Side reactions urethane formation

Unfortunately, the presence of the benzylic alcohol moiety at the focal point of the dendrimer, along with the catalyst (used in the urethane formation) led to the formation of undesired side products, presumably due to carbamate interchange. These side reactions were avoided by switching to monomer 19, methyl-3,5-dihydroxybenzoate. While the carbamate linkages of dendrons 53 and 54 were too unstable under the alkylation conditions required to afford larger dendrons, the merits of the concept was adequately demonstrated for this accelerated synthesis of [G-3] dendrons. 

A satisfactory understanding of polyurethane formation requires an understanding that in addition to the main reaction of urethane formation, other reactions of isocyanates are possible, especially in the presence of certain catalysts. With the proper selection of temperature and catalyst these side reactions can usually be avoided, but the experimentalist should... 

Details of these reactions have been reviewed, and indications of catalysts favouring one or another reaction have been given [116]. In the kinetic studies reported the experimental conditions have generally been chosen so as to give essentially complete urethane formation, free from large amounts of side reactions, except as noted. 

In peptide synthesis the use of a suitable protection for the N-terminal amino group is required not only to prevent the formation of a complex mixture of oligo- and cyclo-peptides, but an additional demand on the functionality applied for this purpose is that it should prevent possible racemization of the activated amino acid. Racemization usually takes place via an intermediate oxazolone (7) that forms readily from A -acyl-protected amino acids (Scheme 2). This side reaction can be mostly suppressed by using a carbamate as an N-terminal-protecting group. Therefore, nearly all blocking functions currently applied in this field are of the urethane type. 

Murphy s law certainly prevails in peptide synthesis. Some important side reactions, such as the formation of urethanes in coupling via alkylcarbonic acid mixed anhydrides or the generation of A-acylureas and dehydration of asparagine side chains when DCC is used for peptide bond formation, have already been mentioned in this chapter. Yet, countless additional side reactions and by-products have been observed and reported, often only as a footnote. Thus, it would be difficult to give a historical account of their discovery. A review [50] of side reactions noted in peptide synthesis reveals that most of them are caused by strong acids and bases, by excessive protonation or deprotonation of the amino add and peptide derivatives brought into reaction. 

Various groupings are produced in polyaddition according to whether there is reactant equivalence or excess of isocyanate groups (Table 28-1). The addition of hydroxyl groups is an equilibrium reaction. A rule of thumb holds that the slower the rate of formation, the more stable are the resulting urethanes. Thus, urethanes based on aliphatic isocyanates are more stable than those from aromatics, and those from secondary alcohols are more stable than those from primary alcohols. An olefin elimination, however, can occur as a side reaction ... 

In summarizing, it must be realized that most of all acidic conditions to remove a synthetic peptide from its gel phase support include the possibility for undesired attacks on either protected or free peptide side functions as well as on the backbone, causing fissions and conversions also during work-up manipulations of already detached raw products. This is the case because most of the usually employed protecting principles — urethanes, esters, and ethers as well as some functional sites of a peptide such as alcoholic, thioUc, and amide side chain groups — can be involved in proton catalyzed eliminations, transesterification, transamidations, and cyclol formations, though some of these side reactions usually are rather feared under basic conditions. 

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. 

In an interesting reaction, pyrrolysis of the urethane leads to extrusion of carbon dioxide and formation of 23, propiomazine Although this agent contains the ethylenediamine side chain, its main use is as a sedative. 

Ring closure of (3-hydroxy-a-amino acids with sulfuryl chloride/triethylamine 68 is accompanied by formation of (3-chloroalanine,16 1 whereas cyclization of urethane-protected serine and threonine by the Mitsunobu reaction 54 69 70 leads to oxazoline and dehydroalanine formation as side products. 47,71 Formation of dehydroalanine can be prevented by bulky carboxy protecting groups such as tert-butyl esters. 69 ... 

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