Thermal and Ru-catalyzed Reactions of Styryl-Substituted Azulenes with Dimethyl Acetylenedicarboxylate

The thermal reaction of 1-[(E)-styrl]azulenes with dimethyl acetylenedicarboxylate (ADM) in decalin at 190–200° does not lead to the formation fo the corresponding heptalene-1,2-dicarboxylates (Scheme 2). Main products are the corresponding azulene-1,2-dicarboxylates (see 4 and 9 ), accompanied by the benzanellated azulenes trans- 10a and trans- 11 , respectively. The latter compounds are formed by a Diels-Alder reaction of the starting azulenes and ADM, followed by an ene reaction with ADM (cf. Scheme 3). The [RuH₂(PPh₃)₄]-catalyzed reaction of 4,6,8-trimethyl-1-[(E)-4-R-styryl]azulenes (R=H, MeO, Cl; Scheme 4) with ADM in MeCN at 110° yields again the azulene-1,2-dicarboxylates as main products. However, in this case, the corresponding heptalene-1,2-dicarboxylates are also formed in small amounts (3–5%; Scheme 4). The benzanellated azulenes trans- 10a and trans- 10b are also found in small amounts (2–3%) in the reaction mixture. ADM Addition products at C(3) of the azulene ring as well as at C(2) of the styryl moiety are also observed in minor amounts (1–3%). Similar results are obtained in the [RuH₂(PPh₃)₄]-catalyzed reaction of 3-[(E)-styryl]guaiazulene ((E)- 8 ; Scheme 5) with ADM in MeCN. However, in this case, no heptalene formation is observed, and the amount of the ADM-addition products at C(2) of the styryl group is remarkably increased (29%). That the substitutent pattern at the seven-membered ring of (E)- 8 is not responsible for the failure of heptalene formation is demonstrated by the Ru-catalyzed reaction of 7-isopropyl-4-methyl-1-[(E)-styryl]azulene ((E)- 23 ; Scheme 11) with ADM in MeCN, yielding the corresponding heptalene-1,2-dicarboxylate (E)- 26 (10%). Again, the main product is the corresponding azulene-1,2-dicarboxylate 25 (20%). Reaction of 4,6,8-trimethyl-2-[(E)-styryl]azulene ((E)- 27 ; Scheme 12) and ADM yields the heptalene-dicarboxylates (E)- 30A / B , purely thermally in decalin (28%) as well as Ru-catalyzed in MeCN (40%). Whereas only small amounts of the azulene-1,2-dicarboxylate 8 (1 and 5%, respectively) are formed, the corresponding benzanellated azulene trans- 29 ist found to be the second main product (21 and 10%, respectively) under both reaction conditions. The thermal reaction yields also the benzanellated azulene 28 which is not found in the catalyzed variant of the reaction. Heptalene-1,2-dicarboxylates are also formed from 4-[(E)-styryl]azulenes (e.g. (E)- 33 and (E)- 34 ; Scheme 14) and ADM at 180–190° in decalin and at 110° in MeCN by [RuH₂(PPh₃)₄] catalysis. The yields (30%) are much better in the catalyzed reaction. The formation of by-products (e.g. 39–41 ; Scheme 14) in small amounts (0.5–5%) in the Ru-catalyzed reactions allows to understand better the reactivity of zwitterions (e.g. 42 ) and their triyclic follow-up products (e.g. 43 ) built from azulenes and ADM (cf. Scheme 15).     

New Results in the Synthesis of Styrylazulene Derivatives: Application of the ‘Anil synthesis’ to the preparation of azulenes substituted with styryl groups at the seven-membered ring

The synthesis of 4,6,8-trimethyl-1-[(E)-4-R-styryl]azulenes 5 (R=H, MeO, Cl) has been performed by Wittig reaction of 4,6,8-trimethylazulene-1-carbaldehyde ( 1 ) and the corresponding 4-(R-benzyl)(triphenyl)phosphonium chlorides 4 in the presence of EtONa/EtOH in boiling toluene (see Table 1). In the same way, guaiazulene-3-carbaldehyde ( 2 ) as well as dihydrolactaroviolin ( 3 ) yielded with 4a the corresponding styrylazulenes 6 and 7 , respectively (see Table 1). It has been found that 1 and 4b yield, in competition to the Wittig reaction, alkylation products, namely 8 and 9 , respectively (cf. Scheme 1). The reaction of 4,6,8-trimethylazulene ( 10 ) with 4b in toluene showed that azulenes can, indeed, be easily alkylated with the phosphonium salt 4b . 4,6,8-Trimethylazulene-2-carbaldehyde ( 12 ) has been synthesized from the corresponding carboxylate 15 by a reduction (LiAlH₄) and dehydrogenation (MnO₂) sequence (see Scheme 2). The Swern oxidation of the intermediate 2-(hydroxymethyl)azulene 16 yielded only 1,3-dichloroazulene derivatives (cf. Scheme 2). The Wittig reaction of 12 with 4a and 4b in the presence of EtONa/EtOH in toluene yielded the expected 2-styryl derivatives 19a and 19b , respectively (see Scheme 3). Again, the yield of 19b was reduced by a competing alkylation reaction of 19b with 4b which led to the formation of the 1-benzylated product 20 (see Scheme 3). The ‘anil synthesis’ of guaiazulene ( 21 ) and the 4-R-benzanils 22 (R=H, MeO, Cl, Me₂N) proceeded smoothyl under standard conditions (powered KOH in DMF) to yield the corresponding 4-[(E)-styryl]azulene derivatives 23 (see Table 4). In minor amounts, bis(azulen-4-yl) compounds of type 24 and 25 were also formed (see Table 4). The ‘anil reaction’ of 21 and 4-NO₂C₆H₄CH=NC₆H₅ ( 22e ) in DMF yielded no corresponding styrylazulene derivative 23e . Instead, (E)-1,2-bis(7-isopropyl-1-methylazulen-4-yl)ethene ( 27 ) was formed (see Scheme 4). The reaction of 4,6,8-trimethylazulene ( 10 ) and benzanil ( 22a ) in the presence of KOH in DMF yielded the benzanil adducts 28 to 31 (cf. Scheme 5). Their direct base-catalyzed transformation into the corresponding styryl-substituted azulenes could not be realized (cf. Scheme 6). However, the transformation succeeded smoothly with KOH in boiling EtOH after N-methylation (cf. Scheme 6).     

A Detailed Investigation of the Reaction of 5,9-Diphenylbenz[a]azulene with Dialkyl Acetylenedicarboxylates Leading to Dialkyl 8,12-Diphenylbenzo[a]heptalene-6,7-dicarboxylates

The synthesis of 5,9-diphenylbenz[a]azulene ( 1 ) from 1,3-diphenylcyclopent[a]indene-2,8-dione ( 4 ) and cyclopropene has been re-investigated. The reduction of the decarbonylated cycloadduct 5 with LiAlH₄/AlCl₃ in Et₂O leads not only to the expected 7,10-dihydrobenz[a]azulene 6 , but also to small amounts of the cyclopropa[b]fluorenes exo- 7 and endo- 7 (cf. Scheme 2), the structures of which have been determined by X-ray crystal-structure analysis (cf. Fig. 1). The reaction of 1 with dialkyl acetylenedicarboxylates (ADR) in MeCN at 100° in the presence of 2 mol-% of catalysts such as [RuH₂(PPh₃)₄] results mainly in the formation of the expected 8,12-diphenylbenzo[a]heptalene-6,7-dicarboxylates 3 . A thorough investigation of the reaction mixture of 1 and dimethyl acetylenedicarboxylate (ADM) revealed the presence of a number of intermediates and side products (Scheme 5). Most important was the isolation and identification of the cyclobutene intermediate 9a (cf. Fig. 4), which is formed by a zwitterionic rearrangement of the primary adduct 2a of 1 and ADM and represents the direct precursor of the heptalene-diester 3a . Compounds of type 9a have so far only been postulated as necessary intermediates in the thermal reaction of azulenes and ADR to give corresponding heptalenedicarboxylates. Compound 9a is photochemically unstable and undergoes rearrangement even under the influence of normal laboratory light into a mixture of trans- 10a and cis- 10a (Scheme 8). Both diastereoisomers are also found in the original reaction mixture of 1 and ADM, but not when the reaction is performed under exclusion of light. On heating in MeCN at 100°, or better in DMF at 150°, trans- 10a and cis- 10a undergo rearrangement to the fluoranthene-1,2-dicarboxylate 11a (Scheme 9), which is also present in the original reaction mixture of 1 and ADM. The catalysts do not accelerate the reaction of 1 and ADR, but they lead to better yields of the benzo[a]heptalene-6,7-dicarboxylates 3 , especially in the reaction of 1 with diisopropyl acetylenedicarboxylate (ADiP) (cf. Tables 1 and 2).     

Introduction of Amino Alcohols in the Ring-Opening Reaction of 3-bromo-2,5-dimethylthiophene 1,1-dioxide. A short diastereoselective synthesis of substituted ‘tetrahydrobenzo[a]pyrrolizidines’ (= octahydro-1H-pyrrolo[2,1-a]isoindoles) using L-prolinol

Tetrahydrobenzo[a]pyrrolizidines (= octahydro-1H-pyrrolo[2,1-a]isoindoles) and tetrahydrobenzo[a]indo-lizidines, (= decahydropyrido[2,1-a]isoindoles) were prepared stereoselectively in four steps through an amineinduced ring-opening of 3-bromo-2,5-dimethylthiophene 1,1-dioxide ( 1 ) with L -prolinol ( 9 ), piperidine-2-methanol ( 10 ), and piperidine-2-ethanol ( 11 ), yielding the dienes (2S)-1-[(2E,4Z)-4-bromohexa-2,4-dienyl]pyrrolidine-2-methanol ( 12 ), 1-[(2E,4Z)-4-bromohexa-2,4-dienyl]piperidine-2-methanol ( 13 ), and 1-[(2E,4Z)-4-bromo-hexa-2,4-dienyl]piperidine-2-ethanol ( 14 ; Scheme2), which, after conversion into their α,β-unsaturated esters, cyclized in a TiCl₄-catalyzed intramolecular Diets-Alder reaction (Scheme3). A discussion on the mechanism of the ring opening reaction including semiempirical and ab initio calculations is also presented.     

An Analysis of the Bonding Properties of Benz[a]azulene by X-Ray,NMR, and Computational Studies

The X-ray crystal structures of 9-phenylbenz[a]azulene ( 4 ) and the corresponding non-benzannelated form, 4-phenylazulene ( 5 ), have been determined (cf. Fig.2). In contrast to 5 , the skeleton of which shows nearly equal C,C bond lengths (cf. Table 1), the seven-membered ring of 4 exhibits clearly alternating C,C bond lengths (cf. Table 1). This is in agreement with a strong accentuation of the heptafulvene substructure in 4 by the [a] benzannelation. The alternating bond lengths of 4 and of its parent structure 3 are also reflected in the corresponding variations of the ³J(H,H) and ¹J(¹³C,¹³C) values of these benz[a]azulenes (cf. Tables 4 and 5). Computations on the MP2/6-31G^* level as well as on the BP86/6-31G^* level for azulene ( 6 ), benz[a]azulene ( 3 ), and heptafulvene ( 7 ) are in good agreement with the experimental values (cf. Tables 6–8).     

Synthesis of pyrrolo[1,2-a]quinoxalines by 1,3-dipolar cycloaddition reaction. An additional reaction mechanism via an aziridine intermediate

The reaction of the 2-substituted 6-chloroquinoxaline 4-oxides 1a or 1b with 2-fold molar amount of methyl propiolate resulted in the 1,3-dipolar cycloaddition reaction to give 8-chloro-1,3-bismethoxycarbonyl-4-(piperidin-1-yl)pyrrolo[1,2-a]quinoxaline 4a or 8-chloro-1,3-bismethoxycarbonyl-4-(morpholin-4-yl)pyrrolo-[1,2-a]quinoxaline 4b , respectively. Compound 4a or 4b was transformed into 8-chloro-3-methoxycarbonyl-4-(piperidin-1-yl)pyrrolo[1,2-a]quinoxaline 5a or 8-chloro-3-methoxycarbonyl-4-(morpholin-4-yl)pyrrolo[1,2-a]-quinoxaline 5b , respectively. The structure of 4a,b was confirmed by the NOE measurement among the C₁ -H , C ₂-H and C ₉-H proton signals of 5a,b . An additional reaction mechanism was proposed for the ring transformation of isoxazolo[2,3-a]quinoxalines into pyrrolo[1,2-a]quinoxalines.     

Approaches to the synthesis of cytochalasans. Part 7. Synthesis of some building blocks for the construction of the macrocyclic moiety

The synthesis of ethyl (2E, 4E, 8R)-8-methyl-10-[(2H-tetrahydropyran-2-yl)oxy]-2,4-decadienoate ( 11 ), methyl (2E, 8R)-8-methyl-10-[(2H-tetrahydropyran-2-yl)oxy]-2-decenoate ( 16 ), synthons for the construction of the macrocyclic moieties of the cytochalasins A, B and F, and of (3R)-[7-(1,3-dioxolan-2-yl)-3-methylheptyl]triphenyl-phosphonium bromide ( 24 ), a C₈-building block for deoxaphomin, proxiphomin and protophomin is described. In all instances (+)-(R)-pulegone ( 5 ) served as starting material.     

Asymmetric hydrogen-transfer hydrogenation on rhodium(I) complexes with new optically active salen ligands derived from (4<Emphasis Type="Italic">S</Emphasis>,5<Emphasis Type="Italic">S</Emphasis>)-4,5-bis(aminomethyl)-2,2-dimethyl-1,3-dioxolane

New optically active C ₂-symmetric salen-type ligands were synthesized on the basis of (4S,5S)-4,5-bis(aminomethyl)-2,2-dimethyl-1,3-dioxolane. These ligands were used to obtain cationic (trifluoromethanesulfonate) and neutral (chloride) rhodium(I) complexes with [(4S,5S)-2,2-dimethyl-5-{[(E)-pyridin-2-ylmethylidene]aminomethyl}-1,3-dioxolan-4-yl]-N-[(E)-pyridin-2-ylmethylidene]methanamine and [2,2-dimethyl-5-{[(E)-quinolin-2-ylmethylidene]aminomethyl}-1,3-dioxolan-4-yl]-N-[(E)-quinolin-2-ylmethylidene] methanamine. The latter complex ensured preparation of (S)-2-phenylethanol with an optical yield of 34.8% by transfer hydrogenation of acetophenone.     

Surprising Formation of Highly Substituted Azulenes on Thermolysis of 4,5,6,7,8‐Pentamethyl‐2H‐cyclohepta[b]furan‐2‐one and Heptalene Formation with the New Azulenes

Heating of 4,5,6,7,8‐pentamethyl‐2H‐cyclohepta[b]furan‐2‐one ( 1a ) in decalin at temperatures >170° leads to the development of a blue color, typical for azulenes. It belongs, indeed, to two formed azulenes, namely 4,5,6,7,8‐pentamethyl‐2‐(2,3,4,5,6‐pentamethylphenyl)azulene ( 4a ) and 4,5,6,7,8‐pentamethylazulene ( 5a ) (cf. Scheme 2 and Table 1). As a third product, 4,5,6,7‐tetramethyl‐2‐(2,3,4,5,6‐pentamethylphenyl)‐1H‐indene ( 6a ) is also found in the reaction mixture. Neither 4,6,8‐trimethyl‐2H‐cyclohepta[b]furan‐2‐one ( 1b ) nor 2H‐cyclohepta[b]furan‐2‐one ( 1c ) exhibit, on heating, such reactivity. However, heating of mixtures 1a / 1b or 1a / 1c results in the formation of crossed azulenes, namely 4,6,8‐trimethyl‐2‐(2,3,4,5,6‐pentamethylphenyl)azulene ( 4ba ) and 2‐(2,3,4,5,6‐pentamethylphenyl)azulene ( 4ca ), respectively (cf. Scheme 3). The formation of small amounts of 4,6,8‐trimethylazulene ( 5ba ) and azulene ( 5ca ), respectively, besides 1H‐indene 6a is also observed. The observed product types speak for an [8+2]‐cycloaddition reaction between two molecules of 1a or between 1b and 1c , respectively, with 1a , whereby 1a plays in the latter two cases the part of the two‐atom component (cf. Figs. 5 – 7 and Schemes 4 – 6). Strain release, due to the five adjacent Me groups in 1a , in the [8+2]‐cycloaddition step seems to be the driving force for these transformations (cf. Table 3), which are further promoted by the consecutive loss of two molecules of CO₂ and concomitant formation of the 10π‐electron system of the azulenes. The new azulenes react with dimethyl acetylenedicarboxylate (ADM) to form the corresponding dimethyl heptalene‐4,5‐dicarboxylates 20 , 22 , and 24 (cf. Scheme 7), which give thermally or photochemically the corresponding double‐bond‐shifted (DBS) isomers 20′ , 22′ , and 24′ , respectively. The five adjacent Me groups in 20 / 20′ and 24 / 24′ exert a certain buttressing effect, whereby their thermal DBS process is distinctly retarded in comparison to 22 / 22′ , which carry `isolated' Me groups at C(6), C(8), and C(10). This view is supported by X‐ray crystal‐structure analyses of 22 and 24 (cf. Fig. 8 and Table 5).     

Synthesen und Eigenschaften ethinylierter und trimethylsilylethinylierter Molekülsysteme mit 1,6-Methano[10]annulen-Partialstruktur

2-Trimethylsilylethinylated 1,6-methano[10]annulene1 a was obtained by reaction of 2-bromo-1,6-methano[10]annulene with trimethylsilylacetylene in the presence of bis-(triphenylphosphin-)-Pd (II) chloride and Cu(I) and also by reaction of 1,1-diiodo-2-(1,6-methano[10]annulene-2-yl)-ethene (2) withn-buthyl-lithium followed by hydrolysis.1 a reacts with 2N NaOH to 2-ethinyl-1,6-methano[10]annulene (1 b). 2,7- and 2,10-dibromo-1,6-methano[10]annulene can be substituted to give the trimethylsilylethinylated compounds3 a–6 a, which then can be transformed with 2N NaOH into the desilylated products3 b–5 b.

Wolfgang Kraus, Stuttgart-Hohenheim, mit den besten Wünschen in Freundschaft zum 60. Geburtstag gewidmet     

An Efficient Straightforward Synthesis of Benz[a]azulene

Benz[a]azulene ( 1 ) is synthesized in five steps (cf. Scheme 2) starting from commercially available 2-iodobenzyl alcohol ( 4 ) and tropylium tetrafluoroborate in an overall yield of 44%. The key step (cf. also Scheme 1) is the intramolecular Heck reaction of the 8-phenylsulfonyl-substituted heptafulvene 7 , which leads in nearly quantitative yield directly to 10-(phenylsulfonyl)benz[a]azulene ( 8 ). The desulfonylation of 8 can be accomplished by Julia's method with Na₂S₂O₄/NaHCO₃ in DMF/H₂O at 85–90°, thus leading to pure 1 in 78% yield. The phenylation of 8 with PhLi or PhCul at ?78° in THF occurs regioselectively at C(9). Dehydrogenation of the formed dihydroazulenes with o-chloroanil in toluene at room temperature gives 9-phenyl-10-(phenylsulfonyl)-benz[a]azulene ( 9 ) in 70% yield (cf. Scheme 3), which, again, can be desulfonylated with Na₂S₂O₄/NaHCO₃ in DMF/H₂O in good yields. The addition of PhLi to 1 in THF occurs at temperatures ? ?25°. Ionic dehydrogenation (1. Ph₃C⁺BF/MeCN; 2. Et₃N) of the dihydro forms leads to 3 , as the main product, and its positional isomers.     

Synthesis and Chiroptical Properties of Dimethyl 8,12-Diphenylbenzo[d]heptalene-6,7-dicarboxylate

6,10-Diphenylbenz[a]azulene ( 3 ) was reacted with dimethyl acetylenedicarboxylate (ADM) in the presence of 2 mol-% of [RuH₂(PPh₃)₄] in MeCN at 100° to yield a 7:1 mixture of dimethyl 2,6-diphenyl-9,10-benzotricyclo[6.2.2.0^1,7]dodeca-2,4,6,9,11-pentaene-11,12-dicarboxylate ( 4 ) and dimethyl 8,12-diphenylbenzo[d]heptalene-6,7-dicarboxylate ( 5 ; Scheme 2). The tricycle 4 , when heated in DMF at 150° for 1 h led to the formation of 81.5% of the heptalene-6,7-dicarboxylate 5 and 15% of the starting azulene 3 . No rearrangement of tricycle 4 was observed, when it was heated at temperatures up to 180° in pseudocumene. The heptalene-6,7-dicarboxylate 5 was easily separated into its antipodes (PM)-and (MP)- 5 on a Chiracel column (cf. Fig. 2). On heating at 150° for 1 h, (MP)- 5 showed no racemization at all. The Ru-catalyzed reaction of benz[a]azulene ( 6 ) with ADM led to the formation of dimethyl 9,10-benzotricyclo[6.2.2.0^1,7]dodeca-2,4,6,9,11-pentaene-11,12-dicarboxylate ( 7 ; Scheme 3). However, the formation of the corresponding heptalene-6,7-dicarboxylate could not be observed.     

New Synthetic Approach to 4-N-Arylaminoazuleno[2,1-d]pyrimides

1-Cyano-2-N,N-dimethylformamidinylazulenes as new synthons directed to heterocycle-fused azulenes were obtained by the condensation of 2-amino-1-cyanoazulenes and N,N-dimethylformamide dimethyl acetal (DMFDMA). 1-Cyano-2-N,N-dimethylformamidinylazulene (2a) and 1-bromo-3-cyano-2-N,N-dimethylformamidinylazulene (2b) reacted with anilines (3a–h) to give 4-N-arylaminoazuleno-[2,1-d]pyrimidines in moderate yields. This reaction provides a new procedure for synthesis of pyrimidine-fused azulenes.     

1-R-2-[(1E,3E)-4-Aminobuta-1,3-dien-1-yl]-1H-benzimidazoles. Synthesis and some transformations

7-Nitropyridobenzimidazolium salts are cleaved with secondary amines to form 2-[(E,E)-4-aminobuta-1,3-dienyl]-1H-benzimidazoles. The latter react with dimethyl acetylene-dicarboxylate to yield 4a-[(E,Z,E)-6-amino-4,5-dimethoxycarbonylhexa-1,3,5-trien-1-yl]-1,2,3,4-tetra(methoxycarbonyl)-4a,5-dihydropyrido[1,2-a]benzimidazoles.     

p<Emphasis Type="Italic">K</Emphasis><Subscript>a</Subscript> Determinations for Montelukast Sodium and Levodropropizine

The pK _a constants and relative abundances of unionized and ionized forms of Montelukast sodium {the sodium salt of 2-[1-[[(1R)-1-[3-[2-(7-chloroquinolin-2-yl)ethenyl] phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanylmethyl]cyclopropyl]acetic acid} and Levodropropizine {(2S)-3-(4-phenylpiperazin-1-yl)propane-1,2-diol} were determined potentiometrically from measurements at various pHs. These determinations were in order to relate their pK _a values with their bioavailability and to provide chemical data to be used in their analysis.     

Synthesis of optically active hydridocarbonyl triosmium clusters with terpene derivatives as ligands. Molecular structure and absolute configuration of a cluster with a bridging dihydroimidazole ligand

Reactions of the triosmium clusters Os₃(CO)₁₁(NCMe) (1) and Os₃(CO)₁₀(NCMe)₂ (2) with terpene derivatives,viz., (1S,3S,4R,6R)-3-(N,N-dimethylamino)-4-amino-3,7,7-trimethylbicyclo [4.1.0]heptane (3). (3bR,4aR)-(3,4,4-trimethyl-3b,4,4a,5-tetrahydrocyclopropa [3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (4a), and (3bR,4aR)-3-(3,4,4-trimethyl-3b, 4,4a,5-tetrahydrocyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)propionic acid (4b), were studied. A complex with the terminally coordinated ligand is formed in the first step of the reaction of diamine3 with cluster1. Heating of the resulting complex is accompanied by activation of one of the methyl groups of the ligand to form diastereomers with the bridging tricyclic dihydroimidazole ligand. One of these diastereomers was studied by X-ray diffraction analysis and its absolute configuration was established. Pyrazolycarboxylic acids react with cluster2 as simple organic acids and are coordinated as a bridge at the Os—Os bond through the carboxyl group. Published inIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1447–1454, August, 2000.     

Some Unusual Products from the Thermal Reaction of Azulenes with Dimethyl Acetylenedicarboxylate

The thermal reaction of azulene-1-carbaldehydes 5 and 6 with excess dimethyl acetylenedicarboxylate (ADM) in decalin leads mainly to the formation of (1 + 1) and (1 + 2) adducts arising from the addition of ADM at the seven-membered ring of the azulenes (cf. Schemes 2 and 4). The (1 + 2) adducts are formed in a homo-Diels-Alder reaction of ADM and isomeric tricyclic carbaldehydes which are derived from the primary tricyclic carbaldehydes by reversible [1s5s]-C shifts (cf. Schemes 3 and 5). The thus formed pentacyclic carbaldehydes seem to undergo deep-seated skeletal rearrangements (cf. Scheme 7) which result finally in the formation of the formyl-tetrahydrocyclopenta[bc]acenaphthylene-tetraesters 12 and 19 , respectively. In other cases, e.g., azulene-1-carbaldehydes 7 and 8 (cf. Scheme 8), the thermal reaction with excess ADM furnishes only the already known tetracycfic (1 + 2) adducts of type anti- 26 to ‘anti’- 29 . The thermal reaction of 1,3,4,8-tetramethylazulene ( 9 ) with excess ADM in decalin resulted in the formation of two (1 + 2) and one (1 + 3) adduct in low yields (cf. Scheme 9). The latter turned out to be the 2,6-bridged barrelene derivative 32 . There are structural evidences that 32 is formed by similar pathways as the formyl-tetrahydrocyclopenta[bc]acenaphthylene-tetraesters (cf. Schemes 7 and 11). [²H₃]Me-Labelling experiments are in agreement with the proposed mechanisms (cf. Scheme 13).     

Synthesis and reactions of 2-[3-(trifluoromethyl)phenyl]furo[3,2-<Emphasis Type="Italic">c</Emphasis>]pyridine

(E)-3-{5-[3-(Trifluoromethyl)phenyl]furan-2-yl}propenoic acid (I) was prepared from 5-[3-(tri-fluoromethyl)phenyl]furan-2-carbaldehyde under the Doebner’s conditions. The obtained acid was converted to the corresponding azide II, which was cyclized by heating in diphenyl ether to 2-[3-(trifluoromethyl)phenyl]-4,5-dihydrofuro[3,2-c]pyridin-4-one (III). This compound was aromatized with phosphorus oxychloride to chloroderivative IV which was reduced with H₂NNH₂-Pd/C to the title compound V. 2-[3-(Trifluoromethyl)phenyl]furo[3,2-c]pyridin-5-oxide (VI) was synthesized by reaction of V with 3-chloroperoxybenzoic acid in dichloromethane. On treatment of VI with benzoyl chloride and potassium cyanide (Reissert-Henze reaction), corresponding 2-[3-(trifluoromethyl)phenyl]furo[3,2-c]pyridine-1-carbonitrile (VII) resulted. 5-Amino-2-[3-(trifluoromethyl)phenyl]furo[3,2-c]pyridin-5-ium-4-methylbenzene sulfonate (VIII) was prepared by direct N-amination of the title compound V with 1-[(aminooxy)sulfonyl]-4-methylbenzene in dichloromethane. Then, VIII was transformed to a non-isolated zwitterionic N-imid IX which afforded the corresponding furo[3,2-c]pyrazolo[1,5-a]pyridine carboxylic acid esters X, XI by 1,3-dipolar cycloaddition reactions with dimethyl but-2-ynedionate (DBD) or ethyl propiolate. The structures of all compounds were confirmed by their IR and NMR spectra. Presented at the 1st International Conference “Applied Natural Sciences” on the occasion of 10th anniversary of the University of St. Cyril and Methodius, Trnava, 7–9 November 2007.     

Mechanistic and Synthetic Studies on the Formation of 1,2,4-Trioxanes Related to Arteannuin. Photooxygenation of a bicyclic dihydropyran

The photooxygenation of (4R,4aS,7R)-4,4a,5,6,7,8-hexahydro-4,7-dimethyl-3H-2-benzopyran ( 16 ) was performed in (i) MeOH, (ii) acetaldehyde, and (iii) acetone at ?78°. The products obtained respectively were (i) (2R)-2-[(1S,4R)-4-methyl-2-oxocyclohexyl]propyl formate ( 17 ; 72% yield), (ii) 17 (54.5%), (1R,4R,4aS,7R)-3,4,4a,5,6,7-hexahydro-4,7-dimethyl-1H-2-benzopyran-2-yl hydroperoxide ( 19 ; 16.7%), a 12:1 ratio of (3R,4aR,7R,7aS,10R,11aR)-7,7a,8,9,10,11-hexahydro-3,7,10-trimethyl-6H-[2]benzopyrano[1,8a-e]-1,2,4-trioxane ( 20 ) and its C(3)-epimer 21 (17%), together with evidence for the 1,2-dioxetane ( 22 ) originating from the addition of dioxygen to the re-re face of the double bond of 16 , and iii) unidentified products and traces of 22 . Addition of trimethylsilyl trifluoromethanesulfonate (Me₃SiOTf) to the acetone solution of 16 after photooxygenation afforded (4aR,7R,7aS,10R,11aR)-7,7a,8,9,10,11-hexahydro-3,3,7,10-tetramethyl-6H-[2]benzopyrano[1,8a-e]-1,2,4,-trioxane ( 23 , 40%). The photooxygenation of 16 in CH₂Cl₂ at ?78° followed by addition of acetone and Me₃SiOTf afforded 17 (11%), 23 (59%), and (4aR,7R,7aS,10R,11aR)-7,7a,8,9,10,11-hexahydro-3,3,7,10-tetramethyl-6H-[2]benzopyrano[8a,1-e]-1,2,4-trioxane ( 24 ; 5%. Repetition of the last experiment, but replacing acetone by cyclopentanone, gave 17 (16%), (4′aR,7′R,7′aS,10′R,11′aR)-7′,7′a,8′,9′,10′,11′-hexahydro-7′,10′-dimethylspiro[cyclopentane-1,3′-6′H-[2]benzopyrano[1,8a-e]-1,2,4-trixane] ( 25 ; 61%), and (4′aR,7′R,7′aS,10′R,11′aR)-7′,7′a,8′,9′,10′,11′-hexahydro-7′,10′-dimethylspiro[cyclopentane-1,3′-6′H-[2]benzopyrano[8a,1-e]-1,2,4-trixane] ( 26 , 4%). The X-ray analysis of 23 was performed, which together with the NMR data, established the structure of the trioxanes 20, 21, 24, 25 , and 26 . Mechanistic and synthesis aspects of these reactions were discussed in relation to the construction of the 1,2,4-trioxane ring in arteannuin and similar molecules.     

Stereoselective Synthesis of 5a-Ethyl-1,2,3,3a,4,5,5a,6,9a,9b-decahydro- 1,3,4-trihydroxy-3a-(hydroxymethyl)-7H-benz[e]inden-7-one Derivatives

Homochiral Diels-Alder cyclodimerization of (±)-6-ethenyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-ol ( 1 ) followed by oxidation gives (1RS,4RS,4aSR,4bSR,5RS,8RS,8aRS)-8a-ethenyl-1,3,4,4a,4b,5,6,8,8a,9-decahydro-1,4:5,8-diepoxyphenanthrene-2,7-dione ( 18 ). Selective hydrogenation followed by epoxidation produced (1RS,4RS,4aRS,5aRS,6aRS,7RS,10RS,10aSR,10bRS)-6a-ethyl-1,4,5a,6,6a,7,9,10,10a,10b-decahydro-1,4:7,10-diepoxyphenanthro[8a,9-b]oxirene-3,8-dione ( 21 ), which was solvolyzed (Me₃SiOSO₂CF₃, Piv₂O) with concomitant pinacol rearrangement involving an acyl-group migration to give a 6-oxo-7-oxabicyclo[2.2.1]hept-2-yl cation intermediate, which finally generated (1RS,3SR,3aRS,4SR,5aRS,6RS,9RS,9aSR,9bSR)-5a-ethyl-1,4,5,5a,6,7,8,9,9a,9b-decahydro-7,10-dioxo-3H-6,9-epoxy-1,3a-ethanonaphtho[1,2-c]furan-3,4-diyl bis(2,2-dimethylpropanoate) ( 24 ). Photo-reductive 7-oxa bridge opening of 24 , followed by water elimination and silylation, provided (1RS,3SR,3aRS,4SR,5aSR,9aSR,9bSR)-7-{[(tert-butyl)dimethylsilyl]oxy}-5a-ethyl-1,4,5,5a,9a,9b-hexahydro-10-oxo-3H-1,3-ethanonaphtho[1,2-c]furan-3,4-diyl bis(2,2-dimethylpropanoate) ( 34 ). Reduction of 34 with NaBH₄ in MeOH followed by desilylation and alcohol protection produced (1RS,3RS,3aRS,4SR,5aSR,9aSR,9bSR)-5a-ethyl-2,3,3a,4,5,5a,6,7,9a,9b-decahydro-1,3-bis(methoxymethoxy)-3a-[(methoxymethoxy)methyl]-7-oxo-1H-benz[e]inden-4-yl 2,2-dimethylpropanoate ( 5 ), a polyoxy-substituted decahydro-1H-benz[e]indene derivative with cis-transoid-trans junction for the two cyclohexane and the cyclopentane rings bearing an angular 3a-(oxymethyl) substituent.