Rapid syntheses of (±)-pterocarpans and isoflavones via the gold-catalyzed annulation of aldehydes and alkynes

Article abstract of DOI:10.1016/j.tetlet.2007.09.122

(±)-Pterocarpan and analogues (4a-c) have been synthesized efficiently via the annulation of salicylaldehydes (1a, 1b and 1c) and o-methoxymethoxylphenylacetylene (2a), followed by a one-pot reduction and acidic cyclization of the ketones (3a-c). In addition, isoflavone derivatives (5a-c) have been synthesized rapidly, in two steps, via the annulation of salicylaldehyde (1a) and arylacetylenes (2b, 2c and 2d), followed by IBX/DMSO oxidation of the isoflavanones (3d, 3e and 3f).

Full text of DOI:10.1016/j.tetlet.2007.09.122

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Tetrahedron Letters 48 (2007) 8343–8346
Rapid syntheses of ( )-pterocarpans and isoflavones via the
gold-catalyzed annulation of aldehydes and alkynes
Rachid Skouta and Chao-Jun Li*
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, QC, Canada H3A 2K6
Received 2 August 2007; revised 7 September 2007; accepted 18 September 2007
Available online 22 September 2007
Abstract—( )-Pterocarpan and analogues (4a–c) have been synthesized efficiently via the annulation of salicylaldehydes (1a, 1b and
1c) and o-methoxymethoxylphenylacetylene (2a), followed by a one-pot reduction and acidic cyclization of the ketones (3a–c). In
addition, isoflavone derivatives (5a–c) have been synthesized rapidly, in two steps, via the annulation of salicylaldehyde (1a) and
arylacetylenes (2b, 2c and 2d), followed by IBX/DMSO oxidation of the isoflavanones (3d, 3e and 3f).
ꢀ 2007 Elsevier Ltd. All rights reserved.
Pterocarpans are the second largest group of natural
isoflavanoids1 (Fig. 1). They are potent phytoalexins2
which are used for their antitoxin,3 antifungal,4 anti-
viral3 and antibacterial5 properties. The classical
methods for synthesizing ( )-pterocarpans are (i) the
reduction and cyclization of the corresponding 20-
hydroxyisoflavanones;6 (ii) 1,3-Michael–Claisen annula-
tion;7a,b (iii) cycloaddition reaction of 2H-chromenes
with 2-alkoxy-1,4-benzo-quinones;8a,b and (iv) Heck
arylation of 2H-chromenes with o-chloromercuriphenol
using lithium chloropalladite as a catalyst.9a–c
20-hydroxy group;11 (ii) oxidative rearrangement of
chalcone by thallium(III) reagent;12 (iii) rearrangement
via an epoxyketone produced by the action of hydrogen
peroxide;13 (iv) the Suzuki coupling reaction of 3-bromo-
chromone with an aryl boronic acid using palla-
dium(0);14 and (v) the treatment of 20-benzoyl-
oxychalcones with hypervalent iodine(III) reagent.15
It is noteworthy that the previous methods for synthesiz-
ing the natural products, ( )-pterocarpans and isoflav-
ones, required several steps and some needed the use of
expensive starting materials and toxic reagents. Recently,
we reported a novel and highly atom economical16 direct
annulation of simple salicylaldehyde with phenylacetyl-
ene or 2-tosylaminobenzenaldehyde catalyzed by gold(I)
to give isoflavanone17a and aza-isoflavanone17b-type
structures efficiently. Herein, we wish to report the
application of this annulation in rapid syntheses of the
two classes of natural products: ( )-pterocarpans and
isoflavones.
Isoflavones such as daidzein10a (Fig. 1) are phytoestro-
gens with weak oestrogenic activity.10b,c They are pres-
ent in the human diet in soy beans and soy derived
products.10d The major synthetic methods of isoflavones
are as follows: (i) cyclization of deoxybenzoin with a free
OH
O
O
Our approach towards ( )-pterocarpans and isoflav-
ones as well as their derivatives based on the annulation
is described in Scheme 1. Both types of natural products
can be formed from the common isoflavanone interme-
diates. Thus, to synthesize ( )-pterocarpan 4a, salicyl-
aldehyde 1a and 2-(methoxymethoxy)-alkynebenzene
2a, which can be obtained readily by the Sonogashira
coupling18 from 2-iodophenol, catalyzed by gold(I)
provided the desired isoflavanone 3a19 in 73% isolated
yield. The treatment of isoflavanone 3a with NaBH4 in
a mixture of THF/MeOH at room temperature for 2 h
followed by the addition of an excess amount of
HO
O
O
daidzein
( )-pterocarpan
Figure 1. Natural products containing ( )-pterocarpan1b and isoflav-
one (daidzein).10b
Keywords: Gold-catalysis; Isoflavanoids; ( )-Pterocarpans; Salicyl-
aldehyde.
*
Corresponding author. Tel.: +1 514 398 8457; fax: +1 514 398
3797; e-mail: cj.li@mcgill.ca
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.122

8344
R. Skouta, C.-J. Li / Tetrahedron Letters 48 (2007) 8343–8346
Y
R
Y
O
O
O
O
R
R
Y=MOMO
O
O
X
X
X
pterocarpans
isoflavones
O
Y
+
R
OH
X
Scheme 1. Retro-synthetic analysis for the synthesis of ( ) pterocarpans and isoflavones.
MOMO
with acetylene 2a under the gold(I)-catalyzed annulation
conditions to isoflavanone 3c19 in 68% yield. Subsequent
reduction by NaBH4 followed by the BF3-catalyzed
cyclization in situ afforded ( )-pterocarpan analogue
4c19 in 75% yield (Scheme 3).
O
O
cat. AuCN
cat. PBu3
MOMO
+
R
R
H
toluene, 150 °C, 36-48 h
O
OH
1a : R= H
1b : R= Cl
3a : R= H, 73%
3b : R= Cl, 70%
2a
In order to obtain the isoflavone derivatives 5a–c
(Scheme 4), we need to find a dehydrogenation method
of the isoflavanone derivatives 3d, 3e and 3f which were
obtained via the annulation between salicylaldehyde (1a)
and phenylacetylenes (2b, 2c and 2d).17a It was found
that common dehydrogenation reagents such as DDQ
and Dess–Martin were less effective as oxidant reagents
for the desired transformation. Only trace amounts of
the isoflavone products were observed and most isoflav-
anones were recovered under these conditions. On the
other hand, Nicolaou et al. reported that o-iodoxy-
benzoic acid (IBX) is a highly effective dehydrogenation
reagent for the synthesis of a,b-unsaturated carbonyl
compounds.20 Following this procedure, isoflavanones
3d, 3e and 3f were mixed with IBX and heated at
1. NaBH4,
THF/MeOH,
rt, 2 h
O
O
2. BF3-OEt2
R
4a : R= H ( )-pterocarpan, 91%
4b : R= Cl ( ) -2-chloropterocarpan, 53%
Scheme 2. Synthesis of ( )-pterocarpan 4a and analogue 4b.
BF3–OEt2 afforded ( )-pterocarpan 4a19 in 91%
(Scheme 2).
1
85 ꢁC in DMSO-d6. The reactions were followed by H
Similarly, the reaction of 5-chloro salicylaldehyde 1b
with acetylene 2a under the same reaction conditions
for 48 h afforded isoflavanone 3b19 in 70% yield. Further
treatment of 3b with NaBH4 and BF3–OEt2 gave ( )-
pterocarpan 4b19 in 53% yield (Scheme 2). By a similar
procedure, 2-hydroxy-1-naphthaldehyde 1c was reacted
NMR until the starting materials were consumed com-
pletely. The desired isoflavone products 5a–c were
obtained successfully in modest to good yields. A slight
increase in the yield of the isoflavones 5a–c21 was
observed when an electro-donating group was attached
on the isoflavanones 3d, 3e and 3f (Scheme 4).
O
MOMO
R
R
O
cat. AuCN
cat. PBu3
O
O
O
cat. AuCN
cat. PBu3
MOMO
+
H
+
H
toluene, 150 °C, 36 h
OH
toluene, 150 °C, 36-48h
O
OH
1a
R= H,
R= CH3, 2c
R= OCH3, 2d
2b
R= H,
R= CH3, 3e
R= OCH3, 3f
3d
3c, 68%
1c
2a
IBX
1. NaBH4,
THF/MeOH,
rt, 2h
DMSOd6
R
85˚C, 48 h
O
2. BF3-OEt2
O
O
O
R= H,
R= CH3,
5a (45%)
5b (54%)
R= OCH3, 5c (63%)
4c : ( )-pterocarpan analogue, 75%
Scheme 3. Synthesis of ( )-pterocarpan analogue 4c.
Scheme 4. Synthesis of isoflavone derivatives 5a–c.

R. Skouta, C.-J. Li / Tetrahedron Letters 48 (2007) 8343–8346
8345
17. (a) Skouta, R.; Li, C.-J. Angew. Chem., Int. Ed. 2007, 46,
1117; (b) Skouta, R.; Li, C.-J. Synlett 2007, 1759.
18. Tsang, K. Y.; Brimble, M. A.; Bremner, J. B. Org. Lett.
2003, 5, 4425, and reference 12.
19. Experimental and characterizations of new compounds: 6-
Chloro-2,3-dihydro-3-(2-(methoxymethoxy)phenyl)chromen-
4-one (3b). Following the reported procedure, the product
was isolated by flash-column chromatography on silica gel
(hexane/ethyl acetate = 15:1; Rf = 0.32). IR (neat, NaCl):
In conclusion, the rapid syntheses of ( )-pterocarpan,
isoflavone and their analogues were succeeded by applying
the gold-catalyzed annulation of hydroxyarylaldehydes
and alkynes. The method provides both natural and
unnatural ( )-pterocarpan and isoflavone derivatives
readily. Further studies regarding the biological activi-
ties of such derivatives are in progress.
mmax 1698, 1603, 1493, 1477, 1457, 1419, 1277, 1236, 1202,
1186, 1154, 1116, 1080, 999, 923, 825, 755 cmꢀ1; 1H NMR
(CDCl3, 400 MHz, ppm) d 7.94 (d, J = 2.8 Hz, 1H), 7.44
(dd, J = 8.8, 2.8 Hz, 1H), 7.28 (dt, J = 8.4, 1.6 Hz, 1H),
7.17–7.11 (m, 2H), 7.02–6.97 (m, 2H), 5.14 (s, 2H), 4.68
(dd, J3ax.2ax = 12.4 Hz, J3ax.2eq = 10.8 Hz, 1H, H-3ax),
4.55 (dd, J2eq.3ax = 10.8 Hz, J2eq.2ax = 5.2 Hz, 1H,
H-2eq), 4.33 (dd, J2ax.3ax = 12.4 Hz, J2ax.2eq = 5.2 Hz,
1H, H-2ax), 3.43 (s, 3H); 13C NMR (CDCl3, 100 MHz,
ppm) d 191.1, 160.3, 155.1, 135.5, 130.5, 129.4, 127.0,
126.9, 123.5, 122.3, 122.1, 119.6, 114.5, 94.5, 70.8, 56.2,
48.8; MS (GC/MS) m/z (%) 318 (M+), 287, 273 (100), 256,
199, 164, 155, 132, 119, 103, 91, 77, 63, 51; HRMS calcd
for C17H15ClO4: 318.06589; found, 318.06524.
Acknowledgements
We are grateful to the Canada Research Chair (Tier I)
Foundation (C.J.L.), the CFI, NSERC and McGill Uni-
versity for the support of our research.
References and notes
1. (a) Dewich, P. M. In Harborne, J. B., Ed.; The Flava-
noids: Advances in Research Since 1986; Chapman and
Hall: London, 1994; (b) Tanaka, H.; Oh-Uchi, T.; Etoh,
H.; Shimizu, H.; Tateishi, Y. Phytochemistry 2002, 60,
789.
2. Mansfield, J. W. In Phytoalexins; Bailey, J. A., Mansfield,
J. W., Eds.; Glasgow, 1982.
3. Nakagawa, M.; Nakanishi, K.; Darko, L. L.; Vick, J. A.
Tetrahedron Lett. 1982, 23, 3855.
2,3-Dihydro-2-(2-(methoxymethoxy)phenyl)benzo[f]chro-
men-1-one (3c). Following the reported procedure, the
product was isolated by flash-column chromatography on
silica gel (hexane/ethyl acetate = 15:1; Rf = 0.13). IR
(neat, NaCl): mmax 1674, 1617, 1597, 1568, 1512, 1493,
1435, 1375, 1344, 1279, 1233, 1207, 1154, 1113, 1079, 992,
1
921, 825, 754 cmꢀ1; H NMR (CDCl3, 400 MHz, ppm) d
9.48 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.78 (d,
J = 7.6 Hz, 1H), 7.62 (dt, J = 7.2, 1.6 Hz, 1H), 7.44 (dt,
J = 6.8, 0.8 Hz, 1H), 7.29 (dd, J = 8.0, 1.6 Hz, 1H), 7.19–
7.13 (m, 3H), 7.01 (dt, J = 7.6, 1.2 Hz, 1H), 5.16 (s, 2H),
4.81 (dd, J3ax.2ax = 11.6 Hz, J3ax.2eq = 10.8 Hz, 1H, H-3ax),
4.66 (dd, J2eq.3ax = 10.8 Hz, J2eq.2ax = 5.6 Hz, 1H, H-2eq),
4.47 (dd, J2ax.3ax = 11.6 Hz, J2ax.2eq = 5.6 Hz, 1H, H-2ax),
3.43 (s, 3H); 13C NMR (CDCl3, 100 MHz, ppm) d 193.4,
163.8, 155.2, 137.3, 131.9, 130.4, 129.6, 129.4, 129.1, 128.4,
126.1, 124.8, 124.7, 122.1, 118.8, 114.5, 113.3, 94.6, 70.6,
56.2,49.5; MS (EI) m/z (%) 334 (M+), 302, 289, 271, 215
(100), 185, 164, 132, 91, 69, 45, 51; HRMS calcd for
C21H18O4: 334.12051; found, 334.12007.
General procedure for the synthesis of ( )-pterocarpans 4a–
c. To a stirred solution of 3a–c in a 1:1 mixture of dry
THF and methanol, sodium borohydride was added at
room temperature. The reaction was monitored by TLC.
After 2 h the reaction mixture was treated with boron
trifluoride diethyl etherate. After 2 h the residue was
washed with 10% aqueous sodium carbonate, then with
water until neutral and dried. The solvent was evapo-
rated in vacuo. The residue was purified by flash-
column chromatography on silica gel with the appropriate
mixture of hexane and EtOAc to give ( )-pterocarpans
4a–c.
´
4. (a) Maximo, P.; Lourenc¸o, A. Phytochemistry 1998, 48,
359; (b) Perrin, D. R. Tetrahedron Lett. 1964, 1, 29.
5. Ingham, J. L. In Progress in the Chemistry of Organic
Natural Products; Herz, W., Grisebach, H., Kirby, G. W.,
Eds.; Springer: New York, 1983; Vol. 43, pp 1–266.
6. Krishna Prasad, A. V.; Kapil, R. S.; Popli, S. P. J. Chem.
Soc., Perkin Trans. 1 1986, 1561.
7. (a) Ozaki, Y.; Mochida, K.; Kim, S.-W. J. Chem. Soc.,
Chem. Commun. 1988, 374; (b) Ozaki, Y.; Mochida, K.;
Kim, S.-W. J. Chem. Soc., Perkin Trans. 1 1989, 1219.
8. (a) Engler, T. A.; Reddy, J. P.; Combrink, K. D.; Vander
Velde, D. J. Org. Chem. 1990, 55, 1248; (b) Subburaj, K.;
Murugesh, M. G.; Trivedi, G. K. J. Chem. Soc., Perkin
Trans. 1 1997, 1875.
9. (a) Horino, H.; Inoue, N. J. Chem. Soc., Chem. Commun.
1976, 500; (b) Ishiguro, M.; Tatsuoka, T.; Nakatsuka, N.
Tetrahedron Lett. 1982, 23, 3859; (c) Narkhede, D. D.;
Iyer, P. R.; Iyer, C. S. R. Tetrahedron 1990, 46, 2031.
10. (a) Dwyer, J. T.; Goldin, B. R.; Saul, N.; Gualfieri, B. S.;
Abdercreutz, H. J. Am. Diet. Assoc. 1994, 94, 739; (b)
Holder, C. L.; Churchwell, M. I.; Doerge, D. R. J. Agric.
Food. Chem. 1999, 47, 3764; (c) Hendrich, S.; Lee, K.-W.;
Xu, X.; Wang, H.-J.; Murphy, P. A. J. Nutr. 1994, 124,
1789S; (d) Murphy, P. A.; Song, T.; Buseman, G.; Barua,
K. J. Agric. Food. Chem. 1997, 45, 4635.
( )-Pterocarpan (4b). Following the above general proce-
dure with 3b (48 mg, 0.15 mmol) and sodium borohydride
(11.4 mg, 0.30 mmol), the residue was neutralized with
dilute aqueous hydrochloric acid, extracted with dichlo-
romethane, passed through a small silica gel column with
hexane/ethyl acetate = 5:1 and then it was treated with
boron trifluoride diethyl etherate (0.1 ml). The residue was
purified by flash-column chromatography on silica gel
(hexane/ethyl acetate = 5:1, Rf = 0.55). IR (neat, NaCl):
11. Wong, E. In The Flavanoids; Harborne, J. B., Mabry, T.
J., Marby, H., Eds.; Chapman and Hall: London, 1975;
184.
12. Mckillop, A.; Swarn, B. P.; Taylor, E. C. Tetrahedron
Lett. 1970, 11, 5281.
13. Jain, A. C.; Lal, P.; Seshadri, T. R. Indian J. Chem. 1969,
7, 305.
14. Hoshino, Y.; Miyaura, N.; Suzuki, A. Bull. Chem. Soc.
Jpn. 1988, 61, 3008.
15. Kawamura, Y.; Maruyama, M.; Tokuoka, T.; Tsukay-
ama, M. Synthesis 2002, 2490.
16. (a) Trost, B. M. Science 1991, 254, 1471; (b) Trost, B. M.
Angew. Chem., Int. Ed. Engl. 1995, 34, 259; (c) Trost, B.
M. Acc. Chem. Res. 2002, 35, 695.
m
max 1610, 1598, 1484, 1463, 1424, 1316, 1254, 1231, 1183,
1
1126, 1083, 1023, 938, 883, 855, 825, 751 cmꢀ1; H NMR
(C6D6, 400 MHz, ppm) d 7.43 (d, J = 2.8 Hz, 1H), 6.91 (t,
J = 7.6 Hz, 1H), 6.86 (dd, J = 8.8, 2.8 Hz, 1H), 6.75–6.72
(m, 2H), 6.67 (t, J = 7.6 Hz, 1H), 6.58 (d, J = 8.8 Hz, 1H),

8346
R. Skouta, C.-J. Li / Tetrahedron Letters 48 (2007) 8343–8346
4.83 (d, J13a.8a = 7.2 Hz, 1H, H-13a), 3.71 (dd, J8eq.8a = 5.6 Hz, 1H, H-8eq), 3.45 (t, J8ax.8eq
=
J8eq.8ax = 11.2 Hz, J8eq.8a = 5.2 Hz, 1H, H-8eq), 3.22 (t,
J8ax.8eq = J8ax.8a = 11.2, 1H, H-8ax), 2.89–2.83 (m, 1H, H-
8a); 13C NMR (C6D6, 75 MHz, ppm) d 159.6, 154.4, 131.0,
130.0, 129.4, 126.8, 126.5, 124.7, 122.2, 120.9, 119.0, 110.3,
76.8, 66.2, 40.2; MS (GC/MS) m/z (%) 258 (M+) (100),
241, 223, 205, 194, 176, 165, 152, 131, 118, 102, 89, 77, 63,
51; HRMS calcd for C15H11ClO2: 258.04476; found,
258.04406.
J8ax.8a = 10.8, 1H, H-8ax), 3.01–2.93 (m, 1H, H-8a); 13C
NMR (C6D6, 100 MHz, ppm) d 159.6, 153.8, 134.2, 130.7,
129.5, 129.1, 128.3, 127.1, 127.0, 124.6, 124.0, 123.9, 120.6,
118.6, 112.2, 110.1, 76.0, 65.9, 39.6; MS (GC/MS) m/z (%)
258 (M+), 170 (100), 241, 223, 205, 194, 176, 165, 152, 131,
118, 102, 89, 77, 63, 51; HRMS calcd for C19H14O2:
274.09938; found, 274.09865.
20. Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong,
Y.-L. J. Am. Chem. Soc. 2002, 124, 2245.
( )-Pterocarpan (4c). Following the above general proce-
dure with 3c (43 mg, 0.129 mmol), sodium borohydride
(10 mg, 0.258 mmol) and boron trifluoride diethyl etherate
(1.5 ml), the residue was purified by flash-column chro-
matography on silica gel (hexane/ethyl acetate = 15:1,
Rf = 0.33). IR (neat, NaCl): mmax 1625, 1600, 1514, 1476,
1438, 1248, 1232, 1090, 1025, 966, 909, 880, 845,
21. General procedure for the synthesis of isoflavone derivatives
5a–c. IBX (3 equiv) was added to a solution of isoflava-
nones 3d, 3e and 3f (1 equiv) in DMSO-d6. The reaction
mixture was heated at 85 ꢁC until complete consumption
of the starting material was observed by 1H NMR. The
reaction mixture was cooled to room temperature and
diluted with ethyl acetate. The organic layer was washed
with 5% NaHCO3 (3·), H2O (1·) and dried (MgSO4)
followed by the removal of the solvent in vacuo. The
residue was purified by flash-column chromatography on
silica gel with the appropriate mixture of hexane and
EtOAc to give the isoflavone derivatives 5a–c.
827,749 cmꢀ1 1H NMR (C6D6, 400 MHz, ppm) d 8.33
;
(d, J = 8.8 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.39 (dt,
J = 8.8, 0.8 Hz, 2H), 7.18 (t, J = 7.2, 1H), 7.07 (d,
J = 8.8 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.82 (dd,
J = 7.6, 1.0 MHz, 2H), 6.70 (t, J = 7.6, 1H), 5.50 (d,
J13a.8a = 6.4 Hz, 1H, H-13a), 3.91 (dd, J8eq.8ax = 10.8 Hz,