Trialkyl orthoformates

Aromatic compounds are formylated also by dichioromethyl methyl ether or trialkyl orthoformates (128). 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

Because of the higher CH acidity (by 7-8 pKa units) of alkylidene malonates (441), as compared with that of dialkyl malonates (87JA809), one-pot syntheses of alkylidene aminomethylenemalonates (442) could be carried out readily with a wide variety of primary and secondary aliphatic and cycloaliphatic amines, anilines, naphthylamines and heterocyclic amines, trialkyl orthoformate, and alkylidene malonates (83MI1 86MI9). It was proposed that the higher CH acidity of alkylidene malonates was a consequence of the electrostatic (dipole-dipole) repulsion effects... 

Using the optimized system for the two-component reaction, the same group [89] tested the three-component reaction, starting from an aldehyde, an amine and a phosphite (Scheme 42). An orthoester (trialkyl orthoformate, methyl or ethyl) was added to remove the formed water and to promote the imine formation, which was beneficial for the reaction however, these trials afforded maximally 49% yield due to the low conversions and low selectivities towards the desired aminophosphonates. 

Scheme 7.49). The requisite activated double bond is generated in situ from the 1,3-dicarbonyl compound and a one-carbon synthon such as a trialkyl orthoformate, diethoxymethyl acetate or Al,Al-dimethylformamide dimethyl acetal. 

Alkyl formates or formic acid and its esters can be converted to trialkyl orthothioformates [74-77] which in turn can be converted to trialkyl orthoformates in good yields [78, 79], It has been reported that acid chlorides of higher carboxylic acids can also be converted to trialkyl orthothioformates [80], but thus far no reports appear in the literature on attempts to convert them to trialkyl ortho esters. 

Since tetraalkyl orthocarbonates are related to the trialkyl orthoformates, attempts have been made to apply to them the transesterification reaction conditions discussed above. Results to date are discouraging. The reaction is difficult to drive to completion, and thus only mixtures of orthocarbonates are produced [81]. 

Preparation of Trialkyl Orthoformates by the Uncatalyzed Transesterification of Ethyl Orthoformate [37]... 

Preparation of peroxy ortho esters by the reaction of trialkyl orthoformates, orthoacetates, orthobenzoates, ketene acetals, and 2-phenyl-2-methoxy-l,3-dioxolanes with hydroperoxides or oxygen [194-197]. 

Preparation of acyclic acyloxy ortho esters by the reaction of acid anhydrides with trialkyl orthoformates and trialkyl orthoacetates [198-200]. 

N-monosubstituted aminomethylene derivatives of 1,3-dicarbonyls are accessible from trialkyl orthoformates, aromatic amines and 1,3-diketones. They are useful synthons for formation of hexahydroquinolinediones by treatment with KOH and malonodinitrile299. Depending on the substituents of the aniline derivative, replacement of the amine results from 1,4-addition-elimination of malonodinitrile or alkyl cyanoacetate to the en-aminedione and lead to quinolones300. The yields are not high but acceptable, since the starting materials are easily accessible (equation 223). 

Alkylation also occurs with acetals or trialkyl orthoformates in the presence of Lewis acids, to give the corresponding / ,y-unsaturated a-(a-alkoxyalkyl) or a-dia-lkoxymethyl carbonyl compound, respectively, on hydrolysis11. 

An efficient pinacol rearrangement mediated by trialkyl orthoformate has been developed [83]. The reactions of various types of 1,2-diol with a catalytic amount of SnCU in the presence of trimethyl orthoformate afford the rearranged product in good yields via a cyclic ortho ester intermediate (Eq. 50). This combined system is applicable not only to cyclic and acyclic tri- and tetrasubstituted diols but also to diols forming acid-sensitive acetals. 

Other alkylating agents which have been used include diazomethane [2], trialkyl phosphates [11], alkoxypho.sphonium salts [12], dimethylformamide dialkyl acetals [13], trialkyl orthoformates [14], alkyl cyanoformates [15], dialkyl carbonates (less toxic) [16] and, where more powerful reagents arc needed, alkyl fluorosulfonates, trialkyloxonium tetrafluoroborates [17], alky] triflates and mesylates [18, 19]. 

Weak bases can assist the reaction. Naturally, the only useful W-acyl substituents of use in lithiation sequences are the acetals (e.g. dialkoxymethyl), which can be made quite readily by treating the imidazole with a trialkyl orthoformate with p-toluenesulfonic acid as a catalyst. The groups are easily removed again, but have the drawback of also being unstable under dilithiation conditions [25, 55]. 

Acetalization with Trialkyl Orthoformates. In an acetal exchange reaction, trialkyl orthoformates will convert carbonyl groups to their corresponding acetal derivatives without concomitant formation of water. Weak acids such as NH4NO3 or amberlyst-15 (a sulfonic acid resin) catalyze the acetalization. ... 

The preparation of dialkyl oxalates by oxidative carbonylation of alcohols was first described by Fenton et al. in the early 1970s [72-74]. For example, the reaction can be carried out at a temperature around 125 °C and a pressure of about 70 bar in the presence of PdCl2 and iron or copper salts. Water is formed as a by-product and has to be removed from the reaction mixture by the addition of water-binding agents such as trialkyl orthoformates. Instead of oxygen benzo-quinone can also be used for the reoxidation of the catalyst system. Ammonia or amines seem to have a positive influence on selectivity and efficiency of the reae-tion. For some more examples, cf. [77-80, 117]. Mechanistic studies give some indication that alkoxycarbonylpalladium species occur as intermediates [52, 75, 76] (eq. (12)). 

Gallagher, M.J.. and Honegger, H., Dialkoxymethylation of phosphorus with trialkyl orthoformates. Reactions of phosphonic and phosphinic acids via then- trivalent tautomers. Tetrahedron Lett., 34, 2987, 1977. 

Etherification [1, 802, before references]. 3/3-Hydroxy-A5-steroids are etherified in 75-85% yield by treatment with a trialkyl orthoformate and 72% perchloric acid (2 1 equivalents).26... 

Trialkyl orthoformates. Trialkyl orthoformates are prepared conveniently in one step by the reaction of formamide and an alcohol in the presence of benzoyl chloride. Yields are 45-60% for lower alcohols.1... 

Aldehyde synthesis from Grignard reagents and trialkyl orthoformate see also Bouveault (see 1st edition). 

Trialkyl orthoformates Solutes appear as mixtures of rotational isomers having staggered arrangements of the R—O bonds in the group HC(OC)3 Aroney, ct al., 1964f... 

N-Alkylation of anthranils has been achieved using r-butyl alcohol in 60% perchloric acid,233,234 methyl fluorosulfonate,235 dimethyl sulfate,236 triethyloxonium tetrafluoroborate,237 and, unusually, trialkyl orthoformates in the presence of boron trifluoride etherate.237 Rate studies for the N-methylation of anthranils in dimethyl sulfate are available.36... 

Trialkyl orthoformates can be prepared by allowing the requisite alcohol and either benzoyl chloride or ethyl chloroformate to react simultaneously with formamide, in a process devised by Ohme and Schmitz 665 ... 

Acetalization. Admixture of carbonyl compounds with a trialkyl orthoformate and WClfi accomplishes the derivatization, usually giving the diethylacetals in >85% yield. 

The reaction of 6-alkylamino-3-methyluracils with trialkyl orthoformates in dimethylformamide gives the pyridodipyrimidines (316). 267... 

The preparation of acetals of the unknown formylphosphonic acid was reported by treating a dialkyl hydrogenphosphonate or a dialkyl trimethylsilyl phosphite wth trialkyl orthoformate in the presence of boron trifluoride. Another method which is reported to yield acylphosphonate ketals is the addition of dialkyl hydrogenphosphonates to ketene acetals (equation 55). For dithioketals, see Section II. C. 4. b. 

In the presence of dehydrating agents, such as trialkyl orthoformates the PdCl2/ CUCI2 redox system catalyzes the reaction of CO, O2 and ROH to form dialkyl oxalates [221,222], equations (167) and (168). 

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