Cycloaddition of terminal alkynes

Torn0e, C.W., Christensen, C., and Meldal, M. (2002) Peptidotriazoles on solid phase [l,2,3]-triazoles by regiospecific copper) I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J. Org. Chem. 67, 3057-3064. 

Disubstituted 1,2,3-triazoles are exclusive products of copper catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. A variety of substituents can be introduced in this way. Many examples of such reactions are discussed in Section 5.01.9. 

The [3+2] cycloaddition of terminal alkynes has been investigated with several dipoles. These dipolarophiles are competent in the cycloaddition, however, the corresponding isoxazolines cannot be isolated. Instead, the cycloadduct undergoes spontaneous rearrangement to provide acylaziridine products (Table 2.52) (229). Disubstituted alkynes also undergo this process, however, in lower yield. This rearrangement occurs with all nitronates studied (Chart 2.3) (66,230,231). 

The discovery of copper catalysis in 1,3-dipolar cycloadditions of terminal alkynes to azides (click chemistry) in 2002 <2002AGE2596, 2002JOC3057> has revolutionized the field . It is not only that the catalyzed reactions proceed faster under mild conditions, but full regioselectivity of the products is also achieved. Terminal alkynes generate only 1,4-disubstituted triazoles. A brief outline of the reaction mechanism is given in Scheme 253 . Some aspects of this new methodology are discussed in a review <2007ALD7>. 

I, 3-dipolar cycloadditions of terminal alkynes to azides, J. Org. Chem. 2002, 67, 3057-3062. 

Scheme 22 Cu-catalyzed cycloaddition of terminal alkynes and sulfonyl azides [79]...

As 1,4-disubstituted 1,2,3-triazoles are usually prepared through copper-catalyzed 1,3-dipolar cycloadditions of terminal alkynes with organic azides, the use of a single copper complex for a direct arylation-based sequential catalysis was probed. Thereby, a modular chemo- and regioselective synthesis of fully-substituted 1,2,3-triazoles was achieved (Scheme 9.43). Notably, the overall reaction involved the selective coupUng of four components through the formation of one C—C- and three C—N-bonds [58]. 

Ru3(CO)i2 coordinated with 2-(diphenylphosphino)benzonitrile catalysed the regioselective 2 + 2 + 2-cyclotrimerization of trifluoromethyl-substituted aryl alkynes in high yields and with a high regio-selectivity4 The alkyne 2 + 2 + 2-cyclotrimerization reaction has been applied to the synthesis of the central 4,5,6-tricyclic core (94) of 4,5,6-trinems (Scheme 30)4 The NbC /DMI-catalysed intermolecular 2 + 2 + 2-cycloadditions of terminal alkynes, internal alkynes, and alkenes produced 1,3,4,5-tetrasubstituted 1,3-cyclohexadienes in excellent yields and with high chemo- and regio-selectivities. ... 

Gao M, He C, Chen H, Bai R, Cheng B, Lei A (2013) Synthesis of pyrroles by click reaction silver-catalyzed cycloaddition of terminal alkynes with isocyanides. Angew Chem Int Ed 52 6958-6961... 

In the intermolecular [2+2+2] cycloaddition of unsymmetiic monoynes, it is difficult to control its regioselectivity. Cationic rhodium(l)/biaryl bisphosphine complexes are highly active and selective catalysts for the 1,2,4-selective [2+2+2] cycloaddition of terminal alkynes (Scheme 21.3) [7]. However, unfortunately, a general and practical catalyst that enables the 1,3,5-selective [2+2+2] cycloaddition of terminal alkynes has not been developed. 

The formal 2 -I- 2-cycloaddition reaction of platinum(ll) acetilides (14) with TCNE and TCNQ initially produced 7,7,8,8-tetracyano-p-quinodimethane cyclobuta-1, 3-dienes that undergo retroelectrocyclization to produce feis-cycloadducts (15, 16). In all examples investigated, the triple bond adjacent to the platinum atom did not react with the TCNE or the TCNQ (Scheme 5). The 2-I-2-cycloaddition of substituted cyclobutadiene-AlCl3 complexes (18) with methyl phenylpropynoate (17) produced Dewar benzene intermediates (19) that readily converted to 1,2,3,4-tetramethyl- and 1,2,3,4-tetraethyl-fluorenes (20) (Scheme 6). The first rhodium-catalysed inter-molecular 2-1-2-cycloaddition of terminal alkynes with e-deflcient alkenes yielded substituted cyclobutenes in high yields (99%) and complete regioselectivity. An 8-quinolinolatorhodium/phosphine catalyst (21) was employed in this reaction. ... 

Maruoka and co-workers reported the first catalytic asymmetric three-component 1,3-dipolar cycloaddition of terminal alkynes with acyclic azomethine imines generated in situ from the corresponding aldehydes and hydrazides, which was realized using CuOAc/Ph-pybox and axially chiral dicarboxylic acid cocatalysts (Scheme 27) [48]. This transformation has abroad tolerance with regard to the substrates, affording diverse chiral 3,4-disubstituted pyrazolines with high enantioselectivities. The role of the axially chiral dicarboxylic acid is to generate the protonated acyclic azomethine imine, which then reacts with chiral Cu-acetylide. 

Rovis and coworkers reported the first enantioselective rhodium-catalyzed [4-I-2-I-2] cycloaddition of terminal alkynes 131 with ( i-dienyl isocyanates 132 to construct the bicyclo[6.3.0]azocines [48]. Heating a toluene solution (110 °C) of 131 and 132 in the presence of a catalytic amount of [Rh(C2H4)2Cl]2 and chiral phosphoramidite afforded the [4-I-2-I-2] cycloadducts 133 in good yields with excellent enantiomeric excesses [49], Initial oxidative cyclization between the diene and the isocyanate moiety of 132 afforded rhodacycle 134. Coordination and insertion of alkyne 131 to 134 followed by reductive elimination of the resulting rhodacycle 135 provided the [4-I-2-I-2] adduct 133 (Scheme 4.27). 

BigeaulL J., Giordano, L., Buono, G. (2005). [2-1-1] cycloadditions of terminal alkynes to norbomene derivatives catalyzed by palladium complexes with phosphinous acid hgands. Angewandte Chemie, International Edition, 44, 4753-4757. 

In the meantime, MeldaL " and Fokin-Sharpless" discovered independently that 1,3-dipolar cycloadditions of terminal alkynes to azides could be very efficient and regioselec-tive when catalyzed by copper(I) salts. This 1,4-disubstituted triazole synthesis became very popular, as the ideal member of the family of click reactionsIts mild reaction conditions, its remarkable efficiency and its wide scope due to a high tolerance of other sensitive functional groups prompted a few research teams, " including ours (see Section... 

Selective intermolecular [2 - - 2 - - 2] cycloaddition of terminal alkynes is more difficult to achieve than internal alkynes, due to their various reactivities toward transition-metal complexes in addition to the regioselectivity problem. Indeed, a neutral rhodium(I)/phosphine complex such as RhCl(PPh3)3 generally reacts with terminal alkynes to give not cyclotrimers but linear dimers [20]. The neutral rhodium(I) and rhodium(III) complexes could be applied to intermolecular [2 - - 2 - - 2] cycloaddition of terminal alkynes (Scheme 4.5) [13,15a and b]. 

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