Three-component formal cycloaddition

Gong, et al. reported a phosphoric acid derivative 258 catalyzed asymmetric three-component formal [4 + 2] cycloaddition reaction of azlactones 257, a,p-unsaturated aldehydes 28, and primary amines 256 to give the 3-amino-3, 4-dihydropyridinones 259 with high enantioselectivities (up to 96% ee), Scheme 3.82 [104],... 

The Lewis acid-catalyzed three-component reaction of dihydropyridines, aldehydes, and />-substituted anilines efficiently yields highly substituted tetrahydroquinolines in a stereoselective manner, through a mechanism believed to be imine formation followed by formal [4-1-2] cycloaddition (Scheme 41). The 1,4-dihydropyridine starting materials were also prepared in situ by the nucleophilic addition of cyanide to pyridinium salts, creating in effect a one-pot four-component reaction <20030L717>. 

Furthermore, a four-component cycloaddition reaction (7]6-thiepine I,l-dioxide)tricarbonylchromium(0) 52 with tethered diynes under photoactivation afforded pentacyclic adducts formally derived from a sequential [671+271]/ [67l+27t]/[2(T+27i] cycloaddition process <1999OL507>. Photocycloaddition of the complex 52 with excess 1,7-octadiyne 66a or 1,8-nonadiyne 66b (C1CH2CH2C1, hv (Pyrex filter)) afforded the pentacyclic triene sulfones 67a and 67b in 45% and 38% yields, respectively (Equation 4). In contrast, 1,6-heptadiyne 66c afforded only the three-component cycloadduct 68 in 56% yield (Equation 5). 

Mechanistically, the term cycloaddition applies in only a formal sense to most of the reactions in the section virtually none of these reactions involves true single-step cycloaddition of all three components that appear in the final product. More typically, cycloaddition involving a transition metal fragment and one or two other components leads to a metallacyclic intermediate whose reaction with the remaining... 

Three-component tandem cyHzations involving [2 -1- 4] and [2 -1- 3] additions can be performed vdth vinyl nitroalkanes bound to the polymer. In some cases, however, high pressure is necessary to perform the conversions [338, 339], Based on the design of the building blocks, reduction of the N-0 bonds formed in cycloaddition may lead to formal O-contraction, resulting in compact polycyclic amines of defined relative configurations [340]. 

The formation of an iminium salt via Michael addition between an azine and an electron-poor olefin was nicely exploited by Mironov et al. for the development of a three-component synthesis of benzo-fused heterocydes (95) (Scheme 5.28) [53], In this case, the intermediate 96 underwent a formal [4+1] cycloaddition with isocyanide that led to the observed heterocycle 95. 

SCHEME 2.24 Three-component synthesis of 3-amino-6-lactams via a formal [4+2] cycloaddition reaction. 

A catalyst-free protocol has been described by Adib for the synthesis in good to excellent yields of 3-aminoimidazo[l,2-o]pyridines and 5-aminoimidazo[2,l-6] [l,3]thiazoles via three-component reactions between 2-aminopyridines or 2-ami-nothiazoles, aldehydes and isocyanides in water (Scheme 1.10) [14]. Presumably, this process involves the initial formation of an imine, which then reacts with the isonitrile in a formal [4+2] cycloaddition. 

Another interesting [3+2] cycloaddition in aqueous media was recently reported by Murakami.131 2-Cyanophenylboronic acid reacted as a three-carbon component with alkynes or alkenes to afford substituted indenones or indanones (Eq. 4.67). The use of an alkynoate even produced benzotropone, a formal [3 + 2 + 2] adduct. 

The first metal-catalyzed [4 +2]-reaction of tethered dienes with 7r-systems was reported by Wender and Jenkins using alkynes initially as the two-carbon component.21 This study was based on the earlier observation by Wender and Ihle that in the [4 + 4]-cycloaddition of bis-dienes a competing side-reaction is the [4 + 2]-cycloaddition of the diene with a mono-ene portion of a second diene. The extension of this reaction to the synthesis of seven-membered rings by trapping the metallacycloheptadiene with CO, a formal [4 + 2 + l]-cycloaddition, has been shown in preliminary studies to be feasible. For example, tethered diene-yne 160 can be converted to cycloheptadienone 163 in an Rh(l)-catalyzed [4 + 2 + l]-reaction with CO, albeit the [4 + 2]- and [2 + 2 + l]-reaction products dominate (Equation (29)). The mechanistic scheme (Scheme 44) illustrates the possible metallacyclic intermediates leading to the observed products and provided the conceptual basis for the realization of three novel reaction types ([4 + 2], [2 + 2 + 1], and [4 + 2 + 1 ]).1... 

The three-atom component of the cycloaddition, the 1,3-dipole, is a compound for which a relatively stable resonance structure can be drawn in which one terminus has a formal positive charge (and is electron-deficient) and the other terminus has a formal negative charge. All of the common 1,3-dipoles have a heteroatom (N or O) in the central position in order to stabilize the electron-deficient terminus. 

---