Synthesis of new (±) pterocarpans by Heck oxyarylation

Article abstract of DOI:10.1007/s10600-005-0158-z

Among a wide variety of synthetic routes to pterocarpan prototypes, a mild approach uses a reaction known as Heck oxyarylation. This method involves a reaction between 2H-chromenes and 2-chloromercuriophenols in the presence of Li₂PdCl₄. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10600-005-0158-z

Chemistry of Natural Compounds, Vol. 41, No. 4, 2005
SYNTHESIS OF NEW (±) PTEROCARPANS
BY HECK OXYARYLATION
S. Sa e Sant’Anna, E. A. Evangelista,
R. B. Alves, and D. S. Raslan
UDC 547.972
Among a wide variety of synthetic routes to pterocarpan prototypes, a mild approach uses a reaction known
as Heck oxyarylation. This method involves a reaction between 2H-chromenes and 2-chloromercuriophenols
in the presence of Li2PdCl4.
Key words: pterocarpans, 2 -chromenes, Heck oxyarylation.
H
Pterocarpans, the second largest group of natural isoflavonoids possessing a 6a,11a-dihydro-6 -benzofuro[3,2-
H
c]chromene skeleton 1, have received considerable attention due to their wide range of biological activities [1]. Many of them
are phytoalexins and some exhibit activities such as antifungal, antimicrobial, antitumoral [2, 3], and anti-HIV [4]. Nakanishi
and co-workers demonstrated that the pterocarpans cabenegrin A-I and A-II are the active components of a Brazilian folk
medicine used against snake venoms [5], and recently Maurich and co-workers described the anti-clastogenic activity of
pterocarpans [6]. The specific activities of these compounds are strongly related to the different substitution patterns at rings
A and D.
5
O
4
4a
3
B
11a
A
6a
7a
1a
7
C
1
O
D
10a
9
10
1
Newtypes ofpterocarpan representativeshavebeen continuouslyisolatedfrom plants. Additionally, synthesis chemists
have an interest in obtaining new pterocarpan prototypes due to their important activities. Thus, our strategy was to synthesize
new pterocarpans involved coupling 2 -chromenes and
-chloromercuriophenols by a Heck oxyarylation reaction. To the
ortho
H
best of our knowledge, we have synthesized four new pterocarpans, 6 and 7a–c, according to the route shown below.
Phenol 2a was prepared by Baeyer-Villiger oxidation of commercial pyperonal with -chloroperbenzoic acid and
meta
subsequent hydrolysis of the formate obtained with NaOH 6 mol.L–1 [7]. Phenols 2b and 2c, which are commerciallyavailable,
were used to prepare their respective 2 -chromenes 3b and 3c by condensation reaction with 3,3-dimethylacrolein in the
H
presence ofphenylboronic acid, and acetic acid in drytoluene under an N2 atmosphere at 150°C for 5–24 hours [8]. As expected,
the Heck oxyarylation reaction between 2 -chromene 3a and 2-chloromercurio-4,5-methylenedioxyphenol (4) in the presence
H
of Li PdCl in dry acetone [9] for 24 hours afforded pterocarpan 6 (43% yield). The reaction of 2 -chromenes 3a–c with 2-
H
2
4
chloromercurio-4-formyl-6-methoxyphenol (5)inthesameconditionsofpterocarpan 6affordedpterocarpans7a–c in lower yield
(11%, 21%, and 20%, respectively). Thus, the synthesis of new (±) pterocarpans was achieved in two single steps. All reactions
were monitored by TLC and all pterocarpans provided satisfactory PMR, 13C NMR, IR, and mass spectra.
Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Av. Antonio Carlos,
6627, 31270-901, Belo Horizonte, MG, Brazil, fax: + (55) 3134995700, e-mail: eruziaevangelista@yahoo.com.br. Published
in Khimiya Prirodnykh Soedinenii, No. 4, pp. 311-312, July-August, 2005. Original article submitted December 21, 2004.
0009-3130/05/4104-0385 ©2005 Springer Science+Business Media, Inc.
385

HO
O
O
R
R
O
B
1
A
ClHg
4
2
C
O
D
O
R
1
OH
O
R
1
O
6
R , R = -OCH O- (43%)
1
2
2
R
2
R
2
2a, b, c
3a, b, c
R
O
B
1
a: R , R = -OCH O-
a: R , R = -OCH O- (86%)
1
2
2
1
2
2
A
b: R = H, R = OMe
b: R = H, R = OMe (25%)
1 2
c: R = OMe, R = H (96%)
1 2
1
2
R
2
CHO
OH
C
c: R = OMe, R = H
1
2
O
CHO
D
MeO
7a, b, c
ClHg
OMe
a: R = R = -OCH O- (11%)
1
2
2
b: R = H, R = OMe (21%)
1
2
5
c: R = OMe, R = H (20%)
1
2
EXPERIMENTAL
Laboratory solvents were purified and pre-dried before use. THF was first distilled from CaH2 and afterwards with Na
using benzophenone as an indicator. Toluene was also distilled from CaH2. Acetone was distilled from K2CO3. Written
procedureswereusedtoprepare2-chloromercurio-4,5-methylenedioxyphenol and2-chloromercurio-4-formyl-6-methoxyphenol
[10, 11]. TLC analyses were carried out on glass plates coated with TLC-grade silica gel. Melting points were determined with
a Mettler FP80HT Central Processor. IR spectra were recorded on a Galaxy 3000, Mattson Instruments. PMR spectra were
recorded on a BRUKER AVANCE DRX/400MHz and DPX/200MHz instrument using tetramethylsilane (TMS) as a standard
and CDCl3 as a solvent. 13C NMR spectra were obtained at 50 and 100 MHz. Mass spectra were recorded on a gas
chromatographer coupled to a mass spectrometer HP5989A.
General Synthesis Procedure of Pterocarpans 6 and 7a-c. To a mixture of PdCl2 (42.5 mg; 0.24 mmol) and LiCl
(20.4 mg; 0.48 mmol) in dry acetone (7.0 mL), 2H-chromene (0.24 mmoL) in acetone (5.0 mL) was added. This mixture was
stirred for 15 minutes and added to 2-chloromercuriophenol (0.24 mmol) in acetone (12 mL), and then the suspension obtained
was stirred for 24 hours at room temperature. After this, brine was added and the mixture was extracted with dichloromethane.
The organic layer was dried over Na2SO4, filtered, and concentrated. The product was purified bycolumn chromatographyand
crystallized from ethyl ether.
(±)-6a,11a-Dihydro-6,6-dimethyl-2,3,8,9-bis-methylenedioxy-6H-benzofuro[3,2c-][1]benzopyran(6). Whitesolid,
mp 172–176 ºC. IRspectrum (KBr, ν, cm–1): 2999, 2990, 1690, 1500, 1470,1450 1150, 1050. PMRspectrum (400MHz, CDCl3,
δ, ppm, J/Hz): 0.90 (3H, s, CH3), 1.49 (3H, s, CH3), 3.25 (1H, d, JH6a-H11a = 8.0, H-6a), 5.41 (1H, d, JH11a-H6a = 8.0, H-11a),
5.91 (2H, s, CH2), 5.93 (2H, s, CH2), 6.43 (1H, s, H-10), 6.44 (1H, s, H-4), 6.73 (1H, s, H-7), 6.92 (1H, s, H-1). 13C NMR
spectrum (100MHz, CDCl3, δ, ppm): 19.76 (CH3), 27.46 (CH3), 49.34 (C-6a), 79.52 (C-11a), 76.59 (C-6), 93.37 (C-10), 99.54
(C-4), 101.14 (CH2), 101.27 (CH2), 105.24 (C-7), 107.90 (C-1), 111.91 (C), 118.94 (C), 141.60 (C), 142.26 (C), 148.00 (C),
+
148.25 (C), 148.69 (C), 154.92 (C). Mass spectrum (EI, 70eV), m/z (Irel, %): 340 [M ] (12), 339 (44), 324 (100), 323 (23).
(±)-6a,11a-Dihydro-2,3-methylenedioxy-8-formyl-10-methoxy-6,6-dimethy-6H-benzofuro[3,2c-][1]benzopyran
(7a). Brown solid, mp 201–203°C. IR (KBr, ν, cm–1): 2977, 2935, 1251, 1045, 1692. PMRspectrum (400MHz, CDCl3, δ, ppm,
J/Hz): 0.91 (3H, s, CH3), 1.57 (3H, s, CH3), 3.50 (1H, d, JH6a-H11a= 7.60, H-6a), 3.96 (3H, s, H-13), 5.63 (1H, d,
JH11a-H6a = 7.60, H-11a), 5.93 (d, 1H, OCH2O, Jgem = 1.36) and 5.95 (d, 1H, OCH2O, Jgem = 1.36), 6.45 (1H, s, H-4), 7.05 (1H,
s, H-1), 7.40 (1H, s, H-9), 7.46 (1H, s, H-7), 9.86 (1H, s, CHO). 13C NMR spectrum (100MHz, CDCl3, δ, ppm): 20.01 (CH3)
and 27.52 (CH3), 49.11 (C-6a), 56.16 (C-13), 76.01 (C-6), 81.31 (C-11a), 99.58 (C-4), 101.29 (CH2), 108.28 (C-1), 110.73 (C-
1a), 112.63 (C-9), 121.28 (C-7), 130.01 (C-7a), 131.43 (C-8), 142.49 (C-2 or C-3), 145.20 (C-10), 148.36 (C-4a), 149.13 (C-3
or C-2), 154.36 (C-10a), 190.77 (CHO). m/z (Irel, %): 353 [M-1] (22), 337 (100), 337 (27), 308 (9).
386

(±)-6a,11a-Dihydro-8-formyl-2,10-dimethoxy-6,6-dimethyl-6H-benzofuro[3,2c-][1]benzopyran(7b). Whitesolid,
mp 131–132°C; IR spectrum (KBr, ν, cm–1): 3030, 2970, 2830, 1240, 1034, 1680. PMR spectrum (200MHz, CDCl3, δ, ppm,
J/Hz): 0.90 (3H, s, CH3), 1.59 (3H, s, CH3), 3.55 (1H, d, JH6a-H11a = 7.92, H-6a), 3.82 (3H, s, OCH3), 3.97 (3H, s, OCH3), 5.70
(1H, d, JH11a-H6a = 7.92, H-11a), 6.86-6.87 (2H, m, H-3 and H-4), 7.17 (1H, d, JH1-H3 = 2.36, H-1), 7.40 (1H, s, H-9), 7.48 (1H,
s, H-7), 9.87 (1H, s, CHO) 13C NMR spectrum (100MHz, CDCl3, δ, ppm): 20.10 (CH3), 27.61 (CH3), 49.46 (C-6a), 75.71
(C-6), 113.40 (C-1), 117.74 (C-1a), 119.00 (C-3), 119.31 (C-4), 121.36 (C-7), 130.10 (C-7a), 146.88 (C-4a), 154.26 (C-10a),
+
154.34 (C-2). Mass spectrum (EI, 70eV), m/z (Irel, %): 340 [M ] (6), 339 (25), 324 (100), 323 (19).
(±)-6a,11a-Dihydro-8-formly-3,10-dimethoxy-6,6-dimethyl-6H-benzofuro[3,2c-][1]benzopyran(7c).Whitesolid,
mp 125–127°C. IR (KBr, ν, cm–1): 3039, 2974, 2836, 1240, 1034, 1683. PMR spectrum (200MHz, CDCl3, δ, ppm, J/Hz): 0.90
(3H, s, CH3), 1.55 (3H, s, CH3), 7.53 (1H, d, JH1-H2 = 8.50, H-1), 6.63 (1H, dd, JH2-H1 =8.50, JH2-H4= 2.40 H-2), 6.47 (1H, d,
J
H4-H2 = 2.40, H-4), 3.52 (1H, d, JH6a-H11a = 7.60, H-6a), 7.48 (1H, s, H-7), 7.40 (1H, s, H-9), 5.69 (1H, d, JH11a-H6a = 7.60,
H-11a), 3.80 (3H, s, OCH3), 3.96 (3H, s, OCH3), 9.86 (1H, s, CHO). 13C NMR spectrum (100MHz, CDCl3, δ, ppm): 20.28
(CH3) and 27.52 (CH3), 49.08 (C-6a), 55.32 (C-12), 56.12 (C-13), 76.12 (C-6), 80.94 (C-11a), 102.29 (C-4), 108.87 (C-2),
111.07 (C-1a), 121.33 (C-7), 131.17 (C-1), 130.09 (C-7a), 154.25 (C-4a), 154.53 (C-10a), 161.41 (C-3), 190.47 (CHO). Mass
+
spectrum (EI, 70eV), m/z (Irel, %): 340 [M ] (6), 339 (19), 324 (100), 175 (3) 323 (18).
ACKNOWLEDGMENT
The authors thank the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) for financial support.
REFERENCES
1.
A. L. Tokes, G. Litkei, K, Gulacsi, S. Antus, E. Baitz-Gacs, C. Szantay, and L. L. Darko, Tetrahedron, 55, 9283,
(1999).
2.
3.
4.
5.
T. A Engler, K. O. LaTessa, R. Iyengar, W. Chai, and K. Agrios, Bioorg. Med. Chem., 4, No. 10, 1755, (1996).
T. G. van Aardt, H.Van Resburg, and D. Ferreira, Tetrahedron, 55, 11773 (1999).
T. A. Engler, K. O. Lynch, J. P. Reddy, and G. S. Gregory, Bioorg. Med. Chem., 3, No. 6, 1299 (1993).
A. J. M da Silva, A. L. Coelho, A. B. C. Simas, R. A. M. Moraes, D. A. Pinheiro, F. F. A. Z. Arruda,
P. R. R. Costa, and P. A. Melo, Bioorg. Med. Chem. Lett., 14, 431 (2004).
T. P. L. Maurich and G. Turchi, Mutat. Res., 561, 75 (2004).
F. Barrero, E. J. Alvarez-Manzaneda, and R. Chahboun, Tetrahedron, 54, 5635 (1998).
B. A. Chauder, C. C. Lopes, R. S. C. Lopes, A. J. M. da Silva, and V. Snieckus, Synthesis, 279 (1998).
R. A. Lichetenfels, A. L. Coelho, and P. R. R. Costa, J. Chem. Soc. Perk. Trans. 1, 949 (1995).
J. C. Breytenbach and G. J. H. Rall, J. Chem. Soc. Perk. I, 1804 (1980).
6.
7.
8.
9.
10.
11.
J. A. Pearl, J. Am. Chem. Soc., 70, 2008 (1948).
387