Synthesis of 5-benzoyl-6-trifluoromethyl-1,2-dihydro-3H-pyrrolo[1,2-a] pyrrole-1-carboxylic acid

Article abstract of DOI:10.3987/com-04-10124

Synthesis of the possible analgesic and/or antiinflammatory agent 5-benzoyl-6-trifluoromethyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid (1) was designed from the already known intermediate ester 3-methoxycarbonyl-4-trifluoromethyl-5-benzyloxy

Full text of DOI:10.3987/com-04-10124

HETEROCYCLES, Vol. 63, No. 9, 2004, pp. 2071 - 2077
Received, 19th May, 2004, Accepted, 16th July, 2004, Published online, 16th July, 2004
SYNTHESIS OF 5-BENZOYL-6- TRIFLUOROMETHYL -1,2 - DIHYDRO-3H-
PYRROLO[1,2-a]PYRROLE-1-CARBOXYLIC ACID
Adrián Covarrubias Zúñiga
Institute of Chemistry, Autonomous National University of México, Circuito
Exterior, Ciudad Universitaria, Coyoacán 04510, México E-mail:
adriancz@servidor.unam.mx
Abstract – Synthesis of the possible analgesic and/or antiinflammatory agent 5-
benzoyl-6-trifluoromethyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid (1)
was designed from the already known intermediate ester 3-methoxycarbonyl-4-
trifluoromethyl-5-benzyloxycarbonylpyrrole-2-acetic acid methyl ester (4) wich is
prepared via a Knorr synthesis.
INTRODUCTION
In connection with a program1,2 related to the development of certain nonesteroidal antiinflammatory
agents with fewer side effects than phenylbutazone and indomethacin, it was found that the pyrrole-2-
acetic acid3-5 (2a) showed good pharmacologic activity; furthermore, it was observed by the
introduction of methyl groups in C4 position of the pyrrolic ring6 and/or in the chain of the acetic acid
to give the derivatives of the propionic acid (2b,c), the antiinflammatory activity increased;
zomepirac (2c)6 is one good example of this structural change. The notion that more rigid bicyclic
sistems present greater analgesic and/or antiinflammatory activity, was substantiated through the
pharmaceutical product ketorolac (3a).7-9 The introduction of CF3 group (comp. 2d) in zomepirac
rendered good analgesic and antiinflammatory activity;10 thus, it was decided to carry out a synthesis
of 1 to evaluate as possible analgesic and/or antiinflammatory agent.
CF3
R1
Me
O
CO2H
O
O
CO2H
CO2H
N
N
N
Ar
R2
Me
2a : R ,R = H
1
1
2
3a
2b : R , R = Me
1
2
2c : R = Me, R = H
1
2
2d : R = CF
, R = H
3
1
2

RESULTS AND DISCUSSION
A synthesis of 1 was designed from the already known intermediate ester (4) which is prepared via a
Knorr synthesis;10 a synthesis is partially depicted on the Scheme 1. 4 was alkylated with the
tetrahydropyranil ether derivative of 2-bromoethanol, NaI, and K2CO3 as base in dry DMF with 82 %
yield; the hydrolysis to the alcohol (6) was achieved with a mixture of acetic acid-H2O 6:4 at 55°C in
92 % yield. 6 was mesylated with MeSO2Cl and Et3N in dry CH2Cl2 and the mesylate was
intramolecularly alkylated using NaH as base in dry DMF in 86 % yield. Alternatingly we could obtain
7 directly from 4 using 1,2-dibromoethane and K2CO3 in dry DMF in 79 % yield, this fact
conveniently placed these conditions as the best in the formation of 7. The hydrogenolysis of the
benzylic ester with 10 % Pd/C in ethyl acetate for 2 h at room temperature afforded the carboxylic
acid (8) in quantitative yield. The synthesis continued (Scheme 2) with the formation of the acid
CF3
CO2Me
CF3
CO2Me
CF3
CO2Me
a
b
BnO2C
CH CO Me
BnO2C
2 2
N
H
CH2CO2Me
BnO2C
N
CH2CO2Me
N
CH2CH2OTHP
CH2CH2OH
4
6
5
c,d
CF3
CO2Me
CO2Me
CF3
CO2Me
d
HO2C
CO2Me
BnO2C
N
N
8
7
Scheme 1. a: BrCH2CH2OTHP, K2CO3, NaI, DMF, b: AcOH-H2O, c: Et3N, MeSO2Cl, CH2Cl2, d:
NaH, DMF, e: H2, 10% Pd/C, AcOEt.
CF3
O
CO2H
CF3
O
CO2Me
a
b
8
CO2H
N
CO2Me
N
9
10
c
CF3
CF3
O
CO2H
e
d
O
1
CO i-Pr
N
2
CO i-Pr
N
2
12
11
Scheme 2. a: (COCl)2, PhMe, PhMgBr, Fe(acac)3, THF, b: EtSLi, HMPA, c:i-PrOH, HClgas, d: CuO,
quinoline, 215°C, e: HCO2H, MeSO3H

chloride of 8 and the subsequent treatment of the crude product with phenylmagnesium bromide and
iron(III) acetylacetonate in dry THF at room temperature11 afforded 9 in 54 % yield. The following
step was the methyl esters cleavage of 9, the hydrolysis with NaOH or KOH in MeOH:H2O solution
at reflux gave only 25 % yield of the diacid (10); this problem was circumvented using lithium
thioethoxide in dry HMPA at room temperature.12 furnishing the dicarboxylic acid (10) in 67 % yield.
It is known that the compounds (13) undergo selective acid decarboxylation in C7 position;13 so, it was
decided to test the selective acid decarboxylation of the diacid (10). Decarboxylation neither was in
R
CO2H
13: R = H, Me, Et,
n-Bu, n-C H
,
5 11
n-C H , Cl, F or Br.
O
6 13
CO2H
N
Ar
13
trifluoroacetic nor trichloroacetic acid succesful; for this reason it was prepared selectively the
monoester (11) from 10 in dry isopropyl alcohol under Fischer conditions14 in 75 % yield. With the
antecedent pyrrole-3-carboxylic acids were decarboxylated under thermal conditions,14 it was decided
to test the thermal decarboxylation of the monoester (11), but it was unsuccesful; however, the
decarboxylation was achieved by heating the acid with CuO/quinoline at 215°C over argon
atmosphere15 furnished the ester (12) in 53 % yield. Finally the ester (12) was hydrolized with a
mixture of HCO2H, MeSO3H and H2O to give the acid (1) in 78 % yield. In conclusion, a synthesis of
compound (1) was accomplished in seven steps from 4 in 11.4 % overall yield.
EXPERIMENTAL
Melting points were determined in a Mel-Temp melting point apparatus and are uncorrected. The IR
spectra were measured with a Perkin Elmer 267 grating infrared spectrophotometer. The UV spectra
1
were recorded on a Perkin-Elmer 402 ultraviolet visible spectrometer. The H NMR spectra were
measured with a Varian T-60 spectrometer and are expressed as parts per million (δ) from internal
tetramethylsilane as an internal standard. The LRMS spectra were measured on, Atlas CH-4
spectrometer. The HRMS spectra were obtained with Varian-MAT 311A mass spectrometer. Column
chromatography was performed over silica 60-230 mesh (MercK). Preparative TLCs were run on a
Merck GF254 plates. The term “dried” signifies dried over Na2SO4 throughout the experimental section.
Commercially available reagents and solvents were used without additional purification unless
otherwise stated.
5-Benzyloxycarbonyl-3-methoxycarbony-4-trifluoromethyl-1-tetrahydropyranyloxyethyl)pyrrole
-2-acetic acid methyl ester (5). 4 (198 mg, 0.496 mmol), dry DMF (7.5 mL), dry K2CO3 (216 mg, 1.7
mmol), dry NaI (150 mg, 1 mmol) and 2-bromotetrahydropyraniloxyethane (224 mg, 1.07 mmol) were

heated under N2 atmosphere to 95°C for 2 h, with magnetic stirring. The reaction mixture was poured
into water (50 mL) and the product was extracted into ether (3 x 20 mL). The extract was washed with
H2O (5 mL) and then it was dried and evaporated in vacuo. The residue was purified by column
chromatography on silica gel (8 g) using hexane-acetone (90:10) to elute the desired material as yellow
oil (5) (209 mg, 80 %). UV (MeOH) λ max (log ε) 213 (4.35), 263 (3.85); IR (CHCl3) 1730, 1070,
1040 cm-1; 1H NMR (CDCl3) δ 7.27 (s, 5H), 5.28 (2, 2H), 4.20-4.45 (m, 3H, NCH2, CH), 4.10 (s, 2H),
3.97 (m, 4H), 3.73 (s, 3H), 3.62 (s, 3H). MS (m/z, %) 527 (M+, 1), 443 (2), 392 (9), 336 (3), 91 (100),
85 (54). Anal. Calcd for C25H28NO8F3: C, 56.87; H, 5.30; N, 2.65; F, 10.80. Found: C, 56.88; H, 5.21;
N, 2.58; F, 10.72.
5-Benzyloxycarbonyl-3-methoxycarbonyl-4-trifluoromethyl-1-(ω-hydroxyethyl)pyrrole-2-acetic
acid methyl ester (6). 5 (7.42 g 14 mmol), H2O (40 mL) and AcOH (60 mL) were heated to 55-60°C
with magnetic stirring for 1.75 h. After the mixture was poured into H2O (250 mL) and the product
was extracted into ether (3 x 80 mL). The extract was washed with H2O (2 x 20 mL) and then it was
dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel (260
g) using hexane-AcOEt (7.5:2.5) to elute 6 as yellow oil (5.97 g, 91 %). UV (MeOH) λ max (log ε)
216 (4.22), 247 (3.82), 264 (3.87); IR CHCl3) 3640, 1720 cm-1; 1H NMR (CDCl3) δ 7.40 (s, 5H), 5.32
(s, 2H), 4.23 (t, 2H, J=7.1 MHz), 4.08 (2, 2H), 3.80 (s, 3H), 3.77 (t, 2H, J=7.1 MHz), 3.70 (s, 3H), 2.25
(m, 1H); MS (m/z, %) 443 (M,+ 2), 411 (6), 323 (3), 91 (100). Anal. Calcd for C20H20NO3F3: C, 54.13;
H, 4.51; N, 3.15; F, 12.85. Found: C, 54.01; H, 4.42; N, 3.08; F, 12.81.
5-Benzyloxycarbonyl-3-methoxycarbonyl-4-trifluoromethyl-1-(ω-methanesulfonyloxyethyl)-
pyrrole-2-acetic acid methyl ester (7). A mixture of 6 (26 g, 58 mmol) and Et3N (12.4 mL, 87 mmol)
in dry CH2Cl2 (260 mL) was cooled with magnetic stirring to 0°C. MeSO2Cl (5.6 mL, 70 mmol) was
added at a rate such that the reaction temperature did not exceed 10°C. The reaction mixture was
stirred for 1 h at rt. The solution was poured into H2O (250 mL), extracted with CH2Cl2, and the
extract was dried. The solvent was removed in vacuo and the residue was dissolved in dry DMF (220
mL), this mixture was cooled to 5°C and NaH (2.38 g, 59.5 mmol, 60 %) was added under N2
atmosphere. The mixture was stirred for 30 min at rt and then was poured into H2O (1.2 L) and the
product was extracted into ethyl acetate (3 x 150 mL). The extract was washed with H2O (40 mL) and
then it was dried and evaporated in vacuo. The residue was purified by column chromatography on
silica gel (1 Kg) using hexane-acetone (9:1) to elute 7 as oil (20.80 g, 83.4 %).
1,7-Dimethoxycarbonyl-5-benzyloxycarbonyl-6-trifluoromethyl-1,2-dihydro-3H-pyrrolo[1,2-
a]pyrrole (7). 4 (0.735 g, 1.84 mmol), dry K2CO3 (0.88 g, 6.35 mmol) and 1,2-dibromoethane (0.32
mL, 3.7 mmol) in dry DMF (10 mL) were heating at 95°C with magnetic stirring for 70 min. The
mixture was poured into H2O (60 mL) and extracted with ether (3 x 15 mL). Dried, filtration and

concentration of the organic layer gave a residue which was subjected to column chromatography on
silica gel (34 g), the compound as yellow oil (7) (0.62 g, 79 %) being eluted with 10 % ethyl acetate in
1
hexane. UV (MeOH) λ max (log ε) 214 (4.35), 268 (4.12); IR (neat) 1740, 1705, cm-1; H NMR
(CDCl3) δ 7.40 (s, 5 H), 5.32 (s, 2H), 4.10-4.47 (m, 3H, NCH2, CH), 3.80 (s, 3H), 3.70 (s, 3H), 2.52-
2.98 (m, 2H); MS m/z (rel intensity) 335 (M,+ 14), 394 (3), 318 (6), 291 (7), 91 (100). Anal. Calcd for
C20H18NO6F3: C, 56.47; H, 4.23; N, 3.29; F, 13.41. Found: C, 56.36; H, 4.09; N, 3.45; F, 13.28.
1,7-Dimethoxycarbonyl-6-trifluoromethyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-5-carboxylic
acid (8). 7 (17 g, 0.04 mol) and Pd/C (10 %, 1.7 g) in ethyl acetate (250 mL) were hydrogenolized at
atmospheric pressure for 2 h. The mixture was filtered through a pad of celite with the aid of two 50
mL portions of ethyl acetate and then concentrated to afford in quantitative yield 8 as a white solid.
mp: 179-180°C (ethyl acetate:hexane); UV (MeOH) 212 nm (ε 15490), 265 nm (ε 9120); IR (KBr)
3520, 1740, 1700 cm-1; 1H NMR δ 7.80 (br s, 1H), 4.20-4.39 (m, 3H, CH, CH2N), 3.80 (s, 3H), 3.73 (s,
3H), 2.50-3.00 (m, 2H); MS (m/z, %) 335 (M,+ 24), 303 (18), 276 (100), 236 (12). Anal. Calcd for
C13H12NO6F3: C, 46.56; H, 3.58; N, 4.17; F, 17.01. Found: C, 46.39; H, 3.73; N, 4.19; F, 16.83.
1,7-Dimethoxycarbonyl-5-benzoyl-6-trifluoromethyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole (9). 8
0.315 g, 0.94 mmol) and oxalyl chloride (1.41 mmol, 0.18 g) in dry toluene were refluxed for 2 h. The
solvent was removed in vacuo, the residue was dissolved in dry THF (4 mL) and iron(III)
acetylacetonate (`10 mg, 0.028 mmol) was added and the mixture was stirred ( inert atmosphere).
Phenylmagnesium bromide (0.94 mmol, 0.91 M) was added dropwise. After 20 min, the mixture was
poured into aqueous HCl ( 10 mL, 5%) and extracted with ether (3 x 20 mL). The organic layer was
washed with saturated aqueous NaCl solution, then with H2O and finally it was dried. The solvent was
removed in vacuo and the residue was purified by column chromatography on silica gel (25 g) with
acetone:hexane (14:86) as eluant affording 10 as yellow oil (0.202 g, 54%). UV (MeOH) λmax (log ε)
218 (4.04), 255 (4.00), 282 (3.86); IR (CHCl3) 1735, 1705, 1645 cm-1; H1 NMR (CDCl3) δ 7.28-7.90
(m, 5H), 4.05-4.42) (m, 3H), 3.82 (s, 3H), 3.76 (s, 3H), 2.46-3.05 (m, 2H); MS (m/z, %) 395 (M,+84),
336 (100), 318 (21), 290 (17), 105 (90), 77 (90). Anal. Calcd for : C19H16NO5F3: C, 57.72; H, 4.05: N,
3.54; F, 14.43. Found: C, 57.63; H, 3.97; N, 3.58; F, 14.35.
5-Benzoyl-6-trifluoromethyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylic acid (10). 9
(2 g, 5.06 mmol) was dissolved in dry HMPA (30 mL), and with magnetic stirring
lithium
thioethoxide (2.8 g, 41.6 mmol) in portionwise was added in 7 h. After 2 h cold water (90 mL) and
aqueous HCl (10 %, 20 mL) were added, the mixture was extracted with ethyl acetate (3 x 30 mL).
The organic layer was washed with saturated aqueous NaCl solution (2 x 20 mL) and dried. The
solvent was removed in vacuo and the residue was purified by column chromatography on silica gel
(70 g) using CH2Cl2-MeOH-HCO2H (198 mL:1.8 mL:0.1 mL) to elute the product, the diacid (10) was

obtained in 67 % (1.2 g). mp: 201-203°C (ethyl acetate-hexane); UV (MeOH) λ max (log ε) 211
1
(4.08), 252 (4.07), 295 (3.84); IR (KBr) 2500-3550, 1705, 1660 cm-1; H NMR (CDCl3) δ 8.15 (br s,
2H), 7.46-8.00 (m, 5H), 3.92-4.52 (m, 3H, NCH2, CH), 3.92-4.52 (m, 3H), 2.52 (m, 2H); MS (m/z, %)
367 (M,+ 1), 323 (39), 303 (80), 262 (24), 105 (72), 77 (100). Anal. Calcd for C17H12NO5F3: C, 55.54;
H, 3.26; N, 3.81; F, 15.51. Found: C, 55.49; H, 3.21; N, 3.79; F, 15.47.
1-Isoproppoxycarbonyl-5-benzoyl-6-trifluoromethyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-7-
carboxylic acid (11). 10 (0.90 g, 2.45 mmol) in dry i-PrOH (10 mL) was cooled to 0°C and HCl gas
was bubbled through the i-PrOH until saturation was achieved. The solution was then left at ambient
temperature and stirred for 2 h and then the solvent was evaporated to dryness in vacuo. Benzene was
added to the residue and the mixture was evaporated to dryness in vacuo again and the solid was then
crystallized from hexane-ethyl ether (2:1) affording 11 (0.76 g, 75 % ). mp: 184-186°C; UV (MeOH) λ
1
max (log ε) 212 (4.07), 252.5 (4.07) 296 (3.85); IR (CHCl3) 2500-3550, 1730, 1700, 1650 cm-1; H
NMR (CDCl3) δ 11.62 (br s, 1H), 7.30-8.10 (m, 5H), 5.05 (hep, 1H, J=7.10 Hz), 4.05-4.50 (m, 3H),
2.42-3.12 (m, 2H), 1.29 (d, 6H, J=7.10 Hz); MS (m/z, %) 409 (M,+ 40), 350 (5), 322 (100), 105 (24),
77 (21). Anal. Calcd for : C20H18NO5F3: C, 58.66; H, 4.39; N, 3.42; F, 13.93. Found: C, 58.60; H, 4.31;
N, 3.37; F, 13.87.
5-Benzoyl-6-trifluoromethyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid isopropyl
ester (12). 11 (41 mg, 0.1 mmol), dry quinoline (1 mL) and CuO (50 mg) were heated under argon
atmosphere to 215°C for 15 min. The reaction mixture was cooled at rt and poured into aqueous HCl
(15 mL, 15%), extracted with ether (3 x 10 mL), the organic layer was separated, dried, filtered and
concentrated. The residue was purified by column chromatography of silica gel (1.5 g) using hexane-
acetone (9:1) as eluant, 12 (19.5 mg, 53%) was obtained as yellow oil. UV (MeOH) UV (MeOH) λ
1
max (log ε) 209 (3.91), 242 (3.93), 294 (3.98); IR (CHCl3) 1730, 1635, 1385, 1368 cm-1; HNMR
(CDCl3) δ 7.14-7.87 (m, 5H), 6.33 (s, 1H), 5.00 (hept, 1H, J=7.1 Hz), 3.78-4.45 (m, 2H, NCH2, CH),
2.37-3.05 (m, 2H), 1.26 (d, 6H, J=7.1 Hz). MS (m/z, %) 365 (M,+ 27), 278 (100), 105 (34), 77 (37).
Anal. Calcd for C19H18NO3F3: C, 62.40; H, 4.92; N, 3.83; F, 15.60. Found: C, 62.32; H, 4.79; N, 3.78;
F, 15.47.
5-Benzoyl-6-trifluoromethyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid (1). 12 (73
mg, 0.20 mmol), MsOH (0.04 mL, 70%), HCO2H (2 mL, 97 %) were heated to 55°C with magnetic
stirring for 16 h, and then poured into water (20 mL), extracted with ethyl acetate (4 x 10 mL). The
organic layer was separated, dried, filtered, and concentrated. The residue was purified by
crystallization from hexane-ethyl ether (2:1) affording 1 (50.3 mg, 78 %).mp: 135-136°C; UV (MeOH)
1
λ max (log ε) 214 (3.87), 252 (3.94), 312 (4.00); IR (CHCl3) 2500-3550, 1720, 1630 cm-1; H NMR

(CDCl3) δ 8.25 (br s, 1H), 7.20-7.90 (m, 5H), 6.45 (s, 1H), 3.90-4.62 (m, 3H, NCH2, CH), 2.60-3.22
(m, 2H); MS (m/z, %) 323 (M,+ 39), 279 (86), 218 (24), 105 (77), 77 (100); HRMS m/z Calcd for:
C16H12NO3F3 (M+) 323.0769. Found: 323.0751. Anal. Calcd for: C16H12NO3F3: C, 59.44; H, 3.71; N,
4.33; F, 17.64. Found: C, 59.64; H, 3.82; N, 4.31; F, 16.93.
REFERENCES
1.
J. P. Dunn, D. M. Green, P. H. Nelson, A. J. Rooks, A. Tomolonis, and K. G. Untch, J. Med.
Chem., 1977, 20, 1557.
2.
J. Ackrell, Y. Antonio, F. Franco, R. Landeros, A. León, J. M. Muchowski, M. L. Maddox, P.
H. Nelson, W. H. Rooks, A. P. Roskowski, and M. B. Wallach, J. Med. Chem., 1978, 21, 1035.
J. P. Dunn, J. M. Muchowski, M. L. Maddox, and P. H. Nelson, J. Med. Chem., 1981, 24, 1097.
S. A. Berkowitz, G. Bernhard, P. J. Bilka, J. M. Marchesano, M. Rosenthal, and G. F.
Wortham, Curr. Ther. Res.,1974, 16, 442.
3.
4.
5.
“Zomepirac: A new Non-Narcotic Analgesic”; Proccedings of the symposium on Zomepirac;
Atlanta, G. A, 1979, J. Clin. Pharmacol., 1980, 20, 213.
6.
7.
8.
9.
J. R. Carson and S. J. Wong, J. Med. Chem., 1973, 16, 172.
F. Franco, R. Greenhouse, and J. M. Muchowski, J. Org. Chem., 1982, 47, 1682.
J. Yee, C. R. Brown, H. Sevelius, and V. Wild, Clin. Pharmacol. Ther., 1984, 35, 285.
S. S. Bloomfield, J. Mitchell, G. Cissell, and T. Barden, Clin. Pharmacol. Ther., 1984, 85,
228.10
10.
R. W. Ward and A. C. Goudie, European Patent Application 0049999 A2, (Chem. Abstr., 1983,
99, 122288).
11.
12.
13.
14.
V. Fiandanese, G. Marchese, V. Martina, and L. Ronzini, Tetrahedron Lett., 1984, 25, 4805.
T. K. Ross, H. M. Dali, and W. G. Tsang, Tetrahedron Lett., 1977, 3859.
J. B. Doherty, U. S. Patent, 1985, 4, 496, 741, (Chem. Abstr., 1985, 102, 166728).
H. Carpio, E. Galeazzi, R. Greenhouse, A. Guzmán, E. Velarde, Y. Antonio, F. Franco, A.
León, V. Pérez, R. Salas, D. Valdés, J. Ackrell, D. Cho, P. Gallegra, O. Halpern, R. Koehler,
M. L. Maddox, J. M. Muchowski, A. Prince, D. Tegg, T. Craig Thyrber, A. R. van Horn, and
D. Wren, J. Can. Chem., 1982, 60, 2295.
15.
A. Covarrubias-Zúñiga, J. G. Ávila-Zárraga, and D. Arias Salas, Synth. Commun., 2003, 33,
3173.