Preparation of orthoesters

Preparation of mixed acetals, 416 Preparation of nitrates, 415 Preparation of orthoesters, 414 Preparation of pregna-5,6-diene-3,20-dione, 316... 

Side Note 7.2. Chemistry of Imidic Acid Ester Hydrochlorides Preparation of Orthoesters and Amidines... 

Mol. wt. 107.15, sp. gr. 0.923, b.p. 142-143°. Suppliers A, B, E, F, KK, MCB. Mazurek and Perlin found this pyridine homolog superior to silver carbonate, the usual acid acceptor, for the preparation of orthoesters (3) from 2,3,4,6-tetra-O-acetyl-a-D-mannopyranosyl bromide (1). Of considerable interest is the fact that... 

Ethyl orthoformate is prepared in 45% yield by adding sodium metal portionwise to a mixture of excess absolute alcohol and chloroform [6]. (See Kaufmann and Dreger [6] for earlier references to this reaction.) A recent references describes this preparation from chloroform with 3 moles of EtONa in excess EtOH [7]. See Table I for additional and related examples with references for the preparation of orthoesters. 

Ketene di(2-melhoxyethyl) acetal has been obtained by the present method with the use of diethylene glycol dimethyl ether as solvent.3 Other methods for the preparation of ketene acetals include the dehydrohalogenation of a halo acetal with potassium t-butoxide 4 and the reaction of an a-bromo orthoester with metallic sodium.5... 

In the presence of orthoester and perchloric acid, 3-acetyltropolone (74) with benzaldehydes affords pyranones 76 directly (90JHC891). The reaction is considered to pass through a carbocation (from 74 and orthoester) which is stabilized by electron-donating substituents in the benzaldehyde (Ar). Therefore, the one-step synthesis might be limited to methoxy- and hydro-xybenzaldehydes. These synthons are also used to prepare corresponding... 

The preparation of several glucofuran [2, l-t/] oxazolines 35 and 36 from reaction of 2-amino-2-deoxy-D-glucose 34 with HF has been described. Compounds 35a and 35b are formed when the reaction is carried out in formic acid, whereas the orthoesters 36a-c are formed when the reaction is carried out using anhydrides. Further reaction of 35 and 36 with methanol gives methyl glycosides. Thus, 35 and 36 may hnd use as potential glycosyl donors for the synthesis of 2-amino-2-deoxy sugars (Scheme 8.14). " ... 

A number of anhydro sugar derivatives have been prepared by treatment of orthoesters with mercuric bromide in nitromethane. Among them are 3-0-acetyl-l,5-anhydro-2-0-benzoyl-/3-L-arabinofuranose,68... 

Incorporation of the tetrahydrofuran ring into condensation polymers has been accomplished (79USP4180646) by transesterification of orthoester (43) with polyols to prepare poly (orthoesters) (44 Scheme 11). This polymerization reaction has been extended to a wide variety of other orthoester and orthocarbonate starting materials. The product polymers are reported to be excellent biodegradable matrices for drug delivery. 

The cyclization of a-hydrazono oximes (635) with orthocarboxylates is an excellent way of preparing 1,2,4-triazine 4-oxides (636) (73TL1429,7lLA(750)12,77LA1713). Using aldehydes or ketones instead of orthoesters provides 2,3-dihydro derivatives (637 Scheme 22) (75S794). Cyclization of a-hydrazonocarboxamides (638) with carbonic acid derivatives such as ethyl chloroformate affords l,2,4-triazine-3,5-diones (639) (68M1808). The a-hydrazonocarboxamides (638) can be prepared by the reaction of diazonium salts with a-activated acetamides such as cyanoacetamide as shown. 

Thiol esters RC(0)SR have been prepared by nucleophilic cleavage of polystyrene-bound /V-acylsulfonamides with mixtures of a thiol and sodium thiophenolate [377] or LiBr [378], or by treatment of Wang or PAM resin bound carboxylic esters with ethanethiol in the presence of a Lewis acid (AlMe2Cl or AlMe3, DCM, 20 °C, 3 h [379,380]). The latter method can also give rise to the formation of orthoesters RC(SEt)3 and ketene thioacetals, which can, however, be hydrolyzed to the desired thiol esters by treatment with TFA [379]. 

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. 

In Reichstein s synthesis15 of convallatoxin (9), 2,3,4-tri-0-acetyl-6-deoxy-a-L-mannosyl bromide (13) (a 1,2-trans halide) was employed. In contrast to the preparation of simple glycosides, the use of silver carbonate did not lead to orthoester formation instead, glycoside formation took... 

One final class of initiators seems to belong in this group. The use of the Lewis acid/orthoester combination reported by Meerwein (3) is similar to the Lewis acid/promotor systems just discussed, in that the tertiary oxonium ion is generated in situ from the reactants. In this case, however, one first needs to consider the preparation of the "tertiary... 

Alkoxy or 2,2-dialkoxy nitriles.10 Ketals or orthoesters are converted into 2-alkoxy or 2,2-dialkoxy nitriles, respectively, by reaction with cyanotrimethylsilane in the presence of SnCl2 or BF3-0(C2H5)2 as catalyst. A typical reaction is the preparation of dimethoxyacetonitrile (1), which is a useful reagent for conversion of alkyl halides to the homologous methyl carboxylate (equation I). 

Finally, it may be noted that 4,6-orthoesters obtained for example by reaction of sucrose with ethyl orthoacrylate can be opened to form either the 6- or 4-esters,146 providing convenient starting materials for the preparation of biodegradable polymers (see Scheme 7). 

Various functionalized alkynes can be submitted to carbocupration reactions, such as alkoxyalkynes,150 alkynyl carbamates,151 acetylenic orthoesters,152 and thioalkynes.153 The carbocupration of orthoesters, for example, 204, has been used to prepare a-substituted esters of the type 206 by acidic hydrolysis of the adduct 205 (Scheme 51).152 This allows the formation of regioisomers that are not accessible by copper-mediated addition to acetylenic esters. A stereoselective synthesis of trisubstituted alkenes has been described by Normant et al.lSd> starting from phenylthio-acetylene 207. Carbocupration with lithium di- -butylcuprate affords the intermediate 208 which, upon addition of /z-butyllithium, undergoes a 1,2-metalate rearrangement to the vinylcuprate 209. The latter can be trapped with various electrophiles, for example, ethyl propiolate, providing product 210 with complete regio- and stereocontrol. 

Deprotonation of amidinium salts gives 1,1-enediamines112 and the method is well suited for the preparation of simple cyclic 1,1-enediamines18, 41. 4,5-Dihydroimidazolium salts 99, prepared easily by alkylation of imidazolines or cyclization of ethylenediamine with orthoesters, react with sodium hydride to afford 2-alkylideneimidazolidines 100 in good to excellent yields (equation 34)18. 

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