Heteroaromatic alkynes

Electrochemical studies are usually performed with compounds which are reactive at potentials within the potential window of the chosen medium i.e. a system is selected so that the compound can be reduced at potentials where the electrolyte, solvent and electrode are inert. The reactions described here are distinctive in that they occur at very negative potentials at the limit of the cathodic potential window . We have focused here on preparative reductions at mercury cathodes in media containing tetraalkylammonium (TAA+) electrolytes. Using these conditions the cathodic reduction of functional groups which are electroinactive within the accessible potential window has been achieved and several simple, but selective organic syntheses were performed. Quite a number of functional groups are reduced at this limit of the cathodic potential window . They include a variety of benzenoid aromatic compounds, heteroaromatics, alkynes, 1,3-dienes, certain alkyl halides, and aliphatic ketones. It seems likely that the list will be increased to include examples of other aliphatic functional groups. 

The reaction of aryl halides 1 with alkynylcopper(I) 2 under reflux in pyridine to prepare internal arylacetylenes is known as the Stephens-Castro reaction [Eq. (1)] [2]. The reaction has proved to be particularly important in the synthesis of a wide range of tolan and heteroaromatic alkynes [3]. Vinyl and allenic halides can also be used and several reviews... 

Lautens and Yoshida reported a similar rhodium-catalyzed hydroarylation of alkynes with arylboronic acids, where ortho nitrogen heteroaromatic alkynes were employed to favor a high regioselectivity [43]. The reaction of 2-(l-hexynyl)pyridine (67a) with 2-methylphenylboronic acid (2v) and [RhCl(cod)]2/69 catalyst in the presence of sodium carbonate and sodium dodecyl sulfate (SDS) in water gave a 84% yield of the addition product 68av with high regioselectivity (Scheme 4.31). Under these conditions, the addition of arylboronic acids was also observed for several other or-... 

Small shift values for CH or CHr protons may indicate cyclopropane units. Proton shifts distinguish between alkyne CH (generally Sh = 2.5 - 3.2), alkene CH (generally 4, = 4.5-6) and aro-matic/heteroaromatic CH (Sh = 6 - 9.5), and also between rr-electron-rich (pyrrole, fiiran, thiophene, 4/ = d - 7) and Tt-electron-deficient heteroaromatic compounds (pyridine, Sh= 7.5 - 9.5). 

The mechanism of attack of 1,3-dipolar reagents on fluoroalkenes can be considered to be either stepwise or concerted. Heteroaromatic N-imines react by a stepwise 1,3 addition to perfluoroalkenes and -alkynes to give fluorinated pyrazolo[l,5-a]pyridines [82JCS(P1)1593]. Pyridinium /-butoxycarbonylmethylide with fluoroalkenes gave pyrrolo[l,2-a]pyri-dines [86JCS(P 1) 1769] and indolizines (22) are obtained with pyridinium phenacylide [91JFC(51)407]. 

Recently, Larock and coworkers used a domino Heck/Suzuki process for the synthesis of a multitude of tamoxifen analogues [48] (Scheme 6/1.20). In their approach, these authors used a three-component coupling reaction of readily available aryl iodides, internal alkynes and aryl boronic acids to give the expected tetrasubsti-tuted olefins in good yields. As an example, treatment of a mixture of phenyliodide, the alkyne 6/1-78 and phenylboronic acid with catalytic amounts of PdCl2(PhCN)2 gave 6/1-79 in 90% yield. In this process, substituted aryl iodides and heteroaromatic boronic acids may also be employed. It can be assumed that, after Pd°-cata-lyzed oxidative addition of the aryl iodide, a ds-carbopalladation of the internal alkyne takes place to form a vinylic palladium intermediate. This then reacts with the ate complex of the aryl boronic acid in a transmetalation, followed by a reductive elimination. 

The Pd-catalyzed C-C coupling (Sonogashira coupling) was applied to polymer synthesis about 20 years ago [23-25], and has especially been developed for the synthesis of n-conjugated poly(aryleneethynylene)s (PAEs) (for reviews, see refs. [16,26-33]). Recently other synthetic routes for PAEs were also developed, e.g., the alkyne metathesis method [28, 34] and the coupling reaction of =C-MR3 with R X (M=Si [35, 36] or Sn [37, 38]). In this review, we are concerned with the synthesis and chemical properties of PAEs with heteroaromatic rings. 

More recently, Pirrung and co-workers established the facility with which the Rh2(OAc)4 catalyzed reaction of 2-diazocyclohexane-l,3-dione (306) and its substituted derivatives (Scheme 8.76) occurs with dihydrofuran and dihydropyran (351-353), vinyl acetates (354) (306 307), terminal alkynes (355) (306 308), methoxyallene (355), trimethylsilylketene (serving as a synthetic equivalent for ketene) (355), and heteroaromatic compounds (353). This reaction is quite useful... 

Insertion can also be carried out on the C-H bonds of heteroaromatics. Masahiro Murakami of Kyoto University has described (J. Am. Chem. Soc. 2003,125,4720) a Ru catalyst that will effect rearrangement of a silyl alkyne such as 10 into the vinylidene carbene. The intermediate Ru carbene complex is then electrophilic enough to insert into the aromatic C-H bond. The insertion is highly regioselective. The Au and the Ru alkylidene insertions are geometrically complementary, as Ru gives the E-alkcne. 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

Selective addition of alkenes and alkynes to aromatic compounds has also been performed by ruthenium-catalyzed aromatic C-H bond activation. Carbon-carbon bond formation occurs at the ortho positions of aromatic compounds, assisted by the neighboring functional group chelation. The reaction, catalyzed by RuH2(CO)(PPh3)3, was efficient with aromatic and heteroaromatic compounds, with various functional groups, and a variety of alkenes and alkynes [ 121 ] (Eq. 90). Activation of vinylic C-H bonds can occur in a similar manner. 

Since perfluoroalkyl-substituted olefins and alkynes possess low-lying frontier orbitals, [4 + 2] cycloaddition reactions to oxazoles and thiazoles without strongly electron-donating substituents are unfavorable. On the other hand, five-membered heteroaromatic compounds possessing an electron-rich diene substructure, like furans, thiophenes, and pyrroles, should be able to add perfluoroalkyl-substituted olefins as well as alkynes in a normal Diels-Alder process. A reaction sequence consisting of a Diels-Alder reaction with perfluoroalkyl-substituted alkynes as dienophile, and a subsequent retro-Diels-Alder process of the cycloadduct initially formed, represents a preparatively valuable method for regioselective introduction of perfluoroalkyl groups into five-membered heteroaromatic systems. 

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