With dimethylformamide and phosphoryl chloride

Methylpyrazine with dimethylformamide and phosphoryl chloride gave 2-(2 -dimethylamino-l -formylvinyl)pyrazine (717), which was hydrolyzed by alkali to 2-(C,C-diformylmethyl)pyrazine (717). 

In a related reaction, 4-amino-l-methyl-5-(methylthio)carbonyltriazole (27c), when warmed with dimethylformamide and phosphoryl chloride, gave... 

With Dimethylformamide and Phosphoryl Chloride Followed by Ammonia or Amines... 

In this important reaction, which provides the only known means of converting oaminoamides to annelated 4-aminopyrimidines, the amide is acted on with dimethylformamide and phosphoryl chloride the product, a cyanodimethylaminomethyleneamino derivative (see 118), is then cyclized with ammonia or an amine (see Section VI,A,4, where it is treated as a reaction of an o-aminonitrile). 

Amino-2-ethoxycarbonyl-4-methylpyrrole was converted to the di-methylaminomethyleneamino analog (178) with dimethylformamide and phosphoryl chloride. The product, set aside for 3 days with cold methanolic ammonia, gave 7-methylpyrrolo[3,2-rf]pyrimidin-4-one 179) in excellent yield.332 The corresponding reaction with methyl anthranilate gave quina-zolin-4-one quantitatively.333... 

The Vilsmeier reaction has attracted some attention as a route to cyclazines. 3H-pyrrolizine (1) gave the Vilsmeier salt (19a) on treatment with dimethylformamide and phosphoryl chloride at — 60°C. A second formylation to (20a) was achieved by treatment of (19a) with dimethyl-thioformamide and acetic anhydride <80JCS(P1)1319>. Similar products were obtained from a chloro-formylation of the ketone (3a) the Vilsmeier reaction at — 50°C gave the salt (19b) in 65% yield. From a reaction at 0 °C, 91 % of the trisubstituted derivative (21) was obtained, which was hydrolysed... 

Vilsmeier formylation has attracted much attention as a route to cyclazines (see Section III,B,6). Jessep and Leaver have obtained the Vilsmeier salt 263 from 1 by using dimethylformamide and phosphoryl chloride at — 65°C, but the formylpyrrolizine was very unstable, and a second Vilsmeier reaction has not been achieved.128 The salt 263 could be converted to the 3,5-bisaldehyde equivalent 264a by treatment with dimethylthioformamide and acetic anhydride. Flitsch et al. prepared l-chloro-3H-pyrrolizine and treated it in situ at — 60°C with the Vilsmeier reagent to obtain the chloro derivative 259 of compound 263. 7 They also obtained the bis(dimethylaminomethylene) derivative 264b and, at room temperature, the tris(dimethylaminomethylene) derivative 265, which was hydrolyzed to give the dialdehyde 266. Reactions... 

The combination of tertiary amides, such as dimethylformamide, and phosphoryl chloride generates reactive electrophiles capable of being attacked by electron-rich nucleophiles and is widely used as the Vilsmeier formylation process. The Vilsmeier process has become more general, with the use of more varied amides, and has been particularly successful for the functionalization of pyrroles and indoles. Greater flexibility has been achieved with the replacement of phosphoryl chloride by trifluoromethanesulfonic anhydride. 

Compounds containing activated double bonds can also be formylated by dimethylformamide and phosphoryl chloride styrene thus gives cinnam-aldehyde,852 and chloroformylation to give / -chloro- -unsaturated aldehydes occurs with acetylenes, e.g. 853... 

In the still more 7t-deficient 1,2,3-triazole series (see 20), several 4-amino-5-formyl derivatives resisted both direct acylation and acetal formation. A successful alternative was to form intermediates with side chains conjugated to the nucleus. For example, 1- and 2-methyl-, as well as 3-benzyl-4-amino-l,2,3-triazole-5-aldehydes reacted with a cold mixture of dimethylformamide and phosphoryl chloride to give excellent yields of, e.g., 3-benzyl-4-dimethyl-aminomethyleneamino-l,2,3-triazole-5-aldehyde (84). This was converted to 9-benzyl-8-azapurine (see 21) in excellent yield by refluxing in methanolic ammonium acetate.87 In a variation of this reaction, an imidate (85) replaced the amidine (84) as intermediate. Thus, 4-amino-l-methyl-l,2,3-triazole-5-aldehyde and triethyl orthoacetate, refluxed for 2 hr, gave an excellent yield of 4-ethoxyethylideneamino-l,2,3-triazole-5-aldehyde (85), cyclized, by stirring in cold ethanolic ammonia, to 2,7-dimethyl-8-azapurine (good yield).87... 

Reaction of dyes containing a primary amino group with dimethylformamide and an inorganic acid chloride, e.g., phosphoryl chloride, permits introduction of the formamidinium group (e.g.,57), which is also scissioned off upon heating in the dye bath [154], A similar reaction occurs with the trialkylhydrazinium moiety obtained by reacting formyl-substituted azo dyes with dialkylhydrazines and subsequent quatemization [155],... 

Chloro-3-methylpyrazine (101,535) and 2-chloro-5-phenylpyrazine (363, 365a, 377, 824, 825) have been prepared from the corresponding hydroxy compound and phosphoryl chloride, 2-chloro-6-methylpyrazine from 2-hydroxy-6-methylpyrazine and phosphoryl chloride with one drop of dimethylformamide (681), and 2-benzyl(or s-butyl, isobutyl, or isopropyl)-3phosphoryl chloride with a trace of concentrated sulfuric acid (80). 2-Chloro-6-methyl-3-propyl- (826), 3[Pg.99]

Dichloro-2,3-diphenyl- and 5,8-dichloropyrazino[2,3-t/]pyndazine are obtained by treatment with phosphorus pentachloride/phosphoryl chloride in the presence of a small amount of dimethylformamide (1 drop) at 125 °C for one hour in a yield of 87% [mp 202-204 °C purified by chromatography (silica gel, CH,CI2)],8J or by refluxing for 8 hours in a yield of 34%,86 respectively. 

Arnold and his colleagues have applied the combination of dimethylformamide with phosgene or phosphoryl chloride also to formylation of aliphatic compounds such as acetals,844,845 ketals,846 vinyl ethers,844,845,847 and ketones848,849 (see also Ziegenbein and his co-workers850). Vinyl ethers afford 2-alkyl-3-(dialkylamino) derivatives of acrylaldehyde 844... 

Nucleophilic processes that generate chloroindoles are largely confined to the displacements of oxy functions and Sandmeyer reactions of diazo-nium salts [81 H( 15)547]. A low yield of 2-chloroindole was obtained by a reaction sequence that involved treatment of oxindole with phosphoryl chloride, and then treatment of the Vilsmeier salt with sodium bicarbonate [66JOC2627 86H(24)2879]. It is, however, much better to prepare this compound from 2-lithioindole (92JOC2495). With phosphoryl chloride and dimethylformamide ethyl l-hydroxyindole-2-carboxylate failed to give the expected 3-formyl derivative. Instead there was a 50% yield of the 3-chloro derivative (84CPB3678). Diazonium salts have been used as precursors in... 

The strategies used in the synthesis of polymethine dyes are illustrated for a series of indoline derivatives in Scheme 6.1. There is an even wider range of synthetic routes to polymethine dyes than is described here, but they are based for the most part on a similar set of principles. The starting material for the synthesis of this group of polymethine dyes is invariably 2-methylene-1,3,3-trimethylindolenine (121), known universally as Fischer s base. As illustrated in the scheme, compound 121 may be converted by formylation using phosphoryl chloride and dimethylformamide into compound 122, referred to as Fischer s aldehyde, which is also a useful starting material for this series of polymethine dyes. When compound 121 (2 mol) is heated with triethylorthoformate (1 mol) in the presence of a base such as pyridine, the symmetrical cyanine dye, C. I. Basic Red 12 109 is formed. The synthesis of some hemicyanines may be achieved by... 

Several variations of this synthetic route have been developed. For example, condensation of the methyltriazole (21) with thiourea gives the thiol derivative (22), and reaction with phosphoryl chloride in dimethylformamide converts the amino-amide to a cyano-amidine, which can be reduced to the 4-amino-5-aminomethyl derivative (Scheme 47). ... 

Schiff bases (112) derived from 4-chlorobenzaldehyde and 1-substituted-5-amino-3-methylthio-l,2,4-triazoles (111) underwent cyclization with phe-noxyacetyl chloride or dichloroacetic acid in the presence of phosphoryl chloride and dimethylformamide to give the 7-(4-chlorophenyl)-fram-6,7-dihydro-3-methylthio-6-phenoxy-l-substituted-l,2,4-triazolo[4,3-a]pyrimidin-5-one 113 and l-substituted-6-chloro-7-(4-chlorophenyl)-3-methylthio 1,2,4-triazolo[4,3-a]pyrimidin-5-one 114, respectively (88JHC173) (Scheme 47). 

Kurasawa and Takada transformed the 2-oxo-2H-pyrido[l,2-u]pyrimi-dine (30) with phosphoryl chloride-dimethylformamide to the pyrido-[l,2-a]pyrimidine (201) and reacted the latter with methylhydrazine to obtain 4°, of the pyrido[l,2-a] pyrimidine (202) and 78% of the pyridazino-[3,4-b]quinoxaline(203 R = Me, R2 = NMeNH2). Reaction with hydrazine gave the pyridazino[3,4-b]quinoxaline (203 R = H, R2 = OEt).26-27... 

Later, it was also claimed that 3-(tetrazolyl)-4//-pyrido[ 1,2-u]pyrimidin-4-ones 159 were obtained in an one-step procedure by heating the appropriate 2-aminopyridine, ethyl (l//-tetrazol-5-yl)acetate, and triethyl orthoformate in dimethylformamide at 90°C for 1 hour, or in boiling tetra-hydrofuran for 6 hours followed by treatment with 1N potassium hydroxide at 50°C for 1 hour, or with anhydrous aluminum chloride under reflux for 6 hours (91EUP462834). 9-Methyl-3-( 1 //-tetrazolyl)-4//-pyrido[ 1,2-a]-pyrimidin-4-one 159 (R = 9-Me) could be prepared when 2-amino-3-meth-ylpyridine hydrochloride and sodium azide were suspended and stirred in dimethylformamide for 1 hour at room temperature, followed by the addition of ethyl ethoxymethylenecyanoacetate, ethoxymethylenemalo-nonitrile, ethyl cyanoacetate and triethyl orthoformate, or malononitrile and triethyl orthoformate and stirring at 90°C for 6-12 hours. Then the reaction mixture was treated with 1 N potassium hydroxide at 50°C for 1 hour, phosphoryl chloride at 90°C for 5 hours, or with concentrated hydrochloric acid at 110°C for 4 hours to give 26-62% yields. 

Chloro derivative 291 was obtained from dioxo derivative 70 by treatment of phosphoryl chloride in dimethylformamide at 100°C for 2 hours (80CPB3537). The treatment of chloro derivative 291 with methylhydra-zine in a mixture of ethanol and chloroform under reflux gave 2H-pyrido[ 1,2-a]pyrimidin-2-one 295 and rearranged pyridazino[3,4-6]-quinoxaline 296 in 4.8% and 78% yields, respectively (Scheme 21) (80CPB3537). 3,4-Dihydroquinoxalinone 70 could not be rearranged into pyridazino[3,4-6]quinoxaline 296 by treatment with methylhydrazine. When hydrazine hydrate was employed instead of methylhydrazine, tricyclic ethyl ester 297 (R1 = Et) was obtained. The latter reaction gave methyl ester 297 (R1 = Me) when carried out in a mixture of methanol and chloroform (80CPB3537). 

Unlike 2-amino-4//-pyrido[l,2-a]pyrimidin-4-ones, 4-amino-2//-pyr-ido[l,2-a]pyrimidin-2-ones did not react with a Vielsmeier-Haack reagent consisting of a mixture of phosphoryl chloride and dimethylformamide at 90°C for 8 hours or at 140°C for 90 minutes (87JHC329). 

Vielsmeier-Haack formylation of 2-oxotetrahydropyridopyrimidine-3-carboxylate 91 (n = 1) with a mixture of phosphoryl chloride and dimethylformamide afforded 9-formyl derivative 302 after hydrolytic work-up [85JCS(P2)1873]. The predominant tautomeric form of the formyl derivative is the 1,6,7,8-tetrahydro form. 

Vielsmeier-Haack formylation of /-substituted 2-phenylamino-4/7-pyrido[ 1,2-a]pyrimidin-4-ones 470 with a mixture of phosphoryl chloride and dimethylformamide at 95°C for 90 minutes gave a near 1 1 mixture of pyrido[r,2 I,2]pyrimido[4,5-6]quinazolin-12-one 472and -12,13 dione 473 in 23-37% and 22-41% yields, respectively (87JHC329). Compounds 472 and 473 probably formed by the disproportionation of the tetracyclic hydroxyl derivatives 471. If the substituent (R) of 470 was the ethoxycar-bonyl group, only N-ethoxycarbonyl derivative 475 could be obtained (92JHC25). No tetracyclic derivative 472 and/or 473 (R = COOEt) was formed. 

Vielsmeier-Haack formylation of 9-(phenylaminomethylene)-6,7,8,9-tetrahydro-4//-pyrido[ 1,2-a ]pyrimidin-4-one 558 (R = COOEt) with a mixture of phosphoryl chloride-dimethylformamide at room temperature for 10 hours gave an E-Z mixture (578 and 579) of the 9-(A-phenyl-AL formylamino)methylene derivative (91H1455). While 9-phenylaminometh-ylene derivative 558 (R = COOEt) exhibited a solvent-dependent E-Z geometric isomerism, the presence of a formyl group on the amino moiety of 558 (R = COOEt) leads to an increase in the activation energy for isomerization around the C=C(9) double bond, thereby permitting the separation of the E and Z isomers (578 and 579) of the formylated product. 

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