Copper-catalyzed oxidative C(sp3)-H/N-H coupling of sulfoximines and amides with simple alkanes via a radical process

Article abstract of DOI:10.1039/c5cc00839e

A copper-catalyzed oxidative C(sp³)-H/N-H coupling of sulfoximines with simple alkanes was developed. This protocol involved C(sp³)-N bond formation via a radical pathway and tolerated a series of functional groups, such as chloro, m

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Copper-catalyzed oxidative C(sp3)-H/N-H coupling of
sulfoximines, amides with simple alkanes via radical
process†
Cite this: DOI: 10.1039/x0xx00000x
Received xxth, xx 2014,
Accepted xxth, xx 2014
Fan Teng, Song Sun, Yan Jiang, Jin-Tao Yu* and Jiang Cheng*
DOI: 10.1039/x0xx00000x
www.rsc.org/chemcomm
copper-catalyzed oxidative C(sp3)-H/N-H coupling of
prefunctionalization; 2) compatible of primary amides and amines
A
and 3) no strong base was required.
sulfoximines with simple alkanes was developed. This pro-
tocol featured with C(sp3)-N bond formation via the radical
pathway and tolerated a series of functional groups, such as
chloro, methyl and aryl on the phenyl rings. Apart from
sulfoximines, amides, saccharin and aniline also worked well
Scheme 1 N-Alkylation of sulfoximines.
to give the corresponding
N-alkylated products.
In the past decades, sulfoximines were widely applied as pivotal
intermediates to construct heterocycle motifs.1 Apart from this, they
also served as chiral auxiliaries or ligands in asymmetric synthesis2
and commonly used as directing group in stereoselective
functionalizations.3 Moreover, sulfoximine is an effective reagent for
insect control and occupied an irreplaceable field in pesticide
chemistry.4 Thus, considerable attention has been paid to the study
on N–functionalization of sulfoximine compounds.5 As far as N-
alkylation was concerned, less strategies to achieve this
transformation has been developed until now. For example, in 1993,
Johnson reported the synthesis of N-alkylated sulfoximines through
nucleophilic substitution.6 Strong base such as alkali metal hydride
was required in this reaction, resulting poor substrate tolerance and
decreasing its practicability (Scheme1, eq 1). Recently, Bolm and
co-workers described the alkylation of sulfoximines with alkyl
halides mediated by KOH (Scheme 1, eq 2).7 Subsequently, they
developed the iron-catalyzed hetero-cross-dehydrogenative coupling
reaction of sulfoximines with diaryl methanes leading to N-alkylated
sulfoximines,8 which provided a new strategy for the synthesis of N-
alkylated sulfoximines with α-branched substituents (Scheme 1, eq
3). In view of simple alkanes facilely available from fossil fuel, a
mild and efficient protocol to achieve the N-alkylation of
sulfoximine analogues using inert alkanes was waiting for
development.9
Initially, sulfonimidoyldibenzene 1a was selected as the model
substrate to optimize the reaction conditions. A first successful
glimpse was observed by using TBHP (4 equiv), CuI (10 mol%) at
o
100 C, which resulted in the N-cyclohexane product 3aa in 32%
yield (Table 1, entry 1). Other oxidants, such as K2S2O8 and DDQ
were inefficiency for this transformation (Table 1, entries 2 and 3).
However, when DTBP was employed, the yield of 3aa was
dramatically increased to 58% (Table 1, entry 4). The oxidant was
crucial to this transformation, since no product was obtained without
the assistance of any oxidant (Table 1, entry 5). Further optimization
revealed that the overall yield could slightly increased to 65% under
115 oC, while the transformation could not proceed under lower
o
temperatures as 80 C (Table 1, entries 6-7). Among metal catalysts
screened, such as FeCl3, AgI, CuBr, Cu(acac)2, Cu(OTf)2 and CuCl2,
Cu(acac)2 showed the better efficiency, providing the desired
product in 81% yield (Table 1, entries 8-13). It is worth to note that
the reaction could not occur in the absence of any metal catalyst
(Table 1, entry 14).
Inspired by those pioneered exploration in the functionalization of
simple alkanes,10 we seek the possibility of achieving N-alkylated
sulfoximines via the coupling of alkyl radical with sulfoximines.
Compared with previous researches, this transformation is featured
with: 1) the employment of simple and inert alkanes without
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excellent tolerance for sulfonimidoyldiarene derivatives and
provided the corresponding N-alkylated products in good to
excellent yields (Figure 1, 3aa-3fa). For example, symmetric
sulfonimidoyldiarenes could produce the desired products in 73%
and 85% yields, respectively (Figure 1, 3ba and 3ca). Unsymmetric
sulfonimidoyldiarene substrates all proceeded well to form the N-
alkylated products (Figure 1, 3da-3fa).
Table 1. Selected results for screening the optimized reaction
conditions.a
Apart from above mentioned sulfonimidoyl substrates, aryl
amides were also good reaction partners and the corresponding N-
alkylated products were isolated in excellent yields (Figure 2, 5a-5f).
Aryl amide substrates bearing electron-donating or electron-
withdrawing groups on the phenyl rings all tolerated well. Moreover,
when aryl imide, saccharin and aniline were subjected to the reaction
under standard procedures, the N-alkylation could go smoothly to
generate the products (Figure 2, 5g-5i), which further expanded the
substrate scopes.
Entry
1
Catalyst
CuI
Oxidant
TBHP
K2S2O8
DDQ
T/oC
100
100
100
100
100
115
80
Yield (%)b
32
2
CuI
< 5
3
CuI
< 5
4
CuI
DTBP
--
58
5
CuI
< 1
65(62)c
Figure 2. Substrate scope of amides.
6
CuI
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
7
CuI
< 1
8
FeCl3
AgI
52
100
115
115
115
115
115
115
9
36
10
11
12
13
CuBr
Cu(acac)2
Cu(OTf)2
CuCl2
--
42
81(79)c
< 5
34
14
a
< 1
Reaction conditions: 1a (0.2 mmol), catalyst (10 mol%), oxidant (4.0
equiv) (DTBP = di-tert-butyl peroxide, TBHP = tert-butyl hydroperoxide,
DDQ = 2,3-dichloro-5,6-dicyano-4-benzoquinone) in cyclohexane 2a (2.0
mL) under air for 12 h in sealed tube. b Isolated yield. c under N2.
Figure 1. Substrate scope of sulfoximines.
Next, various alkanes were employed to react with the
sulfonimidoyldibenzene under the standard procedure. As expected,
cyclopentane, cycloheptane and cyclooctane all went smoothly
leading to N-alkylated products 3ab, 3ac and 3ad in 44%, 81% and
50% yields, respectively. To our delight, toluene was also tolerated
and gave the N-benzylated product 3ea in 43% yield. In particular,
acylic substrates as hexane run smoothly as well and the 2- or 3- N-
substituted products were formed simultaneously in a ratio of 1:0.8
(determined by 1H NMR analysis of the isolated products).
Some experiments were conducted to get insights into the reaction
mechanism. Firstly, under standard procedure, 2.0 equivalents of
2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) was added into the
reaction mixture, and no N-alkylated product 3aa was detected at all.
The reaction adduct formed by cyclohexanyl radical and TEMPO
was determined by GC-MS, which implied the radical process was
included (Scheme 2, eq 1). Subsequently,
a
significant
intermolecular isotopic kinetic effect (KH/KD = 9.0) was observed,
suggesting the cleavage of the sp3 C-H bond of cyclohexane may be
the rate-determining step (Scheme 2, eq 2). Finally, competitive
With the optimal reaction conditions in hand, we explored the
scope of the substrates. Gratifyingly, this transformation showed
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experiments were carried out, where the results indicated that butoxy radical gives the cyclohexanyl radical. At the same time, 1a
electron-withdrawing group was prone to promote this reacts with tert-butoxide anion and provides anion intermediate 6.
transformation which is consistent with the radical pathway (Scheme Subsequently, the key step took place by radical addition between
2, eq 3).
the cyclohexanyl radical and intermediate 6 to provide the radical
anion 7.12 At last, 7 undergo a single electron transfer with Cu(III),
affording the N-alkylated product and regenerating Cu(II).
Figure 3. Substrate scope of alkanes.
Scheme 3. The proposed mechanism.
In conclusion, we have demonstrated a copper-catalyzed
oxidative C(sp3)-H/N-H coupling of sulfoximines with simple
alkanes via radical process leading to N-alkylated sulfoximines,
which means an important progress to sulfoximine chemistry.
Besides, aryl amides, saccharin and aniline were also tolerated
this procedure well to generate the corresponding N-alkylated
products. Indeed, this work represents
a
facile and
straightforward protocol leading to N-alkylated products.
We thank the National Natural Science Foundation of China
(nos.
21272028
and
21202013),
“Innovation
&
Scheme 2. Preliminary mechanism studies.
Entrepreneurship Talents” Introduction Plan of Jiangsu
Province, Jiangsu Key Laboratory of Advanced Catalytic
Materials and Technology (BM2012110), the Priority
Academic Program Development of Jiangsu Higher Education
for financial support.
Notes and references
School of Petrochemical Engineering, Jiangsu Key Laboratory of
Advanced Catalytic Materials and Technology, Jiangsu Province Key
Laboratory of Fine Petrochemical Engineering, Changzhou University,
Changzhou 213164, P. R. China; E-mail: yujintao@cczu.edu.cn;
jiangcheng@cczu.edu.cn
† Electronic Supplementary Information (ESI) available. See DOI:
10.1039/c000000x/
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