Synthesis of hydropersulfides and thioethers

Abstract

Described herein are synthetic routes and methods for synthesizing hydropersulfides and thioethers, and compounds produced by the methods.

Description

[0001] SYNTHESIS OF HYDROPERSULFIDES AND THIOETHERS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No.63 / 709,933, filed on October 21, 2024, and U.S. Provisional Patent Application No.63 / 683,604, filed on August 15, 2024, each of which is incorporated by reference herein in its entirety. BACKGROUND Hydropersulfides (RSSH) are an emerging, understudied functional group. They have cell protective properties such as protecting cysteine residues from oxidation and distinct signaling pathways in physiological systems. Hydropersulfides (RSSH), compared to thiols (RSH), show enhanced reactivities: a more nucleophilic and acidic compound due to the alpha effect. The reactivity study of hydropersulfides has been conducted mainly in physiological systems due to the unstable nature of the hydropersulfides although some alkyl hydropersulfides have been studied in oxidation and addition reactions: oxidation of Ph3P to Ph3PS and addition reaction to succinimide. However, understanding the fundamental chemistry of hydropersulfide functionality remains a pressing challenge since current studies have been limited to in-situ physiological environments. Hence, their reactivity study under a more controlled environment is crucial to develop a new synthetic methodology. Hydropersulfides (RSSH) are currently synthesized through multistep procedures with limited derivatization and low overall yields. Although hydropersulfides have been extensively studied in biological systems as mentioned above, their application in synthetic methodology is limited due to the limited availability and instability of hydropersulfides. In addition, thioethers have been widely used in medicinal chemistry and chemical biology. For example, probucol, butoconazole, and cimetidine were developed to treat high cholesterol, fungal infections, and stomach ulcers, respectively. With the broad application of the thioether motif, synthetic methods to access thioethers have been studied. They are synthesized by addition reactions, nucleophilic substitution reactions, and rearrangement reactions. Furthermore, a hydrothiolation reaction is an attractive strategy to access thioethers from readily available alkene, conjugated diene, or alkyne starting materials. However, current methods rely on metal catalysts and heating conditions. Despite the extensive study on thiol reactivity, the reactivity of hydropersulfides is not well known, and the hydrothiolation of alkenes remains elusive to achieve under mild conditions. SUMMARY One embodiment described herein is a compound of formula (I), or a salt thereof, , wherein: Rzis –S–H, –S–C(O)C1–4alkyl, R1is hydrogen, –C1–4alkyl, or –C6–12aryl; R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –P2, the C8–16phenoxyalkyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; with the proviso that the compound is not benzyldisulfane, (4-methoxybenzyl)disulfane, benzyl(2,3-dimethylbut-2-en-1-yl)sulfane, (E)-benzyl(3,7-dimethylocta-2,6-dien-1- yl)sulfane, bis(1-phenylethyl)sulfane, benzyl(1-phenylethyl)sulfane, benzyl(1- phenylpropyl)sulfane, benzyl(2-phenylpropan-2-yl)sulfane, benzyl(4-phenylbutan- 2-yl)sulfane, benzyl(1-(4-fluorophenyl)ethyl)sulfane, benzyl(1-(4- chlorophenyl)ethyl)sulfane, benzyl(1-(4-methoxyphenyl)ethyl)sulfane, benzyl(1- (naphthalen-1-yl)ethyl)sulfane. In another aspect, R1is hydrogen or –C1–4alkyl. In another aspect, R3is hydrogen or –C1–4alkyl. In another aspect, n is 0 or 1. In another aspect, n is 1. In various . In another aspect, R2, at each occurrence, is independently halogen, –OC1––CN, –NO2, –OH, or –OC(O)C1–4alkyl. In various instances, Rzis –S–H. In Rzis –S–C(O)C1–4alkyl. In another aspect, Rzis –Z1. In various instances, Z1is –C2–12alkyl, –C4–12alkenyl, –C8–16arylalkyl, or–C8–16phenoxyalkyl. In various instances, . In another aspect, Rx is –C6–12aryl. Invarious instances, the C6–12aryl is optionally In another aspect, The compound of any one of clauses 12–14, or the salt thereof, wherein Ryis –P(O)(OC1–4alkyl)2, –P(O)(C6–12aryl)2, P(O)(OC8–16arylalkyl)2, –P(O)(C6–12aryl)(OC1–4alkyl), or –P(O)(OC6–12aryl)2. In another aspect, the compound is selected from the group consisting of: , , , , , , , Another embodiment described herein is a method for preparing compounds of formula (V), or salts thereof, ; wherein: R1is hydrogen, –C1–4alkyl, or –C6–12aryl; R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, or –P(O)(C6–12aryl)2; and wherein, at each occurrence, the C6–12aryl and the C3–8cycloalkyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; the method comprising: (a) providing a compound of formula (II), where LG is a leaving group: ; (b) reacting the intermediate sulfinothioate of formula (II-A), where M is sodium, potassium, O C aryl S6-12M S;in the presence of a of formula (III): ; (c) reacting the of formula (III-A), where M is sodium, potassium, or cesium: ; in the presence of a of formula (IV): (d) reacting the of formula (IV-A): HO-C1–4alkyl (IV-A); in the presence of an acid to provide a compound of formula (V): In another aspect, the Another embodiment described herein is a method for preparing compounds of formula (VI), or salts thereof, ; wherein: R1is hydrogen, –C1–4alkyl, or R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, or –P(O)(C6–12aryl)2; Z1is –C2–12alkyl, –C6–12alkenyl, –C8–16arylalkyl, or –C8–16phenoxyalkyl, wherein, at each occurrence, the C6–12aryl, the C3–8cycloalkyl, the –C8–16arylalkyl and the –C8–16phenoxyalkyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl,–C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; the method comprising: (a) providing a compound of formula (V): (b) reacting the alkene of formula (V-A): , wherein: Raat each occurrence, is independently hydrogen or C1–4alkyl, and R10is hydrogen, –C1–10alkyl, –C4–10alkenyl, –C6–12aryl, –C7–14arylalkyl, or –O-phenyl, wherein, at each occurrence, the –C6–12aryl, the –C7–14arylalkyl, and the –O-phenyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl,–C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; to provide a compound of formula (VI): . In some instances, Raat Another embodiment for preparing compounds of formula (VI), or salts thereof, ; wherein: R1is hydrogen, –C1–4alkyl, or R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, 2, 2, optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; the method comprising: (a) providing a compound of formula (V): (b) reacting the of formula (V-C): in the presence of a solvent to provide a compound of formula (VI): In some2. In another aspect, for preparing compounds of formula (V), or salts thereof, ; wherein: R1is hydrogen, –C1–4alkyl, or –C6–12aryl; R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, or –P(O)(C6–12aryl)2; and wherein, at each occurrence, the C6–12aryl and the C3–8cycloalkyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; the method comprising: (a) providing a compound of formula (VIII): ; (b) reacting the compound of N-(S-acylthio)succinimide of formula (IX): ; in the presence of a of formula (IV) (c) reacting the of formula (IV-A): HO-C1–4alkyl (IV-A); in the presence of an acid to provide a compound of formula (V): . Another embodiment of any of the compounds described herein for industrial, agricultural, or medical applications. DETAILED DESCRIPTION Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of chemistry described herein are well known and commonly used in the art. In case of conflict, the present disclosure, including definitions, will control. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the embodiments and aspects described herein. As used herein, terms such as “include,” “including,” “contain,” “containing,” “having,” and the like mean “comprising.” The present disclosure also contemplates other embodiments “comprising,” “consisting essentially of,” and “consisting of” the embodiments or elements presented herein, whether explicitly set forth or not. As used herein, “comprising,” is an “open- ended” term that does not exclude additional, unrecited elements or method steps. As used herein, “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention. As used herein, “consisting of” excludes any element, step, or ingredient not specified in the claim. As used herein, the term “a,” “an,” “the” and similar terms used in the context of the disclosure (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. In addition, “a,” “an,” or “the” means “one or more” unless otherwise specified. As used herein, the term “or” can be conjunctive or disjunctive. As used herein, the term “and / or” refers to both the conjunctive and disjunctive. As used herein, the term “substantially” means to a great or significant extent, but not completely. As used herein, the term “about” or “approximately” as applied to one or more values of interest, refers to a value that is similar to a stated reference value, or within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, such as the limitations of the measurement system. In one aspect, the term “about” refers to any values, including both integers and fractional components that are within a variation of up to ± 10% of the value modified by the term “about.” Alternatively, “about” can mean within 3 or more standard deviations, per the practice in the art. Alternatively, such as with respect to biological systems or processes, the term “about” can mean within an order of magnitude, in some embodiments within 5-fold, and in some embodiments within 2-fold, of a value. As used herein, the symbol “~” means “about” or “approximately.” All ranges disclosed herein include both points as discrete values as well as all integers and fractions specified within the range. For example, a range of 0.1–2.0 includes 0.1, 0.2, 0.3, 0.4 . . . 2.0. If the end points are modified by the term “about,” the range specified is expanded by a variation of up to ±10% of any value within the range or within 3 or more standard deviations, including the end points, or as described above in the definition of “about.” As used herein, the terms “room temperature,” “RT,” or “ambient temperature” refer to the typical temperature in an indoor laboratory setting. In one aspect, the laboratory setting is climate controlled to maintain the temperature at a substantially uniform temperature or with a specific range of temperatures. In one aspect, “room temperature” refers a temperature of about 15–30 °C, including all integers and endpoints within the specified range. In another aspect, “room temperature” refers a temperature of about 15–30 °C; about 20–30 °C; about 22–30 °C; about 25–30 °C; about 27–30 °C; about 15–22 °C; about 15–25 °C; about 15–27 °C; about 20–22 °C; about 20–25 °C; about 20–27 °C; about 22–25 °C; about 22–27 °C; about 25–27 °C; about 15 °C ± 10%; about 20 °C ± 10%; about 22 °C ± 10%; about 25 °C ± 10%; about 27 °C ± 10%; ~20 °C, ~22 °C, ~25 °C, or ~27 °C, at standard atmospheric pressure. As used herein, the terms “control,” or “reference” are used herein interchangeably. A “reference” or “control” level may be a predetermined value or range, which is employed as a baseline or benchmark against which to assess a measured result. “Control” also refers to control experiments or control cells. As used herein, the terms “active ingredient” or “active pharmaceutical ingredient” refer to a pharmaceutical agent, active ingredient, compound, or substance, compositions, or mixtures thereof, that provide a pharmacological, often beneficial, effect. As used herein, the term “dose” denotes any form of an active ingredient formulation or composition, including cells, that contains an amount sufficient to initiate or produce a therapeutic effect with at least one or more administrations. “Formulation” and “composition” are used interchangeably herein. As used herein, the term “prophylaxis” refers to preventing or reducing the progression of a disorder, either to a statistically significant degree or to a degree detectable by a person of ordinary skill in the art. As used herein, the terms “effective amount” or “therapeutically effective amount,” refers to a substantially non-toxic, but sufficient amount of an action, agent, composition, or cell(s) being administered to a subject that will prevent, treat, or ameliorate to some extent one or more of the symptoms of the disease or condition being experienced or that the subject is susceptible to contracting. The result can be the reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An effective amount may be based on factors individual to each subject, including, but not limited to, the subject’s age, size, type or extent of disease, stage of the disease, route of administration, the type or extent of supplemental therapy used, ongoing disease process, and type of treatment desired. As used herein, the term “subject” refers to an animal. Typically, the subject is a mammal. A subject also refers to primates (e.g., humans, male or female; infant, adolescent, or adult), non- human primates, rats, mice, rabbits, pigs, cows, sheep, goats, horses, dogs, cats, fish, birds, and the like. In one embodiment, the subject is a primate. In one embodiment, the subject is a human. As used herein, a subject is “in need of treatment” if such subject would benefit biologically, medically, or in quality of life from such treatment. A subject in need of treatment does not necessarily present symptoms, particular in the case of preventative or prophylaxis treatments. As used herein, the terms “inhibit,” “inhibition,” or “inhibiting” refer to the reduction or suppression of a given biological process, condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. As used herein, “treatment” or “treating” refers to prophylaxis of, preventing, suppressing, repressing, reversing, alleviating, ameliorating, or inhibiting the progress of biological process including a disorder or disease, or completely eliminating a disease. A treatment may be either performed in an acute or chronic way. The term “treatment” also refers to reducing the severity of a disease or symptoms associated with such disease prior to affliction with the disease. “Repressing” or “ameliorating” a disease, disorder, or the symptoms thereof involves administering a cell, composition, or compound described herein to a subject after clinical appearance of such disease, disorder, or its symptoms. “Prophylaxis of” or “preventing” a disease, disorder, or the symptoms thereof involves administering a cell, composition, or compound described herein to a subject prior to onset of the disease, disorder, or the symptoms thereof. “Suppressing” a disease or disorder involves administering a cell, composition, or compound described herein to a subject after induction of the disease or disorder thereof but before its clinical appearance or symptoms thereof have manifest. Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference. The term “alkyl,” as used herein, means a straight or branched, saturated hydrocarbon chain. The term “lower alkyl” or “C1–6alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “C1–4alkyl” means a straight or branched chain hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n- heptyl, n-octyl, n-nonyl, and n-decyl. The term “alkenyl,” as used herein, means a straight or branched, hydrocarbon chain containing at least one carbon-carbon double bond. The term “alkoxy,” as used herein, refers to a group –O–alkyl. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert- butoxy. The term “alkoxyalkyl,” as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. The term “alkoxyfluoroalkyl,” as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein. The term “alkylene,” as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon of 1 to 10 carbon atoms, for example, of 2 to 5 carbon atoms. Representative examples of alkylene include, but are not limited to, –CH2–, –CD2–, –CH2CH2–, –CH2CH2CH2–, –CH2CH2CH2CH2–, and –CH2CH2CH2CH2CH2–. The term “alkylamino,” as used herein, means at least one alkyl group, as defined herein, is appended to the parent molecular moiety through an amino group, as defined herein. The term “amide,” as used herein, means –C(O)NR– or –NRC(O)–, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl. The term “aminoalkyl,” as used herein, means at least one amino group, as defined herein, is appended to the parent molecular moiety through an alkylene group, as defined herein. The term “amino,” as used herein, means –NRxRy, wherein Rxand Rymay be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl. In the case of an aminoalkyl group or any other moiety where amino appends together two other moieties, amino may be – NRx–, wherein Rxmay be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl. The term “aryl,” as used herein, refers to an optionally substituted phenyl or an optionally substituted phenyl appended to the parent molecular moiety and fused to an optionally substituted cycloalkane group (e.g., the aryl may be indan-4-yl), fused to an optionally substituted 6- membered arene group (i.e., the aryl is naphthyl), or fused to an optionally substituted non- aromatic heterocycle (e.g., the aryl may be benzo[d][1,3]dioxol-5-yl). The term “phenyl” is used when referring to a substituent and the term 6-membered arene is used when referring to a fused ring. The 6-membered arene is monocyclic (e.g., benzene or benzo). The aryl may be monocyclic (phenyl) or bicyclic (e.g., a 9- to 12-membered fused bicyclic system). The term “cycloalkyl” or “cycloalkane,” as used herein, refers to an optionally substituted saturated ring system containing all carbon atoms as ring members and zero double bonds. The term “cycloalkyl” is used herein to refer to an optionally substituted cycloalkane when present as a substituent. A cycloalkyl may be a monocyclic cycloalkyl (e.g., cyclopropyl), a fused bicyclic cycloalkyl (e.g., decahydronaphthalenyl), or a bridged cycloalkyl in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptanyl). Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl. The term “cycloalkenyl” or “cycloalkene,” as used herein, means an optionally substituted non-aromatic monocyclic or multicyclic ring system containing all carbon atoms as ring members and at least one carbon-carbon double bond and preferably having from 5–10 carbon atoms per ring. The term “cycloalkenyl” is used herein to refer to a cycloalkene when present as a substituent. A cycloalkenyl may be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a fused bicyclic cycloalkenyl (e.g., octahydronaphthalenyl), or a bridged cycloalkenyl in which two non- adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptenyl). Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. The term “carbocyclyl” means a “cycloalkyl” or a “cycloalkenyl.” The term “carbocycle” means a “cycloalkane” or a “cycloalkene.” The term “carbocyclyl” refers to a “carbocycle” when present as a substituent. The terms cycloalkylene and heterocyclylene refer to optionally substituted divalent groups derived from the base ring, i.e., cycloalkane, heterocycle. For purposes of illustration, examples of cycloalkylene and heterocyclylene include, . Cycloalkylene and heterocyclylene include a geminal C3-6cycloalkylene ). A further example is 1,1-cyclopropylene ). The term “fluoroalkyl,” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2- trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl such as 3,3,3- trifluoropropyl. The term “halogen” or “halo,” as used herein, means Cl, Br, I, or F. The term “haloalkyl,” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a halogen. The term “haloalkoxy,” as used herein, means at least one haloalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom. The term “heteroalkyl,” as used herein, means an alkyl group, as defined herein, in which one or more of the carbon atoms has been replaced by a heteroatom selected from S, O, P and N. Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, amides, and alkyl sulfides. The term “heteroaryl,” as used herein, refers to an optionally substituted aromatic monocyclic heteroatom-containing ring (monocyclic heteroaryl) or an optionally substituted bicyclic ring system containing at least one monocyclic heteroaromatic ring (bicyclic heteroaryl). The term “heteroaryl” is used herein to refer to a heteroarene when present as a substituent. The monocyclic heteroaryl are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S (e.g., 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N). The five membered aromatic monocyclic rings have two double bonds, and the six membered aromatic monocyclic rings have three double bonds. The bicyclic heteroaryl is an 8- to 12-membered ring system and includes a fused bicyclic heteroaromatic ring system (i.e., 10^ electron system) such as a monocyclic heteroaryl ring fused to a 6-membered arene (e.g., quinolin-4-yl, indol-1-yl), a monocyclic heteroaryl ring fused to a monocyclic heteroarene (e.g., naphthyridinyl), and a phenyl fused to a monocyclic heteroarene (e.g., quinolin-5-yl, indol-4-yl). A bicyclic heteroaryl / heteroarene group includes a 9-membered fused bicyclic heteroaromatic ring system having four double bonds and at least one heteroatom contributing a lone electron pair to a fully aromatic 10^ electron system, such as ring systems with a nitrogen atom at the ring junction (e.g., imidazopyridine) or a benzoxadiazolyl. A bicyclic heteroaryl also includes a fused bicyclic ring system composed of one heteroaromatic ring and one non-aromatic ring such as a monocyclic heteroaryl ring fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridinyl), or a monocyclic heteroaryl ring fused to a monocyclic heterocycle (e.g., 2,3-dihydrofuro[3,2-b]pyridinyl). The bicyclic heteroaryl is attached to the parent molecular moiety at an aromatic ring atom. Other representative examples of heteroaryl include, but are not limited to, indolyl (e.g., indol-1-yl, indol-2-yl, indol-4-yl), pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazol-4-yl), 1,3,4-thiadiazolyl, 1,2,4- thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazol-4-yl), isothiazolyl, thienyl, benzimidazolyl (e.g., benzimidazol-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl (e.g., indazol-4-yl, indazol-5-yl), quinazolinyl, 1,2,4- triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, imidazo[1,2-a]pyridinyl (e.g., imidazo[1,2- a]pyridin-6-yl), naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl, and thiazolo[5,4- d]pyrimidin-2-yl. The term “heterocycle” or “heterocyclic,” as used herein, means an optionally substituted monocyclic heterocycle, bicyclic heterocycle, or tricyclic heterocycle. The term “heterocyclyl” is used herein to refer to an optionally-substituted heterocycle when present as a substituent. The monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six- membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocyclyls include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3- dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3- thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a 6-membered arene, or a monocyclic heterocycle fused to a monocyclic cycloalkane, or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroarene, or a spiro heterocycle group, or a bridged monocyclic heterocycle ring system in which two non- adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. The bicyclic heterocyclyl is attached to the parent molecular moiety at a non-aromatic ring atom (e.g., indolin-1-yl). Representative examples of bicyclic heterocyclyls include, but are not limited to, chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzothien-2-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa- 6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), azabicyclo[3.1.0]hexanyl (including 3-azabicyclo[3.1.0]hexan-3-yl), 2,3-dihydro-1H-indol-1-yl, isoindolin-2-yl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, tetrahydroisoquinolinyl, 7-oxabicyclo[2.2.1]heptanyl, hexahydro-2H-cyclopenta[b]furanyl, 2-oxaspiro[3.3]heptanyl, 3- oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octan-1-yl, and 3-oxabicyclo[3.1.0]hexan-6-yl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a 6-membered arene, or a bicyclic heterocycle fused to a monocyclic cycloalkane, or a bicyclic heterocycle fused to a monocyclic cycloalkene, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5- methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1- azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). The monocyclic, bicyclic, and tricyclic heterocyclyls are connected to the parent molecular moiety at a non-aromatic ring atom. The term “heterocycle” encompasses optionally substituted heterocycles. The term “hydroxyl” or “hydroxy,” as used herein, means an –OH group. The term “hydroxyalkyl,” as used herein, means at least one –OH group is appended to the parent molecular moiety through an alkylene group, as defined herein. The term “arylalkyl” as used herein, means at least one aryl group is appended to the parent molecular moiety through an alkylene group, as defined herein. The term “phenoxyalkyl,” as used herein, means at least one phenoxy (i.e., –OPh) group is appended to the parent molecular moiety through an alkylene group, as defined herein. Terms such as “alkyl,” “cycloalkyl,” “alkylene,” “aryl,” “arylalkyl,” etc. may be preceded by a designation indicating the number of atoms present in the group in a particular instance (e.g., “–C1–4alkyl,” “–C3–6cycloalkyl,” “–C1–4alkylene”, “–C(O)C6–12aryl”). These designations are used as generally understood by those skilled in the art. For example, the representation “C” followed by a subscripted number indicates the number of carbon atoms present in the group that follows. Thus, “–C3alkyl” is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where a range is given, as in “–C1–4,” the members of the group that follows may have any number of carbon atoms falling within the recited range. A “–C1–4alkyl,” for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched). The term “optionally substituted” refers to a group that may be substituted or unsubstituted. The term “substituted” refers to a group that may be further substituted with one or more non-hydrogen substituent groups. Substituent groups include, but are not limited to, halogen, =O (oxo), =S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, phenoxyalkyl, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, –COOH, ketone, amide, carbamate, and acyl. Abbreviations Bn is benzyl; Et2O is diethyl ether; DCM is dichloromethane; OAc is acetate; Ac is acetyl cod is 1,5-cyclooctadiene; OTf is triflate; TFA is trifluoroacetic acid; DMAP is 4-dimethylaminopyridine; Et3N is triethylamine, i.e., N,N-diethylethanamine; 2H or D is deuterium-labeled hydrogen; 3H is tritium-labeled hydrogen; Trt is trityl; Ts is tosyl; MeOH is methanol; EtOH is ethanol; ACN is acetonitrile; TEMPO is (2,2,6,6-tetramethylpiperidin-1-yl)oxyl; BHT is butylated hydroxytoluene, i.e., 2,6-di-tert-butyl-4-methylphenol; THF is tetrahydrofuran; NMR is nuclear magnetic resonance; HRMS is high resolution mass spectrometry; ESI is electron spray ionization; TLC is thin-layer chromatography; TBAI is tetra-n-butylammonium iodide; PPh3is triphenylphosphine; eq. is equation; equiv is equivalent; rt is room temperature; min or min. is minute(s); and h or hr. is hour(s). Described herein is the development of hydropersulfides and the synthetic methods for sulfur-containing compounds. This method reduces synthetic steps and proceeds under mild reaction conditions compared to the conventional method. The hydropersulfides enable various synthetic transformations under toxic metal-, additive-free, and mild reaction conditions. The sulfur-containing compounds have many applications in pharmaceuticals, agrochemicals, and functional materials. Current synthetic approaches toward hydropersulfides require four steps. See Bailey et al., J. Am. Chem. Soc.136(30): 10573-10576 (2014). The method described herein generates hydropersulfides in three steps with a higher yield. Hydrothiolation was performed using these hydropersulfides. This method generates sulfides without catalysts or additives while current methods require expensive transition metal catalysts or harsh reagents and additives. Vinylsuflides were also synthesized using hydropersulfides. Overall, the synthetic methods described herein will facilitate the synthesis of hydropersulfides and the discovery of new synthetic methods for sulfur-containing compounds. Described herein is the development of efficient synthetic methods for hydropersulfides and the development of mild synthetic methods for sulfur containing compounds. Hydropersulfide compounds have been synthesized. In addition, several synthetic transformations employing hydropersulfides to generate sulfur-containing compounds are described. These synthetic transformations will facilitate sulfide derivatives widely applicable for active pharmaceutical ingredients (API), insecticides, pesticides, and other commercially desired sulfur-containing compounds. Compounds of Formula (I) In one aspect, the present disclosure provides compounds of formula (I), or salts thereof, , wherein: Rzis –S–H, –S–C(O) R1is hydrogen, –C1–4alkyl, or –C6–12aryl; R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, 2, Z1is –C2–12alkyl, –C6–12alkenyl, –C8–16arylalkyl, –C8–16phenoxyalkyl, ; Ryis –C6–12aryl, –C(O)C6–12aryl, , –P(O)(OC1–4alkyl)2, –P(O)(C6–12aryl)2, –P(O)(OC8–16arylalkyl)2, –P(O)(C6–12aryl)(OC1–4alkyl), or –P(O)(OC6–12aryl)2; Rx is –C2–12alkyl, –C6–12aryl, –C3–8cycloalkyl, –C(O)C6–12aryl, or ;wherein, at each occurrence, the C6–12aryl, the C3–8cycloalkyl, the C8–16arylalkyl, and the C8–16phenoxyalkyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; with the proviso that the compound is not benzyldisulfane, (4-methoxybenzyl)disulfane, benzyl(2,3-dimethylbut-2-en-1-yl)sulfane, (E)-benzyl(3,7-dimethylocta-2,6-dien-1- yl)sulfane, bis(1-phenylethyl)sulfane, benzyl(1-phenylethyl)sulfane, benzyl(1- phenylpropyl)sulfane, benzyl(2-phenylpropan-2-yl)sulfane, benzyl(4-phenylbutan- 2-yl)sulfane, benzyl(1-(4-fluorophenyl)ethyl)sulfane, benzyl(1-(4- chlorophenyl)ethyl)sulfane, benzyl(1-(4-methoxyphenyl)ethyl)sulfane, benzyl(1- (naphthalen-1-yl)ethyl)sulfane. In various instances, R1is hydrogen or –C1–4alkyl. In various instances, R3is hydrogen or –C1–4alkyl. In various instances, n is 0 or 1. In various instances, n is 1. In various instances, . In various instances, R2, at each occurrence, is independently –CN, –NO2, –OH, or –OC(O)C1–4alkyl. In various instances, Rz Rzis –S–C(O)C1–4alkyl. In various instances, Rzis –Z1. In various instances, Z1is –C2–12alkyl, –C4–12alkenyl, –C8–16arylalkyl, or–C8–16phenoxyalkyl. In various instances, . In various instances, Rx is –C6–12aryl.In various instances, the C6–12aryl is phenyl. In various instances, The compound of any one of clauses 12–14, or the salt thereof, wherein Ryis –P(O)(OC1–4alkyl)2, –P(O)(C6–12aryl)2, P(O)(OC8–16arylalkyl)2, –P(O)(C6–12aryl)(OC1–4alkyl), or –P(O)(OC6–12aryl)2. In various instances, the compound is selected from the group consisting of: , , , , , , , , In the compounds described herein (e.g., compounds of formula (I)), any “hydrogen” or “H,” whether explicitly recited or implicit in the structure, encompasses hydrogen isotopes1H (protium),2H (deuterium). Accordingly, any group comprising one or more hydrogen atoms encompasses corresponding deuterium-labeled and / or tritium-labeled versions of the group. For example, “–CH2–” The present disclosure deuterium labeled), where an atom in the isotopically-labeled compound is specified as a particular isotope of the atom. Examples of isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron-emitting isotopes that may be incorporated in compounds described herein (e.g., compounds of formula (I) are11C,13N,15O, and18F. Isotopically-enriched forms of compounds described herein (e.g., compounds of formula (I)) may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-enriched reagent in place of a non-isotopically-enriched reagent. The extent of isotopic enrichment may be characterized as a percent incorporation of a particular isotope at an isotopically-labeled atom (e.g., % deuterium incorporation at a deuterium label). Methods of Preparation In another aspect, the present disclosure provides methods for preparing compounds of formula (V), or salts thereof, ; wherein: R1is hydrogen, –C1–4alkyl, or –C6–12aryl; R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, 2, optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; the method comprising: (a) providing a compound of formula (II), where LG is a leaving group: ; (b) reacting the intermediate sulfinothioate of formula (II-A), where M is sodium, potassium, O C aryl S6-12M S;in the presence of a of formula (III): ; (c) reacting the of formula (III-A), where M is sodium, potassium, or ; in the presence of a of formula (IV): (d) reacting the of formula (IV-A): HO-C1–4alkyl (IV-A); in the presence of an acid to provide a compound of formula (V): In various instances, the In another aspect, the preparing compounds of formula (VI), or salts thereof, ; wherein: R1is hydrogen, –C1–4alkyl, or –C6–12aryl; R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, or –P(O)(C6–12aryl)2; Z1is –C2–12alkyl, –C6–12alkenyl, –C8–16arylalkyl, or –C8–16phenoxyalkyl, wherein, at each occurrence, the C6–12aryl, the C3–8cycloalkyl, the –C8–16arylalkyl and the –C8–16phenoxyalkyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl,–C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; the method comprising: (a) providing a compound of formula (V): (b) reacting the compound of of formula (V-A): , wherein: Raat each occurrence, is independently hydrogen or C1–4alkyl, and R10is hydrogen, –C1–10alkyl, –C4–10alkenyl, –C6–12aryl, –C7–14arylalkyl, or –O-phenyl, wherein, at each occurrence, the –C6–12aryl, the –C7–14arylalkyl, and the –O-phenyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl,–C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; to provide a compound of formula (VI): I). In various instances, Raat ea drogen. In another aspect, the presen p s methods for preparing compounds of formula (VI), or salts thereof, ; wherein: 1 R is hydrogen, –C1–4alkyl, or R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, 2, 2, optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; the method comprising: (a) providing a compound of formula (V): nd (b) reacting the compound yne of formula (V-C): - ; in the presence of a solvent to provide a compound of formula (VI): . In some instances, Ryis or –P(O)(OC1–4alkyl)2. In another aspect, the present disclosure provides methods for preparing compounds of formula (V), or salts thereof, ; wherein: R1is hydrogen, –C1–4alkyl, or –C6–12aryl; R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, 2, optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; the method comprising: (a) providing a compound of formula (VIII): I); (b) reacting the compound of N-(S-acylthio)succinimide of formula (IX): ; in the presence of a of formula (IV) (c) reacting the of formula (IV-A): HO-C1–4alkyl (IV- ; in the presence of an acid to provide a compound of formula (V): In various instances, the Suitable reagents for readily obtained from commercial sources or prepared by standard methods well known to those skilled in the art. The compounds and intermediates may be isolated and purified by methods well-known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds may include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in “Vogel's Textbook of Practical Organic Chemistry,” 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England. A disclosed compound may have at least one basic nitrogen whereby the compound may be treated with an acid to form a desired salt. For example, a compound may be reacted with an acid at or above room temperature to provide the desired salt, which is deposited, and collected by filtration after cooling. Examples of acids suitable for the reaction include, but are not limited to tartaric acid, lactic acid, succinic acid, as well as mandelic, atrolactic, methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalenesulfonic, benzenesulfonic, carbonic, fumaric, maleic, gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric, hydroxybutyric, camphorsulfonic, malic, phenylacetic, aspartic, or glutamic acid, and the like. Reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and substituents present in the reactants used. Specific procedures are provided in the Examples section. Reactions may be worked up in the conventional manner, e.g., by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or may be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Starting materials, if not commercially available, may be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above-described schemes or the procedures described in the synthetic examples section. Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in PGM Wuts and TW Greene, in Greene’s book titled Protective Groups in Organic Synthesis (4thed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention may be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples. When an optically active form of a disclosed compound is required, it may be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution). Similarly, when a pure geometric isomer of a compound is required, it may be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation. It may be appreciated that the synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the invention as it is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims It will be apparent to one of ordinary skill in the relevant art that suitable modifications and adaptations to the compositions, formulations, methods, processes, and applications described herein can be made without departing from the scope of any embodiments or aspects thereof. The compositions and methods provided are exemplary and are not intended to limit the scope of any of the specified embodiments. All of the various embodiments, aspects, and options disclosed herein can be combined in any variations or iterations. The scope of the compositions, formulations, methods, and processes described herein include all actual or potential combinations of embodiments, aspects, options, examples, and preferences herein described. The exemplary compositions and formulations described herein may omit any component, substitute any component disclosed herein, or include any component disclosed elsewhere herein. The ratios of the mass of any component of any of the compositions or formulations disclosed herein to the mass of any other component in the formulation or to the total mass of the other components in the formulation are hereby disclosed as if they were expressly disclosed. Should the meaning of any terms in any of the patents or publications incorporated by reference conflict with the meaning of the terms used in this disclosure, the meanings of the terms or phrases in this disclosure are controlling. Furthermore, the foregoing discussion discloses and describes merely exemplary embodiments. All patents and publications cited herein are incorporated by reference herein for the specific teachings thereof. Various embodiments and aspects of the inventions described herein are summarized by the following clauses: Clause 1. A compound of formula (I), or a salt thereof, , wherein: Rzis –S–H, –S–C(O)C1–4alkyl, or Z1; R1is hydrogen, –C1–4alkyl, or –C6–12aryl; R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, the are substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; with the proviso that the compound is not benzyldisulfane, (4-methoxybenzyl)disulfane, benzyl(2,3-dimethylbut-2-en-1-yl)sulfane, (E)-benzyl(3,7-dimethylocta-2,6-dien-1- yl)sulfane, bis(1-phenylethyl)sulfane, benzyl(1-phenylethyl)sulfane, benzyl(1- phenylpropyl)sulfane, benzyl(2-phenylpropan-2-yl)sulfane, benzyl(4-phenylbutan- 2-yl)sulfane, benzyl(1-(4-fluorophenyl)ethyl)sulfane, benzyl(1-(4- chlorophenyl)ethyl)sulfane, benzyl(1-(4-methoxyphenyl)ethyl)sulfane, benzyl(1- (naphthalen-1-yl)ethyl)sulfane. Clause 2. The compound of clause 1, or the salt thereof, wherein R1is hydrogen or –C1–4alkyl. Clause 3. The compound of clause 1 or 2, or the salt thereof, wherein R3is hydrogen or – C1–4alkyl. Clause 4. The compound of any one of clauses 1–3, or the salt thereof, wherein n is 0 or 1. Clause 5. The compound of any one of clauses 1–4, or the salt thereof, wherein n is 1. Clause 6. The compound of any one of clauses 1–5, or the salt thereof, wherein . of any one of clauses 1–6, or the salt thereof, wherein R2, at each halogen, –OC1–4alkyl, –C1–4alkyl, –CN, –NO2, –OH, or –OC(O)C1–4alkyl. Clause 8. The compound of any one of clauses 1–7, or the salt thereof, wherein Rzis –S–H. Clause 9. The compound of any one of clauses 1–7, or the salt thereof, wherein Rzis –S– C(O)C1–4alkyl. Clause 10. The compound of any one of clauses 1–7, or the salt thereof, wherein Rzis –Z1. Clause 11. The compound of any one of clauses 1–7, or the salt thereof, wherein Z1is –C2–12alkyl, –C4–12alkenyl, –C8–16arylalkyl, or –C8–16phenoxyalkyl. Clause 12. The compound of any one of clauses 1–7, or the salt thereof, wherein Z1is . compound of clause 12, or the salt thereof, wherein Rxis –C6–12aryl. Clause 14. The compound of any one of clauses 1–13, or the salt thereof, wherein the C6–12aryl is optionally substituted phenyl. Clause 15. The compound of any one of clauses 12–14, or the salt thereof, wherein Ryis –P(O)(OC1–4alkyl)2, –P(O)(C6–12aryl)2, P(O)(OC8–16arylalkyl)2, –P(O)(C6–12aryl)(OC1–4alkyl), or –P(O)(OC6–12aryl)2. Clause 16. The compound of any one of clauses 1–15, or the salt thereof, wherein the compound is selected from the group consisting of: , , ,, , R1is hydrogen, –C1–4alkyl, or –C6–12aryl; R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, or –P(O)(C6–12aryl)2; and wherein, at each occurrence, the C6–12aryl and the C3–8cycloalkyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; the method comprising: (a) providing a compound of formula (II), where LG is a leaving group: ; (b) reacting the intermediate sulfinothioate of formula (II-A), where M is sodium, potassium, or O C6-12aryl S ; in the presence of a of formula (III): ; (c) reacting the of formula (III-A), where M is sodium, potassium, or cesium: ; in the presence of a of formula (IV): (d) reacting the of formula (IV-A): HO-C1–4alkyl (IV-A); in the presence of an acid to provide a compound of formula (V): . Clause 18. The method of clause HBr, HNO3, H2SO4, or H3PO4. Clause 19. A method for preparing (VI), or a salt thereof, ; wherein: 1 R is hydrogen, –C1–4alkyl, or R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, or –P(O)(C6–12aryl)2; Z1is –C2–12alkyl, –C6–12alkenyl, –C8–16arylalkyl, or –C8–16phenoxyalkyl, wherein, at each occurrence, the C6–12aryl, the C3–8cycloalkyl, the –C8–16arylalkyl and the –C8–16phenoxyalkyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl,–C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; the method comprising: (a) providing a compound of formula (V): (b) reacting the compound of of formula (V-A): , wherein: Raat each occurrence, is independently hydrogen or C1–4alkyl, and R10is hydrogen, –C1–10alkyl, –C4–10alkenyl, –C6–12aryl, –C7–14arylalkyl, or –O-phenyl, wherein, at each occurrence, the –C6–12aryl, the –C7–14arylalkyl, and the –O-phenyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl,–C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; to provide a compound of formula (VI): . Clause 20. The method of clause occurrence, is hydrogen. Clause 21. A method for a (VI), or a salt thereof, ; wherein: R1is hydrogen, –C1–4alkyl, or –C6–12aryl; R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, 2, 2, Rx is –C2–12alkyl, –C6–12aryl, –C3–8cycloalky ,wherein, at each occurrence, the C6–12aryl each independently optionally substituted with 1–3 subs group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; the method comprising: (a) providing a compound of formula (V): (b) reacting the of formula (V-C): ; in the presence of a solvent to provide a compound of formula (VI): Clause 22. The method of clause2. Clause 23. A method for preparing a ; wherein: R1is hydrogen, –C1–4alkyl, or –C6–12aryl; R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, or –P(O)(C6–12aryl)2; and wherein, at each occurrence, the C6–12aryl and the C3–8cycloalkyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; the method comprising: (a) providing a compound of formula (VIII): ; (b) reacting the compound of N-(S-acylthio)succinimide of formula (IX): ; in the presence of a of formula (IV) (c) reacting the of formula (IV-A): HO-C1–4alkyl (IV-A); in the presence of an acid to provide a compound of formula (V): . Clause 24. The method of clause HBr, HNO3, H2SO4, or H3PO4. Clause 25. Use of the compounds of any one of clauses 1–16 for industrial, agricultural, or medical applications. EXAMPLES Example 1 Hydropersulfides (RSSH) are an emerging, understudied functional group. They have cell protective properties such as protecting cysteine residues from oxidation and distinct signaling pathways in physiological systems. Hydropersulfides (RSSH), compared to thiols (RSH), show enforced reactivities: a more nucleophilic and acidic compound due to the alpha effect. The reactivity study of hydropersulfides has been conducted mainly in physiological systems due to the unstable nature of the hydropersulfides although some alkyl hydropersulfides have been studied in oxidation and addition reactions: oxidation of Ph3P to Ph3PS and addition reaction to succinimide. However, understanding the fundamental chemistry of hydropersulfide functionality remains a pressing challenge since current studies have been limited to in-situ physiological environments. Hence, their reactivity study under a more controlled environment is crucial to develop a new synthetic methodology. Table 1. Exemplary Thioether Compounds acid) 1- N-(3- 2- Hydrothiolation, the addition of H and RSH across a pi-bond, is a prominent C–S bond- forming method to generate thioether compounds. Thioethers have been widely used in medicinal chemistry and chemical biology (Table 1). For example, probucol, butoconazole, and cimetidine were developed to treat high cholesterol, fungal infections, and stomach ulcers, respectively. In addition, benzylthioethers serve as a key motif for pesticides and insecticides, while thioethers have also been utilized to form micelles, aiding drug delivery. Furthermore, other thioethers such as methionine and biotin are known for antioxidants and support healthy hair and nails. Therefore, hydrothiolation reaction has been extensively studied for thioether synthesis: Brønsted acids-catalyzed thiol-ene reaction, Lewis acid-mediated hydrothiolation, radical thiol- ene reaction, and transition metal-catalyzed hydrothiolation reaction (Scheme 1). However, these current methods require Bronsted acids, Lewis acids, transition metals, additives, and elevated reaction conditions. Hydrothiolation free of catalysts, additives, and solvents under mild reaction conditions remains elusive. Scheme 1. Precedent Hydrothiolation Reactions. BA is Brønsted Acid; LA is Lewis Acid. R1R4R4SR Along the line with the fundamental chemistry study and the development of a new synthetic methodology using hydropersulfides, a new hydrothiolation reaction without catalysts, additives was developed because of their multifunctional roles: Brønsted acid, hydrogen atom donor, and sulfur nucleophile / electrophile (Scheme 2). With resonance stabilization of perthiyl anion by alpha effect, hydropersulfides serve as a proton donor and sulfur nucleophile (Scheme 2, eq. 1). Hydropersulfide also reacts with nucleophiles (PPh3, Et3N, DMAP), serving as electrophiles (Scheme 2, eq. 2). It was hypothesized that hydropersulfides undergo hydrothiolation with alkenes to generate thioether derivatives without catalysts or additives (Scheme 2, eq.3). This new hydrothiolation reaction – no catalysts and additives – will address green and sustainable chemistry: environmentally friendly, atom economic synthesis. Scheme 2. Reactivity of Hydropersulfide Known Hydropersulfide Reactivity New To test this hypothesis, styrene 1a was treated with benzyl hydropersulfide 2a (Table 2). First, the reaction was tested in THF and diethyl ether, and they provided the target product 3a in 47% and 61% yields, respectively (Table 2, entries 1–2). When the reaction was run in ethanol, product 3a was generated in a 15% yield (Table 2, entry 3). This low yield could be due to the H- bonding solvation effects of benzyl hydropersulfide 2a, which reduces the reactivity by heightening the barrier for radical subtraction or through competing proton transfer between the styrene and the solvent. Next, both aprotic polar solvent (acetonitrile) and nonpolar solvent (toluene) were evaluated, and they provided the corresponding product 3a with 48% and 51% yields, respectively (Table 2, entries 4–5). When the solvent was changed to DCM, product 3a was formed in a 73% yield (Table 2, entry 6). Lastly, neat conditions produced the target product 3a in 77% yield (Table 2, entry 7). The polysulfides were detected in crude reaction mixtures, and they were identified by matching with known polysulfides (dibenzyl trisulfide, dibenzyl tetrasulfide, and dibenzyl pentasulfide). However, the formation of polysulfides was suppressed under neat conditions. Presumably, the hydrothiolation reaction rate is faster than the polysulfide formation from the intermolecular reaction of 2a under neat conditions. Table 2. Hydrothiolation Reaction Optimization[a]S 4 ACN 48 5 Toluene 51 6 DCM 73 7 Neat 77 (77)[c][a]1a (0.1 mmol) and 2a (0.1 mmol) in solvent for 1 h at rt.[b]Crude NMR yield determined by mesitylene internal standard.[c]Isolated yield. With the optimized reaction conditions established, the reaction was tested with diverse styrenes to determine the steric and electronic effects on the reaction outcome (Scheme 3). Halogenated styrenes 1b–1d (4-Br, 4-Cl, and 4-F) were well tolerated, giving the target products 3b–3d high yields (77–82%). Styrenes with electron-donating groups 1e–1g (4-Me, 2-Me, 4- OMe) showed increased reactivity providing 3e–3g in 79%-89% yields. Styrene 1h bearing a tertiary amine also afforded 3h in 64% yield. This decreased yield is presumably due to the protonation of basic nitrogen which reduces the styrene nucleophilicity. An electron-withdrawing group on styrene 1i (4-CN) was also tolerated, affording 3i in 80% yield. Next, the reaction was tested with alkyl olefins 1j and 1k, but they formed the target compounds 3j and 3k in low yields. It is postulated that the aliphatic alkene decreases the stability of the electron-deficient carbon intermediates. A bulky naphthyl styrene 1l was also well tolerated, generating 3l in 86% yield. In addition, the substituents on the styrene were modified to test the steric effect on the reaction outcome. Alpha methyl styrene 1m was well tolerated to furnish 3m in a moderate yield of 65%. Beta methyl styrene 1n was dormant under the standard reaction conditions. However, the target product 3n was generated under refluxing toluene in a moderate yield of 53%. Furthermore, 1,3- butadiene 1o yielded the allylic thioether product 3o in 59%. Overall, the hydrothiolation reaction tolerates styrene derivatives bearing electron-donating and withdrawing groups. A decrease in reactivity, however, was observed when the reaction was tested with alkyl or sterically hindered olefins. Scheme 3. Alkene Substrate Scope d After screening alkenes, hydropersulfides 2 were examined to evaluate the electronic and steric effects on the reaction outcome (Scheme 4). First, halogenated hydropersulfide 2b with styrene 1a provided the target product 4a in 67% yield. The reduced yield could be attributed to a reduced alpha effect that affects the acidity of 2b, 4-fluorobenzyl hydropersulfide. Next, when electron-rich benzyl hydropersulfide 2c was employed, 4b was formed in a high yield of 83%. In addition, the steric effect of hydropersulfide was investigated with alpha-methyl hydropersulfide 2d, and it provided symmetrical thioether 4c in 57% yield. These data reflect that the electronic and steric effects on hydropersulfides are tolerable. Scheme 4. Hydropersulfide Substrate Scope To gain an insight into a reaction mechanism, several control experiments were performed (Scheme 5). First, the effect of light on this reaction was evaluated. When the reaction between styrene 1a and hydropersulfide 2a ran under no light, the target product 3a was formed in 73% yield (Scheme 5, eq. 1). When TEMPO was used, no product but tetrapersulfide 3aa was generated (Scheme 5, eq. 2). It is known that hydropersulfide undergoes dimerization in the presence of TEMPO. However, when BHT was introduced to the reaction, the target product 3a was still produced in 65% yield (Scheme 5, eq.3). In addition, when the radical clock experiment was performed with bromomethyl cyclopropane 2aa, no corresponding radical-mediated product 3aaa was generated (Scheme 5, eq. 4). These data suggest that the reaction might proceed through a non-radical pathway. To track the hydropersulfide proton, a deuterated hydropersulfide 1a(D) was used under standard reaction conditions. The corresponding Markovnikov addition product 3a(D) was generated in a 73% yield with 80% deuterium incorporation (Scheme 5, eq. 5). To elucidate the potential byproduct of sulfur derivatives (S8) in this reaction, the sulfur species was attempted to be trapped. (Scheme 5, eq. 6). After 1 hour of the standard reaction, 1 equivalent PPh3was introduced to the reaction, and this one-pot reaction generated both the target product 3g and the triphenylphosphine sulfide 5a in 78% yields. This experiment result implies that S8could be a byproduct. Overall, these control experiments suggest that the reaction proceeds via the proton transfer process of Markovnikov addition. Scheme 5. Mechanism Study Control Experiments

[0002] Based on the results of the control experiments and the literature and without being bound by any theory, a plausible mechanism is proposed (Scheme 6). The styrene 1a reacts with hydropersulfide 2a to form thiosulfoxide intermediate I via a concerted mechanism. The thiosulfoxide intermediate I is postulated to somehow undergo rearrangement / fragmentation to release sulfur element, which is trapped in the control experiment (Scheme 5, eq.6). Scheme 6. Proposed Mechanism Mechanism A: Concerted Ionic Mechanism Mechanism B: Concerted Radical Mechanism (based on Galardon and Padovani, Bioconjugate Chem.26(6): 1013-1016 (2015)) HSS S0 Ph on Med.89: 662–667 (2015)) In summary, a sustainable, highly hydrothiolation reaction of alkenes using hydropersulfides (RSSH) has been developed. The reaction can proceed with Markovnikov selectivity and transition metal-, additive-, and solvent-free under mild conditions. Example 2 Hydropersulfides were employed for the hydrothiolation reaction of alkynes to expand the scope of thioethers. Scheme 7 illustrates the reaction of two differently substituted alkynes 6a and 6b with hydropersulfide 2a to yield vinyl sulfides 7a and 7b. Scheme 7. Hydropersulfide-Mediated Hydrothiolation of Alkynes

[0003] Example 3 Furthermore, an efficient route of hydropersulfide synthesis was developed. Scheme 8 displays the conventional four-step alkyl hydropersulfide synthesis, while Scheme 9 introduces the present three-step alkyl hydropersulfide synthesis. Scheme 8. Conventional Alkyl Persulfide Synthesis (RSSH) Scheme 9. Efficient Alkyl Persulfide Synthesis Scheme 10. Persulfide Synthesis via Transpersulfidation General Methods All reactions were carried out under air atmosphere in oven-dried glassware with magnetic stirring bar. Dry solvents (THF, toluene, ACN, diethyl ether, and DCM) were obtained by solvent purification system under argon. All commercially available reagents were used as received without further purification. IKA Electra Syn 2.0 and commercially available electrodes were used for the reactions. Purification of reaction products was carried out by flash column chromatography using silica gel 60 (230–400 mesh). Analytical thin layer chromatography was performed on 0.25 mm aluminum-backed silica gel 60-F plates. Visualization was accompanied with UV light and KMnO4solution. Concentration under reduced pressure refers to the removal of volatiles using a rotary evaporator attached to a dry diaphragm pump (10-15 mm Hg) followed by pumping to a constant weight with an oil pump (<300 mTorr). Infrared (IR) spectra were recorded on an IR spectrometer with KBr wafers or a film on KBr plate. High-resolution mass spectra (HRMS) were recorded on liquid chromatography ion trap time-of-flight (LCMS-IT-TOF) mass spectrometer using ESI (electrospray ionization) or APCI (atmospheric pressure chemical ionization).1H NMR spectra were recorded in CDCl3on 400 MHz NMR spectrometer. The1H chemical shifts are referenced to residual solvent signals at δ 7.26 (CHCl3) or δ 0.00 (TMS).1H NMR coupling constants (J) are reported in Hertz (Hz) and multiplicities are indicated as follows: s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), tt (triplet of triplets).13C NMR spectra were proton decoupled and recorded in CDCl3on 100.5 MHz NMR spectrometer. The13C chemical shifts are referenced to solvent signals at δ 77.16 (CDCl3).31P NMR spectra were proton decoupled and recorded in CDCl3on 162 MHz NMR spectrometer.31P chemical shifts are reported relative to 85% H3PO4(0.00 ppm) as an external standard.19F chemical shifts are reported relative to the external standard (contained in a coaxial capillary) trifluoroacetic acid in CDCl3: δ – 76.55 ppm. Exemplary Reactions Scheme 11. Synthesis of Hydrogen Persulfide 2 Step One: To a soluti mol) in acetonitrile (15.0 mL) was added alky a e (6.0 mmo) an e reac on was re uxe for 6 hours. The crude mixture was filtered, concentrated under reduced pressure, and purified by column chromatography. Step Two: To a potassium thioacetic acid (5.5 mmol) and the was room The crude mixture was filtered, concentrated under reduced pressure, and purified by column chromatography. Step Three: To a (1.5 mL) under inert conditions was added 5 M methanolic HCl (600 µL) and the reaction was stirred for 30 minutes. The crude reaction was then concentrated under reduced pressure to give hydropersulfide 2. Scheme 12. Synthesis of Alkene 1 To a solution mmol) and potassium carbonate (2.0 mmol) in anhydrous THF (5.0 mL) was added aldehyde (1.0 mmol) and the reaction was refluxed for 12 hours under argon. The crude reaction was diluted with diethyl ether (5.0 mL) and filtered. The crude reaction mixture was then concentrated under reduced pressure and purified by column chromatography to give 1. Scheme 13. Synthesis of Deuterated Benzyl Hydropersulfide 2a(D) To a solution of di L) under inert conditions was added 5 M methanolic DC (300 µL) and t e reacton was strred for 30 minutes. The crude reaction was then concentrated under reduced pressure to give hydropersulfide 2a(D). Scheme 14. General Hydrothiolation Procedure: Synthesis of 3 Alkene 1 neat for 1 hour. The crude reaction mixture was then directly purified by column chromatography to give thioether product 3. Scheme 15. General Hydrothiolation Procedure: Synthesis of 4 Styrene 1a (0.1 for 1 hour. The crude reaction mixture was then directly purified by column chromatography to give thioether product 4. Scheme 16. General Hydrosulfuration of Alkynes Procedure: Synthesis of 7 Alkyne 6 (1.0 equiv) and hydropersulfide 2a (1.0 equiv) were stirred in toluene at room temperature for 12 hours. The crude reaction mixture was then directly purified by column chromatography to give thioether product 7. Compounds Benzyldisulfane (2a). See Bailey and Pluth, Free Radic. Biol. Med.89: 662-667 (2015). 42.5 mg, 91%; as an oil. IR ^ (thin film, cm−1) 3027, 2502, 1601, 1493, 1452, 1232, 1070, 1028, 871, 764, 698.1H NMR (400 MHz, CDCl3): δ 7.34–7.28 (m, 5H), 3.89 (s, 2H), 2.88 (s, 1H).13C NMR (100.5 MHz, CDCl3): δ 136.6, 129.2, 128.5, 127.5, 44.7. (4-Fluorobenzyl)disulfane (2b). 48.9 IR ^ (thin film, cm−1) 3045, 2918, 2499, 1602, 1511, 1223, 1154, 1091, 1016, (400 MHz, CDCl3) δ 7.29–7.26 (m, 2H), 7.04–7.00 (m, 2H), 3.86 (s, 2H), 2.86 (s, 1H).13C NMR (100.5 MHz, CDCl3): δ 161.2 (d, J = 244.9 Hz), 134.4 (d, J = 3.0 Hz), 130.8 (d, J = 8.2 Hz), 115.4 (d, J = 21.6 Hz), 43.8. (4-Methoxybenzyl)disulfane (2c). Chem. Soc. Japan 48 (10): 2993-2994 (2006). 56.0 mg, 99%; as an oil. IR ^ (thin film, cm−1) 3030, 2953, 2501, 1608, 1510, 1460, 1247, 1172, 1103, 1031, 873, 829.1H NMR (400 MHz, CDCl3): δ 7.25–7.21 (m, 2H), 6.87–6.85 (m, 2H), 3.85 (s, 2H), 3.80 (s, 3H), 2.87 (s, 1H).13C NMR (100.5 MHz, CDCl3): δ 159.0, 130.4, 128.6, 113.9, 55.2, 44.3. (1-Phenylethyl)disulfane (2d). 50.0 IR ^ (thin film, cm−1) 3026, 2964, 2501, 1492, 1452, 1371, 1209, 1043, 763, 696.1H NMR (400 MHz, CDCl3): δ 7.36–7.24 (m, 5H), 4.03 (q, J = 6.8 Hz, 1H), 2.77 (s, 1H), 1.68 (d, J = 6.8 Hz, 3H).13C NMR (100.5 MHz, CDCl3): δ 141.4, 128.4, 127.6, 127.5, 50.4, 20.0. 1-Benzyldisulfane-2-d (2a(D)). 45.5 IR ^ (thin film, cm−1) 3026, 2956, 1946, 1492, 1230, 1122, 1070, 761, 696.1H NMR (400 MHz, CDCl3): δ 7.36–7.24 (m, 5H), 3.88 (s, 2H).13C NMR (100.5 MHz, CDCl3): δ 136.7, 129.2, 128.5, 127.5, 44.7. Benzyl(1-phenylethyl)sulfane (3a). S ature Comm. 10 (1): 1752 (2019). 17.5 mg, 77%; as an oil. IR ^ (thin film, cm−) 3060, 2966, 2922, 1601, 1492, 1452, 1222, 1026, 764, 699.1H NMR (400 MHz, CDCl3) δ: 7.38–7.31 (m, 4H), 7.29–7.19 (m, 6H), 3.81 (q, J = 7.2 Hz, 1H), 3.53 (d, J = 13.6 Hz, 1H), 3.44 (d, J = 13.6 Hz, 1H), 1.52 (d, J = 6.8 Hz, 3H).13C NMR (100.5 MHz, CDCl3): δ 143.8, 138.4, 128.8, 128.5, 128.3, 127.4, 127.0, 126.8, 43.5, 35.7, 22.5. Benzyl(1-phenylethyl-2-d)sulfane as an oil. IR ^ (thin film, cm−1) 3027, 2928, 1601, 1492, 1452, 1071, 762, 698.1H NMR (400 MHz, CDCl3): δ 7.37–7.19 (m, 10H), 3.80 (t, J = 6.8 Hz, 1H), 3.53 (d, J = 13.6 Hz, 1H), 3.44 (d, J = 13.6 Hz, 1H), 1.51 (app dt, J = 6.8, 2.0 Hz, 2H).13C NMR (100.5 MHz, CDCl3): δ 143.7, 138.4, 128.8, 128.4, 128.3, 127.4, 127.0, 126.8, 43.4, 35.7, 22.5, 22.2 (t, J = 20.1 Hz). HRMS(ESI): m / z calcd. For C15H15DS ([M+H]+): 230.1109; found 230.1108. Benzyl(1-(4-bromophenyl)ethyl) as an oil. IR ^ (thin film, cm−1) 3027, 2967, 1601, 1486, 1452, 1403, 1072, 1009, 825, 721, 721.1H NMR (400 MHz, CDCl3): δ 7.45– 7.42 (m, 2H), 7.30–7.17 (m, 7H), 3.74 (q, J = 7.2 Hz, 1H), 3.53 (d, J = 13.6 Hz, 1H), 3.42 (d, J = 13.6 Hz, 1H), 1.48 (d, J = 7.2 Hz, 3H).13C NMR (100.5 MHz, CDCl3): δ 142.9, 138.1, 131.5, 129.1, 128.8, 128.4, 126.9, 120.6, 42.9, 35.7, 22.4. HRMS(ESI): m / z calcd. for C15H15BrS ([M+H]+): 307.0156; found 307.0169. Benzyl(1-(4-chlorophenyl)ethyl)sulfane (3c). See Cabrero-Antonino, Adv. Synth. Catalysis 354(4): 678-687 (2012). 20.7 mg, 79%; as an oil. IR ^ (thin film, cm−1) 3027, 2967, 1601, 1492, 1407, 1091, 1014, 830, 698.1H NMR (400 MHz, CDCl3): δ : 7.32–7.19 (m, 9H), 3.75 (q, J = 7.2 Hz, 1H), 3.53 (d, J = 13.2 Hz, 1H), 3.42 (d, J = 13.2 Hz, 1H), 1.49 (d, J = 7.2 Hz, 3H).13C NMR (100.5 MHz, CDCl3): δ 142.3, 138.1, 132.6, 128.9, 128.8, 128.6, 128.4, 126.9, 42.8, 35.7, 22.5. Benzyl(1-(4-fluorophenyl)ethyl) al. Nature Comm.10 (1): 1752 (2019). 18.9 mg, 77%; as an oil. IR ^ (thin 1601, 1508, 1452, 1223, 1156, 835, 702.1H NMR (400 MHz, CDCl3): δ 7.33–7.20 (m, 7H), 7.03–6.98 (m, 2H), 3.78 (q, J = 7.2 Hz, 1H), 3.54 (d, J = 13.2 Hz, 1H), 3.43 (d, J = 13.2 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H).13C NMR (100.5 MHz, CDCl3): δ 161.7 (d, J = 244.2 Hz), 139.5 (d, J = 3.0 Hz), 138.2, 128.9 (d, J = 7.2 Hz), 128.8, 128.4, 126.8, 115.2 (d, J = 21.6 Hz), 42.7, 35.7, 22.6. Benzyl(1-(p-tolyl)ethyl)sulfane (3e). oil. IR ^ (thin−1 film, cm ) 3027, 2922, 1601, 1512, 1452, 1222, 1113, 818, 702.1H NMR (400 MHz, CDCl3): δ 7.30–7.20 (m, 7H), 7.13 (d, J = 8.0 Hz, 2H), 3.78 (q, J = 7.2 Hz, 1H), 3.53 (d, J = 13.6 Hz, 1H), 3.44 (d, J = 13.6 Hz, 1H), 2.34 (s, 3H), 1.51 (d, J = 7.2 Hz, 3H).13C NMR (100.5 MHz, CDCl3): δ 140.7, 138.5, 136.6, 129.1, 128.8, 128.3, 127.3, 126.7, 43.2, 35.6, 22.5, 21.0; HRMS(ESI): m / z calcd. for C16H18S ([M+H]+): 243.1207; found 243.1209. Benzyl(1-(o-tolyl)ethyl)sulfane (3f). oil. IR ^ (thin film, cm−1) 3026, 2922, 1601, 1492, 1453, 1159, 1070, 762, 699.1H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 7.6 Hz, 1H), 7.29–7.18 (m, 6H), 7.14–7.08 (m, 2H), 4.02 (q, J = 6.8 Hz, 1H), 3.61 (d, J = 13.2 Hz, 1H), 3.52 (d, J = 13.2 Hz, 1H), 2.10 (s, 3H), 1.52 (d, J = 6.8 Hz, 3H).13C NMR (100.5 MHz, CDCl3): δ 141.0, 138.3, 135.5, 130.3, 128.8, 128.3, 126.8, 126.7, 126.6, 126.4, 38.7, 35.6, 21.6, 18.9. HRMS(ESI): m / z calcd. for C16H18S ([M+H]+): 243.1207; found 243.1205. (4-Methoxybenzyl)(1-phenylethyl) et al., Beilstein J. Org. Chem. 12: 2627-2635 (2016). 21.4 mg, 83%; cm−1) 3027, 2924, 1610, 1511, 1452, 1300, 1248, 1174, 1035, 830, 764, 699.1H NMR (400 MHz, CDCl3): δ 7.32–7.23 (m, 5H), 7.13 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H), 3.80–3.78 (m, 1H), 3.49 (d, J = 13.2 Hz, 1H), 3.40 (d, J = 13.2 Hz, 1H), 1.52 (d, J = 6.8 Hz, 3H);13C NMR (100.5 MHz, CDCl3): δ 158.4, 143.9, 130.3, 129.9, 128.4, 127.4, 127.0, 113.7, 55.2, 43.4, 35.0, 22.5. 4-(1-(Benzylthio)ethyl)-N,N- 64%; as an oil. IR ^ (thin film, cm−1) 3027, 2921, 1613, 1521, 1452, 1348, 1164, 1062, 946, 818, 699.1H NMR (400 MHz, CDCl3): δ 7.28–7.22 (m, 5H), 7.19 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 3.77 (q, J = 6.8 Hz, 1H), 3.53 (d, J = 13.6 Hz, 1H), 3.44 (d, J = 13.6 Hz, 1H), 2.94 (s, 6H), 1.50 (d, J = 7.2 Hz, 3H).13C NMR (100.5 MHz, CDCl3): δ 149.7, 138.8, 131.3, 128.9, 128.3, 128.1, 126.6, 112.5, 43.0, 40.6, 35.6, 22.6. HRMS(ESI): m / z calcd. for C17H21NS ([M+H]+): 272.1473; found 272.1479. 4-(1-(Benzylthio)ethyl)benzonitrile oil. IR ^ (thin film, cm−1) 3029, 2227, 1605, 1495, 1452, 1222, 840, 700.1H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 6.8 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.30–7.17 (m, 5H), 3.80 (q, J = 7.2 Hz, 1H), 3.56 (d, J = 13.6 Hz, 1H), 3.42 (d, J = 13.6 Hz, 1H), 1.51 (d, J = 7.2 Hz, 3H).13C NMR (100.5 MHz, CDCl3): δ 149.5, 137.6, 132.3, 128.6, 128.5, 128.2, 127.1, 118.8, 110.8, 43.2, 35.8, 22.2. HRMS(ESI): m / z calcd. for C16H15NS ([M+H]+): 254.1003; found 254.1000. Benzyl(4-phenylbutan-2-yl)sulfane , Tetrahedron Lett. 40(15): 2903-2906 (1999). 8.5 mg, 33%; as an oil. IR (thin film, cm−) 3026, 2921, 1601, 1495, 1453, 1236, 746, 698.1H NMR (400 MHz, CDCl3): δ 7.29–7.22 (m, 7H), 7.18–7.15 (m, 1H), 7.12–7.10 (m, 2H), 3.7 (s, 2H), 2.70–2.63 (m, 3H), 1.90–1.73 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H).13C NMR (100.5 MHz, CDCl3): δ 141.9, 138.7, 128.8, 128.5, 128.4, 128.3, 126.8, 125.7, 38.7, 38.4, 34.8, 33.0, 21.2. Benzyl(1-phenoxypropan-2-yl) as an oil. IR ^ (thin film, cm−1) 3027, 2925, 1600, 1495, 1241, 1031, 745, 692.1H NMR (400 MHz, CDCl3): δ 7.36–7.22 (m, 7H), 6.96– 6.92 (m, 1H), 6.86–6.83 (m, 2H), 4.06–4.03 (m, 1H), 3.91–3.81 (m, 3H), 3.07–3.02 (m, 1H), 1.34 (d, J = 6.8 Hz, 3H).13C NMR (100.5 MHz, CDCl3): δ 158.5, 138.4, 129.4, 128.8, 128.5, 127.0, 120.8, 114.5, 72.6, 38.4, 35.6, 18.1. HRMS(ESI): m / z calcd. for C16H18OS ([M+Na]+): 281.0976; found 281.0972. Benzyl(1-(naphthalen-1-yl)ethyl) al., Asian J. Organ. Chem.9(5): 773- 777 (2020). 24.0 mg, 86%; as an oil. IR ^ (thin film, cm−1) 3059, 3029, 2922, 1597, 1493, 1071, 1028, 798, 777, 699.1H NMR (400 MHz, CDCl3): δ 7.86–7.83 (m, 2H), 7.75–7.72 (m, 2H), 7.48– 7.39 (m, 4H), 7.28–7.22 (m, 2H), 7.19–7.16 (m, 2H), 4.62 (q, J = 6.8 Hz, 1H), 3.65 (d, J = 13.2 Hz, 1H), 3.55 (d, J = 13.2 Hz, 1H), 1.70 (d, J = 6.8 Hz, 3H).13C NMR (100.5 MHz, CDCl3): δ 138.7, 138.3, 133.9, 131.0, 129.0, 128.9, 128.4, 127.6, 126.9, 125.8, 125.52, 125.5, 124.4, 123.0, 38.6, 35.9, 22.1. Benzyl(2-phenylpropan-2-yl)sulfane ( %; as an oil. IR ^ (thin film, cm−1) 3029, 2964, 1601, 1493, 1453, 1133, 1098, 768, 696. H NMR (400 MHz, CDCl3): δ 7.59–7.56 (m, 2H), 7.36–7.30 (m, 3H), 7.25–7.16 (m, 3H), 7.13–7.11 (m, 2H), 3.39 (s, 2H), 1.72 (s, 6H).13C NMR (100.5 MHz, CDCl3): δ 146.2, 138.1, 128.9, 128.3, 128.1, 126.7, 126.6, 126.5, 48.5, 34.5, 30.2. Benzyl(1-phenylpropyl)sulfane (3n). Comm.10 (1): 1752 (2019). 12.7 mg, 53%; as an oil. IR ^ (thin film, 3027, 2928, 1601, 1493, 1452, 1238, 1070, 758, 698.1H NMR (400 MHz, CDCl3): δ 7.34–7.19 (m, 10H), 3.56–3.52 (m, 2H), 3.41 (d, J = 13.2 Hz, 1H), 1.90–1.78 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H).13C NMR (100.5 MHz, CDCl3): δ 142.4, 138.5, 128.9, 128.4, 128.3, 128.1, 127.0, 126.7, 50.3, 35.3, 29.5, 12.2. Benzyl(2,3-dimethylbut-2-en-1-yl) et al., ACS Catal. 10(11): 6013-6022 (2020). 12.2 mg, 59%; as an oil. IR ^ (thin film, cm−1) 3027, 2898, 2914, 1661, 1601, 1493, 1452, 1373, 1226, 1070, 762, 689.1H NMR (400 MHz, CDCl3): δ 7.32–7.25 (m, 5H), 3.87 (s, 2H), 3.19 (s, 2H), 1.69 (s, 6H), 1.66 (s, 3H).13C NMR (100.5 MHz, CDCl3): δ 137.6, 130.6, 129.3, 128.5, 127.3, 122.9, 43.8, 43.6, 20.9, 20.7, 18.1. (4-Fluorobenzyl)(1-phenylethyl) as an oil. IR ^ (thin film, cm−1) 3027, 2924, 1600, 1508, 1452, 1223, 1156, 834, 764, 699.1H NMR (400 MHz, CDCl3): δ 7.35–7.28 (m, 5H), 7.26–7.22 (m, 2H), 7.18–7.14 (m, 2H), 3.79 (q, J = 6.8 Hz, 1H), 3.49 (d, J = 13.2 Hz, 1H), 3.41 (d, J = 13.2 Hz, 1H), 1.52 (d, J = 6.8 Hz, 3H).13C NMR (100.5 MHz, CDCl3): δ 160.7 (d, J = 244.1 Hz), 143.6, 134.1 (d, J = 2.3 Hz), 130.3 (d, J = 8.2 Hz), 128.5, 127.4, 127.1, 115.2 (d, J = 21.6 Hz), 43.6, 34.9, 22.5. HRMS(ESI): m / z calcd. for C15H15FS ([M+H]+): 247.0957; found 247.0963 (4-Methoxybenzyl)(1-phenylethyl) 83%; as an oil. IR ^ (thin film, cm−1) 3027, 2924, 1610, 1511, 1452, 830, 764, 699.1H NMR (400 MHz, CDCl3): δ 7.32–7.23 (m, 5H), 7.13 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 3.81–3.77 (m, 1H), 3.78 (s, 3H), 3.49 (d, J = 13.2 Hz, 1H), 3.40 (d, J = 13.2 Hz, 1H), 1.52 (d, J = 6.8 Hz, 3H).13C NMR (100.5 MHz, CDCl3): δ 158.4, 143.9, 130.3, 129.9, 128.4, 127.4, 127.0, 113.7, 55.2, 43.4, 35.0, 22.5. HRMS(ESI): m / z calcd. for C16H18OS ([M+H]+): 259.1157; found 259.1155. Bis(1-phenylethyl)sulfane (4c). See (20): 4286-4291 (2024). 13.9 mg, 57%; as an oil. IR ^ (thin film, cm−1) 3027, 2922, 1601, 1490, 1452, 1373, 1220, 1048, 1026, 764, 698.1H NMR (400 MHz, CDCl3): δ 7.30–7.19 (m, 10H), 3.78 (q, J = 7.2 Hz, 2H), 1.55 (d, J = 7.2 Hz, 6H).13C NMR (100.5 MHz, CDCl3): δ 143.6, 128.4, 127.2, 126.9, 43.5, 22.4. (Z)-3-(1-(benzylthio)-2-phenylvinyl) .1H NMR (400 MHz, CDCl3): δ 7.46– 7.41 (m, 2H), 7.35–7.30 (m, 8H), 6.76(s, 1H), 4.48 (t, J = 7.2 Hz, 2H), 4.01 (s, 2H), 3.81–3.77 (t, J = 7.8 Hz, 2H) (Z)-1,3-diphenyl-3-(phenylthio)prop- NMR (400 MHz, CDCl3): δ 7.96 (s, 1H), 7.50–7.00 (m, 14H), 3.66 (s, 2H). Example 4 Hydrothiolation of Alkenyl Phosphonates Scheme 17 General Procedure 1 (GP1) To a solution of alkynyl phosphonate 1 (0.2 mmol) in t-butanol (1 mL) was added alkyl hydropersulfide 2a (0.2 mmol) in a 2-dram vial. The reaction mixture was stirred at room temperature for 3 h. The crude mixture was then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel to give corresponding thio vinyl phosphonate 3. General Procedure 2 (GP2) To a solution of alkynyl phosphonate 1 (0.2 mmol) in t-butanol (1 mL) was added alkyl hydropersulfide 2a (0.4 mmol) in a 2-dram vial. The reaction mixture was stirred at room temperature for 3 h. The crude mixture was then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel to give corresponding thio vinyl phosphonate 3. Example alkynyl phosphonates 1 are depicted in Table 3, below. Table 3. Example Alkynyl Phosphonates 1 , The following example thio vinyl phosphonates 3 were prepared. Diethyl (E)-(2-(benzylthio)-2- : GP1, 64 mg, 92%; as a colorless oil. Rf= 0.35 (vHexane / vEtOAc= 1:2); vHexane / vEtOAc(3 / 2) and vHexane / vEtOAc(2 / 3) for column.1H NMR (400 MHz, CDCl3): 7.49–7.46 (m, 2H) 7.36–7.35 (m, 2H), 7.33–7.26 (m, 5H), 5.62 =12 Hz, 1H), 3.99 (s, 2H), 3.85–3.71 (m, 4H), 1.09 ( t, J = 7 Hz, 7.2H).13C NMR {1 H decoupled} (100.5 MHz, CDCl3): δ 160.5,134.9, 129.3, 128.9, 128.8, 128.7 (d, J =2.2 Hz), 127.9, 127.6, 61.5(d, J = 5.5 Hz),37.8, 16.1 (d, J = 5.2Hz).31PNMR {1H decoupled} (162 MHz, CDCl3): 15.4 ppm. Diethyl (E)-(2-(benzylthio)-2-(3-chlo honate (3b): GP2, 63 mg, 80%; as a colorless oil. Rf= 0.4 (vHexane / vEtOAc= 1:2); vHexane / vEtOAc(3 / 2) and vHexane / vEtOAc(2 / 3) for column.1H NMR (400 MHz, CDCl3): 7.44–7.35 (m, 1H) 7.35–7.26 (m, 8H), 5.65 (d, J =11.6 Hz, 1H), 4.00 (s, 2H), 3.87–3.77 (m, 4H), 1.14 ( t, J = 7 Hz, 6H).13C NMR {1 H decoupled} (100.5 MHz, CDCl3): δ 158.8 (d, J = 8.1Hz), 138.7( d, J =7.4 Hz), 134.5, 133.7, 129.3( d, J =11.9 Hz), 128.8, 128.7, 126.9,109.7, 107.8, 61.5(d, J = 5.2 Hz),37.8, 16.1 (d, J = 6.7 Hz).31PNMR {1H decoupled} (162 MHz, CDCl3): 14.7 ppm. Diethyl (E)-(2-(benzylthio)-2-(4- (3c): GP2, 60 mg, 80%; as a colorless oil. Rf= 0.45 (vHexane / vEtOAc= 1:2); vHexane / vEtOAc(3 / 2) and vHexane / vEtOAc(2 / 3) for column.1H NMR (400 MHz, CDCl3): 7.49–7.45 (m, 2H) 7.33–7.26(m,4H), 7.06–7.02 (t, J = 8.6 Hz, 2H), 5.62(d, J =12 Hz, 1H), 3.99(s, 2H), 3.87–3.73 (m, 4H), 1.13 ( t, J = 7 Hz, 6H).13C NMR {1 H decoupled} (100.5 MHz, CDCl3): δ 164.5, 162.1, 159.4 (d, J = 8.1Hz) ,134.7, 131.1( d, J =8.2Hz), 133.0 ( d, J = 6.7 Hz), 130.7, 130.6, 128.8, 128.7, 127.6, 115.1 ( d, J =21.6),109.2 ( d, J = 193 Hz), 61.5(d, J = 6 Hz),37.8, 16.1 (d, J = 6.7 Hz).31PNMR {1H decoupled} (162 MHz, CDCl3): 15.1ppm. Diethyl (E)-(2-(benzylthio)-2- (3d): GP2, 69 mg, 85%; as a colorless oil. Rf= 0.35 (vHexane / vEtOAc= 1:2); vHexane / vEtOAc(3 / 2) and vHexane / vEtOAc(2 / 3) for column.1H NMR (400 MHz, CDCl3): 7.97 (s, 1H) 7.84–7. 82(m, 3H) 7.59–7.56(m, 1H), 7.51–7.48 (m, 2H), 7.48–7.32(m, 4H), 5.73 (d, J =12 Hz, 1H), 4.00(s, 2H), 3.82–3.69 (m, 4H), 1.01 (t, J = 7.5 Hz, 6H).31PNMR {1H decoupled} (162 MHz, CDCl3): 20.60 ppm. Diethyl (E)-(2-(benzylthio)-2-(4-(tert sphonate (3e): GP2, 74 mg, 89%; as a colorless oil. Rf= 0.35 (vHexane / vEtOAc= 1:2); vHexane / vEtOAc(3 / 2) and vHexane / vEtOAc(2 / 3) for column.1H NMR (400 MHz, CDCl3): 7.44–7.36 (m,5H), 7.33–7.31(m,4H), 5.59 (d, J =12.4 Hz, 1H), 3.99 (s, 2H), 3.82–3.70 (m, 4H), 1.31(s, 9H), 1.06 (t, J = 7Hz, 6H).13C NMR {1 H decoupled} (100.5 MHz, CDCl3): 160.6( d, J = 8.2Hz), 152.614, 135.0, 134.2 ( d, J = 7.4 Hz), 128.8, 128.6, 128.4, 128.5, 127.5,124.8, 61.4 (d, J = 6Hz), 38.8, 34.7, 31.2, 16.0 (d, J = 7.4 Hz).31PNMR {1H decoupled} (162 MHz, CDCl3): 15.7 ppm. Diethyl (E)-(2-(benzylthio)-2-(4- (3f): GP2, 65 mg, 85%. Rf= 0.3 (vHexane / vEtOAc= 1:2); vHexane / vEtOAc(3 / 2) and vHexane / vEtOAc(2 / 3) for column.1H NMR (400 MHz, CDCl3): 7.97 (s, 1H) 7.84–7.82(m, 3H) 7.59–7.56(m, 1H), 7.51–7.48 (m, 2H), 7.48–7.32(m, 4H), 5.73 (d, J =12 Hz, 1H), 4.00(s, 2H), 3.82–3.69 (m, 4H), 1.01 (t, J = 7.5 Hz, 6H).31PNMR {1H decoupled} (162 MHz, CDCl3): 14.7 ppm. Diethyl (E)-(2-(benzylthio)-2-(4- (3g): GP2, 65 mg, 85%; as a colorless oil. Rf= 0.4 (vHexane / vEtOAc= 1:2); vHexane / vEtOAc(3 / 2) and vHexane / vEtOAc(2 / 3) for column.1H NMR (400 MHz, CDCl3): 7.50–7.47 (m, 2H) , 7.36–7.26 (m, 7H), 5.63 (d, J =11.2 Hz, 1H), 3.99 (s, 2H), 3.86–3.77 (m, 4H), 1.13 (t, J = 7Hz, 6H).13C NMR {1 H decoupled} (100.5 MHz, CDCl3): To be updated.31PNMR {1H decoupled} (162 MHz, CDCl3): 14.9 ppm. Diethyl (E)-(2-(4-acetylphenyl)-2-( onate (3h): GP2, 65 mg 85%; as a colorless oil. Rf= 0.25 (vHexane / vEtOAc= 1:2); vHexane / vEtOAc(3 / 2) and vHexane / vEtOAc(2 / 3) for column.1H NMR (400 MHz, CDCl3): 7.96( d, J = 8.8 Hz, 2H), 7.57( d, J =10 Hz, 2H), 7.34–7.26(m, 5H), 5.67( d, J =11.2Hz), 4.01 (s, 2H), 3.85–3.77 (m, 4H), 2.62( s, 3H), 1.12 (t, J = 7Hz, 6H). Diethyl (E)-(2-(benzylthio)-2-(4- (3i): GP2, 48 mg, 72%; as a colorless oil. Rf= 0.3 = ; and vHexane / vEtOAc(2 / 3) for column.1H NMR (400 MHz, CDCl3): 7.96( d, J = 8.8 Hz, 2H), 7.57( d, J = 10 Hz, 2H), 7.34–7.26(m, 5H), 5.67( d, J =11.2Hz , 1H), 3.97 (s, 2H), 3.85–3.70 (m, 7H), 2.62( s, 3H), 1.12 (t, J = 7.2 Hz, 6H).31PNMR {1H decoupled} (162 MHz, CDCl3): 14.9 ppm. Diethyl (E)-(2-(benzylthio)-2-(2- (3j): GP2, 49 mg, 74%; as a colorless oil. Rf= 0.3 (vHexane / vEtOAc= 1:2); vHexane / vEtOAc(3 / 2) and vHexane / vEtOAc(2 / 3) for column.1H NMR (400 MHz, CDCl3): 7.96( d, J = 8.8 Hz, 2H), 7.57( d, J =10 Hz, 2H), 7.34–7.26(m, 5H), 5.67( d, J =11.2Hz , 1H), 3.97 (s, 2H), 3.85–3.70 (m, 7H), 2.62( s, 3H), 1.12 (t, J = 7.2 Hz, 6H).31PNMR {1H decoupled} (162 MHz, CDCl3): 15.7 ppm. S Dimethyl (E)-(2-(benzylthio)-2- (3k): GP2, 42 mg, 72%; as a colorless oil. Rf= 0.3 (vHexane / vEtOAc= 1:2); vHexane / vEtOAc(3 / 2) and vHexane / vEtOAc(2 / 3) for column.1H NMR (400 MHz, CDCl3): 7.46–7.26(m, 5H), 5.60( d, J =12.4 Hz, 1H), 4.00 (s, 2H), 3.42 (d, J = 11.2 Hz, 6H).31PNMR {1H decoupled} (162 MHz, CDCl3): 18.1ppm. Example 5 One Step Synthesis of Acyl-Persulfides Scheme 18 General Procedure 1 (GP1) To a mixture of thio acyl-succinimide 1 (2 mmol) in MeOH (10 mL) was added alkyl thiol 2a (3 mmol) in a 25 mL round bottom flask. The reaction mixture was stirred at room temperature for 18 h. The crude mixture was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel to give corresponding acyl-persulfide 3. General Procedure 2 (GP2) To a mixture of thio acyl-succinimide 1 (2 mmol) in EtOH (10 mL) was added aryl thiol 2b (2 mmol) in a 25 mL round bottom flask. The reaction mixture was stirred at room temperature for 18 h. The crude mixture was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel to give corresponding acyl-persulfide 3. SS-benzyl ethane(dithioperoxoate) white solid; mp: not determined. Rf= 0.7 (vHexane / vEtOAc= 9:1); vHexane / vDCM (5 / 1) and vHexane / vEtOAc(19 / 1) for column.1H NMR (400 MHz, CDCl3): 7.35–7.25(m, 5H), 3.92 (s, 2H), 2.33 (s, 3H) ppm. SS-(4-(tert-butyl)benzyl) ethane(dithioperoxoate) (3b): GP1, 137mg, 43%, colorless oil. Rf= 0.7 (vHexane / vEtOAc= 9:1); vHexane / vDCM (5 / 1) and vHexane / vEtOAc(19 / 1) for column.1H NMR (400 MHz, CDCl3): 7.35–7.23 (m, 4H), 3.91 (s, 2H), 2.34 (s, 3H), 1.30 (s, 9H).13C NMR {1 H decoupled} (100.5 MHz, CDCl3): 195.2, 150.8, 132. 129.1, 125, 42.8, 34.5, 31.3, 28.6 ppm. De-acylation of Acyl-Persulfide to Synthesize Alkyl Hydropersulfide To a mixture of acyl-persulfide 3a (1 mmol) in methanol (2 mL) was added HCl (1mL, 5M in MeOH) in a 2-dram vial. The reaction mixture was stirred at room temperature for 30 min. The crude mixture was concentrated under reduced pressure to obtain product 4. Benzyldisulfane (4a): 155mg, >99%, = 0.8 (vHexane / vEtOAc= 9:1.1H NMR (400 MHz, CDCl3): 7.34–7.28(m, 5H), 3.89 , 2.88 1H).

Claims

CLAIMS What is claimed:

1. A compound of formula (I), or a salt thereof, , wherein: Rzis –S–H, –S–C(O)R1is hydrogen, –C1–4alkyl, or –C6–12aryl; R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, 2,the C8–16phenoxyalkyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; with the proviso that the compound is not benzyldisulfane, (4-methoxybenzyl)disulfane, benzyl(2,3-dimethylbut-2-en-1-yl)sulfane, (E)-benzyl(3,7-dimethylocta-2,6-dien-1- yl)sulfane, bis(1-phenylethyl)sulfane, benzyl(1-phenylethyl)sulfane, benzyl(1-phenylpropyl)sulfane, benzyl(2-phenylpropan-2-yl)sulfane, benzyl(4-phenylbutan- 2-yl)sulfane, benzyl(1-(4-fluorophenyl)ethyl)sulfane, benzyl(1-(4- chlorophenyl)ethyl)sulfane, benzyl(1-(4-methoxyphenyl)ethyl)sulfane, benzyl(1- (naphthalen-1-yl)ethyl)sulfane.

2. The compound of claim 1, or the salt thereof, wherein R1is hydrogen or –C1–4alkyl.

3. The compound of claim 1, or the salt thereof, wherein R3is hydrogen or –C1–4alkyl.

4. The compound of claim 1, or the salt thereof, wherein n is 0 or 1.

5. The compound of claim 4, or the salt thereof, wherein n is 1.

6. The compound of claim 5, or the salt thereof, .

7. The compound of claim 1, or the salt thereof, wherein R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –CN, –NO2, –OH, or –OC(O)C1–4alkyl.

8. The compound of claim 1, or the salt thereof, wherein Rzis –S–H.

9. The compound of claim 1, or the salt thereof, wherein Rzis –S–C(O)C1–4alkyl.

10. The compound of claim 1, or the salt thereof, wherein Rzis –Z1.

11. The compound of claim 10, or the salt thereof, wherein Z1is –C2–12alkyl, –C4–12alkenyl, –C8–16arylalkyl, or –C8–16phenoxyalkyl.

12. The compound of claim 10, or the salt thereof, wherein .

13. The compound of claim 12, or the salt thereof, wherein Rxis –C6–12aryl.

14. The compound of claim 13, or the salt thereof, wherein the C6–12aryl is optionally substituted phenyl.

15. The compound of claim 12, or the salt thereof, wherein Ryis –P(O)(OC1–4alkyl)2, –P(O)(C6–12aryl)2, P(O)(OC8–16arylalkyl)2, –P(O)(C6–12aryl)(OC1–4alkyl), or –P(O)(OC6–12aryl)2.

16. The compound of claim 1, or the salt thereof, wherein the compound is selected from the group consisting of: , , , ,, 17. , , ; wherein: 1R is hydrogen, –C1–4alkyl, or R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, ; and2wherein, at each occurrence, the C6–12aryl and the C3–8cycloalkyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; the method comprising: (a) providing a compound of formula (II), where LG is a leaving group: ; (b) reacting the intermediatesulfinothioate of formula (II-A), where M is sodium, potassium, or cesium:O C6-1aryl S2M S O ;in the presence of a of formula (III):(III); (c) reacting the a thioate of formula (III-A), where Mis sodium, or ; in the presence of a of formula (IV):(d) reacting the of formula (IV-A):; in the presence of an acid to provide a compound of formula (V): .

18. The method of claim 17, wherein the acid is HCl, HBr, HNO3, H2SO4, or H3PO4.

19. A method for preparing a compound of formula (VI), or a salt thereof, ; wherein:R1is hydrogen, –C1–4alkyl, or –C6–12aryl; R3is n is 0, 1, or 2;R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN,–NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, or –P(O)(C6–12aryl)2; Z1is –C2–12alkyl, –C6–12alkenyl, –C8–16arylalkyl, or –C8–16phenoxyalkyl, wherein, at each occurrence, the C6–12aryl, the C3–8cycloalkyl, the –C8–16arylalkyl and the –C8–16phenoxyalkyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl,–C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; the method comprising: (a) providing a compound of formula (V): (b) reacting the compound of of formula (V-A):, wherein:Raat each occurrence, is independently hydrogen or C1–4alkyl, and R10is hydrogen, –C1–10alkyl, –C4–10alkenyl, –C6–12aryl, –C7–14arylalkyl, or –O-phenyl, wherein, at each occurrence, the –C6–12aryl, the –C7–14arylalkyl, and the –O-phenyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl,–C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; to provide a compound of formula (VI): .

20. The method of claim 19, wherein Raat each occurrence, is hydrogen.

1. A method for preparing a compound of formula (VI), or a salt thereof, ; wherein: R1is hydrogen, –C1–4alkyl, orR3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –OC –C –P2, 2,optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; the method comprising: (a) providing a compound of formula (V): (b) reacting theof formula (V-C): (V-C);in the presence of a solvent to provide a compound of formula (VI): .

22. The method of claim 21, wherein Ryor –P(O)(OC1–4alkyl)2.

23. A method for preparing a compound (V), or a salt thereof, ;R3is hydrogen, –C1–4alkyl, or –C6–12aryl; n is 0, 1, or 2; R2, at each occurrence, is independently halogen, –OC1–4alkyl, –C1–4alkyl, –C3–8cycloalkyl, –C6–12aryl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, or –P(O)(C6–12aryl)2; and wherein, at each occurrence, the C6–12aryl and the C3–8cycloalkyl are each independently optionally substituted with 1–3 substituents selected from the group consisting of halogen, –OC1–4alkyl, –C1–4alkyl, –cyclopropyl, –C1–2fluoroalkyl, –SC1–4alkyl, –N(C1–4alkyl)2, –C(O)N(C1–4alkyl)2, –CN, –NO2, –OH, –OC(O)C1–4alkyl, –C(O)C1–4alkyl, –CO2C1–4alkyl, –P(O)(OC1–4alkyl)2, –P(O)(OC6–12aryl)2, and –P(O)(C6–12aryl)2; the method comprising: (a) providing a compound of formula (VIII): ; (b) reacting the compound ofN-(S-acylthio)succinimide of formula (IX):X); in the presence of a sol mediate of formula (IV) (c) reacting the of formula (IV-A): HO-C alkyl (IV1–4- in the presence of an acid to provide a compound of formula (V): .

24. The method of claim 23, HNO3, H2SO4, or H3PO4.

25. Use of the compounds of any one of claims 1–16 for industrial, agricultural, or medical applications.

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