Copper-catalyzed preparation of N-aroylated sulfoximines from methylarenes

Article abstract of DOI:10.1080/00397911.2017.1318444

A copper-catalyzed methodology for the preparations of N-aroylated sulfoximines from methylarenes was herein demonstrated. The transformation proceeded with the assistance of external oxidant tert-butyl hydroperoxide, requiring for no additional solvents or ligands. The good compatibility and high efficiency of the newly developed protocol were well described by 21 examples and up to 91% yields. Moreover, the protocol was proved by the control reactions to proceed through a radical pathway.

Full text of DOI:10.1080/00397911.2017.1318444

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Copper-Catalyzed Preparation of N-Aroylated
Sulfoximines From Methylarenes
Anguo Hou & Zijian Zhao
To cite this article: Anguo Hou & Zijian Zhao (2017): Copper-Catalyzed Preparation
of N-Aroylated Sulfoximines From Methylarenes, Synthetic Communications, DOI:
10.1080/00397911.2017.1318444
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Date: 23 April 2017, At: 19:21

Copper-Catalyzed Preparation of N-Aroylated Sulfoximines from Methylarenes
1
,2
1
Anguo Hou , Zijian Zhao
1
School of Chemistry and Materials Science, Huaihua University, Huaihua, Hunan, P. R.
2
China School of Chinese Traditional Medicine, Yunnan University of Traditional
Chinese Medicine, Kunming, Yunnan, P. R. China
Corresponding author Zijian Zhao E-mail: zjzhao72@163.com
Abstract
A copper-catalyzed methodology for the preparations of N-aroylated sulfoximines
from methylarenes was herein demonstrated. The transformation proceeded with
the assistance of external oxidant tert-butyl hydroperoxide (TBHP), requiring for
no additional solvents or ligands. The good compatibility and high efficiency of
the newly-developed protocol were well-described by the 21 examples and up to
91% yields. Moreover, the protocol was proved by the control reactions to proceed
through a radical pathway.
KEYWORDS: Copper catalysis, N-aroylated sulfoximines, TBHP, methylarenes,
solvent-free
1. INTRODUCTION
Molecules with a sulfoximine moiety has gained widespread attention for being chiral
[
1]
precursors or ligands in asymmetric synthesis, as well as for the great significance in
1

[
2]
the pharmaceutical and agricultural applications. Also, sulfoximines have been applied
[
3]
broadly for the construction of various heterocyclic molecules. Diverse protocols such
[
4]
[5]
[6]
[7]
[8]
as arylation, alkylation, vinylation, alkynylation and others. have been well
established for the synthesis of different N-substituted sulfoximines. Amongst, different
protocols for the acylation of sulfoximines have aroused exceptional interests for the
[
9]
broad applications in both biology and synthesis. Usually, reactions between benzoyl
chlorides, aromatic carboxylic acids and NH-sulfoximines were well-developed towards
N-aroylated sulfoximines. Recently, benzaldehydes were successfully employed as the
[
10]
aroylation reagent for the coupling with NH-sulfoximines in the presence of Cu(I). The
coupling methodology developed by Bolm and coworkers proceeded through a dual
C-H/N-H activations pathway under the oxidative conditions. Then, readily-accessible
methylarenes were also successfully applied for the aroylation of N-chloro sulfoximines
[
11]
under MnO -mediated system by the same research group. Inspired by the pioneering
2
work, An and Sekar have disclosed different routines towards N-aroylated sulfoximines
[
12]
[13]
from methylarenes in the presence of elemental iodine or a ferric-catalyst. Be aware
of that methylarenes were able to perform as versatile modules for the construction of
[
14]
carbon-heteroatom bonds with the assistance of various metallic catalysts, we wish to
disclosed an practical transformation towards N-aroylated sulfoximines in the presence of
a copper catalyst and tert-butyl hydroperoxide (TBHP) under solvent-free conditions.
2
. DISCUSSION
2

With NH-S-methyl-S-phenyl sulfoximine 1a and toluene 2a as the substrate for the model
reaction, experiments as summarized in Table 1 were carried out for the optimal
conditions of the aroylation protocol. Disappointingly, palladium catalysts such as PdCl2,
Pd(PPh ) Cl and Pd(MeCN) Cl was totally ineffective for the transformation since no
3
2
2
2
2
o
product was detected after 20 h at 80 C (entries 1 - 3). Also, the combination of AgNO
3
and K S O did not give a better result (entry 4). To our delight, copper catalysts
2
2
8
expressed positive effect to the transformation, for usage of CuCl led to trace product
after 20 h (entry 5). And the yields of 3aa dramatically increased to 28% and 82% when
CuBr and CuI were employed for the aroylation protocol (entries 6 and 7). But the
utilizations of copper(II) catalyst such as Cu(OTf) did not lead to the formation of any
2
desired product (entry 8). Moreover, diverse commonly used oxidants were tested in the
system for the best oxidant and TBHP performed better than others, such as di-tert butyl
peroxide (DTBP, entry 9), H O (enry 10), DDQ (entry 11) and oxygen (entry 12). It was
2
2
noteworthy that a lower loading of CuI (5 mol%) led to a decreased yield of the desired
product 3aa, only a 65% ratio was obtained (entry 13).
With the optimal conditions in hand, the scope of the substrates was evaluated for this
transformation as shown in Table 2. Different electron-rich aromatic groups decorated
sulfoximines were well-tolerated under the optimal conditions. For instance,
S-4-methylphenyl-S-methyl sulfoximine (1b), S-4-methoxyphenyl-S-methyl sulfoximine
(1c) and S-2-methylphenyl-S-methyl sulfoximine (1d) reacted with toluene (2a) readily,
3

affording the corresponding N-aroylated sulfoximines 3ba – 3da in yields ranging from
2% to 88% yields (entries 1 - 3). Similarly, halogenated aromatic groups fused
8
sulfoximines like S-4-fluorophenyl-S-methyl sulfoximine (1e),
S-4-chlorophenyl-S-methyl sulfoximine (1f) and S-4-bromophenyl-S-methyl sulfoximine
(1g) underwent the aroylation procedure with toluene (2a) successfully, furnishing the
desired products 3ea – 3ga in medium to good yields, from 79% to 84% (entries 4 - 6).
Pleasingly, other functional groups substituted sulfoximines also showed good
compatibility under the optimal conditions. S-Phenyl-S-ethyl sulfoximine (1h) and
S-phenyl-S-isopropyl sulfoximine (1i) furnished the corresponding N-aroylated
sulfoximines 3ha and 3ia under the optimal conditions, in 80% and 78% yields,
separately (entries 7 and 8). Other sulfoximines such as S,S-diphenyl sulfoximine (1j) and
S,S-dimethyl sulfoximine (1k) also coupled with toluene successfully, leading to the
desired aroylated products 3ja and 3ka in 89% and 76% yields (entries 9 and 10). To our
satisfactory, heteroaryl decorated sulfoximine such as S-(2-pyridinyl)-S-methyl
sulfoximine (1l) reacted with toluene (2a) smoothly under the optimal conditions,
offering the desired product 3la in mediun yield (71% for entry 11).
Encouraged by the broad substrate scope of the aroylation protocol on sulfoximines, the
compatibility on the methyl arenes was also evaluated as shown in Table 3. Firstly,
electron-rich methylarenes were tested in the system under the optimal conditions. For
example, 1,4-dimethylbenzene (2b) and 1-methyl-4-methoxybenzene (2c) afforded the
4

corresponding N-aroylated sulfoximines 3ab and 3ac in good yields, up to 91% (entries 1
and 2). In the same manner, o-xylene (2d) played successfully as the aroylation reagent
for the corresponding product 3da was isolated in 72% yield (entry 3). However, other
benzyl C-H bond did not showed any reactivities in the system. For instance,
ethylbenzene (2l) and isopropylbenzene (2m) failed to give any N-aroylated sulfoximines,
probably because the electron-donating methyl group(s) made the C-H bonds less
acidic (entries 11 and 12).
It was noteworthy that halogenated toluenes such as 4-fluorotoluene (2e), 4-chlorotoluene
(2f), 4-bromotoluene (2g) and 4-iodotoluene (2h) reacted with NH-S-phenyl-S-methyl
sulfoximine (1a) easily under the optimal conditions, yielding the desired sulfoximine
derivatives in ratios up to 87% (entries 4 – 7). Meanwhile, the activities of the
electron-deficient aromatic groups such as 4-methylbenzyl cyanide (2i) and
3
-nitrotoluene (2j) were tested. They exhibited good compatibilities in the transformation
and coupled with NH-sulfoximine 2a smoothly, leading to the desired products in
acceptable yields, up to 79% (entries 8 and 9). To our satisfaction, polyaromatic group
was also well-tolerated in the copper catalysis and the reaction between
2
-methylnaphthalene (2k) and NH-sulfoximine 1a took place smoothly, resulting in
N-aroylated sulfoximine 3ak in 80% yield (entry 10).
5

To probe the mechanism of the aroylation protocol, control experiments were carried out
for clarification as shown in Scheme 1. Despite that the addition of the radical scavenger
like 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) did not afford the formation of the
TEMPO-benzoyl adduct, a dramatic decrease in the generation of 3aa was observed for
only trace product was detected after 20 h (Sheme 1, A). The results indicated that
copper-catalyzed aroylation reaction probably proceeded through a radical pathway.
Meanwhile, to have a better understanding on the role that the catalyst played in the
system, the activities of different copper catalysts, such as CuCl and CuBr, were also
tested when KI was used as the iodine source. Within our expectations, almost the same
yields were obtained, providing 78% and 80% yields, respectively (Scheme 1, B). Based
on the literal investigations, the reaction might proceeded through two different key
intermediates. Thus, the reactions of benzaldehyde or benzyl iodide with NH-sulfoximine
(1a) were carried out separately, offering completely different results. The desired
product 3aa was obtained in 52% yield with benzaldehyde used as the acyl reagent, but
no product was detected when 1a reacted with benzyl iodide (Scheme 1, D). The results
indicated the mechanism likely took place via the acyl radical particles.
Based on the reported precedents and the results of the control experiments, the
mechanism of the demonstrated transformation was proposed as shown in Figure 1.
Firstly, iodide radical particle, which was generated under the oxidative conditions,
reacted with methylarenes 1, offering the acyl intermediate A. Meanwhile, Cu(II)
6

coordinated with 2 for a metal-substrate complex B. Then the two intermediates A and B
coupled, leading to another key intermediate C, which generated the desired aroylated
sulfoximines 3 with a release of a Cu(II) particle.
3
. CONCLUSIONS
In summary, we have disclosed a novel and efficient synthetic method towards
N-aroylated sulfoximines under the copper catalysis. The system exhibited good
functional groups tolerance and broad substrate scope. Moreover, control reactions were
conducted to clarify the transformation proceed through a radial pathway via a key acyl
intermediate. The methodology offers a practical and facile synthetic tool towards the
useful compounds.
4
. EXPERIMENTAL
4
.1 Typical Synthetic Procedure Of N-Benzoyl-S-Methyl-S-Phenyl Sulfoximine 3
A Schlenk tube (25 mL) equipped with a magnetic bar was loaded with the
NH-sulfoximine 2 (0.5 mmol), CuI (9.5 mg, 5 mol%) in dry methyl arene 1 (3.5 mL),
then TBHP (258 mg, 2.0 mmol, 70% in water) was added dropwise, and the reaction
mixture was allowed to stir at 80 °C for 20 h. After cooling to room temperature, the
mixture was filtered through a short celite pad and washed with chloroform (15 mL × 3).
The filtrate was concentrated, and the oily crude product was purified by column
7

chromatography using silica gel (200 – 300 mesh) as stationary phase and a mixture of
n-hexane and ethyl acetate as eluent to give the N-aroylated sulfoximines 3.
4
.2 Spectra Data Of N-Aroyl Sulfoximines 3
N-Benzoyl-S-Methyl-S-Phenyl Sulfoximine (3aa)
o
1
White solid, m.p.: 103 – 105 C. Yield: 82%. H NMR (400 MHz, CDCl ) = 8.17 (d, J
3
=
7.3 Hz, 2H), 8.05 (d, J = 7.5 Hz, 2H), 7.67 (t, J = 7.3 Hz, 1H), 7.60 (t, J = 7.6 Hz, 2H),
1
3
7
.50 (t, J = 7.3 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 3.45 (s, 3H) (ppm). C NMR (100
MHz, CDCl ) = 174.3, 139.0, 135.6, 133.9, 132.3, 129.8, 129.5, 128.1, 127.2, 44.4
3
(ppm). MS (EI): m/z = 77.1 (53), 94.1 (56), 104.1 (48), 105.1 (38), 125.1 (16), 141.1 (9),
1
1
56.1 (100), 157.1 (8), 182.1 (88), 244.1 (15). IR (in KBr): = 3020, 2925, 1628, 1577,
-1
447, 1314, 1281, 1219, 1172, 1136, 1092, 1068, 978, 838, 716 (cm ). HRMS (ESI)
+
(
m/z) [C H NO S+H ]: Calcd. 260.0740, Found 260.0748. The data was in accordance
14
13
2
with Ref 12 and 13.
SUPPORTING INFORMATION
1
13
Full experimental details, H and C NMR spectra are accessible via the “Supplementary
Content” section of this article’s webpage.
ACKNOWLEDGMENTS
8

We are grateful for the financial support from the Fundamental Research for the Key
Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan
Province (No.ZWX2016-11).
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[
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12

[
a]
Table 1. Optimization of reaction conditions
[
b]
Entry Catalyst
Oxidant Yiled (%)
[
c]
1
2
3
4
5
6
7
8
9
1
PdCl2
TBHP
TBHP
n.d.
n.d.
Pd(PPh ) Cl
2
3
2
Pd(MeCN) Cl TBHP
n.d.
2
2
AgNO3
CuCl
CuBr
CuI
K S O n.d.
2
2
8
TBHP
TBHP
TBHP
TBHP
DTBP
H O
trace
28
82
Cu(OTf)2
CuI
n.d.
72
0
CuI
n.d.
n.d.
n.d.
65
2
2
11
CuI
DDQ
[d]
1
1
2
3
CuI
O2
[
e]
CuI
TBHP
Notes: [a] conditions: 1a (0.3 mmol), 2a (2.0 mL), catalyst (10 mol%), oxidant (2.0
o
eqvuialents) at 80 C for 20 h. [b] Isolated yields. [c] stands for not detected. [d] O
2
baloon (1 atm) was used. [e] 5 mol% of the catalyst was used.
13

[
a]
Table 2. Substrate scope of NH-sulfoximines
1
2
[b]
Entry 1
R
R
3
Yield (%)
CH3 3ba 85
1c 4-CH OC H CH3 3ca 88
1
2
3
4
5
6
7
8
9
1
1b 4-CH C H
3
6
4
3
6
4
1d 2-CH C H
CH3 3da 82
CH3 3ea 82
CH3 3fa 79
CH3 3ga 84
3
6
4
1e 4-FC H
6
4
1f 4-ClC H
6
4
1g 4-BrC H
6
4
1h Ph
1i Ph
1j Ph
1k Me
Et
i-Pr 3ia 78
Ph 3ja 89
3ha 80
0
Me 3ka 76
Me 3la 72
11
1l 2-Pyridinyl
Notes: [a] Conditions: 1 (0.5 mmol), 2a (2.0 mL), CuI (10 mol%), TBHP (75% in water,
.0 eq.). [b] Isolated yields.
2
14

[
a]
Table 3. Substrate scope of methylarenes
[
b]
Entry 2
Ar (R)
3
Yield (%)
3ab 89
2c 4-CH OC H (CH ) 3ac 91
1
2
3
4
5
6
7
8
9
1
2b 4-CH C H (CH )
3
6
4
3
3
6
4
3
2d 2- CH C H (CH ) 3ad 72
3
6
4
3
2e 4-FC H (CH )
3ae 87
3af 80
3ag 85
3ah 79
3ai 79
3aj 72
3ak 80
3al n.d.
3am n.d.
6
4
3
2f 4-ClC H (CH )
6
4
3
2g 4-BrC H (CH )
6
4
3
2h 4-IC H (CH )
6
4
3
2i 4-CNC H (CH )
6
4
3
2j 3-NO C H (CH )
2
6
4
3
0
2k 2-Naphthyl (CH3)
2l C H (CH CH )
[
[
c]
c]
11
6
5
2
3
1
2
2m C H [CH(CH ) ]
6
5
3 2
Notes: [a] Conditions: 1a (0.5 mmol), 2 (2.0 mL), CuI (10 mol%), TBHP (75% in water,
.0 eq.). [b] Isolated yields. [c] n.d. for not detected.
2
15

Scheme 1. Control experiments
16

Figure 1. Proposed mechanism
17