The dual role of thiourea in the thiotrifluoromethylation of alkenes

We report the stereoselective and metal-free trifluoromethylation of alkenes followed by S-cyclization using thiourea as the S-source and SET initiator.


Introduction
A large number of pharmaceuticals contain a triuoromethyl group because this structural motif affects the properties of organic molecules. 1 The installation of triuoromethyl groups onto sp 3 hybridized carbon has progressed signicantly with numerous addition reactions of CF 3 across alkenes. Alkene vicinal functionalizations featuring C-CF 3 combined with C-H, C-C or C-heteroatom bond formation have been disclosed, most requiring a transition metal or photoredox catalyst to activate the CF 3 reagent (Scheme 1a). 2 Vicinal difunctionalizations involving sulfur heteroatom are notoriously rare; this process is much more challenging as, in contrast to amines and alcohols, thiols undergo facile S-triuoromethylation with the Togni or Umemoto reagents in the absence of catalyst. 3 A case of alkene thiotriuoromethylation was reported by Langlois in 2000. 4 In this process, photolysis of CF 3 SO 2 SPh generates a CF 3 radical (CF 3 c) that adds to the alkene; this step affords a weakly nucleophilic radical that reacts with CF 3 SO 2 SPh to provide the thioether product and the chain propagating tri-uoromethylsulfonyl radical. The reagent in this reaction serves both as CF 3 and S-source, thereby minimizing S-CF 3 bond formation. In a related approach, Zard reported the net addition of S-triuoromethyl xanthates reagents onto alkenes, a process initiated with lauroyl peroxide. 5 The abundance of sulfur containing heterocycles in medicinal chemistry 6 prompted us to study alkene difunctionalization via C-CF 3 and C-S bond formation where the CF 3 and SR groups would not stem from a single reagent. In 2015, Liu and co-workers reported a case of intermolecular difunctionalization with the copper-catalyzed triuoromethylthiocyanation of alkenes; this process requires trimethylsilylisocyanate, a silicon-based S-source that acts as Lewis acid to activate the Togni reagent. 7 In our design plan, we opted to examine the reactivity of olens with pending thioureas, a decision driven by synthetic and mechanistic considerations. Triuoromethylation followed by C-S bond formation would afford novel triuoromethylated 2-amino-thiazolines and 2-amino-thiazines for applications in medicinal chemistry. 8 Selected 2-amino-thiazines and -thiazolines are important scaffolds in the development of aspartate beta-secretase enzyme (BACE-1) inhibitors, a therapeutic target for Alzheimer's disease, 9 and are common motifs in several bioactive compounds (Scheme 1b). Mechanistically, the ability of thioureas to act as reducing agent 10 and radical scavenger 11 suggests that this group may induce the release of CF 3 c from the Togni reagent, 12 and serve as an S-source capable of adding on a C-centered radical. Here we report that thiourea-substituted alkenes undergo C-CF 3 followed by C-S bond formation with the Togni reagent and TFA. This operationally simple reaction does not require a metal catalyst, and affords diverse CF 3substituted 2-amino-thiazolines and thiazines resulting from overall anti-addition across the C]C p bond (Scheme 1c).

Results and discussion
To identify suitable reaction conditions, we selected the unactivated alkene 1aa, and the Togni I, II 13 and Umemoto III 14 reagents as CF 3 source (Table 1). 15 The desired 2-amino-thiazoline 2aa resulting from triuoromethylation followed by S-cyclization was formed in low yield when the reaction was carried out at room temperature in CHCl 3 with I, II or III in the absence of catalyst or additive (Table 1, entries 1-3). No sideproducts resulting from oxidative dimerization or S-CF 3 bond formation were detected. The conversion of 1aa into 2aa decreased at 60 C (Table 1, entries 2 and 3).
Activation of the Togni reagents by protonation with BrØnsted acid is well documented, 16 but not typically considered for CF 3 addition onto alkenes. We envisioned that upon protonation of II with triuoroacetic acid (TFA), the resulting highly electrophilic iodine centre could undergo S-I(III) coordination with the thiourea functionality followed by single electron transfer (SET) with more effective release of CF 3 radical. Gratifyingly, 62% of 2aa was observed aer 1 h when the reaction was conducted in the presence of 2 equiv. of TFA, and the yield reached 76% aer 24 h (Table 1, entry 4). The reaction was less effective using 1 equiv. of TFA (Table 1, entry 5). The presence of the acid did not induce protocyclization, and its benet was not signicant with Umemoto III (Table 1, entry 6).

Mechanistic experiments
We probed the mechanism of this reaction with a series of experiments (Scheme 3). The presence of 1 equiv. of TEMPO signicantly inhibited the thiotriuoromethylation of 1aa, yielding 23% of TEMPO-CF 3 and 6% of 2aa. 15 Complete inhibition for the formation of 2aa was observed in the presence of benzoquinone. The cyclopentane 5 was isolated in 20% yield when diethyl 2,2-diallylmalonate was submitted to the reaction conditions in the presence of 1 equiv. of N,N-diphenylthiourea (DPTU); 20 in the absence of thiourea, no reaction occurred (eqn (1)). Both E-1na and Z-1na gave anti-2na with d.r. > 20 : 1 (eqn (2)). Collectively, these data indicate that a CF 3 radical is involved in the reaction. Next, we investigated the uniqueness of the thiourea functionality for its ability to induce CF 3 c formation. We compared the reactivity of the thiourea 1ga with the corresponding urea 6 Scheme 2 Substrate scope of the reaction. a The reaction was performed on a 0.3 mmol scale; yield of isolated product; d.r. > 20 : 1 by 19 F NMR of crude reaction. b Relative configuration established by single crystal X-ray diffraction analysis; for 2ga and 2ka, analysis was performed on the derivatives 3 and 4, respectively. c 2gm and 2rc were obtained by in situ deprotection of 2gi and 2rb, respectively; yields from the alkene. d d.r. ¼ 3.5 : 1. e d.r. ¼ 6 : 1. f 61% yield when the reaction was scaled up to 2.3 mmol. g d.r. and amide 8 (eqn (3)). We found that 6 and 8 did not react under the standard reaction conditions. Notably, the cyclized products 7 and 9 were isolated in 13% and 22% yield respectively, when the triuoromethylation was performed in the presence of 1 equiv. of DPTU. In a similar vein, 1-allyl-3-phenylurea 10 did not react under the standard reaction conditions, but was consumed in the presence of DPTU with evidence that CF 3 radical addition to the alkene took place, but cyclization to 11 did not occur (eqn (4)). 15 The thiourea therefore acts as an activator leading to CF 3 c formation, and subsequent addition of this radical on the C]C p bond. The contrasting reactivity of thiourea and urea is consistent with their oxidation potentials (+1.19 V vs. SCE in CH 3 CN for thiourea 1aa and +1.56 V vs. SCE in CH 3 CN for urea 10); similar values were found for cyclic voltammetry measurements performed in CH 3 CN in the presence of TFA. 15 Moreover, thioureas are superior to ureas for their ability to react with radical acceptor, an additional factor that accounts for the observed difference of reactivity. We considered next thioamides and thiols as alternative S-sources. Under our standard reaction conditions, the thioamide 12 failed to provide the product of thiotriuoromethylation, but led instead to the corresponding amide 13 (eqn (5)). 15,21 Pent-4ene-1-thiol 14 underwent intramolecular thiol-ene ring closure and side reactions other than S-CF 3 bond formation or oxidative S-S dimerization (eqn (6)). 15, 22 The thiourea is therefore unique to enable orchestrated alkene triuoromethylation followed by S-cyclization. Mechanistically, we discarded the possibility of S-cyclization prior to triuoromethylation because this sequence would convert alkenes such as 1na into a thiazoline via 5-exo-trig cyclization, and the thiazine anti-2na is the only product observed in the crude reaction mixture (eqn (2)). 23 We propose that activation of the Togni reagent II with TFA affords the highly electrophilic iodine(III) species [II.H] + that can associate with 1aa via iodine-sulphur coordination leading to A. Coordination of thiourea to the highly electrophilic I(III) in [II.H] + is unprecedented, but S-I(III) coordination has been evoked in the S-CF 3 bond formation for thiols reacting with the Togni reagent. 24 Homolytic dissociation releases B, iodobenzoic acid and the electrophilic radical CF 3 c, which is suited to add regioselectively to the alkene substrate 1aa. The alternative dissociative electron transfer pathway towards CF 3 radical formation is also plausible. The resultant carbon radical C undergoes ring closure with C-S bond formation to provide adduct D, which should be easier to oxidize than C; SET to the Togni reagent II, [II.H] + and/or A affords aer proton transfer 2aa, and CF 3 c that starts a new reaction cycle. 25 For radicals arising from CF 3 c addition to aryl-substituted alkenes, oxidation prior to S-cyclization is viable (Scheme 4).

Conclusions
In summary, we developed the rst triuoromethylation followed by S-cyclization across C]C p bonds using thiourea as the S-source. The substrate itself, through its thiourea functionality, acts as an initiator, thereby avoiding metal species or light/photoredox catalysts to induce facile formation of the CF 3 radical that adds to the alkene. Thiourea can react with Ccentered radical, so a range of alkenes including unactivated systems underwent facile thio-triuoromethylation. This reaction is an attractive method for medicinal and other applications, because of its broad substrate scope, anti-selectivity and operational simplicity. The discovery that N,N-diphenylthiourea is an effective additive to induce the triuoromethylationcyclization of ureas and benzamides opens the possibility to investigate the value of this category of activators for the development of novel metal-free triuoromethylation across double bonds.