Azlactones amine reactions

To gain further insight into the reactions of alkenyl azlactones with secondary amines, reaction of 2 with a variety of simple amines was studied. Table 3 lists the results as the ratio of Michael addition to ring-opening as estimated by 100 MHz H-NMR. As can be seen from the... 

Since amines react more readily than alcohols in noncatalyzed reactions with anhydrides, the reaction is more difficult and initially required stoichiometric catalyst loadings [107], but could be performed in a catalytic sense with an O-acylated azlactone as acylating agent, which does not react with a benzylic amine at —50°C, but is capable of acylating the catalyst [108, 109]. Depending on the buUdness of the substrate, selectivities ranged from S = 11 to 27 (s = [ enantiomer l]/[ enantiomer 2])-... 

Compared to the chemo-catalyzed kinetic resolution of alcohols, there are few reports of similar reactions for amines. Building on other work, one elegant example from Berkessel uses bifunctional organocatalysts to enantioselectively hydrolyze a racemic azlactone, and the dynamic kinetic resolution (DKR) is achieved by in-situ acid-catalyzed racemization of the azlactone under mild conditions to give product N-acylarnino esters in, for example, 72% ee and 96% conversion with phenylalanine [6]. 

Catalytic kinetic resolution of amines has been a typical domain of enzymatic transformations. Attempts to use low-molecular-weight catalysts have notoriously been frustrated by the rapid uncatalyzed background reaction of the amine substrate with the acyl donor [40]. The first solution to this problem was recently developed by Fu, who used the planar chiral catalyst 21d and O-acyl azlactone 40 as the acyl donor (Scheme 12.19) [41]. In this process, the acyl transfer from the azlactone 40 to the nucleophilic catalyst 21d is rapid relative to both direct transfer to the substrate and to the transfer from the acylated catalyst to the substrate amine. Under these conditions, which implies use of low reaction temperatures, selectivity factors as high as 27 were achieved (Scheme 12.19) [41]. 

However, most nucleophiles attack 5-oxazolones at the carbonyl group and the products are derivatives of a-amino acids formed by acyl-oxygen fission. Thus the action of alcohols, thiols, ammonia and amines leads, respectively, to esters, thioesters and amides orthophosphate anion gives acyl phosphates (Scheme 18). The use of a-amino acids in this reaction results in the establishment of a peptide link. Cysteine is acylated at the nitrogen atom in preference to the sulfur atom. Enzymes, e.g. a-chymotrypsin and papain, also readily combine with both saturated and unsaturated azlactones. A useful reagent for the introduction of an a-methylalanine residue is compound (202). Both the trifluoroacetamido and ester groups in the product are hydrolyzed by alkali to give a dipeptide. The alkaline hydrolyzate may be converted into the benzyloxycarbonyl derivative, which forms a new oxazolone on dehydration. Reaction with an ester of an amino acid then yields a protected tripeptide (equation 45). 

Gong, et al. reported a phosphoric acid derivative 258 catalyzed asymmetric three-component formal [4 + 2] cycloaddition reaction of azlactones 257, a,p-unsaturated aldehydes 28, and primary amines 256 to give the 3-amino-3, 4-dihydropyridinones 259 with high enantioselectivities (up to 96% ee), Scheme 3.82 [104],... 

Scheme 3.82 Asymmetric three-component [4-t-2] cycloaddition reaction of azlactones, ot.p-unsaturated aldehydes, and primary amines...

FUNCTIONAL, TELECHELIC POLYMERS DERIVED FROM REACTIONS OF NUCLEOPHILIC OLIGOMERS AND ALKEYNL AZLACTONES, PART I TELECHELIC ACRYLAMIDES DERIVED FROM REACTIONS OF ALKEYNL AZLACTONES AND AMINE-TERMINATED OLIGOIERS ... 

Reactions of amine nucleophiles with alkenyl azlactones (2-alkenyl-2-... 

The overall reaction of alkenyl azlactones (J ) and amine-terminated oligomers -6 is depicted in Equation 1, with actual reactants listed in Table 1. 

We anticipated that the Michael addition which is known to occur with bis(acrylamides) and primary amines might be a troublesome side reaction, expecially in the the latter stages of reaction when the concentration of acrylamide groups is very much higher than residual azlactone groups. This Michael addition side reaction is depicted in Equation 2. 

In summary, the reaction of alkenyl azlactones with amine-terminated oligomers has been found to be an excellent method for preparing the corresponding (meth)acrylamide-terminated oligomers. The reaction is characterized by a very simple synthetic sequence in which equivalent quantities of reactants are mixed at room temperature with no catalyst reactions are complete to the almost exclusion of side reactions within 16-18 hours. Furthermore, the reaction is a nucleophilic addition. This is the same manner in which nucleophiles react with isocyanates and epoxides. Indeed, this nucleophilic addition mode of reaction which involves no by-products likely accounts for the widespread use of these latter functional groups by industry. In comparison with isocyanate and epoxide, amine nucleophiles react with azlactones at controlled and predictable rates, intermediate between the very reactive isocyanate and the slow reacting epoxide. 

Michael addition to alkenyl azlactones is not limited to mercaptans, but also occurs to a significane extent with secondary amines. This was first observed upon attempted reaction of azlactone with Jeffamlne CD-2000 (Texaco Chemical, Inc.) (Scheme 9). Initially, no reaction was observed at room temperature over two days time. However, heating the mixture at 50-70°C overnight resulted in clean conversion to the corresponding bisazlactone. As might be expected, the source of the azlactone appears to have no effect upon the course of this reaction. 

The azlactones behave in many respects like acid anhydrides and react with a wide variety of compounds, such as water, alcohols, amines, and hydrogen halides, which contain active hydrogen atoms. As with acid anhydrides, reaction occurs most readily with amines, less readily with alcohols, and least readily with water. 

No systematic study has been made of the reaction of azlactones with amines. Conditions of a widely varying nature have been reported, and many of them obviously are far from optimum. However, the yields of amide or substituted amide are usually excellent, and many are practically quantitative. 

Saturated azlactones react quite vigorously with ammonia and amines. > The reaction usually is effected by treating the... 

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