Sonogashira reactions alkynylation

The Sonogashira reaction frequently serves as a platform for the construction of indoles, and we will explore this application in Chapter 3, but it also is a valuable method for the preparation of alkynyl pyrroles. 

In contrast, an excellent yield was obtained for the reaction between 5-iodoimidazole and propargyl alcohol in the absence of Cul to install the 5-alkynyl derivative [10, 41], The adduct was then deprotected to 5-alkynyl- l-P-D-ribofuranosylimidazole-4-carboxamide 58, an antileukemic agent. It is noteworthy that if the Sonogashira reaction was conducted in the presence of Cul, the yield dropped to 19%. 

The Sonogashira reaction is of considerable value in heterocyclic synthesis. It has been conducted on the pyrazine ring of quinoxaline and the resulting alkynyl- and dialkynyl-quinoxalines were subsequently utilized to synthesize condensed quinoxalines [52-55], Ames et al. prepared unsymmetrical diynes from 2,3-dichloroquinoxalines. Thus, condensation of 2-chloroquinoxaline (93) with an excess of phenylacetylene furnished 2-phenylethynylquinoxaline (94). Displacement of the chloride with the amine also occurred when the condensation was carried out in the presence of diethylamine. Treatment of 94 with a large excess of aqueous dimethylamine led to ketone 95 that exists predominantly in the intramolecularly hydrogen-bonded enol form 96. 

Bromo-6-phenylpyridazin-3-amine 177 and iV-benzyl-4-bromo-6-phenylpyridazin-3-amine 178 which have been used successfully in Suzuki reactions could also be alkynylated via Sonogashira reactions (Equation 43 and Table 10) <2003SL1482>. 

The Sonogashira reaction has become the most widely used of the palladium-catalyzed alkynylation methods due to its generality and reliability, particularly in the context of total synthesis. Some recent examples are shown in Figure 10.1 4,174a-174c... 

Doucet H, Hierso JC (2007) Palladium-based catalytic systems for the synthesis of conjugated enynes by sonogashira reactions and related alkynylations. Angew Chem Int Ed 46 834-871... 

Cu-catalyzed alkynation of L Pd and cross-coupling with R -X, has developed into a widely used method for forming new C-C bonds between alkynyl and aryl or vinyl groups. This transformation is now called Sonogashira cross-coupling. Equation 12.72 shows a typical example of the Sonogashira reaction.146... 

Several groups have successfully used 5-bromo-2-furaldehyde in Sonogashira reactions for the synthesis of 5-alkynyl-2-furaldehydes. Muller s group coupled 5-bromo-... 

Contrasting results were observed in the Pd-catalyzed alkynylation with alkylzincs versus the Sonogashira alkynylation. For example, reaction of iodopyrazine with ethyl-3-bromozinc-propynate (20) provided the coupled product alkynylpyrazine 21 [18]. However, the corresponding Sonogashira reaction of iodopyrazine with propynoate provided 21 in only 37% yield [18]. 

Hitherto, only two papers appeared in the literature in which an alkynyl group was introduced into the 4 position of a monocyclic pyridazine using a Sonogashira reaction [52, 81]. Besides the previously mentioned 4-chloro-3,6-dimethylpyridazine (185), Bourguignon showed that electronically rich and sterically hindered A benzyl-4-bromo-and 4-bromo-6-phenyl-pyridazin-3-amine (82) are valuable coupling partners for different alkynes. 

Alkynyl-5-chloro-2-methylpyridazin-3(277)-ones (214) can also be obtained via chemoselective Sonogashira reaction on 5-chloro-4-iodo-2-methylpyridazin-3(2//)-one (4) as exemplified by the coupling of 4-fluorophenylacetylene with 4 [15]. 

Alternatives to the Sonogashira reaction involve the use of preformed alkynyl organometallics, such as trifluoroborates, or the reverse coupling of haloalkynes with organometaUics. ... 

Cyclisation of ortfto-alkynyl-arylamines can be achieved in varions ways Sonogashira reactions (4.2) provide the starting ort/to-alkynyl-anilines. 

Sonogashira reactions allow easy access to arenes with an alkynyl snbstitnent ortho to nitrogen, for example from ortho-iodo- and -bromo-nitrobenzenes, or ortho-iodo- and -bromo-A -acyl- (or N-sulfonyl)-arylamines, or even by conpUng acetylenes with 2-iodoaniUne itself.Conversion of orf/20-alkynyl-nitrobenzenes and -arylamines into indoles can be achieved in several ways, for example alkoxides add to the triple bond and form nitro-acetals, nitro-gronp rednction then acetal hydrolysis bringing ring closure. ... 

These palladium-catalysed reactions involve insertion of the palladium into the carbon-bromine or carbon-triflate bond, reaction with the organometallic species (alkenyl stannane in a Stille reaction, arylboronic acid in a Suzuki reaction, or alkynyl copper species in a Sonogashira reaction) and reductive elimination to give the products shown below. 

Sonogashira reaction [4,5], A comprehensive review on Pd-catalyzed alkynylation was published recently by Negishi and Anastasia [6], Facile Pd(0)-CuI-catalyzed coupling of aryl and alkenyl halides with 1-alkynes is used extensively for the preparation of arylalkynes or enynes. 

Aryl-Alkynyl Coupling (Sonogashira Reaction) Reaction Conditions and Catalysts... 

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