Volume 59, Issue 4

Keywords The reagent system formed from N,N,N’,N’-tetraformylhydrazine (3) and aluminum chloride allows the formylation of aromatic compounds. The scope of the method is comparable with the Olah formylation and the Groß-Rieche procedure, since benzene and fluorobenzene can be formylated. Two formyl groups are transferred from 3 to the aromatic nuclei when a molar ratio 4:1:4 (aluminum chloride/3/aromatic compound) is chosen.

Keywords 2,5-Dimethyl-1,3,4-thiadiazole (1a) reacts which aromatic carboxylic acid esters 8a - u in the presence of excessive sodium hydride under condensation to give sodium enolates which afford on hydrolysis the phenacyl-1,3,4-thiadiazoles 9a - u. The action of aromatic carboxylic acid chlorides on 1a in the presence of triethylamine gives rise to the formation of mixtures of diacylated thiadiazole derivatives 16 and 18. In some cases the pure 3-acyl-phenacylidene-2,3-dihydro-1,3,4-thiadiazoles 16 can be isolated. Generally the compounds 16 are rearranged on heating in higher boiling solvents to give the enolbenzoates 18. Hydrolysis of the diacylated thiadiazoles 16 and 18 yields the phenacylthiadiazoles 9a, c, d, g - j, v, w.

Enantiopure Boc-protected piperidine derivative (+)-5c, with a quaternary stereocenter, was obtained by copper-catalyzed, L-valine diethylamide-mediated Michael reaction. For determination of the absolute configuration, 5c was derivatized by cyclization with pyrrolidine/AcOH to give compound 6 with bicyclo[4.4.0]-constitution, deprotection of the amino function with TFA and subsequent reaction with 2-iodobenzoic acid to yield the crystalline bicyclic amide 7. X-ray crystallographic analysis confirmed the constitution of compounds 5c and 6 and established the (R) configuration of 7. Thus, starting Michael addition product (+)-5c has to be (S) configured, because an epimerization at the quaternary stereocenter is excluded. This result is in accordance with our working model of the Cu-catalyzed, auxiliary-assisted Michael reaction.

Keywords Reactions of 1-cyano-4-oxo-4H-quinolizine-3-diazonium tetrafluoroborate (1a) and 4-oxo-4Hpyridino[ 1,2-a]pyrimidine-3-diazonium tetrafluoroborate (1b) with aliphatic amines 2a - g were studied. Treatment of heteroaryldiazonium salts 1 with secondary amines 2a - d afforded the corresponding N-alkyl-N’-heteroaryltriazenes 3a - h in high yields. On the other hand, reactions of 1a with aliphatic primary amines 2e - g resulted in an unexpected rearrangements into the corresponding picolinic acid N-alkylcarboxamides 4a - c.

The Fries rearrangement of model aryl formate esters, promoted by boron trichloride, has been investigated by means of NMR spectroscopy (both experimental and computational) and by DFT calculations. Firstly, the 11 B NMR chemical shifts of a series of model boron compounds have been predicted by GIAO-B3LYP/6-31G(d,p) calculations, in order to make predictions of the chemical shifts of transient reaction intermediates observable by 11 B NMR. Such 11 B spectra for the reaction of two esters (phenyl and 3-methyoxyphenyl formates) have been obtained, and are found to follow different patterns which can be rationalized on the basis of computed chemical shifts. Secondly, DFT calculations (B3LYP/6-31G(d,p) level) have been employed to investigate several mechanistic pathways of the rearrangement of phenyl formate. It is found that the pathways leading to the lowest activation energies are those in which formyl chloride is generated from a complex between phenyl formate and BCl 3 , which then acts as the formylating agent.

Treatment of 2(3)-formyl-glycals 1, 3, 5 with alkyl cyanoacetates afforded 2(3)-[(E)-2-cyano-2- alkoxycarbonyl-vinyl]-2(3)-deoxy-1,5(2, 6)-anhydro-hex-1(2)-enitols 2, 4, 6 which were reacted with aniline to yield nicotinonitrile acyclo-C-nucleosides 7, 9. Nicotinic acid ester acylo-C-nucleosides 11 were obtained by the reaction of 2,6-anhydro-1,4,5-tri-O-benzyl-3-[(E)-2-cyano-2-alkoxycarbonylvinyl]- 3-deoxy-D-erythro-hex-2-enitols 6 with ammonia.

In order to obtain sulfur-containing tetraazafulvalenes the derivatives 1 - 3 were cross-coupled with different types of acetylenes via palladium-catalyzed reactions. Starting from the tetrabromoaryl derivative 3a, four bromine atoms could be replaced by 2-ethynylthiophene. Under analogous conditions, the methylsulfanyl esters 7 -11 could be obtained by employing 4-ethynylbenzoic acid 4-(methylsulfanyl)butylester 6. Lipoic acid could be integrated into tetraazafulvalenes successfully in a two step reaction. First, the Sonogashira coupling method yielded the compound 12 possessing two (4-anilino)ethynyl residues which were then condensed with lipoic acid to give derivative 13. Whereas the NMR data suggest the predominance of prototropic form A, UV/vis spectra of the deeply colored tetraazafulvalenes are in favor with structure B rather than with structure A. DFT calculations at the B3LYP/6-31G(d) level showed that tautomeric form B is about 60 kJ/mol more stable than A. In addition, time-dependent density functional theory calculations support the substructure of two crossed diazaheptamethinemerocyanines.

An efficient and convenient two step synthesis of each of the four possible diastereoisomers of the N-terminal amino acid component of nikkomycins is described. We first synthesized α-amino-β-oxo acids by aminoalkylation of ketones with iminium salts. The second step using Pearlman’s catalyst gave directly nonnatural and natural precursors 13 - 16 of nikkomycins 1 which were easily separated by chromatography on silica gel.

N-(Pyridyl)pyridinium salts 7 and 8 as well as 4-phenylpyrido[1,2-a]pyrimidinium salts 4 and 12 have been prepared by reactions of 3-aryl-3-chloropropeniminium salts 5 with aminopyridines (6) using glacial acetic acid as solvent. 2-Phenylpyrido[1,2-a]pyrimidinium salts 2 are formed when ethanol is used as the solvent. The condensation of 2-aminopyridine (6a) with 3-chloro-2,3- dehydromorpholino-2-carbiminium salt 13 is described. The HSAB principle of Pearson is discussed to explain the different regioselective ring closure reactions.

A new general synthesis of substituted luminols (5-amino-2,3-dihydrophthalazine-1,4-diones) is presented. Diversely substituted luminol derivatives can be synthesized in three steps. The products are of interest as new materials, which exhibit chemiluminescence.

The reaction of N,N’-persubstituted selenoacrylamides with alkyl bromoacetates gives rise to the formation of alkyl derivatives of N,N-disubstituted 2-aminoselenophene-5-carboxylates which can be transformed by saponification into corresponding 5-carboxylic acids. These compounds decompose by heating under formation of hitherto unknown N,N-disubstituted 2-amino-5H-selenophenes their spectral and chemical properties were outlined.

The coupling-isomerization reaction (CIR) of electron-deficient halides 1 with N-[1-(hetero)arylprop-2-ynyl] tosyl amides 2 leads to the formation of N-tosyl enimines 3, in good to excellent yields. These electron deficient heterodienes are perfectly suited for Diels-Alder reactions with inverse electron demand. In the sense of a one-pot reaction a three-component CIR-cyclocondensation sequence of 1, 2a, and diethyl ketene acetal gives rise to the formation of 2-ethoxy 6-(p-anisyl)pyridines 4 in moderate to good yields.

A new approach to optically active N-methylamino acids is presented, relying on stereoselective reduction of N-methylisoxazolinium salts with a dioxyethyl side-chain. The diastereoselectivity of the reduction step is studied systematically, in comparison with that of respective isoxazolines. A two-step transformation of isoxazolinium salts - with NaBH 3 (OAc) and subsequent catalytic hydrogenation as well as a one-pot reduction by catalytic hydrogenation led to high (95:5 and 87:13) diastereomeric ratios of protected erythro-N-methylaminopentanetriols. The hydroxyethyl side-chain is elaborated by oxidation to afford the β -N-methylamino acid 37, exemplifying the potential of this strategy.

The domino Knoevenagel-hetero-Diels-Alder reaction of the aldehyde rac-8, Meldrum’s acid 2 and enol ether 3 leads to the cycloadduct rac-17 as the main product which in a second domino process was transformed into the benzoisoquinolizidine rac-18 by solvolysis, hydrogenolysis, condensation and hydrogenation; rac-18 was used as a substrate for the synthesis of the two diastereomeric epiemetine analogues 9 and 10 with > 96% ee (9) and 80% ee (10), respectively, by condensation with the phenylethylamine 23, Bischler-Napieralski reaction and “enantioselective” hydrogenation using the chiral catalyst (R,R)-26.

3-Hydroxy- (17a - j) and 3-alkoxy-4,5,6,7-tetrahydro-benzosultams 18a-m were prepared in good yields by oxidation of the bicyclic isothiazolium salts 10 with magnesium monoperoxyphthalate (MMPP·6H 2 O) in acetonitrile or corresponding alcohol. A HPLC-API-MS(MS) method was used to monitor the oxidation process of 10 with MMPP. 3-Oxo-4,5,6,7-tetrahydro-benzosultams 19a - c, h, j were also obtained.

Hydride reduction of the tetracyclic isoindolium salt derivatives 2a - c yields the neutral isoindole derivatives 9-chloro-1,2,3,4,6,6a,7,12b-octahydrobenzo[ƒ]pyrido[2,1-a]isoindole (3a), 4,4a,5,7,8,9,10,10a-octahydropyrido[2,1-a]thieno[3,2-f]isoindole (3b), and 10-chloro- 2,3,4,5,7,7a,8,13b-octahydro-1H-azepino[ƒ]pyrido[2,1-a]isoindole (3c). Oxidation of 3a with selenium dioxide is accompanied by a ring transformation and yields 8-chloro-5,5a,6,12-tetrahydrobenzo[g]pyrrolo[1,2-b]isoquinolin-12-one (4). Deprotonation of isoindolium salt derivatives 2a,c,d yields cyclic enamines which undergo ring expansion with dimethyl acetylenedicarboxylate resulting in compounds with the 4,5,6,8,8a,9-hexahydroazocino[2,1-a]benzo[ƒ]isoindole (6a), 4,6,7,9,9a,10-hexahydro-5H-azonino[2,1-a]benzo[ƒ]isoindole (6c) and 4a,5,7,8,9,10-hexahydro- 4H-azonino[2,1-a]thieno[3,2- ƒ]isoindole (6d) skeleton. Interactions of 2 with double-stranded nucleic acids are characterized by relatively large NMR upfield shifts (0.25 ppm) and signal broadening (by about 45 Hz) of aromatic ligand signals, indicating at least partial stacking with nucleobases. Rather small effects are observed, however, in melting point and viscosity increase with double strands; this is tentatively ascribed to competitive interactions with unfolded polymer parts.