Alkylation of amides and related compounds

The acidity of amides (pKa 23) is such that it is reasonable to postulate that, in contrast with the analogous reactions of the amines, the phase-transfer catalysed N-alkylation proceeds by way of the initial generation of the amidic anion under basic conditions. It has been demonstrated that the preformed sodium salt of benzamide can be solubilized in toluene upon the addition of Aliquat [1 ] and further evidence [2] has been provided for the postulated deprotonation under the two-phase conditions in which it is assumed that the deprotonation occurs by an interfacial mechanism (see Chapter 1). 

Mono-A-alkylation of the amides occurs under relatively mild liquiddiquid two-phase conditions (Table 5.10), using concentrated aqueous sodium or potassium hydroxide. Under soliddiquid conditions with sodium hydroxide-potassium carbonate or potassium hydroxide, or by using super-saturated aqueous potassium or sodium hydroxide, it is possible to control the reaction to obtain either the mono-or dialkylated derivatives f2-4]. Soliddiquid two-phase conditions also provide the most effective route to mono-AI-alkylalion of weakly acidic aliphatic amides, but it has been suggested that the procedure is not sufficiently selective for the monoalkylation of the more acidic amides [4], 

Method A The haloalkane (0.06 mol) in PhH (10 ml) is added dropwise over a period of ca. 1.5 h to the amide (0.05 mol) and TBA-HS04 (1.7 g, 5 mmol) in a stirred two-phase system of aqueous NaOH (50%, 50 ml) and PhH (50 ml) under reflux. Stirring is continued for a further 2.5 h under reflux and the mixture is then cooled to room temperature and H20 (30 ml) is added. The organic phase is separated, washed with H20 until neutral, dried (MgS04), and evaporated under reduced pressure to yield the alkylated amide. 

Method C The carboxamide (10 mmol), TBA-Br (96 mg, 0.3 mmol), and KOH (0.85 g) are intimately mixed for 15 min at room temperature. The alkylating agent (12.5 mmol) is added and the mixture is stirred at 60-80°C. CH,CL (50 ml) is added to the cooled mixture, filtered, and evaporated to yield the mono-N-alkylated carboxamide. 

---

AIH3 reduces a,p-unsaturated amides to allylic amines [BK5] (Figure 3.87). a,p-Unsaturated amides and related compounds such as 3.224 are reduced to saturated amides by Li or K(5-Bu)3BH [Gl, GL7]. Trapping by alkyl halides has been described in many cases, such as 3.225 [KS1 ] (Figure 3.87). Conjugate reduction of... 

Related to a class of a,y-diketoacids that has previously been shown to bind to NS5B [64], is the mono-ethyl ester of meconic acid 25. This compound was identified as a selective inhibitor of NS5B HCV polymerase (IC50 = 2.3 pM) and is competitive with the diketoacids. SAR studies have demonstrated the requirement for the carboxylic acid. A variety of different permutations of esters, acids, amides, and decarboxylated compounds were prepared without any improvement in binding affinity or in the cell-based replicon assay [65]. The 4,5-dihydroxypyrimidine-6-carboxylic acids, a hybrid of the a,y-diketoacids and meconic acid, envisioned as chelators of the essential Mg2+ ions in the active site of NS5B, are also active in the polymerase assay (26, IC5o = 5.8pM). While alkylation of the phenol of the hybrid is tolerated, methylation of the heterocyclic hydroxyl groups or the carboxylic acid, as well as decarboxylation, leads to... 

Interest in the uses of HMPT has also been maintained, but a warning has been issued (by the E. I. du Pont de Nemours Company and the U.S. National Institute for Occupational Safety and Health) about its potential acute toxicity. HMPT has been used in the synthesis of 2,4-bis(dimethylamino)qui nolines,9 8 as a solvent for reactions between carbonyl compounds and sulphur," for the conversion of iV-benzylcarbox-amides into 3-phenylpropionitriles,100 in reactions between metals or organometallic compounds with a variety of organic substrates,101 and as a solvent for alkylation reactions of /J-keto-esters and related compounds in which the alkylation reaction is accompanied by de(alkoxycarbonylation) (Scheme 7).102... 

Primary and secondary amides and thioamides react with alkyl chlorofoimates with loss of CO2 or COS, forming iminium chlorides (82 equation 52). In some cases this method is complementary to the Pinner imido ester hydrochloride synthesis. The iminium salt (83 Scheme 6) formed by action of ethyl chloroformate on DMF is labile and decomposes rapidly to ethyl chloride. If the reaction is performed in the presence of NaBp4, the iminium salt (85) is isolable. Aryl chlorofoimates react in the same fashion with DMF or DMA, but in these cases the aryloxymethyleneiminium compounds are fairly stable, so this reaction is an important method for the preparation of compounds of this type. - Succinic acid monoamides, phthalic acid monoamides and related compounds are cyclized to iminium salts (86 equation 53) by treatment with acetic anhydride and HC104. ° With the aid of trifluoromethanesulfonic anhydride lactams and amides can be converted to dication ether salts (87) and (88 Scheme 7).22i.222... 

Asymmetric Birch reductions and reductive alkylations using 2-substituted benz-amides and pyrrolobenzodiazepine-5,ll-diones with an (X)-prolinyl chiral auxiliary have provided routes for the synthesis of a wide variety of natural products and related compounds. ... 

In addition to tert-butylimines, aldoximes and related compounds are efficient substrates for isoquinoline formation. Silver(I) and gold(I) complexes promote 6-endo-dig cyclization of benzaldoximes 34 to produce isoquinoline-Ai-oxides 35 (Scheme 19.9) [11], A related synthesis of isoquinolinium-2-yl amides 37 using hydrazide derivatives 36 was also reported [12], The interesting synthetic potential of 0-alkyl oxime redox chemistry was demonstrated in isoquinoline synthesis using 38 and AgOTf (10 mol %)/TfOH (5 mol %) [13],... 

---