Alkynylation protocols

The in situ deprotection/alkynylation protocol has proven to be exceedingly useful. In addition to graphdiyne models, an array of PAM/PDM hybrids have been prepared (76 (R=H), 81, 97-99) [66]. Extension of the simple, one-pot procedure to various iodoarenes has allowed preparation of a series of bis(tri-isopropylsilyl)-protected a,m-polyynes in very good yields. Subsequent depro-... 

Z)-/3-Ethoxyethenyltributylstannane has also been used to give benzofurans, but it is not clear if this procedure provides any advantage over the o-alkynylation protocol. 

In addition to Zn, B, and Sn—three metal countercations that were found to be highly satisfactory for alkynylafiorf —the Sonogashira alkynylation protocol (Sect IIL2X1) has also proved to be generally tqtpUcable to this case. Some representative examples of Pd-catalyzed conjugate substitution with alkynylmetals and terminal alkynes are summarized in Table 3. 

The scope of the alkynylation protocol has also recently been extended to other nucleophiles. Silva Jr. and co-workers reported the first alkynylation of simple aromatic ketones using TMS-EBX 36, TBAF, and potassium tert-butoxide as abase (Scheme 16) [114]. It is noteworthy that the alkynylation reaction is still highly efficient under these strongly basic conditions. Cyclic products could be obtained in 60-93% yield. In the case of an unsubstituted a-position, diynes products were formed in 30-92% yield. Interestingly, the alkynylatimi was also successful with an aldehyde, which needed to be reduced immediately prior to isolation because of its instability. 

Scheme 5-128. Palladium-catalyzed double alkynylation protocol. ...

Negishi also investigated different alkynylation protocols for the synthesis of harynone and tricholomenyn A (Scheme 5-131). Again, zinc salts are superior to... 

In order to minimize the formation of side products, PAM 4 can be assembled via an intramolecular approach [23]. The Sonogashira protocol [15] and conversion of masked iodides [24] comprises most of the chemistry involved in Scheme 7. Using these proven methods, diyne 16 and subsequently triyne 17 can be prepared quickly. lodination, desilylation, and intramolecular alkynylation with Pd(dba)2 under high dilution conditions furnished 4 as the sole product. 

Despite the great success of the transmetalation process in the enantiose-lective arylation of ketones, its extension to allylation or alkynylation reactions failed, providing the corresponding tertiary alcohols with enantiomeric excesses never higher than 50% ee. On the other hand, more success has been found in the alkenylation of ketones. The process started with the hydrozirconation of terminal alkynes to give the corresponding alkenylzirconium intermediates, which were transmetalated by reaction, in this case, with various ketones in the presence of the HOCSAC ligand. This protocol tolerated the presence of other carbon-carbon multiple bonds on the alkyne, as well as different functionalities and achieved excellent results for alkyl ketones, a,(3-unsaturated ketones and even dialkylketones, as shown in Scheme 4.22. 

Anionic complexes of boron (boronates, borinates, etc.) have been introduced as convenient reagents in cross-coupling reactions of broad scope, particularly interesting for the transfer of alkynyl and primary alkyl residues, which cannot be accomplished using the standard protocols of the Suzuki-Miyaura reaction. Readily available Ph4BNa can be used as a convenient reagent for phenylation in place of the much more expensive PhB(OH)2, and all four phenyl groups can be utilized when the reaction is carried out with a phosphine-free catalyst in aqueous solutions.244... 

An alternative method of modifying proteins to contain alkynyl groups is to use the propargyl-PEGj-NHS ester compound described in Chapter 18, Section 2. This reagent will react spontaneously with available amine groups in proteins to form an amide bond without the need to use EDC, as in the following protocol. 

An alternative disconnection of homopropargylic alcohols substrates for intramolecular hydrosilylation is the opening of an epoxide with an alkynyl anion. This strategy was employed in a total synthesis of the macrolide RK-397 (Scheme 20). Epoxide ring opening serves to establish homopropargylic alcohol C with the appropriate stereochemistry. A hydrosilylation/oxidation protocol affords the diol E after liberation of the terminal alkyne. The... 

Here an alkynyl sulfoxide 55 is first carbocuprated with an organocopper reagent 56 to provide a vinylcopper intermediate 57, which is then zinc homologated with the primary zinc sp3-carbenoid 58 to yield the allylzinc intermediate 59. This, in a spontaneous syw-/)-climination, gives the corresponding allene 60. This protocol could also be adopted to the preparation of chiral allenes. 

This reaction has been successfully applied to cyclopentenone annelation onto cycloalkenes. By modifying Danheiser s protocol [15], alkynyl-substituted bi-cyclo[n.l.0]alkanol derivatives are prepared by the reaction of gem-lithio-bromocyclopropanes 27 with alkynylborons, as shown in Scheme 10. 

SCHEME 40. Three discrete protocols for Pd-catalyzed alkynylation... 

Three methods for the Pd-catalyzed a-alkynylation of enones according to Protocol II have been developed and applied to the synthesis of harveynone and tricholomenyn... 

An expedient method for synthesis of 2,3-disubstituted 1-benzoselenophenes (91) by the electrophilic cyclization of various 1 -(1 -alkynyl)-2-(methylseleno)arenes (90) has been reported recently (Scheme 24). This method tolerates a wide of variety of functional groups, and proceeds under exceptionally mild reaction conditions [141], Moreover, an efficient solid phase synthesis of 91 based on a combination of palladium-mediated coupling and iodocyclization protocols has been developed [142],... 

The allylmetallation of an alkynyl metal leads to a vinylic 1,1-organogem-bismetallic derivative,22 and the stereoselective reaction of this latter with different electrophiles gives a new access to the synthesis of stereodefined poly-substituted olefins, as single stereoisomers23 (Equation 7.6 and Protocol 10). 

The reactions of the lithium enolate of diethyl 2-[(diphenylmethylene)amino]malonate with several alkynyliodonium triflates are rare examples of enolate alkynylations with iodonium species other than the ethynyl(phenyl)- and (phenylethynyl)phenyliodonium ions (equation 125)16. Two experimental protocols were followed, i.e. addition of the enolates to the iodonium salts and vice versa, the former procedure giving higher yields of alkynylmalonates. As with other enolate alkynylations, these reactions are thought to involve alkylidenecarbene intermediates. It has been proposed, however, that the carbenes rearrange with migration of the diethyl 2-[(diphenyl) amino] malonate anion 16. 

An example that used this protocol the substrate of which contains a sensitive functionality is depicted in Scheme 45 [202]. 1,3-Diene monoepoxide is easily attacked by a palladium(O) complex to form the corresponding 7r-allylpalladium species. Thus such a process could be banished from the desired selective transformation as depicted in Scheme 46 by the employment of the alkynyltin reagent with an aid of triphenylarsine ligand [203]. Organotin protocol is also convenient for introduction of a small alkynyl moiety such as C2 or C3 or preparation of symmetrical diarylethynes (Scheme 47) [204]. Shirakawa et al. reported recently that iminophosphine 4 is much more effective ligand for palladium than tris(2-furyl)phosphine in this reaction (Scheme 48) [32,205]. 

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