MARKOVNIKOV Regioselectivity

Fluorine and selenium, in the form of a phenylselenenyl group, add to nucleophilic olefins with Markovnikov regioselectivity and anti stereoselectivity on reaction with several reagents that may form phenylselenenyl fluoride in situ [792, 193, 194] (equation 30)... 

The Markovnikov regioselectivity of the gem-alkenes is associated with a chemoselectivity. in favour of methanol attack, significantly greater than that observed for the other alkenes. If no sodium bromide is added to the reaction medium, no dibromide is observed for this series. Therefore, these alkenes behave as highly conjugated olefins, as regards their regio- and chemo-selectivity. In other words, the bromination intermediates of gem-alkenes resemble P-bromocarbocations, rather than bromonium ions. Theoretical calculations (ref. 8) but not kinetic data (ref. 14) support this conclusion. 

Hydroamination of activated alkenes has been reported with complexes 91-93 (Fig. 2.15). For example, 91 catalyses the hydroamination of methacrylonitrile (X = CN in Scheme 2.13) by a range of secondary amines (morpholine, thiomorpholine, piperidine, iV-methylpiperazine or aniline) in good to excellent conversions (67-99%) and anfi-Markovnikov regioselectivity (5 mol%, -80°C or rt, 24-72 h). Low enantioselectivies were induced ee 30-50%) depending on the amine used and the reaction temperature [79]. 

Terminal alkenes react with selenenyl halides with Markovnikov regioselectivity.64 However, the (J-selenyl halide addition products readily rearrange to the isomeric products.65... 

Hosokawa, Murahashi, and coworkers demonstrated the ability of Pd" to catalyze the oxidative conjugate addition of amide and carbamate nucleophiles to electron-deficient alkenes (Eq. 42) [177]. Approximately 10 years later, Stahl and coworkers discovered that Pd-catalyzed oxidative amination of styrene proceeds with either Markovnikov or anti-Markovnikov regioselectivity. The preferred isomer is dictated by the presence or absence of a Bronsted base (e.g., triethylamine or acetate), respectively (Scheme 12) [178,179]. Both of these reaction classes employ O2 as the stoichiometric oxidant, but optimal conditions include a copper cocatalyst. More recently, Stahl and coworkers found that the oxidative amination of unactivated alkyl olefins proceeds most effectively in the absence of a copper cocatalyst (Eq. 43) [180]. In the presence of 5mol% CUCI2, significant alkene amination is observed, but the product consists of a complicated isomeric mixture arising from migration of the double bond into thermodynamically more stable internal positions. 

The reaction w ith styrene in acetonitrile, on the other hand, gives two vicinal fluoro sulfates 4 and 5 with preference for mn/ -Markovnikov regioselectivity, and svn addition with other alkenes.11... 

The Pd[(-)-sparteine]Cl2 complex catalyses the formation of dialkyl acetals ArC (OMe)2Me from styrene derivatives ArCH=CH2 with Markovnikov regioselectivity. Initial mechanistic studies indicate that the reaction proceeds through an enol ether intermediate and a Pd hydride.73... 

In contrast to palladium and rhodium catalyzed monohydroboration of 1,3-dienes,20 no 1,4-addition and only 1,2-addition products were obtained with anri-Markovnikov regioselectivity. Acyclic dienes were more reactive than cyclic dienes, and styrene was unreactive. Among iron(II) and cobalt(II) chloride complexes with dppe, dppp and dppb only CoClz(dppp) showed catalytic activity albeit lower than NiCUIdppe). 

Only compound XII was observed, which illustrates once more the anti-Markovnikov regioselectivity of the addition reaction. However, the divergent fate of intermediate XI must be governed by the relative rates of the two competing processes A and B (Scheme 40.2), so the radical mechanism cannot be dismissed on the basis of this experiment alone [Eq. (2) of Scheme 40.2]. It has been estimated that the rate of step B is of the order of k = 3 X 10 s" and the activation energy is only 13 kcal/mol. This means that if the mean life time of XI—before it is trapped by I—is shorter than 300 thousandths of a second, pathway B will be blocked and only compound XII will be produced. 

Addition of FBr to l-trityl-4-vinyl-l/7-imidazole 756 occurs with Markovnikov regioselectivity to produce 757 (Scheme 186). Elimination of HBr (giving 758) followed by fluorobromination provides 759. The bromide is converted into azide 760, which is reduced to 3, 3-difluorohistamine 761. In contrast, functionalization of l-trityl-4-formyl-l/7-imidazole (cyanohydrin/DAST MeNOz) does not yield useful intermediates for the preparation of 761 <2001JOC4687>. The FBr addition/HBr elimination is compatible with hydroxyl (but not carboxyl) group 762, which is employed in the synthesis of 763 en route to P-fluorourocanic acids 764 <2002JOC3468>. 

So far we have looked at the addition of electrophiles to carbon/carbon double bonds that have followed the Markovnikov regioselectivity. Now we will study reactions that adopt the opposite regioselectivity, i.e. an a Z/-Markovnikov addition. From a synthetic point of view, obviously, it is useful to have the choice. 

The yttrium silanolate complex 11 shows good catalytic activity with high anti-Markovnikov regioselectivity in the hydrosilylation of 1-decene (Tablet) [59]. Cationic silanolate rare-earth metal alkyl species derived from 11 were either inactive or exhibited significantly diminished activity, possibly as a result of tight binding of the benzene solvent as well as decomposition of the cationic metal hydride intermediate. 

Reversing the Markovnikov regioselectivity calls for hydroboration.13 We discussed hydroboration of alkynes in the last chapter and many of the same principles apply here. The reaction is a syn addition of R2B H to an alkene in which the boron bonds to the less substituted end of the alkene. The same sort of hydroborating agents are used - such as 9-BBN -and the mechanism is similar. The most important interaction is between the full n orbital of the alkene (HOMO) and the empty p-orbital on boron (LUMO) 80, but the reverse interaction between o(B-H) and Ji (alkene) also comes into play as the reaction proceeds. The result is syn addition via a transition state 81 with some positive charge on carbon and some negative charge on boron. 

Reversal of the regioselectivity has been observed for the Wacker-Tsuji oxidation of alkene systems. Mechanistically, the regiochemistry of the Wacker-Tsuji oxidation stems from the Markovnikov addition (which takes place for the vast majority of the cases) versus the anti-Markovnikov regioselectivity although methyl-ketone 2 is often the major product and aldehyde 7 is the minor product. However, abnormal regiochemistry has been observed where aldehyde 7 is the major or even sole product in the Wacker-Tsuji oxidation. 

Similar results have been observed for other sulfenylating reagents. The somewhat more electrophilic trifluoroethylsulfenyl group shows a shift toward Markovnikov regioselectivity but retains anti stereospecificity, indicating a bridged intermediate. ... 

Terminal alkenes show anti-Markovnikov regioselectivity, but rearrangement is facile.The Markovnikov product is thermodynamically more stable (see Section 3.1.2.2). 

The addition of S-H compounds to alkenes by a radical chain mechanism is a quite general and efficient reaction.The mechanism is analogous to that for hydrogen bromide addition. The energetics of both the hydrogen abstraction and addition steps are favorable. The reaction exhibits anti-Markovnikov regioselectivity. 

Hydroboration-oxidation A two-step addition of water to a double bond, with anti-Markovnikov regioselectivity. 

Hydrosilylation of alkenes and alkynes This reaction can be effected with 1 and an initiator at 90°. Reaction with monosubstituted and gem-disubstituted alkenes shows high an -Markovnikov regioselectivity. cis- or rrons-Disubstituted and trisubstituted alkenes are hydrosilylated in high yield but require longer reaction times. 

Acid-Catalyzed Hydration of Alkenes Alkenes add water in the presence of an acid catalyst to yield alcohols (Section 8.5). The addition takes place with Markovnikov regioselectivity. The reaction is reversible, and the mechanism for the acid-catalyzed hydration of an alkene is simply the reverse of that for the dehydration of an alcohol (Section 7.7). 

In the first step, boron and hydrogen undergo syn addition to the alkene in the second step, treatment with hydrogen peroxide and base replaces the boron with — OH with retention of configuration. The net addition of —H and —OH occurs with autl-Markovnikov regioselectivity and syn stereoselectivity. Hydroboration-oxidation, therefore, serves as a useful regiochemical complement to oxymercuration-demercuration. 

---