A ligand-free, powerful, and practical method for methoxylation of unactivated aryl bromides by use of the CuCl/HCOOMe/MeONa/MeOH system

Article abstract of DOI:10.1007/s11164-014-1917-x

A ligand-free, powerful, and practical method for mono and polymethoxylation of unactivated aryl bromides has been developed; CuCl was used as catalyst, HCOOMe as cocatalyst, and methanolic MeONa as both nucleophile and solvent. This eco-friendly procedure is characterized by operational simplicity, inexpensive substrates (unactivated mono to polybromoarenes), full conversion, and direct recovery of pure MeOH.

Full text of DOI:10.1007/s11164-014-1917-x

Res Chem Intermed
DOI 10.1007/s11164-014-1917-x
A ligand-free, powerful, and practical method
for methoxylation of unactivated aryl bromides
by use of the CuCl/HCOOMe/MeONa/MeOH system
•
Ying Guo Si-Zhe Ji Cheng Chen Hong-Wei Liu
•
•
•
•
Jian-Hong Zhao Yu-Lin Zheng Ya-Fei Ji
•
Received: 29 October 2014 / Accepted: 26 December 2014
Ó Springer Science+Business Media Dordrecht 2015
Abstract A ligand-free, powerful, and practical method for mono and poly-
methoxylation of unactivated aryl bromides has been developed; CuCl was used as
catalyst, HCOOMe as cocatalyst, and methanolic MeONa as both nucleophile and
solvent. This eco-friendly procedure is characterized by operational simplicity,
inexpensive substrates (unactivated mono to polybromoarenes), full conversion, and
direct recovery of pure MeOH.
Keywords Cu-catalysis ꢀ Unactivated aryl bromides ꢀ Methoxylation ꢀ
Aryl methyl ethers ꢀ Recovery of pure MeOH
Introduction
Over the past century, Cu-catalyzed methoxylation of unactivated aryl halides with
no strong electron-withdrawing groups, for example NO2, CN, and CF3, on the
aromatic ring, a classical Ullmann-type C–O coupling reaction, has been widely
used to prepare aryl methyl ethers [1]. The reaction has many practical applications
in the preparation of pharmaceuticals, agrochemicals, fragrances, dyes, polymers,
Y. Guo ꢀ C. Chen ꢀ H.-W. Liu (&) ꢀ J.-H. Zhao ꢀ Y.-F. Ji (&)
School of Pharmacy, East China University of Science and Technology,
Campus P. O. Box 363, 130 Meilong Road, Shanghai 200237, China
e-mail: hwliu@ecust.edu.cn
Y.-F. Ji
e-mail: jyf@ecust.edu.cn
S.-Z. Ji
College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
Y.-L. Zheng
Shanghai New Asia Pharmaceutical Co. Ltd., 92 Zhangjiang Road, Shanghai 201203, China
123

Y. Guo et al.
and other fine chemicals [2–13]. Typical polymethoxylated arenes include the
classical antibacterial agent trimethoprim [14], the vasodilator agent buflomedil
[15], and the agricultural antifungal agent metrafenone [16] (Fig. 1). Aryl methyl
ethers are also precursors of phenols [17] and these electron-rich aromatic ethers are
also particularly useful for Friedel–Crafts-type reactions [18], ortho metalations
[19], and electrophilic aromatic substitution [20].
Traditionally, ligand-free, Cu-catalyzed methoxylation of unactivated aryl
halides has been conducted with MeONa as nucleophile, Cu(I) salt as catalyst,
and aprotic polar amides, e.g. N,N-dimethylformamide (DMF), N-methyl-2-
pyrrolidinone (NMP), or hexamethylphosphorus triamide (HMPT), as solvents.
However, unsatisfactory efficacy [1–6], troublesome work up [21], and hazards to
reproductive health [22] associated with these solvents do not meet the demands of
eco-awareness and cost-consciousness. Also, in the presence of MeONa, decom-
position of the amides unavoidably complicates the reaction work up. In recent
decades, to overcome these problems, substantial efforts have been made to improve
methoxylation [5, 6, 23–31]; these have mainly involved use of amides [5], esters
[6], carbon dioxide [23], or pyridine [24] as cocatalysts to achieve the transfor-
mation. Other Cu(I)-catalyzed methoxylations with complex ligands also work well
[25–31], but disadvantages associated with ligand chemistry—cost, separation, and
pollution issues—are inevitably encountered in large-scale production (Scheme 1).
From environmental and economic perspectives, a practical method for
methoxylation of unactivated aryl halides should have crucial sustainable features:
1. use of aryl bromides as substrates, rather than aryl chlorides, which are poorly
reactive under ligand-free conditions, or expensive and excessively active aryl
iodides;
2. methanolic MeONa as both nucleophile and solvent;
3. inexpensive CuCl as catalyst rather than expensive CuI or noble metal salts;
4. avoidance of unpractical cocatalysts or ligands; and
5. full conversion and excellent yield.
As part of our work on sustainable and green processes for preparing organic
intermediates and fine chemicals [32–35], we have reported a highly efficient
monomethoxylation using CuCl as catalyst, HCOOMe as cocatalyst, and metha-
nolic MeONa as both methoxylating reagent and solvent with several unactivated
monobromoarenes [36]. This powerful methoxylation was performed in a closed
NH2
O
OMe
OMe
O
OMe
MeO
MeO
OMe
OMe
N
N
N
NH2
MeO
OMe
OMe
Trimethoprim
Br
Buflomedil
Metrafenone
Fig. 1 Selected important compounds bearing polymethoxylated arene moieties
123

A ligand-free, powerful and practical method for methoxylation
Traditional methoxylation:
MeONa
R
R
Cu(I)/aprotic polar solvent
X
OMe
Ref. [1a]
X = Br , I
Evolving methoxylation:
MeONa
Cu(I)/aprotic polar solvent,
ester, pyridine or carbon
dioxide as cocatalysts
R
R
R
OMe
OMe
Br
Ref. [1e, 1f, 10a,10b]
Ref. [10c-i]
MeOH
R
Cu(I)/ligand, base
X
X = Br , I
This work:
inexpensive feedstocks
mono- to polybromoarenes
full conversion
non-contaminating cocatalyst
direct recovery of pure MeOH
MeONa/MeOH
R
R
OMe
CuCl/HCOOMe
Br
Scheme 1 Cu(I)-catalyzed methoxylation of unactivated aryl halides
autoclave to completely avoid loss of low-boiling HCOOMe, in contrast with the
open system used by Capdevielle et al. [6]. Nevertheless, further study of a more
broadly applicable procedure to improve the transformation is highly desired. In this
context, we report herein extensive experiments conducted to study this facile and
sustainable methoxylation reaction further, using a wide range of substrates from
mono to polybromoarenes, and scale-up investigations with decagrams and even on
an industrial scale (Scheme 1).
Results and discussion
First, the model methoxylation of bromobenzene in a Teflon-lined autoclave at
115 °C for 2 h was investigated to optimize the CuCl/HCOOMe catalyst system
(Table 1). When 8 mmol% CuCl and 50 mmol% HCOOMe were used, the reaction
provided anisole (1) quantitatively, with full conversion and 100 % GC yield (entry
1). When 35 mmol% HCOOMe was used, conversion noticeably reduced to 90 %
(entry 3). In comparison, 40 mmol% HCOOMe proved optimum for the methoxy-
lation (entry 2). Further study of the effect of catalyst loading showed that 4 mol%
CuCl was adequate for full conversion (entries 4–6). Thus, the optimized catalyst
system CuCl (4.0 mmol%)/HCOOMe (40 mmol%) was established to achieve
complete methoxylation (entry 5). It was noteworthy that all the methoxylations
123

Y. Guo et al.
Table 1 Optimization of the CuCl/HCOOMe systema
MeONa (2.0 equiv)/MeOH
CuCl (n1 mmol%)/HCOOMe (n2 mmol%)
115 oC, autoclave, 2 h
OMe
Br
1
Entry
CuCl
(n1 mmol%)
HCOOMe
(n2 mmol%)
Substrate/product/
byproduct ratiob
1
8.0
8.0
8.0
5.0
4.0
3.0
None
4.0
4.0
4.0
4.0
4.0
4.0
50
0/100/0
0/100/0
10/90/0
0/100/0
0/100/0
7/93/0
2
40
3
35
4
40
5
40
6
40
7
40
98/2/0
8
None
40c
40d
40
92/8/0
9
16/84/0
2/98/0
10
11e
12f
13g
100/0/0
0/89/11
96/4/0
40
40
Bold signifies the standard conditions
a
Reaction conditions: PhBr (10.0 mmol), MeOH (10 mL), MeONa (20.0 mmol), CuCl (n1 mmol%),
HCOOMe (n2 mmol%) in autoclave
b
Substrate/product/byproduct ratio determined by GC–MS, by use of the area-normalization method
with total ion current chromatography of the volatile products
c
HCOOMe replaced by N,N-diethylformamide
d
HCOOMe replaced by MeCOOEt
e
PhBr replaced by PhCl
PhBr replaced by PhI to give 89 % of the desired 1 and 11 % of the byproduct methyl benzoate (10)
f
g
The ethoxylation reaction performed with HCOOEt as cocatalyst in ethanolic EtONa
consistently supplied 1 as the sole product, indicating the absence of side-reactions
in the transformation of bromobenzene (entries 1–6). In essence, both CuCl and
HCOOMe were crucial for the methoxylation, and the absence of either led to
unsuccessful conversion (entries 7 and 8). Compared with reported cocatalyst
amides [5] and esters [6], indeed, HCOOMe resulted the most excellent outcome
among DMF [36], MeCOOMe [36], N,N-diethylformamide (entry 9), and
MeCOOEt (entry 10). Treatment of poorly reactive chlorobenzene provided no
product (entry 11) whereas methoxylation of highly reactive iodobenzene proceeded
smoothly with full conversion, but with a noticeable amount (11 %) of the
methoxycarbonylation byproduct methyl benzoate (10; entry 12). Furthermore, when
a control ethoxylation of bromobenzene was performed with the corresponding
HCOOEt as cocatalyst and ethanolic sodium ethoxide as both nucleophile and
123

A ligand-free, powerful and practical method for methoxylation
solvent, the method gave only a trace amount of the phenetole with extremely low
conversion (entry 13), presumably because the ethoxide anion is a stronger reducing
agent than the copper(I) ion [6]. As pointed out in Ref. [36], the methoxylation
procedure has the remarkable features of green chemistry, wherein pure MeOH
(colorless, purity[99 %, water content\0.12 %) can be recovered after completion
of the reaction. In the presence of MeONa, HCOOMe was completely degraded into
pure MeOH and carbon monoxide via decarbonylation in the open system [37, 38].
Although unstable carbonyl Cu(I) species are possibly formed [39], no negative
effects have been observed.
Using the optimized monomethoxylation conditions, we then investigated the
substrate scope of the reaction of unactivated aryl bromides (Table 2). In general,
the method achieved perfect methoxylation of all monobromoarenes, irrespective of
whether electron-donating or weak electron-withdrawing substituent(s) were present
on the substrates (1–15). Accordingly, most of the products were obtained with full
conversion and in excellent yields (1–7, 10–15; an additional one equivalent of
MeONa was required for 6 and 7). Even when the substrates had three or more
Table 2 Substrate scope of the methoxylationa
OMe
O
OMe
OMe
OMe
OMe
OMe
3. 0/100/0 (84)
OMe
OMe
O
OH
6.d 0/100/0 (98)
1. 0/100/0b (80c)
2. 0/100/0 (83)
4. 0/99/1 (97)
5. 0/100/0 (99)
MeOOC
MeO
n-PrO
OMe
OMe
OMe
12. 0/100/0 (98)
MeO
OMe
OMe
OMe
OH
OMe
11.e 0/100/0 (97)
10.e 0/100/0 (95)
7.d 0/100/0 (98)
8.0/95/5 (93)
9. 0/95/5 (93)
OMe
Cl
S
OMe
S
OMe
OH
16.d 0/100/0 (98)
MeO
OMe
OMe
13. 0/100/0 (97)
CHO
MeO
OMe
OMe
OH
17.d 0/100/0 (98)
OH
18.d 0/100/0 (99)
14. 0/100/0 (80)
15. 0/100/0 (78)
OMe
OMe
OMe
MeO
OMe
OMe
OMe
MeO
OMe
MeO
OMe
OH
19.d 0/100/0 (98)
OH
22.d 0/100/0 (98)
20. 0/100/0 (98)
21. 0/100/0 (98)
a
Reaction condition: ArBrn (10.0 mmol), MeOH (10 mL), MeONa (10.0(1 ? n) mmol), CuCl ((3(n -
1) ? 4) mmol%), HCOOMe ((20(n - 1) ? 40) mmol%) in autoclave
b
Substrate/product/byproduct ratio determined by GC–MS using area normalization method in the total
ionization chromatography
c
Isolated yield (%; 1, 2, 3, 14, 15 as the volatile products)
d
The substrate with phenolic hydroxyl group needing additional one equivalent of MeONa
e
For a reaction time of 7 h
123

Y. Guo et al.
electron-donating groups, the procedure afforded full conversion and more than
93 % yield (7–9). For ortho, ortho-dimethyl, or ortho-methoxy-ortho-methyl-
substituted substrates, steric effects were observed and resulted in dehalogenation
[40] (product/byproduct ratio 95/5 for 8 and 9). However, when sterically hindered
ortho-monosubstituted bromoarenes 10 and 11 with isopropyl and phenyl groups,
respectively, were subjected to the methoxylation, reaction occurred without
dehalogenation affording the desired products in more than 95 % yield, after a
prolonged reaction time of 7 h. With the electron-rich five-membered heterocyclic
compounds 2-bromothiophene and 3-bromothiophene the method also furnished the
desired products with full conversion, because of their stability under the alkaline
conditions (14 and 15) [41].
More challenging polymethoxylation of unactivated polybromoarenes (ArBrn,
n = 2, 3) was also investigated. The reaction system was further optimized by using
(1 ? n) equiv MeONa, (3(n - 1) ? 4) mmol% CuCl, and (20(n - 1) ? 40)
mmol% HCOOMe for polymethoxylation (16–22). For example, 3 equiv MeONa,
(3 ? 4) mmol% CuCl, and (20 ? 40) mmol% HCOOMe were used for dimeth-
oxylation of dibromoarenes (16–20; an additional one equiv MeONa was required
for 16–19). The method exclusively provided all the dimethoxylation products with
full conversion and satisfactory yields (16–20). Moreover, the results of trimeth-
oxylation clearly revealed that the method was sufficiently powerful to accomplish
full transformation with sole products 21 and 22. It should be noticed that
dehalogenation was not detected for the ortho-hydroxy-ortho-methyl substituted
substrate (22), in comparison with 8 and 9. We speculate that coordination between
the phenolate anion and the active Cu(III) species suppressed debromination.
Unusually, the seemingly labile aldehyde and hydroxyl groups of 4-hydroxyben-
zaldehydes did not need additional protection (19). We therefore concluded the
structure of the sodium enolate was responsible for protecting the original aldehyde
and hydroxyl groups via a dearomatization–enolization process (Scheme 2) [36].
The practical utility of the approach was revealed by the preparation of
syringaldehyde (19) [42, 43], a highly commercially valuable intermediate crucial in
the synthesis of the classical antibacterial agent trimethoprim, and of 1,3,5-
trimethoxybenzene (21) [44, 45], a common pharmaceutical intermediate. Scale-up
experiments revealed that 19 and 21 could be prepared on the decagram scale
without significantly altered reaction efficiency (Scheme 3a, b). It is worthy of note
that major advantages of the methoxylation method are that HCOOMe has both
excellent co-catalytic performance and promotes non-contaminating decarbonyla-
tive decomposition to achieve a completely clean transformation.
H
O
H
ONa
R
MeONa
MeOH
R
sodium enolate
OH
O
Scheme 2 Isomerization of 4-hydroxybenzaldehydes under alkaline conditions
123

A ligand-free, powerful and practical method for methoxylation
CHO
CHO
MeONa (4.0 equiv)/MeOH
(A)
CuCl (7 mol%)
HCOOMe (60 mol%)
115 oC, 2 h
Br
Br
MeO
OMe
OH
OH
(28.0 g, 0.1 mol)
Br
19 (20.6 g, 96%)
OMe
MeONa (4.0 equiv)/MeOH
(B)
CuCl (10 mol%)
HCOOMe (80 mol%)
115 oC, 2 h
Br
Br
MeO
OMe
(31.5 g, 0.1 mol)
21 (16.0 g, 95%)
Industrial application in the plant[18]
CHO
CHO
OMe
CHO
ONa
MeONa/MeOH
(C)
Me2SO4
CuCl/HCOOMe
NaOH/H2O
OMe
Br
Br
MeO
OMe
MeO
OH
3,4,5-trimethoxybenzaldehyde
phenolate of 19
Scheme 3 Practical applications on decagram and industrial scales
Finally, the procedure was successfully used for commercial manufacture of
3,4,5-trimethoxybenzaldehyde, an intermediate in the synthesis of trimethoprim
[43], on an industrial scale, with recovery of pure MeOH in the plant (Scheme 3c)
[46]. Treatment of the recovered pure MeOH with sodium metal could be used for
direct production of methanolic MeONa in the plant to achieve economy of
recycling. The reaction has no significant risk of scale sensitivity, and long-term
process robustness was observed in large-scale production [47].
On the basis of previous investigations [4, 6], a modified mechanism is proposed
for this HCOOMe co-catalyzed reaction (Scheme 4). Crucially, HCOOMe acting as
reactive cocatalyst furnishes the methoxylated intermediate II [48, 49], which
combines with the cuprate-like intermediate I, resulting in the key tetrahedral
intermediate III. Next, oxidative addition of the aryl bromide to the CuI center
generates a new Cu(III) species IV [50, 51], furnishing intermediate V. Reductive
elimination then effectively releases the desired product and regenerates the
Cu(I) species III. In addition, with ortho,ortho-disubstituted aryl bromides (Table 2,
8 and 9), steric effects result in possible dehalogenation during the reductive
elimination.
Conclusions
In summary, we have developed ligand-free, powerful, and practical CuCl/
HCOOMe-catalyzed methoxylation of unactivated aryl bromides to aryl methyl
ethers. The eco-friendly method enables simple operation, and is applicable to a
123

Y. Guo et al.
OMe
O
-MeONa
+MeONa
MeO
MeO
2MeONa
CuI
H
O Na
CuCl
Na
-NaOMe
H
OMe
OMe
II
I
H
OMe
O
Na
R
MeO
Br
I
R
Cu
OMe
MeO
III
R
H
OMe
O
R
Na
H
OMe
O
MeO
CIuII
Na
MeO
Br
MeO
CIuII
IV
OMe
MeO
V
o,o-disubstituted
aryl bromide
MeONa
NaBr
R
dehalogenated byproduct
Scheme 4 Modified mechanism
wide range of inexpensive substrates from unactivated mono to polybromoarenes
with direct recovery of pure MeOH. Its practicability on an industrial-scale plant has
been confirmed. We expect the new methoxylation reaction to have more extensive
applications in chemistry.
Experimental
Unless otherwise indicated, all reagents were obtained from commercial sources and
were used as received without further purification. All reactions were performed in a
˚
Teflon-lined autoclave. All solvents were only dried over 4 A molecular sieves.
Reaction products were purified by silica gel column chromatography with
petroleum ether–ethyl acetate as mobile phase. Melting points were determined
1
by use of open capillaries and are uncorrected. H and 13C NMR spectra were
acquired with a Bruker AV400, at 400 and 100 MHz, respectively, in CDCl3, with
TMS as internal standard. HRMS was performed with a QSTAR Pulsar I LC/TOF
MS mass spectrometer or Micromass GCTTM gas chromatograph–mass spectrom-
eter. GC–MS was also performed with an Agilent 7890A gas chromatograph–mass
spectrometer.
123

A ligand-free, powerful and practical method for methoxylation
Typical procedure for synthesis of 1 (Table 1)
A Teflon-lined autoclave (25 mL) was charged with MeONa (1.08 g, 20.0 mmol),
MeOH (10 mL), CuCl (40 mg, 0.40 mmol), HCOOMe (0.25 mL, 0.97 g/mL,
4.0 mmol), and monohaloarene (10.0 mmol) then heated to 115 °C, with stirring,
for 2 h. After completion of the reaction, the reactor was cooled to room
temperature. The mixture was stirred for 0.5 h in the open, then concentrated to
recover pure MeOH. Diethyl ether (15 mL) and dilute hydrochloric acid (1.6 M,
15 mL) were added to the residue. The mixture separated into two layers, and the
aqueous phase was extracted with diethyl ether (15 mL 9 3). The combined
organic layers were dried over anhydrous Na2SO4 and concentrated to give a residue
which was purified by column chromatography on silica gel (mobile phase:
petroleum ether–ethyl acetate 15:1) to furnish 1 (conversion and selectivity were
determined by GC–MS analysis). The purity of the recovered MeOH was measured
as more than 99 % by GC, and the water content of the recovered MeOH was
measured as less than 0.12 % by use of the Karl Fischer method.
Anisole (1)
Colorless oil, substrate/product/byproduct ratio: 0/100/0, 0.87 g (80 %, as the
1
volatile product); H NMR (400 MHz, CDCl3), d (ppm): 7.31 (t, J = 7.6 Hz, 2H),
6.99–6.91 (m, 3H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3), d (ppm): 159.5,
129.4 (2C), 120.6, 113.8 (2C), 55.0; HRMS (EI): m/z [M?] calcd. for C7H8O:
108.0575; found: 108.0576.
Methyl benzoate (10)
Colorless oil, 0.12 g (9 %); 1H NMR (400 MHz, CDCl3), d (ppm): 8.04 (dd,
J1 = 7.6 Hz, J2 = 1.2 Hz, 2H), 7.56 (dt, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H), 7.44 (t,
J = 7.6 Hz, 2H), 3.92 (s, 3H); 13C NMR (100 MHz, CDCl3), d (ppm): 165.9, 133.0,
130.1, 129.9 (2C), 128.6 (2C), 51.5; HRMS (EI): m/z [M?] calcd. for C8H8O2:
136.0524; found: 136.0526.
1-Methoxy-2-methylbenzene (2)
Colorless oil, substrate/product/byproduct ratio: 0/100/0, 1.01 g (83 %, as the
1
volatile product); H NMR (400 MHz, CDCl3), d (ppm): 7.22 (t, J = 7.6 Hz, 1H),
7.22 (d, J = 7.6 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 3.86
(s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3), d (ppm): 157.7, 130.6, 126.8,
126.6, 120.3, 109.9, 55.2, 16.3; HRMS (EI): m/z [M?] calcd. for C8H10O: 122.0732;
found: 122.0733.
1-Methoxy-4-methylbenzene (3)
Colorless oil, substrate/product/byproduct ratio: 0/100/0, 1.03 g (84 %, as the
1
volatile product); H NMR (400 MHz, CDCl3), d (ppm): 7.10 (d, J = 8.4 Hz, 2H),
123

Y. Guo et al.
6.82 (d, J = 8.4 Hz, 2H), 3.80 (s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3),
d (ppm): 157.5, 129.9 (2C), 129.8, 113.7 (2C), 55.3, 20.5; HRMS (EI): m/z [M?]
calcd. for C8H10O: 122.0732; found: 122.0729.
7-Methoxy-3,4-dihydro-2H-benzo[b]1,4-dioxepine (4)
1
Colorless oil, substrate/product/byproduct ratio: 0/100/0, 1.75 g (97 %); H NMR
(400 MHz, CDCl3), d (ppm): 6.91 (d, J = 8.8 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H),
6.48 (dd, J = 8.8, 2.4 Hz, 1H), 4.18 (t, J = 5.6 Hz, 2H), 4.12 (t, J = 5.6 Hz, 2H),
3.74 (s, 3H), 2.16 (quint, J = 5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3), d (ppm):
155.6, 152.0, 145.3, 121.9, 108.7, 106.8, 70.85, 70.78, 55.6, 32.3; HRMS (ESI): m/
z [M ? H?] calcd. for C10H13O3: 181.0865; found: 181.0872.
1,2-Dimethoxy-4-methylbenzene (5)
Pale yellow solid, substrate/product/byproduct ratio: 0/100/0, 1.51 g (99 %), m.p.
18–20 °C; 1H NMR (400 MHz, CDCl3), d (ppm): 6.70–6.79 (m, 3H), 3.87 (s, 3H),
3.85 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3), d (ppm): 148.8, 146.9,
130.4, 120.8, 112.5, 111.3, 55.9, 55.7, 21.0; HRMS (ESI): m/z [M ? Na?] calcd. for
C9H12O2Na: 175.0735; found: 175.0721.
4-Ethyl-2-methoxyphenol (6)
Pale yellow oil, substrate/product/byproduct ratio: 0/100/0, 1.49 g (98 %); 1H NMR
(400 MHz, CDCl3), d (ppm): 6.84 (d, J = 8.0 Hz, 1H), 6.71 (s, 1H), 6.70 (d,
J = 8.0 Hz, 1H), 5.45 (br s, 1H), 3.89 (s, 3H), 2.59 (quart, J = 7.6 Hz, 2H), 1.22 (t,
J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3), d (ppm): 146.4, 143.5, 136.3,
120.3, 114.2, 110.5, 55.9, 28.6, 16.0; HRMS (ESI): m/z [M ? H?] calcd. for
C9H13O2: 153.0916; found: 153.0924.
2-Methoxy-4-methyl-6-propoxyphenol (7)
Pale yellow oil, substrate/product/byproduct ratio: 0/100/0, 1.92 g (98 %); 1H NMR
(400 MHz, CDCl3), d (ppm): 6.38 (s, 2H), 5.35 (s, 1H), 3.98 (t, J = 7.0 Hz, 2H),
3.87 (s, 3H), 2.28 (s, 3H), 1.84 (sext, J = 7.0 Hz, 2H), 1.03 (t, J = 7.0 Hz, 3H); 13
C
NMR (100 MHz, CDCl3), d (ppm): 146.9, 146.2, 132.7, 128.6, 106.7, 105.7, 70.8,
56.2, 22.6, 21.5, 10.5; HRMS (ESI): m/z [M ? H?] calcd. for C11H17O3: 197.1178;
found: 197.1187.
2-Methoxy-1,3,5-trimethylbenzene (8)
1
Colorless oil, substrate/product/byproduct ratio: 0/95/5, 1.40 g (93 %); H NMR
(400 MHz, CDCl3), d (ppm): 6.83 (s, 2H), 3.70 (s, 3H), 2.26 (s, 6H), 2.25 (s, 3H);
13C NMR (100 MHz, CDCl3), d (ppm): 154.8, 133.1, 130.5 (2C), 129.4 (2C), 59.7,
20.7, 16.0 (2C); HRMS (ESI): m/z [M ? H?] calcd. for C10H15O: 151.1123; found:
151.1122.
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A ligand-free, powerful and practical method for methoxylation
1,2,3,4,5-Pentamethoxy-6-methylbenzene (9)
Pale yellow solid, substrate/product/byproduct ratio: 0/95/5, 2.25 g (93 %), m.p.
28–32 °C; 1H NMR (400 MHz, CDCl3), d (ppm): 3.91 (s, 3H), 3.87 (s, 6H), 3.79 (s,
6H), 2.13 (s, 3H); 13C NMR (100 MHz, CDCl3), d (ppm): 147.5 (2C), 145.1, 143.1
(2C), 120.1, 61.3, 61.1 (2C), 60.6 (2C), 8.8; HRMS (ESI): m/z [M ? H?] calcd. for
C12H19O5: 243.1232; found: 243.1236.
1-Isopropyl-2-methoxybenzene (10)
1
Colorless oil, substrate/product/byproduct ratio: 0/100/0, 1.43 g (95 %); H NMR
(400 MHz, CDCl3), d (ppm): 7.22 (d, J = 7.6 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H),
6.94 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 3.84 (s, 3H), 3.34 (m, 1H), 1.22
(d, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3), d (ppm): 156.8, 137.0, 126.6,
126.0, 120.6, 110.3, 55.3, 26.7, 22.7 (2C); HRMS (EI): m/z [M ?] calcd. for
C10H14O: 150.1045; found: 150.1046.
2-Methyl-1,10-biphenyl (11)
1
Yellow oil, substrate/product/byproduct ratio: 0/100/0, 1.78 g (97 %); H NMR
(400 MHz, CDCl3), d (ppm): 7.53 (d, J = 7.2 Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H),
7.33 (m, 3H), 7.04 (t, J = 8.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H); 13
C
NMR (100 MHz, CDCl3), d (ppm): 156.5, 138.6, 130.9, 130.7, 129.6 (2C), 128.7,
128.0 (2C), 126.9, 120.9, 111.2, 55.6; HRMS (EI): m/z [M ?] calcd. for C13H12O:
184.0888; found: 184.0889.
Methyl 4-methoxybenzoate (12)
Yellow solid, substrate/product/byproduct ratio: 0/100/0, 1.63 g (98 %), m.p.
41–43 °C; 1H NMR (400 MHz, CDCl3), d (ppm): 7.99 (d, J = 8.4 Hz, 2H), 6.91 (d,
J = 8.4 Hz, 2H), 3.88 (s, 3H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3), d (ppm):
166.8, 163.3, 131.5 (2C), 122.6, 113.6 (2C), 55.3, 51.8; HRMS (ESI): m/
z [M ? H?] calcd. for C9H11O3: 167.0708; found: 167.0709.
1-Chloro-4-methoxybenzene (13)
Pale yellow oil, substrate/product/byproduct ratio: 0/100/0, 1.38 g (97 %); 1H NMR
(400 MHz, CDCl3), d (ppm): 7.24 (dt, J = 8.8, 3.6 Hz, 2H), 6.83 (dt, J = 8.8,
3.6 Hz, 2H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3), d (ppm): 158.2, 129.3
(2C), 125.5, 115.2 (2C), 55.4; HRMS (EI): m/z [M?] calcd. for C7H7OCl: 142.0185;
found: 142.0184.
2-Methoxythiophene (14)
Colorless oil, substrate/product/byproduct ratio: 0/100/0, 0.91 g (80 %, as the
volatile product); 1H NMR (400 MHz, CDCl3), d (ppm): 6.72 (dd, J = 5.6, 3.2 Hz,
123

Y. Guo et al.
1H), 6.54 (d, J = 5.6 Hz, 1H), 6.20 (d, J = 3.2 Hz, 1H), 3.89 (s, 3H); 13C NMR
(100 MHz, CDCl3), d (ppm): 166.7, 124.8, 111.7, 103.7, 60.4; HRMS (EI): m/
z [M?] calcd. for C5H6OS: 114.0139; found: 114.0129.
3-Methoxythiophene (15)
Colorless oil, substrate/product/byproduct ratio: 0/100/0, 0.89 g (78 %, as the
volatile product); 1H NMR (400 MHz, CDCl3), d (ppm): 7.18 (dd, J = 5.2, 2.4 Hz,
1H), 6.75 (d, J = 5.2 Hz, 1H), 6.25 (d, J = 2.4 Hz, 1H), 3.82 (s, 3H); 13C NMR
(100 MHz, CDCl3), d (ppm): 158.7, 124.7, 119.2, 96.6, 57.3; HRMS (EI): m/z [M?]
calcd. for C5H6OS: 114.0139; found: 114.0138.
2,4-Dimethoxy-6-methylphenol (16)
White solid, substrate/product/byproduct ratio: 0/100/0, 1.65 g (98 %), m.p.
1
102–104 °C; H NMR (400 MHz, CDCl3), d (ppm): 6.36 (d, J = 2.4 Hz, 1H),
6.29 (d, J = 2.4 Hz, 1H), 5.30 (s, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 2.25 (s, 3H); 13C
NMR (100 MHz, CDCl3), d (ppm): 152.7, 146.7, 137.8, 123.8, 106.6, 96.8, 56.0,
55.7, 15.8; HRMS (EI): m/z [M?] calcd. for C9H12O3: 168.0786; found: 168.0787.
2,6-Dimethoxy-4-methylphenol (17)
Pale yellow solid, substrate/product/byproduct ratio: 0/100/0, 1.65 g (98 %), m.p.
38–40 °C; 1H NMR (400 MHz, CDCl3), d (ppm): 6.39 (s, 2H), 5.37 (s, 1H), 3.86 (s,
6H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3), d (ppm): 146.9 (2C), 132.4, 128.7,
105.6 (2C), 56.2 (2C), 21.6; HRMS (ESI): m/z [M ? H?] calcd. for C9H13O3:
169.0865; found: 169.0879.
4-(tert-Butyl)-2,6-dimethoxyphenol (18)
1
Yellow oil, substrate/product/byproduct ratio: 0/100/0, 2.08 g (99 %); H NMR
(400 MHz, CDCl3), d (ppm): 6.60 (s, 2H), 5.37 (br s, 1H), 3.90 (s, 6H), 1.31 (s, 9H);
13C NMR (100 MHz, CDCl3), d (ppm): 146.5 (2C), 142.5, 132.6, 102.4 (2C), 56.3
(2C), 34.7, 31.6 (3C); HRMS (ESI): m/z [M ? H?] calcd. for C12H19O3: 211.1334;
found: 211.1332.
4-Hydroxy-3,5-dimethoxybenzaldehyde (19)
Pale yellow solid, substrate/product/byproduct ratio: 0/100/0, 1.79 g (98 %), m.p.
110–112 °C; 1H NMR (400 MHz, CDCl3), d (ppm): 9.82 (s, 1H), 7.15 (s, 2H), 6.10
(s, 1H), 3.97 (s, 6H); 13C NMR (100 MHz, CDCl3), d (ppm): 190.8, 147.4 (2C),
140.9, 128.3, 106.7 (2C), 56.5 (2C); HRMS (ESI): m/z [M ? H?] calcd. for
C9H11O4: 183.0657; found: 183.0635.
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A ligand-free, powerful and practical method for methoxylation
1,2,4-Trimethoxybenzene (20)
1
Colorless oil, substrate/product/byproduct ratio: 0/100/0, 1.65 g (98 %); H NMR
(400 MHz, CDCl3), d (ppm): 6.78 (d, J = 8.8 Hz, 1H), 6.51 (d, J = 2.8 Hz, 1H),
6.39 (dd, J = 8.8, 2.8 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H); 13C NMR
(100 MHz, CDCl3), d (ppm): 154.2, 149.8, 143.4, 111.9, 102.9, 100.3, 56.4, 55.7,
55.6; HRMS (ESI): m/z [M ? H?] calcd. for C9H13O3: 169.0865; found: 169.0885.
1,3,5-Trimethoxybenzene (21)
White solid, substrate/product/byproduct ratio: 0/100/0, 1.65 g (98 %), m.p.
1
42–44 °C; H NMR (400 MHz, CDCl3), d (ppm): 6.09 (s, 3H), 3.77 (s, 9H); 13C
NMR (100 MHz, CDCl3), d (ppm): 161.6 (3C), 92.9 (3C), 55.2 (3C); HRMS (ESI):
m/z [M ? H?] calcd. for C9H13O3: 169.0865; found: 169.0850.
2,4,6-Trimethoxy-3-methylphenol (22)
Pale yellow solid, substrate/product/byproduct ratio: 0/100/0, 1.94 g (98 %), m.p.
47–50 °C; 1H NMR (400 MHz, CDCl3), d (ppm): 6.31 (s, 1H), 5.15 (br s, 1H), 3.88
(s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 2.10 (s, 3H); 13C NMR (100 MHz, CDCl3), d
(ppm): 150.8, 146.1, 145.1, 132.9, 112.5, 93.0, 60.5, 56.5, 56.4, 8.5; HRMS (ESI):
m/z [M ? H?] calcd. for C10H15O4: 199.0970; found: 199.0949.
Acknowledgments The authors are grateful to the National Natural Science Foundation of China
(project nos 21176074 and 21476074), the Research Fund for the Doctoral Program of Higher Education
of China (project no. 20130074110009), and the Shandong Rongyuan Pharmaceutical Co. Ltd. for
financial support.
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