Syntheses of aromatic substituted hydrazino-thiazole derivatives to clarify structural characterization and antioxidant activity between 3-arylsydnonyl and aryl substituted hydrazino-thiazoles

This work clarifies the structural characterization and antioxidant activity between aromatic and 3-arylsydnonyl substituted hydrazino-thiazoles by further synthesizing a series of aromatic ring-substituted hydrazino-thiazole derivatives 8a-h and 9a-h. Hydrazino-thiazole derivatives 8a-h and 9a-h were obtained by reacting aromatic or heterocyclic aromatic aldehyde thiosemicarbazones 7a-h with cyclization reagents ethyl 2-chloroacetoacetate (2a) and 2-bromoacetophenone (2b), respectively. The ORTEP drawings of compounds 8g, 8h and 9f provide strong evidence of the structure of aromatic thiazole derivatives 8a-h and 9a-h. Undoubtedly, the structure of compounds 3e-h and 4e-h synthesized by the reaction of 3-aryl-4-formylsydnone thiosemicarbazones 1e-h with cyclization reagents 2a and 2b in the previous work should have the thiazole moiety, and not the thiazoline moiety. Both the new thiazole derivatives 8a-h and 9a-h and the 3-arylsydnonyl-substituted derivatives 3e-h and 4e-h were investigated to determine their antioxidant activity by two tests that have been highly documented-the direct scavenging effect on a stable free 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and the inhibition of the 2,2-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical. Results of this study demonstrate that not only the thiazole ring and the aryl ring has the contribution to the antioxidant activities, the sydnone ring of 3-arylsydnonyl moiety also has its considerable contribution.     

Preferential intramolecular ring closure of aminoalcohols with diethyl carbonate to oxazolidinones

The closure by cyclization with diethyl carbonate (EtO)(2)CO from aminoalcohols 1 as starting material can lead to the oxazolidinones 2a, b and 2c, respectively. In the reaction of trans-isomer (6) and (EtO)(2)CO, isolated products were also only 5-membered oxazolidinone derivative (7), containing its dehydrated derivative 8. The preferential formation of the 5-membered oxazolidinone ring system apparently indicated that this process (5-Exo-Trig ring closure) is more favorable than that of 6- or 7-membered ring derivative (3 or 9) by 6- or 7-Exo-Trig ring closure.     

Acid-catalyzed transannular cyclization of 3aH-cyclopentene[8]annulene-1,4-(5H,9aH)-diones and some proposed mechanisms

Bicyclic 3aH-cyclopentene[8]annulene-1,4-(5H,9aH)-diones underwent three types of acid-induced transannular reactions, Michael cyclization, [3 + 2] cycloaddition, and Friedel-Crafts ipso-alkylation, depending on the cyclopentenone ring substituent (Me or Ph) and the position of [8]annulenone substituent as well as the nature of acids (BF3, MeSO3H, CF3SO3H). The Me-substituent permitted the Michael reaction for all acids used to give tricyclic diones by the activation of cyclopentenone carbonyl group. However, the Ph-substituent inhibited the Michael reaction for BF3 and MeSO3H but allowed the [3 + 2] cycloaddition and Friedel-Crafts reaction for CF3SO3H depending on the position of annulenone substituent. These CF3SO3H reactions exhibited the following novel rearrangements, affording 2-naphthalenone and 7-acenaphthylene derivatives, respectively. The factors that control the reaction mode of these transannular cyclizations were discussed in view of the constraint twist-boat conformation of [8]annulenone ring as well as the ring substituent effects on the intramolecular cyclization. In addition, these [8]annulenone rings were found to easily undergo the intramolecular [2 + 2] photocyclization to provide the tetracyclic cage compounds which exhibited the facile cycloreversion under the influence of acid.     

Synthesis of diversely functionalized hexahydropyrrolo[2,3-b]indoles using domino reactions, olefination, isomerization and Claisen rearrangement followed by reductive cyclization

Hexahydropyrrolo[2,3-b]indoles 6 were synthesized in five steps from indolin-3-one 8 by a general and efficient method, in which elements of molecular diversity were readily added onto the 3a-position of the pyrrolo[2,3-b]indole ring system. Horner-Wadsworth-Emmons reaction of 2-allyloxyindolin-3-ones 7, derived from indolin-3-one 8 and a variety of allylic alcohols, smoothly proceeded with successive Claisen rearrangement to give the corresponding 3-allyl-3-cyanomethylindolin-2-ones 15. Indolin-2-ones 15 were converted into pyrrolo[2,3-b]indoles 6 using partial hydrolysis followed by reductive cyclization with LiAlH(4). Synthesis of N-methylated pyrrolo[2,3-b]indole derivatives 23 and 26 is also described.     

Kinetic results implicating a polar radical reaction pathway in the rearrangement catalyzed by alpha-methyleneglutarate mutase

alpha-Methyleneglutarate mutase (MGM) catalyzes the rearrangement of 2-methyleneglutarate to 3-methylitaconate (2-methylene-3-methylsuccinate). A putative mechanism for the MGM-catalyzed reaction involves 3-exo cyclization of the 2-methyleneglutaric acid-4-yl radical to a cyclopropylcarbinyl radical intermediate that ring opens to the 3-hydroxycarbonyl-2-methylenebutanoic acid-4-yl radical (3-methylitaconic acid radical). Model reactions for this mechanism were studied by laser flash photolysis kinetic methods. alpha-Ester radicals were produced by 266 nm photolysis of alpha-phenylselenyl ester derivatives. Rate constants for cyclizations of the (Z)-1-ethoxycarbonyl-4-(2,2-diphenylcyclopropyl)-3-buten-1-yl radical ((Z)-8a) and (E)- and (Z)-1,3-di(ethoxycarbonyl)-4-(2,2-diphenylcyclopropyl)-3-buten-1-yl radicals ((E)- and (Z)-8b) were determined. The ester group in (Z)-8a accelerates the 3-exo cyclization in comparison to the parent radical lacking an ester group by a factor of 3, an effect ascribed to a polarized transition state. The ester groups at C3 in radicals 8b slow the 3-exo cyclization reaction by a factor of 50. The rate constant for cyclization of the 2-methyleneglutaric acid-4-yl radical is estimated to be k approximately 2000 s(-1) at ambient temperature. When coupled with the estimated partitioning of the intermediate cyclopropylcarbinyl radical, the overall rate constant for the conversion is estimated to be k approximately equal to 1 x 10(-3) s(-1), which is much too small for any radical reaction and several orders of magnitude too small for kinetic competence for the MGM-catalyzed process. The possibility that the radical reaction in nature involves an unusual mechanism in which polar effects are important is discussed.     

Synthesis using pyridinium anhydrobases,preparation of indolizine derivatives

A number of derivatives of indolizine ring system have been prepared from 1-substituted 4,6-diphenyl-2-phenacylidene-1,2-dihydropyridines either by metallation with LDA or acylation and further basic treatment. Similarly, I-arylmethyl-4,6-diphenyl-2-dicyanomethylene-1,2-dihydropyridines by action of LDA undergo cyclization to the corresponding 2-amino-1-cyano-3-aryl indolizines.     

Computational studies on the cyclization of polycyclic aromatic hydrocarbons in the synthesis of curved aromatic derivatives.

Computational studies on the cyclization reactions of some polycyclic aromatic hydrocarbons (PAHs) were performed at the DFT level. Compounds C26H14 and C24H14, which show the connectivity of C60 fullerene fragments, were chosen as suitable models to study the formation of curved derivatives by six- or five-membered ring formation, upon oxidation to their radical cations. Four possible pathways for the cyclization process were considered: a) initial C-C bond formation to afford a curved derivative, followed by dehydrogenation; b) homolytic C-H cleavage prior to cyclization; c) initial concerted H2 elimination and subsequent cyclization; and d) deprotonation of the radical cations prior to cyclization. Computed reaction and activation energies for these reactions show that direct cyclization from radical cations (pathway a) is the lowest-energy mechanism. The formation of five-membered rings is somewhat more favourable than benzannulation. After new cycle formation, homolytic C-H dissociation to afford the corresponding cations is the most favourable process. These cations react with H* without barrier to give H2* Intermediate deprotonations are strongly disfavoured. The relatively low activation energies compared with carbon cage rearrangements suggest that ionization of PAHs can be used for the tailored preparation of nonplanar derivatives from suitable precursors.     

2-Stannyl-1, 3-dithiane Herstellung,Sn/Li-Transmetallierung und Verwendung für Cyclisierungen

2-Stannyl-1,3-dithianes. Preparation, Sn/Li-Transmetallation, and Use for Cyclizations In order to test the possibility of generating nucleophilic 2-lithio-1, 3-dithiane centers in the presence of electrophilic groups in the same molecule, the stannylated dithianes 1 - 3 were prepared or generated. Solutions of the lithio derivatives 2a and 2b could either be obtained by metallation of 1 with lithiumdiisopropylamide (LDA) or by transmetallation of 3 with alkyllithium reagents. Alkylations of 2 led to the alkyl-stannyl-dithianes 4 - 7 . Additions of the trimethylstannylated lithiodithiane 2a to aldehydes and ketones at low temperature led - after hydrolysis - to the adduct alcohols 8 ; warming up to room temperature before hydrolysis furnished keten thioacetals 9 only with acetone (→ 9b ) and cyclohexanone (→ 9c ) as carbonyl component, while still the simple adducts 8a and 8d were isolated with benzaldehyde and cyclohexenone, respectively. Methyl benzoate and benzoic acid anhydride reacted with 2a to produce the tin-free derivatives 12 and 14 , respectively. It is shown that the Sn/Li-exchange at the 2-position of dithianes 4 - 7 , 15 and 16 takes place within minutes at ?78°, whereas H/Li-metallation does not occur at all at this temperature. In situ preparation of the cyclization products 17 - 19 from halo-epoxides is described. The overall yields of Sn/Li-exchange ( 3 → 2 ), epoxyalkylation ( 2 → 15 and 16 , repectively), Sn/Li-exchange in 15 and 16 , cyclization (→ 17 – 19 ) are twice as high (up to 80%) with the tributylin than with the trimethyltin derivatives. The intramolecular 1, 3 nucleophilic reaction 20a → 17 is complete within 5 min at ?78°. The total yields of cyclization products by the tin route ( 3b → 16 → 20b → 18 + 19 ) and by direct metallation (1, 3-dithiane → 21b → 20b → 18 + 19 ) are 63 and 30%, respectively.     

The Synthesis of Adamantane Ring Containing Benzimidazole,Benzoxazole, and Imidazo[4,5‐e]benzoxazole Derivatives from 3‐Aminophenol

Adamantane derivatives containing heterocycles such as benzimidazoles, benzoxazoles, and fused imidazo[4,5‐e]benzoxazoles were synthesized from 3‐aminophenol. The route started with amidation of adamantane‐1‐carboxylic acid chloride with 3‐aminophenol furnishing N‐(3‐hydroxyphenyl)adamantane‐1‐carboxamide. Subsequent nitration gave three regioisomers. After reduction of the nitro groups, the respective aniline derivatives were used in the formation of benzimidazole and benzoxazole rings. The cyclization of the 2‐substituted benzoxazole ring was performed using two methods: via condensation of N‐(2‐amino‐3‐hydroxyphenyl)adamantane‐1‐carboxamide with carbonitriles in the presence of a Lewis acid or via Cu(II)‐catalyzed oxidative coupling of aminophenol with aromatic aldehydes. The benzimidazole ring formed by acid‐catalyzed cyclization of N‐(2‐amino‐5‐hydroxyphenyl)adamantane‐1‐carboxamide was then converted to a tricyclic system after three synthetic steps.     

The synthesis of 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidines. II. 4-Hydroxy, 4-mercapto, 2-amino-4-hydroxy and 2,4-dihydroxy derivatives

Several new types of compounds in the 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine series have been prepared. Included are a 6-acyl derivative unsubstituted in the pyrimidine ring, as well as 4-hydroxy, 4-mercapto, 2-amino-4-hydroxy and 2,4-dihydroxy derivatives. These products were derived directly or indirectly from 4-cyano- or 4-carbethoxy-1-acyl-3-amino-3-pyrroline intermediates. 3-Hydroxy, 3-amino, and 3-thioformylamino-1-acyl-3-pyrroline-4-thiocarboxamides have been obtained and the 3-thioformylamino derivatives shown to undergo base-catalyzed cyclization to close a 4-mercaptopyrimidine ring.     

Synthesis of 6,8-substituted derivatives of imidazo[5,1-c][1,2,4]triazines and 1,4-dihydroimidazo[5,1-c][1,2,4]triazin-4-ones

The cyclization of imidazolylhydrazines, synthesized from 5-diazoimidazoles and cyanoacetic acid derivatives, to 4-aminoimidazo[5,1-c][1,2,4]triazines and imidazo[5,1-c][1,2,4]triazin-4-ones has been studied. It was established that electron-withdrawing substituents at position 4 of the imidazole ring had a weak effect on the cyclization process. On the other hand, electron-donating substituents at positions 4 or 2 of this ring inhibited and in some cases completely prevented the formation of bicyclic products.Urals State Technical University (UPI), Ekaterinburg 620002, Russia. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 805–815, June, 1998.     

Carbodiimide-mediated preparation of the tricyclic pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine ring system and its application to the synthesis of the potent antitumoral marine alkaloid variolin B and analog

A total synthesis of the marine alkaloid variolin B has been completed in 13 steps in an overall yield of 6.5% from 3-formyl-4-methoxypyridine. Our approach is based on the sequential formation of the 7-azaindole ring, the tricyclic pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine ring system, and finally installation of the 2-aminopyrimidine ring at C5. The required 7-azaindole ring appropriately substituted is formed by a modified indole synthesis involving a nitrene insertion process (two steps). Formation of the annelated pyrimidine ring is achieved by two routes both involving a carbodiimide-mediated cyclization process, which allow incorporation of the amine functionality at C9 of the core tricyclic (six steps). Installation of the northeast 2-aminopyrimidine ring at C5 is performed using the Bredereck protocol (three steps). Ultimate, thermal decarboxylation with concomitant O-methyl deprotection and further N-benzyl deprotection by the action of triflic acid completed the synthesis of the target natural product variolin B.     

Excellent blue fluorescent trispirobifluorenes: synthesis, optical properties and thermal behaviors

Tetraiodotrispirobifluorene (1) was synthesized through cyclization of 2,7-diiodofluorene with pentaerythrityl tetrabromide under base condition. Subsequent treatment of 1 with arylboronic acid or arylacetylene under Pd-catalyzed coupling condition led to corresponding tetraaryl trispirobifluorenes (3–8). These trispirobifluorene derivatives exhibited bright-violet to blue photoluminescence (PL) with excellent quantum efficiencies and showed high thermal stabilities. ‘Green-emission tail’ could not be detected for those tetraaryl substituted trispirobifluorenes (3–8) annealed both in N₂ and in air.     

The fischer indolization of 4-acetonyl-2,6-piperidinediones

The PPA induced Fischer indolization of 4-acetonyl-2,6-piperidinediones 4 takes place both at the methylene and the methyl carbons, although the latter regioisomer (3) undergoes a further cyclization of the imide moiety upon the indole 3-position followed by ring-opening of the resulting intermediate 9 to give tetrahydrocarbazolone 8. Fragmentation of the two possible regioisomers 3 and 7 to 2-methylindole occurs at higher temperatures. This process is more pronounced when using 4-acetonyl-3,4-dihydro-2(1H)-pyridone 13 as the substrate for the indolization. The use of N-acetylphenylhydrazone derivatives leads to similar results as a consequence of the deacylation of the initially formed indole derivatives. In this case, an additional C-acylation of the indole ring also occurs.     

Direct and dye-sensitized aqueous photo-oxidation of 3-indoleacetic acid, methyl-3-indoleacetate and 1-methyl-3-indoleacetic acid I: Analysis of products

The products obtained in the direct and riboflavin- or Rose-Bengal-sensitized photo-oxidation of 3-indoleacetic acid (1a), methyl-3-indoleacetate (1b) and 1-methyl-3-indoleacetic acid (1c) in aqueous buffer (pH 5 or pH 8) containing 10% methanol have been analysed. Both the direct and riboflavin-sensitized irradiations give essentially the same products. At pH 5 the main products are 3-oxindolemethanols (2), 3-indolemethanols (6) and 3-acylindoles (8), all resulting from the oxidation of the 3-methylene group, and a polymeric material which probably has the same origin. As primary intermediates, radicals I or II, formed by hydrogen abstraction from the 3-methylene group, are proposed. At pH 8 the breakdown of the 2,3-double bond of the starting indole predominates in both types of photo-oxidation, producing o-formamidobenzoyl derivatives (9), probably through the corresponding intermediate dioxetanes (V). At pH 5 and pH 8 the ring rupture is enhanced when Rose Bengal is used instead of riboflavin. The formation of other compounds can be explained by secondary thermal reactions.     

Two‐step Synthesis of New γ‐Lactones via Cyclization of 7‐Chloro‐2‐(methoxycarbonyl)‐4‐6‐dimethylocta‐(2E,4E,6E)‐trienoic acid

A new rapid synthesis of γ‐lactones, cis fused with a cyclopentenic ring by thermal cyclization of 7‐chloro‐2‐(methoxycarbonyl)‐4‐6‐dimethylocta‐7‐phenyl (or methyl) (2E,4E,6E)‐trienoic acids was reported. The key step implicates an intramolecular cyclization to a cyclopentenyl cation, according to an electrocyclic π_2s + π_2a conrotatory process, published in a recent paper (from the corresponding diacids). We have investigated the thermal behavior of the corresponding half‐esters since; if the cyclization obeys to the proposed mechanism, the diacids, half‐esters must also cyclize in a similar manner. Saponification of these led to γ‐dilactones via intermediary cyclopropanes. Mechanistic pathways were investigated.     

Carboxyketenes, methyleneketenes, vinylketenes, oxetanediones, ynols, and ylidic ketenes from Meldrum's acid derivatives

It has been documented that 5-methylene-Meldrum's acid derivatives (1, 12 ) and their enols (2, 13) can undergo fragmentation to malonic anhydrides (4, 19 ), carboxyketenes (3, 16) and methyleneketene (5, 21 , 35 ), as well as cyclization to pyrrole-3-one and thiophene-3-one derivatives 11a,b (but not furan-3-ones 11c ) under the conditions of flash vacuum thermolysis (FVT). Here we report theoretical calculations at the B3LYP/6-311 + G(2d, p) and G3X(MP2) levels of theory, which allow a rationalization of these observations. The calculated activation barriers for these reactions are all of the order of 37-40 kcal mol(-1). Hydroxyacetylenes (alkynols) 7 are sometimes observed in FVT reactions of Meldrum's acid derivatives. Their formation is now explained as an FVT reaction of the carboxyketenes (e.g. 3-->7 and 32-->34) with a calculated activation barrier of ca. 39 kcal mol(-1). The cyclization of alkylamino- and alkylthio-substituted methyleneketenes 8a,b to pyrrolone and thiophenone derivatives 11a,b is found to be energetically very feasible under FVT conditions, and even in some cases in solution, with activation barriers of 33-39 kcal mol(-1). This cyclization takes place via the fleeting ylidic ketene intermediates 9a,b,25, and 37a,b, which exist in very shallow energy minima. Alkoxy-substituted methyleneketenes 8c do not cyclize in this manner due to the rather high, but in principle not impossible, activation barriers for the initial 1,4-H shifts to the ylidic ketenes 9c (ca. 47 kcal mol(-1)).     

Synthetic studies on mitomycins. 2. A synthesis of 9a-hydroxy-5,8-dideoxomitosane skeleton through a novel retroaldol type of ring-opening reaction.

A synthesis of 9a-hydroxy-5,8-dideoxomitosanes was accomplished by the transannular cyclization of hydro-1-benzazocinone intermediates derived from 3-(2,5-dioxo-1-methylcyclopentyl)-6-methyl-p-phenylenediamine derivatives. These mitosanes were led to the 8-membered ring system by an oxidative ring-opening reaction.     

1,9,8-cyclization of 1,8-disubstituted anthraquinones. 12H-benzo[m,n]chromeno [2,3,4-k,l]kacridine derivatives

The cyclization of 1-(2,5-dihalophenylamino)-8-hydroxyanthraquinones or the corresponding 8-methoxycompounds in concentrated sulfuric acid has given derivatives of a new hexanuclear heterocyclic system —12H-benzo[m,n]chromeno [2,3,4-k,l]acridine. It has been shown that the double cyclization takes place initially through the closure of the pyridine ring with the formation of 9H-napth[3,2,1-k,l]acridine, the product of 1,9-cyclization. Under the reaction conditions the latter undergoes intramolecular aroxylation with the formation of a pyran ring under a-typical conditions.Translated from Khimiya GeterotsiklicheskikhSoedinenii, No. 4, pp. 519–523, April, 1980.     

Suzuki-Miyaura cross-coupling reactions of halo derivatives of 4H-pyrido[1,2-a]pyrimidin-4-ones

The palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of halo derivatives of 4H-pyrido[1,2-a]pyrimidin-4-one with (het)arylboronic acids allow easy access to (het)aryl and vinyl derivatives of this bicycle in good to excellent yields, even from chloro derivatives. The sequence of reactivity of the halogen in the different positions of the ring system was also investigated. 6-Phenyl-4H-pyrido[1,2-a]pyrimidin-4-one could be prepared by thermal cyclization of isopropylidene (6-phenylpyrid-2-ylamino)methylenemalonate, together with a small amount of 7-phenyl-1,4-dihydro-1,8-naphthyridin-4-one.