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
N
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
X
X
N
Nu
2nd
Meisenheimer Complex
1st
Br
83.2
SN(EA)
O
via:
NaNH2, t-BuONa
pyrrolidine
N
87.3
THF, 40ºC
OMe
N
SET Mechanism can also be operative (SRN1)
+
Nu
HetX
Het
+
X
OK
HetNu
N
N
N
+ Nu
Cl
h!, NH3(l)
88%
O
N
JOC 1981, 46, 294
HetNu
+ HetX
HetNu
+
HetX
88.9
88.9
O
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.
N
N
HetX
Br
N
+
HetX + Nu
2nd
Br
Tetrahedron 1982, 38, 427
Het
NH2
H
SNAr or SN(AE)
N
H
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
N
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)
S
Br
O
Cl
Cl
2.5 eq EtSH
TEA, DMSO
H
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
O
Br
Br
O
H
B(OH)2
O
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
90ºC, 12 hrs
71%
t-BuLi, MeI
Br
Br
N
TBS
Br
-78º 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
60º 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
O
(CDCl3)
t-BuLi, MeI
-78ºC, THF
OMe
OMe
OMe
Br
OMe
54%
O
O
Synthesis 2003, 6, 925
Br
MeO2C
Br
Br
Br
O
4% Pd(PPH3)4
DMA, 90ºC, 79%
MeO2C
Thiophene
SnMe4
5% [PdCl2(Po-Tol3)2]
Br
Bu3Sn
O
7.18
1st
S
(CDCl3)
2 steps
Synlett 1998, 11, 1185
MeO2C
64%
O
- 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, 90ºC, 70%
O
Br
rosefuran
Br
46%
S
Br
BnNHCH3
O
NBnMe
O
BnMeN
S
H
O
+
H
Br
S
4:1
Furfural can be selectively arylated in the 5- position directly.
H
OMe
Synlett 2000, 4, 459
PhBr
O
H
O
10% Pd(OH)2, K2CO3
DMA, 130ºC, 75%
O
H
O
Ph
Br
Br
JOC 2005, 70, 7578
7.63
7.23
6.76
last
7.30
7.51
O
S
2.5% [PdCl2(dppf)]
Et2O 63%
S
S
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
S
ClZn
Br
BnZnBr
Pd(PPh3)4
Br
Br
quant
52 - 57%
S
p-TolMgCl
NiCl2(dppp)
S
S
Tet. Lett. 1980, 21, 4017
OMe
Again, Lithium Halogen Exchange shows a different regioselection
Br
OMe
Br
O
S
Eur. JOC 2008, 5, 801
Benzofuran
2nd
Br
Br
ZnCl
S
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
S
Br
Thiophenes, pg 693
Br
nBuLi, Et2O
-78ºC; H2O
79%
Br
S
Haloselectivity of Heterocycles
Baran Group Meeting
Benzothiophene
2nd
7.72
7.26
7.22
last
7.24
7.33
S
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
+
N
Cl
MeS
SMe
7.58
NC
CN
Isoquinolin
7.85
SMe
JOC 1964, 29, 660
NH
NH
Br
S
Pyrazole shows similar reactivity, with a bromide being displaces before an iodide.
Br
Br
S
106ºC
N
S
200ºC
73%
N
Me
N
N
Br
JOC 1973, 88,1365
EtO2C
MeO
I
OMe
MeO
S
EtO2C
Syn. Comm. 2008, 38, 674
Br
Br
Ethyl bromoacetate, rt
80%
I
Me
N
N
S
MeO
B(OH)2
B(OH)2
EtO2C
1.2 eq Na2S, DMF, 100ºC;
Ph
S
3% Pd(PPh3)4
5% Pd(PPh3)4
Na2CO3, EtOH/DME Ba(OH)2, H2O/DME
95%
71%
Br
Ph
S
Synthesis 2002, 2, 213
Ph
S
N
Br
4% PdCl2(PPh3)2
CuI, TEA/MeCN, rt
56%
Br
Ph
N
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
I
Ph
S
7.26
8.14
8.54
2nd
N
I
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, 50ºC
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
O
Br
Br
Tetrahedron 2007, 63, 56
n-BuLi, -78ºC;
Bu3SnCl
77%
Bu3Sn
N
N
Br
Br
S
N
Br
Haloselectivity of Heterocycles
Baran Group Meeting
1,3-Azoles
7.39
1st
O
7.69
7.41
N
N
7.98
2.5% Pd(OAc)2
2.5% Xantphos
O
I
Thiazole (CDCl3)
Oxazole (CCl4)
N-methyl imidazole (CDCl3)
10%
8.88
N
3rd
P
S
7.95
7.09
N
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.
N
O
K3PO4, PhB(OH)2
THF, 64%
N
KCN, DMSO
18-crown-6
N
Br
N
O2N
Br
N
O2N
N
NaH, PhSH
THF
PhS
N
rt, 75%
O2N
N
80ºC, 85%
Br
Br
OMe
N
PhB(OH)2
10% Pd(PPh3)4, Na2CO3 10% Pd(PPh3)4, Na2CO3
N
PhH/MeOH/H2O
94%
MOM
N
MeOH/NaOMe
O2N
N
reflux, 40%
MeO
N
Br
Br
N
Br
N
N
N
SH
EtO2C
Br
N I
N
n-BuLi, THF
33%
S
N
S
X
OH
Br
N
K2CO3, DMF
125-180ºC µw
51-84%
Bioorg. Med. Chem. Lett. 2006, 16, 6078
N
S
S
Br
1,3 azoles selectively C-H arylate at C-5 or C-2
N
H
S
PhBr
PdCl2(PPh3)2
CuI, TEA, THF
80ºC, 53-89%
Ph
S
10% Pd(OH)2, K2CO3
DMA, 130ºC, 82%
N
X
N
JOC 2005, 70, 7578
HN
O
O
Br
Me2N
Heterocycles 2007, 72, 293
O
X
N
S
S
Br
MOM
OMe
EtO2C
i-PrMgCl, THF
-78ºC, 66%
Heterocycles 2007, 72, 293
S
Ph
N
PhH/MeOH/H2O
71%
Br
Br
N
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
N
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
O
K3PO4, PhB(OH)2
THF, 55%
JOC 2010, 75, 1733
Br
N
5% Pd(OAc)2
I
I
N
S
I
O
N
N
MeO
OMe
N
Ph
N
N
5% Pd(OAc)2
Ph
CuI, DMF, 140ºC
76%
JOC 2005, 70, 3997, Eur. JOC 2006, 1379
MeO
I
5% Pd(OAc)2
AsPh3, DMF, CsF MeO
140ºC, 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 20ºC
Cl
Cl
Cl
N
1
Cl
N
N
1.7x102
7.3x103
X
Cl
5.3x104
N
N
>
X
N
4 Cl
5.4x104
N
Cl
N
N
>
N
N
X
N
N
BnHN
Ph
2nd
7.16
3rd
1st
N
(C6D6)
X
N
- 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, 80ºC
90%
Cl
N
Ph
soft nucleophiles
F
Br
OAr
N
NaH, DMSO
Cl
130ºC, 85%
N
N
Cl
N
Cl
N
1:6
1:3
hard nuclephiles
N
Br
cross coupling
In, 4% Pd(PPh3)4
LiI, DMF, 100ºC
Br
+
61%
F
Tetrahedron 2005, 61, 2245
Cl
NaH, THF
+
Br , then
Br
OR
N
65%, one pot
Br
ACIEE 2002, 41,3901
OH
Cl
NH
OH
1) o-tolMgCl
2) DDQ
O
O
KOt-Bu, CuI, py
120ºC, 61%
Cl
NHtBu
98%
KOt-Bu, DMA
THF, 120ºC, 84%
N
Cl
O
N
MeN
O
NHtBu
Cl
O
NHtBu
100ºC, 97%
N
N
MeN
OPRD 2008, 12, 411
JOC 2006, 71, 2000
O
OMe
Cl
N
Ph
Br
OH
N
N
JMC 2000, 43, 4288
7.55
N
Cl
Ph
NH2
Pyridine
8.52
R = CH2CH2OPh
>
N
NHR
140ºC, 93%
Cl
>
BnNH2
NHR
K2CO3, THF
reflux, 61%
Cl
X
>
O
O
OL 2003, 5, 3131
1.3x108
5.8x10
N
N
X
N
>
N
N
X
N
Cl
N
N
PhB(OH)2
5% PXPd2
NHR
Cl
O
PhB(OH)2
5% Pd(PPh3)4
K2CO3, THF
reflux
O
OMe
Ph
N
+
Cl
Cl
5:1
Usefully, Li-Halogen exchange is slow at 2/6 positions due to lone pair repulsion
OMe
N
Ph
n-BuLi, -100ºC;
Br
N
Br
D2SO4, 85%
D
N
Br
N
Haloselectivity of Heterocycles
Baran Group Meeting
Quinoline/ Isoquinoline
7.73
Pyridazine/Pyrazine
2nd
8.05
7.46
7.65
N
8.05
Will Gutekunst
7.56
8.82
7.58
1st
1st
7.5
7.70
7.31
N
9.11
N
9.17
2nd
1st
Isoquinoline (CCl4)
7.85
Quinoline (CCl4)
7.52
8.45
N
N
N
- 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
N
Cl
Cl
I
aq. Me2NH
EtOH, reflux
I
N N
Cl
Cl
I
N N
99%
Cl
Cl
Chem. Eur. J. 2002, 8, 3448
N
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
80ºC, DMF
54%
Tetrahedron 2001, 57, 2507
Cl
5% PdCl2(PPh3)2
80ºC, DMF
77%
Cl
Cl
N N
4% [Pd(dba)2]PPh3
Tol reflux
80%
S
Me2N
OEt
O
SnBu3
SnBu3
SnBu3
OMe
OEt
N
Me2N
JOC 1995, 60, 748
N
Cl
S
Cl
MeOH, NaOMe
N
Bioorg. Med. Chem. 2009, 17, 621
JOC 1999, 64, 453
60%
N
DMA, Na2CO3
74%
N
Pd(PPh3)4 THF
60ºC, 80%
Cl
Cl
N
N
N
CO2Me
N
N
N
NH
Cl
Cl
HO
Cl
MeO2C
ZnBr
N
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, 100ºC
61%
Br
N
OMe
N
Br
N
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
N
7.36
9.26
N
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
N
HN
Cl
N
N
86%
N
N
7.95
N
8.44
N
OH
Cl
N
TMS
N
-68ºC,-rt, 90%
N
Cl
N
PhB(OH)2
5% Pd(PPh3)4
Ph
Cl
N
K2CO3, Tol/DMF
Cl
µw, 185ºC
10 min, 58%
N
N
Cl
N
PhB(OH)2
5% Pd(Pt-Bu3)2
Ph
Cl
K2CO3, Tol/DMF
Cl
µw, 185ºC
10 min, 65%
OTHP
N
Bu
Br
N
N
Cl
2% PdCl2(PPH3)2
CuI, TEA, rt
67%
Acta Chem. Scand. 1996, 50, 914
N
O
Cl
Et2O, -40ºC;
then DDQ, 92%
JMC 2008, 51, 2734
N
N
Cl
EtOH, NaOEt
70ºC, 81%
Me2N
O
S
Et2O, -40ºC;
then DDQ, 72%%
Me2N
S
N
N
Me2N
OTHP
Bu
Li
SH
N
K2CO3, Tol/DMF
Ph
µw, 185ºC
10 min, 70%
Lithium reagents can directly add into C-4/6, which can be oxidized back to aromaticity easily
Me2N
SMe
N
CuI, MeCN, TEA
60ºC, 56%
Cl
Li
Cl
Cl 7.5% Pd(OAc)2, PPh3
Br
O
N
J. Chem. Soc. Perkin 1 2001, 978
N
N
N
Cl
Tet. Lett. 2006, 47, 4415
N
HN
MeCN, 130ºC
84%
SMe
N
PhB(OH)2
5% Pd(PPh3)4
N
2nd
9.35
Quinazoline (CDCl3)
JMC 1993, 36, 2196
N
Chem. Soc. Perkin 2 1989, 1499; J. Het. Chem. 1994, 31, 989
Cl
8.06
Quinoxaline (CDCl3)
NH2
OMe
rt, 90%
N
7.67
N
SMe
MeOH
NaOMe
9.91
7.93
8.84
N
Phthalazine (acetone)
N
n-BuLi, THF
N
Cl
N
7.93
N
TMS
O
8.11
N
N
OPRD 2006, 10, 921
N
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.
N
NH
N
THF, -10 C to rt
92%
Cl
1st
1st
8.01 8.18
Cinnoline (CDCl3)
4.2 eq
Cl
Will Gutekunst
S
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.
N
N
8.5
N
N
H
2nd
Purine (D2O)
Ph
I
N
N
N
TEA, MeCN
95%
I
RHN
N
5% PdCl2(PPh3)2
DCE, 75ºC
63%
N
THP
N
120ºC, 89%
N
H
N
N
CN
NHBn
N
Sug
MeS
BnNH2
N
N
N
N
N
N
50ºC, 95%
MeS
N
N
JMC 2009, 52, 655
N
N
Cl
N
DCM, Et2Ni-Pr
91%
F
SnBu3
S
N
HN
KCN, DMSO
F
SMe
UK-371,104
S
N
DCM, Et2Ni-Pr
86%
Cl
O
NH2
OPRD 2008, 12, 575
Cl
N
N
N
N
F
HN
CO, THF
N
Sug
N
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
F
NH2
Cl
H2N
N
Will Gutekunst
OEt
Cl
N
THP
N
SNAr, Sonogashira
Stille and Suzuki
Cl
N
OEt
N
N
N
R
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
N
MeMgCl
Fe(acac)3
PhB(OH)2
5% Pd(PPh3)4
72%
K2CO3, Tol
100ºC
N
Bn
I
N
N
5% Pd(OAc)2
N
N
CuI, Cs2CO3
DMF, 160ºC
79% (two steps)
Ph
N
N
Bn
Cl
S
B(OH)2
S
PhB(OH)2
5% Pd(PPh3)4 5% Pd(PPh3)4
N
Cl
N
N
K2CO3, Tol Na2CO3, Tol/EtOH
100ºC, 98%
100ºC, 84%
Ph
OL 2007, 9, 4673
OL 2006, 8, 5389
OH
Cl
MeMgCl
30% Fe(acac)3
N
N
Cl
N
Synlett 2004, 6, 889
N
THP
NMP/THF
37%
F
OH
Cl
O
N
N
O
N
N
THP
Br
N
N
Br
Ar
NaHMDS
THF, -10ºC
78%
OPRD 2006, 10, 512
F
O
OH
Br
O
OH
Br
OH
O
N
N
LiHMDS
THF, -40ºC
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