Synthesis of a New Series of N-Mannich Bases and Polyhydroxy Mannich Bases of Pharmaceutical Interest Related to Isatin and Its Schiff Bases

Article abstract of DOI:10.1002/jhet.3097

The reaction of isatin 1 with benzaldehyde and a sec-amine or the appropriate aldimine afforded the N-Mannich bases 2–3 and the bis-base 4. Treatment of 1 with glutaric dialdehyde and morpholine gave the bis-base 5. Mannich reaction of the Schiff bases 6a–f derived from 1, led to the new Mannich bases and bis-bases 7–9. The use of N-methyl-D-glucamine as the amine component in the Mannich reaction with 6b–f led to the polyhydroxy Mannich bases 11–13.

Full text of DOI:10.1002/jhet.3097

Month 2018 Synthesis of a New Series of N-Mannich Bases and Polyhydroxy Mannich
Bases of Pharmaceutical Interest Related to Isatin and Its Schiff Bases
*
Elsayed M. Afsah,
Ahmad A. Fadda, and Ahlam H. Hanash
Chemistry Department, Faculty of Science, Mansoura University, Mansoura ET-35516, Egypt
*
E-mail: emafsah@yahoo.com
Received August 16, 2017
DOI 10.1002/jhet.3097
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
The reaction of isatin 1 with benzaldehyde and a sec-amine or the appropriate aldimine afforded the
N-Mannich bases 2–3 and the bis-base 4. Treatment of 1 with glutaric dialdehyde and morpholine gave the
bis-base 5. Mannich reaction of the Schiff bases 6a–f derived from 1, led to the new Mannich bases and
bis-bases 7–9. The use of N-methyl-D-glucamine as the amine component in the Mannich reaction with
6b–f led to the polyhydroxy Mannich bases 11–13.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
the reaction of 1 with aromatic aldehyde and sec-amines,
has been achieved by treating 1 with benzaldehyde and
morpholine or piperidine to afford 1-(morpholin-4-
ylbenzyl)indolin-2,3-dione (2a) and the 1-(piperidin-1-
ylbenzyl) analog (2b), respectively (Scheme 1). The
analytical and spectral data of 2a and 2b are consistent
with their structures. The 1H NMR spectrum of 2a
revealed the presence of a singlet for (Ph─CH) at
δ = 5.86 and two multiplets at 3.52 (CH2─O─CH2) and
2.66 ppm (CH2─N─CH2). The mass spectra of 2a and 2b
indicated the molecular ion peaks at m/z 322 and 320,
respectively, and exhibited a number of identical peaks at
m/z = 236 (M+–the amine component), 147 (isatin ion),
119 (isatin – CO) and 91.
The scope of the above synthesis was developed by
treating 1 with aldimines derived from benzaldehyde and
primary aromatic or heterocyclic amines to afford
1-(arylaminobenzyl)indoline-2,3-diones (3a–3e). The
reaction allows considerable variation in the aldehyde and
amine components of the aminobenzyl moiety of the
products. The structure of 3a–3e was confirmed on the
basis of analytical and spectral data. The IR spectra of
these compounds showed strong absorption bands around
3425 (NH), 1725 (CO), and 1332–1325 cmꢀ1 (C─N
stretch of sec-aryl amine). Their 1H NMR spectra
revealed the presence of (Ph─CH) proton as a singlet at
δ = 6.14–5.75 and a broad singlet due to (NH) at 4.19–
The N-Mannich bases derived from NH-heterocycles
and their derivatives have received significant attention
due to their wide range of biological and pharmacological
activities [1–8]. In particular, much interest has centered
around N-Mannich bases of isatin, and related
compounds, which possess a broad spectrum of action
including antibacterial [9–12], anticonvulsant [13–15],
anti-HIV [9,16,17], antifungal [3–5], cytotoxic, and
anticancer [18,19] activities.
In connection with our studies in the area of Mannich
bases [20–30], the present work is concerned with
attempts to extend the scope of Mannich reaction with
isatin and its Schiff bases, to include the synthesis of a
new series of their N-Mannich bases and bis(N-Mannich
bases), of potential pharmaceutical applications.
RESULTS AND DISCUSSION
The conventional route to N-Mannich bases of isatin
(indolin-2,3-dione) 1 and related compounds, involves its
reaction with formaldehyde and the appropriate amine
[31]. This reaction is restricted to the use of
formaldehyde as the key component. In the present work,
the synthesis of N-Mannich bases of the type 2, based on
© 2018 Wiley Periodicals, Inc.

E. M. Afsah, A. A. Fadda, and A. H. Hanash
Vol 000
Scheme 1. Synthesis of N-Mannich bases and bis(N-Mannich bases) of isatin.
Scheme 2. Mannich reaction with isatin Schiff bases 6a, 6c, and 6d.
3.44 ppm, and their mass spectra contain peaks of the
respective molecular ions, it underwent fragmentation
pattern that supported their structures.
The reaction of
1
with N1,N4-dibenzylidene-p-
phenylenediamine proceeded equally well, providing N,
N0-bis(indolin-2,3-dione-1-ylbenzyl)-p-phenylenediamine
(4). In the course of this study, the synthesis of the bis(N-
Mannich base) 5 has been achieved by treating 1 with
glutaric dialdehyde and morpholine. Compounds 4 and 5
were characterized by analytical and spectral data. The
mass spectra revealed intense molecular ion peaks at
m/z = 578 and 532 for 4 and 5, respectively.
On the other hand, considerable attention has been
devoted to isatin Schiff bases and their N-Mannich bases
as biologically active compounds [3,10,11]. Accordingly,
we prepared the isatin Schiff bases 6a [32], 6b [10], 6c
[11], and 6f [16] from 1 and the appropriate aryl or
heteroaryl amine. Whereas, the Schiff bases 6d and 6e
were prepared for the first time in this work. Application
of Mannich reaction to compounds 6a–f has been of
considerable importance in the synthesis of certain
N-Mannich bases and bis-bases, which possess considerable
synthetic and pharmaceutical interest (Scheme 2).
Therefore, treatment of 6a with benzaldehyde and aniline
afforded 7. The Mannich reaction with the Schiff bases
6c and 6d, is of particular interest, because the
sulfonamide and the benzamide moieties of these
compounds allows the construction of the new hybridized
bis(N-Mannich bases) of the type 8 and 9.
1
bases) 9a and 9b. The analytical, IR, H NMR, and mass
spectral data are consistent with the structures proposed for
compounds 8a–b and 9a–b. The IR spectrum of 8a
exhibited a strong broad band at 3445 (NH), 1722 (CO),
and two bands at 1329 and 1143 cmꢀ1 (sulfonamide). Its
1H NMR spectrum displays two multiplets at δ = 2.61
(2 × CH2─N─CH2) and 3.58 (2 × CH2─O─CH2), two
singlets at 4.18 (N─CH2─N) and 4.39 (SO2NH─CH2─N),
and a abroad singlet at 3.0 ppm (SO2NH).
One main goal of the present work is to study the
reactivity of N-methyl-D-glucamine 10 as the amine
component in the Mannich reaction with isatin Schiff
bases 6, as a possible route to N-polyhydroxy Mannich
bases. This has been realized by treating 6b, 6e, and 6f
with 10 and formaldehyde to afford the target
Therefore, the synthesis of 4-[1-(morpholinomethyl)-
2-oxoindolin-3-ylideneamino]-N-(morpholinomethyl)-
benzenesulfonamide (8a) and the bis(piperidin-1-ylmethyl)
analog (8b) has been achieved by treating 6c with
formaldehyde and morpholine or piperidine. A similar
reaction takes place with 6d, yielding the bis(N-Mannich
compounds;
aminomethyl]-3-(arylimino)indolin-2-ones
respectively (Scheme 3). No report seems to have
1-[methyl-(2,3,4,5,6-pentahydroxyhexyl)
(11a–c),
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N-Mannich Bases and Polyhydroxy Mannich Bases
Scheme 3. Mannich reaction of isatin Schiff bases with N-methyl-D-glucamine.
appeared in the literature on using N-methyl-D-glucamine
10 as the amine component in the Mannich reaction with
isatin and related compounds.
formation of new N-polyhydroxy Mannich bases and
hybridized bis(N-polyhydroxy Mannich bases), which
have structural features related to glycosides.
It is interesting in this connection that treatment of the
Schiff bases 6c and 6d with 10 and formaldehyde led to
the formation of the hybridized bis(N-polyhydroxy
Mannich bases) 12 and 13, respectively, via a double
N-Mannich reaction. The formation of compounds 12 and
13 is in harmony with the formation of 8a–b and 9a–b
from 6c and 6d. The mass spectra of 12 and 13 revealed
intense molecular ion peaks at m/z = 714 (M+–1) and
EXPERIMENTAL
All melting points (uncorrected) were determined
a Gallenkamp electric melting point apparatus
on
(Sanyo Gallenkamp, Southborough, UK). Elemental
microanalyses were carried out on a Carlo Erba 1108
Elemental Analyzer (Heraeus, Hanau, Germany) at the Mi-
croanalytical Unit, Faculty of Science, Cairo University.
Infrared spectra were measured on a Mattson 5000 FTIR
spectrometer (Mattson Instruments, Inc., Madison, WI,
USA). 1H NMR data were obtained in [D6]DMSO solution
on a Varian XL 300 MHz instrument (Varian, Inc., CA,
USA) using tetramethylsilane as internal standard. Chemi-
cal shifts are reported in ppm (δ) downfield from internal
tetramethylsilane. 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 syn-
thesized compounds were monitored by thin-layer chroma-
tography using EM science silica gel coated plates,
0.25 nm, 60 GF 254 (Merck, Darmstadt, Germany) with
visualization by irradiation with an ultraviolet lamp. Com-
pounds 6a [32], 6b [10], 6c [11], and 6f [16] were prepared
as previously described.
1
679, respectively, and the IR and H NMR spectral data
supported their structures. The N-polyhydroxy Mannich
bases 11a–c, 12, and 13 have structural features related to
glycosides. In addition, introduction of the polyhydroxy
function would increase the hydrophilic character of the
compound and hence the bioavailability of the molecule.
CONCLUSION
In conclusion, a new series N-Mannich bases and bis(N-
Mannich bases) of isatin (1) was synthesized by treating 1
with benzaldehyde or glutaric dialdehyde and the
appropriate amine, or with the appropriate aldimine.
Mannich reaction of Schiff bases derived from 1 and
4-aminobenzamide or sulfanilamide afforded new
hybridized bis(N-Mannich bases). The use of
N-methyl-D-glucamine as the amine component in the
Mannich reaction with isatin Schiff bases led to the
1-(Aminobenzyl)indolin-2,3-diones (2a–2b).
of 1 (1.47 g, 10 mmol), benzaldehyde (1.1 g, 10 mmol),
A mixture
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E. M. Afsah, A. A. Fadda, and A. H. Hanash
Vol 000
and morpholine or piperidine (10 mmol) in ethanol
(20 mL) was heated on a steam bath for 30 min, and
stirred at room temperature for 24 h. The crude product
was purified by column chromatography (aluminum
oxide; n-hexane-ether, 8:1).
IR (KBr): ν = 3426, 1724, 1644, 1605, 1463, 1374, 1336,
1140, 944, 739 cmꢀ1; MS (EI, 70 eV): m/z (%) = 329
(M+) (17), 252 (M+ꢀPh) (15), 147 (33), 119 (100), 92
(81), 91 (22), 77 (4), 52 (59). Anal. Calcd for
C20H15N3O2 (329.35): C 72.94, H 4.59, N 12.76. Found:
C 72.89, H 4.51, N 12.70.
1-(Morpholin-4-ylbenzyl)indolin-2,3-dione (2a).
Red
1
needles, yield 1.51 g (47%), mp 197–198°C; H NMR
([D6]DMSO): δ = 2.66 [m, 4H, CH2─N─CH2], 3.52 (m,
4H, CH2─O─CH2), 5.86 (s, 1H, Ph─CH), 7.12–
7.86 ppm (m, 9H, aromatic); IR (KBr): ν = 1726, 1613,
1459, 1327, 1201, 1101, 932, 767 cmꢀ1; MS (EI, 70 eV):
m/z (%) = 322 (M+) (28), 245 (12), 236 (16), 159 (10),
147 (37), 119 (78), 92 (100), 91 (29), 76 (21). Anal.
Calcd for C19H18N2O3 (322.36): C 70.79, H 5.63, N
8.69. Found: C 70.71, H 5.59, N 8.59.
1-(Antipyrin-4-ylaminobenzyl)indolin-2,3-dione (3d).
Orange crystals, yield 1.18 g (27%), mp 158–160°C; H
1
NMR ([D6]DMSO): δ = 3.44 (br s, 1H, NH), 2.23 (s, 3H,
C─CH3), 2.91 (s, 3H, N─CH3), 5.75 (s, 1H, Ph─CH),
6.91–7.94 ppm (m, 14H, aromatic); IR (KBr): ν = 3386,
1727, 1613, 1399, 1327, 1284, 1196, 1090, 768 cmꢀ1
;
MS (EI, 70 eV): m/z (%) = 438 (M+) (34), 439 (M+ + 1)
(92), 408 (28), 361 (M+ꢀMe) (37), 331 (31), 303 (28),
254 (42), 251 (37), 178 (63), 147 (57), 119 (85), 108
(54), 92 (94), 77 (60), 52 (100). Anal. Calcd for
C26H22N4O3 (438.48): C 71.22, H 5.06, N 12.78. Found:
C 71.19, H 4.98, N 12.71.
1-(Piperidin-1-ylbenzyl)indolin-2,3-dione (2b).
Dark red
1
needles, yield 1.21 g (38%), mp 209–210°C; H NMR
([D6]DMSO): δ = 1.39 [m, 6H, CH2(CH2)2], 2.61 [m,
4H, CH2─N─CH2], 5.88 (s, 1H, Ph─CH), 7.01–
7.77 ppm (m, 9H, aromatic); IR (KBr): ν = 1720, 1698,
1612, 1486, 1311, 1209, 1057, 962, 732 cmꢀ1; MS (EI,
70 eV): m/z (%) = 320 (M+) (18), 236 (12), 147 (26), 119
(81), 92 (84), 91 (23), 76 (12), 52(100). Anal. Calcd for
C20H20N2O2 (320.15): C 74.98, H 6.29, N 8.74. Found:
C 74.90, H 6.22, N 8.69.
1-(1,2,4-Triazol-3-ylaminobenzyl)indolin-2,3-dione (3e).
Pale orange needles, yield 0.51 g (16%), mp 210°C; H
1
NMR ([D6]DMSO): δ = 3.60 (br s, 1H, NH), 5.88 (s, 1H,
Ph─CH), 9.77 (br s, 1H, NH of triazole moiety), 7.01–
7.86 ppm (m, 10H, aromatic); IR (KBr): ν = 3442, 3395,
1700, 1710, 1612, 1332, 1151, 921, 827, 732 cmꢀ1; MS
(EI, 70 eV): m/z (%) = 319 (M+) (76), 320 (M+ + 1) (28),
292 (81), 278 (31), 251 (M+ꢀtriazole ion, (44), 242
(M+–Ph) (100), 236 (46), 173 (33), 144 (48), 117 (26),
91 (39), 85 (33), 77 (22), 51 (65). Anal. Calcd for
C17H13N5O2 (319.32): C 63.94, H 4.10, N 21.93. Found:
C 63.89, H 4.12, N 21.90.
1-(Arylaminobenzyl)indolin-2,3-diones
(3a–3c).
A
solution of 1 (1.47 g, 10 mmol) and the appropriate
aldimine (10 mmol) in ethanol (25 mL) was heated on a
steam bath for 30 min, and the reaction mixture was stirred
at room temperature for 24 h. The products obtained on
cooling were filtered and crystallized from ethanol.
N,N0-Bis(indolin-2,3-dione-1-ylbenzyl)-p-phenylenediamine
1-(Phenylaminobenzyl)indolin-2,3-dione (3a).
Yellow
(4).
A mixture of 1 (1.47 g, 10 mmol) and N1,N4-
1
crystals, yield 2.09 g (64%), mp 179°C; H NMR ([D6]
DMSO): δ = 4.15 (br s, 1H, NH), 5.85 (s, 1H, Ph-CH),
6.92–7.57 ppm (m, 14H, aromatic); IR (KBr): ν = 3368,
dibenzylidenebenzene-1,4-diamine (2.84 g, 10 mmol) in
ethanol (50 mL) was refluxed on a steam bath for 40 min
and stirred at room temperature for 48 h. The crude
product was filtered and crystallized from ethanol and
purified by column chromatography (aluminum oxide;
petroleum ether-EtOAc, 7:3), to give 4 as buff crystals.
Yield 1.50 g (26%), mp 218–220°C; 1H NMR ([D6]
DMSO): δ = 4.23 (br s, 2H, 2 × NH), 6.16 (s, 2H,
2 × Ph─CH), 6.72–7.76 ppm (m, 22H, aromatic); IR
(KBr): ν = 3410, 3392, 1726, 1705, 1611, 1336, 1299,
937, 749 cmꢀ1; MS (EI, 70 eV): m/z (%) = 578 (M+)
(50), 579 (M+ + 1) (60), 432 (12), 342 (25), 329 (48),
261 (60), 223 (52), 147) (51), 119 (35), 92 (34), 77 (22).
Anal. Calcd for C36H26N4O4 (578.62): C 74.73, H 4.53,
N 9.68. Found: C 74.69, H 4.50, N 9.61.
1730, 1654, 1611, 1459, 1332, 1280, 1202, 953 cmꢀ1
;
MS (EI, 70 eV): m/z (%) = 328 (M+) (62), 251 (M+ꢀPh)
(40), 236 (M+ꢀPhNH) (10), 222 (35), 194 (81.44), 167
(15), 146 (4), 77(100), 51 (77). Anal. Calcd for
C21H16N2O2 (328.36): C 76.81, H 4.91, N 8.53. Found:
C 76.79, H 4.88, N 8.48.
1-(p-Tolylaminobenzyl)indolin-2,3-dione
(3b).
Pale
1
orange crystals, yield 1.98 g (58%), mp 180°C; H NMR
([D6]DMSO): δ = 2.28 (s, 3H, CH3), 3.77 (br s, 1H, NH),
5.95 (s, 1H, Ph─CH), 6.87–7.64 ppm (m, 13H,
aromatic); IR (KBr): ν = 3346, 1725, 1618, 1476, 1331,
1266, 1183, 965, 754 cmꢀ1; MS (EI, 70 eV): m/z
(%) = 342 (M+) (57), 327 (M+ꢀMe) (27), 250 (30), 236
(48), 208 (100), 145 (14), 91 (74), 78 (55), 65 (93). Anal.
Calcd for C22H18N2O2 (342.39): C 77.17, H 5.30, N
8.18. Found: C 77.02, H 5.27, N 8.10.
1,5-Bis(indolin-2,3-dione-1-yl)-1,5-Bis(morpholin-4-yl)
pentane (5). To a solution of 1 (2.94 g, 20 mmol) and
morpholine (1.8 g, 20 mmol) in ethanol (40 mL), glutaric
dialdehyde (25%, 4 mL, 10 mmol) was added, and the
mixture was refluxed on a steam bath for 1 h, and stirred
at room temperature for 4 days, and concentrated. The
gummy material that obtained was treated with ether to
1-(Pyridin-2-ylaminobenzyl)indolin-2,3-dione
(3c).
Reddish brown crystals, yield 0.82 g (25%), mp 196–
1
197°C; H NMR ([D6]DMSO): δ = 4.19 (br s, 1H, NH),
6.14 (s, 1H, Ph-CH), 6.81–7.84 ppm (m, 13H, aromatic);
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Month 2018
N-Mannich Bases and Polyhydroxy Mannich Bases
give a pale brown powder, which was crystallized
from ethanol, and purified by preparative thin-layer
chromatography (petroleum ether-EtOAc, 7:3), to give 5.
The product obtained was filtered and crystallized from
ethanol.
4-[1-(Morpholin-4-ylmethyl)-2-oxoindolin-3-ylideneamino]-
N-(morpholin-4-ylmethyl)benzenesulfonamide (8a). Yellow
1
Pale brown powder, yield 3.40 g (32%), mp 156°C; H
1
powder; yield 1.19 g (48%), mp 170°C; H NMR ([D6]
NMR ([D6]DMSO): δ = 1.30 [m, 2H, CH2(CH2)2], 1.73
(q, 4H, >CH─CH2─CH2─CH2─CH<), 2.81 [m, 8H,
2 × N(CH2)2], 3.71 [m, 8H, 2 × O (CH2)2], 4.68 (t, 2H,
2 × CH), 6.82–7.55 ppm (m, 8H, aromatic); IR (KBr):
ν = 1722, 1708, 1618, 1470, 1333, 1298, 1067, 949,
754 cmꢀ1; MS (EI, 70 eV): m/z (%) = 532 (M+) (35),
531 (M+ꢀ1) (20), 484 (21), 328 (23), 223 (20), 149 (26),
104 (28), 100 (41), 98 (18), 92 (21), 89 (21), 52 (100).
Anal. Calcd for C29H32N4O6 (532.59): C 65.40, H 6.06,
N 10.52. Found: C 65.38, H 6.01, N 10.49.
DMSO): δ = 2.61 (m, 8H, 2 × CH2─N─CH2), 3.0 (br s,
1H, SO2NH), 3.58 (m, 8H, 2 × CH2─O─CH2), 4.18
(s, 2H, N─CH2─N), 4.39 (s, 2H, SO2NH─CH2─N),
7.12–7.86 ppm (m, 8H, aromatic); IR (KBr): ν = 3445,
1722, 1612, 1459, 1420, 1329, 1251, 1143, 1043, 933,
821, 714 cmꢀ1; MS (EI, 70 eV): m/z (%) = 499 (M+)
(34), 413 (21), 399 (11), 327 (32), 299 (12), 255 (15),
244 (11), 156 (9), 144 (16), 100 (22), 86 (18), 52 (100).
Anal. Calcd for C24H29N5O5S (499.58): C 57.70, H 5.85,
N 14.02. Found: C 57.68, H 5.80, N 13.95.
4-(2-Oxoindolin-3-ylideneamino)benzamide
(6d).
A
4-[1-(Piperidin-1-ylmethyl)-2-oxoindolin-3-ylideneamino]-N-
(piperidin-1-ylmethyl)benzenesulfonamide (8b). Pale orange
mixture of 1 (1.47 g, 10 mmol) and 4-aminobenzamide
(1.36 g, 10 mmol) in ethanol (40 mL) and acetic acid
(4 mL) was refluxed on a steam bath for 1 h and stirred
at room temperature for 12 h. The product obtained was
filtered and crystallized from ethanol – acetic acid (2:1)
to give orange crystals, 1.78 g (67%). Mp 259–260°C; IR
(KBr): ν = 3391, 3368, 1725, 1658, 1635, 1585, 1460,
1275, 1114, 722 cmꢀ1. Anal. Calcd for C15H11N3O2
(265.27): C 67.92, H 4.18, N 15.84. Found: C 67.90, H
4.11, N 15.79.
1
powder, yield 1.10 g (44%), mp 145°C; H NMR ([D6]
DMSO): δ = 1.35 [m, 12H, 2 × CH2(CH2)2], 2.64
[m, 8H, 2 × CH2─N─CH2], 3.11 (br s, 1H, SO2NH),
4.12 (s, 2H, N─CH2─N), 4.36 (s, 2H, SO2NH─CH2─N),
7.21–7.83 ppm (m, 8H, aromatic); IR (KBr): ν = 3440,
1718, 1610, 1453, 1412, 1323, 1244, 1140, 1038, 931,
818, 712 cmꢀ1; MS (EI, 70 eV): m/z (%) = 495 (M+)
(17), 496 (M+ + 1) (3), 399 (5), 327 (22), 253 (6), 299
(17), 246 (7), 148 (12), 146 (24), 133 (44), 100
(100), 76 (14). Anal. Calcd for C26H33N5O3S (495.64):
C 63.01, H 6.71, N 14.13. Found: C 62.95, H 6.66,
N 14.01.
3-(Antipyrin-4-ylimino)indolin-2-one (6e). This compound
was prepared from equimolar amounts of
1 and
4-aminoantipyrine (10 mmol), following the same
procedure as described earlier. Crystallization of the product
from ethanol gave dark yellow crystals. Yield 2.7 g (81%),
mp 160–162°C; IR (KBr): ν = 3385, 3310, 1720, 1665,
1589, 1412, 1335, 1275, 1122, 772 cmꢀ1. Anal. Calcd for
C19H16N4O2 (332.36): C 68.66, H 4.85, N 16.86. Found: C
68.61, H 4.82, N 16.80.
Synthesis of bis(N-Mannich bases) 9a and 9b.
These
compounds were obtained from 6d (1.3 g, 5 mmol),
morpholine or piperidine (10 mmol), and formalin
(12 mmol), following the general procedure described
earlier for 8a, b. The product obtained was filtered and
crystallized from ethanol.
1-(Phenylaminobenzyl)-3-(phenylimino)indolin-2-one (7).
This compound was prepared from equimolar amounts of
6a, benzaldehyde, and aniline (5 mmol), following the
procedure described above for compounds 3a–e.
Crystallization of the product from ethanol gave 7 as
4-[1-(Morpholin-4-ylmethyl)-2-oxoindolin-3-ylideneamino]-
N-(morpholin-4-ylmethyl)benzamide (9a). Orange powder,
1
yield 1.08 g (47%), mp 186°C; H NMR ([D6]DMSO):
δ = 2.67 (m, 8H, 2 × CH2─N─CH2), 3.70 (m, 8H,
2 × CH2─O─CH2), 3.91 (s, 2H, N─CH2─N), 4.23 (s,
2H, CONH─CH2-N), 6.82–7.76 (m, 8H, aromatic),
8.16 ppm (br s, 1H, CONH); IR (KBr): ν = 3385, 1719,
1685, 1608, 1446, 1333, 1313, 1267, 1150, 1110, 1042,
998, 855, 764 cmꢀ1; MS (EI, 70 eV): m/z (%) = 463
(M+) (15), 464 (M+ + 1) (6), 348 (11), 320 (7), 246 (5),
132 (12), 100 (100), 90 (9), 56 (10). Anal. Calcd for
C25H29N5O4 (463.53): C 64.78, H 6.31, N 15.11. Found:
1
yellow crystals. Yield 1.2 g (60%), mp 217°C; H NMR
([D6]DMSO): δ = 3.81 (br s, 1H, NH), 5.81 (s, 1H, Ph-
CH), 6.75–7.66 ppm (m, 19H, aromatic); IR (KBr):
ν = 3328, 1722, 1655, 1611, 1499, 1335, 1262, 1212,
955 cmꢀ1; MS (EI, 70 eV): m/z (%) = 403 (M+) (48),
326 (M+ꢀPh) (18), 300 (47), 249 (46), 217 (50), 181
(71), 147 (55), 146 (27), 92 (20), 77 (100). Anal. Calcd
for C27H21N3O (403.48): C 80.37, H 5.25, N 10.41.
Found: C 80.31, H 5.20, N 10.38.
C 64.70, H 6.28, N 15.01.
4-[1-(Piperidin-1-ylmethyl)-2-oxoindolin-3-ylideneamino]-N-
(piperidin-1-ylmethyl)benzamide (9b). Pale brown powder,
Synthesis of bis(N-Mannich bases) 8a and 8b.
To a
1
solution of 6c (1.5 g, 5 mmol) and morpholine or
piperidine (10 mmol) in acetic acid (20 mL), there was
added formalin (37%, 1 mL, 12 mmol), and the mixture
was stirred at room temperature for 24 h, then diluted
with water (5 mL) and basified to pH8 by ammonia.
yield 0.98 g (43%), mp 182°C; H NMR ([D6]DMSO):
δ = 1.48 [m, 12H, 2 × CH2(CH2)2], 2.76 [m, 8H,
2 × CH2─N─CH2], 4.02 (s, 2H, N─CH2─N), 4.30
(s, 2H, CONH─CH2─N), 6.71–7.68 (m, 8H, aomatic),
8.25 ppm (br s, 1H, CONH); IR (KBr): ν = 3414, 1715,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. M. Afsah, A. A. Fadda, and A. H. Hanash
Vol 000
1675, 1609, 1416, 1331, 1316, 1262, 1170, 1112, 1012,
948, 853, 764 cmꢀ1; MS (EI, 70 eV): m/z (%) = 459
(M+) (25), 381 (23), 320 (21), 255 (18), 247 (13), 144
(19), 98 (100), 85 (25), 78 (16), 56 (11). Anal. Calcd for
C27H33N5O2 (459.58): C 70.56, H 7.24, N 15.24. Found:
C 70.50, H 7.21, N 15.19.
1362, 1062, 954, 835, 697 cmꢀ1; MS (EI, 70 eV): m/z
(%) = 430 (M+) (21), 429 (M+ꢀ1) (8), 286 (15), 253
(12), 190 (22), 148 (24), 120 (15), 91 (35), 77 (20), 52
(100), 51 (36). Anal. Calcd for C21H26N4O6 (430.45): C
58.59, H 6.09, N 13.02. Found: C 58.51, H 6.01, N 12.90.
Synthesis of bis(N-polyhydroxy Mannich bases) 12 and
13.
To a solution of N-methyl-D-glucamine 10 (2 g,
1-[Methyl-(2,3,4,5,6-pentahydroxyhexyl)aminomethyl]-3-
10 mmol) and 6c or 6d (5 mmol) in ethanol (25 mL),
there was added formalin (37%, 1 mL, 12 mmol), and the
mixture was heated for 30 min, and stirred at room
temperature for 48 h. The product obtained was filtered
and crystallized from ethanol.
aryl(heteroaryl)imino]-indolin-2-ones 11a–11c.
To
a
solution of N-methyl-D-glucamine 10 (1 g, 5 mmol) and
6b, or 6e, or 6f (5 mmol) in ethanol (25 mL), there was
added formalin (37%, 0.5 mL, 6 mmol), and the mixture
was heated for 30 min, and stirred at room temperature
for 24 h. The product obtained was filtered and
crystallized from ethanol.
4-[1-(Methyl-2,3,4,5,6-pentahydroxyhexyl)aminomethyl)-
2-oxoindolin-3-ylideneamino]-N-(methyl-2,3,4,5,6-
pentahydroxyhexyl)aminomethyl) benzenesulfonamide (12).
1-[Methyl-(2,3,4,5,6-pentahydroxyhexyl)aminomethyl]-3-(p-
tolylimino)indolin-2-one (11a). Pale orange powder, yield
Dark yellow powder, yield 1.7 g (47%), mp 234–236°C; 1H
NMR ([D6]DMSO): δ = 1.98 (s, 6H, 2 × NCH3), 2.21 (s,
1H, NH), 2.59 (dd, J = 7.2, 14.4 Hz, 2H, 2 × Ha-6), 2.95
(dd, J = 7.2, 14.4 Hz, 2H, 2 × Hb-6), 3.01 (m, 8H,
8 × CH─OH), 3.51 (dd, J = 7.5, 15 Hz, 2H, 2 × Ha-1),
3.74 (dd, J = 7.5, 15 Hz, 2H, 2 × Hb-1), 4.17 (s, 2H,
N─CH2─N), 4.39 (s, 2H, SO2NH─CH2─N), 4.76 (br s,
10H, 10 × OH), 7.12–7.77 ppm (m, 8H, aromatic); IR
(KBr): ν = 3478, 3272, 1711, 1617, 1539, 1322, 1230,
946, 765, 640 cmꢀ1; MS (EI, 70 eV): m/z (%) = 714
(M+ꢀ1) (52), 712 (16), 627 (30), 540 (22), 458 (44), 299
(13) 235 (51), 151 (12), 91 (31), 83 (100), 52 (25). Anal.
Calcd for C30H45N5O13S (715.77): C 50.34, H 6.34, N
9.78. Found: C 50.29, H 6.30, N 9.71.
0.98 g (44%), mp 205°C; 1H NMR ([D6]DMSO):
δ = 2.21 (s, 3H, NCH3), 2.28 (s, 3H, ArCH3), 2.37 (dd,
J = 7.8, 15.6 Hz, 1H, Ha-6), 2.66 (dd, J = 7.2, 14.4 Hz,
1H, Hb-6), 3.19 (m, 4H, 4 × CH─OH), 3.31 (dd, J = 7.5,
15.0 Hz, 1H, Ha-1), 3.52 (dd, J = 7.2, 14.5 Hz, 1H,
Hb-1), 4.18 (s, 2H, N─CH2─N), 4.56 (br s, 5H, 5 × OH),
7.10–7.81 ppm (m, 8H, aromatic); IR (KBr): ν = 3505,
3192, 1705, 1597, 1321, 1072, 944, 825, 732 cmꢀ1; MS
(EI, 70 eV): m/z (%) = 443 (M+) (10), 444 (M+ + 1) (4),
428 (M+ꢀMe) (8), 236 (50), 208 (100), 180 (23), 91
(70), 77 (6), 65 (24), 52 (12). Anal. Calcd for
C23H29N3O6 (443.49): C 62.29, H 6.59, N 9.47. Found:
C 62.21, H 6.52, N 9.40.
4-[1-(Methyl-2,3,4,5,6-pentahydroxyhexyl)aminomethyl)-
2-oxoindolin-3-ylideneamino]-N-(methyl-2,3,4,5,6-
pentahydroxyhexyl)aminomethyl) benzamide (13). Yellow
1-[Methyl-(2,3,4,5,6-pentahydroxyhexyl)aminomethyl]-3-
(antipyrin-4-ylimino)-indolin-2-one (11b).
Pale orange
1
powder, yield 1.25 g (46%), mp 148°C; H NMR ([D6]
DMSO): δ = 2.17 (s, 3H, NCH3 of glucamine moiety),
2.39 (s, 3H, C─CH3 of antipyrine moiety), 2.59 (s, 3H,
NCH3 of antipyrine moiety), 2.71 (dd, J = 7.5, 15 Hz,
1H, Ha-6), 3.01 (dd, J = 7.5, 15 Hz, 1H, Hb-6), 3.51 (m,
4H, 4 × CH─OH), 3.72 (dd, J = 7.5, 15.0 Hz, 1H, Ha-1),
4.02 (dd, J = 8.1, 16.2 Hz, 1H, Hb-1), 4.40 (br s, 5H,
5 × OH), 4.79 (s, 2H, N─CH2─N), 7.11–7.88 ppm (m,
9H, aromatic); IR (KBr): ν = 3483, 3228, 1709, 1691,
1612, 1421, 1209, 1051, 956, 832 cmꢀ1; MS (EI, 70 eV):
m/z (%) = 539 (M+) (12), 494 (10), 408 (17), 233 (16),
150 (26), 119 (29), 91 (26), 75 (17), 60 (37), 57 (100).
Anal. Calcd for C27H33N5O7 (539.58): C 60.10, H 6.16,
N 12.98. Found: C 60.02, H 6.12, N 12.91.
powder, yield 1.7 g (50%), mp 280–282°C; 1H NMR
([D6]DMSO): δ = 1.81 (s, 6H, 2 × NCH3), 2.16 (s, 1H,
NH), 2.67 (dd, J = 8.1, 16.2 Hz, 2H, 2 × Ha-6), 2.81 (dd,
J = 7.8, 15.6 Hz, 2H, 2 × Hb-6), 3.05 (m, 8H,
8 × CH─OH), 3.41 (dd, J = 7.8, 15.6 Hz, 2H, 2 × Ha-1),
3.64 (dd, J = 7.2, 14.4 Hz, 2H, 2 × Hb-1), 4.02 (s, 2H,
N─CH2─N), 4.23 (s, 2H, CONH─CH2─N), 4.65 (br s,
10H, 10 × OH), 7.21–7.78 ppm (m, 8H, aromatic); IR
(KBr): ν = 3474, 3252, 1705, 1698, 1617, 1412, 1320,
1251, 949, 745, 684 cmꢀ1; MS (EI, 70 eV): m/z
(%) = 679 (M+) (52), 675 (33), 665 (18), 650 (41), 532
(45), 426 (16), 159 (40), 109 (35), 83 (73), 81 (100).
Anal. Calcd for C31H45N5O12 (679.72): C 54.78, H 6.67,
N 10.30. Found: C 54.70, H 6.61, N 10.23.
1-[Methyl-(2,3,4,5,6-pentahydroxyhexyl)aminomethyl]-3-
(pyridin-2-ylimino)indolin-2-one (11c).
Orange powder,
1
yield 0.87 g (40%), mp 142°C; H NMR ([D6]DMSO):
δ = 2.20 (s, 3H, NCH3), 2.43 (dd, J = 7.8, 15.6 Hz, 1H,
Ha-6), 2.74 (dd, J = 7.8, 15.6 Hz, 1H, Hb-6), 3.30 (m,
4H, 4 × CH─OH), 3.81 (dd, J = 7.8, 15.6 Hz, 1H, Ha-1),
3.87 (dd, J = 7.5, 15 Hz, 1H, Hb-1), 4.64 (s, 2H,
N─CH2─N), 4.79 (br s, 5H, 5 × OH), 6.89–7.86 ppm (m,
8H, aromatic); IR (KBr): ν = 3492, 3252, 1710, 1590,
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