Oxidation with DDQ

Dioxopiperazines are amongst the most ubiquitous of natural products (75FOR(32)57) and they are formally derived by the cyclodimerization of a-amino acids (69CCC4000) or their esters. A number of methods are available for their oxidation to the corresponding pyrazines. Treatment of 2,5-dioxopiperazines with triethyl- or trimethyl-oxonium fluorobor-ate followed by oxidation with DDQ, chloranil or iodine results in pyrazine formation, usually in high yields (Scheme 63) (72JCS(P1)2494). 

Sorensen and coworkers used a domino conrotatory electrocydic ring-opening/ 6ji-disrotatory electrocyclization for the formation of ring C in the total synthesis of ( )-viridin (4-327) (Scheme 4.72) [112]. Heating 4-325 in the presence of a base followed by in-situ oxidation with DDQ afforded the tetracyde 4-326 in 83% yield. 

The combination of silyl enol ethers and fluoride ion provides more reactive anions to give alkylated nitro compounds in good yields after oxidation with DDQ, as shown in Eq. 9.22.36 This process provides a new method for synthesis of indoles and oxyindoles (see Chapter 10, Synthesis of Heterocyclic Compounds). 

Formation of the ylide from the substituted pyrrolopyrazine 374 and subsequent [3+2] dipolar cycloaddition with a range of dipoloarophiles gives rise to the substituted 5 6 5 system 375 and the following examples are illustrative (Scheme 29) <1997T9341>. Reaction with acrylonitrile followed by oxidation with DDQ leads to the dihydroinda-cene 376. 

An alternative synthesis of 1 through reduction of BP 7,8-dione with NaBH in ethanol has also been described (22). BP 7,8-dione was prepared from 9,10-dihydro-BP by conversion to the cis-7,8-tetra-hydrodiol by reaction with OsO followed by oxidation with DDQ (23) (Figure 4). This method entails the same number of steps as the original procedure and would appear to offer no advantage. 

Petrillo reported that the bis-acetoxymethylpyrrole 83 undergoes a sequential Diels-Alder reaction of the in situ generated 2,3-dimethylpyrrole with carbodienophiles (such as maleic anhydride, maleimide, ethyl maleate, fumaronitrile, and ethyl acrylate) to afford the octahydrocarbazoles 84 which can be oxidized with DDQ to the corresponding carbazole derivatives . 

Protection of alcohols. Even somewhat hindered secondary alcohols or tertiary alcohols are converted into (p-methoxybenzyloxy)methyl (PMBM) ethers by reaction with 1 and diisopropylethylamine in CH2C12 for 3-30 hours. Deprotection can be effected by oxidation with DDQ (65-95% yield), a method previously recommended for deprotection of p-methoxybenzyl ethers (11, 166-167). 

An intramolecular Diels-Alder reaction of allenic dienamide 181 provided the tet-rahydroindole ring system 182, which was oxidized with DDQ or Mn02 to give indole derivatives [147]. 

Acetylenic dienophiles have also been used in conjunction with a different type of diene (150) for the combinatorial synthesis of isoindolones 151 fused with furan, pyrrole or thiophene rings (Fig. 30) [129]. In this case, the diene involved in IMDA is not the 5-membered heterocycle itself, but the one including the exocyclic double bond. The resulting dihydrobenzene is easily aromatized by oxidation with DDQ or C/O2. The synthetic protocol is accomplished in a one-pot process. 

Hydroxy-l,2,3,4-tetrahydroquinolines 304 were obtained by cyclization of oxime 2,4-dinitrophenyl ethers 303 in the presence of system NaBH3CN/NaH/l,4-dioxane (equation 131) . If the reductive cyclization was followed by oxidation with DDQ (2,3-dichloro-4,5-dicyano-p-benzoquinone) the corresponding 8-hydroxyquinolines 305 were obtained . ... 

Cluster opened bislactams have been obtained in a one-pot reaction by treating diazidobutadiene 30 with Cjq for four days in ODCB at 55 °C [3, 35]. The first step in the reaction sequence can be assumed to be the formation of the bisazafulleroid 31 (Scheme 11.7). Subsequent addition of 2 leads to the endoperoxide intermediate 32, which isomerizes via a electrocyclic ring opening to 33 [36]. Subsequent oxidation with DDQ or O2 afforded the dehydrogenated bislactam 34. 

In an analogous fashion, pyrrolo[l,2-c]pyrimidine (66), the preparation of which was discussed in Section 6.2.2.1, was converted to the corresponding quatemized salt 67 <99JOC7788>. This heterocycle was shown to undergo 1,3-dipolar additions with a variety of dipolarophiles such as aUcynes to produce 68 after oxidation with DDQ. 

In similar transformations, agriculturally and medicinally significant fluorine-containing quinazolines 101, isolated as the hydrates, were produced in good yields from 100 after condensation with various aldehydes in the presence of ammonia followed by oxidation with DDQ <99H2471>. 

The formation of the coumarin (388) from 7-allyloxy-3-methylf avone via a Claisen rearrangement and oxidation with DDQ is of a similar nature to the previous route, though yields are considerably lower (77TL473). 

The speed of alcohol oxidation with DDQ correlates with the following factors ... 

Electron-withdrawing groups close to the alcohol functionality may likewise destabilize intermediate carbocations and result in very slow oxidations. For instance, sterol 88 is oxidized with DDQ at the allylic alcohol two hundred times slower than the corresponding compound lacking the fluorine atom,94 and the treatment of hydrobenzoin (89) with DDQ results in the oxidation of a single alcohol because a second oxidation would involve a carbocation highly destabilized by the presence of a carbonyl group.95f... 

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... 

Functional Group and Protecting Group Sensitivity to Oxidation with DDQ... 

DDQ oxidations are made under almost neutral conditions. Therefore, both base- and acid-sensitive protecting groups and functionalities need not be altered in the presence of DDQ. During DDQ oxidations, the corresponding hydroquinone is generated, which possesses a slight acidity that normally does not cause any interference. However, some acid-catalyzed isomerization of an acetal was observed on a prolonged oxidation with DDQ.108... 

Although phenols are oxidized with DDQ,126 benzylic alcohols activated by phenol groups react so quickly with DDQ—delivering high yields of aldehydes or ketones—that this reagent is proposed as the best one for the oxidation of this kind of benzylic alcohols.127... 

Because of the mechanism of action of DDQ, sulfides and selenides are expected not to react with DDQ during the mild conditions used in the oxidation of unsaturated alcohols. There is one published example in which an alcohol is oxidized with DDQ in the presence of a selenide.130... 

A simple and versatile one-pot synthesis of meso-substituted trans-A2B-corroles (Scheme 7) was reported by Gryko and Jadach (01JOC4267). It affords regioisomerically pure frans-A2B-corroles 11 through the TFA-catalyzed condensation of a dipyrromethane 10 and an aldehyde followed by oxidation with DDQ. The synthesis is compatible with diverse functionalities ester, nitrile, ether, fluoro, hydroxy, etc. on the aryl group of the... 

Synthesis of regioisomerically pure corroles 15 (Scheme 9), possessing up to three different substituents (ABC-type corroles) at the meso-positions, has been achieved (02OL4491) through acid-catalyzed condensation of a dipyr-romethane-dicarbinol 14 with pyrrole followed by oxidation with DDQ. 

Sessler and coworkers reported a new "3+1+1" route for sapphyrins, without using a bipyrrolic moiety (01TL2447). Tripyrrane dialdehyde 133 with two equivalents of a pyrrole under acidic conditions, followed by oxidation with DDQ furnished sapphyrins 134 bearing different substituents in yields lower than by the "3+2" approach (Scheme 51), but the need of a bipyrrole synthesis could be obviated. This method (Scheme 55) allowed the synthesis of otherwise not known sapphyrins that contained various symmetric bipyrrolic subunits. 

Utilizing a modified Rothemund condensation of pyrrole and pentafluo-robenzaldehyde (01JA7190), Furata and coworkers obtained octaphyrin 182 and nonaphyrin 183, as well as several higher homologues in very low yields in the presence of BF3-Et20, followed by oxidation with DDQ. 

The 21,22-dioxaporphyrin 227 was synthesized by "2+2" acid-catalyzed condensation of 5,5 -diformyldifurrylmethane and a dipyrromethane diacid (1969JCS(CC)1480). 21,22-Diheteroporphyrins 229 (X=Y=0, S X=S, Y=0) containing S and O atoms have been obtained from 228 (X=Y=0 X=Y=S and X=S, Y=0) with 5-phenyl dipyrromethane derivative, followed by oxidation with DDQ (1998BKCS314,1999TL8879). 

The metallation behavior of meso-tins ubstitu ted 21-thiaporphyrin 251 (Scheme 98) has been achieved using n-BuLi at 0°C. Subsequent oxidation with DDQ (1998ACI1107) resulted in the formation of meso-butyl porphyrin 252. 

Reaction of the pyrrole complex 341 with acrylate gives 343 via 342, and indole ring 344 is formed by oxidation with DDQ [84], Similarly, the aniline complex 345 reacts with acrylate to afford 347 via 346 [85]. 

The DFT study of the 3 + 2-cycloaddition between ketene and TV-silyl-, IV-germyl-, and TV-stannyl-imines shows that the TV-germylimine reaction is a two-step process the TV-stannylimine reaction is a competition between two- and three-step processes whereas the TV-silyl process follows a three-step process44 A new and convenient synthesis of functionalized furans and benzofurans based on 3 + 2-cycloaddition/oxidation has been reported. The cyclization of cyclic 1,3-bis-silyl enol ethers (48) with l-chloro-2,2-dimethoxyethane (49), via a dianion, produced 5,6-bicyclic 2-alkylidenetetrahydrofurans (50), which are readily oxidized with DDQ to 2,3-unsubstituted benzofurans (51) (Scheme 13)45 The Evans bis(oxazoline)-Cu(II) complex catalyses the asymmetric 1,3-dipolar cycloaddition of a -hydroxyenones with nitrones to produce isoxazolidines.46 The... 

Acyl-2-fluoro-l,4-dihydropyridines 149, easily synthesized by alkylation of 2-fluoropyridinium salts, undergo hydrolysis to form dihydro-2-pyridones 150 in which only the more stable 3,4-/ra t-isomer is formed. 1,4-Dihydropyridines 149 can also be oxidized with DDQ to form 2-pyridones 151 (Scheme 40) <2002JOC7465, 2000CC2459>. 

Two routes for the synthesis of a four-terminal wire compound based on a central porphyrin unit are presented in Scheme 10.25 [13b], In one route, the tetrabro-mide 75 was treated with potassium thioacetate, which resulted in the substitution product 76. Alternatively, reaction of aldehyde 77 with pyrrole 78 at room temperature using mixed acid catalysis conditions provided 76 after oxidation with DDQ. 

Oxidation of chiral esters of phenylacetic acids. These esters can be converted into acetates of mandelic esters by oxidation with DDQ in acetic acid. The reaction is diastereoselective when carried out on esters of chiral alcohols, of which 8-phenylmenthol is the most useful. The presence of substituents on the phenyl group has slight effect on the diastereoselectivity, which depends on formation of a donor-acceptor complex between the substrate and the quinone with removal of a hydrogen atom. The acetoxy group then enters from the opposite, more bulky face. 

Anwer, F., Masaldan, A.S., Kapil, R.S. and Popli, S.P. (1973) Synthesis of murraycine oxidation with DDQ (2,3-dichloro-5,6-dicynobenzoquinone) of the activated aromatic methyl group of the alkaloids of Murraya koenigii. Indian Journal of Chemistry 11, 1314-1315. 

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