An expeditious and convergent synthesis of ailanthoidol

Article abstract of DOI:10.1016/j.tetlet.2010.02.018

An expeditious and concise method has been described for the synthesis of ailanthoidol through convergent route starting from vanillin. The protocol involving intramolecular Wittig as a key reaction afforded ailanthoidol in overall high yield.

Full text of DOI:10.1016/j.tetlet.2010.02.018

Tetrahedron Letters 51 (2010) 1979–1981
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Tetrahedron Letters
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An expeditious and convergent synthesis of ailanthoidol
*
Maddali L. N. Rao , Dheeraj K. Awasthi, Debasis Banerjee
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An expeditious and concise method has been described for the synthesis of ailanthoidol through conver-
gent route starting from vanillin. The protocol involving intramolecular Wittig as a key reaction afforded
ailanthoidol in overall high yield.
Received 21 December 2009
Revised 27 January 2010
Accepted 5 February 2010
Available online 8 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Convergent
Ailanthoidol
Wittig
Expeditious
Concise synthesis
2-Aryl-substituted benzofurans such as ailanthoidol and its
structural analogues belong to neolignan family.1 This class of com-
pounds is known for various biological properties such as antiviral,
anticancer, antiproliferative, antioxidative, anti-inflammatory, anti-
fungal and immuno-suppressive.2a,2b Recently, some groups have
reported the synthesis of ailanthoidol and its analogues.2,3 For
example, a synthesis reported by Chern et al. involves cyclization
of internal alkyne through oxymercuration using mercury acetate
in acetic acid for the generation of benzofuran core of ailanthoidol
(Scheme 1).2a,2b Another synthesis by Bates et al. employed the
palladium-catalyzed Sonogashira coupling followed by the base-
mediated cyclization of alkyne intermediate starting from 5-iodova-
nillin.2c The palladium-catalyzed Stille couplings were involved to
introduce 2-aryl group and for the chain extension of benzofuran
core, reported by Lee and co-workers.2d The 2-bromobenzofuran
needed for Stille couplings was derived from 5-bromo-2-hydroxy-
3-methoxybenzaldehyde. Other methods involve palladium-cata-
lyzed cyclization,2e benzoannulation2f and cuprous acetylide cou-
pling3a–c along with other procedures3d,3e to generate benzofuran
skeleton. However, some of these methods despite being useful for
the synthesis of ailanthoidol also suffer from the use of toxic tin re-
agents, mercuric reagents and cumbersome procedures. Given the
importance of ailanthoidol and its structural analogues in medicinal
chemistry, we describe here an alternate, concise and convergent
synthesis of ailanthoidol starting from vanillin.
Thus, vanillin was viewed as a suitable structural precursor for
the convergent synthesis of benzofuran core using intramolecular
Wittig as the key reaction. The retro-synthetic analysis conceived
for ailanthoidol is illustrated in Scheme 1. As given, benzofuran
skeleton could be easily processed through intramolecular Wittig
reaction of phosphonium salt 3 and acid chloride 4. The phospho-
nium salt in turn could be obtained from functionalized benzyl
chloride 5. The desired benzyl chloride and acid chloride could
be easily prepared from vanillin 6.
Although, the intermolecular Wittig reaction of phosphorane 2
for chain extension of the benzofuran core was employed befor-
Wittig
HO
OH
O
OMe
1
OMe
O
O
H
PPh3 Cl
Cl
Ph3P=CHCO2Et
+
+
OH
OH
2
OMe
OMe
3
4
O
O
H
H
Cl
OH
Our approach was based on the utilization of repetitive aro-
matic nucleus of ailanthoidol as precursor for its synthesis.
OH
OMe
OMe
6 (Vanillin)
5
* Corresponding author. Tel./fax: +91 512 2597532.
E-mail address: maddali@iitk.ac.in (M.L.N. Rao).
Scheme 1. Retrosynthetic analysis of ailanthoidol
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.018

1980
M. L. N. Rao et al. / Tetrahedron Letters 51 (2010) 1979–1981
e,2a,2b intramolecular Wittig for the generation of benzofuran core
was not adopted in the synthesis of ailanthoidol. It is to be noted
that synthetically intramolecular Wittig reaction4 provides a facile
approach for the generation of benzofuran skeleton and has been
applied before in several syntheses.5 Despite this, the convergent
approach from vanillin in combination with intramolecular Wittig
as illustrated above was not realized so far in ailanthoidol synthe-
sis. If adopted this is expected to provide much simplified route for
the synthesis of ailanthoidol in comparison with some of the
known methods.2 So, our synthetic efforts to obtain ailanthoidol
are described below.
The functionalization of vanillin to benzyl derivative 5 (Scheme
2) through direct halomethylation was attempted initially. The
reactions using (i) gaseous hydrogen bromide in acetic acid in
the presence of paraformaldehyde6a,6b (ii) with formaldehyde in
concd hydrochloric acid6c were not effective to provide benzyl
chloride directly from vanillin. Hence, we have followed the proce-
dure6d involving initial aminomethylation to 7 and its further
transformation to benzyl chloride 5. These steps afforded high
yields in a facile manner. The benzyl chloride was then converted
to the phosphonium salt 3.
O
O
O
H
H
HO
(a)
(b)
OH
OBn 96%
OBn
96%
OMe
OMe
8
9
OMe
6
(c)
98%
O
Cl
OBn
10
OMe
Scheme 3. Preparation of benzyl-protected acid chloride 10. Reagents and condi-
tions: (a) BnBr, K2CO3, DMF, rt, 5 h; (b) H3NO3S, NaClO2, H2O, rt, 12 h; (c) SOCl2,
DCM, 1H-benzotriazole, rt, 1 h.
O
O
OHC
H
PPh
3 Cl
(a)
Cl
OBn
OMe
+
O
89%
OH
OBn
11
OMe
OMe
OMe
OH
10
Next, the synthesis of acid chloride 10 was accomplished from
vanillin as given in Scheme 3. The phenolic group in vanillin 6
was first protected as its benzyl ether 8. Oxidation of 8 was carried
out using sodium chlorite to obtain the corresponding acid 9. This
was further converted to its acid chloride derivative 10 smoothly in
quantitative yield.
3
99%
(b)
O
O
EtO
EtO
(c)
91%
OBn
OMe
O
O
OMe
13
OMe
OMe
12
With the two important intermediates phosphonium salt 3 and
acid chloride 10 in hand, intramolecular Wittig reaction4c was then
performed to generate the benzofuran core of ailanthoidol (Scheme
4).
The Wittig reaction of phosphonium salt with acid chloride in
the presence of pyridine followed by the treatment of triethyl-
amine under heating condition afforded 2-arylbenzofuran skeleton
11 in high yield.7 The notable feature of this step is that the formyl
group present in phosphonium salt 3 was not protected and the
intramolecular Wittig reaction afforded the selective coupling to-
wards benzofuran product.
76% (d)
HO
OH
OMe
O
OMe
1
Ailanthoidol,
Scheme 4. Synthesis of ailanthoidol. Reagents and conditions: (a) (i) CHCl3,
pyridine, reflux 2 h; (ii) Et3N, reflux 6 h; (b) compound 2, CH2Cl2, 0 °C, 3 h and rt,
10 h; (c) TiCl4, CH2Cl2, rt, 5 h; (d) LiAlH4, AlCl3, THF, rt, 4 h.
Next, the chain extension of benzofuran core 11 was carried out
using intermolecular Wittig reaction with phosphorane 2. In our
initial attempts, this reaction afforded a cis–trans mixture of ole-
finic ester 12. To avoid this and to obtain pure trans-olefinic ester,
we have studied the reaction under different solvent and temper-
ature conditions as they are known to have a role in selectivity.8
From Table 1, the reaction in toluene,9a tetrahydrofuran2b and
dichloromethane9b solvents afforded a mixture of both cis- and
trans-olefinic esters in different amounts (Table 1, entries 1–7).
However, in dichloromethane solvent at 0 °C initially followed by
Table 1
Optimizing conditions for 12a–c
O
EtO
OBn
11
+
Ph3P=CHCO2Et
O
2
OMe
(1 equiv)
12
OMe
Entry
2 (equiv)
Solvent/temp/time
E/Z (12)
Yield 12 (%)
1
2
3
4
5
6
7
8
1.5
1.5
1.2
1.2
1.2
1.2
1.2
1.2
Toluene, 60 °C,12 h
Toluene, rt
68:32
66:34
62:38
66:34
97:3
84:16
99:1
100:0
50
90
34
53
28
39
75
99
THF, À78 °C, 1 h; rt,3 h
THF, À78 °C, 1 h; 0 °C, 3 h
THF, À78 °C, 3 h
O
O
O
H
NMe2
OH
THF, À78 °C, 6 h
(a)
H
H
Cl
OH
(b)
DCM, rt, 12 h
OH
96%
93%
DCM, 0 °C, 3 h; rt, 10 h
OMe
OMe
OMe
Conditions: (a) compound 11 (0.3 mmol, 1 equiv), phosphorane 2, solvent (5 mL).
(b) Isolated yields. (c) E/Z ratio of the isolated product 12 was determined by HPLC.
6
7
5
(c)
95%
O
H
PPh
3Cl
room temperature stirring, the reaction afforded trans-olefinic es-
ter 12 quantitatively (Table 1, entry 8).10 Next, debenzylation of
the pure trans-ester was carried out with TiCl4 to afford olefinic es-
ter 13.11 This ester was further subjected to LiAlH4/AlCl3 reduction
to give directly ailanthoidol 1 in high yield.12 The present synthesis
starting from phosphonium salt 3 and acid chloride 10 (Scheme 4)
afforded overall 61% yield of ailanthoidol.
OH
OMe
3
Scheme 2. Preparation of phosphonium salt 3. Reagents and conditions: (a)
Me2NH, HCHO, ethanol, reflux for 0.5 h and rt, 24 h; (b) (i) Ac2O, reflux 24 h; (ii)
conc. HCl, rt 1.5 h; (c) PPh3, toluene, reflux 4 h.

M. L. N. Rao et al. / Tetrahedron Letters 51 (2010) 1979–1981
1981
7. Compound 11: To a solution of 3 (1.85 g, 4 mmol) in CHCl3 (20 mL) under
nitrogen atmosphere, 4-benzyloxy-3-methoxy benzoyl chloride 10 (1.66 g,
6 mmol) and pyridine (0.65 mL, 8 mmol) were added with stirring. The mixture
was refluxed for 2 h. After cooling to rt, Et3N (2.2 mL, 16 mmol) was added and
the mixture was refluxed again for 6 h. The reaction mixture was cooled to rt
and extracted with EtOAc (2 Â 30 mL), washed with brine, dried over MgSO4
and concentrated under reduced pressure. The crude product was
chromatographed on silica gel using ethyl acetate/petroleum ether (3:5) as
eluent to give 11 (1.38 g, 89%). White solid; mp 151–153 °C; 1H NMR (CDCl3,
400 MHz) d 9.92 (s, 1H), 7.61 (d, 1H, J = 1.5 Hz), 7.19–7.39 (m, 8H), 6.87–6.89
(m, 2H), 5.14 (s, 2H), 4.01 (s, 3H), 3.93 (s, 3H); 13C NMR (CDCl3, 100 MHz) d
191.6, 157.9, 150.0, 149.4, 147.5, 145.9, 136.8, 133.5, 131.1, 128.6, 128.0, 127.4,
123.1, 118.8, 118.4, 114.2, 109.0, 104.6, 100.7, 71.1, 56.3, 56.2. IR (KBr): 2925,
2856, 1725, 1688, 1608, 1514, 1274, 1213, 1140, 809, 742, 690 cmÀ1. HRMS m/z
calcd for C24H21O5 (M+H)+ 389.1389, found 389.1386.
In conclusion, some highlights of the present synthesis are (a) it
involves a convergent route using intramolecular Wittig reaction;
(b) efficient utilization of commercially available vanillin as its acid
chloride and phosphonium salt derivatives has simplified the over-
all synthesis; (c) only one benzylic protection was employed
throughout the synthesis; (d) majority of the steps were high
yielding and by routinely used reagents. So, we have demonstrated
an expeditious, convergent and concise synthesis of ailanthoidol by
employing precursors derived from vanillin using intramolecular
Wittig as the key reaction.
Acknowledgements
8. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927.
9. (a) Gagey, N.; Neveu, P.; Benbrahim, C.; Goetz, B.; Aujard, I.; Baudin, J.-B.;
Jullien, L. J. Am. Chem. Soc. 2007, 129, 9986–9998; (b) DeZutter, C. B.; Horner, J.
H.; Newcomb, M. J. Phys. Chem. A 2008, 112, 1891–1896.
D.K.A thanks UGC, New Delhi and D.B. thanks IIT Kanpur for re-
search fellowships.
10. Compound 12: To a solution of 11 (1.01 g, 2.6 mmol) in CH2Cl2 (50 mL), under
nitrogen atmosphere, (carbethoxymethylene)triphenyl phosphorane, 2 (1.08 g,
3.1 mmol) was added at 0 °C and stirred for 3 h at the same temperature. The
contents were brought to rt and stirred for 10 h. The mixture was extracted
with CH2Cl2, washed with brine, dried and evaporated. The crude product was
subjected to column chromatography on silica gel using ethyl acetate/
petroleum ether (2:5) as eluent to give 12 (1.18 g, 99%). White solid; mp
Supplementary data
Supplementary data (experimental procedures for compounds
3, 5, 7, 8, 9 and 10 and NMR, mass spectral data for the compounds)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.02.018.
142–144 °C (lit.2d 142–144 °C); 1H NMR (CDCl3, 400 MHz)
d 7.68 (d, 1H,
J = 15.9 Hz), 7.18–7.39 (m, 8H), 6.80–6.88 (m, 3H), 6.33 (d, 1H, J = 15.9 Hz), 5.13
(s, 2H), 4.21 (q, 2H, J = 7.2 Hz), 3.98 (s, 3H), 3.91 (s, 3H), 1.28 (t, 3H, J = 7.1 Hz);
13C NMR (CDCl3, 125 MHz) d 167.2, 157.2, 149.8, 149.0, 145.4, 145.4, 145.2,
136.8, 131.4, 130.6, 128.7, 128.0, 127.3, 123.4, 118.2, 117.0, 114.6, 113.9, 108.7,
105.2, 100.5, 71.0, 60.5, 56.2, 56.1, 14.4. IR (KBr): 1677, 1598, 1515, 1274, 1231,
1185, 997, 697 cmÀ1. HRMS m/z calcd for C28H27O6 (M+H)+ 459.1808, found
459.1807.
References and notes
1. (a) Sheen, W.-S.; Tsai, I.-L.; Teng, C.-M.; Chen, I.-S. Phytochemistry 1994, 36,
213–215; (b) Moss, G. P. Pure Appl. Chem. 2000, 72, 1493–1523.
11. Compound 13: To a stirred solution of 12 (1.10 g, 2.4 mmol) in CH2Cl2 (25 mL),
under nitrogen atmosphere, TiCl4 (0.30 mL, 2.6 mmol) in CH2Cl2 (5 mL) was
added dropwise. The mixture was stirred for 5 h at rt. After cooling, the
reaction was quenched with methanol and the solvent was evaporated under
reduced pressure. The crude product was chromatographed on silica gel using
ethyl acetate/petroleum ether (3:5) as eluent to give 13 (804 mg, 91%). White
solid; mp 149–150 °C (lit.2d 149–151 °C); 1H NMR (CDCl3, 400 MHz) d 7.68 (d,
1H, J = 15.8 Hz), 7.19–7.34 (m, 3H), 6.78–6.92 (m, 3H), 6.34 (d, 1H, J = 16.1 Hz),
5.76 (br s, 1H), 4.21 (q, 2H, J = 7.1 Hz), 3.99 (s, 3H), 3.92 (s, 3H), 1.29 (t, 3H,
J = 7.1 Hz); 13C NMR (CDCl3, 125 MHz) d 167.3, 157.4, 146.8, 146.7, 145.5,
145.4, 145.2, 131.5, 130.6, 122.5, 119.1, 117.0, 114.9, 114.6, 107.7, 105.1, 100.2,
60.6, 56.2, 56.1, 14.5. IR (KBr): 3400, 2944, 2849, 1711, 1637, 1611, 1594, 1510,
1488, 1278, 1171, 1126, 860, 849 cmÀ1. HRMS m/z calcd for C21H21O6 (M+H)+
369.1338, found 369.1335.
12. Synthesis of ailanthoidol (1): To a solution of LiAlH4 (247 mg, 6.52 mmol) in
THF (15 mL), under nitrogen atmosphere, aluminium trichloride (289 mg,
2.17 mmol) was added portionwise. The mixture was stirred for 10 min at rt.
Compound 13 (800 mg, 2.17 mmol) in THF (5 mL) was added dropwise. The
mixture was stirred for 4 h at rt. After completion, the reaction was
quenched with ice water, extracted with EtOAc, washed with brine and
dried over MgSO4. The crude product was subjected to column
chromatography on silica gel using ethyl acetate/petroleum ether (3:5) as
eluent to give ailanthoidol 1 (538 mg, 76%). White solid; mp 199–201 °C
(lit.2d 199–201 °C); 1H NMR (DMSO-d6, 500 MHz) d 9.42 (s, 1H), 7.34 (d, 1H,
J = 1.9 Hz), 7.28 (dd, 1H, J = 1.9, 8.0 Hz) 7.24–7.34 (m, 2H), 7.13 (d, 2H,
J = 5.0 Hz), 6.96 (d, 1H, J = 1.2 Hz), 6.84 (d, 1H, J = 8.1 Hz), 6.57 (d, 1H,
J = 15.7 Hz), 6.34 (dt, 1H, J = 15.7 Hz), 4.83 (t, 1H, J = 5.4 Hz), 4.10 (t, 2H,
J = 4.6 Hz), 3.94 (s, 3H), 3.83 (s, 3H); 13C NMR (CDCl3 + DMSO-d6 125 MHz) d
155.7, 146.8, 146.5, 143.8, 142.1, 132.3, 130.2, 129.1, 127.8, 120.8, 117.4,
114.8, 110.3, 107.4, 103.3, 98.8, 61.4, 55.0, 55.0. IR (KBr): 3332, 2924, 2853,
1656, 1602, 1514, 1443, 1278, 1211, 1150, 1128, 967 cmÀ1. HRMS m/z calcd
for C19H19O5 (M+H)+ 327.1232, found 327.1234.
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