Acyclo C-nucleosides analogues of condensed 1,2,4-triazines

Article abstract of DOI:10.1515/znb-1997-0717

1-Acyclo C-nucleosides of 7-methyl-10H-1,2,4-triazolo[3',4':3,4][1,2,4]triazino[5,6-b]indoles (9) have been prepared by cyclodehydrogenation of the sugar derivatives of 3-hydrazino-8-methyl-5H-1,2,4-triazino[5,6-b]indole (1). The respective linear isomer as 4 has been prepared by a dehydrative cyclization of the amides of 1. Acetylation of the sugar hydrazones and their cyclized products gave the per-N,O-acetyl derivatives. The molecular connectivity of the products was established by ¹H, ¹³C, and 2D H,H Cosy spectra.

Full text of DOI:10.1515/znb-1997-0717

Acyclo C-Nucleosides Analogues of Condensed 1,2,4-Triazines
El Sayed H. El Ashry, Nagwa R ashed, H am ida A bdel H am id, El Sayed R am adan
Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
Z. Naturforsch. 52 b, 873-882 (1997); received February 17, 1997
Acyclo C-Nucleoside, 1,2,4-Triazine, Indole, Triazinoindole, Triazolotriazinoindole
1-Acyclo C-nucleosides of 7-methyl-10//-l,2,4-triazolo[3,,4’:3,4][l,2,4]triazino[5,6-£>]indoles
(9) have been prepared by cyclodehydrogenation of the sugar derivatives of 3-hydrazino-8-
methyl-5//-l,2,4-triazino[5,6-6]indole (1). The respective linear isomer as 4 has been pre-
pared by a dehydrative cyclization of the amides of 1. Acetylation of the sugar hydrazones
and their cyclized products gave the per-7V,0-acetyl derivatives. The molecular connectivity
of the products was established by *H, 13C, and 2D H,H Cosy spectra.
V arious heterocyclic com pounds containing
a
1,2,4-triazine ring show interesting biological
activities including antihypertensive, antiviral and
antibacterial properties [1-7], as well as activity
against Staphylococcus aureus and Bacillus cereus
and P388 Lym phocytic leukem ia [5]. Since the dis-
covery of naturally occurring C-nucleosides,
a
Scheme 1.
rapid grow th in literature on their biological activ-
ity as well as their m ethods of syntheses have been
rep o rted [8,9].
angular [18-21] structure, respectively. In continu-
ation of our study on the regioselective annelation
of a triazole to a triazine ring [16,17,22-26] we
found that the cyclization of 3-hydrazino-5//-l,2,4-
triazino[5,6-fr]indole either via the dehydrative
cyclization of the respective hydrazide or the de-
hydrogenative cyclization of the hydrazones gave
the linear isom er 10//-l,2,4-triazolo[4’,3’:2,3]-
[l,2,4]triazino[5,6-6]indole.
Surprisingly, the introduction of a m ethyl group
on the benzene ring of the hydrazine as in 1 caused
a change in the site of cyclization upon the dehy-
drogenative cyclization of their hydrazones to give
the angular isom er. A m odel study has been car-
ried out on sim ple derivatives of 1 in order to as-
sign the site of annelation. Thus, a num ber of hy-
R ecent interest in the synthesis and biological
activity of acyclic nucleosides follow ed the finding
th at acyclovir [10] possesses a high antiviral activ-
ity th at subsequently was followed by a series of
highly potent acyclo-nucleosides. These findings
led to the conclusion that the furanosyl ring of
classical nucleosides (A ) is not necessary for bio-
logical activity. Consequently; a variety of acyclic
analogues have been synthesized. H aving the
above aspects in m ind, novel types of acyclo-
nucleoside analogues having the furanose ring in
an acyclic form as in (B) w ithout any loss of car-
bon or oxygen atom s and the triazolotriazinoin-
dole as the heterocyclic part have been prepared.
In the m eantim e, the regioselectivity for the
cyclization of 3-hydrazino-8-m ethyl-5//-l,2,4-tria-
zino[5,6-£]indole with one carbon inserting rea-
gents has been investigated.
drazones 2a-2c was prepared from
1
by
condensation with aldehydes. C yclodehydrogena-
tion of 2a-2c was effected by a 2 M solution of
iron(III) chloride in ethanol to give products
which agreed w ith either one of the regioisom eric
structures 3a-3c or 4a-4b. The selection of struc-
ture 3a-3c for the products m ay be confirm ed by
an unequivocal synthesis of 4a by condensing the
am inotriazole 6 w ith 5- m ethylisatin 5 (Schem e 2).
The latter reaction w ould give only one isom er be-
The fusion of a heterocyclic to the 1,2,4-triazine
ring via a functional group on position-3 m ay take
place at N-2 or N-4 to give a linear [11-17] or
Reprint requests to Es. S. A. El Ashry.
0932-0776/97/0700-0873 $06.00 © 1997 Verlag der Zeitschrift für Naturforschung. All rights reserved.
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874
E. S. H. El Ashry et al. - Acyclo C-Nucleoside Analogues of Condensed 1,2,4-Triazines
cause it proceeds by the condensation of the m ore
reactive am ino group of 6 w ith the m ore reactive
carbonyl group of 5. A cetylation of 3a and 3b gave
7a and 7b, respectively, indicating the presence of
only one N H group. The IR spectra of 3a and 4a
are different. The difference in their *H N M R
spectra is shown in the chem ical shift of the two
m ethyl groups. Their mass spectra show ed alm ost
the sam e m olecular ion peaks as base peaks con-
firm ing that the m olecular form ulas of the p ro -
ducts from dehydrogenation lack two hydrogens.
D ehydrative cyclization of 1 w ith acetic acid af-
forded 4a and not 3a which m ay have taken place
by the form ation of the hydrazide derivative fol-
lowed in situ by a dehydrative cyclization process.
This m eans that the latter process of cyclization is
sim ilar to that of the unsubstituted analogue [27]
or its 5-m ethyl analogue [1]. O n the other hand,
a reverse situation was found in the case of the
cyclization by a dehydrogenative process, i.e. the
m ethyl group on the benzene ring directs the site
of cyclization tow ards the angular isom er 3. This
could be attributed to the inductive effect of the
m ethyl group which induces the pair of electrons
on N-5 to be m ore available for contribution in
preserving the arom atic ring character, 10jr-elec-
trons system , of the indole ring. This w ould be the
case w here the interm ediate in the dehydrogena-
tion process does not need m uch space. O n the
other hand, the dehydration of the respective am -
ide m ay encounter an interm ediate of larger size
w hereby the angular one is not form ed and the
linear one prevails.
In order to synthesize the acyclo-C-nucleoside
analogues of 3, a series of hydrazones 8a-8 g w ere
p repared by condensation of 1 with the m onosac-
charides, D -galactose, D-glucose, D -m annose, D-
arabinose, L-arabinose, D -ribose and D-xylose
respectively. Their IR spectra show ed bands at
3346- 3388 cm " 1 (O H ) and 3161-3279 cm ' 1 (N H ).
The !H N M R spectrum of 8a show ed a singlet at
d 2.41 (M e) and a m ultiplet at 6 3.40-4.90 (the
sugar m oiety). The arom atic and m ethine protons
appeared as a m ultiplet at d 7.31-7.92 and the N H
group as a singlet at <3 11.32.
O xidative cyclization of the sugar hydrazones
with iron(III) chloride could be anticipated to give
the triazolotriazinoindole derivatives 9 having the
angular structure, based on the above m odel study.
The IR spectra of 9 showed bands at 3329-3385
(O H ) and 3203-3260 (N H ) cm -1. The acetylation
of 8 with acetic anhydride in pyridine at room tem -
a : R = Me
b : R - O
■R— O
Scheme 2.
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E. S. H. El Ashry et al. • Acyclo C-Nucleoside Analogues of Condensed 1,2,4-Triazines
875
perature caused acetylation of their polyhy-
droxyalkylidene residues in addition to the hydra-
respectively, were assigned to the C -l of the acy-
clic acetate form . The m olecular connectivity was
zone residues to give the peracetyl derivatives 10 then established by the H ,H Cosy spectrum of 10a
(Schem e 4). IR spectra of acetates 10 show ed the
presence of O A c groups (1745-1755 cm -1) and
N A c groups (1700-1725 c m -1). The XH N M R of
10a and 10c show ed the presence of 5 O A c groups
in addition to 2 N A c groups confirm ing their struc-
tures (Table I). M oreover, the signals in 13C N M R
spectra of 10a and 10c at 6C 140.01 and 139.34
(Fig. 1). D raw ing horizontal and vertical lines
starting at the cross peaks, until the diagonal is
intersected, reflected the positions of the signals
of the coupling partners.
A cetylation of 9 with acetic anhydride in pyri-
dine at room tem perature afforded the polyacet-
oxyalkyl derivatives 11 w hose IR spectra show ed
N
NN=CH
I
(CHOAc) nn
CHjOAc
CHjOH
-O A c
-O A c
AcO—
AcO—
—OH
—OH
HO-
HO—
(CHOAc) n
1
(CHOH)n
I
=
AcO—
AcO—
AcO—
=
HO-
HO—
HO—
CHjOAc
c h 2o h
—OAc
—OAc
-O A c
—OAc
-O A c
-O A c
—OH
-O H
-O H
—OH
-O H
-O H
-O A c
-O A c
—OH
—OH
HO—
—OH
- O H
—OH
—OH
—OH
—OH
AcO—
—OH
-O H
—OH
HO—
HO—
H O -
—OAc
-O A c
— OAc
AcO—
AcO—
-O H
-O H
-O H
— OAc
Scheme 3.
Scheme 4.
O Ac
CM e
NAc
Fig. 1. H,H COSY spectrum of 10a.
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876
E. S. H. El Ashry et al. ■Acyclo C-Nucleoside Analogues of Condensed 1,2,4-Triazines
2
3
,
1
4
5 5 '
_1_
i i L
t
^
i
2 , 3
4
Fig. 2. H,H COSY spectrum of 11a.
Experim ental
bands at 1747-1757 (O A c and N A c) cm -1. The
!H N M R spectrum of 11a confirm ed the presence
M elting points w ere determ ined on a M eltem p
apparatus and are uncorrected. IR spectra w ere
recorded with a U nicam SP 1025 Spectrom eter. *H
of
5 O A c groups in addition to N A c group,
w hereas no C H =N signal could be found confirm -
ing that the heterocyclization had taken place. The
th ree arom atic protons appeared in a p attern sim -
ilar to that of 10. The H ,H Cosy of 11a (Fig. 2)
confirm ed the assignm ent.
NM R spectra w ere determ ined w ith
a B ruker
spectrom eter at 500 M Hz. The 13C N M R spectra
w ere recorded with the B ruker AM -500 spectrom -
eter at 500 M Hz. The chem ical shifts are expressed
in the <5 scale using tetram ethylsilane as a refer-
ence. TLC was perform ed on B akerflex silica gel
IB-F (2.5-7.5 cm) plates. M icroanalyses w ere p er-
form ed in the unit of M icroanalysis at C airo
University.
P eriodate oxidation of polyols 8a and 9a gave
the aldehydes 12 and 15 respectively. C ondensa-
tion of 12 with hydroxylam ine hydrochloride gave
13. Similarly, its reaction with hydrazine 1 afforded
the corresponding bishydrazone 14 (Schem e 5).
3-H ydrazino-8-m ethyl-5H -l,2,4-triazino[5,6-
b]indole (1)
It was prepared from 8-m ethyl-5//-l,2,4-tria-
zino[5,6-fr]indole-3-thione [28,29] (m.p. 2 5 0 -
252 °C).
'x
MUM—r
N"
¥
NHN=CH
3-Ethylidenehydrazino-8-m ethyl-5 H -l ,2,4-
triazino[5,6-b]indole (2a)
A solution of 1 (2.14 g, 10.0 m m ol) in ethanol
(100 ml) was treated with acetaldehyde (0.46 ml,
10.0 m m ol) and few drops of acetic acid. The m ix-
ture was heated under reflux for 2 h. The product
that separated out on cooling, was filtered off,
washed with ethanol and dried. It was recrystal-
lized from ethanol/TVJV-dimethylformamide as yel-
low crystals (1.64 g, 61% yield), m.p. 272-275 °C.
IR (KBr): 3278 (N H ) and 1603 cm - 1 (C=N ).
Scheme 5.
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877
E. S. H. El Ashry et al. • Acyclo C-Nucleoside Analogues of Condensed 1,2,4-Triazines
Table I.
NMR spectra of the compounds 10a,c, 11a, b, d, e in solutions of CDC13. Chemical shifts are given on
(<3) scale and coupling constants in Hz.
Compounds
Compounds
lib
Assignment
Assignment
10 c
1 1 a
lid
lie
10a
2.08(s)
2.20(s)
2.25(s)
1.98(s)
2.00(s)
2.09(s)
2.1l(s)
2.03(s)
2.04(s)
2.10(s)
2.12(s)
20Ac
OAc
OAc
OAc
1.98(s)
2.05(s)
2.20(s)
2.23(s)
1.95(s)
2.00(s)
2.10(s)
2.20(s)
2.03(s)
2.18(s)
2.22(s)
OAc
OAc
OAc
OAc
OAc
NAc
CMe
NAc
H-6'
2.58(s)
3.11(s)
2.48(s)
2.52(s)
3.00(s)
3.85(dd)
(7.6)
2.56(s)
2.59(s)
3.04(s)
4.08(dd)
(5.2)
CMe
NAc
2.55(s)
3.10(s)
2.59(s)
3.14(s)
2.56(s)
3.11(s)
H-5'
(■^4,5')
5.5')
3.99(dd)
(7.6)
(11.5)
4.05(dd)
(Jsfi)
(*^6,6')
(11.6)
(12.6)
H-6
4.25(dd)
(5.1)
4.19(dd)
4.28(dd)
(2.7)
H-5
3.35(dd)
(4.9)
(•^4.5)
H-4'
0^3,4')
4A')
H-4
4.28(dd)
(5.1)
(12.5)
4.29(dd)
(5.1)
(12.5)
H-5
(■^4,5)
5.12(t)
T
4.39(dd)
(2.6)
H-4
(•^4,5)
5.49(m)
5.38(d)
(2.3)
5.45(m)
5.18(m)
4.39(dd)
(2.3)
(•^3,4)
5.53(m)
5.51(m)
H-3
5.47(dd)
(2.3)
5.51(dd)
(5.1)
6.57(d)
(5.9)
H-3
5.64(dd)
(2.1)
5.78(dd)
(9.9)
6.60(d)
(2.2)
5.29(dd)
6.28(dd)
6.59(d)
1
(■^3.4)
(•^3.4)
5.78(dd)
(8.4)
6.75(d)
(3.2)
H-2
5.60(t)
H-2
5.81(dd)
(8.5)
6.74(d)
(3.1)
(J2.3)
U2.3)
H-l
6.51(d)
(3.5)
H-l
1,2)
(J1,2)
Protons on the
heterocyclic ring
H-6
8.59(d)
(8.8)
7.62(d)
8.08(s)
8.58(d)
(8.6)
7.62(d)
8.02(s)
8.56(d)
(8.6)
7.61(d)
8.05(s)
8.57(d)
(8.7)
7.59(d)
8.28(s)
8.59(d)
(8.6)
7.61(d)
8.30(s)
8.58(d)
(8.2)
7.60(d)
8.05(s)
(•^6.7)
H-7
H-9
3-(p-N itrobenzylidenehydrazino)-8-m ethyl-5H -
A nalysis for C 12H 12N6 (240.3)
l,2,4-triazino[5,6-b]indole (2c)
C alcd
C 60.0 H 5.0 N 35.0% ,
Found C 59.9 H 5.1 N 35.2% .
A
solution of 1 (2.14 g, 10.0 m m ol) in ethanol
(100 m l) was treated w ith a solution of p-nitroben-
zaldehyde (1.5 g,10.0 m m ol) in ethanol (25 ml) and
few drops of acetic acid. The m ixture was p ro-
cessed as above. The product was recrystallized
from ethanol/A yV -dim ethylform am ide as orange
3-Benzylidenehydrazino-8-m ethyl-5H -l,2,4-
triazino[5,6-b]indole (2b)
To a solution of 1 (2.14 g, 10.0 m m ol) in ethanol
(100 m l), benzaldehyde (1.0 ml, 10.0 m m ol) and
tw o drops of acetic acid w ere added and the reac-
tion m ixture was processed as above. The product
was recrystallized from ethanol/W,./V-dimethylfor-
m am ide as yellow crystals (1.50 g, 50% yield), m.p.
300 °C. IR (KBr): 3326, 3100 (N H ) and 1616 cm “1
(C =N and C=C).
crystals (1.6 g, 46% yield), m.p.
> 350 °C. IR
(K B r): 3211 and 3100 (N H ) and 1597 cm ' 1 (C=N
and C=C).
A nalysis for C 17H 13N 70 2 (347.3)
Calcd
C 58.8 H 3.8 N 28.2% ,
Found C 58.6 H 3.9 N 28.2% .
A nalysis for C i7H 14N6 (302.3)
Calcd
C 67.5 H 4.7 N 27.8% ,
Found C 67.3 H 4.8 N 28.0% .
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878
E. S. H. El Ashry et al. ■Acyclo C-Nucleoside Analogues of Condensed 1,2,4-Triazines
Table II. 13C NMR spectral data for the compounds 8a,
10a, c, 11a, c.
A nalysis for C 12H 10N 6 (238.3)
Calcd
C 60.5 H 4.2 N 35.3%,
Found C 60.3 H 4.2 N 35.0%.
Assignment
Compounds
8a
10a
10c
11a
11c
7-M ethyl-1 -phenyl-1 OH-1,2,4-triazo lo-
f t ’,4 ’:3,4][1,2,4]triazino [5,6-b]indole (3b)
Carbon of the sugar part
C-2
C-2
C-2
C-2
C-2
C-2
139.34
149.42 140.01
72.84
70.64 68.78
70.14
69.45 62.53
63.44
68.52 68.02
70.40 70.26 68.38 67.77
A 2 M solution of iron(III) chloride in ethanol
(1.0 ml) was added dropwise to a boiling solution
of 2b (3.0 g, 10.0 m m ol) in ethanol (100 ml). The
reaction m ixture was processed as before. The p ro -
duct was crystallized from ethanol/N ,N -dim ethyl-
form am ide as yellow crystals (2.20 g, 74% yield),
m.p. > 300 °C. IR (KBr): 1619 cm ' 1 (C=N).
68.54
68.21
63.93
68.08 61.83 64.21 62.03
62.49
Carbons of the heterocyclic
rings
C-l
C-3
136.57
148.02
159.9 154.20 157.30
C-6
C-7
C-8
112.20 118.08 117.63 123.15 135.45
120.34 122.73 122.25 123.15 123.34
119.25 119.35 120.70 123.15 132.63
A nalysis for C 17H 12N6 (300.3)
Calcd
C 68i) H 4 .0 N 28.0% ,
C-9
120.34 122.73 121.10
118.80 116.01
136.57 148.13
Found C 67.8 H 3.9 N 28.0%.
C-3a
C-4a
C-5a
C-5b
C-9a
C-9b
C-lOa
149.20
156.40
135.22 134.70 136.57
138.30
130.20
141.89
118.80 113.29
3,7-D im ethyl-10H -l,2,4-triazolo-
[4 ’,3':2,3][1,2,4]triazino[5,6-b]indole (4a)
118.08
136.57
112.20
118.90
140.86
131.26 136.93 136.40
136.57
144.01
(a)
A solution of 1 (0.2 g, 1.0 mmol) in glacial
acetic acid (20 ml) was boiled under reflux for 8 h.
The yellow product that separated out on cooling,
was filtered, w ashed with ethanol and recrystal-
Miscellanous
XOAc
21.88 20.77 21.23 20.74
21.09 20.66 21.09 20.68
20.99 20.63
lized
from
ethanol/M N -dim ethylform am ide
20.50
(0.16 g, 73% yield), m.p. 320-321 °C. IR (KB r):
3044 (N H ) and 1612 cm " 1 (C=N). !H N M R
(D M SO -d6) Ö = 2.46 and 2.48 (2 s, 6 H, 2 M e),
7.25 (d, 1 H , / 89 8.3 Hz, H -8), 7.48 (d, 1 H, H-9),
7.94 (s, 1 H , H -6) and 11.67 (brs, 1 H, N H ); 13C
N M R dc = 9.55 and 20.45 (2 M e), 112.22 (C-9 and
C-5b), 116.33 (C-7), 122.69 (C-6,8), 131.48 (C-8a),
134.38 (C-5a), 140.0 (C-lOa), 143.80 (C -lla ) and
144.09 (C-3).
27.64
22.37 21.87
177.62 169.76 177.62 170.51
XNAc
28.21
28.51 21.19
xco
170.68
170.15
170.13
170.01
169.73
C-Me
21.28 21.18 21.37 21.26 21.19
1,7-Dimethyl-lOH -1,2,4-triazolo [3 ’,4 ’:3,4]-
[1,2,4]triazino[5,6-b]indoIe (3a)
A nalysis for C 12H 10N6 (238.3)
A 2 M solution of iron(III) chloride in ethanol
(1.0 ml) was added dropw ise to a boiling solution
of 2a (2.4 g, 10.0 m m ol) in ethanol (100 ml). H ea t-
ing was continued for 15 min, and the m ixture was
kept overnight at room tem perature and then con-
centrated under reduced pressure to about 20 ml.
The product that separated out, was filtered,
w ashed repeatedly with w ater and recrystallized
from ethanol/M N -dim ethylform am ide (1.6 g, 67%
yield), m.p. > 340 °C. IR (KB r): 1606 cm "1 (C=N );
lH N M R (D M SO -d6) (3 = 2.45 and 2.74 (2 s, 6 H, 2
M e), 7.33 (d, 1 H J 89 8.5 Hz, H -8), 7.53 (d, 1 H, H-
9), 7.96 (s, 1 H, H -6) and 11.93 (brs, 1 H , N H ), 13C
N M R <5C= 9.6 and 20.5 (2 M e), 112 (C-9 and C-5b),
116.2 (C-7), 122.8 (C -6 and C-8), 127.30 (C-9a),
134.5 (C-5a), 140.3 (C-lOa), 143.4 (C-3a) and 144.0
(C -l).
Calcd
C 60.1 H 4.2 N 35.3%,
Found C 60.1 H 4.2 N 35.1% .
(b)
A solution of 5-m ethylisatin (5) (0.16 g,
1.0 m m ol), 4,5-diam ino-3- m ethyl-1,2,4-triazole
hydrochloride (6) (0.15 g, 1.0 m m ol) and sodium
acetate (0.08 g, 1.0 m m ol) in a m ixture of ethanol
(20 m l) and w ater (5 ml) was heated under reflux
for 1 h. A cetic acid (0.2 ml) was added, and the
reflux was continued for 2 h. The product that sep-
arated out on cooling, was filtered, washed with
ethanol and recrystallized from ethanol/A^/V-di-
m ethylform am ide as yellow crystals (0.18 g, 75% ),
m.p. 320-322 °C. It was found to be identical with
the product obtained from m ethod (a).
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E. S. H. EI Ashry et al. • Acyclo C-Nucleoside Analogues of Condensed 1,2,4-Triazines
879
10-Acetyl-1,7-dim ethyl-l ,2,4-triazolo-
[3 ’,4 ’:3,4][1,2,4]triazino[5,6-b]indole (7a)
8-M ethyl-3-polyhydroxyalky lidenehydrazino-5H -
1,2,4-triazino[5,6-b]indole (8a -8 g)
To a solution of 1 (2.14 g, 10.0 m m ol) in ethanol
(100 ml) was added the solution of the respective
sugar (10.0 m m ol) in w ater (5 ml) and few drops
of acetic acid. The m ixture was heated under re-
flux for 2 h. The product that separated out on
cooling, was collected by filteration, w ashed with
ethanol and dried. The yellow product was recrys-
A
cold solution of 3a (0.5 g, 2.1 m m ol) in dry
pyridine (5 ml) was treated with acetic anhydride
(5 ml) and the m ixture was then kept overnight at
room tem perature with occasional shaking. It was
p oured onto crushed ice and the product that sep-
arated was filtered off, washed repeatedly with
w ater and dried. It was recrystallized from ethanol
as yellow needles (0.45 g, 77% yield), m.p. 2 7 0 -
272 °C. IR (KB r): 1724 (N C O ) and 1610 cm " 1 (C=
N and C=C).
tallized
from
ethanol/M N -dim ethylform am ide
(Table III).
l- ( P olyhydroxyalkyl) -7-m ethyl-10H-1,2,4-triazolo-
[3 ’,4 ’:3,4][1,2,4]triazino[5,6-b]indole (9a-9e)
A nalysis for C 14H 12N60 (280.3)
Calcd
C 60.0 H 4.3 N 30.0% ,
Found C 59.9 H 4.1 N 29.9% .
A 2 M solution of iron(III) chloride in ethanol
(1.0 ml) was added dropw ise to a boiling solution
of 8 (2.5 m m ol) in ethanol (100 ml). The reaction
m ixture was processed as before. The product was
recrystallized from ethanol/AyV -dim ethylform am -
ide as yellow crystals (Table IV).
10-Acetyl-7-m ethyl-1 -phenyl-1,2,4-triazolo-
]3\4':3,4][1,2,4]triazino [5,6-b]-indole (7b)
A
cold solution of 3b (0.5 g, 1.7 m m ol) in dry
pyridine (5 ml) was treated with acetic anhydride
(5 m l) and the reaction m ixture was processed as
above. The product was crystallized from ethanol
as yellow needles (0.3 g, 62% yield), m.p. 2 8 8 -
290 °C. IR (KB r): 1717 (N C O ) and 1611 cm " 1 (C=
N and C=C).
5-A cetyl-3-[N -acetyl-N '-(polyacetoxyalky lidene)-
hydrazino-8-m ethyl-l ,2,4-triazino[5,6-b]indole
(10a-10e)
A cold solution of 8 (1.5 m m ol) in dry pyridine
(5 ml) was treated with acetic anhydride (5 ml)
and the m ixture was kept 3 days at room tem per-
ature with occasional shaking. It was poured onto
crushed ice and the product was filtered, washed
A nalysis for C 19H 14N60 (342.4)
Calcd
C 66.7 H 4.1 N 24.6% ,
Found C 66.8 H 4.3 N 24.2% .
Table III. Elemental analysis and IR spectral data of the compounds 8a-g.
Yield
[%]
M.p.
[°C]
IR (KBr [cm“1])
Analysis [%
]
Compound
Molcular
formula
C
H
N
OH& NH
C=N/C=C
1612
8a
8b
8c
8d
8e
8f
75
65
62
64
63
58
60
190-192
228-230
241-243
193-195
187-189
173-175
183-186
Calcd
Found
Calcd
Found
Calcd
Found
Calcd
Found
Calcd
Found
Calcd
Found
Calcd
Found
51.1 5.4
51.4 5.6
51.1 5.4
51.2 5.0
51.1 5.4
51.0 5.8
52.0 5.2
c I6h 20n 6o 5
Ci6H2oN60 5
Ci6H2oN60 5
c 15h 18n 6o 4
Ci5H18N60 4
Ci5H18N60 4
Ci5Hi8N60 4
22.3 3346,3205
22.0
3373,3216,3161 1615
22.3
22.1
22.3 3358,3279,3203 1609
22.3
1612
1612
1615
1611
24.3 3388,3225
24.0
24.3 3364,3220
24.2
24.3 3361,3221
24.3
24.3 3382,3207
24.4
5.7
52.3
52.0 5.2
52.3 5.1
5.2
52.0
52.5 5.5
52.0 5.2
52.3 4.9
8g
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880
Table IV. Elemental analysis and IR spectral data of the compounds 9a- e.
E. S. H. El Ashry et al. ■Acyclo C-Nucleoside Analogues of Condensed 1,2,4-Triazines
IR (KBr
Yield
[%]
M.p.
[°C]
Analysis [%
[cm“1])
1
Compound
Molcular
formula
N
OH&NH
H
C=N/C=C
1621
C
9a
9b
9c
9d
9e
264-266
243-245
268-270
276-278
244-246
3375,3260
3385,3255
56
54
52
45
48
Ci6H18N60 3
Ci6H18N60 ?
Ci6Hi8N60 5
c)5hI6n60 4
Ci5H16N60 4
Calcd
Found
Calcd
Found
Calcd
Found
Calcd
Found
51.3 4.9
51.6 4.4
51.3 4.9
51.1 5.0
51.3 4.9
51.0 5.1
52.3 4.7
52.6 5.1
22.5
22.0
22.5
22.4
1621
1617
1622
1622
22.5 3360,3203
22.4
24.4
24.2
24.4
24.4
3336,3205
Calcd
Found
52.3 4.7
52.2 4.6
3329,3207
with w ater, dried and recrystallized from ethanol
as colourless needles (Table V).
filtered, w ashed w ith water, sodium thiosulphate
and dried. It was recrystallized from ethanol/MTV-
dim ethylform am ide as yellow crystals (1.60 g, 63%
yield), m.p. 257-259 °C. IR (KBr): 3213 and 3128
(N H ), 1689 (C H O ) and 1614 cm ' 1 (C=N and C=
C).
10-Acetyl-7-m ethyl-1-(polyacetoxyalkyl)-l ,2,4-
triazolo[3’,4':3,4][1,2,4]triazino[5,6-b]indole ( H a -
lle )
A nalysis for C i2H 10N 6O (254.3)
A cold solution of 9 (1.3 m m ol) in dry pyridine
(5 ml) was treated with acetic anhydride (5 ml)
and the m ixture was processed as before. It was
recrystallized from ethanol as yellow needles
(Table V I).
Calcd
C 56.7 H 4.0 N 33.1% ,
Found C 56.7 H 3.7 N 33.0% .
G lyoxal-l-(8-m ethyl-5H -l,2,4-triazino[5,6-b]indol-
3-yl)hydrazone-2-oxim e (13)
3-(2-O xoethylidenehydrazino)-8-m ethyl-5H -l,2,4-
triazino[5,6-b]indole (12)
A
solution of 12 (0.25 g, 1.0 m m ol), hydroxyl-
am ine hydrochloride (0.07 g, 1.0 m m ol) and so-
dium acetate (0.08 g, 1.0 m m ol) in a m ixture of
ethanol (25 ml) and w ater (5 ml) was heated under
reflux for 1 h. The product that separated out on
cooling, was filtered, washed with ethanol and
dried. It was recrystallized from ethanol/M N -di-
A suspension of 8a (3.76 g, 10.0 m m ol) in w ater
(150 ml) was treated with a solution of sodium
m etaperiodate
(8.6 g, 40.0 m m ol)
in
w ater
(100 ml). The m ixture was stirred for 5 h, and kept
overnight at room tem perature. The product was
Table V. Elemental analysis and IR spectral data of the compounds lOa-e.
Analysis [% 1
IR (KBr [cm-1])
C=N/C=C
o c o NCO
Yield
[%]
M.p.
[°C]
Compound
Molcular
formula
H
N
C
1635,1603
1628,1600
1628,1602
1627
53.7 5.1
54.0 5.2
53.7 5.1
12.5
12.5
12.5 1755
12.4
1702
10a
10b
10c
lOd
lOe
80
74
72
68
70
196-198
204-206
176-178
160-162
164-166
Calcd
Found
Calcd
Found
Calcd
Found
Calcd
Found
1753
C3„H34N60 ]2
C30H34N6O 12
c 30h 34n 6o 12
C27H30N6O 10
C27FI30N5O j0
1725(sh)
1700(sh)
1705(sh)
5.2
53.9
53.7 5.1
53.4 4.7
54.2 5.1
53.7 4.8
12.5 1752
12.6
14.0
13.7
14.0 1745
13.7
1751
1715(sh) 1630,1600
Calcd
Found
54.2 5.1
53.9
5.0
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E. S. H. El Ashry et al. • Acyclo C-Nucleoside Analogues of Condensed 1,2,4-Triazines______________________ 881
Table VI. Elemental analysis and IR spectral data of the compounds 11a
-e.
Yield
[%]
M.p.
[°C]
Analysis [%
IR (KBr [cm !])
1
Compound
Molcular
formula
N
OCO&NCO
1753
C
H
C=N/C=C
210-212
202-204
218-220
207-209
222-224
11a
lib
11c
lid
lie
82
78
84
72
65
Calcd
Found
Calcd
Found
Calcd
Found
Calcd
Found
53.7 4.8
53.9
13.4
13.5
13.4 1747
13.1
13.4
13.5
15.2
15.3
1612
1614
1614
1611
1612
C28H3oN6O u
C28H3oN6O n
C28H3oN6On
c 25h 26n 6o 9
c 25h 26n 6o 9
5.0
53.7 4.8
53.6 4.9
53.7 4.8
53.3 4.9
54.2 4.7
53.9 4.8
54.2 4.7
54.1 4.7
1747
1756
Calcd
Found
15.2 1757
15.4
m ethylform am ide as yellow crystals (0.17 g, 64%
yield), m.p. 294-296 °C. IR (K B r): 3338 (O H ),
3210, 3114 (N H ) and 1619 c i r r 1 (C =N and C=C).
A nalysis for C22H 18N 12 (450.5)
Calcd
C 58.7 H 4.0 N 37.3% ,
Found C 58.5 H 3.6 N 37.2% .
Analysis for C 12H n N 70 (269.3)
7-M ethyl-10H -l,2,4-triazolo[3\4’:3,4]-
[l,2,4Jtriazino[5,6-b]indoIe-l-carbaldehyde (15)
Calcd
C 53.5 H 4.1 N 36.4% ,
Found C 53.4 H 4.3 N 36.3% .
A
suspension of 9a (1.9 g, 5.0 m m ol) in w ater
G lyoxal bis(8-methyl-5H -l,2,4-triazino[5,6-bJ-
indol-3-yl)hydrazone (14)
(100 m l) was treated with a solution of sodium
m etaperiodate (4.3 g, 20.0 m m ol) in w ater (50 ml).
The m ixture was then processed as above and the
product was recrystallized from ethanol//V,N-di-
m ethylform am ide as yellow crystals (0.95 g, 50%
yield), m.p. > 300 °C. IR (KBr): 3325 (N H ), 1694
(C H O ) and 1620 cm “1 (C=N and C=C).
To a solution of 12 (0.25 g, 1.0 m m ol) in ethanol
(50 ml), a solution of 1 (0.2 g, 1.0 m m ol) in ethanol
(20 ml) and few drops of acetic acid w ere added.
The m ixture was heated under reflux for 1 h. The
product that separated out on cooling, was fil-
tered, w ashed with ethanol and dried. It was
recrystallized from ethanol/ Ar,N -dim ethylform am -
ide as yellow crystals (0.16 g, 64% yield), m.p.
282-284 °C. IR (KB r): 3275, 3215, 3160, 3110
(N H ), and 1604 cm “1 (C=N and C=C).
A nalysis for C 12H 8N 60 (252.2)
Calcd
C 57.1 H 3.2 N 33.3% ,
Found C 57.2 H 3.3 N 33.2% .
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882
E. S. H. El Ashry et al. • Acyclo C-Nucleoside Analogues of Condensed 1,2,4-Triazines
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