Synthesis of some new mixed azines, Schiff and Mannich bases of pharmaceutical interest related to isatin

Article abstract of DOI:10.1515/znb-2014-0262

The mixed azines 3a-h and 4 were obtained by treating 3-hydrazonoindolin-2-one (2) with the appropriate aldehyde or dialdehyde. Treatment of 3b or 3c with formaldehyde or glutaric dialdehyde and the appropriate amine afforded the azine Mannich bases 5-7. The condensation of isatin or its N-Mannich base 8 with 1-aminopiperidine, 4-aminomorpholine and 1,4-diaminopiperazine gave 10a- d, 12 and 13. The Mannich bases 14 and 15 were obtained from 10a and 10b. Treatment of 2 with succinic, phthalic and quinolinic anhydride and pyromellitic dianhydride afforded compounds 16, 17a, 17b and 18, respectively. The synthesis of isatin Schiff bases incorporating a benzoylpiperidine, benzoylmorpholine and 1,4-dibezoylpiperazine moiety and their N-Mannich bases was investigated.

Full text of DOI:10.1515/znb-2014-0262

Z. Naturforsch. 2015; 70(6)b: 393–402
Elsayed M. Afsah*, Saad S. Elmorsy, Soha M. Abdelmageed and Zaki E. Zaki
Synthesis of some new mixed azines, Schiff
and Mannich bases of pharmaceutical interest
related to isatin
Abstract: The mixed azines 3a–h and 4 were obtained by 22–27] activities, and this has stimulated further research
treating 3-hydrazonoindolin-2-one (2) with the appropriate in this field. On the other hand, a number of azines and
aldehyde or dialdehyde. Treatment of 3b or 3c with formal- mixed azines are receiving attention owing to their promis-
dehyde or glutaric dialdehyde and the appropriate amine ing antibacterial and antifungal [28–30], antimalarial [31],
afforded the azine Mannich bases 5–7. The condensation cytotoxic [32–34] and antioxidant [35] activity.
of isatin or its N-Mannich base 8 with 1-aminopiperidine,
In view of this, the present work is largely concerned
4-aminomorpholine and 1,4-diaminopiperazine gave 10a– with attempts to extend the scope of the reaction of isatin
d, 12 and 13. The Mannich bases 14 and 15 were obtained and its N-Mannich bases with hydrazine and related com-
from 10a and 10b. Treatment of 2 with succinic, phthalic pounds such as N-amino-heterocycles to include the syn-
and quinolinic anhydride and pyromellitic dianhydride thesis of some new mixed azines and Schiff bases having
afforded compounds 16, 17a, 17b and 18, respectively. The a 2-indolinone moiety as a structural unit.
synthesis of isatin Schiff bases incorporating a benzoylpi-
peridine, benzoylmorpholine and 1,4-dibezoylpiperazine
moiety and their N-Mannich bases was investigated.
2 Results and discussion
Keywords: Mannich bases; mixed azines; N-amino-hete-
rocycles; Schiff bases.
In the present study, isatin (1) was treated with hydrazine
to give the hydrazone 2 [36]. The reaction of 2 with the
appropriate aromatic aldehyde afforded a series of mixed
azines 3-(arylidenehydrazono)indolin-2-ones (3a–h) in
good to excellent yields (Scheme 1).
DOI 10.1515/znb-2014-0262
Received December 18, 2014; accepted January 23, 2015
In addition, the reaction of hydrazone 2 with dial-
dehydes such as glyoxal leads to the formation of the
bis-azine, which reacts further with glyoxal to give the
N-hydroxyacetaldehyde derivative 4 as the end-product.
The analytical and spectral data are consistent with the
structures proposed for compounds 3a–h and 4. The mass
spectra of 3a–h contain peaks of the respective molecu-
lar ions and showed very similar cleavage patterns. The
base peak in the spectra of these compounds is due to the
loss of Cꢀ=ꢀO to give ions of type A (Scheme 2), except for
compounds 3c and 3h, which showed intense peaks cor-
responding to the loss of Cꢀ=ꢀO at m/z ꢀ=ꢀ 264 (86 %) and 271
(73 %), respectively. Cleavage at the azino group of com-
pounds 3a–h leads to a peak at m/z ꢀ=ꢀ 145 due to the ion B.
These spectral data are in line with the reported studies on
the mass spectra of isatin and its derivatives [37–39].
Although potentially interesting, the literature of
Mannich bases related to azines is limited [33, 40]. The
Mannich reaction of azines of the type 3 is of particu-
lar interest, because it provides access to mixed azines
having a potential basic side chain of alkaloidal nature.
1 Introduction
The chemistry of isatin (2,3-indolinedione) and its deriva-
tives has been the subject of wide and increasing interest,
due to their wide range of biological and pharmacological
activities. The extensive literature dealing with the chem-
istry and pharmacological activities of isatin and related
compounds has been reviewed [1–7]. In particular, much
interest has centered around Schiff and N-Mannich bases
of isatin, which possess a broad spectrum of action includ-
ing antibacterial [8–14], anticonvulsant [15–17], anti-HIV
[10, 18–21], antifungal [3–7, 10], cytotoxic and anticancer [3,
*Corresponding author: Elsayed M. Afsah, Faculty of Science,
Chemistry Department, Mansoura University, ET-35516, Mansoura,
Egypt, e-mail: emafsah@yahoo.com
Saad S. Elmorsy, Soha M. Abdelmageed and Zaki E. Zaki: Faculty
of Science, Chemistry Department, Mansoura University, ET-35516,
Mansoura, Egypt
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ꢀꢀꢀꢁ
394ꢀ
ꢀE. M. Afsah et al.: Synthesis and some new mixed azines
X
3c
N
O
N CH Ar
Ar−CHO
2 R2NH
Piperazine
2 CH2O
N
N
H
O
CH2(CH2CHO)2
H
CHO
CHO
1: X = O
2: X = NNH2
3a: Ar = C6H5
N
N
CH Ar
Ar−CH
N
N
N N CH Ar
3b: Ar = C6H4-4-NMe2
3c: Ar = C6H4-4-Me
O
O
3d: Ar = C6H4-4-OMe
3e: Ar = C6H4-4-OH
H
O
N
N
O
N
N
3f: Ar = C6H4-3-OMe,4-OH
3g: Ar = C6H3-3,4-(OCH2O)
3h: Ar = 1-naphthyl
NR2
NR2
N
N
N
N
N
N
N
7a: Ar = p-tolyl, NR2 = NMe2
7b: Ar = p-tolyl, NR2 = 1-piperidinyl
O
N
O
4
3b
HO
CHO
Ar CH
N
N
CH2O/R2NH
6: Ar = p-tolyl
N
O
N
CH
NMe2
Scheme 3:ꢀSynthesis of bis-(Mannich bases) of the mixed azine 3c.
N
5
NR2
NR2
and piperazine could be valuable in the synthesis of new
isatin Schiff bases with an alkaloid partial structure, as
depicted in Scheme 4.
a
b
c
d
1-piperidinyl
4-morpholinyl
1,2,3,4-tetrahydroisoquinolin-2-yl
di(2-hydroxyethyl)amino
In view of that, 1 was treated with 1-aminopiperidine
(9a) and 4-aminomorpholine (9b) to give 3-(piperidin-
1-ylimino)indolin-2-one (10a) and the 3-(morpholinoimino)
analogue 10b, respectively. A similar treatment of 1-(piperid-
inomethyl)isatin (8) [42] with 9a and 9b afforded the Schiff–
Mannich bases 10c and 10d. Analogously, treating 1 and 8
with 1,4-diaminopiperazine (11) led to the formation of 12
and the bis-(Mannich base) 13, respectively. In addition,
the Mannich reaction of 10a with formaldehyde and mor-
pholine gave 1-(morpholinomethyl)-3-(piperidin-1-ylimino)
Scheme 1:ꢀSynthesis of 3-(arylidenehydrazono)indolin-2-ones
(3a–h) and Mannich bases of 3b.
This has been realized by treating 3-[(4-(dimethylamino)
benzylidene)hydrazono]indolin-2-one (3b) with formalde-
hyde and piperidine, morpholine, tetrahydroisoquinoline
and diethanolamine to give the corresponding N-Mannich
bases 5a–d, respectively (Scheme 1).
The reaction of the mixed azine 3c with piperazine and
formaldehyde proceeded equally well providing 1,1′-[piper-
azine-1,4-diylbis(methylene)]-bis[3-((4-methylbenzylidene)
hydrazono)indolin-2-one] (6) (Scheme 3). It is interesting in
this connection that treatment of 3c with glutaric dialdehyde
and dimethylamine or piperidine led to the formation of the
bis-(Mannich base) (7a) and the 1,1’-[1,5-di(piperidin-1-yl)]
analogue 7b, respectively, via a double Mannich reaction.
Although the utility of aromatic and heterocyclic
amines in the synthesis of isatin Schiff bases was well
established [1–6], the use of N-amino-heterocycles in such
reactions was less widely recognized and had seen limited
use [41]. The condensation of 1 or the Mannich base 8 with
N-amino-heterocycles related to piperidine, morpholine
O
1: R = H
8: R = CH2-NC5H10
N
R
O
EtOH/AcOH
EtOH/AcOH
H2N N
N NH2
9a: X = CH2
9b: X = O
X
N NH2
11
N
O
N
N
N
N
O
N
X
N
O
N
N
12
H
H
R
10
X
CH2
O
CH2
O
R
H
H
N
O
N
N
N
a
b
c
d
N
O
N
CH2-NC5H10
CH2-NC5H10
13
N
N
3a: m/z = 249 (1) [M]+
m/z = 250 (0.3) [M+1]+
N
N
O
10a
Morpholine
CH2O
m/z = 104 (20)
10b
m/z = 104 (20)
Piperazine/2 CH2O
N
N CH Ph
O
−CO
N
O
N
CH Ph
m/z = 77 (87)
N
NH
N
N
N
A
H
N
O
N
N
m/z = 221 (100 %)
m/z = 145 (5)
N
O
O
N
O
N N
N
N
15
O
14
H
B
m/z = 145 (5)
Scheme 4:ꢀReaction of 1 or its Mannich base 8 with
N-amino-heterocycles.
Scheme 2:ꢀMass fragmentation pattern of 3a.
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E. M. Afsah et al.: Synthesis and some new mixed azinesꢂ
ꢂ395
O
1-(2-oxoindolin-3-ylidenamino)pyrrolidine-2,5-dione (16).
A similar reaction of 2 with phthalic anhydride and qui-
nolinic anhydride led to the formation of compounds 17a
and 17b, respectively. In addition, the pyrrolo[3,4-f]isoin-
dole-1,3,5,7(2H,6H)-tetraone (18) was obtained from 2 and
pyromellitic dianhydride (Scheme 5).
Succinic anhydride
N
O
N
2
N
H
O
O
O
O
16
X
O
O
O
O
O
N
O
N
In the course of this study, the Schiff base 19 [50] has
been used as a precursor for the synthesis of isatin Schiff
bases incorporating a benzoylpiperidine, benzoylmor-
pholine and 1,4-dibenzoylpiperazine moiety. Thus, the
Schiff bases 20a, 20b and 21 were obtained by treating 19
with the appropriate heterocyclic amine (Scheme 6).
Application of the Mannich reaction to the new Schiff
bases 20a and 20b using piperidine and morpholine
is of particular interest, because it offers access to com-
pounds 22a and 22b, incorporating two piperidine or two
morpholine moieties. The analogous reaction of 20a with
X
O
N
H
O
O
17a: X = CH
17b: X = N
O
O
N
O
N
N
N
O
N
H
N
O
O
H
18
Scheme 5:ꢀCondensation of the hydrazone 2 with acid anhydrides.
indolin-2-one (14). A similar reaction takes place between piperazine afforded the 1,4-bis(3-imino-2-oxoindolinyl)
10b and piperazine yielding the bis-(Mannich base) 15. The substituted piperazine 23.
formation of compounds 10–15 is of interest, because piper-
idine, morpholine and piperazine are significant classes of
heterocycles and constituents of various important natural 3 Experimental section
and synthetic bioactive compounds. In addition, Mannich
bases incorporating a morpholine or piperazine moiety are All melting points (uncorrected) were determined on a
known as antimicrobial agents [43–49].
Gallenkamp electric melting point apparatus (Sanyo Gal-
On the other hand, the hydrazone 2 could conceiv- lenkamp, Southborough, UK). Elemental microanalyses
ably function as a precursor to Schiff bases derived were carried out on Carlo Erba 1108 Elemental Analyzer
from N-amino-heterocycles. This has been achieved by (Heraeus, Hanau, Germany) at the Microanalytical Unit,
the condensation of 2 with succinic anhydride to give Faculty of Science, Cairo University. Infrared spectra were
measured on a Mattson 5000 FTIR spectrometer (Mattson
Instruments, Inc., Madison, WI, USA). H and 13C NMR
1
N
N
O
COOEt
data were obtained in [D6]DMSO solution on a Varian XL
300 MHz instrument (Varian, Inc., CA, USA) using TMS
as the internal standard. Chemical shifts are reported in
ppm (δ) downfield from internal TMS. Mass spectra were
recorded on a GC-MS QP-1000 EX Shimadzu instrument
(Shimadzu, Tokyo, Japan). The course of the reaction and
the purity of the synthesized compounds were monitored
by TLC using EM science silica gel coated plates, 0.25 nm,
60 GF 254 (Merck, Germany) with visualization by irradia-
tion with an ultraviolet lamp. Compounds 4, 7a, 7b, 13,
17a, 17b, 18, 21 and 22a are of limited solubility in common
1H NMR solvents. Compounds 2 [14], 8 [20] and 19 [22] were
prepared as previously described. All chemicals used were
of pure grade and were purchased from Aldrich, WI, USA.
O
N
H
O
N
H
C
N
Piperazine
19
N
C
H
N
NH
X
O
O
O
X
N
N
O
C N
21
20a
N
H
20a: X = CH2
20b: X = O
piperazine
2 CH2O
X
NH
O
C
N
N
CH2O
O
O
X
N
N
C N
N
N
N
O
N
O
N
X
3.1 3-(Arylidenehydrazono)indolin-2-ones
3a–h
N
C
N
22a: X = CH2
22b: X = O
O
23
A mixture of 2 [14] (1.61 g, 10 mmol) and the appropri-
ate aromatic aldehyde (10 mmol) in ethanol (80 mL) and
Scheme 6:ꢀSynthesis of Schiff and Mannich bases incorporating
N-benzoyl-heterocycles.
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+
acetic acid (0.5 mL) was refluxed for 4 h. After standing at 1H, NH). – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 279 (2) [M] , 280 (1)
+
+
+
room temperature (r.t.) for 24 h, the product obtained was [M+1] , 264 (6) [M–Me] , 251 (100) [M–CO] , 172 (2) [M–(p-
+
filtered and crystallized from ethanol to give 3a–h.
anisyl)] , 145 (13), 134 (32), 118 (59), 117 (33), 107 (28) [p-ani-
syl] , 92 (68) [C6H4O] . – C16H13N3O2 (279.29): calcd. C 68.81,
H 4.69, N 15.05; found C 68.79, H 4.60, N 14.97.
+
+
3.1.1 3-(Benzylidenehydrazono)indolin-2-one (3a)
3.1.5 3-((4-Hydroxybenzylidene)hydrazono)indolin-
2-one (3e)
M.p. 198 °C. Yield 68 % (red crystals). – IR (KBr): v ꢀ=ꢀ 3412
(NH), 1729 (CO), 1613 (Cꢀ=ꢀN), 1584, 1350, 1265, 750 cm–1.
+
– MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 249 (1) [M] , 221 (100) [M–
M.p. 261 °C. Yield 60 % (red crystals). – IR (KBr): v ꢀ=ꢀ
3350–3196 (broad, NH and OH), 1723 (CO), 1612 (Cꢀ=ꢀN),
1533, 1436, 1285, 1186, 790 cm–1. – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ
+
CO] , 194 (13), 145 (5), 118 (55), 117 (15), 104 (20), 77 (87).
– C15H11N3O (249.27): calcd. C 72.28, H 4.45, N 16.86; found
C 72.20, H 4.41, N 16.79.
+
+
+
265 (2) [M] , 264 (3) [M–1] , 237 (100) [M–CO] , 145 (7),
+
120 (28), 118 (61), 117 (16), 93 (25) [C6H4O] . – C15H11N3O2
3.1.2 3-((4-(Dimethylamino)benzylidene)hydrazono)
indolin-2-one (3b)
(265.27): calcd. C 67.92, H 4.18, N 15.84; found C 67.89, H
4.10, N 15.78.
M.p. 218 °C. Yield 85 % (dark-red crystals). – IR (KBr): v ꢀ=ꢀ
3410 (NH), 1729 (CO), 1609 (Cꢀ=ꢀN), 1521, 1431, 1327, 870 cm–1.
3.1.6 3-((4-Hydroxy-3-methoxybenzylidene)hydrazono)
indolin-2-one (3f)
1
– H NMR ([D6]DMSO): vδ ꢀ=ꢀ 3.09 (s, 6H, NMe2), 6.76–8.24
(m, 8H, aromatic), 8.60 (s, 1H, -Nꢀ=ꢀCH-Ar), 10.73 ppm (s,
M.p. 223 °C. Yield 66 % (dark-red crystals). – IR (KBr): v ꢀ=ꢀ
13
1H, NH). – C NMR ([D6]DMSO): δ ꢀ=ꢀ 40.05 (NMe), 110.46,
3469 (OH), 3317 (NH), 1719 (CO), 1661, 1620, 1427, 1291,
111.70, 117.09, 120.40, 122.05, 128.69, 131.17, 150.03, 153.03
(all Ar C), 132.49 (C-3 of 2-oxoindoline moiety), 144.34
(Ar-CHꢀ=ꢀN), 165.18 ppm (Cꢀ=ꢀO). – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ
1
1210, 680 cm–1. – H NMR ([D6]DMSO): δ ꢀ=ꢀ 3.83 (s, 3H,
OMe), 6.88–8.08 (m, 7H, aromatic), 7.55 (s, 1H, OH), 8.56
(s, 1H, -Nꢀ=ꢀCH-Ar), 10.79 ppm (s, 1H, NH). – MS (EI, 70 eV):
+
+
+
292 (31) [M] , 293 (80) [M+1] , 263 (37), 264 (86) [M–CO] ,
145 (25), 147 (30), 120 (15), 118 (29), 117 (19), 104 (28), 91
(24). – C17H16N4O (292.34): calcd. C 69.85, H 5.52, N 19.17;
found C 69.80, H 5.49, N 19.03.
+
+
m/z (%) ꢀ=ꢀ 295 (21) [M] , 264 (34) [M–OMe] , 237 (100)
+
+
[M–CO] , 236 (19) [M–(OMe+CO)] , 207(100), 179 (62), 152
(9), 102 (10), 90 (11). – C16H13N3O3 (295.29): calcd. C 65.08, H
4.44, N 14.23; found C 64.99, H 4.40, N 14.19.
3.1.3 3-((4-Methylbenzylidene)hydrazono)indolin-
2-one (3c)
3.1.7 3-(2-((Benzo[d][1,3]dioxol-5-yl)methylene)
hydrazono)indolin-2-one (3g)
M.p. 230 °C. Yield 75 % (red crystals). – IR (KBr): v ꢀ=ꢀ 3441
(NH), 1736 (CO), 1611 (Cꢀ=ꢀN), 1457, 1327, 1201, 747 cm–1. – 1H
NMR ([D6]DMSO): δ ꢀ=ꢀ 3.31 (s, 3H, Me), 6.89–7.95 (m, 8H,
aromatic), 8.58 (s, 1H, -Nꢀ=ꢀCH-Ar), 10.83 ppm (s, 1H, NH).
M.p. 243 °C. Yield 76 % (orange crystals). – IR (KBr): v ꢀ=ꢀ
3449 (NH), 1725 (CO), 1614 (Cꢀ=ꢀN), 1422, 1267, 1022, 742 cm–1.
– 1H NMR ([D6]DMSO): δ ꢀ=ꢀ 6.16 (s, 2H, O-CH2-O), 6.88–7.55
(m, 7H, aromatic), 8.57 (s, 1H, -Nꢀ=ꢀCH-Ar), 10.80 ppm (s,
+
+
– MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 263 (2) [M] , 262 (4) [M–1] , 248
+
1H, NH). – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 293 (1) [M] , 265 (100)
+
+
(2) [M–Me] , 235 (100) [M–CO] , 145 (4), 118 (53), 117 (16),
91 (57). – C16H13N3O (263.29): calcd. C 72.99, H 4.98, N 15.96;
found C 72.91, H 4.92, N 15.89.
+
[M–CO] , 238 (11), 146 (13), 121 (28), 118 (36), 117 (18), 102
(10), 91 (26), 90 (35). – C16H11N3O3 (293.28): calcd. C 65.53, H
3.78, N 14.33; found C 65.57, H 3.70, N 14.29.
3.1.4 3-(2-(4-Methoxybenzylidene)hydrazono)indolin-
2-one (3d)
3.1.8 3-(2-((Naphthalen-1-yl)methylene)hydrazono)
indolin-2-one (3h)
M.p. 188 °C. Yield 88 % (orange crystals). – IR (KBr): δ ꢀ=ꢀ M.p. 223 °C. Yield 66 % (dark-red crystals). – IR (KBr): v ꢀ=ꢀ
3449 (NH), 1719 (CO), 1605 (Cꢀ=ꢀN), 1530, 1420, 1260, 1167, 3406 (NH), 1728 (CO), 1612 (Cꢀ=ꢀN), 1436, 1334, 1180, 792 cm–1.
+
+
740 cm–1. – 1H NMR ([D6]DMSO): δ ꢀ=ꢀ 3.90 (s, 3H, OMe), 6.93– – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 299 (3) [M] , 298 (11) [M–1] , 271
+
+
8.23 (m, 8H, aromatic), 8.68 (s, 1H, -Nꢀ=ꢀCH-Ar), 9.13 ppm (s, (73) [M–CO] , 168(23), 145 (20), 127 (100) [1-naphthyl ion] ,
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E. M. Afsah et al.: Synthesis and some new mixed azinesꢂ
ꢂ397
1
118 (32), 117 (17), 90 (27), 77 (35). – C19H13N3O (299.33): calcd. 765 cm–1. – H NMR ([D6]DMSO): δ ꢀ=ꢀ 3.00 (m, 4H, CH2–
C 76.24, H 4.38, N 14.04; found C 76.20, H 4.31, N 13.98.
N–CH2 of morpholine), 3.04 ( s, 6H, NMe2), 3.54 (m, 4H,
CH2–O–CH2 of morpholine), 4.45 (s, 2H, N-CH2-N of side
chain), 6.80–8.30 (m, 8H, aromatic), 8.63 ppm (s, 1H,
-Nꢀ=ꢀCH-Ar). – 13C NMR ([D6]DMSO): δ ꢀ=ꢀ 40.07 (NMe2), 51.54
(C-2, C-6 of morpholine), 61.30 (C-3, C-5 of morpholine),
66.12 (N-CH2-N of side chain), 116.42, 117.80, 120.33, 122.71,
128.39, 131.35, 131.70, 145.22, 153.17 (all Ar C), 132.49 (C-3
of 2-oxoindoline moiety), 149.01 (Ar-CHꢀ=ꢀN), 165.50 ppm
3.2 2-Hydroxy-2-((Z)-2-oxo-3-((E)-
((E)-2-((Z)-(2-oxoindolin-3-ylidene)
hydrazono)-ethylidene)hydrazono)
indolin-1-yl)acetaldehyde (4)
+
(Cꢀ=ꢀO). – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 391(4) [M] , 392 (1)
This compound was obtained from 2 (1.61 g, 10 mmol) and
glyoxal (40 %, 0.7 mL, 5 mmol), following the procedure
described for the synthesis of 3a–h. The product was crys-
tallized from ethanol to give 4. M.p. 264 °C. Yield 60 %
(yellow crystals). – IR (KBr): v ꢀ=ꢀ 3413 (OH), 3329 (NH),
1682 (CO), 1620, 1597, 1554, 1462, 1370, 1173, 730 cm–1. – MS
+
[M+1] , 306 (4), 292 (4), 264 (9), 147 ((7), 145 (4), 120 (3),
+
118 (3), 100 (100) [morpholinomethyl ion] , 91 (3), 56 (10).
– C22H25N5O2 (391.47): calcd. C 67.50, H 6.44, N 17.89; found
C 67.55, H 6.40, N 17.80.
+
+
(EI, 70 eV): m/z (%) ꢀ=ꢀ 401 (11) [M–1] , 400 (41) [M–2] , 290
(20), 199 (21), 173 (44), 146 (43), 144 (16), 118 (100), 117 (34), 3.3.3 3-(2-(4-(Dimethylamino)benzylidene)hydrazono)-
91 (42), 59 (10). – C20H14N6O4 (402.36): calcd. C 59.70, H 3.51,
N 20.89; found C 59.68, H 3.49, N 20.83.
1-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)
indolin-2-one (5c)
M.p. 175 °C. Yield 45 % (orange crystals). – IR (KBr): v ꢀ=ꢀ
1712 (CO), 1610 (Cꢀ=ꢀN), 1515, 1465, 1365, 1176, 1047, 746 cm–
1. – 1H NMR ([D6]DMSO): δ ꢀ=ꢀ 2.69–2.97 (m, 4H, CH2–CH2),
3.3 Synthesis of the N-Mannich bases 5a–d
A solution of 3b (0.87 g, 3 mmol), formalin (37 %, 0.28 mL, 3.09 (s, 6H, NMe2), 3.86 (s, 2H, CH2), 4.60 (s, 2H, N-CH2-N),
3.5 mmol) and the appropriate sec-amine (3 mmol) in 6.76–7.86 (m, 12H, aromatic), 8.72 ppm (s, 1H, -Nꢀ=ꢀCH-Ar).
+
ethanol (40 mL) was heated on a steam bath for 45 min. – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 437 (4) [M] , 305 (2), 291 (3),
After standing at r.t. for 48 h, the product obtained was 264 (10), 158 (15), 147 (69), 146 (80), 145 (62), 144 (100),
filtered and crystallized from ethanol to give 5a–d.
132 (96), 117 (53), 118 (80), 77 (61). – C27H27N5O (437.54):
calcd. C 74.12, H 6.22, N 16.01; found C 74.04, H 6.18, N
16.08.
3.3.1 3-(2-(4-(Dimethylamino)benzylidene)hydrazono)-
1-(piperidin-1-ylmethyl)indolin-2-one (5a)
M.p. 193 °C. Yield 70 % (orange crystals). – IR (KBr): v ꢀ=ꢀ 3.3.4 3-(2-(4-(Dimethylamino)benzylidene)hydrazono)-
1724 (CO), 1607 (Cꢀ=ꢀN), 1557, 1411, 1316, 1206, 1173, 1036,
755 cm–1. – 1H NMR ([D6]DMSO): δ ꢀ=ꢀ 1.35–1.46 (m, 6H, 3-H2,
4-H2, 5-H2 of piperidine), 2.50 (m, 4H, 2-H2, 6-H2 of piperi-
1-((bis(2-hydroxyethyl)amino)-methyl)indolin-
2-one (5d)
dine), 3.07 (s, 6H, NMe2), 4.45 (s, 2H, N-CH2-N of side chain), M.p. 221 °C. Yield 61 % (dark-orange crystals). – IR (KBr):
6.84–8.29 (m, 8H, aromatic), 8.64 ppm (s, 1H, -Nꢀ=ꢀCH-Ar). v ꢀ=ꢀ 3446 (OH), 1707 (CO), 1610 (Cꢀ=ꢀN), 1513, 1465, 1367,
+
1
– MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 294 (3) [M–(CH2NC5H10)] , 292 1174, 1045, 748 cm–1. – H NMR ([D6]DMSO): δ ꢀ=ꢀ 2.51 [t,
(32), 264 (100), 263 (40), 145 (35), 131 (21), 118 (34), 117 4H, N(CH2)2], 2.56 [s, 2H, 2 ꢀ×ꢀ OH], 3.03 (s, 6H, NMe2), 3.46
+
+
(20), 104 (25), 98 (25) [CH2NC5H10] , 84 (52) [NC5H10] . – (t, 4H, 2 ꢀ×ꢀ CH2OH), 4.20 (s, 2H, N-CH2-N), 6.81–8.12 (m, 8H,
C23H27N5O (389.49): calcd. C 70.92, H 6.99, N 17.98; found C aromatic), 8.64 ppm (s, 1H, -Nꢀ=ꢀCH-Ar). – 13C NMR ([D6]
70.89, H 6.90, N 17.91.
DMSO): δ ꢀ=ꢀ 40.31 (NMe2), 53.89 (NCH2), 56.01 (CH2OH),
73.34 (N-CH2-N), 117.06, 120.40, 121.34, 122.09, 125.46,
127.02, 131.20, 132.25, 144.40, 153.09 (all Ar C), 138.06 (C-3
of 2-oxoindoline moiety), 150.03 (Ar-CHꢀ=ꢀN), 165.17 ppm
(Cꢀ=ꢀO). – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 409 (1) [M] , 290 (12),
264 (37), 205 (2), 145 (100), 133 (26), 117 (87), 118 (31), 104
3.3.2 3-((4-(Dimethylamino)benzylidene)hydrazono)-
1-(morpholinomethyl)indolin-2-one (5b)
+
M.p. 224 °C. Yield 75 % (orange crystals). – IR (KBr): v ꢀ=ꢀ (21), 90 (77), 77 (28). – C22H27N5O3 (409.48): calcd. C 64.53,
1725 (CO), 1606 (Cꢀ=ꢀN), 1547, 1410, 1311, 1206, 1166, 1027, H 6.65, N 17.10; found C 64.66, H 6.60, N 17.15.
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398ꢀ ꢀE. M. Afsah et al.: Synthesis and some new mixed azines
3.4 1,1’-[Piperazine-1,4-diylbis(methylene)]- 3.7 Synthesis of the Schiff bases 10a, b
bis[3-((4-methylbenzylidene)-
A solution of 1 (0.88 g, 6 mmol) and 9a (0.6 g, 6 mmol)
hydrazono)-indolin-2-one] (6)
or 9b (0.61 g, 6 mmol) in ethanol (40 mL) and acetic acid
A solution of 3c (0.79 g, 3 mmol), formalin (37 %, 0.3 mL, (0.3 mL) was refluxed for 40 min. The precipitated product
4 mmol) and piperazine (0.13 g, 1.5 mmol) in ethanol (40 was filtered and washed with boiling ethanol (3 ꢀ×ꢀ 15 mL)
mL) was refluxed for 2 h, and then left to stand overnight. to give 10a, b.
The product obtained was filtered and crystallized from
ethanol to give 6. M.p. 235 °C. Yield 72 % (orange crystals).
3.7.1 3-(Piperidin-1-ylimino)indolin-2-one (10a)
– IR (KBr): v ꢀ=ꢀ 1726 (CO), 1629 (Cꢀ=ꢀN), 1605, 1463, 1335,
1
1206, 1161, 754 cm–1. – H NMR (CDCl3): δ ꢀ=ꢀ 2.40 (s, 6H, 2
M.p. 235 °C. Yield 70 % (dark-yellow crystals). – IR (KBr):
Me), 2.57 [br s, 8H, N(CH2CH2)2N], 4.47 (s, 4H, 2 CH2N), 7.09–
1
v ꢀ=ꢀ 3124 (NH), 1702 (CO), 1560, 1453, 1020, 694 cm–1. – H
7.99 (m, 16H, aromatic), 8.59 ppm [s, 2H, 2 ꢀ×ꢀ Nꢀ=ꢀCH-Ar)].
NMR ([D6]DMSO): δ ꢀ=ꢀ 1.39–1.48 (m, 6H, 3-H2, 4-H2, 5-H2 of
+
+
– MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 636 (6) [M] , 637 (3) [M+1] , 621
piperidine), 2.56 (m, 4H, 2-H2, 6-H2 of piperidine), 6.84–
7.25 (m, 4H, aromatic), 10.18 ppm (s, 1H, NH). – MS (EI, 70
+
(6) [M–Me] , 276 (3), 262 (5), 235 (100), 159 (5), 132 (9), 104
+
(13), 84 (14) [N(CH2CH2)2N] . – C38H36N8O2 (636.74): calcd. C
+
+
eV): m/z (%) ꢀ=ꢀ 229 (12) [M] , 228 (14) [M–1] , 147 (21), 145
71.68, H 5.70, N 17.60; found C 71.60, H 5.67, N 17.55.
+
+
(13) [M–(NC5H10)] , 117 (17) [M–(NC5H10+CO)] , 118 (19), 113
+
(15), 98 (21), 84 (51) [NC5H10] , 69 (51), 60 (100). – C13H15N3O
(229.28): calcd. C 68.10, H 6.59, N 18.33; found C 68.18, H
6.54, N 18.28.
3.5 1,1’-[1,5-Bis(dimethylamino)pentane-
1,5-diyl]bis[3-((4-methylbenzylidene)-
hydrazono)-indolin-2-one] (7a)
3.7.2 3-(Morpholinoimino)indolin-2-one (10b)
A mixture of 3c (0.79 g, 3 mmol), dimethylamine (40 %,
0.35 mL, 3 mmol) and glutaric dialdehyde (25 %, 0.6 mL, M.p. 190 °C. Yield 72 % (yellow crystals). – IR (KBr): v ꢀ=ꢀ 3178
1
1.5 mmol) in ethanol (20 mL) was heated on a steam bath (NH), 1708 (CO), 1615, 1561, 1453, 1133, 749 cm–1. – H NMR
for 1 h, and then left to stand overnight. The product ([D6]DMSO): δ ꢀ=ꢀ 3.77 (m, 4H, CH2–N–CH2 of morpholine),
obtained was filtered and crystallized from ethanol to give 3.89 (m, 4H, CH2–O–CH2 of morpholine), 6.77–7.42 (m, 4H,
7a. M.p. 210 °C. Yield 38 % (reddish-brown powder). – IR aromatic), 10.66 ppm (s, 1H, NH). – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ
+
+
(KBr): v ꢀ=ꢀ 1679 (CO), 1614 (Cꢀ=ꢀN), 1605, 1593, 1462, 1368, 231 (11) [M] , 232 (2) [M+1] , 147 (30), 145 (7) [M–(morpholinyl
+
+
1333, 1204, 1175, 748 cm–1. – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 680 ion)] , 118 (86), 117 (24) [M–(morpholinyl ion+CO)] , 90 (15),
+
+
(12) [M] , 445 (13), 235 (100), 234 (27), 208 (22), 201 (13), 86 (100) [morpholinyl ion] , 85 (13). – C12H13N3O2 (231.25):
146 (22), 118 (59), 117 (20), 91(75), 68(15). – C41H44N8O2 calcd. C 62.33, H 5.67, N 18.71; found C 62.29, H 5.60, N 18.69.
(680.84): calcd. C 72.33, H 6.51, N 16.46; found C 72.25,
H 6.48, N 16.40.
3.8 Synthesis of the Schiff–Mannich bases
10c, d
3.6 1,1’-[1,5-Di(piperidin-1-yl)pentane-
These compounds were obtained from the Mannich base 8
1,5-diyl]bis[3-((4-methylbenzylidene)-
hydrazono)-indolin-2-one] (7b)
[20] (0.49 g, 2 mmol) and 9a or 9b (2 mmol), in the manner
described for the synthesis of 10a, b. The product was fil-
tered and washed with boiling ethanol (3 ꢀ×ꢀ 15 mL) to give
10c, d.
This compound was synthesized from 3c (0.79 g, 3 mmol),
piperidine (0.25 g, 3 mmol) and glutaric dialdehyde (25 %,
0.6 mL, 1.5 mmol), following the procedure described for
the synthesis of 7a. The product was crystallized from 3.8.1 3-(Piperidin-1-ylimino)-1-(piperidin-1-ylmethyl)
ethanol to give 7b. M.p. 232 °C. Yield 50 % (yellowish-
brown crystals). – IR (KBr): v ꢀ=ꢀ 1682 (CO), 1620 (Cꢀ=ꢀN),
indolin-2-one (10c)
1550, 1461, 1340, 1187, 749 cm–1. – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ M.p. ꢀ>ꢀ300 °C. Yield 30 % (pale-yellow powder). – IR (KBr):
761 (0.6), 760 [M] , 328 (23), 210 (10), 171 (34), 133 (28), 118 v ꢀ=ꢀ 1701 (CO), 1547, 1398, 1339, 1020, 685 cm–1. – H NMR
+
1
(21), 91 (31), 77 (30). – C47H52N8O2 (760.97): calcd. C 74.18, H ([D6]DMSO): δ ꢀ=ꢀ 1.33–1.49 [m, 12H, 2 ꢀ×ꢀ (3-H2, 4-H2, 5-H2 of
6.89, N 14.73; found C 74.10, H 6.81, N 14.78.
piperidine)], 2.48 (m, 4H, 2-H2, 6-H2 of piperidine), 2.53
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E. M. Afsah et al.: Synthesis and some new mixed azinesꢂ
ꢂ399
(m, 4H, 2-H2, 6-H2 of piperidine), 4.14 (s, 2H, N-CH2-N of to that for obtaining 12. The product was filtered and
side chain), 6.87–7.29 ppm (m, 4H, aromatic).– MS (EI, washed with boiling ethanol (3 ꢀ×ꢀ 15 mL) to give 13. M.p.
+
+
70 eV): m/z (%) ꢀ=ꢀ 326 (20) [M] , 327 (13) [M+1] , 299 (14) 245 °C. Yield 60 % (yellow powder). – IR (KBr): v ꢀ=ꢀ 1719
+
+
[M+1(–CO)] , 240 (14) [M–(NC5H10+2H)] , 229 (13) [M–(CH (CO), 1610 (CN), 1559, 1446, 1056, 844 cm–1. – MS (EI, 70
+
+
+
+
2NC5H10+H)] , 200 (14), 142 (19), 131 (15), 84 (14) [NC5H10] . eV): m/z (%) ꢀ=ꢀ 568 (34) [M] , 569 (28) [M+1] , 567 (29)
+
+
+
– C19H26N4O (231.25): calcd. C 69.91, H 8.03, N 17.16; found C [M–1] , 539 (20) [M–(CO+H)] , 512 (33) [M–(2CO+H)] ,
+
69.88, H 7.93, N 17.02.
469 (25) [M–(CH2NC5H10+H)] , 373 (29), 402 (32), 363 (31),
264 (31), 174 (37), 139 (36), 148 (17), 95 (44). – C32H40N8O2
(568.71): calcd. C 67.58, H 7.09, N 19.70; found C 67.50, H
7.11, N 19.68.
3.8.2 3-(Morpholinoimino)-1-(piperidin-1-ylmethyl)
indolin-2-one (10d)
M.p. 220 °C. Yield 40 % (yellow powder). – IR (KBr): v ꢀ=ꢀ
1708 (CO), 1609, 1565, 1398, 1319, 1028, 748 cm–1. – 1H NMR 3.11 1-(Morpholinomethyl)-3-(piperidin-
([D6]DMSO): δ ꢀ=ꢀ 1.32–1.42 (m, 6H, 3-H2, 4-H2, 5-H2 of piperi-
dine), 2.44 (m, 4H, 2-H2, 6-H2 of piperidine), 3.21 (m, 4H,
1-ylimino)indolin-2-one (14)
CH2–N–CH2 of morpholine), 3.67 (m, 4H, CH2–O–CH2 of A solution of 10a (0.68 g, 3 mmol) and formalin (37 %,
morpholine), 4.10 (s, 2H, N-CH2-N of side chain), 6.81– 0.28 mL, 3.5 mmol) in ethanol (40 mL) was heated on a
7.27 ppm (m, 4H, aromatic). – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ steam bath for 15 min, then morpholine (0.26 g, 3 mmol)
+
+
+
328 (10) [M] , 329 (13) [M+1] , 301 (7), 230 [M–CH2NC5H10] , was added, and the reaction mixture was refluxed for 1
+
147 (24), 145 (11), 130 (15), 118 (67), 98 (25) [CH2NC5H10] , 86 h. After standing at r.t. for 48 h, the product obtained
+
+
(77) [morpholinyl ion] , 84 (30) [NC5H10] , 69 (66), 57 (89). was filtered and crystallized from ethanol to give 14.
– C18H24N4O2 (328.41): calcd. C 65.83, H 7.37, N 17.06; found C M.p. 298 °C. Yield 32 % (orange crystals). – IR (KBr):
65.79, H 7.30, N 16.94.
v ꢀ=ꢀ 1721 (CO), 1630, 1581, 1406, 1338, 1023, 678 cm–1. –
+ +
MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 328 (21) [M] , 329 (16) [M+1] ,
+
229 (15) [M–(morpholinomethyl ion)+H] , 216 (20)
3.9 3,3’-(Piperazine-1,4-diylbis(azan-
1-yl-1-ylidene))diindolin-2-one (12)
+
[M–(CO+NC5H10)] , 200 (15) [M–(CO+morpholinomethyl
+
ion)] , 101 (16), 87 (22), 84 (31). – C18H24N4O2 (328.41):
calcd. C 65.83, H 7.37, N 17.06; found C 65.85, H 7.33,
N 17.11.
This compound was obtained from 1 (0.37 g, 2.5 mmol)
and 11 (0.15 g, 1.26 mmol), following the procedure
described for the synthesis of 10a, b. The product was
filtered and washed with boiling ethanol (3 ꢀ×ꢀ 15 mL) to
give 12. M.p. 248 °C. Yield 38 % (pale-yellow powder). – 3.12 1,1’-(Piperazine-1,4-diylbis(methylene))
IR (KBr): v ꢀ=ꢀ 3446 (NH), 1710 (CO), 1615 (Cꢀ=ꢀN), 1576, 1460,
bis(3-(morpholinoimino)indolin-2-one)
1
1340, 1177, 742 cm–1. – H NMR ([D6]DMSO): δ ꢀ=ꢀ 4.13 [br s,
(15)
8H, N(CH2CH2)2N], 6.79–751 (m, 8H, aromatic), 10.71 ppm
(s, 1H, NH). – 13C NMR ([D6]DMSO): δ ꢀ=ꢀ 55.62 [N(CH2CH2)2N], This compound was obtained from 10b (0.69 g, 3 mmol),
118.51, 121.11, 124.27, 127.60, 131.84, 147.27 (all Ar C), 139.37 formalin (37 %, 0.28 mL, 3.5 mmol) and piperazine (0.13
(Cꢀ=ꢀN), 164.67 ppm (Cꢀ=ꢀO). – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ g, 1.5 mmol), following the procedure described for the
+
+
+
374 (29) [M] , 375 (10) [M+1] , 346 (7) [M–CO] , 318 (7) synthesis of 14. After standing at r.t. for 72 h, the product
+
[M–(2CO+H)] , 320 (18), 229 (17), 228 (41), 145 (14), 147 obtained was filtered and crystallized from ethanol to give
(40), 117 (8), 83 (100). – C20H18N6O2 (374.40): calcd. C 64.16, 15. M.p. 220 °C. Yield 35 % (orange crystals). – IR (KBr): v ꢀ=ꢀ
H 4.85, N 22.45; found C 64.05, H 4.80, N 22.39.
1675 (CO), 1607 (Cꢀ=ꢀN), 1535, 1417, 1344, 1173, 741 cm–1. – 1H
NMR ([D6]DMSO): δ ꢀ=ꢀ 2.33 [br s, 8H, N(CH2CH2)2N], 3.23 (m,
4H, CH2–N–CH2 of morpholine), 3.89 (m, 4H, CH2–O–CH2
of morpholine), 4.45 (s, 4H, 2 CH2N), 6.77–7.42 ppm (m, 8H,
3.10 3,3’-(Piperazine-1,4-diylbis(azan-
1-yl-1-ylidene))bis(1-(piperidin-
1-ylmethyl)indolin-2-one) (13)
+
aromatic). – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 572 (55) [M] , 573
+
(51) [M+1] , 530 (62), 498 (77), 455 (65), 416 (60), 402 (57),
305 (63), 262 (73), 205 (69), 145 (41), 106 (84), 78 (100). –
This compound was synthesized from 8 [20] (0.49 g, C30H36N8O4 (572.66): calcd. C 62.92, H 6.34, N 19.57; found C
2 mmol) and 11 (0.12 g, 1 mmol) by a procedure analogous 62.89, H 6.30, N 19.49.
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400ꢀ ꢀE. M. Afsah et al.: Synthesis and some new mixed azines
3.13 1-(2-Oxoindolin-3-ylideneamino)pyrro-
lidine-2,5-dione (16)
– C15H8N4O3 (292.25): calcd. C 61.65, H 2.76, N 19.17; found C
61.68, H 2.70, N 19.10.
A mixture of 2 (0.6 g, 6 mmol) and succinic anhydride
(0.96 g, 6 mmol) in acetic acid (20 mL) containing fused
sodium acetate (0.2 g) was heated under reflux for 4 h. The
reaction mixture was diluted with water (25 mL) and basi-
fied with ammonia. The product was filtered and crystal-
lized from ethyl acetate to give 16. M.p. 240 °C. Yield 62 %
(pale-brown powder). – IR (KBr): v ꢀ=ꢀ 3221 (NH), 2935 (CH
aliphatic), 1712 (Cꢀ=ꢀO of succinimide), 1678 (Cꢀ=ꢀO), 1620
3.14.3 2,6-Bis(2-oxoindolin-3-ylideneamino)pyrrolo[3,4-f]
isoindole-1,3,5,7(2H,6H)-tetraone (18)
M.p. ꢀ>ꢀ 300 °C. Yield 40 % (dark-red powder). – IR (KBr): v ꢀ=ꢀ
3202 (NH), 1725 (CO), 1615, 1548, 1462, 1337, 1210, 1020, 750
+
cm–1. – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 506 (53) [M+2] , 502 (51)
+
[M–2] , 465 (55), 298 (60), 264 (51), 213 (35), 144 (10), 143
(28), 117 (5), 84 (73), 83 (100). – C26H12N6O6 (504.41): calcd. C
61.91, H 2.40, N 16.66; found C 61.89, H 2.43, N 16.60.
1
(Cꢀ=ꢀN), 1154, 698 cm–1. – H NMR ([D6]DMSO): δ ꢀ=ꢀ 2.60 (s,
4H, 2 ꢀ×ꢀ CH2 of succinimide), 6.92–7.55 (m, 4H, aromatic),
11.22 ppm (s, 1H, NH). – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 243
+
+
+
(7) [M] , 244 (2) [M+1] , 215 (2) [M–CO] , 161 (20), 145 (7) 3.15 Synthesis of the Schiff bases 20a, b
+
[M–pyrrolidinedione ion)] , 132 (20), 117 (7), 98 (22) [pyr-
rolidinedione ion] , 63 (100), 77 (21). – C12H9N3O3 (243.22):
and 21
+
calcd. C 59.26, H 3.73, N 17.28; found C 59.20, H 3.69, N 17.20. A mixture of 19 [22] (0.88 g, 3 mmol) and piperidine (0.25 g,
3 mmol), or morpholine (0.26 g, 3 mmol), or piperazine
(0.13 g, 1.5 mmol), in toluene (20 mL) was heated under
3.14 Synthesis of compounds 17a, b and 18
reflux for 1 h. The product obtained on cooling was filtered
and crystallized from ethanol to give compounds 20a, b
These compounds were obtained from 2 (0.6 g, 6 mmol) and washed with boiling ethanol (3 ꢀ×ꢀ 15 mL) to give 21.
and phthalic anhydride (0.88 g, 6 mmol), or quinolinic
anhydride (0.89 g, 6 mmol), or pyromellitic dianhydride
3.15.1 3-(4-(Piperidine-1-carbonyl)phenylimino)indolin-
(0.65 g, 3 mmol), following the procedure described for
2-one (20a)
the synthesis of 16. The product was filtered and crystal-
lized from ethanol to give 17a, b and from ethyl acetate
M.p. 198 °C. Yield 50 % (yellowish-green crystals). – IR
to give 18.
(KBr): v ꢀ=ꢀ 3280 (NH), 1721 (CO), 1683 (CO), 1618, 1439, 1303,
1
1124, 1013, 783 cm–1. – H NMR ([D6]DMSO): δ ꢀ=ꢀ 1.27–1.31
(m, 6H, 3-H2, 4-H2, 5-H2 of piperidine), 4.10 (m, 4H, 2-H2,
3.14.1 2-(2-Oxoindolin-3-ylideneamino)isoindoline-
6-H2 of piperidine), 6.71–8.07 (m, 8H, aromatic), 11.01 ppm
1,3-dione (17a)
(s, 1H, NH). – C20H19N3O2 (333.38): calcd. C 72.05, H 5.74, N
12.60; found C 72.11, H 5.70, N 12.58.
M.p. 282 °C. Yield 60 % (dark-red powder). – IR (KBr): v ꢀ=ꢀ
3258 (NH), 1724 (CO), 1649 (CO), 1615, 1416, 1336, 1203,
1150, 751 cm–1. – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 291 (8) [M] , 3.15.2 3-(4-(Morpholine-4-carbonyl)phenylimino)
+
+
+
+
292 (1) [M+1] , 290 (40) [M–1] , 263 (2) [M–CO] , 234 (44)
indolin-2-one (20b)
+
+
[M–(2CO+2H)] , 146 (2), 145 (34) [M–(phthalimido ion)] ,
117 (73), 118 (100), 76 (23). – C16H9N3O3 (291.26): calcd. C M.p. 200 °C. Yield 55 % (pale-brown powder). – IR (KBr):
65.98, H 3.11, N 14.43; found C 65.90, H 3.04, N 14.39.
v ꢀ=ꢀ 3188 (NH), 1714 (CO), 1612, 1465, 1329, 1273, 1111, 1022,
879, 745 cm–1. – C19H17N3O3 (335.36): calcd. C 68.05, H 5.11, N
12.53; found C 68.12, H 5.00, N 12.49.
3.14.2 6-(2-Oxoindolin-3-ylideneamino)-
6H-pyrrolo[3,4-b]pyridine-5,7-dione (17b)
3.15.3 3-(4-(1-(4-(2-Oxoindolin-3-ylideneamino)benzoyl)
piperazine-4-carbonyl)-phenylimino)indolin-
2-one (21)
M.p. ꢀ>ꢀ300 °C. Yield 55 % (dark-red powder). – IR (KBr):
v ꢀ=ꢀ 3175 (NH), 1722 (CO), 1705 (CO), 1609 (Cꢀ=ꢀN), 1570, 1466,
1342, 1203, 1109, 741 cm–1. – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ
+
+
+
292 (10) [M] , 293 (2) [M+1] , 264 (3) [M–CO] , 236 (10) M.p. 260 °C. Yield 47 % (pale-brown powder). – IR (KBr):
[M–(2CO+H)] , 161 (38), 123 (59), 117 (11), 118 (8), 77 (100). v ꢀ=ꢀ 3214 (NH), 1714 (CO), 1608, 1512, 1466, 1330, 1199, 1016,
+
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ꢁꢀꢀꢀ
E. M. Afsah et al.: Synthesis and some new mixed azinesꢂ
ꢂ401
+
751 cm–1. – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 582 (18) [M] , 583(16) 218 °C. Yield 46 % (orange powder). – IR (KBr): v ꢀ=ꢀ 1730
+
+
[M+1] , 581 (10) [M–1] , 437 (18), 246 (21), 221 (12), 146 (CO), 1651 (CO), 1611 (Cꢀ=ꢀN), 1469, 1352, 1273, 1196, 1045,
1
(100), 118 (9), 86 (36). – C34H26N6O4 (582.61): calcd. C 70.09, 758 cm–1. – H NMR ([D6]DMSO): δ ꢀ=ꢀ 1.23–1.46 [m, 12H,
H 5.50, N 14.42; found C 70.11, H 5.49, N 14.38.
2 ꢀ×ꢀ (3-H2, 4-H2, 5-H2) of piperidine), 2.45 [m, 8H, 2 ꢀ×ꢀ (2-H2,
6-H2) of piperidine], 2.57 [br s, 8H, N(CH2CH2)2N], 4.34 (s,
4H, N-CH2-N), 7.06–7.65 ppm (m, 16H, aromatic). – MS (EI,
+
3.16 Synthesis of the Schiff–Mannich bases 70 eV): m/z (%) ꢀ=ꢀ 776 (5) [M] , 692 (4), 332 (5), 188 (2), 113
(9), 111 (19), 97 (42), 84 (8) 82 (37), 57 (100). – C46H48N8O4
22a, b
(776.92): calcd. C 71.11, H 6.23, N 14.42; found C 71.01, H
A solution of 20a (1 g, 3 mmol), or 20b (1 g, 3 mmol), forma- 6.26, N 14.39.
lin (37 %, 0.28 mL, 3.5 mmol) and piperidine or morpho-
line (3 mmol) in ethanol (40 mL) was heated on a steam
bath for 45 min. After standing at r.t. for 24 h, the product
References
obtained was filtered and crystallized from ethanol to give
22a, b.
[1] J. F. Da Silva, S. J. Garden, A. C. Pinto, J. Braz. Chem. Soc. 2001,
12, 273.
[2] S. N. Pandeya, S. Smitha, M. Jyoti, S. K. Sridhar, Acta Pharm.
3.16.1 1-(Piperidin-1-ylmethyl)-3-(4-(piperidine-
1-carbonyl)phenylimino)indolin-2-one (22a)
2005, 55, 27.
[3] K. L. Vine, L. Matesic, J. M. Loke, M. Ranson, D. Skropeta,
Anticancer Agents Med. Chem. 2009, 9, 397.
[4] T. Aboul-Fadl, F. A. Bin-Jubair, Int. J. Res. Pharm. Sci. 2010, 1,
113.
M.p. 180 °C. Yield 46 % (pale-brown powder). – IR (KBr):
v ꢀ=ꢀ 1722 (CO), 1611 (Cꢀ=ꢀN), 1469, 1382, 1273, 1112, 1020, 743
[5] B. Bhrigu, D. Pathak, N. Siddiqui, M. S. Alam, W. Ahsan, Int. J.
Pharm. Sci. Drug Res. 2010, 2, 229.
[6] P. Pakravan, S. Kashanian, M. M. Khodaei, F. J. Harding, Phar-
macol. Rep. 2013, 65, 313.
[7] G. Mathur, S. Nain, Med. Chem. 2014, 4, 417.
[8] U. K. Singh, S. N. Pandeya, A. Singh, B. K. Srivastava, M.
Pandey, Int. J. Pharm. Sci. Drug Res. 2010, 2, 151.
[9] G. Cerchiaro, A. C. Ferreira, J. Braz. Chem. Soc. 2006, 17, 1473.
[10] S. N. Pandeya, D. Sriram, G. Nath, E. De Clercq, Arzneim.
Forsch. 2000, 50, 55.
[11] S. K. Sridhar, M. Saravanan, A. Ramesh, Eur. J. Med. Chem.
2001, 36, 615.
[12] V. Ravichandran, S. Mohan, K. Suresh Kumar, Arkivoc 2007,
xiv, 51.
cm–1. – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 431 (5) [M+1] , 277 (5),
+
232 (5), 187 (2), 165 (28), 120 (100), 117 (2), 112 (2), 84 (4).
– C26H30N4O2 (430.54): calcd. C 72.53, H 7.02, N 13.01; found
C 72.50, H 7.10, N 12.88.
3.16.2 3-(4-(Morpholine-4-carbonyl)phenylimino)-
1-(morpholinomethyl)indolin-2-one (22b)
M.p. 191 °C. Yield 51 % (pale-brown powder). – IR (KBr):
v ꢀ=ꢀ 1715 (CO), 1619 (Cꢀ=ꢀN), 1467, 1327, 1273, 1208, 1111, 1023,
747 cm–1. – 1H NMR ([D6]DMSO): δ ꢀ=ꢀ 2.54 [m, 8H, 2 ꢀ×ꢀ (CH2–
N–CH2) of morpholine], 3.45 [m, 8H, 2 ꢀ×ꢀ (CH2–O–CH2) of
morpholine], 4.33 (s, 2H, N-CH2-N), 6.77–7.28 ppm (m, 8H,
[13] S. S. Chhajed, M. S. Padwal, Int. J. Chem. Tech. Res. 2010, 2, 209.
[14] A. Jarrahpour, D. Khalili, E. De Clercq, C. Salmi, J. C. Brunel,
Molecules 2007, 12, 1720.
[15] S. K. Sridhar, S. N. Pandeya, J. P. Stables, A. Ramesh, Eur.
J. Pharm. Sci. 2002, 16, 129.
+
aromatic). – MS (EI, 70 eV): m/z (%) ꢀ=ꢀ 434 (11) [M] , 433
+
(2) [M–1] , 406 (8), 348 (7), 334 (2), 158 (3), 133 (100), 105
[16] M. Varma, S. N. Pandeya, K. N. Singh, J. P. Stables, Acta.
Pharm. 2004, 54, 49.
(50), 77 (21). – C24H26N4O4 (434.49): calcd. C 66.34, H 6.03,
N 12.89; found C 66.30, H 6.08, N 12.81.
[17] A. Gursoy, N. Karali, S. Buyuktimkin, S. Demirayak, A. C. Ekinci,
H. Ozer, Farmaco 1996, 51, 437.
[18] S. K. Sridhar, S. N. Pandeya, E. De Clercq, Boll. Chim. Farm.
2001, 140, 302.
3.17 1,4-Bis(((3-(piperidine-1-carbonyl)
phenylimino)2-oxoindolin-1-yl)methyl)
piperazine (23)
[19] S. N. Pandeya, D. Sriram, G. Nath, E. De Clercq, Eur. J. Med.
Chem. 2000, 35, 249.
[20] S. N. Pandeya, D. Sriram, G. Nath, E. De Clercq, Pharm. Acta
Helv. 1999, 74, 11.
[21] T. R. Ball, B. Anand, P. Yogeeswari, D. Sriram, Bioorg. Med.
Chem. Lett. 2005, 15, 4451.
This compound was obtained from 20a (1 g, 3 mmol), for-
malin (37 %, 0.28 mL, 3.5 mmol) and piperazine (0.13 g,
1.5 mmol), following the procedure described for the syn-
thesis of 22a, b. The product obtained was filtered and
[22] N. Karali, Eur. J. Med. Chem. 2002, 37, 909.
[23] N. Karali, N. Terzioglu, A. Gursoy, Arch. Pharm. (Weinheim)
2002, 335, 374.
washed with boiling ethanol (3 ꢀ×ꢀ 15 mL) to give 23. M.p. [24] V. R. Solomon, C. Hu, H. Lee, Bioorg. Med. Chem. 2009, 17, 7585.
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ꢀꢀꢀꢁ
402ꢀ ꢀE. M. Afsah et al.: Synthesis and some new mixed azines
[25] N. R. Penthala, T. R. Yerramreddy, N. R. Madadi, P. A. Crooks,
Bioorg. Med. Chem. Lett. 2010, 20, 4468.
[26] A. T. Taher, N. A. Khalil, E. M. Ahmed, Arch. Pharm. Res. 2011,
34, 1615.
[37] R. J. Barbuch, N. P. Peet, J. E. Coutant, Org. Mass Spectr. 1986,
21, 521.
[38] R. S. Varma, A. P. Singh, S. P. Singh, Org. Mass Spectr. 1992,
27, 17.
[27] V. I. Chandran, L. Matesic, J. M. Locke, D. Skropeta, M. Ranson,
K. L. Vine, Cancer Lett. 2012, 316, 151.
[39] N. P. Peet, R. J. Barbuch, Org. Mass Spectr. 1984, 19, 171.
[40] H. I. Gul, H. Suleyman, M. Gul, Pharm. Biol. 2009, 47, 968.
[41] O. Bekircan, H. Bektas, Molecules 2008, 13, 2126.
[42] H. Hellmann, I. Löschmann, Chem. Ber. 1954, 87, 1684.
[43] M. Ashok, B. S. Holla, B. Poojary, Eur. J. Med. Chem. 2007, 42,
1095.
[44] V. A. Pal’chikov, Russ. J. Org. Chem. 2013, 49, 787.
[45] H. Bayrak, A. Demirbas, S. A. Karaoglu, N. Demirbas, Eur. J.
Med. Chem. 2009, 44, 1057.
[46] H. Bayrak, A. Demirbas, N. Demirbas, S. A. Karaoglu, Eur. J.
Med. Chem. 2009, 44, 4362.
[47] E. Wyrzykiewicz, M. Wendzonka, B. Kedzia, Eur. J. Med. Chem.
2006, 41, 519.
[48] A. R. Foroumadi, S. Ghodsi, S. Emami, S. Najjari, N. Samadi,
M. A. Faramarzi, L. Beikmohammadi, F. H. Shirazi, A. Shafiee,
Bioorg. Med. Chem. Lett. 2006, 16, 3499.
[28] V. B. Kurteva, S. P. Simeonov, M. Stoilova-Disheva, Pharmacol.
Pharm. 2011, 2, 1.
[29] M. Revanasiddappa, T. Suresh, S. Khasim, S. C. Raghavendray,
C. Basavaraja, S. D. Angadi, E-J. Chem. 2008, 5, 395.
[30] G. Gürkök, N. Altanlar, S. Suzen, Chemotherapy 2009, 55, 15.
[31] J. L. Vennerstrom, M. T. Makler, C. K. Angerhofer, J. A. Williams,
Antimicrob. Agents Chemother. 1995, 39, 2671.
[32] A. I. Khodair, P. Bertrand, Tetrahedron 1998, 54, 4859.
[33] H. I. Gul, M. Gul, J. Vepsälainen, E. Erciyas, O. Hänninen, Biol.
Pharm. Bull. 2003, 26, 631.
[34] N. Haider, T. Kabicher, J. Käferböck, A. Plenk, Molecules 2007,
12, 1900.
[35] G. Gürkök, T. Coban, S. Suzen, J. Enzyme Inhib. Med. Chem.
2009, 24, 506.
[36] B. Srinivas, V. Rajini Priya, G. Sridhar Babu, J. Venkateshwar
Rao, P. S. Malathy, K. Raja Manohar, B. Chandara Prakash,
L. Srikanth, Der Pharma Chemica 2010, 2, 378.
[49] Y. Cui, Y. Dang, Y. Yang, S. Zhang, R. Ji, Bioorg. Med. Chem. Lett.
2005, 15, 209.
[50] T. I. El-Emary, Polish J. Chem. 1996, 70, 1143.
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