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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5493_Библиотеки_им_академика_М_И_Перельмана.pdf
32 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
S
O NH
Ar Ar
+
R
O
S
O
[(p-cymene)RuCl
2
]
2
(2.5 mol%)
AgSbF
6
(20 mol%)
41
(10 mol%)
DCE, 35
N
S
O
Ar
R
Desymmetrization
:
Kinetic resolution (KR)
:
S
R
O NH
Ar
+
Ph
O
S
O
[(p-cymene)RuCl
2
]
2
(2.5 mol%)
AgSbF
6
(20 mol%)
42
(7.5 mol%)
TCE, t-BuOH, 50
o
C
N
S
O
Ar
Ph
Ar
+
Ar
S
O
NH
R
Parallel kinetic resolution (PKR)
:
S
O
NH
R
[(p-cymene)RuCl
2
]
2
(2.5 mol%)
AgSbF
6
(20 mol%)
41
(10 mol%)
DCE, 35
+
Ph
O
S
O
S
N
R
O
Ph
+
N
S
O
R
Ph
CO
2
H
O
N
R
1
R
2
41,
R
1
= R
2
= i
-Pr
42
, R
1
= R
2
= cyclohexyl
28 examples
(75–99%, 96–98% ee)
11 examples
(29–53%, 64–91% ee) (35–41%, 86–98% ee)
3 examples
(49–91%, 96–97% ee)
33
34
35
36
34a
(
S
)-37
(
R
)-36
38
34a
39
40
(1.0 equiv.)
(1.5 equiv.)
(1.0 equiv.)
(0.75 equiv.)
(a)
(b)
o
C
o
C
Scheme 1.33 Desymmetrization, kinetic resolution, and parallel kinetic resolution of sulfoximines
with sulfoxonium ylides under the Ru-catalyzed system
S
O
HN
R
2
R
1
+
X
O O
I
( )
n
[RhCp*Cl
2
]
2
(2.5 mol%)
HOAc(1 equiv.), HFIP
100
o
C, 5 h
R
1
S
N
O
R
2
X
O
( )
n
X = C, O
n = 0, 1
26 examples(40–94%)
Ph
43 44
45
Scheme 1.34 Rhodium-catalyzed strategy for the synthesis of polycyclic 1,2-benzothiazines from
different aryl sulfoximines and iodonium ylides
out, demonstrated that electron-donating sulfoximines are advantageous to the C–H
functionalization process during the reaction. It was found that the mechanism that
was proposed is comparable to the earlier reports (Scheme
1.35). In the beginning,
sulfoximines 43 coordinate with the Rh-catalysis F1 in order to accomplish C–H
activation and generate a five-membered cyclic complex F2. Then, 44 reactions with
F2, which results in the formation of the carbene species F3 and the loss of PhI. After
that, the migratory insertion of Rh–carbene into the C–Rh bond is carried out, which
results in the formation of intermediate F4. The formation of the desired product
45 takes place following the reductive elimination of F4, which is followed by the
intramolecular nucleophilic cyclization and dehydration reactions.
1.2 Synthesis of Cyclic Sulfoximines 33
[RhCp*]
S
O
HN
R
2
Rh
N
S
O
R
2
*Cp
43
Rh
N
S
O
R
2
*Cp
O
O
O
O
I
Ph
PhI
F2
44
F3
Rh
N
S
O
R
2
Cp*
O
O
F4
HOAc
S
O
NH
R
2
O
O
N
S
O
R
2
OH
O
H
2
O
S
N
O
R
2
O
F5
F6
45
F1
R
1
R
1
R
1
R
1
R
1
R
1
R
1
Scheme 1.35 Proposed mechanism of the reaction between sulfoximines and iodonium ylides
Wu et al. reported almost at the same time a very similar method to get good
to excellent yields of polycyclic 1,2-benzothiazines 48 (Scheme
1.36). As an extra,
trimethylacetic acid (PivOH) was used in this case [
71]. Like Yu’s work, this approach
worked with a lot of different substrates and made it easy to get cyclohexa-none-1,2-
benzothiazine scaffolds.
A Ru(II)-catalyzed C–H activation/annulation of sulfoximines 49 with sulfoxo-
nium ylides 50 was proposed by Yoshino and colleagues in 2022 for the purpose of
enantioselective synthesis of 1,2-benzothiazines 51 (Scheme
1.37)[72
]. After exten-
sive testing, the researchers determined that the pseudo-C2-symmetric binaphthyl
S
O
NH
R
2
R
1
+
O
O
I
( )
n
[RhCp*Cl
2
]
2
(2.5 mol%)
PivOH, TFE, 80
o
C,12 h
R
1
S
N
O
R
2
X
O
( )
n
Ph
28 examples (71–92%)
46
47
48
Scheme 1.36 Rhodium-catalyzed strategy for the synthesis of polycyclic 1,2-benzothiazines
34 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
S
O NH
R
1
R
1
+
R
2
O
S
O
[RuCl
2
(p-cymene)]
2
(2.5 mol%)
AgSbF
6
(20 mol%)
CCA
52
(10 mol%)
CHCl
3
, 40
o
C, 24 h
S
O
N
Ar
R
1
R
2
15 examples
(68~>99%, 76:24~92:8 er)
CO
2
H
F
49
50
51
52
Scheme 1.37 Ru(II)-catalyzed C–H functionalization strategy of sulfoximines for the enantiose-
lective synthesis of 1,2-benzothiazines
mono-carboxylic acid 52 (10 mol%) served as the most effective chiral ligand. S-
chiral 1,2-benzothiazine products were prepared in moderate to good yields with up
to 92:8 er. This was accomplished by preparing a wide variety of these compounds.
It was also shown that this method worked with electron-donating substituents,
electron-withdrawing substituents, and steric hindrance substituents.
An example of a catalytic cycle that is feasible is presented in Scheme 1.38.It
is comprised of five primary steps. [RuCl2(p-cymene)]2, AgSbF6, and 52 are the
components that are responsible for the formation of the original Ru-carboxylate
catalyst complex G1. In the next step, the sulfoximines 49 join forces with G1 to
help activate C–H through a process of selective deprotonation. This creates the inter-
mediate G3. After that, the chiral metallacycle complex G3 couples with sulfoxonium
ylides 50. Following that, the insertion of carbene into the Ru-Aryl bond results in
the formation of a six-membered cycle G4, which is accompanied by the loss of
DMSO during the process of the reaction. Finally, we carry out the protonation and
intramolecular condensation processes to obtain the desired products 51.
[RuCl
2
(p-cymene)]
AgSbF
6
CCA (R*CO
2
H)
[Ru]OCOR*(X)
S
O
HN
Ar
R
1
S
O
N
Ar
R
1
[Ru]
OCOR*
X
H
[Ru]
N
S
R
1
O
Ar
X
R
2
O
S
O
DMSO
[Ru]
N
S
R
1
O
Ar
R
2
O
-R*CO
2
H
R*CO
2
H
NH
S
R
1
O
Ar
R
2
O
49
50
51
G1
G2
G3
G4
G5
Scheme 1.38 Proposed mechanism of Ru-catalyzed enantioselective synthesis of 1,2-
benzothiazines
1.2 Synthesis of Cyclic Sulfoximines 35
1.2.4 Metal Nitrene as Coupling Partner
Reactive intermediates that contain a nitrogen atom with a lone pair and a triplet
ground state are known as metal nitrenes. These nitrenes have the potential to be
useful coupling partners in the process of synthesising cyclic sulfoximines. Nitrene
transfer reactions, frequently mediated by transition metals, enable the incorporation
of nitrogen functions into organic compounds. In the context of cyclic sulfoximines,
the following are some examples of possible usage of metal nitrenes as coupling part-
ners: With the help of metal nitrenes, aziridination is a method for adding an aziridine
ring selectively to cyclic sulfoximines. The reaction transfers the nitrene moiety to the
sulfoximine, resulting in the development of a cyclic structure with three members.
You can use metal-catalyzed C–H amination reactions that involve moving nitrene
to cyclic sulfoximines. This process is known as C–H amination. Consequently, this
makes it possible to directly functionalize the C–H bonds that are located next to the
sulfoximine moiety. Furthermore, the development of carbon–nitrogen bonds and
nitrene transfer processes enables the construction of new carbon–nitrogen linkages
within the framework of cyclic sulfoximine. In addition to imido-insertion reactions,
metal nitrenes have the ability to take part in imido-insertion reactions, which include
the incorporation of nitrogen into particular locations of cyclic sulfoximines. This
results in the synthesis of imido-substituted sulfoximines. Additionally, Aza-Wittig
reactions, which are nitrene transfer reactions that involve metal-catalyzed processes,
can be utilized in Aza-Wittig-type reactions. These reactions make it possible for
metal nitrenes to change into imine intermediates. These can then react with cyclic
sulfoximines.
Metal nitrenes enable a diverse method for functionalizing cyclic sulfoximines
with nitrogen-containing groups. The selection of the metal catalyst and the reaction
conditions significantly regulate the regio- and stereoselectivity of these reactions.
The potential utilization of the nitrogen-functionalized cyclic sulfoximines produced
includes various fields such as pharmaceutical chemistry, materials science, and other
areas where there is a desire to incorporate specific nitrogen motifs. As research in
the field of metal nitrene chemistry continues to expand, these reactions present new
potential for the synthesis of nitrogen-containing molecules that are both complex
and diverse.
In 2019, Xu and Dong reported that sulfoximines 53 and benzyl azides 54
were used as starting materials for Rh(III)-catalyzed C–H activation/cyclization to
make dihydro-benzo thiadiazine 1-oxide derivatives 55, as shown in Scheme
1.39
[73
]. Different substrates with different electron-donating and electron-withdrawing
groups didn’t stop this catalytic reaction, but heterocyclic NH-sulfoximines and fluo-
rinated or free benzyl azides didn’t work well. It was also possible to get middling
to good yields of the cyclization products (41–85%).
Scheme 1.40 shows a proposed mechanism that was based on a set of control tests.
To begin, the sulfoximines 53 bind to the active Rh(III) molecule H1. They then go
through the C–H bond cleavage process to create H2, which is a five-membered
36 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
S
O
HN
R
1
R
1
+
N
3
R
2
[RhCp*Cl
2
]
2
(5 mol%)
AgNTf
2
(0.2 equiv.)
MesCO
2
Na (0.1 equiv.)
DCE, air, 110
o
C
R
1
S
N
N
O
R
1
R
2
R
2
2
21 examples(41–85%)
53
54
55
Scheme 1.39 Rh(III)-catalyzed C–H functionalization of sulfoximines to prepare dihydrobenzo
thiadiazine 1-oxide derivatives
rhodacyclic complex. As the benzyl azides 54 come together, the nitrene interme-
diates H3 are made. Then there is migratory insertion, and the creation of a C–N
bond creates a six-membered rhodium cycle H4 with the loss of N
2
. The last step is
pro-tonolysis, which breaks down H4 to make H5 and recover catalyst H1. With the
loss of NH
3
, more cyclization creates the 55 chemicals that have been seen. After
a year had passed, the group led by Dong revealed an Ir(III)-catalyzed amidation/
cyclization of sulfoximines 56 with N-alkoxyamides 57 in order to synthesis thia-
diazine 1-oxides 58 with yields ranging from low to high (28–85%) (Scheme
1.41)
[
74]. In spite of the fact that this approach tolerated a wide variety of substituents and
functional groups, it did not produce a smooth reaction with substrates that contained
strong electron-withdrawing groups.
Based on the mechanism of reaction presented in Scheme 1.42, the breaking of
the N–O bond in intermediate I3 is thought to be a crucial step. This step leads to
the formation of the nitrene complex I4 through protonation.
In the year 2020, Bolm and his colleagues announced an efficient Rh(III)-
catalyzed C–H function-alization cyclization method for the synthesis of
benzothiadiazine-1-oxides 61 from a variety of sulfoximines 59 and 1,4,2-dioxazol-
5-ones 60 (Scheme
1.43)[75
]. It is possible to carry out this routine while in the air
without the need for any additional protective measures.
According to the results of the substrate scope investigations, all of the substrates
that possessed electron-donating groups, electron-withdrawing groups, and a signif-
icant amount of steric hindrance were able to produce benzothiadiazine-1-oxides 61
with yields that ranged from moderate to good (53–91%). Furthermore, this method
was well-suited for S-alkyl-S-aryl-substituted sulfoximines, which were particularly
relevant in comparison to the findings that came before it.
The formation of the five-membered rhodacycles J2 is attributed to sulfoximines
59 and the activated Rh(III) catalyst, consistent with the previously reported process
(Scheme
1.44). After that, they undergo a reaction with 60, which results in the
production of the nitrenoid intermediate J3 and the loss of carbon dioxide. After
that, a traditional method involving insertion, demetallization, and condensation is
used to produce the products 61.
In the year 2022, Yoshino and his colleagues wrote about a method that used
Cp*Co(CO)I
2
/chiral carboxylic acid 66 as a catalyst. This technique was designed
1.2 Synthesis of Cyclic Sulfoximines 37
[Cp*Rh(III)]
Rh
N
S
O
S
O
NH
H
N
3
Rh
N
S
O
Ar
Cp*
Cp*
N
N
N
N
Rh
N
S
O
Ar
Cp*
N
2
Ar
N
3
Ar
NH
N
2
H
S
O
NH
Ar
H
N
S
NH
O
Ar
N
Ar
NH
2
Ar
NH
3
55
53
54
H2
H3
H4
H5
H6
54
R
1
R
1
R
1
R
1
R
2
R
2
R
1
R
1
R
2
R
2
R
1
R
1
H1
Scheme 1.40 Proposed mechanism of C–H functionalization of sulfoximines and annulation with
benzyl azides
S
O
NH
R
2
R
1
+
R
3
N
H
O
OR
4
[Cp*IrCl
2
]
2
(5 mol%)
AgSbF
6
(30 mol%)
DCE, 140
o
C, Ar
N
N
S
R
2
O
R
1
R
3
29 examples(28–85%)
56 57
58
Scheme 1.41 Ir(III)-catalyzed amidation/cyclization for the C–H activation of sulfoximines with
N-alkoxyamides to synthesize the corresponding thiadiazine 1-oxides
to facilitate the C–H functionalization re-action of sulfoximines 62 with dioxazolone
63 for the purpose of enantioselective synthesis of ben-zothiadiazine-1-oxides 65
(Scheme
1.45)[76
]. There were two different reaction phases involved in this method.
To begin, the amidation product 64 was produced by the reaction between sulfox-
imines 62 and dioxa-zolones 63, which took place inside the framework of the tran-
sition metal catalyst system. The cyclic products were then obtained by treating 64
with acetic acid in toluene, which resulted in yields that ranged from moderate to
excellent and e.r. values that were good to excellent. Furthermore, the control exper-
iments and the DFT calculation were carried out in order to support the hypothesis
that the cleavage of the C–H bond is the step that determines the enantiomeric state.
Furthermore, the research conducted on the breadth of the substrates revealed that
38 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
[Cp*Ir(SbF
6
)
2
]
[Cp*IrCl
2
]
2
[Cp*IrCl
2
]
AgSbF
6
Ir
N
S
O
R
2
Cp*
56
H
57
H
Ir
N
S
O
R
2
Cp*
N
OR
4
R
3
O
H
R
4
OH
Ir
N
S
O
R
2
Cp*
R
3
O
N
N
Ir
N
S
R
2
O
Cp*
R
3
O
H
S
NH
O
NH
R
2
R
3
O
H
2
O
58
I2
I3
I4
I5
I6
I1
R
1
R
1
R
1
R
1
R
1
Scheme 1.42 Proposed catalytic cycle
S
O
HN
R
2
R
1
+
N
O
O
O
R
3
[Cp*RhCl
2
]
2
(3 mol%)
AgSbF
6
(12 mol%)
PivOH (1 equiv.)
DCE, 100
o
C, 10 h
N
N
S
O
R
2
R
3
R
1
19 examples
(53–91%)
59 60
61
Scheme 1.43 Rh(III)-catalyzed method to obtain benzothiadiazine-1-oxides using 1,4,2-dioxazol-
5-ones
this approach exhibits exceptional compatibility with a variety of different functional
groups.
1.2 Synthesis of Cyclic Sulfoximines 39
[Cp*RhCl
2
]
2
1/2
AgSbF
6
AgCl
[Cp*RhX]Y
Rh
N
S
O
R
2
Cp*
R
1
59
HX
60
CO
2
Rh
N
S
O
R
2
Cp*
R
1
N
R
3
O
NH
S
O
R
2
R
1
N
O
O
O
R
3
N
Rh
N
S
O
R
2
R
1
Cp*
R
3
O
HX
S
O
NH
R
2
R
1
NH
R
3
O
61
H
2
O
J2
J3
J4
J5
J1
Scheme 1.44 Proposed mechanism
S
O
NH
+
N
OO
O
R
2
Cp*Co(CO)I
2
(10 mol%)
AgOTf (20 mol%), CCA
66
AcOH, toluene
HN
HN
S
O
Ar
R
2
O
N
N
S
O
Ar
R
2
62
63
64
65
CO
2
H
F
66
R
1
R
1
R
1
R
1
26 examples
(51–96%, 91:9–97:3 e.r.)
5A MS, t-AmOH, 30
o
C, 20 h
110
o
C, 24 h
Scheme 1.45 Co(III)-catalyzed enantioselective C–N bond formation of cyclic sulfoximines
1.2.5 Alkenes as Coupling Partner
In the process of synthesizing cyclic sulfoximines, alkenes have the potential to
act as varied coupling partners, which consequently enables the building of a wide
variety of molecular structures. There are a number of different reactions that may
40 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
be used to accomplish the addition of alkenes to cyclic sulfoximines. This provides
a method that is both effective and selective for the introduction of functional groups
or the formation of new carbon–carbon bonds. With cyclic sulfoximines serving
as coupling partners, the following are some examples of possible reactions that
involve alkenes: Reactions of the olefin metathesis: Transition metal complexes
catalyze olefin metathesis reactions, enabling the connection of alkenes with cyclic
sulfoximines. This procedure enables the synthesis of cyclic molecules with defined
stereochemistry while also resulting in the formation of a new double bond. The
formation of cyclic structures with sulfoximines can be accomplished through the
utilization of cycloaddition reactions by means of Diels–Alder or other cycload-
dition reactions that involve alkenes. These reactions contribute to the building of
complex frameworks by providing the regio- and stereoselectivity that is neces-
sary. Hydroamination: Transition metals have the ability to catalyze hydroamination
reactions that include alkenes and cyclic sulfoximines. These reactions result in the
direct addition of an amino group across the double bond. Through the utilization
of this method, nitrogen-containing moieties can be incorporated into the alkene.
It is possible to directly add an aryl group to an alkene through a process known
as hydroarylation. This process involves alkene hydroarylation reactions with cyclic
sulfoximines, which are frequently catalyzed by transition metal complexes. At times,
this approach can accomplish the functionalization of alkenes within the framework
of sulfoximine. An alkene is subjected to an Aza-Michael addition reaction, which
is characterized by the incorporation of a nucleophile that contains nitrogen into
the alkene. To create aminosulfoximine derivatives, this reaction can be utilized to
introduce sulfoximines to alkenes, which ultimately results in the synthesis of the
substances.
Shi’s group synthesized an asymmetric [4 + 3] annulation in 2022. This annulation
was a combination of sulfoximines 67 and α,β-unsaturated ketones 68. The ruthe-
nium (II)/chiral carboxylic acid 71 catalyst system was responsible for promoting this
annulation. The device was capable of producing a wide variety of sulfur-stereogenic
1,2-benzothiazepine 1-oxides, with a yield of up to 90% and an efficiency of up
to > 99%. It is important to take note of the fact that the locations of electron-
donating groups and electron-withdrawing groups frequently lead to the produc-
tion of various primary products. For example, para-substituted diarylsulfoximines
with electron-donating groups (OMe, Ph) often benefited from products that dialky-
lated or cyclized them. On the other hand, para- or meta-substituted diarylsulfox-
imines sulfoximines that contain electron-withdrawing groups would be helpful in
gaining access to monoalkylation/cyclization products. Furthermore, after the oxida-
tive breakage of the double bonds in the products, it is possible to obtain a sequence
of chiral N-benzoyl sulfoximines that have a C–S chiral axis, Scheme
1.46 illustrates
this reaction [
77
].
To sum up, this coupling reaction observed with alkenes enable the regulated
alteration of cyclic sulfoximines, providing a wide range of synthetic possibilities.
When trying to achieve regio- and stereoselectivity, the careful selection of reac-
tion conditions and catalysts is of the utmost importance. These compounds have
the potential to be utilized in various domains, including pharmaceutical chemistry,
1.2 Synthesis of Cyclic Sulfoximines 41
S
O
HN
R
1
R
1
+
R
2
O
CCA
71
(10 mol%), 3 Å MS
t-amylOH/C
6
H
5
Cl, N
2
, 50
o
C, 12 h
S
O
Ar
R
1
N
R
2
+
R
1
N
S
O
Ar
R
2
R
2
O
(90–>99% ee)
(60–99% ee)
67
68
69
70
CO
2
H
O
N
i-Pr
i-Pr
71
Ph
O
O
S
N
O
Ph
O
oxidative cleavage product
[RuCl
2
(p-cymene)]
2
(5 mol%)
AgSbF
6
(20 mol%)
Scheme 1.46 Ru(II)/chiral-carboxylic-acid-catalyzed enantioselectivity synthesis of seven-
membered cyclic sulfoximines
materials science, and other areas requiring the integration of specific functional
groups. In the process of synthesizing cyclic sulfoximines, the versatility of alkenes
as coupling partners is highlighted by the variety of reactions that result from this
process.
1.2.6 Alkynes as Coupling Partners
A diverse framework that may be used for the synthesizing of a wide variety of molec-
ular structures is provided by the use of alkynes as coupling partners in the synthesis
of cyclic sulfoximines. The creation of carbon–carbon triple bonds is made possible
by reactions involving alkynes. Furthermore, when combined with cyclic sulfox-
imines, these chemicals provide a mechanism of introducing functional groups or
developing complicated cyclic structures. Some examples of reactions that could take
place when alkynes are used as coupling partners with cyclic sulfoximines include the
following: The interchange of alkynyl groups is made possible through the process
of alkyne metathesis, which is accelerated by transition metal complexes. In order
to create fresh triple bonds between alkynes and cyclic sulfoximines, this technique
can be utilized. This opens the door for the synthesis of a wide variety of cyclic
structures. The insertion of an amino group across the triple bond is accomplished
through the process of hydroamination, which is a reaction that involves alkynes
and cyclic sulfoximines and is frequently catalyzed by transition metals. Through
the utilization of this method, nitrogen-containing moieties can be incorporated into
the alkyne system. There are a number of different cycloaddition reactions that can
involve alkynes and cyclic sulfoximines. One of these reactions is called alkyne azide
cycloaddition (click chemistry). These reactions have the potential to be invaluable
in the production of a wide variety of cyclic structures that exhibit a high degree
of selectivity. Sonogashira Coupling: Sonogashira coupling reactions involve the