Substituted alkynes

Reactions with mono-substituted alkynes usually give mixtures of both 5-and 6-substituted indoles, although certain combinations of substituents result in good regiosclcctivity. Table 8.2 provides some examples. 

Alkylarylisoxazoles can be obtained from the cycloaddition of nitrile Af-oxides to substituted alkynes or alkenes (Section 4.16.4.1.2(ii)), and from the condensation of the 1,4-dilithio oximes (358) with benzonitriles (72JHC183) or amides (78JOC3015). 

Alkyl-substituted alkynes can react by either the Adg3 or the Adg2 mechanism. The Adg3 mechanism leads to and addition. The preference for one or the other mechanism depends on the individual stmcture and the reaction conditions. Added CP promotes the Adg3 mechanism and increases the overall rate of reaction. 

For alkyl-substituted alkynes, there is a difference in stereochemistry between mono-and disubstituted derivatives. The former give syn addition whereas the latter react by anti addition. The disubstituted (internal) compounds are considerably ( 100 times) more reactive than the monosubstituted (terminal) ones. This result suggests that the transition state of the rate-determining step is stabilized by both of the alkyl substituents and points to a bridged intermediate. This would be consistent with the overall stereochemistry of the reaction for internal alkynes. 

The stereochemistry of addition is usually anti for alkyl-substituted alkynes, whereas die addition to aryl-substituted compounds is not stereospecific. This suggests a termo-iecular mechanism in the alkyl case, as opposed to an aryl-stabilized vinyl cation mtermediate in the aryl case. Aryl-substituted alkynes can be shifted toward anti addition by including bromide salts in the reaction medium. Under these conditions, a species preceding the vinyl cation must be intercepted by bromide ion. This species can be presented as a complex of molecular bromine with the alkyne. An overall mechanistic summary is shown in the following scheme. 

This scheme represents an alkyne-bromine complex as an intermediate in all alkyne brominations. This is analogous to the case of alkenes. The complex may dissociate to a inyl cation when the cation is sufficiently stable, as is the case when there is an aryl substituent. It may collapse to a bridged bromonium ion or undergo reaction with a nucleophile. The latta is the dominant reaction for alkyl-substituted alkynes and leads to stereospecific anti addition. Reactions proceeding through vinyl cations are expected to be nonstereospecific. 

Polymerization of alkynes by Ni" complexes produces a variety of products which depend on conditions and especially on the particular nickel complex used. If, for instance, O-donor ligands such as acetylacetone or salicaldehyde are employed in a solvent such as tetrahydrofuran or dioxan, 4 coordination sites are available and cyclotetramerization occurs to give mainly cyclo-octatetraene (cot). If a less-labile ligand such as PPhj is incorporated, the coordination sites required for tetramerization are not available and cyclic trimerization to benzene predominates (Fig. A). These syntheses are amenable to extensive variation and adaptation. Substituted ring systems can be obtained from the appropriately substituted alkynes while linear polymers can also be produced. 

Because of its generality, acetylide alkylation is an excellent method for preparing substituted alkynes from simpler precursors. A terminal alkyne can be prepared by alkylation of acet dene itself, and an internal alkyne can be prepared by further alkylation of a terminal alkyne. 

The products are yellow or red solids when R = Me, Et, Pr, or Bu, they decompose below —10°, but when R = Ph, or, particularly, when R = Me iCH, the products are more stable. They are oxidized immediately in air to the corresponding distannoxanes, readily exchange the trialkyltin group with trialkyltin hydrides, and add across polar-substituted alkynes or azo compounds. 

The thermolysis of various substituted phosphonium ylides between 600 °C and 900 °C can afford either substituted alkynes [16,25,27] or cyclic dienes [20] by extrusion of PhjPO, or new stabilized ylides by cyclization of the functional groups [27,28]. 

In Sect. 2.2.1 we described the thermolysis of various /1-oxophosphorus yUdes affording either substituted alkynes or cyclic dienes by extrusion of PhjPO, or new stabilized ylides. 

The classic Stille systems, utiHzing (PPh3)2PdCl2 in an aprotic solvent such as DMF, toluene or benzene to couple tin-substituted alkynes to aryl or alkenyl bromides or iodides. The disadvantage of this catalyst system is the relatively high temperature (80- 120°C) needed to conduct the coupling [20a]. 

The ligandless Beletskaya catalysts, PdCl2(CH3CN)2 used in DMF or acetone with tin-substituted alkynes and sp -hybridized iodides and bromides. This system is very reactive and relatively cheap. The disadvantage is that it decomposes quickly under development of catalyticaUy inactive Pd-black particles [20 c]. 

Attempts to use in the alkynylation reaction not tin-substituted alkynes, but to couple 26 directly under the conditions developed by Heck, Cassar, Sono-gashira, and Hagihara, surprisingly enough gave rise to the formation of the corresponding amino-substituted cyclobutadiene complex 30 in good yields. 

The coupling of terminal alkynes with aryl or alkenyl halides catalysed by palladium and a copper co-catalyst in a basic medium is known as the Sonogashira reaction. A Cu(I)-acetylide complex is formed in situ and transmetallates to the Pd(II) complex obtained after oxidative addition of the halide. Through a reductive elimination pathway the reaction delivers substituted alkynes as products. 

The regiochemistry of Al-H addition to unsymmetrically substituted alkynes can be significantly altered by the presence of a catalyst. This was first shown by Eisch and Foxton in the nickel-catalyzed hydroalumination of several disubstituted acetylenes [26, 32]. For example, the product of the uncatalyzed reaction of 1-phenyl-propyne (75) with BujAlH was exclusively ds-[3-methylstyrene (76). Quenching the intermediate organoaluminum compounds with DjO revealed a regioselectivity of 82 18. In the nickel-catalyzed reaction, cis-P-methylstyrene was also the major product (66%), but it was accompanied by 22% of n-propylbenzene (78) and 6% of (E,E)-2,3-dimethyl-l,4-diphenyl-l,3-butadiene (77). The selectivity of Al-H addition was again studied by deuterolytic workup a ratio of 76a 76b = 56 44 was found in this case. Hydroalumination of other unsymmetrical alkynes also showed a decrease in the regioselectivity in the presence of a nickel catalyst (Scheme 2-22). 

In the case of silyl-substituted alkynes (R = MejSi), the initially formed irnine undergoes a subsequent 1,3-sigmatropic silyl shift yielding the corresponding enam-ine (Eq. 4.81). 

As predicted from the comparative rates for C=C over C=C hydrozirconation cited earlier, a (poly)enyne is selectively hydrozirconated at the alkyne moiety, whatever the position of the alkene function [138, 210] in the molecule. It can be exempUfied by the chemoselective hydrozirconation of 1,3-butenyne. One exception to this chemoselectivity has been reported, which showed the terminal alkene to react with 1 but leaving the TMS-substituted alkyne function intact (Scheme 8-25). 

Alkynes react with electrophilic selenium reagents such as phenylselenenyl tosylate.155 The reaction occurs with anti stereoselectivity. Aryl-substituted alkynes are regioselective, but alkyl-substituted alkynes are not. 

Scheme 15 Iridium-catalyzed hydrogen-mediated coupling of alkyl-substituted alkynes to activated ketones and aldehydes. Conditions a ligand = BIPHEP, solvent = toluene, T = 80 °C b ligand = DPPF, solvent = toluene, T = 60 °C c ligand = BIPHEP, solvent = DCE,...

The behavior of the Si—P 7r-bond toward a G=C triple bond was examined in the case of 15a by employing differently substituted alkynes.14 It appeared that 15a does not react with dialkyl, diaryl-, or disilyl-substi-tuted alkynes at 110°C even cyclooctyne, usually a very reactive alkyne, does not react. However, when 15a was stirred with phenylacetylene at 80°C in toluene, the C—H insertion product 24 was isolated as colorless crystals (Eq. 9).14 Its molecular structure has been elucidated by singlecrystal X-ray diffraction (Fig. 9). 

These reactions are found to be promoted by electron-donating substituents in the diene, and by electron-withdrawing substituents in the alkene, the dienophile. Reactions are normally poor with simple, unsubstituted alkenes thus butadiene (63) reacts with ethene only at 200° under pressure, and even then to the extent of but 18 %, compared with 100% yield with maleic anhydride (79) in benzene at 15°. Other common dienophiles include cyclohexadiene-l,4-dione (p-benzoquinone, 83), propenal (acrolein, 84), tetracyanoethene (85), benzyne (86, cf. p. 175), and also suitably substituted alkynes, e.g. diethyl butyne-l,4-dioate ( acetylenedicarboxylic ester , 87) ... 

Chung and coworkers [280] combined a [2+2+1] with a [2+2+2] cycloaddihon for the synthesis of multi-ring skeletons, angular triquinanes, and fenestranes. For the preparation of tetracyclic compounds such a 6/4-17, these authors used diynes as 6/4-16 and CO as substrates (Scheme 6/4.5). Fully substituted alkynes gave low yields, and 1,5- as well as 1,7-dialkynes, did not react... 

On the other hand polysilylalkynes with phenyl or allyl substituents are converted with triflic acid into polymeric alkynylsilyltriflates. These polymers react with many acidic element hydrogen compounds or lithium element compounds with formation of silicon element bonds. Thus we found an easy approach to numerous new functional substituted alkynes [12], Eq.(9) shows selected examples of this reaction type. 

Benzo-fused pyrrolizines can be prepared from the palladium-catalyzed reaction of alkynes with imines of 2-halogenoanilines. Pyrimidine-substituted alkynes react in the same way, to produce the pyrimidine-fused pyrrolizines 161 <2001JOC412> (Scheme 48). 

A three-component coumarin synthesis involves the Pd-catalysed coupling of o-iodophenols with alkynes and subsequent insertion of carbon monoxide. With internal alkynes, pyridine is the crucial base for successful annulation the regioselectivity with unsymmetrically substituted alkynes is only moderate (Scheme 43) . 

Organolithium reagents47 instead of organoaluminum derivatives48, 9 have been used for the carbometallation of unactivated alkynes under iron catalysis (Scheme 9). Thus, variously substituted alkynes 30 and 32, bearing a tertiary... 

Rhodium complexes catalyze hydrosilylation-cyclization of 1,6-allenynes in the presence of (MeO SiH.77 To avoid complex product distributions, the use of substrates possessing fully substituted alkyne and allene termini is imperative. As shown in the cyclization of 1,6-allenyne 62a, the regiochemistry of silane incorporation differs from that observed in the rhodium-catalyzed hydrosilylation-cyclization of 1,6-enynes (see Section 10.10.2.3.2). For allenyne substrates, allene silylation occurs in preference to alkyne silylation (Scheme 40). 

The inter- and intramolecular catalytic reductive couplings of alkynes and aldehydes recently have experienced rapid growth and are the topic of several recent reviews.5 h-8k 107 With respect to early transition metal catalysts, there exists a single example of the catalytic reductive cyclization of an acetylenic aldehyde, which involves the titanocene-catalyzed conversion of 77a to ethylidene cyclopentane 77b mediated by (EtO)3SiH.80 This process is restricted to terminally substituted alkyne partners (Scheme 53). 

The [5 + 2]-cycloadditions of tethered alkyne-VCPs that are 1,2-disubstituted on the cyclopropane ring 5j—1 have been studied and a mechanism has been advanced to explain the regio- and stereoselectivities of the reactions.37 In most cases, the product resulting from cleavage of the less-substituted (sterically less encumbered) carbon-carbon bond is obtained. The [5 + 2]-reaction is stereospecific in that a /ram-rclationship of the substituents on the cyclopropane leads to a m-relationship of the substituents in the product and vice versa (Equations (4) and (5)). For some tethered alkyne-VCPs which contain a functional group that weakens the carbon-carbon bond of the cyclopropane system, the more substituted (weaker) carbon-carbon bond can be cleaved selectively depending on the choice of catalyst. Thus far, the rhodium(l)-catalysts are more selective catalysts than the mthenium(0)-catalysts in the [5 + 2]-reaction of these substituted alkyne-VCPs (Scheme 7).38... 

A single but noteworthy example of a [2 + 2 + 2 + l]-cycloaddition reaction was reported by Takats and Cooke in 1997. In this process, Fe(CO)4(7]2-C2H2) reacts with acetylene to give an iron-tropanone complex in 26% yield (Equation (44)). When the analogous reaction was tried with substituted alkynes under an atmosphere of CO, iron-quinone complexes were observed (Equation (45)).168... 

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