Synthesis of novel polycyclic ring systems containing two pyrano[2,3-c]pyrazol-4-(1H)one moieties

Article abstract of DOI:10.1007/s10593-007-0165-z

Novel penta-or heptacyclic ring systems containing two pyrano[2,3-c] pyrazol-4(1H)-one units are prepared in one or two steps from the reaction of 3-methyl-1-phenyl-2-pyrazolin-5-one and bis(o-chlorocarbonyl chlorides) derived from benzene-or 1,10-phenanthroline.

Full text of DOI:10.1007/s10593-007-0165-z

Chemistry of Heterocyclic Compounds, Vol. 43, No. 8, 2007
SYNTHESIS OF NOVEL POLYCYCLIC
RING SYSTEMS CONTAINING TWO
PYRANO[2,3-c]PYRAZOL-4-(1H)ONE
MOIETIES
G. A. Eller, V. Wimmer, W. Holzer
Novel penta- or heptacyclic ring systems containing two pyrano[2,3-c]pyrazol-4(1H)-one units are prepared
in one or two steps from the reaction of 3-methyl-1-phenyl-2-pyrazolin-5-one and bis(o-chlorocarbonyl
chlorides) derived from benzene- or 1,10-phenanthroline.
Keywords: pyrazolones fused ring systems, acylations.
Recently, we presented a short and efficient synthesis of novel azaxanthones containing a pyrano[2,3-c]-
pyrazol-4(1H)-one moiety by the reaction of 1-substituted 2-pyrazolin-5-ones with o-halo-(hetero)arenecarbonyl
chlorides [1-4]. In continuation of these investigations we here report on the related preparation of hitherto
unknown polyheterocycles, which contain two units of the above-mentioned substructure.
Hence, as the acid chloride reactants we have chosen the dicarbonyl dichlorides 3 and 9, which were
synthesized as outlined in Scheme 1, applying slight modifications of the procedures described in the literature.
Scheme 1
O
Cl
Cl
O
Me
Cl
1. KMnO4
2. SOCl2
X
X
Me
Cl
1
2, 3
Cl
O
Cl
O
O
H
N
H
NHAc
O
N
X
1. AgNO3/NaOH
2. SOCl2
DMF, POCl3
X
Cl
N
AcHN
Cl
N
7
6
8, 9
2, 8 X = OH; 3, 9 X = Cl
__________________________________________________________________________________________
Department of Drug and Natural Product Synthesis, University of Vienna, 90 Vienna, Austria; e-mail:
gernot.eller@univie.ac.at, e-mail: wolfgang.holzer@univie.ac.at. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 8, pp. 1251-1255, August, 2007. Original article submitted May 14, 2007.
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0009-3122/07/4308-1060©2007 Springer Science+Business Media, Inc.

When the terephthaloyl dichloride 3 reacted with pyrazolone 11 under the typical conditions reported by
Jensen [5] (Ca(OH)2, refluxing 1,4-dioxane), (Scheme 2) we isolated the expected 4-aroylpyrazol-5-ol 4. The
latter was subsequently converted into the pentacycle 5 by treatment with NaH in refluxing DMF. The total yield
over two steps (starting from the dicarbonyl dichloride 3) was 23%.
Scheme 2
O
Cl
Ph
N
Me
N
Me
HO
O
Ca(OH)2
N
3
N
+
O
1,4-dioxane
N
N
OH
Me
Ph
11
Ph
Cl
4
O
Ph
N
Me
N
O
O
NaH
N
DMF
N
O
Me
Ph
5
The reaction of pyrazolone 11 with the phenanthrolinedicarbonyl dichloride 9 under Jensen-type
reaction conditions directly led to the target heptacycle 10 in 11% yield (Scheme 3). Such type of spontaneous
intramolecular cyclization of the intermediate 4-aroylpyrazol-5-ols has been previously observed with some
related pyridinecarbonyl chlorides [1, 3, 4].
Scheme 3
Ph
N
N
Me
O
Ca(OH)2
9
11
+
O
O
O
N
1,4-dioxane
Me
N
N
N
Ph
10
EXPERIMENTAL
Melting points were determined on a Reichert–Kofler hot-stage microscope and are uncorrected. Mass
spectra were obtained on a Shimadzu QP 1000 instrument (EI, 70 eV). IR spectra were recorded on a Perkin–
Elmer FTIR 1605 spectrophotometer in KBr. Elemental analyses were performed at the Microanalytical
1
Laboratory, University of Vienna. The H and 13C NMR spectra were recorded on a Varian UnityPlus 300
spectrometer at 28°C or on a Bruker Avance 500 spectrometer at 293 K. The center of the solvent signal
(DMSO-d6) was used as an internal standard which was related to TMS. The digital resolutions were 0.2 Hz/data
1
13
point in the H NMR spectra and 0.4 Hz/data point in the C NMR spectra (1H broadband decoupling or gated
decoupling). 15N NMR spectra were obtained on a Bruker Avance 500 instrument with a directly
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detecting broadband observe probe and were referenced against external nitromethane (coaxial capillary). It is
important to note that owing to the very low solubility or the even practical insolubility of compounds 3-5,7,9
and 10 in common NMR solvents such as DMSO-d6 or CDCl3 only limited NMR spectroscopic investigations
were possible. Systematic names were generated with ACD/Name [6] according to the IUPAC recommendations
and were also checked manually to ensure the correct use of nomenclature within this publication [7]. The
alternative name for compound 4 is according to phane nomenclature [8, 9]. Product yields were not optimized.
1
1,4-Dichloro-2,5-dimethylbenzene (1). This product is commercially available (Aldrich). H NMR
spectrum (300 MHz), δ, ppm: 7.38 (2H, s, H-3,6); 2.25 (6H, s, CH3). 13C NMR spectrum (75 MHz), δ, ppm (J, Hz):
134.7, 131.5, 130.8 (C-3,6; 1J = 165.5), 18.7 (CH3, 1J = 128.4).
2,5-Dichloroterephthalic Acid (2). To a well stirred suspension of 1 g Aliquat© 336 (trioctyl-
methylammonium chloride) of KMnO4 (4.74 g, 30 mmol) and of xylene 1 (5.25 g, 30 mmol) in H2O (50 ml) was
added dropwise a solution of KMnO4 (14.2 g, 90 mmol) in of H2O (150 ml). Then the reaction mixture was
heated to 80°C for 72 h. After cooling the mixture to room temperature, it was filtered off and the remaining
filter cake was extracted twice with 30 ml of Et2O. The combined organic layers were washed with H2O (10 ml),
dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to afford of unreacted
starting material 1 (1.10 g, 21%). The filtrate was treated with small amounts of NaHSO3 and brought to pH 1 by
dropwise addition of 2N HCl. Upon cooling in the refrigerator overnight colorless crystals of 2 separated, which
were filtered off and dried. Yield 4.52 g (64%; 81% based upon unrecovered educt). Alternatively, this product
can be obtained from TCI Europe Organic Chemicals. 1H NMR spectrum (300 MHz), δ, ppm: 13.71 (2H, br. s,
OH); 7.89 (2H, s, H-3,6). 13C NMR spectrum (75 MHz), δ, ppm (J, Hz): 164.9 (CO), 134.8, 132.1 (C-3,6;
1J = 171.3), 130.0. MS, m/z (Irel, %): 238 [M]+ (10), 236 [M]+ (75), 234 [M]+ (100), 221 (11), 219 (62), 217 (90),
135 (23), 133 (32), 109 (21), 74 (51), 73 (27), 45 (26).
2,5-Dichloroterephthaloyl Dichloride (3). A suspension of terephthalic acid 2 (2.35 g, 10 mmol),
cyclohexane (5 ml), DMF (1 drop), and SOCl2 (15 ml) was heated at reflux for 4 h. Excess SOCl2 was removed
under reduced pressure, and the reaction mixture was refrigerated overnight and then filtered off to afford the
acid chloride 3. Yield 2.20 g (81%); mp 77.5-79°C (mp 80.5-81°C [10]). MS, m/z (Irel, %): 276 [M]+ (1), 274
[M]+ (5), 272 [M]+ (11), 270 [M]+ (8), 239 (28), 237 (100), 235 (91), 209 (39), 207 (37), 109 (28), 74 (43), 73
(24).
(2,5-Dichloro-1,4-phenylene)bis[(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)methanone] (4). To a
suspension of pyrazolone 11 (697 mg, 4 mmol) and Ca(OH)2 (593 mg, 8 mmol) in 1,4-dioxane (6 ml) was
added the acid chloride 3 (544 mg, 2 mmol), suspended in 1,4-dioxane (2 ml), and the reaction mixture was
heated at reflux for 3 h. After cooling to room temperature, the mixture was treated with 2N HCl (16 ml) and
then stirred for 1 h before it was poured onto H2O (40 ml). After 30 min, the mixture was filtered off and the
remaining solid was repeatedly washed with H2O to give crude compound 4 (510 mg, 47%). For analytical
purposes 100 mg were recrystallized from EtOH–DMF. Mp 262–268°C. IR spectrum, ν, cm-1: 1622 (C=O).
1H NMR spectrum (500 MHz), δ, ppm: 7.63 (4H, m, NPh H-2,6); 7.51 (2H, s, Ph H-3,5); 7.46 (4H, m, NPh
H-3,5); 7.29 (2H, m, NPh H-4); 2.28 (6H, s, CH3). 13C NMR spectrum (125 MHz), δ, ppm: 185.1 (CO), 141.9
(Cq), 136.8 (NPh C-1), 129.0 (NPh C-3,5), 128.6 (Ph C-3,6), 128.1 (Cq), 126.2 (NPh C-4), 121.0 (NPh C-2,6),
104.0 (pyrazole C-4), 14.2 (CH3). MS, m/z (Irel, %): 550 [M]+ (5), 548 [M]+ (30), 546 [M]+ (30), 513 (26), 511
(54), 475 (45), 355 (36), 327 (32), 325 (77), 311 (40), 238 (26), 201 (32), 92 (29), 91 (76), 88 (64), 77 (100), 67 (69),
58 (35), 43 (40). Found, %: C 60.95; H 3.58; N 10.25. C28H20Cl2N4O4 · 0.2H2O. Calculated, %: C 60.94; H 3.74;
N 10.15.
3-9-Dimethyl-1,7-diphenylbenzo[1'',2'':5',6';4'',5'':5'6']dipyrano[2,3:d;2',3':d']dipyrazole-4,10(1H,7H)-
dione (5). Under anhydrous conditions, a suspension of compound 4 (274 mg, 0.5 mmol) and NaH (50% in
mineral oil, 44 mg, 1 mmol) in DMF (3 ml) was heated at reflux overnight. Then the solvent was removed under
reduced pressure and H2O (5 ml) was added to the residue. The mixture was stirred for 1 h and the precipitate
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formed was filtered off, washed with H2O and petroleum ether, and recrystallized from DMF to afford the pure
1
pentacycle 5. Yield 94 mg (49%); mp > 340°C. IR spectrum, ν, cm−1: 1668 (C=O). H NMR spectrum
(300 MHz), δ, ppm: 8.51 (2H, s, H-5,11); 8.03 (4H, m, NPh H-2,6); 7.65 (4H, m, NPh H-3,5); 7.48 (2H, m, NPh
H-4); 2.62 (6H, s, CH3). MS, m/z (Irel, %): 475 [M]+ (26), 474 (79), 473 (23), 121 (100), 77 (35). Found, %:
C 70.58; H 3.72; N 11.78. C28H18N4O4. Calculated, %: C 70.88; H 3.82; N 11.81.
N,N'-(1,3-Phenylene)diacetamide (6). Similarly to the known procedure [11], to molten 1,3-benzene-
diamine (54.1 g, 0.5 mol) was added dropwise Ac2O (76.6 g, 0.75 mol) under stirring. The solution was heated
to reflux for 2 h, then further Ac2O (25.5 g, 0.25 mol) was added, and the reaction mixture was again refluxed
for 2 h. The solution was cooled to room temperature and then poured into H2O (ca. 300 ml) under stirring.
Upon standing in the refrigerator for 1 h, diacetamide 6 separated as almost colorless crystals, which were dried
1
at 90°C for 1 h. Yield 89.5 g (93%); mp 186-189°C (mp 191°C [12]). H NMR spectrum (300 MHz), δ, ppm:
9.89 (2H, s, NH); 7.87 (1H, br. s, H-2); 7.25 (2H, m, H-4,6); 7.16 (1H, m, H-5); 2.02 (6H, s, CH3). 13C NMR (75
MHz): δ 168.2 (CO), 139.5 (C-1,3), 128.7 (C-5), 113.8 (C-4,6), 109.8 (C-2), 24.0 (CH3). MS, m/z (Irel, %): 192
[M]+ (21), 150 (32), 108 (100), 80 (31), 43 (100).
2,8-Dichloro-1,7-phenanthroline-3,9-dicarbaldehyde (7). Similarly to the known procedure [13],
POCl3 (107 g, 0.7 mol) was added dropwise to DMF (21.9 g, 0.3 mol) at 0°C under stirring. To this solution was
added the diacetamide 6 (9.61 g, 0.05 mol) and the resulting mixture was refluxed for 4 h. The deeply colored
solution was cooled to room temperature and added dropwise to ice water (ca. 500 ml) with stirring. Then the pH
was adjusted to 2–3 by addition of 2 N NaOH to precipitate phenanthroline 7, which was filtered off and washed
with H2O and light petroleum to afford a yellowish powder. Yield 10.9 g (71%). IR spectrum, ν, cm-1: 1685-
1
1695 (2×C=O). H NMR spectrum (300 MHz), δ, ppm (J, Hz): 10.47 (1H, s, 9-CHO); 10.45 (1H, s, 3-CHO);
5
3
3
9.68 (1H, d, J10,6 = 0.7, H-10); 9.15 (1H, s, H-4); 8.62 (1H, d, J5,6 = 9.1, H-5); 8.17 (1H, dd, J6,5 = 9.1,
5J6,10 = 0.7, H-6). MS, m/z (Irel, %): 308 [M]+ (4), 307 (19), 306 [M]+ (59), 305 (56), 304 [M]+ (100), 303 (65),
275 (36), 240 (43), 211 (39), 177 (59), 176 (85), 151 (78), 150 (56), 124 (47), 123 (44), 100 (33), 99 (39), 75
(36), 74 (35).
2,8-Dichloro-1,7-phenanthroline-3,9-dicarboxylic Acid (8). Similarly to the known procedure [13], to
dialdehyde 7 (6.10 g, 20 mmol), suspended in EtOH (96%, 3200 ml), was added AgNO3 (13.6 g, 80 mmol),
dissolved in aqueous EtOH (80%, 200 ml). To the clear solution was added in small portions NaOH (10.0 g,
250 mmol), dissolved in aqueous EtOH (80%, 200 ml), and the dark reaction mixture was stirred at room
temperature for 4 h. Then Ag2O was filtered off and the filtrate was concentrated almost to dryness under
reduced pressure. Water (ca. 50 ml) was added and the solution was filtered again. Upon acidification of the
solution by dropwise addition of conc. HCl a precipitate formed, which was filtered off, washed with H2O, and
dried to give the yellow acid 8, which was used without further purification in the next reaction step. Yield 2.97
g (44%); mp >320°C. 1H NMR spectrum (300 MHz), δ, ppm (J, Hz): 9.50 (1H, s, H-10); 9.01 (1H, s, H-4); 8.36
(1H, d, 3J5,6 = 9.1, H-5); 7.98 (1H, d, 3J6,5 = 9.1, H-6). 13C NMR spectrum (75 MHz), δ, ppm: 165.3 (3-COOH),
165.1 (9-COOH), 149.9 (C-6a), 149.7 (C-8), 147.9 (C-2), 144.9 (C-10b), 141.4 (C-4), 137.2 (C-10), 132.4 (C-5),
127.8 (C-6), 127.1* (C-3), 125.9* (C-9), 124.6* (C-4a), 122.9* (C-10a); 15N NMR spectrum (50 MHz), δ, ppm:
-77.2 (N-7), -86.0 (N-1).
2,8-Dichloro-1,7-phenanthroline-3,9-dicarbonyl Dichloride (9). A suspension of diacid 8 (1.69 g,
5 mmol), cyclohexane (5 ml), DMF (1 drop), and SOCl2 (10 ml) was heated at reflux for 6 h. Then excess SOCl2
was removed under reduced pressure and the reaction mixture was stored in the refrigerator overnight. The
precipitated crystals were filtered off to afford the pure acid chloride 10. Yield 1.56 g (84%). IR spectrum, ν,
cm−1: 1748–1761 (2×C=O). MS, m/z (Irel, %): 376 [M]+ (3), 374 [M]+ (7), 372 [M]+ (6), 341 (36), 339 (97), 337
(100), 151 (25), 123 (37), 105 (25). Found, %: C 45.07; H 1.29; N 7.59. C14H4Cl4N2O4. Calculated, %: C 44.96;
H 1.08; N 7.49.
_______
* Unambiguous differentiation between C-3/C-9 and between C-4a/C-10a was not possible.
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3,12-Dimethyl-1,10-diphenylbis(pyrazolo[4',3':5,6]pyrano)[2,3-b:2',3'-j][1,7]phenanthroline-
4,13(1H,10H)dione (10). To a suspension of pyrazolone 11 (348 mg, 2 mmol) and Ca(OH)2 (296 mg, 4
mmol) in 1,4-dioxane (3 ml) was added acid chloride 9 (374 mg, 1 mmol), suspended in 1,4-dioxane (2 ml),
and the reaction mixture was heated at reflux for 3 h. After cooling to room temperature, the mixture was treated
with 2N HCl (8 ml) and then stirred for 1 h before it was poured onto H2O (20 ml). After 30 min, the mixture
was filtered and the remaining solid was repeatedly washed with H2O. Recrystallization from DMF afforded the
pure heptacycle 10. Yield 64 mg (11%); mp >340°C. IR spectrum, ν, cm−1: 1669-1683 (2×C=O). MS, m/z (Irel,
%): 577 [M + 1]+ (12), 576 [M]+ (14), 91 (45), 77 (73), 44 (100), 41 (37). Found, %: C 69.60; H 3.26; N 14.50.
•
C34H20N6O4 ⅓H2O. Calculated, %: C 69.74; H 3.61; N 14.35.
The authors are grateful to Dr. L. Jirovetz for recording the mass spectra.
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