Tandem cycloaddition

Warrener RN, Abbenante G, Kennard CHL (1994) A tandem cycloaddition protocol for the controlled synthesis of [n]ladderanes new rods and spacers. J Am Chem Soc 116 3645-3646... 

The strategy based on tandem cycloaddition leads to a short and efficient asymmetric synthesis of the pyrrolizidine necine base (-)-hastanecine, as shown in Scheme 8.32.163 Pyrrolizidine alkaloids have a long history for attracting the interest of synthetic chemists because of their physiological properties. The method of Denmark shown in this scheme is very simple and applied to synthesis of various alkaloids. The Lewis acid-promoted [4+2] cycloaddition between 2-acyloxy nitroalkene and chiral vinyl ether gives a nitronate that... 

Asymmetric tandem cycloaddition of a chiral carbohydrate nitroalkene with ethyl vinyl ether in the presence of electron-withdrawing alkenes produces a facile assembly of bicyclic systems, which can further be selectively cleaved to give homologated carbohydrates (Eq. 8.110).176... 

Inter [4 +2]/intra [3+2] This type of tandem reaction using nitroalkenes has been explored most extensively. Four subfamilies of tandem cycloaddition exist, which arise from the four different points of attachment of the dipolarophilic tether. They are defined as fused, spiro, and bridged modes, as depicted in Scheme 8.37.149... 

The extremely high selectivity for tandem cycloaddition, the ease of manipulation of the nitroso acetals, and the release of the vinyl ether appendage in the hydrogenolytic cleavage constitute ideal features for asymmetric modifications of the cycloadditions with chiral vinyl ethers. As discussed in Section 8.3.2.1 (Inter [4+2]/inter [3+2] cycloadditions of nitroalkenes), the stereochemical course depends on the Lewis acids. The results are summarized in Scheme 8.38.179 The high levels and complementary selectivity with three chiral vinyl ethers and two kinds of Lewis acids (Ti- and Al-based Lewis acids) are presented in this scheme. 

The synthesis of pyrrolizidine alkaloid (-)-rosmarinecine illustrates the power of the fused mode tandem cycloaddition, as shown in Scheme 8.40.180 The all-cA relationship at the three contiguous centers C(l), C(7), and C(7a) can be constructed in a single-pot reaction with correct stereochemistry but C(6) cannot. 

When a-tethered nitroalkenes bearing three or four methylene chains and ester-activated dipolarophiles react with vinyl ethers, spiro mode tandem cycloaddition takes place to give tricyclic spiro nitroso acetals in good yield and high diastereoselectivity (Scheme 8.46).184... 

Fused octahydrocycl[3.2.2]azines of the type 392 are obtained by tandem cycloadditions of pyridinium phenacylide with iV-substituted maleimides <1989JOC420>, and other types of fused octahydrocyclazines, viz. 394, result from the attempted preparation of the enamines 393, since these are unstable and undergo intramolecular acylation <1999T1763> (Scheme 114). 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

The asymmetric tandem cycloaddition of the chiral carbohydrate nitroalkene (35) with ethyl vinyl ether involves the initial formation of the nitronate (36) which reacts exclusively with electron-withdrawing alkenes by 3 -I- 2-cycloaddition to yield chiral bicycles (37) and (38) (Scheme 12). ... 

This pressure effect was also observed in the tandem cycloaddition nitroalkene. Combination of methyl acrylate with 2-nitrostyrene and ethyl vinyl ether proceeds at 15 kbar over 1 h to produce a mixmre of diastereomeric nitroso acetals (Eq. 2.24) (83,235,236). 

Figure 2.15. Subclasses of the later [4 + 2]/intra [3 + 2]-tandem cycloadditions.

In view of the multicomponent nature of the tandem [4 + 2] / [3 + 2] cycloaddition, the potential for a combinatorial approach to the synthesis of nitroso acetals has been investigated on solid-phase supports. The incorporation of either the dipolarophile or the starting nitroalkene on a Wang-type resin is compatible with the tandem cycloaddition promoted at high pressures (Schemes 2.28 and 2.29). The solid-supported nitroso acetals are subsequently liberated (in moderate yields from the staring nitroalkene) upon the addition of a catalytic amount of potassium cyanide in triethylamine and methanol or by reduction with lithium aluminum hydride (LAH) (261,264). 

Tricyclic fused tetrazoles were prepared in a microwave-assisted tandem cycloaddition between TMS - N3 and aromatic nitriles, followed by ring closure via an intramolecular N-allylation [96]. 

Scheme 40. Tandem cycloaddition/photobenzannulation approach to benzoindoles.

In a different strategy (Scheme 46), albeit specialized, the tandem cycloaddition-aldol synthesis of triazolo[l,5-a]pyridines (249) from the azidotriazoles (247) proceeds with the intermediacy of the... 

We used this method as the key sequence in the synthesis of ( )-lycopodine (78). The intramolecular isomiinchnone cycloadduct 81 was envisaged as the precursor of the key Stork intermediate 79 (via 80) [42]. The heart of our synthetic plan was the formation of the latter intermediate by a Pictet-Spengler cyclization of the N-acyliminium ion derived from 81. Central to this strategy was the expectation that the bicyclic iminium ion originating from 81 would exist in a chair-like conformation [42,43]. Cyclization of the aromatic ring onto the iminium ion center should take place readily from the axial position. The readily available heptenoic acid 82 would serve as the precursor for the a-dia-zoimide, the direct progenitor of the isomiinchnone dipole. This extension of the tandem cycloaddition-cationic 1-cyclization protocol to the formal synthesis of ( )-lycopodine (78) is outlined below. 

In previous works this group had observed a competition between the PKR and a [2 + 2 + 2] cyclization in the second reaction step of three triple bonds. Thus, when reacting linear triynes 174 under catalytic, high CO pressure, cobalt mediated PKR conditions, they obtained mixtures of products 175 coming from two [2 + 2 + 1] cycloadditions, and 176 from a [2 + 2 + 1]/ [2 + 2 + 2] tandem reaction. When the triple bonds were ether linked, the latter was the favored reaction, while with substrates lacking oxygen atoms, the iterative PKRs was the major pathway (Scheme 51) [166]. When the reaction was performed intramolecularly between a diyne and an alkyne, the only reaction products were the result of a [2 + 2 + 1 ]/[2 + 2 + 2] tandem cycloaddition [167,168]. 

Polycyclic Carbon Skeletons by Tandem Cycloaddition/Annulation Reactions... 

Non-classical criss-cross reaction A parallel tandem cycloaddition. Formation of imidazo[1,5-b] [l,2,4]triazoles... 

Classical" criss-cross reaction antiparallel tandem cycloaddition... 

Non-classical" criss-cross reaction parallel tandem cycloaddition Scheme 2 Criss-cross reactions. The Classical criss-cross reaction, an antiparallel tandem cycloaddition of azines 9 and heterocumulenes 10 (upper equation). The Non-classical" criss-cross reaction, a parallel tandem cycloaddition of azoalkenes 5 and thiocyanic acid 6 (lower equation). 

Similarly, amidyl radicals can be produced by visible light irradiation of unsaturated A -PTOC imidate esters which can be cyclized to prepare lactams127 138, e g., 4 and 5 (tandem cycloaddition)138. The configuration of the prevalent diastereomer of 5 was not determined, but a tram orientation of the substituents on the pyrrolidine ring would be expected. 

Heterocyclic spirans are prepared by [Ni(CO)4]-promoted tandem cycloaddition of diphenylcyclopio-panone (100) to isothiocyanates (101 equation 43) or to carbon disulfide (105 equation 44). When an equimolar mixture of (100), (101) and [Ni(CO)4] is allowed to react in DMF at 65-70 C, two heterocyclic spirans, pyrrolin-2-one-5-spiro-5 -thiolen-4 -one (102), and (103), are formed in addition to the pyrroline derivative (104). Similarly, carbon disulfide (105), reacts with (100) to give thiolen-2-one-5-spiro-5 -thiolen-4 -one (106) along with a small amount of 1 1 cycloadduct (107). ... 

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