2- Methylene indolines

Method B. A solution of 5.80 g (0.020 mol) of 4-indolino-l-nitroso-2-naphthol and 3.46 g (0.020 mol) of 1,3,3-trimethy 1-2-methylene indoline in 100 ml of 1,4-dioxane was heated under reflux for 21 h. The resulting purple solution was evaporated to dryness and the residue purified by flash chromatography over silica with diethyl ether-hexane (1 7 = v v) to give 5.56 g as a green gum or solid, which was further treated by washing with acetone to give compound 7 as a yellow solid mp 255-257°C yield 58%. 

The azaindolenines have been discussed by Ficken and Kendall, who have pointed out that protonation, as well as methylation, of the 7 isomer (31. Scheme 7) occurs at N(7>, which can be seen from the similarity of the acid spectrum of the 2,3,3-trimethyl compound (31) and the alcoholic spectrum of the 7-methiodide (117). The behavior of the 7-methiodide in alkaline media is distinctly different from that of 1,2,3,3-tetramethyl indolenine iodide, which with alkali gives rise to the 2-methylene indoline, the spectrum of which was determined independently and is in agreement with this transformation, although the band appearing at ca. 300 m/i has not been reported in all cases. The bands indicated in Table VII for the MeOH/HCl spectrum of this compound should probably be stepped to the left. The large red shift shown by the 7-methiodide (117) is due to isomerization to the orfAo-quinonoid compound (118). This does not take place in the hydrocarbons. 

The behavior of the 1 -methiodide (179) is more difficult to explain as its spectrum in alcohol is nearly identical to that in alkaline solution, and these both show the same pattern as the 2-methylene indoline, i.e., with an intensified band II and a band III shifted to the red as compared to its methiodide. It seems possible that these compounds exist as the carbinolamine, or pseudobase, in hydroxylic solvents and are in tautomeric equilibrium (179 181). The direction of this equilibrium has been attributed by Beke to the basicity of the nitrogen, as well as other factors. B14ha and Cervinka discuss the importance of steric and polar structural factors, citing examples of stable pyrrolidine pseudobases. Indeed, Ficken and Kendall isolated the 4-azaindoline pseudobase (123), characterizing it by analysis and infrared spectral evidence. They similarly characterized the 2-methylene base (121), and it is unfortunate that their ultraviolet spectra were not determined. The 2-methylene-7-azaindoline... 

A mixture of Meldrum s acid or barbituric acid derivatives, urea and aldehyde gave 99, stereoselectively. Reaction of 2-methylene indoline derivatives with l-nitroso-2-naphthol gave 100. Spiroheterocycles 101 were prepared from a mixture of isatin and aromatic or heterocyclic... 

Condensation of 2-methylene indoline derivatives 816 with l-nitroso-2-naphthol (817) under MWI gave spiro indolinonaphth[2,l-6][l,4]oxazines 818 in 11-61% yields within 12 min. When the same reaction was carried out in the presence of morpholine, 819 were also formed in 19-34% yields (Scheme 155) (04SC315). 

An ale. soln. of o-thiocyanatobenzaldehyde and l,3,3-trimethyl-2-methylene-indoline refluxed 1 hr. crude 2-benzo[b]thien-2-yl-l,3,3-trimethyl-2-indoline-carbonitrile. Y 11%. — This reaction involves the formation of a thianaphthene ring under unusually mild conditions. R. G. Bertelson, J. Org. Chem. 30, 2875 (1965). 

Spiropyrans are prepared via a condensation reaction between an ortho-hydroxy formyl compound and a methylene indoline material (i.e., Fischer base) [17]. See Scheme 10. Also, the corresponding iodo-indolinium salt of the Fischer base may be employed in place of the Fischer base to expedite the purification procedure. 

The transformations of e2-dihydromavacurine discussed in Volume VIII, p. 526, can now be reinterpreted just as readily on the basis of structure X for this compound. e2-Dihydromavacurine (X) with methyl iodide undergoes C-methylation at position 7 to give the quaternary indoline compound (XI) which with base reversibly gives the methylene-indoline XII. An extension of this work has now shown that with methyl iodide XII undergoes a further transannular C-methylation, this time at C-3 to give the quaternary indoline XIII. In contrast to XI the UV-spectrum of XIII does not change on basification, presumably because the stereochemical requirements for a j8-elimination are not fulfilled (J). 

Structurally, both semaxanib and TSU-68 are close analogs of sunitinib (vide supra), and they all share the (Z)-3-((l//-pyrrol-2-yl)methylene)indolin-2-one core. 

Recently, Cook s group described their Mori-Ban indole synthesis of substrate 10, easily assembled from 9 [23]. The intramolecular cyclization gave a 1 1 mixture of indole 11 and exo-3-methylene-indoline 12, which was readily converted to 11 upon treatment with acid. By changing the base from K2CO3 to Ag2C03, the Mori-Ban reaction gave exo-3-methylene-indoline 12 exclusively in 90% yield. 

An imino ene reaction was employed by Burger s group to prepare a-fluoromethyl tryptophans 40 from the union of l-sulfonyl-3-methylene indolines 38 with electrophilic imines 39 (Scheme 7, equation 1) [11]. 

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-... 

Indolines, benzoxazole, and benzothiazole are possible as 2-methylene heterocycles. The number of known spirooxazine derivatives is much less than for the spiropyrans. This may be partly due to lack of many substituted o-nitrosonaphthols and partly due to lack of sufficient stability of spiro-oxazines. The structures of parent spirooxazines and the Xmax of their photomerocyanine forms are listed in Table 5. The Xmax of the colored forms of compounds 41-43 are not described in the literature. 

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... 

A number of novel spiro heterocycles, including the triazepinethione 146 have been derived from 3-hydroxy-3-(2-oxocyclohexyl)indolin-2-one 145 by condensation with active methylene compounds <00SC1257>. A condensation process was also used to prepare tricyclic triazepinones related to the non-nucleoside reverse transcriptase inhibitor nevirapine <00JHC1539>. 

---