Synthesis of Aryl Fluorides on a Solid Support and in Solution by Utilizing a Fluorinated Solvent

Abstract

The conversion of diazonium tetrafluoroborate salts [1][2][3] into fluorinated arenes [4] was discovered more than 80 years ago by Balz and Schiemann, [5] and is widely used owing to the importance of fluorinated compounds in the life sciences [6] and material science [7] in academic as well as industrial laboratories. [8,9] This method has also found application for the synthesis of radioactive-labeled compounds.[10]The yields of the Balz-Schiemann reaction are moderate to good, and a few isolated protocols achieve excellent yields.[11] Therefore many attempts have been made to increase the yields and to lower the reaction temperatures, which in general correspond to the melting points of the tetrafluoroborates, in most cases over 100 8C. Some alternatives rely on, for example, the exchange of the counter ion [12] or the use of other solvents like BF 3 ·Et 2 O [13] and ionic liquids.[14] Modified conditions, for example photochemical methods, [15,16] have also resulted in improved protocols. Herein we describe a variant of the Balz-Schiemann reaction which through the utilization of a perfluorinated solvent leads to very good conversions of diazonium salts and triazenes to provide the corresponding aryl fluorides under mild conditions (Scheme 1). In our search for a method that allows the application of the Balz-Schiemann reaction in combinatorial chemistry, we tested different sets of conditions. Our leitmotiv was the cleavage of triazenes to give diazonium ions followed by their conversion in situ into the corresponding fluoroarenes. This approach, known as Wallach reaction, [17] offers some advantages over conventional methods. First, triazenes can be stored for extended periods without decomposition and they constitute safe alternatives to explosive diazonium salts. For example, our DSC/TG and DTA/TG measurements (DSC = dynamic difference calorimetry, DTA = differential thermoanalysis, TG = thermogravimetry) on triazene 9 (see Scheme 4) gave a decomposition temperature of 202.2 8C (beginning at 136 8C up to 266 8C, with a loss of mass of 98 %), while no reaction with O 2 or H 2 O takes place. The enthalpy of decomposition for 9 is determined to be roughly 40 kJ g À1 . In addition, triazene-masked diazonium ions can be used in reaction sequences in solution as well as on a solid support, and are thus amenable to combinatorial methods.[18] All products of the fluorinating cleavage should first be analyzed in terms of purity, as the isolation of preferably pure crude products plays a pivotal role in combinatorial chemistry.Initial tests were conducted with resin-bound triazenes. We used different solvents (for example, THF, DMF, MeOH) and observed the generation of "traceless" by-products (the reduced cleavage compound). As these compounds account for most of the impurities in the thermal decomposition of diazonium salts as well, we tried to suppress the reduction through the use of a perfluorinated solvent. In perfluorohexane [19] under optimized conditions, cleavage of the aromatic compounds to give the diazo...

Selective Protection of Secondary Amines as the N-Phenyltriazenes. Application to Aminoglycoside Antibiotics

“…6 Alternatively, the same trisubstituted triazenes can be employed to protect secondary amines where they display a useful tolerance of a range of oxidizing and reducing conditions, yet are readily cleaved on exposure to trifluoroacetic acid. 7 A recent report on the palladium-catalyzed carbonylative removal of nitrogen from 1,1-dialkyl-3-aryltriazenes (R 2 N-N 2 Ar) affording amides (R 2 NCOAr) offers the additional possibility of protecting group interconversion in a single step.…”

Preparation of Aromatic Triazenes and Their Application in Silver-Mediated Perfluoroalkylation Reactions

“…Because of the versatile transformation protocols available for the triazene moiety (e.g., transformation into fluorides, 3 iodides, 2e or azides 2d ), these protocols should find application in the synthesis of a range of fluorinated building blocks.…”

“…1 Triazenes, which can be regarded as equivalents of protected diazonium salts, offer unique synthetic opportunities due to the fact that they are easily converted into a range of functional groups, which makes them interesting building blocks for chemistry in solution 1b,2 as well as on solid support. 1a, 3 In contrast to diazonium salts, aromatic triazenes can be isolated, stored, and are suitable for further transformations on the aromatic core. For example, metal-catalyzed crosscoupling reactions as well as metalation protocols are known.…”

“…1 J = 274.2 Hz, CF 3 ), 125.9 (C quat , q, 2 J = 31.3 Hz, C-2, C-6), 133.2 (+, q, 3 J = 5.7 Hz, CH-3, CH-5), 149.9 (C quat , C-1). 19 F NMR (367 MHz, CDCl 3 ): δ = -58.8 (s, 6 F,CF 3 …”

Very Efficient Nucleophilic Aromatic Fluorination Reaction in Molten Salts: A Mechanistic Study

“…Although the nucleophilic aromatic substitution (S N Ar) [1][2][3][4][5][6][7] reactions have been less popular than the electrophilic counterpart in synthetic organic chemistry, the introduction of some nucleophilic groups such as alkoxides, phenoxides, sulfides, amines and fluoride ion, [8][9][10] to aromatic rings may still necessitate the employment of this type of reaction. There are also situations in which the S N Ar reactions are much more advantageous.…”