新型异噁唑啉类化合物的合成及其抗肿瘤活性

以3,4-二氟苯甲醛为起始物,经4步反应合成了关键中间体N-[{3-[3-氟-4-(1-哌嗪基)苯基]4,5-二氢-5-异噁唑}甲基]乙酰胺(4);4与取代苯磺酰氯经亲核取代反应合成了6个新型的异噁唑啉类化合物(6a～6f),其结构经1H NMR和MS表征.采用MTT法对6a～6f进行初步生物活性测试结果表明,部分化合...     

手性1,3,4-噁二唑硫醚衍生物的合成

以5-取代-2-巯基-1,3,4-噁二唑为亲核试剂,与手性5-烷氧基-3,4-二溴-2(5H)-呋喃酮发生Michael反应,合成了6种新的手性1,3,4-噁二唑硫醚衍生物(产率55%～67%),其结构经1H NMR, 13C NMR, IR和HR-MS确证.     

新型N-杂环取代苯乙酮衍生物的合成

以2-溴-4'-氟苯乙酮(1)为原料,在碳酸钾存在下分别与对甲酚(2a)和邻苯基苯酚(2d)反应制得2-芳氧基苯乙酮化合物(3a和3d);3a和3d分别与咪唑,N-甲基哌嗪和1-(2-嘧啶基)哌嗪经取代反应合成了6个新型的N-杂环取代苯乙酮衍生物,收率63%~81%,其结构经1H NMR,13C NMR,IR和HR-MS表征。     

盐酸黄连素的合成研究

以儿茶酚为起始原料,与二氯甲烷在碱性条件下进行亲核取代,再进行氯甲基化反应、亲核取代、水解、脱羧,酰胺化得化合物2~6,后经霍夫曼重排得3,4-亚甲二氧基苯乙胺(8),最后缩合、环化得盐酸黄连素1,合成盐酸黄连素的总收率为13.6%.化合物1~9的结构经过1 H NMR、13C NMR、质谱确认.     

新型N-芳基哌嗪取代苯并呋喃衍生物的合成

以5-二甲氨基水杨醛和2-溴-4'-氟苯乙酮为原料,经缩合和取代反应制得中间体6-二乙氨基-2-[4'-(N-哌嗪基)苯甲酰基]苯并呋喃(2);2与卤代烃反应合成了6个新型的N-芳基哌嗪取代苯并呋喃衍生物(4a~4f),收率76%~93%,其结构经1H NMR,13C NMR和HR-MS(ESI-TOF)表征。     

瑞卢戈利中间体的合成

以4-硝基苯丙酮(2)和氰基乙酸乙酯(3)为原料,经与硫粉环合、缩合、亲核取代、溴代反应、二甲胺取代和水解后得到瑞卢戈利的关键中间体2-[(2,6-二氟苄基)乙氧基羰基氨基]-4-二甲基氨基甲基-5-(4-硝基苯基)噻吩-3-甲酸(1),并对合成路线中反应条件及提纯方法进行优化,总收率51.5%,纯度98.7%以上,中间体的结构经¹H NMR和ESI-MS确证。优化后的工艺操作更加简便,更有利于工业化生产。     

新型N-杂环取代查尔酮衍生物的合成

以4-二甲氨基苯甲醛与4'-氟苯乙酮为原料,经羟醛缩合反应制得4-二甲氨基-4'-氟查尔酮(1);1分别与咪唑、哌嗪等含氮杂环化合物经取代反应合成了6个新型的N-杂环取代查尔酮衍生物,其结构经1H NMR,13C NMR和IR表征。     

替格瑞洛的合成工艺改进

以2-丙硫基-4,6-二氢-5-氨基嘧啶和2-{［(3aR,4S,6R,6aS)-6-氨基-2,2-二甲基四氢-3aH-环戊基［d］［1,3］二氧-4-基］氧}-1-乙醇L-酒石酸盐为原料,经C-N偶联,亲核取代和环合反应制得2-{［(3aR,4S,6R,6aS)-6-(7-氯-5-丙硫基-3H-［1,2,3］三唑［4,5-d］嘧啶-3-基)-2,2-二甲基四氢-3aH-环戊基［d］［1,3］二氧-4-基］氧}-1-乙醇(4); 4与(1R,2S)-2-(3,4-二氟苯基)环丙胺D-扁桃酸盐经亲核取代反应后酸解脱除丙酮叉保护基合成替格瑞洛,总收率58.7%,纯度99.2%,其结构经¹H NMR, MS(ESI)和XRD确证。     

2-氰基-3-[1-(4-取代苯氧基苯基)乙胺基]烯酸乙氧乙酯的合成及除草活性

以取代苯酚4和对氟苯乙酮(5)为原料,经4步反应合成关键中间体1-(4-取代苯氧苯基)乙胺(9),再与3种中间体2-氰基-3-乙氧基-2-戊烯酸乙氧乙酯(1)、2-氰基-3,3-二甲硫基丙烯酸乙氧乙酯(2)和2-氰基-3-氯-4,4,4-三氟丁烯酸乙氧乙酯(3)分别发生缩合反应,合成了3个系列共35个新2-氰基-3-[1-(4-取代苯氧基苯基)乙胺基]烯酸乙氧乙酯类化合物(10,11和12).所有新化合物的结构均经过1H NMR,13C NMR,19F NMR和HRMS的确证,并测试了目标化合物的除草活性,部分化合物在剂量为93.75 g/ha时,对双子叶植物油菜和苋菜的抑制率为100%.     

替格瑞洛的合成工艺改进

以2-丙硫基-4,6-二氯-5-氨基嘧啶(3)、2-[((3aR,4S,6R,6a S)-6-氨基-2,2-二甲基四氢-3a H-环戊基[d][1,3]二氧-4-基)氧]-1-乙醇L-酒石酸盐(4)为起始原料,经亲核取代、环合、与(1R,2S)-2-(3,4-二氟苯基)环丙胺D-扁桃酸盐(2)发生亲核取代、稀盐酸脱保护制得抗血小板药替格瑞洛,所得目标经1H NMR及MS确证,总收率为65%。     

Theoretical investigation of in-plane hydrogen-bonded complexes of ammonia with partially substituted fluorobenzenes

Systematic investigation of in-plane hydrogen-bonded complexes of ammonia with partially substituted fluorobenzenes has revealed that fluorobenzene, difluorobenzene, and trifluorobenzene favor formation of cyclic complexes with a C-H...N-H...F-C binding motif. On the other hand, tetrafluorobenzene and pentafluorobenzene favor formation of linear C-H...N hydrogen-bonded complexes. The complete absence of exclusively linear N-H...F hydrogen-bonded complexes for the entire series indicates that C-F bond in fluorobenzenes is a reluctant hydrogen-bond acceptor. However, fluorine does hydrogen bond when cooperatively stabilized with C-H...N hydrogen bonds for the lower fluoro analogues. The propensity of fluorobenzenes to adapt to the C-H...N-H...F-C binding motif decreases with the progressive fluorination of the benzene ring and disappears completely when benzene ring is substituted with five or more fluorine atoms.     

Recent Advances in C-F Bond Cleavage Enabled by Visible Light Photoredox Catalysis

The creation of new bonds via C-F bond cleavage of readily available per- or oligofluorinated compounds has received growing interest. Using such a strategy, a myriad of valuable partially fluorinated products can be prepared, which otherwise are difficult to make by the conventional C-F bond formation methods. Visible light photoredox catalysis has been proven as an important and powerful tool for defluorinative reactions due to its mild, easy to handle, and environmentally benign characteristics. Compared to the classical C-F activation that proceeds via two-electron processes, radicals are the key intermediates using visible light photoredox catalysis, providing new modes for the cleavage of C-F bonds. In this review, a summary of the visible light-promoted C-F bond cleavage since 2018 was presented. The contents were classified by the fluorosubstrates, including polyfluorinated arenes, gem-difluoroalkenes, trifluoromethyl arenes, and trifluoromethyl alkenes. An emphasis is placed on the discussion of the mechanisms and limitations of these reactions. Finally, my personal perspective on the future development of this rapidly emerging field was provided.     

Vibrational spectra, structure, and theoretical calculations of 2-fluoro- and 3-fluoropyridine

The infrared and Raman spectra of liquid and vapor-phase 2-fluoropyridine and 3-fluoropyridine have been recorded and assigned. Ab initio and DFT calculations were carried out to compute the molecular structures and to verify the vibrational assignments. The observed and calculated spectra agree extremely well. The ring bond distances of the fluoropyridines are very similar to those of pyridine except for a shortening of the C-N(F) bond in 2-fluoropyridine. The C-F bond stretching frequencies are similar to that in fluorobenzene reflecting the influence of the ring π bonding.     

Nickel-Assisted Carbon-Fluorine Bond Activation of 2,4,6-Trifluoropyrimidine: Synthesis of New Pyrimidine and Pyrimidinone Derivatives

Rapid and regioselective activation of the C-F bond of 2,4,6-trifluoropyrimidine occurs on reaction with [Ni(cod)(2)] (cod=1,5-cyclooctadiene) in the presence of PEt(3) to give 1, which can be converted into complex 2, containing a further N(3)-metalated pyrimidin-4-one unit. The novel pyrimidin-4-one 3 is released on protonation of 2.     

Fluorine in medicinal chemistry: β-fluorination of peripheral pyrrolidines attached to acridine ligands affects their interactions with G-quadruplex DNA

Comparative X-ray structure studies reveal that C-F bond incorporation into the peripheral pyrrolidine moieties of the G-quadruplex DNA binding ligand BSU6039 leads to a distinct pyrrolidine ring conformation, relative to the non-fluorinated analogue, and with a different binding mode involving reversal of the pyrrolidinium N(+)-H orientation.     

Aliphatic and aromatic carbon-fluorine bond activation with Cp*(2)ZrH(2): mechanisms of hydrodefluorination.

Cp*(2)ZrH(2) (1) (Cp* = pentamethylcyclopentadienyl) reacts with primary, secondary, and tertiary monofluorinated aliphatic hydrocarbons to give Cp*(2)ZrHF (2) and/or Cp*(2)ZrF(2) and alkane quantitatively through a radical chain mechanism. The reactivity of monofluorinated aliphatic C-F bonds decreases in the order 1 degrees > 2 degrees > 3 degrees. The rate of hydrodefluorination was also greatly reduced with -CF(2)H and -CF(3) groups attached to the hydrocarbon. An atmosphere of H(2) is required to stabilize 1 against C-H activation of the Cp*-methyl groups and subsequent dimerization under the thermal conditions employed in these reactions. Reaction of 1 with fluorobenzene cleanly forms a mixture of Cp*(2)ZrHF, benzene, and Cp*(2)Zr(C(6)H(5))F. Detailed studies indicate that radicals are not involved in this aromatic C-F activation reaction and that dual hydrodefluorination pathways are operative. In one mechanism, hydridic attack by Cp*(2)ZrH(2) on the aromatic ring and fluoride abstraction is involved. In the second mechanism, an initial ortho C-H activation occurs, followed by beta-fluoride elimination to generate a benzyne complex, which then inserts into the zirconium-hydride bond.     

极性分子键角与键偶极矩的关系

研究了基态极性分子的键角和键偶极矩之间的关系。我们采用原子偶极矩校正的Hirshfeld （ADCH）电荷来计算键偶极矩,利用电子的局域函数和键临界点处的局域函数值来分析键的电子结构。通过对IVA族（IVA = C,Si,Ge）、VA族（VA = N,P,As ）、VIA族（VIA = O,S,Se）和VIIA族（VIIA = F,Cl,Br）元素形成的系列共价型基态分子,以及环状基态分子的键角和键偶极矩数据进行分析,发现在键的电子结构类似的情况下,由于键偶极矩的排斥作用,这些分子的键角随键偶极矩的增加而增大。这一发现有助于加深我们对分子几何结构的认识。     

Predicting an Antiaromatic Benzene Ring in the Ground State Caused by Hyperconjugation

Benzene, the prototype of aromatics, has six equivalent C?C bonds (1.397 Å), which are intermediate between a C?C double bond and a C?C single bond. For over 80 years, chemists have spent much effort on freezing a localized structure to obtain a distorted bond‐length alternating benzene ring in the ground state, leading to various localized trisannelated benzene rings. However, most of the central benzene rings are still aromatic or nonaromatic. Here we report an antiaromatic benzene ring caused by hyperconjugation. Specifically, symmetric annulation of 5,5‐difluorocyclopentadiene results in an antiaromatic benzene ring, which is supported by various aromaticity indices, including nucleus‐independent chemical shift, anisotropy of the induced current density, π‐separated electron‐localization function and heat of hydrogenation. Our findings highlight a strong power of hyperconjugation, a “weak” interaction in organic chemistry, paving the way for designing and realizing more novel (anti)aromatics.     

Time-resolved infrared dynamics of C-F bond activation by a tungsten metal-carbonyl

Chemical reactions that break, or activate, C-H and C-F are of tremendous synthetic interest. The intramolecular C-F bond activation of a tungsten carbonyl system has been studied by time-resolved infrared spectroscopy. The formation of solvent complexes and the final product are monitored using time-resolved infrared spectroscopy of the CO stretches. The rate of the reaction is shown to be limited by the formation of an intermolecular complex between the tungsten metal center and a solvent molecule. Comparison with DFT calculations shows that in the absence of solvent molecules the intramolecular complex with the tethered perfluorobenzene ring is energetically favorable, but is not the primary kinetic product because of the initial geometry of the complex.     

Molecular structure, conformation, and potential to internal rotation of 2,6- and 3,5-difluoronitrobenzene studied by gas-phase electron diffraction and quantum chemical calculations

3,5-Difluoronitrobenzene (3,5-DFNB) and 2,6-difluoronitrobenzene (2,6-DFNB) have been studied by gas-phase electron diffraction (GED), MP2 ab initio, and by B3LYP density functional calculations. Refinements of r h1 and r e static and r h1 dynamic GED models were carried out for both molecules. Equilibrium r e structures were determined using anharmonic vibrational corrections to the internuclear distances ( r e - r a) calculated from B3LYP/cc-pVTZ cubic force fields. 3,5-DFNB possesses a planar structure of C 2 v symmetry with the following r e values for bond lengths and bond angles: r(C-C) av = 1.378(4) A, r(C-N) = 1.489(6) A, r(N-O) = 1.217(2) A, r(C-F) = 1.347(5) A, angleC6-C1-C2 = 122.6(6) degrees , angleC1-C2-C3 = 117.3(3) degrees , angleC2-C3-C4 = 123.0(3) degrees , angleC3-C4-C5 = 116.9(6) degrees , angleC-C-N = 118.7(3) degrees , angleC-N-O = 117.3(4) degrees , angleO-N-O = 125.5(7) degrees , angleC-C-F = 118.6(7) degrees . The uncertainties in parentheses are three times the standard deviations. As in the case of nitrobenzene, the barrier to internal rotation of the nitro group in 3,5-DFNB, V 90 = 10 +/- 4 kJ/mol, is substantially lower than that predicted by quantum chemical calculations. The presence of substituents in the ortho positions force the nitro group to rotate about the C-N bond, out of the plane of the benzene ring. For 2,6-DFNB, a nonplanar structure of C 2 symmetry with a torsional angle of phi(C-N) = 53.8(14) degrees and the following r e values for structural parameters was determined by the GED analysis: r(C-C) av = 1.383(5) A, r(C-N) = 1.469(7) A, r(N-O) = 1.212(2) A, r(C-F) = 1.344(4) A, angleC6-C1-C2 = 118.7(5) degrees , angleC1-C2-C3 = 121.2(2) degrees , angleC2-C3-C4 = 119.0(2) degrees , angleC3-C4-C5 = 121.1(4) degrees , angleC-C-N = 120.6(2) degrees , angleC-N-O = 115.7(4) degrees , angleO-N-O = 128.6(7) degrees , angleC-C-F = 118.7(5) degrees . The refinement of a dynamic model led to barriers V 0 = 16.5 +/- 1.5 kJ/mol and V 90 = 2.2 +/- 0.5 kJ/mol, which are in good agreement with values predicted by B3LYP/6-311++G(d,p) and MP2/ cc-pVTZ calculations. The values of C-F bond lengths are similar in both molecules. This is in contrast to the drastic shortening of the C-F bond in the ortho position in 2-fluoronitrobenzene compared to the C-F bond length in the meta and para position in 3- and 4-fluoronitrobenzene observed in an earlier GED study.