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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5493_Библиотеки_им_академика_М_И_Перельмана.pdf
82 2 Transformation of Sulfoximines and Cyclic Sulfoximines
S
N
O
R'
N
H
Y
X R
thiadiazine 1-oxide derivatives
S
N
O
N
H
S
NSC 287474
S
N
O
N
OMe
OMeN
N
O
O
an analog of Prazosin
S
O
MeO
MeO NHCONR'R''
S
O
NH
MeO
MeO
NHCONR'R''
S
O
N
OMe
OMe
N
R''R'N
MeCN
MSH
Scheme 2.35 The typical preparation and structure of thiadiazine 1-oxides
S
O
CF
3
NH
1) n-BuLi, THF, -50
o
C to -30
o
C, 1 h
S
O
CF
3
NH
E
E = X, N
3
, alkyl, OH, SR, B(OR)
2
SnBu
3
, SiMe
3
, etc.
S
O
CF
3
NH
N
3
NaBH
4
, MeOH
Bu
4
NHSO
4
S
O
CF
3
NH
NH
2
(Cl
3
CO)
2
CO
DMA, toluene
N
H
N
S
O
CF
3
O
POCl
3
, H
2
O
N
N
S
O
CF
3
Cl
RR'NH, CH
3
CN
N
N
S
O
CF
3
NR
2
NR
2
=
N
NN
O
O
N
N
O
O
93% 69%
63%
2) E reagent, -50
o
C to rt, 2 h
3) NH
4
Cl
toluene, 30
o
C to rt
1h 98%
0
o
C to rt, 1h
92%
reflux, 1h
82%
reflux, 3-6h
analog of prazosin
Scheme 2.36 Preparation of sulfoximine analogues of hypertensive prazosin
that allows for the obtaining of a wide range of compounds that have synthetic value
[
54
].
In 2017, Chen reported that microwave-assisted Cp*Co(III)-catalyzed the
synthesis of NH-sulfoximines with 1,4,2-dioxazol-5-ones. This reaction, which
involved direct C–H activation and the production of double C–N bonds, was effec-
tive. Using this method, a number of different thiadiazine-1-oxides are successfully
synthesized (Scheme
2.38)[55].
Furthermore, Chen and his colleagues demonstrated in 2018 that Pd/norbornene
helped NH-sulfoximines and aryl iodides cyclize. This created polyheterocyclic
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 83
S
O
R
2
NH
[Cp*Rh(MeCN)
3
](SbF
6
)
2
] (5 mol%)
S
O
NH
NH-Pg
R
1
+
Ar
O
O
N
H
Pg
Pg = COOEt, Cbz, COOnBu, COOiBu, Alloc, Boc
S
O
R
2
NH
NHBoc
TFA, DCM
S
O
R
2
NH
NH
2
CS
2
, 170
o
C, 24 h
S
O
R
2
N
H
N
S
R
2
= Me (90%)
Ph (80%)
R
2
= Me (90%)
Ph (89%) NSC 287474
S
O
R
2
N
H
N
S
S
O
R
2
N
H
N
NMe
2
S
O
R
2
N
H
N
SMe
DMF
170
o
C, 24h
MeI, K
2
CO
3
, DMF
80
o
C, 20h
22%
88%
[Pd
2
dba
3
], TFP
S
O
R
2
N
H
N
R
4
NaOAc, DCE, 100
o
C or 60
o
C
ArB(OH)
2
, CuTC,
THF, 50
o
C, 24 h
(58~73% yield
Scheme 2.37 Rhodium-catalyzed ortho-C-H bond amination of sulfoximines, and synthesis of
thiadiazine 1-oxide derivatives
sulfoximines that were very selective from an organic point of view. It is possible
for the reaction to adapt to a wide variety of functional groups when there are no
external oxidants present (Scheme
2.39, Eq. a) [56]. In 2019, Chen’s group made
more progress in the development of a multicomponent reaction that includes NH-
sulfoximines, aryl iodides, and norbornadiene and was catalyzed by Pd. This reac-
tion produced the high yields of sulfoximine-based polyheterocyclic compounds in a
selective manner. It was found that adding a dibenzylideneacetone ligand helped this
tandem cyclization reaction work better (Scheme
2.39, Eq. b) [57]. Chen proposed
a complicated process that included variations in the valance states of Pd ranging
from 0 to + 4, as shown in Scheme
2.39.
Chen also wrote in the same year that a copper-catalyzed multicomponent reac-
tion of TMSN3, simple NH-sulfoximines, and commonly available aldehydes was
carried out in hot water with oxygen. Considering that it does not require any external
Ag salt, ligand, or alkali, it is a cheap option. Sulfoximine derivatives that are biolog-
ically active were produced as a result of the reaction, which was able to tolerate a
wide range of functional groups, establish three C–N bonds in a single container,
and deliver these derivatives. The water-based catalytic system could be used again
and again without the need for an extra copper catalyst (Scheme
2.40) while the
preparation process for thiadiazine-1-oxide was running continuously [
58].
The cyclization reaction exhibits a broad scope and versatility, accommodating
various Thiadiazine 1-oxides and NH-sulfoximines with diverse substitution patterns
and functional groups. This versatility allows for the selective formation of cyclized
84 2 Transformation of Sulfoximines and Cyclic Sulfoximines
S
NH
O
R
2
R
1
+
O
N
O
O
R
3
Cp*Co(CO)I
2
(5 mol%)
AgNTf
2
(10 mol%)
S
O
R
2
R
1
N
N
R
3
PivOH, MW, t-AmOH/CHCl
3
(1:1)
110
o
C, 2-3 h
S
NH
O
Ph
NH
HO
Ph
S
N
O
Ph
H
N
OH
Ph
H
2
O
S
O
Ph
N
N
Ph
H
S
NH
O
Ph
NH
O
Ph
PivOH
HNTf
2
Cp*Co(CO)I
2
PivOH
HNTf
2
2AgNTf
2
2AgI+CO
*Cp Co
O
O
Piv
NTf
2
S
HN
O
Ph
PivOH
HNTf
2
Co
N
S
O
Ph
Cp*
O
N
O
O
Ph
Co
N
S
O
Ph
Cp*
O
N
O
O
Ph
CO
2
N
Co
N
S
O
Ph
PhO
*Cp
36-87% yield
Scheme 2.38 Cp*Co(III)-catalyzed synthesis of thiadiazine 1-oxides and its plausible mechanism
products, providing access to a range of structurally unique heterocyclic compounds.
The resulting molecules may possess interesting electronic, steric, and physicochem-
ical properties, making them suitable for further exploration in various applications.
Applications in medicinal chemistry: The cyclized products that come from the
cyclization of Thiadiazine 1-oxide and NH-sulfoximine show a lot of promise in
medicinal chemistry. Bioactivity is often found in heterocyclic structures, and adding
the thiadiazine ring and the sulfoximine moiety may create new pharmacophores. It
is possible to use these compounds as useful starting points for designing and making
possible drug candidates.
While significant progress has been made in the cyclization of Thiadiazine 1-
oxides with NH-sulfoximines, challenges remain. Achieving high regioselectivity,
particularly in complex substrates, and developing more sustainable and practical
catalytic systems are areas of ongoing research. Exploring new Thiadiazine 1-oxide
derivatives, NH-sulfoximines, and alternative cyclization methodologies will further
advance the synthetic possibilities and broaden the scope of applicable substrates.
Finally, the cyclization reaction of Thiadiazine 1-oxides with NH-sulfoximines is
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 85
R
Br
S
R
1
O
NH
+
R
3
I
R
2
N
S
O
R
1
R
2
R
3
Pd(OAc)
2
(10 mol%)
PPh
3
(25 mol%)
norbornadiene, K
2
CO
3
MeCN, 85-105
o
C, 12 h
a)
S
NH
O
+
I
MeO
2
C
+
Br
Pd(dba)
2
(10 mol%)
(4-FC
4
H
6
)
3
P (25 mol%)
dba, Cs
2
CO
3
, CH
3
CN
85
o
C, 12 h
NS
O
CO
2
Me
b)
Pd
0
I
R
1
R
1
H
Pd-I
base
ortho C-H
activation
R
1
Pd
II
S
O
HN
R
X
Pd
IV
S
R
O
HN
R
1
R.E.
R
1
XPd
S
O
R
NH
R
1
XPd
S
R
O
NH
Base•HX
S
N
Pd
O
R
R.E.
N
S
R
1
O
R
2
O.A.
2
R
1
Pd
IV
X
R
1
R.E.
R
1
PdI
R
1
R
1
N
R
1
S
O R
X
X
expected
undesired
R.E. = reductive elimination
O.A. = oxidative addition
R
1
Pd-I
Scheme 2.39 Palladium/norbornene-catalyzed multicomponent reaction for the preparation of
sulfoximine-based heterocycles and its mechanism
86 2 Transformation of Sulfoximines and Cyclic Sulfoximines
S
NH
O
R
2
+
Cu
2
O (5 mol%)
TBAI (10 mol%)
S
O
R
2
N
N
R
Br
R
3
CHO
R
1
R
1
TMSN
3
, H
2
O, 90
o
C, air
S
NH
O
Br
Cu
I
OCu
L
-CuOH
L = H
2
O or PTC
S
N
O
Br
CuL
S
N
O
Br
CuL
H
2
O
-L
S
NH
O
Cu
I
Br
TMSN
3
S
NH
O
Cu
III
Br
TMS
N
3
H
2
O
-N
2
-TMSOH
S
O
N
H
Cu
I
N
Br
H
2
O
1/2 O
2
-CuBr
S
NH
O
NH
2
PhCHO
-H
2
O
S
O
H
N
N
Ph
O
2
S
O
N
N
Ph
35-95% yield
Scheme 2.40 Copper-catalyzed synthesis of thiadiazine-1-oxides in reusable aqueous medium
an interesting and chemically rich change that combines two different heterocyclic
motifs to make molecules with complex structures. The cyclized products that are
made show promise in medicinal chemistry and materials science. They provide many
ways to explore new chemical space and create new compounds with specific proper-
ties. More research into the cyclization of thiadiazine 1-oxides with NH-sulfoximines
is likely to lead to new ways of making chemicals, better selectivity, and the creation
of new heterocycles that are biologically relevant.
2.1.10 Synthesis of N-methyl-2-indolyl-
and N-methyl-2-benzo[b]furyl-Substituted
Sulfoximines
The synthesis of N-methyl-2-indolyl- and N-methyl-2-benzo[b]furyl-substituted
sulfoximines is an interesting study that combines the chemistry of indole or
benzo[b]furan with the wide range of reactions that sulfoximines can have. By
combining the electron-rich aromatic systems of indoles or benzo[b]furans with
the unique sulfur–nitrogen double bond in sulfoximines, this synthetic work gives
us access to compounds with unique structural motifs. The molecules that were
made have many useful traits that make them good candidates for further research
in materials science and medicinal chemistry. The synthesis starts with a suitable
indole or benzo[b]furan derivative coming together with a sulfoxide, usually with a
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 87
R
1
S
R
2
O
N
+
I
HZ
PdCl
2
(PPh
3
)
2
(1 mol%)
CuI (5 mol%)
R
1
S
R
2
O
N
Z
Z = O, NTs, NC(O)CF
3
TMG, toluene, 70
o
C
64-95% yield
Scheme 2.41 Synthesis of N-Methyl-2-indolyl-, N-Methyl-2-benzo[b]furyl-Substituted Sulfox-
imines
base present. In this step, the important sulfur–nitrogen bond is made, which sets the
stage for the next changes. Adding a methyl group to the nitrogen atom makes the
sulfoximines even more structurally diverse and increases their possible biological
activities.
Bolm suggested in 2012 that N–Propargylsulfoximines interact with either 2-
iodophenol or 2-iodoaniline through a domino cross coupling/cyclization reaction.
A palladium/copper synergistic system was used to catalyze the reaction, which
resulted in the production of benzofuran or indole derivatives (Scheme
2.41)[59
].
The sulfoximines that are made have interesting electronic properties because
indoles and benzo[b]furans are electron-rich. Some derivatives might be fluorescent,
which could make them useful in materials science, especially for making fluorescent
probes or markers. Which indole or benzo[b]furan precursor is used has a big effect
on how the synthesis turns out. Because indoles have aromatic systems that are full of
electrons, they can be functionalized in many ways. Similarly, benzo[b]furans add a
fused oxygen-containing heterocycle that makes it possible for more molecular diver-
sity. Scholars often pick these precursors based on the properties and uses they want
the final sulfoximines products to have. Usually, a base speed up the condensation
reaction between the sulfoxide and the chosen indole or benzo[b]furan precursor. It
is the nitrogen of the indole or benzo[b]furan that attacks the sulfur of the sulfoxide,
which creates the sulfur–nitrogen bond. To get high yields and selectivity, it is very
important to pick the right base and reaction conditions.
Also, the N-methylation step is added to the reaction sequence after the sulfur–
nitrogen bond is formed. A methyl group is added to the sulfonimine’s nitrogen atom
to make this change happen. To make these steps easier, different methylating agents
are used, like methyl iodide or methyl triflate. N-methylation makes the sulfoximine
more stable and changes its electronic properties, which affects how it reacts and
what it could be used for.
Cyclization reactions are very important for making N-methyl-2-indolyl- and N-
methyl-2-benzo[b]furyl-substituted sulfoximines. There are certain reaction condi-
tions that can cause intramolecular cyclizations, which create cyclic sulfoximines.
The process of cyclization can lead to different heterocyclic structures, which can
change the final compounds’ shape and properties.
Reactions catalyzed by palladium, to give the synthesized sulfoximines more func-
tions, transition metal-catalyzed reactions are often used, especially those involving
palladium. Cross-coupling reactions aided by palladium make it possible for N-
methyl-2-indolyl- and N-methyl-2-benzo[b]furyl-substituted sulfoximines to join
88 2 Transformation of Sulfoximines and Cyclic Sulfoximines
with aryl or alkyl partners. This method lets you make C–N or C–C bonds, which
increases the variety of molecules in the final compounds.
For example, condensation, N-methylation, and cyclization reactions are some
of the carefully planned steps that make up the mechanistic parts of the synthesis.
It is very important to understand the complicated mechanisms in order to get the
best reaction conditions, highest yields, and only the desired sulfoximine deriva-
tives. This synthetic method can be used to make a wide range of N-methyl-2-
indolyl- and N-methyl-2-benzo[b]furyl-substituted sulfoximines. It can also be used
to make different derivatives of indoles and benzo[b]furans. But it’s important to think
about the method’s flaws, like whether the substrates are compatible, the reaction
conditions, and any possible side effects.
Making N-methyl-2-indolyl- and N-methyl-2-benzo[b]furyl-substituted sulfox-
imines is an active area of research that is always changing. In the future, researchers
may look into new catalytic systems, make methods that are better for the environ-
ment, and use these sulfoximines in new fields like bioimaging or catalysis. The N-
methyl-2-indolyl- and N-methyl-2-benzo[b]furyl-substituted sulfoximines that were
made show a lot of promise in medicinal chemistry. The pharmacological activities
of indole and benzo[b]furan derivatives are well known. Adding the sulfoximine
moiety makes the chemical space even more varied. These compounds can be useful
building blocks for designing and making bioactive molecules that could be used in
drug discovery.
To sum up, making N-methyl-2-indolyl- and N-methyl-2-benzo[b]furyl-
substituted sulfoximines is an interesting journey at the intersection of indole or
benzo[b]furan chemistry and sulfoximine reactivity. The compounds that are made
have special structural features and a wide range of properties that make them useful
in materials science and medicinal chemistry. As more synthetic methods are studied
and the biological activities of these sulfoximines are elucidated, they will play a
bigger role in organic synthesis and drug discovery.
2.1.11 Pd(II)-Catalyzed Primary-C(sp
3
)-H Acyloxylation
of NH-Sulfoximines
The C–H acyloxylation of NH-sulfoximines involves the direct functionaliza-
tion of aliphatic C–H bonds adjacent to the nitrogen atom in sulfoximines with
acyloxyl groups. This transformation represents a departure from traditional synthetic
methods, as it streamlines the synthesis by obviating the need for pre-functionalized
starting materials. The regioselectivity of this reaction is controlled by the prox-
imity of the nitrogen atom in sulfoximines, adding an additional layer of synthetic
precision. The Pd(II)-catalyzed primary C(sp
3
)-H acyloxylation of NH-sulfoximines
stands as a sophisticated and transformative synthetic strategy, melding the reactivity
of C–H activation with the versatility of sulfoximines. This powerful transforma-
tion allows for the direct acyloxylation of aliphatic C–H bonds adjacent to nitrogen
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 89
in sulfoximines, thereby enabling the rapid and efficient construction of complex
molecular architectures. The incorporation of palladium catalysis further enhances
the synthetic potential, opening new avenues for the synthesis of diverse molecules
with applications in medicinal chemistry and materials science.
Sulfoximines as special substrates: NH-sulfoximines, which have a sulfur–
nitrogen double bond inside the imine functional group, are the only ones that can
go through this change. The electron-withdrawing sulfoximine part gives the nearby
C–H bonds a unique reactivity, which makes selective acyloxylation easier. Using
NH-sulfoximines’ natural ability to react with C–H groups opens up a wider range
of compounds that can be used. The catalytic power of palladium(II) is used to
speed up the important C–H activation step in this reaction. Palladium(II) species
are important parts of the catalytic cycle because they add oxygen to the C–H bond,
which makes acyloxylation possible, and they also help get rid of oxygen to make the
desired acyloxylation products. A smart choice of palladium catalysts, ligands, and
reaction conditions is very important for getting high selectivity and efficiency. The
C–H acyloxylation of NH-sulfoximines can react with a lot of different substrates,
which lets many different aliphatic C–H bonds be functionalized next to the sulfox-
imine nitrogen. The regioselectivity is controlled by the sulfoximine moiety’s own
electronic properties, which makes sure that the C–H is activated only at the right
position. Because it can selectively control certain regions, this transformation is
very useful for making synthetic materials.
The Pd(II)-catalyzed primary C(sp
3
)-H acyloxylation is made up of several impor-
tant steps. It is common for the catalytic cycle to start with the Pd(II) catalyst
joining with the sulfoximine substrate. The aliphatic C–H bond is then added oxida-
tively, creating a Pd(IV) intermediate. After the acyloxylating reagent is coordinated,
acyloxylation happens. This is followed by reductive elimination, which makes the
final acyloxylation product. Figuring out these technical details about how things
work helps improve reaction conditions and make more substrates usable. Pd(II)-
catalyzed C–H acyloxylation gives the synthesized compounds a lot of different
molecular shapes. By adding different acyloxyl groups, the reaction makes it possible
for molecules with complicated structures to be put together quickly. Being able to
change the acyloxyl substituents causes changes in lipophilicity, polarity, and steric
hindrance, which affects the compounds’ properties and possible uses.
Over the course of the previous few years, Sahoo’s group has reported preliminary
findings regarding the Pd-catalyzed acetoxylation of S-methyl-S-phenylsulfoximine-
N-amide at a temperature of 100 °C [
60]. Their ideas were inspired by this discovery,
and they came up with a new compound called S-methyl-S-2-pyridylsulfinimide
(MPyS) [
61
]. This compound has the potential to act as a directing group and has
the ability to oxidize the C–H bond of alkanes. It’s likely that adding pyridyl and
sulfoximine to MPyS-DG (where DG stands for “directing group”) and a Pd-catalyst
would make the β-C(sp
3
)-H bond of MPyS-N-amides active. A [5
,
5
]-fused-Pd-
bridged system would be involved in this activation, which is an idea that Daugulis
first described [
62]. Additionally, the oxidation of C(sp
3
)-H bonds in amides and
the use of a bi-coordinated DG for the oxidation of C–H bonds present in alkanes
are both extremely uncommon [
19]. In 2012, the Sahoo team reported that they
90 2 Transformation of Sulfoximines and Cyclic Sulfoximines
S
O
N
O
R
1
R
2
H
N
Pd(OAc)
2
(5 mol%)
S
O
N
O
R
1
R
2
OAc
N
PhI(OAc)
2
, AcOH, rt
40-90% yield
Scheme 2.42 Acetoxylation of 1o-β-C(sp
3
)-H bonds of amides
had successfully used Pd to catalyze a very selective direct acetoxylation of the
MPyS-Namides 1-C(sp
3
)-H bond at room temperature (Scheme 2.42)[63].
The synthesized products from this transformation are very important in medic-
inal chemistry. Sulfoximines have functional groups that are often found in bioactive
molecules because acyloxyl groups are directly attached to the nitrogen atom next
to it. Medicinal chemistry can be made more effective by using these compounds as
useful building blocks for making drug candidates or bioactive molecules. Integra-
tion with diversity-oriented synthesis: The C–H acyloxylation of NH-sulfoximines
follows the rules of diversity-oriented synthesis (DOS), a method for making
compound libraries with as many different structures as possible. Researchers can
help build diverse collections of compounds by using this transformation’s synthetic
efficiency and selectivity. These collections are important for exploring biological
space and finding new lead compounds.
Palladium(II) catalysis in long-term synthesis: The use of palladium(II) as a cata-
lyst makes the synthetic process more environmentally friendly. Palladium, a tran-
sition metal catalyst, makes the reaction conditions milder, which means that the
synthesis has less of an effect on the environment. Also, researchers are looking into
catalytic systems that use ligands and reagents that are better for the environment.
This would help the green chemistry side of the reaction.
The Pd(II)-catalyzed primary C(sp
3
)-H acyloxylation of NH-sulfoximines has
come a long way, but there are still problems that need to be solved. Researchers
are working on making catalytic systems that work better, adding more substrates,
and solving problems related to scaling up. In the future, this transformation might
be added to more complicated synthetic sequences, and its use in the synthesis of
natural products might be looked into. Lastly, the Pd(II)-catalyzed primary C(sp
3
)-H
acyloxylation of NH-sulfoximines is a state-of-the-art way to make chemicals that
makes it easier to make a wide range of complex molecules. This change uses the
regioselectivity of the sulfoximine moiety to combine the flexibility of palladium
catalysis with the unique ability of sulfoximines to react. The compounds that were
made can be used in medicinal chemistry and materials science, and they also help the
field of sustainable and diverse synthesis as a whole. Researchers are still looking into
this synthetic strategy, which should lead to new discoveries that will help chemists
make more synthetic tools and move the field of C–H functionalization forward.
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 91
2.1.12 Approach to Sulfonyl Azide-Directed Intermolecular
O–C–H Amidation of Arenes
The sulfonyl azide-directed intermolecular O–C–H amidation of arenes represents
a strategic and powerful synthetic approach, enabling the direct functionalization
of C–H bonds adjacent to oxygen in aromatic compounds. This transformation is
particularly notable for its ability to install amide functionalities at specific posi-
tions on arenes through the guiding influence of sulfonyl azides. The integration
of sulfonyl azides as directing groups allows for the selective activation of C–H
bonds, thereby facilitating the formation of amide linkages, ultimately expanding
the synthetic versatility of arene substrates.
Sulfonyl azide-directed intermolecular O–C–H amidation is a complex way to
make chemicals that uses the natural reactivity of sulfonyl azides to selectively add
a C–H functional group. In this change, sulfonyl azides do two things: they act as
guiding groups to help activate the C–H bonds next to oxygen in arenes selectively,
and they also provide nitrogen for amidation reactions. By skipping the need for
starting materials that have already been functionalized, this method makes it easier
to directly add amide functions to arene substrates.
Sulfonyl azides as flexible directing groups: Sulfonyl azides are useful directing
groups in C–H activation strategies because they react and change in unique ways.
This is because the sulfonyl azide part is next to the C–H bond in the arene and works
with a transition metal catalyst to guide the next C–H functionalization in a specific
way. Using sulfonyl azides as directing groups improves the regioselectivity of the
C–H amidation. This makes sure that only the desired C–H bond is activated.
Acting on C–H bonds with transition metals: For the sulfonyl azide-directed
amidation to work, transition metal catalysts must be used to selectively activate
the C–H bonds. Palladium and other transition metals are often used in this situa-
tion because they can add oxygen to C–H bonds and make it easier for subsequent
amidation reactions to happen. To get high efficiency and regioselectivity, it is very
important to pick the right catalyst and reaction conditions.
Transition metal-catalyzed C–H activation: The success of the sulfonyl azide-
directed amidation relies on the use of transition metal catalysts to affect the selec-
tive activation of C–H bonds. Palladium and other transition metals are commonly
employed in this context due to their ability to undergo oxidative addition to C–H
bonds and facilitate subsequent amidation reactions. The judicious choice of cata-
lyst and reaction conditions plays a critical role in achieving high efficiency and
regioselectivity.
There are several important steps in the process of the sulfonyl azide-directed
O–C–H amidation. The sulfonyl azide first binds to the transition metal catalyst,
which makes it easier to selectively activate the C–H bond next to the oxygen atom
in the arene. The metal catalyst is then put into the C–H bond, which creates a metal–
carbon intermediate. This reacts with an amine source to make the amide product
that is wanted. The sulfonyl azide directing group and the transition metal catalyst
work together to control the reaction as a whole.