Base-catalyzed Isomerization Research Articles

Coupling–Isomerization Synthesis of Chalcones

The Sonogashira coupling of electron-deficient (hetero)aryl halides 1 and (hetero)aryl or alkenyl 1-propargyl alcohols 2 does not terminate at the stage of the expected internal propargyl alcohols, but rather gives rise to the formation of alpha,beta-unsaturated ketones 3 with a variety of acceptor substituents. This new domino reaction, a coupling-isomerization reaction (CIR), can be rationalized as a sequence of rapid Pd/Cu-catalyzed alkynylation followed by a slow amine-base-catalyzed propargyl alcohol-enone isomerization. Performing the CIR in deuterated protic solvents or with a selectively deuterated propargyl alcohol revealed that the base-catalyzed isomerization step proceeds through a formal 1,3-H shift with minimal H/D exchange with the surrounding solvent. Additionally, 19F NMR kinetic measurements on the isomerization step with the fluorinated propargyl alcohol 4 r support the mechanistic rationale.

Catalytic applications of hydrotalcite-like materials and their derived forms

Hydrotalcite-like (HT-like) materials have been studied extensively in the last three decades. Although these materials initially perceived as potential anion exchangers, unrelenting efforts have also been attempted to use them as catalytic materials or as catalytic supports. There are varied ways by which one can use them for catalysis viz.; 1. Use them in as-synthesized form 2. Use them after calcining where the structural integrity of layered lattice is lost 3. Use the interlayer as functional spaces with moieties of catalytic interest 4. Use them after destruction or delamination and restructuring and 5. Use them as support or matrix. In this review, we are reporting the catalytic applications of HT-like materials and their derived forms carried out in our research group for the last 15 years in these various ways, covering reactions such as nitrous oxide decomposition, selective oxidation of organic compounds of industrial relevance and base-catalyzed isomerization of chemicals of perfumery interest. Although this review primarily focuses on our work, wherever applicable, related or relevant works from other groups are also presented to bestow comprehensiveness.

Formation of 2,2′-Diacyl-9,9′-bifluorenylidene Isomers from 2-Acyl-9-bromofluorene and Base-Catalyzed Isomerization of the Formed Alkenes

Abstract We studied the formation of 2,2′-diacyl-9,9′-bifluorenylidene from 2-acyl-9-bromofluorene. The E-isomer was obtained mainly when the acyl group was a short alkyl chain, such as an acetyl group, and Z-isomer was isolated predominantly when a long acyl chain such as stearoyl group was attached. 9,9′-Bifluorenylidene was formed via anti elimination of hydrogen bromide from the intermediate 9-bromo-9,9′-bifluorenyl. This indicated that the stereochemistry of 2,2′-diacyl-9,9′-bifluorenylidene was determined by the configuration of 9-bromo-9,9′-bifluorenyl isomers, giving Z- and E-isomers in a ratio of 1:1. Facile base-catalyzed Z/E isomerization of 9,9′-bifluorenylidenes followed the formation of the alkenes, which showed different stereoselectivity depending upon the length of the acyl side-chain. On the other hand, thermal treatment of 2,2′-diacyl-9,9′-bifluorenylidene afforded a ca. 1:1 mixture of Z- and E-isomers, suggesting that thermal isomerization took place through a different pathway than base-catalyzed isomerization.

Synthesis of Stable 2H-Pyran-5-carboxylates via a Catalyzed Propargyl-Claisen Rearrangement/Oxa-6π Electrocyclization Strategy

[reaction: see text] The application of easily accessed propargyl vinyl ethers for the synthesis of monocyclic 2H-pyrans was achieved. Under the reaction conditions, highly substituted heterocycles were obtained in moderate to excellent yields. The one-pot sequence proceeds via a Ag(I)-catalyzed propargyl-Claisen rearrangement, followed by a base-catalyzed isomerization, and 6pi-oxaelectrocyclization, leading to the formation of stable 2H-pyrans.

Unusual endoperoxide isomerizations: a convenient entry into 2-vinyl-2-cyclopentenones from saturated fulvene endoperoxides

An unusual peroxide base-promoted isomerization is uncovered. Saturated endoperoxides derived from fulvenes give rise to 2-vinyl-2-cyclopentenones upon treatment with DBU in CH 2Cl 2 in a one-pot reaction. This methodology is applied to a convenient synthesis of dihydrojasmone. Moreover, functional groups placed on the side chain at C-6 participate in the base-catalyzed isomerizations via conjugate attack at the enone moiety to give 2-cyclopentenones carrying oxygen heterocycles at C-2.

Enhanced diastereoselectivity in beta-mannopyranosylation through the use of sterically minimal propargyl ether protecting groups.

[reaction: see text] 2-O-Propargyl ethers are shown to be advantageous in the 4,6-O-benzylidene acetal directed beta-mannosylation reaction. The effect is most pronounced when the O3 protecting group is a bulky silyl ether or a glycosidic bond; however, even with a 3-O-benzyl ether, the use of a 2-O-propargyl ether results in a significant increase in diastereoselectivity. The beneficial effect of the propargyl ether is thought to be a combination of its minimal steric bulk, as determined by a measurement of the steric A-value and of its moderately disarming nature, as reflected in the pKa of propargyl alcohol. Conversely, the application of a 3-O-propargyl ether in the benzylidene acetal directed mannosylation has a detrimental effect on stereoselectivity, for which no explanation is at present available. Deprotection is achieved by base-catalyzed isomerization of the propargyl ether group to the corresponding allenyl ether, followed by oxidative cleavage with N-methylmorpholine N-oxide and catalytic osmium tetroxide.

On the Mechanism of DABCO-Catalyzed Isomerization of γ-Hydroxy-α,β-alkynoates to γ-Oxo-α,β-(E)-alkenoates

[reaction: see text] Since the discovery of organic base-catalyzed isomerization of gamma-hydroxy-alpha,beta-acetylenic esters to gamma-oxo-alpha,beta-trans-alkenyl esters in 1949, the mechanism has not been elucidated. This study shows that the mechanism involves cumulene formation, protonation with the conjugate acid of the amine, and protonation of the resulting allenol with water.

Stereospecific solid-state [2+2] autophotocycloaddition of a styryl dye containing a 18-crown-6 fragment

A procedure was developed for the synthesis of a 18-crown-6-containing styryl dye of the pyridine series. Phototransformation products of the dye that formed upon irradiation with visible light in solution, films, and crystals were studied by 1H and 13C NMR spectroscopy and spectrophotometry. Irradiation of solutions of this dye in acetonitrile leads only to reversible E-Z photoisomerization of the C=C bond. Irradiation of a film of the dye induces stereospecific [2+2] photocycloaddition to form exclusively the rctt isomer of tetrasubstituted cyclobutane. The latter was found to undergo base-catalyzed isomerization giving rise to the rcct isomer. X-ray diffraction study showed that photocycloaddition occurs in single crystals without their destruction. The structures of the E isomer of the dye and the resulting rctt isomer of the cyclobutane derivative were established. The characteristic features of the molecular packing of the dye favorable for topochemical photocycloaddition in the crystal and the structural changes that accompany the cyclobutane formation are discussed.

Synthesis of 3‐Benzyl‐2‐hydroxy‐7,8‐dihydro‐6H‐quinolin‐5‐ones from Baylis—Hillman Adducts.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of 3-Benzyl-2-hydroxy-7,8-dihydro-6H-quinolin-5-ones from Baylis-Hillman Adducts

2-Hydroxy-7,8-dihydro-6H-quinolin-5-one skeleton is a useful backbone for the synthesis of numerous biologically interesting compounds such as carbostyrils (2-hydroxyquinolines) or huperzine A analogues, which have shown biological activities including non-steroidal antiinflammatory activity, acetylcholinesterase (AChE) inhibitory activity and antimalarial activity. During the studies on the chemical transformation of the Baylis-Hillman adducts toward synthetically useful heterocyclic compounds we envisioned that we could synthesize 3-benzyl-5-methoxycarbostyril derivatives 5. Our synthetic rationale for 5a is depicted in Scheme 1. Reaction of the Baylis-Hillman acetate 1 and cyclic enaminone 2 would provide the tetrahydroquinoline-2,5-dione skeleton 3 via SN2' type reaction of cyclic enaminones to the BaylisHillman acetates followed by amide bond formation. We thought that the following iodine-assisted oxidative aromatization of cyclohexenone moiety and base-catalyzed isomerization of lactam moiety would afford the desired 3benzyl-5-methoxycarbostyril derivative 5. The reaction of Baylis-Hillman acetate 1a and 3-amino-2cyclohexenone (2a) in refluxing ethanol in the presence of catalytic amount of acetic acid gave 3-benzylidene-4,6,7,8tetrahydro-1H,3H-quinoline-2,5-dione (3a) as the major product (52%) together with small amounts of 4a (< 10%). The reaction could also be conducted in n-butanol without acetic acid catalyst in a similar pattern. But, when we used nbutanol as the solvent, 4a was observed as the major product on TLC presumably due to the effect of higher reaction temperature than in EtOH. But, 3a was not changed completely into 4a even after heating for a long time. Thus we examined the conditions for the effective transformation of 3a into 4a and we found a suitable condition fortunately. Conversion of 3a into 4a could be carried out easily with catalytic amounts of DBU in THF at room temperature (reflux for the conversion of 3g into 4g, entry 7 in Table 1). Thus, we prepared 4a-c according to the following procedures: reaction of 1a-c and 2a in refluxing n-BuOH, separation of 3 and 4 as a mixtures, and finally DBU treatment to form 4a-c as the final products (entries 1-3 in Table 1). It is interesting to note that the easiness for the conversion

Overcrowded 5,10,15‐Trisubstituted Derivatives: Synthesis of 5,10,15‐Tri(fluorenylidene)truxene.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Intramolecular Aromatic Nucleophilic Substitution of the Benzimidazole‐Activated Nitro Group.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Intramolecular aromatic nucleophilic substitution of the benzimidazole-activated nitro group.

A wide range of 2-(2-nitrophenyl)-1H-benzimidazoles undergo high-yielding intramolecular S(N)Ar of nitrite with N-pendant alkoxides under mild conditions (DMF, rt). When this operationally simple process is carried out at elevated temperatures in the presence of excess NaH, the initially formed S(N)Ar products are converted to the corresponding N-vinyl-substituted 2-(2-hydroxyphenyl)-1H-benzimidazoles via base-catalyzed isomerization. [reaction: see text]

CD spectrometric methods for the simultaneous determination of ethisterone and its delta5-isomer.

Quick and accurate direct and indirect circular dichroism (CD) spectrometric methods were developed for the simultaneous determination of ethisterone (17alpha-ethinyl-17-hydroxy-4-androstene-3-one) and its delta(5)-isomer (delta(5)-ethisterone). The direct method is based on the selective negative Cotton effect of the delta(4)-3-oxo group in ethisterone (negative maximum at 348 nm in dioxan) and measurement of the ellipticity at 296 nm (positive maximum of delta(5)-ethisterone), where the measured ellipticity is the sum of those of the two isomers. In the indirect procedure delta(5)-ethisterone is transformed to ethisterone by base-catalysed isomerization and the ellipticities are measured at 339 nm in ethanol before and after isomerization. Preliminary experiments show the usefulness of CD detector in the HPLC determination of the mixture of the isomers. A major advantage of the direct CD spectrometric and the HPLC/CD methods is that the delta(5)-isomer with extremely low UV activity can also be directly measured with high sensitivity.

An efficient conversion of (3R,3'R,6'R)-lutein to (3R,3'S,6'R)-lutein (3'-epilutein) and (3R,3'R)-zeaxanthin.

Two dietary carotenoids, (3R,3'R,6'R)-lutein (1) and (3R,3'R)-zeaxanthin (2), and their metabolite (3R,3'S,6'R)-lutein (3'-epilutein) (3) accumulate in human serum, milk, and ocular tissues. There is increasing evidence that compounds 1 and 2 play an important role in the prevention of age-related macular degeneration. Therefore, the availability of these carotenoids for metabolic studies and clinical trials is essential. Compound 1 is isolated from extracts of marigold flowers (Tagete erecta) and is commercially available, whereas 2 is only accessible by a lengthy total synthesis, and a viable method for synthesis of 3 has not yet been developed. This report describes an efficient conversion of technical grade 1 to 2 via 3. Acid-catalyzed epimerization of 1 yields an equimolar mixture of diastereomers 1 and 3. The mixture was separated by enzyme-mediated acylation with lipase AK from Pseudomonas fluorescens that preferentially esterified 3 and after alkaline hydrolysis yielded this carotenoid in 90% diastereomeric excess (de). Compound 3 was also separated from 1 in 56-88% de by solvent extraction and low-temperature crystallization, Soxhlet extraction, or supercritical fluid extraction. Base-catalyzed isomerization of 3 gave 2 in excellent yield, providing a convenient alternative to the total synthesis of this important dietary carotenoid.

Synthesis and Self‐Association of syn‐5,10,15‐Trialkylated Truxenes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The lsomerization of Olefins Part I. Base-Catalysed lsomerization of Olefins

Isomerization of olefinic and acetylenic compounds have received much attention during las few years both in their theoretical and in practical aspects. The methods used in isomerization of olefins (migration of the olefinic double bond) and related reactions are the subject of the this review; isomerizations involving rearrangement of the carbon skeleton are not considered. Part I deals with base-catalyzed isomerizations. Part II is concerned with isomerizations catalysed by acids, metal complexes, radicals, etc. The knowledge of the conditions under which isomerization of olefins occurs, is not only valuable for the conversion of olefins to their isomers, but is an important consideration when olefins are to be prepared by any other means. Under such conditions as here described an unwanted reaction product may be formed as a result of isomerization.

Hemi-synthesis and Biological Activity of New Analogues of Podophyllotoxin

Various 4-analogues of podophyllotoxin and epipodophyllotoxin were obtained via the formation of the corresponding 4-keto derivatives. Methyloximation of podophyllotoxone, followed by subsequent catalytic hydrogenation, gave stereoselective access to 4-α-amino-4-deoxypodophyllotoxin and from there, to the corresponding acetamido and formamido derivatives. Base-catalyzed isomerisation of 4-α-amino-4-deoxypodophyllotoxin led to the corresponding picropodophyllin isomer while the 4-β-amino afforded a neopodophyllotoxin-like derivative. On the other hand, oxirane and hydroxymethyl-containing analogues were prepared from podophyllotoxin and 4- epi-4′-demethyl-podophyllotoxin, using a Takai olefination strategy. In the latter series, carboxaldehyde- and carboxylic acid-containing derivatives were also synthesized.

Synthesis and self-association of syn-5,10,15-trialkylated truxenes.

syn-Trialkylated truxenes have been synthesized by alkylation of the truxene trianion followed by base-catalyzed isomerization of the anti isomers. 1H NMR studies, including a determination of diffusion coefficients, as well as molecular mechanics calculations, demonstrate that these derivatives self-associate in solution through arene-arene interactions. The benzyl derivatives show the strongest associations, which are a result of both benzyl-benzyl and truxene-truxene interactions.

Base catalysed isomerisation of aldoses of the arabino and lyxo series in the presence of aluminate

Base-catalysed isomerisation of aldoses of the arabino and lyxo series in aluminate solution has been investigated. l-Arabinose and d-galactose give l- erythro-2-pentulose ( l-ribulose) and d- lyxo-2-hexulose ( d-tagatose), respectively, in good yields, whereas lower reactivity is observed for 6-deoxy- d-galactose ( d-fucose). From d-lyxose, d-mannose and 6-deoxy- l-mannose ( l-rhamnose) are obtained mixtures of ketoses and C-2 epimeric aldoses. Small amounts of the 3-epimers of the ketoses were also formed. 6-Deoxy- l- arabino-2-hexulose (6-deoxy- l-fructose) and 6-deoxy- l-glucose ( l-quinovose) were formed in low yields from 6-deoxy- l-mannose and isolated as their O-isopropylidene derivatives. Explanations of the differences in reactivity and course of the reaction have been suggested on the basis of steric effects.