Fischer’s bases

Fischer s base [118-12-7] Fischer-Tropsch Fischer-Tropsch liquids... 

The spiroindolinobenzopyran 2 is a classical example of spiropyran and is easily prepared by the condensation of l,3,3-trimethyl-2-methyleneindo-line (Fischer s base) and salicylaldehyde in anhydrous ethanol or benzene (Scheme 2).ia The nucleophilic attack of Fischer s base on the carbonyl group (like an enamine) gives an aldol product, which undergoes ring closure followed by dehydration. This condensation is reversible therefore, an exchange of the salicylaldehyde component of spiropyran with a different salicylaldehyde is possible. For example, when a solution of spiropyran 2 (Scheme 2) was refluxed with 3,5-dinitro-substituted salicylaldehyde, the open form of 6,8-dinitro-BIPS was obtained.2... 

Fischer s base, a typical starting material, is commercially available and is also obtained in situ from the corresponding quaternary salt, substituted indolines 4 can be prepared by TV-alkylation of 2,3,3-trimethyl-3//-indole followed by alkali treatment, or by exhaustive alkylation of 2,3-dimethylindole (N- and C-alkylation) followed by alkali treatment (Scheme 3). Further, methylation of indoline 5 with methyl iodide leads to C-methylation on the methylene group or the Plancher rearrange-... 

Spiroindolinobenzothiopyrans can be prepared by condensation of Fischer s base with thiosalicylaldehyde derivatives 46 in ethanol, as shown in Scheme 22.71,89 93 Reaction of 1,2,3,3-tetramethylindolinium salt with carbamoylthiobenzaldehyde,92 which is an intermediate for preparation of thiosalicylaldehyde, also gives the spirobenzothiopyran in high yield via the corresponding indolinium salt, as shown in Scheme 22.94 Conversion of spirobenzopyrans to the corresponding spirobenzothiopyran by phosphorous pentasulfide in pyridine or xylene is possible, but the purification of the product is difficult. 

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... 

Of some importance as textile dyes are aza analogues of polymethine (cyanine) dyes. Azacarbocyanines result when Fischer s aldehyde is heated with primary aromatic amines. Thus Cl Basic Yellow 11 (6.220) is obtained when Fischer s aldehyde is condensed with 2,4-dimethoxyaniline. The equivalent reaction with 2-methylindoline gives Cl Basic Yellow 21 (6.221), which has superior light fastness but has been classified by ETAD as toxic [73]. The tinctorially strong golden yellow diazacarbocyanine dye Cl Basic Yellow 28 (6.222) is prepared by coupling diazotised p-anisidine with Fischer s base (6.223), followed by quaternisation with dimethyl sulphate. Some triazacarbocyanine dyes are also used commercially. 

Hemicyanine (styryl) dyes are readily obtained by heating Fischer s base with an appropriate aldehyde. Typical products include Cl Basic Red 14 (6.224) and Cl Basic Violet 16 (6.225). The latter dye has been classified by ETAD as toxic [73]. 

Fischer s base (1.6 R = H) with saUcylaldehyde (1.7). The same route can be used with an indolinium compound bearing different N-alkyl groups (1.6 R = alkyl) and ring substituents synthesised as shown in Figure 1.2 by alkylation of a 2-methylin-dole to produce (1.8 R = alkyl). Substituted saUcylaldehydes and also 2-hydroxy-naphthaldehydes can also be used to give other analogues. 

The commercially available spirooxazines are based on the spiroindolinonaphthoxazines (1.11) ring structure. The synthetic route to this ring system involves the reaction of a l-hydroxy-2-nitoso bearing aromatic ring with a 2-aUcylidene heterocycle, such as Fischer s base (1.6 R = H). The naphthoxazines are the derivatives of choice... 

Several high production products for the dyeing of polyacrylonitrile textile fibres come from the azacarbocyanines class. Example in this class are the azacarbocyanine Basic Yellow 11 (2.27), synthesised from 2,4-dimethoxyaniline (2.26) and Fischer s aldehyde (2.25) the diazacarbocyanine Cl Basic Yellow 28 (2.30), synthesised from the diazonium derivative of (2.29) and Fischer s base (2.28) as shown in Figure 2.16. These dyes, although they are very bright, do tend to suffer from low fasteess to light. 

An important class of cationic dyes, particularly for yellow to bluish-red hues, is derived from Fischer s base by condensation with 4-formyl-substituted anilines, or from Fischer s aldehyde (which may be prepared from Fischer s base via Vilsmeier formylation (B-71MI11205)) and an aromatic amine (Scheme 3). There are many examples of resonating charge dyes of this type which include a variety of aromatic amines and aldehydes. Of heterocyclic interest are the dyes formed by condensation of Fischer s aldehyde with... 

Scheme 3 Synthesis of Astrazon dyes from Fischer s base and Fischer s aldehyde, respectively...

When 2-methyleneindolines (Fischer s bases) are used as the nucleophilic species, 2-spiroannulated indolines result with high diastereomeric purity (95JPR368). When R1 = Ph, an acid catalysed isomerisation leads to a highly substituted benzophenone (23). 

One of the first recorded alkylations of the enamine system was the treatment of dihydroberberine or its alkylated derivatives with alkyl iodides alkylation on the j9-carbon atom prevailed.205 Later, many similar observations were published. Zatti and Ferratini206 showed that l,3,3-trimethyl-2-methyleneindoline ( Fischer s base ) and methyl iodide did not afford a quaternary salt but rather a tertiary base, l,3,3-trimethyl-2-isopropylideneindoline, which is a product of... 

Alkylation of heterocyclic enamines proceeds similarly to the alkylation of Fischer s base discussed above. Lukes and Dedek223 obtained on methylation of l-methyl-2-ethylidenepyrrolidine (51) a C-alkylation product, i.e. 1 -methyl-2-isopropyl-A2-pyrroline (52). Alkylation of the same enamine with ethyl bromoacetate 224 was the first synthetic step in the preparation of DL-pseudoheliotridane. 

Salicylaldehydes give spirobenzo pyrans, often referred to simply as spiropyr-ans. In principle, true monocyclic spiropyrans would be prepared from 3-hydro-xyacrylaldehyde, which is the enol form of malonaldehyde. A reaction of Fischer s base with malonaldehyde or its chloro derivative gave complex mixtures containing the open form, but nitromalonaldehyde sodium salt gave with Fischer s base hydroiodide a 24% yield of beautiful orange crystals of the open form (3) (A. = 483 mm)7 Recently a series of 2-substituted malonaldehydes (4) became... 

The Fischer s bases, 2-alkylidene-l,3,3-trisubstituted indolines, which may be further substituted in the indoline ring, are the most versatile and useful bases for preparing spiropyrans. For convenience, the name Fischer s base will be used hereafter in the general sense indicated above, as well as for the specific compound 2-methylene-l,3,3-trimethylindoline. Substituents in the 1- and 3-positions are methyl unless otherwise specified thus 3-phenylFischer s base denotes the 1,3-dimethyl-3-phenyl compound. 

In a Fischer synthesis, the formation of the hydrazone and its cyclization to the indolenine in the crude reaction mixture can be monitored conveniently by IR spectra. The ketone C=0 absorption near 1720 cm 1 disappears as the phenylhy-drazone C=N absorption in the 1625-1640 cm 1 region appears, which in turn is replaced by the indolenine C=N absorption at 1570-1580 cm-1. If a Fischer s base is formed directly, the IR spectrum exhibits two peaks near 1615 and 1650 cm 1. All these absorption peaks are strong and sharp. 

A Plancher rearrangement also occurs with an isomer of Fischer s base, as shown in Scheme 5. The addition of methyllithium to 1,2,2-trimethylindoxyl (5) gives l,2,2-trimethyl-3-methyleneindoline (6). This base in acid solution at room... 

The reaction of an indolenine with an alkyl halide having the alkyl group ethyl or longer can also lead to elimination rather than alkylation, with the formation of the hydrohalide salt of the indolenine. This salt can be mistaken for the expected quaternary salt. In this case, treatment with base will merely regenerate the starting indolenine, which is easily distinguished by IR spectrum, as indicated earlier, from the Fischer s base formed from the quaternary salt. Often the solid isolated is a mixture of the two salts, and both components can be identified in the spectmm of the corresponding mixture of bases. 

A detailed study of the N-methylation of 2,3,3-trimethylindolenine with methyl sulfate using triethylbenzylammonium chloride as a phase-transfer catalyst has appeared. The reported yields of high-purity (96-99%) Fischer s base were 90-92%.19 N-alkylation is the most practical method for preparing a Fischer s base with alkyl groups having, for example, thienyl,20 hydroxy, carboxy, or sulfonate substituents. 

Reaction between butanesultone and 2,3,3-trimethylindolenine gave a 74% yield of the water-soluble N-(n-butylsulfonate) inner salt of Fischer s base this salt and others from substituted indolenines were used as intermediates for cyanine and merocyanine dyes, but not specifically for spiropyrans. 21... 

The preparation of l-(2-hydroxyethyl)-2,3,3-trimethylindoleninium bromide and its 5-bromo (75% yield) and 5-nitro derivatives by alkylation of the corresponding indolenines with 2-bromoethanol has been described. As indicated in Scheme 7, these salts (10) with base gave the corresponding cyclized Fischer s base (11), 5-bromo-2,3,3-trimethylindolino[l,2- Z>]-oxazolidine. 22... 

The reaction between the perchlorate salt of 2,3,3-trimethylindolenine and crotonaldehyde involves Michael addition (at the 2-methyl group, not the N atom) and spontaneous cyclization to give 8.8,10-trimcthyl-l ()//-pyrido l,2-a indolium perchlorate (16) in 26% overall yield. This can be considered a vinylog of a Fischer s base salt (and also a 4-picolinium salt). This salt has been condensed with aromatic aldehydes to give styryl dyes, but there is no report of reaction with salicylaldehydes.26... 

Vilsmeier formylation of l-(2-hydroxyethyl)Fischer s base (in its cyclic form as trimethylindolino[l,2-6]oxazolidine) (11) gave l-(2-hydroxyethyl)Fischer s aldehyde in 82% yield when the reaction was performed at 35°C, but gave instead 66% of l-(2-chloroethyl)Fischer s aldehyde at 60°C.27... 

A unique oxindole synthesis is the addition of diphenylketene to the mono-A-phenylimine of benzoquinone the resulting spiro-P-lactam (18) rearranges to give a 62% overall yield of 5-hydroxy-l,3,3-triphenyloxindole (19), which can be methylated to the 5-methoxy compound,35 which in turn could be converted to the Fischer s base. 

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