Tertiary amides, reduction

Our investigations showed that in mixed melts of eutectic composition carbamide-NH4(K)Cl, the oxidation and reduction of melt constituents take place mainly independently of each other. The anodic process at platinum electrodes in the range of potentials below 0.9V is associated with the direct oxidation of carbamide to secondary and tertiary amide compounds, accumulation of ammonium ions in the melt, and evolution of the same gaseous products as in carbamide electrolysis [8], The cathodic process is accompanied by the formation of ammonia, CO, and C02, i.e. of the same products as in pure- carbamide electrolysis. In contrast to carbamide melt, a large amount of hydrogen appears in the cathode gases of the mixed melt, and in the anode gases of the carbamide-KCl melt, the presence of chlorine has been established at potentials above 0.9V. In the... 

The conjugate hydrosilylation of a,/S-unsaturated amides can be carried out in high yields with PhSiH3/Mo(CO)6 (Eq. 297)450 or Ph2SiH2/ZnCl2/Pd(PPh3)4.436 Primary, secondary, and tertiary amides are equally reactive 450 The reduction of a J3 -tribu ty I s (annyl-a, /3 -unsaturatcd tosylamide is also reported 469... 

The applications of polyoxometalates in catalytic dehalogenation of halocar-bons have been succinctly reviewed by Hill and coworkers [188]. This reaction involves the photocatalytic transformation of organic halides coupled with the oxidation of sacrificial organic reductants (secondary alcohols or tertiary amides) (Eq. (9)) [189, 190] ... 

Scheme 4.1. Reduction of a tertiary amide with the Schwartz reagent.

General procedure for reduction of tertiary amides to aldehydes using the Schwartz reagent... 

The reluctance of tertiary amides to undergo hydrolysis, especially those produced in the Birch reduction-alkylation with a quaternary center next to the carbonyl group, has inspired the development of a variety of intramolecular transacylation reactions as illustrated by the cleavage of the SEM ether in 16... 

The stoichiometry determines the ratios of lithium aluminum hydride to other compounds to be reduced. Esters or tertiary amides treated with one hydride equivalent (one fourth of a molecule) of lithium aluminum hydride are reduced to the stage of aldehydes (or their nitrogen analogs). In order to reduce an ester to the corresponding alcohol, two hydride equivalents, i.e. 0.5 mol of lithium aluminum hydride, is needed since, after the reduction of the carbonyl, hydrogenolysis requires one more hydride equivalent. 

Reduction of amides to aldehydes was accomplished mainly by complex hydrides. Not every amide is suitable for reduction to aldehyde. Good yields were obtained only with some tertiary amides and lithium aluminum hydride, lithium triethoxyaluminohydride or sodium bis 2-methoxyethoxy)aluminum hydride. The nature of the substituents on nitrogen plays a key role. Amides derived from aromatic amines such as JV-methylaniline [1103] and especially pyrrole, indole and carbazole were found most suitable for the preparation of aldehydes. By adding 0.25 mol of lithium aluminum hydride in ether to 1 mol of the amide in ethereal solution cooled to —10° to —15°, 37-60% yields of benzaldehyde were obtained from the benzoyl derivatives of the above heterocycles [1104] and 68% yield from N-methylbenzanilide [1103]. Similarly 4,4,4-trifluorobutanol was prepared in 83% yield by reduction of N-(4,4,4-trifluorobutanoyl)carbazole in ether at —10° [1105]. 

For the same reason that they resist attack at C=0 by alkyllithiums, tertiary amides can be extremely difficult to hydrolyse—almost impossible in the case of —CONPr-i2, and even —CONEt2 amides are stable to 6 M HCl for 72 h. For reactions in which an amide is not required in the product, it is preferable to use —CONEt2 and to remove the amide from the product by reduction, as in Scheme 14 (note the cooperative effect of the amide and methoxy group in the first step) . Hydrolysis can also be achieved via an imidate (see Scheme 12). 

There are several reports of methods that will selectively reduce a tertiary amide in the presence of a secondary amide[59]. The secondary lactam of 101 was protected as the lactim ether 107 and treated with diborane however, the spectral characteristics of the major products isolated were consistent with reduction of both the tertiary amide and the lactim ether. In 1991 Martin et al. [60] successfully used alane to reduce a tertiary amide in the presence of an oxindole (secondary amide) relying on the known rate difference for reduction between these two groups [61]. 

However, initial experiments with this reagent gave poor results, with the secondary amide undergoing reduction along with the tertiary amide. Compound 101 [and 107, Fig. (29)] is sufficiently twisted such that the gem-dimethyl groups effectively block the (j-face of the tertiary amide, leaving the a-face relatively unencumbered. However, a modification of the alane procedure [60], proved satisfactory for this transformation. The piperazinedione 101 was pretreated with AlEt3, with the expectation that this Lewis acid would form a complex with the more exposed secondary lactam [106, Fig.(29).] and leave the tertiary lactam accessible for 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. 

Reduction of esters, nitriles, and amides. These groups are rapidly reduced by horanc-dimcthyl sulfide in refluxing THF (b.p. 67°) if the dimethyl sulfide (b.p. 38°) is removed as liberated. Under these conditions, the reagent is comparable to uncomplexed diborane. Reduction of secondary and tertiary amides is best effected in the presence of boron trifluoride etherate otherwise, excess reagent is utilized for formation of complexes with the products. 

Mechanisms of sodium borohydride reactions with primary, secondary, and tertiary amides have been investigated both at the B3LYP/6-31+- -G(d,p)//B3LYP/6-31G(d,p) and B3LYP/6-31++G(d,p)//HF/6-31G(d,p) levels of theory. The predicted structures of the key intermediates were then confirmed by experiment.317 For chemoselective reductions of a-substituted and aromatic esters with sodium borohydride, agreement between experimental results and theoretical computations at the B3LYP/6-31+-1-G(d,p)//HF/6-31G(d,p) levels of theory have been reported.318... 

The pungency of the fruits of black pepper (Piper nigrum Piperaceae), a widely used condiment, is mainly due to the piperidine alkaloid piperine (Figure 6.24). In this structure, the piperidine ring forms part of a tertiary amide structure, and is incorporated via piperidine itself, the reduction product of A1 -pipcridcine (Figure 6.22). 

Reduction Nitriles and amides can be easily reduced to alkylamines using lithium aluminium hydride (LiAlH4). In the case of a nitrile, a primary amine is the only possible product. Primary, secondary, and tertiary amines can be prepared from primary, secondary and tertiary amides, respectively. 

Also carboxylic acids (Eq. 91) and tertiary amides (Eq. 92) undergo reduction via hydrosilylation to give the corresponding alcohols and amines, respectively [148],... 

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. 

Borch RF (1968) A New Method for the Reduction of Secondary and Tertiary Amides. Tetrahedron Lett 61... 

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. 

Secondary or tertiary amides have been converted to aldehydes with Ph2SiH2 in the presence of Ti(0-f-Pr)4 (Eq. 133) [327]. It has been proposed that a species such as HTi(0-f-Pr)3 is the active reductant in this reaction. A similar reduction of lactones to lactols has also been reported [328]. 

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. ... 

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