Formamides condensation with

Fluorenylamine, 40,5 Formaldehyde, reaction with diethyl malonate to form diethyl bis-(hydroxymethyl)malonate, 40,27 Formamide, condensation with 4,4-dimethoxy-2-butanone to give 4-methylpyrimidine, 43, 77 Formic acid, and hydrogen peroxide, with indcne, 41, 53... 

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 condensation of a vinylogous formamide with an enamine has been applied to an aza azulene synthesis (351). The point of attachment of the aldehyde to the enamine in condensations with indolenin derived poly-enamines was found to favor the second double bond (352,353). 

A. N,N-Dimeihyljormamide-dimelhyl sulfate complex. In a 500-ml. four-necked flask equipped with mechanical stirrer, reflux condenser with calcium chloride drying tube, dropping funnel, and thermometer is placed 73 g. (1.0 mole) of dimethyl-formamide, and 126 g. (1.0 mole) of dimethyl sulfate is added dropwise with stirring at 50-60° (Note 1). After the addition is complete, the mixture is heated for another 2 hours at 70-80°. The dimethylformamide complex forms as a viscous, colorless or pale yellow ether-insoluble oil. 

Benzaldehyde reacts with formamide and MesSiCl 14 on heating to give, via 435, the N,N-acetal 469, which reacts in situ with p-toluenesulfinic acid, in high yields, to give 470 [58]. The analogous reaction of excess a,)9-unsaturated ahphatic primary amide with aliphatic aldehydes in the presence of TMSOTf 20 in 1,2-di-chloroethane at 25 °C affords the unsaturated N,N-acetals in high yield [58 a]. Benzaldehyde also condenses with excess HMDS 2, in the presence of catalytic amounts of ZnCl2, via 471, to 472 and HMDSO 7 [59] (Scheme 5.21). 

Spirothiopyrans 45b including a benzopyrylium ring have been prepared in one step by condensation of 2-aminovinyl-3-formyl chromone-4-thione 47 with 1,2,3,3-tetramethylindolinium salts in ethanol (Scheme 25).90 The precursor 47 is prepared from 3-carboxymethylene-2-methyl-chromone-4-thione 48. First, oxidation of 48 with pyridinium dichromate in CH2C12, and then condensation with dimethyl formamide dimethyl acetal in benzene gave compound 47. 

Another multistep protocol that initially involves the formation of fused pyrimidines (quinazolines) has been described by Besson and coworkers in the context of synthesizing 8f-/-quinazolino[4,3-b]quinazolin-8-ones via double Niementowski condensation reactions (Scheme 6.250) [437]. In the first step of the sequence, an anthranilic acid was condensed with formamide (5.0 equivalents) under open-vessel microwave conditions (Niementowski condensation). Subsequent chlorination with excess POCl3, again under open-vessel conditions, produced the anticipated 4-chloro-quinazoline derivatives, which were subsequently condensed with anthranilic acids in acetic acid to produce the tetracyclic 8H-quinazolino[4,3-b]quinazolin-8-one target structures. The final condensation reactions were completed within 20 min under open-vessel reflux conditions (ca. 105 °C), but not surprisingly could also be performed within 10 min by sealed-vessel heating at 130 °C. 

The conversion of D-mannose (20) into L-gulose (9) was reported by Evans and Parrish,15 and is shown in Scheme 4. D-Mannose (20) was converted into 21 by condensation with acetone, methanol, and 2,2-di-methoxypropane in the presence of an acid, and mild hydrolysis of 21 afforded 22. Methanesulfonylation of 22 provided 23, which was transformed into 24 with sodium acetate in refluxing N,N-dimethyl-formamide. The overall yield of 24 from D-mannose was >50%. Base hydrolysis, followed by acid hydrolysis, afforded L-gulose (9). 

Aminopyridazine-3-carboxamide condenses with urea and ethyl orthoformate to give pyrimido[5,4-c]pyridazine-6,8-dione and pyrimido[5,4-c]pyridazin-8-one, respectively. In like manner, 8-aminopyrimido[5,4-c]pyridazine is formed by the reaction of 4-amino-3-cyanopyridazine with formamide (68JHC523). 

Azapurines were also synthesized by the condensation of 5-amino-l,2,3-triazole carboxamides 118 or 119 with formamide or with formamidinium acetate. When the triazole carried neutral substituents at N-l such as in 118, the expected 8-azapurin-6-ones 121 were formed, but when an acidic substituent was present in the same positions as in 4-carboxyphenyltri-azolamide 119, the condensation reaction gave a mixture of 6-amino-8-azapurine 120 together with 121 in addition to a small amount of Dimroth isomer 122. However, reaction of 119 with triethyl orthoformate gave a mixture of azapurine 121 and an excess of the isomeric triazole 122 (80FES308 90CZ246) (Scheme 24). 

The reaction of 5-aminopyrazole-4-carboxylates with amides affords pyrazolo[3,4-d]pyrimidines <79AP(312)703, 87MI 712-02). The synthesis of allopurinol (53) by reaction of ethyl ethoxymethyl-enecyanoacetate, hydrazine, and formamide probably proceeds via intermediacy of ethyl 5-amino-1 //-pyrazole-4-carboxylate which then condenses with formamide to yield intermediate (318) which readily cyclizes to allopurinol (53) <74NEP7507554>. 

Azine approach. 4-Amino-5-hydroxypyrimidine condenses with acid anhydrides or esters to form the corresponding 2-substituted oxazolopyrimidine system (77CPB491). Under relatively mild reaction conditions the nucleoside 6-amino-5-hydroxyuridine will undergo cyclocondensation with formamide under the influence of polyphosphate ester to form the oxazolo-fused nucleoside (230) both protected and non-protected pyrimidine nucleosides have been used in this reaction (73CPB1327). 

Andrew D. Batcho and Willy Leimgruber 214 INDOLES FROM 2-METHYLNITROBENZENES BY CONDENSATION WITH FORMAMIDE ACETALS FOLLOWED BY REDUCTION 4-BENZYLOXYINDOLE... 

The reductive cyclization of 2-nitrobenzyl-A, A -bis(formamide) with zinc in acetic acid to quinazoline was first described by RiedelT ° The reaction is used successfully for the synthesis of larger quantities of quinazoline and its benzene-ring-substituted derivatives 12 from 2-ni-trobenzyl-A, A -bis(formamides) 11. The method is suitable only for the preparation of 4-un-substituted quinazolines, because 2-nitro-substituted phenones do not condense with aliphatic amides to yield bis(amide) derivatives. Zinc in acetic acid is the reducing agent of choice, but iron in hydrochloric acid or Raney nickel can also be used. " Applications of compounds other than bis(formamides) [e.g., bis(acetamides) ] and preparation of 2-substituted quinazolines by Riedel s synthesis are scarce. 

The reagents used for the completion of the purine heterocycle are essentially the same as those used for the Traubc synthesis. The purine ring is formed by condensation with derivatives of formic acid or other carboxylic acids. Alternatively, formylation of the amino group is accomplished by a mixture of formic acid and acetic anhydride followed by cyclization. Alkyl esters or trialkyl ortho esters are also versatile synthons for ring closure. Moreover, heating in formamide or cyclization with urea or thiourea provides a satisfactory route. Condensations with isothiocyanates show unusual versatility leading to 2-sulfanylpurin-6-ols. From carbonic acid derivatives, cyclization is reported with chlorocarbonic esters, diethyl carbonate or carbon disulfide. 

The methylene group in 3-oxo-2,3-dihydrobenzotellurophene condenses with dimethyl-formamide, aromatic aldehydes, bis[ethoxy](dimethylamino)methane, and 4-nitroso-A(,(V-dimethylaniline. ... 

Related reactions include the formation of the 2-cyano compounds (190) when 1,2-dimethyl-5-nitroimidazole is heated with nitrosyl chloride or an AT-oxide, and when 2-methyl-l-(o-nitrophenyl)imidazoles (191) cyclize under the influence of iron(II) oxalate (Scheme 98) (74JCS(P1)1970). The last reaction product is contaminated by a large amount of amine reduction product ( 64%) but there is also some cyclization with the 4-methyl isomer of (191). In the presence of trimethylamine, 2-cyanomethylbenzimidazole condenses with acetone to give the unsaturated derivative (192 Scheme 99) (77CPB3087). Neither 2-methylimidazole nor 2-methylbenzimidazole reacts with formamide in the presence of phosphoryl chloride. 

In 1968, the scope of the formamide condensation was greatly expanded by discovery of practical syntheses for the 1- and 2-methyl derivatives of 4-amino-1,2,3-triazole-5-carboxamide. These, for the first time, made possible the direct preparation, and in excellent yields, of 7- and 8-alkyl-substituted 8-azapurines. These new triazoles also underwent condensation with (an excess of) urea and thiourea (175°C, 1 h, no solvent) to give the correspondingly methylated derivatives of 8-azapurine-2,6-dione (64-89% yield) and 2-thioxo-8-azapurin-6-one (55% yield), respectively. ... 

Esterification of starch dialdehyde with chlorosulfonic acid in formamide gave a sulfate ester that could be transformed into an amide and methyl ester.532-536 The classical method of sulfonation, namely, by the action of sulfur trioxide in pyridine, is also applicable.537,538 Hemiacetals of starch dialdehyde result upon treatment with suitable alcohols in the presence of an acidic catalyst. In acetic media amides condensed with the carbonyl groups. Acetylation of starch dialdehyde with acetic anhydride is an obvious reaction. Esters with hexanedioic (adipic) acid were also prepared.537 Starch dialdehyde undergoes etherification with monochloroacetic acid in an alkaline medium.538... 

Substituted phenacyl bromides (61) were condensed with vicinal diols (62), and the resulting bromoketals (63) were then coupled with sodium 1,2,4-triazole in dimethyl formamide solution. 

Diamino-6-methyl-l,3,5-triazine has been shown to react with aldehydes in the presence of potassium hydroxide or methanesulfonic acid <91CPB3I80>. Equation (13) shows a similar type of reaction in which formamide (or lactam) acetals condense with the active methyl group of a 1,3,5-triazinedione <85LA65>. 

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