Second acylation product

An improvement resulting in a decreased amount of the second acylation product is the introduction of mixed anhydrides with a-branched carboxylic acids like isovaleric and pivalic acid, due to deactivating electronic and steric effects. 

In order to keep side reactions at a minimum alkyl-carbonic acid mixed anhydrides are prepared and used for acylation in the cold. Nevertheless, both reactions require a very short time. The byproducts of coupling, CO2 and an alcohol (R OH), do not interfere with the isolation of the desired peptide. These features readily explain the popularity of the approach, but the principal advantage of alkylcarbonic acid mixed anhydrides lies in the fact that they give rise to only small amounts of the undesired second acylation product, a urethane ... 

The obvious advantage of symmetrical anhydrides over many, although certainly not all mixed anhydrides is the absence of a second acylation product. They therefore became the acylating agents of choice in numerous laboratories. 

In the application of mixed anhydrides a small amount of the second acylation product must be expected. No such complication is associated with the use of symmetrical anhydrides. Thus, in spite of wide experimentation with various mixed anhydrides, at this time only the isobutylcarbonic acid mixed anhydride procedure remains a viable competitor of the symmetrical anhydride method. 

The addition of phenylisocyanate (427) to enamines was soon found to lead to double acylation products. In the case of the cyclohexanone derived enamine, the first proposal (428) of a second acylation on nitrogen was... 

The addition of phenylisocyanate to aldehyde-derived enamines resulted in the formation of aminobutyrolactams (438,439). As aminal derivatives these produets can be hydrolyzed to the linear aldehyde amides and thus furnish a route to derivatives of the synthetically valuable malonaldehyde-acid system. With this class of reactions, a second acylation on nitrogen becomes possible and the six-membered cyclization products have been reported (440). Closely related to the reactions of enamines with isocyanates is the condensation of cyclohexanone with urea in base (441). 

The second reported application of the utilization of l,n-ADEQUATE data in the elucidation of a structure is found in the 1996 report of Kock and co-workers71 describing the characterization of an intermediate in the synthesis of euglobal-Gl (29) and euglobal-G2 (30). The synthesis employed a route that involved the acylation of a highly substituted benzaldehyde (see Scheme 1). While there were two possible acylation products, only a single product was formed in the reaction and it was necessary to unequivocally assign the structure. 

The preparation starts much as does that of (3-blockers, by reaction of the phenol (5-1) with epichlorohydrin with the important difference that the reaction is conducted with a controlled amount of the epoxide. The initially formed glycydil ether (5-2) thus reacts with a second phenoxide ion to afford the double ether of glycerol (5-3). This product is then condensed with diethyl oxalate in the presence of a base. The initially formed acylation product (5-4) then undergoes internal hydroxyl exchange to form a coumarone ring. The structure shown for the initial... 

Unlike alkylation, acylation is controlled easily to give monosubstitution, because once an acyl group is attached to a benzene ring, it is not possible to introduce a second acyl group into the same ring. Because of this, a convenient synthesis of alkylbenzenes starts with acylation, followed by reduction of the carbonyl group with zinc and hydrochloric acid (Section 16-6). For example, propylbenzene is prepared best by this two-step route because, as we have noted, the direct alkylation of benzene with propyl chloride produces considerable amounts of isopropylbenzene and polysubstitution products ... 

In the case of 1,3-diphenylfuro[3,2-c]pyrazole (58) most electrophilic substitutions, e.g., Vilsmeier formylation, Friedel-Crafts acylation, and monobromination, take place in the furan ring. Excess bromine gives the second bromination in the 4-position of the 1-phenyl group, but nitration gives the l-(4-nitrophenyl) derivative and a second, uncharacterized, product (78YZ204). 

All three isomerizations discussed above seem to occur by analogous mechanistic pathways similar to the mechanism formulated for the Dakin-West reaction [82]. Deacylation of the starting material H by catalyst G affords, in a fast and reversible step (Scheme 13.47, step I), an acylpyridinium/enolate ion-pair I. From this ion pair, enantioselective C-acylation proceeds in the rate-determining and irreversible second step, furnishing the C-acylated product J (Scheme 13.47, step II). 

The reusability of the catalyst is one of the major advantages of using RE(OTf)3 as a Friedel-Crafts catalyst. RE(OTf)3 can be easily recovered from the reaction mixture by simple extraction. The catalyst is soluble in the aqueous layer rather than in organic layer, and is recovered by removing water to give a crystalline residue, which can be re-used without further purification. The efficiency of recovery and the catalytic activity of the reused RE(OTf)3 were examined in the reaction of 1 with acetic anhydride using Yb(OTf)3 and Sc(OTf)3. As shown in Table 7, more than 90% of Yb(OTf)3 and Sc(OTf)3 were easily recovered, and the yields of acylation product 2 in the second and the third uses were almost the same as in the first. 

In the Sc(0Tf)3-LiC104-system, wider substrate scope was observed as is shown in Table 8. Each acylation reaction in the Table gave a single acylation product and formation of other isomers was not observed. Acetylation of anisole (1) resulted in excellent yield of the product (entry 1). Mesitylene (3) and xylenes were transformed to 2,4,6-trimethylacetophenone and dimethylacetophenones, respectively, in moderate yields (entries 2-5). It is noteworthy that toluene was acylated by the Sc(0Tf)3-LiC104 system to give 4-methylacetophenone in 48 % yield (entry 6) but the acylation did not proceed in the absence of LiC104. Furthermore, recovery and reuse of the RE(0Tf)3-LiC104 system were performed successfully. As shown in Table 9, the yields of 6 in the second and third uses of the catalyst system were almost the same as that in the first use. 

Another biosynthetic issue is the origin of complex hydrocarbon blends, such as the 11 different tetraenes of Ca. hemipterus (Figure 19.3). While there could be separate biosynthetic systems for each of the Ca. hemipterus tetraenes, a more parsimonious explanation, which fits the data, is that a single biosynthetic system exists with imperfect selectivity for acyl units (Bartelt et al., 1992b). If the most abundant tetraene, 5, represents the normal product, then tetraenes 6,7,14, and 18 represent instances of one acyl substitution (or biosynthetic mistake ). There are six possible ways in which two of these substitutions could exist in one compound, and these are represented by 8,15,16,19,20, and 21. Occurrence of two substitutions would be rarer than just one, and the observed abundances reflected this expectation. Tetraenes with three or four substitutions would be even rarer, and these were not detected. Substitutions were never observed for the second acyl unit, which was unfailingly propionate. Related arguments can be made for the patterns of hydrocarbons in Ca. freemani and Ca. davidsoni (Bartelt et al., 1990b Bartelt and Weisleder, 1996). 

This step leaves two cleavage products. The first, derived from the two carbons at the carboxyl end of the fatty acid, is acetyl-CoA, which can be further metabolized in the TCA cycle. The second cleavage product is a shorter fatty acyl-CoA. Thus, for example, the initial step of digesting a fatty acid with 16 carbons is an acyl-CoA molecule where the acyl group has 14 carbons and a molecule of acetyl-CoA. The P-oxidation scheme may be used to accommodate unsaturated fatty acids also. The reactions occur as described previously for the saturated portions of the molecule. Where a trans carbon-carbon double bond occurs between the %- and p-carbons of the acyl-CoA, the accommodation is fairly simple reaction 1 isn t needed. Where the double bonds are in the cis configuration, or are between the P and y carbons, isomerase enzymes change the location of the double bonds to make recognizable substrates for P-oxidation. 

And finally, acylating agents can also be used as electrophiles to react with enamines. Following the hydrolysis of the enaminoketones (i.e., compounds with the substructure R2N-C=C-C(=0)-R ) or enaminoesters (i.e., compounds with the substructure R2N-C=C-C(=0)-0R ) the acylation products of the corresponding ketones are obtained. Figure 12.21 gives the mechanistic details of the acylation with an acid chloride, and Figure 12.22 shows the acylation with ethyl chloroformate. The first acylation yields /1-diketones, the second furnishes a /1-ketoester. 

Under different reaction conditions, esters still other than the ones shown in Figure 10.53 can be employed for the acylation of ester enolates. In such a case, one completely deprotonates two equivalents of an ester with LDA or a comparable amide base and then adds one equivalent of the ester that serves as the acylating agent. The acylation product is a /3-ketoester, and thus a stronger C,H acid than the conjugate acid of the ester enolate employed. Therefore, the initially formed /3-ketoester reacts immediately in an acid/base reaction with the second equivalent of the ester enolate The /3-ketoester protonates this ester enolate and thereby consumes it completely. 

The reaction starts from [4+1] cycloaddition of the isocyanide to the electron-deficient heterodiene moiety of acid 396 to form intermediate iminolactone 397 that loses acetone to give acyl ketene 398 which then reacts with pyrrole at the ketene carbonyl to form the second acyl ketene 399 (Scheme 86). Ring closure of this ketene leads to the final product 400. Similar reaction conditions as described above, were employed for indole and 2-methylindole (Equation 94). 

The potential of the reverse polarity approach has been spectacularly demonstrated in a plethora of synthetic studies. A representative example can be found in Seebach s preparation of the antibiotic vermiculin. The key step of this synthesis involved the preparation of a polyfunctional intermediate 253 via the sequence shown in Scheme 2.102. The first stage of this sequence couples the formyl anion equivalent 244 with bromoepoxide 254. The primary bromide is more active as an electrophile than epoxide and therefore, under carefully controlled conditions, the product 255 is formed selectively. Under somewhat more stringent conditions the epoxide ring present in the latter adduct reacts as an electrophile with the second acyl anion equivalent 256 to yield adduct 257. In this sequence, 254 was used as an equivalent to the 1,4-doubly charged synthon CH2CH2CH(OH)CH. In the final step of this scheme, carbanion 258 was generated and reacted with dimethylformamide to produce the required product 253. It is remarkable that all of these sequential operations are carried out in one reaction vessel without the isolation of any intermediate products. The overall yield of 253 is rather high (approximately 52%). 

The second part is the interesting bit. Now the enol ester itself acts as the acylating agent equilibrium is set up between the O- and C-acylated products. The C-acylated product stable enolate between the two carbonyl groups and this tips the equilibrium in its favour. 

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