Stille coupling carbon nucleophiles

The synthesis starts with 2,4-dibromothiazole (40), a regioselective Pd(0)-catalysed cross coupling step introduces a substituent at the 2-position. Alkyl or aryl zinc halides were employed as the nucleophiles to give 41. The 4-bromothiazole derivative 41 was then converted into a carbon nucleophile either as a zinc derivative (Negishi conditions) or as a tin derivative (Stille conditions) which then underwent a second cross coupling reaction with 2,4-dibromothiazole (40) to give exclusively 2 ,4-disubstituted 2,4 -bithiazoles 42. 

Carbon-carbon bond formation is fundamental to all of organic chemistry. Nucleophilic displacement is still the basis for most of what we do, but over the past thirty years radical addition and organometallic coupling have both been brought to a level of practical importance. 

Replacing the terminal alkyne by an arylzinc, an aryltin, or an arylboron compound leads respectively to the Negishi, Stille, or Suzuki aromatic cross-coupling reactions. There is no need for a cocatalyst, but the Suzuki reaction requires a nucleophilic base such as aqueous carbonate (Figure lie) (or fluoride) [17b, 22]. 

One distinguishes palladium(0)- and palladium(ll)-catalysed reactions. The most common palladium(O) transformations are the Mizoroki-Heck and the cross-coupling transformations such as the Suzuki-Miyaura, the Stille and the Sonogashira reactions, which allow the arylation or alkenylation of C=C double bonds, boronic acid derivates, stan-nanes and alkynes respectively [2]. Another important palladium(O) transformation is the nucleophilic substitution of usually allylic acetates or carbonates known as the Tsuji-Trost reaction [3]. The most versatile palladium(ll)-catalysed transformation is the Wacker oxidation, which is industrially used for the synthesis of acetaldehyde from ethylene [4]. It should be noted that many of these palladium-catalysed transformations can also be performed in an enantioselective way [5]. 

These versatile reactions, commonly referred to as Stille and Suzuki couplings, respectively, are performed with organostannanes or organoboranes as nucleophiles and are tolerant to most functional groups. Ketones are obtained if carbon monoxide is present in the Stille reaction. This gives the possibility to label an aromatic methyl ketone in two different positions by the use of either [ C] carbon monoxide or [ C] methyl iodide, as shown in O Fig. 41.22 (Andersson et al. 1995 Andersson and Langstrom 1995a, b). 

Nucleophilic attack on Pd-bound ligands, be they a, tt, or (t-tt, provides an assortment of excellent methods for the formation of carbon-carbon and carbon-heteroatom bonds, as represented by general transformations shown in Scheme 1. In particular, these processes have provided three major methods for the formation of the carbon-heteroatom bonds, and they have extensively been applied to the synthesis of natural products. More recently, the Pd-catalyzed cross-coupling has also been developed so as to be applicable to the formation of C— N, C—O, and other carbon-heteroatom bonds, as discussed in Sect. III.3, even though the current scope of their application to natural product synthesis is still rather limited. 

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