Sonogashira coupling reactions phenylacetylene

The first report of a Sonogashira coupling reaction of an oxazole was by Yamanaka in 1987. Oxazoles substituted with bromine at the 4- or 5-positions were coupled with phenylacetylene yielded the alkyne in 83% and 89% yield, respectively. The Sonogashira reaction with 2-halooxazoles was not attempted however, 2-halothiazoles and 2-halo-A -methylimidazoles were subjected to Sonogashira conditions. Yields in both cases were low and not synthetically useful. 

In 1980, Ames et al. reported a related pyrrole formation catalyzed by mer-cury(II) [98], Pyrrole-fused quinoxaline 204 was obtained by treatment of a 2-amino-3-alkynylquinoxaline derivative 203 with a catalytic amount of Hg(OAc)2 (Scheme 19.53). On the other hand, dichloroquinoxaline 205, the precursor of 203, was converted directly to 204 under reaction conditions for Sonogashira coupling with phenylacetylene. A related palladium(II)-catalyzed pyrrole synthesis using 1-aminoalk-3-yn-2-ols 206 was reported by Utimoto, Nozaki and co-workers in 1981 (Scheme 19.54) [99]. It should be noted that PdCl2 showed excellent turnover to produce the corresponding pyrroles 207 in good yields with only 0.1 to 1 mol % catalyst loading. 

Sonogashira reactions of both a-halothiophenes [117] and P-halothiophenes [118] proceed smoothly even for fairly complicated molecules as illustrated by the transformation of brotizolam (134) to alkyne 135 [119]. Interestingly, 3,4-bis(trimethylsilyl)thiophene (137), derived from the intermolecular cyclization of 4-phenylthiazole (136) and bis(trimethylsilyl)acetylene, underwent consecutive iodination and Sonogashira reaction to make 3,4-bisalkynylthiophenes [120], Therefore, a regiospecific mono-i/wo-iodination of 137 gave iodothiophene 138, which was coupled with phenylacetylene to afford alkynylthiophene 139. A second iodination and a Sonogashira reaction then provided the unsymmetrically substituted 3,4-bisalkynylthiophene 140. 

Like halopyridines, diazines participate in Sonogashira coupling too. 3,6-dimethyl-2-chloropyrazin, for example on coupling with phenylacetylene under standard conditions, gave the desired compound in good yield, which was further reduced to give a natural product (7.36.)51 (NB. the Heck reaction, which could be considered as an alternate approach would be expected to furnish predominantly the c/.v-olcfin as product). 

Efficiency of the deprotection and coupling reactions are critical to the success of any iterative solid-phase synthesis. Shown in Scheme 1 is a triad of reactions for phenylacetylene oligomer synthesis trimethylsilyl deprotection,28 29 triazene unmasking of an iodobenzene,30 and the Sonogashira coupling of a terminal acetylene with an aryl iodide.31-33 Representative procedures for each step in this sequence are included at the end of this chapter. 

The dendrimers 23a-c were used in a copper-free Sonogashira-type coupling reaction between phenylacetylene and iodobenzene or bromobenzene. The catalyst amount was 1 mol % per catalytic group (i.e., 1/4, 1/8 and 1/16 mol% depending on the dendrimer generation generations 1, 2 and 3), and the temperature range was 25-120 °C. 

The synthesis of derivatized, concave pyridines could be accomplished in a straightforward manner [118]. Thus, 335 could be transformed to 336 upon cross-coupling with phenylacetylene. Furthermore, the Sonogashira reaction was also able to generate dimerized variations 338 of these compounds by reacting 337 with 325. 

The Sonogashira reaction is of considerable value in heterocyclic synthesis. Heteroaryl halides like bromooxazoles are viable substrates for the Pd-catalyzed cross-coupling reactions with terminal acetylene in the presence of Pd/Cu catalyst. In 1987, Yamanaka s group described the Pd-catalyzed reactions of halothiazoles with terminal acetylenes [50]. Submission of 4-bromo- (72) and 5-bromo-4-methyloxazoles (73) to the Sonogashira reaction conditions with phenylacetylene led to the expected acetylenes (74 and 75). 

The reaction can be combined with Sonogashira coupling to give o, o -dialky-lated diphenylacetylenes [11]. Pd-catalyzed reaction of iodobenzene, ethyl bromide, and phenylacetylene (36) afforded 2,6-diethyldiphenylacetylene 37 in 78 % yield with remarkable chemoselectivity. In this reaction, Cul as a cocatalyst was not used. The direct Sonogashira coupling of iodobenzene with phenylacetylene (36) was suppressed by slow addition of excess ethyl bromide and phenylacetylene at room temperature. 

---