In the last years a powerful set of protocols involving C(sp
2 )–N bond formation
have emerged as reliable and convenient alternatives for the assembly of enamine
and enamides. The latter methods consist of mostly palladium-catalyzed oxidative
amidations of alkenes [38] and both palladium-[39] and copper-catalyzed crosscouplings [40] between generally vinyl halides or pseudohalides and amines or
amides. In this review, recent advances in both types of processes will be disclosed
illustrating, likewise, their synthetic value by describing total syntheses of natural
products of high structural complexity.
2 Oxidative Amination/Amidation of Alkenes
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 amination processes
may proceed with Markovnikov or anti-Markovnikov regioselectivity and in the
latter case such products can be obtained as either E or Z isomers (Scheme 1).
Therefore, the ability of the catalyst to control that regiochemistry and stereoselectivity constitutes a challenging 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 s-bonded palladium(II) intermediate resulting
from the addition of the nucleophile to the olefin, and subsequent b-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 E/Z 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 highly stereoselective synthesis of Z-enamides was further developed by
Chang, Kim, and co-workers via palladium/copper co-catalyzed anti-Markovnikov
amidation of conjugated olefins [42]. The authors attributed the preferential formation of Z- vs E-enamides to the favorable b-palladium hydride elimination from the
indicated s-bonded palladium(II) intermediate which places an intramolecular
hydrogen-bond between the amido proton and the carbonyl oxygen (Scheme 3).
This oxidative amidation performed under Wacker-type conditions had a broad
substrate scope and proved efficient for the reactions of different kind of amides
(including aliphatic, aromatic, and vinyl substrates) with terminal olefins conjugated with keto, ester, amide, and phosphonate moieties. However, simple aliphatic
olefins, styrene derivatives, and internal alkenes as well as carbamates proved
unsuitable substrates under this oxidative amidation protocol. Importantly, the use
of tetraethyl methylenediphosphonate (TEMDP) as additive not only resulted in a
clear improvement of the yields but also inhibited the formation of undesired side
products (cyclized enamides).
Metal-Catalyzed C(sp
2
)–N Bond Formation
57
2 )–N bond formation
have emerged as reliable and convenient alternatives for the assembly of enamine
and enamides. The latter methods consist of mostly palladium-catalyzed oxidative
amidations of alkenes [38] and both palladium-[39] and copper-catalyzed crosscouplings [40] between generally vinyl halides or pseudohalides and amines or
amides. In this review, recent advances in both types of processes will be disclosed
illustrating, likewise, their synthetic value by describing total syntheses of natural
products of high structural complexity.
2 Oxidative Amination/Amidation of Alkenes
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 amination processes
may proceed with Markovnikov or anti-Markovnikov regioselectivity and in the
latter case such products can be obtained as either E or Z isomers (Scheme 1).
Therefore, the ability of the catalyst to control that regiochemistry and stereoselectivity constitutes a challenging 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 s-bonded palladium(II) intermediate resulting
from the addition of the nucleophile to the olefin, and subsequent b-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 E/Z 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 highly stereoselective synthesis of Z-enamides was further developed by
Chang, Kim, and co-workers via palladium/copper co-catalyzed anti-Markovnikov
amidation of conjugated olefins [42]. The authors attributed the preferential formation of Z- vs E-enamides to the favorable b-palladium hydride elimination from the
indicated s-bonded palladium(II) intermediate which places an intramolecular
hydrogen-bond between the amido proton and the carbonyl oxygen (Scheme 3).
This oxidative amidation performed under Wacker-type conditions had a broad
substrate scope and proved efficient for the reactions of different kind of amides
(including aliphatic, aromatic, and vinyl substrates) with terminal olefins conjugated with keto, ester, amide, and phosphonate moieties. However, simple aliphatic
olefins, styrene derivatives, and internal alkenes as well as carbamates proved
unsuitable substrates under this oxidative amidation protocol. Importantly, the use
of tetraethyl methylenediphosphonate (TEMDP) as additive not only resulted in a
clear improvement of the yields but also inhibited the formation of undesired side
products (cyclized enamides).
Metal-Catalyzed C(sp
2
)–N Bond Formation
57