Amides, secondary

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. 

Grafting can also occur in the amide nitrogen, either through an anionic-type mechanism which is beheved to operate when ethylene oxide [75-21 -8] and similar copolymers are grafted to polyamides, or through a polycondensation mechanism when secondary amides are formed as graft copolymers (70). 

Spectral Characteristics. The iafrared stretching frequency of the penicillin P-lactam carbonyl group normally occurs at relatively high frequencies (1770 1815 cm ) as compared to the absorptions for the secondary amide (1504-1695 cm ) and ester (1720-1780 cm ) carbonyl groups. 

H-Bonding, Strongly Associative (HBSA) Water Primary amides Secondary amides Polyacids Dicarboy lic acids Monohydro) acids Polyj)henols Oximes Hydroj laniines Amino alcohols Polyols... 

NO BF )" have also been used to cleave amides. Since only tertiary amides are cleaved by potassium r-butoxide (eq. 6), 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. 7) is discussed in a review. ... 

The present authors have found that the preparation of 7V-acetyl aziridine derivates provides the most secure method of differentiating aziridines from primary amines which are alternate reaction products in a number of cases. The infrared spectra of the former derivatives show only a peak at 1690 cm" for a tertiary amide peaks at ca. 3440 and 1530 cm" indicative of a secondary amide are absent. Acetylation also shifts the aziridine ring protons to a lower field in the NMR by ca. 1 ppm relative to the parent aziridine. The A"-acetyl aziridines are hydrolyzed with 3% methanolic potassium hydroxide. " Published NMR spectra of several 16j5,17j -aziridines reveal resonance patterns resembling those of the respective epoxides. " ... 

For primary and secondary amides CUCI2, glyoxal, H2O, pH 3.5, reflux, 92% yield. "... 

In these papers, the carboxylic acid to be protected was a stable, unsubstituted compound. Harsh conditions were acceptable for both formation and cleavage of the amide. Typically, a simple secondary amide is very difficult to cleave. As the pKa of the conjugate acid of an amide decreases, the rate of hydrolysis of amides derived from these amines increases. The dimethylamide of a cephalosporin was prepared as follows using 2,2 -dipyridyl disulfide. ... 

The trityl group was introduced on a primary amide, RCONH2, in the presence of a secondary amide with TrOH, AC2O, H2SO4, AcOH, 60°, 75% yield. It is stable to BOC removal with 1 N HCl in 50% isopropyl alcohol, 30 min, 50°, but can be cleaved with TFA. The following table gives the cleavage rates with TFA for a number of protected primary amides. 

Interestingly, when utilizing a secondary amide, these reactions are limited by the simultaneous formation of the corresponding pyrrole as exemplified in the transformation of 46 to thiophene 47 and pyrrole 48... 

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. ... 

Reaction of Primary or Secondary Amides with Aldehydes or Ketones... 

The most straightforward preparation of A-(l-hydroxyalkyl)amides (or carbamates) involves addition of primary or secondary amides (carbamates) to aldehydes or ketones. This is an equilibrium process in which formation of the adduct is usually disfavored, except for two special cases ... 

Secondary amides also undergo the McLafferty rearrangement ... 

Whereas primary amides such as butyric acid amide, on heating to 140-150 °C with triethylsilane 84b and ZnCl2, give, e.g., 78% butyronitrile 1853 and 95% HMDSO 7 [79], the secondary amide benzanilide is readily converted into 90% O-triethylsilyl imino ether 1854 [80] whereas the tertiary amide N,N-diethylacetamide... 

In classical organic chemistry, nltrosamlnes were considered only as the reaction products of secondary amines with an acidified solution of a nitrite salt or ester. Today, it is recognized that nitrosamines can be produced from primary, secondary, and tertiary amines, and nltrosamides from secondary amides. Douglass et al. (34) have published a good review of nitrosamine formation. For the purposes of this presentation, it will suffice to say that amine and amide precursors for nitrosation reactions to form N-nitroso compounds are indeed ubiquitous in our food supply, environment, and par-... 

Secondary amides can be alkylated on nitrogen by using sodium hydride for deprotonation, followed by reaction with an alkyl halide.62... 

Neutral tertiary and secondary amides react with very reactive alkylating agents, such as triethyloxonium tetrafluoroborate, to give O-alkylation.63 The same reaction occurs, but more slowly, with tosylates and dimethyl sulfate. Neutralization of the resulting salt provides iminoethers. 

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... 

Lithiation has also been observed for deprotonated secondary amides of 3-phenylpro-panoic acid. 

Secondary amides do not undergo the amidation except when cyclic, equation 3. 

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... 

MAMP (Merrifield, Alpha-MethoxyPhenyl) resin 44 is an alternative to aldehyde linkers to construct TV-substituted amides [53], Nucleophilic displacement of the benzylic chloride with an amine followed by acylation yielded a secondary amide which was released upon a low ( 10%) concentration of TFA (Scheme 16). 

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. 

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