Iron-Catalyzed Radical Methylation of Activated Alkenes with tert -Butanol as the Methyl Source

Article abstract of DOI:10.1055/s-0039-1690193

A free-radical-initiated methylation/addition/cyclization of N -arylacrylamides and a methylation/addition/elimination of quinines have been developed in which t -BuOH is used as a methyl source. These reactions provide effective and selective methods for the synthesis of various methylated oxindoles and quinones in moderate to good yields.

Full text of DOI:10.1055/s-0039-1690193

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
Z. Xu et al.
Letter
Synlett
Iron-Catalyzed Radical Methylation of Activated Alkenes with
tert-Butanol as the Methyl Source
Zhengbao Xu*a,c◊
Rui Jiab◊
Zhiwei Mac
Shouhao Caoc
Liang Shen*a,c
Hongfang Ji*a,c
CH3
O
R1
R1
N
O
N
R2
PhI(O2CCF3)2 (2 equiv)
Fe(acac)3 (2 mol %)
R2
OH
CH3
CH3
H3C
+
or
or
120 °C, 9 h
O
O
R1
R1
R1 = alkyl, halogen, methoxy, cyano
R2 = alkyl, phenyl, acetyl
a Institute of Biomedical Research, Shandong University of Technology,
Zibo, 255000, Shandong, P. R. of China
1208241003@qq.com
CH3
O
O
shen@sdut.edu.cn
yields up to 92%
facile and simple system
26 examples
jhf@sdut.edu.cn
b Zibo Meteorological Bureau, Zibo, 255000, Shandong, P. R. of China
c Shandong Provincial Research Center for Bioinformatic Engineering
and Technique, Zibo Key Laboratory of New Drug Development of
Neurodegenerative Diseases, School of Life Sciences, Shandong
University of Technology, Zibo, 255000, Shandong, P. R. of China
◊ These authors contributed equally to this work.
Received: 03.07.2019
Accepted after revision: 13.08.2019
Published online: 27.08.2019
Previous work:
a) Oxidant as the methyl source
DOI: 10.1055/s-0039-1690193; Art ID: st-2019-r0347-l
H3C
O
O
O
I
O
CH3
CH3
O
Abstract A free-radical-initiated methylation/addition/cyclization of
N-arylacrylamides and a methylation/addition/elimination of quinines
have been developed in which t-BuOH is used as a methyl source. These
reactions provide effective and selective methods for the synthesis of
various methylated oxindoles and quinones in moderate to good yields.
R1
R1
CH3
+
or
N
R2
O
N
R2
CH3
CH3
R3
CH3
R3
O O
CH3
Key words methylation, oxinidoles, quinones, arylacrylamides, qui-
nones, cascade reaction
b) DMSO as the methyl source
CH3
O
O
R1
R1
CH3
+
S
The methyl group is one of the most prevalent function-
al groups in biologically active molecules.1 In the field of
pharmaceutical chemistry, the so-called ‘magic methyl ef-
fect’ can often improve a molecule’s biological activity and
physical properties.2 Therefore, synthetic reactions that in-
stall methyl groups onto organic compounds with ease are
of value in organic and pharmaceutical chemistry. In recent
decades, methylation has been achieved by using various
methylated metal reagents,3 MeB(OH)2,4 MeI,5 DMSO,6
H3C
CH3
N
O
N
R2
R2
This work: t-BuOH as the methyl source
CH3
R1
R1
O
N
R2
N
R2
O
OH
CH3
+
H3C
CH3
CH3
O
O
O
R1
CH3
R1
9
AcOH,7 peroxides,8 or PhI(O2CMe)2 as sources of methyl
groups. However, most of these methylating reagents are
toxic and polluting. Therefore, more-efficient methylation
strategies and new methylating reagents are highly desirable.
Oxindoles and quinones are ubiquitous structural mo-
tifs that can be found in various natural products and bio-
logically active molecules.10,11 Recently, many methods
have been reported for the construction of alkylated oxin-
doles and quinones.12,13 Among these, radical-initiated
methylation/addition/cyclizations of N-arylacrylamides
have been reported by Zhu,14 Liu,15 Cheng,16 Li,17 and Chen18
and their respective co-workers (Scheme 1). To the best of
O
R1 = alkyl, halogen, methoxy, cyano
R2 = alkyl, phenyl, acetyl
R3 = methyl, phenyl
Scheme 1 Approaches to the methylation of activated alkenes
our knowledge, radical-initiated methylations of quinones
are rare.19 A longstanding challenging problem is that the
methylating reagents are not economical or environmental-
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Z. Xu et al.
Letter
Synlett
ly friendly. Here, we report the first example of a free-radi-
cal methylation of N-arylacrylamides or quinones by using
t-BuOH as a source of methyl radicals.
yield under the following optimal conditions: N-methyl-N-
phenylmethacrylamide (1 equiv, 0.2 mmol), PIFA (2 equiv,
0.4 mmol), Fe(acac)3 (0.02 equiv, 0.004 mmol), t-BuOH (2
mL), 120 °C, nine hours, sealed tube.
Initially, the reaction of N-methyl-N-phenyl(methacryl-
amide) with t-BuOH was chosen as a model reaction to op-
timize the reaction conditions (Table 1; also see the Sup-
porting Information). The desired product 3-ethyl-1,3-di-
methyl-1,3-dihydro-2H-indol-2-one (1) was obtained in
25% yield (Table 1, entry 1). Encouraged by this result, we
tested a series of other catalysts [Cu2O, CuBr, Cu(OAc)2,
Cu(acac)2, AgNO3, Fe(acac)2, Fe(acac)3, Mn(acac)2, Ni(acac)2,
and Pd(acac)2], and we found that Fe(acac)3 was most effi-
cient (entries 2–13). [Bis(trifluoroacetoxy)iodo]benzene
(PIFA) was found to be more efficient than other iodine re-
agents (entries 14 and 15). The desired product 1 was iso-
lated in 78% yield when 2 mol% of Fe(acac)3 was added (en-
try 16). Additionally, the yield of the product after nine
hours was better than that after six or 12 hours (entries 17
and 18). Finally, the desired product 1 was isolated in 78%
With the optimized conditions in hand, we examined
the scope of the substrates (Scheme 2). When various N-
protected substrates were employed, the desired products 1
and 12 were obtained in yields of 78 and 75%, respectively.
In contrast, N-acetyl- and N-phenyl-substituted substrates
gave the corresponding products 13 and 14 in moderate
yields. N-Arylmethacrylamides with halo (F, Cl, Br, or I), al-
kyl, or methoxy substituents in the para-position afforded
the corresponding products 2–9 in moderate to good yields,
whereas N-(4-cyanophenyl)methacrylamide, containing an
CH3
OH
PIFA
R1
+
R1
O
H3C
CH3
Fe(acac)3 (2 mol%)
N
R2
O
CH3
N
R2
Table 1 Modification of the Typical Conditionsa
CH3
O
CH3
O
CH3
Cl
F
CH3
O
N
OH
conditions
N
N
+
H3C
CH3
CH3
O
N
O
N
1, 78%
2, 80%
3, 83%
1
CH3
CH3
O
CH3
O
Br
I
O
Entry
Catalyst (mol %)
Iodine reagent
Time (h)
Yieldb (%)
N
N
N
1
2
Cu2O (5)
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
I2
9
9
25
5, 70%
6, 72%
4, 74%
CuBr (5)
13
CH3
O
CH3
CH3
O
O
3
Cu(OAc)2 (5)
Cu(acac)2 (5)
AgNO3 (5)
9
12
O
4
9
20
N
N
N
5
9
trace
50
9, 76%
7, 65%
8, 68%
6
Fe(OTf)2 (5)
Fe(acac)2 (5)
FeCl3∙6H2O (5)
Fe(acac)3 (5)
Mn(acac)2 (5)
Ni(acac)2 (5)
Pd(acac)2 (5)
–
9
CH3
O
CH3
O
CH3
O
7
9
66
NC
8
9
70
N
N
N
9
9
73
10, 54%
12, 75%
11, 50%
10
11
12
13
14
15
16c
17c
18c
9
32
CH3
CH3
9
51
CH3
O
O
9
16
O
N
N
N
Ph
9
trace
trace
trace
78
O
O
Fe(acac)3 (5)
Fe(acac)3 (5)
Fe(acac)3 (2)
Fe(acac)3 (2)
Fe(acac)3 (2)
9
13, 52%
14, 50%
15, 42%
I2O5
PIFA
PIFA
PIFA
9
CH3
9
Br
O
6
63
N
12
74
O
a Typical conditions: N-methyl-N-phenylmethacrylamide (1 equiv, 0.2
mmol), PIFA (3 equiv, 0.6 mmol), Fe(acac)3 (5 mol%), t-BuOH (3 mL),
120 °C, 9 h.
16, 40%
Scheme 2 Fe(acac)3-catalyzed free-radical cascade methylation of N-
arylmethacrylamides with t-BuOH. Reaction conditions: N-arylmethac-
rylamide (1 equiv, 0.2 mmol), PIFA (2 equiv, 0.4 mmol), Fe(acac)3 (2
mol%), t-BuOH (2 mL), 120 °C, 9 h.
b Isolated yield.
c Reaction conditions: N-methyl-N-phenylmethacrylamide (1 equiv, 0.2
mmol), PIFA (2 equiv, 0.4 mmol), Fe(acac)3 (2 mol%), t-BuOH (2 mL),
120 °C, 9 h.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

C
Z. Xu et al.
Letter
Synlett
Encouraged by the successful application of this method
to the synthesis of methylated oxindoles, we turned our at-
tention to the synthesis of methylated quinones by this
strategy. As shown in Scheme 3, we found that a wide range
of quinones with either electron-donating or electron-
withdrawing groups gave moderate to good yields of the
desired products 18–24. Furthermore, naphthoquinone and
2,6-dichlorobenzo-1,4-quinone gave 2,3-dimethylnaphtho-
quinone (17) and 2,6-dichloro-3,5-dimethylbenzo-1,4-qui-
none, respectively, as major products in yields of 31 and
30%. In the case of 2-methylbenzo-1,4-quinone, two prod-
ucts, 26 and 27, were obtained.
To verify the reaction mechanism, we performed radi-
cal-trapping experiments, and we found that none of the
desired product was obtained when TEMPO was added to
the system (Scheme 4; see also the Supporting Informa-
tion); moreover, the coupling product of TEMPO and a
methyl radical was detected by GC/MS, indicating that a
free-radical process would be involved in this system.
O
O
O
O
R1
R1
OH
PIFA
+
H3C
CH3
Fe(acac)3 (2 mol%)
CH3
CH3
O
O
O
O
CH3
CH3
Cl
CH3
O
CH3
O
18, 68%
19, 71%
17, 53%
O
O
O
O
O
Br
CH3
CH3
CH3
O
O
O
22, 74%
21, 65%
20, 70%
O
O
O
Cl
H3C
Cl
O
CH3
O
CH3
CH3
O
O
O
23, 92%
24, 62%
25, 56%
OH
PIFA (2 equiv)
O
O
+
N
O
N
Fe(acac)3 (2 mol%)
120 °C
H3C
CH3
CH3
H3C
O
CH3
2 mL
CH3
26, 16%
3 equiv (0.6 mmol)
CH3
detected by GCMS
CH3
O
O
27, 42%
OH
PIFA (2 equiv)
+
O
Scheme 3 Fe(acac)3-catalyzed free-radical cascade methylation of qui-
nones with t-BuOH. Reaction conditions: quinone (1 equiv, 0.2 mmol),
PIFA (2 equiv, 0.4 mmol), Fe(acac)3 (2 mol%), t-BuOH (2 mL), 120 °C, 5 h.
Fe(acac)3 (2 mol%)
TEMPO (3 equiv)
H3C
CH3
N
N
O
CH3
120 °C
2 mL
1 equiv (0.2 mmol)
not detected
Scheme 4 Mechanistic study
electron-withdrawing cyano group, gave product 10 in a
moderate yield. N-Methyl-N-(1-naphthyl)methacrylamide
gave the corresponding product 11 in 50% yield. To expand
the range of substrates further, this method also was con-
firmed to be efficient in the synthesis of the methylated iso-
quinolinediones 15 and 16 in moderate yields.
On the basis of these experiments and reports in the lit-
erature, we proposed the mechanism shown in Scheme 5.
First, PIFA oxidizes t-BuOH to produce a methyl radical,
which adds to the double bond in the N-arylmethacryl-
amide to give the radical intermediate A. Subsequently, in-
F3C
O
O
CF3
I
O
O
R1
N
R2
O
OH
CH3
heat
CH3
R1
CH3
H3C
N
R2
O
CH3
A
PhI
PIFA
GCMS detected
+
F3CCOO
Fe2+
Fe3+
CH3
O
CH3
O
CH3
H
H
R1
R1
R1
O
N
R2
N
R2
N
R2
B
F3CCOOH
GCMS detected
Scheme 5 Plausible mechanism
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

D
Z. Xu et al.
Letter
Synlett
tramolecular cyclization of radical intermediate A generates
radical intermediate B, which undergoes single-electron ox-
idation by Fe(III) and deprotonation by F3COO– to generate
the target product.
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In summary, the Fe-catalyzed methylation of activated
alkenes by using t-BuOH as a green methylating reagent has
been achieved.20 A sequential methyl-radical methyla-
tion/cyclization and methylation/elimination are involved
in this strategy, which provides a new method for the con-
struction of methylated oxindoles and quinones. Further
studies on the development of novel methylating reagents
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Funding Information
This work was supported by the Shandong Provincial Natural Science
Foundation (Grant No. ZR2018MH010), Shandong Provincial Key Re-
search and Development Program (Grant No. 2018GSF121001), and
the Talent Program of Zibo.
N
aturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
S
h
a
n
d
o
n
g
Pro
v
i
n
c
e
(Z
R
2
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1
8
M
H
0
1
0)
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690193.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
Primary Data
for this article are available online at https://doi.org/10.1055/s-0039-
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1690193 and can be cited using the following DOI: 10.4125/pd0106th. Pri
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© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

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Commun. 2014, 50, 3865.
tography (silica gel) to give a colorless liquid; yield: 78%.
1H NMR (400 MHz, CDCl3):  = 7.26 (t, J = 7.6 Hz, 1 H), 7.16 (d,
J = 7.2 Hz, 1 H), 7.07 (t, J = 7.6 Hz, 1 H), 6.85 (d, J = 7.6 Hz, 1 H),
3.21 (s, 3 H), 1.97–1.88 (m, 1 H), 1.81–1.72 (m, 1 H), 1.34 (s, 3
H), 0.57 (t, J = 7.6 Hz, 3 H). 13C NMR (101 MHz, CDCl3):  = 181.2,
143.2, 133.8, 127.6, 122.6, 122.4, 108.0, 49.1, 31.3, 26.1, 23.2,
8.7. MS (EI): m/z (%) = 189 (51.4), 160 (100.0).
(17) Fan, J.-H.; Zhou, M.-B.; Liu, Y.; Wei, W.-T.; Ouyang, X.-H.; Song,
R.-J.; Li, J.-H. Synlett 2014, 25, 657.
(18) Wang, G.; Wang, S.; Wang, J.; Chen, S.-Y.; Yu, X.-Q. Tetrahedron
2014, 70, 3466.
(19) (a) Coppa, F.; Fontana, F.; Minisci, F.; Barbosa, M. C. N.; Vismara,
E. Tetrahedron 1991, 47, 7343. (b) Commandeur, C.; Chalumeau,
C.; Dessolin, J.; Laguerre, M. Eur. J. Org. Chem. 2007, 3045.
2-Chloro-3-methylnaphthoquinone (19); Typical Procedure
A mixture of 2-chloronaphthoquinone (1 equiv, 0.2 mmol),
Fe(acac)3 (2 mol%, 0.004 mmol), PIFA (2 equiv, 0.4 mmol), and t-
BuOH (2 mL) was refluxed at 120 °C for 5 h. When the reaction
was complete, the mixture was concentrated under vacuum and
the residue was purified by flash column chromatography
(silica gel) to give a yellow solid; yield: 71%.
(20) 3-Ethyl-1,3-dimethyl-1,3-dihydro-2H-indol-2-one
(1);
Typical Procedure
A mixture of N-methyl-N-phenylmethacrylamide (1 equiv, 0.2
mmol), Fe(acac)3 (2 mol%, 0.004 mmol), PIFA (2 equiv, 0.4
mmol), and t-BuOH (2 mL) was refluxed at 120 °C for 9 h. When
the reaction was complete, the mixture was concentrated under
vacuum and the residue was purified by flash column chroma-
1H NMR (400 MHz, CDCl3):  = 8.13–8.07 (m, 2 H), 7.74–7.72 (m,
2 H), 2.32 (s, 3 H). 13C NMR (101 MHz, CDCl3):  = 182.5, 177.4,
144.8, 143.2, 134.1, 133.8, 131.5, 131.2, 127.1, 126.9, 14.4. MS
(EI): m/z (%) = 208 (4.1), 206 (13.3), 171 (100.0).
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E