Sodium Methylsulfinylmethylide1

NaDMSO

[15590-23-5]  · C2H5NaOS  · Sodium Methylsulfinylmethylide  · (MW 100.13)

(strong base and nucleophile; very useful for the introduction of the methylsulfinylmethyl group1)

Alternate Names: sodium dimsylate; dimsylsodium.

Solubility: sol DMSO.

Form Supplied in: not commercially available.

Analysis of Reagent Purity: titration with formanilide using triphenylmethane as indicator.2

Preparative Method: prepared by the reaction of Sodium Hydride with Dimethyl Sulfoxide for 1 h at 70 °C. Sodium Amide may also be used as base.3

Handling, Storage, and Precautions: this reagent is not exceptionally stable over long periods of time. Modifications in preparation and storage have led to an increased shelf life.4 However, it is probably best prepared as needed and used quickly. Hydrogen is emitted during the preparation of this reagent and decomposition occurs at elevated temperatures.5 Due caution should be exercised in the preparation, particularly on a large scale. Reports have been made of explosions during the large scale preparation of this reagent or its attempted isolation.1,6

Introduction.

The pKa of DMSO is 35. Consequently, one might expect its conjugate base to be a potent Brønsted base and this is indeed the case. In addition to the sodium salt, both the lithium and potassium salts of DMSO have found widespread use in synthesis (see Lithium Methylsulfinylmethylide and Potassium Methylsulfinylmethylide). After its introduction by Corey,2 explorations of the chemistry of sodium methylsulfinylmethylide (NaDMSO) blossomed and are summarized nicely in two reviews.1

Sodium Methylsulfinylmethylide as Base.

Generation of Ylides.

NaDMSO as a solution in DMSO has been used extensively in the preparation of phosphorus and sulfur ylides.1,7,8 This medium is often the one of choice for the generation and reaction of Wittig reagents (eq 1).7,9 A less common application of Wittig reagents generated with NaDMSO is in an oxidative coupling of a bis-ylide to form a cyclic alkene (eq 2).10

The methylene transfer reagents Dimethylsulfonium Methylide and Dimethylsulfoxonium Methylide are conveniently generated with NaDMSO in DMSO.11 These and other sulfonium ylides are useful in the synthesis of epoxides and cyclopropanes (eqs 3 and 4).8,11 Also intriguing is the use of dimethyloxosulfoxonium methylide to give dienes (eq 5).12

Diaminosulfonium salts can be deprotonated with NaDMSO to give rearrangement products or epoxides upon reaction with aldehydes (eq 6).13 A variety of ammonium ylides have been generated using NaDMSO.14,15 These species are disposed to undergo Wittig, Stevens, or Sommelet-Hauser rearrangements, depending on their specific constitution (eqs 7 and 8). Changes in base and other reaction conditions can change product distributions.14a,b

Eliminations.

Elimination reactions using NaDMSO have apparently not been extensively investigated, although the use of metal alkoxides in DMSO has received considerable attention.16 Whether the active agent in such mixtures is NaDMSO is not clear. Eliminations clearly mediated by NaDMSO are known.17 For example, treatment of (1) with NaDMSO at 25 °C gives the elimination product (2) in 91% yield (eq 9).17a Longer reaction times result in addition of DMSO to the newly formed double bond. Heating results in isolation of a dealkylation product (4), a clear example of the diverse reactivity associated with NaDMSO. Alkynes are generated by the reaction of 1,2-dibromoalkanes with excess NaDMSO.18 Aryl halides can give benzynes in the presence of NaDMSO (eq 10).19 Further, addition of DMSO is possible, leading to a unique mode of functionalization (eq 11).19c

Rearrangements.

NaDMSO has been used to promote double bond isomerization, leading to aromatization in the case shown (eq 12).20 An anionotropic rearrangement of a cyclohexadienone to a substituted hydroquinone has been reported (eq 13).21 The use of NaDMSO in DMSO has been described as an optimal choice for executing the carbanion accelerated Claisen rearrangement (eq 14).22 Grob-type fragmentations mediated by NaDMSO have been used in total synthesis (eq 15).23

Anion Alkylation and Acylation.

NaDMSO has been used as a base to create new anions or carbanions, which then can be functionalized via normal alkylation or acylation procedures. Intramolecular aminolysis of an ester mediated by NaDMSO has been reported (eq 16).24 A tandem double Michael-Dieckmann condensation leading to a complex tricyclic structure has been developed (eq 17).25 Generation of a ketone enolate with NaDMSO followed by an intramolecular alkylation has been a part of a number of total syntheses.26 Alkylations of sulfoximine and sulfone (Ramberg-Bäcklund rearrangement) carbanions derived from NaDMSO are known.27 The intramolecular oxidative coupling of nitro-stabilized carbanions can lead to highly functionalized cyclopropanes which are potentially useful as high energy materials (eq 18).28

Ether Synthesis.

The application of NaDMSO to the Williamson ether synthesis has been documented.29 The potential for alkoxide fragmentation exists and some discretion must be exercised in using this base for ether formation.30 An intramolecular version of the Williamson reaction mediated by NaDMSO leads to an oxetane in high yield.31 The preparation of otherwise difficulty accessible xanthates has been realized using NaDMSO.32 Very common is the modification of oligo- and polysaccharides via Williamson ether synthesis (Hokomori reaction) to facilitate handling and analysis of these compounds.33 Other hydroxylic polymers can also be functionalized in this way.34

Sodium Methylsulfinylmethylide as Nucleophile.

Reactions with Esters.

Perhaps one of the most useful reactions of NaDMSO is its condensation with esters to produce b-keto sulfoxides. The rich chemistry of these difunctional compounds makes accessible a wide variety of other organic compounds.1,35 One of the most straightforward applications of NaDMSO is the synthesis of methyl ketones from esters (eq 19).36 Thermal elimination of methylsulfenic acid after alkylation leads to a,b-unsaturated ketones (eq 20).37 Among the wide variety of possible transformations of b-keto sulfoxides, another which stands out is the Pummerer reaction, which allows for the formation of carbon-carbon bonds via an umpolung of the reactivity adjacent to the carbonyl group (eq 21).38 A synthesis of ninhydrin was developed based on this type of chemistry.38c Methacrylate polymers have been modified by reaction with NaDMSO.39

Reactions with Aldehydes and Ketones.

The reaction of nonenolizable ketones and aldehydes with NaDMSO generally proceeds smoothly to give b-hydroxy sulfoxides.1 The chemistry of the latter is not as rich as that of b-keto sulfoxides, to which they can be converted. However, dehydration leads efficiently to a,b-unsaturated sulfoxides which can be transformed to the corresponding sulfides or sulfones.40 A one-pot procedure using Sodium metal to produce NaDMSO and serve as a reductant leads to a,b-unsaturated sulfides directly.41 Interestingly, a dianion of DMSO can be prepared from the reaction of DMSO with 2.2 equiv of NaNH2. Reaction with benzophenone gives the expected adduct, albeit in only modest yield (eq 22).3 A unique synthesis of 3-phenylindole based upon the reaction of NaDMSO with 2-aminobenzophenone has been reported (eq 23).42

Enolizable ketones and aldehydes often give enolates upon reaction with NaDMSO as well as the expected addition products, limiting the utility of the reagent with these systems. Several unusual reactions of NaDMSO with enolizable ketones have been reported. For example, treatment of 4-heptanone with NaDMSO at elevated temperatures results in diene formation (eq 24).43 Similarly, the reaction of cyclopentanone with NaDMSO gives a diene resulting from condensation followed by nucleophilic addition of NaDMSO and fragmentation (eq 25).44

Reactions with Imines and Related Compounds.

The reaction of imines with NaDMSO has not been extensively studied.2 However, several interesting applications with heterocycles at least formally possessing imine functional groups have been reported. Treatment of 1-methylquinoline with excess NaDMSO results in a tandem 1,4-1,2 addition to give a unique b-amino sulfoxide (eq 26).45 A mechanistically intriguing synthesis of phenanthrene is the result of the reaction of a benzoquinoline N-oxide with NaDMSO (eq 27).46 Finally, a synthesis of dibenzo[a,f]quinolizines has been developed based on the addition of NaDMSO to an imine followed by trapping of the resulting amide with a pendant benzyne (eq 28).47

Reactions with Alkenes and Alkynes.

The reaction of NaDMSO with alkenes or alkynes conjugated to an aryl ring or alkene is well known.1 1,1-Diphenylethene gives a 1:1 addition product in quantitative yield upon reaction with NaDMSO.48 From a synthetic perspective, one of the most useful of these reactions is the alkylation, especially the methylation, of stilbenes (eq 29).49 This occurs by initial attack of NaDMSO on the unsaturated system followed by the elimination of methanesulfenic acid and isomerization. Dienes and other polyenes are subject to the same type of chemistry, but yields are modest and isomer formation can be a problem (eq 30).50 Reaction of NaDMSO with diphenylacetylene can lead to either simple addition products or those based on an addition-elimination sequence, depending on the reaction conditions (eq 31).51 Addition of NaDMSO to unsaturated systems has been used in polymer synthesis.52

Reactions with Aromatics.

The reactions of NaDMSO with aromatic electrophiles can be categorized as occurring through either benzyne or addition-elimination mechanisms. Reaction of NaDMSO with chlorobenzene gives a mixture of sulfoxides, presumably via a benzyne intermediate (eq 32).53 This chemistry has been used in the modification of polystyrenes.54 Various fluoroaromatics react with NaDMSO to produce substitution products via addition-elimination (eq 33).55 A variety of condensed aromatics (e.g. anthracene) undergo methylation analogous to that of stilbene upon reaction with NaDMSO (eq 34).56

Reactions with Halides and Related Compounds.

Alkylation of NaDMSO with primary halides and tosylates results in the formation of the expected sulfoxides.57 However, reaction with benzyl chloride gives stilbene as the major product, suggesting that the basicity of NaDMSO must be considered even with reactive electrophiles.2 More hindered systems favor elimination. 1,2,5,6-Tetrabromocyclooctane debrominates to 1,5-cyclooctadiene upon reaction with NaDMSO (eq 35).58 With Potassium t-Butoxide in DMSO the major product is one of elimination, namely cyclooctatetraene. Monodebromination also occurs with gem-dibromocyclopropanes.59 In a process which presumably proceeds via SN2 substitution, reaction of imidates with NaDMSO leads to amides (eq 36).60

Reactions with Epoxides.

The reaction of NaDMSO with epoxides does not appear to have been widely investigated. Nevertheless, some synthetically useful transformations have been documented. Ring opening with NaDMSO followed by thermal alkene formation was developed as a route to an optically pure secondary allylic alcohol (eq 37).61 A related transformation involves the reaction of trimethylsilyl-substituted epoxides (eq 38).62 Ring opening at the TMS-substituted carbon, followed by desilylation and sulfenate elimination, leads to allyl alcohols in good yield in a one-pot process.

Reactions with Phosphorus and Sulfur Electrophiles.

A one-pot synthesis of a,b-unsaturated sulfoxides begins with the reaction of NaDMSO with Diethyl Phosphorochloridate to give a Horner-Emmons reagent which reacts with aldehydes in an efficient manner (eq 39).63 Bis-sulfoxides are prepared by the reaction of NaDMSO and a diastereomerically pure methyl sulfinate ester.64 Some kinetic resolution is observed in this reaction. The thiophilic addition of NaDMSO to sulfines also leads to bis-sulfoxides (eq 40).65


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Michael Harmata

University of Missouri-Columbia, MO, USA



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