IMDAF Cycloaddition as a Method for the Preparation of Pyrrolophenanthridine Alkaloids

Article abstract of DOI:10.1021/jo980008f

Acylation of 5-amino-2-furancarboxylic acid methyl ester with alkenoyl acid chlorides gives 2-amidofurans that undergo intramolecular Diels-Alder cycloadditions. The reactions occur at 165°C in toluene or at 100°C when 4 M ethereal LiClO₄ was u

Full text of DOI:10.1021/jo980008f

3986
J . Org. Chem. 1998, 63, 3986-3997
IMDAF Cycloa d d ition a s a Meth od for th e P r ep a r a tion of
P yr r olop h en a n th r id in e Alk a loid s
Albert Padwa,* Martin Dimitroff, Alex G. Waterson, and Tianhua Wu
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received J anuary 5, 1998
Acylation of 5-amino-2-furancarboxylic acid methyl ester with alkenoyl acid chlorides gives
2-amidofurans that undergo intramolecular Diels-Alder cycloadditions. The reactions occur at
165 °C in toluene or at 100 °C when 4 M ethereal LiClO4 was used as the solvent. The resultant
dihydroindoles are formed by the nitrogen lone pair assisted ring opening of the initial oxa-bridged
cycloadducts, followed by loss of water. Under certain conditions, alternative cationic cyclization
routes become important pathways. Several members of the pyrrolophenanthridine class of
alkaloids were obtained by a short, efficient method based on the intramolecular Diels-Alder furan
cycloaddition of 2-amidofurans containing a tethered alkenyl group. The resulting dihydroindoles
were elaborated in one step to the 1H-pyrrolo[3,2,1-de]phenanthridine ring system by a free radical
induced cyclization using bis(tributyltin).
The importance and versatility of the Diels-Alder
many cases, however, the Diels-Alder strategy is not
feasible because of the low reactivity of furan toward
monoactivated dienophiles.
reaction for the construction of unsaturated six-mem-
bered ring systems is well documented in the literature.1
An area which is gaining prominence in Diels-Alder
chemistry involves the use of heteroaromatic compounds
as either the diene or dienophile component.2-4 By far
the most extensively studied five-membered heteroaro-
matic system for Diels-Alder cycloaddition is furan and
its substituted derivatives.5-7 The resultant 7-oxabicyclo-
[2.2.1]heptanes are valuable synthetic intermediates
which have been further elaborated to substituted arenes,
carbohydrate derivatives, and various natural products.8-17
A crucial synthetic transformation employing these
intermediates involves cleavage of the oxygen bridge to
produce functionalized cyclohexene derivatives.18-23 In
The intramolecular Diels-Alder reaction of furans,
often designated as IMDAF, helps to overcome the
sluggishness of this heteroaromatic ring system toward
[4 + 2]-cycloaddition. Not only do IMDAF reactions allow
for the preparation of complex oxygenated polycyclic
compounds, they often proceed at lower temperatures
than their intermolecular counterparts.24 Even more
significantly, unactivated π-bonds are often suitable
dienophiles for the internal cycloaddition.7 While the
carbocyclic IMDAF reaction has been the subject of many
reports in the literature,7 much less is known regarding
the cycloaddition behavior of furan Diels-Alder systems
that contain heteroatoms attached directly to the furan
ring.25-27
(1) Denmark, S. E.; Thorensen, A. Chem. Rev. 1996, 96, 137.
Winkler, J . D. Chem. Rev. 1996, 96, 167. Roush, W. R. In Comprehen-
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(3) Wenkert, E.; Moeller, P. D. R.; Piettre, S. R. J . Am. Chem. Soc.
1988, 110, 7188.
In this regard, we have recently demonstrated that
simple 2-aminofurans such as 1 react with various
dienophiles in an intermolecular fashion with high regio-
selectivity. The resultant ring-opened cycloadducts 3 are
readily dehydrated using BF3‚OEt2 to give polysubsti-
(4) Woo, S.; Keay, B. Synthesis 1996, 669. Lautens, M.; Fillion, E.
J . Org. Chem. 1996, 61, 7994.
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In Comprehensive Heterocyclic Chemistry; Bird, C. W., Cheesman, G.
W. H., Eds.; Pergamon Press: London, 1984; Vol. 4, pp 599-656.
(7) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53,
14179.
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S0022-3263(98)00008-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/21/1998

IMDAF Cycloaddition
J . Org. Chem., Vol. 63, No. 12, 1998 3987
ago.31 These research efforts have culminated in a broad
outline of both the scope and limitations of the reaction.
The effect of a number of variables32,33 including (i) tether
length,34 (ii) heteroatom substitution in the tether,35 (iii)
substitution on both the tether and furan ring,36 and (iv)
the use of high pressures,37 aqueous conditions,38 Lewis
acids,39 cyclodextrin catalysts,40 and high temperatures41
was probed. These studies were carried out as a conse-
quence of either the reluctance of the furan of interest
to undergo the desired IMDAF reaction or the ease of
cycloreversion. In our laboratory, these problems have
been overcome by the placement of an amino nitrogen
atom adjacent to the furan oxygen, as exemplified by the
transformations outlined in Scheme 1. In an effort to
further investigate the scope of IMDAF cycloadditions,
a number of new furan substrates have been prepared
and tested for cyclization. Tethered amidofurans 7 and
8 were easily synthesized starting from aminofuran 1 and
4-pentenoyl chloride. Gratifyingly, the thermal reaction
of 7 at 200 °C for 24 h afforded tetrahydroquinolinone 9
in 66% yield. Heating a sample of the N-methylated
analogue 8 at 160 °C furnished a 6:1 mixture of cyclo-
hexadienol 10 (77%) and tetrahydroquinolinone 11 (13%),
the former being easily converted to 11 by treatment with
BF3‚OEt2. In both cases, the initial cycloadducts were
not isolated, as they readily underwent ring opening,
assisted by the lone pair of electrons on the adjacent
nitrogen atom (Scheme 2).
Sch em e 1
tuted anilines 4 (Scheme 1).25 This reaction sequence is
one of only a handful of reports that describe the [4 +
2]-cycloaddition of furans substituted with an amino
group at the 2-position of the heteroaromatic ring.26 The
paucity of examples of this type of reaction is undoubtedly
due to the unavailability of the highly unstable parent
2-aminofuran system.28 However, the presence of the
electron-withdrawing carbomethoxy group stabilizes the
furan ring29 and allows for the preparation of various
polysubstituted anilines.25 Having established the fea-
sibility of 5-substituted 2-aminofurans to undergo bimo-
lecular Diels-Alder reactions, we initiated a study of the
intramolecular reaction. Amidofurans containing olefinic
tethers were prepared to determine their ability to
undergo the IMDAF reaction, thus providing access to
various polyheterocyclic ring systems. In conjunction
with these studies, we now report the application of this
methodology to a general synthesis of the pyrrolophenan-
thridine class of alkaloids (i.e., 6).30
For comparison purposes, we have also investigated
the IMDAF chemistry of the closely related amidofurans
12 and 13 where the carbonyl group has been switched
from “inside” the tether to the “outside” position (Scheme
3). Heating a sample of furan 12 afforded a 2:1 mixture
of cyclohexadienol 14 (52%) and dihydroindole 15 (25%).
As before, cyclohexadienol 14 was converted to 15 (74%)
on treatment with BF3‚OEt2. Similar results were ob-
tained when the tether was lengthened by one methylene
unit as illustrated in Scheme 3 for the conversion of furan
13 into a 2:1 mixture of 16 and 17 (94%). Tetrahydro-
quinoline 17 was formed in 84% yield when 16 was
heated with BF3‚OEt2 at 80 °C.
(31) Cram, D. J .; Knox, G. R. J . Am. Chem. Soc. 1961, 83, 2204.
(32) Parker, K. A.; Adamchuk, M. R. Tetrahedron Lett. 1978, 1689.
Rogers, C.; Keay, B. A. Can. J . Chem. 1993, 71, 611.
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1990, 186.
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E.; Gervay, J . Tetrahedron Lett. 1988, 29, 2429. Sternbach, D. D.;
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S. J .; Derome, A. E.; Edenborough, M. S.; Harwood, L. M.; Leeming,
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Resu lts a n d Discu ssion
The IMDAF reaction has been extensively studied
since its initial report in the literature over three decades
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ington, K. J . Chem. Soc., Perkin Trans. 1 1973, 2523. Nixon, W. J .;
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Chem. 1982, 47, 2483. Schlessinger, R. H.; Bergstrom, C. P. Tetrahe-
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New York, 1987; Vol. 30, Chapter 3, pp 252-369. Cook, J . W.; Loudon,
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771.

3988 J . Org. Chem., Vol. 63, No. 12, 1998
Padwa et al.
Sch em e 2
Sch em e 5
energy of the dienophile and significantly diminishes the
rate of the [4 + 2]-cycloaddition reaction.
Sch em e 3
Lithium perchlorate in diethyl ether has become
recognized as an excellent medium in which Diels-Alder
reactions can be performed.43 Some reactions, which
usually take place only under vigorous conditions, can
occur smoothly under mild conditions when ethereal
lithium perchlorate is used as the solvent. In certain
cases, it also allows for the synthesis of previously
inaccessible cycloadducts. Because many of these slug-
gish reactions were accelerated under high pressure, the
effect of LiClO4/ether on the Diels-Alder reaction was
attributed by Grieco and co-workers to a better aggrega-
tion between the reaction partners owing to a hydropho-
bic effect or “internal pressure” on the reactants encap-
sulated in solvent cavities.44 This correlation is in line
with similar effects observed using water, a solvent with
a very large cohesive pressure.45 More recent work
indicates that these accelerations are not only due to a
solvent effect but also to catalysis by the lithium ion.46
During the course of our studies we have found that
the IMDAF cycloadditions of furanamides such as 21 can
be performed by using 4 M ethereal LiClO4 as solvent.
Thus, the use of LiClO4/ether as solvent allowed the
activated furanamide 21 to undergo cycloaddition whereas
no reaction occurred under strictly thermal conditions.
The Grieco conditions were also successfully employed
using the unactivated four-carbon tethered furanamide
12 which gave dihydroindole 15 in 73% isolated yield.
In the case of furan 21, the IMDAF cycloaddition now
occurred to produce cyclohexenone 23 as the major
product in 68% yield. This reaction presumably involved
an initial [4 + 2]-cycloaddition to give 24 followed by
rapid ring opening to afford iminium ion 25 which was
subsequently converted to 23 upon reaction with water.
When the IMDAF reaction of carbamate 26 was carried
out in 4 M ethereal LiClO4, efficient [4 + 2]-cycloaddition
occurred at 100 °C to give dihydroindole 27 as the
exclusive product in 66% yield. Interestingly, the five-
Sch em e 4
To test the importance of dienophile activation, amido-
furans 20 and 21 were prepared according to the se-
quence of reactions outlined in Scheme 4. Ester activa-
tion of the π-bond had little effect on the efficiency of the
IMDAF cycloadditions. The temperature required for the
reaction (190 °C) and yield of the resulting dihydroindole
22 were similar to that encountered with the unactivated
N-butenyl amidofuran 12 (77%). Incorporation of a
methyl substituent on the alkenyl π-bond, however,
completely suppressed the thermal IMDAF cycloaddition
even at temperatures as high as 240 °C in toluene (sealed
tube). The failure of 21 to undergo the Diels-Alder
reaction is consistent with FMO theory.42 Placement of
an alkyl substituent on the π-bond raises the LUMO
(42) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley-Interscience: New York, 1976.
(43) Grieco, P. A. Aldrichimica Acta 1991, 24, 61. Waldman, H.
Angew. Chem., Int. Ed. Engl. 1991, 30, 1306.
(44) Grieco, P. A.; Nunes, J . J .; Gaul, M. D. J . Am. Chem. Soc. 1990,
112, 4595.
(45) Riedout, D. C.; Breslow, R. J . Am. Chem. Soc. 1980, 102, 7816.
(46) Forman, M. A.; Dailey, W. P. J . Am. Chem. Soc. 1991, 113, 2762.
Desimoni, G.; Faita, G.; Righetti, P. P.; Tacconi, G. Tetrahedron 1991,
47, 8399.

IMDAF Cycloaddition
J . Org. Chem., Vol. 63, No. 12, 1998 3989
Sch em e 6
Sch em e 7
Sch em e 8
We next turned our attention to the thermal behavior
of the closely related imido-substituted furans 36 and 37
which were easily prepared from aminofuran 1 by
standard acylation conditions. Surprisingly, both com-
pounds afforded no products derived from an IMDAF
process. Instead they underwent a Fries-type rearrange-
ment to give the 3-acylated furans 38 (42%) and 39 (51%)
in modest yield. Although the Fries rearrangement is
generally carried out using Lewis acids as promoters,49
there are some examples where the reaction occurs when
N-acyl derivatives of arylamines are heated at 160-250
°C.50 As far as we can tell, there are no examples of this
type of Fries rearrangement using N-acyl-substituted
furans.
As was noted earlier, the presence of the electron-
withdrawing carbomethoxy substituent on the furan
stabilizes the highly reactive 2-amino-substituted furanyl
ring system. In addition to the carbomethoxy group, the
nitro functionality may also serve in this capacity. 2,5-
Dinitrofuran (40) is readily available from 2-nitrofuran
by treatment with concentrated nitric acid.51 Substitu-
tion of one of the nitro groups occurs upon reaction of 40
with various heteronucleophiles, presumably by an ad-
dition-elimination mechanism.52 Using this protocol, we
synthesized N-tosylamino furans 40 and 41 in 94% and
92% yields, respectively. Heating a sample of 40 in
toluene at reflux resulted in a mixture of phenols 44
(25%) and 48 (7%). Similar results were obtained when
the dienophile tether was lengthened by one methylene
unit as illustrated in Scheme 9 for the conversion of
nitrofuran 41 into 45 (55%) and 49 (7%). From these
results it is evident that nitro-substituted aminofurans
display some interesting cycloaddition chemistry. Two
carbon tethered furanamide 13 was unreactive when
LiClO4/ether was used as the solvent. More forcing
conditions resulted in the isolation of dihydroindole 29
(73%) which can be attributed to a 1,3-hydrogen shift to
internalize the double bond (i.e., 28), followed by [4 +
2]-cycloaddition and subsequent elimination of water.
Our attention was next directed toward the synthesis
and cycloaddition behavior of aromatic furanamides such
as 30 under typical Grieco conditions. 2-Amidofurans of
this type are of interest to our group because of their
potential to undergo tandem Diels-Alder/N-acyliminium
ion cyclization and eventually lead to the erythrinane (31)
skeleton of alkaloids.47 It was found, however, that
furanamides 32 and 33 did not undergo the desired
cyclization. Instead, reaction of 32 (or 33) in LiClO4/ether
with a trace of camphorsulfonic acid provided a new
1
compound whose H NMR indicated that the furan ring
was still intact. Moreover, the 1H NMR showed the
presence of two equivalent methyl groups at δ 1.17 (s,
6H). Further spectroscopic analysis (13C NMR, infrared,
and mass spectroscopy) indicated that lactam 34 (or 35)
was the sole product formed from this reaction (Scheme
7). A reasonable mechanism to rationalize this trans-
formation involves alkene protonation to generate a
tertiary carbocation followed by an internal Friedel-
Crafts alkylation. The propensity of activated aromatic
rings to undergo cationic cyclization is well-documented
in the literature,48 thereby providing good analogy for this
reaction.
(48) Olah, G. A.; Krishnamurti, R.; Surya, G. K. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
1991; Vol. 3, pp 293-339.
(49) Martin, R. Org. Prep. Proc. Int. 1992, 24, 369. Heaney, H. In
Comprehensive Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 2, pp 745-747.
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3217.
(51) Hill, H. B.; White, G. R. J . Am. Chem. Soc. 1905, 27, 197.
(52) Shimadzu, M.; Ishikawa, N.; Yamamoto, K.; Tanaka, A. J .
Heterocycl. Chem. 1986, 23, 1179. Doddi, G.; Stegel, F.; Tamasi, M. T.
J . Org. Chem. 1978, 43, 4303. Mencarelli, P.; Stegel, F. J . Org. Chem.
1976, 41, 2824. Doddi, G.; Poretti, A.; Stegel, F. J . Heterocycl. Chem.
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1998, 63, 1144.

3990 J . Org. Chem., Vol. 63, No. 12, 1998
Padwa et al.
Sch em e 9
Sch em e 10
phenanthridine ring system (50) constitutes the core
structural framework of the pyrrolophenanthridine al-
kaloids. Although a number of synthetic routes are
available for this ring system, many of these suffer from
low yields and a lack of generality.58 Our approach to
this skeleton is shown in retrosynthetic format in Scheme
10. This approach is centered on the construction of the
key dihydroindole 54. We reasoned that 54, formed by
an IMDAF cycloaddition of amidofuran 55, should un-
dergo a metal-mediated coupling to form the biaryl
carbon-carbon bond of 53.
A short synthesis of oxoassoanine (51) and anhydro-
lycorin-7-one (52) was carried out as depicted in Scheme
11. Acylation of aminofuran 1 with the appropriate acyl
chloride proceeded in 85-90% yield. It was crucial to
the success of the reaction that the acid chloride be added
slowly to the reaction mixture using a syringe pump.
Alkylation of amides 56 and 57 was carried out as
described earlier to give the advanced intermediates 58
and 59. The IMDAF cycloadditions of these substrates
were successful both thermally (165 °C) or using the
Grieco conditions (80% yield). The next step in the
sequence required the introduction of a new carbon-
carbon bond between the two aromatic rings. Aryl-aryl
bond formation is often the key step in many natural
product syntheses. As such, a variety of methods have
been developed to carry out this coupling reaction.59 Due
to literature precedence,60 we felt that a radical cycliza-
tion would be a particularly attractive method for the
required biaryl coupling. After some experimentation,
it was found that the use of bis(tributyltin) under
photochemical conditions61 afforded the aryl-coupled
products 62 and 63 in 71% and 79% yields, respectively.
Final elaboration to oxoassoanine (51) and anhydroly-
corin-7-one (52) was accomplished in 80% yield by a two-
step sequence composed of ester hydrolysis followed by
distinct reaction pathways are observed: (1) cycloaddition
followed by loss of the nitro group to give phenols (i.e.,
44 and 45) and (2) cycloaddition followed by 1,2-nitro
migration to eventually afford the corresponding o-
nitrophenols 48 and 49. We had previously observed 1,2-
nitro migrations in intermolecular cycloaddition reactions
of related nitrofurans,25 and similar 1,2-shifts have been
reported in cycloadditions involving silyl-substituted
furans,53 thereby providing good precedence for this
rearrangement pathway.
Having established the suitability of 2-amidofurans to
generate dihydroindoles, we turned our attention to the
application of the method toward the synthesis of oxoas-
soanine (51)54,55 and anhydrolycorin-7-one (52).56 These
(57) Grundon, M. F. Nat. Prod. Rep. 1989, 6, 85.
(58) Hutchings, R. H.; Meyers, A. I. J . Org. Chem. 1996, 61, 1004
and references therein.
compounds are members of the pyrrolophenanthridine
class of alkaloids which have been isolated from various
species of Amaryllidaceae.57 The 1H-pyrrolo[3,2,1-de]-
(59) Stanforth, S. P. Tetrahedron 1998, 54, 263. Bringmann, G.;
Walter, R.; Weirich, R. Angew Chem., Int. Ed. Engl. 1990, 29, 977.
Sainsbury, M. M. Tetrahedron 1980, 36, 3327. Estevez, J . C.; Vil-
laverde, M. C.; Estevez, R. J .; Castedo, L. Tetrahedron 1993, 49, 2783.
Narasimhan, N. S.; Aiden, I. S. Tetrahedron Lett. 1988, 29, 2987.
(60) Estevez, J . C.; Villaverde, M. C.; Estevez, R. J .; Castedo, L.
Tetrahedron 1994, 50, 2107. Sakamoto, T.; Yasuhara, A.; Kondo, Y.;
Yamanaka, H. Heterocycles 1993, 36, 2597. Ozlu, Y.; Cladingboel, D.
E.; Parsons, P. J . Tetrahedron 1994, 50, 2183. Kessar, S. V.; Singh,
G.; Balakrishnan, P. Tetrahedron Lett. 1974, 2269. Mondon, A.; Krohn,
K. Chem. Ber. 1972, 105, 3726. Smidrkal, J . Collect. Czech. Chem.
Commun. 1988, 53, 3184. Grimshaw, J .; Haslett, R. J . J . Chem. Soc.,
Perkin Trans. 1 1980, 657.
(53) Wu, H. J .; Yen, Ch. H.; Chuang, C. T. Tetrahedron Lett. 1996,
37, 7395.
(54) Llabres, J . M.; Viladomat, F.; Bastida, J .; Codina, C.; Rubiralta,
M. Phytochemistry 1986, 25, 2637.
(55) Rosa, A. M.; Lobo, A. M.; Branco, P. S.; Prahakar, S.; Sa-da-
Costa, M. Tetrahedron 1997, 53, 299. Shao, H. W.; Cai, J . C. Chin.
Chem. Lett. 1996, 7, 13.
(56) Ghosal, S.; Rao, P. H.; J aiswal, D. K.; Kumar, Y.; Frahm, A.
W. Phytochemistry 1985, 24, 1825. Perez, D.; Bures, G.; Guitian, E.;
Castedo, L. J . Org. Chem. 1996, 61, 1650.
(61) Curran, D. P.; Tamine, J . J . Org. Chem. 1991, 56, 2746.

IMDAF Cycloaddition
J . Org. Chem., Vol. 63, No. 12, 1998 3991
tube can generate considerable pressure and researchers are
advised to utilize a safety shield when carrying out sealed tube
reactions. Also, researchers should handle the resulting
products derived from the LiClO4/ether promoted cycloaddi-
tions with care since contact between organic compounds and
perchlorates are known to result in occasional explosions.63
Sch em e 11
5-(P en t-4-en oyla m in o)fu r a n -2-ca r boxylic Acid Meth yl
Ester (7). A solution containing 0.2 mL (2.0 mmol) of
4-pentenoic acid in 15 mL of CH2Cl2 was treated dropwise with
0.5 mL (5.8 mmol) of oxalyl chloride. The mixture was stirred
at 25 °C for 12 h, and the solvent was removed under reduced
pressure. The resulting 4-pentenoyl chloride was dissolved in
5 mL of CH2Cl2 and was used without further purification. To
a mixture containing 0.15 g (1.1 mmol) of furan 129 and 0.18
mL (2.2 mmol) of pyridine in 10 mL of CH2Cl2 was added
dropwise a solution of the above 4-pentenoyl chloride, and the
mixture was stirred at 0 °C for 3 h. Removal of the solvent
under reduced pressure followed by flash silica gel chroma-
tography gave 0.24 g (96%) of 7 as a white solid: mp 83-84
°C; IR (KBr) 3284, 1696, and 1537 cm-1; 1H NMR (CDCl3, 300
MHz) δ 2.44-2.51 (m, 2H), 2.54-2.60 (m, 2H), 3.86 (s, 3H),
5.02-5.13 (m, 2H), 5.79-5.92 (m, 1H), 6.54 (d, 1H, J ) 3.6
Hz), 7.20 (d, 1H, J ) 3.6 Hz), and 8.89 (brs, 1H); 13C NMR
(CDCl3, 75 MHz) δ 29.0, 35.8, 51.8, 96.4, 116.1, 121.4, 135.9,
136.3, 149.6, 159.2, and 169.1. Anal. Calcd for C11H13NO4:
C, 59.19; H, 5.87; N, 6.27. Found: C, 59.21; H, 5.92; N, 6.26.
2-Oxo-1,2,3,4-tetr a h yd r oqu in olin e-6-ca r boxylic Acid
Meth yl Ester (9). A 0.21 g (0.94 mmol) sample of furan 7 in
10 mL of toluene was heated in a sealed tube at 200 °C for 24
h. Removal of the solvent under reduced pressure followed
by flash silica gel chromatography gave 0.13 g (66%) of 9 as a
white solid: mp 186-187 °C; IR (KBr) 3197, 3125, 1716, and
1
1675 cm-1; H NMR (CDCl3, 300 MHz) δ 2.66-2.71 (m, 2H),
3.03 (t, 2H, J ) 7.6 Hz), 3.90 (s, 3H), 6.88 (d, 1H, J ) 8.7 Hz),
7.87-7.89 (m, 2H), and 9.33 (brs, 1H); 13C NMR (CDCl3, 75
MHz) δ 25.1, 30.4, 52.0, 115.2, 123.3, 124.8, 129.5, 129.5, 141.3,
166.6, and 172.1. Anal. Calcd for C11H11NO3: C, 64.38; H,
5.40; N, 6.83. Found: C, 64.46; H, 5.43; N, 6.77.
5-(Meth ylp en t-4-en oyla m in o)fu r a n -2-ca r boxylic Acid
Meth yl Ester (8). A mixture containing 0.12 g (0.54 mmol)
of furan 7, 0.12 g (2.1 mmol) of powdered KOH, 0.08 g (0.5
mmol) of anhydrous K2CO3, and 0.1 g (0.3 mmol) of Bu4NHSO4
in 5 mL of benzene was stirred at room temperature for 1 h.
To the above mixture was added 0.034 mL (0.7 mmol) of
methyl iodide. After being stirred at room temperature for 1
h, the reaction mixture was filtered through a pad of Celite.
Removal of the solvent under reduced pressure followed by
flash silica gel chromatography gave 0.11 g (86%) of 8 as a
heating the resultant acid in quinoline (220 °C) in the
presence of copper bronze.62
In conclusion, this paper describes a versatile new
approach to dihydroindoles with various substitution
patterns that can be applied to the synthesis of several
pyrrolophenanthridine alkaloids. The synthetic proce-
dure described here involves an intramolecular Diels-
Alder reaction of a 2-amidofuran containing a tethered
alkenyl group on the nitrogen atom. The resultant
dihydroindoles are formed by a subsequent nitrogen atom
lone pair assisted ring opening of the initially formed oxa-
bridged cycloadduct followed by loss of water. Further
studies of the IMDAF cycloaddition of 2-amidofurans are
in progress and will be reported in due course.
1
colorless oil: IR (neat) 2954, 1729, and 1689 cm-1; H NMR
(CDCl3, 300 MHz) δ 2.36 (m, 4H), 3.26 (brs, 3H), 3.90 (s, 3H),
4.95-5.04 (m, 2H), 5.77-5.80 (m, 1H), 6.26 (brs, 1H), and 7.20
(d, 1H, J ) 3.6 Hz); 13C NMR (CDCl3, 75 MHz) δ 28.7, 33.2,
35.6, 51.7, 104.5, 115.4, 119.3, 136.9, 140.8, 152.4, 158.6, and
172.5; HRMS calcd for C12H15NO4 (M+ + Li) 244.1161, found
244.1161.
1-Meth yl-2-oxo-1,2,3,4-tetr a h yd r oqu in olin e-6-ca r box-
ylic Acid Meth yl Ester (11). A 0.13 g (0.5 mmol) sample of
furan 8 in 10 mL of toluene was heated in a sealed tube at
160 °C for 24 h. Removal of the solvent under reduced
pressure followed by flash silica gel chromatography gave 0.10
g (77%) of 6-hydroxy-1-methyl-2-oxo-1,2,3,4,5,6-hexahydro-
quinoline-6-carboxylic acid methyl ester (10) and 0.015 g (13%)
of 1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid
methyl ester (11).
Amide 10 exhibited the following spectral properties: IR
(neat) 3371, 1736, and 1653 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 2.20-2.60 (m, 4H), 2.99 (m, 1H), 3.06 (m, 1H), 3.15 (s, 1H),
3.68 (s, 3H), 3.83 (s, 3H), 5.85 (d, 1H, J ) 9.9 Hz), and 6.35 (d,
1H, J ) 9.9 Hz); 13C NMR (CDCl3, 75 MHz) δ 24.7, 29.1, 30.9,
38.1, 53.2, 70.8, 112.0, 122.4, 125.3, 130.0, 169.7, and 175.3;
HRMS calcd for C12H15NO4 237.1001, found 237.1001.
Exp er im en ta l Section
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed under an atmosphere of dry argon
in flame-dried glassware. Solutions were evaporated under
reduced pressure with a rotary evaporator, and the residue
was chromatographed on a silica gel column using an ethyl
acetate-hexane mixture as the eluent unless specified other-
wise. A cautionary note: heating an ether solution in a sealed
(62) Wiley: R. H.; Smith, N. R. Organic Syntheses; Wiley: New York,
1963; Collect. Vol. 4, p 732.
(63) Lewis, R. J ., Sr. Hazardous Chemicals Desk Reference, 3rd ed.;
Van Nostrand Reinhold: New York, 1993; pp 995-996.

3992 J . Org. Chem., Vol. 63, No. 12, 1998
Padwa et al.
To a solution containing 0.09 g (0.4 mmol) of 10 in 10 mL of
benzene was added 0.07 mL (0.6 mmol) of BF3‚OEt2. The
mixture was heated at reflux for 1 h, quenched with a
saturated NaHCO3 solution, and extracted with CH2Cl2. The
combined organic extracts were dried over Na2SO4. The
solvent was removed under reduced pressure, and the residue
was subjected to flash silica gel chromatography to give 0.076
g (91%) of 11 as a white solid: mp 147-148 °C; IR (KBr) 3395,
1725, 1669, and 1603 cm-1; 1H NMR (CDCl3, 300 MHz) δ 2.66-
2.71 (m, 2H), 2.96 (t, 2H, J ) 7.4 Hz), 3.39 (s, 3H), 3.91 (s,
3H), 7.02 (d, 1H, J ) 8.6 Hz), 7.86 (s, 1H), and 7.95 (dd, 1H,
J ) 8.6 and 2.1 Hz); 13C NMR (CDCl3, 75 MHz) δ 25.2, 29.7,
31.4, 52.0, 114.3, 124.3, 125.9, 129.0, 129.4, 144.5, 166.5, and
170.3. Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98; N, 6.39.
Found: C, 65.81; H, 6.01; N, 6.35.
5-(Ben zoylp en t-4-en yla m in o)fu r a n -2-ca r boxylic Acid
Meth yl Ester (13). To a mixture containing 0.16 g (0.6 mmol)
of furan 18 and 0.6 g (2.0 mmol) of cesium carbonate in 10
mL of a 1:4 mixture of THF/DMF was added 0.23 mL (2.0
mmol) of 5-bromo-1-pentene. The mixture was heated at 75
°C for 5 h, cooled to room temperature, and washed with water.
The aqueous phase was extracted with ether, and the com-
bined organic phase was washed with brine and dried over
MgSO4. Removal of the solvent under reduced pressure
followed by flash silica gel chromatography gave 0.16 g (85%)
of 13 as a yellow oil: IR (neat) 2950, 1731, and 1670 cm-1; 1H
NMR (CDCl3, 300 MHz) δ 1.78 (m, 2H), 2.15 (q, 2H, J ) 7.2
Hz), 3.87 (s, 3H), 3.86-3.91 (m, 2H), 4.96-5.07 (m, 2H), 5.74-
5.87 (m, 2H), 6.95 (d, 1H, J ) 3.3 Hz), and 7.23-7.37 (m, 5H);
13C NMR (CDCl3, 75 MHz) δ 27.0, 30.6, 47.9, 51.7, 106.3, 115.1,
119.1, 127.5, 127.9, 130.4, 135.0, 137.2, 140.2, 151.9, 158.5,
and 169.9; HRMS calcd for C18H19NO4 313.1314, found 313.1312.
1-Ben zoyl-1,2,3,4-tetr ah ydr oqu in olin e-6-car boxylic Acid
Meth yl Ester (17). A 0.13 g (0.42 mmol) sample of furan 13
in 10 mL of toluene was heated in a sealed tube at 190 °C for
20 h. Removal of the solvent under reduced pressure followed
by flash silica gel chromatography afforded 0.04 g (33%) of 17
and 0.08 g (61%) of 1-benzoyl-6-hydroxy-1,2,3,4,5,6-hexahy-
droquinoline-6-carboxylic acid methyl ester (16). The latter
compound exhibited the following spectral properties: IR
(neat) 3354, 1738, 1634, and 1267 cm-1; 1H NMR (CDCl3, 300
MHz) δ 1.95 (brs, 2H), 2.27 (t, 2H, J ) 6.6 Hz), 2.50 (d, 1H, J
) 18.3 Hz), 2.91 (d, 1H, J ) 18.3 Hz), 3.44 (brs, 1H), 3.58 (m,
1H), 3.80 (s, 3H), 3.89 (m, 1H), 5.49 (d, 1H, J ) 3.0 Hz), 5.90
(brs, 1H), and 7.34-7.58 (m, 5H); 13C NMR (CDCl3, 75 MHz)
δ 23.5, 27.7, 38.8, 52.9, 71.3, 119.9, 121.8, 127.8, 128.1, 128.4,
128.5, 129.1, 130.5, 135.9, and 175.0; HRMS calcd for C18H19NO4
313.1314, found 313.1311.
5-(Ben zoyla m in o)fu r a n -2-ca r boxylic Acid Meth yl Es-
ter (18). To a mixture containing 0.74 g (5.2 mmol) of furan
1 and 0.85 mL (10.4 mmol) of pyridine in 40 mL of CH2Cl2
was added dropwise a solution containing 0.67 mL (5.7 mmol)
of benzoyl chloride in 5 mL of CH2Cl2 at 0 °C, and the mixture
was stirred at this temperature for 3 h. Removal of the solvent
under reduced pressure followed by flash silica gel chroma-
tography gave 1.17 g (91%) of 18 as a yellow solid: mp 128-
1
129 °C; IR (KBr) 3309, 3287, 1693, 1679, and 1601 cm-1; H
NMR (CDCl3, 300 MHz) δ 3.82 (s, 3H), 6.68 (d, 1H, J ) 3.6
Hz), 7.21 (d, 1H, J ) 3.6 Hz), 7.44-7.58 (m, 3H), 7.89-7.92
(m, 2H), and 9.21 (brs, 1H); 13C NMR (CDCl3, 75 MHz) δ 51.7,
96.8, 121.2, 127.3, 128.8, 132.5, 132.6, 136.5, 149.6, 159.0, and
163.6. Anal. Calcd for C13H11NO4: C, 63.67; H, 4.52; N, 5.71.
Found: C, 63.56; H, 4.59; N, 5.67.
5-(Ben zoylb u t -3-en yla m in o)fu r a n -2-ca r b oxylic Acid
Meth yl Ester (12). To a mixture containing 0.17 g (0.69
mmol) of furan 18 and 0.6 g (2.1 mmol) of cesium carbonate
in 10 mL of a 1:4 mixture of THF/DMF was added 0.2 mL (2.1
mmol) of 4-bromo-1-butene. The mixture was heated at 75
°C for 5 h, cooled, and washed with water. The aqueous phase
was extracted with ether, and the combined organic phase was
washed with brine and dried over MgSO4. Removal of the
solvent under reduced pressure followed by flash silica gel
chromatography gave 0.14 g (67%) of 12 as a yellow oil: IR
(neat) 2952, 1730, and 1678 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 2.45 (q, 2H, J ) 7.2 Hz), 3.87 (s, 3H), 3.96 (t, 2H, J ) 7.2
Hz), 5.05-5.14 (m, 2H), 5.75 (d, 1H, J ) 3.5 Hz), 5.77-5.89
To a solution containing 0.07 g (0.2 mmol) 16 in 5 mL of
dry benzene was added 0.05 mL (0.4 mmol) of BF3‚OEt2. The
mixture was heated at reflux for 3 h, quenched with a
saturated NaHCO3 solution, and extracted with CH2Cl2. The
combined organic extracts were dried over Na2SO4. After
removal of the solvent under reduced pressure, the residue
was subjected to flash silica gel chromatography to give 0.062
g (84%) of 17 as a white solid: mp 134-135 °C; IR (KBr) 2948,
1
1705, and 1637 cm-1; H NMR (CDCl3, 300 MHz) δ 2.07 (m,
2H), 2.90 (t, 2H, J ) 6.6 Hz), 3.87 (s, 3H), 3.92 (t, 2H, J ) 6.6
Hz), 6.79 (d, 1H, J ) 8.4 Hz), 7.30-7.41 (m, 5H), 7.53 (dd, 1H,
J ) 8.4 and 1.5 Hz), and 7.85 (d, 1H, J ) 1.2 Hz); 13C NMR
(CDCl3, 75 MHz) δ 22.6, 27.0, 44.8, 51.9, 124.8, 125.6, 126.9,
128.2, 128.5, 130.0, 130.5, 130.7, 135.7, 143.4, 166.5, and 170.5.
(m, 1H), 6.95 (d, 1H, J ) 3.5 Hz), and 7.22-7.36 (m, 5H); 13
C
NMR (CDCl3, 75 MHz) δ 32.3, 47.4, 51.8, 106.6, 117.1, 119.1,
127.4, 127.9, 130.4, 134.4, 134.9, 140.2, 151.8, 158.5, and 169.9;
HRMS calcd for C17H17NO4 299.1158, found 299.1156.
1-Ben zoyl-2,3-d ih yd r o-1H -in d ole-5-ca r b oxylic Acid
Meth yl Ester (15). A 0.14 g (0.60 mmol) sample of furan 12
in 10 mL of toluene was heated in a sealed tube at 190 °C for
19 h. Removal of the solvent under reduced pressure followed
by flash silica gel chromatography afforded 0.03 g (25%) of 15,
as well as 0.07 g (52%) of 1-benzoyl-5-hydroxy-2,3,4,5-tetrahy-
dro-1H-indole-5-carboxylic acid methyl ester (14) as a yellow
oil. Dihydroindole 15 exhibited the following properties: mp
Anal. Calcd for C18H17NO3: C, 73.20; H, 5.80; N 4.74.
Found: C, 73.23; H, 5.84; N, 4.79.
5-[Ben zoyl(4-(m eth oxyca r bon yl)bu t-3-en yl)a m in o]fu -
r a n -2-ca r boxylic Acid Met h yl E st er (20). To a mixture
containing 0.2 g (0.8 mmol) of furan 18 and 0.8 g (2.5 mmol)
of cesium carbonate in 15 mL of a 1:4 THF/DMF mixture was
added 0.25 mL (2.0 mmol) of 2-(2-bromoethyl)-1,3-dioxolane.
The mixture was heated at 75 °C for 18 h, cooled to room
temperature, and washed with water. The aqueous phase was
extracted with ether, and the combined organic phase was
washed with brine and dried over MgSO4. Removal of the
solvent under reduced pressure followed by flash silica gel
chromatography gave 0.24 g (84%) of 5-[benzoyl(2-[1,3]dioxo-
lan-2-ylethyl)amino]furan-2-carboxylic acid methyl ester as a
142-143 °C; IR (KBr) 1710, 1652, and 1379 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 3.15 (t, 2H, J ) 8.4 Hz), 3.89 (s, 3H), 4.13
(t, 2H, J ) 8.4 Hz), 7.45-7.57 (m, 6H), and 7.88 (s, 2H); 13C
NMR (CDCl3, 75 MHz) δ 27.6, 50.9, 52.0, 116.1, 125.5, 126.3,
127.1, 128.7, 129.8, 130.7, 132.6, 136.4, 146.7, 166.7, and 169.3.
Anal. Calcd for
C17H15NO3: C, 72.58; H, 5.37; N 4.98.
1
Found: C, 72.47; H, 5.46; N, 4.92.
colorless oil: IR (neat) 1726, 1669, 1534, and 1306 cm-1; H
Cyclohexadienol 14 exhibited the following spectral proper-
ties: 1H NMR (CDCl3, 300 MHz) δ 2.65 (m, 4H), 3.10 (d, 1H,
J ) 15 Hz), 3.34 (s, 1H), 3.83 (s, 3H), 3.90 (brs, 1H), 5.30 (brs,
1H), 5.75 (brs, 1H), and 7.30-7.49 (m, 5H). This compound
was not purified but rather was converted directly to dihy-
droindole 15. To a solution containing 0.07 g (0.24 mmol) of
14 in 10 mL of benzene was added 0.07 mL (0.6 mmol) of
BF3‚OEt2, and the mixture was heated at reflux for 3 h,
quenched with a saturated NaHCO3 solution, and extracted
with CH2Cl2. The combined organic extracts were dried over
Na2SO4. The solvent was removed under reduced pressure,
and the residue was subjected to flash silica gel chromatog-
raphy to give 0.05 g (74%) of 15.
NMR (CDCl3, 300 MHz) δ 2.05-2.11 (m, 2H), 3.85 (m, 2H),
3.88 (s, 3H), 3.95-4.05 (m, 4H), 5.01 (t, 1H, J ) 4.5 Hz), 5.77
(d, 1H, J ) 3.6 Hz), 6.94 (d, 1H, J ) 3.6 Hz), and 7.23-7.36
(m, 5H); 13C NMR (CDCl3, 75 MHz) δ 32.1, 43.8, 51.8, 64.8,
102.4, 106.7, 119.1, 127.5, 127.9, 130.4, 135.0, 140.4, 151.9,
158.5, and 170.0; HRMS calcd for C18H19NO6 345.1212, found
345.1210.
A solution containing 0.2 g (0.58 mmol) of the above methyl
ester and 0.04 g (0.31 mmol) of oxalic acid dihydrate in 10 mL
of a 1:1 MeOH/H2O mixture was heated at 50 °C for 24 h. The
mixture was diluted with H2O and extracted with CH2Cl2. The
organic extracts were dried over Na2SO4. After removal of the
solvent under reduced pressure, the residue was subjected to

IMDAF Cycloaddition
J . Org. Chem., Vol. 63, No. 12, 1998 3993
flash silica gel chromatography to give 0.14 g (77%) of
5-[(benzoyl-3-oxopropyl)amino]furan-2-carboxylic acid methyl
ester (19) as a colorless oil: IR (neat) 1726, 1669, and 1533
followed by removal of the solvent under reduced pressure and
flash silica gel chromatography to give 0.15 g (30%) of
5-[(ethoxycarbonyl)amino]furan-2-carboxylic acid methyl ester
as a white solid: mp 102-103 °C; IR (KBr) 3280, 1730, 1701,
and 1579 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.31 (t, 3H, J )
7.2 Hz), 3.86 (s, 3H), 4.28 (q, 2H, J ) 7.2 Hz), 6.31 (brs, 1H),
7.20 (d, 1H, J ) 3.6 Hz), and 8.40 (brs, 1H); 13C NMR (CDCl3,
75 MHz) δ 14.1, 51.5, 62.1, 94.5, 121.2, 136.3, 149.9, 152.0,
and 158.9; HRMS calcd for C9H11NO5 213.0637, found 213.0635.
5-(Bu t-3-en yl(eth oxyca r bon yl)a m in o)fu r a n -2-ca r box-
ylic Acid Meth yl Ester (26). To a mixture containing 0.16
g (0.8 mmol) of the above furan carbamate and 0.8 g (2.3 mmol)
of cesium carbonate in 10 mL of a 1:4 mixture of THF/DMF
was added 0.24 mL (2.3 mmol) of 4-bromo-1-butene. The
mixture was heated at 50 °C for 1 h, cooled to room temper-
ature, and washed with water. The aqueous phase was
extracted with ether, and the combined organic phase was
washed with brine and dried over MgSO4. Removal of the
solvent under reduced pressure followed by flash silica gel
chromatography afforded 0.18 g (86%) of 26 as a yellow oil:
1
cm-1; H NMR (CDCl3, 300 MHz) δ 2.90 (dt, 2H, J ) 6.8 and
1.2 Hz), 3.88 (s, 3H), 4.21 (t, 2H, J ) 6.8 Hz), 5.77 (d, 1H, J )
3.6 Hz), 6.94 (d, 1H, J ) 3.6 Hz), 7.23-7.39 (m, 5H), and 9.83
(d, 1H, J ) 1.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 42.3, 42.6,
51.9, 107.0, 119.1, 127.7, 128.0, 130.9, 134.3, 140.7, 151.3,
158.5, 170.2, and 199.6; HRMS calcd for C16H15NO5 301.0950,
found 301.0948.
A mixture containing 0.13 g (0.4 mmol) of 19 and 0.17 g
(0.5 mmol) of methyl (triphenylphosphoranylidene)acetate in
10 mL of CH2Cl2 was stirred at room temperature for 3 h.
Filtration through a pad of silica gel followed by removal of
the solvent under reduced pressure left a residue which was
subjected to silica gel chromatography to give 0.13 g (79%) of
the E-isomer of 20 as a colorless oil: IR (neat) 2952, 1725,
1
1671, and 1534 cm-1; H NMR (CDCl3, 300 MHz) δ 2.63 (q,
2H, J ) 7.2 Hz), 3.73 (s, 3H), 3.89 (s, 3H), 4.02 (t, 2H, J ) 7.2
Hz), 5.74 (d, 1H, J ) 3.6 Hz), 5.90 (d, 1H, J ) 15.6 Hz), 6.88-
6.95 (m, 2H), and 7.23-7.38 (m, 5H); 13C NMR (CDCl3, 75
MHz) δ 30.8, 46.8, 51.4, 51.9, 106.8, 119.1, 123.0, 127.5, 128.0,
130.7, 134.6, 140.5, 144.5, 151.5, 158.4, 166.3, and 169.9;
HRMS calcd for C19H19NO6 357.1212, found 357.1216.
1
IR (neat) 2980, 1735, 1718, and 1534 cm-1; H NMR (CDCl3,
300 MHz) δ 1.29 (t, 3H, J ) 7.2 Hz), 2.38 (q, 2H, J ) 7.2 Hz),
3.83-3.89 (m, 2H), 3.87 (s, 3H), 4.24 (q, 2H, J ) 7.2 Hz), 5.01-
5.11 (m, 2H), 5.71-5.85 (m, 1H), 6.25 (brs, 1H), and 7.17 (d,
1H, J ) 3.6 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.2, 33.0, 46.7,
51.5, 62.5, 101.3, 117.1, 120.1, 134.3, 138.3, 151.1, 153.5, and
158.7; HRMS calcd for C13H17NO5 267.1107, found 267.1108.
2,3-Dih yd r oin d ole-1,5-d ica r boxylic Acid 1-Eth yl Ester
5-Meth yl Ester (27). A 0.16 g (0.6 mmol) sample of furan
26 in 4 mL (4.0 M) of lithium perchlorate/ether was heated in
a sealed tube at 100 °C for 26 h. The mixture was cooled,
diluted with ether, washed with water, and dried over MgSO4.
Removal of the solvent under reduced pressure followed by
flash silica gel chromatography gave 0.097 g (66%) of dihy-
droindole 27 as a white solid: mp 96-97 °C; IR (KBr) 3389,
1-Ben zoyl-2,3-d ih yd r o-1H-in d ole-4,5-d ica r boxylic Acid
Dim eth yl Ester (22). A 0.12 g (0.3 mmol) sample of furan
20 in 6 mL of toluene was heated in a sealed tube at 160 °C
for 65 h. Removal of the solvent under reduced pressure
followed by flash silica gel chromatography gave 0.08 g (70%)
of 22 as a white solid: mp 119-120 °C; IR (KBr) 1720, 1649,
and 1377 cm-1; 1H NMR (CDCl3, 300 MHz) δ 3.17 (t, 2H, J )
8.4 Hz), 3.87 (s, 3H), 3.92 (s, 3H), 4.13 (t, 2H, J ) 8.4 Hz),
7.44-7.57 (m, 6H), and 7.78 (d, 1H, J ) 6.9 Hz); 13C NMR
(CDCl3, 75 MHz) δ 26.6, 50.9, 52.4, 52.6, 117.2, 123.8, 127.0,
128.7, 129.8, 130.3, 130.8, 131.5, 131.6, 136.1, 146.4, 166.1,
168.3, and 169.4. Anal. Calcd for C19H17NO5: C, 67.25; H,
5.05; N 4.13. Found: C, 67.33; H, 5.07; N, 4.14.
1712, and 1607 cm-1 1H NMR (CDCl3, 300 MHz) δ 1.37 (t,
;
3H, J ) 6.8 Hz), 3.15 (t, 2H, J ) 8.9 Hz), 3.89 (s, 3H), 4.07 (t,
2H, J ) 8.9 Hz), 4.31 (q, 2H, J ) 6.8 Hz), and 7.83-7.92 (m,
3H); 13C NMR (CDCl3, 75 MHz) δ 14.5, 26.7, 47.8, 51.7, 61.7,
113.8, 124.0, 125.9, 130.0, 130.9, 147.0, 153.0, and 166.7. Anal.
Calcd for C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C,
62.55; H, 6.09; N, 5.55.
5-[Ben zoyl(3-m eth ylbu t-3-en yl)a m in o]fu r a n -2-ca r box-
ylic Acid Meth yl Ester (21). To a mixture containing 0.45
g (1.8 mmol) of furan 18 and 1.8 g (5.5 mmol) of cesium
carbonate in 25 mL of a 1:4 mixture of THF/DMF was added
0.8 g (5.4 mmol) of 4-bromo-2-methyl-1-butene. The mixture
was heated at 80 °C for 24 h, cooled to room temperature, and
washed with water. The aqueous phase was extracted with
ether, and the combined organic phases were washed with
brine and dried with MgSO4. Removal of the solvent under
reduced pressure followed by flash silica gel chromatography
gave 0.38 g (74%) of furan 21 as a yellow oil: IR (neat) 1731,
1-Ben zoyl-4-m eth yl-2,3-d ih yd r o-1H-in d ole-5-ca r boxyl-
ic Acid Meth yl Ester (29). A solution containing 0.25 g (0.6
mmol) of furan 13 and 10 mg of camphorsulfonic acid in 5 mL
(4.0 M) of lithium perchlorate/ether was heated in a sealed
tube at 100 °C for 48 h. The mixture was cooled, diluted with
ether, washed with water, and dried over MgSO4. Removal
of the solvent under reduced pressure followed by flash silica
gel chromatography gave 0.12 g (73%) of dihydroindole 29 as
a white solid: mp 171-172 °C; IR (KBr) 1712, 1638, and 1378
cm-1; 1H NMR (CDCl3, 300 MHz) δ 2.48 (s, 3H), 3.05 (t, 2H, J
) 8.4 Hz), 3.84 (s, 3H), 4.10 (t, 2H, J ) 8.4 Hz), 7.40-7.55 (m,
6H), and 7.76 (brs, 1H); 13C NMR (CDCl3, 75 MHz) δ 17.1,
27.0, 50.4, 51.5, 113.4, 124.7, 126.9, 128.5, 130.4, 131.0, 132.4,
136.4, 136.8, 145.2, 167.4, and 169.2. Anal. Calcd for
1671, and 1533 cm-1 1H NMR (CDCl3, 300 MHz) δ 1.77 (s,
;
3H), 2.39 (t, 2H, J ) 7.5 Hz), 3.88 (s, 3H), 4.01 (t, 2H, J ) 7.5
Hz), 4.75 (s, 1H), 4.81 (s, 1H), 5.74 (d, 1H, J ) 3.6 Hz), 6.95
(d, 1H, J ) 3.6 Hz), and 7.23-7.37 (m, 5H); 13C NMR (CDCl3,
75 MHz) δ 22.0, 35.8, 46.4, 51.6, 106.4, 112.1, 119.0, 127.3,
127.8, 130.2, 134.9, 140.1, 141.9, 151.8, 158.3, and 169.7;
HRMS calcd for C18H19NO4 313.1314, found 313.1312.
5-(2-(Ben zoyla m in o)eth yl)-1-h yd r oxy-5-m eth yl-4-oxo-
cycloh ex-2-en eca r boxylic Acid Meth yl Ester (23). A 0.12
g (0.4 mmol) sample of furan 21 in 5 mL (4.0 M) of lithium
perchlorate/ether was heated in a sealed tube at 95 °C for 24
h. The mixture was cooled, diluted wth ether, washed with
water, and dried over MgSO4 to afford 42 mg (68%) of
cyclohexenone 23 as a yellow oil: IR (KBr) 3338, 1739, 1679,
and 1638 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.19 (s, 3H), 1.97
(m, 1H), 2.12 (m, 1H), 2.28 (d, 1H, J ) 14.8 Hz), 2.36 (d, 1H,
J ) 14.8 Hz), 3.39 (m, 1H), 3.67 (m, 1H), 3.82 (s, 3H), 4.25 (s,
1H), 6.05 (d, 1H, J ) 10.0 Hz), 6.63 (d, 1H, J ) 10.0 Hz), 6.68
C
18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.06; H,
5.83; N, 4.81.
5-[2-(2,3-Dim et h oxyp h en yl)a cet yla m in o]fu r a n -2-ca r -
boxylic Acid Meth yl Ester . To a mixture containing 0.3 g
(2.0 mmol) of furan 1 and 0.3 mL (4.0 mmol) of pyridine in 15
mL of CH2Cl2 was added 0.48 g (2.2 mmol) of 3,4-dimethoxy-
phenylacetyl chloride at 0 °C. The mixture was stirred at this
temperature for 3 h. Removal of the solvent under reduced
pressure followed by flash silica gel chromatography gave 0.62
g (96%) of 5-[2-(2,3-dimethoxyphenyl)acetylamino]furan-2-
carboxylic acid methyl ester as a white solid: mp 126-127
°C; IR (KBr) 3272, 1695, 1536, and 1514 cm-1; 1H NMR (CDCl3,
300 MHz) δ 3.72 (s, 2H), 3.84 (s, 3H), 3.89 (s, 3H), 3.91 (s,
3H), 6.54 (d, 1H, J ) 3.6 Hz), 6.78-6.91 (m, 3H), 7.16 (d, 1H,
J ) 3.6 Hz), and 8.01 (brs, 1H); 13C NMR (CDCl3, 75 MHz) δ
43.6, 51.8, 55.9, 56.0, 96.4, 112.0, 112.4, 121.1, 121.8, 125.3,
136.3, 149.0, 149.1, 149.7, 158.9, and 167.7. Anal. Calcd for
(brs, 1H), 7.39-7.50 (m, 3H), and 7.75 (d, 2H, J ) 6.8 Hz); 13
C
NMR (CDCl3, 100 MHz) δ 22.3, 35.9, 37.1, 42.5, 43.6, 53.6,
71.3, 126.8, 128.5, 128.9, 131.4, 134.3, 143.7, 167.4, 174.6, and
203.0; HRMS calcd for C18H21NO5 331.1420, found 331.1418.
5-[(E t h oxyca r b on yl)a m in o]fu r a n -2-ca r b oxylic Acid
Meth yl Ester . To a mixture containing 0.33 g (2.3 mmol) of
furan 1 and 0.28 mL (3.5 mmol) of pyridine in 30 mL of CH2Cl2
was added dropwise 0.25 mL (2.5 mmol) of ethyl chloroformate
at 0 °C. The mixture was stirred at room temperature for 2 h
C
16H17NO6: C, 60.18; H, 5.37; N, 4.39. Found: C, 60.07; H,
5.42; N, 4.30.

3994 J . Org. Chem., Vol. 63, No. 12, 1998
Padwa et al.
5-[[(3,4-Dim eth oxyp h en yl)a cetyl](3-m eth ylbu t-3-en yl)-
a m in o]fu r a n -2-ca r boxylic Acid Meth yl Ester (32). To a
mixture containing 0.51 g (1.6 mmol) of the above furan and
1.6 g (4.8 mmol) of cesium carbonate in 30 mL of a 1:4 mixture
of THF/DMF was added 0.71 g (4.8 mmol) of 4-bromo-2-methyl-
1-butene. The mixture was heated at 75 °C for 72 h, cooled to
room temperature, and washed with water. The aqueous
phase was extracted with ether, and the combined organic
phase was washed with brine and dried over MgSO4. Removal
of the solvent under reduced pressure followed by flash silica
gel chromatography gave 0.35 g (72%) of furan 32 as a yellow
1H), 4.76 (s, 1H), 6.06 (brs, 1H), 6.66-6.77 (m, 3H), and 7.14
(d, 1H, J ) 3.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 22.3, 30.9,
36.0, 36.3, 46.4, 52.0, 55.7, 55.8, 107.0, 111.1, 111.7, 112.1,
119.0, 120.1, 133.3, 141.4, 142.4, 147.3, 148.7, 151.3, 158.5,
and 172.2; HRMS calcd for C22H27NO6 401.1838, found 401.1836.
5-(9,10-Dim eth oxy-1,1-dim eth yl-5-oxo-1,2,3,5,6,7-h exah y-
d r oben zo[e]a zon in -4-yl)fu r a n -2-ca r boxylic Acid Meth yl
Ester (35). A 0.15 g (0.37 mmol) sample of furan 33 and 10
mg of camphorsulfonic acid in 5 mL (4.0 M) of lithium
perchlorate/ether was heated in a sealed tube at 100 °C for 24
h. The mixture was cooled, diluted with ether, washed with
water, and dried over MgSO4. Removal of the solvent under
reduced pressure followed by flash silica gel chromatography
gave 0.091 g (61%) of 35 as a colorless oil: IR (neat) 1723,
oil: IR (neat) 1731, 1683, and 1519 cm-1 1H NMR (CDCl3,
;
400 MHz) δ 1.71 (s, 3H), 2.25 (t, 2H, J ) 7.2 Hz), 3.50 (brs,
2H), 3.80 (t, 2H, J ) 7.2 Hz), 3.84 (s, 6H), 3.91 (s, 3H), 4.68 (s,
1H), 4.76 (s, 1H), 6.17 (brs, 1H), 6.61 (d, 1H, J ) 8.8 Hz), 6.68
(s, 1H), 6.76 (d, 1H, J ) 8.8 Hz), and 7.18 (d, 1H, J ) 3.6 Hz);
13C NMR (CDCl3, 100 MHz) δ 22.0, 35.7, 40.6, 51.8, 55.4, 55.5,
107.0, 110.8, 111.8, 112.0, 118.9, 120.8, 126.5, 141.1, 141.8,
147.7, 148.5, 151.0, 158.3, and 171.0; HRMS calcd for C21H25NO6
387.1682, found 387.1680.
1676, and 1611 cm-1 1H NMR (CDCl3, 400 MHz) δ 1.20 (s,
;
6H), 1.66 (m, 2H), 3.00 (t, 2H, J ) 7.8 Hz), 3.18 (t, 2H, J ) 7.8
Hz), 3.84 (s, 3H), 3.85 (s, 3H), 3.89 (m, 5H), 6.77-6.86 (m, 3H),
and 7.13 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 29.2, 30.0, 30.9,
37.3, 40.3, 51.4, 55.6, 110.9, 111.7, 114.5, 117.7, 120.1, 133.2,
137.6, 146.2, 147.1, 148.5, 158.4, and 170.1; HRMS calcd for
C22H27NO6 401.1838, found 401.1837.
5-(8,9-Dim eth oxy-6,6-dim eth yl-2-oxo-1,4,5,6-tetr ah ydr o-
2H-ben zo[d ]a zocin -3-yl)fu r a n -2-ca r boxylic Acid Meth yl
Ester (34). A 0.14 g (0.36 mmol) sample of furan 32 and 10
mg of camphorsulfonic acid in 5 mL (4.0 M) of lithium
perchlorate/ether was heated in a sealed tube at 100 °C for 20
h. The mixture was cooled, diluted with ether, washed with
water, and dried over MgSO4. Removal of the solvent under
reduced pressure followed by flash silica gel chromatography
gave 0.11 g (79%) of lactam 34 as a yellow oil: IR (neat) 1722,
5-(Ben zoyla m in o)-4-p en t -4-en oylfu r a n -2-ca r b oxylic
Acid Meth yl Ester (38). A mixture containing 0.15 g (0.67
mmol) of furan 7, 0.19 mL (1.4 mmol) of triethylamine, and
0.086 mL (0.74 mmol) of benzoyl chloride in 10 mL of benzene
was heated at reflux for 50 h. After being cooled to room
temperature, the mixture was washed with water and dried
over Na2SO4. Removal of the solvent under reduced pressure
followed by flash silica gel chromatography gave 0.16 g (73%)
of 5-(benzoylpent-4-enoylamino)furan-2-carboxylic acid methyl
1678, and 1610 cm-1 1H NMR (CDCl3, 400 MHz) δ 1.17 (s,
;
6H), 1.66 (m, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 3.88 (s, 3H), 3.90
(m, 2H), 4.15 (s, 2H), 6.79 (d, 1H, J ) 8.0 Hz), 6.91 (m, 2H),
and 7.11 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 29.3, 30.1, 37.4,
40.8, 42.2, 51.6, 55.7, 55.8, 110.9, 112.5, 115.0, 118.0, 121.3,
126.8, 137.7, 146.2, 147.8, 148.7, 158.7, and 169.3; HRMS calcd
for C21H25NO6 387.1682, found 387.1679.
ester (36) as a yellow oil: IR (neat) 1709, 1517, and 1304 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 2.46 (q, 2H, J ) 7.2 Hz), 2.85 (t,
2H, J ) 7.5 Hz), 3.86 (s, 3H), 5.01-5.12 (m, 2H), 5.77-5.91
(m, 1H), 6.23 (d, 1H, J ) 3.6 Hz), 7.07 (d, 1H, J ) 3.6 Hz),
and 7.33-7.66 (m, 5H); 13C NMR (CDCl3, 75 MHz) δ 28.5, 36.1,
51.9, 110.0, 115.8, 119.1, 128.3, 128.5, 132.6, 133.5, 136.2,
142.3, 146.8, 158.3, 170.3, and 174.5. This material was used
in the next step without further purification.
5-[[3-(3,4-Dim eth yoxyp h en yl)p r op ion yl]a m in o]fu r a n -
2-ca r boxylic Acid Meth yl Ester . A solution containing 1.2
g (5.7 mmol) of 3-(3,4-dimethoxyphenyl)propionic acid in 20
mL of CH2Cl2 was treated dropwise with 0.6 mL (6.9 mmol)
of oxalyl chloride. The mixture was stirred at room temper-
ature for 12 h, and the solvent was removed under reduced
pressure. The residue was diluted with 15 mL of CH2Cl2 and
was used in the next step without further purification. To a
mixture containing 0.73 g (5.2 mmol) of furan 1 and 0.84 mL
(10.4 mmol) of pyridine in 45 mL of CH2Cl2 was added the
above acid chloride solution at 0 °C. The mixture was stirred
at 0 °C for 3 h, poured over 1 N HCl and ice, extracted with
CH2Cl2, and dried over Na2SO4. Removal of the solvent under
reduced pressure followed by flash silica gel chromatography
gave 1.56 g (90%) of 5-[[3-(3,4-dimethyoxyphenyl)propionyl]-
amino]furan-2-carboxylic acid methyl ester as a yellow solid:
mp 113-114 °C; IR (KBr) 3297, 1713, and 1698 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 2.67 (t, 2H, J ) 7.5 Hz), 2.99 (t, 2H, J )
7.5 Hz), 3.82 (s, 3H), 3.84 (s, 3H), 3.86 (s, 3H), 6.52 (d, 1H, J
) 3.6 Hz), 6.72-6.81 (m, 3H), 7.17 (d, 1H, J ) 3.6 Hz), and
7.99 (brs, 1H); 13C NMR (CDCl3, 100 MHz) δ 30.8, 38.6, 51.8,
55.8, 55.9, 96.4, 111.3, 111.5, 120.0, 121.3, 132.7, 136.0, 147,6,
148.9, 149.3, 159.1, and 168.9. Anal. Calcd for C17H19NO6:
C, 61.25; H, 5.75; N, 4.20. Found: C, 61.15; H, 5.74; N, 4.12.
5-[[3-(3,4-Dim eth oxyp h en yl)p r op ion yl](3-m eth ylbu t-3-
en yl)a m in o]fu r a n -2-ca r boxylic Acid Meth yl Ester (33).
To a mixture containing 0.34 g (1.0 mmol) of the above furan
and 1.0 g (3.0 mmol) of cesium carbonate in 25 mL of a 1:4
mixture of THF/DMF was added 0.46 g (3.0 mmol) of 4-bromo-
2-methyl-1-butene. The mixture was heated at 70 °C for 24
h, cooled to room temperature, and washed with water. The
aqueous phase was extracted with ether, and the combined
organic phase was washed with brine and dried over MgSO4.
Removal of the solvent under reduced pressure followed by
flash silica gel chromatography gave 0.24 g (69%) of furan 33
A mixture containing 0.12 g (0.37 mmol) of furan 36 in 5
mL of toluene was heated at 200 °C in a sealed tube for 24 h.
Removal of the solvent under reduced pressure followed by
flash silica gel chromatography gave 15 mg (17%) of furan 18
and 50 mg (42%) of furan 38 as a white solid: mp 114-115
°C; IR (KBr) 1719, 1650, and 1567 cm-1; 1H NMR (CDCl3, 300
MHz) δ 2.49 (m, 2H), 2.89 (t, 2H, J ) 7.2 Hz), 3.93 (s, 3H),
5.03-5.13 (m, 2H), 5.83-5.93 (m, 1H), 7.50-7.66 (m, 4H), 8.02
(d, 2H, J ) 7.5 Hz), and 11.48 (s, 1H); 13C NMR (CDCl3, 75
MHz) δ 27.7, 39.2, 52.2, 106.3, 115.8, 116.6, 127.7, 129.0, 132.0,
133.2, 136.4, 137.6, 155.0, 158.3, 162.6, and 196.9. Anal.
Calcd for C18H17NO5: C, 66.05; H, 5.23; N, 4.28. Found: C,
65.92; H, 5.27; N, 4.19.
5-(Ben zoylh ex-5-en oyla m in o)fu r a n -2-ca r boxylic Acid
Meth yl Ester (37). A solution containing 5-hexenoyl chloride
(3.2 mmol) in 5 mL of CH2Cl2 was added to a mixture
containing 0.22 g (1.6 mmol) of furan 1 and 0.26 mL (3.2 mmol)
of pyridine in 15 mL of CH2Cl2 at 0 °C. The solution was
stirred at 0 °C for 1 h. Removal of the solvent under reduced
pressure followed by flash silica gel chromatography afforded
0.36 g (98%) of 5-(hex-5-enoylamino)furan-2-carboxylic acid
methyl ester as a white solid: mp 71-72 °C; IR (KBr) 3288,
1
3065, and 1699 cm-1; H NMR (CDCl3, 300 MHz) δ 1.75 (m,
2H), 2.04 (q, 2H, J ) 7.2 Hz), 2.45 (t, 2H, J ) 7.5 Hz), 3.77 (s,
3H), 4.86-4.96 (m, 2H), 5.61-5.75 (m, 1H), 6.48 (d, 1H, J )
3.5 Hz), 7.13 (d, 1H, J ) 3.5 Hz), and 8.76 (brs, 1H); 13C NMR
(CDCl3, 75 MHz) δ 24.0, 32.8, 35.3, 51.5, 96.2, 115.1, 121.4,
135.5, 137.3, 150.0, 159.1, and 170.4. Anal. Calcd for
C
16H15NO4: C, 60.75; H, 6.37; N, 5.90. Found: C, 60.65; H,
6.44; N, 5.82.
A solution containing 0.12 g (0.5 mmol) of the above methyl
ester, 0.14 mL (1.0 mmol) of triethylamine, and 0.07 mL (0.6
mmol) of benzoyl chloride in 10 mL of benzene was heated at
reflux for 36 h. The mixture was washed with water and dried
over Na2SO4. Removal of the solvent under reduced pressure
followed by flash silica gel chromatography provided 0.12 g
(70%) of 37 as a yellow oil: IR (neat) 1723, 1517, and 1303
as a colorless oil: IR (neat) 1732, 1684, and 1605 cm-1 1H
;
NMR (CDCl3, 400 MHz) δ 1.72 (s, 3H), 2.23 (t, 2H, J ) 7.4
Hz), 2.44 (t, 2H, J ) 7.4 Hz), 2.88 (t, 2H, J ) 7.6 Hz), 3.78 (t,
2H, J ) 7.6 Hz), 3.84 (s, 3H), 3.86 (s, 3H), 3.89 (s, 3H), 4.68 (s,

IMDAF Cycloaddition
J . Org. Chem., Vol. 63, No. 12, 1998 3995
Hz), 7.32 (d, 3H, J ) 7.2 Hz), and 7.57 (d, 2H, J ) 7.8 Hz); 13
NMR (CDCl3, 75 MHz) δ 21.6, 33.1, 48.8, 107.2, 113.8, 117.9,
127.4, 130.1, 133.4, 134.9, 145.1, and 148.1; HRMS calcd for
C15H16N2O5S 336.0780, found 336.0774.
cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.84 (m, 2H), 2.14 (q, 2H,
J ) 7.2 Hz), 2.76 (t, 2H, J ) 7.2 Hz), 3.88 (s, 3H), 4.98-5.08
(m, 2H), 5.71-5.84 (m, 1H), 6.21 (d, 1H, J ) 3.6 Hz), 7.07 (d,
1H, J ) 3.6 Hz), and 7.33-7.65 (m, 5H); 13C NMR (CDCl3, 75
MHz) δ 23.8, 32.8, 36.2, 52.0, 109.8, 115.5, 119.2, 128.4, 128.6,
132.7, 133.8, 137.5, 142.4, 147.1, 158.4, 170.5, and 175.2;
HRMS calcd for C19H19NO5 341.1263, found 341.1263.
5-(Ben zoylam in o)-4-h ex-5-en oylfu r an -2-car boxylic Acid
Meth yl Ester (39). A 0.12 g (0.35 mmol) sample of furan 37
in 5 mL of toluene was heated at 200 °C in a sealed tube for
24 h. Removal of the solvent under reduced pressure followed
by flash silica gel chromatography gave 0.010 g (12%) of furan
18 and 0.061 g (51%) of furan 39 as a white solid: mp 111-
112 °C; IR (KBr) 1714, 1592, and 1570 cm-1; 1H NMR (CDCl3,
300 MHz) δ 1.84 (m, 2H), 2.16 (q, 2H, J ) 7.2 Hz), 2.79 (t, 2H,
J ) 7.2 Hz), 3.94 (s, 3H), 5.01-5.09 (m, 2H), 5.74-5.88 (m,
1H), 7.48-7.67 (m, 4H), 8.01-8.04 (m, 2H), and 11.51 (s, 1H);
13C NMR (CDCl3, 75 MHz) δ 23.0, 33.0, 39.3, 52.2, 106.4, 115.7,
116.7, 127.8, 129.1, 132.1, 133.2, 137.5, 137.6, 155.0, 158.4,
162.6, and 197.7. Anal. Calcd for C19H19NO5: C, 66.85; H,
5.61; N, 4.10. Found: C, 66.79; H, 5.63; N, 4.08.
C
1-(Tolu en e-4-su lfon yl)-2,3-d ih yd r o-1H-in d ol-5-ol (44).
A 1.0 g (3.1 mmol) sample of furan 40 in 30 mL of toluene
was heated at reflux for 12 h. The solution was allowed to
cool to room temperature, and 10 mL of a saturated NH4Cl
solution was added. The mixture was extracted with CH2Cl2,
dried over Na2SO4, and concentrated under reduced pressure.
The residue was subjected to silica gel chromatography. The
first fraction contained 0.071 g (7%) of 6-nitro-1-(toluene-4-
sulfonyl)-2,3-dihydro-1H-indol-5-ol (48): mp 219-221 °C; IR
(CHCl3) 3324, 2919, 1736, 1642, and 1593 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 2.40 (s, 3H), 2.94 (t, 2H, J ) 8.3 Hz), 3.96
(t, 2H, J ) 8.3 Hz), 6.88 (s, 1H), 7.28 (d, 2H, J ) 8.2 Hz), 7.69
(d, 2H, J ) 8.2 Hz), 8.24 (s, 1H), and 10.69 (s, 1H); 13C NMR
(CDCl3, 75 MHz) δ 21.8, 28.5, 50.1, 109.4, 116.3, 127.6, 130.2,
133.5, 135.5, 144.1, 145.0, 153.0, and 158.6. Anal. Calcd for
C15H14N2O5S: C, 53.89; H, 4.22; N, 8.38. Found: C, 53.95; H,
4.28; N, 8.32.
The second fraction contained 0.226 g (25%) of 1-(toluene-
4-sulfonyl)-2,3-dihydro-1H-indol-5-ol (44): mp 196-197 °C; IR
(neat) 3369, 2909, 1606, 1459, and 1150 cm-1; 1H NMR (CDCl3,
300 MHz) δ 2.37 (s, 3H), 2.71 (t, 2H, J ) 8.2 Hz), 3.90 (t, 2H,
J ) 8.2 Hz), 4.60 (s, 1H), 6.57 (d, 1H, J ) 2.0 Hz), 6.68 (dd,
1H, J ) 8.6 and 2.3 Hz), 7.21 (d, 2H, J ) 8.0 Hz), 7.51 (d, 1H,
J ) 8.6 Hz), and 7.60 (d, 2H, J ) 8.2 Hz); 13C NMR (CDCl3, 75
MHz) δ 21.8, 28.5, 50.6, 112.4, 114.5, 177.1, 127.6, 129.8, 134.1,
N-Bu t -3-en yl-4-m et h yl-N-(5-n it r ofu r a n -2-yl)b en zen e-
su lfon a m id e (40). To a stirred solution containing 4.73 g
(17.4 mmol) of freshly prepared N-(tert-butylcarbamate)sulfon-
amide64 in 20 mL of THF was added 9.1 g (35 mmol) of
triphenylphosphine followed by the addition of 0.84 g (11.6
mmol) of 3-buten-1-ol. The mixture was cooled to 0 °C, and
4.6 mL (29 mmol) of diethyl acetylenedicarboxylate was added
dropwise. The mixture was allowed to stir at room temper-
ature for 3 h, and the solvent was removed under reduced
pressure. The resulting oil was subjected to silica gel chro-
matography to give 3.5 g (93%) of N-(tert-butylcarbamate)-N-
but-3-enyl-4-methylbenzenesulfonamide as a colorless oil: IR
(neat) 2978, 1729, 1642, and 1595 cm-1; 1H NMR (CDCl3, 300
MHz) δ 1.52 (s, 9H), 2.33 (s, 3H), 2.42 (q, 2H, J ) 7.5 Hz),
3.80 (t, 2H, J ) 7.5 Hz), 5.00-5.20 (m, 2H), 5.70-5.80 (m, 1H),
7.21 (d, 2H, J ) 8.1 Hz), and 7.71 (d, 2H, J ) 8.1 Hz); 13C
NMR (CDCl3, 75 MHz) δ 21.5, 27.8, 34.5, 46.3, 84.0, 117.3,
127.8, 129.2, 134.4, 137.4, 144.1, and 150.8; HRMS calcd for
134.5, 135.8, 144.1, 152.8, and 152.8. Anal. Calcd for C15H15
-
NO3S: C, 62.26; H, 5.23; N, 4.84. Found: C, 62.24; H, 5.27;
N, 4.79.
N-P en t-4-en yl-4-m eth yl-N-(5-n itr ofu r a n -2-yl)ben zen e-
su lfon a m id e (41). To a stirred solution containing 4.2 g (15.6
mmol) of freshly prepared N-(tert-butylcarbamate)sulfon-
amide64 in 20 mL of THF was added 8.1 g (23.4 mmol) of
triphenylphosphine followed by 0.9 g (10.4 mmol) of 4-penten-
1-ol. The mixture was cooled to 0 °C, and 4.9 mL (29 mmol)
of diethyl acetylenedicarboxylate was added dropwise. The
reaction mixture was allowed to stir at room temperature for
3 h. The solvent was removed under reduced pressure, and
the resulting oil was subjected to silica gel chromatography
to give 3.35 g (95%) of N-(tert-butylcarbamate)-N-pent-4-enyl-
4-methylbenzenesulfonamide as a colorless oil: IR (neat) 3073,
2973, 1727, 1347, and 1154 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.33 (s, 9H), 1.87 (m, 2H), 2.13 (q, 2H, J ) 7.8 Hz), 2.44 (s,
3H), 3.83 (t, 2H, J ) 7.8 Hz), 5.85 (m, 1H), 5.10 (m, 2H), 7.32
(d, 2H, J ) 10.5 Hz), and 7.79 (d, 2H, J ) 10.5 Hz); 13C NMR
(CDCl3, 75 MHz) δ 21.6, 27.9, 29.2, 30.9, 32.9, 46.8, 115.2,
127.8, 128.5, 129.2, 133.8, 137.5, and 150.9; HRMS calcd for
C
16H23NO4S 325.1348, found 325.1354.
To a stirred solution containing 3.5 g (11 mmol) of the above
sulfonamide in 50 mL of CH2Cl2 was added 2.5 mL (0.3 mol)
trifluoroacetic acid. The solution was allowed to stir at room
temperature for 12 h and was quenched with an aqueous
K2CO3 solution. The organic layer was separated, washed with
brine, dried over Na2SO4, and concentrated under reduced
pressure. Silica gel chromatography of the residue afforded
2.14 g (88%) of N-but-3-enyl-4-methylbenzenesulfonamide65 as
a colorless oil: IR (neat) 3278, 2934, 1641, 1430, and 1325
1
cm-1; H NMR (CDCl3, 300 MHz) δ 2.20 (q, 2H, J ) 6.9 Hz),
C
17H25NO4S 339.1504, found 339.1508.
2.42 (s, 3H), 2.99 (q, 2H, J ) 6.9 Hz), 5.00-5.10 (m, 2H), 5.17
(brs, 1H), 5.6-5.75 (m, 1H), 7.30 (d, 2H, J ) 8.2 Hz), and 7.77
(d, 2H, J ) 8.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 21.5, 33.6,
42.3, 117.8, 127.1, 129.7, 134.3, 136.9, and 143.4; HRMS calcd
for C11H15NO2S 225.0823, found 225.0825.
To a stirred solution containing 3.4 g (9.9 mmol) of the above
sulfonamide in 50 mL of CH2Cl2 was added 2.8 mL (0.3 mol)
of trifluoroacetic acid. The solution was allowed to stir at room
temperature for 12 h and was then quenched with an aqueous
K2CO3 solution. The organic layer was separated, washed with
brine, dried over Na2SO4, and concentrated under reduced
pressure. Silica gel chromatography afforded 2.3 g (96%) of
N-pent-4-enyl-4-methylbenzenesulfonamide65 as a colorless
oil: IR (neat) 3289, 2930, 1636, 1330, and 1150 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 1.49 (m, 2H), 1.97 (q, 2H, J ) 7.0 Hz),
2.35 (s, 3H), 2.86 (q, 2H, J ) 6.5 Hz), 4.88 (m, 2H), 5.30 (s,
1H), 5.63 (m, 1H), 7.24 (d, 2H, J ) 8.1 Hz), and 7.72 (d, 2H, J
) 8.1 Hz); 13C NMR (CDCl3, 75 MHz) δ 21.5, 28.7, 30.6, 42.6,
115.5, 127.1, 129.7, 137.0, 137.2, and 143.4; HRMS calcd for
To a stirred solution containing 1.4 g (6.3 mmol) of the above
sulfonamide in 30 mL of THF at 0 °C was added 0.33 g (8.8
mmol) of 60% NaH in mineral oil. The mixture was stirred
for 30 min at room temperature and cooled to 0 °C; then a
solution of 1.0 g (6.3 mmol) of 2,5-dinitrofuran51 in 5 mL of
THF was added. The mixture was allowed to warm to room
temperature, stirred at this temperature for 3.5 h, and then
quenched with water. The solvent was removed under reduced
pressure, and the residue was extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. Silica gel
chromatography afforded 2.0 g (94%) of 40 as a clear oil: IR
(neat) 3133, 2920, 1600, 1493, and 1347 cm-1; 1H NMR (CDCl3,
300 MHz) δ 2.35 (q, 2H, J ) 7.2 Hz), 2.43 (s, 3H), 3.72 (t, 2H,
J ) 7.2 Hz), 5.06 (m, 2H), 5.71 (m, 1H), 6.49 (d, 1H, J ) 3.6
C
12H17NO2S 239.0979, found 239.0936.
To a stirred solution containing 1.5 g (6.3 mmol) of the above
sulfonamide in 30 mL of THF at 0 °C was added 0.34 g (8.8
mmol) of 60% NaH in mineral oil. The ice bath was removed,
and the mixture was stirred for 30 min at room temperature.
The solution was cooled to 0 °C, and 1.0 g (6.3 mmol) of 2,5-
dinitrofuran in 5 mL of THF was added. The mixture was
allowed to warm to room temperature, stirred at room tem-
perature for 3.5 h, and then quenched with water. The solvent
was removed under reduced pressure, and the residue was
(64) Henry, J . R.; Marcin, L. R.; McIntosh, M. C.; Scoln, D. M.;
Harris, G. D.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709.
(65) Larock, R. C.; Yang, H.; Weinreb, S. M.; Herr, R. J . J . Org.
Chem. 1994, 59, 4172.

3996 J . Org. Chem., Vol. 63, No. 12, 1998
Padwa et al.
extracted with CH2Cl2. The combined organic extracts were
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. Silica gel chromatography afforded 2.04 g
(92%) of 41 as a clear oil: IR (neat) 3136, 2923, 1636, 1489,
and 1343 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.71 (q, 2H, J )
7.2 Hz), 2.10 (q, 2H, J ) 7.2 Hz), 2.43 (s, 3H), 3.66 (t, 2H, J )
7.2 Hz), 5.00 (m, 2H), 5.75 (m, 1H), 6.51 (d, 1H, J ) 3.9 Hz),
7.32 (m, 3H), and 7.64 (d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3,
75 MHz) δ 21.6, 27.8, 30.3, 48.9, 106.9, 113.8, 115.7, 127.4,
130.1, 134.8, 136.8, 145.1, 148.1, and 148.3; HRMS calcd for
150.6, 158.3, and 168.1; HRMS calcd for C19H20NO6Br 437.0474,
found 437.0476.
1-(2-Br om o-4,5-d im et h oxyb en zoyl)-2,3-d ih yd r o-1H -5-
ca r boxylic Acid Meth yl Ester (60). A mixture containing
0.21 g (0.48 mmol) of amidofuran 58 in 5 mL of a 4 M LiClO4/
etherate solution was heated at 100 °C in a sealed tube for 42
h. After being cooled to room temperature, the solution was
diluted with ether, washed with water, and dried over Na2SO4.
Removal of the solvent under reduced pressure followed by
flash silica gel chromatography gave 0.16 g (79%) of 60 as a
white solid: mp 134-135 °C; IR (KBr) 1715, 1656, and 1398
C
16H18N2O5S 350.0936, found 350.0941.
1-(Tolu en e-4-su lfon yl)-1,2,3,4-t et r a h yd r oq u in olin -6-
cm-1 1H NMR (DMSO-d6, 400 MHz) δ 3.15 (t, 2H, J ) 8.4
;
ol (45). A 1.1 g (3.1 mmol) sample of furan 41 in 30 mL of
toluene was heated at reflux for 12 h. The solution was
allowed to cool to room temperature, and 10 mL of a saturated
NH4Cl solution was added. The mixture was extracted with
CH2Cl2, dried over Na2SO4, and concentrated under reduced
pressure. The residue was subjected to silica gel chromatog-
raphy. The first fraction contained 0.077 g (7%) of 6-nitro-1-
(toluene-4-sulfonyl)-1,2,3,4-tetrahydroquinolin-6-ol (49): mp
174-175 °C; IR (CHCl3) 3419, 3119, 1632, 1592, and 1535
cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.66 (m, 2H), 2.40 (s, 3H),
2.46 (t, 2H, J ) 6.5 Hz), 3.79 (t, 2H, J ) 6.5 Hz), 6.81 (s, 1H),
7.24 (d, 2H, J ) 8.2 Hz), 7.52 (d, 2H, J ) 8.2 Hz), 8.52 (s, 1H),
and 10.41 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 21.3, 21.8, 27.4,
46.1, 119.2, 120.9, 127.4, 130.1, 130.1, 132.1, 136.2, 142.8,
144.4, and 151.8. Anal. Calcd for C16H16N2O5S: C, 55.16; H,
4.63; N, 8.04. Found: C, 55.22; H, 4.70; N, 8.08.
Hz), 3.80 (s, 3H), 3.84 (s, 3H), 3.85 (s, 3H), 3.90 (brs, 2H), 7.14
(s, 1H), 7.23 (s, 1H), 7.84 (s, 2H), and 8.10 (brs, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ 26.5, 49.0, 51.4, 55.9, 108.1, 111.2,
115.7, 124.8, 125.6, 128.9, 130.2, 133.0, 148.7, 150.1, and 165.5.
Anal. Calcd for C19H18NO5Br: C, 54.30; H, 4.32; N, 3.33.
Found: C, 54.24; H, 4.28; N, 3.27.
9,10-Dim eth oxy-7-oxo-4,5-dih ydr o-7H-pyr r olo[3,2,1-de]-
p h en a n th r id in e-2-ca r boxylic Acid Meth yl Ester (62). A
solution containing 0.32 g (0.76 mmol) of bromide 60 and 0.8
mL (1.5 mmol) of bis(tributyltin) in 250 mL of benzene was
irradiated with a 250 W sunlamp for 24 h at 80 °C. The
solvent was removed under reduced pressure, and the residue
was subjected to silica gel chromatography to give 0.18 g (71%)
of 62 as a white solid: mp 238-239 °C; IR (KBr) 1719, 1702,
and 1641 cm-1; 1H NMR (CDCl3, 400 MHz) δ 3.44 (t, 2H, J )
8.4 Hz), 3.99 (s, 3H), 4.06 (s, 3H), 4.13 (s, 3H), 4.54 (t, 2H, J
) 8.4 Hz), 7.62 (s, 1H), 7.94 (s, 1H), 7.97 (d, 1H, J ) 1.2 Hz),
and 8.59 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 27.0, 46.9, 52.2,
56.3, 56.4, 103.0, 108.7, 115.9, 121.2, 122.3, 124.4, 125.1, 128.0,
131.1, 142.7, 149.9, 153.1, 159.8, and 167.1. Anal. Calcd for
The second fraction contained 0.52 g (55%) of 1-(toluene-4-
sulfonyl)-1,2,3,4-tetrahydroquinolin-6-ol (45): mp 155-156 °C;
1
IR (CHCl3) 3414, 2919, 1611, 1504, and 1155 cm-1; H NMR
(CDCl3, 300 MHz) δ 1.54 (m, 2H), 2.28 (t, 2H, J ) 6.7 Hz),
2.38 (s, 3H), 3.74 (t, 2H, J ) 6.7 Hz), 5.29 (s, 1H), 6.49 (d, 1H,
J ) 2.8 Hz), 6.68 (dd, 1H, J ) 8.8 and 2.8 Hz), 7.18 (d, 2H, J
) 8.1 Hz), 7.43 (d, 2H, J ) 8.1 Hz), and 7.62 (d, 1H, J ) 8.8
Hz); 13C NMR (CDCl3, 75 MHz) δ 21.2, 21.5, 26.3, 46.4, 113.7,
115.1, 127.1, 127.2, 129.5, 129.7, 133.0, 136.5, 143.5, and 153.2.
Anal. Calcd for C16H17NO3S: C, 63.35; H, 5.65; N, 4.62.
Found: C, 63.28; H, 5.65; N, 4.54.
C
19H17NO5: C, 67.25; H, 5.05; N, 4.13. Found: C, 67.01; H,
5.16; N, 3.96.
Oxoa ssoa n in e (51). A mixture containing 0.13 g (0.38
mmol) of ester 62 in 20 mL of a 10% methanolic KOH solution
was heated at reflux for 2 h. The solvent was removed under
reduced pressure, and the residue was suspended in 15 mL of
a cold 10% HCl solution and stirred at 25 °C for 1 h. The
solution was filtered, and the resulting solid was suspended
in 10 mL of freshly distilled quinoline. After the addition of
180 mg of copper bronze, the mixture was heated at 220-225
°C for 2.5 h. The mixture was cooled to room temperature
and filtered through a pad of Celite. The resulting solution
was washed with a 10% HCl solution and dried over Na2SO4.
Removal of the solvent under reduced pressure followed by
flash silica gel chromatography gave 0.088 g (81%) of oxoas-
soanine (51) as a pale yellow solid: mp 266-267 °C (lit.58 mp
266-269 °C); IR (KBr) 1644, and 1607 cm-1; 1H NMR (CDCl3,
400 MHz) δ 3.45 (t, 2H, J ) 8.4 Hz), 4.05 (s, 3H), 4.09 (s, 3H),
4.50 (t, 2H, J ) 8.4 Hz), 7.22 (t, 1H, J ) 7.2 Hz), 7.29 (dd, 1H,
J ) 7.2 and 1.2 Hz), 7.54 (s, 1H), 7.82 (d, 1H, J ) 7.6 Hz), and
7.95 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 27.4, 46.5, 56.1,
56.2, 102.9, 108.7, 116.7, 119.2, 121.3, 123.1, 123.6, 128.5,
130.9, 139.4, 149.6, 152.8, and 159.6; HRMS calcd for C17H15NO3
281.1052, found 281.1056.
5-[(6-Br om oben zo[1,4]dioxole-5-car bon yl)am in o]fu r an -
2-ca r boxylic Acid Meth yl Ester (57). To a solution con-
taining 4.9 g (0.02 mol) of 6-bromo-1,3-benzodioxole-5-carbox-
aldehyde and 3 drops of a 1 M H3PO4 solution in 200 mL of
acetone at 10 °C was added a solution containing 3.0 g (0.026
mol) of NaClO2 in 100 mL of water. The yellow solution was
warmed to room temperature, and a 35% H2O2 solution was
added dropwise until the mixture became colorless. The
solution was acidified to pH 1 at 0 °C, and the resulting solid
was filtered, washed with cold water, and dried to give 4.9 g
(94%) of 6-bromo-1,3-benzodioxole-5-carboxylic acid as a white
solid: 1H NMR (CDCl3, 300 MHz) δ 6.08 (s, 2H), 7.14 (s, 1H),
7.50 (s, 1H), and 10.50 (brs, 1H). To a suspension of 0.9 g (3.7
mmol) of the above acid in 15 mL of CH2Cl2 at room temper-
ature was added 1.0 mL (11 mmol) of oxalyl chloride. The
mixture was stirred at room temperature for 12 h, and the
solvent was removed under reduced pressure. The resulting
acid chloride was used without further purification. To a
refluxing solution containing 0.5 g (3.5 mmol) of furan 1 and
5-[(2-Br om o-4,5-d im et h yoxyb en zoyl)a m in o]fu r a n -2-
ca r boxylic Acid Meth yl Ester (56). To a suspension of 0.76
g (2.9 mmol) of 2-bromo-4,5-dimethoxybenzoic acid in 10 mL
of CH2Cl2 at room temperature was added 0.6 mL (6.9 mmol)
of oxalyl chloride. The solution was stirred at room temper-
ature for 12 h, and the solvent was removed under reduced
pressure. The residue was rinsed with 20 mL of CH2Cl2 and
concentrated under reduced pressure. The resulting acid
chloride was used without further purification. To a refluxing
solution containing 0.4 g (2.8 mmol) of furan 1 and 0.5 mL
(5.6 mmol) of pyridine in 75 mL of benzene was added a
solution of the above acid chloride in 50 mL of benzene by
syringe pump over a period of 6 h. After the addition was
complete, the mixture was heated at reflux for 12 h. Removal
of the solvent under reduced pressure was followed by flash
silica gel chromatography to give 0.96 g (88%) of 5-[(2-bromo-
4,5-dimethyoxybenzoyl)amino]furan-2-carboxylic acid methyl
ester (56) as a pale yellow oil: IR (neat) 3253, 3022, 1716, and
1531 cm-1; 1H NMR (CDCl3, 400 MHz) δ 3.81 (s, 3H), 3.86 (s,
3H), 3.88 (s, 3H), 6.70 (d, 1H, J ) 3.6 Hz), 6.97 (s, 1H), 7.19
(s, 1H), 7.21 (d, 1H, J ) 3.6 Hz), and 9.58 (brs, 1H); 13C NMR
(CDCl3, 75 MHz) δ 51.6, 55.9, 56.1, 96.9, 110.5, 112.5, 115.7,
121.1, 126.8, 136.4, 148.0, 149.0, 151.1, 158.8, and 162.9;
HRMS calcd for C15H14NO6Br 383.0005, found 383.0004.
5-[(2-Br om o-4,5-d im eth oxyben zoyl)bu t-3-en yla m in o]-
fu r a n -2-ca r boxylic Acid Meth yl Ester (58). To a mixture
containing 0.32 g (0.8 mmol) of amidofuran 56 and 0.9 g (2.6
mmol) of cesium carbonate in 25 mL of 1:4 THF/DMF was
added 0.26 mL (2.6 mmol) of 4-bromo-1-butene. The mixture
was heated at 80 °C for 3 h to give 0.31 g (85%) of 58 as a
yellow oil: IR (neat) 3075, 1723, and 1680 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 2.46 (brs, 2H), 3.78 (s, 3H), 3.83 (s, 3H),
3.85 (s, 3H), 3.95 (m, 2H), 5.07-5.17 (m, 2H), 5.84 (m, 1H),
5.96 (brs, 1H), 6.72 (s, 1H), and 6.89 (brs, 2H); 13C NMR
(CDCl3, 100 MHz) δ 32.2, 46.6, 51.7, 55.9, 56.0, 106.5, 109.9,
110.5, 114.8, 117.2, 118.9, 129.3, 134.3, 140.7, 147.8, 149.8,

IMDAF Cycloaddition
J . Org. Chem., Vol. 63, No. 12, 1998 3997
0.6 mL (7.0 mmol) of pyridine in 75 mL of benzene was added
the above acid chloride in 50 mL of benzene over a period of 6
h. The mixture was heated at reflux for 12 h. The solvent
was removed under reduced pressure, and the residue was
chromatographed on a silica gel column to give 1.11 g (85%)
of 57 as a pale yellow solid: mp 172-173 °C; IR (KBr) 3187,
washed with hexane. Removal of the solvent followed by flash
silica gel chromatography gave 0.08 g of recovered starting
material and 0.22 g (79%) of 63 as a pale yellow solid: mp
280-281 °C; IR (KBr) 1702, 1651, and 1607 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 3.45 (t, 2H, J ) 8.4 Hz), 3.97 (s, 3H), 4.51
(t, 2H, J ) 8.4 Hz), 6.16 (s, 2H), 7.61 (s, 1H), 7.88 (s, 1H), 7.95
(d, 1H, J ) 1.2 Hz), and 8.50 (s, 1H); 13C NMR (CDCl3, 100
MHz) δ 27.0, 46.9, 52.2, 101.0, 102.2, 106.7, 115.9, 122.6, 123.0,
124.6, 125.2, 130.2, 131.0, 142.6, 148.8, 152.1, 159.6, and 166.9.
Anal. Calcd for C18H13NO5: C, 66.87; H, 4.05; N, 4.33.
Found: C, 66.60; H, 4.10; N, 4.23.
1725, and 1672 cm-1 1H NMR (CDCl3, 400 MHz) δ 3.85 (s,
;
3H), 6.07 (s, 2H), 6.68 (d, 1H, J ) 3.6 Hz), 7.04 (s, 1H), 7.17
(s, 1H); 7.23 (d, 1H, J ) 3.6 Hz), and 8.84 (brs, 1H); 13C NMR
(CDCl3, 100 MHz) δ 51.8, 97.0, 102.6, 110.1, 111.3, 113.5,
121.1, 128.5, 136.8, 147.7, 148.6, 150.7, 158.9, and 162.5. Anal.
Calcd for C14H10NO6Br: C, 45.68; H, 2.74; N, 3.80. Found:
C, 45.74; H, 2.81; N, 3.70.
An h yd r olycor in -7-on e (52). A mixture containing 0.090
g (0.28 mmol) of ester 63 in 15 mL of a 10% methanolic KOH
solution was heated at reflux for 2 h. The solvent was removed
under reduced pressure, and the residue was suspended in 15
mL of a cold 10% HCl solution and stirred for 1 h. The solution
was filtered and concentrated under reduced pressure, and the
residue was suspended in 10 mL of freshly distilled quinoline.
To this solution was added 135 mg of copper bronze, and the
mixture was heated at 220-225 °C for 2.5 h. After being
cooled to room temperature, the mixture was filtered through
a pad of Celite, washed with 10% HCl, and dried over Na2SO4.
Removal of the solvent under reduced pressure followed by
flash silica gel chromatography gave 60 mg (80%) of anhydro-
lycorin-7-one (52) as a tan solid: mp 231-232 °C (lit.56 mp
5-[(6-Br om ob en zo[1,3]d ioxole-5-ca r b on yl)b u t -3-en yl-
a m in o]fu r a n -2-ca r boxylic Acid Meth yl Ester (59). To a
mixture containing 0.42 g (1.1 mmol) of amidofuran 57 and
1.1 g (3.4 mmol) of cesium carbonate in 30 mL of 1:4 THF/
DMF was added 0.34 mL (3.3 mmol) of 4-bromo-1-butene. The
mixture was heated at 80 °C for 5 h to give 0.4 g (84%) of 59
as a yellow oil: IR (neat) 1731, 1678, and 1533 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 2.44 (m, 2H), 3.87 (s, 3H), 3.95 (brs, 2H),
5.06-5.15 (m, 2H), 5.82 (m, 1H), 5.96 (brs, 3H), 6.65 (brs, 1H),
6.88 (brs, 1H), and 6.95 (brs, 1H); 13C NMR (CDCl3, 100 MHz)
δ 32.2, 46.6, 51.8, 102.1, 106.3, 107.7, 110.7, 112.6, 117.3, 119.0,
130.5, 134.3, 140.8, 147.0, 149.0, 150.5, 158.4, and 167.7;
HRMS calcd for C18H16NO6Br: 421.0161, found 421.0159.
1-(6-Br om oben zo[1,3]d ioxole-5-ca r bon yl)-2,3-d ih yd r o-
1H-in d ole-5-ca r boxylic Acid Meth yl Ester (61). A mixture
containing 0.14 g (0.33 mmol) of amidofuran 59 in 5 mL of a
5 M LiClO4/etherate solution was heated at 100 °C in a sealed
tube for 36 h. After cooling, the solution was diluted with
ether, washed with water, and dried over Na2SO4. Removal
of the solvent under reduced pressure followed by flash silica
gel chromatography gave 0.11 g (80%) of 61 as a white solid:
1
230-231 °C); IR (KBr) 1644, 1618, and 1468 cm-1; H NMR
(CDCl3, 400 MHz) δ 3.44 (t, 2H, J ) 8.4 Hz), 4.49 (t, 2H, J )
8.4 Hz), 6.14 (s, 2H), 7.20 (t, 1H, J ) 7.9 Hz), 7.30 (dd, 1H, J
) 7.2 and 1.2 Hz), 7.56 (s, 1H), 7.76 (d, 1H, J ) 7.9 Hz), and
7.93 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 27.3, 46.4, 100.7,
102.0, 106.5, 116.5, 119.2, 122.8, 123.0, 123.6, 130.7, 139.1,
148.2, 151.6, and 159.2; HRMS calcd for C16H11NO3 265.0739,
found 265.0740.
mp 139-140 °C; IR (KBr), 1719, 1707, 1658, and 1482 cm-1
;
Ack n ow led gm en t. We gratefully acknowledge the
National Cancer Institute (CA-26750) for generous
support of this work. Use of high-field NMR spectrom-
eters used in these studies was made possible through
equipment grants from the NIH and NSF.
1H NMR (DMSO-d6, 80 °C, 400 MHz) δ 3.17 (t, 2H, J ) 8.6
Hz), 3.84 (s, 3H), 3.90 (brs, 2H), 6.14 (s, 2H), 7.13 (s, 1H), 7.28
(s, 1H), 7.84 (s, 2H) and 8.20 (brs, 1H); 13C NMR (DMSO-d6,
80 °C, 100 MHz) δ 26.5, 49.1, 51.4, 102.1, 107.4, 108.9, 112.2,
116.6, 125.6, 128.9, 131.3, 132.2, 133.1, 146.1, 147.3, 148.8,
149.2, and 165.5. Anal. Calcd for C18H14NO5Br: C, 53.49; H,
3.49; N, 3.47. Found: C, 53.57; H, 3.44; N, 3.47.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for new compounds lacking analyses (28 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
7-Oxo-4,5-d ih yd r o-7H-[1,3]d ioxole[4,5-j]p yr r olo[3,2,1-
d e]p h en a n th r id in e-2-ca r boxylic Acid Meth yl Ester (63).
A solution containing 0.34 g (0.84 mmol) of bromodihyroindole
61 and 0.85 mL (1.7 mmol) of bis(tributyltin) in 250 mL of
benzene at 80 °C was irradiated using a 250 W sunlamp for
24 h. The solvent was removed under reduced pressure, and
the resulting solid was dissolved in 250 mL of CH3CN and
J O980008F