2. metalation of -deficient heteroaromatics. metalation of - deficient heteroaromatics. bare...
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2. Metalation of -Deficient Heteroaromatics 2. Metalation of -Deficient Heteroaromatics
NO
O NLDA
Directed Remote Metalation
(DreM)
Metalation of - Deficient Heteroaromatics. Bare Pyridines. Acidity Considerations
Metalation of - Deficient Heteroaromatics. Bare Pyridines. Acidity Considerations
N H
4
3
2
RLiAddition
Coordination
N
Deprotonation ratios
3
1
6
n-BuLi / t-BuOK (1:1)THF-hex / -100 °C
N1
9.3
12
MeONa / MeOD165 °C
N1
72
240
NaNH2 / liq. NH3(py- d5)
N
n-BuLi / t-BuOKEt2O
N
n-BuLi / t-BuOKTHF / HMPT
90 %
N
28 %
48 %
LiTMPTHF
85 %
Nu- Addition to Pyridines. Synthetic UtilityNu- Addition to Pyridines. Synthetic Utility
N
RCO+
Nu-
1, 4-Dihydropyridines,4-Substituted Pyridines
N
R1
OEtO
Cl
R2
Cu(CN)ZnBr
N
R
OEtO
-78 °C rt
R2
S8 / decalin
reflux
(28 - 89%)
N
R
R2
R1 = EDG EWGOMe CHOHal CO2MeMe CN
R2 = Me, Br
R
Directed ortho Metalation (DoM) Reactivity of PyridinesDirected ortho Metalation (DoM) Reactivity of Pyridines
N
DMGDMG = Directed Metalation Group
Carbon- based DMGs HetAtom- based DMGs
CON-R R= Me, Ph, CH2Ph
CONR2 R = Et, i-Pr
N
O
N
N
O
R1
R2
CF3
OR (R= Me, Et, CH2Ph)
3 - OMOM
OCONR2
N-COR (R = Ot-Bu, t-Bu)
N
NN
Cl
Br
FSO2NR2, SO2N-R
S(O)nt-Bu n= 1, 2
CO2-
C-based Pyridine DoM. DMG = CONEt2 Synthetic Application
C-based Pyridine DoM. DMG = CONEt2 Synthetic Application
NEt2N
ONH
CHO
1. 2 eq. LiTMP
Et2O / -78 °C
2.
(58%)
NH
HO
N
NEt2
O
H2 / Pd / C
HOAc NH
N
O
HO
N
NMe
H H(15%)(89%)
Imipramin analog
C-based Pyridine DoM. DMG = CON-R HetRing Annelation
C-based Pyridine DoM. DMG = CON-R HetRing Annelation
N NHR
O
R = Me, CH2Ph
1. 2 eq. n-BuLi
-65 °C
2. ArCOClN
NR
O
Ar OH
N
OMe
NH
OOMe
1. RLi
2. S83. BrCH2Ph N
OMe
NH
OOMe
SPh
xs t-BuOK
DMF / r.t.
(77 - 84 %)
NS
OH
Ph
OMe
C-Based Methoxypyridine DoM. DMG = CH(O-)NR2C-Based Methoxypyridine DoM. DMG = CH(O-)NR2
NMeO CHO
LiNMP LiTMDA
NMeO
LiNMP
LiTMDA
CHO
2
3
4
5
6
Li-NMP : 70% (97:3) C5:C3
Li-TMDA : 77% (96:4) C3:C5
Li-NMP : 70% (93:7) C5:C4
Li-TMDA : 65% (97:3) C4:C5
NLiNMP
LiTMDA
CHO
Li-NMP : 79% C6
Li-TMDA : 76% (70:30) C4:C6
Me
NMeO CHO
LiTMDA
Li-TMDA : 67% C3
Me
NMeO CHO
LiTMDA
Li-TMDA : 76% (94:6) 3-Me-C5
Me
Standard Conditions
a) 1.2 eq. Li base / THF / - 78 °Cb) 2 eq. n-BuLi /- 78 °C - 42 °C
c) MeI /- 78 °C rt
LiTMDA : Lithium N,N,N'-trimethylethylenediamine
LiNMP : Lithium N-methylpiperazide
HetAtom - Based Pyridine DoM. DMG = OCONR2
HetAtom - Based Pyridine DoM. DMG = OCONR2
1. s-BuLi / TMEDA
THF / -78 °C2. E+N
OCONEt2
(66-83 %)
N
OCONEt2E
N
OCONEt2
1. 1 eq. LDA THF / -70 °C
2. TMSCl
(94 %)
N
OCONEt2
TMS
N
OCONEt2
TMS
E
1. LiTMP / THF / -78°C/ 5 min2. E+
(39- 89 %)
1. 2.2 eq. LDA THF / -70 °C
2. TMSCl(33 %)
N
OCONEt2
TMS
TMS
PhCOClPhH / reflux
N
OCONEt2
TMS
COPh
(33 %)
E+ = RCH(OH), Ph2C(OH), COPh, SPh, SePh, Cl, SiEt3
HetAtom - Based Pyridine DoM.
DMG = OCONR2. Methodology
HetAtom - Based Pyridine DoM.
DMG = OCONR2. Methodology
N
OCONEt2E2
+
E1+2
13
N
E1E2steps 1-3
N
OCONEt2 1. RLi2. ClCONEt23. RLi4. E+
N
OCONEt2
E CONEt21. OH-
2. POCl33. H2/Pd-C
N
E CONEt2
E = Me, TMS
disubstitution
HetAtom - Based Pyridine DoM. DMG = OCONR2. Anionic ortho-Fries Rearrangement
HetAtom - Based Pyridine DoM. DMG = OCONR2. Anionic ortho-Fries Rearrangement
N
OCONR2
N
CONEt2
OH
1. s-BuLi / TMEDA THF / -78 °C
2. rtN
CONR2OH
(40 %)
NH
CONEt2
(74 %)
O
HetAtom - Based Pyridine DoM. DMG = N-COt-Bu. Synthetic Application
HetAtom - Based Pyridine DoM. DMG = N-COt-Bu. Synthetic Application
N
NHCOt-Bu1. n-BuLi
2. [(i-Pr)2NCS]2
S
(98 %) N
NHCOt-Bu
SCSN(i-Pr)2
N
S
HN
S
20% NaOH
EtOH(86 %)
HCl(97%)
N
S
N
10 % aq NaOH
(91 %)
N
NH2
SH
HetAtom-Based Pyridine DoM. DMG = F, Cl. “Catalytic” Metalation. 3-Formyl-2-halopyridines
HetAtom-Based Pyridine DoM. DMG = F, Cl. “Catalytic” Metalation. 3-Formyl-2-halopyridines
N Cl
1.PhLi* / 5% HNEt2 THF / -60 °C
inverse addition2. -40 °C3. E+
N Cl
E
*Prepared in situ : 2 eq. t-BuLi + PhI
E+ = MeI, CH2=CHCH2I, DMF, NCHO , MeCHO, PhCHO, PhCOPh, TMSCl, Br2, I2
N Cl
CHO
N OMe
CHO
N Cl
CHO
R(60 %) (45%) R= Cl (55 %)
R= OMe (55 %)
E+ = NCHO
HetAtom-Based Pyridine DoM. DMG = F, Cl.Methodological Results
HetAtom-Based Pyridine DoM. DMG = F, Cl.Methodological Results
N
X
1. Base
2. E+
N
X
E
X Base Conditions* E+ Yield, %
F
F
F
Cl
ClCl
Cl
n-BuLi
n-BuLi
LDA
n-BuLi
LDALDA
LDA
A
A
A
B
BB
B
MeCOMe
TMSCl
PHCHO
EtCOEt
MeIPhCHO
TMSCl
65
75
65
60
7090
70
*A : 1. TMEDA / THF or Et2O / -60 °C -20 °C;2. -70 °C; 3. E+
B: Et2O > THF / 0 °C; 2. -70 °C; 3. E+
HetAtom-Based Pyridine DoM. DMG = I, F. TandemDoM / Halogen Dance Reactions of Iodopyridines
HetAtom-Based Pyridine DoM. DMG = I, F. TandemDoM / Halogen Dance Reactions of Iodopyridines
N R
I
(54 - 96 %)N R
I
E
N
F
I
(70 - 95 %)N
F
E
I
N F
IMe
(84 - 90 %) N F
EMe
I
N
F
I
Cl(64 - 78 %)
N
F
E
Cl
I
Standard conditions: 1. 1 eq. LDA / THF / - 78 °C2. E+ / -78 °C3. H2O
E+ = D2O, MeI, PhCHO, HCO2Et, I2
HetAtom-Based Pyridine DoM. DMG = SO2NR2, SO2N-RMethodology and Application
HetAtom-Based Pyridine DoM. DMG = SO2NR2, SO2N-RMethodology and Application
N
SO2NR2
1. xs LDA / THF / -70 °C
2. E+
(55-95%)N
SO2NR2E
R = (CH2)n , n=2, 3 ; O
E+ = CO2, DMF, RCHO, RCOR
N
SO2NHt-Bu1. LDA / THF / -78 °C
2. E+
N
SO2NHt-Bu
E
N
SO2
NRO
N SO2
O
PhPh
N
OO2SPh
Ph
HetAtom-Based Quinoline DoM. DMG = OCONEt2
Methodology
HetAtom-Based Quinoline DoM. DMG = OCONEt2
Methodology
N OCONEt2 N OCONEt2
R
OH
NH
O
R
OCONEt2
N
OCONR2
N
OCONR2
E
N
OCONEt2
N
OCONEt2
E
1. LDA / THF
2. RCHO
+-105 °C
R = Et (30%)
R = Ph (28%)
(19%)
(24%)
1. LDA / THF
2. E+
-78 °C
(25 - 90%)R = Me, Et E =D, TMS, MeCH(OH), EtCH(OH)
1. LDA / THF
2. E+
-78 °C
(75 - 95%) E =D, TMS, Me
N
OCONMe2
NH
O
CONMe2LDA / THF-78 °C to rt
(80%)
HetAtom - Based Quinoline DoM. DMG = N-COt-Bu.Methodology
HetAtom - Based Quinoline DoM. DMG = N-COt-Bu.Methodology
N NHCOt-Bu N NHCOt-Bu
N N
NHCOt-Bu
NHCOt-Bu
1. 3 equiv n-BuLi Et2O / 20 oC
2. E+
(12-95%)
E = D, I, TMS, SMe, COOEt, CEt2(OH)
LDA / TMSCl (93%)
Nun-BuLi / TMEDA (100%)
(45%)Nu
s-BuLi / TMSCl THF / -90 oC
E
Diazine DoM. Pyrimidines, DMG = OMe.Methodology
Diazine DoM. Pyrimidines, DMG = OMe.Methodology
N
N
OMe
MeO
N
N
OMe
MeO
N
N
OMe
Cl
N
N
OMe
Cl
N
N
DMG
X
E
E
1. LiTMP
Et2O / 0 oC2. E+
(4-65%)
E+ = TMS, CHO, COMe, CO2H, CO2Et, RCH(OH)
1. 2.3 equiv LiTMPTHF / -70 oC
2. E+
(30-66%)
E+ = TMS, RCH(OH), ArCH(OH)
- LiTMP / TMSCl / THF / 0oCX = H, Cl, OMOMDMG = OMOM (13-18%) =N-COt-Bu (0%)
Diazine DoM. Pyrimidines, DMG = Cl.Methodology and Synthetic Utility
Diazine DoM. Pyrimidines, DMG = Cl.Methodology and Synthetic Utility
N
NCl ClN
N Cl
Cl
N
N Cl
Cl
N
N Cl
N
CHONCHO
N
N
Cl
N
N
N
CHO
Cl
Cl
N
N
Cl
CHO
NNCHO
1. LDA
2.
LDA / THF / -78 oCE+ = PhCHO, TMSCl
1. LDA
2.
(71%)
(40%)
2 : 1
--
N
N
Cl
Ph
O
Cl
N
N
Cl
HN
N
N
N
Cl
NR
N
Ph
N
NH
N
Ph
PhO
NH2
NH2RNHNH2
PhNH2
Diazine DoM. Application to NucleosidesDiazine DoM. Application to Nucleosides
HN
N
O
O
O
OTBSTBSO
1. s-BuLi / TMEDA THF / -78 °C
2. E+
(45 - 58%)
HN
N
O
O
O
OTBSTBSO
EHN
N
O
O
O
OTBSTBSO
E
E = D Me SCH2Ph COPh
53>99>99
::::
1111
Diazine DoM. Pyridazines, DMG = Cl.Methodology
Diazine DoM. Pyridazines, DMG = Cl.Methodology
N
N
Cl
Cl
N
N
Cl
Cl
E1. LiTMP THF / -70 oC
2. E+
(45-65%)
E+ = DMF, MeCHO, ArCHO, PhCOPh, TMSCl, I2
Diazine DoM. Pyridazines, DMG = Cl.Addition of s- and n-BuLi
Diazine DoM. Pyridazines, DMG = Cl.Addition of s- and n-BuLi
NN
R Cl
NN
Cl Cl
s-BuLi-78 °C
THFTMSCl
+
NN
Cl O
H
NN
R Cl
sBu
+
NN
R Cl
sBu
R = Cl
R = OMe, Ph
n-Bu
sBu
1 Rabc
ClMeOPh
2a (43%) 3 (<15%)
2b (41%)2c (34%)
4b (10%)4c (12%)
NN
Cl ClMeLi
THF/-78 °CTMSCl
n-BuLi
THF/-78 °CTMSCl
31% 42%
N N
NN
ClCl
Cl
H
O
NN
Cl Cl
s-Bu
Diazine DoM. Pyrazines, DMG = CON-t-Bu, N-COt-BuUnusual Reactivity
Diazine DoM. Pyrazines, DMG = CON-t-Bu, N-COt-BuUnusual Reactivity
N
N
CONHt-Bu N
N
CONHt-Bu N
N
CONHt-Bu
N
N
CONHt-Bu
N
N
CONHt-Bu N
N
CONHt-Bu
TMS TMS TMS
R
OH
PhR
LiTMP / TMSCl
THF +
1. LiTMP / 0 oC2. RCHO
R = Me (45%)R = Ph (43%)
1. RLi
2. PhCHO
R = mesityl (24%)R = t-BuLi (63%)
Temp. oC Yield % -70 77 0 0 0 67
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