Intramolecular substitution of unactivated aryl groups by thioamide anion

The general reaction of intramolecular nucleophilic substitution of unactivated aryl groups by thioamide anion in dipolar aprotic amide solvent is extended by the syntheses of 6-chloro-5-methoxy-2-methylbenzothiazole from 2′,4′-dichloro-5′-methoxythioacetanilide and 6-methoxy-2-methylbenzothiazole from 4′-methoxy-2′-nitrothioacetanilide. The six-membered fused ring heterocycles, 2-methyl-4H,3-benzothiazine and 6,8-dichloro-3-rnethyl-1H-4,1,2-benzothiadi-azine are also prepared.     

Abnormal Nucleophilic Substitution on Methoxytropone Derivatives: Steric Strategy to Synthesize 5-Substituted Azulenes

Azulene is a non-alternant non-benzenoid aromatic system, and in turn, it possesses unusual photophysical properties. Azulene-based conjugated systems have received increasing interest in recent years as optoelectronic materials. Despite the routes available for the preparation of substituted azulene derivatives, there remain few methods that allow regioselective substitution on the seven-membered ring of azulenes due to the subtle reactivity difference among the various positions. This report explores the reactivity of substituted tropolones as the azulene precursors and also provides a new method to create 5-substituted azulenes. The reaction of cyanoacetate enolate with unsubstituted 2-methoxytropone affords azulene through the attack of the nucleophile on the C-2 center (normal pathway). We have observed that 3-substituted 2-methoxytropones undergo steric-guided nucleophilic addition at the C-7 center (abnormal pathway) to afford 5-substituted azulene derivatives. Based on this observation and DFT calculation, a new synthetic strategy is devised for the regioselective synthesis of 5-substituted multifunctional azulenes, which cannot be accessed by any other method.     

Nitropyrazoles 17. Synthesis of 1-(3,5-dinitrophenyl)-4-methyl-3,5-dinitropyrazole and the study of its chemical transformations

A new one-step method for the synthesis of 4-methyl-3(5)-nitropyrazole by nitration of 4-methylpyrazole is developed. Arylation of 4-methyl-3(5)-nitropyrazole with 1,3,5-trinitrobenzene gives 1-(3,5-dinitrophenyl)-4-methyl-3-nitropyrazole, nitration of which leads to 1-(3,5-dinitrophenyl)-4-methyl-3,5-dinitropyrazole. The action of 1 equiv. of an O- or S-nucleophile (phenolate, p-chlorobenzenethiolate and ethoxide ions; anions of glycolanilide and thioglycolanilide) on 1-(3,5-dinitrophenyl)-4-methyl-3,5-dinitropyrazole led to the substitution of the 5-NO₂ group of the pyrazole ring; under the action of one more equivalent of a nucleophile the NO₂ group of the benzene ring was substituted. The substitution product of the anion of thioglycolanilide for the 5-NO₂ group undergoes the intramolecular cyclization — oxidative nucleophilic hydrogen substitution in the benzene ring under the action of K₂CO₃.     

Addition of carbon nucleophiles to arene-chromium complexes

The electrophilic reactivity of arenes coordinated to the chromium tricarbonyl unit has been developed into several distinct methods for coupling carbon nucleophiles with aromatic rings. Addition of the nucleophile produces stable η⁵-cyclohexadienyl chromium complexes which can be oxidized to induce loss of the endo hydrogen and the metal, overall nucleophilic substitution for hydrogen. Alternatively, the intermediate can be protonated and the resulting cyclohexa-1,3-diene can be detached from the chromium, effecting nucleophilic addition with reduction of one double bond. If a halogen (F, Cl) is present as a ring substituent, and if the nucleophile can migrate about the arene ligand, then loss of halide can occur parallel with classical nucleophilic aromatic substitution for halogen in electron-deficient haloarenes.With substituted arenes, the regioselectivity of addition becomes important and is often very high. Particularly useful are strong resonance donor substituents (RO-, R₂N-, F-) where selectivity for meta attack is high. Indole provides an excellent example of selective activation, as the six-membered ring complexes selectively and is then susceptible to nucleophilic substitution, predominantly at the 4 and 7 positions.Substitution for halogen is a somewhat limited process and depends upon the nature of the nucleophile. Very reactive nucleophiles add to unsubstituted positions and are often slow to isomerize to the ipso position from which loss of halide can occur.     

Synthesis and antibacterial properties of new 8-nitrofluoroquinolone derivatives

The objective of this research was the preparation of new 8-nitrofluoroquinolone models and investigation of their antibacterial properties. The work initially involved large scale preparation of the synthon 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (3), followed by introduction of substituted primary amine appendages at the C-7 position to give derivatives 9a-g, in which the amino group is appended to substituted benzenes or aromatic heterocycles, is part of a primary alpha-amino acid or just a simple primary aliphatic amine. This nucleophilic aromatic substitution step was a very simple procedure since the 8-nitro group of the above synthon facilitated the addition of weak nucleophiles at C-7. All compounds prepared were fully identified and characterized using NMR, IR, EA and MS, and were consistent with expected structures. The prepared targets and the intermediates have shown interesting antibacterial activity against gram positive and/or gram negative strains. In particular, the p-toluidine, p-chloroaniline and aniline derivatives showed good activity against S. aureus with MIC range approximately 2-5 microg/mL. In conclusion, more lipophilic groups seem to enhance activity against gram positive strains.     

Solid-state photodimerization of cholest-4-en-3-one

Crystalline cholest-4-en-3-one undergoes solid-state dimerization by UV radiation to give two ring A - ring A connected dimers. No dimerization occurs in solution. The first dimer, characterized by a cyclobutane ring, is formed by connection of C-2 and C-3 of a moiety with C-5' and C-6' of another moiety, respectively. The latter dimer has a six-membered ketal ring formed by connection of C-2 with C-5' and of O, linked to C-3, with C-3'. The structures have been determined by spectroscopic means. X-ray analysis of title compound evidences the proximity of the axial H-2 of a molecule to the C-4' of a molecule in the upper layer. The transfer of the hydrogen and the connection between C-2 and C-5' might be the driving force of dimerization.     

Substituent dependence of the diastereofacial selectivity in iodination and bromination of glycals and related cyclic enol ethers

The stereochemical course of the electrophilic iodination and bromination of tri-O-benzyl-D-glucal under various conditions has been compared to that of substituted dihydropyrans 2-5. IN(3) addition in acetonitrile affords trans-alpha-iodoazides (80-87%), besides small amounts of trans-beta-adducts, in the presence or the absence of benzyloxy substituents at C-3 or C-4, and in agreement with bridged iodonium ion intermediates. In contrast, the diastereofacial selectivity of bromine addition in dichloroethane going through open bromo oxocarbenium ions depends strongly on the substituents. Whereas the trans-alpha-dibromides are the main (85-95%) adducts in the absence of C-4 and C-5 substituents, in their presence a moderate to exclusive selectivity for cis-alpha-addition (60-99%) is observed. The predominance of trans-alpha-addition is again observed whatever the substituents when the bromination is carried out in the same solvent but with a tribromide ion salt, supporting a concerted addition of the two bromine atoms under these conditions. Finally, bromine addition in methanol exhibits a completely different behavior with the nonselective formation of trans-alpha- and trans-beta-methoxybromides and a small dependence on the substituents. In agreement with the absence of azide trapping of any cationic intermediate, it is concluded that these brominations which do not go through an ionic intermediate are concerted additions of bromine and methanol with very loose rate- and product-determining transition states. Finally, the substituent conformation at C-4 influences drastically the stereoselectivity in all these brominations. Evidence for alpha-anomeric control of the nucleophile approach at C-1 is given by the highly predominant formation of alpha-adducts, except in the methanolic bromination. The factors determining the versatile selectivity of the electrophile approach are discussed in terms of PPFMO theory and of the special mechanisms of glycal reactions.     

非对称氮杂环丙烷的亲核开环反应及其区域选择性

本文系统地总结了各类亲核试剂对非对称氮杂环丙烷(吖丙啶)的亲核开环反应及开环的区域选择性.氮杂环丙烷亲核开环的区域选择性是一种空间效应和电子效应平衡的结果,非芳基和非烯基取代的氮杂环丙烷的亲核开环通常发生在氮杂环丙烷取代少的碳原子上,空间效应起主导作用;而芳基和烯基取代的氮杂环丙烷的亲核开环通常发生在氮杂环丙烷芳甲位和烯丙位的碳原子上,电子效应起主导作用,烯基取代的氮杂环丙烷的亲核开环还可以发生在烯基的β-碳原子上;分子内的亲核开环反应主要受成环时环大小的控制,成环时的倾向是五元环>六元环>七元环.对于亲核试剂,一般的亲核试剂也同时受电子效应和空间效应的影响; 而亲核性强的亲核试剂通常只受空间效应的影响.容易生成稳定自由基的亲核试剂容易发生单电子转移机理的开环反应,生成相当于亲核试剂进攻氮杂环丙烷中取代多的碳原子得到的开环产物.     

CRYSTAL AND MOLECULAR STRUCTURE OF GUANIDINIUM BIS (o-AMINOPHENYLARSENIC) HEXAMOLYBDATE (CN_3H_6)_4[(o NH_2C_6H_4 As)_2Mo_6O_(24)]

<正> Guanidinium bis (o - aminophenylarsenic) hexamolybdate belongs to monoclinic space group P21/c,with a=10. 217(2),b= 18. 870(2),c= 10. 939(2)A,β = 102. 82(3)°,Z = 2,V=2056. 4A3,and Dc=2. 477 g·cm-3. Each molecule contains one [(o-NH2C6H4As)2Mo6O24]4- anion and four CN3H6+ cations. In the anion,six distorted MoO6 octahedra are connected with edges-sharing to form a six-membered Mo ring which is capped above and below by two o - aminophenylarsenic groups. There is half a molecule in an asymmetric unit. It is interesting that both phenyl planes are almost perpendicular to the plane of the Mo atoms. The structure of the anion is similar to that of [ (CH3 As)2Mo6O24]4-,[(n-C3H7As)2Mo6O24]4- or [(C6H5CH2As)2Mo6O24]4-. This is the first example of this type of compounds in which the As atom is directly connected to a substituted phenyl group.     

Intrinsic gas-phase electrophilic reactivity of cyclic N-alkyl- and N-acyliminium ions

The intrinsic gas-phase reactivity of cyclic N-alkyl- and N-acyliminium ions toward addition of allyltrimethylsilane (ATMS) has been compared using MS(2) and MS(3) pentaquadrupole mass spectrometric experiments. An order of electrophilic reactivity has been derived and found to agree with orders of overall reactivity in solution. The prototype five-membered ring N-alkyliminium ion 1a and its N-CH(3) analogue 1b, as well as their six-membered ring analogues 1c and 1d, lack N-acyl activation and they are, accordingly, inert toward ATMS addition. The five- and six-membered ring N-acyliminium ions with N-COCH(3) exocycclic groups, 3a and 3b, respectively, are also not very reactive. The N-acyliminium ions 2a and 2c, with s-trans locked endocyclic N-carbonyl groups, are the most reactive followed closely by 3c and 3d with exocyclic (and unlocked) N-CO(2)CH(3) groups. The five-membered ring N-acyliminium ions are more reactive than their six-membered ring analogues, that is: 2a > 2c and 3c > 3d. In contrast with the high reactivity of 2a, its N-CH(3) analogue 2b is inert toward ATMS addition. For the first time, the transient intermediates of a Mannich-type condensation reaction were isolated-the beta-silyl cations formed by ATMS addition to N-acyliminium ions-and their intrinsic gas-phase behavior toward dissociation and reaction with a nucleophile investigated. When collisionally activated, the beta-silyl cations dissociate preferentially by Grob fragmentation, that is, by retro-addition. With pyridine, they react competitively and to variable extents by proton transfer and by trimethylsilylium ion abstraction-the final and key step postulated for alpha-amidoalkylation. Becke3LYP/6-311G(d,p) reaction energetics, charge densities on the electrophilic C-2 site, and AM1 LUMO energies have been used to rationalize the order of intrinsic gas-phase electrophilic reactivity of cyclic iminium and N-acyliminium ions.     

Conformational analysis—XXVIII : Four-component equilibria in 1,3-dioxanes. Ring deformations and the chair-twist free energy difference

Four-component equilibria in substituted 1,3-dioxanes were applied to the determination of conformational energies not accessible by conventional equilibration, with the following conclusions: 1. The difference in free energy between the chair and twist forms of 2,2,trans - 4,6 - tetramethyl - 1,3 -dioxane is 7·4 kcal/mol. 2. Equatorial Me substituents at C-4,6 exert a palpable buttressing effect on the corresponding axial substituents. 3. Equatorial substituents at C-2 exert a similar buttressing effect on the geminal axial substituent. 4. The effect of equatorial t-Bu substitution or gem-dimethyl substitution at C-5 on conformational energy seems to be of minor importance. The more complex effects of equatorial 4-t-Bu substitution are discussed.     

Synthesis of Substituted Pyridazin-3-ones, 1,2-Oxazin-3-ones,and Furopyrimidines from (Arylmethylidene)furan-2(3<Emphasis Type="Italic">H</Emphasis>)-ones

Reactions of 5-substituted 3-(arylmethylidene)furan-2(3H)-ones with hydrazine hydrate, hydroxylamine, and guanidine involved opening of the furanone ring. Their hydrazinolysis under mild conditions afforded acyclic 4-oxoalkanoic acid hydrazides which underwent heterocyclization to substituted pyridazinones in boiling ethanol. The presence of an alkyl substituent in the 5-position of the initial furanone favored heterocyclization with the formation of pyrazolidinone derivatives. The reactions of 3-(arylmethylidene)furan-2(3H)-ones with hydroxylamine and guanidine also produced new six-membered heterocycles, 2H-1,2-oxazin-3(4H)-ones and 4,6-disubstituted 3,4-dihydrofuro[2,3-d]pyrimidin-2-amines, respectively.     

Studies on Semisynthesis and Antibacterial Activities of 7β-(l-aryl-5-methyl-l,2,3-triazol-4-acylamido)-3-(2-substituted-1,3,4-oxadizol-5-thiomethyl) Cephalosporin

Cephalosporin derivatives have been a subject in the field of β-lactam antibiotics due to their broad-spectrum biological activities in recent years. Chemical manipulation of the C-3 and 7β-position in the cephalosporin molecule has resulted in the discovery of numerous novel antibiotics. In general, the C-3 position of the cephalosporin were substituted with heterocyclyl sulfurs or nitrogens and the 7β-position were substituted with heterocycles or aryl¹. The side chain at 7β-position determined their antibacterial activities and antibacterial spectrum, moreover, the substituted groups at C-3 position not only affect pharmacokinetic properties, but antibacterial activities and antibacterial spectrum as well.² Roche Reiner company found that the activities of cephalosporin can be improved by changing the R of RCONH- at 7β-position of 7ACA and introducing various thioazoleheterocycles into C-3 position of it.³ It is no doubt that these heterocycles increased their activities and wided their antibacterial spectrum. In the course of our studies on the modification of cephalosporin, our efforts have been focused on introducing heterocycles into C-3 and 7β-position of 7ACA with the hope of achieving better antibiotics.     

Nucleophilic substitution of hydrogen in naphthalene by chloride(Cl~-)in ionic liquids

Nucleophilic aromatic substitution of hydrogen in non-activated aromatic ring,a very rare phenomenon in organic chemistry,is found in ionic liquids containing Cl^- as anion under mild reaction conditions.The reaction may be carried out by the addition of the halogen-bonding adduct（Br₂Cl^-） as nucleophile to aromatic ring carbon atom,leading to the formation of the nucleophilic substitution product.     

13C n.m.r. spectra of some pyrylium salts and related compounds

The ¹³C chemical shifts of several alkyl and phenyl substituted pyrylium perchlorates, together with related pyridine and pyridinium salts, are reported. The shifts in the isoelectronic series benzene, pyridine, pyrylium cation correlate well with charge densities calculated by INDO MO theory. Charge densities also account for the shift changes found at C-3, C-4 and C-5 for protonation of pyridine and 2,4,6-trimethylpyridine. The shift changes observed on protonation for C-2 and C-6, along the series pyridine, 2,4,6-trimethylpyridine and 2,4,6-triphenylpyridine can only be rationalized by consideration of both charge density and π-bond order changes. The effects of alkyl substitution on the shifts of the pyrylium cations are not accounted for by charge density changes. Empirical correlations of these shifts with literature data for the alkylbenzenes and the shifts of the phenyl substituted 6-membered heterocycles are discussed.     

Thermal rearrangement of some 3-alkyl-2-aryltetrahydro-1,3-oxazine N-oxides. Synthesis of 2-alkyl-7-aryltetrahydro-1,6,2-dioxazepines

Several 2-alkyl-7-aryltetrahydro-1,6,2-dioxazepines 5a-i have been synthesized by a Meisenheimer-type rearrangement of 3-alkyl-2-aryltetrahydro-1,3-oxazine N-oxides 4a-i . These dioxazepines have not been previously described and for the first time compounds with the tetrahydro-1,6,2-dioxazepine ring-system have been made available. The structure assigned to members of this novel heterocycle is based on elemental analysis, infrared, and ¹H nmr spectral evidence. Further definitive evidence for the structure of these heterocycles is provided by an X-ray crystallographic analysis of 5c .     

Determination of the electrophilicity parameters of diethyl benzylidenemalonates in dimethyl sulfoxide: reference electrophiles for characterizing strong nucleophiles

The second-order rate constants of the reactions of nine substituted diethyl benzylidenemalonates 1 a-i with the carbanions 2 a-e have been determined spectrophotometrically in dimethyl sulfoxide (DMSO). Product studies show that the nucleophiles attack regioselectively at the electrophilic C==C double bond of the Michael acceptors to form the carbanionic adducts 4. The correlation log k(20 degrees C)=s(N+E) allows the determination of the electrophilicity parameters E for the electrophiles 1 a-i from the rate constants determined in this work and the previously published N and s parameters for the nucleophiles 2 a-e. The electrophilicities E for compounds 1 a-i cover a range of six units (-17.7>E>-23.8) and correlate excellently with Hammett's substituent constants sigma(p). The title compounds are roughly ten orders of magnitude less reactive than analogously substituted benzylidene Meldrum's acids, their cyclic analogues. Due to their low reactivities, compounds 1 a-i are suitable reference electrophiles for determining the reactivities of highly reactive nucleophiles, such as carbanions with 16相似文献   

Applications of benzotriazole methodology in heterocycle ring synthesis and substituent introduction and modification

Applications of benzotriazole methodology for the preparation of heterocyclic compounds are reviewed. The characteristic advantages of benzotriazole as a synthetic auxiliary are first briefly considered. This is followed by a summary of its use in ring synthesis in which the construction of small; five-membered; six-membered; and larger heterocyclic rings using benzotriazole methodology are each examined separately. Finally, consideration of the use of benzotriazole in the ring annulation - particularly benzannulation - of heterocycles. Subsequent sections deal with the introduction of substituents into aromatic heterocycles; the ring substitution of saturated heterocycles; and benzotriazole assisted modification of heterocyclic substituents. The present review supplements a recent comprehensive review of benzotriazole chemistry [1] which covers the literature through 1996.     

The profound effect of fluorine substitution on the reactivity and regioselectivity of nucleophilic substitution reactions of strained heterocycles. A study of aziridine and its derivatives

Unlike the synthetically exploited oxiranes and thiiranes, aziridines that lack electron-withdrawing substituents, such as acyl or sulfonyl functionalities at nitrogen, are rather unreactive. As expected, three-membered aziridine 6 was calculated to be significantly more reactive than azetidine 7 in nucleophilic cleavage by ammonia, a typical nucleophile. The reactivity of 7 was about the same as that of an acyclic model compound, 8, when release of ring strain in the transition state was taken into account. Fluorine due to its similar size but vastly different electronegativity has been substituted for hydrogen as a means of modifying chemical properties for varied applications. In the present investigation, the effect of fluorine substitution at aziridine positions other than nitrogen was studied. Computations at the MP2(Full)/6-311++G(d,p)//MP2(Full)/6-31+G(d) level found a vast preference for attack by ammonia at the 3-position of 2-fluoroaziridine in the gas phase at 298 K. When release of ring strain was taken into account, this compound reacted more than 10(11) times faster than 6. The reaction rate with trans-2,3-difluoroaziridine was about twice that of 2-fluoroaziridine, while its diastereomer reacted with ammonia considerably slower. Acyclic fluorinated amine model compounds were employed to assess the generality of the effects produced by fluorine substitution. The results were rationalized by the energy contributions of strain energy releases, stabilization of the leaving group, and the relative electrostatic energies of the heterocycles in the transition states. The more reactive fluoroaziridines underwent nucleophilic attack at rates comparable to those of N-acetylaziridine.     

Effect of progressive benzyl substitution on the conformations of aminocaproic acid-cyclized dipeptides

The constraint of dipeptides into a beta-turn conformation can be accomplished by linking the two ends of a standard dipeptide with a linker derived from aminocaproic acid (Aca). To elucidate the possibility of using substituted Aca linkers in peptidomimetic design, a series of five macrocycles composed of a monobenzylated Aca linker (containing the benzyl group on each of the five methylene groups of the parent linker) and Gly-Gly were synthesized. The requisite linkers were made by regiochemically controlled ring expansion techniques (for substitution on Aca positions C-3, C-4, or C-5), an Evans alkylation route (for C-2), or by chain extension of L-phenylalanal (for C-6). The solution-phase conformations of the macrocycles were examined by NMR and CD techniques; in addition, crystal structures of the C-4- and C-6-benzyl-substituted linkers were obtained. Four out of the five macrocycles were found to exist with the dipeptide portion taking up either a type II or II' beta-turn conformation, but the Gly-Gly unit in the compound derived from 4-benzyl-Aca did not correspond to one of the standard beta-turn types.