Transition Metal Catalyzed Coupling Methods

Mechanistic studies supported the evidence that arylcopper compounds are intermediates in the synthesis of biaryls [60, 61]. This observation smoothed the way for the efficient synthesis of unsymmetric biaryls in a two-step procedure consisting, first, in the preparation of an, e.g. thienylcopper derivative followed by the treatment with different aryl halides. 2-Thienylcopper 42, for example, is prepared from the corresponding Li—Ti—H 9 or Grignard derivative and a copper(I)halide and is then reacted with iodo- or bromoarenes in pyridine or quinoline. By this procedure e.g. H-T2-H 2 is formed in 42% yield by the reaction of Cu-Ti-H 42 and 2-iodothiophene 8 [61] [Eq. (14)]. Analogously, 2-(/i-nitro-phenyl)thiophene is obtained in 70% when Cu—Ti—H 42 is treated with / -iodo-nitrobenzene. Note that the formation of undesired symmetric biaryl products is avoided [60, 61, 63]. 

The Kumada reaction has become the most frequently used method in the synthesis of various types of thiophenes. Since its mechanism is basically valid also for other reactions catalyzed by transition metals, it will be elucidated more thoroughly [69, 70]. The catalytic cycle is depicted in Fig. 3. 

Due to the starting reaction in the catalytic cycle the homo-coupling product may be found to a certain extent which is typically around 0.5-1.5% [72]. Nevertheless, the reaction is usually very selective and gives the cross-coupling products in high yields. 

The reaction is applicable to various types of Grignard reagents (e.g. aryl, alkyl) and organic halides bearing a C pi-carbon (e.g. aryl, vinyl). The reactivity order of the halide component was found to be Ar—I Ar-Br Ar-Cl Ar-F. Grignard reagents are equally prepared either in Et20 or in THF, however, the 

In general, the Pd-complexes are less reactive, but more selective. Rossi et al. discovered that depending on the ratio of the reacting compounds, the Pd(dppf)Cl2-promoted reaction of the Grignard reagents of 2- or 3-bromothiophene with dibromothiophenes results in either mono-coupling to synthetically very valuable bromobithiophenes or in a twofold reaction to terthiophene isomers [76]. 

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As outlined earlier, three methods of polymerization have been established for the preparation of thiophenes, viz. electrochemical polymerization [189, 190], oxidative chemical polymerization using Lewis acid catalysts such as FeCl3 [191,192], and step-growth condensation polymerization using transition metal-catalyzed coupling reactions [lj]. 

Since halogen-substituted benzo[. ]furans play an important role in the transition metal-catalyzed coupling of benzo[. ]furans with other substrates, synthetic methods to regioselectively synthesize substituted benzo[ ]furan halides have become very critical routes. Several syntheses of benzo[ ]furan based aryl halides are described here. 

Acid chlorides are prepared by standard methods and undergo the usual acid chloride reactions. They have found important applications as substrates in the syntheses of ketones by transition metal-catalyzed coupling reactions with organometallics (Section 6.02.5.5.14). Acid chlorides (424) are also good substrates for the preparation of ketones (425) using organomanganese(II) iodide, especially for the preparation of alkyl pyrimidinyl ketones <86ACS(B)764>. 

Transition metal catalyzed coupling polymerization The most popular method for the s)mthesis of BDT based conjugated polymers takes advantage of the well-developed transition-metal mediated coupling reactions, featuring mild reaction conditions, remarkable functional group tolerance and high yields (Scheme 3.6). 

Soluble and weU-characterized polygermane homopolymers, (R Ge), and their copolymers with polysdanes have been prepared by the alkaH metal coupling of diorgano-substituted dihalogermanes (137—139), via electrochemical methods (140), and by transition-metal catalyzed routes (105), as with the synthesis of polysdanes. 

The last method for the preparation of 2-quinolones described in this chapter relies on a intramolecular Heck cyclization starting from heteroaryl-amides (Table 2) [57]. These are synthesized either from commercially available pyrrole- and thiophene-2-carboxylic acids (a, Table 2) or thiophene-and furan-3-carboxylic acids (b, Table 2) in three steps. The Heck cyclization is conventionally performed with W,Ar-dimethylacetamide (DMA) as solvent, KOAc as base and Pd(PPh3)4 as catalyst for 24 h at 120 °C resulting in the coupled products in 56-89% yields. As discussed in Sect. 3.4, transition metal-catalyzed reactions often benefit from microwave irradiation [58-61], and so is the case also for this intramolecular reaction. In fact, derivatives with an aryl iodide were successfully coupled by conventional methods, whereas the heteroarylbromides 18 and 19, shown in Table 2, could only be coupled in satisfying yields by using MAOS (Table 2). 

The transition metal cross-couplings of allenes described here offer practical solutions for the modification of 1,2-dienes and access to the preparation of highly functionalized 1,3-dienes, alkynes and alkenes, which are often not easily accessible in a regio- and stereoselective manner by classical methods. Some of the prepared alkynes or functionalized allenes serve as important intermediates in syntheses of natural products, biologically active compounds, e.g. enynes and enyne-allenes, and new materials. It can be predicted that further synthetic efforts will surely be focused on new applications of allenes in transition metal-catalyzed cross-coupling reactions. 

The increased development of transition metal-catalyzed cross-coupling methods to form C-C bonds has served as an impetus to find methods to synthesize 3-halochromones and 3-haloflavones. The synthesis of 3-halochromones and flavones can be achieved with the addition of halogens across the double bond of the pyrone ring by reaction with a halogenating reagent (e.g., Br2) followed by spontaneous, or base-induced, elimination (Scheme 48). Synthesis of these important compounds has been recently reviewed <2003RCR489>. 

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