Haloselectivity of Heterocycles

Baran Group Meeting

Background

SN(ANRORC) Addition of Nuclophile, Ring Opening, Ring Closure

Polysubstituted heterocycles represent some of the most important compounds in the realm of
pharmaceutical and material sciences. New and more efficient ways to selectively produce these
molecules are of great importance and one approach is though the use of polyhalo heterocycles.
Consider:

Ar3
CO2Me

Ar1

3 Suzuki Couplings

N
H
Ar3

CO2Me

Ar1

1 Triple Suzuki Coupling

N
H
Ar3

CO2Me

Ar1

NH3(l), 90%

NH2

NH
N

CO2Me

NH

N
H

Cross Coupling

CO2Me

Virtually all types of cross coupling have been utilized in regioselective cross coupling reactions:
Kumada, Negishi, Sonogashira, Stille, Suzuki, Hiyama, etc.
In all of these examples, the oxidative addition of the metal to the heterocycle is the selectivity
determining steps and is frequently considered to be irreversible. This addition highly resembles a
nucleophilic substitution and it frequently follows similar regioselectivities in traditional SNAr reactions.
The regioselectivity of cross coupling reaction in polyhalo heterocycles do not always follow the BDE's
of the corresponding C-X bonds.

Nu
Nu
N

Nu

2nd
Meisenheimer Complex

1st

Br
83.2

SN(EA)

via:
NaNH2, t-BuONa
pyrrolidine

87.3

THF, 40C

OMe

SET Mechanism can also be operative (SRN1)

+

Nu

HetX

Het

OK

HetNu

N
N

+ Nu

Cl

h!, NH3(l)
88%

JOC 1981, 46, 294

HetNu

+ HetX

HetNu

HetX

88.9
88.9

Br

1st

Merlic and Houk have determined that the oxidative addition in palladium catalyzed cross coupling
reactions is determined by the distortion energy of the C-X bond (related to BDE) and the interaction of
the LUMO of the heterocycle to the HOMO of the Pd species.

HetX

Br

HetX + Nu

2nd

Br

Tetrahedron 1982, 38, 427

Het

NH2
H

SNAr or SN(AE)

NH2

- Br

Nucleophilic Substitution

Br

N
NH2

N
H

Ar2

1 Triple C-H activation?

N
H

Br

Br

NaNH2

CO2Me
Ar2

1 Triple Halogenation
N
H

Br
N

Ar2

3 Halogenations
N
H

Will Gutekunst

JACS, 2007, 129, 12664; JACS, 2009, 131, 6632

Haloselectivity of Heterocycles

Baran Group Meeting

Predicting Reactivity

Will Gutekunst

Pyrroles can also be selectively monoarylated at C-2 under C-H activation conditions.

The Handy Method

Handy and coworkers disclosed an experimental method in 2006 for predicting the regiochemical
outcome of multiply halogenated heterocycles using 1H-NMR of the dehalogenated substrate. The
proton that displays the largest chemical shift implies it is attached to the most electron deficient
carbon atom and, therefore, the preferred site of cross coupling. While this method is not foolproof
(it does not take into account sterics, directing groups, or interactions noted by Merlic), it is a good
start for predicting regioselectivities of cross coupling reactions.

Ph2I+BF45% IMesPd(OAc)2
N
Me

rt, AcOH, 67%

Ph

N
Me

JACS 2006, 128, 4972

Chem. Comm. 2006, 299

Indole
Pyrroles

2nd
7.55

7.00

- Due to the electron rich nature, SNAr reactions do not readily take place
without strong EWGs.
- Cross coupling reactions occur fastest at the 2/5 positions, in accord with
chemical shift prediction.
- Monocoupling in 2,5 dihalo substrates is difficult, but 3,4 dihalo
substrates can be easily controlled on steric grounds.
-

2nd

6.22
6.68

1st

N
H

(CDCl3)

6.45
7.08

N
H

7.40

last

7.27

- Like pyrrole, SNAr is very difficult without strong EWG's

- Cross coupling occurs first at C-2, with C-4 to C-7 reacting
before electron rich C-3. A C-2 vs C-4/7 has not been reported.

1st

(Acetone)

Br
O
Cl

Cl

2.5 eq EtSH
TEA, DMSO

86%

EtS

H
N
Me

Cl

S
N
TBS

N
TBS

10% Pd(PPh3)4
Na2CO3, Tol/H2O
reflux, 8 hrs
78%

H
N
Me

Br

Br

B(OH)2

Orthogonally, the 3-position could be selectively exchanged with t-BuLi.

Tetrahedron 2005, 61, 5831
Br
Br
Br

Br

N
Me

Br

Tet. Lett. 2009, 49, 1698

Cl

Br

Br

B(OH)2
N
Me

6% Pd(PPh3)4
K3PO4, Tol/H2O
90C, 12 hrs
71%

t-BuLi, MeI

Br

Br
N
TBS

Br

-78 C, THF
81%

N
TBS

Chem. Pharm. Bull. 1996, 44,1831

Cl

The C-H activation conditions for pyrrole are also successful on indole and tolerates aryl bromides
MeO

MeO

OMOM

MeO

B(OH)2

MeO
MeO
TfO
MeO2C

OTf

N
R

CO2Me

B(OH)2

2% Pd(PPh3)4

8% Pd(PPh3)4

aq. Na2CO3, THF

reflux, 4 hrs
78%

aq. Na2CO3, THF

reflux, 20 hrs
58%

Tet. Lett. 2003, 44, 4443

MeO

OMe
Br

Ph2I+BF45% IMesPd(OAc)2

MeO
OMOM
MeO2C

N
R

CO2Me

N
H

60 C, AcOH, 74%

Br

N
H

Ph

Haloselectivity of Heterocycles

Baran Group Meeting

Will Gutekunst

Much like the dibromo indole, after the first Negishi coupling, the lithium halogen exchange
at C-3 is favored.

Furan
- Not as resistant as pyrrole, but SNAr reactions still do not readily take place
without strong EWGs.
- Cross coupling reactions occur fastest at the 2/5 positions, in accord with
chemical shift prediction.
- Halogenated furans have general stability problems, making cross couplings
sometimes troublesome.

2nd

6.24
7.29

1st

(CDCl3)

t-BuLi, MeI
-78C, THF

OMe
OMe

OMe
Br
OMe

54%

Synthesis 2003, 6, 925

Br
MeO2C

Br
Br

Br

4% Pd(PPH3)4
DMA, 90C, 79%

MeO2C

Thiophene

SnMe4
5% [PdCl2(Po-Tol3)2]

Br

Bu3Sn
O

7.18

1st

(CDCl3)

2 steps

Synlett 1998, 11, 1185

MeO2C

64%

- A better substrate for SNAr than furan and two orders of magnitude more
reactive than benzene, but not many examples of haloselective reactions.
- Cross coupling reactions occur fastest at the 2/5 positions and the 3/4
much slower. Selectivity on 2,5 dihalothiophenes is scarcely obtained
though some success has been seen with Sonogashira reaction and cases
with substrate bias.

2nd

6.99

DMA, 90C, 70%

Br

rosefuran
Br

46%

Br

BnNHCH3

NBnMe
O

BnMeN

Br

4:1

Furfural can be selectively arylated in the 5- position directly.

H
OMe

Synlett 2000, 4, 459

PhBr

O
H

10% Pd(OH)2, K2CO3

DMA, 130C, 75%

Ph

Br
Br

JOC 2005, 70, 7578

7.63

7.23

6.76

last

7.30
7.51

2.5% [PdCl2(dppf)]
Et2O 63%

Two more
S

Br cross-couplings

54%

7.78

- Like indole, SNAr is uncommon on benzofuran

- Cross coupling also mimics indole first at C-2, with C-4 to C-7 reacting
before electron rich C-3. Seems to follow Handy rules, though selectivity
among C-4 through C-7 is unknown.

st
(acetone) 1

ClZn

Br

BnZnBr
Pd(PPh3)4

Br

Br

quant

52 - 57%

p-TolMgCl
NiCl2(dppp)

Tet. Lett. 1980, 21, 4017

OMe

Again, Lithium Halogen Exchange shows a different regioselection

Br

OMe
Br

Eur. JOC 2008, 5, 801

Benzofuran
2nd

Br

Br

ZnCl

OMe

MgBr

Br 5% [PdCl2(PPh3)2] 10% [NiCl2(dppe)] 10% [PdCl2(dppf)]

THF, rt, 75%

THF, rt, 86%

Br

MeZnCl
THF, reflux, 93%

OMe
O

Br

Br

Thiophenes, pg 693

Br

nBuLi, Et2O
-78C; H2O
79%

Br

Haloselectivity of Heterocycles

Baran Group Meeting

Benzothiophene
2nd

7.72

7.26

7.22

last

7.24
7.33

7.79

Will Gutekunst

Attempts to displace the second chloride leads to mixtures with ring opened products.
- SNAr occurs readily on benzothiophenes, but they have some strange
reactions with nucleophiles.
- Cross coupling also mimics indole: first at C-2, with C-4 to C-7 reacting
before C-3.

7.70
7.56

Cl

MeS
S
N

NC

1st

1) 2 eq Na2S

(CCl4)

S
NC

2) MeI

Cl

MeS

SMe

7.58

NC

CN

Isoquinolin

7.85

SMe

JOC 1964, 29, 660

NH

NH
Br

Pyrazole shows similar reactivity, with a bromide being displaces before an iodide.

Br

Br

106C

200C
73%

N
Me
N
N

Br

JOC 1973, 88,1365

EtO2C

MeO

OMe

MeO
S

EtO2C

Syn. Comm. 2008, 38, 674

Br
Br

Ethyl bromoacetate, rt
80%

Me
N
N

MeO

B(OH)2

B(OH)2

EtO2C

1.2 eq Na2S, DMF, 100C;

Ph

3% Pd(PPh3)4
5% Pd(PPh3)4
Na2CO3, EtOH/DME Ba(OH)2, H2O/DME
95%
71%

Br

Ph

Synthesis 2002, 2, 213

Ph

Br

4% PdCl2(PPh3)2
CuI, TEA/MeCN, rt
56%

Br

Ph

Br
Br

The remaining two bromides were unreactive in further Sonogashira couplings, even at higher temps

1,2-Azoles
1st
Me
N
N

7.45

8.39

3rd

6.20

Ph
S

7.26
8.14

8.54

2nd

Isothiazole (CCl4)

Isoxazole (CS2)

- Selective SNAr reactions are only known with EWGs on the 4-position, but strongly favors substitution
at the 5-position over the 3. This can be rationalized by both innate electronics (seen by NMR) and
conjugation to the EWG.
- Cross coupling also follows Handy rules: first at C-5, then at C-2 and lastly C-3.

Br

Tribromopyrazoles also lithiate at the most reactive C-5

EtO
S

NC

N
Cl

EtOH (xs)
94%

N
N

S
NC

2% PdCl2(PPh3)2
4% PdCl2(PPh3)2
CuI, TEA/MeCN, rt CuI, TEA/MeCN, 50C
45% (also 45% deiodo)
42%
MeO

Russ. Chem. Bull. 1998, 47, 537

Br
Cl

N
Cl

Ph

MeO

S
N

N
6.28

7.31

N-methyl pyrazole (CDCl3)

8.72

Br

Br

Tetrahedron 2007, 63, 56

n-BuLi, -78C;
Bu3SnCl
77%

Bu3Sn

N
N

Br

Br

S
N
Br

Haloselectivity of Heterocycles

Baran Group Meeting

1,3-Azoles
7.39

1st

7.69

7.41

7.98

2.5% Pd(OAc)2
2.5% Xantphos

O
I

Thiazole (CDCl3)

Oxazole (CCl4)

N-methyl imidazole (CDCl3)

10%

8.88

3rd

7.95

7.09

7.01

Workers at Merck recently disclosed specific ligands to override and reinforce substrate bias in
the 1,3-azoles in a screen of ~200 achiral phosphines.

2nd
Me
N

6.86

Will Gutekunst

Ph

- SNAr reactions occur readily at C-2, though not very well at C-4/5 without assistance, and trends are
not general among the series.
- Cross coupling also does not follow the Handy rules, with usual order of cross coupling being 2>5>4,
Also note that the relative order chemical shifts switches in oxazole.

K3PO4, PhB(OH)2
THF, 64%

KCN, DMSO
18-crown-6

N
Br
N

O2N

Br

O2N

NaH, PhSH
THF

PhS

rt, 75%

O2N

80C, 85%

Br
Br

OMe

PhB(OH)2
10% Pd(PPh3)4, Na2CO3 10% Pd(PPh3)4, Na2CO3

PhH/MeOH/H2O
94%

MOM
N

MeOH/NaOMe

O2N

reflux, 40%

MeO

Br
Br

Br

N
N

SH

EtO2C

Br

N I

n-BuLi, THF
33%

X
OH
Br

K2CO3, DMF
125-180C w
51-84%

Bioorg. Med. Chem. Lett. 2006, 16, 6078

Br

1,3 azoles selectively C-H arylate at C-5 or C-2

N
H

PhBr

PdCl2(PPh3)2
CuI, TEA, THF
80C, 53-89%

Ph

10% Pd(OH)2, K2CO3

DMA, 130C, 82%

N
X

JOC 2005, 70, 7578

HN
O

Br

Me2N

Heterocycles 2007, 72, 293

O
X

Br

MOM
OMe

EtO2C

i-PrMgCl, THF
-78C, 66%

Heterocycles 2007, 72, 293

Ph
N

PhH/MeOH/H2O
71%

Br

Br

Regioselective Mg-Halogen exchange was observed of this dibromothiophene.

EtO2C

Br

Br

Chem. Pharm. Bull. 1996, 44, 1831

Br

J. Het. Chem 2000, 37, 119

EtO2C

B(OH)2

Br

O2N

Ph
I

Similar or better results were obtained for imidazoles, but selective C-4/C-5 over C-2 Suzuki
couplings of dihalo thiophenes was not observed in any cases. No C-4 vs C-5 studies were
undertaken.

CN

CN

K3PO4, PhB(OH)2
THF, 55%

JOC 2010, 75, 1733

Br

5% Pd(OAc)2

I
I

O
N

MeO
OMe

N
Ph

N
5% Pd(OAc)2
Ph
CuI, DMF, 140C
76%
JOC 2005, 70, 3997, Eur. JOC 2006, 1379

MeO

5% Pd(OAc)2
AsPh3, DMF, CsF MeO
140C, 46%

N
N
Ph

Haloselectivity of Heterocycles

Baran Group Meeting

Will Gutekunst

Some Relative Rates of Azines (Joule and Mills 4th Edition)

O

For

EtO-

at 20C

Cl

Cl

Cl
N

Cl

1.7x102

7.3x103

Cl

5.3x104

>
X

4 Cl

5.4x104

Cl

>

BnHN

Ph

2nd

7.16

3rd
1st

(C6D6)

- Pyridines readily undergo SNAr, usually faster at C-4 than C-2/6, but highly
dependent on nucleophile and conditions. C-3/5 react much slower.
- Cross coupling reactions occur fastest at the 2/6 positions followed by C-4
and C-3/5 much slower, much in accord with the Handy predictions. Mono
substitution can usually be acheived with 2,6-dihalo and 3,5-dihalo
pyridines.

Cl

OAr

OH

OR

Cl

Cl
NH2

5% PdCl2(PPH3)2
CuI, TEA, 80C
90%

Cl

N
Ph

soft nucleophiles
F
Br

OAr

NaH, DMSO
Cl
130C, 85%

Cl

Cl

1:6

1:3

hard nuclephiles

Br

cross coupling

In, 4% Pd(PPh3)4
LiI, DMF, 100C

Br

61%

Tetrahedron 2005, 61, 2245

Cl

NaH, THF

Br , then

Br

OR

65%, one pot

Br

ACIEE 2002, 41,3901

OH
Cl

NH

OH

1) o-tolMgCl
2) DDQ

KOt-Bu, CuI, py
120C, 61%

Cl

NHtBu

98%

KOt-Bu, DMA
THF, 120C, 84%

Cl

MeN

NHtBu
Cl

O
NHtBu

100C, 97%
N

N
MeN

OPRD 2008, 12, 411

JOC 2006, 71, 2000
O
OMe
Cl

Ph

Br

OH

JMC 2000, 43, 4288

7.55

Cl

Ph
NH2

Pyridine

8.52

R = CH2CH2OPh

>
N

NHR

140C, 93%

Cl

>

BnNH2
NHR

K2CO3, THF
reflux, 61%

Cl

>

OL 2003, 5, 3131

1.3x108

5.8x10

>

X
N

Cl

PhB(OH)2
5% PXPd2

NHR

Cl

PhB(OH)2
5% Pd(PPh3)4
K2CO3, THF
reflux

O
OMe

Ph

Cl

Cl

5:1

Usefully, Li-Halogen exchange is slow at 2/6 positions due to lone pair repulsion
OMe

Ph

n-BuLi, -100C;

Br
N

Br

D2SO4, 85%

D
N

Br

Haloselectivity of Heterocycles

Baran Group Meeting

Quinoline/ Isoquinoline
7.73

Pyridazine/Pyrazine
2nd

8.05

7.46
7.65

8.05

Will Gutekunst

7.56

8.82

7.58

1st

1st

7.5

7.70

7.31

N
9.11

9.17

2nd

1st
Isoquinoline (CCl4)
7.85

Quinoline (CCl4)

7.52

8.45

- SNAr reactions occur readily at all of the positions. All sites are degenerate on pyrazine, and the
4-position is most activated for nucleophilic attack, despite NMR chemical shift.
- Selective cross coupling reactions have not been well studied on pyridazine, but modest selectivity
can be obtained from 3,6-dichloro compounds.

Cl
Cl

MeO2C

MeO2C

HO

ZnBr

LiCl, DMF, rt
83%
Cl

Cl

Cl

aq. Me2NH
EtOH, reflux

I
N N

Cl

Cl

I
N N

99%

Cl

Cl

Chem. Eur. J. 2002, 8, 3448

B(OH)2

N
N

SnBu3

N
Cl

Tetrahedron 2001, 57, 2507

N N

Br

B(OH)2

3% Pd(PPh3)4
CsF, DME
87%

N N

OEt

5% PdCl2(PPh3)2
80C, DMF
54%

Tetrahedron 2001, 57, 2507

Cl

5% PdCl2(PPh3)2
80C, DMF
77%

Cl

Cl
N N

4% [Pd(dba)2]PPh3
Tol reflux
80%

S
Me2N

OEt

SnBu3

SnBu3

SnBu3

OMe

OEt
N

Me2N

JOC 1995, 60, 748

Cl

Cl

MeOH, NaOMe

Bioorg. Med. Chem. 2009, 17, 621

JOC 1999, 64, 453

60%

DMA, Na2CO3
74%

Pd(PPh3)4 THF
60C, 80%

Cl

Cl
N

CO2Me

N
NH

Cl

Cl

HO

Cl

MeO2C
ZnBr

Pyrazine (C6D6)

Pyridazine (C6D6)

- SNAr reactions of quinoline mimic pyridine largely, with C-4>C-2 generally preferred, but usually
dependent on reaction conditions. Isoquinoline reacts fastest at C-1 followed by C-3 in SNAr.
- Cross coupling reactions in quinoline strongly favor the 2 position followed by 4. Regioselection
between the other positions has not been well investigated. Preference of 1 vs 3 is well established
in isoquinolines, but other positions not as well.

8.6

4% Pd(PPh3)4
DMF, 100C
61%

Br

OMe

Br

JOC 2002, 67, 9392

Br

N
TBS

10% Pd(PPh3)4
Na2CO3, MeOH/PhH
52%

N
N

OMe

NTBS

Br

Haloselectivity of Heterocycles

Baran Group Meeting

Pyrimidine
3rd

Benzannelated Diazines
1st

8.78

7.36

9.26

2nd

Pyrimidine (C6D6)

- Pyrimidines readily undergo SNAr at the 2 and 4/6 positions. 4/6 being
generally more reactive, but is very sensitive to reaction conditions. The 3position is greatly deactivated relative to the others.
- Cross coupling reactions occur fastest at the 4/6 positions followed by C-2
and C-5 much slower, in direct contrast to the Handy predictions.

N
N
H

N
Cl

HN

Cl

86%

7.95

8.44

OH

Cl

TMS

-68C,-rt, 90%

Cl

PhB(OH)2
5% Pd(PPh3)4

Ph
Cl

K2CO3, Tol/DMF
Cl
w, 185C
10 min, 58%

Cl

PhB(OH)2
5% Pd(Pt-Bu3)2

Ph
Cl

K2CO3, Tol/DMF
Cl
w, 185C
10 min, 65%

OTHP

Bu
Br

N
N

Cl

2% PdCl2(PPH3)2
CuI, TEA, rt
67%

Acta Chem. Scand. 1996, 50, 914

O
Cl

Et2O, -40C;
then DDQ, 92%

JMC 2008, 51, 2734

N
N

Cl

EtOH, NaOEt
70C, 81%

Me2N

Et2O, -40C;
then DDQ, 72%%
Me2N

N
N
Me2N

OTHP

Bu

Li
SH

K2CO3, Tol/DMF
Ph
w, 185C
10 min, 70%

Lithium reagents can directly add into C-4/6, which can be oxidized back to aromaticity easily

Me2N

SMe

CuI, MeCN, TEA

60C, 56%

Cl

Li

Cl

Cl 7.5% Pd(OAc)2, PPh3

Br

J. Chem. Soc. Perkin 1 2001, 978

N
N

Cl

Tet. Lett. 2006, 47, 4415

HN

MeCN, 130C
84%

SMe

PhB(OH)2
5% Pd(PPh3)4

2nd

9.35

Quinazoline (CDCl3)

JMC 1993, 36, 2196

Chem. Soc. Perkin 2 1989, 1499; J. Het. Chem. 1994, 31, 989

Cl

8.06

Quinoxaline (CDCl3)

NH2

OMe

rt, 90%

7.67

N
SMe

MeOH
NaOMe

9.91

7.93

8.84

Phthalazine (acetone)

n-BuLi, THF

Cl

7.93

TMS

8.11

OPRD 2006, 10, 921

9.60

8.00

9.29

HN

Cl

8.13

2nd

7.86

7.77

- SNAr reactions occur readily at all of the heterocyclic positions. Behavior seems to be similar to the
diazine counterparts, ie C-4 more reactive than C-2 in quinazolines, C-4>C-3 in cinnoline.
- Cross coupling reactions have not been well studied on these systems, but the few examples mimic
the corresponding diazines well.

NH

THF, -10 C to rt
92%

Cl

1st

1st
8.01 8.18

Cinnoline (CDCl3)

4.2 eq

Cl

Will Gutekunst

N
N

Cl

Haloselectivity of Heterocycles

Baran Group Meeting

Purine
8.83

3rd

8.72

Misc Examples

1st

- Purines can participate in SNAr reactions at all carbon centers. For 9-H
purines, the order of reactivity is 6>8>2. For substitution at 9, reactivity
changes to 8>6>2.
- Cross coupling reactions usually occur fastest at the 6 position, though
C-8 becomes competitive in some cases. C-2 is slowest.

8.5

N
H

2nd

Purine (D2O)
Ph

TEA, MeCN
95%

RHN

5% PdCl2(PPh3)2
DCE, 75C
63%

N
THP

120C, 89%
N
H

N
N

CN

NHBn

N
Sug
MeS

BnNH2

N
N

50C, 95%

MeS

JMC 2009, 52, 655

N

Cl
N

DCM, Et2Ni-Pr
91%

SnBu3

HN

KCN, DMSO

SMe

UK-371,104

DCM, Et2Ni-Pr
86%

Cl

NH2

OPRD 2008, 12, 575

Cl

HN

CO, THF

N
Sug

NH2
N

JMC 2010, 53, 52

1) K2CO3, MeOH, 100%

2) PdCl2(dppf)DCM

HN

Ph

N
N

Cl

Ph

Ph

Cl

N
Sug

Ph

Ph

NH2

Cl
H2N

Will Gutekunst

OEt

Cl
N
THP

SNAr, Sonogashira
Stille and Suzuki

Cl

OEt
N

N
N

Single regioisomer
(no yields reported)

Cl

N
N

Cl

Acta Chem. Scand. 1999, 53, 366

Tet. Lett. 2006, 47, 8917
C-8 can be directly functionalized to give highly flexible syntheses of trisubstituted purines
N
Cl
N

N
Cl

MeMgCl
Fe(acac)3

PhB(OH)2
5% Pd(PPh3)4

72%

K2CO3, Tol
100C

N
Bn

5% Pd(OAc)2

CuI, Cs2CO3
DMF, 160C
79% (two steps)

Ph

N
Bn

Cl

B(OH)2

S
PhB(OH)2
5% Pd(PPh3)4 5% Pd(PPh3)4

Cl

K2CO3, Tol Na2CO3, Tol/EtOH

100C, 98%
100C, 84%

Ph

OL 2007, 9, 4673

OL 2006, 8, 5389
OH
Cl

MeMgCl
30% Fe(acac)3

Cl
N

Synlett 2004, 6, 889

N
THP

NMP/THF
37%

OH

Cl
O

O
N

N
THP
Br

N
N

Br

Ar

NaHMDS
THF, -10C
78%

OPRD 2006, 10, 512

OH

Br

OH

Br
OH
O

N
N

LiHMDS
THF, -40C
60%

HO

N
N

Ar

Baran Group Meeting

Haloselectivity of Heterocycles

Conclusions
Selective reactions of polyhaloheterocycles has proven to be a very powerful method for synthesis of
functionalized heterocycles. Frequently cross-coupling and SNAr are complementary methods, with
C-H functionalization rapidly growing. While the prediction of regioselectivity is difficult to rationalize
at times, common trends are seen in certain heterocyclic motifs and can be extrapolated to more
complex situations, though, screening seems to still be needed for many cases. Future directions
are in the ligand controlled cross coupling and further development of C-H activation reactions.
Key References
Cross coupling reviews:
Tetrahedron 2005, 61, 2245
Chem. Soc. Rev. 2007, 36, 1036
Synthesis 2009, 9, 1405
Computational Analysis of Polyhalo Heterocycles
JACS, 2007, 129, 12664
JACS, 2009, 131, 6632
Handy Predictions
Chem. Comm. 2006, 299

Will Gutekunst