Indole: Lecture -1 (Hetero-cyclic chemistry)

Indole is an aromatic 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.

1. INDOLE:SynthesisandMedicinalImportance
Lecture-1: Heterocyclic Chemistry
MSc final year
Govt RazaPG College Rampur
Email : [email protected]
Dr Mohd Kamil Hussain
Asst. Professor
Department of Chemistry

2. Indoleisanaromaticheterocyclicorganiccompound.Ithasabicyclic
structure,consistingofasix-memberedbenzeneringfusedtoafive-
memberednitrogen-containingpyrrolering.Compoundsthatcontain
anindoleringarecalledindoles.
Theindolenucleusisafundamentalconstituentofanumberof
naturalandsyntheticproductswithdifferentbiologicalactivities
Althoughindolemoietyisverysmallbutisfascinatedby
scientistsbecauseofthediversebiologicalactivitiesbynotonly
indolebutitsvarioussubstitutedderivativesaswell.
Indolealkaloidsformaverylargegroupofphysiologicallyactiveand
pharmacologicallyimportantmoleculesexample:brucine,reserpine,
yohimbine,vincamine,strychinineetcN
H
Indole

3. Duetoitswiderapplicationsinpharmaceuticalindustries,theywill
replacemanyexistingheterocyclicbasedpharmaceuticals.
Nowdays,manydrugsareintheworldmarket,whileseveral
hundredareinclinicaltrials.
indoles
Anti hypertensive drugs
Anti depressant drugs
Anti 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 cannabinoidreceptor
Non-Nucleoside reverse transcriptase inhibitor
Opioid agonist
Sexual dysfunction.
Anti Cancer drug

4. Vincristine VINBLASTINE
Vinorelbine
Vindesin
Vincaalkaloidsareasetofanti-mitoticandanti-microtubuleagentsthat
wereoriginallyderivedfromtheCatharanthusroseus.
Theyareaclassofcell-cycle-specificcytotoxicdrugsthatworkby
inhibitingtheabilityofcancercellstodivide:Actingupontubulin,they
preventitfromformingintomicrotubules,anecessarycomponentfor
cellulardivision.
Vincaalkaloidsarenowproducedsyntheticallyandusedasdrugsin
cancertherapyandasimmunosuppressivedrugs.Thesecompoundsinclude
vinblastine,vincristine,vindesine,andvinorelbine.

5. VINCAMINE
Anti-hypertensive drugs
PINDOLOL
nonselectivebeta blocker with partial beta-
adrenergic receptor agonist activity
OXYPERTINE
Antipsychotic agent
RESERPINE
Anti-hypertensive drugs & antipsychotic
ATEVIRIDINE
Anti-HIV
Strychnine
toxin

6. YOHIMBINE
Stimulant and aphrodisiac effects
DOLASETRON
Serotonin5-HT
3 Receptor antagonist
ZAFIRLUKAST
an oral leukotrienereceptor antagonist LTRA) for
the maintenance treatment of asthma
ARBIDOL
antiviral treatment for influenza
infection
Lysergic acid

7. PROMANULLIN
Amatoxin
BUCINDOLOL
Non selective beta blocker 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 aldehydeor a ketonewith ZnCl
2,H
2SO
4,
BF
3etherate,or polyphosphoricacid to about 180
0
C
Thereactionofa(substituted)phenylhydrazinewithanaldehydeorketoneinitiallyformsa
phenylhydrazonewhichisomerizestotherespectiveenamine(or'ene-hydrazine').After
protonation,acyclic[3,3]-sigmatrpic-rearrangementoccursproducinganimine.Theresulting
imineformsacyclicaminoacital(oraminal),whichunderacidcatalysisthateliminatesNH3,
resultingintheenergeticallyfavorablearomaticindole.

9. The Japp-Klingemannreaction
is a chemical reaction used to synthesize hydrazones from β-keto-acids (or β-keto-esters) and aryl
diazoniumsalts. The hydrazoneproducts of the Japp-Klingemannreaction 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 anindolevia the Fischer indole
synthesis.
The Leimgruber-Batchoindolsynthesis
is an efficient method of sythesizingindoleand substituted indoles. Originally disclosed in a
patent in 1976, this method is high-yielding and can generate substituted indoles.

10. Resonating structure of IndoleN N
H
N
H
H
Low energy iminiumstr
High energy
orthoquinonoidstr
The most reactive position on indolefor electrophilicaromatic substitution is
C-3, which is 1013 times more reactive thanbenzene
ElectrophilicSubstitution in indoleoccurs at position-3, but if this is already
occupied then on the 5 & 7 position.
Thebasicityofindolescorrespondsapprox.tothatofpyrrole.
Although the indoleN-1 nitrogen atom has a lone pair ofelectrons, indoleis not
basic like amines and anilines because the lone pair is delocalisedand contributes
to the aromatic system.
Strong bases like sodiumhydrideor butyl lithium and water-free conditions are
needed for completedeprotonation.

11. N
H
N
H
SO
3H
S
O
3

in

p
y
r
id
in
e
N
H
NO
2
C
2
H
5
N
O
2
C
2
H
5
O
N
a
N
H
Br or I or Cl
Br
2 or I
2 or
SO
2Cl
2
N
H
CHO
H
C
H
O

/

H
C
l
N
H
CHO
M
e
2
N
C
H
O

/

P
O
C
l
3N
H
CH
2N(CH
3)
2
H
C
H
O
(M
e)2
N
H
N
H
N
H
Sn / HCl
H
2

/

N
i
2
5
0
0
c
gramin-nat pdt
isolated from grasses
indoline

12. Multicomponentreactionof2-substitutedindoole
Multicomponentreactionsbetween2-substitutedindoles,benzaldehydeandMeldrum’sacidinthe
presenceofoneequivalentoftriethylamineaffordingstable,crystallineadductsalts1.Onheating
wittht-BuOHitgivesacid-ester2.
Wheninsituformedazides3preparedfrom2,wereheatedintoluene,adiastereomericmixtureof
spirocyclicpyrrolidinone-indolines5wasisolatedvia4resultingfromaCurtiusrearrangement,
followedbyathermalspirocyclisationprocess.N
H
R
CHO
O
OO
O
+
N
H
R
O
O
O
O
Et
3NH
N
H
R
COOtBu
COOH
N
H
R
COOtBu
CON
3
N
H
R
COOtBu
N
C
O
N
H
NH
R
O
OtBu
O
N
H
R
COOtBu
NHCO
2Bn
2
34
5
6
t-BuOH
DPPA
Et
3N
BnOH,Et
3N
Et
3N
1
ARKIVOC 2004 (vii) 208-222

13. Theindolescaffoldisaprominentandprivilegedstructuralmotiffoundinnumerousnatural
productsandvarioussyntheticcompounds.Recently,alargenumberofindole-containing
compoundshaverevealedremarkablepharmacologicalactivityandtheirutilityastherapeutic
agentshasattractedconsiderableattentionfromchemists,Subsequently,thedevelopmentof
efficientmethodsthatallowrapidaccesstofunctionalizedindoleswithdifferentsubstitution
patterns(atC-2,C-3,N-atomandaromaticring,constitutesanemergingarea.
Angew. Chem.2005, 44, 606, J. Am. Chem. Soc.2005, 127, 5342
Novel Synthetic Approaches Toward Substituted IndoleScaffolds

14. one-pot,three-componentprocedureforthesynthesisof2,3-substitutedindoles
basedonCacchi´sprotocol.
ThisregiospecificprocedureconsistedofaPddominoindolizationinvolvingaconsecutivePd-
catalyzedSonogashiracouplingfollowedbyaminopalladationandreductiveeliminationstarting
from2-iodo-N-trifluoroacetylanilide1,asuitableacetylene2andbromoarene3.The
SenanayakegroupoptimizedthereactionconditionsasshowninScheme.theuseof
trifluoroacetylasprotectinggroupin1wasshowntobeadvantageous(readilyhydrolyzable);
additionofbromobenzeneatthebeginningsimplifiedtheprocedureandenhancedthereaction
rate;DMFassolventcombinedwithK
2CO
3asbase,andatemperatureof60ºCgavebetter
results
J. Chem. Soc. Perkin Trans. 12000, 1045
R
1
= H, CO
2
Me, CN
R
2
= Ph, 4-MePh
R
3
= Ph, 4-MeOPh, 4-CO
2
MePh,
2-NO
2
Ph

15. TheLarockgroupoftheIowaStateUniversityreportedonthesynthesisof3-iodoindoles4via
Pd/Cu-catalyzedcouplingofN,N-dialkyl-2-iodoanilines1withterminalacetylenes2andsubsequent
electrophiliccyclizationof3.DuetothehighreactivityofN,N-dialkyl-o-iodoanilinestowardsthe
Sonogashiracoupling,awidevarietyofsubstitutedanilinesandalkyneswereused(witharyl,vinyl,alkyl
andsilylgroups).However,theauthorsreportedthatsubstituentsonthetriplebondof3affecttheyield
ofthefollowingcyclizationstep,sinceincreasedconjugationenhancesthereactionrateandalsoincreases
theproductyield.Inaddition,whileelectron-withdrawinggroupsenhancedcyclization,(strong)
electron-donatinggroupsslowedthereactionandledtoloweryields.
Theauthorsreportedaninterestingfeature;whentherearetwodifferentN-alkylgroups,theless-
hinderedgroupismoreeasilyremoved.Additionally,thisprocedureallowsfurther
derivatization/functionalizationatC-3,since4mightbeusedforcross-couplingreactions.
J. Org. Chem.2006, 71, 62
R
1
= H, 4-NO
2
,4-Me, 4-CO
2
Et, 4-
CO
2
Me
R
2
= Ph, t-Bu, n-Hexyl,
R
4
= Me, n-Bu, Ph

16. TheLautensgroupoftheUniversityofTorontodescribedamodularsynthesisof2-
substitutedindolesviaapalladium-catalyzedcoupling.Thismethodologyinvolvedan
intramolecularBuchwald-HartwigC-N/intermolecularSuzuki-MiyauraC-Ccouplingofo-
gem-dihalovinylanilineswithanorganoboronreagentcatalyzedbyPd(OAc)
2
/S-Phosinthe
presenceofK
3
PO
4
.H
2
O.Interestingly,thefreeanilinefurnishedthedesiredindoledirectlyand
ingoodyield.Thestrategyreportedbytheauthorsshowedawiderangeofapplicabilityin
termsofsubstituents,inparticularforthechallenging4-substitutedindoles.Betterresults
wereobtainedforX=Cl.Moreover,theauthorsexpandedthereactionscopetoobtain1,2,3-
trisubstitutedindolesbyswitchingtheorderofadditionofthetwoboronicacids.
Org. Lett.2005, 7, 3549,J. Org. Chem., Vol. 72, No. 4, 2007
,
R
1
=H,3-Me,3-F,4-F,4-CF
3
,4-CO
2
Me,4-OBn
R
2
-
‘
B
’
=Aryl/HetAryl/Alkyl/VinylBoronicacid/ester
R
3
=H,CF
3,
Me X=Br,Cl

17. NH
R
4
R
1
X
X
R
3
N
R
3
R
4
R
2
R
1
N
R
4
R
1
R
N
R
4
R
1
R
N
R
1
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,LautensgrouphavereportedaPd-catalyzedindolesynthesisviaaC-N/Suzuki
orC-N/HeckorC-NSonogashiracombinationsandaCu-catalyzeddoubleC-Nbond
formation

18. Zn(OTf)2 –Catalyzed Cyclization.
TheLiugroupoftheNationalTsing-huaUniversitypublishedanewindolesyntheticapproach
,usinganilines1asstartingmaterialwiththeappropriatelysubstitutedpropargylalcohols2asthe
sourceoftheC-2―C-3unit.Thismethodprovedtobeveryeffectiveinthepreparationofseveral
indoles3ingoodtohighyields,sinceZn(OTf)
2
hastheadvantageofactivatingnotonlytheC-2-
additionofthealcoholbutalsothesubsequentcyclizationstep.Themechanismelucidatedbythe
authorsproposedthattheisomerizationoftheα-aminoketoneintermediateoccursthrougha1,2-
nitrogenshift,thusexplainingtheobservedchemoselectivity.
J. Org. Chem.2006, 71, 4951

19. Rearrangement of AzirinesviaThermolysis
D.TaberandW.TianoftheUniversityofDelawarehavereportedonthesynthesisofindole3.via
thethermalrearrangementofazirines2thatarereadilyavailablefromtheketones1(Neber
reaction)viathecorrespondingactivatedoxime.Therearrangementoccurredattemperatures
rangingfrom40ºCupto170ºC.Theauthorssuggestthatthecyclizationmechanismproceeds
byaπ-participationofthearomaticringfollowedbyreorganization,beforethenewC-Nbondis
formed.
(J. Am. Chem. Soc.2006, 128, 1058
R
1
= H, 2-Br, 4-Br
R
2
= Me, n-Octyl, R
3
= H, Ph
Activation of Oxime: 1> For monoarylacyclic ketones—MsCl/Et
3
2>For diarylketones—DIAD/n-Bu
3
P orPh
3
P

20. TheNicholasandPenonigroupsoftheUniversityofOklahomaandoftheUniversitàdegliStudi
dell’Insubria,respectively,havereportedonapathwaytoN-methoxyindolesviaanalkylative
cycloadditionreaction..Theauthorsperformedaone-potprocedureforthepreparationofseveral
substitutedN-methoxyindoles3usingasstartingmaterialsthereadilyavailablenitrosoarenes1andthe
alkyne2(Scheme6).Bothelectron-poorandelectron-richnitrosoarenesgavegoodproductyieldsand
regioselectivityforthe3-positionwasobserved.Theauthorsobtainedhigheryieldsfor2-substituted
nitrosoarenes1whencomparedto4-substitutednitrosoarenes1.Additionally,thismethodconstitutesa
formalsynthesisofthecorrespondingindole(NH)sincethelattercanbeformedbyreductionof3.
J. Org. Chem.2006, 71, 823
N-MethoxyindolesviaAlkylativeCycloadditionof Nitrosoareneswith Alkynes

21. Concise Total Synthesis of(+)-cis-TrikentrinA and (+)-Herbindole
A via Intermolecular Indole AryneCycloaddition
ThetrikentrinswereisolatedbyCaponfromthemarinespongeTrikentrionflabelliforme
and display antibacterial activity. The more recently discovered herbindolesby Scheuerfrom the
Australian sponge Axinellasp. possess both cytotoxicand antifeedantproperties.The interesting
biological profiles of these molecules combined with their uncommon structural motifs make them
attractive targets for total synthesis.
Trikentrion flabelliformeN
H
(+)-cis-Trikentrin N
H
HerbindoleA
N
H
HerbindoleB Axinellasp
Org. Lett., 11, 2009,201-204

22. An efficient nine-step total synthesis of the annulated indole natural products ((+)-cis-
trikentrinA and (+)-herbindoleA was accomplished via an intermolecular Diels-Alder
cycloadditionusing indole aryne(indolyne) methodology as the key step.
This strategyprovidesrapid access into the trikentrinsand 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 Bartoliindole
synthesis with substituted nitrobenzenesand vinyl magnesium bromide.
cis-Trikentrin A: Bartoli Indole Synthesis
Diazotization of 2 with t-BuONOfollowed by brominationcatalyzed by CuBr2was carried out to
afford the o-dibromide3.
Application of the Bartoliindole synthesis (CH2CHMgBr, ; THF, -40 °C) proceeded
uneventfully and gave the desired indole 4.
The NH group of the indole was then protected as its TBS group (KHMDS, TBSOTf, THF, -78 °C).NH
2 NH
2
NO
2
Br
NO
2
Br N
H
Br
Br N
Br
Br
TBS
1Ac
2O,
2HNO
3
3NaOH
DCE,H
2O
50-80
0
C,96%
CuBr
2cat,Br
2
t-BuONO
MeCN,50
0
C
82%
MgBr,2eq
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
9
10
n-BuLi,-78
0
C-RT
PhMe,77%
OsO
4,NMO
THF/H
2O,88%
NaIO
4
THF/H
2O
88%
EtSH,BF
3.OEt
2
-78
0
C-RT
91%
Ni(R)
EtOH,
85%
(+)-cis-TrikentrinA With the desired indole 5 in hand, metal-halogen exchange with n-BuLiin the presence of
cyclopentadieneresulted in desired cycloadduct6 in an 77%.
Osmylationof 6 followed by oxidative cleavage of the diol7 afforded the dialdehyde8
Finally, 8 was converted into its corresponding dithioacetal9 with concomitant desilylation
in 91% yield. Raney nickel reduction afforded in nine steps synthetic ((+)-cistrikentrin

24. Mitragyne speciosa
The Opioid Agonistic Indole Alkaloid MitragynineOMe
N
N
H
O
O
O
H
H
OMe
N
H
N
H
O
O
O
H
H
OH
Mitragynine
7-HydroxyMitragynine
MitragyninewasisolatedfromMitragynespeciosaandhasbeenemployedasasubstituteforinthe
treatmentofpaininThailand.Mitragynineitselfisafullopioidagonistandprimarilyactedonu-andδ-
opioidreceptors.Interestinglythemethoxylfunctionalgroupwasfoundessentialfortheanalgesicactivity
Pharm. J. 1907, 78, 453, Life Sci. 2006, 78, 2265,Org. Lett., 9, 2007,3491

25. Total Synthesis of the Opioid Agonistic Indole Alkaloid MitragynineOMe
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
NH
2
OMe
N
H
NH
2
O
O
9-Stapes
+
Pd(OAc)
2,K
2CO
3
LiCl,DMF,100
0
C
6hr,
2NAqHCl,THF
1NaOH,EtOH
2Triphosgene
THF,45
0
C
PhCH
2OH
Et
2O/HCl,24hr
1 2 3
4
5
4-methoxy-D-tryptophanester
the Larockheteroannulationprocess between Boc-protected
2-iodo-3-ethoxyaniline1 and the TMS alkyne2 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 HClin THF to provide 4-methoxy-D-tryptophan
ethyl ester 4 in a single step in 91% yield. 3 was hydrolyzed in
ethanolicNaOHsolution and then converted into the benzyl
ester 5.

26. Indole-3-carbinol(I3C)isacompoundfoundinhighconcentrationsinBrassicafamily
vegetables,includingbroccoli,cauliflower,Brusselssprouts,collardgreens,kaleandcabbage.
Asanutritionalsupplement,I3Chasreceivedattentioninrecentyearsasapromising
preventiveandtreatmentagentforbreastandothertypesofcancers,andmayhavebeneficial
effectinthemanagementofHerpessimplexvirus(HSV)andhumanpapillomavirus(HPV).
I3C Down-Regulates ERα. Protein Levels without Altering ERβProtein Levels in MCF7
T47D Human Breast Cancer Cells and PleiotropicEffects 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
NH
3
,CaTHF,
N
H
O
H
8hHCHO
N
H
N
-33°C;2h
NaOMe
1EtOH,AqH
2O
2
2aqNaOH,Et
2O
N
H
1POCl
3DMF2NaBH
4,EtOH J.Org. Chem. 1996, 61, 1493, Chemico-Biological Interactions 2010186 255–266
Synthesis of Indole

28. AnticancerAgent5,6,11,12,17,18,23,24-Octahydrocyclododeca[1,2-b:4,5-
b’:7,8-b’’:10,11-b’’’]tetraindole(Ctet).
MacrocycliccondensationproductsofindoleandsimplealdehydesN
H
HN
N
H
NH
H
N
HN
NH
NH
37%HCHO,MeOH,96%H
2SO
4,reflux,2h.
HCHO HCHO
Dark Dark
MixtureofCTr&CTet
CTr
CTet
CTetis a potent inhibitor of DNA synthesis in both estrogenreceptor positive (MCF-7) and
estrogenreceptor negative (MDA-MB-231) human breast cell lines (IC50 = 1.20 ±0.04 μMand
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. Chem2012

29. 5-Hydroxy Tetraindole Induces G2 Arrest and Apoptosis in Human Breast Cancer CellsH
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 ±0.03μM(MCF-7)0.88±0.04μM
J. Med. Chem. 2012, 55, 1583−1592

30. H
N
H
N
N
H
OHHO
HO
N
H
OH
CHO
CHO
+
H
N
OH
I
2/MeCN
2h,RT,89% 4-Hydroxytetraindolebearinganaromaticcentralcorestructure,waspreparedin
satisfactoryyieldsbyadditionreactionsofterephthalaldehydewithindoleinthepresence
ofcatalyticamountsofmoleculariodineatroomtemperature.
x.doi.org/10.1021/jm2013425 | J. Med. Chem.2012
Easy is
the Best