Cyclization Thorpe-Ingold effect

Several neutral titanium complexes have been shown to catalyse intramolecular hydroamination reactions of alkenes. The corresponding pyrrolidine and piperidine products were formed in up to 97% yields. However, only the geminally disubstituted aminoalkenes were successfully cyclized (Thorpe-Ingold effect).56... 

Shorter chain dienes have an increased propensity to form stable five-, six-, and seven-membered rings. This thermodynamically controlled phenomenon is known as the Thorpe-Ingold effect.15 Since ADMET polymerization is performed over extended time periods under equilibrium conditions, it is ultimately thermodynamics rather than kinetics that determine the choice between a selected diene monomer undergoing either polycondensation or cyclization. 

The preparation of cyclobutanes via the catalytic conditions can be extremely efficient provided that the radical formed after epoxide opening is sterically shielded and cyclization promoted by the Thorpe-Ingold effect. It... 

Brummond and Shibata independently reported the Rh(i)-catalyzed cycloisomerization of allenynes to cross-conjugated trienes. The rhodium conditions were shown to have broad functional group tolerance. Brummond et al 9 observed rate and selectivity enhancements when they switched to an iridium catalyst (Equation (77)). The rate acceleration observed in the Alder-ene cyclization of aminoester containing allenyne 121 (Equation (78)) was attributed to the Thorpe-Ingold effect.80... 

List and coworkers reasoned that BINOL phosphates (specific Brpnsted acid catalysis) could be suitable catalysts for an asymmetric direct Pictet-Spengler reaction [26], Preliminary experiments revealed that unsubstituted tryptamines do not undergo the desired cyclization. Introduction of two geminal ester groups rendered the substrates more reactive which might be explained by electronic reasons and a Thorpe-Ingold effect. Tryptamines 39 reacted with aldehydes 40 in the presence of phosphoric acid (5)-3o (20 moI%, R = bearing 2,4,6-triisopropyI-... 

In 2008, the Ackennann group reported on the use of phosphoric acid 3r (10 mol%, R = SiPhj) as a Brpnsted acid catalyst in the unprecedented intramolecular hydroaminations of unfunctionaUzed alkenes alike 144 (Scheme 58) [82], BINOL-derived phosphoric acids with bulky substituents at the 3,3 -positions showed improved catalytic activity compared to less sterically hindered representatives. Remarkably, this is the first example of the activation of simple alkenes by a Brpnsted acid. However, the reaction is limited to geminally disubstituted precursors 144. Their cyclization might be favored due to a Thorpe-Ingold effect. An asymmetric version was attempted by means of chiral BINOL phosphate (R)-3( (20 mol%, R = 3,5-(CF3)2-CgH3), albeit with low enantioselectivity (17% ee). 

Radical A-exo cyclizations can also be catalyzed without recourse to the Thorpe-Ingold effect by applying the concept of template catalysis (Fig. 24) [157]. Here, 20 mol% of a cationic titanocene(IV) precatalyst 82 is applied, which contains a coordinating neutral tether. After reductive opening of epoxide 81, a cationic titanocene(III) complexed radical 83 is formed, in which both the epoxide and the xfi-un saturated carboxamide radical acceptor are coordinated. This provides the template to accelerate the slow A-exo radical cyclization step considerably. Cyclobutanes 84 were isolated in 46-84% yield with mostly good / / [Pg.145]

As the box says, it s not only rate that can be affected by additional substitution. Here are the relative equilibrium constants for the formation of an anhydride from a 1,4-dicarboxylic acid (the unsubstituted acid is called succinic acid, and the values are scaled so that Jvre for the formation of succinic anhydride is 1), More substituents mean more cyclized product at equilibrium. The Thorpe-Ingold effect is both a kinetic and a thermodynamic phenomenon. 

The use of optimized substrates and procedures allows for relatively high yields of bicyclic products to be obtained from such cycloisomerizations. For example, the enone derivative 20, which on cyclization benefits from the Thorpe — Ingold effect arising from the geminal... 

The Pictet-Spengler reaction is important for the preparation of tetrahydro-(3-carbolines and tetrahydroquinolines. List and co-workers applied phosphoric acid catalysis to the Pictet-Spengler reaction starting from geminally disubstituted tryptamines (Equation 10.41) [85, 86], The presence of the bis(ethoxycarbonyl) group facilitated the cyclization reactions by virtue of the Thorpe-Ingold effect. Both aliphatic and aromatic aldehydes turned out to be good substrates. 

Why the cyclic acetal It makes the cyclization more efficient by the Thorpe-Ingold effect (see Chapter 31). 

Bromochloromethane was used to introduce a chloromethyl group via a selective reaction at the C-Br bond (Fig. 47).260 The reaction stops at the chlorohydrin stage when nm with aldehydic substrates. From ketones, cyclization to the epoxide occurs spontaneously, possibly because of the so-called Thorpe-Ingold effect.261 This reaction confirms that the reactive species is not a chloromethyl anion, highly unstable at the reaction temperature. 

Sammes has reported a steric acceleration of the Alder-Ene reaetion similar to a Thorpe-Ingold effect which brings the two reacting components into close proximity thus, promoting the reaction. For the conversion of 135 into 136, while the A -trityl compound undergoes reaction in 95% yield to provide 136, the N-H compound shows no sign of cyclization product 136 under the same conditions. 

Forbes MDE, Patton JT, Myers TL, et al. Solvent-free cyclization of linear dienes using olefin metathesis and the Thorpe-Ingold effect. J Am Chem Soc. 1992 114(27) 10978-10980. 

The lactone ring is essential for PAR-1 activity. The lactone ring does not remain opened as the carboxylic acid-alcohol because it spontaneously cyclizes, presumably due to the Thorpe-Ingold effect exerted by the methyl group. Reduced versions of the lactone, such the fused tetrahydrofuran and diol (not shown) are far less active. The C3 methyl group is optimal, whereas the C3... 

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