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).     

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 ).     

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).     

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.     

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).     

Die Aminoalkylierung von Carbonylverbindungen mit Hilfe der Wittig-Reaktion

The Aminoalkylation of Carbonyl Compounds by the Wittig-Reaction The Wittig reaction would be a very suitable way to replace the carbonyl group in aldehydes and ketones by a 2-amino-ethylidene group if a simple and convenient method could be devised for synthesizing (2-amino-ethyl)triphenylphosphonium bromides 3 . We have synthesized compounds of type like (2-dialkylaminoethyl)-, (2-morpholino-ethyl)-, (2-(1-imidazolyl)ethyl)-, and (2-(1-triazolyl)ethyl)-triphenylphosphonium bromides (cf. Table 1), by melting at 150° the hydrobromides of triphenylphosphine and of the appropriate 2-amino-ethanol. The phosphonium bromides of type 3 could be converted with ketones by the Wittig reaction into the desired amino-ethylidene compounds of type 2 , e.g. 18 – 22 (Table 2). In the case of the reaction with 4-chlorobenzaldehyde the steric course of the transformation was studied, and conditions were found favoring either cis or trans compounds (e.g. 27a or 27b in the reaction of the phosphonium bromide 11 , cf. Table 3).     

1H-NMR.-spektroskopische Analyse von prochiralen Allencarbonsäureestern mit optisch aktiven Europium-Verschiebungsreagenzien

¹H-NMR. Spectroscopic Analysis of Prochiral Allenic Esters Using Optically Active Europium Shift Reagents The prochiral allenic methyl esters 1–4 (cf. Scheme) show in the presence of 1 mol-equiv. tris[3-(heptafluorobutyryl)-(+)-camphorato]europium (III) (Eu (hfc)₃) in 1,1,2-trichloro-1,2,2-trifluoroethane (TCFE) induced unlike ¹H-NMR. shift differences (ΔΔδ) for the enantiotopic protons and methyl groups on C(4), respectively (cf. Fig. 2 and 3). This effect allows to determine directly the ²J_H,H coupling constants of the geminal protons on C(4) of the allenic esters 1 (15.5 Hz) and 2 (14.5 Hz) (cf. Table 2).     

Zur Photochemie von 1, 2-Benzisoxazolen in stark saurer Lösung

On the Photochemistry of 1, 2-Benzisoxazoles in Strongly Acidic Solution The 1, 2-benzisoxazoles 1a, 1b and 1d when dissolved in 96% sulfuric acid and irradiated through a quartz filter with a mercury high-presure lamp yield, after work-up, mixtures of 2, 5- and 2, 3-dihydroxy-acylbenzenes ( 2 and 3 , respectively; cf. Schemes 1 and 3 and Table 1). Irradiation of 3, 5-dimethyl-1, 2-benzisoxazole ( 1c ) in 96% sulfuric acid leads to the formation of 2, 3-dihydroxy-5-methyl-acetophenone ( 3c ) in only 6% yield (cf. Table 1). It is assumed that the 1, 2-benzisoxazolium ions react in the excited singlet state by heterolytic cleavage of the N, O-bond to yield the corresponding aryl oxenium ions 7 in the singlet ground state (see Scheme 5). Reaction of 7 with HSO ₄ ? ions, present in 96% sulfuric acid, yields, after hydrolysis, the dihydroxy compounds 2 and 3 . Photolysis of 3-methyl-1, 2-benzisoxazole ( 1b ) in diluted sulfuric acid (0,5 to 9 M ) in methanol or water leads only to the formation of 2-amino-phenol ( 6 ; see Scheme 3), presumable via photo-isomerization of 1b to 2-methylbenzoxazole ( 5b ) which then is hydrolyzed to give 6 .     

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).     

Thermische (E), (Z)-Isomerisierungen bei substituierten Propenylbenzolen

Thermal (E), (Z)-Isomerizations of Substituted Propenylbenzenes The thermal isomerizations of (E)- and (Z)-3,5-dimethyl-2-(1′-propenyl)phenol ((E)- and (Z)- 3 ), (E)- and (Z)-N-methyl-2-(1′-propenyl)anilin ((E)- and (Z)- 4 ), (E)- and (Z)-3,5-dimethyl-2-(1′-propenyl)anilin ((E)- and (Z)- 5 , (E)- and (Z)-2-(1′-propenyl)mesitylene ((E)- and (Z- 6 ), (E)- and (Z)-2-(1′-propenyl)mesitylene ((E)- and (Z)- 7 ), (E)- and (Z)-2-(1′-propenyl)toluene ((E)- and (Z)- 8 ), (E)- and (Z)-4-(1′-propenyl)toulene ((E)- and (Z)- 9 ) as well as of (E)- and (Z)-2-(2′-butenyl)-mesitylene ((E)- and (Z)- 10 ) in decane solution were studied (Scheme 2). Whereas the isomerization of the 2-propenylphenols (E)- and (Z)- 3 occurs already between 130 and 150° (cf. Table 1), the isomerization of the 2-propenylanilins 4 and 5 takes place only at temperatures between 220 and 250° (cf. Tables 2 and 3). The activation values and the experiments using N-deuterated 4 (cf. Scheme 4) show that 2-propenylphenols and -anilins isomerize via sigmatropic [1,5]-hydrogen-shifts. For the isomerization of the methyl-substituted propenylbenzenes temperatures > 360° are required (cf. Tables 4 and 5). The activation values of the isomerization of (E)- and (Z)- 6 and (E)- and (Z)- 9 are in accord with those of other (E), (Z)-isomerizations which occur via vibrationally excited singlet biradicals (cf. Table 7). Nevertheless, thermal isomerization of 2′-d-(Z)- 8 (cf. Scheme 6) demonstrates that during the reaction deuterium is partially transfered into the ortho-methyl group, i.e. 1,5-hydrogen-shifts must have participated in isomerization of (E)- and (Z)- 8 (cf. Scheme 8). Under the equilibrium conditions 2,4,6-trimethylindan ( 17 ) is formed slowly at 368° from (E)- and (Z)- 6 , very probably via a radical 1,4-hydrogen-shift (cf. Scheme 9). In a similar way 2-ethyl-4,6-dimethylindan ( 19 ; cf. Table 6) arises from (E)- and (Z)- 7 . Thermolysis of (E)- and (Z)- 10 in decane solution at 367° results in almost no (E),(Z)-isomerization. At prolonged heating 19 and 2,5,7-trimethyl-1,2,3,4-tetrahydronaphthalene ( 20 ) are formed; these two products arise very likely from an intermolecular radical process (cf. Scheme 10).     

Untersuchungen über aromatische Amino-Claisen-Umlagerungen

Investigations on Aromatic Amino-Claisen Rearrangements The thermal and acid catalysed rearrangement of p-substituted N-(1′,1′-dimethylallyl)anilines (p-substituent=H (5) , CH₃ (6) , iso-C₃H₇ (7) , Cl (8) , OCH₃ (9) , CN (10) ), of N-(1′,1′-dimethylallyl)-2,6-dimethylaniline (11) , of o-substituted N-(1′-methylallyl)anilines (o-substituent=H (12) , CH₃ (13) , t-C₄H₉ (14) , of (E)- and (Z)-N-(2′-butenyl)aniline ((E)- and (Z)- 16 ), of N-(3′-methyl-2′-butenylaniline (17) and of N-allyl- (1) and N-allyl-N-methylaniline (15) was investigated (cf. Scheme 3). The thermal transformations were normally conducted in 3-methyl-2-butanol (MBO), the acid catalysed rearrangements in 2N -0,1N sulfuric acid. - Thermal rearrangements. The N-(1′,1′-dimethylallyl)anilines rearrange in MBO at 200-260° with the exception of the p-cyano compound 10 in a clean reaction to give the corresponding 2-(3′-methyl-2′-butenyl)anilines 22–26 (Table 2 and 3). The amount of splitting into the anilines is <4% ( 10 gives ? 40% splitting). The secondary kinetic deuterium isotope effect (SKIDI) of the rearrangement of 5 and its 2′,3′,3′-d₃-isomer 5 amounts to 0.89±0.09 at 260° (Table 4). This indicates that the partial formation of the new s?-bond C(2), C(3′) occurs already in the transition state, as is known from other established [3,3]-sigmatropic rearrangements. The rearrangement of the N-(1′-methylallyl)anilines 12–14 in MBO takes place at 290–310° to give (E)/(Z)-mixtures of the corresponding 2-(2′-Butenyl)anilines ((E)- and (Z)- 30,-31 , and -32 ) besides the parent anilines (5–23%). Since a dependence is observed between the (E)/(Z)-ratio and the bulkiness of the o-substituent (H: (E)- 30 /(Z)- 30 =4,9; t-C₄H₉: (E)- 32 /(Z)- 32 =35.5; cf. Table 6), it can be concluded, that the thermal amino-Claisen rearrangement occurs preferentially via a chair-like transition state (Scheme 22). Methyl substitution at C(3′) in the allyl chain hinders the thermal amino-Claisen-rearrangement almost completely, since heating of (E)-and (Z)- 16 , in MBO at 335° leads to the formation of the expected 2-(1′-methyl-allyl) aniline (33) to an extent of only 12 and 5%, respectively (Scheme 9). The main reaction (?60%) represents the splitting into aniline. This is the only observable reaction in the case of 17 . The inversion of the allyl chain in 16 - (E)- and (Z)- 30 cannot be detected - indicated that 33 is also formed in a [3, 3]-sigmatropic process. This is also true for the thermal transformation of N-allyl- (1) and N-allyl-N-methylaniline (15) into 2 and 34 , respectively, since the thermal rearrangement of 2′, 3′, 3′-d₃- 1 yields 1′, 1′, 2′-d₃- 2 exclusively (Table 8). These reaction are accompanied to an appreciable extent by homolysis of the N, C (1′) bond: compound 1 yields up to 40% of aniline and 15 even 60% of N-methylaniline ((Scheme 10 and 11). The activation parameters were determined for the thermal rearrangements of 1, 5, 12 and 15 in MBO (Table 22). All rearrangements show little solvent dependence (Table 5, 7 and 9). The observed ΔH^≠ values are in the range of 34-40 kcal/mol and the ΔS^≠ values very between -13 to -19 e.u. These values are only compatible with a cyclic six-membered transition state of little polarity. - Acid catalysed rearrangements. - The rearrangement of the N-(1′, 1′-dimethylallyl) anilines 5-10 occurs in 2N sulfuric acid already at 50-70° to give te 2-(3′-methyl-2′-butenyl)anilines 22-27 accompanied by their hydrated forms, i.e. the 2-(3′-hydroxy-3′-methylbutyl) anilines 35-40 (Tables 10 and 11). The latter are no more present when the rearrangement is conducted in 0.1 N sulfuric acid, whilst the rate of rearrangement is practically the same as in 2 N sulfuric acid (Table 12). The acid catalysed rearrangements take place with almost no splitting. The SKIDI of the rearrangement of 5 and 2′, 3′, 3′-d₃- 5 is 0.84±0.08 (2 N H₂SO₄, 67, 5°, cf. Table 13) and thus in accordance with a [3,3]-sigmatropic process which occurs in the corresponding anilinium ions. Consequently, the rearrangement of a 1:1 mixture of 2′, 3′, 3′-d₃- 5 and 3, 5-d₂- 5 in 2 N sulfuric acid at 67, 5° occurs without the formation of cross-products (Scheme 13). In the acid catalysed rearrangement of the N-1′-methylallyl) anilines 12-14 at 105-125° in 2 N sulfuric acid the corresponding (E)- and (Z)-anilines are the only products formed (Table 14 and 15). Again no splitting is observed. Furthermore, a dependence of the observed (E)/(Z) ratio and the bulkiness of the o-substituent ( H : (E)/(Z)- 30 = 6.5; t- C ₄ H ₉: (E)- 32 /(Z)- 32 = 90; cf. Table 15) indicates that also in the ammonium-Claisen rearrangement a chair-like transition state is preferentially adopted. In contrast to the thermal rearrangement the acid catalysed transformation in 2 N-O, 1 N sulfuric acid (150-170°) of (E)- and (Z)- 16 as well as of 1 and 15 , occurs very cleanly to yield the corresponding 2-allylated anilines 33, 2 and 34 (Scheme 15 and 18). The amounts of the anilines formed by splitting are <2%. During longer reaction periods hydration of the allyl chain of the products occurs, and in the case of the rearrangement of (E)- and )Z)- 16 the indoline 45 is formed (Scheme 15 and 18). All transformations occur with inversion of the allyl chain. This holds also for the rearrangement of 1 , since 3′, 3′-d₂- 1 gives only 1′, 1′-d₂- 2 (Scheme 17). The activation parameters were determined for the acid catalysed rearrangement of 1, 5, 12 and 15 in 2 N sulfuric acid (Table 22). The ΔH^≠ values of 27-30 kcal-mol and the ΔS^≠ values of +9 to -12 e.u. are in agreement with a [3, 3]-sigmatropic process in the corresponding anilinium ions. The acceleration factors (k_H+/k_Δ) calculated from the activation parameters of the acid catalysed and thermal rearrangements of the anilines are in the order of 10⁵ - 10⁷. They demonstrate that the essential driving force of the ammonium-Claisen rearrangement is the ‘delocalisation of the positive charge’ in the transition state of these rearrangements (cf. Table 23). Solvation effects in the anilinium ions, which can be influenced sterically, also seem to play a role. This is impressively demonstrated by N-(1′, 1′-dimethylallyl)-2, 6-dimethylaniline (11) : its rearrangement into 4-(1′, 1′-dimethylallyl)-2, 6-dimethylaniline (43) cannot be achieved thermally, but occurs readily at 30° in 2 N sulfuric acid. From a preparative standpoint the acid catalysed rearrangement in 2 N-0, 1 N sulfuric acid of N-allylanilines into 2-allylanilines, or if the o-positions are occupied into 4-allylanilines, is without doubt a useful synthetic method (cf. also [17]).     

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]).     

Synthesis and Characterization of New Heptalenes with Extended π‐Systems Attached to Them

Methyl heptalenecarboxylates of type A and B with π(1) and π(2) substituents in 1,4‐relation (Scheme 1) were synthetized starting with dimethyl 1‐methylheptalene‐4,5‐dicarboxylates 5b and 6b derived from 7‐isopropyl‐1,4‐dimethylazulene (=guaiazulene) and 1,4,6,8‐tetramethylazulene by thermal reaction with dimethyl acetylenedicarboxylate. The further general way of proceeding for the introduction of the π(1) and π(2) substituents is displayed in Scheme 3, and the thus obtained methyl heptalene‐5‐carboxylates of type A and B are listed in Table 1. The C?C bonds of the 2‐arylethenyl and 4‐arylbuta‐1,3‐dien‐1‐yl groups of π(1) and π(2) were in all cases (E)‐configured and showed s‐trans conformation at the C? C bonds (X‐ray and ¹H‐NOE evidence) in the B ‐type as well as in the A ‐type heptalenes (cf. Figs. 5–12). All B ‐type heptalenes showed a strongly enhanced heptalene band I in the wavelength region 440–490 nm in hexane/CH₂Cl₂ 9 : 1 (cf. Table 4 and Figs. 13–20). The A ‐type heptalenes showed in this region only weak absorption, recognizable as shoulders or simply tailing of the dominating heptalene bands II/III (Table 5). Absorption band I of the B ‐type heptalenes appeared almost at the same wavelength as the longest wavelength absorption band of comparable open‐chain α,ω‐diarylpolyenes (cf. Fig. 21). The cyclic double bond shift (DBS) of the A ‐ and B ‐type heptalenes could be photochemically steered in one or the other direction by selective irradiation (cf. Fig. 22).     

A Direct Route to 3-(D-Ribofuranosyl)pyridine Nucleosides

A route for synthesizing C-nucleosides with 2,6-substituted pyridines as heterocyclic aglycones is described. Condensation of appropriately substituted lithiated pyridines with ribono-1,4-lactone derivatives yields hemiacetal 4a – g (Table 1), which can be reduced by Et₃SiH and BF₃·Et₂O to the corresponding C-nucleoside (see Scheme 1 for 4d → β-D - 5 ). Conditions are presented that optimize the amount of the 2,6-dichloropyridine-derived β-D -anomer β-D - 5 formed (Table 3). Aminolysis of β-D - 5 yields the diaminonucleoside 14 (Scheme 3).     

Preparation and Structures of 2‐Substituted 5‐Benzyl‐3‐methylimidazolidin‐4‐one‐Derived Iminium Salts,Reactive Intermediates in Organocatalytic Transformations Involving α,β‐Unsaturated Aldehydes

Preparations of the title compounds, 5 – 7 (Scheme 1 and Table 1), of their ammonium salts, 9 – 11 (Scheme 2 and Table 2), and of the corresponding cinnamaldehyde‐derived iminium salts 12 – 14 (Scheme 3 and Table 3) are reported. The X‐ray crystal structures of 15 cinnamyliminium PF₆ salts have been determined (Table 4). Selected ¹H‐NMR data (Table 5) of the ammonium and iminium salts are discussed, and structures in solution are compared with those in the solid state.     

New Optically Active 2H‐Azirin‐3‐amines as Synthons for Enantiomerically Pure 2,2‐Disubstituted Glycines: Synthesis of Synthons for Tyr(2Me) and Dopa(2Me), and Their Incorporation into Dipeptides

The synthesis of novel unsymmetrically 2,2‐disubstituted 2H‐azirin‐3‐amines with chiral auxiliary amino groups is described. Chromatographic separation of the mixture of diastereoisomers yielded (1′R,2S)‐ 2a , b and (1′R,2R)‐ 2a , b (c.f. Scheme 1 and Table 1), which are synthons for (S)‐ and (R)‐2‐methyltyrosine and 2‐methyl‐3′,4′‐dihydroxyphenylalanine. Another new synthon 2c , i.e., a synthon for 2‐(azidomethyl)alanine, was prepared but could not be separated into its pure diastereoisomers. The reaction of 2 with thiobenzoic acid, benzoic acid, and the amino acid Fmoc‐Val‐OH yielded the monothiodiamides 11 , the diamides 12 (cf. Scheme 3 and Table 3), and the dipeptides 13 (cf. Scheme 4 and Table 4), respectively. From 13 , each protecting group was removed selectively under standard conditions (cf. Schemes 5–7 and Tables 5–6). The configuration at C(2) of the amino acid derivatives (1R,1′R)‐ 11a , (1R,1′R)‐ 11b , (1S,1′R)‐ 12b , and (1R,1′R)‐ 12b was determined by X‐ray crystallography relative to the known configuration of the chiral auxiliary group.     

Perchloric Acid–Silica (HClO4⋅SiO2)‐Catalyzed Synthesis of 14‐Alkyl‐ or 14‐Aryl‐14H‐dibenzo[a,j]xanthenes and N‐[(2‐Hydroxynaphthalen‐1‐yl)methyl]amides

The synthesis of 14‐aryl‐ or 14‐alkyl‐14H‐dibenzo[a,j]xanthenes 3 involving the treatment of naphthalen‐2‐ol ( 1 ) with arenecarboxaldehydes or alkanals 2 in the presence of HClO₄?SiO₂ as a heterogeneous catalyst was achieved (Table 1), and this reaction was extended to the preparation of N‐[(2‐hydroxynaphthalen‐1‐yl)methyl]amides 5 by a three‐component reaction with urea ( 4a ) or an amide 4b – d as a third reactant (Table 2).     

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).     

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).     

β-Cleavage of Potassium Bicyclo[2.2.2]oct-5-en-2-olates. Stereoselective synthesis of (±)-trichodiene

The transformations of 12 bicyclo[2.2.2]oct-5-en-2-ols ( V or VI ) to 3-(cyclohex-3-enyl)-2-alkanones ( III or IV ), via β-cleavage of their potassium alkoxides in HMPA, has been investigated (cf. Table 1). As an illustration of this synthetic methodology, a stereoselective synthesis of (±)-trichodiene ((±)- 1 ) is described which involves the β-cleavage of the tricyclic potassium alkoxides 46a and 47a to cyclopentanone 4 (cf. Scheme 7).