Pechmanns Synthesis

Synthesis.—PechmanrCs Synthesis. The scope of Pechmann s synthesis, the 1,3-cycloaddition of aryl isothiocyanates to diazomethane, has been extended, using methyl, phenyl, and 1-alkenyl isothiocyanates. The resulting 5-(substituted amino)-l,2,3-thiadiazoles are rearranged, under the influence of an excess of diazomethane, to l-substituted-5-methylthio-l.ff-l,2,3-triazoles (1) (see Vol. 2, p. 717). 

Synthesis.—PechmanrCs Synthesis. The 1,3-dipoIar cycloaddition of diphenyl(or methyl)phosphinic isothiocyanates to diazomethane or phenyl-diazomethane affords low yields (7—29%) of the appropriate substituted 1,2,3-thiadiazoles (5). The method is an extension of Pechmann s old-established synthesis (see Volume 1, p. 444). 

Carbamoyl isothiocyanates (6) similarly afford 40—60% yields of substituted 1,2,3-thiadiazoles of type (7), the structure of which is confirmed by an independent synthesis from the appropriate urethane (8). 

The carbamoyl isothiocyanates (6) thus react without isomerizing to the corresponding thiocarbamoyl isocyanates (compare thiazoles, p. 616). 

Pechmann s Synthesis.—The use of dia zoalkanes in the production of 1,2,3-thiadiazoles has been further developed these routes may be regarded as extensions of Pechmann s old-established synthesis. 

The action of diazoalkanes on thiocarbonyl compounds provides a versatile route to thiirans 1,2,3-thiadiazole derivatives, which function as intermediates, are isolable in suitable cases. Thus, diazomethane reacts with thionesters (1) yielding 5-alkoxy-5-methyl-A -l,2,3-thiadiazolines (2) (ca. 60%) together with the next higher homologous thionester (3) (ca. 30%). Aromatic members (2 R = Ar) decompose readily to the alkenes (5). Ethyl thioformate (1 R = H, R = Et) gives rise, by methylation and aromatiza-tion, to (4), and to linear products. Comparable observations involving diazoethane and diazopropane are also on record. The formulation of the products as 1,2,3-thiadiazolines (2) in preference to the possible A -1,3,4-thiadiazoline structures (6) is supported by the results of n.m.r. studies. However, both isomers, (8) (20%) and (9) (45%), are obtained when diazomethane acts on methyl dithioacetate (7) at —70 C (compare also these Reports, Vol. 1. p. 450).  

In a study of the interaction of electron-depleted thiocarbonyl compounds with diazoalkanes, the C-sulphonylthioformamide derivative flO) and ethyl chlorodithioformate (11) were found to yield mixtures of products that have been provisionally formulated as 1,2,3- and 1,3,4-thiadiazoles.  

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Alkynoates react with electron rich phenols to give coumarins with good regioselectivity in the presence of formic acid and a Pd-catalyst Yields are good even in instances where the Pechmann synthesis is reported to be unreliable <96JA6305>. 

Scheme 12 shows synthesis of 1,2,3-thiadiazoles by the Wolff, Hurd-Mori and Pechmann-Nold methods. Pechmann s and Wolffs are the oldest of the methods. The Pechmann-Nold synthesis involves the [3 + 2] cycloaddition of diazo-compounds to isothiocyanates or thiocarbonyl compounds (modified Pechmann synthesis). The use of thiocarbonyl compounds in the [3 + 2] cycloaddition step has broadened the scope of this reaction and made the starting materials more readily accessible. Wolffs method requires the synthesis of diazoketones that are treated with a thionating reagent to produce 1,2,3-thiadiazoles. With the development of new methods of diazotransfer reactions, the diazoketone precursors have become easily attainable and with further attention to the thionating reagents, this reaction is also useful for the synthesis of 1,2,3-thiadiazoles. 

In the von Pechmann synthesis, originally used to prepare pyran-2-one-5-carboxylic acid (coumalic acid), 2-hydroxybutane-l,4-dioic acid is converted into 3-oxopropanoic acid by treatment with oleum (sulfur trioxide and cone, sulfuric acid), and this product then self-condenses in the acidic medium to give pyran-2-one-5-carboxylic acid (Scheme 4,8a). Pyran-2-one is obtained by decarboxylating coumalic acid by heating it over copper at 650 °C. 

The Pechmann synthesis is unsuitable for acid-sensitive phenols, as for example the furo[2,3 -6]benzofuran derivative (373). An alternative approach uses the enhanced electrophilic character of a vinyl bromide in the presence of zinc carbonate to construct a suitable side-chain adjacent to the phenolic group (71JA746). In the examples cited, ring closure occurred under the mild conditions to form the pyranone ring of the aflatoxins (374). Since neither sodium nor potassium carbonate proved effective, it was considered that chelation of the zinc facilitated the carbon-carbon bond formation (Scheme 115). 

A very low yield of the coumarinoisocoumarin (508) is obtained during the Pechmann synthesis of 4-hydroxy-3-phenylcoumarin (78M1485). Significant amounts of this [2]ben-zopyrano[4,3-c][l]benzopyran-6,ll-dione are formed when the hydroxyphenylcoumarin is heated with either diphenyl carbonate or diethyl phenylmalonate. 

Similar enamine cyclization processes occur in several other successful heterocycle syntheses, e.g. in the Fischer indole synthesis. In this case, however, a labile N—N bond of a l-aryl-2-vinylhydrazine is cleaved in a [3,3]-sigmatropic rearrangement, followed by cyclization and elimination of ammonia to yield the indole (B. Robinson, 1963, 1969 R. J. Sundberg, 1970). Regioselectivity is only observed if R2 contains no enolizable hydrogen, otherwise two structurally isomeric indoles are obtained. Other related cyclization reactions are found in the Pechmann synthesis of triazoles (T.L. Gilchrist, 1974) and in G. Bredereck s (1939) imidazole synthesis (M.R. Grimmett, 1970). 

The Pechmann synthesis of coumarins via condensation of phenols with / -keto esters also involves an intramolecular hydroxyalkylation, following initial... 

From Phenols and 1,3-Keto-Esters The Pechmann Synthesis ... 

Phenols undergo cyclocondensation with p-keto esters under the influence of strong acids (v. Pechmann synthesis) [24a] ... 

This modification allows a regioselective attack of the 1,3-biselectrophile on substituted phenols to occur, which is often not the case in the v.Pechmann synthesis. 

Yields are good even in instances where the v. Pechmann synthesis is reported to be unsatisfactory [26]. 

The long-established Pechmann synthesis of coumarins has been revisited. The reaction of phenols with ethyl acetoacetate (EAA) occurs in better yield at lower temperatures and milder conditions in ionic liquids which act as both solvent and Lewis acid catalyst <01TL9285> and in solvent free reactions catalysed by 4-TsOH <01CL110>. Microwave irradiation of aminophenols and EAA on a solid support of graphite and montmorillonite KIO rapidly gives good yields of 4-substituted 7-aminocoumarins <01TL2791>. 

The Pechmann synthesis of coumarins via condensation of phenols with keto esters also involves an intramolecular hydroxyalkylation, following initial transesterification, and subsequent dehydration. It was found that H-Beta could successfully replace the sulfuric acid conventionally used as catalyst. For example, reaction of resorcinol with ethyl acetoacetate afforded methylumbelliferone (Figure 11.9), a perfumery ingredient and insecticide... 

As an improvement over jS-methylumbelliferone, °" 4-methyl-7-aminocoumarin (44) and 7-dimethylamino-4-methylcoumarin (45) were proposed. These compounds are used for brightening wool and nylon either in soap powders or detergents, or as salts under acid dyeing conditions. They are obtained by the Pechmann synthesis from appropriately substituted phenols (46) and y5-ketocarboxylic acid esters (47) or nitriles in the presence of Lewis acid catalysts. An example for the synthesis of 4-methyl-7-diethylaminocoumarin, compound 48 is shown in Scheme 28.3. 

Phenols undergo acid-promoted cyclocondensation with -ketoesters to give coumarins 13 of variable substitution pattern (Von Pechmann synthesis) [30] ... 

A disadvantage of the von Pechmann synthesis is the lack of regioselectivity in coumarin formation with unsymmetrically substituted phenolic substrates. This is avoided by an alternative protocol [37], in which ortho-metalated phenolic ethers 16 are added to alkoxymethylene malonates as primary step ... 

In this approach, good yields are reported, even in cases in which the von Pechmann synthesis gives unsatisfactory results. 

Parham cycloalkylation 343 Patemo-Btichi reaction 46 von Pechmann synthesis (coumarin) 322 Pellizari synthesis (1,2,4-triazole) 270 Perkin rearrangement 82 Pfitzinger synthesis (quinoline) 398 Pictet-Gams synthesis (isoquinoline) 414 Pictet-Spengler synthesis (isoquinoline) 415 Piloty-Robinson synthesis (pyrrole) 119 Pinner synthesis (pyrimidine) 467 Plancher rearrangement 128 Polonovski reaction 545 Pomeranz-Fritsch synthesis (isoquinoline) 415 Prileschajew reaction 23 Prins reaction 452 Pummerer rearrangement 26, 457... 

In the [2+2] cycloaddition reactions of isothiocyanates to diazo compounds iminoth-iadiazolines are formed, which rearrange into 5-substituted 1,2,3-thiadiazoles 136. This is the von Pechmann synthesis of 1,2,3-thiadiazoles. The reaction is general and some examples are listed in Table 3.14. The reactivity of the isothiocyanates increases with the electrophilicity of the carbon of the isothiocyanate group, which is enhanced by electron withdrawing groups, i.e. R = aryl < EtOCO < PhCO. 

SelectfluorTM as an efficient catalyst has been used in the Pechmann synthesis of coumarin under solvent-free conditions at 120 C. Originally, Selectfluor has been introduced commercially as a fluorinating agent (06JHC477). 

The Pechmann synthesis of 7-hydroxy 4-methyl coumarin using FLSZ and FRSZ was described by G. D.Yadav et al. (12M199).The results showed FLSZ is more active than FRSZ. 

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