Phosphoryl chloride-Dimethylformamide

Vilsmeyer-Haack formylation of the tricyclic compounds of types 205 and 333 with dimethylformamide-phosphoryl chloride reagent gave the formylated products 390 (For the structures of 390... 

The vinamidinium salts needed were prepared from the corresponding arylacetic acids by formylation with dimethylformamide phosphoryl chloride, like (7/)ls ... 

A. Vilsmeiei ami A. Haack, Ber., 60B, 119 (1927), used the roughly cqiiivalcnl combination of phosphoryl chloride and N-tnethylformanilide to prepare p-alkylaminobcn/.aldehydes. Phosgene and phosphorus pentachloride have also been used in place of thionyl chloride. Another combination which can be described as a Vilsmeier-type reagent is listed in this book as Dimethylformamide-Phosphoryl chloride. 

Dimethylformamide-Phosphoryl chloride [1,285, after second paragraph]. 

Vilsmeier acylation of pyrroles, formylation with dimethylformamide/phosphoryl chloride in particnlar, is a generally applicable process. The actual electrophilic species is an Al,Al-diaIkyl-chloromethyleneiminium cation (the chloride is available commercially as a solid). " Here again, the presence of a large pyrrole-A-substituent perturbs the intrinsic a-selectivity, formylation of A-tritylpyrrole favonring the P-position by 2.8 1 and trifluoroacetylation of this pyrrole giving only the 3-ketone " the nse of bulky iV-silyl substituents allows P-acylation with the possibility of subsequent removal of the N-snbstituent." The final intermediate in a Vilsmeier reaction is an iminium salt requiring hydrolysis to prodnce the isolated product aldehyde. When a secondary lactam is used, hydrolysis does not take place and a cyclic imine is obtained." ... 

The dimethylformamide/phosphoryl chloride reagent has been used to cyclize 6-(acylamino)-uracils by introducing the missing carbon unit.201 Thus, treating l,3-dimethyl-6-[(cyanoacetyl)amino]uracil with dimethylformamide/phosphoryl chloride yields 1,3-dimethyl-5-chloropyrido[2,3-rf]pyrimidine-2,4,7(l//,3f/,8//)-trione (8, R = H). 

More recently it has almost always been recommended to use the combination dimethylformamide-phosgene (e.g., for formylation of A, -dimethyl-aniline828) or dimethylformamide-phosphoryl chloride derivatives of 1,2-methylenedioxybenzene836 and of thiophen,837 as well as azulene838 and ferrocene,839 have been formylated in this way, some of them in excellent yield. Organic Syntheses contains directions for formylation of indole (97% yield of the 3-carbaldehyde)840 and W,W-dimethylaniline (80-84% yield of the para-aldehyde).841 The following is a further example in detail ... 

Phosphoryl chloride Carbon disulflde, A,A-dimethylformamide, 2,5-dimethylpyrrole, 2,6-dimethyl-pyridine 1-oxide, dimethylsulfoxide, water, zinc... 

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... 

Poor stirring during formylation of 2,5-dimethylpyrrole with the preformed complex of dimethylformamide with phosphoryl chloride caused eruption of the flask contents. Reaction of the complex with a local excess of the pyrrole may have been involved. 

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). ... 

Treatment of the imine (47) with phosphoryl chloride in dimethylformamide gives the Vilsmeier salt (48) which when reacted with sodium hydrogen sulfide gives the thio compound (49) (Scheme 12) <81AX(B)1449>. 

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). 

Reaction of ethyl 5,6-dihydro-l-oxo-l//-pyrimido[l,2-a]quinoline-2-carboxylate (39, R = OEt) either with phosphoryl chloride in dimethyl-formamid at ambient temperature for 2 h or with AW-dimethylformamide diethylacetal in boiling benzene for 2 h gave ethyl 5-(dimethylamino-methylene)-5,6-dihydro-l-oxo-l//-pyrimido[l,2-a]quinoline-2-carboxylate (150) (79BEP873192). 

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... 

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... 

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. 

Dipyrido[l,2-a 2, 3 -(i]pyrimidine-2,5(l//)-diones 477 were prepared when 2-acylamido-4//-pyrido[l,2-a]pyrimidin-4-ones 382 were heated in a mixture of phosphoryl chloride and dimethylformamide (92JHC25). When the reaction period was only 15 minutes, 2-acetamido derivative 382 (R = Me, R1 = H) gave 3-formyl derivative 478 and tricyclic compound 477 (R = Me, R1 = H) in 31% and 53% yields, respectively. 

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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