Side reactions imide formation

Thus, the best compromises for Boc and Fmoc chemistries seem to be cyclohexyl and 2,4-dimethylpent-3-yl (Dmpn), which is of intermediate stability, and the removal of which by trifluoromethanesulfonic acid with the aid of thioanisole (see Section 6.22) leads to minimal imide formation (see Section 6.13). Points to note are that acidolysis of esters by hydrogen fluoride can lead to fission at the oxy-car-bonyl bond instead of the alkyl-oxy bond, thus generating acylium ions that can react with nucleophiles (see Sections 6.16 and 6.22), and that benzyl esters may undergo transesterification if left in methanol. The side reactions of cyclization (see Section 6.16) and acylation of anisole (see Section 6.22) caused by acylium ion formation do not occur at the side chain of aspartic acid.47-51... 

FIGURE 6.15 Imide formation from a dipeptide sequence containing an aspartyl residue with side-chain functional group in various states followed by generation of two peptide chains resulting from cleavage at the bonds indicated by the dashed arrows. The reaction is catalyzed by base52 or acid. [Merrifield, 1967]. The table shows the effect of the nature of the substituent on the extent of this side reaction. Dmpn = 2,4-dimethylpent-3-yl. 

Initially, water can cause the hydrolysis of the anhydride or the isocyanate, Scheme 28 (reaction 1 and 2), although the isocyanate hydrolysis has been reported to occur much more rapidly [99]. The hydrolyzed isocyanate (car-bamic acid) may then react further with another isocyanate to yield a urea derivative, see Scheme 28 (reaction 3). Either hydrolysis product, carbamic acid or diacid, can then react with isocyanate to form a mixed carbamic carboxylic anhydride, see Scheme 28 (reactions 4 and 5, respectively). The mixed anhydride is believed to represent the major reaction intermediate in addition to the seven-mem bered cyclic intermediate, which upon heating lose C02 to form the desired imide. The formation of the urea derivative, Scheme 28 (reaction 3), does not constitute a molecular weight limiting side-reaction, since it too has been reported to react with anhydride to form imide [100], These reactions, as a whole, would explain the reported reactivity of isocyanates with diesters of tetracarboxylic acids and with mixtures of anhydride as well as tetracarboxylic acid and tetracarboxylic acid diesters [101, 102]. In these cases, tertiary amines are also utilized to catalyze the reaction. Based on these reports, the overall reaction schematic of diisocyanates with tetracarboxylic acid derivatives can thus be illustrated in an idealized fashion as shown in Scheme 29. 

In analogy to proline dipeptides, A1-unprotected 2-carbonylpyrazolidine amino acid dipeptide esters 37 on storage at ambient temperature are prone to conversion into the related triazines 38 that correspond to the aza analogues of piperazine-2,5-diones (Scheme 5). 160 161 An additional side reaction is reported for the 2-azaproline peptides 161 which leads to formation of the cyclic imide 40 from methyl TV -lbenzyloxycarbonylj -carbonylpyra-zolidine glycinate (39) upon treatment with methanolic ammonia (Scheme 6). 

Carbamates are by far the most common type of amine protection used in solid-phase synthesis. Various types of carbamate have been developed that can be cleaved under mild reaction conditions on solid phase. Less well developed, however, are techniques that enable the protection of support-bound amines as carbamates. Protection of amino acids as carbamates (Boc or Fmoc) is usually performed in solution using aqueous base (Schotten-Baumann conditions). These conditions enable the selective protection of amines without simultaneous formation of imides or acylation of hydroxyl groups. Unfortunately, however, Schotten-Baumann conditions are not compatible with insoluble, hydrophobic supports. Other bases and solvents have to be used in order to prepare carbamates on, for example, cross-linked polystyrene, and more side reactions are generally observed than in aqueous solution. 

Nucleophilic attack of ammonia or of a primary or secondary amine on an O-alkyl thiocarboxylate (2) provides a formally straightforward approach to thioamides and a number of examples have been reported (equation l). - However, some limitations should be noted. Thus, there is a tendency of esters (2) to rearrange to their 5-alkyl isomers on heating (cf. Volume 6, Chapter 2.5) and these yield amides with amines rather than thioamides. Besides, excess primary amine will lead to amidine formation, or the tetrahedral intermediate of the substitution reaction may break down to an imidate rather than a thioamide (cf. Volume 6, Chapter 2.7). These unwanted side reactions are favoured in polar, protic solvents such as ethanol. In contrast, THF has proven to be particularly useful in the synthesis of tertiary thioamides according to equation (1). For improved reactivity in the preparation of V-aryl derivatives and milder reaction conditions, it is advantageous to employ the amine in the form of its Mg salt. ... 

Acylation of ketones. Noting that on alkylation of malononitrile in ethanol or benzene with sodium ethoxide as base the yield is only 70% and formation of imide esters is an important side reaction, Bloomfleld was led to try the non-nucleophilic base sodium hydride in dimethyl sulfoxide, a relatively non-nucleophilic solvent capable of dissolving intermediate salts. With this combination he obtained dimethyl-malononitrile in 60% yield. He then studied the acylation of the ketone (1) with the... 

The curing behavior of PMDA-ODA (Figure 1) has been analyzed previously The overall process is characterized by various physical and chemical steps Decomplexation of the complex formed between NMP and polyamic acid 2 3 6 plasticization of the material by the decomplexed NMP n 12 evaporation of the solvent cycloimidization accompanied by re-formation of anhydride and amine, a side reaction which leads to chain scission 2 vitrification caused by solvent evaporation and imidization and finally molecular ordering of the polyimide near and above the glass transition n 13 14. The particular features of all these processes are heating rate dependent (e.g. compare Figure l.a and l.b) 2 n. 

The intramolecular version of this reaction gives tricyclic oxetanes such as 4 which undergoes acid-catalyzed rearrangement to give the seven-membered cyclic amide 5H4 86. The irradiation of a similar phthalimide derivative 6 gives a different product type, presumably by intramolecular oxetane formation 7 and metathetic cleavage to 888. Another side reaction results from intramolecular hydrogen abstraction, for example, 13 is formed via 12 from the imide 9 in addition to the expected main product spiroazepinedione 1189. 

With increasing use of Fmoc SPS, a number of base-mediated side reactions have been identified and reported that require careful awareness [61]. Some of these are described elsewhere in this volume (Chapters 2 and 4). The principal base-mediated side reactions are diketopiperazine formatioii caused by cyclization, particularly during A -deprotection of the residue adjacent to C-terminal resin-linked proline [62], and aspartimide formation, particularly at Asp-X residues [63,64]. The former can now be prevented by use of the substantially sterically hindered 2-chlorotrityl linker [65]. The latter side reaction is more difficult to control and appears to be largely sequence dependent. Asp-Gly, -Ser, -Thr, -Asn, and -Gin pairs are most at risk of potential imide formation, although several other Asp-X combinations have also been observed to cyclize [66,67]. For one sensitive peptide sequence, use of piperazine for A -deprotection eliminated this side reaction [68]. However, for another peptide, this base was ineffective (J Wade, unpublished). Reduction of the basicity of the piperidine solution by addition of... 

Carbodiimide method, a procedure for peptide bond formation using carbodi-imides, R-N=C=N-R, such as dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIC) and water-soluble carbodi-imides. The carbodiimide reacts in a one-pot procedure with the carboxylate anion of the carboxy component to form a highly reactive O-acylisourea intermediate. The former reacts immediately with the amino function of the amino component to yield the desired peptide derivative and the urea byproduct. Indeed, a more complex mechanism must be taken into consideration. Unwanted side reactions are racemization via the oxazolone mechanism and formation of the unreactive N-acylurea by base-catalyzed acyl migration from the isourea oxygen to nitrogen. The side reactions can be diminished by preparing the O-acylisourea at 0 °C... 

At higher polymerization temperatures, however, side reactions occur. Among them are Claisen-type condensations. They lead to two types of N-acylated j -keto imide structures and take place readily above 2(X) C. Formation of these imides decreases the concentration of lactam anions ... 

The use of secondary amides as nucleophiles has been also documented by Mori et al.f Synthesis of imides by this method is not always satisfactory, but phthalimides are prepared in high yield (Scheme 44). An interesting modification of this method consists of the double carbonylation of o-aryl diiodides and proceeds via an initial intermole-cular amidation, followed by the intramolecular one described by Mori (Scheme 45). ° The formation of seven-membered rings was demonstrated by the synthesis of diazepam and a number of anthramycin alkaloids, including Prothracarcin and Tomaymycin (Scheme 46). As mentioned above, for seven-membered rings direct amination is observed as a side reaction. Secondary ureas are also substrates for this reaction, yielding seven-membered cyclic ureas. ... 

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