Alternate and efficient method for the total synthesis of egonol via Sonogashira coupling reaction

Article abstract of DOI:10.1002/jhet.770

Efficient method for the total synthesis of egonol in five steps via Sonogashira coupling reaction is reported. Copyright

Full text of DOI:10.1002/jhet.770

Month 2013
Alternate and Efficient Method for the Total Synthesis of Egonol
via Sonogashira Coupling Reaction
M. Naveen,a,b Ch. Upendar Reddy,b Md. Manzoor Hussain,b
c
a
*
M. Chaitanya and Golla Narayanaswamy
aDepartment of Chemistry, Sri Krishnadevaraya University, Anantapur,
Andhra Pradesh 515003, India
bInstitute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad, Andhra
Pradesh 500 046, India
cDepartment of Bio-Chemistry, Sri Krishnadevaraya University, Anantapur, Andhra Pradesh
515003, India
*
E-mail: narayanaswamy.golla@gmail.com
Received September 13, 2010
DOI 10.1002/jhet.770
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
Efficient method for the total synthesis of egonol in five steps via Sonogashira coupling reaction is
reported.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
(4), which was easily prepared from piperonal via Colvin
rearrangement [14], by using 10% Pd—C, CuI and Et3N
in DMF yielded benzofuran 5 in 95% yield through succes-
sive coupling and cyclization in one-step. Wittig reaction
of 5 with (carbethoxymethylene) triphenylphosphorane
produced carbethoxyethenylbenzofuran 6 in 99% yield,
which was reduced to 7 in quantitative yield by H2/Pd-C.
Reduction of ester 7 with DIBAL-H gave egonol 1 in
99% yields.
Egonol (1) is an aryl-benzofuran, which was first iso-
lated in 1915 by Okada from the seed oil of S. japonicum
[1] and was formulated by Kawai [2] as 5-[3-(hydroxy)
propyl]-7-methoxy-2-(3,4-methylenedioxyphenyl)benzofuran,
condensing an o-hydroxybenzaldehyde with an α-
chlorophenylacetic acid and known to be an effective
pyrethrum synergist [3]. Seeds of the fruit of S. japonicum,
S. obassia, S. formasanum, S. suberifolium, and S.
officinalis are known to contain various egonol deriva-
tives [4–7]. Egonol and its derivatives obtained from
the seeds of Styrax species has attracted the attention
of synthetic organic chemists, as a result of its activity against
human leukaemic cells [8] in addition to anticomplement
activity [9], cytotoxic activity [10], and antifungal and
antibacterial activity [11]. A number of total synthesis
methods of egonol have been reported [12]. Recently,
synthesis and biological activity of egonol analogs have
been extensively studied [13]. We report herein the most
effective total synthesis of egonol (1, Fig. 1) in five steps
from vanillin by using Sonogashira coupling reaction.
CONCLUSIONS
In conclusion, the five steps reaction procedures
including iodination, Sonogashira coupling, Wittig
reaction, hydrogenation and metal hydride reduction
produced egonol from vanillin. This synthetic method
provides the most effective egonol total synthesis in our
best knowledge.
EXPERIMENTAL
All chemicals used were purchased from commercial sources
and used as received unless otherwise stated. NMR spectra were
1
RESULTS AND DISCUSSION
recorded at Mercury Plus (Varian-400 MHz) for H NMR and
100 MHz for 13C NMR, with the chemical shifts (δ) reported in
parts per million (ppm) relative to TMS and the coupling con-
stants (J) quoted in Hz, CDCl3 was used as a solvent. For analyt-
ical purposes the mass spectra were recorded on a JEOL JMS-5X
10217 in the ES mode.
Vanillin (2) reacted with I2 in presence of NaHCO3 as a
base and water as a solvent medium at room temperature to
give iodovanillin 3 in 90% yield (Scheme 1). Sonogashira
coupling of 3 with 3,4-methylenedioxyphenylacetylene
Copyright © 2013 HeteroCorporation

M. Naveen, Ch. U. Reddy, Md. M. Hussain, M. Chaitanya, and G. Narayanaswamy
Vol 000
5-Formyl-7-methoxy-2-(3,4-methylenedioxyphenyl)benzo-
furan (5). To a solution of iodovanillin (3) (0.22 mmol), 10%
Pd-C (0.02 mmol), 3,4-methylenedioxyphenylacetylene (4,
0.32 mmol) and CuI (0.004 mmol) in DMF (3 mL) under
nitrogen atmosphere was added Et3N (0.22 mmol) and stirred
for 15 h at rt. The organic product was extracted with CHCl3,
washed with brine, dried and concentrated to give the solid.
The solid was chromatographed (EtOAc: Hexane = 1:4) to give
the yellow solid 5 (95%).
Rf 0.28 (EtOAc:Hexane = 1:3); mp 176–178°C; 1H NMR (400
MHz, CDCl3) δ 4.08 (3H, s, OMe), 6.02 (2H, s, O—CH2—O),
6.88 (1H, d, J = 8.4 Hz, C5′—H), 6.93 (1H, s, C3—H), 7.31
(1H, d, J = 1.8 Hz, C2′—H), 7.33 (1H, br d, C6—H), 7.41 (1H,
dd, J = 1.8, 8.0 Hz, C6′—H), 7.66 (1H, d, J = 0.6 Hz, C4-H),
9.97 (1H, s, CHO); 13C NMR (100 MHz, CDCl3) δ 56.5, 100.9,
101.7, 104.6, 105.8, 108.2, 109.0, 119.3, 119.8, 123.9, 131.1,
133.6, 146.1, 148.4, 148.8, 157.8, 191.9; MS (ES mass): m/z
297 (M+1, 100%); Elemental analysis: Calcd for C17H12O5: C,
68.92; H, 4.08. Found: C, 68.90; H, 4.05.
Figure 1. Chemical structure of egonol (1).
4-Hydroxy-3-iodo-5-methoxybenzaldehyde (3). To a solution of
vanillin (2) (6.57 mmol) in H2O (50 mL) was added I2 (7.89 mmol)
with NaHCO3 (7.89 mmol) and stirred for overnight at rt.
Solvent was removed by evaporation and the organic product
was extracted with CH2Cl2, washed with brine, dried and
concentrated to give the solid. The solid was chromatographed
(EtOAc:Hexane = 1:2) to give the white solid 3 (90%).
Rf 0.34 (EtOAc:Hexane = 1:3); mp 179–182°C; 1H NMR (400
MHz, CDCl3) δ 3.87 (3H, s, OMe), 6.69 (1H, s, OH), 7.44 (1H, s,
ArH), 7.89 (1H, s, ArH), 10.45 (1H, s, CHO); 13C NMR (100
MHz, CDCl3) δ 55.91, 82.39, 110.19, 130.00, 132.17, 148.30,
150.96, 194.85; MS (ES mass): m/z 279 (M+1, 100%); HRMS:
Calcd, for C8H7IO3 279.0632. found 279.0841; Elemental analy-
sis: Calcd for C8H7IO3: C, 34.56; H, 2.54; I, 45.64. Found: C,
34.53; H, 2.50; I, 45.61.
5-Carbethoxyethenyl-7-methoxy-2-(3,4-methylenedioxyphenyl)
benzofuran (6). To a solution of 5 (0.17 mmol) in CH2Cl2 (5 mL)
under nitrogen atmosphere was added (carbethoxymethylene)
triphenylphosphorane (0.25 mmol) and refluxed for 7 h. The
organic product was extracted with CH2Cl2, washed with brine,
dried and concentrated to give the solid. The solid was
chromatographed (EtOAc:Hexane = 1:3) to give the white solid
6 (99%).
Scheme 1. Total synthesis of egonol via Sonogashira coupling reaction.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Alternate and Efficient Method for the Total Synthesis of Egonol
via Sonogashira Coupling Reaction
Month 2013
Rf 0.44 (EtOAc:Hexane = 1:3); mp 160–162°C; 1H NMR (400
MHz, CDCl3) δ 1.35 (3H, t, J = 7.2 Hz, CH3), 4.05 (3H, s, OMe),
4.27 (2H, q, J = 7.2 Hz, OCH2), 6.01 (2H, s, O—CH2—O), 6.39
(1H, d, J = 15.6 Hz, trans ethenyl C1—H), 6.83 (1H, s, C6—H),
6.86 (1H, d, J = 8.4 Hz, C5′—H), 6.94 (1H, br s, C3—H), 7.30
(2H, br s, C2′—H, C4—H), 7.39 (1H, dd, J = 1.5, 8.7 Hz,
C6′—H), 7.73 (1H, d, J = 15.9 Hz, trans ethenyl C2—H); 13C
NMR (100 MHz, CDCl3) δ 14.8, 56.4, 60.7, 100.7, 101.6,
105.5, 105.8, 108.9, 114.7, 117.1, 119.6, 124.3, 128.8, 130.8,
131.5, 145.3, 145.5, 148.3, 148.5, 157.1, 167.3; MS (ES mass):
m/z 367 (M+1, 100%); Elemental analysis: Calcd for C21H18O6:
C, 68.85; H, 4.95. Found: C, 68.83; H, 4.91.
Rf 0.22 (EtOAc: Hexane = 1:1); mp 100–103°C; 1H NMR (400
MHz, CDCl3) δ 1.94 (2H, quintet, J = 6.7 Hz, propyl C2—H), 2.77
(2H, t, J = 7.5 Hz, propyl C1—H), 3.71 (2H, t, J = 6.5 Hz, CH2OH),
4.02 (3H, s, OCH3), 5.99 (2H, s, O—CH2—O), 6.62 (1H, br
s, C6—H), 6.77 (1H, s,C3—H), 6.85 (1H, d, J = 7.8 Hz, C5′
—H), 6.95 (1H, br s, C4—H), 7.31 (1H, d, J = 1.5 Hz, C2′—H),
7.38 (1H, dd, J = 8.2, 1.5 Hz, C6′—H); 13C NMR (100
MHz, CDCl3) δ 32.8, 35.1, 56.5, 62.6, 100.6, 101.4, 101.5, 107.6,
108.8, 112.5, 119.4, 124.9, 131.2, 137.7, 142.6, 144.9, 148.1, 148.2,
156.2. MS (ES mass): m/z 327 (M+1, 100%); Elemental analysis:
Calcd for C19H18O5: C, 69.93; H, 5.56. Found: C, 69.90; H, 5.51.
5-Carbethoxyethyl-7-methoxy-2-(3,4-methylenedioxyphenyl)
benzofuran (7). To a solution of 6 (1.19 mmol) in MeOH (1 mL)
under hydrogen atmosphere was added 10% Pd-C and stirred
for 3 h at rt. The organic product was filtered and concentrated
to give the solid. The solid was purified by column
chromatography to give the white solid 7 (99%).
REFERENCES AND NOTES
[1] Okada, H. J Pharm Soc Jpn 1915, 35, 657.
[2] Kawai, S.; Nakamura, T.; Sugiyama, N. Ber dt Chem Ges
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[3] Takanashi, M.; Takizawa, Y. Phytochemistry 1988, 27, 1224.
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[5] Anil, H. Photochemistry 1980, 19, 2784.
Rf 0.60 (EtOAc:Hexane = 1:2); mp 88–90°C; 1H NMR
(400 MHz, CDCl3) δ 1.24 (3H, t, J = 7.2 Hz, CH3), 2.66
(2H, t, J = 8.1 Hz, CH2), 3.01 (2H, t, J = 8.1 Hz, CH2),
4.02 (3H, s, OCH3), 4.13 (2H, q, J = 7.1 Hz, OCH2), 6.00
(2H, s, O—CH2—O), 6.62 (1H, br s, C6—H), 6.78 (1H, s,
C3—H), 6.85 (1H, d, J = 8.4 Hz, C5′—H), 6.96 (1H, br s,
C4—H), 7.30 (1H, d, J = 1.8 Hz, C2′—H), 7.38 (1H, dd,
J = 8.1, 1.5 Hz, C6′—H); 13C NMR (100 MHz, CDCl3) δ
14.0, 31.1, 36.3, 55.8, 60.1, 100.0, 100.9, 105.1, 106.8, 108.2,
111.8, 118.8, 124.2, 130.6, 135.9, 144.3, 147.5, 147.6, 155.6,
172.5; MS (ES mass): m/z 369 (M+1, 100%); Elemental analysis:
Calcd for C21H20O6: C, 68.47; H, 5.47. Found: C, 68.45; H, 5.44.
[6] Yun-Kyung, J.; Min-Byung, S.; Ji-Yeon, K.; Kyung-Tae, L.
Biol Pharm Bull 2007, 30, 139.
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Kim, E. H.; Lee, H. K. Planta Med 2004, 70, 1210.
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Med 2005, 71, 847.
[11] Pauletti, P. M.; Araujo, A. R.; Young, M. C. M.; Giesbrecht, A. M.;
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[12] (a) Schreiber, F. G.; Stevenson, R. J. Chem Soc Perkin Trans 1
1976, 1514 (b) Wang, J. J.; Lee, K. I.; Kim, M. H.; Shim, Y. K. Bull Ko-
rean Chem Soc 2004, 25, 1449; (c) Choi, D. H.; Hwang, J. W.; Lee, H. S.;
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[14] Colvin, E. W.; Hamill, B. J. J Chem Soc Perkin Trans 1 1977,
869.
Egonol (1). To a solution of 7 (0.11 mmol) in THF (4 mL)
under nitrogen atmosphere was added DIBAL-H (1.0 M, 0.25
mL) and stirred for 1.5 h at rt. The reaction was quenched by
addition of aqueous Na2CO3 solution. The organic product was
extracted with CH2Cl2, washed with brine, dried and
concentrated to give the solid. The solid was purified by column
chromatography to give the yellow solid 1 (99%).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet