Regio- and Stereocontrolled Nucleophilic Trifluoromethylthiolation of Morita–Baylis–Hillman Carbonates

Abstract

Reactions of Morita–Baylis–Hillman carbonates with metal-free sources of trifluoromethylthio anion have been studied. The combination of CF₃SiMe₃/S₈/KF/DMF gave the primary allylic SCF₃ products through apparent S_N2′ reaction whereas the use of Zard’s reagent, CF₃SCO₂C₁₈H₃₇, allowed us to intercept the fleeting secondary allylic SCF₃ product.

Key words

fluorine - sulphur - Morita–Baylis–Hillman adduct - substitution - stereocontrol

Organofluorine chemistry has become, more than ever, an area of tremendous expansion. It is not only because fluorinated compounds play a key role in pharmaceutical, agrochemical, and material sciences, but also because fluorine is a fascinating atom revealing subtle effects.[1] Fluorine has sparked the imagination of chemists for the synthesis of a plethora of novel architectures featuring fluo­rine atom(s). Among the fluorinated motifs in vogue, the trifluoromethylthio group occupies a place of choice owing to its exceptional lipophilicity that it confers to molecules (Hansch hydrophobic parameter: π = 1.44 versus 0.88 for CF₃ and 1.04 for OCF₃)[2] and its high electron-withdrawing character (Hammett substituent constants: σ_m = 0.40, σ_p = 0.50 versus 0.43, 0.54, respectively for the CF₃ group).[3] Indeed, the SCF₃ group is very appealing for the conception of new drugs with enhanced capacity to pass cell membranes.[4] Several synthetic routes to SCF₃-bearing compounds have been elaborated including the direct introduction of the SCF₃ group, the trifluoromethylation of sulfur compounds, and various functional group interconversions.[5] Many of the direct approaches involved C(sp ²)–S bond-forming reactions because aryl– and heteroaryl–SCF₃ compounds are predominant in biologically active compounds bearing a SCF₃ group such as Toltrazuril,[6a] Tiflorex,[6b] and Vaniliprole[7] (Figure [1]). Much less evaluated were the compounds featuring the C(sp ³)–SCF₃ sequence, as encountered in Cefazaflur[8] (Figure [1]). The reason for this relative lack of C(sp ³)–SCF₃ compounds is due to the paucity of synthetic methods despite the growing interest for SCF₃ chemistry.

Figure 1 Examples of SCF₃ bioactive compounds

Recently, several laboratories reported on electrophilic trifluoromethylthiolation at sp ³ carbons thanks to the availability of easy-to-handle reagents,[9] including asymmetric reactions.[10] Regarding the nucleophilic trifluoromethylthiolation, reactions of alkyl, benzyl, allyl, and propargyl halides with trifluoromethylthio metal compounds (Hg, Ag, Cu, Cs)[11] [12a] or organic SCF₃ salts [NMe₄, S(NMe₂)₃, TDAE][12] were reported. In addition, the displacement of bromide in α-bromoketones was described.[13] [14] Transformation of alcohols into trifluoromethyl sulfides through phosphitylation and reaction with bis(trifluoromethyl) disulfide was also reported.[15] Various α-diazo compounds reacted with AgSCF₃ in copper-mediated trifluoromethylthiolations to form C(sp ³)–SCF₃ bonds.[16] For a cheap and storable crystalline source of SCF₃ anion, Li and Zard reported the synthesis of O-octadecyl-S-trifluorothiolcarbonate, CF₃SCO₂C₁₈H₃₇, and reactions with gramines and α-bromoketones and -ester in the presence of KF and pyrrolidine.[14] Except these nucleophilic substitutions, there is no report of other types of substitution reactions. In order to complement the toolbox for the construction of new SCF₃ derivatives, we herein describe the regio- and stereocontrolled direct introduction of the nucleophilic SCF₃ group onto Morita–Baylis–Hillman (MBH) carbonates.

Among the sources of SCF₃ anion, we firstly selected the tetramethylammonium trifluoromethylthiolate [NMe₄]⁺[SCF₃]^–, a metal-free reagent prepared from Me₄NF, S₈, and Ruppert–Prakash reagent (CF₃SiMe₃).[12a] Treatment of the MBH adduct 1a with [NMe₄]⁺[SCF₃]^– in the presence of 10 mol% of DABCO in a mixture THF–MeCN (2:5) gave only a trace amount of a new SCF₃ compound as evidenced by its ¹⁹F NMR spectrum (δ = –42.3 ppm). Instead, the monofluorinated secondary allylic ­fluoride 2 was formed as the major product (δ = –171.0 ppm) (Scheme [1]).

Scheme 1

Attempts to favor the SCF₃ compound were unsuccessful: these included the evaluation of MBH carbonate 1a in various solvents, the use of additives such as CuI or KF, as well as the handling of silver trifluoromethylthiolate, AgSCF₃. Although monofluorinated compound 2 was not the expected target, it is nevertheless interesting because 2 is otherwise difficult to prepare. Indeed, MBH adducts reacted with DAST (diethylaminosulfur trifluoride) to give a mixture of primary and secondary allylic fluorides.[17] In our case, only the secondary allylic fluoride 2 was obtained; however, this method to install a single ­fluorine atom, which makes use of [NMe₄]⁺[SCF₃]^–, is far from atom-economical. The decomposition of [NMe₄]⁺[SCF₃]^– into thiocarbonyl fluoride (F₂CS) and fluoride was a major obstacle in our quest for SCF₃ compounds.[18]

In order to solve this problem, we next investigated another metal-free approach to generate the SCF₃ anion by means of the combination of CF₃SiMe₃/S₈/KF/DMF by analogy to the oxidative trifluoromethylthiolation of terminal alkynes described by Qing and co-workers.[19] We anticipated the two possible SCF₃ products depicted in Scheme [2]. The primary allylic SCF₃ product 3 having the alkene double bond conjugated with the aromatic ring is the result of an apparent S_N2′ reaction whereas the secondary allylic SCF₃ product 4 retains the terminal alkene motif in an overall process that may be viewed as a simple S_N reaction.

Scheme 2

The addition of Me₃SiCF₃ to a DMF solution of sulfur and KF followed by the successive addition of the MBH carbonate and DABCO, gave after 22 hours the primary allylic SCF₃ product 3 as the main product without detection of 4. It is worth noting that 3 (¹⁹F NMR: δ = –42.3 ppm) was the product obtained in trace amounts in the reaction with [NMe₄]⁺[SCF₃]^–. The order of addition of the reagents as well as the quantity of KF (10 equiv) were revealed to be important in reaching high yields of 3. Further optimization of the reaction conditions was performed with MBH carbonate 1i for easy monitoring by ¹⁹F NMR. We were pleased to obtain the SCF₃ product 3i in DMF at 20 °C in the presence of 10 mol% of DABCO in 84% isolated yield (Table [1], entry 1) and even in 94% yield in a more concentrated medium. The assignment of configuration was done by NOESY NMR experiment. Interestingly, 3i was obtained as a single Z-isomer with a trans arrangement of the Ar function and the methyl ester. Other solvents were tested (Table [1], entries 3–6), leading either to no product formation in CH₂Cl₂, toluene, and acetonitrile or to a poor yield in THF. We also evaluated DBU, DMAP and PCy₃ as alternative Lewis bases, but lower yields were obtained compared to those obtained with the use of DABCO (Table [1], entries 1 and 7–9). Moreover, without Lewis base, 3i was obtained in 69% yield (Table [1], entry 10), indicating that the active SCF₃ anion could directly add to the MBH carbonate through a S_N2′ addition–elimination mechanism. Running the reaction at higher temperature (50 °C) did not contribute to enhance the yield of the reaction (Table [1], entry 11). The use of Me₄NF as fluoride source instead of KF was detrimental to the reaction (Table [1], entry 12).

Table 1 Screening of Reaction Parameters^a

Entry	Solvent	Fluoride source	Lewis base	Temp (°C)	Yield (%)
1	DMF	KF	DABCO	20	84 (94)b
2	DMF	KFc	DABCO	20	58
3	CH2Cl2	KF	DABCO	20	0
4	toluene	KF	DABCO	20	0
5	THF	KF	DABCO	20	5
6	MeCN	KF	DABCO	20	0
7	DMF	KF	DBU	20	46
8	DMF	KF	DMAP	20	36
9	DMF	KF	PCy3	20	75
10	DMF	KF	–	20	69
11	DMF	KF	DABCO	50	75
12	DMF	Me4NF	DABCO	20	0

^a The reactions were performed with 10 mol% of Lewis base, 10 equiv of fluoride source and with a combination of CF₃SiMe₃/S₈/KF = 5:6:10 in solvent (4 mL) for 22 h under dry air.

^b The reaction was run in DMF (2 mL).

^c The amount of KF used was 2 equiv.

Encouraged by these promising results, we examined the substrate scope for the regio- and stereoselective allylic trifluoromethylthiolation of other MBH carbonates and acetates, aryl and alkyl derivatives, conjugated esters, ketone, and nitrile (Table [2]). First, the reaction with MBH acetate 1a′ was realized but 3a was isolated only in 34% yield as compared to the 93% of the corresponding carbonate 1a; this might be due to the difficulty of elimination of the acetoxy group (Table [2], entries 1 and 2). Hence, the carbonates were chosen as starting material for screening the impact of both R and EWG groups. For aryl esters, either electron-withdrawing (Cl, Br, F) or electron-donating (Me, MeO) substituents on the aromatic ring provided good to excellent yields of 3 after 22 hours (Table [2], entries 3–13). The metal-free approach is particularly suitable to avoid undesired reactions with halogen substituents on the aromatic ring that sometimes occur when transition metals are used. Sterically more demanding naphthyl groups and the 2-thienyl heteroaromatic also led to high yields (Table [2], entries 14–16). The trifluoromethylthiolation worked as well with the alkyl MBH carbonate 1p but in a much lower yield probably caused by the absence of conjugation with the phenyl ring (Table [2], entry 17). The impact of the steric hindrance of the ester moiety was examined and it was found that increasing the size of the alkyl group tended to reduce the yield of the reaction (Table [2], entries 18 and 19). MBH carbonates derived from the methylvinylketone 1s and acrylonitrile 1t were well tolerated in the trifluoromethylthiolation reaction giving the corresponding SCF₃ products 3s and 3t, respectively, in good yields (Table [2], entries 20 and 21). In contrast to ester and ketone products, which were obtained as single Z-isomers, nitrile 3t was produced with a E/Z ratio of 82:18.[20]

Table 2 Substrate Scope

Entry	Substrate	R	LG	EWG	Product	Yield (%)a
1	1a	Ph	OBoc	CO2Me	3a	93
2	1a′	Ph	OAc	CO2Me	3a	34
3	1b	2-ClC6H4	OBoc	CO2Me	3b	79
4	1c	3-ClC6H4	OBoc	CO2Me	3c	80
5	1d	4-ClC6H4	OBoc	CO2Me	3d	86
6	1e	2,4-Cl2C6H3	OBoc	CO2Me	3e	93
7	1f	2-BrC6H4	OBoc	CO2Me	3f	86
8	1g	3-BrC6H4	OBoc	CO2Me	3g	69
9	1h	4-BrC6H4	OBoc	CO2Me	3h	99
10	1i	4-FC6H4	OBoc	CO2Me	3i	94
11	1j	2-OMeC6H4	OBoc	CO2Me	3j	64
12	1k	4-OMeC6H4	OBoc	CO2Me	3k	88
13	1l	4-MeC6H4	OBoc	CO2Me	3l	93
14	1m	1-naphthyl	OBoc	CO2Me	3m	95
15	1n	2-naphthyl	OBoc	CO2Me	3n	94
16	1o	2-thienyl	OBoc	CO2Me	3o	88
17	1p	PhCH2CH2	OBoc	CO2Me	3p	20
18	1q	Ph	OBoc	CO2Et	3q	84
19	1r	Ph	OBoc	CO2 t-Bu	3r	28
20	1s	Ph	OBoc	COMe	3s	65
21	1t	Ph	OBoc	CN	3t	79b

^a Yield of the isolated pure product as single Z-isomer.

^b E/Z ratio = 82:18.

Although we have found appropriate conditions to prepare the primary allylic SCF₃ products 3 through a regio- and stereoselective allylic trifluoromethylthiolation, the access to secondary allylic SCF₃ products 4, which contain a stereogenic carbon, would be of high interest as well.

As mentioned earlier in the text, Zard demonstrated that O-octadecyl-S-trifluorothiolcarbonate, CF₃SCO₂C₁₈H₃₇, could be used as an efficient SCF₃ anion donor by activation with the aid of an amine.[14] We surmised that DABCO could play a dual role in activating both the nucleophilic reagent and the MBH carbonate. The trifluoromethylthiolation was examined with Zard’s reagent and DABCO at room temperature in THF (Scheme [3]). The reaction was very fast and full conversion was reached within five minutes. ¹⁹F NMR monitoring of the reaction revealed the kinetic formation of the secondary allylic SCF₃ product 4i that rapidly isomerized to the primary allylic SCF₃ product 3i (thermodynamic product) when the reaction time was extended. Compared to the combination of CF₃SiMe₃/S₈/KF/DMF, Zard’s reagent allowed to catch the fleeting secondary allylic SCF₃ (kinetic product) during its brief existence. Indeed, by quenching the reaction mixture after five minutes and purification on silica gel, we were pleased to isolate the kinetic product 4i in 78% yield although with some contamination by the long chain alcohol side product. Interestingly, the reaction only required a catalytic amount of DABCO to activate Zard’s reagent.

Scheme 3

In summary, we have found the appropriate conditions for the regio- and stereocontrolled trifluoromethylthiolation of MBH carbonates: the thermodynamically more stable primary allylic SCF₃ derivatives were synthesized by means of the metal-free combination of CF₃SiMe₃/S₈/KF/DMF whereas the kinetic secondary allylic SCF₃ derivatives were obtained by using Zard’s reagent.[21] Further studies that include mechanistic investigation, asymmetric variant, and chemical transformations of these novel SCF₃ products are underway in our laboratory.[22]

Acknowledgment

We thank the China Scholarship Council for a PhD grant to Xiaoyang Dai, and Chuan-Le Zhu for the preparation of some MBH adducts. Mr Shi-Guang Li and Dr Samir Zard are thanked for the gift of CF₃SCO₂C₁₈H₃₇ reagent and for fruitful discussions.

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• 21 General Procedure for the Preparation of Compounds 3: Caution! This reaction should be conducted with a gas pressure regulator and in a well-ventilated hood to avoid exposure to toxic bis(trifluoromethyl)sulfide and higher analogues. In an oven-dried tube, sulfur (19.2 mg, 0.6 mmol) and KF (58.1 mg, 1 mmol) in anhydrous DMF (2 mL) were stirred at r.t. under dry air for 30 min. Me₃SiCF₃ (71 mg, 0.5 mmol) was then added to the mixture followed by addition of the MBH carbonate (0.1 mmol) and DABCO (1.12 mg, 0.01 mmol). After 22 h, the reaction went to completion (monitored by ¹⁹F NMR analysis). The reaction was quenched with H₂O and extracted with Et₂O. The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether–EtOAc, 40:1) to give the corresponding primary allylic SCF₃ compound.
• 22 Shi M, Wang F.-J, Zhao M.-X, Wei Y. The Chemistry of the Morita–Baylis–Hillman Reaction. RSC Publishing; Cambridge: 2011