ACYL AMMONIUM

There are some problems associated with the use of functional derivatives of carboxylic acids. Long-chain acid anhydrides are not commercially available, and one half of the acylation reagent is not utilized. Acyl chlorides require the use of tertiary base catalysts, whose double role has been explained before. Some of the intermediate acyl ammonium compounds formed are, however, insoluble in the solvent system. Examples include RCO - N+EtsCL in LiCl/DMAc, where RCO refers to the propionyl, hexanoyl, and stearoyl moiety, respectively. Hexanoyl- and stearoyl-pyridinium chlorides are also insoluble in the same solvent system [185]. 

Additional work was carried out by the GE group on optimization of the reaction yield and to eliminate unwanted linear oligomers [14], Three side reactions which interfere with synthesis of cyclics were identified reaction of the amine with acid chloride to form an acyl ammonium salt, followed by decomposition to an amide (Equation (3.2)) reaction with CH2CI2 to form a salt (Equation (3.3)) hydrolysis of the acid chloride, forming carboxylate via catalysis... 

HYDROLYSIS OF DIAMIDES, LACTAMS AND N-acyl-ammonium IONS... 

In 1982, Wynberg and coworkers discovered the cinchona alkaloid catalyzed enantioselective aldol lactonization of ketenes with chloral or trichloroacetone [35], in which the zwitterionic acyl ammonium enolate provides the carbon nucleophile. This work is probably one of the most important early contributions to enantioselective organocatalysis [36], One drawback associated with this process is the severe substrate limitations. The aldehydes should be highly reactive, presumably due to the relatively limited nudeophilicity of ammonium enolates. Nelson and coworkers first addressed the scope and reactivity problems associated with Wynberg s original protocol by combining a cinchona alkaloid derivative (O-trimethylsilylquinine (12) or O-trimethylsilylquinidine (13)) with a metal Lewis acid as a cocatalyst to... 

Discussing the stereochemical outcome of the Claisen rearrangements, two aspects had to be considered. On one hand, the relative configuration of the new stereogenic centers was found to be exclusively syn in 308 and 309 suggesting a chair-like transition state c-a and c-fS, respectively, including a Z acyl ammonium enolate structure (complete simple diastereoselectivity/internal asymmetric induction, Scheme 10.64). 

Stereoselective [4 + 2] cycloadditions ofketenes and thioacylimines 509, both created in situ are catalyzed by an optically pure cinchona alkaloid (TMSQ) in the presence of LiC104/i-Pr2NEt (9 1 CH2Cl2/Et20, 78 °C) via the quinine-derived enolate 510 to afford the enantio-enriched ds-4,5-disubstituted 1,3-thiazin-6-one 512 via sulfur addition to the acyl ammonium ion 511, with 95 to >98% ee and cis/trans 95 5 to >97 3 (Scheme 167) (2007JA11690). 

If the amine acts as an acylation catalyst, the potential exists for an unwanted side reaction to occur. It is well known that under anhydrous conditions acyl ammonium salts derived from the reaction of a chloroformate and a tertiary amine can decompose to form urethanes. We have recently reported a rate constant (1.3 0.2 min ) for the case involving triethylamine and phenyl chloroformate in methylene chloride at 39°C (see Scheme 4). Formation of urethanes in this manner under normal interfacial conditions to form high MW polymer would have minimal effects on the properties of the polymer and may not even be observed. However, urethane formation in the cyclization reaction would produce a capped oligomer which cannot cyclize, therefore leading only to polymer. In this manner, a fraction of the amine used in the reaction could produce a significant level of unwanted high MW polymer. Evidence for the formation of urethanes during the preparation of cyclics will be presented later in this paper. 

The reaction of a chloroformate with a tertiary amine to form an acyl ammonium salt is potentially a reversible reaction (see Equation 1).10... 

If so, an equilibrium mixture of the acyl ammonium salt and the starting materials would exist, and the relative proportions in solution would depend on the concentration of the... 

The other amines listed in Table 1 also displayed unique resonances in the NMR. Although no acyl ammonium salt was observed for the very hindered N-ethyl diisopropylamine (entry 12), peak broadening of the methylene protons and the methine protons was again observed. The sterically unhindered amine, MeNEt2, reacts completely with phenyl chloroformate to form the acyl ammonium salt, and produces two nonequivalent sets of methylenes (multiplets at 4.98 ppm and 4.11 ppm) indicative of a single conformational isomer, unlike the triethylamine case. 

Use of these various amines in cyclization reactions produced results which correlated well with the NMR data. The extremely sterically hindered N-ethyl diisopropylamine, which produced no acyl ammonium salt by NMR, left the chloroformate virtually unreacted under standard cyclization reaction conditions. Although tributylamine does form acyl ammonium salts, it has an equilibrium constant nearly an order of magnitude lower than triethylamine when compared at the same temperatures (Table 1, entries 7 and 4). This amine produced cyclics, but required much higher catalyst loadings, similar to tripropylamine which was aphically represented in Figure 1. The equilibrium constant for N-ethylpiperidine was twice the value for triethylamine at similar temperatures (Table 1, entries 8 and 4), and affords an optimum yield of cyclics at half the amine concentration required for triethylamine. 

Having established the necessary existence of an acyl ammonium salt intermediate for hydrolysis reactions and its likely existence for condensation reactions, and also the premise that the ratio of hydrolysis to condensation will control the relative proportions of cyclic and linear oligomers, the working model for cyclics formation under pseudo high... 

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