Coupling with alkynyl halides

Yields of the coupling products with alkynyl bromides are relatively low as compared with those obtained with allyl chloride or benzyl chloride. One reason for this is the instability of the product. The dienediynes 51 are slowly cyclized under the influence of light to give pentacyclic dimers 52 (Eq. 2.36), one of which has been characterized by X-ray analysis. 

The second reason for the lower yields is the high reactivity of the intermediate. Two molecules of the alkynyl bromide react in a stepwise manner with the zirconacyclopentadiene. When one alkynyl halide molecule couples with the zirconacyclopentadiene, the intermediate bears a metalladienyne moiety (as in 50), as shown in Eq. 2.36 

The remaining alkenyl copper moiety in 50 can react intramolecularly with the carbon—carbon triple bond to give metallofulvene derivatives 53. However, the coupling of the intermediate with the second molecule of alkynyl halide would seem to be faster than the cyclization reaction. Therefore, the dienediyne is obtained as the major product. 

Coupling reaction of zirconacyclopentadienes with alkynyl bromides. 

The coupling with alkynyl iodides in the presence of CuCl and DMPU proceeds quite differently from that with alkynyl bromides. Although the first step of the coupling is the same, the subsequent Cu/I exchange reaction of the intermediate is different. As the final product, iododienyne 54 is obtained in high yields, as shown in Eq. 2.37 [35]. In the case of alkynyl bromides, Cu/Br exchange does not proceed. Therefore, the alkenyl copper moiety couples with the second alkynyl bromide molecule. 

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Much of the new chemistry on the coupling of alkynyl halides has dealt mostly with applications of known methods. The Cadiot-Chodkiewicz-type coupling reactions (i.e. terminal acetylene coupling with alkynyl halides) have formed the cornerstone of synthesis of acetylenic retinoids (i.e. 9)58. 

As the third palladium-catalyzed method, transmetalation from alkynyl metals like boron, aluminum, and zinc is possible. These reactions will be discussed in 4.16.4. The fourth method—cross-coupling with alkynyl halides—is discussed in the other paragraphs (e.g., Suzuki reaction). 

Achiral 2-stannyloxazolines are known to undergo Shlle coupling with aromahc halides. However, Stille couplings with chiral 2-halooxazolines were not reported until Meyers and Novachek prepared the requisite 2-bromooxazoline 365 (see Scheme 8.116) and successfully coupled 365 with a variety of alkynyl and alkenylstannanes to afford chiral 2-substituted oxazolines 635 in reasonable yields (Scheme 8.200). ... 

Bromination of the enol ether product with two equivalents of bromine followed by dehydrobromination afforded the Z-bromoenol ether (Eq. 79) which could be converted to the zinc reagent and cross-coupled with aryl halides [242]. Dehydrobromination in the presence of thiophenol followed by bromination/dehydrobromination affords an enol thioether [243]. Oxidation to the sulfone, followed by exposure to triethylamine in ether, resulted in dehydrobromination to the unstable alkynyl sulfone which could be trapped with dienes in situ. Alternatively, dehydrobromination of the sulfide in the presence of allylic alcohols results in the formation of allyl vinyl ethers which undergo Claisen rearrangements [244]. Further oxidation followed by sulfoxide elimination results in highly unsaturated trifluoromethyl ketonic products (Eq. 80). 

Various metal acetylides are used for smooth coupling with propargylic halides and acetates. 2,3-Alkadien-5-yn-l -ols are obtained by the reaction of 2-(l -alkynyl)oxiranes [28,29], As a synthetic application, the unstable 2,3-octadiene-5,7-diyn-l-ol (136), a fungus metabolite, has been synthesized by the coupling of 4-trimethylsilylbutadiy-nylzinc chloride (134) with 2-ethynyloxirane (135) followed by desilylation [31]. 

Reaction of (diisopropylamino)chloroboryl ethers of alkynols (57) with alkynyl-stannanes (58) in the presence of nickel catalysts has been reported to afford formal f/ms-alkynylboration products (60), which could undergo the Suzuki-Miyaura coupling with organic halides. The 2-borylalkenylnickel(II) complex (59) was isolated as an intermediate in a reaction of the chloroboryl ether (57) with 1 equiv. of a nickel(0)-phosphine complex and characterized by X-ray crystallography.61... 

F. Cross-coupling Reactions with Alkynyl Halides. 1288... 

Alkynyl(trimethyl)silanes smoothly couple with alkenyl halides at room temperature in the presence of a palladium catalyst and TASF (Eq. 5) [4]. The difference in reactivity between alkynylstannanes and -silanes were utilized in a palladium-catalyzed three component cross-coupling reaction. Thus, the palladium-catalyzed sequential reaction of tributylstannyl(trimethylsilyl)ethyne... 

Sodium tetralkynylaluminates 162, prepared from NaAIftj and terminal alkynes, are used for the coupling with aryl halides such as 3-bromofuran (163) to give the coupled product 164 cleanly in high yield. Most importantly, all four alkynyl moieties can be utilized for the coupling [76]. 

Alkynyl(trimethyl)silanes smoothly couple with alkenyl halides at room temperature in the presence of a palladium catalyst and TASF (Scheme The difference in... 

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]. 

Phenethylzinc(II) bromide (PhCH2CH2ZnBr) is widely used in homobenzyUc couplings with aryl halides and alkenyl halides to generate 1,5-dienes [35c, 219-221]. Homoalkenyl- and homopropargylzinc halides are also reported to react with aryl halides [35c, 222, 223]. Recent examples of Pd-catalyzed cross-coupling reactions with aryl or alkenyl halides are highlighted in Scheme 3.57. However, the use of alkynyl halides in these reactions does not appear to have been reported [18c]. 

AUcynylstannanes can cross-couple with a variety of other functional groups employing the Stille protocol. Couphng to acyl chlorides is a well-known procedure that affords aUcynylketones in respectable yields. Other reports include alkynyltin cross-couplings with a-haloethers and a-halocarbonyls, enol phosphinates and phosphonates, alkenyl(phenyl)iodonium salts, alkynyl halides, and allyl hahdes (Table 9.18). Alkynylstannanes have also been shown to cross-couple with iron halides under the Stille conditions to effectively form iron-carbon bonds. 

Several of the new reactions of unsaturated boranes are notable. Vinylboranes can be induced by a Pd catalyst to couple with aryl halides, giving substituted styrenes in high yield,and with vinyl bromides to give E,E-dienes stereo-specifically. " Allylboranes (60) give eryt/iro-alcohols (61) in high stereoselectivity on reaction with RCHO, and S-alkynyl-9-BBN react with RN=C=0 to give (62). ... 

In related transformations, in situ-generated benzynes have been coupled with aUyUc halides and alkynyl stannanes or aryl metal reagents. ... 

In an early example of this reaction aryl and benzyl zinc halides were coupled with aryl halides (equation 40) (102). Alkynyl zinc compounds cross-couple with aryl halides (iodides or bromides) in the presence of a Pd catalyst (equation 41) (103) or alkynyl iodides can be coupled with aryl and alkenyl zinc compounds (equation 42) (100). 

Alkenylboranes (R2C=CHBZ2 Z — various groups) couple in high yields with vinylic, alkynyl, aryl, benzylic, and allylic halides in the presence of tetra-kis(triphenylphosphine)palladium, Pd(PPh3)4, and a base to give R C CHR. 9-Alkyl-9-BBN compounds (p. 1013) also couple with vinylic and aryl halides " as well as with a-halo ketones, nitriles, and esters.Aryl halides couple with ArB(IR2 ) species with a palladium catalyst. ... 

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