Alkylation-amidation reaction

Conversion of the C-2 amide to a biologically inactive nitrile, which can be further taken via a Ritter reaction (29) to the corresponding alkylated amide, has been accomphshed. When the 6-hydroxyl derivatives are used, dehydration occurs at this step to give the anhydro amide. Substituting an A/-hydroxymethylimide for isobutylene in the Ritter reaction yields the acylaminomethyl derivative (30). Hydrolysis affords an aminomethyl compound. Numerous examples (31—35) have been reported of the conversion of a C-2 amide to active Mannich adducts which are extremely labile and easily undergo hydrolysis to the parent tetracycline. This reverse reaction probably accounts for the antibacterial activity of these tetracyclines. 

We ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide (Sections 21.4 and 21.5). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine. 

Niobium, tris(diethyldilhiocarbamato)oxy-stereochemistry, 1,82 structure, 1, 83 Niobium, tris(oxa ato)oxy-stereochcmistry, 1, 82 Niobium, tris(phcnylcncdirhio)-structure, 1, 63 Niobium alanate, 3, 685 Niobium complexes alkyl alkoxy reactions, 2, 358 amides, 2,164 properties, 2, 168 synthesis, 2, 165 applications, 6,1014 carbamicacid, 2, 450 clusters, 3, 672,673,675 hexamethylbenzene ligands, 3, 669 cyanides synthesis, 2, 9 p-dinitrogen, 3, 418 fluoro... 

Tungsten complexes, 3, 973-1015 alkoxy carbonyl reactions, 2, 355 alkyl alkoxy reactions, 2, 358 amides... 

R= H, alkyl or aryl group Figure 3.13 Amidation reaction scheme.10... 

Treatment with sodium hypochlorite or hypobromite converts primary amines into N-halo- or N,N-dihaloamines. Secondary amines can be converted to N-halo secondary amines. Similar reactions can be carried out on unsubstituted and N-substituted amides and on sulfonamides. With unsubstituted amides the N-halo-gen product is seldom isolated but usually rearranges (see 18-13) however, N-halo-N-alkyl amides and N-halo imides are quite stable. The important reagent NBS is made in this manner. N-Halogenation has also been accomplished with other reagents, (e.g., sodium bromite NaBr02) benzyltrimethylammonium tribromide (PhCH2NMe3 Br3"), and NCS. The mechanisms of these reactions involve attack by a positive halogen and are probably similar to those of 12-47 and 12-49.N-Fluorination can be accomplished by direct treatment of amines °° or... 

Zinc carbamate complexes are well known, and the structural types and stabilities can be compared with thiocarbamates and dithiocarbamates which are discussed in Sections 6.8.11.1.3 and 6.8.7.1.4482 Carbamates of zinc can be formed from the reaction of carbon dioxide with alkylzinc alkyl amides and further reaction with alkylzinc can give a distorted cubane structure.483 The tetrameric diethylcarbamate species initially formed can also be used to produce monomeric or dimeric carbamate structures in reaction with amines tetramethylethylenediamine forms a monomer [(Me2NCH2)2Zn(02CN(C2H5)2)2] with an octahedral zinc center and pyridine forms a dimer[CsH5NZn2Me(02CN(C2H5)2)3] with tetrahedral zinc centers.484... 

In our earlier efforts to synthesize dendritic amphiphiles, we described a triden-dron (43) which was prepared by a two-step (alkylation-amidation or triester-tris) reaction sequence applied to l,3,5-tris(bromomethyl)benzene [117]. TEM and light scattering experiments suggested that 43 aggregated by stacking of its hydrophilic exterior into a spherical array of ca. 20 nm (diameter) reminiscent of globular micelles. 

This first reaction sequence on the exposed dendron (Figure 1.14) creates G = 0 (i.e. the core branch cell), wherein the number of arms (i.e. dendrons) anchored to the core is determined by Nc. Iteration of the alkylation/amidation sequence produces an amplification of terminal groups from 1 to 2 with the in situ creation of a branch cell at the anchoring site of the dendron that constitutes G = 1. Repeating these iterative sequences (Scheme 3), produces additional shells (generations) of branch cells that amplify mass and terminal groups according to the mathematical expressions described in the box opposite. 

Amide Method Alkylating agent Reaction time % yield... 

In isolated examples, reactions of specific amides and thioamides with dihalo-carbenes can take unusual pathways. Thus, for example, using procedure 7.1.1, A,A-dialkylamides are converted into a-chloromethylene derivatives of the amides [48]. The initial step in which the carbene attacks the carbonyl oxygen atom is the same as for the dehydration of the A-alkyl amides, but subsequent steps, for which there is evidence from 2H/ H labelling experiments, lead to the formation of an enamine and further reaction with the carbene (Scheme 7.34). 

N-Alkyl isoindolo[2,l-fc][2,4]benzodiazepines 190 (R = alkyl. Scheme 38, Section 3.1.1.2) are synthesized by an intramolecular N-acyliminium ion-amide reaction (1997TL2985, 1998T1497). Isothiocyanates 23 undergo under basic conditions in DMF ring closure by an intramolecular substitution between N1 of the pyrrole ring and isothiocyanate group to afford benzo[/]pyrrolo[l,2-c] [l,3]diazepine-5-thiones 25 (Scheme 2, Section 2.1.1.1 (2005BMCL3220)). 

Another useful method for introducing formyl and acyl groups is the Vilsmeier-Haack reaction.61 An Ac. V-di alkyl amide reacts with phosphorus oxychloride or oxalyl chloride62 to give a chloroiminium ion, which is the reactive electrophile. 

This section deals with the alkylation reactions of such enolates. In the presence of strong bases, amides carrying at least one a-hydrogen 1 can be deprotonated to form enolate ions which, on subsequent alkylation, give alkylated amides. Further reaction, e g., hydrolysis or reduction, furnishes the corresponding acids or primary alcohols, respectively. The pKa values for deprotonation are typically around 35 (extrapolated value DMSO3 7) unless electron-withdrawing substituents are present in the a-position. Thus, deprotonation usually requires non-nucleophilic bases such as lithium diisopropylamide (extrapolated 8 pKa for the amine in DMSO is around 44) or sodium hexamethyldisilazanide. 

Rotation is hindered in the enolate. Thus, if the a-substituent R1 4= R2, the enolate can exist in two forms, the syn- and anti-forms (enolates 2 and 3, respectively, if R2 has higher priority than R1). Attack of an electrophile on either face of the enolates, 2 or 3, leads to a mixture of the alkylated amides, 4 and 5. If R1 and R2 and the A-substituents R3 and R4 are all achiral, the two alkylated amides will be mirror images and thus a racemate results. If, however, any of the R substituents are chiral, enolate 2 will give a certain ratio of alkylated amide 4/5, whereas enolate 3 will give a different, usually inverted, ratio. Thus, for the successful design of stereoselective alkylation reactions of chiral amide enolates it is of prime importance to control the formation of the enolate so that one of the possible syn- or anti-isomers is produced in large excess over the other,... 

N-Alkyl amides or imides can also be prepared starting from alcohols by treatment of the latter with equimolar amounts of the amide or imide, Ph3P, and diethyl azodicarboxylate (EtOOCN=NCOOEt) at room temperature (the Mitsunobu reaction, see p. 396).925... 

Tantalum complexes alkyl alkoxy reactions, 358 amides synthesis, 165 imido... 

Stepwise Selective Amine and Amide Alkylation (Fig. 14) 44 A first alkylation step is performed by suspending (78) in a 2 M solution of a suitable alkyl halide in DMF at 50° for 24-48 h. After thorough washing with DMF (3x), CH2C12 (3x), and THF (3x) intermediate (79) (usually formed with >85% purity) is subjected to the final alkylation. The reaction flask is sealed with a fresh rubber septum and flushed with nitrogen followed by cooling to 0°. In a separate flame-dried 25-ml round-bottom flask 12 equiv. (with respect to 79) of 5-phenylmethyl-2-oxazolidinone is added. To the reaction flask freshly distilled THF is added (the appropriate volume to provide a 0.2 M solution of the 5-phenylmethyl-2-oxazolidi-none). The resulting clear solution is then cooled to —78° and 1.6 M n-butyl... 

In the presence of an activator, for example, an alkyl-amide, polymerization begins with a high reaction rate between molecules of the activator and the catalyst. 

More general solutions come from the replacement of alkylations by reactions with carbonyl compounds. These generally occur once only and in many cases cannot occur twice as the products—amides 12 or imines 15 for example—are much less nucleophilic than the starting amine. The products are reduced to the target amines. The amide route is restricted to amines with a CH2 group next to nitrogen 13 but the imine route is very general and is known as reductive animation.1 It is the most important way to make amines and a recent survey showed that the majority of amines made in the pharmaceutical industry are made this way. 

Amides, N-alkyl amides, lactams, hydantoins have been identified in both Murchison and Yamoto-791198 meteorites [63,65], confirming preliminary results from Cooper and Cronin [66]. The only peptides identified until now are diglycine and diketopiperazine (cyclic diglycine). Since only N1-unsubstituted hydantoins have been detected, this provides a good argument for the involvement of the Biicherer-Bergs reaction in their formation (cf. Sect. 2.1.4). 

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