The copper-catalyzed oxidative N-acylation of sulfoximines

Article abstract of DOI:10.1002/adsc.201300273

An oxidative cross-coupling reaction between aldehydes and sulfoximines involving dual C-H/N-H functionalization has been developed. This reaction process is facilitated by a simple copper catalyst (1 mol% loading) and tert-butyl hydroperoxide (TBHP) as the oxidant and proceeds under mild reaction conditions to afford a series of valuable N-acylated sulfoximine derivatives in excellent yields. Copyright

Full text of DOI:10.1002/adsc.201300273

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DOI: 10.1002/adsc.201300273
The Copper-Catalyzed Oxidative N-Acylation of Sulfoximines
Long Wang,a Daniel L. Priebbenow,a Liang-Hua Zou,a and Carsten Bolma,*
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-241-809-2391; phone: (+49)-241-809-4675
E .; e-mail: carsten.bolm@oc.rwth-aachen.de
Received: April 3, 2013; Revised: May 8, 2013; Published online: May 17, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300273.
Abstract: An oxidative cross-coupling reaction be-
tween aldehydes and sulfoximines involving dual
À
À
C H/N H functionalization has been developed.
This reaction process is facilitated by a simple
copper catalyst (1 mol% loading) and tert-butyl hy-
droperoxide (TBHP) as the oxidant and proceeds
under mild reaction conditions to afford a series of
valuable N-acylated sulfoximine derivatives in ex-
cellent yields.
Keywords: acylation; copper catalysts; oxidative
coupling; sulfoximines
The recent increase in the utilization of the sulfox-
ACHTUNGTRENNUNGimine moiety in medicinal and agricultural applica- Scheme 1. Previous syntheses of N-acylsulfoximines and the
new approach presented here.
tions is of significant interest to our research group
and others.[1] In addition, chiral sulfoximine-based li-
gands have been successfully employed to induce high
levels of stereochemistry during numerous bond form- boxylic acid derivatives (that require the use of acti-
ing processes.[2] One class of sulfoximines, namely the vating agents such as carbodiimide-type additives) are
À
N-acylsulfoximines, have been traditionally prepared commonly used. Recently, similar C N bond forming
using pre-activated coupling partners, such as acyl transformations have been achieved using a combina-
chlorides,[3] or aliphatic carboxylic acids (Scheme 1).[4] tion of transition metal catalysts and oxidants facili-
To allow the sulfoximine moiety to be more widely tating an oxidative cross-coupling processes through
applied in organic and medicinal chemistry, it is essen- dual C H and N H bond activation.[7] In such a catal-
tial that new, efficient methods for their preparation ysis, advantageously, readily available aldehydes can
À
À
and derivatization are realized.
be used as coupling partners, and cheap transition
In the last decade, significant progress has been metals serve as catalysts in low catalyst loadings
À
made in the field of C H activation, permitting the under mild reaction conditions without requiring ad-
formation of new bonds between two coupling part- ditional ligands or base. Hence, the previous need for
ners without the need for additional leaving groups or additional derivatization or activation of carbonyl
prior activation.[5] Among those, several transition compounds during C N bond formation is circum-
À
metal-catalyzed oxidative (dehydrogenative) cross- vented, and the subsequent generation of halide-con-
coupling reactions have been developed for the syn- taining waste is eliminated.
thesis of heterocycles, biaryl compounds, aryl halides,
We herein disclose our recent efforts in the synthe-
sis of N-acylsulfoximines from aldehydes, employing
and substituted alkynes (such as ynamides).[6]
For the preparation of functionalized amides,
imides, or ureas, coupling partners that include toxic through a dual C H/N H bond functionalization pro-
isocyanates, sensitive acyl chloride substrates, or car- cess (Scheme 1). The inclusion of an appropriate oxi-
a
copper-catalyzed oxidative coupling reaction
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The Copper-Catalyzed Oxidative N-Acylation of Sulfoximines
Table 1. Optimization of the sulfoximine N-acylation condi-
(Table 2). In addition to S,S-methylphenyl sulfoximine
(2a), the reaction with aldehyde 6b also proceeded
smoothly with the S,S-dimethyl- (2b) and S,S-tetrame-
thylenesulfoximines (2c) (Table 2, entries 1–3). Both
para- and meta-nitrobenzaldehyde performed well,
furnishing the corresponding N-acylsulfoximines in
excellent yields (Table 2, entries 1–5). Advantageous-
ly, when the synthesis of N-acylsulfoximine 3b was
performed using enantiopure (R)-S,S-methylphenyl-
sulfoximine, it was determined that the reaction pro-
cess was entirely enantiospecific.[9]
In general, both electron-withdrawing and electron-
donating groups on the aryl ring of the initial alde-
hyde substrate were well tolerated, affording a series
of N-benzoylsulfoximines containing additional func-
tionality including aryl halide, p-methoxyphenyl, tert-
butylphenyl and biphenyl groups (Table 2, entries 6–
10). In addition, 1-naphthaldehyde and benzaldehyde
were readily converted to the corresponding N-acyl-
sulfoximines in high yields (Table 2, entries 11 and
12). Whereas the protocol previously reported by
Garimallaprabhakaran and Harmata was only suc-
tions.[a]
Entry Catalyst
Catalyst load- Oxidant
ing [mol%]
Yield
[%]
1
2
3
4
5
6
7
8
9
CuBr
CuBr
CuBr
CuBr
FeSO4·7H2O
CuCl2
CuBr
CuBr
–
5
5
5
5
5
5
1
0.1
air
O2
NBS
t-BuOOH
t-BuOOH
t-BuOOH
t-BuOOH 95
t-BuOOH
0
0
53
95
90
91
94
trace
–
t-BuOOH
[a]
Reaction conditions: 6b (0.50 mmol), 2a (0.75 mmol), cat-
alyst, oxidant (1.00 mmol), MeCN (1 mL), 808C, 12 h.
À
dant in such dehydrogenative C N cross-coupling cessful for the synthesis of aliphatic substituted N-
protocols is also an essential requirement.[6d,8] Initial acylsulfoximines,[4] the method reported herein af-
investigations into the oxidative N-acylation of sulfox- forded a diverse range of aromatic substituted N-acyl-
imines focused on identifying a suitable transition sulfoximines. Additionally, isopropyl aldehyde reacted
metal catalyst and oxidant to facilitate this process cleanly under our conditions (Table 2, entry 13). A
(Table 1). Trial reactions were carried out combining keto-N-acylsulfoximine derivative 3n was also readily
p-nitrobenzaldehyde (6b, 1.0 equiv.) and S,S-methyl- obtained in 86% yield following the reaction of 2-
phenylsulfoximine (2a, 1.5 equiv.) in acetonitrile in oxo-2-phenylacetaldehyde with S,S-methylphenylsulf-
the presence of 5 mol% catalyst and an oxidant
(2.0 equiv.).
ACHTUNGTRENNUNG
The first reaction attempts used copper (I) bromide the oxidative cross-coupling process. As this reaction
as a catalyst, and the oxidant was varied (Table 1, en- also proceeded well using CuCl2 as catalyst (see
tries 1–4). These trials revealed that the use of tert- Table 1) and considering the presence of an excess of
butyl hydroperoxide (TBHP, 70% solution in H2O) TBHP in the reaction mixture, we regard it highly un-
was superior to NBS, air or dioxygen. In addition, al- likely that a Cu(I) species is active in the catalytic
though both iron sulfate (Table 1, entry 5) and CuCl2 cycle. Most probably, the applied CuBr is immediately
(Table 1, entry 6) afforded the desired product 3b in oxidized to a Cu(II)-based catalyst (Scheme 2).
excellent yields, the use of CuBr proved optimal,
In a recent related report, Zhu and co-workers sug-
leading to the desired N-acylsulfoximine 3b in 95% gested the presence of a radical acyl species formed
yield after 12 h. It was subsequently determined that by the copper/TBHP combination.[7a,9] Taking that
the amount of catalyst employed could be decreased scenario into account, a plausible pathway for the re-
(Table 1, entries 7 and 8), with the sulfoximine prod- action process described herein involves a redox pro-
uct 3b isolated in exceptional yields, when even a sub- cess (Scheme 2) whereby the Cu(II) catalyst interacts
molar catalyst loading (0.1 mol%, Table 1, entry 8) with sulfoximine 2 leading to an intermediate I, which
was used. In the absence of a metal salt (Table 1, reacts with an acyl radical formed from aldehyde 6.
entry 9), the tert-butyl ester derivative of the aldehyde Subsequent electron transfer processes result in the
was identified as the major product. Additional stud- formation of the product, N-acylsulfoximine 3, and
ies revealed that when the catalyst loading was re- a Cu(I) species, which is then re-oxidized to Cu(II) by
duced to less than 1 mol% when using substrates TBHP, completing the catalytic cycle (Scheme 2).
other than p-nitrobenzaldehyde (6b), poor levels of
To further investigate the role of a radical species
conversion to the product were observed. As such, in this reaction process, the oxidative coupling reac-
a catalyst loading of 1 mol% was used for the remain- tion between S,S-methylphenylsulfoximine (2a) and
der of the study.
p-nitrobenzaldehyde (6b) was repeated in the pres-
With the optimal conditions in hand, we then inves- ence of TEMPO (3.0 equiv.). After 12 h of reaction
tigated the substrate scope of this reaction process time, as expected, none of the desired N-acylsulfox-
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Table 2. Investigation into the substrate scope.[a]
Entry
1
Product
Yield [%]
95
Entry
8
Product
Yield [%]
88
2
3
85
83
9
89
80
10
4
85
11
80
5
6
78
85
12
13
85
72
7
78
14
86
[a]
Reaction conditions: sulfoximine (0.75 mmol), aldehyde (0.5 mmol), CuBr (1 mol%), TBHP (1.0 mmol), CH3CN (1 mL),
808C, 12 h.
Scheme 2. The proposed mechanistic pathway of this oxidative coupling process.
ACHTUNGTRENNUNG
reaction mixture.[9]
a stable directing group in a palladium-catalyzed
[3e]
À
Wondering about the subsequent functionalization ortho-C H acetoxylation process. This reaction was
of the N-acylsulfoximine products 3 we became inter- performed using palladium acetate as catalyst and po-
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The Copper-Catalyzed Oxidative N-Acylation of Sulfoximines
the Alexander von Humboldt Foundation for a postdoctoral
fellowship.
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À
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À
À
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À
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