A formal, metal-free, [2 + 2 + 2] cycloaddition strategy is described based on a cascade of two pericyclic processes. The first step involves an intramolecular propargylic ene reaction of a 1,6-diyne to generate a vinylallene, which then reacts in an inter-or intramolecular Diels-Alder reaction with an alkenyl or alkynyl dienophile. Reactions involving unsymmetrical alkenyl and alkynyl dienophiles proceed with good to excellent regioselectivity, and the diastereoselectivity in the Diels-Alder step is also high, with endo cycloadducts produced as the exclusive products of the reaction. In the case of alkynyl dienophiles, [4 + 2] cycloaddition initially generates an isotoluene-type intermediate that isomerizes to the isolated aromatic product upon exposure to a catalytic amount of DBU at room temperature. The mechanism of several earlier fully intramolecular related transformations have been shown to involve an analogous process rather than the diradical-mediated pathways proposed previously.

Two metal-free, formal [2 + 2 + 2] cycloaddition strategies for the construction of polycyclic pyridine derivatives are described that proceed via pericyclic cascade mechanisms featuring the participation of unactivated cyano groups as enophile and dienophile cycloaddition partners.The nitrile functional group rarely participates as an enophile or dienophile in Alder ene and Diels-Alder cycloadditions.i , ii Herein we describe two formal [2 + 2 + 2] strategies for the synthesis of substituted pyridines that proceed via pericyclic cascade processes involving the unusual reaction of unactivated nitriles as 2-π cycloaddition components. As outlined in Scheme 1, the first strategy begins with a propargylic ene reactioniii which is followed by an intramolecular Diels-Alder reaction in which an unactivated cyano group functions as the dienophile. When the initial propargylic ene step is blocked (e.g., by substitution at the appropriate propargylic carbon), then a second cascade sequence is operative which leads to the same pyridine products. This alternate pathway begins with an intramolecular propargylic ene reaction in which an unactivated cyano group serves as the enophilic π-bond. To our knowledge, the participation of an unactivated cyano group in a thermal ene reaction is unprecedented.iv , v The resulting allenylimine then functions as a 1-azadiene in an intramolecular hetero Diels-Alder reaction vi leading (after tautomerization) to the isolated pyridine product. Overall, these transformations provide strategies for achieving metal-free, formal [2 + 2 + 2] cycloadditionsvii that complement the well established transition-metal-catalyzed methodologyviii for the synthesis of this important heterocyclic ring system.ix Tables 1 and 2 present examples of transformations leading to pyridines that proceed via the first pathway outlined in Scheme 1. x In this pathway the first step involves a propargylic ene reaction in which the alkyne rather than cyano group functions as the enophile component. The observations summarized below suggest that this pathway is dominant even when both pathways are possible.In the case of substrate 2, substitution of two methyl groups at one propargylic carbon precludes cyano ene reaction as the first step in the cascade so that it is pathway A that must be operative. Comparison of the relative rates of reactions of substrates lacking gemdimethyl substitution suggest that these transformations also proceed via the propargylic ene/cyano Diels-Alder mechanism. For example, activation of the terminal alkyne with an danheisr@mit.edu . Supporting Information Available: Experimental procedures, characterization data, and 1 H and 13 C NMR spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. alkynyl substituent leads to a significant increase in the rate of disappearance of starting material (entries 1 and 4). This observation is consistent with an initial propargylic ene step, and would not be expected if the first step in the ...

The external chiral ligand-controlled asymmetric conjugate addition reaction of lithium amides with alpha,beta-unsaturated esters provided beta-amino esters in high yields and high enantioselectivities.

Tetracyanothiophene and tetracyano-1,4-dithiin react with a leaving group substituted carbon nucleophile such as ethyl benzenesulfonylacetate to afford substituted tetracyanocyclopentadienyl sodium derivatives in moderate to high yields through a putative condensation and desulfurization pathway. Subsequent functional-group transformation reactions on the Cp anion ring provided various C5R(CN)4(-) derivatives.

One-pot processes, the sequential conjugation of multiple bond-forming reactions, are powerful tools in organic synthesis. [1] Conjugate addition [2] of lithium amide 2 to enoate 3 forms an N À C bond and generates lithium enolate 5, which is further applicable as a carbonucleophile reacting in an S N 2 manner with alkyl halide. When the halide has two reaction sites like dihalide 6, the initially introduced nitrogen atom in 7 should undergo an intramolecular S N 2 reaction to form piperidine 8 (Scheme 1). This one-pot [N+2+3] cyclization, however, has not been realized, despite several reports on sequential C-alkylation following conjugate addition of lithium amide. [3,4] We describe herein the total synthesis of (À)-kopsinine (1) [5] using the asymmetric one-pot [N+2+3] cyclization based on our asymmetric conjugate aminolithiation [6] of a lithium amide with an enoate.An asymmetric conjugate addition of lithium N-benzyltrimethylsilylamide (2) was performed with tert-butyl N-Boc-indole-3-propenoate (3) using chiral diether 4 in toluene at À78 8C for 0.25 h to afford, after quenching with saturated aqueous ammonium chloride, 3-aminoester 9 with 97 % ee in 89 % yield (Table 1, entry 1). Extension of the reaction time to 3 h did not affect the results, giving 9 with comparable enantiomeric excess and yield (Table 1, entry 2). The same reaction in the presence of internal chlorotrimethylsilane [6a] (TMSCl) gave 9 with 97 % ee in 93 % yield after 1 h (Table 1, entry 3). These data indicated the completion of the conjugate aminolithiation at À78 8C within 0.25 h.Then, alkylation of enolate 5 as the second step was examined. After the aminolithiation at À78 8C for 1.5 h and then at À40 8C for 2 h, alkylation was performed at À40 8C for 4 h by the addition of 3-tert-butyldimethylsilyloxypropyl iodide (6 a; X= I, Y = OTBS) in dimethylformamide [7] (DMF; 233 equiv) to give, after treatment with TBAF to remove the TBS group, 10 with 95 % ee as a sole diastereomer in 60 % yield and enoate 11 in 18 % yield ( Table 2, entry 1). N,N'-Dimethylpropyleneurea (DMPU; 133 equiv) was a better co-solvent, giving 10 with 95 % ee in 73 % yield and 11 in 13 % yield (Table 2, entry 2). Surprisingly, 11 was [a] Dr. Scheme 1. One-pot [N+2+3] cyclization strategy. Bn = benzyl, TMS = trimethylsilyl, Boc = tert-butoxycarbonyl, Ind = indolyl, TBAF = tetrabutylammonium fluoride. X,Y = halide. Table 1. Asymmetric conjugate aminolithiation followed by protonation. Entry T [8C] t [h] Quench Yield 9 [%] ee 9 [%] Yield 3 [%] Yield 12 [%] 1 À78 0.25 aq NH