Dicyclohexylcarbodiimide, DMSO

The use of carbodiimides in organic synthesis includes the Moffat oxidation of primary alcohols to aldehydes using a dicyclohexylcarbodiimide/DMSO adduct as reagent. Also, conversion of alcohols or phenols into hydrocarbons via hydrogenation of acylisoureas derived from the corresponding carbodiimide adducts is a useful reaction. Furthermore, aldoximes, on treatment with carbodiimides, are converted into nitriles, and numerous uses of carbodiimides as condensation agents or catalysts are known (see Chapter 13). 

Miscellaneous Methods for the Oxidation of Alcohols Dicyclohexylcarbodiimide/DMSO... 

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. 

Whereas the original Moffat-Pfitzner oxidation employs dicyclohexylcarbodiimide to convert DMSO into the reactive intermediate DMSO species 1297, which oxidizes primary or secondary alcohols via 1298 and 1299 to the carbonyl compounds and dicyclohexylurea [78-80], subsequent versions of the Moffat-Pfitzner oxidation used other reagents such as S03/pyridine [80a, 83] or oxalyl chloride [81-83] to avoid the formation of dicyclohexylurea, which is often difficult to remove. The so-called Swern oxidation, a version of the Moffat-Pfitzner oxidation employing DMSO/oxalyl chloride at -60°C in CH2CI2 and generating Me2SCl2 1277 with formation of CO/CO2, has become a standard reaction in preparative organic chemistry (Scheme 8.31). 

A very useful group of procedures for oxidation of alcohols to ketones have been developed which involve DMSO and any one of several electrophilic reagents, such as dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride, oxalyl chloride, or... 

There are several methods reported in the literature for transforming vicinal diols into ct-diketones while avoiding the risk of C-C bond cleavage.26 Examples include the standard Swem conditions (dimethyl sulfoxide and oxalyl chloride followed by triethylamine), or the use of DMSO activated by acetic anhydride, pyridine-sulfur trioxide complex, or dicyclohexylcarbodiimide (Mq/J-att oxidation). Diones are also obtained by treatment with benzalacetone as a hydride acceptor in the presence of catalytic amounts of tris(triphenylphosphine)ruthenium dichlonde [(PPh RuCFl.27 Recent developments include the use of w-iodoxyben/.oic acid28 or the oxoammonium salt of 4-acctamidoletramethylpipcridine-1-oxyl and y -toluencNulfonic acid.29... 

The synthesis of hexakis(cyclohexylsilsesquioxane) in 10% yield by the treatment of cyclohexyltrichlorosilane with water was first reported in 1965108. The X-ray structure of hexakis(cyclohexylsilsesquioxane) was determined by Molloy and coworkers in 1994109. The hexasilsesquioxanes (80) substituted by /-butyl or 1,1,2-trimethylpropyl groups are prepared by condensation of the corresponding silanetriol (78) or tetrahydroxysiloxane (79) using dicyclohexylcarbodiimide (DCC) as a dehydrating reagent in DMSO or DMF (Scheme 20)no. 

Vitamin A terpenes.2 A novel entry to retinal (5) involves reaction of the chloride (2) with 1 to give an intermediate (3) in 55% yield. Oxidation of 4 with DMSO in the presence of N,N-dicyclohexylcarbodiimide gives rise to the four 11,13-stereoisomeric retinals (5). Addition of I2 increases the proportion of the all-/rara-retinal (E,E-5). 

CAN Ceric ammonium nitrate CDI N,N -Carbonyldiimidazole DCC N,N -Dicyclohexylcarbodiimide DIC N,N -Diisopropylcarbodiimide DMAP 4-(Dimethylamino)pyridine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide... 

DBPO DBU DCC DDQ DEAD DET DIBAL-H DIPT DMAP DMB DME DMF DMPU DMSO EDDA Eu(dppm)3 Eu(fod)3 dibenzoyl peroxide 1.8- diazabicyclo [ 5.4.0] undec-7-ene dicyclohexylcarbodiimide 2.3- dichloro-5,6-dicyano-l,4-benzoquinone diethyl azodicarboxylate diethyl tartrate diisobutylaluminium hydride diisopropyl tartrate iMM-dimethylaminopyridine 3.4- dimethoxybenzyl 1.2- dimethoxyethane dimethylformamide 1.3- dimethyl-3,4,5,6-tetrahydro-2(lH)pyrimidinone dimethyl sulfoxide ethylene diammonium diacetate di(perfluoro-2-propoxypropionyl)methanato europium 6.6.7.7.8.8.8- heptafluoro-2,2-dimethyl-3,5-octanedionato... 

Different electrophiles have been used to effect this oxidation. For example, in Pfitzner-Moffatt oxidation, alcohols are oxidized to aldehydes and ketones by the DMSO and DCC (dicyclohexylcarbodiimide). The resulting alkoxysulfonium ylide C rearranges to generate aldehydes and ketones (Scheme 7.6). 

Abbreviations Standard abbreviations as recommended by IUPAC-1UB Commission are used in this review (1). Other abbreviations include Acm, acetamidomethyl Bn, benzyl Boc t-butyloxycarbonyl Bom, benzyloxymethyl BHA, benzhydrylamine Cbz, benzyloxycarbonyl cHx, cyclohexyl DCC, N,N-dicyclohexylcarbodiimide DCM, dichloromethane Die, N,N-diisopropylcarbodiimide DMF, N,N-dimethylformamide DMSO, dimethyl sulphoxide For, formyl Fmoc, 9-fluorenylmethyloxycarbonyl HMP, 4-hydroxymethylphenoxyacetyl HOAt,... 

The mechanism of the reactions of DMSO with alcohols is shown in equation 26 and in a few more examples. Dicyclohexylcarbodiimide is sometimes used in addition to the acid catalysts (equation 26). 

Dimethyl sulfoxide (DMSO), which is successfully used to dehydrogenate primary alcohols to aldehydes, converts secondary alcohols into ketones in very high yields and under very gentle conditions. The mechanism is discussed in a previous section. Dehydrogenation and Oxidation of Primary Alcohols to Aldehydes (equation 217). The first oxidations were carried out in the presence of dicyclohexylcarbodiimide and an acid catalyst such as pyridinium trifluoroacetate [1016], which protonates the diimide and facilitates the attack by dimethyl sulfoxide (equation 259). 

Ac AIBN 9-BBN Bn Boc Bu Bz CAN Cbz CD CSA DABCO DAST DBN DBU DCC DDQ DEAD DHP DIAD DIBAL-H DMAP DME DMF DMP DMSO DNB EE Ee Eq Et Fmoc GLC HLADH HMDS HMPA HOBt HPLC Im acetyl 2,2/-azobisisobutyronitrile 9-borabicyclo[3.3.1]nonane benzyl f-butoxycarbonyl butyl benzoyl ceric ammonium nitrate benzyloxycarbonyl circular dichroism camphorsulfonic acid 1.4- diazabicyclo[2.2.2]octane A,A-Diethylaminosulfur trifluoride 1.5- diazabicyclo[4.3.0]non-5-ene l,8-diazabicyclo[5.4.0]undec-7-ene A,A -dicyclohexylcarbodiimide 2.3- dichloro-5,6-dicyano-1,4-benzoquinone diethyl azodicarboxylate 3.4- dihydro-2//-pyrane diisopropyl azodicarboxylate diisobutylaluminum hydride 4-A,A -dimethylaminopyridine 1,2-dimethoxyethane A,A -dimethylformamide Dess -Martin periodinane [1,1,1 -tris(acetyloxy)-1,1 -dihydro-1,2-benziodoxol-3-( IH) -one] dimethyl sulfoxide 3.5- dinitrobenzoyl 2-ethoxyethyl enantiomeric excess molar equivalent ethyl 9-fluorenylmethoxycarbonyl gas-liquid chromatography horse liver alcohol dehydrogenase 1,1,1,3,3,3 -hexamethyldisilazane hexamethylphosphoric triamide 1 -hydroxybenzotriazole high-performance liquid chromatography 1-imidazolyl or imidazole... 

Abbreviations IgGl. immunoglobulin Gl KLH, keyhole limpet hemocyanin BSA, bovine serum albumin RNase A. ribonuclease A LDH. lactate dehydrogenase MHC, major histocompatibility complex LHRH, luteneizing hormone releasing hormone CCK. cholecystokinin VIP. vasoactive intestinal peptide TASP, template-assembled synthetic proteins MAPS, multiple antigen presenting system SUV, small unilamellar vesicle DCC. dicyclohexylcarbodiimide HOSu. N-hydroxysuccinimide Mal>. maleimido TFA, trifluoroacelic acid TFE. triiluoroethanol DMF, dimethylformamide DMSO. 

The Pfitzner-Moffatt oxidation utilises 1,3-dicyclohexylcarbodiimide as the DMSO activator in the presence of acid to afford oxidation of alcohols to carbonyls.2,24,25 Initial work was carried out on steroids and thymidine residues although the procedure has since been found to be applicable to a large range of alcohols. In the following example, the Pfitzner-Moffatt method was used as an alternative to the Swem reaction which had resulted in the formation of an unwanted a-chloroketone (see later).26 Other oxidation procedures were attempted (PDC, PCC, Dess-Martin periodinane) however the Pfitzner-Moffatt gave the best, albeit modest, yield. 

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