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62 2 Transformation of Sulfoximines and Cyclic Sulfoximines
R
1
S
NH
O
R
2
+
N
3
O
DCE or MeCN
80
o
C, 3 h
R
1
S
N
O
R
2
H
N
O
OMe
MeO
52-99% yield
Scheme 2.7 Synthesis of unsymmetrical Sulfoximine urea by Curtius rearrangement
Scheme 2.8 Visible light
promoted synthesis of
N-aroylsulfoximines via
oxidative dehydrogenation
coupling reaction
R H
O
+
R
1
S
O
NH
R
2
R N
O
S
O
R
2
R
1
K
2
S
2
O
8
(1.0 equiv)
TBHP(3.0 equiv)
CH
3
CN, visible light
rt, 12h 78-94% yield
range of functionalized molecules that are useful in areas like materials science,
polymer synthesis, and medical chemistry. This flexible method lets different acyl
groups be added to sulfoximines, giving scientists a more personalized way to create
molecules and making sulfoximines more useful in modern synthetic research. It is
expected that further research into N-acylation processes involving sulfoximines will
open up new areas in chemical synthesis and help make new materials and bioactive
compounds.
2.1.2 N-Arylation of NH-Sulfoximines with Halobenzenes
NH-sulfoximines with halobenzenes result from the r eaction between sulfoximines
and halobenzenes. The nitrogen atom of the sulfoximine must directly react with the
halobenzene substrate. This change is a strategic synthesis that uses the reactivity
of both parts to make NH-sulfoximines with halogen functions that have different
structures. The compounds that were made show promise in many areas, such as
medicinal chemistry, materials science, and the production of functionalized inter-
mediates. Using halobenzenes to synthesize NH-sulfoximines is an interesting area
of organic chemistry because it combines the unique properties of sulfoximines with
the versatility of halobenzenes. NH-sulfoximines are special because they have a
nitrogen atom directly connected to the sulfur–oxygen double bond within the imine
functional group. They also have unique properties that make them useful building
blocks for complex molecules. The addition of halobenzenes to these reactions makes
them more interesting by letting halogen substituents be added to the sulfoximine
scaffold. This study goes into detail about how to make NH-sulfoximines, how they
react with halobenzenes, and what they could be used for.
There are different synthetic strategies that can be used to make NH-sulfoximines
from halobenzenes. Sulfoximines and halobenzenes are often mixed together in a
common method that requires the right activating agents or catalysts. Using transi-
tion metals to speed up cross-coupling reactions, like palladium-catalyzed reactions,
has been shown to help NH-sulfoximines and halobenzenes join together. By using
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 63
the right conditions and chemicals, it is possible to selectively form C–N and C–S
bonds, which creates NH-sulfoximine products that have halogen on them. The NH-
sulfoximine with halobenzene transformation works with a lot of different haloben-
zenes that have different halogen types and substitution patterns. Halobenzenes,
which include fluorobenzenes and iodobenzenes, can be involved in these reactions.
This means that there are many ways that they can be functionalized. Because this
method is so flexible, it can be used to change the physical and chemical properties of
compounds by adding specific halogen substituents to NH-sulfoximines. Haloben-
zenes can be used as directing groups to make NH-sulfoximines, which changes how
selective the reaction is in certain areas. For example, the halogen substituent might
tell the reaction to happen at a certain spot on the halobenzene ring, which would
help make NH-sulfoximines with very specific patterns of substitution. This feature
improves the synthetic control and makes it possible to build molecular structures
with more complex structures.
Using transition metal-catalyzed reactions to make NH-sulfoximines from
halobenzenes has a number of benefits. Transition metal catalysts, like palladium
or copper complexes, make it easier for the nitrogen atom of the sulfoximine to join
with the halobenzene. This makes the reaction very efficient and selective. These
catalytic systems make it possible for C–N and C–S bonds to form, which leads
to the production of NH-sulfoximine products. As we look more closely at how the
NH-sulfoximine and halobenzene change works, we can see that the catalytic system
turns on both of the substrates. The halobenzene goes through oxidative addition,
which creates a metal-halogen intermediate when the right catalyst is present. After
this, the sulfoximine’s nitrogen atom attacks with a nucleophile, which creates the
C–N and C–S bonds. I t is very important to understand these steps in order to improve
reaction conditions and make more substrates work.
The N-arylation of NH-sulfoximines with halobenzenes mostly relies on metal
catalysts made of copper, lead, iron, or other elements, and it needs ligands to work.
Bolm and Hildebrand reported in 1998 that NH-sulfoximines were coupled with
aryl bromides in a number of substitution methods to get N-arylated products with
yields as high as 96% (Scheme
2.9, Eq. a). This happened with a catalytic amount
of Pd(OAc)
2
and a chelated bisphosphine ligand present [14
a]. At t he same time,
they discovered that when the aromatic ring contains two halogen atoms, only one
molecule of sulfoximines can react with it (Scheme
2.9, Eq. b). A pair of methods
for the N-arylation of NH-sulfoximines were developed by Bolm in 2007 using
Cu and Fe catalysts [
19a]. This study showed that combining FeCl
3
and N,N
-
dimethylethylenediamine (DMEDA) can consistently produce a wide range of N-
arylsulfoximines in large amounts (Scheme
2.10). This is in contrast to the reaction
between NH-sulfoximines and aryl iodides, which is unstable.
In addition to this, they developed a copper-catalyzed coupling method that is
both simple and ligand-free. This method is not only appropriate for the N-arylation
of NH-sulfoximines (Scheme
2.11, Eq. a), but it is also acceptable f or the N-arylation
of a wide range of other nitrogen nucleophiles to react with the N-arylation of aryl
iodides, bromides, and chlorides that have been substituted in a number of ways
(Scheme
2.11, Eq. b) [20].
64 2 Transformation of Sulfoximines and Cyclic Sulfoximines
Br
+
R
1
R
2
S
O
NH
R
3
Pd(OAc)
2
,
bisphosphine
R
2
S
O
R
3
N
R
1
Br
+
R
2
S O
NH
R
3
Pd(OAc)
2
,
bisphosphine
R
2
S
O
R
3
N
Br
Br
a)
b)
Pd(OAc)
2
-2L +2L
L
2
Pd
0
L
2
Pd
Ar
Br
Ar Br
R
1
S
O
NH
R
2
R
1
S
O
N
R
2
L
2
Pd
BrAr
H
L
2
Pd
Ar
N
S
R
1
O
R
2
base
base.HBr
R
1
S
O
N
R
2
Ar
Cs
2
CO
3
, toluene, 110
o
C
Cs
2
CO
3
, toluene, 110
o
C
74-95% yield
Scheme 2.9 Pd-catalyzed N-arylation of NH-sulfoximines and its mechanism
X
+
R
1
R
2
SO
NH
R
3
FeCl
3
, DMEDA, K
2
CO
3
R
2
S
O
R
3
N
R
1
toluene, 135
o
C, 24 h
9-96% yield
Scheme 2.10 Fe-catalyzed N-arylation of NH-sulfoximines
X
+
R
2
SO
NH
R
3
Cu
2
O, Cs
2
CO
3
R
2
S
O
R
3
N
X = Br, I
X
+
NH
n
Cu
2
O, Cs
2
CO
3
N
n
a)
b)
X = I, Br, Cl
n = 1,2,3...
DMF, 100
o
C, 18 h
DMF, 100
o
C, 18 h
64-99% yield
9-96% yield
Scheme 2.11 Cu-catalyzed N-arylation of NH-sulfoximine
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 65
Cl
+
R
S
O
HN
Ph
Pd
2
(dba)
3
(2.5 mol%)
RuPhos (7.5 mol%)
S
O
N
R
1
Ph
Cs
2
CO
3
, toluene, 135
o
C, 24 h
60-99% yield
Scheme 2.12 The work of Harmata and his coworkers
When the N-arylation process is carried out in the presence of the base Cs
2
CO
3
,
the use of Cu
2
O as a catalyst is required. Pd
2
(dba)
3
is used as a catalyst and RuPhos
is used as a ligand, which resulted in halobenzenes undergoing N-arylation with
NH-sulfoximines (Scheme
2.12). Harmata and his colleagues were responsible for
this accomplishment in 2011 [
14].
2.1.3 N-Arylation of NH-Sulfoximines with Aryl Boronic
Acids
In 2005, Bolm wrote about a Chan-Lam coupling reaction that involved N-arylation
of sulfoximines with aryl boronic acids and did not use any alkalis. This new method
can also synthesize N-arylsulfoximines, which were hard to get before (Scheme
2.13,
Eq. a) [14].
In 2019, Kandasamy and his colleagues used copper (I) iodide and DMAP to
speed up the N-arylation of NH-sulfoximines with different aryl boronic acids
(including boronic acid that is sterically hindered) at room temperature. Also, they
got the biologically related N-aryl L-methionine sulfoximines for the first time
(Scheme
2.13, Eq. b) [20].
2.1.3.1 Other Methods
In the year 2000, Bolm carried out the palladium-catalyzed N-arylation synthesis of
arylated sulfoximines. The substrates that were utilized were aryl nonaflates and aryl
R
1
S
NH
O
R
2
+
B(OH)
2
CuI (0.1 equiv), DMAP
R
R
1
S
N
O
R
2
R
MeOH, rt
R
1
S
NH
O
R
2
+
B(OH)
2
Cu(OAc)
2
(0.1 equiv)
R
R
1
S
N
O
R
2
R
MeOH, rt
a)
b)
62-93% yield
71-93% yield
Scheme 2.13 Cu-catalyzed N-arylation of NH-sulfoximines with aryl boronic acids
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 67
R
1
OTf
TMS
+
SR
3
O
R
2
NH
S
R
3
O
R
2
N
R
1
KF/18-crown-6
THF, rt, 2-4 h
43-77% yield
Scheme 2.16 N-arylation of NH-sulfoximines with trifluoromethyl aryl sulfonates
R
1
(MeO)
3
Si
+
SR
3
O
R
2
NH
S
R
3
O
R
2
N
R
1
CuI (10 mol%)
TBAF
3H
2
O (10 mol%)
O
2
, CH
2
Cl
2
, rt, 12 h
66-92% yield
Scheme 2.17 N-arylation of NH-sulfoximines with arylsiloxanes
the necessary N-arylsulfoximines in good yield [15]. The writers think that this
reaction with arylsiloxanes as the arylation reagent is helpful because it is s afe,
simple to handle, stable, good for the environment, and has mild reaction conditions
(Scheme
2.17). However, as we know, arylsiloxanes are the downstream products of
aryl halides, which means that they are more expensive and have a much lower atom
economy.
To synthesize N-arylated sulfoximines, Bolm proposed a method that involves
the functionalization of C–H positions. Stoichiometric copper acetate increased the
C–H activation and oxidative C–N cross-coupling of 2-arylpyridines with a number
of NH-sulfoximine derivatives, as shown in Scheme
2.18 [7].
Additionally, in 2012, the group led by Varma established an ultrasonically accel-
erated route for the fast N-arylation of NH-sulfoximines. Copper (I) bromide is
used to catalyze this reaction, which takes place at room temperature in an aqueous
solution of polyethylene glycol 400 catalyst. A reaction between the aryl iodonium
salts and the NH-sulfoximines resulted in the formation of N-arylated sulfoximines
(Scheme
2.19)[17].
Even though progress has been made in making NH-sulfoximines with haloben-
zenes, there are still problems to solve. A big goal of research is still to get high regios-
electivity, especially when there are many reactive sites. Researchers are working on
making catalytic systems that last longer and are more useful, finding new haloben-
zene substrates, and looking into other types of halogens. The progress in this field
+
SR
2
O
R
1
NH
S
R
2
O
R
1
N
O
2
(1 atm), Cu(OAc)
2
H
2
O
N
R
3
R
4
H
N
R
4
R
3
AcOH, EtCN, 150
o
C, 24 h
55-82% yield
Scheme 2.18 C–H functionalization of 2-arylpyridines with NH-sulfoximines
68 2 Transformation of Sulfoximines and Cyclic Sulfoximines
+
S
R
2
O
R
1
NH
S
R
2
O
R
1
N
I
OTf
R
3
R
3
R
3
CuBr, PEG
400
/H
2
O (1:1)
RT, ultrasound, 5 min
87-95% yield
Scheme 2.19 N-arylation of NH-sulfoximines with aryl iodonium salts
will be helped by the constant improvement of synthetic methods. As a conclu-
sion, making NH-sulfoximines with halobenzenes is a dynamic and flexible way to
make organic compounds. This change uses the reactivity of both sulfoximines and
halobenzenes, giving us access to a wide range of NH-sulfoximine products that have
halogen functions. The compounds that are made can be used in medicinal chem-
istry, materials science, and other fields. This shows how important this method is
in modern organic synthesis. As research into NH-sulfoximines with halobenzenes
continues, it is likely to reveal new ways to make functionalized molecules with
specific properties that can be used in a variety of situations.
2.1.4 N-Alkylation of NH-Sulfoximines
The N-alkylation of NH-sulfoximines involves the addition of alkyl groups to the
nitrogen atom directly connected to the sulfur–oxygen double bond. This synthetic
strategy allows for the selective modification of NH-sulfoximines, providing a means
to tailor their reactivity, lipophilicity, and overall chemical properties. The resulting
N-alkylated NH-sulfoximines serve as versatile building blocks for the construc-
tion of more complex molecules. An important change in organic synthesis is the
N-alkylation of NH-sulfoximines, which alter the nitrogen atom that is directly
connected to the sulfur–oxygen double bond in the imine functional group. NH-
sulfoximines have special electronic and steric properties, and when they are N-
alkylated, they can be changed into a wide range of compounds with different func-
tions. During this chemical change, alkyl groups are added to the sulfoximine’s
nitrogen atom. This makes N-alkylated NH-sulfoximines. The making of these
compounds uses a number of different methods and is important in both medicinal
chemistry and materials science. It also helps to make molecules that are specifically
designed for different uses.
There are various synthetic approaches that can be used to carry out N-Alkylation
reactions of NH-sulfoximines. Most of the time, NH-sulfoximines are mixed with
alkyl halides, alkyl tosylates, or alkyl sulfonates along with the right bases. The
N-alkylation process is more or less selective and efficient depending on the base
and reaction conditions that are used. Another way is to use transition metals to
speed up reactions, like palladium-catalyzed cross-coupling reactions, which allow
NH-sulfoximines to join with alkyl-containing substrates. The N-alkylation of NH-
sulfoximines can be done with a lot of different alkylating agents that have different
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 69
chain lengths, substitution patterns, and functional groups. Because they are so flex-
ible, different alkyl groups can be added to NH-sulfoximines. This lets scientists
make molecules with specific properties for different uses. It is possible to selec-
tively functionalize the nitrogen atom, which helps make compounds with different
steric and electronic environments.
Many methods have been developed with the objective of synthesizing N-
methyl sulfoximine. One of these ways is to methylate NH-sulfoximine under the
Eschweiler-Clark condition and use a strong methyl transfer agent, like trimethyloxo-
nium salt. On the other hand, because the nitrogen atom of NH-sulfoximines has a low
nucleophilicity, the reaction of N-alkylation of NH-sulfoximines is more challenging,
which is why there are fewer studies in this regard [
22
]. Considering the N-alkylation
of NH-sulfoximines, there are two different methods. The first method involves using
an alkyl halide in a direct manner in order to react with NH-sulfoximines. In the
past, in order for this method to be successful, it was required to take into account
the existence of a phase transfer catalyst and a strong base, such as an alkali metal
hydride (MH) or butyl lithium (Scheme
2.20, Eq. a) [23]. In 2014, Bolm’s team made
improvements to the method by using a KOH/DMSO system to directly synthesize
N-alkylated sulfoximine (Scheme
2.20, Eq. b) [22]. The second method starts with
adding an N-acyl group to the NH-sulfoximines. Then, the acyl group is reduced,
creating N-alkyl sulfoximines. In comparison to the method that makes use of butyl
lithium (Scheme
2.20, Eq. c), this method is smoother [24
]. Copper (II)-catalyzed
N-alkylation of sulfoximines with alkylboronic acids was a Chan-Lam coupling reac-
tion that was carried out by Kandasamy group in the year 2017 (Scheme
2.20,Eq.
d) [
25
].
Bolm and his colleagues discovered a method of intermolecular palladium-
catalyzed C–N coupling between sulfoximines and vinyl bromides for the N-
vinylation of sulfoximines. This resulted in the formation of N-vinyl sulfoximines.
As demonstrated in Scheme
2.21, the hydrogenation of the vinyl moiety paved the
way for the discovery of a new route to R-branched N-alkyl sulfoximines [
12]. In
2015, it was discovered that palladium and copper can work together to speed up
the dehydroamido-bromination of NH-sulfoximines and β,β-unsaturated esters or
sulfones. This was achieved by two interesting oxidative coupling reactions that
took place in the presence of LiBr and an oxygen environment, as depicted in
Scheme
2.22 [14
]. By using this method, highly functionalized olefins can be obtained
from compounds that are α,α-unsaturated.
R
1
S
O
NH
R
2
R
1
S
O
N
R
2
R
(a) R-X, (MH) or RLi
(b) R-Br, KOH, DMSO
(c) N-acylation; reduction
(d) R-B(OH)
2
, Cu(OAc)
2
, pyr.
Scheme 2.20 N-Alkylation of NH-sulfoximines
70 2 Transformation of Sulfoximines and Cyclic Sulfoximines
Scheme 2.21 N-vinylation
of NH-sulfoximines
R
2
S
O
NH
R
1
+
Br
R
5
R
4
R
3
R
2
S
O
N
R
1
R
4
R
5
R
3
Pd(OAc)
2
, BINAP
NaO-t-Bu, 110
o
C
98% yield
R
2
S
O
NH
R
1
+
H
EWG
R
2
S
O
N
R
1
EWG
Br
Pd(MeCN)
2
Cl
2
(5 mol%)
CuCl (10 mol%), LiBr
EWG = CO
2
R, SO
2
Ph
O
2
(1atm), toluene, 80
o
C, 48 h
23-98% yield
Scheme 2.22 Pd/Cu co-catalyzed dehydroamido-bromination of NH-sulfoximines and α,β-
unsaturated esters or sulfones
When making NH-sulfoximines, it is very important to think about the regiose-
lectivity and stereoselectivity of N-alkylation reactions. There are several places on
the nitrogen atom in NH-sulfoximines that can be alkylated, and controlling regios-
electivity makes sure that alkyl groups are only added to the right spots. Using chiral
alkylating agents or asymmetric catalysis can help with stereoselective N-alkylation
reactions. This creates enantioenriched N-alkylated NH-sulfoximine products. In
order to make NH-sulfoximines, base-catalyzed N-alkylation reactions are often
used. Amine bases, like potassium tert-butoxide or sodium hydride, help the nitrogen
atom lose its protons, which makes it a nucleophile. The nucleophilic nitrogen that is
left over then reacts with an alkylating agent to make the N-alkylated product. A lot
of people use this method to get to different kinds of N-alkylated NH-sulfoximines,
and it works well. Additionally, transition metal-catalyzed N-alkylation reactions are
different ways to make chemicals that have clear benefits. When palladium is used
to help with cross-coupling reactions, for example, NH-sulfoximines can directly
join with alkyl halides or alkyl triflates. This method for catalysis works very well,
doesn’t cause too many problems during the reaction, and works with many different
types of functional groups.
When NH-sulfoximines are involved in N-alkylation reactions, a nucleophilic
nitrogen species is usually made through deprotonation. It is then the nucleophilic
nitrogen that attacks the alkylating agent, which makes the N-alkylated product. To
get the best reaction conditions, regioselectivity, and control over the stereoselectivity
of the transformation, you need to understand how it works. Making N-alkylated
NH-sulfoximines has come a long way, but there are still problems to solve. A lot of
work is still being done to get high regio- and stereoselectivity, especially when there
are many alkylatable positions. Researchers are working on making new catalytic
systems, using more alkylating agents, and fixing problems with scaling up.
N-alkylation of NH-sulfoximines is a useful and strong synthetic method that lets
these specific nitrogen-containing compounds be changed in specific ways. The N-
alkylated NH-sulfoximines that are made are useful in medicinal chemistry, materials
science, and other fields. This shows how important this change is in modern organic
2.1 Transformation of Sulfoximines into Sulfoximine Derivatives 71
synthesis. More work in this area is likely to reveal new methods, boost selectivity,
and expand the types of substrates that can be used. This will make N-alkylated
NH-sulfoximines even more useful in many different areas of chemical research.
2.1.5 N-Alkynylation of NH-Sulfoximines
N-Alkynylation of NH-sulfoximines involves the addition of alkynyl groups to the
nitrogen atom directly linked to the sulfur–oxygen double bond. This transforma-
tion offers a unique way to functionalize NH-sulfoximines with acetylenic moieties,
resulting in the creation of N-alkynylated NH-sulfoximines. The incorporation of
alkynyl groups enriches the chemical diversity of the resulting compounds, opening
up avenues for further elaboration and exploration in organic synthesis. The N-
alkynylation of NH-sulfoximines is an interesting and useful change in organic
synthesis. It combines the unique properties of NH-sulfoximines with the wide range
of chemistry found in alkynes. The imine functional group has a nitrogen atom
directly attached to the sulfur–oxygen double bond. NH-sulfoximines are special
building blocks because they have this bond. When alkynyl groups are added to the
nitrogen atom of NH-sulfoximines, N-alkynylated products are formed. This makes
the synthetic toolbox even more complex and varied. This study looks into how N-
alkynylation reactions with NH-sulfoximines can be used to make new chemicals,
how they work, and what they might be used for.
The N-alkynylation reaction with NH-sulfoximines is very broad and flexible, as
it can work with a lot of different alkynylating agents that have different functional
groups and substitution patterns. This flexibility lets you add alkynyl groups selec-
tively, giving you access to N-alkynylated NH-sulfoximines with specific properties.
The compounds that are made are useful building blocks for making more complex
molecules and materials. To N-alkynylate NH-sulfoximines, different synthetic
strategies can be used. NH-sulfoximines are usually joined with alkynylating agents,
like terminal alkynes or alkynyl halides, in this reaction. How the reaction is set up and
the catalysts used are very important for getting high yields and selectivity. Copper-
catalyzed Sonogashira couplings and other transition metal-catalyzed reactions have
been shown to help the N-alkynylation of NH-sulfoximines.
For N-alkynylation reactions involving NH-sulfoximines, transition metals are
often used to speed up the process. Sonogashira couplings with copper as a cata-
lyst, for example, let NH-sulfoximines and terminal alkynes couple directly. The
catalytic system helps bring about the formation of C–N and C–C bonds, which
makes N-alkynylated products. This method has benefits like mild reaction condi-
tions and the ability to work with many functional groups. The N-alkynylation process
usually starts with the alkyne being activated and then the nitrogen atom of the NH-
sulfoximine attacking it. The alkynylating agent and the transition metal catalyst
work together to make it easier for the C–C bond to form. It is important to under-
stand the details of how the reaction works in order to improve reaction conditions,
achieve high regio- and stereoselectivity, and make more substrates usable.