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12 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
R
S
R'
t-BuOK (1.2 equiv)
MeOH, rt 30-95% yield
R
S
R'
N
m-CPBA
K
2
CO
3
EtOH, rt
R
S
R'
N
O
(i) TFAA, CH
2
Cl
2
, rt
(ii) K
2
CO
3
, MeOH, rt
RS
R'
O
NH
NBS/I
2
(1.5 equiv)
H
2
NCN (1.3 equiv)
CN
CN
Scheme 1.11 Synthesis of sulfoximines from N-cyanosulfilimines
Scheme 1.12 a Continuous
flow strategy to synthesize
NH-sulfoximines. b Reboul
team’s synthesis strategy.
c The sulfoximine synthetic
method of Xu’s team
R
S
R'
HN
O
NH
3
, 0
o
C, 30 min
R
S
R'
MeOH, rt, 30min
PhI(OAc)
2
,(NH
4
)
2
CO
3
2 wt% TPGS-750-M
H
2
O, rt, 16 h
(NH
4
)
2
CO
3
1,2,3-trifluoro-5-iodobenzene diacetate
(a)
(b)
(c)
PhI(OAc)
2
R
S
R'
R
S
R'
R
S
R'
HN
O
R
S
R'
HN
O
In 2017, the Luisi team developed a practical and sustainable continuous flow
method for the synthesis of NH-sulfoximines. The method used thioethers as the raw
material, PhI(OAc)
2
as the oxidant, and ammonia solution as the source of nitrogen.
It was discovered that the flow method was more convenient than the traditional
batch processing method (Scheme
1.12, path (a) was used) [37, 38].
In addition, in 2017, Reboul’s group published an investigation on the process for
synthesizing NH-sulfoximines from thioethers by using phenyliodine (III) diacetate
as the oxidant and ammonium carbamate as the source of ammonia. With methanol
as a solvent, it was suggested that acetoxy and methoxy-λ6-sulfoxynitriles could
be made as starting materials. Both of these sulfoxynitriles are converted into NH-
sulfoximines, as shown in Scheme
1.12,Eq. b[39
]. In the year 2019, Xu and his
team created a new synthetic method. In order to synthesize NH-sulfoximines from
thioethers, the surfactant TPGS-750-M, which is a solution of DL-alpha-Tocopherol
methoxypolyethylene glycol succinate, is used as a catalyst. This process is carried
out under moderate conditions. Regenerating the needed high-valent iodine (III) is
achieved by the utilization of a straightforward and practical recovery method in
this recently discovered process. By using liquid–liquid extraction, it was possible
to get back almost the same amount of the 1,2,3-trifluoro-5-iodobenzene that was
made from the mixture. After that, the iodine (III) that matched it was obtained by
oxidation (Scheme
1.12, Eq. c) [40
].
The synthesis of sulfoximines from thioethers holds particular significance in
medicinal chemistry due to the impact of structural modifications on the pharmacoki-
netic and pharmacodynamic properties of the resulting compounds. Sulfoximines
have shown promise as flexible building blocks for making bioactive chemicals that
can be used to find new drugs. This synthetic method lets medicinal chemists change
the structure of sulfoximines, which is a useful tool for improving the properties of
possible therapeutic agents. A lot of progress has been made in making sulfoximines
from thioethers, but there are still problems to solve. Researchers are working on
1.1 Synthesis of Sulfoximines 13
problems like reaction specificity, scalability, and making synthetic routes that last
longer. Taking care of these problems will help this s ynthetic method keep getting
better, making it more useful and applicable to more people.
To sum up, making sulfoximines from thioethers is an area of organic chemistry
that is in constant change. Researchers are always improving and adding to the tools
they use to get to these useful compounds, ranging from old oxidative methods
to newer transition metal-catalyzed methods. Adding a nitrogen atom to the imine
structure in a smart way makes sulfoximines more useful in many chemical situations.
As the field moves forward, making sulfoximines from thioethers will likely be very
important for creating new materials, medicinal molecules, and other uses. This
shows how important this revolutionary way of making chemicals will always be.
1.1.4 Synthesis of Sulfoximines from Sulfilimines
The synthesis of sulfoximines from sulfilimines involves a key oxidation step to
introduce an oxygen atom into the sulfur–nitrogen double bond. The realization of
this transformation is essential in order to acquire sulfoximines, which have uses in a
variety of sectors. The technique as a whole offers a flexible approach to the incorpo-
ration of oxygen functionality into the sulfur–nitrogen link, which ultimately results
in the production of sulfoximines. The parameters of the reaction, the oxidizing
agents, and the starting materials are frequently modified by researchers in order to
optimize the synthesis for particular purposes. Sulfoximines are shown to be versatile
in a variety of chemical transformations through the use of this method, which also
highlights the significance of sulfoximines in the synthesis of complex compounds.
There is a sulfur–nitrogen double bond inside the imine moiety that makes sulfil-
imines a special type of chemical with its own way of reacting and building itself.
Sulfilimines are changed into sulfoximines by adding an oxygen atom in a planned
way. This creates the sulfur–oxygen double bond that is typical of sulfoximines. This
change not only shows how flexible compounds with sulfur can be, but it also opens
up a wide range of uses because sulfoximines have unique qualities. The goal of
making sulfoximines from sulfilimines is to use the unique properties of sulfilimines
as building blocks for sulfoximines. During this change, oxygen can be added selec-
tively to the imine structure, creating a nitrogen–oxygen double bond while keeping
the sulfur–nitrogen double bond. The resulting sulfoximines have a structure that
combines the ways that oxygen and sulfur respond with each other. This method of
synthetic chemistry makes it possible to make compounds with specific qualities that
can be used in a wide range of organic synthesis tasks.
There are different synthetic strategies used to make sulfoximines from sulfilim-
ines, and each one is tailored to the needs of the target molecule. One of the tradi-
tional ways is to specifically change sulfilimines by oxidizing them with oxidizing
agents like peroxides or metal catalysts. Transition metal-catalyzed methods have
also become more popular because they give you more control over regioselec-
tivity and stereoselectivity. In the past, oxidative methods were very important for
14 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
Scheme 1.13 Synthesis of
sulfoximines with KO
2
as
oxidant, 18-crown-6 ether as
phase transfer catalyst
R
S
R'
R
S
R'
HN
O
rt, CH
2
Cl
2
R'-X / 18-Crown-6
NH
+
KO
2
86-94% yield
Scheme 1.14
N-unsubstituted sulfilimines
generated sulfoximines in
sodium hypochlorite
R
S
R'
R
S
R'
HN
O
NaOH, MeOH,H
2
O
NaOCl, MeOH, H
2
O
NH
44-90% yield
changing sulfilimines into sulfoximines. In these methods, peroxides or metal cata-
lysts are often used to help add oxygen selectively to the sulfur–nitrogen double
bond of sulfilimines. To get good selectivity and avoid over-oxidation to sulfones, it
is very important to choose the right oxidizing agent and reaction conditions. Clas-
sical approaches to oxidation have taught us a lot about the basic rules that control
this change. Recent years have seen the rise of transition metal-catalyzed methods
as powerful ways to make sulfoximines from sulfilimines. Palladium, copper, or
iron are some of the catalysts that are very important for the oxidative coupling
between sulfilimines and molecules that contain oxygen. There are some benefits
to using these catalytic systems, like the fact that they can handle a wider range of
sulfoximines and make the reaction conditions softer. The transition metal-catalyzed
method has opened up more synthetic options by making it easier to change different
sulfilimine sources into sulfoximines.
A method for the synthesis of sulfoximines was established by Oae and colleagues
in 1984. This method used sulfilimines as the starting materials. Nucleophilic
oxidation of S,S-diaryl-N-(p-tolylsulfonyl)sulfilimines and N-unsubstituted diaryl-
sulfilimines with potassium superoxide (KO
2
) resulted in a synthesis of the required
sulfoximines (Scheme
1.13). This reaction take place in the presence of phase transfer
catalyst 18-crown-6 with 1-bromopropane/benzene [
41]. In the same year, Oae et al.
discovered that N-unsubstituted sulfilimines can be transformed into N-unsubstituted
sulfoximines or mono-N-tosylsulfonediimines when reacted with sodium hypochlo-
rite in an alkaline methanol aqueous solution or with chloramine-T in dry acetonitrile
in the presence of excess tosylate [
42], as shown in Scheme 1.14.
1.1.5 Synthesis of Chiral Sulfoximines
Chiral sulfoximines are a type of sulfoximine where the molecule is not symmetrical
because the stereocenter is on the sulfur atom. Stereochemistry has a big effect on
the properties and activities of these molecules, so making chiral sulfoximines is
very important. A lot of progress has been made in this area, which has opened up
new ways to create enantioenriched molecules that can be used in everything from
medicine to materials science. The reason for making chiral sulfoximines is to use
1.1 Synthesis of Sulfoximines 15
enantioselectivity, which is an important part of current organic synthesis. Chirality
has a big effect on how molecules work in living things, and chiral sulfoximines
let you precisely change the structures of molecules. When this happens, enantioen-
riched sulfoximines are created, which are useful for making drugs, catalysts, and
intricate materials.
The synthesis of chiral sulfoximines requires a series of processes to be carried
out in order to induce chirality and selectively oxidize the sulfur atom. Outlined
below is a general description of the procedure: Initial component of chiral amine
complex, a chiral amine should be used as the beginning material to get started. There
are two possible forms of this chiral amine: enantiopure and generated from a chiral
auxiliary. Formation of sulfilimine, the formation of a chiral sulfilimine intermediate
can be achieved by reacting the chiral amine with either a sulfonyl chloride or a
sulfinyl chloride. Under the proper conditions, the reaction can be carried out, and
the chiral amine or auxiliary is responsible for imparting the stereochemistry. As
an optional measure, protection of the chiral center: In the event that it is required,
protect the chiral center in order to avoid side reactions during the succeeding process.
Following an asymmetric oxidation of sulfilimine, Sulfilimine s hould be oxidized
in an asymmetric environment. It is possible to selectively oxidize the sulfur atom
while maintaining the chiral integrity by employing a variety of oxidizing agents or
chiral catalysts. For example, peracids, peroxides, and metal-based oxidants are all
examples of common oxidants. In the circumstance that it is required, deprotection
involves removing any protective group that was inserted in the previous steps, which
will result in the chiral sulfoximine product being revealed.
When it comes to asymmetric synthesis, the chiral sulfoximines that result through
this particular method of synthesis are quite useful since they serve as intermediates
in the process of producing enantioenriched substances.
To begin, the Fe-catalyzed synthesis of achiral sulfoximines that was developed
by the Bolm group and discussed above is also appropriate for the synthesis of chiral
sulfoximines. This is mainly done by starting with (S)-methyl phenyl sulfoxide in
order to produce (S)-methyl phenyl sulfoximine (Scheme
1.15).
Maruoka and his colleagues have recently reported the asymmetric synthesis of
chiral sulfoximines containing aryl groups. This was achieved by sulfur-selective
arylation of chiral sulfinamides. With the use of a Cu(I) catalyst mixed with diaryl
iodonium salts, they were able to establish the S-arylation of chiral sulfinamide
derivatives that contained either alkyl or aryl groups. There is also the possi-
bility of obtaining various kinds of arylsulfoximines through the arylation of tert-
butanesulfinamide derivatives, followed by tert-butylation under either acidic or basic
conditions. Through the use of this method, it is possible to easily produce a wide
Scheme 1.15 Fe-catalyzed
synthesis of chiral
sulfoximines
Ph
S
O
(1) Fe(acac)
3
(10 mol %)
X-NH
2
, PhI(OAc)
2
, MeCN, rt
Ph
S
O
NH
(2) Cs
2
CO
3
, PhSH
MeCN, rt
79% yield, 83% ee
16 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
S
N
H
S
N
O
DMSO, 4A MS, 60
o
C, 24 h
53-90% yield
CuI (10 mol%)
(Ar')ArIX, Cy
2
NMe
O
Piv
t-Bu
Piv
t-Bu
Ar
LiAlH
4
(3 equiv)
THF, 0
o
C, 20 min
81% yield
S
HN
O
t-Bu
Ar
Piv
= pivaloyl
Scheme 1.16 CuI-catalyzed synthesis of chiral sulfoximines
range of chiral sulfoximines in an optically pure form. This includes bioactive chiral
sulfoximines that have known stereochemistry. As a result of the chiral HPLC study,
it was found that the S-arylation was stereospecific (as shown in Scheme
1.16)[43].
Recent studies carried out by Stockman group reported the development of a chiral
pool method for the synthesis of enantiomer-enriched NH-sulfoximines. The method
involves the ring opening of cyclic sulfonimide esters using Grignard reagents. After
that, the chiral auxiliary is easily extracted from the sulfoximines that were produced
by the use of the oxidative debenzylation method, which used molecular oxygen as
the final oxidant. Through the use of a three-step process, a wide range of chiral
NH-sulfoximines were successfully produced (shown in Scheme
1.17)[44]. The ee
values are above 93%, mostly around 98%.
There are many different ways to make chiral sulfoximines, and they are all
intended to selectively cause asymmetry at the sulfur atom. There are several ways
to achieve asymmetric induction, such as using chiral auxiliaries, which are very
useful for making chiral sulfoximines because they create a short-term chiral envi-
ronment that controls the reaction’s stereochemistry. These extra groups, which are
usually connected to the sulfur atom, they help to make the sulfoximine. They can
then be taken away to get the enantioenriched product. This method has been used
successfully to make many different kinds of chiral sulfoximines, showing how useful
chiral intermediates can be in asymmetric induction.
Asymmetric catalysis: An uneven reaction called asymmetric catalysis has
become the most important and useful way to make chiral sulfoximines. To make
enantioselective sulfoximine, transition metal catalysts like rhodium, iridium, and
R
S
O
N
H
OH
oxidation
R
S
O
O
N
Ph
+
S
O
O
N
Ph
R
Ph
RS
O
O
N
Ph
S
O
O
N
Ph
R
SO
R
2
N
R
R
S
O
N
R
2
R
2
MgBr (2 equiv)
THF, -78
o
C~rt
THF, -78
o
C ~ rt
MTBE, 40
o
C
MTBE, 40
o
C
S
O
R
2
NH
R
RS
O
NH
R
2
Ph
HO
R
2
MgBr
NaOH
NaOH
Ph
HO
Scheme 1.17 Chiral sulfoximines obtained from cyclic sulfonimide esters
1.1 Synthesis of Sulfoximines 17
copper complexes, as well as organo-catalysts, have been very helpful. These cata-
lysts take part in different bond-forming processes, which makes it possible to make
chiral sulfoximines that are very selective for their stereochemistry. Asymmetric
catalysis is a long-lasting and cost-effective method that shows how metal and organic
catalysts can be used to control the stereochemistry of sulfoximine products.
Also, dynamic resolution: In this methods, racemic sulfoximine intermediates are
formed and resolved at the same time. This separates enantioenriched chiral sulfox-
imines. This approach depends on the reversible change of racemic sulfoximines,
which can happen chemically or with enzymes. This lets only one enantiomer build
up. When other methods may not work well, dynamic resolution processes can be
used as an additional way to get to chiral sulfoximines.
Understanding the complicated mechanisms behind the creation of chiral sulfox-
imines is important for improving and creating new manufacturing methods. In asym-
metric catalysis, for instance, the chiral catalyst controls the face separation during the
key bond-forming step, which in turn controls the sulfoximine product’s stereochem-
istry. Mechanistic studies help scientists finetune reaction conditions for best results
by giving them useful information about the factors that affect stereoselectivity.
Chiral sulfoximines are important in medicinal chemistry because the way atoms
are arranged in three dimensions can have a big effect on the biological properties
of a molecule. In the process of making medicines, enantioenriched sulfoximines
have shown promise as useful building blocks, especially when chiral sulfoximine
motifs are found in bioactive molecules. Chiral sulfoximines work well as ligands
for transition metal catalysts in catalysis, which allows enantioselective reactions in
many synthetic processes. Making chiral sulfoximines has come a long way, but there
are still problems that need to be solved. Catalytic systems that last longer and cost
less are being worked on, as well as substrates that can be used for more processes
and systems that can change more things. Asymmetric synthesis methods for chiral
sulfoximines are getting better all the time, which could lead to new chemistry spaces
and uses.
The synthesis of chiral sulfoximines is an interesting and important area of asym-
metric synthesis. The addition of chirality to the sulfur atom in a planned way
changes the way sulfoximines respond and can be used in new ways. Researchers
keep improving and adding to the synthetic tools they use to get to enantioen-
riched sulfoximines. These tools include chiral auxiliaries, asymmetric catalysis,
and dynamic resolution methods. Chiral sulfoximines will become more important
in the design of bioactive molecules, catalytic processes, and the study of new fron-
tiers in asymmetric synthesis as the field moves forward. One of the most important
things about chiral sulfoximines is that they can connect basic stereochemical ideas
with game-changing uses in organic chemistry.
18 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
1.1.6 Summary
Sulfoximines are useful building blocks in drug discovery and development due
to their varied chemical structure. Exploring novel applications of sulfoximines in
medicine is an active area of research at the moment. The unique properties of
sulfoximines, such as their ability to participate in different reactions and to serve as
chiral scaffolds, contribute to their importance in medicinal chemistry. An important
component in the development of innovative materials with customized properties,
sulfoximines are versatile in terms of reactivity and functional group modifications.
Novel synthetic approaches and materials science uses for sulfoximines are still the
subject of active investigation. Sulfoximines have the potential to revolutionize catal-
ysis with their exceptional electrical and steric properties, opening up new avenues
for the creation of selective and efficient catalytic processes. New applications and
principles for sulfoximines in catalysis are being investigated in ongoing research.
1.2 Synthesis of Cyclic Sulfoximines
Cyclic sulfoximines are a class of molecules that possess a sulfur–nitrogen double
bond. They have become increasingly important in the field of organic chemistry
due to the fact that they have a wide range of uses and a flexible reactivity. For
example, intermolecular C–H bond activation, a t ransformative process that involves
the direct activation of carbon-hydrogen bonds to produce new chemical bonds,
has been a significant contributor to the significant advancements that have been
reported in their synthesis. This technique provides a method that is both effective
and environmentally friendly for gaining access to cyclic sulfoximines. It also offers
a wide variety of compounds that have the potential to be utilized in the fields
of medical chemistry and materials research. At one point in time, the fact that
sulfoximine derivatives offer desirable qualities as viable medication candidates was
disregarded; nevertheless, in recent times, this point has been brought back into focus.
In addition, the C–H activation of sulfoximines has been widely recognized to be
an effective way for the construction of complex scaffolds that have the potential to
exhibit bioactivities. This is especially true ever since Bolm found the first effective
strategy for the Rh-catalyzed annulation of sulfoximines and alkynes in 2013 [
45].
Furthermore, it was demonstrated that methyl phenyl sulfoximine (MPS) possesses
superior coordination adaptation to the transition metal center in C–H activation
steps in comparison to other nitrogen hetero groups [
46
]. In a nutshell, the cyclic
sulfoximines are characterized by their exceptional qualities, particularly in the field
of medicine. With the aforementioned ideas in mind, and on the basis of our extensive
research on the synthesis of sulfoximines [
47
–
51], the focus of this review is on the
developments that have occurred in the synthesis of cyclic sulfoximines through
the activation of C–H bonds since 2018. Although it was important to note that the
1.2 Synthesis of Cyclic Sulfoximines 19
Co-catalyzed technique was challenging to carry out without any hiccups, current
developments in this field have also led to significant advancements [
52
–
57
].
In this chapter, the cyclic sulfoximines that are synthesized through the activa-
tion of intermolecular C–H bonds are discussed. Also, investigates the synthetic
techniques and highlight the significance of different approaches within the larger
context of organic synthesis.
1.2.1 Metal Carbenoids as Coupling Partners
In organic chemistry, within the field of organic synthesis the utilization of metal
carbenoids as coupling partners has emerged as a potent method for the formation
of carbon–carbon bonds. Metal carbenoids are reactive intermediates that include a
divalent carbon bonded to a metal center. They are frequently produced from diazo
compounds which are the source of their formation. Due to the fact that these species
have a varied range of transformations and a remarkable reactivity profile, they are
extremely useful in the process of carbon–carbon bond formation. One of the most
notable applications includes the utilization of metal carbenoids in transition metal-
catalyzed reactions. In these reactions, the metal acts as an essential mediator in order
to facilitate the coupling process [
58
]. As an illustration, catalysts made of rhodium
and copper are widely utilized in order to facilitate reactions with metal carbenoids.
Utilization of the metal carbenoid coupling approach can be found in a variety of
carbon–carbon bond-forming processes, such as cyclopropanation, olefination, and
ylide production. Through the utilization of this method, it is possible to design
intricate molecular structures that are both highly efficient and selective.
Furthermore, the adaptability of metal carbenoids as coupling partners extends
to their engagement with a wide variety of functional groups, making them an
extremely useful instrument for the synthesis of a wide variety of organic molecules.
As researchers continue to investigate and improve upon this technology, the utiliza-
tion of metal carbenoids in coupling reactions has a great deal of promise for the
advancement of the field of organic synthesis. It provides novel methods for the
development of complex molecular architectures.
In cyclic sulfoximines, one interesting way to make organic compounds is to use
metal carbenoids as binding partners with cyclic sulfoximines. Because they have a
sulfur–nitrogen double bond inside a cyclic structure, cyclic sulfoximines combine
in a unique way that can be used with metal carbenoids to create a wide range of
bonds. One important use is the metal-catalyzed cyclopropanation of cyclic sulfox-
imines with metal carbenoids. Rhodium and copper are often used as catalysts in
these processes, which make it easier for cyclopropane rings to form in the sulfox-
imine framework. This method makes it easy to build complicated three-dimensional
structures quickly and is useful for making a wide range of cyclic sulfoximine
derivatives.
20 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
Additionally, metal carbenoids can react with cyclic sulfoximines to make new
carbon–carbon double bonds through olefination. This method lets you change the
cyclic sulfoximine scaffold’s electronic and steric properties, which could change its
biology or chemical properties. Using metal carbenoids as binding partners in cyclic
sulfoximine chemistry shows how well the unique reactions of sulfoximines and the
wide range of metal-catalyzed reactions work together. As more s tudy is done on
these methods and made better, this approach shows promise for making complex
molecular structures quickly and accurately, which could have uses in materials
science and medicinal chemistry.
1.2.2 Diazo Compounds as Carbene Precursors
Diazocompounds, including diazoalkanes, serve as versatile and widely applicable
carbene precursors in a wide range of organic transformations. These compounds can
produce carbenes through a process known as diazo transfer, in addition to having a
nitrogen-nitrogen double bond (N=N). This is why diazocompounds are considered
valuable synthetic intermediates, as the carbenes they produce can participate in a
variety of reactions [
59
]. It is usual practice to make use of rhodium and copper
catalysts in order to successfully assist these conversions.
Several important processes employ diazocompounds as carbene precursors,
including: C–H Insertion Processes: In these reactions, diazocompounds can be
utilized for C–H insertion reactions, in which the carbene intermediate inserts itself
into a carbon-hydrogen bond, therefore generating a new carbon–carbon bond.
Cyclopropanation is a process that results in the creation of cyclopropane rings. This
chemical reaction involves the transfer of carbenes from diazocompounds to olefins
or alkynes. Rhodium and copper are examples of transition metals that are respon-
sible for catalyzing this reaction. Aziridination, which is similar to cyclopropanation,
the generation of carbenes for the aziridination of olefins, which results in the forma-
tion of three-membered cyclic structures, can be accomplished by diazocompounds.
Furthermore, carbenes can also be transferred to aldehydes Carbenes, produced from
diazocompounds, can undergo carbene transfer reactions with aldehydes, ultimately
resulting in the synthesis of cyclopropanols.
Also, under catalytic conditions, diazocompounds can react with phosphine oxides
in the presence of an appropriate catalyst, leading to the formation of phosphinyl
carbenes. This opens the door for Wittig-type reactions with aldehydes or ketones.
The three outlined reactions offer a strategic approach for synthesizing complex
and functionalized molecular structures. These reactions highlight the synergistic
reactivity that exists between diazo compounds and cyclic sulfoximines. Utilizing
transition metal catalysts in these transformations improves control over regio- and
stereoselectivity, enabling the production of complex structures with potential appli-
cations in medical chemistry and materials science. Given the progress made in this
field of study, the interaction between diazo compounds and cyclic sulfoximines
could lead to the creation of new and useful synthetic methods.
1.2 Synthesis of Cyclic Sulfoximines 21
A Rh(III)-catalyzed intermolecular an-nulation between sulfoximines 1 and diazo
compounds was initially explained by Bolm and colleagues in 2015. This an-nulation
was used for the synthesis of 1,2-benzothiazine products (Scheme
1.18)byuse of the
domino C–H activation/cyclization/condensation pathway. In the presence of NaOAc
(1.0 equiv) as a base, it was demonstrated that DCE is the most effective solvent,
and the yield of the products that were expected to be produced reached up to 99%.
Furthermore, this particular type of C–H activation exhibited a wide tolerance for
substitution and made it possible to obtain the necessary adducts with exceptional
yields ranging from 32–99%.
Pawar and colleagues [60], were the first to report on the Ir(III)-catalyzed C–
H functionalization of sulfoximines with α-diazocarbonyl compounds in 2018, as
shown in (Scheme
1.19). In addition, this C–H functionalization system demonstrated
compatibility with a wide range of sulfoximines, encompassing electron-donating
substituents, halogen substituents, and olefin motifs. Nevertheless, the inclusion of
potent electron-withdrawing groups as NO
2
and CN led to notably diminished yields.
Furthermore, this procedure demonstrated tolerance towards diazo compounds with
diverse substituents.
There are three steps involved in the feasible process, which is referred to as
Scheme 3. Initially, the reaction between pivalic acid and the neutral Ir(III) species
A1 with catalytic activity is created by the reaction of [Cp*IrCl
2
]
2
. Through the
processes of deprotonation and metallization, the next step is for NH-sulfoximines
S
O
NH
R
2
R
1
+
R
3
R
4
N
2
O
[Cp*Rh(MeCN)
3
][SbF
6
]
2
(2 mol%)
NaOAc, DCE, 100
o
C
S
O
R
2
R
1
N
R
3
R
4
R
1
= H, Me, OMe, Br, Cl, NO
2
, naphthyl
R
2
= Me, Et, i-Pr, cyclopropyl, hexyl, octyl
R
3
= CO
2
Et, Ts, PO(OMe)
2
, COEt
R
4
= H, Ph, Me, Et, OMe-C
6
H
4
, Br-C
6
H
4
, F-C
6
H
4
, 2-furanyl, 2-naphthyl
30 examples
(32–99% yield)
Scheme 1.18 Rhodium-catalyzed annulation reactions for the synthesis of 1,2-benzothiazines
S
O
NH
R
R
1
+
R
2
N
2
R
3
O
[IrCp*Cl
2
]
2
, PivOH
TFE, 25
o
C, 3h
N
S
O R
R
1
R
3
R
2
R = Me, Et, i-Pr, cyclopropyl
R
1
= H, Me, OMe, Ph, F, Cl, Br, NO
2
, CN, COPh, C
2
H
3
, C
2
H
2
CO
2
Et, naphthyl
R
2
= CO
2
Et, CO
2
Me, CO
2
t-Bu, CO
2
Ph, PO(OMe)
2
R
3
= H, Me, Et, n-Pr, i-Pr, cyclopropyl, CH
2
Cl, Ph, 2-thienyl, 2-furyl
35 examples (49–94%)
Scheme 1.19 Ir(III)-catalyzed C–H functionalization of sulfoximines with α-diazocarbonyl
compounds