DDQ oxidation

The p-methoxybenzylidene ketal can be prepared by DDQ oxidation of a methoxybenzyl group that has a neighboring hydroxyl. This methodolc... 

L DDQ oxidation. Cleavage occurs selectively in the presence of a benzyl and p-nitrobenzyl group. 

The p-methoxybenzylidene ketal can be prepared by DDQ oxidation of a p-methoxybenzyl group that has a neighboring hydroxyl. This methodology has been used to advantage in a number of syntheses. " In one case, to prevent an unwanted acid-catalyzed acetal isomerization, it was necessary to recrystallize the DDQ and use molecular sieves. The following examples serve to illustrate the reaction " ... 

Vinyl- and acetylenic tricarbonyl compounds are reactive dienophilic components in Diels-Alder reactions. Cycloadditions of these compounds with substituted butadienes were recently used to develop a new synthetic approach to indole derivatives [14] (Scheme 2.9) by a three-step procedure including (i) condensation with primary amines, (ii) dehydration and (iii) DDQ oxidation. 

Utilizing an alternate mode of Diels-Alder reactivity, Harman has examined the cycloaddition reactions of 4,5-T -Os(II)pentaammine-3-vinylpyrrole complexes with suitably activated dienophiles <96JA7117>. For instance, cycloaddition of the p-vinylpyrrole complex 58 with 4-cyclopentene-l,3-dione, followed by DDQ oxidation affords 59, possessing the fused-ring indole skeleton of the marine cytotoxic agent, herbindole B. 

The C(9)-C(14) segment VI was prepared by Steps D-l to D-3. The formation of the vinyl iodide in Step D-3 was difficult and proceeded in only 25-30% yield. The C(15)-C(21) segment VII was synthesized from the common intermediate 17 by Steps E-l to E-6. A DDQ oxidation led to formation of a 1,3-dioxane ring in Step E-l. The A-methoxy amide was converted to an aldehyde by LiAlH4 reduction and the chain was extended to include C(14) and C(15) using a boron enolate of an oxazo-lidinone chiral auxiliary. After reductive removal of the chiral auxiliary, the primary alcohol group was converted to a primary iodide. The overall yield for these steps was about 25%. 

Another convenient entry to fused cyclobutene-1,2-diesters was via site selective modification of the norbomene rt-bond in Smith s fe-alkene 49, e.g. treatment with 3,6-di(2 -pyridyl)-s-tetrazine 51 followed by DDQ oxidation afforded the cyclobutene-derivative 53 <97AA119>, while direct coupling with 3,5-f> (trifluoromethyl)-l,3,4-oxadiazo]e 54 furnished the tas(cyclobutene-l,2-diester) 55 (Scheme 6) <97SL196>. 

A high yield approach to the hexahydropyrrolo[3,2-e [l,4]diazepine-2,5-diones, 105 and their tetrahydrofuro analogues, 106, based on rearrangements of cyclopropylketimines and the cyclopropylketones, derived by acid hydrolysis, have been described. Thermolysis followed by DDQ oxidation of the unstable dihydro intermediates then gave compounds 105 (eg. R1 = Me, R2 = i-Bu) and 106 (eg. R = 4-Cl(C6H4)CH2) . 

Miki effected Pd-catalyzed cross-coupling between dimethyl 7-bromoindole-2,3-dicarboxylate and both tributylvinyltin and tributyl-1-ethoxyvinyltin to yield the expected 7-vinylindoles [197]. Hydrolysis of the crude reaction product from using tributyl-1-ethoxyvinyltin gave the 7-acetylindole. Sakamoto used dibromide 192, which was prepared by acylation of 7-bromoindole, in a very concise and efficient synthesis of hippadine [36]. The overall yield from commercial materials is 39%. Somewhat earlier, Grigg employed the same strategy to craft hippadine from the diiodoindoline version of 192 using similar cyclization reaction conditions ((Me3Sn)2/Pd(OAc)2), followed by DDQ oxidation (90%) [198]. 

For the first time, application of sequential Diels-Alder reactions to an in situ-generated 2,3-dimethylenepyrrole was shown with various dienophiles 548 to afford 2,3,6,7-tetrasubstituted carbazoles (549). This novel tandem Diels-Alder reaction leads to carbazole derivatives in two steps, starting from pyrrole 547 and 2 equivalents of a dienophile, and is followed by 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) oxidation of the intermediate octahydrocarbazole. Mechanistically, the formation of the intermediate octahydrocarbazole appears to involve two sequential [4+2] cycloadditions between the exocyclic diene generated by the thermal elimination of acetic acid and a dienophile (529) (Scheme 5.17). 

Possibly, the most common protocols used in the generation of azomethine ylides are those based on the in situ, fluorine-mediated desilyation of cyanoami-nosilanes developed by Padwa et al. (2). Typically, treatment of precursor 1 with AgF, in the presence of dimethyl acetylenedicarboxylate (DMAD), led to the formation of the intermediate cycloadduct 2, which was subjected to immediate DDQ oxidation to give pyrrole 3. The mechanistic rationale invokes fluoride-mediated desilyation to form the intermediate anion 4, which then undergoes loss of cyanide furnishing the corresponding azomethine yhde (Scheme 3.1). 

Indolocarbazole is prepared from l,2-bis(3-indolyl)ethane upon treatment with TFA followed by DDQ oxidation (Equation 83). The related indolobenzofuran derivative has been synthesized in a similar fashion <1999JOC5670, 2004BMC1955>. 

The natural products xanthoxyletin 64 and alloxanthoxyletin 65 have been prepared by DDQ oxidation of intermediates 66 and 67 (Equations 10 and 11) <2003JA4518>. 

The conversion of 7, which has a stereogenic center, into 8 which has a stereogenic axis, by DDQ oxidation (for assignment, see p437, see also p424)147. 

DDQ oxidation of 5 furnishes 6 where the relative configuration around the stereogenic axis was determined by X-ray analysis. Note the difference in the problem of configurational assignment when compared to a similar reaction (see Section 4.3.3.2.4.1) where the absolute configuration needed to be determined (also see p 437). 

Studies directed toward the synthesis of bicyclomycin have resulted in the discovery of efficient routes to the construction of the 2-oxa-8,10-diazabicyclo[4.2.2]decane system (160). Thus, the monolactim ether (155) with a hydroxypropyl side chain at position 3, on oxidation with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), gave the product (156) in good yield, presumably via an iminium species (Scheme 51). No trace of the spiro compound (157) could be detected in this reaction. The formation of (156) is probably kinetically controlled. Prior protection of the alcohol as a silyl ether, followed by DDQ oxidation, gave the pyrazinone (158) subsequent deprotection and acid treatment gave the thermodynamically preferred spiro compound (159). The method has been extended to the synthesis of (160), having an exocyclic methylene this compound is a key intermediate in the total synthesis of bicyclomycin [88JCS(P1)2585]. 

Elimination of phenylsulfinate anion, induced by base, introduces one double bond. The second double bond can be introduced by DDQ oxidation, as in Scheme 43. 

Interestingly, the reverse trend is observed with other oxidizing agents, such as chromic acid. Thus, chromic acid is known to oxidize quicker axial alcohols, which is explained by the release of steric congestion exerted by 1,3-f/rm-diaxial interactions.102 Apparently, a proper orbital alignment plays a greater role in DDQ oxidations than the release of steric congestion. 

However, in molecules where the axial alcohol is subject to very severe steric interactions, the release of steric tension may become the major factor affecting DDQ oxidation velocity. For example, the 3 -acetoxy-6 —hydroxy-5a-cholest-7-ene (92) is oxidized faster than the corresponding 6a isomer (93). 

Quite unsurprisingly, apart from stereoelectronic factors, DDQ oxidation of unsaturared alcohols is also subject to steric factors. For instance, the highly hindered allylic alcohol 94 could not be oxidized with DDQ in benzene at room temperature, being necessary to employ Jones oxidation.103... 

Since the DDQ hydroquinone is quite weakly acidic and—if a proper solvent is chosen—only a very small proportion remains in solution, DDQ oxidations are performed under almost neutral conditions. Nevertheless, a slow equilibration of isomeric acetals has been described in a DDQ oxidation.108... 

Thanks to the easy removal of the precipitated DDQ hydroquinone after a DDQ oxidation, it is very practical to recover the pricey DDQ by oxidizing the corresponding hydroquinone with nitric acid.109... 

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