Recent Advances in the Use of Dimethyl Sulfoxide as a Synthon in Organic Chemistry

Abstract

Dimethyl sulfoxide (DMSO), as extremely important aprotic polar solvent and reaction medium, has attracted widespread attention from chemists in recent years due to its wide range of uses and the multiple functions it displays in various chemical processes. Especially in the past decade, dimethyl sulfoxide has become increasingly favored as a synthon in organic chemistry, resulting in great progress in this research field. In this context, this review provides a comprehensive summary of the literature on the recent progress in organic synthesis using dimethyl sulfoxide as a synthon, covering all the reports from 1 January 2016 to 11 May 2022. This type of reaction is mainly performed by transferring one or more units of dimethyl sulfoxide, such as oxygen (–O–, =O), methyl (–CH₃), methylene (–CH₂–), methylidene (=CH₂), methine (=CH–), donor of formylation (–CHO), sulfur (–S–), methylthio (–SMe), methyl sulfoxide (–SOMe), donor of methyl thiomethylation (–CH₂SMe), or donor of methyl sulfoxide methylation (–CH₂SOMe), to the target molecules. At the same time, we hope that this review will stimulate future studies and promote developments in this area.

Graphical Abstract

1 Introduction

Dimethyl sulfoxide (DMSO) has been widely used as an important high-polarity reaction medium in organic synthetic chemistry due to its good thermal stability, high boiling point, low price, and low toxicity [1,2,3,4,5,6]. In terms of molecular structure, it is composed of two hydrophobic methyl groups and one strongly polar sulfoxide group, which gives DMSO excellent properties [7, 8]. In addition to be widely used as a solvent and reaction reagent, DMSO is also valuable in pharmaceuticals [9, 10], pesticides [11, 12], materials [13], analysis [14], etc. In the pharmaceutical industry, DMSO is used as a raw material for drugs and their carriers, and is often added to drugs as the active ingredient in painkillers [15]. At the same time, DMSO can be used as an additive for pesticides by taking advantage of its carrier properties. The addition of small amounts of DMSO to certain pesticides helps the pesticide penetrate into the plant to improve its efficacy [16]. DMSO was one of the first transdermal penetration enhancers used for its ability to denature proteins within skin keratinocytes, thereby removing keratin-layer lipids and lipoproteins [17]. In addition, DMSO exhibits good solubility for various resins, and can be used as a solubilizer in some lacquers [18]. More importantly, DMSO is used as a paint remover. By adding alkali to DMSO, various kinds of varnishes including epoxy resins can be removed effectively [19]. These results indicate that DMSO is an efficient and highly versatile aprotic polar solvent with various current applications in everyday life.

DMSO plays the dual role of reaction solvent and reaction reagent in chemical reactions, and some unrealizable reactions can be carried out smoothly in DMSO. It is also used as a general reagent for many well-known reactions, such as nucleophilic substitution [20, 21], elimination [22,23,24], electrophilic [25], and substitution reactions [26]. In conclusion, DMSO has opened up a new pathway in chemical preparation by which many new substances have been prepared, and is of great significance in theory and practice as a new means of synthesizing substrates via chemical reactions. To date, a few reports have systematically summarized the synthetic transformations using fragments of dimethyl sulfoxide as building blocks [27,28,29,30]. We focus instead on a more comprehensive and updated review of DMSO as a synthon, based on a review published by Magolan in 2016 and summarizing the latest reports in the field from 1 January 2016 to 11 May 2022.

The current review presents the latest research progress on the use of dimethyl sulfoxide as a synthon by transferring one or more of its units after binding to target molecules. The notable uses described in this review are: (i) as an oxygen source (–O–, =O); (ii) as carbon sources, involving methyl (–CH₃), methylene (–CH₂–), methylidene (=CH₂), methine (=CH–), and donor of formylation (–CHO); (iii) as a sulfur source (–S–); (iv) as a methylthio source (–SMe), methyl sulfoxide source (–SOMe), methyl thiomethylation donor (–CH₂SMe), and methyl sulfoxide methylation donor (–CH₂SOMe) (Fig. 1). Moreover, typical reactions, selected examples, reaction mechanisms, and potential applications in synthesis are discussed. It is worth noting that this review covers various synthetic methods that have been recently reviewed elsewhere and which will thus not be discussed in detail.

Fig. 1

Transfers of DMSO in organic synthesis

2 As Oxygen Source (–O– and =O)

In 2016, Jiao’s group reported an efficient strategy for preparation of substituted catechols via I₂-catalyzed oxidation of cheap and readily available cyclohexanones [31]. In that work, the protocol was made greener and more practical by using DMSO as oxygen source, oxidant, and solvent. 3,3′,4,4′-Tetrahydroxybiphenyl 2 is a very useful drug molecule and is widely used as a transition-metal ligand. The conventional method to obtain it is based on Pd-catalyzed Suzuki coupling followed by addition of boron tribromide for cleavage of methyl ether. In contrast, it can be easily obtained in higher yields from the readily marketed 4,4′-bicyclohexanone 1 and DMSO (Scheme 1a). Also, cholesterol derivative 3 as well as norethindrone 5 can convert smoothly to catechol product 4 (Scheme 1b) and α-carbonylation product 6 (Scheme 1c) under standard conditions. Interesting mechanistic studies, kinetic profile, and density functional theory (DFT) calculations provided valuable information on the reaction mechanism. Cyclohexanones were subjected to electrophilic iodination, Kornblum oxidation, HI elimination, and isomerization to give the final catechol products (Scheme 2). The success of this protocol provides a viable pathway for the modification of bioactive compounds.

Scheme 1

Synthesis using DMSO as oxygen source, oxidant, and solvent [31]

Scheme 2

The proposed mechanism [31]

The same year, Wang and colleagues disclosed a procedure for synthesis of β-amino ketones 11 from acetyl-containing five-membered heterocycles 9 with azoles 10 under selective fluorine promotion using dimethyl sulfoxide as oxygen source and solvent (Scheme 2) [32]. Meanwhile, the strategy exhibited excellent substrate adaptability and functional group tolerance, thus providing an attractive addition to the traditional Mannich-type reaction (Scheme 3).

Scheme 3

Synthesis of β-amino ketones 11 using 2′-heterocyclic ketones and azoles [32]

A CuI/DMSO-promoted method for synthesis of benzobicyclo[3.2.1]octanes 13 using o-carbonyl allylbenzenes 12 as starting materials was developed by Chang’s group in 2017 (Scheme 4) [33]. Among them, the structures of some compounds 13 were confirmed by X-ray crystallographic analysis, confirming that these critical products have the core framework structure of benzofused dioxabicyclo[3.2.1]octane.

Scheme 4

Plausible mechanism for synthesis of benzobicyclo[3.2.1]octanes 13 by using o-carbonyl allylbenzenes [33]

In 2018, Glorius et al. described a visible-light-mediated synthesis of α-alkyl acetophenones 16 through reaction of styrenes 14 and N-(acyloxy)phthalimides 15 in good yields (Scheme 5) [34]. The protocol has the remarkable features of simple operation, mild conditions, high efficiency, and low photocatalyst loading. It is worth mentioning that the para-position of styrenes tolerates various electron-donating and electron-withdrawing functional groups very well. This synthetic method is also applicable for some biologically active compounds such as deoxycholic acid, gemfibrozil, and Boc-protected γ-aminobutyric acid.

Scheme 5

Synthesis of α-alkyl-acetophenones 16 by oxidative alkylation reaction [34]

After that, Zhong’s group developed a novel route for synthesis of sulfonated 1,3-oxazolidines and oxazolidines 19 with high selectivity for the first time (Scheme 6) [35]. The protocol is a thia-aza-Prins cyclization of alkenylamines 17 and disulfides 18 with DMSO as reaction medium via formaldehyde substitution. Using this efficient and inexpensive catalytic system, various useful oxazolidines can be readily prepared under air. Also, disulfides have many advantages as a source of sulfited reagents, such as adjustable stability, remarkable biocompatibility, and ready availability.

Scheme 6

Copper-catalyzed thia-aza-Prins cyclization for synthesis of 1,3-oxazinanes 19 [35]

In 2019, Ma et al. described a procedure for obtaining 1,6-fluoroalkyl ketones 22 by visible-light-mediated highly selective activation of alkenes 20 at room temperature for the first time (Scheme 7) [36]. The attractive feature of this protocol is the Kornblum reaction of remote-benzyl C–H bond activation by 1,5-H transfer of highly controlled olefin fluorination 21 sites using DMSO as a green oxygen source and solvent. In addition, no target product was detected when adding 4 equiv. of TEMPO to the reaction system. Also, free radical adducts were detected by high-resolution mass spectrometry (HRMS) when using this strategy, indicating that the process is a free radical reaction.

Scheme 7

Plausible mechanism for synthesis of 1,6-fluoroalkyl ketones 22 [36]

On the other hand, Liu et al. revealed a similar process by using a photocatalytic strategy (Scheme 8). Various γ-ketoesters 25 were obtained in excellent yields by oxidative coupling reactions of styrenes 23 with bromocarboxylates 24 when using DMSO as terminal oxidant and solvent [37]. Considering the practicality of the protocol, scale-up to tenfold gram level also proceeded smoothly under standard conditions, with γ-ketoester 25a being obtained in 71% isolation yield.

Scheme 8

Plausible mechanism for synthesis of γ‑ketoesters 25 [37]

Additionally, Guo and coworkers reported four-component cyclization of ketones 26–27, ammonium, and DMSO for synthesis of substituted oxazoles 28 (Scheme 9) [38]. This protocol provided 22 examples of 2,4-disubstituted oxazoles in excellent yields when using DMSO as cyclization oxygen source. 2,4,5-Trisubstituted oxazoles can also be obtained by this method via cross-condensation reaction of methyl and nonmethyl ketones. The successful implementation of the protocol on gram scale confirms its potential utility in organic synthesis.

Scheme 9

Plausible mechanism for synthesis of substituted oxazoles 28 [38]

Similarly, Tang et al. revealed a photoredox-catalyzed cascade reaction of styrenes 29 and bromodifluoro compounds 30 to synthesize difluorinated ketones 31 (Scheme 10) [39]. AgTFA as an additive gave significantly higher yields compared with other additives for this reaction. Meanwhile, the protocol offers many advantages such as mild conditions, simple operation, and efficient regioselectivity.

Scheme 10

Alkene oxydifluoroalkylation [39]

In 2020, Li et al. revealed a novel visible-light-induced fluoroalkylation 33 of remote alkynes 32 in high yields to obtain various ε-oxygenated fluoroalkylated (Z)-alkenes 34 (Scheme 11) [40]. The protocol enables remote oxygen alkylation of heterocyclic hydrocarbons using DMSO as green oxygen source. Replacement of DMSO with H₂O as oxygen source also enabled remote hydroxytrifluoromethylation. Additionally, the experimental results of the mechanism studies indicated that DMSO can act as an oxygen donor for the formation of carbonyl groups.

Scheme 11

Synthesis of complex fluoroalkylated (Z)‑alkenes 34 [40]

In the same year, Liu’s group developed an interesting procedure for preparation of 1,2-disubstituted epoxides 37 from alcohols or alkyl bromides 35 and benzyl bromides 36 at room temperature (Scheme 12) [41]. In this reaction, dimethyl sulfide produced by oxidation of DMSO formed substituted dimethyl sulfides in situ, which involved the Corey–Chaykovsky epoxidation reaction. The results of four sets of control experiments further indicated that Kornblum oxidation was the decisive step in the domino reaction, and the formation of sulfonium salt is likely to be reversible. The successful preparation of a series of useful epoxides will provide an efficient pathway in this field.

Scheme 12

Synthesis of 1,2-disubstituted epoxides 37 by Kornblum oxidation reaction [41]

Subsequently, Li’s group developed a novel reaction to prepare various 1,2-dicarbonyl compounds 39 by oxidative tandem reaction using 2-alkynyl carbonyl compounds 38 and dimethyl sulfoxide (Scheme 13) [42]. The significant advantages of this protocol are high chemoselectivity, wide range of substrate adaptability, and good tolerance of functional groups. This would provide an alternative activation mode for 1,2-dicarbonyl unit coupling reaction.

Scheme 13

Possible mechanisms for synthesis of various 1,2-dicarbonyl compounds 39 [42]

Immediately thereafter, an interesting visible-light-catalyzed oxidation of 1,6-dienes for synthesis of CF₃-containing five-membered heterocycles was reported by Zhu et al. (Scheme 14) [43]. This mild protocol produced various tetrahydropyrrole and tetrahydrofuran compounds containing trifluoromethyl in good yields with excellent diastereoselectivity. Two gram-scale syntheses were successfully achieved at the same time, further demonstrating the practicality of this synthesis protocol.

Scheme 14

Remote oxidative cyclization of 1,6-dienes [43]

In 2021, Liang et al. reported a synthetic method to obtain 34 N-acylbenzoxazoles 44 in moderate to good yields by three-component tandem cyclization reaction of phenols 42 with nitriles 43 and dimethyl sulfoxide using catalytic equivalents of (COCl)₂ (Scheme 15) [44]. The 6 equiv. of DMSO in this cyclization system not only replace formaldehyde as an oxygen source, but also provide two methylene sources.

Scheme 15

Preparation of N-acylbenzoxazines 44 [44]

After that, Xu’s group reported efficient synthesis of β-keto thiosulfones 46 using easily available ethylsulfonyl raw materials 45 and DMSO (Scheme 16) [45]. This bifunctionalization method is characterized by simple operation, readily available raw materials, and the absence of other additives. Nine sets of control experiments allowed better verification of the reaction mechanism.

Scheme 16

Preparation of β-keto thiosulfones [45]

Then, Wu’s group reported an interesting I₂-mediated Povarov reaction for synthesis of various 2,4-substituted quinolines 49 (Scheme 17) [46]. In this work, oxidative carbonylation of C(sp)–H of arylacetylenes followed by [4+2] cycloaddition was achieved by using common arylacetylenes 47 and anilines 48 as starting materials. This discovery significantly broadens the novel diene precursors in the Povarov reaction for the construction of more nitrogen-containing heterocycles.

Scheme 17

Synthesis of 2,4-substituted quinolones 49 [46]

Immediately after, Wu’s group went on to develop a new cyclization reaction of aryl methyl ketones 50 with enaminone 51 using the I₂/DMSO system as a simple method for synthesis of various 2-hydroxy-pyrrol-3(2H)-ones 52 (Scheme 18) [47]. The purification of products 52 was achieved simply by washing with CH₂Cl₂ solvent, which saves more time as well as avoiding traditional chromatographic methods. The drawback of this protocol is that the range of substrates for enaminones is too narrow, and it is unknown whether other substituents can be adapted to this reaction.

Scheme 18

Proposed mechanism for synthesis of 2-hydroxy-pyrrol-3(2H)-ones 52 [47]

In 2022, Liang et al. revealed a visible-light-promoted conversion of thioacids 53 to carboxylic acids 54 via substitution protocols, obtaining various carboxylic acids 54 in yields exceeding 90% and up to 99% (Scheme 19) [48]. DMSO plays the role of solvent, initiator, and oxygen source in this efficient transformation. It is worth mentioning that a wide variety of alkyl thioacids can also be converted smoothly to corresponding alkyl carboxylic acids in excellent yields. In addition, this plausible reaction mechanism demonstrates the good potential of hydrogen-bonding adducts in atomic substitution reactions.

Scheme 19

Proposed mechanism for synthesis of carboxylic acids 54 [48]

3 As Carbon Source (–CH₃, –CH₂–, =CH₂, =CH–, and –CHO)

3.1 Methyl Donor (–CH₃)

Methyl group is one of the more prevalent functional groups in many biologically active molecules. Whereas methylation is particularly important in the synthesis of some drugs, often the pharmacological properties of some drugs can be positively influenced depending on the introduction of methyl groups [49, 50]. The usage of dimethyl sulfoxide as the methyl source is characterized by low toxicity, low cost, and simple operation. The following is a summary of the use of dimethyl sulfoxide as a methylation reagent from 2016 to 2021.

In 2016, Antonchick and coworkers reported a method for synthesis of labeled heterocycles and trideuterated compounds 55–58 by using deuterated dimethyl sulfoxide as deuterated methyl reagent at room temperature (Scheme 20) [51]. The reaction conditions were screened accordingly, and FeCl₂ was found to significantly increase the reaction yield compared with other iron salts. The successful conversion of this strategy under free radical reaction conditions can be applied to many biomolecules that require selective deuteration.

Scheme 20

Deuterated methylation reactions [51]

In 2017, Wang’s group reported a visible-light-promoted reaction route for synthesis of 3-ethyl-3-methyl oxindoles 60 (Scheme 21) [52]. Various N-arylacrylamides 59 were successfully used in the cascade reaction with dimethyl sulfoxide catalyzed by iron salts to obtain corresponding methyl oxindoles derivatives in favorable yields. A variety of N-arylacrylamides with different electronic groups and substitution patterns were investigated, showing good results. At the same time, the method offers many advantages such as the simplicity of the reaction process, the versatility of the products, and the mildness of the reaction conditions.

Scheme 21

Synthesis by methylation of N-arylacrylamides [52]

In the same year, Zhang et al. developed radical methylation or trideuterium methylation reaction procedures for selective access to phenanthridines 63 and isoquinolines 64 via cyclization of various 2-isocyano-1,1′-biphenyls 61 or ethyl 2-cyano-3,3-diphenylacrylates 62 with dimethyl sulfoxide (Scheme 22) [53]. This protocol is similar to previously described reaction conditions, which also require catalysis by iron salts and promotion of H₂O₂ to proceed smoothly at room temperature. The methylation and trideuteromethylation can be achieved by using dimethyl sulfoxide, thus providing an option for labeling experiments.

Scheme 22

Preparation of phenanthridines or isoquinolines [53]

Then, in 2018, Zhang et al. further reported a similar free radical methylation reaction (Scheme 23) [54]. Different from the previous reaction, this reaction is based on the three-component cascade of radically active alkenes 65–66 with TMSN₃ and dimethyl sulfoxide, achieving radical azide methylation of various alkenes. The introduction of azido and methyl groups can lead to conversion to related amine derivatives and heterocyclic compounds 67–68. This three-component method offers an attractive option for preparation of valuable organic azides owing to its advantages of low cost, mildness, and simple operation. At the same time, the protocol can be scaled up, and the resulting products can undergo other useful transformations.

Scheme 23

Preparation of azide-methylated and azide-trideuterated methylated derivatives [54]

In 2018, Wang et al. described a procedure for N-methylation and N-sulfonylation of azobenzenes 69 under FeSO₄·7H₂O/H₂O₂ and photocatalytic conditions, obtaining various symmetrical and asymmetrical N′-methyl-N,N′-diphenylmethanesulfonohydrazides 70 in moderate to good yields (Scheme 24) [55]. It is worth mentioning that the reaction obtained the target products 70 via light-induced bifunctionalization by radical addition to N=N of the azo compound.

Scheme 24

Preparation of N′-methyl-N,N′-diphenylmethanesulfonohydrazides [55]

Wu et al. developed a four-component tandem cyclization reaction of 5-methyl pyrimidine derivatives 73 via K₂S₂O₈-mediated methyl ketones 71, amidine hydrochlorides 72, and dimethyl sulfoxide (Scheme 25) [56]. Methyl ketones and amidine hydrochlorides are cheap and readily available as starting materials, while dimethyl sulfoxide acts as a dual synthesis substrate, i.e., as a methyl source and a methyl precursor. The advantages of this protocol are simplicity of operation, good functional group tolerance, and wide substrate range.

Scheme 25

Preparation of 5-methyl pyrimidines [56]

In 2019, Chen’s group revealed a practical pathway for straightforward α-methylation of 1,8-naphthyridines 74 under base promotion to obtain various important 2-methyl-1,8-naphthyridine compounds 75 in good yields (Scheme 26) [57]. This methylation method shows good chemoselectivity as well as good functional group tolerance. Meanwhile, the 2-methyl of the N-heterocycles as a single-carbon bridge is a good reactive site to obtain various (E)-2-alkenylazepines and imidazole-fused N-heterocyclic compounds in moderate to good yields.

Scheme 26

Preparation of 2-methyl-1,8-naphthyridines [57]

In the same year, Wang et al. reported one-pot synthesis of the trideuterated reagent TDMSOI 77 by heating a mixture of TMSOI 76 and DMSO-d₆ for thiosubstitution (Scheme 27) [58]. The obtained new reagent TDMSOI can then participate in trideuterated methylation reactions with phenols, thiophenols, acidic amines, and enolizable methylene units 78 to synthesize trideuterated methylation products 79 with higher yields and high deuteration rates. This new protocol can remove the need for the expensive CD₃I and (CD₃)₂SO₄ reagents involved in some tridemethylation reactions.

Scheme 27

Synthesis of tridemethylation reagents [58]

Subsequently, Wang’s group described synthesis of disubstituted 2-arylindoles and benzofurans 81 by N- or O-benzylbenzaldehydes 80 with dimethyl sulfoxide in good yields on the basis of promotion of tBuOK (Scheme 28) [59]. The suggested reaction mechanism relies on a four-step sequence including aldol condensation, Michael addition, dehydrosulfenation reaction, and isomerization reaction. This protocol allowed short-time access to various 2-aryl-3-methylindoles and benzofurans under mild conditions.

Scheme 28

Preparation of disubstituted 2-arylindoles and benzofurans [59]

3.2 Methylene (–CH₂–)

In 2016, Cui’s group reported a convenient route to synthesize 1,2-disubstituted indoles 84 from readily available 2-alkylanilines 82 and diaryliodonium salts 83 [60]. Meanwhile, 84 can be further converted to bis(1,2-diphenyl-1H-indol-3-yl)methanes 85 under palladium catalyst synergistic with dimethyl sulfoxide conditions (Scheme 29). The simple protocol provided 28 indole derivatives in up to 90% yield under efficient conditions. The results of isotopic labeling experiments indicated that the methylene in 3,3′-diindolylmethane was sourced from dimethyl sulfoxide.

Scheme 29

Plausible mechanisms for preparation of indole derivatives [60]

In the same year, Yadav’s group revealed a new route for efficient synthesis of various 3,3′-bisimidazolopyridylmethanes 87 by functionalizing imidazo[1,2-a]pyridines 86 with dimethyl sulfoxide using H₂O₂ as oxidant (Scheme 30) [61]. The protocol identified a reliable possible radical mechanism through radical capture experiments, labeling experiments, and electrospray ionization mass spectrometry (ESI–MS) analysis experiments. The mechanistic results showed that H₂O₂ underwent C(sp²)–H/C(sp³)-H activation in a cascade mode to provide symmetrical and asymmetrical target products in good yields.

Scheme 30

Plausible mechanisms for preparation of 3,3′-bisimidazopyridinylmethanes [61]

Interestingly, in the same year, Sun’s group reported a procedure to obtain symmetric methylene-bridged imidazole heterocycles 89 similar to the type of Yadav’s group [62]. The method used H₃PO₄ as promoter for efficient regioselective methylenation of imidazole heterocycles 88, and effectively provided various 89 in good yields (Scheme 31). Mechanistic studies have shown that, firstly, H₃PO₄ is involved in the decomposition of dimethyl sulfoxide to produce formaldehyde, followed by addition of formaldehyde as a methylene bridge to imidazo[1,2-a]pyridines. Therefore, the synergistic effect of H₃PO₄/DMSO in this reaction is crucial.

Scheme 31

Plausible mechanisms for methylenation of imidazo-[1,2-a]pyridines [62]

A new route to obtain arylsulfonyl dibromomethanes 92 by free radical coupling reaction of sodium arylsulfates 90–91 and dimethyl sulfoxide under air atmosphere was reported by Wang et al. (Scheme 32) [63]. This protocol provides a novel method of bridging bridges using DMSO as C₁ source. The mechanistic results indicated that the reaction is a radical coupling reaction.

Scheme 32

Plausible mechanisms for preparation of arylsulfonyl dibromomethanes [63]

In 2018, Liu et al. revealed a three-component cyclization reaction of o-iodoanilines 93, potassium sulfide, with dimethyl sulfoxide to obtain various benzothiazoles 94 in moderate to good yields (Scheme 33) [64]. The protocol was carried out without addition of catalysts or additives, reflecting its characteristics of ecofriendliness, simplicity of operation, and novelty. Also, thioureas can be prepared from primary diamines by this method.

Scheme 33

Preparation of benzothiazolethiones [64]

In the same year, Wu et al. reported a palladium-catalyzed three-component cross-coupling strategy using benzonitriles 95, arylboronic acids 96, and dimethyl sulfoxide with high selectivity to obtain various N-benzylbenzamides 97 (Scheme 34) [65]. In addition, this is a valuable approach for using dimethyl sulfoxide as a source of bridging carbon (–CH₂–) articulation.

Scheme 34

Preparation of benzothiazolethiones [65]

Interestingly, Ma’s group reported a strategy for methylation of 1,3-diketones 98 using dimethyl sulfoxide with promotion by Selectfluor. Various bis-1,3-dicarbonyl derivatives 99 bridged with methylene were obtained in moderate to high yields (Scheme 35a) [66]. Also, addition of ammonium salts to 1,3-diketones can enable efficient conversion to Hantzsch-type pyridines by three-component cyclization reaction. Selectfluor was selected as a thermally stable and ecofriendly oxidant, making the protocol efficient and easy to operate.

Scheme 35

Preparation of methylene-bridged compounds 99 and 101 [66, 67]

In the same year, Ma’s group further used the Selectfluor/DMSO system to achieve direct methylenation of amides 100 and thereby obtain 18 methylene-bridged bis-amide derivatives 101 (Scheme 35b) [67]. The successful implementation of this method proved the practicality and universality of the Selectfluor/DMSO system.

In 2019, Yi et al. reported cobalt-catalyzed allylation of amides 102 with styrenes 103 for highly selective synthesis of various privileged allylamines 104 (Scheme 36) [68]. DMSO was used as bridging carbon source with K₂S₂O₈-mediated sequential oxidation in this transformation. Also, this reaction offered high yields as well as high selectivity of (E)-isomers.

Scheme 36

Preparation of privileged allylic amines 104 [68]

Guo et al. reported efficient synthesis of various 3,6-dihydro-2H-pyrans 107 by a strategy based on three-component [3+2+1] cyclization of 2-substituted propylenes 105, aldehydes 106, and dimethyl sulfoxide promoted by K₂S₂O₈ (Scheme 37) [69]. DMSO plays a dual role as solvent and bridging carbon in the reaction. At the same time, the strategy was equally applicable to direct C–H activation of propylene units and DMSO for synthesis of 2,4-disubstituted 3,6-dihydro-2H-pyrans via [4+2] cyclization, reflecting the generality and versatility of the process.

Scheme 37

Preparation of 3,6-dihydro-2H-pyrans 107 [69]

In the same year, Kumari et al. reported graphene oxide (GO)-promoted three-component cascade cyclization reaction of benzylamines 108, isovaleric anhydride 109, and DMSO to prepare 3-substituted quinazolinones 110 in good yields (Scheme 38) [70]. Among them, graphene oxide was used as a recyclable accelerator. The obtained graphene oxide was characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), and energy-dispersive x-ray (EDX) analyses, while its thermal stability was confirmed by thermogravimetric analysis (TGA).

Scheme 38

Preparation of 3-substituted quinazolinones [70]

Interestingly, Xu et al. reported a strategy to induce formation of electrophile unit (thiomethyl)methylammonium carbons from dimethyl sulfoxide via the HCl-DMPU system followed by cyclization with allylamines 110, giving a variety of 4-chloropiperidines 112 in good yields (Scheme 39) [71]. The reaction demonstrates a very broad range of substrates, and allyl amines can be applied to a variety of aromatic and aliphatic amines. The reaction produces an imine ion intermediate followed by cyclization to form 4-chloropiperidines 110 by means of the za-Pummerer reaction.

Scheme 39

Preparation of 4-chloropiperidines 112 [71]

In 2020, Yan et al. reported a one-pot cyclization pathway using cyclopropanemethanols 113 and dimethyl sulfoxide to prepare 3-benzylidene-tetrahydrofurans 114 (Scheme 40) [72]. The reaction proceeded smoothly with various common substituent groups on cyclopropanemethanols, obtaining 114 in moderate to good yields. The reaction mechanism shows that, in the presence of Tf₂O, the cyclopropane moiety undergoes a ring-opening reaction with water to form homoenol units, which then react with DMSO to form 3-benzylidene-tetrahydrofuran.

Scheme 40

Preparation of 3-benzylidene-tetrahydrofurans 114 [72]

In the same year, Sawant’s group revealed a novel method for synthesis of double heterocyclic scaffolds (Scheme 41) [73]. The formation of new C–C bonds activates DMSO to insert smoothly into pyridines 115 in the methylene form, and various symmetric, asymmetric bispyrazoles, and pyrazole-based bisheterocyclic molecules 116 can be obtained in moderate to high yields. DFT calculations reconfirmed the possible mechanism. Also, a chiral center was generated by further modification of the bridging methylene in the asymmetric pyrazole, expanding the application of the method.

Scheme 41

Preparation of bispyrazoles and pyrazole-based bisheterocyclic molecules [73]

In 2021, Ma’s group reported a selective fluorine-promoted cascade cyclization reaction of amidines 117 and dimethyl sulfoxide to obtain various 1,3,5-oxadiazines 118 with high selectivity (Scheme 42) [74]. In this case, DMSO is used as a two-carbon synthesis source and water is used as an oxygen source to construct the oxadiazine ring. Meanwhile the oxygen in the structure of the oxadiazine ring was confirmed by controlled experiments. The reacting substrates are widely applicable, and 1,3,5-oxadiazines 118 can be synthesized in good yields with various electron-donating and electron-withdrawing groups on the amidine 117 moiety.

Scheme 42

Plausible mechanism for synthesis 1,3,5-oxadiazines [74]

Interestingly, Guo et al. reported for the first time a [3+1+1+1] cascade cyclization reaction of propylenes 119, ketones 120, and DMSO with promotion by K₂S₂O₈, resulting in highly selective synthesis of 39 examples of spirocyclohexene backbones 121 (Scheme 43) [75]. The reaction involved the formation of four new C–C bonds and the use of dimethyl sulfoxide as a bridging carbon skeleton to provide two carbons for the six-membered carbon ring. Based on multiple sets of detailed control experiments, a plausible mechanism was proposed.

Scheme 43

Plausible mechanism for synthesis of spirocyclohexene backbones [75]

A new strategy for highly selective synthesis of cyclopentenes 124 (Scheme 44X) and cyclohexenes 125 (Scheme 44Y) by cobalt(II)-catalyzed three-component coupling of β-1,3-dione 122, alkenes 123, and dimethyl sulfoxide was reported by Zhang’s group [76]. This convenient strategy uses DMSO as a solvent and bridging carbon source, demonstrating a wide range of substrates, simplicity, and readily available starting materials. Informative mechanistic research experiments further validated the plausible mechanism.

Scheme 44

Plausible mechanism for synthesis of cyclopentenes and cyclohexenes [76]

Recently, Rode et al. reported Selectfluor-mediated three-component synthesis of methylene-tethered aryl sulfonates 127 and benzotriazoles 128 from imidazoles 126, aryl sulfonates, or benzotriazoles with DMSO, in which DMSO is activated by Selectfluor as a solvent and bridge carbon source (Scheme 45) [77]. Benzotriazolylation of β-naphthol and methylene-tethered aromatic sulfonation can be achieved by this protocol, as well, showing that the reaction has wide applicability.

Scheme 45

Plausible mechanism for synthesis of methylene-tethered arylsulfonation and benzotriazolation of imidazopyridines [77]

In 2022, Zhang, Liu et al. revealed a protocol for hydroxymethylation of carbonyl compounds 129 under AcCl/Na₂CO₃ promotion to obtain various α-hydroxymethylated carbonyl compounds 130 with full quaternary carbon centers in excellent yields under mild conditions (Scheme 46) [78]. In this efficient conversion, H₂O is used as a green oxygen source and DMSO as a methylene (–CH₂–) source as well as solvent. In addition, the reaction conditions are mild, and it can be carried out at room temperature. Detailed mechanistic studies further demonstrated the effectiveness of the conversion.

Scheme 46

Plausible mechanism for synthesis of α-hydroxymethylated carbonyl compounds 130 [78]

3.3 Methylidene Donor (=CH₂)

In 2017, Namitharan et al. developed an efficient three-component (amidines 131, hypervalent aromatic reagents 132, and dimethyl sulfoxide) transition-metal-free C–H functionalization reaction to synthesize various 1,2-diaryl acrylamides 133 in good yields with a wide range of applications (Scheme 47) [79]. Dimethyl sulfoxide as C₁ source was confirmed by deuterated labeling experiments. The method is universal in its ability to sequentially combine olefin aromatizations for C–H functionalization under palladium catalysis, and various 2,3-diaryl acrylamides 134 were obtained in good yields.

Scheme 47

Methods for preparation of acrylamides [79]

In the same year, Guo et al. reported a direct α-Csp³-H methylation strategy of dimethyl sulfoxide with aryl ketones 135 to obtain a variety of α,β-unsaturated carbonyl compounds 136 in 42–90% yields (Scheme 48) [80]. The protocol is characterized by a wide range of substrates, no addition of transition metals, as well as simple and readily available raw materials.

Scheme 48

Preparation of α,β-unsaturated carbonyl compounds 136 [80]

Immediately afterwards, Guo et al. reported a three-component cascade assembly strategy of aromatic aldehydes 137, azoles 138, and dimethyl sulfoxide for efficient preparation of multiple substituted N-vinylazoles 139 (Scheme 49) [81]. DMSO was used as terminal carbon source and formed a new C=C bond. Simultaneous 10 mmol amplification gram-scale experiments demonstrated the utility and effectiveness of the protocol.

Scheme 49

Preparation of N-vinylazoles 139 [81]

In 2021, Patel et al. presented a one-pot, four-component cascade reaction of o-alkynyl anilines 140, propanedial, dimethyl sulfoxide, and ammonium thiocyanate under Pd(II)/Cu(II) to synthesize various tricyanovinylidoles 141 in moderate to good yields (Scheme 50) [82]. This strategy utilizes dimethyl sulfoxide as a bridge carbon substitute to efficiently construct new C=C, C–C, and C–N bonds. Meanwhile, further modification of tricyanovinylidoles 141 demonstrated the utility of this four-component cascade reaction to obtain interesting 4-cyano-3-indolylmaleimides.

Scheme 50

Preparation of tricyanoindoles 141 [82]

3.4 Methine Donor (=CH–, Used for Cyclization or Aromatization)

In 2016, Ma et al. reported a copper-catalyzed three-component reaction of 2-aminobenzophenones 142, aqueous ammonia, and dimethyl sulfoxide to synthesize a series of quinazoline derivatives 143 in moderate to good yields (Scheme 51) [83]. The protocol was environmentally friendly, using clean oxygen as oxidant and avoiding the use of peroxides and iodides. Also, ammonium acetate as an N source involves direct inorganic to organic conversion through [4+1+1] cycloaddition reaction.

Scheme 51

Preparation of quinazoline derivatives 143 [83]

Next, Wu et al. reported an efficient method for synthesis of substituted pyridines 145 by three-component cyclization of aryl methyl ketones 144, ammonium formate, and DMSO (Scheme 52a) [84]. The transformation is carried out by cleaving the C–S bond of DMSO to provide a methylene intermediate to participate in the subsequent cyclization. Interestingly, the protocol demonstrated a broad range of substrates, and α-substituted ketones could also produce a variety of corresponding substituted pyridines 146 in good yields (Scheme 52b). In addition, seven sets of control experiments further showed the feasibility of the mechanism.

Scheme 52

Synthesis of substituted pyridines [84]

In 2017, Tiwari et al. revealed a one-pot metal-free cascade reaction of acetophenones 147, dimethyl sulfoxide, and anthranils 148 to prepare 26 functionalized 3-substituted quinoline compounds 149 in good yields (Scheme 53) [85]. As described above, DMSO acts as both solvent and methylene unit in this reaction. The successful conversion of 1,4-benzodiazepine heterocycle and 3-phenylquinoline via 149 demonstrated the effective applicability of the method. In 2019, Ma et al. also reported the efficient transformation of Selectfluor-promoted acetophenones 150 with dimethyl sulfoxide and anthranils 151 for three-component synthesis of 3-functionalized quinolines 152 (Scheme 54) [86]. Both cascade cyclizations benefit from a wide range of substrates and simple reaction conditions.

Scheme 53

Synthesis of 3-substituted quinolines [85]

Scheme 54

Mechanism for synthesis of 3-substituted quinolines [86]

Interestingly, an efficient method for synthesis of novel N-heterocycle-fused quinoxalines 154 was reported by Ma’s group (Scheme 55) [87]. 2-(1H-pyrrol-1-yl)anilines 153 with dimethyl sulfoxide were successfully constructed as interesting starting materials for 34 useful products 154. This protocol with simple conditions and ease of operation provides a pathway for organic and medicinal chemistry synthesis.

Scheme 55

Synthesis of N-heterocycle-fused quinoxalines [87]

In the same year, Cheng et al. revealed a Pd(dba)₂/DABSO-activated cyclization reaction of o-vinylanilines 155 with DMSO to synthesize various 4-aryl quinolines 156 in moderate to good yields (Scheme 56) [88]. Interestingly, both DMSO and DABSO played dual roles in the reaction, where DMSO acted as solvent and cyclized the methylene unit while DABSO acted as oxidant in addition to activating DMSO.

Scheme 56

Preparation of 4-arylquinolines 156 [88]

Singh and Jadhav reported an efficient strategy for one-pot synthesis of 4-arylquinolines 159 (Scheme 57) from readily available methyl ketones 157, anilines 158, and dimethyl sulfoxide promoted by K₂S₂O₈ [89]. Under standard conditions of substitution of anilines for formamide without addition of FeCl₃, 4-aryl pyrimidines can also be obtained by this protocol. The successful implementation of this strategy effectively avoids the use of expensive transition metals and also provides an efficient route for synthesis of 4-substituted quinolines. Interestingly in 2018, Jiang et al. reported the same method for synthesis of 4-arylquinolines [90] using anilines with aryl methyl ketones and dimethyl sulfoxide. The difference is that Jiang used CH₃SO₃H as the oxidant for 36 h.

Scheme 57

Preparation of 4-arylquinolines 159 [89, 90]

Interestingly, Cheng et al. reported Cs₂CO₃-promoted three-component [4+1+1] oxidative cyclization of aldehydes 160, dimethyl sulfoxide, and N-benzylamidines 161 to obtain 2,4,6-triaryl pyrimidines 162 in moderate to good yields (Scheme 58) [91]. DMSO as carbon source was susceptible to methylation when promoted by a base, allowing for better subsequent cyclization reactions. At the same time, the substitution of O₂ for other oxidants in this conversion makes the protocol environmentally friendly.

Scheme 58

Preparation of 2,4,6-triaryl pyrimidines 162 [91]

In 2018, Guo et al. reported a Cu(II)-catalyzed three-component oxidative cyclization reaction from readily available aryl methyl ketones 163, anilines 164, and dimethyl sulfoxide to obtain various 2-arylquinolines 165 in moderate to good yields (Scheme 59) [92]. Five sets of control experiments further demonstrated the effectiveness of the method. The protocol conditions were simple and used oxygen as the oxygen source. Five sets of control experiments provided strong evidence for a possible mechanism.

Scheme 59

Preparation of various 2-arylquinolines 165 [92]

Encouragingly, Liu et al. reported an interesting method for construction of benzothiazolethiones 167 by three-component cyclization of o-iodoanilines 166 with dimethyl sulfoxide and potassium sulfide (Scheme 60) [64]. The reaction conditions were simple and effective without additional catalysts or additives, giving a novel and environmentally friendly protocol. In addition, DMSO acts as a bridging carbon and oxidant in the reaction.

Scheme 60

Preparation of various benzothiazolethiones 167 [64]

Then, Tiwari’s group reported three-component oxidative cyclization of anilines 168 with terminal alkynes 169 and dimethyl sulfoxide under promotion by K₂S₂O₈ to synthesize various 4-arylquinolines 170 in moderate to good yields (Scheme 61) [93]. The synthetic utility of the protocol reflected the practicality of the reaction, while five sets of control experiments provided very important evidence for the possible mechanism.

Scheme 61

Preparation of various 4-arylquinolines 170 [93]

Interestingly, Wu’s group reported I₂-mediated three-component [2+1+1+1] cascade oxidative cyclization of aryl methyl ketones 171 with dimethyl sulfoxide and 1,2,3,4-tetrahydroisoquinoline (THIQ) to obtain a series of pyrrolo[2,1-a]isoquinolines 172 in moderate to excellent yields (Scheme 62) [94]. Adequate mechanistic validation indicated that dimethyl sulfoxide as methylene source led to the formation of three C–C bonds and one C–N bond. The protocol was characterized by readily available starting materials, simple reaction conditions, and a wide range of substrates.

Scheme 62

Preparation of various pyrrolo[2,1-a]isoquinolines 172 [94]

Yi et al. first reported a Co(III)-catalyzed three-component [3+2+1] oxidative cyclization strategy based on anilines 173 with alkynes 174 and dimethyl sulfoxide to obtain various 4-arylquinolines 175 in good to excellent yields (Scheme 63) [95]. The starting materials used for this transformation are readily available and inexpensive. The experimental results of the mechanistic study further indicate that DMSO is not only used as a solvent but also acts as a bridge carbon (C₁) in the protocol. Interestingly, Yi’s group reported a TFA-controlled three-component [3+2+1] cyclization of anilines 176 with terminal alkynes 177 and dimethyl sulfoxide for one-pot highly regioselective synthesis of various 3-arylquinolines 178 in 2019 (Scheme 64) [96]. This method provides a viable option for quinoline intercalation aromatization.

Scheme 63

Plausible mechanism for synthesis of 4-arylquinolines 175 [95]

Scheme 64

Synthesis of 3-arylquinolines 178 [96]

In 2019, Wu et al. revealed a cascade oxidative cyclization reaction of pyridinium salts 179 with DMSO under K₂S₂O₈ oxidation to synthesize a series of indolizine derivatives 180 in moderate to excellent yields (Scheme 65) [97]. DMSO plays a very important role in this cyclization strategy as a solvent and bridge single carbon source. Also, the presence of trimethylethylenediamine (TMEDA) plays a crucial role for I⁻ and Br⁻ dissociation.

Scheme 65

Synthesis of indolizine derivatives 180 [97]

In the same year, Wu’s group further reported a cascade oxidative cyclization strategy using dimethyl sulfoxide as C₁ source with stabilized sulfonium salts 181, successfully preparing polyfunctional furan compounds 182 in good yields (Scheme 66) [98]. Mechanistic validation results showed that the one-pot conversion by activation of dimethyl sulfoxide of the α-methylsulfonium salts generated in situ further underwent [4+1] oxidative cyclization with the sulfurylimines.

Scheme 66

Synthesis of polyfunctional furan compounds 182 [98]

Remarkably, Jung et al. revealed a strategy of [5+1] cascade oxidative cyclization of 2-aminobenzamides 183 and dimethyl sulfoxide promoted by K₂S₂O₈ to obtain a series of biologically significant quinazolinones 184 in moderate to good yields (Scheme 67) [99]. The advantages of this protocol are the reaction time of only 2 h, the wide range of substrates, and the absence of transition metals. Interestingly, the central nervous system depressant drug methaqualone could able be prepared by this method.

Scheme 67

Mechanisms for preparation of quinazolinones 184 [99]

In the same year, p-toluenesulfonic acid-mediated three-component cascade cyclization of anilines 185 with dimethyl sulfoxide and enaminones 186 for preparation of 3-ketoquinolines 187 was reported by Jiang et al. (Scheme 68) [100]. In this protocol, DMSO is activated by TsOH·H₂O to provide the bridge carbon, enabling the reaction to proceed smoothly. The mechanistic results suggest that DMSO may undergo Pummerer rearrangement under acidic conditions. Interestingly, Tiwari et al. also reported K₂S₂O₈-promoted three-component synthesis of a series of 3-ketoquinolines 190 (Scheme 69) with good yields and high selectivity by [3+2+1] oxidative cyclization of anilines 188 with enaminones 189 and dimethyl sulfoxide [101]. The method mainly consists of oxidation of K₂S₂O₈ to activate DMSO, which leads to in situ generation of intermediate A by DMSO before the reaction.

Scheme 68

Preparation of 3-ketoquinolines 187 [100]

Scheme 69

Mechanisms for preparation of 3-ketoquinolines 190 [101]

In 2020, Ma’s group described a one-pot, two-step oxidative cascade cyclization strategy based on arylboronic acids 191 with dimethyl sulfoxide and o-bromoaryl amides 192 to prepare various phenanthridines 193 in moderate to good yields (Scheme 70) [102]. Fifty phenanthridines were obtained by a two-step pathway of Pd-catalyzed and K₂S₂O₈ oxidation. Simultaneous mechanistic verification showed that DMSO acts as both a solvent and a bridging single carbon donor.

Scheme 70

Synthesis of phenanthridines 193 [102]

Interestingly, Zhu et al. reported a three-component oxidative cyclization strategy based on o-iodoanilines 194 with dimethyl sulfoxide and K₂S to obtain 2-unsubstituted benzothiazoles 196 in moderate to good yields (Scheme 71) [103]. The substitution of 194 by aromatic amines 195 enabled successful preparation of 196 under standard conditions without addition of copper catalyst. The results of control experiments indicated that dimethyl sulfoxide acts as a single carbon donor in addition to an oxidant and solvent in this reaction.

Scheme 71

Synthesis of 2-unsubstituted benzothiazoles 196 [103]

In the same year, Wu et al. reported a one-pot three-component sequential oxidative cyclization reaction of aryl methyl ketones 197 with anilines 198 and dimethyl sulfoxide to obtain a series of aryl quinazolinones 199 in moderate yields (Scheme 72) [104]. The transformation is characterized by cleavage of dimethyl sulfoxide as a methylene donor to achieve sequential cyclization. Multicomponent control experiments provided valid evidence for potential mechanistic studies.

Scheme 72

Synthesis of aryl quinazolinones 199 [104]

In 2021, Tiwari’s group further reported a TFA-promoted three-component tandem cyclization reaction of anilines 200 with dimethyl sulfoxide and pyrazolones 201 to obtain a series of pyrazolo[3,4-b]quinolones 202 in good to excellent yields (Scheme 73) [105]. Also DMSO plays a dual role in the reaction, not only as a reaction solvent but also as a donor of cyclization bridge carbon. Furthermore, the application of the method further demonstrated the practicality of the reaction.

Scheme 73

Synthesis of pyrazolo[3,4-b]quinolones 202 [105]

Then, Wu’s group revealed for the first time a three-component cyclization strategy of amino acids 203 with anilines 204 and dimethyl sulfoxide to synthesize 2-arylquinazolines 205 in moderate to good yields (Scheme 74) [106]. The mechanistic results indicated a sequential HI-mediated decomposition of amino acids to aldehydes followed by reconstitution with anilines. The validity of this result was further verified by controlled experiments.

Scheme 74

Synthesis of 2-arylquinazolines 205 [106]

Interestingly, Wang et al. reported a CuSO₄·5H₂O-catalyzed cyclization strategy based on 1,3-dicarbonyl compounds 206 and dimethyl sulfoxide to synthesize phenolic derivatives 207 with isomers in up to 93% isolated yields (Scheme 75) [107]. Deuterium labeling experiments indicated that the C₂ of phenol derivatives was derived from dimethyl sulfoxide.

Scheme 75

Synthesis of phenolic derivatives 207 [107]

Recently, Ma et al. reported a three-component cascade cyclization strategy based on 2-amino-N-heterocycles 208 with aryl methyl ketones 209 and dimethyl sulfoxide under synergistic promotion by K₂S₂O₈/I₂ to synthesize 3‑aroylimidazo[1,2‑a]‑N‑heterocycles 210 in moderate to good yields (Scheme 76) [108]. This one-pot protocol also involved dimethyl sulfoxide as the solvent and methylene source for the cyclization procedure.

Scheme 76

Synthesis of 3‑aroylimidazo[1,2‑a]‑N‑heterocycles 210 [108]

Also recently, Jiang’s group revealed a metal-free three-component cascade cyclization reaction of ketones 211 with amidine hydrochlorides 212 and dimethyl sulfoxide for highly selective synthesis of a series of pyrimidines 213 (Scheme 77) [109]. Interestingly, amidine hydrochlorides not only acted as a reactant in this transformation, but also activated DMSO to participate smoothly in the subsequent cyclization procedure.

Scheme 77

Synthesis of a series of pyrimidines 213 [109]

In 2022, Wan et al. revealed an I₂-catalyzed one-pot three-component cascade cyclization procedure based on enaminones 214, dimethyl sulfoxide, and hydrazines 215 to obtain various 1,4-disubstituted pyrazoles 216 in moderate to good yields (Scheme 78) [110]. The results of control experiments demonstrated that dimethyl sulfoxide acted as a donor of C₁ at two sites of the pyrazole ring, while dimethyl sulfoxide served as an effective solvent. This transformation is characterized by easy availability of starting materials, a wide range of substrates, and a short reaction time of 10 min. In addition, the ability of pyrazole 216a to proceed smoothly in the reaction with styrene and diphenylacetylene demonstrated the practical application of pyrazole.

Scheme 78

Synthesis of various 1,4-disubstituted pyrazoles 216 [110]

Just recently, Guo et al. developed tBuOK-promoted one-pot [3+1+1+1] cascade cyclization of aromatic aldehydes 217, dimethyl sulfoxide, and arylamines 218 to synthesize various 3-arylquinolines 219 in good yields (Scheme 79) [111]. Interestingly, DMSO provided two nonadjacent C₁ donors for the pyridine ring in the 3-substituted quinoline molecules, in addition to acting as a solvent. Deuterium labeling experiments demonstrated that the two nonadjacent carbons were derived from dimethyl sulfoxide. It is worth mentioning that, when the reaction was carried out using phenyl methyl sulfoxide instead of dimethyl sulfoxide, the product 219a was also obtained, but in a lower yield of 19%.

Scheme 79

Synthesis of various 3-arylquinolines 219 [111]

3.5 Donors of Formylation (–CHO)

In 2021, a three-component synthesis based on dihydropyrrole isoquinolines 220 with dimethyl sulfoxide and bromobutyric acid, giving a series of formylated pyrrole isoquinolines 221 in up to 94% isolated yield, was reported by Cui et al. (Scheme 80) [112]. The protocol is an efficient method to achieve formylation by using dimethyl sulfoxide as a carbonyl source. Meanwhile, the gram-scale experiment and transformation experiment of 221a further demonstrated the practicality of the reaction.

Scheme 80

Synthesis of formylated pyrrole isoquinolines 221 [112]

Recently, Hajra et al. revealed a method for functionalization of 2H‑indazoles 222 at the C₃ position using dimethyl sulfoxide as a formylation donor (Scheme 81) [113]. This facile and efficient method synthesized a series of formylated indazole derivatives 223 in moderate to good yields under the condition of K₂S₂O₈ as oxidant. The results of controlled experiments and mechanistic studies indicated that the protocol proceeded via the radical pathway. At the same time, this transformation was characterized by easy access to substrates, simple operation, and a wide range of substrates.

Scheme 81

Synthesis of formylated indazole derivatives 223 [113]

4 As Sulfur Source (–S–)

Thiophene rings are found widely in natural products as one of the most common sulfur-containing heterocycles [114,115,116]. Just recently, Chen’s group reported a one-pot redox strategy for synthesis of dihydrothiophenes 225, thiophenes 226, and bromothiophenes 227 from readily available allylic alcohols 224 with DMSO and HBr with high regioselectivity (Scheme 82) [117]. This high selectivity was mainly achieved by modulating the dosage regulation of DMSO and HBr. In addition, mechanistic findings further indicated that dimethyl sulfoxide acts as both oxidant and sulfur donor. Various biologically active molecules could be successfully transformed by this protocol, demonstrating its practicality.

Scheme 82

Redox strategy for DMSO and HBr [117]

5 As Methylthio Source (–SMe)

In 2016, Wu et al. reported a protocol for I₂/Cu(II)-mediated C(sp³)–H functionalization of aryl methyl ketones 228 to obtain a series of 2,4,5-trisubstituted furans 229 in good to excellent isolated yields (Scheme 83) [118]. The ability of the gram-scale reactions to proceed smoothly further demonstrated the practicality of the protocol. In addition, the results of the mechanistic study showed that dimethyl sulfoxide plays a pivotal role in this transformation and provides a sulfur methyl source for the 3-position of furan.

Scheme 83

I₂/Cu(II)-mediated protocol for C(sp³)–H functionalization of aryl methyl ketones 228 [118]

In the same year, Batra et al. revealed an I₂-promoted three-component α-C–H functionalization strategy for propiophenones 230 with NaNO₂ and dimethyl sulfoxide to obtain various thiohydroximic acids 231 in moderate to excellent isolation yields (Scheme 84) [119]. The protocol is characterized by simplicity of operation, the absence of transition-metal catalysis, a wide range of substrates, and the availability of commercially available starting materials.

Scheme 84

Synthesis of thiohydroximic acids 231 [119]

Interestingly, I₂/TBHP-promoted tandem cyclization synthesis of 3-methylthiofurans 233 from homopropargylic alcohols 232 and dimethyl sulfoxide protocol was reported by Yan et al. (Scheme 85) [120]. The results of the mechanism study showed that DMSO was used as a solvent in addition to acting as a methylthio donor. In addition, the reaction proceeded smoothly with homopropargylic alcohols containing various substituent groups, with moderate to good yields.

Scheme 85

I₂/TBHP-promoted tandem cyclization protocol [120]

In 2017, Tan et al. revealed a copper-catalyzed one-pot protocol using potassium aryl carboxylates 234 and dimethyl sulfoxide to obtain various aryl methyl sulfides 235 in moderate to good yields (Scheme 86) [121]. The transformation successfully used dimethyl sulfoxide as a methylthio source. Optimization of the conditions showed that the use of 2 equiv. of Zn(OTf)₂ as an additive greatly improved the yields of the target products, while the reaction needed to be carried out directly in air.

Scheme 86

Synthesis of aryl methyl sulfides 235 [121]

In 2019, Guo’s group further reported an I₂-mediated one-pot C(sp³)–H functionalization protocol for aryl methyl ketones 236 with DMSO to give a series of multisubstituted furans 237 in moderate to good yields (Scheme 87) [122]. DMSO acted as a solvent in this transformation, but also as a methylthio donor and a methylene single carbon source. The results for the optimization of the conditions indicated that K₂S₂O₈ was critical as a promoter for this reaction. Furthermore, the reaction with 236w proceeded smoothly on gram scale under standard conditions, clearly demonstrating the potential utility of this transformation in organic synthesis.

Scheme 87

Synthesis of multisubstituted furans 237 [122]

In the same year, He et al. revealed a strategy based on intermolecular bifunctionalization of alkenes 238 under NH₄I promotion for highly selective synthesis of various bis-dimethyl sulfanes 239 and β-hydroxysulfides 240 (Scheme 88) [123]. Interestingly, water played a key role in this transformation, and the amount of water used could modulate the transformation of different products. Mechanistic studies indicated that dimethyl sulfoxide was first decomposed to CH₃SH at 130 °C, followed by the involvement of CH₃SH with I^· in the subsequent conversion.

Scheme 88

Synthesis of bis-dimethyl sulfanes 239 and β-hydroxysulfides 240 [123]

Next, Xu et al. reported an amino acid ligand-promoted one-pot protocol using 2-phenylpyridines 241 and dimethyl sulfoxide to synthesize a series of aryl methyl sulfides 242 in moderate to good yields (Scheme 89) [124]. This highly regioselective protocol did not require additional solvents, while being compatible with a wide range of functional groups.

Scheme 89

Synthesis of aryl methyl sulfides 242 [124]

In 2021, Wu’s group developed a strategy for one-pot iodomethylation of alkynes 243 with aqueous HI solution and dimethyl sulfoxide to prepare various (E)-2-iodo-3(methylthio)acrylates 244 in good to excellent yields (Scheme 90) [125]. This transformation was characterized by simple reaction conditions, very good functional group tolerance, a wide range of substrates, and no need for additional catalysts or additives.

Scheme 90

Preparation of various (E)-2-iodo-3(methylthio)acrylates 244 [125]

In the same year, Xing et al. revealed a one-pot methanethiolation protocol using electron-rich heterocyclic compounds 245 with dimethyl sulfoxide for synthesis of various pyrrole, furan, and thiophene derivatives 246 with high regioselectivity in yields up to 96% (Scheme 91) [126]. The success of four combined application experiments and 10 mmol scale-up experiments further demonstrated the potential utility of this transformation in organic synthesis.

Scheme 91

Direct methanethiolation of electron-rich heterocyclic compounds [126]

Interestingly, Du’s group reported the use of SOCl₂-interacting 2-alkynyl anisoles/sulfides 247 to synthesize biologically conceptual 3-(methylthio)-benzo[b]furans/thiophenes 248 in good to excellent yields by an intramolecular cyclization strategy under dimethyl sulfoxide as a methylthio source (Scheme 92) [127]. This intramolecular cyclization transformation protocol proceeded smoothly when using DMSO-d₆ instead of DMSO.

Scheme 92

Intramolecular cyclization strategy with DMSO as methylthio donor [127]

Just recently, Du et al. went on to report a protocol for intramolecular electrophilic cyclization of N-aryl propynamides 249 using dimethyl sulfoxide as methylthio donor to obtain spiro[4,5]trienones 250 and quinolin-2-ones 251 in good to excellent yields (Scheme 93) [128]. This intramolecular electrophilic cyclization protocol was characterized by mild reaction conditions, no need for additional metals, and a wide range of substrates. At the same time, the quantum chemical approach provided an effective demonstration of the possible mechanism.

Scheme 93

Intramolecular electrophilic cyclization protocol based on N-aryl propynamides [128]

6 As Methyl Sulfoxide Source (–SOMe)

In 2016, Pramanik and Rastogi reported for the first time a visible-light-induced protocol for methyl oxysulfide of aryl diazonium salts 252 using dimethyl sulfoxide as methyl sulfoxide donor, obtaining various aryl methanesulfonates 253 in moderate to good yields at room temperature (Scheme 94) [129]. Various functional groups are widely tolerated in this transformation, which is compatible with various functional groups on diazonium salt aryl and heteroaryl groups, including –OMe, –NO₂, –CN, –SCN, etc. This transformation proceeds smoothly when using DMSO-d₆ instead of DMSO.

Scheme 94

Synthesis of aryl methanesulfonates 253 [129]

In 2017, Lei’s group reported a Cu/Pd-catalyzed one-pot oxysulfonation protocol of olefins 254 with dimethyl sulfoxide to synthesize a series of biologically valuable oxosulfonates 255 in moderate to good yields (Scheme 95) [130]. This conversion was able to proceed smoothly with cleavage of carbon–carbon and carbon–heteroatom bonds under the assistance of CO/O₂. The advantages of this protocol are mild reaction conditions, a wide range of substrates, and easy availability of starting materials.

Scheme 95

Synthesis of biologically valuable oxosulfonates 255 [130]

In 2018, Jiang et al. reported a protocol for visible-light-induced bicyclization of C(sp³)-based 1,7-olefins 256 using DMSO in concert with H₂O as methanesulfonation source to synthesize various benzo[a]fluoren-5-ones 257 with functionalization in moderate to good yields (Scheme 96) [131]. The advantages of this dual cyclization strategy are mild reaction conditions, a wide range of substrates, and the use of H₂O as an oxygen source. No production of 257a was observed when TEMPO and BHT were used as free radical scavengers under standard conditions, suggesting that this protocol may be a free radical process.

Scheme 96

Synthesis of various benzo[a]fluoren-5-ones 257 [131]

In the same year, Sun et al. revealed an NH₄I-promoted one-pot cascade cyclization procedure for oxygen-linked 1,6-enynes 258 with dimethyl sulfoxide to obtain dual-functional benzofurans 259 in good yields (Scheme 97) [132]. This protocol had utility in organic synthesis and could synthesize benzothiophene from sulfur-linked 1,6-enyne. In addition, the transformation was able to tolerate various functional groups, such as –OMe, –CF₃, –CN, –COMe, etc.

Scheme 97

Synthesis of various dual-functional benzofurans 259 [132]

In 2019, Wu’s group developed a three-component protocol based on I₂/PhI(OAc)₂ co-promotion of aryl methyl ketones 260 with DMSO and ammonium bicarbonate to obtain α-dicarbonyl sulfoximines 261 in moderate to good yields (Scheme 98) [133]. Interestingly, tetramethylene sulfoxide as a substitute for DMSO was also able to perform this ammonification strategy under standard conditions. In addition, the aryl methyl ketones offered a broad range of substrates that could be applied to various functional groups and different sites.

Scheme 98

Synthesis of various α-dicarbonyl sulfoximines 261 [133]

In the same year, Liu et al. reported for the first time an iodination–methylsulfoxidation strategy using I₂ with DMSO and alkynes 262 to synthesize a series of (E)-α-iodo-β-methylsulfonyl alkenes 263 in good yields (Scheme 99) [134]. This four-component transformation is characterized by water as oxygen source, a wide range of substrates, and high chemoselectivity. In addition, labeling experiments with ¹⁸O further demonstrated that one oxygen atom in the –SO₂Me group is derived from water.

Scheme 99

Proposed mechanism for synthesis of 263 [134]

In 2020, Xu et al. reported a one-pot nucleophilic substitution protocol using benzyl halides 264 and dimethyl sulfoxide to obtain various benzyl methyl sulfides 265 in moderate to good yields (Scheme 100) [135]. This protocol has a wide range of substrates and can be applied with a variety of functional groups such as benzo, halo, CN, CF₃, MeO, CHO, etc. Furthermore, when the reaction time was shortened to 2 h under standard conditions, 2% of the by-product benzyl (methyl) sulfide was obtained, suggesting that benzyl (methyl) sulfide may be produced from benzyl chloride.

Scheme 100

Synthesis of various benzyl methyl sulfides 265 [135]

7 As Methyl Thiomethylation Source (–CH₂SMe)

In 2017, Guo et al. reported a one-pot cross-coupling strategy for methyl ketones 266 with DMSO to obtain β-methylthio isopropenylketones 267 with various substituted functional groups in moderate to good yields (Scheme 101) [136]. Seven sets of detailed control experiments confirmed the rationality of the reaction mechanism. In addition, gram-scale experiments further demonstrated the potential utility of this cross-coupling of C(sp³)–H bonds.

Scheme 101

Synthesis of β-methylthio isopropenylketones 267 [136]

In the same year, Yang et al. developed an Fe(III)-catalyzed one-pot Pummerer rearrangement procedure for acyl chlorides 268 with dimethyl sulfoxide to obtain various alkyl thiomethyl esters 269 in good to excellent yields (Scheme 102) [137]. This procedure is characterized by inexpensive starting materials, mild reaction conditions, simplicity of operation, a wide range of substrates, and high product yields.

Scheme 102

Proposed mechanism for synthesis of alkyl thiomethyl esters 269 [137]

Then, in 2019, Cai et al. went on to report a method for synthesis of alkyl thiomethyl esters 271 using readily available carboxylic acids 270 and dimethyl sulfoxide via a Pummerer-type rearrangement protocol (Scheme 103) [138]. This transformation is characterized by a wide range of substrates and inexpensive starting materials. Moreover, this transformation was achieved using Et₃N as promoter for 20 h. On the downside, the reaction time is long and the temperature is high.

Scheme 103

Proposed mechanism for synthesis of alkyl thiomethyl esters 271 [138]

In 2020, Ma et al. revealed an efficient one-pot AcOH-promoted procedure for benzamides 272 with dimethyl sulfoxide to obtain N-[(methylthio)methyl]benzamides 273 in good yields (Scheme 104) [139]. In this conversion, dimethyl sulfoxide plays a pivotal dual role as solvent and donor for methyl sulfide. Interestingly, 272 and 273 could be further converted to asymmetric methylene-bridged bisamides in the presence of dimethyl sulfoxide as a bridging carbon donor. This reaction provides a new approach for efficient synthesis of asymmetric bisamides.

Scheme 104

Synthesis of N-[(methylthio)methyl]benzamides 273 [139]

In 2022, Jiang et al. revealed an HOAc-promoted protocol for cascade cyclization of o-hydroxyacetophenones 274 with dimethyl sulfoxide to obtain a series of 3-(methylthiomethyl)chromanones 275 in moderate to good yields (Scheme 105) [140]. The protocol involved the activation of two molecules of dimethyl sulfoxide by HOAc followed by cascade cyclization as two molecules of synthons and o-hydroxyacetophenones 174. The advantages of this transformation are high selectivity and the absence of any additives.

Scheme 105

Synthesis of chroman-4-ones 275 [140]

Just recently, Cui et al. reported a methylthio strategy for pyrroloquinolines and pyrroloisoquinolines 276 in the presence of TsOH/NH₄OAc, obtaining various thioethers 277′ in moderate to good yields (Scheme 106) [141]. It is worth mentioning that DMSO can be used as a methylene-bridging carbon source 277″ in addition to solvent and methyl thiomethylation source in this transformation. The method is characterized by simple reaction conditions, scalability to gram scale, and conversion to sulfone and sulfoxide by simple oxidation.

Scheme 106

Methylthiomethylation and methylenation transformations [141]

8 As Methyl Sulfoxide Methylation Donor (–CH₂SOMe)

In 2017, Wen et al. reported a one-pot direct cross-coupling strategy for aryl methyl ketones 278 with dimethyl sulfoxide to obtain various β-acyl allylic methylsulfones 279 in moderate to good yields (Scheme 107) [142]. The protocol could provide β-acyl allylic methylsulfides under similar reaction conditions. Seven sets of control experiments further validated the rationality of the reaction mechanism.

Scheme 107

Synthesis of β-acyl allylic methylsulfones 279 [142]

In 2019, Chang et al. revealed an NH₂OH·HCl-mediated intermolecular umpolung α-methanesulfonation protocol for α-sulfonyl ketones 280 with dimethyl sulfoxide to obtain a variety of α,β-bissulfonyl arylketones 281 in good to excellent yields (Scheme 108) [143]. This novel and efficient route is characterized by simple reaction conditions, a wide range of substrates, and easy preparation of starting materials. The practicality of the method was further illustrated by synthetic transformation experiments of α,β-bis(sulfonyl)aryl ketones.

Scheme 108

Plausible mechanism for synthesis of α,β-bis(sulfonyl)aryl ketones 281 [143]

In 2020, Tang et al. revealed for the first time an NBS-promoted cross-dehydroesterification procedure for carboxylic acids 282 with DMSO to obtain various (methylsulfinyl)methyl esters 283 via Pummerer-type rearrangement (Scheme 109) [144]. This transformation is characterized by mild reaction conditions, easy availability of starting materials, a wide range of substrates, and simplicity of operation. In addition, the preparation of deuterated 283 by using deuterated labeled DMSO as a reagent is of potential practical value.

Scheme 109

Synthesis of (methylsulfinyl)methyl esters 283 [144]

In the same year, Zhang’s group reported an HCl-promoted one-pot dehydrogenation coupling protocol for β-keto sulfones 284 with dimethyl sulfoxide to obtain various α,β-disulfonyl ketones 285 in good to excellent yields (Scheme 110) [145]. Interestingly, the reaction conditions afforded smooth access to β-sulfinyl ketones without addition of HCl. The potential of the mechanism was further verified by eight sets of control experiments.

Scheme 110

Synthesis of α,β-disulfonyl ketones 285 [145]

Interestingly, Barriault et al. reported a one-pot base-promoted single-electron-transfer protocol for phenols 286 and 2,6-dichloroiodobenzene 287 with DMSO to obtain methylthiomethyl ethers 288 in moderate yields (Scheme 111) [146]. Mechanistic studies showed that dimethyl sulfoxide acts as a single-electron reductant in the presence of base, in addition to its role as a solvent. Meanwhile, four sets of control experiments further validated the mechanistic possibility.

Scheme 111

Plausible mechanism for synthesis of methylthiomethyl ethers 288 [146]

9 Summary and Outlook

This review focuses on recent advances in the use of dimethyl sulfoxide as a synthon in organic chemistry and covers all the reports from 1 January 2016 to 11 May 2022, providing more than 110 reactions using dimethyl sulfoxide as an organic synthon. The reactions are summarized based on the use of dimethyl sulfoxide as oxygen (–O–, =O), methyl (–CH₃), methylene (–CH₂–), methylidene (=CH₂), methine (=CH–), donor of formylation (–CHO), sulfur (–S–), methylthio (–SMe), methyl sulfoxide (–SOMe), donor of methyl thiomethylation (–CH₂SMe), donor of methyl sulfoxide methylation (–CH₂SOMe), highlighting various synthetic pathways.

Despite the excellent progress that has been made in this area with dimethyl sulfoxide, a number of challenges remain. First, there are few examples of the use of dimethyl sulfoxide as a sulfur-derived precursor for construction of thiophene and new C–S bonds. Secondly, the use of dimethyl sulfoxide as a donor in the synthesis of some useful natural products as well as the transformation of important drug molecules remains less successful. Finally, some reaction conditions may need to be further optimized to accommodate more functional groups and milder reaction conditions. This review covers almost all the literature from 1 January 2016 to 11 May 2022 using dimethyl sulfoxide as a donor, providing scientists with easy access to the literature. The success stories achieved so far lead us to boldly predict that new types of reactions, more interesting reaction mechanisms, and milder reaction conditions will be discovered and reported in the near future. We also anticipate that dimethyl sulfoxide will be used more widely in organic synthesis, bioengineering, and drug discovery procedures.