Trifluoroacetic acid reaction with alkynes

The triphenyl derivative (91, R = R = R = Ph, R = H) is formed in a mechanistically interesting reaction between benzoyl formic acid anil (Ph-N=CPh-C02H), trifluoroacetic anhydride, and pyridine. Its 1,3-dipolar cycloaddition reactions with alkynes and alkenes have been reported. ... 

Alkynes react when heated with trifluoroacetic acid to give addition products. Mixtures of syn and anti addition products are obtained. Similar addition reactions occur with trifluoromethanesulfonic acid. These reactions are analogous to acid-catalyzed hydration and proceed through a vinyl cation intermediate. 

In our attempt to extend the coupling reaction of arenes with alkenes to the coupling with alkynes, as shown in Scheme 4, it was found that the reaction of arenes with ethyl propiolate in TFA (trifluoroacetic acid) gave addition products instead of a coupling product [3]. This addition reaction has been extended to various alkynes and various arenes and also to intramolecular reactions for synthesis of heterocycles such as coumarins, quinolines, and thiocoumarins. 

Cleavage with an ensuing Heck reaction was developed by using the T1 triazene linker [51] (Scheme 6.1.20). On cleavage with trifluoroacetic acid a diazonium ion is first formed this can couple to an added alkene under the action of palladium catalysis. The coupling proceeds well with simple terminal alkenes, styrenes, and di- and even trisubstituted alkenes. The advantage of this process is clearly the possibility of using volatile alkenes (and alkynes) without contamination by any salt or other less volatile by-product, particularly with the use of palladium on charcoal as the catalyst. 

Van der Eycken s group developed a silver(I)-mediated synthesis of substituted furo[2,3-6]pyrazines.53 Starting from -methoxybenzyl-protected 3,5-dichloropyr-azine-2(l//)-ones 26 (Scheme 5.13), after a regioselective microwave-assisted Sonogashira reaction with various terminal alkynes, the cycloisomerization reaction could occur using AgOTf (2 mol%) with trifluoroacetic acid (TFA, 5 equiv) to yield... 

Another resin-capture approach has been pubhshed in relation to the synthesis of tetrasubstituted ethylenes via Suzuki coupling reactions (Scheme 20) [42, 53]. A 25-member hbrary was synthesized using five alkynes, five aryl halides, and a polymer-bound aryl iodide. The alkynes 55 were converted into bis(boryl)alkenes 56 in solution, and the crude intermediates were used in Suzuki reactions with an excess of aryl halide. When all of the bis(boryl)alkene 56 had been consumed, the aryl iodide resin 59 was added to the reaction mixture and the reaction continued on the solid support. Side products such as 58, arising from a double Suzuki reaction, remained in solution and could be washed away. Compounds 60 were cleaved from the polymer using trifluoroacetic acid and products 61 were obtained in > 90% purity. 

Alkynes are common precursors to ejco-methylene compounds, as in Sha s synthesis of (-)-dendrobine.l27 The iodide in 178 was removed to form a radical, which added to the alkyne to form a five-membered ring with an exo-methylene unit in 179 [69% yield, E/Z) = 1 9]. The trimethylsilyl group is important to sterically inhibit a 6-endo-dig reaction that can complete with the 5-exo-dig process. The silyl group was removed by treating 179 with trifluoroacetic acid in benzene, giving 180 in 84% yield. 

In a series of papers, Wong and co-workers detailed the preparation and use of 3,4-bis(trimethylsilyl)furans. Thus, after heating an equimolar mixture of 4-phenyloxazole and bis(trimethylsilyl)acetylene with 5 mol % of triethylamine in a sealed tube at 250°C for 2 days, an 80% yield of the desired furan 130 was obtained (Fig. 3.38). If the same reaction is performed in the presence of a catalytic amount of formic or trifluoroacetic acid instead of triethylamine, the analogous 2,4-bis-trimethylsilylfuran is obtained in good yield. Furan 130 itself reacts with alkynes in a tandem Diels-Alder retro-Diels-Alder sequence to provide other fiirans, e.g., 3,4-furandicarboxylic acid dimethyl ester 131. Friedel-Crafts acylations can also be performed using 130. In addition, 130 reacted with boron... 

Pd-catalyzed hydroarylation of alkynes via aromatic C—bond activation has been reported by Fujiwara. The reaction offers a good synthetic method of arylalkenes, which are usually prepared by Heck reaction of alkenes. Electron-rich arenes bearing more than one OH, OMe, and alkyl groups react with electron-deficient alkynes [6], The reaction proceeds with a catalytic amount of Pd(OAc)2 in trifluoroacetic acid (TEA) at room temperature. Hydroarylation of ethyl propiolate (15) with / -dimethoxybenzene yielded ethyl (Z)-3-(2,5-dimethoxyphenyl)-2-propenoate (16). Mesitylene (17) is an active arene and the reaction of 17 with 3-butyn-2-one (18) afforded the imsaturated ketone 19 which has f-form [7]. 

A major factor in determining the magnitude of relative rates is the solvent used. Thus, high alkene alkyne reactivity ratios are found in organic solvents of low dielectric constant (acetic acid), but the rates of reaction are comparable when water is the solvent. This is true not only for the hydration but also for bromination. Polar solvents, water in particular, are evidently capable of minimizing the energy difference between the two transition states. Whether this is accomplished by very strong solvation or by some other mechanism is not entirely clear. Addition reactions of alkenes and alkynes with trifluoroacetic acid also take place at comparable rates. ... 

Pd-mediated heteroannulation of alkynes with resin-bound o-iodoaniHnes 16 gives trisubstituted indoles with good yields. Zhang and coworkers have used Rink amide AM resin as solid support and the iodoanihne was linked by formation of an amide bond (1997TL2439 Scheme 7). After the heteroannulation reaction, cleavage with trifluoroacetic acid gave the indoloamide functionalized compounds 17. 

In 2006, the group of Artok showed that 5-aryl-2(5H)-furanones could be prepared in moderate to good yields by a rhodium-catalyzed carbonylative arylation of internal alkynes with aryl boronic acids (Scheme 1.9a) [22]. a,P-Unsaturated ketones (chal-cone derivatives) were formed as the major product when some TFA (trifluoroacetic acid) was added under the same reaction conditions [23a]. By varying the catalytic system, indanones could be produced as the main product [23b]. The chemical behavior of terminal alkynes is different, and either a,P-unsaturated ketones or furans starting from propargylic alcohols can be achieved (Scheme 1.9b) [24, 25]. In the case of vinyl ketones, 1,4-diketones were obtained by rhodium-catalyzed coupling of arylboronic acids in the presence of 20-40 bar of CO [26]. In 2007, Chatani demonstrated that indenones could be accessed by a carbonylative rhodium-catalyzed cyclization of alkynes with 2-bromophenylboronic adds (Scheme 1.9c) [27]. Here, the key intermediate is a vinylrhodium(I) spedes that is formed by transmetaUation of RhCl with 2-bromophenylboronic acid followed by insertion of... 

Dipolar cycloadditions of nitrile oxides with alkenes or alkynes give isoxazolines or isoxazoles, respectively. Typically, nitrile oxides are generated in situ, and the cycloaddition reaction occurs smoothly at room temperature. Awide variety of nitrile oxide cycloadditions have been studied on solid support since Yedidia and Leznoff published their smdies in 1980. ° Dimerization of the nitrile oxides has limited the utility of nitrile oxide cycloadditions in solution. Solid-supported reactions enabled the formation of resin-bound nitrile oxide in situ and trapped the reactive 1,3-dipole with an excess of the dipolarophile in solution (Scheme 11.32). Trityl resin-bound cycloadducts were then cleaved with highly diluted trifluoroacetic acid and the products were obtained as phenols. 

A tetrahydropyranyl linker is an acid-sensitive linker for alcohols. Nitrile oxides were generated in situ from tetrahydropyranyl-linked nitro alkanes and phenyl isocyanate under Mukaiyama conditions, and reactions with various alkynes gave resin-bound isoxazoles (Scheme 11.39). Cleavage with diluted trifluoroacetic acid gave isoxazoles as primary alcohols in a traceless manner. A library of 3-hydroxymethyl-4,5-disubstituted isoxazoles was prepared in a parallel and automated fashion by a 96-well plate synthesizer with an average yield of 60%. 

Reactive Enophile in [4 + 2] Cycloadditions. Vinylketenes are not effective as dienes in Diels-Alder reactions because they undergo only [2 + 2] cycloaddition with alkenes, as predicted by frontier molecular orbital theory. However, silylketenes exhibit dramatically different properties from those found for most ketenes. (Trimethylsilyl)vinylketene (1) is a relatively stable isolable compound which does not enter into typical [2 + 2] cy do additions with electron-rich alkenes. Instead, (1) participates in Diels-Alder reactions with a variety of alkenic and alkynic dienophiles. The directing effect of the carhonyl group dominates in controlling the regiochemical course of cycloadditions using this diene. For example, reaction of (1) with methyl propiolate produced methyl 3-(trimethylsilyl)sahcylate with the expected regiochemical orientation. ProtodesUylation of this adduct with trifluoroacetic acid in chloroform (25 °C, 24 h) afforded methyl salicylate in 78% yield (eq 2). 

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