First synthesis of antitubercular natural product 2-hydroxy-5-(4- hydroxybenzyl) benzaldehyde (forkienin)

Article abstract of DOI:10.3184/030823408X304032

The synthesis of 2-hydroxy-5-(4-hydroxybenzyl)benzaldehyde an antitubercular compound, from the readily available starting compound p-hydroxybenzoic acid in 4 steps is described.

Full text of DOI:10.3184/030823408X304032

148 RESEARCH PAPER
MARCH, 148–149
JOURNAL OF CHEMICAL RESEARCH 2008
First synthesis of antitubercular natural product 2-hydroxy-5-(4-hydroxy-
benzyl) benzaldehyde (Forkienin)
Ashima Singh, M.L. Sharma and Jasvinder Singh*
Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh-160014, India
The synthesis of 2-hydroxy-5-(4-hydroxybenzyl)benzaldehyde an antitubercular compound, from the readily
available starting compound p-hydroxybenzoic acid in 4 steps is described.
Keywords: antitubercular, microwave, solvent less, natural product
3'
2'
4
3
Tuberculosis (TB) is one of the most devastating diseases and
presents a global health threat of escalating proportions.1 TB is
the second leading infectious cause of mortality today behind
only HIV/AIDS. The impetus for developing new structural
classes of anti-tuberculosis drugs comes from the emergence
of multi-drug resistant (MDR) strains that are resistant to
commonly used drugs. Substantially longer treatment is
needed as a result of resistance, and there is a resurgence of
disease in immuno-compromised patients. Recently many
new structural classes of anti-TB agents, exhibiting promising
activity against drug-sensitive and drug-resistant strains of
the causative organism Mycobacterium tuberculosis have
appeared.
H2
C
4'
1'
2
HO
OH
5
1
6'
6
5'
CHO
Fig.1
microwave assisted Wolf-Kishner reduction.16 Formylation of
5 by a Reimer–Tiemann reaction17 gave the natural product
forkienin 1, the spectral data of which was in good agreement
with that reported in literature.8
Microtropis fokienensis Dunn (Celastraceae) is a small shrub
that grows in the high-altitude forests throughout southern
China and Taiwan.2 Various triterpenes,3,4 sesquiterpenes
alkaloids,5 dihydroagarofuranoid sesquiterpenes6,7 are
widely distributed in plants of the family Celastraceae.
Many of these compounds exhibit antitumour,3,4 anti-
inflammatory,7 insecticidal,6 and anti-AIDS3 activities. A new
hydroxybenzylsalicylaldehyde (Forkienin) has been isolated
and identified from the root of M. fokienesis.8 Its antitubercular
activities against M. tuberculosis has been evaluated in vitro.
Some reactions without solvent9 are more efficient and
selective as compared to reactions carried out in solvents.
Organictransformationsundermicrowaveirradiationgenerally
proceed with greater selectivity,1°-13 under simpler reaction
conditions than the analogues homogeneous reactions.
We report here the novel synthesis of the title compound
through the use of microwave irradiation as the key step. p-
Hydroxybenzoic acid 2 was transformed into corresponding
acid chloride 3 with thionyl chloride.14 Solvent free Friedal
craft acylation15 of phenol with p-hydroxybenzoyl chloride
3 under microwave irradiation in presence of TiO2, which is
non toxic, inexpensive and commercially available, gave bis-
(4-hydroxy-phenyl)-methanone 4 in 70% yield. Compound 4
was then converted into bis-(4-hydroxy-phenyl)-methane 5 via
Experimental
Melting points were determined with a Sunbim melting point
apparatus. IR spectra were determined on a Perkin Elmer model
1430 spectrometer. 1H NMR and 13C NMR spectra were recorded
using Joel 300 MHz spectrometer. Chemical shifts (δ) are reported in
ppm with tetramethylsilane as internal standard. Microwave induced
reactions were carried out in a domestic microwave (MG-396 W A,
2450 MHz, 800W).
4-Hydroxybenzoylchloride (3): A 100 ml two-necked flask fitted
with a dropping funnel and a gas absorption trap connected at the
top to reflux condenser was charged with 4-hydroxybenzoic acid (2)
(2.0 g, 14.49 mmol). Redistilled thionyl chloride 2.05 g (17.38 mmol),
was added drop wise through dropping funnel. The flask was heated
gently on a water bath for 30–40 minutes. The product was distilled
to give the pure acid chloride (3) (1.69 g, 75%). b.p. 268–272°C at
atmospheric pressure (278.9 ± 23.0°C18), IR(CHCl3)/νmax cm-1: 3390,
1810, 872. 1H NMR (CDCl3, 300 MHz) δ: 5.27 (bs, 1H, –OH, D2O
exchangeable), 7.40 (d, J = 7.8 Hz, 2H), 8.29 (d, J = 7.8 Hz, 2H).
13C NMR (CDCl3, 300 MHz) δ: 166.1, 156.0, 133.2, 126.5, 122.3.
Bis-(4-hydroxy-phenyl)-methanone (4): A mixture of phenol
(0.96 g, 10.25 mmol) and TiO2 (0.40 g, 5.06 mmol) with
4-hydroxybenzoylchloride (3) (1.60 g, 10.25 mmol) was irradiated
in a microwave oven (320 W) for 25 s. The workup followed by
chromatographic purification afforded pure bis-(4-hydroxy-phenyl)-
methanone (4) (1.53 g, 70%). m.p. 214–217°C (215–219°C19),
OH
OH
O
a
b
c
HO
OH
COOH
COCl
2
3
4
CHO
d
HO
HO
OH
OH
1
5
Scheme 1 (a) SOCl2, heat (b) Phenol, TiO2, MWI (c) NH2NH2, KOH, triethyleneglycol, MWI (d) CHCl3, NaOH.
* Correspondent. E-mail: jsbrar_pu@yahoo.com
PAPER: 08/5115

JOURNAL OF CHEMICAL RESEARCH 2008 149
IR(CHCl3)/νmax cm-1: 3255, 2923, 1724, 1592, 1473, 1375, 1164.
1H NMR (CDCl3, 300 MHz) δ: 5.80 (bs, 1H, –OH, D2O exchangeable),
6.68 (d, J = 8.4 Hz, 4H), 7.74 (d, J = 8.4 Hz, 4H). 13C NMR (CDCl3,
300 MHz): 170.1, 156.2, 132.1,129.2, 115.6
OH, D2O exchangeable), 6.80 (d, J = 8.2 Hz, 2H), 6.95 (d, J = 8.2 Hz,
1H), 7.10 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 2.3 Hz, 1H), 7.40 (dd, J = 8.2,
2.3 Hz, 1H), 9.81 (s, 1H, CHO–), 10.72 (bs, 1H, –OH, D2O
exchangeable). 13C NMR (CDCl3, 300 MHz) δ: 190, 163.5, 156.9,
136.5, 135.5, 133.2, 131.8, 129.7, 128.7, 119.2, 115.7, 39.8.
Bis-(4-hydroxy-phenyl)-methane (5):
A solution of bis-(4-
hydroxy-phenyl)-methanone (4) (1.50 g, 7.0 mmol) and 55%
hydrazine hydrate (1.07 g, 1.7 mmol) in a conical flask was treated
with ethylene glycol (1 ml) and the contents of the flask were
irradiated in the microwave oven at 320 W for 30 s. The mixture was
cooled in an ice bath for 5 min. The compound was collected in a
suction flask, washed with cold ethanol and air dried to get bis-(4-
hydroxy-phenyl)-methanehydrazone (1.31 g, 82%). Ethylene glycol
(1.0 ml) and potassium hydroxide (1.40 g, 25 mmol) were irradiated
in the microwave oven for 10 s to dissolve the base. Bis-(4-hydroxy-
phenyl)-methanehydrazone (1.30 g, 5.74 mmol) was then added to the
conical flask containing the mixture of ethylene glycol and potassium
hydroxide and irradiated in the microwave oven (320 W) for 10 s.
The brown solution was then diluted with 1 ml of deionised water,
acidified with 6M HCl until pH = 2, and extracted with diethyl ether
(3 × 10 ml). The ether solution was dried over anhydrous sodium
sulfate and the solvent evaporated in vacuo to give bis-(4-hydroxy-
phenyl)-methane (5) (0.45 g, 40%). m.p. 159–162°C (literature value
159–162°C2°), IR(CHCl3)/νmax cm-1: 3347, 2937, 1499, 887, 753.
1H NMR (CDCl3, 300 MHz) δ: 3.6 (s, 2H), 5.30 (bs, 1H, –OH, D2O
The authors thank UGC, New Delhi, for financial assistance.
Received 25 February 2008; accepted 15 March 2008
Paper 08/5115
doi: 10.3184/030823408X304032
References
1
S.K. Das, G. Panda, V. Chaturvadi, Y.S. Manju, A.K. Gaikwad and
S. Sinha, Bioorg. Med. Chem. Lett., 2007, 17, 5586.
S.U. Lu and Y.P. Yang, Celastraceae in Flora of Taiwan, 2nd edn.,
Editorial Committee of the Flora of Taiwan, Taipei, Taiwan, 1993, 3, 640.
Y.H. Kuo and L.M. Yang, Phytochemistry, 1997, 44, 1275.
H. Nozaki, H. Suzuki, T. Hirayama, R. Kasai, R.Y. Wu and K.H. Lee,
Phytochemistry, 1986, 25, 479.
2
3
4
5
6
7
8
9
H. Duan, Y. Takaishi, H. Momota, Y. Ohmoto, T. Taki, Y. Jia and D. Li,
J. Nat. Prod., 2001, 64, 582.
W. Wu, M. Wang, J. Zhu, W. Zhou, Z. Hu and Z. Ji, J. Nat. Prod., 2001,
64, 364.
H.Z Jin, B.Y. Hwang, H.S. Kim, J.H. Lee, Y.H. Kim and J.J. Lee, J. Nat.
Prod., 2002, 65, 89.
J.J. Chen, T.H. Chou, C.F. Peng, I.S. Chen and S.Z. Yang, J. Nat. Prod.,
2007, 70, 202.
exchangeable), 6.92 (d, J = 8.4 Hz, 4H), 7.21 (d, J = 8.4 Hz, 4H). 13
NMR (CDCl3, 300 MHz) δ: 156.6, 130.0, 129.6, 115.6, 45.3.
C
2-Hydroxy-5-(4-hydroxybenzyl)benzaldehyde (1): A stirred warm
solution of sodium hydroxide 2.5 g in water (2.5 ml) in the flask was
treated with a solution of bis-(4-hydroxy-phenyl)-methane (5) (0.45 g,
2.27 mmol) in water (2.0 ml). Chloroform (0.50 g, 4.26 mmol) was
added in three portions at intervals of 15 min. The mixture was
heated on a boiling water bath for 1 h to complete the reaction and
the excess chloroform was removed by evaporation under vacuum.
The solution was cooled and acidified cautiously with dilute sulfuric
acid and steam distilled. Extracted the distillate at once with ether
and removed most of the ether from the extract. Added about twice
the volume of saturated sodium metabisulfite solution to the crude
2-hydroxy-5-(4-hydroxybenzyl)benzaldehyde (1), stirred vigorously
for at least half an hour and allowed to stand for 1 h. The paste of the
bisulfite compound was washed with alcohol 4 ml, and with ether
4 ml. The bisulfite compound was decomposed by warming in round
bottomed flask on a water bath with dilute sulfuric acid, allowed
to cool and the aldehyde was extracted with ether. The work-up
yielded 2-hydroxy-5-(4-hydroxybenzyl)benzaldehyde (1) (0.21 g,
42%). Amorphous powder5 IR(CHCl3)/νmax cm-1: 3470, 1670, 1215.
1H NMR (CDCl3, 300 MHz) δ: 3.90 (s, 2H, –CH2–), 4.80 (bs, 1H, –
G.L. Kad, M. Bhandari, J. Kaur, R. Rathee and J. Singh, Green Chem.,
2001, 3, 275.
10 G.L. Kad, V. Singh, K. Kaur and J. Singh, Tetrahedron Lett., 1997, 38,
1079.
11 J. Singh, M. Sharma, G.L. Kad and B.R. Chhabra, J. Chem. Res. (S),
1997, 264.
12 G.L. Kad, J. Kaur, P. Bansal and J. Singh, J. Chem. Res. (S), 1996, 188.
13 J. Singh, N. Gupta and G.L. Kad, Synth. Commun., 2006, 36, 2893.
14 B.S. Furniss, A.J. Hannaford, V. Rogers, P.W.G. Smith and A.R. Tatchell,
Vogel’s textbook of practical organic chemistry, 4th edn.; Longman
GP. Ltd, New York, 1978, p.497.
15 M.F. Pasha, K. Manjula and P. Jayashankara, Synt. React. Inorg., Met.
Org. Nano-Metal Chem., 2006, 36, 321.
16 E. Parquet and Q. Lin, J. Chem. Educ., 1997, 74, 1225.
17 B.S. Furniss, A.J. Hannaford, V. Rogers, P.W.G. Smith and A.R. Tatchell,
Vogel’s textbook of practical organic chemistry, 4th edn., Longman
GP. Ltd, New York, 1978, 761.
18 H.X. Ying, X. Liu and T.H. Lu, Shiyou Huagong Gaodeng Xuexiao
Xuebao, 2006, 19 (3), 45.
19 J. Magano, M.H. Chen, J.D. Clark and T. Nussbaumer, J. Org. Chem.,
2006, 71(18), 7103.
20 R.W. Martin, J. Org. Chem., 1952, 17(3), 342.
PAPER: 08/5115