Efficient Catalytic Kinetic Resolution of Spiro‐epoxyoxindoles with Concomitant Asymmetric Friedel–Crafts Alkylation of Indoles

An efficient process involving the catalytic kinetic resolution of racemic spiro‐epoxyoxindoles with the simultaneous enantioselective Friedel–Crafts alkylation of indoles has been realized using a chiral phosphoric acid catalyst. The reaction provides two useful intermediates in high yields and excellent enantioselectivities. Performing the catalysis on a gram scale led to (R)‐3‐(3‐indolyl)‐oxindole‐3‐methanol, which was used in the asymmetric formal total synthesis of (+)‐gliocladin C. Notably, the enantiomers (S)‐3‐(3‐indolyl)‐oxindole‐3‐methanol can be obtained easily by the reaction of the resolved spiro‐epoxyoxindole with indole.     

Synthesis and thermal self-crosslinking reaction of polymer containing spiro ortho ester and carboxylic acid

Polymers with both pendant spiro ortho ester and carboxylic acid moieties were synthesized by partial esterification of poly(methacrylic acid), poly(methacrylic acid-co-methyl methacrylate), or poly(methacrylic acid-co-styrene) with halomethylated spiro ortho esters in the presence of 1,8-diazabicyclo[5,4,0]undecene-7 in dimethyl sulfoxide. The extent of esterification increased with increasing reaction temperature. The reaction of polymeric carboxylic acids with chloromethylated spiro ortho esters proceeded to 80% of conversion at 100°C for 120 h. In contrast, the degree of esterification with bromomethylated spiro ortho ester reached 80% at 60°C within 24 h. Thermo-crosslinking of polymers having pendant spiro ortho ester moiety and carboxylic acid could be effected in films. The rate of spiro ortho ester ring-opening increased with increasing reaction temperature and with increasing content of carboxylic acid groups in the polymer. Further, the rates of gel production were also measured. The polymer containing an equimolar mixture of spiro ortho ester moieties and carboxylic acids exhibited the highest reactivity. In addition, it was found that thermal crosslinking reaction of the polymer occurred with minimum volume shrinkage.     

Heterocyclic Thiones and Their Analogs in Reactions of 1,3-Dipolar Cycloaddition: III. Reaction of Benzothiazole-2-thione with a Double Excess of Nitrilimine

Main products of reaction between benzothiazole-2-thione and a double excess of nitrilimine are substituted 1-aryl-1-(1,3-benzothiazol-2-yl)-2-(2,3-dihydro-1,3,4-thiadiazol-2-yl)hydrazines. In the first step presumably forms a spiro compound via 1,3-dipolar cycloaddition of nitrilimine molecule to the C=S bond of the benzothiazolethione. The second nitrilimine molecule adds to the new C=S bond of the intermediate product arising by the rupture of CS bond in the thiadiazole ring of the spiro compound.     

Ultrasonic Aptitude of Regioselective Reaction of 6‐bromo‐spiro‐3,1‐benzoxazinone2,1′‐isobenzofuran‐3′,4‐dione Towards Some Electrophilic and Nucleophilic Reagents

In the present work, the 2‐benzoxazinonyl benzoic acid (BBA) could be isomerized to the stereogenic spiro products (SBI) via ultrasonic and basic reaction conditions. The spiro compounds (SBI) have both electrophilic and nucleophilic centers. A series of nitrogen nucleophiles such as hydrazine hydrate, glycine, 2‐aminopyridine, 2‐picolinylamine, 4‐anisidine, 4‐aminoacetophenone and carbon electrophiles such as oxiranylmethylchloride, ethylchloroacetate, chloroacetylchloride, Mannich reagents, for example, formaldehyde with piperidine or morpholine can be treated with 2‐benzoxazine‐2‐yl benzoic acid (BBA) via multicomponent reaction. The basicity of previous nucleophiles can be controlled on the course of reaction of 2‐benzoxazinonyl benzoic acid. The chemical structure of the synthesized compounds can be confirmed by microanalytical, spectral data and optimized by quantum chemical parameters.     

Michael addition approach for the synthesis of novel spiro compounds and 2-substituted malonic acid derivatives from Meldrum’s acid

Novel routes for the synthesis of spiro derivatives of Meldrum’s acid and 2-substituted malonic acid derivatives have been developed. Meldrum’s acid was monoalkylated using a Michael addition reaction. Mono-Michael adducts were then alkylated using substituted haloalkanes, which on condensation gave spiro derivatives of Meldrum’s acid. Bis Michael addition of Meldrum’s acid with 1,5-diaryl-1,4-pentadien-3-one gave directly a spiro derivative of Meldrum’s acid. These compounds and bis alkylated Meldrum’s acid derivatives, on acidic methanolysis gave 2-substituted malonic acids.     

IMPROVED SYNTHESIS OF 3-SPIRO INDOLINES IN DRY MEDIA UNDER MICROWAVE IRRADIATION

An efficient, one-pot synthesis of novel spiro [indole-dipyrrolopyridines] (8) was achieved under microwave irradiation by the interaction of spiro [indole-dipyrrolopyrans] (3) with ammonium acetate (7) in the presence of acetic acid. Spiro [indole-dipyrrolopyrans] (3) were synthesized “in situ” by the reaction of indole-2,3-diones (1) and 2-pyrrolidone (2) in 1:2 molar ratio by microwave induced techniques for the first time. Comparative studies have been made between (a) microwave irradiation of (i) neat reaction of reactants in the absence of any solvent or catalyst (ii) reaction in presence of o-dichlorobenzene and (b) classical heating.     

Spiro beta-lactams as beta-turn mimetics. Design, synthesis, and NMR conformational analysis

Molecular modeling calculations using high-level ab initio methods (MP2/6-31+G) of a new type of spiro beta-lactams predict that these systems could adopt a beta-turn secondary structure in solution. Strong intramolecular hydrogen bonds stabilize the beta-turn conformation with a geometry that is very close to the ideal type II beta-turns. The synthesis of the spiro beta-lactams is achieved by Staudinger reaction of a cyclic ketene derived from N-bencyloxycarbonyl-L-proline acid chloride with an imine. This reaction allows the formation of the spiranic backbone in a single-step with high diastereoselectivity and good yields. The new spiro beta-lactams obtained are the core for the preparation of different types of peptidomimetics using well-established peptide chemistry. The NMR conformational analysis shows that these compounds adopt beta-turn conformation as predicted by the theoretical studies.     

Novel Synthesis of some Spiro Heterocycles Derived from 3-Hydroxy-3(2-Oxocyclohexyl)-Indolin-2-One

The reaction of 3-hydroxy-3(2-oxocyclohexyl)indolin-2-one 1 with some active methylene, bidentates, phenylisocyanate, phenylisothiocyanate, carbon disulfide, benzaldehyde, ketoketene S,S-acetal, cyanoketene S,S-acetal, active halo compounds or benzylidenemalononitrile affords a series of new spiro heterocyclic systems.     

Synthesis of (+/-)- and (-)-vibralactone and vibralactone C

Mander reductive alkylation of methyl 2-methoxybenzoate with prenyl bromide and hydrolysis of the enol ether afforded methyl 6-oxo-1-prenyl-2-cyclohexenecarboxylate. This was converted in five steps (reduction of the ketone, saponification, iodolactonization, ozonolysis, and intramolecular aldol reaction) to a spiro lactone cyclopentenal. An efficient first synthesis of (+/-)-vibralactone was completed by retro-iodolactonization with activated Zn, formation of the beta-lactone (vibralactone C), and reduction of the aldehyde. Except for the novel use of an iodolactone to protect both the prenyl double bond and carboxylic acid, no protecting groups were used. A similar sequence starting with asymmetric reductive alkylation of the (2S)-2-methoxymethoxymethylpyrrolidine amide of 2-methoxybenzoic acid with prenyl bromide afforded (-)-vibralactone confirming the absolute stereochemical assignment that was based on computational methods.     

Well-defined binuclear chiral spiro copper catalysts for enantioselective N-H insertion

An asymmetric N-H insertion of α-diazoesters with anilines catalyzed by well-defined copper complexes of chiral spiro bisoxazoline ligands was studied in detail. The copper-catalyzed asymmetric N-H insertion of a wide range of α-alkyl-α-diazoacetates with anilines was accomplished with excellent enantioselectivity (up to 98% ee) and provided an efficient method for the preparation of optically active α-amino acid derivatives. A correlation study of the electronic properties of the substrates with the enantioselectivity of the N-H insertion reaction supports a stepwise insertion mechanism, and the significant first-order kinetic isotope effect proves that the proton transfer is most likely the rate-limiting step. A binuclear chiral spiro copper catalyst having 14-electron copper centers, a trans coordination model, a perfect C(2)-symmetric chiral pocket, and significant Cu-Cu interaction was isolated and extensively studied. The novel structure of the binuclear chiral spiro copper catalyst leads to unique reactivity as well as enantioselectivity in the N-H insertion reaction.     

Synthesis of Thione-Propiolic Acid Adducts

Abstract

Reaction of adamantane-2-thione with propiolic acid gave a novel type of cycloadducts, spiro[adamantane-2,2′-(1,3)-oxathiin]6-one, quantitatively. Thiocamphor and thiofenchone also reacted with propiolic acid to give the corresponding adducts stereoselectively. The observation of second-order reaction kinetics and highly stereoselective addition strongly support a cycloaddition mechanism for the thermal addition. The reaction of selenoketones with propiolic acid afforded a similar cylcoadduct. This is the first example of the reaction of monomeric thiones or selones with acetylenic acids.     

Syntheses of novel exo and endo isomers of ansa-substituted fluorophosphazenes and their facile transformations into spiro isomers in the presence of fluoride ions

Reactions of the dilithiated diols RCH2P(S)(CH2OLi)2 [R = Fc (1), Ph (2) (Fc = ferrocenyl)] with N3P3F6 in equimolar ratios at -80 degrees C result exclusively in the formation of two structural isomers of ansa-substituted compounds, endo-RCH2P(S)(CH2O)2[P(F)N]2(F2PN) [R = Fc (3a), Ph (4a)] and exo-RCH2P(S)(CH2O)2[P(F)N]2(F2PN) [R = Fc (3b), Ph (4b)], which are separated by column chromatography. Increasing the reaction temperature to -40 degrees C results in more of the exo isomers 3b and 4b at the expense of the endo isomers. The formation of the ansa-substituted compounds is found to depend on the dilithiation of the diols, as a reaction of the silylated phosphine sulfide FcCH2P(S)(CH2OSiMe3)2 (5) with N3P3F6 in the presence of CsF does not yield either 3a or 3b but instead gives the spiro isomer [FcCH2P(S)(CH2O)2 PN](F2PN)2 (6) as the disubstitution product of N3P3F6. The ansa isomers 3a and 3b are transformed into the spiro compound 6 in the presence of catalytic amounts of CsF at room temperature in THF, while 4a and 4b are transformed into the spiro compound [PhCH2P(S)(CH2O)2PN](F2PN)2 (7) under similar conditions. The novel conversions of ansa-substituted phosphazenes into spirocyclic phosphazenes were monitored by time-dependent 31P NMR spectroscopy. The effect of temperature on a transformation was studied by carrying out reactions at various temperatures in the range from -60 to +33 degrees C for 3b. In addition, compounds 3a, 3b, 4a, and 6 were structurally characterized. In the case of the ansa compounds, the nitrogen atom flanked by the bridging phosphorus sites was found to deviate significantly from the plane defined by the five remaining atoms of the phosphazene ring.     

Intramolecular nonbonded S...N interaction in rabeprazole

Intramolecular nonbonded S...N interactions in the crystal structures of the derivatives (7a-d) of sodium rabeprazole (1) and an intermolecular nonbonded S...N interaction between ethylmethylsulfoxide and pyridine in a solution were recognized. These results made us estimate that the intramolecular nonbonded S...N interaction existed in 1 and its derivatives in a solution, and formed the 4-membered quasi-ring in 2 (Fig. 1) followed by the increase of the reactivity of 2 to give the putative spiro sulfoxide 3, which is the key intermediate in the reaction cascade of 1 (Chart 1).     

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.     

Condensed Heterotricycles. Synthesis and Reactions of b-Fused 1(2H)-Isoquinolinones with unusual enaminic properties

Homophthalic acid ( 1 ) undergoes reaction with 1,2-, 1,3-, and 1,4-diamines to give condensed 1(2H)-isoquinolinones like 2 , 4 , 13 , and 25 , which exhibit marked enamine character. These are attacked by electrophiles at the N or C terminus. Some notable reactions of imidazoisoquinolone 2 are those with maleic and acrylic acids to form the tetracycles 48 and 51 , respectively. With propiolic acid, 5 underwent an interesting reaction to form the benzimidazonaphthyridine 53 . An equally interesting behaviour was elicited from 2 in its reaction with formaldehyde, when in addition to the expected methylene-bridged molecule 59 , the novel spiro derivative 60 was formed by the dimerisation of a presumed azadiene intermediate 63 .     

Reaction of thioketones with propiolic acids

The reaction of adamantane-2-thione with propiolic acid afforded a novel type of cycloadduct, spiro[adamantane-2,2'-6'H-[1,3]-oxathiin]-6'-one (3a), in quantitative yield. The reaction of thiobenzophenone with propiolic acid gave 2,2-diphenyl-6'H-[1,3]-oxathiin]-6'-one and 4-phenyl-3-thia-3,4-dihydronaphthoic acid in 34% and 35% yields, respectively. The reaction might proceed through a concerted process, as confirmed by kinetics. The reaction of adamantane-2-thione with 2-butynoic acid or phenylpropiolic acid gave the corresponding adducts regioselectively. Interestingly, only one isomer was obtained by the reaction of thiofenchone with propiolic acid, suggesting that the reaction proceeded diastereospecifically. Oxidation of adducts by dimethyldioxirane or m-chloroperoxybenzoic acid gave the corresponding sulfoxides and sulfones. The sulfoxides were thermally decomposed to give disulfide or another type of 1,3-oxathiin-6-one.     

Mecanisme de formation et de transformation des spirophosphoranes—IX: Reactions des spirophosphoranes a liaison PH avec les ethers vinyliques et les enamines

The reaction of 1,4,6,9-tetraoxa-5-phospha(V)spiro[4,4]nonane 1 with ethyl vinyl ether gives a spirophosphorane containing a PC bond, 5-(β-ethosyethyl)-1,4,6,9-tetra-oxa-5-phospha(V) spiro[4,4]nonane 2 (radical reaction), and a tricoordinated phosphorus compound, 2-(3,5-di-oxa-4-methylheptanoxyl)-1,3,2-dioxaphospholane 3 (ionic reaction). 2,2,3,3,7,7,9-Heptamethyl-1,4,6-trioxa-9-aza-5-phospha(V) spiro[4,4]nonane 6 gives exclusively a spirophosphorane containing a PC bond, 5(β-ethoxyethyl)-2,2,3,3,7,7,9-heptamethyl-1,4,6-trioxa-9-aza-5-phospha(V)spiro[4,4]nonane 7. The reaction of 1 with alcohol or ethyleneglycol and enamine yields a pentaoxyspirophosphorane and an amine by an oxidation-reduction condensation. Suggested mechanisms of these reactions are presented.     

Synthesis of pipecolic acid-based spiro bicyclic lactam scaffolds as beta-turn mimics

A series of 6.5.5 spiro bicyclic lactam scaffolds were synthesized from pipecolic acid in a sequence of reactions that was initiated with the alpha-allylation of tert-butoxycarbonyl pipecolic acid. Oxidative cleavage of the olefin to give an aldehyde followed by condensation with D-cysteine methyl ester gave a mixture of pipecolyl thiazolidines. Cyclization of the pipecolyl thiazolidines with Mukaiyama's reagent yielded the spiro bicyclic lactams 4a-d. Epimerization of the 7'a bridgehead carbon under acidic conditions was observed for those spiro bicyclic lactam scaffolds with an S stereochemistry at this position. The 6.5.5 spiro bicyclic lactam scaffold with the 3'S,6'R,7'aR stereochemistry mimicked a type II beta-turn, while the scaffold with the 3'S,6'S,7'aR stereochemistry mimicked a right-handed poly-d-proline II helix.     

Synthesis and mass spectral fragmentations of new spiro heterocycles

The reaction of dichlorodiphenoxymethane (2) with ortho-functionlized benzoic acids 1a-c yielded the spiro derivatives of bezodioxinone 4a, benzoxazinone 4b and benzodioxepinone 4c. The same reaction with 1,8-diaminonaphthalene afforded the spiro perimidine 6, while with 1,1'-binaphthy1-2,2'-diol gave the semi-cyclized derivative 2,2-diphenoxydinaphthodioxepine 8.     

An expedient domino three-component [3+2]-cycloaddition/annulation protocol: regio- and stereoselective assembly of novel polycyclic hybrid heterocycles with five contiguous stereocentres

A novel three-component strategy for the efficient synthesis of unprecedented polycyclic hybrid heterocycles comprising fused, bridged, and spiro rings with five contiguous stereocentres in a regio- and stereoselective manner is described. This transformation proceeds via 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the reaction of sarcosine/thiazolidine-4-carboxylic acid and acenaphthoquinone to a series of 2-[arylmethylidene]-3,4-dihydro-1(2H)-acridinones and concomitant annulation through an intramolecular aldol-type reaction.