Radical N-arylation/alkylation of sulfoximines

Article abstract of DOI:10.1016/j.tetlet.2016.04.042

A novel copper-catalyzed N-arylation/alkylation of sulfoximines with acyl peroxides as aryl/alkyl source was developed. This approach undergoes a radical pathway, representing an alternative complement to construct N-arylated/alkylated sulfoximines.

Full text of DOI:10.1016/j.tetlet.2016.04.042

Tetrahedron Letters 57 (2016) 2372–2374
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Radical N-arylation/alkylation of sulfoximines
⇑
Hui Zhu, Fan Teng, Changduo Pan, Jiang Cheng, Jin-Tao Yu
School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Advanced Catalysis and Green Manufacturing Collaborative
Innovation Center, Changzhou University, Changzhou 213164, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel copper-catalyzed N-arylation/alkylation of sulfoximines with acyl peroxides as aryl/alkyl source
was developed. This approach undergoes a radical pathway, representing an alternative complement to
construct N-arylated/alkylated sulfoximines.
Received 16 February 2016
Revised 11 April 2016
Accepted 13 April 2016
Available online 22 April 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Arylation
Radical pathway
Copper
Acyl peroxide
Sulfoximine
Introduction
Letter, N-arylated sulfoximines were accessed using aryl acyl per-
oxides as aryl donors via radical pathway (Scheme 1, Eq. 2).
Sulfoximines are a versatile class of compounds applied as chi-
ral auxiliaries, as ligands in asymmetric catalysis, and as building
blocks in pseudopeptides.1 They have also gained significant atten-
tion in medicinal chemistry.2 In light of their remarkable impor-
tance, extensive sulfoximine derivatives have been synthesized
through direct functionalization of sulfoximines.3 For example,
Bolm’s group pioneered the generation of N-arylated sulfoximines
by palladium-catalyzed coupling reaction between sulfoximines
and aryl bromides.4 Afterward, various aryl donors such as aryl
halides, aryl triflates, nonaflates, tosylates, arylboronic acids,
diaryliodonium salts, aryl siloxanes, and arynes were employed
to access N-arylated sulfoximines (Scheme 1, Eq. 1).5
Results and discussion
We commenced our investigation using diphenylsulfoximine 1a
and benzoyl peroxide 2a in phenylfluoroform at 130 °C under N2 as
the model reaction (Table 1). Unfortunately, common simple cata-
lyst, such as CuI, CuCl2, Cu(OAc)2, Fe(acac)2, etc. failed to deliver the
N-arylating product or delivered in trace amount (Table 1, entries
1–4). Surprising, Cu(acac)2 was proved to be the best catalyst, pro-
viding N-phenyl diphenylsulfoximine 3aa in 26% yield (Table 1,
entry 5). Increasing the amount of catalyst to 0.4 equiv resulted
in a satisfying 76% yield of 3aa, but there was no further increase
Recently, aryl acylperoxides have been demonstrated as favor-
able aryl radical precursors through homolytic O–O bond cleavage
followed by CO2 extrusion and applied in the arylation processes.
In 2009, Yu demonstrated the first Pd-catalyzed decarboxylative
ortho-arylation of 2-phenylpyridines with aryl acylperoxides via
radical pathway.6 In 2014, Pd-catalyzed decarboxylative ortho-ary-
lation of amides and azoarenes was developed by Wang and Zeng
(Scheme 1, Eq. 3).7 Very recently, radical oxidative decarboxyla-
tion/cyclization of acylperoxides with 2-isocyanobiphenyls was
achieved by Zhu.8 However, aryl acyl peroxides as aryl radical pre-
cursors in the formation of C–N bond has not been reported. In this
O
O
S
NH
Me
cat. Pd, Cu or Fe
S
Ar'
Ar'
Me
ArX
Ar'
eq. 1
N
Ar
X = I, Br, Cl, OTf, ONf, OTs, B(OH)2, Si(OMe)3
O
S
NH
O
O
O
Me
cat. Cu
Me
S
O
O
R
eq. 2
eq. 3
Ar'
R
O
O
O
N R
Radical pathway
O
this work
DG
DG
Ar
H
cat. Pd
Ar
Ar
⇑
Corresponding author.
E-mail address: yujintao@cczu.edu.cn (J.-T. Yu).
Scheme 1. Arylation of N–H and C–H bonds.
http://dx.doi.org/10.1016/j.tetlet.2016.04.042
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

H. Zhu et al. / Tetrahedron Letters 57 (2016) 2372–2374
2373
Table 1
O
R
N
O
NH
Ph
Optimization of reaction conditionsa
Cu(acac)2 (0.4 equiv.)
PhCF3, 130 oC, N2
O
O
R
+
S
R
O
S
3
Ph
Ph
Ph
O
1a
2
Ph
N
O
O
NH
Ph
O
Me
F
O
Ph
S
+
S
Me
Cl
Ph
O
Ph
Ph
Ph
O
1a
2a
3aa
O
N
O
N
Entry
Catalyst (equvalent)
Solvent
Yieldb (%)
O
N
O
N
S
S
S
S
Ph
Ph
Ph
Ph
1
2
3
4
5
6
7
8
CuI (0.1)
Cu(OAc)2 (0.1)
CuCl2 (0.1)
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
DMF
PhCH3
HOAc
1,4-Dioxane
PhCF3
< 5
7
5
—
26
48
Ph
3ab, 45%
Ph
3ad
Ph
Ph
, 36%
3ac
, 63%
3ae, 74%
Br
Fe(acac)2 (0.1)
Cu(acac)2 (0.1)
Cu(acac)2 (0.3)
Cu(acac)2 (0.4)
Cu(acac)2 (0.4)
Cu(acac)2 (0.4)
Cu(acac)2 (0.4)
Cu(acac)2 (0.4)
—
(CH2)8CH3
N
(CH2)13CH3
N
Me
N
O
O
O
S
S
S
76 (45)c (38)d
—
17
46
—
Ph
O
N
Ph
Ph
Ph Ph
Ph
S
Ph Ph
3af
9
b
3ah
3ag
, 69%
, 35%
, 70%
3ai
, 58%
10
11
12
Figure 2. Scope of acyl peroxides. Reaction conditions: 1a (0.1 mmol),
2
—
(0.5 mmol), and Cu(acac)2 (0.4 equiv) in PhCF3 (1 mL) at 130 °C under N2 for 15 h.
a
bDi-tert-butyl peroxide (DTBP) was used instead of acyl peroxide.
Reaction conditions: 1a (0.1 mmol), BPO 2a (0.5 mmol), and catalyst in solvent
(1 mL) at 130 °C under N2 for 15 h.
b
Isolated yield.
Air.
Oxygen.
c
Ph
O
d
tBu
O
O
NH
standard condition
BHT (4.0 equiv.)
O
Ph
+
3aa +
S
Ph
O
Ph Ph
1a
O
tBu
detected by GCMS
2a
trace
O
Ph
N
O
NH
Cu(acac)2 (0.4 equiv.)
PhCF3, 130 oC, N2
O
O
Ph
S
+
S
Ph
O
S
R1 R2
Scheme 2. Mechanism study.
R1
R2
O
1
2a
3
Ph
N
Ph
N
Ph
N
expected, a variety of S,S-diaryl sulfoximines were good reaction
partners leading to the corresponding N-arylated sulfoximines in
good yields. The electro nature of the substituents on phenyls
has little effect on the reaction efficiency. Phenyls with either elec-
tron-donating or electron-withdrawing groups were all well toler-
ated to achieve the desired products in good yields (3aa–3ia). In
addition, S-alkyl-S-aryl sulfoximines were also reacted smoothly
to give the corresponding arylated products although in relatively
lower yields (Fig. 1, 3ja–3oa). Particularly, substrates with halo
groups could be tolerated well, which provided convenient handles
for further functionalizations (3ga, 3ha, 3ma, and 3na). The practi-
cability of this procedure was further evaluated by conducting on a
1 mmol scale, giving the desired 3aa in a comparable 65% yield.
Finally, catalyst recycle experiment was carried out, while unfortu-
nately, only 40% of the desired product was obtained after the sec-
ond run.
O
O
O
S
S
Me
Me Cl
Cl
3aa, 76%
3ba, 74%
3ca, 87%
Ph
N
Ph
Ph
O
O
N
O
N
S
S
S
Ph
Ph
Me
Me
3da
3ea
3fa
, 80%
Ph
, 77%
Ph
, 71%
Ph
N
O
O
O
N
N
S
S
S
CO2Me
Me
Br
Br
3ga, 89%
3ha
3ia
, 88%
, 76%
Ph
N
Ph
N
Ph
O
O
O
N
S
S
S
Next, various acyl peroxides were examined for this transfor-
mation. As shown in Figure 2, aryl acyl peroxides with methyl, flu-
oro, chloro, and bromo were all well tolerated in this arylation
procedure to afford the corresponding N-arylated sulfoximines in
good to moderate yields. To further explore the scope of the perox-
ides, alkyl acyl peroxides, such as decanoic peroxyanhydride (2m)
and pentadecanoic peroxyanhydride (2n) were subjected to the
procedure, and the corresponding N-alkylated products were
obtained in good yields (Fig. 2, 3ah and 3ai). Moreover, when di-
tert-butyl peroxide (DTBP) was utilized in the place of acyl perox-
ide, N-methyl sulfoximine 3ag was obtained in 70% yield.
O2N
NC
3ja, 66%
3ka, 56%
3la, 49%
Ph
Ph
Ph
O
N
O
N
O
N
S
S
S
F
Cl
3ma
3na
3oa
, 71%
, 58%
, 50%
Figure 1. Scope of sulfoximines. Reaction conditions: 1 (0.1 mmol), 2a (0.5 mmol),
and Cu(acac)2 (0.4 equiv) in PhCF3 (1 mL) at 130 °C under N2 for 15 h.
The reactions were obviously inhibited when radical scavenger
2,6-di-tert-butyl-4-methylphenol (BHT) was added to the proce-
dure and the adduct formed by radical scavenger with phenyl rad-
ical was detected by GC–MS, which indicated the arylation
conducted via radical pathway (Scheme 2 and see ESI for details).
Thus, the proposed mechanism is illustrated in Scheme 3. Firstly,
Cu(II) assisted cleavage of benzoyl peroxide (2a) produces the ben-
zoyl anion and benzoyl radical, the later converts into phenyl rad-
ical upon heating along with the release of CO2. Next, anion
intermediate 4 is generated after proton abstraction by benzoyl
anion. Then, the addition of aryl radical to 4 provides anion radical
if more catalyst was used. The yields decreased slightly if the reac-
tion was conducted under the atmosphere of air or oxygen (Table 1,
entry 7). Next, other common solvents, such as DMF, toluene,
HOAc, and dioxane were investigated. The results showed that
they were all inferior to phenylfluoroform (Table 1, entries 8–11).
The reaction couldn’t occur in the absence of any catalyst (Table 1,
entry 12).
With the optimal reaction conditions established, a great num-
ber of sulfoximine derivatives were investigated to discover the
scope and limitation of the reaction as shown in Figure 1. As

2374
H. Zhu et al. / Tetrahedron Letters 57 (2016) 2372–2374
O
O
of Advanced Catalytic Materials and Technology (BM2012110) for
financial supports.
O
Ph
Ph
O
Ph
O
O
2a
O
1a
Supplementary data
- CO2
Ph
O
O
Supplementary data (experimental details and the characteriza-
tion data) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2016.04.042.
CuII
Ph
CuIII
Ph
OH
O
N
S
Ph
Ph
References and notes
4
Ph
N
O
N
O
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Ph
S
Ph
Ph
Ph
3aa
Ph
5
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In conclusion, we have demonstrated a novel copper-catalyzed
N-arylation/alkylation of sulfoximines with acyl peroxides, leading
to N-arylated/alkylated products in moderate to good yields. This is
the first case of radical arylation of sulfoximines, which represents
an important complement to construct N-arylated sulfoximine
derivatives.
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Acknowledgments
We thank the National Natural Science Foundation of China
(Nos. 21202013 and 21572025), University Science Research Pro-
ject of Jiangsu Province (15KJA150001) and Jiangsu Key Laboratory
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