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52 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
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54 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
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Chapter 2
Transformation of Sulfoximines
and Cyclic Sulfoximines
2.1 Transformation of Sulfoximines into Sulfoximine
Derivatives
There are different ways that NH-sulfoximines can be transformed, but the most
common reaction position is on the N atom. A lot of them make N–C, N–S, and N–P
bonds by using nucleophilic substitution reaction. Some reactions are also said to
have occurred on the aryl groups that are connected to the S atom. Sulfoximines are
capable of undergoing a wide range of transformations, which can result in the devel-
opment of a wide variety of chemical entities with distinctive characteristics. The
following is a list of common transformations that sulfoximines undergo: The process
of reducing sulfoximines to their corresponding sulfides is known as reduction. This
process typically involves the utilization of reducing agents such as hydrides or metal
catalysts. Using more powerful oxidizing agents to oxidize sulfoximines results in
the creation of sulfones. This process is referred as oxidation to sulfones.
The introduction of different chemical moieties can be accomplished through the
process of functional group transformations. In addition, sulfoximines are capable of
undergoing a variety of functional group transformations, such as substitutions, addi-
tions, and eliminations. This product is a nucleophilic addition. Amination processes:
Sulfoximines can be subjected to amination processes in order to introduce addi-
tional amine groups. These reactions are referred to as nucleophilic addition reac-
tions. Cross-Coupling Reactions: Sulfoximines have the ability to take part in cross-
coupling reactions, which enables the formation of carbon–carbon bonds with other
organic or organometallic compounds. Sulfoximines have the potential to partici-
pate in ring-closing processes, which are mechanisms that result in the formation of
cyclic structures. In the process of metalation reactions, sulfoximines are capable of
undergoing metalation reactions, which include the introduction of a metal onto the
atom of sulfur or nitrogen.
The changes that sulfoximines go through are very interesting in the field of
organic chemistry. They allow for a huge number of reactions that take advantage of
55
56 2 Transformation of Sulfoximines and Cyclic Sulfoximines
the special properties of these molecules. Sulfoximines have many useful qualities
that make them useful building blocks in many synthetic processes. They are identi-
fied by a sulfur–oxygen double bond within the imine functional group. This study
looks into the many changes that sulfoximines can go through, showing how useful
they are for making complicated molecular structures, how they work in medicinal
chemistry, and how they might be used in catalysis. Oxidative transformations: One
of the main ways that sulfoximines change is through oxidative processes, in which
the sulfur atom is changed into sulfoxides or sulfones. To make this change, standard
oxidizing agents like hydrogen peroxide or m-CPBA (meta-chloroperoxybenzoic
acid) are used. In many processes that follow, this oxidation step is a key building
block. This makes it possible to make more sulfoximines. Reductive transformations:
Sulfoximines’ reactive changes in reductive transformations show how flexible they
are. Metal hydrides or borohydrides are some of the reducing agents that can be used
to turn sulfoximines into their matching sulfides. This change is very helpful for
making many different chemicals that contain sulfur, and it shows how sulfoximines
can be used as building blocks in complicated multistep reactions. Halogenation
processes: To change sulfoximines in another way, halogenation processes can be
used. It is possible to add halogen substituents to sulfoximines by chlorinating or
brominating them with the right halogenating agents. This halogenation method
opens up new ways to add functions and change the shape of sulfoximines, which
lets scientists make molecules that are more reactive or have different physical and
chemical properties. Amination reactions: Functional groups containing nitrogen can
be added to sulfoximines through amination reactions. When sulfoximines are mixed
with amines or ammonia, nitrogen is added to the molecule. This creates sulfilim-
ines or sulfonamides. These changes make sulfoximines more structurally diverse
and make them more useful as flexible synthetic intermediates. Cross-coupling reac-
tions: In recent years, cross-coupling reactions involving sulfoximines have become
more well known. Using palladium to speed up coupling reactions, like the Suzuki–
Miyaura or Heck reactions, sulfoximines can join with aryl or vinyl substrates. These
cross-coupling changes make it possible to make compounds with different struc-
tures, which makes it easier to build molecular structures that are very complicated.
Changes in functional groups: Sulfoximines can change their functional groups in a
number of ways, which makes them useful in organic chemistry. In sulfoximines, the
nitrogen–sulfur double bond can take part in nucleophilic addition processes, which
can make new carbon–nitrogen bonds. Sulfoximines can also go through substi-
tutions, rearrangements, or cyclizations, which lets scientists make a wide range of
molecules with complex structures. Asymmetric transformations: Asymmetric trans-
formations of sulfoximines are very important for making chiral sulfoximines. Using
chiral catalysts for asymmetric catalysis makes it possible to make sulfoximines that
are rich in specific enantiomers. This uneven control is very important in medical
chemistry and other fields where stereochemistry has a big effect on how molecules
behave and what they can do.
Reactions catalyzed by metals: Sulfoximines can be used in a lot of different metal-
catalyzed reactions that change a lot of things. Rhodium-catalyzed reactions are
one example of a transition metal-catalyzed process that can quickly build complex
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 57
chemical frameworks. In these processes, sulfoximines often show how versatile they
are by acting as both nucleophiles and electrophiles, which allows for a wide range
of bond-forming events. Cycloaddition reactions: Reactions that use sulfoximines
to cyclically combine substances give us access to special structures that are cyclic
in nature. It is possible to make fused ring systems using Diels–Alder processes
or [3 + 2] cycloadditions with the right dienophiles or dipolarophiles. Naturally
occurring substances and useful molecules are made through these cycloaddition
changes. Catalytic asymmetric transformations: There have been big steps forward
in catalytic asymmetric transformations of sulfoximines. The controlled production
of chiral sulfoximine products is made possible by chiral catalysts, which are used for
enantioselective sulfoximine synthesis. When it comes to making pharmaceuticals
and bioactive compounds, where chirality is very important, this method has huge
effects. Sulfoximine rearrangements: Sulfoximine rearrangements, such as breaking
the nitrogen–sulfur link and then rearranging the molecules, can lead to the creation
of many different nitrogen-containing products. Different chemicals can cause these
rearrangements to happen.
The versatility of sulfoximines in organic synthesis is demonstrated by these trans-
formations, which make it possible to create a large variety of compounds with a
variety of structures and functions. It is possible to achieve certain transformations by
tailoring the reaction conditions and reagents that are used, depending on the output
that is sought from the synthetic process. The changes that sulfoximines go through
have many uses in medicinal chemistry. Because they have good pharmacokinetic
qualities and unique ways of interacting with biological targets, sulfoximines have
become useful building blocks for drug design. By changing the structure of sulfox-
imines in different ways, it is possible to make bioactive chemicals that work better
and more specifically.
2.1.1 N-Acylation of Sulfoximines
The N-acylation of sulfoximines involves the reaction of sulfoximines with acylating
agents, leading to the formation of N-acylated sulfoximines. This change is important
from a strategic point of view because it makes it possible to add different acyl groups
to the nitrogen atom of the sulfoximine scaffold. These can be simple alkyl or aryl
groups or more complex moieties. The N-acylated sulfoximines that are made have
different chemical properties, are more stable, and are often useful building blocks
for further synthetic development. The N-acylation of sulfoximines is a powerful and
flexible way to make chemicals, because it lets you change their properties and how
they respond in different situations. Sulfoximines have a sulfur–oxygen double bond
inside the imine functional group. They have special electronic and steric features
that make them interesting starting materials for N-acylation reactions. A molecular
change takes place when acyl groups are added to the sulfoximine’s nitrogen atom.
This creates N-acylated sulfoximine products. Adding N-acyl groups to sulfoximines
58 2 Transformation of Sulfoximines and Cyclic Sulfoximines
is a key step in the development of bioactive chemicals, materials science, and other
areas of organic synthesis. It also helps make more complicated compounds.
There are different synthetic methods that can be used to N-acetylate sulfox-
imines. In one of the oldest ways, sulfoximines are mixed with acyl chlorides or
anhydrides and a base is present. This creates N-acylated products. A different way
to do the N-acylation is to use amide coupling tools, like carbodiimides or activated
esters. You can fine-tune the selectivity and efficiency of the N-acylation process
by picking the right acylating agent and reaction conditions. Adding acyl groups
to sulfoximines through N-acylation gives you a lot of options. This change works
with different functional groups and substitution patterns, which lets a wide range of
N-acylated sulfoximine derivatives be made. This process is very flexible, so it can
be used to change many kinds of molecules, from natural products to pharmaceutical
intermediates.
N-Acylation is a useful method for adding functions to sulfoximines, which lets
them have a lot of different functions. The acyl group can lead further changes,
making it easier to change only certain parts of the sulfoximine scaffold. This
approach for functionalization helps make molecules that are exactly what are needed
for different uses by giving them the right properties. The reaction conditions and
acylating agents used can change the regioselectivity and stereoselectivity of N-
acylation processes. It is very important to have control over regioselectivity when
sulfoximines have a lot of nitrogen atoms or other reactive sites. Stereoselective N-
acylation processes are useful for making chiral sulfoximines because they let you
make more of the desired enantiomers when you use the right chiral acylating agents
or catalysts.
Cross-coupling methods that use N-acylation of sulfoximines offer a flexible way
to make molecules that are more complicated. N-acylation processes sped up by
transition metals, like Suzuki–Miyaura or Stille couplings, let sulfoximines join with
substrates that contain acyl groups. You can make different molecular structures with
more complexity and usefulness by using these cross-coupling transformations.
Sulfoximines can be N-acylated and used in polymer synthesis to help make
functionalized polymer materials. N-acylation changes the properties of polymers
that contain sulfoximine, which makes them useful for certain uses in materials
science, such as medicine delivery systems, coatings, or electronic devices.
The group of compounds known as α-ketoamides holds major significance as they
serve as essential intermediates in the process of synthesis of several other interesting
products [
1]. It is often found that α-ketoamides synthesized by the reaction of amines
with acid halides (seen in Scheme
2.1, reaction a) [2
], or carboxylic acids (seen in
Scheme
2.1, reaction b) [3
].
Bolm and his colleagues published a method for the synthesis of 2-oxo-2-
phenylacetylsulfoximines using an oxidative coupling method. This method involves
the reaction of α-ketoaldehydes with NH-sulfoximines, which is catalyzed by CuBr
(Scheme
2.2)[4].
In 2016, this investigation led by Bolm was successful in producing an efficient
kinetic resolution of sulfoximines by the use of a chiral N-heterocyclic carbene
catalyst. There is the possibility of obtaining two enantiomers of N–Substituted
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 59
a)
b)
Cl
O
+
R
1
S
O
NH
R
2
N
O
S
R
2
O
R
1
NEt
3
DMAP
HO
O
+
R
1
S
O
NH
R
2
N
O
S
R
2
O
R
1
B(OH)
3
, PhMe
CH
2
Cl
2
25
o
C 5 h
reflux 24 h
Scheme 2.1 Reaction of acid halides, carboxylic acids with NH-sulfoximines
(R)Ar H
O
+
R
1
S
O
NH
R
2
ArN
O
S
R
2
O
R
1
ArH
O
TBHP
Cu(II)L
n
O
Ar
Ar
N
O
S
R
2
O
R
1
R
1
S
O
HN
R
2
Cu(II)L
n
R
1
S
O
HN
R
2
Cu(I)
Cu(II)
TBHP
CuBr TBHP
MeCN, 80
o
C, 12 h
72-95% yield
Scheme 2.2 CuBr-catalyzed oxidative coupling reaction of α-ketoaldehydes with NH-
sulfoximines
sulfoximines 3 and NH-sulfoximine 1 with excellent ee values (up to 99%ee and
-97%ee, respectively) [5]. Catalysts are 4, 5 and 6 as well as an oxidant 7, as shown
in Scheme
2.3. Compound 4 has a catalytic effect that is not ideal, which is one of
them.
An I
2
-catalyzed production of N-aroylated sulfoximines from NH-sulfoximines
and methyl arenes was reported by An et al. (Scheme
2.4). The oxidant used in this
reaction is tert-butyl hydroperoxide (TBHP) [
6]. After that, Hou and Zhao published a
work in 2017 that described the copper-catalyzed production of N-acyl sulfoximines
from methyl aromatic hydrocarbons. The transformation was carried out with the
help of an exogenous oxidant known as TBHP; no solvents or ligands are required
for the reaction. Through the use of control reactions, it is shown that this reaction
occurs through a free radical pathway (Scheme
2.5). In addition, they also developed
a CuI-catalyzed α-ketolation of sulfoximines (Scheme
2.6)[7
].
A successful method for synthesizing asymmetric sulfoximine ureas was estab-
lished by Chen and his colleagues [
8
]. There is a traditional Curtius rearrange-
ment that brings together simple NH-sulfoximines and acyl azides. This is the most
important step in the reaction (Scheme
2.7).
60 2 Transformation of Sulfoximines and Cyclic Sulfoximines
S
HN
O
+
NO
2
H
O
catalyst (5 mol%)
oxidant (5 equiv)
DBU (1 equiv)
4A MS, THF
S
N
O
O
NO
2
S
NH
O
1
2
3
1'
Mes
N
N
O
N
BF
4
4
O
N
N
N
Bn
R
BF
4
5
N
N
N
R
t-Bu
BF
4
6
O
O
t-Bu
t-Bu
t-Bu
t-Bu
7
Scheme 2.3 Organocatalytic kinetic resolution of sulfoximines
Scheme 2.4 I
2
-catalyzed
N-acylation of methyl
aromatics with
NH-sulfoximines
Ar
+
R
1
S
O
NH
R
2
TBHP, 80
o
C, 6 h
Ar
N
O
S
R
2
O
R
1
I
2
, Na
2
CO
3
58-92% yield
Isocyanates and carbamoyl chlorides were used in previous investigations, and
this reaction adds to those results. In 2019, our group was successful in developing a
visible light-promoted synthesis of N-aroylsulfoximines. Utilizing oxidative dehy-
drogenation coupling in air at room temperature, this was possible. A metal catalyst,
alkali, or photosensitizer are not required in this reaction. The method showed a high
level of functional group tolerance and the ability to effectively produce a wide range
of N-aroylsulfoximines in very high yields, as shown in Scheme
2.8 [9
].
NH-sulfoximines and N-arylation products are a group of useful chiral ligands
for a number of asymmetric reactions. Gnamm et al. additionally reported that N-
arylsulfoximines have interesting chemical and physical properties and general char-
acteristics [
10
], which is very important for drug development. If you want to add
an N-arylation to NH-sulfoximines, you can use aryl halide, arylboronic acid, aryl
sulfonate, arylsiloxane, aromatics, aryl iodonium salt, and many more [
11–18].
The N-acylation of sulfoximines opens up a lot of synthetic options, but there are
still some problems to solve, especially when it comes to getting high regio- and
stereoselectivity in complex substrates. These problems need to be fixed, and more
study needs to be done to find more N-acylation reactions that involve sulfoximines.
New catalytic systems are being made, new acylating agents are being looked into,
and the processes of reactions are being better understood. In conclusion, the N-
acylation of sulfoximines is a key step in organic synthesis. It helps make a wide
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 61
O
S
R
1
O
R
2
N
Cu
O
Cu(I)+[O]
R
1
S
O
NH
R
2
R
1
S
O
N
R
2
Cu
H
Cu(II)
N
O
S
R
2
O
R
1
I
I
[O]
Ar R
+
R
1
S
O NH
R
2
Ar
N
O
S
R
2
O
R
1
80
o
C, 20 h
CuI TBHP
72-91% yield
Scheme 2.5 CuI-catalyzed N-acylation of toluenes with NH-sulfoximines and its mechanism
Ar
O
+
R
1
S
O
NH
R
2
Ar
O
N
O
S
O
R
2
R
1
CuI, DTBP
Cu(I)
Cu(II)
R
1
S
O
NH
R
2
R
1
S
O
N
R
2
H
Cu(II)
Ar
O
N
O
S
O
R
2
R
1
Ar
O
N
S
O
R
2
R
1
[O], H
2
O
I
I
2
Ar
O
I
Ar
O
90
o
C 12 h
79-93% yield
Scheme 2.6 CuI-catalyzed α-Ketoacylation and its mechanism