An alternative route for the synthesis of 2,3,4,5-tetramethoxytoluene

Article abstract of DOI:10.3184/030823409X424885

The transformation of the commercially available 2,3,4- trimetho×ybenzaldehyde to 2,3,4,5-tetrametho×ytoluene using a Dakin reaction to insert the extra oxygen, formylation, reduction and methylation of the phenolic hydro×yl group is described.

Full text of DOI:10.3184/030823409X424885

1
86 RESEARCH PAPER
MARCH, 186-187
JOURNAL OF CHEMICAL RESEARCH 2009
An alternative route for the synthesis of 2,3,4,5-tetramethoxytoluene
William J. Vera, Kimberly Chinea and Ajoy K. Banerjee*
Centro de Quimica, IVIC., Apartado-21827,
Caracas-l020A,
Venezuela
The transformation
using Dakin reaction to insert the extra oxygen, formylation,
hydroxyl group is described.
of the commercially available 2,3.4-trimethoxybenzaldehyde
to 2,3,4,5-tetramethoxytoluene
of the phenolic
a
reduction and methylation
Keywords: 2,3,4-methoxybenzaldehyde, coenzyme QlO, Dakin reaction, formylation, catalytic hydrogenation, methoxylation
Coenzyme QlO 6 (also known as ubiquinone) has been used
as a drug in the treatment of various heart-related diseases.!
Its role as an anti-oxidant in preventing lipid and DNA
and Vilsmeier-Haack reactionS but the yield of the aldehyde 3
could not be improved. The methylphenol 4 on methylation
with dimethylsulfate and sodium hydroxide furnished the target
compound 2,3,4,5-tetramethoxytoluene 5 in 73% yield whose
identity was confirmed by spectroscopic data.
oxidation and quenching free radicals2,3 has encouraged several
organic chemists to seek an efficient synthetic route
4
for the
preparation of coenzyme QlO' In connection with our studies on
bioactive natural products, we needed to develop a simple and
efficient route for the synthesis of 2,3,4,5-tetramethoxytoluene.
The results of our efforts are described in the present report.
The synthetic route is described in Scheme 1.
In conclusion a simple approach for the synthesis of the
compound 5 has been achieved in moderate yield. We believe
that the yield of the aldehyde 3 can be improved by changing
the experimental conditions for formylation and such
a
project is under investigation along with the accumulation
of sufficient material of compound 5 for its conversion to the
coenzyme QlO'
The commercially available 2,3,4-trimethoxybenzaldehyde
1
was considered a promising starting material for the
synthetic entry into the title compound 4. Dakin reactionS
of the aldehyde 1 in methanol with sulfuric acid (conc.) and
hydrogen peroxide (30%) furnished 2,3,4-trimethoxyphenol
Experimental
Unless otherwise stated, IR spectra were taken on a Nicolet FT
spectrophotometer, a Broker AM 300 MHz spectrometer was
employed for the determinationof 'H and l3CNMR spectra with
deuteriumchloroformas solvent. Mass spectra were run on Kratos
MS25RFAand GCMs-ma-HewlettPackard 5890 Quadrupole5972
SeriesS.Theexpression"workup" indicatesthatthereactionmixture
was diluted with water, extracted with ether, washed with brine,
2
in 95% yield. It was formylated6 with paraformaldehyde,
triethylamine and magnesium chloride to obtain the aldehyde
. The formation of the aldehyde 3 was confirmed by its
H NMR spectrum which exhibited aldehyde proton at Ii 9.72
3
!
ppm and also by the signal at Ii 194.81 ppm in the 13CNMR
spectrum. It showed a band at 1650 cm-! in the 1R spectrum
and a molecular ion at 212 amu (M+) in the mass spectrum.
dried over MgS0
Columnchromatographywas performedon silica gel (Merckgrade
4
and solvent evaporatedunder reduced pressure.
As the aldehyde 3 and phenol 2 had very similar R values
f
6
0, 70-230 mesh). Microanalyseswere carriedout at the Chemistry
on TLC plates their separation could not be achieved by any
chromatographic technique. An analysis of the !H NMR
spectrum of the mixture of phenol 2 and aldehyde 3 clearly
indicated the formation of the aldehyde 3 in 33% yield.
The mixture was hydrogenated over Pd-C (10%) in ethanol
under hydrogen at 500 psi (35 atm) at room temperature.
The methylphenol 4 was obtained almost in quantitative yield.
The formylation was also attempted by Reimer- Tiemerreaction 7
Department,IVIC,Caracas,Venezuela.
2,3,4-Trimethoxyphenol2: Cone.Sulfuricacid(0.5mL, 6.4mmol)
was added to a stirred solutionof the aldehyde1 (2 g, 10.2mmol)
dissolvedin methanol(20 mL), cooledto lOoC,and then hydrogen
peroxide(30%, I mL, 32.6mmol)was addeddropwise.Thereaction
mixturewas stirredat 10°Cfor 30min and24h atroomtemperature,
dilutedwith water and extractedwith dichloromethane .T he organic
extract was washed with brine, then with an aqueous solution of
sodiumbicarbonate(5%). It was dried andthe solventevaporatedto
CHO
OH
OH
(
1)
(ii)
..
.. O"~O"'
9
:0 "' 9:0 "'
.
#
OMe
. #
OMe
. #
OMe
OMe
OMe
OMe
2
3
!
(iii)
OH
0
OMe
MeO
MeO
(
iv)
"
,*0",
_
-------"'* 0 ".,
.
#
OMe
H
. #
OMe
OMe
Me
10
OMe
6
5
4
*
Correspondent.E-mail:abanerje@ivic.ve

JOURNAL OF CHEMICAL RESEARCH 2009 187
give the phenol 2 (1.78 g, 95%); Urn", 3418 (OH) cm-'; 'H NMR:
) 3.75 (s, 3H), 3.85 (s,3H), 3.89 (s,3H) (2,3,4-0Me), 5.67 (s, lH,
OH), 6.49-6.60 ('lAB,2H, J 8 Hz), (5-H, 6-H). l3C NMR: 1) 146.9
C4), 143.4 (CI), 142.3 (C2), 140.5 (C3), 108.7 (C6), 107.6 (C5),
a solution of the phenol 4 (352 mg, 1.77 mmol) in ethanol (100 mL).
The resulting mixture was stirred at room temperature and then heated
under reflux at 80°C for 2 h. The reaction mixture was cooled, diluted
with water and extracted with ether. The organic extract was washed,
dried and evaporated under reduced pressure. Preparative TLC of
the residue on silica gel (eluant hexane-chloroform 6: 4) yielded the
target compound 5 (274 mg, 73%); 'HNMR: 1) 2.17 (s, 3H, Me), 3.73
1
=
(
6
1.1 (C7), 60.8 (C8), 56.6 (C9); MS: 184 (M+); Anal. Calcd for
1204: C,58.69; H, 6.57. Found: C, 58.84; H, 6.69%
-Formyl-2,3, 4-trimethoxyphenol3: A mixture of phenol 2 (1.01 g,
.4 mmol), anhydrous magnesium chloride (1 g, 10.5 mmol),
triethylamine (1.5 mL, 10.8 mmol) and paraformaldehyde (0.5 g,
6.7 mmol) under nitrogen and in dry THF (50 mL) was heated under
C H
9
6
5
(s, 3H), 3.76 (s, 3H), 3.81 (s, 3H), 3.87 (s, 3H) (2,3,4,5-0Me), 6.39
(s, lH, 5-H); l3C NMR: 1) 149.1 (C4), 147 (C2), 145.5 (CI), 140.9
(C3), 125.8 (C6), 108.4 (C5), 61.1 and 61.6 (C7, C8), 60.5 (ClI),
1
reflux for 4 h. The reaction mixture was cooled, acidified (5% HCI)
and extracted with dicWoromethane. The usual work up yielded an oil
5
6
6.1 (C9), 15.8 (CIO); MS: 212 (M+); Anal.Calcd. for CllH,604: C,
2.25; H, 7.60. Found: C, 62.41; H, 7.69%
(1.03 g) which contained a mixture of phenol 2 (615 mg, 62%) and
aldehyde 3 (382 mg, 33%); urn", 1650 (CO) cm-'; 'H NMR: 1) 3.75
(s,3H), 3.84 (s,3H), 3.89 (s,3H), (2,3,4-0Me), 6.73 (s,lH, 5-H), 9.72
(s, lH, CHO), 10.93 (s, lH, OH); l3C NMR: 1) 194.8(CHO), 151.7
(CI), 150.3 (C4), 143.3 (C3), 140.9 (C2), 115.2 (C6), 107.6 (C5),
We thank LOCTI for financial support of this work
Received 16 January 2009; accepted 9 February 2009
Paper 09/0395 doi: 10.3184/030823409X424885
Published online: 6 April 2009
6
1.1 (C7), 60.8 (C8), 56.4 (C9); MS: 212 (M+). As we were unable
to separate the phenol 2 and aldehyde 3, an analytical sample of the
aldehyde 3 could not be prepared.
2
,3,4- Trimethoxy-6-methylphenoI4: The mixture (1.03 g) of phenol
2
and aldehyde 3 was dissolved in ethanol (40 mL) and hydrogenated
References
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up followed by chromatographic purification over silica gel (eluant
hexane) furnished phenol 4 (352 mg, 98%); Urn", 3418 (OH) cm-';
1
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2
2
'
H NMR: 1) 2.16 (s, 3H, Me), 3.75 (s, 3H), 3.89 (s, 3H) (2,3,4-
OMe), 5.65 (s, lH, OH), 6.40 (s, lH, 5-H); l3C NMR: 1) 145.9 (C4),
41.1 (CI), 140 (C2), 139 (C3), 118.1 (C6), 109.5 (C5), 60.8 (C7),
1.1 (C8), 56.5 (C9), 15.4 (CIO); MS: 198 (M+); Anal. Calcd. For
CIOH,404: C, 60.59; H, 7.12. Found: C, 60.76; H, 7.26%
,3,4,5- Tetramethoxytoluene 5: Freshly distilled dimethylsulfate
13 mL, 0.13 mmol) and sodium hydroxide (13 mL 10%) was added to
2
3
4
5
6
7
8
1
6
2
(