A convenient synthesis of 2-formyl-1,8:4,5-bis(methylenedioxy) naphthalene

Article abstract of DOI:10.3184/030823407X266216

2,3-Dihydronaphazarin was prepared from 1,4-dimethoxybenzene and dichloromaleic anhydride. Reaction with bromochloromethane gave 1,8:4,5-bis(methylenedioxy)naphthalene which with NBS, gave 2-bromo-1,8:4,5-bis- (methylenedioxy)naphthalene. Reaction of the Grignard derivative with DMF afforded 2-formyl-1,8:4,5-bis(methylenedioxy)naphthalene. This method had several advantages compared with the reported synthesis, including fewer steps, milder condition and higher yields.

Full text of DOI:10.3184/030823407X266216

JOURNAL OF CHEMICAL RESEARCH 2007
NOVEMBER, 647–648
RESEARCH PAPER 647
A convenient synthesis of 2-formyl-1,8:4,5-bis(methylenedioxy)naphthalene
Ai-Hong Zhao, De-Feng Xu, Wen Zhuo, Zhen Rao and Shao-Shun Li*
School of Pharmacy, Shanghai Jiaotong University, Minghang, Shanghai 200240, P.R.China
2,3-Dihydronaphazarin was prepared from 1,4-dimethoxybenzene and dichloromaleic anhydride. Reaction with
bromochloromethane gave 1,8:4,5-bis(methylenedioxy)naphthalene which with NBS, gave 2-bromo-1,8:4,5-bis-
(methylenedioxy)naphthalene. Reaction of the Grignard derivative with DMF afforded 2-formyl-1,8:4,5-bis(methylene-
dioxy)naphthalene. This method had several advantages compared with the reported synthesis, including fewer
steps, milder condition and higher yields.
Keywords: 2-formyl-1,8:4,5-bis(methylenedioxy)naphthalene, Grignard reagent, shikonin, intermediate, synthesis
Shikonin 8, the active ingredient of the traditional Chinese
medicine redroot gromwell, exhibits a wide variety of
pharmacological effects, including antibacterial, anti-
inflammatory, antivirus and anti-tumor activity.1 Shikonin is
a natural pigment which has been used in the food, cosmetics,
printing and dyeing industries. Substantial quantities of
shikonin are therefore required. The total synthesis of shikonin
involves a key intermediate 2-formyl-1,4,5,8-tetramethoxy-
naphthalene, which involves a tedious preparation.2,3 Progress
was made by Nicolaou et al. who used a naphthazarin
intermediate protected by a methylene in the total synthesis
of shikonin.4,5
Experimental
General
Reagents and solvents were obtained from commercial suppliers
and were used without further purification. All melting points
were determined on a XT34 binocular microscope (Beijing Tech
Instrument Co., China) and were not corrected. 1H NMR spectra
were recorded on Mercuryplus 400 (300 MHz) spectrometer,
chemical shifts (δ) 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. chemical shifts
were reported in parts per million relative to the solvent resonance
as the internal standard (CDCl3, δ = 7.16 ppm). Analytical TLC and
column chromatography were performed on silica gel GF254, and
silica gel H60, respectively.
The naphthazarin intermediate reported by Nicolaou was
synthesised by the reaction of DMF with an organolithium
compound obtained by the reaction of 2-bromo-1,8:4,5-
bis(methylenedioxy)naphthalene and n-butylithium at –78°C.
However, the harsh reaction condition and expensive reagent
made it difficult to use this in multigram preparations. Kim
has reported that5 the intermediate 1 could be obtained from a
formylation of 1,8:4,5-bis(methylenedioxy)naphthalene with
Vilsmeier (POCl3 and DMF) in CHCl3. However we found
that this reaction did not proceed smoothly. A new route based
on the literature was designed as follows.
2,3-Dichloronaphthazarin (4): This compound was prepared
in 98.2% yield from dichloromaleic anhydride and 1,4-
dimethoxybenzene according to the method described by Hour and
Brasard.6 Crystallisation fom petrolroleum ether gave the quinone
m.p. 197–199°C (lit.6 yield 97% m.p. 198-199°C).
2,3-Dihydronaphazarin (5):Amixture of 2, 3-dichloronaphthazarin
(5.2 g, 0.02 mol), SnCl2.H2O (31.2 g, 0.14 mol), 300 ml 4M HCl
was refluxed for 5 h. The green solution was formed after 30 min
of reflux. The reaction was monitored by TLC. After the reaction
was completed, the mixture was filtered while heated and the filtrate
was cooled to room temperature and filtered to give a green crystal 5
(3.4 g, 89.1%), m.p. 147–149°C (lit.7 yield 73% m.p. 148–151°C).
1,8:4,5-Bis(methylenedioxy)naphthalene (6): To a solution of
2,3-dihydronaphazarin 5 (2.0 g, 10.4 mmol) and dry K2CO3 (7.3 g,
52.9 mmol) in DMF (100 ml), bromochloromethane (3.3 g, 25.5 mol)
was added dropwise under N2. The reaction mixture was stirred for
24 h at 80–85°C. The solvent was evaporated under reduced pressure.
The residue was dissolved in ethyl acetate, washed with water, dried
with MgSO4 and recrystallised with petroleum ether to give white
crystals 6 (1.61 g, 72.2%). m.p.149–151°C. 1H NMR (CDCl3):
δ = 6.83 (s, 4H, ArH × 4), 5.58 (s,4H, –OCH2O- × 2). (lit.5 m.p. 154–
156°C, 1H NMR (CDCl3): δ = 6.8 (s, 4H), 5.5 (s,4H)).
2,3-dihydronaphazarin
5
was obtained from 1,4-
dimethoxybenzene and dichloromaleic anhydride, by Friedel–
Crafts condensation and reduction. Compound 5 was then
protected by methylene groups using bromochloromethane
and reacted with NBS to give 6. This was transformed into
a Grignard reagent, and treated with DMF to afford the
important intermediate 2-formyl-1,8:4,5-bis (methylenedioxy)
naphthalene for the synthesis of shikonin 1. This method had
several advantages compared with the synthesis reported
including fewer steps, mild condition and high yields. The
overall yield was 39.9% based on 2.
2-Bromo-1,8:4,5-bis(methylenedioxy)naphthalene(7):8 NBS(1.9g,
11.9 mol) was added. To 1,8:4,5-bis(methylenedioxy)naphthalene
6 (2.2 g, 11.5 mmol) in CHCl3 (100 ml), The reaction mixture was
OH
O
OH
O
OMe
O
Cl
Cl
Cl
SnCl2
AlCl3/NaCl
180oC
+
O
4M HCl
Cl
O
OH
O
O
O
OH
O
OMe
2
5
3
4
O
O
O
O
O
O
Br
ClCH2Br/DMF
K2CO3
NBS
CHCl3
CHO
Mg/THF
DMF
O
O
O
O
6
7
1
Scheme 1
* Correspondent. E-mail: ssli@sjtu.edu.cn
PAPER: 07/4927

648 JOURNAL OF CHEMICAL RESEARCH 2007
stirred at room temperature for 24 h. Then the solution was washed
with 10% KOH (100 ml) and water (200 ml × 3), dried over anhydrous
MgSO4. and then evaporated to dryness. The residue was crystallised
with isopropanol to give the white crystals 7 (2.65 g, 88.2%)
m.p. 167–168°C. H NMR (CDCl3): δ = 6.84 (s, 1H, ArH), 6.82 (d,
J = 3.6, 1H, ArH), 6.82 (d, J = 3.6, 1H, ArH), 5.53 (s, 2H, OCH2O),
5.52 (s, 2H, OCH2O).
This article is supported by the Natural Science Foundation of
Shanghai (07ZR14052).
Received 1 November 2007; accepted 26 November 2007
1
Paper 07/4927
doi: 10.3184/030823407X266216
2-Formyl-1,8:4,5-bis(methylenedioxy)naphthalene (1): To the
mixture of Mg (240 mg, 10 mmol) and I2 which was heated and
activated for 1 hr in anhydrous THF (30 ml), the solution of 2-bromo-
1,8:4,5-bis(methylenedioxy)naphthalene (200 mg, 0.68 mmol) in
THF (10 ml) was added dropwise. After 3 h, DMF (10 ml) was added
and the reaction mixtue was stirred for 8 h. Then the solution was
hydrolysed with aq. NH4Cl (15 ml) and extracted by ethyl acetate
(50 ml × 3). The organic phase was dried by MgSO4 and condensed.
The residue was crystallised with isopropanol to give light crystal 1
References
1
2
3
X. Chem, L. Yang, J. Oppenheim and D.M. Howard, Phytother. Res.
2002, 16, 199.
A. Terada, Y. Tanoue, A. Hetada and H. Sakamoto, J. Chem. Soc., Chem.
Commum., 1983, 987.
A. Terada, Y. Tanoue, A. Hetada and H. Sakamoto, Bull. Chem. Soc. Jpn.,
1987, 60, 205.
4
5
6
7
8
K.C. Nicolaou and D. Hepworth, Angew. Chem. Int. Ed., 1998, 37, 839.
J.C. Kim, J.C. Jung and O.S. Park, Synth. Commun., 2000, 30, 1023.
R. Huor and P. Brassard, Canad. J. Chem., 1974, 52, 838.
R. Lewis and J. Paul, Z. Naturforsch. B, 1977, 32, 1473.
F. Dallacker, J. Jacobs and W. Coerver, Z. Naturforsch. B, 1983, 38,
1000.
1
(117 mg, 71.2%). m.p. 190–191°C. H NMR(CDCl3): δ = 10.52 (s,
1H, ArCHO), 7.25 (s, 1H, ArH), 7.03 (d, J = 7.6, 1 H, ArH), 6.95 (d,
J = 7.6, 1H, ArH), 5.63 (s, 2H, OCH2O), 5.51 (s, 2H, OCH2O). (lit.5
1
m.p. 184°C, H NMR(CDCl3): δ = 10.52 (s, 1H), 7.25 (s, 1H), 7.04
(d, J = 8.34, 1 H), 6.96 (d, J = 8.34, 1H), 5.64 (s, 2H), 5.52 (s, 2H)).
PAPER: 07/4927