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Notes: Synthesis of 3-(2-Carboxy-4-pyridyl)-and 3-(6-Carboxy-3-pyridyl)-DL-alanineAs starting materials for potential photochemical approaches to betalaines C(R = COOH) and to muscaflavine F(R = COOH), β-(2-carboxy-4-pyridyl)- and β-(6(carboxy-3-pyridyl))-DL-alanine (A and D with R = COOH or 4 and 11), respectively, were prepared (Scheme 1). The synthesis of 4 (= A, R = COOH) started with the 2-[(4-pyridyl)methyl]malonate 1 and proceeded via the N-oxide 2, cyanation and hydrolysis (Scheme 2). Amino acid 11 was obtained from (3-pyridyl)methyl-bromide (6) via the malonate 7 by an analogous sequence of reactions (Scheme 3).

Notes: Triaziridines. II. First Examples: Alkyl 2,3-Dialkyl-triaziridine-1-carboxylatesThe first examples of substituted triaziridines 2 are described; they carry an alkoxycarbonyl and two alkyl groups (as in 4). The preparation of these novel threemembered nitrogen homocycles was achieved by photolysis of 1-alkoxycarbonylazimines 3c. In this way, methyl 2, 3-(cis-1, 3-cyclopentylene)triaziridine-1-carboxylate (6a), methyl trans-2, 3-diisopropyl-triaziridine- 1 -carboxylate (8a) and their ethyl ester analogues 6b and 8b were obtained in 50, 18, 65 and 21 % yield, respectively. The structure of the triaziridines 6 and 8 was deduced from their spectroscopic properties which reveal several interesting features: 1) N (2) and N (3), carrying alkyl groups, are pyramidal and invert slowly; 2) the isopropyl groups of 8 are situated trans to each other on the three-membered ring, whereas the two alkyl groups of 6 are cis as forced by the C-ring system; 3) N (1) is also pyramidal, despite its «amidic» nature; it inverts with an activation energy of 62 (± 4) kJ/mol; 4) the alkoxycarbonyl, group does not conjugate with N (1) and rotates rapidly.The triaziridines 6 and 8 are thermally labile, isomerizing slowly at room temperature into the corresponding azimines 5 and 7 by cleavage of one of the bonds to N (1 ). The velocity of this ring opening reaction is almost the same for 6 and 8, so that a dependence on the relative configuration at N (2) and N (3) is not evident. The Arrhenius activation energy for the isornerization of 6a to the corresponding azimine 5a and the enthalpy difference between 6a and 5a were both determined as 100 (± 4) kJ/mol.The photolysis of 1-alkoxycarbonyl-2, 3-diisopropyl-azimines (7) in diethyl ether was accompanied by a side reaction leading to methyl and ethyl N-(1-ethoxyethyl)carbamate (9a and 9b, resp.), presumably by insertion of the alkoxycarbonylnitrene, generated by photofragmentation of the azimines, into the ethereal solvent.

Notes: Total Synthesis of Decarboxybetalaines by Photochemical Ring Opening of 3-(4-Pyridyl)alanineA photochemical approach is presented for the total synthesis of the decarboxybetalaines, which were previously known from the mild decarboxylation of the natural plant colorants, the betalaines: Irradiation of rac-3-(4-pyridyl)alanine (1) yielded the rac-2-decarboxybetalamic-acid-imine (4, 86%), presumably via a Dewar pyridine 2, a cyclic aminal 3 and an electrocyclic ring opening. The imine-zwitterion 4 was treated with three amines, namely (S)-cyclodopa (6), (S)-proline (7), and indoline (8), to afford three decarboxybetalaines, namely (2S)-17-decarboxybetanidine (9, red, 34%), (2S)-13-decarboxyindicaxanthine (10, yellow, 56%), and rac-16-decarboxyindobetalaine (11, orange, 78%), respectively. The structures of these coloring matters were confirmed by their electrophoretic behavior and their spectroscopic properties. 17-Decarboxybetanidine 9 was shown to be a ca. 1:1 mixture of two C(15)-epimers 9a and 9b, separable by chromatography. The configuration of 9a was determined as (2S, 15S) and that of 9b as (2S, 15R), by correlating their optical rotations with those of betanidine (12a) and isobetanidine (12b), respectively. The decarboxybetalaines 9, 10, and 11 did not show the double-bond isomerism at C(β), (Cγ) of the chromophore which had been found characteristic for the corresponding betalaines 12, 13, and 14.

Notes: Triaziridines. Synthesis of cis-2,3-Diisopropyltriaziridine-1-carboxylic EstersIrradiation of the (Z)-azimines 1a, b in Et2O with a Hg high pressure lamp through Corex yielded (besides 30% of the previously described trans-triaziridines 3a, b) 15% of the new cis-triaziridines 4a, b. The same irradiation of the (E)-azimines 2a, b afforded only 15-18% of 3a, b but 20-23% of 4a, b. Thus, these azimine photocyclizations show some stereospecificity. The triaziridines 3a, b and 4a, b formed in this way were always accompanied by the same three types of by-products, namely 10-15% of the ‘triazones’ 5a, b, 11-20% of the carbamic esters 6a, b, and 5-10% of the ether/nitrene insertion products 7a, b. The constitution and configuration of the new cis-triaziridines 4 followed from their spectral properties. Of particular interest are the symmetry properties of 4 derived from the 1H-, 13C-, and 15N-NMR spectra: The stereoisomers 3 and 4 differ only in that the isochronicity of the two constitutionally equivalent molecular halves is temperature dependent in 3 but independent in 4. Both triaziridines 3 and 4 exhibit the IR CO band at (for carbamates) remarkably high frequency. The results confirm that the alkyl-substituted N-atoms of triaziridines are pyramidally stable, that the corresponding acyl-substituted N-atoms (N(1)) are also pyramidal, but can invert more readily, and that rotation around the N(1), C(=O) bond is rapid. Thus, there can be only little amide-type delocalization between a triaziridine N-atom and an acyl substituent of the carbamate type attached to it.

Notes: Oxidative Aryl-Aryl-Coupling of 6,6′,7,7′-Tetramethoxy-1,1′,2,2′,3,3′,4,4′-octahydro-1,1′-biisoquinoline DerivativesWe describe the synthesis of 2 by intramolecular oxidative coupling of 1, 1′-biisoquinoline derivatives 1 (Scheme 1). This heterocyclic system can be considered as a union of two apomorphine molecules and may thus exhibit dopaminergic activity. - The readily available tetrahydrobiisoquinoline 6 was methylated to 11 (Scheme 4) and reduced (with NaBH3CN) to rac-7 and (catalytically) to meso-7 (Scheme 3). Reduction of 11 with NaBH4 and of the biurethane rac-9 with LiAlH4/AlCl3 afforded meso- and rac-10, respectively (Scheme 4). Demethylation of 6, meso-10, meso- and rac-7 led to 12, meso-14, meso- and rac-13, respectively (Scheme 5). The latter two phenols were converted with chloroformic ester to the hexaethoxycarbonyl derivatives meso- and rac-15 and subsequently saponified to the biurethanes meso- and rac-16, respectively (Scheme 5). - In order to assure proximity of the two aromatic rings, the ethano-bridged derivatives meso- and rac-18 were prepared by condensing meso- and rac-7 with oxalic ester and reducing the oxalyl derivatives meso- and rac-17 with LiAlH4/AlCl3, respectively (Scheme 6). The 1H-NMR, spectra at different temperatures showed that rac-18 populated two conformers but rac-17 only one, all with C2-symmetry, and that meso-17 as well as meso-18 populated two enantiomeric conformers with C1-symmetry. Whereas both oxalyl derivatives 17 were fairly rigid due to the two amide groupings, the ethano derivatives 18 exhibited coalescence temperatures of -20 and 30°. - The intramolecular coupling of the two aromatic rings was successful under ‘non-phenolic oxidative’ conditions with the tetramethoxy derivatives 7, 10 and 18, the rac-isomers leading to the desired dibenzophenanthrolines, the meso-isomers, however, mostly to dienones (Scheme 9): With VOF3 and FSO3H in CF3COOH/CH2Cl2 rac-7 was converted to rac-19, rac-18 to rac-21 and rac-10 to a mixture of rac-20 and the dienone 23b of the morphinane type. Under the same conditions meso-10 was transformed to the dienone 23a of the morphinane type, whereas meso-18 yielded the dienone 24 of the neospirine type, both in lower yields. The analysis of the spectral data of the six coupling products offers evidence for their structures. With the demethylation of rac-20 and rac-21 to rac-25 and rac-26, respectively, the synthetic goal of the work was reached, but only in the rac-series (Scheme 10). - In the course of this work two cleavages of octahydro-1,1′-biisoquinolines at the C(1), C(1′)-bond were observed: (1) The biurethanes 9 and 16 in both the meso- and rac-series reacted with oxygen in CF3COOH solution to give the 3,4-dihydroisoquinolinium salts 27 and 28; the latter was deprotonated to the quinomethide 30 (Scheme 11). (2) Under the Clarke-Eschweiler reductive-methylation conditions meso- and rac-7 were cleaved to the tetrahydroisoquinoline derivative 32.

Notes: The products of the thermolysis of N-(1-pyridinio)-2-nitroanilides (1) had previously been interpreted as tris (2-nitrophenyl)-triaziridines (3). The present work shows them to be actually 1, 2-bis[(Z)-(2′-nitrophenyl)-ONN-azoxy]benzenes (5). The revised structural assignment is based on the chemical and the spectroscopic (especially 1H-NMR.) properties of 5 and on the results of a X-ray structural analysis.

Notes: On the Total Synthesis of BetalainsImproved total syntheses of the red-violet aglucone of the beet coloring matter and of the yellow cactus coloring matter indicaxanthine are presented. Formyl-olefination of the piperidone-diester 6 with the acetaldehyde synthon 5 led to the piperidylidene-acetaldehyde derivative 8, which was converted into the 2,4,4-trimethylsemicarbazone of rac-betalamic acid dimethyl ester (10) by treatment with t-BuOCl and then Et3N. Exchanging the semicarbazone moiety with the (S)-cyclodopa derivative 18, with (S)-proline (19) and with indoline (20) transformed 10 to betanidin (21/22), to indicaxantihin (23/24) and to rac-indo-betalaine (25), respectively. The latter, a new, relatively stable betalaine, was hydrolyzed and esterified to rac-betalamic acid dimethyl ester (29). Under the influence of NH3/MeOH, 26 (the dimethyl ester of 25) was dehydrogenated spontaneously to indo-neobetalaine dimethyl ester (27).Synthetic betanidin consisted of a 4:6 mixture of the (natural) (2S, 15S)- (21) and the (2S, 15R)-isomer (22) and both of a 75:25 mixture of the (E)- and the (Z)-isomer. Synthetic indicaxanthin (23/24) and the indo-betalaine (25) represented a 65:35 and a 70:30 mixture, respectively, of (E)- and the (Z)-isomers. All (E)- and (Z)-isomers are rapidly interconvertible. Temperature-dependent 1H-NMR-measurements of 25 established ΔG≠ = 84.7 kJ/mole for the (E)-to-(Z)-conversion.The t-BuOCl/NEt3 method for the introduction of an enaminic double bond was applied to the model transformations of the amines 6, 12 and 15 to the conjugated enamiens 11, 13 and 17, respectively.

Notes: Reduction of 1,2-Bis[(Z)-(2-nitrophenyl)-NNO-azoxy]benzene1: Synthesis of Cyclotrisazobenzene ( = (5E,6aZ,11E,12aZ,17E,18aZ)-5,6,11,12,17,18-Hexaazatribenzo[aei][1,3,5,7,9,11]cyclododeca-hexaene)Na2S reduction of 1,2-bis[(Z)-(2-nitrophenyl)-NNO-azoxy]benzene (2) yielded 3 deoxygenated products: the (known) red 2,2′-((E,E)-1,2-phenylenbisazo)dianiline (3, 23%), the orange 2-[2-((E)-2-aminophenylazo)phenyl]-2H-benzotriazol (4, 55%) and the colorless 2,2′-(1,2-phenylene)di-2H-benzotriazol (5, 13%). The constitutions of 3-5 and of 6, the N-acetyl derivative of 4, were deduced from their 1H-NMR spectra (chemical shifts, couplings, and symmetry properties), and the configurations of 3, 4, and 6 at their N,N-double bonds are assumed to be the same as in 2. Oxidation of 3 with 2 mol-equiv. of Pb(OAc)4 afforded 5 (47%) and a novel, highly symmetrical macrocycle, called cyclotrisazobenzene (7, 24%). The constitution of 7 as a tribenzo-hexaaza[12]annulene and its (E)-configuration at the N,N-bonds was confirmed by X-ray analysis. The molecular symmetry expressed by the 1H-, 13C- and 15N-NMR spectra of 7 reveals a rapid torsional motion around the six N,C bonds. This implies that the N,N-double bonds in the cyclic 12π-electron system (or 24π-electron system if the benzene rings are included) of 7 are highly localized.

Notes: The 15N-NMR spectra of cis- and trans-2,3-dialkyl-substituted triaziridines are reported. The assignment of the 15N-NMR resonances is described, and the chemical-shift and coupling data are compared with those of aziridines and diaziridines. The 1J(N,H) coupling constants allow one to deduce the relative configuration of the involved N-atom. In CDCl3, a 1J(N,H) value of 58.1 ± 0.5 Hz is assigned to an N—H bond cis to two lone-pairs of electrons at neighboring N-atoms, i.e. to the cis,trans-triaziridinesThe first stereodescriptor denotes the relative configuration of the two equal alkyl substituents, the second the relative configuration of one alkyl substituent and the H-atom., and a value of 51.7 ± 0.5 Hz is assigned to a N—H bond cis to only one lone-pair of electrons, i.e. to trans, cis-triaziridines.

Notes: Synthesis of Betenamine and of Betalaine Model SubstancesFor comparisons of color, spectroscopic properties, pKa values, and stabilities, a number of model substances containing the 1,7-diazaheptamethinium chromophore 8 of the yellow and red betalaine plant pigments were prepared by the thermal or photolytic ring opening of simple pyridine derivatives (such as 2 and 14-16), followed by the introduction of amines. Among the novel compounds prepared were betenamine perchlorate (5), the ‘naked’ ring system of the beet-pigment betanine (C) as well as two 1,7-diazaheptamethinium salts 25 and 27 with terminal amono acids. The synthesis of 5 started with 4-(2-aminoethyl)pyridine (1) and proceeded via 2, ring opening with indoline to 4, saponification, and intramolecular amine replacement (Scheme 1). The syntheses of 25 and 27 involved only one step, namely ring opening of γ-picoline using (S)-cyclodopa (24) and (S)-proline (26), respectively (Scheme 3).