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Studies on Condensed Triazines and Related Compounds.

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312179
Condensed niazines
147
e r y t h r o - 3 - D i b e n z y l a m i n o - 2 - h y d r o x y - 3 - p h e n y C p (3h)
1,35 g (5 mmol) (3j), 2,5 g KzCOJ, 3,O g Benzylchlorid und 20 ml Toluol werden 3 h a m Ruckflu5 gekocht. Aus dem Filtrat des erkalteten Ansatzes kristallisiert bei langerem Stehen 3h aus
und wird aus Ethanol umkristallisiert. Ausb.: 560 mg (31,l % d. Th.). Die Substanz ist identisch
mit dem durch Aminolyse von ZPhenylglycidsaureamid mit Dibenzylamin erhaitenen 3h.
C u H ~ N z O (360,2)
z
Ber.: C 76.6 H 6.66 N 7.8;Gef.: C 76.3 H 6.61 N 7.6.
Literatur
1 E. Kamandi, A.W. Frahm und F. Zymalkowski, Arch. Pharm. (Weinheim) 307, (1974); 308,
135 (1975).
2 K. Vogler, Helv. Chim. A d a 33, 21 11 (1950).
3 F. Zymalkowski, Arch. Pharm. (Weinheim) 287, 505 (1954).
4 F. Zymalkowski und F. Koppe, Arch. Pharm. (Weinheim) 294, 453 (1961).
5 J. Lehmann und F. Zymalkowski, Arch. Pharm. (Weinheim) 309, 427 (1976).
6 F. Zymalkowski, Arch. Pharm. (Weinheim) 288, 303 (1955).
7 Kwan-Chung Tsou und N.H. Cromwell, J . Org. Chem. 15, 1293 (1950).
8 E. Fourneau und J. Billetier, Bull. Soc. C h m . Fr. 7, 593 (1940).
9 A. Elker, J. Lehmann und F. Zymalkowski, Arch. Pharm. (Weinheim) 3 1 2 , 2 6 (1979).
10 E. Erlenmeyer, Ber. Dtsch. Chem. Ges. 39, 791 (1906).
[Ph965]
Arch. Pharm. (Weinheim) 312, 147---15311979)
Studies on Condensed Triazines and Related Cornpourids
Vishnu Ji Ram
Department of Chemistry, S. C. College Ballia (U.P.) India
Eingegangen am 6. M a n 1978
Acenaphthone monosemicarbazone was cyclised to acenaphtheno[l,24] 1,2,4-triazine-3a1e (2).
ItsN-alkyl derivative 3 was prepared by the reaction with an alkyl halide in alkaline medium. The
triazinone 2 was further converted into the corresponding chloro compound 4 which underwent
nucleophilic substitutions with hydrazine and amines 3-Hydrazinoacenaphtheno[l,2-e]-1,2,4triazine (9) was transformed into pyrazolotriazines 12, 13, 14 by reaction with acetylacetone,
ethyl acetoacetate and ethyl ethoxymethylenecyanoacetate. With formic acid and nitrous acid
9 yielded the new heterocycles acenaphtheno [1,2-e]-1,2,4-triazino[2,34]-1,2,4-triazole
(1 1)
and acenaphtheno [1,2e] -1,2,4-triazino[2,34]-tetrazole (1 0).
@ Verlag Chemie, GmbH, Weinheim 1979
148
Ram
Arch. Pharm.
Untersuchungen iiber kondensierte Triazine und verwandte Verbindungen
Accnaphthonmonosemicarbazon wurde zu Acenaphtheno[l,2-~]-1,2,4-triazin-3-0n
(2) zyklisiert.
Das N-Alkyldcrivat 3 wurdc durch Umsetzung mit cincm Alkylhalogenid in alkalischem Milieu
hergestcllt. 2 wurdc ferner zur entsprechenden Chlorverbindung 4 umgcsetzt, die mit Hydrazin
und Aminen nucleophile Substitutionsreaktionen einging. 3-Hydrazinoacenaphtheno[ 1,2-e]1,2,4-triazin (9) wurde durch Umsetzung mit Acetylaceton, Essigsaureethylester und Ethoxymcthy1encymessigs;iureethylester in die Pyrazolotriazine 12, 13 und 14 umgcwandclt. Mit Ameiscnsaure und mit salpetriger Saure ergab 9 die neuen Heterocyclen Acenaphtheno[l,2-e]-1,2,4triazino [ 2,3-d] -1,2,4-triazol (1 1) und Accnaphtheno [I ,2-e]-1,2,4triazino [2,3-d] tetrazol(10).
Due to the great importance of triazines as versatile therapeutic agents, the attention
of chemists and drugists has been attracted to the investigation of their biological
activity since the past two decades. A simple triazine i. e. &amuracil has shown to
inhibit the growth of certain strains of micro-organisms and a number of transplantable neuplasms in mice’). The ribofuranoside analogue of 6-azauracil has also demonstrated growth inhibition*) of sarcoma 180 cells in tissue culture. The antibiotic
Toxaflavin and Fervenulin, derivatives of the pyrimidino[S,4e] -1,2,4-triazine system,
have aroused considerable interest3) because of their broad spectrum antibacetia14),
antifungal, antiparasitic and anticancer activity’).
Symmetrical triazolo[2,3-a] triazines which are structurally analogous to potent
purine in which positions 3 and /or 7 are the sites for the bonding to the receptor
sites of enzyme systems. The bonding is presumably a consequence of the basisity
of the 1,3 and/or 7 nitrogen atoms.
The antibacterial activity of 3,S-diamino-6-(3,4-dichlorophenyl)-as-triazine
which
was potent against Plasmodium berghei in mice was extensively studied by Russel6).
Several compounds derived from 3-mercapto-6-alkyl-as-triazin-5-ol
and 6-alkyl-astriazin-3,s-diolhave demonstrated antiviral7) activity against P-R 8 strain of Influenza virus.
Recognition of triazines as a class of diuretic agents stemmed from the work of
Lzpschitz undHudidiun’) who reported the diuretic activity of sym-triazines in man.
Thus the therapeutic importance of triazines led to synthesize condensed triazine
and their various derivatives. Acenaphthone monosemicarbazone, prepared by the
reaction of acenaphthone and semicarbazide was readily cyclised into acenaptheno[ 1,2-e]-1,2,4-triazine (2) and converted to N-alkyl derivatives 3 by reaction with alkyl halide. The hydroxy compound 2 on treatment with POC13 was converted into
the corresponding 3-chlorotriazine (4) which underwent nucleophilic displacement
reactions with amines and hydrazine. The chloro derivative 4, on reaction with
thiourea yielded acenaphtheno[ 1,2-e]-3-mercapto-l,2,4-triazine
which reacting with
mono/dihalide afforded the corresponding sulphides 7 , 8 . The 3-hydrazinoacenaphtheno[ 1,2-e]-1,2,4-triazine (9) was cyclised into acenaphtheno[ 1,2-e]-1,2,4-triazino[2,3-d]-1,2,4-triazole (1 1) with formic acid and acenaphtheno[ 1,2-e]-1,2,4triazino-
312179
149
Ondensed Triazines
[2,3-d]tetrazole (1 0) with nitrous acid. Further hydrazino triazine 9 reacted with
ethylacetoacetate, acetylacetone and ethoxy-methylenecyanoacetate,yielding the
corresponding 3{pyrazol-l -yl)acenaphtheno[ 1,2-e] - 1,2,4-triazines 12, 13,14.
Scheme I
- &Io1*
011-
\ /
2
RNIb
Q-Cl
....A
Q-SHR
S
13
14
150
Ram
Arch. Pharm.
Experimental
All the m. ps. are uncorrected.
Acenap htheno [1,2-e] 1,2,4-triazine-3-one (2)
~
5,2 g Acenaphtheno monosemicarbazone were refluxed with KOH (4 70, 180 ml) for 3 h, cooled
and filtered. The filtrate was neutralised.with 5 N HCl and cooled. The yellow precipitate thus
separated was washed with water and crystallised with water-DhC mixture, yield: 3.5 g (73 %),
m.p. 287-291' (dec.).
NMR, 6 (ppm) = 7.64-8.3 (Aromatic, m); 9.04 (NH). M+, 221; 1 9 3 (-CO); 178 (-CONH); 165
(-N 2. CO).
U.V. (methanol) hmax (log E ) : 315 (4.38); 304 (4.41); 232 (4.70); 216 nm (4.57).
C u H 7 N 3 0 . HzO Calcd. : C 65.3 H 3.76 N 17.6 Found: C 65.4 H 3.54 N 17.5.
2-N-Methyl acenaphtheno[1.2-e] -1,2,4-triazine-3-one (3a)
0.1 g 2 was dissolved in KOH (5 %, 2 ml) and stirred overnight with methyl iodide. The precipitate
thus obtained was washed with water and crystallised with water-DMF mixture, yield: 75 mg (70 %),
m. p. 287'. M+ 235; 220 (-CH3); 192 (-Nz);
164 (-Nz, CO).
U.V. (methanol) hmax (log E) 317 (4.49); 306 (4.46); 232 (4.68); 220 nm (4.59). C M H ~ N ~ O
Calcd.: C 71.5 H 3.83 N 17.9. Found: C 71.6 H 3.84 N 17.6.
2-N-Benzyl acenaphrheno [ I ,2- e] - l 2,4-rriazine-3-one
,
(3b)
A solution of 0.1 g 2 in KOH (5 %, 2 ml) was stirred with 0.1 ml benzyl chloride m presence of
little ethanol for 3 h a t 40' C. The precipitate thus separated was washed with ethanol and crystallised with water-DMF mixture, yield: 60 mg (42.6 %), m.p. 198-200'.
M+ 311; 220 (-CH2CaHs); 192 (220-N2); 164 (192-CO).
CzoH13N30 Calcd.: C 77.2 II 4.18 N 13.5; Found: C 77.3 H 3.9 N 13.4.
3-Chloroace~phtheno[1,2-e]
- I ,2,4-niozine (4)
A mixture of 3.2 g 2 and 15 ml POQ3 was refluxed for 2 h at 140'. Excess of POCIS was removed
under reduced pressure and the residue poured on crushed ice with vigorous stirring. The brwon
solid thus obtained was washed with 2 % KOH to remove unreacted parent compound and crystallised with ethanol, yield: 2.8 g (51 %), n p . 203'. M + 239.5.
C13H6ClN3 Calcd.: C 65.1 H 2.50 N 17.5; Found: C 65.3 H 2.62 N 17.8.
Bis[acenaphtheno[l,2-e]-1 2,4-triazin-3-yl]piperazine (5m)
I
A mixture of 0.2 g 6 and 0.08 g piperazine in 15 ml ethanol was refluxed for 2 h. The yellow
precipitate thus separated was washed with ethanol and crystallised with DMF, yield: 100 mg,
M'492, m.p. 315'. U.V. (methanol) hmax (log E ) 370 (4.11); 335 (4.57); 226.5 nm (4.77).
C3oHzoN80.5HzO Calcd.: C 71.9 H 4.19 N 22.3;Found: C 71.9 H 3.80 N 220.
3-Morpholinoacenaphtheno[1,2-e]- I ,2,4-trinzine
A solution of 0.1 g 4 in ethanol was refluxed with 0.1 g morpholine for 5 h and excess of solvent
was removed under reduced pressure. The residue was washed with little ethanol and crystallised
with water-DMF mixture as an yellow crystalline solid, yield: 50 mg, mp. 175', M+ 290.
U.V. (methanol) h m x (log E) 333 (4.47); 273 (4.15); 226 nm (4.69).
C17H14N40 Calcd.: C 63.4 H 4.83 N 19.3;Found: C 63.6 H 4.62 N 19.5.
312179
(bndensed niazines
151
3-pFluorophenylaminoacenaphtheno[I.2-e]-1,2,4-triazine (5)
A solution of 0.1 g 4 in 8 ml ethanol was treated with 0.1 ml p-fluoroaniline and the mixture was
refluxed for 3 -4 h. After cooling the precipitate was washed with water and ethanol successively
and crystauised with water-DMF mixture, yield: 70 %, m p . 306'.
M+ 314; 286 (-N2); 191 (CbH4F); 164 (191-HCN).
C19HliNqF Calcd.: C 72.6 H 3.52 N 17.8;Found: C 73.0 H 3.55 N 18.0.
Compounds 5a-5j prepared in this series are presented in the Table 1 along with their relevant
data.
Acenaphthmo[l,2-e] -1,2,4-triazine-3-thione (6)
A mixture of 0.8 g 4 and 0.56 g thiourea in ethanol wasrefluxed for 2 h. Excess of solvent was
removed and the residue dissolved in KOH (2 %, 60 ml), filtered and neutralised with acetic acid.
The red precipitate was washed with water and crystallised with water-DMF mixture, yield: 0.6
g, m.p. 262'.
U.V. (methanol) hmax (log E ) 335 (4.26); 282.5 (4.38); 217.5 nm (4.46).
C13H7N3SCacld.: C 65.8 H 2.95 N 17.7;Found: C 65.8 H 3.01 N 18.1.
3-Methylmercaptoacenaphtheno[ I ,2-e]-l,2,4-triazine(7a)
A solution of 0.1 g 6 in KOH (5 %, 3 ml) was stirred with 0.2 ml methyl iodide at room temp.
for 2 h. The precipitate thus separated was washed with water and aystallised with water-DMF
mixture, yield: 70 mg,m.p. 162'.
U.V. (methanol) hmax (log E ) 324 (34.52); 280 (4.18); 232 nm (4.64).
C14HgN3S Calcd.: C 66.9 H 3.58 N 16.7; Found: C 66.9 H 3.68 N 17.1.
3-Ethy lmercaptoacenaphtheno [ I ,2-e]- I .2,4trwrine (7b)
A mixture of 0.1 g 6 and 0.2 ml ethyl iodide in aqueous KOH (5 %, 3 ml) was stirred for 2 h
and isolated as desaibed above, m.p. 1ISo, M+ 265.
ClsHllN3S Calcd.: C 67.9 H 4.18 N 15.8;Found: C 68.2 H 4.23 N 16.0.
3-Benzy lmercaptoacenaphth eno [1,2-e]- 1,2,4-niazin e (7c)
It was prepared from 0.1 g 6 and 0.2 ml benzyl chloride in KOH (5 %, 3 ml) as described in preceding experiments, m.p. 179O, Ivl+ 327.
C~0H13N3SCalcd.:C73.4H3.97N12.8;Found:C73.5H4.11 N12.6.
S-G~rboxymethylacenaphtheno[
1,2-e] -1,2,4triazine (7d)
A solution of 0,l g 6 in sodium hydroxide (5 %, 3 ml) was treated with 0.05 g chbroacetic acid
and stirred overnight at rom temp. The solution was then neutralised with concentrataed hydrochloric acid which afforded yellow solid and crystallised with DMF, yield: 0.12 g, m.p. 2 0 P
(dec.).
M+ = 295; 278 (-OH);
250 (278-CO); 236 (25bCH2); 208 (236-N2); IR: 1735 ( G O )
C15H9N302S Calcd.: C 61.0 H 3.1 N 14.2;Found: C 61.2 H 3.3 N 14.5.
3-Acetamidomercaptoacenaphtheno[l,2-e]-I.2,Ctriazine (7e)
A mixture of 0.1 g 6 and 0.05 g chloroacetamide in aqueous sodium hydroxide (5 %, 3 ml) was
stirred ovcmight and the solution was neutralised with hydrochloric acid. The yellow precipitate
152
Ram
Arch. Pharm.
was washed with water, methanol and crystallised with DMF, yield: 0.13 g, m.p. 208' (dec.).
M + = 294; 278 (-NH2): 250 (278-CO); 236 (250-CH2): 208 ( 2 3 6 - N ~ ) .
IR: 3400 (NH2): 1734 cm-' (C=O).
CisHloN40S Calcd.: C 61.2 H 3.4 N 19.0;E'ound: C 61.3 H 3.5 N 19.3.
Methylenedi(acenaphtheno[ I , 2 - e ]- I , 2,4triazine-3-yl)sulphide ( 8 )
A clear solution of 0.1 g 6 in 3 ml 5 % KOH was treated with 0.3 ml methylenechloride and stirred
overnight. The residue thus separated was washed with water and crystallised with DMF, yield:
20 mg, m.p. 305', M+ 486.
C27H14NbS2 Calcd.: C 66.7 H 2.9 N 17.3;Found: C 66.8 H 2.9N 17.5.
3-llydrazinoacenaph theno [l,2-e] - lI2,4-triazine( 9 )
Method A: To a solution of 0.2 g 4 in 10 ml absol. ethanol, 1 ml hydrazine hydrate (100 76)was
added and the mixture refluxed for 5 h. During this period an yellow precipitate separated which
was washed with methanol and crystallised with DMF; yield: 0.13 g, mp. 226'.
C13H9N5 Calcd.: C 66.4 H 3.9 N 29.8;Found: C 66.3 H 3.7 N 29.9.
Method 8 : A nuxture of 0.1 g 7a and 2 ml hydrazme hydrate (100 %) in little ethanol was reflwed
for 2 h. The yellow precipitate thus separated was crystaUised with DMF. Mass spectra and Rf
values of both the products obtained by method A and B were identical.
Acenaphtheno [I , 2-e ]-1,2,4-friazino[2,3-d]
fetrazole (1 0 )
A suspension of 0.1 g 9 in 5 ml, 12 70 acetic acid was mixed with 90 mg aqueous sodium nitrite
slowly with vigorous stirring. The mixture was further stirred for an additional hour at 40° and
the precipitate obtained was washed with water and crystallised with DMF-water mixture, yield:
70 mg,m.p. 286-287' (dec.).
M + = 246; 218(-N2); 190(-N2): 164 (190-CN).
U.V. (methanol) Xmax (log E ) 310(sh) (4.37); 292.5 (4.45); 233 nm (4.88).
CI3H6N6Calcd.: C 63.4 H 2.5 N 34.1 ;Found: C 63.7 H 2.7 N 33.7.
Acenaphtheno[ 1,2-e]- 1,2,4-triazino[2,3-d]
- 1,2,4-triazoIe (1 1)
A mixture of 0.1 g 9 was dissolved in 3 ml formic acid and reflwed for 2 h. At the end, excess of
solvent was removed under reduced pressure and residue was triturated with ethanol. The crude
product was crystallised with DMF; yield: 0.1 g, m.p. 310'.
NMR (DMSO d 6 ) 6 (ppm) = 7.74-8.32 (m, aromatic); 9.5 (s, CH).
U.V. (methanol) Xmax (log E ) 320 (sh) (4.27); 292.5 (4.49); 234 (4.86); 218 nm (4.53).
C ~ ~ H Cdlcd.:
T N ~ C 68.6 H 2.9; Found: C 69.1 H 2.8
3-(3'-MethyI-S'-pyrazolon-1'-yl)acenaphtheno [l,2-e]- 1 2.4-triazine ( 1 2)
~
To a solution of 0.1 g 9 in 5 ml ethanol containing a few drops of acetic acid, 0.5 ml ethylacetoacetate were added and the mixture was refluxed for 1 h. The solvent was removed under
reduced pressure and the product recrystallised with water-ethanol mixture, yield: 50 mg, m.p.
183O.
M+ = 301: 286 (-CH3): 260 (-CH3CN).
U.V.(methanol) Xmax (loge) 332 (4.42); 275 (4.18); 227.5 nm (4.52).
NMR: 6 (ppm) = 166 (s, OH); 2.18 (s, CH3); 3.58 Is, CH); 7.82-8.52 (m,aromatic).
C17HllN5O Cdkd.: C 67.8 H 3.65 N 23.3;Found: C 67.8 H 3.8N 23.4.
312/79
153
Condensed Trhzines
3-(3',5'-Dimethylpyrazolo-l
'-yl)acenaphtheno[l.2-e]1,2,4-triazine (1 3)
A mixture of 1 ml acetylacetone and 0.1 g 9 in 5 ml ethanol was refluxed for 2 h in presence of
a few drops of acetic acid and cooled. The solution was poured inot cold water whereby a colour.
less solid separated which was crystallised with waterethanol mixture, yield: 80 mg,m.p. 184O,
M+ 299.
U.V. (methanol) hmax (log E ) 316 (4.60); 260 (4.23); 232.5 n m (4.63).
NMR 6 (ppm) = 1.6 (5, CH); 2.4 (s, 3'-CH3); 2.79 (s, 5'-CH3): 7.81-8.7 (aromatic).
C I 8 H 1 3 N s Cdkd.: C 72.2 H 4.34 N 23.4; Found: C 72.3 H 4.4 N 23.6.
3-(4'-Ethoxycarbonyl-5'-aminopyrozol-l'-yl)
acenaphtheno[l,2-e]-1,2,4-triazine(1 4)
A solution of 0.1 g 9 in 1 0 ml ethanol was refluxed with 80 mg ethoxymethylene ethylcyanoacetate for 2 h and cooled. The precipitate was crystallised with DMF,m p. 249'. M+ 358; 329
(-Et); 285 (329-CO2).
U.V. (methanol) hmac (log E ) 311 (3.67); 250 (sh) (4.53); 233.5 n m (4.81).
C I 9 H 1 4 N b O 2Calcd.: C 63.7 H 3.9;Found: C 64.1 H 3.8.
Table I : 3-Arylaminoacenaphtheno[I ,2-e]-1,2,4-triazines5
5
R
Yield M.P. Molecular
OC
formula
C
a
b
C
d
e
f
8
h
I
j
o4:luorophenylmFluorophen ylp-Chlorophenylp- Bro mop he nylm-lodophenylplodophenylp-AcurylaminophenylpSulphonamidopheny1p-Naph thylpPheny lazophenyl-
68
70
66
69
65
70
71
81
75
68
182
280
315
310
310
310
315
315
287
310
C I ~ H L I N ~ F 72.6
C19HllN41.'
72.6
Ci9HliN4C7
69.0
C 1 9 H ~ ~ N 4 H r 60.8
C19HllN41
54.0
Ci9Hi1N41
54.0
CzlIlisNSO
71.4
C ~ ~ H ~ ~ N 68.8
S O
79.8
C23Hi4N4
75.0
C251116N6
Analysis
Cdlcd.
H
N
3.5
3.5
3.3
2.9
2.6
2.6
4.3
~3.5
S
4.1
4.0
17.8
17.8
16.9
14.9
13.3
13.3
19.8
18.7
16.2
21.0
C
Found
H
N
72.6
72.7
69.1
60.2
54.2
54.1
71.5
68.8
79.6
75.2
3.4
3.6
3,s
3.2
2.8
2.6
4.3
3.5
3.9
4.3
18.1
18.1
16.6
15.2
13.4
13.3
20.1
18.9
16.3
21.2
Literatur
F. Sorm, A. Kakobovic and L. Slechta, Experientia 12, 271 (1956).
R. Schindler and A. D. Welch, Science 125, 548 (1957).
G. D. Daves, J. Am. Chem. SOC.84, 1724 (1962).
P. A. van Damme, A. G. Johannes, H. C. C o x and W. Berends, Rec. Trav. Chim. Pays-Bas 79,
255 (1960).
5 C. DeBoer, A. Dietz, J. S. Evans and R. M. Michaels, Antibiot. Annu. 1959/1960, 220.
6 P. B. Russel, Br. J. Pharmacol. Chemother. 6 , 185 (1951).
7 W. L. Lipschitz and Z. Hadidian, J. Pharmacol. Exp. Ther. 81, 84 (1944).
1
2
3
4
[Ph 9771
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