Sterically hindered enamines

Reaction of Grignard reagents with N,N-dialkylformamides gives acyclic enamines440. Sterically hindered enamines can be synthesized in this manner. 

Sterically hindered enamines can be synthesized from an a-chloroenamine by treating it with t-butyllithium at — 70 °C and then adding water516 (equation 34). N-Benzoylhep-... 

TiCU is both a strong Lewis acid and a powerful dehydrating agent, and hence useful as a water scavenger in the synthesis of enamines. It is particularly useful for the preparation of enamines of acyclic ketones. It is recommended that TiCU is complexed with the amine before addition of the ketone. Highly sterically hindered enamines are available by this method (eq 51 ). Primary amines generally react very slowly with aromatic ketones to form imines. TiCU is a good catalyst (eq 52). ... 

In 1992, Bergman et al. reported that zirconium bisamides Cp2Zr(NHR)2 catalyze the intermolecular hydroamination of alkynes with sterically hindered primary amines to give enamines or their tautomeric imines (e.g., Eq. 4.77) [126]. 

At present, the enamines can be obtained fairly easily either in pure Z- or in pure -isomeric form and enamines derived from a series of sterically hindered amines have been prepared18-21. 

A significant improvement in the alkylation of ketone and aldehyde enamines involves the use of sterically hindered amines63. N-Alkylation is prevented with consequent increase in C-alkylation. For example, reaction of the w-butylisobutylamine enamine of cyclohexanone (29) with methyl iodide in boiling acetonitrile (Scheme 16), or trimethy-loxonium tetrafluoroborate at room temperature gave 2-methylcyclohexanone in increased yields of 56% and 74%, respectively63 (compare Scheme 10). 

Preparation of imines and enamines from carbonyl compounds and amines can be achieved with a dehydrating agent under acid/base catalysis [563]. Basically, primary amines afford imines unless isomerization to an enamine is favored as a result of conjugation, etc (see Eq. 252), and secondary amines afford iminium salts or enamines. These transformations can be conducted efficiently with a catalytic or stoichiometric amount of a titanium salt such as TiCU or Ti(0-/-Pr)4. Equation (247) illustrates an advantageous feature of this method in the imination of a hindered ketone. f-Butyl propyl ketone resisted the formation of the imine even by some methods reported useful for sterically hindered ketones [564,565]. The TiCU-based method works well, however, for this compound, giving the desired imine in high yield within a relatively short reaction period [566]. Imine derivatives such as iV-sulfonylimines could be... 

A comparison of the results of the methylation of the pyrrolidine enamine of cyclohexanone (81 Scheme 42) with those shown in Scheme 43 for the methylation of the n-butylisobutylamine derivative (86) shows that yields are improved with the latter compound. Presumably, the more sterically hindered amine reduces the amount of iV-alkylation and retards the rate of proton transfer between the C-al-kylated iminium salt and the unreacted enamine. 

This example furnishes an illustration of the step-wise approach to experimental studies The experimental domain of the experiments in Table 12.13 was not arbitrarily chosen. The optimum conditions for previously studied enamine syntheses were well within this domain, but pinacolone is a different case as it is sterically hindered and the rate of enamine formation was rather slow. To prevent the formation of the byproduct, a large excess of reagents was necessary. The direction for changing the experimental conditions was determined from the initial response surface study. 

The enamine is formed even in the cold from acetaldehyde and diethyl-amine.961 Adding a stoichiometric amount of titanium tetrachloride appears to provide a generally applicable method of preparing enamines in the cold even sterically hindered ketones then afford remarkably high yields.962... 

The starting ketone here is unsymmetrical, so two enamines are possible. However, the formation of solely the less substituted enamine is typical. The outcome may be explained as the result of thermodynamic control enamine formation is reversible so the less hindered enamine predominates. For the more substituted enamine, steric hindrance forces the enamine to lose planarity, and destabilizes it. The less substituted enamine, on the other hand, is rather more stable. 

Arsenic and titanium amides have been used for the amination of 0X0 compds. to gem-diamines and enamines as well as for the amination of acid derivatives . Recently, the preparation of enamines, including sterically hindered compounds, with free amines and titanium tetrachloride has been reported . A Claisen-type rearrangement to form /,(3-unsatd. amines has been used for the preparation of 17-disubst. steroids . 

In organocatalytic cross-aldol reactions of two different aldehydes through the enamine intermediate first reported by MacMillan and Northrop, the a d-cross-aldol adduct could be obtained in a highly stereoselective fashion. However, most such reactions required the use of sterically hindered aliphatic aldehydes, from which the enamine intermediates are rather difficult to form, or aromatic aldehydes as electrophile. In the direct aldol reaction between simple aliphatic aldehydes (enolisable aldehydes), both aldehydes can perform the double role of nucleophile and electrophile, and consequently, two cross-aldol adducts and two homo-aldol adducts would be possible products with each having four stereoisomers. To differentiate two... 

The cross-aldol reaction between two enolizable aldehydes is not an easy task. Proper selection of reaction partners is of great importance. The most frequently studied reactions involved sterically hindered aldehydes since they form enamines... 

Surprisingly, such selectivity was observed only recently in an aldehyde series. Indeed the group of Barbas developed a catalyst able to perform anti-selective Michael addition of aldehydes [26]. To facilitate such a transformation, several parameters were adjusted to promote the formation of (Z)-enamine, which is necessary to obtain an anti-selectivity (i) the classical secondary amine catalyst was changed for primary amine 17, which is less sterically hindered, favoring the (Z)-enamine, and (ii) the substrate was chosen to be able to form a stabilizing intramolecular H-bonding in favor of the (Z)-enamine. For these reasons (tert-butyldimethylsilyloxy)acetaldehyde (18) was selected as pro-nucleophile. Excellent level of enantio- and diastereoselectivity were obtained on combining these both parameters (Scheme 34.1). In the postulated transition state, covalent interaction... 

---