Access to indoles via Diels-Alder reactions of 3-vinylpyrroles

Article abstract of DOI:10.1002/jhet.228

(Chemical Equation Presented) N-p-Toluenesulfonyl-3-vinylpyrrole underwent endo-addition [4 + 2] cycloaddition reactions with maleimides and benzoquinones, followed by isomerization to give tetrahydroindoles in good yields. Dehydrogenation with activated MnO₂ in refluxing toluene gave the corresponding indoles in fair to good yields. Detosylation via saponification or with magnesium in refluxing methanol gave the N-H indoles in moderate to good yields. This method for formation of indoles is both convergent and versatile and uses starting materials that are conveniently prepared.

Full text of DOI:10.1002/jhet.228

November 2009
Access to Indoles via Diels-Alder Reactions of 3-Vinylpyrroles
1285
Wayland E. Noland* and Nicholas P. Lanzatella
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455
*E-mail: nolan001@umn.edu
Additional Supporting Information may be found in the online version of this article.
Received April 10, 2009
DOI 10.1002/jhet.228
Published online 10 November 2009 in Wiley InterScience (www.interscience.wiley.com).
N-p-Toluenesulfonyl-3-vinylpyrrole underwent endo-addition [4 þ 2] cycloaddition reactions with
maleimides and benzoquinones, followed by isomerization to give tetrahydroindoles in good yields.
Dehydrogenation with activated MnO2 in refluxing toluene gave the corresponding indoles in fair to
good yields. Detosylation via saponification or with magnesium in refluxing methanol gave the N-H
indoles in moderate to good yields. This method for formation of indoles is both convergent and versa-
tile and uses starting materials that are conveniently prepared.
J. Heterocyclic Chem., 46, 1285 (2009).
INTRODUCTION
To the best of our knowledge, only four reports of 3-
vinylpyrroles being used in Diels-Alder reactions exist
[8,9,11,12]. Jones et al. reported the Diels-Alder reaction
of N-t-butyl-3-vinylpyrrole with DMAD and oxidation
with DDQ to give the corresponding indoles [8]. Murase et
al. reported Diels-Alder reactions of sulfur-substituted N-
methyl-3-vinylpyrrole generated in situ from the corre-
sponding 3-thioacetylpyrrole, using as the dienophile
DMAD, maleic anhydride, N-methylmaleimide, 1,4-naph-
thoquinone, and several unsymmetrical alkenes, followed
by DDQ aromatization of the indoles [11]. The Diels-Alder
adducts were not isolated, but were oxidized directly to the
indoles in a maximum of 31% yield over three steps. Xiao
and Ketcha reported Diels-Alder reactions of N-benzene-
sulfonyl-3-vinylpyrrole and ethyl 3-(1-(benzenesulfonyl)-
1H-2-pyrrolyl)acrylate with N-phenylmaleimide and ma-
leic anhydride, without taking the adducts through to the
indoles [9]. Most recently, Hodges et al. reported Diels-
Alder reactions of osmium-complexed N-methyl-3-vinyl-
pyrroles with N-phenylmaleimide to give tetrahydroin-
doles, which were then oxidized with DDQ to give the cor-
responding indoles, but difficulties with oxidation and pyr-
role polymerization were experienced [12]. In most of the
prior examples of Diels-Alder reactions of 3-vinylpyrroles,
the isolated tetrahydroindole had isomerized from the orig-
inally formed adducts, with a double bond having moved
into the five-membered ring to form the aromatic pyrrole.
In the one exception, the work by Hodges et al. [12], the
Synthesis of the indole nucleus continues to receive
much attention [1] due to its common occurrence in the
molecules of living systems and also the biological ac-
tivity exhibited in both natural [2] and synthetic [3]
indole-containing products. We have reported that tetra-
hydroindoles are available via 2-vinylpyrroles derived
from an acid-catalyzed condensation of pyrrole with
cyclic ketones, followed by in situ trapping by various
maleimides in a Diels-Alder reaction [4,5]. We recently
reported that indoles are available from oxidation of tet-
rahydroindoles synthesized by Diels-Alder reactions of
both N-H and N-alkyl-2-vinylpyrroles with a wide range
of N-substituted maleimides [6]. To expand upon this
general methodology, in a desire to find improved syn-
thetic methods towards indole and to generate novel
indoles for biological testing, we chose to study the use
of 3-vinylpyrroles as the diene in Diels-Alder reactions.
Pyrrole preferentially undergoes electrophilic attack at
its 2-position as the most stable resonance structure of
the reactive species has its greatest electron density a to
the iminium nitrogen. Therefore, 2-vinylpyrroles are the
most obviously accessible vinylated pyrroles, and there
are numerous examples of 2-vinylpyrroles being used as
dienes in Diels-Alder reactions [4,7–10]. Several of
these studies report biological activity from the resulting
class of compounds and the corresponding aromatized
indoles, particularly anti-cancer activity [4,10].
C
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W. E. Noland and N. P. Lanzatella
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Scheme 1. Synthesis of N-p-toluenesulfonyl-3-vinylpyrrole 3.
unrearranged adduct was complexed with osmium when
isolated.
of N-H-2-vinylpyrroles, whereas an N-p-toluenesulfonyl
group decreases reactivity, increases stability, and may
be removed later to give the N-H-indole derivative, or
the H can then be replaced with another group of
choice.
The synthesis of 3-vinylpyrrole was first reported, to
the best of our knowledge, in 1979 by Jones et al., by
the photoaddition of acetaldehyde and N-methylpyrrole
followed by dehydration of the resulting alcohol to N-
methyl-3-vinylpyrrole in 32% overall yield [13]. A more
efficient method uses 3-(N-t-butylpyrrole)carboxalde-
hyde in a Wittig methylenation in 55% overall yield
[14]. The t-butyl group, due to its steric bulk, directs
selective Vilsmeier-Haack formylation to the 3-position.
The most efficient method to 3-vinylate pyrrole is likely
via N-benzenesulfonylation followed by 3-acetylation
under Friedel-Crafts acylation conditions using AlCl3 as
the Lewis acid, which selectively acetylates the 3-posi-
tion [15–17]. The resulting acetylpyrrole is then reduced
and dehydrated to the 3-vinylpyrrole [9,17]. An exten-
sive study by Huffman et al. indicates that subjecting
N-p-toluenesulfonylpyrrole to Friedel-Crafts acylation
conditions using AlCl3 does not result in a Friedel-
Crafts-type acylation, but instead causes reversible for-
mation of 2- and 3-dichloroaluminum intermediates, the
latter being sterically favored, and the former possibly
experiencing a stabilizing electronic interaction between
the electrophilic aluminum and an oxygen of the N-sul-
fonyl group [18]. The predominant and more reactive 3-
substituted organoaluminum intermediate then reacts
with the acylating agent to give mainly 3-acylpyrroles.
While altering the side to which the dienophile-com-
ponent is fused in the resulting tetrahydroindole, using
3-vinylpyrroles in Diels-Alder reactions is significantly
advantageous over the use of 2-vinylpyrroles. 2-Vinyl-
pyrroles are generally volatile liquids which polymerize
or decompose on exposure to air and light, but N-p-tol-
uenesulfonyl-3-vinylpyrroles are robust crystalline solids
which are easy to store and handle. 2-Vinylpyrroles are
most efficiently made from pyrrole-2-carboxaldehyde or
from the 2-acylpyrrole via a Wittig reaction in ꢀ50%
yield over two steps from N-H-pyrrole [6,19]. In com-
parison, N-p-toluenesulfonyl-3-vinylpyrrole is generated
using the Lewis Acid-catalyzed process outlined above
in 83% yield from N-H-pyrrole over four steps, a sizable
increase in efficiency. In most of the prior examples, the
2-vinylpyrroles are N-alkylated due to the high reactivity
and tendency towards polymerization and decomposition
RESULTS AND DISCUSSION
Synthesis of starting materials. Vinylpyrrole 3 was
prepared in 83% overall yield in four steps from pyrrole
by literature methods (Scheme 1) [9,15,17,20].
Commercial p-benzoquinone 4 and 1,4-naphthoqui-
none 5 were used. N-(4-Isopropylphenyl)maleimide 6
and N-(4-phenoxyphenyl)maleimide 7 were synthesized
by reported procedures [6,21]. Flash chromatography on
silica gel, followed by recrystallization, was used to
purify the maleimides.
Diels-Alder reactions. Diels-Alder reactions of N-p-
toluenesulfonyl-3-vinylpyrrole 3 with p-benzoquinone 4,
1,4-naphthoquinone 5, N-(4-isopropylphenyl)maleimide
6, and N-(4-phenoxyphenyl)maleimide 7 in chloroform
gave compounds 8, 9, 10, and 11, respectively (Schemes 2
and 3). The reactions were monitored by TLC. While
the maleimide-containing reactions which gave adducts
10 and 11 went to completion at rt over 5 days, the
Diels-Alder reactions giving 8 and 9 required, for com-
pletion, refluxing for 48 h and 5 days, respectively. In
each reaction, the vinylpyrrole was used in slight
excess (1.1 equiv.) to simplify the required chromato-
graphic purification procedure, because the vinylpyr-
roles were always eluted first, unreacted maleimides or
quinones were eluted very close to the adducts. Chro-
matography on silica gel, followed by recrystallization,
was used to purify the adducts. Conditions for the
Diels-Alder reactions were not optimized, except that
chloroform was used as the solvent, which is based on
the considerably higher yields obtained in our earlier
work in Diels-Alder reactions with 2-vinylpyrroles in
chloroform versus toluene [6].
In Diels-Alder reactions with p-benzoquinone and
1,4-naphthoquinone, unisomerized adducts were not
isolated or detected; instead compounds 8 and 9 were
isolated, in which a double-bond had moved into the
five-membered ring, giving the more stable aromatic
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Access to Indoles via Diels-Alder Reactions of 3-Vinylpyrroles
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Scheme 2. Diels-Alder reactions of N-p-toluenesulfonyl-2-vinylpyrrole 3 with quinones 4 and 5.
pyrrole. In Diels-Alder reactions with maleimides, how-
ever, the unisomerized adducts 10 and 11 were isolated
first, and quantitative isomerization of these compounds
into the aromatic 12 and 13 occured in chloroform at rt
over a month, or over several days at reflux (Scheme 3).
Although unisomerized adducts were not isolated in our
2-vinylpyrrole work, evidence of them as intermediates
was provided by the isolation of products likely result-
ing from a Michael addition of an unisomerized adduct
with a maleimide [6]. NOE experiments were used to
confirm the stereochemistry of 10 and 11. This seems to
be the first report of the isolation of unisomerized Diels-
Alder adducts being formed from vinylpyrroles. The av-
erage yield of the Diels-Alder products 8, 9, 10, and 11
was 74%, nearly identical with the 73% average for
Diels-Alder products from 2-vinylpyrrole obtained in
chloroform in our prior work [6], although a greater
number of Diels-Alder reactions of 3-vinylpyrroles
would be needed for an accurate comparison of the rela-
tive efficiency of the two procedures.
constant of about 3.0 Hz [9,22]. For isomerized adduct
8, the 7-H proton is coupled not only to the 8-H proton
but also to the 5aa-H proton, with a coupling constant
of about 1.2 Hz [23].
Diels-Alder dimerization. In an effort to extend our
method to allow for a highly convergent synthetic step
after indole formation via a potential Suzuki coupling
[24], a Diels-Alder reaction between N-p-toluenesul-
fonyl-3-vinylpyrrole 3 and commercially available vinyl-
boronic acid 2-methyl-2,4-pentanediol ester 14 was
attempted (Scheme 4) [25]. Although Diels-Alder reac-
tions of vinylboranes [26], vinylboronates [27], and of
14 [28] are known, to the best of our knowledge they
are not reported to have occurred with vinylpyrroles. No
reaction was observed to occur in chloroform at room
temperature over 5 days, so the solution was refluxed.
After 3 days, a new TLC spot had appeared, and no fur-
ther consumption of the vinylpyrrole 3 seemed to be
occurring. Isolation of the single new product from the
remaining starting materials and purification revealed
1
For descriptions of orientation, the diastereomer with
the cis-protons at the points of diene fusion protruding
from the a-face and the fused-dienophile protruding
from the b-face will always be used; this convention is
via H NMR that the new product was in fact not the
expected Diels-Alder adduct 15 and/or 16, as it lacked
any of the characteristic aliphatic methyl groups from
vinyl boronate 14. Characterization of this product using
HRMS, COSY, and NOE studies showed it to be the
result of a formal Diels-Alder reaction between two
molecules of N-p-toluenesulfonyl-3-vinylpyrrole 3, giv-
1
also used throughout the Experimental. In the H NMR
spectra of unisomerized adducts 10 and 11, the 5a-H
proton appears as a doublet of doublet of doublet of
doublets; COSY experiments indicate that the 5a-H pro-
ton is coupled not only to the 5b-H, 4-H, and 5aa-H
protons, but also to the 8ba-H proton, with a coupling
1
ing the dimer 17 (Fig. 1). In the H NMR, the 4a-H and
4b-H protons were overlapped, which prevented distin-
guishing between them in the NOE study.
Scheme 3. Diels-Alder reactions of N-p-toluenesulfonyl-2-vinylpyrrole 3 with maleimides 6 and 7.
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W. E. Noland and N. P. Lanzatella
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Scheme 4. Attempted Diels-Alder reaction of N-p-toluenesulfonyl-3-vinylpyrrole 3 with vinylboronate 14.
Formation of dimer 17 would occur when two vinyl-
Lewis acid. This can be rationalized if one molecule
of 3 complexes with the boronate 14 acting as a Lewis
acid present at the more basic, terminal end of 3. This
may cause the terminal end of the vinylpyrrole to be
so sterically bulky as to prohibit approach by either a
free vinylpyrrole in the normal ortho/para regiochemis-
try or another Lewis acid-complexed vinylpyrrole (stat-
istically unlikely), allowing only the approach of a free
vinylpyrrole with the pyrrole ring farthest from the
complexing-Lewis acid. The electrons of the nitrogen
of the noncomplexed vinylpyrrole may then drive an
attack from the a-carbon of that pyrrole to the a-car-
bon of the vinyl group of the complexed pyrrole, the
positive charge of which is induced by complexation
with the Lewis acid (Fig. 2). This is followed by dis-
sociation of the catalyst and concomitant formation of
pyrroles approach each other with the terminal ends of
their vinyl groups nearest to one another, but would
seem to maximize proximity of repulsive like partial-
charges and to violate the ortho/para rule [29] of adduct
substitution in Diels-Alder reactions. Refluxing N-p-tol-
uenesulfonyl-3-vinylpyrrole 3 in toluene or chloroform
without vinylboronate 14 for 2 weeks produced no sign
1
of dimer 17 by H NMR and HRMS analysis; only start-
ing materials were shown to be present by 1H NMR.
Refluxing 100 mg of N-p-toluenesulfonyl-3-vinylpyrrole
3 in 10 mL of chloroform with one drop of concentrated
hydrochloric acid for several days produced no sign of
dimer 17 by TLC analysis; only starting materials were
present. It is likely that the vinylboronate acted as a
Lewis acid and activated a vinylpyrrole to form the
dimer 17.
a
bond between the terminal carbons of each
Considering the electron-rich nature of vinylpyrrole
systems, the reaction reported above seems unexpected.
Examples of compounds undergoing Diels-Alder-dimeri-
zation include butadiene [30], natural products [31], 2-
styrylindolizine [32], 2-vinylindoles [33,34], 3-vinylin-
doles [35,36], and 2-vinylpyrroles [37]. Several of these di-
meric products violate the ‘ortho/para’ rule [34,36,37],
and in each case the diene and the dienophile is con-
nected to an electron-donating substituent, the nitrogen
atom of the pyrrole ring, as in the present case, but no
Lewis acid was present. This type of ‘meta’ regioselec-
tivity in Diels-Alder reactions having electron-donating
substituents on the diene and dienophile was predicted
by Houk in 1972 using frontier molecular orbital
theory [38,39], and it has been experimentally observed
in nondimerization Diels-Alder reactions not involving
pyrrole as well (between the diene generated from ben-
zocyclobutenes with the dienophiles propyne and
ethoxyethene) [40]. As in some of the examples of
ortho/para rule violation [34,36,37,40], a steric argu-
ment may also be made to help explain the formation
of the dimer 17, especially considering that in the pres-
ent case dimer formation did not occur without the
Figure 1. Relevant NOE interactions for Diels-Alder dimer 17*.
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Access to Indoles via Diels-Alder Reactions of 3-Vinylpyrroles
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Figure 2. Formation of the 3-vinylpyrrole dimer 17.
vinylpyrrole. Then, isomerization of the double bond in
the adduct gives the observed 7-pyrrolyl-substituted tet-
rahydroindole 17. In this proposed mechanism, nucleo-
philic attack by the free pyrrole in the first step effec-
tively allows reversal of the normal polarity of the ter-
minus of its vinyl group, allowing the second carbon-
carbon bond formation, an example of umpolung [41].
Further studies are currently underway in our labs to
determine the scope of such a dimerization approach
towards indoles.
detosylate an N-tosyl compound containing such a dione
portion [49], an N-p-toluenesulfonyl-1H-indole-4,7-
dione, but some precedent exists for detosylation of
such compounds using TBAF in THF [50]. However,
1H-indole-4,7-diones may be distinguished from 20
because the carbonyls of these compounds are in more
direct conjugation with the electron-releasing nitrogen,
causing deactivation. If the conjugated dione of com-
pound 20 indeed prevented its detosylation by the means
attempted, then a masking technique could be used,
such as reduction of 20 and formation of the bis-silyl
ether [51], detosylation via conventional means, then
desilylation followed by tautomerization to the quinone
[52] to give N-H indole 24. Such a route toward 24 is
currently under investigation in our labs.
Aromatization
of
Diels-Alder
adducts.
Tetrahydroindoles 12, 13, 8, and 9 were aromatized
using MnO2 in refluxing toluene for 3–72 h, giving 18,
19, 20, and 21 in 71, 75, 78, and 72% yields, respec-
tively (Scheme 5). The most consistent and high-yield-
ing results were achieved using MnO2 generated from
manganese(II) sulfate and potassium permanganate [42],
which was also used in our 2-vinylpyrrole work [6]. The
average yield from dehydrogenations was 74%, higher
than the 54% average achieved in aromatizing the
adducts resulting from 2-vinylpyrrole, indicating that the
tosyl group may help to facilitate the reaction or provide
some degree of stability to the tetrahydroindoles during
the aromatization process [6].
Scheme 5. Aromatization and detosylation of tetrahydroindoles 8, 9,
12, and 13.
Detosylation of N-p-toluenesulfonylindoles. Detosyla-
tion of maleimide-derived indoles 18 and 19 was
accomplished by magnesium in refluxing methanol for 5
h, giving 22 and 23 in 59 and 55% yield, respectively
(Scheme 5) [43]. Detosylation of 1,4-naphthoquinone-
derived indole 21 [44] was effected by saponification
with aqueous sodium carbonate in methanol under reflux
for 6 h. With saponification of 18 and 19, competition
between removal of the p-toluenesulfonyl group and hy-
drolysis of the imide was observed. When these two
methods were applied to the p-benzoquinone-derived
indole 20, decomposition occurred with no recovery of
starting materials. Various other methods were
attempted, such as TBAF in refluxing THF/MeOH [45],
5% sodium-mercury amalgam in THF/MeOH [46], the
dilithium salt of thioglycolate in DMF [47], and concen-
trated sulfuric acid [48], but none of these methods gave
the desired N-H indole 24. The failure to achieve com-
pound 24 is likely due to the a,b-unsaturated dione por-
tion of indole 20, which is acting as a strong Michael
acceptor. An example exists of saponification failing to
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W. E. Noland and N. P. Lanzatella
Vol 46
was detosylated with magnesium in refluxing methanol,
giving the N-H indoles in moderate to good yields.
This efficient method for formation of indoles offers
high convergency and easily accessible starting
materials.
Biological activity. While participating in the Devel-
opmental Therapeutics Program at the National Cancer
Institute (NCI), we submitted eight compounds to the
NCI for a one-dose 60-human tumor cell line pre-
screen: compounds 8, 9, 12, 13, 18, 19, 20, and 21. Of
these, four compounds, 8, 9, 20, and 21, were judged by
the NCI to have sufficient activity to justify screening
with 60 human-tumor cell lines at five concentrations
with 10-fold dilutions, from 1 ꢁ 10ꢂ4 M to 1 ꢁ 10ꢂ8
M. All four of these compounds were found to have
high levels of activity against many of the 60 different
cell lines tested. Compound 8 was most active against
colon cancer HCT-116, melanoma M14, and nonsmall
cell lung cancer, with IC50’s of 67, 63, and 37 ng/mL,
respectively. Compound 9 was most active against mela-
noma M14, and leukemia cell lines CCRF-CEM and
HL-60(TB), with IC50’s of 11, 13, and 11 ng/mL,
respectively. Compound 20 was most active against
melanoma UACC-257, and leukemia cell lines MOLT-4
and SR, with IC50’s of 21, 56, and 50 ng/mL, respec-
tively. Compound 21 was most active against CNS can-
cer SF-295, ovarian cancer OVCAR-3, and melanoma
MDA-MB-435, with IC50’s of 10, 9.6, and 9.1 ng/mL,
respectively. Compounds 8 and 20 were selected by the
NCI for toxicity testing and subsequent hollow fiber
testing. Compound 8 had a maximum tolerated dose of
100 mg/Kg body wt in athymic nude mice, with death
resulting in 3 days at 200 mg/Kg body wt and 2 days at
400 mg/Kg body wt. Hollow fiber testing of compound
8 against breast cancer MDA-MB-231, nonsmall cell
lung cancer NCI-H23 and NCI-H522, colon cancer SW-
620 and COLO 205, melanoma LOX IMVI, UACC-62,
and MDA-MB-435, ovarian cancer OVCAR-3, CNS
cancer U251 and SF-295 gave a score of 4/96 with no
cell kill, below the 20/96 minimum score required for
selection for xenograft testing. Toxicity and hollow fiber
testing data for compound 20 were pending at the time
of submission of this article.
EXPERIMENTAL
General. Solvents and reagents were purchased and used as
received. Flash chromatography was performed using 230–450
mesh silica gel. MPLC refers to medium pressure liquid chro-
matography was performed using 325–635 mesh silica gel.
Ethyl acetate/hexanes were used as eluent unless otherwise
specified. TLC analyses were performed on plastic-backed
plates pre-coated with 0.2 mm silica with F254 indicator. Infra-
red spectra were recorded on a 4000 FT IR spectrometer; only
the most intense and/or diagnostic peaks are reported. High-
resolution mass spectra were recorded with a time-of-flight
instrument using electrospray ionization with PEG as an inter-
nal calibrant. For NMR spectra, chemical shifts (d) were com-
pared to the solvent. 13C NMR spectra were proton-decoupled.
Melting points are uncalibrated. Elemental analyses were per-
formed by M-H-W Laboratories, Phoenix, AZ. Petroleum ether
refers to the 35–60ꢃC boiling point fraction.
General method for Diels-Alder reactions. A mixture of
N-p-toluenesulfonyl-3-vinylpyrrole 3 (1.237 g, 0.005 mol) and
the dienophile (0.0045 mol, 1.1 equiv.) in chloroform (20 mL)
was stirred at rt for 24 h and, if TLC analysis indicated insig-
nificant consumption of the dienophile, was refluxed until the
reaction was complete. The solvent was removed using a rotat-
ing evaporator. The crude adduct was purified by MPLC using
ethyl acetate/hexanes as eluent, followed by recrystallization
from dichloromethane/petroleum ether, giving the desired
product in good yields.
General method for dehydrogenation of Diels-Alder
adducts. A mixture of the adduct (0.003 mol) and activated
MnO2 [42] (0.015 mol, 5 equiv.) in toluene (30 mL) was
stirred under reflux until the reaction was complete, as indi-
cated by TLC analysis. The mixture was cooled to rt and vac-
uum-filtered through a fine glass fritted funnel. The insoluble
manganese salts were washed using several portions of
dichloromethane until the washings ran clear (5 ꢁ 20 mL).
The combined organic filtrate and washings were evaporated
to dryness using a rotating evaporator. MPLC with ethyl ace-
tate/hexanes as eluant, followed by recrystallization from
dichloromethane/petroleum ether, gave the desired product in
fair to good yields.
CONCLUSION
N-p-Toluenesulfonyl-3-vinylpyrrole underwent endo-
addition [4 þ 2] cycloaddition reactions with p-benzo-
quinone, 1,4-naphthoquinone, and maleimides giving
isomerized aromatic tetrahydroindoles with p-benzoqui-
none and 1,4-naphthoquinone, and unisomerized tetrahy-
droindoles with maleimides. In the presence of vinylboronic
acid 2-methyl-2,4-pentanediol ester, N-tosyl-3-vinylpyr-
role underwent a Diels-Alder dimerization. Dehydro-
genation of the tetrahydroindoles with activated MnO2
in refluxing toluene gave the corresponding indoles.
The maleimide-fused indoles were detosylated via sa-
ponification, and the 1,4-naphthoquinone-fused indole
1-p-Toluenesulfonyl-4,5,5aꢀ,9aꢀ-tetrahydro-1H-benzo[g]in-
dole-6,9-dione (8). The general method with quinone 4 and
reflux for 48 h gave 8 (1.325 g, 82%) as light-yellow crystals:
mp 172–174ꢃC; 1H NMR (300 MHz, CDCl3, d) 7.74 (d, J ¼
8.4 Hz, 2H, Ts), 7.33 (d, J ¼ 8.1 Hz, 2H, Ts), 7.20 (d, J ¼
3.5 Hz, 1H, 2-H), 6.88 (d, J ¼ 10.2 Hz, 1H, 8-H), 6.70 (dd, J
¼ 10.4, 1.4 Hz, 1H, 7-H), 6.17 (d, J ¼ 3.6 Hz, 1H, 3-H), 4.84
(d, J ¼ 5.7 Hz, 1H, 9aa-H), 3.06 (ddddd, J ¼ 13.2, 5.5, 2.7,
1.4, 0.9 Hz, 1H, 5aa-H), 2.54–2.70 (m, 2H, 4a-H, 4b-H), 2.43
(s, 3H, Ts-CH3), 2.07 (dddd, J ¼ 13.6, 5.0, 2.5, 2.5 Hz, 1H,
5b-H), 1.68 (dddd, J ¼ 13.2, 13.2, 10.4, 7.4 Hz, 1H, 5aa-H);
13C NMR (75 MHz, CDCl3, d) 200.6, 196.5, 145.0, 141.5,
138.9, 136.5, 129.9, 127.2, 124.2, 123.9, 123.3, 112.6, 49.8,
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47.3, 26.3, 22.8, 21.8; IR (KBr, cmꢂ1) 3382(w), 3137(w),
3101(w), 3051(m), 2946(m), 2853(m), 1702(s), 1673(s),
1595(m), 1486(w), 1433(w), 1379(s), 1276(m), 1260(m),
1228(m), 1209(w), 1173(s), 1137(m), 1121(s), 1089(s),
1061(m), 1033(m), 986(m), 923(w), 902(w), 850(m), 813(m),
775(w), 734(w), 704(m), 673(s); HRMS m/z (M þ Naþ) calcd
378.0771, found 378.0782. Anal. Calcd for C19H17NO4S: C,
64.21; H, 4.82; N, 3.94. Found: C, 64.35; H, 4.73; N, 3.88.
1-p-Toluenesulfonyl-4,5,5aꢀ,11aꢀ-tetrahydro-1H-naphtho[2,
3-g]indole-6,11-dione (9). The general method with naphtho-
quinone 5 and reflux for 5 d gave 9 (1.235 g, 67%) as a dark-
orange powder: mp 114–116ꢃC; 1H NMR (300 MHz, CDCl3,
d) 8.11–8.17 (m, 1H, 10-H), 7.97–8.03 (m, 1H, 7-H), 7.74–
7.83 (m, 4H, 8-H, 9-H, Ts), 7.34 (d, J ¼ 8.4 Hz, 2H, Ts), 7.40
(d, J ¼ 3.3 Hz, 1H, 2-H), 6.20 (d, J ¼ 3.3 Hz, 1H, 3-H), 4.99
(d, J ¼ 5.4 Hz, 1H, 11aa-H), 3.25 (ddd, J ¼ 13.4, 5.3, 2.7 Hz,
1H, 5aa-H), 2.64–2.69 (m, 2H, 4a-H, 4b-H), 2.46 (s, 3H, Ts-
CH3), 2.13 (dddd, J ¼ 12.7, 4.1, 2.6, 1.4 Hz, 1H, 5b-H), 1.71
(dddd, J ¼ 12.7, 12.7, 8.8, 7.4 Hz, 1H, 5a-H); 13C NMR (75
MHz, CDCl3, d) 198.5, 195.5, 144.9, 136.6, 135.9, 134.8,
134.4, 133.3, 129.9, 127.3, 127.2, 127.0, 124.9, 123.8, 123.1,
112.6, 50.1, 47.4, 26.0, 23.0, 21.8; IR (KBr, cmꢂ1) 3140(w),
3067(w), 2920(m), 2853(w), 1702(s), 1687(s), 1594(m),
1485(w), 1434(w), 1400(w), 1364(s), 1291(m), 1272(m),
1243(m), 1208(m), 1175(s), 1142(m), 1127(s), 1106(m),
1089(m), 1058(w), 1043(w), 1027(w), 986(w), 903(w), 812(w),
759(w), 716(m), 703(m), 669(s), 611(w); HRMS m/z (M þ
Naþ) calcd 428.0928, found 428.0943. Anal. Calcd for
C23H19NO4S: C, 68.13; H, 4.72; N, 3.45. Found: C, 67.86; H,
4.71; N, 3.36.
3.9 Hz, 1H, 3-H), 5.56 (ddd, J ¼ 7.3, 3.7, 3.6 Hz, 1H, 4-H),
4.23 (ddd, J ¼ 6.8, 3.2, 3.2 Hz, 1H, 8ba-H), 3.99 (dd, J ¼
9.0, 7.2 Hz, 1H, 8aa-H), 3.24 (ddd, J ¼ 8.9, 7.1, 1.7 Hz, 1H,
5aa-H), 3.02 (ddd, J ¼ 15.5, 7.4, 1.4 Hz, 1H, 5b-H), 2.45 (s,
3H, Ts-CH3), 2.06 (dddd, J ¼ 15.9, 6.9, 4.0, 2.7 Hz, 1H, 5a-
H); 1H NMR (300 MHz, DMSO-d6, d) 7.80 (d, J ¼ 8.1 Hz,
2H, Ts), 7.38–7.46 (m, 4H, PhOPh), 7.15–7.21 (m, 1H,
PhOPh), 7.03–7.07 (m, 6H, PhOPh), 6.76 (d, J ¼ 3.9 Hz, 1H,
2-H), 5.80 (d, J ¼ 4.2 Hz, 1H, 3-H), 5.53 (ddd, J ¼ 7.1, 3.7,
3.7 Hz, 1H, 4-H), 4.29 (ddd, J ¼ 7.1, 3.3, 3.3 Hz, 1H, 8ba-H),
3.89 (dd, J ¼ 8.7, 7.2 Hz, 1H, 8aa-H), 3.28 (ddd, J ¼ 8.9, 7.1,
1.4 Hz, 1H, 5aa-H), 2.66 (ddd, J ¼ 15.2, 7.1, 1.7 Hz, 1H, 5b-
H), 2.40 (s, 3H, Ts-CH3), 2.12 (dddd, J ¼ 15.2, 7.1, 3.7, 3.3
Hz, 1H, 5a-H); 13C NMR (75 MHz, DMSO-d6, d) 178.9,
174.1, 157.0, 156.6, 144.8, 142.3, 138.0, 133.5, 130.7, 130.5,
129.0, 127.9, 127.8, 124.5, 119.6, 119.1, 111.9, 111.4, 59.8,
43.3, 36.9, 25.7, 21.6; IR (KBr, cmꢂ1) 3458(w), 3103(m),
3064(m), 2929(w), 2903(w), 2853(w), 1772(w), 1702(s),
1651(w), 1586(m), 1564(w), 1504(m), 1483(m), 1360(m),
1342(m), 1294(w), 1235(s), 1195(s), 1165(s), 1107(m),
1094(m), 1063(m), 1018(w), 991(w), 963(w), 912(w), 874(w),
845(m), 801(m), 730(m), 615(m); HRMS m/z (M þ Naþ)
calcd 535.1299, found 535.1311. Anal. Calcd for
C29H24N2O5S: C, 67.95; H, 4.72; N, 5.47. Found: C, 68.13; H,
4.59; N, 5.16.
7-(4-Isopropylphenyl)-1-p-toluenesulfonyl-4,5,5aꢀ,8aꢀ-tet-
rahydropyrrolo-1H,7H-benzo[g]indole-6,8-dione (12). Diels-
Alder adduct 10 (1.000 g, 2.162 mmol) was dissolved in chlo-
roform (30 mL) and refluxed for 4 d. The solvent was
removed with a rotating evaporator, giving 12 (1.000 g, quant.)
1
7-(4-Isopropylphenyl)-1-p-toluenesulfonyl-5,5aꢀ,8aꢀ,8bꢀ-
tetrahydropyrrolo-1H,7H-benzo[g]indole-6,8-dione (10). The
general method with maleimide 6 and rt for 5 d gave 10
(1.472 g, 70%) as light-orange crystals: mp 96–98ꢃC; 1H
NMR (300 MHz, CDCl3, d) 7.81 (d, J ¼ 8.4 Hz, 2H, Ts), 7.35
(d, J ¼ 8.4 Hz, 2H, Ts), 7.27 (d, J ¼ 8.4 Hz, 2H, iPrPh), 7.08
(d, J ¼ 8.4 Hz, 2H, iPrPh), 6.83 (d, J ¼ 4.2 Hz, 1H, 2-H),
5.69 (d, J ¼ 3.9 Hz, 1H, 3-H), 5.56 (ddd, J ¼ 7.4, 3.8, 3.8 Hz,
1H, 4-H), 4.23 (ddd, J ¼ 6.9, 3.3, 3.4 Hz, 1H, 8ba-H), 3.97
(dd, J ¼ 9.0, 7.2 Hz, 1H, 8aa-H), 3.23 (ddd, J ¼ 9.0, 7.2, 1.8
Hz, 1H, 5aa-H), 3.01 (ddd, J ¼ 15.5, 7.4, 1.9 Hz, 1H, 5b-H),
2.91 (septet, J ¼ 6.9 Hz, 1H, ACH(CH3)2), 2.45 (s, 3H, Ts-
CH3), 2.05 (dddd, J ¼ 15.3, 7.2, 4.1, 3.0 Hz, 1H, 5a-H), 1.23
(d, J ¼ 7.2 Hz, 6H, ACH(CH3)2); 13C NMR (75 MHz, CDCl3,
d) 178.1, 173.1, 149.4, 144.5, 142.5, 137.7, 133.8, 130.1,
129.3, 127.7, 127.2, 126.2, 110.8, 110.6, 59.5, 42.3, 36.3, 34.0,
26.1, 24.0, 21.7; IR (KBr, cmꢂ1) 3472(w), 3138(w), 3104(w),
3049(w), 2960(m), 2929(m), 2870(m), 1781(w), 1714(s),
1596(m), 1565(w), 1514(m), 1491(w), 1449(m), 1371(s),
1306(m), 1294(m), 1170(s), 1123(s), 1091(m), 1056(m),
1018(m), 991(m), 900(w), 874(w), 832(m), 812(m), 767(w),
704(m), 669(s); HRMS m/z (M þ Naþ) calcd 485.1506, found
485.1523. Anal. Calcd for C26H26N2O4S: C, 67.51; H, 5.67; N,
6.06. Found: C, 67.46; H, 5.61; N, 6.17.
as a white powder: mp 96–98ꢃC; H NMR (300 MHz, CDCl3,
d) 7.99 (d, J ¼ 8.4 Hz, 2H, Ts), 7.28–7.34 (m, 4H, Ts, iPrPh),
7.18 (d, J ¼ 8.7 Hz, 2H, iPrPh), 7.12 (d, J ¼ 3.6 Hz, 1H, 2-
H), 6.16 (d, J ¼ 3.3 Hz, 1H, 3-H), 5.02 (d, J ¼ 8.4 Hz, 1H,
8aa-H), 3.42 (ddd, J ¼ 8.6, 5.9, 5.9 Hz, 1H, 5aa-H), 2.94
(septet, J ¼ 7.1 Hz, 1H, ACH(CH3)2), 2.59 (ddd, J ¼ 16.0,
5.5, 5.5 Hz, 1H, 4a-H), 2.43 (ddd, J ¼ 16.3, 8.6, 4.6 Hz, 1H,
4b-H), 2.42 (s, 3H, Ts-CH3), 2.29 (dddd, J ¼ 13.3, 6.1, 6.1,
4.4 Hz, 1H, 5b-H), 1.99 (dddd, J ¼ 14.0, 8.3, 5.2, 4.8 Hz, 1H,
5a-H), 1.26 (d, J ¼ 6.9 Hz, 6H, ACH(CH3)2); 13C NMR (75
MHz, CDCl3, d) 178.1, 173.8, 149.4, 145.0, 136.5, 129.8,
129.5, 127.8, 127.3, 126.4, 125.6, 123.6, 123.0, 112.6, 41.2,
39.5, 34.0, 25.1, 24.0, 21.8, 21.2; IR (KBr, cmꢂ1) 3478(w),
3137(w), 3103(w), 3037(w), 2959(s), 2929(m), 2868(m),
1783(m), 1718(s), 1595(m), 1514(m), 1484(m), 1451(m),
1370(s), 1306(w), 1295(w), 1226(m), 1171(s), 1123(s),
1090(m), 1017(w), 990(m), 898(w), 873(w), 835(w), 812(m),
766(w), 702(m), 668(s); HRMS m/z (M þ Naþ) calcd
485.1506, found 485.1527. Anal. Calcd for C26H26N2O4S: C,
67.51; H, 5.67; N, 6.06. Found: C, 67.24; H, 5.68; N, 6.16.
7-(4-Phenoxyphenyl)-1-p-toluenesulfonyl-4,5,5aꢀ,8aꢀ-tetra-
hydropyrrolo-1H,7H-benzo[g]indole-6,8-dione
(13). Diels-
Alder adduct 11 (1.000 g, 1.951 mmol) was dissolved in chlo-
roform (30 mL) and refluxed for 4 d. The solvent was
removed with a rotating evaporator, giving 13 (1.000 g, quant.)
as an orange powder: mp 217–218ꢃC; 1H NMR (300 MHz,
CDCl3, d) 7.97 (d, J ¼ 8.4 Hz, 2H, Ts), 7.30–7.41 (m, 4H, Ts,
PhOPh), 7.13–7.25 (m, 4H, PhOPh), 7.02–7.08 (m, 4H,
PhOPh, 2-H), 6.16 (d, J ¼ 3.3 Hz, 1H, 3-H), 5.02 (d, J ¼ 8.4
Hz, 1H, 8aa-H), 3.43 (ddd, J ¼ 8.6, 5.9, 5.9 Hz, 1H, 5aa-H),
2.59 (ddd, J ¼ 16.1, 5.4, 5.4 Hz, 1H, 4a-H), 2.43 (ddd, J ¼
7-(4-Phenoxyphenyl)-1-p-toluenesulfonyl-5,5aꢀ,8aꢀ,8bꢀ-
tetrahydropyrrolo-1H,7H-benzo[g]indole-6,8-dione (11). The
general method with maleimide 7 and rt for 5 d gave 11
(1.794 g, 77%) as white crystals: mp 217–218ꢃC; 1H NMR
(300 MHz, CDCl3, d) 7.80 (d, J ¼ 8.1 Hz, 2H, Ts), 7.32–7.40
(m, 4H, Ts, PhOPh), 7.14–7.17 (m, 3H, PhOPh), 6.99–7.05
(m, 4H, PhOPh), 6.85 (d, J ¼ 3.9 Hz, 1H, 2-H), 5.69 (d, J ¼
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1292
W. E. Noland and N. P. Lanzatella
Vol 46
16.2, 8.6, 4.7 Hz, 1H, 4b-H), 2.42 (s, 3H, Ts-CH3), 2.29
(dddd, J ¼ 13.4, 6.0, 6.0, 4.3 Hz, 1H, 5b-H), 1.99 (dddd, J ¼
13.6, 8.5, 5.4, 4.7 Hz, 1H, 5a-H); 13C NMR (75 MHz, CDCl3,
d) 178.0, 173.8, 157.6, 156.5, 145.0, 136.5, 130.0, 129.9,
128.0, 127.7, 126.6, 125.7, 124.0, 123.7, 122.8, 119.6, 118.8,
112.6, 41.2, 39.5, 25.0, 21.8, 21.2; IR (KBr, cmꢂ1) 3464(w),
3146(w), 3111(m), 3065(m), 2943(m), 2850(w), 1773(w),
1707(s), 1586(m), 1505(m), 1484(m), 1445(w), 1397(m),
1372(m), 1335(m), 1293(w), 1232(s), 1203(m), 1187(s),
1167(s), 1120(m), 1091(m), 1017(w), 989(w), 916(w), 901(w),
885(m), 811(m), 782(m), 743(w), 703(m), 646(m); HRMS m/z
(M þ Naþ) calcd 535.1299, found 535.1318. Anal. Calcd for
C29H24N2O5S: C, 67.95; H, 4.72; N, 5.47. Found: C, 67.93; H,
4.64; N, 5.26.
1722(s), 1619(w), 1595(m), 1537(w), 1515(m), 1453(w),
1424(m), 1402(s), 1374(s), 1309(w), 1266(m), 1247(m),
1226(w), 1190(m), 1173(s), 1150(s), 1124(m), 1093(s),
1056(w), 1016(m), 991(m), 880(w), 839(m), 811(m), 750(m),
739(m), 711(m), 666(s), 608(m); HRMS m/z (M þ Naþ) calcd
481.1193, found 481.1206. Anal. Calcd for C26H22N2O4S: C,
68.10; H, 4.84; N, 6.11. Found: C, 68.02; H, 5.03; N, 6.19.
7-(4-Phenoxyphenyl)-1-p-toluenesulfonyl-1H,7H-benzo[g]
indole-6,8-dione (19). The general method with tetrahydroin-
dole 13 and reflux for 3 d gave 19 (1.144 g, 75%) as yellow
1
crystals: mp 216–217ꢃC; H NMR (300 MHz, CDCl3, d) 8.12
(d, J ¼ 3.6 Hz, 1H, 2-H), 8.00 (d, J ¼ 7.8 Hz, 1H, 4-H), 7.94
(d, J ¼ 8.1 Hz, 2H, Ts), 7.88 (d, J ¼ 7.8 Hz, 1H, 5-H), 7.31–
7.45 (m, 6H, Ts, PhOPh), 7.06–7.20 (m, 5H, PhOPh), 6.91 (d,
J ¼ 3.9 Hz, 1H, 3-H), 2.43 (s, 3H, Ts-CH3); 13C NMR (75
MHz, DMSO-d6, d) 167.4, 164.7, 157.1, 156.6, 145.3, 138.6,
136.5, 134.7, 130.8, 130.3, 130.0, 129.9, 128.8, 128.1, 127.6,
127.4, 124.6, 119.8, 118.9, 118.8, 117.4, 109.4, 21.6; IR (KBr,
1-p-Toluenesulfonyl-7ꢀ-(1-p-toluenesulfonyl-1H-pyrrol-3-
yl)-4,5,6,7ꢁ-tetrahydro-1H-indole (17). A mixture of N-p-tol-
uenesulfonyl-3-vinylpyrrole 3 (1.237 g, 0.005 mol) and vinyl-
boronic acid 2-methyl-2,4-pentanediol ester 14 (693 mg,
0.0045 mol, 1.1 equiv.) in chloroform (20 mL) was stirred
under reflux for 3 d, at which point TLC analysis indicated
that a new spot had formed and no starting materials were
being consumed. The solvent was removed using a rotating
evaporator. The crude mixture was purified by MPLC with
ethyl acetate/hexanes as eluant, followed by recrystallization
from dichloromethane/petroleum ether, giving 17 (210 mg,
cmꢂ1
)
3159(m), 3114(m), 1773(w), 1716(s), 1587(w),
1536(w), 1506(s), 1487(m), 1454(w), 1428(m), 1398(m),
1365(s), 1320(w), 1266(m), 1233(s), 1178(m), 1147(m),
1121(m), 1093(m), 1017(m), 990(m), 938(w), 909(w), 864(w),
830(m), 806(m), 777(w), 740(m), 665(m); HRMS m/z (M þ
Naþ) calcd 531.0986, found 531.1006. Anal. Calcd for
C29H20N2O5S: C, 68.49; H, 3.96; N, 5.51. Found: C, 68.57; H,
4.03; N, 5.33.
1
9%) as a white powder: mp 157–158ꢃC; H NMR (300 MHz,
CDCl3, d) 7.61 (d, J ¼ 8.4 Hz, 2H, 10-Ts), 7.31 (d, J ¼ 8.4
Hz, 2H, 1-Ts), 7.26 (d, J ¼ 8.4 Hz, 2H, 10-Ts), 7.26 (d, J ¼
3.3 Hz, 1H, 2-H), 7.12 (d, J ¼ 8.1 Hz, 2H, 1-Ts), 6.87 (dd, J
¼ 3.3, 2.4 Hz, 1H, 50-H), 6.20 (dd, J ¼ 2.4, 2.1 Hz, 1H, 20-H),
6.12 (d, J ¼ 3.3 Hz, 1H, 3-H), 6.02 (dd, J ¼ 3.2, 1.7 Hz, 1H,
40-H), 4.41 (dd, J ¼ 5.1, 2.4 Hz, 1H, 7b-H), 2.31–2.54 (m,
2H, 4-H), 2.41 (s, 3H, Ts-CH3), 2.39 (s, 3H, Ts-CH3), 1.84
(dddd, J ¼ 13.1, 13.1, 5.2, 3.1 Hz, 1H, 6b-H), 1.69 (dddd, J ¼
12.8, 3.8, 2.8, 2.8 Hz, 1H, 6a-H), 1.44–1.60 (m, 1H, 5b-H),
1.24–1.48 (m, 1H, 5a-H); 13C NMR (75 MHz, CDCl3, d)
144.8, 144.6, 136.4, 135.8, 132.8, 130.1, 130.0, 129.6, 126.6,
124.0, 121.9, 120.3, 118.9, 114.4, 111.9, 31.1, 31.0, 22.9,
1-p-Toluenesulfonyl-1H-benzo[g]indole-6,9-dione (20). The
general method with tetrahydroindole 8 and reflux for 24 h
gave 20 (822 mg, 78%) as light-orange crystals: mp 186–
1
187ꢃC; H NMR (300 MHz, CDCl3, d) 8.08 (d, J ¼ 8.08 Hz,
1H, 4-H), 7.91 (d, J ¼ 3.9 Hz, 1H, 2-H), 7.89 (d, J ¼ 8.4 Hz,
1H, 5-H), 7.89 (J ¼ 8.7 Hz, 2H, Ts), 7.41 (d, J ¼ 8.4 Hz, 2H,
Ts), 6.97 (d, J ¼ 10.2 Hz, 1H, 8-H), 6.90 (d, J ¼ 10.2 Hz,
1H, 7-H), 6.83 (d, J ¼ 3.9 Hz, 1H, 3-H), 2.49 (s, 3H, Ts-
1
CH3); H NMR (300 MHz, acetone-d6, d) 8.11 (d, J ¼ 3.9 Hz,
1H, 2-H), 8.08 (d, J ¼ 8.4 Hz, 1H, 4-H), 8.04 (d, J ¼ 8.1 Hz,
1H, 5-H), 7.94 (d, J ¼ 8.4 Hz, 2H, Ts), 7.50 (d, J ¼
8.1 Hz, 2H, Ts), 7.09 (d, J ¼ 10.2 Hz, 1H, 8-H), 7.04 (d, J ¼
3.6 Hz, 1H, 3-H), 7.01 (d, J ¼ 10.5 Hz, 1H, 7-H), 2.45 (s, 3H,
Ts-CH3); 13C NMR (75 MHz, DMSO-d6, d) 185.3, 184.8,
145.3, 139.4, 138.0, 137.8, 136.9, 136.7, 131.6, 130.1, 129.5,
21.72, 21.69, 17.0; IR (KBr, cmꢂ1
) 3144(m), 3113(m),
3065(w), 3031(w), 2944(s), 2925(s), 2856(m), 1596(m),
1490(m), 1473(w), 1442(w), 1424(w), 1401(w), 1365(s),
1243(m), 1232(m), 1175(s), 1146(m), 1124(s), 1094(s),
1056(s), 1019(w), 996(m), 953(w), 905(w), 874(w), 855(w),
799(m), 780(m), 775(m), 748(m), 722(m), 673(s), 630(w);
HRMS m/z (M þ Naþ) calcd 517.1227, found 517.1241.
Anal. Calcd for C26H26N2O4S2: C, 63.13; H, 5.30; N, 5.66.
Found: C, 62.91; H, 5.25; N, 5.71.
127.4, 127.3, 123.2, 122.5, 110.8, 21.6; IR (KBr, cmꢂ1
)
3311(m), 3153(m), 3116(w), 3065(m), 1718(w), 1660(s),
1609(m), 1594(m), 1533(m), 1494(w), 1459(w), 1415(w),
1380(m), 1354(s), 1301(s), 1282(m), 1252(m), 1241(w),
1189(m), 1163(s), 1119(m), 1088(m), 1070(s), 997(m), 967(w),
956(w), 882(w), 860(w), 831(m), 810(m), 756(w), 720(m),
666(s), 622(w); HRMS m/z (M þ Naþ) calcd 374.0458, found
374.0464. Anal. Calcd for C19H13NO4S: C, 64.95; H, 3.73; N,
3.99. Found: C, 64.82; H, 4.10; N, 4.10.
7-(4-Isopropylphenyl)-1-p-toluenesulfonyl-1H,7H-benzo[g]
indole-6,8-dione (18). The general method with tetrahydroin-
dole 12 and reflux for 3 h gave 18 (977 mg, 71%) as a white
1
powder: mp 106–108ꢃC; H NMR (300 MHz, CDCl3, d) 8.10
1-p-Toluenesulfonyl-1H-naphtho[2,3-g]indole-6,11-dione (21).
The general method with tetrahydroindole 9 and reflux for
24 h gave 21 (867 mg, 72%) as light-orange crystals: mp 139–
(d, J ¼ 3.9 Hz, 1H, 2-H), 8.00 (d, J ¼ 8.1 Hz, 1H, 4-H), 7.94
(d, J ¼ 8.4 Hz, 2H, Ts), 7.88 (d, J ¼ 7.8 Hz, 1H, 5-H), 7.35
(d, J ¼ 8.4 Hz, 2H, iPrPh), 7.29 (d, J ¼ 8.7 Hz, 4H, iPrPh,
Ts), 6.91 (d, J ¼ 3.9 Hz, 1H, 3-H), 2.97 (septet, J ¼ 6.9 Hz,
1H, ACH(CH3)2), 2.43 (s, 3H, Ts-CH3), 1.29 (d, J ¼ 6.9 Hz,
6H, ACH(CH3)2); 13C NMR (75 MHz, CDCl3, d) 167.5,
164.6, 148.7, 144.8, 138.4, 136.5, 133.6, 129.73, 129.68,
129.5, 128.2, 127.7, 127.6, 127.1, 126.7, 118.4, 117.3, 108.0,
34.0, 24.0, 21.8; IR (KBr, cmꢂ1) 3648(w), 3475(w), 3154(w),
3123(w), 3070(w), 2959(s), 2901(m), 2871(m), 1776(m),
1
140ꢃC; H NMR (300 MHz, CDCl3, d) 381 (d, J ¼ 8.1 Hz, 1H,
4-H), 8.26–8.28 (m, 1H, 8-H), 8.14–8.17 (m, 1H, 9-H), 7.91–
7.95 (m, 4H, Ts, 2-H, 5-H), 7.77–7.81 (m, 2H, 7-H, 10-H),
7.43 (d, J ¼ 7.8 Hz, 2H, Ts), 6.84 (d, J ¼ 3.6 Hz, 1H, 3-H),
2.51 (s, 3H, Ts-CH3); 13C NMR (75 MHz, DMSO-d6, d)
184.1, 182.6, 145.4, 137.8, 136.8, 135.1, 134.8, 134.7, 133.0,
132.1, 130.7, 130.1, 127.7, 127.6, 127.4, 127.0, 126.9, 125.2,
123.1, 110.8, 21.7; IR (KBr, cmꢂ1
) 3180(m), 3066(m),
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Access to Indoles via Diels-Alder Reactions of 3-Vinylpyrroles
1293
2915(w), 1668(s), 1593(m), 1529(w), 1458(w), 1412(w),
1379(w), 1352(m), 1324(m), 1286(s), 1258(m), 1195(w),
1172(m), 1130(w), 1095(m), 1044(w), 1014(m), 955(w),
884(w), 851(w), 811(w), 737(w), 715(m), 705(w), 669(m),
636(w); HRMS m/z (M þ Naþ) calcd 424.0615, found
424.0622. Anal. Calcd for C23H15NO4S: C, 68.81; H, 3.77; N,
3.49. Found: C, 68.70; H, 3.79; N, 3.51.
tered on a fritted-glass funnel, and the remaining solids were
washed with dichloromethane (3 ꢁ 10 mL). The filtrate and
washings were diluted with water (50 mL), and extracted with
dichloromethane (3 ꢁ 10 mL). The dichloromethane was
washed with saturated aqueous sodium bicarbonate (10 mL),
water (10 mL), and brine (10 mL), and dried over anhydrous
sodium sulfate. The solvent was removed using a rotating
evaporator. The crude product was purified by MPLC with
ethyl acetate/hexanes as eluent, and recrystallized from
dichloromethane/petroleum ether, giving 23 (38 mg, 55%) as
7-(4-Isopropylphenyl)-1H,7H-benzo[g]indole-6,8-dione (22).
Forty mesh magnesium metal powder (245 mg, 101 mmol, 20
equiv.) was ground with a mortar and pestle by hand for 1
min, and then placed immediately in anhydrous methanol (20
mL, ꢄ0.100% water). The indole 18 (231 mg, 0.504 mmol)
was added, and the mixture was stirred under reflux for 5 h, at
which time TLC analysis indicated that the starting materials
were completely converted. The mixture was cooled to rt, vac-
uum-filtered on a fritted-glass funnel, and the remaining solids
were washed several times with dichloromethane (3 ꢁ 20
mL). The filtrate and washings were diluted with water (100
mL), and extracted with dichloromethane (3 ꢁ 20 mL). The
dichloromethane was washed with saturated aqueous sodium
bicarbonate (20 mL), water (20 mL), and brine (20 mL), and
dried over anhydrous sodium sulfate. The solvent was removed
using a rotating evaporator. The crude product was purified
using MPLC with ethyl acetate/hexanes as eluent, and recrys-
tallized from dichloromethane/petroleum ether, giving 22 (90
1
yellow crystals: mp 206–207ꢃC; H NMR (300 MHz, DMSO-
d6, d) 12.19 (s, 1H, 1-H), 8.05 (d, J ¼ 7.8 Hz, 1H, 4-H), 7.70
(dd, J ¼ 2.9, 2.9 Hz, 1H, 2-H), 7.56 (d, J ¼ 8.1 Hz, 1H, 5-H),
7.42–7.51 (m, 4H, PhOPh), 7.09–7.23 (m, 5H, PhOPh), 6.76
(dd, J ¼ 3.0, 1.8 Hz, 1H, 3-H); 13C NMR (75 MHz, DMSO-
d6, d) 169.0, 167.9, 156.7, 135.5, 132.3, 130.8, 129.7, 129.4,
127.8, 126.8, 125.6, 124.5, 119.7, 119.0, 114.0, 105.0, 104.3,
103.7; IR (KBr, cmꢂ1) 3346(bs), 2960(m), 2922(s), 2853(m),
1761(m), 1698(s), 1590(w), 1509(m), 1486(m), 1447(m),
1392(m), 1368(m), 1332(w), 1291(w), 1245(m), 1159(w),
1109(m), 1074(m), 1009(w), 871(w), 828(w), 803(w), 756(w),
722(w); HRMS m/z (M þ Naþ) calcd for C22H14N2O3:
377.0897, found 377.0891.
1H-Naphtho[2,3-g]indole-6,11-dione (25) [44]. A mixture
of indole 21 (105 mg, 0.262 mmol), saturated aqueous sodium
carbonate (10 mL), and methanol (10 mL) were stirred under
reflux for 6 h, at which time TLC analysis indicated complete
conversion of the starting materials. The mixture was cooled
to rt, diluted with water (100 mL), and extracted with
dichloromethane (3 ꢁ 20 mL). The dichloromethane was
washed with saturated aqueous ammonium chloride (20 mL),
and brine (20 mL), and dried over anhydrous sodium sulfate.
The solvent was removed using a rotating evaporator, and the
product was recrystallized from dichloromethane/petroleum
ether, giving 25 (51 mg, 79%) as light-orange crystals: mp
205–206ꢃC; 1H NMR (300 MHz, CDCl3, d) 10.66 (s, 1H, 1-
H), 8.07 (d, J ¼ 8.4 Hz, 1H, 4-H), 8.00 (d, J ¼ 8.1 Hz, 1H, 5-
H), 8.23–8.34 (m, 2H, 8-H, 9-H), 7.75–7.81 (m, 2H, 7-H, 10-
H), 7.57 (dd, J ¼ 3.0, 2.4 Hz, 1H, 2-H), 6.68 (dd, J ¼ 3.3, 1.8
Hz, 1H, 3-H); 13C NMR (75 MHz, DMSO-d6, d) 185.0, 183.5,
135.0, 134.8, 134.70, 134.65, 133.8, 133.3, 132.8, 128.0,
1
mg, 59%) as bright-yellow crystals: mp 185–186ꢃC; H NMR
(300 MHz, CDCl3, d) 9.48 (s, 1H, 1-H), 7.99 (d, J ¼ 8.1 Hz,
1H, 4-H), 7.69 (d, J ¼ 8.1 Hz, 1H, 5-H), 7.49 (dd, J ¼ 3.0,
2.4 Hz, 1H, 2-H), 7.41 (d, J ¼ 8.1 Hz, 2H, iPrPh), 7.38 (d, J
¼ 8.1 Hz, 2H, iPrPh), 6.74 (dd, J ¼ 3.3, 1.8 Hz, 1H, 3-H),
2.99 (septet, J ¼ 7.1 Hz, 1H, ACH(CH3)2), 1.31 (d, J ¼ 7.2
1
Hz, 6H, ACH(CH3)2); H NMR (300 MHz, DMSO-d6, d) 2.19
(s, 1H, 1-H), 8.04 (d, J ¼ 7.8 Hz, 1H, 4-H), 7.69 (dd, J ¼ 2.9,
2.9 Hz, 1H, 2-H), 7.54 (d, J ¼ 7.8 Hz, 1H, 5-H), 7.40 (d, J ¼
9.0 Hz, 2H, iPrPh), 7.37 (d, J ¼ 9.0 Hz, 2H, iPrPh), 6.75 (dd
J ¼ 3.2, 1.7 Hz, 1H, 3-H), 2.96 (septet, J ¼ 6.9 Hz, 1H,
ACH(CH3)2), 1.25 (d, J ¼ 6.9 Hz, 6H, ACH(CH3)2); 1H
NMR (300 MHz, acetone-d6, d) 11.22 (s, 1H, 1-H), 8.10 (d, J
¼ 7.8 Hz, 1H, 4-H), 7.77 (d, J ¼ 2.7, 2.7 Hz, 1H, 2-H), 7.60
(d, J ¼ 7.8 Hz, 1H, 5-H), 7.46 (d, J ¼ 9.0 Hz, 2H, iPrPh),
7.42 (d, J ¼ 8.7 Hz, 2H, iPrPh), 6.82 (dd, J ¼ 3.2, 2.0 Hz,
1H, 3-H), 3.02 (septet, J ¼ 7.1 Hz, 1H, ACH(CH3)2), 1.31 (d,
J ¼ 6.9 Hz, 6H, ACH(CH3)2); 13C NMR (75 MHz, DMSO-d6,
d) 169.0, 168.0, 148.5, 135.5, 132.3, 130.4, 129.3, 127.9,
127.3, 126.8, 125.6, 115.0, 114.0, 103.7, 33.8, 24.4; IR
(KBr, cmꢂ1) 3392(bs), 3115(w), 3041(w), 2965(m), 2873(m),
1764(m), 1702(s), 1603(w), 1579(w), 1511(s), 1481(m),
1447(m), 1414(m), 1390(s), 1366(s), 1330(m), 1294(m),
1241(m), 1229(m), 1160(w), 1128(w), 1098(s), 1082(m),
971(w), 944(w), 888(w), 851(m), 825(m), 796(w), 762(m),
730(m), 670(m); HRMS m/z (M þ Naþ) calcd 327.1105,
found 327.1102. Anal. Calcd for C19H16N2O2: C, 74.98; H,
5.30; N, 9.20. Found: C, 74.78; H, 5.16; N, 9.21.
127.6, 127.2, 126.7, 118.0, 117.8, 103.2; IR (KBr, cmꢂ1
)
3095(w), 2960(m), 2923(m), 2852(w), 1719(w), 1668(s),
1660(m), 1590(m), 1572(w), 1545(w), 1487(m), 1445(w),
1405(w), 1329(m), 1289(s), 1235(w), 1199(w), 1158(m),
1090(s), 1048(m), 1008(m), 898(w), 844(w), 816(m), 724(s),
716(s), 638(w); HRMS m/z (M þ Naþ) calcd 270.0526, found
270.0538. Anal. Calcd for C16H9NO2: C, 77.72; H, 3.67; N,
5.67. Found: C, 77.74; H, 3.80; N, 5.49.
1H and 13C NMR spectra for 8, 9, 10, 11, 12, 13, 17, 18,
19, 20, 21, 22, 23, and 25. This material is available online
free of charge (see Supporting Information).
7-(4-Phenoxyphenyl)-1H,7H-benzo[g]indole-6,8-dione (23).
Forty mesh magnesium metal powder (96 mg, 933 mmol, 20
equiv.) was ground with a mortar and pestle by hand for 1
min, and then placed immediately in anhydrous methanol (10
mL, ꢄ0.100% water). The indole 19 (100 mg, 0.196 mmol)
was added, and the mixture was stirred under reflux for 5 h, at
which time TLC analysis indicated complete conversion of the
starting materials. The mixture was cooled to rt, vacuum-fil-
Acknowledgments. N.P.L. thanks the Wayland E. Noland
Research Fund for generous financial support of this project.
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