Microwave-assisted methylation of phenols with tetramethylammonium chloride in the presence of K2CO3 or Cs2CO3

Article abstract of DOI:10.1016/j.tet.2008.10.024

We have evaluated the potential of using tetramethylammonium chloride (Me₄NCl) as an alternative methylating agent for phenols under microwave-assisted conditions. Its chemical behavior was tested in a reaction with 2-naphthol in the presence of various bases and solvents. The method was then applied in 1,2-dimethoxyethane or toluene under heterogeneous conditions for the O-methylation of a series of phenolic compounds. We found that many simple phenols can be methylated in the presence of K₂CO₃, whereas some other less-reactive phenols require the presence of the more reactive Cs₂CO₃.

Full text of DOI:10.1016/j.tet.2008.10.024

Tetrahedron 64 (2008) 11618–11624
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Microwave-assisted methylation of phenols with tetramethylammonium
chloride in the presence of K CO or Cs CO
2
3
2
3
Nenad Mara sˇ , Slovenko Polanc, Marijan Ko cˇ evar *
Faculty of Chemistry and Chemical Technology, University of Ljubljana, A sˇ ker cˇ eva 5, SI-1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2008
Received in revised form
We have evaluated the potential of using tetramethylammonium chloride (Me NCl) as an alternative
methylating agent for phenols under microwave-assisted conditions. Its chemical behavior was tested in
a reaction with 2-naphthol in the presence of various bases and solvents. The method was then applied
in 1,2-dimethoxyethane or toluene under heterogeneous conditions for the O-methylation of a series of
4
24 September 2008
Accepted 9 October 2008
Available online 15 October 2008
phenolic compounds. We found that many simple phenols can be methylated in the presence of K
whereas some other less-reactive phenols require the presence of the more reactive Cs CO
2 3
CO ,
2
3
.
Dedicated to the memory of the late
Professor Ljubo Golicˇ
Ó 2008 Elsevier Ltd. All rights reserved.
1
. Introduction
esters under harsh conditions has also been reported.9 On
the other hand, onium salts, such as trialkylsulfonium and tri-
10
Many reagents already exist for the O-methylation of phenols.
Methyl iodide, dimethyl sulfate, and diazomethane are the most
commonly used. Methyl chloride and methyl bromide are gases at
room temperature, which means they have a very limited usability.
However, the above reagents present serious toxicological and
carcinogenic risks due to their volatility and their ability to meth-
ylate nucleic acids in living organisms.2 Diazomethane, as well as
being a very toxic gas, presents additional risks due to its explosive
nature, and needs to be freshly prepared in special apparatus prior
to use. As a consequence, trimethylsilyldiazomethane has been
proposed as a less-hazardous alternative to diazomethane. Sul-
fonic acids’ methyl esters, especially methyl p-toluenesulfonate, are
suitable reagents for laboratory-scale reactions. Trimethyl phos-
phite and trimethyl phosphate were also found to be efficient for
methylating phenols. Finally, these methylations can also be ach-
ieved using methanol under standard Mitsunobo conditions.
Environmental and toxicological concerns have resulted in an
increased interest in new methylating reagents in general, of which
dimethyl carbonate seems to be the most promising for industrial
use. It is inexpensive, nontoxic, biodegradable and requires only
alkylselenonium salts, and tetraalkylammonium salts can also be
used for alkylations. Over a century ago it was shown that the
phenolate salts of quaternary amines decompose on strong heating
1
11
into phenyl alkyl ethers and tertiary amines. Tetramethylammo-
nium, phenyltrimethylammonium and other quaternary amine
hydroxides have long been known as reagents in gas-chromato-
graphy analysis, and used for the on-column derivatization of
12
phenols, thiols, carboxylic acids, amines, and acidic NH groups.
Regardless of their relatively common use in gas chromatography,
there have only been relatively few reports of quaternary amines
being used as alkylating reagents in preparative synthesis. Phe-
nyltrimethylammonium salts, being some of the most reactive,
have found limited use in the O-methylation of phenols, particu-
larly phenolic morphinans, where methyl iodide or dimethyl sul-
3
4
5
13
fate might cause quaternization at the tertiary amine function.
6
Other quaternary salts, however, have mostly been neglected as
alkylating reagents, primarily because of their much lower re-
activity. For example, betaine (2-trimethylammonioacetate) was
reported to methylate a wide assortment of simple phenols under
ꢀ
harsh conditions (200–230 C), with the evolution of CO
2
and tri-
7
14
catalytic amounts of bases for reactions involving methylations.
The O-methylation of phenols generally requires temperatures of
methylamine, applying CaO as a base. Tetramethylammonium
hydroxide (Me NOH) was reported to be a useful reagent for the
4
ꢀ
120–200 C, but more convenient methods have also been de-
methylation of estradiol and estriol, giving excellent yields of
8
15
scribed. The O-methylation of phenol with other, less-reactive
products with O-methylated phenolic groups. When using a ten-
4
fold excess of Me NOH it was possible to O-methylate, not only
phenolic, but also the aliphatic hydroxy groups of the two steroids.
A report in Chinese was published on the O-, N-, and S-alkylation of
some carboxylic acids, amines, anilines, and thiophenol, with
*
Corresponding author. Tel.: þ386 1 2419230; fax: þ386 1 2419220.
E-mail address: marijan.kocevar@fkkt.uni-lj.si (M. Ko cˇ evar).
0
040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.024

N. Mara sˇ et al. / Tetrahedron 64 (2008) 11618–11624
11619
ꢀ
several quaternary ammonium halides at 160 C in 1-methyl-2-
IR sensor of the microwave reactor). The reaction mixture was then
acidified and analyzed by means of HPLC and the conversion
established by the use of authentic standards. No 2-methoxy-
naphtalene (3a) could be detected in the absence of the base
(entry 1). Nucleophilic organic bases like pyridine and 1,4-(dia-
zabicyclo[2.2.2]octan) (DABCO) also did not give detectable
amounts of 2-methoxynaphthalene (entries 2 and 3). The use of
16
pyrrolidinone (NMP) as a solvent. However, when searching for
preparative procedures of phenolic compounds O-alkylation with
tetramethylammonium halides we only found two patents: one
describing the methylation of 3,4-dihydroxybenzaldehyde with
17
Me
4
NBr and KOH to give isovanillin in an 11% yield and the other
NCl and
describing the methylation of 4-phenylphenol with Me
4
18
ꢀ
K
2
CO
3
in NMP at 160 C with a nearly quantitative yield.
During our work we were in need of small amounts of some
Cs
2
CO
3
, KOH, and NaOH gave the best results (entries 9, 10, and 11).
O gave negligible conversions (entry 6), perhaps due to the
LiOH$H
2
simple, substituted methyl aryl ethers. We were, however, sur-
prised to find so little information in the scientific literature related
to tetramethylammonium salts as methylating reagents and thus
decided to explore this method further. The possibility of avoiding
the use of carcinogenic reagents for such routine laboratory prep-
presence of hydration water or as a reflection of the Lewis-acid
nature of lithium salts in aprotic solvents. The inhibition of the
methylation by the presence of water might also explain the
somewhat better performance of NaOH in comparison to KOH
pellets, which generally contain up to 15% of water. In addition,
arations was attractive enough for us to try using Me
4
NCl under
2 3 2 3
K CO (entry 8) was somewhat less efficient than Cs CO , KOH, and
heterogeneous reaction condition in conjunction with a micro-
NaOH. However, since our aim was to develop a method suitable for
a microwave reactor, we had to avoid the use of alkali hydroxides
since they represent a hazard because of the very high microwave
absorption in their melts and their ability to etch the walls of the
reaction vessel (which can result in the reaction vessel exploding
when under pressure). Using alkali hydroxides also inevitably
narrows the spectrum of tolerated functional groups. On the other
hand, Cs CO seems to be too expensive to be used in any pre-
2 3
parative method involving simple, reactive substrates. We there-
fore decided to investigate the scope and the limitations of the use
19,20
wave-accelerated reaction.
4
Me NCl is an inexpensive, non-
ꢀ
volatile crystalline solid (mp >300 C), and though quite toxic if
ingested, it presents no such toxicity hazards originating from
volatility, as is the case with diazomethane, methyl iodide, and
4
dimethyl sulfate. But most importantly, Me NCl is not a suspected
carcinogen. Its molecular weight is also low enough to make its use
as a methylation reagent practical and economical on the basis of its
weight. The side products of its use in methylation are trimethyl-
amine, which leaves the reaction mixture as a gas, and the chloride
salt of the base employed.
of K
application of Cs
Table 2 shows the influence of the choice of solvent on the same
system using K CO as a base. Water as a solvent gave the lowest
conversion to 2-methoxynaphthalene, even though it is the only
solvent that efficiently dissolves Me NCl as well as the base (entry
). Among the alcohols, 2-propanol was the best solvent (entries 2,
, and 4). Though N,N-dimethylformamide (DMF), 1-methyl-2-
2
CO
3
as the base of choice for simple substrates, and the
2
CO for the more precious ones.
3
2
. Results and discussion
2
3
We report here the results of our investigation of the methyla-
tion of a series of phenols 1 with tetramethylammonium chloride
toward aryl methyl ethers 3 via tetramethylammonium phenolates
4
1
3
2
(Scheme 1).
pyrrolidinone (NMP), and acetonitrile perform excellently as sol-
vents in classical S 2-type O-alkylations of phenols, in this reaction
N
+
Me NCl
they were inferior to all the less-polar, aprotic solvents tested
(entries 5, 6, and 7). In fact, 1,2-dimethoxyethane (DME), ethyl ac-
etate, and toluene all gave better results (entries 8, 9, and 10). DME
was thus selected as the solvent of choice because of its complete
inertness under the conditions used and due to its relative vola-
tility, making the isolation easier. For comparison, in some cases
toluene was also applied as a solvent.
4
Ar O- Me N+
Ar OH
Ar OMe
+ Me N
3
4
base / MW
1
2
3
Scheme 1. Methylation of phenols using Me
4
NCl.
We first investigated the influence of the base used on the
conversion in a model system of 2-naphthol (1a) and Me NCl in
4
a 1:1 ratio in 1,2-dimethoxyethane (DME) as a solvent (0.5 mmol
substrate in 2 mL solvent); 1 mol equiv of the base was used
Such alkylations, where both the nucleophile and the alkylating
reagent are charged ions, are of a less-common type (designated as
type-III S 2 by Smith and March). The detrimental effects of the
N
21
(
Table 1). The reactions involved 10 min of microwave heating in a
ꢀ
standard, closed reaction vessel (10 mL) at 145 C (according to the
water on the reaction conversion can be explained on the basis of
Table 1
Influence of the base on the methylation of 2-naphthol with Me
4
NCl in DME
Table 2
ꢀ
Influence of the solvent on the methylation of 2-naphthol with Me NCl using K CO
as a base at 145
at 145
C
4
2
3
ꢀ
C
OH
OMe
+
Me NCl, base
4
OH
OMe
+
Me NCl, K CO
4 2 3
MW
-
KCl, KHCO
MW
3
1a
3a
1
a
3a
Entry
Base
Conversion %
Entry
Solvent
Conversion %
1
2
3
4
5
6
7
8
9
d
0
0
0
Pyridine
DABCO
1
2
3
4
5
6
7
8
9
10
Water
MeOH
EtOH
2-PrOH
DMF
MeCN
NMP
DME
<1
<1
5
16
17
20
27
40
46
51
Mg(OH)
Li CO
LiOH$H
Na CO
CO
CO
2
<1
<1
w1
3
40
63
67
82
2
3
2
O
2
3
K
2
3
Cs
2
3
1
0
KOH
NaOH
AcOEt
PhMe
11

11620
N. Mara sˇ et al. / Tetrahedron 64 (2008) 11618–11624
Table 3
ꢀ
2 3 2 3
NCl in the presence of K CO or Cs CO under microwave irradiation for 25 or 60 min at 145 C
Methylation of phenols with Me
4
Entry
Phenol
Product
Solvent
Reaction
Yielda (%)
Yielda (%)
time (min)
using K
2
CO
3
2 3
using Cs CO
OH
OMe
1
(1a)
(3a)
DME
25
87
d
OH
OMe
2
6
5
0
66
78
57
85
2
3
(1b)
(3b)
(3c)
DME
DME
MeO
Br
MeO
Br
OH
OMe
(1c)
60
91
92
4
5
MeO C
OH
(1d)
(1e)
MeO C
OMe
OMe
(3d)
(3e)
DME
DME
25
25
54
74
d
d
2
2
O
O
OH
EtO
EtO
OH
OMe
6
7
O
(1f)
O
O
(3f)
DME
25
71
d
H C
H3C
3
O
O
OH
OMe
DME
PhMe
25
25
28
61
d
d
O
O
(1g)
(3g)
O
Me
Me
8
9
OMe
(1h)
(1i)
OMe
OMe
(3h)
(3i)
DME
DME
25
25
98
65
d
d
O
O
AcHN
OH
OH
AcHN
OHC
OHC
10
(1j)
DME
DME
DME
25
25
25
60
19
45
92
OMe
OMe
OH
OHC
OHC
OMe
(
3j)
OMe
11
(1k)
OHC
OH
OMe
OEt
OMe
OMe
OMe
OMe
39
d
48
96
12
(1l)
(3l)
60
OEt
OMe
DME
PhMe
25
60
33
38
96
d
13
OHC
Cl
OH
(1m)
OHC
Cl
(3m)
OMe
OH
DME
DME
25
27
68
d
d
14
(1n)
(1o)
(3n)
(3o)
60
OH
OMe
15
60
60
55
59
d
Cl
Cl
Cl
Cl
16
Cl
Cl
OH
OH
(1r)
Cl
Cl
OMe
(3r)
DME
85
Cl
Cl
Cl
Cl
OMe
17
(1s)
(1t)
(3s)
(3t)
PhMe
DME
25
25
58
61
d
d
18
OH
OMe
Me
Me

N. Mara sˇ et al. / Tetrahedron 64 (2008) 11618–11624
11621
Table 3 (continued )
Entry
Phenol
Product
Solvent
DME
Reaction
time (min)
Yielda (%)
Yielda (%)
using Cs CO
2 3
using K
2
CO
3
Me
OH
Me
19
(1u)
(3u)
25
54
d
OMe
2
6
5
0
38
78
d
d
2
0
MeO
Br
OH
(1v)
MeO
Br
OMe
(3v)
DME
DME
21
OH
(1w)
OMe
(3w)
60
60
60
76
71
43
d
d
72
OH
OMe
Me
Me
2
2
3
(1x)
(1y)
(3x)
(3y)
DME
DME
Me
HO
Me
HO
Me
OH
Me
OMe
2
Me O
H
Me O
H
H
60
20
d
44
90
24
(1z)
(3z)
DME
1
61
H
H
H
HO
Isolated yields are given.
MeO
a
the solvation of both the nucleophile (phenoxide anion) and elec-
trophile (ammonium cation). Since only the unsolvated ions can
efficiently interact in an S 2 nucleophilic substitution, the solvation
N
represents a barrier, inhibiting the formation of the reaction tran-
sition state. However, when the reaction is performed in aprotic,
nonpolar solvents, unsolvated opposite ions are free to associate in
p-hydroxybenzoic acid among the reaction products. In the meth-
ylation of benzyl p-hydroxybenzoate (1g) we observed a much
better yield when using toluene (61%) as opposed to DME (28%).
The influence of the carbonyl group at the para position is
particularly evident in the methylations of vanillin (1j) and iso-
vanillin (1k), leading to the identical product (3j), but in 60% and
19% yields, respectively. This effect might be attributed to the in-
creased acidity of the phenolic group in vanillin, resulting in a faster
consumption of the carbonate under the heterogeneous conditions
used.
Chlorophenols (1n–1r) gave low yields for short reaction times,
but prolonging the reaction time to 60 min resulted in better yields.
A similar effect of prolonged heating was also observed with
p-methoxyphenol (1v) and p-bromophenol (1w).
No methylation of the benzylic alcohol group was observed
during the methylation of 3-hydroxybenzyl alcohol (1y), but the
reaction gave a relatively low yield (43%) of 3-methoxybenzyl
alcohol (3y), even after prolonged heating.
Steric factors appear to be of some importance, as indicated by
the low yield of syringaldehyde (1m) methylation (33%, entry 13) as
opposed to vanillin (60%, entry 10), though the electronic and
chelating factors of the additional methoxy group could also play an
important role. Nevertheless, thymol (1x) with the isopropyl group
at the ortho position, required longer reaction times than the other
alkyl substituted phenols, like 1t and 1u, in order to give compa-
rable yields, thus additionally indicating some steric influence on
the reaction (entries 18, 19, and 22).
We were unable to obtain reproducible yields from p-nitro-
phenol methylation under such conditions. The yields varied from
15–41% (not shown in Table 3), apparently due to decomposition to
a tarry material.
N
an ion-pair complex, where the S 2 reaction can produce a neutral
molecule.
The solvation of the tetramethylammonium cation by polar,
aprotic solvents (DMF, acetonitrile, and NMP) might explain their
lower efficiency in comparison with the less-polar, aprotic solvents
(
DME, ethyl acetate, and toluene). On the other hand, we would
expect a much more dramatic solvation effect when using protic
solvents, which are able to solvate both the phenoxide anion as well
as the tetramethylammonium cation. The formation of an ion-pair
complex in such protic solvent is less likely, thus explaining the
unusually low conversions observed in water and methanol. In
accordance with this hypothesis, nonpolar, aprotic solvents gave
the best conversions in the methylation of 2-naphthol, even though
such media are most unfavorable in view of the lower solubility of
Me
Finally, we performed a series of preparative O-methylations of
various simple phenols to evaluate the potential of Me NCl for
synthetic use. The reactions were performed under heterogeneous
conditions using K CO as the base and DME or toluene as the sol-
4 2 3
NCl and K CO .
4
2
3
vent in the microwave reactor. For an easier comparison of the re-
sults, the reaction time used was generally 25 or 60 min. As shown in
Table 3, longer reaction times often lead to yield improvements,
unless the substrate is unstable in the reaction conditions.
We observed a marked influence of the phenol substitution on
the isolated reaction yields. However, simple generalizations are
hard to draw, especially when considering the heterogenous nature
of the reaction. Nevertheless, phenols para substituted with a car-
bonyl group consistently gave better results. For example,
p-hydroxypropiophenone (1h) gave an almost quantitative yield of
Based on an optimization study, cesium carbonate, which is an
2
2
excellent base in aprotic solvents, was expected to give better
results, and some less-simple or problematic substrates certainly
warrant its use. Syringaldehyde (1m), which gave poor yields using
3
h. p-Hydroxybenzoic acid esters (1d–g) gave moderate yields of
K
Cs
2
CO
CO
were obtained for 2,4,6-trichlorophenol (1r) and 3-hydroxybenzyl
3
in both DME and toluene, gave excellent yields in DME with
the products, except for the methyl ester (1d), which underwent
partial hydrolysis, as indicated by the chromatographic detection of
2
3
as a base. Similar improvements, though less dramatic,

11622
N. Mara sˇ et al. / Tetrahedron 64 (2008) 11618–11624
alcohol (1y). Substituted 2-naphthol substrates like 1b and 1c,
which after prolonged heating gave good results with K CO as
a base, also performed well under such conditions. However, the
most surprising results were obtained with vanillin (1j) and iso-
vanillin (1k), whose performance under such conditions was the
magnetic stirring bar in the vessel. High-performance liquid chro-
matography was performed on a Nucleosil C-18 column using an
acetonitrile/water mobile phase and a UV detector at 254 nm. NMR
spectra were recorded on a Bruker Avance DPX 300-MHz spec-
2
3
trometer in CDCl
3
with tetramethylsilane (TMS) as the internal
ꢀ
opposite of what was obtained with K
vanillin gave an excellent improvement with Cs
a poorer yield than that obtained with K CO . Similarly, 3-ethoxy-
-hydroxybenzaldehyde (1l), a compound homologous to vanillin,
gave only a slight improvement using Cs CO , though excellent
2
CO
3
as a base. While iso-
standard at 29 C. MS spectra were recorded with a VG-Analytical
AutoSpec Q instrument. Melting points are uncorrected and were
measured on a Kofler micro hot stage. All reagents used were
commercially available or prepared using published methods.
Potassium and cesium carbonates were finely ground and dried at
2
CO , vanillin gave
3
2
3
4
2
3
ꢀ
yields were obtained with a longer reaction time. Estrone (1z),
a phenolic steroid, gave a good yield of O-methylestrone (3z) in 2 h
of reaction time. Reaction time of 1 h did not give satisfactory yield,
perhaps indicating that more complex phenols generally require
longer reaction times under such conditions. When we tried to
150 C for 12 h.
4.2. General procedure for the methylation of phenols with
trimethylammonium chloride
methylate p-nitrophenol,
a violent decomposition occurred,
resulting in a sudden pressure increase, which was shown to be
dangerous to the microwave equipment.
Into a 10-mL microwave reaction vessel was added the
phenolic substrate (2 mmol), tetramethylammonium chloride
The reaction mixtures were diluted with ethyl acetate, insoluble
solids removed by filtration, and the corresponding product was
isolated using radial chromatography. However, the isolation of
several phenols can also be simplified by performing an extraction
with diethyl ether and removing the unreacted phenols by washing
the extract with 2 M aqueous sodium hydroxide. This method often
resulted in products of comparable purity.
To evaluate the possibility of scaling up the reactions we used
the standard 80 mL microwave reaction vessel. All the reaction
components were scaled up 25-times, again using 2-naphthol (1a)
2 3 2 3
(290 mg, 2.5 mmol), anhydrous base (2.5 mmol K CO or Cs CO ),
and the solvent (2 mL; 1,2-dimethoxyethane or toluene; see Table
3). The reaction vessel was purged with argon before closing and
ꢀ
irradiated in the microwave reactor for the specified time at 145 C
with magnetic stirring (the microwave power limit was set to
50 W for K CO and 100 W for Cs CO based reactions). The vessel
2 3 2 3
was vented in a fume hood to remove the trimethylamine. The
reaction mixture was diluted with ethyl acetate (5 mL), the solids
filtered off and then washed with additional ethyl acetate
(2ꢁ5 mL). The filtrate was evaporated in vacuo and the product
isolated with radial chromatography using petroleum ether/ethyl
acetate or petroleum ether/diethyl ether as eluents. The product
as the model substrate (50 mmol; 7.2 g) applying K
2
CO
3
as a base
ꢀ
and DME as a solvent. The reaction proceeded sluggishly at 145 C
and even prolonging the reaction time up to 2 h gave only a 37% of
isolated yield of 2-methoxynaphthalene (3a). Heating the reaction
1
identity was confirmed by H NMR and IR spectroscopy as well as
mp, where applicable.
ꢀ
mixture for 3 h at 160 C was required to achieve an 89% isolated
yield of 3a. Thus, for scaling up this heterogeneous reaction harsher
reaction conditions are required than those used at 2 mmol scale.
4.3. Analytical and spectroscopic data of products
2
3
3
. Conclusions
4.3.1. 2-Methoxynaphthalene (3a)
ꢀ
23
ꢀ
1
Mp 70–71 C (lit. 71–72 C); H NMR
d 3.92 (s, 3H), 7.10–7.18
We have developed a new method for the microwave-assisted
(m, 2H), 7.33 (m, 1H), 7.43 (m, 1H), 7.75 (m, 3H); IR (KBr) 1632, 1597,
ꢂ1
O-methylation of phenolic compounds using tetramethylammo-
nium chloride as a noncarcinogenic reagent. The heterogeneous
reaction conditions with potassium carbonate as a base generally
give moderate to excellent yields that can generally be improved by
using cesium carbonate when required. Nonpolar, aprotic solvents
were found to be the best for this reaction. CAUTION: We do not
recommend using nitrophenols as substrates under such micro-
wave conditions because of the possibility of their rapid
decomposition.
1506, 1476, 1462 cm
.
2
4
4.3.2. 2,6-Dimethoxynaphthalene (3b)
ꢀ
24
ꢀ
1
Mp 149–151 C (lit. 149 C); H NMR
d 3.90 (s, 6H), 7.07–7.16
(m, 4H), 7.64 (d, J¼8.7 Hz, 2H); IR (KBr) 1603, 1503, 1453, 1389,
ꢂ1
1234 cm
.
2
5
4.3.3. 2-Bromo-6-methoxynaphthalene (3c)
ꢀ
ꢀ
1
Mp 101–103 C (lit.25 105–107 C); H NMR
d 3.91 (s, 3H), 7.09
(
d, J¼2.5 Hz, 1H), 7.16 (dd, J
1
¼2.5 Hz, J ¼8.9 Hz, 1H), 7.49 (dd,
2
4
4
. Experimental
J
1
¼2.0 Hz, J
2
¼8.7 Hz, 1H), 7.62 (m, 2H), 7.91 (d, J¼1.7 Hz, 1H); IR
ꢂ1
(KBr) 1626, 1587, 1499, 1387, 1266 cm
.
.1. General
2
6
4
.3.4. Methyl 4-methoxybenzoate (3d)
ꢀ
26
ꢀ
1
Microwave reactions were conducted using a focused micro-
Mp 47–48 C (lit. 48 C); H NMR
d
3.86 (s, 3H), 3.88 (s, 3H),
0
0
0
0
wave unit (Discover by CEM Corporation, Matthews, NC). The ma-
chine consists of a continuous, focused microwave power-delivery
system with an operator-selectable power output from 0 to 300 W.
Reactions were performed in glass vessels (10 mL) sealed with
a septum. The pressure was controlled by a load cell connected to
the vessel via the septum. The temperature of the contents of the
vessel was monitored using a calibrated infrared temperature
controller mounted under the reaction vessel. Large scale reaction
was conducted in a hermetically closed 80 mL glass vessel equip-
ped with an external temperature controller measuring the
temperature trough a fiber optic immersed in the reaction media.
All the reaction mixtures were stirred with a Teflon-coated
6.92 (AA XX , J¼9.0 Hz, 2H), 7.99 (AA XX , J¼9.0 Hz, 2H); IR (KBr)
ꢂ1
1711, 1609, 1512, 1430, 1321 cm
.
27
4.3.5. Ethyl 4-methoxybenzoate (3e)
1
H NMR
d
1.38 (t, J¼7.2 Hz, 2H), 3.86 (s, 3H), 4.34 (q, J¼7.2 Hz,
0
0
0
0
2H), 6.91 (AA XX , J¼8.4 Hz, 2H), 8.00 (AA XX , J¼8.4 Hz, 2H); IR
ꢂ1
(NaCl) 1711 br, 1607, 1513, 1462, 1367 cm
.
2
8
4.3.6. Pentyl 4-methoxybenzoate (3f)
1
H NMR
d
0.93 (t, J¼7.1 Hz, 3H), 1.30–1.49 (m, 4H), 1.76 (m, 2H),
3.86 (s, 3H), 4.28 (t, J¼6.7 Hz), 6.9 (d, J¼9.0 Hz, 2H), 7.97 (d,
ꢂ1
J¼9.0 Hz, 2H); IR (NaCl) 1712, 1607, 1512, 1465 cm
.

N. Mara sˇ et al. / Tetrahedron 64 (2008) 11618–11624
11623
2
8
41
4
.3.7. Benzyl 4-methoxybenzoate (3g)
4.3.21. 2-Methoxy-4-methyl-1-isopropylbenzene (3x)
1
0
0
1
H NMR
d
3.85 (s, 3H), 5.34 (s, 2H), 6.91 (AA XX , J¼9.0 Hz, 2H),
H NMR
d
1.19 (d, J¼6.9 Hz, 6H), 2.32 (s, 3H), 3.27 (sept.,
0
0
7
.29–7.47 (m, 5H), 8.03 (AA XX , J¼9.0 Hz, 2H); IR (NaCl) 1711, 1606,
J¼6.9 Hz,1H), 3.81 (s, 3H), 6.67 (s,1H), 6.74 (d, J¼7.8 Hz,1H), 7.09 (d,
ꢂ1
ꢂ1
1
4
d
581, 1511, 1456 cm
.
J¼7.8 Hz, 1H); IR (NaCl) 1612, 1580, 1504, 1460 cm
.
2
9
42
.3.8. 1-(4-Methoxyphenyl)propan-1-one (3h)
4.3.22. (3-Methoxyphenyl)methanol (3y)
Mp 25–27 C (from petroleum ether) (lit. 27 C); 1H NMR
ꢀ
29
ꢀ
1
H NMR
d
1.82 (brs,1H), 3.81 (s, 3H), 4.66(s, 2H), 6.83 (m,1H), 6.92
(m, 2H), 7.27 (t, J¼8.1 Hz,1H); IR (NaCl) 1595, 1490, 1457, 1264 cm
ꢂ1
1.21 (t, J¼7.2 Hz, 3H), 2.95 (q, J¼7.2 Hz, 2H), 3.87 (s, 3H), 6.93
.
0
0
0
0
(
AA XX , J¼9.0 Hz, 2H), 7.95 (AA XX , J¼9.0 Hz, 2H); IR (KBr) 1679,
ꢂ1
8f
1602, 1510, 1460, 1418 cm
.
4.3.23. O-Methylestrone (3z)
ꢀ
f
ꢀ
1
Mp 167–168.5 C (lit.8 168 C); H NMR
d
0.91 (s, 3H), 1.34–1.72
3
0
4
.3.9. N-(4-Methoxyphenyl)acetamide (3i)
(m, 6H), 1.87–2.6 (m, 7H), 2.90 (m, 2H), 3.78 (s, 3H), 6.64 (d,
J¼2.8 Hz, 1H), 6.72 (dd, J ¼8.6 Hz, J ¼2.8 Hz, 1H), 7.20 (d, J¼8.6 Hz,
1H); IR (KBr) 2914, 1738, 1608, 1503, 1453 cm
CHCl ).
ꢀ
30
ꢀ
1
Mp 128–130 C (lit. 129–130 C); H NMR
d
2.15 (s, 3H), 3.79 (s,
1
2
0
0
0
0
ꢂ1
25
3
H), 6.85 (AA XX , J¼9.0 Hz, 2H), 7.14 (br s, 1H), 7.38 (AA XX ,
;
a
þ133 (c 5,
5
46
ꢂ1
J¼9.0 Hz, 2H); IR (KBr) 1650, 1606, 1560, 1512 cm
.
3
3
1
4
.3.10. 3,4-Dimethoxybenzaldehyde (3j)
Mp 41–43 C (lit. 42 C); H NMR
Acknowledgements
ꢀ
31
ꢀ
1
d 3.95 (s, 3H), 3.97 (s, 3H), 6.98
(
d, J¼8.1 Hz,1H), 7.42 (d, J¼1.8 Hz,1H), 7.46 (dd, J
1
¼8.1 Hz, J
2
¼1.8 Hz,
We thank the Ministry of Higher Education, Science and Tech-
nology of the Republic of Slovenia and the Slovenian Research
Agency for financial support (P1-0230-0103). Dr. B. Kralj and Dr. D.
ꢂ1
2
4
3
H), 9.86 (s, 1H); IR (KBr) 1686 br, 1587 br, 1513, 1466, 1424 cm
.
3
2
.3.11. 3-Ethoxy-4-methoxybenzaldehyde (3l)
ˇ
ꢀ
Zigon (Center for Mass Spectroscopy, ‘Jozef Stefan’ Institute, Ljubl-
jana, Slovenia) are gratefully acknowledged for the mass
measurement.
ꢀ
32
ꢀ
1
Mp 47–49 C (lit. 49.5–50.5 C); H NMR
d
1.49 (t, J¼7.0 Hz,
H), 3.96 (s, 3H), 4.17 (q, J¼7.0 Hz, 2H), 6.98 (d, J¼8.2 Hz, 1H), 7.43
(
dt, J
1
¼8.2 Hz, J ¼1.9 Hz, 2H), 9.85 (s, 1H); IR (KBr) 1691, 1677, 1599,
2
ꢂ1
1
511, 1440 cm
.
References and notes
3
3
4
.3.12. 3,4,5-Trimethoxybenzaldehyde (3m)
ꢀ
33
ꢀ
1
1. Tipical protocols of phenolic compounds methylation with dimethyl sulfate,
methyl iodide and diazomethane are common laboratory knowledge and are
described in laboratory handbooks, for example: Furniss, B. S.; Hannaford, A. J.;
Smith, P. W. G.; Tatchell, A. R. Vogel’s Textbook of Practical Organic Chemistry, 5th
ed.; John Wiley & Sons: New York, NY, 1989.
Mp 72–74 C (lit. 72–74 C); H NMR
d
3.94 (s, 6H), 3.95 (s, 3H),
ꢂ1
7.14 (s, 2H), 9.87 (s, 1H); IR (KBr) 1686, 1588, 1506, 1459, 1425 cm
.
3
4
4
.3.13. 4-Chloroanisole (3n)
2
3
. Bolt, H. M.; Gansewendt, B. Crit. Rev. Toxicol. 1993, 23, 237–253.
. Aoyama, T.; Terasawa, S.; Sudo, K.; Shioiri, T. Chem. Pharm. Bull. 1984, 32, 3759–
3760.
1
0
0
0
0
H NMR
d
3.78 (s, 3H), 6.82 (AA XX , J¼9.0 Hz, 2H), 7.23 (AA XX ,
ꢂ1
J¼9.0 Hz, 2H); IR (NaCl) 1594, 1581, 1493, 1462, 1441 cm
.
4. Ogura, F.; Yamaguchi, H.; Otsubo, T.; Nakano, T.; Saito, T. Bull. Chem. Soc. Jpn.
1983, 56, 1257–1258.
3
4
4
.3.14. 2-Chloroanisole (3o)
5. (a) Saidi, M. R.; Rajabi, F. Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 2343–
2348; (b) Randall, N. B. U.S. Patent 4,453,017 1984; Chem. Abstr. 1984, 101,
1
H NMR
d
3.90 (s, 3H), 6.91 (m, 2H), 7.22 (m, 1H), 7.35 (m, 1H); IR
ꢂ1
54713.
(
NaCl) 1589, 1487, 1463, 1450, 1436 cm
.
6. Bitter, I.; Csokai, V. Tetrahedron Lett. 2003, 44, 2261–2265.
7
. (a) Tundo, P.; Selva, M. Acc. Chem. Res. 2002, 35, 706–716; (b) Ono, Y. Pure Appl.
3
5
4
2
4
.3.15. 2,4,6-Trichloroanisole (3r)
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1986, 382–383.
Mp 61–63 C (lit. 61–62 C); 1H NMR
H); IR (KBr) 1551, 1472, 1418, 1385, 1370 cm
ꢀ
35
ꢀ
d 3.88 (s, 3H), 7.30 (s,
ꢂ1
.
3
6
.3.16. 2,4-Dichloroanisole (3s)
1
H NMR
d
3.88 (s, 3H), 6.84 (d, J¼8.8 Hz, 1H), 7.19 (dd, J ¼8.8 Hz,
1
9
. (a) Nasadyuk, V. A.; Fedevich, E. V.; Pazderskii, Yu. A.; Moiseev, I. I. Izv. Akad.
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J
2
¼2.5 Hz, 1H), 7.36 (d, J¼2.5 Hz, 1H); IR (NaCl) 1489, 1463, 1440,
ꢂ1
1292, 1263 cm
.
1
0. Umemura, K.; Matsuyama, H.; Kamigata, N. Bull. Chem. Soc. Jpn. 1990, 63, 2593–
3
7
4
.3.17. 1-Methoxy-4-propylbenzene (3t)
2600.
1
H NMR
d
0.92 (t, J¼7.3 Hz, 3H), 1.61 (m, 2H), 2.52 (t, J¼7.5, 2H),
11. (a) H a¨ hle, H. J. Prakt. Chem. 1890, 43, 62–75; (b) Hanhart, W.; Kelk Ingold, C.
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0
0
0
0
3
2
.78 (s, 3H), 6.82 (AA XX , J¼8.7 Hz, 2H), 7.09 (AA XX , J¼8.7 Hz,
ꢂ1
H); IR (NaCl) 1613, 1512, 1465, 1300, 1246 cm
.
1
3. (a) Carlsen, P. H. J.; Liberkova, K.; Harrex, R.; Røe, J. Acta Chem. Scand. 1997, 51,
3
8
343–344; (b) Spetea, M.; Greiner, E.; Aceto, M. D.; Harris, L. S.; Coop, A.;
4
.3.18. 1-Methoxy-2-propylbenzene (3u)
1
Schmidhammer, H. J. Med. Chem. 2005, 48, 5052–5055; (c) Klomp, D.; Dja-
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d
0.95 (t, J¼7.4 Hz, 3H), 1.59 (m, 2H), 2.58 (t, J¼7.6, 2H),
3
.81 (s, 3H), 6.80–6.91 (m, 2H), 7.09–7.20 (m, 2H); IR (NaCl) 1601,
ꢂ1 þ
494,1462,1439,1242 cm ; MS (EI) m/z 150 (M , 32),121 (100), 91
4
89; (d) Huang, W.; Chen, C.; Singh, O. V.; Lee, S.; Lee, S. Synth. Commun. 2002,
1
þ
81); HRMS (EI) calcd for C10H14O [M] 150.1045, found 150.1048.
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273–279.
(
3
9
4
4
4
.3.19. 1,4-Dimethoxybenzene (3v)
Mp 54–56 C (lit. 54–56 C); 1H NMR
ꢀ
39
ꢀ
14. Wittmann, H.; M o¨ ller, G.; Ziegler, E. Monatsh. Chem. 1966, 97, 1207–1216.
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d
3.77 (s, 6H), 6.84 (s,
1
1
ꢂ1
H); IR (KBr) 1638, 1510, 1468, 1439, 1298, 1240 cm
.
4
0
.3.20. 4-Bromoanisole (3w)
2
48953.
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0
0
0
0
H NMR
d
3.79 (s, 3H), 6.78 (AA XX , J¼9.0 Hz), 7.37 (AA XX ,
1
ꢂ1
J¼9.0 Hz); IR (NaCl) 1579, 1489, 1461, 1290, 1246 cm
.

11624
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