Synthesis of pterocarpans by means of a "Disfavored" 5-endo-trig radical cyclization reaction

Article abstract of DOI:10.1002/1099-0690(200109)2001:18<3461::aid-ejoc3461>3.0.co;2-9

A successful synthesis of pterocarpans 1, based on a "disfavored" 5-endo-trig radical cyclization reaction, has been accomplished. The radical precursor 4-(2′-bromoaryloxy)-2H-chromene 8 was synthesized in six steps, starting from aryl propynyl ether 2. O

Full text of DOI:10.1002/1099-0690(200109)2001:18<3461::aid-ejoc3461>3.0.co;2-9

FULL PAPER
Synthesis of Pterocarpans by Means of a ‘‘Disfavored’’ 5-endo-trig Radical
Cyclization Reaction
Kalpathy Chidambareswaran Santhosh,[a] Ariamala Gopalsamy,[a] and
Kalputtu Kuppuswamy Balasubramanian*[a]
Dedicated to Professor Jean F. Normant on the occasion of his 65th birthday
Keywords: Cyclizations / Heterocycles / Natural products / Radical reactions / Reaction mechanisms
A successful synthesis of pterocarpans 1, based on a ‘‘disfav- was performed to prove the occurrence of 5-endo-trig radical
ored’’ 5-endo-trig radical cyclization reaction, has been ac-
cyclization. This methodology was extended further to syn-
complished. The radical precursor 4-(2Ј-bromoaryloxy)-2H- thesize a class of hitherto unknown pterocarpans 13. A novel
chromene 8 was synthesized in six steps, starting from aryl
propynyl ether 2. On treatment with tributyltin hydride in
and stereoselective route towards the synthesis of aryl ethers
of bromohydrins by means of the Mitsunobu reaction is also
refluxing benzene, aryl enol ether 8 underwent radical cyc- described.
lization to furnish the pterocarpan 1. A deuterium label study
Introduction
has not so far been attempted. As part of a general study
of the synthesis of condensed oxygen heterocycles, we un-
dertook the synthesis of pterocarpans and related systems
by means of radical cyclization reactions. This method[5]
produces the furan CϪC bond of pterocarpan in the key
step, which involves an intramolecular radical arylation,
making use of the stereospecific and regiospecific nature of
the radical cyclization reaction. This route permits a more
general and effective synthesis of pterocarpans.
The chemistry of free radicals has witnessed stupendous
growth in recent years. Free radical reactions are extensively
used for carbonϪcarbon bond formation in organic syn-
thesis.[1] The tin hydride method[2] has established itself as
the most important and versatile method for conducting
radical reactions, and has proven to be potentially useful
for the construction of carbo-, hetero-, and macrocycles.
Pterocarpans are an important class of naturally occurring
isoflavanoids,[3] many of which act as phytoalexins. 6a,11a-
Dihydro-6H-benzo[4,5]furo[3,2-c]chromene 1c is represent-
ative of a wide range of pterocarpan phytoalexins produced
by ‘‘leguminosae’’ plants when challenged by fungal infec-
tions. Pterocarpan analogues cabenegrins A-1 and A-2,
which are potent anti-snake venom antidotes, have been
isolated and synthesized by Nakanishi.[3e] Pterocarpans are
also known to exhibit anti-tumor properties.[3f] Owing to
their interesting biological activities, pterocarpans have at-
tracted considerable attention and a few synthetic routes
have been developed.[4] The earlier methods for the syn-
thesis of pterocapans commonly employed reduction and
cyclization of the corresponding 2-hydroxyisoflavan-
ones.[4bϪ4d] Other approaches to the synthesis of ptero-
carpans are Heck arylation,[4eϪ4h] 1,3-MichaelϪClaisen an-
nulation reaction,[4i] and Lewis acid catalyzed cycloaddition
of 1,4-benzoquinones to chromenes.[4jϪ4l] Recently, an aldol
condensation of phenyl acetates with benzaldehydes to af-
ford pterocarpans has been reported.[4m,4n] The synthesis of
pterocarpans by radical cyclization approaches, however,
Results and Discussion
From the retrosynthetic perspective, 1 can be discon-
nected at the CϪC bond ‘‘a’’ (Figure 1), giving the radical
precursor 8. The syntheses of variously substituted enol
ethers 8aϪc involved the use of aryl propynyl ethers 2aϪc
as starting materials.[6] Thermal rearrangement[7] of 2a was
carried out in polyethylene glycol 200 (PEG 200), affording
the 2H-chromene 3a. The olefin 3a was converted[8] into
bromohydrin 4a in 80% yield, by use of N-bromosuccinim-
ide in wet dimethyl sulfoxide. On treatment with powdered
potassium hydroxide,[9] this trans-bromohydrin afforded
3,4-epoxychroman 5a in 85% yield. Treatment of 5a with 1-
bromo-2-naphthol furnished the alcohol 6a in 94% yield.[10]
[a]
Department of Chemistry, Indian Institute of Technology
Chennai 600036, India
Fax: (internat.) ϩ 91-44/235-0509
Supporting information for this article is available on the
WWW under http://www.eurjoc.com or from the author.
Figure 1. Structure of 1
Eur. J. Org. Chem. 2001, 3461Ϫ3466
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3461

K. C. Santhosh, A. Gopalsamy, K. K. Balasubramanian
FULL PAPER
Conversion of alcohol 6a into the tosylate, followed by Mechanistic Investigation
elimination using potassium tert-butoxide in DMSO,
In radical reactions, the determining factors for regiose-
yielded the enol ether 8a. This synthetic sequence, depicted
in Scheme 1, was found to be general when extended to the
other substrates, 8b and 8c.
lectivity and stereoselectivity are the steric and stereoelec-
tronic effects.[1] The rules for ring-closure, though originally
formulated for ionic cyclizations, were found to be ex-
tendable to radical reactions.[2a] Thus, according to Bald-
win’s rule,[11] 5-endo-trig is a disfavored process. It may be
noted that only a few examples of 5-endo-trig cyclization
processes are known.[12] The facile radical ring closure in
this study prompted us to probe the mechanistic aspects
more deeply.
Under the radical reaction conditions detailed in
Scheme 1, substrate 8 might yield compound 1 either
through a disallowed 5-endo-trig cyclization, or through an
allowed 4-exo-trig cyclization followed by an aryl group mi-
gration. The 4-exo-trig cyclization can easily be ruled out,
as the CϪC bond breakage is not as facile as that of CϪO,
since the latter would generate a more conjugated and
stable primary radical. In order to establish the occurrence
of 5-endo-trig radical cyclization unambiguously, a deuter-
ium label study was carried out. Thus, when the cyclization
of 8a was performed using tributyltin deuteride, a smooth
reaction was observed, resulting in the isolation of a white
1
solid 1d in 90% yield (Scheme 2). The H NMR spectrum
showed the absence of any signal at δ ϭ 5.6 due to the
benzylic proton 4-H. The deuterium label study thus pro-
vided clear evidence of the 5-endo-trig radical cyclization.
Scheme 2
Encouraged by the success of this unusual cyclization
procedure, we extended this methodology to the synthesis
of a new class of pterocarpans by a slightly modified route.
To this end, the required key substrate 12 was synthesized
in five steps. The intermediate aryl 1,1-dimethyl-2-propynyl
Scheme 1
When refluxed in benzene with tributyltin hydride in the ethers and 2,2-dimethyl-2H-chromenes were prepared by
presence of AIBN, substrate 8a afforded the cyclized prod- literature procedures.[13] Chromene 9a was converted into
uct 1a as a white solid (m.p. 205 °C) in 88% yield. The the corresponding trans-bromohydrins 10a in 85% yield by
presence of long range coupling (Jbd ϭ 1.5 Hz), together Dalton’s method.[8] Conversion of the bromohydrin 10a to
1
with the vicinal coupling (Jba ϭ 11.5 Hz), in the H NMR the trans-aryl ether 11a was achieved in a stereoselective
spectrum of 1a suggests a half-chair conformation for the manner by means of a Mitsunobu reaction with 1-bromo-
pyran ring in the molecule. The cis ring junction favored by 2-naphthol in the presence of triphenylphosphane and
thermodynamic considerations is evident from Jcd
7.5 Hz.
ϭ
DEAD.[14] It is worth mentioning here that the synthesis of
aryl ethers of bromohydrins under basic or acidic condi-
When extended to the other enol ethers 8b and 8c, the tions is very difficult.[15] The observed coupling constant
cyclization furnished cyclized products 1b and 1c in good between 3-H and 4-H (J ϭ 5.38 Hz) clearly indicated that
yields. The spectral characteristics and melting point of the the relative stereochemistry at C-3 and C-4 was trans.
pterocarpan 1c were found to be identical with those re-
Treatment of 11a with potassium tert-butoxide in dry
ported in the literature.[4a] The crude product was in all DMSO at room temperature resulted in a clean conversion
1
cases found to be homogenous, and H NMR revealed the into the enol ether 12a, in 81% yield. The enol ether was
absence of the simple reduced product.
found to be extremely unstable and underwent hydrolysis
3462
Eur. J. Org. Chem. 2001, 3461Ϫ3466

Synthesis of Pterocarpans by Means of a “Disfavored” 5-end-trig Radical Cyclization Reaction
FULL PAPER
otherwise specified). Ϫ Low-resolution electron impact mass spec-
tra were taken at an ionization potential of 70 eV. Ϫ IR spectra
were recorded as solutions or neat with a PerkinϪElmer 1310 spec-
trometer. Ϫ The elemental analyses were obtained from RSIC, IIT,
Madras. Ϫ Compounds 2aϪc, 3aϪc, 4aϪc, 5aϪc, and 9aϪc were
prepared according to literature procedures.[8,13,16]
to form 2,2-dimethylchroman-4-one upon chromatographic
purification over silica gel. When 12a was refluxed with tri-
butyltin hydride and AIBN in benzene for 20 h, a colorless
solid (m.p. 118Ϫ119 °C) was obtained. The spectroscopic
data clearly indicated that the obtained compound was the
corresponding pterocarpan 13a (Scheme 3). The other enol
ethers 12bϪd underwent similar cyclization to afford the
hitherto unknown pterocarpans 13bϪd in good yields.
General Procedure for the Synthesis of Chromenols 6: Bromophenol
or 1-bromo-2-naphthol (1.1 mmol) was added at room temperature
to a solution of epoxide 5 (1 mmol) in ether (10 mL). The reaction
mixture was stirred for 1 h. Removal of the solvent, followed by
purification by column chromatography on silica gel (ethyl acetate/
hexane ϭ 1:9), afforded 6.
(3R*,4R*)-4-[(1-Bromo-2-naphthyl)oxy]-6-chloro-3,4-dihydro-
2H-3-chromenol (6a): Yield 94%. Ϫ M.p. 117Ϫ118 ° C. Ϫ IR
(CHCl3): ν ϭ 3500, 3020Ϫ2850, 1480, 1250Ϫ1180, 1010 cmϪ1. Ϫ
˜
1H NMR (CDCl3): δ ϭ 2.3 (br. s, 1 H, 3-H), 4.1Ϫ4.5 (m, 3 H, 2-
H), 5.0 (m, 1 H, 4-H), 6.5Ϫ7.5 (m, 8 H, Ar-H), 7.9 (d, J ϭ 0.8 Hz,
1 H, Ar-H). Ϫ MS: m/z (%) ϭ 404 (24) [Mϩ]. Ϫ C19H14BrClO3
(403.98): calcd. C 56.25; H 3.48; found C 56.37; H 3.62.
(3R*,4R*)-4-[(1-Bromo-2-naphthyl)oxy]-6-methoxy-3,4-dihydro-
2H-3-chromenol (6b): Yield 96%. Ϫ M.p. 142 °C. Ϫ IR (CHCl3):
1
ν ϭ 3500, 3000Ϫ2800, 1480, 1250Ϫ1180, 1010 cmϪ1. Ϫ H NMR
˜
(CDCl3): δ ϭ 2.32 (br. s, 1 H, 3-H) 3.6 (s, 3 H, OCH3), 4.1Ϫ4.5
(m, 2 H, 2-H), 5.0 (m, 1 H, 4-H), 6.4Ϫ7.5 (m, 8 H, Ar-H), 7.9
(d, J ϭ 0.8 Hz, 1 H Ar-H). Ϫ MS: m/z (%) ϭ 400 (56) [Mϩ]. Ϫ
C20H17BrClO4 (400.03): calcd. C 59.87, H 4.27; found C 59.98,
H 4.42.
(3R*,4R*)-4-(2-Bromophenoxy)-3,4-dihydro-2H-3-chromenol
(6c): Yield 82%. Ϫ IR (neat): ν˜ ϭ 3500Ϫ3200, 3050Ϫ2820, 1580,
1
1480, 1200 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ2.8 (br. s, 1 H, 3-H),
4.2Ϫ4.6 (m, 3 H, 2-H), 5.3 (m, 1 H, 4-H), 6.4Ϫ7.4 (m, 8 H, Ar-
H). Ϫ MS: m/z (%) ϭ 320 (62) [Mϩ].
General Procedure for the Synthesis of Tosylates 7: Alcohol 6
(1 mmol) in ether (10 mL) was added at room temperature to a
suspension of sodium hydride (1.2 mmol) in ether (5 mL). The mix-
ture was stirred for 1 h. The reaction mixture was cooled to Ϫ22
°C, p-toluenesulfonyl chloride (1.1 mmol) was added in one por-
tion, and stirring was continued for 1 h. Inorganic salts were fil-
tered off and the filtrate was washed with water (10 ϫ 2 mL) and
dried (MgSO4). Removal of the solvent afforded the tosylate 7,
which was further purified by recrystallization, (hexane/benzene,
8:2).
Scheme 3
Conclusion
This report describes a novel and general method, based
on radical cyclization, for the synthesis of pterocarpans.
The deuterium label study provided unambiguous evidence
for the occurrence of 5-endo-trig radical cyclization. Stereo-
selective syntheses of variously substituted aryl ethers of
bromohydrins were achieved by use of the Mitsunobu reac-
tion. This investigation also resulted in the synthesis of 6,6-
dimethylpterocarpans.
(3R*,4R*)-4-[(1-Bromo-2-naphthyl)oxy]-6-chloro-3,4-dihydro-
2H-3-chromen-3-yl Tosylate (7a): Yield 91%. Ϫ M.p. 165Ϫ166 °C.
˜
Ϫ IR (CHCl3): ν ϭ 3010Ϫ2900, 1590, 1480, 1200Ϫ1180, 1000, 850
cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 2.01 (s, 3 H, Ar-CH3),
3.95Ϫ40.1(m, 1 H, 3-H), 4.5 (t, J ϭ10 Hz, 2-Ha), 4.6 (m, 1 H, 2-
Hb), 5.1 (d, J ϭ 3.0 Hz, 1 H, 4-H), 6.4Ϫ7.5 (m, 12 H, Ar-H), 7.9
(d, J ϭ 0.8 Hz, 1 H, Ar-H). Ϫ MS: m/z (%) ϭ 558 (12) [Mϩ]. Ϫ
C26H20BrClO5S (557.99): calcd. C, 55.78, H 3.60; found C 55.62,
H 3.90.
(3R*,4R*)-4-[(1-Bromo-2-naphthyl)oxy]-6-methoxy-3,4-dihydro-
Experimental Section
2H-3-chromen-3-yl Tosylate (7b): Yield 88%. Ϫ M.p. 132 °C. Ϫ IR
Ϫ1
˜
(CHCl3): ν ϭ 3010Ϫ2800, 1585, 1480, 1200Ϫ1180, 1000, 850 cm
.
General Remarks: Reported melting points were determined with a
Toshniwal melting point apparatus, and are uncorrected. Ϫ 1H and
13C NMR spectra were recorded with a Jeol GS ϫ 400 spectro-
meter at 400 MHz and 100.5 MHz, respectively. Spectra were re-
Ϫ 1H NMR (CDCl3): δ ϭ 2.0 (s, 3 H, Ar-CH3), 3.75 (s, 3 H, OCH3)
4.10Ϫ4.25 (m, 1 H, 3-H), 4.80 (t, J ϭ10 Hz, 1 H, 2-Ha), 5.10 (m,
1 H, 2-Hb) 5.60 (d, J ϭ 3.0 Hz, 1 H, 4-H), 6.80Ϫ8.01 (m, 12 H,
Ar-H), 8.1 (d, J ϭ 0.8 Hz, 1 H, Ar-H). Ϫ MS: m/z (%) ϭ 554 (10)
corded at ambient temperature, with CDCl3 as solvent. Chemical [Mϩ]. Ϫ C27H23BrClO6S (554.04): calcd. C, 58.38, H 4.17; found
shifts are reported in ppm relative to tetramethylsilane (unless
C 58.22, H 4.32.
Eur. J. Org. Chem. 2001, 3461Ϫ3466
3463

K. C. Santhosh, A. Gopalsamy, K. K. Balasubramanian
FULL PAPER
(3R*,4R*)-4-(2-Bromophenoxy)-3,4-dihydro-2H-3-chromen-3-yl (6aS*,13aS*)-2-Methoxy-6a,13a-dihydro-6H-5,13-dioxadibenzo-
[a,g]fluorene (Pterocarpan 1b): Yield 90%. Ϫ M.p. 201 °C. Ϫ IR
˜
Tosylate(7c): Yield 80%, oil. Ϫ IR (neat): ν ϭ 3050, 2800, 1600,
1480, 1210, 1175, 1000, 850 cmϪ1. Ϫ 1H NMR (CDCl3) δ ϭ 2.2 (CHCl3): ν ϭ 3020Ϫ2850, 1600, 1450, 1210Ϫ1180, 1000 cmϪ1. Ϫ
(s, 3 H, Ar-CH3), 3.9Ϫ4.05 (m, 1 H, 3-H), 4.7 (t, J ϭ10 Hz, 2 H,
1H NMR (CDCl3): δ ϭ 3.6 (t, J ϭ 11.5 Hz, 1 H, 6a-H), 3.85 (s, 3
˜
2-H), 5.4 (d, J ϭ 3 Hz, 1 H, 4-H), 6.8Ϫ7.9 (m, 12 H, Ar-H). Ϫ H, OCH3), 4.0Ϫ4.1 (m, 1 H, 6-Ha), 4.55Ϫ4.65 (ddd, J ϭ 11.5, 6,
MS: m/z (%) ϭ 474 (22) [Mϩ].
1.5 Hz, 1 H, 6-Hb), 5.7 (br. d, J ϭ 7.5 Hz, 1 H, 11a-H), 6.9Ϫ7.9
(m, 9 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 39.6 (C-6a),
56.7(OCH3), 77.9 (C-6), 78.0 (C-13a), 112.4, 118.6, 119.0, 121.5,
122.7, 123.4 126.7, 127.4, 129.1, 129.8, 130.2, 130.7, 154.2, 157.2.
Ϫ MS: m/z (%) ϭ 304 (100) [Mϩ]. Ϫ C20H16O3 (304.11): calcd. C
78.94, H 5.26. found C 78.80; H 5.28.
General Procedure for the Synthesis of Chromenes 8 and 10: The
tosylate 7 (1 mmol) in DMSO (3 mL) was added dropwise at room
temperature, over a period of 10 min, to a suspension of potassium
tert-butoxide (2 mmol) in DMSO (10 mL). The resulting mixture
was stirred for 1 h. The reaction mixture was quenched with water
and extracted with ether (3 ϫ 20 mL). The combined ether extracts (6aS*,11aS*)-6a,11a-Dihydro-6H-benzo[4,5]furo[3,2-c]chromene
were washed with water (2 ϫ 20 mL) and brine (2 ϫ 20 mL), and
(Pterocarpan 1c): Yield 82%. Ϫ M.p. 125Ϫ126 °C (ref.[4a] m.p.
dried (Na2SO4). The organic layer was concentrated under reduced 125Ϫ126 °C). Ϫ IR (CHCl3): ν ϭ 3000Ϫ2900, 1600, 1450,
˜
1
pressure. The crude product was further purified by column chro-
matography on neutral alumina, using hexane as eluent. A similar
procedure was adopted to yield 12 from 11.
1240Ϫ1180 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 3.6Ϫ3.8 (m, 1 H, 6a-
H), 4.25Ϫ4.37 (m, 2 H, 6-H), 4.55(d, J ϭ 6 Hz, 1 H, 11a-H),
6.87Ϫ7.57 (m, 8 H, Ar-H). Ϫ MS: m/z (%) ϭ 224 (100) [Mϩ]. Ϫ
HRMS (C15H12O2): calcd. 224.0837, found 224.0822.
4-(1-Bromonaphthalen-2-yloxy)-6-chloro-2H-chromene (8a): Yield
78%. Ϫ M.p. 132Ϫ133 °C. Ϫ IR (CHCl3): 3010Ϫ2900, 1580, 1420, (6aS*,13aS*)-2-Chloro-6a-hydro-13a-deuterio-6H-5,13-dioxadi-
1210Ϫ1190, 1000, 850 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 4.6 (t, J ϭ benzo[a,g]fluorene (Pterocarpan 1d): Yield 90%. Ϫ M.p. 205 °C. Ϫ
1
4.0 Hz, 1 H, 3-H), 4.9 (d, J ϭ 4.0 Hz, 2 H, 2-H), 6.75Ϫ7.0 (m, 8 IR (CHCl3): ν ϭ 3010Ϫ2800, 1600, 1450, 1210Ϫ1180 cmϪ1. Ϫ H
˜
H, Ar-H), 8.2 (d, J ϭ 0.8 Hz, 1 H, Ar-H). Ϫ MS: m/z (%) ϭ 386 NMR (CDCl3): δ ϭ 3.5 (t, J ϭ 11.5 Hz, 1 H, 6a-H), 4.0Ϫ4.1 (m,
(100) [Mϩ].
1 H, 6-Ha), 4.6 (dd, J ϭ 11.5, 6 Hz, 1 H, 6-Hb), 6.9Ϫ7.9 (m, 9 H,
Ar-H). Ϫ HRMS (C19H12ClDO2): calcd. 309.0657; found 309.0660.
Ϫ C19H12ClDO2 (309.06): calcd. C 73.67, H 4.55; found C 73.32,
H 4.38.
4-(1-Bromonaphthalen-2-yloxy)-6-methoxy-2H-chromene (8b): Yield
76%. Ϫ M.p. 136 °C. Ϫ IR (CHCl3): ν˜ ϭ 3010Ϫ2900, 1580, 1420,
1200Ϫ1190, 1000, 850 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ 3.8 (s, 3
H, OCH3), 4.65 (t, J ϭ 4.0 Hz, 1 H, 3-H), 4.8 (d, J ϭ 4.0 Hz, 2 H, (3S*,4R*)-3-Bromo-2,2-dimethyl-3,4-dihydro-2H-chromen-4-ol
2-H), 6.75Ϫ6.85 (m, 2 H, Ar-H), 7.2Ϫ7.9 (m, 6 H, Ar-H), 8.3 (d,
(10a): Yield 85%. Ϫ M.p. 105 °C (ref.[16] 106 °C). Ϫ IR (CHCl3):
Ϫ1
1
J ϭ 0.8 Hz, 1 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 55.9 (OCH3),
ν ϭ 3600, 2870Ϫ3000, 1480, 1420, 1252, 1180 cm Ϫ H NMR
˜
65.5 (C-2), 98.0 (C-3), 107.5, 114.1, 116.0 116.5, 120.3, 121.0, 125.9, (CDCl3): δ ϭ 1.40 (s, 3 H, CH3), 1.60 (s, 3 H, CH3) 2.6 (br. s, 1 H,
126.9, 127.8, 128.2, 129.1, 131.9, 133.2, 149.1, 149.4, 149.8, 154.3.
exchangeable with D2O, OH) 4.2 (d, J ϭ 9.28 Hz, 1 H, 4-H) 4.92
(d, J ϭ 9.28 Hz, 1 H, 4-H), 6.8Ϫ7.6 (m, 4 H, Ar-H). Ϫ 13C NMR
(CDCl3): δ ϭ 19.8 (CH3), 28.8 (CH3), 63.0 (C-3), 70.3 (C-2), 78.8
(C-4), 116.9, 121.1, 122.3, 127.5, 129.7, 151.9. Ϫ MS: m/z (%) ϭ
256 (28) [Mϩ].
Ϫ MS: m/z (%) ϭ 382 (100) [Mϩ].
4-(2-Bromophenoxy)-2H-chromene (8c): Yield 72%, viscous liquid.
1
Ϫ IR (neat): ν˜ ϭ 3050Ϫ2850, 1575 1400, 1220Ϫ1190 cmϪ1. Ϫ H
NMR (CDCl3): δ ϭ 4.7 (t, J ϭ 4.0 Hz, 1 H, 3-H), 4.9 (d, J ϭ
4.0 Hz, 2 H, 2-H), 6.6Ϫ7.7 (m, 8 H, Ar-H). Ϫ MS: m/z (%) ϭ 302 (3S*,4R*)-3-Bromo-2,2,6-trimethyl-3,4-dihydro-2H-chromen-4-ol
(100) [Mϩ].
(10b): Yield 85%. Ϫ M.p. 123 °C. Ϫ IR (CHCl3): ν ϭ 3580,
2870Ϫ3000, 1480, 1260, 1180, 1060 cmϪ1. Ϫ 1H NMR (CDCl3):
δ ϭ1.39 (s, 3 H, CH3), 1.59 (s, 3 H, CH3) 2.29 (s, 3 H, Ar-CH3)
2.40 (br. s, 1 H exchangeable with D2O, OH) 3.91Ϫ4.11 (d, J ϭ
˜
General Procedure for the Synthesis of Pterocarpans 1 and 13: Tribu-
tyltin hydride (1.1 mmol) and a catalytic amount of AIBN (ca.
20 mg) were added to a solution of enol ether 8 (1 mmol) in ben-
zene (50 mL) and the solution was refluxed for 4 h (20 h for com-
pound 13). The solvent was removed under reduced pressure and
the residue was then dissolved in ether (20 mL). Saturated KF solu-
9.9 Hz,
1 H, 3-H) 4.69Ϫ4.9 (d, J ϭ 9.9 Hz, 1 H, 4-H),
6.81Ϫ7.31(m, 3 H, Ar-H). Ϫ MS: m/z (%) ϭ 270 (24) [Mϩ].
(3S*,4R*)-3-Bromo-6-methoxy-2,2-dimethyl-3,4-dihydro-2H-
˜
tion (10 mL) was added and the mixture was stirred for 3 h. The chromen-4-ol (10c): Yield 82%. Ϫ M.p. 75 °C. Ϫ IR (CHCl3): ν ϭ
ether layer was separated and washed with water (3 ϫ 20 mL), aq.
NaHCO3 (2 ϫ 20 mL), and brine (2 ϫ 20 mL). Concentration and
chromatography on silica gel, using hexane as eluent, gave the cy-
clized products. A similar procedure was applied to obtain 13 from
compound 12.
3580, 2870Ϫ3000, 1480, 1260, 1175, 1050 cmϪ1. Ϫ 1H NMR
(CDCl3): δ ϭ 1.37 (s, 3 H, CH3), 1.57 (s, 3 H, CH3) 2.53 (br. s, 1
H exchangeable with D2O, OH) 3.76 (s, 3 H, OCH3), 3.95Ϫ4.13
(d, J ϭ 9.8 Hz, 1 H, 3-H) 4.72Ϫ4.87 (d, J ϭ 9.8 Hz, 1 H, 4-H),
6.68Ϫ7.28 (m, 3 H, Ar-H). Ϫ MS: m/z (%) ϭ 286 (20) [Mϩ].
(6aS*,13aS*)-2-Chloro-6a,13a-dihydro-6H-5,13-dioxadibenzo- General Procedure for the Mitsunobu Coupling Reactions: Triphen-
[a,g]fluorene (Pterocarpan 1a): Yield 88%. Ϫ M.p. 205 °C. Ϫ IR
ylphosphane (1.1 mmol), bromohydrin 12 (1 mmol), bromophenol
(CHCl3): ν ϭ 3010Ϫ2800, 1600, 1450, 1210Ϫ1180 cmϪ1. Ϫ 1H (1.2 mmol), and dry benzene (10 mL) were placed in a dry, three-
NMR (CDCl3): δ ϭ 3.6 (t, J ϭ 11.5 Hz, 1 H, 3-H), 4.0Ϫ4.1(m, 1 necked flask purged with argon. DEAD (1.2 mmol) was injected
˜
H, 2-Ha), 4.62 (ddd, J ϭ 11.5, 6, 1.5 Hz, 1 H, 2-Hb), 5.65 (br. d,
J ϭ 7.5 Hz, 1 H, 4-H), 6.9Ϫ7.9 (m, 9 H, Ar-H). Ϫ 13C NMR
dropwise through a septum over a period of 10 min. The reaction
was strongly exothermic and the color of the DEAD slowly disap-
(CDCl3): δ ϭ 39.9 (C-6a), 75.9 (C-6), 76.2 (C-13a), 112.4, 114.2, peared. The reaction mixture was stirred for 8 h. The precipitated
117.5, 118.4, 118.9, 120.3, 122.2, 123.2, 127.3, 129.1, 129.7, 130.1, diethyl hydrazodicarboxylate was filtered and the organic layer was
130.9, 149.7, 154.5, 157.3. HRMS (C19H13ClO2): calcd. washed with 5% sodium hydroxide solution (2 ϫ 20 mL) and then
308.0604; found 308.0596. Ϫ C19H13ClO2 (308.06): calcd. C 73.91, with water (3 ϫ 20 mL). After drying with anhydrous sodium sulf-
Ϫ
H 4.24; found C 73.54, H 4.16.
ate, the solvent was removed under vacuum and the residue was
3464
Eur. J. Org. Chem. 2001, 3461Ϫ3466

Synthesis of Pterocarpans by Means of a “Disfavored” 5-end-trig Radical Cyclization Reaction
FULL PAPER
purified by flash chromatography on silica gel, using hexane as
eluent, to afford the aryl ethers of bromohydrins 11.
4-(1-Bromonaphthalen-2-yloxy)-6-methoxy-2,2-dimethyl-2H-
chromene (12c): Yield 80%. Ϫ M.p. 103Ϫ104 °C. Ϫ IR (CHCl3):
˜
ν ϭ 2962, 1612, 1603, 1459, 1385, 1308, 1227, 1152, 1120, 1030
1
cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.42 (s, 6 H, CH3), 3.82 (s, 3 H,
(3S*,4R*)-3-Bromo-4-(1-bromonaphthalen-2-yloxy)-2,2-dimethyl-
chromane (11a): Yield 84%. Ϫ M.p. 143Ϫ144 °C. Ϫ IR (CHCl3):
ν˜ ϭ 2976, 1621, 1592, 1486, 1458, 1340, 1226, 1118, 1040 cmϪ1 Ϫ
1H NMR (CDCl3): δ ϭ 1.47 (s, 3 H, CH3), 1.59 (s, 3 H, CH3) 4.44
(d, J ϭ 5.37 Hz, 1 H, 3-H) 5.7 (d, J ϭ 5.37 Hz, 1 H, 4-H),
6.82Ϫ8.18 (m, 10 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 24.9 (CH3),
26.4 (CH3), 56.7 (C-3), 77.3 (C-2), 78.3 (C-4), 110.7, 115.8, 117.6,
119.0, 121.3, 124.9, 126.6, 127.9, 128.1, 129.1, 129.4, 130.3, 130.4,
133.4, 152.5, 152.5. Ϫ HRMS (C21H18Br2O2): calcd. 459.9673;
found 459.9696.
OCH3), 4.64 (s, 1 H, 3-H) 6.87Ϫ8.40 (m, 9 H, Ar-H). Ϫ 13C NMR
(CDCl3): δ ϭ 28.3 (CH3), 55.8 (OCH3), 77.3 (C-2), 107.0 (C-3),
107.7, 113.8, 115.9, 117.1, 118.8, 120.9, 125.9, 126.8, 127.8, 128.2,
129.1, 131.7, 133.1, 147.7, 147.7, 149.9, 153.8.
(C21H17BrO2): calcd. 410.0575; found 410.0563.
Ϫ HRMS
4-(2-Bromo-4-methylphenoxy)-2,2,6-trimethyl-2H-chromene (12d):
Yield 85%. Ϫ M.p. 88Ϫ89 °C. Ϫ IR (CHCl3): ν˜ ϭ 2960, 1612,
1603, 1458, 1459, 1411, 1353, 1267, 1164, 1065 cmϪ1. Ϫ H NMR
1
(CDCl3): δ ϭ 1.39 (s, 6 H, CH3) 2.28 (s, 3 H, Ar-CH3), 2.33 (s, 3
H, Ar-CH3), 4.48 (s, 1 H, 3-H), 6.64Ϫ7.40 (m, 6 H, Ar-H). Ϫ 13C
NMR (CDCl3): δ ϭ 20.5 (CH3), 20.73 (Ar-CH3), 28.5 (Ar-CH3),
77.4 (C-2), 106.4 (C-3), 115.1, 116.1, 116.2, 117.9, 122.4, 126.8,
129.3, 129.8, 130.6, 130.8, 134.0, 135.7, 147.9, 151.8. Ϫ HRMS
(C19H19BrO2): calcd. 358.0568; found 358.0594.
(3S*,4R*)-3-Bromo-4-(1-bromonaphthalen-2-yloxy)-2,2,6-trimethyl-
chromane (11b): Yield 82%. Ϫ M.p. 130Ϫ131 °C. Ϫ IR (CHCl3):
ν˜ ϭ 2976, 1622, 1590, 1491, 1452, 1340 cmϪ1 Ϫ 1H NMR (CDCl3):
δ ϭ 1.53 (s, 3 H, CH3), 1.66 (s, 3 H, CH3) 2.24 (s, 3 H, Ar-CH3),
4.50 (d, J ϭ 5.37 Hz, 1 H 3-H) 5.76 (d, J ϭ 5.37 Hz, 1 H, 4-H),
6.81Ϫ8.27 (m, 9 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 20.6 (CH3),
24.9 (CH3), 26.3 (Ar-CH3), 56.9 (C-3), 77.1(C-2), 78.4 (C-4), 110.7,
115.7, 117.4, 118.6, 124.9, 126.6, 127.9, 128.1, 129.2, 129.5, 130.3,
130.6, 131.3, 133.4, 150.3, 152.6. Ϫ HRMS (C22H20Br2O2): calcd.
473.9830; found 473.9862.
(6aR*,13aS*)-6,6-Dimethyl-6a,13a-dihydro-6H-5,13-dioxadibenzo-
[a,g]fluorene (Pterocarpan 13a): Yield 82%. Ϫ M.p. 118Ϫ119 °C. Ϫ
IR (CHCl3): ν˜ ϭ 2990, 1622, 1582, 1490, 1462, 1360, 1264, 1036,
1
950 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 0.93 (s, 3 H, CH3), 1.68 (s, 3
H, CH3), 3.86 (d, J ϭ 7.32 Hz, 1 H, 6a-H), 5.65 (d, J ϭ 7.32 Hz,
1 H, 13a-H), 6.96Ϫ7.85 (m, 10 H, Ar-H). Ϫ 13C NMR (CDCl3):
δ ϭ 20.0 (CH3), 30.6 (CH3), 48.4 (C-6a), 76.5 (C-6), 80.0 (C-13a),
112.3, 118.0, 119.5, 120.3, 121.3, 122.9, 123.9, 126.7, 129.1, 129.8,
130.0, 130.1, 130.3, 130.9, 153.3, 158.6. Ϫ HRMS (C21H18O2):
calcd. 302.1306; found 302.1316.
(3S*,4R*)-3-Bromo-4-(1-bromonaphthalen-2-yloxy)-6-methoxy-
2,2-dimethylchromane (11c): Yield 84%. Ϫ M.p. 135Ϫ136 °C. Ϫ IR
(CHCl3): ν˜ ϭ 2976, 1619, 1596, 1491, 1459, 1350, 1264, 1155, 1132,
1040 cmϪ1 Ϫ 1H NMR (CDCl3): δ ϭ 1.50 (s, 3 H, CH3), 1.68 (s,
·
3 H, CH3) 3.67 (s, 3 H, OCH3), 4.50 (d, J ϭ 5.37 Hz, 1 H, 3-H)
5.78 (s, J ϭ 5.37 Hz, 1 H, 4-H), 6.82Ϫ8.28 (m, 9 H, Ar-H). Ϫ 13C
NMR (CDCl3): δ ϭ 24.9 (CH3), 26.2 (CH3), 55.7 (OCH3), 56.8 (C-
3), 77.1 (C-2), 78.6 (C-4), 110.8, 112.9, 115.83, 117.4, 118.4, 119.3,
125.0, 126.6, 127.9, 128.1, 129.2, 130.3, 133.4, 146.4, 152.5, 153.9.
Ϫ HRMS (C22H20Br2O3): calcd. 489.9779; found 489.9778.
(6aR*,13aS*)-2,6,6-Trimethyl-6a,13a-dihydro-6H-5,13-dioxadi-
benzo[a,g]fluorene (Pterocarpan 13b): Yield 85%. Ϫ M.p. 123 °C. Ϫ
IR (CHCl3): ν˜ ϭ 2991, 1628, 1554, 1484, 1462, 1372, 1254, 1120,
1
950 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 0.80 (s, 3 H, CH3) 1.58 (s, 3
H, CH3), 2.3 (s, 3 H, Ar-CH3), 3.8 (d, J ϭ 7.44 Hz, 1 H, 6a-H)
5.55 (d, J ϭ 7.44 Hz, 1 H, 13a-H), 6.8Ϫ7.82 (m, 9 H, Ar-H). Ϫ
13C NMR (CDCl3): δ ϭ 20.0 (CH3), 20.6 (CH3), 30.6 (Ar-CH3),
48.5 (C-6a), 77.4 (C-6), 80.1 (C-13a), 112.2, 117.7, 119.1, 120.40,
122.9, 123.9, 126.7, 129.0, 129.8, 130.1, 130.3, 130.6, 130.9, 131.0,
(3S*,4R*)-3-Bromo-4-(2-bromo-4-methylphenoxy)-2,2,6-trimethyl-
˜
chromane (11d): Yield 82%. Ϫ M.p. 105 °C. Ϫ IR (CHCl3): ν ϭ
2960, 1596, 1488, 1411, 1273, 1129, 1049 cmϪ1. Ϫ 1H NMR
(CDCl3): δ ϭ 1.44 (s, 3 H, CH3), 1.54 (s, 3 H, CH3) 2.19 (s, 3 H,
Ar-CH3) 2.24 (s, 3 H, Ar-CH3), 4.32 (d, J ϭ 4.89 Hz, 1 H, 3-H)
5.48 (s, J ϭ 4.89 Hz, 1 H, 4-H), 6.70Ϫ7.36 (m, 6 H, Ar-H). Ϫ 13C
NMR (CDCl3): δ ϭ 20.5 (CH3), 20.9 (CH3), 26.0 (Ar-CH3), 26.1
(Ar-CH3), 56.6 (C-3), 77.9 (C-4), 113.1, 114.8, 117.6, 118.6, 129.3,
151.0, 158.5.
316.1482.
Ϫ HRMS (C22H20O2): calcd. 316.1463; found
(6aR*,13aS*)-2-Methoxy-6,6-dimethyl-6a,13a-dihydro-6H-5,13-di-
oxadibenzo[a,g]fluorene (Pterocarpan 13c): Yield 82%. Ϫ M.p.
130.1, 130.8, 131.5, 133.0, 134.7, 150.6, 152.7.
(C19H20Br2O2): calcd. 437.9830; found 437.9848.
Ϫ HRMS
˜
159Ϫ160 °C. Ϫ IR (CHCl3): ν ϭ 2992, 1625, 1580, 1491, 1459,
1366, 1264, 1161, 1129, 1056, 950 cmϪ1. Ϫ 1H NMR (CDCl3): δ ϭ
0.90 (s, 3 H, CH3) 1.65 (s, 3 H, CH3), 3.82 (d, J ϭ 7.32 Hz, 1 H,
6a-H), 3.83 (s, 3 H, OCH3), 5.60 (d, J ϭ 7.32 Hz, 1 H, 13a-H),
6.89Ϫ7.84 (m, 9 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 19.8 (CH3),
30.6 (CH3), 48.5 (C-6a), 55.8 (OCH3), 76.7 (C-6), 80.2 (C-13a),
112.2, 113.2, 117.3, 118.8, 119.8, 120.3, 122.9, 123.9, 126.7, 129.0,
129.8, 130.3, 130.9, 147.1, 154.0, 158.4. Ϫ HRMS (C22H20O3):
calcd. 332.1412; found 332.1432.
4-(1-Bromonaphthalen-2-yloxy)-2,2-dimethyl-2H-chromene (12a):
˜
Yield 81%. Ϫ M.p. 100Ϫ101 °C. Ϫ IR CHCl3): ν ϭ 2972, 1622,
1604, 1596, 1492, 1440, 1352, 1292, 1170, 1139, 1072 cmϪ1. Ϫ H
1
NMR (CDCl3): δ ϭ 1.42 (s, 6 H, CH3) 4.57 (s, 1 H, 3-H),
6.85Ϫ8.30 (m, 9 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 28.4 (CH3),
78.8 (C-2), 106.8 (C-3), 113.4, 116.0, 117.9, 118.0, 120.3, 120.5,
121.9, 125.0, 125.5, 126.5, 127.5, 127.9, 128.7, 129.9, 147.3, 149.7,
153.6. Ϫ HRMS (C22H19BrO3): calcd. 380.0412; found 380.0423.
(6aR*,11aS*)-2,6,6,8-Tetramethyl-6a,11a-dihydro-6H-benzo[4,5]-
furo[3,2-c]chromene (Pterocarpan 13d): Yield 84%. Ϫ M.p. 106 °C.
˜
4-(1-Bromonaphthalen-2-yloxy)-2,2,6-trimethyl-2H-chromene Ϫ IR (CHCl3): ν ϭ 2992, 1616, 1588, 1490, 1459, 1260, 1129, 1035
1
(12b): Yield 78%. Ϫ M.p. 106Ϫ107 °C. Ϫ IR (CHCl3): ν˜ ϭ 2960, cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 0.87 (s, 3 H, CH3) 1.56 (s, 3 H,
1
1625, 1598, 1491, 1442, 1356, 1292, 1168, 1139, 1072 cmϪ1. Ϫ H
CH3), 2.31 (s, 3 H, Ar-CH3), 2.33 (s, 3 H, Ar-CH3), 3.37 (d, J ϭ
7.55 Hz, 1 H, 6a-H) 5.46 (d, J ϭ 7.55 Hz, 1 H, 13a-H), 6.74Ϫ7.36
NMR (CDCl3): δ ϭ 1.39 (s, 6 H, CH3) 2.30 (s, 3 H, Ar-CH3), 4.52
(s, 1 H, 3-H), 6.75Ϫ8.31 (m, 9 H, Ar-H). Ϫ 13C NMR (CDCl3): (m, 6 H, Ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 20.0 (CH3), 20.6 (CH3),
δ ϭ 20.8 (CH3), 28.5 (Ar-CH3), 77.4 (C-2), 106.9 (C-3), 113.9,
20.9 (Ar-CH3), 27.6 (Ar-CH3), 49.6 (C-6a), 76.1 (C-6), 78.4 (C-
116.2, 118.0, 121.0, 122.4, 125.9, 126.8, 127.8, 128.2, 129.1, 130.0, 13a), 109.4, 117.7, 119.9, 125.9, 128.3, 129.4, 130.0, 130.1, 130.6,
130.7, 131.7, 133.1, 147.9, 150.0, 151.7. Ϫ HRMS (C21H17BrO2): 130.7, 150.8, 158.0. Ϫ HRMS (C19H20O2): calcd. 280.1463; found
calcd. 394.0568; found 394.0588.
280.1488.
Eur. J. Org. Chem. 2001, 3461Ϫ3466
3465

K. C. Santhosh, A. Gopalsamy, K. K. Balasubramanian
FULL PAPER
Engler, J. P. Reddy, K. D. Combrink, D. V. Velde, J. Org. Chem.
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