Short Course

Aromatic Heterocyclic Chemistry

An Outline of Fundamental Reactivity of Thiophenes, Furans, Pyrroles, Indole and Pyridine

Professor Daniel L. Comins

Department of Chemistry
North Carolina State University N
N Raleigh, North Carolina USA H
 Scheme 1. Typical Reactivity of Thiophenes, Furans and Pyrroles D. Comins-2

Electrophilic Aromatic Substitution: α-Attack Predominates

β
E E E
E
α
Z Z Z H Z H
H
Z = S, O, NH, NR

Electron rich heterocycles H

The heteroatom activates the ring toward electrophilic

substitution; mild conditions are generally required.
Since these heterocycles are electron rich, they are not E
prone to nucleophilic attack. Z

Electrophilic Aromatic Substitution: Effect of Substituents

major R electron R electron

minor minor minor donating withdrawing

minor
R R
Z Z Z Z
major electron electron major major
donating withdrawing

Further information, see: (1) Handbook of Heterocyclic Chemistry, Katritzky and Pozharskii,
p. 302-304; (2) Heterocyclic Chemistry, J. A. Joule and K. Mills, 5th Ed., Wiley, 2010.
 D. Comins-3

Scheme 2. Typical Reactivity of Thiophenes, Furans and Pyrroles

Substitution via Ring Metalation: α-Deprotonation Predominates

β
R-Li E
α
Li E
Z Z Z
Z = S, O, NR

Electron rich heterocycles

Since these heterocycles are electron rich, they undergo deprotonation instead of nucleophilic
attack with alkyllithiums.

Substitution via Ring Metalation: Effect of Directing Groups

DG
minor
major

minor minor
DG
Z Z
major
 D. Comins-4

Scheme 3. General Synthesis of Thiophenes, Furans and Pyrroles

Preparation from 1,4-Dicarbonyl Compounds: The Paal-Knorr Synthesis

The Paal-Knorr Synthesis is a synthetically valuable method that generates either furans, pyrroles, or
thiophenes from 1,4-diketones.

H+
R R
R R
O O O

R'-NH2
R R
R R
N
O O
R'

P4S10
R R
R R
S
O O
 Scheme 4. Reactions of Thiophenes D. Comins-5

Electrophilic Aromatic Substitution: Nitration

NO2
β
conc. HNO3 , Ac2O
α
AcOH, 0 °C NO2
S S S
70 %
6:1

acetyl nitrate

O2N

NO2
NO2 NO2 O2 N NO2
S S S

1:1

conc. HNO3

(CF3CO)2O NO2
S S
78 %
Katritzky, et. al., ARKIVOC, 2005, 179.
 D. Comins-6

Scheme 5. Reactions of Thiophenes

Electrophilic Aromatic Substitution: Nitration-cont.

O2N NO2

NO2

Me Me Me
S S S

major minor

Me Me Me

NO2

O2N NO2
S S S

minor major
 D. Comins-7

Scheme 6. Reactions of Thiophenes

Electrophilic Aromatic Substitution: Sulfonation

ClSO3H, PCl5, rt

70% SO2Cl
S S
 Scheme 7. Reactions of Thiophenes D. Comins-8

Electrophilic Aromatic Substitution: Halogenation

The rate of halogenation of thiophene at rt is about 108 x that of benzene.

1 eq. NCS, cat. HClO4

hexane, rt, 12 h Cl
S S

88%

1 eq. NBS, cat. HClO4

hexane, rt, 1 h Br
S S

90%

2 eq. NBS, cat. HClO4

Br Br
hexane, rt, 24 h S
S

95%

Reference: Goldberg and Alper, J. Org. Chem. 1993, 58, 3072.

 Scheme 8. Reactions of Thiophenes D. Comins-9

Electrophilic Aromatic Substitution: Halogenation-cont.

1 eq. NBS, cat. HClO4

Me hexane, rt, 18 h Br Me
S S

80%

1 eq. NCS, cat. HClO4

I hexane, rt, 24 h Cl I
S S

70%
Br
Br
1 eq. NBS, cat. HClO4

Br
hexane, rt, 24 h S
S

93%

Reference: Goldberg and Alper, J. Org. Chem. 1993, 58, 3072.

 Scheme 9. Reactions of Thiophenes D. Comins-10

Electrophilic Aromatic Substitution: Halogenation-cont.

Br

3 eq Br2, 48% HBr

rt to 75 °C Br Br
S S

75%

Br

Zn/AcOH, heat
Br
90% S

Br
Br Br NaBH4, Pd cat.
S

MeCN, reflux Br
S
83%

Note: Zinc/AcOH will selectively remove α-halogens from polyhalothiophenes.

Reference: See: Heterocyclic Chemistry, J. A. Joule and K. Mills, 5th Ed., Wiley, 2010.
 Scheme 10. Reactions of Thiophenes D. Comins-11

Electrophilic Aromatic Substitution: Acylation

The Friedel-Crafts acylation of thiophenes generally gives good yields.

MeCOCl, SnCl4
O
benzene, 0 °C
S S
80% Me

O
Cl

ClCH2COCl, AlCl3

Me Me Py/ClCH2CH2Cl, Me Me
S S
-20 °C to rt
90%

EtO2C(CH2)5COCl, SnCl4
O
Ph ClCH2CH2Cl, Ph
S S
5 °C to rt
(CH2)5CO2Et
58%
 Scheme 11. Reactions of Thiophenes D. Comins-12

Electrophilic Aromatic Substitution: Acylation-cont.

i-PrCO2H, PPA O

S
75 °C
S
77%

PhCO2H, TfOTf O

S
S MeNO2, 45 °C
Ph
93%

PhN(Me)CHO, POCl3
O
35 °C
S S
78% H

(Vilsmeier-Haack)
 Scheme 12. Reactions of Thiophenes D. Comins-13

Electrophilic Aromatic Substitution: Alkylations

The Friedel-Crafts alkyation of thiophenes is not a good reaction.

HCHO, HCl Cl

S
0 °C
S
41%

Cl

HCHO, HCl, ZnCl

MeO2C Me
MeO2C Me CHCl3, rt S
S
93%

Me2N=CH2 Cl
NMe2
MeCN, reflux
S S
55%
(Mannich Rxn)
 Scheme 13. Reactions of Thiophenes D. Comins-14

Electrophilic Addition at Sulfur

The thiophene sulfur can react with strong electrophiles.

MeOTf

S
80 °C; NaPF6
S PF6
95%
Me

(EtO2C)2CN2

Rh(OAc)2 S
S
95%
EtO2C CO2Et

60 °C
70%

CO2Et

S
CO2Et
 D. Comins-15

Scheme 14. Reactions of Thiophenes

Oxidation at Sulfur

Apart from S-oxidations, the thiophene ring is relatively stable to oxidation.

t-Bu t-Bu t-Bu t-Bu

xs MCPBA

S 93% S

O O

TFAA/H2O2

Br Br MeCN Br Br
S S
82% O
O
 Scheme 15. Reactions of Thiophenes D. Comins-16

Nucleophilic Attack on Thiophene Derivatives

The thiophene ring needs to be activated for facile nucleophilic substitution reactions.

piperidine, MeOH

O2 N Br
rt O2 N N
S S
90%

HS
S

I rt S S S
S

84%

MeONa, CuBr
Br
S MeOH, 100 °C OMe
S

83%

Br
OMe

MeONa, CuBr

S MeOH, 100 °C S

88%
 Scheme 16. Reactions of Thiophenes D. Comins-17

Metalation of Thiophene and Derivatives

Mono- and dilithiation of thiophene occurs at the α-positions.

1 eq n-BuLi E
Li E
S Et2O, -10 °C to rt S S

2 eq n-BuLi
E
Li Li E E
S THF, -20 °C S S

Br Br
Br
LDA DMF

Li 80% CHO
THF, 0 °C S S
S

Li SnBu3
Br

1 eq n-BuLi Bu3SnCl

Et2O, -78 °C S 86% S

S
(Lithium-halogen exchange)
 D. Comins-18
Scheme 17. Reactions of Thiophenes

Metalation of Thiophene and Derivatives-cont.

Br
Br
1 eq n-BuLi E

Li E
Br Et2O, -78 °C to rt S S
S

Me2N

Br Br Br OHC CHO
OLi

1) 1 eq n-BuLi 1) 1 eq t-BuLi

S 2) DMF -78 °C S 2) DMF -78 °C S

3) H3O+

Mg, Et2O E

heat MgBr E
Br S S
S
 Scheme 18. Reactions of Thiophenes D. Comins-19

Reactions with Reducing Agents

(CH2)3CO2H (CH2)3CO2H

Raney Ni

Me Me H2O, 100 °C Me Me
S
93%

Et3SiH

Me
Me TFA, 50 °C S
S
80%

1) 3 Li/NH3

2) NH4Cl CO2Me
CO2H S
S 3) CH2N2
78%
 D. Comins-20
Scheme 19. Reactions of Thiophenes

Oxy- and Amino-Thiophenes

These derivatives are not very stable.

H2O2, CuSO4 TBSOTf

O
2,6-lutidine, rt OTBS
S aq H2SO4, rt S S
80%
59%

PhCHO
Ph
O HCl, EtOH, 95 °C O
S S
70%

"reduction"
NH2
NO2 S
S
(not stable)
 D. Comins-21
Scheme 20. Reactions of Thiophenes

Miscellaneous Reactions

H CO2Et
CO2Et
ClCO2Et, Et2O
MgCl
72% Me
S S S

RO OR RO OR

Cu, quinoline

HO2C CO2H 200 °C

S S
88%

Me3Si SiMe3 Me3Si I(OTf)Ph

PhI(OAc)2, TfOH Diels-Alder
KF

CH2Cl2, rt 18-crown-6 S
S S
53%
 D. Comins-22

FURANS

1. Furans are more reactive than thiophenes.

2. They are sensitive to strong acids.
3. Many undergo facile Diels-Alder reactions.
D. Comins-23
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D. Comins-42
D. Comins-43
 D. Comins-44

PYRROLES

1. Pyrroles are more reactive than thiophenes.

2. They are polymerised by strong acids.
3. They darken by autoxidation.
D. Comins-45
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 D. Comins-64

INDOLES

1. Indoles are more stable than pyrroles.

2. They are common in medicinal agents.
D. Comins-65
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 D. Comins-75

PYRIDINES
Synthesis and Synthetic Utility of Pyridine
Derivatives

N
 D. Comins-76
Scheme 1. Clasical Substitution

Electrophilic Aromatic Substitution

N N N N

The nitrogen atom deactivates the ring toward electrophilic substitution; harsh conditions
are generally required.

NO2
KNO3, HNO3

H2SO4, Fe
N N N
300 °C 22% yield

SO3H
H2SO4 KNO3,
H2SO4
230 °C, 24 h
N 71% yield

NO2

Br
Br2, fuming H2SO4

130 °C
N N
66% yield
90% yield O

Note: Friedel-Crafts acylation and alkylation fail in the pyridine series.

 D. Comins-77
Scheme 2. Clasical Substitution

Nucleophilic Aromatic Substitution

N N N N

The nitrogen atom activates the ring toward nucleophilic substitution; however, strong
nucleophiles are generally required with the free base.

Nu
H
Nu

N N N Nu
H

NaNH2
The Chichibabin amination
xylene, Δ
N NH2

75% yield

RLi
moderate yields
Et2O or THF
low temrerature N R

Grignards react only with heating to give poor yields and regioselectivity; in general, it's not a
good reaction.
 Scheme 3. Substitution via Dihydropyridine Intermediates D. Comins-78

Nucleophilic Addition to N-Acylpyridinium Salts

nucleophilic attack

R'COCl

THF
N N
( acid chlorides or chloroformates) Cl

O R'

Et

1. EtMgBr, THF

2. EtOCOCl, -20 °C
N N Et N
80%
CO2Et 64:36 CO2Et

However:
Ph

1. PhMgBr, THF

2. EtOCOCl, -20 °C
N N Ph N
80%
CO2Et 93:7 CO2Et

Note: Aryl, alkenyl, and alkynyl Grignards add mainly or exclusively at the 2-position. When the
pyridine ring has the 4-position blocked with a substituent, an alkyl Grignard reagent adds
exclusively at C-2.
 D. Comins-79
Scheme 4. Substitution via Dihydropyridine Intermediates

Nucleophilic Addition to N-Acylpyridinium Salts at C-4

RMgX, 5% CuI
nucleophilic attack

R'COCl

THF
N N RMgX
Cl (major)
( acid chlorides or chloroformates)
O R'

Et

1. EtMgBr, THF,
5% CuI

2. EtOCOCl, -20 °C
N N
80%
CO2Et
Regioselectivity > 95%

Note: This reaction works well for alkyl and aryl Grignards.

Et

Me 1. EtMgBr, THF, Me
5% CuI

2. EtOCOCl, -20 °C
N N
~80%
CO2Et

Note: This reaction will work with 2-picoline but the yields are lower. Pyridines with
large or electron-withdrawing groups at C-2 fail by inhibiting N-acyl salt formation.
 D. Comins-80

Scheme 5. Substitution via Dihydropyridine Intermediates

Aromatization of N-Acyldihydropyridine Intermediates

R R

S8 , Δ
or or
or
N N R chloranil N N R

COR' COR'

An example:

Et Et

Me Me Me
1. EtOCOCl,THF,
5% CuI S8 , Δ

2. EtMgBr, -20 °C
N N N

CO2Et
68% overall
distilled

Note: This reaction was run on a 0.1 mol scale.

 D. Comins-81

Scheme 6. Substitution via Dihydropyridine Intermediates

R
CO2Me CO2Me CO2Me
1. RMgX, PhOCOCl
+
N 2. S8, naphthalene R N N

R
Selectivity not good!
Me 40 : 60
n-Bu 43 : 57
c-C6H11 16 : 84
Ph 84 : 16

R
CO2Me 1. 5 % CuI, RMgX, CO2Me CO2Me
PhOCOCl
+
N 2. S8, naphthalene R N N

R
Selectivity excellent! Me 1 : 99
n-Bu 7 : 93
c-C6H11 4 : 96
Ph 5 : 95
 D. Comins-82

Scheme 7. Substitution via Dihydropyridine Intermediates

R
Cl 1. 5 % CuI, RMgX, Cl
PhOCOCl

N 2. o-chloranil
N

Without CuI selectivity is poor! R = alkyl, aryl

overall yields: 45-61%

R
Br 1. 5 % CuI, RMgX, Br
PhOCOCl

2. o-chloranil
N N

R = alkyl, aryl
Selectivity excellent!
overall yields: 37-68%

Ph Ph Ph
PhMgX,
Br Br Br
PhOCOCl
o-chloranil

N Ph N Ph N
CO2Ph
50% overall
 D. Comins-83
Scheme 8. Substitution via Dihydropyridine Intermediates

O R
1. 5 % CuI, RMgX, CHO
O PhOCOCl

N
2. S8, Δ N
3. H3O+
R = alkyl, aryl
overall yields: 30-62%

O O
R
1. 5 % CuI, RMgX,
R' PhOCOCl R'

N 2. S8, Δ N

Ketone does not need protection! R,R' = alkyl, aryl

overall yields: 19-41%

Ph
R
O 1. 5 % CuI, RMgX, OH
PhOCOCl

N 2. o-chloranil N
3. H2, Pd/C
R = alkyl, aryl
overall yields: 36-56%
 Scheme 9. Substitution via Dihydropyridine Intermediates D. Comins-84

R OTi(iPrO)4Li+ R
R1
1. R1
PhOCOCl
R2 R2

N
2. S8, Δ N
3. H3O+
R, R2 = H, alkyl
Titanium "ate" complexes gave the best C-4 R1 = alkyl, aryl, OEt
selectivity.
overall yields: 30-50%

Reactions with silyl enol ethers; Contributions by Kin-ya Akiba and coworkers, Hiroshima University
O

R1 OTMS R1
R2
R2 42-69%
1.
EtOCOCl, CH2Cl2

N 2. O2 or AgNO3 24-65% N

R1 = H, alkyl, aryl
R2 = alkyl, aryl, OMe
O O

Me OTMS
CO2Me CO2Me CO2Me
Me Me DDQ

N
MeOCOCl N 63% N
93% CO2Me
 D. Comins-85
Scheme 10. Substitution via Dihydropyridine Intermediates

O 1. LDA Me OTi(iPrO)4Li+

2. Ti(iPrO)4
N N NMe
Me Py
I

Me
Ti enolate I NPy
H 1.1 MeMgCl
Me
N THF THF
Cl
CO2Ph 67%
N

CO2Ph

O
O
Me
Me
Me
H Me
5% Pd/C, S8

N naphthalene, Δ
N
76%
CO2Ph

This sequence is tantamount to the addition of a "thermodynamic" enolate to the

4-position of pyridine.
 D. Comins-86
Scheme 11. Substitution via Dihydropyridine Intermediates
Contributions by Ryohei Yamaguchi and coworkers, Kyoto University

SnMe3

Me N CH2Cl2, rt Me N
Cl
CO2Me 65% CO2Me

C-2 Selectivity: 95%

Cl
Cl SnBu3

N
N Cl CH2Cl2, -78 °C
CO2Me
CO2Me 87%
C-2 Selectivity: 93%

OAc SnBu3 OAc

N Cl CH2Cl2, -78 °C N

CO2Me 96% CO2Me

C-2 Selectivity: 91%

This chemistry nicely compliments the Grignard reactions and is carried out under mild
conditions with excellent selectivity and yields.
 D. Comins-87
Scheme 12. Substitution via Dihydropyridine Intermediates
Contributions by Ryohei Yamaguchi and coworkers, Kyoto University

Ph

SnMe3

N CH2Cl2, rt N
Cl
CO2Me 68% CO2Me

C-4 Selectivity: 100%

Ph

CHO SnMe3 CHO

N CH2Cl2, rt N
Cl
CO2Me 92% CO2Me

C-4 Selectivity: 100%

Ph

CN SnMe3 CN

N CH2Cl2, rt N
Cl
CO2Me 90% CO2Me

C-4 Selectivity: 100%

 Scheme 13. Substitution via Dihydropyridine Intermediates D. Comins-88

Cl
Cl
1. RMgX,
PhOCOCl

N 2. o-chloranil N R

Phenyl chloroformate is best in this case. R = alkyl, aryl

overall yields: 36-64%

Br
Br
1. RMgX,
PhOCOCl

2. o-chloranil
N N R

R = alkyl, aryl
overall yields: 50-59%

SnMe3 SnMe3

RMgX,
PhOCOCl oxalic acid
H H

N N N
R
R
CO2Ph
CO2Ph

R = alkyl, aryl
overall yields: 49-70%

The halo and trimethylstannyl groups can be utilized in cross coupling reactions to provide
access to 2,4-disubstituted pyridines.
 D. Comins-89

Scheme 14. Substitution via Dihydropyridine Intermediates

Cl
Cl
Si(iPr)3 RMgX, TIPS
PhOCOCl

N R N

CO2Ph
Phenyl chloroformate is best in this case. R = alkyl, aryl
Regioselectivity: 100%

TIPS TIPS
RMgX,
PhOCOCl

N R N

CO2Ph
R = alkyl, aryl
Regioselectivity: 100%

R R R

1. PhOCOCl S8, Δ
H
2. R'ZnI N N
N R'
R'
35-81% CO2Ph R, R' = alkyl, aryl

A convenient synthesis of 2,4-disubstituted pyridines.

 D. Comins-90
Scheme 15. C-3 Substitution via Dihydropyridine Intermediates

R'

R R'MgX, R
PhOCOCl POCl3/DMF

N 5% CuI N 43-71%

CO2Ph
R,R' = alkyl, aryl

R' R'
OHC R OHC R
S8, Δ

N 53-69% N

CO2Ph R = alkyl, aryl

Regioselectivity: 100%

R R OHC R
PhOCOCl 1. POCl3/DMF

N NaBH4 N 2. S8, Δ N
35-56% step 1: 57-65%
CO2Ph
step 2: 51-71% R = alkyl, halo, MeO

An indirect Villsmeier-Haak formylation of pyridines.

 D. Comins-91

Scheme 16. C-3 Substitution via Dihydropyridine Intermediates

R R
RMgX,
PhOCOCl Li-NEt2

5% CuI N 80-92% N
N
(one pot)
R = alkyl, aryl CO2Ph CONEt2

R R

COR' COR'
R'COCl-SnCl4 S8, Δ

CH2Cl2
N N

CONEt2 R,R' = alkyl, aryl

Not purified 28-49% overall

TMS TMS Ac
EtOCOCl 1. AcCl-SnCl4 35%
PhMgCl N 2. ο−chloranil N
N Ph Ph
80% 67%
CO2Et

An indirect silicon-mediated Friedel-Crafts acylation of pyridines.

 D. Comins-92

Scheme 17. C-3 Substitution via Dihydropyridine Intermediates

Br Br
o-chloranil

Ph N ~70% Ph N
CO2Ph
NBS
SnBu3 87%

Ph N 45%
CO2Ph AcCl, COMe COMe
Cl2Pd(Ph3)2
o-chloranil

Ph N ~70% Ph N
PhMgCl, 80%
PhOCOCl CO2Ph

SnBu3

A C-2 arylation and a regioselective tin-mediated halogenation/acylation of pyridine.

 D. Comins-93
Scheme 18. C-2 Substitution via Dihydropyridine Intermediates

R R
1. RMgX,
PhOCOCl,
5% CuI 1. s-BuLi

2. t-BuOK 2. E+
N N N E

CO2t-Bu CO2t-Bu
R = alkyl, aryl
E = Me 72%
E = CO2Me 89%
R
Cl
o-chloranil

or S8, Δ N E
Bu N SMe
57-79%
63%

o-chloranil

Cl Cl Cl
1. BuMgX,
PhOCOCl 1. n-BuLi

N 2. t-BuOK N 2. MeSSMe N SMe

Bu Bu
88%
CO2t-Bu CO2t-Bu

Uniquely substituted pyridines can be prepared by these routes.

 D. Comins-94
Scheme 19. C-2 Substitution via Dihydropyridine Intermediates

Me Me
1. MeMgX,
Me PhOCOCl, Me Me
5% CuI 1. MesLi, -42 °C

2. t-BuOK 2. MeI
N N Me N
72%
CO2t-Bu CO2t-Bu
regioselectivity: 93:7

Me Me
Me
OCONEt2 OCONEt2
1. PhLi, -78 °C OCONEt2
o-chloranil
N 2. MeI N Me 39% N Me
70%
CO2t-Bu CO2t-Bu
regioselectivity: 98:2

OH

OH
N

N
This methodology is tantamount to the
disubstitution of the pyridinol synthon in the box.

Uniquely substituted pyridines can be prepared by these routes.

 D. Comins-95

Scheme 20. Synthesis and Reactions of 2,3-Dihydro-4-pyridones

OMe OMe O

RMgCl H3O+

N Cl R N R N

CO2R CO2R
O OR

NaOMe,
MeOH
ROCOCl, THF

O
OMe

R N
N
H
D. Comins-96
 D. Comins-97
Scheme 22. The Versatile N-Acyl-2,3-dihydro-4-pyridones-cont.
O
R3

R1 N
CO2R2
OH
R4
R3

R3 = H, CHO
R1 N
R1 N R4 = H, Cl
CO2R2
CO2R2
O
4
3
5
2
6
R1 1N
CO2R2
O

O R3

R1 N
CO2R2
R1 N
CO2R2
O

R1 N R3
CO2R2
 D. Comins-98

Scheme 23. The Versatile N-Acyl-2,3-dihydro-4-pyridones-cont.

OH
CH3
H H3C N CH3
N

N (-)-perhydrohistrionicotoxin

indolizidine (-)-235B (+)-metazocine

H
O O
N
H H
Ac
*
R N
N N
H O OR' H
Me Me

(+)-luciduline Nα-acetyl-Nβ−methylphlegmarine

O N
Me H H

(-)-porantheridine (+)-trans-219A
 Scheme 24. Ring Opening Methodology D. Comins-99

OMe O

1) PhOCOCl MeMgBr

N 2) PhMgBr Ph N CuBr, BF3 OEt2

85% CO2Ph
75%

O OH

LAH Ac2O, DMAP

or
Ph N Ph N
73% TBDMSCl, DMAP
CO2Ph Me
80-85%

OR
OR Br
BrCN
N Ph
CHCl3
Ph N CN
Me 95-97% R = Ac, TBDMS

SN2 OR

Br
via
Ph N
Me CN
 Scheme 25. Ring Opening Methodology-Cont. D. Comins-100

O O

1) LiHMDS MeMgBr

Ph N 2) MeI Ph N CuBr, BF3 OEt2

99%
CO2Ph CO2Ph
75%

O O

1) LiHMDS L-Selectride

2) MeI, HMPA
Ph N Ph N 74%
67% CO2Ph
CO2Ph

OH
OH
BrCN
LAH

CHCl3
99% Ph N
Ph N 60%
Me
CO2Ph

OH Br
OH N3
NaN3
N Ph
HMPA N Ph
CN
90% CN
5 contiguous centers
 D. Comins-101
Scheme 26. Lithiation of Halopyridines

Li X

Li X Li
LDA, THF
X
-78 °C
N N X N N
X = F, Cl, Br

Br Br

CHO
1) LDA, THF

2) DMF 61%
N N

Cl Cl
1) LDA, THF

2) I2 65%
N N

TMS
1) LDA, THF

2) TMSCl 74%
N Cl
N Cl
 D. Comins-102
Scheme 27. Lithiation of Dihalopyridines

Me F Me F
1) LDA, THF

2) I2 95%
Me N Cl Me N Cl

Cl Cl

E
1) LDA, THF

2) E+ 71-90%
N Cl N Cl

E = CH(OH)Ph, TMS, CHO, etc.

Br Br
Br Br
1) LDA, THF

2) E+ 59-94%
N
N

TMS

Cl Cl
1) LDA, THF

2) TMSCl 90%
N Cl N Cl
 Scheme 28. The Halogen-Dance Reaction D. Comins-103

E
I
1) LDA, THF

2) E+ 54-96%
N Cl (F)
N Cl (F)

I E

F I F
1) LDA, THF

2) E+ 64-78%
N Cl N Cl

E = H, CH(OH)Ph, Me, I, etc.

E
I
1) LDA, THF
80-97%
2) E+
N CON(i-Pr)2
N CON(i-Pr)2

I E

F I F
1) LDA, THF

2) E+
N N

t-BuCONH t-BuCONH
52-91%
 Scheme 29. Lithiation with Fort's Base D. Comins-104

1) n-BuLi-LiDMAE, hexane

2) MeSSMe
N Cl MeS N Cl

92%

H
Bu N X
via Li
Li
O NMe2

1) n-BuLi-LiDMAE

2) TMSCl Me3Si N OMe

N OMe
77%

1) n-BuLi-LiDMAE, hexane

2) MeSSMe
N Ph MeS N Ph

92%

NMe2 NMe2

1) n-BuLi-LiDMAE

2) I2 N I
N
81%
 D. Comins-105

Scheme 30. Synthesis of Heterocycles by Halogen-Magnesium Exchange

HO Ph
I

1) i-PrMgBr, -40 °C, 0.5 h

2) PhCHO
N Cl N Cl
92%

O Ph
I

CO2Et CO2Et
1) i-PrMgBr, -40 °C, 0.5 h

2) CuCN; PhCO2Cl
N Cl N Cl
84%

CN
CN
1) i-PrMgBr, -78 °C
HO
2) PhCHO N
I N
Ph 67%

1) i-PrMgCl, THF, rt, 2 h

Ph
N Br 2) PhCHO N

80% HO
 D. Comins-106
Scheme 31. Lithiation of Methoxypyridines

1) 1.2 LDA, THF TMS

0 °C, 1 h

N OMe 2) 2 TMSCl, 0 °C to N OMe

rt, 20 min
83%

OMe OMe OMe

1) 1.2 LDA, THF TMS TMS TMS
0 °C, 1 h

2) 2 TMSCl, 0 °C to
N rt, 20 min N N
61% 16%

TMS TMS
OMe 1.2 LDA, THF OMe OMe OMe
-42 °C, 1 h
2.0 TMSCl
N N TMS N N TMS

42% 33% 0.4%

Queguiner, et al.:

OEt OEt OEt

n-BuLi, THF
E
TMEDA, -40 °C
N N Li N E
 D. Comins-107
Scheme 32. Lithiation of Methoxypyridines

1) 1.3 MesLi, THF CHO

0 °C, 1 h; rt, 1 h

N OMe 2) DMF N OMe

63%

OMe OMe

1) 1.3 MesLi, THF CHO

-23 °C, 3 h

2) DMF
N N
77%

OMe
1) 1.3 MesLi, THF OMe
-23 °C, 3 h

2) DMF N CHO
N

85%

Other electrophiles can be used: 62-85% yields

 D. Comins-108
Scheme 33. α-Amino Alkoxide Directed Lithiation

H H
LiO N LiO
N N
CHO Li
N Bu N
1) Li N Li
H
(LTMDA)
N N N
2) n-BuLi

SnMe3
CHO N
1) Li N CHO
(LTMDA)

N 2) n-BuLi 60%
N
3) Me3SnCl; H2O

97
4 96 70
3 CHO MeO CHO

30
MeO N CHO MeO N N

OMe
>98 >98
>98
CHO OMe CHO

N OMe N CHO N
 D. Comins-109

Scheme 34. α-Amino Alkoxide Directed Lithiation-cont.

N
H
LiO N
CHO
Li N N
1)
(LNMP)
N N

3
97 3
97 CHO MeO CHO

>98
MeO N CHO MeO N N

>98 OMe
OMe >98
CHO

N CHO
N