Enamines transition state effects

The reactions of enamines as 1,3-dipolarophiles provide the most extensive examples of applications to heterocyclic syntheses. Thus the addition of aryl azides to a large number of cyclic (596-598) and acyclic (599-602) enamines has led to aminotriazolines which could be converted to triazoles with acid. Particular attention has been given to the direction of azide addition (601,603). While the observed products suggest a transition state in which the development of charges gives greater directional control than steric factors, kinetic data and solvent effects (604-606) speak against zwitterionic intermediates and support the usual 1,3-dipolar addition mechanism. 

Kinetic template effects have been postulated in more typical organic aldol condensations, where metals such as lithium and zinc are likely to coordinate both the enolate or enamine nucleophile and the aldehyde in the transition state. The examples shown in Schemes 58184 and 59185 are illustrative of these reactions and the degree of selectivity obtained. The carboxylation of ketones and nitroalkanes by methyl magnesium carbonate to produce P-keto acids and a-nitro acids respectively provides early examples of similar reactions (Scheme 60).186 187 See also Section 61.1.4.4. 

The high trans selectivity of this transformation may be explained by means of stereoelectronic effects. Therefore the attack of the hydrogen atom on enamine 53 has to proceed anti toward 15-H under formation of the 15,20-franv-compound 16.18 Conformation 56 with pseudoequatorial orientation of the ethyl group at C-20 is assumed to be energetically most favored. An attack on C-20 anti toward 15-H proceeds via a more favorable chair-like transition state, whereas an attack syn toward 15-H results in a less favorable boat-like transition state. 

Stereospecificity, stereoselectivity and regioselectivity combined in Diels-Alder reactions give unprecedented control and you should now see why it is so important. The analgesic tilidine 47, effective in cases of severe pain, is an obvious Diels-Alder product.8 The regioselectivity is correctly ortho and the endo transition state 51 shows that the trans -enamine 49 is needed. This is the geometry we get when the enamine is made in the normal way from the enal 50 and Me2NH. 

Diethyl azodicarboxylate (DAD) behaves like a reactive electrophilic alkene and attack on a substituted cyclohexanone enamine can occur from an axial or equatorial direction depending on the steric effects in the transition state. For example, DAD reacts with 159 to give 160 by equatorial attack, together with 161 (ratio 1 9), whereas the... 

The addition of a radical to the C=C bond of enamines generates an a-amino radical, stabilized via spin delocalization onto the nitrogen atom15. The extent of this stabilization as compared to the unsubstituted methyl radical has been determined by theoretical calculations16 and experimental studies17 to be about 9-10 kcal mol-1. However, the contribution of this stability effect to the reactivity in radical addition to enamines is important only if the addition process has a late transition state, which is usually not the case for radical addition to alkenes. 

Structural effects on the C-basicity of enamines are, however, more complex. Because of the paucity of values for pX H+, we shall anticipate our discussion of the kinetics of C-protonation (see Section III) so that some of the information presented there can be incorporated into the present section. The justification for doing so is that many of the effects that influence the stability of the iminium ion are expected to be operational in the transition state. In particular, the coplanarity of the atoms about the C=N bond in the iminium ion (already preferred for some enamines, but only when geometrically possible24) should be maintained or improved in the transition state in order to maximize p-n overlap (equation 4)25. This means that, besides the ability of the amino nitrogen to bear a positive charge, other factors such as formation of the C=N double bond (with attendant rehybridization at nitrogen), and steric interactions between groups attached to the alkene and amine moieties will be important both in the transition state and in the iminium ion product. 

For all three series the secondary enamines produce pkli+ values which are identical within experimental error. By this criterion, transition state conjugation between the 7V-arylamino group and the alkenyl part of the molecule is not restricted, at least in the transition state. These values can therefore be taken as representative of Af-aryl substituent effects on the rates of hydration of simple secondary enamines. It is noteworthy in this context that even when steric hindrance is strongly implicated, as in the tertiary series (29, L = CH3), the pkH+ value is —2.38, a much larger value than the... 

Alkylation at Cp retards protonation at that site as it does for enols44 and enolates (see also Table 6). The effect is a modest one when steric hindrance to conjugation in the transition state is not too great the secondary enamines of series 29 are hydrolyzed but 4 to 7 times slower than those in series 28. Huge differences, factors of ca 106, exist between some of the tertiary members of 28 and 29, however. As discussed above, these differences are dominated by the inability of 29 (L == CH3) to take full advantage of conjugative stabilization in the transition state. 

Capon and Wu have shown that the rate of hydrolysis of secondary enamines of cyclohexanone (13 and 14) is decreased only slightly by the 2) methyl group. They have therefore concluded that the methyl substituent has little effect on the ground state or the transition state conformations of secondary enamines . However, in this case there is no developing allylic strain whether the transition state is reactant-like or product-like (see also Section VIII) and pn-conjugation is uninhibited. The pn-conjuga-tion in secondary, -disubstituted acyclic enamines (15) compared to the corresponding tertiary enamines (16) is also demonstrated by the UV and NMR evidence provided by Capon and Wu . 

It remains to discuss the structure-reactivity results obtained by Capon and Wu this will be done in the context of equation 15 rate-controlling C-protonation by H30. One noteworthy result (see Table 10) is that, for the cyclohexenyl series 28, the change from a secondary to a tertiary enamine has very little effect on ky. By contrast, for series 27, the A -methylenamines are hydrolyzed at rates ranging from 20-800 times slower than the secondary analogues, while for series 29 the A-methylenamines are slower than their secondary counterparts by a factor of 15,000 to more than 400,000. For 27, L = CH3 and 29, L = CH3 it is apparently difficult to achieve the desired coplanarity of the amino and alkenyl moieties in the transition state (cf equation 4) which permits the conjugative donor properties of the amino group to be fully exploited. In agreement with this interpretation is the fact that for series 28, where the rates of hydrolysis of secondary and tertiary members are very similar, the p values for hydrolysis are also very similar = —3.45 and —3.26, respectively. For series 27 and more so... 

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