Recent developments in the chemistry of heteroaromatic N -oxides

Article abstract of DOI:10.1055/s-0034-1379884

Selected developments in the chemistry of heteroaromatic N-oxides since 2001 are presented in this review. The use of these N-oxides, both in late-transition-metal-catalyzed oxidations of carbon-carbon triple bonds and in regioselective C-H functionalizations of the heteroarene, are contemporary topics of interest and the focus of the discussion. 1 Introduction 2 Synthesis of Heteroaromatic N-Oxides 2.1 Direct Oxidation of Hindered Heteroarenes 2.2 Through Construction of Heteroaromatic Rings 3 Heteroaromatic N-Oxides as Oxidants 3.1 Alkyne Oxidation 3.2 Allene Oxidation 3.3 Carbene Oxidation 4 Heteroaromatic N-Oxides as Substrates 4.1 Deoxygenative ortho-C-H Functionalization with Prior Activation 4.2 Deoxygenative ortho-C-H Functionalization with Nonstabilized Carbanions 4.3 Nondeoxygenative C-H Functionalization 4.3.1 ortho-C-H Functionalization 4.3.2 N-Oxide Directed ortho-Alkyl C-H Functionalization 4.3.3 N-Oxide Directed Remote C-H Functionalization 4.4 1,3-Dipolar Cycloaddition 5 Conclusion and Outlook.

Full text of DOI:10.1055/s-0034-1379884

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, A–Q
review
A
Y. Wang, L. Zhang
Review
Synthesis
Recent Developments in the Chemistry of Heteroaromatic N-Oxides
versatile template for C–H
functionalization
versatile nucleophilic oxidants
Youliang Wang
Liming Zhang*
NuH
Department of Chemistry and Biochemistry, University of
California, Santa Barbara, CA 93106, USA
zhang@chem.ucsb.edu
N
Nu
[M]
O
ortho
C–H activation
N
O
[M]
R–X/R–H
R
N
O
M = Au, Rh
directed C–H
reactive metal
carbene intermediates
activation
N
O
N
O
N
Ar
FG
Received: 01.09.2014
Accepted after revision: 23.10.2014
Published online: 14.01.2015
review. For the typically drawn dipolar structure A, the pos-
itive charge on nitrogen can delocalize to the ortho posi-
tions as in the resonance structures of B and C and the para
position as in D, therefore rendering those sites electrophil-
ic and susceptible toward nucleophilic attack; consequent-
ly, electron-donating substituents at these sites enhance
the contribution of these canonical forms to the overall sta-
bility of the N-oxide and increase the nucleophilicity of the
negatively charged oxygen. Alternatively, the negative
charge on the oxygen atom can delocalize into the pyridine
ring, thereby generating the resonance structures E, F and G
and rendering the very same sites on the pyridine ring dis-
cussed above nucleophilic and reactive in electrophilic aro-
matic substitutions. The relatively short N–O bond (1.28 Å,
compared to the 1.383 Å observed in N-methylmorpholine
N-oxide1) and the much smaller increase of dipole moment
over pyridine (2.02D) than that of trimethylamine N-oxide
(4.37D) are indicative of the contribution of these canonical
forms. As a consequence, electron-withdrawing substitu-
ents also stabilize pyridine N-oxides, thereby permitting
their ready preparation.
DOI: 10.1055/s-0034-1379884; Art ID: ss-2014-e0541-r
Abstract Selected developments in the chemistry of heteroaromatic
N-oxides since 2001 are presented in this review. The use of these N-
oxides, both in late-transition-metal-catalyzed oxidations of carbon–
carbon triple bonds and in regioselective C–H functionalizations of the
heteroarene, are contemporary topics of interest and the focus of the
discussion.
1 Introduction
2 Synthesis of Heteroaromatic N-Oxides
2.1 Direct Oxidation of Hindered Heteroarenes
2.2 Through Construction of Heteroaromatic Rings
3 Heteroaromatic N-Oxides as Oxidants
3.1 Alkyne Oxidation
3.2 Allene Oxidation
3.3 Carbene Oxidation
4 Heteroaromatic N-Oxides as Substrates
4.1 Deoxygenative ortho-C–H Functionalization with Prior Activation
4.2 Deoxygenative ortho-C–H Functionalization with Nonstabilized Car-
banions
4.3 Nondeoxygenative C–H Functionalization
4.3.1 ortho-C–H Functionalization
4.3.2 N-Oxide Directed ortho-Alkyl C–H Functionalization
4.3.3 N-Oxide Directed Remote C–H Functionalization
4.4 1,3-Dipolar Cycloaddition
5 Conclusion and Outlook
N
O
N
O
N
O
Key words oxidations, alkynes, cycloadditions, carbenes, pyridines
D
C
A
F
B
1 Introduction
N
O
Heteroaromatic N-oxides possess a 1,2-dipolar nitro-
gen–oxygen bond, where the nitrogen atom is part of the
heteroaromatic ring. The formally negatively charged oxy-
gen has a substantial impact on the physical properties and
reactivities of the arene ring, which can be mostly rational-
ized by electron delocalization. Scheme 1 depicts the im-
portant canonical forms of pyridine N-oxide, which along
with its congeners represents a synthetically versatile sub-
set of heteroaromatic N-oxides and will be the focus of this
N
N
O
N
O
O
G
E
Scheme 1 Canonical forms of pyridine N-oxide
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q

B
Y. Wang, L. Zhang
Review
Synthesis
The negatively charged oxygen, besides impacting the
heteroarene electronically, offers a versatile nucleophilic
oxidation site and enables directed C–H functionalizations.
Pyridine N-oxides are weak bases and less basic than
the corresponding pyridines. The pKa values of the conju-
gate acids of pyridine N-oxides in water are around 1.0.2 In
contrast, the conjugate acids of the corresponding pyridines
have pKa values around 5. This phenomenon is attributed to
the solvation effect, as there is little difference in their ba-
sicity in the gas phase.3
byproduct m-chlorobenzoic acid, which results in de-
creased isolated yields. Sharpless and co-workers developed
a generally preferred methyltrioxorhenium-catalyzed oxi-
dation using hydrogen peroxide as the stoichiometric oxi-
dant.9 While this method is often highly efficient for unhin-
dered pyridines and quinolines, it appears to be sensitive to
steric hindrance and does not work well with pyridines
containing 2-substitutents, except for a small methyl or cy-
ano group.
The oxidation of 1,10-phenanthroline into its N,N′-diox-
ide is extremely challenging owing to the necessity of
twisting the tricyclic ring system out of planarity in order
to accommodate the two anionic oxygen atoms; hence, it
was not achieved with either m-choroperoxybenzoic acid
or dimethyldioxirane. However, HOF·MeCN, perhaps the
best oxygen-transfer agent and easily accessible from fluo-
rine gas (commercially available as a mixture with an inert
gas) and aqueous acetonitrile, readily accomplished this
and related transformations in two minutes and with fair to
good yields (Equation 1). This method offers a potential
solution to the oxidation of other highly hindered sub-
strates.10
A monograph3 in 1991 and a review4 in 2001 elegantly
summarized the properties and reactivities of heteroaro-
matic N-oxides. In this review, we limit the literature cover-
age to selected and representative developments in the
chemistry of heteroaromatic N-oxides since 2001 and focus
mostly on versatile metal-catalyzed oxidations of alkynes
using them as oxidants, and their C–H functionalization re-
actions, both of which have been among the intensely stud-
ied areas of contemporary organic chemistry.
2 Synthesis of Heteroaromatic N-Oxides
F2, H2O, MeCN
5
2.1 Direct Oxidation of Hindered Heteroarenes
R
R
HOF⋅MeCN
3
Direct oxidation of heteroarenes to heteroaromatic N-
oxides can be realized with strong oxidants such as m-
choroperoxybenzoic acid,5 magnesium monoperphthalate,6
in situ generated percarboxylic acids7 and dimethyldiox-
irane (DMDO).8 A common problem with the often-used m-
choroperoxybenzoic acid is the difficulty of removing the
r.t., 2 min
N
N
N
N
1
O
O
R = H, 60%
R = 4-Ph, 74%
R = 5-Cl, 67%
R = 3,4-Me2, 67%
Equation 1
Biographical Sketches
Youliang Wang was born in
Shandong, P. R. of China, in
1989. He received his B.S. de-
gree in 2011 from the Universi-
ty of Science and Technology of
China where he conducted
undergraduate research under
the direction of Professor Guan-
Wu Wang. In the same year, he
started his doctoral studies at
the University of California –
Santa Barbara under the direc-
tion of Professor Liming Zhang.
His current research interest is
gold-catalyzed oxidative trans-
formations of alkynes.
Liming Zhang was born in
Pingxiang, P. R. of China, in
1972. He received his B.S. de-
gree in chemistry from Nan-
chang University in 1993, his
first Master’s degree in organo-
metallic chemistry from Nankai
University in 1996, and his sec-
ond Master’s degree in organic
chemistry from the University
of Alabama with Professor
Michael P. Cava in 1998. He ob-
tained his Ph.D. with Professor
Masato Koreeda from the me-
dicinal chemistry program at
the University of Michigan in
2003 and then carried out a
postdoctoral study with profes-
sor Sergey A. Kozmin at the Uni-
versity of Chicago. He started
his independent academic ca-
reer as Assistant Professor in the
Department of Chemistry at the
University of Nevada, Reno in
2005 and continued at the Uni-
versity of California – Santa Bar-
bara in 2009. His research
interests include reactions cata-
lyzed by late transition metals,
natural product synthesis and
medicinal chemistry.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q

C
Y. Wang, L. Zhang
Review
Synthesis
2.2 Through Construction of Heteroaromatic Rings
O
N
JohnPhosAuCl (5 mol%)
AgNTf2 (5 mol%)
DCE, r.t., 2 h
NO
N-Heteroarene N-oxides can also be prepared from sub-
strates with pre-existing nitrogen–oxygen bonds via the
construction of the arene ring. For example, a direct prepa-
ration of isoquinoline N-oxides from ortho-alkynylbenzal-
doximes was realized by the use of alkynophilic catalysts
such as cationic gold(I) complexes or simple silver triflate
(Equation 2).11 A gold-catalyzed [3+3] cycloaddition be-
tween nitrosobenzene and a β,γ-unsaturated α-diazo ester
offers a modular access to quinoline N-oxides, which entails
the generation of a capto-dative gold carbene, its regiose-
lective nitrogen-trapping by nitrosobenzene, electrocyclic
ring closure and dehydrogenative aromatization (Scheme
2).12 A rhodium(III)-catalyzed annulation between an ox-
ime and an α-diazo-β-keto ester or diketone offers modular
access to multi-substituted isoquinoline and pyridine N-ox-
ides (Scheme 3).13 Mechanistically, the reaction is proposed
to undergo tandem rhodium-mediated C–H activation, car-
bene insertion and cyclization.
R1
N2
+
R2
CO2Et
CO2Et
Et
R1
R2
CO2Et
[O]
[Au]
O
N
OH
OH
R2
R2
R2
[Au]
N
N
R1
R1
R1
R1
CO2Et
CO2Et
CO2Et
[Au]
[Au]
[Au]
O
N
O
O
O
N
N
N
nBu
Ph
Br
CO2Et
72%
CO2Et
72%
CO2Et
77%
CO2Et
68%
Scheme 2
As direct oxidations14 of imidazole compounds into
their N-oxides have met with limited success,5 this type of
oxide can be readily prepared by way of the condensation
between α-keto oximes and imines.15 Scheme 4 outlines a
highly efficient example where the understood reaction
mechanism includes the imine part, methylimine, being
generated in situ from 1,3,5-trimethyltriazinane.15c
OH
O
N
CH2Cl2, r.t., 0.5 h
N
Ph
Ph
with AgOTf, 85%
with Au(IMes)OTf, 96%
Equation 2
R1
[(Cp*RhCl2)2] (2.5 mol%)
AgSbF6 (10 mol%)
R1
O
O
MeOH, 60 °C, 12 h
N2
N
OH
+
R3
N
R2
R3
R2
1.2 equiv
Rh(III)
R1
R1
R1
carbene
insertion
OH
R3
OH
R3
OH
N
N
N
O
OH
RhCp*
R2
R2
Me
Me
R
Me
O
N
O
Me
O
O
N
N
N
Me
Ph
Me
Me
CO2Et
CO2Et
42%
CO2Et
CO2Et
80%
R = H, 99%
R = 3-Me, 58%
R = 1-F, 58%
72%
Scheme 3
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q

D
Y. Wang, L. Zhang
Review
Synthesis
O
O
Me
N
O
O
N
N
N
Me
Et2O, r.t., 20 h
Sub
+
Me
Me
N
N
Sub
[M]
O
N
91%
N
Me
N
O
O
N
Me
Me
Me
HO
Me
N
N
O
Sub
Sub
O
O
[M]
OH
– H2O
O
O
O
Me
Me
Me
H
[M]
Scheme 5
Me
[M]
Me
N Me
N
N
N
HO
HO
Scheme 4
Among the heteroaromatic N-oxides, pyridine and quin-
oline N-oxides are the most frequently used oxidants.
Through a mechanistically similar strategy, oxazole N-
oxides such as 116 were prepared from α-keto oximes and
aldehydes under acidic conditions (Equation 3).16,17
3.1 Alkyne Oxidation
F
O
The first case of alkyne oxidation by a pyridine N-oxide
was realized intramolecularly without metal catalysis.19
Under short-time-thermolysis conditions (contact time ca.
10 s), the enynyl pyridine N-oxide 2 undergoes a [6π+2n]
electrocyclization to generate cyclic allene intermediate 3.
Its labile nitrogen–oxygen bond then experiences either
heterolytic fission to directly generate the α-oxo carbene 4
or homolysis and subsequent orbital rearrangement to ar-
rive at the same intermediate. Two competing pathways en-
sues: the nascent pyridine ring cyclizes to the carbene cen-
ter to form the indolizine product 5, or a Wolff rearrange-
ment followed by a cyclization results in the formation of
the quinolizinone 6 (Scheme 6).
CHO 4 M HCl
EtOAc
Me
Me
O
N
Me
+
Me
OH
85%
N
O
F
1
Equation 3
3 Heteroaromatic N-Oxides as Oxidants
As reagents, heteroarene N-oxides are versatile and yet
mild nucleophilic oxidants that can effect a diverse range of
powerful oxidative transformations mostly in the presence
of metal catalysts. Two features make them unique: 1) their
oxygen atoms possess sufficient nucleophilicity due to their
negatively charged nature and minimal steric size, yet they
are nearly non-basic (vide supra); and 2) the nitrogen–oxy-
gen bond is weak, with a bond dissociation energy of 63.3
kcal/mol for pyridine N-oxide,18 and therefore prone to het-
erolytic fragmentation. This fragmentation follows an ini-
tial nucleophilic attack by the oxygen atom. The net result
of this two-step sequence is nucleophilic oxidation, which
manifests two distinct scenarios: 1) N-oxides form covalent
bonds with substrates and are intimately involved in their
conversions into products; and 2) they oxidize metal cata-
lysts into corresponding higher-valence metal oxides,
which then carry out the intended substrate transforma-
tions (Scheme 5). The discussion in this section focuses on
the first scenario as the reactivities tend to be unique to
these heteroarene N-oxides. In contrast, the second scenar-
io does not engage direct interactions between substrates
and oxidants; as a result, heteroaromatic N-oxides can be
just one of various types of effective oxidants.
380 °C
N
N
N
R
10 s
O
O
O
R
2
R
3
R1 = H, tBu, Ph
N
O
N
N
O
O
R
R
4
R
6/5
R = H
6.1:1
2:1
R = Ph
R = tBu
N
N
R
1.7:1
R
O
50–60%
O
5
6
Scheme 6
The advent of homogeneous gold catalysis20 recently led
to the development of various alkyne oxidations by het-
eroarene N-oxides. Owing to the potent π acidities of cat-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q

E
Y. Wang, L. Zhang
Review
Synthesis
ionic gold(I) complexes, they can readily coordinate to
alkynes and effectively activate the carbon–carbon triple
bond toward attack by nucleophiles. Among a range of nuc-
leophiles examined, pyridine N-oxides and specifically 2-
bromopyridine N-oxide and 3,5-dichloropyridine N-oxide,
were first employed by Zhang and co-workers in 201021 as
suitable oxidants for gold-catalyzed oxidations of homo-
propargylic alcohols, which resulted in the formation of di-
hydrofuranones in fair to good yields (Scheme 7). Mecha-
nistically,22 the ynophilic cationic gold(I) complex, Ph3PAu+,
first coordinates to the carbon–carbon triple bond23 of the
substrate and hence activates it toward nucleophilic attack
by the pyridine N-oxide. The thus-generated alkenylgold in-
termediate H then undergoes heterolytic fragmentation of
the weak nitrogen–oxygen bond, thereby revealing an α-
oxo gold carbene intermediate, namely I. This highly elec-
trophilic metal carbene is trapped by the tethered hydroxy
group to afford the isolated product. Notably, pyridine N-
oxides were uniquely effective in this reaction while other
nucleophilic oxidants such as various sulfoxides24 and ter-
tiary amine N-oxides led to poor or no reaction. Methane-
sulfonic acid (1.2 equiv) was necessary in this reaction in
order to prevent catalyst coordination and hence deactiva-
tion by the pyridine byproduct. However, acid-sensitive
MOMO and NHBoc groups were tolerated due to the buffer-
ing by the slightly basic N-oxide.
Of importance is that the net result of such a gold-cata-
lyzed oxidation of a carbon–carbon triple bond, as exempli-
fied by the above study, is the generation of an α-oxo gold
carbene moiety as in I. As α-oxo metal carbenes/carbenoids
are typically accessed via metal-promoted dediazotization
of α-diazo ketones,25 this oxidative approach permits the
replacement of hazardous, potentially explosive and mostly
not commercially available diazo compounds with benign
and readily available alkynes in the realm of gold catalysis
(Scheme 8).
O
O
[Au]
N2
[Au]
hazardous,
potentially explosive
[Au]
[O]
replacing
heteroarene
N-oxides
safe, cheap,
readily available
Scheme 8
Ph3PAuNTf2 (5 mol%)
OH
MsOH (1.2 equiv), DCE, r.t., 2.5 h
O
This facile and safe access to synthetically versatile α-
oxo gold carbenes has attracted broad interest, and many
additional synthetic methods have been developed.26
Among them, a later work26b by the same research group re-
vealed that 8-alkylquinoline N-oxides (alkyl = Me, Et, or i-
Pr) are better oxidants than substituted pyridine N-oxides
in the oxidation of internal alkynes (Scheme 9). This obser-
vation is generally true with other substrate types, and can
be attributed to a combination of the decent nucleophilici-
ties of these quinoline N-oxides and their labile nitrogen–
oxygen bond. In addition, as the reduced quinoline possess-
es a ring nitrogen shielded by the 8-alkyl group, it is no lon-
ger able to coordinate to catalytically active cationic gold(I)
to a significant extent; as a result, no acid additive is need-
ed, and the oxidative gold catalysis under these non-acidic
conditions can tolerate a broad range of functional groups.
As shown in the scheme, the oxidation with 8-isopro-
pylquinoline N-oxide could be performed at a temperature
as low as –20 °C, indicating facile formation of the gold car-
bene intermediate; moreover, the oxidant attacks highly re-
gioselectively at the less hindered end of a sterically biased
carbon–carbon triple bond, thereby leading to selective for-
mation of the enone products such as 7. In addition, elec-
tronic factors such as conjugation27 and inductive effects
can also impose good to excellent regioselectivity under the
reaction conditions, as demonstrated in the cases of 8 and
9. This regioselective oxidation of alkynes into enones of-
fers a synthetically useful strategy of masking enones as
O
Cl
Cl
R
R
N
Br
N
O
O
Ph3PAu+
(2 equiv)
(2 equiv)
78%
75%
X
X
X
O
N
PPh3
O
N
N
Au
OH
O
OH
R
R
OH
R
Au
PPh3
Au
H
I
PPh3
O
O
O
Me
Ph
Ar
O
BocHN
4
OMOM
62%
O
O
O
O
75%
64%
H
58%
(Ar = 4-MeOC6H4)
H
O
O
O
O
N3
4
O
O
O
H
TsN
68%
O
H
82%
82%
88%
Scheme 7
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q

F
Y. Wang, L. Zhang
Review
Synthesis
DFT calculations. 8-Methylquinoline N-oxide was again the
preferred oxidant, and without any acid additive, the reac-
tion offered the facile preparation of various 2,4-disubsti-
tuted oxazoles.
n-Pr
IPrAuNTf2 (5 mol%)
THF, –20 °C, 14 h
n-Pr
O
+
Cy
n-Pr
n-Pr
Cy
O
(1.2 equiv)
7
N
O
13
:
1
R
R2
O
LAuCl (5 mol%)
O
n-Pr
NaBArF4 (10 mol%)
+
N
+
+
O
R1
R = n-Pr, 90%
R2
NH2
8-methylquinoline
N-oxide (2.2 equiv)
syringe pump addn
PhCl, 60 °C, 16 h
LAu
AuL n-Pr
R1
preferred
R
(1.5 equiv)
[Au]
Cy
Cy
Cy
O
+
AuL
[O]
O
N
R = Me, 88% yield with Ph3PAuNTf2 (5 mol%) at r.t.
R2
R1
H2N
R2
O
O
N
O
O
HO
R1
R1
O
O
O
O
P
Au
[Au]
Me
R2
n-Pr
H2N
n-Pr
Ph
Me
5
N
O
O
71% (11:1)
(–20 °C; 48 h)
8
9
Mor-DalPhos
J
85% (>50:1)
84% (11:1)
R
(r.t., 1 h)
(r.t., 26 h)
N
O
R
N
R
N
OMe
Scheme 9
Me
O
O
Me
95%
82%
[R = (CH2)4NPhth]
73%
alkynes, which may prove to be of unique synthetic utility
when functional group compatibility is an issue due to the
diverse reactivities of the enone functionality. Indeed, this
chemistry has been applied as a key step in the total syn-
theses of both citrinadins A28 and B (Scheme 10).29 Of note
is the range of functional groups tolerated in these transfor-
mations.
Another notable development of this topic was reported
in 2012,30 where the highly electrophilic α-oxo gold car-
bene moiety, capable of halide abstraction from dichlo-
roethane solvent,31 was tempered toward efficient intermo-
lecular trapping by stoichiometric nucleophiles such as car-
boxamides (Scheme 11). The key feature was the use of
Mor-DalPhos,32 a P,N-bidentate ligand, which enabled the
formation of a tris-coordinated gold center in the carbene
intermediate J; owing to the additional electron donation
by the nitrogen atom to the gold center, a better back-dona-
tion by the metal to the electrophilic carbene center is ex-
pected, which should lower its reactivity and in turn facili-
tate its selective trapping. This rationale was supported by
[R = (CH2)9Me]
[R = (CH2)9Me]
Scheme 11
In some cases,33,34 however, gold-catalyzed oxidation of
alkynes by pyridine or quinoline N-oxides might diverge to
more facile pathways from vinyloxypyridinium intermedi-
ates of type H (see Scheme 7) and hence not engage the in-
termediacy of an α-oxo gold carbene. For example, Liu and
co-workers reported that a gold-catalyzed oxidative cy-
clization using 8-methylquinoline N-oxide as the oxidant
offered a highly efficient access to cyclopentenone deriva-
tives (Scheme 12).33 While the net outcomes appear to be
intramolecular C–H insertions by α-oxo gold carbenes, de-
tailed mechanistic studies suggested that a 1,5-hydride mi-
gration by the initially formed vinyloxyquinolinium K
might be preferred over, and hence bypass, the carbene for-
mation, as the corresponding diazo substrates exhibited a
contrasting trend of reactivity.
Ph3PAuNTf2
O
OH
N3
H
N
THF
OH
N3
H
N
OH
H
N
HN
O
O
HN
HN
Br
N
O
O
NHMe
O
O
73%
(+)-citrinadin B (revised)
Scheme 10
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q

G
Y. Wang, L. Zhang
Review
Synthesis
R
O
EWG
H
IPrAuCl–AgNTf2 (5 mol%)
DCE, 80 °C, 0.5–3 h
R
R2
R1
EWG
+
IPrAuCl (5 mol%)
AgNTf2 (10 mol%)
+
R2
R1
+
N
O
N
N
Z (1.5 equiv)
DCE, 80 °C
Me
Me O–
Z = 8-methylquinoline
H
3 equiv
Z+-O–
Me
O
Z+-O–
Z
O
LAu+
[Au]
R
R
O
Z
R
O
IPr
IPr
H
1,5-H
shift
R2
R1
R2
R1
Z
EWG
EWG
EWG
AuL
R2
– LAu+
R1
Au
Au
Z
Me
slow
IPr
fast
Au
H
AuL
N
N
O
O
H
O
Z
Z
Me
O
K
M
L
Ph
R
R
H
yield
83%
R
O
R
n
1
1
2
yield
88%
81%
85%
Ph
Bn
Ph
NC
Bn 85%
Ph 83%
NC
H
allyl 90%
CH2Cl 71%
O
CH2Cl 2 81%
n
n = 0, 67%
n = 1, 61%
O
80%
N
N
H
Scheme 12
H
n
Me
O
Me
O
10, 78%
(34% without extra Z)
The heteroaromatic byproduct generated during the ox-
idative gold catalysis is not necessarily a bystander and can
trap the nascent highly electrophilic gold carbene interme-
diate.21 For example, during the study of intramolecular cy-
clopropanation reaction by Liu,26d the polycyclic tetrahy-
dropyrroloquinoline 10 was formed in 34% yield (Scheme
13).35 The yield of 10 could be improved by the addition of
1.5 equivalents of extra 8-methylquinoline. The reaction
likely proceeds via the quinolinium gold intermediate L,
which upon releasing the gold catalyst delivers the azo-
methine ylide M. The ensuing diastereoselective intramo-
lecular 1,3-dipolar cycloaddition affords the observed prod-
uct. An intramolecular oxidation of carbon–carbon triple
bond by a tethered pyridine N-oxide also engages the het-
eroarene in subsequent transformations.36
In addition to the gold-catalyzed oxidation of alkynes
with pyridine or quinoline N-oxides, related oxidations us-
ing rhodium catalysts have been developed.37 As shown in
Scheme 14, with electronically activated ynamide sub-
strates, the active rhodium catalyst generated from
[Rh(CO)2Cl]2 and P[OCH(CF3)2]3 behaves as a π Lewis acid,
similar to cationic gold(I), and promotes nucleophilic attack
by 3,5-dichloropyridine N-oxide. The adduct is then trans-
formed into an α-oxo rhodium carbene intermediate (i.e.,
N), which should possess different reactivity from its gold
counterpart. In this case, the rhodium carbene moiety in N
can cyclopropanate a tethered alkene or, as shown, undergo
metathesis with a similarly tethered alkyne. The new rhodi-
um carbene generated (i.e., O) would be oxidized by the
same N-oxide to deliver the 4-acyl-2-oxopyrroline product.
Notably, the related rhodium-catalyzed oxidation of normal
or electron-deficient alkynes is not known, indicating that
cationic gold(I) catalysts are in general better π Lewis acids
than rhodium(II) catalysts.
Scheme 13
O
Ts
Ts
N
R2
[Rh(CO)2Cl]2 (5 mol %)
N
P[OCH(CF3)2]3 (0.2 equiv)
R2
Z+–O– (3 equiv)
dioxane, 80 °C, 4 h
R1
R1
O
R1
Ph
R2
Ph
yield
67%
76%
56%
80%
Z = 3,5-Cl2Py
4-MeOC6H4 Ph
Z
Z
Me
Ph
H
O
[Rh]
4-MeOC6H4
O
4-MeOC6H4 2-FC6H4 75%
O
Z
O
O
Ts
R2
N
R2
Ts
Ts
R2
N
N
[Rh]
[Rh]
R1
R1
[Rh]
R1
O
N
Scheme 14
A palladium-catalyzed double oxidation of diphenyl-
acetylene by pyridine N-oxide was realized under rather
harsh conditions (Scheme 15).38 It was proposed that a cat-
alytically active palladium(II) species is generated via the
oxidation of palladium-on-carbon with the N-oxide and
acts as a π Lewis acid to promote the addition of the oxi-
dant to the carbon–carbon triple bond. Instead of invoking
a probable formation of a palladium carbene, the authors
proposed that the adduct P would be attacked by another
molecule of pyridine N-oxide in an SN2′-like manner. Nota-
bly, the pyridine N-oxides with either an electron-donating
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q

H
Y. Wang, L. Zhang
Review
Synthesis
4-methoxy or an electron-withdrawing 4-nitro substituent
were much less effective, affording the diketone product in
52% and 34% yield, respectively.
Ar
O
Z
O
(2 equiv)
Ar
Ar
Cu(NCMe)4NTf2 (4 mol%)
MeCN, 80 °C, 8 h
O
O
O
O
11
12
O
Ar = 4-t-BuC6H4
10% Pd/C (10 mol%)
Ph
Ph
Ph
Z
Ph
Z
pyridine N-oxide (5 equiv)
Z
O
[Cu]+
air, 120 °C, 24 h
Ar
[Cu]
Ar
O
Ar
O
O
94%
•
•
O
Ar
Z
Pd(II)
[Cu]
O
H
O
N
O
O
O
[Cu]
Q
N
MeO
N
O
O
O
N
Ph
Ph
oxidant:
N
O
N
N
Ph
Ph
Br
O
Pd(II)
Ph
O
O
Pd(II)
yield
11/12
84%
1.9:1
85%
1:0
74%
0:1
Ph
Pd(II)
P
Scheme 15
Scheme 16
lactams.44 Notably, sulfoxides, another class of nucleophilic
oxidants, were suitable only for the intramolecular cases. A
related ruthenium catalysis was also realized using tethered
sulfoxides as oxidants at around the same time.45
The copper(I) complex Cu(NCMe)4NTf2 was shown by
Gagosz39 to catalyze the oxidative cycloisomerization of
alkynyl oxiranes and oxetanes. While the oxirane substrates
are transformed into various butenolides, the reactions
with alkynyl oxetanes exhibit two competing pathways, the
preferences of which are controlled by the pyridine N-oxide
used. As shown in Scheme 16, the Lewis acidic copper(I)
complex likely activates the substrate via coordination to
both the carbon–carbon triple bond and the oxetane ring
oxygen. As such, a nucleophilic pyridine N-oxide would at-
tack the alkyne terminus to arrive at the allenoxypyridium
intermediate Q, which would undergo either a direct SN2′-
type cyclization to afford the aldehyde 11 or a copper(I)-
promoted 6-endo-trig cyclization followed by elimination
to afford the unsaturated lactone 12. What is interesting is
that a moderate selectivity (1.9:1) toward 11 in the case of
pyridine N-oxide was dramatically enhanced with a more
electron-deficient 3-bromopyridine N-oxide, which was as-
cribed to the improved nucleofugality of 3-bromopyridine;
in contrast, the use of a more electron-rich 4-methoxypyri-
dine N-oxide led to a complete reversal of selectivity, and
12 was the only isolated product in 74% yield. This outcome
was attributed to the decreased nucleofugality of 4-meth-
oxypyridine and its enhanced ability to accommodate posi-
tive charges.
Me
N
O
O
(1.2 equiv)
Ar
+
EtOH
Ar
[{Rh(cod)Cl}2] (3 mol%)
P(4-FC6H4)3 (12 mol%)
MeCN, 60 °C, 2 h
OEt
(3 equiv)
Ar = PMP
[Rh]
89%
EtOH
Me
O
[Rh]
[Rh]
Z
O
N
Ar
Ar
[Rh]
Ph
Me
N O
PMP
Ph
O
Me
N
+
(1.3 equiv)
Ar
N
Rh(PPh3)3Cl (5 mol%)
MeCN, 50 °C, 24 h
Ph
Me
(1.3 equiv)
93%
Scheme 17
Despite the widespread use of metal catalysis in the oxi-
dation of alkynes by heteroarene N-oxides, there are several
metal-free exceptions. For example, with 2-ethynylaniline
substrates, a Brønsted acid was used to promote the addi-
tion of pyridine N-oxides via the protonated – and hence
activated – intermediates R; synthetically useful tetrahy-
dropyrroloquinolinone products were eventually formed in
moderate to good yields (Scheme 18).46 Notably, the
alkynes used in this case can be considered as vinylogous
ynamines and are electron-rich, which is necessary as elec-
tron-neutral alkynes cannot be readily activated under the
employed acidic conditions.
The isomerization of terminal alkynes to metal vi-
nylidenes is a much employed strategy for method develop-
ment.40 However, there has been only limited success in ox-
idizing metal vinylidenes into ketenes.41 In a recent study
by Lee,42 pyridine N-oxides were proven to be versatile oxi-
dants for the transformation (Scheme 17). The ketene or
rhodium–ketene complex generated underwent either fac-
ile nucleophilic trapping to yield carboxylic acid derivatives,
or a Staudinger ketene imine cycloaddition43 to deliver β-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q

I
Y. Wang, L. Zhang
Review
Synthesis
O
N
O
N
2,6-dibromopyridine N-oxide (2 equiv)
MsOH (4 equiv), CH2Cl2, 30 °C, 3 h
72%
N
O
Z
H+
Z
•
N
O
N
R
O
N
O
N
R
R
4-F
yield
75%
4-CF3 51%
3-F 72%
Ph
N
Bn
56%
40%
Scheme 18
Another case of metal-free oxidization was also
achieved with electron-rich alkynes under acidic condi-
tions. As shown in Scheme 19, the alkynyl aryl ether 13 un-
derwent oxidative cyclization to form the benzofuranone
14 in a good yield (as determined by gas chromatrogra-
phy).47 A likely mechanism entails an initial protonation of
the carbon–carbon triple bond and a subsequent N-oxide
attack. The conversion of the thus-formed adduct 15 to 14,
although not allowed under Baldwin’s rules, was also pro-
posed in an earlier related report.34
lyst, namely (4-CF3Ph)3PAuNTf2, and 3,5-dichloropyridine
N-oxide as the oxidant. The proposed mechanism involves
an initial gold-catalyzed regioselective addition of the N-
oxide to the allene sp-hybridized carbon, a subsequent pro-
todeauration and a final SN2′-type attack by mesylate.
3,5-Cl2Py N-oxide (2 equiv)
MsOH (5 equiv)
(4-F3CC6H4)3PAuNTf2 (5 mol%)
OMs
O
Me
R
yield
R
•
R
DCE, 40 °C, 8 h
80%
Me(CH2)9 77%
AcO(CH2)4 79%
TsO(CH2)4 80%
BnO(CH2)2 61%
[Au]
O
Z
OMs
2,6-lutidine N-oxide
O
O
Ph(CH2)2
60%
MsOH
(1 equiv)
R
[Au]
Me
Z
O
cyclopentyl 72%
R
O
HBF4⋅OEt2 (0.1 equiv)
MeO
MeO
Z
O
dioxane, 80 °C, 3 h
13
H+
14
– H+
O
86%
Scheme 20
Z
O
O
•
3.3 Carbene Oxidation
MeO
81%
MeO
O
Z
O
15
Pyridine N-oxide was also utilized for the oxidative de-
metalation of Fischer carbene complexes.49 For example,
the Fischer carbenes 16, synthesized from [3+2] cycloaddi-
tion between an azomethine imine and 1-alkynyl Fischer
carbene complexes, were converted into the corresponding
bicyclic ester 17 by using pyridine N-oxide (Equation 4).49e
O
O
O
O
O
F3C
83%
30%
Scheme 19
Ph
Ph
O
Ph
Ph
O
3.2 Allene Oxidation
N
O
N
N
(1.1 equiv)
N
N
The oxidation of allenes by heteroaromatic N-oxides
has, surprisingly, attracted little effort, which might be at-
tributable to the difficulty in controlling the regiochemistry
of the initial addition. An early study is shown in Scheme
20.48 Terminal allenes were converted into α-methanesulfo-
nyloxy methyl ketones by using a highly active gold(I) cata-
Ph
Ph
CH2Cl2, r.t.
M = Cr, 81%
M = W, 76%
M
OEt
O
OEt
17
16
Equation 4
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q

J
Y. Wang, L. Zhang
Review
Synthesis
4 Heteroaromatic N-Oxides as Substrates
CO2Me
CO2Me
1. Ts2O, CHCl3
Among the many types of reactions using heteroaro-
matic N-oxides and their functionalized derivatives as sub-
strates, the regioselective functionalization of carbon–
hydrogen bonds offers streamlined synthetic routes and is
of significant synthetic utility. Lately, much progress has
been reported in this area, as discussed in this section.
2. t-BuNH2
3. TFA
N
N
NH2
O
Equation 5
PyBroP (1.3 equiv)
NuH (1.25 equiv)
N
P
N
DIPEA (3.75 equiv)
CH2Cl2, r.t., 15 h
N
O
N
Nu
PF6
N
Br
4.1 Deoxygenative ortho-C–H Functionalization
with Prior Activation
O
O
N
NH2
PyBroP
Complementary to nucleophilic aromatic substitutions
of ortho-halogenated N-heteroarenes, non-functionalized
heteroaromatic N-oxides have been employed widely to
achieve ortho-substitutions, resulting in net C–H function-
alizations.50 With weak nucleophiles such as amines, chlo-
rides and cyanides, direct attack at the ortho position does
not occur, owing to its weak electrophilicity. However, as
shown in Scheme 21, initial activation of an N-oxide by at-
taching an electrophilic species to the negatively charged
oxygen would enhance the electrophilicity of the ortho po-
sition and thereby dramatically accelerate nucleophilic at-
tack, which would in turn yield an ortho-substituted het-
eroarene (i.e., 18) upon subsequent rearomatization, al-
though 4-substituted side products may be formed as well.
Commonly employed activating agents include methyl tri-
flate, p-toluenesulfonic anhydride, p-toluenesulfonyl chlo-
ride, benzoyl chloride, bromotripyrrolidinophosphonium
hexafluorophosphate (PyBroP), and triphosgene. In cases
where substituents other than the counter-anion of the ac-
tivating reagent are desired, the reactions are typically per-
formed in two steps and weakly nucleophilic counter-an-
ions are used. For example, methyl triflate50a and p-toluene-
sulfonic anhydride (Equation 5)50c,e were used in the
synthesis of 2-aminated pyridines under mild conditions. In
a mild, one-step reaction using PyBroP as the activating re-
agent, an amazingly broad scope of nucleophiles including
amines,50d azoles, phenols, amides, thiols and stabilized
carbonucleophiles50i were used to effect deoxygenative or-
tho-substitution of pyridine N-oxides (Equation 6). Notably,
this reaction is devoid of 4-substituted and halogenated
side products and, moreover, the one-step protocol sug-
gests that the reactions between nucleophiles and PyBroP,
if any, might be reversible.
HN
95%
82%
66%
H
N
t-Bu
NH
BnSH
61%
S
O
O
O
OH
72%
96%
84%
Equation 6
When the counter-anion of the activating reagent is the
desired 2-substituent, this deoxygenative substitution can
be readily performed in one step. An example is shown in
Equation 7.50a Interestingly, in the case of 1-alkylpyrazole-
2-oxides, halogenation occurred at C5 instead of C3 (Equa-
tion 8).50n
O
O
TMSCN
MeCN, reflux
NC
N
O
N
O
O
59%
OTBS
OTBS
Equation 7
POX3 (4 equiv )
CHCl3, 0 °C to 50 °C
R = Me R = allyl
N
N
O
X = Cl 70%
X = Br 78%
83%
85%
N
X
N
R
R
Equation 8
A versatile approach to installing amide groups at the
pyridine 2-position involves the reaction of pyridine N-ox-
ides with imide chloride, in the so-called Abramovitch reac-
tion.51 In an improved mild protocol (Scheme 22),50f the re-
active chloride, generated in situ from treating a secondary
carboxamide with stoichiometric oxalyl chloride in the
presence of a moderate base, reacted with a pyridine N-ox-
ide to form the intermediate 19, which likely underwent
electrocyclic closure to form the bicyclic dihydropyridine
20. A base-promoted fragmentation of the oxadiazoline
ring of 20 then regenerated the pyridine ring and installed
the amide group at the ring C2 position. A similar transfor-
mation using triflic anhydride and 2-fluoropyridine has
been reported.50j With primary amides, however, similar
R
E-X
NuH
N
O
Nu
N
O
activating
agent
X
– HX
N
O
– HOE
N
Nu
E
E
18
Scheme 21
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q

K
Y. Wang, L. Zhang
Review
Synthesis
R1
R2
Ph
Ph
Ph
treatments with oxalyl chloride in the absence of base gen-
erated acylisocyanates instead of the imido chlorides; they
subsequently reacted with quinoline N-oxides to yield
quinolines possessing a secondary amide at their C2 posi-
tion.50h
yield
54%
66%
68%
63%
77%
R1
H
R1
4-OMe
4-Cl
MeOH (1.3 equiv)
then TFAA (1.1 equiv)
–40 °C to r.t.
N
R2
N
O
4-CO2Me Ph
2-C6H4 vinyl
R2MgCl
O
Cl
R1
(COCl)2
(1.2 equiv)
R3
R1
+
R2
R2
THF, –40 °C
R1
N
H
R1
N
N
O
R2
NaBH4 (3 equiv)
MeOH, –78 °C
2,6-lutidine
CH2Cl2, 0 °C
N
O
21
0 °C to r.t.
BrMg
N
R2
Ph
R2
R2
Li-(+)-BINOL-ate
R2MgBr, THF
–78 °C
R2
N
R3
H
OH
R1
N
N
R1
R3
AcOH
chloranil
–40 °C to r.t.
R3
N
O
N
R1
N
O
75%
Ar
O
N
R1 R2
Ph Ph
yield ee
O
86% 70%
one-pot, up to 100%
N
20
O
19
Ph 4-ClC6H4 71% 80%
(Ar = 4-MeOC6H4)
Bn
Scheme 24
Me
Me
N
Me
N
Me
N
Me
O
N
O
N
O
N
An improved, one-step deoxygenative ortho-substitu-
tion of N-oxides was catalyzed by copper(I) chloride (Equa-
tion 9).57 The addition of Lewis acidic magnesium chloride
or lithium fluoride improved the yield dramatically. The re-
action featured mild reaction conditions, no need for a de-
hydrating reagent, and a broad reaction scope as alkyl, aryl
and alkenyl Grignard reagents were all suitable, and func-
tional substituents on the heteroarene ring such as bromine
and free hydroxy groups were tolerated. Notably, the two-
step method in Scheme 24 did not work well with alkyl
Grignard reagents.
Me
73%
Scheme 22
90%
73%
4.2 Deoxygenative ortho-C–H Functionalization
with Nonstabilized Carbanions
The reaction of heteroaromatic N-oxides with strongly
nucleophilic Grignard reagents typically do not require
much substrate activation. An early study52 reported the
low-yielding formation of the ring-opened product dienal
oximes 22, instead of the originally proposed dihydropyri-
dine, upon protonation of 21 (Scheme 23). Olsson, Almqvist
and Andersson discovered in 2011 that the ring opening of
21 to 22 did not occur as long as the temperature was below
–20 °C. As a result, they developed preparations of 2-substi-
tuted pyridines and stereoselective syntheses of substituted
piperidines and piperazines under exceptionally mild con-
ditions.53 For example, in a one-pot process, 2-substituted
pyridines were prepared in fair yields upon treatment of
the initial adduct of type 21 with a dehydrating reagent
such as trifluoroacetic anhydride (Scheme 24).54 Of note is
that the reaction was not contaminated with 4-substituted
side products and functional groups such as carboxylate
and chloride were tolerated. In addition to the dehydration,
the initial adduct could be oxidized back to the pyridine N-
oxide,54,55 or formed asymmetrically en route to chiral
piperidines following reduction (Scheme 24).56
CuCl (5–10%)
R2MgCl⋅LiF or R2MgCl⋅MgCl2
X
X
(1.5–4 equiv)
R1
R1
Et2O, r.t., Ar
N
R2
N
O
Br
N
N
Ph
Ph
N
Me
N
n-C5H11
Ar
N
OH
61%
76%
78%
71%
(Ar = F3CC6H4)
Equation 9
Metal-free reactions between quinoline N-oxide and si-
lylated arylacetylenes or 2-trimethylsilylbenzothiazole
were realized with the use of organic superbase P4-t-Bu
(pKBH+ in acetonitrile = 42.7) as catalyst, and 2-substituted
quinolines were obtained in good yields (Equation 10).58
THF, r.t.
+
ArMgBr
N
Ar
N
O
Ar
N
O
OH
Ar = Ph, Tol,
2-thienyl
BrMg
22
10–45%
21
Scheme 23
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q

L
Y. Wang, L. Zhang
Review
Synthesis
Br
Pd(OAc)2 (5 mol%)
t-Bu3P-HBF4 (6 mol%)
K2CO3 ( 2 equiv)
3 P Nt-Bu
N
(Me2N)3P
(10–20 mol%)
N
O
N
Nu
+
Me
N
Ar
Me
N
O
PhMe, 110 °C
S
N
O
Me
ArBr
TMS
NuH =
PMP
DMF, r.t., 1 h
87%
TMS
56%
cyclopentyl methyl ether
r.t., 17 h, 77%
Pd(OAc)2 (5 mol%)
PhDave-Phos (10 mol%)
K2CO3 (15 equiv)
O
N
O
Equation 10
N
PivOH (0.2 equiv)
+
PMPBr
PMP
PhMe (0.2 M), 25 °C
88%
S
Me
S
4.3 Nondeoxygenative C–H Functionalization
Me
(1.1 equiv) (1 equiv)
In contrast to the deoxygenative approach discussed
above, transition-metal-catalyzed C–H activation of N-ox-
ides of pyridine or other heteroarenes offers a direct and
versatile strategy for the functionalization of N-het-
eroarenes not only at the ortho position but also at posi-
tions further away. Moreover, readily available halides, in-
cluding alkyl halides, instead of Grignard reagents are em-
ployed as reaction partners, thereby promising better
functional group tolerance. Notably, the N-oxide moiety
stays intact during the transformation and hence is avail-
able for promoting or directing further functionalization of
the heteroarene ring, even though an addition reduction
step is required to access heteroarene products.
Pd(OAc)2 (5 mol%)
PhDave-Phos (10 mol%)
K2CO3 (2 equiv)
O
N
O
OMe
N
PivOH (0.3 equiv)
Ar
+
CuBr (10 mol%)
N
N
Ph
Ph
MeCN, 25 °C
Br
OMe
Me
Me
ArBr
94%
Pd(OAc)2 (5 mol%)
DavePhos (15 mol%)
Cs2CO3 (2 equiv)
+
PMPBr
N
PivOH (0.3 equiv)
N
N
O
N
O
PhMe, 110 °C
Me
Me
PMP
(2 equiv)
Scheme 25
(1 equiv)
68%
4.3.1 ortho-C–H Functionalization
The Fagnou research group pioneered a palladium-cata-
lyzed ortho-selective C–H functionalization of a range of
azine and azole N-oxides using aryl bromides as the cross-
coupling partners.5,59 Scheme 25 shows some examples
that exhibited high regioselectivities. Mechanistic studies59f
pointed to an inner-sphere concerted metallation–depro-
tonation pathway instead of an SEAr and a critical role
played by a carboxylate base in the carbon–hydrogen bond
cleavage. Notably, the negatively charged N-bound oxygen
was not involved in directing the C–H activation. The ob-
served regioselectivity may be attributed to the more elec-
tropositive nature of the ortho position.
Pd(OAc)2 (5 mol%)
dppf (10 mol%)
Cs2CO3 (2 equiv)
Alkyl-Br
(1 equiv)
+
Me
N
O
Alkyl
Me
Me
N
O
PhMe, 100 °C, 12 h
(2 equiv)
N
MeO
N
O
N
O
Cy
N
O
Cy
N
O
Cy
n
71%
62%
44%
n = 0, 56%
n = 1, 88%
n = 2, 62%
A notable advance in this approach was the use of sec-
ondary alkyl halides to replace aryl halides (Equation 11),60
which provided a practical method to synthesize alkylated
pyridine N-oxides. The involvement of radical species
during the carbon–bromine bond cleavage was supported
by the observed stereochemistry scrambling and radical re-
arrangement.
Equation 11
In addition to palladium catalysis, a copper-catalyzed
C–H activation and sulfonylation of quinoline N-oxides us-
ing arenesulfonyl chlorides was also realized (Equation
12).61
CuI (10 mol%)
K2CO3 (2 equiv)
+
TsCl
N
O
Ts
DCE, 100 °C, 24 h
N
O
91%
(4 equiv)
(1 equiv)
Equation 12
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q

M
Y. Wang, L. Zhang
Review
Synthesis
Instead of C–X bonds, the use of C–H bonds as coupling
partners to functionalize the ortho C–H bonds of the N-ox-
ides offers, in principle, even better step-economy and syn-
thetic efficiency. This oxidative dehydrogenation approach
has been successfully applied to ethers, alkenes, arenes and
even heteroarene N-oxides. Some representative examples
are shown in Scheme 26. For example, simple pyridine N-
oxide was arylated selectively at the C2 position with 40
equivalents of benzene using silver carbonate as the stoi-
chiometric oxidant and palladium(II) acetate as the cata-
lyst,62 1,2,3-triazole N-oxides were regioselectively alke-
nylated using methyl acrylate in an oxidative Heck reaction
or coupled with another N-oxide (e.g., pyridine N-oxide),63
and pyridine or quinoline N-oxides were alkylated regiose-
lectively by cyclic ethers.64 In the last case, the stoichiomet-
ric oxidant, tert-butyl hydroperoxide, was involved in the
generation of α-ethereal radicals via hydrogen abstraction.
O
O
O
N
Cu(OAc)2
Ag2CO3
O
N
N
H2N
+
PhH, 120 °C
24 h
93%
Equation 13
R1
O
O
N
CuI (10 mol%)
R1
toluene
N
N
H
+
R2
N
R2
air, 50 °C
7–12 h
R
O
N
O
N
N
N
R
n
R = Me, 91%
R = Et, 78%
R = Ph, 25%
n = 0, 86%
n = 1, 91%
Equation 14
Pd(OAc)2 (10 mol%)
Ag2CO3 (2 equiv)
There are other notable ortho-C–H functionalization re-
actions of heteroarene N-oxides. For example, nickel-cata-
lyzed additions of pyridine N-oxides across internal alkynes
have been developed based on regioselective activation of
the heteroarene C2–H bond (Equation 15).67 The reported
reaction conditions were mild, but the scope of the alkyne,
due to poor control of regioselectivity, was rather limited.
Another case is a direct C2-carboxylation of quinoline N-ox-
ide, which entailed a copper(I)-catalyzed and tert-butyl hy-
drogen peroxide mediated cross dehydrogenative coupling
between aldehydes and quinoline N-oxides (Equation 16).68
N
O
Ph
Ph
:
N
O
Ph
N
O
PhH ( 40 equiv)
130 °C, 16 h
3
1
79%
Pd(OAc)2, Ag2CO3
pyridine
CO2Me
CO2Me
N
+
N
O
20% t-BuOH–dioxane
125 °C, 8 h
N
N
N
O
Tol
92%
N
Tol
Pd(OAc)2, Ag2CO3
N
O
N
N
O
+
N
dioxane
N
O
[Ni(cod)2] (10 mol%)
N
N
120 °C, 24 h
O
Tol
N
Cy3P (10 mol%)
Pr
Pr
Pr
+
N
O
Tol
PhMe, 35 °C, 15 h
N
O
(1.5 equiv)
O
N
O
O
O
N
Pr
O
O
Pd(OAc)2, TBHP
TBAB, H2O
67%, E/Z = 93:7
+
Equation 15
77%
O
O
N
CuOTf (5 mol%)
TBHP (3 equiv)
Scheme 26
N
OBz
+
PhCHO
DCE, 70 °C, 8 h
(3 equiv)
A copper-catalyzed regioselective direct cross coupling
between quinoline N-oxides and lactams or secondary
amines was realized through the use of silver carbonate as
oxidant (Equation 13).65 This reaction offered a simple yet
direct construction of 2-amino/amidoquinolines and was
found to tolerate various nitrogen coupling partners. A later
study revealed that the amination reaction could be per-
formed under much milder conditions (50 °C instead of 120
°C) and, moreover, by using air as the stoichiometric oxi-
dant (Equation 14).66 The key difference was the use of cop-
per(I) iodide as the catalyst.
84%
Equation 16
4.3.2 N-Oxide Directed ortho-Alkyl C–H Functionaliza-
tion
By using a much stronger base (i.e., sodium tert-butox-
ide instead of potassium or cesium carbonate5,59) and a dif-
ferent phosphine ligand, Fagnou and co-workers realized a
selective palladium-catalyzed activation of the ortho-alkyl
C–H bond over the ortho-C(sp2)–H bond of 2-alkylpyridine
N-oxide, which eventually led to arylation at the 2-alkyl
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q

N
Y. Wang, L. Zhang
Review
Synthesis
R
group instead of at the pyridine ring C6 position (Scheme
27).59a,e The palladacycle intermediate S, formed upon the
deprotonation of the 2-alkyl group of the pyridine N-oxide
by strongly basic sodium tert-butoxide, was proposed as
the key intermediate that furnished the desired product
with the observed chemoselectivity.
[Rh(cod)2]OTf (10 mol%)
xylylBINAP (10 mol%)
R
Ph
+
PhCl (0.2 M), 135 °C
N
Ph
N
O
O
R = 2-Me, 64%, E/Z = 6:1
R = 4-Me, 50%, E/Z > 20:1
R = 6-Cl, 84%, E/Z = 20:1
Ph
Ph
R
Ph
Pd2dba3 (2.5 mol%)
XPhos (5 mol%)
R
R
Ph
R
R
NaOt-Bu (3 equiv)
ArBr (1 equiv), PhMe
MW, 110 °C
N
O
N
O
N
O
N
[Rh]
Ar
N
O
[Rh]
H
Ph
[Rh]
O
(1.5 equiv)
R = H, Ar = Tol, 89%
R = Me, Ar = Tol, 51%
LnPd(0)
H
T
U
H
Ph
NaOt-Bu
Scheme 28
LnPd(0)
PdLn(Ar)Br
ArBr
S
N
O
PdLn
N
23
N
24
Ar
I
O
NHTs O
Scheme 27
82%
89%
[RhCp⋅Cl2]2 (4 mol%)
[IrCp⋅Cl2]2 (4 mol%)
AgNTf2 (16 mol%)
TsN3 (1.1 equiv)
AgNTf2 (16 mol%)
4.3.3 N-Oxide Directed Remote C–H Functionalization
NIS, DCE, 50 °C, 12 h
AcOH, DCE, 50 °C, 12 h
Aside from C–H functionalization at the C2 position of
quinoline N-oxides, directed activation of the relatively re-
mote C8–H bond and its subsequent functionalization was
recently realized via rhodium catalysis by Matsuo and
Shibata.69 In the presence of a cationic rhodium(I) catalyst,
the addition of the C8–H bond across an alkyne was
achieved in fair to good yields (Scheme 28).69 The reaction
resembles that shown in Equation 15, but occurs at a differ-
ent carbon–hydrogen bond, highlighting the key roles of
different metal catalysts. Mechanistically, a five-membered
metallacycle (i.e., U) is formed upon C–H activation, which
is preferred for subsequent reaction with alkynes likely due
to its relative stability over the C2–H activation isomer T.
This type of remote C–H functionalization was inde-
pendently developed and later expanded by Chang and co-
workers70,71 to include a range of other functional groups.
As shown in Scheme 29, a rhodium-catalyzed direct iodina-
tion delivered synthetically versatile iodide 23 in a good
yield, an iridium-catalyzed amidation was highly efficient
when tosyl azide was used as the nitrene source, a rhodi-
um-catalyzed alkynylation using TIPS-EBX (25) afforded 8-
alkynylquinoline N-oxide 26 in 93% yield, and an 8-alkyla-
tion was readily achieved with the use of diazomaleate.
These direct remote C–H functionalizations feature very
mild reaction conditions, excellent functional group toler-
ance and broad reaction scopes.
[RhCp⋅Cl2]2 (2 mol%)
[RhCp⋅(MeCN)3][SbF6]2
N
O
AgSbF6 (8 mol%)
(4 mol%)
(MeO2C)2C=N2 (1.1 equiv)
PivOH (20 mol%), DCE
r.t., 12 h
PivOH (20 mol%), 4 Å MS
DCE, r.t., 12 h
93%
82%
O
I
TIPS
N
O
N
O
O
25
26
(1.1 equiv)
MeO2C
CO2Me
TIPS
Scheme 29
4.4 1,3-Dipolar Cycloaddition
Heteroaromatic N-oxides can react as 1,3-dipoles in
[3+2]-cycloaddition reactions with electron-deficient
alkenes. Some selected examples reported after 2001 are
presented in Scheme 30.72 For example, the dipolar cycload-
dition between N-methyl maleimide and the quinoline N-
oxide 27 proceeded readily at ambient temperature to af-
ford two diastereomeric cycloadducts in a good combined
yield.72a The [3+2] reaction between pyridine N-oxide and
phenyl isocyanate led to the formation of primary product
28, which was thermally unstable and transformed at
150 °C into 2,3-dihydropyridine derivative 29 by way of a
1,5-sigmatropic rearrangement and eventually decom-
posed to 2-anilinopyridine in a good yield.72b Two research
groups72c,d independently studied the [3+2] cycloaddition
between in situ generated benzyne and pyridine N-oxide.
Interestingly, the cycloadduct 30, under different condi-
tions, rearranged to either 3-(2-hydroxyphenyl)pyridine
(31) or 2-(2-hydroxyphenyl)pyridine (32). The reaction be-
tween quinoline N-oxide and electron-deficient hexafluo-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q

O
Y. Wang, L. Zhang
Review
Synthesis
Me
N
Me
N
O
O
O
O
THF, r.t.
30 min
H
H
O
H
H
H
H
N
O
O
N
N
O
O
N
Ph
Me
54%
17%
27
Ph
Ph
CO2
O
N
PhNCO
Ph
N
O
N
O
DMSO
50 °C
12 h
O
N
O
N
NHPh
N
Ph
79%
28
29
N
O
N
N
OH
O
TMS
OTf
HO
32
N
31
30
CsF, MeCN, r.t.
TBAF, CH2Cl2, r.t.
88%
–
–
71%
CF2=CFCF3
H
DMF
r.t., 1.5 h
F
CF3
CF3
N
N
O
F
N
O
F
F
33
34, 73%
O
Me
MeOH, THF
70 °C, 48 h
CO2Me
F
F
N
N
Me
N
+
70%
Me
N
Me
Bn
Bn
Scheme 30
ropropene proceeded at room temperature to give the cyc-
loadduct intermediate 33, which underwent sequential
elimination, rearomatization, and fragmentation to furnish
the final fluorinated 2-ethylquinoline 34.72e,f Other N-ox-
ides such as imidazole N-oxide and thiazole N-oxide reacted
similarly with difluorinated 1-vinylnaphthalene to furnish
aryl(heteroaryl)acetates upon subsequent rearomatization
and reaction with methanol.72g
gold catalysis, the oxidation can offer access to highly elec-
trophilic α-oxo gold carbene intermediates and thus permit
the development of a range of valuable synthetic transfor-
mations. The negatively charged oxygen also impacts the
heteroarene ring electronically via delocalization and in-
duction and can facilitate regioselective ortho C–H func-
tionalizations either in an overall deoxygenative process or
by way of transition-metal-catalyzed C–H activations.
Moreover, it can act as a Lewis basic directing group to en-
able activation of remote C–H bonds, thereby allowing valu-
able alternative C–H functionalizations. Further applica-
tions of heteroaromatic N-oxides in oxidation reactions cat-
alyzed by transition metals, especially those that are
inexpensive and abundant, and in regioselective C–H func-
tionalizations of a broader range of heterocycles are expect-
ed to continue to enrich the chemistry of heteroaromatic N-
oxides.
5 Conclusion and Outlook
The chemistry of heteroaromatic N-oxides has experi-
enced rapid growth since 2001. The combination of a nega-
tively charged and nucleophilic oxygen and a weak nitro-
gen–oxygen bond enables these N-oxides to be used as ver-
satile nucleophilic oxidants in late-transition-metal-
catalyzed oxidation of alkynes and allenes. In the cases of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q

P
Y. Wang, L. Zhang
Review
Synthesis
Acknowledgment
(26) (a) Zhang, L. Acc. Chem. Res. 2014, 47, 877. (b) Lu, B.; Li, C.;
Zhang, L. J. Am. Chem. Soc. 2010, 132, 14070. (c) Ye, L.; He, W.;
Zhang, L. J. Am. Chem. Soc. 2010, 132, 8550. (d) Vasu, D.; Hung,
H.-H.; Bhunia, S.; Gawade, S. A.; Das, A.; Liu, R.-S. Angew. Chem.
Int. Ed. 2011, 50, 6911. (e) Hashmi, A. S. K.; Wang, T.; Shi, S.;
Rudolph, M. J. Org. Chem. 2012, 77, 7761. (f) Wang, L.; Xie, X.;
Liu, Y. Angew. Chem. Int. Ed. 2013, 52, 13302.
The authors thank ACS PRF (52040-ND1) and NSF CHE-1301343 for
financial support.
References
(27) Ji, K.; Nelson, J.; Zhang, L. Beilstein J. Org. Chem. 2013, 9, 1925.
(28) Bian, Z.; Marvin, C. C.; Martin, S. F. J. Am. Chem. Soc. 2013, 135,
10886.
(29) Kong, K.; Enquist, J. A.; McCallum, M. E.; Smith, G. M.;
Matsumaru, T.; Menhaji-Klotz, E.; Wood, J. L. J. Am. Chem. Soc.
2013, 135, 10890.
(30) Luo, Y.; Ji, K.; Li, Y.; Zhang, L. J. Am. Chem. Soc. 2012, 134, 17412.
(31) He, W.; Xie, L.; Xu, Y.; Xiang, J.; Zhang, L. Org. Biomol. Chem.
2012, 10, 3168.
(32) Lundgren, R. J.; Peters, B. D.; Alsabeh, P. G.; Stradiotto, M. Angew.
Chem. Int. Ed. 2010, 49, 4071.
(33) Bhunia, S.; Ghorpade, S.; Huple, D. B.; Liu, R.-S. Angew. Chem. Int.
Ed. 2012, 51, 2939.
(34) Henrion, G.; Chavas, T. E. J.; Le Goff, X.; Gagosz, F. Angew. Chem.
Int. Ed. 2013, 52, 6277.
(35) Huple, D. B.; Ghorpade, S.; Liu, R.-S. Chem. Eur. J. 2013, 19,
12965.
(36) Murai, M.; Kitabata, S.; Okamoto, K.; Ohe, K. Chem. Commun.
2012, 48, 7622.
(37) Liu, R.; Winston-McPherson, G. N.; Yang, Z.-Y.; Zhou, X.; Song,
W.; Guzei, I. A.; Xu, X.; Tang, W. J. Am. Chem. Soc. 2013, 135,
8201.
(38) Sawama, Y.; Takubo, M.; Mori, S.; Monguchi, Y.; Sajiki, H. Eur. J.
Org. Chem. 2011, 3361.
(39) Gronnier, C.; Kramer, S.; Odabachian, Y.; Gagosz, F. J. Am. Chem.
Soc. 2012, 134, 828.
(40) Murahashi, S. Ruthenium in Organic Synthesis; Wiley-VCH:
Weinheim, 2004.
(41) (a) Madhushaw, R. J.; Lin, M.-Y.; Sohel, S. M. A.; Liu, R.-S. J. Am.
Chem. Soc. 2004, 126, 6895. (b) Lin, M.-Y.; Madhushaw, R. J.; Liu,
R.-S. J. Org. Chem. 2004, 69, 7700. (c) Lin, M.-Y.; Maddirala, S. J.;
Liu, R.-S. Org. Lett. 2005, 7, 1745. (d) Pati, K.; Liu, R.-S. Chem.
Commun. 2009, 5233.
(42) Kim, I.; Lee, C. Angew. Chem. Int. Ed. 2013, 52, 10023.
(43) Cossío, F. P.; Arrieta, A.; Sierra, M. A. Acc. Chem. Res. 2008, 41,
925.
(1) Chanzy, H.; Maia, E.; Perez, S. Acta Crystallogr., Sect. B 1982, 38,
852.
(2) Jaffé, H. H.; Doak, G. O. J. Am. Chem. Soc. 1955, 77, 4441.
(3) Albini, A.; Pietra, S. Heterocyclic N-Oxides; CRC Press: Boca
Raton, 1991.
(4) Youssif, S. ARKIVOC 2001, (i), 242.
(5) Campeau, L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-Laperle, M.;
Villemure, E.; Sun, H.-Y.; Lasserre, S.; Guimond, N.; Lecavallier,
M.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 3291.
(6) Brougham, P.; Cooper, M. S.; Cummerson, D. A.; Heaney, H.;
Thompson, N. Synthesis 1987, 1015.
(7) Rong, D.; Phillips, V. A.; Rubio, R. S.; Ángeles Castro, M.;
Wheelhouse, R. T. Tetrahedron Lett. 2008, 49, 6933.
(8) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847.
(9) Copéret, C.; Adolfsson, H.; Khuong, T.-A. V.; Yudin, A. K.;
Sharpless, K. B. J. Org. Chem. 1998, 63, 1740.
(10) Carmeli, M.; Rozen, S. J. Org. Chem. 2005, 70, 2131.
(11) Yeom, H.-S.; Kim, S.; Shin, S. Synlett 2008, 924.
(12) Pagar, V. V.; Jadhav, A. M.; Liu, R.-S. J. Am. Chem. Soc. 2011, 133,
20728.
(13) Shi, Z.; Koester, D. C.; Boultadakis-Arapinis, M.; Glorius, F. J. Am.
Chem. Soc. 2013, 135, 12204.
(14) Lin, Y.-S.; Liu, C.-W.; Tsai, T. Y. R. Tetrahedron Lett. 2005, 46,
1859.
(15) (a) Ferguson, I. J.; Schofield, K. J. Chem. Soc., Perkin Trans. 1 1975,
275. (b) Jasiński, M.; Mlostoń, G.; Linden, A.; Heimgartner, H.
Helv. Chim. Acta 2008, 91, 1916. (c) Mlostoń, G.; Jasiński, M.;
Heimgartner, H. Eur. J. Org. Chem. 2011, 2542.
(16) Shibata, Y.; Kagechika, K.; Yamaguchi, M.; Yoshikawa, K.; Chiba,
K.; Takano, H.; Akiyama, C.; Ono, M.; Nishi, M.; Kubo, H.;
Kobayashi, Y.; Usui, H. Chem. Pharm. Bull. 2013, 61, 1248.
(17) (a) Goto, Y.; Yamazaki, M.; Hamana, M. Chem. Pharm. Bull. 1971,
19, 2050. (b) Bénardeau, A.; Benz, J.; Binggeli, A.; Blum, D.;
Boehringer, M.; Grether, U.; Hilpert, H.; Kuhn, B.; Märki, H. P.;
Meyer, M.; Püntener, K.; Raab, S.; Ruf, A.; Schlatter, D.; Mohr, P.
Bioorg. Med. Chem. Lett. 2009, 19, 2468.
(44) Kim, I.; Roh, S. W.; Lee, D. G.; Lee, C. Org. Lett. 2014, 16, 2482.
(45) Wang, Y.; Zheng, Z.; Zhang, L. Angew. Chem. Int. Ed. 2014, 53,
9572.
(18) Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic
Compounds; CRC Press: Boca Raton, 2003.
(19) Eberbach, W.; Maier, W. Tetrahedron Lett. 1989, 30, 5591.
(20) (a) Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth. Catal. 2006, 348,
2271. (b) Fürstner, A.; Davies, P. W. Angew. Chem. Int. Ed. 2007,
46, 3410. (c) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180.
(d) Jiménez-Núñez, E.; Echavarren, A. M. Chem. Rev. 2008, 108,
3326. (e) Abu Sohel, S. M.; Liu, R.-S. Chem. Soc. Rev. 2009, 38,
2269.
(21) Ye, L.; Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2010, 132,
3258.
(22) Hashmi, A. S. K. Angew. Chem. Int. Ed. 2010, 49, 5232.
(23) Hashmi, A. S. K. Gold Bull. 2003, 36, 3.
(24) Cuenca, A. B.; Montserrai, S.; Hossain, K. M.; Mancha, G.; Lledos,
A.; Medio-Simon, M.; Ujaque, G.; Asensio, G. Org. Lett. 2009, 11,
4906.
(25) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopro-
panes to Ylides; Wiley: New York, 1998.
(46) Chen, D.-F.; Han, Z.-Y.; He, Y.-P.; Yu, J.; Gong, L.-Z. Angew. Chem.
Int. Ed. 2012, 51, 12307.
(47) Graf, K.; Rühl, C. L.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K.
Angew. Chem. Int. Ed. 2013, 52, 12727.
(48) Luo, Y.; Zhang, G.; Hwang, E. S.; Wilcoxon, T. A.; Zhang, L. Beil-
stein J. Org. Chem. 2011, 7, 596.
(49) (a) Barluenga, J.; Bernad, P. L. Jr.; Concellón, J. Tetrahedron Lett.
1995, 36, 3937. (b) Barluenga, J.; Fernández-Marí, F.; González,
R.; Aguilar, E.; Revelli, G. A.; Viado, A. L.; Fañanás, F. J.; Olano, B.
Eur. J. Org. Chem. 2000, 1773. (c) Barluenga, J.; García-Rodríguez,
J.; Martínez, S.; Suárez-Sobrino, A. L.; Tomás, M. Chem. Eur. J.
2006, 12, 3201. (d) Barluenga, J.; Martínez, S.; Suárez-Sobrino, A.
L.; Tomás, M. Organometallics 2006, 25, 2337. (e) Luo, N.; Zheng,
Z.; Yu, Z. Org. Lett. 2011, 13, 3384. (f) Zheng, Z.; Chen, J.; Luo, N.;
Yu, Z.; Han, X. Organometallics 2006, 25, 5301. (g) Zheng, Z.; Yu,
Z.; Luo, N.; Han, X. J. Org. Chem. 2006, 71, 9695.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q

Q
Y. Wang, L. Zhang
Review
Synthesis
(50) (a) Alcázar, J.; Alonso, J. M.; Bartolomé, J. M.; Iturrino, L.;
Matesanz, E. Tetrahedron Lett. 2003, 44, 8983. (b) Yoo, E.; Crall,
B. M.; Balakrishna, R.; Malladi, S. S.; Fox, L. M.; Hermanson, A.
R.; David, S. A. Org. Biomol. Chem. 2013, 11, 6526. (c) De Schut-
ter, J. W.; Shaw, J.; Lin, Y.-S.; Tsantrizos, Y. S. Bioorg. Med. Chem.
2012, 20, 5583. (d) Londregan, A. T.; Jennings, S.; Wei, L. Org.
Lett. 2010, 12, 5254. (e) Yin, J.; Xiang, B.; Huffman, M. A.; Raab,
C. E.; Davies, I. W. J. Org. Chem. 2007, 72, 4554. (f) Manley, P. J.;
Bilodeau, M. T. Org. Lett. 2002, 4, 3127. (g) Chen, X.; Li, X.; Qu, Z.;
Ke, D.; Qu, L.; Duan, L.; Mai, W.; Yuan, J.; Chen, J.; Zhao, Y. Adv.
Synth. Catal. 2014, 356, 1979. (h) Couturier, M.; Caron, L.;
Tumidajski, S.; Jones, K.; White, T. D. Org. Lett. 2006, 8, 1929.
(i) Londregan, A. T.; Jennings, S.; Wei, L. Org. Lett. 2011, 13, 1840.
(j) Medley, J. W.; Movassaghi, M. J. Org. Chem. 2008, 74, 1341.
(k) Kokatla, H. P.; Yoo, E.; Salunke, D. B.; Sil, D.; Ng, C. F.;
Balakrishna, R.; Malladi, S. S.; Fox, L. M.; David, S. A. Org. Biomol.
Chem. 2013, 11, 1179. (l) Ichihara, Y.; Fujimura, R.; Tsuneki, H.;
Wada, T.; Okamoto, K.; Gouda, H.; Hirono, S.; Sugimoto, K.;
Matsuya, Y.; Sasaoka, T.; Toyooka, N. Eur. J. Med. Chem. 2013, 62,
649. (m) Farrell, R. P.; Silva Elipe, M. V.; Bartberger, M. D.;
Tedrow, J. S.; Vounatsos, F. Org. Lett. 2013, 15, 168. (n) Eskildsen,
J.; Vedsø, P.; Begtrup, M. Synthesis 2001, 1053.
(59) (a) Campeau, L.-C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 3266. (b) Campeau, L.-C.; Bertrand-Laperle, M.;
Leclerc, J.-P.; Villemure, E.; Gorelsky, S.; Fagnou, K. J. Am. Chem.
Soc. 2008, 130, 3276. (c) Campeau, L.-C.; Rousseaux, S.; Fagnou,
K. J. Am. Chem. Soc. 2005, 127, 18020. (d) Huestis, M. P.; Fagnou,
K. Org. Lett. 2009, 11, 1357. (e) Schipper, D. J.; Campeau, L.-C.;
Fagnou, K. Tetrahedron 2009, 65, 3155. (f) Sun, H.-Y.; Gorelsky, S.
I.; Stuart, D. R.; Campeau, L.-C.; Fagnou, K. J. Org. Chem. 2010, 75,
8180. (g) Tan, Y.; Barrios-Landeros, F.; Hartwig, J. F. J. Am. Chem.
Soc. 2012, 134, 3683.
(60) Xiao, B.; Liu, Z.-J.; Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 616.
(61) Wu, Z.; Song, H.; Cui, X.; Pi, C.; Du, W.; Wu, Y. Org. Lett. 2013, 15,
1270.
(62) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130,
9254.
(63) (a) Liu, W.; Li, Y.; Xu, B.; Kuang, C. Org. Lett. 2013, 15, 2342.
(b) Liu, W.; Li, Y.; Wang, Y.; Kuang, C. Org. Lett. 2013, 15, 4682.
(64) Wu, Z.; Pi, C.; Cui, X.; Bai, J.; Wu, Y. Adv. Synth. Catal. 2013, 355,
1971.
(65) Li, G.; Jia, C.; Sun, K. Org. Lett. 2013, 15, 5198.
(66) Zhu, C.; Yi, M.; Wei, D.; Chen, X.; Wu, Y.; Cui, X. Org. Lett. 2014,
16, 1840.
(51) Abramovitch, R. A.; Singer, G. M. J. Am. Chem. Soc. 1969, 91,
5672.
(67) Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Angew. Chem. Int. Ed. 2007,
46, 8872.
(52) Kellogg, R. M.; Van Bergen, T. J. J. Org. Chem. 1971, 36, 1705.
(53) Andersson, H.; Olsson, R.; Almqvist, F. Org. Biomol. Chem. 2011,
9, 337.
(54) Andersson, H.; Sainte-Luce Banchelin, T.; Das, S.; Olsson, R.;
Almqvist, F. Chem. Commun. 2010, 46, 3384.
(55) Zhang, S.; Liao, L.-Y.; Zhang, F.; Duan, X.-F. J. Org. Chem. 2013,
78, 2720.
(56) Hussain, M.; Banchelin, T. S.-L.; Andersson, H.; Olsson, R.;
Almqvist, F. Org. Lett. 2013, 15, 54.
(57) Larionov, O. V.; Stephens, D.; Mfuh, A.; Chavez, G. Org. Lett.
2014, 16, 864.
(58) Araki, Y.; Kobayashi, K.; Yonemoto, M.; Kondo, Y. Org. Biomol.
Chem. 2011, 9, 78.
(68) Chen, X.; Zhu, C.; Cui, X.; Wu, Y. Chem. Commun. 2013, 49, 6900.
(69) Shibata, T.; Matsuo, Y. Adv. Synth. Catal. 2014, 356, 1516.
(70) Hwang, H.; Kim, J.; Jeong, J.; Chang, S. J. Am. Chem. Soc. 2014,
136, 10770.
(71) Jeong, J.; Patel, P.; Hwang, H.; Chang, S. Org. Lett. 2014, 16, 4598.
(72) (a) Heaney, F.; Lawless, E.; Mahon, M.; McArdle, P.;
Cunningham, D. Org. Biomol. Chem. 2006, 4, 2408. (b) Holt, J.;
Fiksdahl, A. J. Heterocycl. Chem. 2007, 44, 375. (c) Raminelli, C.;
Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 4689. (d) Shaibu, B. S.;
Kawade, R. K.; Liu, R.-S. Org. Biomol. Chem. 2012, 10, 6834.
(e) Loska, R.; Mąkosza, M. Mendeleev Commun. 2006, 16, 161.
(f) Loska, R.; Mąkosza, M. Chem. Eur. J. 2008, 14, 2577. (g) Loska,
R.; Szachowicz, K.; Szydlik, D. Org. Lett. 2013, 15, 5706.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–Q