Suzuki-Miyaura Cross-Coupling of 3-Pyridyl Triflates with Alk-1-enyl-2-pinacol Boronates

Abstract

Palladium-catalyzed Suzuki-type couplings of 3-pyridyl triflates with alkenyl pinacol boronates proceed in good to excellent yield. Optimized conditions use Pd(PPh 3 ) 4 (10 mol %) as catalyst with K 3 PO 4 (3 equiv) as base in dioxane. Keywordsboron; cross-coupling; heterocycles; palladium; pyridines Since its development 30 years ago,1 the Suzuki-Miyaura cross-coupling of organoboron compounds has become one of the most widely used methods for forming C-C bonds.2 Given the myriad examples of Suzuki-Miyaura couplings, and the fact that there are a number of interesting branched 3-alkylpyridine natural products, such as cananodine (1)3 , 4 and xestamine C (2),5 we were surprised to find very few examples of reactions between 3-pyridyl triflates and alkenyl/alkyl boronates.6 Similarly, there are few examples of coupling 3-pyridyl boron derivatives with alkenyl halides or triflates.7In a retrosynthetic analysis of cananodine (1) and xestamine C (2), we identified branched pyridyl alkene 3 as a key intermediate prepared by cross-coupling a 3-pyridyl triflate 4 with alkenyl boronate 6 (Figure 1). Alternatively, the roles of the components could be reversed, such that pyridyl boronate 5 could be coupled with alkenyl triflate 7. Since preparation of the coupling partners require the same number of synthetic steps, we planned to explore both permutations of the coupling reaction.8Appropriately substituted 3-hydroxypyridines are more readily available than the corresponding 3-halo derivatives, and they are easily converted to the corresponding aryl triflates 4 with Comins' triflimide9 in the presence of base. The simple pyridyl triflates 4a -4c are known,10 and we also desired to examine the cross-coupling reaction with pyridines functionalized at the 2-position to provide a functional group handle for subsequent manipulations (Scheme 1). Triflate 4d was readily prepared from 3-hydroxy-6-methyl-2-pyridinemethanol (8). Selective protection of the primary hydroxyl group as the pivaloate ester using pivaloyl chloride and 4-dimethylaminopyridine (DMAP) provided ester 9. The 3-hydroxy group was then cleanly converted to the triflate using Comins' triflimide and triethylamine to give 4d in excellent yield. The preparation of triflate 4e commenced with Fax: (360) 650-2826, vyvyan@chem.wwu.edu. Dedicated to Professor Thomas R. Hoye on the occasion of his 60 th birthday.Supporting Information for this article is available online at http://www.thieme-connect.de/ejournals/toc/synthesis. NIH Public AccessAuthor Manuscript Synthesis (Stuttg). Author manuscript; available in PMC 2011 November 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the protection of the 3-hydroxyl group of 8 as the allyl ether to yield 10. Reaction of the primary hydroxyl group with N-bromosuccinimide and triphenylphospine provided bromide 11, which in turn was converted to the sulfone 12 by treatment of the bromide with sodium phenylsulfinate. Cleavage of the allyl ether using standard conditions yielded 13 which was c...

Enantioselective Synthesis of the Guaipyridine Alkaloid (+)- and (−)-Cananodine

“…The synthesis of (+)-cananodine ( 1 ) commenced with the alkylation of oxazolidinone 4 with picolyl bromide 5 (prepared in 3 steps from 6-methylpyridin-3-ol) , to produce 3 in good yield and >96% diastereomeric excess (Scheme ). We initially attempted this alkylation with the corresponding aryl triflate derivative of 5 instead of the allyl ether-protected phenol.…”

Synthesis of cananodine by intramolecular epoxide opening

“…The epoxide 2 would be prepared from pyridyl diene 3 , which in turn is formed by Suzuki-Miyaura coupling of pyridyl halide/triflate 4 and alkenyl boronate 5 . 20 …”

“…Thus, cleavage of the pivaloate group in 6 20 gave primary alcohol 7 which was converted to sulfone 8 in a two-step process (Scheme 2). Cleavage of the acetonide followed by conversion of the resulting diol to the trisubstituted epoxide via the mesylate yielded 9 .…”

“…Chemoselective asymmetric dihydroxylation of the monosubstituted olefin of 11 20 produced diol 12 in good yield (Scheme 3). A portion of the diol was converted to the corresponding acetonide for analysis by chiral GC, which showed an enantiomeric excess of 76%.…”

“…(Scheme 4). Pd-catalyzed cross coupling of pyridyl iodide 17 with dienylboronate 5b 20 in the presence of Ag 2 O 25 was found to be the most efficient method to obtain 18 in high yield. Asymmetric dihydroxylation of the more electron rich olefin of 18 gave diol 19 in moderate yield.…”