Reduction secondary amides

Amides are reduced to amines because the nitrogen is a poorer leaving group than oxygen at the intermediate stage of the reduction. Primary and secondary amides are rapidly deprotonated by the strongly basic LiAlH4, so the addition step involves... 

Contrary to an alkoxy benzene scaffold, secondary amides were generated via novel aldehyde linker 43 based upon an indole scaffold (Scheme 15) [52]. The indole resin was prepared from indole-3-carboxy-aldehyde in two steps and reacted with amines under reductive conditions to generate resin-bound secondary amines. Treatment of the resin with... 

V-Acylsaccharins prepared by treatment of the sodium salt of saccharin with acyl chlorides were reduced by 0.5 molar amounts of sodium bis(2-methoxyethoxy)aluminum hydride in benzene at 0-5° to give 63-80% yields of aliphatic, aromatic and unsaturated aldehydes [1108 Fair yields (45-58%) of some aliphatic aldehydes were obtained by electrolytic reduction of tertiary and even secondary amides in undivided cells fitted with platinum electrodes and filled with solutions of lithium chloride in methylamine. However, many secondary and especially primary amides gave 51-97% yields of alcohols under the same conditions [130]. 

Diborane is also a useful reagent for reducing amides. Tertiary and secondary amides are easily reduced, but primary amides react only slowly.59 The electrophilicity of diborane is involved in the reduction of amides. The boron coordinates at the carbonyl oxygen,... 

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. 

Reductions in methanol-containing solvents Primary amides can be reduced selectively in the presence of carboxylic acid salts or of secondary amides by LiBHj in diglyme-CH,OH. Esters and epoxides are reduced selectively in the presence of nitro, chloro, or amide groups by LiBHj in ether containing some CH,OH. 

With primary or secondary amides, reaction with LiAlH4 is wasteful in that hydrogen gas is evolved and reduction usually proceeds through to the amine. Nevertheless, it has been shown that r-butylamides, refluxed with an excess of LiAlD4 for 15 h in diethyl ether, give very good yields of deuteriated aldehydes, RCDO. O ... 

Aminocyclopropanes were easily acylated by acid chlorides, isocyanates or isothiocyanates (e.g. Refs 3, 24, 27, 36, 71, 80, 82, 125, 178, 179, 184, 224). Polyureas, polyurethanes or polyamides have been prepared from 1,2-diaminocyclopropane Reduction of the carbonyl group in 423 by lithium aluminum hydride worked quite well for tertiary amides 5,473.495. longer reaction times effected a ring-opening in the case of a secondary amide (423, R = H) (LiAlH4 reduction of secondary... 

It was recently discovered, however, that the bulky protecting group was unnecessary and that efficient 5-exo-trig cyclizations were also possible for secondary amides [45]. It was found that variation of substitution at the a carbon, ipso to the radical formed, and at the acceptor alkene also influenced the efficiency of these cyclizations (Eq. (13.33)). Substitution as in 107 allowed for the formation of 108 as the trans-trans adduct in 40-56% yield. Higher yields were obtained in refluxing toluene. Minor products included the simple reduction product of the halogen and the other diastereomers, which account for about 25% of the overall yield. 

Physical properties of these poly[2] catenaries have been explored in expectation of unique properties based on the catenane structure [239, 246]. While various interesting physical properties were found in polyrotaxane, no characteristic property has been reported in [2]catenanes so far. Although poly[2]catenane has highly mobile moiety due to the mechanical bond, it has been suggested that the connection between [2]catenane subunit restricted the mobility in motion of [2]catenane. Further, intramolecular interaction in [2]catenane subunit may decrease its mobility. Secondary amide-based [2]catenanes can easily be prepared from commercially available compounds. Takata et al. found that the borane-reduction of the [2]catenanes afforded good yields of the amine-based [2]catenanes that can be useful for polymer synthesis [247, 148] (Scheme 51). Although the origi-... 

DIBAH forms ate complexes by action of n-BuLi in hexane [KAl]. In THF-hexane, these ate complexes selectively reduce esters to alcohols, tertiary amides to aldehydes (at 0°C), and a-enones to allyl alcohols (at -78°C). Primary and secondary amides as well as nitriles are unaffected at low temperatures. Primary halides are only reduced at room temperature so these reagents perform selective reductions according to the reaction conditions (Sections 2.1,3.2.5,3.2.9). The uses of DIB AH-Z-Buj A1 ate complexes have also been described [PP2]. 

Secondary amides remain intact in the presence of LiBH4-MeOH [S03], while at lower temperature or in the absence of MeOH, reduction of tertiary amides seldom takes place. However, an exception has been found with fused xanthines [CK4]. 

One important variation of this linker is Barany s B AL linker 13, which contains a formyl group [45-51]. Primary amines [45] and O-protected hydroxylamines [52] are attached to this linker by reductive animation. The resulting secondary amines can be acylated and the corresponding secondary amides or hydroxamates cleaved with TFA. Anilines [53] and enamines [54] can be cleaved without needing to be acylated. 

Several linkers have been developed that rely on the formation of highly stabilized aromatic carbocations. The most frequently used are the eponymous Sieber amide linker 36 [3] and Barany s 3-XAL linker 6 [4]. Both are based on a 3-methoxyxanthine scaffold, which owing to the highly stabilized nature of the xan-thenium ion can provide primary amides on treatment with 1% TFA in DCM, making them excellent tools for the synthesis of protected peptide carboxamides. The Sieber amide resin has also been used to prepare secondary amides via reductive alkylation of the amino group, acylation of the resultant amine and cleavage with dilute TFA [88]. Brill et al. [67] have effected transamination of trifluoroacety-lated Sieber amide resin in good yield. This approach offers considerable potential for the immobilization of amines on this support. 

Reduction of secondary amides by Ru-catalysis to provide simple secondary amines or tertiary amines is dependent on the hydrosilane used. ... 

Reactions 1 and 2 (see Figure 4) demonstrate the quantitative reduction of common secondary amides without any bond cleavage or cycliza-tion as possible side reactions. 

The oxindole construction mentioned above is a variation of an oxindole synthesis developed by Jones. An application of this method to the synthesis of horsfi-line is outlined in Eq. (11) [21], It is notable that whereas the cyclization of 37 is quite efficient, attempts to cyclize amide 38 gave only reduction of the aryl bromide. This is a common problem in radical cyclizations involving secondary amides as the ii-geometry of the amide precludes cyclization. This general problem was first... 

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. 

Reductive alkylation of RAM resin 7c using aldehydes or ketones provides a route to resin-bound secondary amines that is an alternative to the reductive amination of aldehyde resins discussed in Section III. After acylation, secondary amides can be cleaved from the support using TFA-CH2CI2 (1 19) [284]. Ileductive alkylation of the Knorr resin by aldehydes has also been reported. The products were further alkylated and the resulting tertiary amines could be cleaved directly from the support using TFA-CH2CI2 (1 1) [285]. 

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