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22 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
4 to coordinate with the metal center in order to produce a five-membered iridacycle
A2. After that, A2 is coordinated with diazo precursors 5, and the loss of N
2
results
in the generation of carbene species A4. Finally, the alkylated mi-gratory insertion
takes place, and the subsequent protonolysis results in the production of the alkylated
product A6 as well as the Ir(III) species A1. Finally, the acid-promoted cyclization/
dehydration process is carried out on A6 in order to produce the product that was
expected, which is 6 (Scheme
1.20).
In the same year, Cramer’s group reported the enantioselective [4 + 2] annu-
lative coupling reaction of diaryl sulfoximines 7 and acyl diazo compounds 8 for
the synthesis of chiral-at-sulfur 1,2-benzothiazines 9 catalyzed by [RhCp*Cl
2
]2 and
N-protected amino acid 10 (Scheme
1.21)[61
]. When the conditions were ideal, a
number of substituted cyclic compounds were produced with yields ranging from
good to excellent (61–95%) and enantioselectivities ranging from moderate to excel-
lent (77:23–96:4 e.r.). The use of polyfluoro-substituted alcohols as solvents, such
[IrCp*Cl
2
]
2
PivOH
Me
Me
Me
Me
Me
Ir
PivCO
2
O
O
Piv
Ir
N
S
O
R
2
Cp*
S
O
NH
R
2
2PivOH
R
3
N
2
R
4
O
Ir
N
S
O
R
2
Cp*
R
3
N
R
4
O
N
N
2
Ir
N
S
O
R
2
Cp*
R
3
R
4
O
Ir
N
S
O
R
2
Cp*
R
3
R
4
O
2PivOH
S
O
NH
R
2
R
3
R
4
O
-H
2
O
6
4
5
R
1
A1
A2
A3
A4
A5
A6
R
1
R
1
R
1
R
1
R
1
Scheme 1.20 Proposed mechanism of the formation of 1,2-benzothiazines in the Ir(III) catalytic
system
1.2 Synthesis of Cyclic Sulfoximines 23
S
O NH
+
R
1
R
1
R
2
O
R
3
N
2
[RhCp
x
Cl
2
]
2
(2.5 mol%)
10
(30 mol%)
NaSbF
6
, tBuOH, 35
o
C
N
S
O
Ar
R
1
R
2
R
3
OMe
OMe
Rh
i-Pr
Cl
Cl
2
[RhCp
x
Cl
2
]
2
N
O
O
CO
2
H
t-Bu
10
R
1
= H, Me, OMe, Br, F, CF
3
, Cl
R
2
= Me, C
2
H
2
Ph, H, Et, Ph, PMP, 4-F-C
6
H
5
, 2-furyl
R
3
= CO
2
Et. CO
2
Bn, PO(OMe)
2
, Ts, COEt, Ph, H
24 examples
(61–96%, 77:23–96:4 e.r.)
7
8
9
Scheme 1.21 Synthesis of chiral-at-sulfur 1,2-benzothiazines via C–H functionalization of sulfox-
imines
as TFE and HFIP, had a significant impact on the enantioselectivity of this reaction,
which resulted in the production of the opposite major enantiomeric products. This
is something that should be brought to the attention of other researchers.
Scheme 1.22 illustrates a mechanism that is conceivable, which is identical to
the achiral version that Bolm presented. Initially, sulfoximines 7 align to the Rh(III)
center in order to make B1 (perhaps B2 or B3). This causes the enantiodetermining
ortho-C–H activation step to be initiated through a concerted metalation depro-
tonation pathway, which ultimately results in the formation of intermediates B4.
After that, the adjuvant of the N-protected amino acid causes the formation of five-
membered cyclic rhodium complexes B5. For the purpose of gaining access to B7,
subsequent insertion and protonation are performed on carbenoid intermediates B6,
which were produced through the coordination of the diazo species 8. Following this,
the step of dehydration cyclization results in the production of 1,2-benzothiazines 9.
Li and others worked together in 2018 to create an enantiodivergent annulation
between sulfoximines 10 and diazo compounds 11 that was aided by rhodium(III)
complexes [
62
]. In this plan, the writers used Cramer type Cp*Rh(III) complexes
and different carboxylic acids with different steric bulks to flip the product’s abso-
lute configuration. This produced (R)-12 and (S)-12, respectively, under the best
conditions A and B (Scheme
1.23).
One year later, Wang and Wu reported a sustained Rh(III)-catalyzed C–H
activation/cyclization of sulfoximines 13 with diazo derivatives 14 to yield 1,2-
benzothiazines 15 in the ionic liquid [BMIM][PF6] (1-butyl-3-methylimidazolium-
hexafluorophosphate) as a solvent (Scheme
1.24)[63
]. This led to the production
of 1,2-benzothiazines 15 during the reaction. In this particular method, a high level
of tolerance was demonstrated for both electron-donating and electron-withdrawing
24 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
[RhCp
x
Cl
2
]
2
R*CO
2
H
NaSbF
6
[Cp
x
Rh(R*CO
2
)]SbF
6
S
O NH
S
N
O
Rh
Cp
x
O
O
R*
B1
7
S
HN
O
Rh
Cp
x
O
O
R*
SbF
6
B2
S
O
NH
Rh
Cp
x
O
O
R*
SbF
6
B3
or
Rh
N
S
O
Ar
*
Cp
x
O
HO R*
R*CO
2
H
Rh
N
S
O
Ar
Cp
x
R
2
O
R
3
N
2
N
2
Rh
N
S
O
Ar
Cp
x
R
3
R
2
O
S
O
NH
Ar
R
3
O
R
2
-H
2
O
9
B4
B5
B6
B7
8
R
1
R
1
R
1
R
1
R
1
R
1
R
1
R
1
R
1
R
1
R
1
R
1
R*CO
2
H
Scheme 1.22 Proposed mechanism of Rh-catalyzed chiral-at-sulfur 1,2-benzothiazines formation
S
O
NH
R
1
R
1
+
R
2
R
3
N
2
O
conditions A or conditions B
R
1
S
N
O
Ar
R
3
R
2
(R)-
12
conditions A (R major)
R
1
S
N
O
R
3
R
2
Ar
(S)-
12
conditions B (S major)
+
R
1
= H, Me, OMe, t-Bu, CN,
NO
2
, CO
2
Et, CF
3
, F, Cl, Br, naphthyl
R
2
= Me, Et, Ph
R
3
= CO
2
Et, CO
2
Me, CO
2
i-Pr, CO
2
t-Bu,
CO
2
Bn, Ac, COEt, COPh, SO
2
Ph
conditions A: [RhCp
X
I
2
]
2
(2.5 mol%). AgNTf
2
(20 mol%), 2-methoxybenzoic acid (0.5 equiv.), MeOH, 25
o
C, 12h
conditions B: [RhCp
X
I
2
]
2
(2.5 mol%). AgNTf
2
(20 mol%), 2,6-dimethoxybenzoic acid (2.0 equiv.), TCE, 30
o
C, 24h
32 examples
(30
97%, 92:8
99.5:0.5 e.r.)
31 examples
(60
94%, 12:88
4:96 e.r.)
OMe
OMe
Rh
I
I
2
(R)- [RhCp
X
I
2
]
2
10 11
(1.0 equiv.)
(1.2 equiv.)
Scheme 1.23 Rhodium-catalyzed strategy for the enantiodivergent desymmetrization of sulfox-
imines
1.2 Synthesis of Cyclic Sulfoximines 25
S
O
NH
R
2
R
1
+
R
3
O
R
4
N
2
[RhCp*Cl
2
]
2
(5 mol%)
AgSbF
6
(20 mol%)
[BMIM][PF6], 30
o
C
N
S
O
R
2
R
1
R
3
R
4
R
1
= H, OMe, Me, F
R
2
= Me, i-Pr, n-C
8
H
17
, Cy
R
3
= Me,
n-Pr, i-Pr, Ph, CH
2
Cl
R
4
= CO
2
Et, COMe, COPh, PO(OMe)
2
17 examples (41–98%)
13 14 15
(1.0 equiv.) (1.2 equiv.)
Scheme 1.24 Sustainable Rh(III)-catalyzed C–H activation/cyclization of sulfoximines to form
1,2-benzothiazines
sulfoximine substituents. In addition, this catalyst system has the capability to recycle
at least ten times before it gradually loses its high-efficiency catalytic action.
The catalytic circle that has been proposed is shown in Scheme 1.25.Inthe
beginning, the dissociation of the ionic liquid [BMIM] [PF6] results in the formation
of PF6*, which acts as a replacement anion to activate the catalyst [RhCp*Cl2]2 when
it is present in the setting of AgSbF6. The activated catalyst C1 is then coordinated
with sulfoximines 13, which results in the formation of five-membered Rh complexes
C2 and the release of HSbF6 that is produced. After that, the diazo derivatives
14 achieve coordination with the Rh center, which results in the formation of the
carbene species C3. The insertion process of carbenes then results in the formation
of six-membered intermediates, which are then followed by demetallization and
intramolecular condensation, which ultimately results in the formation of product
15.
In the same year, Cramer developed a method using Rh(III) catalyst to selec-
tively modify the C–H bonds of racemic sulfoximines 16, resulting in the production
of S-chiral 1,2-benzothiazines 18 [
64]. In comparison to Cramer’s prior research
conducted in 2018, this approach has the potential to yield a higher e.r. (efficiency
ratio) number. The sulfoximines were subjected to treatment with diazoketoesters 17,
resulting in the formation of the desired products with a high s-value (Scheme
1.26).
In addition, many substituted aryl sulfoximines exhibited efficient reactivity, with
enantioselectivity reaching a maximum of > 99:1. This includes groups with signif-
icant steric hindrance, such as i-Pr and cyclohexyl. Para-nitrophenyl methyl sulfox-
imine exhibited exceptional performance as a s ubstrate in these specific conditions,
yielding both products with a remarkable s-value over 200 and a 47% yield for each.
Bioactive molecules contain a lot of highly joined polycyclic scaffolds, so methods
for making them have also gotten a lot of attention. Li and Liu showed in 2020
a Rh(III)-catalyzed way to make combined 1,2-benzothiazines 22 from different
sulfoximines 20 and 4-diazoisochroman-3-imines 21 (Scheme
1.27)[65]. It was
found that [RhCp*Cl
2
]
2
(5 mol%) could work well as a catalyst with AgOPiv (20
mol%) as an addition in TFE at room temperature and in the presence of air. With
this plan, haloalkanes were shown to be bad for the results because they were not
26 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
[RhCp*Cl
2
]
2
AgSbF
6
[BMIM][PF6]
[RhCp*(PF
6
)(SbF
6
)]
Rh
N
S
O
R
2
Cp*
Rh
N
S
O
R
2
Cp*
R
4
R
3
O
Rh
N
S
O
R
2
Cp*
R
4
R
3
O
S
O
NH
R
2
R
3
O
R
4
15
H
2
O
R
4
N
2
R
3
O
N
2
S
O
NH
R
2
HSbF
6
13
C2
14
C3
C4
C5
C1
R
1
R
1
R
1
R
1
R
1
Scheme 1.25 Proposed catalytic circle
polar. Additionally, this reaction was tolerant of a wide range of substituents and
produced good to excellent yields. The ortho- and para-Me substrates, on the other
hand, did not produce the desired products in large amounts as planned. The meta-
Br substrate, on the other hand, produced a single site-selective product, while the
meta-OMe substrate produced a mix of two products.
According to the findings of the mechanistic investigation, the catalytic cycle
(Scheme
1.28) starts with the creation of the rhodacycle intermediate D2. This inter-
mediate is produced by the coordination of sulfoximine 20 to the Rh center of the
activated catalyst [RhCp*(OPiv)2] D1 and the electrophilic cleavage of the C–H
bond. Afterwards, the coordination of D2 with diazo compound 21 results in the
formation of the rhodium carbenoid complex D3, which is accomplished through
the release of nitrogen gas. After that, the insertion into the Ph–Rh bond results in
the formation of intermediate D4, and after that, the catalyst is recycled by the proto-
nation of D4, which results in the formation of intermediate D5. After everything
is said and done, the product 22 is created through the condensation of D5 with the
addition of TsNH
2
.
A method for the synthesis of highly conjugated 1,2-benzothiazine scaffolds 25
was presented by Ye and Liu and their colleagues in 2021 [
66
]. This process involved
1.2 Synthesis of Cyclic Sulfoximines 27
rac-
16
+
R
3
N
2
O
17
[RhCp
X
(MeCN)
3
] (3 mol%)
amino acid
19
(10 mol%)
MeOH, 40
o
C, 12 h
S
O
NH
R
1
Ar
(S)-
16
+
N
S
O
R
3
R
2
R
1
(R)-
18
OMe
OMe
Rh
Me
N
Me
N
Me
N
[RhCp
X
(MeCN)
3
]
N
O
O
CO
2
H
Bn
19
S
O
NH
R
1
Ar
R
2
Ar
21 examples
(39–49%,
93:7–>99:1 e.r.)
(42–50%,
91:9–98.5:1.5 e.r.)
(1.0 equiv.)
(0.6 equiv.)
Scheme 1.26 Rh(III)-catalyzed C–H functionalization strategy for the kinetic resolution of racemic
sulfoximines
S
O
NH
R
2
R
1
+
O
N
2
NTs
R
3
[RhCp*Cl
2
]
2
(5 mol%)
AgOPiv (20 mol%)
TFE, rt, 18h
R
1
N
S
O
R
2
O
R
3
R
1
= H, Me, OMe, CH
2
OH, F, Cl, Br, NO
2
, Ac, CH
2
COOEt, NHBoc
R
2
= Me, Et, cyclopropyl, CH
2
OH, CH
2
Cl, Ph, Bn
R
3
= Me, OMe, Cl, F, CF
3
31 examples(42–93%)
20 21
22
(1.0 equiv.) (1.1 equiv.)
Scheme 1.27 Rh(III)-catalyzed method for the synthesis of fused 1,2-benzothiazines from
sulfoximines and 4-diazoisochroman-3-imines
the use of sulfoximines 23 and 2-diazo-1H-indene-1,3(2H)-diones 24. In order to
get high yields, it was found that the silver addition was essential. Furthermore,
this method was able to cope with a wide variety of substituted sulfoximines and
successfully synthesize target products with yields ranging from 74 to 88%. It is
also important to note that the C–H bond activation of meta-substituted sulfoximines
tends to proceed in the more hindered ortho-positions. In addition, a number of mono-
substituted diazo compounds were able to undergo a smooth reaction; however, the
products that resulted from this reaction were a combination of regional isomers
(Scheme
1.29).
28 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
[RhCp*Cl
2
]
2
AgOPiv
[RhCp*(OPiv)
2
]
Rh
N
S
O
R
2
Cp*
S
O
NH
R
2
H
O
N
2
NTs
N
2
Rh
N
S
O
R
2
Cp*
O
NTs
Rh
N
S
O
R
2
Cp*
O
TsN
H
O
NTs
S
O
NH
R
2
TsNH
2
22
D2
D3
D4
D5
20
21
D1
R
1
R
1
R
1
R
1
R
1
R
3
R
3
R
3
R
3
Scheme 1.28 Proposed mechanism of the annulation between sulfoximines and
4-diazoisochroman-3-imines
S
R
2
HN
O
+
O
O
N
2
[Cp*RhCl
2
]
2
(5 mol%)
AgSbF
6
(20 mol%)
CsOAc, TFE, 100
2h
N
S
OR
2
O
R
1
R
3
R
1
R
3
33 examples(34–93%)
R
1
= H, Me, OMe, Cl, F, Cl, Br, NO
2
, CH
2
OH, Ac, NHBoc, CH
2
CO
2
Et
R
2
= Me, Ph, Bn, cyclopropyl, Et, allyl, CH
2
CH
2
OH, CH
2
Cl
R
3
= Me, OMe, Cl, F
23
24
25
(1.0 equiv.)
(1.2 equiv.)
o
C
,
Scheme 1.29 Rh-catalyzed synthesis of highly conjugated 1,2-benzothiazine scaffolds
Hong and Shi have only recently revealed a C–H activation/annulation tech-
nique that is catalyzed by Ir(III) for the purpose of synthesizing chiral 1,2-
benzothiazines. This strategy involves the desymmetrization of sulfoximines 26
with diazo compounds 27 in the presence of chiral carboxylic acid 29 as a ligand,
as shown in Scheme
1.30 [67]. Several electron-withdrawing groups on the diazo
1.2 Synthesis of Cyclic Sulfoximines 29
+
R
O
EWG
N
2
[Cp*IrCl
2
]
2
(2.5 mol%)
AgSbF
6
(10 mol%)
chiral carboxylic acid
29
(10 mol%)
t-amyl-OH, 35
o
C, 12 h
S
ONH
Ar
Ar
Ar
N
S
O
Ar
R
EWG
26 examples
(60–94%, 92–97% ee)
CO
2
H
O
N(i-Pr)
2
26
27
28
29
(1.0 equiv.)
(1.5 equiv.)
Scheme 1.30 Ir(III)-catalyzed C–H activation/annulation strategy for the synthesis of chiral 1,2-
benzothiazines
compounds were tested to see whether or not they were well tolerated, and the ee
value reached up to 97% across the board. It was also possible for sulfoximines to
undergo a smooth transformation with electron-donating and electron-withdrawing
substituents. It is important to note that the authors used this method to develop both
the kinetic resolution and the parallel kinetic resolution of racemic sulfoximines.
1.2.3 Ylide Active Intermediates as Carbene Precursors
Ylides, specifically phosphorus ylides and sulfur ylides are actively serve as inter-
mediates in organic synthesis, capable of transformation into carbenes. That is why
they are considered to be valuable carbene precursors. As a result of the presence of
both positive and negative charges on neighboring atoms, ylides are characterized
by the formation of a dipole structure. Subjecting these ylides to suitable reactions
or conditions can give rise to carbenes. Carbenes are highly reactive entities that are
capable of partaking in a variety of transformations.
The following are some characteristics of ylide-active intermediates in their role
as carbene precursors: During the Wittig reaction, phosphorus ylides, which are also
known as Wittig reagents, can react with carbonyl compounds to make carbenes. The
resultant carbenes have the potential to participate in olefination processes, which
can give rise to double bonds between carbon atoms. The Staudinger reaction is
a chemical process that involves the interaction of phosphorus ylides with azides,
which results in the production of a carbene intermediate. A number of different
transformations, including cycloaddition processes, are possible for this intermediate
to take part in. Utilization of sulfur ylides in the Corey-Chaykovsky Reaction, sulfur
ylides are used to make carbenes by reacting with carbonyl compounds. Specifically,
the creation of epoxides is accomplished through the utilization of this process.
During cyclopropanation, sulfur ylides can be utilized to cyclopropanate olefins.
During this process, the ylide reacts to make a carbene intermediate, which leads
to the creation of cyclopropane rings. Ylides containing stabilizing groups, such as
phosphonium ylides or sulfonium ylides, provide carbene precursors. Researchers
can utilize these ylides in a variety of transformations. The stabilizing groups help
control the reactivity and stability of the formed carbenes. Catalytic ylide creation:
Catalytic approaches for ylide creation, which frequently involve the utilization of
30 1 Synthesis of Sulfoximines and Cyclic Sulfoximines
S
O
HN
R
2
+
R
1
R
3
S
O
O
Cp*Rh(MeCN)
3
(SbF
6
)
2
(5 mol%)
Zn(OTf)
2
(30 mol%)
DCE, N
2
, 100
o
C, 36 h
30
31
N
S
OR
2
R
3
32
31 examples(64–98%)
(1.0 equiv.)
(2.0 equiv.)
Scheme 1.31 The synthesis of 1,2-benzothiazine through rhodium(III)-catalyzed annulative
couplings
transition metal catalysts, offer a means of accessing ylide active intermediates in a
regulated manner. Once these ylides have been created through catalysis, they are
capable of being transformed into carbenes under mild circumstances.
The use of ylides as carbene precursors provides chemists with a wide range of
synthetic options, enabling them to access a variety of carbene species that exhibit
different reactivity. The regulated creation of carbenes from ylides makes it easier for
these compounds to be utilized in a wide variety of organic transformations. These
transformations include cycloadditions, rearrangements, and cyclopropanations, all
of which contribute to the synthesis of different kinds of complex molecules.
In 2018, Li’s group published a new method for making 1,2-benzothiazines 32
by using rhodium(III) to help with annulative coupling between sulfoximines 30 and
sulfox-onium ylides 31 (Scheme
1.31)[68]. Different modified substrates worked
well together. Also, different N-protected benz-amidines and benzophenone NH-
imines could be used, and they were able to make a lot of different isoquinoline
products. To better understand how the reaction worked, a H/D exchange experiment
was done. The results showed that there was some H/D exchange at the ortho-position
of the product. The clear evidence showed that the C–H activation can be undone. It
was also possible to measure the kinetic isotope effect of this reaction. The results
showed that the C–H activation step played a part in the turnover-limiting process.
The catalytic mechanism is outlined in Scheme 15. Initially, the RhCp*X2
complex E1 is coordinated with sulfoximine 30 to create intermediate E2 through a
metalation deprotonation mechanism. Next, the sulfoxonium ylides 31 bind to the
rhodium core, resulting in the formation of intermediate E3. Afterwards, DMSO
undergoes α-elimination, resulting in the formation of the active carbene complex
E4. Furthermore, the Rh–Ar bond of the carbene species undergoes the migratory
insertion process, resulting in the formation of intermediate E5. Finally, the process
of reductive elimination and intramolecular dehydration results in the formation of
product 32 (Scheme
1.32).
In 2021, Shi’s group reported an enantioselective C–H functionalization of sulfox-
imines 33 with sulfoxonium ylides 34. This was accomplished by using chiral
binaphthyl carboxylic acids 41 as the optimal chiral ligand together with [(p-
cymene)RuCl
2
]
2
as a catalyst. The result was the production of 1,2-benzothiazines
35 with good to excellent yields (75–99%) and excellent enantioselectivities (96–
98% ee) (Scheme
1.33, Eq. a) [69
]. Furthermore, the kinetic resolution of racemic
sulfoximines 36 could also be accomplished by using chiral binaphthyl carboxylic
1.2 Synthesis of Cyclic Sulfoximines 31
RhCp*X
2
S
NH
O
R
2
2HX
Rh
N
S
O
R
2
Cp*
O
S
O
Rh
N
S
O
R
2
Cp*
S
O
R
3
O
Rh
N
S
O
R
2
Cp*
O
R
3
Rh
N
S
O R
2
Cp*
R
3
O
2HX
S
NH
O
R
2
O
R
3
Dehydration
elimination
32
30
E2
31
E3
E4
E5
E6
E1
R
1
R
3
R
1
R
1
R
1
R
1
R
1
Scheme 1.32 Proposed mechanism of the tandem annulative coupling between sulfoximines and
sulfoxonium ylides
acids 42 as the ligand. This resulted in the production of cyclization products (S)-37
with yields ranging from low to moderate (29–53%) and enantioselectivities ranging
from moderate to outstanding (64–91%) (Scheme
1.33, Eq. b). Additionally, we
could also produce the unreacted (R)-36 with yields ranging from 35 to 41% and
excellent enantioselectivities ranging from 86 to 98%. It is a fortunate circumstance
that the parallel kinetic resolution of racemic diaryl sulfoximines 38 could be carried
out without any difficulties and with high ee values (up to 95%) under standard
circumstances (Scheme
1.33, Eq. c).
In 2021, Yu and Pan presented a rhodium-catalyzed technique for the synthesis of
polycyclic 1,2-benzothiazines 45. This strategy utilized a variety of aryl sulfoximines
43 and iodonium ylides 44 as substrates, as shown in Scheme
1.34 [70
]. As a result
of the catalyst screening, it was determined that [RhCp*Cl
2
]
2
is the most effective
catalyst for this particular chemical system. In addition, a wide range of polycyclic
1,2-benzothiazines that have a relatively high tolerance for functional groups were
produced in yields that ranged from moderate to excellent.
It was necessary to carry out the H/D exchange experiment as well as the KIE
investigation in order to find out the mechanism of the reaction. Furthermore, the
results suggested that the C–H activation step can be irreversible, and that the cleavage
of the C–H bond cannot be involved in the step that determines the rate of the reaction.
The findings of the intermolecular competition studies, which were also carried