Efficient synthesis of new 1-[Alkyl(aryl)]-5-(3,3,3-trihalo-2-oxopropylidene)pyrrolidin-2-ones

Flores, Alex F. C.; Flores, Darlene C.; Oliveira, Graciela; Pizzuti, Lucas; Silva, Rubia M. S. da; Martins, Marcos A. P.; Bonacorso, Helio G.

doi:10.1590/S0103-50532008000100026

Abstracts

Reactions of methyl 4-methoxy-6-oxo-7,7,7-trihalo-4-heptenoates 1 and 2 with primary amines RNH2, where R = PhCH2, PhCH2CH2, Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4, 2-pyridyl, 5-methyl-3-isoxazolyl, 4-NH2C6H4 affording methyl 4-[alkyl(aryl)amino]-6-oxo-7,7,7-trihalo-4-heptenoates 3, 4, in good yields (57-95%), which suffer quantitative intramolecular cyclocondensation to produce 1-alkyl(aryl)-5-(2-oxo-3,3,3-trihalopropylidene)pyrrolidin-2-ones 5, 6, are reported. The structures of the isolated new products were assigned by means of ¹H,13C NMR measurements and mass spectrometry. The Z and E configuration of compounds 3d and 5b respectively were established from X-ray crystallography.

pyrrolidin-2-ones; [CCCC+N] cyclisation; methyl 4-methoxy-6-oxo-7,7,7-trihalo-4-heptenoates

Este trabalho mostra a síntese, em bons rendimentos (57-95%), de duas séries de 1-alquil(aril)amino-2-oxo-5-(2-oxo-3,3,3-trialopropiliden)-pirrolidinas 5 e 6, a partir dos intermediários 4-[alquil(aril)amino]-6-oxo-7,7,7-trialo-4-hepteno-atos de metila 3 e 4 obtidos por substituição da metoxila-beta nos precursores 4-metoxi-6-oxo-7,7,7-trialo-4-heptenoatos de metila 1 e 2, pela série de aminas primárias RNH2, onde R = PhCH2, PhCH2CH2, Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4, 2-piridnil, 5-metil-3-isoxazolil, 4-NH2C6H4. A estrutura molecular dos produtos inéditos foi atribuída a partir dos dados de RMN ¹H, 13C e espectrometria de massas. A configuração geométrica dos compostos 3d e 5b foi confirmada pelos dados de difração de raios-X em monocristal.

ARTICLE

Efficient synthesis of new 1-[Alkyl(aryl)]-5-(3,3,3-trihalo-2-oxopropylidene)pyrrolidin-2-ones

Alex F. C. Flores^* * e-mail: alexflores@smail.ufsm.br ; Darlene C. Flores; Graciela Oliveira; Lucas Pizzuti; Rubia M. S. da Silva; Marcos A. P. Martins; Helio G. Bonacorso

NUQUIMHE - Departamento de Química, Universidade Federal de Santa Maria 97105 900 Santa Maria-RS, Brazil

ABSTRACT

Reactions of methyl 4-methoxy-6-oxo-7,7,7-trihalo-4-heptenoates 1 and 2 with primary amines RNH₂, where R = PhCH₂, PhCH₂CH₂, Ph, 4-MeC₆H₄, 4-MeOC₆H₄, 4-ClC₆H₄, 4-BrC₆H₄, 2-pyridyl, 5-methyl-3-isoxazolyl, 4-NH₂C₆H₄ affording methyl 4-[alkyl(aryl)amino]-6-oxo-7,7,7-trihalo-4-heptenoates 3, 4, in good yields (57-95%), which suffer quantitative intramolecular cyclocondensation to produce 1-alkyl(aryl)-5-(2-oxo-3,3,3-trihalopropylidene)pyrrolidin-2-ones 5, 6, are reported. The structures of the isolated new products were assigned by means of ¹H,¹³C NMR measurements and mass spectrometry. The Z and E configuration of compounds 3d and 5b respectively were established from X-ray crystallography.

Keywords: pyrrolidin-2-ones, [CCCC+N] cyclisation, methyl 4-methoxy-6-oxo-7,7,7-trihalo-4-heptenoates

RESUMO

Este trabalho mostra a síntese, em bons rendimentos (57-95%), de duas séries de 1-alquil(aril)amino-2-oxo-5-(2-oxo-3,3,3-trialopropiliden)-pirrolidinas 5 e 6, a partir dos intermediários 4-[alquil(aril)amino]-6-oxo-7,7,7-trialo-4-hepteno-atos de metila 3 e 4 obtidos por substituição da metoxila-b nos precursores 4-metoxi-6-oxo-7,7,7-trialo-4-heptenoatos de metila 1 e 2, pela série de aminas primárias RNH₂, onde R = PhCH₂, PhCH₂CH₂, Ph, 4-MeC₆H₄, 4-MeOC₆H₄, 4-ClC₆H₄, 4-BrC₆H₄, 2-piridnil, 5-metil-3-isoxazolil, 4-NH₂C₆H₄. A estrutura molecular dos produtos inéditos foi atribuída a partir dos dados de RMN ¹H, ¹³C e espectrometria de massas. A configuração geométrica dos compostos 3d e 5b foi confirmada pelos dados de difração de raios-X em monocristal.

Introduction

We have systematically used the acetals acylation method for synthesis of wide range of 4-alkoxy-1,1,1-trihalo-3-alken-2-ones. These 1,3-dielectrophilic precursors have proved to be important building blocks for regiospecific synthesis of heterocyclic compounds bearing trihalomethyl group^{2, 3} with important pharmacological^{4, 5} and synthetic applications.⁶ The levulinic acid (4-oxopentanoic acid) is an important fine organic material from renewable source, with acetyl group attractive for us.⁷ Our continuing interest in 1,3-dielectrophilic compounds has led us to study a new aspect of the application of the acetal acylation method for producing methyl 4-methoxy-6-oxo-7,7,7-trihalo-4-heptenoates 1 and 2.⁸

On the other hand, the pyrrolidin-2-ones, have received considerable attention due to their activity in CNS as nootropic drugs. Piracetam-like nootropics revert amnesia induced by scopolamine and other amnesing drugs, electroconvulsive shock and hypoxia with an unknown mechanism.⁹ In general, they show no affinity for the most important central receptors, but are able to modulate the action of these most important central neurotransmitters, in particular acetylcholine and glutamate. Extensive study of the modes of action of the 2-pyrrolidinones has revealed various pharmacological effects, with striking differences between drugs.^{10, 11}

Continuing with our systematic studies on synthesis and application of 4-alkoxy-1,1,1-trihalo-3-alken-2-ones we report an efficient approach for synthesis of a series of 1-[alkyl(aryl)]-5-(3,3,3-trihalo-2-oxopropylidene)pyrrolidin-2-nes from 1 and 2. This study deals with formation of the methyl 4-alkyl[aryl]amino-6-oxo-7,7,7-trihalo-4-heptenoates 3 and 4, and their intramolecular cyclisations to new 1-alkyl[aryl]-5-(3,3,3-trihalo-2-oxopropylidene)pyrrolidin-2-ones 5 and 6.

Results and Discussion

The precursors methyl 4-methoxy-6-oxo-7,7,7-trihalo-4-heptenoates 1 and 2 were obtained by acetal acylation method as described previously.⁸

The fluorinated enaminones 3 were synthesized and isolated by reaction of the methyl 4-methoxy-6-oxo-7,7,7-trifluoro-4-heptenoate (1) with primary alkyl[aryl]amines in CH₃CN at variable temperatures depending on used amine. The analytical data have demonstrated the formation of the methyl 4-alkyl[aryl]amino-6-oxo-7,7,7-trifluoro-4-heptenoates 3,b-k (Table 1, Supplementary Information), with (Z)-4-alkyl[aryl]amino-1,1,1-trifluoro-3-alken-2-one moiety.² Primary alkylamines (b, c) reacted readily with 4-methoxy-1,1,1-trifluoro-3-alken-2-ones in MeOH, EtOH or i-PrOH by displacement of b-methoxy substituent, in these cases, the intramolecular cyclocondensation of the resulting methyl 4-alkylamino-6-oxo-7,7,7-trifluoro-4-heptenoates 3,b,c to pyrrolidin-2-ones also took place, affording mixtures of products 3 and 5 at room temperature. However, when the least reactive primary arylamines were employed, and the reaction was carried out in MeOH or EtOH at room temperature, unreacted 1 or mixtures of methyl 4-ethoxy-6-oxo-7,7,7-trifluoro-4-heptenoate and 1 were recovered. The methyl 4-arylamino-6-oxo-7,7,7-trifluoro-4-heptenoates 3,d-j were obtained in refluxing MeCN or at room temperature, by addition of equimolar amount of Et₃N or lutidine (Table 1, Supplementary Information). Reaction of the methyl 4-methoxy-6-oxo-7,7,7-trifluoro-4-heptenoate 1 with 1,4-diaminobenzene in a stoichiometric ratio 1:1 or in 2:1 mol-equiv ratio in MeCN at room temperature lead to the methyl 4-(4-aminophenylamino)-6-oxo-7,7,7-trifluoro-4-heptenoate 3k, but under reflux conditions the intramolecular cyclisation took place under formation of only 1,1-(1,4-phenylene)-bis(5-(3,3,3-trifluoro-2-oxopropylidene)-2-pyrrolidin-2-one) 5k (Scheme 1).

The structures of fluorinated enaminones 3 were confirmed by elemental analysis, mass spectrometry and ¹H, ¹³C NMR spectral data. The ¹H NMR spectra showed characteristic broad signals from N-H between 12.4-13.2 ppm, the vinylic hydrogen singlet at 5.47-5.68 ppm and for methyl group of ester as intense singlet at 3.64-3.70 ppm.^{12, 13} The ¹³C NMR spectra showed the signals of methoxy group at 51.5-51.9 ppm and carboxylic ester carbon at 169.8 170.7 ppm confirming the propionyl chain, two characteristic quartets for carbonyl carbon C6, ca. 176-178 ppm, ²J_CF 34 Hz and trifluoromethyl group C7, ca. 116.5-117.5 ppm, ¹J_CF288 Hz, all confirming acyclic enaminone structures 3b-k .

Reacting 1 or 2 with 5-amino-3-methyl-1H-pyrazole under conditions described above, the products of cyclocondensation [3 + 3], the methyl 3-(2-methyl-7-(trihalomethyl)pyrazolo[1,5-a]pyrimidin-5-yl)propanoates 7 and 8 (Scheme 2). Their structures were confirmed by elemental analysis and ¹H, ¹³C NMR data.¹⁵

The easy intramolecular cyclization of methyl 4-alkylamino-6-oxo-7,7,7-trifluoro-4-heptenoates 3b,c to pyrrolidin-2-ones 5b,c occurred in MeOH, EtOH or MeCN. The intramolecular cyclisation of methyl 4-alkylamino-6-oxo-7,7,7-trifluoro-4-heptenoates 3d-j to 5-(3,3,3-trifluoro-2-oxopropylidene)-pyrrolidin-2-ones 5d-j occurred only in refluxing MeCN in the presence of equimolar amount of Et₃N for reaction periods varying between 8-24 h. The products 5,b-k can be obtained in one pot process by the reaction of precursor 1 and amine in MeCN followed by Et₃N addition and/or reflux (85 °C) affording similar yields.

The 1-Alkyl(aryl)-5-(3,3,3-trifluoro-2-oxopropylidene)pyrrolidin-2-ones 5,b-k were characterised by elemental analysis, mass spectrometry and ¹H, ¹³C NMR data. The ¹H NMR spectra showed characteristic signals for vinylic hydrogen at 5.66-5.94 ppm and the signals for cyclic CH₂ as multiplet at 2.67-2.83 and 3.33-3.57 ppm. The ¹³C NMR spectra showed the signals of amide carbon at 167.8-169.2 ppm, two characteristic quartets of carbonyl carbon at propylidene chain ca. 178-179.3 ppm, ²J_CF 34 Hz, for trifluoromethyl group CF₃ca. 116.2-116.4 ppm, ¹J_CF291 Hz and for vinylic carbon at 90.3-93.7 ppm, all confirming 1-alkyl[aryl]-5-(3,3,3-trifluoro-2-oxopropylidene)pyrrolidin-2-one structures 5,b-k.

Compounds 3d and 5b were subjected to single crystal X-ray analysis (Tables 4 and 5). This measurement has showed in solid state the molecular structure with Z-configuration on alkene moiety and intramolecular hydrogen bond O3---H1N1 for methyl 6-oxo-4-phenylamino-7,7,7-trifluoro-4-heptenoate (3d) (Figure 2). X-ray diffraction analysis performed on 1-benzyl-5-(3,3,3-trifluoro-2-oxopropylidene)pyrrolidin-2-one (5b) showed the E-configuration for enaminoketone moiety (Figure 3), confirming that the intramolecular cyclisation occurred with the inversion of configuration. In both structures the trifluoromethyl group suffers a rotational disorder and was refined as two components as approximately 60%/40% occupancy (Tables 1 and 2).

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The methyl 4-methoxy-6-oxo-7,7,7-trichloro-4-heptenoate demonstrated high reactivity for nucleophilic attack of alkylamines at b-carbon of the vinyl group, taking place of methoxy group, followed by fast intramolecular cyclisation to 1-alkyl-5-(3,3,3-trichloro-2-oxopropylidene)-pyrrolidin-2-ones. With the intention to isolate of the methyl 4-alkylamino-6-oxo-7,7,7-trichloro-4-heptenoates 4,a,c, the heptanoate precursor 2 was reacted with primary alkylamines in dichloromethane or chloroform at -5 - 0 ºC for 2 hours. Primary arylamines were reacted in MeCN at room temperature (Scheme 1) for 6 hours, and 4-arylamino-6-oxo-7,7,7-trichloro-4-heptenoates 4,d-j were isolated in good yields and in high purity (Table 2, Supplementary Information). Reactions in EtOH or i-PrOH gave poor yields with complex mixtures of unidentified products, maybe involving transesterication and/or chloroform elimination.

The molecular structures of methyl 4-alkyl[aryl]amino-6-oxo-7,7,7-trichloro-4-heptenoates 4,a,c-j were confirmed by elemental analysis, mass spectrometry and ¹H, ¹³C NMR spectral data. The ¹H NMR spectra showed characteristic broad signals for N-H between 13.4-13.8 ppm, the vinylic hydrogen at 5.85-5.89 ppm and for methoxy group as intense singlet at 3.60-3.67 ppm.^{12, 13} The ¹³C NMR spectra showed the signals of methoxy group at characteristic region 51.9-52.9 ppm, for the carboxylic ester carbon at 181.2-181.7 ppm and low intense signal at 96-99.1 for trichloromethyl carbon confirming the attributed structure for methyl 4-alkyl[aryl]amino-6-oxo-7,7,7-trichloro-4-heptenoates 4,a,c-j.

The intramolecular cyclisation of isolated methyl 4-alkyl[aryl]amino-6-oxo-7,7,7-trichloro-4-heptenoates 4,a,c to 5-(3,3,3-trichloro-2-oxopropylidene)pyrrolidin-2-ones 6,a,c occurred in MeCN, affording quantitative yields without Et₃N addition. The products 6,d-f and 6h were obtained in good yields by stirring of 4 in MeCN at variable temperatures for 2 to 6 h. In general, the products 6 can be readily obtained in excellent yields without isolation of enaminones intermediates, by the reaction of precursor 2 and appropriate amine in MeCN under reflux temperature (80-85 ºC). The 1,1-(ethane-1,2-diyl)bis(5-(3,3,3-trichloro-2-oxopropylidene)pyrrolidin-2-one) 6l was obtained by the reaction of 2 and ethylenediamine in 2:1 equiv ratio in MeCN at room temperature (Scheme 1).

The 1-alkyl[aryl]-5-(3,3,3-trichloro-2-oxopropylidene)pyrrolidin-2-ones 6a, 6c-f and 6h were characterised by elemental analysis, mass spectrometry and ¹H, ¹³C NMR data. 2D COSY (HH and CH) and DEPT experiments were used for signal assignment.

The synthesis of 5-(3,3,3-trifluoro-2-oxopropylidene)pyrrolidin-2-ones from methyl 7,7,7-trihalo-4-methoxy-6-oxo-4-heptenoates and primary amines can be characterised as an Paal-Knorr process for pyrrole heterocyclic from [CCCC + N] building blocks. Mechanistically, it is conceivable that the reaction involves an initial attack from amines to b-position, leading to enaminoketone moiety,¹⁴ then an imino intermediate as shown in Scheme 3, which allow the rotation of trihalocarbonyl group around C4-C5 bond on 4-amino-6-oxo-7,7,7-trihalo-4-heptenoates, and intramolecular nucleophilic attack of imino nitrogen to ester carbonyl lead to pyrrolidin-2-ones.

Experimental

General

EtOH, MeOH, MeCN and Et₃N were purchased from Merck and Aldrich, R¹NH₂ was purchased from Aldrich, all used as obtained from suppliers. The methyl 7,7,7-trifluoro [chloro]-4-methoxy-6-oxo-4-heptenoates 1 and 2 were prepared according to reference 8. All melting points were determined on a Reichert Thermovar instrument and are uncorrected. ¹H and ¹³C NMR spectra were obtained on a Bruker DPX 400 spectrometer (¹H at 400.13 MHz and ¹³C at 100.62 MHz) 5 mm sample tubes, 298 K, digital resolution ± 0.01 ppm, in CDCl₃ 0.02-0.05 g.mL^-1, using TMS as internal standard. Mass spectra were registered with a HP 6890 GC connected to a HP 5973 MSD and interfaced by a Pentium PC. The GC was equipped with a capillary column (30 m, 0.32 mm of internal diameter), and helium was used as the carrier gas. The elemental analyses were performed on a Perkin-Elmer 2400 CHN elemental analyser (São Paulo University/Brazil).

Methyl 4-alkylamino-6-oxo-7,7,7-trifluoro-4-heptenoates ( 3b and 3c )

To a stirred solution of methyl 7,7,7-trifluoro-4-methoxy-6-oxo-3-heptenoate 1 (5 mmol, 1.28 g) in MeCN (5 mL), kept at 25 ºC, was added benzylamine (5.1 mmol, 0.56 mL) or phenethylamine (5.1 mmol, 0.62 mL) in MeCN (5 mL). The mixture was stirred for 6 h. The solvent was evaporated and the solid residue was dried under vacuum. The enaminones 3b and 3c were purified on silica-gel chromatographic column using chloroform-hexane (2:1) as eluent, yield refers to purified product.

3b:Yield 57 %; oil; Anal. Calcd. for C₁₅H₁₆F₃NO₃ (315.29 g.mol^-1): C, 57.14; H, 5.11, N, 4.44. Found: C, 58.10; H, 5.40; N, 4.65. ¹H NMR (400 MHz, CDCl₃) d 2.56 (m, H2), 2.67 (m, H3), 5.37 (s, H5), 3.69 (s, OMe), 4.61 (d, ²J_HH 6.0 Hz, CH₂), 7.26 - 7.4 (m, Ph), 11.49 (NH, br). ¹³C NMR (100 MHz, CDCl₃) d 176.2 (q, ²J_CF 33 Hz, C6), 171.6 (C4), 171.3 (C1), 135.9 (C1, Ph), 129.0 (C3 and C5, Ph), 128.1 (C4, Ph), 126.9 ( C2 and C6, Ph), 117.5 (q, ¹J_CF 288 Hz, C7), 87.5 (C5), 51.9 (OMe), 47.2 (-CH₂-), 31.2 (C2), 26.7 (C3). MS (EI, 70 eV) m/z (%): 315 (M⁺, 29), 284 (5), 246(68), 218 (36), 91 (100), 65 (75).

3c: Yield 92 %; oil; Anal. Calcd. for C₁₆H₁₈F₃NO₃ (329.32 g.mol^-1): C, 58.36; H, 5.51, N, 4.25. Found: C, 57.70; H, 5.11; N, 4.44. ¹H NMR (400 MHz, CDCl₃) d 2.93 (t, ³J_HH 7.0 Hz, H2), 2.48 (m, 4H, H3, CH₂), 5.25 (s, H5), 3.66 (s, OMe), 3.64 (t, ³J_HH 7.5 Hz, CH₂), 7.18 - 7.3 (m, Ph), 11.25 (NH, br). ¹³C NMR (100 MHz, CDCl₃) d 175.6 (q, ²J_CF 33 Hz, C6), 171.5 (C4), 171.1 (C1), 137.2 (C1, Ph), 128.6 (C3 and C5, Ph), 128.5 (C2 and C6, Ph), 126.8 (C4, Ph), 117.5 (q, ¹J_CF 288 Hz, C7), 87.1 (C5), 51.7 (OMe), 44.9 (NCH₂-), 36.0 (-CH₂Ph), 31.0 (C2), 26.3 (C3). MS (EI, 70 eV): m/z (%): 329 (M⁺, 38), 298 (23), 238 (92), 206 (92), 178 (84), 104 (100), 77 (39).

Methyl 4-arylamino-6-oxo-7,7,7-trifluoro-4-heptenoates (3,d-k)

To a stirred solution of methyl 7,7,7-trifluoro-4-methoxy-6-oxo-3-heptenoate 1 (5 mmol, 1.28 g) in MeCN (5 mL), was added the appropriate arylamine (Aldrich, 5.1 mmol) in MeCN (5 mL). The mixture was refluxed for 6 to 24 h. Then the solvent was evaporated and solid residue was dried under vacuum. Enaminones 3,d-k were recrystallised from hexane-chloroform (2:1), yield refers to purified product.

3d: Yield 76 %; mp 51-53 ºC; Anal. Calcd. for C₁₄H₁₄F₃NO₃ (301.27 g.mol^-1): C, 55.82; H, 4.68, N, 4.65. Found: C, 56.07; H, 4.65; N, 4.35. ¹H NMR (400 MHz, CDCl₃) d 2.53 (t, ³J_HH 7.5 Hz, H2), 2.72 (t, ³J_HH 7.6 Hz, H3), 5.54 (s, H5), 3.64 (s, OMe), 7.14 - 7.5 (m, Ph), 12.6 (NH, br). ¹³C NMR (100 MHz, CDCl₃) d 177.0 (q, ²J_CF 33 Hz, C6), 171.5 (C4), 170.0 (C1), 136.4 (C1, Ph), 129.6 (C3 and C5, Ph), 127.1, (C4, Ph), 125.7 (C2 and C6, Ph), 117.3 (q, ¹J_CF 288 Hz, C7), 88.6 (C5), 51.8 (OMe), 31.4 (C2), 27.1 (C3). MS (EI, 70 eV): m/z (%): 301 (M⁺, 39), 270 (19), 200 (82), 172 (78), 144 (48), 130 (49), 77 (100).

3e: Yield 92 %; mp 43-45 ºC; Anal. Calcd. for C₁₅H₁₆F₃NO₃ (315.29 g.mol^-1): C, 57.14; H, 5.11, N, 4.44. Found: C, 57.48; H, 4.99; N, 4.65. ¹H NMR (400 MHz, CDCl₃) d 2.52 (t, ³J_HH 7.0 Hz, H2), 2.70 (t, ³J_HH 7.2 Hz, H3), 5.51 (s, H5), 3.66 (s, OMe), 2.38 (s, 4-CH₃), 7.07 (m, 2H, Ph), 7.23 (m, 2H, Ph), 12.5 (NH, br). ¹³C NMR (100 MHz, CDCl₃) d 177.0 (q, ²J_CF 33 Hz, C6), 170.6 (C4), 170.0 (C1), 137.9 (C1, Ph), 133.8 (C4, Ph), 130.2 (C3 and C5, Ph), 125.6 (C2 and C6, Ph), 117.4 (q, ¹J_CF 288 Hz, C7), 88.5 (C5), 51.9 (OMe), 31.4 (C2), 27.1 (C3), 20.9 (4-CH₃). MS (EI, 70 eV): m/z (%): 315 (M⁺, 61), 284 (16), 228 (25), 214 (100), 186 (73), 158 (34), 144 (41), 91 (59).

3f: Yield 74 %; mp 52-54 ºC; Anal. Calcd. for C₁₅H₁₆F₃NO₄ (331.29 g.mol^-1): C, 54.38; H, 4.87, N, 4.23. Found: C, 54.25; H, 4.93; N, 3.87. ¹H NMR (400 MHz, CDCl₃) d 2.51 (t, ³J_HH 7.8 Hz, H2), 2.66 (t, ³J_HH 7.8 Hz, H3), 5.50 (s, H5), 3.66 (s, OMe), 3.83 (s, 4-OMe), 6.93 (m, 2H, Ph), 7.11 (m, 2H, Ph), 12.4 (NH, br).¹³C NMR (100 MHz, CDCl₃) d 176.9 (q, ²J_CF 33 Hz, C6), 171.6 (C4), 170.5 (C1), 159.1 (C4, Ph), 129.2.(C1, Ph), 127.2 (C3 and C5, Ph), 117.4 (q, ¹J_CF 288 Hz, C7), 114.8 (C2 and C6, Ph), 88.4 (C5), 55.5 (4-OMe), 51.9 (OMe), 31.5 (C2), 27.2 (C3). MS (EI, 70 eV): m/z (%): 331 (M⁺, 100), 300 (15), 272 (24), 230 (78), 202 (38), 160 (27), 132 (13), 92 (15).

3g: Yield 98 %; mp 81-83 ºC; Anal. Calcd. for C₁₄H₁₃ClF₃NO₃ (335.71 g.mol^-1): C, 50.09; H, 3.90, N, 4.71. Found: C, 50.18; H, 3.91; N, 4.97. ¹H NMR (400 MHz, CDCl₃) d 2.54 (t, ³J_HH 7.2 Hz, H2), 2.70 (t, ³J_HH 7.2 Hz, H3), 5.55 (s, H5), 3.66 (s, OMe), 7.16 (m, 2H, Ph), 7.40 (m, 2H, Ph), 12.5 (NH, br). ¹³C NMR (100 MHz, CDCl₃) d 177.3 (q, ²J_CF 33 Hz, C6), 171.4 (C4), 169.8 (C1), 135.0 (C1, Ph), 133.5 (C4, Ph), 129.7 (C3 and C5, Ph), 127.0 ( C2 and C6, Ph), 117.2 (q, ¹J_CF 288 Hz, C7), 88.9 (C5), 51.8 (OMe), 31.3 (C2), 26.9 (C3). MS (EI, 70 eV): m/z (%): 335 (M⁺, 31), 304 (14), 276 (18), 234 (100), 206 (96), 178 (60), 143 (39), 111 (81), 75 (82).

3h: Yield 95 %; mp 77-79 ºC; Anal. Calcd. for C₁₄H₁₃BrF₃NO₃ (380.16 g.mol^-1): C, 44.23; H, 3.45, N, 3.68. Found: C, 44.37; H, 3.44; N, 3.57. ¹H NMR (400 MHz, CDCl₃) d = 2.54 (t, ³J_HH = 7.2 Hz, H2), 2.70 (t, ³J_HH = 7.2 Hz, H3), 5.55 (s, H5), 3.67 (s, OMe), 7.10 (m, 2H, Ph), 7.56 (m, 2H, Ph), 12.5 (NH, br).¹³C NMR (100 MHz, CDCl₃) d 177.3 (q, ²J_CF 34 Hz, C6), 171.4 (C4), 169.7 (C1), 135.4 (C1, Ph), 132.7 (C3 and C5, Ph), 127.3 (C2 and C6, Ph), 121.4 (C4, Ph), 117.1 (q, ¹J_CF 288 Hz, C7), 88.9 (C5), 51.9 (OMe), 31.2 (C2), 26.9 (C3). MS (EI, 70 eV): m/z (%): 380 (M⁺, 69), 348 (21), 310 (34), 278 (100), 250 (52), 231 (57), 199 (61), 172 (70), 143 (86), 76 (77).

3i: Yield 95 %; mp 68-70 ºC; Anal. Calcd. for C₁₂H₁₃F₃N₂O₄ (306.24 g.mol^-1): C, 47.06; H, 4.28, N, 9.15. Found: C, 46.97; H, 4.19; N, 8.98. ¹H NMR (400 MHz, CDCl₃) d 2.72 (t, ³J_HH 7.6 Hz, H2), 3.13 (t, ³J_HH 7.6 Hz, H3), 5.68 (s, H5), 3.70 (s, OMe), 2.43 (s, 3-CH₃, isox), 5.98 (s, H5, isox), 12.4 (NH, br). ¹³C NMR (100 MHz, CDCl₃) d 178.5 (q, ²J_CF 34 Hz, C6), 171.6 (C4), 170.7 (C1), 168.3 (C5, isox), 157.6 (C3, isox), 116.6 (q, ¹J_CF 288 Hz, C7), 96.7 (C4, isox), 92.2 (C5), 51.5 (OMe), 31.3 (C2), 29.4 (C3), 11.9 (3-Me, isox). MS (EI, 70 eV): m/z (%): 306 (M⁺, 9), 275 (18), 237 (100), 278 (100), 205 (60), 149 (43), 135 (47), 119 (46), 68 (58).

3j: Yield 95 %; mp 65-68 ºC; Anal. Calcd. for C₁₃H₁₃F₃N₂O₃ (302.26 g.mol^-1): C, 51.66; H, 4.34, N, 9.27. Found: C, 51.41; H, 4.18; N, 9.30. ¹H NMR (400 MHz, CDCl₃) d 2.76 (t, ³J_HH 7.2 Hz, H2), 3.33 (t, ³J_HH 7.2 Hz, H3), 5.61 (s, H5), 3.70 (s, OMe), 7.0, 7.1, 7.7, 8.4 (2-pyridyl), 12.9 (NH, br). ¹³C NMR (100 MHz, CDCl₃) d 177.8 (q, ²J_CF 34 Hz, C6), 172.1 (C4), 168.7 (C1), 151.1 (C2, pyr), 148.3 (C6, pyr), 138.4 (C4, pyr), 120.2 (C3, pyr), 115.5 (C5, pyr), 117.0 (q, ¹J_CF 288 Hz, C7), 92.5 (C5), 51.1 (OMe), 32.3 (C2), 29.5 (C3). MS (EI, 70 eV): m/z (%): 271 (M⁺-OMe, 34), 233 (21), 205 (100), 173 (98), 131 (88), 96 (18), 78 (97), 51 (38).

3k: Yield 95 %; mp 65-68 ºC; Anal. Calcd. for C₁₄H₁₅F₃N₂O₃ (316.28 g.mol^-1): C, 53.17; H, 4.78, N, 8.86. Found: C, 55.00; H, 5.28; N, 9.90. ¹H NMR (400 MHz, CDCl₃) d 2.50 (t, ³J_HH 7.5 Hz, H2), 2.66 (t, ³J_HH 7.5 Hz, H3), 5.47 (s, H5), 3.66 (s, OMe), 6.68 (m, 2H, Ph), 6.96 (m, 2H, Ph), 13.2 (NH, br). ¹³C NMR (100 MHz, CDCl₃) d 177.6 (q, ²J_CF 34 Hz, C6), 171.7 (C4), 170.8 (C1), 146.3 (C4, Ph), 126.9 (C3, C4 and C5, Ph), 115.4 (C2 and C6, Ph), 88.2 (C5), 31.5 (C2), 27.2 (C3). MS (EI, 70 eV): m/z (%): 316 (M⁺, 100), 285 (10), 257 (15), 215 (36), 187 (33), 173 (32), 92 (19).

Methyl 7,7,7-trichloro-4-alkylamino-6-oxo-4-heptenoates ( 4a and 4c )

To a stirred solution of methyl 7,7,7-trichloro-4-methoxy-6-oxo-3-heptenoate 2 (5 mmol, 1.52 g) in CHCl₃ (5 mL), kept at 25 ºC, was added n-propylamine (Aldrich, 18570-1, 5.1 mmol, 0.42 mL) or phenethylamine (Aldrich, 24095-8, 5.1 mmol, 0.62 mL) in CHCl₃ (5 mL). The mixture was stirred for 2 h. Then the solvent was evaporated and solid residue was dried under vacuum. The enaminones 4a and 4c were purified on silica-gel chromatographic column using chloroform-hexane (2:1) as eluent, yield refers to purified product.

4a: Yield 94 %; Oil; Anal. Calcd. for C₁₁H₁₆Cl₃NO₃ (316.61 g.mol^-1): C, 41.73; H, 5.09, N, 4.42. Found: C, 41.39; H, 4.95; N, 4.30. ¹H NMR (400 MHz, CDCl₃) d 2.69 (m, H2 and H3), 5.67 (s, H5), 3.73 (s, OMe), 3.36 (t, CH₂), 1.72 (q, CH₂), 1.05 (t, CH₃), 12.8 (NH, br). ¹³C NMR (100 MHz, CDCl₃) d 180.1 (C6), 171.6 (C4), 170.3 (C1), 96.9 (C7), 84.2 (C5) 51.8 (OMe), 44.9 (NCH₂-), 31.2 (C2), 27.0 (C3), 22.7 (-CH₂-), 11.1 (Me). MS (EI, 70 eV): m/z (%): 318 (M⁺+ 2, 10), 316 (M⁺, 10), 252 (39), 198 (100), 166 (36).

4c: Yield 98 %; Oil; Anal. Calcd. for C₁₆H₁₈Cl₃NO₃ (378.69 g.mol^-1): C, 50.75; H, 4.79, N, 3.70. Found: C, 52.0; H, 4.97; N, 4.0. ¹H NMR (400 MHz, CDCl₃) d 2.53 (t, ³J_HH 7.2 Hz, H2), 2.95 (t, ³J_HH 7.2 Hz, H3), 5.64 (s, H5), 3.69 (s, OMe), 2.53 (CH₂), 3.61 (CH₂), 7.2 - 7.33 (Ph), 12.8 (NH, br). ¹³C NMR (100 MHz, CDCl₃) d 180.3 (C6), 171.6 (C4), 170.2 (C1), 137.3 (C1, Ph), 128.6 (C3 and C5, Ph), 128.5 (C4, Ph), 126.8 (C2 and C6, Ph), 96.9 (C7), 84.5 (C5), 51.9 (OMe), 45.0 (NCH₂-), 36.1 (-CH₂Ph), 31.2 (C2), 26.8 (C3). MS (EI, 70 eV): m/z (%): 381 (M⁺+ 2, 13), 379 (M⁺, 10), 314 (44), 286 (50), 260 (100), 228 (23), 105 (100), 77 (50).

Methyl 7,7,7-trichloro-4-arylamino-6-oxo-4-heptenoates (4d-4i)

To a stirred solution of methyl 7,7,7-trichloro-4-methoxy-6-oxo-3-heptenoate 2 (5 mmol, 1.52 g) in MeCN (5 mL), kept at 25 ºC, was added appropriate arylamine (Aldrich, 5.1 mmol) in MeCN (5 mL). The mixture was refluxed for 2 to 6 h. The solvent was evaporated and the solid residue was dried under reduced pressure. The enaminones 4d-i, 4k were recrystallised from hexane: CHCl₃ (2:1), yield refers to purified product.

4d: Yield 73 %; mp 79-82 ºC; Anal. Calcd. for C₁₄H₁₄Cl₃NO₃ (350.63 g.mol^-1): C, 47.96; H, 4.02, N, 3.99. Found: C, 48.0; H, 4.50; N, 3.90. ¹H NMR (400 MHz, CDCl₃) d 2.52 (t, ³J_HH 7.0 Hz, H2), 2.75 (t, ³J_HH 7.0 Hz, H3), 5.88 (s, H5), 3.66 (s, OMe), 7.2 - 7.44 (Ph), 13.8 (NH, br). ¹³C NMR (100 MHz, CDCl₃) d 181.4 (C6), 171.6 (C4), 168.8 (C1), 136.8 (C1, Ph), 129.6 (C3 and C5, Ph), 127.5 (C4, Ph), 125.7 (C2 and C6, Ph), 96.9 (C7), 86.5 (C5), 51.9 (OMe), 31.6 (C2), 27.5 (C3). MS (EI, 70 eV): m/z (%): 352 (M⁺+ 2, <5), 350 (M⁺, 10), 232 (85), 200 (100), 172 (61), 144 (27), 77 (60).

4e: Yield 76 %; mp 53-55 ºC; Anal. Calcd. for C₁₄H₁₄Cl₃NO₃ (364.66 g.mol^-1): C, 49.41; H, 4.42, N, 3.84. Found: C, 49.90; H, 5.0; N, 3.55. ¹H NMR (400 MHz, CDCl₃) d 2.52 (t, ³J_HH 7.7 Hz, H2), 2.73 (t, ³J_HH 7.5 Hz, H3), 5.86 (s, H5), 3.65 (s, OMe), 2.37 (4-Me), 7.1 (3H, Ph), 7.3 (2H, Ph), 13.6 (NH, br). ¹³C NMR (100 MHz, CDCl₃) d 181.2 (C6), 171.7 (C4), 169.2 (C1), 137.6 (C1, Ph), 134.1 (C3 and C5, Ph), 130.1 (C4, Ph), 125.5 (C2 and C6, Ph), 96.9 (C7), 86.2 (C5) 51.9 (OMe), 31.7 (C2), 27.5 (C3), 20.9 (4-Me). MS (EI, 70 eV): m/z (%): 367 (M⁺+2, 7), 365 (M⁺, 7), 246 (70), 214 (100), 186 (47), 158 (14), 91 (39).

4f: Yield 70 %; mp 79-81 ºC; Anal. Calcd. for C₁₅H₁₆Cl₃NO₄ (380.66 g.mol^-1): C, 47.33; H, 4.24, N, 3.68. Found: C, 47.10; H, 4.20; N, 4.0. ¹H NMR (400 MHz, CDCl₃) d 2.52 (t, ³J_HH 7.5 Hz, H2), 2.70 (t, ³J_HH 7.5 Hz, H3), 5.86 (s, H5), 3.66 (s, OMe), 3.84 (4-OMe), 6.9 (3H, Ph), 7.13 (2H, Ph), 13.6 (NH, br). ¹³C NMR (100 MHz, CDCl₃) d 181.2 (C6), 171.7 (C4), 169.5 (C1), 158.9 (C4, Ph), 129.2 (C1, Ph), 127.2 (C3 and C5, Ph), 114.7 (C2 and C6, Ph), 97.0 (C7), 86.0 (C5), 55.4 (4-OMe), 51.9 (OMe), 31.7 (C2), 27.5 (C3). MS (EI, 70 eV): m/z (%): 381 (M⁺+2, 15), 379 (M⁺, 14), 262 (75), 230 (100), 202 (28), 174 (10), 77 (16).

4g: Yield 88 %; mp 105-107 ºC; Anal. Calcd. for C₁₄H₁₃Cl₄NO₃ (385.08 g.mol^-1): C, 43.67; H, 3.40, N, 3.64. Found: C, 44.87; H, 4.10; N, 3.90. ¹H NMR (400 MHz, CDCl₃) d 2.54 (t, ³J_HH 7.8 Hz, H2), 2.73 (t, ³J_HH 7.6 Hz, H3), 5.89 (s, H5), 3.66 (s, OMe), 7.15 (3H, Ph), 7.40 (2H, Ph), 13.4 (NH, br). ¹³C NMR (100 MHz, CDCl₃) d 181.7 (C6), 171.5 (C4), 168.6 (C1), 135.4 (C1, Ph), 133.3 (C3 and C5, Ph), 129.8 (C4, Ph), 127.0 (C2 and C6, Ph), 96.8 (C7), 86.9 (C5), 52.0 (OMe), 31.6 (C2), 27.4 (C3). MS (EI, 70 eV): m/z (%): 385 (M⁺+2, 10), 383 (M⁺, 6), 266 (70), 234 (100), 206 (40), 178 (10), 111 (10).

4h: Yield 85 %; mp 97-100 ºC; Anal. Calcd. for C₁₄H₁₃BrCl₃NO₃ (429.53 g.mol^-1): C, 39.15; H, 3.05, N, 3.26. Found: C, 39.17; H, 3.10; N, 3.50. ¹H NMR (400 MHz, CDCl₃) d 2.54 (t, ³J_HH 7.5 Hz, H2), 2.74 (t, ³J_HH 7.6 Hz, H3), 5.89 (s, H5), 3.67 (s, OMe), 7.1 (3H, Ph), 7.56 (2H, Ph), 13.0 (NH, br). ¹³C NMR (100 MHz, CDCl₃) d 181.6 (C6), 171.5 (C4), 168.4 (C1), 135.4 (C1, Ph), 133.3 (C3 and C5, Ph), 129.8 (C4, Ph), 127.0 (C2 and C6, Ph), 96.7 (C7), 86.9 (C5), 52.0 (OMe), 31.5 (C2), 27.4 (C3). MS (EI, 70 eV): m/z (%): 430 (M⁺+2, 16), 428 (M⁺, 10), 310 (86), 278 (100), 250 (30), 231 (70).

4k: Yield 90 %; mp 114-116 ºC; Anal. Calcd. for C₁₄H₁₅Cl₃N₂O₃ (366.65 g.mol^-1): C, 45.99; H, 4.13, N, 7.66. Found: C, 47.17; H, 4.83; N, 8.20.¹H NMR (400 MHz, CDCl₃) d 2.57 (t, ³J_HH 7.0 Hz, H2), 2.74 (t, ³J_HH 7.2 Hz, H3), 5.85 (s, H5), 3.60 (s, OMe), 6.75 (3H, Ph), 7.0 (2H, Ph), 13.8 (NH, br). ¹³C NMR (100 MHz, CDCl₃) d 181.7 (C6), 173.3 (C4), 172.3 (C1), 149.6 (C4, Ph), 128.6 (C3 and C5, Ph), 127.5 (C1, Ph), 116.4 (C2 and C6, Ph), 99.1 (C7), 86.6 (C5), 52.9 (OMe), 33.0 (C2), 29.0 (C3). MS (EI, 70 eV): m/z (%): 366 (M⁺+2, 16), 364 (M⁺, 15), 247 (46), 215 (100), 187 (38), 173 (50), 159 (12), 92 (16).

1-[Alkyl(aryl)]-5-(3,3,3-trifluoro[chloro]-2-oxopropylidene)pyrrolidin-2-ones (5, 6)

To a stirred solution of appropriate methyl 7,7,7-trihalo-4-alkyl(aryl)amino-6-oxo-3-heptenoate (3 or 4, 2 mmol) in MeCN (5 mL), kept at 25 °C, was added Et₃N (2 mmol, 0.3 mL) in MeCN (1 mL). The mixture was refluxed for 1 to 24 h and the solvent was removed under reduced pressure. The residue was crystallised from hexane, yield refers to purified product.

5b: Yield 69 %; mp 96-98 ºC; Anal. Calcd. for C₁₄H₁₂F₃NO₂ (283.25 g.mol^-1): C, 59.37; H, 4.27, N, 4.94. Found: C, 60.10; H, 4.01; N, 5.03. ¹H NMR (400 MHz, CDCl₃) d 2.67 (m, H3), 3.33 (m, H4), 5.89 (s, CH), 4.79 (s, CH₂), 7.23 (3H, Ph), 7.4 (2H, Ph). ¹³C NMR (100 MHz, CDCl₃) d 178.6 (²J_CF 34 Hz, C2, propylidene), 177.1 (C5, pyrrolidin-2-one), 167.8 (C2, pyrrolidin-2-one), 133.9 (C1, Ph), 128.9 (C4, Ph), 128.1 (C2 and C6, Ph), 127.3 (C3 and C5, Ph), 116.3 (¹J_CF 292 Hz, C3, propylidene), 92.0 (C1, propylidene), 44.5 (-CH₂-), 27.2 (C4, pyrrolidin-2-one), 26.6 (C3, pyrrolidin-2-one). MS (EI, 70 eV): m/z (%): 283 (M⁺, 5), 214 (28), 186 (17), 91 (100), 65 (22).

5c: Yield 87 %; mp 103-105 ºC; Anal. Calcd. for C₁₅H₁₄F₃NO₂ (297.28 g.mol^-1): C, 60.61; H, 4.75, N, 4.71. Found: C, 60.41; H, 4.60; N, 4.57. ¹H NMR (400 MHz, CDCl₃) d 2.56 (m, H3, pyrrolidin-2-one), 3.29 (m, H4, pyrrolidin-2-one), 5.78 (s, H1, propylidene), 2.88 (CH₂), 3.82 (CH₂), 7.1 - 7.4 (Ph).¹³C NMR (100 MHz, CDCl₃) d 178.6 (²J_CF 34 Hz, C2, propylidene), 176.8 (C5, pyrrolidin-2-one), 168.2 (C2, pyrrolidin-2-one), 137.0 (C1, Ph), 128.7 (C3 and C5, Ph), 128.6 (C2 and C6, Ph), 127 (C4, Ph), 116.4 (¹J_CF 292 Hz, C3, propylidene), 91.0 (C1, propylidene), 42.3 (NCH₂), 32.6 (CH₂Ph), 26.7 (C3, pyrrolidin-2-one), 27.1 (C4, pyrrolidin-2-one). MS (EI, 70 eV): m/z (%): 297 (M⁺, 5), 228 (24), 178 (10), 104 (100), 77 (13).

5d: Yield 77 %; mp 146-149 ºC; Anal. Calcd. for C₁₃H₁₀F₃NO₂ (269.23 g.mol^-1): C, 58.00; H, 3.74, N, 5.20. Found: C, 57.78; H, 3.81; N, 4.90. ¹H NMR (400 MHz, CDCl₃) d 2.83 (m, H3), 3.53 (m, H4), 5.66 (s, CH), 7.2 (3H, Ph), 7.5 (2H, Ph).¹³C NMR (100 MHz, CDCl₃) d 179.2 (²J_CF 34 Hz, C2, propylidene), 176.5 (C5, pyrrolidin-2-one), 169.2 (C2, pyrrolidin-2-one), 133.2 (C1, Ph), 130.1 (C3 and C5, Ph), 129.8 (C2 and C5, Ph), 127.1 (C4, Ph), 116.4 (¹J_CF 292 Hz, C3, propylidene), 92.7 (C1, propylidene), 27.8 (C4, pyrrolidin-2-one), 26.9 (C3, pyrrolidin-2-one). MS (EI, 70 eV): m/z (%): 269 (M⁺, 13), 200 (100), 172 (68), 144 (29), 77 (69), 51 (41).

5e: Yield 86 %; mp 129-131 ºC; Anal. Calcd. for C₁₄H₁₂F₃NO₂ (283.25 g.mol^-1): C, 59.37; H, 4.27, N, 4.94. Found: C, 59.28; H, 4.38; N, 4.79. ¹H NMR (400 MHz, CDCl₃) d 2.80 (m, H3, pyrrolidin-2-one), 3.50 (m, H4, pyrrolidin-2-one), 5.67 (s, H1, propylidene), 2.43 (4-Me), 7.06 (3H, Ph), 7.34 (2H, Ph).¹³C NMR (100 MHz, CDCl₃) d 179.0 (²J_CF 34 Hz, C2, propylidene), 176.7 (C5, pyrrolidin-2-one), 169.5 (C2, pyrrolidin-2-one), 139.9 (C1, Ph), 130.7 (C2 and C6, Ph), 130.4 (C4, Ph), 126.8 (C3 and C5, Ph), 116.2 (¹J_CF 291 Hz, C3, propylidene), 92.6 (C1, propylidene), 27.7 (C4, pyrrolidin-2-one), 26.9 (C3, pyrrolidin-2-one), 21.1 (4-Me). MS (EI, 70 eV): m/z (%): 283 (M⁺, 24), 214 (100), 186 (53), 158 (17), 91 (43).

5f: Yield 91 %; mp 88-90 ºC; Anal. Calcd. for C₁₄H₁₂F₃NO₃ (299.25 g.mol^-1): C, 56.19; H, 4.04, N, 4.68. Found: C, 55.91; H, 4.10; N, 4.51. ¹H NMR (400 MHz, CDCl₃) d 2.81 (m, H3), 3.50 (m, H4), 5.66 (s, CH), 3.87 (OMe), 7.05 (3H, Ph), 7.12 (2H, Ph).¹³C NMR (100 MHz, CDCl3) d 178.9 (²J_CF 34 Hz, C2, propylidene), 176.6 (C5, pyrrolidin-2-one), 169.7 (C2, pyrrolidin-2-one), 160.3 (C4, Ph), 128.2 (C1, Ph), 125.6 (C3 and C5, Ph), 115.3 (C2 and C6, Ph), 116.3 (¹J_CF 291 Hz, C3, propylidene), 92.4 (C1, propylidene), 55.4 (OMe), 27.6 (C4, pyrrolidin-2-one), 26.8 (C3, pyrrolidin2-one). MS (EI, 70 eV): m/z (%): 299 (M⁺, 53), 230 (100), 202 (28), 188 (31), 159 (24), 131 (14), 77 (21).

5g: Yield 70 %; mp 163-165 ºC; Anal. Calcd. for C₁₃H₉ClF₃NO₂ (303.67 g.mol^-1): C, 56.19; H, 4.04, N, 4.68. Found: C, 55.91; H, 4.10; N, 4.51. ¹H NMR (200 MHz, CDCl₃) d 2.82 (m, H3), 3.52 (m, H4), 5.66 (s, CH), 7.16 (3H, Ph), 7.54 (2H, Ph). ¹³C NMR (50 MHz, CDCl₃) d 168.7 (C2), 26.9 (C3), 27.7 (C4), 176.3 (C5), 92.7 (CH) 178.0 (²J_CF 35 Hz, C=O), 116.2 (¹J_CF 291 Hz, CF₃), 128.5, 130.4, 131.5, 135.8 (Ph). MS (EI, 70 eV): m/z (%): 303 (M⁺, 23), 234 (100), 206 (62), 178 (21), 143 (23), 111 (28), 75 (41).

5h: Yield 95 %; mp 151-153 ºC; Anal. Calcd. for C₁₃H₉BrF₃NO₂ (348.12 g.mol^-1): C, 44.85; H, 2.61, N, 4.02. Found: C, 44.75; H, 2.63; N, 3.95. ¹H NMR (200 MHz, CDCl₃) d 2.82 (m, H3), 3.52 (m, H4), 5.66 (s, CH), 7.1 (3H, Ph), 7.7 (2H, Ph). ¹³C NMR (50 MHz, CDCl₃) d 168.5 (C2), 26.9 (C3), 27.8 (C4), 176.2 (C5), 92.9 (CH) 179.2 (²J_CF 35 Hz, C=O), 116.2 (¹J_CF 291 Hz, CF₃), 124.0, 128.8, 132.1, 133.5 (Ph). MS (EI, 70 eV): m/z (%): 348 (M⁺, 29), 278 (100), 250 (29), 222 (14), 199 (37), 143 (39), 76 (41).

5j: Yield 73 %; mp 165-167 ºC; Anal. Calcd. for C₁₂H₉F₃N₂O₂ (270.21 g.mol^-1): C, 53.34; H, 3.36, N, 10.37. Found: C, 53.30; H, 3.50; N, 10.60. ¹H NMR (200 MHz, CDCl₃) d 2.83 (m, H3), 3.54 (m, H4), 5.94 (s, CH), 7.36 (1H, Py), 7.46 (1H, Py), 7.95 (1H, Py), 8.69 (1H, Py). ¹³C NMR (50 MHz, CDCl₃) d = 167.1 (C2), 26.9 (C3), 28.0 (C4), 176.3 (C5), 93.7 (CH) 179.2 (²J_CF 34 Hz, C=O), 116.2 (¹J_CF 292 Hz, CF₃), 122.5, 124.5, 139.1, 147.2, 150.1 (Py). MS (EI, 70 eV): m/z (%): 201 (18), 173 (100), 145 (20), 131 (43), 78 (52), 69 (8).

5k: Yield 71 %; mp 256-258 ºC; Anal. Calcd. for C₂₀H₁₄F₆N₂O₄ (460.34 g.mol^-1): C, 52.18; H, 3.07, N, 6.09. Found: C, 52.80; H, 3.10; N, 6.50. ¹H NMR (400 MHz, CDCl₃) d 2.88 (m, H3), 3.57 (m, H4), 5.77 (s, CH), 7.4 (Ph). ¹³C NMR (100 MHz, CDCl₃) d 179.3 (²J_CF 35 Hz, C2, propylidene), 176.2 (C5, pyrrolidin-2-one), 168.2 (C2, pyrrolidin-2-one), 134.2 (2C, C1, Ph), 129.1 (4C, C2, C3, Ph), 116.2 (¹J_CF 291 Hz, C3, propylidene), 93.0 (C1, propylidene), 27.8 (C4, pyrrolidin-2-one), 26.9 (C3, pyrrolidin-2-one). MS (EI, 70 eV): m/z (%): 460 (M⁺, 36), 391 (100), 363 (10), 161 (20), 143 (15), 69 (15), 55 (33).

6a: Yield 75 %; mp 78-80 ºC; Anal. Calcd. for C₁₀H₁₂Cl₃NO₂ (284.57 g.mol^-1): C, 42.21; H, 4.25, N, 4.92. Found: C, 42.80; H, 4.50; N, 5.30. ¹H NMR (400 MHz, CDCl₃) d 2.63 (m, H3), 3.35 (m, H4), 6.17 (s, CH), 3.6 (CH₂), 1.65 (CH₂), 0.95 (Me). ¹³C NMR (100 MHz, CDCl₃) d 180.2 (C2, propylidene), 177.0 (C5, pyrrolidin-2-one), 167.2 (C2, pyrrolidin-2-one), 97.4 (C3, propylidene), , 90.3 (C1, propylidene), 42.5 (NCH₂), 27.5 (C4, pyrrolidin-2-one), 26.3 (C3, pyrrolidin-2-one), 19.9 (CH₂), 11.3 (Me). MS (EI, 70 eV): m/z (%): 285 (M⁺+2, 10), 283 (M⁺, 10), 220 (22), 166 (100), 124 (73), 68 (61).

6c: Yield 87 %; mp 145-148 ºC; Anal. Calcd. for C₁₀H₁₂Cl₃NO₂ (346.64 g.mol^-1): C, 51.97; H, 4.07, N, 4.04. Found: C, 51.30; H, 3.80; N, 4.00. ¹H NMR (400 MHz, CDCl₃) d 2.58 (m, H3), 3.32 (m, H4), 6.18 (s, CH), 2.9 (CH₂), 3.85 (CH₂), 7.1- 7.4 (Ph). ¹³C NMR (100 MHz, CDCl₃) d 180.0 (C2, propylidene), 176.6 (C5, pyrrolidin-2-one), 166.8 (C2, pyrrolidin-2-one), 137 (C1, Ph), 128.7 (C3 and C5, Ph), 128,5 (C4, Ph), 126.9 (C2 and C6, Ph), 97.3 (C3, propylidene), 90.3 (C1, propylidene), 42.2 (NCH₂), 32.7 (CH₂Ph), 27.4 (C4, pyrrolidin-2-one), 26.2 (C3, pyrrolidin-2-one). MS (EI, 70 eV): m/z (%): 347 (M⁺+2, 7), 345 (M⁺, 7), 282 (20), 228 (100), 124 (35), 105 (90).

6d: Yield 93 %; mp 158-160 ºC; Anal. Calcd. for C₁₃H₉Cl₃NO₂ (318.59 g.mol^-1): C, 49.01; H, 3.16, N, 4.40. Found: C, 50.05; H, 3.20; N, 3.80. ¹H NMR (200 MHz, CDCl₃) d 2.82 (m, H3), 3.53 (m, H4), 5.97 (s, CH), 7.2 (2H, Ph), 7.56 (3H, Ph).¹³C NMR (50 MHz, CDCl₃) d 180.4 (C2, propylidene), 176.5 (C5, pyrrolidin-2-one), 167.9 (C2, pyrrolidin-2-one), 133.3 (C1, Ph), 130 (C3 and C5, Ph), 129.6 (C2 and C6, Ph) 127.1 (C4, Ph), 97 (C3, propylidene), 92 (C1, propylidene), 28 (C4, pyrrolidin-2-one), 26.4 (C3, pyrrolidin-2-one). MS (EI, 70 eV): m/z (%): 319 (M⁺+2, <5), 317 (M⁺, <5), 256 (5), 254 (10), 202 (15), 200 (100), 172 (30), 77 (20).

6e: Yield 95 %; mp 175-178 ºC; Anal. Calcd. for C₁₄H₁₂Cl₃NO₂ (332.62 g.mol^-1): C, 50.56; H, 3.64, N, 4.21. Found: C, 50.30; H, 3.50; N, 4.60. ¹H NMR (200 MHz, CDCl₃) d 2.83 (m, H3), 3.52 (m, H4), 5.98 (s, CH), 2.43 (4-Me), 7.1 (2H, Ph), 7.35 (3H, Ph). ¹³C NMR (50 MHz, CDCl₃) d 180.5 (C2, propylidene), 176.5 (C5, pyrrolidin-2-one), 168.2 (C2, pyrrolidin-2-one), 133.3 (C1, Ph), 130.0 (C3 and C5, Ph), 129.6 (C4, Ph), 127.1 (C2 and C6, Ph), 97.0 (C3, propylidene), 92.0 (C1, propylidene), 28.0 (C4, pyrrolidin-2-one), 26.4 (C3, pyrrolidin-2-one), 21.2 (4-Me). MS (EI, 70 eV): m/z (%): 333 (M⁺+2, < 5), 331 (M⁺, < 5), 270 (7), 268 (10), 216 (15), 214 (100).

6f: Yield 95 %; mp 169-171 ºC; Anal. Calcd. for C₁₄H₁₂Cl₃NO₃ (348.62 g.mol^-1): C, 48.24; H, 3.47, N, 4.02. Found: C, 48.90; H, 4.0; N, 3.78. ¹H NMR (200 MHz, CDCl₃) d 2.79 (m, H3), 3.50 (m, H4), 5.98 (s, CH), 3.86 (4-OMe), 7.05 (2H, Ph), 7.15 (3H, Ph).¹³C NMR (50 MHz, CDCl₃) d 168.4 (C2), 26.4 (C3), 27.9 (C4), 176.7 (C5), 92.0 (CH) 180.5 (C=O), 97.1 (CCl₃), 55.5 (4-Me), 115.3, 125.8, 128.3, 160.2 (Ph). MS (EI, 70 eV): m/z (%): 349 (M⁺+2, 15), 347 (M⁺, 15), 284 (22), 230 (100), 188 (78), 159 (44).

6h: Yield 86 %; mp 167-170 ºC; Anal. Calcd. for C₁₃H₉BrCl₃NO₂ (397.49 g.mol^-1): C, 39.28; H, 2.28, N, 3.52. Found: C, 39.73; H, 2.5; N, 3.70. ¹H NMR (200 MHz, CDCl₃) d 2.83 (m, H3), 3.53 (m, H4), 5.98 (s, CH), 3.86 (4-OMe), 7.10 (2H, Ph), 7.69 (3H, Ph).¹³C NMR (50 MHz, CDCl₃) d 167.2 (C2), 26.4 (C3), 27.9 (C4), 176.2 (C5), 92.2 (CH) 180.3 (C=O), 96.9 (CCl₃), 123.6, 128.8, 132.3, 133.3 (Ph). MS (EI, 70 eV): m/z (%): 398 (M⁺+2, < 5), 396 (M⁺, < 5), 280 (100), 278 (100), 252 (10), 250 (10), 199 (15).

6l: Yield 85 %; mp > 300 ºC; Anal. Calcd. for C₁₆H₁₄Cl₆N₂O₄ (511.02 g.mol^-1): C, 37.61; H, 2.76, N, 5.48. Found: C, 37.41; H, 2.90; N, 5.70. ¹H NMR (400 MHz, CDCl₃) d 2.52 (m, H3), 3.17 (m, H4), 6.22 (s, CH), 3.83 (CH₂).¹³C NMR (100 MHz, CDCl₃) d 169.1 (C2), 26.7 (C3), 28.0 (C4), 177.6 (C5), 88.0 (CH) 179.3 (C=O), 97.1 (CCl₃), 37.2 (CH₂). MS (EI, 70 eV): m/z (%): 359 (70), 357 (100), 236 (20), 234 (35), 150 (32).

Supplementary Information

Supplementary data shown in Tables S1 and S2, ¹H, ¹³C NMR and mass spectra are available free of charge as PDF file at http://jbcs.sbq.org.br

Acknowledgments

Thanks are due to financial support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Rio Grande do Sul (FAPERGS). The Bruker X-ray diffractometer was funded by infrastructure grant from the Financiadora de Estudos e Projetos (CT-INFRA/FINEP). Students thank CNPq for fellowships.

Received: June 26, 2007

Published on the web: January 31, 2008

Supplementary Information

¹H and ¹³C NMR spectra were aquired on a Bruker DPX 400 spectrometer (¹H at 400.13 MHz and ¹³C at 100.62 MHz) 5 mm sample tubes, 298-305 K, digital resolution ± 0.01 ppm, in CDCl 3 0.02-0.05 g mL^-1, using TMS as internal reference.

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1. Bonacorso, H. G.; Martins, M. A. P., Bittencourt, S. R. T.; Lourega, R. V.; Zanatta, N.; Flores, A. F. C.; J. Fluorine Chem. 1999, 99, 177 and references cited therein.
2. Druzhinin, S. V.; Balenkova, E. S.; Nenajdenko, V. G.; Tetrahedron 2007, 63, 7753.
3. Martins, M. A. P.; Cunico, W.; Pereira, C. M. P.; Sinhorin, A. P.; Flores, A. F. C.; Bonacorso, H.; Zanatta, N.; Curr. Org. Chem. 2004, 1, 391.
4. Cechin, S. R.; Schetinger, M. R. C.; Zanatta, N.; Madruga, C. C.; Pacholski, I. L.; Flores, D. C.; Bonacorso, H. G.; Martins, M. A. P.; Morsch, V. M. Chem. Res. Toxicol. 2003, 16, 1433.
5. Godoy, M. C.; Fighera, M. R.; Souza, F. R.; Flores, A. E.; Rubin, M. A.; Oliveira, M. R.; Zanatta, N.; Martins, M. A. P.; Bonacorso, H. G.; Mello, C. F.; Eur. J. Pharmacol. 2004, 496, 93.
6. Zanatta, N.; Flores, D. C.; Madruga, C. C.; Flores, A. F. C. ; Bonacorso, H. G.; Martins, M. A. P. Tetrahedron Lett. 2006, 47, 573.
7. Timokhin, B. V.; Baransky, V. A.; Eliseeva, G. D.; Russ. Chem. Rev. 1999, 68, 73.
8. Oliveira, G.; Master Dissertation 2005, Universidade Federal de Santa Maria, Brazil. Precursors 1 and 2 were identified from mass spectrometric and ¹H /¹³C NMR data.
9. Shorvon, S.; The Lancet 2001, 358, 1885.
10. Van der Schyf, C. Geldenhuys, W. J.; Youdim, M. B. H.; J Neurochem. 2006, 99, 1033.
11. Nomura, T.; Nishizaki, T.; Brain Res. 2000, 870, 157.
12. Gorbunova, M. G.; Gerus, I. I.; Kukhar, V. P. Synthesis 2000, 738, and references therein.
13. Gesser, J. C.; Zucco, C.; Nome, F. J. Phys. Org. Chem. 1995, 8, 97.
14. Vdovenko, S. I.; Gerus, I. I.; Wójcik, J.; J. Phys. Org. Chem. 2001, 14, 533.
15. Data for methyl 3-(2-methyl-7-(trifluoromethyl)pyrazolo-[1,5-a]-pyrimidin-5-yl)propanoate (7) yield 94 %, mp 124-125 şC, anal. calcd for C₁₂H₁₂F₃N₃O₂: C, 50.18; H, 4.21; N, 14.63, found C, 50.35; H, 4.02; N, 13.83, ¹H NMR (400 MHz, CDCl₃): d 2.55 (s, Me), 2.91 (t, ³J_HH 7.5 Hz, CH₂), 3.20 (t, ³J_HH 7.5 Hz, CH₂), 3.7 (s, OMe), 6.51 (s, 1H), 6.99 (s, 1H); ¹³C NMR (100 MHz, CDCl₃): d 14.7 (Me), 31.2 (CH₂), 32.4 (CH₂), 51.8 (OMe), 96.9 (Pyrim), 105.7 (Pyr), 119.4 (q, ¹J_CF 285 Hz, CF₃), 133.3 (q, ¹J_CF 32 Hz, C7), 156.4 (C2), 159.1 (C5), 150.5 (C3a) 172.9 (COOR) and 3-(2-methyl-7-(trichloromethyl)pyrazolo-[1,5-a]-pyrimidin-5-yl)propanoate (8) yield 84 %, mp 191-193 şC, anal. calcd for C₁₂H₁₂Cl₃N₃O₂: C, 42.82; H, 3.59; N, 12.48, found C, 42.55; H, 4.00; N, 12.20, ¹H NMR (400 MHz, CDCl₃): d = 2.25 (s, Me), 2.72 (t, ³J_HH 7.2 Hz, CH₂), 2.99 (t, ³J_HH 7.2 Hz, CH₂), 3.57 (s, OMe), 5.59 (s, 1H), 5.91 (s, 1H); ¹³C NMR (100 MHz, CDCl₃): d 14.1 (Me), 28.0 (CH₂), 32.1 (CH₂), 51.9 (OMe), 89.6 (CCl₃), 94.6 (Pyrim), 102.1(Pyr), 142.2 (C7), 152.8 (C3a), 153.4 (C2), 157.9 (C5), 172.3 (COOR). For experimental details see Martins, M. A. P.; Cunico, W.; Scapin, E.; Emerich, D. J.; Fiss, G. F.; Rosa, F. A.; Zanatta, N.; Bonacorso, H. G.; Flores, A. F. C.; Lett. Org. Chem. 2006, 3, 358.

*

e-mail:

alexflores@smail.ufsm.br

Publication Dates

Publication in this collection
10 Mar 2008
Date of issue
2008

History

Accepted
31 Jan 2008
Received
26 June 2007

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Bonacorso, H. G.; Martins, M. A. P., Bittencourt, S. R. T.; Lourega, R. V.; Zanatta, N.; Flores, A. F. C.; J. Fluorine Chem. 1999, 99, 177 and references cited therein.

[2] 2. Druzhinin, S. V.; Balenkova, E. S.; Nenajdenko, V. G.; Tetrahedron 2007, 63, 7753.

[3] 3. Martins, M. A. P.; Cunico, W.; Pereira, C. M. P.; Sinhorin, A. P.; Flores, A. F. C.; Bonacorso, H.; Zanatta, N.; Curr. Org. Chem. 2004, 1, 391.

[4] 4. Cechin, S. R.; Schetinger, M. R. C.; Zanatta, N.; Madruga, C. C.; Pacholski, I. L.; Flores, D. C.; Bonacorso, H. G.; Martins, M. A. P.; Morsch, V. M. Chem. Res. Toxicol. 2003, 16, 1433.

[5] 5. Godoy, M. C.; Fighera, M. R.; Souza, F. R.; Flores, A. E.; Rubin, M. A.; Oliveira, M. R.; Zanatta, N.; Martins, M. A. P.; Bonacorso, H. G.; Mello, C. F.; Eur. J. Pharmacol. 2004, 496, 93.

[6] 6. Zanatta, N.; Flores, D. C.; Madruga, C. C.; Flores, A. F. C. ; Bonacorso, H. G.; Martins, M. A. P. Tetrahedron Lett. 2006, 47, 573.

[7] 7. Timokhin, B. V.; Baransky, V. A.; Eliseeva, G. D.; Russ. Chem. Rev. 1999, 68, 73.

[8] 8. Oliveira, G.; Master Dissertation 2005, Universidade Federal de Santa Maria, Brazil. Precursors 1 and 2 were identified from mass spectrometric and ¹H /¹³C NMR data.

[9] 9. Shorvon, S.; The Lancet 2001, 358, 1885.

[10] 10. Van der Schyf, C. Geldenhuys, W. J.; Youdim, M. B. H.; J Neurochem. 2006, 99, 1033.

[11] 11. Nomura, T.; Nishizaki, T.; Brain Res. 2000, 870, 157.

[12] 12. Gorbunova, M. G.; Gerus, I. I.; Kukhar, V. P. Synthesis 2000, 738, and references therein.

[13] 13. Gesser, J. C.; Zucco, C.; Nome, F. J. Phys. Org. Chem. 1995, 8, 97.

[14] 14. Vdovenko, S. I.; Gerus, I. I.; Wójcik, J.; J. Phys. Org. Chem. 2001, 14, 533.

[15] 15. Data for methyl 3-(2-methyl-7-(trifluoromethyl)pyrazolo-[1,5-a]-pyrimidin-5-yl)propanoate (7) yield 94 %, mp 124-125 şC, anal. calcd for C₁₂H₁₂F₃N₃O₂: C, 50.18; H, 4.21; N, 14.63, found C, 50.35; H, 4.02; N, 13.83, ¹H NMR (400 MHz, CDCl₃): d 2.55 (s, Me), 2.91 (t, ³J_HH 7.5 Hz, CH₂), 3.20 (t, ³J_HH 7.5 Hz, CH₂), 3.7 (s, OMe), 6.51 (s, 1H), 6.99 (s, 1H); ¹³C NMR (100 MHz, CDCl₃): d 14.7 (Me), 31.2 (CH₂), 32.4 (CH₂), 51.8 (OMe), 96.9 (Pyrim), 105.7 (Pyr), 119.4 (q, ¹J_CF 285 Hz, CF₃), 133.3 (q, ¹J_CF 32 Hz, C7), 156.4 (C2), 159.1 (C5), 150.5 (C3a) 172.9 (COOR) and 3-(2-methyl-7-(trichloromethyl)pyrazolo-[1,5-a]-pyrimidin-5-yl)propanoate (8) yield 84 %, mp 191-193 şC, anal. calcd for C₁₂H₁₂Cl₃N₃O₂: C, 42.82; H, 3.59; N, 12.48, found C, 42.55; H, 4.00; N, 12.20, ¹H NMR (400 MHz, CDCl₃): d = 2.25 (s, Me), 2.72 (t, ³J_HH 7.2 Hz, CH₂), 2.99 (t, ³J_HH 7.2 Hz, CH₂), 3.57 (s, OMe), 5.59 (s, 1H), 5.91 (s, 1H); ¹³C NMR (100 MHz, CDCl₃): d 14.1 (Me), 28.0 (CH₂), 32.1 (CH₂), 51.9 (OMe), 89.6 (CCl₃), 94.6 (Pyrim), 102.1(Pyr), 142.2 (C7), 152.8 (C3a), 153.4 (C2), 157.9 (C5), 172.3 (COOR). For experimental details see Martins, M. A. P.; Cunico, W.; Scapin, E.; Emerich, D. J.; Fiss, G. F.; Rosa, F. A.; Zanatta, N.; Bonacorso, H. G.; Flores, A. F. C.; Lett. Org. Chem. 2006, 3, 358.

Brasil

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Efficient synthesis of new 1-[Alkyl(aryl)]-5-(3,3,3-trihalo-2-oxopropylidene)pyrrolidin-2-ones

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