BOX A-type monopyrrolic heterocycles modified via the Suzuki-Miyaura cross-coupling reaction

2.1 Synthesis of BOX A

The total synthesis of BOX A is a multi-step procedure involving the synthesis of methyl (Z)-2-(3-bromo-4-methyl-5-oxofuran-2(5H)-ylidene)acetate (1) [11]. During conversion of 1 to methyl (Z)-2-(3-bromo-4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)acetate (3) via reaction with ammonium acetate in glacial acetic acid, intermediately formed and hitherto unknown methyl 2-(3-bromo-2-hydroxy-4-methyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)acetate (2) could be isolated (Scheme 2). In order to avoid mixtures of 2 and 3, prolonged reaction time of 6 h and a temperature of 120°C were mandatory to quantitatively convert 1 to 3 without the necessity to isolate intermediate 2. The Suzuki-Miyaura cross-coupling reaction proved to be a suitable method to substitute the bromo functionality of 3 with potassium vinyl-trifluoroborate (4a) by a vinyl group yielding methyl (Z)-2-(4-methyl-5-oxo-3-vinyl-1,5-dihydro-2H-pyrrol-2-ylidene)acetate (R=CH=CH₂, 5a). Here we studied the scope of the Suzuki-Miyaura cross-coupling reaction to also attach aromatic hydrocarbyl groups or propenyl substituents. Thereafter, conversion of the ester functionality into an carboxylic amide via the carboxylic acid (6a) and the corresponding acid chloride (7a) yielded (Z)-2-(4-methyl-5-oxo-3-vinyl-1,5-dihydro-2H-pyrrol-2-ylidene)acetamide (BOX A, R=CH=CH₂, 8a). This reaction sequence is depicted in Scheme 2.

Scheme 2:

The reaction sequence for the total synthesis of BOX A-type compounds 8. BOX A (R=CH=CH₂, 8a) is a metabolite of the oxidative degradation of bilirubin.

The molecular structure and atom labeling scheme of methyl 2-(3-bromo-2-hydroxy-4-methyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)acetate (2) are depicted in Fig. 1. Due to a centric space group the crystalline phase consists of a racemate of this chiral compound. Within the five-membered heterocycle significantly different C–C bond lengths are observed, excluding effective charge delocalization between the carbonyl fragment C5–O51 and the C3=C4 double bond. The N1–C2 bond is more than 10 pm longer than the N1–C5 bond. This elongation is a consequence of sp³ hybridization of C2 and a rather crowded environment of this quaternary carbon atom. Therefore it is not astonishing that the C2–C3 and C2–C21 bond lengths are larger than the C4–C5 and C4–C41 single bonds.

Fig. 1:

Molecular structure and atom labeling scheme of methyl 2-(3-bromo-2-hydroxy-4-methyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)acetate (2, top). The ellipsoids represent a probability of 30%. Hydrogen atoms are shown with arbitrary radii. Selected bond lengths (pm): N1–C5 135.0(2), C4–C5 149.3(2), C3–C4 133.2(2), C2–C3 152.3(2), N1–C2 145.8(2), N1–H1 83(2), C5–O51 123.5(2), C4–C41 148.3(2), C3–Br31 186.54(16), C2–O26 139.8(2), O26–H26 82(3), C2–C21 153.9(2), C21–C22 150.5(2), C22–O23 120.8(2), C22–O24 133.5(2), O24–C25 145.0(2). At the bottom, aggregation via hydrogen bonds is depicted. The atoms are shown with arbitrary radii, hydrogen atoms are omitted for clarity reasons.

In the crystalline state methyl 2-(3-bromo-2-hydroxy-4-methyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)acetate (2) aggregates via intermolecular N1–H1⋯O23′ hydrogen bonds to the ester carbonyl moieties of the neighboring molecule (−x, y, −z+0.5). Furthermore, the hydroxyl group forms an O26–H26⋯O51′ hydrogen bond to the carbonyl group of the nearby oxopyrrole fragment (−x, −y, −z). Both hydrogen bonds are nearly linear with N1–H1⋯O23′ and O26–H26⋯O51′ bond angles of 170(2)° and 172(3)° and N1⋯O23′ and O26⋯O51′ distances of 295.81(17) and 275.58(16) pm, respectively. This hydrogen bonding network leads to the formation of a strand structure in the solid state (Fig. 1, bottom).

2.2 Suzuki-Miyaura cross-coupling

The Suzuki-Miyaura cross-coupling step offers the opportunity to introduce groups other than the vinyl moiety. This alteration allows to bind substituents with functionalities that allow tracking of these monopyrrolic compounds in living organisms (such as ¹⁹F-containing groups for ¹⁹F{¹H} NMR spectroscopic experiments). Therefore we studied the scope of this C–C bond forming reaction between sp²-hybridized carbon atoms that in general gave excellent isolated yields above 80%. In a typical procedure, methyl (Z)-2-(3-bromo-4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)acetate (3) and 1.5 equivalents of the corresponding potassium aryl- or alkenyl-trifluoroborate (4b–4k, 1.5 mmol, 1.5 equiv.) were dissolved in a solvent mixture of tetrahydrofuran and water (ratio 4:1) in the presence of 5 mol-% of Pd(PPh₃)₂Cl₂ and three equivalents of CsF. Then the reaction mixture was heated under reflux for 18 h in a nitrogen atmosphere. In all cases the Z-isomeric form was isolated because this diastereomer is stabilized via formation of an intramolecular N–H⋯O hydrogen bond between the pyrrole unit and the ester carbonyl functionality. The outcome of this screening is summarized in Table 1.

Due to the fact that ¹⁹F-labeled BOX A derivatives attracted our special interest, the molecular structure and the atom labeling scheme of methyl (Z)-2-(4-methyl-5-oxo-3-(4-trifluoromethylphenyl)-1,5-dihydro-2H-pyrrol-2-ylidene)acetate (5h) are depicted in Fig. 2. The molecular representations of the derivatives 5b–5g and 5j are shown in the Supporting Information (available online) verifying that exclusively Z-isomeric congeners were isolated and crystallized.

Fig. 2:

Molecular structure and atom labeling scheme of methyl (Z)-2-(4-methyl-5-oxo-3-(4-trifluoromethyl)-1,5-dihydro-2H-pyrrol-2-ylidene)acetate (5h, top). The ellipsoids represent a probability of 30%, hydrogen atoms are drawn with arbitrary radii. Selected bond lengths (pm) are listed in Table 2. At the bottom, dimerization via intermolecular hydrogen bonds is depicted. All atoms are shown with arbitrary radii.

For comparison reasons selected structural parameters of 3-alkenyl- (entries 2 and 3) and 3-aryl-substituted (entries 4–9) methyl (Z)-2-(4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)acetates 5 are listed in Table 2. The numbering of the carbon atoms obeys to the IUPAC recommendation as used for the atom denominations in these compounds. The bond lengths of all compounds deviate in a very narrow range with the phenyl (entry 4, 5d) and naphthyl derivatives (entry 9, 5j) showing the shortest C3=C4 double bonds and the longest C3–C31 and N1–C5 bonds. However, these differences are very small and in the order of the estimated standard deviations. In summary, the substituents in 3-position show a negligible influence on the structural parameters of the 3-alkenyl- (entries 2 and 3) and 3-aryl-substituted (entries 4–9) methyl (Z)-2-(4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)acetates.

The 3-alkenyl- (entries 1 and 2, Table 3) and 3-aryl-substituted (entries 3–8) methyl (Z)-2-(4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)acetates 5 form dimers in the crystalline state due to aggregation via intermolecular N1–H1⋯O51′ hydrogen bonds (Table 3). These highly asymmetric hydrogen bonds are rather weak and the intermolecular N1⋯O51′ distances adopt values between 290 and 320 pm. The N–H stretching vibrations show values around 3300 cm⁻¹ supporting the weak nature of these hydrogen bonds. The N1–H1⋯O51′ bond angles adopt rather large values between 145° and 165°. At the bottom of Fig. 2, dimerization via intermolecular hydrogen bonds is depicted.

2.3 Syntheses and molecular structures of BOX A-derived congeners

As outlined above, we were especially interested in the ¹⁹F labeled congeners for future studies on degradation and fate of the monopyrrolic compounds in biological systems. Therefore, we converted the ester functionalities of 5h and 5i with LiOH at T=0°C into the corresponding carboxylic acids yielding (Z)-2-(4-methyl-5-oxo-3-(4-trifluoromethylphenyl)-1,5-dihydro-2H-pyrrol-2-ylidene)acetic acid (6h) and (Z)-2-(4-methyl-5-oxo-3-(3,5-bis(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrol-2-ylidene)acetic acid (6i), respectively. An additional purification was not necessary, but the purity was then sufficient for the subsequent derivatization protocol. The reaction of these acids with oxalyl chloride at room temperature yielded the corresponding acetyl chlorides, (Z)-2-(4-methyl-5-oxo-3-(4-trifluoromethylphenyl)-1,5-dihydro-2H-pyrrol-2-ylidene)acetyl chloride (7h) and (Z)-2-(4-methyl-5-oxo-3-(3,5-bis(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrol-2-ylidene)acetyl chloride (7i) as depicted in Scheme 2. Finally, these compounds were dissolved in THF and ammonia was added at T=0°C. Then the reaction mixture was warmed to room temperature. Contrary to the yields of 6 and 7 which were excellent, the final step proceeded with yields of only 67% and 53% for (Z)-2-(4-methyl-5-oxo-3-(4-trifluoromethylphenyl)-1,5-dihydro-2H-pyrrol-2-ylidene)acetamide (8h) and (Z)-2-(4-methyl-5-oxo-3-(3,5-bis(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrol-2-ylidene)acetamide (8i).

The molecular structures and atom labeling schemes of 8h and 8i are depicted in Figs. 3 and 4. The crystal structure of 8h contains two crystallographically independent molecules A and B with very similar structural parameters and an additional methanol molecule which is involved in an extended hydrogen bonding network.

Fig. 3:

Molecular structure and atom labeling scheme of (Z)-2-(4-methyl-5-oxo-3-(4-trifluoromethylphenyl)-1,5-dihydro-2H-pyrrol-2-ylidene)acetamide (8h, top). The ellipsoids represent a probability of 30%, hydrogen atoms are shown with arbitrary radii. At the bottom, aggregation via hydrogen bonds (dotted lines) is shown. Only the non-hydrogen atoms are drawn with arbitrary radii.

Fig. 4:

Molecular structure and atom labeling scheme of (Z)-2-(4-methyl-5-oxo-3-(3,5-bis(trifluoromethyl)phenyl)-1,5-dihydro-2H-pyrrol-2-ylidene)acetamide (8i, top). The ellipsoids represent a probability of 30%, hydrogen atoms are shown with arbitrary radii. At the bottom, dimerization via hydrogen bonds (dotted lines) is depicted. All atoms are shown with arbitrary radii for clarity reasons.

Selected bond lengths of BOX A (8a) [11], 8h (molecules A and B), and 8i are compared in Table 4. The structural parameters of the pyrrole ring are very similar and the transformation of the ester functionality into an amide does not affect the endocyclic N–C and C–C bond lengths. The exocyclic aryl groups at C3 are orientated nearly perpendicular to the pyrrole ring prohibiting significant interactions between these π systems. Hence, typical C3–C31 single bonds are observed which are comparable to the C4–C41 bond lengths to the methyl substituents. The amide functionality shows a slight charge delocalization within the O23–C22–N23 unit, leading to larger C22–O23 bond lengths compared to C5–O51 and shorter C22–N23 bonds in comparison to the endocyclic N1–C2/5 bond lengths.

Compound 8h forms an extended hydrogen bonding network via intermolecular N1A–H1A⋯O23B (146.1(18)°, N1A⋯O23B 273.72(15) pm) and N1B–H1B⋯O51A (155.8(18)°, N1B⋯O51A 305.68(16) pm) bridges. In addition, the methanol molecule is connected to the amide functionalities (N23A–H23A⋯O1M and O1M–H1M⋯O23B). The other amide N23A–H23B coordinates to the amide carbonyl group of the neighboring molecule. This extended hydrogen bonding network significantly reduces the solubility of 8h in common organic solvents. In contrast to this aggregation, compound 8i with the bulkier 3,5-bis(trifluoromethyl)phenyl groups only forms dimers in the crystalline state but of a different nature than observed for the derivative 5. Dimerization occurs via intermolecular hydrogen bonds between the amide functionalities (N23–H23A⋯O23′ 178(4)°, N23⋯O23′ 293.8(3) pm) whereas the N1–H1 fragment shows no short contacts to Lewis basic sites of neighboring molecules.

2.4 NMR spectroscopy

The ¹³C{¹H} NMR chemical shifts of the pyrrole units of 3-aryl- and 3-alkenyl-substituted methyl (Z)-2-(4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)acetates 5 as well as methyl (Z)-2-(4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)acetamides 8 are listed in Table 5. The atom numbering is in accordance with the IUPAC nomenclature and identical to the molecule representations in Figs. 2–4. Furthermore, the δ values of the groups at C2 and C4 are included in this table. The solubility of the methyl acetates 5 in common organic solvents is significantly higher than the solubility of the acetamides 8. Therefore the latter compounds had to be dissolved in DMSO-d₆ in order to break down the hydrogen bonding network and to obtain reliable and meaningful ¹³C{¹H} NMR spectra.

The ¹³C{¹H} NMR shifts of the pyrrole carbon atoms C2 and C5, which bind to N1, vary within very narrow ranges around 171 and 149 ppm, respectively. The C3 atoms are bound to alkenyl and aryl groups and the influence of these substituents on the chemical shifts are also very small. In addition, the nature of the functional group of C22 (ester for entries 1–11, compound 5; amide for entries 12–14, derivative 8) shows a negligible influence on the chemical shift of this carbon atom. In agreement with the negligible influence of the substituents at C3 on the chemical shifts of the carbon atoms of the pyrrole ring, also the δ(¹³C{¹H}) values of the C4-bound methyl group C41 vary only within a very narrow range of 9.5±0.5 ppm. However, the methyl resonances are high field-shifted compared to simple compounds with methyl groups bound to alkene moieties as in propene (δ(CH₃)=19.4 ppm), (Z)-2-butene (δ(CH₃)=11.4 ppm), (E)-2-butene (δ(CH₃)=16.8 ppm), (Z)-penta-1,3-diene (δ(CH₃)=12.8 ppm), and (E)-penta-1,3-diene (δ(CH₃)=17.2 ppm) [25].

4.1 Methyl 2-(3-bromo-2-hydroxy-4-methyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)acetate (2)

Method A: A solution of methyl (Z)-2-(3-bromo-4-methyl-5-oxofuran-2(5H)-ylidene)acetate (1) (150 mg, 0.61 mmol), ammonium acetate (234 mg, 3.04 mmol) and acetic anhydride (1 drop) in glacial acetic acid (4 mL) was stirred at 70°C for 5 h. After cooling to r. t., the solvent was evaporated to dryness and the solid residue taken up in 30 mL of ethyl acetate. The solution was washed with water (2×10 mL) and brine (10 mL) and the combined aqueous layers were extracted once with ethyl acetate (10 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and the solvent removed in vacuo. The residue was transferred into a frit, washed with a small amount of dichloromethane and dried in vacuo to provide 2 as a colorless solid (yield: 125 mg, 78%).

Method B: An aqueous ammonia solution (1 mL, 25%) was added to a solution of methyl (Z)-2-(3-bromo-4-methyl-5-oxofuran-2(5H)-ylidene)acetate (1) (230 mg, 0.93 mmol) in 10 mL of methanol. After stirring at r. t. for 1 h the solvent was removed in vacuo and the remaining orange solid was taken up in water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and the solvents removed in vacuo, yielding a pale yellow solid which was recrystallized from ethyl acetate to provide colorless needles of 2. The crystals were collected, washed with a small amount of ethyl acetate and dried in vacuo (yield: 72 mg, 29%).

Physical data of 2: ¹H NMR (400 MHz, CDCl₃, 297 K): δ=7.03 (s, 1H, NH), 3.78 (s, 3H, COOCH₃), 3.43 (s, 1H, OH), 3.17 (d, J=16.2 Hz, 1H, CH_AH_B), 2.50 (d, J=16.2 Hz, 1H, CH_AH_B), 1.88 (s, 3H, CH₃). – ¹H NMR (400 MHz, DMSO-d₆, 297 K): δ=8.68 (s, 1H, NH), 6.45 (s, 1H, OH), 3.54 (s, 3H, COOCH₃), 2.80 (d, J=15.0 Hz, 1H, CH_AH_B), 2.76 (d, J=15.0 Hz, 1H, CH_AH_B), 1.70 (s, 3H, CH₃). – ¹³C{¹H} NMR (101 MHz, DMSO-d₆, 297 K): δ=168.70 (CONH), 168.29 (COOCH₃), 139.65 (C–Br), 132.97 (C–CH₃), 85.82 (C–OH), 51.39 (COOCH₃), 41.30 (CH₂), 9.87 (CH₃). – MS (DEI): m/z (%)=265 (22) [M(⁸¹Br)]⁺, 263 (20) [M(⁷⁹Br)]⁺, 248 (37), 246 (36), 234 (50), 232 (52), 216 (11), 214 (13), 192 (87), 190 (94), 184 (100), 174 (27), 172 (25). – Elemental analysis (C₈H₁₀BrNO₄, 264.08): calcd.: C 36.39, H 3.82, N 5.30; found C 36.33, H 3.70, N 5.43.

4.2 General procedure for 3-aryl- and 3-alkenyl-substituted methyl (Z)-2-(4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)acetates (5b–5k)

A solution of 246 mg of methyl (Z)-2-(3-bromo-4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)acetate (3) (1 mmol), the corresponding potassium aryl- or alkenyl-trifluoroborate (4b–4k, 1.5 mmol, 1.5 equiv.), 35.1 mg of Pd(PPh₃)₂Cl₂ (0.05 mmol, 5 mol-%) and 456 mg of CsF (3 mmol, 3 equiv.) in 10 mL of a degassed mixture of tetrahydrofuran and water (ratio 4:1) was heated under reflux for 18 h in a nitrogen atmosphere. After complete conversion and cooling to r. t. 50 mL of diethyl ether was added. The organic layer was separated, washed twice with 25 mL of water and three times with 25 mL of brine. The organic phase was dried over anhydrous sodium sulfate. Then the volatiles were removed in vacuo and a subsequent chromatographic purification (silica gel, petroleum ether-ethyl acetate 1:1) gave analytically pure products 5b–5k.

Physical data of 5h: Yield: 238 mg (0.76 mmol, 94%), colorless solid. – ¹H NMR (400.21 MHz, CDCl₃, 297 K): δ=9.30 (s, br, 1H, NH), 7.75 (d, ³J_H,H=8.2 Hz, 2H, m-CH_pCF3Ph), 7.42 (d, ³J_H,H=8.1 Hz, 2H, o-CH_pCF3Ph), 5.21 (s, 1H, CH), 3.76 (s, 3H, COOCH₃), 2.01 (s, 3H, CH₃). – ¹³C{¹H} NMR (100.61 MHz, CDCl₃, 297 K): δ=170.7 (CONH), 167.6 (COOCH₃), 150.0 (C=CH), 142.8 (C−C₆H₄CF₃), 134.6 (C−CH₃), 134.1 (d, ⁵J_C,F=1.3 Hz, ipso-C_pCF3Ph), 131.4 (q, ²J_C,F=32.8 Hz, C−CF₃), 129.7 (s, o-CH_pCF3Ph), 125.9 (q, ³J_C,F=3.7 Hz, m-CH_pCF3Ph), 123.9 (q, ¹J_C,F=272.5 Hz, CF₃), 96.5 (C=CH), 52.0 (COOCH₃), 9.6 (CH₃). – ¹⁹F NMR (376.58 MHz, CDCl₃, 297 K): δ=−62.84 (s, CF₃). – IR (ATR): 3247 (m, br), 3082 (m), 3001 (m), 2952 (m), 1687 (s), 1625 (m), 1428 (m), 1408 (m), 1380 (m), 1357 (m), 1319 (s), 1266 (m), 1173 (s), 1106 (s), 1064 (s), 1048 (s), 1014 (s), 991 (m), 957 (m), 876 (m), 862 (m), 845 (s), 765 (s), 747 (m), 733 (m), 704 (m), 694 (s), 634 (m), 612 (m), 586 (m), 535 (m), 493 (m), 437 (m), 421 (m). – MS (DEI): m/z (%)=311 (100) [M]⁺, 283 (56) [M–CO]⁺, 280(34) [M–CH₃O]⁺, 251(32) [M–CH₃OH–CO]⁺, 223 (41) [M–CH₃OH–2CO]⁺, 154 (18) [C₁₁H₈N]⁺, 115 (11) [C₉H₇]⁺. – Elemental analysis (C₁₅H₁₂F₃NO₃, 311.26): calcd.: C 57.88, H 3.89, N 4.50; found C 57.81, H 3.96, N 4.47.

Physical data of 5i: Yield: 227 mg (0.60 mmol, 98%), colorless solid. – ¹H NMR (400.21 MHz, CDCl₃, 297 K): δ=9.38 (s, 1H, NH), 7.99 (s, 1H, p-CH_m(CF3)2Ph), 7.75 (s, 2H, o-CH_m(CF3)2Ph), 5.14 (s, 1H, CH), 3.78 (s, 3H, COOCH₃), 2.02 (s, 3H, CH₃). – ¹³C{¹H} NMR (100.63 MHz, CDCl₃, 297 K): δ=170.1 (CONH), 167.4 (COOCH₃), 149.5 (C=CH), 141.1 (C−C₆H₃(CF₃)₂), 136.0 (C−CH₃), 132.7 (ipso-C_m(CF3)2Ph), 132.7 (q, ²J_C,F=33.9 Hz, C−CF₃), 129.4 (d, ³J_C,F=3.1 Hz, o-CH_m(CF3)2Ph), 123.2 (q, ³J_C,F=3.8 Hz, p-CH_m(CF3)2Ph), 123.0 (q, ¹J_C,F=272.8 Hz, CF₃), 96.5 (C=CH), 52.1 (COOCH₃), 9.7 (CH₃). – ¹⁹F NMR (376.58 MHz, CDCl₃, 297 K): δ=−62.90 (s, CF₃). – IR (ATR): 3404 (m), 3060 (w), 2957 (w), 1720 (s), 1691 (s), 1665 (m), 1638 (s), 1444 (m), 1411 (m), 1396 (m), 1380 (m), 1321 (m), 1281 (s), 1261 (s), 1206 (m), 1176 (s), 1158 (s), 1111 (s), 1049 (m), 1033 (m), 1000 (m), 955 (m), 934 (m), 913 (s), 873 (m), 848 (m), 831 (s), 759 (m), 712 (m), 681 (s), 650 (m), 627 (m), 600 (s), 493 (m), 447 (m), 417 (m). – MS (DEI): m/z (%)=379 (100) [M]⁺, 351 (47) [M–CO]⁺, 348 (99) [M–CH₃O]⁺, 319 (23) [M–CH₃OH–CO]⁺, 291 (36) [M–CH₃OH–2CO]⁺. – Elemental analysis (C₁₆H₁₁F₆NO₃, 379.26): calcd.: C 50.67, H 2.92, N 3.69; found C 50.54, H 3.06, N 3.38.

4.3 General procedure for 3-(4-(trifluoromethyl)phenyl)- and 3-(3,5-bis(trifluoromethyl)phenyl)-substituted methyl (Z)-2-(4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)acetic acids (6h and 6i)

Solutions of the methyl esters 5h and 5k in THF (3.9–4.7 mL mmol⁻¹) were reacted with 3 equiv. of an aqueous 2 m LiOH solution at 0°C and then at r. t. for additional 25–27 h. Diluted hydrochloric acid was added till a pH value of 2 was realized. Then 20 mL of ethyl acetate was added and the remaining aqueous phase extracted three times with 10 mL of ethyl acetate. The combined organic phases were washed with 10 mL of a saturated NaCl solution and dried over anhydrous Na₂SO₄. After filtration, the solvent of the filtrate was removed in vacuo. Purity was checked by NMR spectroscopy and the acids 6h and 6i were used for transformations without further purification.

Physical data of 6h: Yield: 175 mg (0.59 mmol, 92%). – ¹H NMR (400.13 MHz, DMSO-d₆, 296 K): δ=12.68 (s, br, 1H, COOH), 10.04 (s, 1H, NH), 7.89 (d, ³J_H,H=8.1 Hz, 2H, m-CH_pCF3Ph), 7.62 (d, ³J_H,H=8.0 Hz, 2H, o-CH_pCF3Ph), 5.03 (s, 1H, CH), 1.88 (s, 3H, CH₃). – ¹³C{¹H} NMR (100.61 MHz, DMSO-d₆, 296 K): δ=170.5 (CONH), 167.2 (COOH), 148.9 (C=CH), 142.3 (C−C₆H₄CF₃), 134.5 (d, ⁵J_C,F=1.4 Hz, ipso-C_pCF3Ph), 133.5 (C−CH₃), 130.2 (s, o-CH_pCF3Ph), 129.3 (q, ²J_C,F=32.0 Hz, C−CF₃), 125.7 (q, ³J_C,F=3.7 Hz, m-CH_pCF3Ph), 124.1 (q, ¹J_C,F=272.3 Hz, CF₃), 97.4 (C=CH), 9.2 (CH₃). – ¹⁹F NMR (376.58 MHz, DMSO-d₆, 297 K): δ=−61.21 (s, CF₃). – IR (ATR): 3416 (w), 3268 (w), 3219–2231 (m, br), 2929 (m), 1726 (m), 1707 (m), 1676 (m), 1643 (m), 1618 (m), 1450 (m), 1409 (m), 1382 (w), 1356 (m), 1322 (s), 1296 (m), 1253 (m), 1229 (m), 1206 (m), 1167 (m), 1110 (s), 1067 (m), 1018 (m), 995 (m), 948 (m), 842 (m), 776 (m), 761 (m), 743 (m), 695 (m), 670 (m), 635 (m), 617 (m), 578 (m), 535 (m), 491 (m), 458 (m), 441 (m). – MS (DEI): m/z (%)=297 (100) [M]⁺, 280 (11) [M–OH]⁺, 269 (36) [M–CO]⁺, 251 (22) [M–H₂O–CO]⁺, 225 (60) [M+H–COOH–CO]⁺, 154 (28) [C₁₁H₈N]⁺, 115 (21) [C₉H₇]⁺. – Elemental analysis (C₁₄H₁₀F₃NO₃, 297.23): calcd.: C 56.57, H 3.39, N 4.71; found C 56.68, H 3.83, N 4.27.

Physical data of 6i: Yield: 192 mg (0.53 mmol, 99%), pale yellow solid. – ¹H NMR (400.21 MHz, DMSO-d₆, 297 K): δ=12.70 (s, br, 1H, COOH), 10.10 (s, 1H, NH), 8.24 (s, 1H, p-CH_m(CF3)2Ph), 8.12 (s, 2H, o-CH_m(CF3)2Ph), 4.97 (s, 1H, CH), 1.87 (s, 3H, CH₃). – ¹³C{¹H} NMR (100.63 MHz, DMSO-d₆, 297 K): δ=170.2 (CONH), 167.1 (COOH), 148.7 (C=CH), 140.9 (C−C₆H₃(CF₃)₂), 134.7 (C−CH₃), 133.0 (ipso-C_m(CF3)2Ph), 130.8 (q, ²J_C,F=33.2 Hz, C−CF₃), 130.2 (d, ³J_C,F=3.1 Hz, o-CH_m(CF3)2Ph), 123.1 (q, ¹J_C,F=273.1 Hz, CF₃), 122.8 (q, ³J_C,F=3.6 Hz, p-CH_m(CF3)2Ph), 97.5 (C=CH), 9.2 (CH₃). – ¹⁹F NMR (376.58 MHz, DMSO-d₆, 297 K): δ=−61.20 (s, CF₃). – IR (ATR): 3271 (w), 3215–2285 (w, br), 2927 (w), 1706 (m), 1679 (m), 1651 (m), 1468 (m), 1439 (m), 1404 (m), 1379 (m), 1322 (m), 1276 (s), 1213 (m), 1167 (s), 1124 (s), 1032 (m), 903 (m), 885 (m), 847 (m), 832 (m), 760 (m), 706 (m), 681 (s), 644 (m), 628 (m), 576 (m), 509 (m), 443 (m), 417 (m). – MS (DEI): m/z (%)=365 (100) [M]⁺, 348 (22) [M–OH]⁺, 337 (29) [M–CO]⁺, 319 (22) [M–H₂O–CO]⁺, 293 (72) [M+H–COOH–CO]⁺. – Elemental analysis (C₁₅H₉F₆NO₃, 365.23): calcd.: C 49.33, H 2.48, N 3.84; found C 49.83, H 3.07, N 3.38.

4.4 General procedure for 3-(4-trifluoromethylphenyl)- and 3-(3,5-bis(trifluoromethyl)phenyl)-substituted methyl (Z)-2-(4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)acetyl chlorides (7h and 7i)

A drop of DMF and 1.3 equivalents of DCM were added at r. t. to a solution of the acetic acids 6h and 6i. After stirring for 2 h and ceased gas evolution the volatiles were removed in vacuo. The remaining solid was dried in vacuo and these products 7h and 7i were used for the final conversion without further purification.

Physical data of 7h: Yield: 170 mg (0.54 mmol, 95%), light brown solid. – ¹H NMR (400.13 MHz, [D₈]THF, 297 K): δ=10.24 (s, br, 1H, NH), 7.85 (d, ³J_H,H=8.2 Hz, 2H, m-CH_pCF3Ph), 7.58 (d, ³J_H,H=8.1 Hz, 2H, o-CH_pCF3Ph), 5.40 (s, 1H, CH), 1.95 (s, 3H, CH₃). – ¹³C{¹H} NMR (100.61 MHz, [D₈]THF, 297 K): δ=171.8 (CONH), 164.4 (COCl), 153.8 (CCH), 143.8 (C−C₆H₄CF₃), 136.8 (C−CH₃), 135.0 (ipso-C_pCF3Ph), 131.9 (q, ²J_C,F=32.4 Hz, C−CF₃), 130.9 (s, o-CH_pCF3Ph), 126.7 (q, ³J_C,F=3.8 Hz, m-CH_pCF3Ph), 125.1 (q, ¹J_C,F=272.2 Hz, CF₃), 100.4 (C=CH), 9.4 (CH₃). – ¹⁹F NMR (376.58 MHz, [D₈]THF, 297 K): δ=−63.60 (s, CF₃). – MS (DEI): m/z (%)=315 (41) [M]⁺, 280 (100) [M–Cl]⁺.– HRMS (EI): m/z=315.0279 (calcd. 315.0274 for C₁₄H₉ClF₃NO₂, [M]⁺.

Physical data for 7i: Yield: 160 mg (0.42 mmol, 99%), brown solid. – ¹H NMR (400.13 MHz, [D₈]THF, 297 K): δ=10.34 (s, br, 1H, NH), 8.19 (s, 1H, p-CH_m(CF3)2Ph), 8.02 (s, 2H, o-CH_m(CF3)2Ph), 5.37 (s, 1H, CH), 1.94 (s, 3H, CH₃). – ¹³C{¹H} NMR (100.61 MHz, [D₈]THF, 297 K): δ=171.5 (CONH), 164.4 (COCl), 153.4 (CCH), 142.5 (C−C₆H₃(CF₃)₂), 138.0 (C−CH₃), 133.7 (ipso-C_m(CF3)2Ph), 133.0 (q, ²J_C,F=33.5 Hz, C−CF₃), 130.8 (q, ³J_C,F=3.9 Hz, o-CH_m(CF3)2Ph), 124.3 (q, ¹J_C,F=272.7 Hz, CF₃), 124.1 (q, ³J_C,F=3.6 Hz, p-CH_m(CF3)2Ph), 100.6 (C=CH), 9.4 (CH₃). – ¹⁹F NMR (376.58 MHz, [D₈]THF, 297 K): δ=−65.52 (s, CF)₃. – MS (DEI): m/z (%)=383 (19) [M]⁺, 348 (100) [M–Cl]⁺.

4.5 General procedure for 3-(4-trifluoromethylphenyl)- and 3-(3,5-bis(trifluoromethyl)phenyl)-substituted methyl (Z)-2-(4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)acetamides (8h and 8i)

Ammonia was passed into a solution of the acetyl chlorides 7h and 7i in anhydrous THF at 0°C. After 30 min the cooling bath was removed and ammonia was passed into this reaction mixture for approximately an additional hour. During this time the clouding of the solution intensified. Thereafter the solvent was removed in vacuo and the residue was purified as given below.

Purification and physical data for 8h: The residue was washed four times with 3 mL of water and dried in vacuo. Recrystallization from methanol yielded yellow crystals of 8h·0.55MeOH. Yield: 106 mg (0.34 mmol, 67%). Methanol-free samples were obtained by dissolution of 8h·0.55MeOH in acetone and distillation to remove MeOH. The residue was suspended in diethyl ether and the solvent removed in vacuo. Thereafter, the colorless residue was thoroughly dried in vacuo. – ¹H NMR (400.13 MHz, DMSO-d₆, 297 K): δ=10.09 (s, 1H, NH), 7.91 (d, ³J_H,H=8.1 Hz, 2H, m-CH_pCF3Ph), 7.68 (s, 1H, NH₂), 7.63 (d, ³J_H,H=8.0 Hz, 2H, o-CH_pCF3Ph), 7.27 (s, 1H, NH₂), 5.36 (s, 1H, CH), 1.88 (s, 3H, CH₃). – ¹³C{¹H} NMR (100.61 MHz, DMSO-d₆, 297 K): δ=170.0 (CONH), 167.7 (CONH₂), 146.0 (C=CH), 142.1 (C−C₆H₄CF₃), 134.9 (d, ⁵J_C,F=1.2 Hz, ipso-C_pCF3Ph), 132.7 (C−CH₃), 130,2 (s, o-CH_pCF3Ph), 129.2 (q, ²J_C,F=31.9 Hz, C−CF₃), 125.7 (q, ³J_C,F=3.7 Hz, m-CH_pCF3Ph), 124.1 (q, ¹J_C,F=272.3 Hz, CF₃), 100.3 (C=CH), 9.1 (CH₃). – ¹⁹F NMR (376.58 MHz, DMSO-d₆, 297 K): δ=−61.21 (s, CF₃). – IR (ATR): 3359 (m), 3151 (m), 2920 (w), 2790 (w), 1703 (s), 1665 (s), 1649 (s), 1609 (s), 1434 (m), 1410 (m), 1388 (m), 1360 (m), 1321 (s), 1299 (s), 1262 (m), 1175 (s), 1137 (s), 1112 (s), 1066 (s), 1042 (m), 1021 (m), 997 (m), 959 (m), 933 (m), 854 (m), 838 (s), 760 (m), 743 (m), 722 (m), 706 (m), 695 (m), 647 (s), 609 (s), 586 (s), 533 (m), 491 (m), 444 (m), 419 (m). – MS (DEI): m/z (%)=296 (100) [M]⁺, 280 (23) [M–NH₂]⁺, 268 (22) [M–CO]⁺, 251 (58) [M–NH₃–CO]⁺, 225 (94) [M+H–CONH₂–CO]⁺, 154 (18) [C₁₁H₈N]⁺, 115 (21) [C₉H₇]⁺. – Elemental analysis (C₁₄H₁₁F₃N₂O₂, 296.25): calcd.: C 56.76, H 3.74, N 9.46; found C 56.31, H 3.94, N 9.13.

Purification and physical data for 8i: The product was washed with water (4×3 mL) and dried in vacuo. The solid residue was dissolved in methanol and at 4°C an amorphous solid precipitated, which was collected, washed with a few milliliters of methanol and dried in vacuo. Yield: 68 mg (0.19 mmol, 53%), colorless solid. Single crystals were obtained by evaporation of the solvent from the methanol mother liquor. – ¹H NMR (400.13 MHz, DMSO-d₆, 297 K): δ=10.14 (s, 1H, NH), 8.27 (s, 1H, p-CH_m(CF3)2Ph), 8.12 (s, 2H, o-CH_m(CF3)2Ph), 7.69 (s, 1H, NH₂), 7.28 (s, 1H, NH₂), 5.25 (s, 1H, CH), 1.86 (s, 3H, CH₃). – ¹³C{¹H} NMR (100.63 MHz, DMSO-d₆, 297 K): δ=169.7 (CONH), 167.6 (CONH₂), 146.0 (C=CH), 140.7 (C−C₆H₃(CF₃)₂), 134.0 (C−CH₃), 133.4 (ipso-C_m(CF3)2Ph), 130.8 (q, ²J_C,F=33.2 Hz, C−CF₃), 130.2 (d, ³J_C,F=2.5 Hz, o-CH_m(CF3)2Ph), 123.1 (q, ¹J_C,F=273.0 Hz, CF₃), 122.8 (q, ³J_C,F=3.8 Hz, p-CH_m(CF3)2Ph), 100.2 (C=CH), 9.1 (CH₃). – ¹⁹F NMR (376.58 MHz, DMSO-d₆, 297 K): δ=−61.15 (s, CF₃). – IR (ATR): 3500 (m), 3417 (m), 3311 (w), 3257 (w), 3168 (m), 3066 (m), 1722 (m), 1679 (m), 1638 (m), 1600 (m), 1470 (m), 1437 (m), 1406 (m), 1376 (m), 1353 (m), 1322 (m), 1280 (s), 1238 (m), 1170 (s), 1122 (s), 1030 (m), 917 (m), 870 (m), 848 (m), 827 (m), 779 (m), 763 (m), 712 (m), 706 (m), 680 (m), 666 (m), 630 (m), 616 (m), 593 (s), 533 (m), 508 (m), 479 (s), 441 (m), 419 (m). – MS (DEI): m/z (%)=364 (88) [M]⁺, 348 (83) [M–NH₂]⁺, 336 (9) [M–CO]⁺, 319 (83) [M–NH₃–CO]⁺, 293 (100) [M+H–CONH₂–CO]⁺. – Elemental analysis (C₁₅H₁₀F₆N₂O₂, 364.25): calcd.: C 49.46, H 2.77, N 7.69; found C 49.79, H 3.43, N 7.33.

4.6 X-ray structure determinations

The intensity data for the compounds was collected on a Nonius KappaCCD diffractometer using graphite-monochromatized MoKα radiation. Data was corrected for Lorentz and polarization effects; absorption was taken into account on a semi-empirical basis using multiple-scans [27], [28], [29]. The structures were solved by direct methods (Shelxs) [30] and refined by full-matrix least squares techniques against Fo2 (Shelxl-97) [31]. The hydrogen atoms bonded to the amine groups N1A–N1D of 5f and all other hydrogen atoms (with exception of the methyl groups C33A and C41B of 5c) were located by difference Fourier synthesis and refined isotropically. The remaining hydrogen atoms of 5f were included at calculated positions with fixed thermal parameters. All non-hydrogen atoms were refined anisotropically [31]. Crystallographic data as well as structure solution and refinement details are summarized in Table S2 (see Supporting Information). XP [32] and POV-Ray [33] were used for structure representations.

Crystallographic data (excluding structure factors) has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC 1945677 for 2, CCDC 1945678 for 5b, CCDC 1945679 for 5c, CCDC 1945680 for 5d, CCDC 1945681 for 5e, CCDC 1945682 for 5f, CCDC 1945683 for 5g, CCDC 1945684 for 5h, CCDC 1945685 for 5j, CCDC 1945686 for 8h, and CCDC 1945687 for 8i. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre viawww.ccdc.cam.ac.uk/data_request/cif.