Ammonia condensation sequence

In classical Hantzsch procedure, an enaminocarbonyl is formed in sim by condensation of ammonia source onto the 1,3-dicarbonyl substrate. But many groups have used a three-component modified-Hantzsch protocol in which the preformed enamine is introduced as a partner. Thus, utilization of cyclic or acyclic 1,3-dicarbonyl compounds, aldehydes, and acyclic or cyclic enamines has been reported, leading regioselectively to diversely substituted 1,4-DHP derivatives (Scheme 7). The sequence involving such starting materials was performed in numerous efficient systems, and more particularly in the following (1) microwave-assisted reaction in acetic acid [50], DMF [51], or an acetic acid/DMF system [52] (2) sonification in ethylene glycol [53] and (3) use of ionic liquids such as [bmim]BF4 [54]. 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

Interposition of a methylene group between the phenyl ring and the heterocycle leads to the benzyldiami nopyrimidines, a class of compounds notable for their antibacterial activity. Condensation of hydrocinnamate 54 with ethyl formate leads to the hydroxymethylene derivative 55. In this case, too, the heterocyclic ring is formed by reaction with guanidine. This sequence probably involves initial addition-elimination to the formyl carbon to form 56 cyclization in this case involves simple amide formation. Tautomerization then affords the hydroxy derivative 57. This is converted to tetroxoprim (58) by first replacing the hydro) l by chlorine and then- displacement of halogen with ammonia. 

In this sequence a radical, possibly a btradical derived from unpairing the electrons of the oxazirane oxygen-nitrogen bond, abstracts the a-hydrogen atom of the A -alkyl group to form (XXI) which subsequently isomerizes to (XXII). Alternatively the formation of (XXII) may take place directly by a concerted, reaction. In either event the iminoaikoxy radical (XXII) carries the chain. The ammonia which is formed presumably comes from aldol-like condensations of the imine (XXIV). The fact that vapor-phase pyrolysis does not take this course simply reflects tbo low probability of a chain reaction in the vapor phase. 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

As discussed, condensation reactions form the basis of the synthesis of the cyclic trimer, (NPC12)3. The reaction between phosphorus pentachloride and ammonia or ammonium chloride proceeds in a stepwise fashion, as shown in reaction sequence (18), by elimination of hydrogen chloride first to form a monomer (3.40), then a linear dimer (3.41), trimer (3.42), tetramer, and so on. Cyclization could occur to give cyclic chlorophosphazenes at any stage beyond the dimer, but in practice is less likely as the chains grow beyond a certain length. Several authors have extended this process to produce relatively low molecular weight poly(dichlorophosphazene).36-39... 

The gas phase acid-catalyzed synthesis of pyridines from formaldehyde, ammonia and an alkanal is a complex reaction sequence, comprising at least two aldol condensations, an imine formation, a cyclization and a dehydrogenation (9). With acetaldehyde as the alkanal, a mixture of pyridine and picolines (methylpyridines) is formed. In comparison with amorphous catalysts, zeolites display superior performance, particularly those with MFI or BEA topology. Because formation of higher alkylpyridines is impeded in the shape-selective environment, the lifetime of zeolites is much improved in comparison with that of amorphous materials. Moreover, the catalytic performance can be enhanced by doping the structure with metals such as Pb, Co or Tl, which assist in the dehydrogenation. 

Applicability of the reaction sequence to the preparation of 2-substituted imidazoles rests on the use of more complex amides than formamide. This constitutes a severe limitation to the process since it has only proved possible to substitute acetamide in a few cases, with the formation of 2-methylimidazoles. Nevertheless, the method still has many applications in the preparation of 4- and 5-substituted imidazoles. Best results are obtained if a large excess of formamide is used at 180-200 °C, or passage of a stream of ammonia at 150-175 C for 4-6 hours is maintained. The use of sulfuric acid as a condensing agent is also of value. Should these conditions not be adhered to then oxazoles may be formed preferentially. 

Either antipode of bromoborane 332 can be prepared in a six-step sequence from benzil (330, Scheme 11-19) [127, 254, 258J. Reaction of benzil with cyclohexanone in the presence of ammonium acetate and acetic acid generates a cyclic bis-imine which is subsequently reduced with lithium in ammonia. The resulting racemic fra .s-imidazolidine is subsequently hydrolyzed to the diamine 331. Resolution of 331 is accomplished by crystallization with either antipode of tartaric acid. The enantiomerically enriched stein ligand 331 is then sulfonylated and condensed with boron tribromide, giving the chiral bromoborane 332. Transmetalla-tion of allyltri-n-butylstannane with bromoborane (R,/ )-332 then affords the allyl-boron reagent (R,/ )-198. 

The product from the classical Hantzsch synthesis is necessarily a symmetrically substituted 1,4-dihydro-pyridine, since two mole equivalents of one dicarbonyl component are utilised, the aldehyde carbonyl carbon becoming the pyridine C-4. The precise sequence of intermediate steps is not known for certain, and may indeed vary from case to case, for example the ammonia may become involved early or late, but a reasonable sequence would be aldol condensation followed by Michael addition generating, in situ, a... 

Elongation can occur if the aldehyde functionality in 113 undergoes reductive condensation with ammonia, another equivalent of propenal and one terminus of another dialdehyde chain to give the dimer 114 that has a second dihydropyridine ring. Multiple repetitions of the elongation sequence are necessary to generate the halitoxins 31 and 32. Ultimately the oligomerization has to be terminated. 

The mechanism of the Strecker reaction has received considerable attention over its lifespan.4 The conversion of a carbonyl compound into an a-amino acid, by this method, requires a two-step process. The first step consists of the three-component condensation of cyanide and ammonia with the carbonyl compound 1 to produce an intermediate, a-aminonitrile 3. The second step involves the hydrolysis of the nitrile functional group to reveal the latent carboxylic acid 4. Whereas the second step is fairly straightforward and can be done under basic or acid conditions, the first step is more involved than one may expect. The widely accepted sequence for the first step is the nucleophilic addition of ammonia to the carbonyl carbon to produce the corresponding imine derivative 2. Once formed, this initial species is captured by the cyanide anion to generate the requisite a-aminonitrile 3. 

Contrary to some reports, electrophilic addition reactions may occur in other multiple-bond systems. In many of the reactions of aldehydes and ketones the first stage involves the addition of some entity across the carbon-oxygen bond, e.g., the formation of oximes, semicarbazones, hydrazones, hydrates (1,1-diols) and their ethers, and the aldol condensation. Most of these reactions entail a subsequent loss (elimination) of a small molecule e.g. water, ammonia, ethanol) and, while one must be careful to determine whether the rate-determining stage involves attack on the carbonyl compound or elimination from the adduct , there are some systems in which it is evident that electrophilic attack is involved in the slow stage of the reaction sequence. Examples of such reactions are the acid-catalysed formation of oximes of aliphatic - and aromatic carbonyl compounds, of furfural semi-carbazone , and of 1,1-diols from aldehydes or ketones . 

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