Total synthesis of anhydrolycorinone utilizing sequential intramolecular Diels-Alder reactions of a 1,3,4-oxadiazole

Article abstract of DOI:10.1021/jo020437k

A convergent total synthesis of anhydrolycorinone is detailed, enlisting sequential intramolecular Diels-Alder reactions of a suitably substituted 2-amino-1,3,4-oxadiazole defining a novel oxadiazole → furan → benzene Diels-Alder strategy.

Full text of DOI:10.1021/jo020437k

Tota l Syn th esis of An h yd r olycor in on e Utilizin g Sequ en tia l
In tr a m olecu la r Diels-Ald er Rea ction s of a 1,3,4-Oxa d ia zole
Scott E. Wolkenberg and Dale L. Boger*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La J olla, California 92037
boger@scripps.edu
Received J une 28, 2002
A convergent total synthesis of anhydrolycorinone is detailed, enlisting sequential intramolecular
Diels-Alder reactions of a suitably substituted 2-amino-1,3,4-oxadiazole defining a novel oxadiazole
f furan f benzene Diels-Alder strategy.
Anhydrolycorinone (1, Figure 1) is a member of the
pyrrolophenanthridine class of natural products isolated
from Amaryllidaceae plants.1 In addition to containing
the ring system characteristic of the larger class of
lycorine alkaloids, it has served as an advanced inter-
mediate in syntheses of the biologically active natural
products anhydrolycorinium chloride2 (2, cytotoxic agent)3
and hippadine1 (3, reversibly inhibits fertility in male
mice).4
We recently disclosed a synthetic approach toward this
class of alkaloids that utilized sequential intramolecular
inverse electron demand (LUMOdiene-controlled) Diels-
Alder reactions of an unsymmetrically substituted 1,2,4,5-
tetrazine.5 This approach, based on a tetrazine f diazine
f benzene Diels-Alder strategy,6 distinguished itself
from preceding efforts2,7-9 by assembling both the pyr-
rolidine and pyridone rings along with the D-ring via
tandem intramolecular cycloaddition reactions.9 Herein,
we describe an alternative sequential heterocyclic cy-
cloaddition approach to anhydrolycorinone (1) using a
suitably substituted 2-amino-1,3,4-oxadiazole.
Although a limited number of reports describe the
cycloaddition reactivity of electron-deficient 1,3,4-oxa-
diazoles, they typically employ symmetrical oxadiazoles
bearing strongly electron-withdrawing substituents (CF3,
SO2Et, CO2Me) in intermolecular reactions.10 Reactions
with olefinic dienophiles proceed through an initial [4 +
F IGURE 1.
2] cycloadduct that undergoes a loss of N2 to generate a
carbonyl ylide, which reacts further with the olefins in a
(7) N-Alkylation, Diels-Alder reaction: Hayakawa, K.; Yasukouchi,
T.; Kanematsu, K. Tetrahedron Lett. 1987, 28, 5895. Gonza´lez, C.; Pe´re,
D.; Guitia´n, E.; Castedo, L. J . Org. Chem. 1995, 60, 6318. Pe´rez, D.;
Bure´s, G.; Guitia´n, E.; Castedo, L. J . Org. Chem. 1996, 61, 1650. Metal-
catalyzed [2 + 2 + 2] cycloaddition: Grotjahn, D. B.; Vollhardt, K. P.
C. Synthesis 1993, 579. N-Alkylation, electrophilic aromatic substitu-
tion: Benington, F.; Morin, R. D. J . Org. Chem. 1962, 27, 142. Olson,
D. R.; Wheeler, W. J .; Wells, J . N. J . Med. Chem. 1974, 17, 167.
Bunnell, A. E.; Flippin, L. A.; Liu, Y. J . Org. Chem. 1997, 62, 9305.
N-Alkylation, metal-catalyzed ring closure: Carruthers, W.; Evans,
N. J . Chem. Soc., Perkin Trans. 1 1974, 1523. Onaka, T.; Kanda, Y.;
Natsume, M. Tetrahedron Lett. 1974, 15, 1179. Black, D. St. C.; Keller,
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A.; Sridharan, V. Tetrahedron Lett. 1991, 32, 3859. Black, D. St. C.;
Keller, P. A.; Kumar, N. Tetrahedron 1993, 49, 151. Sakamoto, T.;
Yasuhara, A.; Kondo, Y.; Yamanaka, H. Heterocycles 1993, 36, 2597.
Harrowven, D. C.; Lai, D.; Lucas, M. C. Synthesis 1999, 1300. Miki,
Y.; Shirokoshi, H.; Matsushita, K. Tetrahedron Lett. 1999, 40, 4347.
N-Alkylation, radical ring closure: Hara, H.; Hoshino, O.; Umezawa,
B. Tetrahedron Lett. 1972, 13, 5031. Iida, H.; Yuasa, Y.; Kibayashi, C.
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Fischer, W. Tetrahedron Lett. 1991, 32, 65. Xiong, Y.; Moore, H. W. J .
Org. Chem. 1996, 61, 9168. Tsuge, O.; Hatta, T.; Tsuchiyama, H. Chem.
Lett. 1998, 155. Biaryl formation, N-alkylation: Prabhakar, S.; Lobo,
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10.1021/jo020437k CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/24/2002
J . Org. Chem. 2002, 67, 7361-7364
7361

Wolkenberg and Boger
SCHEME 1
F IGURE 2.
systems are well-documented,9,14 and this reactivity
defines a novel oxadiazole f furan f benzene strategy
(Scheme 1). Herein, we describe the application of this
strategy to the total synthesis of anhydrolycorinone.
The starting 2-amino-1,3,4-oxadiazole 6 was prepared
from 4-amino-1-butene15 in three steps as indicated in
Scheme 2. Treatment of the hydrochloride salt of 4-amino-
1-butene with carbonyl diimidazole and Et3N afforded 4
in 91% yield, which was converted to the oxadiazole
precursor 5 by treatment with methyl oxalylhydrazide16
in THF-HOAc (64%). Cyclization of 5 to form the
corresponding oxadiazole was mediated by TsCl and Et3N
and proceeded in superb yield (86%). Coupling of 6
with the known carboxylic acid 75 was effected by EDCI
(1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydro-
chloride), DMAP, and NaHCO3 to provide the Diels-
Alder reaction substrate 8.
Sequential cycloaddition reactions were observed upon
warming 8 first at 165 °C for 30 min and then at 230 °C
for 18 h. The mild conditions required for the first Diels-
Alder reaction indicate a favorable electronic pairing of
the dienophile and oxadiazole diene in agreement with
the expectation that the initial [4 + 2] cycloaddition is
LUMOdiene-controlled (inverse electron demand). The
observed product 9 is consistent with an initial cycload-
1,3-dipolar cycloaddition (Figure 2, left). In recent efforts,
we have extended the scope of this reaction beyond that
which provides symmetrical 2:1 cycloadducts by imple-
menting the reaction cascade in an intramolecular fash-
ion.11 In the cases examined, olefinic dienophiles tethered
toa 2-amino-1,3,4-oxadiazole react toform fused oxabicyclo-
[2.2.1]heptane products with complete control of the
regio- and diastereoselectivity.
In these studies, it was observed that tethered alkynyl
dienophiles generate high yields of the furan products
resulting from a single cycloaddition reaction (Figure 2,
right).11 Additionally, some tethered olefin dienophiles
bearing a leaving group were shown to serve as alkyne
equivalents providing the analogous furan cycloaddition
reaction products presumably arising from the interme-
diate carbonyl ylide via elimination of the dienophile
substituent. This furan-forming cycloaddition reactivity
is complementary to the well-established oxazole to furan
Diels-Alder transformation12 and represents a novel
alternative strategy for construction of substituted furans
in which the retro-Diels-Alder reversion entails the more
facile loss of N2 (NtN) versus a nitrile (RCtN).13 The
furan products, themselves reactive toward intramolecu-
lar cycloadditions, offer the potential to further extend
the scope of this oxadiazole reactivity to include the
synthesis of fused carbocyclic aromatic products. The
intramolecular [4 + 2] cycloaddition reactions of furans
with tethered alkenes or alkynes to generate benzene
(12) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology
in Organic Synthesis; Academic: San Diego, 1987; pp 301-310. For
examples, see: Grigg, R.; J ackson, J . L. J . Chem. Soc. C 1970, 552.
Ansell, M. F.; Caton, M. P. L.; North, P. C. Tetrahedron Lett. 1981,
22, 1727. J acobi, P. A.; Walker, D. G.; Odeh, I. M. A. J . Org. Chem.
1981, 46, 5. Liotta, D.; Saindane, M.; Ott, W. Tetrahedron Lett. 1983,
24, 2473. J acobi, P. A.; Craig, T. A.; Walker, D. G.; Arrick, B. A.;
Frechette, R. F. J . Am. Chem. Soc. 1984, 106, 5585. Selnick, H. G.;
Brookes, L. M. Tetrahedron Lett. 1989, 30, 6607. J acobi, P. A.; Blum,
C. A.; DeSimone, R. W.; Udodong, U. E. S. J . Am. Chem. Soc. 1991,
113, 5384. Yadav, J . S.; Valluri, M.; Rao, A. V. R. Tetrahedron Lett.
1994, 35, 3609. Rao, A. V. R.; Yadav, J . S.; Valluri, M. Tetrahedron
Lett. 1994, 35, 3613.
(13) Aside from oxazoles, few cycloaddition approaches to substituted
furans have been described: Gotthardt, H.; Huisgen, R.; Bayer, H. O.
J . Am. Chem. Soc. 1970, 92, 4340. Wilson, W. S.; Warrener, R. N. J .
Chem. Soc., Chem. Commun. 1972, 211. Ho, M. S.; Wong, H. N. C. J .
Chem. Soc., Chem. Commun. 1989, 1238.
(14) Heaney, H.; Ahn, J . S. In Comprehensive Heterocylic Chemistry,
2nd ed.; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Elsevier: New York, 1996; Vol. 2, pp 328-335. For examples, see:
Parker, K. A.; Adamchuk, M. R. Tetrahedron Lett. 1978, 18, 1689.
Sternbach, D. D.; Rossana, D. M. J . Am. Chem. Soc. 1982, 104, 5853.
Van Royen, L. A.; Mijngheer, R.; De Clercq, P. J . Tetrahedron Lett.
1983, 24, 3145. Sternbach, D. D.; Rossana, D. M.; Onan, K. D. J . Org.
Chem. 1984, 49, 3427. Trost, B. M.; Lautens, M.; Hung, M.-H.;
Carmichael, C. S. J . Am. Chem. Soc. 1984, 106, 7641. J ung, M. E.;
Street, L. J . J . Am. Chem. Soc. 1984, 106, 8327.
(9) A similar sequential cycloaddition strategy has been described
employing a substituted oxazole: Padwa, A.; Brodney, M. A.; Liu, B.;
Satake, K.; Wu, T. J . Org. Chem. 1999, 64, 3595.
(10) Vasil´ıev, N. V.; Lyashenko, Y. E.; Kolomiets, A. F.; Sokolskii,
G. A. Khim. Geterotsikl. Soedin. 1987, 562. Vasil´ıev, N. V.; Lyashenko,
Y. E.; Galakhov, M. V.; Kolomiets, A. F.; Gontar, A. F.; Sokolskii, G.
A. Khim. Geterotsikl. Soedin. 1990, 95. Vasil´ıev, N. V.; Lyashenko, Y.
E.; Patalakha, A. E.; Sokolskii, G. A. J . Fluorine Chem. 1993, 65, 227.
Thalhammer, F.; Wallfahrer, U.; Sauer, J . Tetrahedron Lett. 1988, 29,
3231. Seitz, G.; Gerninghaus, C. H. Pharmazie 1994, 49, 102. Seitz,
G.; Wassmuth, H. Chem.-Ztg. 1988, 112, 80. Review: Warrener, R. N.
Eur. J . Org. Chem. 2000, 3363. Warrener, R. N.; Margetic, D.; Foley,
P. J .; Butler, D. N.; Winling, A.; Beales, K. A.; Russell, R. A.
Tetrahedron 2001, 57, 571. Warrener, R. N.; Wang, S.; Maksimovic,
L.; Tepperman, P. M.; Butler, D. N. Tetrahedron Lett. 1995, 36, 6141.
Warrener, R. N.; Elsey, G. M.; Russell, R. A.; Tiekink, E. R. T.
Tetrahedron Lett. 1995, 36, 5275. Warrener, R. N.; Maksimovic, L.;
Butler, D. N. J . Chem. Soc., Chem. Commun. 1994, 1831. Warrener,
R. N.; Butler, D. N.; Liao, W. Y.; Pitt, I. G.; Russell, R. A. Tetrahedron
Lett. 1991, 32, 1889. Warrener, R. N.; Groundwater, P.; Pitt, I. G.;
Butler, D. N.; Russell, R. A. Tetrahedron Lett. 1991, 32, 1885.
Warrener, R. N.; Margetic, D.; Tiekink, E. R. T.; Russell, R. A. Synlett
1997, 196.
(15) Gagne´, M. R.; Stern, C. L.; Marks, T. J . J . Am. Chem. Soc. 1992,
114, 275.
(16) Szmuszkovicz, J .; Greig, M. E. J . Med. Pharm. Chem. 1961, 4,
259.
(11) Wilkie, G. D.; Elliott, G. I.; Blagg, B. S. J .; Wolkenberg, S. E.;
Soenen, D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J . Am. Chem.
Soc. 2002, 124, 11292.
7362 J . Org. Chem., Vol. 67, No. 21, 2002

Total Synthesis of Anhydrolycorinone
mmol) and Et3N (0.325 mL, 2.92 mmol) in 7.5 mL of CH2Cl2
dropwise over 30 min. After being stirred for an additional 3
h, the reaction mixture was concentrated under reduced
pressure and subjected to flash chromatography (SiO2, 2.5 ×
12 cm, 5% CH3OH/CHCl3) to provide 4 (436 mg, 91%) as a
colorless oil: 1H NMR (CDCl3, 400 MHz) δ 8.17 (s, 1H), 7.90
(br s, 1H), 7.47 (s, 1H), 6.96 (s, 1H), 5.79-5.69 (m, 1H), 5.09-
5.03 (m, 1H), 3.42 (dt, J ) 5.8, 7.0 Hz, 2H), 2.33 (dt, J ) 6.7,
7.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 149.1, 135.9, 134.7,
129.5, 117.5, 116.6, 40.1, 33.6; IR (film) νmax 3448, 1729, 1528,
1477 cm-1; MALDIFTMS (DHB) m/z 166.0975 (C8H11N3O +
H+ requires 166.0975).
SCHEME 2
1-Meth oxa lyl-4-(bu t-3-en -1-yla m id e)sem ica r ba zid e (5).
A solution of 4 (138 mg, 0.84 mmol) in 2 mL of anhydrous THF
was treated with methyl oxalyl hydrazide16 (98 mg, 0.84 mmol)
and acetic acid (0.21 mL, 3.4 mmol) and allowed to stir at 30
°C under N2 for 18 h. The reaction mixture was cooled to room
temperature, concentrated under reduced pressure, and sub-
jected to flash chromatography (SiO2, 2 × 10 cm, 2.5%
CH3OH/25% acetone/CH2Cl2) to provide 5 (116 mg, 64%) as a
1
white solid: mp 107-109 °C; H NMR (DMSO-d6, 500 MHz)
δ 10.45 (s, 1H), 7.99 (s, 1H), 6.50 (br s, 1H), 5.81-5.73 (m,
1H), 5.07-4.99 (m, 2H), 3.79 (s, 3H), 3.05 (dt, J ) 6.3, 7.0 Hz,
2H), 2.13 (dt, J ) 7.0, 7.0 Hz, 2H); 13C NMR (DMSO-d6, 125
MHz) δ 161.1, 158.1, 157.6, 137.0, 117.1, 53.7, 39.6, 35.0; IR
(film) νmax 3374, 1728, 1708, 1528 cm-1; FABHRMS (NBA/NaI)
m/z 216.0986 (C8H13N3O4 + H+ requires 216.0984).
Meth yl 5-(Bu t-3-en -1-yl)a m in o-1,3,4-oxa d ia zole-2-ca r -
boxyla te (6). A solution of 5 (100 mg, 0.4 mmol) in 5 mL of
anhydrous CH2Cl2 was treated with TsCl (76 mg, 0.4 mmol)
and Et3N (0.14 mL, 2.5 mmol) and stirred at 25 °C under N2.
After 18 h, the reaction mixture was diluted with 10 mL of
H2O and extracted with CH2Cl2 (3 × 10 mL). The combined
extracts were dried (Na2SO4), concentrated under reduced
pressure, and subjected to flash chromatography (SiO2, 3 ×
10 cm, 5% CH3OH/CH2Cl2) to provide 6 (80 mg, 86%) as a
white solid: mp 92-93 °C (EtOAc-hexanes); 1H NMR (CDCl3,
400 MHz) δ 5.75 (m, 2H), 5.12 (m, 2H), 3.98 (s, 3H), 3.51 (dt,
J ) 6.2, 6.5 Hz, 2H), 2.40 (dt, J ) 6.7, 6.7 Hz, 2H); 13C NMR
(CDCl3, 100 MHz) δ 164.3, 154.8, 150.8, 134.0, 118.4, 53.3,
42.4, 33.5; IR (film) νmax 3422, 1743, 1620, 1155 cm-1; FAB-
HRMS (NBA/NaI) m/z 198.0881 (C8H11N3O3 + H+ requires
198.0879).
Met h yl 5-[(Bu t -3-en -1-yl)(6-(2-m et h oxyvin yl)b en zo-
[1,3]d ioxole-5-ca r b on yl)a m in o)]-1,3,4-oxa d ia zole-2-ca r -
boxyla te (8). A solution of 6 (6.0 mg, 0.030 mmol) and 6-(2-
methoxyvinyl)benzo[1,3]dioxole-5-carboxylic acid5 (7, 14 mg,
0.060 mmol) in 0.3 mL of DMF was treated with NaHCO3 (7.5
mg, 0.090 mmol), EDCI (12 mg, 0.060 mmol), and DMAP (11
mg, 0.090 mmol) and stirred under Ar at 25 °C for 18 h. The
reaction mixture was diluted with EtOAc (5 mL) and washed
with H2O (3 × 5 mL). The organic extract was dried (Na2SO4)
and concentrated under reduced pressure before being sub-
jected to flash chromatography (SiO2, 1 × 5 cm, 25% EtOAc/
hexanes) to provide 8 (8.5 mg, 72%) as a colorless oil: 1H NMR
(acetone-d6, 500 MHz) δ 6.90 (d, J ) 12.9 Hz, 1H), 6.88 (s,
1H), 6.82 (s, 1H), 6.02 (s, 2H), 5.88-5.80 (m, 1H), 5.83 (d, J )
12.9 Hz, 1H), 5.13-5.10 (m, 1H), 5.06-5.03 (m, 1H), 4.13 (dd,
J ) 7.0, 7.4 Hz, 2H), 3.92 (s, 3H), 3.62 (s, 3H), 2.55 (dt, J )
7.0, 7.4 Hz, 2H); 13C NMR (acetone-d6, 125 MHz) δ 168.8,
162.2, 154.6, 154.5, 150.9, 150.3, 146.3, 135.0, 130.3, 126.2,
117.3, 108.0, 105.3, 102.2, 101.8, 56.5, 53.2, 47.5, 32.8; IR (film)
νmax 2963, 1748, 1564, 1258 cm-1; MALDIFTMS (DHB) m/z
402.1299 (C19H19N3O7 + H+ requires 402.1301).
dition reaction followed by loss of N2 to generate a
carbonyl ylide that eliminates methanol to furnish the
furan. Consistent with expectations based on earlier
work, especially that of Padwa with the more reactive
2-aminofurans,8,9,14 9 serves as a competent substrate for
a further cycloaddition reaction at elevated temperatures.
The excellent conversion of 9 to 10 (77%) under the
conditions employed compares favorably with other in-
tramolecular Diels-Alder reactions of the reactive 2-ami-
nofurans that form indolines.9 The only observed product
was 10 resulting from the initial [4 + 2] cycloaddition
reaction followed by ring-opening of the resulting oxa-
bicyclo[2.2.1]heptane cycloadduct and elimination of H2O.
The two sequential Diels-Alder reactions could be
conducted in a single step by warming 8 at 230 °C (TIPB,
24 h) to provide 10 in better conversions (72%). As
anticipated, the conversion of 8 to 9 was complete within
1 h and 9 more slowly converts to 10 under these
conditions. Ester saponification of 10 and decarboxyla-
tion8 provided anhydrolycorinone (1) identical in all
respects (1H and 13C NMR, IR, mp) with properties
reported for authentic material1 and a sample of our own
earlier synthetic material.5
A convergent total synthesis of anhydrolycorinone (1),
which provides access to hippadine (3) and anhydroly-
corinium chloride (2), was developed by enlisting a novel
oxadiazole f furan f benzene strategy featuring two
sequential intramolecular [4 + 2] cycloaddition reactions
of a substituted 2-amino-1,3,4-oxadiazole. Further studies
of the scope of such reactions and their applications are
in progress and will be reported in due course.
Meth yl 4-(Bu t-3-en -1-yl)-5-oxo-4,5-d ih yd r o-3,7,9-tr ioxa -
4-a za d icyclop en ta [a ,g]n a p h th a len e-2-ca r boxyla te (9). A
solution of 8 (7.1 mg, 0.018 mmol) in 1.5 mL of anhydrous,
degassed 1,2-dichlorobenzene was warmed under Ar at 165-
170 °C for 30 min. The reaction mixture was cooled and loaded
directly onto SiO2 (1 × 6 cm) equilibrated in hexanes. 1,2-
Dichlorobenzene was eluted with hexanes, and the column was
then eluted with 25% EtOAc/hexanes to provide 9 (4.8 mg,
Exp er im en ta l Section
N-Ca r bon ylim id a zole Bu t-3-en -1-yla m id e (4). A suspen-
sion of carbonyldiimidazole (950 mg, 5.84 mmol) in 23 mL of
anhydrous THF was cooled to 0 °C under N2 and treated with
a solution of 4-amino-1-butene hydrochloride15 (250 mg, 2.92
J . Org. Chem, Vol. 67, No. 21, 2002 7363

Wolkenberg and Boger
78%) as a white solid: mp 182-184 °C (EtOAc-hexanes); 1H
NMR (acetone-d6, 500 MHz) δ 7.96 (s, 1H), 7.65 (s, 1H), 7.48
(s, 1H), 6.20 (s, 2H), 5.93-5.85 (m, 1H), 5.04-5.00 (m, 1H),
4.98-4.95 (m, 1H), 4.35 (dd, J ) 7.0, 7.3 Hz, 2H), 3.89 (s, 3H),
2.60 (dt, J ) 7.0, 7.0 Hz, 2H); 13C NMR (acetone-d6, 125 MHz)
δ 160.1, 158.8, 153.2, 150.8, 147.8, 147.6, 139.4, 135.1, 128.8,
118.9, 117.1, 115.3, 106.9, 102.8, 101.6, 51.6, 41.8, 32.7; IR
(film) νmax 2913, 1712, 1649, 1563, 1469 cm-1; MALDIFTMS
(DHB) m/z 342.0966 (C18H15NO6 + H+ requires 342.0978).
Meth yl 4,5-Dih yd r o[1,3]d ioxolo[4,5-j]p yr r olo[3,2,1-d e]-
p h en a n th r id in -7-on e-2-ca r boxyla te (10). From 9: A solu-
tion of 9 (4.8 mg, 0.014 mmol) in 2 mL of anhydrous, degassed
1,3,5-triisopropylbenzene was warmed under Ar at 230 °C for
18 h. The reaction mixture was cooled and loaded directly onto
SiO2 (1 × 6 cm) equilibrated in hexanes. 1,3,5-Triisopropyl-
benzene was eluted with hexanes, and the column was then
eluted with 50% EtOAc/hexanes to provide 10 (3.5 mg, 77%)
min. The solvent was removed under reduced pressure and
the residue suspended in 0.5 mL of cold 10% aqueous HCl.
After being stirred at 0 °C for 15 min, the suspension was
filtered, and the filtrate was concentrated under reduced
pressure and dried under vacuum. The residue was then
dissolved in 1 mL of freshly distilled quinoline, treated with 8
mg of Cu bronze, and warmed at 225 °C under N2 for 2.5 h.
The reaction mixture was cooled, filtered through Celite
(CH2Cl2 wash), washed with 10% aqueous HCl (3 × 5 mL),
dried (Na2SO4), and concentrated under reduced pressure
before being subjected to flash chromatography (SiO2, 0.4 × 4
cm, 10% ethyl ether/CH2Cl2) to provide 1 (1.5 mg, 61%) as a
1
white solid: mp 231-232 °C (lit.1 mp 228-230 °C); H NMR
(CDCl3, 500 MHz) δ 7.93 (s, 1H), 7.75 (d, J ) 8.1 Hz, 1H),
7.56 (s, 1H), 7.29 (d, J ) 7.3 Hz, 1H), 7.19 (t, J ) 7.7 Hz, 1H),
6.12 (s, 2H), 4.48 (t, J ) 8.1 Hz, 2H), 3.43 (t, J ) 8.5 Hz, 2H);
13C NMR (CDCl3, 125 MHz) δ 160.0, 152.3, 148.9, 139.9, 131.3,
131.1, 124.3, 123.7, 123.6, 119.9, 117.2, 107.3, 102.5, 101.3,
1
as a white solid: mp 277-278 °C (lit.8 mp 280-281 °C); H
NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 7.95 (d, J ) 1.2 Hz,
1H), 7.89 (s, 1H), 7.62 (s, 1H), 6.14 (s, 2H), 4.51 (dd, J ) 8.2,
8.5 Hz, 2H), 3.96 (s, 3H), 3.45 (dd, J ) 8.2, 8.2 Hz, 2H); 13C
NMR (CDCl3, 100 MHz) δ 167.1, 159.8, 152.4, 149.0, 142.9,
131.2, 130.4, 125.5, 124.9, 122.9, 122.8, 116.2, 107.0, 102.4,
101.3, 52.4, 47.1, 27.2; IR (film) νmax 2916, 1704, 1645, 1606,
1241 cm-1; MALDIFTMS (DHB) m/z 324.0871 (C18H13NO5 +
H+ requires 324.0866).
From 8: A solution of 8 (8.5 mg, 0.021 mmol) in 1 mL of
anhydrous, degassed 1,3,5-triisopropylbenzene was warmed
under Ar at 230 °C for 24 h. The reaction mixture was cooled
and loaded directly onto SiO2 (1 × 5 cm) equilibrated in
hexanes. 1,3,5-Triisopropylbenzene was eluted with hexanes,
and the column was then eluted with 50% EtOAc/hexanes to
provide 10 (4.9 mg, 72%) as a white solid.
47.0, 27.9; IR (film) νmax 2923, 1608, 1557, 1254 cm-1
;
MALDIFTMS (DHB) m/z 266.0821 (C16H11NO3 + H+ requires
266.0812).
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the National Institutes of Health
(CA42056) and the Skaggs Institute for Chemical Biol-
ogy. S.E.W. is the recipient of an ACS Organic Division
predoctoral fellowship (Procter and Gamble, 2001-2002)
and an ARCS foundation fellowship and is a Skaggs
Fellow.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of 4-6, 8-10, and 1 are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
An h yd r olycor in -7-on e (1). According to the method of
Padwa et al.,8 a solution of 10 (3.0 mg, 0.009 mmol) in 0.5 mL
of a 10% methanolic KOH solution was heated at 80 °C for 15
J O020437K
7364 J . Org. Chem., Vol. 67, No. 21, 2002