Copper-catalyzed N-methylation/ethylation of sulfoximines

Article abstract of DOI:10.1039/c5ob01558h

A protocol for the copper-catalyzed N-methylation of sulfoximines with di-tert-butyl peroxide (DTBP) was developed. This protocol has good functional group tolerance leading to N-methylated sulfoximines in moderate to good yields. Besides, N-ethylation of sulfoximines was achieved in the presence of bis(1,1-dimethylpropyl)peroxide as the ethylating agent under a standard procedure.

Full text of DOI:10.1039/c5ob01558h

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: J. Yu, F. Teng and
J. Cheng, Org. Biomol. Chem., 2015, DOI: 10.1039/C5OB01558H.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

View Article Online
DOI: 10.1039/C5OB01558H
Page 1 of 4
Organic & Biomolecular Chemistry
Organic &
Biomolecular Chemistry
RSCPublishing
COMMUNICATION
Copper-catalyzed
N-methylation/ethylation
of
sulfoximines†
Cite this: DOI: 10.1039/x0xx00000x
Fan Teng, Jiang Cheng and Jin-Tao Yu*
Received xxth, xx 2015,
Accepted xxth, xx 2015
DOI: 10.1039/x0xx00000x
www.rsc.org/chemcomm
The copper-catalyzed
tert-butyl peroxide (DTBP) is developed. This protocol has
good functional group tolerance leading to -methylated
sulfoximines in moderate to good yields. Besides, -ethylation
N-methylation of sulfoximines with di-
N
N
of sulfoximines was achieved in the presence of bis(1,1-
dimethylpropyl)peroxide as ethylating agent under standard
procedure.
Methyl group is ubiquitously found in bioactivity molecules
and medicinal compounds, and the introduction of a methyl
group can evidently improve a molecule’s biological activity
and physical properties.1 Besides, it also plays an irreplaceable
role as an efficient handle for further functionalizations leading
to carboxyl,2 cyano,3 carbonyl4 or halo-substituted alkyl
groups.5 As a result, methylation has attracted extensive
attentions among chemists in the past decades.6 In particular,
peroxides were increasingly employed as effective methyl
source in this realm via extruding methyl radical. Recently, our
and other groups have developed some works in this field
utilizing peroxides as methyl source.7
Sulfoximine is widely used in the pesticide field and is the
core moiety of several pharmaceutical molecules.8 Additionally,
it was also employed as directing group in C-H bond activation9
and worked as auxiliary ligands for asymmetric synthesis.10
Thus, considerable attentions have been paid to the study on N-
functionalization of sulfoximine compounds.11 Indeed, N-
methylated sulfoximine motifs are existed in several
pharmaceutical molecules as well.12 For example, inhibitors of
HIF-Luciferase exhibit high efficiency on hyperproliferative
and angiogenesis disorders.12b Although some methodologies
have been utilized to provide N-methylated sulfoximines, their
drawbacks are still obvious, such as the using of toxic reagents
and long reaction time.13 Thus, a more direct, safe and efficient
methylation process is highly desired. Here, we report an
unprecedented approach to achieve the N-methylation of
sulfoximines using peroxide as methyl source (Scheme 1).
Scheme 1 N-Methylation of sulfoximines.
To address this problem,
firstly,
we
chose
diphenylsulfoximine (1a) as model substrate and di-tert-butyl
peroxide (DTBP, 2a) as the methylating agent. Disappointedly,
this initial endeavor failed to provide the desired product
without any catalyst (Table 1, entry 1). Catalysts such as
AgOAc and FeCl2 also failed to deliver the N-methylated
sulfoximine (Table 1, entries 2-3). To our delight, the N-
methylated product 3a could be generated in 26% yield in the
presence of CuSO4 in DMSO (Table 1, entry 4). Encouraged by
the exciting result, we subsequently screened other copper salts
such as Cu(acac)2, CuI, CuCl and Cu(OAc)2 (Table 1, entries 5-
8). The results showed that Cu(OAc)2 was the best catalyst,
providing the product 3a in 85% yield. Subsequently, several
other common peroxides were tested, but with lower efficiency
(Table 1, entries 9-11). Other common solvents, such as MeCN,
PhCF3, PhF, PhCl and EtOH, were inferior to DMSO (Table 1,
entries 12-16). Under air, the transformation could proceed
smoothly but the yield slightly dropped to 79% (Table 1, entry
8).
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 1

View Article Online
Organic & Biomolecular Chemistry
DOI: 10.1039/C5OB01P55a8gHe 2 of 4
COMMUNICATION
Table 1. Screening the optimized reaction conditions.a
Journal Name
Entry
1
Catalyst
--
2
Solvent
Yield (%)b
< 1
< 5
< 5
26
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DCP
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
MeCN
PhCF3
PhF
2
AgOAc
FeCl2
3
4
CuSO4
5
Cu(acac)2
CuI
58
6
18
7
CuCl
76
85 (79)c
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
9
80
10
11
12
13
14
15
TBHP
TBPB
DTBP
DTBP
DTBP
DTBP
DTBP
63
38
< 5
37
44
36
PhCl
16
a
< 1
EtOH
Reaction conditions: 1a (0.2 mmol), catalyst (10 mol%) and peroxide 2
(0.6 mmol, 3 equiv.) (DTBP = di-tert-butyl peroxide, TBHP = tert-butyl
hydroperoxide, TBPB
peroxide ) in solvent (2 mL) under N2 at 110 C for 16 h. Isolated yields.
Under Air.
= tert-Butyl peroxybenzoate, DCP = dicumyl
o
b
c
With the optimal reaction conditions established, a great
number of S,S-diarylsulfoximine derivatives were tested as
shown in Fig. 1. To our delight, substrates with either electron-
donating or electron-withdrawing groups on the phenyl rings
could be tolerated well to achieve the desired products in
Fig. 1 Substrate scope of sulfoximines in N-methylation.
moderate to good yields
(3a-3j). For example, 4-
methoxyldiphenyl sulfoximine (1f) provided the methylated
product 3f in 81% yield. Especially, substrates with halo groups
could be tolerated well, which provided convenient handles for
further functionalizations
(3c, 3g and 3h). Acetyl and
methoxycarbonyl groups were well survived under this mild
reaction conditions to generate the methylated products in 51%
and 72% yields (Fig. 1, 3i and 3j). In parallel with S,S-
diarylsulfoximines, S-aryl-S-alkyl sulfoximines gave the
corresponding methylated products in yields ranging from 42%
to 73% (Fig. 1, 3k-3n). Particularly, aryl imide (1o) could be
methylated under the standard procedure as well, although in
relatively lower yield. To further evaluate the practicability of
this procedure, the reaction was conducted on a 2 mmol scale,
giving the product 3a in a comparable 82% yield.
Except for methylation, this procedure could be applied to
ethylation process as well. As shown in Fig. 2, when bis(1,1-
dimethylpropyl)peroxide 4a was used as ethyl source under standard
conditions, the ethylation proceeded well and gave the
corresponding products in moderate to good yields (5a-5f).
Fig. 2 Substrate scope of sulfoximines in N-ethylation.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

View Article Online
DOI: 10.1039/C5OB01558H
Page 3 of 4
Journal Name
Organic & Biomolecular Chemistry
COMMUNICATION
Several experiments were conducted to gain deep insights into the
In conclusion, we have demonstrated a novel copper- catalyzed N-
mechanism. Initially, d6-DMSO was used as solvent and no methylation/ethylation approach using peroxides as methyl/ethyl
deuterated product was detected, which ruled out the possibility of source leading to N-methylated/ethylated sulfoximines in moderate
DMSO as methyl provider. Secondly, both reactions were obviously to good yields. The mild transformation is conducted under redox
inhibited when normal radical scavengers such as 2,2,6,6- neutral conditions without the participation of acids or bases. It
tetramethylpiperidine N-oxide (TEMPO) and 2,6-di-tert-butyl-4- represents
a facile avenue to access N-methylated/ethylated
methylphenol (BHT) were added to the procedures. Besides, these sulfoximines and is an important complement to sulfoximine
adducts formed by radical scavengers with methyl radical were chemistry.
detected by GC-MS (Scheme 3 and see ESI† for details).
We thank the National Natural Science Foundation of China (nos.
According to above mentioned experiment results and reported 21202013 and 21272028), Jiangsu Key Laboratory of Advanced
works,7a,7b,14 the proposed mechanism is outlined in Scheme 3. Catalytic Materials and Technology (BM2012110) and the Priority
Initially, the Cu(II) assisted cleavage of DTBP produces tert-butoxy Academic Program Development of Jiangsu Higher Education
anion and tert-butoxy radical, the later converts to methyl radical by Institutions (PARD) for financial supports.
releasing of acetone. Subsequently, tert-butoxide anion absorbs one
proton from sulfoximine 1a to generate tert-butanol and anion
Notes and references
intermediate 8. Then, the addition of methyl radical to 8 provides
intermediate 9. Finally, 9 is oxidized by Cu(III) to produce N-
methylated products 3a and regenerates Cu(II). (Acetone and tert-
butanol were detected by GC-MS, see ESI†.)
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
† Electronic Supplementary Information (ESI) available. See DOI:
10.1039/c000000x.
1
(a) E. J. Barreiro, A. E. Kümmerle and C. A. M. Fraga, Chem. Rev.,
2011, 111, 5215; (b) H. Schoherr and T. Cernak, Angew. Chem., Int.
Ed., 2013, 52, 12256.
2
3
(a) T. Lu, Y. Mao, K. Yao, J. Xu and M. Lu, Catal. Commun., 2012,
27, 124; (b) T. Sugai and A. Itoh, Tetrahedron Lett., 2007, 48, 9096.
(a) W. Zhou, L. Zhang and N. Jiao, Angew. Chem., Int. Ed., 2009, 48
,
7094; (b) S. Guo, G. Wan, S. Sun, Y. Jiang, J.-T. Yu and J. Cheng,
Chem. Commun., 2015, 51, 5085. (c) D. Tsuchiya, Y. Kawagoe, K.
Moriyama and H. Togo, Org. Lett., 2013, 15, 4194; (d) D. Tsuchiya,
Y. Kawagoe, K. Moriyama and H. Togo, Org. Lett., 2013, 15, 4194;
(e) Z. Shu, Y. Ye, Y. Deng, Y. Zhang and J. Wang, Angew. Chem.,
Int. Ed., 2013, 52, 10573.
4
(a) B. Nammalwar, C. Fortenberry, R. A. Bunce, S. K. Lageshetty
and K. D. Ausman, Tetrahedron Lett., 2013, 54, 2010; (b) P. K.
Chaurasiaa, S. Yadavaa, S. L. Bharatia and S. K. Singha, Synth.
Commun., 2014, 44, 2535; (c) C. Jin, L. Zhang and W. Su, Synlett,
2011, 1435.
5
6
7
(a) G. R. Newkome, Newkome, G. E. Kiefer, Y. J. Xia and V. K
Gupta, Synthesis, 1984, 676; (b) X. F. Jiang M. H. Shen, Y. Tang
and C. Z. Li, Tetrahedron Lett., 2005, 46, 487.
Scheme 2. Preliminary mechanism studies.
Scheme 3. Proposed mechanism.
(a) G. Yan, A. J. Borah, L. Wang and M. Yang, Adv. Synth. Catal.
2015, 357, 1333; (b) K. Endo and T. Shibata, Synthesis, 2012, 44
1427.
,
(a) S. Guo, Q. Wang, Y. Jiang and J.-T. Yu, J. Org. Chem., 2014, 79
,
11285; (b) Q. Dai, J.-T. Yu, Y. Jiang, S. Guo, H. Yang and J. Cheng,
Chem. Commun., 2014, 50, 3865; (c) Q. Dai, J.-T. Yu, X. Feng, Y.
Jiang, H. Yang and J. Cheng, Adv. Synth. Catal., 2014, 356, 3341; (d)
Q. Xia, X. Liu, Y. Zhang, C. Chen and W. Chen, Org. Lett., 2013,
15, 3326; (e) Y. Zhu, H. Yan, L. Lu, D. Liu, G. Rong and J. Mao, J.
Org. Chem., 2013, 78, 9898; (f) Z. Xu, C. Yan and Z.-Q. Liu, Org.
Lett., 2014, 16, 5670; (g) Y. Zhang, J. Feng and C.-J. Li, J. Am.
Chem. Soc., 2008, 130, 2900.
8
9
(a) S. J. Park, H. Buschmann and C. Bolm, Bioorg. Med. Chem. Lett.,
2011, 21, 4888; (b) X. Y. Chen, S. J. Park, H. Buschmann, M. De
Rosa and C. Bolm, Bioorg. Med. Chem. Lett., 2012, 22, 4307; (c) U.
Lüking, Angew. Chem., Int. Ed., 2013, 52, 9399.
(a) M W. Dong, L. Wang, K. Parthasarathy, F. Pan and C. Bolm,
Angew. Chem., Int. Ed., 2013, 52, 11573; (b) M. R. Yadav, R. K. Rit
and A. K. Sahoo, Chem. Eur. J., 2012, 18, 5541; (c) M. R. Yadav, R.
K. Rit and A. K. Sahoo, Org. Lett., 2013, 15, 1638; (d) R. K. Rit, M.
R. Yadav, A. K. Sahoo, Org. Lett., 2014, 16, 968; (e) R. Yadav, R.
K. Rit, M. Shankar and A. K. Sahoo, J. Org. Chem., 2014, 79, 6123;
(f) K. Parthasarathy and C. Bolm, Chem. Eur. J., 2014, 20, 4896; (g)
W. Dong, K. Parthasarathy, Y. Cheng, F. Pan and C. Bolm, Chem.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 3

View Article Online
Organic & Biomolecular Chemistry
DOI: 10.1039/C5OB01P55a8gHe 4 of 4
COMMUNICATION
Journal Name
Eur. J., 2014, 20, 15732. (h) Y. Cheng and C. Bolm, Angew. Chem.,
Int. Ed., 2015, DOI: 10.1002/anie.201501583.
10 (a) C. R. Johnson, Acc. Chem. Res., 1973, 6, 341; (b) M. Reggelin
and C. Zur, Synthesis, 2000, 1; (c) D. Craig, F. Grellepois and A. J.
P. White, J. Org. Chem., 2005, 70, 6827; (d) H. Okamura and C.
Bolm, Chem. Lett., 2004, 33, 482.
11 (a) L. Wang, H. Huang, D. L. Priebbenow, F.-F. Pan and C. Bolm,
Angew. Chem., Int. Ed., 2013, 52, 3478; (b) F. Teng, J.-T. Yu, Y.
Jiang, H. Yang and J. Cheng, Chem. Commun., 2014, 50, 8412. (c)
O. G. Mancheño and C. Bolm, Org. Lett., 2007, 9, 2951; (d) D. L.
Priebbenow and C. Bolm, Org. Lett., 2014, 16, 1650; (e) X. Y. Chen,
L. Wang, M. Frings and C. Bolm, Org. Lett., 2014, 16, 3796; (f) N.
Yongpruksa, N. L. Calkins and M. Harmata, Chem. Commun., 2011,
47, 7665; (g) F. Teng, J. Cheng and C. Bolm, Org. Lett., 2015, 17
,
3166; (h) F. Teng, J.-T. Yu, Z. Zhou, H. Chu and J. Cheng, J. Org.
Chem., 2015, 80, 2822. (i) C. Bohnen and C. Bolm, Org. Lett., 2015,
17, 3011; (j) F. Teng, S. Sun, Y. Jiang, J.-T. Yu and J. Cheng, Chem.
Commun., 2015, 51, 5902.
12 (a) V. Bizet, R. Kowalczyk and C. Bolm, Chem. Soc. Rev., 2014, 43
,
2426; (b) M. Haerter, H. Beck, P. Ellinghaus, K. Berhoerster, S.
Greschat, K.-H. Thierauch and F. Suessmeier, German Pat., WO
2010054764, 2010.
13 (a) F. Lemasson, H.-J. Gais, J. Runsink and G. Raabe, Eur. J. Org.
Chem., 2010, 2157; (b) S. Noritake, N. Shibata, S. Nakamura, T.
Toru and M. Shirgo, Eur. J. Org. Chem., 2008, 3465.
14 (a) C. Liu, D. Liu and A. Lei, Acc. Chem. Res., 2014, 47, 3459; (b) Q.
Liu, R. Jackstell and M. Beller, Angew. Chem., Int. Ed., 2013, 52
,
13871; (c) J. Wang, C. Liu, J. Yuan and A. Lei, Angew. Chem. Int.
Ed., 2013, 52, 2256.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012