尼达尼布的合成新方法

以N-甲基-4-硝基苯胺作为起始原料,依次经氯乙酰化、取代及氢化还原反应制得关键中间体N-(4-氨基苯基)-甲基-2-(4-甲基-1-哌嗪基)乙酰胺（4）;以4-氯-3-硝基苯甲酸为原料,依次经酯化、取代、氢化还原及环合反应制得6-甲氧羰基-2-吲哚酮（8）; 8与原苯甲酸三乙酯和乙酸酐经“一锅煮”反应制得中间体1-乙酰基-3-甲氧基(苯基)亚甲烯基-2-氧代吲哚环-6-羧酸甲酯（9）; 4和9进行取代反应的同时脱除保护,经“一锅煮”反应合成尼达尼布,总收率57.2%,其结构经¹H NMR,¹³C NMR和MS(ESI)确证。     

Formation of transient intermediates in low-temperature photosensitized oxidation of an 8-(13)C-guanosine derivative

An 8-(13)C-labeled guanosine derivative, 2',3',5'-O-tert-butyldimethylsilyl-N-tert-butyldimethylsilyl-8-(13)C-guanosine, was synthesized and its photosensitized oxidation with singlet oxygen carried out below -100 degrees C. Two transient intermediates that decompose directly to the final major product 5 and CO(2) were detected by (13)C NMR between -100 and -43 degrees C. The two intermediates are carbamic acids based on (13)C NMR and 2D NMR (HMQC, HMBC) spectra and the formation of final product 5 and of 8-CO(2). No endoperoxide intermediate could be detected by low-temperature NMR spectroscopy even at -100 degrees C. A reaction mechanism is proposed involving initial [4 + 2] cycloaddition of singlet oxygen to the imidazole ring to form an unstable endoperoxide, subsequent rearrangement of the endoperoxide to a dioxirane, and decomposition of the dioxirane to the two observed intermediates. Both oxygen atoms of CO(2) are derived from a single oxygen molecule, which strongly supports a dioxirane structure for the precursor of the two observed intermediates. The distribution of products estimated by (13)C NMR accounts for all the (13)C-containing products in the reaction mixture.     

Structure and synthesis of 6-(substituted-imidazol-1-yl)purines: versatile substrates for regiospecific alkylation and glycosylation at N9

X-ray crystal structures of several 6-(azolyl)purine base and nucleoside derivatives show essentially coplanar conformations of the purine and appended 6-(azolyl) rings. However, the planes of the purine and imidazole rings are twisted approximately 57 degrees in a 2-chloro-6-(4,5-diphenylimidazol-1-yl)purine nucleoside, and a twist angle of approximately 61 degrees was measured between the planes of the purine and pyrrole rings in the structure of a 6-(2,5-dimethylpyrrol-1-yl)purine nucleoside derivative. Shielding "above" N7 of the purine ring by a proximal C-H on the 6-azolyl moiety is apparent with the coplanar compounds, but this effect is diminished in those without coplanarity. Syntheses of 6-(azolyl)purines from both base and nucleoside starting materials are described. Treatment of 2,6-dichloropurine with imidazole gave 2-chloro-6-(imidazol-1-yl)purine. Modified Appel reactions at C6 of trityl-protected hypoxanthine and guanine derivatives followed by detritylation gave 6-(imidazol-1-yl)- and 2-amino-6-(imidazol-1-yl)purines. Imidazole was introduced at C6 of 2',3',5'-tri-O-acetylinosine by a modified Appel reaction, and solvolysis of the glycosyl linkage gave 6-(imidazol-1-yl)purine. Guanosine triacetate was transformed into the protected 2,6-dichloropurine nucleoside, which was subjected to S(N)Ar displacement with imidazoles at C6 followed by glycosyl solvolysis to provide 2-chloro-6-(substituted-imidazol-1-yl)purines. Potential applications of these purine derivatives are outlined.     

Use of 13C as an indirect tag in 15N specifically labeled nucleosides. Syntheses of [8-13C-1,7,NH2-15N3]adenosine, -guanosine, and their deoxy analogues

We have previously reported the use of a 13C tag at the C2 of 15N-multilabeled purine nucleosides to distinguish the adjacent-labeled 15N atoms from those in an untagged nucleoside. We now introduce the use of an indirect tag at the C8 of 15N7-labeled purine nucleosides. This tag allows unambiguous differentiation between a pair of 15N7-labeled purines in which only one is 13C8 labeled. Although the very small C8-N7 coupling (<1 Hz) precludes its direct detection in 1D 15N spectra, 2D 1H-15N NMR experiments display the large C8-H8 coupling (>200 Hz) because H8 is coupled to both N7 and C8. The 13C8 atom is introduced by means of a ring closure of the exocyclic amino groups of a pyrimidinone using [13C]sodium ethyl xanthate. Here, we present methods for the syntheses of [8-13C-1,7,NH2-15N3]adenosine, -guanosine, and their deoxy analogues.     

S(N)Ar displacements with 6-(fluoro, chloro, bromo, iodo, and alkylsulfonyl)purine nucleosides: synthesis, kinetics, and mechanism1

SNAr reactions with 6-(fluoro, chloro, bromo, iodo, and alkylsulfonyl)purine nucleosides and nitrogen, oxygen, and sulfur nucleophiles were studied. Pseudo-first-order kinetics were measured with 6-halopurine compounds, and comparative reactivities were determined versus a 6-(alkylsulfonyl)purine nucleoside. The displacement reactivity order was: F > Br > Cl > I (with BuNH2/MeCN), F > Cl approximately Br > I (with MeOH/1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)/MeCN), and F > Br > I > Cl [with K+ -SCOCH3/dimethyl sulfoxide (DMSO)]. The order of reactivity with a weakly basic arylamine (aniline) was: I > Br > Cl > F (with 5 equiv of aniline in MeCN at 70 degrees C). However, those reactions with aniline were autocatalytic and had significant induction periods ( approximately 50 min for the iodo compound and approximately 6 h for the fluoro analogue). Addition of trifluoroacetic acid (TFA) eliminated the induction period, and the order then was F > I > Br > Cl (with 5 equiv of aniline and 2 equiv of TFA in MeCN at 50 degrees C). The 6-(alkylsulfonyl)purine nucleoside analogue was more reactive than the 6-fluoropurine compound with both MeOH/DBU/MeCN and iPentSH/DBU/MeCN and was more reactive than the Cl, Br, and I compounds with BuNH2 and aniline/TFA. Titration of the 6-halopurine nucleosides in CDCl3 with TFA showed progressive downfield 1H NMR chemical shifts for H8 (larger) and H2 (smaller). The major site of protonation as N7 for both the 6-fluoro and 6-bromo analogues was confirmed by large upfield shifts ( approximately 16 ppm) of the 15N NMR signal for N7 upon addition of TFA (1.6 equiv). Mechanistic considerations and resolution of prior conflicting results are presented.     

Interpretation of substituent effects on 13C and 15N NMR chemical shifts in 6-substituted purines

A range of purine derivatives modified at position 6 of the basic purine skeleton exhibit a variety of biological activities. Several derivatives are used or tested nowadays for pharmacological treatments. The present work aims to analyze the effects of substituents on the electron distribution in the purine core as reflected by NMR chemical shifts. We collected a comprehensive set of experimental NMR data for a variety of 6-substituted purines (-NH(2), -NHMe, -NMe(2), -OMe, -Me, -CCH, and -CN) and determined the molecular and crystal structures of three derivatives (-NHMe, -CCH, and -CN) by X-ray diffraction. The density-functional methods calibrated in our recent study (Phys. Chem. Chem. Phys., 2010, 12, 5126) have been employed to enable understanding of the substituent-induced changes in the NMR chemical shifts of the atoms in the purine skeleton. Analyses of the nuclear shielding using localized molecular orbitals (LMOs), specifically the natural LMOs (NLMOs) and Pipek-Mezey LMOs, were used to break down the values of the isotropic (13)C and (15)N NMR chemical shifts and the chemical shift tensors into the contributions of the individual LMOs. The experimental and calculated trends in the chemical shift of the N-3 atom correlate nicely with the Hammett constants (σ(para)) and the calculated natural charges on N-3, whereas the contributions of the LMOs to the N-1 and C-6 chemical shifts are found to be more complex.     

First generation of pentazole (HN5, pentazolic acid), the final azole,and a zinc pentazolate salt in solution: A new N-dearylation of 1-(p-methoxyphenyl) pyrazoles,a 2-(p-methoxyphenyl) tetrazole and application of the methodology to 1-(p-methoxyphenyl) pentazole

Ceric ammonium nitrate (CAN) in methanol-water gave a new N-dearylation of a series of substituted 1-(p-methoxyphenyl) pyrazoles and a 2-(p-methoxyphenyl)tetrazole producing p-benzoquinone and the parent azole in a mole for mole ratio. Application of this reaction to 1-(p-methoxyphenyl) pentazole at -40 degrees C produced p-benzoquinone. 15N NMR spectra suggest that pentazole, HN5, was also produced and held in solution as N5- with Zn2+ ion. The 15N signal from N5- was -10.0 +/- 2.0 ppm in agreement with calculated values.     

Multinuclear 1H, 13C and 15N NMR study of some substituted 2-amino-4-nitropyridines and their N-oxides

1H, 13C and 15N NMR chemical shift assignments based on pulsed field gradient selected PFG 1H,X (X = 15C and 15N) HMQC and HMBC experiments are reported for three 4-nitropyridine N-oxides and four 4-nitropyridines. It was found that an ortho effect of a methyl group inhibits the deshielding effect of the 4-nitro group and that this effect and the so-called back donation is influenced by electronegativity and position of substituents in the multisubstituted pyridine N-oxides. The shielding effect of N-oxide group is most pronounced in the 15N NMR chemical shifts of the studied compounds. This effect is further modified by methylamino, methylnitramino, 5- or 3-methyl and 4-nitro groups. Among them the 4-nitro group exerts the highest influence on the shielding effect of the N-oxide functionality. Experimental 1H, 13C and 15N NMR chemical shifts and GIAO/DFT theoretical calculations are consistent with each other and supported by the reactivity on nucleophilic substitution, the UV spectral and the dipole moment data.     

Isotopic scrambling in Di-13C-labeled 2-butyl cation: evidence for a protonated cyclopropane intermediate

The (13)C NMR spectrum of 2-butyl-1,2-(13)C(2) cation (1) is unchanged on heating the sample to -78 degrees C, indicating no isomerization to another isotopomer. In contrast, the spectrum of 2-butyl-2,3-(13)C(2) cation (2) shows rapid formation of all of the other isotopomers except 1. These results are consistent with a protonated cyclopropane intermediate in the rearrangement process. In this mechanism, either C(1) and C(2) or C(3) and C(4) interchange. Only the bond between C(2) and C(3) breaks.     

Regiospecific N9 alkylation of 6-(heteroaryl)purines: shielding of N7 by a proximal heteroaryl C-H1

Purine alkylations have been plagued with formation of mixtures of N9 (usually desired), N7, and other regioisomers. We have developed methods for synthesis of 6-(azolyl)purine derivatives whose X-ray crystal structures show essentially coplanar conformations of the linked azole-purine rings. Such ring orientations position the C-H of the azole above N7 of the purine, which results in protection of N7 from alkylating agents. Treatment of 6-(2-butylimidazol-1-yl)-2-chloropurine (9) with sodium hydride in DMF followed by addition of ethyl iodide resulted in exclusive formation of 6-(2-butylimidazol-1-yl)-2-chloro-9-ethylpurine (10), whereas identical treatment of 2-chloro-6-(4,5-diphenylimidazol-1-yl)purine (11) produced a regioisomeric mixture 12/13 (N9/N7, approximately 5:1). The linked imidazole and purine rings are coplanar in 9 (the butyl side chain is extended away from the purine ring and C-H is over N7) but are rotated approximately 57 degrees in 11, and the more bulky azole substituent in 11 did not prevent formation of the minor N7 regioisomer 13. Access to various regioisomerically pure 9-alkylpurines is now readily available.     

Platinum-modified adenines: unprecedented protonation behavior revealed by NMR spectroscopy and relativistic density-functional theory calculations

Two novel Pt(IV) complexes of aromatic cytokinins with possible antitumor properties were prepared by reaction of selected aminopurines with K(2)PtCl(6). The structures of both complexes, 9-[6-(benzylamino)purine] pentachloroplatinate (IV) and 9-[6-(furfurylamino)purine] pentachloroplatinate (IV), were characterized in detail by using two-dimensional NMR spectroscopy ((1)H, (13)C, (15)N, and (195)Pt) in solution and CP/MAS NMR techniques in the solid state. We report for the first time the X-ray structure of a nucleobase adenine derivative coordinated to Pt(IV) via the N9 atom. The protonation equilibria for the complexes in solution were characterized by using NMR spectroscopy (isotropic chemical shifts and indirect nuclear spin-spin coupling constants) and the structural conclusions drawn from the NMR analysis are supported by relativistic density-functional theory (DFT) calculations. Because of the presence of the Pt atom, hybrid GGA functionals and scalar-relativistic and spin-orbit corrections were employed for both the DFT calculations of the molecular structure and particularly for the NMR chemical shifts. In particular, the populations of the N7-protonated and neutral forms of the complexes in solution were characterized by correlating the experimental and the DFT-calculated NMR chemical shifts. In contrast to the chemical exchange process involving the N7-H group, the hydrogen atom at N3 was determined to be unexpectedly rigid, probably because of the presence of the stabilizing intramolecular interaction N3-H···Cl. The described methodology combining the NMR spectroscopy and relativistic DFT calculations can be employed for characterizing the tautomeric and protonation equilibria in a large family of transition-metal-modified purine bases.     

Synthesis and structure of 6-azido-2,4-bis(2,2,2-trinitroethylamino)-1,3,5-triazine and its <Emphasis Type="Italic">N</Emphasis>-nitro derivatives

Methods were developed for the synthesis of 6-azido-2,4-bis(2,2,2-trinitroethylamino)- 1,3,5-triazine and its N-nitro derivatives (6-azido-2,4-bis(2,2,2-trinitroethyl)nitramino-1,3,5-triazine and 6-azido-2-(2,2,2-trinitroethylamino)-4-(2,2,2-trinitroethyl)nitramino-1,3,5-triazine) containing combinations of azido, trinitroethyl, and nitramine groups. These compounds are of interest as components of energetic composites. The molecular and crystal structures of 6-azido-2,4-bis(2,2,2-trinitroethylamino)-1,3,5-triazine and 6-azido-2,4-bis(2,2,2-trinitroethyl) nitramino-1,3,5-triazine were studied by X-ray diffraction and NMR spectroscopy.     

Thiol-catalysed radical-chain redox rearrangement reactions of benzylidene acetals derived from terpenoid diols

The thiol-catalysed radical-chain redox rearrangement of cyclic benzylidene acetals derived from 1,2- and 1,3-diols of terpene origin has been investigated from both synthetic and mechanistic standpoints. The redox rearrangement was carried out either at ca. 70 degrees C (using Bu(t)ON=NOBu(t) as initiator) or at ca. 130 degrees C (using Bu(t)OOBu(t) as initiator) in the presence of triisopropylsilanethiol or methyl thioglycolate as catalyst; the silanethiol was usually more effective. This general reaction affords the benzoate ester of the monodeoxygenated diol, unless rearrangement of intermediate carbon-centred radicals takes place prior to final trapping by the thiol to give the product, in which case structurally rearranged esters are obtained. For the benzylidene acetals of 1,2-diols prepared by vicinal cis-dihydroxylation of 2-carene, alpha-pinene or beta-pinene, intermediate cyclopropylcarbinyl or cyclobutylcarbinyl radicals are involved and ring opening of these leads ultimately to unsaturated monocyclic benzoates. 1,2-Migration of the benzoate group in the intermediate beta-benzoyloxyalkyl radical sometimes also competes with thiol trapping during the redox rearrangement of benzylidene acetals derived from 1,2-diols. Redox rearrangement of the benzylidene acetal from carane-3,4-diol, obtained by cis-dihydroxylation of 3-carene, does not involve intermediate cyclopropylcarbinyl radicals and leads to benzoate ester in which the bicyclic carane skeleton is retained. The inefficient redox rearrangement of the relatively rigid benzylidene acetal from exo,exo-norbornane-2,3-diol is attributed to comparatively slow chain-propagating beta-scission of the intermediate 2-phenyl-1,3-dioxolan-2-yl radical, probably caused by the development of adverse angle strain in the transition state for this cleavage. Similar angle strain effects are thought to influence the regioselectivities of redox rearrangement of bicyclic [4.4.0]benzylidene acetals resulting from selected 1,3-diols, themselves prepared by reduction of aldol adducts derived from reactions of aldehydes with the kinetic lithium enolates obtained from menthone and from isomenthone.     

7-Deazapurine biosynthesis: NMR study of toyocamycin biosynthesis in Streptomyces rimosus using 2-13C-7-15N-adenine

Although 7-deazapurines are well known and feature in the hypermodified RNA base queuosine, and in a range of nucleoside antibiotics such as toyocamycin, a mechanistic understanding of their biosynthesis is a longstanding problem. In particular, the obligatory loss of the N-7 nitrogen atom is puzzling, and in order to address this mechanistic conundrum a novel doubly labeled purine, [2-(13)C, 7-(15)N]-adenine, has been prepared and used as a biosynthetic precursor to toyocamycin in Streptomyces rimosus. NMR spectroscopy and mass spectrometry clearly showed incorporation of (13)C but loss of (15)N in the toyocamycin produced.     

Wagner-Meerwein rearrangement of a [3.3.3]- to a [4.3.3]propellane: deuterium tracer and conformational analysis

Formation of (-)-[4.3.3]propellane 4 from (-)-14-hydroxymodhephene (2) proceeds through a Wagner-Meerwein rearrangement via C3--C4 bond-shift to give a stable intermediate, dimethylcyclohexadienyl cation A, which undergoes deprotonation. Herein, this mechanism was investigated by using a deuterium labeled substrate at the C-14 methylene group of (-)-2, which was incorporated into the C-4 position of (-)-[4.3.3]propellane 4. The stereostructure of (-)-4 was investigated by applying a combination of NMR experimental and theoretical approaches.     

Rearrangement of N-(3-pyridyl)nitramine

Contrary to other N-(pyridyl)nitramines, the title compound cannot be rearranged to 3-amino-2-nitropyridine or other isomers. Hypothetical products of its transformation under influence of concentrated sulphuric acid, viz. 3-hydroxypyridine, 3,3′-azoxypyridine and 3,3′-azopyridine, were obtained from 3-nitro- and 3-aminopyridine in oxidation and reduction reactions. N-(3-Pyridyl)nitramine was prepared and rearranged in concentrated sulphuric acid. 3-Hydroxypyridine and 3,3′-azoxypyridine were isolated from the reaction mixture, other products were identified by the HPLC and GCMS methods. The results indicate that N-(3-pyridyl)hydroxylamine is an intermediate formed from N-(3-pyridyl)nitramine under the influence of concentrated sulphuric acid. The reaction path, leading to the final products, is discussed in context of the mechanism of nitramine rearrangement.     

14N NMR spectroscopy of nitrofuroxans-qualitative and quantitative method for their determination

For the first time, the¹⁴N NMR spectra of nitrofuroxans were investigated, and it was shown that the¹⁴N signals are narrow; this allows this method to be utilized analytically. Taking the example of nitrochlorofuroxan, the unusual rearrangement of the 4-nitro isomer to the 3-nitro isomer was found.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 5, pp. 1020–1023, May, 1990.     

Isocyanates of N alpha-[(9-fluorenylmethyl)oxy]carbonyl amino acids: synthesis,isolation, characterization,and application to the efficient synthesis of urea peptidomimetics

The Curtius rearrangement of Fmoc-amino acid azides 1 was carried out in toluene by refluxing the solution for 30 min. The resulting isocyanates 2 have been isolated as crystalline solids and are fully characterized by IR, (1)H NMR, (13)C NMR, and mass spectra. They are found to be stable for several months when stored at 4 degrees C. The acyl azides of Asp, Glu, Ser, Tyr, and Lys with side-chain protection having tert-butyl, benzyl, and Boc groups were also converted to the corresponding isocyanates 2h-m. The rearrangement of Fmoc-amino acid azides in toluene to isocyanates 2 under microwave irradiation was also accomplished. The direct exposure of solid azides to microwaves for 60 s led to the completion of the rearrangement. The resulting isocyanates, after recrystallization, were found to be analytically pure. The scale-up of the rearrangement, under microwave irradiation as tested up to 0.75 mol, posed no problems and led to the isolation of the isocyanates in 91-96% yield. The utility of isocyanates as building blocks in the synthesis of urea peptides 4 is demonstrated. Further, the coupling of isocyantes 2 directly with N,O-bis(trimethylsilyl) derivatives of amino acids 6 resulted in urea peptide acids 7 with good yield in high purity. Thus, the synthesis of urea peptide acids 7d-g containing Asp, Glu, Ser, and Tyr with a free side-chain functional group have been carried out.     

Regioselective ortho-nitration of N-phenyl carboxamides and primary anilines using bismuth nitrate/acetic anhydride

An efficient and one-pot synthetic method for the regioselective ortho-nitration of the N-phenyl carboxamides and primary anilines has been developed by using bismuth nitrate and acetic anhydride as the nitrating reagents. Reaction proceeds at room temperature and results in corresponding ortho-nitrated products in moderate to excellent yields. This method provides an operationally simple, regioselective, and efficient access to synthesize o-nitro anilines under the mild conditions.     

Differential effects of Mg(ii) and N(alpha)-4-tosyl-l-arginine methyl ester hydrochloride on the recognition and catalysis in ATP hydrolysis

The supramolecular interactions of Mg(ii) and N(alpha)-4-tosyl-l-arginine methyl ester hydrochloride (TAME) with ATP have been investigated using (1)H and (31)P NMR spectra. Furthermore, the hydrolysis of ATP catalyzed by Mg(ii) and TAME has been studied at 60 degrees C and pH 7 using (31)P NMR spectra. In the Mg(ii)-ATP-TAME ternary system, the binding interaction of Mg(2+) with ATP involves not only N1 and N7 in the adenine ring but also beta- and gamma-phosphate of ATP. The binding forces are mainly electrostatic interaction and cation (Mg(2+))-pi interaction. The guanidinium group and the aromatic ring of TAME interacts with ATP by beta and gamma phosphate and the adenine ring of ATP. The binding forces are mainly electrostatic interactions and pi-pi stacking. A significant difference between the binary and the ternary system indicates that TAME is essential to the stablization of the intermediate. Kinetic studies show that the hydrolysis rate constant of ATP is 2.16 x 10(-2) h(-1) at pH 7 in the Mg(ii)-TAME-ATP ternary system. The Mg(ii) ion and TAME can accelerate the ATP hydrolysis process. A possible mechanism has been proposed that the hydrolysis occurs through an addition-elimination, in which the phosphoramidate intermediate was observed at 3.21 ppm in the (31)P NMR of the ternary system. These results provide further information concerning the effect of the key amino acid residue and metal ions as cofactors of ATPase on ATP synthesis/hydrolysis at the molecular level.