BIDIRECTIONAL METALATION OF HYDROBENZOIN: DIRECT ACCESS TO NEW
1. Metalation of p -Excessive Heteroaromatics
32
1. Metalation of -Excessive Heteroaromatics S Et 2 N O E +
description
1. Metalation of p -Excessive Heteroaromatics. Thermodynamic Acidities of π - Excessive Heteroaromatics. Kinetic Acidities of π - Excessive Heteroaromatics. Synthetic Use of Metalated non-DMG Furans and Thiophenes. Conversions into other Heterocycles. - PowerPoint PPT Presentation
Transcript of 1. Metalation of p -Excessive Heteroaromatics
1. Metalation of -Excessive Heteroaromatics1. Metalation of -Excessive Heteroaromatics
S
Et2N
O
E+
Thermodynamic Acidities of π - Excessive HeteroaromaticsThermodynamic Acidities of π - Excessive Heteroaromatics
Se H>
S HO H
>>NR
H
pKa < 34 ~ 35 36
(Streitwieser orPolarographic scale)
X
Inductive
empty d orbital (for S and Se)
Lone pair effect
Kinetic Acidities of π - Excessive Heteroaromatics.Kinetic Acidities of π - Excessive Heteroaromatics.
Se HS
H OH
NR
H
H H H H
0.015 0.002 0.002
700 500 1.0
?
?
S H
Z
H
Z
OMe
SMe
Me 0.18
>30
0.05
>200
>100
kexch
t-BuOK / DMSO
Synthetic Use of Metalated non-DMG Furans andThiophenes. Conversions into other Heterocycles
Synthetic Use of Metalated non-DMG Furans andThiophenes. Conversions into other Heterocycles
R
O
O Li
1.
2. H3O+R
HO
O
mCPBA
R
O OH
O
- OH 80 %-OH 20 %
ONH2
ClSi
ClSi
Me2
Me2
Et3N / CH2Cl2O
N
SiMe2
Me2Si1. n-BuLi
2. ArCHO ON
SiMe2
Me2Si
OH
Ar
3. HCl / -78°C
4. refluxN
Ar
OH
Synthetic Use of Metalated non-DMG Furans andThiophenes. Oxidative Pathways
Synthetic Use of Metalated non-DMG Furans andThiophenes. Oxidative Pathways
O
1. n-BuLi
2. TMSClO TMS
1. n-BuLi
2. E+
3. MeCO3H OE
S
1. n-BuLi
2. B(OMe)3
G
S
G
B(OMe)2
H2O2
S
G
O
O
Metalated Furans. Additions on Glycosyl Nitrones
O
N
OR
Bn
OO Li
THF/-80 °C
OO
O
N
OR
Bn
OH
OO
O
(80-90%)
1. TiCl3/MeOH2. SiO2/H2O3. Ac2O or CbzCl
O
NHAc
ORO
O
O
(57-14%)
1. RuO2/NaIO42. CH2N2
O
NHAc
ORO
O
MeO2C
(51-69%)
Use of Metalated non-DMG Thiophenes. Historical Industrial Practice
Use of Metalated non-DMG Thiophenes. Historical Industrial Practice
S
1. n-BuLiTHF / spont reflux
2. +10°CO
keep < 25°CS OH
3. HCl
(79 % 110 mole scale)
1. TsCl /Et3N
2. ArCH2NH2
(71% )S NH
Ar
1. 35 % aq CH2O
2. HCl / DMF
(85 % )
N
S
Ar
anti-inflammatory,vasodilator,blood plate aggregation inhibitor
Directed ortho Metalation (DoM) Reactivity of Furans and Thiophenes
Directed ortho Metalation (DoM) Reactivity of Furans and Thiophenes
XHDMG
CoordinationInherent Kinetic Acidity
DMG = Directed Metalation GroupX = O, S
Carbon - based DMGs Het Atom - based DMGs
CON-R
CONR2
N
CO2-
NR2
O
CH2OR
CH2O-
OR
SR
OP(NMe2)2SO2N-R
S(O)nR n = 1,2
N-COt-Bu
DoM Chemistry of Furans and Thiophenes. Carbon-Based DMG’s. DMG = 2-oxazolino
DoM Chemistry of Furans and Thiophenes. Carbon-Based DMG’s. DMG = 2-oxazolino
-78°C
SN
O
3
5
LDA / THF or DME
n-BuLi / Et2O-78°C
C3 : C5 Conditions E+
91 : 5
59 : 41
29 : 46
0 : 100
n-BuLi / -78°C / 15 min
n-BuLi / DME / -78°C
n-BuLi / DME / -78°C
n-BuLi / Et2O/ 2 eq HMPA
PhCHO
TMSCl
MeI
TMSCl
ON
O
3
5
C3 : C5 Conditions E+
21 : 74
87 : 9
n-BuLi / Et2O / -78°C 0°C
n-BuLi / DME / -78°C
PhCHO
PhCHO
E+ = DMF, CO2, I2, TsN3, MVK,O Br
,
Thiophene
Furan
DoM Chemistry of Furans. DMG = CON-R. ApplicationDoM Chemistry of Furans. DMG = CON-R. Application
O
OTBDMS
1. n-BuLi / hex
2. O=C=Nt-Bu
61 %
O
OTBDMS
CONHt-Bu O
OTBDMS
CONHt-Bu
Me
1. n-BuLi (2eq)
2. MeI
(69 %)
O CONHt-Bu
Me
MeO2C
1. n-TBAF / HOAc
2. (COCl)2 / DMSOEt3N
3. Ph3PC(Me)CO2Me
O
Me
HO
O
H
H
Kallolidediterpine
(antiinflammatory)
DoM Reactivity of Furans and Thiophenes. Dianion Equivalents with Carbon-based DMGs
DoM Reactivity of Furans and Thiophenes. Dianion Equivalents with Carbon-based DMGs
S
E1+
E2+ (CONEt2)
s-BuLi/ TMEDATHF / -78°C
E1 E2
PhCH(OH)CONEt2
SMeTMS
TMSSMeSMe
SMeTMSCONEt2
26 - 85 %
X
E1+
E2+
N
O
E = CO2H, SMe, TMS, I
88 - 97 %
X = S 3.3 eq s-BuLiTHF / -20°C / 0.5h
X = S 3.3 eq s-BuLi / TMEDATHF / -78°C / 2h
DoM Reactivity of Furans and Thiophenes.“DMG” = CO2
-
DoM Reactivity of Furans and Thiophenes.“DMG” = CO2
-
n-BuLi / TMEDA / THF / -78 °C
X CO2-
X
CO2-
X = S, OLDA / THF / -78 °C
E+ = MeI, EtI, PhCHO, TMSCl, .....
O
CO2-R
R = alkyl, SR, CH(OR)2, Br
E+ = 1. SO2; 2. NH2OSO3; 3. SO2Cl2
S CO2-
X CO2-
XCO2
-
X
CO2-
X = O, S
E+ = MeI, PhCH2Br, (Me)2S, TMSCl, I2
LDA / THF / -90 °C LDA / THF / -78 °C
E+ = RX, RCHO, ArCHO, TMSCl
DoM Chemistry of Furans. DMG = CH2O- DoM Chemistry of Furans. DMG = CH2O-
OTMS SPh
TBDMSO
O
OH1. n-BuLi2. Ph2S2
3. TBDMSCl4. n-BuLi5. TMSCl 2 1
O
OTBDMS
TMS
1. TBDMSClimidazole
2. n-BuLi / DME3. TMSCl
O
OTBDMS
OO
OTBDMS
O
O
OTBDMS n-BuLi / DME
HMPA / -20 °CO
OH
TBDMS O
OH
TBDMS
DME1. 2 eq. n-BuLi /
0 °C2. E+
(90% )
TBAF / THF
O
OH
E
E
E = D, M, (CH2)3Cl, CO2Me, CONEt2, TMSO
R
O-
minor majorR = (CH2)nMe
(87 %)
DoM Chemistry of Furans and Thiophenes. Heteroatom - Based DMGs, DMG = SO2R
DoM Chemistry of Furans and Thiophenes. Heteroatom - Based DMGs, DMG = SO2R
X
1. 2 eq. n-BuLi
X = O,S
2. E+
SO2NHt-Bu
X
SO2NHt-Bu
E
E = BrX = S
S
SO2NHt-Bu
R
R = CN, Ph,N
NN
S
SO2NHt-BuBr
1. LDA
2. E+
S
SO2NHt-BuBr
E S
SO2NHt-BuBr
R
R = CN, Ph, Ar, HetAr
DoM Reactivity of N-DMG PyrrolesDoM Reactivity of N-DMG Pyrroles
NSEM
1. n-BuLi / DME
2. E+
0° CNSEM
E
anhydrTBAF
THF / 0 °C NH
E
SEM = CH2OCH2CH2TMS
E = CO2Me, COPh, i-PrCH(OH), CH2=CHCH(OH), TMS
OMeO OMeH2NNMe2
HOAc NNMe2
1. n-BuLi
2. E+ NNMe2
ECr2(OAc)4
NH
E
E+ = RCHO, ClSnR3
OOH
S
NO
+NNMe2
BrMg OOH
O
NH
DoM Reactivity of N-DMG PyrrolesDoM Reactivity of N-DMG Pyrroles
NCOHNt-Bu
1. 2.2 eq n-BuLi / THF / -78 °C
2. E+ NCOHNt-Bu
E
E = CO2H, PhCH(OH), TMS, D, (CH3)2CHOH
NH
1. n-BuLi / THF -78 °C -25 °C
2. CO23. n-BuLi / THF
-78 °C -25 °C
NCO2
1. E+
2. H3O+ / 0 °C5 min
NH
E
E = CO2H, CONHPh, CHO, C(OH)Ph2, Ts
DoM Reactivity of Indoles. N - DMGsDoM Reactivity of Indoles. N - DMGs
NDMG
DMG = SO2Pha,b
CO2t-Bua,c
CH2OCH2CH2TMS (SEM)b
CO2- d,e,f
CH2OMea,g
DMG = CH2NMe2h
CONEt2i
CON-t-Buj
OCH2OMek
SO2NMe2l
DoM Reactivity of Indoles. N-DMG = CO2t-Bu.
Indirect C-7 Substitution
DoM Reactivity of Indoles. N-DMG = CO2t-Bu.
Indirect C-7 Substitution
NDMG
NDMG
PG
?
N
1. s-BuLi / TMEDA
Et2O / -78 °C2. E+
(40 - 83 %)OtBuO
X
N
OtBuO
X
E
NH
X
E
X = H, OMe, Cl
E = Me, CO2H, TMS, Bu3Sn, PhS, I, Br, Cl
E = CHO
NH
X
HO
E =
N
RCH(OH)
O OR
DoM Reactivity of Indoles. Non-N DMG Indoles. DMG = CONR2
DoM Reactivity of Indoles. Non-N DMG Indoles. DMG = CONR2
NDMG
CONR1R2NDMG
CONR1R2
E
NHSO2Ph
NR1R2
O
NSO2Ph
N
NSO2Ph
N
COMe
NH
N
OH
n-BuLi
N
NHSO2Ph
1. s-BuLi / TMEDA
2. E+
DMG = CH2OMeR1 = R2 = Et
n-BuLi
DMG = SO2PhR1 = R2 = EtR1 = H R2 = t-Bu
THF / -78 °C
DMG = Me, R1= H, R2 = t-Buno ring opening
2. OHCMe
3. MnO2
1. n-BuLi / -78 °C
1. NaOH
2. I2
-78 °C 50 °C
DoM Reactivity of Indoles. Non-N DMG Indoles. DMG = CH2NR2
DoM Reactivity of Indoles. Non-N DMG Indoles. DMG = CH2NR2
NZ
DMG
Z = DMG or non DMG
NMe
NMe2
t-BuLi / EtO2
-78 °C / 1 h
N
NMe2
Si
1. t-BuLi / EtO20 °C / 1 h
2. E+
(57 - 88%)
N
NMe2
Si
E
E = CHO, TMS, Bu3Sn, PhS, I, Br, Cl, NH2, (N3CH2TMS)
e.g. E = Cl
TBAFTHF / rt
NH
Cl
CO2H
plant growth hormone
DoM Reactivity of Non-N DMG Indoles.
DMG = OCONEt2. Benzenoid Ring Functionalization
DoM Reactivity of Non-N DMG Indoles.
DMG = OCONEt2. Benzenoid Ring Functionalization
NTBS
AmO
E
NTBS
AmORR = H
1. s-BuLi / TMEDA
THF/ -78 °C2. E+
(43 - 99%)
R = CH2CH2OH, CH2CH2OTBS
1. s-BuLi / TMEDA
THF/ -78 °C2. E+
(57 - 70%)
NTBS
AmOR
E
1. s-BuLi / TMEDATHF/ -78 °C
2. ZnBr2 / THF
3. Pd(PPh3)4 / THF / ArBr
R'MgX / Ni(acac)2
PhMe / refluxNTBS
AmO
Ar
NTBS
R'
R' = TMSCH2, PhAm = CONEt2
E+ = TMSCl, MeI, DMF, ClCO2Et,
C2Cl6, I2, t-BuSSO2Ph
R = H
DoM Reactivity of -Excessive Heteroaromatics. Pyrrazoles. N DMGs
DoM Reactivity of -Excessive Heteroaromatics. Pyrrazoles. N DMGs
NN
R
base
NN
Me
R
H5
n-BuLi minor
major
NN
H
H
n-BuLi
major
minor
NN
R
H
R = SO2NMe2 : n-BuLiR = Ts : t-BuLi
NN H
N
R
R
n-BuLi
NN H
O
n-BuLi
NN H
N
N
HHLDA / 0 °C
n-BuLi / 25 °CE+ = RX
n-BuLi /25 °C
E+ = RCOX,RCO2R'
DoM Reactivity of Pyrrazoles. Non-N DMGs.DMG = SO2N-R
DoM Reactivity of Pyrrazoles. Non-N DMGs.DMG = SO2N-R
NN
Me
1. n-BuLi
2. DMFN
N
Me
CHO
SO2NHt-Bu
NN
Me
X
SO2NHt-Bu
X = CF2H, CH=NOMe,N
O
SO2NHt-Bu
DoM Reactivity of Pyrrazoles. Total Synthesis Application
DoM Reactivity of Pyrrazoles. Total Synthesis Application
N
N
SO2Ph
1. t-BuLi / 0 °C
2. Br
( 30 %)
N
N
SO2Ph
1. BH3 / Me2S
2.H2O2 / NaOH
N
N
SO2Ph
HO
1. TsCl / Py
2. MeONa
N
N
Withasomnineex Withania
somnifera (Solanaceae)
Metalation Reactivity of ImidazolesMetalation Reactivity of Imidazoles
N
NR
H
n-BuLi
N
NMe
Me
major
H
minor
N
NMe
MeMe3Sn
n-BuLi / Et2O / 20 °Cn-BuLi / Et2O / 20 °C
N
NMe
Me
100%
TMS
n-BuLi
N
NMe
H
n-BuLi
Br
DoM Reactivity of Imidazoles. DMG = N-SO2NR2.
Silicon Protection
DoM Reactivity of Imidazoles. DMG = N-SO2NR2.
Silicon Protection
N
NSO2NMe2
N
NSO2NMe2
E+TMS+ H+
F-
1. n-BuLi THF / -78 °C
2. TBDMSCl
3. n-BuLiMe
Me
Cl
O
4.
Me
Me
Me
N
NH
Me
Me
O
NSO2NMe2
N
TBDMS
1.5 N HCl
reflux
( 79% overall)
DoM Reactivity of Imidazoles in Context of NucleosidesDoM Reactivity of Imidazoles in Context of Nucleosides
O
OPG OPG
RON
N
N
NH
X
O
OPG OPG
RON
N
N
NE
X
ArCHODMFR2COCO2R
O
OPG OPG
PGON
N
Cl
CO2Me
O
OPG OPG
PGON
N
Cl
CO2Me
OHO
HO OH
HON
N NH
O
1. LDA / THF -78 °C
2. E+
R= or TBDMSX = Cl, NH2
X= NH2, Cl
E+= RXAlkylCHO
1. LDA / THF2. HCO2Et
3. NaBH4
NH2
3-deazaguanosine
(antiviral)
DoM Reactivity of OxazolesDoM Reactivity of Oxazoles
N
O H
N
O CH3
N
O CH2R2
R1=R2= H
R1= t-BuR2= SO2Ph
N
O CH3
HO2C1. 2.5 eq. t-BuLi
2. 5 eq. TMSClN
O CH3
HO2C
TMS
1. 2.5eq. t-BuLi
2. E+
3. CsF
N
O
HO2C
E
E = D, Me, RCH(OH), R2C(OH)
R1OOC
Metalation Reactivity of ThiazolesMetalation Reactivity of Thiazoles
N
S H
n-BuLi
N
S CH3
n-BuLi
H
major minor
N
S
n-BuLi / Et2O / -78 °C
E2+ E1
+
E1 = TMS, E2 = SnMe3
Ipso chemistry
N
STMS
1.O
OCHO
CH2Cl22. TBAF
OO
S
N
HO
anti > 95
OO
HO
CHO
CHOPhCH2O
O
OH
PhCH2O
O
OH
OCH2PhOH
OCO2Ph
S
N
Metalation and DoM Reactivity of Methyl Substituted Oxazoles and Thiazoles
Metalation and DoM Reactivity of Methyl Substituted Oxazoles and Thiazoles
N
X CH3O2C
X = O, SLDA or n-BuLi
-78 °C or 0 °C
N
S PhH3C
-78 °Cn-BuLi
O2C
N
S PhO2C
H3C
LDA-30 °C
N
X CH3H3C
n-BuLi / -78 °C
O2C
X = O, SLDA or n-BuLi
various tempmixtures
N
X CH3H3C
Et2NOC
only
X = O, S
DoM Reactivity of Aminoisoxazoles
N O
MeBocHN
N O
MeBocN
N O
MeBocHN
25 °C
E+
25 °C
LiLi E
N O
NHBocMe
N O
NHBocMes-BuLi / TMEDA
- 50 °C
E+
25 °C
E
E+ E yield (%)
CO2 then CH2N2MeIEtIallyl bromideTMSClDMFbenzyl bromidePhSSPh
CO2MeMeEtallylTMSCHObenzylSPh
8192929750776567
E+ E
CO2 then CH2N2MeI
CO2Me (80%)MeI (76%)
n-BuLi
DoM Reactivity of 1-Substituted 1,2,4-Triazoles
N
NN
n-Bu
N
NN
n-C8H17
N
NN
N
NN
N
NN
N
A = 1. BuLi 2. E+
B = 1. BuLi 2. E+
3. BuLi 4. E+
C = 1. BuLi (2 eq) 2. E+ (2 eq)D = 1. BuLi (2 eq) 2. E+ (1 eq)
3. H2OE = 1. BuLi (3 eq) 2. E+ (1 eq)
3. H2O
A A A A
A
N
NN
n-C8H17
B
N
NN
B
N
NN
C,D
N
NN
C,D
N
NN
E
N
N
B
N
