Heteroatomic nucleophiles intramolecular additions

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). 

Concerning the M=Co, bond, most of the reported examples result from inter- or intramolecular additions of anionic nucleophiles containing at least two reactive heteroatoms. Thus, sodium dimethyldithiocarbamate was found to react with the cationic allenylidene [RuTp(=C=C=CPh2)(PPh3)2] [PFg] (76) to generate the alle-nyl-metallacycle 77 (Scheme 26) as the result of the nucleophilic addition of one of the sulfur atoms at the Cq, carbon and subsequent coordination of the second sulfur to the ruthenium center, with concomitant release of a triphenylphosphine ligand [282]. Complex 77 could also be synthesized by treatment of the neutral derivative... 

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. 

Electron-withdrawing groups at C-2 have been successful in activating indoles for nucleophilic substitution chemistry. For example, loss of phenylsulfinate with the intramolecular addition of heteroatom nucleophiles to the C-3 position of indole has been demonstrated as early as 1977 [39]. This example involved the intramolecular attack of an alcohol onto C-3 of 77 with the concomitant loss of phenylsulfinate to produce a pyrido[4, 3 5,6]oxepino[3,2-b]indole 78. 

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]. 

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... 

Apart from some special cases, the ring-closure step in the course of the synthetic pathway is often condensation reaction and, thus, these transformations can be considered as cyclocondensations . Reactions following a few other mechanisms like cycloaddition, electrocyclization, and intramolecular nucleophilic addition of electron pair of an atom to a multiple bond also occur relatively often. Because of the fairly large complexity of the ring systems belonging to this chapter, the treatment according to the heteroatomic combinations seemed the most straightforward. Thus, the fused... 

The chemical behavior of heteroatom-substituted vinylcarbene complexes is similar to that of a,(3-unsaturated carbonyl compounds (Figure 2.17) [206]. It is possible to perform Michael additions [217,230], 1,4-addition of cuprates [151], additions of nucleophilic radicals [231], 1,3-dipolar cycloadditions [232,233], inter-[234-241] or intramolecular [220,242] Diels-Alder reactions, as well as Simmons-Smith- [243], sulfur ylide- [244] or diazomethane-mediated [151] cyclopropanati-ons of the vinylcarbene C-C double bond. The treatment of arylcarbene complexes with organolithium reagents ean lead via conjugate addition to substituted 1,4-cyclohexadien-6-ylidene complexes [245]. 

On the other hand, protecting groups can be used to thwart heteroatom-assisted delivery. Reaction of the a,f -unsaturated sulfone 51.1 with trimethylsilylethynyl-lithium resulted in intramolecular delivery of the nucleophile to afford adduct 51.2 with a dr = 100 1 [Scheme 1.51].88 When the hydroxy group was protected as its trivnethylsilyl ether, conjugate addition took place from the opposite face to give the diastereoisomeric adduct 51.4, again with a dr = 100 l. 

Intramolecular cyclopropanations of pendant alkenes are more favorable. Heteroatom-substituted 2-aza- and 2-oxabicyclo[3.1.0]hexanes, together with 2-oxabicyclo[4.1.0] heptanes, can be prepared from chromium and tungsten Fischer carbenes having a tethered alkene chain. An interesting carbene formation via a cationic alkylidene intermediate, nucleophilic addition (see Nucleophilic Addition Rules for Predicting Direction), and intramolecular cyclopropanation is shown in Scheme 59. An intramolecular cyclopropanation via reaction of alkenyl Fischer carbene complex (28) andpropyne was used in a formal synthesis of carabrone (Scheme 60). 

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