haloselectivity of heterocycles

Will GutekunstBaran Group MeetingHaloselectivity of Heterocycles

Background

SNAr or SN(AE)

N X

Nu

N X

Nu

N Nu

Meisenheimer Complex

SET Mechanism can also be operative (SRN1)

N

N

Cl

OK

N

N O

h!, NH3(l)88%

HetX HetX

HetX Het X

Het

HetX HetX

+

+

+

+

+

+

SN(EA)

JOC 1981, 46, 294

N

Br

NN

NNNaNH2, t-BuONa

pyrrolidine

THF, 40ºC

via:

N

+

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

N

Br NaNH2

NH3(l), 90%N

Br

NH2

N

Br

NH2

HH

- Br

N

NH2

H

NH

NHN

NH2

Nucleophilic Substitution

Cross Coupling

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.

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.

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

Tetrahedron 1982, 38, 427

83.2

O87.3

Br

OMe

Br1st

2nd

88.9

88.9

OBr

Br

1st

2nd

Nu

Nu

Nu

HetNu

HetNu HetNu

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:

NH

CO2Me

3 Halogenations

3 Suzuki Couplings NH

CO2MeAr1

Ar3 Ar2

NH

CO2Me

1 Triple Halogenation

1 Triple Suzuki Coupling NH

CO2MeAr1

Ar3 Ar2

NH

CO2Me

1 Triple C-H activation?

NH

CO2MeAr1

Ar3 Ar2


Predicting Reactivity

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.

- 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.-

Pyrroles

1st

2nd

NMe

O

H

H

O

Cl

Cl NMe

O

H

H

O

Cl

EtS

2.5 eq EtSHTEA, DMSO

86%

NCO2MeMeO2C

TfO OTf

R

MeO

MeO B(OH)2

MeO

MeO B(OH)2

OMOM

NCO2MeMeO2C

R

MeO

MeO

MeO OMe

OMOM2% Pd(PPh3)4

aq. Na2CO3, THFreflux, 4 hrs

78%

8% Pd(PPh3)4

aq. Na2CO3, THFreflux, 20 hrs

58%

Tet. Lett. 2003, 44, 4443

NMe

BrBr

BrBr Cl B(OH)2

6% Pd(PPh3)4

K3PO4, Tol/H2O90ºC, 12 hrs

71%

NMe

Br

BrBr

Cl

Tet. Lett. 2009, 49, 1698


Indole

7.27

6.45

NH

7.557.00

7.08

7.40

- 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.

NTBS

Br

Br

10% Pd(PPh3)4Na2CO3, Tol/H2O

reflux, 8 hrs78%

SB(OH)2

NTBS

Br

S

2nd

1st

last

NTBS

Br

Brt-BuLi, MeI

-78º C, THF81%

NTBS

Br

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

Chem. Pharm. Bull. 1996, 44,1831

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

NMe

Ph2I+BF4-

5% IMesPd(OAc)2

rt, AcOH, 67%NMe

Ph

JACS 2006, 128, 4972

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

Ph2I+BF4

-

5% IMesPd(OAc)2

60º C, AcOH, 74%NH

Br

NH

Br

Ph

Chem. Comm. 2006, 299

6.68

6.22

NH

(CDCl3)

(Acetone)


Synlett 1998, 11, 1185

Furan

7.29

6.24

O 1st

2nd

- 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.

O

Br

BrMeO2C

Bu3Sn

4% Pd(PPH3)4DMA, 90ºC, 79%

O

Br

MeO2C

SnMe4

5% [PdCl2(Po-Tol3)2]

DMA, 90ºC, 70%

OMeO2C

2 steps

64%O

Benzofuran

2nd

1st

last

7.78

6.76

O

7.637.23

7.30

7.51

- 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.

OBr

BrBr

ClZn OMe

OMe

O

OMe

OMe

5% [PdCl2(PPh3)2]THF, rt, 75%

10% [NiCl2(dppe)]THF, rt, 86%

MgBr MeZnCl

10% [PdCl2(dppf)]THF, reflux, 93%

rosefuran

Thiophene

1st

2nd

- 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.

7.18

6.99

S

S

Br

BrO

H

BnNHCH3

46% S

Br

BnMeNO

HS

NBnMe

BrO

H

+

4:1

Synlett 2000, 4, 459

SBr

Br

Br 2.5% [PdCl2(dppf)]Et2O 63%

S ZnCl

S

Br

Br

S SS

OMe

S

Two more

cross-couplings54%

Eur. JOC 2008, 5, 801

S

Br Br

S

Br

S

BnZnBrPd(PPh3)4

52 - 57%

p-TolMgClNiCl2(dppp)

quant

SBr

Br

Br

Again, Lithium Halogen Exchange shows a different regioselection

nBuLi, Et2O-78ºC; H2O

79%

Thiophenes, pg 693

SBr

Br

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

O

Br OMe

OMe

O

OMe

OMe

BrBr

t-BuLi, MeI-78ºC, THF

54%

Synthesis 2003, 6, 925

O

O

H

PhBr

10% Pd(OH)2, K2CO3

DMA, 130ºC, 75%

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

O

O

HPh

JOC 2005, 70, 7578

Tet. Lett. 1980, 21, 4017

(CDCl3)

(acetone)

(CDCl3)


7.33

7.22

S

7.727.26

7.24

7.79

Benzothiophene

last

1st

2nd - 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.

S

Br

Br

NH

106ºC S

Br

N

NH

SN

JOC 1973, 88,1365

S

Br

Br 3% Pd(PPh3)4Na2CO3, EtOH/DME

95%

B(OH)2

MeO

B(OH)2

MeO

5% Pd(PPh3)4Ba(OH)2, H2O/DME

71%

S

MeO

OMe

Synthesis 2002, 2, 213

200ºC73%

1,2-Azoles

7.45

6.207.31

N

MeN

8.39

6.288.14

N

O8.72

7.268.54

N

S

Isoxazole (CS2) Isothiazole (CCl4)N-methyl pyrazole (CDCl3)

- 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.

N

S

NC

Cl

Cl

N

S

NC

EtO

Cl

EtOH (xs)

94%

Attempts to displace the second chloride leads to mixtures with ring opened products.

N

S

NC

Cl

Cl

1) 2 eq Na2S

2) MeIN

S

NC

MeS

SMe

+SMeMeS

CNNC

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

N

MeNBr

IEtO2C

1.2 eq Na2S, DMF, 100ºC;

Ethyl bromoacetate, rt80%

N

MeNS

IEtO2C

EtO2C

Syn. Comm. 2008, 38, 674

JOC 1964, 29, 660

N

S

Br

Br

Br

N

S

Br

Br

Ph

N

S

I

I

Br

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

56%

PhPhPh

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

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

45% (also 45% deiodo)

Ph

4% PdCl2(PPh3)2CuI, TEA/MeCN, 50ºC

42%

MeO

N

S

Br

Ph

MeO

Russ. Chem. Bull. 1998, 47, 537

Tribromopyrazoles also lithiate at the most reactive C-5

N

NBr

BrBr

n-BuLi, -78ºC;Bu3SnCl

77%

N

NBu3Sn

BrBr


9.11

N

8.45

7.5

Isoquinoline (CCl4)

7.70

7.56

7.58

7.85

1st

2nd

3rd

(CCl4)


1,3-Azoles

- 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.

J. Het. Chem 2000, 37, 119

6.86

7.01 N

7.39

MeN

N-methyl imidazole (CDCl3)

7.69

7.09N

7.95

O

Oxazole (CCl4)

7.41

7.98 N

8.88

S

Thiazole (CDCl3)

N

N

N

N

O2N

O2N

Br

Br

Br

Br

N

N

O2N

CN

Br

N

N

O2N

CN

PhS

N

NO2N

Br

MeO

KCN, DMSO18-crown-6

80ºC, 85%

NaH, PhSHTHF

rt, 75%

MeOH/NaOMe

reflux, 40%

N

S

Br

Br

N

S

O

Br

N

S

O

HN

O

XX

OHX

K2CO3, DMF125-180ºC µw

51-84%

NH

O

PdCl2(PPh3)2CuI, TEA, THF80ºC, 53-89%

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

S

N

Br

Br

EtO2C N SH

n-BuLi, THF33%

S

N

Br

S

EtO2C

N

Heterocycles 2007, 72, 293

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

N

O

I

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.

2.5% Pd(OAc)22.5% Xantphos

K3PO4, PhB(OH)2THF, 64%

N

O

I

PhN

O

Ph

I

5% Pd(OAc)2

K3PO4, PhB(OH)2THF, 55%

NN

N

P

10%

JOC 2010, 75, 1733

N

NBr

MOM

Br

Br N

NBr

MOM

Ph

OMe

PhB(OH)210% Pd(PPh3)4, Na2CO3

PhH/MeOH/H2O94%

10% Pd(PPh3)4, Na2CO3

PhH/MeOH/H2O71%

OMe

B(OH)2

Chem. Pharm. Bull. 1996, 44, 1831

S

N

Br

Br

EtO2C

Heterocycles 2007, 72, 293

Regioselective Mg-Halogen exchange was observed of this dibromothiophene.

i-PrMgCl, THF-78ºC, 66%

N I

S

N

Br

EtO2C

Me2N

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

PhBr

10% Pd(OH)2, K2CO3

DMA, 130ºC, 82%N

S

N

SPh

JOC 2005, 70, 7578

N

NPh

N

NPh

MeO

MeO I

N

NPh

OMe

MeO

I

5% Pd(OAc)2CuI, DMF, 140ºC

76%

5% Pd(OAc)2AsPh3, DMF, CsF

140ºC, 46%

JOC 2005, 70, 3997, Eur. JOC 2006, 1379

1st2nd

3rd


Pyridine

N8.52

7.16

7.55

- 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.

1st

2nd

3rd

N Cl

ClOH

NaH, DMSO130ºC, 85%

N OAr

Cl

N Cl

OAr

N Cl

OR

N OR

Cl

OH

NaH, THF

61%

++

1:61:3

N Cl

Cl OH

KOt-Bu, CuI, py120ºC, 61%

OH

KOt-Bu, DMATHF, 120ºC, 84% N O

O

N

O

OMe

ClCl

OPRD 2008, 12, 411

PhB(OH)2

5% Pd(PPh3)4

K2CO3, THFreflux

N

O

OMe

ClPh N

O

OMe

PhCl

+

5:1

N

O

NHR

ClCl

R = CH2CH2OPhN

O

NHR

PhCl N

O

NHR

PhBnHN

BnNH2

140ºC, 93%

PhB(OH)25% PXPd2

K2CO3, THFreflux, 61%

OL 2003, 5, 3131

5% PdCl2(PPH3)2CuI, TEA, 80ºC

90%

Ph

N

Cl

Cl

NH2

N

Cl

NH2

Ph

JMC 2000, 43, 4288

N Br

Br

Br

FF


soft nucleophiles

hard nuclephiles

cross coupling

NCl

O

NHtBu

NCl

O

NHtBu

1) o-tolMgCl2) DDQ

98%

NN

O

NHtBu

MeN

NH

MeN

100ºC, 97%

JOC 2006, 71, 2000

N

Br

Br

In, 4% Pd(PPh3)4

LiI, DMF, 100ºC

Br

Br

, then N

65%, one pot

ACIEE 2002, 41,3901

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

N

Br

Br

n-BuLi, -100ºC;

D2SO4, 85%N

D

Br

N

N

N

N

NN

NN

N

N

N N

> > > > > >

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

X

X

X

X

X

X

X

For EtO- at 20ºC

N N N NN

N

N

N

Cl

Cl

Cl

Cl

Cl

Cl

Cl

1 1.7x102 7.3x103 5.3x104 5.4x104 5.8x104 1.3x108

(C6D6)


Quinoline/ Isoquinoline


N8.82

7.31

8.05

Quinoline (CCl4)

7.73

7.46

7.65

8.05 9.11

N

8.45

7.5

Isoquinoline (CCl4)

7.70

7.56

7.58

7.85

- 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.

N

Cl

ClN Cl

N

ClMeO2C

MeO2C

ZnBr

MeO2C

ZnBr

LiCl, DMF, rt83%

Pd(PPh3)4 THF60ºC, 80%

CO2Me

JOC 1999, 64, 453

N

Cl

ClMeOH, NaOMe

60%N

OMe

Cl

N

Cl

Cl4% [Pd(dba)2]PPh3

Tol reflux80%

SnBu3

OEt

NCl

O


N3% Pd(PPh3)4

CsF, DME87%

Cl

ClN

4% Pd(PPh3)4

DMF, 100ºC61%

B(OH)2 N SnBu3

N

Pyridazine/Pyrazine

- 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.

NN

9.17

7.52

Pyridazine (C6D6)

N8.6

N

Pyrazine (C6D6)

N

N

ClCl

Cl

N

N

Cl

N

Cl

NHO

NH

NHO

DMA, Na2CO374%

Bioorg. Med. Chem. 2009, 17, 621

N N

ClCl5% PdCl2(PPh3)2

80ºC, DMF54%

SnBu3

OEt

N N

Cl

OEt

Chem. Eur. J. 2002, 8, 3448

N N

II

N N

IMe2N

aq. Me2NHEtOH, reflux

99%

SSnBu3

5% PdCl2(PPh3)280ºC, DMF

77%

N N

Me2N

S

JOC 1995, 60, 748

N

N OMe

Br

Br NTBS

B(OH)2

Br

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

52%

NTBS

Br

N

N OMeBr

JOC 2002, 67, 9392

1st

2nd

1st

1st

2nd


Pyrimidine

OPRD 2006, 10, 921

7.36

N9.26

N

8.78

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 3- position 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

Cl

Cl

Cl N

N

N

N

Cl N

N

N

N

N

NH

4.2 eq

THF, -10 C to rt92%

HN NH

HN

86%

N

N

Cl

ClMeOH

NaOMe

rt, 90%N

N

Cl

OMeTMSOH

n-BuLi, THF

-68ºC,-rt, 90%N

N

O

Cl

TMS

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

N

N

Cl

Cl PhB(OH)2

5% Pd(PPh3)4

K2CO3, Tol/DMFµw, 185ºC

10 min, 58%

N

N

Cl

PhCl

Cl

PhB(OH)2

5% Pd(PPh3)4


10 min, 65%N

N

Ph

Ph

Cl

PhB(OH)2

5% Pd(Pt-Bu3)2


10 min, 70%

Tet. Lett. 2006, 47, 4415

N

N

Cl

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

OLi

Et2O, -40ºC;then DDQ, 92% N

N

Cl

O

EtOH, NaOEt70ºC, 81%

Me2NSH

N

N

S

O

SMe2N

Me2N

SMe2N

Li

Et2O, -40ºC;then DDQ, 72%%

JMC 2008, 51, 2734

Benzannelated Diazines

N

8.84N

Quinoxaline (CDCl3)

8.11

7.77

NN

9.29

8.18

Cinnoline (CDCl3)

8.01

7.86

7.95

8.44

N

N

9.60

Phthalazine (acetone)

8.13

8.00

N9.35

N

9.91

Quinazoline (CDCl3)

7.93

7.93

7.67

8.06

- 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.

N

N

SMe

SMe

NH2

MeCN, 130ºC84% N

N

HN

SMe

JMC 1993, 36, 2196

N

N

N

NCl

Cl

Cl

OTHP

OTHP

7.5% Pd(OAc)2, PPh3

CuI, MeCN, TEA 60ºC, 56%

J. Chem. Soc. Perkin 1 2001, 978

N

NBr

Cl

Cl N

NBr

Cl

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

67%

Bu

Bu

Acta Chem. Scand. 1996, 50, 914

1st

2nd

3rd 1st

2nd

1st

2nd


Purine- 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.

N

8.72 N

8.83

NH

8.5

N

Purine (D2O)

N

N NTHP

N

Cl

Cl

SSnBu3

5% PdCl2(PPh3)2

DCE, 75ºC63%

N

N NTHP

N

Cl

S

Acta Chem. Scand. 1999, 53, 366

N

N NSug

N

Cl

I

N

N NSug

N

HN

I

PhPh

N

N NSug

N

HN

PhPh

O

RHN

H2N

Ph

Ph

TEA, MeCN95%

1) K2CO3, MeOH, 100%2) PdCl2(dppf)DCM

CO, THF

NNH2

OPRD 2008, 12, 575UK-371,104

C-8 can be directly functionalized to give highly flexible syntheses of trisubstituted purines

N

N NBn

N

Cl

Cl

N

N NBn

N

Ph

MeMgClFe(acac)3

72%

PhB(OH)2

5% Pd(PPh3)4

K2CO3, Tol100ºC

I

5% Pd(OAc)2

CuI, Cs2CO3 DMF, 160ºC

79% (two steps)

OL 2006, 8, 5389

Misc Examples

MeMgCl30% Fe(acac)3

NMP/THF37%

N

N NTHP

N

Cl

ClN

N NTHP

N

Cl

Synlett 2004, 6, 889

N

N

N

Cl

ClClN

N

N

HN

CNNH

NH2

DCM, Et2Ni-Pr86%

F F

NH2

DCM, Et2Ni-Pr91%

KCN, DMSO

120ºC, 89%

F

F

JMC 2010, 53, 52

N

NN

N

SMe

MeS

N

NN

N

NHBn

MeS

BnNH2

50ºC, 95%

JMC 2009, 52, 655

N

N

N

OEt Cl

Cl

N

N

N

OEt R

Cl

SNAr, SonogashiraStille and Suzuki

Single regioisomer(no yields reported)

Tet. Lett. 2006, 47, 8917

NN

N Cl

Cl

PhB(OH)2

5% Pd(PPh3)4

K2CO3, Tol100ºC, 84%

5% Pd(PPh3)4

Na2CO3, Tol/EtOH100ºC, 98%

SB(OH)2

NN

N

Ph

S

OL 2007, 9, 4673

N

N

O

F

F

Br

BrN

N

O

O

Br

Ar

N

N

O

Br

O

ArOH

OH

OH

OH

NaHMDSTHF, -10ºC

78%

OH

HO

LiHMDSTHF, -40ºC

60%

OPRD 2006, 10, 512

2nd

1st

3rd


Conclusions

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

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.

haloselectivity of heterocycles

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