Syntheses and properties of benzodipyrrinones

Article abstract of DOI:10.1002/jhet.5570400127

2,3-Benzannelated dipyrrinone analogs (1 and 2) of xanthobilirubic acid (3) are prepared by base-catalyzed condensation of isoindolinone (5) and indolin-2-one (6) respectively, with methyl 3-(2-formyl-3,5-dimethyl-1H-pyrrol-4-yl)propanoate (4). Nuclear Overhauser effect H-nmr studies indicate that both 1 and 2 adopt preferentially a syn-Z configuration. The former forms a hydrogen-bonded homodimer in nonpolar solvents; the latter is intramolecularly hydrogen bonded.

Full text of DOI:10.1002/jhet.5570400127

Jan-Feb 2003
Syntheses and Properties of Benzodipyrrinones
181
Stefan E. Boiadjiev and David A. Lightner*
Department of Chemistry, University of Nevada
Reno, NV 89557-0020
Received September 30, 2002
2,3-Benzannelated dipyrrinone analogs (1 and 2) of xanthobilirubic acid (3) are prepared by base-cat-
alyzed condensation of isoindolinone (5) and indolin-2-one (6) respectively, with methyl 3-(2-formyl-3,5-
dimethyl-1H-pyrrol-4-yl)propanoate (4). Nuclear Overhauser effect H-nmr studies indicate that both 1 and
2 adopt preferentially a syn-Z configuration. The former forms a hydrogen-bonded homodimer in nonpolar
solvents; the latter is intramolecularly hydrogen bonded.
J. Heterocyclic Chem., 40, 181 (2003).
commercially available 6 with 1.1 equivalents of 4b in
methanol at reflux in the presence of 0.5 equivalents of
piperidine. Condensation of the free propionic acid-alde-
hyde 4a with 6 was conducted at a higher temperature in
ethanol (reflux), using excess (2 equivalents) of piperidine.
Condensation of 4b with 5 proved to be unexpectedly dif-
ficult, suggesting that 5 was less reactive than 3,4-alkyl-
substituted pyrrolinones in the same reaction. Although a
literature report [8] that various salicylaldehydes condense
in high yields with 6 in aqueous sodium hydroxide at
reflux, reaction of 4b or 4a with 5 in the same type of con-
densation conditions afforded only a 6% yield of 1b after
treatment with diazomethane. Numerous combinations of
bases (1,8-diazabicyclo[5.4.0]undec-7-ene, diethyl amine,
piperidine) and solvents (t-butanol, 1,2-dimethoxyethane,
dimethylsulfoxide, acetonitrile), with or without t-Boc
protection on the nitrogen of 4b or 5 were ineffective,
affording only low yields of 1b or inducing decomposi-
tion. The best yields (21-32%) of 1b were obtained by car-
rying out the condensation of 4b and 5 in dry, deoxy-
genated dimethylformamide with 2.5 equivalents of
piperidine at 85-90 °C for 48 hours.
Introduction.
Porphyrins with aromatic rings fused at the β-positions
have been a subject of recent syntheses and investigations
[1]. Although linear tetrapyrroles have been prepared with
aromatic rings attached [2], those with fused aromatic
rings are largely unknown. In the following, we report the
first 2,3-benzodipyrrinone analog (1, Figure 1) of methyl
xanthobilirubinate (3b) [3], a synthetic precursor to meso-
bilirubin-XIIIα and its verdin [4] and related linear
tetrapyrroles [5]. In addition, we report on 2, a lactam
moiety reversed constitutional isomer of 1, and compare
the properties of these two dipyrrinones.
The constitutional structures of 1b and 2b follow from
the structures of the reactants and the reaction mechanism,
and they are confirmed by their carbon-13 nmr spectral
assignments, assisted by HMQC and HMBC 2D experi-
ments. Switching the orientation of the lactam (−NH−
C=O) moiety in going from 1 to 2 strongly affects most of
the carbon-13 nmr chemical shifts. Only a few remain
1
constant: lactam C=O, 7′–CH , 10–CH , 8 –CH ,
3
3
2
2
3
8 –CH , 8 C=O and OCH . All benzo ring carbons of 1b
2
3
are more deshielded than their counterparts in 2b, except
C(2), which is ~10 ppm more shielded. In contrast, the
pyrrole ring carbons and C(5) are generally more shielded
in 1b than the corresponding carbons in 2b.
Distinctions also appear in comparing the H-nmr spectra
of 1b and 2b: the methine hydrogen at C(5) is ~0.8 ppm
more shielded in 1b than in 2b, and the aromatic ring
hydrogens of 1b are all more deshielded than in 2b. The
pyrrole and lactam NHs of 1b appear in the typical places
for dipyrrinones that form hydrogen-bonded dimers in deu-
teriochloroform. However, in 2b, the pyrrole NH is very
Figure 1. Structures, numbering system and preferred conformations of
benzo analogs 1 and 2 of xanthobilirubic acid 3a.
Synthesis.
The common pyrrole reactant for the syntheses of 1 and
2 is pyrrole aldehyde 4b [6] which was condensed with
isoindolinone 5 (prepared from o-toluic acid, as reported
previously [7]) to give 1b and 2-indolinone (6) to give 2b
(Scheme 1). The condensation to give 2b proceeded
rapidly and smoothly in high yield (79%) from reaction of

182
S. E. Boiadjiev and D. A. Lightner
Vol. 40
[a] Reagents and conditions: i, piperidine in N,N-dimethylformamide at 90 °C; ii, aqueous sodium hydroxide in methanol; iii, piperidine in methanol
at 65 °C, or in ethanol at 78 °C.
Table 1
strongly deshielded, which suggests a strong intramolecular
Nmr Spectral Assignments for Dipyrrinone 1b and Its Isomer 2b in
hydrogen bond (to the nearby lactam carbonyl).
The syn-Z configuration in both 1b and 2b is revealed by
Deuteriochloroform at 25 °C
nuclear Overhauser effect (nOe) nmr measurements (Figure
Assignment
1b (δ, ppm)
C
2b (δ, ppm)
C
13
1
13
1
2). Thus, the strong nOe seen between the C(5) methine and
the ortho′ ring hydrogen confirms a Z configuration in both
1b and in 2b. In the former, the nOe seen between the
pyrrole and lactam NHs is also consistent with the Z. A syn
orientation is confirmed by nOe's observed between the
C(5) methine and the C(7′)-methyl in both 1b and 2b. The
likelihood that 1b is actually present as an intermolecularly
hydrogen-bonded dimer is suggested by the weak nOe seen
between the C(10)-methyl and the ortho hydrogen, consis-
tent with studies of other dipyrrinones [9].
H
H
lactam CO
170.39
126.94
139.28
123.84
99.14
122.08
122.89
9.61
170.02
137.13
126.53
111.92
123.37
126.34
130.02
9.74
2
3
4
5
6
7
6.55
2.19
7.39
2.28
7'–CH
3
8
9
119.02
130.95
11.68
123.05
118.96
126.83
131.60
19.89
121.72
134.75
12.22
109.28
117.21
125.41
121.38
19.84
10–CH
2.52
7.76
7.79
7.39
7.57
2.77
2.49
2.36
6.89
7.47
7.12
7.04
2.78
2.48
3
o
o'
m
m'
1
8 –CH
2
2
8 –CH
35.13
34.78
2
3
8 –CO
173.75
51.57
173.46
51.60
OCH
3.70
10.25
11.82
3.68
13.19
8.35
3
pyrrole NH
lactam NH
solvent. In 1b, both the lactam and pyrrole chemical shifts
drift upfield with increasing dilution, as has been seen pre-
viously with 3b [9a]. In 2b, only the lactam NH moves
upfield with increasing dilution; the pyrrole NH remains at
a nearly constant chemical shift. These observations are
consistent with a tightly intramolecularly hydrogen
bonded pyrrole NH and a lactam to lactam type intermole-
Figure 2. Nuclear Overhauser effect enhancements observed for 1b and
2b in deuteriochloroform solvent are shown by double headed curved
arrows. A weak nOe is denoted by the dotted arrow.
cularly hydrogen-bonded dimer. The observation that the
-3
lactam chemical shift levels out at approximately 10
M
A concentration-dependence of the NH H-nmr chemical
shifts in 1b and 2b (Table 2) further suggests the presence
of a monomer-dimer equilibrium in deuteriochloroform
concentration indicates that the dimer association constant
in 2b is much less than that of 1b (Figure 3).

Jan-Feb 2003
Syntheses and Properties of Benzodipyrrinones
183
Table
2
Concentration Dependence of Lactam and Pyrrole NH Chemical Shifts
of 1b and 2b in Deuteriochloroform Solvent at 25 °C
1b
Concentration Lactam
(moles/liter) NH
δ (ppm)
2b
Pyrrole Concentration Lactam Pyrrole
NH
δ (ppm)
(moles/liter)
NH
NH
δ (ppm) δ (ppm)
-2
-2
4.84 x 10
2.75 x 10
1.04 x 10
1.04 x 10
1.04 x 10
1.04 x 10
11.832
11.785
11.795
11.495
10.686
9.75 – 8.68
10.251 3.78 x 10
10.245 2.28 x 10
10.240 1.02 x 10
10.059 1.02 x 10
8.913
8.352
7.699
7.508
7.484
7.482
13.211
13.190
13.158
13.148
13.148
13.149
-2
-2
-3
-4
-5
-2
-2
-3
-4
-5
9.535
1.02 x 10
1.02 x 10
Figure 4. UV-vis spectra of dipyrrinone 1b ( - - - - -), 2b (–––––) and 3b
(ÆÆÆÆÆ) in chloroform (upper), methanol (middle) and dimethyl sulfox-
ide (lower).
EXPERIMENTAL
Figure 3. Concentration dependence of NH chemical shifts of dipyrrinone
1b (upper) and its regioisomer 2b (lower) in CDCl solution at 25 °C (pC
3
Nuclear magnetic resonance (nmr) spectra were obtained on a
Varian Unity Plus spectrometer operating at 500 MHz (proton)
= -log concentration).
10
and 125 MHz (C-13) in dimethylsulfoxide-d solvent, unless oth-
6
erwise indicated. Chemical shifts are reported in ppm referenced
The colors of 1b and 2b differ, with the latter being more
reddish. Thus, the long wavelength uv-visible absorption
in 2b is typically strongly red-shifted relative to that of 1b,
which is only slightly red-shifted relative to that of 3b
(Figure 4). The absorption intensitities are comparable,
and quite similar uv-visible spectral differences are found
for the corresponding carboxylic acids (1a, 2a and 3a).
to the residual dimethylsulfoxide-d proton signal at 2.49 ppm
5
and the C-13 signal at 39.5 ppm. Melting points were taken on a
Mel-Temp capillary apparatus and are uncorrected. Analytical
thin layer chromatography was performed on J.T. Baker silica gel
IB-F plates (125 µm layers). Radial chromatography used Merck
silica gel PF
with calcium sulfate binder. All solvents were
254
reagent grade obtained from Fisher. N,N-Dimethylformamide

184
S. E. Boiadjiev and D. A. Lightner
Vol. 40
and methanol were from Fisher; piperidine and 2-indolinone (6)
were purchased from Acros. Deuterated chloroform and
2.60 (2H, t, J = 7.6 Hz), 3.57 (3H, s), 6.51 (1H, s), 7.40 (1H,
3
3
dd, J = 7.5; 7.6 Hz), 7.59 (1H, dd, J = 7.5; 7.6 Hz), 7.68 (1H,
3
3
dimethylsulfoxide-d were from Cambridge Isotope
d, J = 7.6 Hz), 8.03 (1H, d, J = 7.6 Hz), 10.39 (1H, s), 10.52
6
13
Laboratories. Oxisoindole (5) [7] and 3,5-dimethyl-4-(2-
methoxycarbonylethyl)-1H-pyrrole-2-aldehyde [6] were pre-
pared according to modified literature procedures.
(1H, s) ppm; C nmr: δ 9.21, 10.9, 19.4, 34.6, 51.2, 96.5,
118.3, 119.6, 121.5, 121.9, 122.5, 123.1, 126.9, 127.1, 129.2,
131.5, 139.0, 168.0, 172.9 ppm; uv-visible (carbon tetrachlo-
ride): λ sh 450, ε, 20600; λ
26600; (N-methylformamide): λ
420, ε, 38200; λ sh 400, ε,
max
3,5-Dimethyl-4-(2-methoxycarbonylethyl)-1H-pyrrole-2-alde-
hyde (4b).
415, ε, 33200.
max
Anal. Calcd for C H N O (324.4): C, 70.35; H, 6.22; N,
19 20
2 3
To a solution of 5.62 g (20 mmoles) tert-butyl 3,5-dimethyl-4-
(2-methoxycarbonylethyl)-1H-pyrrole-2-carboxylate [10] in 15
ml of anhydrous dichloromethane was added 40 ml of trifluo-
roacetic acid, and the mixture was stirred for 20 minutes while
cooling with an ice bath. Then triethylorthoformate (11 ml, 100
mmoles) was added at 4 °C during 5 minutes and stirring was
continued for 15 minutes more. The mixture was poured into 100
ml of water-ice and then diluted with a solution of 12.0 g of
sodium hydroxide in 30 ml of water. The product was extracted
into chloroform (3 x 100 ml). The combined extracts were
washed with 5% aqueous sodium bicarbonate (2 x 50 ml), water
(3 x 50 ml) and dried over anhydrous sodium sulfate. After fil-
tration through a short pad of silica gel, the solvent was evapo-
rated under vacuum, and the residue was recrystallized from
hexane-dichloromethane to afford 3.65 g (87%) of aldehyde 4b.
8.64. Found: C, 70.44; H, 6.34; N, 8.60.
(Z)-[(3,5-Dimethyl-4-(2-carboxyethyl)-1H-pyrrol-2-yl)-methyli-
denyl]-isoindolinone (1a).
A mixture of 162 mg (0.50 mmoles) of methyl ester 1b, 20 ml
of dichloromethane, 7 ml of methanol and 5 ml of 1 M aqueous
sodium hydroxide (5.00 mmoles) was heated at reflux, and the
dichloromethane was removed completely by distillation. The
homogeneous residue was heated at reflux for 3 hours. After
cooling, water (10 ml) was added, and the methanol solvent was
evaporated under vacuum. The residue was cooled in an ice bath
and acidified with 10% aqueous hydrochloric acid to pH <4. The
precipitated product was collected by filtration, washed with
water (3 x 5 ml) and dried under vacuum for 24 hours (P O ) to
2
5
1
afford 146 mg (94%) of acid 1a; mp 303-305 °C (dec.); H nmr:
δ 2.10 (3H, s), 2.20 (3H, s), 2.29 (2H, t, J = 7.7 Hz), 2.57 (2H, t,
1
It had mp 129-130 °C (lit [6a] 123-125 °C); H nmr (deuterio-
3
chloroform): δ 2.26 (3H, s), 2.27 (3H, s), 2.45 (2H, t, J = 7.8 Hz),
2.71 (2H, t, J = 7.8 Hz), 3.66 (3H, s), 9.43 (1H, s), 10.29 (1H,
J = 7.7 Hz), 6.52 (1H, s), 7.40 (1H, dd, J = 7.6; 7.4 Hz), 7.59
3
3
(1H, dd, J = 7.8; 7.4 Hz); 7.68 (1H, d, J = 7.6 Hz), 8.03 (1H, d,
3
13
J = 7.8 Hz), 10.38 (1H, s), 10.52 (1H, s), 12.01 (1H, br.s) ppm;
C nmr: δ 9.27, 11.0, 19.5, 35.0, 96.6, 118.7, 119.6, 121.4,
br.s) ppm; C nmr: δ 8.71, 11.5, 19.2, 34.6, 51.6, 120.9, 127.9,
13
132.4, 136.4, 173.3, 175.7 ppm.
122.0, 122.5, 123.0, 126.9, 127.1, 129.2, 131.5, 139.0, 168.0,
3,5-Dimethyl-4-(2-carboxyethyl)-1H-pyrrole-2-aldehyde (4a).
174.1 ppm; uv-visible (dichloromethane): λ
413, ε, 33100;
max
A mixture of 1.05 g (5 mmoles) ester 4b, 10 ml of methanol,
1.00 g (25 mmoles) of sodium hydroxide, and 3 ml of water was
heated at gentle reflux for 3.5 hours under Ar. After cooling, the
mixture was diluted with 10 ml of water, and the methanol sol-
vent was evaporated under vacuum. The residue was cooled in
an ice bath and slowly acidified with 10% aqueous hydrochloric
acid to pH <4. The separated solid was collected by filtration,
washed with cold water (3 x 20 ml) and dried overnight under
(N-methylformamide): λ
419, ε, 32700.
max
(Z)-3-[(3,5-Dimethyl-4-(2-methoxycarbonylethyl)-1H-pyrrol-2-
yl)-methylidenyl]-indolin-2-one (2b).
A mixture of 460 mg (2.2 mmoles) of aldehyde 4b, 266 mg
(2.0 mmoles) of indolin-2-one (6), 0.1 ml (1.0 mmole) of piperi-
dine, and 20 ml of anhydrous methanol was heated at reflux for 8
hours. After cooling, the mixture was chilled at -20 °C overnight.
The separated product was collected by filtration and washed
with cold methanol. Purification by radial chromatography (elu-
ent 2.0-3.5% v/v methanol in dichloromethane) and recrystalliza-
tion from dichloromethane-methanol afforded 513 mg (79%) of
vacuum (over P O ) to afford 0.86 g (88%) of acid 4a; mp 157-
2
5
1
158 °C; H nmr: δ 2.14 (3H, s), 2.19 (3H, s), 2.29 (2H, t, J = 7.6
Hz), 2.55 (2H, t, J = 7.6 Hz), 9.40 (1H, s), 11.39 (1H, br.s), 12.04
13
(1H, s) ppm; C nmr: δ 8.52, 11.0, 18.9, 34.5, 120.4, 127.5,
1
deep orange 2b; mp 216-217 °C; H nmr: δ 2.24 (3H, s), 2.27
130.7, 135.3, 174.0, 175.5 ppm.
(3H, s), 2.44 (2H, t, J = 7.6 Hz), 2.66 (2H, t, J = 7.6 Hz), 3.57
(Z)-[(3,5-Dimethyl-4-(2-methoxycarbonylethyl)-1H-pyrrol-2-
yl)-methylidenyl]-isoindolinone (1b).
3
3
(3H, s), 6.85 (1H, d, J = 7.6 Hz), 6.95 (1H, dd, J = 7.6, 7.6 Hz),
3
3
7.07 (1H, dd, J = 7.6, 7.6 Hz), 7.54 (1H, s), 7.69 (1H, d, J = 7.6
13
A mixture of 627 mg (3.00 mmoles) of aldehyde 4b, 532 mg
(4.00 mmoles) of oxisoindole 5 [7], 4 ml of anhydrous N,N-
dimethylformamide, and 1.0 ml (10.0 mmoles) of piperidine
was purged with Ar for 15 minutes, then sealed in a thick wall
glass tube and heated at 85-90 °C for 48 h. After cooling, the
mixture was diluted with 100 ml of chloroform and washed
with 5% aqueous hydrochloric acid (100 ml) and water (3 x
100 ml). After drying over anhydrous sodium sulfate, filtra-
tion and removal of the solvent under vacuum, the residue was
purified by radial chromatography (eluent 2.5-3.5% vol/vol
methanol in dichloromethane). The pure fractions, after evap-
oration, were recrystallized from dichloromethane-methanol
to afford 309 mg (32%) of bright yellow 1b; mp 248-249 °C;
Hz), 10.73 (1H, s), 13.39 (1H, s) ppm; C nmr: δ 9.35, 11.8,
19.4, 34.2, 51.2, 109.2, 112.4, 117.9, 120.7, 121.5, 123.2, 125.5,
125.7, 125.9, 129.5, 133.8, 138.0, 169.3, 172.8 ppm; uv-visible
(carbon tetrachloride): λ sh 476, ε, 26400; λ
451, ε, 36200; λ
max
sh 428, ε, 26700; λ
sh 476, ε, 22200; λ
280, ε, 8900.
278, ε, 8300; (N-methylformamide):
449, ε, 34100; λ sh 430, ε, 28400; λ
λ
max
max
max
Anal. Calcd for C H N O (324.4): C, 70.35; H, 6.22; N,
19 20
2 3
8.64. Found: C, 70.49; H, 6.26; N, 8.64.
(Z)-3-[(3,5-Dimethyl-4-(2-carboxyethyl)-1H-pyrrol-2-yl)-
methylidenyl]-indolin-2-one (2a).
A mixture of 390 mg (2.0 mmoles) of aldehyde 4a, 253 mg
(1.9 mmoles) of indolin-2-one (6), 0.4 ml (4 mmoles) of
1
H nmr: δ 2.09 (3H, s), 2.19 (3H, s), 2.39 (2H, t, J = 7.6 Hz),

Jan-Feb 2003
Syntheses and Properties of Benzodipyrrinones
185
REFERENCES AND NOTES
piperidine, and 10 ml of anhydrous ethanol was heated at gentle
reflux for 15 hours. After cooling, acetic acid (1 ml) was added
slowly followed by 0.2 ml of 10% aqueous HCl, and the mixture
was chilled at -20 °C for 6 hours. The separated product was col-
lected by filtration, washed with cold ethanol-water (9:1 v/v) and
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dried overnight under vacuum (over P O ) to afford 515 mg
2
5
1
(87%) of bright orange 2a; mp 265-267°C; H nmr: δ 2.25 (3H,
s), 2.28 (3H, s), 2.34 (2H, t, J = 7.7 Hz), 2.63 (2H, t, J = 7.7 Hz),
3
3
4
6.85 (1H, br.d, J = 7.6 Hz), 6.95 (1H, ddd, J = 7.6, 7.6 Hz, J =
3
4
1.0 Hz), 7.07 (1H, ddd, J = 7.6, 7.6 Hz, J = 1.0 Hz), 7.54 (1H,
s), 7.69 (1H, br.d, J = 7.6 Hz), 10.72 (1H, s), 12.05 (1H, br.s),
13.38 (1H, s) ppm;
3
13
C nmr: δ 9.40, 11.9, 19.5, 34.6, 109.2,
112.3, 117.9, 120.7, 121.9, 123.2, 125.5, 125.7, 126.0, 129.6,
133.8, 137.9, 169.3, 173.9 ppm; uv-visible (dichloromethane): λ
sh 473, ε, 26200; λ
281, ε, 8500; (N-methylformamide): λ sh 475, ε, 26100; λ
451, ε, 35400; λ sh 430, ε, 28000; λ
max
max
max
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Chem., 40, 796 (1975).
452, ε, 34900; λ sh 431, ε, 27300; λ
281, ε, 8900.
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(1977).
max
Acknowledgments.
We thank the National Institutes of Health (HD 17776) for sup-
port of this work. Dr. Stefan E. Boiadjiev is on leave from the
Institute of Organic Chemistry, Bulgarian Academy of Sciences,
Sofia.
[10] K. M. Smith and R. K. Pandey, J. Heterocyclic Chem., 20,
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