Journal of Fluorine Chemistry 146 (2013) 66–69

Mono and difluorination of centers a to sulfonates and phosphonates using AcOF

Inna Vints, Julia Gatenyo, Shlomo Rozen *

School of Chemistry, Tel-Aviv University, Tel-Aviv 69978, Israel

A R T I C L E I N F O

Article history:

Received 21 September 2012

Received in revised form 1 January 2013

Accepted 2 January 2013

Available online 11 January 2013

Keywords:

F2

AcOF

Fluorosulfonate

Difluorosulfonate

Fluoroketophosphonate

Difluoroketophosphonate

A B S T R A C T

Acetyl hypofluorite, made easily from diluted fluorine and AcONa is very efficient in fluorinating anionic

centers. Compounds containing the moieties –CH2SO2– or –COCH2PO– react with bases to create the

corresponding anions which can react with AcOF to produce derivatives containing either the –CHFSO2–

or –COCHFPO– groups. Larger excess of base and AcOF result in the difluoro compounds containing the –

CF2SO2– or –COCF2PO– sub-structures. The fluorinations proceed fast and smoothly and usually with

very good yield even when the base is dissolved in aqueous solution as is the case with K2CO3 or NaHCO3.

� 2013 Elsevier B.V. All rights reserved.

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1. Introduction

There is a growing interest in developing new methodologiesfor the introduction of fluorine containing groups such as CF2 [1]and CF2H [2], into organic compounds due to their usefulness inmaterial science, pharmaceuticals, and agrochemical industries[3].

These compounds usually have unique physical, chemical, andbiological properties that are highly important in many fieldsincluding drug development since introducing fluorine atom into abioactive molecule can significantly enhance its chance to becomea drug candidate and eventually a drug [4,5].

The diflouoromethyl group can act, among other roles, as alipophilic isostere of the hydroxyl group as well as hydrogen donorfor hydrogen bonding [6]. This group has been also used in sugarchemistry as well [7], and plays an important role in the field ofherbicides [8], liquid crystals [9], and is essential part of modernanesthetics such as desflurane and isoflurane [10].

Monofluorinated compounds could be obtained either by directaction of fluorine on a substrate [11], or by numerous nucleophilicsubstitutions. Those analogs which happen to be biologically activeare very important class of drug candidates, and are considered tobe promising bioisosteres of the respective parent molecules[7,12]. An important sub-group consists of compounds havingfluorine atom a to some oxygen containing functional group such

* Corresponding author. Tel.: +972 3 6408378; fax: +972 3 6409293.

E-mail address: rozens@post.tau.ac.il (S. Rozen).

0022-1139/$ – see front matter � 2013 Elsevier B.V. All rights reserved.

http://dx.doi.org/10.1016/j.jfluchem.2013.01.003

as the family of a-fluoro carbonyls. Many materials of this typehave potentially interesting biological activities [13].

Mono- and di-fluoro(phenylsulfonyl)methane derivativescould be useful for the synthesis of functionalized mono anddifluoromethylated compounds, which could undergo varioustransformations such as Michael addition, nucleophilic fluoroalk-ylation of epoxides and more [14]. Another advantage of thesederivatives is the fact that the phenylsulfonyl moiety can be easilyremoved to produce fluoromethyl-substituted compounds [15].

Since many of the most important biochemicals are organopho-sphates, found in DNA and RNA as well as in many cofactors thatare essential to life, the organophosphorus chemistry has beenrapidly developing recently [16]. In particular, a-mono-haloge-nated and a,a-dihalogenated phosphonates have been designed asphosphate mimics used as metabolite probes, anticancer drugs,antidiabetes, and enzyme inhibitors due to their structural andelectronic similarities to the parent phosphate groups [17].Obviously a variety of successful inhibitors including a,a-difluoromethyl phosphonates have also been synthesized [18].

Successful attempts to prepare fluoro(phenylsulfonyl)methaneand a-fluoro-b-ketophosphonates compounds by using Select-fluor or other NF reagents have been described [14a,19]. Some ofthese fluorinating agents are commercially available and thereforequite popular for laboratory work. Nevertheless, they are preparedfrom elemental fluorine, are relatively weak electrophiles requir-ing usually non hydrated anionic centers, quite expensive andcarry a large amine residue, which eventually is wasted. Acetylhypofluorite – AcOF is also prepared by F2 [20], but uses muchcheaper and more readily available starting material – sodiumacetate. Its reactions are usually very fast, a few minutes at room

Table 1Fluorination of (phenylsulfonyl)methane derivatives with AcOF. Ph � SO2 � CH2 � X1 ��������������!

1: Base

2: AcOF; Fewmin; R:T:Ph � SO2 � CHF � X2 or Ph � SO2 � CF2 � X3 .

Entry X Base (eq.) Solvent AcOF (eq.) Product Yield (%)a

1a COPh K2CO3 (1) MeOH/H2O 1 2a 90

1a COPh K2CO3 (4) MeOH/H2O 3 3a 70

1a COPh t-BuOK (3) t-BuOH 3 3a 100

1b COMe K2CO3 (1) MeOH/H2O 1 2b 90

1b COMe K2CO3 (4) MeOH/H2O 3 3b 90

1c NO2 NaHCO3 (0.5) MeOH/H2O 1 2c 70

1c NO2 K2CO3 (1) MeOH/H2O 3 3c 100

1d CN t-BuOK (0.5) t-BuOH 3 2d 85

1d CN K2CO3 (5) MeOH/H2O 3 3d 75

1e SO2Ph K2CO3 (1.5) MeOH/H2O 3 2e 70

1e SO2Ph t-BuOK (0.7) t-BuOH 3 2e 80

1e SO2Ph t-BuOK (7) t-BuOH 3 3e 90

a Isolated yields.

I. Vints et al. / Journal of Fluorine Chemistry 146 (2013) 66–69 67

temperature, and usually the yields are very good. These are someof the reasons why at the time AcOF was the reagent which gavethe positron emitting tomography (PET) a new life by enablingefficient synthesis of the [18]F fluorodeoxyglucose (18FDG) and isstill used for introducing the [18]F nuclide into organic moleculeswhen no alternative to electrophilic fluorination is available [21].In the past we have used acetyl hypofluorite for quite afew processes such as aromatic fluorinations [22], reactionswith enolates resulting in a-fluoro carbonyl derivatives [23],and activation of the a position of pyridine derivatives [24].We present here a general method for introducing one ortwo fluorine atoms a – to a sulfonate or a phosphonate moietyby using AcOF.

2. Results and discussion

A series of a-mono- and a,a-difluoro-sulfones, and a-mono-,and a,a-difluoro-b-ketophosphonates, were synthesized in goodyields via electrophilic fluorination using AcOF. Unlike most otherelectrophilic processes the present reaction offers the option ofusing aqueous solutions whenever appropriate without affectingthe final outcome.

Thus, an aqueous methanol solution of 1-phenyl-2-(phenyl-sulfonyl)ethanone (1a) containing 0.7 mol eq. K2CO3 was treatedwith 1 mol eq. of AcOF to give 2-fluoro-1-phenyl-2-(phenylsul-fonyl)ethanone (2a) [25] in 90% yield. To obtain the difluoroderivative the concentration of the basic aqueous solution wasincreased to 4 mol eq. and an excess of AcOF was used. The 2,2-difluoro-1-phenyl-2-(phenylsulfonyl)ethanone (3a) [25] wasformed in 70% yield. If the yield of 3a is important the aqueousconditions have to be abandoned and t-BuOK in t-BuOH has tobe used. Such change brings the yield of 3a to practically 100%.

Similarly, when phenylsulfonylacetone (1b) was treated with1 mol eq. of K2CO3 followed by 1 mol eq. of AcOF, 1-fluoro-1-(phenylsulfonyl)propan-2-one (2b) [14a] was generated in 90%yield. Using 4-fold excess of K2CO3 led to the difluorinated product– 1,1-difluoro-1-(phenylsulfonyl)propane-2-one (3b) [25] in 90%yield.

Since protons alpha to nitro compounds have higher aciditythan those neighboring the carbonyl moiety, using weaker base

Table 2Fluorination of b-ketophosphonates with AcOF. R � CO � CH2 � PO ðXÞ24 ��������������

1: Base

2: AcOF; Few min;

Entry R X Base (eq.)

4a Ph OEt t-BuOK (0.5)

4a Ph OEt t-BuOK (3)

4b Me OMe t-BuOK (3)

a Isolated yields.

such as NaHCO3 is sufficient. Thus, treating nitromethyl phenylsulfone (1c) with 0.5 mol eq. of NaHCO3 followed by 1 mol eq. ofAcOF led to the formation of (fluoro(nitro)methylsulfonyl)benzene(2c)[14a] in 70% yield. It was enough to use 1 mol eq. of thestronger base K2CO3 followed by 3 mol eq. of AcOF to formquantitatively the difluorinated product – (difluoro(nitro)methyl-sulfonyl)benzene (3c).

Acidity of (phenylsulfonyl)acetonitrile (1d) is similar to 1a andis lower than 1c. The best results in this case were obtained whenusing 0.5 mol eq. of t-BuOK and 3 mol eq. of AcOF to form 2-fluoro-2-(phenylsulfonyl)ethane nitrile (2d) [14a] in 85% yield. By adding5 mol eq. of K2CO3 and 3 mol eq. of AcOF the difluorinated 2,2-difluoro-2-(phenylsulfonyl)ethane nitrile (3d) was obtained in 75%yield.

Successful mono fluorination was also achieved withbis(phenylsulfonyl)methane (1e) by using 1.5 mol eq. ofK2CO3 followed by 3 mol eq. of AcOF. The product formed in70% yield was identified as 1-fluoro-1,1-bis(phenylsulfonyl)-methane (2e) [25]. The yield could be increased to 80% whent-BuOK was used as the base. When large excess of t-BuOK(7 mol eq.) was employed the difluorinated product 1,1-difluoro-1,1-bis(phenylsulfonyl)methane (3e) [26] was obtainedin 90% yield. The results and conditions are summarized inTable 1.

With b-ketophosphonates, K2CO3 was not strong enough baseto deprotonate the substrate so we had to replace it with t-BuOK togenerate the desired products. Thus, when diethyl 2-oxo-2-phenylethylphosphonate (4a) was treated with 0.5 mol eq. of t-BuOK and 1 mol eq. of AcOF, 5a [19] was produced in 65% yield.Reacting 4a and dimethyl 2-oxopropylphosphonate (4b) with3 mol eq. of t-BuOK followed by excess of AcOF produced thedifluorinated products 6a [19] and 6b [27] in quantitative yields(Table 2).

In conclusion, it has been shown that among its many versatilereactions AcOF can be also useful as a fluorinating agent not only ato carbonyls, but also a to other electron withdrawing groups.Whenever an anion can be formed, even in aqueous solutions, thereaction proceeds well and usually with very good yields. Since thereactions with the acetyl hypofluorite are very fast the reaction isalso very suitable for PET studies.

! R:T:

R � CO � CHF � PO ðXÞ25 or R � CO � CF2 � PO ðXÞ26 .

Solvent AcOF (eq.) Product Yield (%)a

t-BuOH 1 5a 65

t-BuOH 3.5 6a 100

t-BuOH 3 6b 100

I. Vints et al. / Journal of Fluorine Chemistry 146 (2013) 66–6968

3. Experimental

1H NMR spectra were recorded using a 400 MHz spectrometerwith CDCl3 as a solvent and Me4Si as an internal standard. The 19FNMR spectra were measured at 188.1 and 376.8 MHz with CFCl3,serving as an internal standard. The proton broadband decoupled13C NMR spectra were recorded at either 50.2 MHz or at100.5 MHz. Here too, CDCl3 served as a solvent and Me4Si as aninternal standard. Known compounds described in this paper, havethe same spectral properties and mps (for the solids) as the onesreported in the literature.

3.1. General fluorination procedure

Fluorine is a strong oxidant and corrosive material. In organicchemistry, it is mostly used after dilution with nitrogen or helium.Such dilution can be achieved by using either an appropriatecopper or monel vacuum line constructed in a well-ventilated areaor simply purchasing prediluted fluorine. A detailed description ofa simple setup had appeared in the past [28]. The reactionsthemselves can be carried out in regular glassware. If elementaryprecautions are taken, work with F2 is simple and we have had nobad experience working with it.

3.2. Preparation of AcOF and its reaction with b-ketophosphonates

and (phenylsulfonyl)methane derivatives

A mixture of 10–15% F2 in N2 was bubbled into a cold (�30 8C)suspension of 2 g of AcONa�AcOH dispersed in 100 mL of CH3CNand 10 mL of AcOH all placed in a standard glass vessel. Thesolvated salt could be made by leaving anhydrous AcONa overAcOH in a closed desiccator for at least 24 h. It is quite important tohave a good stirring since the reaction is between the gas phase anda solid one. The amount of the AcOF thus obtained could be easilydetermined by reacting aliquots of the reaction mixture withaqueous KI solution and titrating the liberated iodine. Typicalconcentration are around 0.25 M.

The substrates were first treated with a base at roomtemperature, and after 0.5 h AcOF was added in one portion.When deprotonation could be achieved with K2CO3 or NaHCO3

water/methanol mixture was used as a solvent. When conditionswere modified to accommodate t-BuOK for a base, the solvent ofchoice was t-butanol. The reactions were carried out on scales of 1–10 mmol using 1–3 fold excess of AcOF. They were usuallymonitored by TLC or NMR and in most cases were completedwithin a few minutes. The reaction was terminated by pouring itinto NaHCO3 solution followed by water until neutral. In the case ofmono fluorination just water was added, drying the organic layerover MgSO4 and evaporation of the solvent. The crude product waspurified by vacuum flash chromatography (Merck silica gel 60H)with petroleum ether/dichloromethane serving as eluent. Most ofthe products are known and referenced. Their physical propertiesmatched the ones appearing in the literature. All new compoundswere fully characterized.

2-Fluoro-1-phenyl-2-(phenylsulfonyl)ethanone (2a) [25]was prepared from 2-(phenylsulfonyl)acetophenone (1a) (0.53 g,2.0 mmol) as described above, using 1 mol eq. of K2CO3 and1 mol eq. of AcOF solution. A white solid, mp 95 8C, (0.50 g, 90%yield) was obtained.

2,2-Difluoro-1-phenyl-2-(phenylsulfonyl)ethanone (3a) [25]was prepared from 2-(phenylsulfonyl)acetophenone (1a) (0.56 g,2.2 mmol) as described above, using 3 mol eq. of t-BuOK and 3 eq.of the AcOF solution. A white solid, mp 80 8C, (0.64 g, 100% yield)was obtained.

1-Fluoro-1-(phenylsulfonyl)propan-2-one (2b) [14a] wasprepared from phenylsulfonylacetone (1b) (0.43 g, 2.2 mmol) as

described above, using 1 mol eq. of K2CO3 and 1 eq. of the AcOFsolution. A colorless liquid (0.43 g, 90% yield) was obtained.

1,1-Difluoro-1-(phenylsulfonyl)propan-2-one (3b) [25] wasprepared from phenylsulfonylacetone (1b) (0.20 g, 1.0 mmol) asdescribed above, using 4 mol eq. of K2CO3 and 3 mol eq. of theAcOF solution. A colorless liquid (0.21 g, 90% yield) was obtained.

(Fluoro(nitro)methylsulfonyl)benzene (2c) [14] was preparedfrom nitro methyl phenyl sulfone (1c) (0.10 g, 0.47 mmol) asdescribed above, using 0.5 mol eq. of NaHCO3 and 1 mol eq. of theAcOF solution. A colorless liquid (0.07 g, 70% yield) was obtained.

(Difluoro(nitro)methylsulfonyl)benzene (3c) was preparedfrom nitro methyl phenyl sulfone (1c) (0.63 g, 3.13 mmol) asdescribed above, using 1 mol eq. of K2CO3 and 3 mol eq. of theAcOF solution. A colorless liquid (0.74 g, 100% yield) was obtained:1H NMR: d 7.71–7.75 (2H, m), 7.90–7.94 (1H, m), 8.03–8.05 (2H,m). 13C NMR: d 137.6, 131.3, 130.4, 130.3, 118.8 (t, JC–F = 332.5 Hz).19F NMR: d �92.0 (s). Anal. calculated for C7H5F2NO4S: C, 35.45; H,2.12; F, 16.02. Found: C, 35.55; H, 1.93; F, 15.56.

2-Fluoro-2-(phenylsulfonyl)ethane nitrile (2d) [14] wasprepared from (phenylsulfonyl)acetonitrile (1d) (0.56 g,3.08 mmol) as described above, using 0.5 mol eq. of t-BuOK and3 mol eq. of the AcOF solution. A colorless liquid (0.52 g, 85% yield)was obtained.

2,2-Difluoro-2-(phenylsulfonyl)ethane nitrile (3d) was pre-pared from (phenylsulfonyl)acetonitrile (1d) (0.76 g, 4.22 mmol)as described above, using 5 mol eq. of K2CO3 and 3 mol eq. of theAcOF solution. A colorless liquid (0.69 g, 75% yield) was obtained:1H NMR: d 7.73 (2H, t, J = 8.0 Hz), 7.91 (1H, t, J = 7.5 Hz), 8.06 (2H, d,J = 8.0 Hz). 13C NMR: d 137.5, 131.6, 130.3, 129.8, 108.6 (t, JC–

F = 287.4 Hz). 19F NMR: d �98.1 (s). Anal. calculated forC8H5F2NO2S: C, 44.24; H, 2.32; S, 14.76; N, 6.45; F, 17.49. Found:C, 43.87; H, 2.24; S, 14.11; N, 6.17; F, 17.61.

1-Fluoro-1,1-bis(phenylsulfonyl)methane (2e) [25] was pre-pared from bis(phenylsulfonyl)methane (1e) (0.36 g, 1.2 mmol) asdescribed above, using 0.7 mol eq. of t-BuOK and 3 eq. of the AcOFsolution. A white solid, mp 109 8C, (0.31 g, 80% yield) was obtained.

Difluorobis(phenylsulfonyl)methane (3e) [26] was preparedfrom bis(phenylsulfonyl)methane (1e) (0.27 g, 0.93 mmol) as de-scribed above, using 7 mol eq. of t-BuOK and 3 mol eq. of the AcOFsolution. A white solid, mp 119 8C, (0.28 g, 90% yield) was obtained.

Diethyl 1-fluoro-2-oxo-2-phenylethylphosphonate (5a) [19]was prepared from diethyl 2-oxo-2-phenylethylphosphonate (4a)(0.45 g, 1.8 mmol) as described above, using 0.5 mol eq. of t-BuOKand 1 mol eq. of the AcOF solution. A colorless liquid (0.32 g, 65%yield) was obtained.

Diethyl 1,1-difluoro-2-oxo-2-phenylethylphosphonate (6a)[19] was prepared from diethyl 2-oxo-2-phenylethylphosphonate(4a) (0.36 g, 1.4 mmol) as described above, using 3.5 mol eq. of t-BuOK and 3 mol eq. of the AcOF solution. A colorless liquid (0.41 g,100% yield) was obtained.

Dimethyl 1,1-difluoro-2-oxopropylphosphonate (6b) [27]was prepared from dimethyl 2-oxopropylphosphonate (4b)(1.14 g, 6.9 mmol) as described above, using 3 mol eq. of t-BuOKand 3 mol eq. of the AcOF solution. A colorless liquid (1.39 g, 100%yield) was obtained.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.jfluchem.2013.01.003.

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