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Chapter 3
Synthesis of aromatic heterocycles
SYNTHESIS OF AROMATIC HETEROCYCLESCONSTRUCTION OF THE RING SKELETON
I. Carbonyl condensation type reactionsII. Cycloadditions
a) with 1,3-dipolesb) with ortho-quinodimethanes (DA type react.)
III. Nitrene insertion
Carbonyl condensations
X
a
bX
X
X
a
b
X
X
Strategy a) - 5-membered rings
XX
1,4 dicarbonyl
X=N: NH3, RNH2
OO
HH LR
SS
HHc.f. furan
S
PS
MeO SPSS
OMe
LH: Lawesons reagent
Pyrrole
Furan
Thiophene
(Paal-Knorr Synthesis s 255)
OO
HH
±HHNO
HH
OHR
±H NR
HH
OHHO - 2 H2O NR
R-NH2
OO
HH
OOH
H
±H O
H
OHO
H- H2O
Strategy a) - 6-membered rings
X X
1,5-dicarbonyl
X=N: NH3
HO O
NH3
NHHO OH
H
- 2 H2O N
X X
Strategy b
5-membered rings
6-membered ringsX X
Enol(or phenol)
Enamine(or aniline)
O
EWGH
H
O
EWG HHX
O
EWG: CN, COR etc.X: NR; O, S
O
EWGH OH
XH±H ±H
X
H OHEWG
HOHH
- 2 H2O
X
EWG
HOHX
O
X
NHHO
HOH
- 2 H2O
NO
OH
H
N ±HNH
HOH
O
H
NH2
OH
O
H
H
H±H
1,3-Dipolar Cycloaddition
Only 5-membered rings
OO
O O OO
Ex. ozonolysis
ab
c
d e d e
cb
a
Alkene / alkyne
1,3-dipol
NO
nitriloxide
NO O
POCl3R3N- H2O
R
RN
O
R
R
isoxazole
I. Carbonyl condensation type reactionsII. Cycloadditions
a) with 1,3-dipolesb) with ortho-quinodimethanes (DA type react.)
III. Nitrene insertion
Cycloaddition with ortho-Quinodimethanes
NMe
Br
BrNaIΔ N
Me
O
O
O
NMe
OO
O
Electrocyclicring opening
X
X- 2 HX
- SO2
SOO
Diels-Alder
X
X X X
X
Ring formed carbocyclic
Generation of nitrenes
R N N N R N N N R N
R C
R
RN
OS
Ar
H O O
azide(1,3-dipol)
R NO
O
Δ or hν
Nitrene
(c.f. carbene)- N2
B
P(OEt)3
I. Carbonyl condensation type reactionsII. Cycloadditions
a) with 1,3-dipolesb) with ortho-quinodimethanes (DA type react.)
III. Nitrene insertion
Insertion R'-N + R3C-H R3C NR'
H
Add. to double bonds R'-N + R2C=CR2N
R R
R RR'
Rearrangement C NH
R'R C N
H
R'
RDominating react alkyl nitrenes
Abstraction R'-N + R3C-H R'-N-H + R3C
Dimerisation 2 R'-N R'-N=N-R'
React. of nitrenes
H NO2 H N NH
Nitrene insertion - Heterocyclic synthesis
N+H R NH
R
Chapter 5
Pyridines: reactions and synthesis
Chapter 4
Typical reactivity of pyridines, quinolines and isoquinolines
PyridineN
QuinolineN
Isoquinoline
N
Pyridine
N1
2
34
5
6 α
β
γ
α
β
Synthesis - Carbonyl condensations
X X
1,5-dicarbonyl
X=N: NH3
Strategy a - Chapt 3
X X
Strategy b - Chapt 3
From 2 equivs. 1,3-dicarbonyl , aldehyde and ammonia - Hantzsch Synthesis
X X
C
O
OH
O
OH
O
NH
-3 H2O
H OO
Dihydropyridine
ox
N
OO
SymmetriNH3
(- H2)
Pyridine - Reactivity
Reaction with electrophiles - react. on N:•Protonation•Nitration•Sulfonation•Amination•Halogenation•Alkylation•Acylation
N
E
N
E
Mild, not acidicelectrophile
NuE-Nu +
N
NF OTf
NNO2
NS OOO
BF4
N
N
DMAP
N
N
O
Ac2O
AcO
ROH
Reaction with electrophiles - react. on C - E-fil Ar subst
•Nitration•Sulfonation•Halogenation
NOT:•FC Alkylation•FC Acylation
N N N N N
in the 3/5 pos
Difficult:•Electron defficient ring (poor Nu)•Electrophiles may react at N
N
conc. H2SO4cat. HgSO4
N
SO3H
70%220 oC
N NHgSO4
N
Hg-SO4H
N
SO3H
- HgO
Sulfonation
Possible intermed.
N
Br2 / conc. H2SO4or Cl2 / AlCl3
N
X
X=Br; 66%X=Cl; 33%
X2PdCl2
N XNH
O
POX3
PdCl
Cl
NN
Via:(See reactivity of pyridones)
Nitration
Halogenation
N
KNO3 / H2SO4
24 h, 300 oC NH
N
NO2
6%
N RR
NNO2
R=H
R=Cl
N ClCl
NO2
NO2 BF4
BF4
Nitration - Bakke (NTNU, http://www.chem.ntnu.no/organisk/ansatte/Bakke/jb.html)
NN
ON
O
O
O
O NNO2
Pyridinium cationactivated for Nu-attack
SO
O OH
NOSO2HH
NO2N H
OSO2H
NO2H
N
NO2
68%
NO3
Na
- HOSO2H
H
123
4
5 H5
1
[1,5]-sigmatropic rearrangement
OH
OH
More electrophil C than neutral carbonyl
Reaction with nucleophiles
N N N N N
a) X=H, Substitution with “hydride” transfer
Nu: NaNH2 - amination - Chichibabin reaction
Nu: BuLi, PhLi etc - alkylation / arylation
Nu: NaOH - “hydroxylation” - NB! High temp} Attack in the 2-pos (not 4-pos)
a) X=Hb) X=Good leaving group
b) X=LG, Displacement of good leaving group
X: Halogen (F>>Cl,>Br,>I), -OSO2R, -NO2, -OR
N X
NuN Nu N
NuN
X Nu
N
X Nu
X Nu XNu
X
Nu
X
NuNu
+ X
SNAr
•SNAr •SN1: Via diazonuim salts and arylic cation•Benzyne•SRN1: Involves radicals•VNS: Vicarious nucl. Subst.
N
Br NaNH2, ButOKR2NH
N N
NaNH2, ButOKR2NH Br Nu
N
NR2
N
NR2+
HH
BB
NN
Br
BHMore difficult to generate
Metallation and reactions with electrophiles
Direct metallation
Direct metallation with ortho directing group (ODG)
Metal halogen exchange
N
Cl
LDA
N
ClLi E
N
ClE
N Bu-Li
N Br
Br 1) BuLi
- 78 oC
2) E
- 78 oC - r.t. N Br
E1) BuLi2) E
- 90 oCN E
Br
N
BuLi / ButOKlow temp N K
Kinetic
N
K
N
K
E
NE
Mixt of isom.
Metallation and reactions with electrophiles
N
Li
R R'
O1)
2) H+/H2O
N
HO RR'
DMFN
O
1) ArCN
2) H+/H2O N
O
Ar
Br
N
I2
N
I
R3SnX
R3SiX
ZnX2
N
SnR3
N
SiR3
N
ZnX
Pd-Catalyzed Coupling reactions
a) On metallated pyridines
N
Met Ar-Xcat. "Pd"
N
Ar Met = -SnR3; Stille couplingMet= -B(OR)2; SuzukiMet= -ZnX; Negishi
b) On halopyridines
N
X Ar-Metcat. "Pd"
N
Ar Met = -SnR3; Stille couplingMet= -B(OR)2; SuzukiMet= -ZnX; Negishi
N
XR
cat. Pd, CuX, R3N
N
RSonogashira coupling
N
X cat. Pd, Base
N
Heck coupling
R R
N
RR'NH, cat. "Pd", Base
NHartvig - Buchwald
Br NR
R'
N X N
X
N
X
Reactivity
X=IX=Br / OTfX=Cl
Pd(0)
Ar'-Met
Ar-Pd-Ar'
Met-X
Oxidativeaddition
transmetallation
reductiveelimination
Ar-X
Ar-Pd-X+II+II
Ar-Ar'
Polarity in couplings
ArX + Ar’Met or Ar’X + ArMet??
ca. electrophile
ca. nucleophlile
Substituted pyridines - Structure and reactivity•Oxy-, Thio- and Aminopyridines•Alkyl- and Vinylpyridines•Quartenary Pyridinium Salts•Pyridine N-oxides
Oxy-, Thio- and Aminopyridines - Structure; Tautomery
NHO NH
ON
HO
N NH
OH O
NH
O
NH
O
2-Pyridone 3-Hydroxypyridine(c.f. phenol)
4-Pyridone
NH
S
N
HS
Thio:
NH
S
NH2N NH
HNNH
HN N
H2N
Amino
N
NH2
Oxypyridines - Reactivity
Reaction with electrophiles
N
OH
H
E o/p-directing
NH
OH
N
EOH
N
OH
N
OH
E E
N-protonation as pyridine
NH
O
N OHo/p-directing
NH
O
E
NH
O
E
NH
O H NH
O H
O-protonation as amides
NH
O
pKa≈11
BaseN O N O
R-X
Ambident anion
N O N O RR
and / or
NH
O
Me3SiNHSiMe3(HMDS)
Δ N O SiMe3R-X
N OR
Replacement of Oxygen
N OH
(CF3SO2)2OBase
N OSO2CF3
Pd-cat. couplings etc
Triflate
Deprotonation - O or N substitution
c.f. silyl enol ethers
N O
P
O
ClCl
Cl
H
NH
OP
O
ClCl
NH
Cl
O P
O
ClCl
N Cl
Cl
B
Thiopyridines - Reactivity
N S
H
Cl
O
R Base
N S
O
R
Useful synthetic intermedites
R'MgXR'
O
R
ketone
N S
O
R
NHProt + H2NProt
R'
ONH
O
R
NHProtR'
Prot
O
Peptide
N S
OOHn
NH
S
OO
heat
n
N SH
O n
O
Lactone
Aminopyridines - Reactivity
N NH2
H
N NH2H
NH
NH2
pKa 7.2
HN
H
NH
NH
pKa 9.1
HNH2
NH2
NH2
NH
NH2
N
NH2
HpKa 6.6
HN
NH3
HpKa -1.5
Aminopyridines - Reactivity
Alkylpyridines - Reactivity
Vinylpyridines - Reactivity
N
NH2NaNO2, acid
N
N2
HBrBr2
NH
O
N
Br
N
F
H2O
HF
c.f. enolate anionR
CH3O O
R
CH2 O
R
CH2
N CH3
Base N CH2
N CH2
E
N CH2E
Basec.f. Michael type add.
N N
Nu-H
N
Nu
R
O
R
O
Nu
Quartenary pyridinium salts
NR
NR
NR
Nu
NR
Nu
Hand / or
NR
H Nu
R-X
X
N
Add of: -hydrides -dithionite -organometallics -stab. carbanions etc. etc.
Hard Nu Soft NuBig R
NR
PhMgBrCuI
NR
H PhCleav. of ROx.
N
PhR: -SiMe2But -SO2R -CO2R
Co-enz.NAD+
N
O
NH2+ Sub-H2
NAD+
N
O
NH2
NADH
H H
+ Sub + H
Hydride add. to NAD+, SubH2 oxidizedNicotine amide: Vit. B3Adenine: Vit. B4
N
ONH2
O
OHHO
OPOP
OO
O OO
ON
HOHO
N
NN
NH2
N
N
Nicotine
[ox]N
CO2H
Nicotinic acid
Pyridine N-oxides
N
HO OH
(or peracid etc)
NOH
+ OH N
O
+ H2O
O
OO
H
Cl mCPBA
N
O
+ PPh3N
+ O=PPh3
NN
OO
Pyridine N-oxides
N N N N N2.22D
4.25DNO
NO
NO
Neg. charge i α,γ pos.
NO
NO
More activated for electrophilic and nucleophilic attack
Pyridine N-oxidesElectrophilic Ar. subst
N
O
E N
O
E
N
O
H E
N
OH
N
O
E
c.f. Electrophilic Ar. subst on pyridine / pyridinium cation(difficult reactions)
H
B
+ resonanse forms
N
KNO3 / H2SO4
24 h, 300 oC NH
N
NO2
6%
N
O
conc. HNO3conc. H2SO4
160 oC N
O
NO2
48%N
O
H NO2
+ resonanse forms
Pyridine N-oxidesRearrangements etc.
N
O
N
OAcNOAc
HOAc N OAc
hydrolysis
NH
O
Ac2O
OAc -AcOH
N
O
CH3 N
OAc
CH2
H NO O N
O
O
Ac2O
OAc