Expedient Synthesis of α-Substituted Fluoroethenes

Abstract

A mild and efficient synthesis of 1-aryl-1-fluoroethenes from benzothiazolyl (aryl)fluoromethyl sulfones and paraformaldehyde, under DBU- or Cs₂CO₃-mediated conditions at room temperature, is described. A comparable diethyl fluoro(naphthalen-2-yl)methylphosphonate reagent does not react with paraformaldehyde under these mild conditions. The utility of the methodology for terminal α-fluoroalkene synthesis bearing electron-withdrawing functionalities is also shown.

The unique influence fluorine atom exerts on the properties of organic molecules¹ is reflected in wide interest in fluorinated compounds, ranging from agrochemicals, pharmaceuticals, to drug discovery purposes, and materials.^2-4 Regiospecific introduction of fluorine into organic molecules therefore continues to be of significance.⁵ In this context, terminal 1-aryl-1-fluoroethenes are synthetically useful building blocks,⁶ and recently potent antibacterial activity of an arene containing a terminal α-fluorovinyl group has been shown as well.⁷ Current synthetic approaches for the preparation⁸ of 1-aryl-1-fluoroethenes involve a halofluorination-elimination sequence on styrenes,⁹ elimination from fluorohydrin tosylates,^9b fluoroselenenylation-elimination,¹⁰ cross-coupling methods,¹¹ and hydrofluorination-elimination reaction of phenylacetylene.¹²

We¹³ and others¹⁴ have been involved with development of the Julia-Kocienski olefination¹⁵ for the synthesis of variously functionalized fluoro alkenes.¹⁶ However, to the best of our knowledge, there are no reports on the use of this approach for the synthesis of 1-aryl-1-fluoroethenes. In order to evaluate its use for the synthesis of 1-aryl-1-fluoroethenes, appropriate 1,3-benzothiazol-2-yl (BT) reagents were synthesized following our protocol of heterogeneous metalation-electrophilic fluorination.^13a These were subjected to olefinations with paraformaldehyde (Table 1). Condensations of paraformaldehyde with Horner-Wadsworth-Emmons (HWE) reagents containing reactive methylene groups have been reported either with strong base^17-19 or under mild conditions.^14e We have previously shown fluorinated BT-sulfones to be more reactive than their HWE counterparts.^13b,c Thus, we wanted to assess whether olefinations of fluorinated BT-sulfones not containing a highly activated methylene group would proceed under mild conditions. Mild conditions would be important in the case of relatively complex and/or labile aryl derivatives.

Table 1.

Screening of reaction conditions^a

Entry	Base (molar equiv)	Solvent	Yield (%)
1	NEt3 (10)	CH2Cl2	NRb
2	K2CO3 (10)	Acetone	NRb
3	K2CO3 (10)	THF-H2O	23c
4	Cs2CO3 (10)	CH2Cl2	57d
5	Cs2CO3 (2)	CH2Cl2	49d
6	TMGe (10)	CH2Cl2	25d
7	DBUe (10)	CH2Cl2	67d
8	DBU (3)	CH2Cl2	62d
9	DBU (10)	THF	68d
10	Cs2CO3 (10)	THF	67d
11	Cs2CO3 (2)	THF	71d

^aFor synthesis of 2a, 1a, and the sulfide precursor, see the Supporting Information.

^bNo reaction.

^cNot isolated, conversion determined by ¹⁹F NMR.

^dIsolated yield.

^eTMG: 1,1,3,3-tetramethylguanidine; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.

Olefination conditions using mild bases were screened in reactions of fluoro(1-naphthyl)methyl BT-sulfone (2a, Table 1) and paraformaldehyde (10 molar equiv) at room temperature. When either NEt₃ or K₃CO₃ were used as base, no reaction (entries 1, 2) or low conversion was observed (entry 3). On the other hand, (1-naphthyl)fluoroethene 3a (Table 1) was isolated in 57% yield with Cs₂CO₃, but the yield decreased to 49% when a lower excess of the base was used (entries 4, 5). When TMG was used as base, no starting sulfone was observed after an overnight reaction, but 3a was isolated in only 25% yield (entry 6). Good yield of product 3a was obtained in DBU-mediated condensation in CH₂Cl₂ (entry 7), and the yield was slightly lowered with a lower excess of DBU (entry 8). Changing the solvent to THF gave a comparable yield in DBU-mediated reaction (compare entries 7 and 9). Use of Cs₂CO₃ (10 molar equiv, entry 10) in THF gave 3a in 67% yield, which was comparable to the 71% yield when a lower excess of Cs₂CO₃ (2 molar equiv, entry 11) was used.

To assess the generality of condensations, a series of BT-sulfides was prepared either from benzyl bromides or from alcohols via the Mitsunobu reaction. Oxidation of the sulfides gave sulfones 1b–1h. For experimental procedures and NMR data of sulfides and sulfones, please see the Supporting Information. Metalation-fluorination of 1b–1h yielded fluoro BT-sulfones 2b–2h (isolated yields of 76%–90%). Sulfones 2b–2h were reacted with paraformaldehyde using Method A (DBU, CH₂Cl₂) and/or Method B (2 molar equiv of Cs₂CO₃, for economic considerations) and the results are shown in Table 2. In the cases tested, comparable results were obtained with either 3 or 10 molar equiv of DBU, except for sulfone 2f, where the use of 3 molar equiv gave a much better yield (entry 12).

Table 2.

1-Aryl-1-fluoroethenes synthesized^a

Entry	Product: Ar =	Methodb (Solvent)	Yieldc (%)
1		A (CH2Cl2)	71
2		B (CH2Cl2)	86
3		A (CH2Cl2)	57, 51d
4		B (CH2Cl2)	61
5		B (THF)	54
6		A (CH2Cl2)	92, 95d
7		B (CH2Cl2)	81
8		B (THF)	90
9		A (CH2Cl2)	76d
10		B (CH2Cl2)	78
11		B (THF)	71
12		A (CH2Cl2)	69, 92d
13		B (CH2Cl2)	74
14		B (THF)	91
15		B (CH2Cl2)	53
16		B (THF)	63
17		A (CH2Cl2)	99
18		B (CH2Cl2)	92
19		B (THF)	83

^aSulfone 2b–h: 1 molar equiv; paraformaldehyde: 10 molar equiv.

^bMethod A: DBU (10 molar equiv); Method B: Cs₂CO₃ (2 molar equiv).

^cYield of isolated, purified products.

^d3 Molar equiv of DBU were used.

To evaluate the influence of the heteroaryl moiety on reactivity, (phenyl)methyl 1-phenyl-1H-tetrazol-5-yl (PT) sulfone (PT analog of BT-sulfone 1b) was subjected to metalation-electrophilic fluorination under our heterogeneous conditions.^13a In an unoptimized experiment, only 30% of the desired fluoro(phenyl)methyl 1-phenyl-1H-tetrazol-5-yl sulfone (PT analog of BT-sulfone 2b) was isolated, and the remaining material was the starting unfluorinated PT-sulfone. Reaction of the fluorinated PT-sulfone with paraformaldehyde (DBU, CH₂Cl₂) proceeded to completion and 3b was formed in the reaction, but due to the low fluorination yield, no further attempts were made to optimize and pursue this.

Next, the reactivity of paraformaldehyde was compared to that of aqueous formaldehyde (37 wt%). Reaction of fluoro(1-naphthyl)methyl BT-sulfone 2a with this formaldehyde solution (10 molar equiv of CH₂O) was performed in THF, with either Cs₂CO₃ (2 molar equiv), or with DBU (10 molar equiv). Only starting sulfone 2a and no product was observed in the Cs₂CO₃ mediated condensation after 24 h at room temperature. In the DBU-mediated reaction, 2a disappeared but only small amount of 3a was formed (8% isolated yield of a slighly impure product after a 24 h reaction).

In order to compare the reactivity of (aryl)fluoromethyl sulfones 2 to Horner-Wadsworth-Emmons (HWE) reagents, the HWE analog of Julia reagent 2f was synthesized. The unknown HWE reagent 4 was obtained by fluorination of the known diethyl (naphthalen-2-yl)methylphosphonate²⁰ (see the Supporting Information) and reacted with paraformaldehyde under various conditions (Scheme 1). No reaction was observed in 24 h under DBU/THF, DBU/CH₂Cl₂, or Cs₂CO₃/CH₂Cl₂ conditions. This shows a higher reactivity of the Julia reagent, as compared to the HWE analog, likely due to the differences in the pK_a values of the proton being abstracted.

Scheme 1.

Reactivity of the Horner-Wadsworth-Emmons analog under mild conditions

We were curious to evaluate whether reaction of unfluorinated (aryl)methyl BT-sulfone would also proceed under mild conditions. An overnight room-temperature reaction of 1a (1 molar equiv) with paraformaldehyde (10 molar equiv) in CH₂Cl₂ using Cs₂CO₃ (2 molar equiv) gave 1-vinylnaphthalene in 58% isolated yield. This preliminary result indicates that this approach could be useful for mild synthesis of unfluorinated styrene-like compounds as well.

We next wanted to assess whether benzothiazolyl fluoromethyl sulfones, activated with an additional electron-withdrawing substituent, could also be reacted with paraformaldehyde under these mild conditions. As described earlier, a single condensation reaction of paraformaldehyde and an activated HWE-analog (a fluorinated arylsulfonylmethanephosphonate) under mild conditions, has been reported.^14e Therefore, fluoromethyl BT-sulfones with electron withdrawing groups (EWG) were synthesized (5a–e, for synthesis and spectral data please see the Supporting Information). Olefinations of 5a–e (Table 3) gave typically good yields with Cs₂CO₃ in CH₂Cl₂ (compare entries 1 and 2, as well as 4 and 5). A comparative reaction of HWE reagent PhSO₂CH(F)P(O)(OEt)₂, on the other hand, gave a better yield with DBU in CH₂Cl₂ (compare entries 8, 9).

Table 3.

Synthesis of EWG-substituted α-fluoroolefins^a

Entry	Product: EWG =	Methodb (Solvent)	Yieldc (%)
1		B (CH2Cl2)	75
2		B (THF)	39d
3		B (CH2Cl2)	64
4		A (CH2Cl2)	54
5		B (CH2Cl2)	66
6		B (CH2Cl2)	68
7		B (CH2Cl2)	89
8e		A (CH2Cl2)	89
9e		B (CH2Cl2)	76

^aSulfone 5a-e: 1 molar equiv; paraformaldehyde: 10 molar equiv.

^bMethod A: DBU (3 molar equiv); Method B: Cs₂CO₃ (2 molar equiv).

^cYield of isolated, purified product.

^dOther unidentified products were formed.

^eReaction was performed with Horner-Wadsworth-Emmons reagent Ph-SO₂-CH(F)-P(O)(OEt)₂.

The initially synthesized 1-aryl-1-fluoroethenes can be converted to more elaborate compounds. To demonstrate this, preliminary conversions of 3c via Suzuki-coupling reactions were investigated. Suzuki reactions of stilbene-like β-aryl-α-fluoro-α-(2-bromophenyl)ethenes have recently been reported, and isomerization of alkene geometry under Suzuki coupling conditions can occur.^14h In our work, 4-methoxy and 4-acetylphenylboronic acids were reacted with α-fluoro-α-(2-bromophenyl)ethene 3c using Pd₂(dba)₃/2’-(dicyclohexylphosphino)-2-N,N-dimethylaminobiphenyl (L)/CsF in 1,4-dioxane (Scheme 2). Not unexpectedly, the electron-rich 4-methoxyphenylboronic acid gave a high 82% yield of the biphenyl product 7, whereas the electron-deficient 4-acetylphenylboronic acid gave 8 in a lower but reasonable 59% yield. These results clearly indicate that these α-fluorostyrenes can be used in further transformations without significant difficulties.

Scheme 2.

Suzuki conversions of α-fluorovinyl derivative 3c

In summary, 1-aryl-1-fluoroethenes can be synthesized under mild, Cs₂CO₃- or DBU-mediated conditions from benzothiazolyl (aryl)fluoromethyl sulfones and paraformaldehyde, at room temperature. By comparison, diethyl fluoro(naphthalen-2-yl)methylphosphonate does not undergo condensation with paraformaldehyde under these mild conditions. Further conversion of α-fluoro-α-(2-bromophenyl)vinyl product was demonstrated in a Suzuki coupling. This simple methodology is also effective for the preparation of terminal fluoroalkenes bearing electron withdrawing substituents, demonstrating its broad generality.