Amides Anti-Markovnikov addition

With terminal olefins the principal product corresponds to anti-Markovnikov addition. With nonterminal olefins, mixtures of the two possible amides result ... 

Scheme 10.16 Enamides from anti-Markovnikov addition of amides to alkynes.

An Ru-catalysed anti-Markovnikov addition of secondary amides, anilides, lactams, ureas, bislactams, and carbamates to terminal alkynes has been investigated. Two ( ) complementary protocols have been developed that provide stereoselective entries to either the E- or the Z-isomers of the resulting enamides.106... 

In the case of terminal olefins it was found that the major product of the reaction was the 1 1 adduct resulting from an anti-Markovnikov addition of formamide to the double bond. Products resulting from Mar-kovnikov-addition of formamide to olefins were also obtained, but in poor yields. In addition, smaller yields of higher telomers were also formed. In the case of nonterminal olefins mixtures of the two possible amides (1 1 adducts) were obtained. These amides resulted from addition... 

Hydroamination. Amides, lactams, carbamates and ureas add to 1-alkynes to give enamide derivatives. The stereoselectivity of this anti-Markovnikov addition is sensitive to phosphine ligands that are present. ... 

The transition metal catalyzed addition of amides to alkynes provides a useful approach to the preparation of enamides. In this context, Gooden and coworkers have developed efficient ruthenium catalysts, which allow the anti-Markovnikov addition of amide to terminal alkynes (Scheme 4.46) [187]. 

Now let s draw the forward scheme. The 3° alcohol is converted to 2-methylpropene using strong acid. Anti-Markovnikov addition of HBr (with peroxides) produces l-bromo-2-methylpropane. Subsequent reaction with sodium acetylide (produced from the 1° alcohol by dehydration, bromination and double elimation/deprotonation as shown) produces 4-methyl-1-pentyne. Deprotonation with sodium amide followed by reaction with 1-bromopentane (made from the 2° alcohol by tosylation, elimination and anfi -Markovnikov addition) yields 2-methyl-4-decyne. Reduction using sodium in liquid ammonia produces the E alkene. Ozonolysis followed by treatment with dimethylsulfide produces an equimolar ratio of the two products, 3-methylbutanal and hexanal. 

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 composition of the reaction products (1 1 adducts) needs further clarification. In the case of terminal olefins the anti-Markovnikov 1 1 addition product is almost the only 1 1 adduct, whereas the isomeric amide is formed in minute amounts only. Markovnikov-additions of free radicals to olefins have been observed in other cases too as side products (28). The point of initial attack in the free radical addition to an olefin of the type RCH=CH2 is at the terminal carbon. The intermediate radical (I) produced by this process (anti-Markovnikov) has a higher degree of resonance stabilization than the alternative radical (II) (4, 78). This means that in the present reaction,... 

Intermolecnlar Additions. The radical chain nature and the anti-Markovnikov regiochemistry of radical addition reactions were originally discovered by Kharasch in the 1930s. Since then, these reactions have been used extensively for the formation of carbon-carbon and carbon-heteroatom bonds. Substrates that are suitable for the former include polyhalomethanes, alcohols, ethers, esters, amides, and amines. The prototypical examples compiled in Table 1 are from reviews by Walling and Ghosez et al. ... 

Metal-catalyzed oxidative addition of nitrogen nucleophiles such as amines and amides to olefins represents a straightforward atom economical approach for the preparation of enamines and enamides, respectively. These aminatimi processes may proceed with Markovnikov or anti-Markovnikov regioselectivity and in the latter case such products can be obtained as either or Z isomers (Scheme 1). Therefore, the ability of the catalyst to control that regiochemistry and stereoselectivity constitutes a chaUenging issue for synthetic chemists. 

In 1992 Murahashi, Hosokawa, and co-workers described the anti-Markovnikov oxidative addition of amides and carbamates to electron-deficient olefins by applying a palladium and copper cooperative catalysis under oxygen atmosphere [41]. The proposed mechanism involved a ff-bonded palladium(II) intermediate resulting from the addition of the nucleophile to the olefin, and subsequent ) -palladium hydride elimination to yield the functionalized alkene. Interestingly, both lactams and cyclic carbamates gave predominantly the corresponding E-enamide derivatives. Acyclic amides, conversely, afforded ElZ mixtures of products. The addition of a catalytic amount (5 mol%) of hexamethylphosphoric triamide (HMPA) was found notably beneficial for the reaction of 5-membered lactams and reduced the reaction time of such particular oxidative amidations (Scheme 2). 

A-Alkylation of amides and amines and dehydrative -alkylation of secondary alcohols and a-alkylation of methyl ketones " have been carried out by an activation of alcohols by aerobic oxidation to aldehydes, with copper(II) acetate as the only catalyst. A relay race process rather than the conventional borrowing hydrogen-type mechanisms has been proposed for the aerobic C-alkylation reactions, based on results of mechanistic studies. A Winterfeldt oxidation of substituted 1,2,3,4-tetrahydro-y-carboline derivatives provides a convenient and efiflcient method for the synthesis of the corresponding dihydropyrrolo[3,2-fc]quinolone derivatives in moderate to excellent yields. The generality and substrate scope of this aerobic oxidation have been explored and a possible reaction mechanism has been proposed. Direct oxidative synthesis of amides from acetylenes and secondary amines by using oxygen as an oxidant has been developed in which l,8-diazabicyclo[5.4.0]undec-7-ene was used as the key additive and copper(I) bromide as the catalyst. It has been postulated that initially formed copper(I) acetylide plays an important role in the oxidative process. Furthermore, it has been postulated that an ct-aminovinylcopper(I) complex, the anti-Markovnikov hydroamination product of copper acetylide, is involved in the reported reaction system. Copper(I) bromide... 

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