Direct cross-coupling

Our third approach to 27 addressed the unavailability of 3-methoxy-2-cyclopentenone (31) in bulk quantities which necessitated the discovery of an alternative route (Scheme 7.7). Fortunately, the precursor to 31,1,3-cyclopentandione (35), was available in the required quantities and our efforts shifted to the use of this reagent Bromination of 35 with NBS, employing either KHC03 or KOH as the base, gave brominated dione 36 in 85% isolated yield. Unfortunately, direct cross-coupling of alkyl bromide 36 with boronic acid 12 under a variety of Suzuki-... 

Kabalka and co-workers reported the direct cross-coupling of cinnamyl alcohols with aryl- and vinylboronic acids using simple rhodium salts in an environmentally benign ionic liquid medium (Eq. 6) [30]. The ability to utilize allylic alcohols, without activation, is significant from the viewpoint of atom economy, yet challenging due to the poor leaving group ability of hydroxide. 

Intramolecular coupling reactions bear some important advantages namely, the opportunity of directed cross coupling and, in most cases, a reliable regioselectivity by kinetic or thermodynamic control of the atropisomer ratio. 

Besides the high chemical and optical yields, this example demonstrates the possibility of directed cross coupling. 

Scheme 5.18 Radical cyclication versus direct cross-coupling.

A particularly interesting application of this protocol, in conjunction with the direct cross-coupling with terminal acetylenes is shown in Scheme 5-2. Here, the first coupling occurs between the alkynyltin reagent 50 and the cyclized palladium intermediate 49 and is followed by the second direct coupling with the terminal acetylene 52 at the vinyl bromide moiety to yield unsymmetrical cyclic dienediyne 53 [32]. 

This protocol and the Pd-Cu-catalyzed direct cross-coupling with terminal acetylenes (Section 5.3.5) directly complement each other. The following examples, which cannot be applied to the latter, give normal coupling products only by Stille method [Eqs. 17-20] [28-31]. This method is especially useful for the cross-coupling reactions of organometallic complexes with cyclopentadienyl ligand that are sensitive to amines [Eq. 19] [30]. 

As described above (Section 5.2), the Stephens-Castro reaction of alkynylcopper with aryl and vinyl halides in boiling pyridine is a useful route to aryl and vinyl acetylenes. Direct cross-coupling of organic halides, such as sp halides, with terminal alkynes is a more convenient procedure. Such a reaction is not so easy, but it can be done using a Pd-complex catalyst [41]. Especially facile Pd-catalyzed cross-coupling of aryl and alkenyl halides with terminal alkynes proceeds smoothly under mild conditions in the presence of a cocatalyst of cuprous iodide in amine solvents [Eq. (28)] [42]. This methodology is now used widely for the constiuction of conjugated arylalkyne or enyne systems [43], as described below. It is attractive from a synthetic point of view because mild reaction conditions and simplicity of the procedure are associated with recent developments in modem acetylene chemistry [44]. 

Whereas the direct cross-coupling reactions of zinc organometallics with organic electrophiles is of limited utility, the scope of these reagents after transmetallation... 

A milder route to arylacetylenes is the Sonogashira reaction, the direct cross-coupling of terminal alkynes with aryl halides or aryl triflates in the presence of catalytic amounts of Pd(PPh3)4 or (PPh3)2PdCl2 and using cuprous iodide as a cocatalyst in... 

The Sonogashira reaction allows for the direct cross-coupling of terminal alkynes with aryl halides under mild conditions through use of catalytic bis(triphenylphosphine)-palladium dichloride and Cul as the co-catalyst in the presence of an aliphatic amine. The formation of diphenylacetylene exemplifies the original Sonogashira reaction conditions ... 

Arylaluminums have not been used as extensively as some other arylmetals in Pd-catalyzed cross-coupling. However, the intrinsic reactivity of arylaluminums appears to be somewhere between that of Zn and Sn. It is this relatively low intrinsic reactivity of arylaluminums that is critically required in the cyclic carbopalladation-cross-coupUng tandem process shown in Scheme 44. The high intrinsic reactivity of Zn leads to the formation of the unwanted direct cross-coupling prodnct in 57% yield, while the corresponding reaction of PhSnBus does not produce either product under the conditions used. ... 

Pd(CF3CO)2 catalyses the decarboxylation of electron-rich aromatic acids (e.g. with OMe groups) in DMSO/DMF at 70-90° (1 to 24 hours) in high yields and is not affected by steric hinderance [Dickstein et al. Org Lett 9 2441 2007], and (in the presence of Cu(OAc)2 with Cesium pivalate + 3-nitropyridine as additives at 110-140° in a microwave) it catalysed direct cross-coupling between unactivated arenes and A-acetylindoles with coupling mostly at C3 of indoles but with no homo-coupling [Stuart Fangou Science 316 1172 2007]. 

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