Indazoles:
Purines:
R1
R1
CuO,
K2CO3,
O
R2
Heterocyclic Chemistry
Essentials of Heterocyclic Chemistry-III
Baran, Hafensteiner, Richter
NaNO2
R''
N
N
R3
NH2NHR3
X
CHO
N
H
NH2
N
N
H+
N
N
H
Ac2O
Δ
NH2
NC
Me
N
H
N
NH2
Me
N
N
Me
N
N
Δ
N
H2 N
Traube Synthesis
HCONH2
N
N
N
X = F, Cl, Br
RONO
N
Ac
NHAc
NaNO2,
N
O
N
H
AcOH
NH2
N
R1
MeO
i. TsOH,
HC(OMe)3
N
H
O
R1
O
CO2R
R2
CO2R
Base
+
R1
CO2R1
R2O2C
R1
O
O
OR2
R2O2C
R
O
O
R1
Base
Me
R1
H2O2
R
Me
Ar
OH
(R1CO)2O
R1CO2M
R
O
Ar
R
OH
OH
O
R1
Base
O
O
OH
OH
N
H
X
+
RO2C
i. NH2Cl
N
N
H
N
n-BuLi;
ii. PhNO2, H+
N
DMF
Me
AcOH
N
N
Δ
OHC
O
Triazolopyridines:
Base
N
K3Fe(CN)6,
N
O
Pd
O
NaHCO3, Δ
Ph
N
N
N
N
NH
N
N N
Chloramine-T
Ph
N
Δ
Ph
CO2Et
O
O
CO
R
NH
Trost Synthesis
O
+
R3
Biginelli Synthesis
R2
R
von Richter Synthesis
N
H2N
Perkin Condensation
I
NH2
H
Cyclazines:
Pechmann Synthesis
O
Δ
NH2
R1
OH
O
R1
R4
R2
OH
R
R1
+
Auwers Flavone Synthesis
+
R1
R2
CO2R
R2
Br
CO2R
O
O
O
O
O
Kostanecki-Robinson Reaction
O
NaOH
R1
R3
R2
R1
X
O
R3
HNO2, HX;
R
Δ
O
Algar-Flynn-Oyamada Reaction
R
X = O or S
R
O
OH
O Br Ar
R4N
R1=Alkyl, Aryl, R2=Carbonyl, R3=Alkyl, X=O, S
R2
N
R1
R2
NaOH
R2
HN C X
X
NH
Cinnolines:
O
O
R2
NH2
R2
Chromanones and Coumarins:
Ar
R4
N
Pinner Synthesis
MeO
OH
R3
Cl
Me
R1
NH
R2
Ugi Reaction
R4
O
R2
O
+
O
O
R1
NH
R
R1 N3
R3NH2,
C N R4 ,
O
O
Pyrimidines and Pyrimidones:
O
O
R2
Bucherer-Bergs Synthesis
Base
+
CO2R
(NH4)2CO3
R2
R
O
R1 H
N
KCN,
O
Pyrones:
R2
N
Δ
Chichibabin Synthesis
N
H
NH2
NaHCO3
Hydantoins:
N
N
R
Me
N
CO2H
OMe
O
RCOCH2Br
N
H2SO4
ii. NaH,
DppONH2
R
Me
NR2
NHR1
O
Me
PIFA
NHR2
N
Δ
Indolizidines:
O
O
R
R
Me
H2N
ROCl
N
N
Pd0
HC CCO2Et
N
N
N
O
R
OH
O
R
N
H2N
N
t-BuNC,
PhCHO,
HClO4
NHt-Bu
N
N
N
N
Essentials of Heterocyclic Chemistry-III
Baran, Hafensteiner, Richter
Useful Methods of Forming Aryl C–N and C–O Bonds:
Useful Methods of Forming Aryl C–N and C–O Bonds:
FeCl2
ArMgCl
+
Ar'NO2
"Pd Source"
ArNHAr'
NaBH4
+
ArX
J. Am. Chem. Soc. 2002, 124, 9390
RYHZ
X = I, Br, Cl
Y = N, O, S
Z = C, H
Electron-donating and electron-withdrawing functional groups are tolerated on both coupling partners.
"Cu Source"
ArB(OH)2
+
RYH
Y = NH, O, S
Heterocyclic Chemistry
ArYR
Base
Applicable to a wide variety of nucleophilic partners, including phenols, amines, anilines, amides,
imides, ureas, carbamates, sulfonamides, thiols, and thiophenols. Can use a variety of
heterocycles, including imidazoles, pyrazoles, triazoles, tetrazoles, benzimidazoles, and
indazoles. Even styryl boronic acids are tolerated in the reaction. α-Amino esters can be arylated
in good yields and purines have been shown to react selectively at N-9. Catalytic reactions can
be performed and a wide variety of copper sources, ligands, and bases can be used.
Tetrahedron Lett. 1998, 39, 2933
Tetrahedron Lett. 1998, 39, 2937
Tetrahedron Lett. 1998, 39, 2941
Org. Lett. 2000, 2, 2019
Tetrahedron Lett. 2001, 42, 3415
Tetrahedron Lett. 2003, 44, 1691
Tetrahedron Lett. 2003, 44, 3359
ArYRZ
Base
Applicable to a wide variety of nucleophilic partners, including amines, amides, silyloxides,
sulfonamides, anilines, carbamates, ureas, alkoxides, vinylogous amides, phenoxides,
cyclopropylamines, tert-butylcarbamates, sulfoximes, hydrazines, hydrazones, and imines.
Various heterocycles can be N-arylated including indole, pyrrole, imidazole, carbazole,
benzotriazole, and phenoxazole. A variety of aryl donors are tolerated, including electronrich, electron-poor, hindered, unhindered, and heterocyclic. A tropone has even been
aminated using this procedure. Five and six (not seven) membered heterocycles can
routinely be formed via intramolecular cyclizations.
"Cu source"
ArB(OH)2
+
PhthNOH
Pyr, DCE
ArONPhth
Org. Lett. 2001, 3, 139
A wide variety of boronic acids are tolerated and hydrazinolysis reveals the O-arylhydroxylamine. Requires two equivalents of the boronic acid.
J. Am. Chem. Soc. 1997, 119, 10539
J. Am. Chem. Soc. 1998, 120, 12459
+
ArX
RYHZ
ArYRZ
Base
Tetrahedron Lett. 1999, 40, 2657
X = I, Br, Cl
Y = N, O, S
J. Org. Chem. 1999, 64, 670
Z = C, H
Tetrahedron Lett. 2000, 41, 1283
Applicable to a wide variety of nucleophilic partners, including anilines, phenols, thiophenols,
Tetrahedron Lett. 2001, 42, 4791
aliphatic alcohols, thiols, amines, amino alcohols, amino acids, amino esters, guanidines,
J. Am. Chem. Soc. 2001, 123, 7727
amides, diamines, hydrazones, carbazoles, imidazoles, indoles, acylhydrazides, pyrroles,
Synlett. 2002, 231
pyrazoles, benzimidazoles, indazoles, azaindoles, and carbamates. The aryl ring can be a
Synlett. 2002, 427
wide variety of heterocycles and the reaction tolerates a wide range of substituents, including
Org. Lett. 2002, 4, 581
electron-donating and electron-withdrawing groups. Inter- and intramolecular reactions are
both possible. Unprotected functionality of all sorts is tolerated. Various ring sizes can be
Org. Lett. 2002, 4, 973
formed/are tolerated in the reaction. A wide variety of copper sources and oxidation states work
Org. Lett. 2002, 4, 3517
in the reaction. A variety of bases and ligands can be used and the reaction can even be run
Org. Lett. 2002, 4, 3703
with catalytic copper loadings.
J. Am. Chem. Soc. 2002, 124, 7421
J. Org. Chem. 2005, 70, 5164.Tetrahedron, 2005, 61, 6553. Synlett, 2006,18, 3105.
J. Am. Chem. Soc. 2002, 124, 11684
Tetrahedron, 2006, 62, 4435. Tetrahedron, 2006, 62, 4756. J. Org. Chem. 2007, 72, 2737.
Org. Lett. 2003, 5, 793
Tetrahedron Letters, 2007, 48, 6573. Angew. Chem. Int. Ed. 2007, 46, 934.
Org. Lett. 2003, 5, 133
J. Org. Chem. 2007, 72, 3863. Org. Lett. 2007, 9, 643. Tetrahedron Letters, 2007, 48, 7199.
"Cu Source"
ArSnR3
YNHZ
Z = C, H
ArNYZ
Base
Tetrahedron Lett. 2002, 43, 3091
Applicable to a wide variety of aryl stannanes. Nucleophilic partners include amines, anilines, indazoles, benzimiazolones, pyridones,
and aryl amides.
ArX
Ni(0)
+
NaOR
X = Cl, Br
J. Org. Chem. 1997, 62, 5413
J. Am. Chem. Soc. 1997, 199, 6054
ArOR
R = alkyl
Various nucleophilic parters can be used, specifically alkoxides, silyloxides, anilines, and amines. A variety of electron-withdrawing and
electron-donating groups are tolerated on the aromatic ring.
R
+
F
M
M = Cr(CO)3
FeCpPF6
RuCpPF6
i. Base
HN
X
R
N
ii. Demetalate
X = NH, CH2
X
Tetrahedron Lett. 1993, 34, 1395
J. Org. Chem. 1996, 61, 6581
Tetrahedron Lett. 1996, 37, 8487
Tetrahedron Lett. 1997, 38, 5123
J. Am. Chem. Soc. 1997, 119, 6488
For chromium: will tolerate electron-donating groups on the aromatic ring and a variety (lack of) protecting groups on the piperazine. For
iron: a range of amine nucleophiles can be used and some susbstitution on the aromatic ring is tolerable.
R
R
+
Br
R'NH2
+
X = Cl, O2CR'
RYHZ
Tetrahedron Lett. 1986, 27, 3615
Synthesis. 1994, 775
Tetrahedron. 1997, 53, 4137
Tetrahedron. 1999, 55, 1341
ArYRZ
Y = N, O
Z = C, H
Can use with various substituted aryl groups, however phenyl is the most common. The nucleophilic partner can be an amide, aniline,
alcohol, phenol, amine, or hydrazone.
EWG
EWG
+
Tetrahedron Lett. 1996, 37, 7343
J. Chem. Soc. Perkin Trans. 1. 1997, 2229
J. Org. Chem. 1997, 62, 3874
Base
R2NH
NR2
F
Various amines and electron-withdrawing groups can be used.
R'
R'
+
Base
R2NH
J. Org. Chem. 1993, 58, 5101
OMe
NR2
A variety of amines can undergo the displacement. Electron-withdrawing groups are not required on the aromatic ring.
"Cu Source"
+
Cu(II)
Ar3BiX2
Tetrahedron Lett. 1995, 36, 3609
Angew. Chem. Int. Ed. 1995, 34, 1348
J. Org. Chem. 1996, 61, 1133
J. Am. Chem. Soc. 1996, 118, 7215, 7217
J. Org. Chem. 1996, 61, 7240
Tetrahedron 1996, 52, 7525
J. Org. Chem. 1997, 62, 1264, 1268
J. Am. Chem. Soc. 1997, 119, 3395
J. Org. Chem. 1997, 62, 5413
Tetrahedron Lett. 1997, 38, 6367
J. Am. Chem. Soc. 1998, 120, 827
Tetrahedron Lett. 1998, 39, 5731
J. Am. Chem. Soc. 1998, 120, 9722
J. Am. Chem. Soc. 1999, 121, 3224
Tetrahedron Lett. 1999, 40, 3543
J. Org. Chem. 1999, 64, 5575
Org. Lett. 2000, 2, 219
Tetrahedron. 2001, 57, 2953
Tetrahedron Lett. 2001, 42, 4381
Org. Lett. 2000, 2, 1109
Base
J. Org. Chem. 1987, 52, 2619
NHR'
Ammonia, primary, and secondary amines can be used. Gives regioisomeric product mixtures if unsymmetrical.
R'
R'
+
OMe
TMSX
X = N3, OAc, SCN, SPh
X
PIFA
OMe
Tetrahedron Lett. 1991, 32, 4321
J. Am. Chem. Soc. 1994, 116, 3684
Synlett. 1995, 211
J. Org. Chem. 1995, 60, 7144
Pure Appl. Chem. 1996, 68, 627
A variety of substitution can be tolerated on the aromatic ring. R can be either alkyl or methoxy. The reaction has even been performed in
the absence of methoxy group.
For Reviews on the Subject See:
1. Ley, S. V.; Thomas, A. W. "Modern Synthetic Methods for Copper-Mediated C(aryl)–O, C(aryl)–N, and C(aryl)–S Bond Formation"
Angew. Chem. Int. Ed. 2003, 42, 5400 – 5449.
2. Koser, G. F. "C-Heteroatom-Bond Forming Reactions" Top. Curr. Chem. 2003, 224, 137 – 172.
3. Muci, A. R.; Buchwald, S. L. "Practical Palladium Catalysts for C-N and C-O Bond Formation" Top. Curr. Chem. 2002, 219, 131 – 209.
4. Hartwig, J. F. "Palladium-Catalyzed Amination of Aryl Halides: Mechanism and Rational Catalyst Design" Synlett. 1997, 329 – 340.
5. Hartwig, J. F. "Transition Metal Catalyzed Synthesis of Arylamines and Aryl Ethers from Aryl Halides and Triflates: Scope and
Mechanism" Angew. Chem. Int. Ed. 1998, 37, 2046 – 2067.
6. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. "Rational Development of Practical Catalysts for Aromatic Carbon–Nitrogen
Bond Formation" Acc. Chem. Res. 1998, 31, 805 – 818.
7. Hartwig, J. F. "Carbon–Heteroatom Bond-Forming Reductive Eliminations of Amines, Ethers, and Sulfides" Acc. Chem. Res. 1998, 31,
852 – 860.
8. Frost, C. G.; Mendonça, P. "Recent developments in aromatic heteroatom coupling reactions" J. Chem. Soc. Perkin Trans. 1. 1998,
2615 – 2623.
9. Yang, B. H.; Buchwald, S. L. "Palladium-catalyzed amination of aryl halides and sulfonates" J. Organometallic Chem. 1999, 576, 125 –
146.
10. Belfield, A. J.; Brown, G. R.; Foubister, A. J. "Recent Synthetic Advances in the Nucleophilic Amination of Benzenes" Tetrahedron.
1999, 55, 11399 – 11428.
11. Hartwig, J. F. "Approaches to catalyst discovery. New carbon-heteroatom and carbon-carbon bond formation" Pure Appl. Chem. 1999,
71, 1417 – 1423.
12. Prim, D.; Campagnew, J.-M.; Joseph, D.; Andrioletti, B. "Palladium-catalysed reactions of aryl halides with soft, non-organomettalic
nucleophiles" Tetrahedron. 2002, 58, 2041 – 2075.