Spiro Adducts Research Articles

Thermodynamic control synthesis of spiro[oxindole-3,3'-pyrrolines] via 1,4-dipolar cycloaddition utilizing imidazo[1,5-a]quinoline.

A series of novel 2-(quinolin-2-yl)-spiro[oxindole-3,3'-pyrrolines] were synthesized by one-pot three-component reaction involving dimethyl acetylenedicarboxylate, 1-phenylimidazo[1,5-a]quinoline and N-alkylisatins in chloroform at ∼60°C for 24h. Structures of these new spiro derivatives were deduced from HRMS and NMR spectral data. A plausible mechanism for the observed thermodynamic control pathway is presented herewith. Interestingly, the spiro adduct, derived from 5-chloro-1-methylisatin, exhibited excellent antiproliferative activity on MCF7, A549 and Hela human cell lines (IC50≃7μM).

DFT Studies on the Molecular Structure, Regioisomerism, Ground and Excited state Charge Transfer Properties of Spiro‐heterocycles

AbstractThe electronic structure, stereochemical aspects and charge transfer properties of the spiro compound (5S,8S) spiro‐{6‐phenyl‐1‐aza‐3‐oxa‐7‐thia‐bicyclo[3,3,0]‐octene‐8,3’(2’H)‐indol}‐2’‐one (spiro bicyclo adduct) synthesized using the multi‐component reaction via 1,3‐dipolar cycloaddition of isatin and thioproline with the dipolarophile phenylacetylene have been studied. The two lowest energy regio‐isomers of the spiro heterocycle formed from the stereospecific dipolar reaction have been analysed along with the electron‐withdrawing and releasing substituents using DFT method at the CAM‐B3LYP/6‐311++G(d,p) level of theory. The atomic charges and the stabilization energy due to the intramolecular charge delocalization process calculated using the natural orbitals at the different molecular sites reveal the different donor‐acceptor interactions occurring in the system. The intramolecular electronic transitions (specifically n to π* and π to π*) is found to occur from the localized donor end component to the acceptor end components in the multi‐component system. The hole produced by the ionization of the entities is found to migrate from the thioproline component to the phenyl acetylene part in a time scale of around 4 fs. The electron‐withdrawing and donating substituents on the spirobicyclo adduct have been proven to tune the excited and ground state charge transfer properties uniquely. The results can shed light on how multi‐component reactions can be directed to produce spiro adducts with versatile applications.

Self Cycloaddition of o-Naphthoquinone Nitrosomethide to (±) Spiro{naphthalene(naphthopyranofurazan)}-one Oxide: An Insight into its Formation.

2-Hydroxy-1-naphthaldehyde oxime was oxidized by AgO (or Ag2 O), in presence of N-methyl morpholine N-oxide (NMMO), to the title spiro adduct-dimer (±)-Spiro{naphthalene-1(2H),4'-(naphtho[2',1':2,3]pyrano[4,5-c]furazan)}-2-one-11'-oxide by a Diels-Alder(D-A) type self-cycloaddition, through the agency of an o-naphthoquinone nitrosomethide (o-NQM). Moreover, 2-hydroxy-8-methoxy-1-naphthaldehyde oxime was prepared and subjected to the same oxidation conditions. Its sterically guided result, 9-methoxynaphtho[1,2-d]isoxazole, was isolated, instead of the expected spiro adduct. The peri intramolecular H bonding in the oxime is considered to have a key contribution to the outcome. Geometry and energy features of the oxidant- and stereo-guided selectivity of both oxidation outcomes have been explored by DFT, perturbation theory and coupled cluster calculations. The reaction free energy of the D-A intermolecular cycloaddition is calculated at -82.0 kcal/mol, indicating its predominance over the intramolecular cyclization of ca. -37.6 kcal/mol. The cycloaddition is facilitated by NMMO through dipolar interactions and hydrogen bonding with both metal complexes and o-NQM. The 8(peri)-OMe substitution of the reactant oxime sterically impedes formation of the spiro adduct, instead it undergoes a more facile cyclodehydration to the isoxazole structure by ca. 4.9 kcal/mol.

New Trends in 1,4-Dipolar Cycloaddition Reactions. Thermodynamic Control Synthesis of Model 2'-(isoquinolin-1-yl)-spiro[oxindole-3,3'-pyrrolines

Background: A direct synthesis of functionalized spiro[oxindole-3,3'-pyrrolines] is achieved via thermodynamic control (~60 oC), three-component 1,4-dipolar cycloaddition reaction involving 3-phenylimidazo[5,1-a]isoquinoline, dimethyl acetylenedicarboxylate, and N-alkylisatins. Methods: Conversely, this one-pot reaction furnished, upon conduction at 25–38 oC, the expected 1,3-oxazepino[7,6-b]indoles as the main kinetic control products. The calculated energy of the optimized molecular structures of model spiro-oxindole and its isomeric oxazepinoindole indicate that spiro-oxindole is more stable by 76.1 kJ/mol. Results: The structures of the synthesized spiro adducts were evidenced from NMR and MS spectral data and further confirmed by single-crystal X-ray diffraction. Characteristic features of the spiro-oxindoles are displaced in their 13C-spectra as diagnostic signals at ~53 and ~70 ppm assigned, respectively, to the spiro carbon-3 and sp3 CH-2' of the pyrroline ring. Conclusion: This unprecedented thermally induced pathway in 1,4-dipolar cycloaddition, utilizing imidazo[5,1- a]isoquinoline and related congeners, would serve as a new route towards the synthesis of spiro[oxindole-3,3'- pyrrolines], a class of diverse biological activities. An insight into the thermodynamic control pathway is presented.

Stable Carbenes as Structural Components of Partially Saturated Sulfur-Containing Heterocycles.

Recently, an unusual elongation of the C-S bond was observed experimentally for some sulfur-containing heterocycles. Using a superior ab initio (SCS-MP2/cc-pVTZ) level of theory, we showed that the phenomenon can be explained by a contribution of a donor–acceptor adduct of a carbene with an unsaturated ligand. One may achieve further elongation of the C-S bond, eventually turning it to a coordinate one, by increasing the stability of each part of the system as, e.g., in the utmost case of spiro adducts with Arduengo carbenes. The effect of carbene stability was quantified by employing the isodesmic reactions of carbene exchange.

Synthesis, biological evaluation, density functional calculation and molecular docking analysis of novel spiropyrrolizidines derivatives as potential anti-microbial and anti-coagulant agents

The three-component cascade reaction of (E)-3-arylidene-1-methyl-pyrrolidine-2,5-diones, L-proline and isatin have been well established. It forms a new series of spiropyrrolizidine derivatives with wide structural complexity and diversity through an unprecedented isomerization with moderate to excellent yield. Spiro adducts were formatted by treatment of the dipolarophiles with in situ generated azomethine ylides from L-proline and isatin. In addition, these cycloadducts underwent retro 1,3-dipolar cycloaddition yielding unexpected regioisomers. The structures of obtained spiro[pyrrolizidin-2,3-oxindoles] 4–6 were elucidated by NMR spectroscopic and elemental analyses. Further, it was simulated through theoretical calculation in methanol at DFT-B3LYP/6–31G* level of theory. The synthetized compounds were then evaluated in vitro to study their antimicrobial activity against different species of bacteria and fungi as well as their anticoagulant activity. The antimicrobial and anticoagulant activities of our oxindoles show moderate to strong activity as compared to standard drugs. The structure-activity relationship (SAR) is discussed based on the molecular docking analysis.

Chemoselective Oxidative Spiroetherification and Spiroamination of Arenols Using I+/Oxone Catalysis.

We developed a chemoselective oxidative dearomative spiroetherification and spiroamination of arenols using I+/oxone catalysis. The intramolecular dearomative C-O and C-N couplings proceeded much more efficiently under slightly acidic conditions to give the corresponding spiro adducts in higher yields compared with previous methods using transition metal or hypervalent iodine catalysts. Control experiments suggested that both hypoiodous acid and iodine might be active species for these reactions.

Glucosamine-6-phosphate synthase inhibiting C3-β-cholesterol tethered spiro heterocyclic conjugates: Synthesis and their insight of DFT and docking study

A series of novel covalent cholesterol-spiro pyrrolidine/pyrrolizidine heterocyclic hybrids possessing biologically active oxindole, indanedione, and acenaphthylene-1-one have been synthesized by the reaction of C3-β-cholesteroalacrylate with heterocyclic di- and tri-ketones. All the sixteen compounds were obtained as a single isomer in good yield through a stereo- and regio- selective 1,3-dipolar cycloaddition methodology. Stereochemistry of the spiranic cycloadducts has been established by spectroscopic analysis and the regioselectivity outcome of the spiro adducts has been accomplished by DFT calculations at B3LYP/6-31G (d,p) level study. In vitro antibacterial activity of the newly synthesized cycloadducts were evaluated against highly pathogenic Gram-positive and Gram-negative bacteria and the most active compounds 5a, 13, and 14 underwent automated in silico molecular docking analysis in order to validate their effective orientation as a inhibitors bound in the active site of glucosamine-6-phosphate synthase (1XFF) enzyme by employing AutoDock Tools.

Thermal, acid-catalyzed, and photolytic transformations of spirocyclic 3H-pyrazoles formed by reactions of methyl, phenyl, and p-tolyl phenylethynyl sulfones with 9-diazofluorene

Methyl, phenyl, and p-tolyl phenylethynyl sulfones react with 9-diazofluorene in diethyl ether at 20°C to give 1,3-dipolar cycloaddition products according to von Auwers’ rule, the corresponding spirocyclic 3H-pyrazoles. The spiro adducts undergo isomerization into 5-R-sulfonyl-3-phenylpyrazolo[1,5-f]phenanthridines on heating in boiling toluene for 2 h; heating of the same pyrazoles in boiling benzene, acetonitrile, or ethanol leads to mixtures of 5-R-sulfonyl-3-phenylpyrazolo[1,5-f]phenanthridines and 3-R-sulfonyl-3a-phenyl-3aH-dibenzo[e,g]indazoles, the latter prevailing. The indazoles are kinetically controlled thermolysis products which are quantitatively converted into phenanthridines on heating in toluene. Sulfonyl-substituted spirocyclic 3H-pyrazoles and indazoles in glacial acetic acid at 20°C in the presence of a catalytic amount of sulfuric acid are transformed into 3a-phenyl-2H-dibenzo[e,g]indazol-3(3aH)-one. Under analogous conditions, sulfonyl-substituted phenanhtridines give rise to 3-phenyl-1H-dibenzo[e,g]indazole. Photolysis of spirocyclic 3H-pyrazoles yields mixtures of sulfonylcyclopropenes and 2H-cyclopenta[j,k]fluorenes.

Ninhydrin as a building block in scaffold-linked chromophoric dyad construction

The reaction of ninhydrin with ester-activated cyclobutene epoxide (CE-1) containing the fused 1,4- dimethoxynaphthalene ( DMN ) chromophore, gave adducts formed by 1,3-dipolar cycloaddition at the central (C 2)-CO (major) and the outer (C 1,3 )-CO (minor) positions. Conversion of the minor adduct to quinoxalines ( QIN ) by reaction with o-phenylenediamines at the α-dione moiety, albeit in poor yield, led to spiro-DMN-1,4 σ σ σ σ-QIN dyad in which the plane of the chromophore was orthogonally orientated yet angled to the plane of the DMN chromophore. Reaction of ninhydrin with o-phenylenediamines yielded the corresponding 11-oxoindeno(1,2-b)quinoxalines which were coupled with CE-BLOCKs to form spiro adducts by reaction at the carbonyl site; the product from CE -1 was identical with that formed above. Another class of spiro-fused dyads was produced by reaction of ninhydrin with a primary amine followed by cycloaddition of CE-BLOCKs at the carbonyl site, where the amine was available to deliver one chromophore and the CE-BLOCK another.

Benzonitrile Oxide Cycloadditions with Exocyclic Methylene Benzothiazepine Dioxides

N-substituted 5-methylene-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxides underwent 1,3-dipolar cycloaddition with benzonitrile oxide, generated in situ, to give isoxazoline spiro adducts. The cycloadditions were completely regioselective to give the hitherto unreported 3,4-dihydro-2H,4′H-spiro[benzo[f][1,2]thiazepine-5,5′-isoxazole] 1,1-dioxide cycloadduct. Where the N-substituent on the sulfonamide cycloaddition precursor was a 2-substituted arene, the resulting atropisomerism along the N-aryl bond led to facial selectivity in the cycloaddition reaction, with greater than 90 % diastereoselectivity.

ChemInform Abstract: Unexpected Formation of Diels-Alder Spiro Adducts from 4-Hydroxymethyl Derivatives of ′Proton Sponge′.

Treatment of 4-hydroxymethyl derivatives of 1,8-bis(dimethylamino)naphthalenes 1a and 1b with concentrated hydrochloric acid leads to the formation of spiro compounds 7a and b in high yield.

ChemInform Abstract: Addition of Twisted 1,1-Bis(thioacyl)-2,2-diaminoethylenes to Dimethyl Acetylenedicarboxylate. Part 2. Structure Determination of Two Isomeric Spiro Adducts by X-Ray Crystallography and of a Rearrangement Product by the 2D INADEQUATE

ChemInform Abstract: Addition of Twisted 1,1-Bis(thioacyl)-2,2-diaminoethylenes to Dimethyl Acetylenedicarboxylate. Part 2. Structure Determination of Two Isomeric Spiro Adducts by X-Ray Crystallography and of a Rearrangement Product by the 2D INADEQUATE

S EAr–S NAr couplings of indolizines and related pyrrole derivatives with superelectrophilic nitrobenzoxadiazoles

The nucleophilic aromatic substitutions of 7-chloro-4,6-dinitrobenzofurazan (DNBZ-Cl) and 7-chloro-4,6-dinitrobenzofuroxan (DNBF-Cl) with a series of differently substituted indolizines ( 5a– f) and a series of dihyropyrroloisoquinolines ( 11a– f) have been investigated. In accord with previous reports emphasizing the superelectrophilic character of these compounds in σ-complexation processes, DNBZ-Cl and DNBF-Cl react very readily and quantitatively with the weak carbon nucleophiles 5a– f and 11a– f at room temperature in acetonitrile. In the case of DNBZ-Cl, the resulting products ( 7Z, a– f and 12Z, a– f) are those expected from the displacement of the chlorine atom through a S EAr–S NAr mechanism. A significant result is that these compounds, despite the lack of coplanarity of the two rings, are characterized by an intense intramolecular charge transfer between the donor pyrrole-type moiety and the electron-deficient acceptor DNBZ moiety. Contrasting with this behaviour, the DNBF-Cl reactions show a totally different pattern, proceeding with loss of the N-oxide functionality and expansion of the pyrrole moiety to afford stable zwitterionic spiro adducts ( 8F, a– f and 13F, a– f) of a so far unknown type. Rapid NMR recordings have revealed that the formation of these adducts occurs after initial formation of the expected substitution products 7F, a– f and 12F, a– f. A mechanism accounting for the overall rearrangement leading to the spirobenzofurazan adducts is suggested. It is based on an initial nucleophilic attack of the oxygen atom of the N-oxide functionality at the electron-deficient and strongly olefinic C–C coupling bond generated by the aforementioned intramolecular charge transfer. This results in the formation of an unstable five-membered isoxazole ring whose decomposition goes along with loss of the N-oxide functionality and enlargement of the pyrrole moiety into a pyridine one. Also discussed are the factors accounting for the high thermodynamic stability of the spiro adducts, and their relevance to the stability of previously reported spiro adducts.

Diels-alder reactions with cyclic sulfones: X. Synthesis of 4-carbamoyl- and 4-hydrazido-substituted hexahydro-1-benzothiophene S,S-dioxides

Reactions of spiro[1-benzothiophene-4,5′-[1,3]dioxane]-4′,6′-diones with various amines led to the formation of 4-carbamoylhexahydrobenzo[b]thiophene-4-carboxylic acid 1,1-dioxides or their decarboxylation products, depending on the conditions. Hydrazinolysis of the spiro adducts in DMF gave the corresponding monohydrazides. The structure of 4-carbamoyl-7-methyl-5-phenyl-2,3,3a,4,5,6-hexahydro-1-benzothiophene-4-carboxylic acid 1,1-dioxide was proved by X-ray analysis.

Isolation and X-ray structural characterization of a dicationic homotrimer of 2,3,6,7-tetramethoxy-9,10-dimethylanthracene cation radical

Electrochemical oxidation of 2,3,6,7-tetramethoxy-9,10-dimethylanthracene ( 1) showed that it undergoes a highly reversible electrochemical oxidation ( E ox = 0.81 V vs SCE) and forms a modestly stable cation-radical salt in solution. X-ray crystallography established that 1 + SbCl 6 - crystallizes as a (centrosymmetric) dicationic homotrimer via a close cofacial association of a pair of cationic and one neutral molecule of 1 with an interplanar separation of ∼3.2 Å. The structure of the dicationic homotrimer was also reproduced by DFT calculations. Furthermore, the structure of a dicationic spiro adduct, formed by a slow decomposition of a solution of 1 + SbCl 6 - , was also established by X-ray crystallography.

Stable Spirocyclic Meisenheimer Complexes

Meisenheimer complexes are important intermediates in Nucleophilic Aromatic Substitution Reactions (SNAr). They are formed by the addition of electron rich species to polynitro aromatic compounds or aromatic compounds with strong electron withdrawing groups. It is possible to distinguish two types of Meisenheimer or σ-complexes, the σH-complex or σX-complex (also named ipso), depending on the aromatic ring position attacked by the nucleophile (a non-substituted or substituted one, respectively). Special examples of σX- or ipso-complexes are formed through intermediate spiro adducts, via intramolecular SNAr. Some of these spirocyclic Meisenheimer complexes, a type of σX-complex, are exceptionally stable in solution and/or as solids. They can be isolated and characterized using X-ray, and various spectroscopic techniques such as NMR, UV-Vis, IR, and fluorescence. A few of these stable spirocyclic Meisenheimer complexes are zwitterionic and exhibit interesting photophysical and redox properties. We will review recent advances, synthesis and potential applications of these stable spirocyclic Meisenheimer complexes.

Dimerization of 3-(2-aryl-2-oxoethylidene)oxindoles

6-Aroyl-7-arylindolo[3,4-jk]phenanthridin-5(4H)-ones (2a–i) were synthesized by heating 3-(2-aryl-2-oxoethylidene)-2,3-dihydroindol-2-ones (1a–i) in DMF. Compounds 2a–i are formed via the dimerization of two molecules of unsaturated ketones 1a–i proceeding as the [2+4] cycloaddition through the formation of intermediate spiro adducts. The further Pfitzinger rearrangement, decarboxylation, and heteroaromatization afford compounds 2a–i. The structures of the reaction products were established by spectroscopic methods and X-ray diffraction.

Diels–Alder Reactions with Cyclic Sulfones: VII. Synthesis of 1-Benzothiophene 1,1-Dioxide Derivatives

5-Arylmethylene-2,2-dimethyl-1,3-dioxane-4,6-diones reacted with 5-isopropenyl-2,3-dihydrothio-phene 1,1-dioxide to give the corresponding ortho-addition products, 5-aryl-2',2',7-trimethyl-3,3a,5,6-tetra-hydro-2H-spiro[1-benzothiophene-4,5'-[1,3]dioxane]-4',6'-dione 1,1-dioxides. Their aminolysis resulted in opening of the 1,3-dioxane ring and formation of 4-carbamoyl-7-methyl-2,3,3a,4,5,6-hexahydro-1-benzo-thiophene-4-carboxylic acid 1,1-dioxide whose structure was determined by X-ray analysis. Reactions of the spiro adducts with amines and hydrazine hydrate afforded the corresponding mono- or dicarboxylic acid monoamides (hydrazide).

Novel [3 + 2] 1,3-Cycloaddition of the Ionized Carbonyl Ylide +CH2OCH2• with Carbonyl Compounds in the Gas Phase

For the first time [3 + 2] 1,3-cycloaddition of an ionized carbonyl ylide has been observed in gas phase ion−molecule reactions of +CH2OCH2• (1) with several carbonyl compounds. The reaction, which competes with electrophilic addition that leads to net CH2•+ transfer, occurs across the CO double bond of acetaldehyde and several acyclic ketones yielding ionized 4,4-dialkyl-1,3-dioxolanes as unstable cycloadducts. Rapid dissociation of the nascent cycloadducts by loss of a 4-alkyl substituent as a radical leads to the observed products, that is cyclic 4-alkyl-1,3-dioxolanylium ions. Cycloaddition of 1 with cyclic ketones yields bicyclic spiro adducts, which also undergo rapid dissociation. Cyclobutanone yields ionized 1,3-dioxaspiro[4,3]octane, which dissociates exclusively by neutral ethene loss to ionized 4-methylene-1,3-dioxolane. Ionized 1,3-dioxaspiro[4,4]nonane is formed in reactions with cyclopentanone, and its rapid dissociation by loss of C3H6 and C2H5• yields the ionized 4-methylene-1,3-dioxolanylium and the 4-ethenyl-1,3-dioxolanylium product ions, respectively. A systematic study of this novel reaction and characterization of the product ions carried out via pentaquadrupole (QqQqQ) multiple stage (MS2 and MS3) mass spectrometric experiments provide experimental evidence for the cycloaddition mechanism. The dissociation chemistry observed for the cycloaddition products correlate well with their proposed structures and was compared to that of both isomeric and reference ions. Ab initio MP2/6-31G(d,p)//HF/6-31G(d,p) + ZPE potential energy surface diagrams for the reactions of 1 with acetone, fluoroacetone, and 1,1,1-trifluoroacetone support the operation of the two competitive reaction pathways, that is CH2•+ transfer and [3 + 2] 1,3-cycloaddition/dissociation, and show that the cycloaddition process is favored by electron-withdrawing substituents.