Copper-catalyzed oxidative methylation of sulfonamides by dicumyl peroxide

Article abstract of DOI:10.1080/00397911.2020.1859118

A novel and facile copper-catalyzed methylation of sulfonamides was herein demonstrated. The practical transformation took place readily under the oxidative conditions, and N-methyl amides (23 examples) were successfully furnished in high efficiency (up to 90% yields). Dicumyl peroxide was considered to act not only as the oxidant in the system, but also methyl donor for the methylation protocol.

Full text of DOI:10.1080/00397911.2020.1859118

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Copper-catalyzed oxidative methylation of
sulfonamides by dicumyl peroxide
Shiying Che, Qiao Zhu, Zhenghong Luo, Yan Lian & Zijian Zhao
To cite this article: Shiying Che, Qiao Zhu, Zhenghong Luo, Yan Lian & Zijian Zhao (2021)
Copper-catalyzed oxidative methylation of sulfonamides by dicumyl peroxide, Synthetic
Communications, 51:6, 935-942, DOI: 10.1080/00397911.2020.1859118
To link to this article: https://doi.org/10.1080/00397911.2020.1859118
View supplementary material
Published online: 28 Dec 2020.
Submit your article to this journal
Article views: 64
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
2021, VOL. 51, NO. 6, 935–942
https://doi.org/10.1080/00397911.2020.1859118
Copper-catalyzed oxidative methylation of sulfonamides by
dicumyl peroxide
Shiying Chea,b,c, Qiao Zhua,b,c, Zhenghong Luob, Yan Lianb, and Zijian Zhaoa,b,c
b
aCollege of Pharmacy, Shaanxi University of Chinese Medicine, Shaanxi, P.R. China; School of
c
Chemistry and Materials Science, Huaihua University, Huaihua, P.R. China; Key Laboratory of Research
and Utilization of Ethnomedicinal Plant Resources of Hunan Province, Huaihua University, Huaihua,
P.R. China
ABSTRACT
ARTICLE HISTORY
Received 3 October 2020
A novel and facile copper-catalyzed methylation of sulfonamides was
herein demonstrated. The practical transformation took place readily
under the oxidative conditions, and N-methyl amides (23 examples)
were successfully furnished in high efficiency (up to 90% yields).
Dicumyl peroxide was considered to act not only as the oxidant in
the system, but also methyl donor for the methylation protocol.
KEYWORDS
Copper catalysis; dicumyl
peroxide; ligand-free;
oxidative methylation;
sulfonamides
GRAPHICAL ABSTRACT
H3C CH3
Cu(acac)2
O
O
O
O
+
CH3
S
O
S
Acetone, 120 oC, 8 h
sealed tube, under air
NH2
O
N
H
Ar
Ar
H3C CH3
R
R
Dicumyl Peroxide
Oxidant and methyl source
23 examples
62% - 90% yields
Introduction
Sulfonamides,[1] which became popular not only for the unique structure but also for exten-
sive applications in pharmaceutical and clinical chemistry, have attracted broad interests in
the organic synthetic community. Thus, development has been broadly observed for the past
decade and different methodologies have been well documented for the N-functionalization
of sulfonamides. For example, N-arylation has successfully been realized with different aryl
donors, including aryl halides, aryl boronic acids in the presence of ruthenium,[2] gold,[3]
copper-catalysis,[4] or even in water as solvent under aerobic conditions.[4a] Moreover, tri-
fluoromethylthiolation of the useful compounds was achieved in the presence of palla-
dium,[5] silver-catalyzed system,[6] or even under transition metal-free conditions.[7]
Sulfonamides have been regarded as pivotal intermediates for the formation of heterocycles
such as sultams, which are biologically active.[8] Currently, it was noteworthy that the methy-
lation of sulfonamides have been severely desired for the magic methyl effect[9] and subse-
quent medicinal explorations. Thus, great effort has been devoted to the development of the
CONTACT Zijian Zhao
P.R. China; Zhenghong Luo
Materials Science, Huaihua University, Huaihua 418000, P.R. China.
zjzhao72@163.com
College of Pharmacy, Shaanxi University of Chinese Medicine, Shaanxi,
2447151770@qq.com; Yan Lian
arline7419@163.com School of Chemistry and
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

936
S. CHE ET AL.
novel methodology to install a methyl group on sulfonamides. Many methylating agentings
have been screened for this transformation. Traditionally, methyl idodie has been employed
for the methylation of sulfonamides under strong basic conditions.[10] Methodologies utiliz-
ing methanol as the methyl source also became attractive for the formation of N-methyl sul-
fonamides due to the generality and low-cost. Expensive ruthenium[11] and iridium[12]
complexes were crucial to the transformation, so restrictions still existed for the potential
industrial utilizations of the methods. Very recently, Cai and coworkers disclosed a creative
method for the preparation of N-methyl sulfonamides and di-tert-butyl peroxide (DTBP)
played dual role in the system, as the methyl group supplier as well as the oxidant in the
transformation. Nickel[13a] and iron[13b] catalysts rendered the C-H/N-H activation through
the free radical pathway. However, the protocols were still suffering from issues including
moderate efficiency (yields below 80%),[13] necessary addition of a phosphorus ligand and an
external oxidant.[13b] Inspired by the fruitful results,[14] we now wished to disclose a novel
system, using Cu(acac)2 as the catalyst and di-cumyl peroxide (DCP) as the oxidant and
methyl provider, without any organic ligands.
Discussion
Initially, reactions between model substrates phenyl sulfonamide (1a) and dicumyl per-
oxide were carried out to investigate the optimal conditions of the methylation protocol,
as summarized in Table 1. Disappointingly, in the presence of palladium dichloride as
the catalyst, acetonitrile as the solvent and 2.0 equivalents of DCP failed to methylate
the sulfonamide and trace amount of N-methyl sulfonamide was detected at 120 ꢀC after
8 h (entry 1). Similarly, other palladium catalysts, such as Pd(OAc)2, Pd(TFA)2 (TFA for
trifluoroacetyl) and Pd(PPh3)2Cl2 resulted in little amount of the desired transformation
(entries 2–4). Successively, the activities of different copper catalysts were also evaluated
in the system, and generally speaking, Cu(II)-salts (entries 5–8) offered better perform-
ance than Cu(I)-salts did in the transformation (entries 9–11). Worthy of note, amongst
all the Cu(II)-catalysts, Cu(acac)2 gave the best 80% yield in acetonitrile, prior to other
Cu(II)-salts did, such as CuCl2, CuBr2, Cu(OAc)2. Then, iron catalysts were also reacted
but proved ineffective to the transformation and only trace amounts of the desired
product was observed upon the consumption of DCP. To our disappointment, cobalt
and nickel salts, including CoCl3, Co(acac)2, NiCl2 and Ni(acac)2 did not render the
occurrence of the reaction, for no reaction was detected after 8 h (entries 16–19). With
reduced loadings of DCP (1.0 equiv. as the methyl reagent), the examination of the
effects of other external oxidants, such as di-tertbutyl peroxide (DTBP for entry 20),
TBHP (tert-butyl hydroperoxide, 70% in water, for entry 21), m-CPBA (3-chloroperben-
zoic acid for entry 22), K2S2O8 (entry 23), was conducted, and it was found that exter-
nal oxidant could not afford effective results to the protocol, and the highest of 35%
yield was obtained in acetonitrile with the assistance of Cu(acac)2. Then, different
organic solvents were also screened for the oxidative methylation protocol. Chlorinated
organic solvents, such as chloroform (entry 24), 1,2-dichloroethane (entry 25), chloro-
benzene (entry 26) gave moderate yields in the presence of Cu(acac)2 at 120 ꢀC for 8 h
(62–70%). Beyond our expectation, when the reaction was conducted in acetone, a yield
of 85% was obtained in the sealed reaction tube at 120 ꢀC for 8 h (entry 27), superior to

R
SYNTHETIC COMMUNICATIONSV
937
Table 1. Conditions optimization.a
Entry
Cat.
[O]
Sol.
Yieldb
1
2
3
4
5
6
7
8
PdCl2
Pd(OAc)2
Pd(TFA)2
Pd(PPh3)2Cl2
CuCl2
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Chloroform
1,2-DCE
Tracec
Trace
Trace
Trace
20%
n.d.d
78%
80%
50%
62%
68%
Trace
Trace
Trace
Trace
n.d.
CuBr2
Cu(OAc)2
Cu(acac)2
CuCl
CuBr
CuI
FeCl3
FeBr3
FeCl2
FeBr2
9
10
11
12
13
14
15
16
17
18
19
20e
21e
22e
23e
24
25
26
27f
28
29
30
31g
32h
33i
CoCl2
Co(acac)2
NiCl2
–
–
–
n.d.
n.d.
n.d.
Ni(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
DTBP
TBHP
mCPBA
K2S2O8
–
–
–
–
–
–
–
–
–
–
35%
30%
Trace
Trace
62%
64%
70%
85%
62%
55%
60%
45%
60%
82%
Chlorobenzene
Acetone
Toluene
DMF
DMSO
Acetone
Acetone
Acetone
aReaction conditions: 1 (0.3 mmol), DCP (0.6 mmol), Cat. (10 mol%) under air in Sol. (1.5 mL) at 120 ꢀC for 8 h.
bIsolated yields.
cTrace means <10% yields.
dn.d. means not detected.
eReaction conditions: 1 (0.3 mmol), DCP (0.36 mmol), Cat. (10 mol%), [O] (0.6 mmol) under air in Sol. (1.5 mL) at 120 ꢀC
for 8 h.
fBold text means the optimal conditions.
gThe reaction was conducted at 80 ꢀC instead of 120 ꢀC.
h5 mol% loading of Cu(acac)2 was used.
i20 mol% loading of Cu(acac)2 was used.
other organic solvents did in the system, including toluene, DMF (N,N-dimethyl forma-
mide), DMSO (dimethyl sulfonamide) (entries 28–30). Finally, the reaction was carried
out at the reduced temperature (80 ꢀC), and the yield of 2a decreased sharply to 45%
yield (entry 31). Finally, loadings of the copper catalyst was also optimized in the sys-
tem and 5 mol% was found to be insufficient to make the reaction take place and only

938
S. CHE ET AL.
Table 2. Scope of the methylation reaction.a
2b, 82%
2c, 80%
2d, 84%
2e, 88%
2h, 78%
2f, 83%
2i, 75%
2g, 76%
2j, 90%
2k, 72%
2n, 72%
2l, 68%
2o, 70%
2m, 73%
2p, 72%
2q, 68%
2t, 70%
2r, 72%
2u, 70%
2s, 62%
2v, 80%
aReaction conditions: 1 (0.5 mmol), DCP (1.0 mmol), Cu(acac)2 (10 mol%) under air in acetone (2.5 mL) at
120 ꢀC for 8 h.
60% yield was obtained. Meantime, when 20 mol% of the catalyst was used, a slight
decrease was also observed and 82% of 2a was isolated (entries 32 and 33).
With the optimal reaction conditions in hand, examination of the substrate scope
was successively carried out (Table 2).
In the presence of optimized conditions, p-tolyl sulfonamide (1b) was readily trans-
formed into N-methyl-p-tolyl sulfonamide (2b) in 82% yield. Highly steric hindered
substrates were also subjected to the Cu(II)-mediated system, but no significance

R
SYNTHETIC COMMUNICATIONSV
939
reduction was observed in the efficiency of the transformation. For example, 2,4,6-mesi-
tyl sulfonamide (1c) and 4-tert-butylphenyl sulfonamide (1d) reacted with DCP in the
presence of Cu(acac)2, affording the desired products 2c and 2d in 80% and 84% yields,
respectively. The effect of electron-donating functional groups was also examined,
resulting in the formation of N-methyl-p-methoxyphenyl sulfonamide (1e) in 88% yield.
Pleasingly, halogen groups were also found to be compatible in the transformation, and
the positions of the groups affected the efficiency of the protocol slightly. For example,
p-fluorophenyl sulfonamide (1f) furnished the desired methylated product 2f in 83%
yield, while 2,6-difluorophenyl sulfonamide (1g) allowed the formation of the corre-
sponding product 2g in 76% yield. p-Chlorophenyl sulfonamide (1h) was also success-
fully alkylated and the corresponding product 2h was isolated by the column
chromatography in 78% yield. The positions of the bromo-group were also examined in
the transformation. For instance, N-methyl-para-bromophenyl sulfonamide (2i) was fur-
nished in 75% yield, N-methyl-meta-bromophenyl sulfonamide (2j) was isolated in 90%
yield. However, N-methyl-ortha-bromophenyl sulfonamide (2k) was separated in a
lower yield, up to 72% ratio. Iodophenyl sulfonamide (1l) reacted with DCP in the
Cu(acac)2-mediated system, allowing the formation of the corresponding N-methyl sul-
fonamide 2l in 68% yield. Electron-withdrawing groups such as nitro group, trifluoro-
methyl and cyano functionalities, were also found to be well-tolerated in the oxidative
transformation, and the corresponding methylated products, N-methyl-p-nitrophenyl
sulfonamide (2m), N-methyl-p-trifluoromethylphenyl sulfonamide (2n) and N-methyl-p-
cyanophenyl sulfonamide (2o) were readily formed in yields from 70% to 73%. Beyond
our expectation, substrate with highly-active hydroxyl group (1p) were also compatible
and went through the oxidative reaction successfully, forming the desired N-methyl-p-
hydroxylphenyl sulfonamide (2p) in a very good yield of 72%. Polyaryl sulfonamides,
which were illustrated by the utilization of 4,40-biphenyl sulfonamide (1q) and 8-qui-
nolyl sulfonamide (1r), were compatible, giving the desired polyaryl-maintained sub-
strates 2q and 2r in 68% and 72% yields, respectively. Heteroaryl groups were also
examined in the system for the tolerance of the functional groups. 2-
Pyridinylsulfonamide (1s) and 2-thiophenylsulfonamide (1t) offered an easy access to
the corresponding N-methyl heteroarylsulfonamides 2s and 2t in 62% and 70% yields,
respectively. Benzylsulfonamide (1u) was also tolerated well in the system, and fur-
nished the desired N-methyl sulfonamide 2u in relative high yield of 70%. This method
was furthered to benzamide (1v), which was also readily methylated, furnishing N-
methyl benzamide (2v) in 80% yield.
Further methylation of the methylated products were also successively explored,
which was conducted readily only on the substrate N-methyl 4-cyanophenyl sulfona-
mide (2o), and subjection of 2o gave the N,N-dimethyl 4-cyanophenyl sulfonamide (3o)
in moderate yield (50% yield for Scheme 1).
To gain insight into the mechanism of the methylation protocol, control reactions
with addition of different radical scavengers, such as TEMPO (2,2,6,6-tetramethyl
piperidine 1-oxyl) or BHT (2,6-di-tert-butyl-4-methyl phenol), were successively con-
ducted under the standard conditions (Scheme 2). Although no free radical-scavenger
adducts were successfully detected by TLC analysis or isolated, the yield of the oxidative
methylation protocol was decreased dramatically and only trace amount of 2a was

940
S. CHE ET AL.
Scheme 1. Further methylation of the methylated product.
Scheme 2. Control reactions with additions of TEMPO or BHT.
Scheme 3. Plausible mechanism.
observed by TLC analysis. These results indicate that the reaction may take place by a
free radical pathway.
Based on the results of the control reactions and the previous literature explora-
tions,[14] a plausible mechanism of the facile reaction shown in Scheme 3 was proposed
through a free radical intermediate, as illustrated by the reaction between 1a and DCP
toward 2a.

R
SYNTHETIC COMMUNICATIONSV
941
By heating or in the presence of the Cu(II)-catalyst, DCP decomposed quickly, form-
ing a methyl free radical particle, and the side product acetophenone, which could be
checked easily by TLC analysis (Eq. A). Meanwhile, coordination between the substrate
1a and the copper salt takes place to Cu(II)-intermediate A (Eq. B). The newly-formed
Cu(II)-intermediate A then reacts with the methyl free radical particle, allowing the
formation of another key methylated Cu(III)-ligand intermediate B (Eq. C).
Successively, the Cu(III)-intermediate B afforded the desired methylated product 2a,
and at the same time Cu(I) was formed through the elimination reduction procedure
(Eq. D), which could be easily re-oxidized by DCP to Cu(II)-catalyst for the next cata-
lytic circle.
Conclusions
In conclusion, we have demonstrated a facile and easy-operated N-methylation of sulfo-
namides in the presence of a copper-catalyst under the oxidative conditions. The
transformation was shown to tolerate different function groups and substrates was high-
efficiency in the synthesis of N-methyl sulfonamides and benzamides. Further explora-
tions for the synthetic and clinical applications of the products are still on-going in
our laboratory.
Experimental
Typical synthetic procedure of N-aryl-S-aryl sulfonamides 2
Under the air atmosphere, a Schlenk tube (35 mL) equipped with a magnetic bar, DCP
(1.0 mmol) was added to the mixture of sulfonamide 1 (0.5 mmol), Cu(acac)2 (10 mol%)
in acetone (2.5 mL). The tube was sealed and the reaction mixture was allowed to stir at
120 ꢀC for 8 h. After the comsumption of 1, as monitored by TLC analysis, the mixture
was filtered through a short celite pad and washed with methanol (15 mL ꢁ 3). The fil-
trate was concentrated, and the oilyresidue was purified by column chromatography
using silica gel (200–300 mesh) as stationary phase and a mixture of n-hexane and ethyl
acetate (ca. 5:1) as eluent to give the corresponding methylated products 2 (Rf ¼ ca.0.3
otherwise noted).
Spectra data of N,S-diphenyl sulfonamide (2a)
Yield: 85%. White solid, m.p.: 31–32 ꢀC. 1H NMR (400 MHz, CDCl3) d ¼ 7.80 (d,
J ¼ 7.4 Hz, 2H), 7.56–7.39 (m, 3H), 5.36 (br, 1H), 2.53 (br, 3H). 13C NMR (100 MHz,
CDCl3) d ¼ 138.6, 132.7, 129.2 127.1, 29.2 (ppm). IR: ꢀ ¼ 2926, 1594, 1496, 1339, 1256,
1147, 1090, 1020, 830, 681, 582 (cmꢂ1). MS (EI) m/z (%) ¼ 171.0 (95.04, Mþ), 141.0,
106.1, 90.0, 77.0. HRMS (ESI) (m/z) [M þ Hþ]: Calcd.: 171.0354, Found: 171.0387.
Full experimental details, 1H and 13C NMR spectra are accessible via the
“Supplementary Content” section of this article’s webpage.

942
S. CHE ET AL.
Funding
The authors are grateful for the financial support from the Foundation of Hunan Double First-
rate Discipline Construction Projects [grant number YYZW2018-9, ZWX2016-11).
References
[1] Amino Group Chemistry: From Synthesis to the Life Sciences; A. Ricci, Ed.; Wiley-VCH:
Weinheim, 2008.
[2] Kim, T.; McCarver, S. J.; Lee, C.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2018, 57,
3488–3492. DOI: 10.1002/anie.201800699.
[3] Rodriguez, J.; Adet, N.; Saffon-Merceron, N.; Bourissou, D. Chem. Commun. 2020, 56,
94–97. DOI: 10.1039/c9cc07666b.
[4] (a) Nasrollahzadeh, M.; Ehsani, A.; Maham, M. Synlett 2014, 25, 505–508. DOI: 10.1055/
s-0033-1340475.(b) Nasrollahzadeh, M.; Rostami-Vartooni, A.; Ehsani, A.; Moghadam, M.
J. Mol. Catal. A-Chem. 2014, 387, 123–129. DOI: 10.1016/j.molcata.2014.02.017.(c)
Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M. Chemistry 2004, 10, 5607–5622.
DOI: 10.1002/chem.200400582.
[5] Kesavan, A.; Chaitanya, M.; Anbarasan, P. Eur. J. Org. Chem. 2018, 2018, 3276–3279.
DOI: 10.1002/ejoc.201800451.
[6] Xiong, H.-Y.; Pannecoucke, X.; Besset, T. Org. Chem. Front. 2016, 3, 620–624. DOI: 10.
1039/C6QO00064A.
[7] Alazet, S.; Ismalaj, E.; Glenadel, Q.; Le Bars, D.; Billard, T. Eur. J. Org. Chem. 2015, 2015,
4607–4610. DOI: 10.1002/ejoc.201500710.
[8] (a) Feng, S.; Li, S.; Li, J.; Wei, J. Org. Chem. Front. 2019, 6, 517–522. DOI: 10.1039/
ꢀ
C8QO01311J. (b) Conde, N.; Churruca, F.; SanMartin, R.; Herrero, M. T.; Domınguez, E.
Adv. Synth. Catal. 2015, 357, 1525–1531. DOI: 10.1002/adsc.201401129. (c) Pham, M. V.;
Ye, B.; Cramer, N. Angew. Chem. Int. Ed. Engl. 2012, 51, 10610–10614. DOI: 10.1002/
anie.201206191.
€
[9] Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. Engl. 2013, 52, 12256–12267. DOI: 10.
1002/anie.201303207.
[10] Maclean, D.; Hale, R.; Chen, M. Org. Lett. 2001, 3, 2977–2980. DOI: 10.1021/ol0163124.
[11] Dang, T. T.; Ramalingam, B.; Seayad, A. M. ACS Catal. 2015, 5, 4082–4088. DOI: 10.
1021/acscatal.5b00606.
[12] (a) Li, F.; Xie, J.; Shan, H.; Sun, C.; Chen, L. RSC Adv. 2012, 2, 8645–8652. DOI: 10.1039/
c2ra21487c. (b) Liang, R.; Li, S.; Wang, R.; Lu, L.; Li, F. Org. Lett. 2017, 19, 5790–5793.
DOI: 10.1021/acs.orglett.7b02723. (c) Deng, D.; Hu, B.; Yang, M.; Chen, D.
Organometallics 2018, 37, 3353–3359. DOI: 10.1021/acs.organomet.8b00575.
[13] (a) Li, Z.-L.; Cai, C. Org. Chem. Front. 2017, 4, 2207–2210. DOI: 10.1039/C7QO00625J.
(b) Li, Z-l.; Cai, C. ChemistrySelect 2017, 2, 8076–8079. DOI: 10.1002/slct.201701537.
[14] Xiao, J.; Su, Q.; Dong, W.; Peng, Z.; Zhang, Y.; An, D. J. Org. Chem. 2017, 82, 9497–9504.
DOI: 10.1021/acs.joc.7b01527.