Antonio Simón-Fuentes

Improved Regioselectivity in Pyrazole Formation through the Use of Fluorinated Alcohols as Solvents: Synthesis and Biological Activity of Fluorinated Tebufenpyrad Analogs

The preparation of N-methylpyrazoles is usually accomplished through reaction of a suitable 1,3-diketone with methylhydrazine in ethanol as the solvent. This strategy, however, leads to the formation of regioisomeric mixtures of N-methylpyrazoles, which sometimes are difficult to separate. We have determined that the use of fluorinated alcohols such as 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as solvents dramatically increases the regioselectivity in the pyrazole formation, and we have used this modification in a straightforward synthesis of fluorinated analogs of Tebufenpyrad with acaricide activity.

Recent Advances in the Synthesis of Pyrazoles. A Review

Introduction ..........................................................................................254 I. 1H-Pyrazoles .........................................................................................255 1. 3(5)-Substituted-1H-pyrazoles ...............................................................255 2. 3,4and 3,5-Disubstituted-1H-pyrazoles ................................................256 a. 3,4-Disubstituted-1H-pyrazoles ..........................................................256 b. 3,5-Disubstituted-1H-pyrazoles ..........................................................257 3. 3,4,5-Trisubstituted-1H-pyrazoles ..........................................................261 II. N-Substituted Pyrazoles .......................................................................262 1. 1,3,5-Trisubstituted Pyrazoles................................................................262 a. From 1,3-Dicarbonyl Compounds.......................................................262 b. From α,β-Unsaturated Ketones ..........................................................264 c. From β-Aminoenones and Related Compounds....................................264 d. By 1,3-Dipolar Cycloadditions ...........................................................265 e. Other Methods..................................................................................266 2. 1,3,4,5-Tetrasubstituted Pyrazoles ..........................................................266 3. Miscellaneous Pyrazoles .......................................................................269 III. Substituted Pyrazole-3(5)-carboxylic Acid Derivatives .....................271 1. From 1,3-Diketoesters...........................................................................271 2. From α,β-Unsaturated β-Ketoesters ......................................................271 3. From α-Enamino-β-ketoesters(amides) and Related Compounds ............273 4. Other Methods .....................................................................................274 IV. Fluorinated Pyrazole Derivatives ........................................................275 1. From β-Aminoenones...........................................................................276 2. From β-Alkoxyvinylketones ..................................................................276 3. From 1,3-Dicarbonyl Compounds..........................................................278 Conclusions............................................................................................285 References..............................................................................................285

Synthesis of New Fluorinated Tebufenpyrad Analogs with Acaricidal Activity Through Regioselective Pyrazole Formation

In previous studies, our group has shown that the use of fluorinated alcohols such as trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP) as solvents dramatically increases the regioselectivity in the pyrazole formation from 1,3-diketone with methylhydrazine. We have now applied this synthetic method to the preparation of new fluorinated pyrazoles, which have then been used as synthetic intermediates in the preparation of fluorinated analogs of Tebufenpyrad, a commercial acaricide. These compounds display a strong acaricidal activity that is either comparable to or better than that of the commercial compound.

Tandem asymmetric Michael reaction-intramolecular Michael addition. An easy entry to chiral fluorinated 1,4-dihydropyridines.

A novel one-pot tandem asymmetric Hantzsch-type process has been employed to generate fluorinated 1,4-dihydropyridines (1,4-DHPs) as single diastereoisomers. It involves the condensation of (R)-(+)-allyl p-tolyl sulfoxide, fluorinated nitriles, and alkyl propiolates, giving access to a new family of enantiomerically pure fluorine-containing 1,4-DHPs.

Solution-, Solid-Phase, and Fluorous Synthesis of β,β-Difluorinated Cyclic Quaternary α-Amino Acid Derivatives : A Comparative Study

The diastereoselective synthesis of cyclic beta,beta-difluorinated alpha-amino acid derivatives bearing a quaternary stereocenter is described. The process relies on the chemo- and diastereoselective addition of allylic organometallic reagents to fluorinated alpha-imino esters and a subsequent ring-closing metathesis reaction (RCM). Complete selectivity in the nucleophilic addition was achieved with (R)-phenylglycinol methyl ether as a chiral auxiliary. The resulting amino acids were introduced into peptide chains, which could facilitate the preparation of potentially bioactive dipeptide derivatives. In addition, the solution synthesis of these cyclic fluorinated alpha-amino acids was successfully adapted to solid-phase and fluorous-phase techniques. The reaction times and final deprotection were clearly more favorable in the latter, in which a fluorous trimethylsilylethanol (TMSE) tag was used. The tag was then easily removed upon treatment with TBAF in a high-yield transesterification process.

Asymmetric allylation/Pauson-Khand reaction: a simple entry to polycyclic amines. Application to the synthesis of aminosteroid analogues.

Asymmetric allylation of o-iodoarylsulfinylimines has been achieved in high diastereoselectivities. The thus-obtained o-iodoarylhomoallylic sulfinamides participate in a subsequent Sonogashira coupling followed by a diastereoselective intramolecular Pauson-Khand reaction. In this way, tricyclic amines showing a unique benzo-fused indenyl backbone were obtained. The methodology has been applied to the synthesis of amino steroid analogues.

Diastereoselective intramolecular additions of allyl- and propargylsilanes to iminium ions: synthesis of cyclic and bicyclic quaternary amino acids.

Chiral imino lactones derived from (R)-phenylglycinol containing an allyl- or propargyltrimethylsilyl group in the side chain readily cyclized in the presence of acidic reagents to afford spirocyclic compounds with high diastereoselectivity. Removal of the chiral auxiliary produced 2-substituted 1-aminocycloalkanecarboxylic acids, whereas further cyclizations by means of metathesis or hydroamination reactions led to bicyclic derivatives of pipecolic acid and proline.

N-Substituted β-Enamino Acid Derivatives: A New Approach to Fluorinated β-Enamino Esters

Abstract Reaction of fluorinated imidoyl chlorides 1 with lithium ester enolates 2 gave N-substituted γ-fluorinated β-enamino and/or β-imino esters 4 in good to excellent yields. β-Enamino esters were obtained exclusively as Z isomers.

Diastereodivergent Synthesis of Fluorinated Cyclic β3-Amino Acid Derivatives

The ability of 2-p-tolylbenzyl carbanions to behave as a source of chiral benzylic nucleophiles has been shown in its reaction with fluorinated imines. The process takes place with high levels of stereocontrol, rendering the corresponding amines as single diastereoisomers. Subsequent cross-metathesis followed by intramolecular aza-Michael reaction makes the synthesis of fluorinated homoproline derivatives bearing three stereogenic centers possible. Furthermore, the selectivity of the cyclization process can easily be tuned up in a diastereodivergent manner simply by changing the reaction conditions.

Fluorinated Pyrazoles and Indazoles

The synthesis of fluorine containing pyrazoles has been boosted in the past decades due to the interesting properties that confer these building blocks in pharmaceutical and agricultural active ingredients. There are two main methods for the synthesis of fluorine-containing organic compounds, namely, the direct replacement of an atom or functional group such as diazo, hydroxyl, halogen or hydrogen by fluorine, and the modification of fluorine-containing building blocks. In the case of fluorinated pyrazoles the latter approach is the most commonly applied. This chapter deals primarily with the pivotal procedures that allow the preparation of fluoro- and fluoroalkyl- pyrazoles. Their benzocondensed derivatives, indazoles, have been studied to a much lesser extent. The fundamental applications of this class of compounds in different fields are also discussed.