Coupling of acid chlorides with terminal alkynes

An alternative approach to multicomponent heterocycle synthesis involves the use of palladium catalysis to construct keto-alkynes for cycloaddition reactions. Muller has demonstrated the power of this approach in the construction of a range of aromatic heterocycles. For example, the palladium-catalyzed coupling of acid chlorides with terminal alkynes provides a method to assemble 36. The trapping of this substrate can provide routes to aromatic heterocycles. As an example, the addition of amidines provides a multicomponent synthesis of pyrimidines (Scheme 6.69) [97]. This same substrate 36 is available via the carhonylative coupling of aryl halides with terminal alkynes, providing a four-component synthesis of pyrimidines (98j. 36 can also be employed in 1,3-dipolar cydoaddition reactions. For example, cydoaddition... 

A carbonyl group in conjugation with the triple bond exerts a strong polarization of the alkyne. Thus, Sonogashira coupling of acid chlorides 7 and terminal alkynes... 

Trisubstituted isoxazoles 14 with ferrocenyl groups in 4- and 5-position can be synthesized utilizing acid chlorides 4, terminal alkynes 5, and hydroximinoyl chlorides 13 in a sequence consisting of modified Sonoga-shira cross-coupling I and cyclocondensation. Hydroximinoyl chlorides 13 are employed as synthetic equivalents of the corresponding aromatic nitrile... 

Zanina et al. have reported a method for the synthesis of a, acetylenic ketones from terminal alkynes and acid chlorides using cuprous iodide as a catalyst. The use of high temperature and toluene as the solvent in this protocol prompted Kundu and co-workers to develop a new procedure with triethylamine as the solvent and the base, which obviated many of the difficulties and enabled the reactions to be carried out at room temperature (eq 30). Zhang and co-workers have modified the conditions in order to couple monooxalyl chloride with terminal alkynes THE was used as the solvent with 2 equiv of triethylamine and 5 mol % of Cul. It is noteworthy that CuCl, CuBr, and Cul showed similar reactivity, while CuOTf was totally inert. 

A palladium catalyst with a less electron-rich ligand, 2,2-dipyridyl-methylamine-based palladium complexes (4.2), is effective for coupling of aryl iodides or bromides with terminal alkynes in the presence of pyrrolidine and tetrabutylammonium acetate (TBAB) at 100°C in water.37 However, the reactions were shown to be faster in NMP solvent than in water under the reaction conditions. Palladium-phosphinous acid (POPd) was also reported as an effective catalyst for the Sonogashira cross-coupling reaction of aryl alkynes with aryl iodides, bromides, or chlorides in water (Eq. 4.18).38... 

A common feature of the above described processes is that only aryl substituents are tolerated on the side of the acid chloride 4 and aryl iodide 6 due to ketene formation and jd-H elimination from aliphatic derivatives. However, primary alkyl-substituted alkynones 1 can be obtained by a palladium-catalyzed cross-coupling of corresponding thiol-esters 9 with terminal alkynes 5 in the presence of overstoichiometric amounts of copper (2003SL1512, 2010SL1239) (Scheme 4). 

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]. 

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... 

Dien-4-ynes 136 (R -R = alkyl) are produced from propargylic carbonates 135 and terminal alkynes in the presence of a palladium-phosphine complex and copper(I) iodide. The linear co-dimerization of terminal acetylenes and 1,3-dienes is catalyzed by ruthenium(cyclooctadiene)(cyclooctatriene)(trialkylphosphine) (alkyl = Et, Bu or octyl) thus 1-hexyne and methyl penta-2,4-dienoate give a mixture of the eneynes 137 and 138. Coupling of octa-l,7-diyne (139) with the acetylenic bromo acid 140 in aqueous THF-methanol containing butylamine, hydroxylamine hydrochloride and copper(I) chloride gave a mixture of the triynyl acids 141 and 142. ... 

A v ety of reactions are catalyzed by electrochemically generated Ni(0) (62). Electrochemical reduction of Ni(bipy)3Br2 affords a reagent that couples acid chlorides and alkyl or aryl halides to form unsymmetrical ketones (63). Symmetrical ketones are formed from alkyl halides and carbon dioxide (64). Reductive electrochemical carboxylation of terminal alkynes, enynes and diynes can be accomplished with 10% Ni(bipy)3(Bp4)2 in DMF (65-68). Terminal allies lead selectively to a-substituted acrylic acids. Electrocatalytic hydrogenation on hydrogen-active electrodes has been reviewed (69). Radical cyclizations of vinyl, alkyl and aryl radicals can be carried out by indirect electrochemical reduction with a Ni(II) complex as a mediator (70). 

Won et al. [19], have reported synthesis of polyesters with valine, leucine, isoleucine, methionine, and phenylalanine (Table 12.1). This three-step process involves synthesis of a diester and a dinitro compound that are copolymerized [19], An amino acid is first coupled with a diol (with 3, 4, or 6 methylene groups) in the presence of tosyl to yield a diester with acid salts of diamine at the terminal ends. The second monomer, di-p-nitrophenyl ester of carboxylic acids, is synthesized by a condensation reaction of adipoyl or se-bacoyl chloride with p-nitro phenol. The final polymerization step involves an arduous condensation reaction in the presence of a strong proton abstractor between acid salt of bis(amino acid-alkyne diester) and di-p-nitrophenyl ester of dicarboxylic acids. Following along the same lines, Chu and Guo [22] have copolymerized a mixture of nitro phenyl ester of succinate, adipate, or sebacate and nitrophenyl fumarate with toluenesulfonic acid salt of phenylalanine butane-1,4-diester. The addition of fumarate derivative to the monomer mixture provides an unsaturated double bond in the polymer backbone that can be functionalized for specific biomedical... 

Triazole-containing compounds exhibit various biological effects, such as antiviral (Moorhouse and Moses, 2008), antibacterial (Hon et al., 2012), antifungal (Agalave et al, 2011), and anticancer (Jordao et al., 2009). Heravia et al. (2006) developed an easy and eco-friendly method for the synthesis of thiazolo[3,2-fc]l,2,4-triazoles using SSA as an efficient catalyst. This method involved the condensation of 3-mercapto-l,2,4-triazoles with allyl bromide. Keivanloo et al. (2013) also reported silica-supported zinc bromide as an efficient heterogeneous catalyst for the one-pot synthesis of 4,5-disubstituted-l,2,3-(NH)-triazoles. The reaction involved the cross-coupling of 1,3-dipolar cycloaddition with various acid chlorides, terminal alkynes, and sodium azide in the presence of silica-supported zinc bromide under aerobic conditions. The reaction is described in Scheme 6.34. 

The enaminones 67 are readily prepared via Sonogashira coupling of terminal alkynes with acid chlorides, followed by conjugate addition of propargylamine and further Sonogashira coupling with aryl iodides ... 

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