s reactions with electrophiles at c preferably at c-2 / c ... · thiophenes s reactions with...

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


-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


-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 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


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


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''

Cycloadditions

N

S

R

SiMe3Me3Si

Sealed tubeDBU, 340 oC N

S

SiMe3

SiMe3

R- RCN S

Me3Si SiMe3

s reactions with electrophiles at c preferably at c-2 / c ... · thiophenes s reactions with...

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