Synthesis of Formamides

Hydrocarbonylation of aromatic nitro compounds yields the corresponding aromatic formamides [74]  

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Problem 16.47. Amides can also be synthesized by using the acid chloride or acid anhydride instead of the carboxylic acid. Give equations for the synthesis of formamide from formyl chloride and formic anhydride. 

While entry 5 (CYPHOS IL 163) may be considered a borderline ionic, to date, of all the phosphonium-based ILs, it has received the most attention. Garayt et al. have patented a process to fluorinate aromatics [20]. Previously, Knifton, lin et al. have published and patented an enormous number of petrochemical applications using entry 5 as the solvent-alcohols from syngas [21-29], synthesis of acetaldehyde and acetic acid from syngas [40-45], synthesis of esters from syngas [46, 47], and synthesis of formamides and amines [48, 49],... 

The synthesis of formamides was discovered by W. Reppe in the 40s using iron, nickel or cobalt catalysts under high pressure. Use of bases (NaOH, NaOMe, etc.) in alcohohc medium has recently allowed much milder conditions hence dimethylformamide can, for example, be prepared at room temperature under only 5 to 10 bar with excellent yields (Table IX). 

Formamides are useful protecting groups in organic synthesis and serve as key building blocks in the synthesis of isocyanides and heterocycles. Current methods to access formamides rely on the use of moisture sensitive or toxic reagents. Williams and co-workers reported the synthesis of formamides... 

Scheme 12.25 Amine/paraformaldehyde eoupling for the synthesis of formamides.

Glorius and co-workers reported an alternative approach for the synthesis of formamides by dehydrogenative coupling of methanol with amines. The dehydrogenation of methanol is energetically disfavoured AH=84 kJmol ) compared to ethanol and higher alcohols [AH = 68 kj moP ) and few reports of couplings with methanol exist presumably for this reason. ... 

Ai,A/-bis(hydroxymethyl) formamide [6921-98-8] (21), which in solution is in equiUbrium with the monomethylol derivative [13052-19-2] and formaldehyde. With ben2aldehyde in the presence of pyridine, formamide condenses to yield ben2yhdene bisformamide [14328-12-2]. Similar reactions occur with ketones, which, however, requite more drastic reaction conditions. Formamide is a valuable reagent in the synthesis of heterocycHc compounds. Synthetic routes to various types of compounds like imida2oles, oxa2oles, pyrimidines, tria2ines, xanthines, and even complex purine alkaloids, eg, theophylline [58-55-9] theobromine [83-67-0], and caffeine [58-08-2], have been devised (22). 

The estimated capacity of formamide was approximately 100,000 t/yr worldwide in 1990. In 1993, there are only three significant producers BASE in Germany is the leading manufacturer. Smaller quantities of formamide are produced in the former Czechoslovakia (Sokolov) and Japan (Nitto) by direct synthesis from carbon monoxide and ammonia. Most of the formamide produced is utilized direcdy by the manufacturers. The market price for formamide (ca 1993) is about 2.00/kg. 

Aromatic and heterocycHc compounds are formylated by reaction with dialkyl- or alkylarylformamides in the presence of phosphoms oxychloride or phosgene (Vilsmeier aldehyde synthesis) (125). The Vilsmeier reaction is a Friedel-Crafts type formylation (126), since the intermediate cation formed by the interaction of phosphoms oxychloride with formamide is a typical electrophilic reagent. Ionic addition compounds of formamide with phosgene or phosphoms oxychloride are also known (127). 

Finally, some results obtained from indazoles substituted in the carbocycle are of interest, even though in these cases the reaction does not involve the heterocyclic moiety (Section 4.04.2.3.2(ii)). For example, pyrazolo[3,4-/]- (566) and pyrazolo[4,3-/]-quinolines (567) have been obtained from aminoindazoles by the Skraup synthesis (76JHC899). Diethylethoxy-methylenemalonate can also be used to give (566 R = C02Et, R = OH) (77JHC1175). Pyrazolo-[4,3-/]- and -[4,3-g]-quinazolones (568) and (569) have been obtained from the reaction of formamide with 5-amino-4-methoxycarbonyl- and 6-amino-5-carboxyindazole, respectively (81CB1624). 

ATHERTON TODD Phosphoramidate Synihasis Synthesis of phosphoramidates from formamides and dialkyl phosphite. 

With optically active formamide-derived aminocarbene complexes high enantioselectivity was observed in most cases (Table 5). This chemistry was used in the synthesis of 1-carbacephalathin and 3-ANA precursors (Eq. 9) [48], as well as the synthesis of a,a -disubstituted amino acids (Scheme 1) [49]. 

An alternative approach towards the PASP synthesis of isocyanides was developed by Bradley [100,101]. It involved the use of a polymer-supported sul-fonyl chloride in the presence of base to afford the dehydration of formamides (Scheme 21). The formamides required could be easily prepared by reaction of the corresponding amines with a formylated benzotriazole resin. Opti-... 

Several reactions have been demonstrated using microreactors. One of the potentially more important is the direct synthesis of MIC from oxygen and methyl formamide over a silver catalyst. Dupont have demonstrated this process using a microreactor cell similar to that described above in which the two reactants are mixed, then heated to 300 °C in a separate layer and subsequently passed through another tube coated with the silver catalyst. The estimated capacity of a single cell with tube diameters of a few millimetres is 18 tpa. 

Transition metal complexes have been used in a number of reactions leading to the direct synthesis of pyridine derivatives from acyclic compounds and from other heterocycles. It is pertinent also to describe two methods that have been employed to prepare difficultly accessible 3-alkyl-, 3-formyl-, and 3-acylpyridines. By elaborating on reported194,195 procedures used in aromatic reactions, it is possible to convert 3-bromopyridines to products containing a 3-oxoalkyl function196 (Scheme 129). A minor problem in this simple catalytic process is caused by the formation in some cases of 2-substituted pyridines but this is minimized by using dimethyl-formamide as the solvent.196... 

A test library with three novel p38a inhibitory activity has been prepared, among them pyrazolo[3,4-c/]pyrimidine and pyrazolo[3,4-h]pyrazine with potent in vivo activity <06BMCL262>. A convenient route for the synthesis of pyrazolo[3,4-<7]pyrimidine involving Friedlander condensation of 5-aminopyrazole-4-carbaldehyde with formamide or benzamide has been reported <06JHC1169>. A facile synthesis of pyrazolo[3,4-<7]pyrimidines and pyrimido[4,5-<7]pyrimidin-4-one derivatives has been published <06SC2963>. 

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