DMSO and DCC

Oxidation of alcohols using DCC and DMSO, also known as Pfitzner-Moffatt oxidation . 

Only a few modifications of mycinose itself, on either demycarosyltylosin or mycinamicin, have been reported. The 4"-hydroxyl was readily oxidized to the ketone with DCC and DMSO or with diisopropylsulfide and N-chlorosuccin-imide [131, 133] however, attempts at conventional reductive amination resulted in cleavage of mycinose instead [130, 133]. Since reduction of the 4"-oxime produced an imine which was unstable toward hydrolysis back to the ketone, a convenient method for one-step reduction of the 4"-oxime to the 4"-amino derivative using TiCl3 and NaBH3CN was devised [133]. lodination at 4" by methyl triphenoxyphosphonium iodide has been observed as a side reaction subsequent elimination of HI yielded a 3",4"-anhydro derivative [134]. It should also be noted that a number of structural variations in this saccharide already exist due to the compounds isolated from the mutant strains of these macrolide-producing organisms [70, 75, 135]. 

The most intensively studied oxidizing system is that developed by Pfitzner and Moflatt in which the oxidation is carried out at room temperature in the presence of dicyclohexylcarbodiimide (DCC) and a weak acid such as pyridinium trifluoroacetate or phosphoric acid. The DCC activates the DMSO which in turn reacts with the carbinol to give an oxysulfonium intermediate. This breaks down under mild base catalysis to give the desired ketone and dimethyl sulfide. 

The phenyl ether linkage of butoxy substituted 44 was cleaved with boron tribromide to give a hexaphenol derivative (45) in 60% yield (Scheme 14). The hexaphenol derivative was found to be remarkably soluble in most polar organic solvents, such as ethanol, DMF, DMSO, and dioxane, as well as in aqueous base solution. Condensation with octanoic acid in the presence of DCC and catalytic H+ afforded the inverse ester (46) in high yield. 

These reagents have a number of drawbacks. First of all, they are toxic especially via contact with skin. The LD50 (dermal, rat) of DCC is 71 mg kg. This should always be considered if the reaction is used for the preparation of materials for biological applications. Moreover, the N.N -dialkylurea formed during the reaction is hard to remove from the polymer except for preparation in DMF and DMSO, where it can be filtered off. In case of esterification of polysaccharides in DMSO in the presence of these reagents, oxidation of hydroxyl functions may occur due to a Moffatt type reaction (Fig. 25, [188]). The oxidation products formed can be detected with the aid of 2,4-dinitrophenylhydrazine, e.g. in case of the conversion of dextran with DCC in DMSO [189],... 

Nevertheless, the reagent is still used for a large number of esterification reactions of dextran. The synthesis of dextran amino acid esters is achieved by conversion of the polysaccharide in DMSO with the N-ben-zyloxycarbonyl protected acids for 48 h at 20 °C using DCC and pyridine. 0-(N-B enzyloxycarbonylglycyl) dextran with DS 1.1, 0-(AT-benzyloxycarbo-nyl-aminoenanthyl) dextran with DS 2.2, and 0-(N-acelyl-i,-histidinyl)dcx-tran with DS 1.1 are accessible. Deprotection was achieved with oxalic acid and Pd/C [190,191],... 

Nonapeptides are constructed using DCC and N-hydroxybenzodiazole, this method is also used in the synthesis of prothimosin o (pro Ta), a polypeptide consisting of 109 amino acids. In the latter reaction the coupling is conducted using DMSO as solvent. Similarly, glycoproteins are synthesized, but in this case piperidine/DMF is used as solvent. " The synthesis of cyclosporin, a cyclopeptide formed from 11 amino acids also uses DCC in the formation of the heptapeptide intermediate. ... 

In the Pfitzner-Moffatt oxidation,4 an alcohol is oxidised by treatment with a mixture of dicydohexylcarbodiimide (DCC) (22), DMSO and an acid source, e.g. polyphosphoric acid, sulfur trioxide-pyridine, pyridine trifluoroacetate or acetic... 

A quite similar method is employed in the one-carbon chain extension of a 5 -phosphonate isostere of pyridoxal 5 -phosphate (Scheme 5.50) The a , 3-O-isopropylideneisopyridoxal is converted into an oc,P-unsaturated phosphonate in yields up to 65% by condensation with sodium tetraethyl methylenediphosphonate. Selective hydrolysis with 10% HCOjH at reflux gives the key diethyl 2-(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)vinylphosphonate intermediate in 98% yield. After catalytic hydrogenation of the double bond using 5% Pd/C in EtOH, a comparison of methods for the oxidation of the alcohol has been made, including use of MnOi in water, CrO, Py, and DMSO-DCC. Finally, oxidation with activated MnO2 in CHCl, was found to proceed smoothly to give the diethyl 2-(4-formyl-3-hydroxy-2-methyl-5-pyridyl)cthylphosphonate. ... 

Heterocyclic compounds. DCC and carbonyl hydrazide in equimolar amounts react in refluxing DMF to give 4-cyclohexyl-3-cyclohexylamine-l,2,4-triazoline-5-one (1) in 45-50% yield. The reaction of carbonyl hydrazide (1 equivalent) and DCC (3 equivalents) in DMSO at 100° also yields (1), but the predominant product is 4-cyclohexyl-3,5-biscyclohexylamino-l,2,4-triazole (2). The reaction is applicable to other carbodiimides.4... 

Actually, the direct oxidation of (I) to (2) can be carried out in 81% yield with (he Pfitzner-Moffatt reagent (DMSO, DCC, and H3P04).15... 

In the first attempt to test the concept of electron availability at N °, 2 -azafolic acid (V.18) and 3 -azafolic acid (V.19) were synthesized [211]. 5-Nitropicolinic acid was sequentially condensed with diethyl L-glutamate in the presence of DCC, and reduced catalytically with Raney nickel at atmospheric pressure to give an amine. Condensation of the amine with 2-acetam-ido-4(3/7)-oxopteridine-6-carboxaldehyde in DMSO in the presence of molecular sieves for 4 days yielded a SchifFs base, which on reduction... 

Sulfoxides (essentially DMSO) can be used for oxidation of alcohols to carbonyl compounds as in the Moffatt, Swern and related oxidations [237, 238]. These mild and useful processes proceed through an oxosulfonium salt. In the Pfitzner-Moffatt procedure the alcohol is treated with DMSO, DCC and anhydrous phosphoric acid. The proposed mechanism involves an alkylsulfonium ylide as an intermediate. 

Moffatt oxidation has several problems associated with it. One is formation of the urea product 64, which can be very difficult to remove. Treatment with oxalic acid is the most common method employed for the removal of the last vestiges of the dicyclohexylurea byproduct. Oxidation of homoallylic alcohols is sometimes accompanied by isomerization of the double bond into conjugation with the carbonyl group. This can be minimized or prevented by addition of pyridinium trifluoroacetate. A threefold excess of DCC and an excess of DMSO are usually required for Moffatt oxidation and these must be removed from the product. The... 

The condensation of salicylaldehyde or its derivatives with various derivatives of ethyl acetate in the presence of piperidine led to the synthesis of coumarins 95 in 55-94% yields under solvent-free conditions using MWI. Similarly, the benzo analogs 96 were prepared in 75-82% yields from 2-hydroxy-1-naphthaldehyde within 3-lOmin (Scheme 19) (98JCR(S)468). However, naphtho[2,l-Z ]pyran-3-ones 96 were prepared in 58-67% yields from the same aldehyde and substituted acetic acids under MWI for 6-8 min but in the presence of DCC and using DMSO as a solvent (Scheme 19) (97JCR(S)178). 

Reaction of carbodiimides with malonates or acetoacetic esters affords the insertion products. For example, reaction of barbituric acids 137 and DCC in DMSO at 150 °C gives the C-H insertion products 138 °. 

In a two-necked flask, [t-BuSi(OH)2]20 (0.25 g, 1.0 mmol), DCC (0.62 g, 3.0 mmol) and DMSO (5 mL) were placed, and the solution was heated to 130°C for 72 h. The reaction mixture was poured into hexane and water and finally separated. The organic phase was washed three times with water to remove the remaining dicyclohexylurea and DMSO and dried and concentrated. Resulting in a semisolid (0.17 g) that was triturated with 5 mL of acetone to give pure hexa(tert-butylsilsesquioxane) (54 mg, 25%). 

In a two-necked flask, all-cis-[i-PrSi(0H)0]4 (1.25 g, 3.00 mmol), DCC (2.04 g, 9.90 mmol), and DMSO (15 mb) were placed and the solution was heated to 180°C for 3 d. Benzene (15 mb) was added to the mixture, and the generated dicyclohexylurea was removed by filtration. The filtrate was washed with water (60 mb), and the aqueous phase was extracted three times with hexane. The combined organic phase was dried over anhydrous magnesium sulfate and evaporated. The resulting semisolid was triturated with acetone to afford octa(isopropylsilsesquioxane) (0.52 g, 45%). 

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