Studies on Pyrazines; 38: Acylation of Bromopyrazines and 2-Bromopyridine via Copper-Cocatalytic Stille Reaction

Abstract

Synthesis of acetylpyrazines 3 and propionylpyrazines 5 was achieved by copper-cocatalytic Stille reaction of bromopyrazines 1 with tributyl(1-ethoxyalkenyl)tin and then acidic hydrolysis. The optimal reaction conditions involve the combination of 15 mol% CuI with 5 mol% of PdCl 2 (Ph 3 P) 2 . Similarly, 2-acylpyridines and propionylbenzenes were prepared from the corresponding aryl bromides.The Stille cross-coupling of bromobenzenes with trialkyl(1-ethoxyvinyl)tin followed by acidic hydrolysis has been shown as a convenient method for the synthesis of acetophenones. 2,3 In a preceding paper, we reported this methodology to be also effective in the dehalogenative acylation of electron-deficient nitrogen heteroaromatics, thus high yields of 1,3-dihydro-6-propionylpterin-2,4-diones were synthesized via Pd-catalyzed reaction of the 6-bromopteridines with tributyl(1-ethoxyprop-1-enyl)tin. 1 The key for the successful transformation was the use of CuI under the traditional Stille conditions, in other words the cross-coupling did not proceed at all without the additive. The cocatalytic effect of CuI in the Stille coupling was first reported by Liebeskind and Fengl, 4 and the many subsequent applications have stimulated a considerable development in this chemistry. 5 Much less is known, however, about the couplings of aryl halides with trialkyl(1-ethoxyalkenyl)tin in the presence of CuI. 6 On the other hand, acylpyrazines are of interest as the constituents in foodstuffs or pheromones, which have been often prepared by the Minisci-type radical reaction of pyrazines 7 or lithiation followed by reaction of the resultant lithiopyrazines with N,N-dialkylamides. 8 These methods suffer from some drawbacks, especially the regioselectivity of aromatic substitution. In this respect, acylation via displacement of halogeno substituent is a promising synthetic route to the desired acylpyrazines. We are currently investigating the acylation of bromopyrazines through copper-cocatalytic Stille reaction with 1-ethoxyvinyl or 1-ethoxypropenyl tin compounds (Scheme 1). Additionally, the cross-coupling of halogenopyridines and bromobenzenes was carried out under similar conditions for comparison of reactivity with pyrazine series.We first examined Pd-catalysts in the cross-coupling of 2-bromo-5-phenylpyrazine (1a) 9 with tributyl(1-ethoxyvinyl)tin (2), in which 5 mol% each of Pd catalyst and CuI were employed in refluxing MeCN containing triethylamine (Table 1, entries 1-3) according to our previous procedure. 1 Consequently, PdCl 2 (Ph 3 P) 2 induced the best yield (81%) of 2-acetyl-5-phenylpyrazine (3a). When toluene 2 was used as the solvent instead of MeCN, the yield of 3a decreased to 72%. The effects of Pd-catalyst, CuI and triethylamine can be realized from the experiments lacking each additive (entries 4-9). Without the Pdcatalyst, the coupling proceeded only slightly. The addition of CuI unexpectedly led to an appreciable increase in the yield of acetylpyrazine 3a. Our previous cross-coupling of bromopteridines necessitated cat...

B-973, a Novel α7 nAChR Ago-PAM: Racemic and Asymmetric Synthesis, Electrophysiological Studies, and in Vivo Evaluation

“…We further attempted installing the ketone moiety under mild Pd-catalyzed crosscoupling conditions. 17 Stille cross coupling of compound 9 with tributyl (1-ethoxyvinyl)tin and Pd(PPh 3 ) 2 Cl 2 in the presence of CuI yielded the enol ether 10. The crude product was hydrolyzed with aq.…”

“…Our initial efforts were plagued by the formation of a range of undesired products, which was presumably due to the sensitivity of the pyrazine ring to these conditions. We further attempted installing the ketone moiety under mild Pd-catalyzed cross-coupling conditions . Stille cross coupling of compound 9 with tributyl (1-ethoxyvinyl)tin and Pd­(PPh 3 ) 2 Cl 2 in the presence of CuI yielded the enol ether 10 .…”