Synthesis of pyrrolo[1,2-a]indoles: vilsmeier formylation of some 3-methylindol-2-yl ketones and 3(3-methylindol-2-yl)propenoic ester

3-Methylindol-2-yl methyl ketone reacted with phosphoryl chloride in dimethylformamide to give 3-chloro-3(3-methylindol-2-yl), propenal (4). 2-Carbomethoxy- and 2-carbethoxy-1-chloro- 9H-pyrrolo[1,2-a]indol-9-ylidene acetaldehyde (10a and b) were formed by reaction with the same reagent of 3(3-methylindol-2-yl) propenoate (7) and 3(3-methylindol-2-yl)-3-oxopropanoate (2) respectively. In the latter case, 2-carbethoxy-1-chloro-3-dimethylamino-9-methyl-3H-pyrrolo[1,2-a]indole (9b) was isolated as an intermediate. The structure of the pyrroloindolylidene acetaldehydes was proved by synthesis of the chromophore from 4-acetyl-3-methyl-1-phenyl-pyrrole-2-carboxylate (26). The preparation and behaviour of 1-phenylpyrrole-2,4- and 3,4-dicarboxylates, monomethylated in the pyrrole ring, is described. These compounds were prepared during a search for a satisfactory route to a starting material for the synthesis of compounds related to 10a and b. The saponification of such diesters is remarkably selective, and in the case of the 2,4-dicarboxylates, contradicts accepted generalisations concerning the lability of pyrrole α,β-diesters to selective hydrolysis.     

Synthesis and crystal structure analysis of 2-(4-fluorobenzyl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazole and its chlorophenyl derivative

Preparations of 2-(4-fluorobenzyl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazole (3a) and its chlorophenyl derivative (3b) are described. Preliminary analysis was done spectroscopically by means of ¹H NMR, ¹³C NMR spectra, mass spectra and elemental analyses. Further the structures were confirmed by X-ray crystal structure analyses. The compound (3a) has crystallized in a triclinic P-1 space group with three independent molecules in the asymmetric unit, while the compound (3b) belongs to P2₁/c space group with one molecule in the asymmetric unit. The molecule (3b) differs from molecule (3a) by the presence of chlorine substituent. Additionally, the imidazo-thiadiazole entity is as usual planar. Intramolecular C–H⋯N hydrogen bonding between the imidazole and the phenyl ring of the molecule can be observed in (3a) & (3b). The molecules of (3a) are linked into two dimensional supramolecular hexagonal hydrogen bonded network sustained by C–H⋯F interaction, while those of (3b) are linked by bifurcated C–H⋯N interactions. Further, the molecular packing of both the compounds is stabilized by π–π stacking interactions between the benzene and imidazo-thiadiazole ring systems.     

Reactions of azulenes with 1,2-diaryl-1,2-ethanediols in methanol in the presence of hydrochloric acid: comparative studies on products, crystal structures, and spectroscopic and electrochemical properties

Although reaction of guaiazulene (1a) with 1,2-diphenyl-1,2-ethanediol (2a) in methanol in the presence of hydrochloric acid at 60 °C for 3 h under aerobic conditions gives no product, reaction of 1a with 1,2-bis(4-methoxyphenyl)-1,2-ethanediol (2b) under the same reaction conditions as 2a gives a new ethylene derivative, 2-(3-guaiazulenyl)-1,1-bis(4-methoxyphenyl)ethylene (3), in 97% yield. Similarly, reaction of methyl azulene-1-carboxylate (1b) with 2b under the same reaction conditions as 1a gives no product; however, reactions of 1-chloroazulene (1c) and the parent azulene (1d) with 2b under the same reaction conditions as 1a give 2-[3-(1-chloroazulenyl)]-1,1-bis(4-methoxyphenyl)ethylene (4) (81% yield) and 2-azulenyl-1,1-bis(4-methoxyphenyl)ethylene (5) (15% yield), respectively. Along with the above reactions, reactions of 1a with 1,2-bis(4-hydroxyphenyl)-1,2-ethanediol (2c) and 1-[4-(dimethylamino)phenyl]-2-phenyl-1,2-ethanediol (2d) under the same reaction conditions as 2b give 2-(3-guaiazulenyl)-1,1-bis(4-hydroxyphenyl)ethylene (6) (73% yield) and (Z)-2-[4-(dimethylamino)phenyl]-1-(3-guaiazulenyl)-1-phenylethylene (7) (17% yield), respectively. Comparative studies of the above reaction products and their yields, crystal structures, spectroscopic and electrochemical properties are reported and, further, a plausible reaction pathway for the formation of the products 3-7 is described.     

Diastereoselective synthesis of new polyhydroxylated indolizidines from (l)-glutamic acid

A diastereoselective synthesis of two new swainsonine's analogues 1a and 1b with the piperidine ring fused to a phenyl nucleus at C6-C7, namely (1R, 2S, 10R, 10aR)-(+)-1,2,10-trihydroxy-1,2,3,5,10,10a-hexahydrobenzo[f] indolizine (1a) and (1S, 2R, 10R, 10aR)-(+)-1,2,10-trihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[f] indolizine (1b), is described. Throughout this work, the effectiveness of the tricyclic indolizidine dione 5, readily available in three steps from the cheap l-glutamic acid, as an attractive platform for chemo- and stereodivergent transformations is illustrated. The key steps involved totally diastereoselective ketone reduction of compound 5 and catalytic cis-dihydroxylation of the unsaturated amide 10. The synthetic strategy also allowed for the diastereoselective synthesis of benzoanalogues of the 1,8a-di-epi-lentiginosine 3a ((1R, 2S, 10aR)-(+)-1,2-dihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[f]indolizine) and 2,8a-di-epi-lentiginosine 3b ((1S, 2R, 10aR)-(+)-1,2-dihydroxy-1,2,3,5,10,10a-hexahydrobenzo[f]indolizine).     

[4+2] Cycloaddition reactions of 4-sulfur-substituted 2-pyridones with electron-deficient dienophiles

[4+2] Cycloaddition reactions of 4-(phenylthio)-1-tosyl-2-pyridone (6a) and 4-(phenylsulfonyl)-1-tosyl-2-pyridone (6b) with electron-deficient dienophiles 7 (N-methylmaleimide, N-phenylmaleimide, and methyl acrylate) gave new isoquinuclidine products 8-10. The N-tosyl group of 6a and 6b was also efficiently converted to N-alkyl derivatives 6c-f, which showed different stereoselectivity toward reactions with dienophiles 7. Several other dienophiles 15 (dimethyl acetylenedicarboxylate, methyl vinyl ketone, ethyl vinyl ether, and methyl methacrylate) were found not to react with 6a or 6b, but led to the formation of tosyl migration products 4-(phenylthio)-O-tosyl-pyridinol (16a) and 4-(phenylsulfonyl)-O-tosyl-2-pyridinol (16b), respectively. The reactivity, regioselectivity, and stereoselectivity of the cycloaddition reactions were also compared with semi-empirical calculations.     

Structure and spectral property of 8-(2-(5-(4-methylphenyl)-2-thienyl)vinyl)-10,10-dimethyl-10H-pyrido[1,2-a]indolium perchlorate

The title compound 8-(2-(5-(4-methylphenyl)-2-thienyl)vinyl)l-10,10-dimethyl-10H-pyrido[1,2-a]indolium perchlorate (3) has been synthesized by cycloaddition and condensation reactions, and characterized by elemental analysis, IR, ¹H NMR, and single-crystal X-ray diffraction. The crystal structure analysis exhibits that the molecule of 3 possesses good coplanarity, and the three rings (10H-pyrido[1,2-a]indolium, thienyl and phenyl) and vinyl moiety can make up a large conjugated system. Its UV-Vis and fluorescence spectra were measured, and found that it displays larger maximum absorptions and emission wavelengths in comparison with 8-(4-methylphenyl)vinyl analogue.     

Photolysis and emission spectra of substituted polyacrylophenones

Poly-[3′,4′-dimethoxyacrylophenone], poly-4′-phenylacrylophenone, poly-2′-acrylonaphthone and copolymers of acrylophenone monomers with styrene and methyl methacrylate were prepared. Quantum yields of main chain scission in chlorobenzene by 313 nm radiation were 10³ times lower for all homopolymers and copolymers studied than for polyacrylophenone. The emission spectra of the polymers, copolymers and model compounds were taken for films at 77 K. The 3′,4′-dimethoxyacrylophenone, 4′-phenylacrylophenone and 2′-acrylonaphthone structural units exhibited poorly resolved emission spectra in homopolymer, copolymer and model compound. No difference in the emission spectra of films and dispersed homopolymer or copolymer in a poly(methyl methacrylate) matrix was observed. The decay of the emission of all homopolymers and copolymers under study was exponential, the life-time exceeding 0.20 sec.     

Synthesis,structures and photophysical properties of (o-carboranyl)-(pyridyl)methanols

The reaction of o-carboranyllithium with two equiv. of 2-pyridinecarboxaldehyde affords 1-[(hydroxy)(pyridyl)methyl]-o-carborane (1) and 1,2-bis[(hydroxy)(pyridyl)methyl]-o-carborane (2), which have been characterized by IR and NMR spectroscopy, mass spectrometry and single-crystal X-ray diffraction. Compound 2 exhibits interesting polymorphism (monoclinic 2a and triclinic 2b). The solid state structures of the new carboranes feature intermolecular and intramolecular hydrogen bonding interactions involving all the N and O atoms, leading to one dimensional (1, 2b) or two-dimensional (2a) supramolecular structures. The photoluminescence of 1 and 2b was investigated in the solid and solution states at room temperature, respectively.     

Stabilization of (N-methyleneamino)imidoylketenes: synthesis of dipyrazolo[1,2-a;1′,2′-d][1,2,4,5]tetrazines

Thermolysis of substituted methyl 1-methyleneamino-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates 2a,b led to substituted dimethyl 3,9-dioxo-1,5,7,11-tetrahydro-1H,7H-dipyrazolo[1,2-a;1′,2′-d][1,2,4,5]tetrazine-1,7-dicarboxylates 4a,b and methyl 2,5-dihydro-5-oxo-1H-pyrazole-3-carboxylates 5a,b as minor products. The structure of compound 4a was determined by X-ray crystallography. The proposed mechanism of this conversion includes generation of (N-methyleneamino)imidoylketenes 6a,b and its intramolecular transformation to azomethine imines—5-oxo-2,5-dihydropyrazole-1-methylium-2-ides 7a,b, which undergo dimerization in head-to-tail manner yielding products 4a,b and partially hydrolyse to compounds 5a,b.     

New cyclic aminals derived from rac-trans-1,2-diaminocyclohexane: synthesis and crystal structure of racemic 1,8,10,12-tetraazatetracyclo[8.3.1.1.8,1202,7] pentadecane and a route to its enantiomerically pure (R,R) and (S,S) isomers

New enantiomerically pure macrocyclic aminals (2R,7R)- and (2S,7S)-1,8,10,12-tetraazatetracyclo[8.3.1.1.^8,120^2,7]pentadecane (4a and 4b) were obtained by a three component reaction between their respective pure enantiomer of trans-1,2-diaminocyclohexane, ammonia, and formaldehyde. Additionally, the X-ray structure of the racemic compound 4 and the specific rotations of the racemic and optically pure compounds were determined. To further understand the synthetic utilities of enantiomers 4a and 4b, Mannich-type reactions with 1H-benzotriazole were performed, affording (3aR,7aR)- and (3aS,7aS)-1,1′-{[2,3,3a,4,5,6,7,7a-octahydro-1H-1,3-benzimidazole-1,3-diyl]bis(methylene)}bis-1H-benzotriazole (9 and 10) and allowing for new possibilities related to the preparation of chiral ligands for asymmetric catalysis.     

Diastereoselective synthesis of enantiopure 5-[2-(alkoxyalkyl)-1-(hydroperoxypropyl)]-3-alkoxycarbonyl-2-alkyl furans

The diastereoselective approach to enantiomerically pure furyl hydroperoxides of general type 1 has been accomplished starting from (S)-(−)-ethyl lactate. In the first part of the synthesis the alkylating reagents 7a,b were efficiently produced to be used in the second part for a 4-step known methodology to obtain furyl hydroperoxides. The most relevant transformation of the synthesis is the first reported diastereoselective iodoenoletherification of 2-acetyl-4-heptenoate esters 8a,b possessing a φ-chiral center. Furthermore, the final radical oxidation performed on (E)-5-alkylidene-4,5-dihydrofurans 11a,b led to formation of hydroperoxides (S,S)-12a,b in a diastereocontrolled manner due to 1,2-asymmetric induction.     

Heterolytic CH-bond activation in the synthesis of Ni{(2-aryl-κC)pyridine-κN}2 and derivatives

Thermolysis of Ni(OTf)₂ in 2-phenyl-pyridine or 2-tolyl-pyridine afforded the cationic chelate derivatives, [bis(2-aryl-pyridine)Ni{(2-aryl-κC²)pyridine-κN}]OTf (aryl = phenyl, 1a; tolyl, 1b). Addition of KBr to 1a and LiBr to 1b provided the bromides, (2-aryl-pyridine)BrNi{(2-aryl-κC²)pyridine-κN} (aryl = phenyl, 2a; tolyl, 2b). When subjected to KO^tBu in Et₂O, the bromides generated the entitled bis-cyclometalated compounds, Ni{(2-aryl-κC²)pyridine-κN}₂ (aryl = phenyl, 3a; tolyl, 3b). These compounds insert diphenylacetylene into one cyclometalate arm to produce [(2-aryl-κC²)pyridine-κN]Ni[2-(2-(1,2-diphenylethenyl-κC²)aryl)pyridine-κN] (aryl = phenyl, 4a; p-tolyl, 4b). X-ray crystallographic studies were conducted on 1a, 2a, 3a and 4a, and a brief DFT study of 3a confirmed its low spin configuration and rippled geometry.     

An efficient synthesis of (7S,10R)-2-bromo-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole: application in the preparation and structural confirmation of a potent 5-HT6 antagonist

(7S,10R)-5-Methyl-2-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole 1a is a potent 5-HT₆ antagonist (h5-HT₆ K_i = 1.5 nM) which is derived from an epiminocyclohept[b]indole scaffold. In order to synthesize 1a on a multi-gram scale to support advanced biological testing, an efficient chiral resolution of the intermediate tert-butyl 2-bromo-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate 2 was developed. After derivatizing 2 with (1R)-(?)-menthyl chloroformate it was found that a single diastereomer 7a could be isolated by selective precipitation from n-hexane. The absolute stereochemistry of 7a was determined by X-ray crystallography and the structure was confirmed as (7S,10R)-tert-butyl 2-bromo-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate. Removal of the chiral auxiliary under basic conditions afforded intermediate 2a in >99% enantiomeric purity and with 80% yield based on recovery from the racemic compound 2. Intermediate 2a was used successfully to synthesize 5-HT₆ antagonist 1a on a multi-gram scale.     

Zum verhalten von mono- und diolefinen gegenüber thallium(III)trifluoracetat

Cis-butene-2 yields with Tl(III)trifluoroacetate by cis-addition of two trifluoroacetoxygroups the bis-2,3-trifluoroacetate 1a of the mesobutane diol, whereas the trans-butene-2 affords the bis-2,3-trifluoroacetate of the racemic threo-compound as expected 2a. Cyclohexene is transformed by Tl(III)trifluoroacetate to the cyclotrimeric form 3a of cyclopentylaldehyde. Cis-cyclooctene is oxidized to trifluoroacetate 4a of cyclooctene-1-ol-3. The homoallylic alcohol 5 (cyclohexene-1-ol-4) suffers a remarkable—but not unexpected—fragmentation to Z-trifluoroacetoxy-hexene-4-al-55a. By treating the conjugated dienes cyclohexadiene and cyclopentadiene with this reagent only cis-addition of two trifluoroacetoxygroups takes place under formation of the mixture of cis-1,4-bis-trifluoroacetoxy-cyclohexene-2(8a) and cis-1,2-bis-trifluoroacetoxy-cyclohexene-3(8b) on the one and cis-1,4-bis-trifluoroacetoxy-cyclopentene-2(9a) plus cis-1,2-bis-trifluoroacetoxy-cyclopentene-3(9b) on the other side. 1,3-Butadiene and 2,3-dimethyl-butadiene are transformed under solely 1,2-addition of the trifluoroacetoxygroups to the bis-trifluoroacetoxy compounds 6a and 7a.     

Asymmetric michael additions of ester enolates to enantiomerically pure vinylic sulfoxides: Synthesis of 3-substituted glutarate esters in high enantiomeric purity

Various ester enolate ions add as Michael donors to enantiomerically pure Michael acceptor cycloalkenone sulfoxides 1a and 1b and unsaturated lactone sulfoxides 3a and 3b. The level of asymmetric induction in some cases is extraordinarily high (95% e.e. of final 1,5-dicarbonyl products). Adduct ester lactones 5 and 6 can be converted easily into some synthetically versatile, trifunctional, 3-substituted glutarate esters of high enantiomeric purity. An efficient route to enantiomerically pure pentenolide sulfoxide (S)-(+)-3b is presented.     

A synthesis of (±)-Δ2-α-Lycoren-7-one,the key intermediate for the total synthesis of (±)-lycorine

(±)-α-Lycoran-3,5-dione (14a) was prepared from octahydrophenanthridin-3-one (8b) obtained by two methods starting from 5-aryl-4-nitrocyclohexene (2) and 1-hydroxyl-2-aryl-5-oxo-cyclohexanecarboxylic acid (10), both of which were prepared by the Diels-Alder reaction of 3,4-methylenedioxy - ω - nitrostyrene with butadiene and the Robinson annelation of 3,4-methyl- enedioxy - phenylpyruvic acid (9) with methyl vinyl ketone, respectively, 14a was converted into (±)Δ²-α-lycoren-7-one (22b), which has been transformed into (±)-lycorine (1) by Torssell     

Synthesis and properties of 3-arylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and related compounds: photo-induced autorecycling oxidation of some amines

Novel 3-phenyl- and 3-(4-nitrophenyl)cyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and the corresponding imino derivatives 5a,b and 6a,b were synthesized in modest to moderate yields by the abnormal and normal aza-Wittig reaction of 2-(1,3-diazaazulen-2-ylimino)triphenylphosphorane with aryl isocyanates and subsequent heterocyclization reaction with a second isocyanate. The related cationic compound, 1-methyl-3-phenylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-dionylium tetrafluoroborate 7a, was also prepared. The electrochemical reduction of these compounds exhibited more positive reduction potentials as compared with those of the related compounds of 3,10-disubstituted cyclohepta[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1H,3H)-dione systems. In a search of the oxidizing ability, compounds 5a, 6a, and 7a were demonstrated to oxidize some amines to give the corresponding imines in more than 100% yield under aerobic and photo-irradiation conditions, while even benzylamine was not oxidized under aerobic and thermal conditions at 100 °C. The oxidation reactions by cation 7a are more efficient than that by 5a and 6a. Quenching of the fluorescence of 5a was observed, and thus, the oxidation reaction by 5a probably proceeds via electron-transfer from amine to the excited singlet state of 5a. In the case of cation 7a, the oxidation reaction is proposed to proceed via formation of an amine-adduct of 7a and subsequent photo-induced radical cleavage reaction.     

Photochemistry—xiii: The photokomerization of pyridazine 1 ,2-dioxides: formation of 3a,6a-dihydroisoxazolo[5,4-d]isoxazole

Products, generated from a photolysis of 1,2-dioxides (1) of unsubstituted (a), 3-Me-(b), 4-Me-(c), 3,6-diMe (d), 3-Ph-(e), 3-Me-6-Ph-(f) and 3,6-diPh-(g) pyridazines, have been investigated.Dioxides (1a–g) afforded 3a,6a-dihydroisoxazolo[5,4-d]isoxazoles (2a-g). Dioxides (1e and 1g) afforded 3-phenylisoxazole(7) besides 2. The structure of 2a was examined by X-ray crystallography.The compound 2d was also obtained by oxidation of the hexa-3-ene-2,5-dione dioxime. A mechanism generating those products has been speculated.     

Untersuchungen an diazoverbindungen und aziden—XLV: Elektrophile diazoalkansubstitution an phosphoryldiazomethanen mit thiapyryliumsalzen

Electrophilic diazoalkane substitution of the phosphoryl diazomethanes 2a–2e with 2,6-di-tert-butylthiapyrylium-tetrafluoroborate (1) yields the 4-(diazomethyl)-4H-thiapyranes 3a–3e; the olefin 5 is formed as by-product in all cases. The μ-allylpalladium chloride catalyzed decomposition of 3a and c leads via a 1,2-H-shift to the 4-methylen-4H-thiapyranes 6a and b; competing 1,2-C-migration, which should afford the thiepines 7, could not be observed. The 4-methylen-4H-thiapyranes are characterized by addition of perchloric acid (6a→8) and 4-phenyl-1,2,4-triazolin-3,5-dione (6a,b→9a,b). Corresponding substitution reactions with 2,4,6-triphenylthiapyrylium-perchlorate (10) at 3a–3c in so far take an unusual way as the bis(6H-pyrrolino[1,2-b]pyrazoles) 11a–11c are formed instead of (diazomethyl)-4-(or 2)H-thiapyranes. The constitution of the heterobicycles is established by X-ray structure analysis of 11c.     

New A-ring analogs of the hormone 1α,25-dihydroxyvitamin D3: (2′-hydroxymethyl)tetrahydrofuro[1,2-a]-25-hydroxyvitamin D3

Conceptually new, enantiomerically pure bicyclic tetrahydrofuro[1,2-a]-A-ring phosphine oxides (+)-4 and (−)-4 were successfully prepared from methyl 2-pyrone-3-carboxylate and (S)- or (R)-2-(tert-butyldimethylsilyloxy)methyl-2,3-dihydrofuran, respectively. In addition, (2′-hydroxymethyl)tetrahydrofuro[1,2-a]-25-hydroxyvitamin D₃3a and 3b as new A-ring-modified analogs of the natural hormone 1α,25-dihydroxyvitamin D₃ were readily synthesized by using Lythgoe-type coupling of the A-ring phosphine oxides (+)-4 and (−)-4 with C,D-ring ketone (+)-5.