Sonogashira reaction alkyne arylation/alkenylation

The coupling of terminal alkynes with aryl or alkenyl halides catalysed by palladium and a copper co-catalyst in a basic medium is known as the Sonogashira reaction. A Cu(I)-acetylide complex is formed in situ and transmetallates to the Pd(II) complex obtained after oxidative addition of the halide. Through a reductive elimination pathway the reaction delivers substituted alkynes as products. 

Transition metal-catalyzed transformations are of major importance in synthetic organic chemistry [1], This reflects also the increasing number of domino processes starting with such a reaction. In particular, Pd-catalyzed domino transformations have seen an astounding development over the past years with the Heck reaction [2] - the Pd-catalyzed transformation of aryl halides or triflates as well as of alkenyl halides or triflates with alkenes or alkynes - being used most often. This has been combined with another Heck reaction or a cross-coupling reaction [3] such as Suzuki, Stille, and Sonogashira reactions. Moreover, several examples have been published with a Tsuji-Trost reaction [lb, 4], a carbonylation, a pericyclic or an aldol reaction as the second step. 

The palladium-catalyzed arylation and alkenylation of terminal alkynes with aryl or alkenyl hahdes in presence of a copper(l) co-catalyst is called Sonogashira reaction. In the same way as in the other cross-coupling reactions described before, it is possible to immobihze the alkyne or the aromatic bromides, iodides or triflates on sohd supports (Scheme 3.15). 

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 iodides, bromides, and inflates are used for Sonogashira coupling. But so far few smooth reactions of aryl chlorides with alkynes have been reported. On the other hand, smooth coupling takes place with alkenyl chlorides. The Pd-catalyzed reaction of 1-alkynes with alkenyl chlorides, which are inert in many other Pd-catalyzed reactions, proceeds smoothly without special activation of the chlorides. For example, cw-l,2-dichloroethylene (31) can be coupled with 1-alkynes smoothly, and the coupling has wide synthetic applications, particularly for the synthesis of enediyne structures [30]. The reaction of 31 with two different 1-alkynes is extensively used for construction of highly strained enediyne structures present in naturally occurring anticancer antibiotics such as espermicin and calichemicin [31,32]. The asymmetric (Z)-enediyne 34 can be prepared by a one-pot reaction of 31 with two different 1-alkynes 32 and 33. Similarly the asymmetric ( )-enediyne 37 was obtained in a one-pot reaction of 1-alkynes 33 and 23 with 1,2-dichloroethylene 35. 

One distinguishes palladium(0)- and palladium(ll)-catalysed reactions. The most common palladium(O) transformations are the Mizoroki-Heck and the cross-coupling transformations such as the Suzuki-Miyaura, the Stille and the Sonogashira reactions, which allow the arylation or alkenylation of C=C double bonds, boronic acid derivates, stan-nanes and alkynes respectively [2]. Another important palladium(O) transformation is the nucleophilic substitution of usually allylic acetates or carbonates known as the Tsuji-Trost reaction [3]. The most versatile palladium(ll)-catalysed transformation is the Wacker oxidation, which is industrially used for the synthesis of acetaldehyde from ethylene [4]. It should be noted that many of these palladium-catalysed transformations can also be performed in an enantioselective way [5]. 

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 couples the sp-hybridized carbon of a terminal alkyne to aryl and alkenyl halides. The reaction requires a palladium catalyst and a catalytic amount of Cul. The reaction is carried out in an amine solvent. 

Based on these precedents for C—X bond formation between C=N and alkene intermediates (derived from alkynes), the Larock group developed the first transition-metal-mediated pyridine ring formation by direct reaction between C=N and alkynes. Using terminal alkynes 11, rcrt-butylimines 10 were subjected to Sonogashira coupling followed by Cu(I)-catalyzed annulation to afford isoquinolines or pyridines 12 in moderate to good yields (46 to 95%, Scheme 19.5) [5]. A variety of terminal alkynes and aryl/alkenyl halides can be used in the reaction. The stepwise reaction also worked well to form the same products. Similarly, p- and y -carbolines were synthesized effectively, as shown in Scheme 19.6 [6]. 

A rapid MW-assisted palladium-catalyzed coupling of heteroaryl and aryl boronic acids with iodo- and bromo-substituted benzoic acids, anchored on TentaGel has been achieved [174]. An environmentally friendly Suzuki cross-coupling reaction has been developed that uses polyethylene glycol (PEG) as the reaction medium and palladium chloride as a catalyst [175]. A solventless Suzuki coupling has also been reported on palladium-doped alumina in the presence of potassium fluoride as a base [176], This approach has been extended to Sonogashira coupling reaction wherein terminal alkynes couple readily with aryl or alkenyl iodides on palladium-doped alumina in the presence of triphenylphosphine and cuprous iodide (Scheme 6.52) [177]. 

Terminal alkynes can be alkenylated by alkenyl triflates (bromides, iodides) in the presence of catalytic amounts of a palladium(O) complex (or a precursor thereof) and usually an additional substoichiometric amount of copper(I) iodide (Cul), and they can be arylated by aryl triflates (bromides, iodides). These reactions are called Cacchi coupling reactions if triflate reagents are employed, and Sonogashira-Hagihara coupling reactions if halides are used. 

Aryl and alkyl-substituted diynes and tetraynes have been synthesized in good yields (82-99%) by TBAF-promoted desily-lation and Cu-catalyzed oxidative dimerization of triisopropylsi-lyl (TlPS)-protected acetylenes (eq 38). Copper acetate was used as oxidant in this reaction. Aryl- and alkenyl alkynes were made under similar conditions (eq 39). Pd/C with TBAF was used in ligand- and copper-free, one-pot, domino Halex-Sono-gashira reactions. Similarly, TBAF promoted the synthesis of 2-substituted indoles by a tandem Sonogashira/cyclization reaction of 2-iodoanilines and terminal alkynes. ... 

Direct introduction of sp carbon to alkynes by the reaction of Cu acetylides with aryl and alkenyl halides to form arylalkynes and alkenylalkynes is known as the Castro reaction [1]. Later it was found that coupling of terminal alkynes (1-alkynes) with halides proceeds more smoothly by using Pd catalysts. There are two methods of Pd-catalyzed coupling, hi 1975 direct coupling of 1-alkynes catalyzed by a phosphine-Pd(O) complex in the presence of amines was reported by Heck and Cassar as an extension of the Heck reaction to 1-alkynes [2,3]. In the same year, Sonogashira and Hagihara found that the addition of Cul as a co-catalyst gave better results, and the Pd(0)-CuI-catalyzed reaction is called the... 

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