Introduction

The combination of aryl methyl ketones with molecular iodine (I₂)/dimethyl sulfoxide (DMSO) can participate in a variety of heterocycle-forming reactions. At first glance, these methods lead to different structures, such as imidazopyridines, benzothiazoles, and benzofurans. From the perspective of the reaction pathway, however, a considerable number of these methods share the same initial sequence: an aryl methyl ketone first undergoes α-iodination followed by oxidation to generate an aryl glyoxal, which is then trapped by subsequent reactants and undergoes condensation and cyclization. A review published by Jalani in 2024 systematically summarized this class of I₂/DMSO reactions involving the “in situ generation of aryl glyoxals from methyl ketones.” [1]

The core reaction sequence discussed in this article can be represented as:

Ar–CO–CH₃ → Ar–CO–CH₂I → Ar–CO–CHO → nucleophilic trapping → condensation/cyclization → target product

Here, Ar denotes an aryl group. The first two steps accomplish the oxidative conversion of a methyl ketone into an aryl glyoxal. The structure of the subsequent product depends on the nucleophilic centers of the trapping reagent, the relative positions of these reactive sites, and the manner in which consecutive bond-forming events occur. [1–4]

This reaction sequence does not apply to all I₂/DMSO reactions. I₂/DMSO can also participate in other types of oxidation and bond-forming processes. This article focuses on the experimentally supported reaction pathway involving aryl methyl ketone → α-iodoketone → aryl glyoxal.

1. How Does Reactivity Change from a Methyl Ketone to an Aryl Glyoxal?

An aryl methyl ketone can be represented as:

Ar–CO–CH₃

The aryl glyoxal formed after I₂/DMSO oxidation can be represented as:

Ar–CO–CHO

From the structural formula, the change is concentrated in the methyl group:

–CH₃ → –CHO

From the perspective of organic synthesis, however, this transformation changes the bond-forming capability of the entire molecule.

1.1 Aryl Methyl Ketones Mainly Provide One Carbonyl Electrophilic Center

An aryl methyl ketone contains one carbonyl group. The carbonyl carbon can undergo nucleophilic attack, while the α-position can also participate in reactions such as halogenation and condensation through enolization.

However, the α-C–H bond itself does not possess good leaving-group character. If this carbon atom is to be further converted into a second carbonyl group, prior activation is generally required.

1.2 Aryl Glyoxals Contain Two Adjacent Carbonyl Groups

The basic structure of an aryl glyoxal is:

Ar–CO–CHO

It contains both a ketone carbonyl and an aldehyde carbonyl and therefore belongs to the class of 1,2-dicarbonyl compounds. Both adjacent carbonyl carbons are electrophilic, although their reactivities are not identical. In general, the aldehyde carbonyl is more susceptible to nucleophilic attack, whereas the ketone carbonyl can participate in a second bond-forming event or remain intact in the final product.

Therefore, once a methyl ketone is converted into an aryl glyoxal, the reactant no longer contains only one carbonyl reaction center; instead, it possesses two adjacent electrophilic carbon centers that can participate consecutively in bond formation.

This structural feature is an important basis for the ability of aryl glyoxals to participate in a variety of condensation reactions and heterocycle-forming transformations. [1]

2. How Does I₂/DMSO Generate Aryl Glyoxals In Situ?

This process can be divided into two consecutive functional-group transformations:

α-C–H → α-C–I → α-C=O

The corresponding substrate transformation is:

Ar–CO–CH₃ → Ar–CO–CH₂I → Ar–CO–CHO

In their studies of I₂-mediated reactions of aryl methyl ketones, Zhu and co-workers described the corresponding process as a cascade involving iodination, Kornblum oxidation, and subsequent bond-forming reactions. [3]

2.1 α-Iodination Converts a C–H Site into a C–I Site That Can Undergo Further Oxidation

The α-position of an aryl methyl ketone can form an enol or a corresponding enol-type species and undergo α-iodination with I₂:

Ar–CO–CH₃ → Ar–CO–CH₂I

This reaction generates an α-iodoketone.

From the perspective of the subsequent oxidation, the key transformation is:

C–H → C–I

Iodine in the C–I bond serves as a good leaving group. The α-carbon is therefore converted from the original C–H structure into an activated structure that can undergo nucleophilic attack by DMSO and subsequent oxidation. The function of α-iodination is to create the conditions required for formation of the next carbonyl group.

2.2 DMSO Converts α-Iodoketones into α-Keto Aldehydes through Kornblum Oxidation

The α-iodoketone subsequently reacts with DMSO:

Ar–CO–CH₂I → Ar–CO–CHO

This transformation belongs to the Kornblum oxidation type. Classical Kornblum oxidation is a method in which DMSO oxidizes a carbon center bearing a suitable leaving group into a carbonyl compound. It was established by Kornblum and co-workers in the 1950s. [6]

According to the general mechanism of Kornblum oxidation, DMSO first participates in nucleophilic substitution at the carbon center bearing the halogen leaving group, forming a sulfonium-containing intermediate, which subsequently undergoes proton transfer and elimination to generate the carbonyl group.

In the aryl methyl ketone system, this step formally accomplishes:

–CH₂I → –CHO

Therefore, the net result of the two consecutive steps is:

In this type of reaction, DMSO commonly serves both as the reaction medium and as a participant in the oxidation rather than acting solely as a solvent. [1,3]

2.3 The α-Iodoketone and Aryl Glyoxal Pathway Is Supported by Experimental Evidence

The conversion of an aryl methyl ketone through an α-iodoketone into an aryl glyoxal is not merely a mechanistic proposal inferred from the final product. In their study of the I₂-promoted synthesis of 2-acylbenzothiazoles from aryl methyl ketones and 2-aminothiophenol, Zhu and co-workers performed proton nuclear magnetic resonance (¹H NMR) monitoring and control experiments on a representative reaction. [2] Acetophenone was used as the model substrate, and the corresponding 2-acylbenzothiazole could be generated under standard I₂/DMSO conditions.

2.3.1 NMR Experiments Revealed Signals Associated with Key Intermediates

The researchers first recorded the ¹H NMR spectra of acetophenone and an authentic sample of α-iodoacetophenone and then monitored the reaction process. The Supporting Information also provided ¹H NMR signals for the aldehydic proton of phenylglyoxal and related hemiacetal species, which were used to identify intermediates appearing during the reaction. [2]

The authors also examined the progress of the reaction between acetophenone and 2-aminothiophenol at different amounts of I₂. As the amount of I₂ increased, the conversion of acetophenone accelerated significantly, indicating that I₂ participates in the conversion of the methyl ketone into subsequent reactive intermediates. [2]

Based on these experimental results, the initial part of the reaction can be represented as:

acetophenone → α-iodoacetophenone → phenylglyoxal-related species

These results provide experimental support for the “α-iodination–further oxidation” reaction pathway.

2.3.2 Independent Intermediate Experiments Further Validated the Reaction Pathway

The authors subsequently carried out reactions directly using possible intermediates. [2]

① α-Iodoacetophenone reacted with 2-aminothiophenol in the presence of I₂ to afford the target 2-acylbenzothiazole in an isolated yield of 85%;

② The phenylglyoxal-related hemiacetal intermediate designated by the authors as 1ab also reacted smoothly with 2-aminothiophenol to generate the target product in a yield of more than 95%.

Based on the NMR monitoring and independent intermediate experiments, the authors considered α-iodoacetophenone and phenylglyoxal to be key intermediates in this transformation. [2]

It should be noted that mechanistic schemes generally simplify aryl glyoxals as:

Ar–CO–CHO

where Ar denotes an aryl group. In the actual reaction system, phenylglyoxal does not necessarily exist exclusively as a single free dicarbonyl species at all times. The ¹H NMR results from the study described above showed signals corresponding to both the aldehydic proton of phenylglyoxal and related hemiacetal species. [2]

Accordingly, the key initial sequence of the I₂/DMSO-mediated transformation of acetophenone can be summarized as:

Ar–CO–CH₃ → Ar–CO–CH₂I → Ar–CO–CHO

That is, the aryl methyl ketone first undergoes α-iodination, after which the α-iodoketone is further oxidized to form an aryl glyoxal-type 1,2-dicarbonyl intermediate, which then enters subsequent nucleophilic trapping and cyclization reactions. [2]

3. Why Are Aryl Glyoxals Well Suited for Further Heterocycle Construction?

The synthetic value of aryl glyoxals arises from their 1,2-dicarbonyl structure:

Ar–CO–CHO

Once this structural feature is understood, many subsequent reactions can be summarized as the following basic process:

first nucleophilic addition or condensation → formation of a new C–N, C–O, C–S, or C–C bond → continued bond formation at the remaining reactive sites → cyclization or further functionalization

Two points should be noted here.

3.1 Both Carbonyl Groups Do Not Necessarily Become Part of the Newly Formed Ring

Different reactions utilize the two carbonyl groups in different ways.

In one scenario, both carbonyl groups participate in consecutive condensation and ring formation. In another, one carbonyl participates in cyclization while the other is retained as an acyl group in the product. It is also possible for two different nucleophilic components to participate separately in the reaction, followed by intramolecular bond formation to generate the ring system.

Therefore, the role of the aryl glyoxal is not to predetermine the product structure, but rather to provide a pair of adjacent carbonyl reaction centers.

3.2 The Arrangement of Functional Groups in the Trapping Reagent Influences the Subsequent Mode of Cyclization

After the first nucleophilic attack, whether a second effective bond-forming event can occur is closely related to the position of the remaining nucleophilic center in the trapping reagent.

For a substrate containing two nucleophilic centers, the following factors should be considered:

① which atoms or carbon centers constitute the two nucleophilic sites;

② how far the second nucleophilic center is from the remaining electrophilic center after the first bond-forming event;

③ whether subsequent intramolecular bond formation can generate a stable five-membered, six-membered, or fused ring;

④ whether one of the carbonyl groups is better retained as an acyl group rather than continuing to participate in cyclization.

Different trapping reagents can therefore direct the same aryl glyoxal toward different structures. [1,2,4,5]

4. How Different Trapping Modes Generate Different Product Scaffolds

Three representative reactions illustrate the structural divergence that can occur after formation of the aryl glyoxal.

4.1 N/S Dinucleophiles: Conversion of Aryl Glyoxals into 2-Acylbenzothiazoles

Zhu and co-workers reported a method for synthesizing 2-acylbenzothiazoles from aryl methyl ketones and 2-aminothiophenol under I₂/DMSO conditions. [2] In this method, aryl methyl ketones or related substrates serve as carbonyl precursors, and tandem oxidative cyclization is accomplished without transition metals or peroxides.

2-Aminothiophenol contains an amino group and a thiol group arranged at adjacent positions. After the aryl glyoxal is formed, its aldehyde terminus can participate in condensation and subsequent cyclization, while the original aroyl moiety is retained in the product.

Therefore:

Ar–CO–CHO → 2-acylbenzothiazole

The two carbonyl groups are not both consumed. Instead, one carbonyl provides the carbon center required for ring formation, while the other is retained as an acyl group.

This example demonstrates that the two carbonyl groups in a 1,2-dicarbonyl compound can perform different functions.

4.2 Nitrogen-Containing Nucleophiles: Consecutive Bond Formation to Generate the Imidazo[1,2-a]pyridine Scaffold

Fei and co-workers reported the direct synthesis of 2-aryl-3-(pyridin-2-ylamino)imidazo[1,2-a]pyridines from aryl methyl ketones and 2-aminopyridines under I₂/DMSO conditions. [5] The original paper states that the reaction proceeds in one pot in I₂/DMSO without the need for additional metals, bases, or ligands.

From the product structure, the final product contains two nitrogen-containing fragments derived from 2-aminopyridine. 2-Aminopyridine contains different nitrogen-containing reactive sites, including an exocyclic amino group and the pyridine nitrogen; the aryl glyoxal-related intermediate provides the adjacent carbonyl carbons required for consecutive bond formation.

The structural features of this type of reaction mainly arise from two components:

The aryl glyoxal-related intermediate provides carbon centers that participate consecutively in bond formation; nitrogen-containing fragments derived from 2-aminopyridine provide the reactive sites required for subsequent C–N bond formation and cyclization.

Together, these components determine the fused nitrogen-containing heterocycle ultimately formed.

4.3 Multicomponent Trapping: Reactive Sites from Different Molecules Cooperatively Construct Benzofurans

Cheng, Liu, and Gu reported a three-component synthesis of benzofurans from methyl ketones, phenols, and nucleophiles. [4]

The study first established a three-component reaction involving aryl glyoxals and subsequently replaced preformed aryl glyoxals with aryl methyl ketones: the methyl ketone is first converted into an aryl glyoxal in the I₂/DMSO system, after which phenols and nucleophilic components such as indoles participate in subsequent bond-forming reactions to generate polysubstituted benzofurans. [4]

Unlike the reaction with 2-aminothiophenol, the nucleophilic centers required for this transformation are not concentrated within a single molecule but are instead provided separately by different reactants.

This demonstrates that aryl glyoxals can also serve as connecting units in multicomponent reactions:

methyl ketone oxidation → aryl glyoxal formation → sequential trapping by different nucleophilic components → intramolecular cyclization

This process affords more structurally complex oxygen-containing heterocycles.

5. Why Is the In Situ Generation of Aryl Glyoxals Often Combined with a “One-Pot Stepwise” Reaction?

Aryl glyoxals possess high carbonyl reactivity. This property facilitates subsequent nucleophilic trapping, but it also means that they may undergo competing reactions with other components in the reaction system.

Therefore, a one-pot reaction does not necessarily mean that all starting materials are added simultaneously at the beginning of the reaction.

The benzofuran method reported by Cheng and co-workers explicitly employs a one-pot stepwise reaction: the methyl ketone is first allowed to undergo oxidation in the I₂/DMSO system, followed by the subsequent three-component reaction. [4]

This operation can be divided into two stages:

First stage:

Ar–CO–CH₃ → Ar–CO–CHO

Second stage:

Ar–CO–CHO + trapping components → condensation/cyclization product

This approach temporally separates the generation of the aryl glyoxal from its subsequent trapping.

For similar reactions, the choice of reaction sequence mainly involves three factors:

① Rate of aryl glyoxal formation

A sufficient proportion of the precursor must be converted into the 1,2-dicarbonyl intermediate.

② Tolerance of the trapping reagent toward I₂/DMSO conditions

Substrates containing electron-rich aromatic rings, sulfur-containing groups, amines, and other functional groups may undergo additional iodination or oxidation, and this must be evaluated for the specific substrate.

③ Competing reactions of the aryl glyoxal

Aryl glyoxals are highly reactive. Whether they can enter the desired trapping process promptly after formation can affect product selectivity.

Therefore, in this type of tandem reaction, when the intermediate is generated and when the trapping reagent is added are of practical importance, just as the choice of reactants is.

6. How to Evaluate a New Reaction Combination from a Mechanistic Perspective

Once the “methyl ketone–aryl glyoxal–trapping–cyclization” pathway is understood, a new substrate combination can be analyzed according to the sequence in which the reactions occur.

6.1 Determine Whether the Methyl Ketone Can Undergo α-Iodination and Subsequent Oxidation

First, consider the α-position of the aryl methyl ketone and the other functional groups present in the molecule:

① whether α-iodination can occur;

② whether competing iodination sites are present;

③ whether the molecule contains functional groups that can be readily oxidized further under I₂/DMSO conditions;

④ whether the substrate can tolerate the corresponding reaction temperature and oxidative conditions.

This step determines whether the aryl glyoxal can be formed efficiently.

6.2 Determine Which Nucleophilic Center First Traps the Aryl Glyoxal

For Ar–CO–CHO, the aldehyde carbonyl is generally more electrophilic than the ketone carbonyl, although the actual selectivity is also influenced by the nature of the nucleophile, acid–base conditions, and the structure of the intermediate.

Therefore, for a specific substrate, it is necessary to determine:

where the first new bond forms and which nucleophilic and electrophilic centers remain after the first bond-forming event.

6.3 Determine Whether the Second Bond-Forming Event Can Generate a Reasonable Ring System

After the first bond-forming event, the positional relationship between the remaining nucleophilic center and the remaining electrophilic center should be further examined.

For example:

① whether a five-membered or six-membered ring can be formed;

② whether a significantly unfavorable conformation would be required;

③ whether a faster intermolecular side reaction may occur;

④ whether the second carbonyl should continue to participate in ring formation or is better retained as an acyl group.

This analysis can explain why structurally similar trapping reagents may produce different products.

6.4 Determine Whether Intermediate Formation and Trapping Are Better Performed in Separate Stages

If the trapping reagent is readily affected by I₂, or if the conditions required for aryl glyoxal formation differ substantially from those required for cyclization, oxidation can be performed first, followed by addition of the trapping components.

Based on the reaction pathway described above, related experiments typically involve aryl methyl ketone precursors, the I₂/DMSO system, aryl glyoxal intermediates, and different types of nucleophilic trapping reagents. Representative products are summarized below.

7. Representative Product Classification Tables Related to I₂/DMSO-Mediated Oxidation of Aryl Methyl Ketones and Aryl Glyoxal Trapping and Cyclization

Table 1. Core Reaction Reagents, Key Intermediates, and Auxiliary Reagents

Table 2. Aryl Methyl Ketone Precursors

Table 3. Reagents for Aryl Glyoxal Trapping and Heterocycle Construction

Note: The products listed above are representative Aladdin products relevant to scientific research. Their specific use should be determined according to product specifications, batch COAs, and the target reaction or evaluation system. Additional information on product specifications, grades, and COAs can be searched on the Aladdin website using the “product name/CAS/catalog number.”

References

[1] Jalani, H. B. Recent Development on the Heterocycles Derived From In Situ Formation of Aryl Glyoxals by Iodine/DMSO Mediated Oxidation of Methyl Ketones. Journal of Heterocyclic Chemistry, 2024, 61(11), 1668–1703. DOI: 10.1002/jhet.4880.

[2] Zhu, Y.-P.; Lian, M.; Jia, F.-C.; Liu, M.-C.; Yuan, J.-J.; Gao, Q.-H.; Wu, A.-X. I₂ Promoted Domino Oxidative Cyclization for One-Pot Synthesis of 2-Acylbenzothiazoles via Metal-Free sp³ C–H Functionalization. Chemical Communications, 2012, 48, 9086–9088. DOI: 10.1039/C2CC34561G.

[3] Zhu, Y.-P.; Liu, M.-C.; Jia, F.-C.; Yuan, J.-J.; Gao, Q.-H.; Lian, M.; Wu, A.-X. Metal-Free sp³ C–H Bond Dual-(Het)arylation: I₂-Promoted Domino Process to Construct 2,2-Bisindolyl-1-arylethanones. Organic Letters, 2012, 14(13), 3392–3395. DOI: 10.1021/ol301366p.

[4] Cheng, C.; Liu, C.; Gu, Y. One-Pot Three-Component Reactions of Methyl Ketones, Phenols and a Nucleophile: An Expedient Way to Synthesize Densely Substituted Benzofurans. Tetrahedron, 2015, 71, 8009–8017. DOI: 10.1016/j.tet.2015.08.058.

[5] Fei, Z.; Zhu, Y.-P.; Liu, M.-C.; Jia, F.-C.; Wu, A.-X. I₂-Promoted Direct One-Pot Synthesis of 2-Aryl-3-(pyridine-2-ylamino)imidazo[1,2-a]pyridines from Aromatic Ketones and 2-Aminopyridines. Tetrahedron Letters, 2013, 54(10), 1222–1226. DOI: 10.1016/j.tetlet.2012.12.072.

[6] Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W. J.; Larson, H. O.; Levand, O.; Weaver, W. M. A New and Selective Method of Oxidation. Journal of the American Chemical Society, 1957, 79(24), 6562. DOI: 10.1021/ja01581a057.

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