1,2-Dioxetanes with nucleophiles

There have been extensive studies on the reaction of dioxetanes and dioxetanones with nucleophiles (C, N, P, and S) and the reader is directed to CHEC-II(1996) for an exhaustive list up to 1996. The most common reactions of dioxetanes have been with phosphorus nucleophiles. The phosphines and phosphites first insert into the 0-0 bond. The phosphorane intermediate then collapses to afford phosphine oxide or the trialkylphosphate and the corresponding epoxide (Scheme 6). The same is true for the treatment of a-peroxy lactones with phosphines and phosphites except that the so-formed a-lactone intermediate undergoes decarboxylation and ultimately furnishes a ketone <1997JOC1623>. 

Investigation of the reaction of 3,3-disubstituted 1,2-dioxetanes with various heteroatom nucleophiles establishes the SN2 reactivity of these strained peroxides [134]. As reported in Sch. 80 for dioxetane 141, the sterically exposed oxygen of the peroxide bond becomes the site of nucleophilic attack to produce an anionic or zwitterionic adduct 142. Different reaction channels become available for the intermediate which depend on the chemical nature of the nucleophile. So epoxy alcohol 143, p-hydroxy hydroxylamine 144, diol 145, cyclic carbonate 146, and cyclic sulfite 147 can be obtained (Sch. 80) [134],... 

However, formation of the dioxetane intermediate might be preceded by the formation of a peroxide intermediate, which could be trapped as an addition product with an alcohol or an amine (half-life of the peroxide (R = Me) is ca 20 min at 30 °C in CDC13)19. As neither dioxetanes nor peroxiranes are known to react with nucleophiles, an initially formed peroxide zwitterion is probably the species intercepted by a nucleophile or competitively rearranges to a dioxetane (Scheme 5). 

Besides their thermal decompositions into carbonyl fragments, the chemistry of 1,2-dioxetanes is quite limited. Obviously one of the reasons for this is the great lability of the dioxetane ring system. However, a number of reactions with nucleophiles and electrophiles have been performed and will be briefly reviewed here. 

Reaction with sulfur nucleophiles has also been investigated. For example, dioxene-dioxetane (Eq. 76) gave on reaction with diphenylsulfide, the dioxene-epoxide and the acetal of benzil. On the other hand, the reaction of dimethyl-1,2-dioxetane with dimethyl sulfoxylate gave the sulfurane (Eq. 77). ... 

Adam, W., Fuchs, R., and Kirchgassner, U., Functionalized 1,2-dioxetanes as potential photogenotoxic agents. 1,2-dioxetanes with electrophilic chemical handles for the functionalization with protic nucleophiles. Chem. Ber. 120, 1565-1571 (1987). 

Tetrasubstituted-l,2-dioxetanes (9.26) are electrophilic reagents that form stable adducts with nucleophiles, e. g., with carbanions (Adam and Heil, 1992). Adam and Treiber (1994) demonstrated that the sterically less hindered oxygen atom of these dioxetanes add at the C(a)- and at the N()ff)-atom of diazoalkane to form the 0,N-dipole (9.27) and the 0,C-dipole (9.29), respectively. Dediazoniation and cycliza-tion of 9.27 leads to 1,3-dioxolanes (9.28) and that of 9.29 to fragmentation, i.e., to the ketones 9.30 and 9.31 (9-18). 

In contrast, the a-peroxy lactones, also members of the dioxetane family, display a higher reactivity toward nucleophiles, in view of the inherent polarization of the peroxide bond by the carbonyl functionality. Consequently, the nucleophilic attack is expected to take place at the more sterically hindered but more electrophilic alkoxy-type oxygen atom of the peroxide bond. A recent detailed study of the oxidation of various di-, tri-and tetrasubstituted alkenes 6 with dimethyl a-peroxy lactone (7) revealed, however, much complexity, as illustrated in Scheme 7 for R = CH3, since cycloaddition (8), ene-reaction (9 and 10) and epoxidation (11) products were observed. In the presence of methanol, additionally the trapping products 12 and 13 were obtained, at the expense of the polyester 14. The preferred reaction mode is a sensitive function of the steric demand imposed by the attacking alkene nucleophile. 

The mechanism of 1,2-dioxetane formation in the reaction of lucigenin with hydrogen peroxide suggests a nucleophilic attack of peroxide anion on position 9 of the acri-dinium ring, followed by deprotonation and subsequent formation of 1,2-dioxetane ring... 

As was noted in Scheme 12, distonic radical cations obtained from cyclopropane bond cleavages add oxygen rapidly, producing products with two CO bonds. So do some alkene radical cations. Addition of O2 to an alkene radical cation is formally a nucleophilic attack by the single alkene n electron on O2, and oxidizes both carbon atoms (an alkene radical cations has formally two -f carbons, and the adduct a 1+ and an oxygen-bound carbon). The oxygenation of the radical cation of bia-damantylidine (96) leads to dioxetanes such as 98 in chain reactions (see Scheme 21) [110]. The reactions may be initiated electrochemically or photochemically, but tris(o,p-dibromophenyl)amine hexafluoroantimonate, 97, is a superior catalyst for the dark reaction of certain tetraalkylalkenes, with turnovers up to ca. 800 at... 

Superoxide ion reacts with vicinal dibromoalkanes to form aldehydes (Table 7-1), The mechanism proposed for these reactions (Scheme 7-5) is a nucleophilic attack on carbon, followed by a one-electron reduction of the peroxy radical and nucleophilic displacement on the adjacent carbon to form a dioxetane that subsequently cleaves to form two moles of aldehyde.21... 

Guarini, A., and P. Tundo, Rose Bengal Functionalized Phase-Transfer Catalysts Promoting Photoxidations with Singlet C gen. Nucleophilic Displacements on Dioxetanic and Endoperoxidic Intermediates, J. Org. Chem., 52, 3501 (1987). 

An interesting approach to 1,4,22 -dioxaphosphinanes has been reported. Methyl-substituted 1,2-dioxetans (357) react with triphenylalkylidenephosphoranes (358) by nucleophilic attack of the ylide carbon at the peroxide bond of (357) the 2,2,2-triphenyl-1,4,22 -dioxaphosphinanes (360) are... 

Besides thermal and photolytic decompositions of 1,2-dioxetanes, there has been relatively little other chemistry explored with these high energy molecules. Several nucleophilic substitution reactions have been documented. 

Interesting chemistry has been discovered by Bartlett and co-workers124 in the reaction of 1,2-dioxetane lb with trivalent phosphorus nucleophiles. At low temperature the cyclic phosphorane 62 could be isolated [Eq. (49)], which at 55° smoothly decomposed into... 

Analogous chemistry was observed by Denney and co-workers11 when divalent sulfur nucleophiles were allowed to react with dioxetanes. Thus, diphenyl sulfide gave epoxide and diphenyl sulfoxide, presumably via the sulfurane (63), as shown in Eq. (50). When the ligands on the sulfur nucleophile were alkoxy groups, NMR evidence for the intermediary sulfuranes was provided. Similar results were observed by Wasserman... 

The catalytic mechanism for IDO and TDO is believed to proceed via the formation of a hydroperoxide at C-3 of the indole ring, followed either by dioxetane formation or Criegee rearrangement, as shown in Figure 26. Formation of the hydroperoxide could either take place via nucleophilic attack upon heme-bound dioxygen, or via the formation of an indole radical, followed by recombination with iron(III)-superoxide. The structure of human IDO was published in 2006. Site-directed mutagenesis of active site residues has established that Phe-226, Phe-227, and Arg-231 contribute toward catalysis. ... 

Electron-donor (nucleophilic) olefins react with 1Oa to give dioxetans in competition with, or to the exclusion of, formation of allylic hydroperoxides. Foote and co-workers have reported that photo-oxidation of indenes apparently... 

Even in anhydrous MeOH with NaOMe as catalyst butyric acid (in the case of (6)) was formed in 70% yield. Thus attack on the carbonyl group must be by the peroxide anion (presumably to form a transient dioxetan) rather than the external nucleophile methoxide which would yield the ester (some methyl isobutyrate is formed in very low yield). The reaction scheme is shown below. Blue-green light is visible from the reaction. 

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