Orthoformic acid synthesis

The preparation of orthoformic acid esters from chloroform and alkali metal alkoxides is a long known procedure, " which can be performed under phase transfer catalysis. If small amounts of alcohol are present in the phase-catalyz process, cyclopropanes (372 Scheme 67) can be produced by aHHifinn of dichlorocarbene to l,2-dialkoxy-l,2-dichloroethylenes, which are thought to be intermediates. " Al-kenes of this kind, e.g. (373 equation 176), have been observed as byproducts in the synthesis of tri-r-butylorthoformate from chlorodifluoromethane or dichlorofluoromethane and potassium r-butoxide. Trimethoxyacetonitrile was prepared from trichloroacetonitrile and sodium methoxide. ... 

Acetals from orthoformic acid esters Synthesis with addition of 1 C-atom... 

The intramolecular oxidative earbonylation has wide synthetie applieation. The 7-lactone 247 is prepared by intramolecular oxycarbonylation of the alke-nediol 244 with a stoichiometric amount of Pd(OAc)2 under atmospheric pres-sure[223]. The intermediate 245 is formed by oxypalladation, and subsequent CO insertion gives the acylpalladium 246. The oxycarbonylation of alkenols and alkanediols can be carried out with a catalytic amount of PdCl2 and a stoichiometric amount of CuCb, and has been applied to the synthesis of frenolicin(224] and frendicin B (249) from 248[225]. The carbonylation of the 4-penten-l,3-diol 250, catalyzed by PdCl2 and CuCl2, afforded in the c -3-hydroxytetrahydrofuran-2-aeetie acid lactone 251[226J. The cyclic acetal 253 is prepared from the dienone 252 in the presence of trimethyl orthoformate as an accepter of water formed by the oxidative reaction[227]. 

Fig. 2. Synthesis of uma2enil (18). The isonitrosoacetanihde is synthesized from 4-f1iioroani1ine. Cyclization using sulfuric acid is followed by oxidization using peracetic acid to the isatoic anhydride. Reaction of sarcosine in DMF and acetic acid leads to the benzodiazepine-2,5-dione. Deprotonation, phosphorylation, and subsequent reaction with diethyl malonate leads to the diester. After selective hydrolysis and decarboxylation the resulting monoester is nitrosated and catalyticaHy hydrogenated to the aminoester. Introduction of the final carbon atom is accompHshed by reaction of triethyl orthoformate to...

As inert as the C-25 lactone carbonyl has been during the course of this synthesis, it can serve the role of electrophile in a reaction with a nucleophile. For example, addition of benzyloxymethyl-lithium29 to a cold (-78 °C) solution of 41 in THF, followed by treatment of the intermediate hemiketal with methyl orthoformate under acidic conditions, provides intermediate 42 in 80% overall yield. Reduction of the carbon-bromine bond in 42 with concomitant -elimination of the C-9 ether oxygen is achieved with Zn-Cu couple and sodium iodide at 60 °C in DMF. Under these reaction conditions, it is conceivable that the bromine substituent in 42 is replaced by iodine, after which event reductive elimination occurs. Silylation of the newly formed tertiary hydroxyl group at C-12 with triethylsilyl perchlorate, followed by oxidative cleavage of the olefin with ozone, results in the formation of key intermediate 3 in 85 % yield from 42. 

The cyclization of 1,19-dideoxybilene-i-dicarboxylic acid esters has been widely used for the synthesis of porphyrins. In this case, the use of tert-butyl esters which can be hydrolyzed with trifluoroacetic acid prior to the cyclization step is necessary. The cyclization step also requires trifluoroacetic acid and orthoformates. However, attempts to prepare porphyrins with /f-acceptor substituents can give rise to problems with side products and yields. 

The one-pot MCR of methylene active nitriles 47 has been used in the synthesis of both pyrano- and pyrido[2,3-d]pyrimidine-2,4-diones in a single-mode microwave reactor [90]. Microwave irradiation of either barbituric acids 61 or 6-amino- or 6-(hydroxyamino)uracils 62 with triethyl-orthoformate and nitriles 47 (Z = CN, C02Et) with acetic anhydride at 75 °C for 2-8 min gave pyrano- and pyrido[2,3-d]pyrimidines in excellent yield and also provided a direct route to pyrido[2,3-d]pyrimidine N-oxides (Scheme 27). 

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). 

A patent procedure for formation of compounds 19 from simple tartaric acid derivatives has appeared <06USP047129> and various new routes to chiral dioxolanones include synthesis of dioxolan-2-ones either by transition metal-mediated asymmetric synthesis <06T1864> or enzyme-mediated kinetic resolution <06H(68)1329> and a new synthesis of the chiral dioxolan-4-ones 21 from lactic or mandelic acid involving initial formation of intermediates 20 with trimethyl orthoformate in cyclohexane followed by reaction with pivalaldehyde <06S3915>. 

The synthesis of the corresponding naphthyridone scaffold was carried out according to the methods reported by Chu et al. [12] and Sanchez et al. [13]. Namely, the hydrolysis of ethyl 2,6-dichloro-5-fluoronicotinate (3) [14] followed by reaction with thionyl chloride results in the formation of 2,6-dichloro-5-fluoronicotinyl chloride (4). Treatment of this compound with monoethyl malonate in THF under n-butyllithium followed by acidification and decarboxylation gives rise to ethyl 2,6-dichloro-5-fluoronicotinylacetate (5). Reaction of compound 5 with ethyl orthoformate in acetic acid followed by cyclopropylamine results in the formation of 3-cyclopropylamino-2-(2,6-dichloro-5-fluoronicotinyl)acrylate (6), the cyclization reaction of which under NaH/THF gives rise to the required ethyl l-cyclopropyl-6-fluoro-7-chloro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate (7), as shown in Scheme 3. 

The synthesis of compound 27 was initiated with the treatment of ke-toester 29, reported by Yoshida et al. [25], with ethyl orthoformate in acetic acid, followed by reaction with (l.R,2S)-2-fluoro-1-cyclopropylamine p-toluenesulfonic acid salt in the presence of triethylamine to yield an enam-inoketoester intermediate, cyclization of which under NaH in dioxane yields the 5-nitroquinolone derivative (30). Reduction of the nitro group of compound 30 followed by acid hydrolysis provides compound 27 via the amino-quinolone derivative (31), according to Scheme 7. 

The synthesis of the moxifloxacin core (de Souza, 2006 Martel et al., 1997 Seidel et al., 2000) proceeds from a Grohe-Heitzer sequence as described earlier in the chapter. Unlike the traditional Grohe-Heitzer sequence, however, the opening step involved the reaction between acid chloride 101 with the mono potassium salt of malonic acid monoethyl ester (102) in the presence of triethylamine to deliver ketoester 103 (Scheme 4.18). Treatment of 103 with ethyl orthoformate furnished acrylate 104, which reacted with cyclopropyl amine to afford 105. Cyclization of 105 in the presence of sodium fluoride in DMF gave the moxifloxicin core 106. 

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