Heterocyclic Chemistry 5th Edition 2010

All Answers to Exercises

Chapter 8
OEt ch8 1(i) N f. HNO3, c. H2SO4 100 C N OEt NO2 Electrophilic substitution ortho to EtO

Me Br2, c. H2SO4 oleum ch8 1(ii) N

Me Br N KMnO4, heat

CO2H Br N Electrophilic !substitution then side-chain oxidation

KHN(CH2)2NMe2 heat ch8 2 N N NH(CH2)2NMe2 Chichibabin reaction (!-substitution)

N2H4 ch8 3(i)(a) N Cl N NHNH2 Nucleophilic displacement of an !-chlorine

H2O ch8 3(i)(b) N Cl N OH N H O

Nucleophilic displacement of an !-chlorine then tautomerism to 2-pyridone

NO2 H2O, 60 C ch8 3(ii) N

OH

N H

Nucleophilic displacement of a !-nitro then tautomerism to 4-pyridone

Cl NaOMe ch8 4 N

OMe MeI N

OMe 185 C + N Me I

N Me

Nucleophilic displacement of a !-chlorine then quaternisation at ring nitrogen then de-O-methylation by iodide attack
Br NaNH2, NH3(liq) ch8 5 N Br NaOMe N N Nucleophilic displacement of a !-bromine HBr N 3,4-pyridyne OMe + NH3 N NH2 NH2 + N

i-Pr2N

i-Pr2N LDA

O Li Ph2CO

i-Pr2N

OH

Ph Ph

ch8 6(i)

N ortho-lithiation

N O O Ph Ph N

acid, heat lactonisation

Li LDA ch8 6(ii) N Cl N Cl ortho-lithiation I2 N

I Cl

Li F LDA ch8 6(iii) N N ortho-lithiation selective for C-4 F Me2CO

Me

OH Me F N

n-BuLi, 78 C ch8 6(iv) N Br N Li

Me3SnCl N SnMe3

metal/halogen exchange then Me3SnCl as an electrophile

O2N + ch8 7 N Me Br

O Me

O2N + N

NaHCO3 Me Deprotonation of acidified methyl O Me

O 2N N O Me

Ring nitrogen quaternisation O2N

Br

O 2N + N OH Me H+ H 2O

N Me

+ ch8 8 N

Ring nitrogen quaternisation

I I

+ N

n-Bu3SnH, AIBN Intramolecular radical substitution I

+ N

Me h! ch8 9 N H O

Me O3 then NaBH4 N H O HO HN

HO

H Me O

Me NaNH2 ch8 10 N Chichibabin substitution

Me NaNO2, H2SO4 0 C to rt N NH2 Diazotisation

Me H2O N + N2 Very easy nucleophilic displacement of nitrogen then tautomerism

O

Me MeI, NaOMe N H O O-Methylation of pyridone anion

Me (CO2Et)2, KOEt N OMe N

CO2Et

OMe

Deprotonation of !-methyl then condensation with diethyl oxalate

NH2 has no activating substituent and NH2 do have activating amino substituent

ch8 11

+ NH3

+ N H

+ N H

OH + ch8 12 N Br Quaternisation of ring nitrogen Intramolecular 1,3-dipolar cycloaddition N Br + N

OH base H+ + N

ch8 13

N H O O

CO2

N H

Me

Final tautomerism to aromatic product

AcHN

CO2Et

AcHN

CO2Et

AcHN

CO2Et

+ H+ ch8 14 N N N

Me n-BuLi ch8 15(i) N Me Selective deprotonation of 2-methyl N

Me PhSSPh CH2Li N

Me SPh

Me NBS ch8 15(ii) N Me Selective N radical bromination of 3-methyl

CH2Br Me

PhSH N Me

SPh

CN ch8 16 + N Me I K3Fe(CN)6, NaOH H HO

CN + N N Me Me Hydroxide !-adducts trapped by oxidant

CN H OH [O] O N Me

CN
4:3

CN N Me O

+D ch8 17 + N n-Bu I

H + H+ H Enamine N n-Bu D !-protonation H H + N n-Bu D +D D N Bu D

ClCO2Me then NaBH4 ch8 18 N + N Cl CO2Me

+H N CO2Me

h! N

Acylation of ring nitrogen then hydride addition to C-2 then electrocyclisation

CO2Me

NO2 c. HNO3, c. H2SO4 heat ch8 19 + N O

NO2 PCl3 + N O

NO2 H2, Pd/C N Nitration at C-4 assisted by electron release by N-oxide De-oxygenation of N-oxide producing POCl3

NH2

O MeO ch8 20 Me H O

CH2Ph O O

O OMe Me NH3 MeO

Me

O OMe [O] MeO

Me

O OMe

Me

N H

Me

Me

Me

Hantzsch synthesis

+ ch8 21 O O O Hetero DielsAlder cycloaddition O

H2NOH, HCl No final oxidation required using H2NOH N

(CH2)2OH

(CH2)2OH

O O

Synthon for a 1,5-dialdehyde

Et O ch8 22(a)(i) EtO O CN + H 2N O HO

Et CN N H O Oxidation level of ester leads to oxy-pyridine

CN O ch8 22(a)(ii) Me O + H2N O Me CN EtO ch8 22(a)(iii) + H2N O HO N H O N H O CN Oxidation level of ester leads to oxy-pyridine CN

O Synthon for 1,3-aldehydo-ester

CO2Et Me ch8 22(b)(i) + Me Me N

CO2Et

O H2N Synthon for 1,3-keto-aldehyde OEt EtO2C +

Me

CO2Et

EtO2C

CO2Et

ch8 22(b)(ii)

Me

H2N

Me

Me

Me

Synthon for 1,3-keto-aldehyde

ONa

O Me

O Me Me N

+
ch8 23 Me O H2N

Chapter 9
+ NO2 ch9 1(i) N N

NO2

Substituent benzene ring much more reactive than the isoquinoline benzene ring

NO2 MeO ch9 1(ii) N MeO + NO2

NO2 ortho to the activating group and at C-5 rather than C-7

+ NO2 ch9 1(iii) MeO NO2 N MeO NO2 N

ortho to the activating group and at C-8 rather than C-7

H Br2 ch9 2 N + N Br + Br Br Br HBr + N Br N Br

Br Br2 enamine !-bromination

Br

Br H

+ N Br

Br Br2

Br N

Cl NaCH(CO2Et)2 ch9 3 Cl N N

Cl

CH(CO2Et)2

Of the two !-type positions the isoquinoline 1-position is much more reactive

3n-BuLi ch9 4 N NHCOt-Bu

Li N N ortho-Lithiation

Li t-Bu

MeSSMe N

SMe NHCO-t-Bu

H + NMe I NaBH4 NMe H H enamine !-protonation H

H + NMe H

ch9 5

NaBH4 NMe

OH OH ch9 6 N O NH N OH N

O + ch9 7 NH2 H O CO2Me N H Me

O OMe H2O

H CO2Me N H H Cl CO2Me Me
HCl

Me

DMF, POCl3 enamine !-formylation (Vilsmeier reaction) CO2Me N Me

+ N probable intermediate H Me for electrophilic ring closure

CO2Me + ch9 8(i) MeO NH2 CO2Me N H

O H CO2Me CO2Me MeOH MeO N H CO2Me

MeO Addition of the aniline to activated alkyne is an alternative to condensation with 1,3-dicarbonyl compond

EtO2C + ch9 8(ii)Cl O C CO2Me Cl CO2Me probable intermediate for electrocyclic ring closure N NH2 H

CO2Et OEt Cl O

EtO2C CO2Me N H CO2Me

250 C EtOH O

CO2Me Cl N H

CO2H aq. NaOH Cl N H

O O ch9 9(i) N H NaOH

CO2Na O NH2 Me + O Ph

CO2H

Ph

Pfitzinger variation of Friedlnder synthesis

O O ch9 9(ii) N H KOH

CO2K O NH2 CO2H OH N CO2 CO2H Like decarboxylation of a !-keto-acid N Cl + O CO2H CO2H OH

O O ch9 9(iii) N Ac NaOH

NaO2C O Me N H O

CO2H

N H

H O ch9 10(i) NH2 + O

O NH N H O N

O NH N H O

Friedlnder synthesis many variations are possible

H O ch9 10(ii) O O +

CO2Me O O

H O CO2Me N H CO2Me Addition of the aniline to activated alkyne produces likely intermediate CO2Me N CO2Me

NH2 CO2Me Friedlnder synthesis many variations are possible O O

Me O ch9 10(iii) + NH2 O Me S

Me

Friedlnder synthesis many variations are possible

Ph O ch9 10(iv) NH2 + O

O Me Me N

O Me Me

Friedlnder synthesis many variations are possible

H O ch9 10(v) N NH2 SO2Ph + O Me N N Me SO2Ph Friedlnder synthesis many variations are possible

H N ch9 10(vi) N NH2 O + O N N N

Friedlnder synthesis many variations are possible

Chapter 11
Me PhNH2 ch11 1 Me + O Me Me O Me Me NHPh Me Me O HN Ph Me Me HO Me N Ph Me Me

+ H+ H 2O

Me

+ N Ph

Me

Nucleophilic addition at C-2 then electrocyclic ring opening and ring closure

Ph Ph3P=CH2 ch11 2 Ph + O Ph Ph

Ph Ph

Ph

Ph + CH2PPh3 Electrocyclic ring opening

O Ph3P+

Ph

Ph Ph3P=CH2 H+ Ph Wittig reaction to close Ph

O HO MeOTf ch11 3 O Me HO TfO

OMe

OMe O Me + O Me OMe O CN 1,3-Dipolar cycloaddition O Me CN

+ O

Powerful alkylating agent reacts at carbonyl oxygen

O PhNH2 ch11 4 O + H

O H H

NHPh

O HN Ph

HO

N Ph

H2O

N Ph

MeO2C O O

MeO2C PhCH2NH2 H O NH Bn O H2O

MeO2C N Bn O

Amine attack at carbonyl carbon ring opening and reclosure

t-Bu t-Bu O Me ch11 5(i) t-Bu O Aldol t-Bu O O H CH3 t-Bu t-Bu Michael

t-Bu Ph3C+ ClO4 O O t-Bu t-Bu

t-Bu

+ O

t-Bu

Oxidation required at end to achieve aromatic oxidaiton level

ch11 5(ii)

Ac2O, HClO4 Me Me Me O O O H 2O Me + O Me

Alkene acylations 'Aliphatic FriedelCrafts reactions'

H ch11 5(iii) Me Me O O O Ph Ac2O HClO4 Aldol Me O O Ph + H+ H2O

Me

+ O

Ph

O Me c. HCl, heat Me

O CO2H Me CO2 H2O

ch11 6

Me

OH

O O

Me

Me

Me EtO2C ch11 7 Me OH O CO2Et EtO2C Me

Me

OH EtO2C O CO2Et Me

Me

OH

OH

CO2Et Me

EtO2C EtOH H2O Me O O

Ph Me ch11 8(i) Ph O + CO2Et NaOEt

Ph Enolate addition to activated alkyne then lactonisation

Ph

Et

CO2H + CO2H

Et CO2H HO2C n-Pr PPA, 200 C CO2

O Et n-Pr O Et n-Pr

ch11 8(ii)

n-Pr

O HO2C + ch11 8(iii) n-Bu O CO2H COn-Bu CDI n-Bu O OH COn-Bu First step probably activation of acid by CDI then C-acylation

O Me ch11 8(iv) + Ph O MeO2C C6H4-p-Cl NaH Ph

O First step probably Claisen condensaation C6H4-p-Cl

O Cl + ch11 8(v) Ph O OMe Me KOt-Bu Ph

O First step probably acylation by acid chloride Note enol ether synthon for aldehyde

Chapter 12
H Me ch12 1 + O Cl + Me O HO Selective condensation at !-methyl + O Cl HO Me

pyridine O O

Me

O CO2Me ch12 2 O Me NaOH then HCl

O Me O MeOH

O Ac O OH

OH OMe O CO2Me Me OH Initial addition at C-2 O

H O ch12 3 OH OMe + CO2Na Ac2O, heat O OMe PhMgBr then HCl O + O Cl OMe Ph

Perkin condensation then lactonisation

Ph + ch12 4(i) HO OH O Ph H2O O O Me HCl, AcOH HO O

Ph

+ O Cl

Me

Ph

HO

OH

HO

Me Probable first intermediates

Me

O MeO2C + ch12 4(ii) HO OH O MeO H2SO4 HO O HO O Probably via

Chapter 14
O ch14 1(i) Cl POCl3 NaOMe Nucleophilic displacement of !-chlorine N N OMe + NH OPOCl2 N Nucleophilic displacement of !-dichlorophosphate by chloride

N NH N N Attack at amide-type carbonyl oxygen

N ch14 1(ii) N Cl

BuNH2, 120 C

N N NHBu Nucleophilic displacement of !-chlorine

SMe MeI ch14 2(i) N N + N N Me I

SMe Me N N

Cl MeI Me + N N

Cl

Me I

Regioselectivity of quaternisation of nitrogen in diazines is not easy to predict

N LiTMP ch14 2(ii) Cl N Cl

Li HCO2Et Cl

N N

CHO Cl

Cl N Cl ortho-Lithiation

Ph N ch14 2(iii) MeO N LiTMP then I2 MeO OMe ortho-Lithiation N N I HC!CPh, Pd(0) N N OMe

OMe MeO Sonogashira coupling

N ch14 3(i) N NH2

HNO2, 5 C N

N + N2

Me2NH N

N NMe2

Easy nucleophilic displacement of nitrogen at !-position

Me PhCHO, Ac2O, heat ch14 3(ii) Ph N N Ph N N

Ph Condensation with methyl at an !-position

CO2H + 14 4(i) Cl O O O AlCl 3 Cl O Br2, AcOH HBr Ar N NH O N2H4 Ar N

O NH

FriedelCrafts

Br2, MeOH 14 4(ii) O

Me O

Me OMe

aq. acid

MeO 1,4-Addition to furan

Me O O Me

Me

N2H4 2H2O Me N

Me O 14 5(i) + NH2 + H 2N NH2 HCO3

Me N N NH2

CH(OMe)2 Synthon for 1,3-keto-aldehyde

OEt O 14 5(ii) N + HN NH2 NH2 NaOEt H2N

O NH N NH2 Nitrile leads to amino-heterocycle Ester leads to oxy-heterocycle

OEt O 14 5(iii) N + H2N NH2 O NaOEt H2N

O NH N H O Nitrile leads to amino-heterocycle Ester leads to oxy-heterocycle

14 5(iv)

CH(OEt)2 NH2 + CH(OEt)2 O H2N

NaOEt N H

N O

1,1,3,3-Tetraethoxypropane synthon for malondialdehyde

MeO HCO2Et, Na 14 6(i) Me

MeO O

+ H 2N

NH2 S MeO

MeO Me N N H

N S

O Claisen Me condensation

H2, Ni

Me N Hydrogenolysis of sulfur with Raney nickel

Ph 14 6(ii) O CO2Me + HN NH2 Et O

Ph N N H Et

O 14 6(iii) Me

NH2 + NH2

O O

Ph

O Me

H N N

Ph

Chapter 16
NO2 HNO3, Ac2O ch16 1 N H Me O 2N + Me 6:1 Me !-Position preferred for electrophilic substitution Even mild electrophiles react well.

N H

N H

ch16 2(i)

CCl3COCl N N H !-Position preferred H for electrophilic substitution

Br N tendency for !-position H O substitution dominant

CCl3

Br2

CCl3 O

NaOMe

Br

OMe N H O

Ac DMF, POCl3 ch16 2(ii) N H N !-Position preferred H for Vilsmeier substitution CHO AcCl, AlCl3

N H Deactivated pyrrole requires Lewis acid catalyst for reaction. meta-Directing group controls regiochemistry

CHO

ch16 2(iii)

N H

DMF, POCl3 Cl OHC !-Position preferred for Vilsmeier substitution via HO

N H

Cl

LiAlH4 Me N H Cl

N H

Cl

H 2O

Cl

PhCONMe2, POCl3 ch16 3(i) N H N H O

Ph

Vilsmeier !-substitution

+ ch16 3(ii) N H

Me2N O N H

POCl3 N H O N H

Vilsmeier !-substitution

+ ch16 3(iii) N H

POCl3 N H N H N

Cyclic nature of this Vilsmeier intermediate ensures that it does not hydrolyse to ketone

HCl ch16 4 N H Me Me N H HN

H+ Me Me N H + HN

H H Me

ketone-like iminium ion not sufficiently reactive to attack a third pyrrole + H Me N H N

Me

ch16 5

Me

N H

Me

Zn, HCl

Me

N H

Me

Me

N H

Me

H Me + NH Me

Reduction involves protonated pyrrole

CO2Me N + MeO2C CO2Me 160 C CO2Me H H N CO2Me MeO2C CO2Me

ch16 6(i)

N CO2Me

CO2Me DielsAlder addition and then reverse DielsAlder loss of ethyne

NCO2Me
1O 2

NCO2Me N Me O N N CO2Me Me
via

ch16 6(ii)

O O

N CO2Me

SnCl2

DielsAlder addition of singlet oxygen

CH2O, Me2NH AcOH N H Mannich substitution at pyrrole !"position electrophile = N H + N Me Me

ch16 7

NMe2

MeI N H

+ NMe3

C5H11N N H via

N H+

HN

H ch16 8(i) MeO

n-PrNH2, H+ N n-Pr

OMe O Synthon for succindialdehyde

H ch16 8(ii) MeO

NH2 N S

OMe O Synthon for succindialdehyde

H ch16 8(iii) MeO

PhSO2NH2 N O S O Ph

OMe O Synthon for succindialdehyde

Me 16 9 EtO2C

O O HNO2 EtO2C Me O NOH Me Zn, AcOH EtO2C O + NH2 O Me Me

Me

Ac

hydrolyse, then CO2, then N2H4, EtONa Me

Me

Et

EtO2C

N H

N H

Me

Me 16 10(i) Cl

O + NH2 + O

CO2Et CO2Et

Me

CO2Et CO2Et

N H

Me 16 10(ii) Me

O + NOH O

CO2Et Me

Me Na2S2O4 Me N H

CO2Et Me Reduction of oxime to amino in situ

16 10(iii)

CN + NH2 O

CO2Et Me

H 2N

CO2Et Me Nitrile instead of carbonyl leads to amino-substituted heterocycle

N H

Me 16 10(iv) Me

Me Me O O + H2N CO2Et Enamine formation Me

Me O N H CO2Et NaOEt Aldol

Me

Me

Me

N H

CO2Et

Chapter 17
O2N ClSO3H ch17 1 S !-Position preferred for electrophilic substitution S f. HNO3 SO3H S meta-Directing group dominates SO3H AcONO2 S O2N S H2O, heat S H O2N

NO2 OMe HNO3, AcOH 20 C O2N > OMe OMe !-Selectivity dominates

ch17 2

(EtCO)2O, H3PO4 ch17 3(i) S S O

Et

Strong benzene-type conditions can be used with thiophenes

t-Bu PhN(Me)CHO, POCl3 ch17 3(ii) S OHC S

t-Bu Selectivity for the less-hindered of two !-positions

Tl(O2CCF3)2 ch17 3(iii) S S TlO2CCF3

aq. KI S

OMe OMe n-BuLi n-BuLi Li OMe S

OMe

ch17 4

S Selectivity for !-position in lithiation dominates over ortho-directivity

Li S Selectivity for that !-position which is also ortho to methoxyl

Br

Br Mg then H2O

Br

Br Mg then H2O

Br

Br

ch17 5

Br

Grignard formation preferred at an !-position

Br

Br

n-BuLi ch17 6 S S Lithiation selective for an !-position Li

CO2 S CO2H

P4O10 S O

S FriedelCrafts type conditions usable with thiophenes

NC ch17 7(i) NC

CN H2S CN

NC H2N

CN NH2 Nitrile cyclisations lead to amino-substituted heterocycles

EtO ch17 7(ii) EtO2C O S

OEt O CO2Et NaOEt

HO EtO2C

OH aq. NaOH, MeI S CO2Et

MeO

OMe

HO2C

CO2H

Double Claisen condensation

ch17 7(iii) O O

Me

P4S10 S

Me

Chapter 18
+ +H H + O H + +H " protonation H + O OMe + HO H H O O OMe H O OMe + HO O OMe O H H+ CO2Me MeOH O O

ch18 1

OMe

! protonation H

OMe

ch18 2(i)

Ph

DMF, POCl3 then aq. NaOH

OHC

Ph

Furan ring far more reactive than substituent phenyl ring

ch18 2(ii)

CO2Et

Ac2O, SnCl4

Ac

CO2Et

!-Position preferred for electrophilic substitution Mild Lewis acids must be used

CN HNO3, Ac2O ch18 2(iii) O O 2N

CN Nitrile substitutent stabilises the system and allows use of more vigorous reagents

ch18 2(iv)

CO2Me

Cl3CCHO Cl3C H2SO4 HO O

CO2Et

CO2Me H2O

Cl3C via + O

CO2Et

!-Position preferred for electrophilic substitution of furans

MeO2C

O CCl3

CO2Me

ch18 3

Me

CH2OH

[O] MeOH

MeO Me O

OMe CH2OH

H2, catalyst O

MeO Me O

OMe CH2OH

1,4-Diketone synthon

+ H3O

O Me O CH2OH H2O Aldol OH Me

CO2Me Me LiAlH4 then SOCl2 O Me MeO O OMe Me H2O, 60 C

CH2Cl LiAlH4 Me O Me OHC O

Me Br2, MeOH Me

ch18 4

Me NaBH4 HOH2C HO H Me

H 1,4-Keto-aldehyde synthon

Me

ch18 5(i)

O Lithiation selective for an !"position

Li

c-C6H10O O HO

ch18 5(ii)

Li

Br(CH2)7Cl O

Cl

Lithiation selective for an !"position

Me DMF, POCl3 then aq. NaOH ch18 6(i) O

Me Vilsmeier substitution at the less-hindered !-position

OHC

Br ch18 6(ii) O n-BuLi then H2O Br Metallation O selective for !-position

Br

Br

Li

Br LDA then CH2O ch18 6(iii) O O Lithiation at that !-position which is also ortho to Br

Br

Br

Li

CH2OH

ch18 6(iv)

CHO

EtOH, H+

CH(OEt)2 O Lithiation selective for an !-position

n-BuLi then B(OBu)3

Li

CH(OEt)2

(BuO)2B

CHO

+ H3O

(HO)2B

CHO

O Br n-BuLi, 78 C then n-Bu3SnCl ch18 6(v) O O Sn-n-Bu3 MeCOCl, PdCl2 ipso substitution of tin O allows formation of 3-acyl-furan Me

CN 18 7(i) O CH2OH C

O CH OH 2 CN CH2 Furans behave like 1,3-dienes and undergo DielsAlder cycloadditions

O Me 18 7(ii) Me O Me Me

Me Ac Furans behave like 1,3-dienes and undergo DielsAlder cycloadditions

Cl + O Et3N, LiClO4 O

O Furans behave like 1,3-dienes and undergo cycloadditionsm with 1,3-dipoles O

18 7(iii)

18 8(i)

TMSCl Et3N, ZnCl2

OTMS

O-Silylation of butenolides gives 2-trimethylsilyloxy-furans

18 8(ii)

OTMS

ICH2CN, AgO2CCF3

NCCH2

Electrophilic substitution of 2-trimethylsilyloxy-furans O produces 5-substituted butenolides

18 9

Ot-Bu

n-BuLi

O Lithiation of furans selective for an !"position TsOH C4H8 Ph O HO

Li

Ot-Bu

PhCHO

Ph O HO

Ot-Bu

O H 18 10(i) O Et MgBr HO Et m-CPBA HO BF3 O Et CrO3 pyridine

O Et

O O

Et

via

HO

Et

ClMg 18 10(ii)

Me HC(OEt)3 OHC

Me m-CPBA OHC

Me O

+ H3O H2O O

Me OH

Me O via

Me 18 10(iii) (MeO)2HC O ClCH2CO2Me, NaOMe Darzens reaction (MeO)2HC

Me O CO2Me

Me heat O CO2Me

CO2Me MeNH2 ch18 11 CO2Me

MeHN MeHN MeO2C HO + H3O O O CO2Me LiAlH4 MeHN HOH2C CO2Me + H O O

Selective reduction other ester is a vinylogous amide

Chapter 20
O NHMe

+ ch20 1 N H O

POCl3 N Vilsmeier reaction Me N H Electrophilic substitution of indoles preferred at a !-position

Me + ch20 2 N H Cl HO Me Me

Me

Me

+ N HO Me H Electrophilic attach on an indole Me preferred at a !-position

Me O N H Me

ch20 3

NH

indole, H +

NH2

via

+ NH2

N H

N H

N H

N H

NMe2 CH2O, Me2NH AcOH ch20 4 N Mannich reaction H preferred at indole !"position N H MeI selective quaternisation of amine KCN N H

+ NMe3 I via

NC

CN NH2 N H LiAlH4 N H + H3O N H

CO2H

I Br ch20 5(i) N PhSO2

Ph PhB(OH)2, Pd(PPh3)4 aq. Na2CO3 Suzuki coupling Br N PhSO2

I Br ch20 5(ii) N PhSO2

CO2Et Pd(OAc)2, Ph3P, Et3N Heck reaction

CO2Et Br N PhSO2

H ch20 6 N H

+ Ph3PCH=CH2 Br NaH N

H O Ph3P+

Wittig N

O Deprotonation of indole Nhydrogen gives indolyl anion nucleophilic at nitrogen

Et Me Et Me Et + H+ + N H Me N H 1,2-Migration then loss of proton and Me Et N H

ch20 7

N ch20 8 N H

NaH PhSO2Cl

N PhSO2 Deprotonation of indole Nhydrogen gives indolyl anion nucleophilic at nitrogen OH Li N N PhSO2 O N PhSO2 N

t-BuLi, 100 C

Lithiation with ortho-assistance from pyridine N

OH aq. NaOH N H N + N N H Br

HBr

I n-BuLi then I2 ch20 9 N H Indolyl anion can react on N or C LDA then PhSO2Cl N H Indolyl anion can react on N or C

LDA then I2

I I N PhSO2

N PhSO2 Lithiation at preferred !-position

CH2OH + heat, H H2O

CH2 starting indole + N H N H

HO

ch20 10

N H

+ N H

CH2O N H N H

OH + H N N H Fischer synthesis N H

OH

+ ch20 11 NHNH2

O Synthon for 4-hydroxybutanal

N ch20 12

Me

(CO2Et)2, NaOEt

N O NO2

CO2Et

H2, Pd/C

N CO2Et N H

NO2 Easy deprotonation of pyridine 2-methyl also ortho to nitro gorup

Reduction of nitro to amino then condensation with loss of water

Me N

(CO2Et)2, NaOEt O NO2

CO2Et

H2, Pd/C N N H

N NO2 Easy deprotonation of pyridine 4-methyl also ortho to nitro gorup

CO2Et

Reduction of nitro to amino then condensation with loss of water

DMFDMA NO2 Me ch20 13(i) NO2

MeO

MeO + H

+ N

Deprotonation of methyl ortho to nitro then reaction with MeO(H)C=NMe2 Me then loss of MeOH NH2 NO2 Me NMe2 TiCl3 NO2 Reduction of nitro !-protonation of enamine, cyclisation and loss of Me2NH N H

DMFDMA, heat

DMFDMA BnO Me ch20 13(ii) NO2

MeO

MeO + H

+ N

Deprotonation of methyl ortho to nitro then reaction with MeO(H)C=NMe2 Me then loss of MeOH BnO BnO Me NMe2 NO2 Reduction of nitro !-protonation of enamine, cyclisation and loss of Me2NH H2, Pt N H

DMFDMA, heat

DMFDMA Me

MeO

MeO + H

+ N

Me Me

Deprotonation of methyl ortho to nitro then reaction with MeO(H)C=NMe2 then loss of MeOH NMe2 NO2 H2, Pd MeO N H

DMFDMA, heat ch20 13(iii) MeO NO2 MeO

Reduction of nitro !-protonation of enamine, cyclisation and loss of Me2NH

DMFDMA Me

MeO

MeO + H

+ N

Me Me

Deprotonation of methyl ortho to nitro then reaction with MeO(H)C=NMe2 then loss of MeOH NMe2 H2, Pd N H NH

DMFDMA, heat ch20 13(iv) Me NO2 NO2 Me2N NO2 NO2

Reduction of nitro !-protonation of enamine, cyclisation and loss of Me2NH

Chapter 21
CO2Et O EtO2CCH2COCH2Cl ch21 1 SH CONH2 NH3 S LIAlH4 S N POCl3, heat S Intramolecular Vilsmeier S CO2Et PPA, heat H2O NH2 HCO2H, heat S O

S NH H

O Me Me Cl ch21 2(i) Me OH Me Me Me

Me O O Me Me c. H2SO4 Me Me

Me

Me Me O

Me

Br ch21 2(ii) O O MeO OH

K2CO3 O O MeO

heat O O O Claisen rearrangement MeO OH

O3 O O MeO O OH

H+ H2O O O MeO

F3C ch21 2(iii)

F3C LDA then DMF F ortho lithiation

CHO F

HSCH2CO2Me

F 3C CO2Me S

O2N ch21 2(iv) F

Me2C=NO Na+

O2N

Me O N

Me c. HCl NH3

O2N Me O

O Cl ch21 3 S PCl3 then AlCl3 CO2H H N N PhNHNH2 AcOH, heat Cl Fischer indole synthesis S S Cl Cl O Cl Cl S H N

FriedelCrafts

Chapter 22
O t-Bu ch22 1 CH2Br CH2Br O O 500 C t-Bu NH NPh O t-Bu O NH H2NCH2C!CH t-Bu H O N H

O NPh O

Typical DielsAlder reactivity of isoindoles

CHO ch22 2(i) CHO

NaHSO3 then MeNH2

OSO3H NMe 2KCN

CN NMe

OSO3H CN NMe

CN

HCN

NEt2 O ch22 2(ii) n-BuLi then PhCHO ortho Lithiation

NEt2 O OH Ph Ph Ph
1O 2

O H+ O H Ph

PhMgBr then H+

O Ph

O Ph

O O Cycloaddition of singlet oxygen

O CHO ch22 3 CHO TsOH MeO2CC!CCO2Me (CH2OH)2, CuSO4 O CHO NaBH4

O O OH CO2Me

O CO2Me

Typical DielsAlder reactivity of isobenzofurans

O S ch22 4 O Typical DielsAlder reactivity of benzo[c]thiophenes NaOH, heat then H + + O S

O O O

CO2H CO2H

Chapter 24
Cl N ch24 1(i) N H NaOCl Cl N H N Electrophilic substitution preferred at C-4(5)

Br N ch24 1(ii) N Me Br2, AcOH Br N N Me Br EtMgBr then H2O Br

Br N N Me MgBr

Sective Grignard formation at C-2 Li N N Me

Br N Br N Me

n-BuLi then (MeO)2CO H Sective metal/halogen Br exchange at C-4

MeO2C N Br N Me

Ph N ch24 2(i) + O H O heat Ph N

O Ac PhCN Retro DielsAlder loss of benzonitrile O

Ac

Me Oxazoles (like furans) take part in DielsAlder cycloadditions

O N ch24 2(ii) EtO O heat + MeO2CH2 CO2Me Oxazoles (like furans) take part in DielsAlder cycloadditions N EtO CO2Me CO2Me MeO2C HCN Retro DielsAlder loss of HCN CO2Me OEt

N ch24 3i/ii O 2N N Me Me

(t-BuO)2NMe2 heat

N O2N N Me N NMe2 Ac2O, heat

enamine !-acetylation

O 2N NH2 HN N O2N N N Me Me N NH2 NH2

O Me 1,3-aldehydo-ketone synthon MeNHNH2 N O 2N N Me Me NMe N

N Me

NMe2

N ch24 4 N Me N Li N Me SiMe3

n-BuLi then TMSCl Selective lithiation at C-2

N N Me Li

N N Me

n-BuLi then TMSCl SiMe3 Selective lithiation at C-5 if C-2 blocked N

N Me3Si N Me SiMe3 MeOH Selective ipso protonolysis Me3Si

N Me

Br N ch24 5 Br N N Me N Me n-BuLi, 78 C then DMF

Li N N Me Li n-BuLi, 78 C ! 0 C then DMF N

OHC N N Me N N N Me CHO

Li N N Me equilibration to Me more stable lithium compond

NH ch24 6 S S

Br(CH2)3Br S-Alkylation S

+ NH Br S(CH2)3Br H+ S

N S(CH2)3Br

Br + N S S

Et ch24 7(i) Cl

O + S

Et NH2 NH2 S N NH2

H ch24 7(ii) Cl

O + S

NH2 Ph S

N Ph

EtO2C ch24 7(iii) Br

O + S

HO NH2 H S N ester oxidation level leads to oxy-heterocycle

Ph ch24 8 Br

Ph + NH4 HCO2 O O AcOCH2 CH2OAc CH2OAc PhCN N AcOH2C

heat CH2OAc

CH2OAc DielsAlder then retro-DielsAlder

N Ph

N ch24 9(i) Me N C n-BuLi LiH2C N C PhCN Ph N H

Ph ch24 9(ii) Ph

O + NH2

NH2 N Ph

Ph N N H NH2 Use of nitrile in cyclisation leads to amino-heterocycle

Chapter 25
O2N N c. HNO3, c. H2SO4 N Ph N via attack on salt (but positively charged heterocycle still more reactive than the phenyl group) + NH

ch25 1(i)

N Ph

N Ph

ch25 1(ii)

N Ph

HNO3, Ac2O O2N N Ph

via attack on the neutral pyrazole

Me N NaNH2 NaH2C O

Me n-PrBr N n-Pr O

Me N

ch25 2(i)

Me

Selective deprotonation of 5-methyl

Me N NaNH2 NaH2C O

Me N CO2 HO2C O

Me N

ch25 2(ii)

Me

O Selective deprotonation of 5-methyl

Me N NaNH2 NaH2C O

Me N PhCO2Me Ph

O O

Me N

ch25 2(iii)

Me

Selective deprotonation of 5-methyl

Cl N SO2Cl2 Me Selective electrophilic substitution at C-4 O N aq. NaOH

Cl Me HO Cl via H N

CN O

ch25 3

Me

Me

CO2Me O ch25 4 Me O BnNHNH2

CO2Me Me N + MeO2C

Me N

N Bn

N Bn

ch25 5

N H

N Li N SO2NMe2 Removal of acidic N-hydrogen Selective only requires weak base lithiation at C-5

Me2NSO2Cl, Et3N

n-BuLi then TMSCl

N N SO2NMe2

Me3Si

N SO2NMe2

PhCHO, CsF

Ph HO

N N SO2NMe2

Ph O ch25 6 H O H2NOH O

Ph N + Ph N

ch25 7(i)

N HO

2n-BuLi then DMF

Li O

N Li

OHC O

N Li

H 2O

ch25 7(ii)

S NOH

Br

Me3Si

Li

MeOH, K2CO3 S N O

SiMe3

via

S NOH

SiMe3

Me N ch25 7(iii)

Me O NHPh (EtO)2P(O)CH2SEt, n-BuLi

Me N

Me via N Ph

Me N

Me SEt NHPh HSEt

ch25 8

Me3Si

SiMe3

H2NOH

Me3SiCH2

Chapter 27
OP(O)Cl2 O HN ch27 1(i) H 2N AcO N O N POCl3 N H2N AcO via + HN N N O Cl N N t-BuONO, CH2I2 via the diazonium salt I AcO N N O Cl N N

AcO

OAc NH2 N N N O N

AcO

OAc NH2 N N O N

AcO

OAc

NH3, MeOH I HO Selective nucleophilic displacement of 6-chlorine

PhB(OH)2 Pd(PPh3)4, Na2CO3 Suzuki coupling Ph HO

HO

OH

HO

OH

O H2N H2N HO O N N PhCO2Et NaOEt Ph H2N N H O N N Ph H2N N H

O N N O

Ac2O

ch27 1(ii)

O HO

O AcO

HO

OH O

HO

OH Cl

AcO

OAc NH2

POCl3

HN via Ph AcO N O

N N Ph AcO

N N O

N N

NH3 Ph HO

N N O

N N

AcO

OAc

AcO

OAc

HO

OH

NH2 N ch27 2 HO N O N N HO Selective bromination at C-8 Br2 AcOH N

NH2 N Br N O N PhB(OH)2 Pd(0) Suzuki coupling HO N

NH2 N Ph N O N

HO

OH

HO

OH

HO

OH

NH2 N ch27 3 HO N O N N HO N-1-quaternisation then N-deprotonation Me2SO4 MeN

NH N N O Hydrolytic removal of sugar H+ N N H N H H2N O N aq. HCl MeN

NH N N N H

HO

OH

HO

OH NH

NHMe aq. NH3 N N N N H via Dimroth process MeN H O

NMe N N H N H H 2O

NH2 N ch27 4(i) N NH2 NH2 HCONH2, heat N

NH2 N N N H

O HN ch27 4(ii) Me N NH2 NH2 Na+ HCS2 quinoline heat Me HN

O N SH N N H

Chapter 28

+ N ch28 1 Br

LiAlH4

N Electrocyclic ring opening

H2, Pd

n-Bu

ch28 2

LDA then EtO(CH2)2CH=O Side-chain Me lithiation

HI, heat N CH2Li EtO N H OH

+ N I

Ac2O, heat H 2O H OH I + N

Pd/C, heat + N I Dehydrogenation to aromatic molecule

Me N ch28 3(i)(a) Me + Br O Me NaHCO3 N

Quaternisation of nitrogen Me O Br via N+ Me N Me O

N ch28 3(i)(b)

Me + Br

O H

NaHCO3

Me

Quaternisation of Me nitrogen H Me Br via N+ O Me Me N

H O

Me N ch28 3(ii) NH2 + Br Quaternisation of ring nitrogen Me O Br via N+ NH2 N Me O NH O Me N NaHCO3 N

NH2 +

O Br H

N NaHCO3 Me N

Quaternisation of Me ring nitrogen H Me Br via N+ O NH2 Me N H O NH

Me N ch28 4 OMe KNH2, i-AmONO Side-chain lihtiation

HON N

H Zn, AcOH

H 2N N HCO2Me, PPE

N N

OMe

OMe

OMe

H+ NO N N ch28 5 Electrophilic nitrosation of five-membered ring H2O N N O N HNO2 N N H H O HN N

O N H

O HO N HN N

HNO2

ON

Electrophilic nitrosation of five-membered ring

N ch28 6(i) S NHNH2

HNO2 S

N N via S

N N H

+ N N

Ph N ch28 6(ii) S NH2 + Br O Ph S N N Ph via S + N O NH2 Br

Chapter 29

N N ch29 1(i)(a) N N + N N via N N N

N HCN pyrrolidine

N N ch29 1(i)(b) N N + via N N N N

N N2 pyrrolidine

EtO N ch29 1(ii) N N N Ph EtO + N OEt N Ph via

EtO

OEt Ph N2 EtOH

N N N

Cl ch29 2 Cl S

NaN3 Cl

N S

N N

MeNH2 MeHN

N S

N N MeN

HN S

N N

NH2 ch29 3(a) Ph O

DMFDMA Ph

N O

NMe2

N2H4

N Ph N H Me N

DMFDMA

MeO

MeO +

+ N

H Me attacks the NH2

NH2 ch29 3(b) Ph O

DMFDMA Ph MeO

N O

NMe2

H2NOH Ph Me

N O N

MeO +

DMFDMA

+ N

H Me attacks the NH2

N ch29 4(i) N

H 2N

NH2 NH2

N N H

NH2 NH2

N N H

N N H

N N N H

NH2 NH2

NH H N NH2

NH N N NH2

N H HN N

N ch29 4(ii) N

CH2(CO2Et)2

N N H

H CO2Et

N N H2

N CO2Et CO2Et

N N O NH2

CO2Et OEt

CO2Et N + N CO2Et O NH2 N N H CO2Et O