An Expeditious Synthetic Route to Furolignans having Two Different Aryl Groups

Article abstract of DOI:10.1039/a700131b

3,4-Dimethyl-2-piperonyl-5-veratrylfuran has been synthesized starting from vanillin and piperonal by employing as the key steps cross-coupling of a bromo β-oxo ester and the sodium salt of another β-oxo ester, affording a 1,4-diketone, and selective reductive removal of an allylic hydroxy group by palladium oxide.

Full text of DOI:10.1039/a700131b

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136 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 136±137$
An Expeditious Synthetic Route to Furolignans having
Two Different Aryl Groups$
Wu Anxin, Wang Mingyi, Gan Yonghong and Pan Xinfu*
Department of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 73000, China
3,4-Dimethyl-2-piperonyl-5-veratrylfuran has been synthesized starting from vanillin and piperonal by employing as the key steps
cross-coupling of a bromo ꢀ-oxo ester and the sodium salt of another ꢀ-oxo ester, affording a1,4-diketone, and selective reductive
removal of an allylic hydroxy group by palladium oxide.
The furolignans are a class of naturally occurring lignans,1±3
and can be used as intermediates in the synthesis of other
lignans such as tetrahydrofuran or aryltetralin derivatives.4
Some elegant synthetic methods for furanoids have pre-
viously been reported5,6 and we now present a simple and
e€ective synthetic route to furolignans having two di€erent
aryl groups. 3,4-Dimethyl-2-piperonyl-5-veratrylfuran 107
was chosen as the target molecule, and we have successfully
completed a synthesis of compound 10 using this strategy
(outlined in Scheme 1).
Experimental
IR spectra (KBr) were recorded on a Nicolet 170 SXFT-IR spec-
trometer and 1H NMR spectra on a Bruker AM400 spectrometer
using Me4Si as internal standard. Mass spectra were recorded on
a
ZAB-HS spectrometer. Microanalyses were performed on a
MOD-1106 elemental analyser. Standard ¯ash column techniques
were employed to purify the crude reaction mixture using 300±400
mesh silica gel under positive nitrogen pressure. Light petroleum
used for chromatography was the fraction of bp range 60±90 8C.
Diethyl 2-(3,4-Dimethoxybenzoyl)-3-(3,4-methylenedioxybenzoyl)-
butane-1,4-dioate (7).ÐSodium hydride (0.4 g; 80%) was washed
Ar1
Ar1
i–v
vi
Ar1CHO
O
O
O
O
CO2Et
CO2Et
CO2Et
Na+
1
O
O
O
O
–
Ar1
OEt
Ar2
viii
2
3
EtO
Ar2
Ar2
ii–v
vii
Ar2CHO
CO2Et
7
4
Br
5
ix
6
Me
Ar1
Me
HOCH2
Ar1
CH2OH
Ar2
EtO2C
Ar1
CO2Et
Ar2
xi
x
Ar2
O
O
O
10
9
8
Ar1
=
Ar2
=
OH
;
O
O
OMe
Scheme 1 Reagents: i, Me2SO4^NaOH; ii, KMnO4; iii, SOCl2; iv, MeCOCH2CO2Et^EtONa; v, NH3^NH4Cl; vi, EtONa; vii, Br2; viii, CH2Cl2;
ix, p-MeC6H4SO3H^PhH; x, LiAlH4^THF; xi, PdO^H2
with dry pentane and then suspended in dry dichloromethane
As shown in Scheme 1, the starting materials were vanillin
1 and piperonal 4 from which, based on an earlier report,8
(10 ml). To this was added a solution of ethyl (3,4-dimethoxy-
benzoyl)acetate (2) (3 g, 12 mmol) in dry dichloromethane (15 ml).
were conveniently prepared the sodium salt 3 and bromo
This mixture was re¯uxed for 15 min and then a solution of ethyl
bromo(3,4-methylenedioxybenzoyl)acetate (6) (3.8 g, 12 mmol) in
derivative 6 of the corresponding b-oxo esters. By a cross-
coupling reaction, compounds 3 and 6 were converted into
the diester 7.
dry dichloromethane (15 ml) was added. The product was then
re¯uxed with stirring for 3 h. The suspension was cooled, washed
with water (2Â 10 ml), and dried (Na2SO4). After removal of the
solvent, the residue was puri®ed through column chromatography
using light petroleum±ethyl acetate (3:2, v/v) as eluant, to give com-
pound 7 (4.7 g, 9.7 mmol), yield 80%. Recrystallization from ethanol
Acid-catalysed cyclization of 7 led to the furan 8 which
was then reduced with LiAlH4 to produce 9, both steps
being easily achieved in good yield. Conversion of com-
pound 9 into the target compound 10 was achieved com-
pletion in a mixed solvent (THF±CHCl3, 10:1, v/v) under
hydrogen with palladium oxide as catalyst, when a high
yield was obtained.
1
gave a white crystalline solid, mp 114±116 8C; ꢁmax/cm (KBr)
2980±2880, 1730, 1665, 1610; ꢂH (CDCl3) 1.10 (6 H, t, J 7.1 Hz),
3.86 (6 H, s), 4.01 (4 H, q, J 7.1 Hz), 5.16 (2 H, s), 5.90 (2 H, s),
6.65±7.67 (6 H, m), ꢂC (CDCl3) 13.64, 13.83, 52.96, 53.88, 55.90,
61.88, 61.90, 101.92, 107.88, 108.78, 110.00, 110.99, 124.7, 126.36,
128.66, 130.62, 148.12, 148.84, 152.42, 153.97, 167.13, 167.73,
191.19, 191.80; m/z (EI) 486 (M+), 395, 291, 263, 165 (base), 149
(Found: C, 61.56; H, 5.24. C25H26O10 requires C; 61.73; H, 5.35%).
Diethyl 2-(3,4-Dimethoxyphenyl)-5-(3,4-methylenedioxyphenyl)-
furan-3,4-dicarboxylate (8).ÐToluene-p-sulfonic acid (0.5 g) was
added to a solution of compound 7 (2.5 g, 5.1 mmol) in dry benzene
*To receive any correspondence.
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).

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J. CHEM. RESEARCH (S), 1998 137
(50 ml). The mixture was re¯uxed for 8 h, and then concentrated.
The residue was chromatographed on silica gel (light petroleum±
ethyl acetate; 8:1, v/v) to give the furan 8 (1.9 g, 79%) as a white
and chromatography of the residue on silica gel H using light
petroleum±ethyl acetate (8.1, v/v) as eluant gave the furan, 10
(394 mg, 86%) as a white solid, mp 123±124 8C (lit,7 166±169 8C);
1
1
solid, mp 117±118 8C;
ꢁmax/cm
(KBr) 1725, 1706, 1505; ꢂH
ꢁ
max/cm (KBr) 2924, 1603, 1501, 1445, 1251; ꢂH (CDCl3) 2.22
(CDCl3) 1.30 (6 H, t, J 7.09 Hz), 3.83 (6 H, s,), 4.26 (4 H, q, J
7.09 Hz), 5.87 (2 H, s), 6.6±7.5 (6 H, m); m/z (EI) 468 (M+, base),
423, 234, 149 (Found: C, 63.92; H, 5.24. C25H24O9 requires C,
64.10; H 5.16%).
(6 H, s), 3.94, 3.97 (6 H, 2 s), 6.02 (2 H, s), 6.6±7.3 (6 H, m); m/z
(EI) 352 (M+, base), 337, 165, 149, 135 (Found: C, 71.33; H, 5.60.
C21H20O5 requires C, 71.57; H, 5.72%). All the spectral data were
in good agreement with those reported.7
2-(3,4-Dimethoxyphenyl)-2-(3,4-methylenedioxyphenyl)-3,4-bis(hy-
droxymethyl)furan (9).ÐLiAlH4 (0.5 g) was suspended in dry THF
(50 ml), and a solution of compound 8 (1.0 g, 2.1 mmol) in THF
(30 ml) was added dropwise with stirring. The mixture was re¯uxed
for 8 h, stirred overnight at room temperature and then carefully
decomposed with ethyl acetate (10 ml) and hydrochloric acid
(5 ml; 6 M). Removal of solvent under reduced pressure and sub-
sequent puri®cation by ¯ash chromatography (acetone as eluent)
Received, 6th January 1997; Accepted, 25th November 1997
Paper E/7/00131B
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a€orded the furan 9 (780 mg, 95%) as a white solid, mp 148±149 8C;
1
ꢁ
max/cm (KBr) 3431, 1510; ꢂH (CDCl3) 3.67 (2 H, s, disappeared
on D2O exchange), 3.86 and 3.70 (6 H, 2 s), 4.56 (4 H, s), 5.80 (2 H,
s) 6.7±7.44 (6 H, M); m/z (EI) 384 (M+ base), 366, 352, 165, 149
(note: this product is not stable).
3,4-Dimethyl-2-piperonyl-5-veratrylfuran (10).ÐIn an autoclave,
PdO (150 mg) was added to a solution of the furan 9 (500 mg,
1.3 mmol) in THF±CHCl3 (10:1 v/v; 50 ml). The mixture was stirred
under hydrogen (6 MPa) at 80 8C for 24 h and at room temperature
for 24 h, then ®ltered to remove the solid residue. Evaporation
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