An efficient synthesis of 2-formyM,4,5,8-tetramethoxynaphthalene

Article abstract of DOI:10.3184/030823410X12843836823191

An improved synthetic method of 2-formyl-1,4,5,8-tetramethoxynaphthalene in 73% overall yield is described. This method has several advantages compared with the reported synthesis: first, the reactant is cheaper and the yield is higher; second, the reaction condition is milder and the reagent used is more friendly to environment; third, the work-up of each step is simpler; fourth, the protocol reported is more suitable for large-scale preparation.

Full text of DOI:10.3184/030823410X12843836823191

5
20 RESEARCH PAPER
SEPTEMBER, 520–521
JOURNAL OF CHEMICAL RESEARCH 2010
An efficient synthesis of 2-formyl-1,4,5,8-tetramethoxynaphthalene
Rubing Wang, Xiaogang Zheng, Wen Zhou, Ying Peng, Mengyuan Zhu and Shaoshun Li*
School of Pharmacy, Shanghai Jiaotong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
An improved synthetic method of 2-formyl-1,4,5,8-tetramethoxynaphthalene in 73% overall yield is described. This
method has several advantages compared with the reported synthesis: first, the reactant is cheaper and the yield is
higher; second, the reaction condition is milder and the reagent used is more friendly to environment; third, the
work-up of each step is simpler; fourth, the protocol reported is more suitable for large-scale preparation.
Keywords: shikonin, 2-formyl-1,4,5,8-tetramethoxynaphthalene, synthesis, methylation
Shikonin, one of the major active components of the traditional
Chinese medicine redroot gromwell, exhibits a wide variety
recrystallisation and the acetonitrile used in this step can be
recovered; When preparing 1,5-dibromo-4,8-dimethoxynaph-
thalene 4 according to Terada’s method, it was found that the
yield of this step in practice was very low (20–30%) and the
toxic reagent CCl and reactant Br was used. In this study,
1
of pharmacological effects, including anti-bacterial, anti-
2
3
4
5
inflammatory, antiviral, analgesic, immunostimulatory,
6
7
8
angiostatic, anti-thrombotic and anti-tumour activities.
Furthermore, it is also a natural pigment which has been used
in the food, cosmetics and dyeing industries. Therefore,
4
2
NBS was used instead of Br as a bromination reagent at low
2
9
temperature affording a yield of 88%. The best ratio of 1,5-
dimethoxynaphthalene 3 to NBS (1: 2.5) was established by
the analysis of a series of experimental conditions. The reac-
tion temperature of this step appeared to be very critical and
should be carefully controlled. If not, some monobromo-
substituent was produced and the yield decreased by 10–20%.
The 1,4,5,8-tetramethoxynaphthalene 5 was obtained by
refluxing with sodium methoxide (86%); Treatment of 5
substantial quantities of shikonin are required. Most processes
for the total synthesis of shikonin involve the reactant 2-
formyl-1,4,5,8-tetramethoxynaphthalene 1 as a key inter-
mediate. Although several synthetic routes of 1 have been
10–13
reported,
most of these routes have drawbacks such as
low-yield, expensive materials, high temperature, operational
difficulties, and pollute the environment. It is, therefore, neces-
sary to develop a new process. A convenient and efficient way
to synthesise 2-formyl-1,4,5,8-tetramethoxynaphthalene is
now reported using 1,5-dihydroxynaphthalene 2 as starting
material (Scheme 1).
with Vilsmeier reagent (POCl , DMF) gave 2-formyl-1,4,5,8-
3
tetramethoxynaphthalene 1 in 99% yield.
Conclusion
Result and discussion
A convenient and efficient method to synthesise 1,4,5,8-
tetramethoxynaphthalene was developed. Compared with the
method reported by Terada, 1,5-dimethoxynaphthalene 3
was synthesised with increased yield from 80 to 98% and
decreased reaction temperature from reflux to stirring at room
temperature. Moreover, the work-up was simpler. Product 3 of
adequate purity can be obtained by filtration without further
An improved synthesis of 2-formyl-1,4,5,8-tetramethoxynaph-
thalene in 73% total yield is described. 1,5-Dimethoxynaph-
thalene was synthesised almost quantitatively under mild and
friendly condition. This methylation method is also available
for other similar preparations. This overall method has several
advantages: first, the material and reactant is cheaper and the
yield is higher; second, the reaction condition is milder and
more friendly to environment, avoiding using toxic solvent
1
0
Scheme 1 a, (CH
3
2
) SO
4
, NaOH, (C
4
H
9
)
4
Br, THF-H
2
O, 98%; b, NBS, CH
3 3 3
CN, 88%; c, CH ONa, Cul, DMF-CH OH, 86%;
d, DMF, POCl
3
, CH Cl , 99%.
2
2
*
Correspondent. E-mail: ssli@sjtu.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2010 521
CCl and reactant Br ; third, the work-up of each step is sim-
recrystallised from ethyl acetate to afford 6.78 g white needles of 5
4
2
10
(
86%). m.p. 166–167 °C (lit. 167–168 °C). δ 6.86 (s, 4H, ArH × 4),
pler and the solvent can be recovered; fourth, the protocol
reported in this paper is more suitable for large-scale prepara-
tion of 2-formyl-1,4,5,8-tetramethoxynaphthalene for total
synthesis of shikonin and its derivatives.
3
.75(s, 12H, OCH × 4).
3
2
-Formyl-1,4,5,8-tetramethoxynaphthalene (1): A solution of 1,4,
5
,8-tetramethoxynaphthalene (6 g, 24.3 mmol) in chloroform (40 mL)
was added to a mixture of phosphoryl chloride (18.2 g, 120.8 mmol)
and N, N-dimethylformamide (8.8 g, 120.8 mmol) and the mixture
was refluxed for 10 h. Evaporation of the solvent gave a residue. The
residue was decomposed with ice water. The mixture was filtered and
recrystallised from hexane to obtain 6.63 g yellow crystals of 1 (99%),
Experimental
Reagents and solvents were obtained from commercial suppliers and
were used without further purification. All melting points were deter-
mined on XT34 binocular microscope (Beijing Tech Instrument Co.,
10
m.p. 124–125 °C (lit. 124–125.5 °C). δ 10.56 (s, 1H, ArCHO), 7.16
(s, 1H, ArH), 7.01 (d, J = 7.8, 1H, ArH), 6.93 (d, J = 7.4, 1H, ArH),
1
China). H NMR spectra were recorded on Mercuryplus 400 (300
MHz) spectrometer, chemical shifts were reported in parts per million
relative to tetramethylsilane. Splitting patterns were designated as s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Chem-
ical shifts were reported in parts per million relative to the solvent
3.99 (s, 3H, OCH ), 3.98 (s, 3H, OCH ), 3.92 (s, 3H, OCH ), 3.91 (s,
3 3 3
3H, OCH ).
3
This work was supported by National Natural Science Founda-
tion (No. 30973604) and Key Program of Basic Research of
Shanghai (No. 08JC1410800)
resonance as the internal standard (CDCl , δ = 7.16 ppm). Analytical
3
TLC and column chromatography were performed on silica GF254,
and silica gel H60, respectively.
1
,5-Dimethoxynaphthalene (3): Tetrabutylammonium bromide
Received 20 July 2010; accepted 6 August 2010
Paper 1000259 doi: 10.3184/030823410X12843836823191
Published online: 7 October 2010
(
(
1.6 g, 5 mmol), sodium dithionite (1 g, 5 mmol) sodium hydroxide
7.2 g, 180 mmol) were added to the solution of 1,5-dihydroxynaph-
thalene (12 g, 75 mmol) in THF-H O 150 mL (2:1) in portions under
2
N . Then dimethyl sulfate (14.3 mL, 150 mmol) was added dropwise
2
to the solution keeping the temperature below 30 °C. The resulting
mixture was stirred at room temperature. After 4 h, the solid was col-
lected by filtration to give 13.8 g yellow solid of 3 (98%). m.p. 183–
References
1
2
3
V.P. Papageorgiou, Planta Med., 1980, 38, 193.
S. Tanaka and M. Tajima, J. Nat. Prod., 1986, 49, 466.
X. Chem, L.Yang, J. Oppenheim and D.M. Howard, Phytother. Res., 2002,
16, 199.
10
1
1
85 °C, (lit. 183–184 °C). H NMR(CDCl3): δ 6.86 (s, 4H,ArH × 4),
3
.75 (s, 12H, OCH × 4).
3
4
5
M. Hayashi, Nippon Yakurigaku Zasshi., 1977, 73, 205.
H. Wagner, B. Kreher and K. Jurcic, Arzneim. Forsch./Drug Res., 1988, 38,
1
,5-Dibromo-4,8-dimethoxynaphthalene (4): A solution of N-
bromosuccinimide (22.2 g, 125 mmol) in acetonitrile (150 mL) was
added dropwise to a suspension of 1,5-dimethoxynaphthalene (9.4 g,
2
73.
T. Hisa,Y. Kimura, K. Takada, F. Suzuki and M. Takigawa, Anticaner Res.,
988, 18, 783.
Y.S. Chang, S.C. Kuo, S.H. Weng, S.C. Jan, F.N. Ko and C.M. Teng, Planta
Med., 1993, 59, 401.
6
7
5
0 mmol) in acetonitrile (100 mL), which was cooled in a salt-ice
1
bath. The resulting mixture was stirred at 10 °C under N for 2 h. The
2
resulting solid was collected by filtration, washed with methanol and
then with petroleum ether to afford 15.2 g greenish powder of 4 (88%).
8
9
0
B.Z. Ahn, K.U. Baik and G.R. Kweon, J. Med. Chem., 1995, 38, 1044.
A.H. Zhao, D.F. Xu, W. Zhou and S.S. Li, J. Chem. Res., 2007, 11, 647.
A. Terada, Y. Tanoue, A. Hatada and H. Sakamoto, Bull. Chem. Soc. Jpn.,
14
m.p. 183–185 °C (lit. 185–187 °C).
,4,5,8-Tetramethoxynaphthalene (5): A mixture of 1,5-dibromo-
,8-dimethoxynaphthalene (11 g, 32 mmol), sodium methoxide
5.7 g, 106 mmol), copper (I) iodide (20 g, 106 mmol), N, N-dimeth-
1
1
1
987, 60, 205.
4
(
1
1
1
2
H. Futagoishi and T. Abe, Cosmet. Perfum., 1973, 88, 51.
D.F. Xu, P.J. Guan, Z.Q. Mao, Z.M. Wang and S.S. Li, Chin. J. Pharm.,
ylformamide (150 mL) and methanol (150 mL) was refluxed for 36 h.
The mixture was filtered when it was hot. The filtrate was poured into
ice water and the resulting precipitate was filtered. The residue was
2
004, 35, 583.
13 D.F. Xu, P.J. Guan and S.S. Li, J. Chem. Res., 2006, 779.
14 Y.C. Pan and Z.H. Peng, Tetrahedron Lett., 2000, 41, 4537–4540.

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.