An Iron(II) Chloride-Promoted Radical Cascade Methylation or α-Chloro-β-methylation of N-Arylacrylamides with Dimethyl Sulfoxide

Article abstract of DOI:10.1002/adsc.201601001

A free radical-initiated methylation and/or α-chloro-β-methylation of N-arylacrylamides with dimethyl sulfoxide under the analogous Fenton reaction condition has been developed, which provides an effective and facile cascade strategy for the synthesis of oxindoles and chlorinated amides. (Figure presented.).

Full text of DOI:10.1002/adsc.201601001

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DOI: 10.1002/adsc.201601001
An Iron(II) Chloride-Promoted Radical Cascade Methylation or
a-Chloro-b-methylation of N-Arylacrylamides with Dimethyl
Sulfoxide
Zejiang Li,a,* Xiaosong Cui,+a Lin Niu,+a Yingming Ren,+a Menghua Bian,+a
Xuebiao Yang,+a Biao Yang,+a Qinqin Yan,a,* and Jincan Zhaoa
a
College of Chemistry & Environmental Science, Hebei University, Baoding, Hebei 071002, Peopleꢀs Republic of China
E-mail: lizejiang898@126.com or yanqin_9397@126.com
+
These authors contributed equally to this work.
Received: September 8, 2016; Revised: October 26, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201601001.
Abstract: A free radical-initiated methylation and/
or a-chloro-b-methylation of N-arylacrylamides
with dimethyl sulfoxide under the analogous
Fenton reaction condition has been developed,
which provides an effective and facile cascade strat-
egy for the synthesis of oxindoles and chlorinated
amides.
ation. After a lot of attempts, we successfully accom-
plished the first example of a free radical cascade
methylarylation or a-chloro-b-methylation of N-aryl-
AHCTUNGTREGUNaNN crylamides by making use of dimethyl sulfoxide as
methyl regent, iron(II) chloride as catalyst and chlor-
ine source, and hydrogen peroxide as oxidant, which
is similar to the Fenton reaction conditions
(Scheme 1).[17]
Keywords: N-arylacrylamides; a-chloro-b-methyla-
tion; cyclization; methylation; radical reactions
The so-called “magic methyl effect” makes methyla-
tion very popular in synthetic organic chemistry.[1]
The introduction of a methyl group into organic mole-
cules could improve their biological and chemical
properties.[2] In the past decades, although several
methylating protocols have been achieved by using
Scheme 1. Methylation or methylchlorination of alkenes
with dimethyl sulfoxide.
methyl-metal
reagents,[3]
MeI,[4]
DMSO,[5]
MeCOOH,[6] peroxides[7–8] etc. as methylating re-
agents, more practical methods remain highly desira-
ble.
Initially, N,N-diphenylmethacrylamide and dimethyl
sulfoxide were chosen as the model molecules to test
Oxindole and its derivatives have drawn much at- the reaction conditions (Table 1, also see the Support-
tention from chemists.[9,10] Recently, alkyl-substituted ing Information for details). It was found that the
oxindoles which are prepared from cascade methyla- yield of the product in 18 hours is better than that in
tion of N-arylacrylamides by employing oxides or per- 6 and 12 hours (entries 1–3). No product was obtained
oxides as the methyl source have been reported by without any catalyst (entry 4). Variation of the
Liu,[7,8] Zhu,[11] Cheng,[12] Li,[13] Chen,[14,15] and others. amount of iron(II) chloride and hydrogen peroxide
But challenging problems such as high-cost methyl re- greatly affected the reaction efficiency (entries 5–12).
agents and oxidants remain to be addressed so far. Addition of 1 mL, 2 mL and 4 mL of dimethyl sulfox-
Herein, in combination with our studies on radical ide generated the desired product 1 in 61%, 70%, and
cascade reactions,[16] we have developed a system 83% yields, respectively (entries 13–15). Finally, the
which holds the advantages of common and economi- terminal product 1 was isolated in 85% yield under
cal methyl sources as well as oxidants, and easy oper- the optimal conditions: N-arylacrylamides (1 equiv.,
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Table 1. Optimization of the typical conditions.[a]
Table 2. Iron-promoted free radical cascade methylation of
N-arylacrylamides with dimethyl sulfoxide.
Entry Iron(II) chlo- Hydrogen peroxide Time Yield
ride [equiv.]
(30%) [equiv.]
[h]
[%][b]
1
2
3
4
5
6
7
8
0.5
0.5
0.5
–
0.1
0.2
0.3
1.0
0.5
0.5
0.5
0.5
0.5
5
5
5
5
5
5
5
5
1
2
3
4
5
5
5
6
50
58
85
n. r.
6
59
64
75
47
69
73
75
61
70
83
12
18
18
18
18
18
18
18
18
18
18
18
18
18
9
10
11
12
13[c]
14[d] 0.5
15[e] 0.5
[a]
Reaction
conditions:
N,N-diphenylmethacrylamides
(1 equiv., 0.25 mmol), DMSO (3 mL), 258C, N2.
Isolated yields.
DMSO (1 mL).
DMSO (2 mL).
DMSO (4 mL).
[b]
[c]
[d]
[e]
[a]
Reaction
conditions:
N-arylacrylamides
(1 equiv.,
0.25 mmol), iron(II) chloride (0.5 equiv., 0.125 mmol),
hydrogen peroxide (30%, 5 equiv., 1.25 mmol) and
DMSO (3 mL), 258C, N2, 18 h.
0.25 mmol), FeCl2 (0.5 equiv., 0.125 mmol), H2O2
(30%, 5 equiv., 1.25 mmol) and DMSO (3 mL), 258C,
N2, 18 h, sealed tube.
[b]
Isolated yields.
With the modified conditions in hand, this system
was used to investigate the substrate scope (Table 2). methyl]-N-methyl-N-phenylacrylamide resulted in the
As can be seen, the N-methyl- and N-benzyl-substitut- products 12 and 13 in 76% and 53% yields, respec-
ed substrates gave the corresponding desired products tively. Meanwhile, under the best conditions, this reac-
in 60% and 76% yields, respectively (2 and 3). Halo- tion could be scaled up to the gram level easily [Eq.
gen atoms such as Cl, Br and I substituted on the (1)].
acrylamides afforded the products in moderate yields
We next found that N–H substituted N-phenylme-
(4–6). Only the N-arylacrylamides with electron-do- thacrylamides underwent an a-chloro-b-methylation
nating groups could react well in the system (7–11), reaction rather than the methylarylation reaction. The
which also indicated that the steric effect was not so reason is that it is difficult to bring in a conformation
obvious. Notably, 2- [methyl(phenyl)carbamoyl]allyl for direct N–H substituted substrates. A series of ex-
acetate and 2-[(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)- periments was also complied to modify the reaction
conditions (see the Supporting Information for de-
tails). Then, we began to study the substrate scopes
under the optative condition (Table 3). We can see
that substrates with both electron-donating and with-
drawing groups could be tolerated in the system (14–
21), although the desired products were isolated in
low yields. Furthermore, N-naphthyl- and N-benzyl-
substituted methacrylamides gave products 22 and 23
in 31% and 30% yields, respectively.
The reaction was inhibited when TEMPO was
added to the system. It suggests that a free radical
process would be involved in this system. According
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Table 3. Iron-promoted free radical a-chloro-b-methylation
of N-arylacrylamides with dimethyl sulfoxide.
tance of iron(II) chloride, intermediate A undergoes
a heterolysis reaction and forms hydroxy ion and free
radical B. Methyl radical and methylsulfinyl acid are
gained by b-cleavage of radical B. Next, radical C is
formed via the additon of methyl radical to the
double bond of N-arylacrylamides. Then, radical C
adds to the aromatic ring and generates radical D,
which can be oxidized by iron(III) and yields the car-
bocation E. The terminal product is produced by the
hydroxy ion pulling the proton from the carbocation
E. With N–H substituted substrates, the radical C ab-
stracts a chlorine atom from iron(II) chloride and
gives the a-chloro-b-methylation product.
In summary, we have achieved the first economical
and convenient protocol for free radical-triggered cas-
cade methylation or a-chloro-b-methylation of N-ary-
lacrylamides by means of dimethyl sulfoxide as
methyl source, iron(II) chloride as both catalyst and
chlorine source. Further studies on methylation reac-
tions via the novel free radical approach are under
way in our laboratory.
Experimental Section
General Experimental Procedure
A
mixture of N,N-diphenylmethacrylamide (1 equiv.,
0.25 mmol), iron(II) chloride (0.5 equiv., 0.125 mmol), hy-
drogen peroxide (5 equiv., 1.25 mmol) and DMSO (3 mL)
was stirred at room temperature under nitrogen conditions
for 18 h in a sealed tube (15 mL). After the reaction had fin-
ished, the mixture was extracted with ethyl acetate and
water, evaporated under vacuum and purified by column
chromatography to afford the desired methylation product.
[a]
Reaction
conditions:
N-arylacrylamides
(1 equiv.,
0.25 mmol), iron(II) chloride (1 equiv., 0.25 mmol), hy-
drogen peroxide (30%, 5 equiv., 1.25 mmol) and DMSO
(3 mL), 258C, N2, 18 h.
A
mixture of N-phenylmethacrylamide (1 equiv.,
[b]
Isolated yields.
0.25 mmol), iron(II) chloride (1 equiv., 0.25 mmol), hydro-
gen peroxide (5 equiv., 1.25 mmol) and DMSO (3 mL) was
stirred at room temperature under nitrogen conditions for
18 h in a sealed tube (15 mL). After the reaction finished,
the mixture was extracted with ethyl acetate and water,
evaporated under vacuum and purified by column chroma-
tography to afford the desired a-chloro-b-methylation prod-
to the literature[18] precedent study and experimental
data, a possible mechanism is shown in Scheme 2. The
intermediate A is produced by the reaction of dimeth-
yl sulfoxide with hydrogen peroxide. With the assis- uct.
Scheme 2. Plausible mechanism.
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This project is supported by College of Chemistry & Envi-
ronmental Science, Hebei University, and the Fundamental
Research Funds for The Midwest Universities Comprehensive
Strength Promotion Project. We also thank science technolo-
gy research and development Guidance programme project
of Baoding City (No. 15ZG040) for financial support.
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An Iron(II) Chloride-Promoted Radical Cascade
Methylation or a-Chloro-b-methylation of N-
Arylacrylamides with Dimethyl Sulfoxide
5
Adv. Synth. Catal. 2017, 359, 1 – 5
Zejiang Li,* Xiaosong Cui, Lin Niu, Yingming Ren,
Menghua Bian, Xuebiao Yang, Biao Yang, Qinqin Yan,*
Jincan Zhao
Adv. Synth. Catal. 0000, 000, 0 – 0
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