Metal-free radical C-H methylation of pyrimidinones and pyridinones with dicumyl peroxide

Article abstract of DOI:10.1039/c6gc03355e

A new method for free radical methylation of pyrimidinones and pyridinones with dicumyl peroxide (DCP) under metal-free conditions is introduced. A 50 g-scale reaction could be performed safely at the desired concentration. The reaction solvent and DCP derivative were readily recovered by distillation. The product was purified by crystallization to minimize the amount of waste.

Full text of DOI:10.1039/c6gc03355e

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Metal-free radical C-H methylation of pyrimidinones and
pyridinones with dicumyl peroxide
Received 00th January 20xx,
Accepted 00th January 20xx
Pei-Zhi Zhang,a Jian-An Li,a Ling Zhang,a Adedamola Shoberu,a Jian-Ping Zou,a∗ Wei Zhangb*
DOI: 10.1039/x0xx00000x
www.rsc.org/
CH3
CH3
CH3
A new method for free radical methylation of pyrimidinones and
pyridinones with dicumyl peroxide (DCP) under metal-free
conditions is introduced. A 50 g-scale reaction could be performed
safely at desired concentration. The reaction solvent and DCP
derivative were readily recovered by distillation. The product was
purified by crystallization to minimize the amount of waste.
Ph
CH3
Ph
CH3
O
O
O
O
O
O
O
O
OH
O
OH
Ph
Ph
TBHP
CH3
DCP
CHP
DTBP
TBPB
previous work
Introduction of a methyl group could have a significant impact on
biological properties of the parent molecules.1 In the past decade, a
series C-H bond methylation reagents including organometals,2
methylborons,3 MeI/[Pd],4 organo-peroxides5 and other agents6
have been developed a valuable tool for late stage structure
modification in medicinal chemistry. Since the pioneer work from
CJ Li’s group,[5a] peroxide-promoted radical methylation reactions
with dicumyl peroxide (DCP), cumyl hydroperoxide (CHP), di-tert-
butyl peroxide (DTBP), tert-butyl hydroperoxide (TBHP), and tert-
butyl peroxybenzoate (TBPB) have been introduced for the
functionalization of C(sp2 )-H bonds.[5] These reported methods rely
on metal catalysis such as [Pd], [Cu], and [Fe] to produce the methyl
radical (Scheme 1). Introduced in this paper is a metal-free protocol
for methylation of pyrimidinones and pyridinones.
DCP
N
N
Pd(OAc)2
ref. 5a
CH3
R2
R2
DCP or
DTBP
R3
R3
FeCl2 or
Fe(OAc)2
N
R1
O
N
R1
ref. 5c-e
this work
O
O
NH
R2
DCP
CH3
R1
NH
R2
metal-free
R1
X
X
X = CH, N
Scheme 1 Peroxide-promoted radical methylation
Privileged pyrimidinone and pyridinone rings could be found in
natural products, agrochemicals and pharmaceuticals (Figure 1).7
They have been used as physiochemical templates in drug
discovery.8 Pyrimidinone and pyridinone scaffolds could be readily
assembled by condensation reactions of corresponding carbonyl
and amino compounds.9,10 We have recently reported a method for
direct trifluoromethylation of pyrimidinones and pyridinones.11
Introduced in this paper is
a method for methylation of
pyrimidinones and pyridinones with peroxides.
We started the project by screening peroxides and catalysts, and
exploring the reaction conditions for methylation of 2,6-
diphenylpyrimidin-4(3H)-one 1a. A set of reactions with TBPB in the
Fig. 1 Biologically acive pyrimidinones and pyridinones
presence of 10 mol% Cu(I&II) and Fe(II) catalysts afforded 5-
methylated product 3a in less than 31% (Table 1, entries 1−4). An
improved yield of 52% of 3a was obtained using AgNO3 as a catalyst
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(Table 1, entry 5). Surprisingly, we found that product could be
obtained in 54% yield in the absence of a catalyst (Table 1, entry 6).
After exploring other peroxides such as DTBP, TBHP, and DCP (Table
1, entries 7−14), it was found that DCP is a better reagent for
methylation. Further optimization of the reaction conditions
including the amount of DCP, reaction temperature, and solvents
intermediates are less stable. The reaction of 3-methylpyrimidin-
4(3H)-one afforded corresponding product 3a’ in 87% yield.
Extention of the reaction scope using pyridinones and other
heteroarenes was attempted (Table 3). 4,6-Diarylpyridinones
t
(HOAc, BuOH, DMSO, PhCl and H2O) (entries 15−21), it was found
that the reaction using 3 equiv. of DCP at 120 oC for 5 h in HOAc
could afford methylated product 3a in 73% yield (Table 1, entry 15).
HOAc is a good solvent which easily dissolves pyrimidinones and
pyridinones for reactions. Since no metal catalyst is required, the
reaction could be performed under air without special protection. It
is worth noting that reactions using 3 or 1.5 equiv. of DCP gave
similar results (Table 1, entries 15 and 16), but the reaction time is
significantly different.
Table 1 Optimization of reaction conditionsa
aReaction conditions: 1a (1 mmol), 2 (3 mmol) and catalyst (10 mol%, if
needed) in air. bIsolated yield. c1.5 equiv. of 2. d1:1 H2O and HOAc
Entry Catalyst
2
Solvent
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
tBuOH
DMSO
PhCl
Temp (oC) Time (h) Yield (%)b
1
2
CuCl
CuBr
Cu(OAc)2
FeCl2
AgNO3
—
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
DTBP
DTBP
TBHP
TBHP
CHP
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
120
120
120
120
10
10
10
10
10
5
25
21
31
15
52
54
35
56
10
32
22
40
37
72
73
71
45
25
43
30
34
3
4
5
6
7
CuBr
—
5
8
10
5
9
CuBr
—
10
11
12
13
14
15
16c
17
18
19
20
21
48
10
5
—
Table 2 Reactions of pyrimidinones 1 with DCPa,b
CuBr
Cu(OAc)2
AgNO3
—
DCP
DCP
5
DCP
10
5
a
Reaction conditions: 4 (1 mmol) and DCP (3 mmol) in HOAc (2 mL) at 120
DCP
DCP
oC for 5 h in air; b Isolated yield; c4 h; d24 h; eN.D. means not detected
—
10
5
—
DCP
bearing an electron-donating group such as Me and MeO on the
phenyl ring gave 3-methylated products in 55% to 79% yields (5a-g,
5l, 5n). Reactions of 4,6-diarylpyridinones bearing electron-
withdrawing groups such as F and Cl on the phenyl ring afforded
products in 61% and 62% yields, respectively (5h and 5i). However,
reactions of 4,6-diarylpyridinones containing a bromo substituent
only gave products in low yields of 33-41% (5j, 5k and 5m) probably
due to low stability of the bromine group under radical conditions.
—
DCP
5
—
DCP
5
—
DCP
5
—
DCP
H2O+HOAcd
5
Under the optimized reaction conditions, a series of pyrimidin-
4(3H)-ones 1 was employed for methylation (Table 2).12 Most
reactions occurred smoothly to afford corresponding C-5
methylated products 3. A variety of substituents, such as Me, MeO,
F, Br and Cl, on the phenyl ring of pyrimidinones are tolerated to
give products in good to excellent yields (Table 2, 3a-k). As a result
of steric hindrance, yields of 3c and 3f were slightly lower than 3b
and 3g. Reactions of 6-methyl-2-phenylpyrimidinone and 2-methyl-
6-phenylpyrimidinone also gave 3l and 3m in satisfactory yields.
However, reactions of nonphenyl-substituted pyrimidinones could
not afford methylated products 3n-p probably because their radical
Reactions
of
6-methyl-4-phenylpyridinone
and
4-
isopropyloxycarbonyl-6-methylpyridinone-2 gave products 5o and
5p in 65% and 51% yields, respectively. Reaction of quinolin-2(1H)-
one and methyl indolyl-2-carboxylate afforded the corresponding
products 5q and 5r, but in low yields. No product 5s was observed
from the reaction of pyridin-2-one.
To demonstrate the scalability of the methylation reaction, a 50
g-scale reaction of 5-methyl-2,6-diphenylpyrimidin-4(3H)-one 3a
2 | J. Name., 2012, 00, 1-3
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was performed as illustrated in Scheme 2. A mixture of 2,6- Scheme 2 Scale-up reaction with 50 g of 1a
diphenylpyrimidin-4(3H)-one 1a (50.85 g, 205 mmol) and DCP
(166.1 g，615 mmol) in HOAc (400 mL) was stirred at 120 oC until
A radical-trapping experiment was carried out to gain the insight
the completion of the reaction (monitored by TLC). The reaction
mixture was distilled under reduced pressure to give the crude
product along with the recovered HOAc (390 mL) and DCP
derivative acetophenone (130 mL, 133.9 g, 1.116 mol). After work-
up, the crude product was recrystallized in EtOAc to afford pure
compound 3a (37.7 g, 70% yield). It is a greener process in which
solvent AcOH and DCP derivative acetophenone were recovered,
and the product was purified by simple crystallization. It is
noteworthy that heating large amount of peroxide at high
temperature is potentially dangerous. Caution should be taken to
control the reaction at relatively low concentration (< 0.1 M) to
ensure a safe operation.
of the reaction mechanism. The result shown that the yield of 3a
was decreased to 9% if
2 equiv. of 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) was added to the reaction system (Scheme
3 (a)). Detection of methylated TEMPO 6 by LC-MS indicated the
methylation is
a radical reaction process. On the basis of
experimental data and literature information,5f a mechanism for the
reaction of 2,6-diphenylpyrimidin-4(3H)-one 1a is proposed in
Scheme 3 (b). Upon heating, homolysis of DCP produces cumyloxyl
radical 7. β-Scission of alkoxy radical generates a methyl radical and
acetophenone 8. The methyl radical selectively adds to the 5-
position of 1a to form radical 9 followed by aromatization to form
product 3a.
Table 3 Reactions of pyridinones 4 with DCPa,b
O
O
H3C
Ph
DCP (3 equiv)
NH
Ph
NH
N
O
+
Ph
(a)
TEMPO (2 equiv)
O
O
Ph
N
HOAc, 120 o
C
N
CH3
H3C
R1
DCP
NH
R2
NH
R2
1a
3a, 9%
6
HOAc
R1
120 oC, air
4
CH3
5
Ph
O
H3C
O
120 o
C
O
O
O
O
O
H3C
H3C
H3C
H3C
H3C
NH
NH
NH
DCP
7
8
Ph
CH3
(b)
O
O
O
5a
5d
H
, 74%
5b
, 67%
5c, 55%
7
CH3
CH3
Ph
NH
NH
Ph
NH
Ph
O
O
O
H3C
H3C
Ph
N
Ph
N
OH
Ph
Ph
N
NH
NH
NH
3a
9
1a
H3CO
CH3O
5e, 79 %c
, 61%
O
5f
, 71%
O
Scheme 3 Radical-trapping and proposed reaction mechanism
O
H3C
H3C
NH
NH
NH
Conclusions
OCH3
F
Cl
In conclusion, we have developed a method for metal-free radical
methylation of pyrimidinones and pyridinones using dicumyl
5i
5h
, 62%
5g
, 61%
, 61%
O
O
O
H3C
peroxide (DCP) as
a methylation reagent. This protocol has
H3C
H3C
NH
NH
NH
potential application for other heteroarenes such as quinolinones
and indoles. Without using an air sensitive metal-catalyst, the
reaction could be carried out under air. A scale-up reaction with 50
g of a pyrimidinone derivative afforded methylated product in 70%
yield. Reaction solvent (HOAc) and the DCP derivative
(acetophenone) could be readily recovered by distillation, and the
product was purified by crystallization. A minimal amount of waste
was produced from this reaction process.
OCH3
Br
Br
Br
5j
, 35%
5k, 41%
5l, 66%d
O
O
O
H3C
H3C
H3C
NH
NH
NH
CH3O
Br
Br
5o, 65%
5n
, 74%
5m
, 33%
O
H
N
H
O
O
N
H3C
NH
CO2CH3
NH
Acknowledgements
H3C
PrO2C
CH3
, 22%
5p, 51%e
5q
, 45%
5s, N.D.f
5r
J.-P.Z. expresses gratitude to the National Natural Science
Foundation of China for providing grants (Nos. 20772088,
21172163, 21472133), and also the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD) &
State and Local Joint Engineering Laboratory for Novel Functional
Polymeric Materials for their financial support.
a
Reaction conditions: 4 (1 mmol) and DCP (3 mmol) in HOAc (2 mL) at 120
oC for 5 h in air; b Isolated yield; c4 h; d3 h; e24 h; fN.D. means not detected
Notes and references
1. For selected recent reviews on the methylation reactions, see:
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methylpyrimidinone
3a.
To
a
solution
of
2,6-
diphenylpyrimidin-4-one 1a (0.25 g, 1 mmol) in acetic acid (2
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6GC03355E
Journal Name
mL) was added dicumyl peroxide (DCP) (0.81 g, 3 mmol). The
COMMUNICATION
mixture was stirred at 120 oC in air for 5 h, after the
completion of the reaction, water (10 mL) was added and then
extracted with AcOEt (3 x 10 mL). The combined organic
fractions were washed with aqueous NaHCO3 (3 x 15 mL) and
water (2 x 15 mL), and then dried over anhydrous Na2SO4. The
concentrated crude product was purified by flash column
chromatography (silica gel, 10:1 petroleum ether/AcOEt) to
give 2,6-diphenyl-5-methyl pyrimidinone 3a (191 mg, 73%
yield).
Graphical Abstract
Abstract: A method for free radical methylation of pyrimidinones and pyridinones with dicumyl peroxide (DCP)
under metal-free condition is introduced. A 50 g-scale reaction could be performed safely at desired
concentration. The reaction solvent and DCP derivative were readily recovered by distillation. The product was
purified by crystallization to minimize the amount of waste
.
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