Synthesis of tetrahydroindolo[2,3-b]carbazoles

condensation of indoles with aldehydes has been reported as a method for the preparation of a mixture of substituted isomers of tetrahydroindolo[3,2-b]carbazole (trans isomer) and tetrahydroindolo[2,3-b]carbazoles (cis-isomer), in the presence of phosphoryl chloride as acid catalyst directly with indole itself ^244(d). However the products are not stable under this reaction condition where they readily converted via oxidation with air to the dihydroindolocarbazoles, figure (44). The formation of the trans isomer has also recently confirmed and published by Rong Gu and et al^245(a) however the reaction has been done under a completely different reaction conditions of using indoles with aromatic aldehydes in (1:1) molar ratio in presence of 2 mol % of iodine as a catalyst in acetonitrile under refluxing for 14 hours (long time reaction) afforded 6,12-trans–isomer, tetrahydroindolo[3,2-b]carbazole derivative, which was confirmed by X-ray crystallography.

NH NH

R R₁

R₂ R₁

R₂

11117777

11117777_aaaa: R₁=R₂=H, R=Ph 11117777_bbbb: R₁=R₂=H, R=p-NO₂- Ph 11117777_cccc: R₁=R₂=H, R=p-Cl- P h 11117777_dddd: R₁=R₂=H, R=p-Br- Ph 11117777_eeee: R₁=R₂=H, R=p-N( Me)₂- Ph 11117777_ffff: R₁=R₂=H, R=m-Br 11117777_gggg: R₁=R₂=H, R=m-OCH₂Ph- Ph 11117777_hhhh: R₁=R₂=H, R=p ,m-OH- Ph 11117777_iiii: R₁=R₂=H, R=p-MeO-m-OCH₂Ph- Ph 11117777_jjjj: R₁=R₂=H, R=m-MeO-p-OCH₂Ph- Ph 11117777_kkkk:::: R₁=R₂=H, R=m-Me,2,4,6-trif louro- Ph 11117777_llll: R₁=R₂=H, R=1-naphthyl

11117777_mmmm: R₁=R₂=H, R=3-pridyl 11117777_nnnn: R₁=R₂=H, R=3-indolyl

11117777_oooo: R₁=Cl, R₂=H, R=p-MeO-m-O CH₂Ph- Ph 11117777_pppp:::: R₁=H, R₂=Cl, R=p-MeO-m-OCH₂Ph- Ph NH

NH

R R₁

R₂ R₁

R₂

R

MeOH, conc. H₂SO₄

11118888_aaaa: R₁=R₂=H, R=Ph 11118888_bbbb: R₁=R₂=H, R=p-Cl-Ph 11118888_cccc: R₁=R₂=H, R=p-Br-Ph 11118888_dddd: R₁=R₂=H, R=p-N(Me)₂-Ph 11118888_eeee: R₁=R₂=H, R=m-Br-Ph 11118888_ffff: R₁=R₂=H, R=m-OCH₂Ph-Ph 11118888_gggg: R₁=R₂=H, R=p,m-OH-Ph 11118888_hhhh: R₁=R₂=H, R=p-MeO-m-O CH₂Ph-Ph 11118888_iiii: R₁=R₂=H, R=m-MeO-p-OCH₂Ph-Ph 11118888_jjjj: R₁=R₂=H, R=3-pridyl

11118888_kkkk: R₁=R₂=H, R=3-indolyl

11118888_llll: R₁=Cl, R₂=H, R=p-MeO-m-OCH₂Ph-Ph 11118888_mmmm: R₁=H, R₂=Cl, R=p-MeO-m-OCH₂Ph-P h

11118888

ref lux, 1h RCHO

(1:1)mr. N

N H H

HN HN

O O

,

(2:1)mr.

MeOH, conc. H

2SO reflux, 1h4

22220000

11117777aaaa

Scheme (26a): Synthesis of tetrahydroindolo[2,3-b]carbazoles.

11117777

iiii (1:1) mr MeOH, conc. H

2SO ref lux, 1h4

O O

N NH NH

11119999

p-dimethyaminobenzaldehyde

18 % yield

This behaviour is due to that the iodine catalyze the transformation or the isomerisation of 3,3^/-BIMs into 2,3-BIMs under a long time reaction conditions (The The The The Plancher Rearrangement

Plancher Rearrangement Plancher Rearrangement

Plancher Rearrangement))))^245(b). 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]carbazoles²⁴⁶. The reaction of indoles with aromatic aldehydes using iodine as a catalyst is a selective reaction for the preparation of tetrahydroindolo[3,2-b]carbazoles and none of the other isomer tetrahydroindolo[2,3-b]carbazoles were observed in the reaction mixture. In our reaction using BIMs and

aldehydes in methanolic sulphuric acid solution under refluxing for one hour (short time reaction) afforded the cis-isomer, tetrahydroindolo[2,3-b]carbazoles (18181818_aaaa----mmmm) in good yields which were given without isolation of other trans isomer, tetrahydroindolo[3,2-b]carbazoles. Scheme (26b) showed the mechanism for the formation of our [2,3-b] carbazoles (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 direction of forming our cis-isomer (18181818aaaa----mmmm)²⁴⁶. The products 18181818aaaa----mmmm which were prepared by this method were found to be more stable than the same products using POCl₃ as a catalyst which were quickly oxidized to form dihydroindolo[2,3-b]carbazoles.

N H N

H

tetrahydroindolo[2,3-b]carbazole(11118888_aaaa)

HN N

H

tetrahydroindolo[3,2-b]carbazole

C i s- isomer T r an s- isomer

HN N

H

dihydroindolo[3,2-b]carbazole dehydra ted form

Figure (44): Cis and Trans isomers of indolocarbazoles.

R

R

R

R

In this context and as a continuation of our work concerning the synthesis of tetrahydroindolo[2,3-b]carbazoles with an attempt to prepare the mixed indolocarbazoles (with two different aldehydes). The reaction of BIMs (17171717_iiii) (1 mole equivalent) and p-dimethylaminobenzaldehyde (1 mole equivalent) has been done by the method of methanol sulphuric acid solution as a possible route for the synthesis of 4-(8-(3-(benzyloxy)-4-methoxyphenyl)1,1a,2,2a,3,7b,8,8a-octahydroindolo[2,3-b]carbazol -2-yl)-N,N-dimethylanilin (19999). The desired compound 19 19 19 19 was formed with a low yield of 18 % and confirmed by the means of ¹H-NMR, ESI-MS and IR spectra, where the

1H-NMR spectra of 191919, indicated the single signal for 2-protons at 5.79 ppm for two 19 aliphatic CH protons.

N H

+

H+

-H2O

N H

N H R1

azafulven salt A

N H N

H

H

N H N

H C

R1

R2

R2 R

R 1 2

C O

R1

R2

R1

R2

R2

R1

azafulven salt B

-H2O

N H N

H R2

N H N

H R2

R2 R

1

R1 R

1

C O

R1

R2

OH +

N H N

H

R1

R2

3,3-BI alkane

H

R2 R

1

H

-H

-H

Tetrahydroindolo[2,3-b]carbazoles

after short time reaction after long time

reaction, catalyst I

2

N H

NH

2,3-BI alkane

R1 R

2

reflux 14 h NH

HN R1

R2

R2

R1

Tetrahydroindolo[3,2-b]carbazoles

scheme (26 b): Mechanism for the formation of tetrahydroindolo carbazoles.

C O

R1

R2

The extended spirocyclic structure (202020) was synthesized in a better yield of 52 %, by 20 the way of MeOH and conc.H₂SO₄ using BIM (17171717_aaaa) (2 moles equivalent) and 1,4-cyclohexanedione (1 mole equivalent). The reaction solution turned from pink colour to dark violet by leaving it stirring for one hour under reflux. The product was detected, purified and confirmed by means of ESI-MS (m/z): 719.29 [M⁺-H] and EI-MS (m/z):

720 [M⁺] 32 %. Its ¹H-NMR spectrum showed a single signal at δ = 5.91 ppm value for 2 protons (2 CH), and two triplet signals every one for 4 protons (2 CH₂) at δ = 2.03 ppm and 2.27 ppm. The four NH indole protons appeared at 9.94 ppm as a broad signal. The structure was confirmed additionally by its APT ¹³C-NMR spectrum that showed the presence of only twenty six carbon signals as two signals for 2CH₂ carbon, eleven signals for quaternary carbons, one carbon signal for one CH aliphatic carbon

and thirteen carbon signals for 13 CH aromatic carbons. These data proved that the novel spirocyclic compound 20202020 is a symmetrical structure.

. 3.1.3.3. Oxidation reactions of BIMs

The antibiotic agent turbomycin A has been isolated as a product of saccharomyces cerevisiae fermentation and identified as the salt of tris(indol-3-yl)methylium¹⁷¹. Turbomycin A and Turbomycin B were obtained from soil microorganisms by a metagenomic approach using a 24.546-member DNA library expressed in Escherichia coli³², in which turbomycin A was designated as tris(indol-3-yl)methylium and turbomycin B as bis(indol-3-yl)phenyl)methylium, figure (7). Both of these agents were capable of killing gram-negative and gram-positive microorganisms³². These results provided strong evidence that turbomycins comprise a perspective class of biologically active compounds.

In view of this, we will introduce a novel class of biologically active turbomycines via oxidation reaction of some previously prepared BIMs (17171717aaaa----pppp). The diindolylmethenes were first named "Rosindoles" by Fisher²⁴⁷. The substituted di- or tri- indolylmethenes have been synthesized in literature by the oxidation of the analogous BIMs using oxidizing agents such as DDQ, TCQ^{171, 33}, tritylperchlorate²⁴⁸ or FeCl₃²⁴⁹, where if the reaction was accomplished in presence of acid (H⁺X^-) as a source of the anion it will afford the corresponding methylium salts e.g. turbomycin A and turbomycin B, compounds 22222222_aaaa and 22222222_bbbb in presence of conc. sulphuric acid. In the absence of the acid the reaction afforded only the free bases compounds (21212121aaaa----kkkk). BIMs are found to be very sensitive compounds against the oxidizing agents. Our prepared BIMs (17171717aaaa----pppp)))) were dissolved in methanol and 1.5 mole equivalent of TCQ or DDQ (as oxidized agents) were added. The reaction solution turned from light yellow to dark red and allowed to reflux for 30 to 60 minutes yielding our bisindolylmethenes of type 21212121aaaa----kkkk as a free base due to the absence of the anion source (the acid), scheme (27).

NH NH

R R₁

R₂ R₁

R₂

11117777_aaaa: R₁=R₂=H, R=Ph 11117777_bbbb: R₁=R₂=H, R=p-NO₂- Ph 11117777_cccc: R₁=R₂=H, R=p-Cl- Ph 11117777_dddd: R₁=R₂=H, R=p-Br- Ph 11117777_eeee: R₁=R₂=H, R=p-N(Me)₂- Ph 11117777_ffff: R₁=R₂=H, R=m-Br 11117777_gggg: R₁=R₂=H, R=m-OCH₂Ph- Ph 11117777_hhhh: R₁=R₂=H, R=p ,m-OH- Ph 11117777_iiii: R₁=R₂=H, R=p-MeO-m-OCH₂Ph- Ph 11117777_jjjj: R₁=R₂=H, R=m-MeO-p-OCH₂Ph- Ph 11117777_kkkk:::: R₁=R₂=H, R=m-Me,2,4,6-trif louro- Ph 11117777_llll: R₁=R₂=H, R=1-na phthyl

11117777_mmmm: R₁=R₂=H, R=3-pridyl 11117777_nnnn: R₁=R₂=H, R=3-indolyl

11117777_oooo: R₁=Cl, R₂=H, R=p-MeO-m-OCH₂Ph- Ph 11117777_pppp:::: R₁=H, R₂=Cl, R=p-MeO-m-OCH₂Ph- Ph

N NH

R R₁

R₂ R₁

R₂

22221111_aaaa: R₁=R₂=H, R=Ph 22221111_bbbb: R₁=R₂=H, R=3-indolyl 22221111_cccc: R₁=R₂=H, R=p-Cl- Ph 22221111_dddd: R₁=R₂=H, R=m-Br- Ph 22221111_eeee: R₁=R₂=H, R=p ,m-OH- Ph

22221111_ffff: R₁=R₂=H, R=2,4,6-trif luro-3-methylphenyl 22221111_gggg: R₁=R₂=H, R=p-MeO-m-OCH₂Ph- Ph 22221111_hhhh: R₁=Cl, R₂=H, R=p-MeO-m-OCH₂Ph- Ph 22221111_iiii: R₁=H, R₂=Cl, R=p-M eO-m-OCH₂Ph- Ph 22221111_jjjj: R₁=R₂=H, R=1-naphthyl

22221111_kkkk:::: R₁=R₂=H, R=3-pridyl 22221111_llll:::: R₁=R₂=H, R=p-N(Me)₂-Ph TTT

TCCCCQQQQ ....

MeOH, reflux

30 min. N

N H H

R R₁

R₂ R₁

R₂

HSO₄ 22222222_aaaa: R₁=R₂=H, R=Ph (Turbomycin B) 22222222_bbbb: R₁=R₂=H, R=3-indolyl (Turbomycin A) ccccoooonnnncccc....

H HH H2222SSSSOOOO boiling 10 min4444

11117777 22221111 22222222

Scheme (27): Synthesis of bisindolylmethenes and its salt formation

The structural features of the free base 21212121aaaa----llll

were determined by its analytical and spectral data ESI-MS, ¹H-NMR, ¹³C-NMR and IR, where the ¹H-NMR gives strong indication for the disappearance of the protons related to the

aliphatic CH function and no detection for the NH indole protons. The disappearance of the remaining indolic NH has been explained as in the previous reported cases of these bisindolylmethenes, due to the high delocalization which resulted from the conjugation of the remaining strong acidic NH indole. This fact was well documented by the reported monoprotonated form of diindolylpyridylmethene, figure (45)¹⁷². This indolic NH proton has not also been found in the IR spectra. Figure (46), shows the two IR spectra of the known compound 17171717_aaaa (BIM) and compound 21212121_aaaa (oxidized form), in which 17171717_aaaa has a sharp peak at 3410 for the NH indole, however compound 21212121_{a a a a} has no detection for the remaining NH indole.

N N

N

H H

Figure (45): Reported monoprotonated f orm of diindolylpyridylmethene

The ¹H-NMR and ¹³C-NMR spectrums illustrated that these structures (21212121aaaa----llll) show not any isomerisation as E/Z or cis/trans forms because the pure spectra did not show any repetition for the signals of the protons related to the presence of E/Z forms as it is in the published examples of these compounds. The spectral data of our prepared compounds 21212121_aaaa, 21212121_bbbb and 21212121_kkkk were found to be identically to those of the published compounds^{171, 32}. The synthesized BIMs and bisindolylmethenes were recently reported as new host molecules for anion recognition and sensing by hydrogen bonding interaction²⁵⁰. Indole based receptors have attracted considerable attention due to the acidity of the indole NH group which was expected to be enhanced by the conjugation with benzene which would lead to higher binding affinity for anions²⁵¹. These anions have a wide range of importance in medicinal, environmental and biological process²⁵². The large conjugated bis(3-indolyl)methene skeleton has been demonstrated to be an efficient chromogenic and fluorescent moiety for metal ions sensing by Kim and coworkers²⁵³. In view of this recent documentation the mono sulphate salts 22222222_{a; ba; b a; ba; b} can easily be synthesized just by the addition of the anion as an acid or in its tetrabutylammonium salt in methanol or acetonitrile solution and boiling the mixture for 10 minutes. The crude product can be crystallized or purified by column chromatography. There were a lot of acids which have been used for this reactions^174-177, that have been known in the branch of physical chemistry by colorimetric chemosensors. Bisindolylmethenes (21212121aaaa----llll) and its monosulfate salts (22222222_{a, ba, ba, ba, b}) were formed with a high yield over 76 %. The ¹H-NMR spectra of the sulphate salt 22222222_{a, ba, ba, ba, b} appear to be the same that of the free bases 21212121_aaaa and 21212121_bbbb respectively upon addition of 0.5 to 2.5 equivalents of the anion, and it showed broading of the signals after the addition of 5 to 10 equivalents^{174, 254}. This has been illustrated by the reported ¹H-NMR spectra in DMSO-d₆ of bisindolylmethene 21212121_aaaa before and after the addition of various quantities of the fluoride anion F^- in zero, 0.4, 2.5, 5 and 10 equivalents as shown in figure (47)¹⁷⁴. The ¹H-NMR spectrum of our synthesized monosulfate salts 22222222_a,a,a,a,bbbb appeared to be identical to the case of the addition of 5 to 10 equivalents of the anion which indicates that we have used an excess of conc. H₂SO_4.

NH NH

BIM 11117777

aaaa

N NH

22221111

aaaa

Figure (46): IR spectra of BIM 11117777

aaaaand its oxidized form 22221111

aaaa

Figure (47): ¹H NMR spectra in DMSO-d 6 of 22221111

aaaabef ore and after addition of various quantities of f luoride anion (F )¹⁷⁴.

The salts 22222222_a,a,a,a,bbbb recorded lower Rf values than the free bases 21212121_{a,b a,b a,b a,b} and different melting points. It has been recently reported that, the salts of type 22222222_a,ba,ba,ba,b have two possible structures the indolyl methylium cation form and the indolenine form as illustrated in

figure (48). However the quantum chemical calculations of the two structures showed that the delocalized form of the inolylmethylium cation is more stable than the indolenine form by 1.4 kcal/mol²⁵⁴.

N H N

H HN

N H N

H YHN Y

Indolylmethylium cation f orm Indolenine f orm Figure (48): Resonance stabilization of turbomycin A

3.1.4. Condensation reactions of indoles with different types of

Im Dokument Development of novel indolyl-derived biologically active compounds (Seite 86-96)