Indoles in Organic Synthesis: Something Old, Something New ... · Something Old, Something New, Something Heterocyclic, Something Blue Antoinette E. Nibbs Long Literature Presentation

Indoles in Organic Synthesis:Something Old, Something New,

Something Heterocyclic, Something Blue

Antoinette E. NibbsLong Literature Presentation

3-March-2008

Indoles in Organic Synthesis

Synthesis of Substituted Indoles

Old School (earth, fire, wind, water, and heart)

New School (transition metal-catalyzed chemistry)

Synthesis of Indole-Containing Natural and Commercial Products

Sumatriptan

Indomethacin

CDEF Parent Tetracycle of Nudolisporic Acids A and B

Fuchsiaefoline

Aspidophytine

Indole

N

H

N lone pair

Not basic; pKa 16.0 in H2O(21.0 in DMSO)

N

O

H

N

O

H

indigotin

Indole = indigo + oleumNH

indole

2

34

5

6

7

NH

2

3

5

7

NH

NH

Electrophilic Aromatic Substitution

NCS

NH

Cl

NH

Cl

NH

H2O

OH

H

-HClO

oxindole

Indoles in Nature

Indole structure found in many organic compoundstryptophan and its derivativesproteinsalkaloidspigments

tryptophan

H2N CO2H

HN

seratoninneurotransmitter

melatoninregulation of circadian rhythm

psilocybinhallucinogen

indomethacinNSAID

NH

HO NH2

NH

MeO HN

Me

ONH

MeO OH

Me

O

NH

NHMe2

PHO O

OO

NH

indole

Bond Disconnections

NH

NH

NH

NH

NH

NH

NH

NH

indole

FischerBartoli

LiebeskindMori-Ban

MadelungFukuyama

HegedusVanderwal

HemetsburgerNeber

Nenitzescu

RiessertBatcho-Leimbruger

Bischler-MuhlauSugasawaGassmanCastroLarock

Fischer Indole Synthesis

Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16, 2241.NH

NH

NH2R1

R2

O

NH

N

R1

R2

H+

NH

R1

R2

+

–NH3

aldehydes afford

3-substituted indoles

NH

N

R1

R2

NH

NH2

R1

R2

[3,3]

NHNH2

R1

R2

NH2NH2

R1

R2

NH2

R1

R2

NH2+H+NH

R1

R2

NH3

H

NH

R1

R2–H+–NH3

Mechanism:

+H+

–H+ H

Japp-Klingemann Synthesis

Japp, F. R.; Klingemann, F. Ber. 1887 20, 2942, 3284, 3398.NH

N2

R1 R3

O O

R2

NH

R2

COR3Cl

KOH

EtOH

works for compounds

with acidic H between

two or three EWGs

ArN2

R1 R3

O O

R2

R1 R3

O O

R2

N

NPh

OH

R1 R3

O O

R2

N

NPh

HO

R3

O

R2

NNH

Ph

Mechanism:

NH

N

COR3

R2

NH

R2

COR3

Cl

mixed 1,3-diketones

fragment differently

alkali metal salts of B-keto acids (R3 =OM) decarboxylate

Bartoli Indole Synthesis

Bartoli, G.; Leardini, R.; Medici, A.; Rosini, D. J. Chem. Soc., Perkin Trans. 1 1978, 892.NH

MgBr

R1

NO

R1

NO

OMgBr R1

NO

R

NO

MgBr

[3,3]

R

N

MgBr

O

O

MgBr

N

R1

OMgBr

H

R2

R3

R2

R3R2

R3

R2

R3

R2

R3H

R3

R2NH

R1

R2

R3

3 equiv of Grignard necessary for nitroarenes

substitution ortho to thenitro group is necessary

Mechanism:

R1

NO2

MgBr

NH

R1

1.

2. H2O

R2

R3R2

R3

Liebeskind Synthesis

Zhang, D.; Liebeskind, L. J. Org. Chem. 1996, 61, 2594-2595.

quench with pro-chiralcarbonyl compounds

NH

Cl

Cl

Cl

Cl

O

O

N

MeO

Me

H

H

Cl

Cl

Cl

Cl

OH

O

N

MeO

Me

H

H

Mechanism:

N

MeO

Me

H

o-chloranil

unintentional cyclolithiation

MeO Br

N

2 equiv t-BuLi

TBME, –78 °C to rt N

MeOLi

1. H2O

N

MeO Me

2. o-chloroanil TBME, rt

82%

C2-C3 Bond Disconnection

NH

Tokuyama, H.; Kaburagi,Y.; Chen, X.; Fukuyama, T. J. Am. Chem. Soc. 1999, 121, 3791-3792.

Madelung Indole SynthesisR3

NR1

O

R2

NaNH2 or NaOR

NR1

R2

R3

Madelung, W. Ber. Dtsch. Chem. Ges. 1912, 45, 1128.

harsh reaction conditions limited scope

Fukuyama Indole Synthesis

N

NH

I

1. nBu3SnH, AIBN MeCN, 80 °C

2. I2, rt

CO2MeCO2Me

OMe

MeOOMe

MeO N

N

MeO

OMe

H

O O

aspidophytine

Me

also applied tovinblastine and

strychnine

C

Hemetsberger Indole Synthesis

Hemetsberger, H.; Knittel, D. Monatsh. Chem. 1972, 103, 194.NH

azirine intermediates isolated

CO2R

N

N3

CO2R H+

NH

CO2R

!

generally high yielding, but

not a popular reaction

N

CO2R

Mechanism:

N

N

NH

CO2R

N

N

H+

! NH

CO2R-N2

!H

NH

CO2R

Neber Route

Taber, D.; Tian, W. J. Am. Chem. Soc. 2005, 128, 1058-1059.NH

N3

CO2Et CO2Et

NNH

CO2Et

!!

Neber Rearrangement

PhMe

NOTs

EtOK/EtOHPh

Me

NOTs

PhMe

N

H2OPh

Me

NH2

O

Mechanism:

CO2Et

N

CO2Et

N

N

-N2

N

CO2Et

N N

CO2Et

NH

CO2Et

H

varying temperature for

rearrangement

varying azirine stability

4! ERC

Reissert Indole Synthesis

Reissert, A. Ber. 1897, 30, 1030.NH

Me

NO2

1. (CO2Et)2, NaOEt

2. Zn, AcOHNH

CO2H

Me

NO2

EtOOEt

O

O

NaOEt NO2

O CO2Et

Zn, AcOHAcOH

NH

CO2H

Mechanism:

NO2

O CO2H

Batcho-Leimgruber Indole Synthesis

Batcho, A.D.; Leimgruber, W. United States Patent 3,732,245; 1973.NH

Me

NO22. Pd/C, H2

N

Me Me

MeO OMe

HN

NH

1.

, !

other reducing agents: SnCl2, NaS2O4, Fe in AcOH, Raney Ni

N

Mechanism:

HN

N

MeO OMe

N

MeO OMe

Me Me Me

NO2NO2

N

NH2

NH

Pd/C, H2

Bischler Procedure

Mohlau, R. Ber. Dtsch. Chem. Ges. 1881, 14, 171.

excess aniline needed

NH

NH2X

O

R

HX

NH

Ar

!

X = Cl, Br, I

X

O

RNH

O

R

H2NNH

R

N

N

R

H

N

R

NH

R

NH2

Mechanism:

-H+/+H+

PhNH2

R

N

Ph

Gassman Indole Synthesis

NH

Gassman, P.G.; van Bergen, T.J.; Gilbert, D.P.; Cue, B.W. J. Am. Chem. Soc. 1974, 96, 5495, 5508, 5512.

one-pot procedure

NHR1

1. R2OCl

2.

3. base4. Raney Ni, H2

MeS

O

R2

NR1

R2

NHR1

t-BuOCl

N

R1

Cl

MeSR2

O

N

R1

SMe

O

R2H

N

R1

SMe

O

R2

Mechanism:

[2,3]

N

R1

O

R2

H

NH

R1

O

R2

N

R2

OH

R1

H

N

R2

R1

electron rich anilines

tend to fail

Sugasawa Procedure

NH Sugasawa, T.; Adachi, M.; Sasakura, K.; Kitagawa, A. J. Org. Chem. 1978, 44, 578-586.

Mechanism:

NH2

Cl

CN BCl3

Cl

N

NH

NBCl2

Cl

NH2

NBCl2

Cl

H

NH

NBCl2

BHCl2

NaBH4

NH

NBCl2

HNH

electron poor anilines

do not undergo

acetylation

NH2Cl

CN 1. BCl3

2. NaBH4

NH

Nenitzescu Synthesis

Nenitzescu, C.D. Bull. Soc. Chim. Romania 1929, 11, 37.NH

O

O

R3

R2R1HN

+

HO

O

R3

NR1

R2

H

NR1

R3

R2

HO

Mechanism:

Michael addition

OH

H

NR1

R3

R2

HO

regioselectiive reaction

O

O

R3

R2R1HN NR1

HO

R3

R2+

!

solvent

solvent = acetone, EtOH, MeNO2, AcOH, CHCl3mono-, di-, or tri-substituted

regioselectiive reaction

Cycloaddition Procedure

Dunetz, J.; Danheiser, R. J. Am. Chem. Soc. 2005, 127, 5776-5777.

R1N

R2

Me [4+2]

NR1

Me

R2

NR1

Me

R2

Mechanism:

HNR1

1. , CuI, PdCl2(PPh3)2, THF-piperidine

2. KHMDS, CI, pyr

Br R2

Br

Me

R1N

R2

Me

toluene, BHT

NR1

R2

Me

R1 = Ts, Tf, CO2MeR2 = H, TMS, ,SiMe3 CH2OTIPS

40-74%

NR1

R2

Me

110-210 °C

o-chloranil, benzene

41-88%

Me

t-But-Bu

OH

BHT

Synthesis of Nitrogen Heterocycles by the RingOpening of Pyridinium Salts

Kearny, A.; Vanderwal, C. Angew. Chem. Int. Ed. 2006, 45, 7803-7806.NH

NH2N

BrCN, EtOH, 45 °C, 20-60 min

then aq. NH4Cl, 1-3 h NH

O

63-80%

NH2N

N-cyanoimineCN

NH

N

CN NH

N

CN

BrCN aq. NH4Cl

Br

6! ERO

Transition Metals in the Synthesis of Indoles

NH

NH

Mori, M.; Chiba, K.; Ban, Y. Tetrahedron Lett. 1977, 18, 1037.

discovered independently by Hegedus, Mori, and HeckLiebeskind synthesis is similar

Hegedus, L.S.; Allen, G.F.; Waterman, E.L. J. Am. Chem. Soc. 1976, 98, 2674.

PdII

NH2

PdCl2

Et3N

NPdCl2

NEt3

NH

PdCl2NEt3

-HCl•Et3N-PdHCl

H H

HH

Mori-Ban Indole Synthesis

X

NH

cat. Pd(OAc)2, PPh3

NH

TMEDA, !

CO2Me CO2Me

X = Br or I

Hegedus Indole Synthesis

NH2

cat. PdCl2(MeCN)2, Et3N, THF

NH

Me

Transition Metals and Acetylides

NH

Larock, R.C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.

Castro, C.E.; Gaughan, E. J.; Owsley, D.C. J. Org. Chem., 1966, 31, 4071.

I

NHR1

R2

cat. CuI

NR1

R2

Castro Indole Synthesis

DMF, 120 °C

17-90%

"general and competitive with the Fischer synthesis as a route to 2-substituted indoles"

LiCl gave better results

regioselective annulation

Larock Indole Synthesis

I

NHR1

R2 R3

cat. Pd(OAc)2, PPh3, n-Bu4Cl or LiCl, base

NR1

R3

R2

DMF, 100 °C

A General Synthesis of Substituted Indoles fromCyclic Enol Ethers and Enol Lactones

one-pot synthesisuses commercially available starting materials

regioselective synthesis of 2,3-disubstituted indolesapplications to synthesis of commercial drugs

NH

“Among the diverse and creative approaches that have been discovered, the Fischerindole reaction remains the benchmark to which other methods are compared.”

NH

NH2• HCl

OR2

( )n

4% H2SO4(aq) / co-solvent, 100 °CNH

R2

OH

( )n

X = H2 or OR2 = H, alkyl

60-95%

X

X

Campos, K.; Woo, J.; Lee, S.; Tillyer, R. Org. Lett. 2003, 6, 79-82.

General Mechanism

NH

Campos, K.; Woo, J.; Lee, S.; Tillyer, R. Org. Lett. 2003, 6, 79-82.

NH

NH2• HCl

4% H2SO4(aq) / DMAc, 100 °C NH

R2

O

X X

60-90%X = Me, Br, Cl, F, OMe, CO2H

1

3

5

1

3

OH5

OO

NH

NX

OH

5

1

3

NH

NHX

OH

5

1

3

[3,3]

NHNH

X

OH

5

1

3

generation of the hydrazone in situ and [3,3] rearrangement in the same pot

Me N

Me

Me

O

DMAc

Application to Synthesis of Commercial Drugs

NH Campos, K.; Woo, J.; Lee, S.; Tillyer, R. Org. Lett. 2003, 6, 79-82.

Indomethacin – Merck anti-inflammatory drug

MeO

NNH2

O

Cl

OMeO

MeCN, reflux1 equiv H2SO4

65%

N

MeO

Me

CO2H

O

Cl

NH

SO2NHMe

NH

NH2

SO2NHMe

• HCl

O

4% H2SO4 (aq) MeCN

NH

SO2NHMe1. MsCl, Et3N

2. NaI, DIPEA, HNMe2

45% unoptimizeddocumented difficulty

with hydrazine

HO Me2N

Sumatriptan - GSK anti-migraine drug

A New Modular Indole Synthesis. Construction ofthe Highly Strained CDEF Parent Tetracycle of

Nodolisporic Acids A and B

N

O

MeMe

MeMe

HO

Me Me

OHMe

O

OHHMe

XMe

A

B C

D

EF

X = O; (+)-Nodulisporic Acid AX = H2; (+)-Nodulisporic Acid B

2'

18

19

24

Smith, A.B III, Kürti, L.; Davulcu, A. Org. Lett. 2006, 8, 2167-2170.

Elaboration of the CDE Tricycle

NH

Ph

PhOMe

MeO

1. (COCl)2, benzene, rt, 45 min

2. pyridine, benzene, rt, 24h (84% over two steps)

N

Ph

PhOMe

MeO

O O

Black, D.S.C.; Bowher, M.C.; Catalano, M.M.; Ivory, A.J.; Keller, P.A.; Kumar, N.; Nugent, S.J. Tetrahedron, 1994, 50, 10497-10508.

N

X

NN

X

Xdifficulty in tautomerizing

hydrazone to ene-hydrazine


NN

O

AcOH/conc. HCl

reflux, 1h(89%)

N

O

van Winjgaarden, I.; Hamminga, D.; van Hes, R.; Standaar, P.J.; Tipker, J.; Tulp, M.T.M.; Mol, F.; Olivier, B.; de Jonge, A. J. Med. Chem., 1993, 36, 3693-3699.

Alternative Protocols

NH

R

R

O

N2

metal carbene N-H insertion

N

Br

intramolecular Heck carbonylation

N

CO2Me CO2Me

Dieckmann condensationX X

XSmith, A.B III, Kürti, L.; Davulcu, A. Org. Lett. 2006, 8, 2167-2170.

Inherent ring strain of CDE tricyclic core!

transition metal catalyzed approach

NH

R

R

O

Br

intramolecular nucleophilic displacementX

Retrosynthetic Analysis


Buchwald-Hartwig

Coupling

NHOTf

Enol Triflate

Formation

NHO

SnBu3

NBoc

O

I

+

Stille Coupling

N

O

MeMe

MeMe

HO

Me Me

OHMe

O

OHHMe

XMe

A

B C

D

E

F

X = O; (+)-Nodulisporic Acid AX = H2; (+)-Nodulisporic Acid B

N

C

D

E

F

Stille Cross-Coupling/Buchwald-HartwigUnion/Cyclization Tactic


Pd-catalyzed intramolecular C-Nbond forming reaction between anenol triflate and a secondary amine

L-Selectride/THF

NBoc

O

( )n

1. HCl/MeOH

2. C6H6, reflux

N

n = 2

NBoc

OTf

LiHMDS/THF

then Comins'reagent

conditions

L-Selectride/THF, –78 °C

then Comins' reagent

NBoc

OTf

( )n

N

Cl

N

SO2CF3

SO2CF3

Comin's reagent

O

PPh2 PPh2

MeMe

Xantphos

SnBu3

NBoc

cat. Pd2(dba)3•CHCl3, P(2-furyl)3, CuI, NMP, 100-120 °C

I

O

NBoc

O

( )n n = 1 or 2

( )n

1. TMSI/CH2Cl2 –78 °C2. cat. Pd2(dba)3, xantphos, Cs2CO3, THF, reflux

n = 2

Total Synthesis of the 12-Alkoxy-SubstitutedIndole Alkaloid Fuchsiaefoline

NH

isolated from species of Rauwolfia, which are used in traditional Chinese medicinefirst synthesis of an optically pure 7-alkoxy-tryptophan

NN

Me

H

MeO

Me

H CO2EtMe

Cl

(–)-fuchsiaefoline

H

Zhou, H.; Liao, X.; Cook, J. Org. Lett. 2004, 6, 249-252.



NN

Me

H

MeO

Me

H CO2Et

Me

Cl


H

NN

Me

H

MeO

Me

H CHO

oxidation H

NN

Me

H

MeO

Me

OWittig H

NMeO

Me

NBn

O

H

H

Pd-catalyzed Cross Coupling

I Me

Br

NMeO

Me

NBn

CO2Et

CO2Me

Dieckmann

NMeO

Me

NBn

CO2Et

CO2Me

Pictet-Spengler

N

OMe

NH2

CO2Et

Me

H

O

OMe

O

Larock

HeteroannulationI

NH2

OMe

N

N

EtO

OEt

Me

Me

SET

Synthesis of Tricyclic Indole


I

NH2

OMe

N

N

EtO

OEt

Me

Me

TES

Larock Heteroannulation with Schöllkopf-based chiral auxiliary

Pd(OAc)2, K2CO3, LiCl, DMF, 100 °C

(75%)

OMe

NH

TES

N

N

EtO

OEt

Me

Me

OMe

NH

N

N

EtO OEt

Me

Me

(1:15)

N

OMe

NH2

CO2Et

Me

NaH, MeI, DMF;2N HCl, THF, 0 °C to rt

(90%)

1. PhCHO, EtOH, Na2SO4, 0 °C; NaBH4, –5 °C (90%)

2a.

HOAc, CH2Cl2, 0° C to rt

N

OMe

NBn

CO2Et

Me

CO2Me

N

OMe

NHBn

CO2Et

Me

H

CO2Me

Pictet-Spengler

H CO2Me

O

N

OMeMe

NBn

CO2Et

CO2Me

2b. 1% TFA/CH2Cl2, rt, 7d

(92%)N

OMeMe

NBn

CO2Et

CO2Me

cis/trans 1:2

Synthesis of Fused Core


N

OMeMe

NBn

CO2Et

CO2Me

NaH, MeOH, toluene, !

33% KOH, dioxane, !(80%) NMeO

Me

NBn

O

H

H

NMeO

Me

N

O

H

H

1. 10% Pd/C, EtOH/HCl(92%)

2.

K2CO3,THF, !, 24h (90%)

MeI

Br

I

Me

cat. Pd(OAc)2, PPh3, Bu4NBr, K2CO3

NN

H

Me

H

MeO

Me

O

DMF/H2O (9:1), 65 °C, 12h (80%)

NN

H

Me

H

MeO

Me

O

PdLn

NN

H

Me

H

MeO

Me

O

LnPd

I

I

Functional Group Conversion


NN

Me

H

MeO

Me

HO

MeOCH2PPh3Cl, KOtBu, benzene, rt;

2N HCl/THF, 55 °C(90%)

NN

Me

H

MeO

Me

H CHO

H

KOH, I2, EtOH

(85%) NN

Me

H

MeO

Me

HH

O

OEtH

NN

Me

H

MeO

Me

HH

O

OEtH

II

I2

MeI/THF, 0 °C; AgCl, EtOH, rtN

N

Me

H

MeO

Me

H CO2EtMe

Cl


H

(81%)N

N

Me

H

MeO

Me

H CO2Et

H

Enantioselective Total Synthesis of Aspidophytine

He, F.; Bo, Y; Altom, J.; Corey, E.J. J. Am. Chem. Soc. 1999, 121, 6771-6772.

N

N

MeO

OMe

H

O O

Aspidophytine

Me

N

N

MeO

OMe

H

O O

Haplophytine

Me

N

Me

O

NO

HO



N

N

MeO

OMe

H

O O

aspidophytine

MeN

N

MeO

OMe

H

OO

Me

O

Carbonyl Deletion

Oxidative Cleavage

N

N

MeO

OMe

H

OO

Me

N

N

MeO

OMe

H

iPr-OO

Me

Oxidative

Lactonization

NMeO

OMe Me

NH2 OHC

CHO

Me3Si

O

OR

Pictet-Spengler of Dihydropyridinium

MeO

OMe

NO2

NO2

Reductive Cyclization

Fragment A: Substituted Tryptamine Synthesis


OMe

MeO NH

Mechanism:

H N

O

Me

MePOCl3

H N

Me

Me

OPOCl2Cl

H N

Me

Me

Cl

Vilsmaeyer Reagent

H N

Me

Me

Cl

OMe

MeO NH

NMe2

H

OMe

MeO NH

NMe2

H

-NMe2

OMe

MeO NH

CHO

OMe

MeO NO2

NO2 1. Fe, HOAc, silica gel, toluene, ! (71%)

2. MeI, KOH, Bu4NI, THF, 23 °C (94%)

OMe

MeO N

1. POCl3, DMF, 35 °C; then aq. NaOH, ! (99%)

2. CH3NO2, NH4OAc, ! (92%)

OMe

MeO N

NO2

LAH, THF, !

OMe

MeO N

NH2

(88%)

Me

MeMe

Fragment B: Chiral Dialdehyde Synthesis


MeO

Br

O

1. Na(Hg), MeOH (82%)2. Ac2O, Et3N, DMAP, CH2Cl2 (97%)

H

TMS

OAc1. LDA, TBSCl2. EDCl, iPrOH, DMAP (57% for two steps)

TMS

O

iPr-O

Ireland-Claisen2. NaIO4, THF–H2O (98%)

CHO CHO

TMS

O

iPr-O

1. OsO4, NMO, acetone–H2O (57%)

Br

TMS

OH

ON B

Ph

Ph

O

Br

R

B

Me

H

O

O

(94% yield, 97% ee)

CBS [H]Br

OTMS

BrMg

CeCl3, THF,

then H+ (82%) TMS

1,2 addition, followed by carbonyl transposition

Fragment Coupling


CHOCHO

TMS

O

iPr-O

NMeO

OMe

NH2

Me

MeCN, 23 °C;TFAA, 0 °C;NaBH3CN

NMeO

OMe

N

TMS

O

O-iPr

Me

NMeO

OMe Me

N

O

O-iPrH

TMS

Pictet-Spengler

(66%)

NMeO

OMeMe

N

H

O

O-iPrH

NaBH3CN

NMeO

OMeMe

N

H

O

O-iPrH

NMeO

OMeMe

N

H

O

O-iPrH

Aza-PrinsH+

Functional Group Conversion


NMeO

OMeMe

N

H

O

O-iPrH

1. NaOH, EtOH, 75 °C (88%)

2. K3Fe(CN)6, NaHCO3, t-BuOH–H2O (92%)

NMeO

OMe Me

N

H

O O

oxidative lactonization

1. OsO4, DMAP, tBuOH/H2O, then NaSO3

2. Pb(OAc)4, AcOH, CH2Cl2 (54% over two steps)

NMeO

OMe Me

N

H

OOO

N

N

MeO

OMe

H

O O

aspidophytine

Me

1. KHMDS, THF, –78 °C, then PhNTf2 (54%)

2. Pd(PPh3)4, Bu3SnH, THF, 23 °C (86%)

Just a Few Ways…

NH

NH

NH

NH

NH

NH

NH

NH

indole

FischerBartoli

LiebeskindMori-Ban

MadelungFukuyama

HegedusVanderwal

HemetsburgerNeber

Nenitzescu

RiessertBatcho-Leimbruger

Bischler-MuhlauSugasawaGassmanCastroLarock

Documents

Indoles in Organic Synthesis: Something Old, Something New ... · Something Old, Something New, Something Heterocyclic, Something Blue Antoinette E. Nibbs Long Literature Presentation