Synthesis and Characterization of Enantiomerically Pure cis‐ and trans‐3‐Fluoro‐2,4‐dioxa‐9‐aza‐3‐phosphadecalin 3‐Oxides as Acetylcholine Mimetics and Inhibitors of Acetylcholinesterase

The title compounds, the P(3)‐axially and P(3)‐equatorially substituted cis‐ and trans‐configured 9‐benzyl‐3‐fluoro‐2,4‐dioxa‐9‐aza‐3‐phosphadecalin 3‐oxides (=9‐benzyl‐3‐fluoro‐2,4‐dioxa‐9‐aza‐3‐phosphabicyclo[4.4.0]decane 3‐oxides=7‐benzyl‐2‐fluorohexahydro‐4H‐1,3,2‐dioxaphosphorino[4,5‐c]pyridine 2‐oxides) were prepared (ee >99%) and fully characterized (Schemes 2 and 4). The absolute configurations were deduced from that of their precursors, the enantiomerically pure ethyl 1‐benzyl‐3‐hydroxypiperidine‐4‐carboxylates and 1‐benzyl‐3‐hydroxypiperidine‐4‐methanols which were unambiguously assigned. Being configuratively fixed and conformationally constrained phosphorus analogues of acetylcholine, the title compounds represent acetylcholine mimetics and are suitable probes for the investigation of molecular interactions with acetylcholinesterase. As determined by kinetic methods, all of the compounds are moderate irreversible inhibitors of the enzyme.     

Synthesis and Characterization of Enantiomerically Pure cis‐ and trans‐3‐Fluoro‐2,4‐dioxa‐7‐aza‐3‐phosphadecalin 3‐Oxides as Acetylcholine Mimetics and Inhibitors of Acetylcholinesterase

The title compounds, the P(3)‐axially and P(3)‐equatorially substituted cis‐ and trans‐configured 7‐benzyl‐3‐fluoro‐2,4‐dioxa‐7‐aza‐3‐phosphadecalin 3‐oxides (=7‐benzyl‐3‐fluoro‐2,4‐dioxa‐7‐aza‐3‐phosphabicyclo[4.4.0]decane 3‐oxides=5‐benzyl‐2‐fluorohexahydro‐4H‐1,3,2‐dioxaphosphorino[5,4‐b]pyridine 2‐oxides) were prepared (ee>99%) and fully characterized (Schemes 2 and 4). The absolute configurations were established from that of their precursors, the enantiomerically pure cis‐ and trans‐1‐benzyl‐3‐hydroxypiperidine‐2‐methanols which were unambiguously assigned. Being configuratively fixed and conformationally constrained phosphorus analogues of acetylcholine, they mimic rotamers of acetylcholine and are suitable probes for the investigation of molecular interactions with acetylcholinesterase. As determined by kinetic methods, the compounds are irreversible inhibitors of the enzyme displaying significant stereoselectivity.     

3‐Fluoro‐2,4‐dioxa‐7‐aza‐3‐phosphadecalin 3‐Oxides as Rigid Acetylcholine Mimetics: Conformational Analysis and Direct Evidence of the Anomeric Effect

Conformational analyses of the P(3)‐axially and P(3)‐equatorially F‐substituted (±)‐cis‐ and (±)‐trans‐2,4‐dioxa‐7‐aza‐3‐phosphadecalin 3‐oxides (3‐fluoro‐2,4‐dioxa‐7‐aza‐3‐phosphabicyclo[4.4.0]decane 3‐oxides) were performed. The results are based on independent studies in both solution and the solid state by ¹H‐ and ³¹P‐NMR experiments and computational and X‐ray crystallographic data. As expected, the axial epimers adopt neat double‐chair conformations in solution and in the crystal. Due to the anomeric effect of the electron withdrawing F‐substituent, the 2,4‐dioxa‐3‐phospha moiety in the equatorial epimers adopts a mixture of conformations in solution, mainly chair and twist‐boat; whereas a neat twist‐boat (trans‐isomer) and the unusual envelope conformation (cis‐isomer) were detected in the solid state. This is the first report of a straight visualization of these conformations and the impact of the anomeric effect in such systems.     

Synthesis and Characterization of Enantiomerically Pure cis‐ and trans‐3‐Fluoro‐2,4‐dioxa‐8‐aza‐3‐phosphadecalin 3‐Oxides as γ‐Homoacetylcholine Mimetics and Inhibitors of Acetylcholinesterase

The title compounds, the P(3)‐axially and P(3)‐equatorially substituted cis‐ and trans‐configured 8‐benzyl‐3‐fluoro‐2,4‐dioxa‐8‐aza‐3‐phosphadecalin 3‐oxides (=8‐benzyl‐3‐fluoro‐2,4‐dioxa‐8‐aza‐3‐phosphabicyclo[4.4.0]decane 3‐oxides=2‐fluorohexahydro‐6‐(phenylmethyl)‐4H‐1,3,2‐dioxaphosphorino[5,4‐c]pyridine 2‐oxides) were prepared (ee>98%) and fully characterized (Schemes 2 and 3). The absolute configurations were established from that of their precursors, the enantiomerically pure cis‐ and trans‐1‐benzyl‐4‐hydroxypiperidine‐3‐methanols which were unambiguously assigned. Being configuratively fixed and conformationally constrained phosphorus analogues of acetyl γ‐homocholine (=3‐(acetyloxy)‐N,N,N‐trimethylpropan‐1‐aminium), they are suitable probes for the investigation of molecular interactions with acetylcholinesterase. As determined by kinetic methods, all of the compounds are weak inhibitors of the enzyme.     

Synthesis of Enantiomerically Pure 1,5,5‐Trideuterated cis‐ and trans‐2,4‐Dioxa‐3‐phosphadecalins. 31P‐NMR Evidence of Covalent‐Bond Formation and the Stereochemical Implications in the Course of the Inhibition of δ‐Chymotrypsin

The irreversible inhibition of δ‐chymotrypsin with the enantiomerically pure, P(3)‐axially and P(3)‐equatorially X‐substituted cis‐ and trans‐configurated 2,4‐dioxa‐3‐phospha(1,5,5‐²H₃)bicyclo[4.4.0]decane 3‐oxides (X=F, 2,4‐dinitrophenoxy) was monitored by ³¹P‐NMR spectroscopy. ¹H‐Correlated ³¹P{²H}‐NMR spectra enabled the direct observation of the vicinal coupling (³J) between the P‐atom of the inhibitor and the CH₂O moiety of Ser¹⁹⁵ (=‘Ser¹⁹⁵’(CH₂O)), thus establishing the covalent nature of the ‘Ser¹⁹⁵’(CH₂O? P) bond in the inhibited enzyme. The stereochemical course of the phosphorylation is dependent on the structure of the inhibitor, and neat inversion, both inversion and retention, as well as neat retention of the configuration at the P‐atom was found.     

Covalent‐Bond Formation in the Course of the Inhibition of δ‐Chymotrypsin with trans‐Decalin‐Type Organophosphates: 31P‐NMR Evidence

Earlier investigations have shown that the irreversible inhibition of δ‐chymotrypsin with the axially substituted trans‐3‐(2,4‐dinitrophenoxy)‐2,4‐dioxa‐3λ⁵‐phosphabicyclo[4.4.0]decan‐3‐one (=2‐(2,4‐dinitrophenoxy)hexahydro‐4H‐1,3,2‐benzodioxaphosphorin 2‐oxide) proceeds under inversion of the configuration at the P‐atom. Since this assignment is based on the comparison of the respective chemical shifts with model compounds, the covalent nature of the binding interaction between enzyme and inhibitor was formulated in analogy. To prove this assumption, inhibition experiments were performed with the deuterated inhibitor (±)‐trans‐3‐(2,4‐dinitrophenoxy)‐2,4‐dioxa‐3λ⁵‐phospha(1,5,5‐²H₃)bicyclo[4.4.0]decan‐3‐one ((±)‐ 6a ). ³¹P{²H}‐NMR‐Spectroscopic monitoring of the reaction of stoichiometric amounts of the enzyme with (±)‐ 6a at pH 7.8 yielded the diastereoisomeric adducts 9 (−3.88 ppm) and 9′ (−3.96 ppm). Comparing the ³¹P chemical shifts of the corresponding deuterated covalent phosphoserine model compounds 8a/8a′ (−6.70 ppm, axial) and 8b/8b′ (−4.11/−4.13 ppm, equatorial) confirmed the inversion of the configuration at the P‐atom. ¹H‐Correlated ³¹P{²H}‐NMR spectra revealed a cross peak of the Ser¹⁹⁵‐H₂ (4.45 ppm) with the P‐atom of the inhibitor at −3.88/−3.96 ppm, thus establishing the covalent nature of the Ser¹⁹⁵−O−P bond.     

Synthesis of 7‐aza‐5,8,10‐trideazafolic acid and its 4‐amino‐derivative as potential antifolates

o‐Aminoamide 8 , an intermediate in our multistep synthesisof the title compounds was prepared from 1,3‐diketone 3 . The following condensation of 8 with chloroformamidine‐HCl ( 9 ) gave pyrido[3,4‐d]pyrimidine 10 . Dehydratisation of amide 8 led to o‐aminonitrile 15 , which was cyclocondensated with guanidine ( 16 ) to yield pyrido[3,4‐d]pyrimidine‐2,4‐diamine 17 . Coupling of the acids 11 and 18 with diethyl L‐glutamate ( 12 ) and following saponification provided 7‐aza‐5,8,10‐trideazafolic acid 14 and its 4‐amino‐derivative 20 .     

Synthesis of 2,2,5,5‐Tetrasubstituted 1,4‐Dioxa‐2,5‐disilacyclohexanes via Organotin(IV)‐Catalyzed Transesterification of (Acetoxymethyl)alkoxysilanes

(Acetoxymethyl)silanes 2 , 7 a – c , and 10 a – c with at least one alkoxy group, of the general formula (AcOCH₂)Si(OR)_3?n(CH₃)_n (R: Me, Et, iPr; n=0, 1, 2), were synthesized from the corresponding (chloromethyl)silanes 1 , 6 a – c , and 9 a – c by treatment with potassium acetate under phase‐transfer‐catalysis conditions. These compounds were found to provide 2,2,5,5‐organo‐substituted 1,4‐dioxa‐2,5‐disilacyclohexanes 3 , 8 a – c , and 11 a – c if treated with organotin(IV) catalysts such as dioctyltin oxide. The reaction proceeds through transesterification of the acetoxy and alkoxy units followed by ring‐closure to form a dimeric six‐membered ring. The corresponding alkyl acetates are formed as the reaction by‐products. With these mild conditions, the method overcomes the drawbacks of previously reported synthetic routes to furnish 2,2,5,5‐tetramethyl‐1,4‐dioxa‐2,5‐disilacyclohexane ( 3 ) and even allows the synthesis of 1,4‐dioxa‐2,5‐disilacyclohexanes bearing hydrolytically labile alkoxy substituents at the silicon atom in good yields and high purity. These new materials were fully characterized by NMR spectroscopy, elemental analysis, mass spectrometry, and X‐ray analysis (trans‐ 8 a ).     

Synthesis of Bis{(S‐methyl)azolespoly(ethylene oxide)} from 3,6‐dioxa‐1,8‐octanedithiol

Bis(1,3,4‐oxadiazoles) 4 , 5 and bis(1,2,4‐triazoles) 6a , 6b have been prepared from 3,6‐dioxa‐1,8‐octanedithiol 1 through a multistep reaction sequence. Compound 4 reacted with the appropriate alkyl halide in the presence of potassium carbonate in refluxing acetone to give the corresponding bis(S‐alkylated‐1,3,4‐oxadiazoles) 7a , 7b . The title compound 8 was prepared by condensing 4 with benzoyl bromide in the presence of triethylamine. Further, 6,9‐dioxa‐3,12‐dithiotetradecanedihydrazide 3 was converted to bis{N′‐(phenylaminocarbonyl) hydrazides} and bis{N′‐(phenylaminocarbonothioyl)hydrazides} 9a , 9b using phenylisocyanate and phenylthioisocyanate, respectively, which underwent cyclization in alkaline medium to produce 6,9‐dioxa‐3,12‐dithiotetradecane bis(4‐phenyl‐2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐one) and their 3‐thio analogs 10a , 10b . The new compounds 4 , 5 , 6 , 7 , 8 , 9 , 10 were characterized by their IR, ¹H‐NMR, ¹³C‐NMR, MS, and elemental analyses.     

7‐Iodo‐5‐aza‐7‐deazaguanine: Syntheses of Anomeric D‐ and L‐Configured 2‐Deoxyribonucleosides

Iodination of N²‐isobutyryl‐5‐aza‐7‐deazaguanine ( 7 ) with N‐iodosuccinimide (NIS) gave 7‐iodo‐N²‐isobutyryl‐5‐aza‐7‐deazaguanine ( 8 ) in a regioselective reaction (Scheme 1). Nucleobase‐anion glycosylation of 8 with 2‐deoxy‐3,5‐di‐O‐toluoyl‐α‐D ‐ or α‐L ‐erythro‐pentofuranosyl chloride furnished anomeric mixtures of D ‐ and L ‐nucleosides. The anomeric D ‐nucleosides were separated by crystallization to give the α‐D ‐anomer and β‐D ‐anomer with excellent optical purity. Deprotection gave the 7‐iodo‐5‐aza‐7‐deazaguanine 2′‐deoxyribonucleosides 3 (β‐D ; ≥99% de) and 4 (α‐D ; ≥99% de). The reaction sequence performed with the D ‐series was also applied to L ‐nucleosides to furnish compounds 5 (β‐L ; ≥99% de) and 6 (α‐L ; ≥95% de).     

Reaction of 3‐Hydroxyquinoline‐2,4‐diones with Isocyanates and Thermally Induced Transformation of the Reaction Products

3‐Hydroxyquinoline‐2,4‐diones 1 react with isocyanates to give novel 1,2,3,4‐tetrahydro‐2,4‐dioxoquinolin‐3‐yl (alkyl/aryl)carbamates 2 and/or 1,9b‐dihydro‐9b‐hydroxyoxazolo[5,4‐c]quinoline‐2,4(3aH,5H)‐diones 3 . Both of these compounds are converted, by boiling in cyclohexylbenzene solution in the presence of Ph₃P or 4‐(dimethylamino)pyridine, to give 3‐(acyloxy)‐1,3‐dihydro‐2H‐indol‐2‐ones 8 . All compounds were characterized by IR, and ¹H‐ and ¹³C‐NMR spectroscopy, as well as by EI mass spectrometry.     

Reaction of 3‐aminoquinoline‐2,4‐diones with isocyanates. Synthesis of novel 3‐(3′‐alkyl/arylureido)quinoline‐2,4‐diones and their cyclic carbinolamide isomers

3‐Alkyl/aryl‐3‐amino‐1H,3H‐quinoline‐2,4‐diones react with alkyl/aryl isocyanates to give novel 3‐alkyl/aryl‐3‐ureido‐1H,3H‐quinoline‐2,4‐diones or 3a‐alkyl/aryl‐9b‐hydroxy‐3,3a,5,9b‐tetrahydro‐1H‐imidazo[4,5‐c]quinoline‐2,4‐diones. In some cases, a mixture of both products was obtained and separated by fractional crystallization. All compounds were characterized by their ¹H, ¹³C, ir and ms data and some of them also by ¹⁵N nmr data.     

Synthesis and stereochemistry of 3‐acetyl‐5‐aminospiro[1,3,4‐thiadiazoline‐2,4′‐thioflavans]

Under acetylating conditions racemic thioflavanone thiosemicarbazones cyclize into racemic 3‐acetyl‐spiro[1,3,4‐thiadiazoline‐2,4′‐thioflavans] and a racemic 3‐acetylspiro[1,3,4‐oxadiazoline‐2,4′‐thioflavan] with trans O(1) or S(1) and Ph(2′_eq). Hindered rotation of the endocyclic N(3) acetyl group spirothia‐diazolines caused the formation of isomers separable by HPLC. X‐ray diffraction analyses, ¹H‐, ¹³C‐, and ¹⁵N NMR measurements as well as MOPAC QM calculations were performed to reveal the structures of these isomers.     

Energetic Materials Based on the 5‐Azido‐3‐nitro‐1, 2,4‐tri­azolate Anion

This study presents the preparation of 5‐azido‐3‐nitro‐1H‐1, 2,4‐triazole ( 1 ) in both good yield and high purity, starting from commercially available chemicals in a three step synthesis. Furthermore, several metal and nitrogen‐rich salts with sodium ( 3 ), potassium ( 4 ), cesium ( 5 ), silver ( 6 ), lead ( 7 ), ammonium ( 8 ), guanidinium ( 9 ), and aminoguanidinium ( 10 ) were prepared by simple acid‐base reactions. All compounds were well characterized by various means, including vibrational (IR, Raman) and multinuclear (¹H, ¹³C, ¹⁴N, ¹⁵N) NMR spectroscopy, mass spectrometry, and DSC. Additionally the structure of 7 was determined by single‐crystal X‐ray diffraction. The sensitivities towards various outer stimuli (impact, friction, electrostatic discharge) were determined according to BAM standards. The metal salts were tested as potential primary explosives utilizing various preliminary tests.     

Novel azaandrostane derivatives for the synthesis of 17β‐(N‐tert‐butyl carbamoyl)‐4‐aza‐5α‐androst‐1‐ene‐3‐one

A new industrially viable process for the preparation of 1β‐(N‐tert‐butyl carbamoyl)‐4‐aza‐5α‐androst‐1‐ene‐3‐one, also known by the generic name finasteride ( 6 ) from the new azaandrostane derivatives such as 1β‐(N‐tert‐butyl carbamoyl)‐4‐benzoyl‐4‐aza‐5α‐androstane‐3‐one ( 4 ), 1β‐(N‐tert‐butyl carbamoyl)‐4‐benzoyl‐4‐aza‐5α‐androst‐1‐ene‐3‐one ( 5 ) is reported. In this process, benzoyl group is demonstrated as a novel protecting group for lactamic NH group. The structures of newly prepared compounds were established on the basis of spectral data (IR, ¹H‐NMR, and MS).     

Synthesis of 2‐formyl‐1‐aza‐dibenzo[e,h]azulenes

Synthesis of a novel heterocyclic class of compounds, 1‐aza‐dibenzo[e,h]azulenes [1] ( 6a‐c and 7a‐c ), derived from dibenzo[b,f]oxepin, its 8‐chloro analogue and dibenzo[b,f]thiepin, respectively, is described. Aldol condensation of the starting ketones 4a‐c with (dimethyl‐hydrazono)‐acetaldehyde affords hydrazonoethylidene derivatives 5a‐c , which on reduction with sodium dithionite and subsequent cyclization provide the target tetracyclic 1‐aza‐dibenzo[e,h]azulenes 6a‐c . Regiospecific formylation of 6a‐c with Vilsmeier reagent leads to 2‐formyl derivatives 7a‐c . A series of derivatives 6a‐c and 7a‐c was tested for antiinflammatory activity as potential inhibitors of tumor necrosis factor alpha (TNF‐α) production in vitro.     

Synthesis,Molecular Structure and Coordination Chemistry of the First 1‐Aza‐3,7‐diphosphacyclooctanes

The first representatives of a novel type of cyclic bis‐phosphines, namely, 1‐aza‐3,7‐diphosphacyclooctanes ( 4 , 5 ), were synthesized by condensation of 1,3‐bis(arylphosphino)propanes ( 2 , 3 ; aryl = phenyl or mesityl), formaldehyde and 5‐aminoisophthalic acid. Only the meso isomers were obtained, in good to satisfactory yield. The cyclic bis‐phosphines readily form P,P chelate complexes ( 6 , 7 ) with [PtCl₂(cod)] (cod = 1,5‐cyclooctadiene). The bisphosphine 4 and the corresponding complex 6 are soluble in water in the presence of two equivalents of alkali metal hydroxide. The molecular structures of 1‐(meta‐dicarboxyphenyl)‐3,7‐dimesityl‐1‐aza‐3,7‐diphosphacyclooctanes ( 5 ) and cis‐{P,P‐1‐(meta‐dicarboxyphenyl)‐3,7‐diphenyl‐1‐aza‐3,7‐diphosphacyclooctane}dichloroplatinum(II) ( 6 ) are reported.     

Synthesis and Structure of 2‐Substituted Thieno[3′,2′:5,6]pyrido[4,3‐d]pyrimidin‐4(3H)‐one Derivatives

A series of new 2‐substituted 3‐(4‐chlorophenyl)‐5,8,9‐trimethylthieno[3′,2′: 5,6]pyrido[4,3‐d]pyrimidin‐4(3H)‐ones 8 were synthesized via an aza‐Wittig reaction. Phosphoranylideneamino derivatives 6a or 6b reacted with 4‐chlorophenyl isocyanate to give carbodiimide derivatives 7a or 7b , respectively, which were further treated with amines or phenols to give compounds 8 in the presence of a catalytic amount of EtONa or K₂CO₃. The structure of 2‐(4‐chlorophenoxy)‐3‐(4‐chlorophenyl)‐5,8,9‐trimethylthieno[3′,2′: 5,6]pyrido[4,3‐d]pyrimidin‐4(3H)‐one ( 8j ) was comfirmed by X‐ray analysis.     

New isomeric N‐substituted hydrazones of 2‐, 3‐ and 4‐pyridinecarboxaldehydes and methyl‐3‐pyridylketone

Twelve compounds unknown in the literature N‐(E)‐2‐stilbenyloxymethylenecarbonyl substituted hydrazones of 2‐, 3‐ and 4‐pyridinecarboxaldehydes, as well as methyl‐3‐pyridylketone have been prepared. The stereochemical behavior of these compounds in dimethyl‐d₆ sulfoxide solution has been studied by ¹H NMR technique. The E geometrical isomers and cis/trans amide conformers have been found for N‐substituted hydrazones 1–12. EI induced mass spectral fragmentation of these compounds were also investigated. The data obtained create the basis for distinguishing isomers.