THIOPHENES
S
Reactions with electrophiles at C
Preferably at C-2 / C-5 (cf pyrroles)
E
X
X
H
H
X
H
H
most stable
E
H
H
H
-Protonation
X
H
H
X
H
X: NR, S, O
X
• Much more stable under acidic conditions than pyrroles and furans
• Protonation at C-2 /C-5
100% H3PO4
90 oC
S
S
H
H
S
H
H
S
H
H
Reactions with electrophiles at C
-Nitration
NO2
• Not complete selectivity
• Not HNO3 (explotions)
NO2
BF4
or
NO2
AcO
+
S
S
NO2
ca 9 : 1
" NO2
S
+"
O2N
+
NO2
S
NO2
O2N
S
NO2
ca 1 : 1
NO2
" NO2
S
NO2
+"
O2N
NO2: m-Directing
S
S
Reactions with electrophiles at C
-Halogenation
ca 108 times more reactive than PhH
Chlorination
NCS,
HClO4
SnCl4
Pb(OAc)4
Cl
S
Cl
Cl
"Zeolite"
S
S
Cl
Br
S
S
250 oC
Bromination
Br
S
S
Br
Br
S
Br
NaBH4
DMSO, r.t.
Br
S
S
Br
Br
3 Br2, 48% HBr
NaBH4, Pd(0)
Br
S
Br
MeCN, Δ
Zn
AcOH, Δ
S
Br
Br
S
S
90 oC
Br
2 Br2, 48% HBr
75 oC
S
I2, HNO3(aq)
-25 — 5 oC
-10 — r.t
DMF
Cl
Iodination
2 Br2, 48% HBr
S
CuCl
CuI
DMF
I
S
I
Reactions with electrophiles at C
-Acylation
(FC alkylation not good react)
RCOCl
SnCl4
S
R
S
FC acyl.
(strong Lewis acid, AlCl3, polym.)
ketone
O
POCl3, DMF
(Vilsmeier)
S
aldehyde
O
-Condensation with carbonyl comps
H
O
R
OH
R'
R
S H
R'
S
- H
+ res forms
c.f.
H+,
N
H
RCHO
R=H, alkyl
N
H
OH
R
H
H
S
±H+
N
H
OH
R'
R
OH2
RH
- H2O
H
Decomp
N
H
H
R
Polymer
Reactions with electrophiles at C
-Condensation with carbonyl comps, cont.
CH2O, conc. HCl
S
0 oC
Cl
S
-Condensation with imines / iminium ions
Mannich react.
in case of pyrrol,
Mannich reag. generated in situ
CH2O, R2NH, H+
R
N
N
H
R
iminium ion gen. in situ
N
H
HR
N
R
-H
N
H
R
N
R
Thiophene (and furan): Preformed reagent generally required
But:
Me2N=CH2 Cl
S
MeCN, Δ
S
H2CO (aq)
NH4Cl
N
S
S
NH2
Reactions with electrophiles at Sulfur
•Possible for thiophene; S in 3rd row
•Not possible for furan / pyrrole; O and N in 2nd row
E
S
S
E
Me Me
Me
S
Me
O
O S F
Me O
•Probably sp3 S. tetrahedral
•Works best for electron rich thiophenes
Me Me
Me Me
NaPF6
Me
S
Me
Me
S
Me
Me
O
O S F
O
Me
PF6
+ FSO3Na
Reactions with electrophiles at Sulfur
React. with carbenes
N
N
RO2C
CO2R
S
Rh2(OAc)4
RO2C
N2
N
CO2R
95%
Carbene
RO2C
S
CO2R
RO2C
Stable ylide
N
RO2C
S
CO2R
S
RO2C
60 oC
CO2R
S
H
CO2R
S
CO2R
CO2R
CO2R
CO2R
Reactions with electrophiles at Sulfur
React. with carbenes
H
N
1) Rh2(OAc)4
S
N
S
2)
CO2R
CO2R
S
H CO2R
S
CO2R
??????
H
H
O
H
OR
S
H
H
H
S
CO2R
O
OR
CO2R
S
H
H
Reactions with electrophiles at Sulfur
[ox]
[ox]
S
O
S
S
O
O
Not aromatic
R
R
R
R
O S
R
EWG
mCPBA
S
S
O
O
O
R
EWG
R≠ H
rel. stable
R
- SO2
- EWG-H
R
Reactions with nucleophiles
NB! Electron rich Aryl
X
S
N
O
ca 100 times for reactive than
O
Nu
X S
O
N
Nu
O
Nu
Sulfur
stab. neg, charge
on α-C
Nu
X S
O
N
O
S
NO2
X
NO2
Reactions with nucleophiles
Vicarious Nu subst (VNS)
H
EWG
R
X
S
N
EWG
R X
Base
H O
N
O
S
O
O
X
Br
CuX
X=Cl, I
S
S
CuBr
MeONa
Mechanism??
OMe
S
EWG
EWG
R
R
O
S
N
O
S
NO2
C-metallation and further reactions
Ex. E = OR
In the 2 / 5 pos.
"E+"
n-BuLi
1 equiv.
Li
S
E
S
Li
S
R O
O
R
S
O
R
O
S
TsOH
R = t-Bu
n-BuLi
2 equivs.
"E+"
Li
S
Li
E
S
E
S
OH
(Taut. later)
In the 3 / 4 pos.
Li
Br
n-Buli
- 70 oC
S
S
E
"E+"
S
3-Litiation with ODG
Li
Stable in hexane
n-BuLi
In Et2O over -25 oC:
Met
Li
S
S
O
S
SLi
Met: ZnX, MgX
Stable at RT
OLi
S
CO2H
LDA
Li
S
CO2Li
Pd cat. couplings
Ar-X etc
cat Pd
Met
S
Br
Ar
S
Br
Br
Ar-Met
cat Pd
Ar
S
S
Reat with radicals
Seldom synthetically usefull
Cycloadditions
15 kBar
100 oC
S
+
45 %
O
O
R
O
S
R
EWG
O
O
S
O
O
R≠ H
rel. stable
O
Easier with furan
O S
R
R
O
EWG
Oxythiophenes
c.f.
S
O
S
OH
S
Not detectable
O
N O
H
Major tautomer
N
H
OH
N O
H
NB! sp3 C
N
H
O
N O
H
NB! sp3 C
Aminothiophenes
NH2
S
NH2
S
Only amino
Generally unstable
c.f. Aminopyrroles
-Amino (not iminoform) - unstable
Synthesis of Thiophenes
S
a
Carbonyl condensations
b
S
c
S
d
S
Strategy a
S
H
H
H
LR
H
S S
O O
MeO
P
S
S
S
P
OMe
H
H
SH S
LR: Lawesons reagent
S
H
±H
S SH
- H2S
S
Strategy a, cont.
S
a
P4S10
NaO
ONa
S
O O
b
Mechanism ???
S
H2S, NaOH
R
d
R
R'
S
c
HS
R
R'
S
R'
S
Strategy b
S
Ph3P
O
Ph3P
O
S
S
HS
[ox]
(chloroanil)
Wittig
S
Strategy c
RO
R
O
O
O
R
H
OH
OH
R
O
HS
R
O
HO
S
OR
O
H
- H2O
S
R
OR
OH
- H2O
S
CO2R
Strategy d
d
Hinsberg synth.
RO2C
S
CO2R
Base
S
S
R
R
O
O
RO2C
S
CO2R
R
O
R
O
RO2C
S
R
R
RO2C
OR
O
O
O
H
O
S
Bsae
R
R
R
OH
RO2C
S
CO2
- OH
H
R
RO2C
R
S
CO2R
O
RO2C
S
R O
R O
R
CO2
R
RO2C
O
S
O
Base
R
RO2C
O
S
O
Miscellaneous carbonyl reactions
S
O
O
R'
O
1) Base
O
2) S=C=S
R'
R'
Base
R'
R'
S
S
O
O
R'
Br
O
S
S
R
O
O
R'
R'
S
R
S
O
Base
O
R'
R'' S
Water elim.
S-alylation (R''X)
R'
R
S
O
R'
O
O
S
R
S
R'
O
O
S
O
R'
R4
O O
R3
R5
S
R2
TiCl4
Zn
HO OH
R4
R3
R5
R2
S
H
H
R'
S
O
R4 R3
- H2O
R5
S
R
S
R2
Cycloadditions
R
N
S
Me3Si
SiMe3
Sealed tube
DBU, 340 oC
S
N
R
Me3Si
SiMe3
SiMe3
- RCN
SiMe3
S