Heterocyclic Spiro-naphthalenones. Part III. Synthesis and reactions of some spiro [naphthalene-1,2′-pyrrolidin]-2-ones and spiro [naphthalene-2,2′-pyrrolidin]-1-ones

The spironaphthalen-2-ones 2, 10 and 18 were prepared by N-bromosuccinimide (NBS) oxidation of 1, 9 and 17 respectively, whereas spironaphthalen-1-ones 24 and 25 were obtained by treating 23 with NBS. The stereoisomeric reduction products 29, 30 and 32 obtained from 24 and 25 , gave the pentacyclic compound 33 on treatment with polyphosphoric acid.     

Heterocyclic Spiro-naphthalenones. Part II. Synthesis and reactions of some spiro [tetrahydrofuran-2,1′-(2′H-naphthalene)]-2′,5-diones and Spiro [tetrahydrofuran-2,2′-(1′H-naphthalene)]-1′,5-diones

The spiro-lactone 3 was obtained by N-bromosuccinimide (NBS) oxidation of the carboxylate 2 at ? 20°. When 2 was oxidized at 10° the spiro-lactone 4 was the main product. Compound 4 was rearranged with triethylamine to the spiro-lactone 9 whereas the stereoisomeric spiro-lactones 14 and 15 were obtained by NBS oxidation of the carboxylate 13 . The ketones 3, 4, 9, 14 and 15 were reduced with NaBH₄ to the corresponding alcohols 5, 6, 10, 16 and 18 respectively; these were hydrogenated to the alcohols 7, 8, 11 and 20 . The allylic alcohols 5 and 6 gave the benzochromanone 1 when heated in polyphosphoric acid whereas the benzochromanones 12 and 21 were obtained from the alcohols 10 and 16 respectively.     

Synthesis of spiro[2H-indole-2,1′-1H-isoindole]-3,3′-diones,spiro[1H-isobenzofuran-1,2′-2H-indole]-3,3′-diones and spiro[benzofuran-2,1′-isobenzofuran]-3,3′-diones via transannular reactions of eight membered ring intermediates

An auto oxidation-rearrangement product 4 was isolated from a high dilution reaction of ninhydrin with 3,4,5-trimethoxyaniline in water. A general synthesis of this compound and its derivatives 4–6 was devised by oxidation of tetrahydroindeno[1,2-b]indol-10-ones 1–3 with sodium periodate to give isoindolo[2,1-a]-indole-6,11-diones 4–6 in good yield. Compounds 4–6 can be easily transformed into spiro[1H-isobenzofuran-1,2′-2H-indole]-3,3′-diones 8–10 , spiro[2H-indole-2,1′-1H-isoindole]-3,3′-diones 11–13 and isoindole[1,2-a:2′,1′-b]pyrimidine-5,15-diones 15, 16 in high yields. Analogous reactions were performed on 3-amino-5a, 10a-dihydroxybenzo[b]indeno[2,1-d]furan-10-one ( 17 ) to give a dibenzoxocintrione 18 , spiro-[benzofuran-2,1′-isobenzofuran]-3,3′-dione 19 and an isoindol-1-one 20 .     

Synthesis of spiro[3H-indole-3,2′-tetrahydro-1,3-thiazine]-2,4′(1H)-diones

The title compounds have been prepared by the cyclocondensation of 3-mercaptopropanoic acid with isat-in-3-imines. The 1-benzyl derivatives have been synthesized by simultaneously reacting 1-benzylisatin, substituted anilines and 3-mercaptopropanoic acid. Mannich condensation of the spiro thiazanones with secondary amines gave the corresponding 1-aminomethyl derivatives.     

Studies in alkylation. I. Synthesis and reactions of spiro[oxirane-2,4-piperidines]

Spiro[oxirane-2, 4′-piperidines] have been prepared by the action of dimethyloxosulfonium methylide on 4-piperidones. The spiro[oxirane-2,4′-piperidines] act as alkylating agents to introduce (4-hydroxy-4-piperidyl) methyl moieties onto heteroaromatic compounds such as 4(3H)-quinazolone.     

Heterocyclic Spiro-naphthalenones. Part V. Synthesis of Some 2-Benzazepines from 3,4-Dihydrospiro [furan-2-(5H), 1′(2′H)-naphthalene]-2,5-dione

Compound 2 was rearranged on treatment with 2N NaOH to the 2-benzazepine-3-propanoic

1 See footnote (5) of the preceding paper.

acid 3 . Some aspects of the chemistry of this acid were studied.     

Heterocyclic Spiro-naphthalenones. Part VI. Some reactions with spiro [naphthalene-2 (1H), 2′-pyrrolidine]-1,5′-dione leading to various 6-, 7-, 8-, 9-, 10- and 11-membered azacycloalkanes

The spirolactam 5 was reduced to the spiro[naphthalene, pyrrolidine] 7 which was N-aralkylated to give 9 and 17 . Cyclization of 9 gave the phenanthridines 10 and 11 ; similarly, 17 afforded the 7- and 8-membered heterocycles 18 and 19 . Compounds 10, 18 and 19 when subjected to an intramolecular Hofmann elimination yielded the 9-, 10- and 11-membered ring systems, respectively 16, 22 and 23 .     

Regiocontrolled syntheses of some new spiro[polycyclic-1′-isothiochroman]-4′-one derivatives

Indan-1-one (1a), 1-tetralone (1b), fluorenone (1c), and anthrone (1d) reacted with mercaptoacetic acid in toluene in the presence of p-toluenesulfonic acid to give spiro[indan-1,2′-[1′,3′]oxathialan]-5′-one (2a), spiro[tetrahydro-naphthalene-1,2′-[1,3′]oxathialan]-5′-one (2b), spiro[fluorene9,2′-[1′,3′]-oxathialan]-5′-one (2c), and spiro[anthracene-9(10H)-2′-[1′,3′]-oxathialan]-5′-one (2d), respectively. Compounds 2a–d reacted with arenes in the presence of aluminum chloride to yield spiro[polycyclic-1′-isothiochroman]-4′-one derivatives 3a–t. The mechanisms of these reactions are discussed. All the synthesized spiroheterocycle derivatives were identified by conventional methods (IR, ¹H-NMR spectroscopy) and elemental analyses. © 1996 John Wiley & Sons, Inc.     

Studies in spiroheterocycles. Part XIII. Synthesis of a novel spiro system: Spiro[9H-acridine-9,3′-[3h]indol]-2′(1′H)-one and related compounds from new fluorinated spiro[3H-indole-3,9′-[9H]xanthen]-2(1H)-ones

A new spiroheterocyclic system spiro[9H-acridine-9,3′-[3H]indol]-2′(1′H)-one and related compounds have been prepared by the reaction of spiro[3H-indole-3,9′-[9H]xanthen]-2(1H)-ones with aromatic amine or ammonium acetate. The latter were prepared by heating fluorinated indole-2,3-diones with m-/p-cresols or α-naphthol in the presence of sulphuric acid at 230-240°. The synthesized compounds have been characterized on the basis of their elemental analyses, ir, nmr (1_H, 13_C, 19_F) and mass spectral data.     

Synthesis of ansa-2,2′-bis[(4,7-dimethyl-inden-1-yl)methyl]-1,1′-binaphthyl and nsa-2,2′-bis[(4,5,6,7-tetrahydroinden1-yl)methyl]-1,1′-binaphthyltitanium and -zirconium dichlorides

2,2′-Bis[(4,7-dimethyl-inden-1-yl)methyl]-1,1′-binaphthyl and [2,2′-bis[(4,5,6,7-tetrahydroinden-1-yl)methyl]-1,1′-binaphthyl]titanium and -zirconium dichlorides have been synthesized from 2,2′-bis(bromomethyl)-1,1′-binaphthylene. 2,2′-Bis(bromomethyl)-1,1′-binaphthylene was alkylated with the lithium salt of 4,7-dimethylindene to yield 2,2′-bis[1-(4,7-dimethyl-indenylmethyl)]-1,1′-binaphthylene (S)-(−)-9. The lithium salt of 9 was metalated with either titanium trichloride followed by oxidation or zirconium tetrachloride to give titanocene dichloride (S)-(+)-10 and zirconocene dichloride 11. The known complexes ansa-[2,2′-bis[(1-indenyl)methyl]-1,1′-binaphthyl]titanium and -zirconium dichlorides were formed and hydrogenated to ansa-[2,2′-bis[(4,5,6,7-tetrahydroinden-1-yl)methyl]-1,1′-binaphthyl]titanium and -zirconium dichlorides 12 and 14 or to ansa-[2,2′-bis[(4,5,6,7-tetrahydroinden-1-yl)methyl]-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl]titanium dichloride 13 whose solid state structure was determined by X-ray crystallography. Complex 13 adopts a C₁-symmetrical conformation in the solid state, but is conformationally mobile in solution, exhibiting C₂-symmetry in its room temperature NMR spectra.     

Some reactions of 4-[(2′,3′-diphenyl-6′-methoxy-5′-benzofuranyl)-methylene]- and 4-[(2′,3′-diphenyl-5′-methoxy-6′-benzofuranyl)-methylene]-2-phenyloxazolin-5-one

2,3-Diphenyl-5-formyl-6-methoxybenzofuran was reacted with hippuric acid to give 4-[(2′,3′-diphenyl-6′-methoxy-5′-benzofuranyl)methylene]-2-phenyloxazolin-5-one. The above mentioned oxazolone yielded 2,3-diphenyl-6-methoxybenzofuranylacetic acid by reaction with hydrazine hydrate, nitrous acid, benzene followed by acid hydrolysis. The reactions of the oxazolone with hydroxylamine hydrochloride and primary or secondary amines were also investigated.     

Heterocyclic spiro-naphthalenones. Part IV. Synthesis of some 3,4-dihydrospiro [naphthalene-2(1H),2′-pyrrolidine]-1-ols from 3,4-dihydrospiro [furan-2(5H),1′(2′H)-naphthalene]-2′,5-dione

Depending on the experimental conditions the spirolactone 3 on treatment with methylamine gave compounds 6, 7 or the rearranged product 4 . Compound 4 was used to prepare the title compounds 11–13, 15, 18–20 and other derivatives.     

Amidomethylation of indoles and cyclisations to spiro[pyrrolo[4,3,2-de]isoquinoline-3,4′-piperidines]

4-Aminomethylindoles react with aldehydes and ketones to form pyrrolo[4,3,2-de]isoquinolines. The structures of starting materials and end products were determined using 1D and 2D ¹H nmr techniques.     

Synthesis and antileukemic activity of spiro[indoline-3,2′-thiazolidine]-2,4′-diones

A number of spiro[indoline-3,2′-thiazolidine]-2,4′-diones have been prepared via the cyclocondensation of isatin-3-imines with α-mercaptoacids. 1-Benzyl-5′,5′-dimethylspiro[indoline-3,2′-thiazolidine]-2,4′-diones were prepared by simultaneously refluxing 1-benzylisatin, α-mercaptoisobutyric acid and various anilines in toluene. 3′-(4-Chlorophenyl)-5,5′-dimethylspiro[indoline-3,2′-thiazolidine]-2,4′-dione was active in the P388 and the L1210 leukemia screen tests. A number of analogs of the active spiro compound have been prepared and submitted for antileukemic screening. Anticonvulsant screening results of related compounds are also included.     

Synthesis and 1H-NMR spectra of halogenated spiro[isobenzofuran-1(3H),9′(9H)-6′-(methylcyclohexylamino)-3′-methyl-2′-anilinoxanthene]-3-ones

Reaction of spiro[isobenzofuran-1(3H).9′(9H)-6′-(methylcyclohexylamino)-3′-methyl-2′-anilinoxanthene]-3-one ( 1 ), which is typical leuco fluoran dye, with N-bromosuccinimide and N-chlorosuccinimide leads to halogenated derivatives 2a–2c and 3 , respectively. Their structures were established by two-dimensional proton-proton (COSY) experiment and their thermal properties examined by means of DSC and compared with commercially available 1 .     

Synthesis of 2,3-dihydrospiro[benzofuran-2,4′ -piperidines] and 2,3-dihydrospiro[benzofuran-2,3′-pyrrolidines]

The synthesis of 2,3-dihydrospiro[benzofuran-2,4′-piperidines] 3 and 2,3-dihydrospiro[benzofuran-2,3′]-pyrrolidine] 6 is described. The synthesis was achieved by a Grignard reaction of a 2-fluorobenzylhalide with an appropriate cycloazaalkyl ketone to yield the tertiary alcohols 1 and 4 . Subsequent intramolecular displacement of the aromatic fluoride by the derived alkoxides provided the novel system. Nitration of 1′-acetyl-2,3-dihydrospiro[benzofuran-2,4′-piperidine] 7 resulted in a 5-nitro derivative.     

Investigation of the reactions of fluorinated isatins and N-acetylisatins with thiocarbohydrazide: Synthesis of a novel spiro system: 2-oxo-1′,2′,4′,5′-tetrahydrospiro[3H-indole-3,3′-1,2,4,5-tetrazine]-6′-thione

A novel system 2-oxo-1′,2′,4′,5′-tetrahydrospiro[3H-indole-3,3′-1,2,4,5-tetrazine]-6′-thione has been synthesized by the treatment of fluorinated isatins with thiocarbohydrazide in aqueous ethanolic medium. Under exactly similar conditions, N-acetylisatin gave exclusively thiocarbohydrazone. The spiro product, on treatment with acetic acid, gave fluorinated isoindigo. Characterization of these products have been done by elemental analyses, ir, pmr and mass spectral studies.     

Synthesis of spiro[cycloalkane-1,3′-[3H]indoles] from cycloalkanecarbaldehydes. Acid-catalyzed rearrangement to cycloalkano[b]indoles

Spiro[cycloalkane-1,3′-[3H]indoles] 2 can be obtained from the cycloalkanecarbaldehydes 1 by the Fischer reaction of their phenylhydrazones. These cyclizations are sensitive to the acid catalyst, solvent and temperature employed. Rearrangement of the 2 to the homologous cycloalkane derivatives 3 can occur by an acid catalyst or by thermal treatment of 2 in ethyleneglycol.     

Pyrido[2,3-H]-2,6-naphthyridines. I. Synthesis and thermal reactions of the 2,2′bisacylazide of 3,3′ bipyridine

2 The2′-bisacylazide of 3,3′-bipyridine (1) has been synthesized from the (4,7)-phenantholine-5,6-dione ( 3 ) and the thermal decomposition of this new bisacylazide has been shown to give rise to the Curtius rearrangement and subsequent cyclization to the pyrido[2,3-h]-2,6-naph-thridinone ring system 8 .     

Synthesis of symmetrical 2,2′,4,4′-tetrasubstituted[4,4′-bioxazole]-5,5′(4H,4′H)-diones and their reactions with some nucleophiles

Several symmetrical 2,2′,4,4′-tetrasubstituted[4,4′-bioxazole]-5,5′(4H,4′H)-diones 1a-f were obtained by dehydrodimerization of 5(4H)-oxazolones 2a-f . The configurations of four were established; one by X-ray crystallography rac- 1c , and three rac- 1a , meso- 1a and rac- 1b by ¹H nmr spectroscopy of their derivatives. Upon being heated, the bioxazolones isomerized, presumably by breakage of the 4,4′-carbon? carbon bond to form free radicals followed by their recombination. The results of a crossover experiment were consistent with a radical nature for this isomerization reaction. Treatment of three of the bioxazolones rac- 1a , meso- 1a and rac- 1c with methanol and amine nucleophiles led to ester and amide derivatives 7–11 of α,α'-dehydrodimeric amino acids.