Sonogashira synthesis aryl iodides

Efficiency of the deprotection and coupling reactions are critical to the success of any iterative solid-phase synthesis. Shown in Scheme 1 is a triad of reactions for phenylacetylene oligomer synthesis trimethylsilyl deprotection,28 29 triazene unmasking of an iodobenzene,30 and the Sonogashira coupling of a terminal acetylene with an aryl iodide.31-33 Representative procedures for each step in this sequence are included at the end of this chapter. 

The novel heliannane-type sesquiterpenoid (-)-heliannuol E was synthesized in the laboratory of K. Shishido. Interest in the total synthesis of this natural product was not only spurred by its irregular terpenoid structure and significant biological activity but the need to establish the absolute stereochemistry at the C2 and C4 stereocenters. The Sonogashira reaction was utilized to prepare the 3-arylpropargyl alcohol by coupling of a heavily substituted aryl iodide with an unprotected propargyl alcohol in quantitative yield. 

Palladium-eatalyzed reaction of bicyclic hydrazines 175 with allyltributylstannane 176 in ionic liquid provided a facile method for the synthesis of substituted l,2,4-triazole-3,5-dionecyclopentenes 177 <05SL2273>. Sonogashira coupling of 3-mercaptopropargy 1-1,2,4-triazoles 178 with various aryl iodides led to the regioselective synthesis of 6-benzylthiazolo[3,2-()] 1,2,4-triazoles 179 <05TL1607>. 

More recently, Lautens has also employed l-(2-iodophenyl)-pyrrole as a bifunctional aryl iodide/acceptor for the synthesis of substituted pyrrolo[l,2]quinolines (Scheme 34)[82], During Catellani s application of the Cassar-Sonogashira reaction to the ort/m-alkylation sequence [70] it was found that alkynes can undergo further carbopalladation reactions with arylpalladium(II) species. It was this reactivity which led Lautens to explore the use of bromoalkylalkynes as species which can undergo an ort/zo-alkylation, followed by a cyclocarbopalladation onto the alkyne,... 

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. 

In 2008, Xia and Chen described a recyclable phosphine-free catalyst system for alkynone synthesis [45]. Using palladium on charcoal (Pd/C) and NEta, the carbonylative Sonogashira coupling of aryl iodides with alkynes was smoothly carried out and the desired products were isolated in moderate to excellent yields (Scheme 5.17). 

With the development of Buchwald-Hartwig amination reactions, the amine component of these indoles can also be introduced into these precursors via palladium catalysis [8]. As shown by Ackermann, this can be coupled with aryl halide alkynylation and cyclization to provide a one-pot, three-component synthesis of substituted indoles (Scheme 6.6) [9]. In this case, simple ortho-dihaloarene derivatives S were employed as starting materials, with Sonogashira coupling occurring at the more activated aryl-iodide bond, followed by selective coupling of various alkyl or arylamines. Alternatively, Zhao has recently demonstrated that amination can be performed on both bromoalkyne 6, followed by the aryl-bromide bond, to provide a route to 2-amidoindoles (Scheme 6.7) [10]. 

H. Nakamura, T. Kamakura, S. Onagi, 1,2-Bis(diphenylphosphino)carborane as a dual mode ligand for both the sonogashira coupling and hydride-transfer steps in palladium-catalyzed one-pot synthesis of allenes from aryl iodides, Org. Lett. 2006, 8, 2095. 

A nice substituted carbazole synthesis begins with installation of propargyl alcohol via its Sonogashira coupling with aryl iodide 69. Subsequent oxidation of propargylic alcohol 70 to the aldehyde, followed by stabilized Wittig reaction, affords a conjugated intermediate ene-yne 71,... 

In 2007, Pinto et al. developed a novel palladium-catalyzed three-component synthesis of 3-(diarylmethylene)oxindoles through a cascade Sonogashira/carbopalladation/C—H activation/ C—C bond-formation sequence from readily available A-aryl-A-alkyl propiolamides 160, aryl iodides, and a second aryl iodide [63] (Scheme 6.42). This is the first example of three different palladium-catalyzed reactions involving... 

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