Reactions aminofluorination

In 2010, Brenner-Moyer and co-workers [80] reported an organocatalytic enantioselective olefin aminofluorination reaction, in which an iminium-catalyzed aza-Michael addition preceded an enamine-catalyzed a-fluorination reaction (Scheme 13.41) [80]. This reaction was a rare example of a catalytic enantioselective olefin aminohalogenation reaction, and it furnished precursors to enan-tioenriched a-fluoro-(3-amino acids. 

An unprecedented aminofluorination was reported by Liu et al. [86]. This reaction proceeds from 124 through another rare intramolecular trans-aminopaUadation and again with complete endo-selectivity to 125. In the presence of a hypervalent iodine(III), it then forms a Pd(IV) intermediate, which accommodates a fluoride for subsequent reductive elimination with retention of configuration. This mechanistic proposal was again arrived at from deuterium labeling studies. For chiral substrates, reasonable diastereoselectivities can be obtained from this reaction. 

Experimental procedure In a dried glass tube, Pd(OAc)2 (4.5mg, 0.02 mmol, 5 mol %), bathocuproine (10.8 mg, 0.03 mmol, 7.5 mol %), NFSI (315.0 mg, 1.0 mmol, 2.5 equiv) were dissolved in 1,4-dioxane (1.0 ml), and then the respective styrene (0.4 mmol, 1.0 equiv) was added. After the reaction mixture was stirred at 40-50°C for lOh, the solvent was removed under reduced pressure. The crade product was purified by column chromatography on silica gel with a gradient eluant of petroleum ether and ethyl acetate to afford the aminofluorination product... 

The corresponding aminofluorination reaction of aUcenes was developed by Nevado (Scheme 16) [55]. Key to its successful realization was the synthesis of the new chiral difluoroiodine(lll) reagent 73 based on chiral information by the lactate side chains. It was obtained from the related chiral aryliodide by oxidation with... 

The aminofluorination reaction could also be conducted within its inter-molecular version [55]. Oxidation of styrenes 78 with excess of the difluoride reagent 79 in the presence of 7/-methyl tosylamide 80 leads to the correspmiding aminofluorination products 81 in very good isolated yields and with complete regioselectivity. Drawbacks are that the reaction requires a sixfold excess of starting material to provide reasonable product formation and that the related diamination products 82 were formed as by-products, although in amounts less than 15% yield. 

The intramolecular enantioselective aminofluorination of unactivated olefins, such as (1), has been attained by using the chiral iodo(III) difluoride (5) with <88% ee (Scheme 1). The reaction is believed to proceed via an intramolecular aziridination (1) (2) - (3), followed by a nucleophilic attack with to produce (4). A regio-selective aminofluorination of styrenes ArCH=CH2 with p-xylene IFj and TsNHR... 

Liu and coworkers have recently published the synthesis of (3) and (4), as well as several other fluorinated pyrrole analogues (not shown), by aminofluorination of allenes the synthetic approach is shown in Scheme 3 [15], This strategy takes advantage of a selective, silver-catalyzed intramolecular fluorination reaction, but the approach works best with substrates that possess electron-withdrawing R -groups on the 3-position. Because of this limitation, the yield of (3) is significantly higher than (4), 80 % versus 28 %, respectively. 4-Fluoro-pyrrole-2-carboxylic acid (5a, Fig. 2), synthesized from a fluorinated proline, was explored as a potential intermediate on the route to (3), but only extensive decomposition products were observed when (5a) was subject to flash pyrolysis [16]. 

Aminofluorination is a valuable approach to the simultaneous incorporation of multiple functional groups. Using this approach, a variety of styrene derivatives were functionahzed (Scheme 3.35) [33], While a number of copper compounds promoted the reaction, the combination of a simple copper salt along with a bathocuproine ligand was the most effective. The reaction was highly regioselective and added to the fluorine to the a-position. 

The starting material is a styrene derivative. Can an aminofluorination reaction be carried out on these substrates ... 

One of the most efficient methods of incorporating multiple functional groups into the same compound is through a halofunctionalization reaction [3], To this end, an iron-catalyzed aminofluorination reaction has been developed using hydroxylamines as substrates (Example 7.4) [21], Control reactions revealed that both triethylamine-HF and XtalFluor-E were needed to promote the chemistry and the latter was proposed to suppress a competing... 

An organocascade aminofluorination reaction of a, 3-unsaturated aldehydes with 174 and NFSI (A-fluorobenzenesulfonimide) as an electrophilic fluorination agent was developed to produce chiral a-fluoro-P-amino aldehydes using catalyst 34 (Scheme 1.74) [ 116]. Up to 85% yield, 98 2 dr, and 99% ee of the reduced alcohols 175 were achieved. 

In recent years, a number of novel palladium-catalyzed diaslereoselective alkene difunctionalization reactions, such as aminohalogenation [34], aminoacetoxylation [35], aminofluorination [36], and diamination [37], have been studied intensively by the combination of other reactions with an amino- or oxopaUadation reaction. In some of these transformations, a Pd(IV) species is believed to be the key intermediate (Scheme 6.21). 

---