A-alkoxymethylenation

Trifluoroacetamidine (585) is most widely used for the principal synthesis of pyrimidines. Compound 585 can be prepared from ethyl trifluoroacetate by ammo-nolysis, followed by dehydration with P2O5 and reaction with ammonia (Scheme 124) [335,336]. Amidine 585 has been introduced into reaction with various p-dicarbonyl compounds and their synthetic equivalents (Table 27), including p-ketoesters (Entries 1-6), in particular p-ketopyruvates (Entry 3) and a-alkoxymethylene-p-ketoesters (Entries 4-6), p-enaminocarbonyl compounds (Entries 7-9), malonic acid derivatives (Entry 10), fluorinated p-diketones (Entry 11), vinamidinium salts (Entry 12), a,p-unsaturated nitriles with leaving group at p position (Entries 13-15) and other bis-electrophiles (Entries 16, 17). Usually, the reaction gives moderate yields of the target 2-CF3-pyrimidines (ca. 50 %). 

A-Amino derivatives, e.g. (71), are converted to the corresponding NH compounds by nitrous acid and give acyl and alkoxymethylene derivatives with the usual reagents. 

Substituted malondialdehydes form pyrimidines substituted in the 5-position with an alkyl, aryl, halo, or hetero substituent. The pyrimidine is unsubstituted in the 4- and 6-positions. /3-Dialdehyde equivalents are frequently used in these reactions, for example, 3-alkoxy- or 3-aminoacroleins. With aldehydo ketones, the pyrimidine carries a substituent in the 4- or 6-position. The formyl group in the ketone is normally masked as an alkoxymethylene ketone or as an aminomethylene ketone. A commonly used procedure involves the preparation of a dimethylaminomethyl-ene ketone 645 by reaction of a methyl ketone 644 with DMF dimethylacetal and subsequent reaction with an amidine or guanidine to form the target pyrimidine 646 <2003MI237, 2004JHC461>. 

There are few cases in which free /3-aldehydo esters have been condensed successfully with ureas. Commonly, alkoxymethylene esters are used. The initial reaction leads to an acyclic intermediate that may require a separate treatment to induce ring closure. The reaction of a /3-keto ester with urea may be a two-step process in which case acid catalysis can be used in the formation of an acyclic intermediate, with ring closure effected by strong alkali. When the ester component is a lactone or chromone, the product contains a hydroxyalkyl <2000JME3837> or 2-hydroxyphenyl substituent <2004S942>, as shown by the synthesis of the 5-(2-hydroxyethyl)-4-pyrimidinone 657 and the 6-(2-hydroxyphenyl)-pyrimidine 659. 

The use of 4-heteroarylmethylene- and 4-aryhnethylene-5(47/)-oxazolones as dienophiles in the Diels-Alder reaction has been recently reviewed. More recently the reactivity of the exocyclic double bond of 4-(alkoxymethylene)-5(4//)-oxazolones with several dienes has been assessed. Reaction of 4-(methoxymethyl-ene)-2-phenyl-5(477)-oxazolone and 1,3-butadiene requires the presence of Et2AlCl as a catalyst and even then the Diels-Alder cycloadduct is obtained in low yield. 

The reaction of halogenotriphenylphosphonium halides (triphenyl-phosphine dihalides) with alcohols is a useful method for the synthesis of alkyl halides (see Section II,2b p. 239). It has been found88 that (alkoxymethylene)dimethyliminium halides are formed in the reactions of these reagents with alcohols in N,N-dimethylformamide a possible mechanism is shown. Hydrolysis of the (alkoxymethylene)-dimethyliminium halide intermediate affords a formic ester, whereas... 

X2M(TV21-TV22-alkoxymethylene-TPP) are the only examples of TV,TV -dialkylporphyrin complexes (Scheme 39).16 TV-Aminoporphyrins are stable enough to be metallated only as their amide forms (Scheme 40).158 The X-ray structure analysis of Ni(TV-NTs-TPP) revealed that the Ni ion is coordinated with the macrocycle through three pyrrolic nitrogens and an amide nitrogen. A porphyrin TV-oxide, (7V-0)H2(0EP), and its Cu complex have been reported, but the complex appears to be unstable in solution (Scheme 41),159... 

Allopurinol, 1,5-dihydro-4//-pyrazolo[3,4-d]pyrimidin-4-one (53), was first synthesized by Robins <56JA784> and by Schmidt <58HCA1052) from 5-aminopyrazole-4-carboxylic acid derivatives. Several syntheses starting from a simple acyclic intermediate have been reported. Thus, reacting ethyl alkoxymethylene cyanoacetate with hydrazine and formamide at 14(M80°C gave allopurinol in high yield. An acid catalyst lowers the temperature required for cyclization of the intermediate 4-alkoxycarbonyl-3-aminopyrazole and raises the purity and the yield of allopurinol <69BRPI 284084). 

Enaminones react98 with alkoxymethylene compounds derived from 1,3-dicarbonyl derivatives according to Bottorf and coworkers99 to give substituted pyridines as a result of Michael addition of the enaminone nitrogen (equation 68). Similarly, nitroolefines can be condensed with enaminone derivatives to give 3-nitropyridine derivatives100 (equation 69). 

The tricyclic core (164) has been prepared by a number of different routes, most commonly by a Diels-Alder reaction. Three approaches to the Diels-Alder have been followed. Pandit, at the University of Amsterdam, first prepared the tricyclic core (132, 133) focusing on the concurrent construction of the C(6)-C(7) and C(5)-C(10) bonds via an intramoleculer Diels-Alder reaction (Scheme 11). The stereochemical preference for 168 results from an unfavorable interaction of the alkoxymethylene (R in 168) with the dienophile, leading to a 3.5 1 mixture in favor of the desired diastereomer 168 (134). 

Two other intramolecular Diels-Alder reactions focus on concurrent formation of the C(5)-C(10) and C(8)-C(9) bonds (135-138). Martin and coworkers at the University of Texas at Austin (135, 136) found that Lewis acid catalysis of 169 provided the desired diastereomeric product, 170 (Scheme 12) the stereochemical consequences of cyclization of 169 was investigated with respect to the A3 stereochemistry, demonstrating maximum selectivity (8 1), over the C(5) epimer, when the A3 olefin was cis (136). A subsequent extension of this method by Martin resulted in the introduction of an alkoxymethylene group to C(6) of 170, thus setting up intermediate 170 for attachment of the P-carboline ring system (136). The... 

To a well-stirred solution of 98% methylhydrazine (0.3 mL, 5.64 mmol) in anhyd MeCN (10 mL), cooled in an ice-water bath, was added 2-[(alkoxymethylene)aminopyridine-3-carbonitrile, prepared from 2-amino-nicotinonitrile (0.6 g, 5.7 mmol). The mixture was stirred overnight under N2. The solvent was removed on a Kugelrohr apparatus (25°C/0.7 Torr) to furnish the product which was obtained as a solid and recrystallized (McCN) as bright yellow needles yield 400 mg (46%) mp 156-158 C. 

It is not always necessary to start from the pre-formed alkoxymethylene compound (2, 3, 4, etc.) they can be prepared from an orthformic ester and a compound containing a reactive methylene group and treated with the amine in one operation.1088... 

Alkoxymethylen-iminium-592,595 und 2-Alkoxy-pyridinium-Salze596,597 sind Zwischenprodukte in zahlreichen Syntheseverfahren (vgl. a. S.77f.). 

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