Preparation of Novel Trifluoroacetylketene O , N-Acetals and Trifluoromethyl-Containing S , S-Sulfoximido N-Substituted Heterocycles

Este trabalho descreve a síntese de dois novos trifluoracetilceteno O,N-acetais [CF 3 C(O) CH=C(OEt)(NS(O)R 2 ), onde R = CH 3 , Ph], obtidos da reação de 4,4-dietóxi-1,1,1-trifluorbut-3en-2-ona [CF 3 C(O)CH=C(OEt) 2 ] com S,S-dimetile S-metil-S-fenil-sulfoximida [HN=S(O)R 2 ], na presença de trietilamina, com rendimentos de 60-72%, e suas aplicações na obtenção de pirazóis, isoxazóis e pirimidinas S,S-dimetilsulfoximido substituídos, em 55-89% de rendimento, a partir de reações de 4-etóxi-4-(S,S-dimetilsulfoximido)-1,1,1-trifluorbut-3-en-2-ona com hidrazinas, hidrazidas, cloridrato de hidroxilamina e acetilguanidina.


Introduction
The synthetic potential of β-alkoxyvinyl trihalomethyl ketones to obtain series of novel trihalomethylated heterocycles of five-, 1 six-, 2 and seven-membered rings, 3 and more recently bisheterocyclic compounds 4 has been reported exhaustively by our research group over the last twenty years.On the other hand, the very interesting and no less important trihaloacetylketene O,O-acetal analogues and their synthetic applications have been little studied.
In 1986, Hojo et al. 5 reported for the first time the synthesis of trihaloacetylketene O,O-acetals by trichloro-and trifluoroacetylation reactions of ethyl orthoacetate with trichloroacetyl chloride and trifluoroacetic anhydride, respectively.In the same paper, the reactions of 1,1,1-trichloro-4,4-diethoxy-3-buten-2-one with dimethylamine to obtain the corresponding trichloroacetylketene O,N-acetal was reported (Scheme 1, equation 1).In 1990, Hojo et al. 5 demonstrated that trifluoroacetylketene O,N-, S,N-and N,N-acetals are easily obtained by O-N and S-N exchange reactions of trifluoroacetylketene O,O-and S,S-acetals with ammonia and primary and secondary alkyl-and arylamines (Scheme 1, equation 2).
In 1994 and 1997, Venkataratnam and co-workers 6 successfully employed trifluoroacetylketene O,O-diethyl acetal to introduce the trifluoroacetonyl group in imidazoles, oxazoles, quinazolines and perimidines with the objective of incorporating juvenile hormone esterase inhibitory activity.
The reactions of acylketene S,S-acetals are very interesting because examples of similar N-substituted sulfoximido heterocyles have been prepared only by the thermal decomposition of azides 12 or by the trapping of nitrenes by sulfoxides. 13Reactions involving trifluoroacetylketene O,Odiethyl-acetal and N-unsubstituted S,S-dialkylsulfoximides to obtain interesting acyclic and heterocyclic compounds are so far unknown.On the other hand, fluorine-containing heterocycles are of significant interest due to the biological properties of fluorine, which play a pivotal role in bioactive compounds. 14Routes to aromatic heterocycles are of ongoing interest, especially,methods of selectively placing fluorine on heterocycle moieties since these derivates often exhibit bioactivity. 15hus, the aim of this work is to report the synthesis of new acyclic sulfoximido enones (3) and heterocyclic trifluoromethylated S,S-dimethylsulfoximide derivatives (4-8) from O,N-exchange reactions of 4,4-diethoxy-1,1,1-trifluorobut-3-en-2-one (1) with S,S-dimethyl-and S-methyl-S-phenyl-sulfoximides (2).Their application to obtain S,S-sulfoximido-substituted pyrazoles, isoxazoles and pyrimides from the reactions of 3a with four hydrazines, hydroxylamine hydrochloride and acetylguanidine, respectively, is also demonstrated.
Subsequently, 5-hydroxy-2-pyrazolines 4c-e were submitted to dehydration reactions using thionyl chloride/ pyridine in refluxing benzene as solvent.Due to the strong electron-withdrawing effect of the nicotinoyl substituent, it was not possible to isolate the aromatic pyrazole 5e.Compounds 5c and 5d were isolated after the reaction time, as solids, in high purity and in satisfactory yields (68-73%) by a simple evaporation of the solvent under vacuum.
The structure of all compounds was determined from 1 H, 13 C NMR, mass spectra and by comparison with NMR data of other sulfoximides 10 and heterocycles [1][2][3][4]7 previously synthesized in our laboratory. Inall compounds 4-8 the carbon attached to the CF 3 presented a characteristic quartet in the range of 90.7-158.0ppm with a carbon-fluorine coupling constant ( 2 J CF ) in the range of 32-41 Hz.The CF 3 group shows a typical quartet in the range of 117.7-123.3ppm due to the 1 J CF in the range of 267-287 Hz.
Sulfoximido-enones 3a-b presented 1 H chemical shifts of vinyl hydrogen H3 as a characteristic singlet at ca. 5.14 ppm.Also, compounds 3a-b presented the typical 13 C chemical shifts of acyclic carbons, on average at 79.3 ppm (C3) and 169.1 ppm (C4).The C2 (C=O) presented a characteristic quartet, due to attachment to the CF 3 group, on average at 175.3 ppm (32 Hz).The C1 (CF 3 group) showed a typical quartet at ca. 117.3 ppm and a CF-coupling constant on average of 292 Hz, due to the carbon-fluorine coupling.
Compounds 4 and 5 were identified as 1,5-isomers, which indicates the position of the N-1 substituent in relation to the CF 3 group.Thus, the 2-pyrazolines 4c-e presented 1 H chemical shifts of the S,S-dimethylsulfoximido group as two characteristic singlets at ca. 3.34 ppm and 3.32 ppm and presented the typical 13 C chemical shifts of both methyl carbons on average at 41 ppm.The heterocyclic compounds 5-8 presented 1 H chemical shifts of the S,Sdimethylsulfoximido group as a characteristic singlet at ca. 3.37 ppm and presented the typical 13 C chemical shifts of both methyl carbons on average at 41.4 ppm.
The 4,5-dihydropyrazoles 4c-e and 4,5-dihydroisozaxole 6 presented 1 H chemical shifts of H4a and H4b as two doublets at ca. 3.29 ppm and 2.99 ppm (4c-e) and two doublets at 3.33 ppm and 2.94 ppm (6), with a geminal-HH coupling constant of ca.18 Hz for both heterocyclic classes.Also, compounds 4c-e presented the typical 13 C chemical shifts of ring carbons on average at 154.8 ppm (C3) and 45.2 ppm (C4) while 6 presented the typical 13 C chemical shifts of ring carbons at 157.9 ppm (C3) and 44.0 ppm (C4).The C5 presented a characteristic quartet, due to attachment to the CF 3 group, on average at 91.2 ppm (33 Hz) for 4c-e and at 101.4 ppm (32 Hz) for 6.The CF 3 group showed a typical quartet at ca. 123.1 ppm (4c-e) and 122.5 ppm (6) due to the carbon-fluorine coupling with the CF-coupling constant on average of 279 Hz for 4c-e and 284 Hz for dihydroisoxazole 6.
The aromatic pyrazoles 5a-d and isoxazole 7 presented 1 H chemical shifts of H4 as a characteristic singlet in a range of 5.98 to 6.87 ppm (5a-d) and at 6.35 ppm (7).The compounds 5a-d presented the typical 13 C chemical shifts of ring carbons on average at 149.3 ppm (C3) and 98.7 ppm (C4).Compound 7 presented the typical 13 C chemical shifts of ring carbons at 162.9 ppm (C3) and 102.5 ppm (C4).The C5 for 5a-d and 7 presented a characteristic quartet at ca. 136.8 ppm for 5a-d and 158 ppm for 7, due to attachment to the CF 3 group, on average of 38 Hz (5a-d) and 42 Hz (7).The CF 3 group shows a typical quartet at ca. 120.6 ppm (5a-d) and 117.7 ppm (7) due to the carbon-fluorine coupling with the CF-coupling constant on average of 268 Hz (5a-d) and 270 Hz (7).
The pyrimidine 8 presented 1 H chemical shifts of H5 as a characteristic singlet at 6.69 ppm.This compound presented the typical 13 C chemical shifts of ring carbons at 156.9 ppm (C2), 103.5 ppm (C5) and 167 ppm (C6).The C4 presented a characteristic quartet at 155.3 ppm due to attachment to the CF 3 group of 34 Hz.The CF 3 group showed a typical quartet at 120.7 ppm due to the carbonfluorine coupling with CF-coupling constant of 275 Hz.Vol. 20, No. 7, 2009

Experimental
Unless otherwise indicated, all common reagents and solvents were used as obtained from commercial suppliers without further purification.All melting points were determined on a Reichert Thermovar apparatus. 1H and 13 C NMR spectra were acquired on a Bruker DPX 200 spectrometer ( 1 H at 200.13 MHz and 13 C at 50.32 MHz), 5 mm sample tubes, 298 K, digital resolution ±0.01 ppm, in DMSO-d 6 for 4, 5a, 5c-d, 6 and 8 and in chloroform-d 1 for 3a-b, 5b and 7 using TMS as internal reference.Mass spectra were registered in a HP 6890 GC connected to a HP 5973 MSD and interfaced by a Pentium PC.The GC was equipped with a split-splitless injector, autosampler, cross-linked HP-5 capillary column (30m, 0.32mm of internal diameter), and helium was used as the carrier gas.The CHN elemental analyses were performed on a Perkin Elmer 2400 CHN elemental analyzer (São Paulo University, USP / Brazil).

General procedure for the preparation of 3-(S,Sdimethylsulfoximido)-5-(trifluoromethyl)-1H-pyrazoles (5c, 5d)
A solution of 5-hydroxy-2-pyrazolines 4c, 4d (2.6 mmol) and pyridine (33.8 mmol) in 50 mL of benzene was cooled to 5-10 ºC and thionyl chloride (16.8 mmol, 1.22 mL) diluted in 25 ml of benzene was added dropwise over 10 min.The solution was stirred for an additional 30 min, during which time the temperature was allowed to rise to 25 ºC.The mixture was then heated under reflux (bath temperature 80 ºC) for 1 h and filtered to remove pyridine hydrochloride at room temperature.The solution was washed twice with water and dried over sodium sulfate.The evaporation of the solvent under vacuum left to the solid products 5c, 5d with a high level of purity.

General procedure for the preparation of 3-(S,S-dimethylsulfoximido)-5-(trifluoromethyl)isoxazole (7)
A solution of isoxazoline 6 (2.6 mmol) and pyridine (33.8 mmol) in 50 mL of benzene was cooled to 0 ºC and thionyl chloride (16.8 mmol, 1.22 mL) diluted in 25 mL of benzene was added dropwise over 10 min.The solution was stirred for an additional 30 min, during which time the temperature was allowed to rise to 25 ºC.The mixture was then heated under reflux (bath temperature 80 ºC) for 1 h and filtered to remove pyridine hydrochloride at room temperature.The solution was washed twice with water and dried over sodium sulfate.The evaporation of the solvent under vacuum left the solid product 7, which was recrystallized from hexane.