Mild Radical Oxidative sp3-Carbon-Hydrogen Functionalization: Innovative Construction of Isoxazoline and Dibenz[ b, f ]oxepine/azepine Derivatives

Article abstract of DOI:10.1055/s-0035-1560908

Direct carbon-hydrogen bond functionalization has emerged as a powerful synthetic method for the straightforward and modular functionalization of organic molecules. In this account, we described our latest contributions in the area of oxidative sp³-carbon-hydrogen bond functionalization using mild radical oxidants for the construction of structurally important heterocycles. We have developed two new methodologies in which a new class of substrate and an uncommon nucleophilic reagent have been introduced to the existing palette of reaction partners for oxidative carbon-hydrogen functionalization. To achieve these results, the 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO) radical and a benzoyl peroxide/copper(I) system have been employed as oxidants for the dehydrogenative one-pot synthesis of N-alkoxycarbonyl-protected isoxazolines from hydroxylamines and for the synthesis of dibenz[b,f]oxepines, dibenzo[b,f]thiepines, and dibenz[b,f]azepines from simple xanthenes, thioxanthenes, and acridanes, respectively. 1 Introduction 2 2,2,6,6-Tetramethylpiperidinyloxyl-Mediated Dehydrogenative Formation and Trapping of Unstable Nitrones: Synthesis of N-Alkoxycarbonyl-Protected Isoxazoline Derivatives 3 Oxidative sp³-Carbon-Hydrogen Bond Functionalization and Ring Expansion with Trimethylsilyldiazomethane: Synthesis of Dibenzoxepines, Dibenzothiepines, and Dibenzazepines 4 Conclusions and Outlook.

Full text of DOI:10.1055/s-0035-1560908

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 526–539
account
526
A. Gini, O. G. Mancheño
Account
Synlett
Mild Radical Oxidative sp3-Carbon–Hydrogen Functionalization:
Innovative Construction of Isoxazoline and Dibenz[b,f]oxepine/
azepine Derivatives
Andrea Ginia,b
Construction of Isoxazoline and Dibenz[b,f]oxepine/azepine Derivatives
O
O
O
R3
R3
R1
O
O
Olga García Mancheño*a,b
OH
N
R1
N
R1
N
R3
TEMPO
R2
R2
unstable
a Institute for Organic Chemistry, University of Regensburg,
Universitätsstr. 31, 93053 Regensburg, Germany
b Straubing Center of Science for Renewable Resources (WZS),
Schulgasse 16, 94315 Straubing, Germany
R2
H
R3
mild
radical
oxidant
olga.garcia-mancheno@chemie.uni-regensburg.de
H
benzoyl peroxide
TMSCHN2
ring
expansion
X
X
X
X: O, NR4
Received: 28.08.2015
Accepted after revision: 09.10.2015
Published online: 18.01.2016
direct substitution of the hydrogen atom by the desired
fragment or functional group is an attractive alternative to
the more common multistep synthetic approaches.
In the standard methodologies (Scheme 1, top), selec-
tive functionalization at a specific sp3-carbon–hydrogen
bond requires the initial installation of a common function-
al group (e.g., by halogenation or oxygenation). This pre-
installed simple unit then acts as a leaving group (LG) for
the final introduction of the desired functionality (Nu).
Thus, inevitably, stoichiometric amounts of waste (H–X and
LG–) are generated.2
Instead, a method directly involving the carbon–hydro-
gen bond provides a significant reduction of synthetic steps
and intrinsic waste owing to the absence of the sacrificial
functional group LG (Scheme 1, bottom).3 In this context,
oxidative sp3-carbon–hydrogen functionalization reactions
have become an important and valuable synthetic ap-
proach. In the last decade, practical applications of this
methodology in carbon–carbon and carbon–heteroatom
coupling reactions have relentlessly increased.4
DOI: 10.1055/s-0035-1560908; Art ID: St-2015-a0680-a
Abstract Direct carbon–hydrogen bond functionalization has
emerged as a powerful synthetic method for the straightforward and
modular functionalization of organic molecules. In this account, we de-
scribed our latest contributions in the area of oxidative sp3-carbon–hy-
drogen bond functionalization using mild radical oxidants for the con-
struction of structurally important heterocycles. We have developed
two new methodologies in which a new class of substrate and an un-
common nucleophilic reagent have been introduced to the existing pal-
ette of reaction partners for oxidative carbon–hydrogen functionaliza-
tion. To achieve these results, the 2,2,6,6-tetramethylpiperidinyloxyl
(TEMPO) radical and a benzoyl peroxide/copper(I) system have been
employed as oxidants for the dehydrogenative one-pot synthesis of
N-alkoxycarbonyl-protected isoxazolines from hydroxylamines and for
the synthesis of dibenz[b,f]oxepines, dibenzo[b,f]thiepines, and
dibenz[b,f]azepines from simple xanthenes, thioxanthenes, and acrid-
anes, respectively.
1
2
Introduction
2,2,6,6-Tetramethylpiperidinyloxyl-Mediated Dehydrogenative
Formation and Trapping of Unstable Nitrones: Synthesis of
N-Alkoxycarbonyl-Protected Isoxazoline Derivatives
Oxidative sp3-Carbon–Hydrogen Bond Functionalization and
Ring Expansion with Trimethylsilyldiazomethane: Synthesis of
Dibenzoxepines, Dibenzothiepines, and Dibenzazepines
Conclusions and Outlook
3
4
prefunctionalization pathway
LG
X
H
LG–
R3
Nu
+
R1
R2
X
LG
Key words carbon–hydrogen functionalization, oxidations, radicals,
peroxides, heterocycles
H
Nu
+
Nu
R1
R3
R1
R3
R2
R2
1 Introduction
[O]
+
Nu
R1
R3
The activation and direct functionalization of carbon–
hydrogen bonds, especially sp3-carbon–hydrogen, has al-
ways been a crucial topic in chemical synthesis.1 Carbon–
hydrogen bonds are ubiquitous in organic molecules, and a
R2
[O]H
oxidative C–H activation pathway
Scheme 1 Classical and oxidative sp3-carbon–hydrogen bond func-
tionalization approaches
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 2, 526–539

527
A. Gini, O. G. Mancheño
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However, there are some important current limitations
and unsolved issues within the above-mentioned oxidative
sp3-carbon–hydrogen bond coupling methods. Among
them, it is worth mentioning the still-restricted substrate
and reagent scope.4
typical substrates
R1
R2
N
H
H
R2
R1
R1
R
R2
H
X
N
H
O
H
X
The typical substrates enrolled present the sp3-carbon–
hydrogen bond α to functional groups (such as a nitrogen,
an oxygen, or an arene) able to stabilize the formal ionic in-
termediate and/or to an electron-withdrawing group
(EWG) to make the carbon more electrophilic (Figure 1), fa-
cilitating the oxidation step. The nucleophiles employed are
mostly restricted to enolizable carbonyl compounds, ni-
troalkanes, electron-rich aromatic compounds, (in situ gen-
erated) organometallic reagents, (activated) olefins, and
small, charged nucleophiles such as cyano and trifluoro-
methyl anions (Figure 1).
EWG
X = NAr, O
typical nucleophiles
R
EDG
O
O
O
R2
R
NO2
N
R1
R2 R1
H
enolizable pro-nucleophiles
electron-rich (het)arenes
nitroalkanes
OTMS
R
EWG
R
H
/ [TM]
CN
small charged CNu
CF3
organometallics
activated olefins
oxidants
O
Another crucial factor to achieve the desired reactivity
and selectivity on the target substrate is the choice of ap-
propriate oxidant. The classical oxidants in oxidative sp3-
carbon–hydrogen functionalization can be classified into
three big branches: oxygen,5 quinones such as DDQ (2,3-di-
chloro-5,6-dicyano-1,4-benzoquinone),6 and organic per-
oxides such as TBHP (tert-butyl hydroperoxide) or DTBP
(di-tert-butyl peroxide) (Figure 1).7
Cl
Cl
CN
O2
O
O
O
O
CN
H
O
DDQ
TBHP
DTBP
organic peroxides
(benzo)quinones
Figure 1 Most commonly used types of substrates, reagents, and oxi-
dants
Molecular oxygen is the cheapest and greenest oxidant,
but lacks reactivity and often needs a transition-metal cata-
Biographical Sketches
Andrea Gini was born in Pisa in
1987. He received his bachelor’s
degree in chemistry in 2010
from the Università degli studi
di Pisa under the supervision of
Professor Dr. Fabio Bellina. In
2013, he received his master’s
degree in organic chemistry
with magna cum laude from the
Università degli studi di Pisa un-
der the supervision of Professor
Dr. Adriano Carpita. He joined
the group of Professor Dr. Olga
García Mancheño in 2014 and
currently he is carrying out his
Ph.D. between the University of
Regensburg and the Straubing
Center of Science for Renewable
Resources. His current research
activity focuses on the develop-
ment of new carbon–hydrogen
activation methods using un-
usual oxidants and reagents,
and their application in the syn-
thesis of highly valuable hetero-
cycles.
Olga García Mancheño re-
ceived her Ph.D. in 2005 from
the Universidad Autónoma de
Madrid under the supervision of
Professor Juan C. Carretero.
During her Ph.D., she also car-
ried out two three-month re-
search stays with Professor
Manfred T. Reetz (Max-Planck-
Institut für Kohlenforschung)
and Professor Karl Anker Jør-
gensen (University of Aarhus).
She next carried out a postdoc-
toral stay in the group of Profes-
sor Carsten Bolm at RWTH-
at the University of Regensburg
and the Straubing Center of Sci-
ence for Renewable Resources.
Her main research interests in-
clude the development of new
synthetic methods, with a spe-
cial focus on catalytic approach-
es, and their application in the
synthesis of bioactive com-
pounds and heterocycles.
Aachen
University
(2005–
2008). At the end of 2008, she
started her independent career
as an assistant professor (Habil-
itand, mentor: Professor Frank
Glorius) at the Westfälische Wil-
helms University of Münster. In
2013, she was appointed as a
professor of organic chemistry
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A. Gini, O. G. Mancheño
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lyst as an intermediate oxidant. However, when the metal
catalyst is nontoxic and cheap, such as iron (or copper), the
use of molecular oxygen as a terminal oxidant can be very
appealing.
As an alternative, DDQ and the other reactive benzoqui-
nones are widely employed as active species or secondary
oxidants in dehydrogenative cross-coupling reactions.6
However, the higher reactivity of DDQ with respect to oxy-
gen and the nucleophilic behavior of the generated reduced
hydroquinone form give some problems with sensitive sub-
strates. In addition, the toxicity of benzoquinones discour-
ages their use in large-scale applications.
N-alkyl-substituted anilines14,15 were developed in our lab-
oratory. Despite the excellent results already obtained with
this ‘new generation’ of oxidants, to extend further the
scope of mild oxidative carbon–hydrogen functionalization,
fine-tuned specific oxidation systems are still required.
R4
R2
O
X
R3
R1
R2
H
R1O2C
CO2R1
n = 0,1
O
CO2R1
CO2R1
H
R
R3
R1
R
X
Lastly, organic peroxides, such as TBHP,7 are the most
prominent oxidants in this type of carbon–hydrogen func-
tionalization. Conversely, they might be considered the last
choice because of their strong reactivity and therefore, in
many cases, low selectivity.8 As a result, the identification
of new oxidation systems able to cover the deficiencies of
the above-mentioned classical oxidants is crucial for future
advances in the research area of oxidative carbon–hydrogen
functionalization.
O
Ar
n = 0,1
R2
N
O
R
X
H
Y
Y
X = NR, O
Ar
TEMPO
N
O
or
H
or
H
R4
R3
R2
R = H, NHAc
Y = BF4, etc
O
R1
N
EWG
Ar
R1
EWG
N
R2 R3
Ar
R1
H
R2
In our research program on carbon–hydrogen bond
functionalization, we address the challenge of designing in-
novative transformations, aiming at the development of
novel, mild oxidative reactions for the synthesis of valuable
(bioactive) heterocycles. Since the first synthesis of the per-
sistent 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO) radical
by Lebedev and Kazarnovskii9 in 1959, the versatility of this
oxidative agent has been extensively demonstrated, both as
the N-oxyl radical and as its N-oxoammonium salt deriva-
tives (TEMPO+ Y–).10 The oxidized form TEMPO+ Y–, in par-
ticular, presents unexplored potential as a valuable oxidant
in sp3-carbon–hydrogen functionalization. In fact, TEMPO
salts are nontoxic and milder than typical organic peroxides
or DDQ, probably the most used oxidants in oxidative sp3-
carbon–hydrogen functionalization.
In the last few years, our group has been dedicated to
exploring further novel and valuable applications of this
type of oxidant in dehydrogenative-type coupling reactions
with sp3-carbon–hydrogen bonds (Scheme 2).11–15 We
found that the tetrafluoroborate salt TEMPO+ BF4– (R = H) or
its related 4-acetamido derivative (R = NHAc) were able to
easily activate isochromanes and tetrahydroisoquinolines
by oxidation of the benzylic carbon–hydrogen bond α to the
oxygen or nitrogen, respectively. The corresponding ionic
intermediates were then able to react with enolizable pro-
nucleophiles, such as malonates,11 ketones, or aldehydes,12
in the presence of a catalytic amount of an iron or copper
Lewis acid species.
N
EWG
Ar
N
EWG
R2
R3
R
N
EWG
R1
Scheme 2 Our previous achievements in oxidative sp3-carbon–hydro-
gen functionalization with TEMPO+ Y– oxidants
Our goal is to contribute to the development of more
general and applicable oxidative carbon–hydrogen func-
tionalization reactions by targeting the use of unexplored
novel sensitive substrates and uncommon nucleophilic re-
agents that do not tolerate or react with the classical oxi-
dants, but will lead to important types of heterocyclic
structures. Following this aim, we initially focused our at-
tention on two different targets: (1) the in-situ formation
and trapping of unstable N-alkoxycarbonyl-substituted ni-
trones from the corresponding hydroxylamines16 and (2)
the use of trimethylsilyldiazomethane (TMSCHN2) as an un-
usual reagent in oxidative carbon–hydrogen functionaliza-
tion (Scheme 3).17
We found that in the first case the normal oxidants
were too strong, leading to overoxidation and/or decompo-
sition of both the substrate and the product, whereas sim-
ple TEMPO could be employed as a selective, mild radical
oxidant. On the other hand, the reaction of xanthene and
acridane derivatives with TMSCHN2 required a more po-
tent, but finely adjusted copper(I)/benzoyl peroxide oxida-
tion system to promote a carbon–hydrogen functionaliza-
tion/ring-expansion reaction.
More interestingly, this type of oxidant also permitted
the more challenging enrolment of simple, nonactivated,
substituted olefins as reagent partners (Scheme 2). Thus,
several oxidative carbon–hydrogen functionalization/cy-
clization tandem reactions with benzylic carbamates13 and
In this account, these two recent contributions will be
presented, including our original objectives, surprises,
problems encountered, and achievements.
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A. Gini, O. G. Mancheño
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kyl- and N-aryl-substituted nitrones (Figure 2, left).20 This
leads to isoxazolines where the protecting group is difficult
to cleave or, in the worst case, it is irremovable.21 Therefore,
the synthetic scope for further applications embracing
these methodologies is significantly restricted.
However, nitrones bearing removable electron-with-
drawing groups, such N-acyl and N-alkoxycarbonyl moi-
eties, are very attractive. Unfortunately, these dipole spe-
cies are difficult to isolate and handle owing to their intrin-
sic instability. Only a few examples of 1,3-DCs as efficient
methods to synthesize N-alkoxycarbonyl-protected isoxaz-
olines have been reported in which the corresponding un-
stable nitrone intermediates are formed in situ.22,23 Howev-
er, the employed hydroxylamines must have a good leaving
group, such as a sulfonyl, at the α-position to the nitrogen
which can be removed under mild basic conditions
(Scheme 4, top).22a,b
O
R1
O
N
R3
R2
R3
R3
O
R3
OH
R1
N
O
R2
H
O
R1
N
TEMPO
R2
mild
radical
oxidant
unstable
benzoyl peroxide
H
X
ring
expansion
X
TMSCHN2
X = O, NR
Alternatively, the procedures to directly synthesize
N-protected nitrones lacking functionalization at the α-po-
sition from simple hydroxylamines generally involve con-
densation of an N-protected hydroxylamine with an alde-
hyde.20,24 Nonetheless, the low nucleophilicity of the carba-
moyl nitrogen means strong basic or acidic conditions are
required to form the nitrone upon releasing an equivalent
of water. Thus, the medium is not suitable for the cycliza-
tion process and the stability of the nitrone is compro-
mised.22,23 To solve this synthetic issue, we proposed an ‘ox-
idative dehydrogenative’ approach under mild conditions.
The key strategy here was to find the right oxidant able to
oxidize selectively the N-protected hydroxylamine without
decomposing the in situ formed nitrone and allowing at the
same time the subsequent cycloaddition reaction (Scheme
4, bottom).16
X
Scheme 3 Novel contributions with uncommon substrates and re-
agents
2 2,2,6,6-Tetramethylpiperidinyloxyl-Medi-
ated Dehydrogenative Formation and Trap-
ping of Unstable Nitrones: Synthesis of N-
Alkoxycarbonyl-Protected Isoxazoline Deriva-
tives
Among the five-membered heterocycles, 4-isoxazolines
(2,3-dihydroisoxazoles)18 constitute a privileged structure
owing to their interesting biological activities as well as
their wide applicability as building blocks for the prepara-
tion of several different functional groups (Figure 2).19
LG approach
LG = SO2Ph
R3
additive = base
β-amino acids
1,3-amino alcohols
O
O
R1
N
R4
R4
R3
R1
R2
O
R1
R2
stable
nitrone
O
R2
N
R4
N
+
O
R3
O
R3
R3
R1
O
N
OH
LG
R3
R1
N
additive
– LG
+
R1 = alkyl, aryl
R2
β-lactams
R2
aziridines
R4
bioactive
and
natural compounds
O
O
R3
R4
R1
N
Figure 2 Versatility of 4-isoxazolines as building blocks and bioactive
units
R2
LG = [H]
additive = oxidant
Several methods for the preparation of isoxazolines and
isoxazolidines have already been described. They are main-
ly based on the 1,3-dipolar cycloaddition reaction (1,3-DC)
between isolated, stable nitrones and a dipolarophile. How-
ever, these methodologies are essentially restricted to N-al-
dehydrogenative
approach
Scheme 4 Approaches for the in-situ generation and trapping of N-acyl-
and N-alkoxycarbonyl-protected nitrones
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A. Gini, O. G. Mancheño
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Based on our experience of mild oxidative carbon–hy-
drogen functionalization, several oxidants were tested us-
ing the model reaction between N-benzyl-N-(tert-butoxy-
carbonyl)hydroxylamine (1a) and dimethyl acetylenedicar-
boxylate (DMAD, 2a) as the dipolarophile at room
temperature (Table 1). We first explored TEMPO+ BF4– as the
oxidant (entry 1)11,15 which has shown large flexibility in
several dehydrogenative cross-coupling reactions. However,
with this type of substrate it did not provide the desired
product. Other typical oxidants in dehydrogenative cross-
coupling reactions, such as TBHP and DDQ, were employed,
however without any success (entries 2 and 3, respectively).
It is interesting to note that all of these oxidants led to full
conversion of hydroxylamine 1a. This might indicate that
these reagents may be capable of the oxidation of 1a, but
not be compatible with the in situ formed nitrones.
ing in carbamate derivatives, such as ethyl carbamate 3b
(84% yield) and benzyl carbamate 3c (40% yield), were also
well tolerated (Scheme 5). However, the sterically hindered
2,2,2-trichloroethoxycarbonyl (Troc) group led to a very
low yield of product 3d (21% yield) and there were high de-
composition levels under these reaction conditions.
Considering the high efficiency of the Boc protecting
group, a broad variety of N-Boc-protected substituted
N-benzylhydroxylamines were tested next (Scheme 5).
The reaction showed a broad scope, tolerating well elec-
tron-withdrawing, electron-donating, and halogen para
substituents on the phenyl ring (63–84% yield). A more ste-
rically demanding substrate such as an ortho-substituted N-
benzylhydroxylamine also participated in the reaction, but
the final isoxazoline was obtained in lower yield (e.g., 3i,
43% yield). More interestingly, simple aliphatic and allyl-
substituted hydroxylamines were also able to react under
these conditions to form the desired products 3 in moder-
ate to high yields (up to 74% yield). These are very appealing
results, since in most of the previous reports on the in-situ
generation and further use of this type of N-protected ni-
trone only the benzylic or only the aliphatic substrates
were reactive.
Therefore, we next explored the possibility of employ-
ing a milder radical oxidant, since soft, nonradical condi-
tions (e.g., with TEMPO+ BF4 as a hydride-abstractor-type
–
oxidant) were unsatisfactory. Thus, the TEMPO radical was
chosen, although it is not a common oxidant in oxidative
carbon–hydrogen functionalization.10a–d Gratifyingly, TEMPO
provided a promising 25% yield at room temperature (entry
4). To improve the conversion the temperature was in-
creased, leading to full conversion at 70 °C and good yield
(87% yield) (entry 6).
R2
O
R2
OH
N
TEMPO (2 equiv)
MeO2C CO2Me
N
CO2Me
R1
R1
H
2a (4 equiv)
CO2Me
Table 1 Optimization of the Model Reactiona
1 (0.25 mmol)
0.125 M CH2Cl2, 70 °C, 24 h
3
O
R
1 = Ph
Boc
O
Boc
Ph
OH
H
Cbz
oxidant
N
O
O
EtO
N
N
N
CO2Me
CO2Me
CO2Me
MeO2C
CO2Me
Ph
Ph
Ph
2a
CO2Me
3c
3b
1a
3a
CO2Me
CO2Me
84%
40%
Entry
Oxidant (equiv)
Solvent
Temp (°C)
Yieldb (%)
Pv
Ph
Troc
Ph
O
O
N
N
CO2Me
CO2Me
1
2
3
4
5
6
TEMPO+ BF4– (2)
TBHP (2)
CH2Cl2
neat
r.t.
r.t.
r.t.
r.t.
50
70
<5
–
3d
3e
CO2Me
CO2Me
17%
21%
DDQ (2)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
<5
25
75
87
R2 = Boc
TEMPO (2)
TEMPO (2)
TEMPO (2)
Boc
Boc
O
N
O
N
CO2Me
CO2Me
CO2Me
CO2Me
3g
3f
63%
a 1a (0.25 mmol, 1 equiv), 2a (4 equiv), and oxidant in 0.125 M CH2Cl2 at
the corresponding temperature for 24 h.
b Isolated yields.
84%
MeO
F3C
Boc
Boc
O
O
N
N
CO2Me
CO2Me
Having this promising result in hand, the scope of the
reaction with DMAD (2a) was extended to several different-
ly substituted nitrones (Scheme 5). Initially, the effect of
various acyl and alkoxycarbonyl nitrogen-protecting
groups on N-benzylhydroxylamine was investigated. The
N-Boc group (N-tert-butoxycarbonyl) showed a substantial-
ly better performance compared with the related acyl group
N-pivaloyl (3a vs 3e, 87 vs 17% yield, respectively) (Table 1,
entry 6, and Scheme 5). Furthermore, other groups result-
CO2Me
CO2Me
3h
3i
OMe
Br
80%
43%
Boc
Boc
Boc
O
O
O
N
N
N
CO2Me
CO2Me
CO2Me
CO2Me
3j
74%
3k
50%
CO2Me
CO2Me
3l
50%
Scheme 5 Scope of the reaction with different hydroxylamines
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A. Gini, O. G. Mancheño
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Various dipolarophiles were next investigated (Scheme
6). The reaction was not affected by the use of differently
substituted acetylenedicarboxylate esters, such as the di-
ethyl and di-tert-butyl derivatives giving 3m and 3n, re-
spectively. However, it was found that the dipolarophile
needed to have two electron-withdrawing groups to pro-
mote an efficient 1,3-DC, e.g. no reaction was observed to
give products 3o, 3p, and 3q. Additionally, the formation of
byproducts 4a–c, TEMPO–dipolarophile adducts,25 in al-
most stoichiometric amounts was found when using the
corresponding acetylenedicarboxylate esters as dipolaro-
philes.
The importance of this byproduct was recognized the
first time during the screening of the different dipolaro-
philes. Thus, when this methodology was applied to oth-
er classes of typical dipolarophiles, such as N-phenyl-
and N-methylmaleimide to give 3r and 3s, respectively, sig-
nificant low conversions were observed and the addition
byproduct was not detected. This can be explained by the
better Michael acceptor nature of the acetylenedicarboxyl-
ate esters compared with maleimides, although maleimides
are generally considered more efficient dipolarophile part-
ners in 1,3-DCs.
Based on these observations, we envisioned an im-
provement of the conversion with the less-reactive ma-
leimides by making use of the formation of byproduct 4a
using cheap DMAD (2a) as a co-reagent (Scheme 7). Thus,
by adding 2a as a sacrificial reagent in the reactions involv-
ing maleimides 2b and 2c, the yields of 3r and 3s increased
up to approximately 10 or 2 times, respectively. It is inter-
esting to note that the cycloaddition took place mostly on
the maleimide, with only traces of the product with 2a be-
ing formed (3a, <2–5% yield) along with byproduct 4a in
stoichiometric amounts. Unfortunately, other less-electron-
deficient dipolarophiles, such as styrenes or vinyl ethers,
did not provide the desired products, despite the presence
of the sacrificial DMAD (2a) and the full consumption of hy-
droxylamine 1a.
O
Boc
with 2a
(2 equiv)
O
N
O
H
N
+
1a
N
Ph
+
Ph
O
N
(1 equiv)
TEMPO
(2 equiv)
CH2Cl2
CO2Me
CO2Me
Ph
O
2b
O
3r
44%
(3a, 5%)
4a
80%
70 °C, 96 h
Boc
Ph
O
with 2a
(2 equiv)
O
N
O
H
N
+
R
+
1a
N
Me
Boc
Ph
OH
H
O
N
Boc
Ph
TEMPO
(2 equiv)
CH2Cl2
(1 equiv)
CO2Me
CO2Me
O
N
TEMPO (2 equiv)
Me
N
4
+
R
O
O
0.125 M CH2Cl2, 70 °C, 24 h
2c
3s
50%
4a
95%
R
70 °C, 96 h
R
1a
2
3
(3a, <2%)
Boc
O
H
CO2Me
CO2Me
N
O
CO2Me
+
TEMPO
(2 equiv)
Bn
Ph
Bn
Ph
OH
H
O
N
N
O
Ph
TEMPO
N-Me
+
4a
4b
4c
CO2Me
3a
84%
CH2Cl2, r.t., 48 h
78%
N
O
2c
Me
1b
3t
O
Boc
Ph
O
H
CO2Et
CO2Et
N
Scheme 7 Enrollment of maleimides: dimethyl acetylenedicarboxylate
as a cheap sacrificial reagent
CO2Et
+
+
TEMPO
CO2Et
3m
84%
In contrast, the reaction conducted with N,N-dibenzyl-
hydroxylamine (1b) and maleimide 2b under standard con-
ditions proceeded smoothly at room temperature providing
the corresponding isoxazoline derivative in good yield (78%
yield) (Scheme 7). It could be assumed then that the TEMPO
radical can react easily for the formation of stable nitrones,
like the N-benzyl derivative. Conversely, with unstable tar-
get molecules, the decomposition might be faster than the
further reaction of those nitrones. Thus, to explain the good
results obtained with the N-Boc-protected substrates, we
envisioned that a transitory species and/or a more efficient
radical intermediate would be involved. This radical species
might be the first radical addition product between TEMPO
and alkyne 2a (intermediate E, Scheme 8). This hypothesis
was made based on a similar radical intermediate in a radi-
cal 5-exo-dig cyclization postulated by König and Schreiner
and co-workers.26
Boc
Ph
O
H
CO2t-Bu
CO2t-Bu
N
CO2t-Bu
TEMPO
3n CO2t-Bu
52%
Boc
Boc
Boc
Ph
O
O
O
N
N
N
Ph
Ph
Ph
Ph
3p
3q
CO2Et
3o
Ph
no reaction, 96 h
no reaction, 96 h
no reaction, 96 h
Boc
O
Boc
O
N
N
O
O
Ph
Ph
N
N
3s
3r
Ph
Me
O
O
<5%, 96 h
22%, 96 h
Scheme 6 Scope of the reaction with different dipolarophiles
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532
A. Gini, O. G. Mancheño
Account
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of the unstable N-alkoxycarbonyl-protected nitroxides A.
That could be a possible explanation for the lower perfor-
mance with those substrates in the absence of DMAD (2a).
The course of the model reaction was followed by gas
chromatography with a flame ionization detector during
the first 7 hours (Figure 3). It was observed that hydroxyl-
amine 1a was rapidly consumed, even though the cycload-
dition product arose comparably slowly. At the same time,
almost two equivalents of 2a were consumed, while the
TEMPO addition byproduct 4a formed at a similar rate. Fur-
thermore, the nitrones could not be detected in any of the
analysis conducted. Most probably the cycloaddition is a
faster step of the process in comparison with the nitrone
formation. Thus, it can be assumed that the nitrones would
be consumed immediately after being generated. Since 1a
reacted comparably faster than the formation of 3a, the
rate-determining step of the reaction should take place af-
ter the formation of the first radical intermediate.
CO2Me
2a
Boc
O
Boc
Ph
O
N
N
CO2Me
+
Ph
D
3a
CO2Me
CO2Me
Boc
Ph
O
Ph
Boc
Ph
O
N
N
+
A
N
Boc
O
H
C
B
Boc
Ph
O
Boc
OH
N
disproportionation
via single-electron transfer
+ deprotonation
N
H
A
Ph
H
1a
CO2Me
2a
CO2Me
+
2a
+
N
N
CO2Me
CO2Me
O
T
OH
TOH
H
CO2Me
CO2Me
CO2Me
4a
E
CO2Me
TEMPO
TEMPO
Scheme 8 The proposed mechanism
To further describe this curious behavior, a control reac-
tion between TEMPO and 2a in the absence of an N-pro-
tected hydroxylamine was conducted, but did not take
place. On the other hand, the reaction with 2a at 0 °C was
incredibly fast using 2,2,6,6-tetramethylpiperidin-1-ol
(TEMPOH), leading to near-quantitative yield of addition
product 4a (Scheme 9).27
Figure 3 Kinetic study of the model reaction
H
OH
N
CO2Me
CO2Me
CO2Me
CH2Cl2
O
+
0 °C
5 min
With all this information, a plausible mechanism was
proposed (Scheme 8). First, a hydrogen radical is removed
from the hydroxylamine by TEMPO or the DMAD–TEMPO
adduct to form nitroxide A. Unfortunately, neither of these
two pathways, i.e. (1) direct hydrogen radical abstraction
by TEMPO or (2) radical addition to the dipolarophile and
subsequent hydrogen radical abstraction from the hydrox-
ylamine, can be excluded. The formed radical A then dispro-
portionates to anion B and oxoammonium species C via a
single-electron transfer process. This is followed by depro-
tonation of C by B to give nitrone D and the substrate hy-
droxylamine 1a. Finally, cycloaddition between nitrone D
and the dipolarophile takes place to form the desired prod-
uct.
To reinforce all of these assumptions, density functional
theory (DFT) calculations were performed on the reaction
pathway (Figure 4).28 We were especially interested in
studying the energetic differences between the two radical
pathways involved in the formation of nitroxide A, byprod-
uct 4a, and nitrone D.
N
CO2Me
2a
(1 equiv)
4a
>99%
Scheme 9 Addition of 2,2,6,6-tetramethylpiperidin-1-ol to the elec-
tron-poor Michael acceptor dimethyl acetylenedicarboxylate
Considering that the radical addition of TEMPO to
DMAD (2a) is not a commonly reported easy process, a sec-
ond hypothesis was then postulated: since the reduced
form of the oxidant TEMPOH is a reactive nucleophilic spe-
cies in the presence of Michael acceptors, a direct hydrogen
radical abstraction from 1a by TEMPO to form nitroxide in-
termediate A and TEMPOH might also be feasible (Scheme
8). With poor Michael acceptor molecules, such as ethyl
methylacetylenecarboxylate or diphenylacetylene that
would have produced 3o and 3p, respectively (see Scheme
6), the conjugate addition seems to be inefficient and the
presence of free TEMPOH might assist in the decomposition
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533
A. Gini, O. G. Mancheño
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Hrel
(kcal/mol)
Hrel
(kcal/mol)
O
TOH, 2a,
E, 1a
23.0
R1
A
R2
19.8
∗
TS
4.4
R2
NO2
EWG
EWG
a)
D, 2a
0.0
b)
O
0.0
T, 2a,
1a
catalyst
O
N
R1
O
EWG
EWG
4a, A
-65.2
3a
-51.9
R1
EWG =
CO2R, CN
R2
D, 1a
-84.4
formation of D and 4a
R2
NO2
cycloaddition
disproportionation
H
X
C-9
Figure 4 Density functional theory computational studies (B2PLYP-
EDG
d3/TZVP//BP86-d3/TZVP) of the reaction pathways
X
X
R2
X = O, NR1
EDG
The DFT calculations confirmed the difficulty in exclud-
ing one of the two possible endothermic routes, a and b,
owing to the small difference between the relative enthalp-
ies of the two pathways (Figure 4). Moreover no transition
states could be found for the formation of radicals A and E.
The DFT calculations also indicated that the disproportion-
ation of A is an exothermic process. In addition, the final
cycloaddition presented a low activation barrier of around
4.4 kcal/mol. Therefore, the 1,3-DC step should be fast
enough to rapidly consume the nitrone and keep its con-
centration low during the reaction. This supports the lack of
detection of nitrone D, upholding the kinetic studies. More-
over, the rate-determining step is likely to be one involved
in the formation of the intermediate nitroxide A or nitrone
D, and not the relatively favorable cycloaddition step.
+ oxidant
R2
t-BuOOH
DDQ
TfOH or MsOH
O2
TEMPO / O2
etc...
N
R1
/
O
EDG = electron-donating group
Scheme 10 Oxidative carbon–hydrogen bond functionalization of
xanthenes and acridanes
classical alkylating agents, 9-alkyl-substituted compounds
are especially difficult to obtain and multistep approaches
are usually required.33 Thus, milder and more affordable al-
kylating nucleophilic agents are generally not suitable un-
der the typical oxidative conditions used in this class of car-
bon–hydrogen bond functionalization. As a result, it is still
very challenging to find a compromise for the reactivity be-
tween the oxidant and the nucleophilic species.34
We decided to tackle this problem by investigating, for
the first time, the use of the less-explosive and -toxic ver-
sion of diazomethane, TMSCHN2, as a methylating or meth-
ylenating reagent in the carbon–hydrogen functionalization
of xanthene (5a) (Scheme 11).35,36
3 Oxidative sp3-Carbon–Hydrogen Bond
Functionalization and Ring Expansion with
Trimethylsilyldiazomethane: Synthesis of
Dibenzoxepines, Dibenzothiepines, and
Dibenzazepines
Oxidative cleavage of the carbon–hydrogen bond at C-9
of xanthene and acridane derivatives is an easy way to acti-
vate this position for cross-coupling reactions.29 This car-
bon–hydrogen bond is quite weak (bond-dissociation ener-
gy of around 75 kcal/mol) and, consequently, the oxidation
may be promoted with a wide spectrum of oxidants.30 De-
spite the easy carbon–hydrogen bond cleavage in those sub-
strates, the scope of the coupling reaction shown in Scheme
10 is still considerably limited by the nature of the nucleo-
phile.31
H
H
H
H
H
H
C
C
C-9
TMSCHN2
oxidant
or
[Cu] cat.
O
O
6a
O
7a
– [N2]/– [OxH]
5a
possible known oxidant–diazo reagent incompatibility
O
N2
oxidant = O2, H2O2
TBHP, mCPBA, etc.
+
oxidant
R1
R2
R1
R2
- [N2]
Many examples of the oxidative carbon–hydrogen func-
tionalization of xanthenes and acridanes using enolizable
nucleophiles, such as carbonyls or nitroalkanes, have been
reported. However, in order to introduce different types of
substituents at the C-9 position, such as alkyl or electron-
poor aryl groups, in most cases it is necessary to use a Gri-
gnard or an organoboron reagent.32 Owing to functional
group incompatibilities based on the intrinsic reactivity of
Scheme 11 Our initial oxidative carbon–hydrogen methylation/meth-
ylenation approach and possible undesired reaction
The TMSCHN2 reagent presents various attractive ad-
vantages over the less-benign and ‘explosive’ diazomethane
while conserving the carbene reactivity. It has (1) a lower
reactivity than diazomethane,37 (2) a higher selectivity
compared with classical methylating agents,38 and (3) a sec-
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534
A. Gini, O. G. Mancheño
Account
Synlett
ond good leaving group, trimethylsilyl (TMS), that can be
eliminated or promote further transformations. Having in
mind the development of a new methylation or methylena-
tion methodology, the use of a copper catalyst was initially
explored to promote the formation of a reactive copper–
carbene complex.39,40 Thus, various oxidants were tested
with xanthene (5a) and TMSCHN2 in the presence of cop-
per(II) triflate, which is reduced in situ by the diazo com-
Therefore, the expansion of the inner ring took place in-
stead of a simple nucleophilic addition to a postulated car-
bocation intermediate followed by TMS cleavage.
Although this result deviated from our initial targeted
transformation, this synthetic approach to form dibenzox-
epines that we had casually found was really appealing.
These molecules are an important class of bioactive com-
pounds42 that lack literature-reported easy and fast syn-
thetic methods for their preparation. The classical synthesis
of dibenzoxepine, dibenzothiepine, and dibenzazepines
from xanthene, thioxanthene, and acridanes, respectively,
involves multistep processes to functionalize the benzylic
position and introduce a CH2LG unit (Scheme 12).43 Fur-
thermore, harsh heating and acidic conditions are then re-
quired to promote the elimination of the incorporated LG
and subsequent Wagner–Meerwein-type rearrangement to
obtain the desired product.43
The newly discovered synthetic procedure, however,
needed some improvement to make it synthetically appli-
cable. A better performing oxidant, strong enough to acti-
vate the substrate, but at the same time mild enough to
avoid the complete decomposition of TMSCHN2, was re-
quired. Benzoyl peroxide was therefore tried as nonprotic,
mild, stable organic peroxide. To avoid the thermal break of
pound to copper(I) (Table 2).40
–
As expected, the typical oxidants TBHP, TEMPO+ BF4
,
and DDQ were inefficient (entries 2–4, respectively), most
probably because they more readily oxidize TMSCHN2 than
the substrate. Nevertheless, DDQ slightly promoted the re-
action, leading to 7% yield of a new product (entry 4). How-
ever, the product was something unexpected. Initially, we
assumed two possibilities involving in situ TMS group elim-
ination to give methylation product 6a or, with standard
copper–carbene chemistry, methylenation product 7a.
Mass spectrometry and NMR spectroscopic analysis con-
firmed the TMS elimination and the major product seemed
to be 7a. However, the NMR spectra were not in concor-
dance with those reported in literature.41 This led us to car-
ry out a more accurate examination by X-ray analysis of this
new product which showed that it was dibenzoxepine (8a).
Table 2 Optimization of the Reaction with Xanthene (5a)a
Entry
Catalyst
Oxidant (equiv)
Solvent
Ligand
Yieldb (%)
1
2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
FeCl3
-
MeCN
neat
–
–
TBHP (1.2)
–
trace
trace
7
3
TEMPO+ BF4–(1.2)
DDQ (1.2)
MeCN
MeCN
MeCN
CH2Cl2
MeCN
CH2Cl2
MeCN
MeCN
MeCN
MeCN
–
4
–
5
(PhCO2)2 (1.2)
(PhCO2)2 (1.2)
(PhCO2)2 (1.2)
(PhCO2)2 (1.2)
(PhCO2)2 (1.2)
(PhCO2)2 (1.2)
(PhCO2)2 (1.2)
(PhCO2)2 (1.2)
–
29
9
6
–
7
–
12
24
15
19
44
55
8
FeCl3
–
9
NiCl2
–
10
11
12
RhCl3
–
Cu(OTf)2
Cu(OTf)2
1,10-phenanthroline
2,2′-bipyridine
a 5a (0.20 mmol), TMSCHN2 (0.48 mmol), oxidant, catalyst (10 mol%), and ligand in MeCN or CH2Cl2 (2.0 mL) at r.t. for 18 h under an argon atmosphere.
b Isolated yields.
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535
A. Gini, O. G. Mancheño
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a mixture of two dibenzazepines. Accordingly, in some cas-
es the use of 1.1 equivalents of potassium fluoride (KF) pro-
vided higher yields of the desired product 8. The presence
of KF might help in the removal of the TMS group, especial-
ly for substrates where the elimination of this group is slow.
Fortunately, the elimination problem was only observed in
the case of acridanes with electron-withdrawing groups,
such as that containing fluorine, providing 8j along with the
corresponding TMS-containing dibenzazepine as an insepa-
rable mixture.
LG
X
X
X = O, S, NR
Δ, strong acid
LG
X
– H
– LG
X
Finally, thioxanthene also reacted to give 8m in moder-
ate yield, despite the possible poisoning of the catalysts by
coordination with the sulfur group.
Scheme 12 Dibenzoxepine, dibenzothiepine, and dibenzazepine syn-
thesis by a multistep approach involving a Wagner–Meerwein-type re-
arrangement
It is important to mention that a critical issue in this
transformation is the presence of water. Even traces in the
catalyst, wet reagents and/or solvent can hinder the reac-
tion, leading almost exclusively to 9-oxo compounds in sig-
nificant amounts.
Based on all our experimental observations, a reaction
mechanism was postulated (Scheme 14). The exact role of
the metal catalyst is still not fully understood, however we
have excluded a carbene intermediate since similar results
the peroxide oxygen–oxygen bond, a metal catalyst such
as copper(I), generated in situ from copper(II) triflate and
TMSCHN2, was employed to allow the reductive homolytic
cleavage at room temperature.44 Thus, a very promising 29%
yield of ring-expansion product 8a was obtained (Table 2,
entry 5).
Other solvents and transition-metal catalysts were next
tested (entries 6–10). Among these catalysts, iron(III) chlo-
ride gave a similar result to copper(II) triflate on changing
the solvent to dichloromethane (entry 8). Based on the
most encouraging result with Cu(OTf)2 and benzoyl perox-
ide (entry 5), we next attempted to stabilize the copper cat-
alyst in solution under the oxidative reaction conditions. To
improve the performance of the catalyst, available, cheap,
and simple N,N-bidentate ligands 1,10-phenanthroline and
2,2′-bipyridine were used (entries 11 and 12, respectively).
The best result was obtained with 2,2′-bipyridine, leading
to 8a in 55% yield (entry 12). This methodology was then
extended to differently substituted xanthenes and acrid-
anes, as well as the less-reactive sulfur-derivative thioxan-
thene (Scheme 13).
R
Cu(OTf)2 (10 mol%)
2,2'-bypiridine (30 mol%)
TMSCHN2 (2.4 equiv)
R
X
(PhCO2)2 (1.2 equiv)
MeCN (2.0 mL), r.t., 18 h
X
5 0.2 mmol
8
OMe
F
O
O
O
8b
8c
8d
48%
40%
46%
Xanthenes provided dibenzoxepines in moderate to rea-
sonably good yields (40–55%), whereas N-aryl- and N-alkyl-
substituted acridanes led to dibenzazepines in typically
higher yields (58–75%).45 Interestingly, N-Boc-protected
acridane also participated in this reaction, providing a
dibenzazepine with an easily removable protecting group
(8e, 41% yield). Both electron-withdrawing and -donating
substituents on the aromatic rings of N-methylacridanes
were well tolerated, providing 8i–k in generally good yields.
It is interesting to note that in the carbon–hydrogen
functionalization of N-benzyl-protected acridane, complete
C-9 selectivity was achieved, resulting in 8f. Thus, no prod-
uct of the reaction at the benzylic position of the protecting
group was observed. On the other hand, substitution at the
C-9 position was not tolerated, leading to no reaction (e.g.,
8l was not observed).
N
N
N
Ph
Boc
Bn
8e
41%
8f
58%
8g
75%
OMe
F
N
N
N
Me
Me
8i
74% [in KF (1.1 equiv)] 68% [in KF (1.1 equiv)]
Me
8h
74%
8j
N
N
S
Me
Me
8k
8l
8m
36%
no reaction
55% [in KF (1.1 equiv)]
An interesting point to mention is the potential compet-
itive elimination between the TMS group and a proton for
the final formation of the double bond which would lead to
Scheme 13 Scope of the reaction with differently substituted xanthe-
nes, thioxanthene, and acridanes
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536
A. Gini, O. G. Mancheño
Account
Synlett
were obtained with different transition metals, including
well-known and more efficient carbene precursors.
moted by the elimination of nitrogen. Ring expansion and
restoration of aromaticity leads to carbocationic species K,
which provides the final product by subsequent elimination
of the silyl group with the assistance of the in situ generat-
ed phenyl carboxylate. This was supported by the formation
of trimethylsilyl benzoate, the presence of which was con-
firmed by NMR spectroscopic analysis.
Lastly, to gain more insight into the mechanism and find
out if our supposition about the unexpected ring-expansion
process was reasonable, high-level DFT calculations in the
gas phase were performed (Figure 5).46
Consequently, we proposed a copper(I)-catalyzed re-
ductive homolytic cleavage of the oxygen–oxygen bond of
the benzoyl peroxide, giving a benzoyloxy radical and cop-
per(II) benzoate. Then, the radical abstracts a hydrogen
from the C-9 position of 5, forming radical intermediate F.
The copper(II) species then oxidizes intermediate F to gen-
erate carbocation H and regenerate the copper(I) catalyst.
Besides this copper reduction step, it cannot be excluded
that the excess of TMSCHN2 operates as the main reducing
agent, helping the metal species to return to its catalytically
active oxidation state. Thus, an alternative mechanism may
be involved in the formation of carbocation H.
Erel
(kcal/mol)
N2
TMS
This carbocation can also be formed by the reaction be-
tween the benzoyloxy radical and F. In this case, an unsta-
ble covalent intermediate G is formed which is in equilibri-
um with the reactive ionic form H.
N2
TMS
C
H
H
TMS
H
+
H
O
Next the TMSCHN2 reagent reacts as a nucleophile with
the carbocation intermediate. After the addition, the reac-
tion evolves to form three-membered ring system J pro-
TS 1
17.3
O
5.8
0
TS 3
H
TS 2
N
–11.3
TMS
N
–15.6
H
–15.4
–16.7
[CuII]
H
O
I'
J
TMS
O
–28.0
K
TMSCHN2
[CuI]
Ph
O
O
Ph
O
O
PhCO2
PhCO2
[CuII]
+
K'
Figure 5 Density functional theory computational calculations on the
reaction course
X
5
The DFT calculations further support our proposed
mechanism. Thus, high-energy carbocation H reacts exo-
thermically with TMSCHN2 to give intermediate I′ (the most
stable conformer of I). This species leads to cyclopropane
derivate J through an exothermic intramolecular SN2-type
reaction, where molecular nitrogen acts as the leaving
group. The ring expansion then takes place giving a tricyclic
carbocation with a strained conformation K′, which evolves
quickly by ring inversion to give K.
X
F
PhCO2 [CuII]
PhCO2
O
Ph
O
PhCO2
X
X
H
G
N
N
C
4 Conclusions and Outlook
H
N
H
TMS
TMS
N
C
C
TMS
H
Important breakthroughs in the chemistry of oxidative
sp3-carbon–hydrogen bond functionalization reactions
have been achieved in the last few years. However, there are
still some important limitations and unsolved issues since
most of the current efforts are focused only on the further
use of standard oxidants to find new reaction partners. To
get new substrates and reagents involved and to be able to
expand this chemistry, it is crucial to explore other types of
oxidants and systems.
X
X
J
I
H
TMS
H
C
C
PhCO2
X
8
+
X
K
PhCO2 TMS
Scheme 14 The proposed mechanism
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 2, 526–539

537
A. Gini, O. G. Mancheño
Account
Synlett
In this account, we have presented innovative approach-
es dealing with this challenging issue. Two new easy one-
step methods to obtain important classes of heterocycles,
such as isoxazoline and dibenz[b,f]oxepine/azepine deriva-
tives, have been achieved avoiding the classical multistep
approaches. The key was the appropriate choice of oxidant
for each targeted transformation, since it is essential to pre-
vent overoxidation or undesired reactions of both the sub-
strates and the coupling reagent partners. Moreover, we
have shown within the second part of this account that this
new focus can lead to further novel and/or unexpected car-
bon–hydrogen bond transformations.
(6) For recent examples of carbon-hydrogen functionalization with
DDQ, see: (a) Correia, C. A.; Li, C. J. Adv. Synth. Catal. 2010, 352,
1446. (b) Mitsudera, H.; Li, C. J. Tetrahedron Lett. 2011, 52, 1898.
(c) Li, Y.; Cao, L.; Luo, X.; Deng, W. P. Tetrahedron 2014, 70, 5974.
(d) Liu, X.; Sun, S.; Meng, Z.; Lou, H.; Liu, L. Org. Lett. 2015, 17,
2396.
(7) For selected recent examples of carbon-hydrogen functionaliza-
tion with TBHP, see: (a) He, T.; Yu, L.; Zhang, L.; Wang, L.; Wang,
M. Org. Lett. 2011, 13, 5016. (b) Zhou, M. B.; Song, R. J.; Ouyang,
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Acknowledgment
The Deutsche Forschungsgemeinschaft is gratefully acknowledged for
generous support.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 2, 526–539