Alkyl with amides

The usual precursor is an appropriately orf/to-disubstituted benzene. Thus, quinazolines (290) can be prepared by the reaction of o-acylanilines (289 R = alkyl) with amides RCONH2. Heating anthranilic acid (289 R = OH) with amides or amidines yields 4-quinazolinones (291). The second nitrogen can be introduced into (289) before ring closure, as in (292) + HC(OEt)3 — (293). 

Without additional reagents N-Alkylation with amide acetals... 

Ketenimines are usually prepared from carboxyHc acid derivatives such as amides and imino chlorides via elimination and from nitriles via alkylation with alkyl haHdes under strong basic conditions (21,64). 

Other methods of converting amides to esters have been described (78). Alkyl haUdes can be treated with amides to give esters (79). Also, esters can be synthesized from A/-aIkyl-A/-nitrosoamides, which are derived from the corresponding amides (80). 

Alkylation of enamines with epoxides or acetoxybromoalkanes provided intermediates for cyclic enol ethers (668) and branched chain sugars were obtained by enamine alkylation (669). Sodium enolates of vinylogous amides underwent carbon and nitrogen methylation (570), while vicinal endiamines formed bis-quaternary amonium salts (647). Reactions of enamines with a cyclopropenyl cation gave alkylated imonium products (57/), and 2-benzylidene-3-methylbenzothiazoline was shown to undergo enamine alkylation and acylation (572). A cyclic enamine was alkylated with methylbromoacetate and the product reduced with sodium borohydride to the key intermediate in a synthesis of the quebrachamine skeleton (57i). 

Alkylation takes an entirely unexceptional course. The nitrogen atom of the 7r-excessive five-membered ring of the indole nucleus resists alkylation, md-A-Alkylation with alkyl halides can be achieved only after forcing deprotonation with, for example, sodamide, potassium amide or ethoxide. In this manner... 

Heterocyclic structures analogous to the intermediate complex result from azinium derivatives and amines, hydroxide or alkoxides, or Grignard reagents from quinazoline and orgahometallics, cyanide, bisulfite, etc. from various heterocycles with amide ion, metal hydrides,or lithium alkyls from A-acylazinium compounds and cyanide ion (Reissert compounds) many other examples are known. Factors favorable to nucleophilic addition rather than substitution reactions have been discussed by Albert, who has studied examples of easy covalent hydration of heterocycles. 

Condensation of the anion obtained on reaction of acetonitrile with sodium amide, with o-chlorobenzophenone (36), affords the hydroxynitrile, 37. Catalytic reduction leads to the corresponding amino alcohol (note that the benzhydryl alcohol is not hydrogenolyzed). Reductive alkylation with formaldehyde and hydrogen in the presence of Raney nickel gives the antitussive a-gent, chlorphedianol (39). °... 

In a further development on this theme, the thiol, 153, is first alkylated to the corresponding benzyl ether (158). Treatment with sodium methoxide removes the proton on the amide nitrogen to afford the ambient anion (159). This undergoes alkylation with methyl bromide on the ring nitrogen thus it locks amide into the imine form (160). Chlorolysis serves both to oxidize the sulfur to the sulfone stage and to cleave the benzyl ether linkage there is thus obtained the sulfonyl chloride, 161. 

Of the several syntheses available for the phenothiazine ring system, perhaps the simplest is the sulfuration reaction. This consists of treating the corresponding diphenylamine with a mixture of sulfur and iodine to afford directly the desired heterocycle. Since the proton on the nitrogen of the resultant molecule is but weakly acidic, strong bases are required to form the corresponding anion in order to carry out subsequent alkylation reactions. In practice such diverse bases as ethylmagnesium bromide, sodium amide, and sodium hydride have all been used. Alkylation with (chloroethyl)diethylamine affords diethazine (1), a compound that exhibits both antihista-minic and antiParkinsonian activity. Substitution of w-(2-chloroethyl)pyrrolidine in this sequence leads to pyrathiazine (2), an antihistamine of moderate potency. 

Chlorpromazine (33) can probably be considered the prototype of the phenothiazine major tranquilizers. The antipsychotic potential of the phenothiazines was in fact discovered in the course of research with this agent. It is of note that, despite the great number of alternate analogs now available to clinicians, the original agent still finds considerable use. The first recorded preparation of this compound relies on the sulfuration reaction. Thus, heating 3-chlorodiphenylamine (30) with sulfur and iodine affords the desired phenothiazine (31) as well as a lesser amount of the isomeric product (32) produced by reaction at the 2 position. The predominance of reaction at 6 is perhaps due to the sterically hindered nature of the 2 position. Alkylation with w-C3-chloropropyl)dimethylamine by means of sodium amide affords chlorpromazine (33). ... 

Schiff s base (j ) derived by reaction of p-chloro-anil ine and borohydride followed by acylation with phenylacetyl chloride produces amide 22,. Selective hydrolysis with HBr followed by alkylation with isopropyl bromide completes the synthesis of lorcainide (20). ... 

These constitutions have recently received support from the work of A. Haller. If they are correct, then thujone should be capable of yielding trialkyl substitution products, whilst isothujone should not be able to go beyond the dialkyl stage. By alkylation with the assistance of sodium amide, triallylthujone could be prepared, but no higher substitution product than dimethylisothujone could be prepared from isothujone. In the course of his work, Haller prepared the following alkyl derivatives of the two ketones —... 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

With ammonia (refs. 14 - 25), alkyl (refs. 26 - 28) or arylamines (refs. 29 - 44) as well with amides (refs. 37,45-49) (the Goldberg reaction (ref. 50)) the reaction affords substituted anilines. 

Amides can also be alkylated with diazo compounds, as in 10-49. Salts of sulfonamides (ArS02NH ) can be used to attack alkyl halides to prepare N-alkyl sulfonamides (ArS02NHR) that can be further alkylated to ArS02NRR. Hydrolysis of the latter is a good method for the preparation of secondary amines. Secondary amines can also be made by crown ether assisted alkylation of F3CCONHR (R = alkyl or aryl) and hydrolysis of the resulting F3CCONRR. ... 

N-Alkyl-substituted amides can be converted to nitriles and alkyl chlorides by treatment with PCI5. This is called the von Braun reaction (not to be confused with the other von Braun reaction, 10-76). 

Ester enolates are somewhat less stable than ketone enolates because of the potential for elimination of alkoxide. The sodium and potassium enolates are rather unstable, but Rathke and co-workers found that the lithium enolates can be generated at -78° C.69 Alkylations of simple esters require a strong base because relatively weak bases such as alkoxides promote condensation reactions (see Section 2.3.1). The successful formation of ester enolates typically involves an amide base, usually LDA or LiHDMS, at low temperature.70 The resulting enolates can be successfully alkylated with alkyl bromides or iodides. HMPA is sometimes added to accelerate the alkylation reaction. 

Imidazolides can also be activated by N-alkylation with methyl triflate.116 Imidazolides react with alcohols on heating to give esters and react at room temperature with amines to give amides. Imidazolides are particularly appropriate for acylation of acid-sensitive materials. 

Acylamino)-substituted carboxylate esters and amides can be alkylated with good anti-2,4 stereoselectivity using two equivalents of a strong base. The stereoselectivity is independent of the steric bulk of the remainder of the carboxylate structure. Propose a TS that is consistent with these observations. 

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