Secondary amides, synthesis

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

Equations 1-10 illustrate some mild methods that can be used to cleave amides. Equations 1 and 2 indicate the conditions that were used by Woodward and Eschenmoser, respectively, in their synthesis of vitamin B12. Butyl nitrite, nitrosyl chloride, and nitrosonium tetrafluoroborate (NO BF4 ) have also been used to cleave amides. Since only tertiary amides are cleaved by potassium -butoxide (eq. 3), this method can be used to effect selective cleavage of tertiary amides in the presence of primary or secondary amides.(Esters, however, are cleaved by similar conditions.) Photolytic cleavage of nitro amides (eq. 4) is discussed in a review. 

In a useful extension to the Meth-Cohn quinoline synthesis, pyridoquinolin-2-ones 27 are readily prepared in a one-pot procedure by sequential treatment of an acetanilide 3, firstly with the Vilsmeier reagent from DMF and POCI3 to afford the intermediate 16, which is then further reacted in situ with another secondary amide. ... 

Brown DS, Revill JM, Shute RE. Merrifield Alpha-Methoxyphenyl (MAMP) Resin A new versatile solid support for the synthesis of secondary amides. Tetrahedron Lett 1998 39 8533-8536. 

Like with primary amides (see Sect. 4.2.1), bacterial amidases can be useful for the transformation of secondary amides in drug synthesis. Bacterial amidases have been extensively studied in the presence of penicillins and other [i-lactam antibiotics, for which two hydrolysis reactions are possible. One of these is carried out by enzymes known as penicillinases or /3-lactamases that open the /3-lactam ring this aspect will be discussed in Chapt. 5. The second type of hydrolysis involves cleavage of the side-chain amide bond (4.47 to 4.48) and is carried out by an enzyme called penicillinacylase (penicillin amidohydrolase, EC 3.5.1.11). Both types of hydrolysis inactivate the antibiotic [29-31],... 

Pyridines bearing secondary amides may be lithiated with n-BuLi at —78°C with tertiary amides the optimum conditions are LiTMP, DME, 5-15 min (Scheme 23) . Lithiated tertiary amidopyridines react well with carbonyl electrophiles but poorly with alkylating agents. Lithiation of the bromopyridine 49 with LDA is a key step in the synthesis of eupoluramine . ... 

Lactams are another interesting class of compounds that have been thoroughly explored by Zhang [25]. Methods that are typically used in the synthesis of nonracemic lactams involve C-N bond formation of substrates with preset chiral centers. The Alder-ene carbon-carbon bond forming strategy allows for chiral centers to be set without the use of other pre-existing chirality in the substrate. Initially, enynes with secondary amide tethers were studied but no cyclization was observed. Zhang reasoned that the favored transoid conformation of the secondary amide prevents the necessary conformation required for cyclization (Scheme 8.2). 

Alternatively, starting this time from aryl isocyanides, the secondary amide can be activated by conversion into an imide by the treatment with B0C2O [29, 38,41]. This strategy was employed in the synthesis of compounds 15,17 and 19 [29], and is particularly appropriate for solid-phase library synthesis. 

Synthesis of secondary amides via the oxidative coupling (dehydrogenation) of primary alcohols R CH3(OH) and primary amines R (CH3)NH3 to the amides... 

Reich SH, Melnick M, Pino M, Fuhry MA, Trippe AJ, Appelt K, Davies JF, Wu B-W, Musick L. Structure-based design and synthesis of substituted 2-butanols as nonpeptidic inhibitors of HIV protease secondary amide series. J. Med. Chem. 1996 39 2781-2794. 

Amide hydrolysis is carried out in water and requires some solubility of the substrate, while amide synthesis is carried out in a suitable solvent with an acylating reagent. The substrates are most commonly primary amines, with few reports of secondary amines [5]. The acylating reagent is selected to be unreactive toward the amine in the absence of the enzyme, but must be compatible with the enzyme providing acceptable rates. Enzymes that selectively hydrolyze or acylate the (R) amide or primary amine are most common, for example. Pseudomonas fiuorescens... 

The Willgerodt reaction allows amide synthesis from aromatic aldehydes or ketones, using a secondary amine and a thiating agent. The mechanism of the more convenient Kindler modification, employing sulfur and morpholine, has been reviewed.281... 

A simple example of using combinatorial chemistry to prepare a library of small molecules is the synthesis of secondary amides (9.46) from primary amines (9.44) and acid chlorides (9.45) (Scheme 9.4). Amides of type 9.46 have two points of variation the R-group of the amine and the R -group from the acid chloride. A third point of variation may be introduced by V- a I k y I ation with an alkyl halide (9.47) to form a tertiary amide (9.48). With just 15 building blocks—five amines, five acid chlorides, and five alkyl halides—125 (53) different tertiary amides may be prepared. 

The procedure developed by Elmorsy has been adjusted to the synthesis of 1,5-disubstituted tetrazoles from secondary amides <2000CHE878, 2004RJ0443, 2004RJ01528, 2004RJ01532>. By analogy with the mechanism in Scheme 65, the formation of 1,5-disubstituted tetrazoles 5 from the secondary amides may be presented as going through an intermediate imidoyl azides 150 (Scheme 66). 

In 1991, Duncia et al. reported on the synthesis of 1,5-disubstituted tetrazoles from secondary amides and azidotrimethylsilane under the conditions of the Mitsunobu reaction <1996CHEC-II(4)621>. The Mitsunobu protocol was successfully applied to the conversion of AT(cyanoethyl)amide into tetrazole 510. The tetrazole ring in this event forms by the cyclization of an imidoyl azide (not shown in the scheme) whose precursor is the phosphonium imidate 509 (Scheme 67) <2000JME488>. 

Microreactors offer a radical alternative platform for chemical synthesis, normally undertaken in macroscale flasks [68-70]. When reactions in microcapillary-scale reactors are compared with those in flask-scale batch reactors, they have been shown to offer yield, rate or selectivity advantages in a diversity of reactions schemes including carbonylative cross-coupling of arylhalides to secondary amides [32],... 

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