Pd-catalyzed a-alkynylation

Three methods for the Pd-catalyzed a-alkynylation of enones according to Protocol II have been developed and applied to the synthesis of harveynone and tricholomenyn... 

SCHEME 57. Pd-catalyzed a-alkenylation and a-alkynylation of a-iodo-cr,fi-unsaturated carbonyl compounds... 

Zn is the most versatile with respect to leaving groups and most satisfactory. This reaction has been applied to the synthesis of 2,3-octadiene-5,7-diyn-l-ol, a metabolite from the fungus Cortinellus berkeleyanus (Scheme 3.52) [174bj. To our knowledge, there does not appear to be any reported example of the Pd-catalyzed propargyl-alkynyl coupling. 

Scheme 3.86 Synthesis of (+)-harveynone and (-)-tricholomenyn A by Pd-catalyzed Negishi alkynyl-alkenyl coupling [176, 275f].

Application of Pd-catalyzed cross-coupling to a-alkynylation, a-alkenylation, and a-arylationt of heteroaromatic a,/3-unsaturated carbonyl derivatives, such as 5-iodouracil derivatives, has been known since the early 1980s (Scheme 50). Although these reactions are formally related to the Pd-catalyzed a-substitution discussed herein, the robust aromatic nature of the heteroaromatic substrates makes the requirements for their a-substitution less demanding. These reactions should therefore be viewed as a class of CTOss-coupling reactions involving aryl hahdes rather than a-halo-a,/3-unsaturated carbonyl compounds. In most... 

Propargylic (or 2-alkynyl) compounds are derivatives of alkynes. However, Pd-catalyzed reactions of propargylic derivatives, particularly esters and halides, are very different mechanistically from those of simple alkynes, except in a few cases. Therefore, the reactions of propargylic esters and halides are treated in this section separately from those of other alkynes. However, some reactions of propargylic alcohols, which behave similarly to simple alkynes, are treated in Section 6. 

Overman et al. <1996JA9062> and Kibayashi et al. <2002JOC5517> have utilized the same alkynyl intermediate 222 as a substrate in their chemistry (Scheme 47). While the first group uses a nucleophilic attack of the triple bond on the iminium cation 223, the second group performs a regioselective hydrostannylation, followed by Pd-catalyzed carbonylation, to provide the precursor 224 to the cyclization step. 

Attempts to directly iodinate quinoxaline failed, and the synthesis of 2,3-diphenyl-5,8-dibromoquinoxaline is somewhat more involved (Scheme 9) [61]. Starting from ort/zo-phenylenediamine, reaction with SOCI2 gives benzothia-diazole in high yield. Bromination in HBr furnishes 4,7-dibromobenzothiadi-azole, which can be alkynylated or directly reduced [62]. Reduction of the dibromide with sodium borohydride leaves the halide substituents unmolested but opens the ring to furnish l,4-dibromo-2,3-diaminobenzene. Reaction of this intermediate with a 1,2-dione furnishes a 2,3-disubstituted 5,8-dibromo-quinoxaline. Pd-catalyzed alkynylation finishes the sequence off and removal of the TMS groups yields the desired 5,8-diethynylquinoxaline monomers (Table 9, entries 13,14). 

The heterocyclic PAEs are useful for low-bandgap applications, as n-type semiconductors, and in sensory applications. Again, as long as the alkynylated or iodinated monomers are available, the synthesis of the corresponding PAE is not a problem, and either the Pd-catalyzed couplings or alkyne metathesis can be utilized toward that end. 

TMS alkynes were also examined as precursors to allenylzinc bromides15. Pd-catalyzed coupling of these reagents with / -iodo acrylates afforded enynes as sole products (Table 13). However, although o-iodotoluene also gave the alkynyl product, both iodobenzene and 1-iodonaphthalene gave rise to mixtures of alkynyl and allenyl adducts. In the latter case, replacement of the TMS substituent with the bulkier TBS resulted in complete conversion to the alkynyl product, no doubt the consequence of a steric directing effect. 

The Pd-catalyzed alkynylation is one of the most widely used —C bond formation reactions. It has been thoroughly and extensively reviewed recently15-17. So only a brief overview and a discussion of some of the most recent advances will be presented in this section. As in the case of alkenyl-alkenyl coupling, Ni catalysts have rarely been used for alkynylation, even though Ni catalysts do affect the desired alkynylation in some cases. One main reason for disfavoring Ni is that Ni can readily react with alkynes to undergo alkyne cyclooligomerization represented by arene formation. The Pd-catalyzed alkynylation can, in principle, be performed in three discrete manners, as shown in Scheme 40. 

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