Synthesis of Novel Indolo-Spirocyclic Compounds

Article abstract of DOI:10.1002/jhet.2402

(Chemical Equation Presented) In the present work, we succeeded to synthesize the novel indolo-spirocyclic compounds (4, 5, 6, 7 and 11) via electrophilic condensation reactions of indoles with carbonyl compounds including different types of ketones, for

Full text of DOI:10.1002/jhet.2402

Month 2015
Synthesis of Novel Indolo-Spirocyclic Compounds
a
a
b
Mardia T. El-Sayed,a,b Kazem Mahmoud, Andreas Hilgeroth, and Issa M. I. Fakhr
*
aMartin Luther University, Institute of Pharmacy, Research Group of Drug Development and Analysis,
Wolfgang-Langenbeck-Straße 4, 06120 Halle (Saale), Germany
bApplied Organic Chemistry Department, National Research Centre, Cairo, Egypt
*
E-mail: mardia_elsayed2009@yahoo.com
Additional Supporting Information may be found in the online version of this article.
Received October 26, 2014
DOI 10.1002/jhet.2402
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
In the present work, we succeeded to synthesize the novel indolo-spirocyclic compounds (4–7 and 11)
via electrophilic condensation reactions of indoles with carbonyl compounds including different types of
ketones, for example, heteroacetyl ketones (3-acetylindole and 3-acetylpyridine), cyclohexanone, isatin,
cyclohexane-1,4-dione, whereas an attempt to prepare the spirocyclic 9 failed. This new idea will open a high
prospective for continuous investigations related to the synthesis of novel indolo-spirocyclic compounds.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
is frequently found as a core structure of a large family of
bioactive natural products and series of compounds of
pharmaceutical significance, for instance, alstonisine and
spirotyprostatine [7]. In addition, several spirocyclic
Spirocyclic compounds are essentially important be-
cause of their unique structure characteristics and diverse
biological activities [1–9]. The indolo-spirocyclic scaffold
© 2015 HeteroCorporation

M. T. El-Sayed, K. Mahmoud A. Hilgeroth, and I. M. I. Fakhr
Vol 000
compounds have been used for the synthesis of new
ligands and catalysts, such as spinol [10]. Indolo-carbazoles
and indolo-spirocyclic compounds have been reported as
primary compounds for the synthesis of various drugs and
possess important biological, pharmacological, and medic-
inal activities [11–13]. Indolo-carbazoles are associated
with anticancer, antimicrobial, and antifungal activities. In
most of these cases, the biological activity is correlated with
indolo-carbazoles that contain one heteroatom. The biolog-
ical activity depends on the interaction ability with DNA
[14,15]. Furthermore, most of the experimental studies
have indicated that the size, shape, and planarity of this
structure are very important criteria for such potential
DNA interactions [16]. The electron-rich indole nucleus in-
dicates an enhanced reactivity towards carbon electrophiles
that generally results in the formation of a substitution at the
3-position of the indole ring [1–5]. The 3-position of the
indole is the preferred site for the electrophilic substitution
reactions. A 3-alkyl or 3-acyl indoles are important interme-
diates for the synthesis of a wide range of indole derivatives
[17]. A direct method for the synthesis of 3-alkylated
indoles involves the condensation with aliphatic or aromatic
aldehydes. Normally, these reactions occur in the presence of
several types of catalysts, for example, protic or Lewis acids.
Protic acids are used to catalyze the reaction, for example,
silica sulphuric acid [18], oxalic acid [19], zeolites HY
[1,2] and ZnY [3], amberlyst [20,21], HBr [22,23], HCl
[24,25], HCOOH [26,27], CH3COOH [28–30], p-TsOH
[31], NaHSO3 [32], KHSO4 [33], H3PO4-SiO2 [13]. Lewis
acids are lanthanide resins [34], zeolite (ZnY) [14], bentonic
clay/infrared (IR) [35], montmorillonite clay K-10 [36,37],
cerium ammonium nitrate [15], ZrCl4 [16], IndF3 [38],
Bi(OTf)3 [39], TiCl4 [40], and Al(OTf)3 [41]. As seen
from the reported literature, numerous catalysts can effi-
ciently promote the reaction of aldehydes or ketones and
indoles affording 3-alkylated indole compounds in good
to high yield in a reasonable time.
promote the reaction in direction of forming our cis isomer.
While the formation of the trans isomer of the
tetrahydroindolo[3,2-b]carbazoles has also been confirmed
by Rong Gu et al. [40] However, the reaction has been
done under completely different reaction conditions of
using indoles with aromatic aldehydes in a (1:1) molar
ratio in the presence of 2 mol% of iodine as a catalyst in
acetonitrile under refluxing for 14h affording the 6,12 trans
isomer of tetrahydroindolo[3,2-b]carbazole derivative. Our
derivatives were synthesized by using indole (two equiva-
lents) through condensation reaction with acetyl indole or
acetyl pyridine (one equivalent) in methanolic solution
containing drops of conc. H2SO4 under reflux [42]. The
reaction afforded BIMs of type 1a,b in yields of 52% and
55%, respectively. The formed moderate yield is because
of the lower reactivity of ketones if compared with
aldehydes. Thus, the reaction was accomplished under
vigorous conditions and producing moderate yields. Under
similar reaction conditions, we had the primary intention to
use ketones as precursors for the preparation of the corre-
sponding tetrahydroindolo[2,3-b]carbazoles of type 2a,b,
(Scheme 1). BIMs 1a,b were isolated from the reaction mix-
ture and were used in a new reaction flask with an equivalent
amount of the desired ketone in methanol sulphuric acid solu-
tion under reflux affording compounds 2a,b. Compounds 1a,b
and 2a,b have been identified by means of their spectroscopic
data. Isatin, as an example of a 1,2-diketone, was condensed
with indole for the preparation of the indole trimer by follow-
ing the similar reaction conditions. The use of methanol
sulphuric acid solution with a molar ratio of two equivalents
of indole and one equivalent of isatin under reflux for 2h
yielded the trisindole 3 in an 87% yield. This method is
considered to be simple and efficient if compared with the
reported chemical procedures for the preparation of 3 [43].
The spectral data of our synthesized trisindoline (3) were
identical with those of the natural product isolated from the
marine sponge Hyrtios alum [43]. The trisindoline (3) was
used as a precursor for a condensation with an equimolar
amount of isatin as a possible way for the synthesis of the
expected novel spirocyclic structure 4. The structure of 4
was confirmed on the basis of its spectroscopic data, where
RESULTS AND DISCUSSION
The condensation of ketones was carried out in a molar
ratio of (1:2), 1 mole of ketone with 2 moles of indole to
afford the corresponding bisindolylmethanes (BIMs).
These BIMs were isolated from the reaction mixture as in
the case of compounds 1a,b or directly used without an
isolation from the reaction mixture to condense with
another equivalent mole of ketones for the formation of
tetrahydroindolo[2,3-b]carbazole (2a, b). The main purpose
of this work was an attempt to synthesize novel spirocyclic
based on indole structures. The formation of BIMs derived
from ketone follows the similar reaction mechanism of the
formation of BIMs derived from aldehydes and their corre-
sponding tetrahydroindolocarbazoles (Scheme 1). It has
been reported that the short reaction time is important to
1
the H-NMR spectrum demonstrated the presence of four
multiplet signals, each one for four aromatic protons, and
two broad signals, each one for two NH protons. Cyclohexa-
none was condensed with indole using different types of
catalysts as well as aldehyde. Using the method of
MeOH/conc. H2SO4 in the reaction of indole with cyclohex-
anone in a molar ratio of 2:1, the known (3,3/-(cyclohexane-
1,1-diyl)bis(1-H-indole)) was isolated. It was detected by
thin-layer chromatography (TLC) and ESIMS (electrospray
ionization mass spectroscopy)of the reaction mixture and
not isolated from the reaction mixture but directly used into
the second condensation step with the second mole of cyclo-
hexanone under the same conditions of MeOH/conc. H2SO4
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Synthesis of Novel Indolo-Spirocyclic Compounds
Scheme 1. Condensation reactions of indole or bisindolylmethanes with different types of ketones.
4-(dimethylamino)pyridine (DMAP) as a catalyst. The reac-
tion afforded two products; one was determined as
monoacetylated product (6) in a 59% yield and was con-
leading to our second novel spirocyclic structure 5 in a 97%
yield. Compound 5 was determined to be the 2,8,2/,8/-bis
(cyclohexane-1,1-diyl)-1,2,3,8-tetrahydroindolo- [2,3-b]car-
bazole (5) (Scheme 1). The spirocyclic structure 5 exhibited
1
firmed by its ESIMS, H-NMR, 13C-NMR, and IR spectra.
1
an EI-MS with m/z 395 [M+], and its H-NMR spectra
These data showed the presence of the carbonyl group in
the 13C-NMR spectrum at δ= 169.66ppm and a carbon signal
at δ=14.54ppm for the methyl group. The IR spectrum of
compound 6 exhibited a strong peak at 1670cm-1 for the
C¼O group.
showed five multiplet signals for the 20 aliphatic protons
(10 CH2) of the cyclohexyl groups and one singlet signal at
10.66ppm for two NH indole protons. The 13C-NMR (Apt)
spectra of compound 5 showed the presence of five carbon
signals for the five CH2 groups and one signal for the
spirocyclic atom. Eight signals were observed for the
aromatic indole carbons. Based on these data, it was sug-
gested that compound 5 possesses an asymmetrical structure.
In order to verify the structure of compound 5, it was
acetylated using acetic anhydride in the presence of
The 1H-NMR indicated the disappearance of one NH in-
dole proton and the presence of singlet signal at
δ= 2.69 ppm integrated for three protons for the acetyl
methyl group. ESIMS showed the molecular weight of com-
pound 5 plus only one acetyl group. The second reaction
product had a lower Rf value and was identified based on its
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M. T. El-Sayed, K. Mahmoud A. Hilgeroth, and I. M. I. Fakhr
Vol 000
spectroscopic data as the diacetylated product (7) in a lower
yield of 32% than that of the monoacetylated product 6. Thus,
the acetylation reaction takes place stepwise, and the forma-
tion of the diacetylated products needs some more time.
The electrophilic substitution reactions of indoles with
cyclohexan-1,4-dione has been reported in the literature
as a possible way for the synthesis of the extended supra-
molecular compounds 8a,b named as 1,1,4,4-tetrakis(1H-
indol-3-yl)cyclohexane (8a). The reaction takes place in the
presence of catalyst such as iodine and N-bromosuccinimide
(NBS) [40] affording the tetra-substituted product in good
yield. In the course of this study, cyclohexan-1,4-dione was
condensed with indole in MeOH/conc. H2SO4 solution in
a molar ratio of 1:4 yielding compounds 8a,b in 82% and
87% yield, respectively, after refluxing for 2h (Scheme 1).
The spectroscopic data of compound 8a were identical to
the data of the reported tetra-substituted indole product
[35,36]. The other novel derivative 8b using 5-chloroindole
was synthesized and elucidated in the same manner. An
attempt to prepare the spirocyclic compound 9 under similar
reaction conditions failed.
The extended spirocyclic structure (11) was synthesized
in better yield of 52%, by the way of MeOH and conc.
H2SO4 using BIM (10) [1,3,36] (2 mole equivalents) and
1,4-cyclohexanedione (1mole equivalent). The reaction
solution turned from pink to dark violet by leaving it
stirring for 1h under reflux. The product was detected,
purified, and confirmed by means of ESIMS (m/z):719.29
[M+-H] and EI-MS (m/z):720 [M+]. Its 1H-NMR spectrum
showed a single signal at δ= 5.91 ppm value for two protons
(2 CH) and two triplet signals every one for four protons for
two CH2 at δ=2.03 and 2.27ppm. The four NH indole
protons appeared at 9.94ppm as a broad signal. The structure
was confirmed additionally by its APT 13C-NMR spectrum
that showed the presence of only 26 carbon signals as two
signals for two CH2 carbons, 11 signals for quaternary
carbons, 1 carbon signal for one CH aliphatic carbon, and
13 carbon signals for 13 CH aromatic carbons. These data
proved that the novel spirocyclic compound 11 owns a
symmetrical structure.
PROPOSED REACTION MECHANISM
The mechanism of the reaction follows the same previ-
ous mechanism of condensation reactions of indoles with
aldehydes. In our reaction, using BIMs and ketones in
methanolic sulphuric acid solution under refluxing for 1 h
(short time reaction) afforded the cis-isomer and
tetrahydroindolo[2,3-b]carbazoles (2a,b) in good yields
which were given without isolation of the other trans iso-
meric tetrahydroindolo[3,2-b]carbazoles. Scheme
2
showed the mechanism for the formation of our [2,3-b]car-
bazoles (cis form) and the other [3,2-b]carbazoles (trans
form). It has been reported that the short reaction time is
important to promote the reaction in the direction of
forming our cis-isomer (2a,b). While, the trans form was
formed under long time reaction in the presence of iodine
as a catalyst. This behavior is due to that the iodine cata-
lyzes the transformation or the isomerization of 3,3/-BIMs
into 2,3-BIMs under a long time reaction conditions in ace-
tonitrile as solvent (the Plancher rearrangement). Then, the
2,3-BIMs can undergo an electrophilic attack at a carbonyl
group of the second molecule of aldehyde leading to the
formation of tetrahydroindolo[3,2-b]carbazoles. The reac-
tion of indoles with aromatic ketones or aldehydes using
iodine as a catalyst is a selective reaction for the
Scheme 2. Reaction mechanism. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
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Synthesis of Novel Indolo-Spirocyclic Compounds
preparation of tetrahydroindolo[3,2-b]carbazoles, and none
of the other isomer tetrahydroindolo[2,3-b]carbazoles was
observed in the reaction mixture [40–42]. Whereas, the ap-
plication of the reaction with a short reaction time is selec-
tive for the formation of the cis form. Our novel spirocyclic
compounds have been formed under a short reaction time
conditions as in the reported formation of the
tetrahydroindolo[2,3-b]carbazoles. The acetylation reac-
tion of compound 5 was formed in the presence of
4-(Dimethylamino)pyridine (DMAP) as catalyst. The reac-
tion tends to the final products that are either mono or di,
acetic acid, and regenerated 4-DMAP [44].
neutralized by NH4OH. The water phase was extracted
with 100mL ethyl acetate,for two times washed with
200mL water and 200mL brine, dried over anhydrous
Na2SO4, filtered, and concentrated in vacuum. The crude
reaction mixture was purified via column chromatography.
3,3′,3′′-(Ethane-1,1,1-Triyl)Tris(1H-Indole )1a). C26H21N3,
375.47g/mol, light brown powder mp: 110–115°C, ESIMS:
(m/z)= 376.14 [M++H], 374 [M+-H], IR. (ATR, cm-1)
= 2923 (CH3), 3403 (NH), 1H-NMR: (400MHz, acetone-d6)
δ (ppm): 2.44 (s, 3H, Me), 6.76 (t, 3H, J= 7.5 Hz), 6.92
(d, 3H, J=2Hz), 6.97 (t, 3H, J= 7.6 Hz), 7.34 (d, 2H,
J=8.1Hz), 7.38 (d, 4H, J= 8.1 Hz), 9.89 (s, 3H, 3NH),
13C-NMR: (100MHz, acetone-d6) δ (ppm): 8.60 (Me),
39.86 (CMe), 111.87, 111.92, 118.50, 121.21, 122.28, 123.75,
123.91, 124.12, 124.16, 127.45, 127.48, 138.15, 138.31,
EA: calcd. C, 83.17; H, 5.64; N, 11.19. Found: C, 83.18,
H, 5.68; N, 11.22, Rf. 0.7 (CH2Cl2). yield: (391mg), 52%.
3,3′-(Pyridin-3-yl)Ethane-1,1-Diyl)bis(1H-Indole (1b).
C23H19N3, 337.42g/mol, light yellow crystals, mp.
180–182°C, ESIMS: (m/z)=338.17 [M++H], EI-MS (m/z):
337 [M+] 45%, 322 [M+-Me] 100%, 259 [M+-pyridyl]
15%, 220 [M+-indolyl] 99%, 205 [M+-Me-indolyl] 55%,
117 [indolyl] 98%, 90 [Ph.CH] 90%, IR. (ATR, cm-1):
2920 (CH3), 3411 (NH), 1H-NMR (400MHz, DMSO-d6) δ
(ppm): 2.33 (s, 3H, Me), 6.81 (t, 2H, J=7.6Hz), 6.86
(d, 2H, J=7.3Hz), 7.01–7.07 (m, 4H), 7.39 (d, 2H,
J=8.1Hz), 7.95 (dd, 1H, J=7.6, 8.1Hz), 8.46 (d, 1H,
J=8.3Hz), 8.65 (s, 1H), 8.77 (d, 1H, J=7.4Hz), 11.13
(d, 2H, 2NH), 13C-NMR: (100MHz, DMSO-d6) δ (ppm)
=28.27 (Me), 42.19 (C-Me), 111.88, 118.47, 119.98,
120.13, 120.89, 124.02, 125.15, 126.40, 137.09, 139.58,
140.19, 144.54, 147.79, EA: calcd. C, 81.87; H, 5.68; N,
12.45. Found: C, 81.89, H, 5.75; N, 12.48, Rf. 0.48
(7% MeOH/CH2Cl2), yield: (371mg), 55%.
CONCLUSION
The novel indolo-spirocyclic compounds 4–7 and 11
have been successfully synthesized via condensation reac-
tion of indole or bisindolylmethanes with ketones in the
presence of strong acid (conc. H2SO4) as catalyst under
short time reflux. The successful synthesis of this important
class of organic heterocyclic compounds will open a new
prospective for continuous investigation of novel indolo-
spirocyclic compounds.
EXPERIMENTAL SECTION
The melting points were measured on a Boetius-
Mikroheiztisch from the company VEB weighing Rapido
Radebeul/VEB NAGEMA (Dresden, Germany) measured
and are uncorrected. The TLC for the analyses were per-
formed with aluminum foil fluorescent indicator from
Merck KGaA (silica gel 60 F254, layer thickness 0.2 mm;
Darmsdadt, Germany). Rf -values (run level relative to
the solvent front) were given on the next sections. The sep-
arations were carried out on column chromatography at at-
mospheric pressure on silica gel 60 (grain size from 0.063
to 0.200 mm) from Merck KGaA. The NMR spectra were
recorded on a Gemini 2000 (400/100MHz; CA, USA).
The ATR spectra were recorded on a Fourier transform in-
frared spectrometer IFS 28 from Bruker Corp. (MA,
USA). The ESI mass spectra were recorded on a Finnigan
LCQ Classic (MA, USA). The EI mass spectra were re-
corded on an Intel 402.
Procedure for the Preparation of Compounds 2a,b
.
Compound 1a 1 mmol (0.375 g) or 1mmol (0.337 g) of
compound 1b and 1 mmol (0.159 g) of acetylindole or
1 mmol (0.121g) of acetylpyridine, respectively, were added
to a flask containing 50mL MeOH under heating until it
completely dissolved. When the reaction solution became
clear, a few drops of conc. H2SO4 were added. The reaction
solution became pink; then, the color turned to dark red by
leaving it stirring under reflux for 1h. Upon the reaction
completion, as monitored by TLC (7.5% MeOH/CH2Cl2),
the reaction was worked up by adding 50mL of water and
neutralized by NH4OH; the water phase was extracted with
100 mL ethyl acetate, for two times washed with 200mL
water and 200 mL brine, dried over anhydrous Na2SO4,
filtered, and concentrated in vacuum. The crude reaction
mixture was purified via column chromatography on silica
gel eluted with (7.5% MeOH/CH2Cl2) affording compounds
2a and 2b, respectively.
Procedure for Preparation of Compound 1a,b
.
A 1mmol
(0.159 g) of acetylindole or 1mmol (0.121 g) of
acetylpyridine and 2mmol (0.234g) of indole were added
to a flask that contained 50mL MeOH under heating until
it completely dissolved. The reaction mixture was stirred
under heating until the reaction solution became clear.
Then, a few drops of conc. H2SO4 were added. The
reaction solution became pink. The color turned to dark red
by leaving it to stir under reflux for 1h. Upon the reaction
completion as monitored by TLC (5% MeOH/CH2Cl2), the
reaction was worked up by adding 50mL water and
2,8-Di(1H-Indol-3-yl)-2,8-Dimethyl-1,2,3,8-Tetrahydroindolo
[2,3-b]Carbazole (2a).
C36H28N4, 516.63g/mol, violet
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M. T. El-Sayed, K. Mahmoud A. Hilgeroth, and I. M. I. Fakhr
Vol 000
powder, mp. 190–193°C, ESIMS: (m/z) = 517.45 [M++H],
EI-MS: (m/z) = 516 [M+] 25%, 501 [M+-Me] 100%, 117
[indolyl] 30%, IR. (ATR, cm-1): 2851, 2923 (CH3), 3255
6.78–6.82 (m, 2H), 6.97–7.05 (m(t,d), 4H, J = 7, 7.4 Hz),
7.13–7.23 (m, 6H), 7.94 (s, br., 2H, 2NH), 8.45 (s, br.,
1H, 1NH), 13C-NMR: (100MHz, CDCl3) δ (ppm): 53.25,
110.02, 111.36, 114.87, 119.41, 119.66, 120.00, 121.19,
121.61, 121.67, 122.61, 124.05, 125.51, 125.44, 125.82,
126.01, 126.39, 127.96, 134.52, 136.02, 136.92, 139.94,
141.00, 180.03 (C = O), EA: calcd. C, 79.32; H, 4.72; N,
11.56. Found: C, 79.40, H, 4.75; N, 11.61, Rf: 0.43 (7%
MeOH/CH2Cl2), Yield: (316mg), 87%.
1
(NH), H-NMR: (400 MHz, acetone-d6) δ (ppm): 2.31 (s,
3H, Me), 3.29 (s, 3H, Me), 6.99 (t, 2H, J = 7.4 Hz), 7.11
(t, 1H, J= 7.4Hz), 7.26 (t, 1H, J= 7.5 Hz), 7.34 (d, 3H,
J =7.8 Hz), 7.39 (t, 1H, J =7.8 Hz), 7.44 (d, 1H,
J =8.4 Hz), 7.64 (d, 1H, J =8 Hz), 7.69 (d, 1H,
J =8.4 Hz), 7.79–7.84 (m, 3H), 8.19 (d, 1H, J =8 Hz),
8.29 (s, 1H), 8.35 (s, 1H), 8.40 (s, 1H), 11.88 (s, 2H,
2NH), 12.72 (s, 2H, 2NH), 13C-NMR: (400MHz,
acetone-d6) δ (ppm): 26.05 (Me), 26.39 (Me), 48.75
(C-Me), 53.27 (C-Me), 113.46, 114.12, 119.36, 120.92,
121.38, 121.62, 122.79, 123.71, 123.79, 123.98, 125.06,
125.37, 126.87, 134.37, 139.17, 141.72, Rf -value: 0.15
(10% MeOH/CH2Cl2), Yield: (434mg), 42%.
Preparation of 2,8,2′,8′-Bis(1H-Indolonyl)-1,2,3,8-
Tetrahydroindolo[2,3-b]Carbazole
(4).
A
1 mmol
(0.147 g) of isatin and 1 mmol (0.363 g) of compound 3
were added to the flask that contained 50mL of MeOH
under stirring and heating until it completely dissolved.
Upon the reaction solution became clear, a few drops of
conc. H2SO4 were added dropwisely. The reaction
solution became pink and the color turned to dark red by
leaving it stirring under reflux for about 1h. Upon the
reaction completion, as monitored by TLC (5%
MeOH/CH2Cl2), the reaction was worked up by adding
50 mL of water, neutralized by NH4OH, extracted with
100 mL ethyl acetate, for two times washed with water
and brine, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuum. The crude reaction mixture
was purified via column chromatography on silica gel
eluted with (7% MeOH/CH2Cl2) to afford compound
4, C32H20N4O2, 492.53 g/mol, light green powder, mp.
> 350°C, ESIMS: (m/z) 493.16 [M++H], IR-Spectrum:
(ATR, cm-1): 1699 (C = O), 3273–3450 (br., NH),
1H-NMR: (400 MHz, DMSO-d6) δ (ppm): 6.80–6.90 (m,
4H), 6.92–7.01 (m, 4H), 7.12–7.24 (m, 4H), 7.26–7.42
(m, 4H), 10.66 (s, br., 2H, 2NH), 10.93 (s, br., 2H,
2NH), EA: calcd. C, 78.03; H, 4.09; N, 11.38. Found: C,
78.00, H, 4.06; N, 11.39, Rf . 0.28 (7% MeOH/CH2Cl2),
yield: (355 mg), 72%.
2,8-Dimethyl-2,8-di(Pyridin-3-yl)-1,2,3,8-Tetrahydroindolo
[2,3-b]Carbazole(2b).
C30H24N4, 440.54 g/mol, dark
yellow powder, mp. 155–160°C, ESIMS (m/z): 442.18
[M++H], 440.28 [M+-H]. 1H-NMR: (400MHz,
acetone-d6) δ (ppm): 1.43 (s, 3H, Me), 1.85 (s, 3H, Me),
6.74 (s, 1H), 6.80 (t, 1H, J = 7.8 Hz), 6.99–7.05 (m, 2H),
7.09–7.17 (m, 2H), 7.28–7.33 (m, 2H), 7.40 (t, 2H,
J =9 Hz), 7.73 (dd, 1H, J= 1.6, 7.4 Hz), 7.78 (dd, 1H,
J =1.6, 7.4Hz), 8.31 (dd, 1H, J =1.53, 7.73Hz), 8.43 (dd,
1H, J = 1.53, 7.73 Hz), 8.67 (t, 2H, J = 7.8 Hz), 10.12
(s, 1H, 1NH), 10.48 (s, 1H, 1NH) , 13C-NMR: (100MHz,
acetone-d6) δ (ppm): 18.99 (Me), 28.16 (C), 112.37,
113.19, 119.31, 119.54, 120.25, 120.69, 121.62, 121.85,
122.12, 123.56, 123.61, 123.71, 124.32, 124.43, 126.41,
134.28, 135.54, 138.33, 142.68, 143.18, 145.81, 147.11,
147.61, 148.15, 148.91, 149.89, EA: calcd. C, 81.79, H,
5.49, N, 12.72. Found: C, 81.78, H, 5.52; N, 12.59, Rf.
0.7 (10% MeOH/CH2Cl2), Yield: (414 mg), 47%.
Preparation of 3,3-Di(3-Indolyl)-2-Indoline (3).
A
2,8,2′,8′-Bis(Cyclohexyl)-1,2,3,8-
1 mmol (0.147 g) of isatin and 2 mmol (0.234g) of indole
were added to a flask which contained 50 mL of MeOH
under stirring and heating until it completely dissolved.
When the reaction solution became clear, a few drops of
conc. H2SO4 were added. The reaction solution became
pink; the color was turned to dark red by leaving it to
about 2 h under stirring and reflux. Upon the reaction
completion, as monitored by TLC (5% MeOH/CH2Cl2),
the reaction was worked up by adding 50 mL of water,
neutralized by NH4OH, extracted with 100mL ethyl
acetate, for two times washed with 200mL water and
200mL brine, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuum. The crude reaction mixture was
purified via column chromatography on silica gel eluted
with (5% MeOH/CH2Cl2) to afford compound 3,
C24H17N3O, 363.41g/mol, light pink powder, mp.
290–293°C, ESIMS: (m/z): 363.20 [M+], 362.28 [M+-H].
IR.(ATR,cm-1): 1687 (C = O), 3439 (NH), 1H-NMR:
(400 MHz, CDCl3) δ (ppm): 6.69 (d, 2H, J= 1.9 Hz),
Preparation
of
Tetrahydroindolo[2,3-b]Carbazole (5).
A
2.5 Mmol
(0.25 g) of cyclohexanone and 2mmol (0.234g) of
indole were added to a flask that contained 50mL
MeOH under stirring and heating until it completely
dissolved. When the reaction solution became clear, a
few drops of conc. H2SO4 were added. The reaction
solution became pink; then the color turned to dark red
by leaving it to stir under reflux for about 1 h. Upon the
reaction completion, as monitored by TLC (100%
CH2Cl2), the reaction was worked up by adding 50mL
of water. The reaction mixture was neutralized with
NH4OH, extracted with 100mL ethyl acetate, for two
times washed with 200mL water and 200 mL brine,
dried over anhydrous Na2SO4, filtered, and concentrated
in vacuum. The crude reaction mixture was purified via
column chromatography on silica gel eluted with (100%
CH2Cl2) to afford compound 6, C28H30N2, 394.55 g/mol,
light yellow crystals, mp. 90–92°C, EI-MS (m/z): 395
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis of Novel Indolo-Spirocyclic Compounds
[M+] 20%, 394 [M+-H] 65%, 393 [M+-2H] 40%, 314 [M+-
cyclohexanone-2H] 100%, 285 [314-2CH2] 20%, 271
[314-3CH2] 99%, 257 [314-4CH2] 65%, 245 [indolyl.CH.
indolyl] 20%, 130 [indolyl.CH] 98%, 117 [indolyl] 95%,
90 [PhCH] 97%, IR: (ATR, cm-1): 2925 (CH2), 3404
(NH), 1H-NMR: (400 MHz, DMSO-d6) δ (ppm): 1.48–
1.49 (m, 4H), 1.50–1.60 (m, 4H), 1.70–1.74 (m, 4H),
2.19–2.29 (m(tt), 4H, J = 6.64, 6.5 Hz), 2.39–2.46 (m,
4H), 6.65 (t, 2H, J =7.6 Hz), 6.85 (t, 2H, J = 7.5 Hz), 7.22
(d, 1H, J= 8 Hz), 7.26 (d, 1H, J= 7.5 Hz), 7.32 (d, 2H,
J =7.9 Hz), 10.66 (s, br., 2H, 2NH), 13C-NMR: (100MHz,
DMSO-d6) δ (ppm): 22.55 (CH2), 26.30 (CH2), 26.35
(CH2), 36.63 (CH2), 38.87 (CH2), 40.13 (C), 111.21,
117.35, 120.01, 120.49, 121.94, 122.03, 125.85, 136.90,
EA: calcd. C, 85.24; H, 7.66; N, 7.10. Found: C, 85.18, H,
7.69, N, 7.15, Rf. 0.75 (100% CH2Cl2), Yield: (383 mg), 97%.
1.90–1.92 (m, 4H, 2CH2), 2.14 (d, 4H, J= 7.8 Hz), 2.42
(t, 4H, CH2, J=7.9Hz), 2.63 (s, 6H, 2COMe), 6.79–6.83
(m, 2H), 6.99 (t, 2H, J= 7Hz), 7.42 (d, 2H, J= 7.8 Hz), 7.84
(s, 1H), 8.24 (d, 1H, J=8.3Hz), 13C-NMR: (100MHz,
acetone-d6) δ (ppm): 19.67 (Me), 22.51 (CH2), 23.37 (Me),
26.44 (CH2), 26.64 (CH2), 28.49 (CH2), 28.65 (CH2), 28.79
(CH2), 29.11 (CH2), 29.20 (CH2), 29.27 (CH2), 29.42
(CH2), 35.99, 38.89, 100.81, 116.14, 121.09, 122.55,
123.63, 124.12, 127.21, 129.39, 136.59, 162.02 (C = O),
168.90 (C =O), Rf : 0.58 (CH2Cl2), Yield: (153mg),
32 %.
Procedure for the Preparation of Compound (8a,b). A 1
mmol
(0.112 g)
of
cyclohexane-1,4-dione
and
4 mmol (0.468 g) of indole or 4 mmol (0.606 g) of
5-chloroindole were added to a flask without solvent,
and 22mmol (0.39 g) of N-bromosuccinimide was
slowly added to the mixture and the reaction mixture
was left for stirring at room temperature overnight.
Upon the reaction completion, as monitored by TLC
(100% CH2Cl2), the reaction was worked up by adding
50mL of water, the solution was extracted with 100mL
ethyl acetate for two times, washed with 200mL
water and 200mL brine, dried over Na2SO4
anhydrous, filtered, and concentrated in vacuum. The
crude reaction mixture was purified via column
chromatography on silica gel eluted with (100%
CH2Cl2) to afford compound 9a,b, respectively.
General Procedure for Acetylation Reaction (Compounds 6
and 7). Compound 5 (1mmol, 0.395g) was added to a flask
containing 5 mL CH2Cl2, 0.1 mmol of 4-(dimethylamino)
pyridine (DMAP), 1.2 mmol of triethylamine, and
2.2mmol of acetic anhydride. The reaction mixture was
left for stirring at room temperature for several days.
The products formation was detected by TLC (100%
CH2Cl2). After several days, the reaction was worked
up, and the solution was neutralized with NH4OH
solution, extracted with CH2Cl2, washed with 200mL
water and 200mL brine, and dried over anhydrous
sodium sulphate. The product was purified by using 100%
CH2Cl2 to collect the monoacetylated spirocyclic product
7 first and then the diacetylated spirocyclic product 7.
2,8,2′,8′-Bis(Cyclohexyl)-1-Acetylindolyl-1,2,3,8-
1,1,4,4-Tetrakis(1H-Indol-3-yl)Cyclohexane (8a). C38H32N4,
544.69 g/mol, light green crystals mp. 122–125°C, ESIMS:
(m/z)=543.19 [M+-H], EI-MS: (m/z)=544 [M+] 50%, 427
[M+-indolyl] 58%, 399 [M+-indolyl-2CH2] 100%, 310
[M+-2indolyl] 25%, 258 [indolyl.C.CH2.indolyl] 55%, 117
[indolyl] 60%, 90 [Ph.CH] 30%, IR-Spectrum: (ATR,cm-1)
Tetrahydroindolo[2,3-b]Carbazole
(6).
C30H32N2O,
436.59 g/mol, white powder, mp. 290–293°C, ESIMS:
(m/z) =435.34 [M+-H], IR. (ATR, cm-1): 1677 (C = O),
2949 (CH2), 3287 (NH), 1H-NMR: (400MHz,
1
= 2923 (CH2), 3399 (NH), H-NMR: (400MHz, CDCl3) δ
(ppm): 2.06 (s, 4H), 2.09–2.14 (m, 2H), 2.18–2.22 (m, 8H),
2.27–2.31 (m, 4H), 2.49–2.62 (m, 2H), 2.65–2.69 (m, 2H),
2.72–2.76 (m, 2H), 6.49 (d, H, J=8 Hz), 6.60 (d, H,
J=7.5Hz), 6.84 (t, H, J=7.6Hz), 6.98 (t, H, J=7.2Hz),
7.05–7.07 (m, H), 7.09–7.21 (m, H), 7.26 (t, H, J=6.9Hz),
7.30 (t, H, J=7.6Hz), 7.45 (d, H, J= 7.9 Hz), 7.51 (d, H,
J=8.23 Hz), 7.62 (d, H, J= 7.9 Hz), 7.71 (d, H, J=7.6Hz),
7.77 (s, H), 7.92 (s, H), 8.23 (s, 2H, 2NH), 8.46 (s, 2H,
2NH), 13C-NMR: (100 MHz, CDCl3) δ (ppm): 33.61 (CH2),
33.92 (CH2), 37.05 (CH2), 38.09 (CH2), 51.85 (C), 60.40
(C), 110.78, 111.20, 111.39, 111.73, 115.48, 117.98, 118.13,
119.42, 119.59, 119.66, 119.73, 119.98, 120.28, 120.38,
120.81, 120.93, 121.02, 121.28, 121.38, 121.99, 122.33,
124.28, 125.99, 127.78, 128.65, 134.62, 135.66, 136.02,
136.94, 136.99, 137.08, 137.18, 141.35, 143.62, Rf. 0.66
(CH2Cl2), Yield: (447 mg), 82%.
DMSO-d6)
δ
(ppm): 1.52–1.59 (m, 4H, 2CH2),
1.67–1.73 (m, 6H, 3CH2), 2.07 (d, 4H, J= 7.9 Hz, 2
CH2), 2.69 (s, 3H, COMe), 6.94–6.96 (m, 4H),
7.15–7.21 (m, 2H), 7.69 (t, 1H, J = 10 Hz), 8.33 (d, 1H,
J =9.95 Hz), 10.66 (s, 1H, 1NH), 13C-NMR: (100MHz,
DMSO-d6) δ (ppm): 14.54 (Me), 23.23 (CH2), 23.33
(CH2), 23.89 (CH2), 24.47 (CH2), 24.82 (CH2), 25.71
(CH2), 31.13 (CH2), 35.48 (CH2), 43.39 (CH2), 48.82,
55.35, 112.47, 116.45, 118.98, 119.84, 120.63, 120.72,
122.29, 123.37, 124.64, 124.69, 124.91, 126.00, 129.68,
136.21, 140.83, 149.74, 169.66 (C =O), EA: calcd. C,
82.53; H, 7.39; N, 6.42. Found: C, 82.56, H, 7.42; N,
6.50, Rf. 0.66 (100% CH2Cl2), Yield: (258 mg), 59%.
2,8,2′,8′-Bis(Cyclohexyl)-bis(1-Acetylindolyl)-1,2,3,8-
Tetrahydroindolo[2,3-b]Carbazole
(7).
C32H34N2O2,
478.62 g/mol, white powder, mp. >350°C, ESIMS: (m/z)
1,1,4,4-Tetrakis(5-Chloro-1H-Indol-3-yl)Cyclohexane
= 477.52 [M+-H], IR. (ATR, cm-1) =1680 (C =O), 2949
(8b).
C38H28Cl4N4, 682.47 g/mol, white powder mp.
320–323°C, ESIMS: (m/z) =681.11 [M+-H], IR: (ATR,
(CH2), 1H-NMR: (400 MHz, acetone-d6)
δ
(ppm):
1
cm-1)= 1194 (CCl), 2993 (CH2), 3373 (NH), H-NMR:
1.41–1.43 (m,4H, 2CH2), 1.46–1.59 (m,4H, 2CH2),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. T. El-Sayed, K. Mahmoud A. Hilgeroth, and I. M. I. Fakhr
Vol 000
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(400 MHz, DMSO-d6) δ (ppm): 2.48–2.53 (m, 8H, 4CH2),
6.89 (dd, 4H, J = 1.9, 8.6 Hz), 7.22 (d, 4H, J =7.9Hz), 7.28
(d, 4H, J =8.6Hz), 7.37–7.49 (m, 4H), 10.98 (s, 4H, 4NH),
13C-NMR: (100 MHz, DMSO-d6) δ (ppm): 28.39 (CH2),
30.54 (CH2), 47.62 (C), 48.57 (C), 99.88, 112.92,
119.37, 120.20, 122.15, 126.71, 135.49, 147.08, EA:
calcd. C, 66.88; H, 4.14; N, 8.21. Found: C, 66.79, H,
4.20, Cl, 20.82, N, 8.25, Rf: 0.72 (CH2Cl2), Yield:
(594 mg), 87%.
Procedure of the Preparation of the Spirocyclic Structure
(11).
In a round bottom flask containing 50mL of
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MeOH 2 mmol (0.65 g) of diindolylmethane, derivative
10 was added under stirring until it completely
dissolved. Cyclohexane-1,4-dione (1 mmol, 0.112 g) was
added to the reaction mixture. When the reaction
solution became clear, few drops of conc. H2SO4 were
added slowly. The reaction solution became pink, and
the color turned to dark violet by leaving it stirring
under reflux for 1h. Upon the reaction completion as
monitored by TLC (100% CH2Cl2), the reaction was
worked up by adding 50 mL of water, neutralized by
NH4OH, extracted with 200 mL ethyl acetate, for two
times washed with 200 mL water and 200mL brine,
dried over anhydrous Na2SO4, filtered, and concentrated
in vacuum. The crude reaction mixture was purified via
column chromatography on silica gel eluted with (30%
EtAc/hexane) to afford compound 11 in a moderate
yield 52% as light pink powder, mp 149–152°C,
C52H40N4, 720.90 g/mol, ESIMS 719.29[M+-H], EI-MS:
720 [M+] 32%, 322 [3,3’-(phenylmethylene)bis
(1H-indole)] 100%, 245 [indolyl.CH.indolyl] 75%, 117
[indolyl] 75%, 90 [Ph.CH] 31%, IR(ATR,cm-1): 3409
(NH), 1H-NMR(400 MHz,acetone-d6): δ (ppm): 2.03
(t, 4H, 2CH2, J =7Hz), 2.27(t, 4H, 2CH2, J= 11.4Hz),
5.91(s, 2H, 2CH), 6.79(s, 2H), 6.88(t, 2H, J = 7.5Hz),
7.04(t, 4H, J =7.6Hz), 7.11-7.20(m, 4H), 7.25(t, 4H,
J =7.5Hz), 7.35(dd, 4H, J =7.9, 15.8Hz), 7.38(d, 4H,
J =8Hz), 7.47(t, 2H, J = 8.8Hz), 9.94(s, br., 2H, 2NH),
13C-NMR(100MHz, acetone-d6)δ(ppm): 26.69(CH2),
26.96(CH2), 29.66(CH), 29.69(C), 110.22, 111.73, 117.21,
118.48, 120.39, 122.24, 123.27, 125.58, 125.65, 126.72,
127.82, 128.22, 128.50, 128.82, 128.84, 129.46, 130.09,
130.86, 130.89, 134.11, 137.03, 140.96, Rf 0.97 (CH2Cl2).
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Acknowledgments. The authors are grateful to Egyptian culture
affairs and missions sectors for the financial support as PhD
scholarship for Mardia El-Sayed at Martin Luther University,
Germany.
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