Secondary halides oxidation

Detailed investigations of the chemical reactivity of the diketiminato-stabilized phosphenium cations like 28 (Scheme 17) are to date rare and include only two reports dealing with the substitution and reduction of P-halogen-derivatives. Thus, reaction of 28 (X=Br) with sodium hydroxide in toluene was reported to proceed with displacement of the halide substituent at phosphorus and conservation of the heterocyclic ring to give a mixture of bromide and triflate salts containing a P-hydroxy-substituted cation, both of which were isolated in small yields [89], The products are remarkable as they represent one of very few examples of a stable phosphinous acid which does not rearrange to the tautomeric secondary phosphine oxide. Potassium reduction of the P-chloro-substituted derivative 34 produced the... 

This can be used for oxidations in aqneons base of primary alcohols, aldehydes, activated alkyl halides, ctT-diols and nitroalkanes to carboxylic acids, and of secondary alcohols and secondary halides to ketones. 

Phosphinous halides can be prepared from secondary phosphine oxides and phosphorus trichloride. The starting secondary phosphine oxides are easy to handle and can be prepared by treating readily available diethyl or dibutylphos-phite with an organometallic reagent.33... 

The palladium-catalysed cross-coupling of aryl halides or vinyl halides with dialkyl phosphonates (31) to yield dialkyl arylphosphonates and dialkyl vinylphosphonates, respectively, was first reported by Hirao and co-workers 69 the halides used most frequently are bromides and the reaction is stereospecific with haloalkenes. Subsequently, analogous reactions of alkyl alkylphosphinates (32), alkyl arylphosphinates (32), alkyl phosphinates (33), and secondary phosphine oxides (34), replacing [P—H] bonds with [P—C] bonds to yield various phosphinates and tertiary phosphine oxides, have been developed (Figure 7.1). Alkyl phosphinates (33) may be mono- or diarylated as desired by the selection of appropriate conditions. Aiyl and vinyl triflates have also found limited... 

The popularity of the Nef reaction is due in part to the ready availability of nitro compounds. Primary and secondary halides react with sodium nitrite in dimeAyl sulfoxide (DMSO) or dimethylform-amide (DMF) to give useful yields of nitro compounds. Primary amines can be oxidized to nitro compounds with potassium permanganate, m-chloroperbenzoic acitP or ozone. Chlorination of oximes with hypochlorous acid and reduction with magnesium, zinc or hydrogen/lpalladium gives secondary nitro compounds. Stabilized carbanions can be nitrated by treauitent with a nitrate ester, and enol acetates are nitrated by acetyl nitrate to give nitro ketones. ... 

There are some important limitations on the Komblum oxidation, however, as would be expected for a reaction relying on an 5n2 displacement as the first step. Secondary halides are prone to elimination under these conditions. Similarly, if the approach of the DMSO is hindered, e.g. by a 1,3-diaxial interaction, the oxidation proceeds poorly (equation 1). Overoxidation can also occur, at least in steroidal a-bromo ketones (Scheme 3). ... 

Representative examples of the reaction are shown in equations (16)-(20). The method works well for primary allylic and benzylic chlorides and bromides, lliere appear to be no examples of the oxidation of secondary halides to ketones by this method, presumably for reasons of lower reactivity. Neither are there any reports of the oxidation of a-halocarbonyl compounds, which is curious since these would be expected to be good substrates. 

C-Alkylation of the sodio derivative is accomplished by a technique similar to the alkylation of malonic ester. Primary halogen compounds, quaternary ammonium salts,and an alkene oxide have been used as alkylating agents. Alkylation by secondary halides has been less successful. Hydrolysis of the substituted esters to acetylated amino acids is described for leucine (64%) and phenylalanine (83%). Hydrolysis with deacylation has been used to prepare histidine (45%) and phenylalanine (67%). Glutamic acid (75%) is obtained from substituted acylaminomalonates prepared by the Michael condensation of methyl acrylate and the acylated amino esters. ... 

Whereas nucleophilic substitution occurs on heating with water, aqueous potassium carbonate, silver oxide or sodium acetate, elimination reactions occur on heating an alkyl halide with ethanolic potassium hydroxide. Both unimolecular (El) and bimolecular (E2) pathways occur, the former with tertiary and the latter with primary and secondary halides. The reactions of alkyl halides with oxygen nucleophiles are summarized in Scheme 2.3. 

Oxidations with chromic oxide encompass hydroxylation of methylene [544] and methine [544, 545, 546] groups conversion of methyl groups into formyl groups [539, 547, 548, 549] or carboxylic groups [550, 55i] and of methylene groups into carbonyls [275, 552, 553, 554, 555] oxidation of aromatic hydrocarbons [556, 557, 555] and phenols [559] to quinones, of primary halides to aldehydes [540], and of secondary halides to ketones [560, 561] epoxidation of alkenes [562, 563,564, and oxidation of alkenes to ketones [565, 566] and to carboxylic acids [567, 565, 569]. 

The in situ synthesis of organoboranes via reaction of alkyl halides with magnesium in the presence of diborane can also be used to prepare coupled products (equations 20 and 21). Oxidation of the reaction mixture with alkaline silver nitrate leads to good yields of dimeric products. The reaction is successful for primary and secondary halides. A related reaction is the coupling of secondary alkyl halides in the presence of catalytic quantities of thallium salts. This procedure fails for primary alkyl halides and gives modest yields for secondary alkyl halides (equation 22). 

The ratio of the two Zr(IV) products that one observes depends on the nature of RX primary alkyl halides highly favor the formation of the Zr alkyl complex, tertiary alkyl and acyl halides almost exclusively form the Zr dihalide complex, while mixtures of the two organometallic complexes are observed for secondary halides. The coordinated phosphine ligands invariably are quaternized to phosphonium salts, but this conversion is slower than the rates of oxidation of Zr. 

Oxidation. Oxidation of alkyl halides by DMSO requires high temperatures (100-150°), and yields are relatively low except for primary iodides (1, 303). Epstein and Ollinger11 find that halides can be oxidized to carbonyl compounds by DMSO at room temperature (4-48 hours) in the presence of silver perchlorate as assisting agent. Chlorides are relatively unreactive, but bromides and iodides are oxidized relatively easily. Yields are higher with primary halides than with secondary halides. Cyclohexyl halides are oxidized to only a slight extent to cyclohexanone, the main product being cyclohexene, formed by elimination. 

A simple method of preparing tertiary phosphine oxides is to alkylate, by alkyl halides, the metalated secondary phosphine oxides which are intermediates 425,426... 

From Secondary Phosphine Oxides and Sulphides.—A novel reaction of phosphinates with sodium bis-(2-methoxyethoxy)aluminium hydride has been used to synthesize phosphine oxides, The complex hydride is believed to generate a secondary phosphine oxide anion from the phosphinate, and this ion may be trapped by an alkyl halide to give a phosphine oxide. The reaction is general for tetrahedral esters, and is... 

If the intermediate from the first stage was treated with an alkyl halide, a tertiary phosphine oxide was isolated along with the secondary phosphine oxide. The case with hexyl Grignard reagent is illustrative. When ethyl Grignard reagent was added to diethyl hydrogenphosphonate... 

In the presence of a Lewis acid, silyl enol ethers can be alkylated with reactive secondary halides, such as substituted benzyl halides, and with chloromethylphenyl sulfide (ClCH2SPh), an activated primary halide. Thus, reaction of the benzyl chloride 10 in the presence of zinc bromide with the trimethylsilyl enol ether derived from mesityl oxide allowed a short and efficient route to the sesquiterpene ( )-ar-turmerone (1.22). Reaction of ClCH2SPh with the trimethylsilyl enol ethers of lactones in the presence of zinc bromide, followed by 5-oxidation and pyrolytic ehmination of the resulting sulfoxide (see Section 2.2), provides a good route to the a-methylene lactone unit common in many cytotoxic sesquiterpenes (1.23). Desulfurization with Raney nickel, instead of oxidation and elimination, affords the a-methyl (or a-alkyl starting with RCH(Cl)SPh) derivatives. ... 

Primary and secondary halides are oxidized to the corresponding aldehydes or ketones, respectively, in good yields and short reaction times using sodium periodate in DMF at reflux (eq 35). In an interesting result, a one carbon moiety is lost whenphenacyl bromide furnishes benzaldehyde as a single isolated product un-... 

The similar reaction of diarylphosphine oxides with aryl halides and triflates has been used more recently to prepare a variety of ligands for asymmetric catalysis. Many of these reactions involve additions of secondary phosphine oxides to di- or monotriflates derived from binaphthol because the triflates are more accessible than 2,2 -l,l -dibro-mobinaphthol. Workers at Syntex described a procedure to use the ditriflate of binaphthol to prepare mixed phosphine oxide, hydroxo ligands, and the monophosphine oxide, bi-naphthyldiphenylphosphine oxide. Hayashi then developed a route to a number of chiral monodentate phosphine ligands with a 2-(diphenylphosphino)-2 -alkoxy-l,l -binaphthyl structure (Eq. Reaction of the ditriflate with diphenylphosphine oxide in the... 

Phosphinous acids represent a promising new class of phosphorus ligands for Suzuki cross-couphngs of unactivated aryl chlorides. The hydrolysis of diorgano-phosphorus halides generates secondary phosphine oxides in an equilibrium with their less-stable phosphinous acid tautomers (Equation 2.29). 

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