Carboxylic acids orthoesters

A series of cyclohept[l,2-A5,4-3 ]bisindole derivatives have been obtained by the reaction of l,2-bis(17/-indol-2-yl)-ethane 208 with carboxylic acids, orthoesters, aldehydes, or ketones under acid conditions (Equation 138 Table 17) <2000T1911>. In the case of the reaction with TEA, the major product is the fully conjugated derivative (Section 10.21.5.1.3). 

In order to become useful dmg delivery devices, biodegradable polymers must be formable into desired shapes of appropriate size, have adequate dimensional stability and appropriate strength-loss characteristics, be completely biodegradable, and be sterilizahle (70). The polymers most often studied for biodegradable dmg delivery applications are carboxylic acid derivatives such as polyamides poly(a-hydroxy acids) such as poly(lactic acid) [26100-51-6] and poly(glycolic acid) [26124-68-5], cross-linked polyesters poly(orthoesters) poly anhydrides and poly(alkyl 2-cyanoacrylates). The relative stabiUty of hydrolytically labile linkages ia these polymers (70) is as follows ... 

Carboxylic acids can also be protected as orthoesters. Orthoesters derived from simple alcohols are very easily hydrolyzed, and the 4-methyl-2,6,7-trioxabicyclo[2.2.2]octane structure is a more useful orthoester protecting group. These... 

As in Section 5.06.9.1, the assignments are sometimes arbitrary. Important routes to oxadiazoles, aminooxadiazoles, oxadiazolinones, and oxadiazolinethiones involving the reaction of hydrazides RCONHNH2 with carboxylic acids, acyl chlorides, alkyl esters, or trialkyl orthoesters are described in Section 5.06.9.2.1, reactions with carbon disulfide... 

Under mild conditions the [4,3-a] intermediate is isolable in many cases, and always with aliphatic orthoesters contrary reports (66JHC269) can be attributed to admixture of the corresponding carboxylic acid (77AJC2515). Orthobenzoic ester leads to the rearranged product (77AJC2515). 

Treatment of salicylic hydrazide in toluene with a single carbon insertion unit, such as carboxylic acid anhydride, acid chloride, and orthoester, in the presence of an equimolecular amount of methanesulfonic acid gave the l,3,4-benzoxadiazepin-5-ones (530) (43-68% yield), via the O-acylation intermediates (529) (92S929). 

Although Z-alkene isosteres have been obtained from Wittig alkenation reactions of a-amino aldehydes using triphenyl[3-(trimethylsilyl)prop-2-ynylidene]phosphorane (Section 10.5.2.1.2.1), this stereoisomer was always obtained in minor amounts. Z-Selective alkena-tions were obtained using ylides containing dioxolane-protected aldehydes 42 or orthoester-protected carboxylic acid functions. 58 No experimental data were published, however. 

Numerous solid-phase preparations of quinazolinones have been reported. The main synthetic strategies used are summarized in Figure 15.16. Quinazolin-2,4-diones can be prepared from anthranilic acid derived ureas or from N-(alkoxycarbonyl)-anthranilamides. These reactions have been performed on insoluble supports either in such a way that the cyclized product remains linked to the support, or such that it is simultaneously cleaved from the support upon ring formation. Quinazolin-4-ones can be prepared by cyclocondensation of anthranilamides with aldehydes, orthoesters [342], or other carboxylic acid derivatives [343]. The selection of examples listed in Table 15.29 illustrates the variety of substitution patterns accessible by means of these cyclizations. 

As a class of compounds, nitriles have broad commercial utility that includes their use as solvents, feedstocks, pharmaceuticals, catalysts, and pesticides. The versatile reactivity of organonitriles arises both from the reactivity of the C=N bond, and from the ability of the cyano substituent to activate adjacent bonds, especially C—H bonds. Nitriles can be used to prepare amines, amides, amidines, carboxylic acids and esters, aldehydes, ketones, large-ring cyclic ketones, imines, heterocycles, orthoesters, and other compounds. Some of the more common transformations involve hydrolysis or alcoholysis to produce amides, acids and esters, and hydrogenation to produce amines, which are intermediates for the production of polyurethanes and polyamides. An extensive review on hydrogenation of nitriles has been recendy published (10). 

Orthoesters. As model experiments (1) phenyl Cellosolve and tetraphenyl orthocarbonate, and (2) hydroxyethyl benzoate and tetra-phenyl orthocarbonate reacted at 275°C. Diphenyl carbonate was obtained from the latter reaction but not from the former. The facts that the distillate from the latter reaction contained ethylene oxide and that diphenyl carbonate was formed quantitatively from the reaction of carboxylic acid and tetraphenyl orthocarbonate suggest the following reaction mechanism ... 

In the Johnson orthoester variant a weak carboxylic acid catalyzes the first two steps of the reaction... 

Fig. 7.5. Application of the reaction principle underlying Figure 7.4 for the conversion of tertiary carboxylic acid amides into acylating agents for alcohols. Very mild workup conditions lead to the orthoesters D, while the normal carboxylic acid esters B are obtained with aqueous standard workup.

Another interpretation of the initial reactions of Figure 9.14 is that formic acid orthoester under acidic conditions produces a carboxonium ion that can add an O nucleophile. It thus becomes immediately clear how an orthoformate reacts with carboxylic acids under acidic conditions. This is documented in the left row of Figure 9.15. When the carboxonium ion F is thus obtained, two more steps lead to the formation of the carboxonium ion H, which is an... 

We have already mentioned that one of the factors that makes acyclic ftemiacetals unstable is the unfavourable decrease in entropy when two molecules of starting material (aldehyde or ketone plus alcohol) become one of product. The same is true for acetal formation, when three molecules of starting material (aldehyde or ketone plus 2 x alcohol) become two of product (acetal plus H2O). We can improve matters if we tie the two alcohol molecules together in a diol and make a cyclic acetal we discuss cyclic acetals in the next section. Alternatively, we can use an orthoester as a source of alcohol. Orthoesters can be viewed as the acetals of esters or as the triesters of the unknown orthoacids —the hydrates of carboxylic acids. They are hydrolysed by water, catalysed by acid, to ester + 2 x alcohol. 

The rearrangement of isopent-3-enyl epoxy esters with Cp2ZrCl2/AgC104 yields asymmetric bicyclo octane esters which are base-stable protecting groups for carboxylic acids (Scheme 48). However, the orthoesters are only the kinetic products and can rearrange under reaction conditions to more stable THF derivatives. 

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