Substitution alkyl-substituted alkynes

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. 

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. 

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,...

Investigations by Vermeer and co-workers have shown that 3-substituted allenyl methyl thioethers 309 can be prepared by regioselective addition of an alkyl silver species to the terminal C=C bond of enyne sulfides 308 (Scheme 8.83) [172], Remarkably, this method can also be applied to the preparation of several allenyl-phosphines starting from the corresponding phosphorus-substituted alkynes. 

Allenylcobaloximes, e.g. 26, react with bromotrichloromethane, carbon tetrachloride, trichloroacetonitrile, methyl trichloroacetate and bromoform to afford functionalized terminal alkynes in synthetically useful yields (Scheme 11.10). The nature of the products formed in this transformation points to a y-specific attack of polyhaloethyl radicals to the allenyl group, with either a concerted or a stepwise formation of coba-loxime(II) 27 and the substituted alkyne [62, 63]. Cobalt(II) radical 27 abstracts a bromine atom (from BrCCl3) or a chlorine atom (e.g. from C13CCN), which leads to a regeneration of the chain-carrying radical. It is worth mentioning that the reverse reaction, i.e. the addition of alkyl radicals to stannylmethyl-substituted alkynes, has been applied in the synthesis of, e.g., allenyl-substituted thymidine derivatives [64],... 

Comparable selectivities have been published for the intramolecular competition of an ester- and an alkyl-substituted alkyne [89] or a silyl- and an alkyl-substituted alkyne [90],... 

It has already been seen (see Section II,B and V,E) that vinylketene complexes of cobalt6,95 and chromium22 react with alkynes to produce cyclo-pentadienones, indanones, and substituted phenols. It has been shown108,109,144,145 that similar products may be derived from the alkyne adducts 247. Indeed, when alkyl or aryl substituted alkynes were reacted with vinylketene complex 221.e, a mixture of organic and organometallic products was isolated. In the cases where the alkyne is attached to an aromatic substituent, the expected alkyne adduct (247.h and 247.i) is isolated in low yield. However, when the vinylketene complex was treated... 

Arene(alkoxy)carbene chromium complexes react with aryl-, alkyl-, terminal, or internal alkynes in ethers or acetonitrile to yield 4-alkoxy-1-naphthols, with the sterically more demanding substituent of the alkyne (Rl Figure 2.24) ortho to the hydroxy group. Acceptor-substituted alkynes can also be used in this reaction (Entry 4, Table 2.17) [331]. Donor-substituted alkynes can however lead to the formation of other products [191,192]. Also (diarylcarbene)pentacarbonyl chromium complexes can react with alkynes to yield phenols [332]. 

The Lee group originated rhodium alkenylidene-mediated catalysis by combining acetylide/alkenylidene interconversion with known metal vinylidene functionalization reactions [31], Thus, the first all-intramolecular three-component coupling between alkyl iodides, alkynes, and olefins was realized (Scheme 9.17). Prior to their work, such tandem reaction sequences required several distinct chemical operations. The optimized reaction conditions are identical to those of their original two-component cycloisomerization of enynes (see Section 9.2.2, Equation 9.1) except for the addition of an external base (Et3N). Various substituted [4.3.0]-bicyclononene derivatives were synthesized under mild conditions. Oxacycles and azacycles were also formed. The use of DMF as a solvent proved essential reactions in THF afforded only enyne cycloisomerization products, leaving the alkyl iodide moiety intact. 

The carbomagnesiation reaction proceeds with a range of organomagnesium compounds (Scheme 30) °. Not only aryl, alkenyl and aUcynyl groups, but also alkyl groups were found to add across a triple bond. The enhanced reactivity of cyano-substituted alkynes is worthwhile, and this may be due to accelerated alkyl transfer from 53 with activation of the cyano group by MgX2 (Scheme 29). 

Despite these favorable results, the Pd-catalyzed lactonization with alkyl-substituted alkynes generally gives unattractive mixtures of five- and six-membered lactones. In marked contrast, the Pd-catalyzed reaction of alkynylzincs with (Z)-/J-iodoacrylic acid gives only the expected enynoic acids135, which can then be selectively lactonized to give either five- or six-membered lactones136 (Scheme 41). 

As most pharmaceuticals are heterocyclic, there is continuing interest in methods for the direct enantioselective construction of heterocycles. Greg Fu of reports (J. Am. Chem. Soc. 125 10778, 2003) that the addition of the dipole 1 to alkynes is catalyzed by Cul, and that in the presence of the planar-chiral ligand 2 the reaction proceeds in high enantiomeric excess. The is maintained with aryl-substituted alkynes, and is higher when there are alkyl substituents on the heterocyclic ring of 1. 

The anti stereoselectivity originates from the preferential attack of the chloride ion on 17 from the less hindered side. Stereoselectivity, therefore, is determined by the relative effect of the two p substituents. Alkyl-substituted alkynes show decreased stereoselectivity compared with that of aryl-substituted acetylenes.59 60... 

Secondary and tertiary dialkylcuprates, lithium dialkenyl-, and even diphenyl-cuprates, add in very good yields to the reactive propionaldehyde diethyl acetal. The syn addition products may be trapped with a variety of electrophiles such as alkyl, alkenyl, alkynyl and aryl halides. The method has been used for the synthesis of several natural products. Substituted alkynic acetals also react with lithium dialkylcuprates in ether to furnish stable dialkenylcuprates of type (128) which do not eliminate to the corresponding alkoxy allenes (129) if the temperature is maintained below -20 C.164-179... 

Likewise, alkynyliodonium tosylates can be coupled with dialkyl- and diphenyl cuprates 136 to afford the respective alkyl- and phenyl-substituted alkynes 137 (Scheme 56) [114]. An interesting example of this reaction involves the coupling of (trimethylsilyl)ethynyl iodonium triflate with cubyl cuprate generated in situ from iodocubane 138 [116]. 

Primary alkyl, secondary alkyl, and aryl groups all migrate readily, and migration occurs with retention of configuration. The reaction is thus more versatile than the deprotonation/alkylation approach to substituted alkynes, which is generally only efficient for primary electrophiles and does not proceed at all for aryl halides. For example, triphenylborane may be used to incorporate a phenyl group into an alkyne (Equation B4.6). 

The reaction of an acetylide ion with a primary alkyl halide allows the synthesis of di-substituted alkynes [Following fig.(a)]. 

Oxetenes (oxets) have been postulated as primary photoadducts between carbonyl compounds to alkyl- and aryl-substituted alkynes and alkylthio-acetylens [66]. The first evidence for an unstable intermediate with a lifetime of several hours at — 35 °C was reported for the benzaldehyde 55/2-butyne-photoproduct 76 [67]. On further irradiation in the presence of excess benzaldehyde, a Z /s-oxetane 77 was formed (Sch. 21). 

Exo cyclisations of vinyllithiums onto phenyl-substituted alkynes 392 and 394 are also syn stereospecific, and give the sort of stereodefined dienes 393 and 395 of value in Diels Alder reactions.180 6-Exo cyclisations are also possible but are much slower, though they still give geometrically pure products (in contrast to 6-exo cyclisations onto silyl alkynes see below). Vinyllithiums cyclise onto alkyl-substituted alkynes (such as 396) only in the presence of TMEDA, and they do so very slowly. Nonetheless, a single geometrical isomer of the product 397 is obtained. 

Negishi182 generalised this cyclisation to show that trialkylsilylalkynes will trap alkyl- (403, 404), vinyl- (405, 406), allenyl- (407) and aryllithiums (408) intramolecularly. Piers183 has cyclised a cyclopropyllithium onto an alkynylsilane (409 - phenyl and alkyl substituted alkynes performed less well), and Coldham61 found that the oc-amino organolithium cyclises onto a silyl alkyne (410) though in low yield. 

Lithium dialkynylcuprates behave similarly with alkynyliodonium tosylates and lead to conjugated diynes (equation 133)109. Unsymmetrical diynes can be prepared with moderate selectivity by this method, although they are accompanied by symmetrical diynes derived from the alkynyliodonium component. The treatment of lithium diphenyl- and dialkylcuprates with alkynyliodonium tosylates has also been investigated and affords alkyl- and phenyl-substituted alkynes (equation 134)109. 

Acetylide ions are strong nucleophiles. In fact, one of the best methods for synthesizing substituted alkynes is a nucleophilic attack by an acetylide ion on an unhindered alkyl halide. We consider this displacement reaction in detail in Section 9-7A. 

Following these findings, Gleiter and co-workers reported that in a series of S-alkyl-substituted alkynes, the regiochemical outcome of the reaction... 

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