Hetero cross-coupling

Snieckus et al. enlisted a combination of directed orrAo-lithiation and Suzuki coupling to assemble some unsymmetrical heterobiaryls [22], Carboxamidophenylboronic acid 30 was derived from sequential metalation of amide 29 and treatment with B(OMe)3 followed by acidic workup. Hetero cross-coupling of 30 with 2-bromothiazole occurred smoothly to furnish phenylthiazole 31. Similarly, a hetero cross-coupling between 2-bromothiazole and 3-formyl-4-methoxyphenylboronic acid produced a heterobiaryl as an intermediate of an orally bioavailable NKi receptor antagonist [23]. 

The formation of the C-X bond in hetero-cross coupling reactions is thought to proceed via a migration of the hetero atom to the aryl group, which develops a negative charge, which is Jt-stabilised by mesomeric interaction with acceptor substituents. Both for this reductive elimination and its reverse (oxidative addition) resonance-stabilised Meisenheimer complexes have been proposed [42,49,50,51], This stabilised structure is depicted in Figure 12.18. 

Scheme 12.30. Synthesis of theonelladin D using a three-component hetero-cross-coupling reaction, by Larock and co-workers [108] dba = dibenzylideneacetone,...

Paul, F., Patt, J., Hartwig, J. F. Palladium-catalyzed formation of carbon-nitrogen bonds. Reaction intermediates and catalyst improvements in the hetero cross-coupling of aryl halides and tin amides. J. Am. Chem. Soc. 1994,116, 5969-5970. 

Our group has recently developed an alternative method for alkyl-(hetero)aryl- as well as aryl-heteroaryl cross coupling reactions catalyzed by iron salts.3 4 This methodology was inspired by early reports of Kochi et al.5>6 on iron-catalyzed cross coupling of vinyl halides and is distinguished by several notable advantages. 

Another recent development in the field of palladium-catalyzed reactions with alkynes is a novel multicomponent approach devised by the Lee group. Starting from a-bromovinyl arenes and propargyl bromides, the assembly ofeight-membered car-bocycles can be realized via a cross-coupling/[4+4] cycloaddition reaction. The authors also presented the combination of a cross-coupling and homo [4+2], hetero [4+2], hetero [4+4] or [4+4+1] annulation leading to various cyclic products [147]. 

The cross-coupling alternative yields halide salts as co-products. During the preparation of aryl halides from the aromatic ring and dihalogen also one equivalent of halide salt is produced and thus there is further room for improvement if we could directly substitute a hydrogen atom by the hetero atoms mentioned ... 

For reviews of the Pd-catalyzed acylation and other cross-coupling reactions with a-hetero-substituted organic electrophiles, see ... 

Anctil, E. J.-G. Snieckus, V. The directed ortho metalation-cross coupling symbiosis. Regioselective methodologies for biaryls and heterobiaryls. Deployment in aromatic and hetero-... 

The R- radicals can also undergo cross coupling with alkenes and with hetero-arenes.2... 

The preparation of amphimedine 7-46 published by Echavarren and Stille [512] is a noteworthy application of 2-aza-1,3-butadienes in natural product synthesis since it is an interesting combination of hetero Diels-Alder methodology with a palladium catalysed cross coupling. Thus, dienophile 7-44 was formed by Stille coupling of the triflate 7-42 with the stannyl aniline 7-43. This qui-none then underwent cycloaddition to the 2-aza-l,3-butadiene 7-45 an acid catalysed hydrolysis of the cycloadduct 7-47 and subsequent N-methylation completed the synthesis of amphimedine 7-46 (Fig. 7-11). 

As a consequence of the mild reaction conditions in the sequence to 3-halo furans 55 the palladium catalyst should be still intact to trigger another Pd-catalyzed coupling in the sense of a sequentially Pd-catalyzed process [31]. As a consequence, a sequential Sonogashira-deprotection-addition-cyclocondensation-Suzuki reaction, where the same catalyst system is applied in two consecutive significantly different cross-coupling reactions in the same reaction vessel should be feasible. Therefore, upon consecutive reactions of (hetero)aroyl chlorides 7 and THP-protected propargyl alcohols 54, Nal and PTSA, and finally, addition of 1.05 equiv of boronic acids 60 and sodium carbonate, the substituted 3-aryl furans 61 can be obtained in decent yields (Scheme 35). 

The concise formal total synthesis of mappicine was accomplished using an intramolecular hetero Diels-Alder reaction as the key step by M. lhara and co-workers. Introduction of the necessary acetylenic moiety at the C2 position was achieved by the Sonogashira cross-coupling of a 2-chloroquinoline derivative with TMS-acetylene. Several substituents at the C3 position were investigated, and it was found that the unprotected hydroxymethyl substituent gave almost quantitative yield of the desired disubstituted alkyne product. 

Negishi, E.-i. Palladium-catalyzed cross-coupling involving 3-hetero-substituted compounds. Palladium-catalyzed a-substitution reactions of enolates and related derivatives other than the Tsuji-Trost allylation reaction. Handbook of Organopalladium Chemistry for Organic Synthesis 2002, 1, 693-719. 

This reaction consists of a Pd-catalyzed cross-coupling reaction of a (hetero)aryl... 

In this variation of the Pd-catalyzed cross-coupling reaction, which is closely related to the Stephen-Castro reaction, copper acetylides are reacted with (hetero)aryl halides or triflates to produce (hetero)aryl alkynes [111]. The Sonogashira reaction is comparable to the Suzuki or Stille reactions in its scope and functional group tolerability. 

Whether the reaction is inter- or intramolecular, the Heck reaction generates vinyl(hetero)arenes or dienes from an alkene and a (hetero)aryl or alkenyl halide [130]. This reaction has great versatility and is applicable to a wide range of aryl and alkene species. Mechanistically, the Heck reaction varies from that depicted in Fig. 4.3. While the oxidative addition of the halogen species occurs, the transmetalation step is replaced by the coordination of the alkene. This is followed by a migratory insertion which essentially substitutes for the cross-coupling step. The product is released not by a reductive elimination, but by a 3-hydride elimination sequence (Fig. 4.5). 

The transition-metal catalyzed cross-coupling reaction of (hetero)aryl hahdes and triflates with primary and secondary amines or (hetero)aryl amines is know as the Buchwald-Hartwig reaction [144]. Mechanistically, this reaction is related to the crosscoupling reactions outlined thus far (Fig. 4.6). The modification arises at the point of transmetalation. This step in the process is substituted with the coordination of the amine reactant. Deprotonation of the amine nitrogen now precedes the reductive elimination step to generate the aryl amine product. This reaction has foimd utility in the academic setting, for use in natural product total synthesis, and in industry, for the preparation of materials up to the multi-hundred kilogram scale. 

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