Preferential protonation and methylation at the nitrogen atoms of N,N-dimethylamino derivatives of pyridine

The relative reactivity toward protonation and methylation of the two nitrogen atoms in N,N-dimethylaminopyridines has been examined by ¹H NMR. The ring position of the dimethylamino group has no influence on protonation, which occurs in all the derivatives at the heterocyclic nitrogen. The N-methylation reaction does not follow a homogeneous behaviour, occurring at the exocyclic nitrogen in the 2-substituted dimethylamino derivative. The electronic characteristics of the molecules, determined by MO calculations at a semi-empirical level, indicate that both protonation and methylation should occur at the heterocyclic nitrogen; the calculated relative stabilites, however, of the N-protonated and N-methylated forms are in full agreement with the experimental results, and it appears that the anomalous behaviour of 2-dimethylaminopyridine in the N-methylation reaction is caused by steric factors.     

1,3-Dipolar cycloadditions of diazoalkanes to pyridazine derivatives. Thermal 1,5-sigmatropic rearrangement of methyl groups in 3,3-dimethyl-3H-pyrazolo[3,4-d]pyridazine derivatives

Thermal 1,5-sigmatropic rearrangements of one of the methyl group attached at position 3 of 3,3-dimethyl-3H-pyrazolo[3,4-d]pyridazin-4(5H)-ones 1–3 taking place either in a clock-wise or anti-clockwise direction gave N₂-methylated products 4–6 and C_3a-methylated products 7– 9 . The -7(6)-one derivative 10 and -4,7(5H,6H)-dione derivative 12 gave only N₂-methylated products 11 and 13 respectively, and 1,2-dihydro derivative 14 produced after elimination of methane, 15 .     

Mammalian alkaloids: Synthesis and O-methylation of (S)- and (R)-3′-hydroxycoclaurine and their N-methylated analogues with S-adenosyl-L-[methyl-14C]methionine in presence of mammalian catechol O-methyltransferase

O-Methylation of the optically active 3′-hydroxycoclaurines 3a and 3b and of the N-methylated analogs 5a,b with S-adenosyl-L -[methyl-¹⁴C]methionine in presence of mammalian COMT was investigated in vitro. The N-unsubstituted (1S)- and (1R )-isomers 3a and 3b , respectively, afforded almost equal amounts of the corresponding N-norreticuline 4 and N-nororientaline 19 , besides two unknown by-products (see Fig. and Table 1). The N-methylated (1S)-isoquinoline 5a , on the other hand, afforded largely (S)-orientaline ((S)- 19 ), while an almost equal mixture of (R)-reticuline ( 6b ) and (R)-orientaline ((R)- 19 ) was obtained from the (1R)-enantiomer 5b . The isoquinolines 3a,b and 5a,b were prepared by a Bischler-Napieralski cyclization yielding O-benzyl-protected isoquinoline 10 (Scheme 1). The optical resolution of 10 was accomplished with 2′-bromotartranilic acid. The N-methylated isoquinolines were prepared by N-formylation of 10a,b and reduction of the formamides 13a,b with diborane (→ 14a,b ). Deblocking of the benzyl-ether moieties of 10a,b and 14a,b was accomplished by catalytic hydrogenation in presence of HCl, affording directly 3a,b ·HCl and 5a,b ·HCl, respectively.     

Fragmentation at Electron Impact of Nitro Derivatives of 1,2,4-Oxadiazole and 1,2,3-Triazole

Mass spectra were investigated of a series of 3-aryl-5-(nitromethyl)-1,2,4-oxadiazole derivatives and of N-methylated (benzylated) isomeric 4-(dinitromethyl)-1,2,3-triazoles. The principal fragmentation processes of these compounds involve the heterocycle opening and/or liberation of nitrogen-containing fragments followed by formation of the most stable fragment ions.     

Les β-cétonitriles groupes protecteurs de la fonction amine. Préparation d'amino-alcools

β-Ketonitrile-Derived Protecting Groups of the Amino Function. Synthesis of Amino Alcohols The amino group of natural L -amino acid esters is protected by condensation with 2-oxocyclopentanenitrile ( 1 ) or 2-formyl-2-phenylacetonitrile ( 10 ). Only the ester group of the formed cyanoenamino esters 2 and 11 reacts with nucleophilic reagents such as organometallics (RMgX, RLi), borohydrides, or metal amides, whereas the cyanoenamino group is unchanged (Schemes 1 and 2). Cyanoenamino alcohols obtained by reduction of cyanoenamino esters 2 are hydrolyzed under acidic conditions to amino alcohols with retention of the configuration of the starting amino acid. This sequence of reactions allows to prepare derivatives of L -tyrosinol from (?)-L -tyrosine (see, e.g., Scheme 4). Cyanoenamino esters 11 are readily methylated at the N-atom to give N-methylated cyanoenamino esters (Scheme 3). This property is exploited on the way of a multistep procedure to obtain N-methylated amino alcohols homologous to natural (?)-(1R,2S)-ephedrine.     

Highly efficient microwave assisted α-trichlorination reaction of α-methylated nitrogen containing heterocycles

A new methodology permitting the chlorination of different α-methylated nitrogen containing heterocycles into N-α-trichloromethylated derivatives is described here. The combination of microwave technology with a PCl₅/POCl₃ protocol has allowed to reach trichloromethyl derivatives with high yields in a few minutes.     

Nitrofuranyl heterocycles. XIII N-methyl-3-methylthio-5-(5-nitro-2-furanyl)-1H-1,2,4-triazoles

A continuing search for new nitrofurans which might possess useful antimicrobial activity led to the synthesis of several 3-mercapto-5-(5-nitro-2-furanyl)-1H-1,2,4-triazoles and their methylated derivatives. This paper describes the preparation of these compounds together with proof of structure of the N-methylated products.     

Synthesis and properties of <Emphasis Type="Italic">N</Emphasis>-nitro-<Emphasis Type="Italic">O</Emphasis>-(4-nitrophenyl)hydroxylamine

Salts of N-nitro-O-(4-nitrophenyl)hydroxylamine were synthesized by a new method of oxidative nitration, involving the reaction of O-(4-nitrophenyl)hydroxylamine with KNO₂ or NaNO₂ in the presence of PhI(OAc)₂ or PhIO as oxidants. When using Na¹⁵NO₂, the samples containing the nitro group labeled with the ¹⁵N isotope were obtained. Acidification of the appropriate salt gave N-nitro-O-(4-nitrophenyl)hydroxylamine. It is the first N-nitrohydroxylamine isolated in the H-form. Its thermal stability was investigated and the probable mechanism of decomposition was suggested. From a comparison of the ¹⁴N and ¹⁵N NMR spectra of N-nitro-O-(4-nitrophenyl)hydroxylamine with those of its O- and N-methylated derivatives, its equilibrium with the aci-form (N=NOOH) was inferred.     

Spontaneous fragmentations of protonated benzaldimines mediated by intermediate ion-neutral complexes

4-Methoxymethylbenzaldimmonium ions (a) and the corresponding N-methylated ions (b) and N,N-dimethylated ions (c) were easily generated in the ion source by electron impact-induced dissociation from 1-(4-methoxymethylphenyl)ethylamine and its N-methylated derivatives. The spontaneous fragmentations of metastable ions a-c and of specifically deuterated derivatives in the second field-free region of a VG ZAB-2F mass spectrometer were studied by mass-analysed ion kinetic energy Spectrometry. The formation of an amino-p-quinodimethane radical cation by loss of the methoxy group is observed for all ions. In the case of a and b carrying at least one proton at the immonium group, competing fragmentations are the loss of CH₂O and CH₃OH, respectively, and the formation of ions CH₃OCH₂ ⁺, m/z 45, and C₇H₇ ⁺, m/z 91. Deuterium-labelling experiments indicated the migration of a proton from the protonated imino group of a and b to the aromatic ring followed by the loss of methanol from the methoxymethyl side-chain or protolysis of the bond to either side-chain to form ion-neutral complexes, in close analogy with the reactions of the corresponding protonated benzaldehydes. The intermediate ion-neutral complexes dissociate eventually by internal ion-neutral reactions resulting in the loss of CH₂ O and the formation of C₇H₇ ⁺, respectively.     

N- And S-Alkylation of 3-(1-Aadamantyl)-4-methyl-1,2,4-triazole-5-thiol and 2-(1-Adamantyl)-1,3,4-oxadiazole-5-thiol

ABSTRACT

-The reaction of 3-(1-adamantyl)-4-methyl-1,2,4-triazole-5-thiol 1 with certain 2-aminoethyl chlorides in alkaline medium yielded a separable mixture of the S-(2-aminoethyl) derivatives 2 and the N-(2-aminoethyl) derivatives 3. Meanwhile, alkylation of 2-(1-adamantyl)-1,3,4-oxadiazole-5-thiol 4 with 2-aminoethyl chlorides under the same conditions yielded only the S-alkyl derivatives 5. Interaction of 4 with primary or secondary amines and formaldehyde solution yielded the corresponding N-aminomethyl derivatives in high yields.     

Novel Cysteine Tags for the Sequencing of Non-Tryptic Disulfide Peptides of Anurans: ESI-MS Study of Fragmentation Efficiency

Mass spectrometry faces considerable difficulties in de novo sequencing of long non-tryptic peptides with S–S bonds. Long disulfide-containing peptides brevinins 1E and 2Ec from frog Rana ridibunda were reduced and alkylated with nine novel and three known derivatizing agents. Eight of the novel reagents are maleimide derivatives. Modified samples were subjected to MS/MS studies on FT-ICR and Orbitrap mass spectrometers using CAD/HCD or ECD/ETD techniques. Procedures, fragmentation patterns, and sequence coverage for two peptides modified with 12 tags are described. ECD/ETD and CAD fragmentation revealed complementary sequence information. Higher-energy collisionally activated dissociation (HCD) sufficiently enhanced y-ions formation for brevinin 1E, but not for brevinin 2Ec. Some novel tags [N-benzylmaleimide, N-(2,6-dimethylphenyl)maleimide] along with known N-phenylmaleimide and iodoacetic acid showed high total sequence coverage taking into account combined ETD and HCD fragmentation. Moreover, modification of long (34 residues) brevinin 2Ec with N-benzylmaleimide or N-(2,6-dimethylphenyl)maleimide yielded high sequence coverage and full C-terminal sequence determination with ECD alone.     

Synthesis of enantiopure (αMe)Dip and other α-methylated β-branched amino acid derivatives

This report describes the synthesis of the two enantiomerically pure α-methylated β-branched phenylalanine derivatives, (S)- and (R)-α-methyl-β,β-diphenylalanine—(αMe)Dip—starting from the chiral building blocks (R)- and (S)-N-Boc-N,O-isopropylidene-α-methylserine methyl esters, respectively. The key step involves a double alkylation with a Grignard reagent on an ester group. The use of the same protocol for the preparation of other α-methylated β-branched serine derivatives is also described.     

Massenspektrometrische Identifizierung und Synthese isomerer und homologer Spermidin- und Spermin-Derivate. 25. Mitteilung über das massenspektrometrische Verhalten von Stickstoffverbindungen. 161. Mitteilung über Alkaloide

Synthesis of isomeric and homologous spermidine and spermine derivatives and their identification by mass spectrometry. The structure of homologous and isomeric spermidines and spermines follows from mass-spectroscopical analysis of their peracetyl (see text, footnote 3) (Table 1) or tosyl-acetyl (Table 2) derivatives. In the case of the peracetyl compounds, triads of peaks are recorded which, according to the number of methylene groups between the nitrogen atoms, show mass numbers characteristic for each of the substances (Scheme 1, ions b , d , e and c ). On the basis of cyclic ions of type f (Scheme 2), occurring in the mass spectra of N-acetyl derivatives, tosylated on a secondary amino nitrogen atom, deductions can be drawn as to the number of methylene groups between neighbouring tosylated and acetylated nitrogen atoms in these compounds.     

Nouvelle Synthese de L'Acide 3-Desoxy-D-Erythro-2-Hexulosonique (KDG). A Partir De La D-Glucono-1,5-Lactone Synthese Et Etude De RMN De Derives O-Methyles Du KDG

ABSTRACT

3-Deoxy-D-erythro-2-hexulosonic acid (KDG), an important metabolite of bacterial polysaccharide degradation, was prepared from D-glucono-1,5-lactone through a six-step sequence, with a 45% overall yield. Using suitable intermediates. KDG methyl ester and its 5- and 6-O-methylated derivatives were also synthesized. ¹H and ¹³C NMR studies of 5- and 6-O-methylated derivatives (pyranoid and furanoid forms respectively) compared to those of KDG and its methyl ester allowed us to conclude that these two latter compounds exist in equilibrium as forms whose percentages were determined.     

Versatile Stereoselective Synthesis of Completely Protected Trifunctional α-Methylated α-Amino Acids Starting from Alanine

A new route to completely protected α-methylated α-amino acids starting from alanine is described (see Scheme). These derivatives, which are obtained via base-catalyzed opening of the oxazolidinones (2S,4R)- and (2R,4S)- 2 , can be directly employed in peptide synthesis. The synthesis of both enantiomers of Z-protected α-methylaspartic acid β-(tert-butyl)ester (O⁴-(tert-butyl) hydrogen 2-methylaspartates (R) or (S)- 4a ), α-methyl-glutamic acid γ-(tert-butyl) ester (O⁵-(tert-butyl) hydrogen 2-methylglutamate (R)- or (S)- 4b ), and of N^ε-bis-Boc-protected α-methyllysine (N⁶,N⁶-bis[(tert-butyloxy)carbonyl]-2-methyllysine (R)- or (S)- 4c ) is described in full detail.     

Zum Mechanismus massenspektrometrischer Fragmentierungsreaktionen: XII-Einfluß einer sterischen Hinderung der Mesomerie bei der Fragmentierung von N,N-Dimethyl-N′-4-Biphenylformamidinen

The formation of cyclic [M ? H]⁺ ions (a) in the mass spectra of N,N-dimethyl-N′-arylformamidines is suppressed by electron donating groups in the aryl group para to the formamidine group, due to the participation of resonance structures of type c. This effect is also observed in the mass spectra of N,N-dimethyl-N′-4-biphenylformamidines (III) substituted in the 4′-position. By substitution in the 2-, 2′-, 6- and 6′- positions of III, the formation of resonance structure c′ in the molecular ions is so difficult that these derivatives show the normal fragmentations. This is observed with two methyl groups in the 2- and 2′- positions of III.     

1,2-Fused pyrimidines. III. Derivatives of 12H-pyrido[1′,2′:1,2]pyrimido[4,5-b]quinoline,a novel heterocyclic system

Reactivities of 2-amino-4H-pyrido[1,2-a]pyrimidin-4-ones and 4-amino-2H-pyrido[1,2-a]pyrimidin-2-ones, both N,N-dialkyl and (N-alkyl, N-phenyl)substituted, when treated with the N,N-dimethylformamide/phosphorus oxychloride Vilsmeier-Haack reagent XII were compared. Starting from 2-[(N-alkyl, N-phenyl)amino] compounds IXa,b , the expected XVIa,b and XVIIa,b were obtained, which are derivatives of 12H-pyrido[1′,2′:1,2]pyrimido[4,5-b]quinoline, a novel heterocyclic system. When 2-(phenylamino) compound IXc was used a mixture of 3-formylderivative XVIII and 12H-pyrido-[1′,2′:1,2]pyrimido[4,5-b]quinolin-12-one ( XIX ) resulted from the reaction. On the other hand, 2-(dialkylamino)-4H-pyrido[1,2-a]pyrimidin-4-ones IIIa-c plainly afforded high yields of 3-formylderivatives XIVa-c. In contrast, no significant reaction occurred when 4-(dialkylamino) and 4-[(N-alkyl,N-phenyl)amino] compounds IIa-c and VIIIa,b were treated with the reagent XII , under the same as well as more severe conditions. A clear difference in the nucleophilic reactivity of C-3 position between these two classes of isomers is pointed out by the above summarized results.     

Synthesis and photochemical degradation of N-arylmethyl derivatives of the herbicide 3-amino-1,2,4-triazole

Reaction of an arylmethyl halide with 3-amino-1,2,4-triazole ( 1 ) allows the preparation of the three N-aryl-methyl derivatives of 1 bearing the substituent on the heterocyclic nitrogen atoms. In basic medium (methoxide anion in DMF or methanol, or in benzene by phase transfer catalysis), the isomers 3 and 5 substituted at N-1 and N-2 respectively are obtained, while the isomer 4 is isolated from neutral medium (DMF). The isomers 3 and 4 may be also prepared by cyclization of appropriate formylguanidinium derivatives. 3-Arylmethylamino-1,2,4-triazoles 2 may be obtained through reaction of 3-chloro-1,2,4-triazole ( 6 ) with arylmethylamines. Photolysis of the N-arylmethyl-3-amino-1,2,4-triazoles 2-5 in methanol or water-methanol mixture, induces homolytic and heterolytic cleavage of the arylmethyl-C-N bond giving rise to 3-amino-1,2,4-triazole ( 1 ). Thus, compounds 2-5 with arylmethyl groups able to absorb solar light may be considered as potential photoactivatable herbicides.     

Transition metal ion complexes of thiosemicarbazones derived from 2-acetylpyridineN-oxide. I. The 4-methyl derivative

Summary TheN-methyl-2-[1-(2-pyridinyl-1-oxide)ethylidene]hydrazinecarbothioamide, HLO4M, has been used to prepare a series of Co^III, Ni^II and Cu^II complexes. Species with two deprotonated LO4M ligands, one LO4M and one HLO4M ligand, two HLO4M ligands and one HLO4M ligand with two small anionic ligands have been isolated. The deprotonated LO4M bonds as a tridentate ligandvia theN-oxide oxygen, the imine nitrogen (N¹ and the sulphur while the HLO4M ligand coordinates primarily as a bidentate ligandvia only the first two atoms listed above. I.r., electronic, mass and e.s.r. spectra have been used to determine the nature of these complexes. One of the more striking differences between these compounds and those prepared with other thiosemicarbazones of 2-acetylpyridine and 2-acetylpyridineN-oxide is that tetrahedral yellow [Ni(HL)X₂] rather than planar brown [NiLX] (X=Cl or Br) solids have been isolated with this ligand. Other differences in the nature of the coordination spheres of the various metal ions occur with this particular ligand when compared to previously studied thiosemicarbazone complexes.NATO Fellow, on leave from Medical Faculty, Istanbul University.