Heterocyclic Chemistry 5th Edition 2010 All Answers to Exercises Chapter 8 N OEt NO 2 ch8 1(i) f. HNO 3 , c. H 2 SO 4 100 °C N OEt Electrophilic substitution ortho to EtO ch8 1(ii) N Br CO 2 H N Me Br 2 , c. H 2 SO 4 oleum N Me Br KMnO 4 , heat Electrophilic !- substitution then side-chain oxidation N ch8 2 N NH(CH 2 ) 2 NMe 2 KHN(CH 2 ) 2 NMe 2 heat Chichibabin reaction (!-substitution) N Cl ch8 3(i)(a) N NHNH 2 N 2 H 4 Nucleophilic displacement of an !-chlorine ch8 3(i)(b) N Cl N OH H 2 O Nucleophilic displacement of an !-chlorine then tautomerism to 2-pyridone N H O N H O N NO 2 ch8 3(ii) H 2 O, 60 °C N OH Nucleophilic displacement of a !-nitro then tautomerism to 4-pyridone
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Heterocyclic Chemistry 5th Edition 2010 All Answers to Exercises Chapter 8
N
OEt
NO2ch8 1(i)
f. HNO3, c. H2SO4100 °C
N
OEt
Electrophilic substitution ortho to EtO
ch8 1(ii) N
Br
CO2H
N
MeBr2, c. H2SO4
oleum
N
Me
BrKMnO4, heat
Electrophilic !-substitution
then side-chain oxidation
Nch8 2 N NH(CH2)2NMe2
KHN(CH2)2NMe2heat
Chichibabin reaction (!-substitution)
N Clch8 3(i)(a) N NHNH2
N2H4
Nucleophilic displacement of an !-chlorine
ch8 3(i)(b) N Cl N OH
H2O
Nucleophilic displacement of an !-chlorinethen tautomerism to 2-pyridone
NH
O
NH
O
N
NO2
ch8 3(ii)
H2O, 60 °C
N
OH
Nucleophilic displacement of a !-nitrothen tautomerism to 4-pyridone
ch8 4 N
Cl
N
OMe
NaOMe MeI
NMe
OMe
+
I–
185 °C
NMe
O
Nucleophilic displacement of a !-chlorinethen quaternisation at ring nitrogenthen de-O-methylation by iodide attack
ch8 5 N
Br
NaNH2, NH3(liq)
N N
NH2
N
+NH2
– HBr
3,4-pyridyne
+ NH3
N
Br
NaOMe
N
OMe
Nucleophilic displacement of a !-bromine
N
OO
Ph
Ph
ch8 6(i) N
i-Pr2N O
LDA
N
i-Pr2N O
LiPh2CO
N
i-Pr2N O
ortho-lithiation
OHPh
Ph
acid, heat
lactonisation
N
Li
Clch8 6(ii) N Cl
I2
ortho-lithiation
LDA
N
I
Cl
N
F
N
F
ch8 6(iii)
LDA
N
F
Li
OHMe Me
Me2CO
ortho-lithiationselective for C-4
N SnMe3ch8 6(iv) N Br
n-BuLi, –78 °C
N Li
Me3SnCl
metal/halogen exchangethen Me3SnCl as an electrophile
N
O2N
Me
N
O2N
Me
+
Br–ch8 7 N
O2N
MeBr
Me
O+
Me
O
Deprotonation ofacidified methyl
NaHCO3
N
O2N
Me
O
N
O2N
Me
OH
+ – H– H2O
+
Ring nitrogenquaternisation
N NI
ch8 8+ +
–I –IN
+
Ring nitrogenquaternisation
II
n-Bu3SnH, AIBN
Intramolecularradical substitution
HNO
Me
HHO
ch8 9 NH
O
Me
h!
NH
O
Me
O3then NaBH4 HO
N
Me
NH2ch8 10 N
Me
NaNH2
Chichibabinsubstitution
NaNO2, H2SO40 °C to rt
N
Me
N2Diazotisation +
H2O
Very easy nucleophilicdisplacement of nitrogen
then tautomerism
NH
Me
O
MeI, NaOMe
N
Me
OMeO-Methylation ofpyridone anion N OMe
CO2Et
O
(CO2Et)2, KOEt
Deprotonation of !-methylthen condensation with diethyl oxalate
NH
NH2
do have activating amino
substituent+ch8 11has no
activatingsubstituentNH3
+ NH+
NH2
and
Quaternisation ofring nitrogen
N
OH
N
O
N
O
ch8 12 –+ +
–
BrN
OH
+Br base
– H+
Intramolecular1,3-dipolar cycloaddition
N
HO O
ch8 13 – CO2 NH
N MeFinal tautomerism
to aromatic product
Nch8 14
CO2EtAcHN
N
CO2EtAcHN–
N
CO2EtAcHN
–
+ H+
Me
MeNch8 15(i)
Me
CH2LiN
Me
N
n-BuLi
Selectivedeprotonation
of 2-methyl
PhS–SPhSPh
MeNch8 15(ii)
Me
MeN
NBSCH2Br
MeN
SPhPhSH
Selectiveradical bromination
of 3-methyl
CNCN
NMe
O NMe
Och8 164:3
NMe
CN
+I–
K3Fe(CN)6, NaOH
NMe
CN
NMe
CN
HOH
HHO
+[O] +
Hydroxide !-adductstrapped by oxidant
D DNBu
ch8 17 Nn-Bu+
I–
+ D–
Nn-Bu
HD
+ HEnamine
!-protonation Nn-Bu
HD
H
H+
+ D–+
ch8 18 N
CO2Me
N
ClCO2Methen NaBH4
N
CO2Me
+
Cl–
+ H– h!
N
CO2Me
Acylation of ring nitrogenthen hydride addition to C-2then electrocyclisation
ON
NO2
N
NO2
ch8 19 +
–
c. HNO3, c. H2SO4heat
O–
+
PCl3
N
NO2
H2, Pd/C
N
NH2
Nitration at C-4assisted by electron release
by N-oxideDe-oxygenation of N-oxide
producing POCl3
ch8 20 NH
CH2Ph
OH
Me Me
MeO
O
MeO
O
Me O
OMe
O
Me
OMe
OO
NMe Me
MeO OMe
OOMe H Me
NH3 [O]Hantzschsynthesis
N
(CH2)2OH
OOch8 21 O+
OHetero Diels–Alder
cycloaddition
H2NOH, HCl
Synthon for a 1,5-dialdehyde
O O
(CH2)2OH
No final oxidationrequired using H2NOH
ch8 22(a)(i) NH
Et
HO
CN
OH2N
CN
O
+O
Et
EtO OOxidation level of esterleads to oxy-pyridine
H2N NMe
N
CO2Et
Me Me
ch8 23
NH
CN
OMe
NH
HO
CN
O
ch8 22(a)(ii) H2N
CN
O
+
Me O
O
ch8 22(a)(iii) H2N
CN
O
+
O
EtO
ch8 22(b)(i) H2N
CO2Et
Me
+
O
Me
ch8 22(b)(ii) N
CO2Et
Me MeH2N
CO2Et
Me
OEt
Me O
EtO2C+
EtO2C
Me O
+
ONa O
Me Me
O
Synthon for1,3-aldehydo-ester
Synthon for1,3-keto-aldehyde
Oxidation level of esterleads to oxy-pyridine
Synthon for1,3-keto-aldehyde
Chapter 9
Nch9 1(i)
NO2+
N
NO2
Substituent benzene ringmuch more reactive than the isoquinoline benzene ring
N
MeO
NO2
ch9 1(ii) N
MeO
NO2
NO2+
ortho to the activating groupand at C-5 rather than C-7
NMeO
NO2
ch9 1(iii) NMeO
NO2
NO2+
ortho to the activating groupand at C-8 rather than C-7
NBr
+ Br+
–
ch9 2Br–
N
Br2
NBr
+
H Br
enamine!-bromination
Br2
NBr
H BrBrH
– HBrNBr
+
BrBr–
– Br2 N
Br
ch9 3 N N
Cl
CH(CO2Et)2
Cl
Cl
NaCH(CO2Et)2
Of the two !-type positionsthe isoquinoline 1-position is much more reactive
N NHCOt-Buch9 4
N
SMe
NHCO-t-Bu
N
Li
N
3n-BuLi
t-Bu
OLi
MeS–SMe
ortho-Lithiation
NMe
H H
ch9 5 NMe+ –I
NaBH4enamine
!-protonationNMe
H H
+
H H
NaBH4NMe
NN
OH
NH N
OH
OH
O
ch9 6
ch9 7 NH2
+ Me OMe
O O
– H2ONH Me
HCO2Me
enamine!-formylation
(Vilsmeier reaction)
DMF, POCl3
NH Me
CO2Me
H
O
N
CO2Me
MeNH Me
CO2Me
H
Cl
+probable intermediate
for electrophilic ring closure
– HCl
NH
O
MeO
CO2Mech9 8(i) NH2
MeO
+
CO2Me
CO2MeNH CO2Me
HCO2Me
MeO
– MeOH
Addition of the aniline to activated alkyneis an alternative to condensation with 1,3-dicarbonyl compond
ch9 8(ii)Cl NH2
+OEtH
EtO2C CO2Et
NH CO2Me
EtO2CCO2Me
Cl
250 °C
CO2Me
Cl NH
O
probable intermediatefor electrocyclic ring closure
– EtOH
NCO2Me
CCO2Me
Cl
O
aq. NaOHCO2H
Cl NH
O
N
CO2H
Phch9 9(i) NH
O
O NaOH
NH2
CO2Na
O+
Me
O Ph
Pfitzinger variationof Friedländer synthesis
ch9 9(ii) NH
O
O KOH
NH2
CO2K
O+
O CO2H
N
CO2H
OH
Cl
N
CO2H
OH
CO2H– CO2
Like decarboxylationof a !-keto-acid
NH
CO2H
Och9 9(iii) NAc
O
ONaOH
NH
MeO
O
NaO2C
N NH
NH
O
Och9 10(i) NH2
O
H
+O N
H
NH
O
O
Friedländer synthesismany variations are possible
N
CO2Me
CO2Me
O
O
ch9 10(ii) NH2
O
H
O
O
CO2Me
CO2Me
+
Addition of the aniline to activated alkyneproduces likely intermediate
O
O NH
O
H
CO2Me
CO2Me
Friedländer synthesismany variations are possible
N
Me
ch9 10(iii) NH2
O
Me
+Me
OS S
Friedländer synthesismany variations are possible
ch9 10(iv) N
O
NH2
O
Ph
+O
O
Me
Me
Me
Me
Friedländer synthesismany variations are possible
N N Me
SO2Ph
ch9 10(v)N NH2
O
H
+
O Me
SO2PhFriedländer synthesis
many variations are possible
N
N Nch9 10(vi)
N
N NH2
O
H
O+
Friedländer synthesismany variations are possible
Chapter 11
O
Me
NHPhMe
Me
O HN
Me
Me MePh
ch11 1
– H2O
O MeMe
Me
PhNH2
NPh
Me
Me
HO
Me
NPh
Me
Me Me
+ H+
+
+
Nucleophilic addition at C-2then electrocyclic ring opening
and ring closure
O
Ph
CH2PPh3Ph
Ph
+ch11 2 O PhPh
Ph
+
Ph3P=CH2
O
Ph
Ph Ph
Ph3P+
Ph3P=CH2
– H+Ph
Ph
Ph
Electrocyclicring opening
Wittig reaction to close
O
OMe
HO
Me O
OMe
O
Me
O
OMe
O
Me
CN
–
++ch11 3 TfO–O
O
HO
Me
MeOTf
CN
Powerful alkylating agentreacts at carbonyl oxygen
1,3-Dipolarcycloaddition
O
NBn
O
MeO2C
NHPh
O
O HN
O
PhNPh
O
HOch11 4– H2O
O
O
PhNH2
HH
H+
NPh
O
O O
MeO2CPhCH2NH2
Amine attack at carbonyl carbonring opening and reclosure
O NH
MeO2C
OH
Bn
– H2O
O
t-Bu
Ot-Bu O
t-Bu
t-Bu t-Bu O
t-Bu
t-Bu t-Bu+ch11 5(i)
O
t-Bu
O
Me
t-Bu
H
O
CH3
t-Bu
– Ph3C+ ClO4–
Aldol Michael Oxidation required at endto achieve aromatic oxidaiton level