Visible light promoted synthesis of N-aroylsulfoximines by oxidative C-H acylation of NH-sulfoximines

Article abstract of DOI:10.1007/s11426-019-9499-5

The visible light-promoted synthesis of N-aroylsulfoximines has been accomplished via an oxidative dehydrogenative coupling at room temperature under air without the addition of a photosensitizer, metal catalyst, or base. This process exhibits good functional group tolerance, allows facile isolation and purification, and affords N-aroylsulfoximines with high efficiency. The efficiency of the newly developed protocol is described in detail with 27 examples with yields ranging from 80% to 96%. Furthermore, the chirality of the NH-sulfoximine is completely maintained in the desired N-aroylsulfoximine product (<99% ee).

Full text of DOI:10.1007/s11426-019-9499-5

SCIENCE CHINA
Chemistry
•ARTICLES•
https://doi.org/10.1007/s11426-019-9499-5
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Visible light promoted synthesis of N-aroylsulfoximines by
oxidative C–H acylation of NH-sulfoximines
Wenlong Jiang1, Youming Huang1, Lihong Zhou2 & Qingle Zeng1*
1State Key Laboratory of Geohazard Prevention and Geoenvironment Protection, College of Materials, Chemistry & Chemical Engineering,
Chengdu University of Technology, Chengdu 610059, China;
2College of Environment and Ecology, Chengdu University of Technology, Chengdu 610059, China
Received March 28, 2019; accepted May 10, 2019; published online July 11, 2019
The visible light-promoted synthesis of N-aroylsulfoximines has been accomplished via an oxidative dehydrogenative coupling
at room temperature under air without the addition of a photosensitizer, metal catalyst, or base. This process exhibits good
functional group tolerance, allows facile isolation and purification, and affords N-aroylsulfoximines with high efficiency. The
efficiency of the newly developed protocol is described in detail with 27 examples with yields ranging from 80% to 96%.
Furthermore, the chirality of the NH-sulfoximine is completely maintained in the desired N-aroylsulfoximine product (>99% ee).
visible light, aldehyde, sulfoximines, acylation, oxidative dehydrogenative coupling
Citation:
Jiang W, Huang Y, Zhou L, Zeng Q. Visible light promoted synthesis of N-aroylsulfoximines by oxidative C–H acylation of NH-sulfoximines. Sci
China Chem, 2019, 62, https://doi.org/10.1007/s11426-019-9499-5
1 Introduction
struction of various heterocyclic molecules [9,10].
With the development of chemical synthesis, alkylations
[11], vinylations [12], alkynylations [13], arylations [14,15]
and other reactions [16,17] have been reported for the
synthesis of various N-substituted sulfoximines. N-Acylsul-
foximines are an important class of sulfoximine derivatives
that have found wide applications in both pharmaceutical
and synthetic chemistry [18,19].
The traditional syntheses of N-acylsulfoximines, important
sulfoximine derivatives, mainly rely on the N-acylation of
NH-sulfoximines with acyl chlorides [20,21]. In recent years,
some new synthetic methods via oxidative C–N cross-cou-
pling processes [22,23] or oxidative decarboxylative cou-
pling reactions [24] have been developed. Notably, in 2013,
Bolm’s group [24] developed copper-catalyzed oxidative N-
acylations of sulfoximines with aldehydes (Scheme 1, eq.
(1)). In 2015, the Deng’s group [25] developed TBAI/TBHP
catalysts, but low yields were achieved (eq. (2)). In 2016, the
Guin’s group [26] developed an NHC (N-heterocyclic car-
bene) catalytic system with bisquinone as the oxidant, but the
Molecules with sulfoximine structures are of interest because
they are widely used in medicine and agriculture (Figure 1)
[1]. nAChR agonist I represents a novel insecticide targeting
sap-feeding pests with unique resistance and mode-of-action
characteristics [2]. The second molecule (II) selectively in-
hibits COX-2 and hERG [3], and it has been identified as a
new agent for insect control due to its nicotinic receptor
activity [4]. pan-CDK inhibitor III, which was developed by
Bayer (BAY 1000394, now in clinical trials), retains the
required high biological activity, improves the solubility, and
greatly reduced the carbon anhydrase off-target activity of
the drug [5]. Human FXa inhibitor IV was developed to treat
thrombotic disease, and it works as a novel replacement of
the highly basic amidine group of Betrixaban [6]. In addition,
sulfoximines are commonly used as chiral precursors and
chiral ligands in asymmetric synthesis [7,8] and in the con-
*Corresponding author (email: qinglezeng@hotmail.com)
© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019
chem.scichina.com link.springer.com

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Jiang et al. Sci China Chem
complexity of the system made separation and purification
more difficult (eq. (3)). Although these synthetic strategies
are effective, the use of preactivated coupling agents or
transition-metal catalysts is not sufficient for either industrial
production or green chemistry.
On the other hand, photochemical synthesis as a new,
energy-saving, greener solution and has thus attracted sub-
stantial attention from chemists resulting in its rapid devel-
opment [27–29]. Aldehydes are inexpensive and
commercially available. They are useful surrogates for the
facile generation of acyl radicals via visible light [30–32].
However, photochemical approaches for preparing N-acyl-
sulfoximines are rare. Currently, only Bolm et al. [18] has
developed a photocatalytic approach for preparing N-acyl-
sulfoximines, and it requires the preparation of highly active
Ru catalyst precursors and special substrates (Scheme 1, eq.
(4)).
Based on our research on organic sulfur chemistry [33–
Figure 1 Selected examples of bioactive sulfoximines (color online).
Scheme 1 Synthetic methods for accessing N-aroylsulfoximines (color online).

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Jiang et al. Sci China Chem
35], selective cross couplings [36,37] and oxidative cross
couplings [38], we developed a visible light-promoted oxi-
dative cross-coupling reaction for the synthesis of N-ar-
oylsulfoximines under mild conditions without a transition-
metal catalyst, an exogenous photosensitizer or a base
(Scheme 1, eq. (5)).
We tested different light sources and found that target pro-
duct 3aa could also be generated under ultraviolet light, but
the yield was substantially lower (Table 1, entry 2). The
reaction did not proceed in the dark (entry 3). When we
increased the temperature and protected the reaction from
light, the yield was less than 10% (entry 4), which means that
this is a visible light promoted reaction.
We speculated that this synthesis might occur via a free
radical reaction; thus, the selection of an appropriate free
radical initiator was of great importance. Therefore, in-
itiators, such as H2O2, m-CPBA, di-t-butyl peroxide (DTBP),
K2S2O8 and (NH4)2S2O8, were tested. We found that when
the reaction system had only a single initiator, the reaction
did not proceed (Table 1, entries 5, 6). However, not all of the
mixed initiator systems were successful, for example, H2O2/
K2S2O8 (entry 7). Mixed initiator systems including TBHP
and K2S2O8, TBHP and (NH4)2S2O8, and DTBP and K2S2O8
2 Results and discussion
Initially, we adopted 0.55 mmol of p-nitrobenzaldehyde (1a)
and 0.5 mmol of S-methyl-S-phenylsulfoximine (2a) as
model substrates and a mixture of TBHP (70% aqueous so-
lution) and K2S2O8 as oxidants. These model substrates and
the mixed oxidant in CH3CN under an air atmosphere were
irradiated with simulated sunlight (xenon arc lamp) for 12 h,
and the reaction afforded 3aa in 80% yield (Table 1, entry 1).
Table 1 Optimization of the reaction conditionsa)
Entry
1
2c)
Oxidant (mole ratio)
TBHP/K2S2O8 (2:1)
TBHP/K2S2O8 (2:1)
Time (h)
Solvent
CH3CN
CH3CN
Yield (%)b)
12
12
80
57
3d)
TBHP/K2S2O8 (2:1)
TBHP/K2S2O8 (2:1)
12
12
CH3CN
CH3CN
Trace
<10
4e)
5
6
TBHP/K2S2O8 (0:1)
TBHP/K2S2O8 (1:0)
H2O2/K2S2O8 (2:1)
MCPBA/K2S2O8 (2:1)
DTBP/K2S2O8 (2:1)
TBHP/(NH4)2S2O8 (2:1)
TBHP/K2S2O8 (2:1)
TBHP/K2S2O8 (2:1)
TBHP/K2S2O8 (2:1)
TBHP/K2S2O8 (2:0.5)
TBHP/K2S2O8 (3:1)
TBHP/K2S2O8 (4:1)
TBHP/K2S2O8 (3:1)
TBHP/K2S2O8 (3:1)
TBHP/K2S2O8 (3:1)
TBHP/K2S2O8 (3:1)
TBHP/K2S2O8 (3:1)
TBHP/K2S2O8 (3:1)
12
12
12
12
12
12
12
12
12
12
12
12
12
12
4
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
Trace
Trace
Trace
Trace
30
7
8
9
10
11
12
13
14f)
15
16
17g)
18h)
19
20
21
22i)
52
42
DMSO
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
<10
24
69
85
84
93
73
60
8
80
16
12
91
95
a) Reaction conditions: 1a (0.55 mmol, 1.1 equiv.), 2a (0.5 mmol, 1.0 equiv.), TBHP (1.0 mmol, 2.0 equiv.), K2S2O8 (0.5 mmol, 1.0 equiv.), CH3CN
(1.0 mL), irradiation (visible light, 250 W, xenon arc lamp), rt, air. b) Yields correspond to isolated products. c) Irradiation (UV, 250 W, mercury lamp). d) In
the dark. e) In the dark, 80 °C. f) TBHP (1.0 mmol, 2.0 equiv), K2S2O8 (0.25 mmol, 0.5 equiv.). g) 1a (0.75 mmol, 1.5 equiv.), 2a (0.5 mmol, 1.0 equiv.). h) 1a
(0.5 mmol, 1.0 equiv.), 2a (0.55 mmol, 1.1 equiv.). i) 50 °C.

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Jiang et al. Sci China Chem
afforded target product 3aa (entries 8–10). Subsequently, the
effects of the solvent were investigated. The outcome of the
reaction performed in DMSO was the worst, and the out-
comes of the reactions conducted in CH2Cl2 and THF were
also poor (entries 11–13). Fortunately, CH3CN, which was
chosen for our initial experimental conditions, was the best
solvent (entry 1). Then, the reactant ratio was screened, and it
was found that the best reaction result was obtained when
TBHP/K2S2O8 was 3:1 and 1a/2a was 1.5:1.0 (Table 1, en-
tries 14–18). Finally, the reaction time was found to greatly
influence the yield. The yield was 60% in 4 h and 80% in 8 h,
but the yield did not noticeably change when the reaction
time was increased to 16 h (entries 19–21). In addition, the
effect of temperature was investigated, and it was found that
the yield did not change significantly when the temperature
was increased (entry 22). Therefore, room temperature was
selected as the optimal temperature for the reaction system.
With the optimized conditions in hand, the scope of var-
ious aldehydes was evaluated (Table 2). 4-Nitrobenzal-
dehyde (1a) was used as the standard substrate for the re-
action, and this substrate afforded the corresponding amide
(3aa) in 93% yield. In addition, benzaldehyde without a
substituent on the benzene ring gave 3ab in a yield of 92%.
Benzaldehydes with various electron-donating substituents,
such as p-methyl (3ac), m-methyl (3ad) and methoxy (3ak),
provided the desired products in yields of 89%–94%. Various
benzaldehydes with halogen substituents were also effi-
ciently converted to amides (3ae–3aj) in high yields. Sub-
strates with electron-withdrawing groups, such as cyano
(3al) and ester groups (3am), also provided high yields of the
corresponding products. It seems that the electronic proper-
ties of the substituents on the benzaldehyde had no sig-
Table 2 Scope of aldehydesa), b)
a) Reaction conditions: aldehyde 1 (0.75 mmol, 1.5 equiv.), S-methyl-S-phenylsulfoximine 2a (0.5 mmol, 1.0 equiv.), TBHP (1.5 mmol, 3.0 equiv.),
K2S2O8(0.5 mmol, 1.0 equiv.), CH3CN (1.0 mL), irradiation (visible light, 250 W, xenon arc lamp), air, rt, 12 h. b) Yields correspond to isolated products.

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Jiang et al. Sci China Chem
a), b)
Table 3 Scope of N-aroylated sulfoximines
a) Reaction conditions: aldehyde 1 (0.75 mmol, 1.5 equiv.), S-methyl-S-phenylsulfoximine 2a (0.5 mmol, 1.0 equiv.), TBHP (1.5 mmol, 3.0 equiv.),
K2S2O8(0.5 mmol, 1.0 equiv.), CH3CN (1.0 mL), irradiation (visible light, 250 W, xenon arc lamp), air, rt, 12 h. b) Yields correspond to isolated products.
nificant influence on the reaction outcome.
fanone (3bi), dibutyl (imino)-sulfanone (3bj), and dibenzyl
(imino)-sulfanone (3bk) are also excellent substrates and
provided yields in the range of 80%–92%. Furthermore, a
cyclic sulfoximine, S,S-tetramethylenesulfoximine (3bl),
was also tolerated in this reaction.
Sulfoximines serve as potential chiral ligands for asym-
metric catalysis [7,8], so we synthesized chiral N-benzoy-
lated sulfoximines. The reaction of commercially available
(R)-S-methyl-S-phenylsulfoximine ((R)-2a, >99% ee) and
p-nitrobenzaldehyde (1a) and 4-bromobenzaldehyde (1h)
afforded (R)-3aa and (R)-3ah with>99% ee in 91% and 87%
yields, respectively (Scheme 2, eq. (6)) [21]. The results
show that the chirality of the enantiomerically enriched
sulfoximine is well preserved in this transformation as no
racemization occurred during the reaction. We believe that
this strategy will facilitate the development of sulfoximine-
type chiral drugs and chiral ligands.
When substrate 1 was 2-naphthalaldehyde, the corre-
sponding amide was generated in 85% yield. Unexpectedly,
the yields of the amides from heteroaromatic aldehydes (3ao
and 3ap) could reach 84%–86%. In addition, a conjugated
system such as cinnamaldehyde (3aq) could be converted
into the desired product in a good yield.
Next, the scope of the NH-sulfoximines was evaluated
(Table 3). Various substituents, such as methyl (3ba), F
(3bb), Cl (3bc), Br (3bd), methoxy (3bf) and nitro (3bh), on
the benzene ring of the NH-sulfoximine were well tolerated
in the reaction, and the yields of their corresponding products
were in the range of 85%–96%. The yields obtained with
S-methyl-S-phenylsulfoximines with a bromo substituent at
the ortho- or para- position of the phenyl ring (3bd and 3be)
demonstrate that the position of the substituents on the sul-
foximines has a minor effect in this reaction. In addition, bis-
aryl and bis-alkyl sulfoximines such as iminodiphenyl-sul-
To verify the effectiveness of our synthetic method in

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Jiang et al. Sci China Chem
practice, a gram-scale experiment was conducted. With
10 mmol of the corresponding NH-sulfoximines as the
starting materials, 3aa and 3ac were obtained in 87% and
83% yields, respectively, within 12 h. Interestingly, hetero-
aromatic aldehyde 3ap gave a good yield after increasing the
reaction time to 16 h (Scheme 3, eq. (7)).
To study the mechanism of the reaction, we conducted
control experiments (Scheme 4). The above experimental
results were obtained in a photochemical instrument using a
xenon arc lamp as the light source to simulate sunlight. Here,
we conducted a reaction under sunlight alone and found that
the yield of the targeted amide reached 84% (eq. (8)).
We further studied whether this reaction involves a free
radical. Thus, we added 2.0 equiv. of TEMPO to the reaction
system, and after 12 h, no 3aa was detected. The TEMPO-
aldehyde adduct was identified as the major product of this
reaction (eq. (9)) [24]. This control experiment verifies that
this is a free radical-type reaction.
Scheme 2 The synthesis of chiral N-benzoylated sulfoximines.
Scheme 3 Gram-scale synthesis.
Scheme 4 Controlled experiments.

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Jiang et al. Sci China Chem
To verify if the aldehyde in the reaction is first converted to
the carboxylic acid before being further transformed, p-ni-
trobenzoic acid (5) and S-methyl-S-phenylsulfoximine (2a)
were reacted for 12 h under the optimized conditions, but no
reaction was observed (eq. (10)). Therefore, the reaction did
not follow this pathway.
be used as a practical alternative to existing methods for the
preparation of N-acylsulfoximines.
Acknowledgements This work was supported by the National Natural
Science Foundation of China (21372034) and the State Key Laboratory of
Geohazard Prevention and Geoenvironment Protection (SKLGP2018Z002).
Based on the above control experiments and related lit-
erature reports of photoinduced reactions conducted under
visible light [39–41], a free radical reaction mechanism was
proposed (Scheme 5). K2S2O8 generated sulfate radical an-
ions (SO4•−) 6 under visible light [42,43]. TBHP produced t-
butyloxy radical 7 and hydroxyl radical under the action of
visible light or produced peroxy-t-butyl radicals 8 under the
action of sulfate radical anion (SO4•−) 6. Then, free radicals 7
or 8 reacted with aldehyde 1 to produce t-butyl alcohol or t-
butyl hydrogen peroxide and aldehyde radical 9, which can
be trapped with TEMPO by the experimental verification
(eq. 9, Scheme 4), [44,45]. In the assistance of free radicals 7
or 8, aldehyde radical 9 reacted with NH-sulfoximines 2 to
afford the amidation product 3 and t-butyl alcohol or t-butyl
hydrogen peroxide [46].
Conflict of interest The authors declare that they have no conflict of
interest.
Supporting information The supporting information is available online at
http://chem.scichina.com and http://link.springer.com/journal/11426. The
supporting materials are published as submitted, without typesetting or
editing. The responsibility for scientific accuracy and content remains en-
tirely with the authors.
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3 Conclusions
We developed the first visible light-promoted synthesis of N-
acylsulfoximines with TBHP/K2S2O8 as a free radical
source. This synthetic method has some notable features,
including good functional group tolerance, a broad substrate
scope with respect to both sulfoximines and aldehydes, and
easy separation and purification of the product. In addition,
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