Cob(I)alamin als Katalysator, 5. Mitteilung [1]. Enantioselektive Reduktion α,β-ungesättigter Carbonylderivate

Cob(I)alamin as Catalyst. 5. Communication [1]. Enantioselective Reduction of α,β-Unsaturated Carbonyl Derivatives The cob(I)alamin-catalyzed reduction of an α,β-unsaturated ethyl ester in aqueous acetic acid produced the (S)-configurated saturated derivative 2 with an enantiomeric excess of 21%. The starting material 1 is not reduced at pH = 7.0 in the presence of catalytic amounts of cob(I)alamin (see Scheme 2). It is shown that the attack of cob(I)alamin and not of cob(II)alamin, also present in Zn/CH₃COOH/H₂O, accounts for the enantioselective reduction observed. All the (Z)-configurated starting materials 1 , 3 , 5 , 7 , 9 and 11 have been transformed to the corresponding (S)-configurated saturated derivatives 2 , 4 , 6 , 8 , 10 and 12 , respectively. The highest enantiomeric excess revealed to be present in the saturated product 12 (32,7%, S) derived from the (Z)-configurated methyl ketone 11 (see Scheme 3 and Table 1). The reduction of the (E)-configurated starting materials led mainly to racemic products. A saturated product having the (R)-configuration with a rather weak enantiomeric excess (5.9%) has been obtained starting from the (E)-configurated methyl ketone 23 (see Scheme 5 and Table 2). The allylic alcohols 16 and 24 have been reduced to the saturated racemic derivative 17 .     

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).     

Synthesis of Polyalkylphenyl Prop‐2‐ynoates and Their Flash Vacuum Pyrolysis to Polyalkylcyclohepta[b]furan‐2(2H)‐ones

A new method for the smooth and highly efficient preparation of polyalkylated aryl propiolates has been developed. It is based on the formation of the corresponding aryl carbonochloridates (cf. Scheme 1 and Table 1) that react with sodium (or lithium) propiolate in THF at 25 – 65°, with intermediate generation of the mixed anhydrides of the arylcarbonic acids and prop‐2‐ynoic acid, which then decompose almost quantitatively into CO₂ and the aryl propiolates (cf. Scheme 11). This procedure is superior to the transformation of propynoic acid into its difficult‐to‐handle acid chloride, which is then reacted with sodium (or lithium) arenolates. A number of the polyalkylated aryl propiolates were subjected to flash vacuum pyrolysis (FVP) at 600 – 650° and 10⁻² Torr which led to the formation of the corresponding cyclohepta[b]furan‐2(2H)‐ones in average yields of 25 – 45% (cf. Scheme 14). It has further been found in pilot experiments that the polyalkylated cyclohepta[b]furan‐2(2H)‐ones react with 1‐(pyrrolidin‐1‐yl)cyclohexene in toluene at 120 – 130° to yield the corresponding 1,2,3,4‐tetrahydrobenz[a]azulenes, which become, with the growing number of Me groups at the seven‐membered ring, more and more sensitive to oxidative destruction by air (cf. Scheme 15).     

Unexpected Thermal Transformation of Aryl 3‐Arylprop‐2‐ynoates: Formation of 3‐(Diarylmethylidene)‐2,3‐dihydrofuran‐2‐ones

A number of aryl 3‐arylprop‐2‐ynoates 3 has been prepared (cf. Table 1 and Schemes 3 – 5). In contrast to aryl prop‐2‐ynoates and but‐2‐ynoates, 3‐arylprop‐2‐ynoates 3 (with the exception of 3b ) do not undergo, by flash vacuum pyrolysis (FVP), rearrangement to corresponding cyclohepta[b]furan‐2(2H)‐ones 2 (cf. Schemes 1 and 2). On melting, however, or in solution at temperatures >150°, the compounds 3 are converted stereospecifically to the dimers 3‐[(Z)‐diarylmethylidene]‐2,3‐dihydrofuran‐2‐ones (Z)‐ 11 and the cyclic anhydrides 12 of 1,4‐diarylnaphthalene‐2,3‐dicarboxylic acids, which also represent dimers of 3 , formed by loss of one molecule of the corresponding phenol from the aryloxy part (cf. Scheme 6). Small amounts of diaryl naphthalene‐2,3‐dicarboxylates 13 accompanied the product types (Z)‐ 11 and 12 , when the thermal transformation of 3 was performed in the molten state or at high concentration of 3 in solution (cf. Tables 2 and 4). The structure of the dihydrofuranone (Z)‐ 11c was established by an X‐ray crystal‐structure analysis (Fig. 1). The structures of the dihydrofuranones 11 and the cyclic anhydrides 12 indicate that the 3‐arylprop‐2‐ynoates 3 , on heating, must undergo an aryl O→C(3) migration leading to a reactive intermediate, which attacks a second molecule of 3 , finally under formation of (Z)‐ 11 or 12 . Formation of the diaryl dicarboxylates 13 , on the other hand, are the result of the well‐known thermal Diels‐Alder‐type dimerization of 3 without rearrangement (cf. Scheme 7). At low concentration of 3 in decalin, the decrease of 3 follows up to ca. 20% conversion first‐order kinetics (cf. Table 5), which is in agreement with a monomolecular rearrangement of 3 . Moreover, heating the highly reactive 2,4,6‐trimethylphenyl 3‐(4‐nitrophenyl)prop‐2‐ynonate ( 3f ) in the presence of a twofold molar amount of the much less reactive phenyl 3‐(4‐nitrophenyl)prop‐2‐ynonate ( 3g ) led, beside (Z)‐ 11f , to the cross products (Z)‐ 11fg , and, due to subsequent thermal isomerization, (E)‐ 11fg (cf. Scheme 10), the structures of which indicated that they were composed, as expected, of rearranged 3f and structurally unaltered 3g . Finally, thermal transposition of [¹⁷O]‐ 3i with the ¹⁷O‐label at the aryloxy group gave (Z)‐ and (E)‐[¹⁷O₂]‐ 11i with the ¹⁷O‐label of rearranged [¹⁷O]‐ 3i specifically at the oxo group of the two isomeric dihydrofuranones (cf. Scheme 8), indicating a highly ordered cyclic transition state of the aryl O→C(3) migration (cf. Scheme 9).     

Tetramethylheptalenes and Their Tricarbonylchromium Complexes: Synthesis,Structures, and Thermal Rearrangements

The thermal 4 : 1 equilibrium mixture of 1,3,5,6- and 1,3,5,10-tetramethylheptalene ( 13a and 13b , resp.) has been prepared, starting from the thermal equilibrium mixture of dimethyl 6,8,10-trimethylheptalene-1,2- and -4,5-dicarboxylate ( 6a and 6b , resp.; cf. Scheme 5). These heptalenes undergo double-bond shifts (DBS) even at ambient temperature. Treatment of the mixture 13a / 13b 4 : 1 with [Cr(CO)₃(NH₃)₃] in boiling 1,2-dimethoxyethane resulted in the formation of all four possible mononuclear Cr(CO)₃ complexes 19a – 19d of 13a and 13b , as well as two binuclear Cr(CO)₃ complexes 20a and 20b , respectively, in a total yield of 87% (cf. Scheme 7). The mixture of complexes was separated by column chromatography, followed by preparative HPLC (cf. Fig. 2). The structures of all complexes were established by X-ray crystal-structure analyses (complex 19b and 20b ; cf. Figs. 6 – 8) and extensive ¹H-NMR measurements (cf. Table 3). In 20b , the two Cr(CO)₃ groups are linked in a `syn'-mode to the highly twisted heptalene π-skeleton. The correspondence of the <sup>1</sup>H-NMR data of 20a with that of 20b indicates that the two Cr(CO)<sub>3</sub> groups in 20a also have a `syn'-arrangement. The thermal behavior of the mononuclear complexes 19a – 19d has been studied at 85° in hexafluorobenzene (HFB). At this temperature, all four complexes undergo rearrangement to the same thermal equilibrium mixture (cf. Table 8). The rates for the thermal equilibration of each complex have been determined by ¹H-NMR measurements (cf. Figs. 9 – 12) and analyzed by seven different kinetic schemes (Chapt. 2). The equilibration rates are in agreement with two different haptotropic rearrangements that take place, namely intra- and inter-ring shifts of the Cr(CO)₃ group, whereby both rearrangements are accompanied by DBS of the heptalene π-skeleton (cf. Scheme 9). All individual kinetic steps possess similar ΔG^≠ values in the range of 29 – 31 kcal⋅mol⁻¹ (cf. Table 8). The occurrence of inter-ring haptotropic migrations of Cr(CO)₃ groups has already been established for anellated aromatic systems (cf. Scheme 10); however, it is the first time that these rearrangements have been unequivocally demonstrated for Cr(CO)₃ complexes of non-planar bicyclic [4n]annulenes, such as heptalenes. The mechanism of migration may be similar to that proposed for aromatic systems (cf. Schemes 10 and 11).     

New Products from the Heptalene‐Forming Reaction of Azulenes and Acetylenedicarboxylates in Polar Media

A number of azulenes 1 , in particular those with π‐substituents at C(6) such as phenyl, 3,5‐dimethylphenyl, and 4‐biphenyl, have been reacted with 3 mol‐equiv. of dimethyl acetylenedicarboxylate (ADM) in MeCN at 110° (cf. Scheme 1). Main products had been, in all cases, the corresponding heptalene‐4,5‐dicarboxylates 2 . However, a whole number of side products, mainly rearranged (1+2)‐adducts with two molecules of ADM, in amounts of 0.2–9% were also isolated and characterized (cf. Scheme 2). The 2a,8a‐dihydro‐3,4‐ethenoazulene‐1,2‐dicarboxylates 14 , formed by energetically favorable ring closure from the solvent‐stabilized zwitterions 15 , resulting from bond heterolysis in the primary cycloadducts 12 (cf. Scheme 3), have been mechanistically identified as the pivotal intermediates responsible for the formation of all side product (cf. Schemes 5, 9, 12, and 13). Deuterium‐labeling experiments were in agreement with the proposed mechanisms, indicating that sigmatropic [1,5s]‐H shifts in 14 (cf. Scheme 6) as well as isoconjugate [1,4s]‐H shifts in resonance‐stabilized zwitterions of type 21 (cf. Scheme 9) are the crucial steps for side‐product formation. It is postulated that a concluding antarafacial 8e‐dyotropic rearrangement is responsible for the appearance of the 2,4a‐dihydrophenanthrene‐tetracarboxylates of type trans‐ 6 (cf. Scheme 9) in the reaction mixtures, which further rearrange thermally by a not fully understood mechanism into the isomeric tetracarboxylates 7 (cf. Schemes 10 and 11). Most surprising is the presence of a small amount (0.3–1%) of the azulene‐4,5,7,8‐tetracarboxylate 9 in the reaction mixture of azulene 1a and ADM. It is proposed that the formation of 9 is the result of a [1,5s]‐C shift in the spiro‐linked intermediates 24 , which, after prototropic shift and take‐up of a third molecule of ADM, disintegrate by a retro‐Diels‐Alder reaction into 9 and the phthalic diesters 30 (cf. Scheme 12). The UV/VIS spectra of the π‐substituted heptalene‐4,5‐dicarboxylates 2d – 2f and their double‐bond shifted (DBS) forms 2d – 2f (cf. Table 4 and Figs. 9–12) exhibit in comparison with the heptalene‐dicarboxylates 2a and 2′a , carrying a t‐Bu group at C(8), only marginal differences, which are mainly found in the relative intensity and position of heptalene bands II and III .     

Photoreaktionen von 1-Alkylbenztriazolen

The irradiation of benzotriazoles (cf. Scheme 2) with light of 225–325 nm in protic and in aromatic solvents was investigated. In aqueous 0.1N H₂SO₄ benzotriazole ( 5 ) and 1-methyl-benzotriazole ( 6 ) yielded 2-amino- and 2-methylaminophenol ( 25 and 26 ), respectively (Scheme 3). In 2-propanol 6 , 5-chloro- and 6-chloro-1-methyl-benzotriazole ( 14 and 15 ) were reduced to N-methylaniline, 4-chloro- and 3-chloro-N-methyl-aniline ( 27 , 28 and 29 ), respectively (Scheme 4). When the benzotriazoles were irradiated in aromatic solvents only C, C coupling products were observed (cf. Scheme 6 and Tables 1–4). It is of importance that 5-chloro-1-methyl-benztriazole ( 14 ) when decomposed photolytically in benzene solution yielded only 4-chloro-2-phenyl-N-methyl-aniline ( 49 ) and its 6-chloro isomer only 5-chloro-2-phenyl-N-methyl-aniline ( 50 ), i.e. the intervention of benzo-1H-azirine intermediates (e.g. 53 , Scheme 8) can be excluded. The substitution patterns which are observed when 6 is irradiated in toluene, anisole, fluoro-, chloro-, bromobenzene and benzonitrile (cf. Table 4) can best be explained by assuming that 6 , after loss of nitrogen, forms a diradical intermediate in the singlet state with highly zwitterionic character. 1-(1′-Alkenyl)-benzotriazoles (cf. Table 7) form on irradiation in cyclohexane solution indoles by intramolecular ring closure of the diradical intermediate and proton shift. After irradiation of 1-decyl-benzotriazole ( 8 ) in a glassy matrix at 77K a 7-line ESR. spectrum characteristic of a triplet radical is observed. This is in agreement with the fact that the lowest lying state of intermediates of type 2 (Scheme 1) should be a triplet state (cf. [21] [26]).     

Geltungsbereich und Mechamismus der durch Silberionen katalysierten Propargylester-Allenylester-Umlagerung nach Saucy und Marbet

The mechanism of the catalysis of the reversible (propargyl ester)/(allenyl ester) rearrangement ( 10 ? 11 ) by silver(I) ions was investigated, using optically active and diastereoisomeric esters as well as ¹⁴C- and ¹⁸O-labelling. In order to work with crystalline materials, mainly p-nitrobenzoates ( 10 , 11 : R⁴ = p? O₂N? C₆H₄) were used. In some cases the rearrangement 10 ? 11 was studied using acetates (R⁴ = CH₃). The alkyl substituents R¹, R², R³, were widely varied (cf. Tables 1, 2). The solvents in which the rearrangements were performed were in most cases dry chlorobenzene and 96% aqueous dioxane. Silver tetrafluoroborate, the benzene complex of the latter, and silver trifluoroacetate (in chlorobenzene) as well as silver nitrate (in aqueous dioxane) served as catalysts. The amounts of the silver catalysts used varied between 0,5 and 10 mol-%; reaction temperatures applied were in the range 35–95°, The results obtained are as follows:

• 1 The rate-determining step of the (propargyl ester)/(allenyl ester) rearrangement ( 10 ? 11 ) occurs in a silver(I) complex with the substrates ( 10 , 11 ), which is formed in a pre-equilibrium. This follows from kinetic experiments (cf. Fig. 6, 7, 8, 10) and the fact that the rate of rearrangement (of 10a ) is strongly decreased when cyclohexene is added (cf. Fig. 9). In solvents which are known to form complexes with silver(I) ions the rate of rearrangement (of 10a )is much slower than in solvents with similar dielectric constants but with small capacity for complex formation with silver(I) ions (cf. Table 4). Taking into account what is known about silver(I)-alkene and -alkyne complexes (cf. [18]), it is obvious that the (propargyl ester)/(allenyl ester) rearrangement occurs in a π-complex of the silver(I) ion with the triple bond in the propargyl ester or one of the two C,C double bonds in the allenyl ester, respectively.
• 2 The shift of the carboxyl moiety in the reversible rearrangement 10 ? 11 occurs intramolecularly. p-Nitrobenzoic acid-[carboxyl-¹⁴C] is not incorporated during the rearrangement, neither in the reactant 10 nor in the product 11 and vice versa. A crossing experiment gave no mixed products (cf. Scheme 2, p. 882).
• 3 An internal ion pair can be excluded for the rearrangement 10 ? 11 because the ¹⁸O-carbonyl label in the reactant is found exclusively in the alkoxy part of the product (cf. Scheme 3, p. 886, and Table 9). Thus, the rearrangement 10 ? 11 occurs with inversion of the carboxyl moiety.
• 4 The rearrangement of optically active propargyl esters ( 10g , 10i ) leads to completely racemic allenyl esters ( 11g , 11i ). However, rearrangement of erythro- and threo- 10j -[carbonyl-¹⁸O] (Scheme 3) shows that the stereospecifically formed allenyl esters erythro- and threo- 11j -[¹⁸O]-epimerize rapidly in the presence of silver(I) ions. This epimerization is twice and forty times, respectively, as fast as the rearrangement of the corresponding propargyl esters (cf. Fig. 1–5). During epimerization or racemization the ¹⁸O-label is not randomized (cf. also Scheme 4, p. 898).
• 5 The equilibrium of the rearrangement 10 ? 11 depends on the bulkiness of the substituents R¹, R², R³ and of the carboxyl moiety (cf. Table 2).

Taking into account these facts (points 1–5), the reversible (propargyl ester)/(allenyl ester) rearrangement promoted by silver(I) ions can be described as a [3s, 3s]-sigmatropic reaction occurring in a silver(I)-π-complex with the C,C triple bond in 10 and a C,C double bond in 11 . It is suggested that complex formation in 10 and 11 occurs with the π-bond which is not involved in the quasicyclic (containing six orbitals and six electrons) transition state of the rearrangement (Fig. 11). Thus, the rearrangement is of a type which has recently been called a charge-induced sigmatropic reaction (cf. [26]). Therefore, in our case, the catalysis by silver(I) ions is of a different type from that of transformations of strained cyclic molecules promoted by silver(I) ions (cf. [14] [16] [27]–[31]). Side reactions. Whereas the rearrangement of propargyl esters 10 in presence of silver tetra- fluoroborate in chlorobenzene or silver nitrate in aqueous dioxane leads to the corresponding allenyl esters 11 , the rearrangement of 10 with silver trifluoroacetate, especially in the presence of trifluoroacetic acid, results in the formation of the dienol esters 12 and 13 , which clearly are derived from 11 (see Scheme 1, p. 881). As shown by the rearrangement of 11 in the presence of p-nitrobenzoic acid-[carboxyl-¹⁴C], 12 and 13 arise in part from a not isolated di-p-nitrobenzoate (cf. Scheme 6, p. 905), since radioactivity is found in 12 and 13 .     

Aspects of the Reduction of Double Bonds Using Cob (I)alamin as Catalys

The olefinic system in 3β-methoxy-4-cholesten-6 a-ol ( 2 ) is reduced using cob (I)alamin ( 1 ( I ); see Scheme 1) as catalyst, aqueous acetic acid as solvent and metallic zinc as electron source (cf. Schemes 2 and 3). Experimental evidence for an attack of 1 ( I ) on both faces of the double bond is presented. By the same catalyst (1 R)-10, 10-dimethyl-2-pinene- 10-carbonitrile ( 9 ) is first transformed to the menthene derivative 11 (see Schemes 4 and 5). The ring opening is then followed by a fast saturation of the disubstituted olefinic system in 11 , and ultimately the remaining double bond is reduced in a slow reaction. The cis-configurated saturated menthane derivative 16 is the main final product ( 16 / 17 ≈ 10:1).     

Formation of Heptaleno[1,2-c]furans and Heptaleno[1,2-c]furanones

The dehydrogenation reaction of the heptalene-4,5-dimethanols 4a and 4d , which do not undergo the double-bond-shift (DBS) process at ambient temperature, with basic MnO₂ in CH₂Cl₂ at room temperature, leads to the formation of the corresponding heptaleno[1,2-c]furans 6a and 6d , respectively, as well as to the corresponding heptaleno[1,2-c]furan-3-ones 7a and 7d , respectively (cf. Scheme 2 and 8). The formation of both product types necessarily involves a DBS process (cf. Scheme 7). The dehydrogenation reaction of the DBS isomer of 4a , i.e., 5a , with MnO₂ in CH₂Cl₂ at room temperature results, in addition to 6a and 7a , in the formation of the heptaleno[1,2-c]-furan-1-one 8a and, in small amounts, of the heptalene-4,5-dicarbaldehyde 9a (cf. Scheme 3). The benzo[a]heptalene-6,7-dimethanol 4c with a fixed position of the C?C bonds of the heptalene skeleton, on dehydrogenation with MnO₂ in CH₂Cl₂, gives only the corresponding furanone 11b (Scheme 4). By [²H₂]-labelling of the methanol function at C(7), it could be shown that the furanone formation takes place at the stage of the corresponding lactol [3-²H₂]- 15b (cf. Scheme 6). Heptalene-1,2-dimethanols 4c and 4e , which are, at room temperature, in thermal equilibrium with their corresponding DBS forms 5c and 5e , respectively, are dehydrogenated by MnO₂ in CH₂Cl₂ to give the corresponding heptaleno[1,2-c]furans 6c and 6e as well as the heptaleno[1,2-c]furan-3-ones 7c and 7e and, again, in small amounts, the heptaleno[1,2-c]furan-1-ones 8c and 8e , respectively (cf. Scheme 8). Therefore, it seems that the heptalene-1,2-dimethanols are responsible for the formation of the furan-1-ones (cf. Scheme 7). The methylenation of the furan-3-ones 7a and 7e with Tebbe's reagent leads to the formation of the 3-methyl-substituted heptaleno[1,2-c]furans 23a and 23e , respectively (cf. Scheme 9). The heptaleno[1,2-c]furans 6a, 6d , and 23a can be resolved into their antipodes on a Chiralcel OD column. The (P)-configuration is assigned to the heptaleno[1,2-c]furans showing a negative Cotton effect at ca. 320 nm in the CD spectrum in hexane (cf. Figs. 3–5 as well as Table 7). The (P)-configuration of (–)- 6a is correlated with the established (P)-configuration of the dimethanol (–)- 5a via dehydrogenation with MnO₂. The degree of twisting of the heptalene skeleton of 6 and 23 is determined by the Me-substitution pattern (cf. Table 9). The larger the heptalene gauche torsion angles are, the more hypsochromically shifted is the heptalene absorption band above 300 nm (cf. Table 7 and 8, as well as Figs. 6–9).     

Totalsynthese von (–)-Norgestrel

Total-Synthesis of (–)-Norgestrel (–)-Norgestrel ( 1a ) or (–)-norethindrone ( 1b ), two active progestational ingredients of currently used contraceptives have been synthesized stereoselectively. Compound 1a has been obtained starting from m-cresol methyl ether, dimethyl malonate, and (E)-1,4-dibromo-2-butene. The steroid skeleton has been constructed using an intramolecular Diels-Alder reaction of an o-quinodimethane derivative preceeded by a photo-enolization of an appropriate methyl-substituted acetophenone derivative. Chirality has been introduced at an early stage during an S_cN′ reaction (cf. Scheme 1). Compound 1b has been obtained similarly using a previously reported mixture of the enantiomerically pure constitutional isomers 18b / 19b (cf. Scheme 3).     

Zur Photochemie von 1H- und 2H-Indazolen in saurer Lösung

On the Photochemistry of 1H- and 2H-Indazoles in Acidic Solution It is shown that 1H- and 2H-indazoles (cf. Scheme 2) on protonation (0, 1N H₂SO₄ in water or alcoholic solution) give analogous indazolium ions (see Fig. 1 and 2) which on irradiation undergo heterolytic cleavage of the N (1), N (2) bond whereby aromatic nitrenium ions in the singlet ground state are formed (cf. Scheme 13). If the para position of these nitrenium ions is not occupied by a substituent (e.g. a methyl group) they are readily trapped by nucleophiles present (e.g. water, alcohols, chloride ions) to yield the corresponding 5-substituted 2-amino-benzaldehydes or acetophenones (cf. Schemes 4–10). Photolysis of indazole ( 4 ) and 3-methyl-indazole ( 5 ) in 0,75N H₂SO₄ in alcoholic solutions gives in addition minor amounts of the corresponding 3-substituted 2-amino-benzaldehydes and acetophenones, respectively (cf. Schemes 6 and 8 and Table 2). Phenylnitrenium ions carrying a methyl group in the para position give in aqueous sulfuric acid mainly the reduction products, i.e. 2-amino-5-methyl-benzaldehydes (cf. Schemes 11 and 12 and Table 3). In methanolic sulfuric acid, in addition to the reduction products, 6-methoxy substituted benzaldehydes are found (cf. Schemes 11 and 12 and Table 3) which are presumably formed by an addition-elimination mechanism (cf. Scheme 18). It is assumed that precursors of the reduction products are the corresponding nitrenium ions in the triplet ground state. Singlet-triplet conversion of the nitrenium ions may become efficient when addition of nucleophiles to the singlet nitrenium ions is reversible (cf. Scheme 22) thus, enhancing the probability of conversion or when conjugation in the singlet nitrenium ions is disturbed by steric effects (cf. Scheme 20) thus, destabilizing the singlet state relative to the triplet state.     

Double-Bond Shifts in [4n]Annulenes as a New Principle for Molecular Switches: First Results with Dimethyl Heptalene-1,2- and -4,5-dicarboxylates

A new concept for molecular switches, based on thermal or photochemical double-bond shifts (DBS) in [4n]annulenes such as heptalenes or cyclooctatetraenes, is introduced (cf. Scheme 2). Several heptalene-1,2- and -4,5-dicarboxylates (cf. Scheme 4) with (E)-styryl and Ph groups at C(5) and C(1), or C(4) and C(2), respectively, have been investigated. Several X-ray crystal-structure analyses (cf. Figs. 1–5) showed that the (E)-styryl group occupies in the crystals an almost perfect s-trans-conformation with respect to the C?C bond of the (E)-styryl moiety and the adjacent C?C bond of the heptalene core. Supplementary ¹H-NOE measurements showed that the s-trans-conformations are also adopted in solution (cf. Schemes 6 and 9). Therefore, the DBS process in heptalenes (cf. Schemes 5 and 8) is always accompanied by a 180° torsion of the (E)-styryl group with respect to its adjacent C?C bond of the heptalene core. The UV/VIS spectra of the heptalene-1,2- and -4,5-dicarboxylates illustrated that it can indeed be differentiated between an ‘off-state’, which possesses no ‘through-conjugation’ of the π-donor substituent and the corresponding MeOCO group and an ‘on-state’ where this ‘through-conjugation’ is realized. The ‘through-conjugation’, i.e., conjugative interaction via the involved s-cis-butadiene substructure of the heptalene skeleton, is indicated by a strong enhancement of the intensities of the heptalene absorption bands I and II (cf. Tables 3–6). The most impressive examples are the heptalene-dicarboxylates 11a , representing the off-state, and 11b which stands for the on-state (cf. Fig.8).     

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).     

Über Umlagerungen bei der Cyclialkylierung von Arylpentanolen zu 2,3‐Dihydro‐1H‐inden‐Derivaten, 5. Mitteilung

On Rearrangements by Cyclialkylations of Arylpentanols to 2,3‐Dihydro‐1 H ‐indene Derivatives. Part 5. The Acid‐Catalyzed Cyclialkylation of 2‐(2‐Chlorophenyl)‐2,4‐dimethylpentan‐3‐ol The mechanism proposed in [1] to explain the surprising result of the cyclialkylation of 4‐(2‐chlorophenyl)‐2,4‐dimethylpentan‐2‐ol ( 3 , R=Me), which gives not only the ‘normal' product, i.e., the 4‐chloro‐2,3‐dihydro‐1,1,3,3‐tetramethyl‐ ( 4 ), but also the isomer trans‐4‐chloro‐2,3‐dihydro‐1,1,2,3‐tetramethyl‐1H‐inden ( 5 ), could be differentiated in two sections (cf. Scheme 2): the first from 3 to the intermediary ion IIa ⇌ IIb , and the second from the latter ions to the final product 5 . For the first section, a sufficiently satisfactory explanation has been given in [1]; the second section has received important support from the mechanisms of the cyclialkylation of 2,4‐dimethyl‐2‐phenylpentan‐3‐ol ( 6 ), the precursor of II′a , the ion IIa without the o‐Cl substituent (cf. Schemes 2, 3 and 5 and [4]). The present communication gives an explanation of the influence of the o‐Cl substituent: a mechanism is proposed for the very complex cyclialkylation of 2‐(2‐chlorophenyl)‐2,4‐dimethylpentan‐3‐ol ( 11 ; cf. Scheme 9). Both mechanism may be considered as definitive. It is very surprising that, by the cyclialkylation of the compounds 1, 3, 8, 11, 15 , and 17 , only compound 1 gives the ‘normal' product; the cyclialkylation of all other phenylpentanols follows complex pathways including Et, i‐Pr, and Ph migrations, which could not be expected. In addition, it has been established that the transformation of 21 to 22 (cf. Scheme 12) and that of 23 to 24 (cf. Scheme 13) occur through two consecutive 1,2‐ and not through a single 1,3‐hydride migration or through an elimination‐addition process (cf. Scheme 13). It can be assumed that the transformation of ion IV (the 2‐(2‐chlorophenyl)‐3,4‐dimethylpent‐2‐ylium ion) to the ion V (the 4‐(2‐chlorophenyl)‐3,4‐dimethylpent‐2‐ylium ion (both shown in Scheme 9 as D‐isomers) occurs through the same pathway.     

Acid-Catalyzed [3,3]-Sigmatropic Rearrangements of N-Propargylanilines

The acid-catalyzed rearrangement of N-(1′,1′-dimethylprop-2′-ynyl)-, N-(1′-methylprop-2′-ynyl)-, and N-(1′-arylprop-2′-ynyl)-2,6-, 2,4,6-, 2,3,5,6-, and 2,3,4,5,6-substituted anilines in mixtures of 1N aqueous H₂SO₄ and ROH such as EtOH, PrOH, BuOH etc., or in CDCl₃ or CCl₄ in the presence of 4 to 9 mol-equiv. trifluoroacetic acid (TFA)has been investigated (cf. Scheme 12-25 and Tables 6 and 7). The rearrangement of N-(3′-X-1′,1′-dimethyl-prop-2′-ynyl)-2,6- and 2,4,6-trimethylanilines (X = Cl, Br, I) in CDCl₃/TFA occurs already at 20° with τ_1/2 of ca. 1 to 5 h to yield the corresponding 6-(1-X-3′-methylbuta-1,2′-dienyl)-2,6-dimethyl- or 2,4,6-trimethylcyclohexa-2,4-dien-1-iminium ions (cf. Scheme 13 and Footnotes 26 and 34) When the 4 position is not substituted, a consecutive [3,3]-sigmatropic rearrangement takes place to yield 2,6-dimethyl-4-(3′-X-1′,1′-dimethylprop-2′-ynyl)anilines (cf. Footnotes 26 and 34). A comparable behavior is exhibited by N-(3′-chloro-1′-phenylprop-2′-ynyl)-2,6-dimethylaniline ( 45 ., cf. Table 7). The acid-catalyzed rearrangement of the anilines with a Cl substituent at C(3′) in 1N aqueous H₂SO₄/ROH at 85-95°, in addition, leads to the formation of 7-chlorotricyclo[3.2.1.0^2,7]oct-3-en-8-ones as the result of an intramolecular Diels-Alder reaction of the primarily formed iminium ions followed by hydrolysis of the iminium function (or vice versa; cf. Schemes 13,23, and 25 as well as Table 7). When there is no X substituent at C(1′) of the iminium-ion intermediate, a [1,2]-sigmatropic shift of the allenyl moiety at C(6) occurs in competition to the [3,3]-sigmatropic rearrangement to yield the corresponding 3-allenyl-substituted anilines (cf. Schemes 12,14–18, and 20 as well as Tables 6 and 7). The rearrangement of (?)?(S)-N-(1′-phenylprop-2′-ynyl)-2,6-dimethylaniline ((?)- 38 ; cf. Table 7) in a mixture of 1N H₂SO₄/PrOH at 86° leads to the formation of (?)-(R)-3-(3′-phenylpropa-1′,2′-dienyl)-2,6-dimethylaniline ((?)- 91 ), (+)-(E)- and (?)-(Z)-6-benzylidene-1,5-dimethyltricyclo[3.2.1.0^2′7]oct-3-en-8-one ((+)-(E)- and (?)-(Z)- 92 , respectively), and (?)-(S)-2,6-dimethyl-4-( 1′-phenylprop-2′-ynyl)aniline((?)- 93 ). Recovered starting material (10%) showed a loss of 18% of its original optical purity. On the other hand, (+)-(E)- and (?)-(Z)- 92 showed the same optical purity as (minus;)- 38 , as expected for intramolecular concerted processes. The CD of (+)-(E)- and (?)-(Z)- 92 clearly showed that their tricyclic skeletons possess enantiomorphic structures (cf. Fig. 1). Similar results were obtained from the acid-catalyzed rearrangement of (?)-(S)-N-(3′-chloro-1′phenylprop-2′-ynyl)-2,6-dimethylaniline ((?)- 45 ; cf. Table 7). The recovered starting material exhibited in this case a loss of 48% of its original optical purity, showing that the Cl substituent favors the heterolytic cleavage of the N–C(1′) bond in (?)- 45. A still higher degree (78%) of loss of optical activity of the starting aniline was observed in the acid-catalyzed rearrangement of (?)-(S)-2,6-dimethyl-N-[1′-(p-tolyl)prop-2′-ynyl]aniline ((?)- 42 ; cf. Scheme 25). N-[1′-(p-anisyl)prop-2-ynyl]-2,4,6-trimethylaniline( 43 ; cf. Scheme 25) underwent no acid-catalyzed [3,3]-sigmatropic rearrangement at all. The acid-catalyzed rearrangement of N-(1′,1′-dimethylprop-2′-ynyl)aniline ( 25 ; cf. Scheme 10) in 1N H₂SO₄/BuOH at 100° led to no product formation due to the sensitivity of the expected product 53 against the reaction conditions. On the other hand, the acid-catalyzed rearrangement of the corresponding 3′-Cl derivative at 130° in aqueous H₂SO₄ in ethylene glycol led to the formation of 1,2,3,4-tetrahydro-2,2-dimethylquinolin-4-on ( 54 ; cf. Scheme 10), the hydrolysis product of the expected 4-chloro-1,2-dihydro-2,2-dimethylquinoline ( 56 ). Similarly, the acid-catalyzed rearrangement of N-(3′-bromo-1′-methylprop-2′-ynyl)-2,6-diisopropylaniline ( 37 ; cf. Scheme 21) yielded, by loss of one i-Pr group, 1,2,3,4-tetrahydro-8-isopropyl-2-methylquinolin-4-one ( 59 ).     

Synthese stereoisomerer Pinanthromboxane und Evaluation der Verbindungen als Plättchenaggregationsinhibitoren

Synthesis of Stereisomeric Pinanthromboxane Derivatives and Evaluation of the Compounds as Platelet Aggregation Inhibitors Starting from the two enantiomeric myrtenols ((?)- 1 and (+)- 1 ; cf. Scheme 1), the synthesis of twelve stereoisomeric pinanthromboxane derivatives ((+)- and (?)- 10, -11, -14, -15, -21 and -22 ) is described (cf. Schemes 1–4). Biological data from the evaluation as platelet aggregation inhibitors (cf. Table 6 and 7), thromboxane synthetase inhibitors (cf. Table 8) and from the assessment as antagonists of leukotriene E₄ induced bronchoconstriction (cf. Table 9) are presented.     

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).     

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).     

Synthesis of Benzo[a]heptalene

Benzo[a]heptalene has been synthesized by two different approaches. The first one follows a pathway to hexahydrobenzo[a]heptalenone 19a that has been already described by Wenkert and Kim(Scheme). Indeed, 19a was obtained in a mixture with its double-bond-shifted isomer 19b . Reduction of this mixture to the corresponding secondary alcohols 26a/26b and elimination of H₂O lead to a mixture of the tetrahydrobenzo[a]heptalenes 23a-d (Scheme7 and 8). Reaction of 23a-d with 2 equiv. of triphenylmethylium tetrafluoroborate in boiling CHCl₃, followed by treatment with Me₃N in CH₂Cl₂, generated directly 2 , unfortunately in a mixture with Ph₃CH that could not be separated from 2 (Scheme 10 and 11). The second approach via dimethyl benzo[a]heptalene-6,7-dicarboxylate ( 30 ) (Scheme 12) that was gradually transformed into the corresponding carbaldehydes 37 and 43 (Scheme 14) both of which, on treatment with the Wilkinson catalyst [RhCl(PPh₃)₃] at 130° in toluene, smoothly decarbonylated, finally gave pure 2 as an unstable orange, viscous oil. UV/VIS, NMR, and mass spectra of 2 are discussed in detail (cf. Chapt.3).