Alkynylated products

TMS alkynes were also examined as precursors to allenylzinc bromides15. Pd-catalyzed coupling of these reagents with / -iodo acrylates afforded enynes as sole products (Table 13). However, although o-iodotoluene also gave the alkynyl product, both iodobenzene and 1-iodonaphthalene gave rise to mixtures of alkynyl and allenyl adducts. In the latter case, replacement of the TMS substituent with the bulkier TBS resulted in complete conversion to the alkynyl product, no doubt the consequence of a steric directing effect. 

Alkynyl(phenyl)iodonium salts can be used for the preparation of substituted alkynes by the reaction with carbon nucleophiles. The parent ethynyliodonium tetrafluoroborate 124 reacts with various enolates of /J-dicarbonyl compounds 123 to give the respective alkynylated products 125 in a high yield (Scheme 51) [109]. The anion of nitrocyclohexane can also be ethynylated under these conditions. A similar alkynylation of 2-methyl-1,3-cyclopentanedione by ethynyliodonium salt 124 was applied in the key step of the synthesis of chiral methylene lactones [110]. 

For the introduction of carbosubstituents into purine, palladium-catalyzed coupling of halo-purines with terminal acetylenes has also been widely used. The reaction is sensitive to substrates protection of N9 by the acetyl group in 6-chloropurine gives higher yields of the alkynylated products 25. ... 

Similarly, 6-chloro-9-phenylpurine undergoes alkynylation by heating in dimethylformamide, whereas 6-iodopurine can be coupled at room temperature, e.g. to give 26, with significant improvements in yields of alkynylated products. ... 

A highly effective catalytic method for alkynylation of epoxides has recently been reported this involves the chelation-controlled alkylation of hetero-substituted epoxides with Mc3A1 and alkynyllithiums via pentacoordinate organoaluminum complexes [82]. For instance, reaction of epoxy ether, (l-benzyloxy)-3-butene oxide (75) in toluene with PhC = CLi under the influence of catalytic MesAl (10 mol%) proceeded smoothly at 0 °C for 5 h to furnish the alkynylation product l-(benzyloxy)-6-phenylhex-5-yn-3-ol (76) in 76 % yield. The yield of the product was very low (3 %) without MeaAl as catalyst under similar conditions. This is the first catalytic procedure for amphiphilic alkylation of epoxides. The participation of pentacoordinate MesAl complexes of epoxy ethers of type 75 is emphasized by comparing the reactivity with the corresponding simple epoxide, 5-phenyl-l-pentene oxide (77), which was not susceptible to nucleophilic attack of PhC s CLi with catalytic Me3Al under similar conditions (Sch. 50). 

This catalytic system was successfully applied to the alkynylation of tosyl aziridine with adjacent ether functionality this should provide a promising method for the synthesis of amino alcohols. Treatment of tosyl aziridine 81 with PhC CLi in the presence of catalytic Mc3Al in toluene at 0 °C for 5 h gave rise to the corresponding alkynylation product 82 in 66 % yield (Sch. 53), whereas reaction in the absence of Me3Al proceeded sluggishly under similar reaction conditions (7 % yield). The control experiment with simple aziridine 83, in which addition of catalytic McaAl had almost no influence on the reaction rate, supports the proposed catalytic cycle its efficacy is based on the formation of the pentacoordinate organoaluminum complex. 

In 2007, the same group also explored the direct a-alkynylation of the cyclic (3-ketoester, 2-(tert-butoxycarbonyl)indanone (86), in the presence of the PTC 79 (Scheme 6.26) [51]. The alkynylated products 87 were obtained with excellent optical purities, and this transformation was extended to a wide range of substrates, including five-, six-, and seven-membered and aromatic conjugated (3-ketoesters. 

Alkynylation products of ortho-iodo phenols (32) readily undergo cychzation to give benzofuran derivatives (33) [135, 160, 161]. A reaction involving cychzation occurring with incorporation of CO has been reported by Liao et al. (Scheme 5) [161]. However, an extensive screening of reaction conditions had to be performed to avoid ... 

When the alkynylation reaction described by Beringer was reproduced using (p-l C-phenylethynyl) phenyliodonium tetrafluoroborate (82) as a reagent, it appeared that the substituted indanedione was largely enriched with C at the a-carbon of the ethynyl group. Only 6% of the alkynylation product could be ascribed to a classical Ad-E pathway or rather the alternative ligand coupling pathway,... 

Li found that a variety of copper salt could catalyze both the activation of the sp C-H bond of the terminal alkyne and the activation of the peroxide. The nature of the alkyne was shown to have a strong influence upon the success of the reaction. In all cases, aromatic alkynes were found to provide the oxidative alkynylated product 28 in good yields, while aliphatic alkynes resulted in lower yields. The reaction was also shown to tolerate various functional groups such as alcohols and esters. 

While low to modest yields were obtained for the alkynylated product 31, high catalyst loading (40 mol%) was required. The work by Fu clearly demonstrates the limitation of the oxidative alkynylation reaction with tertiary amines. The problem with the strict requirement for aryl substituted tertiary amines has been solved recently by Li and co-workers (Scheme 18) [36]. 

When the reaction with propargyl alcohol is run in an amine solution at elevated temperature, the alkynylated product first formed is further transformed by a cyclization reaction with the pyridine nitrogen 3-piperidinoindolizine (35) is formed (36% yield) in piperidine at 80°C. Corresponding cyclization products result from the reaction with 1-bromoisoquinoline or 2-bromoquinoline with propargyl alcohol (80BCJ3273). Alkynylation (38) of 2-chloro-, 3-bromo-, and 4-iodopyrimi-dines, which are vicinally substituted by a cyano, carbamoyl, or ethoxy-carbonyl group, has been effected with phenylacetylene by heating the... 

Phenyl-substituted propargyl alcohol couples with 3-iodopyridine to furnish (49) (Scheme 10). On reaction of the 2-iodopyridine (50), however, it was found that the initial alkynylation product (51) rearranged to form the corresponding chalcone (52). The same rearrangement occurs in pyrimidines when the iodine is located in an electrophilic position. In reactions with the corresponding methylpropargyl alcohol, the reaction stops after... 

Pyridyl triflates in the benzenoid 3-position readily couple with terminal acetylenes (88JOC386). When the phenylacetylene is substituted in the phenyl ring by an o-amino group, the alkynylated product (56) can be cyclized by Pd(II)-catalysis to an indole, in this case to 2-(3-pyridyl)indole (89TL2581). 

Reaction of the 4-TV-oxide of 2-chloropyrazine proceeds without interference from the N-oxide function to give (79) (Scheme 16). In the 1 -N-oxide (80), however, alkynylation is difficult, and the reaction failed in most cases. From phenylacetylene 18% of the alkynylated product (81) was isolated (86CPB1447). 

Alkynyl derivatives have been prepared by the Stephens-Castro reaction (Scheme 82). 3,5-Diiodo-4( 1H)-pyridinone without 0-protection is monocoupled with phenylethynylcopper. The 5-alkynyl product subsequently suffers Michael attack from the vicinal oxygen function to form a fused product, a furo[3,2-c]pyridine (355) [66JOC4071 87ACSA(B)219 89JCS(P1)1165]. 

A coupling reaction that does not involve prior preparation of a Cu(I) acetylide is provided by Pd-catalyzed cross-coupling of aryl halides with acetylenes in the presence of Cul. The 4-alkynylated product (357) was obtained from the corresponding 4-iodo derivative in 84% yield using Pd-catalysis, and in 54% yield from preformed Cu(I) acetylide without catalysis [87ACSA(B)219]. 

In the Stephens-Castro reaction 0-methylated 5-iodouracil has been reacted with THP-protected propargyl alcohol as a Cu-derivative to give the 5-alkynyl product (362). 

As a consequence of the superior migratory aptitude of hydrogen, the parent ethynyliodonium salt gives exclusively rearrangement (alkynylation) products with diverse P-dicarbonyl nucleophiles in 63-78<7o yield (Scheme 3-4) [28]. This reaction represents a very convenient way of introducing the HC = C — functionality into keto and ester P-dicarbonyl compounds. 

Analogously, malonate 54 gave exclusively alkynylation products 55 in 33-95% yields with a variety of alkynyliodonium triflates [Eq. (21)] [20 a]. 

More complex nucleophiles can be reacted with alkynyl(phenyl)iodonium salts as well. For example, protected aminomalonates (50) and 18 give the corresponding alkynylmalonates 51 in 30-90% isolated yields (equation 19). Likewise, a variety of dicarbonyl enolates 52-54 react with 55 to give alkynyl products 56-58 (equations 20-22). These reactions may be looked upon as alkynylations or, in other words, the triple-bond analogs of the well-established alkylation reactions. Unfortunately, they only work with soft nucleophiles such as 52-54 (OTs, PhC02 PhsP, etc.). Nucleophiles such as RO, or simple enolates, do not seem to work. 

Cul as cocatalyst seems to be necessary for the conversion of dibromoarenes into the corresponding alkynylated products, but Linstrumelle demonstrated that if iodoarenes are coupled in the presence of a suitable amine, Cul can be omitted. The presence of Cul however does not seem to harm the progress of the reaction, and insofar it can always be added. Its proposed role is the formation of a copper(I) o- or jT-acetylide to activate the alkyne toward transmeta-lation. The matter has been discussed thoroughly by Osakada and Yamamoto. ... 

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