of 19 /19
Richter D i s c l a i m e r : This lecture will only cover methodology for the construction of the indole and pyrrole ring systems, rather than functionalionalization of pre-existing heterocycles, which would be the topic of another series of lectures. P a r t i a l L i s t o f T r a n s f o r m s D i s c u s s e d : 1. Batcho-Leimgruber Indole Synthesis 2. Reissert Indole Synthesis 3. Hegedus Indole Synthesis 4. Fukuyama Indole Synthesis 5. Sugasawa Indole Synthesis 6. Bischler Indole Synthesis 7. Gassman Indole Synthesis 8. Fischer Indole Synthesis 9. Japp-Klingemann Indole Synthesis 10. Buchwald Indole Synthesis 11. Bucherer Carbazole Synthesis 12. Japp-Maitland Carbazole Synthesis 13. Larock Indole Synthesis 14. Bartoli Indole Synthesis 15. Castro Indole Synthesis 16. Hemetsberger Indole Synthesis 17. Mori-Ban Indole Synthesis 18. Graebe-Ullmann Carbazole Synthesis 19. Madelung Indole Synthesis 20. Nenitzescu Indole Synthesis 21. Piloty Pyrrole Synthesis 22. Barton-Zard Pyrrole Synthesis 23. Huisgen Pyrrole Synthesis 24. Trofimov Pyrrole Synthesis 25. Knorr Pyrrole Synthesis 26. Hantzsch Pyrrole Synthesis 27. Paal-Knorr Pyrrole Synthesis 28. Zav'Yalov Pyrrole Synthesis 29. Wolff Rearrangement I n d o l e : Nature: – The most abundant heterocycle in nature – Found in tryptophan, indole-3-acetic acid (plant growth hormone), serotonin (neurotransmitter), natural products, drugs – Isolated industrially from coal tar – Biosynthesis of tryptophan Reactivity: – Isoelectronic with naphthalene (slightly lower stabilization energy) – Indole has a higher stabilization energy than benzene – Very weakly basic: pK a of protonated indole: –2.4 – Protonation occurs at C–3 preferentially – Easily oxidized (atmospheric oxygen) – very electron rich – Less prone to oxidation of EWG's on the ring – less electron rich – Electrophilic attack occurs at C–3 (site of most electron density) – C–3 is 10 13 times more reactive to electrophilic attack than benzene – C–2 is the second most reactive site on the molecule, but most easily functionalized by directed lithiation – pK a of N–H is 16.7 (20.9 DMSO) – N–1 is the most nucleophilic site on indole – Nucleophilic substitution at benzylic carbons enhanced – Regiospecific functionalization of the carbocycle is difficult without pre-functionalization of the ring (i.e. halogenation) glucose 15 Steps CO 2 H NH 2 anthranilate 3 Steps N H serine tryptophan N H C–3 C–4 C–6 C–2 C–5 C–7 9/1/04 Group Meeting Indole and Pyrrole Synthesis: " " Sundberg, R.J. Indoles. Academic Press Ltd. San Diego: 1996

Manual de Síntesis de Indoles

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Page 1: Manual de Síntesis de Indoles

Richter

Disclaimer:This lecture will only cover methodology for the construction of the indole and pyrrole ring systems, rather than functionalionalization of pre-existing heterocycles, which would be the topic of another series of lectures.

Partial List of Transforms Discussed:

1. Batcho-Leimgruber Indole Synthesis2. Reissert Indole Synthesis3. Hegedus Indole Synthesis4. Fukuyama Indole Synthesis5. Sugasawa Indole Synthesis6. Bischler Indole Synthesis7. Gassman Indole Synthesis8. Fischer Indole Synthesis9. Japp-Klingemann Indole Synthesis10. Buchwald Indole Synthesis11. Bucherer Carbazole Synthesis12. Japp-Maitland Carbazole Synthesis13. Larock Indole Synthesis14. Bartoli Indole Synthesis15. Castro Indole Synthesis16. Hemetsberger Indole Synthesis17. Mori-Ban Indole Synthesis18. Graebe-Ullmann Carbazole Synthesis19. Madelung Indole Synthesis20. Nenitzescu Indole Synthesis21. Piloty Pyrrole Synthesis22. Barton-Zard Pyrrole Synthesis23. Huisgen Pyrrole Synthesis24. Trofimov Pyrrole Synthesis25. Knorr Pyrrole Synthesis26. Hantzsch Pyrrole Synthesis27. Paal-Knorr Pyrrole Synthesis28. Zav'Yalov Pyrrole Synthesis29. Wolff Rearrangement

Indole:

Nature: – The most abundant heterocycle in nature – Found in tryptophan, indole-3-acetic acid (plant growth hormone), serotonin (neurotransmitter), natural products, drugs – Isolated industrially from coal tar – Biosynthesis of tryptophan

Reactivity:

– Isoelectronic with naphthalene (slightly lower stabilization energy) – Indole has a higher stabilization energy than benzene – Very weakly basic: pKa of protonated indole: –2.4 – Protonation occurs at C–3 preferentially – Easily oxidized (atmospheric oxygen) – very electron rich – Less prone to oxidation of EWG's on the ring – less electron rich – Electrophilic attack occurs at C–3 (site of most electron density) – C–3 is 1013 times more reactive to electrophilic attack than benzene – C–2 is the second most reactive site on the molecule, but most easily functionalized by directed lithiation – pKa of N–H is 16.7 (20.9 DMSO) – N–1 is the most nucleophilic site on indole – Nucleophilic substitution at benzylic carbons enhanced – Regiospecific functionalization of the carbocycle is difficult without pre-functionalization of the ring (i.e. halogenation)

glucose15

Steps

CO2H

NH2

anthranilate

3

Steps NH

serine

tryptophan

NH

C–3C–4

C–6C–2

C–5

C–7

9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Sundberg, R.J. Indoles. Academic Press Ltd. San Diego: 1996

Page 2: Manual de Síntesis de Indoles

NH

Sundberg, R.J. Indoles. Academic Press Ltd. San Diego: 1996

1

2

3

4567

8

9

1011 12 N

H

NH

NH

NHN

HNH

NH

NH

NH

NH

NH

NH

NH2

X

NH2

NH2

NH2

NH2

Y

X

O

S

NHCl

NHOH

X

NHNH2 ONH2NH2

Y

X

NH

X

NH

X

NH

R+O

NH O

X

NH

X

O

NH O

O

NH

NH

NH

NH

X

H2N

O

O

NH

R

R

+ + +

+

+

+

+

++

1a 1b

1c

1d

3a

3b

3c3d

8a

8b

8c

9a

9b

9c

13

RingContracton

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Page 3: Manual de Síntesis de Indoles

Disconnection 1a:

Batcho-Leimgruber Indole Synthesis:

– Typical [H] = H2, Pd/C; hydrazine, Raney Ni – Other side products from reductive cyclization include N–O – Yields: 50's – 90's

Variants:

– If R = carbonyl, use KF / 18-c-6 / i-PrOH for the Henry reaction – Use classic Henry conditions otherwise –Typical [H] = Fe, Fe/SiO2 – Yields: 40's – 90's

NO2

MeR

NMe

MeOMe

OMe

NH NO2

RN

RNH

[H]

NO2

MeR

NO2

RNO2

RNH

[H]

CH3NO2

RNO2

HNO3

Disconnection 1a:

– 1: Reduction, then acid – 2: Reduction, then acid – 3: Oxidation, then reduction, then acid Can oxidize the alcohol and not the aniline with Ru(PPh3)2Cl2 Can convert the nitro-alcohol into indole with Pd/C or Rh/C and Ru(PPh3)2Cl2 – 4: Reduction of nitro and cyano (one or two steps), then acid – 5: Wacker oxidation, reduction, then acid – 6: Ozonolysis, reduction, then acid

Reissert Indole Synthesis:

R

ONH2

R

ONO2

OCOR

NO2

R

OHNO2

CN

NO2NO2

R

NO2

1 2

3

45

6

Sundberg, R.J. Indoles. Sundberg, R.J. Indoles; Reissert, A. Ber. 1897, 30, 1030

NO2

Me Base

(CO2Et)2

CO2Et

ONO2

[H]NH

CO2Me

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Page 4: Manual de Síntesis de Indoles

Sundberg, R.J. Indoles.

Disconnection 1b:

Palladium Synthesis:

– X can be either H, Ac, Ms, TFA – The intermediate organopalladium can be intercepted – Yields: 40's – 90's

Disconnection 1c:

– Reductive cyclization mediated by (EtO)3P or PdCl2/PPh3/SnCl2 and CO – Migratory aptitudes unknown – Unknown mechanism – does not involve a nitrene

Disconnection 1d:

Hegedus Indole Synthesis:

– Applied to the total synthesis of rac-aurantioclavine by Hegedus (Hegedus, L.S. J. Org. Chem. 1987, 52, 3319)

– Applied to the total synthesis of arcyriacyanin A by Steglich (Steglich, W. Chem. Eur. J. 1997, 3, 70)

Disconnection 1–Misc.:

Fukuyama Indole Synthesis:

NHX

PdII

NH

R

R

PdII NH

R

R'

NH

R

R'M

H+

NO2

R

NO2

R

R

NH

R

NH

R

R

NH2

PdII, then [H] or

PdII, Cu(OAc)2,benzoquinone

NH

Me

Hegedus, L.S. J. Am. Chem. Soc. 1976, 98, 2674; ibid 1978, 100, 5800; e.g. Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137.

NH

HN

NH

Br I

NTs

Br

NH

NH

HN

O O

NH

R

SnBu3SnH

AIBN NH

R

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Page 5: Manual de Síntesis de Indoles

Sundberg, R.J. Indoles.

Disconnection 2:

Pyrrone Diels-Alder:

– Little regiocontrol observed in most reactions – pyrrole-quinodimethanes are not stable and therefore not amenable for Diels-Alders directly

Disconnection 3a:

Sugasawa Indole Synthesis:

– Requires very strong Lewis Acids so many functionalities are not stable – Choice of second Lewis acid depends on substitution pattern

Bischler Indole Synthesis:

– Not very general: requires HBr (1 eq) and 200+ oC – Mechanism?

Disconnection 3b:

Gassman Indole Synthesis:

– Good regiocontrol observed with ortho or para substitution – ortho/para methoxy substituents failed completely

Disconnection 3c:

– Quite mild, if the O-vinyl derivatives can be synthesized

Gassman, P.G. J. Am. Chem. Soc. 1974, 96, 5495; Sundberg, R.J. Indoles.

NH

O

O

NH

NH2

CN

Cl+

BCl3

ZnCl2, AlCl3or TiCl4

NH2

CN NaBH4

NaOMe NH

NH2

+X

Ar

O

NH

Ar

NHR

R'

1. t-BuOCl2.

3. base

S R''O R

N

SMe

R''

R'

Raney-Ni RN

R''

R'

NAc

OH

NR

O-

NR

OH

H

Z

O

O

O

OMe

NH

O

Li2PdCl4

NH

RR

acid

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Page 6: Manual de Síntesis de Indoles

Sundberg, R.J. Indoles; Buchwald S.L. J. Am. Chem. Soc. 1998, 120, 6621

Disconnection 3d:

Fischer Indole Synthesis:

– Common acids: HCl, H2SO4, PPA, BF3/AcOH, ZnCl2, FeCl3, AlCl3, CoCl2, NiCl2, TsOH – Regioselectivity not great with unsymmetrical ketones – Tolerates a wide range of substitution – Product regioselectivity affected by choice of acid, solvent, temperature

Japp-Klingemann Modification:

Buchwald Modification:

Pharmaceutical Applications of the Fischer Indole Synthesis:

Disconnection 3d:

Bucherer Carbazole Synthesis:

Japp-Maitland Condensation:

Disconnection 3–Misc.:

Larock Indole Synthesis: (Larock, R.C. J. Org. Chem. 1998, 63, 7652)

– Base additives vary by reaction – High functional group tolerance – Bulkier R group placed at C–2 of the indole

Bucherer, H.T. J. Prakt. Chem. 1908, 77, 403; Japp, F.R. ; Maitland, W.J. J. Chem. Soc. 1903, 83, 273

NHNH2 R

OR'

+ acid

NH

R'

RH2O

N2+ R

O+ acid

NH

R'

CO2R''D

CH2R'OR''

O

Br

R

NNH

R'+

1. Pd//BINAP

2. TsOH NH

R'

R

N

N

SO

O

O

OBnO

NH2•MsOHMK-677Merck

T, 1997, 53, 10983

NH

NMe

MeS

O

HN

O

MeImitrex®Glaxo

e.g. Heterocycles, 2000, 53, 665

X

NHNH2

+ NaHSO3

acid NH

Mechanism?

OH NHNH2

0.5 eq

HCl NH

NH

I

R

+R'

R''

Pd(OAc)2

Base NR

R''

R'

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

X=OH, NH2

Page 7: Manual de Síntesis de Indoles

Bartoli, G. Tetrahedron Lett. 1989, 30, 2129; Castro, C.E. J Org. Chem. 1966, 31, 4071

Disconnection 3–Misc.:

Bartoli Indole Synthesis:

– Mechanism? – Only works well with 2-substituted nitrobenzenes

Castro Indole Synthesis:

Disconnection 4:

Hemetsberger Indole Synthesis:

– Formed by condensation of aromatic aldehyde with a-azoester with NaOEt, under very carefully controlled conditions to prevent N2 loss – Yields = 30's – 90's – Unknown mechanism – not a nitrene insertion reaction

Disconnection 5:

Stepwise:

One pot:

Disconnection 6:

Disconnection 7:

NO2R

BrMg

R' R''+

NH

R''

R'

R

NH2

I+

R

NH

RCuOTf

CO2R

N3

CO2RN

NH

CO2RD

N(TMS)2

Br1. Zn2. CuCN, LiCl

3. RCOCl NH

R

NHX

1. 2.2 BuLi

2. RCO2Me NH

R

X = TMS, Boc

N

NH

CHORO2C

Sundberg, R.J. Indoles.

O

HO

N

NH

CHORO2C

TBDMSTf

OH

NHR

O

TsOHNH

R

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

2 eq

Page 8: Manual de Síntesis de Indoles

Disconnection 8a:

Heck Approach:

– Yields = 70's – 90's – Choice of base and protecting group on the nitrogen can affect the yield

More Palladium:

– Can intercept the intermediate organopalladium species – Any organozinc reagent can be used to transmetallate.

Mori-Ban Indole Synthesis:

– Requires stoichiometric nickel – Yields only about 50%.

Disconnection 8b:

More Palladium:

– Works best with an EWG on the olefin

Photochemical:

Disconnection 8c:

Acid Catalyzed Cyclization:

– LA commonly ZnCl2 – Can also use ketals with BF3 or TiCl4

Disconnection 8–Misc.:

Graebe-Ullmann Carbazole Synthesis:

– Mechanism? – Generally problematic and not widely applicable

NH

X

NH

Sundberg, R.J. Indoles; Mori, M.; Ban, Y. Tetrahedron Lett. 1976, 17, 1803.

NR'

XR Pdo

NR'

R

Pdo;

RZnCl

R

NMe

Cl

NMe

(Ph3P)4Ni

NR'

X CO2R

NR'

CO2R

Pd(OAc)2

NH

NH

hn

taut.

NX

NX

LAO R

RX = TFA, alkyl, solfonyl

NPh

NN

D

NH

Sundberg, R.J. Indoles; Graebe, C.; Ullmann, F. Ann. 1896, 291, 16

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Page 9: Manual de Síntesis de Indoles

Disconnection 9a:

Madelung Synthesis:

– Yields = 40's – 90's

Variant of Madelung:

– Where X is a phosphorous, nitrogen, silicon, or oxygen to stabilize a negative charge – If X is phosphorous, then it is an intramolecular Wittig.

Disconnection 9b:

Base/Acid Catalyzed closure:

Disconnection 9c:

McMurray Type Closures:

Disconnection 10:

Diels-Alder:

– Works best when matched

Disconnection 11:

Diels-Alder:

– Works best when matched

Disconnection 12:

Nenitzescu Synthesis:

– Mechanism? – Substitution on the quinone ring is acceptable and predictable – Substitution on the enamine is tolerated, but R' is best as an EWG – Used in the synthesis of LY311727 (Lilly)

Sundberg, R.J. Indoles.

NAr N

Ar

Acid or

Base

Sundberg, R.J. Indoles; Ninetzescu, C.D. Bull. Soc. Chim. Romania. 1929, 11, 37; J. Org. Chem. 1996, 61, 9055

R

NH O

3 BuLiNH

X

NH O

BaseNH

O

RR

NAr N

Ar

TiCl3

Zn

O

O

NH

NH

EDG

EWGEWG

EDG

NH

NH

EWG

EDG

EWG

EDG

O

O NH

R''R

H R'D

NR''

HOR'

R'

NBn

CO2NH2P

MeO

O

OMe

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

R

Page 10: Manual de Síntesis de Indoles

Disconnection 13:

Wolff Rearrrangement:

From Quinolines:

Katritzky, A.R. Handbook of Heterocyclic Chemistry. Pergamon. San Diego, 2000

N

ON2 hn

NO

Ph

NH

CO2H

N+

O-Ph

hn

NH

CHO

Ph

Pyrrole:

Nature: – Very abundant in nature – Found in porphyrins, natural products, drugs – Isolated industrially from coal tar and/or bone oil

Reactivity:

– Protonation occurs at C–2 preferentially – Easily oxidized (atmospheric oxygen) – very electron rich – Quickly colorizes upon exposure to air – Less prone to oxidation of EWG's on the ring – less electron rich – Decomposition and polymerization rapid with acid – Electrophilic attack occurs at C–2 (site of most electron density) – C–3 is the second most reactive site on the molecule – pKa of N–H is 23 (DMSO) – N–1 is the most nucleophilic site on pyrrole

NH

C–3

C–2

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Mass, G. Science of Synthesis. Thieme. New York: 2001

Page 11: Manual de Síntesis de Indoles

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

NH

RingContraction

RingExpansion

12

3

4

5

67

891011

12

13

14

15

1617 18

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Page 12: Manual de Síntesis de Indoles

Mass, G. Science of Synthesis. Thieme. New York: 2001

Disconnection 1:

Palladium with Alkenes:

– Exists mainly in the tautomeric form

Palladium with Alkynes:

Disconnection 2:

Disconnection 3:

Disconnection 3:

Piloty Synthesis:

– Mechanism?

Disconnection 4:

Thermal Cyclization:

Carbene Insertion:

Disconnection 5:

Rhodium:

N OR

PdCl2

NH

OH

NCbz

NCbz

Pd/C

TEA, MeOH

Ts NC

Ph

CO2Et

CN+ NaOEt

NH

CNPh

Ph

Ph

O O Ph

PhHO+

NH4OAc

AcOH NH

PhPh

PhPh

O

H2NNH2

CoI2, D NH

MeMe

EtEt

N3

CO2EtNH

CO2EtD

R'

O

R

NHR'''

R''1. TMSCLiN2

2. MnO2 NR'''

R'R

R''

PhNH2

H2, CO

[Rh], PPh3 NH

Ph

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Page 13: Manual de Síntesis de Indoles

Mass, G. Science of Synthesis. Ferriera, V. Org. Prep. Proceed. Int. 2001, 33, 411; Katritzky, A.R. Handbook of Heterocyclic Chemistry, 2nd ed. Pergamon. San Diego: 2000

Disconnection 5 Continued:

Iron:

Niobium:

2-Aminopyrroles:

From Cyclopropenes:

Disconnection 6:

Barton-Zard Pyrrole Synthesis:

– Original Barton-Zard used NO2 as the LG.

Bis-Nucleophile/Bis-Electrophile:

Extrusion (Huisgen Pyrrole Synthesis):

– X is usually S or NR

Disconnection 7:

Knorr Pyrrole Synthesis:

Trofimov Pyrrole Synthesis:

NPh

Ph

NH

Ph

MeMe

Fe2(CO)9

MeLi; tBuBr

NR

Ph

NbCl3RHN O

PhOMe

Ph

NbO

Ph

OMe

NR

ONbPh

Me

NR

PhMe

PhPh

R''

R'N

R R'''NC

D NR

NHR'''

R''R'

Ar

ClN

RR'+

hn

or D NR

Ar

R'

RR'

LGCN CO2R''

+

+base

NR

CO2R''

RR'

Ph

OO

Ph

EtO2C NPh

CN+ KOtBu

NPh

CN

PhPh

N+

XPh

-ODMAD

NPh

MeO2CCO2Me

R NH2

R' O

O R'''

R''

O

+

NH

R'''

COR''R'

R

NOH NH

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Base

Page 14: Manual de Síntesis de Indoles

Mass, G. Science of Synthesis. Ferriera, V. Org. Prep. Proceed. Int. 2001, 33, 411; Katritzky, A.R. Handbook of Heterocyclic Chemistry, 2nd ed. Pergamon. San Diego: 2000

Disconnection 7 Continued:

Hantzsch Pyrrole Synthesis:

Formal 3+2:

Stepwise:

Ugi Approach:

Disconnection 8:

Paal-Knorr Pyrrole Synthesis:

– Can access the diketone in-situ by reduction of the bis-cyano compound – Can access via reduction of the g-nitro ketone

Palladium:

Zav'Yalov Pyrrole Synthesis:

+

+

+

R

OBr

H2N R

R''

NH

R'

R''

R

NBn

NO2

R D

NBn

R

R NNMe2

R IO

O 1. Base2. Acid

3. H2, Ni NHR

R

O

Ph

NH3Cl

HO2C CN

NC

RCHO

NO

NC O Ph

RO

HN

NMeO

NCPh

RCONCy

CH2N2

R'

OR''

O

RNH2+

NRR'

R''

PdCl2, Cu(OAc)2;

AgBF4, PPh3, BnNH2 NBn

O

OAc Pd(PPh3)4

BnNH2 NBn

R'R

O

NMe2

NH2HO2C

R''+

R'R

O

NH

CO2HR''

Ac2O

TEA NAc

R'R

R''

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Page 15: Manual de Síntesis de Indoles

Mass, G. Science of Synthesis. Ferriera, V. Org. Prep. Proceed. Int. 2001, 33, 411; Katritzky, A.R. Handbook of Heterocyclic Chemistry, 2nd ed. Pergamon. San Diego: 2000

Disconnection 9:

Wolff Rearrangement/Photolytic:

Reductive Ring Contractions:

Disconnection 10:

Base Catalyzed:

McMurray Type Coupling:

Disconnection 11:

Disconnection 12:

Allenes:

Rhodium:

Cobalt:

N

N2

O NH

CO2H

N+

O-N3

hn

hn

NH

CN

N

N ClAr

CO2Et NHMeO2C

CO2Et

Zn

HOAc

NN

CO2Me

MeO2C

MeOZn

HOAc NHMeO2C

OMe

CO2Me

N

R

ClKOtBu

NH

R

R

O

R'

NHR''

O

TiCl3

Zn NH

R'R''

R

R

O

R'

NHR''

H CO2Et

N2+ Cu(acac)2

NR''

R'EtO2C

R

• CO2MeTsN

Ph1. PPh32. DDQ

3. NaOMe NH

Ph

CO2Me

CN CO2EtR

O

R'R''

O

+

+ Rh2(CO)12

NH

CO2Et

R''R'

R

PhOH

R1. Co2(CO)62. BF3•OEt2

3.( )n

HNMeO2C

Me

PhN

R

( )n

CO2Me

LDA, DDQ

n=1n=2

NH

RPh

MeO2CNH

R

BnMeO2C

1. BuLi;

2. BuLi;NBn

NN Br OMe

OMe

Ph NPh NPh

Ph

PhNHPh

Ph

Ph

OMeOMe

Btacid

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Page 16: Manual de Síntesis de Indoles

Mass, G. Science of Synthesis. Ferriera, V. Org. Prep. Proceed. Int. 2001, 33, 411; Katritzky, A.R. Handbook of Heterocyclic Chemistry, 2nd ed. Pergamon. San Diego: 2000

Disconnection 13:

Disconnection 14:

Disconnection 15:

Palladium:

Titanium:

Zirconium:

Disconnection 16:

Disconnection 17:

Disconnection 18:

From Cyclopropanes:

From Cyclobutanes:

Ph O

H CO2MeCN

CO2MeCN+ DBU

NH

CO2Me

PhMeO2C

RNH2

OR'

EtNO2 SmCl3

R'NR

R'

NR

MeR'

R'

Ph Ph

TMSCN

PdCl2

or NiCl2+

NH

N(TMS)2

PhPh

NC

R R'Ti(OiPr)4

2 iPrMgClTi(OiPr)2

R

R'

R'' NR'''

CONR'''

R''

R'R

LiNPh

TMSCp2(Me)ZrCl

Cp2ZrNTMS

Ph Ph

CO NH

PhPh

RCHO

R'NH2 R''CO2H

PhNC

YXN+

OR''O-

RR' N

R'

R

XY

R''

R''1. BuLi

2.

R

OBr

R'' O

R

R'NH2

NR'

R

R''

CO2MeN

Phhn

NR'

MeO2C

Ph

NR

BzO SPh

PhS

AlEt2Cl

NR

SPh

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Page 17: Manual de Síntesis de Indoles

Selected Syntheses:

Strychnine: Woodward (Classics I)

Strychnine: Overman (Classics I)

N

O

N

OH

H

H

H

NHNH2

OOMe

OMe

PPA

NH

OMe

OMe

Fischer Indole Synthesis

N

O

N

OH

H

H

H

NHMeO2C

N

H

OH

MeO2C

N

H

OH

NH2HO

Disconnection 1a

Selected Syntheses:

Isochrysohermidin: Boger (Classics II)

Aspidophytine: Corey (Classics II)

NMe

NMe

O

O

MeO

MeO

OH

MeO2C

CO2Me

HO

N N

NN

MeOMeO

CO2MeCO2Me

MeO2C

MeO2C

NH

NH

CO2Me

CO2Me

MeO

MeO

MeO2C

CO2Me

Disconnection 9

NMe

N

H

O O

MeO

MeO

MeOOMe

NO2

NO2 Fe, AcOHsilica gel

NHMeO

OMeBatcho-Leimgruber Indole Synthesis Variant

Syntheses were only included if they synthesized the indole or pyrrole

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Page 18: Manual de Síntesis de Indoles

Selected Syntheses:

Vinblastine: Fukuyama (Classics II)

Mitosene: Rebek (J. Org. Chem. 1984, 49, 5164)

Selected Syntheses:

Lipitor®: Pfizer (Li, J.J. Contemporary Drug Synthesis. Wiley. 2004)

MsO NH

THPO

S

CO2Bn

CO2Bn

nBu3SnH

AIBNNHMsO CO2Bn

CO2Bn

OTHP

NH

N

NMe

N

CO2Me

OHOAc

H

HMeOMeO2C

OH

H

Fukuyama Indole Synthesis

N

NHO

-O2COH

OHF

N

OHO2C

F

OO

CONHPh

Ac2O

N

F

OO

CONHPh

Huisgen Pyrrole Synthesis

CONHPhO

OF

N

F

OEtEtO

CONHPh

H2N OEt

OEt

Paal-Knorr Pyrrole Synthesis

N

OCONH2

OMe

NH2O

OH2N

O

N+

O-

OAc

MeO2C DMADN

CO2Me

OAc

MeO2CMeO2C

Huisgen Pyrrole Synthesis

Syntheses were only included if they synthesized the indole or pyrrole

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Page 19: Manual de Síntesis de Indoles

Selected Syntheses:

Axert®: Janssen (Li, J.J. Contemporary Drug Synthesis. Wiley. 2004)

Hapalindole G: Fukuyama (J. Am. Chem. Soc. 1994, 116, 3125)

Disconnection 8a

NH

SN

OO

NH2

SN

OOI

N

O CF3

CO2Me

Pd(OAc)2

Bu4NBrTEA N

H

SN

OO

CO2Me

Syntheses were only included if they synthesized the indole or pyrrole

NH

NCHH

H

Cl

H

Cl

O

S

LiOMeMe

O

1.

2. HgCl2, HClO4NAlloc

H

H

Cl

O

NHAlloc Disconnection 1a

Richter 9/1/04 Group MeetingIndole and Pyrrole Synthesis: " "

Selected Syntheses:

Ketorolac®: Syntex (Muchowski, Adv. Med. Chem. 1992, 1, 109) – 1st Generation strategies utilize pyrrole syntheses – Process synthesis uses annulation starting from pyrrole

O

NCO2HH

NH

CO2Me

CO2MeHO

OBr

NCO2Me

CO2Me

HO

Hantzsch Pyrrole Synthesis

OMeO OMe

H2NOH

AcOHN

HO

Paal-Knorr Pyrrole Synthesis