Amides, tertiary

The conversion of carboxylic acid derivatives (halides, esters and lactones, tertiary amides and lactams, nitriles) into aldehydes can be achieved with bulky aluminum hydrides (e.g. DIBAL = diisobutylaluminum hydride, lithium trialkoxyalanates). Simple addition of three equivalents of an alcohol to LiAlH, in THF solution produces those deactivated and selective reagents, e.g. lithium triisopropoxyalanate, LiAlH(OPr )j (J. Malek, 1972). 

The role of IR spectroscopy in the early penicillin structure studies has been described (B-49MI51103) and the results of more recent work have been summarized (B-72MI51101). The most noteworthy aspect of a penicillin IR spectrum is the stretching frequency of the /3-lactam carbonyl, which comes at approximately 1780 cm" This is in contrast to a linear tertiary amide which absorbs at approximately 1650 cm and a /3-lactam which is not fused to another ring (e.g. benzyldethiopenicillin), which absorbs at approximately 1740 cm (the exact absorption frequency will, of course, depend upon the specific compound and technique of spectrum determination). The /3-lactam carbonyl absorptions of penicillin sulfoxides and sulfones occur at approximately 1805 and 1810 cm respectively. The high absorption frequency of the penicillin /3-lactam carbonyl is interpreted in terms of the increased double bond character of that bond as a consequence of decreased amide resonance, as discussed in the X-ray crystallographic section. Other aspects of the penicillin IR spectrum, e.g. the side chain amide absorptions at approximately 1680 and 1510 cm and the carboxylate absorption at approximately 1610 cm are as expected. 

H-Bond Acceptor (HBA) Acyl chlorides Acyl fluorides Hetero nitrogen aromatics Hetero oj gen aromatics Tertiary amides Tertiary amines Other nitriles Other nitros Isocyanates Peroxides Aldehydes Anhydrides Cyclo ketones Ahphatic ketones Esters Ethers Aromatic esters Aromatic nitriles Aromatic ethers Sulfones Sulfolanes... 

Anhydrous hydroxide also cleaves tertiary amides. 4. RCHCO2R u RCHCO.H, 60-85%... 

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. " ... 

Anhydrous hydroxide also cleaves tertiary amides. 

The OBO ester (2,6,7-trioxabicyclo[2.2.2]octyl ester) can also be prepared from a secondary or tertiary amide (Tf20, CH2CI2, Pyr then 2,2-bis(hydroxymethyl)-l-propanol, 10-88% yield). ... 

Another example is the synthesis of 1,2,5-triazocine 6 11 however, for this tertiary amide there is no uncharged, fully conjugated tautomeric form possible. 

More recently, the same group has used a simpler and more easily prepared chiral ammonium phase-transfer catalyst 99 derived from BINOL in asymmetric Darzens reactions with a-halo amides 97 to generate glycidic tertiary amides 98 (Table 1.13). Unfortunately the selectivities were only moderate to low [48]. As mentioned in Section 1.2.3.1, tertiary amides can be converted to ketones. 

You will see that this structure contains a tertiary amide. 

Primary amines with a-methyl groups Secondary amines unbranched on the a-carbon Tertiary amides... 

The C-6 carboxamide analogues of zanamivir, represented by the general structure 24, provided an avenue to introduce more hydrophobic side-chains onto the dihydropyran scaffold to interact with the hydrophobic regions of subsites S4 and S5 (reviewed in Islam and von Itzstein 2007). The most active tertiary amides (24 = alkyl) showed comparable inhibitory activity to their glycerol side-... 

This procedure, which is based on the work of Ishii and co-workers, affords a mild and general method for converting a wide variety of esters to primary, secondary, and tertiary amides (Table 1). While the preparation of the tertiary amide, N,N-dimethylcyclohexanecarboxamide, described here is carried out in benzene, aluminum amides derived from ammonia and a variety of primary amines have been prepared by reaction with trimethylaluminum in dichloromethane and utilized for aminolysis in this solvent. Although 1 equivalent of the dimethylaluminum amides from amines was generally sufficient for high conversion within 5-48 hours, best results were obtained when 2 equivalents of the aluminum reagent from ammonia was used. Diethyl-aluminum amides can also effect aminolysis, but with considerably slower rates. 

The tertiary amide containing thiourea (Scheme 38 with Ri = R2 = Me) and urea (Scheme 36) were used for a wide range of substrates as depicted in... 

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... 

A series of palmitoylethanolamine-derived inhibitors has been described in the literature as FAAH inhibitors [77, 78]. This study explored the effect of shortening the chain length and replacement of the ethanolamine head group with primary, secondary and tertiary amide alternatives. Of the compounds synthesised and tested, two compounds gave reasonable affinities for FAAH inhibition, palmitoyl-isopropylamide (63) (IC50 = 13/rM) and palmitoyl-allylamide (64) (IC50 = 3.4/rM). Both these compounds had little affinity for either CBi or CB2 receptors. 

Similar reactions have also been observed with tertiary amides and the adducts can be alkylated by tandem SN2 reactions. 

Tertiary amides with carbanion stabilization at the (3-carbon give (3-lithiation.61... 

Tertiary amides 9-1, 9-2, and 9-3 are lithiated at the (3-carbon, rather than the a-carbon by s-butyllithium-TMEDA. It is estimated that the intrinsic acidity of the a-position exceeds that of the (3-position by about 9 pK units. What causes the (3-deprotonation to be kinetically preferred ... 

Phthalimide and N-alkyl-toluenesulfonamide salts are similarly alkylated, and can furthermore be cleaved to polymer-bound secondary and primary amines respectively (57). Potassium pyrrolidonide gives polymer-bound tertiary amide, of interest as a solid cosolvent catalyst ... 

It is the tertiary amides that tend to be the most problematic in terms of proton NMR. They usually exhibit two rotametric forms, the relative proportion of each being determined by both electronic factors and by the relative sizes of the two groups, R1 and R2. Note this in no way implies that the rotameric forms of a tertiary amide could ever be physically separated as the inter-conversion rate between the two forms is generally in the order of seconds. A 50/50 ratio of rotamers is only guaranteed where R =R2 (as in the case of a primary amide where R1=R2=H). Consider the two compounds in Structures 6.14 and 6.15. 

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 microwave-assisted thionation of amides has been studied by Ley and coworkers using a polymer-supported thionating reagent [115]. This polymer-supported amino thiophosphate serves as a convenient substitute for its homogeneous analogue in the microwave-induced rapid conversion of amides to thioamides. Under microwave conditions, the reaction is complete within 15 min, as opposed to 30 h by conventional reflux in toluene (Scheme 7.95). The reaction has been studied for a range of secondary and tertiary amides and GC-MS monitoring showed that it proceeded almost quantitatively. More importantly, this work was the first incidence of the use of the ionic liquid l-ethyl-3-methylimidazolium hexafluorophosphate... 

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