Sonogashira reaction acetylene synthesis

The Sonogashira reaction is a transition metal-catalyzed coupling reaction which is widely used for the preparation of alkyl-, aryl- and diaryl-substituted acetylenes (Table 4.7) [120]. This reaction is a key step in natural product synthesis and is also applied in optical and electronic applications. Sonogashira reactions involve the use of an organic solvent with a stoichiometric portion of a base for capturing the... 

Removal of the tri-wo-propylsilyl (TIPS) and tm-butyldimethylsilyl (TBS) protecting groups could be accomplished concomitantly with TBAF in tetrahydrofuran at 0 °C, but here competing elimination of the secondary bromide was observed. Better overall yields and cleaner conversion was observed when TBS ether was cleaved with 5 % aqueous HF in acetonitrile at 0 °C followed by removal of the acetylenic TIPS with TBAF under milder conditions of -78 °C.10 The diastereomers are not separated before the desilylation process therefore even a 3 1 mixture of E- and Z-enyne is obtained. Prelaureatin 4 and its F-isomer 17 are likewise goals in natural product synthesis. Crimmins and co-workers developed an own synthetic route to 4. The reaction sequence is similar up to aldehyde 55. Afterwards a Z-vinyl-iodide is selectively formed and the alkyne is introduced via a Sonogashira reaction. 

The formation of liquid crystals (LC) from suitably functionalized acetylenic SPMs has often been the motivation for their synthesis. A number of groups have sought to capitalize on the planar or nearly planar disk-like geometry of SPMs to promote the formation one-dimensional columnar stacks based on a combination of n-n stacking, van der Waals, dipole, and hydrophobic interactions. For example, Heiney, Moore, and coworkers have reported the high-resolution X-ray diffraction analysis (XRD) of a tubular, discotic LC based on SPM 133, which has been synthesized via a Sonogashira reaction [106]. These studies reveal an unanticipated distortion and... 

Jutand, A. Dual role of nucleophiles in palladium-catalyzed Heck, Stille, and Sonogashira reactions. Pure Appl. Chem. 2004, 76, 565-576. Li, C.-J., Slaven, W. T., John, V. T., Banerjee, S. Palladium catalyzed polymerization of aryl diiodides with acetylene gas in aqueous medium a novel synthesis of areneethynylene polymers and oligomers. Chem. Commun. 1997,1569-1570. 

The Sonogashira reaction is of considerable value in heterocyclic synthesis. Heteroaryl halides like bromooxazoles are viable substrates for the Pd-catalyzed cross-coupling reactions with terminal acetylene in the presence of Pd/Cu catalyst. In 1987, Yamanaka s group described the Pd-catalyzed reactions of halothiazoles with terminal acetylenes [50]. Submission of 4-bromo- (72) and 5-bromo-4-methyloxazoles (73) to the Sonogashira reaction conditions with phenylacetylene led to the expected acetylenes (74 and 75). 

In the synthesis of Vemurafenib (Scheme 26) the 5-bromo-7-azaindole part of 113 is made by a Sonogashira reaction (Scheme 42) [73]. Thus, reaction between pyridine 161 and 2-methyl-but-3-yne-2-ol 162 catalysed by PdCl2(PPh3)2, Cul and Et3N yielded the protected pyridine-acetylene 163 in 93% yield. This was deprotected under basic conditions to yield 164, which was cyclised to 165 using tBuOK in NMP for an overall 62% yield. 

There are numerous applications of the Sonogashira reaction in the solid phase synthesis of molecules of biological interest, in some cases as part of a synthetic sequence but in the majority of examples for scaffold diversification purposes, and only a few can be mentioned here. Takahashi and coworkers prepared a Ubrary of 96 cross-conjugated dienones by subjecting a pendant acetylenic moiety on a cyclopentenone scaffold, attached to polystyrene via the Ellman THP-linker, to a Sonogashira coupling reaction... 

In 1980 Sonogashira reported a convenient synthesis of ethynylarenes - the Pd-catalyzed cross-coupfing of bromo- or iodoarenes with trimethylsilylacetylene followed by protiodesilylation in basic solution [15]. Prior to this discovery, formation of terminal acetylenes required manipulation of a preformed, two-carbon side chain via methods that include halogenation/dehydrohalogenation of vinyl- and acetylarenes, dehalogenation of /1,/1-dihaloalkenes, and the Vils-meier procedure [ 14]. With the ready availability of trialkylsilylacetylenes, the two-step Sonogashira sequence has become the cornerstone reaction for the construction of virtually all ethynylated arenes used in PAM and PDM synthesis (vide infra). 

Cross-coupling of terminal acetylenes used as nucleophiles with aryl or alkenyl halides (referred to as the Sonogashira-Hagihara, or SH, reaction) is a versatile method of synthesis for acetylenic compounds, which are rapidly gaining importance as advanced new materials and building blocks for implementing unusual molecular architectures. 

Bowman et al. reported the total synthesis of ellipticine (228) involving an imidoyl radical cascade reaction (730). For this key step, the required imidoyl radical was generated from the imidoyl selanide 1290, which was obtained from ethyl 2-(4-pyridyl)acetate (1286). Reaction of 1286 with LDA, followed by addition of methyl iodide, led to the corresponding methyl derivative 1287. Treatment of 1287 with 2-iodoaniline (743) in the presence of trimethylaluminum (AlMes) afforded the amide 1288. Using Sonogashira conditions, propyne is coupled with the amide 1288 to afford the aryl acetylene 1289. The aryl acetylene 1289 was transformed to the... 

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. 

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