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72 2 Transformation of Sulfoximines and Cyclic Sulfoximines
Organic synthesis reactions face a major challenge in achieving the result of cross-
coupling reactions between two nucleophiles that are rich in electrons [
26]. There
have been reports of various synthetic methods that are comparable to these in the
past few years. An example of this is the use of transition metal catalysis in order to
help with oxidative coupling reactions that result in the formation of C–C or C–N
bonds between two nucleophilic substrates [
27]. One study was published on the
N-alkynylation of NH-sulfoximines; however, the yield was extremely inadequate,
and the use of sodium azide, which is a potentially hazardous chemical, was required
(Scheme
2.23)[28].
Bolm described an oxidative cross-coupling method with a high yield to synthesize
N-alkynyl sulfoximines. As shown in Scheme
2.24 (Eq. a), hydrogen peroxide was
used as the oxidizer and copper (II) salt as the catalyst for this method. Furthermore,
the N-acylated sulfoximines could be easily gotten in large amounts by making a
simple change to the purification method (Scheme
2.24, Eq. b).
In the same year, Bolm reported that aryl propiolic acids and sulfoximines could
be coupled decarboxylatively to make N-alkynyl sulfoximines. Scheme
2.25 shows
that both the aryl propiolic acids and the sulfoximines can bond to a wider range of
substrates.
R
2
S
O
NH
R
1
+
Ph
Cl
R
2
S
O
N
R
1
Ph
NaN
3
, DMSO
rt, 3 days
Scheme 2.23 N-Alkynylation of NH-sulfoximines promoted by NaN
3
R
1
S
O
NH
R
2
+
R
3
CuCl
2
(10 mol%)
O
2
(1 atm),Na
2
CO
3
, pyr.
R
1
S
O
N
R
2
R
3
1,4-dioxane, 70
o
C, 6 h
a)
R
1
S
O
NH
R
2
+
R
3
CuCl
2
(10 mol%)
O
2
(1 atm), pyr., Na
2
CO
3
R
1
S
O
N
R
2
O
R
3
1,4-dioxane, 70
o
C, 6 h
b)
48-84% yield
55-80% yield
Scheme 2.24 a CuCl
2
-catalyzed oxidative coupling of NH-sulfoximines and terminal alkynes
b N-Acylated sulfoximines under the same conditions
R
1
S O
NH
+
R
2
CuBr
2
(10 mol%)
pyridine (20 mol%)
R
1
S
O
N R
2
OH
O
K
3
PO
4
, toluene,
air, 80
o
C, 16 h
59-94% yield
Scheme 2.25 CuBr
2
-catalyzed decarboxylation coupling reaction to achieve N-alkynylation of
NH-sulfoximines
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 73
R
1
S
O
NH
R
2
+
R
3
Br
Cu(OAc)
2
(10 mol%)
phenanthroline (20 mol%)
R
1
S
O
N
R
2
R
3
K
2
CO
3
, toluene
argon, 60
o
C, 48 h
24-86% yield
Scheme 2.26 Cu(OAc)
2
-catalyzed C–N coupling to achieve N-alkynylation of NH-sulfoximines
Scheme 2.27
N-Trifluoromethylation of
NH-sulfoximines
R
1
S
O
R
2
NH
+
Me
3
SiCF
3
Ag
2
CO
3
(0.2 equiv)
1,10-phen (0.4 equiv)
R
1
S
O
R
2
N
CF
3
1,4-dioxane, O
2
, 60
o
C
33-85% yield
According to Scheme 2.26, Bolm’s group carried out a copper-catalyzed C–
N cross-coupling s ynthesis of NH-sulfoximines and bromoacetylenes during the
following year. This reaction resulted in the production of N-alkynyl sulfoximines
with yields that ranged from average to good.
The addition of CF
3
groups to organic compounds has the potential to change
various chemical properties, including lipophilicity, metabolic stability, and confor-
mational behavior, among others [
29]. Contrary to the C-trifluoromethylation that
has been developed [
30], the bonding of N-CF
3
bonds is still difficult to achieve. This
is mostly due to the fact that it frequently requires the use of hazardous chemicals
in combination with severe reaction conditions [
31
]. It is without any doubt that N-
trifluoromethylation must be performed with trifluoromethylation reagents that are
easily available on the market and are completely safe [
32]. The Ag
2
CO
3
-catalyzed
N-trifluoromethylation of sulfoximines with trifluoromethyltrimethylsilane was
developed by Bolm’s team in 2015 (Scheme
2.27)[33].
It is very important to be able to control the stereoselectivity and regioselectivity
of N-alkynylation reactions, especially when NH-sulfoximines have more than one
reactive site. There are different places on the nitrogen atom in NH-sulfoximines
where it can participate in alkynylation. Achieving regioselectivity makes sure that
only certain alkynyl groups are introduced. To make enantioenriched N-alkynylated
NH-sulfoximine products, stereoselective methods can be used. A lot of progress has
been made in N-alkynylating NH-sulfoximines, but there are still problems to solve.
Getting high regioselectivity is still something that is being researched, especially
when it comes to complex substrates. Future research could focus on making catalytic
systems that last longer and are easier to use, finding new alkynylating agents, and
fixing problems with scaling up.
In conclusion, N-alkynylation of NH-sulfoximines is a powerful way to make new
chemicals because it combines the special properties of NH-sulfoximines with the
flexibility of alkynes. The N-alkynylated products that are made are used in medic-
inal chemistry, materials science, and other fields. This shows how important this
change is in modern organic synthesis. More research into N-alkynylation reactions
involving NH-sulfoximines is likely to reveal new ways to make chemicals, increase
74 2 Transformation of Sulfoximines and Cyclic Sulfoximines
the number of substrates that can be used, and help create new compounds with
specific properties.
2.1.6 Oxidative N–P Coupling of NH-Sulfoximines
One way that NH-sulfoximines are N-coupled is by making a new bond between
the sulfoximine’s nitrogen atom and a phosphorus-containing moiety. This method
for making things lets different kinds of phosphorus functions be added to the NH-
sulfoximine structure, which makes N–P coupled products. The compounds that
are made are useful building blocks for making complex molecules that are used
in many areas of organic chemistry. The N–P coupling of NH-sulfoximines is an
interesting way to make organic compounds because it uses the unique properties of
NH-sulfoximines and the wide range of chemistry found in compounds that contain
phosphorus. NH-sulfoximines are different because t hey have a nitrogen atom that
is directly connected to the sulfur–oxygen double bond within the imine functional
group. They can be used in a number of different ways to form N–P bonds. Coupled
NH-sulfoximines are joined with reagents that contain phosphorus in this transfor-
mative reaction, creating N–P coupled products. This study goes into detail about
how to make N–P coupling reactions with NH-sulfoximines, how they work, and
what they might be used for.
The N–P coupling reaction with NH-sulfoximines can be used with a wide range
of phosphorus-containing substances that have different functional groups and substi-
tution patterns. Because of this, phosphorus moieties can be added selectively, giving
scientists access to N–P coupled products with specific properties. The compounds
that are made can be used as building blocks to make phosphine oxides, phospho-
nates, or other structures with phosphorus. There are a number of different synthetic
strategies that can be used to couple NH-sulfoximines to N–P bond molecules. One
common method is to mix NH-sulfoximines with reagents that contain phosphorus,
like phosphines or phosphorus halides, while using the right catalysts. How the reac-
tion is set up and the catalysts used are very important for getting high yields and selec-
tivity. Transition metal-catalyzed reactions, such as palladium or nickel-catalyzed
processes, are often used to make the N–P coupling reaction easier.
The mechanism of N–P coupling reactions usually involves the coordination of the
phosphorus-containing reagent to the transition metal catalyst. This makes it easier
for the N–P bond to form. It is the nucleophilic nitrogen atom of the NH-sulfoximine
that attacks the phosphorus center, which makes the N–P coupled product. It is impor-
tant to understand the details of how the reaction works in order to improve reac-
tion conditions, achieve high regio- and stereoselectivity, and make more substrates
usable.
For N–P coupling reactions involving NH-sulfoximines, transition metal-
catalyzed reactions are usually the best choice. Through cross-coupling reactions
sped up by palladium or nickel, NH-sulfoximines can directly connect with reagents
that contain phosphorus. These catalytic systems help the N–P bond form, offering
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 75
R
1
S
NH
O
R
2
+
P
H
O
R
3
R
3
I
2
, H
2
O
2
R
1
S
N
O
R
2
P
O
R
3
R
3
PEG400, 60
o
C, 24 h
51-88% yield
Scheme 2.28 Oxidative N–P coupling of NH-sulfoximines
high efficiency, mild reaction conditions, and the ability to work with a wide range
of functional groups.
A more environmentally friendly method for the synthesis of N–Phosphinosul-
foximines was originally published by Zeng’s group in 2019 [
34]. An I
2
-catalyzed
oxidative N–P cross-coupling reaction made this method possible. Sulfoximines and
diarylphosphine oxides were used as starting materials for the direct synthesis of
N–Phosphonyl sulfoximines (as shown in Scheme
2.28).
A lot of progress has been made in the N–P coupling of NH-sulfoximines, but there
are still problems to solve. A lot of work is being done to get high regioselectivity,
especially in substrates that are complicated, and to make catalytic systems that
last longer and are easier to use. Finding new reagents that contain phosphorus and
fixing problems with scaling up will make this transformation even more useful.
Finally, the N–P coupling of NH-sulfoximines shows itself to be a strong way to
make new chemicals because it combines the special properties of NH-sulfoximines
with the wide range of chemistry found in compounds that contain phosphorus. The
N–P coupled products that are made are useful in medicinal chemistry, materials
science, and other fields. This shows how important this change is in modern organic
synthesis. More research into N–P coupling reactions involving NH-sulfoximines is
likely to lead to new ways of making chemicals, a wider range of substrates that can
be used, and the creation of new compounds with specific properties.
2.1.7 The N–S Coupling of Sulfoximines
N–S coupling of sulfoximines involves the formation of a new bond between the
nitrogen atom of the sulfoximine and a sulfur-containing moiety. This synthetic
strategy offers a versatile means to introduce sulfur functionalities onto the sulfox-
imine scaffold, leading to the creation of N–S coupled products. The resulting
compounds serve as valuable intermediates. The N–S coupling of sulfoximines
constitutes a compelling and versatile synthetic transformation, capitalizing on the
unique reactivity of sulfoximines and enabling the creation of structurally diverse
compounds. Sulfoximines, characterized by a sulfur–oxygen double bond within the
imine functional group, serve as excellent substrates for the formation of N–S bonds.
This reaction involves the coupling of sulfoximines with sulfur-containing reagents,
leading to the generation of N–S coupled products. The following exploration delves
76 2 Transformation of Sulfoximines and Cyclic Sulfoximines
into the synthetic strategies, key reaction mechanisms, and potential applications
of N–S coupling reactions involving sulfoximines synthesis of bioactive molecules,
materials, and diverse organic compounds.
There are different synthetic strategies that can be used to connect sulfoximines
on the N–S side. Most of the time, sulfoximines react with reagents that contain
sulfur, like thiols or disulfides, while catalysts or activating agents help the reaction
go smoothly. Picking the right reaction conditions is very important for getting high
yields and selectivity. Transition metal-catalyzed reactions, like copper-catalyzed
processes, have been shown to help the N–S coupling happen. The N–S coupling
reaction with sulfoximines can be used with a wide range of sulfur-containing chem-
icals that have different functional groups and substitution patterns. Because of this,
selectively adding sulfur moieties i s possible, giving us access to N–S coupled prod-
ucts with specific properties. The compounds that are made are used in materials
science, medicinal chemistry, and as important building blocks in the production of
complex molecules.
It is very important to be able to control the regioselectivity and stereoselectivity
of N–S coupling reactions, especially when sulfoximines have more than one reactive
site. In sulfoximines, the nitrogen atom can couple with sulfur at different locations,
and achieving regioselectivity makes sure that only certain sulfur moieties are intro-
duced. To make enantioenriched N–S coupled sulfoximine products, stereoselective
methods can be used. For N–S coupling reactions involving sulfoximines, transition
metal-catalyzed reactions are often the best choice. Processes that use copper as a
catalyst, for example, let sulfoximines directly combine with chemicals that contain
sulfur. These catalytic systems help the N–S bond form, offering high efficiency, mild
reaction conditions, and the ability to work with a wide range of functional groups.
The way that N–S coupling reactions work is that the sulfur-containing reagent binds
to the transition metal catalyst, which makes it easier for the N–S bond to form. I t
is the nucleophilic nitrogen atom of the sulfoximine that attacks the sulfur center,
which makes the N–S coupled product. It is important to understand the details of
how the reaction works in order to improve reaction conditions, achieve high regio-
and stereoselectivity, and make more substrates usable.
Through the process of sulfur substitution, NH-sulfoximines are capable of under-
going chemical changes in nitrogen [
35
]. The importance of this fundamental varia-
tion has been demonstrated clearly by its recent use in the industrial sector [
36
]. The
synthesis of N-alkylthiosulfoximines was traditionally done by a nucleophilic substi-
tution reaction involving sulfoximine and alkyl hypochlorothioites (Scheme
2.29)
[
37
].
Scheme 2.29 Conventional
synthesis of
N-alkylthiosulfoximines
with alkyl hypochlorothioites
as reactants
R
1
S
R
2
O
NH
+
R
3
S
Cl
NaH, PhH
R
1
S
R
2
O
N
S
R
3
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 77
Through the use of the corresponding N-Br derivatives, the Bolm-led team
was able to successfully synthesize N-trifluoromethylthiosulfoximines from NH-
sulfoximines in 2015. The reaction was carried out in two stages: first, the bromi-
nation took place on the nitrogen of the sulfoximines, and then the nucleophilic
substitution was performed using silver trifluoromethanethiolate (Scheme
2.30)[38].
The preparation of the products was difficult when using a one-pot reaction. The
N-alkylthioetherification of NH-sulfoximines was accomplished by Cheng in 2016
through the development of a copper-catalyzed oxidative coupling reaction that was
carried out under mild reaction conditions. The formation of a N–S bond was achieved
through the use of a readily available dialkyl disulfide as the source of sulfur in this
method, as shown in Scheme
2.31 [39
].
In addition, the reaction of thiols and thiophenols can also perform the N–S
coupling of sulfoximines. There is a special focus given to the following three
methods:
The iodine-catalyzed N–H/S–H oxidative coupling reaction of sulfoximines and
different thiols to produce sulfur–nitrogen bonds is the first approach that Zeng has
reported on. This process is used to make sulfur–nitrogen bonds. In the presence
of hydrogen peroxide, the reaction was carried out in PEG400 under noN–Severe
conditions (Scheme
2.32, Eq. a) [40].
R
1
S R
2
O
NH
R
1
S
R
2
O
N
S
CF
3
NBS, CH
2
Cl
2
R
1
S
R
2
O
N
Br
AgSCF
3
, CH
3
CN
rt, 20 min
rt, 30 min
86-99% yield
51-98% yield
Scheme 2.30 Bolm’s two-step synthesis of N-trifluoromethylthiosulfoximines
R
1
S R
2
O
NH
R
1
S
R
2
O
N
S
CuI (20 mol%)
NaOAc (3 equiv)
+
R
3
S
S
R
3
R
3
DMSO, 60
o
C, 15 h
Ph
S
Ph
O
NH
Ph
S
Ph
O
N
base
or heat
Ph
S
Ph
O
N
S
Ph
PhSCu(I)
Ph S
SPh
Cu(I)
disproportionation
Cu(0) + (PhS)
2
Cu(II)
O
2
Cu(I)
PhSSPh
PhSSPh
43-89% yield
Scheme 2.31 CuI-catalyzed N–S bond oxidative coupling
78 2 Transformation of Sulfoximines and Cyclic Sulfoximines
I
2
(10 mol%), H
2
O
2
(2.5 equiv)
PEG400, 50
o
C, 4 h
59-97% yield
R
1
S R
2
O
NH
R
1
S
R
2
O
N
S
[Cu(DMAP)
4
I]I (30 mol%)
+
R
3
SH
R
3
CH
2
Cl
2
, rt, overnight, O
2
60-95% yield
h-BN@Y-CD@Cu(OAc)
2
(0.1 equiv)
H
2
O-EtOH, rt, 24 h, air
44.3-98% yield
a
b
c
Scheme 2.32 a I
2
-catalyzed N–S oxidative coupling reaction; b [Cu(DMAP)
4
I]I-catalyzed N–S
oxidative coupling reaction; c h-BN@γ-CD@Cu(OAc)
2
-catalyzed N–S oxidative coupling reaction
[Cu(DMAP)
4
I] Catalytic oxidative coupling of thiophenols with NH-
sulfoximines at room temperature is a second method that can be used to achieve the
synthesis of N-alkylthiolation sulfoximines (Scheme
2.32, Eq. b) [41]. In addition,
Wu’s team is working on developing another method. Through the reaction of oxida-
tive coupling, the h-BN–Supported copper (II) nanomaterials are used as catalysts
for the synthesis of N–S-substituted sulfoximines (Scheme
2.32, Eq. c) [42].
An environmentally friendly oxidative coupling method has been developed by
Zeng team for the N–Sulfonylation of NH-sulfoximines in water, which is catalyzed
by ammonia in the air at room temperature. The synthesis of N–Sulfonyl sulfox-
imines was carried out with sodium arylsulfinate functioning as the sulfonyl source
(Scheme
2.33)[43
]. This occurred in the presence of a catalytic amount of carbon
dioxide and hydrogen peroxide.
Coupling N–S to sulfoximines is a strong and flexible way to make chemicals
because it lets you make a wide range of compounds with sulfur functions. The N–S
coupled products that are made are useful in many areas, such as medicinal chemistry
and materials science. This shows how important this change is in modern organic
synthesis. Researchers who keep looking into N–S coupling reactions involving
sulfoximines are likely to find new ways to make chemicals, make the substrates that
can be used bigger, and help make new compounds with specific properties.
R
1
S R
2
O
NH
R
1
S
R
2
O
N
S
I
2
(0.2 equiv), H
2
O
2
(0.2 equiv)
+
R
3
S
R
3
O
ONa
O
O
H
2
O, rt, 24 h, air
45-81% yield
Scheme 2.33 N–Sulfonylation of NH-sulfoximines
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 79
2.1.8 C–N Bond Coupling of Imidazo[1,2-ɑ]pyridines
with NH-Sulfoximines
The C–N bond coupling of imidazo[1,2-ɑ]pyridines with NH-sulfoximines repre-
sents a noteworthy and chemically intricate synthetic transformation, merging the
unique structural features of imidazo[1,2-ɑ]pyridines with the reactivity of NH-
sulfoximines. Imidazo[1,2-ɑ]pyridines, characterized by a fused imidazole and pyri-
dine ring system, serve as versatile heterocyclic scaffolds with diverse biolog-
ical and pharmaceutical relevance. The coupling of these structures with NH-
sulfoximines, which contain a nitrogen atom directly bonded to a sulfur–oxygen
double bond, results in the creation of C–N bonds, adding complexity and diversity
to the synthesized compounds. The C–N bond coupling of imidazo[1,2-ɑ]pyridines
with NH-sulfoximines involves the formation of a new bond between the carbon
atom of the imidazo[1,2-ɑ]pyridine and the nitrogen atom of the sulfoximine. This
synthetic strategy enables the incorporation of the imidazo[1,2-ɑ]pyridine scaffold
with the nitrogen-containing moiety of the sulfoximine, leading to the generation of
structurally diverse products. The resulting compounds hold promise in medicinal
chemistry, materials science, and the synthesis of biologically active molecules.
The synthesis of imidazo[1,2-ɑ]pyridines with NH-sulfoximines often involves
the reaction of imidazo[1,2-ɑ]pyridines with NH-sulfoximines under suitable reac-
tion conditions. The choice of conditions, catalysts, and reagents plays a crucial role in
achieving high yields and regioselectivity. Transition metal-catalyzed processes, such
as palladium-catalyzed cross-coupling reactions, have proven effective in facilitating
the C–N bond coupling. The C–N bond coupling of imidazo[1,2-ɑ]pyridines with
NH-sulfoximines exhibits a broad scope and versatility, accommodating a variety
of imidazo[1,2-ɑ]pyridines and NH-sulfoximines with diverse substitution patterns
and functional groups. This versatility allows for the selective introduction of the
sulfoximine moiety onto the imidazo[1,2-ɑ]pyridine scaffold, providing access to a
range of structurally unique compounds.
Using transition metals to speed up reactions, palladium-catalyzed cross-coupling
reactions are one type of transition metal that is often used to connect imidazo[1,2-
ɑ]pyridines with NH-sulfoximines through a C–N bond. The imidazo[1,2-ɑ]pyridine
carbon atom can directly couple with the sulfoximine nitrogen atom through these
catalytic systems. They offer high efficiency, mild reaction conditions, and compati-
bility with a wide range of functional groups. The C–N bond coupling reaction works
by turning on both the imidazo[1,2-ɑ]pyridine and the NH-sulfoximine with the help
of a catalytic system. The imidazo[1,2-ɑ]pyridine goes through oxidative addition,
which creates a metal-intermediate when the right catalyst is present. When this
happens, the sulfoximine’s nitrogen atom attacks with nucleophilia, which makes
the C–N bond. It is very important to understand these steps in order to improve
reaction conditions and make more substrates work.
Using diacetoxy iodobenzene as an oxidant, Wu et al. reported an oxidative C–N
bond coupling of the C-3 C–H bond of imidazo[1,2-ɑ]pyridine and NH-sulfoximines.
80 2 Transformation of Sulfoximines and Cyclic Sulfoximines
R
1
S R
2
O
NH
R
1
S
R
2
O
N
PhI(OAc)
2
(1.2 equiv)
+
N
N
R
4
R
3
N
N
R
4
R
3
DMSO, 30
o
C, 3 h
57-91% yield
Scheme 2.34 Oxidative C–N bond coupling of imidazo[1,2-α]pyridines with NH-sulfoximines
This coupling resulted in the selective synthesis of a series of C-3 sulfenimido-
functionalized imidazo[1,2]pyridine products (as shown in Scheme
2.34)[44].
While significant strides have been made in the C–N bond coupling of
imidazo[1,2-ɑ]pyridines with NH-sulfoximines, challenges remain. Achieving high
regioselectivity, particularly in the presence of multiple reactive s ites, and devel-
oping more sustainable and practical catalytic systems are areas of ongoing research.
The continuous exploration of new imidazo[1,2-ɑ]pyridine derivatives and NH-
sulfoximines, as well as the investigation of alternative coupling methods, will
further advance the synthetic possibilities and broaden the scope of applicable
substrates. In conclusion, the C–N bond coupling of imidazo[1,2-ɑ]pyridines with
NH-sulfoximines represents a dynamic and versatile synthetic strategy, combining
the structural features of imidazo[1,2-ɑ]pyridines with the reactivity of NH-
sulfoximines. The resulting compounds hold promise in medicinal chemistry and
materials science, offering new avenues for the design and synthesis of biologi-
cally relevant molecules with diverse applications. The ongoing exploration of this
coupling reaction is expected to uncover new synthetic methodologies, enhance
selectivity, and contribute to the synthesis of novel and complex molecular archi-
tectures.
2.1.9 Cyclization Reaction of Thiadiazine 1-Oxides
and NH-Sulfoximines
The cyclization reaction of Thiadiazine 1-oxides with NH-sulfoximines is an inter-
esting and useful chemical change that combines the unique properties of Thiadiazine
1-oxides with the ability to react with other chemicals. Thiadiazine 1-oxides, which
have a sulfur–nitrogen ring with an oxygen atom inside, are useful building blocks
for organic synthesis. The reaction with NH-sulfoximines creates a cyclized product.
This often leads to structurally complex molecules that can be used in many areas,
such as medicinal chemistry, materials science, and the creation of biologically active
compounds. It is very important to control the cyclization reaction’s regioselectivity
and stereoselectivity, especially when Thiadiazine 1-oxides and NH-sulfoximines
have more than one reactive site. Getting regioselectivity makes sure that the cyclized
product forms only in the right places, and stereoselective methods can be used to
make products that are either enantioenriched or diastereomerically pure.
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 81
The cyclization reaction involves the transformation of Thiadiazine 1-oxides,
which typically possess an oxygen atom within the sulfur–nitrogen ring, with NH-
sulfoximines. This synthetic strategy leads to the formation of a cyclized product
through the reaction between the oxygen of the Thiadiazine 1-oxide and the nitrogen
of the sulfoximine. The resulting cyclized compounds represent a unique class of
heterocyclic molecules with potential applications in various fields of organic chem-
istry. The mechanism of the cyclization reaction involves the interaction between the
oxygen atom of the Thiadiazine 1-oxide and the nitrogen atom of the sulfoximine.
The reaction may proceed through nucleophilic attack, ring closure, or other intricate
pathways depending on the specific conditions employed. Understanding the mech-
anistic details is essential for optimizing reaction conditions, achieving high regio-
and stereoselectivity, and expanding the scope of applicable substrates.
Thiadiazine 1-oxides and NH-sulfoximines are often used to make cyclized prod-
ucts by reacting with each other in the right conditions. To get high yields and
selectivity, it is very important to choose the right catalysts, solvents, and reaction
temperatures. The synthetic route can be different, and methods that don’t use metals
or metal catalysts have been studied. This gives designers more freedom in how they
design this cyclization.
Wagner and Reinchtl are the ones who initially reported the presence of derivatives
of thiadiazine 1-oxides in 1964 [
46
]. A few years later, Williams and Cram [
46
], along
with their professional colleagues at Beiersdorf [
47
], and Godecke [
48
], discovered
new synthetic methods for the production of compounds of this type. These first
investigations laid the foundation for further studies on the biological activity of
thiadiazine 1-oxides. The results of these investigations revealed some interesting
characteristics of thiadiazine 1-oxide derivatives (Scheme
2.35, Compound 1) that
have possible uses in the medical field [
49, 50]. As a case study, it was discovered that
NSC287474 (Scheme
2.35, Compound 2) is a possible enzyme reverse transcriptase
agent that protects cells against HIV invasion [
51]. According to the results of tests
on animals, thiadiazine 1-oxide has a blood pressure-lowering action that is similar
to that of the commonly used hypertension medication Prazosin [
53
], as shown in
Scheme
2.35, Compound 3.
In order to make thiadiazine 1-oxides, N–Protected sulfoxides must first be
changed into sulfinimides using O-(mesitylenesulfonyl)hydroxylamine (MSH) as
a key amination reagent (Scheme
2.35).
In 2016, it was stated that S-trifluoromethyl sulfoximines were used for the first
time as an ortho-directing group for the purpose of functionalizing aryl groups that
were attached to sulfur atoms. The aromatic ring undergoes the addition of a number
of electrophiles, including halogen, carbon, oxygen, sulfur, and boron, among others.
Electrophiles or o-azidosulfoximines that have been carefully chosen can react with
cyclic S-trifluoromethyl sulfoximines to make this compound (Scheme
2.36)[54].
In addition to this, a series of fluorinated analogs of prazosin were synthesized.
A rhodium-catalyzed ortho-amidation of sulfoximines was developed by Bolm’s
group in 2016 with the purpose of synthesizing thiadiazine 1-oxide intermediates
(Scheme
2.37). For the purpose of gaining possible biologically active products, it is
possible to avoid the traditional multi-step method by following an easy procedure