Copper-catalyzed methylation of 1,3-diketones with tert-butyl peroxybenzoate

Article abstract of DOI:10.1016/j.tet.2017.03.058

Copper-catalyzed radical methylation of 1,3-diketones with tert-butyl peroxybenzoate in air is described, providing a general pathway to α-methyl 1,3-diketones in moderate to good yields. This protocol has been scaled up to 50?g, and one of the synthesized products can be used in the synthesis of medicine, Rosuvastatin.

Full text of DOI:10.1016/j.tet.2017.03.058

Accepted Manuscript
Copper-catalyzed methylation of 1,3-diketones with tert-butyl peroxybenzoate
Zhi-Hao Zhou, Cheng-Kun Li, Shao-Fang Zhou, Adedamola Shoberu, Jian-Ping Zou
PII:
S0040-4020(17)30307-1
10.1016/j.tet.2017.03.058
TET 28564
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 February 2017
Revised Date: 19 March 2017
Accepted Date: 21 March 2017
Please cite this article as: Zhou Z-H, Li C-K, Zhou S-F, Shoberu A, Zou J-P, Copper-catalyzed
methylation of 1,3-diketones with tert-butyl peroxybenzoate, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.03.058.
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Copper-catalyzed methylation of 1,3-diketones with
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tert-butyl peroxybenzoate
Zhi-Hao Zhou, Cheng-Kun Li, Shao-Fang Zhou, Adedamola Shoberu and Jian-Ping Zou *
Key Laboratory of Organic Synthesis of Jiangsu Province,,College of Chemistry and Chemical Engineering,
Soochow University, 199 Renai Street, Suzhou, Jiangsu 215123, China.

1
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Tetrahedron
journal homepage: www.elsevier.com
Copper-catalyzed methylation of 1,3-diketones with tert-butyl peroxybenzoate
Zhi-Hao Zhou, Cheng-Kun Li, Shao-Fang Zhou, Adedamola Shoberu and Jian-Ping Zou *
Key Laboratory of Organic Synthesis of Jiangsu Province,,College of Chemistry and Chemical Engineering, Soochow University, 199 Renai Street, Suzhou,
Jiangsu 215123, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Copper-catalyzed radical methylation of 1,3-diketones with tert-butyl peroxybenzoate in air is
described, providing a general pathway to α-methyl 1,3-diketones in moderate to good yields.
This protocol has been scaled up to 50g, and one of the synthesized products can be used in the
synthesis of medicine, Rosuvastatin.
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
Keyword_1 1,3-diketone
Keyword_2 methylation
Keyword_3 copper catalyst
Keyword_4 radical reaction
1. Introduction
The introduction of methyl groups into organic molecules can
improve the physical properties and bioactivities of biologically
active molecules, hence, methylation reaction has aroused much
1
interest in recent years. α-Methyl-1,3-diketones are widely
employed for the preparation of medicines and agrochemicals,2
e.g. 1-(4-fluorophenyl)-2,4-dimethylpentane-1,3-dione (I) has
been used for the preparation of Rosuvastatin calcium (II)
(Scheme 1, eq 1) which could treat hyperchol-esterolemia,
3
hyperlipoproteinemia and atherosclerosis;
α-Methyl-1,3-
diketones (III) have been employed in the synthesis of pesticides
(IV, V)4 and fungicides (VI)5 (Scheme 1, eqs 2 and 3). One of the
most important routes to α-methyl-1,3-diketones is through
methylation reaction. The traditional process involves the use of
a strong base and poisonous methyl iodide (Scheme 2, eq 1). 3b, 6
Thus, the development of new routes and reagents for the
methylation of 1,3-diketones is highly desirable. In 2008, the Li’s
group first reported that organic peroxides could be used as a
methyl source for the methylation of arenes in the presence of
palladium catalysts.7 Thereafter, several groups have employed
organic peroxides as the methylating reagent for N-, O- or C-
methylation and oxidative methylation–cyclization of alkenes.1c,
Scheme 1. Application of
α-methyl-1,3-diketones in medicines,
pesticides and fungicides synthesis.
O
O
O
O
O
O
Base / CH3I
R1
eq 1
O
R
R1
R
R
O
O
Ph
O O
1f, 1g, 1h, 1k, 1l
eq 2
In continuation of our effort on the organic peroxides
R
R1
R1
promoted methylation of organic molecules,8 herein, we report a
novel methylation protocol for the preparation of α-methyl-1,3-
diketones (Scheme 2, eq 2), this protocol features selective
monomethylation in air with tert-butyl peroxybenzoate (TBPB),
short reaction time (0.5 h), thus avoiding the use of poisonous
methyl iodide, scaling up to 50g level, and applying the
synthesized 1-(4-fluorophenyl)-2,4-dimethylpentane-1,3-dione
(I) for synthesis of the medicine, Rosuvastatin.
R, R1 = aryl, heteroaryl, alkyl
This work
Scheme 2. α-Methylation of 1,3-diketones
2. Results and Discussion
Initially, we began by investigating the reaction of 1,3-
diphenylpropane-1,3-dione (1a) with di-tert-butyl peroxide
(DTBP) (1.0 mmol)) using CuI catalyst (10 mol %) in 10 mL
AcOH under air at 100 °C. To our delight, the desired product 2a

2
Tetrahedron
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was obtained in a low yield of 33% (Table 1, entry 1). By
yield respectively. Also, an enol substrate underwent methylation
increasing the amount of DTBP used, we found that an optimal
use of 3 eq. of the oxidant resulted in an improved 71% yield of
2a (Table 1, entries 2-4). No reaction was observed in the
absence of CuI (Table 1, entry 5) which indicates that the Cu salt
was essential for the formation of product. Also, we employed
other Cu salts and found CuCl to be the most effective catalyst
giving product 2a in 87% yield (Table 1, entries 6-7). The choice
of oxidant was also varied; when tert-butyl hydroperoxide
(TBHP) was used in place of DTBP, the reaction became
complex and only 30% yield of product 2a could be obtained
(Table 1, entry 8). However, the use of tert-butyl peroxybenzoate
(TBPB) gave a very satisfactory yield of 91% (Table 1, entry 9).
After screening the reaction temperature and time, the optimized
to produce a good yield of product 2o. Remarkably, the reaction
involving aliphatic and cyclic 1,3-diketones also occurred giving
products 2m and 2n respectively; the low yield of 2m (41%) may
be attributed to the steric hindrance caused by the tertiary butyl
group. Finally, the benzoyl ethyl acetate was reacted with TBPB,
no reaction was observed (2r), hence this protocol is selective.
Table 2. Scope of 1,3-dicarbonyl compoundsa
reaction conditions were
a combination of 1,3-diketone
/TBPB/CuCl (1:3:0.1) in AcOH for 0.5 h under air at 120 °C
(Table 1, entry 10).
Table 1. Optimization of the reaction conditionsa
a Reaction conditions: the mixture of 1 (1.0 mmol), CuCl (10 mol %),
and tert-butyl peroxybenzoate (TBPB) was heated in HOAc (10 mL)
at 120 oC for 30 mins under air.
b The reaction was performed at 140 oC for 4h.
Subsequently, we investigated the scope of mono- or bis-
heteroaryl 1,3-diketones. As shown in Table 3, a wide range of
substrates reacted readily including both electron-deficient and
electron-rich heteroaryls, thereby producing the corresponding
methylated products in varying yields. Notably, α-
monomethylation 4g and bismethylation 4g' were generated by
substrate 1-(pyridin-2-yl)butane-1,3-dione (3g) under standard
procedure, however only 4g was produced when 1.2 equivalent
TBPB was used. In addition, we found that the isolated product
4g can be totally converted to 4g' when reacted with 5
equivalents of TBPB; this result indicated that the bismethylation
product was generated from the α-monomethylation compound.
A reasonable explanation for this experimental result could be the
chelation of the Cu salt with N-atom and methine carbon. 9 This
metal-chelate function may activate the methine so that the
bismethylation derivatives can also be generated. To verify this
hypothesis, we carried out the reactions of substrates 1-(quinolin-
2-yl)butane-1,3-dione (3h), 1-(1H-pyrrol-2-yl)butane-1,3-dione
(3i) and 1-(1-methyl-1H-pyrrol-2-yl)butane-1,3-dione (3i’) under
standard conditions. Fortunately, a similar result was observed
with 3h where the ratio of derivatives 4h/4h’ was 3:1; with 3i
however, the bismethylation product was not detected but rather
the N-methylation compound 4i’ after 10 minutes (see footnote
e). Meanwhile, only product 4i’ was obtained when 3i’ was
employed (see footnote g), this is probably because the angle of
chelation between Cu salt and N-atom was too wide. Another
a Reaction conditions: the mixture of 1a (1.0 mmol), catalyst (10 mol %),
and oxidant (di-tert-butyl peroxide (DTBP), tert-butyl hydroperoxide
(TBHP), tert-butyl peroxybenzoate (TBPB)) was heated in HOAc
(10 mL) under air.
b Isolated yield.
c N. R. means no reaction.
With the optimal reaction conditions in hand, we explored the
scope of 1,3-dicarbonyl derivatives (Table 2). A variety of
substituted aromatic, aliphatic and cyclic 1,3-diketones reacted
with TBPB to give methylated products in moderate to good
yields (30 90%). Electronic effect was found to play a
significant role during the methylation process. With diketones
bearing electron-donating groups on the aromatic rings, the
reaction took place smoothly resulting in good yields (2b-2g). It
is noteworthy that halogens were also tolerated under our copper-
catalyzed protocol (2h-2j, 2q). However, low yields of products
were obtained when the phenyl rings contains an electron-
withdrawing substituent (e.g. 2k) or different substituent types
(e.g. 2j). In addition, the reactions of unsymmetrical diketones
containing aromatic-ethyl, aromatic-cyclohexyl and aromatic-
isopropyl 1,3-dicarbonyl derivatives all occurred smoothly to
afford methylated products, 2l, 2p and I in 68%, 77% and 61%

3
interesting result was the simultaneous formation of products 4j
and 4j’ even when TBPB was decreased to 0.99 equivalent. Thus,
an acetone molecule. The CuII species generated from CuI by
ACCEPTED MANUSCRIPT
SET process, could coordinate with 1a to form complex 6, which
was attacked by methyl radical to afford α-monomethylation
product 2a along with the release of CuI, which participated in
the reaction again.
a
competing reaction was taking place between α-
monomethylation on 1,3-dicarbonyls and methylation on 2-furyl
ring.
Table 3. Scope of 1,3-diketones bearing heteroaryl ring
Scheme 3. Synthetic applications
a Reaction conditions: 3 (1.0 mmol), TBPB (3.0 mmol), CuCl (10 mol %)
in HOAc (10 mL) at 120 for 30 mins under air except for otherwise
noted;
b Generated by substrate 3g, 4g:4g' = 4:1;
c 1.2 mmol TBPB;
d Generated by substrate 3h, 4h:4h' = 3:1.
e Generated by substrate 3i, 4i:4i' =3:1;
f 10 mins;
Scheme 4. Radical capture experiment and proposed mechanism
g Generated by substrate 3i';
3. Conclusion
h Generated by substrate 3j, 4j:4j' =1.6:1.
In summary, we have developed a copper-catalyzed, direct and
selective radical methylation of 1,3-diketones with tert-butyl
peroxybenzoate, providing a friendly and general way for
synthesis of α-methyl-1,3-diketones in moderate to good yields.
This methodology involves neither the use of methyl iodide, or
inert conditions. It requires a short reaction time and can be
scaled up to 50g level. Also, the synthesized 1-(4-fluorophenyl)-
2,4-dimethylpentane-1,3-dione was shown to be a vital starting
material in the synthesis of the medicine, Rosuvastatin.
To further demonstrate the practicability of this methodology,
30 gram-scale preparation of α-mono-methylated 1,3-dicarbonyl
compounds was performed as illustrated in Scheme 3 (a). 1,3-
Diphenylpropane-1,3-dione 1a (50.0 g, 222.5 mmol) was
converted to 2a (31.8 g, 133.5 mmol) in 60% isolated yield.
Besides, another utility is shown in Scheme 3 (b), where I can be
employed as an important intermediate in the synthesis of
Rosuvastatin. Compared with the traditional method of
synthesizing I which involves the use of poisonous MeI and
refluxing for 48 h, this copper-catalyst protocol offers a friendly
and rapid method of carrying out the α-monomethylation of 1-(4-
fluorophenyl)-2,4-dimethylpent-ane-1,3-dione.
4. Experimental Section
4.1. General
1H NMR (400 MHz) and 13C NMR (101 MHz) spectra were
determined with CDCl3 or DMSO-d6 as solvent and
tetramethylsilane (TMS) as internal standard. Chemical shifts were
reported in ppm from internal TMS (δ); all coupling constants (J
values) were reported in hertz (Hz). High-resolution mass spectra
were recorded on a TOF machine (ESI). Column chromatography
was performed with 300−400 mesh silica gel using flash column
techniques. All of the reagents were obtained commercially and used
directly unless otherwise noted.
Furthermore, a radical capture experiment was conducted to
help gain insight on the reaction pathway. As shown in Scheme 4,
the addition of the widely known radical-scavenger, 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO, 3.0 eq) inhibited the
methylation reaction completely and 2a was not detected.
Moreover, the structure 5 formed from a methyl radical capture
by TEMPO was detected by LC-MS, thus this result
impliedstrongly the involvement of a radical intermediate.
On the basis of these experimental results, a proposed
mechanism is outlined in Scheme 4. Initially, a tert-butoxy
radical could be generated by single-electron transfer of CuI to
TBPB, then it converted to a methyl radical through the loss of
4.2. General procedure for the methylation of 1,3-diketones (1
and 3).

4
Tetrahedron
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Typical procedure for the preparation of 2-methyl-1,3-
Yellow oil, 88% yield (236 mg); 1H NMR (400 MHz, CDCl3):
diphenylpropane-1,3-dione (2a). To a solution of acetic acid (10
mL) containing 1,3-diphenylpropane-1,3-dione (1a) (0.224 g, 1.0
mmol) and CuCl (0.010 g, 0.1 mmol) was added tert-butyl
peroxybenzoate (0.56 mL, 3.0 mmol), then the mixture was
δ 8.00–7.90 (m, 4H), 7.58–7.51 (m, 1H), 7.43 (t, J = 7.7 Hz, 2H),
6.98–6.89 (m, 2H), 5.22 (q, J = 7.0 Hz, 1H), 3.85 (s, 3H), 1.58 (d,
J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 197.4, 196.0,
163.9, 135.8, 133.5, 131.0, 128.9, 128.6, 114.2, 55.6, 51.0, 14.6.
MS (ESI-TOF) m/z: (M+H)+ Calcd for C17H17O3 269.1, found
269.1.
heated at 120
for 0.5 hours, after completion of reaction
(monitored by TLC), the solvent was removed under vacuum and
the residue was neutralized by aqueous NaHCO3 solution and
extracted with DCM (10 mL × 3). The combined organic
fractions were dried over anhydrous MgSO4, and concentrated
under vacuum to obtain the crude product, which was purified by
column chromatography (silica gel, petroleum ether/EtOAc
(95:5)) to give pure 2-methyl-1,3-diphenylpropane-1,3-dione
(2a).
2-Methyl-1,3-bis (p-tolyl) propane-1,3-dione (2e) 11
1
Yellow solid, 74% yield (197 mg), mp 135–137 ℃; H NMR
(400 MHz, CDCl3): δ 7.85 (d, J = 8.3 Hz, 4H), 7.23 (d, J = 8.0
Hz, 4H), 5.20 (q, J = 7.0 Hz, 1H), 2.39 (s, 6H), 1.58 (d, J = 7.0
Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 197.1, 144.5, 133.3,
129.7, 128.8, 51.2, 21.8, 14.6. MS (ESI-TOF) m/z: (M+H)+ Calcd
for C18H19O2 267.1, found 267.1.
Scale-up procedure for the preparation of 2-methyl-1,3-
diphenylpropane-1,3-dione (2a). To a three-necked flask were
added acetic acid (450 mL), 1,3-diphenylpropane-1,3-dione (1a)
(50.0 g, 222.5 mmol) and CuCl (2.207 g, 22.3 mmol). After the
mixture was heated to 120 ℃, tert-butyl peroxybenzoate (124.5
mL, 669 mmol) was added in dropwise for 1 hour, then stirred
for about 2.5 hours. After completion of reaction (monitored by
TLC), the solvent was removed under vacuum and
dichloromethane (200 mL) was added to the residue, filtered with
celite. The filtrate was washed with water (300 mL × 3),
neutralized by aqueous NaHCO3 solution, and concentrated
under vacuum to obtain the red oily crude product, which was
recrystallized from petroleum ether to give pure 2-methyl-1,3-
diphenylpropane-1,3-dione (2a, 31.8 g, 60% yield).
12
1,3-Bis(4-methoxyphenyl)-2-methylpropane-1,3-dione (2f)
Yellow oil, 70% yield (209 mg); 1H NMR (400 MHz, CDCl3):
δ 7.94 (d, J = 8.9 Hz, 4H), 6.89 (d, J = 8.9 Hz, 4H), 5.18 (q, J =
7.0 Hz, 1H), 3.80 (s, 6H), 1.55 (d, J = 7.0 Hz, 3H). 13C NMR
(101 MHz, CDCl3): δ 196.0, 163.7, 130.8, 128.6, 114.0, 55.4,
50.6, 14.5. MS (ESI-TOF) m/z: (M+H)+ Calcd for C18H19O4
299.1, found 299.1.
1,3-Bis(2-methoxyphenyl)-2-methylpropane-1,3-dione (2g)
Colorless solid, 81% yield (241 mg), mp 134–136 ℃; 1H
NMR (400 MHz, CDCl3): δ 7.81 (dd, J = 7.8, 1.6 Hz, 2H), 7.40–
7.47 (m, 2H), 6.99 (t, J = 7.5 Hz, 2H), 6.89 (d, J = 8.3 Hz, 2H),
5.45 (q, J = 7.0 Hz, 1H), 3.68 (s, 6H), 1.45 (d, J = 7.0 Hz, 3H).
13C NMR (101 MHz, CDCl3): δ 198.6, 158.5, 133.9, 131.4, 126.9,
120.9, 111.5, 59.3, 55.2, 13.3. HRMS (CI-TOF) m/z: (M+H)+
Calcd for C18H19O4 299.1283, found 299.1294.
4.3 Characterization
2-Methyl-1,3-diphenylpropane-1,3-dione (2a) 9
1
Colorless solid, 90% yield (214 mg), mp 75−79 °C; H NMR
1-(4-Chlorophenyl)-2-methyl-3-phenylpropane-1,3-dione (2h) 13
(400 MHz, CDCl3): δ 7.99−7.92 (m, 4H), 7.60−7.53 (m, 2H),
7.50−7.41 (m, 4H), 5.27 (q, J = 7.0 Hz, 1H), 1.61 (d, J = 7.0 Hz,
3H). 13C NMR (101 MHz, CDCl3): δ 197.3, 135.8, 133.6, 129.0,
128.7, 51.2, 14.5. MS (ESI-TOF) m/z: (M+H)+ Calcd for
C16H15O2 239.1, found 239.1.
Yellow oil, 68% yield (185 mg); 1H NMR (400 MHz, CDCl3):
δ 8.00–7.93 (m, 2H), 7.91–7.84 (m, 2H), 7.62–7.54 (m, 1H),
7.51–7.37 (m, 4H), 5.20 (q, J = 7.0 Hz, 1H), 1.60 (d, J = 7.0 Hz,
3H). 13C NMR (101 MHz, CDCl3): δ 197.2, 196.0, 140.1, 135.6,
134.2, 133.8, 130.0, 129.4, 129.1, 128.7, 51.3, 14.5. MS (ESI-
TOF) m/z: (M+H)+ Calcd for C16H14ClO2 273.1, found 273.1.
2-Methyl-1-phenyl-3-(p-tolyl)propane-1,3-dione (2b) 9
1
Colorless solid, 74% yield (186 mg), mp 92–95 ℃; H NMR
1-(4-Bromophenyl)-2-methyl-3-phenylpropane-1,3-dione (2i)
(400 MHz, CDCl3): δ 7.98–7.92 (m, 2H), 7.87 (d, J = 8.2 Hz, 2H),
7.58–7.52 (m, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.26 (d, J = 8.2 Hz,
2H), 5.24 (q, J = 7.0 Hz, 1H), 2.40 (s, 3H), 1.59 (d, J = 7.0 Hz,
3H). 13C NMR (101 MHz, CDCl3): δ 197.4, 197.0, 144.6, 135.8,
133.5, 133.2, 129.7, 129.0, 128.8, 128.6, 51.1, 21.8, 14.5. MS
(ESI-TOF) m/z: (M+H)+ Calcd for C17H17O2 253.1, found 253.1.
Yellow oil, 71% yield (224 mg); 1H NMR (400 MHz, CDCl3):
δ 8.00–7.92 (m, 2H), 7.91–7.85 (m, 2H), 7.59 (t, J = 7.4 Hz, 1H),
7.52–7.38 (m, 4H), 5.20 (q, J = 7.0 Hz, 1H), 1.60 (d, J = 7.0 Hz,
3H). 13C NMR (101 MHz, CDCl3): δ 197.2, 196.1, 140.1, 135.6,
134.1, 133.8, 129.5, 129.4, 129.1, 128.7, 51.3, 14.5. HRMS (CI-
TOF) m/z: (M+H)+ Calcd for C16H14BrO2 317.0177, found
317.0189.
1-Phenyl-3-(o-tolyl)propane-1,3-dione (2c)10
There is an equilibrium of keto/enol in CDCl3 solution for 2c,
in which keto is major. Yellow oil, 75% yield (189 mg); 1H NMR
(400 MHz, CDCl3): δ 7.97–7.90 (m, 1.98H, keto/enol), 7.70–7.63
(m, 1.41H, keto/enol), 7.61–7.53 (m, 1.05H, keto/enol), 7.52–
7.42 (m, 2.65H, keto/enol), 7.41–7.32 (m, 1.26H, keto/enol),
7.31–7.20 (m, 2.85H, keto/enol), 5.22 (q, J = 7.0 Hz, 1H, keto),
2.45 (s, 3H, keto), 2.37 (s, 0.56H, enol ), 1.75 (s, 0.53H, enol),
1.60 (d, J = 7.0 Hz, 3H, keto). 13C NMR (101 MHz, CDCl3): δ
200.6 (keto), 197.5 (keto), 192.2 (enol), 189.4 (enol), 139.4,
137.5, 137.3, 137.0, 136.1, 134.7, 133.5, 132.4, 131.7, 130.7,
130.6, 129.4, 128.9, 128.6, 128.3, 128.1, 126.7, 125.83, 125.77,
105.4, 53.2 (keto), 21.3 (keto), 19.3 (enol), 15.5 (enol), 14.4
(keto). MS (ESI-TOF) m/z: (M+H)+ Calcd for C17H17O2 253.1,
found 253.1.
1-(4-Bromophenyl)-3-(4-methoxyphenyl)-2-methylpropane-1,3-
dione (2j)
1
Colorless solid, 44% yield (152 mg), mp 96–98 ℃; H NMR
(400 MHz, CDCl3): δ 7.94 (d, J = 9.0 Hz, 2H), 7.79 (d, J = 8.7
Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 9.0 Hz, 2H), 5.12
(q, J = 7.0 Hz, 1H), 3.87 (s, 3H), 1.59 (d, J = 7.0 Hz, 3H). 13C
NMR (101 MHz, CDCl3): δ 196.4, 195.8, 164.1, 134.7, 132.3,
131.1, 130.1, 128.7, 128.5, 114.3, 55.7, 51.4, 14.6. HRMS (CI-
TOF) m/z: (M+H)+ Calcd for C17H16BrO3 347.0283, found
347.0296.
2-Methyl-1-(4-nitrophenyl)-3-phenylpropane-1,3-dione (2k)
Yellow oil, 30% yield (85 mg); 1H NMR (400 MHz, DMSO-
d6): δ 8.35 (d, J = 8.9 Hz, 2H), 8.18 (d, J = 8.9 Hz, 2H), 8.05–
7.99 (m, 2H), 7.69 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.7 Hz, 2H),
1-(4-Methoxyphenyl)-2-methyl-3-phenylpropane-1,3-dione (2d) 9

5
5.91 (q, J = 6.9 Hz, 1H), 1.41 (d, J = 6.9 Hz, 3H). 13C NMR (101
MHz, CDCl3): δ 198.1, 197.2, 150.1, 140.3, 135.0, 134.0, 129.6,
129.1, 128.6, 124.2, 50.3, 13.9. HRMS (CI-TOF) m/z: (M+H)+
Calcd for C16H14NO4 284.0923, found 284.0934.
Yellow oil, 70% yield (167 mg). 1H NMR (400 MHz,
ACCEPTED MANUSCRIPT
CDCl3): δ 8.52 (d, J = 4.3 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H),
8.07–8.03 (m, 2H), 7.83 (td, J = 7.7, 1.6 Hz, 1H), 7.61–7.52 (m,
1H), 7.51–7.45 (m, 2H), 7.44–7.38 (m, 1H), 5.74 (q, J = 7.0 Hz,
1H), 1.52 (d, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ
198.8, 198.7, 151.9, 148.9, 137.2, 136.4, 133.1, 128.9, 128.8,
127.4, 122.6, 49.7, 13.5. HRMS (ESI-TOF) m/z: (M+H)+ Calcd
for C15H14NO2 240.1024, found 240.1025.
2-Methyl-1-phenylpentane-1,3-dione (2l) 14
Yellow oil, 68% yield (129 mg); 1H NMR (400 MHz, CDCl3):
δ 8.00−7.92 (m, 2H), 7.61–7.53 (m, 1H), 7.51–7.42 (m, 2H), 4.50
(q, J = 7.0 Hz, 1H), 2.61–2.48 (m, 1H), 2.47–2.32 (m, 1H), 1.43
(d, J = 7.0 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 207.8, 197.6, 136.1, 133.7, 129.0, 128.7, 56.0, 34.1,
13.8, 7.8. MS (ESI-TOF) m/z: (M+H)+ Calcd for C12H15O2 191.1,
found 191.1.
2-Methyl-1,3-di(thiophen-2-yl)propane-1,3-dione (4c)
Yellow oil, 79% yield (197 mg). 1H NMR (400 MHz, CDCl3):
δ 7.78 (dd, J = 3.9, 1.0 Hz, 2H), 7.66 (dd, J = 5.0, 1.0 Hz, 2H),
7.14–7.08 (m, 2H), 4.90 (q, J = 7.0 Hz, 1H), 1.64 (d, J = 7.1 Hz,
3H). 13C NMR (101 MHz, CDCl3): δ 189.3, 143.0, 134.8, 133.0,
128.6, 54.9, 14.9. HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C12H11O2S2 251.0200, found 251.0195.
2,2,4,6,6-Pentamethylheptane-3,5-dione (2m) 15
Colorless oil, 41% yield (81 mg); 1H NMR (400 MHz, CDCl3):
δ 4.45 (q, J = 6.9 Hz, 1H), 1.27 (d, J = 6.9 Hz, 3H), 1.15 (s, 18H).
13C NMR (101 MHz, CDCl3): δ 212.1, 49.0, 44.6, 27.5, 15.7. MS
(ESI-TOF) m/z: (M+H)+ Calcd for C12H23O2 199.2, found 199.2.
2-Methyl-1,3-di(pyridin-2-yl)propane-1,3-dione (4d)
Yellow oil, 65% yield (156 mg). 1H NMR (400 MHz, DMSO-
d6): δ 8.54 (d, J = 4.3 Hz, 2H), 8.00 (d, J = 3.9 Hz, 4H), 7.63–
7.54 (m, 2H), 5.77–5.67 (m, 1H), 1.39 (d, J = 7.0 Hz, 3H). 13C
NMR (101 MHz, DMSO-d6): δ 198.6, 151.3, 148.9, 137.8, 127.6,
121.9, 49.2, 12.9. HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C14H13N2O2 241.0977, found 241.0971.
3-Hydroxy-2,5,5-trimethylcyclohex-2-en-1-one (2n) 16
Yellow oil, 68% yield (105 mg); 1H NMR (400 MHz, CDCl3):
δ 5.37 (s, 1H), 3.70 (s, 3H), 2.28 (s, 2H), 2.22 (s, 2H), 1.07 (s,
6H). 13C NMR (101 MHz, CDCl3): δ 199.7, 177.1, 101.3, 55.8,
50.9, 42.8, 32.7, 28.4. MS (ESI-TOF) m/z: (M+H)+ Calcd for
C9H15O2 155.1, found 155.1.
2-Methyl-1-(pyridin-2-yl)-3-(thiophen-2-yl)propane-1,3-dione
(4e)
2-Hydroxy-3-methylnaphthalene-1,4-dione (2o)
1
Yellow solid, 68% yield (167 mg), mp 82–83 . H NMR
Yellow solid, 82% yield (154 mg), mp 164–166 . 1H NMR
(400 MHz, CDCl3): δ 8.13 (dd, J = 7.6, 1.0 Hz, 1H), 8.08 (dd, J =
7.5, 1.1 Hz, 1H), 7.75 (td, J = 7.6, 1.4 Hz, 1H), 7.68 (td, J = 7.5,
1.3 Hz, 1H), 7.31 (s, 1H), 2.11 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 185.2, 181.3, 153.3, 135.0, 133.0, 129.6, 126.9, 126.3,
120.7, 8.8. HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for
C11H8NaO3 211.0371, found 211.0365.
(400 MHz, CDCl3) : δ 8.56 (d, J = 4.3 Hz, 1H), 8.08 (d, J = 7.8
Hz, 1H), 7.85–7.80 (m, 2H), 7.64 (d, J = 4.9 Hz, 1H), 7.48–7.40
(m, 1H), 7.16–7.10 (m, 1H), 5.65 (q, J = 7.1 Hz, 1H), 1.56 (d, J =
7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 1987.9, 191.1,
151.8, 148.9, 143.6, 137.3, 134.0, 132.7, 128.3, 127.5, 122.7,
51.0, 13.9. HRMS (ESI-TOF) m/z: (M+H)+ Calcd for
C13H12NO2S 246.0589, found 246.0588.
2-Methyl-1-(thiophen-2-yl)butane-1,3-dione (4f)
1-Cyclohexyl-2-methyl-3-phenylpropane-1,3-dione (2p)
Yellow oil, 72% yield (131 mg). 1H NMR (400 MHz, CDCl3):
δ 7.79 (d, J = 3.8 Hz, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.17 (t, J =
4.4 Hz, 1H), 4.33 (q, J = 7.0 Hz, 1H), 2.19 (s, 3H), 1.48 (d, J =
7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 204.4, 189.8, 143.3,
135.1, 133.3, 128.6, 58.2, 27.8, 13.7. HRMS (ESI-TOF) m/z:
(M+H)+ Calcd for C9H11O2S 183.0480, found 183.0478.
Yellow oil, 82% yield (188 mg). 1H NMR (400 MHz, CDCl3):
δ 8.00–7.92 (m, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz,
2H), 4.60 (q, J = 7.0 Hz, 1H), 2.56–2.44 (m, 1H), 1.85–1.65 (m,
4H), 1.43 (d, J = 7.0 Hz, 3H), 1.31–1.10 (m, 6H). 13C NMR (101
MHz, CDCl3): δ 210.3, 197.8, 136.3, 133.7, 129.0, 128.7, 54.8,
49.6, 29.4, 28.8, 25.8, 25.5, 13.8. HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C16H21O2 245.1541, found 245.1542.
2-Methyl-1-(pyridin-2-yl)butane-1,3-dione (4g)
1-(4-Fluorophenyl)-2,4-dimethylpentane-1,3-dione (I)
1
Yellow oil, 56% yield (99 mg). H NMR (400 MHz, CDCl3):
1
δ 8.65 (d, J = 4.2 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.85 (td, J =
7.7, 1.6 Hz, 1H), 7.51–7.44 (m, 1H), 4.89 (q, J = 7.1 Hz, 1H),
2.36 (s, 3H), 1.41 (d, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 206.3, 198.4, 152.1, 148.9, 137.2, 127.5, 122.5, 54.8,
29.5, 12.6. HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C10H12NO2
178.0868, found 178.0867.
Colorless oil, 61% yield (135 mg). H NMR (400 MHz,
CDCl3): δ 8.05–7.89 (m, 2H), 7.19–7.09 (m, 2H), 4.57 (q, J = 7.0
Hz, 1H), 2.80–2.69 (m, 1H), 1.42 (d, J = 7.0 Hz, 3H), 1.07 (d, J =
6.8 Hz, 3H), 1.00 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 210.9, 196.0, 166.1 (d, J = 256.5 Hz), 132.6 (d, J = 3.0
Hz), 131.5 (d, J = 10.0 Hz), 116.1 (d, J = 20.0 Hz), 54.7, 39.4,
19.2, 18.7, 13.8. HRMS (ESI-TOF) m/z: (M+Na)+ Calcd for
C13H15FNaO2 245.0954, found 245.0955.
2,2-Dimethyl-1-(pyridin-2-yl)butane-1,3-dione (4g’)
1
Yellow oil, 14% yield (26 mg). H NMR (400 MHz, CDCl3):
2-Methyl-1-phenyl-3-(thiophen-2-yl)propane-1,3-dione (4a)
δ 8.59 (d, J = 4.2 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.84 (td, J =
7.7, 1.6 Hz, 1H), 7.46–7.38 (m, 1H), 2.21 (s, 3H), 1.45 (s, 6H).
13C NMR (101 MHz, CDCl3): δ 207.8, 200.9, 151.2, 148.3, 137.3,
127.1, 123.5, 29.7, 26.8, 22.8. HRMS (ESI-TOF) m/z: (M+H)+
Calcd for C11H14NO2 192.1025, found 192.1021.
Yellow oil, 88% yield (214 mg). 1H NMR (400 MHz, CDCl3):
δ 8.02–7.95 (m, 2H), 7.73 (dd, J = 3.8, 1.0 Hz, 1H), 7.65 (dd, J =
5.0, 1.0 Hz, 1H), 7.60–7.52 (m, 1H), 7.50–7.40 (m, 2H), 7.14–
7.08 (m, 1H), 5.08 (q, J = 7.0 Hz, 1H), 1.63 (d, J = 7.0 Hz, 3H).
13C NMR (101 MHz, CDCl3): δ 196.6, 189.0, 143.1, 135.9, 134.6,
133.7, 132.8, 129.0, 128.8, 128.5, 53.1, 14.8. HRMS (ESI-TOF)
m/z: (M+H)+ Calcd for C14H13O2S 245.0636, found 245.0624.
2-Methyl-1-(quinolin-2-yl)butane-1,3-dione (4h)
Yellow oil, 53% yield (118 mg). 1H NMR (400 MHz, CDCl3):
δ 8.28 (d, J = 8.5 Hz, 1H), 8.14 (d, J = 8.5 Hz, 2H), 7.87 (d, J =
8.2 Hz, 1H), 7.82–7.74 (m, 1H), 7.69–7.60 (m, 1H), 5.09 (q, J =
2-Methyl-1-phenyl-3-(pyridin-2-yl)propane-1,3-dione (4b)

6
Tetrahedron
ACCEPTED MANUSCRIPT
7.1 Hz, 1H), 2.49 (s, 3H), 1.47 (d, J = 7.1 Hz, 3H). 13C NMR
1. For selected recent reviews on the methylation reactions,
(101 MHz, CDCl3): δ 206.4, 198.5, 151.6, 147.1, 137.4, 130.4,
130.3 129.9, 128.9, 127.9, 118.6, 54.9, 29.8, 12.7. HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C14H14NO2 228.1025, found
228.1017.
see: (a) Schoherr, H.; Cernak, T. Angew. Chem., Int. Ed.
2013, 52, 12256. (b) Barreiro, E. J.; Kummerle, A. E.;
Fraga, C. A. M. Chem. Rev. 2011, 111, 5215. For
selected recent papers on the methylation reactions, see:
(c) Bao, Y. J.; Yan, Y. Z.; Xu, K.; Su, J. H.; Zha, Z. G.;
Wang, Z. Y. J. Org. Chem. 2015, 80, 4736. (d) Chan, L.
K. M.; Poole, D. L.; Shen, D.; Healy, M. P.; Donohoe,
T. J. Angew. Chem., Int. Ed. 2014, 53, 761. (e) Li, Y.;
Xue, D.; Lu, W.; Wang, C.; Liu, Z. T.; Xiao, J. Org.
Lett. 2014, 16, 66. (f) Dai, Q.; Yu, J. T.; Jiang, Y.; Guo,
S. J.; Yang, H. T.; Cheng, J. Chem. Commun. 2014, 50,
3865. (g) Fan, J. H.; Zhou, M. B.; Liu, Y.; Wei, W. T.;
Ouyang, X. H.; Song, R. J.; Li, J. H. Synlett. 2014, 25,
0657. (h) Guo, S. J.; Wang, Q.; Jiang, Y.; Yu, J. T. J.
Org. Chem. 2014, 79, 11285. (i) Zhang, S. Y.; Li, Q.;
He, G.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2013,
135, 12135. (j) Zhang, S. Y.; He, G.; Nack, W. A.; Zhao,
Y. S.; Li, Q.; Chen, G. J. Am. Chem. Soc. 2013, 135,
2124. (k) Xia, Q. Q.; Liu, X. L.; Zhang, Y. J.; Chen, C.;
Chen, W. Z. Org. Lett. 2013, 15, 3326. (l) Zhu, Y.; Yan,
H.; Lu, L. H.; Liu, D. F.; Rong, G. W.; Mao, J. C. J.
Org. Chem. 2013, 78, 9898. (m) Yu, D. G.; Wang, X.;
Zhu, R. Y.; Luo, S.; Zhang, X. B.; Wang, B. Q.; Wang,
L.; Shi, Z. J. J. Am. Chem. Soc. 2012, 134, 14638. (n)
Yao, B.; Song, R. J.; Liu, Y.; Xie, Y. X.; Li, J. H.;
Wang, M. K.; Tang, R. Y.; Zhang, X. G.; Deng, C. L.
Adv. Synth. Catal. 2012, 354, 1890.
2,2-Dimethyl-1-(quinolin-2-yl)butane-1,3-dione (4h’)
Colorless solid, 17% yield (41 mg), mp 62–63 . 1H NMR
(400 MHz, CDCl3): δ 8.29 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.5
Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.81–
7.73 (m, 1H), 7.69–7.60 (m, 1H), 2.32 (s, 3H), 1.53 (s, 6H). 13C
NMR (101 MHz, CDCl3): δ 207.7, 201.2, 150.5, 146.6, 137.4,
130.32, 130.30, 129.6, 129.0, 127.8, 119.3, 59.1, 27.0, 23.1.
HRMS (ESI-TOF) m/z: (M+H)+ Calcd for C15H16NO2 242.1181,
found 242.1180.
2-Methyl-1-(1H-pyrrol-2-yl)butane-1,3-dione (4i)
Yellow oil, 58% yield (96 mg). 1H NMR (400 MHz, CDCl3): δ
10.01 (s, 1H), 7.12 (s, 1H), 7.01 (s, 1H), 6.34–6.28 (m, 1H), 4.22
(q, J = 7.0 Hz, 1H), 2.17 (s, 3H), 1.43 (d, J = 7.0 Hz, 3H). 13C
NMR (101 MHz, CDCl3): δ 204.9, 187.0, 131.2, 126.4, 118.1,
111.3, 56.9, 28.1, 13.8. HRMS (ESI-TOF) m/z: (M+Na)+ Calcd
for C9H11NNaO2 188.0687, found 188.0687.
2-Methyl-1-(1-methyl-1H-pyrrol-2-yl)butane-1,3-dione (4i’)
Yellow oil, 72% yield (129 mg). 1H NMR (400 MHz, CDCl3):
δ 7.03 (dd, J = 4.2, 1.6 Hz, 1H), 6.90–6.85 (m, 1H), 6.19–6.14 (m,
1H), 4.23 (q, J = 7.0 Hz, 1H), 3.95 (s, 3H), 2.16 (s, 3H), 1.40 (d,
J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 205.4, 187.4,
132.4, 130.2, 120.7, 108.7, 57.6, 37.9, 27.9, 14.0. HRMS (ESI-
TOF) m/z: (M+H)+ Calcd for C10H14NO2 180.1025, found
180.1016.
2. (a) Liao, Q.; Yang, X. H.; Xi, C. J. J. Org. Chem. 2014,
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(i) Fustero, S.; Sánchez Roselló, M.; Barrio, P.; Simón
Fuentes, A. Chem. Rev. 2011, 111, 6984. (j) Chen, X.;
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Mixture of 1-(furan-2-yl)-2-methyl-3-phenylpropane-1,3-dione
(4j) and 2-methyl-1-(5-methylfuran-2-yl)-3-phenylpropane-1,3-
dione (4j’)
1
Yellow oil, 4j/4j’ = 1/0.6 (calculated on the basis of H NMR
integral), total yield 76% (178 mg). 1H NMR (400 MHz, CDCl3):
δ 8.03–7.95 (m, 3.23H), 7.60–7.51 (m, 2.72H), 7.50–7.41 (m,
3.31H), 7.25 (dd, J = 3.6, 0.6 Hz, 0.93H), 7.16 (d, J = 3.5 Hz,
0.62H), 6.52 (dd, J = 3.6, 1.7 Hz, 0.98H), 6.15 (dd, J = 3.5, 0.8
Hz, 0.61H), 5.09 (q, J = 7.1 Hz, 1H), 5.01 (q, J = 7.0 Hz, 0.62H),
2.32 (s, 1.91H), 1.56 (d, J = 7.1 Hz, 5.01H). 13C NMR (101 MHz,
CDCl3): δ 197.1, 197.0, 186.1, 185.3, 158.3, 151.8, 150.3, 146.7,
136.2, 136.0, 133.6, 133.5, 128.94, 128.87, 128.71, 128.69, 120.3,
118.1, 112.8, 109.6, 51.8, 51.7, 14.2, 13.8. HRMS (ESI-TOF)
m/z: (M+H)+ Calcd for C14H13O3 229.0865, found 229.0859;
(M+H)+ Calcd for C15H15O3 243.1021, found 243.1029.
1-Methoxy-2,2,6,6-tetramethylpiperidine (5)
MS (ESI-TOF) m/z: (M+H)+ Calcd for C10H22NO 172.2, found
172.2.
3. (a) Hirai, K.; Ishiba, T.; Koike, H.; Watanabe, M. US
5260440, 1993. (b) Yin, X. L.; Liu, Y. Y.; Xu, C. T.; Ji,
M.; Wan, X. Q.; Pan, X. Z. CN102936225A, 2013.
4. (a) Fujiwara, J. Japan Kokai. 2003, 221384. (b)
Ackermann, P.; Stierli, D.; Jung, P.; Marcel, J.; Maien
Fisch, P.; Ceder Baum, F. E. M.; Wenger, G. F.
WO03/047347 A1, 2003. (c) Ogura, T.; Murakami, H.;
Numata, A.; Miyachi, R.; Miyake, T.; Mimori, N.; Takii,
S. US 6063734, 2000. (d) Atobe, M.; Naganuma, K.;
Kawanishi, M.; Morimoto, A.; Kasahara, K.; Ohashi, S.;
Suzuki, H.; Hayashi, T.; Miyoshi, S. Bioorg. Med.
Chem. Lett. 2013, 23, 6569.
Supplementary data
Experimental procedures, characterization data, and copies of
the 1H NMR and 13C NMR spectra for the products are available.
Acknowledgements
J.-P.Z. specially thanks the grant support by National Natural
Science Foundation of China (Nos. 20772088, 21172163,
21472133), the Priority Academic Program Development of
Jiangsu Higher Education Institutions & State and Local Joint
Engineering Laboratory for Novel Functional Polymeric
Materials for their financial support.
5. Müller, B.; Sauter, H.; Bayer, H.; Cullmann, O.;
Gewehr, M.; Grammenos, W.; Gypser, A.; Ptock, A.;
Götz, N.; Grote, T.; Rack, M.; Ammermann, E.; Lorenz,
G.; Strath mann, S.; Speakman, J. B. US 6562833, 2003.
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