Alkynes, halo halogenation

Both ( )- and (Z)-l-halo-l-alkenes can be prepared by hydroboration of 1-alkynes or 1-halo-l-alkynes followed by halogenation of the intermediate boronic esters (244,245). Differences in the addition—elimination mechanisms operating in these reactions lead to the opposite configurations of iodides as compared to bromides and chlorides. 

The mildness of these reagents tolerates the presence of various functional groups such as ester, ether, halogen, and nitrile. The stereospecific cis nature of hydroboration gives exclusively the tram alkenylboranes, often also in high regioisomeric purity (Eq. 53). On the other hand, highly pure (Z)-l-alkenyl-dialkylboranes are prepared without any difficulty via the monohydroboration of 1-halo-1-alkynes with disiamyl-borane or dicyclohexylborane, followed by treatment with t-butyllithium (Eq. 55)106). 

First attemps to achieve nucleophilic substitutions of halogene in chloro- and bromo-alkynes using protic solvents met invariably with failure. Consequently such reactions were considered as hopelessl, 2). Yet evidence gradually accumulated that 1-halo-alkynes are not inherently inert and the year 1962 was a real breakthrough 1,3 4). Nucleophilic substitutions on an sp carbon became routine with the advent of dipolar aprotic solvents such as DMF, DMSO and HMPT, but their use is not always... 

Tin-functionalized 1-phosphanorbornadienes can be prepared from tin-substituted alkynes using this type of methodology. Subsequent tin-halogen exchange affords the corresponding halo derivatives, which may be further elaborated using palladium-catalyzed reactions such as Stille coupling, for example (see Section 3.15.12.1.2). 

A strongly solvent-dependent electrophilic reaction is the addition of halogens to alkenes [79-81] and alkynes [81a]. In a rapid equilibrium, a loose transitory EPD/EPA complex (1 1) between halogen and alkene is formed [512]. This is followed by the ratedetermining step, which involves an SNl-hke unimolecular ionization to form a halo-nium intermediate which can be either symmetrical or unsymmetrical. This then reacts with a nucleophile Nu to give the products cf. Eq. (5-29). 

The method has been of particular value in the preparation of difunctional compounds. For example, the action of elemental halogen on sodium acetylides or alkynylmagnesium halides gives 1-halo-1-alkynes (70-90%). t Also, halo esters, phenols, or acids result when the appropriate aromatic mercurial is treated. Sometimes p-toyl-sulfonyl chloride is substituted for chlorine gas. p-Iododimethylaniline is easily made in 42-54% yield by the reaction of p-dimethylaminophenyl-lithium and iodine. ... 

When the acylcobalt species is derived from a compound containing halogen on an activated carbon (e.g. an a-halo ester or nitrile) an elimination may occur to introduce an exocyclic double bond in the final product. This sequence, leading to lactones of pentadienoic acids, is general for both terminal and internal alkynes in the presence of amine bases (equation 17). ... 

Terminal and internal (Z)-l-alkenylboronates are prepared from (Z)-(l-halo-l-alkenyl)boronates [23]. which can be readily obtained by hydroboration of 1-halo-1-alkynes (Scheme 16.2). The internal Sv,2-like displacement of the halogen with hydrides [24] or organolithiums [25] takes place wath complete inversion of configuration at the sp carbon. On the other hand, the palladium-catalyzed alkylation of the C—X bond with organozinc reagents provides ( )-l-alkenylboronates [26] which are not available by conventional hydroboration of internal alkynes. 

Et3B is an effective tool for halogen atom transfer radical reactions (see also Chap. 1.5). Perfluoroalkyl iodide [29], a-halo nitrile and a-halo ester [30] added to alkenes and alkynes at low temperature. Not only terminal alkenes but also internal alkenes can be employed to furnish iodine atom transfer adducts (Scheme 23). Furthermore, addition of perfluoroalkyl iodide to silyl and germyl enolate provided a-perfluoroalkyl ketones [31]. The reaction would involve the elimination of a tri-... 

The addition of a hydrogen halide to an alkyne can be stopped after the addition of one equivalent of HBr or HCl because an alkyne is more reactive than the halo-substituted alkene that is the product of the first addition reaction. The halogen substituent withdraws electrons inductively (through the cr bond), thereby decreasing the nucleophilic character of the double bond. 

Syn hydroboration of internal alkynes tends to give a mixture of two possible regioisomers. In cases where 1-halo-l-alkynes are used as internal alkynes, the reaction is nearly 100% regioselective placing B at the halogen-bound carbon. The resultant (Z)-a-haloaIkenylboranes can be used to prepare (i) (Z)-l-alkenylboranes (Type IV) [59], (ii) (Z)-a,P-disubstituted alkenylboranes (Type V) [60], and (iii) ( )-a,P-disubstituted alkenylboranes (Type VI) [61] as summarized in Scheme 3.9. 

As mostly discussed earlier. Type III alkenyl derivatives, that is, ( )-R CH= CHM(or X), are widely and satisfactorily generated by (i) alkyne hydrometallation (M = B, Zr or, in some cases, Al, etc.) (Table 3.2, Scheme 3.6), (ii) polar halogenation reactions ofalkynes (Eqs. (1), (2), and (7), Scheme 3.15), and additionally, (iii) anti bromoboration of ethyne [53] followed by Negishi coupling (Eq. (1), Scheme 3.12). On the other hand. Type IV alkenyl derivatives may be prepared by (i) Normant alkylcupration of ethyne [67, 68] (Eqs. (5) and (6), Scheme 3.11), (ii) Zr-catalyzed alkylalumination of ethyne, (iii) syn hydroboration of 1-halo-l-alkynes followed by hydride-induced inversion of configuration [59] (Scheme 3.9), (iv) hydroboration of 1-alkynes followed by brominolysis (but not iodinolysis) with inversion [95], and (v) syn hydrozirconation or syn hydroalumination of 1-boryl- or 1-silyl-l-alkynes followed by protonolysis of the C-Al or C-Zr bond [96-98]. 

The relative effects of halogens in 1-halo-1-alkynes are summarized in Table 4.16 [2]. 

A consecutive three-component synthesis of pyrazoles [67] starting from (hetero)aroyl chlorides, terminal alkynes, and hydrazines represents an excellent entry to more sophisticated one-pot transformations on the regioselectively substituted heterocyclic core. For instance, the catenation of an electrophilic halogenation step led to a one-pot four-component synthesis of 4-halo pyrazoles 36 (halo = chloro or bromo) in good to excellent yield (Scheme 12.24) [68]. 

During the course of some work aimed at the selective reduction of a substituted alkyne to the c/5-alkene, Olsen et al have discovered the novel synthesis of a rare ring system. Lithiated alkynes were found to react with the halo-substituted phthalimide (360) at the carbonyl group rather than at the halogen-bearing carbon as expected. The intermediate cyclized to this position to give an oxazolo[2,3-a] isoindole (361). 

Zweifel s group has developed two complementary syntheses of 1,1-dihalo-alkenes this permits mixed dihaloalkenes to be prepared. Thus, the hydro-boration of 1-halo-l-alkynes (117) followed by oxidation gives the borinic alkenes (118), which are converted into the bromohaloalkenes (119) stereo-specifically. Alternatively, tra 5-halogenation of ( )-haloalkenylsilanes (120) followed by a/iti-desilicohalogenation gives the ( )-dihaloalkenes (121) [similarly. 

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