Sonogashira reaction pyrimidines

In conclusion, the Pd chemistry of pyrimidines has its own characteristics when compared to carbocyclic arenes and other nitrogen-containing heterocycles such as pyridine and imidazole. One salient feature of halopyrimidines is that the C(4) and C(6) positions are more activated than C(2). As a result, 2-, 4- and 6-chloropyrimidines are viable substrates for Pd-catalyzed reactions and 4- and 6-chloropyrimidines react more readily than 2-chloropyrimidines. For the Sonogashira reaction, though, there is little difference in the reactivity among 2-, 4- and 5-positions of substituted halopyrimidines. Not only is the Sonogashira reaction a reliable method... 

Alonso DA, Najera C, Pacheco MC (2004) Synthesis of ynones by palladium-catalyzed acylation of terminal alkynes with acid chlorides. J Org Chem 69 1615-1619 D Souza DM, Miiller TJJ (2008) Catalytic alkynone generation by Sonogashira reaction and its application in three-component pyrimidine synthesis. Nat Protoc 3 1660-1665 Karpov AS, Miiller TJJ (2003) A new entry to a three component pyrimidine synthesis by TMS-ynones via sonogashira-coupling. Org Lett 5 3451-3454... 

Yamanaka and associates developed a method for the synthesis of 2-butylindole from the Sonogashira adduct of ethyl 2-bromophenylcarbamate and 1-hexyne [97, 98]. Extension of that method to pyridines led to the synthesis of pyrrolopyridines [99]. However, the method was not applicable to the synthesis of pyrrolo[2,3-6/]pyrimidines. They then developed an alternative route involving an initial S Ar displacement at the 4-position of 4,5-dihalopyrimidine followed by a Sonogashira coupling at the 5-position [100]. Thus, 5-iodopyrimidine 200 was obtained from an S Ar displacement at the 4-position of a 4-chloro-5-iodo-2-methylthiopyrimidine (199). The subsequent Sonogashira reaction of 200 with trimethylacetylene at 80°C resulted in adduct 201, which spontaneously cyclized to pyrrolo[2,3-6/]pyrimidine 202. 

Dichloropyrimidine gives a selective Sonogashira coupling at and 2,4,6-trichloropyrimidine shows clean sequential Suzuki couplings C-4, then C-6, then C-2. In Sonogashira reactions on dihalo-pyrimidines, a 4-chloro reacts in preference to a 5-bromo, but not a S-iodo. ... 

Scheme 9.10 Bis(pyrimidine)-based Pd-bound polymer 30 active in the Sonogashira reaction obtained by ring-opening metathesis polymerization (ROMP) of the norbornene 31 with the diene 32 and subsequent treatment with PdClj [110].

Reddy and collaborators reported a new one-pot, three-component procedure toward the synthesis of novel 4-phenyl-2-[3-(alkynyl/alkenyl/aryl) phenyl] pyrimidine libraries starting with the Michael addition of enaminone 64 with 3-bromobenzimidamide hydrochloride (65) (Scheme 28) (13S75). This was followed by a cyclization, an isomerization, a dehydration, and a subsequent Sonogashira reaction with terminal alkynes or a Suzuki reaction with arylboronic acids or a Heck coupling reaction with alkenes. 

The Sonogashira reaction with TMSA could also be succes-fully accomplished in the coupling with different heteroaryles such as pyrroles, thiophenes, pyrimidines, purines, and quinazolines. ... 

SCHEME 32 One-pot synthesis of pyrimidines 46 catalyzed by carbon nanotube-supported palladium nanoparticles by acyl Sonogashira reaction. 

Recent developments in palladium-catalyzed coupling reactions have arisen in the pyrimidine field as well. The Sonogashira coupling of bromopyrimidine 85 with alkynes 86 produced pyrimidines 87, important intermediates reported by Hart and co-workers in their approach to the cylindrospermopsin substructure . 

Several Sonogashira adducts of heteroaromatics including some pyridines (see Section 4.3) and pyrimidines underwent an unexpected isomerization [69]. This observed isomerization appeared to be idiosyncratic, and substrate-dependent. The normal Sonogashira adduct 100 was obtained when 2-methylthio-5-iodo-6-methylpyrimidine (99) was reacted with but-3-yn-ol, whereas chalcone 101, derived from isomerization of the normal Sonogashira adduct, was the major product when the reaction was carried out with l-phenylprop-2-yn-l-ol. 

Annulation Via Heterosubstituent. In the alkynylation of 5-iodo-l-methyluracil under Sonogashira conditions (Scheme 102) a minor product (9%) from the reaction was furo[2,3-(i]pyrimidin-6-one 299. The latter arises from the initial coupling product by a... 

Other metal-catalyzed reactions have been also combined with the Ugi-Smiles reaction. Thus, substituted pyrrolo[2,3-base-catalyzed intramolecular cyclization (Scheme 7.51) [108]. 

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