Ketones tertiary amide reduction

The at complex from DIB AH and butyllithium is a selective reducing agent.16 It is used tor the 1,2-reduction of acyclic and cyclic enones. Esters and lactones are reduced at room temperature to alcohols, and at -78 C to alcohols and aldehydes. Acid chlorides are rapidly reduced with excess reagent at -78 C to alcohols, but a mixture of alcohols, aldehydes, and acid chlorides results from use of an equimolar amount of reagent at -78 C. Acid anhydrides are reduced at -78 C to alcohols and carboxylic acids. Carboxylic acids and both primary and secondary amides are inert at room temperature, whereas tertiary amides (as in the present case) are reduced between 0 C and room temperature to aldehydes. The at complex rapidly reduces primary alkyl, benzylic, and allylic bromides, while tertiary alkyl and aryl halides are inert. Epoxides are reduced exclusively to the more highly substituted alcohols. Disulfides lead to thiols, but both sulfoxides and sulfones are inert. Moreover, this at complex from DIBAH and butyllithium is able to reduce ketones selectively in the presence of esters. 

The reagent is prepared by reaction or toluene with hexane, ng agent comparable to other lithium VC 1,2-rcduction of enoncs. Reduction proceeds at —78°. However, ketones cr. Esters arc reduced to a mixture of in alcohol can be effected by reduction sodium borohydride. Tertiary amides Ics in generally high yield. Selective ondary halides is possible. 

Reductions. This hydride is a strong reducing agent comparable to other lithium trialkylhydrides. It is superior to DIBAH for selective 1,2-reduction of enones. Reduction of ketones, esters, acid chlorides, and anhydrides proceeds at -78°. However, ketones can be reduced selectively in the presence of an ester. Esters are reduced to a mixture of an alcohol and an aldehyde. Complete reduction to an alcohol can be effected by reduction at -78° with 2 equiv. of 1 and then with excess sodium borohydride. Tertiary amides are reduced by 1 equiv. of the reagent to aldehydes in generally high yield. Selective reduction of primary halides in the presence of secondary halides is possible. 

The free radical chain reaction of 0-acyl thiohydroxamates with a tertiary thiol (r-butyl, triethylmethyl or more recently t-dodecyl) is by far the most wide-ranging reductive decarboxylation method describe to date7 A wide variety of functional groups, including aldehydes, ketones, esters, amides, isolated and conjugated double bonds, are tolerated. Representative examples are given in equations (10) and (11). ... 

Hydroboration. Thexylborane stabilized as the triethylamine complex is not useful for hydroboration, because 2,3-dimethyl-2-butene is displaced with formation of RBH2-N( 2145)3. However, TBDA is a useful reagent for hydroboration and for various reductions. Thus it reacts with 1-octene to form di- -octylthexylborane in quantitative yield. It is comparable to thexylborane-THF for reduction of aldehydes and ketones. Carboxylic acids are reduced to the corresponding alcohol. 10-Undecenoic acid is reduced selectively to undecanoic acid (90% yield). Tertiary amides are reduced very rapidly to f-amines. Acid chlorides and nitriles are reduced very slowly. 

Zinc-modified cyanoborohydride, prepared from anhydrous zinc chloride and sodium cyanoborohy-dride in the ratio 1 2 in ether, selectively reduced aldehydes and ketones but not acids, anhydrides, esters and tertiary amides. In methanol the reactivity paralleled the unmodified reagent. Zinc and cadmium borohydrides form solid complexes with DMF, which may prove to be convenient sources of the reducing agents.Aromatic and a,p-unsaturated ketones were reduced much more slowly than saturated ketones, so chemoselective reduction should be possible. 

Alane (AIH3) and its derivatives have also been utilized in the reduction of carboxylic acids to primary alcohols. It rapidly reduces aldehydes, ketones, acid chlorides, lactones, esters, carboxylic acids and salts, tertiary amides, nitriles and epoxides. In contrast, nitro compounds and alkenes are slow to react. AIH3 is particularly useful for the chemoselective reduction of carboxylic acids containing halogen or nitro substituents, to produce the corresponding primary alcohols. DIBAL-H reduces aliphatic or aromatic carboxylic acids to produce either aldehydes (-75 °C) or primary alcohols (25 C) Aminoalu-minum hydrides are less reactive reagents and are superior for aldehyde synthesis. ... 

Conjugate reduction. The double bond of a,p-unsaturated ketones, esters, nitriles, and tertiary amides are reduced by Dibal-H in the pre.sence of Co(acac)2. 

Finally, the strategy should be of interest because it only requires two reactions steps. This is possible because ketimine isolation is not required, and while rarely discussed can be time consuming, may provide mediocre yield, and unnecessarily lengthens the synthesis of amines. Furthermore, all the reagents are already in use by the pharmaceutical industry, a broad range of ketone substrates are suitable (even aliphatic ketones), either enantiomeric form of the a-chiral amine product can be produced, and the process has been demonstrated on a 20 g scale. The method is compatible with acetonides, ethers, silyl ethers, bulky esters, secondary amides, tertiary amides, carbamates, urethanes, etc. With these beneficial qualities noted, the method suffers when non-branched 2-alkanones are used (product des <75%). In these cases, HCl salt formation allows further enrichment via crystallization, alternatively stoichiometric Yb(OAc)3 can be used during the reductive amination to allow enhanced de. Both of these solutions require additional processing time and/or cost and require consideration before scale-up. 

The reactivity of various functional groups toward 9-BBN thus is classified into five broad categories as (1) very rapid-reduction aldehyde and ketone (2) rapid reduction-reaction olefin, quinone, tertiary amide, acid anhydride, acid chloride, and lactone (3) slow-reduction ester, epoxide, and oxime (4) very slow-reduction carboxylic acid, sulfoxide, and azoxy and (5) inert (no reaction)... 

In summary, the reactivity of various functional groups toward Li 9-BBNH is classified into four broad categories [18] (1) rapid- or fast-reduction aldehyde, ketone, ester, lactone, acylchloride, acid anhydride, epoxide, disulfide, -alkyli-odide, and tosylate (2) slow-reduction tertiary amide, alkylbromide, and aromatic nitrile (3) sluggish-reduction carboxylic acid, aliphatic nitrile, primary amide, nitro and azoxy compounds, and secondary alkylbromide and tosylate (4) inert olefin, oxime, alkylchloride, sulfoxide, azo-compound, sulfide, sulfone, and sulfonic acid. 

The imides, primaiy and secondary nitro compounds, oximes and sulphon amides of Solubility Group III are weakly acidic nitrogen compounds they cannot be titrated satisfactorily with a standard alkaU nor do they exhibit the reactions characteristic of phenols. The neutral nitrogen compounds of Solubility Group VII include tertiary nitro compounds amides (simple and substituted) derivatives of aldehydes and ketones (hydrazones, semlcarb-azones, ete.) nitriles nitroso, azo, hydrazo and other Intermediate reduction products of aromatic nitro compounds. All the above nitrogen compounds, and also the sulphonamides of Solubility Group VII, respond, with few exceptions, to the same classification reactions (reduction and hydrolysis) and hence will be considered together. 

The lower members of the homologous series of 1. Alcohols 2. Aldehydes 3. Ketones 4. Acids 5. Esters 6. Phenols 7. Anhydrides 8. Amines 9. Nitriles 10. Polyhydroxy phenols 1. Polybasic acids and hydro-oxy acids. 2. Glycols, poly-hydric alcohols, polyhydroxy aldehydes and ketones (sugars) 3. Some amides, ammo acids, di-and polyamino compounds, amino alcohols 4. Sulphonic acids 5. Sulphinic acids 6. Salts 1. Acids 2. Phenols 3. Imides 4. Some primary and secondary nitro compounds oximes 5. Mercaptans and thiophenols 6. Sulphonic acids, sulphinic acids, sulphuric acids, and sul-phonamides 7. Some diketones and (3-keto esters 1. Primary amines 2. Secondary aliphatic and aryl-alkyl amines 3. Aliphatic and some aryl-alkyl tertiary amines 4. Hydrazines 1. Unsaturated hydrocarbons 2. Some poly-alkylated aromatic hydrocarbons 3. Alcohols 4. Aldehydes 5. Ketones 6. Esters 7. Anhydrides 8. Ethers and acetals 9. Lactones 10. Acyl halides 1. Saturated aliphatic hydrocarbons Cyclic paraffin hydrocarbons 3. Aromatic hydrocarbons 4. Halogen derivatives of 1, 2 and 3 5. Diaryl ethers 1. Nitro compounds (tertiary) 2. Amides and derivatives of aldehydes and ketones 3. Nitriles 4. Negatively substituted amines 5. Nitroso, azo, hy-drazo, and other intermediate reduction products of nitro com-pounds 6. Sulphones, sul-phonamides of secondary amines, sulphides, sulphates and other Sulphur compounds... 

Polystyrene-bound Weinreb and related amides react with organolithium or Grignard reagents to yield ketones (Table 12.2). Amides have also been used for this purpose, without significant formation of tertiary alcohols. Aldehydes can be prepared on solid phase by reduction of A/,0-dialkylhydroxamates with LiAlH4 (Entry 1, Table... 

Reduction of halides.1 The reagent prepared from NaBH3CN and SnCl2 in a 2 1 ratio does not reduce primary or secondary alkyl halides or aryl halides in ether at 25°, but does reduce tertiary, allyl, and benzyl halides. It is thus comparable to NaBH3CN-ZnCl2 (12, 446). Aldehydes, ketones, and acid chlorides are reduced to alcohols, but esters and amides are inert. 

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