Synthesis of Substituted Arenes

The trimerization of alkynes is a general and useful method for the preparation of aromatic compounds [152]. However, this method has serious limitations when three different alkynes are used, as numerous regioisomers may be formed. Taka-hashi and co-workers have reported the beginnings of a solution using zirconocy-clopentadienes prepared in situ from two different alkynes. Substituted arenes were obtained upon addition of a third alkyne to the organometallic complex in the presence of copper chloride [153] or a nickel complex [154], This approach is nevertheless limited by the fact that at least one of the alkynes must be symmetrical, and by 

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This reaction is a powerful tool and represents an alternative for the synthesis of substituted arenes difficult to prepare via classical electrophilic or nucleophilic aromatic substitution. Using bi- or polyfunctional arenes as starting materials, this reaction affords novel organoiron polymers [76] (Scheme 1.35). 

Abstract Stoichiometric cycloruthenation reactions of substrates containing Lewis-basic functionalities set the stage for efficient ruthenium-catalyzed C-H bond functionalization reactions. Thereby, selective addition reactions of C-H bonds across alkenes or alkynes enabled atom-economical synthesis of substituted arenes. More recently, ruthenium-catalyzed direct arylation reactions were examined, which display an unparalleled scope and, hence, represent economically and environmentally benign alternatives to traditional cross-coupling chemistry. 

Since their discovery during the 1860s, electrophilic aromatic substitution reactions played the dominant role for functionalizations of arenes, and were often the method of choice for the synthesis of substituted arenes. For example, Hermann Kolbe, a student of Friedrich Wohler, devised a synthesis for salicylic acid (7) [13, 14], which set the stage for the industrial preparation of acetylsalicylic acid (ASA, aspirin) (1) by Arthur Eichengriin and Felix Hoffmann at Bayer in 1897 (Scheme 1.2). 

Transition metal-vinylidene complexes [58] are generated through the reaction of transition metal complexes and terminal aUtynes via 1,2-hydrogen transfer (Scheme 21.52). The reactive transition metal-vinylidene complexes thns generated have been used in organic synthesis including the synthesis of substituted arenes [59]. 

This last fact, coupled with the observation that significant quantities of benchrotrene itself are present in the reaction medium (and thus susceptible to nucleophilic attack) has led to the synthesis of substituted arenes and... 

Scheme 5-19. Solid-phase synthesis of substituted arenes using a Heck-Matsuda type sequence. ...

The development of synthetic methods for solving the problem of the synthesis of substituted arenes by Friedel-Crafts substitution has focused on three-component coupling of acetylenes. However, there are certain restrictions since attempts at trimerizing two or three different alkynes led to complex mixtures (Scheme 2.3) [9]. Synthesis of trisubstituted benzenes is also problematic in terms of the lack of selectivity during the initial formation of metallocycle as well as the reaction with the third alkyne [9]. 

In recent years, several new approaches have been published on the synthesis of substituted arenes using [2+2+2] cycloaddition catalyzed by transition metals. This includes the selective trimerization of three different alkyne components used in stoichiometric amounts, in the... 

This method ensures the deposition of very reactive metal nanoparticles that require no activation steps before use. We shall review here the following examples of catalytic reactions that are of interest in line chemical synthesis (a) the hydrogenation of substituted arenes, (b) the selective hydrogenation of a, 3-unsaturated carbonyl compounds, (c) the arylation of alkenes with aryl halides (Heck reaction). The efficiency and selectivity of commercial catalysts and of differently prepared nanosized metal systems will be compared. 

A clever application of this reaction has recently been carried out to achieve a high yield synthesis of arene oxides and other dihydroaromatic, as well as aromatic, compounds. Fused-ring /3-lactones, such as 1-substituted 5-bromo-7-oxabicyclo[4.2.0]oct-2-en-8-ones (32) can be readily prepared by bromolactonization of 1,4-dihydrobenzoic acids (obtainable by Birch reduction of benzoic acids) (75JOC2843). After suitable transformation of substituents, mild heating of the lactone results in decarboxylation and formation of aromatic derivatives which would often be difficult to make otherwise. An example is the synthesis of the arene oxide (33) shown (78JA352, 78JA353). 

The synthetic potential of transition metal atoms in organometallic chemistry was first demonstrated by the formation of dibenzenechrom-ium (127). Apart from chromium, Ti, V, Nb, Mo, W, Mn, and Fe atoms each form well-defined complexes with arenes on condensation at low temperatures. Interaction has also been observed between arenes and the vapors of Co, Ni, and some lanthanides. Most important, the synthesis of metal-arene complexes from metal vapors has been successful with a wide range of substituted benzenes, providing routes to many compounds inaccessible by conventional reductive preparations of metal-arene compounds. 

A gentle procedure has made these complexes available with a variety of substituted arenes.36 Direct displacement of CO from the perchlorate salts of [Mn(CO)s]+ or [Mn(CO)3(acetone)3]+ with the arene in dichloromethane at reflux leads to precipitation of the [(arene)Mn(CO)3] salt. The conditions are milder than the AlCh-promoted procedure employed earlier.37 Only a handful of substituted arenes have been attached to [Mn(CO)3]+, but the general synthesis method suggests few limitations (equation 5). 

Although significant improvements have been made in the synthesis of phenol from benzene, the practical utility of direct radical hydroxylation of substituted arenes remains very low. A mixture of ortho-, meta- and para-substituted phenols is typically formed. Alkyl substituents are subject to radical H-atom abstraction, giving benzyl alcohol, benzaldehyde, and benzoic acid in addition to the mixture of cresols. Hydroxylation of phenylacetic acid leads to decarboxylation and gives benzyl alcohol along with phenolic products [2], A mixture of naphthols is produced in radical oxidations of naphthalene, in addition to diols and hydroxyketones [19]. 

Trityl resins are particularly suitable for immobilization of nucleophilic substrates such as acids, alcohols, thiols, and amines. They are quite acid-sensitive and are cleavable even with acetic acid this is useful when acid-labile protecting groups are used. The stability of trityl resin can be tailored by use of substituted arene rings, as shown by chlorotrityl resin, which furnishes a more stable linker than the trityl resin itself. Steric hindrance also prohibits formation of diketopiperazines during the synthesis of peptides. Orthogonality toward allyl-based protective groups was demonstrated in the reverse solid-phase peptide synthesis of oligopeptides [30] (Scheme 6.1.4). 

The use of Bu3SnH and AIBN has become commonplace in the synthesis of annulated arenes by the intramolecular aromatic substitution via aryl and heteroaryl radicals (see Chapter 13). Nevertheless, a simpler and more environmentally friendly protocol should be the direct generation of the o-aryl or heteroaryl radicals by UV-induced homo lytic cleavage of an aryl halide with subsequent intramolecular attack onto an arene in proximity. Accordingly, tricyclic [2,1-a] fused heterocycles were regioselectively formed in high yields from N-(2-arylethyl)-2-iodoimidazoles upon irradiation in acetonitrile (Scheme 14.18) [92]. 

Kurono N, Honda E, Komatsu F, Orito K, Tokuda M (2004) Regioselective synthesis of substituted 1-indanols, 2,3-dihydrobenzofurans and 2,3-dihydroindoles by electrochemical radical cyclization using an arene mediatra. Tetrahedron 60 1791—1801... 

The intramolecular hydroarylation of alkynes is a useful method for the synthesis of fused arenes. For example, biphenyl derivatives, bearing an alkyne unit at the ortho position, were converted into substituted phenanthrene derivatives in the presence of various jc-electrophihc transition metal catalysts such as platinum, palladium, gold, gaUium, indium, iron, and so on (Scheme 21.48) [54]. 

An overview of the effect of catalyst in the reaction of arenes with chromium hexacarbrmyl has been published. The reactivity of 17-, 18-, and 19-etectron catkMis generated electrochemically from mesitylene-tungsten tricarbonyl has been examined. The gas phase ion chemistry of a range of arene tricarbonylchromium complexes has been investigated by F.T. mass spectrometry. An improved synthesis of substituted naphthalene chromium carbonyls has appeared. ... 

Chapter 15 described the use of this transformation in the preparation of monosubstituted benzenes. In this chapter we analyze the effect of such a first substituent on the reactivity and regioselectivity (orientation) of a subsequent electrophilic substitution reaction. Specifically, we shall see that substituents on benzene can be grouped into (1) activators (electron donors), which generally direct a second electrophilic attack to the ortho and para positions, and (2) deactivators (electron acceptors), which generally direct electrophiles to the meta positions. We will then devise strategies toward the synthesis of polysubstituted arenes, such as the analgesics depicted on the previous page. 

Synthesis of Substituted Benzenes The coupling reaction of zircona-cyclopentadiene with halogenated arenes provides a direct method of aromatic ring extension. As shown in Scheme 11.25, the reaction of zirconacyclopentadienes 4 with diiodobenzene in the presence of CuCl and DMPU afforded 1,2,3,4-tetra-substituted naphthalenes 60 in good yields. When tetraiodobenzene was used under similar conditions, 1,2,3,4,5,6,7,8-octa-substituted anthracene derivatives 61 could also be prepared [28]. 

Many articles have been published on the formation of substituted arenes by this type of reaction in the presence of transition metals. The current development of the field of organic synthesis focuses on the design of intermolecular substituted arenes, which makes it possible to control the construction of a precursor in the synthesis of the product... 

The preparation of amines by the methods described m this section involves the prior synthesis and isolation of some reducible material that has a carbon-nitrogen bond an azide a nitrile a nitro substituted arene or an amide The following section describes a method that combines the two steps of carbon-nitrogen bond formation and reduction into a single operation Like the reduction of amides it offers the possibility of prepar mg primary secondary or tertiary amines by proper choice of starting materials... 

Yosida et al. [41] found that p-t< rr-butylcalix[6]ar-ene can extract Cu from the alkaline-ammonia solution to the organic solvent. Nagasaki and Shinkai [42] described the synthesis of carboxyl, derivatives of calix-[n]arenes ( = 4 and 6) and their selective extraction capacity of transition metal cations from aqueous phase to the organic phase. Gutsche and Nam [43] have synthesized various substituted calix[n]arenes and examined the complexes of the p-bromo benzene sulfonate of p-(2-aminoethyl)calix[4]arene with Ni, Cu , Co-, and Fe. ... 

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