solid product separated was collected by filtration and crystallised from water.

Compound 19 a formed pale yellow crystals; m.p. >300 °C; yield 1.2 g; IR : 3450-3350, 3190 cm-1 (NH vibration); 2800 -2400 cm"1 (OH dimer) and 1720 cm -1 (carboxyl CO). C9Hio02N4S2

Found C 40.12 H 3.82 N 20.78 S 24.10, Calcd C 40.00 H 3.73 N 20.74 S 23.73. Compound 19b formed pale yellow crystals; m.p.

300 °C; yield 1.0 g; 3460-3365, 3200 cm"1 (NH vibrations); 2800-2400 cm"1 (OH dimer) and 1715 cm-1 (carboxyl CO).

C 1 4 H 1 2 O 2 N 4 S 2

Found C 50.68 H 3.50 N 17.00 S 19.14, Calcd C 50.60 H 3.64 N 16.86 S 19.24.

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800 M. H. ELNAGDI ET AL. • SYNTHESIS OF SOME N E W P Y R A Z O L O P Y R I M I D I N E DERIVATIVES

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