Solucionario Joule
46
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
Transcript of Solucionario Joule
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
ch11 5(ii) Ac2O, HClO4
OMe O
Me
Me
O O MeMe+
– H2O
Alkene acylations'Aliphatic Friedel–Crafts reactions'
OMe Ph+ch11 5(iii)
Me
Me O O Ph
O
H
Aldol O OMe Ph– H2O+ H+
Ac2OHClO4
CO2H
O O
O
Me Mech11 6 – CO2
c. HCl, heat
O OHMe
O
Me
O
O MeMe
O
– H2O
CO2EtOH
OEtO2C
Me
Me
ch11 7O
EtO2C
Me
Me OH
CO2Et
O
Me
Me O
EtO2C
OH
EtO2C
Me
Me OH
CO2Et
– EtOH – H2O
O
Ph
Ph Och11 8(i) O
Me
Ph
Ph
CO2Et+NaOEt
Enolate addition toactivated alkynethen lactonisation
O
Et Et
n-Pr n-PrOch11 8(ii) n-PrCO2H
CO2HEt
n-PrHO2C PPA, 200 °C
CO2H
Et
– CO2
+
O
COn-Bu
n-Bu OHOch11 8(iii)
COn-Bu
CO2Hn-Bu OCDI+
First step probablyactivation of acid by CDI
then C-acylation
HO2C
O
Ph C6H4-p-ClOch11 8(iv)
Me
O
Ph O C6H4-p-ClMeO2C
NaH+
First step probablyClaisen condensaation
O
Ph Och11 8(v) Ph O
Cl
O
Me
OMe+ KOt-Bu
First step probablyacylation by acid chloride
Note enol ethersynthon for aldehyde
Chapter 12
O
Me
O
Me
ch12 1 +–Cl
O Me
Me
+–Cl
+HO
O
H
HO
pyridine
O
Selective condensationat !-methyl
O
O
OH
Ac
ch12 2 O
O
Me
CO2Me NaOHthen HCl
OH OMe
O
O
Me
O
– MeOH
Initial addition at C-2
O
O
Me
CO2Me
OH
–
PhO
OMe
ch12 3
O
OH
H
CO2Na
OMe
+Ac2O, heat
O O
OMe PhMgBrthen HCl
–Cl
+Perkin condensation
then lactonisation
O MeHO
Ph
+–Cl
ch12 4(i) OHHO O
O
Me
Ph
+HCl, AcOH
Probable first intermediates
HO O
Ph
Me
O
OH– H2O
HO O
Ph
Me
O
OHO
O
ch12 4(ii)
MeO2C
OOHHO+
H2SO4
HO O
MeOO
Probably via Chapter 14
NN
Cl
NN
OMe
ch14 1(i) NHN
OPOCl3 NaOMe
Nucleophilicdisplacementof !-chlorine
NHN
OPOCl2+
Nucleophilic displacementof !-dichlorophosphate by chloride
Attack at amide-typecarbonyl oxygen
ch14 1(ii)
N
N Cl
BuNH2, 120 °CN
N NHBu
Nucleophilicdisplacementof !-chlorine
NN
Me
SMe
NN
Me
Cl
Mech14 2(i) +
– –
+
I I
NN
SMeMeI
NN
Cl
Me
MeI
Regioselectivity of quaternisationof nitrogen in diazines is not easy to predict
N
N Cl
CHO
Clch14 2(ii)
N
N ClCl
LiTMPN
N ClCl
LiHCO2Et
ortho-Lithiation
N
N OMeMeO
Ph
ch14 2(iii)
N
N OMe
I
MeO
N
N OMeMeO
LiTMPthen I2 HC!CPh, Pd(0)
ortho-Lithiation Sonogashira coupling
N
N NH2ch14 3(i)
N
N N2
N
N NMe2
HNO2, –5 °C+
Me2NH
Easy nucleophilic displacementof nitrogen at !-position
NNPh
Ph
ch14 3(ii)N
N
Me
Ph
PhCHO, Ac2O, heatCondensation with
methyl at an !-position
14 4(i) Cl
+OO O
Cl
AlCl3 O
CO2H
N2H4
Ar NNH
O
Ar NNH
OBr2, AcOH
– HBr
Friedel–Crafts
O
Me
MeO
Me
OMe
NN
Me
Me
14 4(ii) O
Br2, MeOH aq. acid
O OMeMe
– 2H2ON2H4
1,4-Addition to furan
N
N
Me
NH214 5(i)
NH2
H2N NH2+
HCO3–
O
CH(OMe)2
Me
+
Synthon for1,3-keto-aldehyde
NH
N
O
NH2H2N14 5(ii)
NH2
HN NH2
+
OEt
O
N
NaOEtNitrile leads to amino-heterocycle
Ester leads to oxy-heterocycle
NH
NH
O
OH2N14 5(iii)
OEt
O
N
NH2
H2N O
+ NaOEtNitrile leads to amino-heterocycle
Ester leads to oxy-heterocycle
14 5(iv)
N
NH
O
NH2
H2N O+
NaOEtCH(OEt)2
CH(OEt)2
1,1,3,3-Tetraethoxypropanesynthon for malondialdehyde
N
NH
SMe
MeO
N
NMe
MeO
14 6(i)O
OMe
MeO NH2
H2N S
+
OMe
MeOHCO2Et, Na
H2, Ni
Claisencondensation
Hydrogenolysis of sulfurwith Raney nickel
N
NH
Ph
EtO14 6(ii)
NH2
HN Et
O
CO2Me
Ph
+
HN
N
O
Me
Ph
14 6(iii)
NH2
NH2
O
Me
O
O
Ph+
Chapter 16
NH
O2N Me NH
Me
NO2
ch16 1 6:1NH
MeHNO3, Ac2O + !-Position preferred
for electrophilic substitutionEven mild electrophiles react well.
ch16 2(i) NH
CCl3COClNH O
CCl3 Br2
NH O
CCl3Br
NaOMeNH
BrOMe
O
tendency for !-positionsubstitution dominant
!-Position preferredfor electrophilic substitution
NH
Ac
CHOch16 2(ii) NH
NH
CHOAcCl, AlCl3
Deactivated pyrrole requiresLewis acid catalyst for reaction.
meta-Directing groupcontrols regiochemistry
DMF, POCl3
!-Position preferredfor Vilsmeier substitution
ch16 2(iii) NH
ClDMF, POCl3
NH
ClOHCLiAlH4
NH
ClMe
viaN ClH–
!-Position preferredfor Vilsmeier substitution
NH
ClHO
– H2O
ch16 3(i) NH
PhCONMe2, POCl3
NH O
PhVilsmeier !-substitution
NH
NH O
ch16 3(ii) NH
POCl3NHO
Me2N+ Vilsmeier !-substitution
ch16 3(iii) NH
POCl3NH
O+
NH N
Cyclic nature of this Vilsmeier intermediateensures that it does not hydrolyse to ketone
ch16 4 NH
HCl
ketone-like iminium ion notsufficiently reactive
to attack a third pyrrole
Me NH HN
NH HN
HH
H+
+Me
Me
Me
Me
– H+ N
H N
Me
Me
ch16 5 NH
Me MeZn, HCl
NH
Me Me NH
Me Me
Reduction involvesprotonated pyrroleNHMe
Me
H+
+
CO2Me
N
CO2Me
CO2Mech16 6(i) N
CO2Me
MeO2C CO2Me+ 160 °C– H H N
CO2Me
CO2MeMeO2C
Diels–Alder addition and then reverse Diels–Alder loss of ethyne
N NMeCO2Me
ch16 6(ii) NCO2Me
1O2
NCO2Me
O
O
NCO2Me
O
O SnCl2via
NMe
Diels–Alder addition of singlet oxygen
ch16 7NH
CH2O, Me2NHAcOH
NH
NMe2 MeINH
NMe3+
C5H11N
NH
N
viaN HN
H+
Mannich substitutionat pyrrole !"position
electrophile = NMe
Me
+
O
H
MeO
H
OMech16 8(i)n-PrNH2, H
Nn-PrSynthon for
succindialdehyde
+
O
H
MeO
H
OMech16 8(ii)S NH2
N
SSynthon for
succindialdehyde
O
H
MeO
H
OMech16 8(iii)
PhSO2NH2
N
S
Ph
OOSynthon forsuccindialdehyde
NOHEtO2C
Me O
MeO
16 9
hydrolyse,then – CO2,
then N2H4, EtONa
EtO2C
Me OHNO2 Zn, AcOH
NH2EtO2C
Me OMe
O
+
NH
EtO2C
Me Ac
Me NH
Me Et
MeH
NH
Me CO2Et
CO2EtNH2
Me O
CO2EtO
CO2Et
– ++16 10(i)
Cl
NOH
Me O
MeO
CO2Et
Me+16 10(ii)
Na2S2O4
NH
Me CO2Et
MeMeReduction of oxime to
amino in situ
CN
NH2 MeO
CO2Et
+16 10(iii)
NH
H2N CO2Et
Me
Nitrile instead of carbonylleads to amino-substituted
heterocycle
O
OMe
Me Me
H2N CO2Et+16 10(iv)
NH
O
Me
Me
Me
CO2Et
NaOEt
NH
Me Me
CO2EtMeAldolEnamineformation
Chapter 17
Sch17 1 S SO3HClSO3H f. HNO3
S SO3H
O2N
H2O, heat
S
O2N
SO2NS
AcONO2
H!-Position preferred
for electrophilic substitutionmeta-Directing group
dominates
S OMe S OMeO2N
NO2
>
ch17 2 S OMe
HNO3, AcOH–20 °C
!-Selectivity dominates
Sch17 3(i) S
(EtCO)2O, H3PO4 Et
O
Strong benzene-typeconditions can be used
with thiophenes
S
t-Bu
OHCch17 3(ii) S
t-Bu
PhN(Me)CHO, POCl3 Selectivity for the less-hinderedof two !-positions
S Ich17 3(iii) S
Tl(O2CCF3)2
S TlO2CCF3
aq. KI
S Li
OMe
ch17 4 S OMeLiS OMen-BuLi
S
OMe
n-BuLi
Selectivity for !-positionin lithiation dominates over ortho-directivity
Selectivity for that !-positionwhich is also ortho to methoxyl
S H
Br Br
ch17 5 S Br
Br Br
BrMg then H2O
Br S H
Br Br
Mg then H2OH
Grignard formationpreferred at an !-position
S SO
ch17 6 S
n-BuLi
S LiCO2
S CO2HS P4O10
Lithiation selectivefor an !-position
Friedel–Crafts typeconditions usable with thiophenes
ch17 7(i)
CN
CNNC
NCH2S
S NH2
CNNC
H2NNitrile cyclisations
lead to amino-substituted heterocycles
S CO2H
MeO OMe
HO2Cch17 7(ii)EtO2C S CO2Et
OEt
OO
EtO
NaOEt
S CO2Et
OHHO
EtO2C
aq. NaOH, MeI
Double Claisen condensation
ch17 7(iii)
O
Me
O
P4S10
S Me Chapter 18
O OMeH
H O
OMe
O
O OMe O OCO2Me
HOMeH
O
H
H+
+ch18 1 O OMe+ H+ + HO–
! protonation H O O– MeOH
O OMe+ H+
" protonation
+ HO–
H
H+
ch18 2(i) OHC O PhO Ph
DMF, POCl3then aq. NaOH
Furan ring far more reactivethan substituent phenyl ring
Ac O CO2EtO CO2Etch18 2(ii)Ac2O, SnCl4
!-Position preferredfor electrophilic substitution
Mild Lewis acids must be used
CN
OO2NOch18 2(iii)
HNO3, Ac2O
CN
Nitrile substitutent stabilises the systemand allows use of more vigorous reagents
CO2MeOMeO2C
CCl3O
O CO2EtO CO2Mech18 2(iv)
Cl3CCHOH2SO4
Cl3C
HO
O CO2Me
– H2OO CO2Et
Cl3C
via +
!-Position preferredfor electrophilic substitution
of furans
Me O CH2OH
MeO OMe
Me
OH
O
ch18 3 Me O CH2OH[O] MeOH H2, catalyst
Me O CH2OH
MeO OMe
H3O+
Me O CH2OH
O– H2O
1,4-Diketone synthon
Aldol
O Me
Me
O Me
CO2MeLiAlH4
then SOCl2O Me
CH2Cl
LiAlH4 Br2, MeOH
O Me
Me
OMeMeO
H
H2O, 60 °C NaBH4OHC Me
Me
OHOH2C Me
Me
HO H1,4-Keto-aldehyde synthon
ch18 4
ch18 5(i) O Lic-C6H10O
O HOLithiation selectivefor an !"position
O Li Och18 5(ii)Br(CH2)7Cl Cl
Lithiation selectivefor an !"position
O
Me
OHCch18 6(i) O
MeDMF, POCl3then aq. NaOH Vilsmeier substitution
at the less-hindered !-position
ch18 6(ii)O
Br
Br
n-BuLithen H2O
O
Br
Li O
Br
HMetallationselective for !-position
O
Br
CH2OHch18 6(iii) O
BrLDA
then CH2O
O
Br
LiLithiation at that !-position
which is also ortho to Br
O CHO EtOH, H+
O CH(OEt)2
n-BuLithen B(OBu)3
O CH(OEt)2
O CHO(HO)2B
Li
H3O+
O CHO(BuO)2B
Lithiation selectivefor an !-position
ch18 6(iv)
ch18 6(v) O
Sn-n-Bu3
OO
Brn-BuLi, –78 °Cthen n-Bu3SnCl MeCOCl, PdCl2
MeO
ipso substitution of tinallows formation of 3-acyl-furan
O
CN
CH2
CH2OH
18 7(i) O CH2OHC
CN
Furans behave like 1,3-dienes and undergoDiels–Alder cycloadditions
O
AcMe
Me18 7(ii) O MeMe
OMe Furans behave like 1,3-dienes and undergo
Diels–Alder cycloadditions
O
O18 7(iii) O O
Cl
+ Et3N, LiClO4Furans behave like 1,3-dienes and undergo
cycloadditionsm with 1,3-dipoles
O O
TMSClEt3N, ZnCl2
18 8(i) O OTMS O-Silylation of butenolidesgives 2-trimethylsilyloxy-furans
18 8(ii) O OTMSICH2CN, AgO2CCF3
O ONCCH2
Electrophilic substitutionof 2-trimethylsilyloxy-furans
produces 5-substituted butenolides
18 9 O Ot-Bun-BuLi
O Ot-BuLiPhCHO
O Ot-Bu
HO
Ph
TsOH– C4H8 O O
HO
Ph
Lithiation of furansselective for an !"position
O Et
18 10(i) O Et
H MgBr
HO Et m-CPBAHO Et
OCrO3pyridine
O Et
O
BF3via HO Et
O
O
Me
– H2O18 10(ii)
MeClMgHC(OEt)3
Me
OHCm-CPBA
Me
OHCO H3O+
via
MeO
OH
Me
O CO2Me18 10(iii)
Me
(MeO)2HC OClCH2CO2Me, NaOMe
Me
(MeO)2HCO
CO2Me
heatDarzens reaction
MeO2C
MeHN
CO2Me HOH2C
MeHN
CO2Me
MeHN
OOch18 11
CO2Me
CO2Me
MeNH2 LiAlH4 H+
H3O+HO
OO
Selective reduction – otherester is a vinylogous amide
Chapter 20
ch20 1 NH
+
NMe
O
POCl3
NH
ONHMe
Electrophilic substitution of indolespreferred at a !-positionVilsmeier reaction
NH
O
Me
Me
Me
ch20 2 NH
+
Me
Me
Cl
HO NH
Me Me
HO
Me
Me+
Electrophilic attach on an indolepreferred at a !-position
ch20 3 indole,
NH
NH H+
NH
NH2
NH
via
NH
NH2+
ch20 4 NH
CH2O, Me2NHAcOH
NH
NMe2
MeI
NH
NMe3 I+ –
KCN
NH
CN
LiAlH4 H3O+
NH
NH
CO2H
viaN
NC–
Mannich reactionpreferred at indole !"position
NH2
selectivequaternisation
of amine
N
PhBr
PhSO2
ch20 5(i) N
IBr
PhSO2
PhB(OH)2, Pd(PPh3)4aq. Na2CO3
Suzuki coupling
N
Br
CO2Et
PhSO2
ch20 5(ii) N
IBr
PhSO2
CO2Et
Pd(OAc)2, Ph3P, Et3N
Heck reaction
NN
H
O
Ph3P+–
ch20 6 NH
H
O
Ph3PCH=CH2+
Br–
NaH Wittig
Deprotonation of indole N–hydrogengives indolyl anion nucleophilic at nitrogen
NH
Et
Me
and
NH
Me
Et
ch20 7 N
EtMe
+ H
NH
Et Me
+
1,2-Migrationthen loss of proton+
NH
ch20 8
N
N
N
PhSO2
NaHPhSO2Cl
t-BuLi, –100 °C
N
N
PhSO2
Li
Deprotonation of indole N–hydrogengives indolyl anion nucleophilic at nitrogen
Lithiation withortho-assistance from pyridine N
+
O
N
N
PhSO2
OH
aq. NaOH
NH
N
OH
HBr
NH
N
Br–
NH
I
ch20 9 NH
n-BuLithen I2
LDAthen PhSO2Cl
PhSO2N
ILDA
then I2
PhSO2N
I
I
Indolyl anion can reacton N or C
Indolyl anion can reacton N or C
Lithiation atpreferred !-position
NH N
H
CH2HO
NH
+
– CH2O
ch20 10 NH
CH2OH
heat, H+
– H2O +
startingindole
NH
NH
NH
ch20 11 NHNH2
+O
H+
NH
N
H
OHOH
Fischersynthesis
Synthon for 4-hydroxybutanal
NH
N
CO2Etch20 12
N Me
NO2
(CO2Et)2, NaOEtN
NO2
CO2Et
O
H2, Pd/C
NH
NCO2Et
N
Me
NO2
(CO2Et)2, NaOEtN
NO2
CO2Et
O
H2, Pd/C
Easy deprotonationof pyridine 2-methyl
also ortho to nitro gorup
Easy deprotonationof pyridine 4-methyl
also ortho to nitro gorup
Reduction of nitro to aminothen condensation with loss of water
Reduction of nitro to aminothen condensation with loss of water
NH
NH2
ch20 13(i)
NO2
NO2
NMe2TiCl3
NO2
Me
NO2
DMFDMA, heat
DMFDMA MeO NMe
Me
+–
H
MeO+
Deprotonation of methylortho to nitro
then reaction with MeO(H)C=NMe2then loss of MeOH
Reduction of nitro!-protonation of enamine, cyclisation
and loss of Me2NH
NH
BnO
ch20 13(ii)
H2, PtDMFDMA, heat
BnO
NO2
NMe2
BnO
Me
NO2
DMFDMA MeO NMe
Me
+–
H
MeO+
Deprotonation of methylortho to nitro
then reaction with MeO(H)C=NMe2then loss of MeOH
Reduction of nitro!-protonation of enamine, cyclisation
and loss of Me2NH
NHMeOch20 13(iii) NO2
NMe2
MeO
H2, PdMe
NO2MeO
DMFDMA, heat
DMFDMA MeO NMe
Me
+–
H
MeO+
Deprotonation of methylortho to nitro
then reaction with MeO(H)C=NMe2then loss of MeOH
Reduction of nitro!-protonation of enamine, cyclisation
and loss of Me2NH
NH
NH
ch20 13(iv)
H2, Pd
NO2
NO2
NMe2
Me2N
Me
NO2
NO2
Me
DMFDMA, heat
DMFDMA MeO NMe
Me
+–
H
MeO+
Deprotonation of methylortho to nitro
then reaction with MeO(H)C=NMe2then loss of MeOH
Reduction of nitro!-protonation of enamine, cyclisation
and loss of Me2NH
Chapter 21
S
S
N
ch21 1 SH S
OCO2Et PPA, heat
CO2Et
– H2O
NH3
S
CONH2
LIAlH4
S
NH2
HCO2H, heat
SO
NH
H
POCl3, heat
EtO2CCH2COCH2Cl
Intramolecular Vilsmeier
O
Me
Me
Me
Me
Mech21 2(i)
Me
Me
Me
OH
MeMe
Cl
O
Me
Me
Me
O Me
O Mec. H2SO4
O
MeO
OO
ch21 2(ii)
MeO
OO OH
BrK2CO3
MeO
OO O
heat
MeO
OO OH
O3
MeO
OO OH
H
OH+
– H2O
Claisen rearrangement
S
F3C
CO2Mech21 2(iii)
F3C
F
LDAthen DMF
F3C
F
CHOHSCH2CO2Me
ortho lithiation
O
O2N
Mech21 2(iv)
O2N
F
Me2C=NO Na+–O2N
ON
Me Mec. HCl– NH3
S
ClO
S
Cl
HN
ch21 3
Cl
S CO2H
PCl3then AlCl3
Cl
S
O Cl
PhNHNH2AcOH, heat
S
ClN
HN
Fischer indole synthesis
Friedel–Crafts
Chapter 22
NH
N
t-Bu
O
t-Bu
O
H Hch22 1
NPh
O
O
t-Bu
OCH2Br
CH2Br
H2NCH2C!CH
NHt-Bu
O
500 °C
NPh
O
O
Typical Diels–Alder reactivity of isoindoles
NMe
H CN
H CN
NMe
CN
ch22 2(i)
CHO
CHO
NaHSO3then MeNH2 NMe
H OSO3H
H OSO3H
2KCN
– HCN
O
O
HPh
O
Ph
Ph
O
Ph
Ph
O
O
ch22 2(ii)
O
NEt2n-BuLi
then PhCHO O
NEt2
OH
Ph
+H
PhMgBrthen H+ 1O2
ortho Lithiation
Cycloaddition of singlet oxygen
CHO
O
CO2Me
CO2Me
O
O
ch22 3
CHO
CHO
(CH2OH)2, CuSO4 NaBH4O
O
OH
TsOHMeO2CC!CCO2Me
O
Typical Diels–Alder reactivityof isobenzofurans
S
CO2H
CO2H
O
O
Och22 4
S O
O
O
+
NaOH, heatthen H+
Typical Diels–Alder reactivityof benzo[c]thiophenes
Chapter 24
NH
N
Cl
Cl
ch24 1(i) NH
NNaOCl Electrophilic substitution
preferred at C-4(5)
NMe
N
Br
Br
NMe
N
Br
Li
BrNMe
NBr2, AcOH
EtMgBrthen H2O
NMe
N
Br
Br
MgBr
NMe
N
Br
Br
H
n-BuLithen (MeO)2CO
NMe
N
Br
MeO2C
Sective metal/halogenexchange at C-4
Sective Grignardformation at C-2
ch24 1(ii)
N
O
Ph
Ac
Ac
O– PhCNch24 2(i) O
NPh
+ HMe
Oheat
Oxazoles (like furans)take part in Diels–Alder cycloadditions
Retro Diels–Alderloss of benzonitrile
N
O
CO2Me
CO2Me
O
CO2MeEtO
MeO2C
OEt– HCN
ch24 2(ii) O
N
EtO+ MeO2CH2 CO2Me heat
Oxazoles (like furans)take part in Diels–Alder cycloadditions
Retro Diels–Alderloss of HCN
ch24 3i/ii NMe
N
O2N Me
(t-BuO)2NMe2heat
NMe
N
O2N NMe2Ac2O, heat
NMe
N
O2N NMe2
Me O
enamine !-acetylation
NMe
N
O2N
N
N
MeNH2
NH2
NH2HN
NMe
N
O2N
NNMe
Me
MeNHNH2
1,3-aldehydo-ketonesynthon
ch24 4 NMe
N n-BuLithen TMSCl
NMe
N
Li
n-BuLithen TMSCl
NMe
N
SiMe3
NMe
N
SiMe3 NMe
N
SiMe3Li Me3SiMeOH
Selectiveipso protonolysis
NMe
N
HMe3Si
Selective lithiationat C-2
Selective lithiationat C-5 if C-2 blocked
ch24 5 NMe
NBr
n-BuLi, –78 °Cthen DMF
NMe
NLi
NMe
NOHC
NMe
NBr
n-BuLi, –78 °C ! 0 °Cthen DMF
NMe
NLi
NMe
N
Li NMe
N
CHO
equilibration tomore stable lithium compond
S
NH
S S
NH
S(CH2)3BrS
N
S(CH2)3Br
S
N
S
–+
–+
– H
Br
Br
+ch24 6
Br(CH2)3Br
S-Alkylation
S
N
NH2
Et
ch24 7(i) S
NH2
NH2+
Cl
OEt
S
N
Phch24 7(ii) Cl
OH
S
NH2
Ph+
S
NHO
ch24 7(iii) Br
OEtO2C
S
NH2
H+ ester oxidation level
leads to oxy-heterocycle
O
NPh
N
O
CH2OAc
CH2OAcPh O
AcOCH2 CH2OAc
ch24 8
– PhCN
Br
OPhNH4 HCO2+ – AcOH2C CH2OAc
heat
Diels–Alderthen retro-Diels–Alder
NH
N
Phch24 9(i) N CMen-BuLi
N CLiH2CPhCN
NH
N
Ph
Ph
NH2
ch24 9(ii)NH2
Ph
Ph
O+
N
NH2
Use of nitrile in cyclisationleads to amino-heterocycle
Chapter 25
O2N
NPh
Nch25 1(i) N
Ph
Nc. HNO3, c. H2SO4 via attack on salt
(but positively charged heterocyclestill more reactive than the phenyl group) N
Ph
NH+
ch25 1(ii) NPh
NHNO3, Ac2O
NPh
NO2N via attack on the neutral pyrazole
ON
Me
Mech25 2(i)
NaNH2
ON
Me
NaH2C ON
Me
n-Prn-PrBr
Selective deprotonationof 5-methyl
ch25 2(ii) ON
Me
MeNaNH2
ON
Me
NaH2C ON
Me
HO2CCO2
Selective deprotonationof 5-methyl
ch25 2(iii) ON
Me
MeNaNH2
ON
Me
NaH2C ON
Me
PhCO2MePh
O
Selective deprotonationof 5-methyl
ONMe O
CN
Me
ClCl
ch25 3 ONMe
SO2Cl2 aq. NaOH
via
ONMe
Cl HHO–
Selective electrophilicsubstitution at C-4
Me NBn
N
CO2Me
NBn
N
Me
MeO2Cch25 4OMe
O
CO2Me
BnNHNH2 +
NSO2NMe2
NMe3Si NSO2NMe2
N
ch25 5 NH
NMe2NSO2Cl, Et3N
NSO2NMe2
N
n-BuLithen TMSCl
NSO2NMe2
NLi
PhCHO, CsFPh
HO
Removal of acidic N-hydrogenonly requires weak base
Selective lithiation at C-5
ON
ON
Ph
Phch25 6 OH
O
Ph
H2NOH +
ON
ch25 7(i) HON
2n-BuLithen DMF
ONLi
LiO
NOHC
Li
– H2O
ch25 7(ii) SNOH
Br Me3Si Li MeOH, K2CO3
SN O
SiMe3
SNOH
SiMe3via
NNPh
MeMe
ch25 7(iii)N
Me Me
ONHPh
(EtO)2P(O)CH2SEt, n-BuLi via N
Me Me
NHPhSEt – HSEt
ONMe3SiCH2ch25 8 Me3Si SiMe3
H2NOH
Chapter 27
ch27 1(i)
HN
N N
N
O
OAcO
AcO OAc
H2N
N
N N
N
NH2
OHO
HO OH
I
N
N N
N
NH2
OHO
HO OH
Ph
POCl3N
N N
N
Cl
OAcO
AcO OAc
H2N
t-BuONO, CH2I2
via the diazonium salt
N
N N
N
Cl
OAcO
AcO OAc
I
NH3, MeOH
PhB(OH)2Pd(PPh3)4, Na2CO3
Selective nucleophilicdisplacement of 6-chlorine
Suzuki coupling
viaHN
OP(O)Cl2+
PhCO2EtNaOEt Ac2O
POCl3 NH3
N
NH2N
H2N
OHO
HO OH
N
NH2N
NH
O
OHO
HO OH
O
Ph
N
NH2N
NH
O
OAcO
AcO OAc
O
Ph
N
N N
N
Cl
OAcO
AcO OAc
Ph
N
N N
N
NH2
OHO
HO OH
Ph
ch27 1(ii)
HN
N N
N
O
OAcO
AcO OAc
Phvia
PhB(OH)2Pd(0)
Br2AcOH
ch27 2
N
N N
N
NH2
OHO
HO OH
N
N N
N
NH2
OHO
HO OH
BrN
N N
N
NH2
OHO
HO OH
Ph
Selectivebromination
at C-8
Suzuki coupling
NH
NMeN
N
NH
NH
NN
N
NHMe
MeN
N N
N
NH
ch27 3
N
N N
N
NH2
OHO
HO OH
Me2SO4
OHO
HO OH
aq. HCl
aq. NH3 via Dimrothprocess
NH
NMeN
NH
NH
O NH
NH2N
NH
NMe
OH
H+
– H2O
N-1-quaternisationthen N-deprotonation
Hydrolytic removalof sugar
NH
NN
N
NH2
N
N
NH2
ch27 4(i)
NH2
NH2
HCONH2, heat
NH
NHN
N
O
Me
SH
ch27 4(ii)
HN
N
O
NH2
NH2Me
HCS2 Na+– quinolineheat
Chapter 28
N N N n-Bu
ch28 1
N+
Br–
LiAlH4 H2, Pd
Electrocyclicring opening
N
–
+
I
ch28 2 N Me
LDAthen EtO(CH2)2CH=O
N CH2Li N
EtO
H
OH
HI, heat
NH
OH
+
–I
Pd/C, heat
N+
–I
Ac2O, heat
Side-chainlithiation
– H2O Dehydrogenationto aromatic molecule
N
Me
ch28 3(i)(a)
N Me
+ BrMe
ONaHCO3
via
N Me
Me
O+–Br N
Me
O
Quaternisation ofnitrogen
NMe
ch28 3(i)(b)
N Me+ Br
H
ONaHCO3
Me
via
N Me
H
O+–Br N
H
OMe Me
Quaternisation ofnitrogen
ch28 3(ii) N
NMe
N
N
Me
N NH2
+ BrMe
ONaHCO3
N NH2+ Br
H
ONaHCO3
Me
via
N NH2
Me
O+–Br N NH
Me
O
via
N NH2
H
O+–Br N NH
H
OMe Me
Quaternisation ofring nitrogen
Quaternisation ofring nitrogen
N
N
OMe
ch28 4
N
Me
OMe
KNH2, i-AmONO N
OMe
HON H
Zn, AcOH N
OMe
H2N
HCO2Me, PPE
Side-chain lihtiation
N
N
HNN
Nch28 5
HNO2
N
N
NOHN
N
N
H
OH
OH+HOO
H
– H2ON
NO
N
Electrophilic nitrosationof five-membered ring
NONNHNO2
Electrophilic nitrosationof five-membered ring
S
N
N
NN
ch28 6(i) S
N
NHNH2
HNO2 viaS
N
NH
NN+
S
N
N
Ph
ch28 6(ii) S
N
NH2+ Br
Ph
O
viaS
N
NH2
Ph
O+ –Br
Chapter 29
N
N
ch29 1(i)(a)
N
N
NN
+ via – HCN
N N
N
N
– pyrrolidine
N
N
NN
N
+ via – N2
N NN
N
– pyrrolidinech29 1(i)(b)
NN
Ph
EtO
ch29 1(ii)
N
NN
N Ph
+
EtO OEt via – N2
N NN N
EtO OEt
– EtOHPh
N
SN
N
Cl
N
SN
N
MeHN
HN
SN
N
MeNch29 2
Cl
SCl
NaN3 MeNH2
N
NH
NPhch29 3(a)
NH2
OPh
DMFDMAN
OPh
NMe2 N2H4
DMFDMA MeO NMe
Me
+–
H
MeO+
attacks the NH2
N
ONPhch29 3(b)
NH2
OPh
DMFDMAN
OPh
NMe2 H2NOH
DMFDMA MeO NMe
Me
+–
H
MeO+
attacks the NH2
N
NH
NH
NH
N
NH2NH2
N
NH
N
NH
N
NH2NH2
ch29 4(i)
N
N
N+ H2N
N NH2
NH2
NH
NH
N
HN N
HNH
NH2 NN
NH
NH2
N
NH
NH
CO2EtCO2Etch29 4(ii)
N
N
N+ CH2(CO2Et)2
N
NH2
N
CO2EtCO2Et
N
N OOEt
CO2Et
NH2
N
N
CO2Et
O
NH2
+
N
NH
CO2Et
O
