Introduction

During lead optimization, medicinal chemists often need to introduce small C(sp³) fragments—such as methyl, cyclopropyl, difluoromethyl, hydroxymethyl, oxetanyl, and bicyclo[1.1.1]pentyl groups—onto the same molecular scaffold to investigate how changes in substituents affect biological activity, preferred conformation, local polarity, metabolic stability, and three-dimensional shape. The challenge is that, despite their small size, these fragments often require different synthetic precursors, catalytic systems, and reaction conditions. Even after the position to be optimized has been identified, researchers may still have to redesign the synthetic route because a direct bond-forming method is unavailable.

This article focuses on the work reported by Tsien, Péter, and co-workers in Angewandte Chemie International Edition, entitled “Accelerating Medicinal Chemistry: A C(sp³)-Rich Fragment Toolbox for Redox-Neutral Cross-Coupling.” In this study, sulfonyl hydrazides were used as precursors to C(sp³) fragments to construct a synthetic toolbox comprising 15 sulfonyl hydrazide reagents. The platform enables the introduction of 14 classes of small C(sp³) fragments onto aryl and heteroaryl halides and was validated across more than 60 aryl and heteroaryl halides.[1]

The basic concept of the method is to convert C(sp³) fragments of different origins and structures into a common class of sulfonyl hydrazide reagents, which are then subjected to redox-neutral nickel-catalyzed radical cross-coupling to form new C(sp²)—C(sp³) bonds. In the reaction, the sulfonyl hydrazide not only supplies the alkyl fragment to be transferred but also participates in radical generation and the redox cycling of the nickel catalyst. As a result, the reaction generally does not require an additional stoichiometric oxidant or reductant.

The principal significance of this work lies not in the development of an individual methylation, cyclopropylation, or difluoromethylation reaction, but in the conversion of multiple C(sp³) fragments into coupling reagents that share a similar format, can be isolated, and are convenient to handle. Corresponding nickel-catalyzed conditions are then selected according to the reactivity of each fragment. In this way, the same aryl or heteroaryl halide can be used to prepare a series of analogues with different structures and properties, reducing the need to prepare fragment-specific precursors or repeatedly redesign synthetic routes and thereby improving the efficiency of structural validation during hit-to-lead and lead-optimization campaigns.

1 Why Small C(sp³) Fragments Merit Systematic Comparison

The so-called “magic methyl effect” generally refers to a substantial improvement in biological activity or pharmacokinetic properties following the introduction of a methyl group at a specific position in a molecule. However, this change does not arise from an intrinsic or fixed effect of the methyl group. Rather, it results from the combined influence of the methyl group, the specific molecular structure, the protein-binding site, and the relevant metabolic pathways.

Introducing a methyl group may have the following effects:

① Fill a small hydrophobic cavity in a protein-binding site and increase favorable hydrophobic contacts;

② Alter the rotational freedom of adjacent bonds and bias the molecule toward a conformation favorable for binding;

③ Shield a metabolically labile site from oxidation and reduce the rate of certain metabolic pathways;

④ Modify the electronic environment of neighboring functional groups through inductive effects or hyperconjugation;

⑤ Alter lipophilicity, solubility, membrane permeability, and nonspecific binding.

These effects do not necessarily occur simultaneously, nor do they necessarily lead to favorable outcomes. A methyl group may improve activity, but it may also introduce steric clashes, reduce solubility, or redirect metabolism to another site. Methylation should therefore be regarded as a structural design strategy that requires experimental validation, rather than as an optimization rule that is inherently beneficial.

The same principle applies to fragments such as cyclopropyl, oxetanyl, and bicyclo[1.1.1]pentyl groups. These fragments provide different combinations of size, rigidity, polarity, and spatial orientation rather than predetermined pharmacological advantages.

1.2 Fsp³ Is Not a Direct Measure of Drug Quality

The fraction of sp³-hybridized carbons is commonly abbreviated as Fsp³ and is calculated as follows:

Fsp³ = Number of sp³-hybridized carbon atoms in the molecule ÷ Total number of carbon atoms in the molecule

Fsp³ describes the hybridization composition of the carbon atoms in a molecule and primarily reflects its degree of saturation. It does not directly represent the molecule’s actual three-dimensional conformation, nor does it fully capture stereogenic centers, ring rigidity, substituent orientation, or conformational distribution.

Early statistical studies identified correlations between higher Fsp³ values and certain indicators associated with clinical development. However, subsequent reanalyses have shown that these correlations cannot be converted into a universal rule that “the higher the Fsp³, the better the drug-like properties.”

Accordingly, the rational purpose of introducing C(sp³) fragments is not simply to increase Fsp³, but to address specific design questions by modifying:

① The spatial complementarity between the molecule and the target-binding site;

② The preferred conformation and conformational freedom of the molecule;

③ Local hydrophobicity, polarity, and electronic properties;

④ Potential metabolic soft spots;

⑤ Functional groups available for subsequent derivatization.

2 Major Synthetic Challenges in Introducing Small C(sp³) Fragments

2.1 Different Fragments Usually Require Different Coupling Precursors

Classical cross-coupling reactions can efficiently construct a wide range of carbon–carbon bonds. Nevertheless, the introduction of small C(sp³) fragments still frequently relies on specially designed organoboron, organozinc, organomagnesium, or organotin reagents.

These precursors may differ substantially in terms of:

① The number of preparation steps and the availability of starting materials;

② Sensitivity to air, moisture, and temperature;

③ Compatibility with amides, ketones, esters, alcohols, amines, and nitrogen-containing heterocycles;

④ Whether low-temperature, anhydrous, or rigorously oxygen-free conditions are required;

⑤ Suitability for milligram-scale parallel synthesis.

Conditions used for methyl coupling generally cannot be applied directly to difluoromethyl, oxetanyl, or bicyclo[1.1.1]pentyl fragments. When the fragment is changed, researchers often need to prepare a new coupling precursor, screen a different catalytic system, or even modify the upstream synthetic route.

2.2 Existing Radical Coupling Methods May Still Increase Operational Complexity

Nickel-catalyzed radical cross-coupling provides an important complementary approach to C(sp²)—C(sp³) bond formation. However, some methods require:

① Stoichiometric reductants such as zinc or manganese;

② A photoredox catalyst and a specific light source;

③ Electrochemical equipment;

④ Redox-active esters or other specialized radical precursors.

Each of these approaches has its own advantages. However, when the goal is to prepare analogues containing multiple small fragments around the same lead scaffold, frequent changes in precursor type and experimental setup can still increase the synthetic workload.

3 Design of the Sulfonyl Hydrazide Reagent System

3.1 Fragments from Different Sources Are Converted into a Common Reagent Class

The researchers used five types of synthetic routes to prepare 15 sulfonyl hydrazide reagents from starting materials including hydrazines, alkyl halides, alcohols, ketones, and amines.[1]

Although the five routes rely on different reaction principles, they all ultimately furnish sulfonyl hydrazide compounds. Consequently, different C(sp³) fragments can be handled using similar weighing, charging, and nickel-catalyzed coupling procedures.

These reagents are generally isolable white or pale-yellow solids and can be prepared on gram scale. However, their stability varies depending on structure:

① Some reagents can be stored in air at room temperature;

② Some less stable reagents require low-temperature storage;

③ Being an “isolable solid” does not mean that every reagent can be stored for extended periods at room temperature.

In practice, storage conditions should therefore be selected according to the stability data for each specific reagent rather than applying the same storage protocol to all sulfonyl hydrazides.

3.2 Sulfonyl Hydrazides Perform Three Functions in the Reaction

Using R to represent the C(sp³) fragment to be transferred and Ar′ to represent the aryl group of the sulfonyl moiety, an alkyl sulfonyl hydrazide can be represented in simplified form as:

R—NH—NH—SO₂Ar′

It performs three interrelated functions in the reaction:

① Fragment carrier: It stably carries a methyl, cyclopropyl, cyanomethyl, or other C(sp³) fragment before the reaction;

② Radical precursor: Under basic, thermal, and nickel-catalyzed conditions, it forms a nitrogen-containing intermediate capable of releasing an alkyl radical;

③ Internal electron source: During radical generation, it simultaneously forms a low-valent nickel species, thereby providing the reducing capacity required for the nickel catalytic cycle.

The third function allows the reaction to proceed without an additional stoichiometric reductant and without relying on photocatalytic or electrochemical equipment.

4 Formation of the C(sp²)—C(sp³) Bond

4.1 Simplified Reaction Scheme

The bond-forming process between a sulfonyl hydrazide and an aryl or heteroaryl halide can be represented in simplified form as:

(Het)Ar—X + R—NH—NH—SO₂Ar′

—Ni catalyst, ligand, base, heat→

(Het)Ar—R + N₂↑ + Ar′SO₂⁻

Where:

① (Het)Ar represents an aryl or heteroaryl group;

② X primarily represents chlorine, bromine, or iodine;

③ R represents a C(sp³) fragment such as methyl, cycloalkyl, or a functionalized methyl group;

④ Ar′SO₂⁻ represents the sulfinate formed during the reaction.

4.2 Initial Formation of an Isodiazene-Related Intermediate

Subsequent mechanistic studies first used a representative aryl chloride coupling reaction as a model and investigated it by temperature-scanning reaction calorimetry, reaction-progress kinetic analysis, quantitative nuclear magnetic resonance spectroscopy, and density functional theory calculations. Temperature-scanning kinetic analysis was subsequently extended to six sulfonyl hydrazides and six aryl halides.

The available evidence supports the following sequence:

① A base first deprotonates the sulfonyl hydrazide to form a sulfonyl hydrazide anion;

② The anion eliminates a sulfinate to form an isodiazene-related intermediate;

③ The isodiazene coordinates to a Ni(II) species and undergoes further deprotonation;

④ Homolysis of the Ni—N and C—N bonds occurs with simultaneous release of nitrogen gas, generating an alkyl radical, R·, and a Ni(I) species.

In the representative reaction, kinetic experiments showed that the reaction rate was approximately proportional to the concentration of the sulfonyl hydrazide. By contrast, changes in the concentrations of the aryl halide, nickel catalyst, or base had relatively little effect on the overall reaction rate. These findings suggest that, under the conditions examined, the key process controlling the overall rate is primarily the elimination of sulfinate from the sulfonyl hydrazide anion and formation of the isodiazene-related intermediate, rather than the subsequent activation of the aryl halide or formation of the C—C bond.

It should be noted that this rate law was validated across the series of six sulfonyl hydrazides and six aryl halides examined in the study. However, changing the ligand, solvent, base, or reaction mode may alter the reaction orders and rate-determining step. This kinetic behavior should therefore not be generalized unconditionally to all sulfonyl hydrazide coupling reactions.

4.3 The Nickel Catalyst Connects the Aryl Halide and Alkyl Radical

After decomposition of the isodiazene produces the alkyl radical, the nickel-catalyzed portion of the reaction can be summarized as follows:

① A Ni(I) species undergoes oxidative addition with an aryl or heteroaryl halide to form a high-valent arylnickel species;

② The high-valent nickel species undergoes comproportionation with another Ni(I) species to generate a Ni(II) aryl intermediate and a Ni(II) halide;

③ The Ni(II) aryl intermediate captures the alkyl radical, R·;

④ A new C(sp²)—C(sp³) bond is then formed, and the Ni(I) species is regenerated.

The simplified bond-forming sequence is:

(Het)Ar—Ni(II) + R· → [(Het)Ar—Ni—R] → (Het)Ar—R

This mechanism is not a single linear catalytic cycle. Rather, it is a multicycle reaction network involving sulfonyl hydrazide activation, radical generation, aryl halide activation, and interconversion among nickel species.

5 Why Reaction Efficiency Depends on Rate Matching

5.1 Radical Generation and Aryl Halide Activation Must Be Coordinated

Whether the reaction proceeds efficiently depends on the coordination of two principal processes:

① Activation of the sulfonyl hydrazide and generation of the alkyl radical;

② Activation of the aryl halide by the nickel catalyst and capture of the alkyl radical.

If the sulfonyl hydrazide decomposes too rapidly while oxidative addition of the aryl halide is slow, the following outcomes may occur:

① The alkyl radical undergoes reduction, dimerization, or other side reactions;

② The generated Ni(I) species is not consumed in a timely manner;

③ Low-valent nickel species become deactivated and form nickel black;

④ The sulfonyl hydrazide is consumed, but the desired product is obtained in low yield.

If sulfonyl hydrazide activation is too slow, the arylnickel intermediate may not receive a sufficient supply of alkyl radicals, and the reaction may likewise stall.

5.2 Electronic Effects of the Sulfonyl Group Can Regulate the Rate of Sulfonyl Hydrazide Activation

Before a sulfonyl hydrazide can generate an alkyl radical, it must first eliminate a sulfinate and form an isodiazene-related intermediate. In the model reaction studied, this step was a key determinant of the overall reaction rate. Consequently, substituents on the aryl ring of the sulfonyl group directly affect the activation rate of the sulfonyl hydrazide.

The general trends are as follows:

① Electron-withdrawing substituents generally accelerate activation.

Electron-withdrawing groups help stabilize the departing sulfinate, facilitating formation of the isodiazene and thereby accelerating subsequent radical generation.

② Electron-donating substituents generally slow activation.

Electron-donating groups make sulfinate departure less favorable, resulting in slower sulfonyl hydrazide activation but often greater thermal stability.

Mechanistic studies showed that changing only the substituents on the aryl ring of the sulfonyl group could alter the activation rate of representative sulfonyl hydrazides by approximately two orders of magnitude.

This trend helps explain the selection of reaction conditions. Sulfonyl hydrazide activation should be neither too fast nor too slow but should instead be matched to the rates of aryl halide activation and radical capture by nickel. If radicals are generated too rapidly to be captured efficiently, unproductive sulfonyl hydrazide decomposition, radical side reactions, or nickel-catalyst deactivation may occur.

5.3 Different Fragments Require Different Ligands and Conditions

In addition to the activation rate of the sulfonyl hydrazide, the electronic properties and structures of different alkyl radicals also affect the reaction.

① Common small alkyl radicals: For methyl and certain simple alkyl radicals, the main requirement is to coordinate the rates of radical generation and nickel-mediated radical capture;

② Radicals bearing electron-withdrawing groups: Cyanomethyl, carboxymethyl, and difluoromethyl radicals have polarities different from those of ordinary alkyl radicals, requiring adjustment of the electronic properties of the nickel center;

③ Highly strained radicals: Cyclopropyl and bicyclo[1.1.1]pentyl radicals possess distinctive orbital and steric characteristics and require rapid and efficient capture;

④ Fragments bearing coordinating groups: The oxygen and nitrogen atoms in hydroxymethyl and aminomethyl fragments may coordinate to nickel and interfere with catalysis.

Adjustments to the ligand, solvent, and temperature are primarily used to control:

① Oxidative addition of the aryl halide;

② Stability of the nickel species;

③ Efficiency of alkyl-radical capture;

④ Competition between C—C bond formation and side reactions such as dehalogenation and homocoupling.

Thus, although the method uses a unified reagent class and a common bond-forming principle, individual fragments still require appropriately tailored reaction conditions.

6 Introducible Fragments and Their Medicinal Chemistry Applications

The choice of fragment should address a clearly defined medicinal chemistry question rather than merely increasing the number of sp³-hybridized carbons in the molecule.

For example, when the activity of a methylated compound is improved, the following comparisons can be made deliberately:

① Whether a trideuteriomethyl group affects metabolic processes involving C—H bond cleavage;

② Whether a cyclopropyl group further improves activity by increasing rigidity or hydrophobic contacts;

③ Whether a difluoromethyl group alters binding and metabolism through electronic effects;

④ Whether a hydroxymethyl group improves polarity or solubility;

⑤ Whether an oxetanyl group introduces an oxygen atom while maintaining a similar degree of steric occupancy.

Such comparisons help distinguish whether changes in activity arise from differences in size, conformation, polarity, electronic effects, or metabolic stability.

7 Substrate Scope and Practical Applications

7.1 Broad Coverage of Heterocycles Commonly Used in Medicinal Chemistry

The method was validated on more than 60 aryl and heteroaryl halides, including a range of structures commonly encountered in medicinal chemistry, such as pyridines, quinolines, pyrazines, thiophenes, benzofurans, and fused nitrogen-containing heterocycles.

Under specific reaction conditions, compatible functional groups included:

① Amides and lactams;

② Esters and ketones;

③ Certain thioethers;

④ Boronic esters;

⑤ Protected alcohols and amines;

⑥ Certain strongly electron-withdrawing substituents.

It should be emphasized that “functional-group compatibility” applies to a specific sulfonyl hydrazide, substrate, and set of reaction conditions. A successful example does not establish that the same functional group will be tolerated in every fragment-coupling reaction.

7.2 Types of Synthetic Tasks for Which the Method Is Particularly Suitable

The method is particularly suitable in the following situations:

① The molecule already contains an aryl or heteroaryl chloride, bromide, or iodide;

② The halogen is located at the position targeted for structural optimization;

③ Multiple small fragments need to be compared around the same core scaffold;

④ Redesigning the upstream route for each fragment is undesirable;

⑤ The objective is to obtain milligram- to gram-scale quantities of analogues rapidly for biological-activity and physicochemical-property testing.

If the target molecule does not contain a suitable aryl halide, the total number of steps and practical feasibility of “installing a halogen first and then performing the coupling” should be compared with those of alternative synthetic routes.

7.3 Representative Examples of Route Simplification

The researchers introduced a trideuteriomethyl group into a precursor of a mesenchymal–epithelial transition factor (MET) kinase inhibitor. A previously reported Kumada coupling route gave a yield of 14%, whereas use of the corresponding sulfonyl hydrazide afforded the target product in 51% yield.

Another example involved cyclobutylation of an intermediate used in the synthesis of an NOD-like receptor family pyrin domain-containing 3 (NLRP3) inhibitor. The existing route required four steps and provided an overall yield of less than 5%. Sulfonyl hydrazide coupling constructed the target C—C bond in a single step and afforded the product in 41% yield.

These two cases illustrate two distinct advantages of the method:

① Replacement of organometallic reagents that are difficult to prepare or handle with isolable sulfonyl hydrazides;

② Reduction of protecting-group operations, functional-group interconversions, and multistep synthetic detours through direct construction of a C(sp²)—C(sp³) bond.

During hit-to-lead and lead-optimization campaigns, the usual objective is to obtain sufficient quantities of analogues for testing as quickly as possible. Reducing the total number of steps and the amount of precursor-preparation work is therefore often more important than maximizing the isolated yield of a single reaction.

8 Method Limitations and Practical Considerations

Sulfonyl hydrazide reagents expand the range of C(sp³) fragments that can be introduced directly, but the method is not applicable to every substrate or functional group.

8.1 Major Limitations

① Some electron-rich substrates are difficult to react.

Certain electron-rich aryl and heteroaryl substrates may show low conversion or low yield in hydroxymethylation, aminomethylation, or difluoromethylation reactions.

② Free hydroxy and amino groups may interfere with the nickel catalyst.

Alcohols and amines can coordinate to nickel and may also participate in proton-transfer processes or side reactions. Hydroxymethyl groups are therefore often protected as tert-butyldimethylsilyl (TBS) derivatives, while amino groups are commonly protected as tert-butoxycarbonyl (Boc) derivatives.

③ Nitro-group compatibility is condition-dependent.

Some nitro-containing substrates can furnish the desired products under specific conditions. However, nitro groups may also be affected by hydrazines, hydrazones, or other reducing intermediates. Nitro groups should therefore not be described as either “fully compatible” or “completely incompatible” across the entire method.

④ Some reactions require relatively high nickel loadings.

More reactive substrates can be coupled using lower catalyst loadings, whereas more challenging substrates may require approximately 20 mol% nickel catalyst.

⑤ An inert atmosphere is generally required.

The reactions are typically performed under nitrogen or argon, although glovebox operation is generally unnecessary.

8.2 Common Side Reactions

Potentially observed by-products include:

① Dehalogenated products derived from the aryl halide;

② Homocoupling products of the aryl substrate;

③ Reduction or dimerization products of the alkyl radical;

④ Coupling products formed after radical rearrangement;

⑤ Sulfonylation-related by-products;

⑥ Sulfinate salts formed through decomposition of the sulfonyl hydrazide.

These side reactions reflect competition among radical generation, nickel-species interconversion, and formation of the desired bond. During optimization, it is important to determine whether the problem arises from excessively rapid sulfonyl hydrazide activation, slow aryl halide activation, or unfavorable coordination of the substrate or product to the nickel catalyst.

9 Chemicals Related to the Sulfonyl Hydrazide-Mediated Introduction of Small C(sp³) Fragments

Table 1. Catalysts, Ligands, Reaction Bases, and Solvents

Table 2. Reagents for Sulfonyl Hydrazide Construction, Reduction, and Functional-Group Protection

Table 3. Precursors for Deuterated Methyl and Functionalized Acyclic Fragments

Table 4. Precursors for Cyclic and Rigid C(sp³) Fragments

Note: The products listed above are representative Aladdin products relevant to scientific research and formulation studies. Additional specifications, grades, and certificates of analysis can be found on the Aladdin website by searching the product name, CAS number, or catalog number.

References

[1] Tsien J, Péter Á, Zeng X, et al. Accelerating Medicinal Chemistry: A C(sp³)-Rich Fragment Toolbox for Redox-Neutral Cross-Coupling. Angewandte Chemie International Edition, 2025, 64(51): e202517207. DOI: 10.1002/anie.202517207.

[2] Sun J, Péter Á, He J, et al. Sulfonyl Hydrazides as a General Redox-Neutral Platform for Radical Cross-Coupling. Science, 2025, 387(6741): 1377–1383. DOI: 10.1126/science.adu6406.

[3] Cagan D A, Péter Á, Vokits B P, et al. Decoding the Nested, Multicycle Mechanism of Ni-Catalyzed Redox-Neutral Cross-Coupling through Temperature Scanning Reaction Calorimetry. Journal of the American Chemical Society, 2026, 148(1): 677–691. DOI: 10.1021/jacs.5c15506.

[4] Lovering F, Bikker J, Humblet C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. Journal of Medicinal Chemistry, 2009, 52(21): 6752–6756. DOI: 10.1021/jm901241e.

[5] Churcher I, Newbold S, Murray C W. Return to Flatland. Nature Reviews Chemistry, 2025, 9: 140–141. DOI: 10.1038/s41570-025-00688-5.

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