Imine Diels–Alder reaction

The imine Diels–Alder reaction involves the transformation of all-carbon dienes and imine dienophiles into tetrahydropyridines.^[1]

Mechanism

The imino Diels-Alder (IDA) reaction may occur either by a concerted or stepwise process. The lowest-energy transition state for the concerted process places the imine lone pair (or coordinated Lewis acid) in an exo position. Thus, (E) imines, in which the lone pair and larger imine carbon substituent are cis, tend to give exo products.^[2]

(2)

When the imine nitrogen is protonated or coordinated to a strong Lewis acid, the mechanism shifts to a stepwise, Mannich-Michael pathway.^[3]

(3)

Stereoselective variants

In many cases, cyclic dienes give higher diastereoselectivities than acyclic dienes. Use of amino-acid-based chiral auxiliaries, for instance, leads to good diastereoselectivities in reactions of cyclopentadiene, but not in reactions of acyclic dienes.^[4]

(6)

Chiral auxiliaries have been employed on either the imino nitrogen^[5] or imino carbon^[6] to effect diastereoselection.

(5)

Scope and limitations

Attaching an electron-withdrawing group to the imine nitrogen increases the reactivity of the imine. The exo isomer usually predominates (particularly when cyclic dienes are used), although selectivities vary.^[7]

(7)

Tosylimines may be generated in situ from tosylisocyanate and aldehydes. Cycloadditions of these intermediates with dienes give single constitutional isomers, but proceed with moderate stereoselectivity.^[8]

(8)

Lewis-acid catalyzed reactions of sulfonyl imines also exhibit moderate stereoselectivity.^[9]

(9)

Simple unactivated imines react with hydrocarbon dienes only with the help of a Lewis acid; however, both electron-rich and electron-poor dienes react with unactivated imines when heated. Vinylketenes, for instance, afford dihydropyridones upon [4+2] cycloaddition with imines. Regio- and stereoselectivity are unusually high in reactions of this class of dienes.^[10]

(10)

Vinylallenes react similarly in the presence of a Lewis acid, often with high diastereoselectivity.^[11]

(11)

The IDA reaction has been applied to the synthesis of a number of alkaloid natural products. Danishefsky's diene is used to form a six-membered ring en route to phyllanthine.^[12]

(12)

Actyliminium substrates

Acyliminium ions also participate in cycloadditions. These cations are generated by removal of chloride from chloromethylated amides:^[13]

RCONRCH₂Cl → RCONR/dCH+2 + Cl⁻

The resulting acyl iminium cations serve as hetero

See also

• Oxo Diels–Alder reaction
• Aza-Diels–Alder reaction

References