Synthesis of 2,3-dimethoxy-5-methyl-1,4-benzoquinone: A key fragment in coenzyme-q series

Article abstract of DOI:10.1081/SCC-100103252

Preparation of the title compound by a reaction sequence starting from gallic acid present in mango kernel is described.

Full text of DOI:10.1081/SCC-100103252

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SYNTHESIS OF 2,3-
DIMETHOXY-5-METHYL-1,4-
BENZOQUINONE: A KEY
FRAGMENT IN COENZYME-Q
SERIES*
Asiya Seema Chida a , Parimi V. S. N. Vani a
, Malapaka Chandrasekharam a , Rajagopal
Srinivasan a & Ashok Kumar Singh b
a Bio-Organic Laboratory , Division of Organic
Chemistry – III , Indian Institute of Chemical
Technology , Hyderabad, 500 007, India
b Bio-Organic Laboratory , Division of Organic
Chemistry – III , Indian Institute of Chemical
Technology , Hyderabad, 500 007, India
Published online: 16 Aug 2006.
To cite this article: Asiya Seema Chida , Parimi V. S. N. Vani , Malapaka
Chandrasekharam , Rajagopal Srinivasan & Ashok Kumar Singh (2001) SYNTHESIS
OF 2,3-DIMETHOXY-5-METHYL-1,4-BENZOQUINONE: A KEY FRAGMENT IN COENZYME-
Q SERIES* , Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:5, 657-660, DOI: 10.1081/
SCC-100103252
To link to this article: http://dx.doi.org/10.1081/SCC-100103252

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SYNTHETIC COMMUNICATIONS, 31(5), 657–660 (2001)
SYNTHESIS OF 2,3-DIMETHOXY-
5-METHYL-1,4-BENZOQUINONE: A KEY
FRAGMENT IN COENZYME-Q SERIES*
Asiya Seema Chida, Parimi V. S. N. Vani,
Malapaka Chandrasekharam, Rajagopal Srinivasan, and
Ashok Kumar Singh{
Bio-Organic Laboratory, Division of Organic
Chemistry – III, Indian Institute of Chemical Technology,
Hyderabad – 500 007, India
ABSTRACT
Preparation of the title compound by a reaction
sequence starting from gallic acid present in mango kernel is
described.
2,3-Dimethoxy-5-methyl-1,4-benzoquinone (Ubiquinone Q0) is used
for treatment of degenerative nervous system disorder1a and hair direct
dye compound. There are several methods1c to synthesise Ubiquinone Q0.
We present here a convenient synthesis from gallic acid obtained from
mango kernel.1d Our attempts to obtain the compound 2 in one pot reaction
from gallic acid using dimethyl sulphate and K2CO3 in acetone required
longer reaction time and resulted in moderate yield. However the yield is
quantitative when a catalytic amount of tetra-n-butylammonium iodide
(TBAI) is used as PTC in the above reaction. The ester 2 is treated with
* IICT communication number 4478.
{ Corresponding author.
657
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

658
CHIDA ET AL.
99% N2H4.H2O in methanol to obtain the hydrazide 4 in 86.4% yield2a and
it is subjected to oxidation using K3Fe(CN)6 in the presence of ammonia
solution to form the corresponding aldehyde 52b,o. This reaction has been
tried in 1,2-dichloroethane,2b benzene 2c and methylene chloride (DCM). An
optimum yield (85%) of product 5 is obtained with DCM.
The reduction of aldehyde 5 to toluene 6 with LiAlH4-AlCl3/Ether or
NaBH4-Pd/C/iPrOH or Fe-NH4Cl/EtOH or CuCl-NH4Cl/EtOH was failed
and Li or Na/NH3/THF and Zn-Hg/EtOH gave poor yield. When the
Clemmensen reduction was performed in acetic acid and toluene medium,
the reaction was completed within 45min in 65% yield alongwith a side
product 3,4,5-trimethoxybenzyl alcohol. Oxidation of compound 6 to
Ubiquinone Q0 (7) was carried out in 30% H2O2, HCOOH and phospho-
molybdic acid in 57% yield.2d When 50% H2O2 is used in this conversion,
yield of product 7 is improved to 80%. Gallic acid can be converted to an
important drug intermediate 3.1b
1
Experimental: H NMR spectra were recorded at 200 MHz (CDCl3/
TMS) on a Varian-Gemini spectrometer. IR spectra (cm-1) were recorded on
Schimadzu IR-470 and Mass spectrum (EI) on Finnigan Mat-1210 spectro-
meter.
Compound 2: Gallic acid (50 g, 0.294 mol), Me2SO4 (178.1 g, 1.413 mol),
anhy. K2CO3 (175.5 g, 1.293 mol), and TBAI (1 g) in acetone (375 ml)
were refluxed for 12 h. Filtered, washed with acetone (3ꢀ150 ml) and the

UBIQUINONE Q0
659
washings were combined to the filtrate. Removal of solvent afforded the
compound 2 in quantitative yield. Rf ¼ 0.55 (EtOAc-Pet. ether, 1:1) m.p.:
85ꢁC (lit1b 82–83ꢁC). IR: 1717. 1H-NMR: ꢀ 1.60 (s, 3H), 3.92 (s, 9H),
7.33 (s, 2H). MS (m/e): 226(Mþ).
Compound 4: Ester 2 (96 g, 0.424 mol), 99% N2H4.H2O solution
(155.2 g, 3.099 mol), and MeOH (325 ml) were refluxed for 5 h and then
kept at RT overnight. The solid obtained was filtered and recrystallised
from hot MeOH to afford the compound 4 in 86.4% (83 g). Rf ¼ 0.55
(MeOH-EtOAc-Pet. ether, 1.5:4:4.5) m.p.: 158–160ꢁC (lit2e 168ꢁC). IR:
1
3200–3435, 1708. H-NMR: ꢀ 3.80 (s, 3H), 3.90 (s, 6H), 7.18 (s, 2H), 9.55
(brs, NH). MS (m/e): 226(Mþ).
Compound 5: Hydrazide 4 (30 g, 0.132 mol), K3Fe(CN)6 (113.4 g,
0.333 mol), and 25% ammonia solution (14.2 g, 0.833 mol) were taken in a
mixture of distilled water (300 ml) and DCM (750 ml) stirred at room tem-
perature for 4 h. The two layers were separated and the aqueous layer
extracted with DCM (2 ꢀ 250 ml). The extracts were combined to the
organic layer and concentrated to give compound 5. It was purified by
silica gel column chromatography using EtOAc-Pet. ether (1:3) as eluent
to give a colourless solid in 85% yield (22.2 g). Rf ¼ 0.74 (EtOAc-Pet.
ether, 1:1) m.p: 74–75ꢁC (lit.2f 77–78ꢁC). IR: 1686. H-NMR: ꢀ 3.98 (s,
1
9H), 7.20 (s, 2H), 9.90 (s, 1H). MS (m/e): 196(Mþ).
Compound 6: Aldehyde 5 (10 g, 0.051 mol), Zn–Hg (25.0 g) were taken
in a mixture of water (10 ml), acetic acid (5ml), and toluene (25ml) and
refluxed for 45min. The reaction mixture was filtered and washed with
toluene. The filtrate was neutralized with 10% NaOH solution. The organic
layer was separated, washed with water, dried over anhy. Na2SO4 and
concentrated. The crude compound chromatographed over silica gel
column using EtOAc-Pet. ether (0.2:9.8) as eluent to isolate pure compound
61b,c as liquid in 65% yield (6.1 g) Rf ¼ 0.46 (EtOAc-Pet. ether, 1:9).
1H-NMR: ꢀ 2.28 (s, 3H), 3.75(s, 3H), 3.82 (s, 6H), 6.33 (s, 2H). MS
(m/e): 182 (Mþ).
Ubiquinone Q0 (7): Compound 6 (5.4 g, 0.0297 mol), 50% H2O2
(7.5ml, 0.1092 mol), phosphomolybdic acid (0.2 g) and 98% formic acid
(7.5ml, 0.1582 mol) were stirred at RT for 15min. Excess formic acid was
removed, extracted with CHCl3 (3 ꢀ 35ml), dried over anhy. Na 2SO4 and
concentrated. The residue was chromatographed over silica gel column
using EtOAc-Pet. ether (1:24) to obtain compound 7 as an orange crystalline
solid in 80% yield (4.3 g). Rf ¼ 0.24 (EtOAc-Pet. ether, 1:9) m.p.: 55–57ꢁC

660
CHIDA ET AL.
ꢁ
1
(lit1c. 5 9C). IR: 1662, 1600. H-NMR: ꢀ 2.05(s, 3H), 4.02 (s, 3H), 4.04
(s, 3H), 6.40 (s, 1H). MS (m/e): 182(Mþ).
ACKNOWLEDGMENT
A.S.C. and P.V.S.N.V. thank Dr. K. V. Raghavan, Director, IICT,
Hyderabad for allowing to work in this project and for financial support.
REFERENCES
1. (a) Goto, G.; Hayashi, K.; Can. Pat. Appl. CA 2, 011, 587 (CI A 61
K311/085); (b) Sugihara, H.; Watanabe, M.; Kawamatsu, Y.;
Morimoto, H. Justus Liebigs Ann. Chem. 1972, 763, 109–120 (Ger);
(c) Keinan, E.; Eren, D. J. Org. Chem. 1987, 52, 3872–3875and ref.
therein; (d) Personal communication.
2. (a) Wang, Q.; Liu, J. CA 130, 281827q, 1999. (b) Dietz, A.; Jakfalvi, E.;
Beck, I.; Takacs, Z.; Gubis, F.; Tompe, P.; Ladinyi, L.; Kiss, C.;
Tompe, J.; (E.Gy.T.Gyogyszar Vegyeszeti Gyar) Hung.Teljes HU 23,
214 (C1 C07C47/565); (c) Okuno, T.; Nishihara, T.; Nishimoto, S.;
Seruma, M.; Hiramatsu, H. Japan 74 28, 184 (C1 C07c, B 01j); (d)
Orita, H.; Shimizu, M.; Hayakawa; Takehira, K.; Eur. Pat. Appl. EP
347, 021 (C1 C07c46/02); (e) Buchanan, G.L.; Cook, J.W.; Loudon,
J.D., CA 38: 58202, 1944; (f) Perkin, W.H.; Weizmann, C. J. Chem.
Soc., 1906, 89, 1649.