Synthesis and some reactions of functionalized benzo[b]azonines and Bi(benzo[b]azonines)

Article abstract of DOI:10.1515/znb-2009-0410

Tetrahydro-lf.-benzo[fo]azonin-2,7-dione (2a) has been used as a precursor in the synthesis of di-benzo[b,f][l,5]diazacyclododecene and dibenzo[b,g][l,6]diazacyclododecene ring systems 4 and 5, respectively, via periodate oxidation of the appropriate indo

Full text of DOI:10.1515/znb-2009-0410

Synthesis and Some Reactions of Functionalized Benzo[b]azonines
and Bi(benzo[b]azonines)
Elsayed M. Afsah, Ahmed A. Fadda, Samir Bondock, and Mohamed M. Hammouda
Chemistry Department, Faculty of Science, Mansoura University, ET-35516, Mansoura, Egypt
Reprint requests to Prof. Dr. E. M. Afsah. E-mail: emafsah@yahoo.com
Z. Naturforsch. 2009, 64b, 415 – 422; received December 10, 2008
Tetrahydro-1H-benzo[b]azonin-2,7-dione (2a) has been used as a precursor in the synthesis of di-
benzo[b,f ][1,5]diazacyclododecene and dibenzo[b,g][1,6]diazacyclododecene ring systems 4 and 5,
respectively, via periodate oxidation of the appropriate indolo-benzo[b]azonines 3 and 7. The syn-
thesis of hexahydro-benzo[b][1,4]diazecin-2,7-dione (10) has been achieved by the Schmidt reaction
of 2a.
The periodate oxidation of 9,9ꢀ-methylenebis(2,3,4,9-tetrahydro-1H-carbazole) (11) afforded 1,1ꢀ-
methylenebis(3,4,5,6-tetrahydro-1H-benzo[b]azonin-2,7-dione) (12). Its 6,6ꢀ-methylenebis isomer
13 was obtained by treating 2a with formaldehyde. Oxidation of 16 gave the unsymmetrical bi(benzo
[b]azonine) 17.
The Mannich reaction of 2a led to a mixture of its 6-methylene derivative 19 and the spirocyclic
system 20. The reactions of 2a with aldimines and aromatic aldehydes were also investigated.
Key words: Benzo[b]azonines, Bi(benzo[b]azonines), Bis-(Mannich Bases), Periodate Oxidation
Introduction
The dibenz[d, f]azonine ring system is the main part
in laurifonine, laurifine and laurifinine alkaloids [11].
The azonine core is present in vinblastine and vin-
cristine alkaloids [12, 13] which possess significant an-
titumor activity and have been widely used clinically.
However, the literature of benzoazonines, dibenzo-
azonines, azoninoindoles and related compounds is
relatively limited [14– 19], and there is no report on
the synthesis of bi(benzoazonines) and related com-
pounds. We report here on the synthesis and function-
alization of the title compounds which possess consid-
erable synthetic and pharmaceutical interest.
Nine-membered N-heterocycles (heteronins) are
significant classes of heterocyclic systems and con-
stituents of various important naturally occurring and
synthetic compounds. The azonine ring system has
been the object of considerable synthetic efforts [1 – 6],
because this system is present in various alkaloids.
A number of azonines and benzo-annulated azonines
have been studied with interest centered on their po-
tential pharmaceutical activity as antimalarials [7] and
analgesics [8], and on their antihypertensive [9] and
CNS activity [10].
Results and Discussion
The periodate oxidation of 1,2,3,4-tetrahydrocarb-
azole (1) afforded 3,4,5,6-tetrahydro-1H-benzo[b]azo-
nin-2,7-dione (2a) according to an earlier report [20].
The present work is concerned with attempts to ex-
tend the scope of the periodate oxidation of indoles
to include the indolo-benzo[b]azonines of the type 3,
as a route to higher heterocyclic systems. This has
been realized via a reaction sequence which involves
the Fischer indolization of the phenylhydrazone 2b
to give 5,6,7,8- tetrahydro-9H-indolo[2,3-d]benzo[b]
azonin-6-one (3) (Scheme 1). The periodate oxida-
tion of 3 took place quite smoothly and indicated the
Scheme 1.
c
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E. M. Afsah et al. · Functionalized Benzo[b]azonines and Bi(benzo[b]azonines)
Scheme 3.
In the course of our investigation, compound 2a
was subjected to a Schmidt rearrangement to af-
ford 1,3,4,5,6,8-hexahydro-benzo[b][1,4]diazecin-2,7-
dione (10), as the sole product (Scheme 2). The assign-
ment of the (NH) group between the (CO) group and
the aryl moiety of 10 is based on previous studies on
the Schmidt rearrangement [21 – 23], and also by anal-
ogy with the formation of tetrahydro-benzo[b]azepin-
2-one [24] and tetrahydro-1H-benzo[b]azocin-2-one
[25] from α-tetralone and 1-benzosuberone, respec-
tively. In addition, there is much evidence that bulky
substituents at the α-position exert stereocontrol on the
reaction [24– 28]. The mass spectrum of 10 showed
the molecular ion at m/z = 218 [M]+ and a fragmenta-
tion pattern which is in line with the proposed structure
(Scheme 3).
Scheme 2.
preparative value of this route to the 12-membered
macrocyclic system 4. The identity of 4 was demon-
strated by the formation of a phenylhydrazone and by
its spectral data.
In an alternative route to the dibenzo-diazacyclo-
dodecene ring system starting from 2a, via the Fi-
scher indolization periodate oxidation sequence, com-
pound 2a was treated with diazotized p-toluidine or
p-nitroaniline to give 6-arylhydrazono-3,4,5,6-tetra-
hydro-1H-benzo[b]azonin-2,7-diones 5a, b. A simi-
lar reaction of 2a with bis(diazotized) p-phenyl-
enediamine gave 6,6ꢀ-(1,4-phenylenedihydrazono)-bis
(3,4,5,6-tetrahydro-1H-benzo[b]azonin-2,7-dione) (6)
(Scheme 2).
The o-phenylenediamine moiety could be identified
by two peaks at m/z = 108 (100%, base peak) and
107 (36 %). The main fragmentation pathways encoun-
1
tered for 10 are indicated in Scheme 3. Its H NMR
spectrum revealed two triplets at δ = 1.83 (4-H2 and
5-H2) and 2.12 (3-H2 and 6-H2), and a singlet at 9.22
(2 × CONH).
The potential importance of the periodate oxi-
Fischer indolization of 5a and 6 afforded the indolo- dation of indoles of the type 1 was established
benzoazonines 7 and 8, respectively. The periodate ox- by its application to the synthesis of bi(benzoazo-
idation of 7 generated the macrocyclic system 9. On nines) and related compounds (Scheme 4). This
the contrary, oxidation of 8 was not feasible due to its has been realized by treating 1 with formalde-
insolubility in commonly used solvents.
hyde to give 9,9ꢀ-methylenebis(2,3,4,9-tetrahydro-
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E. M. Afsah et al. · Functionalized Benzo[b]azonines and Bi(benzo[b]azonines)
417
Scheme 4.
Scheme 6.
On the other hand, an attempt to prepare the
Mannich base 14 by treating 1 with benzylamine and
formaldehyde led to the formation of 1-methylene-9-
(1,2,3,4-tetrahydro-9H-carbazol-9-ylmethyl)-2,3,4,9-
tetrahydro-1H-carbazole (16), which was subjected to
the periodate oxidation to afford the unsymmetrical
bi(benzoazonine) 17 (Scheme 5). The structures of
compounds 16 and 17 were supported by analytical
and spectral data.
In view of the pharmacological activity and the syn-
thetic potential of ketonic Mannich bases [26, 29– 34],
we investigated the Mannich reaction of 2a with piper-
idine and formaldehyde anticipating the formation of
the Mannich base 18. Unexpectedly, however, it gave a
Scheme 5.
1H-carbazole) (11), the periodate oxidation of mixture of 6-methylene-3,4,5,6-tetrahydro-1H-benzo
which afforded 1,1ꢀ-methylenebis(3,4,5,6-tetrahydro- [b]azonin-2,7-dione(19) (8 %) and the spirocyclic sys-
1H-benzo[b]azonin-2,7-dione)(12). Its mass spectrum tem 20 (53%). The mass spectra of 19 and 20 showed
indicated the molecular ion peak at m/z = 416 [M–2]+. the molecular ions at m/z = 215 and 430 [M]+, re-
Its isomer 6,6ꢀ-methylenebis(3,4,5,6-tetrahydro-1H- spectively. The spontaneous deamination of 18 to give
benzo[b]azonin-2,7-dione) (13) was obtained by treat- 19, which undergoes Diels-Alder dimerization to af-
ing 2a with formaldehyde. The IR spectrum of 13 dis- ford 20, is in line with the reported results of the Man-
played strong bands at 3347 (NH), 1720 (CONH) and nich reaction with thiochromanone [35] and [1]benz-
1680 cm−1 (CO).
azepin-2,5-(3H,4H)-dione [36] (Scheme 6).
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418
E. M. Afsah et al. · Functionalized Benzo[b]azonines and Bi(benzo[b]azonines)
In line with this, compound 23 was obtained as the
main product (66 %) besides the 6-benzylidene deriva-
tive 25 (12 %), on treating 2a with benzaldehyde in the
presence of piperidine as a catalyst.
Experimental Section
All melting points were determined on a Gallenkamp
electric melting point apparatus and are uncorrected. Ele-
mental microanalyses were carried out at Microanalytical
Unit, Faculty of Science, Cairo University. Infrared spec-
tra were measured on a Mattson 5000 FTIR spectrometer.
1H NMR data were obtained in CDCl3 or [D6]DMSO so-
lution on a Varian XL 200 MHz instrument using TMS as
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. The course
of the reaction and the purity of the synthesized compounds
were monitored by TLC using EM science silica gel coated
plates with visualization by irradiation with an ultraviolet
lamp. Due to the limited solubility of the products in com-
1
mon solvents, the H NMR spectra were recorded for com-
pounds 3, 5a, 10, 11, 16, 20, 24, and 25 as representative
examples. Compounds 1 [40] and 2a [20] were prepared as
previously described.
7-(Phenylhydrazono)-1,3,4,5,6,7-hexahydro-benzo[b]
azonin-2-one (2b)
Scheme 7.
To a solution of 2a (1 g, 5 mmol) in ethanol (10 mL),
phenylhydrazine (0.54 g, 5 mmol) and acetic acid (0.2 mL)
were added. The reaction mixture was heated on a water
bath for 5 min and stirred for 90 min at r. t. The product ob-
tained on cooling was filtered and crystallized from ethanol
to give 2b. M. p. 192 ◦C. Yield 40 % (yellow leaflets). –
IR (KBr): ν = 3445 (NH hydrazone), 3399 (NH lactam),
1709 (CO), 1431, 1322, 1120 cm−1. – C18H19N3O (293.36):
calcd. C 73.69, H 6.53, N 14.32; found C 73.64, H 6.48,
N 14.19.
On the other hand, the reaction of aldimines with
cyclic ketones has opened routes to the corresponding
Mannich bases [37, 38]. Thus, the synthesis of the bis-
(Mannich base) 21 has been achieved by treating com-
pound 2a with N,Nꢀ-bis(p-methoxybenzylidene)ethyl-
enediamine (Scheme 6). It is interesting in this con-
nection that attempted reaction of benzalaniline with
2a failed to give the required base 22, leading instead
to the formation of 9-phenylamino-1H-cyclopenta[b]
quinoline (24) (Scheme 7). The IR spectrum of 24 re-
vealed the absence of carbonyl groups and showed a
strong band at 3290 cm−1 (NH). Its mass spectrum ex-
hibited a molecular ion peak at m/z = 260 (65 %); the
base peak at m/z = 259 (100%) is due to the [M–1]+
ion. The 1H NMR spectrum revealed a multiplet at δ =
2.02– 2.50 (1-H2, 2-H2 and 3-H2) and a broad singlet
at δ = 3.28 (Ph-NH).
5,6,7,8-Tetrahydro-9H-indolo[2,3-d]benzo[b]azonin-6-one
(3)
A solution of 2b (0.59 g, 2 mmol) in 20 % sulfuric acid
(10 mL) was heated on a water bath for 30 min, poured onto
water (30 mL) and basified with NH4OH. The obtained prod-
uct was filtered and crystallized from ethyl acetate-pet. ether
40 – 60 ◦C (2 : 1) to give 3. M. p. 221 ◦C. Yield 58 % (greenish
crystals). – IR (KBr): ν = 3447 (NH indole), 3390 (NH lac-
tam), 1705 (CO), 1613 (C=C◦), 1420, 1210 cm−1. – 1H NMR
(200 MHz, [D6]DMSO, 25 C, TMS): δ = 1.83 – 1.98 (m,
6H, 7-H2, 8-H2, 9-H2), 6.97 – 7.53 (m, 8H, aromatic), 8.95
(s, 1H, CONH), 10.87 (s, 1H, NH indole). – MS (EI, 70 eV):
The formation of 24 rather than 22 may be attributed
to the tendency of 2a to cyclize readily under mild ba-
sic conditions to give 1,2,3,4-terahydro-cyclopenta[b]
quinolin-9-one (23), as reported earlier by Witkop et
al. [39]. Further reaction of 23 with aniline, resulting
from the decomposition of benzalaniline, afforded 24. m/z (%) = 276 (100) [M]+, 248 (25) [M–CO]+, 233 (53), 219
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E. M. Afsah et al. · Functionalized Benzo[b]azonines and Bi(benzo[b]azonines)
419
(87), 77(12). – C18H16N2O (276.33): calcd. C 78.24, H 5.85, 6,6ꢀ-(1,4-Phenylenedihydrazono)-bis(3,4,5,6-tetrahydro-
N 10.14; found C 78.02, H 5.80, N 10.07.
1H-benzo[b]azonin-2,7-dione) (6)
This compound was obtained from 2a (1 g, 5 mmol) and
bis(diazotized) p-phenylenediamine (2.5 mmol) in pyridine
(15 mL), following the same procedure as described above.
The product was purified by preparative chromatography on
Al2O3 using chloroform – methanol (2 : 1) as eluent. M. p.
8,9-Dihydrodibenzo[b,f][1,5]diazacyclododecene-6,10,16
(5H,7H,15H)-trione (4)
A solution of 3 (0.55 g, 2 mmol) in methanol (80 mL)
and acetone (40 mL) was added to a solution of sodium pe-
riodate (0.85 g, 4 mmol) in water (5 mL). After standing
at r. t. for 13 h, the solvent was removed at reduced pres-
sure, and the product was washed successively with water
(3 × 10 mL) and boiling chloroform (3 × 10 mL) to give 4.
M. p. > 350 ◦C. Yield 41 % (pale green powder). – IR (KBr):
ν = 3422 (NH lactam), 1770 and 1753 (CON), 1655 (CO),
1533, 1212 cm−1. – MS (EI, 70 eV): m/z (%) = 306 (17)
[M–2]+, 305 (26) [M–3]+, 213 (39), 144 (100), 121 (36),
92 (19), 77 (26). – C18H16N2O3 (308.33): calcd. C 70.12,
H 5.33, N 9.09; found C 70.06, H 5.11, N 8.99.
◦
> 350 C. Yield 35 % (dark brown powder). – IR (KBr):
ν = 3404 (NH lactam), 3330 (NH hydrazone), 1709 (CON),
1680 (CO), 1585, 1315, 1210 cm−1. – MS (EI, 70 eV): m/z
(%) = 534 (5) [M–2]+, 533 (4) [M–3]+, 336 (8) [M–C12H11
NO2]+, 232 (41), 214 (7), 210 (10), 184 (100), 136 (18). –
C30H28N6O4 (536.58): calcd. C 67.15, H 5.26, N 15.66;
found C 67.09, H 5.14, N 15.57.
8,13-Dihydro-10-methyl-indolo[2,3-e]benzo[b]azonin-6,14
(5H,7H)-dione (7)
This compound was obtained by treating 5a (0.8 g,
2.5 mmol) with hot 20 % sulfuric acid (10 mL), following the
procedure described above for the synthesis of 3. The prod-
uct was purified by crystallization from DMSO to give 7.
M. p. 235 ◦C. Yield 15 % (dark brown powder). – IR (KBr):
ν = 3410 (NH indole), 3340 (NH lactam), 1715 (CON), 1670
(CO), 1576, 1330, 1212 cm−1. – MS (EI, 70 eV): m/z (%) =
306 (17) [M+2]+, 305 (26) [M+1]+, 291 (14), 264 (15), 240
(16), 215 (22), 201 (20), 144 (100), 77 (26). – C19H16N2O2
(304.34): calcd. C 74.98, H 5.30, N 9.20; found C 74.89,
H 5.26, N 9.16.
6-Arylhydrazono-3,4,5,6-tetrahydro-1H-benzo[b]azonin-
2,7-diones 5a, b
Diazotized p-toluidine or p-nitroaniline (5 mmol) was
added with stirring to a cold solution of 2a (1 g, 5 mmol)
in pyridine (15 mL). The reaction mixture was stirred for
◦
30 min at 5 – 10 C and for 2 h at r. t. The reaction mixture
was diluted with water (20 mL) and extracted with ethyl ac-
etate, washed with water and dried over sodium sulfate. The
solvent was removed at reduced pressure to give 5a, b.
6-(p-Tolylhydrazono)-3,4,5,6-tetrahydro-1H-benzo[b]
azonin-2,7-dione (5a)
7,8,10,18,19,21-Hexahydro-benzo[b]azonino[5ꢀꢀ ,6ꢀꢀ : 4ꢀ,5ꢀ]
pyrrolo[2ꢀ,3ꢀ : 5,6]indolo[2,3-e]benzo[b]azonin-6,11,17,22
(5H,16H)-tetraone (8)
◦
M. p. 244 C (ethanol). Yield 33 % (red needles). – IR
(KBr): ν = 3420 (NH lactam), 3240 (NH hydrazone), 1720
(CON), 1680 (CO), 1333, 1210 cm−1. – 1H NMR (200 MHz,
[D6]DMSO, 25 ◦C, TMS): δ = 1.40 – 1.71 (m, 6H, 3-H2, 4-
H2, 5-H2), 2.20 (s, 3H, Ar-CH3), 7.12 – 7.53 (m, 8H, aro-
matic), 9.21 (s, 1H, CONH), 10.53 (s, 1H, NH hydrazone). –
MS (EI, 70 ev): m/z (%) = 321 (17) [M]+, 244 (4), 200
(16), 184 (8), 138 (20), 122 (100), 76 (50). – C19H19N3O2
(321.37): calcd. C 71.01, H 5.96, N 13.08; found C 70.97,
H 5.90, N 12.97.
A mixture of 6 (0.4 g, 0.7 mmol) and 20 % sulfuric acid
(10 mL) was heated on a water bath for 30 min, poured onto
water (25 mL) and basified with NH4OH. The product was
filtered and washed with boiling pyridine to give 8. M. p.
> 350 ◦C. Yield 40 % (dark brown powder). – IR (KBr): ν =
3475 (NH indole), 3420 (NH lactam), 1709 (CON), 1670
(CO), 1322, 1212 cm−1. – MS (EI, 70 eV): m/z (%) = 502
(2) [M]+, 337 (27), 274 (16), 260 (26), 216 (20), 184 (100),
166 (35), 154 (21), 92 (17). – C30H22N4O4 (502.52): calcd.
C 71.70, H 4.41, N 11.15; found C 71.63, H 4.33, N 11.02.
6-(p-Nitrophenylhydrazono)-3,4,5,6-tetrahydro-1H-benzo
[b]azonin-2,7-dione (5b)
18-Methyl-2,11-diaza-tricyclo[14.4.0.05,10]eicosa-1(20),
5(10),6,8,16,18-hexaene-3,4,12,15-tetraone (9)
◦
M. p. 205 C (chloroform). Yield 15 % (dark green pow-
der). – IR (KBr): ν = 3432 (NH lactam), 3269 (NH hy-
A solution of 7 (0.2 g, 0.65 mmol) in pyridine (10 mL)
drazone), 1733 (CON), 1670 (CO), 1517, 1341 (NO2), was added to a solution of sodium periodate (0.28 g,
1210 cm−1. – MS (EI, 70 eV): m/z (%) = 353 (1) [M+1]+, 1.3 mmol) in water (5 mL). After standing at r. t. for 18 h,
230 (2) [M–C6H4NO2]+, 229 (4), 200 (16), 150 (55), 122 the solvent was removed at reduced pressure, and the product
(100) [M–C12H12N3O2]+. – C18H16N4O4 (352.34): calcd. was washed successively with water (3 × 10 mL) and boiling
◦
C 61.36, H 4.58, N 15.90; found C 61.29, H 4.44, N 15.87.
pyridine (3 × 10 mL) to give 9. M. p. > 350 C. Yield 55 %
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E. M. Afsah et al. · Functionalized Benzo[b]azonines and Bi(benzo[b]azonines)
(white powder). – IR (KBr): ν = 3420 (NH lactam), 1730 (8), 105 (29), 91 (27), 77 (33), 55 (100). – C25H26N2O4
(CON), 1710 (CO), 1690 (CO), 1620 (C=C), 1210 cm−1. – (418.48): calcd. C 71.75, H 6.26, N 6.69; found C 71.70,
MS (EI, 70 eV): m/z (%) = 338 (59) [M+2]+, 311 (40), 310 H 6.21, N 6.62.
(100), 309 (80), 247 (17), 203 (18), 179 (36), 76 (66). –
C19H16N2O4 (336.34): calcd. C 67.85, H 4.79, N 8.33; found
C 67.79, H 4.71, N 8.28.
6,6ꢀ-Methylenebis(3,4,5,6-tetrahydro-1H-benzo[b]azonin-
2,7-dione) (13)
A solution of 2a (0.5 g, 2.5 mmol) and paraformaldehyde
(0.042 g, 1.4 mmol) in acetic acid (15 mL) was heated on a
water bath at 90 C for 15 min. The precipitated solid was
1,3,4,5,6,8-Hexahydro-benzo[b][1,4]diazecin-2,7-dione
(10)
◦
filtered and washed with boiling chloroform to give 13. M. p.
> 350 ◦C. Yield 35 % (white powder). – IR (KBr): ν = 3347
(NH lactam), 1720 (CON), 1680 (CO), 1210, 1105 cm−1. –
MS (EI, 70 eV): m/z ( %) = 416 (6) [M–2]+, 361 (3), 208
(12), 202 (13), 149 (20), 105 (35), 91 (37), 77 (27), 55
(100). – C25H26N2O4 (418.48): calcd. C 71.75, H 6.26,
N 6.69; found C 71.72, H 6.23, N 6.65.
To a solution of 2a (0.5 g, 2.5 mmol) in chloroform
◦
(30 mL) containing 90 % sulfuric acid (4 mL) at 0 C was
added sodium azide (0.16 g, 2.5 mmol). After stirring for 1 h
at 0 ◦C and 4 h at 25 ◦C, the reaction mixture was diluted with
ice water (50 mL) and basified with NH4OH. The product
was filtered and crystallized from ethyl acetate – pet. ether
40 – 60 ◦C (2 : 1) to give 10. M. p. 191 ◦C. Yield 53 % (white
powder). – IR (KBr): ν = 3399 (NH), 1708 (CON), 1613,
1425, 1315, 1212 cm−1. – 1H NMR (200 MHz, [D6]DMSO,
25 ◦C, TMS): δ = 1.83 (t, J = 7.5 Hz, 4H, 4-H2, 5-H2), 2.12 (t,
J = 7.5 Hz, 4H, 3-H2, 6-H2), 7.15 – 7.24 (m, 4H, aromatic),
9.22 (s, 2H, 2 × CONH). – MS (EI, 70 eV): m/z (%) = 218
(6) [M]+, 200 (12), 171 (25), 145 (84), 134 (30), 119 (13),
108 (100) [M–C6H8O2]+, 93 (9), 77 (70). – C12H14N2O2
(218.25): calcd. C 66.04, H 6.47, N 12.84; found C 66.15,
H 6.33, N 12.79.
1-Methylene-9-(1,2,3,4-tetrahydro-9H-carbazol-9-yl-
methyl)-2,3,4,9-tetrahydro-1H-carbazole (16)
A solution of 1 (3.42 g, 20 mmol), benzylamine (2.14 g,
20 mmol) and formalin (37 %, 2.2 mL, 30 mmol) in acetic
acid (40 mL) was heated on a steam bath for 1 h. The product
obtained on cooling and dilution with water (70 mL) was fil-
tered and crystallized from chloroform – pet. ether 40 – 60 ◦C
(1 : 1) to give 16. M. p. 169 ◦C. Yield 75 % (redish powder). –
IR (KBr): ν = 3074, 2933, 1611, 1515, 1225 cm−1. 1H NMR
◦
(200 MHz, CDCl3, 25 C, TMS): δ = 1.85 – 2.69 (m, 14H,
9,9ꢀ-Methylenebis(2,3,4,9-tetrahydro-1H-carbazole) (11)
7 × CH2), 5.24 (s, 2H, CH2=), 6.01 (s, 2H, NCH2N), 7.12 –
7.49 (m, 8H, aromatic). – MS (EI, 70 eV): m/z ( %) = 368 (84)
[M+2]+, 367 (62) [M+1]+, 352 (88) [M–CH2]+, 196 (30)
[M–C12H12N]+, 184 (100), 171 (43), 156 (42), 143 (58), 129
(15), 90 (10), 77 (2). – C26H26N2 (366.50): calcd. C 85.21,
H 7.15, N 7.64; found C 85.17, H 7.05, N 7.57.
A solution of 1 (3.42 g, 20 mmol) and formalin (37 %,
1.2 mL, 15 mmol) in acetic acid (40 mL) was heated on
a steam bath for 15 min. The reaction mixture was chilled
and diluted with water (50 mL). The product obtained was
filtered and crystallized from 1,2-dichloroethane to give 11.
◦
M. p. 188 C. Yield 32 % (yellow powder). – IR (KBr): ν =
1-[(2,7-Dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[b]
azonin-yl)methyl]-3-methylene-3,4,5,6-tetrahydro-1H-
benzo[b]azonin-2,7-dione (17)
1620 (C=C), 1525, 1410, 1225, 1109 cm−1. – 1H NMR
◦
(200 MHz, [D6]DMSO, 25 C, TMS): δ = 1.88 – 2.76 (m,
16H, 2 × (CH2)4), 6.17 (s, 2H, NCH2N), 7.13 – 7.52 (m, 8H,
aromatic). – MS (EI, 70 eV): m/z (%) = 354 (12) [M]+, 184
(100), 170 (6), 156 (21), 143 (9), 115 (12). – C25H26N2
(354.48): calcd. C 84.63, H 7.33, N 7.89; found C 84.59,
H 7.25, N 7.80.
This compound was obtained from 16 (0.51 g, 1.4 mmol)
in pyridine (10 mL) and sodium periodate (0.7 g, 3.2 mmol)
in water (5 mL), following the procedure described above
for the synthesis of 12. The product was purified by washing
with boiling pyridine (3 × 10 mL) to give 17. M. p. > 350 ◦C.
Yield 18 % (white powder). – IR (KBr): ν = 1774 (CON),
1754 (CON), 1719 (CO), 1702 (CO), 1213, 1110 cm−1. –
MS (EI, 70 eV): m/z (%) = 430 (73) [M]+, 361 (50), 332
(72), 215 (100), 184 (70), 104 (78), 76 (64). – C26H26N2O4
(430.50): calcd. C 72.54, H 6.09, N 6.51; found C 72.50,
H 6.11, N 6.44.
1,1ꢀ-Methylenebis(3,4,5,6-tetrahydro-1H-benzo[b]azonin-
2,7-dione) (12)
This compound was obtained from 11 (0.42 g, 1.2 mmol)
in pyridine (10 mL) and sodium periodate (0.58 g, 2.7 mmol)
in water (5 mL), following the procedure described above
for the synthesis of 9. The product was purified by washing
with boiling pyridine (3 × 10 mL) to give 12. M. p. > 350 ◦C.
Yield 25 % (white powder). – IR (KBr): ν = 1750 (CON),
1701 (CO), 1535, 1345, 1220 cm−1. – MS (EI, 70 eV): m/z
Attempted Mannich reaction with 2a: Synthesis of
compounds 19 and 20
A solution of 2a (0.5 g, 2.5 mmol), piperidine (0.26 g,
(%) = 416 (7) [M–2]+, 361 (7), 202 (10), 149 (16), 119 3 mmol) and paraformaldehyde (0.1 g, 3 mmol) in acetic acid
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E. M. Afsah et al. · Functionalized Benzo[b]azonines and Bi(benzo[b]azonines)
421
◦
(15 mL) was heated on a water bath at 90 C for 90 min. 9-Phenylamino-1H-cyclopenta[b]quinoline (24)
The reaction mixture was diluted with ice water (40 mL),
A solution of 2a (1 g, 5 mmol) and benzalaniline (0.91 g,
5 mmol) in ethanol (15 mL) and one drop of conc. hydrochlo-
ric acid was heated on a water bath for 5 min. After stand-
ing at r. t. for 8 h and neutralization with NH4OH, the sol-
vent was removed at reduced pressure, and the product was
crystallized from ethanol to give 24. M. p. 186 ◦C. Yield
43 % (pale yellow powder). – IR (KBr): ν = 3290 (NH),
1634 (C=N), 1611, 1312, 1225, 1100 cm−1. – 1H NMR
basified with NH4OH, and subjected to preparative thin layer
chromatography on Al2O3 using ether-chloroform (2 : 1) as
eluent to give 19 and 20.
6-Methylene-3,4,5,6-tetrahydro-1H-benzo[b]azonin-2,7-
dione (19)
M. p. 179 ◦C. Yield 8 % (white powder). – IR (KBr): ν =
3395 (NH lactam), 1705 (CON), 1678 (CO), 1325, 1212,
1105 cm−1. – MS (EI, 70 eV): m/z (%) = 215 (13) [M]+,
187 (12) [M–CO]+, 169 (35), 144 (22), 127 (53), 113 (16),
91 (25), 77 (16), 55 (100). – C13H13NO2 (215.25): calcd.
C 72.54, H 6.08, N 6.51; found C 72.51, H 6.00, N 6.47.
◦
(200 MHz, CD3OD, 25 C, TMS): δ = 2.02 – 2.50 (m, 6H,
1-H2, 2-H2, 3-H2), 3.28 (br s, 1H, NH), 6.90 – 8.10 (m, 9H,
aromatic). – MS (EI, 70 eV): m/z (%) = 260 (65) [M]+,
259 (100) [M–1]+, 167 (26), 128 (17), 77 (18). – C18H16N2
(260.33): calcd. C 83.04, H 6.19, N 10.76; found C 82.99,
H 6.12, N 10.70.
4,4aꢀ,5,5ꢀ,6ꢀ,7ꢀ,9ꢀ,13bꢀ-Octahydro-3ꢀH-spiro[1-benzazonine-
6,2ꢀ-pyrano[3,2-f][1] benzazonin]-4,7,8ꢀ(1H,3H,4ꢀH)-trione
(20)
Base-catalyzed condensation of 2a with benzaldehyde:
Synthesis of 23 and 25
A solution of 2a (1 g, 5 mmol), benzaldehyde (0.53 g,
5 mmol) and 2 drops of piperidine in ethanol (15 mL) was
refluxed on a water bath for 2 h. After cooling to r. t., the re-
action mixture yielded two products which were separated by
their different solubility in ethanol. The insoluble component
was identified as 23, and the soluble one as 25.
M. p. 210 ◦C. Yield 53 % (white powder). – IR (KBr): ν =
3450 (NH lactam), 3410 (NH lactam), 1780 (CON), 1768
(CON), 1678 (CO), 1335, 1222, 1100 cm−1. – 1H NMR
◦
(200 MHz, [D6]DMSO, 25 C, TMS): δ = 1.63 – 2.10 (m,
14H, 7 × CH2), 2.5 (t, 2H, CH2), 7.15 – 7.53 (m, 8H, aro-
matic), 8.9 (s, 1H, CONH), 9.4 (s, 1H, CONH). – MS (EI,
70 eV): m/z (%) = 430 (4) [M]+, 412 (21) [M–18]+, 230
(14), 214 (28), 186 (70), 146 (40), 120 (56), 105 (7), 92 (50),
77 (25), 50 (100). – C26H26N2O4 (430.50): calcd. C 72.54,
H 6.09, N 6.51; found C 72.52, H 6.03, N 6.48.
1,2,3,4-Tetrahydro-cyclopenta[b]quinolin-9-one (23)
◦
◦
M. p. 326 C (327 C [39]) (benzene). Yield 66 %, color-
less crystals. The structure was confirmed by a comparison
of IR data, m. p. and TLC with an authentic sample obtained
from 2a and 2 N NaOH solution as previously reported [39].
N,Nꢀ-Bis[(3,4,5,6-tetrahydro-2,7-dioxo-1H-benzo[b]azonin-
6-yl)-(4-methoxyphenyl)-methyl]ethane-1,2-diamine (21)
6-Benzylidene-3,4,5,6-tetrahydro-1H-benzo[b]azonin-2,7-
dione (25)
A solution of 2a (1 g, 5 mmol) and N,Nꢀy-bis(4-methoxy-
benzylidene)ethane-1,2-diamine (0.74 g, 2.5 mmol) in ethan-
ol (15 mL) and 2 drops of conc. hydrochloric acid was heated
◦
M. p. 195 C (ethanol). Yield 12 % (yellow crystals). –
on a water bath for 5 min. The precipitated solid was filtered IR (KBr): ν = 3407 (NH lactam), 1765 (CON), 1670 (CO),
and washed with boiling ethanol to give 21. M. p. > 350 ◦C. 1315, 1220, 1110 cm−1. – 1H NMR (200 MHz, [D6]DMSO,
Yield 15 % (white powder). – IR (KBr): ν = 3344 (NH lac- 25 ◦C, TMS): δ = 1.60 – 1.80 (m, 6H, 1-H2, 2-H2, 3-H2), 4.5
tam), 3316 (NH), 3176 (NH), 1766 (CON), 1668 (CO), 1213, (s, 1H, Ph-CH=), 6.90 – 7.40 (m, 9H, aromatic), 9.2 (s,1H,
1115 cm−1. – MS (EI, 70 eV): m/z (%) = 703 (14) [M]+, CONH). – MS (EI, 70 eV): m/z (%) = 291 (16) [M]+, 200
362 (17), 263 (14), 214 (19), 109 (21), 139 (31), 117 (18), (94), 170 (12), 91 (53), 77 (12), 55 (100). – C19H17NO2
83 (41), 77 (20), 57 (100). – C42H46N4O6 (702.84): calcd. (291.34): calcd. C 78.33, H 5.88, N 4.81; found C 78.28,
C 71.77, H 6.60, N 7.97; found C 71.70, H 6.58, N 7.87.
H 5.82, N 4.77.
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422
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