Direct radical trifluoromethylthiolation and thiocyanation of aryl alkynoate esters: mild and facile synthesis of 3-trifluoromethylthiolated and 3-thiocyanated coumarins

Abstract

A mild and convenient oxidative radical cyclization of aryl alkynoate esters for the synthesis of 3-trifluoromethylthiolated and 3-thiocyanated coumarins has been developed using AgSCF₃ and AgSCN as the corresponding radical sources, respectively. This protocol is characterized by readily available starting materials, excellent functional group tolerance and good yields.

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Introduction

Coumarins represent a privileged class of structural scaffolds in medicinal chemistry due to their wide spectrum of biological activities, such as anti-HIV,¹ antibacterial,² anti-inflammatory,³ antitumor,⁴ and antimalarial activities.⁵ As such, the development of efficient methods for the construction of structurally diverse coumarins bearing valuable functional groups from easily accessible starting materials is in high demand. Recently, the tandem functionalization/cyclization of aryl alkynoate esters has emerged as a powerful strategy to synthesize 3-functionalized coumarins.⁶ For instance, it was reported that 3-trifluoromethylated coumarins could be prepared by the reaction of aryl alkynoate esters with Togni's reagent following a radical addition/cyclization mechanism.^6a Similarly, various 3-substituted coumarins have been accessed via radical alkyne sulfonation,^6b phosphorylation,^6c acylation,^6d–f and difluoroacetylation^6f/cyclization pathways under oxidative or redox-neutral reaction conditions. Herein, we report our realization of a mild and facile synthesis of 3-trifluoromethylthiolated and thiocyanated coumarins by using AgSCF₃ and AgSCN as the radical sources, respectively. A broad substrate scope and good functional group tolerance were observed.

Due to the typically desirable strong electron-withdrawing effect and high lipophilicity properties, the trifluoromethylthio group is frequently incorporated into bioactive compounds.⁷ Therefore, numerous trifluoromethylthiolation approaches have been developed by using either nucleophilic⁸ or electrophilic SCF₃ reagents.⁹ Nevertheless, the introduction of the SCF₃ group through a radical pathway has been relatively less explored.^10–15 Recently, Wang disclosed the synthesis of SCF₃-containing oxindoles through a ˙SCF₃ addition/cyclization pathway.¹¹ Wang and Xu reported that an intramolecular oxytrifluoromethylthiolation of alkenes is feasible under the catalysis of copper.¹² Silver-meditated direct trifluoromethylthiolation of C(sp³)–H bonds have been developed by Tang¹³ and Chen,¹⁴ respectively. Very recently, Liang disclosed an AgSCF₃-mediated radical cascade cyclization/trifluoromethylthiolation of 1,6-enynes.¹⁵

On the other hand, the thiocyano group is a versatile synthon which could be readily converted into other functional groups, such as sulfide,¹⁶ thiocarbamate,¹⁷ trifluoromethylthio¹⁸ and thiotetrazole.¹⁹ A variety of thiocyanation methods with the involvement of SCN are known.²⁰ However, the tandem thiocyanation/cyclization reactions of unsaturated C–C bonds remain less explored.²¹ In particular, no precedent exists for thiocyanation/cyclization reactions of alkynes.

Results and discussion

Initially, we investigated the reaction of phenyl 3-phenylpropiolate (1a) with AgSCF₃ using K₂S₂O₈ as the oxidant in the presence of HMPA at 75 °C under argon (Table 1, entry 1).¹¹ To our delight, the desired cyclized 3-trifluoromethylthiolated coumarin 2a was obtained in 25% yield. Further screening of solvents showed that DMSO was superior to others, increasing the yield to 42% (entries 1–5). When HMPA was removed from the reaction mixture, the yield was improved to 57% (entry 6). The increasing of reaction temperature to 100 °C gave a similar yield (entry 7). However, a lower temperature of 30 °C gave an increased yield of 71% (entry 8). Next, the effects of various oxidants such as oxone, PhI(OAc)₂, and Cu(OAc)₂·H₂O were investigated (entries 9–11). Disappointedly, none of them were effective for the reaction. By increasing the loading of K₂S₂O₈ (4.0 equiv.) and AgSCF₃ (2.0 equiv.), the yield was further improved to 78% (entry 12). A slightly lower yield of 74% was observed when the reaction was performed under air (entry 13). Additional control experiments demonstrated that K₂S₂O₈ was essential for the reaction as its omission gave no desired product (entry 14).

Table 1 Optimization of the reaction conditions^a

Entry	Oxidant (equiv.)	Solvent	Additive (equiv.)	Temp (°C)	Yield^b (%)
a Unless otherwise noted, all reactions were conducted with 1a (0.1 mmol), AgSCF3 (1.5 equiv.), and oxidant (3.0 equiv.) in solvent (1.0 mL) at 30 °C for 15 h under Ar. b ^1H NMR yield based on 1a using methyl 4-bromobenzoate as the internal standard. c Isolated yield. d Oxidant (4.0 equiv.), AgSCF3 (2.0 equiv.). e The reaction was performed under air.
1	K2S2O8 (3.0)	CH3CN	HMPA (0.5)	75	25^c
2	K2S2O8 (3.0)	DMSO	HMPA (0.5)	75	42
3	K2S2O8 (3.0)	Toluene	HMPA (0.5)	75	0
4	K2S2O8 (3.0)	DCE	HMPA (0.5)	75	Trace
5	K2S2O8 (3.0)	DMF	HMPA (0.5)	75	20
6	K2S2O8 (3.0)	DMSO	—	75	57
7	K2S2O8 (3.0)	DMSO	—	100	58
8	K2S2O8 (3.0)	DMSO	—	30	71
9	Oxone (3.0)	DMSO	—	30	Trace
10	PhI(OAc) (3.0)	DMSO	—	30	Trace
11	Cu(OAc)2·H2O (3.0)	DMSO	—	30	0
12	K 2 S 2 O 8 (4.0)	DMSO	—	30	78
13^d^,^e	K2S2O8 (4.0)	DMSO	—	30	74
14	—	DMSO	—	30	0

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With the optimized conditions in hand, various substituted aryl alkynoates 1a–z were synthesized and subjected to evaluate the scope and limitation of this transformation. As depicted in Table 2, alkynoates with different substituents on the phenoxy ring, regardless of the electron-withdrawing or -donating properties, could be converted to the corresponding products in moderate to good yields (2a–m). A variety of functional groups, such as methoxyl (2d), halogen (2e–h), trifluoromethoxyl (2i), ester (2j), and acetyl (2k) were well tolerated under the reaction conditions. Interestingly, the di-meta-substituted substrate did not hamper the reactivity, giving a good yield of 79% (2l). Two regioisomers 2m and 2m‘ were obtained in a ratio of 1.4 : 1 when a meta-methyl substituted phenoxy ring was employed. No desired product was detected with a methyl group substituted at the ortho-position of the phenoxy (2n). Next, the compatibility of the substituents on the alkynyl moiety was also investigated (2o–w). Arylpropilates with substituents at the ortho-, meta-, or para-position of the phenyl ring were all well tolerated in the reaction, affording the products in moderate to good yields. The heterocyclic 2-thienyl group was also compatible (2x). Delightedly, phenyl 2-octynoate (2y) and phenyl 3-cyclohexylpropiolate (2z) bearing an alkyl substituent were also suitable substrates, thus greatly extending the scope of this transformation.

Table 2 Scope of the trifluoromethylthiolation reaction of aryl alkynoate esters with AgSCF₃ ^a

a Reaction conditions: 1 (0.2 mmol), AgSCF₃ (2.0 equiv.), K₂S₂O₈ (4.0 equiv.), DMSO (1.0 mL), 30 °C, under Ar, 15 h. b At 50 °C.

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Encouraged by the above results, we then turned our attention to investigate the feasibility of thiocyanation of alkynoates using a similar protocol (Table 3). To our disappointment, the desired 3-thiocyanated coumarin products were not produced under the above standard conditions using AgSCN as the thiocyano source. It was reported that the thiocyanate radical could be formed by the oxidation of a thiocyanate anion with various oxidants, such as CAN (Cerium (IV) ammonium nitrate), hypervalent iodine reagents, oxone, and so on.²⁰ Therefore, screening of different oxidants and thiocyanate salts proved that the combination of CAN (Ce(NH₄)₂(NO₃)₆, 2.0 equiv.) and silver thiocyanate (2.0 equiv.) in DMSO (2.0 mL) at 60 °C was effective for the reaction, affording the product in 48% yield (3a). Similar to the trifluoromethylthiolation reaction, aryl alkynoates with various substituents were also compatible with the reaction conditions to give the corresponding products in moderate yields. Phenyl 2-octynoate could also be converted to the cyclization product with CH₃CN as the solvent, albeit in a low yield of 22% (3y).

Table 3 Scope of the thiocyanation reaction of aryl alkynoate esters with AgSCN^a

a Reaction conditions: 1 (0.2 mmol), AgSCN (2.0 equiv.), CAN (2.0 equiv.), DMSO (2.0 mL), 60 °C, 15 h, under air. b Solvent: CH₃CN (2.0 mL).

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To demonstrate the scalability of our protocol, the reaction of 1g on the 5 mmol scale was conducted under the standard conditions, giving 1.1 gram of the product in 57% yield (Scheme 1).

Scheme 1 Gram scale synthesis of 2g.

To probe the possible reaction mechanism, a series of control experiments were carried out (Scheme 2). Firstly, radical trapping experiments were conducted. When 4.0 equiv. of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was added, only 9% yield was detected (eqn (1)). Additionally, BHT (butylhydroxytoluene) also inhibited the transformation significantly and the BHT–SCF₃ (MS = 320) adduct was detected by GC-MS analysis (eqn (2)), indicating a radical pathway involved and that a ˙SCF₃ radical might be generated in the reaction. An intermolecular kinetic isotope effect (KIE) value of 1.4 suggested the C–H bond cleavage step was not rate-determining (eqn (3)). To determine the possible intermediate of this transformation, coumarin 4a was subjected to the standard conditions. Trifluoromethylthiolation coumarin 2a could not be obtained (eqn (4)). Finally, the role of silver in the reaction system was studied. No product was formed when AgSCF₃ was replaced by CuSCF₃, which indicated that silver was essential for the reactivity (eqn (5)). It was reported that F₃CSSCF₃ might act as the ˙SCF₃ source in some reactions.¹¹ Therefore, F₃CSSCF₃ was prepared according to a known procedure²² and used for our reaction. In the presence of AgNO₃, the trifluoromethylthiolation product was obtained in 20% yield (eqn (7)), while no desired product was observed without silver (eqn (6)).

Scheme 2 Mechanistic studies.

Based on the above observations and previous reports,^6,11–15,23 a plausible mechanism was outlined in Scheme 3. Initially, AgSCF₃ is oxidized by K₂S₂O₈ to generate [Ag^IISCF₃] species A, which could produce the ˙SCF₃ radical through single electron transfer. Alternatively, F₃CSSCF₃, generated from [Ag^IISCF₃], might be a possible source of ˙SCF₃. Regio-selective addition of the ˙SCF₃ to 1a affords vinyl radical B. Thereafter, an intramolecular cyclization gives radical intermediate C, which is further oxidized by Ag^II to deliver F–C reaction Wheland intermediate D. The deprotonation/rearomatization yields final product 2a.

Scheme 3 Proposed mechanism.

Conclusions

In conclusion, we have developed a novel oxidative radical cyclization of aryl alkynoate esters. This method provides a simple and efficient synthesis of various 3-trifluoromethylthiolated or 3-thiocyanated coumarins from readily accessible starting materials. Mild reaction conditions, excellent functional group tolerance, and generally good yields were observed. Preliminary mechanistic studies suggested that a radical reaction pathway is involved.

Acknowledgements

We are grateful for the support of this work by the “1000-Youth Talents Plan”, a Start-up Grant from Sun Yat-sen University and the National Natural Science Foundation of China (81402794 and 21472250).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1409264. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5qo00271k

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