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

"I thought you said it was spot to spot."