Route Selection for Thiol Synthesis: C–S Bond Construction, Sulfur Source Forms, and Thiol Release

Abstract

Thiols are important compounds in organic synthesis, medicinal chemistry, bioconjugation, and functional materials research. Their synthesis is not simply a matter of replacing a functional group with —SH, but instead requires the coordination of three processes: constructing a carbon–sulfur bond at the target position, controlling the stability of sulfur-containing intermediates during subsequent reactions, and releasing the free thiol group under conditions tolerated by the other functional groups present.

Different carbon centers require different methods of C–S bond formation. Primary alkyl halides and certain secondary alkyl substrates can undergo nucleophilic substitution; alcohols require prior activation of the hydroxy group or deoxythiolation; aryl halides generally rely on nucleophilic aromatic substitution or transition-metal-catalyzed coupling; sulfur can be introduced into epoxides and alkenes through addition reactions; and carboxylic acids can be converted through decarboxylative radical processes into thiols containing one fewer carbon atom. Thiourea, thioacetates, silyl sulfur sources, and other releasable sulfur precursors make it possible to control C–S bond formation and free-thiol generation separately.

This article summarizes the principal routes for thiol synthesis according to carbon-center type, bond-forming mechanism, sulfur-source form, and method of thiol release. It also discusses the effects of stereochemistry, competing reactions, functional-group compatibility, and practical operating conditions on route selection.

Keywords: thiols; thiol group; C–S bond construction; isothiouronium salts; thioacetates; silyl sulfur sources; aryl thiols; decarboxylative thiolation; thiol release; route selection

1 Introduction

Thiols have the general formula R—SH. The thiol group can participate in nucleophilic substitution, radical addition, disulfide-bond formation, metal coordination, and various subsequent functional-group transformations, making thiols important intermediates in the preparation of thioethers, disulfides, thioesters, and other organosulfur compounds.

Their relatively high reactivity also increases the complexity of thiol synthesis and isolation. Under basic conditions, free thiols can form highly nucleophilic thiolates. If alkyl halides or other electrophilic reagents remain in the system, the thiolate may react further to form a thioether. Thiols may also be converted into disulfides in the presence of air, light, metal ions, or other oxidizing conditions, and they may coordinate to certain transition-metal catalysts.[1]

The design of a thiol synthesis must therefore consider the method of C–S bond formation, the form in which sulfur is present during the synthesis, and the stage at which the free thiol group is released. Evaluating these three aspects as an integrated process makes it possible to determine whether a particular method is suitable for a specific target structure.

2 Fundamental Design of Thiol Synthesis Routes

2.1 Target Carbon Atom and C–S Bond-Forming Mechanism

Before selecting a sulfur source, the hybridization state, degree of substitution, and steric environment of the carbon atom involved in the target C–S bond should first be determined.

2.1.1 Saturated sp³ Carbon

Primary alkyl halides, primary alkyl sulfonates, and certain secondary alkyl substrates can undergo bimolecular nucleophilic substitution reactions (S_N2) to introduce sulfur.

Primary carbon centers are generally subject to relatively little steric hindrance. For secondary carbon substrates, substitution, elimination, and stereochemistry must all be considered. Tertiary carbon centers are highly sterically hindered and are generally unsuitable for conventional S_N2 routes. Alkene addition, radical reactions, or transformations involving carbocation intermediates may be considered instead.

2.1.2 Aryl and Alkenyl sp² Carbon

The C(sp²)—X bond in an aryl halide cannot undergo backside attack through the conventional S_N2 mechanism applicable to alkyl substrates. Aryl halides bearing suitable electron-withdrawing groups can undergo nucleophilic aromatic substitution, whereas insufficiently activated aryl halides generally require copper, nickel, or palladium catalysis to form a C(sp²)—S bond.

2.1.3 Epoxides and Alkenes

Epoxides can undergo ring opening by sulfur nucleophiles, forming a hydroxy group and a sulfur-containing functional group on adjacent carbon atoms. Alkenes can form C–S bonds through ionic, radical, or metal-catalyzed addition. Both types of reactions require consideration of regioselectivity and stereochemistry.

2.1.4 Carbon Skeletons Derived from Carboxylic Acids

Carboxylic acids can undergo decarboxylation to generate alkyl radicals, which are subsequently trapped by sulfur-containing reagents. The carboxyl carbon is lost as carbon dioxide, and the resulting thiol contains one fewer carbon atom than the starting carboxylic acid.

2.2 Sulfur-Source Forms and the Logic of Two-Stage Synthesis

2.2.1 Direct Sulfur Sources

Hydrogen sulfide (H₂S), sodium hydrosulfide (NaSH), and potassium hydrosulfide (KSH) can directly provide H₂S, hydrosulfide ions (HS⁻), or related sulfur-containing species.

The net transformation between an alkyl halide and HS⁻ can be represented as:

R—X + HS⁻ → R—SH + X⁻

Direct sulfur sources can reduce the number of subsequent deprotection steps, but they may also create problems involving H₂S toxicity and corrosiveness, gas–liquid mass transfer, overalkylation, and thioether formation.

2.2.2 Releasable Sulfur Precursors

Many routes do not directly form R—SH, but instead initially produce an intermediate of the type R—S—Z:

R—X + ZS⁻ → R—S—Z + X⁻

R—S—Z → R—SH

Here, X represents a leaving group, while Z represents a structural group that remains temporarily attached to sulfur after C–S bond formation and can be removed in a subsequent step.

Common forms include:

① Isothiouronium salts formed from thiourea;

② Thioacetates formed from thioacetate salts;

③ Silyl sulfides formed from silyl sulfur sources;

④ Organic thiocyanates formed from thiocyanate salts;

⑤ Xanthates formed from xanthate salts;

⑥ Reducible disulfides or polysulfides.

2.2.3 Separate Evaluation of C–S Bond Formation and Thiol Release

Taking the thioacetate route as an example:

R—X + CH₃C(O)S⁻ → R—S—C(O)CH₃ + X⁻

The target R—S bond has already been formed in the first step. Subsequent deacylation changes the linkage between sulfur and the acetyl group:

R—S—C(O)CH₃ → R—SH

The following aspects of the route should be evaluated separately:

① Conversion, regioselectivity, and stereochemical outcome of C–S bond formation;

② Stability, purification method, and storage conditions of the sulfur-containing intermediate;

③ Compatibility of the thiol-release conditions with other functional groups;

④ Stability of the free thiol during workup and storage.

3 Thiol Synthesis at Saturated Carbon Centers

3.1 Starting from Alkyl Halides or Sulfonates

3.1.1 Thiourea–Isothiouronium Salt Route

Thiourea reacts with alkyl halides to form S-alkylisothiouronium salts:

R—X + NH₂C(=S)NH₂ → [RSC(NH₂)₂]⁺X⁻

The isothiouronium salt can release the thiol through hydrolysis, aminolysis, or another suitable cleavage process:

[RSC(NH₂)₂]⁺X⁻ → R—SH

In this route, sulfur remains temporarily in the form of an ionic intermediate after C–S bond formation, reducing the likelihood that the free thiol will react further with residual electrophilic substrate to form a thioether.[1]

Primary alkyl halides are generally well suited to this route. Secondary substrates may undergo competing elimination, while substrates containing multiple reactive halides or sulfonates may produce multiply substituted products. The cleavage conditions for the isothiouronium salt must also be compatible with esters, amides, and other base-sensitive functional groups.

3.1.2 Thioacetate Route

Thioacetate ions can undergo S_N2 reactions to form thioacetates:

R—X + CH₃C(O)S⁻ → R—S—C(O)CH₃ + X⁻

Thioacetates are generally easier to isolate and store than the corresponding free thiols and can be retained until a late stage of the synthesis before deacylation.

Deacylation can be accomplished through hydrolysis, alcoholysis, or nucleophilic catalysis. Holmes and Snow reported that tetrabutylammonium cyanide (TBACN) promotes the conversion of various aliphatic thioacetates into free thiols in protic solvents, although the method was not applicable to the thiophenol-type substrates examined in their study.[3]

Aliphatic, benzylic, and aryl thioacetates differ in their electronic structures. The fact that they contain the same —S—C(O)CH₃ group does not necessarily mean that identical deprotection conditions can be used in every case.

3.1.3 Silyl Sulfur-Source Route

Deprotonation of a silanethiol can generate a silanethiolate. Its nucleophilic substitution process can be represented as:

R—X + R₃SiS⁻ → R—S—SiR₃ + X⁻

Using fluoride-mediated desilylation as an example, the subsequent process can be represented as:

R—S—SiR₃ + F⁻ → R—S⁻ + R₃SiF

R—S⁻ + H⁺ → R—SH

Bulky silyl groups such as triisopropylsilyl (TIPS) can improve the handling characteristics of sulfur-containing intermediates and can be used as H₂S equivalents.[1]

If the molecule also contains silyl ethers, silyl alkynes, or other silyl protecting groups, it is necessary to determine whether the desilylation conditions can selectively cleave the target S—Si bond.

3.1.4 Thiocyanate and Xanthate Routes

Thiocyanate ions, SCN⁻, can react with suitable alkyl electrophiles to form organic thiocyanates:

R—X + SCN⁻ → R—SCN + X⁻

R—SCN can subsequently be converted into R—SH through reduction or selective cleavage. This route does not generate the thiol directly in a single step. Instead, it first constructs the R—S bond and then converts the S—CN group.

Xanthate salts generally form intermediates of the type R—S—C(=S)OR′, which are subsequently converted into thiols through reduction, hydrolysis, or radical cleavage. Xanthates can also participate in radical chain-transfer reactions, and their applications are therefore not limited to thiol release.[1]

3.1.5 Comparison of Common Releasable Sulfur Precursors

Sulfur source or intermediate	Structure formed after C–S bond formation	Common method of thiol release	Main characteristics	Points requiring verification
Thiourea	Isothiouronium salt	Hydrolysis, aminolysis, or reductive cleavage	The salt-form intermediate reduces premature formation of the free thiol	Cleavage conditions, elimination, and salt separation
Thioacetate salt	R—S—C(O)CH₃	Deacylation	Relatively stable intermediate suitable for late-stage release	Simple esters and other acyl protecting groups
Silyl sulfur source	R—S—SiR₃	Desilylation followed by protonation	Can serve as an H₂S equivalent	Other silyl functional groups
Thiocyanate salt	R—SCN	Reduction or selective cleavage	Relatively stable intermediate	Reduction-sensitive groups and cyanide-containing by-products
Xanthate salt	R—S—C(=S)OR′	Reduction, hydrolysis, or radical cleavage	Can connect nucleophilic substitution with radical reactions	Thiocarbonyl by-products and cleavage selectivity
Disulfide	R—S—S—R′	Reduction	Can serve as a relatively stable storage form	Other reducible functional groups

3.2 Starting from Alcohols

The hydroxy group itself is not a good leaving group. When converting an alcohol into a thiol, it is necessary either to increase the leaving ability of the C—O bond or to use a reagent system that simultaneously activates the alcohol and introduces sulfur.

3.2.1 Hydroxy-Group Activation–Nucleophilic Substitution Route

An alcohol can first be converted into a halide, mesylate, tosylate, or another activated derivative:

R—OH → R—LG → R—S—Z → R—SH

Here, LG represents a leaving group.

Snow and Foos reported examples in which certain ethylene glycol oligomers and 2-(4-hydroxyphenyl)ethanol were converted into thiols through tosylate intermediates and thiourea, and they compared this route with the corresponding bromide route.[2]

This stepwise approach allows the hydroxy-group activation, C–S bond formation, and thiol-release conditions to be adjusted separately, although the number of steps and the need to isolate intermediates are correspondingly increased.

3.2.2 Mitsunobu-Type Thioesterification

The Mitsunobu reaction uses a phosphine reagent and an azo reagent to activate a primary or secondary alcohol in situ, allowing an acidic nucleophile to displace the hydroxy group. Commonly used reagents include triphenylphosphine (PPh₃), diethyl azodicarboxylate (DEAD), and diisopropyl azodicarboxylate (DIAD).

When thioacetic acid is used, the net transformation can be represented as:

R¹R²CH—OH + CH₃C(O)SH → R¹R²CH—S—C(O)CH₃

The product is subsequently deacylated to give the corresponding thiol.

For chiral secondary alcohols, classical Mitsunobu substitution generally exhibits S_N2-type behavior, resulting in inversion of configuration at the reacting carbon center. It should be noted that inversion of configuration does not necessarily correspond to a simple interchange of the product’s R/S descriptor, because changes in the functional groups may also alter the Cahn–Ingold–Prelog priority order.[4]

Traditional Mitsunobu reactions generate stoichiometric quantities of phosphine oxide and hydrazine-derived by-products. Sterically hindered secondary alcohols and substrates prone to elimination may also exhibit reduced conversion or competing reactions.[5]

3.2.3 Lawesson’s Reagent-Mediated Deoxythiolation

Lawesson’s reagent can convert certain alcohols into the corresponding thiols under one-pot conditions. The net functional-group transformation can be represented as:

R—OH → R—SH

This equation represents only the overall transformation and does not imply that the hydroxy group is directly replaced by —SH in a single elementary step.

Nishio reported that a series of alcohols produced thiols under the action of Lawesson’s reagent, with dehydration products such as alkenes also being formed in some cases. Certain 1,4-diols and ortho-bis(hydroxymethyl)arenes underwent diene formation or cyclization reactions.[6]

This route does not require prior preparation of a halide or sulfonate, but dehydration and rearrangement of secondary and tertiary alcohols must be considered, as must the possible thionation of carbonyl groups, amides, and other functional groups.

4 C(sp²)–S Bond Construction for Aryl Thiols

4.1 Nucleophilic Aromatic Substitution

When an aryl halide contains an electron-withdrawing group capable of stabilizing a negatively charged intermediate at the ortho or para position relative to the halogen, HS⁻ or another sulfur nucleophile can replace the halogen through an addition–elimination process:

Ar—X + HS⁻ → Ar—SH + X⁻

Whether the reaction can proceed depends primarily on the degree of electronic activation of the aromatic ring. Unactivated chlorobenzene or bromobenzene generally cannot be efficiently converted into thiophenols through conventional nucleophilic aromatic substitution.

4.2 Transition-Metal-Catalyzed Coupling

Copper, nickel, and palladium catalysts can activate aryl halides or similar aryl electrophiles and promote the formation of C(sp²)—S bonds.

Liu et al. reported a copper(II)-catalyzed reaction of aryl halides with 1,2-ethanedithiol that provided various aryl thiols in a single step. The resulting aryl thiols could also be further converted into diaryl sulfides or benzothiophenes in the same reaction system.[7]

This capacity for subsequent reaction also demonstrates the importance of selectivity control. If aryl halide and an active catalyst remain in the system, the Ar—SH that has already formed may undergo further coupling to generate Ar—S—Ar′.

4.3 Catalytic Coupling Using H₂S as the Sulfur Source

The synthesis of aryl thiols using H₂S as the sulfur source can be represented in simplified form as:

Ar—X + H₂S → Ar—SH

The actual reaction also produces the corresponding hydrogen halide or salt by-products, the precise form of which depends on the catalyst and additives.

In 2025, Kitamura et al. reported a nickel/photoredox continuous-flow C(sp²)—S coupling method using H₂S gas as the sulfur source. The continuous-flow reactor was used to control gas delivery and gas–liquid contact, while the catalyst, acid additive, residence time, and other conditions were adjusted to reduce the formation of symmetrical diaryl sulfides.[8]

Continuous flow helps reduce the instantaneous inventory of H₂S within the reactor and improves mass transfer, but gas-tight equipment, corrosion-resistant materials, off-gas scrubbing, and leak monitoring are still required. The method also has limitations, including relatively low conversion for certain sterically hindered substrates and deposition within the reactor.

5 Addition-Based Routes for Epoxides and Alkenes

5.1 Nucleophilic Ring Opening of Epoxides

Epoxides can undergo ring opening by sulfur nucleophiles to form β-hydroxy sulfur-containing compounds. Depending on the sulfur source and workup method, the products may include:

① β-Hydroxy thioethers;

② β-Hydroxy thioesters;

③ Protected β-hydroxy thiols;

④ β-Hydroxy thiols obtained through subsequent cleavage.

Under common basic or neutral nucleophilic conditions, the sulfur nucleophile generally attacks the less sterically hindered epoxide carbon. Under acidic or Lewis acid activation conditions, electronic effects become more important, and the regioselectivity may change. The attacked epoxide carbon generally undergoes inversion of configuration.

5.2 Asymmetric Epoxide Ring Opening

Monaco, Prévost, and List reported the asymmetric thiocarboxylic acidolysis of meso epoxides catalyzed by a confined chiral phosphoric acid. The reaction initially forms a chiral thioester intermediate, followed by intramolecular transesterification to afford an O-protected β-hydroxy thiol. Under modified conditions, the intermediate thioester can also be obtained selectively.[9]

The selectivity of this reaction arises from a cascade process consisting of chiral-catalyst-controlled epoxide ring opening followed by intramolecular acyl transfer, rather than from simple hydrolysis after conventional ring opening.

5.3 Hydrothiolation of Alkenes

When an alkene undergoes addition with a sulfur-containing reagent, it is necessary to distinguish whether the target product is a thioether or a thiol:

① Addition of an alkene with a conventional organic thiol, R′—SH, generally gives a thioether;

② Addition of an alkene with H₂S or a sulfur source capable of subsequently releasing —SH may form a new thiol.

Ionic, radical, and metal-catalyzed hydrothiolation can produce different regioselectivities. For unsymmetrical alkenes, the position of sulfur attachment, Markovnikov or anti-Markovnikov orientation, and the possible formation of regioisomers and stereoisomers must be evaluated separately.[1]

6 Decarboxylative Radical Thiolation of Carboxylic Acids

The skeletal transformation involved in decarboxylative thiolation of a carboxylic acid can be represented as:

R—CO₂H → R· + CO₂

R· + sulfur-containing trapping reagent → R—S—Z → R—SH

The overall skeletal transformation can be abbreviated as:

R—CO₂H → R—SH + CO₂

This expression is not a complete stoichiometric equation and is used only to indicate that the carboxyl carbon is lost as CO₂.

6.1 Redox-Active Ester Route

A carboxylic acid can first be converted into a redox-active ester (RAE), which then accepts a single electron under visible-light photocatalytic conditions, undergoes decarboxylation, and generates an alkyl radical.

In 2020, Cao et al. reported the decarboxylative thiolation of carboxylic acid-derived RAEs using an aryl thioamide-based sulfur source. The resulting free thiols could also be converted in situ into sulfur-containing products such as thioethers, disulfides, and thiocyanates.[10]

The method is applicable to multiple classes of carboxylic acid-derived alkyl skeletons, but it requires an additional carboxylic acid preactivation step. Route evaluation should therefore consider RAE preparation, the photochemical reaction, and the workup process.

6.2 Radical Relay Route from Unactivated Carboxylic Acids

In 2024, Lipilin et al. reported the one-pot conversion of free carboxylic acids into free thiols. The method uses a thiocarbonate-type reagent containing an N—O bond to trap the alkyl radical and participate in regeneration of the acridine-type photocatalyst, followed by mild basic workup to release the thiol group.[11]

This design separates radical sulfur trapping from the generation of the free thiol. If a free thiol is formed prematurely, it may donate a hydrogen atom to the alkyl radical and generate an alkane, thereby reducing the efficiency of C–S bond formation. A purpose-designed sulfur reagent can reduce this competing process.

6.3 Elemental Sulfur as the Sulfur Source

Elemental sulfur is widely available, but reaction of an alkyl radical with S₈ may form disulfides, polysulfides, or oligomeric sulfur-containing intermediates. Further cleavage of the S—S bonds is required to obtain the thiol.

In 2024, Porey et al. reported a multimodal acridine-photocatalyzed reaction of carboxylic acids with elemental sulfur. In the first stage, proton-coupled electron transfer (PCET) promotes decarboxylation and C–S bond formation. In the second stage, photoinduced hydrogen atom transfer (HAT) promotes reductive cleavage of disulfide or polysulfide bonds, ultimately producing thiols.[12]

This method avoids the need to convert the carboxylic acid into an RAE in advance, but the photocatalyst, silane, amount of elemental sulfur, polysulfide intermediates, and irradiation equipment must still be evaluated comprehensively.

6.4 Comparison of Three Carboxylic Acid Routes

Route	Carboxylic acid preactivation required	Sulfur source	Main process	Points requiring attention
RAE decarboxylative thiolation	Yes	Aryl thioamides and related sources	Single-electron reduction, decarboxylation, and radical sulfur trapping	Additional carboxylic acid preactivation step
Radical relay using an N—O sulfur reagent	No	Purpose-designed thiocarbonate-type reagent	Decarboxylation, radical addition, and N—O bond cleavage	Preparation of the sulfur reagent and workup
Carboxylic acid–elemental sulfur photocatalysis	No	S₈	Decarboxylation, radical sulfur incorporation, and reductive cleavage of polysulfide bonds	Polysulfide intermediates, silane, and photochemical equipment

7 Thiol Release and Management of Sulfur-Containing Intermediates

7.1 Release Methods for Different Sulfur-Containing Intermediates

Sulfur-containing intermediate	Main process forming the free thiol	Principal bond cleavage or transformation site	Functional-group compatibility requiring verification
Isothiouronium salt	Hydrolysis, aminolysis, or reductive cleavage	S—C bond between sulfur and the isothiouronium carbon, with the R—S bond retained	Esters, amides, and base-sensitive structures
Thioacetate	Deacylation	S—C(O)CH₃	Simple esters and other acyl protecting groups
Silyl sulfide	Desilylation and protonation	S—Si	Silyl ethers, silyl alkynes, and other silyl protecting groups
Thiocyanate	Reduction or selective cleavage	S—CN	Halogens and other reduction-sensitive structures
Xanthate	Reduction, hydrolysis, or radical cleavage	S—C(=S)	Radical-sensitive structures and thiocarbonyl by-products
Disulfide	Reduction	S—S	Other reducible groups in the molecule
Polysulfide	Reductive cleavage and hydrogen atom transfer	One or more S—S bonds	Over-reduction and complex sulfur-containing by-products

Thiol-release conditions should not be selected solely on the basis of acid or base strength or reaction temperature. It is also necessary to determine whether the release conditions can distinguish the target sulfur-containing bond from other sensitive bonds in the molecule.

7.2 Selection of the Thiol-Release Stage

Release strategy	Applicable situation	Main purpose	Questions requiring verification
Late-stage release	Subsequent steps still include oxidation, electrophilic reactions, metal catalysis, or multiple purification operations	Reduces oxidation, overalkylation, metal coordination, and purification losses	Whether the final release conditions damage other functional groups
In situ release followed by immediate reaction	Immediate maleimide addition, disulfide exchange, or surface grafting after thiol formation	Avoids isolation and storage of unstable thiols	Whether the release step is compatible with the subsequent reaction

Late-stage release is suitable for longer synthetic routes, but the final deprotection must have sufficient chemoselectivity. In situ release can shorten the exposure time of the free thiol, but it increases the potential interaction between two consecutive reactions.

8 Stereochemistry and Competing Reactions in Route Selection

8.1 Effects of Different Bond-Forming Mechanisms on Stereochemistry

C–S bond-forming mechanism	Main stereochemical effect
S_N2 substitution	The attacked carbon center generally undergoes inversion of configuration
Mitsunobu-type substitution	The secondary alcohol carbon center generally undergoes S_N2-type inversion
Nucleophilic epoxide ring opening	The attacked epoxide carbon generally undergoes inversion of configuration
Nucleophilic aromatic substitution	Generally does not involve configuration at the aryl carbon; the substitution position is controlled by the electronic structure of the aromatic ring
Carbocation process	May result in racemization, partial stereoselectivity, or skeletal rearrangement
Conventional radical trapping	Existing stereochemical information may be eroded or lost
Chiral-catalyzed ring opening or coupling	The stereoselectivity of the newly formed C–S bond can be controlled by a chiral catalyst

8.2 Competition among Substitution, Elimination, and Rearrangement

Competition between S_N2 substitution and elimination is mainly affected by the following factors:

① Degree of substitution and steric hindrance at the carbon center;

② Nucleophilicity and basicity of the sulfur reagent;

③ Nature of the leaving group;

④ Solvent and solvation effects;

⑤ Reaction temperature;

⑥ Stability of the alkene that may be formed;

⑦ Tendency toward neighboring-group participation or carbocation formation.

Primary substrates generally favor S_N2 substitution. For secondary substrates, substitution and elimination must be compared simultaneously. Tertiary substrates are more likely to undergo elimination, rearrangement, or carbocation-related reactions.

If elimination remains the dominant pathway, increasing the amount of sulfur reagent or extending the reaction time may not improve the outcome. Alternative bond-forming mechanisms, such as alkene hydrothiolation, epoxide ring opening, or radical thiolation, may instead be considered.

8.3 Principal Subsequent Reactions of Free Thiols

Subsequent reaction	Main product or effect	Common conditions	Control strategy
Further alkylation after deprotonation	Thioether	Coexistence of base and residual electrophilic reagent	Delay thiol release and control stoichiometry and order of addition
Oxidation	Disulfide	Air, light, metal ions, or oxidants	Limit oxygen exposure and, when necessary, store in disulfide form
Coordination to transition metals	Changes in catalyst activity or metal deposition	Copper-, nickel-, or palladium-catalyzed systems	Release the thiol at a late stage or modify the catalytic system
Further reaction with radicals or alkenes	Addition or chain-transfer products	Radical conditions or the presence of residual double bonds	Generate the thiol at a separate stage and trap it promptly

9 Methods for Selecting a Thiol Synthesis Route

9.1 Five Criteria for Route Selection

For a specific target thiol, the following considerations can be evaluated in sequence:

① Determine whether the target C–S bond is connected to a primary carbon, secondary carbon, tertiary carbon, aryl carbon, epoxide carbon, or a carbon formed after decarboxylation of a carboxylic acid;

② Determine whether the target structure requires retention, inversion, or re-establishment of stereochemical configuration;

③ Select a direct sulfur source or releasable sulfur precursor according to the bond-forming mechanism and subsequent steps;

④ Evaluate the functional-group compatibility of both the C–S bond-forming conditions and the thiol-release conditions;

⑤ Evaluate reaction safety, isolation and purification, intermediate storage, and scale-up conditions.

Functional-group compatibility can be assessed preliminarily using the following table:

Reaction conditions	Functional groups or structures that may be affected
Strongly basic or strongly nucleophilic conditions	Esters, elimination-prone substrates, and certain stereogenic centers
Acidic conditions	Acetals, silyl ethers, and other acid-sensitive protecting groups
Reducing conditions	Disulfide bonds, nitro groups, halogens, carbonyl groups, and other reducible functionalities
Oxidizing conditions	Thiols, alkenes, aldehydes, and readily oxidized amines
Fluoride-mediated desilylation	Silyl ethers, silyl alkynes, and other silyl protecting groups
Transition-metal catalysis	Thiols, amines, phosphines, and strongly coordinating heterocycles
Photochemical or radical conditions	Photosensitive groups, radical acceptors, and alkenes
Heating conditions	Elimination-prone, rearrangement-prone, and thermally sensitive structures

9.2 Route-Selection Reference for Common Starting Materials

Starting material or target structure	Principal bond-forming mechanism	Routes that may be prioritized for evaluation	Stereochemical effect	Main competing reactions and operational issues
Primary alkyl halide	S_N2	Thiourea, thioacetate salts, or silyl sulfur sources	A stereogenic center involved in substitution undergoes inversion	Overalkylation and disulfide formation
Secondary alkyl halide	S_N2 or another substitution process	Mild sulfur nucleophiles or releasable sulfur precursors	Generally undergoes inversion of configuration	Elimination, racemization, or rearrangement
Tertiary alkyl structure	Addition, radical, or carbocation process	Alkene hydrothiolation or radical routes	May undergo racemization or form isomers	Elimination, rearrangement, and regioselectivity
Primary alcohol	Substitution after hydroxy-group activation or deoxythiolation	Sulfonate–thiourea, thioacetate, or Lawesson’s reagent routes	Generally does not involve stereochemistry	Activation-related side reactions and increased number of steps
Chiral secondary alcohol	Mitsunobu or activation–S_N2	Thiocarboxylic acids, thiourea, or thioacetate salts	Generally undergoes inversion of configuration	Elimination, steric hindrance, and by-product separation
Activated aryl halide	Nucleophilic aromatic substitution	HS⁻ or another sulfur nucleophile	Does not involve configuration at the aryl carbon	Substitution at multiple positions and electronic effects
Unactivated aryl halide	Transition-metal-catalyzed coupling	1,2-Ethanedithiol, H₂S, or another sulfur source	Depends on other stereogenic elements in the substrate	Catalyst deactivation and diaryl sulfide formation
Epoxide	Nucleophilic ring opening	Thiolates, thiocarboxylic acids, or releasable sulfur precursors	The attacked carbon generally undergoes inversion	Regioselectivity and reaction at multiple sites
Alkene	Ionic, radical, or metal-catalyzed addition	H₂S or an H₂S equivalent	May form regioisomers or stereoisomers	Markovnikov/anti-Markovnikov selectivity and multiple addition
Carboxylic acid	Decarboxylative radical thiolation	RAE, N—O sulfur reagent, or elemental sulfur	Conventional radical processes may result in loss of stereochemical information	Loss of the carboxyl carbon and radical side reactions
Multifunctional complex molecule	Bond-forming mechanism selected according to the target carbon	Releasable sulfur precursor with late-stage release of —SH	Requires stepwise evaluation	Orthogonality of deprotection and stability during purification

This table is intended to identify an initial direction for route selection. A specific reaction must still be evaluated in relation to the target structure, the substrate scope reported in the literature, the reaction scale, and the subsequent synthetic steps.

10 Classification and Typical Research Applications of Chemicals Related to Thiol Synthesis Routes—C–S Bond Construction, Sulfur Source Forms, and Thiol Release

Table 1. Sulfur Sources, Sulfur-Transfer Reagents, and Direct Thiolation Reagents

Category	CAS No.	Aladdin Product No.	Name	Specification or Purity	Product Features and Applications
Isothiouronium-type sulfur source	62-56-6	T112512	Thiourea	Guaranteed reagent, ≥99%	Forms isothiouronium salts with alkyl halides or sulfonates, followed by hydrolysis, aminolysis, or reductive cleavage to release thiols; used for the indirect thiolation of primary alkyl substrates and certain secondary alkyl substrates.
Thioacetyl sulfur source	10387-40-3	P106179	Potassium thioacetate	≥98%	Provides thioacetate ions, which undergo bimolecular nucleophilic substitution with alkyl halides or sulfonates to form isolable thioacetates; subsequent deacylation releases the thiol group.
Thioacetyl sulfur source	507-09-5	T112604	Thioacetic acid	≥95%	Serves as an acidic sulfur nucleophile in stereoinvertive substitution of alcohols, epoxide ring opening, and thioacetate preparation; deacylation affords the free thiol.
Thiocyano sulfur source	540-72-7	S111729	Sodium thiocyanate	PrimorTrace™, ≥99.99% metals basis	Forms organic thiocyanates with alkyl halides or activated alcohol derivatives, which can subsequently be converted into thiols through reduction or selective cleavage.
Xanthate sulfur source	140-89-6	P111000	Potassium ethyl xanthate	≥98%	Forms xanthates with alkyl electrophiles, which can generate thiols through reduction, hydrolysis, or radical cleavage; used in studies of nucleophilic sulfur substitution and radical chain transfer.
Silyl sulfur source	14606-42-9	T338235	Triphenylsilanethiol	≥98%	Serves as a silyl sulfur source and hydrogen sulfide equivalent in nucleophilic substitution and catalytic sulfur introduction; the resulting silyl sulfides release thiols through desilylation and protonation.
Silyl sulfur source	156275-96-6	T337322	Triisopropylsilanethiol (TIPS-SH)	≥97%	Serves as a sterically hindered silyl sulfur source and hydrogen sulfide equivalent for constructing protected thiols and silyl sulfides; subsequent cleavage of the silicon–sulfur bond releases the thiol group.
Silyl sulfur-transfer reagent	3385-94-2	B152534	Bis(trimethylsilyl) sulfide	≥97%	Serves as an anhydrous silylated sulfur source for sulfur introduction into electrophilic substrates, metal-catalyzed carbon–sulfur coupling, and preparation of silylated sulfur-containing intermediates; subsequent desilylation or hydrolysis affords thiol-containing products.
Dithiol sulfur-transfer reagent	540-63-6	E106222	1,2-Ethanedithiol	≥97%	Serves as a dithiol sulfur source in the catalytic conversion of aryl halides into aryl thiols and is also used to construct dithiacyclic structures, thioacetals, and sulfur-containing crosslinked structures.
Elemental sulfur source	7704-34-9	S106611	Sublimed sulfur (subject to explosive-precursor controls)	AR, ≥99.5% (T)	Serves as an elemental sulfur source in radical thiolation, decarboxylative sulfur incorporation from carboxylic acids, and construction of polysulfide intermediates; used in studies of photocatalytic carbon–sulfur bond formation and reductive cleavage of polysulfide bonds.
Thionating reagent	1314-80-3	P1508472	Phosphorus pentasulfide, anhydrous	≥99.95% metals basis, powder	Used for the thionation of carbonyl groups and oxygen-containing functional groups, as well as sulfur-containing transformations of certain thiocyanate or alcohol substrates; suitable for screening oxygen–sulfur exchange and sulfurization conditions.
Deoxythiolation reagent	19172-47-5	L101823	Lawesson’s reagent	≥97%	Used for the deoxythiolation of certain alcohols and the thionation of carbonyl compounds; applicable to the evaluation of routes for the direct conversion of alcohols into thiols and the sulfurization of oxygen-containing functional groups.

Table 2. Alcohol Activation and Stereoinvertive Thiolation Reagents

Category	CAS No.	Aladdin Product No.	Name	Specification or Purity	Product Features and Applications
Alcohol sulfonylation reagent	98-59-9	T485782	p-Toluenesulfonyl chloride (PTSC)	Suitable for synthesis	Converts alcohols into tosylates, improving the leaving ability of the hydroxy group and facilitating bimolecular nucleophilic substitution by thiourea, thioacetates, and other sulfur nucleophiles.
Alcohol halogenation reagent	7719-09-7	T433841	Thionyl chloride	Reagent grade, high purity, ≥99.5%, low iron	Converts alcohols into chlorides for stepwise alcohol–halide–thiol synthesis routes; also used for carboxylic acid activation and the preparation of related sulfur-containing derivatives.
Azo activating reagent	1972-28-7	D111046	Diethyl azodicarboxylate	Industrial grade, ≥85%	Forms an alcohol-activation system with triphenylphosphine, promoting substitution of alcohols by acidic sulfur nucleophiles such as thioacetic acid with inversion of configuration to generate deprotectable thioesters.
Phosphine activating reagent	603-35-0	T104475	Triphenylphosphine	≥99% (GC)	Forms an alcohol-activation system with azodicarboxylates and is used in substitution reactions between alcohols and thiocarboxylic acids, as well as stereoinvertive thiolation of chiral secondary alcohols.
Azo activating reagent	2446-83-5	D106304	Diisopropyl azodicarboxylate	≥95%	Used with triphenylphosphine to activate alcohol hydroxy groups and promote substitution by acidic sulfur nucleophiles such as thioacetic acid; used for thioester preparation and subsequent thiol release.

Table 3. Carbon–Sulfur Coupling Catalysts, Ligands, and Photocatalysts

Category	CAS No.	Aladdin Product No.	Name	Specification or Purity	Product Features and Applications
Nickel catalyst precursor	13462-88-9	N431943	Nickel bromide	Anhydrous grade, PrimorTrace™, ≥99.99% metals basis, powder	Can be used as a nickel catalyst precursor for carbon–sulfur coupling of aryl halides and for screening conditions in related photoredox systems.
Copper catalyst	7681-65-4	C433811	Copper(I) iodide	Anhydrous grade, ≥99.995% metals basis	Used for carbon–sulfur coupling between aryl halides and sulfur nucleophiles and may be employed in the preparation of aryl thiols, thioethers, and protected aryl sulfur-containing compounds.
Copper catalyst precursor	142-71-2	C1520978	Copper acetate, anhydrous	≥99.9% metals basis	Serves as a copper catalyst precursor in carbon–sulfur coupling of aryl halides and aryl thiol synthesis; used for screening ligands, sulfur sources, and reaction conditions.
Nitrogen-containing bidentate ligand	66-71-7	P111141	1,10-Phenanthroline, anhydrous	Moligand™, ≥99%	Forms bidentate coordination complexes with copper or nickel centers and is used to regulate catalytic activity, substrate conversion, and the product distribution between thiols and thioethers in aryl carbon–sulfur coupling.
Nitrogen-containing bidentate ligand	366-18-7	D108977	2,2′-Bipyridine	AR, ≥99%	Used in nickel- or copper-catalyzed carbon–sulfur bond construction and may participate in aryl halide sulfurization, photoredox-assisted coupling, and catalytic-condition screening.
Bidentate ligand for nickel catalysis	72914-19-3	D119895	4,4′-Di-tert-butyl-2,2′-bipyridine	≥98%	Forms photoredox cooperative catalytic systems with nickel salts and is used for screening conditions for carbon–sulfur coupling of aryl halides and related radical reactions.
Organic photocatalyst	1416881-52-1	T302842	2,4,5,6-Tetrakis(9-carbazolyl)isophthalonitrile	≥99% (HPLC)	Used in visible-light-induced single-electron transfer, generation of decarboxylative radicals, nickel-assisted carbon–sulfur coupling, and radical sulfur-trapping reactions.
Acridinium photocatalyst	674783-97-2	M157877	9-Mesityl-10-methylacridinium perchlorate	≥98% (HPLC)	Serves as an acridinium-type organic photoredox catalyst for visible-light-induced single-electron transfer and related photocatalytic reactions.

Table 4. Thiol Release, Reductive Control, and Representative Thiol Compounds

Category	CAS No.	Aladdin Product No.	Name	Specification or Purity	Product Features and Applications
Mild inorganic base	584-08-7	P485463	Potassium carbonate	Anhydrous grade, reagent grade, high purity, ≥99%	Provides mildly basic conditions for thioacetate deacylation, activation of sulfur nucleophiles, thiolate generation, and acid–base regulation of reaction systems.
Alcoholysis and deacylation reagent	124-41-4	S108356	Sodium methoxide	≥97%	Used for the alcoholysis and deacylation of thioacetates, generating thiolates that afford thiols after protonation; also used for activation of sulfur nucleophiles.
Thioacetate deprotection reagent	10442-39-4	T476926	Tetrabutylammonium cyanide	Industrial grade, ≥80%	Used for nucleophilically catalyzed deacylation of aliphatic thioacetates to release free thiol groups; suitable for studies involving removal of thioacetyl protecting groups.
Desilylation reagent for silyl sulfides	87749-50-6	T100870	Tetrabutylammonium fluoride trihydrate	≥98% (T)	Cleaves silicon–sulfur bonds to form thiolates, which release thiols after protonation; used to remove sulfur-protecting groups such as triisopropylsilyl and triphenylsilyl groups.
Strong reducing agent	16853-85-3	L432195	Lithium aluminum hydride (LAH)	Suitable for synthesis, powder	Used for reductive cleavage and thiol release from thiocyanates, xanthates, disulfides, and other sulfur-containing intermediates; suitable for substrates that tolerate strongly reducing conditions.
Reducing agent	16940-66-2	S432207	Sodium borohydride (subject to explosive-precursor controls)	purum p.a., ≥96%	Used to reduce disulfides and certain sulfur-containing intermediates, generating or restoring free thiol groups; applicable to screening mild reductive release conditions.
Disulfide-bond reducing agent	3483-12-3	D104859	DL-Dithiothreitol (DTT)	≥99%	Used for disulfide-bond reduction and free-thiol release, and to maintain thiol groups in their reduced state; applied in research on biomolecules, proteins, and thiol-containing materials.
Aqueous-phase disulfide-bond reducing agent	51805-45-9	T107252	Tris(2-carboxyethyl)phosphine hydrochloride (TCEP HCl)	≥98%	Used for aqueous disulfide-bond reduction and thiol release; applied in bioconjugation, thiol labeling, protein modification, and water-soluble sulfur-containing systems.
Small-molecule thiol reducing agent	60-24-2	M755744	2-Mercaptoethanol	UltraBio™, molecular biology grade, ≥99% (GC)	Used for disulfide-bond reduction and maintenance of thiols in their reduced state; it can also serve as a hydroxythiol model substrate in studies of disulfide exchange and thiol reactivity.
Bifunctional thiol	107-96-0	M103036	3-Mercaptopropionic acid (3-MPA)	Biochemical reagent, ≥99%	Contains both thiol and carboxyl groups and is used in thiol–ene addition, material-surface modification, ligand exchange on nanomaterials, coupling reactions, and thiol derivatization studies.
Bifunctional thiol	68-11-1	T105002	Thioglycolic acid (TGA)	Chemically pure (CP), ≥85%	Contains both thiol and carboxyl groups and can serve as a nucleophilic sulfur reagent, chain-transfer agent, and surface-functionalization reagent; used in studies of thiol oxidation, coordination, and derivatization.

Note: The products listed above are representative Aladdin products related to scientific research. Their specific applications should be determined in conjunction with the product specifications, batch certificate of analysis (COA), and the target reaction or evaluation system. Additional product specifications, grades, and COA information can be retrieved from the Aladdin website using the product name, CAS number, or product number.

References

[1] Monga A.; Nandini D. Synthetic Access to Thiols: A Review. Journal of Chemical Sciences, 2024, 136: 67. DOI: 10.1007/s12039-024-02300-7.

[2] Snow A. W.; Foos E. E. Conversion of Alcohols to Thiols via Tosylate Intermediates. Synthesis, 2003: 509–512. DOI: 10.1055/s-2003-37650.

[3] Holmes B. T.; Snow A. W. Aliphatic Thioacetate Deprotection Using Catalytic Tetrabutylammonium Cyanide. Tetrahedron, 2005, 61: 12339–12342. DOI: 10.1016/j.tet.2005.09.092.

[4] Fletcher S. The Mitsunobu Reaction in the 21st Century. Organic Chemistry Frontiers, 2015, 2: 739–752. DOI: 10.1039/C5QO00016E.

[5] Beddoe R. H.; Sneddon H. F.; Denton R. M. The Catalytic Mitsunobu Reaction: A Critical Analysis of the Current State-of-the-Art. Organic & Biomolecular Chemistry, 2018, 16: 7774–7781. DOI: 10.1039/C8OB01929K.

[6] Nishio T. Direct Conversion of Alcohols into Thiols. Journal of the Chemical Society, Perkin Transactions 1, 1993: 1113–1117. DOI: 10.1039/P19930001113.

[7] Liu Y.; Kim J.; Seo H.; Park S.; Chae J. Copper(II)-Catalyzed Single-Step Synthesis of Aryl Thiols from Aryl Halides and 1,2-Ethanedithiol. Advanced Synthesis & Catalysis, 2015, 357: 2205–2212. DOI: 10.1002/adsc.201400941.

[8] Kitamura H.; Nikitin M.; Ghosh I.; König B.; Kappe C. O.; Ötvös S. B. Direct Utilization of Hydrogen Sulfide Gas for Aryl Thiol Synthesis via Adaptive Dynamic Homogeneous Catalysis in a Flow System. Chemical Communications, 2025, 61: 18681–18684. DOI: 10.1039/D5CC04825G.

[9] Monaco M. R.; Prévost S.; List B. Catalytic Asymmetric Synthesis of Thiols. Journal of the American Chemical Society, 2014, 136: 16982–16985. DOI: 10.1021/ja510069w.

[10] Cao T.; Xu T.; Xu R.; Shu X.; Liao S. Decarboxylative Thiolation of Redox-Active Esters to Free Thiols and Further Diversification. Nature Communications, 2020, 11: 5340. DOI: 10.1038/s41467-020-19195-w.

[11] Lipilin D. L.; Zubkov M. O.; Kosobokov M. D.; Dilman A. D. Direct Conversion of Carboxylic Acids to Free Thiols via Radical Relay Acridine Photocatalysis Enabled by N—O Bond Cleavage. Chemical Science, 2024, 15: 644–650. DOI: 10.1039/D3SC05513B.

[12] Porey A.; Fremin S. O.; Nand S.; Trevino R.; Hughes W. B.; Dhakal S. K.; Nguyen V. D.; Greco S. G.; Arman H. D.; Larionov O. V. Multimodal Acridine Photocatalysis Enables Direct Access to Thiols from Carboxylic Acids and Elemental Sulfur. ACS Catalysis, 2024, 14: 6973–6980. DOI: 10.1021/acscatal.4c01289.

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