Fluorination

Living Edition
| Editors: Jinbo Hu, Teruo Umemoto

Fluolead (Ar-SF3) Deoxofluorination

  • Benqiang Cui
  • Norio ShibataEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-981-10-1855-8_17-1

Introduction

Fluorine has become a crucial element in medicinal chemistry, and nowadays, 20–25% of marked drugs are estimated to contain at least one fluorine atom in their structures. Introduction of fluorine into biologically active organic molecules significantly affects their lipophilicity, solubility, acidity, and basicity causing the modulation and/or improvement of their binding affinity, pharmacokinetic properties, and bioavailability [14, 24, 31, 39]. Therefore, numerous efforts have concentrated on the development of effective methods for fluorination reactions. Fluorinating reagents are one of the keys for the success of the transformation [1, 2, 5, 9, 11, 23, 25, 42, 43]. A variety of deoxofluorinating reagents have been developed for this purpose, which enable oxygen-containing compounds such as alcohols and carbonyls to be transformed into corresponding fluorides.

Deoxofluorinating reagents are divided into next categories: α-fluorinated alkylamines (NCF reagents) and CpFluors [13, 20, 22, 35, 37] (Fig. 1a) and sulfur fluorides and their derivatives (SF reagents) [3, 17, 21, 26, 38, 41] (Fig. 1b). Deoxofluorinations using these reagents are powerful for the fluorination of alcohols, aldehydes, ketones, and carboxylic acids, although with some possible disadvantages such as toxic, thermally unstable, harsh reaction conditions, and high cost depend on the reagents and reaction substrates. However, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead) is believed to be more stable, versatile, safe, and easy to handle than other SF reagents [SF4, DAST (N,N-diethylaminosulfur trifluoride), Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride), and XtalFluor-M (morpholinodifluorosulfinium tetrafluoroborate)] [38]. Better stereoselectivity is sometimes observed in fluorination reactions that use Fluolead rather than when using other reagents. Deoxofluorination and dethioxofluorination of alcohols, aldehydes, ketones, diketones, carboxylic acids, and various sulfur compounds smoothly proceed with Fluolead to provide the corresponding fluorides in good to high yields.
Fig. 1

Deoxo- and dethioxofluorination reagents

Synthesis and Properties of 4-tert-Butyl-2,6-dimethylphenylsulfur Trifluoride (Fluolead)

Arylsulfur trifluorides (ArSF3) can be prepared by employing the oxidation of diaryl disulfides or arylthiols with various oxidative reagents, such as F2/N2 [6, 7], AgF2 [32, 33], XeF2 [28], Cl2/KF [29, 38], or Br2/KF [41]. Umemoto initially reported that when 4-tert-butyl-2,6-dimethylphenyl disulfide 1 was treated with an excess amount of oxidative reagent, AgF2 in 1,1,2-trichlorotrifluoroethane in a fluoropolymer bottle under 35–40 °C for 20 min, Fluolead formed as white crystalline powder, which was purified by distillation under reduced pressure, b.p. 92–93 °C/0.5 mmHg, m.p. 59.1 °C (by DSC) [38], Fig. 2. The large-scale production of Fluolead was also successfully conducted by the reaction of 1 with Cl2/KF or Cl2/CsF. Thus, 3.5 equiv. of chlorine was slowly bubbled into ice-bath-cooled acetonitrile solution in the presence of 10 equiv. of anhydrous KF over a period of 2 h [38], Fig. 2. Dolbier improved the synthesis of ArSF3 by treatment of diaryl disulfide 1 with excess Br2 and dry KF in acetonitrile at room temperature [41], Fig. 2.
Fig. 2

Synthesis of Fluolead

Fluolead is a nucleophilic-type fluorinating reagent which is useful for deoxo- and dethioxofluorination reactions and is a crystalline solid with excellent physical and chemical properties. It possesses excellent thermal stability, up to 232 °C by DSC, that fluorinates a broad range of substrates, more efficiently and selectively than currently available deoxofluorinating reagents, such as DAST, Deoxo-Fluor, and others. Fluolead may also be handled in open air. The crystalline Fluolead does not fume and reacts with water very slowly. Thus, Fluolead can be safely applied to a variety of processes including industrial scale production [38].

The structure of the sulfur trifluoride (SF3) moiety in Fluolead is trigonal bipyramidal, which exists in equilibrium between structures A and B with two apical fluorine atoms (Fa) and an equatorial fluorine atom (Fe), Fig. 3. Two broad peaks of SF3 of Fluolead in CD3CN appear at 53 ppm and −57 ppm with an intensity of 2:1. The choice of NMR solvent has a strong effect on the spectra of arylsulfur trifluorides. When a fraction of anhydrous diethyl ether is added into the NMR tube (giving CD3CN/Et2O, 3/1 v/v), two independent 19F NMR broad peaks of Fluolead in CD3CN become sharp and give a prominent split of a doublet and a triplet [38].
Fig. 3

Structure of Fluolead

Fluolead-Mediated Fluorination Reactions

Fluorination of Alcohols

DAST and Deoxo-Fluor are conventional deoxofluorinating reagents that convert the hydroxyl (OH) group to corresponding monofluorides. Fluolead is also used to convert the OH group in alcohols into corresponding monofluorides [38]. Various alcohols were converted into corresponding fluorides with Fluolead with or without additives (Table 1). Most of these OH/F replacement reactions occur at room temperature, but in some cases either higher or lower temperatures are required. Primary and secondary alcohols and its silyl ether 2, 4, and 5 reacted with Fluolead at reflux or room temperature to give fluoroalkanes 3 and 6 in moderate to good yields. The yields could be improved by the addition of HF-pyridine (7:3 w/w) or Et3N(HF)3. Tertiary alcohol 7 reacted with Fluolead in the absence of additives to give a high yield of 8. Allyl alcohol 9 provided a 43:57 mixture of two isomeric fluorinations 10 and 11. The reaction with a high concentration of Fluolead reduced deoxofluorination of benzyl alcohol 12. Nevertheless, a high yield of 13 was obtained in the presence of Et3N(HF)3. p-Bromobenzyl alcohol 14 reacted with Fluolead without additives to give a fluorinated product in high yield. Secondary alcohols 16 and 18 gave a mixture of fluoride products, 17 and 19 with an HF-elimination product. Rearrangement product 21 was produced by treatment of 20 with Fluolead, in a phenomenon similar to DAST [40]. Fluorination of 22 and 24 with Fluolead proceeded in an inversion manner to produce 23 and 25 in high yield. The diastereoselectivity of α/β-fluoro products 27 by treatment of 26 with Fluolead is excellent and better than that by DAST [30] and Deoxo-Fluor [21].
Table 1

Fluorination of alcohols

 

Alcohol

Fluolead

(equiv)

Additive

(equiv)

Conditions

Product

Yield

(%)a

 

Open image in new window

1.5

in DCE, 85 °C, 4 h

Open image in new window

58b

 

Open image in new window

1.5

HF-py (0.6)

in DCM, 50 °C

Open image in new window

74

 

Open image in new window

1.3

Et3N(HF)3 (1)

in DCM, 0 °C, 0.5 h → r.t. 3 h

Open image in new window

64b

 

Open image in new window

1.5

in DCM, 0 °C, 0.5 h → r.t. 3 h

Open image in new window

90

 

Open image in new window

1.5

Et3N(HF)3 (1)

in DCM, 0 °C, 0.5 h → r.t. 4 h

Open image in new window (43)

Open image in new window (57)

82

 

Open image in new window

1.2

Et3N(HF)3 (1.3)

in DCM, 0 °C, 0.5 h → r.t. 3 h

Open image in new window

79b

 

Open image in new window

1.5

in DCM, 0 °C, 0.5 h → r.t. 3 h

Open image in new window

80

 

Open image in new window

1.5

in CDCl3, 0 °C, r.t. 2 h

Open image in new window

Open image in new window

45c

 

Open image in new window

1.5

in CDCl3, 0 °C, r.t. 2 h

Open image in new window

Open image in new window

59c

 

Open image in new window

1.5

in DCM, 0 °C, 0.5 h → r.t. 3 h

Open image in new window

45b

 

Open image in new window

1.5

in DCM, 0 °C, 1 h → r.t. 60 h

Open image in new window

85

 

Open image in new window

1.5

NaF (1)

in DCM, r.t. 65 h

Open image in new window

74b

 

Open image in new window

1.5

in DCM, r.t. 2 h

Open image in new window

84(99b)

aIsolated yields

bYield determined by 19F NMR

cYield determined by 1H NMR

4-Fluoropyrrolidine derivatives are useful building blocks in medicinal chemistry applications. (2S,4R)-4-hydroxyprolines react with Fluolead to give (2S,4S)-4-fluoropyrrolidine-2-carbonyl fluorides stereoselectively. In this reaction, OH moieties in both alcohol and carboxylate are converted into fluorides [34], Fig. 4. Trans-isomer 4-hydroxyprolines with four kinds of N-protected group substitutions 28, 30, 32, and 34 reacted with Fluolead smoothly in dichloromethane between 0 °C and room temperature to produce fluorination products in good yields. Although the deprotection of the acid-sensitive tert-butoxycarbonyl (Boc) group of 34 occurred under these reaction conditions, the yield of 35 was greatly improved in the presence of pyridine as a HF-trap agent. Fluorination of the cis-isomer 36 with Fluolead was initiated to produce trans-isomer 37 in 36% NMR yield.
Fig. 4

Fluorination of hydroxyproline

The conversion of a chiral benzyl alcohol into a benzyl fluoride using Fluolead is a SN2 process with inverted stereochemistry. The competing SN1 process in this reaction can be significantly suppressed by the addition of trimethylsilylamines (TMS-NR2). The Fluolead/TMS-NR2 complex is formed and serves as the reactive reagent in these transformations. The stereoselective deoxofluorination of (R)-1-phenylethanol 38 and methyl (R)-mandelate 39 were initiated by treatment with Fluolead in the presence of 3 equivalents of TMS-morpholine or TMS-pyrrolidine as an additive to produce fluoride products with high enentioselectivities, respectively, Fig. 5 [4].
Fig. 5

Fluorination of chiral benzyl alcohol with TMS-amine/Fluolead

(3R)-3-Fluoro-N-tosylpiperidine 41 was selectively synthesized from N-tosyl-l-prolinol 40 using Fluolead in the presence of an HF-pyridine additive with an isolated yield of 95%, Fig. 6 [18]. A ring expansion process of 4041 via route a is involved. On the other hand, the reaction using DAST or Deoxo-Fluor led to mixtures of fluorinated products containing pyrrolidine and piperidine derivatives [10, 12, 44].
Fig. 6

Reaction of l-prolinol with Fluolead

Reaction Mechanism of Benzyl Alcohol with Fluolead

The reaction of alcohol with Fluolead provided high-yielding fluoride products, without polymerization. The mechanism is shown in Fig. 7 [38]. High yields of fluorination product can be explained by the steric effect of the bulky tert-butyl group in Fluolead inhibiting the participation of the activated phenyl ring in the polymerization reaction, as shown in route b, in Fig. 7. In addition, the electron-donating effect of tert-butyl and two methyl groups should contribute to the formation of ionic intermediate II resulting in easy formation of the fluorination product, as shown in route a. The two methyl groups may interfere with the formation of IV, which may lead to an ether by-product, as shown in route c. The intermediate I or II is less likely reacted with benzyl alcohol to give an ether by-product (route d). Thus, both the tert-butyl and two methyl groups of Fluolead make significant contributions, sterically and electronically, to the high yields of fluorinated products.
Fig. 7

Reaction mechanism of benzyl alcohol with Fluolead

Fluorination of Aldehydes, Ketones, Keto Amides, Keto Esters, and Diketones

Various carbonyl compounds, including aliphatic and aromatic aldehydes, ketones, keto esters, and keto amides, are smoothly deoxo-fluorinated by Fluolead as shown in Fig. 8. A small amount of hydrogen fluoride is formed after the addition of ethanol to the reaction mixture, which is necessary for the successful deoxofluorination reaction with Fluolead. The substrates 43, 45, 47, 49, and 51 were converted into their respective fluorides 44, 46, 48, 50, and 52 with Fluolead in the presence of ethanol in high yields. Compared with the fluorination by DAST and Deoxo-Fluor [15], Fluolead performed superiorly specific deoxofluorination of 53, giving a 99:1 mixture of difluoro product 54 and mono-fluoro-olefin 55 in high yield. Non-enolizable ketones and diketones were fluorinated with Fluolead in the presence of HF-py, giving high yields of products 57, 59, 61, 63, and 65 (the conditions from 56 to 57 require some wthat different, i.e., 50 °C, in dichloroethane for 24 h). Nevertheless, the fluorination of non-enolizable ketones requires severe conditions using SF4, DAST, and Deoxo-Fluor [8, 17, 19].
Fig. 8

Fluorination of carbonyl compounds

Dolbier reported a pot method for the deoxofluorination of aldehydes and ketones 43, 66, 68, 70, 72, and 74 with Fluolead generated in situ from diaryl disulfide 1 with Br2 and KF in acetonitrile at room temperature. The yields were moderate to good, Fig. 9 [41].
Fig. 9

A pot method for the deoxofluorination of aldehyde and ketone

Fluorination of Carboxylic Acids

The fluorination reaction of carboxylic acids with Fluolead is shown in Table 2 [38]. The corresponding acid fluorides were produced in high yields by the treatment of carboxylic acids 76 and 78 with an equimolar amount of Fluolead. It should be noted that CF3 compounds 79b, 81, 83, 85, and 87 were produced instead in moderate to good yields by the reaction with an increasing equivalent of Fluolead in a sealed Teflon reactor at 100 °C without solvent. The deoxofluorination of 4-methoxycinnamic acid 88 required a 0.3 equimolar amount of Et3N (HF)3 to produce the CF3 compound 89 in 75% yield. Remarkably, dicarboxylic acids 90, 94, 96, and 98 were smoothly converted with Fluolead to bis-(CF3) compounds 91, 95, 97, and 99 in high yields.
Table 2

Fluorination of carboxylic acids

 

Carboxylic acid

Fluolead

(equiv)

Additive

(equiv)

Conditions

Product

Yield

(%)a

 

Open image in new window

1

in DCM, r.t. 0.5 h

Open image in new window

100b

 

PhCO2H 78

1

in DCM, r.t. 0.5 h

PhCOF 79a

100b

 

PhCO2H 78

3

100 °C, 3 h

PhCF3 79b

100b

 

Open image in new window

3

100 °C, 3 h

Open image in new window

75

 

Open image in new window

3

100 °C, 5 h

Open image in new window

88

 

Open image in new window

3

100 °C, 5 h

Open image in new window

82

 

Open image in new window

3

100 °C, 3.5 h

Open image in new window

80

 

Open image in new window

3.5

Et3N(HF)3 (0.3)

100 °C, 20 h

Open image in new window

75

 

Open image in new window

6

100 °C, 8 h

Open image in new window

95

 

Open image in new window

3

100 °C, 3.5 h

Open image in new window

42

 

Open image in new window

6

100 °C, 18 h

Open image in new window

87

 

Open image in new window

6

100 °C, 15 h

Open image in new window

92

 

Open image in new window

6

100 °C, 18 h

Open image in new window

90

aIsolated yields

bYield determined by 19F NMR

Fluorination of Thioacetals, Thioketones, Thioesters, and Thiocarbonates

Fluolead is also a useful reagent for the conversion of various thio derivatives to corresponding difluoromethylene and trifluoromethyl compounds [38], Fig. 10. Thio-substrates 100 and 101 were reacted with Fluolead in dichloromethane at room temperature to give difluoro compounds 44 and 63, respectively, in high yields. Fluorination of thioester 102 with Fluolead required severe conditions, including high temperature without any solvent, to provide difluoro compound 103 in 75% yield. Aromatic and aliphatic compounds 104, 106, 108, and 110 were easily converted to corresponding difluoromethene (CF2) and trifluoromethoxy (CF3O) compounds 105, 107, 109, and 111 in the presence of a catalytic amount of SbCl3 in good to high yields.
Fig. 10

Fluolead-mediated fluorination of thio derivatives

Deoxofluoro-arylsulfinylation of Diols

Selective monofluorination of diols using N,N-diethyl-α,α-difluoro(m-methylbenzyl)amine has been reported, under a high reaction temperature or microwave irradiation conditions [16, 36, 45]. Fluolead also allows the fluorination of diols to be performed with excellent selectivity, as shown in Fig. 11 [38]. Ethylene glycol 112 was treated with Fluolead at room temperature to produce fluoroethyl arylsulfinate 113 in good yield. TMS ether 114 was also converted to 115 by Fluolead in the presence of a catalytic amount of Bu4NF. The reaction of tri-, tetra-, and penta-methylenediols 116, 118, and 120 took place to give the corresponding products 117, 119, and 121 in moderate to good yields. Unsymmetrical diols 122 and 125 provided selective deoxofluorination, in which major products 123 and 126 resulted from fluorination substitution at secondary alcohol sites. The reaction with cis cyclic diol 130 and 131 gave corresponding trans products 127 and 129 with high stereoselectivity of two diastereomers on the basis of the conformation of the sulfoxide sulfur atom. The hydrolysis of products 131 and 133 with Zn in acetic acid gave trans-fluoro alcohols.
Fig. 11

Deoxofluoro-arylsulfinylation of diols

Deoxofluoro-arylsulfinylation of Amino Alcohols

N,N-Diethyl-α,α-difluoro-m-methylbenzylamine (DFMBA) reacts with amino alcohols without solvent at 70 °C or more or with microwave irradiation to give N-fluoroalkyl benzamides in high yields [27]. Fluolead also reacts with amino alcohols via a bi-functionalization reaction to provide N-fluoroalkyl arylsulfinamides as shown in Fig. 12 [38]. Various amino alcohols were treated with Fluolead via a two-step method, including the treatment with Fluolead and Et3N(HF)3 or HF-py, followed by the reaction with Et3N, to furnish N-arylsulfinyl fluoro products 135, 137, 139, and 141 in good to high yields, Fig. 12 [38].
Fig. 12

Deoxofluoro-arylsulfinylation of amino alcohols

Conclusion and Future Directions

This entry summarized the synthesis of Fluolead and its applications for deoxofluorination or dethioxofluorination reactions. A wide range of alcohols, aldehydes, ketones, keto amides, keto esters, diketones, carboxylic acids, thioacetals, thioketones, thioesters, thiocarbonates, diols, and amino alcohols are efficiently converted into fluoride compounds when treated with Fluolead. Fluolead possesses high thermal stability and resistance to aqueous hydrolysis and has the advantage of commercial availability at an industrial scale, unlike a well-explored reagent, DAST, which has poor thermal stability. Thus, fluorination reactions using Fluolead should be expanded in the future.

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© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of Nanopharmaceutical Sciences, Department of Life Science and Applied ChemistryNagoya Institute of TechnologyGokiso, Showa-kuJapan