Enamines stereochemistry

An example of the use of NMR spectroscopy to ascertain with reasonable certainty the stereochemistry of a series of enamines has been provided by Paquette (25). Based on a study of the NMR spectra of the endo- and exo-5-norbornene-2-carboxaldehydes (168), the enamine mixtures were estimated to contain 80 to 90 % of the transoid form (170). 

Although the emphasis in this chapter has been on tbe synthesis and mechanism of formation of simple enamines, brief mention will be made of the addition of amines to activated acetylenes to indicate the interest and activity in this area of substituted enamines. Since such additions tend to be stereospecific, inclusion in this section seems apropos. The addition of amines to acetylenes has been much studied 130), but the assigning of the stereochemistry about the newly formed double bond could not be done unequivocally until the techniques of NMR spectroscopy were well developed. In the research efforts described below, NMR spectroscopy was used to determine isomer content and to follow the progress of some of the reactions. 

The photocyclization of N-aryl enamines derived from cyclic or acyclic ketones proceeds under mild conditions to produce 2,3-dihydroindole derivatives (178b). The stereochemistry of the products is predominantly trans, which follows from a photochemical electrocyclic process which should take place in a conrotatory manner (178c,I78d). However, the presence of some cis products is not as easily explained. 

The most general method for synthesis of cyclic enamines is the oxidation of tertiary amines with mercuric acetate, which has been investigated primarily by Leonard 111-116) and applied in numerous examples of structural investigation and in syntheses of alkaloids 102,117-121). The requirement of a tram-coplanar arrangement of an a proton and mercury complexed on nitrogen, in the optimum transition state, confers valuable selectivity to the reaction. It may thus be used as a kinetic probe for stereochemistry as well as for the formation of specific enamine isomers. 

Solvents and pH may have a marked effect on stereochemistry as was illustrated in Chapter 1, and the generality given there is useful, A further example of the stereochemical influence that may be exerted by proper choice of catalyst and solvent is shown in the hydrogenation of a complex enamine, By proper choice of conditions high yields of either the cis or trans product could be obtained. Selected results are shown below (52) (data used with permission). 

Oare, D. A., Stereochemistry of the Base-Promoted Michael Addition Reaction, 19, 227 Acyclic Stereocontrol in Michael Addition Reactions of Enamines and Enol Ethers, 20, 87 Okamoto, Yoshio, Optically Active Polymers with Chiral Recognition Ability, 24, 157. 

Addition of amines to allenephosphonates yields C-phosphorylated enamines, the stereochemistry of which partly depends on the nature of R2 and R3 (147). When Ra is hydrogen, intramolecular hydrogen bonding with the phosphoryl group is possible in the Z-isomer, and indeed this is the isomer which is then produced in greater yield. The carbon-carbon double bond can be reduced with KBH4.116... 

One of the most widely applied cycloaddition techniques for the preparation of thietanes is the reaction of sulfenes with enamines. The stereochemistry of these reactions has been extensively investigated by Truce and Rach. Whether the mechanism is a two-step or a concerted process, both in accordance with the stereoselective formation of the cis form in Scheme 1, is still unresolved. The special orientation of the 1,4-dipolar intermediate 64, in which the charged phenyl and dimethylamino moieties are in proximity, enforces the cis geometry of the resulting thietane dioxide. In the concerted mode of reaction, formation of the orthogonal oriented unsaturated system, 65 should also yield the cis cycloadduct. 

The stereochemistry of sulfene-enamine cycloaddition has also been followed by Drozd et who studied the method of asymmetric induction in the preparation of compounds 66 and 67. 

Azadienes of this sort were studied simultaneously by Mariano et al., who reacted mixtures of (1 ,3 ) and (1E, 3Z)-l-phenyl-2-aza-l,3-pentadiene 275 with several electron-rich alkenes, e.g., enamines and enol ethers (85JOC5678) (Scheme 61). They found the (l ,3 )-stereoisomer to be reactive in this process affording stereoselectively endo 276 or exo 277 piperidine cycloadducts in 5-39% yield, after reductive work-up with sodium borohydride. The stereochemistry of the resulting adducts is in agreement with an endo transition state in the case of dienophiles lacking a cis alkyl substituent at the /8-carbon (n-butyl vinyl ether, benzyl vinyl ether, and 1-morpholino cyclopentene), whereas an exo transition state was involved when dihydropyrane or c/s-propenyl benzyl ether were used. Finally, the authors reported that cyclohexene and dimethyl acetylenedi-carboxylate failed to react with these unactivated 2-azadienes. 

Copper(I) salts of enamines have been allylated with the 2-allyloxybenzimidazoles to give y,5-unsaturated ketones upon hydrolysis (79CL957). Primary allylic ethers react preferentially at their a-carbon with retention of double bond configuration whereas secondary allylic ethers react mainly at the y-carbon to afford alkenes of predominantly (E)-stereochemistry. 

The stereochemistry of the alkylation of enamine 482 has been reported by Karady, Lenfant, and Wolff (149) to give mainly the axial alkylated product... 

With regard to the mechanism of the a-amination step, the stereochemistry has been explained on the basis of a transition state involving a proline-enamine struc-... 

Allylic double bonds can be isomerized by some transition metal complexes. Isomerization of alkyl allyl ethers 480 to vinyl ethers 481 is catalysed by Pd on carbon [205] and the Wilkinson complex [206], and the vinyl ethers are hydrolysed to aldehydes. Isomerization of the allylic amines to enamines is catalysed by Rh complexes [207]. The asymmetric isomerization of A jV-diethylgeranylamine (483), catalysed by Rh-(5)-BINAP (XXXI) complex to produce the (f )-enaminc 484 with high optical purity, has been achieved with a 300 000 turnover of the Rh catalyst, and citronellal (485) with nearly 100% ee is obtained by the hydrolysis of the enamine 484 [208]. Now optically pure /-menthol (486) is commerically produced in five steps from myrcene (482) via citronellal (485) by Takasago International Corporation. This is the largest industrial process of asymmetric synthesis in the world [209]. The following stereochemical corelation between the stereochemistries of the chiral Rh catalysts, diethylgeranylamine (483), diethylnerylamine (487) and the (R)- and (5)-enamines 484... 

These differences in the control of the product stereochemistry have recently been investigated by molecular modeling techniques [60,154], From these studies, the relevance of the side-chain of isoleucine 476 (PDCS.c.) (Table 2) for the stereo-control during the formation of aromatic a-hydroxy ketones became obvious, since this side-chain may protect one site of the ot-carbanion/enamine 6 (Scheme 3) against the bulky aromatic cosubstrate. Nevertheless, the smaller methyl group of acetaldehyde can bind to both sites of the a-carbanion/en-amine. The preference for one of the two acetoin enantiomers has been interpre-tated in terms of different Boltzmann distributions between the two binding modes of the bound acetaldehyde [155],... 

CPCM) solvation, to study the mechanisms and stereochemistries of this important synthetic reaction. Interestingly, from these calculations, it was concluded that secondary enamine-mediated aldols have high activation energies if there is no proton source, and oxetane intermediates such as 1 can be formed (Equation 1) <2001JA11273>. 

Initiated by Stork and co-workers,47 the scope and stereochemistry of enamine alkylations have been well explored. In general, good stereoselectivities can be obtained using bulky directing groups, polar aprotic solvents, and low temperatures. 

The stereochemistry of such photocyclizations was also explored [71] by irradiating enamines of type 141 which gave trans-indolines 142 as the major reaction product, along with minor cis-143 (Scheme 8.41). 

Interestingly, the enamine of cyclopentanone 144, upon irradiation [72], gave only the cis-indoline 145 in 52% yield this indicated the effect of ring-strain on the stereochemistry of the indolines (Scheme 8.42). Mechanistically, several pathways... 

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