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![The Fischer indole synthesis:
It consists of heating the phenyl hydrazones of an aldehyde or a ketone with ZnCl2,H2SO4 ,
BF3etherate,or polyphosphoric acid to about 1800C
The reaction of a (substituted) phenylhydrazine with an aldehyde or ketone initially forms a
phenylhydrazone which isomerizes to the respective enamine (or 'ene-hydrazine'). After
protonation , a cyclic [3,3]-sigmatrpic-rearrangement occurs producing an imine. The resulting
imine forms a cyclic aminoacital (or aminal), which under acid catalysis that eliminates NH3,
resulting in the energetically favorable aromatic indole.](https://image.slidesharecdn.com/indole-200409095121/75/Indole-Lecture-1-Hetero-cyclic-chemistry-8-2048.jpg)
![Anticancer Agent 5,6,11,12,17,18,23,24-Octahydrocyclododeca[1,2-b:4,5-
b’:7,8-b’’:10,11-b’’’] tetraindole (Ctet).
Macrocyclic condensation products of indole and simple aldehydes
N
H
HN
N
H
NH
H
N
HN
NH
NH
37% HCHO, MeOH, 96% H2SO4, reflux, 2 h.
HCHO HCHO
Dark Dark
Mixture of CTr & CTet
CTr CTet
CTet is a potent inhibitor of DNA synthesis in both estrogen receptor positive (MCF-7) and
estrogen receptor negative (MDA-MB-231) human breast cell lines (IC50 = 1.20 ± 0.04 μM and
1.0 ± 0.1 μM, respectively).
Molecules 2010, 15, 4085-4093,Tetrahedron 1970, 26, 3347–3352, Cancer Res 2007; 67, 7815
dx.doi.org/10.1021/jm2013425 | J. Med. Chem 2012](https://image.slidesharecdn.com/indole-200409095121/75/Indole-Lecture-1-Hetero-cyclic-chemistry-28-2048.jpg)
Indole: Lecture -1 (Hetero-cyclic chemistry)
The document discusses the indole molecule, including its structure, biological activities, and importance in pharmaceuticals. It provides examples of many indole-containing drugs and toxins. Synthetic routes for producing indoles are also covered, such as the Fischer indole synthesis and methods involving phenylhydrazones, diazonium salts, and propargyl alcohols. The indole nucleus is an important scaffold in natural products and drugs.
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Indole: Lecture -1 (Hetero-cyclic chemistry)
- 1. INDOLE: Synthesis andMedicinal Importance Lecture- 1: Heterocyclic Chemistry MSc final year Govt Raza PG College Rampur Email : [email protected] Dr Mohd Kamil Hussain Asst. Professor Department of Chemistry
- 2. Indole is anaromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five- membered nitrogen-containing pyrrole ring. Compounds that contain an indole ring are called indoles. The indole nucleus is a fundamental constituent of a number of natural and synthetic products with different biological activities Although indole moiety is very small but is fascinated by scientists because of the diverse biological activities by not only indole but its various substituted derivatives as well. Indole alkaloids form a very large group of physiologically active and pharmacologically important molecules example:brucine, reserpine, yohimbine, vincamine, strychinine etc N H Indole
- 3. Due to itswider applications in pharmaceutical industries, they will replace many existing heterocyclic based pharmaceuticals. Now days, many drugs are in the world market, while several hundred are in clinical trials. indoles Anti hypertensive drugs Anti depressant drugsAnti psychotic agents NSAIDS Anti emetic drug Analgesic drug Anti asthmatic drug Anti viral drug.Anti arrhythmic drug B-blocker drug ToxinsInhibitor of RNA Polymerase-11 Agonist for the cannabinoid receptor Non- Nucleoside reverse transcriptase inhibitor Opioid agonist Sexual dysfunction. Anti Cancer drug
- 4. Vincristine VINBLASTINE VinorelbineVindesin Vincaalkaloids are a set of anti-mitotic and anti-microtubule agents that were originally derived from the Catharanthus roseus. They are a class of cell-cycle-specific cytotoxic drugs that work by inhibiting the ability of cancer cells to divide: Acting upon tubulin, they prevent it from forming into microtubules, a necessary component for cellular division. Vinca alkaloids are now produced synthetically and used as drugs in cancer therapy and as immunosuppressive drugs. These compounds include vinblastine, vincristine, vindesine, and vinorelbine.
- 5. VINCAMINE Anti-hypertensive drugs PINDOLOL nonselective betablocker with partial beta- adrenergic receptor agonist activity OXYPERTINE Antipsychotic agent RESERPINE Anti-hypertensive drugs & antipsychotic ATEVIRIDINE Anti-HIV Strychnine toxin
- 6. YOHIMBINE Stimulant and aphrodisiaceffects DOLASETRON Serotonin 5-HT3 Receptor antagonist ZAFIRLUKAST an oral leukotriene receptor antagonist LTRA) for the maintenance treatment of asthma ARBIDOL antiviral treatment for influenza infection Lysergic acid
- 7. PROMANULLIN Amatoxin BUCINDOLOL Non selective betablocker with additional weak alpha-blocking properties Delavirdine non-nucleoside reverse transcriptase inhibitor MITRAGYNINE Opioid agonist PERICINE Opioid agonist
- 8. The Fischer indolesynthesis: It consists of heating the phenyl hydrazones of an aldehyde or a ketone with ZnCl2,H2SO4 , BF3etherate,or polyphosphoric acid to about 1800C The reaction of a (substituted) phenylhydrazine with an aldehyde or ketone initially forms a phenylhydrazone which isomerizes to the respective enamine (or 'ene-hydrazine'). After protonation , a cyclic [3,3]-sigmatrpic-rearrangement occurs producing an imine. The resulting imine forms a cyclic aminoacital (or aminal), which under acid catalysis that eliminates NH3, resulting in the energetically favorable aromatic indole.
- 9. The Japp-Klingemann reaction isa chemical reaction used to synthesize hydrazones from β-keto-acids (or β-keto-esters) and aryl diazonium salts.The hydrazone products of the Japp-Klingemann reaction are most often used as intermediates in synthesis of more complex organic molecules. For example, a phenylhydrazone product can be heated in the presence of strong acid to produce anindole via the Fischer indole synthesis. The Leimgruber-Batcho indol synthesis is an efficient method of sythesizing indole and substituted indoles. Originally disclosed in a patent in 1976, this method is high-yielding and can generate substituted indoles.
- 10. Resonating structure ofIndole N N H N HH Low energy iminium str High energy orthoquinonoid str The most reactive position on indole for electrophilic aromatic substitution is C-3, which is 1013 times more reactive thanbenzene Electrophilic Substitution in indole occurs at position- 3, but if this is already occupied then on the 5 & 7 position. The basicity of indoles corresponds approx.to that of pyrrole. Although the indole N-1 nitrogen atom has a lone pair ofelectrons, indole is not basic like amines and anilines because the lone pair is delocalised and contributes to the aromatic system. Strong bases like sodiumhydride or butyl lithium and water-free conditions are needed for completedeprotonation.
- 11. N H N H SO3H SO3inpyridine N H NO2 C 2H 5NO 2 C 2H 5O Na N H Br or Ior Cl Br2 or I2 or SO2Cl2 N H CHO HCHO / HCl N H CHO Me2NCHO/POCl3 N H CH2N(CH3)2 HCHO (Me) 2 NH N H N H Sn / HCl H2 / Ni250 0 c gramin-nat pdt isolated from grasses indoline
- 12. Multicomponent reaction of2-substituted indoole Multicomponent reactions between 2-substituted indoles , benzaldehyde and Meldrum’s acid in the presence of one equivalent of triethylamine affording stable, crystalline adduct salts 1.On heating witth t-BuOH it gives acid-ester 2. When in situ formed azides 3 prepared from 2, were heated in toluene, a diastereomeric mixture of spirocyclic pyrrolidinone-indolines 5 was isolated via 4 resulting from a Curtius rearrangement, followed by a thermal spirocyclisation process. N H R CHO O OO O + N H R O O O OEt3NH N H R COOtBu COOH N H R COOtBu CON3 N H R COOtBu N C O N H NH R O OtBuO N H R COOtBu NHCO2Bn 2 34 5 6 t-BuOH DPPA Et3N BnOH,Et3N Et3N 1 ARKIVOC 2004 (vii) 208-222
- 13. The indole scaffoldis a prominent and privileged structural motif found in numerous natural products and various synthetic compounds. Recently, a large number of indole-containing compounds have revealed remarkable pharmacological activity and their utility as therapeutic agents has attracted considerable attention from chemists, Subsequently, the development of efficient methods that allow rapid access to functionalized indoles with different substitution patterns (at C-2, C-3, N-atom and aromatic ring, constitutes an emerging area. Angew.Chem. 2005, 44, 606, J.Am.Chem.Soc. 2005, 127, 5342 Novel Synthetic Approaches Toward Substituted Indole Scaffolds
- 14. one-pot, three-component procedurefor the synthesis of 2,3-substituted indoles based on Cacchi´s protocol. This regiospecific procedure consisted of a Pd domino indolization involving a consecutive Pd- catalyzed Sonogashira coupling followed by aminopalladation and reductive elimination starting from 2-iodo-N-trifluoroacetylanilide 1, a suitable acetylene 2 and bromoarene 3. The Senanayake group optimized the reaction conditions as shown in Scheme. the use of trifluoroacetyl as protecting group in 1 was shown to be advantageous (readily hydrolyzable); addition of bromobenzene at the beginning simplified the procedure and enhanced the reaction rate; DMF as solvent combined with K2CO3 as base, and a temperature of 60 ºC gave better results J.Chem.Soc.PerkinTrans.1 2000, 1045 R1 = H, CO2Me, CN R2 = Ph, 4-MePh R3 = Ph, 4-MeOPh, 4-CO2MePh, 2-NO2Ph
- 15. The Larock groupof the Iowa State University reported on the synthesis of 3-iodoindoles 4 via Pd/Cu-catalyzed coupling of N,N-dialkyl-2-iodoanilines 1 with terminal acetylenes 2 and subsequent electrophilic cyclization of 3. Due to the high reactivity of N,N-dialkyl-o-iodoanilines towards the Sonogashira coupling, a wide variety of substituted anilines and alkynes were used (with aryl, vinyl, alkyl and silyl groups). However, the authors reported that substituents on the triple bond of 3 affect the yield of the following cyclization step, since increased conjugation enhances the reaction rate and also increases the product yield. In addition, while electron-withdrawing groups enhanced cyclization, (strong) electron-donating groups slowed the reaction and led to lower yields. The authors reported an interesting feature; when there are two different N-alkyl groups, the less- hindered group is more easily removed. Additionally, this procedure allows further derivatization/functionalization at C-3, since 4 might be used for cross-coupling reactions. J.Org.Chem. 2006, 71, 62 R1 = H, 4-NO2 ,4-Me, 4-CO2Et, 4- CO2Me R2 = Ph, t-Bu, n-Hexyl, R4 = Me, n-Bu, Ph
- 16. The Lautens groupof the University of Toronto described a modular synthesis of 2- substituted indoles via a palladium-catalyzed coupling. This methodology involved an intramolecular Buchwald-Hartwig C-N/intermolecular Suzuki-Miyaura C-C coupling of o- gem-dihalovinylanilines with an organoboron reagent catalyzed by Pd(OAc)2/S-Phos in the presence of K3PO4.H2O. Interestingly, the free aniline furnished the desired indole directly and in good yield. The strategy reported by the authors showed a wide range of applicability in terms of substituents, in particular for the challenging 4-substituted indoles. Better results were obtained for X = Cl. Moreover, the authors expanded the reaction scope to obtain 1,2,3- trisubstituted indoles by switching the order of addition of the two boronic acids. Org. Lett. 2005, 7, 3549 ,J. Org. Chem.,Vol. 72, No. 4, 2007 , R1 = H, 3-Me, 3-F, 4-F, 4-CF3, 4-CO2Me, 4-OBn R2-‘B’ = Aryl/HetAryl/Alkyl/ Vinyl Boronic acid/ester R3 = H, CF3, Me X = Br, Cl
- 17. NH R4 R1 X X R3 N R3 R4 R2 R1 N R4 R1 R N R4 R1 R N R1 N O R Cbz C-N/ Suzuki Pd/L C-N/Heck Pd/L C-N/ Sonogashira Pd/ Cu/L C-N/C-N Cu/L Org. Lett. 2005, 7, 3549 Org. Lett. 2006, 8, 4203 Org. Lett. 2007, 9, 2955. Org. Lett. 2006, 8, 653. Recently, Lautens group have reported a Pd-catalyzed indole synthesis via a C- N/Suzuki or C-N/Heck or C-N Sonogashira combinations and a Cu-catalyzed double C-N bond formation
- 18. Zn(OTf)2 –Catalyzed Cyclization. TheLiu group of the National Tsing-hua University published a new indole synthetic approach , using anilines 1 as starting material with the appropriately substituted propargyl alcohols 2 as the source of the C-2―C-3 unit. This method proved to be very effective in the preparation of several indoles 3 in good to high yields ,since Zn(OTf)2 has the advantage of activating not only the C-2- addition of the alcohol but also the subsequent cyclization step. The mechanism elucidated by the authors proposed that the isomerization of the α-amino ketone intermediate occurs through a 1,2- nitrogen shift, thus explaining the observed chemoselectivity. J. Org. Chem. 2006, 71, 4951
- 19. Rearrangement of AzirinesviaThermolysis D. Taber and W. Tian of the University of Delaware have reported on the synthesis of indole 3.via the thermal rearrangement of azirines 2 that are readily available from the ketones 1 (Neber reaction) via the corresponding activated oxime. The rearrangement occurred at temperatures ranging from 40 ºC up to 170 ºC. The authors suggest that the cyclization mechanism proceeds by a π-participation of the aromatic ring followed by reorganization, before the new C-N bond is formed. (J.Am.Chem.Soc. 2006, 128, 1058 R1 = H, 2-Br, 4-Br R2 = Me, n-Octyl , R3 = H, Ph Activationof Oxime: 1> For monoarylacyclic ketones—MsCl/Et3 2>For diaryl ketones—DIAD/n-Bu3P orPh3P
- 20. The Nicholas andPenoni groups of the University of Oklahoma and of the Università degli Studi dell’Insubria, respectively, have reported on a pathway to N-methoxyindoles via an alkylative cycloaddition reaction .. The authors performed a one-pot procedure for the preparation of several substituted N-methoxyindoles 3 using as starting materials the readily available nitrosoarenes 1 and the alkyne 2 (Scheme 6). Both electron-poor and electron-rich nitrosoarenes gave good product yields and regioselectivity for the 3-position was observed. The authors obtained higher yields for 2-substituted nitrosoarenes 1when compared to 4-substituted nitrosoarenes 1. Additionally, this method constitutes a formal synthesis of the corresponding indole (NH) since the latter can be formed by reduction of 3. J. Org. Chem. 2006, 71, 823 N-Methoxyindoles via Alkylative Cycloaddition of Nitrosoarenes with Alkynes
- 21. Concise Total Synthesisof(+)-cis-Trikentrin A and (+)-Herbindole A via Intermolecular Indole Aryne Cycloaddition The trikentrins were isolated by Capon from the marine spongeTrikentrion flabelliforme and display antibacterial activity.The more recently discovered herbindoles by Scheuer from the Australian spongeAxinella sp. possess both cytotoxic and antifeedant properties.The interesting biological profiles of these molecules combined with their uncommon structural motifs make them attractive targets for total synthesis. Trikentrion flabelliforme N H (+)-cis-Trikentrin N H Herbindole A N H Herbindole B Axinella sp Org.Lett., 11, 2009,201-204
- 22. An efficient nine-steptotal synthesis of the annulated indole natural products ((+)-cis- trikentrin A and (+)-herbindoleA was accomplished via an intermolecular Diels-Alder cycloaddition using indole aryne (indolyne) methodology as the key step. This strategyprovides rapid access into the trikentrins and the related herbindoles and represents the first application of this methodology to natural products total synthesis. The required 6,7-indolyne precursor was readily constructed by means of the Bartoli indole synthesis with substituted nitrobenzenes and vinyl magnesium bromide. cis-Trikentrin A: Bartoli Indole Synthesis Diazotization of 2 with t-BuONO followed by bromination catalyzed by CuBr2 was carried out to afford the o-dibromide 3. Application of the Bartoli indole synthesis (CH2CHMgBr, ;THF, -40 °C) proceeded uneventfully and gave the desired indole 4. The NH group of the indole was then protected as itsTBS group (KHMDS,TBSOTf,THF, -78 °C). NH2 NH2 NO2 Br NO2 Br N H Br Br N Br Br TBS 1 Ac2O, 2 HNO3 3 NaOH DCE, H2O 50-80 0 C, 96% CuBr2 cat, Br2 t-BuONO MeCN, 500 C 82% MgBr,2 eq THF, -40 0 C 52% KHMDS TBSOTf THF, -78 0 C 73% 1 2 3 4 5
- 23. N Br Br TBS 5 N TBS N TBS OH HO N TBS CHO OHC N H CH(EtS)2 (SEt)2HC N H Me Me 6 7 8 910 n-BuLi , -780C-RT PhMe,77% OsO4 ,NMO THF/H2O, 88% NaIO4 THF/H2O 88% EtSH,BF3.OEt2 -78 0C-RT 91% Ni (R) EtOH, 85% (+)-cis-Trikentrin A With the desired indole 5 in hand, metal-halogen exchange with n-BuLi in the presence of cyclopentadiene resulted in desired cycloadduct 6 in an 77%. Osmylation of 6 followed by oxidative cleavage of the diol 7 afforded the dialdehyde 8 Finally, 8 was converted into its corresponding dithioacetal 9 with concomitant desilylation in 91% yield. Raney nickel reduction afforded in nine steps synthetic ((+)-cis trikentrin
- 24. Mitragyne speciosa The OpioidAgonistic Indole Alkaloid Mitragynine OMe N N H O O O H H OMe N H N H O O O H H OH Mitragynine 7-Hydroxy Mitragynine Mitragynine was isolated from Mitragyne speciosa and has been employed as a substitute forin the treatment of pain in Thailand. Mitragynine itself is a full opioid agonist and primarily acted on u- and δ- opioid receptors. Interestingly the methoxyl functional group was found essential for the analgesic activity Pharm. J. 1907, 78, 453, Life Sci. 2006, 78, 2265, Org. Lett., 9, 2007,3491
- 25. Total Synthesis ofthe Opioid Agonistic Indole Alkaloid Mitragynine OMe N H N H O O O H H Mitragynine OMe I NHBoc N N TMS EtO OEt OMe N N N EtO OEt BoC TMS OMe N H COOEt NH2 OMe N H NH2 O O 9-Stapes + Pd(OAc)2 ,K2CO3 LiCl , DMF,100 0 C 6 hr, 2N Aq HCl, THF 1NaOH, EtOH 2 Triphosgene THF,45 0 C PhCH2OH Et2O/HCl, 24 hr 1 2 3 4 5 4-methoxy-D-tryptophan ester the Larock heteroannulation process between Boc-protected 2-iodo-3- ethoxyaniline1 and theTMS alkyne 2 gave the N- Boc-protected indole derivative 3. The hydrolysis of the3 was accompanied by concomitant loss of the indole2-silyl group of .This smoothly took place in aqueous 2 N HCl inTHF to provide 4-methoxy-D-tryptophan ethyl ester 4 in a single step in 91% yield. 3 was hydrolyzed in ethanolic NaOH solution and then converted into the benzyl ester 5.
- 26. Indole-3-carbinol (I3C) isa compound found in high concentrations in Brassica family vegetables, including broccoli, cauliflower, Brussels sprouts, collard greens, kale and cabbage. As a nutritional supplement, I3C has received attention in recent years as a promising preventive and treatment agent for breast and other types of cancers, and may have beneficial effect in the management of Herpes simplex virus (HSV) and human papilloma virus (HPV). I3C Down-Regulates ERα. Protein Levels without Altering ERβ Protein Levels in MCF7 T47D Human Breast Cancer Cells and Pleiotropic Effects on Multiple Signaling Pathways in Prostate Cancer Cells. Indole-3-Carbinol ( I3C)I3C Alternative Medicine Review, 2005, 10, 337-341,Mol Endocrinol, 2006, 20,3070–3082 Cancer Res 2007; 67, 7815 ,
- 27. N H OH N H O H NH3,Ca THF, N H O H 8 hHCHO N H N -33°C;2 h NaOMe 1 EtOH,Aq H2O2 2 aq NaOH,Et2O N H 1 POCl3 DMF 2 NaBH4,EtOH J.Org.Chem. 1996 , 61, 1493, Chemico-Biological Interactions 2010 186 255–266 Synthesis of Indole
- 28. Anticancer Agent 5,6,11,12,17,18,23,24-Octahydrocyclododeca[1,2-b:4,5- b’:7,8-b’’:10,11-b’’’]tetraindole (Ctet). Macrocyclic condensation products of indole and simple aldehydes N H HN N H NH H N HN NH NH 37% HCHO, MeOH, 96% H2SO4, reflux, 2 h. HCHO HCHO Dark Dark Mixture of CTr & CTet CTr CTet CTet is a potent inhibitor of DNA synthesis in both estrogen receptor positive (MCF-7) and estrogen receptor negative (MDA-MB-231) human breast cell lines (IC50 = 1.20 ± 0.04 μM and 1.0 ± 0.1 μM, respectively). Molecules 2010, 15, 4085-4093,Tetrahedron 1970, 26, 3347–3352, Cancer Res 2007; 67, 7815 dx.doi.org/10.1021/jm2013425 | J. Med. Chem 2012
- 29. 5-Hydroxy Tetraindole InducesG2 Arrest and Apoptosis in Human Breast Cancer Cells H N H N N H OHHO HO N H OH Anti proliferative activity against breast adenocarcinoma (MCF 7and MDA-MB-231) cells Induces G2 arrest in cell cycle with a distinctive increase in the expression of cyclin B1 and phospho-cdc2 Induces apoptosis through externalization of membrane phosphatidylserine, DNA fragmentation, and activation of caspase-3. IC50 (MDA-MB-231) 0.45 ± 0.03 μM (MCF-7) 0.88 ± 0.04 μM J. Med. Chem. 2012, 55, 1583−1592
- 30. H N H N N H OHHO HO N H OH CHO CHO + H N OH I2 / MeCN 2h,RT,89% 4-Hydroxytetraindole bearing an aromatic central core structure, was prepared in satisfactory yields by addition reactions of terephthalaldehyde with indole in the presence of catalytic amounts of molecular iodine at room temperature . x.doi.org/10.1021/jm2013425 | J. Med. Chem.2012 Easy is the Best