Alkynes heteroatom nucleophilic addition

The electrophile-induced cyclization of heteroatom nucleophiles onto an adjacent alkene function is a common strategy in heterocycle synthesis (319,320) and has been extended to electrophile-assisted nitrone generation (Scheme 1.62). The formation of a cyclic cationic species 296 from the reaction of an electrophile (E ), such as a halogen, with an alkene is well known and can be used to N-alkylate an oxime and so generate a nitrone (297). Thus, electrophile-promoted oxime-alkene reactions can occur at room temperature rather than under thermolysis as is common with 1,3-APT reactions. The induction of the addition of oximes to alkenes has been performed in an intramolecular sense with A-bromosuccinimide (NBS) (321-323), A-iodosuccinimide (NIS) (321), h (321,322), and ICl (321) for subsequent cycloaddition reactions of the cyclic nitrones with alkenes and alkynes. 

ADDITION OF HETEROATOM NUCLEOPHILES TO METAL-ACTIVATED ALKYNES 567... 

The same transition metal systems which activate alkenes, alkadienes and alkynes to undergo nucleophilic attack by heteroatom nucleophiles also promote the reaction of carbon nucleophiles with these unsaturated compounds, and most of the chemistry in Scheme 1 in Section 3.1.2 of this volume is also applicable in these systems. However two additional problems which seriously limit the synthetic utility of these reactions are encountered with carbon nucleophiles. Most carbanions arc strong reducing agents, while many electrophilic metals such as palladium(II) are readily reduced. Thus, oxidative coupling of the carbanion, with concomitant reduction of the metal, is often encountered when carbon nucleophiles arc studied. In addition, catalytic cycles invariably require reoxidation of the metal used to activate the alkene [usually palladium(II)]. Since carbanions are more readily oxidized than are the metals used, catalysis of alkene, diene and alkyne alkylation has rarely been achieved. Thus, virtually all of the reactions discussed below require stoichiometric quantities of the transition metal, and are practical only when the ease of the transformation or the value of the product overcomes the inherent cost of using large amounts of often expensive transition metals. 

The C-C bond formation can also be obtained via a first-step addition of a heteroatom to alkynes. Thus, the reaction of the three components terminal alkyne, water and enone led to 1,5-diketone with atom economy, using the system CpRuCl(COD)/NH4PF6 and In(0S02CF3)3 as a cocatalyst [58,59] (Eq. 43). The mechanism is postulated to proceed by the ruthenium-catalyzed nucleophilic addition of water to alkynes to generate a ruthenium enolate intermediate allowing further insertion of enone and formation of 1,5-diketones after protonation. 

Several heteroatom nucleophiles, for example, amines, alcohols, thiols, carboxylates, and dialkylphosphines, undergo Michael addition reactions with alkene- and alkyne-substituted carbene complexes. Reaction of alkyne-substituted chromium carbenes with urea affords products derived from Michael... 

The Wacker-type addition is the anti-addition of (most commonly) a heteroatom and a Pd(II) species across a C-C double bond. The Wacker-type oxidations are Pd(II)-catalyzed transformations involving heteroatom nucleophiles and alkenes or alkynes as electrophiles.27 In most of these reactions, the Pd(II) catalyst is converted to an inactive Pd(0) species in the final step of the process, and use of stoichiometric oxidants is required to effect catalytic turnover. For example, the synthesis of furan 33 from a-allyl-p-diketone 32 is achieved via treatment of the substrates with a catalytic amount of Pd(OAc)2 in the presence of a stoichiometric amount of CuCh-28 This transformation proceeds via Pd(II) activation of the alkene to afford 34, which undergoes nucleophilic attack of the enol oxygen onto the alkene double bond to provide alkylpalladium complex 35. p-Hydride elimination of 35 gives 36, which undergoes... 

The metal-bound carbonyl ligand is readily subjected to the attack of not only carbanions but heteroatom nucleophiles such as alcohols and amines to form ligands useful for formation of compounds containing ester and amide functionalities. The ease with which the nucleophilic attack takes place at metal-coordinated alkenes and alkynes provides a basis for oxidation of these molecules in the presence of a transition metal complex catalyst [3,4a], as exemplified by the Wacker type alkene oxidation by the use of a Pd catalyst. Metal catalyzed addition of alcohols or amines to alkenes and alkynes also involve the analogous nucleophilic attack [4b-e]. The attack of carbanions and heteroatom nucleophiles... 

Nucleophilic additions to alkenes and alkynes are also possible, but these reactions generally require that the substrate have substituents that can stabilize a carbanionic intermediate. Therefore, nucleophilic additions are most likely for compoimds with carbon-heteroatom multiple bonds, such as carbonyl compounds, imines, and cyano compounds. We may distinguish two main types of substituents that activate alkenes and alkynes for nucleophilic attack. The first type consists of those activating groups (labeled AG in equation 9.79) that can stabilize an adjacent carbanion by induction. ... 

An extension of Hashmi s Au(III)-catalyzed phenol synthesis [81] to furan substrates 9 bearing an additional alkyne moiety allowed the preparation of C6-C7-heterofused benzofuran 11 (Scheme 9.3) [82]. According to the proposed mechanism, the Au(III)-catalyzed arene formation reaction generates o-alkynylphenol 10. A subsequent Au(III)-catalyzed cycloisomerization of the latter, following the general mechanism for an intramolecular nucleophilic addition of heteroatom to transition metal-activated carbon-carbon multiple bonds, gives 11 (Scheme 9.3). 

A number of intramolecular Pd-catalyzed 1,4-oxidations of conjugated dienes were developed.f In these reactions, two nucleophiles are added across the diene, one of which adds intramolecularly. So far, only heteroatom nucleophiles have been employed. In order to extend these intramolecular 1,4-oxidations to carbon nucleophiles, it was found that a vinylpalladium species can be obtained in situ from an alkyne via a chloropalladation. The approach is particularly attractive since it involves a Pd(II) chloride salt and could be compatible with the rest of the catalytic cycle. Reaction of dienyne with LiCl, and benzoquinone in the presence of palladium acetate as the catalyst, afforded the carbocyclization products. The reaction resulted in an overall stereoselective fltiri-addition of carbon and chlorine across the diene t B (Scheme 23). 

Prins cyclizations, which proceed by intramolecular addition of alkenes to oxocarbenium ions, provide a simple, efficient method for the stereoselective synthesis of carbocycles and cyclic ethers [77]. Halosilanes and (la) have been used for Prins cyclizations not only as Lewis acids but also as heteroatom nucleophiles. For instance, in the presence of MesSil or MesSiBr, and lutidine, mixed acetals (26) are efficiently cyclized to 4-halotetrahydropyrans (27) with high diastereoselectivity [78]. The halide is introduced into the axial site of the C(4) position. The proposed mechanism for the MesSiBr-promoted reaction involves the initial formation of a-bromoethers (28) from (26). Solvolysis of (28) provides the intimate ion pair (29). Cyclization to the chair transition structure (30) and proximal addition of the bromide produces the observed axial adduct (27). The role of lutidine is to suppress a less selective HBr-promoted cyclization (Scheme 9.23). Acetals bearing an alkyne or allene moiety also undergo the halosilane-promoted cyclization to form haloalkenes [79, 80]. 

In addition to the heteroatom nucleophiles, carbon nuleophiles such as pyrroles were found by Cho and Chang [65] to be able to take part in the three-component reaction with sulfonyl azides and terminal alkynes to give the dual-functionalized pyrroles 98 (Scheme 5.63). The reaction depended on the presence of the N—H bond. When N-substituted pyrroles were used, reactions were sluggish and gave poor yields. Moreover, either indole or Af-methyl indole did not participate in the reaction. 

We also reported on the synthesis of 2,3-dihydroquino-lin-4(lfl)-one derivatives 309, which are expected to possess attractive pharmacological properties and serve as important synthetic intermediates. Thus, the catalytic alkyne-carbonyl metathesis of arylalkyne 307 followed by intramolecular addition of heteroatom nucleophile afforded... 

Terminal alkynes readily react with coordinatively unsaturated transition metal complexes to yield vinylidene complexes. If the vinylidene complex is sufficiently electrophilic, nucleophiles such as amides, alcohols or water can add to the a-carbon atom to yield heteroatom-substituted carbene complexes (Figure 2.10) [129 -135]. If the nucleophile is bound to the alkyne, intramolecular addition to the intermediate vinylidene will lead to the formation of heterocyclic carbene complexes [136-141]. Vinylidene complexes can further undergo [2 -i- 2] cycloadditions with imines, forming azetidin-2-ylidene complexes [142,143]. Cycloaddition to azines leads to the formation of pyrazolidin-3-ylidene complexes [143] (Table 2.7). 

Additional methods for preparing non-heteroatom-substituted carbene complexes include nucleophilic or electrophilic additions to carbyne complexes (Section 3.1.4), electrophilic additions to alkenyl or alkynyl complexes (Section 3.1.5), and the isomerization of alkyne or cyclopropene complexes (Section 3.1.6). 

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