Synthesis of NH-Sulfoximines by Using Recyclable Hypervalent Iodine(III) Reagents under Aqueous Micellar Conditions

Article abstract of DOI:10.1002/cssc.201903430

The synthesis of NH-sulfoximines from sulfides has been first developed under mild conditions in an aqueous solution with surfactant TPGS-750-M as the catalyst at room temperature. In this newly developed process, a simple and convenient recycling strategy to regenerate the indispensable hypervalent iodine(III) is used. The resulting 1,2,3-trifluoro-5-iodobezene can be recovered almost quantitively from the mixture by liquid–liquid extraction and then oxidized to give the corresponding iodine(III) species. This optimized procedure is compatible with a broad range of functional groups and can be easily performed on a gram scale, providing a green protocol for the synthesis of sulfoximines.

Full text of DOI:10.1002/cssc.201903430

Accepted Article
Title: Synthesis of NH-Sulfoximines Using Recyclable Hypervalent
Iodine (III) Reagents under Aqueous Micellar Conditions
Authors: Guocai Zhang, Hongsheng Tan, Weichun Chen, Hong C.
Shen, Yue Lu, Changwu Zheng, and Hongxi Xu
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To be cited as: ChemSusChem 10.1002/cssc.201903430
Link to VoR: http://dx.doi.org/10.1002/cssc.201903430
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Synthesis of NH-Sulfoximines Using Recyclable Hypervalent
Iodine (III) Reagents under Aqueous Micellar Conditions
Guocai Zhang,#[a][b] Hongsheng Tan,#[a] Weichun Chen,[b] Hong C. Shen,[b] Yue Lu,[a] Changwu
Zheng*[a] and Hongxi Xu*[c]
Abstract: The synthesis of NH-sulfoximines from sulfides has been
first developed under a mild, sustainable condition in an aqueous
solution with surfactant TPGS-750-M as the catalyst at room
of NH-sulfoximines has been achieved from sulfides under metal-
free conditions by Bull, Luisi, and two other research groups
separately (Scheme 1a).[9] Using excess diacetoxyiodobenzene
as the oxidant, a highly chemo-selective N and O group transfer
to sulfides was achieved in MeOH.
temperature. In this newly developed process,
a simple and
convenient recyclable strategy to regenerate the indispensable
hypervalent iodine(III) was utilized. The resulting 1,2,3-trifluoro-5-
iodobezene could be recovered almost quantitively from the mixture
by liquid-liquid extraction, and then oxidized to the corresponding
iodine (III) species. This optimized protocol is compatible with a broad
range of functional groups and could be easily performed on a gram
scale. Thus, this novel method provides a new and green protocol for
the synthesis of sulfoximines.
Sulfoximine-containing compounds have been studied
extensively over the past decades for their biological activities and
potential medicinal utilities.[1] The interesting dual functionality of
sulfoximine as both a hydrogen donor and acceptor increase its
utility in drug discovery.[2] Several sulfoximine-containing
compounds have been reported as drug candidates (Figure 1).
For example, the analogue of the COX-2 inhibitor Rofecoxib
showed a good COX-2 selectivity and a lower hERG activity, and
the pan-CDK inhibitor BAY 100394 is used to treat solid tumor
with an abnormality in Mcl-1, Myc or CCNE, which is currently in
phase II clinical trials.[3]
Figure 1. Representative sulfoximine-containing compounds with important
biological activities.
Due to the importance of sulfoximines in medicinal chemistry,
tremendous efforts have been dedicated to the development of
practical synthetic methods to access sulfoximines.[4] Typical
method involves the use of sulfoxides as starting materials and
transition metals (Fe, Rh, Cu) as the catalysts, by which the N-
protected sulfoximines can be prepared via electrophilic transfer
of an NR group from sulfonamide, trifluoroacetamide, carbamate
or amide.[5,6] In order to obtain the free NH-sulfoximines, an
additional de-protection step is herein needed.[7] To improve the
synthetic efficacy, direct synthesis of NH-sulfoximines from
sulfoxides was then developed by several groups[8] using
hydroxylamines (or salts) as the NH source under metal catalysis
or using ammonium carbamate with diacetoxyiodobenzene as the
oxidant. The free nitrogen group on NH-sulfoximines increases
the molecular diversity and provides the possibility for further
functionalization. Recently, a more efficient and direct synthesis
[a]
Dr. G. Zhang, Dr. H. Tan, Dr. Y. Lu, Prof. C. Zheng
School of Pharmacy, Shanghai University of Traditional Chinese
Medicine, Shanghai 201203, People’s Republic of China.
Email: zhengcw@shutcm.edu.cn
[b]
[c]
Dr. W. C. Chen, Dr. H. C. Shen
Scheme 1. Direct synthesis of NH-sulfoximines from sulfides and the
sustainable strategy.
Roche Innovation Center Shanghai, Roche Pharma Research and
Early Development, 720 Cai Lun Road, Shanghai 201203, China.
Prof. H. Xu
Shuguang Hospital Afliated to Shanghai University of Traditional
Chinese Medicine, Shanghai, P.R. China.
Email: xuhongxi88@gmail.com
These authors contributed equally.
Supporting information for this article is given via a link at the end of
the document.
Following these pioneer work, Luisi group then developed a
convenient, mild, and green synthesis of NH-sulfoximines in flow
reactors in view of efficient and safe synthesis for industrial
#
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10.1002/cssc.201903430
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applications[10] (Scheme 1b). Similar continuous flow strategy was
surfactants have been designed and applied, including TPGS-
750-M and Nok (SPGS-550-M) under micellar catalysis to
overcome the challenges of running reactions in water.[17]
Therefore, several surfactants including the TPGS-750-M were
added to water separately to improve the solubility of the lipophilic
reagents. To our delight, the addition of 2 wt% PEG-400 in
reaction afforded the product in 77% yield (Table 1, entry 2).
However, only 55% yield of sulfoximine (2a) was obtained with 2
wt% tween 80, likely due to a lot of white solid precipitation (Table
1, entry 3). Interestingly, TPGS-750-M as a promoter in water
showed great compatibility, leading to a 76% yield of the desired
product. Further screening of the weight ratio of TPGS-750-M
from 2% wt to 5% wt concluded that the reaction was most
efficient when it was performed at 2 wt% (Table 1, entries 4-7). In
addition, 2% Nok, which is the third generation of amphiphilic
surfactant, also provided an excellent yield (Table 1, entry 8). A
screening of other ammonium source (Table 1, entries 9-14)
revealed that the yield of 2a could be improved to 91% by utilizing
ammonium carbonate probably due to its good solubility in water
and rapid reaction with AcOH from iodine (III) reagents to provide
NH3 smoothly in the aqueous medium (Table 1, entry 14).
also used in the synthesis of N-protected sulfoximines[11] and
pharmaceutically relevant morpholino-pyrimidines with
a
sulfoximine moiety[12] by Lebel and Kappe group, respectively.
Notwithstanding the enormous progress made for preparing the
sulfoximines, and with respect to large-scale manufacturing,
sustainability and environmentally friendly process development,
it would be greatly ideal to perform the reactions in water[13] and
recycle the excess oxidants. However, commonly used
hypervalent iodine(III) compounds such as PhI(OAc)2 and
PhI(OCOCF3)2 have low solubility in water and it is difficult to
recycle. To improve the solubility, Kita’s group has developed a
micellar system using quaternary ammonium salt as the
surfactant on the oxidation of sulfides to sulfoxides with
iodosobenzene in water.[14] Recently, a versatile and highly
reactive polyfluorinated hypervalent iodine(III) compound was
reported by Wirth group and the application to synthesize
sulfoximines from sulfides was also demonstrated (Scheme
1c).[15] Because polyfluorinated hypervalent iodine(III) compounds
show increased reactivity and solubility and are easy to recycle,[16]
therefore, a combination of the polyfluorinated hypervalent iodine
reagents and surfactants in water would be an ideal solution for
the environmentally benign synthesis of sulfoximines.
Table 2. Screening of hypervalent iodine (III) reagent[a],[b]
Table 1. Optimization of reaction conditions[a]
Entry
1
Solvent
N sources (equiv.)
NH2CO2NH4 (2.0)
NH2CO2NH4 (2.0)
NH2CO2NH4 (2.0)
NH2CO2NH4 (2.0)
NH2CO2NH4 (2.0)
NH2CO2NH4 (2.0)
NH2CO2NH4 (2.0)
NH2CO2NH4 (2.0)
NH2OAc (2.0)
Yieldb
64%
77%
55%
76%
85%
79%
82%
81%
83%
55%
0%
Neat water
2
2 wt% PEG 400
2 wt% Tween 80
1 wt% TPGS-750-M
2 wt% TPGS-750-M
3 wt% TPGS-750-M
5 wt% TPGS-750-M
2 wt% Nok
3
4
5
6
7
8
9
2 wt% TPGS-750-M
2 wt% TPGS-750-M
2 wt% TPGS-750-M
2 wt% TPGS-750-M
2 wt% TPGS-750-M
2 wt% TPGS-750-M
.
10
11
12
13
14
NH3 H2O (2.0)
NH4Cl (2.0)
NH4Br (2.0)
NH4I (2.0)
0%
[a] Reaction conditions: 1a (0.25 mmol), 3 (0.75 mmol), ammonium carbonate
(1.0 mmol), water (1 mL), room temperature, 16 h. [b] isolated yield. [c] ○P is
poly styrene.
0%
(NH4)2CO3 (2.0)
91%
In order to develop a more sustainable synthetic method,
various hypervalent iodine (III) reagents were investigated so as
to develop a recyclable oxidation reagent to decrease the amount
of major by-product iodobenzene. As anticipated, the hypervalent
iodine (III) reagents play a pivotal role in the outcome of the
process, since the reactivity of iodine (III) reagent highly depends
on its ligands (Table 2).[18] Only a 19% yield of the expected
product was produced in the presence of PhI(OTFA)2 (3a), while
PhI(OPiv)2 (3b) just gave 50% yield. Poly(diacetoxyiodo)styrene
3c[19], 3d[20], 3e and 3f,[21] known for their good properties to
facilitate the separation of the iodoarene co-products from the
reaction mixture and the reuse of reagents, did not afford a good
[a] Reaction conditions: 1a (0.25 mmol), PhI(OAc)2 (0.75 mmol), ammonium
source (1.0 mmol), water (1 mL), room temperature, 16 h. [b] Isolated yield.
At the outset, we began our investigation by using thioanisole
as the model substrate, PhI(OAc)2 as the initial oxidant and
NH2CO2NH4 as the nitrogen source in water at room temperature.
Without the surfactant, the desired sulfoximine was obtained in
only 64% yield probably due to the poor solubility of thioanisole
and PhI(OAc)2 in water (Table 1, entry 1). Since 2008, the
Lipshutz group has published a series of papers, aiming to mimic
nature's processes that produce chemicals by employing water as
the reaction medium. For this purpose, several generations of
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10.1002/cssc.201903430
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conversion. The reaction efficiency was obviously affected by the
electronic nature of the substituents, as electron-withdrawing
groups on the benzene ring generally resulted in a higher
conversion in comparison with those containing an electron-
donating group (3g-3h, 3j-3l). Only a trace amount of target
compound was detected when Iodosolactone 3i were employed.
Notably, the highest conversion of 2a was achieved with the newly
prepared diacetoxytrifluoro iodobenzene (3l) probably because
the fluorine groups on the aromatic moiety enhance the rate
initially to form the active intermediate via its electrophilicity and
add considerable lipophilicity to 3l to increase its location inside
the micellar cores. The other advantage with the use of 3l is that
it can be easily regenerated by re-oxidation[22] of
trifluoroiodobenzene, which can be recovered from the reaction
mixture by liquid-liquid extraction in over 80% yield.[23] Compared
to the recycling of fluorinated iodine compounds in the reactions
with organic solvents,[16] the recovery and isolation procedure in
water are more convenient. After the reaction, concentrated
aqueous ammonia (35%) was added to the reaction suspension
which turned to be a homogeneous phase after stirring. The
ammonia acts as a reductant to consume the excess hypervalent
iodine (III) reagent and neutralize the acetic acid generated in the
reaction. Furthermore, the sulfoximine products exhibit a certain
degree of acidity, herein, the addition of concentrated aqueous
ammonia (35%) to the mixture also promotes the dissolution of
the products in aqueous phase. The mixture was then extracted
with n-heptane to separate trifluoroiodobenzene almost in
quantitive yield. The desired sulfoximines can be directly obtained
by additional extraction with dichloromethane from aqueous layer
under basic environment with a good yield and high purity (Figure
2). After extraction, the organic phase was dried and distilled
under atmospheric pressure. Over 90% of the organic solvents,
CH2Cl2 and n-heptane, can be recycled and reused.
of sulfoximins 2, and the results are summarized in Scheme 2. In
the first reactions, substrates bearing either electron-donating or
electron-withdrawing substituents (Me, OMe, Cl, Br, NO2, CN,
MeC=O) at different positions of the aryl moiety could be
accommodated to afford the corresponding products (2a–2m) in
70%–99% yields. The electronic nature of the aryl moiety and the
substituent position on the benzene ring seemed to have little
influence on the reaction efficiency. Most of the sulfoximines were
obtained in excellent yields. Subsequently, the substrate scope of
substituents on both sides of sulfur was then investigated.
Generally, the steric effect did not substantially affect the
transformation. The substrates bearing phenyl, ethyl, isopropyl,
allyl or benzyl group on either side worked well in this reaction
(2n-2u). In addition, heterocycles-containing sulfoximines could
be achieved in moderated yields (2v-2w). However, during the
reactions to produce 2u-2w, several undetermined by-products
were observed and the yields were decreased, probably due to
the over-oxidation of alkene and heteroatoms under these
conditions. After the reactions, the trifluoroiodobenzene and
sulfoximines were recovered and isolated respectively, according
to the standard process in Figure 2. In case of a few sulfoximines
with poor solubility in aqueous phase, a small amount of
hexafluoroisopropanol (HFIP) can be added as a co-solvent to
form a homogeneous phase before the extraction.[24] To evaluate
the scalability of the developed method and recyclability of the
hypervalent iodine (III) reagent 3l, the synthesis of 2a was then
conducted in a 10 mmol scale reaction. Gratifyingly, a high yield
(93%, 1.4 g) of product was detected after 16 hours with a simple
work up process. Upon recycling, trifluoroiodobenzene was
recovered from the reaction mixture in 91% yield, and then re-
oxidized to 3l by treating with sodium perborate tetrahydrate and
trifluoromethanesulfonic acid in acetic acid solution.[22] The results
confirmed the excellent performance of this new protocol that
features mild reaction conditions, high efficiency, and an
environmentally friendly and simple workup.
Scheme 2. Substrate scope under standard conditions in water.
Figure 2. The recovery and isolation process.
Considering the broad applications of these sulfoximines as
biologically and medicinally active compounds for improved
Having this optimized reaction condition and recycling method
in hand, we explored the scope of substrates 1 for direct synthesis
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10.1002/cssc.201903430
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solubility and oral bioavailability over non-sulfoximine analogs, we
attempted to apply this method and modify the structure of natural
products in order to obtain better physicochemical properties.
Xanthones are present in many nature products and is well known
for their anti-cancer activities. However, almost all of these
compounds raised a solubility concern in most of the solvents.[25]
Thus we explored our newly developed procedure for the
modification of the xanthones (4)[26] bearing a sulfide group. As
shown in Scheme 3, The desired product xanthone sulfoximine
5 was synthesized with the newly developed standard conditions
in 60% yield, which has shown a good solubility in various
solvents. Another application of this methodology is the synthesis
of Bay 1143572 (PTEFb Inhibitor, Phase I). In 2018, Reboul
reported a 5-step synthesis of Bay 1143572 with a late-stage
sulfoximination.[27] Under our method that applies green chemistry,
the desired PTEFb inhibitor BAY 1143572 in racemic form was
prepared in 90% yield.
water may take place outside the micelle inner core to afford the
product, which then re-enters to undergo the following conversion.
The ammonium carbonate supplying ammonia could be either
inside, or out, depending upon its distribution to provide the NH3.
Scheme 4. Plausible reaction mechanism under aqueous micellar conditions.
In summary, we have developed a green, efficient, and
economical method for the synthesis of sulfoximines from sulfides
with diacetoxytrifluoroiodobenzene (3I) in water. In this protocol,
TPGS-750-M was used to enable an NH transfer and oxidation
through nanomicelles. The use of ammonium carbonate as the N
source ensured a relatively safe condition. Importantly, a newly
developed hypervalent iodine (III) reagent can readily oxidize
sulfides and afford the corresponding trifluoroiodobenzene, which
can be efficiently recovered from the reaction mixture by a simple
liquid–liquid biphasic extraction procedure. Moreover, this
reaction could be conducted on a gram scale, and has been
successfully applied for the synthesis of xanthones derivative 5
and the racemate Bay 1143572. This newly developed synthetic
method to prepare the sulfoximines has exemplified many
desirable features of green chemistry.
Scheme 3. Synthesis of xanthone derivative 5 and Bay 1143572 in water.
The mechanism of the NH-sulfoximination of sulfide or
sulfoxide with PhI(OAc)2 in MeOH, trifluoroethanol or other
organic solvents has been fully studied and proposed by Reboul,
Luisi and Bull group. In these studies, the key intermediates
similar to trifluoroiodosylbenzene (B), nitrene (C) and thiazyne (E)
have been detected in the reactions via the NMR and HRMS
analysis (Scheme 4).[8][9] Based on these pioneering work, a
modified reaction mechanism to form NH-sulfoximines in water
was proposed in Scheme 4. In the absence of MeOH, water was
supposed to participate in the reaction with 3l to form the
trifluoroiodosylbenzene B, which then directly reacted with NH3 to
afford the key intermediate nitrene C. Apparently, the introduction
of the fluorine groups on the benzene ring enhances the rate via
its electrophilicity to generate intermediate A and initiates the
reaction cycle. Then the active nitrene C is captured by sulfide to
afford the sulfilimine D. The formation of D was indirectly verified
by the reaction of sulfoximine with PhI(OAc)2, which afforded an
iodonium salt containing an I-N single bond characterized by Luisi
and Bull group.[8b] The nucleophilic attack of an acetate anion or
H2O on D delivers the sulfanenitrile intermediate E, which was
attacked by H2O to afford the sulfoximines in good yields under
mild conditions. Under the surfactant catalysis, the water-
promoted aggregation of TPGS-750-M enables the formation of
nanomicelles,[17a] which surround water-insoluble organic
substrates and provide a facile environment for reactions. As
water is supposed to participate in the reaction, the organizational
aspects of the formed micelles by placing the water within the
PEG region and close to the inner cores also facilitate the
essential conversion.[28] During the reactions, the steps that need
Experimental Section
General procedure for the synthesis of NH-sulfoximines, and
recycling of iodoarene and solvents.
To a 10 mL single neck tube was charged with sulfide 1 (0.5 mmol), TPGS-
750-M (2% wt, 2 mL), ammonium carbonate (2.0 mmol, 4.0 eq.) at room
temperature, and then compound 3l was added in one portion. The
resulting reaction mixture was stirred at 25 °C for 16 h. It was quenched
with concentrated aqueous ammonia (35%) (2 mL) and stirred for 10
minutes. hexafluoroisopropanol (1 mL) was added if sulfoximines shown a
little low solubility. The resulting mixture was extracted sequentially with n-
heptane (10 mL × 3) and CH2Cl2 (5 mL × 3) to separate the 1,2,3-trifluoro-
5-iodobenzene and sulfoximines 2, respectively. The two combined
organic layers were dried over anhydrous MgSO4 and distilled under
atmospheric pressure to recycle the organic solvents, CH2Cl2 and n-
heptane. The product 2 was further purified by column chromatography
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Acknowledgements
We are grateful to the National Natural Science Foundation of
China
(81602990),
Fok Ying-Tong Education Foundation
(161039), The Three-year development plan project for
Traditional Chinese Medicine (ZY(2018-2020)-CCCX-2001-02),
A Professor of Special Appointment (Eastern Scholar) at
Shanghai Institutions of Higher Learning and Shanghai Sailing
Program (17YF1419500) for financial support.
Keywords: Sulfoximines • Surfactant • Green chemistry •
Oxidation • Recyclable
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This article is protected by copyright. All rights reserved.

10.1002/cssc.201903430
ChemSusChem
COMMUNICATION
COMMUNICATION
Guocai Zhang, Hongsheng Tan,
Weichun Chen, Hong C. Shen, Yue Lu,
Changwu Zheng* and Hongxi Xu*
Page No. – Page No.
Synthesis of NH-Sulfoximines Using
Recyclable Hypervalent Iodine (III)
Reagents under Aqueous Micellar
Conditions
The synthesis of NH-sulfoximines has been first developed in a mild, sustainable
conditions in an aqueous solution using surfactant TPGS-750-M catalyst at room
temperature. In this newly developed process, convenient recyclable strategy to
regenerate the indispensable hypervalent iodine(III) was utilized. This optimized
protocol is compatible with a broad range of functional groups and could be easily
performed on a gram scale.
This article is protected by copyright. All rights reserved.