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When a large amount of energy is suddenly placed in an aromatic molecule, it can dissociate via a rather complex path. Measurements of translational energy distributions of the dissociated fragments of a variety of related molecules at different wave lengths clarify the dissociation processes. The reactions considered are

Reaction of a variety of N- t -butoxycarbonyl compounds with t -butyl-dimethylsilyl trifluoromethanesulfonate afforded the N- t -butyldimethyl-silyloxycarbonyl compounds, chemoselectively, which upon treatment with an alkyl or aryl halide provided the corresponding N-alkoxy- or N-aryl-oxycarbonyl compounds, efficiently.

The major applications of organic photochemical processes to synthetic problems have to date focused for the most part on the use of photocycloadditions and electrocyclizations in the preparation of strained ring compounds in target systems or key synthetic intermediates. The utility of these methods in selected preparative sequences for construction of natural and/or theoretically interesting products has been reviewed.(1) In general, these excited-state reactions share several unique features which make their utility in synthetic chemistry particularly advantageous. For example, photocycloadditions serve as useful methods for generating carbon-carbon bonds in strained ring systems which, due to their high energy content, are capable of participating in facile ring cleavage processes leading to desired intermediates. Similarly, electrocyclizations lead to the installation of difficultly prepared cyclic units from more readily available acyclic precursors. The applications of these reactions to synthetic problems is further broadened by their predictable regiochemical and stereochemical courses utilizing simple molecular orbital methods. Other classes of excited-state reactions have been used for the introduction and interconversion of functionality in molecular systems. Thus, several classes of photochemical processes appear compatible with the criteria established for evaluation of synthetically useful gound-state transformations.

A number of patented applications utilize the release of monomeric species under specific conditions. An example is found in the Kodak patent1 describing the use of the photochemically triggered release of phenanthrene (3-2) from stilbene (3-1).

It has been found that seventeen nickel complexes of the Ni–O4, Ni–S4, Ni–O2N2, Ni–O3N3, Ni–N4, Ni–N6, and Ni–(C5)2 types exhibit a high catalytic activity for the selective cross-coupling reaction of an aryl Grignard reagent with aryl iodide, which make possible the synthesis of unsymmetrical aromatics of a high purity and in a high yield.

A line of research from our laboratory has been concerned, for several years, with the pathogenetic mechanisms of the liver damage produced by glutathione (GSH)-depleting agents. The present report deals with the main results obtained in in vivo studies with the use of the prototype aryl halide, bromobenzene.

The reaction of aryl iodides or bromides with olefins in the presence of 1 mol % of and 3 equiv. of in carbon monoxide atmosphere gave the corresponding aryl vinyl ketones in good yields with small amount of vinylated 1-aryl olefins. But, when the reaction was proceeded under the 10 atm of carbon monoxide, aryl vinyl -diketones and aryl vinyl ketones were obtained in moderate to good yields. The reaction was tolerant of a wide variety of functional groups on either the aryl halides or olefin compounds. Reactivity of aryl halide decrease in the order; aryl iodide > aryl bromide aryl chloride. In general, the reaction proceeded well and gave good yields of aryl vinyl ketones and aryl vinyl -diketones when reactants are substituted with electron withdrawing groups.

The well-documented effects of ultrasound on heterogeneous systems have been exploited to produce beneficial increases in the rates of a number of reactions that would more commonly be executed under homogeneous conditions. For instance, the reduction of aryl halides with lithium aluminium hydride occurs extremely slowly in THF solution. However, Han and Boud- jouk have reported that the reaction can be carried out in a fraction of the time if the reaction mixture is sonicated in dimethoxyethane (DME) solution [6].’ Sonolysis of the heterogeneous reaction mixture gives high yields (70–99%) of the reduced product. The effect was particularly marked in the case of deactivated aryl halides; for example, /?-bromotoluene gave a 97% yield of toluene in 5 h. In contrast, the yield of the stirred reaction was a modest 21% after 24 h at room temperature in THF (Scheme 112).

Carbon monoxide reacts with unsaturated compounds, such as olefins and acetylenes, in the presence of a variety of protic co-substrates and transition metal carbonyl catalysts to afford carboxylic acid derivatives (Reactions 1–6). These transformations are generally referred to as Reppe carbonylations after their discoverer [1].

During the first period of this contract our work has focused on the synthesis of appropriate aryl ethers to use in testing ether cleavage reactions. These compounds were prepared by standard literature conditions. Generally, an appropriate aryl halide was treated with sodium phenoxide at 150 to 250/sup 0/C using a copper powder catalyst. After separating from the copper and extracting the unreacted sodium phenoxide with water, the residual crude phenyl ether was purified by crystallization, distillation or column chromatography. Several grams of each ether has been obtained. The study of the reductive cleavage of ethers by electrochemical means has been initiated. Cyclic voltammetry was used to determine the reduction potentials and radical anion stabilities for a series of aryl ethers in N,N'-dimethylformamide (DMF). Table 1 summarizes the ethers, which have been currently investigated by cyclic voltammetry. All of these ethers are reduced to a radical anion in a one-electron step at a platinum electrode in DMF using tetrabutylammonium perchlorate (TBAP) as the supporting electrolyte. The stability of the resultant anion radical of the ether is apparently determined by the ability of the anion to delocalize charge away from the carbon-oxygen bond of the ether. The diphenyl ether radical anion ismore » unstable on the time scale of the electrochemical experiment. For example, the radical anion appears to be virtually absent during the reverse scan at a scan rate of 1.0 V/s. This would imply a half-life of less than 10/sup -1/ seconds for the radical anion of diphenyl ether. In contrast, the radical anion of dibenzofuran is quite stable on the electrochemical experimental time scale; there appears to be very little decomposition of the radical anion at reverse scan rates of 0.01 V/s. This is indicative of a half-life of greater than 10/sup 2/ seconds for the dibenzofuran radical anion at 25/sup 0/C.« less

The reactions of perfluoroalkyl iodides with allyl, vinyl or aryl halides with ultrasonically dispersed zinc in the presence of palladium catalyst proceeded smoothly to give the corresponding allyl...

Publisher Summary This chapter discusses the various reactions of interest in medicinal chemistry, such as aromatic substitution, halogenation, oxidation, by the use of oxidants absorbed on alumina or silica, reactions regarding carboxylic acids and derivatives, and various miscellaneous reactions. Several improvements in the aldol reaction have been noted. Coupling of an α-bromocarbonyl compound with another carbonyl compound via dialkylaluminum chloride–zinc, produces aldol regiospecifically in high yield. Fluoride ion catalyzed reaction of enol sily ethers and carbonyl compounds prepares aldol products regiospecifically. Aldol type products are stereoselectively synthesized by Claisen rearrangement of silylketene acetals. For aromatic substitution, arylamines are directly converted to aromatic hydrocarbons by alkyl nitrites in DMF­. Alternatively, an aryl halide is produced when cupric halides are added in acetonitrile. The alkyl-nitrite deamination method also provides a convenient variant of the meerwein arylation reaction. In a related method, diazonium ions are converted to phenols with cuprous oxide-cupric nitrate. This radical process avoids the problems of the strongly acidic classical transformation. Phenols may also be converted to anilines via smiles rearrangement that is greatly accelerated by HMPA solvent. An interesting anionic equivalent of the Friedel–Crafts cycloacylation is demonstrated in this chapter. The oxidative reagents absorbed on alumina or silica are generally milder and more selective, and provide for convenient reaction workup. Oxidations of cyclobutanol to cyclobutanone, and β-hydroxysulfides and selenides to the β-keto compounds are accomplished by trichloroacetaldehyde on alumina.

In this chapter we will consider reactions which involve substitution on the aromatic ring but not reactions of a substituent such as methyl on the ring. Mechanistic discussion will be delayed until the very end of the chapter since all the reactions have mechanistic aspects in common.

The two books mentioned in Chapter 7 by Kochi(1) and by Collman and Hegedus(2) should be included once again in this chapter. The 18 months under survey have produced many interesting papers, so that selection has been difficult. The reviewer has found particularly fascinating the attempts to discover what individual steps occur during oxidative addition processes (namely, those processes which formally involve the loss of two electrons from the metal). The work, in what must be a difficult field experimentally, on the mechanism of formation of Grignard reagents should also be highlighted.

At the outset of this work, two mechanisms for the oxidative addition1 of alkyl halides to low valent metal complexes had been postulated.

The preparation of a series of O-aryloximes of various steroids by two different routes is described. These compounds were prepared by reacting a keto steroid with a substituted O-arylhydroxylamine in the presence of an acid catalyst or, alternatively, by the reaction of a steroidal oxime with a substituted aryl halide in the presence of a suitable base. These compounds were examined for their ability to interrupt postimplantive gestation in female rats. The most significant contragestational activity was seen with compounds in which the basic steroid structure was a 5alpha-androstane and the 3-oxime was of the p-nitrophenyl series. One of the most active compounds in the series (16) was shown to have the ability to terminate pregnancy, when orally administered to rats at 2.5 mg/kg on days 9-12 of gestation. This compound was found to be devoid of androgenic activity at this dose level.

Formation of the azetidinonethiol (10) by treatment of the aryl halide (6) with tributylstannane involves an unusually rapid 1,7-hydrogen atom transfer followed by β-fission of the resultant radical (8).

Luehe and Damiano initially reported that sonication of alkyl or aryl halides and lithium gave THF-solutions of organolithium reagents in 1980 [83]. The reaction was shown to be generally applicable and excellent yields of n-propyl, n-butyl, and phenyllithiums could be obtained (61–95%) even in wet technical grade THF! Reaction with isopropyl and i-butyl halides was sluggish, but this reaction should hold potential for large scale industrial applications. Its advantages lie in its rapidity and efficiency, allowing instantaneous initiation of the reaction. This is especially important when working on a large scale where the unpredictability of the initiation period can present a serious problem.

Polyarylethersulphones were reported [1,2,3] in the patent literature as new materials prepared by novel polycondensation reactions during the early 1960s. By this time the basic theory of polycondensation was well established [4] and qualitative theories linking the bulk properties of polymers to their molecular structure had been formulated in some detail [5]. This led polymer chemists engaged in adapting reactions known for monomeric compounds to polymer synthesis to guide their work towards those polymer structures which could be expected to show particularly useful properties. The effects of chain rigidity and polarity on Tg and Tm, increase in either of these parameters leading usually to an increase in the transition temperatures, was well known [6] and incorporating phenylene rings in polymer chains was an obvious method of increasing chain rigidity. However, the predictive power of the knowledge available was limited by its qualitative nature and there was (and still is) a major problem in predicting the softening points of aromatic polymers because the relationships between crystallisability and molecular structure were less well known for these polymers than for their aliphatic analogues.

Hydrogen and halogen substitution in organomercury compounds have been extensively studied and a number of reviews [1–4] and one book [5] have appeared covering this topic. The primary emphasis of most of this work has been on studying the mechanism of electrophilic aliphatic substitution. Considerable kinetic and stereochemical information on these reactions is now available. The emphasis here, however, will be on possible synthetic applications of these reactions.

$$2{\text{M}} + n{\text{RX}} = {R_n}M + M{X_n}(or{R_x}M{X_y}:x + y = n)$$ The reaction between a metal and an organic halogen compound provides a fairly general route to organometallic compounds. One of the earliest organometallic compounds ever to be prepared, ethylzinc iodide, was made in this way from zinc/copper couple and ethyl iodide.

Heterocyclic sulfinates are effective reagents in palladium-catalyzed coupling reactions with aryl and heteroaryl halides, often providing high yields of the targeted biaryl. However, the preparation and purification of complex heterocylic sulfinates can be problematic. In addition, sulfinate functionality is not tolerant of the majority of synthetic transformations, making these reagents unsuitable for multistep elaboration. Herein, we show that heterocyclic allylsulfones can function as latent sulfinate reagents and, when treated with a Pd(0) catalyst and an aryl halide, undergo deallylation, followed by efficient desulfinylative cross-coupling. A broad range of allyl heteroarylsulfones are conveniently prepared, using several complementary routes, and are shown to be effective coupling partners with a variety of aryl and heteroaryl halides. We demonstrate that the allylsulfone functional group can tolerate a range of standard synthetic transformations, including orthogonal C- and N-coupling reactions, allowing multistep elaboration. The allylsulfones are successfully coupled with a variety of medicinally relevant substrates, demonstrating their applicability in demanding cross-coupling transformations. In addition, pharmaceutical agents crizotinib and etoricoxib were prepared using allyl heteroaryl sulfone coupling partners, further demonstrating the utility of these new reagents.

The first Ru(II)-catalyzed arylation of substrates without a directing group was recently developed. Remarkably, this process only worked in the presence of a benzoate additive, found to be crucial for the oxidative addition step at Ru(II). However, the exact mode of action of the benzoate was unknown. Herein, we disclose a mechanistic study that elucidates the key role of the benzoate salt in the C–H arylation of fluoroarenes with aryl halides. Through a combination of rationally designed stoichiometric experiments and DFT studies, we demonstrate that the aryl–Ru(II) species arising from initial C–H activation of the fluoroarene undergoes cyclometalation with the benzoate to generate an anionic Ru(II) intermediate. The enhanced lability of this intermediate, coupled with the electron-rich anionic Ru(II) metal center renders the oxidative addition of the aryl halide accessible. The role of an additional (NMe4)OC(CF3)3 additive in facilitating the overall arylation process is also shown to be linked to a s...

5,6-Disubstituted phenanthridinium cations have a range of redox, fluorescence and biological properties. Some properties rely on phenanthridiniums intercalating into DNA, but the use of these cations as exomarkers for the reactive oxygen species (ROS), superoxide, and as inhibitors of acetylcholine esterase (AChE) do not require intercalation. A versatile modular synthesis of 5,6-disubstituted phenanthridiniums that introduces diversity by Suzuki–Miyaura coupling, imine formation and microwave-assisted cyclisation is presented. Computational modelling at the density functional theory (DFT) level reveals that the novel displacement of the aryl halide by an acyclic N-alkylimine proceeds by an SNAr mechanism rather than electrocyclisation. It is found that the displacement of halide is concerted and there is no stable Meisenheimer intermediate, provided the calculations consistently use a polarisable solvent model and a diffuse basis set.

The Ni-catalyzed trifluoromethylthiolation of aryl halides with [NMe4][SCF3] has been studied with DFT methodology to find out the mechanism governing the reaction. Two different cross-coupling pathways have been explored; the first one, involving the classical Ni(0)/Ni(II) catalytic cycle, does not provide a good explanation for the experimental outcomes. In contrast, an alternative Ni(I)/Ni(III) catalytic cycle affords a much better agreement with what is observed experimentally: a low reaction barrier that allows the reaction to work at room temperature for aryl iodides, and an interpretation of the reactivity for other aryl halides and substituted iodobenzenes. The active Ni(I) catalyst is generated through a two-step process consisting of a singlet to triplet transformation of the initial nickel species followed by a subsequent halogen atom transfer from the aryl halide.

This paper describes the synthesis of Pd-containing catalysts based on nonfunctionalized hypercrosslinked polystyrene via impregnation with Pd acetate. Developed Pd nanoparticulate catalyst allowed achieving conversion of aryl halide up to 90% in Suzuki cross-coupling reaction under mild conditions and at the absence of phase-transfer agents. During the selective hydrogenation of triple C-C bond of 2-methyl-3-butyn-2-ol, up to 96% selectivity with respect to corresponding olefinic alcohol was found at 95% conversion. The influences of the procedure of catalyst synthesis like precursor decomposition and reductive activation method on Pd nanoparticle formation are discussed.

It has been found that seventeen nickel complexes of the Ni–O4, Ni–S4, Ni–O2N2, Ni–O3N3, Ni–N4, Ni–N6, and Ni–(C5)2 types exhibit a high catalytic activity for the selective cross-coupling reaction of an aryl Grignard reagent with aryl iodide, which make possible the synthesis of unsymmetrical aromatics of a high purity and in a high yield.

Reaction of ethyl α-(tributylstannyl)acetate with aryl bromides in the presence of zinc bromide or chloride and a catalytic amount of dichlorobis(tri-o-tolylphosphine)palladium was found to give ethyl arylacetates in good yields except with the aryl bromide having p-acetyl or p-nitro group.

Addition of an alkyl or aryl halide RX to Sn[CH(SiMe3)2]2, (1), occurs readily at 20 °C in C6H6 or n-C6H14 to give SnX[CH(SiMe3)2]2R, (2). Similarly CH2X′2(X′= Br or I) and (1) give CH2{SnX′[CH(SiMe3)2]2}2, (3). A side-product of some of the former reactions is SnX2[CH(SiMe3)2]2; a radical mechanism is proposed with SnX[CH(SiMe3)2]2˙ as the intermediate, for which R· and RX are in competition. Infrared spectra support a covalent monomeric tin(IV) structure for the chlorides (2). Hydrogen-1, and in some cases 13C, n.m.r. spectra for (2) or (3) in benzene or methylene chloride solutions are consistent with a monomeric Cs molecular structure, showing diastereotopically distinct SiMe3 groups. Addition of (CD3)2SO or C5D5N leads to collapse of these doublets or, for R = But, a decrease in their separation, suggestive (with i.r. data) of a stereochemically non-rigid, five-co-ordinate, tin compound. A single-crystal X-ray analysis of SnCl[CH(SiMe3)2]3 shows a covalent monomeric structure with the three alkyl groups slightly flattened from the tetrahedral : Sn–Cl 2.380(3), Sn–C (av.)ca. 2.18 A; C–Sn–Cl (av.)ca. 103.9, C–Sn–C (av.)ca. 114.4°.

The reaction of 2,3-dichloronitrobenzene with copper bronze gives, in a total yield of 100%, 1,5-dinitrobiphenylene and 1,5,9-trinitrotriphenylene. The formation of these compounds necessarily implies an initial ortho–meta coupling, which rules out a free-radical process, and a mechanism involving the coupling of two molecules of an organocopper intermediate. The results are, on the contrary, in good accord with the ionic mechanism, proposed by Fanta, according to which the organocopper intermediate reacts with a molecule of the aryl halide.

A Transient intermediate which decays in a first-order process with k= 12.6 s–1 in the photochemical cyclization of 5-(2-chlorophenyl)-1,3-diphenylpyrazole has been observed; because of the relatively long lifetime this is probably a cyclohexadienyl radical.

The addition of an alkyl or phenyl halide RX to Sn[CH(SiMe3)2]2(X = Cl, Br, or I) or Sn[N(SiMe3)2]2(X = Br or I) in n-hexane at 20 °C readily affords the 1 : 1-adducts (or 1:2-adduct for RX = CH2Br2 or CH2I2) which shows two sets of diastereotopically distinct Me3Si3 groups for Sn[CH(SiMe3)2]2(X)R but not the nitrogen analogue; optical-activity and e.s.r data suggest a free-radical mechanism with ·SnY2(X) and R· as intermediatesd [Y =(Me3Si)2CH or (Me3Si)2N].

Formation of the azetidinonethiol (10) by treatment of the aryl halide (6) with tributylstannane involves an unusually rapid 1,7-hydrogen atom transfer followed by β-fission of the resultant radical (8).

Electron addition to C6F5I, C6F5Br, the corresponding di-iodo and dibromo derivatives, and C6F5Cl gave only σ* radicals, as deduced from the e.s.r. spectra. Addition was achieved by exposing dilute solutions at 77 K to 60Co γ-rays, and was confirmed by observing a reduction in yield when electron-scavenging solutes were added. The σ* orbital containing the unpaired electron is shown to be largely confined to a single C—Cl, C—Br or C—I bond. However, for the ortho-disubstituted derivatives, the halogen hyperfine parameters were clearly reduced, indicating slight delocalisation into the neighbouring C—halogen bond. No features of the type characteristic of π* anions or the delocalized C6F6– system were observed. The results are compared with those for the corresponding aryl halide σ* anions, which exhibit less delocalisation of the excess electron onto halogen.

In general 4-thioquinoline ethers may be obtained using following procedures: 1. The reaction of 4-thioquinolones with organic halogen derivatives or other alkylating reagents \e.g. sulfates\. The reaction is usually carried out in the alkaline medium. This procedure is suitable for the synthesis of 4-alkylthioquinolines and in some cases 4-arylthioquinolines providing that the halogen of aryl halide is strongly activated by electron withdraving substituents. 2. The reaction of 4-halogenoquinolines with thiols. This reaction is suitable for the synthesis of both aliphatic and aromatic 4-thioquinoline ethers. If conditions of the reaction are carefully choosen the second procedure can give exellent results. Thiosalicylic acid reacted with 4-chloroquinolines in dry pyridine to give o-carboxyphenyl-4-thioquinoline ethers with % 85–99 yields. The precipitation of the product was achieved by addition of a few drops of water. The water is needed for the formation of hydrates. More facile purification b...

Reaction of 3-bromobenzofuran with trifluoromethyl iodide and copper powder in pyridine gave 2-(trifluoromethyl)-, 2- and 3-(pentafluoroethyl)-, and 2,3-bis(trifluoromethyl)-benzofuran, as well as the expected product, 3-(trifluoromethyl)benzofuran. Bromoanisole also gave (trifluoromethyl)anisole and (pentafluoroethyl)anisole, but introduction of the perfluoroalkyl group occurred at the position originally occupied by the bromine. Formation of pentafluoroethyl compounds is explained by decomposition of trifluoromethylcopper to cuprous fluoride and difluorocarbene, which can then react with a further molecule of trifluoromethylcopper to form pentafluoroethylcopper. This then reacts with aryl halide to give pentafluoroethyl compounds. Perfluoroalkylcopper is thermally cleaved to perfluoroalkyl radical, which then reacts with pyridine to give perfluoroalkylpyridines. This mechanism must be involved in the formation of 2,3-bis(trifluoromethyl)benzofuran. Introduction of a perfluoroalkyl group to the position originally unoccupied with halogen might be due to the rather localized double bond in benzofuran.

The molecular structure and absolute configuration of maytansine (Ia) have been found from a three-dimensional single-crystal X-ray analysis of its (3-bromopropyl) ether (Ib). Crystals are orthorhombic, space group P212121 with a= 24·239(4), b= 16·044(4), c= 10·415(2)A, and Z= 4. The structure was solved by the heavy-atom method and refined by Fourier and least-squares methods to R 0·101 for 927 independent reflections measured by counter diffractometry. The absolute configuration was established by the anomalous dispersion method.The molecule contains a 19-membered ring with the nitrogen-containing aliphatic portion bridging a substituted phenyl group in a 1,3-ansa-fashion. The structure shows similarities to those of the ansamycin antibiotics, but has novel epoxide, carbinolamine ether, and aryl halide functions.

fluoride, chloride, bromide, and iodide, and copper(I) was present as the chloride, bromide, iodide, cyanide, thiocyanate, or thiophenoxide. In addition rate constants were obtained for the exchange between an aryl bromide and copper(I) chloride in twelve basic solvents at 110.50 and 144.50C. Since the experimental results can be interpreted by more than one mechanism, it is the purpose of this note to present an alternative treatment emphasizing: a) the somewhat specific function of the copper(I) structure in the reaction; and b) the influence exerted by the solvent upon the reaction rate. The following conclusions drawn by Bacon and Hill(2) must form the experimental basis for any proposed mechanism for the copper(I) salt-aryl halide reactions. (1) Only for copper(I) salts does the reaction proceed at a significant and measurable rate. (Chlorides of lithium, silver(I), gold(I), thallium (I), zinc (II), mercury (II), iron (II), and cobalt (II) were included in the study.) (2) The overall rate equation is second order and bimolecular between the aryl halide and the copper(I) salt, and the rate is inhibited by certain ligands. (3) The rate constant is dependent upon the solvent, and changes by a factor as great as 200 in the extremes. (4) The sequence for the ease of displacement of the halide from the aryl nucleus is I > Br > Cl >> F. (5) The order of increasing ease of substitution on the aryl nucleus by the halide from CuX is Cl > Br > I >CN > SCN. Three mechanisms given by Bacon and Hill for the bond-breaking step in the activated complex include: (a) a four-center process without