Investigations of the reaction mechanisms of 1,2-indanediones with amino acids

Article abstract of DOI:10.1021/jo0105179

The reaction mechanisms of amino acids with a new class of fluorogenic reagents were investigated. The structures of colored and fluorescent species formed in these reactions were partially confirmed by experimental evidence. Reaction intermediates, C-N-C 1,3-dipoles derived from imines, were trapped with dipolarophiles in 3 + 2 cycloadditions to form spiropyrrolidines.

Full text of DOI:10.1021/jo0105179

7
666
J . Org. Chem. 2001, 66, 7666-7675
In vestiga tion s of th e Rea ction Mech a n ism s of 1,2-In d a n ed ion es
w ith Am in o Acid s
Olga Petrovskaia, Bruce M. Taylor, Diane B. Hauze, Patrick J . Carroll, and
Madeleine M. J oulli e´ *
Department of Chemistry, University of Pennsylvania, 231 South 34th Street,
Philadelphia, Pennsylvania 19104-6323
mjoullie@sas.upenn.edu
Received May 22, 2001
The reaction mechanisms of amino acids with a new class of fluorogenic reagents were investigated.
The structures of colored and fluorescent species formed in these reactions were partially confirmed
by experimental evidence. Reaction intermediates, C-N-C 1,3-dipoles derived from imines, were
trapped with dipolarophiles in 3 + 2 cycloadditions to form spiropyrrolidines.
In tr od u ction
The growing need for reagents that allow the identi-
Sch em e 1
fication of latent fingerprints on paper led us to inves-
tigate novel reagents for this purpose. Ninhydrin (1,
Scheme 1) has been the reagent of choice for many years,
mainly due to low cost and ease of use.1 However,
chromogenic (colored) imaging has long been considered
less sensitive than fluorogenic (fluorescent) imaging for
a variety of reasons, and there is a growing demand for
fluorogenic reagents.
Fluorogenic reagents such as DFO (1,8-diazafluo-
renone), NBD-Cl, dansyl chloride, and fluorescein can
produce extremely good results. However, the reagent of
choice over the past few years has been DFO because of
its reasonably long wavelength emission and its ability
to differentiate between amines and amino acids. Upon
reaction with amino acids, this reagent affords a fluo-
rescent product that offers high quantum yield, good
stability, and a reasonable Stokes shift that is beyond
Ba ck gr ou n d
2
the background luminescence of most paper types. We
Amino acids are known to undergo Strecker degrada-
tion in the presence of aldehydes and ketones. In the
overall transformation, the aldehyde or ketone is reduced
to an amine, whereas the amino acid is decarboxylated
and converted to an aldehyde. Shoenberg and Moubacher
have reported new fluorogenic reagents, 1,2-indanedi-
ones, that offer the same desirable properties with the
added benefits of being more affordable, more soluble,
and easier to use.3
7
-5
Modifications of reagents in order to improve the color/
fluorescence of the reaction products is best achieved by
a complete understanding of the nature of the reaction.
While the ninhydrin/amino acid reaction has been well
8,9
gave a general outline of this reaction. The proposed
mechanism was consistent with experimental observa-
tions that both amino acids and amines with an R-hy-
drogen can reduce ketones and aldehydes. Later Fried-
man and co-workers devised mechanisms for the reactions
of ninhydrin with amines and amino acids (Scheme 1).
The authors accounted for the observed difference in the
respective reaction rates.1
1
6
investigated and is still the subject of some reports, the
,2-indanedione reaction with amines and amino acids
1
has not been elucidated. We now present our attempts
to understand the reaction mechanism of 1,2-indanedi-
ones and amino acids.
0-12
As early as 1970 an alternative mechanistic interpre-
tation of Strecker degradation was offered by Rizzi. This
1
3
(
1) J oulli e´ , M. M.; Thompson, T. R.; Nemeroff, N. H. Tetrahedron
991, 47, 8791-8830.
2) Grigg, R.; Mongkolaussavaratana, T.; Pounds, C. A. Tetrahedron
Lett. 1990, 31, 7215-7218
3) Ramotowski, R.; Cantu, A.; J oulli e´ , M. M.; Petrovskaia, O.
Fingerprint Whorld 1997, 23, 131-140.
4) Hauze, D. B.; Petrovskaia, O.; Taylor, B.; J oulli e´ , M. M.;
1
(7) Strecker, A. Ann. Chim. 1862, 123, 363-365.
(8) Schoenberg, A.; Moubasher, R.; Mostafa, A. J . Chem. Soc. 1948,
176-182.
(9) Schoenberg, A.; Moubacher, R. Chem. Rev. 1952, 50, 261-277.
(10) Friedman, M.; Siegel, C. W. Biochemistry 1966, 5, 478-485.
(11) Friedman, M. Can. J . Chem. 1967, 45, 2271-2275.
(12) Friedman, M.; Williams, L. D. Bioorg. Chem. 1974, 3, 267-
280.
(
(
(
Ramotowski, R.; Cantu, A. A. J . Forensic Sci. 1998, 43, 744-747.
(
(
5) J oulli e´ , M. M.; Petrovskaia, O. CHEMTECH 1998, 28, 41-44.
6) Breur, B.; Breur, H. Prax. Naturwiss., Chem. 1996, 45, 18-20.
(13) Rizzi, G. P. J . Org. Chem. 1970, 35, 2069-2072.
1
0.1021/jo0105179 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/16/2001

Reaction of 1,2-Indanediones with Amino Acids
J . Org. Chem., Vol. 66, No. 23, 2001 7667
Sch em e 2
Sch em e 5
Sch em e 3
Sch em e 6
Sch em e 4
author reported chemical evidence for resonance-stabi-
lized azomethine ylide formation in the reactions of
sarcosine with benzophenone or benzaldehyde. The azo-
methine ylide (a C-N-C 1,3-dipole) is generated by
decarboxylation of an iminium zwitterion. It reacts with
excess ketone or aldehyde in a 3 + 2 cycloaddition
reaction to yield oxazolidines that can be isolated and
characterized (Scheme 2).
al. have observed glycine to form dipoles via deprotona-
tion (Scheme 5). The observation involved direct depro-
tonation of a zwitterion with an external base, but the
initial intramolecular deprotonation of imines in the
ninhydrin reaction is a possibility.16 This deprotonation
can be also described as a 1,5-shift. The concept of a 1,5-
shift facilitating dipole formation was applied not only
to amino acid reactions, but to reactions of primary and
secondary amines as well.17 The carbonyl compound in
this case contains a OdC-CdX moiety, where the CdX
group can be a part of an aldehyde, ketone, amide, ester,
or a heterocycle, such as pyridine or thiazole. The role of
the CdX group is 2-fold: it enables the proton transfer
and increases the partial positive charge on the reactive
carbonyl.
Once formed, a 1,3-dipole can undergo an internal or
solvent-assisted 1,2-proton shift to yield either the parent
imine or its regioisomer. These imines can then undergo
hydrolysis resulting in either regeneration of the initial
ketone or in its reduction to the corresponding amine.
When ninhydrin (1) plays the role of the initial ketone,
it is reduced to 2-amino-1,3-indanedione (2, Scheme 6).
Later Grigg and co-workers extensively investigated
the mechanistic aspects and the scope of C-N-C dipole
formation from imines.14 Decarboxylation of the initial
imine formed in the ninhydrin reaction may be the major
route to a 1,3-dipole. This dipole was trapped in a 3 + 2
cycloaddition reaction with N-phenyl maleimide as di-
polarophile (Scheme 3).
The species that undergoes decarboxylation in the
ninhydrin-amino acid reaction may exist not only in an
open form, but also in a cyclic, oxazolidinone form.
Although oxazolidinones were not detected in ninhydrin
reactions, they are known to form in the reactions of other
carbonyl compounds with R-amino acids. Several oxazo-
lidinones have been isolated and shown to undergo
concerted cycloreversion reactions yielding carbon dioxide
and the corresponding 1,3-dipoles upon heating (Scheme
1
5
4
).
A less common pathway of C-N-C dipole formation
in the ninhydrin-amino acid reaction is via deprotona-
tion of parent imines, without decarboxylation. Grigg et
(
14) Grigg, R.; Sridharan, V. In Advances in Cycloaddition; Curran,
D. P., Ed.; J AI Press: Greenwich, CT, 1993; Vol. 3, pp 161-204.
15) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J . Am. Chem.
Soc. 1983, 105, 5390-5398.
(16) Ardill, H.; Grigg, R.; Sridharan, V.; Surendrakumar, S.; Thia-
patangul, S.; Kanajun, S. J . Chem. Soc., Chem. Commun. 1986, 602-
604.
(
(17) Grigg, R. Chem. Soc. Rev. 1987, 16, 89-121.

7
668 J . Org. Chem., Vol. 66, No. 23, 2001
Petrovskaia et al.
Sch em e 7
F igu r e 1. Geometric Isomers of -C-N-C- 1,3-Dipoles.
such as malonic acid dinitrile attack 1,2-indanediones at
the C-2 carbonyl.21
It has been suggested in the literature that oxygen
nucleophiles (alcohols) may display the same type of
reactivity with 1,2-indanediones, but no hemiketals were
isolated. We have obtained 2,2-dimethoxy-1-indanone (9)
by treating 8 with methanol at reflux, in the presence of
a catalytic amount of acetic acid (Scheme 8). The struc-
tural assignment was confirmed by the presence of NOE
between the methyl protons of the ketal and the meth-
ylene protons at C-3.
2
-Amino-1,3-indanedione (2) reacts with excess nin-
hydrin to yield an imine (3), which in turn can undergo
fast deprotonation to form the anionic chromophore
Ruhemann’s purple (4), a highly stabilized aza-allylic
anion with a high molar extinction coefficient (Scheme
6
). It is the formation of Ruhemann’s purple that allows
2
-Thiosemicarbazones and 2-oximes are known to form
one to visually detect patterns of amino acid distribution
on surfaces, thus ensuring applications of ninhydrin in
forensic science for latent fingerprint detection.
Imine 3 is not a stable form of protonated Ruhemann’s
purple. Experiments conducted by Grigg and co-workers
demonstrated that the protonated form of Ruhemann’s
purple exists as a 1,3-dipole (5, Scheme 6) and displays
the corresponding reactivity.18
in the reactions of 1,2-indanediones with thiosemicarba-
zides and hydroxylamine. Similarly, the reaction of
22
23
4
,5-methylenedioxy-1,2-indanedione with 2-(3-hydroxy-
2
4,25
4-methoxyphenyl)ethylamine generated the 2-imine.
The reaction of 1,2-indanedione with 3,5-dimethoxy-
aniline in benzene afforded several products. The initial
mode of addition occurred through attack of nitrogen at
the C-2 position of the 1,2-indanedione generating an
2
6
1
,8-Diazafluoren-9-one (6, DFO, Scheme 7), a reagent
enamine which underwent subsequent reactions. The
only known example of a 1,2-indanedione reaction with
an amino acid is its reaction with 3,4-dehydroproline
2
developed by Pounds and co-workers, is structurally
similar to ninhydrin. Its carbonyl is activated by two
flanking electron-withdrawing moieties. Upon reaction
with amino acids it forms a chromophore (7, Scheme 8)
which is not unlike Ruhemann’s purple. The structures
of dipolar intermediates shown in Scheme 7 were con-
firmed by trapping the 1,3-dipoles with N-methyl male-
imide as a dipolarophile.
2
7
(Scheme 8) to form an N-substituted pyrrole.
We have observed the formation of fluorescent species
when 1,2-indanediones were reacted with R-amino acids
both in solutions and on paper surfaces. The fluorescence
intensity was affected by substitution on the aromatic
ring. We have synthesized a series of 10 1,2-indanediones
(8, 10a -i, Scheme 9), of which 5,6-dimethoxyindane-1,2-
dione (10b) showed the highest fluorogenic activity in the
reactions with R-amino acids.
To elucidate the mechanisms involved in the reactions
of 1,2-indanedione with amino acids, we first investigated
the possibility of C-N-C 1,3-dipole formation. The
C-N-C dipoles (azomethine ylides) can exist as several
geometric isomers (Figure 1) that differ in their relative
stability. Z,Z, syn dipoles (U dipoles) are the least favored
due to intramolecular steric interactions. The nature of
R substituents as well as changes in solvent polarity may
affect the relative stabilization of S and W dipoles, since
Unlike ninhydrin, which produces nonfluorescent dark
purple traces in the amino acid reactions, 1,8-diaza-9-
fluorenone (6) produces somewhat faint pink traces. The
advantage of 6 lies in the intense fluorescence of devel-
oped amino acid stains; it is one of the most sensitive
fluorogenic reagents currently employed for latent fin-
gerprint detection.1
9,20
The nature of the fluorophore has
not been ascertained.
Resu lts a n d Discu ssion
,2-Indanedione (8), which has a carbonyl group acti-
1
vated toward nucleophilic attack, is similar to both
ninhydrin and DFO in this respect. The C-2 keto group
of 8 is the more reactive of the two: carbon nucleophiles
(21) Fatiadi, A. J . Synthesis 1978, 165-204.
(22) Tomchin, A. B.; Marysheva, V. V. Zh. Org. Khim. 1988, 24,
1
827-1835.
23) Koelsch, C. F.; LeClaire, C. D. J . Org. Chem. 1941, 6, 516-
533.
(24) McLean, S.; Whelan, J . Can. J . Chem. 1973, 51, 2457-2462.
(25) Irie, H.; Kishimoto, T.; Uyeo, S. J . Chem. Soc. (C) 1968, 3051-
3057.
(26) Taylor, B. M.; J oulli e´ , M. M. Tetrahedron 1998, 54, 15121-
15126.
(27) Hudson, C. B.; Robertson, A. V. Aust. J . Chem. 1967, 20, 1511-
1520.
(
(
18) Grigg, R.; Malone, J . F.; Mongkolaussavaratana, T.; Thianpa-
tanagul, S. J . Chem. Soc., Chem. Commun. 1986, 421-422.
19) Pounds, C. A.; Allman, D. S. The Use of 1,8-Diazafluoren-9-one
DFO) for the Fluorescent Detection of Latent Fingerprints on Paper.
(
(
Results of Laboratory and Operational Trials; Central Research and
Support Establishment, Home Office Forensic Science Service: UK,
1
991.
20) Stoilovic, M. Forensic Sci. Int. 1993, 60, 141-153.
(

Reaction of 1,2-Indanediones with Amino Acids
J . Org. Chem., Vol. 66, No. 23, 2001 7669
Sch em e 8
Sch em e 9
Sch em e 10
Sch em e 11
they differ in the magnitude of their dipole moments.
Assuming that the 1,3-dipolar cycloaddition to these
species occurs in a concerted fashion, one may deduce
dipole geometry from the structure of cycloaddition
products.
Dipole formation via 1,2-proton shift was the first
pathway to be studied. Glycine methyl ester, a compound
that could not undergo decarboxylation, was reacted with
1
,2-indanedione. Addition of N-methylmaleimide (NMM)
solvent on the diastereomeric ratio of products and
overall yields. L-Phenylalanine-derived product 13 was
obtained in 80-90% yields when the reaction was carried
out in chloroform. The cycloaddition product (13) is
predominantly derived from the W-dipole; no more than
1% of the other isomer (14) was observed. The same
reaction in aqueous dimethoxyethane resulted in an
approximately equal ratio of W- and S-derived cycload-
dition products; the overall yield decreased substantially.
L-Serine gave a 36% yield of S-derived cycloaddition
product (15) in aqueous dimethoxyethane (Scheme 13).
A side product presumed to be a W-derived cycloaddition
product (16) was also isolated.
to the reaction mixture resulted in formation of a spiro
indene pyrrolo[3,4-c]pyrrole 11 (Scheme 10) as a single
diastereomer in a 52% yield. The stereochemistry of this
product, as well as of other cycloadducts in this study,
was confirmed by X-ray crystallography. Compound 11
can be obtained via endo-addition to a Z,E, anti 1,3-dipole
(
Scheme 10, pathway a). Alternatively, the same dia-
stereomer can be obtained via exo-addition to E,Z, anti
,3-dipole (pathway b). The endo pathway is a more likely
1
one: the Z,E, anti 1,3-dipole is more stabilized than its
isomer, and endo addition allows for the more favorable
alignment of the dipole moments.
Formation of compound 12 (Scheme 11) in the reaction
of 1,2-indanedione with glycine confirmed the decarbox-
ylation pathway to C-N-C 1,3-dipoles.
Reactions of 1,2-indanedione with amino acids such as
L-phenylalanine (Scheme 12) illustrate the impact of
Amino acids with a secondary amino group (L-proline
and L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid)
were shown to generate 1,3-dipolar intermediates as well.
Two electron-deficient dipolarophiles were utilized to trap
the proline-dione adduct to give the diastereomerically

7
670 J . Org. Chem., Vol. 66, No. 23, 2001
Petrovskaia et al.
Sch em e 12
Sch em e 13
change from a colorless solution with negligible absorp-
tion above 400 nm to a purple solution with absorption
maxima at 518 and 550 nm (solvent: dimethoxyethane/
water, 1:1). Excitation at the long-wave absorption
maxima did not induce any luminescence. Short-wave
excitation (383 nm) resulted in the appearance of a strong
and broad emission band with a 418 nm maximum. The
emission band extended into the visible range (up to 520
nm). These observations suggested that the chromophore
and the fluorophore generated upon addition of base to
2
-amino-1-indanone hydrochloride solutions are different
species.
Compound 20 was reacted with 1,2-indanedione (8) in
an attempt to promote formation of Ruhemann’s purple
protonated analogue 21 (Scheme 16). Upon heating in
methanol, the yellow reaction solution became dark red
pure cycloadducts 17 and 18 (Scheme 14) in comparable
yields. The Z,E, anti dipole shown in Scheme 14 is the
major intermediate in the proline reaction.
(a broad absorption band with λmax ) 516 nm was
observed) and fluorescent. Upon addition of N-methyl-
maleimide, a precipitate was formed. On the basis of
NMR, MS, and elemental analysis data, it was assigned
structure 22 (11% yield). Due to difficulties in crystal-
lizing this compound, which showed a poor solubility in
most solvents, we could not obtain its X-ray crystal
structure, and we do not have direct proof of the relative
stereochemistry of this meso-compound. However, we
obtained an X-ray crystal structure of 23 (Scheme 16), a
dimethoxy analogue of 22, and extrapolated the result
to assign the stereochemistry of 22. A single diastereomer
L-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid gen-
erated a 1,3-dipole of the same geometry as the proline-
derived dipole (Scheme 15). Dipole generation proceeded
via decarboxylation. Cycloadducts generated via carbon-
yl-assisted 1,5-H shift were not identified in the reaction
mixture. The yield of the cycloadduct (19, 11%) was much
lower than in the proline reaction. This can be explained
by the lower nucleophilicity of the tetrahydroisoquinoline
nitrogen as compared to the proline nitrogen.
Having established the presence of C-N-C 1,3-dipoles
in the 1,2-indanedione/R-amino acid reaction mixtures,
we attempted to identify the presence of Ruhemann’s
purple analogues in these systems. Reaction of glycine
with excess 1,2-indanedione, followed by subsequent
addition of N-methylmaleimide, did not yield the desired
product. Since we were interested in evaluating the
properties of this compound, we explored a stepwise
approach to Ruhemann’s purple analogue formation (21,
Scheme 16).
2
4 was also obtained in the reaction of 2-amino-1-
indanone with ninhydrin (1) and N-phenylmaleimide
(Scheme 16).
It is of interest to note that addition of excess N-
methylmaleimide to 1,2-indanedione/amino acid reaction
mixtures as well as to 1,2-indanedione/2-amino-1-in-
danone reaction mixtures would invariably result in an
observed decrease of fluorescence both in solution and
on porous surfaces (paper). On the other hand, addition
of excess N-methylmaleimide to 2-amino-1-indanone
would not visibly affect the fluorescence.
Using L-phenylalanine as the starting material,28,29 we
first synthesized 2-amino-1-indanone hydrochloride 20
The nature of the fluorophore(s) in the 2-amino-1-
indanone reaction is still elusive. It could be the result
of a reaction sequence initiated by tautomerization and
subsequent condensation reactions. A short-wave fluo-
rophore that is the product of the self-condensation and
oxidation of 20 was identified, and its structure was
confirmed by X-ray crystallography. This product (25)
(Scheme 16) in 50% yield. This compound displayed
interesting properties. Addition of inorganic base to the
solutions of compound 20 resulted in a dramatic color
(
(
28) Levine, S. J . Am. Chem. Soc. 1954, 76, 1382.
29) Effenberger, F.; Steegmueller, D.; Null, V.; Ziegler, T. Chem.
Ber. 1988, 121, 125-130.

Reaction of 1,2-Indanediones with Amino Acids
J . Org. Chem., Vol. 66, No. 23, 2001 7671
Sch em e 14
Sch em e 15
Sch em e 16
displayed intense short-wave fluorescence when its solu-
tions were irradiated (λex ) 366 nm). This fluorescence
was perceived as blue and corresponds to higher-energy
transitions than the yellow fluorescence noted above.
Scheme 17 represents a summary of general reaction
pathways in the system under study. A plausible first
step in the reaction of 1,2-indanedione with an R-amino
acid is imine formation, followed by decarboxylation to

7
672 J . Org. Chem., Vol. 66, No. 23, 2001
Petrovskaia et al.
Sch em e 17
form 1,3-dipolar species of various geometries. These
dipoles can be trapped as cycloaddition products. Collapse
of the resulting dipoles to aziridines is a possibility.
Equilibria between azomethine ylides and aziridines have
been documented,30 and although we did not observe
aziridines in our experiments, we cannot rule out their
existence. Another possible pathway for the C-N-C 1,3-
dipolar species is the Strecker degradation. This reaction
would afford 2-amino-1-indanone, which could react
further with an excess of 1,2-indanedione to form a
indicated. Infrared spectra (IR) were obtained on a Perkin-
Elmer 1600 FT-IR spectrometer. High-resolution mass spectra
(HRMS) were obtained on either a VG 70-70HS or VG ZAB-E
mass spectrometer, using either Chemical Ionization (CI), fast
atom bombardment (FAB) using a cesium (Cs) ion gun, or
electron spray ionization (ESI). The mass spectrometers were
interfaced with a VG/DEC 11-73 data system. Elemental
Analyses (EA) were performed at the Analytical Facility of the
Department of Chemistry at the University of Pennsylvania.
Analytical thin-layer chromatography (TLC) was performed
on Merck silica gel (60F-254) plates (0.25 mm), precoated with
a fluorescent indicator. Visualization was effected with ultra-
violet light. Flash column chromatography was carried out on
E. Merck silica gel 60 (240-400 mesh) using the solvent
systems indicated in the individual experiments.
“Ruhemann’s purple”-like dipole.
Exp er im en ta l Section
Gen er a l P r oced u r es. All solvents were reagent grade and
distilled from the appropriate drying agents. Melting points
were determined using a Thomas-Hoover melting point ap-
paratus and are uncorrected. Proton magnetic resonance
spectra ( H NMR) and carbon magnetic resonance spectra ( C
NMR) were recorded on a Bruker Ac-250 (250 MHz) or a
Bruker AMX-500 (500 MHz) spectrometer in the solvents
Gen er a l Meth od for th e P r ep a r a tion of 1,2-In d a n ed i-
on es. 5,6-Dim eth oxy-1,2-in d a n ed ion e (10b). To a solution
of concentrated aqueous formaldehyde (36%, 1 mL) and
concentrated aqueous HCl (37%, 2 mL) at room temperature
was added 5,6-dimethoxy-1,2-indanedione 2-oxime (663 mg,
3.0 mmol). The reaction mixture turned from a light yellow
suspension to a dark yellow suspension within 5 min of the
addition. The reaction was allowed to stir overnight at room
temperature. The precipitate was collected by filtration,
washed with water (3 × 2 mL), and allowed to dry at ambient
1
13
(30) Trozzolo, A. M.; Leslie, T. M.; Sarpotdar, A. S.; Small, R. D.;
Ferraudi, G. J . Pure Appl. Chem. 1979, 51, 261-270.

Reaction of 1,2-Indanediones with Amino Acids
J . Org. Chem., Vol. 66, No. 23, 2001 7673
)+: m/z 210.0589, found 210.0591.
temperature to yield 566 mg (91.6%) of 10b as a yellow solid.
for C10
H
12NO
2
S (M + NH
4
1
H NMR (250 MHz, DMSO-d
s, 3H), 7.19 (s, 1H), 7.24 (s, 1H). C NMR (125 MHz, CDCl
δ 35.9, 56.3, 56.6, 105.9, 107.9, 131.4, 143.3, 150.1, 157.9, 185.0,
6
) δ 3.48 (s, 2H), 3.83 (s, 3H), 3.92
Anal. Calcd for C10
H, 4.30.
8 2
H O S: C, 62.48; H, 4.19. Found C, 62.83;
1
3
(
3
)
2,2-Dim eth oxy-1-in d a n on e (9). To a solution of 8 (292 mg,
2 mmol) in methanol (10 mL) was added acetic acid (1 drop).
The reaction was heated at reflux for 24 h. The reaction was
cooled, and the solvent was removed under reduced pressure.
The crude yellow oil was purified by column chromatography
-
1
1
(
C
10 4
99.9. IR (KBr) 1756, 1704 cm . HRMS calcd for C11H O N
+
M + NH
4
) : m/z 224.0923, found 224.0930. Anal. Calcd for
: C, 64.08; H, 4.89. Found: C, 63.81; H, 4.94.
,2-In d a n ed ion e (8): 3.36 g, 85.2%, mp 114-115 °C; R
11 10 4
H O
1
f
1
0
.71 (EtOAc/petroleum ether, 40:60). H NMR (250 MHz,
DMSO-d ) δ 3.58 (s, 2H), 7.46-7.53 (m, 1H), 7.60-7.7.63 (m,
H), 7.75-7.81 (m, 2H). 13C NMR (125 MHz, CDCl
) δ 36.6,
25.7, 127.5, 128.7, 136.7, 137.6, 146.5, 187.1, 199.7. IR (KBr)
(20% Et
colorless oil, which solidified upon prolonged storage at 4 °C.
0.31 (Et
O/petroleum ether, 20:80). 1H NMR (250 MHz,
CDCl ) δ 3.25 (s, 2H), 3.43 (s, 6H), 7.34-7.40 (m, 2H), 7.56-
7.63 (m, 1H), 7.77 (m, 1H). C NMR (125 MHz, CDCl
50.6, 101.9, 125.0, 126.6, 127.7, 133.8, 135.8, 149.4, 197.3. IR
2
O/petroleum ether) to provide 9 (150 mg, 39%) as a
6
1
1
1
NH
C
3
R
f
2
3
-
1
13
763, 1707 cm . HRMS (FAB) calcd for C
9
H
10
O
2
N (M +
) : m/z 164.0711, found 164.0709. Anal. Calcd for
: C, 73.97; H, 4.14. Found: C, 73.59; H, 4.09.
-Nitr o-1,2-in d a n ed ion e (10a ). Compound 10a exists in
equilibrium with its enol form in DMSO (ketone:enol ) 2:0.9).
3
) δ 38.5,
+
4
-
1
9
H
6
O
2
(KBr) 1727, 1048 cm . HRMS calcd for C11
H
16
O
3
N (M +
) : m/z 210.1130, found 210.1128. Anal. Calcd for
: C, 68.74; H, 6.29. Found: C, 68.42; H, 6.35.
1′R,3′R-(3′â,3′aâ,6′aâ)-3′a,6′a-Dih ydr o-5′-m eth ylspir o (2H-
+
6
NH
4
11 12 3
C H O
1
1
5
0
6
.27 g, 93.6%. H NMR (250 MHz, DMSO-d ) δ 3.67 (s, 2H),
.45 (s, 0.9 H), 7.10 (d, J ) 8.1 Hz, 0.9 H), 7.79 (d, J ) 1.6 Hz,
.9 H), 7.88 (d, J ) 8.5 Hz, 1H), 8.22 (dd, J ) 8.0 Hz, J ) 2.2
in d en e-2,1′(2′H)-p yr r olo(3,4-c)p yr r ole)1,4′,6′(3′H,5′H)-tr i-
on e 3′-Ca r boxylic Acid Meth yl Ester (11). To a yellow
solution of 8 (730 mg, 3.0 mmol) and N-methylmaleimide (333
mg, 5.0 mmol) in methanol (35 mL) was added glycine methyl
ester hydrochloride (377 mg, 3.0 mmol) with stirring. A
solution of KOH (170 mg, 3.0 mmol) in methanol (5 mL) was
added, and the reaction mixture was heated at reflux over-
night. The brown reaction mixture was cooled to room tem-
perature, and the solvent was removed under reduced pres-
sure. The crude solid was treated with boiling methanol to
Hz, 0.9 H), 8.40 (d, J ) 2.3 Hz, 1H), 8.55 (dd, J ) 8.4 Hz, J )
2
1
1
3
.3 Hz, 1H). C NMR (125 MHz, CDCl
3
) δ 36.9, 120.7, 129.0,
31.2, 136.8, 151.6 (note: signal for one aromatic carbon was
-
1
not detected) 185.7, 196.9. IR (KBr) 1767, 1726 cm . HRMS
+
4
) : m/z 209.0562, found 209.0569.
calcd for C
9
H
9
O
4
N
2
(M + NH
5
-Ch lor o-1,2-in d a n ed ion e (10c): 455 mg, 84%, mp 144-
1
1
45 °C. H NMR (250 MHz, DMSO-d
J ) 8.2 Hz, J ) 1.7 Hz, 1H), 7.73-7.80 (m, 2H). C NMR
125 MHz, CDCl
6
) δ 3.56 (s, 2H), 7.55 (dd,
13
(
1
3
) δ 36.4, 127.0, 127.7, 129.6, 135.1, 144.1,
yield 511 mg (52%) of 11 as a white solid: mp 197.5-198 °C;
-
1
1
47.8, 185.7, 198.5. IR (KBr) 1766, 1719 cm . HRMS calcd
R
f
0.46 (acetone/petroleum ether, 40:60). H NMR (250 MHz,
+
for C
9
H
9
O
2
ClN (M + NH
4
) : m/z 198.0322, found 198.0328.
6
acetone-d ) δ 2.88 (s, 3H), 3.04 (d, J ) 17.9 Hz, 1H), 3.43 (d,
Anal. Calcd for C
H, 2.75.
9
H
5
O
2
Cl: C, 59.86; H, 2.79. Found: C, 59.80;
J ) 7.7 Hz, 1H), 3.71 (s, 3H), 3.84 (dd, J ) 7.9 Hz, J ) 7.9 Hz,
1H), 4.06 (d, J ) 17.9 Hz, 1H), 4.44 (d, J ) 8.1 Hz, 1H), 7.41-
1
13
6
-Br om o-1,2-in d a n ed ion e (10d ): 0.43 g, 91.8%. H NMR
7.47 (m, 1H), 7.54 (d, J ) 7.5, 1H), 7.66-7.72 (m, 2H).
C
(
250 MHz, DMSO-d
6
) δ 3.51 (s, 2H), 7.59 (d, J ) 7.8 Hz, 1H),
.91-7.96 (m, 2H). 13C NMR (125 MHz, CDCl
) δ 36.2, 122.9,
28.5, 129.1, 137.8, 140.4, 144.9, 185.8, 198.4. IR (KBr) 1766,
NMR (125 MHz, CDCl
71.5, 125.2, 126.4, 128.0, 132.6, 135.8, 151.9, 170.6, 175.9,
3
) δ 25.3, 35.1, 48.6, 49.9, 52.5, 60.0,
7
1
1
2
3
-
1
176.1, 203.5. IR (KBr) 3284, 2952, 1774, 1742, 1698, 1607 cm
.
-
1
+
+
715 cm . HRMS calcd for C
9
H
9
O
2
NBr (M + NH
4
) : m/z
HRMS calcd for C17
found 351.0967. Anal. Calcd for C17
N, 8.53. Found: C, 62.51; H, 4.87; N, 8.54.
H
16
N
2
O
5
Na (M + Na) : m/z 351.0957,
41.9817, found 241.9825. Anal. Calcd for C
9
H
5
O
2
Br: C, 48.04;
16 2 5
H N O
: C, 62.19; H, 4.91;
H, 2.24. Found: C, 48.42; H, 2.22.
In d a n o[5,6-d ][1,3]d ioxole-5,6-d ion e (10e): 1.0 g, 98%. H
1
1′R-(3′aâ,6′aâ)-3′a,6′a-Dih ydr o-5′-ph en ylspir o(2H-in den e-
2,1′(2′H)-p yr r olo(3,4-c)p yr r ole)-1,4′,6′(3′H,5′H)-tr ion e (12).
A solution of 8 (200 mg, 1.37 mmol), glycine (300 mg, 4.1
NMR (250 MHz, DMSO-d
(
6
) δ 3.47 (s, 2H), 6.22 (s, 2H), 7.16
s, 1H), 7.23 (s, 1H). C NMR (125 MHz, CDCl ) δ 36.5, 102.6,
04.1, 106.4, 133.0, 145.5, 148.8, 156.0, 184.6, 199.2. IR (KBr)
1
3
3
1
1
1
mmol), and N-phenylmaleimide (1.0 g, 5.78 mmol) in CHCl
3
-
1
+
757, 1690 cm . HRMS calcd for C10
H
7
O
4
(M + H ): m/z
(100 mL, anhydrous) was heated at reflux for 48 h. The
reaction mixture was cooled to room temperature and filtered
to collect the precipitate. The filtrate was concentrated under
reduced pressure. The residue was purified by column chro-
91.0344, found 191.0343. Anal. Calcd for C10
6 4
H O
: C, 63.16;
H, 3.18. Found: C, 63.09; H, 3.06.
4
,5,6-Tr im eth oxy-1,2-in d a n ed ion e (10f): 434 mg, 95%.
H NMR (250 MHz, DMSO-d ) δ 3.47 (s, 2H), 3.86 (s, 3H), 3.87
3
s, 3H), 3.89 (s, 3H), 7.16 (s, 1H). C NMR (125 MHz, CDCl )
1
6
matography (30% acetone/hexanes). The product with R
f
0.24
1
3
(
was recrystallized from acetone/hexanes, to provide 12 as
1
δ 33.1, 56.4, 60.9, 61.3, 102.7, 132.4, 134.6, 150.0, 150.4, 154.7,
3
colorless needles (63 mg, 14%): mp 125 °C. H NMR (CDCl ,
-
1
1
C
85.6, 199.4. IR (KBr) 1758, 1720 cm . HRMS calcd for
500 MHz) δ 1.71 (br, 1H), 2.81 (d, J ) 17.44 Hz, 1H), 3.39 (d,
J ) 7.86 Hz, 1H), 3.48 (d, J ) 10.35 Hz, 1H), 3.59-3.62 (m,
2H), 4.05 (d, J ) 17.42 Hz, 1H), 7.26 (d, J ) 7.76 Hz, 2H),
+
12
H
13
O
5
(M + H ): m/z 237.0763, found 237.0776. Anal. Calcd
: C, 61.02; H, 5.12. Found: C, 60.70; H, 5.15.
,6,7-Tr im eth oxy-1,2-in d a n ed ion e (10g): 264 mg, 85%.
H NMR (250 MHz, CDCl ) δ 3.48 (s, 2H), 3.85 (s, 3H), 3.98
s, 3H), 4.10 (s, 3H), 6.70 (s, 1H). 13C NMR (125 MHz, CDCl
for C12
12 5
H O
5
7.34-7.44 (m, 5H), 7.55 (dd, J ) 7.31, 4.82 Hz, 1H), 7.70 (d,
1
13
3
J ) 7.66 Hz, 1H). C NMR (CDCl , 125 MHz) δ 35.9, 46.9,
3
(
3
)
47.5, 47.8, 72.1, 125.1, 126.43, 126.45, 128.0, 128.8, 129.2,
131.9, 132.9, 134.3, 135.7, 136.2, 152.0, 176.3, 178.2, 203.3.
δ 36.2, 56.7, 61.5, 62.1, 104.1, 125.0, 140.4, 144.4, 153.7, 162.3,
-
1
-1
1
C
82.3, 199.7. IR (KBr) 1752, 1697 cm . HRMS calcd for
IR (KBr) 3317, 2921, 2850, 1707 cm . HRMS calcd for
+
+
12
H
16
O
5
N (M + NH
4
) : m/z 254.1029, found 254.1036. Anal.
Calcd for C12 : C, 61.02; H, 5.12. Found: C, 60.62; H,
C
20
H
17
N
2
O
3
(M + H) : m/z 333.1239, found 333.1239.
H
12
O
5
1′S,3′S-(3′â,3′a â,6′a â)-3′a ,6′a -Dih yd r o-3′-ben zyl-5′-p h en -
4
.93.
-F lu or o-1,2-in d a n ed ion e (10h ): 281 mg, 68%, mp 100-
ylsp ir o(2H-in d en e-2,1′(2′H)-p yr r olo(3,4-c)p yr r ole)1,4′,6′-
(3′H,5′H)-tr ion e (13). A solution of 8 (200 mg, 1.37 mmol),
L-phenylalanine (670 mg, 4.11 mmol), and N-phenylmaleimide
5
1
1
7
5
1
1
03 °C. H NMR (500 MHz, acetone-d
.33 (m, 1H), 7.45 (dt, J ) 1.01, 8.83 Hz, 1H), 7.91 (dd, J )
.52, 8.45 Hz, 1H). 13C NMR (125 MHz, acetone-d
) δ 37.4,
15.1, 117.1, 128.7, 134.7, 151.8, 167.3, 186.5, 199.5. IR (KBr)
6
) δ 3.71 (s, 2H), 7.28-
3
(1.0 g, 5.78 mmol) in CHCl (150 mL, anhydrous) was heated
6
at reflux for 18 h. The reaction mixture was cooled to room
temperature and separated by filtration. The filtrate was
concentrated under reduced pressure. The residue was purified
by column chromatography (30% acetone/hexanes) to produce
13 as a white solid. Recrystallization from acetone/hexanes
-
1
763, 1718 cm
-(Meth ylth io)-1,2-in d a n ed ion e (10i). The crude solid
was recrystallized from 10% EtOAc/Et O to afford 10i (0.338
g) as golden needles in 66% yield. H NMR (500 MHz, acetone-
) δ 2.59 (s, 3H), 3.62 (s, 2H), 7.61-7.62 (m, 2H), 7.70 (dd,
.
6
2
1
afforded 13 as colorless needles in 80% yield: mp 141-145
1
d
6
°C; R
f
0.28 (30% acetone/hexanes). H NMR (CDCl
3
, 500 MHz)
1
3
J ) 1.91, 8.19 Hz, 1H). C NMR (125 MHz, acetone-d
6
) δ
5.31, 36.81, 121.27, 128.87, 135.87, 138.15, 140.83, 145.11,
87.77, 200.21. IR (KBr) 1760, 1705 cm-1. HRMS m/z calcd
δ 2.36 (br, 1H), 2.93 (dd, J ) 14.20, 8.06 Hz, 1H), 3.14 (d, J )
16.58 Hz, 1H), 3.29 (d, J ) 6.77 Hz, 1H), 3.33 (d, J ) 15.51
Hz, 1H), 3.45-3.55 (m, 2H), 3.68-3.78 (m, 1H), 7.21-7.49 (m,
1
1

7
674 J . Org. Chem., Vol. 66, No. 23, 2001
Petrovskaia et al.
1
1
7
1
2H), 7.62 (dd, J ) 7.75, 7.70 Hz, 1H), 7.81 (d, J ) 7.54 Hz,
3.18 (d, J ) 17.8 Hz, 1H), 3.35 (d, J ) 8.0 Hz, 1H), 3.51 (dd,
J )8 0.2 Hz, 1H), 4.16-4.23 (m, 2H), 7.34-7.46 (m, 2H), 7.57-
1
3
H). C NMR (CDCl , 125 MHz) δ 36.1, 45.2, 50.7, 58.3, 64.3,
3
1
3
4.9, 124.8, 126.4, 126.5, 126.6, 128.3, 128.5, 128.7, 128.9,
29.1, 131.7, 135.3, 136.1, 139.2, 150.3, 174.5, 174.8, 203.3.
7.63 (m, 1H), 7.71-7.74 (d, J ) 7.6 Hz, 1H). C NMR (125
MHz, CDCl ) δ 24.3, 24.6, 25.1, 32.5, 48.0, 48.3, 50.8, 64.7,
3
IR (KBr) 3320, 3062, 3028, 2922, 1708, 1606, 1497, 1384, 1191
74.4, 124.9, 126.1, 127.9, 133.6, 135.5, 151.6, 177.6, 177.8,
+
-1
cm-1. HRMS calcd for C27
found 423.1699. Anal. Calcd for C27
N, 6.63. Found: C, 76.71; H, 5.32; N, 6.60.
The other isomer (14) (R 0.37, 30% acetone/hexanes) was
observed as a minor product (<1%), and correctly characterized
from the next experiment.
H
23
N
2
O
3
(M + H) : m/z 422.1630,
203.0; IR (KBr) 2962, 1768, 1696, 1607 cm . HRMS calcd for
+
H
22
N
2
O
3
: C, 76.76; H, 5.25;
C
18
H
19
O
3
N
2
(M + H) : m/z 311.1396, found 311.1393. Anal.
Calcd for C18
9.35; H, 5.97; N, 8.88.
1′R,5′R-(5′a â)-3′,4′,5′,5′a -Tet r a h yd r osp ir o(2H -in d en e-
18 3 2
H O N : C, 69.66; H, 5.85; N, 9.03. Found: C,
6
f
2,1′(1′H )-p yr r olizin e)-1-on e-6′,7′-d ica r b oxylic Acid Di-
m eth yl Ester (18). Compound 8 (584 mg, 4.0 mmol) and
1
′R,3′S-(3′r,3′a â,6′a â)-3′a ,6′a -Dih yd r o-3′-ben zyl-5′-p h en -
ylsp ir o (2H-in d en e-2,1′(2′H)-p yr r olo[3,4-c]p yr r ole)1,4′,6′-
3′H,5′H)-tr ion e (14). A solution of 8 (200 mg, 1.37 mmol)
L-proline (1.38 g, 12 mmol) were placed in a solution of Et
10 mL) and CHCl (10 mL). The reaction mixture was heated
at reflux for 1 h. Dimethyl ester of acetylenedicarboxylic acid
852 mg, 6.0 mmol) was added, and the reaction mixture was
2
O
(
3
(
and L-phenylalanine (670 mg, 4.11 mmol) in 5% aqueous
dimethoxyethane (20 mL) was heated at reflux for 10 min. The
solution turned pink/red; no 8 was detected by TLC analysis.
To the red solution was added N-phenylmaleimide (1.0 g, 5.78
mmol). The reaction was heated at reflux for 12 h. The solution
was cooled to room temperature and concentrated under
reduced pressure. The residue was purified by column chro-
matography (30% acetone/hexanes) to provide 13 (0.11 g, 19%
(
heated at reflux for 24 h. The reaction mixture was cooled to
room temperature, and solvents were removed under reduced
pressure. The crude oil was purified by column chromatogra-
phy (30% acetone/petroleum ether) to afford 888 mg (65%) of
18 as a clear oil that solidified on standing: mp 89-90 °C; R
f
1
0.29 (30% acetone/petroleum ether). H NMR (500 MHz,
CDCl ) δ 1.77-1.86 (m, 3H), 2.22-2.26 (m, 1H), 2.64-2.70 (m,
yield), and 14 (0.138 g, 22% yield). R
f
0.37 (30% acetone/
hexanes); mp 182-183 °C. H NMR (CDCl , 500 MHz) δ 1.83
br, 1H), 2.52 (dd, J ) 13.60, 10.50 Hz, 1H), 2.89 (d, J ) 17.90
3
1
1H), 2.99-3.04 (m, 1H), 3.47 (s, 3H), 3.52 (s, 2H), 3.78 (s, 3H),
4.88 (dd, J ) 8.0 Hz, J ) 5.9 Hz, 1H), 7.34-7.43 (m, 2H), 7.55-
3
(
1
3
Hz, 1H), 3.41 (dd, J ) 13.83, 3.45 Hz, 1H), 3.43 (d, J ) 7.83
Hz, 1H), 3.75 (dd, J ) 8.05, 8.06 Hz, 1H), 4.23 (d, J ) 17.70
Hz, 1H), 7.15-7.18 (m, 1H), 7.21-7.26 (m, 4H), 7.34-7.44 (m,
7.62 (m, 1H), 7.76 (d, J ) 7.5 Hz, 1H). C NMR (125 MHz,
CDCl ) δ 25.3, 29.5, 33.1, 51.0, 52.1, 52.2, 70.7, 81.2, 125.2,
3
126.0, 127.9, 134.2, 135.3, 139.4, 142.0, 151.1, 164.1, 164.2,
5
H), 7.52 (dd, J ) 7.68, J ) 7.82 Hz, 2H), 7.58 (dd, J ) 7.43,
201.9. IR (KBr) 2952, 1721, 1650, 1606 cm-1. HRMS calcd for
1
3
+
J ) 7.55 Hz, 1H), 7.69 (d, J ) 7.83 Hz, 1H). C NMR (CDCl
3
,
C
19
H
19NO
5
Na (M + Na) : m/z 364.1161, found 364.1168. Anal.
1
1
1
1
25 MHz) δ 35.8, 38.3, 47.8, 48.2, 58.1, 70.6, 125.1, 126.4,
Calcd for C19
H
19NO
5
: C, 66.85; H, 5.61; N, 4.10. Found: C,
26.6, 127.9, 128.6, 128.8, 128.9, 129.19, 131.91, 132.94, 134.2,
35.7, 139.2, 152.4, 175.6, 176.1, 204.1. IR (KBr) 1707, 1607,
66.48; H, 5.67; N, 4.05.
1′,3′,8′,8′a â,8′bâ,10′,11′,11′a â-Octa h yd r o-2-m eth ylsp ir o-
(2H -in d en e-2,1′ (1′H )p yr r olo(3′,4′:3,4)p yr r olo(1,2-b)iso-
qu in olin e-1,9′,11′-tr ion e (19). 1,2-Indanedione 8 (438 mg, 3.0
mmol) and L-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
(532 mg, 3.0 mmol) were placed in 30 mL of DME. The reaction
mixture was refluxed for 1 h. The color of the reaction mixture
gradually turned to dark brown. N-Methylmaleimide (333 mg,
3.0 mmol) was added, and the reaction mixture was refluxed
for 24 h. The solvent was removed under reduced pressure,
and the resulting solids were separated on a column (40%
acetone/petroleum ether, 40:60) to yield 124 mg (11%) of 19
as a yellow solid. (A single diastereomer was obtained, one
-
1
+
497, 1384, 1195 cm . HRMS calcd for C27
H
23
N
2
O
H
3
(M + H) :
22 2 3
m/z 422.1630, found 422.1723. Anal. Calcd for C27
N O : C,
7
6.76; H, 5.25; N 6.63. Found: C, 76.91; H, 5.22; N, 6.63.
′-(1′R,3′R-(3′â,3′aâ,6′aâ)-3′a,6′a-Dih ydr o-5′-ph en ylspir o-
2H-in den e-2,1′(2′H)-pyr r olo(3,4-c)pyr r ole)-1,4′,6′-(3′H,5′H)-
3
(
tr ion e)m eth a n ol (15). A solution of 8 (200 mg, 1.37 mmol),
L-serine (200 mg, 1.9 mmol), and N-phenylmaleimide (1.0 g,
5
for 18 h. The reaction mixture was cooled to room temperature,
and the solvent was removed under reduced pressure. The
crude solid was purified by column chromatography (50%
.78 mmol) in 5% aqueous DME (20 mL) was heated at reflux
acetone/hexanes) to afford 15 (180 mg) as a white solid in a
enantiomer is shown): mp 230-231 °C; R
f
0.63 (40% acetone/
1
1
3
5
1
4
2
6% yield. R
f
0.43 (50% acetone/hexanes). H NMR (CDCl
3
,
petroleum ether). H NMR (250 MHz, CDCl ) δ 2.58-2.69 (m,
3
00 MHz) δ 2.93 (d, J ) 17.73 Hz, 1H), 3.44 (d, J ) 8.10 Hz,
H), 3.76-3.80 (m, 2H), 3.94 (dd, J ) 11.70, 3.64 Hz, 1H),
.10-4.13 (m, 1H), 4.30 (d, J ) 17.73 Hz, 1H), 7.31 (dd, J )
.72, 0.95 Hz, 2H), 7.39-7.59 (m, 5H), 7.61 (dd, J ) 7.33, 7.42
1H), 3.01 (s, 3H), 3.07 (d, J ) 18.8 Hz, 1H), 3.13 (dd, J ) 5.9
Hz, J ) 3.3 Hz, 1H), 3.21 (d, J ) 7.6 Hz, 1H), 3.42 (d, J ) 14.2
Hz, 1H), 3.71 (d, J ) 14.3 Hz, 1H), 3.82 (dd, J ) 9.2 Hz, J )
7.7 Hz, 1H), 3.81-3.95 (m, 1H), 4.52 (d, J ) 18.8 Hz, 1H), 6.80
(d, J ) 6.2 Hz, 1H), 7.01-7.06 (m, 1H), 7.09-7.11 (m, 2H),
1
3
Hz, 1H), 7.76 (d, J ) 7.66 Hz, 1H). C NMR (CDCl
δ 35.4, 47.3, 48.6, 59.1, 61.0, 71.6, 125.2, 126.5, 128.0, 128.8,
1
3
3
, 125 MHz)
1
3
7.42 (m, 1H), 7.54 (d, J ) 7.8 Hz, 1H), 7.67-7.73 (m, 2H).
C
29.2, 131.8, 132.9, 135.8, 152.2, 175.8, 177.0, 203.9. IR (KBr)
NMR (125 MHz, CDCl ) δ 25.1, 32.5, 33.1, 47.0, 48.3, 49.0,
3
-
1
465, 3309, 1701, 1597, 1494, 1376, 1178 cm . HRMS calcd
57.1, 73.8, 123.5, 126.0, 126.4, 126.5, 126.6, 128.0, 129.2, 133.4,
134.2, 134.9, 136.3, 153.0, 176.5, 176.7, 203.0. IR (KBr) 3020,
+
for C21
Calcd for C21
9.40; H, 4.88; N, 7.68. The minor product was isolated as an
oil (R 0.20, 50% acetone/hexanes) and is presumed to be 16
H
19
N
2
O
H
4
363.1345 (M + H) , found 363.1344. Anal.
-
1
18
N
2
O
4
: C, 69.60; H, 5.01; N, 7.73. Found: C,
2934, 1772, 1698, 1607 cm . HRMS calcd for C23
H
20
N
2
O
3
Na
(M + Na) : m/z 395.1372, found 395.1359. Anal. Calcd for
: C, 74.18; H, 5.41; N, 7.51. Found: C, 74.20; H,
5.52; N, 7.51.
+
6
f
23 20 2 3
C H N O
+
(
3
19 2 4
35 mg, 8%). HRMS calcd for C21H N O (M + H) : m/z
63.1345, found 363.1343.
2
-Am in o-1-in d a n on e Hyd r och lor id e (20). A solution of
1
′R,5′a S-(5′a â,5′bâ,8′a â)-Hexa h yd r o-7-m eth ylsp ir o(2H-
L-phenylalanine (11 g, 66.67 mmol) and phosphorus pentachlo-
in den e-2,1′(2′H)-pyr r olo[3,4-a ]pyr r olizin e-1,6′,8′-(5′aH,7′H)-
tr ion e (17). A solution of 8 (186 mg, 1.27 mmol) and L-proline
146 mg, 1.27 mmol) in MeOH (20 mL) was stirred at ambient
temperature until the reaction mixture turned brown. N-
Methylmaleimide (141 mg, 1.27 mmol) was added, and the
reaction mixture was heated at reflux for 24 h. The reaction
mixture was cooled to room temperature, and the solvent was
removed under reduced pressure. The crude solid was purified
by column chromatography (30% acetone:petroleum ether) to
ride (15 g, 72 mmol) in CCl
for 10 h in a flame-dried, round-bottomed flask equipped with
a CaCl drying tube. The flask was transferred into a glovebag
filled with nitrogen. A solid was collected by filtration and
washed with CCl
(3 × 30 mL, anhydrous) to remove the traces
of POCl . The solid showed a single IR band in the carbonyl
region (1787 cm , KBr pellet). The solid was placed in a flame-
dried flask, equipped with a condenser and a CaCl drying
tube. Anhydrous AlCl (17.6 g, 132 mmol) and CS (200 mL,
4
(200 mL, anhydrous) was stirred
(
2
4
3
-1
2
3
2
yield 249 mg (63.3%) of 17 as a white solid: mp 166.5 °C; R
f
anhydrous) were added. The reaction mixture was stirred at
50 °C for 4 h. The flask was then placed in an ice-salt bath,
and the reaction mixture was cooled to 0 °C and slowly
quenched by addition of a mixture of ice (200 g), water (100
1
0
.38 (30% acetone/petroleum ether). H NMR (250 MHz,
acetone-d ) δ 1.63-1.90 (m, 2H), 1.96-2.23 (m, 2H), 2.38 (dd,
6
J ) 17.3 Hz, J ) 9.9 Hz, 1H), 2.72-2.82 (m, 1H), 2.95 (s, 3H),

Reaction of 1,2-Indanediones with Amino Acids
J . Org. Chem., Vol. 66, No. 23, 2001 7675
g), and concentrated aqueous HCl (20 mL). The aqueous phase
was then separated and concentrated on a rotary evaporator
at 40 °C (bath temperature). Concentrated HCl (80 mL) was
added, and the resulting slurry was separated by filtration.
The filtrate was concentrated to yield a beige solid, which was
1′R-(3′a â,6′a â)-3′a ,6′a -Dih yd r o-5′-p h en ylsp ir o((2H -in -
d en e-2,1′)(2′′H-in d en e-2′′,3′)(2′H)-p yr r olo(3,4-c)p yr r ole)-
1,1′′,3′′,4′,6′ (3′H,5′H)-p en ton e (24). A solution of 1 (260 mg,
1.47 mmol), 20 (250 mg, 1.35 mmol), and N-phenylmaleimide
(1.0 g, 6.25 mmol) in MeOH (50 mL, anhydrous) was stirred
for 48 h. A white precipitate formed after several hours. The
1
recrystallized from methanol to yield 6.09 g (49.8%) of 20. H
NMR (250 MHz, DMSO-d
Hz, 1H), 3.35 (dd, J ) 16.9 Hz, J ) 8.3 Hz, 1H), 4.28 (dd, J )
6
) δ 3.14 (dd, J ) 16.9 Hz, J ) 5.2
mixture was diluted with Et
2
O (50 mL). The precipitate was
collected by filtration to afford 24 (58 mg) as a white solid in
1
8
.2 Hz, J ) 5.3 Hz, 1H), 7.47-7.53 (m, 1H), 7.64 (d, J ) 7.5
3
10% yield: mp 295 °C (dec). H NMR (CDCl , 500 MHz) δ 3.53
1
3
Hz, 1H), 7.72-7.80 (m, 2H), 8.65 (s, <2H, exchangeable).
NMR (125 MHz, DMSO-d ) δ 31.3, 53.2, 123.7, 127.0, 128.2,
1
1
C
(d, J ) 15.24 Hz, 1H), 3.69 (d, J ) 8.55 Hz, 1H), 3.74 (d, J )
15.25 Hz, 1H), 3.84 (d, J ) 7.88 Hz, 1H), 7.34-7.56 (m, 7H),
6
34.1, 136.1, 151.5, 200.4. IR (KBr) 2927, 1720, 1610, 1465,
7.69-7.71 (m, 1H), 7.89 (d, J ) 7.5 Hz, 1H), 7.96-8.00 (m,
-
1
13
300, 1218 987, 746 cm . HRMS calcd for C
9
H
10NO (M-Cl):
2H), 8.09-8.12 (m, 2H). C NMR (125 MHz, CDCl ) δ 47.0,
3
m/z 148.0762, found 148.0762.
′R,3′S-(3′a â,6′a â)-3′a ,6′a -Dih yd r o-5′-m eth ylsp ir o((2H-
in den e-2,1′)(2′′H-in den e-2′′,3′)(2′H)-pyr r olo(3,4-c)pyr r ole)-
,1′′,4′,6′ (3′H,5′H)-tetr on e (22). A solution of 8 (438 mg, 3
54.6, 60.4, 74.6, 77.8, 124.4, 124.5, 125.0, 126.67, 126.71, 128.4,
128.9, 129.2, 131.4, 132.5, 135.1, 136.2, 136.9, 137.0, 140.0,
1
141.7, 150.3, 173.4, 176.9, 198.6, 202.0. HRMS calcd for
+
1
C
28
H
18
N
2
O
5
(M + H) : m/z 463.1293, found 463.1215.
mmol), 20 (643 mg, 3.5 mmol), and N-methylmaleimide (333
mg, 3 mmol) in MeOH (60 mL) was brought to reflux. Upon
heating, the yellow solution became pink with green fluores-
cence. In approximately 40 min precipitate formation was
observed and fluorescence disappeared. The reaction mixture
was cooled to room temperature. The precipitate was collected
by filtration and washed with MeOH (3 × 1 mL) to yield 160
mg (13.7%) of 22 as a pale yellow solid insoluble in most
Diin d a n o[1,2-b;1′,2′-e]p yr a zin e (25). To a solution of 20
(0.92 g, 5 mmol) in MeOH (8 mL) was added aqueous NaOH
(5 mL, 2M) dropwise, with stirring at ambient temperature.
The clear solution instantly turned red, and gradual precipi-
tate formation was observed. The reaction mixture was stirred
overnight at room temperature. The precipitate was collected
by filtration, washed with MeOH (2 × 1 mL), and purified by
2 2
column chromatography (20% EtOAc/CH Cl ) to provide 25 as
1
solvents with the exception of DMSO: mp > 320 °C. H NMR
a light yellow solid (0.10 g) in a 15.6% yield: mp 273-274 °C;
1
(
3
7
250 MHz, DMSO-d
6
) δ 2.74 (s, 3H), 3.24 (d, J ) 16.4 Hz, 2H),
R
f
0.67 (20% EtOAc/CH
2 2 3
Cl ). H NMR (250 MHz, CDCl ) δ 4.05
.57 (s, 2H), 3.72 (d, J ) 16.5 Hz, 2H), 7.51-7.57 (m, 2H),
.64 (d, J ) 7.5 Hz, 2H), 7.76-7.83 (m, 4H). 13C NMR (125
) δ 24.6, 44.3, 59.5, 75.8, 124.0, 127.2, 128.3,
34.8, 136.2, 150.5, 174.8, 202.7. IR (KBr) 3458, 3264, 2953,
(s, 4H), 7.44-7.49 (m, 4H), 7.62 (d, J ) 6.4 Hz, 2H), 8.11 (d,
13
J ) 7.6 Hz, 2H). C NMR (62.5 MHz, CDCl
3
) δ 36.1, 121.1,
MHz, DMSO-d
1
1
6
125.5, 127.7, 129.1, 138.9, 142.2, 151.7, 157.3. IR (KBr) 3045,
-
1
+
2885, 1390, 1361 cm . HRMS calcd for C18
H
13
N
2
(M + H) :
: C,
-
1
779, 1716, 1697, 1608 cm . HRMS calcd for C23
H
18
N
2
O
4
m/z 257.1078, found 257.1072. Anal. Calcd for C18H N
84.35; H, 4.72; N, 10.93. Found: C, 84.06; H, 4.84; N, 10.57.
12 2
+
(
M + H) : m/z 387.1345, found 387.1342. Anal. Calcd for
: C, 71.49; H, 4.70; N, 7.25. Found: C, 71.33; H,
.63; N, 7.09.
′R,3′S-(3′aâ,6′aâ)-3′a,6′a-Dih ydr o-5,6-dim eth oxy-5′-ph en -
ylsp ir o((2H-in d en e-2,1′)(2′′H-in d en e-2′′,3′)(2′H)-p yr r olo-
3,4-c)p yr r ole)-1,1′′,4′,6′ (3′H,5′H)-tetr on e (23). A solution
23 18 2 4
C H N O
Ack n ow led gm en t. We are grateful for the financial
support provided by the National Institutes of J ustice
(92-IJ -CX-K015), Unites States Secret Service, National
Institutes of Health (CA-40081), and National Science
Foundation (CHE-01449). We thank Dr. Antonio Cantu
and Mr. Robert Ramotowski of the United States Secret
Service, and Dr. J osef Almog of the Israel National
Police for fluorescence testing of compounds and for
helpful discussions.
4
1
(
of 10b (206 mg, 1.00 mmol), 20 (185 mg, 1.00 mmol), and
N-phenylmaleimide (1.0 g, 6.25 mmol) in MeOH (22 mL,
anhydrous) was stirred for 48 h. A white precipitate was
formed after several hours. The mixture was diluted with ether
(50 mL) and filtered to provide 23 (43 mg) as a white solid in
1
3
a 8.5% yield: mp > 310 °C (dec). H NMR (CDCl , 500 MHz)
δ 3.39 (s, 2H), 3.44 (d, J ) 8.54 Hz, 2H), 3.53 (s, 2H), 3.91 (s,
Su p p or tin g In for m a tion Ava ila ble: General procedures
and X-ray data for compounds 11, 13-15, 17-19, 23-25. This
material is available free of charge via the Internet at
http://pubs.acs.org.
3
7
8
5
H), 3.99 (s, 3H), 6.89 (s, 1H), 7.30 (s, 1H), 7.33-7.35 (m, 3H),
.41-7.49 (m, 4H), 7.66 (dd, J ) 6.6, 6.5 Hz, 1H), 7.89 (d, J )
+
.77 Hz, 1H). HRMS calcd for C30
H
25
N
2
O
6
(M + H) : m/z
09.1712, found 509.1703. Due to the insoluble nature of this
1
3
compound a C NMR could not be performed.
J O0105179