s reactions with electrophiles at c preferably at c-2 / c ... · s reactions with electrophiles at...
TRANSCRIPT
THIOPHENES
S
Reactions with electrophiles at CPreferably at C-2 / C-5 (cf pyrroles)
-Protonation• Much more stable under acidic conditions than pyrroles and furans• Protonation at C-2 /C-5
S
100% H3PO490 oC
SH
H SHH S
HH
X XHH X
HH X
HH
X
HH
X
HH
most stable
E
E
X: NR, S, O
-Nitration• Not complete selectivity• Not HNO3 (explotions)
S
NO2 BF4or
NO2 AcOS NO2
+S
NO2
ca 9 : 1
S NO2
" NO2+"
S NO2
O2N+
S NO2O2N
ca 1 : 1
S" NO2
+"S
NO2 NO2
O2NNO2: m-Directing
Reactions with electrophiles at C
-Halogenationca 108 times more reactive than PhH
S
SnCl4Pb(OAc)4
NCS, HClO4
S ClCl S Cl"Zeolite"
250 oC S
Cl
Chlorination
S
Br CuCl
DMF S
Cl
Bromination
S
2 Br2, 48% HBr
-25 — 5 oC S Br
2 Br2, 48% HBr
-10 — r.t S BrBr
3 Br2, 48% HBr
75 oC S BrBr
Br
NaBH4
DMSO, r.t. SBr
Br
NaBH4, Pd(0)MeCN, Δ S Br
Br
ZnAcOH, Δ S
Br
Iodination
S 90 oC
I2, HNO3(aq)S I
S
Br CuI
DMF S
I
Reactions with electrophiles at C
-Acylation(FC alkylation not good react)
S S
RCOClSnCl4
FC acyl. OR
POCl3, DMF(Vilsmeier)
SO
aldehyde
ketone (strong Lewis acid, AlCl3, polym.)
-Condensation with carbonyl comps
S
ROR'
H
S H
OHR'R
+ res formsH-
SOHR'
R
H Decomp
c.f.
NH
H+, RCHONHR=H, alkyl H
OHR
H±H+
NH R H
OH2- H2O N
H RH Polymer
Reactions with electrophiles at C
-Condensation with carbonyl comps, cont.
S
CH2O, conc. HCl
0 oC S Cl
-Condensation with imines / iminium ions
CH2O, R2NH, H+
NR
RNH iminium ion gen. in situ
NH
HNR
RH-
NH
N RR
Mannich react.in case of pyrrol, Mannich reag. generated in situ
Thiophene (and furan): Preformed reagent generally required
S MeCN, Δ S NMe2N=CH2 Cl
S S NH2
H2CO (aq)NH4Cl
But:
Reactions with electrophiles at C
Reactions with electrophiles at Sulfur
S
E
S
E
•Possible for thiophene; S in 3rd row•Not possible for furan / pyrrole; O and N in 2nd row•Probably sp3 S. tetrahedral•Works best for electron rich thiophenes
S S
Me
Me Me
Me Me
O SMe
O
OF
Me Me
Me Me
O SO
OF
NaPF6
S
Me
Me Me
Me Me
PF6
+ FSO3Na
Reactions with electrophiles at Sulfur
React. with carbenes
S
NN
RO2C CO2R
NN
RO2C CO2R
Rh2(OAc)4
N2RO2C CO2R
Carbene
S
RO2C CO2R95%
Stable ylide
S
RO2C CO2R
S
RO2C CO2R
60 oC SCO2R
CO2R
H
SCO2R
CO2R
Reactions with electrophiles at SulfurReact. with carbenes
NN
CO2R
1) Rh2(OAc)4 S
CO2RS
CO2R
CO2R
H
2)S
S
H
H
CO2R
H
??????
S
H
HH
OOR
H
S
H OOR
H
S
CO2R
Reactions with electrophiles at Sulfur
S[ox][ox]
SO O
SO
Not aromatic
SS
O O
R RmCPBA
R R
R≠ Hrel. stable
EWG SR
R
OO
EWG- SO2- EWG-H
R
R
Reactions with nucleophilesNB! Electron rich Aryl
S NX
Nu
O
OS
NuX N
O
OS NO2Nu
ca 100 times for reactive than
NO2X
Sulfurstab. neg, chargeon α-C
SNuX N
O
O
Reactions with nucleophiles
S NO
OS N
O
O
Vicarious Nu subst (VNS)
EWGR
XH
REWG X Base
S N
O
O
EWG R
H
S NO2
EWGR
S
Br CuX
X=Cl, I S
X
CuBrMeONa
S
OMeMechanism??
C-metallation and further reactionsIn the 2 / 5 pos.
S
n-BuLi1 equiv. S Li
"E+"S E
n-BuLi2 equivs.
S Li"E+"
S ELi E
In the 3 / 4 pos.
S
Brn-Buli- 70 oC S
Li"E+"
S
E
Stable in hexane
S
Li
In Et2O over -25 oC:
SLiS
Met
Met: ZnX, MgXStable at RT
3-Litiation with ODG
S CO2H
n-BuLi
LDAS CO2LiLi
S
Li
OOLi
S Li
Ex. E = OR
R OO
R
OS O R
TsOHR = t-Bu
S OH
(Taut. later)
Pd cat. couplings
Reat with radicalsSeldom synthetically usefull
Cycloadditions
SMet Ar-X etc
cat PdS
Ar
S
Br
Br
Ar-Metcat Pd
S
Br
Ar
S
OO O
+
15 kBar100 oC S O
O
O
45 %
Easier with furan
SO O
R R
R≠ Hrel. stable
EWG SR
R
OO
EWG
Oxythiophenes
Aminothiophenes
NH
OH NH
ONH
O
Major tautomer
NH
O NH
O
NB! sp3 C NB! sp3 C
S OH S OS O
Not detectable
c.f.
c.f. Aminopyrroles-Amino (not iminoform) - unstableS NH2 S
NH2
Only aminoGenerally unstable
Synthesis of Thiophenes
Carbonyl condensations
S
a
b
c
d
S
S
S
S
Strategy a
OO
HH LRSS
HH
PS
MeO SPSS
OMe
LR: Lawesons reagent
SSH
H±H S
H
SH- H2S S
H
Strategy a, cont.
S
a
b
c
d
S
S
S
S
OONaNaO
O S
P4S10
Mechanism ???
SR R'H2S, NaOH
RR'HS
R R'
Strategy b
SPh3P
HS
O
S
OPh3P WittigS
[ox](chloroanil)
Strategy c
OO
R H
OHO
RHS
ORO
SHO
OR
OOR H
- H2O S
OR
OHOR
H
- H2O S
R
CO2R
Strategy d
Hinsberg synth.
RO2C S CO2R BaseRO2C S CO2R
R R
O O
RO2C SOROR
S
O
OOR RO2C
R
ORO
H
Bsae
SR
OR
ORO2COBase
SR
OR
ORO2CO
SRO2C
R R
CO2
OSRO2C
R R
CO2
OH
- OH
H
S
R R
CO2RRO2C
S
d
S
Miscellaneous carbonyl reactions
OR4
S
R3O TiCl4Zn
R2R5 S
HO OHR4 R3
R5H
R2H S
R4 R3
R5 R2- H2OS
S
R'
O R'O
1) Base
2) S=C=S R'
O R'O
SS
Base
R'
O R'O
SS
Br RO R'
O R'O
SS OR
Base
R'
O R'O
SS ORSS
OR
OR' R'
OWater elim.S-alylation (R''X)
SSO
R
OR' R'
R''