Introduction

The methylsulfonyl group (–SO₂CH₃, commonly abbreviated as –SO₂Me) is a common polar substituent with important applications in medicinal chemistry, agrochemistry, and organic synthesis. Compared with conventional aryl and aliphatic methyl sulfones, heteroaryl methyl sulfones have been explored to a relatively limited extent. One important reason is that the efficient introduction of –SO₂Me at a specific position of a heterocycle often requires the prior installation of a suitable reactive handle.[1]

In 2025, Poplavskyi et al. published a study in Nature Communications in which they designed a three-carbon vinamidinium salt reagent prefunctionalized with –SO₂Me and used it with dinucleophilic reagents to directly construct multiple classes of methylsulfone-containing heterocycles.[1] The significance of this work lies not merely in adding another reagent for methyl sulfone synthesis, but more importantly in changing the retrosynthetic logic for the target molecules:

Instead of first constructing the heterocycle and then introducing the methyl sulfone onto it, the carbon atom already bearing the methyl sulfone is directly incorporated into the formation of the heterocyclic framework.

1. Why the Synthesis of Heteroaryl Methyl Sulfones Is Often Constrained by the Synthetic Route

1.1 Common Methods Start from a Pre-existing Heterocycle

A variety of methods are available for the synthesis of heteroaryl methyl sulfones. The original paper summarizes two commonly used strategies as follows:[1]

The first strategy: formation of a methylthio group followed by oxidation to a methyl sulfone

Heteroaryl–SMe → Heteroaryl–SO₂Me

In this route, a C–S bond is first formed to introduce a methylthio group (–SMe) onto the heterocycle, after which sulfur is oxidized to the sulfone oxidation state.

The second strategy: formation of a C–S bond using a prefunctionalized heterocycle

For example, halogenated heterocycles or heteroaryl boronic acid derivatives can be used as starting materials and coupled with sulfur-containing reagents such as methanesulfinate salts. Another class of methods constructs the sulfone group through reactions involving sulfur dioxide.[5–7]

Although the specific reaction mechanisms of these methods differ, they share a common feature in terms of route design:

The heterocyclic framework is generally already present, and –SO₂Me is subsequently introduced at the desired position through transformation of an existing functional group.

The synthetic difficulty of such routes lies not only in the subsequent construction of the C–S bond or functional-group interconversion, but is also constrained by the accessibility of the required prefunctionalized heterocyclic precursor. If the target position is difficult to halogenate, borylate, metalate, or prefunctionalize with a sulfur-containing group, subsequent installation of the methyl sulfone will also be limited.

2. Limitations of Traditional Synthetic Routes: 4-(Methylsulfonyl)-1H-pyrazole as an Example

The authors initially needed to prepare 4-(methylsulfonyl)-1H-pyrazole.

An existing patent route started from a brominated pyrazole, which was first treated with n-butyllithium and then reacted with dimethyl disulfide to form a methylthio intermediate, followed by oxidation with meta-chloroperoxybenzoic acid (mCPBA). After purification by column chromatography, the route was reported to provide 51 mg of the target compound in 26% yield.[1]

Viewed as individual transformations, none of the steps in this route is particularly unusual; the difficulty arises from the combination of several requirements:

① obtaining a halogenated pyrazole with substitution at the correct position;

② carrying out an organolithium reaction;

③ introducing the methylthio group;

④ oxidizing the sulfide to the sulfone;

⑤ finally purifying the product.

Rather than continuing to optimize the original route step by step, the authors changed the retrosynthetic direction:

If the target product requires –SO₂Me at the C4 position of the pyrazole, could the carbon atom that will ultimately become C4 already bear –SO₂Me before ring formation?

The question thus shifted from “how to install a methyl sulfone onto a pyrazole” to “how to construct a pyrazole using a carbon source that already carries a methyl sulfone.”

3. A 1,3-Disconnection of the Heterocycle Changes How the Methyl Sulfone Enters the Molecule

3.1 Differences Between the Two Retrosynthetic Approaches

Traditional routes generally start from an already constructed heterocycle and are designed retrosynthetically around sulfur-containing functional-group transformations or C–S bond formation at the target position:

Target heteroaryl methyl sulfone ← prefunctionalized heterocycle or methylthio-containing heterocycle ← pre-existing heterocyclic framework

In contrast, the present study shifts the focus from the C–SO₂Me bond to the way in which the heterocycle itself is formed.

The authors adopted a 1,3-disconnection strategy for the heterocycle, breaking the target heterocycle down into:

Three-carbon synthon prefunctionalized with –SO₂Me + dinucleophilic reactant → methylsulfone-substituted heterocycle

Here, a “dinucleophilic reactant” refers to a single reactant containing two nucleophilic sites capable of participating in bond formation, such as hydrazines, amidines, and certain compounds containing both a nitrogen nucleophilic site and a carbon nucleophilic site.

The differences between the two strategies can be further summarized as follows:

4. Methylsulfone-Containing Three-Carbon Vinamidinium Salts: Preinstalling –SO₂Me into the Carbon Framework for Cyclization

4.1 What Is Reagent 1?

To realize the retrosynthetic concept described above, the authors designed and prepared a 2-(methylsulfonyl)-substituted three-carbon vinamidinium hexafluorophosphate salt. In the original paper, this compound is designated as compound 1; therefore, it is referred to hereafter as reagent 1.[1]

From a structural and functional perspective, reagent 1 can be viewed as a three-carbon synthon in which the central carbon is prefunctionalized with –SO₂Me. Its three contiguous carbon atoms can participate in subsequent heterocycle construction, while –SO₂Me is already attached to the central carbon before cyclization.

For clarity, the three-carbon segment involved in cyclization can be represented in simplified form as:

C₁–C₂(–SO₂Me)–C₃

Here, C₁, C₂, and C₃ are the three carbon atoms that subsequently enter the heterocyclic framework, and C₂ already bears –SO₂Me before the reaction begins. Therefore, when these three carbon atoms are incorporated into a new heterocycle through cyclization, –SO₂Me enters the target framework together with C₂.

4.2 Why Use a Three-Carbon Vinamidinium Salt as a Framework-Building Unit?

Reagent 1 belongs to a class of conjugated amidinium salts commonly known as vinamidinium salts. In the following discussion, these are referred to collectively as three-carbon vinamidinium salts.

An important synthetic feature of these compounds is that their structures contain three contiguous carbon atoms, allowing them to serve as C₃ synthetic units that undergo sequential bond formation with suitable dinucleophilic reactants to generate heterocycles. Earlier studies had already used 2-substituted three-carbon vinamidinium salts to synthesize heterocycles such as pyrroles. Gupton et al. also investigated related 2-(arylsulfonyl)-substituted compounds and their reactions with nucleophiles such as hydrazines and amidines.[2,3] Davies et al. subsequently developed a practical method for preparing the corresponding hexafluorophosphate salts.[4]

4.3 Preparation and Stability of Reagent 1

Starting from commercially available sodium methanesulfinate, the authors first obtained ester intermediate 6, which was then saponified to give 2-(methylsulfonyl)acetic acid. The three-carbon vinamidinium framework was subsequently constructed under Vilsmeier–Haack reaction conditions.[1]

The process uses phosphorus oxychloride (POCl₃) and N,N-dimethylformamide (DMF). After optimization of the reaction conditions, reagent 1 was obtained at 90 °C in an isolated yield of 58%.

The Methods section further reports that 315 g of reagent 1 could be obtained from 215 g of 2-(methylsulfonyl)acetic acid, again in 58% yield. Reagent 1 was obtained as a yellow crystalline solid, remained stable in air at room temperature for at least one year, and its structure was confirmed by single-crystal X-ray diffraction.[1]

These properties mean that reagent 1 not only enables experimental validation of the retrosynthetic concept, but also offers favorable practical handling characteristics. For a framework-building reagent, preparative accessibility, isolability, storage stability, and scalability are as important as its chemical reactivity.

5. Why Cyclization Can Achieve Both “Framework Formation” and “Methyl Sulfone Positioning”

5.1 Understanding the Origin of the Atoms Using Pyrazole Formation as an Example

Reaction of reagent 1 with hydrazine hydrate (N₂H₄·H₂O) directly affords 4-(methylsulfonyl)-1H-pyrazole.[1]

From the perspective of atomic composition, the reaction is straightforward:

① the three-carbon vinamidinium salt provides the three carbon atoms in the pyrazole ring;

② hydrazine hydrate provides the two nitrogen atoms in the pyrazole ring;

③ the –SO₂Me group attached to the central carbon of the three-carbon unit enters the newly formed five-membered ring together with that carbon atom.

This process can be understood through the following atomic assembly relationship:

–SO₂Me-bearing C₃ unit + N–N dinucleophilic unit → pyrazole ring containing three carbon atoms and two nitrogen atoms

Specifically:

C₁–C₂(–SO₂Me)–C₃ → C₂ ultimately becomes the ring carbon bearing –SO₂Me

The regiochemical position of the methyl sulfone is predetermined by the atomic arrangement of the three-carbon synthon.

6. Changing the Dinucleophilic Reactant Gives Access to Different Types of Heterocycles

Once the three-carbon unit is fixed, the type of heterocycle ultimately formed depends primarily on the dinucleophilic component participating in the reaction.

The paper examined two representative classes of reactants.[1]

6.1 N,N-Dinucleophilic Reactants

In this class of reactants, two nitrogen nucleophilic sites participate in cyclization.

Taking hydrazines and amidines as examples, although the two types of reactions generate rings of different sizes and compositions, they follow the same retrosynthetic logic: the three-carbon vinamidinium salt provides three contiguous carbon atoms, while the dinucleophilic reactant provides the remaining atoms required for ring formation.

6.2 N,C-Dinucleophilic Reactants

If the reactant provides one nitrogen nucleophilic site and one carbon nucleophilic site, a different class of heterocyclic structures can be accessed.

For example:[1]

① glycine derivatives generate pyrroles in 49%–95% yield;

② corresponding substrates can form pyridones and pyridines in 46%–92% yield;

③ aminopyrazoles, aminoisoxazoles, aminothiazoles, aminopyrroles, and aminothiophenes can form a variety of fused heterocycles in 76%–93% yield.

A common principle emerges from these results:

By keeping the C₃ unit bearing a predefined substituent unchanged while varying the cyclization partner, the composition and substitution pattern of the resulting heterocycle can be altered.

This is an important reason why a single reagent can provide access to multiple classes of heteroaryl methyl sulfones.

7. Practical Effects of the Route Change: Reducing Late-Stage Functional-Group Transformations

In the initial synthesis of the target pyrazole, the authors reacted reagent 1 with hydrazine hydrate. According to the Methods section, 575 g of reagent 1 ultimately afforded 170 g of the target pyrazole in 71% isolated yield.[1]

Compared with the previous route, which gave 51 mg of product in 26% yield, the difference extends beyond the change in yield. The new route no longer includes the organolithium treatment, methylthio-group introduction, and subsequent sulfide oxidation required in the original approach. Instead, a three-carbon starting material already bearing –SO₂Me is used to construct the pyrazole directly.

The authors also compared the preparation of several other previously reported compounds.[1]

These examples show that the benefit of optimizing a retrosynthetic route is not limited to improving the yield of an individual reaction step.

If a new disconnection strategy eliminates several prefunctionalization and functional-group interconversion steps, the overall synthetic route can be fundamentally altered.

8. Successful Cyclization Is Closely Related to the Reactivity of the Dinucleophile

Although the three-carbon vinamidinium salt can undergo cyclization with a broad range of substrates, the paper also shows that these reactions impose clear requirements on substrate electronic properties and cyclization capability.

The authors noted that the method performs better with relatively electron-rich reaction systems. Some insufficiently reactive anilines did not give the expected heterocycles and instead formed by-products; other designed target structures produced complex mixtures.[1]

A particularly illustrative example involves methyl 5-aminofuran-2-carboxylate. When reacted with reagent 1 under pyridine conditions, it can form the corresponding fused heterocyclic product 47. Under a different set of conditions using K₂CO₃/acetonitrile at 60 °C, however, the uncyclized product 48 is selectively obtained (47 and 48 are the compound numbers used in the original paper).[1]

This result illustrates that:

Completion of the first intermolecular bond-forming event does not necessarily mean that the subsequent intramolecular ring closure will proceed with comparable efficiency.

For this type of reaction, at least the following factors need to be considered together:

① the reactivity of the first nucleophilic site toward the three-carbon vinamidinium salt;

② whether the second nucleophilic site retains suitable reactivity after the initial bond-forming event;

③ whether the structure of the intermediate is favorable for intramolecular cyclization;

④ whether the solvent, base, and temperature favor ring closure and subsequent product formation.

The applicability of this method is closely related to the reactivity match between the dinucleophilic reactant and the three-carbon electrophilic synthon. This also explains why substrates that appear structurally similar can display markedly different cyclization outcomes.

9. Starting from Methyl Sulfones: A General Synthetic Design Principle

Using a similar design strategy, the authors also prepared other substituted three-carbon vinamidinium salts and used them to access ethylsulfonyl, isopropylsulfonyl, difluoromethylsulfonyl (–SO₂CHF₂), trifluoromethylsulfonyl (–SO₂CF₃), and bicyclo[1.1.1]pentane-related sulfone derivatives.[1]

These extension studies show that what is worth adopting is not merely reagent 1 itself, but also the underlying synthetic design principle:

First identify the skeletal atom on which an important substituent must ultimately reside in the target molecule, and then consider whether that skeletal atom can already carry the desired substituent before entering the cyclization reaction.

Following this logic:

Traditional late-stage functionalization focuses on:

The target framework already exists

→ identify a suitable reaction site

→ introduce the target substituent

In contrast, the design of a prefunctionalized synthon focuses on:

Determine which skeletal atoms are required in the target structure

→ determine which synthons provide those atoms

→ install the substituent in advance before cyclization

→ complete the target structure through framework construction

The two strategies do not have a simple relationship of superiority or inferiority. For molecules that are readily amenable to late-stage functionalization, direct modification of an existing framework can be highly effective. When the late-stage introduction of a particular substituent requires multiple prefunctionalization steps, oxidation-state adjustments, or harsh reaction conditions, reconsidering the origin of the skeletal atoms may provide a more concise synthetic route.

10. Representative Chemicals Related to the Direct Construction of Methyl Sulfone Frameworks: Key Precursors, Cyclization Substrates, and Reaction Reagents

Table 1. Precursors and Construction Reagents for Methyl Sulfone Synthons

Table 2. Dinucleophiles and Substrates for Heterocyclic Framework Construction

Table 3. Cyclization-Auxiliary Reagents, Reaction Media, and Reagents for Comparison with Traditional Routes

Note: The products listed above are representative Aladdin products relevant to scientific research. Specific applications should be determined with reference to product specifications, batch-specific COAs, and the intended reaction or evaluation system. Additional information on product specifications, grades, and COAs can be retrieved from the Aladdin website using the “product name/CAS number/catalog number.”

References

[1] Poplavskyi Y, Ripenko V, Bova S, et al. A reagent to access methyl sulfones. Nature Communications, 2025, 16: 1132. DOI: 10.1038/s41467-024-55027-x.

[2] Gupton J T, Krolikowski D A, Yu R H, Riesinger S W, Sikorski J A. Application of 2-substituted vinamidinium salts to the synthesis of 2,4-disubstituted pyrroles. The Journal of Organic Chemistry, 1990, 55(15): 4735–4740. DOI: 10.1021/jo00302a047.

[3] Gupton J T, Riesinger S W, Shah A S, Gall J E, Bevirt K M. The preparation and some reactions of 2-(arylsulfonyl)vinamidinium salts. The Journal of Organic Chemistry, 1991, 56(3): 976–980. DOI: 10.1021/jo00003a015.

[4] Davies I W, Marcoux J F, Wu J, et al. An efficient preparation of vinamidinium hexafluorophosphate salts. The Journal of Organic Chemistry, 2000, 65(15): 4571–4574. DOI: 10.1021/jo000159u.

[5] Baskin J M, Wang Z. An efficient copper catalyst for the formation of sulfones from sulfinic acid salts and aryl iodides. Organic Letters, 2002, 4(25): 4423–4425. DOI: 10.1021/ol0269190.

[6] Beaulieu C, Guay D, Wang Z, Evans D A. A mild and efficient new synthesis of aryl sulfones from boronic acids and sulfinic acid salts. Tetrahedron Letters, 2004, 45(16): 3233–3236. DOI: 10.1016/j.tetlet.2004.02.127.

[7] Wang M, Zhao J, Jiang X. Aryl methyl sulfone construction from eco-friendly inorganic sulfur dioxide and methyl reagents. ChemSusChem, 2019, 12(13): 3064–3068. DOI: 10.1002/cssc.201802919.

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