Hypervalent iodide(III)-mediated thiofluorination of alkenes and alkynes from thioureas/thiocarbamoyl fluorides with water and a nucleophilic fluoride source

Abstract

The hypervalent iodine(III) mediated oxo/aza/carbon/difluorination of alkenes has made significant progress, although the corresponding fluorination of alkynes cannot be accomplished. However, hypervalent iodine(III) mediated thiofluorination of both alkenes and alkynes has never been achieved before. Herein, three-component alkenyl thiocarbamoyl fluorides, water, and Et₃N·3HF or two-component alkenyl thioureas and Et₃N·3HF proceeded through cascade hydrolysis/thiofluorination or thiofluorination of terminal/internal unactivated/activated alkenes upon phenyliodine(III)bis(pivalate) in toluene at room temperature, providing access to diversified monofluorinated 1,3-thiazolidin-2-ones, 1,3-thiazinan-2-ones, 2-imino-thiazolidines and 1,3-thiazinan-2-imines with a broad substrate scope, excellent functional group tolerance and excellent regioselectivity. Configurations of some products were found to be opposite to those expected from the traditional mechanism of olefin activation by hypervalent iodines(III). Based on mechanistic studies and product configurations, another mechanism involving a cyclic sulfonium ion intermediate was proposed. This inspired us to further discover that phenyliodine(III)bis(pivalate) with dioxane as solvent enabled thiofuorination of alkynes from alkynyl thioureas and Et₃N·3HF, furnishing 2-imino-thiazolidines bearing an exocyclicfluoromethylene as tetrasubstituted fluorinated alkenes with remarkable regio-, chemo- and stereoselectivity (absolute E-isomer). These transformations represent the unprecedented thiofluorination of alkenes/alkynes in one operation directly from nucleophilic sulfur reagents and nucleophilic fluorine reagents.

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Introduction

Fluorine has witnessed an increasing popularity in the pharmaceutical field because incorporation of fluorine into preclinical drug candidates or drugs often enhances their physicochemical and pharmacological properties, such as conformation, lipophilicity, membrane permeability, and metabolic stability, facilitating bioavailability.¹ Fluorine also plays an important role in agrochemicals² and materials,³ and ¹⁸F serves as radiotracers for positron emission tomography (PET).⁴ Thus, great efforts has been devoted to develop methods for construction of carbon-fluorine bonds.^5,6 Among them hypervalent iodines(III) have emerged as an efficient, cost and convenient tool to form carbon–fluorine bonds, especially from cheap but less reactive nucleophilic fluorine reagents.⁶ For example, the hypervalent iodine(III) mediated oxo/aza/carbon/difluorination of alkenes has made significant progress,⁶ and most of these transformations involve activation of alkenes by a hypervalent iodine(III)/fluorination sequence. However, hypervalent iodine(III) mediated oxo/aza/carbon/difluorination of alkynes with nucleophilic fluorine reagents has never been achieved, possibly because alkynes are less electron-rich than alkenes and are not easily activated by hypervalent iodine(III) (Fig. 1, previous work 1). In 2004, Tingoli reported the 1,2-phenylselenofluorination of alkenes/alkynes from Ph₂Se₂, Et₃N·3HF and alkenes/alkynes in the presence of difluoroiodotoluene (DFIT), in which the rapid oxidation of Ph₂Se₂ by DFIT was observed, generating in situ an electrophilic, highly reactive PhSeF species (Fig. 1, previous work 2).⁷ Surprisingly, twenty years later, the corresponding hypervalent iodine(III) mediated thiofluorination of alkenes/alkynes has not yet been reported. In fact, when using Ph₂S₂ instead of Ph₂Se₂, Et₃N·3HF, phenyliodine(III)bis(pivalate) (PIDP) (for in situ generated DFIT), and cyclohexene reacted in CH₂Cl₂, Ph₂S₂ remained unchanged and no desired alkene 1,2-phenylthiofluorination product was obtained. Thiophenol/thioalcohol instead of Ph₂S₂ at otherwise the same conditions also did not afford the desired alkene 1,2-phenylthiofluorination products. PhSF or alkyl-SF species was not detected by high resolution mass spectrometry (HRMS) in these reaction systems (ESI†). Thus hypervalent iodine(III) mediated thiofluorination of alkenes/alkynes still remains an unexplored and challenging space in this realm.

Fig. 1 Difunctionalization of alkenes/alkynes involving nucleophilic fluorination.

Sulfur could assume oxidation states ranging from −2 to +6, resulting in multiple bond-forming styles and chemical diversity. Thiofluorination of alkenes/alkynes form both carbon–sulfur bonds and carbon–fluorine bonds to quickly increase molecular complexity. However, reported methods for thiofluorination of alkenes/alkynes consistently require the use of electrophilic sulfur reagents, such as PhSCl,⁸ MeS⁺SMe₂,⁹ ArNHSPh,¹⁰N-phenylsulfanylphthalimide¹¹ or ArS(ArSSAr)⁺,¹² which need to be prepared in advance with hazardous and unstable reagents or via electrochemical oxidation at −78 °C with excess reagent (over 10 equiv. ArSSAr), leading to a lack of atom-economy, step-economy, and benign conditions (Fig. 1, previous work 3). Although nucleophilic sulfur reagents are cheap and easily available, thiofluorination of alkenes and alkynes directly from nucleophilic sulfur reagents and nucleophilic fluoride reagents in one step at mild conditions in a step-economy fashion has never been accomplished and is in high demand.

Nitrogen- and sulfur-containing heterocycles are important structural motifs in biological compounds,¹³ medicines,¹⁴ materials,¹⁵ and natural products,¹⁶ demonstrating a variety of biological properties. For instance, 2-imino-thiazolidine derivatives exhibit antidepressant,^17a antihypertensive,^17b inflammatory,^17c anti-Alzheimer,^17d and insecticidal activities,^17e,f and are used as progesterone receptor binding agents.^17g 1,3-Thiazinan-2-imines have antimicrobial,^18a antitumor,^18b antioxidant,^18c and antipyretic activities^18a,d and are used as calcium channel modulators^18e–i and cannabinoid receptor ligands.^18j Thiazolidin-2-one derivatives show anticancer,^19a,b anti-HIV,^19c anti-inflammatory,^19d anticonvulsant,^19d bactericidal,^19d and pesticidal activities.^19d,e 1,3-Thiazinan-2-one derivatives are use as agonists of the EP₄ subtype of prostaglandin E2 receptor for treating glaucoma.²⁰ Although great efforts have been devoted to synthesize these four types of biologically relevant S,N-containing heterocycle derivatives,²¹ mono-fluorine has never been incorporated into them. In addition, reported methods for the synthesis of thiazolidin-2-ones or 1,3-thiazinan-2-ones require multiple steps relying on the use of sulfur reagents with strong and unpleasant odors as well as highly toxic, hazardous or moisture sensitive reagents to introduce the carbonyl group.^21g–k Recently, our group developed a cobalt-catalyzed hydrolysis/dehydrogenative coupling cascade reaction of N-aryl thiocarbamoyl fluorides and water to prepare 3-alkyl-2(3H)-benzothiazolones avoiding the use of bad-smelling and toxic reagents.²² We envision that if N-allyl/homoallyl thiocarbamoyl fluorides (sulfur ultimately from S₈)²³ and water under suitable conditions could not only cyclize onto the tethered olefin to form C–S bonds after hydrolysis but also introduce the privileged fluorine with a cheap nucleophilic fluorine reagent to form C–F bonds on the other carbon of the olefin to form three bonds in one operation, providing monofluoro-containing 1,3-thiazolidin-2-ones and even 1,3-thiazinan-2-ones, in which the oxygen of the carbonyl is from water. We also envision that N-allyl/homoallyl thioureas and nucleophilic fluorine reagents might undergo similar thiofluorination of olefins to access diverse monofluorinated 2-imino-thiazolidines and even 1,3-thiazinan-2-imines.

A means was sought to use hypervalent iodines(III) to promote our above designed novel reactions, although there has been a lack of reports on thiofluorination of alkenes/alkynes mediated by hypervalent iodine(III) after some attempts via metal catalysis under oxidants failed. However, the challenge lies in the potential production of disulfur products which are stable under hypervalent iodine(III) or sulfur–sulfur alkene difunctionalization products. When another substitution on the nitrogen of thioureas/thiocarbamoyl fluorides was aryl or benzyl, thiocyclization to the benzene ring instead of the olefin is also competitive. Sulfur carbonyl is also notorious for being oxidized to form carbonyl in the presence of oxidants. In addition, for N-allyl/homoallyl thiocarbamoyl fluorides, the C–F bond is an inert bond and whether the speed of hydrolysis matches the subsequent alkene sulfur-fluorination speed is also a challenge. Without a cascade reaction to immediately consume the hydrolysis products, thiocarbamoyl fluorides are very stable even under strong acid. On the other hand, when hypervalent iodine(III) activates olefins to form active intermediates, slow hydrolysis of thiocarbamoyl fluorines to the corresponding carbamothioic S-acids might also lead to undesired side reactions due to the lack of thiolation in time. Herein, we report that three-component alkenyl thiocarbamoyl fluorides, water, and Et₃N·3HF or two-component alkenyl thioureas and Et₃N·3HF proceeded through cascade hydrolysis/thiofluorination or thiofluorination of alkenes upon phenyliodine(III)bis(pivalate) in toluene at room temperature, providing access to diversified monofluoro-containing 1,3-thiazolidin-2-ones, 1,3-thiazinan-2-ones, 2-imino-thiazolidines and 1,3-thiazinan-2-imines in moderate to excellent yields with a broad substrate scope, excellent functional group tolerance and regioselectivity (Fig. 1, this work). Notably, configurations of some of the products are opposite to those expected from the mechanism of activation olefins by hypervalent iodine(III). Based on experiments and product configurations, another mechanism involving the cyclic sulfonium ion intermediate was proposed. This mechanism inspired us to further explore and realize thiofluorination of alkynes from alkynyl thioureas and Et₃N·3HF via hypervalent iodine(III) and dioxane as solvent at room temperature even though it is more challenging as the product containing double bonds may be activated and oxidized by hypervalent iodine(III), leading to further undesired transformation. The obtained thiazolidin-2-imines bearing an exocyclicfluoromethylene as tetrasubstituted alkenyl fluorides with remarkable regio-, chemo- and stereoselectivity (the absolute E-isomer as we anticipated) (Fig. 1, this work). Alkenyl fluorides exist in a number of bioactive compounds and serve as amide bond bioisosteres or enol mimics.^1d These transformations represent the first thiofluorination of alkenes and alkynes directly from nucleophilic sulfur reagents and nucleophilic fluoride reagents in one operation. This is also the first discovery that hypervalent iodine(III) enables thiofluorination of alkenes and alkynes.

Results and discussion

We initially attempted to use cobalt, palladium, or nickel as a catalyst to facilitate our designed three-component reaction of N-phenyl-N-allyl thiocarbamoyl fluorides, water and fluoride source, whether using an electrophilic fluorine source such as selectfluor or a nucleophilic fluorine source with an oxidant, none of the desired alkene thiofluorination product was obtained. Although we knew that thiofluorination of alkenes has never been achieved by hypervalent iodines(III) before, N-phenyl-N-allyl thiocarbamoyl fluorides, 3.0 equiv. of Et₃N·3HF, 2.0 equiv. of PhI(OAc)₂ and MeCN without anhydrous treatment were stirred at room temperature. To our surprise, the desired alkene thiofluorination product was obtained in 29% yield (ESI†). This result aroused our curiosity regarding whether the N-allyl thiourea and nucleophilic fluorine source under hypervalent iodine(III) could also provide the desired alkene thiofluorination products without formation of undesired disulfur products which are stable under hypervalent iodine(III). Thus N-allyl thiourea 1a was evaluated as a model nucleophilic substrate for the thiofluorination of alkenes. Results are shown in Table 1. When N-allyl urea 1a, 2.0 equiv. of PhI(OAc)₂ as the oxidant, 3.0 equiv. of Et₃N·3HF as a nucleophilic fluoride source and acetonitrile as a solvent reacted at room temperature for 2 hours, the desired alkene thiofluorination product 2a was indeed generated in 54% ¹H NMR yield (Table 1, entry 1). Stirring PhI(OAc)₂ and Et₃N·3HF in acetonitrile for 5 minutes to in situ generate ArIF₂ species before adding N-allyl urea 1a did not improve the yield of 2a (entry 2). Additionally, 20 mol% PhI and 2.0 equiv. of m-CPBA afforded 2a in 45% yield (entry 3). Subsequently, PhI(OAd)₂ or PhI(OPiv)₂ with greater steric hindrance instead of PhI(OAc)₂ was employed to reduce alkene thio-oxofunctionalization side products (entries 4 and 5), and PhI(OPiv)₂ was found to be superior (entry 5). Then solvents were screened. Although dichloromethane and diethylether led to a lower yield of 2a (entries 6 and 7), toluene enabled an enhancement in the yield of 2a (entry 8). PhI(OPiv)₂ and Et₃N·3HF stirred in toluene for 5 minutes before N-allyl urea 1a was added, which was found to be beneficial to the alkene thiofluorination process, providing 2a in up to ¹H NMR 84% yield (entry 9), which was in sharp contrast to the unchanged result with acetonitrile as solvent (entries 1 and 2). Then other substituted benzenes as solvents including chlorobenzene, trifluoromethylbenzene, and xylene were screened and were all inferior to toluene (entries 10–12). Notably, decreasing the amount of PhI(OPiv)₂ to 1.15 equiv. gave rise to 2a in 86% ¹H NMR yield and 84% isolated yield (entry 13), which helped to identify the optimized conditions. Decreasing the amounts of Et₃N·3HF led to lower yields (entries 14 and 15). The use of Py·3HF or BF₃·OEt₂ as a fluorine source instead of Et₃N·3HF resulted in traces or none of the desired 2a, demonstrating that Et₃N·3HF as fluorine source is crucial for this novel transformation. Employing selectfluor instead of PhI(OPiv)₂ and Et₃N·3HF or PhI(OPiv)₂ led to no yield of 2a.

Table 1 Optimization of reaction conditions^a

Entry	Iodine(III)	F source	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), oxidant (0.4 mmol), and fluorinating reagent (0.6 mmol) in 3 mL solvent for 2 h. b ^1H NMR yield with CH2Br2 as an internal standard. c Oxidant (0.4 mmol) and fluorinating reagent (0.6 mmol) stirred 5 minutes before 1a (0.2 mmol) was added and then the mixture was stirred for 2 h. d PhI (20 mol%) and m-CPBA (0.4 mmol) at −20 °C for 4 h. e PhI(OPiv)2 (0.23 mmol). f Isolated yield. g Et3N·3HF (0.5 mmol). h Et3N·3HF (0.4 mmol). i Stirred for 10 h, observed by TLC.
1	PhI(OAc)2	Et3N·3HF	MeCN	54
2^c	PhI(OAc)2	Et3N·3HF	MeCN	54
3	PhI, m-CPBA^d	Et3N·3HF	MeCN	45
4	PhI(OAd)2	Et3N·3HF	MeCN	56
5	PhI(OPiv)2	Et3N·3HF	MeCN	64
6	PhI(OPiv)2	Et3N·3HF	CH2Cl2	34
7	PhI(OPiv)2	Et3N·3HF	Et2O	56
8	PhI(OPiv)2	Et3N·3HF	PhMe	68
9^c	PhI(OPiv)2	Et3N·3HF	PhMe	84
10^c	PhI(OPiv)2	Et3N·3HF	PhCl	72
11^c	PhI(OPiv)2	Et3N·3HF	PhCF3	81
12^c	PhI(OPiv)2	Et3N·3HF	Xylene	79
13^c	PhI(OPiv)2^e	Et3N·3HF	PhMe	86(84^f)
14^c	PhI(OPiv)2^e	Et3N·3HF^g	PhMe	77
15^c	PhI(OPiv)2^e	Et3N·3HF^h	PhMe	75
Verified from standard condition (entry 12)
16^c	Py·3HF instead of Et3N·3HF			Trace^i
17^c	BF3·OEt2 instead of Et3N·3HF			0
18	Selectfluor instead of PhI(OPiv)2 and Et3N·3HF			0
19	Selectfluor instead of PhI(OPiv)2			0

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With the optimized reaction conditions in hand, we investigated the reaction scope (Table 2). When N-substituents R¹ in substrates 1 were para-electron-withdrawing substituted aryls, the corresponding products were obtained in good to excellent yields (2b–2f). Various functional groups were tolerated, including fluoro (2b), chloro (2c), bromo (2d), iodine (2e), and trifluoromethyl (2f). Especially, even a R¹ bearing frail iodine group furnished the corresponding product 2e in 85% yield. When the N-substituent R¹ was a strongly para-electron-donating substituted aryl such as para-methoxy phenyl, the corresponding product's yield was reduced (2g) whereas thiocyclization to strongly electron-rich phenyl is the main byproduct. N-Substituents R¹ which were ortho- and meta-substituted aryls worked well (2h, 2i). The N-substituent R¹ as benzyl or diphenylmethyl also proceeds smoothly (2j, 2k). N-Substituents R¹ were various alkyls, providing access to corresponding products in moderate to excellent yields (2l–2o). For example, R¹ as an alkyl bearing thienyl was tolerated (2l). R¹ as an alkyl-containing heteroatom such as bearing ether or N-Boc piperidine furnished the corresponding products in good to excellent yields (2n, 2o). The reaction was relatively insensitive to substituents R². Whether substituents R² were ortho-, meta-, or para-electron-donating or electron-withdrawing substituted aryls, they consistently yielded the corresponding products in good to excellent yields (2p–2w). The methoxy group (2p), fluoro (2q, 2v), chloro (2r), bromo (2s), iodo (2t) and esters (2u) are all well tolerated. Substituents R² as heterocycles such as furyl and thienyl performed well (2x, 2y). Substituents R² as alkyls including tert-butyl (2z), cyclohexyl (2aa), and benzyl (2ab) were also tolerated albeit bulky cyclohexyl led to a decreased yield (2aa). Besides monosubstituted terminal alkenes, other type of alkenes in substrates 1 were also evaluated, demonstrating broad adaptability. Substrate 1 bearing 1,1-disubstituted alkene underwent this transformation smoothly (2ac). Notably, substrates 1 bearing the trisubstituted alkene worked very well (2ad, 2ae). It is noteworthy that substrates 1 bearing the trisubstituted alkene with R¹ as a strong electron-donating para-methoxy substituted phenyl was well tolerated, yielding the desired product 2ae in 83% yield, demonstrating that R¹ as a para-strong electron-donating group could be well tolerated when substrates 1 bear internal alkenes. Substrates 1 bearing cyclohexene afforded the product 2af with three stereocenters in 80% yield as a single diastereoisomer (R*, R*, R*), and the relative configuration was assigned by X-ray single crystal structure analysis (ESI†) and 1D NOESY spectra of 2af (ESI†). Substrates 1 bearing 1-alkyl-2-phenyl substituted alkene gave the desired product 2ag in 70% yield as a single anti-diastereoisomer, and the relative configuration was assigned by 1D NOESY spectra of 2ag (ESI†). Substrates 1 bearing 1,2-dialkyl substituted alkenes along with n-butyl on the allyl position smoothly afforded the corresponding product 2ah in 76% yield with 2.2 : 1 dr. Besides obtaining above diversified monofluoro-substituted 2-imino- thiazolidines, monofluoro-substituted 1,3-thiazinan-2-imines are also within reach via this methodology (2ai–2al). N-Substituents R¹ as alkyls such as phenylethyl or bearing ester gave better yields of the corresponding monofluoro-substituted 1,3-thiazinan-2-imines (2aj, 2ak) than that of N-substituents R¹ as an aryl (2ai). In addition, the 6-membered S,N-heterocycle 2al was obtained in an excellent yield of 91% from the corresponding N-homoallyl thiourea substrate 1al bearing a trisubstituted alkene. On a 4.0 mmol scale of 1a, the reaction proceeds to afford 4a (0.87 g, 2.8 mmol) in 69% yield.

Table 2 Substrate scope for thiofluorination of alkenes from alkenyl thioureas and Et₃N·3HF with PhI(OPiv)₂^a

a Reaction conditions: PhI(OPiv)₂ (0.23 mmol) and Et₃N·3HF (0.6 mmol) in 3 mL PhMe stirred for 5 minutes, then 1 (0.2 mmol) was added and stirred at room temperature for 2–4 h.

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After further optimization of reaction conditions, we were pleased to find that improving the amount of PhI(OPiv)₂ to 2.0 equiv. under otherwise the same conditions enabled a three-component reaction of alkenyl thiocarbamoyl fluorides, water, and Et₃N·3HF, accessing various monofluoro-substituted 1,3-thiazolidin-2-ones and 1,3-thiazinan-2-ones, in which water is from the solvent toluene without anhydrous treatment and does not require additional addition (Table 3). Thiocarbamoyl fluoride bearing trisubstituted alkene with N-substituents R¹ as ortho-, meta-, and para- both electron-donating and electron-withdrawing substituted aryls consistently afforded the corresponding products in excellent yields (4b–4e). Even nitro and iodo groups were well tolerated, affording the corresponding products in 91% (4c) and 93% yields (4e), respectively. N-Substituents R¹ as naphthyl afforded the corresponding product 4f in up to 96% yield. When N-substituents R¹ were alkyls such as benzyl, cyclohexyl, N-Boc-piperidin-4-yl, the corresponding products were smoothly obtained in good to excellent yields (4g–4i). The antihypertensive drug amlodipine derived alkenyl thiocarbamoyl fluoride also smoothly transformed to the corresponding product 4j. Thiocarbamoyl fluorides bearing 1,2-disubstituted alkenes also performed very well. For example, thiocarbamoyl fluoride bearing 1-alkyl-2-phenyl substituted alkene 3k afforded the corresponding product 4k in 75% yield as the sole anti-diastereoisomer, the relative configuration was assigned by the 1D NOESY spectra of 4k (ESI†). Thiocarbamoyl fluoride bearing cyclohexene afforded the product 4l with three stereocenters in 84% yield as a single diastereoisomer (R*, R*, R*), and the relative configuration was assigned by 1D NOESY spectra of 4l (ESI†). Thiocarbamoyl fluorides bearing 1,2-dialkyl substituted alkenes including n-butyl on the allyl position furnished the corresponding products in high yields with moderate dr (4m, 4n). Interestingly, the thiocarbamoyl fluoride bearing a 1,2-dialkyl substituted alkene with p-methoxyphenylthio substitution on the allyl position (3o) gave the product 4o as a single anti-diastereoisomer, in which we found that the p-methoxyphenylthio group migrated from the allyl position of 3o to the adjacent position and fluorination occurred at the allyl position. Thiocarbamoyl fluorides bearing 1-substituted or 1,1-disubstituted terminal alkenes produced the desired products in moderate yields (4p, 4q). Notably, the monofluoro-substituted 6-membered heterocycle 1,3-thiazinan-2-imines are also accessed via this methodology (4r–4t). N-Aryl-N-but-3-en-1-yl substituted thiocarbamoyl fluorides gave higher yields of the corresponding product (4r) than N-alkyl-N-but-3-en-1-y substituted thiocarbamoyl fluorides (4s, 4t), which show the opposite trend compared to alkenyl urea substrates. On a 10 mmol scale of 3a, the reaction also proceeds readily to afford 4a (1.92 g, 8.0 mmol) in 80% yield.

Table 3 Substrate scope for thiofluorination of alkenes from alkenyl thiocarbamoyl fluorides, water and Et₃N·3HF with PhI(OPiv)₂^a

a Reaction conditions: PhI(OPiv)₂ (0.40 mmol) and Et₃N·3HF (0.6 mmol) in 3 mL PhMe stirred for 5 minutes, then 3 (0.2 mmol) was added and stirred at room temperature for 2–4 h.

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Adding 2.0 equiv. of H₂O¹⁸ to the standard reaction conditions of the three-component reaction of thiocarbamoyl fluoride, water, and Et₃N·3HF, and the corresponding product 4a′-[O¹⁸] with O¹⁸ on carbonyl was detected by Lc-Ms (Fig. 2, 1.a and ESI†), supporting the assumption that the oxygen of the products of the three-component reaction is derived from water. Adding 2.0 equiv. of BHT or 2.0 equiv. TEMPO to model reactions of the above three-component or two-component reactions afforded the corresponding products 4a and 2a in 80% yield and 79% yield, respectively (Fig. 2, 1.b), slightly lower than the 93% yield and 84% yield of the respective model reactions, suggesting that these novel reactions might not involve radical mechanism. The C–F bond of thiocarbamoyl fluorides is an inert bond. For the above three-component reactions, the sulfur of thiocarbamoyl fluorides first attacks the intramolecular olefin activated by hypervalent iodine(III) and then hydrolysis or first hydrolysis forms the corresponding thioacid and subsequently thiofluorination. Both of the two sequences are possible. In order to find out the order of the cascade three-component transformation, the model three-component reaction with the absence of the component Et₃N·3HF under otherwise the same standard conditions was carried out, and almost no reaction occurred. Whereas the model two-component reaction with the absence of the component Et₃N·3HF under otherwise the same standard conditions afforded the alkene thio-esterification product 7a in 32% yield (Fig. 2, 2.b). These results support the idea that hydrolysis of thiocarbamoyl fluorides under strong acid conditions of Et₃N·3HF first occurs in the N-allyl/homoallyl thiocarbamoyl fluorides, water and Et₃N·3HF cascade three-component reactions. (Fig. 2, 2.a), and otherwise the corresponding alkene thio-esterification product would produce if the sulfur of thiocarbamoyl fluorides first attacks the intramolecular olefin activated by hypervalent iodine(III) followed by hydrolysis. Thiourea 1a′ without bearing alkenes or alkynes instead of N-allyl/homoallyl thioureas under otherwise the same model two-component standard reactions was reacted and detected by HRMS, the corresponding carbamimidic thiol fluoride species I′ was not detected by HRMS. In particular, we noticed that the steric relative configuration of products 2ae, 2af, 4k, and 4l were net anti-stereoisomers.

Fig. 2 Mechanistic study and proposed mechanism.

Based on the mechanistic study and product configuration, we consider there are three possible mechanistic pathways for the reaction of alkenyl thioureas and Et₃N·3HF under PhI(OPiv)₂ (PIDP), as shown in Fig. 2. In one scenario, hypervalent iodine(III) PIDP and Et₃N·3HF form difluoroiodotoluene (DFIT), which was activated by acid and then formed highly electrophilic π-complexes I in the presence of alkenes. Internal sulfur attacks the π-complex to generate an alkyl iodane intermediate II (S-first), followed by substitution of the alkyl iodane II by the fluoride anion nucleophile to afford the product 2 as the syn-stereoisomer. Alternatively, the two substitution steps are reversed (F-first). Both of the two possible mechanisms result in the same outcome of the net syn-product (Fig. 2, 2.a, path A). However, the steric configuration of products 2ae and 2af were net anti-stereoisomers. Thus, we proposed another possible mechanism. The sulfur moiety of thiourea after isomerization under acid conditions might attack the difluoroiodotoluene to form the intermediate IV. That is, the sulfur was in situ oxidized by hypervalent iodine(III). The in situ generated electrophilic sulfur might be trapped by the tethered internal olefin to form a cyclic sulfonium ion intermediate V. Then the fluoride anion attacks the cyclic sulfonium ion V to furnish the net anti-product (Fig. 2, 2.a, path B). We think that the three-component reactions of thiocarbamoyl fluoride, water, and Et₃N·3HF after hydrolysis—first under strong acid conditions of Et₃N·3HF to in situ generate the corresponding carbamothioic S-acids—could undergo cascade alkene thiofluorination via a similar above proposed mechanism. The third mechanism (path B) could rationalize the net anti-configuration of 4k, 4l.

The third proposed mechanism to rationalize the anti-stereoconfiguration of some products inspired us to further explore the chance of thiofluorination of alkynes with hypervalent iodines(III) from alkynyl thioureas and nucleophilic fluorine reagents. We think the in situ generated electrophilic sulfur intermediate VI from alkynyl thioureas and hypervalent iodines(III) difluoroiodotoluene might be trapped by a tethered internal alkyne to form the cyclic sulfonium ion intermediate VII, which was subsequently attacked by a fluoride anion to furnish the corresponding alkyne thiofluorination product bearing net fluorinated E-olefin (Fig. 2, 2.b).

We applied the optimized reaction conditions (Table 2, entry 13) of alkenyl urea 1a and Et₃N·3HF to the reaction of alkynyl urea 5a and Et₃N·3HF. To our delight, the desired alkyne thiofluorination product 6a was indeed obtained in 46% yield (Table 4, entry 1). Replacing PhI(OPiv)₂ with PhI(OAc)₂ or PhI(OAd)₂ gave a decreased or a slight increased yield of 6a (Table 4, entries 2 and 3). Increasing the amount of PhI(OPiv)₂ from 1.15 equiv. to 2.0 equiv. led to a decreased yield of 31% (Table 4, entry 4). Then a series of solvents including CH₂Cl₂, Et₂O, DMF, DMSO, MeCN, EA, and acetone were screened (Table 3, entries 5–11), and Et₂O was found to be optimal (Table 4, entry 6). Thus, other ether solvents including THF, dioxane, dimethoxyethane (DME), and methyl tert-butyl ether (MTBE) were further examined (Table 4, entries 12–15), and dioxane was found to be best, furnishing 6a in 77% yield (Table 4, entry 13). The use of py·8HF instead of Et₃N·3HF resulted in a decreased yield of 50% (Table 4, entry 16). Decreasing the amount of PhI(OPiv)₂ from 1.15 equiv. to 1.05 equiv. led to an enhancement in the yield of 6a to 82% (Table 4, entry 17). Increasing the amount of Et₃N·3HF from 3.0 equiv. to 3.5 equiv. gave rise to 6a in 92% ¹H NMR yield and 82% isolated yield, which was identified as the optimized conditions for thiofluorination of alkynes from alkynyl ureas and Et₃N·3HF (Table 4, entry 19).

Table 4 Optimization of reaction conditions^a

Entry	Iodine(III)	F source	Solvent	Yield^b (%)
a Reaction conditions: oxidant (0.22 mmol) and fluorinating reagent (0.6 mmol) stirred 5 minutes before 1a (0.2 mmol) was added and then the mixture stirred for 1 h. b ^1H NMR yield with CH2Br2 as the internal standard. c 0.6 mmol PhI(OPiv)2. d 0.21 mmol PhI(OPiv)2. e 0.5 mmol Et3N·3HF. f 0.7 mmol Et3N·3HF.
1	PhI(OPiv)2	Et3N·3HF	PhMe	46
2	PhI(OAc)2	Et3N·3HF	PhMe	36
3	PhI(OAd)2	Et3N·3HF	PhMe	48
4^c	PhI(OPiv)2^c	Et3N·3HF	PhMe	31
5	PhI(OPiv)2	Et3N·3HF	CH2Cl2	30
6	PhI(OPiv)2	Et3N·3HF	Et2O	56
7	PhI(OPiv)2	Et3N·3HF	DMF	Trace
8	PhI(OPiv)2	Et3N·3HF	DMSO	Trace
9	PhI(OPiv)2	Et3N·3HF	MeCN	17
10	PhI(OPiv)2	Et3N·3HF	EA	38
11	PhI(OPiv)2	Et3N·3HF	Acetone	Trace
12	PhI(OPiv)2	Et3N·3HF	THF	53
13	PhI(OPiv)2	Et3N·3HF	Dioxane	77
14	PhI(OPiv)2	Et3N·3HF	DME	67
15	PhI(OPiv)2	Et3N·3HF	MTBE	36
16	PhI(OPiv)2	py·8HF	Dioxane	50
17	PhI(OPiv)2^d	Et3N·3HF	Dioxane	82
18	PhI(OPiv)2^d	Et3N·3HF^e	Dioxane	82
19	PhI(OPiv)2^d	Et3N·3HF^f	Dioxane	92(82)

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With optimized reaction conditions in hand, we investigated the reaction scope (shown in Table 5). Thiourea 5 bearing but-2-yn-1-yl with N-substituents R¹ as para-electron-donating methoxy or para-electron-withdrawing acetyl substituted aryl both afforded the corresponding products in good yields (6b, 6c). When R¹ was iodo-substituted aryl and R² was tert-butyl, the corresponding product 6d was obtained in moderate yields. N-Substituent R¹ as meta-fluoro substituted aryl and R² as ortho-methoxy substituted aryl furnished the corresponding product 6e in good yields. When R¹ was ortho-fluoro substituted aryl and R² was bulky cyclohexyl the corresponding product was obtained in good yield (6f). Thiourea 5 with R¹ as naphthyl and R² as the ortho-bromo substituted aryl was also tolerated (6g). Thiourea 5 with R¹ as the benzyl worked well (6h). When R¹ was N-Boc-piperidin-4-yl and R² was a para-methoxy substituted aryl the corresponding product 6i was obtained in a moderate yield. R² as a heterocycle such as thienyl was well tolerated (6j). In particular, the substituent group R³ at the propargyl position was n-heptanyl and substituent R⁴ of the internal alkyne was a bulky tert-butyl, furnishing the corresponding product 6k in 79% yield. Thiourea 5 with R³ as n-propyl and R⁴ as alkyl bearing heteroatom oxygen also smoothly gave the product 6l in 67% yield. It is noteworthy that all of the above products are net E-configuration, and only E-products were obtained, while Z-products was not observed, which is consistent with the mechanism we proposed (Fig. 2, b).

Table 5 Substrate scope for thiofluorination of alkynes from alkynyl thiourea and Et₃N·3HF with PhI(OPiv)₂^a

a Reaction conditions: PhI(OPiv)₂ (0.21 mmol) and Et₃N·3HF (0.7 mmol) in 3 mL dioxane stirred for 5 minutes, then 5 (0.2 mmol) was added and stirred at room temperature for 2 h.

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Conclusions

The first hypervalent iodide(III)-mediated thiofluorination of alkenes and alkynes from the nucleophilic sulfur reagent and nucleophilic fluorine reagent was realized. Alkenyl thioureas and Et₃N·3HF under 1.15 equiv. of phenyliodine(III)bis(pivalate) in toluene at room temperature afforded a variety of monofluoro-substituted 2-imino-thiazolidines and 1,3-thiazinan-2-imines in good to excellent yields with excellent regioselectivity. Three-component alkenyl thiocarbamoyl fluorides, water, and Et₃N·3HF undergo cascade in situ hydrolysis/thiofluorination of unactivated/activated internal/terminal olefins under 2.0 equiv. of phenyliodine(III)bis(pivalate) in toluene at room temperature, providing monofluoro-substituted 1,3-thiazolidin-2-ones and 1,3-thiazinan-2-ones in moderate to excellent yields with excellent regioselectivity. These novel reactions or cascade reactions feature a broad substrate scope, remarkable functional group tolerance, mild reaction conditions, step-economy, easy availability, and odorless and non-toxic starting materials, precluding toxic and bad-smell reagents. Notably, based on experimental results and mechanistic rationale, another possible mechanism involving the cyclic sulfonium ion intermediate was proposed. This inspired us to discover that 1.05 equiv. of phenyliodine(III)bis(pivalate) with dioxane as a solvent at room temperature enabled thiofluorination of alkynes from alkynyl thioureas and Et₃N·3HF, furnishing 2-imino-thiazolidines bearing an exocyclicfluoromethylene as tetrasubstituted fluorinated alkenes in moderate to good yields with remarkable regio-, chemo and stereoselectivity (absolute E-isomer). This is the first time that hypervalent iodine(III) was discovered to enable thiofluorination of alkenes and alkynes, expanding the scope of hypervalent iodine(III) mediated fluorination to the sulfur field. These transformations also represent unprecedented thiofluorination of alkenes and alkynes direct from nucleophilic sulfur reagent and nucleophilic fluorine reagent. All the obtained diverse monofluoro-substituted 5/6-membered thio-azaheterocycle molecules are novel molecules, which are being researched for their biological reactivities in our co-operated laboratory.

Author contributions

Liqin Jiang conceived the project. Liqin Jiang directed the research. Liqin Jiang and Junyi Zhou designed the experiments. Junyi Zhou carried out most of the experiments. Xiang Wang synthesized some starting materials and conducted some mechanistic experiments. Wenjun Tang discussed the project. Liqin Jiang and Junyi Zhou analyzed the results. Liqin Jiang wrote the manuscript. Junyi Zhou wrote the ESI and Liqin Jiang checked the ESI.†

Data availability

The data supporting this article have been included in the manuscript and the ESI.†

Crystallographic data for compound 2af have been deposited with the Cambridge crystallographic data centre (CCDC 2364347†).

Conflicts of interest

The authors declare no competing interests.

Acknowledgements

We are grateful for financial support from the Science and Technology Commission of Shanghai Municipality (No. 21ZR1419300) and the open fund of State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Institute of Organic Chemistry, Chinese Academy of Sciences.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2364347. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01569j

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