Acylations side-reactions

There is no commercial Synthesiser currently recommended for PNA synthesis. We have found acceptable results using an APEX 396 Robotic Peptide Synthesiser and we have recently obtained good PNA assembly using a Liberty microwave Peptide Synthesiser. Key to success is minimization of times of piperidine treatment. Extended treatments can lead to a trans-acylation side reaction that will result in lower yields. PyBop must be dissolved freshly and on no account should be used after standing for more than 2 days. 

By varying the lactamate counterion in the polymerization of CL, a comparison regarding the formation of side products has been made." At high temperatures, the content of diaminoketone units formed during C-acylation side reactions is almost the same for sodium, potassium, and lithium e-caprolaaamate but much lower when CLMgBr has been used (Table 8). 

Then N-Boc-O-benzylserine is coupled to the free amino group with DCC. This concludes one cycle (N° -deprotection, neutralization, coupling) in solid-phase synthesis. All three steps can be driven to very high total yields (< 99.5%) since excesses of Boc-amino acids and DCC (about fourfold) in CHjClj can be used and since side-reactions which lead to soluble products do not lower the yield of condensation product. One side-reaction in DCC-promoted condensations leads to N-acylated ureas. These products will remain in solution and not reaa with the polymer-bound amine. At the end of the reaction time, the polymer is filtered off and washed. The times consumed for 99% completion of condensation vary from 5 min for small amino acids to several hours for a bulky amino acid, e.g. Boc-Ile, with other bulky amino acids on a resin. A new cycle can begin without any workup problems (R.B. Merrifield, 1969 B.W. Erickson, 1976 M. Bodanszky, 1976). 

MPD-1 fibers may be obtained by the polymeriza tion of isophthaloyl chloride and y -phenylenediamine in dimethyl acetamide with 5% lithium chloride. The reactants must be very carefully dried since the presence of water would upset the stoichiometry and lead to low molecular weight products. Temperatures in the range of 0 to —40° C are desirable to avoid such side reactions as transamidation by the amide solvent and acylation of y -phenylenediamine by the amide solvent. Both reactions would lead to an imbalance in the stoichiometry and result in forming low molecular weight polymer. Fibers are dry spun direcdy from solution. 

Acyl Side-Chain Reactions. Many reactions occur in the R group of the fatty acid residue (see Carboxylic acids Fats and fatty oils). 

Isomerization of 3-cephems (27) to 2-cephems (28) takes place in the presence of organic bases (e.g. pyridine) and is most facile when the carboxyl is esterified. Normally an equilibrium mixture of 3 7 (3-cephem/2-cephem) is reached. Since the 2-cephem isomers are not active as antibacterial agents, the rearrangement proved to be an undesirable side reaction that complicated acylation of the C-7 amine under certain conditions. A method for converting such mixtures to the desired 3-cephem isomer involves oxidation with concomitant rearrangement to the 3-cephem sulfoxide followed by reduction. Additions... 

The treatment of enamines with acid halides which possess no a hydrogens results in the simple acylation of the enamine (7,12,62-67). If the acid halide possesses an a hydrogen, however, ketenes are produced in situ through base-catalyzed elimination of hydrogen chloride from the acid halide. The base catalyst for this reaction may be the enamine itself or some other base introduced into the reaction mixture such as triethylamine. However, if the ketene is produced in situ instead of externally, there still remains the possibility of a side reaction between the acid halide and the enamine other than the production of ketene (67,84). 

The acyl residue controls the formation and stability of the carbonium ion. If the carbonium ion is destabilized (by electron withdrawing groups), then cyclization to the phenanthridine nucleus will be sluggish. The slower the rate of cyclization, the greater the chance of side reactions with the cyclization reagent. Therefore, the yield of the phenanthridine will depend on the relative rates of cyclization and side reactions, which is controlled by the stability of the carbonium ion. 

Introduction of an additional methyl group on the donor atom of TMM moiety gives a low 33% yield of the perhydroindans (49, X=H2) and (50, X=H2) with substantial production of the diene by-products [24]. However, it is still remarkable that the reaction works at all since the corresponding intermolecular cycloaddition failed. Incorporation of a carbonyl moiety adjacent to the donor carbon atom doubles the yield of the cycloadducts to 66% (Scheme 2.15). This so-called acyl effect works by making the donor carbon of the TMM unit "softer," thus facilitating the initial step of the conjugate addition, as well as inhibiting base-induced side reactions [22]. 

Drawbacks as known from the Friedel-Crafts alkylation are not found for the Friedel-Crafts acylation. In some cases a decarbonylation may be observed as a side-reaction, e.g. if loss of CO from the acylium ion will lead to a stable carbenium species 8. The reaction product of the attempted acylation will then be rather an alkylated aromatic compound 9 ... 

The known methods for the preparation of D- -)-a-aminobenzylpenicillin by the acylation of 6-aminopenicillanic acid result in the preparation of aqueous mixtures which contain, in addition to the desired penicillin, unreacted 6-aminopenicillanic acid, hydrolyzed acylat-ing agent, and products of side reactions such as the products of the acylating agent reacted with itself and/or with the desired penicillin, as well as other impurities. 

The metabolic breakdown of triacylglycerols begins with their hydrolysis to yield glycerol plus fatty acids. The reaction is catalyzed by a lipase, whose mechanism of action is shown in Figure 29.2. The active site of the enzyme contains a catalytic triad of aspartic acid, histidine, and serine residues, which act cooperatively to provide the necessary acid and base catalysis for the individual steps. Hydrolysis is accomplished by two sequential nucleophilic acyl substitution reactions, one that covalently binds an acyl group to the side chain -OH of a serine residue on the enzyme and a second that frees the fatty acid from the enzyme. 

However, according to Mehrotra209,272-294,322 many side reactions take place Thus intramolecular reactions are due to the fact that titanium diacylates are more stable than other acylates ... 

When the reagent is the thiocyanate ion, S-alkylation is an important side reaction (10-43), but the cyanate ion practically always gives exclusive N-alkylation. ° Primary alkyl halides have been converted to isocyanates by treatment with sodium nitrocyanamide (NaNCNN02) and m-chloroperoxybenzoic acid, followed by heating of the initially produced RN(N02)CN. ° When alkyl halides are treated with NCO in the presence of ethanol, carbamates can be prepared directly (see 16-7). ° Acyl halides give the corresponding acyl isocyanates and isothiocyanates. For the formation of isocyanides, see 10-111. 

Although the synthesis of multiple-pyrrolyl compounds can be achieved by SnAt reactions of perfluoroaromatics with pyrrolylsodium at ambient temperature <96JOC9012>, deleterious side reactions are often observed during attempted A-alkylations of the alkali salts of pyrrole. A protocol has therefore been developed for the preparation of N-arylmethylenepyrroles by reduction of the corresponding AT-acyl derivatives by treatment with sodium borohydride/boron trifluoride etherate in a sealed tube <96S457>. ... 

The strategy for the asymmetric reductive acylation of ketones was extended to ketoximes (Scheme 9). The asymmetric reactions of ketoximes were performed with CALB and Pd/C in the presence of hydrogen, diisopropylethylamine, and ethyl acetate in toluene at 60° C for 5 days (Table 20) In comparison to the direct DKR of amines, the yields of chiral amides increased significantly. Diisopropylethylamine was responsible for the increase in yields. However, the major factor would be the slow generation of amines, which maintains the amine concentration low enough to suppress side reactions including the reductive aminafion. Disappointingly, this process is limited to benzylic amines. Additionally, low turnover frequencies also need to be overcome. 

The results presented in Tables 3 and 4 deserve some comments. First, a variety of enzymes, including whole-cell preparations, proved suitable for the resolution of different hydroxyalkanephosphorus compounds, giving both unreacted substrates and the products of the enzymatic transformation in good yields and, in some cases, even with full stereoselectivity. Application of both methodologies, acylation of hydroxy substrates rac-41 and rac-43 or the reverse (hydrolysis of the acylated substrates rac-42 and rac-44), enables one to obtain each desired enantiomer of the product. This turned out to be particularly important in those cases when a chemical transformation OH OAc or reverse was difficult to perform. As an example, our work is shown in Scheme 3. In this case, chemical hydrolysis of the acetyl derivative 46 proved difficult due to some side reactions and therefore an enzymatic hydrolysis, using the same enzyme as that in the acylation reaction, was applied. Not only did this provide access to the desired hydroxy derivative 45 but it also allowed to improve its enantiomeric excess. In this way. 

There are only a few examples of low-temperature conditions reported to lead to a species behaving as an o-QM. All of these, except for our O-acyl transfer methods that will be discussed later, use a fluoride ion to trigger the formation of the o-QM in an almost instantaneous manner. In these examples, a high concentration of the intended nucleophile is necessary to prevent any side reactions with the o-QM, because given the low-temperature conditions its formation is usually irreversible. 

The preparation of imidazolides by acylation of imidazole with acid chlorides is sometimes limited by the inaccessibility or instability of the required acid chlorides (e.g., formyl chloride, highly unsaturated acid chlorides, etc.) or by side-reactions in the case of multifunctional systems. For these reasons and due to the availability of an easy and convenient procedure involving very mild conditions, imidazolides today are usually prepared directly from the corresponding carboxylic acids with jV -carbonyldiimida-zole (CDI) or one of its analoga (see page 16). Use of these reagents has become more and more the preferred method for activation of carboxylic acids to azolides and their further transacylation to esters, amides, peptides, etc. (see subsequent Chapters). 

The major side reaction to the desired acylation product is hydrolysis of the anhydride. In aqueous solutions anhydrides may break down by the addition of one molecule of water to yield two carboxylate groups. The presence of an excess of the anhydride in the reaction medium usually is enough to minimize the effects of competing hydrolysis. 

Maleic acid is a linear four carbon molecule with carboxylate groups on both ends and a double bond between the central carbon atoms. The anhydride of maleic acid is a cyclic molecule containing five atoms. Although the reactivity of maleic anhydride is similar to other cyclic anhydrides, the products of maleylation are much more unstable toward hydrolysis, and the site of unsaturation lends itself to additional side reactions. Acylation products of amino groups with maleic anhydride are stable at neutral pH and above, but they readily hydrolyze at acid pH values around pH 3.5 (Butler et al., 1967). Maleylation of sulfhydryls and the phe-nolate of tyrosine are even more sensitive to hydrolysis. Thus, maleic anhydride is an excellent reversible blocker of amino groups to temporarily mask them from reactivity while another... 

Interception of the reaction sequence at the alkylcobalt carbonyl stage before carbonyl insertion, and hydrogenation of this intermediate, produces an alkane. This undesired side reaction is only minor (1-3%) in cobalt-catalyzed hydroformylation of a nonfunctional olefin, but may become predominant with phenyl- or acyl-substituted olefins. Ethylbenzene has been obtained in >50% yield from styrene (37), and even more alkane was obtained from a-methylstyrene (35). 

Stevens [164] standardised the preparation of azoxy compounds from the O2-tosylated acyl diazeniumdiolates. The reaction of Grignard reagents with 02-alkyl diazeniumdiolates was found to produce azoxy compounds (Scheme 3.17), although radical side reactions can sometimes interfere in some solvents [165, 166]. 

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