Transcript 2. Metalation of p Deficient Heteroaromatics N

2. Metalation of p-Deficient Heteroaromatics
N
O
LDA
O
N
Directed Remote Metalation
(DreM)
Metalation of p- Deficient Heteroaromatics.
Bare Pyridines. Acidity Considerations
4
RLi
Addition
3
2
N
H
Coordination
Deprotonation ratios
12
6
240
9.3
1
72
1
3
N
N
n-BuLi / t-BuOK (1:1)
THF-hex / -100 °C
MeONa / MeOD
165 °C
1
N
NaNH2 / liq. NH3
(py- d5)
90 %
N
n-BuLi / t-BuOK
Et2O
28 %
 85 %
48 %
N
n-BuLi / t-BuOK
THF / HMPT
N
LiTMP
THF
Nu- Addition to Pyridines. Synthetic Utility
Nu-
1, 4-Dihydropyridines,
4-Substituted Pyridines
N
R
RCO +
R2
R1
R2
R2
N
R
Cl
O
OEt
Cu(CN)ZnBr
S8 / decalin
reflux
-78 °C  rt
N
O
R
(28 - 89%)
N
OEt
R1 = EDG
OMe
Hal
Me
R2 = Me, Br
EWG
CHO
CO2Me
CN
Directed ortho Metalation (DoM) Reactivity of Pyridines
DMG
N
Carbon- based DMGs
CON-R R= Me, Ph, CH2Ph
DMG = Directed
Metalation
Group
HetAtom- based DMGs
CONR2 R = Et, i-Pr
OR (R= Me, Et, CH2Ph)
3 - OMOM
CO2-
OCONR2
O
N
N
N
CF3
R1
R2
O
N-COR (R = Ot-Bu, t-Bu)
N N
N
Cl
Br
F
SO2NR2, SO2N-R
S(O)nt-Bu n= 1, 2
C-based Pyridine DoM. DMG = CONEt2
Synthetic Application
1. 2 eq. LiTMP
Et2O / -78 °C
Et2N
N
2.
N
H
O
N
H
HO
CHO
(58%)
N
O
NEt2
H2 / Pd / C
HOAc
N
H
N
(15%)
(89%)
H
H
N
HO
Me
O
N
Imipramin analog
C-based Pyridine DoM. DMG = CON-R
HetRing Annelation
Ar
1. 2 eq. n-BuLi
-65 °C
NHR
N
2. ArCOCl
OH
NR
N
O
O
R = Me, CH2Ph
O
O
OMe
1. RLi
NH
2. S8
3. BrCH2Ph
N
OMe
xs t-BuOK
DMF / r.t.
NH
N
S
OMe
OH
Ph
N
S
(77 - 84 %)
OMe
OMe
Ph
C-Based Methoxypyridine DoM. DMG = CH(O-)NR2
LiTMD
A
LiTMDA
LiNMP
4
LiNMP
5
LiTMDA
3
Me
CHO
6
MeO
N
2
CHO
MeO
LiNMP
N
CHO
N
Li-NMP : 70% (97:3) C5:C3
Li-NMP : 70% (93:7) C5:C4
Li-NMP : 79% C6
Li-TMDA : 77% (96:4) C3:C5
Li-TMDA : 65% (97:3) C4:C5
Li-TMDA : 76% (70:30) C4:C6
LiTMDA
Me
MeO
N
CHO
Li-TMDA : 67% C3
Standard Conditions
a) 1.2 eq. Li base / THF / - 78 °C
b) 2 eq. n-BuLi /- 78 °C  - 42 °C
c) MeI /- 78 °C rt
Me
MeO
N
LiTMDA
CHO
Li-TMDA : 76% (94:6) 3-Me-C5
LiTMDA : Lithium N,N,N'-trimethylethylenediamine
LiNMP : Lithium N-methylpiperazide
HetAtom - Based Pyridine DoM.
DMG = OCONR2
OCONEt2
1. s-BuLi / TMEDA
THF / -78 °C
2. E+
N
E
OCONEt2
N
(66-83 %)
OCONEt2
1. 1 eq. LDA
THF / -70 °C
2. TMSCl
N
(94 %)
TMS
1. 2.2 eq. LDA
THF / -70 °C
2. TMSCl
(33 %)
TMS
OCONEt2
OCONEt2
N
N
1. LiTMP / THF / -78°C/ 5 min
2.
E+ (39- 89 %)
(33 %)
OCONEt2
OCONEt2
N
PhCOCl
PhH / reflux
TMS
TMS
+
TMS
E
E = RCH(OH), Ph2C(OH), COPh, SPh, SePh, Cl, SiEt3
N
COPh
HetAtom - Based Pyridine DoM.
DMG = OCONR2. Methodology
E2
OCONEt2
+
2
3
1
E1
+
E2
steps 1-3
N
disubstitution
N
OCONEt2
N
1. RLi
2. ClCONEt2
3. RLi
4. E+
E1
OCONEt2
1. OHCONEt 2 2. POCl
3
E
3. H2/Pd-C
N
E
CONEt 2
N
E = Me, TMS
HetAtom - Based Pyridine DoM.
DMG = OCONR2. Anionic ortho-Fries Rearrangement
OCONR2
CONR 2
OH
1. s-BuLi / TMEDA
THF / -78 °C
2.  rt
N
N
CONEt 2
O
CONEt 2
OH
N
(40 %)
N
H
(74 %)
HetAtom - Based Pyridine DoM.
DMG = N-COt-Bu. Synthetic Application
S
NHCOt-Bu
NHCOt-Bu
1. n-BuLi
SCSN(i-Pr)2 20% NaOH
S
2. [(i-Pr)2NCS]2
N
HN
EtOH
(86 %)
N
(98 %)
S
N
HCl
(97%)
NH 2
N
S
SH
10 % aq NaOH
(91 %)
N
N
HetAtom-Based Pyridine DoM. DMG = F, Cl.
“Catalytic” Metalation. 3-Formyl-2-halopyridines
E
1.PhLi* / 5% HNEt2
THF / -60 °C
N
Cl
inverse addition
2.  -40 °C
3. E+
N
Cl
*Prepared in situ : 2 eq. t-BuLi + PhI
E+ = MeI, CH2=CHCH2I, DMF,
CHO
N
Cl
(60 %)
E+ =
NCHO
NCHO
, MeCHO, PhCHO, PhCOPh, TMSCl, Br2, I2
CHO
N
OMe
(45%)
CHO
R
N
Cl
R= Cl (55 %)
R= OMe (55 %)
HetAtom-Based Pyridine DoM. DMG = F, Cl.
Methodological Results
X
X
1. Base
E
2. E+
N
N
Conditions*
E+
Yield, %
n-BuLi
A
MeCOMe
65
F
n-BuLi
A
TMSCl
75
F
LDA
B
PHCHO
65
Cl
n-BuLi
A
EtCOEt
60
Cl
Cl
LDA
LDA
B
B
MeI
PhCHO
70
90
Cl
LDA
B
TMSCl
70
X
Base
F
*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. Tandem
DoM / Halogen Dance Reactions of Iodopyridines
I
I
N
R
I
E
(54 - 96 %)
I
N
R
E
F
Me
I
N
F
F
N
(84 - 90 %)
I
F
E
F
N
E
N
I
(70 - 95 %)
N
Me
Cl
I
(64 - 78 %)
F
N
Standard conditions: 1. 1 eq. LDA / THF / - 78 °C
2. E+ / -78 °C
3. H2O
E+ = D2O, MeI, PhCHO, HCO2Et, I2
Cl
HetAtom-Based Pyridine DoM. DMG = SO2NR2, SO2N-R
Methodology and Application
SO2NR2
E
SO2NR2
1. xs LDA / THF / -70 °C
2. E+
N
N
(55-95%)
R=
O
(CH2)n , n=2, 3 ;
E+ = CO2, DMF, RCHO, RCOR
E
SO2NHt-Bu
SO2NHt-Bu
1. LDA / THF / -78 °C
2. E+
N
N
O
Ph
Ph
NR
SO2
N
O2S
S
O2
Ph
Ph
O
N
O
N
HetAtom-Based Quinoline DoM. DMG = OCONEt2
Methodology
OH
1. LDA / THF
-105 °C
N
OCONEt2
R
OCONEt2 2. RCHO
N
R
+
OCONEt2
N
H
R = Et (30%)
(19%)
R = Ph (28%)
(24%)
E
OCONR2 1. LDA / THF
-78 °C
2. E+
(25 - 90%)
N
R = Me, Et
OCONEt2
OCONR2
N
E =D, TMS, MeCH(OH), EtCH(OH)
OCONEt2
1. LDA / THF
-78 °C
N
2. E+
(75 - 95%)
OCONMe2
E
N
E =D, TMS, Me
O
LDA / THF
-78 °C to rt
N
(80%)
CONMe2
N
H
O
HetAtom - Based Quinoline DoM. DMG = N-COt-Bu.
Methodology
1. 3 equiv n-BuLi
Et2O / 20 oC
N
NHCOt-Bu
E
2. E+
N
NHCOt-Bu
(12-95%)
E = D, I, TMS, SMe, COOEt, CEt2(OH)
NHCOt-Bu
NHCOt-Bu
N
LDA / TMSCl
(93%)
N
Nu
n-BuLi / TMEDA
(100%)
(45%)
Nu
s-BuLi / TMSCl
THF / -90 oC
Diazine DoM. Pyrimidines, DMG = OMe.
Methodology
OMe
Et2O / 0 oC
2. E+
N
MeO
OMe
1. LiTMP
N
(4-65%)
E
N
MeO
N
E+ = TMS, CHO, COMe, CO2H, CO2Et, RCH(OH)
OMe
OMe
1. 2.3 equiv
LiTMP
THF / -70 oC
N
Cl
Cl
2. E+
N
E
N
N
(30-66%)
E+ = TMS, RCH(OH), ArCH(OH)
DMG
N
X
N
LiTMP / TMSCl / THF / 0oC
X = H, Cl, OMOM
DMG = OMOM (13-18%)
=N-COt-Bu (0%)
Diazine DoM. Pyrimidines, DMG = Cl.
Methodology and Synthetic Utility
-
Cl
N
Cl
N
N
Cl
N
LDA / THF / -78 oC
E+ = PhCHO, TMSCl
Cl
1. LDA
N
2.
N
N
NCHO
CHO
N
Cl
(71%)
N
Cl
Cl
Cl
1. LDA
N
Cl
Cl
2.
N
NCHO
CHO
N
N
(40%)
CHO
N
N
Cl
N
N
2
Cl
:
1
O
N
Ph
NH2
N
RNHNH 2
Cl
PhNH2
Ph
N
O
N
N
N
R
Cl
Ph
NH2
Cl
N
N
N
HN
N
N
Ph
N
H
Diazine
DiazineDoM.
DoM.Application
Applicationto
toNucleosides
Nucleosides
E
HN
HN
1. s-BuLi / TMEDA
THF / -78 °C
N
O
O
O
O
O
N
O
N
O
2. E+
HN
E
O
O
(45 - 58%)
TBSO
OTBS
TBSO
E= D
Me
SCH2Ph
COPh
OTBS
5
3
>99
>99
OTBS
TBSO
:
:
:
:
1
1
1
1
Diazine DoM. Pyridazines, DMG = Cl.
Methodology
Cl
Cl
1. LiTMP
THF / -70 oC
N
N
2. E+
(45-65%)
E
N
N
Cl
E+ = DMF, MeCHO, ArCHO, PhCOPh, TMSCl, I2
Cl
Diazine DoM. Pyridazines, DMG = Cl.
Addition of s- and n-BuLi
H
N
Cl
R = Cl
N
s-BuLi
-78 °C
N
R
Cl
N
N
Cl
+
Cl
O
sBu
s-Bu
2a (43%)
THF
TMSCl
N
3 (<15%)
R = OMe, Ph
1
a
b
c
R
N
Cl
MeO
Ph
N
R
N
Cl
+
N
R
Cl
sBu
sBu
2b (41%)
2c (34%)
4b (10%)
4c (12%)
H
N
N
Cl
N
N
Cl
Cl
n-Bu
n-BuLi
THF/-78 °C
TMSCl
N
Cl
N
Cl
MeLi
THF/-78 °C
TMSCl
Cl
Cl
N
31%
O
N
42%
Diazine DoM. Pyrazines, DMG = CON-t-Bu, N-COt-Bu
Unusual Reactivity
N
TMS
LiTMP / TMSCl
N
TMS
CONH t-Bu
1. LiTMP / 0 oC
2. RCHO
TMS
N
CONH t-Bu
+
THF
N
N
N
o
Temp.
-70
0
CONH t-Bu
C
Yield %
77
0
0
67
OH
N
N
R
CONH t-Bu
R = Me (45%)
R = Ph (43%)
N
1. RLi
R
N
2. PhCHO
N
CONH t-Bu
N
Ph
CONH t-Bu
R = mesityl (24%)
R = t-BuLi (63%)
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