An alternate preparation of 3,4,5-trimethoxyphenol

Full text of DOI:10.1080/00304948.2013.798570

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An Alternate Preparation of 3,4,5-
Trimethoxyphenol
a
a
a
a
a
Qi-Xue Qin , Jian Yang , Duo-Zhi Chen , Bo Yang & Ji Zhang
a
Faculty of Life Science and Technology , Kunming University of
Science and Technology (ChengGong Campus) , Kunming , 650500 ,
Yunnan Province , P. R. China
Published online: 24 Jun 2013.
To cite this article: Qi-Xue Qin , Jian Yang , Duo-Zhi Chen , Bo Yang & Ji Zhang (2013) An Alternate
Preparation of 3,4,5-Trimethoxyphenol, Organic Preparations and Procedures International: The New
Journal for Organic Synthesis, 45:4, 321-324, DOI: 10.1080/00304948.2013.798570
To link to this article: http://dx.doi.org/10.1080/00304948.2013.798570
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Organic Preparations and Procedures International, 45:321–324, 2013
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2013.798570
OPPI BRIEF
An Alternate Preparation
of 3,4,5-Trimethoxyphenol
Qi-xue Qin, Jian Yang, Duo-zhi Chen, Bo Yang, and Ji Zhang
Faculty of Life Science and Technology, Kunming University of Science and
Technology (ChengGong Campus), Kunming 650500, Yunnan Province,
P. R. China
3,4,5-Trimethoxyphenol (4) is an important intermediate for the preparation of baicalein,
a natural product possessing significant pharmacological activities and whose derivatives
and analogs are under current investigation. 1
–7
Scheme 1
Structure of baicalein
Of the many methods for its preparation,8–11 the simplest employs the Baeyer-Villiger re-
arrangement of commercially available and expensive 3,4,5-trimethoxybenzaldehyde fol-
lowed by hydrolysis to produce 4 in 46% yield. However, the reaction conditions are
very harsh and employ catalysts or reagents that are toxic and environmentally unfriendly.
The methylation of 2,6-dimethoxyhydroquinone also gave 4 albeit in poor yields (<5%)
12
because of the poor regioselectivity of the reaction as would be expected. More re-
cently, inexpensive and commercially available 3,4,5-trimethoxybenzoic acid (1) has been
used as a source of 4 via substitutive ipso nitration to 3,4,5-trimethoxynitrobenzene fol-
13
lowed by reduction to the aniline, diazotization and hydrolysis. As part of our program
for the development of natural biological compounds and in the investigation on their
structure-activities relationships,1
4,15
we now report an alternative and efficient process to
Received December 27, 2012.
Address correspondence to Jian Yang, Faculty of Life Science and Technology, Kunming Uni-
versity of Science and Technology (ChengGong Campus), Kunming 650500, Yunnan Province, P. R.
China. E-mail: pharmacistkg101@gmail.com
321

322
Yang et al.
prepare aniline 3 from 1 and improved the yield of the conversion of 3 to 4 from 56% to
0%.
8
Scheme 2
In conclusion, the process is concise, safe, easily performed and can be scaled-up. The
overall yield of 4 from 1 was 58%. Avoidance of highly toxic and expensive reagents makes
the procedure cost-effective and environment friendly.
Experimental Section
All reactions were monitored by TLC on silica gel GF254 with mixed solvents (hexane :
1
ethyl acetate, 2:1) as developer. H NMR spectra were measured at 500 MHz (CDCl3/TMS)
on a Bruker Dr ×500 spectrometer and chemical shift are reported in ppm (δ) relative to
TMS as internal standard. Mass spectra were determined (FABMS) on VG Auto Spec-3000
spectrometer and reported as m/z. Melting points are uncorrected.
3,4,5-Trimethoxybenzamide (2)
To a mixture of 3,4,5-trimethoxybenzoic acid 1 (106.0 g, 0.5 mol) in 200 ml CH2Cl2, 0.2 ml
◦
DMF and 45 ml SOCl2 were added. The reaction mixture was stirred at 45 C for 3 h and the
gases generated were absorbed in an aqueous alkali solution. Then, the solvent CH2Cl2 and
excess SOCl2 were evaporated under reduced pressure to give a pale-yellow solid residue
of 3,4,5-trimehoxybenzoyl chloride, which was dissolved in 100 ml dry acetone at room
◦
temperature and slowly added into 92 ml 25% ammonia at 0 C under vigorous stirring. The
◦
mixture was stirred for another 1 h at 0 C and the solid was collected and recrystallized
◦
6
◦
from water to give colorless needles (95.0 g, 90% yield), mp. 173–175 C, lit. 174–176 C.
1
+
H NMR: δ7.06 (s, 2H), 3.92 (s, 6H), 3.91(s, 3H). MS (m/e): 211(M ).
3,4,5-Trimethoxyaniline (3)
To 600 ml of 12% commercial sodium hypochlorite solution and 600 ml 2 M NaOH,
compound 2 (160.0g, 0.75 mol) was addedin portions over 30 minutes. Thereaction mixture
◦
was vigorously stirred below 25 C until TLC showed that compound 2 had disappeared; the
◦
reaction mixture was then heated to 100 C under stirring. After the reaction was complete,

Alternate Preparation of 3,4,5-Trimethoxyphenol
323
it was cooled and the solid was collected and saved. The filtrate was extracted with CH2Cl2
(
2 × 2000 ml) and the extracts were dried over anhydrous magnesium sulfate, filtered
and evaporated in vacuo to give a solid. This solid was combined the solid above and
recrystallized from water to give compound 3 as white crystals (109.7 g, 80% yield), mp.
◦
13
◦
1
1
1
11–113 C, lit. 110–110.5 C. H NMR: δ5.95(s, 2H), 3.82(s, 6H), 3.77(s, 3H). MS (m/e):
+
83(M ).
3,4,5-Trimethoxyphenol (4)
To a solution of 3,4,5-trimethoxyaniline (3, 91.5 g, 0.5 mol) in 2000 ml of 10% H2SO4
◦
cooled to 15 C was added dropwise a solution of NaNO2 (35.0 g, 0.5 mol) in 200 ml
water over 30 minutes. Once the addition was complete, the reaction mixture was stirred
◦
for another 2–3 h at 10–15 C and then the diazonium salt solution (CAUTION!) was
slowly added dropwise into a boiling solution of 1500 ml 10% H2SO4 and 200 g CuSO4
over 2 h. The reaction mixture was stirred for another 10 minutes and then cooled to
room temperature and extracted with CH2Cl2 (2 × 2000 ml). The extracts were dried over
anhydrous magnesium sulfate and evaporated in vacuo to give a solid. The residue were
recrystallized from petroleum-ethyl acetate (1:1) to give compound 4 as white crystals
◦
9
◦
1
(
3
73.0 g, 80% yield), mp. 145–147 C, lit. 144–145 C. H NMR: δ 6.09(s, 2H), 3.80(s, 6H),
.76(s, 3H). MS (m/e): 184(M ).
+
Note: The 10% H2SO4 aqueous waste solution containing CuSO4 should be recovered
and use repeatedly.
Acknowledgment
This work was supported by National Natural Science Foundation of China (NSFC) (No.
21062009) and the Natural Science Foundation of Yunnan Province (No. 2011FZ059),
which are gratefully acknowledged.
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