Synthesis, structure, and fluorescence of isomeric indolizinediones. Carbonyl-bridged isodipyrrinones

Article abstract of DOI:10.1007/s00706-004-0247-x

In "one-pot" reactions, pyrrole-α- and β-aldehydes condense readily with 4-ethyl-3-methyl-3-pyrrolin-2-one to give isodipyrrinone analogs, which undergo intramolecular cyclization when the pyrrolealdehyde possesses an α or β-CO₂R group. The res

Full text of DOI:10.1007/s00706-004-0247-x

Monatshefte f€ur Chemie 136, 553–565 (2005)
DOI 10.1007/s00706-004-0247-x
Synthesis, Structure, and Fluorescence
of Isomeric Indolizinediones.
Carbonyl-Bridged Isodipyrrinones
ꢀ
Stefan E. Boiadjiev and David A. Lightner
Department of Chemistry, University of Nevada, Reno, Nevada 89557-0020
Received July 22, 2004; accepted July 26, 2004
Published online November 24, 2004 # Springer-Verlag 2004
Summary. In ‘‘one-pot’’ reactions, pyrrole-ꢀ- and ꢁ-aldehydes condense readily with 4-ethyl-3-
methyl-3-pyrrolin-2-one to give isodipyrrinone analogs, which undergo intramolecular cyclization
when the pyrrolealdehyde possesses an ꢀ or ꢁ-CO2R group. The resulting regioisomeric pyrroloindo-
lizinediones, with structures confirmed by NMR analysis, exhibit strong fluorescence, with quantum
yields (ꢂF) as high as 0.91 at ꢃem ꢁ 450–550 nm.
Keywords. Pyrrole; Indolizinedione; Fluorescence quantum yield.
Introduction
Dipyrrinones, such as xanthobilirubic acid (XBR, Fig. 1A), are yellow pigments
with UV-visible absorption (" ꢁ 30000 dm3 ꢂ molꢃ1 cmꢃ1) near 410 nm and the
important chromophore of bilirubin (BR), the yellow pigment of jaundice and a
bisdipyrrinone [1]. In both XBR and BR, the dipyrrinone chromophore has the (4Z)
exocyclic configuration and adopts the syn conformation (Fig. 1B). The lowest
lying (singlet) excited state of XBR and of BR relaxes rapidly by Z ! E diaste-
reomerization, with only extremely weak fluorescence at room temperature [1].
However, when Z ! E isomerization is inhibited by linking the two nitrogens – by
a carbonyl group, as in xanthoglow [2] (Fig. 1B), or by a methylene group – the
pigment becomes strongly fluorescent [3–5].
Recently, we explored the possibility of synthesizing xanthoglow [2, 6] analogs
with the anti- rather than the syn-(Z) stereochemistry (Fig. 1B) of the dipyrrinone
core [7]. From the anti-(4Z) stereochemistry, the lactam nitrogen and C(7) of the
pyrrole are linked to a carbonyl, thereby giving the ꢀꢀꢁ-type of skeleton (Fig. 1C),
in contrast to the ꢀꢀN skeleton of xanthoglow (Fig. 1B), where the two nitrogens
ꢀ
Corresponding author. E-mail: lightner@scs.unr.edu

554
S. E. Boiadjiev and D. A. Lightner
Fig. 1. (A) Xanthobilirubic acid, a dipyrrinone obtained from heating bilirubin in molten resorcinol,
and bilirubin, a naturally-occurring bis-dipyrrinone; (B) the dipyrrinone skeleton in syn- and anti-
conformations, and xanthoglow, a derivative of xanthobilirubic acid with both nitrogens connected to
a carbonyl bridge; (C) the parent chromophores of carbonyl-bridged dipyrrinones with C(5) con-
necting the lactam ꢀ-carbon with a pyrrole ꢀ- or ꢁ-carbon, or the nitrogen, and with the carbonyl
bridge connecting the lactam nitrogen and the pyrrole ꢀ- or ꢁ-carbon; the atom connectivity can be
described in terms of ꢀ, ꢁ, and N, e.g., xanthoglow belongs to the ꢀꢀN connectivity, with the lactam
C(4) ꢀ-carbon connected to C(5), which is connected to the pyrrole ꢀ-carbon 6, an ꢀ-carbon, and
with the carbonyl bridge connected to the pyrrole nitrogen; in contrast, the ꢀꢀꢁ skeleton would be
the same as ꢀꢀN, except the carbonyl bridge would be to the pyrrole ꢁ-carbon (the original (4Z)-
dipyrrinone in the anti-conformation)
are linked to a common carbonyl group. The ꢀꢀꢁ tricyclic skeletal designation
signifies that the lactam and pyrrole rings are connected to ¼C(5), which links the
lactam ꢀ-carbon to a pyrrole ꢀ-carbon, and the pyrrole ꢁ-carbon is linked to the
lactam N by a C¼O group. The ꢀꢀꢁ-type carbonyl-bridged dipyrrinone (called:
pyrrolo[3,2-f]indolizine-4,6-dione) is strongly fluorescent [7], but many simple
ꢀꢀꢁ-type bridged dipyrrinones were found to be much less soluble in organic
solvents than the ꢀꢀN-type (called: 3H,5H-dipyrrolo[1,2-c:20,10-f]pyrimidine-3,5-
dione), exemplified by xanthoglow and its analogs [2, 6]. In order to explore
fluorescence from new types of carbonyl-bridged configurationally-restricted

Carbonyl-Bridged Isodipyrrinones
555
Fig. 2. (A) The target tricyclic compounds and (B) their monopyrrole precursors for the ‘‘one-pot’’
syntheses of carbonyl-bridged dipyrrinones 1–8
dipyrrinones, we considered three new types of tricyclic skeletons: ꢀꢁꢁ, ꢀꢁꢀ,
ꢀNꢀ (Fig. 1C). The first two have the unusual isodipyrrinone skeleton, with
C(5) linked to a pyrrole ꢁ-carbon rather than the typical ꢀ-carbon linkage found
in bilirubin, porphyrins, and dipyrrinones. The last, the ꢀNꢀ skeleton is an en-
amine type, and that system is not reported herein. The fluorescence and other
spectroscopic properties of novel ꢀꢁꢁ and ꢀꢁꢀ and new ꢀꢀꢁ target compounds
of this work (1–8, Fig. 2A), are compared with those of the recently reported ꢀꢀꢁ
and ꢀꢀN analogs [2, 6, 7].
Results and Discussion
Mechanism
The syntheses of the ꢀꢁꢁ, ꢀꢁꢀ, and ꢀꢀꢁ tricyclic, dipyrrinone-based compounds
were inspired by the observation of Clezy and Liepa [8] that acid-catalyzed
condensation of 4-acetyl-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid with

556
S. E. Boiadjiev and D. A. Lightner
Fig. 3. (A) Unexpected indolizine formation by condensation of two pyrroles; (B) intramolecular
cyclization of a dipyrrylmethane from a deprotonated pyrrole nitrogen to the neighboring pyrrole ꢁ-
CO2Et group; (C) pyrokoll, from 1880; (D) the minimum components and orientations required for
intramolecular cyclization between a (deprotonated) lactam nitrogen and neighboring CO2Et group
to produce indolizinediones 1–8
4-(ethoxycarbonylethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid afforded not
the expected dipyrrylmethene product, but rather an unexpected product, the in-
dolizine formed by intramolecular cyclization of the dipyrrylmethene intermediate
(Fig. 3A). Studies of similar acid-catalyzed condensations leading to 6-methylene-
pyrrolo[3,2-f]indolizines were reported by Mironov et al. [9].
Even earlier work by Corwin and Ellingson [10] showed the feasibility of
using a (deprotonated) pyrrole nitrogen-nucleophile to accomplish an intramo-
lecular cyclization with a neighboring pyrrole ꢁ-carboethoxy group (Fig. 3B).
Here, the N-methylated nitrogen does not react, and if both pyrroles are N-
methylated, no reaction proceeds. Such a NꢃC(¼O)ꢃC bridged system was
not without precedence and had been described (pyrokoll, Fig. 3C) in 1880 by
Ciamician [11]. Accordingly, for the syntheses of the ꢀꢁꢁ compounds of this
work (1 and 2) the ꢀꢁꢀ (3–6) and the ꢀꢀꢁ (7 and 8) (Fig. 2), we envisioned

Carbonyl-Bridged Isodipyrrinones
557
intramolecular cyclizations emanating from the dipyrrinone skeletons oriented as
in Fig. 3D.
Synthesis
It appeared to us that the most economical routes to the target compounds would
be one-pot syntheses (Fig. 2) in which 4-ethyl-3-methyl-3-pyrrolin-2-one (9) [12]
was condensed with a pyrrole-ꢁ-aldehyde (to form 1–6) or pyrrole-ꢀ-aldehyde (to
form 7 and 8) to give first the appropriate isodipyrrinone or dipyrrinone (Fig. 3D),
to be followed by lactam NH deprotonation and cyclization with a neighboring
carboalkoxy group. A non-nucleophilic base such as DBU (1,8-diazabicyclo[5.4.0]
undec-7-ene) seemed appropriate to the task while avoiding saponification of the
important carboalkoxy group. Thus, by reacting 9 with pyrrolealdehydes 10 and 11
(Fig. 2B) under these conditions, we obtained ꢀꢁꢁ products 1 and 2, in good yield
(62–73%), proving that the method works – even in the face of steric hindrance
due to the ‘‘ortho’’ effect. Similarly, 9 reacted smoothly i) with 12–15 to afford
3–6 in 35–75% yield, and ii) with 16 and 17 to afford 7a and 8 in 88 and 7% yield.
The N-methylated aldehydes (13 and 15) afforded much lower yields of tricyclic
products than those from the N-H aldehydes 12 and 14 – possibly due to decreased
electrophilicity at the ꢀ-ester carbonyl carbon reaction center. The very low yield
of 8 is unexplained but is possibly related to steric hindrance from the iso-amyl
group in the dipyrrinone-forming condensation step. Since 7a was too insoluble for
spectroscopic measurements, it was N-alkylated to give 7b. The required mono-
pyrrolealdehydes were prepared by formylation of known ꢁ-H or ꢀ-H precursors.
N-Methyl and N-iso-amyl pyrroles 11, 13, 15, and 17 were synthesized from the
N-H pyrrole by methylation using potassium tert-butoxide plus methyl or iso-amyl
iodide.
Properties
All of the bridged dipyrrinones of this work were yellow and had rather high
melting points, with the N-alkylated compounds having lower values (211–
250ꢄC) and the others having higher values (298–367ꢄC) and poorer solubility
in organic solvents, especially 7a. The solubility and melting point properties stand
in strong contrast to the ꢀꢀN series of bridged dipyrrinones related to xanthoglow
[2], which are quite soluble in organic solvents over a wide range of polarity. The
1H NMR, 13C NMR (APT), and gHMBC spectra provided firm proof of structure
of 1–8, which followed logically from the method of synthesis. The UV-visible
spectra (Table 1) of 1–8 show multiple bands centered near 400 nm with
" ꢁ 15000, weaker bands centered near 300–350 nm (" ꢁ 5000), and a more intense
band located near 250–300 nm (" ꢁ 25000). The position and composition of
the bands varies with the structural types and type of number substituents on
the pyrrole ring. One might distinguish the ꢀꢁꢁ type (ꢃmax ꢁ 380–410, ꢁ 300,
ꢁ250 nm) from the ꢀꢁꢀ type (ꢃmax ꢁ 410–420, ꢁ 350, ꢁ 250–300 nm) and ꢀꢀꢁ
type (ꢃmax ꢁ 400–420, ꢁ 240–260 nm) on the basis of their UV-visible spectral
profiles.

558
S. E. Boiadjiev and D. A. Lightner
Table 1. Solvent dependence of the UV-visible spectra of 1–8
Compound
ꢃ )
max=nm ("=dm3 molꢃ1 cmꢃ1
n-C6H14
C6H6
CHCl3
CH3OH
(15300) 409
(CH3)2SO
(16200) 403
1
insoluble
404
384
318
305
(16200) 407
(16800) 389
(16700)
(4300)
(16000)
(4800)
(4500)
(4600)
308
253
246
309
(3900)
308
(23500) 252
(23600) 245
(26400)
(27300)
2
403
381
316
301
253
245
(17800) 409
(18400) 389
(17200) 413
(17800) 395
(15700) 409
(16600)
(16400) 404
(17100)
(4700)
(4600)
(5000)
(25100)
(25500)
319
305
(4200)
(4600)
321
307
256
249
(4100)
(4700)
299
(4500)
300
(28500) 253
(27000) 248
(30800)
(30100)
3
4
sh 410 (4600)
sh 413 (5000)
(9500)
sh 412 (4300)
sh 415 (4300)
sh 411 (5100)
355
294
(10000) 355
356
293
267
(9700)
(2500)
(18500)
361
295
(10900) 361 (10700)
(2100)
293
(2300)
(2800)
296
(2900)
416
394
356
280
270
(6400)
(6900)
(9200)
(8800)
(12500)
sh 418 (6400)
sh 415 (5600)
sh 411 (5700)
366
sh 413 (6200)
397
361
(6900)
(9500)
365
245
(9900)
(10400) 366
(10100)
sh 273 (13800)
(26700) 244
(6100)
(29500)
5
6
insoluble
403
382
335
293
283
(7100)
(7400)
(3900)
405
386
336
406
390
(6900)
(7100)
(6400)
(3900)
393
336
(6300)
(4100)
(36400) 293
(31900) 283
(42900) 292
(37300) 283
(39800) 295
(38000) 285
(37300)
(34700)
404
382
340
293
285
(8900)
(9200)
(4600)
409
387
342
(8200)
(8500)
(4400)
411
392
340
(7200)
(7500)
(4400)
407
393
339
(7000)
(7100)
(4300)
411
393
(7400)
(7700)
sh 339 (4400)
(29600) 296
(32600) 290
(29100) 296
(29100) 290
(32000) 291
(32500) 287
(31700) 296
(32100) 289
(31100)
(30800)
7b
8
422
397
(11100) 424
(12500) 399
(12300) 424
(13100) 400
(11200) 420
(12000) 400
(10200) 425
(10600) 402
(11100)
(11600)
sh 298 (3200)
sh 300 (3200)
sh 298 (4100)
sh 299 (4600)
sh 298 (4500)
261
(15000)
263
(17300) 260 (19300) 261
(19300)
425
401
(7300)
(9200)
427
404
(10000) 426
(10800) 404
(9700)
sh 422 (8800)
sh 426 (9100)
(10500) 403
(9300)
407
sh 301 (5600)
(21400) 261 (21700)
(25300)
(9700)
sh 297 (3900)
sh 256 (15100)
sh 299 (4400)
sh 300 (5100)
sh 299 (5800)
(19800) 261
(22800) 243
261
244
All of the pigments studied, 1–8, were fluorescent, in some cases the fluo-
rescence was exceptionally strong with fluorescence quantum yields (ꢂF) ꢁ 0.9
(Table 2). The fluorescence was clearly influenced by the choice of solvent. For

Carbonyl-Bridged Isodipyrrinones
559
Table 2. Solvent dependence of the fluorescence excitation (ꢃex=nm) and emission (ꢃem=nm) wave-
lengths and quantum yields (ꢂF) of 1–8
Compound
Cyclo-C6H12
C6H6
CHCl3
ꢃex
ꢃem
ꢂF
ꢃex
ꢃem
ꢂF
ꢃex
ꢃem
ꢂF
1 (ꢀꢁꢁ)
2 (ꢀꢁꢁ)
3 (ꢀꢁꢀ)
4 (ꢀꢁꢀ)
5 (ꢀꢁꢀ)
6 (ꢀꢁꢀ)
7b (ꢀꢀꢁ)
8 (ꢀꢀꢁ)
385
381
356
359
364
396
400
396
435
441
474
466
407
449
453
465
0.02
0.21
0.13
0.12
0.01
0.02
0.01
0.27
381
408
355
361
396
408
400
400
449
453
476
480
451
453
456
456
0.70
0.75
0.22
0.27
0.09
0.10
0.06
0.82
388
396
359
365
404
410
398
399
455
450
494
498
459
467
455
477
0.86
0.86
0.29
0.31
0.54
0.60
0.14
0.87
Compound
CH3OH
(CH3)2SO
ꢃex
ꢃem
ꢂF
ꢃex
ꢃem
ꢂF
1 (ꢀꢁꢁ)
2 (ꢀꢁꢁ)
3 (ꢀꢁꢀ)
4 (ꢀꢁꢀ)
5 (ꢀꢁꢀ)
6 (ꢀꢁꢀ)
7b (ꢀꢀꢁ)
8 (ꢀꢀꢁ)
411
410
363
369
398
396
397
397
489
492
548
542
508
505
502
513
0.73
0.71
0.02
0.04
0.10
0.13
0.56
0.28
411
397
365
368
397
396
398
407
479
479
514
510
475
476
484
499
0.91
0.88
0.08
0.15
0.59
0.67
0.46
0.71
example, 1 exhibits large ꢂF values in all solvents studied, except for cyclohex-
ane, in which it was least soluble. In such instances, diminished fluorescence
attended 2 (in cyclohexane) and 3 (insoluble in most solvents), 4, 5, 6, and 7 in
all but CHCl3 and (CH3)2SO (where they are most soluble). The fluorescence is
probably quenched by self-association (aggregation). This possibility is supported
by the hypsochromic shifts of both ꢃex and ꢃem from weakly fluorescing so-
lutions of 1–8, vs. solutions with strong fluorescence: typically (CH3)2SO and
CHCl3. Selected fluorescence emission and UV-visible absorption curves for
1–8 may be seen in Fig. 4, and a comparison of the normalized fluorescence
emission spectra of 2, 4, 7b, and xanthoglow (XG) may be seen in Fig. 5. From
the latter, the xanthoglow emission ꢃmax (Fig. 1) is clearly redshifted from those
of 1–8, and the most soluble of 1–8 tend to give the larger emission intensities
(and ꢂF, Table 2).
Concluding Comments
New tricyclic skeletal types (ꢀꢁꢁ and ꢀꢁꢀ, 1–6) based on isodipyrrinones are
readily prepared in ‘‘one-pot’’ syntheses. The new carbonyl-bridged isodipyrri-
nones are intensely fluorescent (ꢂF ꢁ 0.9, ꢃem ꢁ 450–515 nm) in organic solvents

560
S. E. Boiadjiev and D. A. Lightner
Fig. 4. Comparison of the fluorescence emission and excitation spectra (upper) and UV-visible
absorption spectra (lower) of dipyrrinones 1, 4, 5, and 8 in CHCl3 and CH3OH
in which they exhibit good solubility (CHCl3, (CH3)2SO), but only weak fluores-
cence (ꢂF ꢁ 0.01–0.1, ꢃem ꢁ 450–550 nm) in solvents such as cyclohexane. Similar
results are found with new members (7 and 8) of the ꢀꢀꢁ skeletal type based on
bridged (4Z)-dipyrrinones in the anti conformation.

Carbonyl-Bridged Isodipyrrinones
561
Fig. 5. Normalized relative fluorescence of 2, 4, 7b, and xanthoglow (XG) in CHCl3
Experimental
All fluorescence spectra were measured on a Jobin Yvon Fluorolog 3 model FL 3-22 instrument by
using constant spectral parameters: step resolution (increment) of 1 nm, both excitation and emission
slits of 2 nm and integration time of 0.5 sec and were uncorrected. The UV-visible spectra were
recorded on a Perkin-Elmer Lambda 12 spectrophotometer. NMR spectra were acquired on a Varian
Unity Plus spectrometer at 11.75 T magnetic field strength operating at 1H frequency of 500MHz and
1
13C frequency of 125 MHz in solutions of CDCl3 (referenced at 7.26ppm for H and 77.00 ppm for
1
13C) or (CD3)2SO (referenced at 2.49 ppm for H and 39.50 ppm for 13C). J-Modulated spin-echo
(Attached Proton Test) and gHMBC experiments were used to assign the 13C NMR spectra. Gas
chromatography-mass spectrometry analyses were carried out on a Hewlett-Packard 5890A gas chro-
matograph (30 m DB-1 column) equipped with a Hewlett-Packard 5970 mass selective detector. Radial
chromatography was carried out on Merck silica gel PF254 with CaSO4 binder preparative layer grade,
using a Chromatotron (Harrison Research, Inc., Palo Alto, CA) with 1, 2, or 4 mm thick rotors and
analytical thin-layer chromatography was carried out on J. T. Baker silica gel IB-F plates (125 ꢄm
layer). Melting points were determined on a Mel-Temp capillary apparatus and are uncorrected. The
combustion analyses were carried out by Desert Analytics, Tucson, AZ; their results agreed favourably
with the calculated values.

562
S. E. Boiadjiev and D. A. Lightner
The spectral data were obtained in spectral grade solvents (Aldrich or Fisher) which were distilled
under Ar stream just prior to use. Before the distillation CHCl3 was passed through a basic alumina
column. Distillation of (CH3)2SO was carried out at 0.5 mm Hg vacuum collecting the solvent at
0ꢄC and thawing it under Ar. The starting compounds, 4-ethyl-3-methyl-3-pyrrolin-2-one (9) [12],
ethyl 2,5-dimethyl-1H-pyrrole-3-carboxylate [13], benzyl 4,5-dimethyl-1H-pyrrole-2-carboxylate [14],
dimethyl 3-formyl-4-methyl-1H-pyrrole-2,5-dicarboxylate (14) [15], and diethyl 1H-pyrrole-3,4-dicar-
boxylate [16], were synthesized according to literature methods.
Ethyl 2,5-dimethyl-4-formyl-1H-pyrrole-3-carboxylate (10, C10H13NO3)
To N2-protected anhydrous DMF (1.55 cm3, 20mmol) were added 1.49cm3 (16 mmol) of phosphorus
oxychloride during 8 min at 0ꢄC, and the mixture was stirred at the same temperature for 30 min. 1,2-
Dichloroethane (8cm3) was added, followed by a solution of ethyl 2,5-dimethyl-1H-pyrrole-3-carbox-
ylate [13] (1.67 g, 10 mmol) in 15 cm3 of 1,2-dichloroethane and the mixture was heated at reflux for
45min. After slight cooling, a solution of 7.00g (50 mmol) of sodium acetate trihydrate in 15cm3 of
H2O was added and the mixture was reheated at reflux for 30min. After cooling, the product was
extracted with CH2Cl2, washed with H2O, dried (MgSO4), filtered through a short silica pad, and the
solvent was evaporated under vacuum. The residue was recrystallized from ethyl acetate-hexane to
afford 10. Yield 1.70g (87%); mp 151–152ꢄC (Ref. [17] 151–152ꢄC); 1H NMR (CDCl3): ꢅ ¼ 1.36 (3H,
t, J ¼ 7.2 Hz), 2.49 (3H, s), 2.52 (3H, s), 4.32 (2H, q, J ¼ 7.2 Hz), 9.35 (1H, br.s), 10.41 (1H, s) ppm;
13C NMR (CDCl3): ꢅ ¼ 13.20, 13.44, 14.39, 60.06, 111.88, 120.15, 135.39, 135.72, 165.18,
190.30 ppm.
Ethyl 4-formyl-1,2,5-trimethyl-1H-pyrrole-3-carboxylate (11, C11H15NO3)
To a solution of 1.95 g (10 mmol) of pyrrole 10 in 25cm3 of anh. DMSO, protected under N2, was
added 1.23g (11 mmol) of potassium t-butoxide, and the mixture was stirred for 1 h. Methyl iodide
(0.92 cm3, 15mmol) was then added, and stirring was continued at 60ꢄC for 2 h. After cooling, the
mixture was diluted with 100 cm3 of CHCl3 and washed with 2% aq. HCl (50cm3) and H2O
(4ꢅ 50cm3). The solution was dried (MgSO4) and filtered, and the solvent was evaporated under
vacuum. Recrystallization of the residue from ethyl acetate-hexane afforded 11. Yield 1.67g (80%);
mp 89–90ꢄC; 1H NMR (CDCl3): ꢅ ¼ 1.35 (3H, t, J ¼ 7.2 Hz), 2.50 (3H, s), 2.53 (3H, s), 3.42 (3H, s),
4.30 (2H, q, J ¼ 7.2 Hz), 10.39 (1H, s) ppm; 13C NMR (CDCl3): ꢅ ¼ 11.46, 11.56, 14.39, 30.01, 59.92,
111.76, 119.66, 136.34, 136.56, 164.99, 189.93ppm.
Benzyl 4,5-dimethyl-3-formyl-1H-pyrrole-2-carboxylate (12, C15H15NO3)
Aldehyde 12 was obtained following the same procedure for Vilsmeier formylation as for 10. Yield
69% (after recrystallization from CH3OH–H2O); mp 146–147ꢄC; 1H NMR (CDCl3): ꢅ ¼ 2.21 (3H, s),
2.24 (3H, s), 5.35 (2H, s), 7.34–7.44 (5H, m), 9.20 (1H, br.s), 10.55 (1H, s) ppm; 13C NMR (CDCl3):
ꢅ ¼ 10.41, 10.45, 66.74, 119.52, 123.68, 126.59, 128.18, 128.40, 128.56, 130.98, 135.17, 160.00,
189.50 ppm.
Benzyl 3-formyl-1,4,5-trimethyl-1H-pyrrole-2-carboxylate (13, C16H17NO3)
Following the same procedure as above for 11, formylpyrrole 12 was N-methylated to afford 13. Yield
86%; mp 71–72ꢄC; 1H NMR (CDCl3): ꢅ ¼ 2.17 (3H, s), 2.25 (3H, s), 3.83 (3H, s), 5.36 (2H, s), 7.32–
7.42 (5H, m), 10.47 (1H, s) ppm; 13C NMR (CDCl3): ꢅ ¼ 9.66, 10.70, 33.25, 66.56, 118.60, 124.98,
127.01, 128.35, 128.40, 128.65, 133.98, 135.48, 160.39, 189.86ppm.

Carbonyl-Bridged Isodipyrrinones
563
Dimethyl 1,4-dimethyl-3-formyl-1H-pyrrole-2,5-dicarboxylate (15, C11H13NO5)
Formylpyrrole 14 [15] (1.13 g, 5 mmol) was dissolved in a solution of 0.28g (5mmol) of KOH in
5 cm3 of CH3OH at ꢁ55ꢄC. Dimethylsulfate (0.65 cm3, 6.5mmol) was added during 2 min, and the
mixture was stirred for 45min while cooling slowly from 55ꢄC to ambient temperature. The separated
product was collected by filtration, purified by radial chromatography, and recrystallized from ethyl
1
acetate-hexane to give 15. Yield 0.91 g (76%); mp 110–111ꢄC; H NMR (CDCl3): ꢅ ¼ 2.54 (3H, s),
3.91 (3H, s), 3.96 (3H, s), 4.11 (3H, s), 10.32 (1H, s) ppm; 13C NMR (CDCl3): ꢅ ¼ 11.80, 35.59, 51.69,
52.45, 125.67, 125.82, 129.56, 131.21, 160.59, 161.80, 188.53 ppm.
Diethyl 2-formyl-1H-pyrrole-3,4-dicarboxylate (16, C11H13NO5)
Aldehyde 16 was synthesized following the same procedure for Vilsmeier formylation as above for 10,
except the reaction time was 1.5h. Yield 73% (after recrystallization from ethyl acetate-hexane);
1
mp 70–71ꢄC; H NMR (CDCl3): ꢅ ¼ 1.34 (3H, t, J ¼ 7.2Hz), 1.39 (3H, t, J ¼ 7.2 Hz), 4.31 (2H, q,
J ¼ 7.2 Hz), 4.41 (2H, q, J ¼ 7.2 Hz), 7.59 (1H, dd, 3J ¼ 3.3 Hz, 5J ¼ 0.9Hz), 9.88 (1H, d, 5J ¼ 0.9 Hz),
10.53 (1H, br.s) ppm; 13C NMR (CDCl3): ꢅ ¼ 14.05, 14.10, 60.74, 61.69, 118.07, 124.32, 129.02,
132.34, 162.74, 163.23, 180.97 ppm.
Diethyl 2-formyl-1-(3-methylbutyl)-1H-pyrrole-3,4-dicarboxylate (17, C16H23NO5)
Following the same procedure as above for 11, the formylpyrrole 16 was N-alkylated using iso-amyl
iodide to afford 17 as a colorless oil. Yield 90%; 1H NMR (CDCl3): ꢅ ¼ 0.95 (6H, d, J ¼ 6.2 Hz), 1.32
(3H, t, J ¼ 7.2 Hz), 1.38 (3H, t, J ¼ 7.2 Hz), 1.56–1.65 (3H, m), 4.28 (2H, q, J ¼ 7.2 Hz), 4.32 (2H, t,
J ¼ 7.4 Hz), 4.40 (2H, q, J ¼ 7.2 Hz), 7.38 (1H, s), 9.82 (1H, s) ppm; 13C NMR (CDCl3): ꢅ ¼ 14.04,
14.15, 22.22, 25.51, 39.82, 48.54, 60.52, 61.75, 115.51, 128.43, 129.66, 132.37, 162.29, 163.80,
180.16 ppm.
General Procedure for Condensation-Cyclization
A mixture of 6.0 mmol of pyrrolinone 9 [12], 4.0 mmol of the corresponding pyrrolealdehyde, 15cm3
of abs. ethanol and 2.25cm3 (15.0 mmol) of DBU was heated in a thick walled sealed tube under Ar at
85–90ꢄC for 72h. After cooling, about 7 cm3 of ethanol were evaporated under a stream of N2, and the
residue was diluted with 2 cm3 of acetic acid and 6 cm3 of H2O. The mixture was cooled at 0ꢄC to
ꢃ10ꢄC, and the precipitated product was collected by filtration (or in cases of incomplete crystal-
lization – extracted with CHCl3). Purification by recrystallization or radial chromatography afforded
pure bright yellow tricyclics.
8-Ethyl-1,3,7-trimethylpyrrolo[3,4-f]indolizine-4,6-dione (1, C15H16N2O2)
1
Yield 62%; mp 353–355ꢄC (dec.); H NMR ((CD3)2SO at 60ꢄC): ꢅ ¼ 1.14 (3H, t, J ¼ 7.6 Hz), 1.81
(3H, s), 2.30 (3H, s), 2.48 (3H, s), 2.54 (2H, q, J ¼ 7.6 Hz), 6.78 (1H, s), 11.59 (1H, br.s) ppm; 13C
NMR ((CD3)2SO at 60ꢄC): ꢅ ¼ 7.63, 10.08, 11.75, 13.55, 17.00, 101.38, 109.87, 117.53, 123.34,
124.41, 133.30, 133.57, 146.63, 157.48, 167.77ppm.
8-Ethyl-1,2,3,7-tetramethylpyrrolo[3,4-f]indolizine-4,6-dione (2, C16H18N2O2)
Yield 73%; mp 252–254ꢄC; 1H NMR (CDCl3): ꢅ ¼ 1.19 (3H, t, J ¼ 7.7 Hz), 1.91 (3H, s), 2.30 (3H, s),
2.50 (2H, q, J ¼ 7.7 Hz), 2.63 (3H, s), 3.46 (3H, s), 6.32 (1H, s) ppm; 13C NMR (CDCl3): ꢅ ¼ 8.21,
10.15, 11.06, 13.90, 17.89, 30.43, 99.77, 110.49, 117.88, 124.21, 126.09, 134.63, 135.44, 146.38,
158.37, 169.04 ppm.

564
S. E. Boiadjiev and D. A. Lightner
5-Ethyl-2,3,6-trimethylpyrrolo[2,3-f]indolizine-7,9-dione (3, C15H16N2O2)
1
Yield 75%; mp 337–339ꢄC (dec); H NMR ((CD3)2SO at 60ꢄC): ꢅ ¼ 1.15 (3H, t, J ¼ 7.6 Hz), 1.82
(3H, s), 2.06 (3H, s), 2.20 (3H, s), 2.55 (2H, q, J ¼ 7.6 Hz), 6.75 (1H, s), 11.90 (1H, br.s) ppm; 13C
NMR ((CD3)2SO at 60ꢄC): ꢅ ¼ 7.44, 7.80, 10.59, 13.14, 17.00, 100.29, 111.35, 121.52, 124.34, 128.18,
134.80, 135.52, 148.03, 150.94, 168.20 ppm.
5-Ethyl-1,2,3,6-tetramethylpyrrolo[2,3-f]indolizine-7,9-dione (4, C16H18N2O2)
Yield 47%; mp 211–213ꢄC; 1H NMR (CDCl3): ꢅ ¼ 1.20 (3H, t, J ¼ 7.7 Hz), 1.91 (3H, s), 2.08 (3H, s),
2.19 (3H, s), 2.50 (2H, q, J ¼ 7.7Hz), 4.00 (3H, s), 6.37 (1H, s) ppm; 13C NMR (CDCl3): ꢅ ¼ 8.15,
8.69, 9.90, 13.66, 17.92, 32.21, 99.42, 111.40, 121.78, 125.92, 128.29, 135.45, 137.37, 147.48, 153.08,
169.35 ppm.
Methyl 3,6-dimethyl-5-ethylpyrrolo[2,3-f]indolizine-7,9-dione-
2-carboxylate (5, C16H16N2O4)
1
Yield 65%; mp 298–300ꢄC (dec); H NMR ((CD3)2SO at 60ꢄC): ꢅ ¼ 1.16 (3H, t, J ¼ 7.6 Hz), 1.84
(3H, s), 2.39 (3H, s), 2.58 (2H, q, J ¼ 7.6 Hz), 3.82 (3H, s), 6.88 (1H, s), 12.73 (1H, br.s) ppm; 13C
NMR ((CD3)2SO at 60ꢄC): ꢅ ¼ 7.50, 9.41, 13.03, 17.02, 51.16, 99.63, 121.71, 125.06, 125.65, 126.09,
127.65, 135.35, 148.31, 151.21, 160.55, 167.85ppm.
Methyl 5-ethyl-1,3,6-trimethylpyrrolo[2,3-f]indolizine-7,9-dione-
2-carboxylate (6, C17H18N2O4)
Yield 35%; mp 219–220ꢄC; 1H NMR (CDCl3): ꢅ ¼ 1.22 (3H, t, J ¼ 7.7 Hz), 1.93 (3H, s), 2.37 (3H, s),
2.53 (2H, q, J ¼ 7.7 Hz), 3.91 (3H, s), 4.38 (3H, s), 6.44 (1H, s) ppm; 13C NMR (CDCl3): ꢅ ¼ 8.22,
10.85, 13.59, 17.98, 35.04, 51.66, 98.78, 122.45, 125.85, 126.64, 127.49, 128.24, 135.82, 147.74,
153.49, 161.81, 168.83 ppm.
Ethyl 8-ethyl-7-methylpyrrolo[3,2-f]indolizine-4,6-dione-3-carboxylate (7a, C16H16N2O4)
1
Yield 88% (crude product); mp 363–367ꢄC (dec); H NMR ((CD3)2SO at 90ꢄC): ꢅ ¼ 1.18 (3H, t,
J ¼ 7.6 Hz), 1.30 (3H, t, J ¼ 7.1Hz), 1.87 (3H, s), 2.57 (2H, q, J ¼ 7.6 Hz), 4.23 (2H, q, J ¼ 7.1 Hz), 6.69
(1H, s), 7.62 (1H, d, J ¼ 2.7 Hz), 12.00 (1H, br.s) ppm; 13C NMR ((CD3)2SO at 90ꢄC): ꢅ ¼ 7.35, 12.59,
13.66, 16.77, 59.08, 94.92, 113.67, 115.14, 126.33, 128.69, 137.54, 138.48, 146.21, 153.50, 162.22,
7
167.84ppm; HRMS (FAB, 3-NBA þ Li): calcd for C16H16N2O4 ꢂ Li 307.1270; found 307.1275.
Ethyl 8-ethyl-7-methyl-1-(3-methylbutyl)pyrrolo[3,2-f]indolizine-4,6-dione-
3-carboxylate (7b, C21H26N2O4)
To a mixture of 300 mg (1.0mmol) of 7a and 8 cm3 of anh. DMF under Ar was added Cs2CO3
(652 mg, 2.0mmol) followed by 1.3 cm3 (10.0 mmol) of iso-amyl iodide, and the mixture was stirred
at 85–90ꢄC for 16 h. After cooling, the product was partitioned between 100cm3 of CHCl3 and
100 cm3 of H2O. The organic layer was washed with 1% aq. HCl (100cm3) and H2O (4ꢅ 50cm3),
and then dried (anh. Na2SO4). After filtration and removal of solvent, the residue was purified by radial
chromatography and recrystallization from ethyl acetate–hexane to give 318 mg (86%) of 7b. Yield
1
86%; mp 158–159ꢄC; H NMR (CDCl3): ꢅ ¼ 0.96 (6H, d, J ¼ 6.6 Hz), 1.19 (3H, t, J ¼ 7.7 Hz), 1.38
(3H, t, J ¼ 7.2 Hz), 1.54–1.64 (1H, m), 1.66–1.70 (2H, m), 1.91 (3H, s), 2.51 (2H, q, J ¼ 7.7 Hz), 4.00
(2H, t, J ¼ 7.5 Hz), 4.35 (2H, q, J ¼ 7.2Hz), 6.26 (1H, s), 7.38 (1H, s) ppm; 13C NMR (CDCl3):

Carbonyl-Bridged Isodipyrrinones
565
ꢅ ¼ 8.30, 13.53, 14.36, 17.85, 22.25, 25.44, 39.29, 45.54, 60.65, 92.21, 115.14, 116.28, 128.03, 131.32,
137.92, 139.54, 146.15, 154.61, 163.41, 168.68ppm.
3-Carboxy-8-ethyl-7-methyl-1-(3-methylbutyl)pyrrolo[3,2-f]indolizine-
4,6-dione (8, C19H22N2O4)
1
Yield 7%; mp 255–256ꢄC; H NMR (CDCl3): ꢅ ¼ 0.97 (6H, d, J ¼ 6.5 Hz), 1.24 (3H, t, J ¼ 7.7 Hz),
1.55–1.63 (1H, m), 1.70 (2H, dt, J ¼ 7.5, 7.2Hz), 1.96 (3H, s), 2.60 (2H, q, J ¼ 7.7 Hz), 4.07 (2H, t,
J ¼ 7.5 Hz), 6.45 (1H, s), 7.51 (1H, s), 14.07 (1H, s) ppm; 13C NMR (CDCl3): ꢅ ¼ 8.33, 13.19, 18.15,
22.21, 25.43, 38.95, 45.94, 93.61, 113.19, 116.22, 127.89, 133.52, 138.44, 139.16, 148.96, 158.71,
162.79, 167.73 ppm.
Acknowledgements
We thank the U.S. National Institutes of Health (HD 17779) for generous support of this research. We
also thank Prof. S.-W. Tam-Chang for use of the spectrofluorimeter. Dr. S. E. Boiadjiev is on leave from
the Institute of Organic Chemistry, Sofia, Bulgaria.
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