Graphical Abstract: HCA 1/2003

The low solubility of pterins can drastically be improved by N²‐acylation or formation of the N²‐[(dimethylamino)methylene] derivatives. Both types of compounds can be alkylated under Mitsunobu conditions to form from N²‐acylpterins (see 2 and 3 ) and their derivatives (see 5, 6, 8, 9, 11, 13, 15 , and 17 ) selectively the O⁴‐alkyl derivatives 22 – 31 , whereas the electron‐donating [(dimethylamino)methyleneamino function in 46 – 51 gives, in a selective reaction, the N(3)‐substitution (→ 52 – 61 ). N²,N²‐Dimethylpterins and 18 and 19 and N²‐methylpterins 20 and 21 direct alkylation also to the O⁴‐position (→ 32 – 35, 38 and 39 ). Deacylation can be achieved under very mild conditions by solvolysis with MeOH ( 22 → 40, 26 → 41 ), and displacement of the O⁴‐[2‐(4‐nitrophenyl)ethyl] group proceeds with ammonia at room temperature to the corresponding pteridin‐2,4‐diamines 42 – 45 . Cleavage of the N²‐[(dimethylamino)methylene] group works well with ammonia (→ 62 – 67 ). The advantage of applying the 2‐(4‐nitrophenyl)ethyl (npe) group as blocking group is seen in its selective removal by 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) under aprotic conditions without harming the other substituents.     

Synthese von N-Methyl- und N,N-Dimethylmerucathin sowie von N-Methyl- und N,N-Dimethylpseudomerucathin aus L-Alanin

Synthesis of N-Methyl- and N,N-Dimethylmerucathine and of N-Methyl- and N,N--Dimethylpseudomerucathine Starting from L -Alanine Starting form L -alanine, N-methylmerucathine (= (3R,4S)-4-(methylamino)1-phenyl-1-penten-3-ol; (3R,4S,)- 6 ), N,N-dimethylmerucathine (= (3R,4S)-4-(dimethylamino)-1-phenyl-1-penten-3-ol; (3R,4S)- 9 ), N-methylpseudomerucathine (= (3S,4S)-4-(methylamino)-1-phenyl-1-penten-3-01; (3S,4S)-6), and N,N-dimethylpseudomerucathine (= (3S,4S)-4-(dimethylamino)-1-phenyl-1-penten-3-ol; (3S,4S)- 9 ) were synthesized. The four compounds were analyzed by HPLC and compared with a natural khat extract.     

Synthesis and activity of four (N,N‐dimethylamino)benzamide nonsteroidal anti‐inflammatory drugs based on thiazole and thiazoline

Four compounds derived from 2‐aminothiazole and 2‐amino‐2‐thiazoline were prepared by coupling the respective bases with the acid chlorides of either 3‐ or 4‐(N,N‐dimethylamino)benzoic acid. Products were identified using infrared spectroscopy, ¹H NMR spectroscopy and electrospray mass spectroscopy and in two cases by single‐crystal X‐ray diffraction. Of the four, N‐(thiazol‐2‐yl)‐3‐(N,N‐dimethylamino)‐benzamide (1), N‐(thiazolin‐2‐yl)‐4‐(N,N‐dimethylamino)benzamide (2), N‐(thiazolin‐2‐yl)‐3‐(N,N‐dimethylamino) benzamide (3) and N‐(thiazolin‐2‐yl)‐4‐(N,N‐dimethylamino)benzamide (4), the hydrochloride salts of compounds 3 and 4 showed anti‐inflammatory activity across a concentration range of 10^?2?5 × 10^?4 M while 3 (at a concentration of 10^?5 M) was found to have no adverse effect on myocardial function. The X‐ray crystal structure of 2 and the 1:1 adduct structure of 3 with 3‐(N,N‐dimethylamino)benzoic acid are reported.     

Ab initio Structure Determination of [(Dimethylamino)methylene]bis[phosphonic Acid] Dihydrate from X-Ray Powder Diffraction Data: Comparison with the Corresponding Monohydrate and Unhydrated Form

The structure of [(dimethylamino)methylene]bis[phosphonic acid] dihydrate (C₃H₁₁NO₆P₂⋅2 H₂O; 1 ) was solved ab initio from synchrotron powder X-ray diffraction data. The structure determination was based on direct methods combined with difference Fourier techniques, and the refinement was carried out using the Rietveld method. Using this high-quality diffraction pattern, it was possible to index a second phase which corresponds to the structure of the known [(dimethylamino)methylene]bis[phosphonic acid] monohydrate ( 2 ). [(Dimethylamino)methylene]bis[phosphonic acid] dihydrate ( 1 ) is monoclinic, space group P2₁/c, Z=4, with a=10.6644(1), b=9.1599(1), c=10.5213(1) Å, and β=98.353(1)°. The structure analysis indicates two non-equivalent P-atoms in the molecule of 1 which are also observed in the corresponding monohydrate 2 and unhydrated form 3 . All three compounds exhibit extended H-bonding networks which result in remarkably different ³¹P-NMR spectra. The [(dimethylamino)methylene]bis[phosphonic acids] 1 – 3 crystallize in the betaine-type structure which, therefore, contains two nonequivalent P-atoms. The −P(=O)(OH)₂ and −P(=O)(OH)O⁻ groups of 1 – 3 are involved in a number of strong H-bonds which can be characterized by the different ³¹P-NMR chemical shifts of the two P-atoms of 1 – 3 .     

New Cholinesterase‐Inhibiting Steroidal Alkaloids from Sarcococca saligna

Seven new steroidal alkaloids, 2‐hydroxysalignarine‐E (=(2′E,20S)‐20‐(dimethylamino)‐2β‐hydroxy‐3β‐(tigloylamino)pregn‐4‐ene; 1 ), 5,6‐dihydrosarconidine (=(20S)‐20‐(dimethylamino)‐3β‐(methylamino)‐5α‐pregn‐16‐ene; 2 ), salignamine (=(20S)‐20‐(methylamino)‐3β‐methoxypregna‐5,16‐diene; 3 ), 2‐hydroxysalignamine (=(20S)‐20‐(dimethylamino)‐2β‐hydroxy‐3β‐methoxypregna‐5,16‐diene; 4 ), salignarine‐F (=(2′E, 20S)‐20‐(dimethylamino)‐4β‐hydroxy‐3β‐(tigloylamino)pregn‐5‐ene; 5 ), salonine‐C (=(2′E,20S)‐20‐(dimethylamino)‐3β‐(tigloylamino)pregna‐4,14‐diene; 6 ), and N‐[formyl(methyl)amino]salonine‐B (=(20S)‐20‐[formyl(methyl)amino]‐3β‐methoxypregna‐5,16‐diene; 7 ) have been isolated from the MeOH extract of Sarcococca saligna, along with the six known alkaloids dictyophlebine ( 8 ), epipachysamine‐D ( 9 ), saracosine ( 10 ), iso‐N‐formylchonemorphine ( 11 ), sarcodinine ( 12 ), and alkaloid‐C ( 13 ). The structures of 1 – 7 were deduced from spectral data. Compounds 1 – 13 demonstrated significant activity against acetyl‐ and butyrylcholinesterase.     

Synthesis of Dispirocyclopentyl‐3,3′‐bisoxindoles via Domino Cycloaddition Reactions of 4‐Dimethylaminopyridinium Bromides with 3‐Phenacylideneoxindoles

The base mediated cycloaddition reactions of 4‐dimethylamino‐1‐phenacylpyridinium bromides with two molecular 3‐phenacylideneoxindoles in methylene dichloride afforded functionalized dispirocyclopentyl‐3,3′‐bisoxindoles in good yields and with high diastereoselectivity. The similar cycloaddition reactions of 1‐(N,N‐dialkylcarbamoylmethyl) and 1‐cyanomethyl 4‐dimethylamino‐pyridinium bromide in refluxing ethanol in the presence of triethylamine also resulted in dispirocyclopentyl‐3,3′‐bisoxindoles with high diastereoselectivity. The stereochemistry of dispirocyclopentyl‐3,3′‐bisoxindoles was elucidated on the basis of ¹H NMR data and single crystal structures.     

Barriers to rotation of the dimethylamino group in some 2-amino-4-(N,N-dimethylamino)pyrimidines

The free energy of activation for rotation about the exocyclic C? N bond of the dimethylamino group of some 6-substituted 2-amino-4-(N,N-dimethylamino)pyrmidines has been determined using ¹H NMR line shape analysis. The results are discussed in terms of the relative electron-withdrawing and electron-releasing effects of the substituents.     

Polar aspects of intramolecular interactions in 2‐amino‐5‐nitro‐4‐methylpyridines and 2‐amino‐3‐nitro‐4‐methylpyridines

The dipole moments of twelve 2‐N‐substituted amino‐5‐nitro‐4‐methylpyridines ( I‐XII ) and three 2‐N‐substituted amino‐3‐nitro‐4‐methylpyridines ( XIII‐XV ) were determined in benzene. The polar aspects of intramolecular charge‐transfer and intramolecular hydrogen bonding were discussed. The interaction dipole moments, μ_int, were calculated for 2‐N‐alkyl(or aryl)amino‐5‐nitro‐4‐methylpyridines. Increased alkylation of amino nitrogen brought about an intensified push‐pull interaction between the amino and nitro groups. The solvent effects on the dipole moments of 2‐N‐methylamino‐5‐nitro‐4‐methyl‐( I ), 2‐N,N‐dimethylamino‐5‐nitro‐4‐methyl‐ ( II ) and 2‐N‐methylamino‐3‐nitro‐4‐methylpyridines ( XIII ) were different. Specific hydrogen bond solute‐solvent interactions increased the charge‐transfer effect in I , but it did not disrupt the intramolecular hydrogen bond in XIII.     

Cocrystallization of two tautomers: 4‐(1‐{[4‐(dimethylamino)benzylidene]hydrazono}ethyl)benzene‐1,3‐diol and 6‐[(E)‐1‐{[4‐(dimethylamino)benzylidene]hydrazino}ethylidene]‐3‐hydroxycyclohexa‐2,4‐dien‐1‐one (1/1)

Two different tautomeric forms of a new Schiff base, C₁₇H₁₉N₃O₂·C₁₇H₁₉N₃O₂, are present in the crystal in a 1:1 ratio, namely the enol–imine form 4‐(1‐{[4‐(dimethylamino)benzylidene]hydrazono}ethyl)benzene‐1,3‐diol and the keto–amine form 6‐[(E)‐1‐{[4‐(dimethylamino)benzylidene]hydrazino}ethylidene]‐3‐hydroxycyclohexa‐2,4‐dien‐1‐one. The tautomers are formed by proton transfer between the hydroxy O atom and the imine N atom and are hydrogen bonded to each other to form a one‐dimensional zigzag chain along the crystallographic b axis via intermolecular hydrogen bonds.     

FeIII in a low‐spin state in caesium bis[3‐ethoxysalicylaldehyde 4‐methylthiosemicarbazonato(2–)‐κ3O2,N1,S]ferrate(III) methanol monosolvate

The synthesis and crystal structure (at 100 K) of the title compound, Cs[Fe(C₁₁H₁₃N₃O₂S₂)₂]·CH₃OH, is reported. The asymmetric unit consists of an octahedral [Fe^III(L)₂]⁻ fragment, where L²⁻ is 3‐ethoxysalicylaldehyde 4‐methylthiosemicarbazonate(2−) {systematic name: [2‐(3‐ethoxy‐2‐oxidobenzylidene)hydrazin‐1‐ylidene](methylamino)methanethiolate}, a caesium cation and a methanol solvent molecule. Each L²⁻ ligand binds through the thiolate S, the imine N and the phenolate O atoms as donors, resulting in an Fe^IIIS₂N₂O₂ chromophore. The O,N,S‐coordinating ligands are orientated in two perpendicular planes, with the O and S atoms in cis positions and the N atoms in trans positions. The Fe^III cation is in the low‐spin state at 100 K.     

A study concerning the synthesis,basicity and hydrolysis of 4‐amino‐2‐(N,N‐diethylamino)quinazoline derivatives

A group of 2‐(N,N‐diethylamino)‐4‐aminoquinazoline derivatives have been synthesized in the reaction of N¹,N¹‐diethyl‐N²‐arylchlorocarboxyamidines with cyanamide in the presence of T1Cl₄ as a catalyst. Such quinazolines decompose into the corresponding quinazolones in dilute aqueous HC1 solutions at higher temperature. Hydrolysis rates of 2‐(N,N‐diethylamino)‐4‐aminoquinazoline and 2‐(N,N‐diethylamino)‐4‐(N,N‐dimethylamino)‐quinazoline have been determined to observe the influence of substituents at the 4‐amino group upon the hydrolysis. pK_a values have been also determined for these compounds and analyzed in conjunction with the Hammett σ constants.     

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.     

3‐Cyano‐6‐hydroxy‐4‐methyl‐2‐pyridone: two new pseudopolymorphs and two cocrystals with products of an in situ nucleophilic aromatic substitution

Four crystal structures of 3‐cyano‐6‐hydroxy‐4‐methyl‐2‐pyridone (CMP), viz. the dimethyl sulfoxide monosolvate, C₇H₆N₂O₂·C₂H₆OS, (1), the N,N‐dimethylacetamide monosolvate, C₇H₆N₂O₂·C₄H₉NO, (2), a cocrystal with 2‐amino‐4‐dimethylamino‐6‐methylpyrimidine (as the salt 2‐amino‐4‐dimethylamino‐6‐methylpyrimidin‐1‐ium 5‐cyano‐4‐methyl‐6‐oxo‐1,6‐dihydropyridin‐2‐olate), C₇H₁₃N₄⁺·C₇H₅N₂O₂⁻, (3), and a cocrystal with N,N‐dimethylacetamide and 4,6‐diamino‐2‐dimethylamino‐1,3,5‐triazine [as the solvated salt 2,6‐diamino‐4‐dimethylamino‐1,3,5‐triazin‐1‐ium 5‐cyano‐4‐methyl‐6‐oxo‐1,6‐dihydropyridin‐2‐olate–N,N‐dimethylacetamide (1/1)], C₅H₁₁N₆⁺·C₇H₅N₂O₂⁻·C₄H₉NO, (4), are reported. Solvates (1) and (2) both contain the hydroxy group in a para position with respect to the cyano group of CMP, acting as a hydrogen‐bond donor and leading to rather similar packing motifs. In cocrystals (3) and (4), hydrolysis of the solvent molecules occurs and an in situ nucleophilic aromatic substitution of a Cl atom with a dimethylamino group has taken place. Within all four structures, an R₂²(8) N—H...O hydrogen‐bonding pattern is observed, connecting the CMP molecules, but the pattern differs depending on which O atom participates in the motif, either the ortho or para O atom with respect to the cyano group. Solvents and coformers are attached to these arrangements via single‐point O—H...O interactions in (1) and (2) or by additional R₄⁴(16) hydrogen‐bonding patterns in (3) and (4). Since the in situ nucleophilic aromatic substitution of the coformers occurs, the possible Watson–Crick C–G base‐pair‐like arrangement is inhibited, yet the cyano group of the CMP molecules participates in hydrogen bonds with their coformers, influencing the crystal packing to form chains.     

Proximity effects in the mass spectra of crowded bis(dimethylamino)arenes: Part II—Rearrangements of the molecular radical cations of ‘proton sponges’ by reciprocal methyl/hydrogen transfer

The EI induced fragmentation pathways of 4,5-bis(dimethylamino)fluorene, 4-(d₆-dimethylamino)-5-(dimethylamino)fluorene, 4,5-bis(d₆-dimethylamino)fluorene, 4-(dimethylamino)-5-methylaminofluorene, 4,5-bis-(methylamino)fluorene, 4-amino-5-methylaminofluorene, 1,8-bis(dimethylamino)naphthalene, 1,8-bis(d₆-dimethyl-amino)-naphthalene and 1,8-bis(dimethylamino)-2,7-dimethoxynaphthalene were investigated. A mechanism is pro-posed for the surprising elimination of CH₃? NH₂ from the molecular ion, followed by loss of C₂H₅·, C₂H₄ and CH₃CN and for the accompanying cyclizations to stable heterocyclic ions: prior to fragmentation the molecular radical ion rearranges to new, distonic radical ions by reciprocal H and CH₃ transfers between the adjacent dimethylamino groups. Each of these new, isomeric molecular ions decomposes subsequently in a characteristic way.     

Unimolecular reactions of the isolated immonium ions CH3CH = NH+C4H9, CH3CH2Ch = NH+C4H9 and (CH3)2C = NH+C4H9

The reactions of ten metastable immonium ions of general structure R¹R²C?NH⁺C₄H₉ (R¹ = H, R² = CH₃, C₂H₅; R¹ = R² = CH₃) are reported and discussed. Elimination of C₄H₈ is usually the dominant fragmentation pathway. This process gives rise to a Gaussian metastable peak; it is interpreted in terms of a mechanism involving ion-neutral complexes containing incipient butyl) cations. Metastable immonium ions ontaining an isobutyl group are unique in undergoing a minor amount of imine (R¹R²C?NH) loss. This decomposition route, which also produces a Gaussian metastable peak, decreases in importance as the basicity of the imine increases. The correlation between imine loss and the presence of an isobutyl group is rationalized by the rearrangement of the appropriate ion-neutral complexes in which there are isobutyl cations to the isomeric complexes containing the thermodynamically more stable tert-butyl cations. A sizeable amount of a third reaction, expulsion of C₃H₆, is observed for metastable n-C₄H₉ ⁺NH?CR¹R² ions; in contrast to C₄H₈ and R¹R²C?NH loss, C₃H₆ elimination occurs with a large kinetic energy release (40–48 kJ mol^?1) and is evidenced by a dish-topped metastable peak. This process is explained using a two-step mechanism involving a 1,5-hydride shift, followed by cleavage of the resultant secondary open-chain cations, CH₃CH⁺ CH₂CH₂NHCHR¹R².     

A one‐dimensional CdII coordination polymer constructed from 4‐(dimethylamino)pyridinium‐1‐acetate ligands and thiocyanate coordination bridges

A new cadmium–thiocyanate complex, namely catena‐poly[1‐carboxymethyl‐4‐(dimethylamino)pyridinium [cadmium(II)‐tri‐μ‐thiocyanato‐κ⁴N:S;κ²S:N] [[[4‐(dimethylamino)pyridinium‐1‐acetate‐κ²O,O′]cadmium(II)]‐di‐μ‐thiocyanato‐κ²N:S;κ²S:N]], {(C₉H₁₃N₂O₂)[Cd(NCS)₃][Cd(NCS)₂(C₉H₁₂N₂O₂)]}_n, was synthesized by the reaction of 4‐(dimethylamino)pyridinium‐1‐acetate, cadmium nitrate tetrahydrate and potassium thiocyanide in aqueous solution. In the crystal structure, two types of Cd^II atoms are observed in distorted octahedral coordination environments. One type of Cd^II atom is coordinated by two O atoms from the carboxylate group of the 4‐(dimethylamino)pyridinium‐1‐acetate ligand and by two N atoms and two S atoms from four different thiocyanate ligands, while the second type of Cd^II atom is coordinated by three N atoms and three S atoms from six different thiocyanate ligands. Neighbouring Cd^II atoms are linked by thiocyanate bridges to form a one‐dimensional zigzag chain and a one‐dimensional coordination polymer. Hydrogen‐bond interactions are involved in the formation of the supramolecular network.     

Synthesis,characterization and crystal structures of the bidentate Schiff base N,N′‐bis(2‐nitrocinnamaldehyde)ethylenediamine and its complex with CuNCS and triphenylphosphane

Reaction of copper(I) thiocyanate and triphenylphosphane with the bidentate Schiff base N,N′‐bis(trans‐2‐nitrocinnamaldehyde)ethylenediamine {Nca₂en, (1); systematic name (1E,1′E,2E,2′E)‐N,N′‐(ethane‐1,2‐diyl)bis[3‐(2‐nitrophenyl)prop‐2‐en‐1‐imine]}, C₂₀H₁₈N₄O₄, in a 1:1:1 molar ratio in acetonitrile resulted in the formation of the complex {(1E,1′E,2E,2′E)‐N,N′‐(ethane‐1,2‐diyl)bis[3‐(2‐nitrophenyl)prop‐2‐en‐1‐imine]‐κ²N,N′}(thiocyanato‐κN)(triphenylphosphane‐κP)copper(I)], [Cu(NCS)(C₂₀H₁₈N₄O₄)(C₁₈H₁₅P)] or [Cu(NCS)(Nca₂en)(PPh₃)], (2). The Schiff base and copper(I) complex have been characterized by elemental analyses, IR, electronic and ¹H NMR spectroscopy, and X‐ray crystallography [from synchrotron data for (1)]. The molecule of (1) lies on a crystallographic inversion centre, with a trans conformation for the ethylenediamine unit, and displays significant twists from coplanarity of its nitro group, aromatic ring, conjugated chain and especially ethylenediamine segments. It acts as a bidentate ligand coordinating via the imine N atoms to the Cu^I atom in complex (2), in which the ethylenediamine unit necessarily adopts a somewhat flattened gauche conformation, resulting in a rather bowed shape overall for the ligand. The NCS⁻ ligand is coordinated through its N atom. The geometry around the Cu^I atom is distorted tetrahedral, with a small N—Cu—N bite angle of 81.56 (12)° and an enlarged opposite angle of 117.29 (9)° for SCN—Cu—P. Comparisons are made with the analogous Schiff base having no nitro substituents and with metal complexes of both ligands.     

Mechanistic study of the decomposition reactions of azobenzene

The electron impact-induced fragmentation of azobenzenes and its d₁, d₂, d₅, d₁₀, and ¹⁵N analogues was studied by mass Spectrometry and ion kinetic energy spectroscopy. The main fragment ions found in the mass spectrum of azobenzene are due to two parallel stepwise processes from the molecular ion: the expulsion of N₂ and two hydrogen radicals producing an ion at m/z 152 having possibly a biphenylene radical cation structure and loss of C₆H₅? and N₂. Except in the elimination of two hydrogen atoms from [M ? N₂]^+· ions, hydrogen scrambling between the phenyl rings does not feature in azobenzene upon electron impact.     

Hindered rotation of the dimethylamino and dimethylthioamide groups in two ortho substituted N,N-dimethylthiobenzamides

Hindered rotation in two o-substituted N,N-dimethylthiobenzamides was investigated by variable temperature ¹H NMR spectroscopy. For one compound, the enthalpies and entropies of activation for (i) thioamide group rotation around the Ar? C bond and (ii) dimethylamino group rotation around the C? N bond were obtained by full line shape analysis; a possible coupling between the two processes is discussed. A new simple method has also been applied to the analysis of dimethylamino exchange and results are in complete agreement with the full line shape analysis with somewhat better precision.     

Syntheses and evaluation of fluorinated benzothiazole anilines as potential tracers for β-amyloid plaques in Alzheimer's disease

[¹¹C]2-(4′-(Methylamino)phenyl)-6-hydroxybenzothiazole ([¹¹C]PIB) is a most potential PET tracer for detecting the β-amyloid plaques in Alzheimer's disease. Here the syntheses of three fluorinated PIB, namely 2-(4′-(methylamino)phenyl)-6-fluoroethoxybenzothiazole (O-FEt-PIB), 2-(4′-(methylamino)phenyl)-6-fluoro-benzothiazole (F-N-Me) and 2-(4′-(dimethylamino)phenyl)-6-fluorobenzo-thiazole (F-N,N-Me), and the radiosynthesis of one corresponding ¹⁸F-labeled PIB compound, [¹⁸F]O-FEt-PIB, as well as their in vitro/in vivo biological characters were reported. The structures of the products were confirmed by IR, ¹H NMR, EI/ESI-MS, elemental analysis and HRMS techniques. The radiolabeled product was characterized by radio-TLC and radio-HPLC and purified by semi-preparative radio-HPLC. The suitable biological characters showed these tracers were potential to be developed as probes for detecting β-amyloid plaques in Alzheimer's disease.