A facile synthesis of biogenetic precursor, puerarone, isolated from Pueraria sp

Article abstract of DOI:10.1002/jhet.5570380434

Puerarone was synthesized using chalcone oxidation with thallium (III) trinitrate and chromenation of the resulting isoflavone using 3-hydroxyisovaleraldehyde dimethylacetal. The key demethylation step was achieved with boron tribromide.

Full text of DOI:10.1002/jhet.5570380434

Jul-Aug 2001
A Facile Synthesis of Biogenetic Precursor, Puerarone,
Isolated from Pueraria sp
1007
Riaz A. Khan* and Randhir S. Kapil
Central Drug Research Institue, Lucknow, 226 001, India
Received January 30, 2001
Puerarone was synthesized using chalcone oxidation with thallium (III) trinitrate and chromenation of the
resulting isoflavone using 3-hydroxyisovaleraldehyde dimethylacetal. The key demethylation step was
achieved with boron tribromide.
J. Heterocyclic Chem., 38, 1007 (2001).
Synthesis of the chromenoisoflavone, puerarone 1,
MS spectrum of compound 13 showed molecular ion peak
at m/z 464 along with prominent ion peak at m/z 373,
formed by the loss of one benzyl group, which together
established the structure of isoflavone 13. The hydrogenoly-
sis of 13 in acetone on 10% palladium-carbon as catalyst
furnished a mixture of products which was purified to give
2',4'-dihydroxy-7-methoxyisoflavone 14 and this on con-
densation with 3-hydroxyisovaleraldehyde dimethylacetal
which is considered to be the precursor in biosynthesis of
Pueraria pterocarponoids [1], has been attempted. Jain et
al. [2] reported the synthesis of dihydropuerarone 4, in an
attempt to synthesize puerarone 1 from 2,4'-dibenzyloxy-
2'-hydroxy-2'',2''-dimethyl-2H-pyrano-[2,3-c]-chalcone 5.
The conversion of chalcone 5 to the chromenoisoflavone,
2',7-dibenzyloxypuerarone 2 was attempted by
thallium(III) nitrate-methanol oxidation. The approach
was abandoned for the preparation of dihydropyranochal-
cone 6, which gave dihydropuerarone 4 from 2',7-
dibenzyloxydihydropuerarone 3. However, 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ) dehydrogenation
of 2',7-dibenzyloxydihydropuerarone 3 furnished 1, but
there is no experimental detail given and no spectro-ana-
lytical support provided [2].
In the present study, the total synthesis of puerarone 1 is
achieved utilizing 2,4-dibenzyloxy-2'-hydroxy-4'-
methoxychalcone 11 as the key intermediate (Scheme 1)
which was converted to 2',4'-dihydroxy-7-methoxy-
isoflavone 14 and later to 7-methoxypuerarone 15 which
on demethylation using boron tribromide furnished the
desired product, puerarone 1.
in pyridine furnished the chromenoisoflavone, 7-methoxy-
1
puerarone, 15. The H NMR spectrum of 15 showed the C
3'
and C proton singlets at δ 7.30 and δ 7.10 respectively, and
6'
a characteristic one proton C isoflavone singlet at δ 8.13. In
2
the mass spectrum molecular ion peak at m/z 350 along with
prominent ion peak at m/z 335 formed by the loss of one
methyl group, which is characteristic for 2'',2''-dimethyl
chromene ring system in the molecule 15 [8], is observed.
The isoflavone 15 was demethylated using boron tribromide
[9] at -78 °C in dry dichloromethane under nitrogen atmos-
phere to furnish the puerarone 1, as an oil, identified by
spectroscopic means and comparison with the natural sam-
ple. The UV spectrum of 1 showed absorption values at
λmax 230 and 305 nm, IR absorptions are observed at 3400
1
1
cm- corresponding to the hydroxyl group and at 1665 cm-
The chalcone 11 was obtained by condensation of
2-hydroxy-4-methoxyacetophenone 8 and 2,4-dibenzyloxy-
benzaldehyde 10 in aqueous sodium hydroxide [3,4]. The
corresponding to the conjugated carbonyl. In the mass spec-
trum of 1, molecular ion peak at m/z 336 and prominent ion
peak at m/z 321, due to the loss of one methyl group from
1
formation of chalcone 11 was confirmed by IR, H NMR,
the 2'',2''-dimethylchromene moiety [8], are observed. The
1
MS & UV spectral analysis. The presence of absorptions at
H NMR of 1 displayed characteristic C isoflavone proton
2
-1
1630 and 1540 cm in the IR spectrum corresponding to an
singlet at δ 8.34, a six protons singlet at δ 1.40 and a set of
α,β-unsaturated carbonyl group, the observation of molecu-
lar ion peak at m/z 466 in the MS spectrum and the lack of
methyl ketone singlet and of aldehydic protons of the corre-
AB quartets for the C and C protons at δ 5.62 and δ 6.35
3''
4''
(J = 10.0 Hz, both) for the 2'',2''-dimethylchromene ring [8].
The protons at C , C and C are observed at δ 8.14 (d, J =
5
6
8
1
sponding starting materials in the H NMR spectrum con-
8.5 Hz), δ 7.20 (dd, J = 8.5, 2.0 Hz) and δ 7.02 (d,J = 2.0 Hz)
firmed the chalcone structure 11 [5,6]. The chalcone 11 on
reacting with thallium(III) nitrate [7] in dry methanol at
room temperature for 6 hours, afforded the acetal 12 which
was cyclised using 10% aqueous hydrochloric acid to give
the desired product, 2',4'-dibenzyloxy-7-methoxyisoflavone
13 after purification by silica gel column chromatography in
76% yield. The IR spectrum of 13 exhibited absorptions at
respectively while protons at C and C resonate at δ 6.37
3'
6'
1
& δ 7.04 as singlets in the H NMR spectrum of 1, which
confirms the structure 1. A comparison of the H NMR
spectrum of 1 with the reported H NMR data of naturally
1
1
occurring puerarone [1] showed a downfield shift, i.e., a
maximum shift of δ 0.12 for individual resonances (e.g.,
C ) and an overall downfield shift of δ 0.09 for the whole
3''
1
1650 and 1620 cm- corresponding to the conjugated car-
spectrum. The observed chemical shift values are close to
1
1
bonyl while the H NMR spectrum showed characteristic
the reported H NMR data and the spectral analyses (UV,
1
one proton C isoflavone singlet at δ 7.90, a methoxy singlet
IR, H NMR & MS) of 1 unequivocally established the
2
at δ 3.78, two benzylic methylenes at δ 5.00 as singlet. The
puerarone structure 1.

1008
R. A. Khan and R. S. Kapil
Vol. 38
Scheme 1
Reagents and conditions: a) CH I, acetone, K CO , reflux b) PhCH Cl, K CO , NaI, EtOH, reflux c) 50% aq. NaOH, EtOH, reflux d) Th(III)NO , dry
3
2
3
2
2
3
3
MeOH e) 10% aq. HCl, reflux f) 10% Pd-C, H , acetone g) 3-Hydroxy isovaleraldehyde dimethylacetal, pyridine, reflux h) dry CH Cl , -78 °C , BBr
2
2
2
3.
EXPERIMENTAL
To a stirred solution of 2,4-dihydroxyacetophenone (7) (15.0
g) in dry acetone (150 ml), anhydrous potassium carbonate (15.0
g) and methyl iodide (40 ml) were added. The reaction mixture
was refluxed for 4 hours, cooled, filtered and washed with hot
acetone. The evaporation of solvent yielded a residue that was
dissolved in chloroform, washed with water, dried over anhy-
drous sodium sulphate and the solvent evaporated to give an oil
that was crystallized from hexane-ether (1:1) to furnish (8) , 12.4
g, 75.7%. mp 47 °C.
General.
Melting points are uncorrected and expressed in degree
Celsius. UV spectra were recorded on Hitachi-320 spectropho-
tometer and IR spectra were recorded on Perkin-Elmer 157 as
1
potassium bromide pellets, unless otherwise stated. The H NMR
spectra were acquired on Perkin-Elmer R-32 and Bruker WM
400 FT spectrometer. The mass spectra were recorded on Jeol
JMS D-300 instrument in EI mode at 70 eV. Precoated silica gel
TLC plates (Merck, Darmstadt) were used and visualized by
spraying with a 2 N sulphuric acid solution of Ceric Sulfate.
2,4-Dibenzyloxybenzaldehyde (10).
2,4-Dihydroxybenzaldehyde (9) (15.0 g) in ethanol (150 ml)
was mixed with potassium carbonate (30.0 g), benzyl chloride
(30 ml) and sodium iodide (0.5 g). The suspension was refluxed
2-Hydroxy-4-methoxyacetophenone (8).

Jul-Aug 2001
A Facile Synthesis of Biogenetic Precursor, Puerarone, Isolated from Pueraria sp
1009
for 6 hours and the solvent evaporated to afford a residue that was
crystallized from hexane-dichloromethane (1:1) to give (10),
27.5 g, 72.3%. mp 82 °C.
NMR (acetone-d ): δ 1.26 (s, 6H, 2 x CH ), 3.90 (s, 3H,Ar-OCH ),
6
3
3
5.35 (d, IH, J = 10.0 Hz, H-3''), 6.54 (d, 1H, J = 10.0 Hz, H-4''), 6.82
(m, 1H, H-6), 7.10 (s, 1H, H-6'), 7.30 (s, 1H, H-3'), 7.83 (m, 2H, H-
+
5, 8), 8.13 (s, 1H, H-2). MS (m/z): 350 (M ), 335, 174, 163.
2,4-Dibenzyloxy-2'-hydroxy-4'-methoxychalcone (11).
Puerarone (1).
To a mixture of 2-hydroxy-4-methoxyacetophenone (8) (10.0 g)
and 2,4-dibenzyloxybenzaldehyde (10) (20.0 g) in ethanol (250 ml)
was added 50% aqueous sodium hydroxide (30.0 ml) and the mix-
ture was refluxed for 2 hours to furnish a yellow precipitate that was
filtered and washed with dilute hydrochloric acid and water.
Recrystallization from ether-dichloromethane (1:1) yielded yellow
crystals (11), 13.6 g, 46.6%, mp 155 °C. IR (KBr): 1630, 1540,
To the stirring solution of 7-methoxypuerarone (15) (1.0 g) in
dry dichloromethane, cooled by dry ice and acetone at -78 °C
under nitrogen atmosphere was added boron tribromide (20 ml)
in 2 portions and stirring continued for 30 minutes. The reaction
mixture was allowed to warm to room temperature and the sol-
vent was removed under vacuum to afford an oil which on
preparative thin layer chromatographic purification using
hexane-ethyl acetate (2:1) furnished puerarone (1) as an oil, 482
mg, 50.2%. UV (MeOH) 230, 305 cm . IR (Neat): 3400, 1665,
1450, 1050, 840. H NMR (acetone-d ): δ 1.40 (s, 6H, 2xCH ),
5.62 (d, 1H, J = 10.0 Hz, H-3''), 6.35 (d, IH, J = 10.0 Hz, H-4''),
6.37 (s, 1H, H-3'), 7.02 (d, 1H, J = 2.0 Hz, H-8), 7.04(s, IH, H-6'),
7.20 (dd, IH, J = 8.5,2.0 Hz, H-6), 8.14 (d, IH, J = 8.5 Hz, H-5),
-1
1
1320, 1225, 1150,1010 and 825 cm . H NMR (CDC1 ): δ 3.70
3
(S,3H,OCH ), 5.00 (S, 4H, 2xPhCH -O-), 6.00-6.70 (m, 3H, H-3,
3
2
+
-1
3' 5'), 7.15-7.82 (m, 13H, ArH). MS (m/z): 466 (M ).
1
6
3
2', 4'-Dibenzyloxy-7-methoxyisoflavone (13).
To stirred suspension of chalcone (11) (15.0 g) in methanol
(450 ml) was added thallium(III) nitrate (20.0 g) in four small
portions in 1 hour and stirring continued for a total of 6 hours at
room temperature. The reaction mixture was filtered and 10%
HCl (30.0 ml) was added to the filtrate. The acidified filtrate was
refluxed for 4 hours, concentrated to give a mass to which water
was added and extracted with chloroform. Evaporation of the
solvent gave an oil product, which was purified by silica gel col-
umn chromatography using hexane-benzene (1:1) to give (13),
11.4 g, 76%, mp 139 °C. IR (KBr): 1650, 1620, 1440, 1260,
+
8.34 (s, 1H, H-2). MS (m/z): 336 (M ), 321, 200, 185, 170, 134.
REFERENCES AND NOTES
*
Address for communication, Riaz A. Khan, National
Center for Natural Products Research, School of Pharmacy, The
University of Mississippi, University, MS 38677,USA.
[1] K.V. Ramakrishna, R. A. Khan and R. S. Kapil, Indian J.
Chem., 27 B, 285 (1988).
[2] A. C. Jain and P. Paliwal, Indian J. Chem., 29B,757
(1990).
[3] G. N. Vyas and N. M. Shahi, J. Indian Chem. Soc., 27, 189
(1950).
[4] J. L. Ingham and P. M. Dewick, Phytochemistry, 17, 535
(1978).
[5] A. V. K. Prasad, R. S. Kapil and S. P. Popli, J. Chem. Soc.
Perkin I, 1561 (1986).
[6] L. Farkas, A. Gottsegen, M. Nogardi and S. Antus, J.
Chem. Soc. Perkin I, 305 (1974).
[7] Thallium(III) nitrate; [CAS: 13453-38-8]. Primary target
organs skin, eyes and upper respiratory tracts, handling and storage
precautions to be strictly followed. 'Sigma-Aldrich Library of
Chemical Safety Data', Edition II, Vol. 2, p. 3317, Robert E. Lenga
(Editor), Sigma-Aldrich Corporation, Milwaukee, WI 53201, USA,
1988.
-1
1
1240, 1035 and 840 cm . H NMR (acetone-d ): δ 3.78 (s, 3H,
6
OCH ), 5.00 (s, 4H, 2xPhCH -O), 6.60-7.50(m, 16H, ArH), 7.90
(s, 1H, C -H). MS (m/z): 464 (M ), 373.
3
2
+
2
2', 4'-Dihydroxy-7-methoxyisoflavone (14).
To a stirring solution of 2',4'-dibenzyloxy-7-methoxy-
isoflavone (13) (10 g) in acetone (150 ml) was added 10% Pd-C
(1.0 g) and stirring was continued for 3 hours under hydrogen.
The catalyst was filtered, acetone was evaporated and the oily
residue obtained purified by column chromatography over silica
gel to furnish 2',4'-dihydroxy-7-methoxyisoflavone (14), 1.6 g,
1
27%, mp 210 °C. UV (MeOH): 248, 264, 290 nm- . IR (KBr):
-1
1
3400,1640,1620 cm . H NMR (acetone-d + DMSO-d ): δ
6
6
3.85 (s, 3H, ArOCH ), 6.25-6.60 (m, 2H, H-3', 5'), 6.70-7.45 (m,
3
3H, H-6, 8, 6'), 8.00(s, 1H, H-2), 8.15(d, 1H, J = 8.5 Hz, H-5).
+
MS (m/z): 284 (M ), 267, 254, 151, 134.
7-Methoxypuerarone (15).
[8] C. S. Barnes, J. L. Occolowitz, N. L. Dutta, P. M. Nair, P.
S. Phadke and K. Venketraman, Tetrahedran. Lett., 5, 281(1963).
[9] Boron tri bromide; [CAS: 10294-33-4]. Extremely
destructive to the tissues of mucous membrane & respiratory tract.
Reacts with water to give toxic fumes, explodes on heating, incom-
patible with Sodium and Potassium.'Hazardous Chemicals Desk
Reference', IIIrd ed., p. 188, Richard J. Lewis Sr. (Editor), Van
Nostrand Reinhold, New York,1993.
The mixture of 2',4'-dihydroxy-7-methoxyisoflavone (14) (2.0 g)
and 3-hydroxyisovaleraldehyde dimethylacetal (10 ml) in pyridine
(50 ml) was refluxed at 150 °C for 48 hours. The reaction mixture
was concentrated under vacuum and the residue obtained was chro-
matographed over a silica gel column eluting with chloroform to
give 7-methoxypuerarone (15) as an oil, 1.4 g, 55.6%. UV (MeOH):
-1
-1 1
248, 310 cm . IR (Neat): 3400, 1660, 1570, 1480, 835 cm . H