7‐Halogenated 7‐Deazapurine 2′‐Deoxyribonucleosides Related to 2′‐Deoxyadenosine, 2′‐Deoxyxanthosine,and 2′‐Deoxyisoguanosine: Syntheses and Properties

A series of 7‐fluorinated 7‐deazapurine 2′‐deoxyribonucleosides related to 2′‐deoxyadenosine, 2′‐deoxyxanthosine, and 2′‐deoxyisoguanosine as well as intermediates 4b – 7b, 8, 9b, 10b , and 17b were synthesized. The 7‐fluoro substituent was introduced in 2,6‐dichloro‐7‐deaza‐9H‐purine ( 11a ) with Selectfluor (Scheme 1). Apart from 2,6‐dichloro‐7‐fluoro‐7‐deaza‐9H‐purine ( 11b ), the 7‐chloro compound 11c was formed as by‐product. The mixture 11b / 11c was used for the glycosylation reaction; the separation of the 7‐fluoro from the 7‐chloro compound was performed on the level of the unprotected nucleosides. Other halogen substituents were introduced with N‐halogenosuccinimides ( 11a → 11c – 11e ). Nucleobase‐anion glycosylation afforded the nucleoside intermediates 13a – 13e (Scheme 2). The 7‐fluoro‐ and the 7‐chloro‐7‐deaza‐2′‐deoxyxanthosines, 5b and 5c , respectively, were obtained from the corresponding MeO compounds 17b and 17c , or 18 (Scheme 6). The 2′‐deoxyisoguanosine derivative 4b was prepared from 2‐chloro‐7‐fluoro‐7‐deaza‐2′‐deoxyadenosine 6b via a photochemically induced nucleophilic displacement reaction (Scheme 5). The pK_a values of the halogenated nucleosides were determined (Table 3). ¹³C‐NMR Chemical‐shift dependencies of C(7), C(5), and C(8) were related to the electronegativity of the 7‐halogen substituents (Fig. 3). In aqueous solution, 7‐halogenated 2′‐deoxyribonucleosides show an approximately 70% S population (Fig. 2 and Table 1).     

Nucleotides. Part LXXVIII

Several N(‐hydroxyalkyl)‐2,4‐dinitroanilines were transformed into their phosphoramidites (see 5 and 6 in Scheme 1) in view of their use as fluorescence quenchers, and modified 2‐aminobenzamides (see 9, 10, 18 , and 19 in Scheme 1) were applied in model reactions as fluorophors to determine the relative fluorescence quantum yields of the 3′‐Aba and 5′‐Dnp‐3′‐Aba conjugates (Aba=aminobenzamide, Dnp=dinitroaniline). Thymidine was alkylated with N‐(2‐chloroethyl)‐2,4‐dinitroaniline ( 24 ) to give 25 which was further modified to the building blocks 27 and 28 (Scheme 3). The 2‐amino group in 29 was transformed by diazotation into the 2‐fluoroinosine derivative 30 used as starting material for several reactions at the pyrimidine nucleus (→ 31, 33 , and 35 ; Scheme 4). The 3′,5′‐di‐O‐acetyl‐2′‐deoxy‐N²‐[(dimethylamino)methylene]guanosine ( 37 ) was alkylated with methyl and ethyl iodide preferentially at N(1) to 43 and 44 , and similarly reacted N‐(2‐chloroethyl)‐2,4‐dinitroaniline ( 24 ) to 38 and the N‐(2‐iodoethyl)‐N‐methyl analog 50 to 53 (Scheme 5). The 2′‐deoxyguanosine derivative 53 was transformed into 3′,5′‐di‐O‐acetyl‐2‐fluoro‐1‐{2‐[(2,4‐dinitrophenyl)methylamino]ethyl}inosine ( 54 ; Scheme 5) which reacted with 2,2′‐[ethane‐1,2‐diylbis(oxy)]bis[ethanamine] to modify the 2‐position with an amino spacer resulting in 56 (Scheme 6). Attachment of the fluorescein moiety 55 at 56 via a urea linkage led to the doubly labeled 2′‐deoxyguanosine derivative 57 (Scheme 6). Dimethoxytritylation to 58 and further reaction to the 3′‐succinate 59 and 3′‐phosphoramidite 60 afforded the common building blocks for the oligonucleotide synthesis (Scheme 6). Similarly, 30 reacted with N‐(2‐aminoethyl)‐2,4‐dinitroaniline ( 61 ) thus attaching the quencher at the 2‐position to yield 62 (Scheme 7). The amino spacer was again attached at the same site via a urea bridge to form 64 . The labeling of 64 with the fluorescein derivative 55 was straigthforward giving 65 . and dimethoxytritylation to 66 and further phosphitylation to 67 followed known procedures (Scheme 7). Several oligo‐2′‐deoxynucleotides containing the doubly labeled 2′‐deoxyguanosines at various positions of the chain were formed in a DNA synthesizer, and their fluorescence properties and the T_ms in comparison to their parent duplexes were measured (Tables 1–5).     

Studies on Reactions of Thioketones with Trimethyl(trifluoromethyl)silane Catalyzed by Fluoride Ions

Treatment of 2,2,4,4‐tetramethylcyclobutane‐1,3‐dione ( 6 ) in THF with CF₃SiMe₃ in the presence of tetrabutylammonium fluoride (TBAF) yielded the corresponding 3‐(trifluoromethyl)‐3‐[(trimethylsilyl)oxy]cyclobutanone 7 (Scheme 1) via nucleophilic addition of a CF anion at the CO group and subsequent silylation of the alcoholate. Under similar conditions, the ‘monothione' 1 reacted to give thietane derivative 8 (Scheme 2), whereas in the case of ‘dithione' 2 only the dispirodithietane 9 , the dimer of 2 , was formed (Scheme 3). A conceivable mechanism for the formation of 8 is the ring opening of the primarily formed CF₃ adduct A followed by ring closure via the S‐atom (Scheme 2). In the case of thiobenzophenones 4 , complex mixtures of products were obtained including diarylmethyl trifluoromethyl sulfide 10 and 1,1‐diaryl‐2,2‐difluoroethene 11 (Scheme 4). Obviously, competing thiophilic and carbophilic addition of the CF anion took place. The reaction with 9H‐fluorene‐9‐thione ( 5 ) yielded only 9,9′‐bifluorenylidene ( 14 ; Scheme 6); this product was also formed when 5 was treated with TBAF alone. Treatment of 4a with TBAF in THF gave dibenzhydryl disulfide ( 15 ; Scheme 7), whereas, under similar conditions, 1 yielded the 3‐oxopentanedithioate 17 (Scheme 9). The reaction of dithione 2 with TBAF led to the isomeric dithiolactone 16 (Scheme 8), and 3 was transformed into 1,2,4‐trithiolane 18 (Scheme 10).     

On the Preparation of 2‐Substituted Cephalosporins,Part 2

Cephalosporin sulfoxides 1 and 2 containing an enone‐ or dienone‐type moiety at position 2 were treated with 2,3‐dimethylbuta‐1,3‐diene or diethyl azodicarboxylate to synthesize, in Diels? Alder reactions, the new cephalosporin derivatives 4 and 5 with a cyclic substituent (Scheme 1). Under the same conditions, ethyl diazoacetate and diazomethane reacted differently: while reactions of 1 and 3 with the former lead to compounds 7 – 10 corresponding to the 1,3‐dipolar cycloaddition route (Scheme 2), diazomethane produced only enol ethers 12 and 13 , respectively (Scheme 3). This difference could be rationalized by assuming two different reaction pathways: an orbital‐symmetry‐controlled concerted cycloaddition and an ionic one.     

Reaktion von 3-(Dimethylamino)-2H-azirinen mit 1,3-Thiazolidin-2-thion

Reaction of 3-(Dimethylamino)-2H-azirines with 1,3-Thiazolidine-2-thione Reaction of 3-(dimethylamino)-2H-azirines 1 and 1,3-thiazolidine-2-thione ( 6 ) in MeCN at room temperature leads to a mixture of perhydroimidazo[4,3-b]thiazole-5-thiones 7 and N-[1-(4,5-dihydro-1,3-thiazol-2-yl)alkyl]-N′,N′-dimethylthioureas 8 (Scheme 2), whereas, in i-PrOH at ca. 60°, 8 is the only product (Scheme 4). It has been shown that, in polar solvents or under Me₂NH catalysis, the primarily formed 7 isomerizes to 8 (Scheme 4). The hydrolysis of 7 and 8 leads to the same 2-thiohydantoine 9 (Scheme 3 and 5). The structure of 7a, 8c , and 9b has been established by X-ray crystallography (Chapt. 4). Reaction mechanisms for the formation and the hydrolysis of 7 and 8 are suggested.     

New Studies on [2+3] Cycloadditions of Thermally Generated N‐Isopropyl‐ and N‐(4‐Methoxyphenyl)‐Substituted Azomethine Ylides

The thermal reaction of 1‐substituted 2,3‐diphenylaziridines 2 with thiobenzophenone ( 6a ) and 9H‐fluorene‐9‐thione ( 6b ) led to the corresponding 1,3‐thiazolidines (Scheme 2). Whereas the cis‐disubstituted aziridines and 6a yielded only trans‐2,4,5,5‐tetraphenyl‐1,3‐thiazolidines of type 7 , the analogous reaction with 6b gave a mixture of trans‐ and cis‐2,4‐diphenyl‐1,3‐thiazolidines 7 and 8 . During chromatography on SiO₂, the trans‐configured spiro[9H‐fluorene‐9,5′‐[1,3]thiazolidines] 7c and 7d isomerized to the cis‐isomers. The substituent at N(1) of the aziridine influences the reaction rate significantly, i.e., the more sterically demanding the substituent the slower the reaction. The reaction of cis‐2,3‐diphenylaziridines 2 with dimethyl azodicarboxylate ( 9 ) and dimethyl acetylenedicarboxylate ( 11 ) gave the trans‐cycloadducts 10 and 12 , respectively (Schemes 3 and 4). In the latter case, a partial dehydrogenation led to the corresponding pyrroles. Two stereoisomeric cycloadducts, 15 and 16 , with a trans‐relationship of the Ph groups were obtained from the reaction with dimethyl fumarate ( 14 ; Scheme 5); with dimethyl maleate ( 17 ), the expected cycloadduct 18 together with the 2,3‐dihydropyrrole 19 was obtained (Scheme 6). The structures of the cycloadducts 7b, 8a, 15b , and 16b were established by X‐ray crystallography.     

Bildung von 4-, 5- und 6gliedrigen Heterocyclen durch ambidoselektive Ringschlüsse von Enolat-Ionen

Formation of 4-, 5- and 6-membered heterocycles by ambidoselective cyclization of enolate anions N-Acylmethyl-N-chloracetyl-2,6-dimethylanilines 4 were cyclized with base to 4-, 5- or 6-membered ring compounds, depending on the substituent R² (Scheme 2). All products can be rationalized as derived from the intermediate enolate anions a and b . The enolate anion a reacts by intramolecular alkylation to yield either 1, 4-oxazines 5 or azetidines 6 (Schemes 1, 3 and 7). The regioselectivity observed is expected on the basis of the allopolarization principle. The enolate anion b reacts only with formation of a new C? C bond (Scheme 5). Comparison with the behaviour of the 2, 6-unsubstituted anilines 9, 1a and 12 , shows a strong dependence not only on electronic but also on steric factors (Scheme 4 and 6).     

Exceptional Products of the Desulfurization of N,2-Diaryl-5-(arylimino)- 2,5-dihydro-4-nitroisothiazol-3-amines

The desulfurization of several N,2-diaryl-5-(arylimino)-2,5-dihydro-4-nitroisothiazol-3-amines 5 with Ph₃P led to complex mixtures of products in low yields. For instance, quinoxaline-2-carboxamide 1-oxides of type 6 (Scheme 2) and, in some cases, also 3-nitroquinolines of type 7 (Scheme 5) were isolated. By the desulfurization of the substituted derivatives 5b – e , a rearrangement of the intermediates yielded 6 and 7 with a different substitution pattern from that expected from the starting materials (Scheme 3). The additional formation of two isomeric 1,2,5-oxadiazole-3-carboxamides 8 was observed only in the case of 5d (R¹=R²=F) (Scheme 6). Under the same reaction conditions, the major product of the desulfurization of 5c was the quinoxaline-2-carboxamide 1-oxide 9 (Scheme 7). Reaction mechanisms involving intermediate ketene imines and O transfer from the NO₂ group to the neighboring ketene imine are proposed. The structures of 6a , 6e , 6k , 7b , and 8d were established by X-ray crystallography, while the structure of 9 was elucidated by 2D-NMR spectroscopy and corroborated by X-ray crystallography.     

Synthesis and Reactivity of π‐Electron‐Deficient (Arylsulfonyl)acetates

Different π‐electron‐deficient (arylsulfonyl)acetates 9 were synthesized (Scheme 1, Table 1), and their behavior as soft nucleophiles in the dialkylation reaction under phase‐transfer catalysis conditions was studied (Schemes 2 and 3, Tables 2 and 3). The [3,5‐bis(trifluoromethyl)phenyl]sulfonyl group was shown to be the best substituent for the stereoselective synthesis of (E)‐aconitates 18 via an alkylation hydro‐sulfonyl‐elimination integrated process under very mild phase‐transfer‐catalysis conditions (Scheme 5, Table 4). Sulfonylacetates 9h , i also underwent smooth Diels‐Alder reactions with acyclic and cyclic dienes via in situ formation of the appropriate dienophile through a Knoevenagel condensation with paraformaldehyde (Scheme 6). Reductive desulfonylation with Zn and NH₄Cl in THF was shown to be an efficient method for removal of the synthetically useful sulfonyl moiety (Scheme 7).     

Eine neue Aminoazirin-Reaktion. Bildung von 3,6-Dihydropyrazin-2(1H)-onen

A New Aminoazirine Reaction. Formation of 3,6-Dihydropyrazin-2(1H)-ones The reaction of 3-(dimethylamino)-2H-azirines 1 and 2-(trifluoromethyl)-1,3-oxazol-5(2H)-ones 5 in MeCN or THF at 50–80° leads to 5-(dimethylamino)-3,6-dihydropyrazin-2(1H)-ones 6 (Scheme 3). Reaction mechanisms for the formation of 6 are discussed: either the oxazolones 5 react as CH-acidic heterocycles with 1 (Scheme 4), or the azirines 1 undergo a nucleophilic attack onto the carbonyl group of 5 (Scheme 6). The reaction via intermediate formation of N-(trifluoroacetyl)dipeptide amide 8 (Scheme 5) is excluded.     

Versuche zur Synthese von Calicen aus trisubstituierten Cyclopropanen und Cyclopentenon

Attempted Synthesis of Calicene from Trisubstitued Cyclopropanes and Cyclopentenone The Li carbenoids 4 , prepared by treatment of substituted 1,1-dihalocyclopropanes with BuLi, are reacted with cyclopent-2-enone under thermodynamic and kinetic control (Scheme 1). In general, the latter procedure gives better yields of cyclopropylcyclopentenols 5a – e , but the reaction seems to be controlled mainly by the steric and electronic properties of the substituent Y. So, with 4b and 4e , the main reaction is the attack of the carbenoid at C(1) of cyclopent-2-enone, while 4a (Y = PhS) predominantly deprotonates the ketone (Scheme 4). Whereas 5d and 5e can easily be converted to the dihydrocalicenes 6d and 6e (Scheme 6), the attempted elimination of H₂O from 5a – c leads to the rearranged products 13 – 2 due to the opening of the cyclopropane ring (Scheme 5). Finally, the generation of the parent compound 2 from the silylated precursor 6d is attempted: treatment with MeO^? gives the addition products 18A/18B , while the reaction with Br₂ provides 19 by a bromination/dehydrobromination sequence (Scheme 7).     

Oligonucleosides with a Nucleobase‐Including Backbone,Part 4, A Convergent Synthesis of Ethynediyl‐Linked Adenosine Tetramers

Deprotection of the tetramer 24 , obtained by coupling the iodinated dimer 18 with the alkyne 23 gave the 8′,5‐ethynediyl‐linked adenosine‐derived tetramer 27 (Scheme 3). As direct iodination of C(5′)‐ethynylated adenosine derivatives failed, we prepared 18 via the 8‐amino derivative 17 that was available by coupling the imine 15 with the iodide 7 ; 15 , in its turn, was obtained from the 8‐chloro derivative 12 via the 4‐methoxybenzylamine 14 (Scheme 2). This method for the introduction of the 8‐iodo substituent was worked out with the N‐benzoyladenosine 1 that was transformed into the azide 2 by lithiation and treatment with tosyl azide (Scheme 1). Reduction of 2 led to the amine 3 that was transformed into 7 . 1,3‐Dipolar cycloaddition of 3 and (trimethylsilyl)acetylene gave 6 . The 8‐substituted derivatives 4a – d were prepared similarly to 2 , but could not be transformed into 7 . The known chloride 8 was transformed into the iodide 11 via the amines 9 and 10 . The amines 3 , 10 , and 16 form more or less completely persistent intramolecular C(8)N−H⋅⋅⋅O(5′) H‐bonds, while the dimeric amine 17 forms a ca. 50% persistent H‐bond. There is no UV evidence for a base‐base interaction in the protected and deprotected dimers and tetramers.     

S‐Functionalized Cysteine: Powerful Ligands for the Labelling of Bioactive Molecules with Triaquatricarbonyltechnetium‐99m(1+) ([99mTc(OH2)3(CO)3]+)

S‐Alkylated cysteines are used as efficient tridentate N,O,S‐donor‐atom ligands for the fac‐[M(CO)₃]⁺ moiety (M=^99mTc or Re). Reaction of (Et₄N)₂[ReBr₃(CO)₃] ( 3 ) with the model S‐benzyl‐L ‐cysteine ( 2 ) leads to the formation of [Re( 2′ )(CO)₃] ( 4 ) as the exclusive product ( 2′ =C‐terminal anion of 2 ). The tridentate nature of the alkylated cysteine in 4 was established by X‐ray crystallography. Compound 2 reacts with [^99mTc(OH₂)₃(CO)₃]⁺ under mild conditions (10⁻⁴ M , 50°, 30 min) to afford [^99mTc( 2′ )(CO)₃] ( 5 ) and represents, therefore, an efficient chelator for the labelling of biomolecules. L ‐Cysteine, S‐alkylated with a 3‐aminopropyl group (→ 7 ), was conjugated via a peptide coupling sequence with Coα‐[α‐(5,6‐dimethyl‐1H‐benzimidazolyl)]‐Coβ‐cyanocobamic b‐acid ( 6 ), the b‐acid of cyanocob(III)alamin (vitamin B₁₂) (Scheme 3). More convenient was a one‐pot procedure with a derivative of vitamin B₁₂ comprising a free amine group at the b‐position. This amine 15 was treated with NHS (N‐hydroxysuccinimide)‐activated 1‐iodoacetic acid 14 to introduce an I‐substituent in vitamin B₁₂. Subsequent addition of unprotected L ‐cysteine resulted in nucleophilic displacement of the I‐atom by the S‐substituent, affording the vitamin B₁₂ alkylated cysteine fragment 17 (Scheme 4). The procedure was quantitative and did not require purification of intermediates. Both cobalamin–cysteine conjugates could be efficiently labelled with [^99mTc(OH₂)₃(CO)₃]⁺ ( 1 ) under conditions identical to those of the model complex 5 . Biodistribution studies of the cobalamin conjugates in mice bearing B10‐F16 melanoma tumors showed a tumor uptake of 8.1±0.6% and 4.4±0.5% injected dose per gram of tumor tissue after 4 h and 24 h, respectively (Table 1).     

Regioselectivity of the 1,3‐Oxathiolane Formation in the Lewis Acid‐Catalyzed Reaction of Thioketones with Asymmetrically Substituted Oxiranes

The reactions of the aromatic thioketone 4,4′‐dimethoxythiobenzophenone ( 1 ) with three monosubstituted oxiranes 3a – c in the presence of BF₃⋅Et₂O or SnCl₄ in dry CH₂Cl₂ led to the corresponding 1 : 1 adducts, i.e., 1,3‐oxathiolanes 4a – b with R at C(5) and 8c with Ph at C(4). In addition, 1,3‐dioxolanes 7a and 7c , and the unexpected 1 : 2 adducts 6a – b were obtained (Scheme 2 and Table 1). In the case of the aliphatic, nonenolizable thioketone 1,1,3,3‐tetramethylindane‐2‐thione ( 2 ) and 3a – c with BF₃⋅Et₂O as catalyst, only 1 : 1 adducts, i.e. 1,3‐oxathiolanes 10a – b with R at C(5) and 11a – c with R or Ph at C(4), were formed (Scheme 6 and Table 2). In control experiments, the 1 : 1 adducts 4a and 4b were treated with 2‐methyloxirane ( 3a ) in the presence of BF₃⋅Et₂O to yield the 1 : 2 adduct 6a and 1 : 1 : 1 adduct 9 , respectively (Scheme 5). The structures of 6a , 8c , 10a , 11a , and 11c were confirmed by X‐ray crystallography (Figs. 1 – 5). The results described in the present paper show that alkyl and aryl substituents have significant influence upon the regioselectivity in the process of the ring opening of the complexed oxirane by the nucleophilic attack of the thiocarbonyl S‐atom: the preferred nucleophilic attack occurs at C(3) of alkyl‐substituted oxiranes (O−C(3) cleavage) but at C(2) of phenyloxirane (O−C(2) cleavage).     

Synthesis and Reactions of a New Cyclobutanethione Derivative

The 3,3‐dichloro‐2,2,4,4‐tetramethylcyclobutanethione ( 4b ) was prepared from the parent diketone by successive reaction with PCl₅ and Lawesson reagent in pyridine. This new thioketone 4b was transformed into 1‐chlorocyclobutanesulfanyl chloride 5 and chloro 1‐chlorocyclobutyl disulfide 9 by treatment with PCl₅ and SCl₂, respectively, in chlorinated solvents (Schemes 1 and 2). These products reacted with S‐ and P‐nucleophiles by substitution of Cl⁻ at the S‐atom; e.g., the reaction with 4b yielded the di‐ and trisulfides 6b and 11 , respectively. Surprisingly, only pentasulfide 12 was formed in the reaction of 9 with thiobenzophenone (Scheme 3). In contrast to 5 and 9 , the corresponding chloro 1‐chlorocyclobutyl trisulfide 13 could not be detected, but reacted immediately with the starting thioketone 4b to give the tetrasulfide 14 (Scheme 4). Oxidation of 4b with 3‐chloroperbenzoic acid (mCPBA) yielded the corresponding thione oxides (= sulfine) 15 , which underwent 1,3‐dipolar cycloadditions with thioketones 3a and 4b (Scheme 5). Furthermore, 4b was shown to be a good dipolarophile in reactions with thiocarbonylium methanides (Scheme 6) and iminium ylides (= azomethine ylides; Scheme 7). In the case of phenyl azide, the reaction with 4b gave the symmetrical trithiolane 25 (Scheme 8).     

Synthesis of (±)‐Kempa‐6,8‐dien‐3‐ol (=(2aRS,3SR,4aSR,7RS,7aSR,10bSR,10cSR)‐2,2a,3,4,4a,5,6,7,7a,8,10b,10c‐Dodecahydro‐2a,7,10,10c‐tetramethylnaphth[2,18‐cde]azulen‐3‐ol)

The synthesis of kempa‐6,8‐dien‐3β‐ol ( 4a ), as a synthetic leading model of the natural product 4b , was carried out starting from intermediate 12 , the synthetic route of which has been developed previously (Scheme 1). The conversion of 12 to the model compound 4a involved the elaboration of three structure modifications by three processes, Tasks A, B, and C (see Scheme 2). Task A was achieved by epoxy‐ring opening of 41 with Me₃SiCl (Scheme 9), and Task B being performed by oxidation at the 13‐position, followed by hydrogenation, and then epimerization (Schemes 4 and 5). The removal of the 2‐OH group from 12 (Task C) was achieved via 30b according to Scheme 6, whereby 30b was formed exclusively from 30a / 31a 1 : 1 (Scheme 7). In addition, some useful reactions from the synthetic viewpoint were developed during the course of the present experiments.     

Dipolare (1:1)-Addukte aus der Reaktion von 3-Amino-2H-azirinen mit 1,3,4-Oxadiazol- und 1,3,4-Thiadiazol-2(3H)-onen

Dipolar 1:1 Adducts from the Reaction of 3-Amino-2H-azirines with 1,3,4-Oxadiazol- and 1,3,4-Thiadiazol-2(3H)-ones 3-Amino-2H-azirines 1 react with 5-(trifluoromethyl)-1,3,4-oxadiazol-2(3H)-one ( 2 ) as well as with different 5-substituted 1,3,4-thiadiazol-2(3H)-ones ( 5a–e ) in 2-propanol at room temperature to give dipolar 1:1 adducts of type 3 and 6 , respectively, in reasonable-to-good yields (Schemes 3 and 6, Tab. 1 and 2). The structure of two of these dipolar adducts, 6a and 6e , which are formally donor-acceptor-stabilized azomethin imines, have been elucidated by X-ray crystallography (Figs. 1-4). In the reaction of 2 and sterically crowded 3-amino-2H-azirines 1c–e with a 2-propyl and 2-propenyl substituent, respectively, at C(2), a 4,5-dihydro-1,2,4-triazin-3(2H)-one of type 4 is formed as minor product (Scheme 3 and Table 1). Independent syntheses of these products proved the structure of 4 . Several reaction mechanisms for the formation of compounds 3 and 4 are discussed, the most likely ones are described in Scheme 4: reaction of 2 as an NH-acidic compound leads, via a bicyclic zwitterion of type A , to 3 as well as to 4 . In the latter reaction, a ring-expanded intermediate B is most probable.     

Umsetzung von Diazoessigsäure-ethylester mit 1,3-Thiazol-5(4H)-thionen

Reaction of Ethyl Diazoacetate with 1,3-Thiazole-5(4H)-thiones Reaction of ethyl diazoacetate ( 2a ) and 1,3-thiazole-5(4H)-thiones 1a,b in Et₂O at room temperature leads to a complex mixture of the products 5–9 (Scheme 2). Without solvent, 1a and 2a react to give 10a in addition to 5a–9a . In Et₂O in the presence of aniline, reaction of 1a,b with 2a affords the ethyl 1,3,4-thiadiazole-2-carboxylate 10a and 10b , respectively, as major products. The structures of the unexpected products 6a, 7a , and 10a have been established by X-ray crystallography. Ethyl 4H-1,3-thiazine-carboxylate 8b was transformed into ethyl 7H-thieno[2,3-e][1,3]thiazine-carboxylate 11 (Scheme 3) by treatment with aqueous NaOH or during chromatography. The structure of the latter has also been established by X-ray crystallography. In the presence of thiols and alcohols, the reaction of 1a and 2a yields mainly adducts of type 12 (Scheme 4), compounds 5a,7a , and 9a being by-products (Table 1). Reaction mechanisms for the formation of the isolated products are delineated in Schemes 4–7: the primary cycloadduct 3 of the diazo compound and the C?S bond of 1 undergoes a base-catalyzed ring opening of the 1,3-thiazole-ring to give 10 . In the absence of a base, elimination of N₂ yields the thiocarbonyl ylide A ′, which is trapped by nucleophiles to give 12 . Trapping of A ′, by H₂O yields 1,3-thiazole-5(4H)-one 9 and ethyl mercaptoacetate, which is also a trapping agent for A ′, yielding the diester 7 . The formation of products 6 and 8 can be explained again via trapping of thiocarbonyl ylide A ′, either by thiirane C (Scheme 6) or by 2a (Scheme 7). The latter adduct F yields 8 via a Demjanoff-Tiffeneau-type ring expansion of a 1,3-thiazole to give the 1,3-thiazine.     

Synthesis of (±)‐Glaucine and (±)‐Neospirodienone via an One‐Pot Bischler?Napieralski Reaction and Oxidative Coupling by a Hypervalent Iodine Reagent

Condensation of 3,4‐dimethoxybenzeneethanamine ( 3d ) and various benzeneacetic acids, i.e., 4a – e , via a practical and efficient one‐pot Bischler–Napieralski reaction, followed by NaBH₄ reduction, produced a series of 1‐benzyl‐1,2,3,4‐tetrahydroisoquinolines, i.e., 5a – e , in satisfactory yields (Scheme 3). Oxidative coupling of the N‐acyl and N‐methyl derivatives 6a – e of the latter with hypervalent iodine ([IPh(CF₃COO)₂]) yielded products with two different skeletons (Scheme 4). The major products from N‐acyl derivatives 6a – c were (±)‐N‐acylneospirodienones 2a – c , while the minor was the 3,4‐dihydroisoquinoline 7 . (±)‐Glaucine ( 1 ), however, was the major product starting from N‐methyl derivative 6e . Possible reaction mechanisms for the formation of these two types of skeleton are proposed (Scheme 5).     

Thermal [2+3]‐Cycloadditions of trans‐1‐Methyl‐2,3‐diphenylaziridine with CS and CC Dipolarophiles: An Unexpected Course with Dimethyl Dicyanofumarate

The thermal reaction of trans‐1‐methyl‐2,3‐diphenylaziridine (trans‐ 1a ) with aromatic and cycloaliphatic thioketones 2 in boiling toluene yielded the corresponding cis‐2,4‐diphenyl‐1,3‐thiazolidines cis‐ 4 via conrotatory ring opening of trans‐ 1a and a concerted [2+3]‐cycloaddition of the intermediate (E,E)‐configured azomethine ylide 3a (Scheme 1). The analogous reaction of cis‐ 1a with dimethyl acetylenedicarboxylate ( 5 ) gave dimethyl trans‐2,5‐dihydro‐1‐methyl‐2,5‐diphenylpyrrole‐3,4‐dicarboxylate (trans‐ 6 ) in accord with orbital‐symmetry‐controlled reactions (Scheme 2). On the other hand, the reactions of cis‐ 1a and trans‐ 1a with dimethyl dicyanofumarate ( 7a ), as well as that of cis‐ 1a and dimethyl dicyanomaleate ( 7b ), led to mixtures of the same two stereoisomeric dimethyl 3,4‐dicyano‐1‐methyl‐2,5‐diphenylpyrrolidine‐3,4‐dicarboxylates 8a and 8b (Scheme 3). This result has to be explained via a stepwise reaction mechanism, in which the intermediate zwitterions 11a and 11b equilibrate (Scheme 6). In contrast, cis‐1,2,3‐triphenylaziridine (cis‐ 1b ) and 7a gave only one stereoisomeric pyrrolidine‐3,4‐dicarboxylate 10 , with the configuration expected on the basis of orbital‐symmetry control, i.e., via concerted reaction steps (Scheme 10). The configuration of 8a and 10 , as well as that of a derivative of 8b , were established by X‐ray crystallography.