Nucleophilic conjugate tri uoromethylation of chromones and activated alkenes under the action of Ruppert ’ s reagent

This review summarizes data on the reactions of chromones and activated alkenes with trimethyl(trifluoromethyl)silane (Ruppert’s reagent), which occures as a nucleophilic 1,4-trifluoromethylation with high regioselectivity and good yields. The most important chemical properties of the formed products are also considered.

Th e nucleophilic trifl uoromethylation of organic compounds is complicated by the instability of free trifl uoromethyl anion, which easily breaks down into the fl uoride anion and difl uorocarbene [1].Th e use of trimethyl(trifl uoromethyl)silane (Ruppert's reagent) in the presence of fl uoride anion as an initiator allows to avoid this unwanted reaction and to realize the direct introduction of the CF 3 group to organic substrates.It is well known that the Ruppert's reagent interacts easily with both saturated and α, β-unsaturated carbonyl compounds via 1,2-nucleophilic addition with formation of the corresponding trifl uoromethyl carbinols [2][3][4].It is important to note that in the case of α, β-unsaturated ketones, the formation of products of nucleophilic 1,4-trifl uoromethylation (Michael addition) was not observed (Scheme 1).Th e fi rst example of the conjugate trifl uoromethylation of α, β-enone system was discovered by us on the example of the reaction R F SiMe 3 (R F = CF 3 , C 2 F 5 ) with 2-trifl uoromethylchromones 1 [5,6].Moni-toring using 19 F NMR spectroscopy showed that chromones 1 in the presence of the nucleophilic initiator Me 4 NF (THF, 0 °C, 4 h) almost quantitatively and with high regioselectively react with CF 3 SiMe 3 towards the way of 1,4-addition, giving trimethylsilyl ethers 2 (the content in the reaction mixture of 1,2-addition products 3 does not exceed 5-10 %).When processing of the reaction mixture with diluted HCl only the products of 1,4-addition 2 are subjected to hydrolysis to give 2-trifl uoromethyl-2-perfl uoroalkylchroman-4-ones 4. As expected, when increasing of the length of the R F group to C 2 F 5 the regioselectivity of the reaction is reduced to 80-85 % (Scheme 2).
Currently, this reaction represents the shortest and most eff ective way of synthesis of partially fl uorinated analogues of natural chromanones, chromanes and chromenes with gem-dimethyl group at the atom C(2).Th us, 4-oxo-2,2-bis(trifl uoromethyl)chroman-6-carbaldehyde 5a, an analogue of natural lactarochromal, metabolite of Lactarius deliciosus mushrooms [7], in which both methyl groups are replaced by CF 3 groups, was synthesized by oxidation of 6-Me group of chromanone 4b by the mixture of CuSO 4 and K 2 S 2 O 8 in acetonitrile with the yield 17 % [8].In addition to hexafl uorolactarochromal 5a was obtained and the corresponding acid 5b (yield 35 %), which is also a fl uorinated analogue of the natural acid, isolated from Chrysothamnus viscidifl orus [9] (Scheme 4).
Th e presence of the electron withdrawing R F group at the β-C-atom of enone system is desirable, but not indispensable, if to carry out the reaction in the presence of bulky Lewis acids, which under coordination at the carbonyl oxygen atom complicate 1,2-addition and increase the electrophilicity of the β-C atom.So, in the presence of tris( 2 Recently, Chinese chemists [18] in the course of work on the study of antitumor activity of trifl uoromethylated fl avonoids held trifl uoromethylation of fl avone 18 and isofl avone 19 in our conditions and found that in the fi rst case is a 1,2-addition and in the second is 1,4-addition with the formation of products 20 and 21, respectively (Scheme 10).
Th us, both electronic and steric factors are greatly infl uenced to the successful course of the discussing reaction, the most favorable combination of which is observed in the case of 2-CF 3 -and 2-CF 2 H-chromones.
Along with the conjugate 1,4-trifl uoromethylation and 1,6-addition of trifl uoromethyl anion is possible.Recently, we have shown [19] that methylidene derivatives 22a, b obtained by Knoevenagel condensation from chromone 1a, diethyl malonate and ethyl cyanoacetate react with excess of  11).Th is reaction is the fi rst and the only example of regioselective nucleophilic 1,6-trifl uoromethylation that extends the synthetic possibilities of this method.
In the works of Dilman with coworkers [20][21][22], the method of nucleophilic conjugated trifl uoromethylation using the Ruppert's reagent in the presence of basic activators was further developed.Since 2008, in the orbit of this reaction the various electron defi cient alkenes, such as arylidene derivatives of malononitrile, Meldrum's acid and nitroacetic ester, were involved.It was shown that arylidene malononitriles 24 react with CF 3 SiMe 3 in Scheme 10 Scheme 11 the presence of sodium acetate in DMF at room temperature according to the type 1,4-addition and give products 25 in high yields (75-98 %) regardless of the nature of the substituent in the aromatic ring of the substrate.In addition to trifl uoromethyl group, benzylidene malononitrile 24 was also able to attach pentafl uoroethyl, pentafl uorophenyl and dichlorofl uoromethyl groups, to give compounds 26 in 81-99 % yields [20] (Scheme 12).
Despite the fact that arylidene malonates not enter into this reaction due to their lower electrophilicity, arylidene derivatives of Meldrum's acid 27 smoothly added trifl uoromethyl anion and aft er acidic hydrolysis give the acids 28, which in their pure form were not isolated but were immediately methylated with methyl iodide in the presence of potassium carbonate to esters 29 or reduced by sodium borohydride and boron trifl uoride etherate to alcohols 30 [21] (Scheme 13).
In the work [22] the interaction of 2-nitrocinnamates 31 with the silicon reagents R F SiMe 3 (R F = CF 3 , C 2 F 5 , C 6 F 5 ) in the presence of sodium acetate in DMF (method A) or tetrabutylammonium acetate in dichloromethane (method B) was described.Th e reaction proceeds as the conjugated addition of fl uorinated carbanion on the С=С bond and with good yields leads to obtaining of 3-aryl-2-nitroalkanoates with perfl uorinated substituents.Th ese compounds are formed in the form of an isomeric mixture with a ratio of diastereomers from 1:1 to 1.6:1, and the possibility of their transformation to the corresponding amino derivative is shown by the example of methyl 4,4,4-trifl uoro-2-nitro-3-phenylbutanoate 32 (R F = CF 3 , Ar = Ph).Reduction was carried out at atmospheric pressure with Pd/C in the presence of acylating agent and gave N-Boc-protected product 33 in 79 % yield (Scheme 14).