Synthesis of Fatty Trichloromethyl-β-diketones and New 1H-Pyrazoles as Unusual FAMEs and FAEEs

A síntese eficiente de novas 1,1,1-tricloro-4-metoxi-3-alquen-2-onas graxas [Cl3CC(O)C(R )=C(R)OMe, onde R = n-hexil, heptil, nonil, undecil, tridecil e R = H] e 1,1,1-tricloro-2,4-alkanediones [Cl3CC(O)CHR C (O) R, onde R = n-pentil e R = Me, R = Et e R = n-butil, R = n-butil e R = n-propil] é apresentada, com bons rendimentos (85-95%) a partir da acilação dos respectivos acetais com cloreto de tricloroacetila. As 1,1,1-tricloro-4-metoxi-3-alquen2-onas e 1,1,1-tricloro-2,4-alkanediones graxas reagem com cloridrato de hidrazina produzindo os respectivos 1H-pirazol-5-carboxilatos, uma classe de novos ésteres metílicos (FAMEs) e etílicos (FAEEs) graxos não comuns. As estruturas moleculares dos compostos sintetizados foram confirmadas por análise elementar e ressonância magnética nuclear (NMR) de H e C. As 1,1,1-tricloro-4-metoxi-3-alquen-2-onas graxas e seus derivados 1H-pirazol-5-carboxilatos são novos oleoquímicos com propriedades diferenciadas e potencialmente interessantes.


Introduction
5][6] Conventionally, enol ethers have been prepared from symmetrical ketone or aldehyde acetals.However, the isolation of these enol ethers involves a tedious distillation process and in some cases (e.g., those derived from asymmetrical ketones) a mixture of kinetic and thermodynamic enol ethers is obtained. 7,8ur method, with in situ generating of enol ether, offers a convenient alternative to produce acylated regiospecific derivatives 1,1,1-trihalomethyl-4-alkoxy-3-alken-2-ones.Moreover, the transformation of the trichloromethyl group under mild conditions into carboxylic groups prompted us to devote special attention to these substrates. 9,10][19] There is a constant commitment to developing new surfactants and detergents with potentially interesting properties. 20,21As a continuation of our research project on the synthetic potential of acetal acylating method, it is here reported the preparation of a series of new fatty 1,1,1-trichloro-4-alkoxy-3-alken-2-ones derived from fatty ketones and their conversion into 1H-pyrazole-carboxylate derivatives substituted with a long fatty chain, which are unusual fatty acid methyl (FAMEs) and ethyl (FAEEs) esters.

Results and Discussion
Dimethoxy ketals 1a-g were synthesized from the acetalization of the respective fatty ketones a-g with trimethylorthoformate in the presence of p-toluenesulfonic acid. 19The trichloroacylation reactions were carried out in chloroform and pyridine at 30 to 50 °C for 12 h as outlined in Scheme 1. Two equivalents of acylating agent per acetal were required to obtain the fatty 1,1,1-trichloro-4-methoxy-3-alken-2-ones 2a-g since one molecule of the acylating reagent promotes the formation of enol ether by trapping a methoxy group from acetal, and the second molecule of acylating reagent promotes the formation of C-C bonds.As previously reported, acetals of alkyl methyl ketones are always acylated at methyl sites. 22The acylated products 2a-e were obtained as black oil in very good yields of 85-95% (see Supplementary Information (SI) section, Table S1) and high purity (Scheme 1).
From alkyl methyl ketones (alken-2-ones), acylated products were obtained as 1,1,1-trichloro-4-methoxy-3-alken-2-ones without hydrolysis products from the work-up of acid water solutions.However, acylated products from octan-3-one and nonan-5-one were obtained as the respective trichloromethyl-β-diketones (3f,g).A mixture of 1,1,1-trichloro-3-methylnonan-2,4-dione (3f) and 1,1,1-trichloro-3-butylhexan-2,4-dione (3f') was obtained from octan-3-one, and 1,1,1-trichloro-3-propyloctan-2,4-dione (3g) was obtained from nonan-5-one.During the acylation of 3,3-dimethoxyoctane with trichloroacetyl chloride, there was a preference for reactions at ethyl sites, leading to 3f in larger quantities than the isomer 3f', demonstrating that the reaction had some degree of regioselectivity, probably for steric reasons as the reaction selects the lowest substituent between the carbonyl groups.The large sterical volume of the trichloromethyl group is likely one of the factors that prompted hydrolysis of 1,1,1-trichloro-4-methoxy-3-alken-2-ones substituted at position-3 and could help explain the preference of the respective trichloromethyl diketones for nonplanar keto-keto forms (Scheme 2). 23he structures of acylated products were characterized based on their nuclear magnetic resonance (NMR) spectra.The 1 H NMR signal of the vinylic hydrogen for pattern H-3 of the 1,1,1-trichloro-4-methoxy-3-alken-2-one 3a appeared during high field analysis, d 5.9 ppm, and the spectrum showed the characteristic signals of the fatty alkyl chain: a triplet at d 2.7 ppm (2H, 5-CH 2 ), a multiplet at d 1.5 ppm (2H, 6-CH 2 ), the broad signal from the inner -CH 2at d 1.25 ppm, and the triplet from the terminal methyl at d 0.8 ppm.Further support for fatty acylated products was provided by the 13 C NMR spectra.Pattern 3a showed high field signals from carbonyl C-2 and enol ether C-4 at d 179.8 and 183.9 ppm, respectively.There was a signal from vinylic C-3 at d 89.6 ppm, a short signal from CCl 3 at d 98.05 ppm, an intense signal from the methoxy group at d 56.1 ppm, signals from methylenes at 22-34 ppm, and a methyl signal at d 13 ppm from the fatty alkyl chain.For tricloromethyl-β-diketones, the 1 H NMR spectrum showed signals from H-3 at 4.5 ppm, for 3b as a quartet with J HH 6.8 Hz, together with the methyl doublet (J HH 6,8 Hz), demonstrating the presence of the keto form in CDCl 3 solution.Signals from the C5 chain were also detected.For 3b', the H-3 signal appeared as a doublet of doublets (J HH 8.6 and 5.5 Hz) and the signals from alkyl chains were hidden by those from the predominant product (Scheme 2).The same pattern was observed in the 1 H NMR spectrum from 3d, in winch the signal from H-3 was a doublet of doublets (J HH 8.8 and 5.2 Hz) and the spectrum showed all of the signals from 4-propyl and 3-butyl substituents.The NMR data for the fatty trichlomethylketones obtained are shown in the SI section.
Cyclization of 1,3-dielectrophilic precursors 2a-g and 3f,g with hydrazine hydrochloride proceeded smoothly in alcohol (methanol or ethanol) at reflux for 8 h to produce pyrazole-5-carboxylic esters 4, 5a-g in isolated yields of 93-96% (Table 1).After completion of the reaction, solvent was evaporated and the product was dried in a desiccator with anhydrous CaCl 2 (Scheme 3).
Mechanistically, cyclocondensation between precursors 2 and hydrazine hydrochloride proceeds via conjugate addition of nitrogen into the C-4 of 1,1,1-trichloro-4-methoxy-3-alken-2-ones.Then, one molecule of methanol is eliminated to give the enaminoketone intermediate, which isomerizes to thermodynamically more stable hydrazone.Subsequent cyclization affords the 5-trichloromethyl-5-hydroxy-4,5-dihydro-1H-pyrazole intermediates, which are unstable in alcohol medium. 24hen, one molecule of water is eliminated to give the aromatic 5-trichloromethyl-1H-pyrazole intermediate.Further elimination of chloride with the aid of the adjacent nitrogen atom leads to reactive intermediate I, which is attacked by water in the reaction medium, leading to the formation of an acid chloride that reacts with the solvent used in the reaction (MeOH or EtOH) (Scheme 4).
For compounds substituted at C-4, the carbon C-4 was deshielded to 122 ppm and C-5 was shielded to 136 ppm.The signal from the carboxyl carbon appeared at 162 ppm.

Conclusion
In conclusion, we have established the versatility of the acetal acylation process for synthesizing fatty 1,1,1-trichloro-4-methoxy-3-alken-2-ones, which are versatile building blocks for heterocyclic compounds.It was found that trichloromethylated precursors react with hydrazine hydrochloride, leading to new methyl or ethyl 1H-pyrazole-5-carboxylates, fatty substances with potentially interesting properties.

Experimental
Unless indicated otherwise, all common reagents were used as obtained from commercial suppliers without further purification.All melting points were measured using a Reichert-Thermovar apparatus.Listed yields are of isolated compounds. 1H and 13 C NMR spectra were acquired on a Bruker DPX 200 or Bruker DPX 400 spectrometer ( 1 H at 200.13 or 400.13 MHz and 13 C at 50.32 or 100.63 MHz) at 300 K, using 5 mm sample tubes, and with a digital resolution of ± 0.01 ppm.CDCl 3 was used as a solvent with TMS (tetramethylsilane) as the internal standard.
General procedure for 1H-pyrazole-5-carboxylate derivatives (4, 5) A mixture of one precursor 2a-e or 3f,g (10 mmol) and NH 2 NH 2. HCl (12 mmol, 0.82 g) in 10 mL alcohol (MeOH or EtOH) was stirred under reflux for 4 to 8 h.Then solvent was evaporated, the residue was dissolved in CH 2 Cl 2 (20 mL) and washed with water (15 mL) twice, and the organic layer was dried with Na 2 SO 4 .After evaporation of the solvent, the residues were obtained as reddish orange oils (R = hexyl, heptyl and nonyl) or brown greases (R = undecyl and tridecyl).Spectroscopic data for derivatives 1H-pyrazole carboxylate 4a-g and 5a-g and the full data series can be seen in the SI section.

Table 1 .
Yields of the compounds 4a-g and 5a-g