Enamines, from allyl amines

This transformation includes formation of cyclic acetals and ketals and, if R SH is used, thioacetals or thioketals. The R and R groups can be alkyl, hydrogen, or aryl. Imines are available from primary amines and enamines from secondary amines. Similarly, R and R can be hydrogen, alkyl, or aryl R is usually allyl or aryl. 

Aromatic enamines were prepared by dehydroha logenation of /3-bromo-amines with strong base. While trans enamines were thus formed, one obtained mostly cis enamines from rearrangement of the corresponding allylic amines under similar reaction conditions (646). Vicinal endiamines were obtained from S-dichloroamines and lithium amides (647). 

The formation of an enamine from an a,a-disubstituted cyclopentanone and its reaction with methyl acrylate was used in a synthesis of clovene (JOS). In a synthetic route to aspidospermine, a cyclic enamine reacted with methyl acrylate to form an imonium salt, which regenerated a new cyclic enamine and allowed a subsequent internal enamine acylation reaction (309,310). The required cyclic enamine could not be obtained in this instance by base isomerization of the allylic amine precursor, but was obtained by mercuric acetate oxidation of its reduction product. Condensation of a dihydronaphthalene carboxylic ester with an enamine has also been reported (311). 

The isomerization of an allylic amine to an enamine by means of a formal 1,3-hydrogen shift constitutes a relatively small structural change. However, this transformation could be extremely valuable if it could be rendered stereoselective. In important early studies, Otsuka and Tani showed that a chiral cobalt catalyst, prepared in situ from a Co(ii) salt, a chiral phosphine, and diisobutylaluminum hydride (Dibal-H), can bring about the conversion of certain pro-chiral olefins to chiral, isomeric olefins by double bond migra-... 

The disclosure, in 1982, that cationic, enantiopure BINAP-Rh(i) complexes can induce highly enantioselective isomerizations of allylic amines in THF or acetone, at or below room temperature, to afford optically active enamines in >95 % yield and >95 % ee, thus constituted a major breakthrough.67-68 This important discovery emerged from an impressive collaborative effort between chemists representing Osaka University, the Takasago Corporation, the Institute for Molecular Science at Okazaki, Japan, and Nagoya University. BINAP, 2,2 -bis(diphenylphosphino)-l,l -binaphthyl (Scheme 7), is a fully arylated, chiral diphosphine which was introduced in... 

Separation of catalysts from high-value products such as fine chemicals or pharmaceuticals is often accomplished by precipitating the catalyst from the product solution. Recycling of these catalysts is feasible, provided that they do not decompose. In industry, catalyst recovery by means of catalyst precipitation is applied only in relatively small batch processes. An example of such a process is the production of (—)-menthol (id) in which an Rh-BINAP isomerization catalyst converts the allylic amine substrate into (R)-citronellal (after hydrolysis of the enamine) in high yield (99%) and with high enantioselectivity (98.5% ee). After distillation of the solvent (THF) and product, the catalyst is recovered from the residue by precipitation with -heptane. 

A synthesis of optically active citronellal uses myrcene (7), which is produced from P-pinene. Reaction of diethyl amine with myrcene gives AyV-diethylgeranyl- and nerylamines. Treatment of the allylic amines with a homogeneous chiral rhodium catalyst causes isomerization and also induces asymmetry to give the chiral enamines, which can be readily hydrolyzed to (H-)-citronellal (151). 

The reactions of tertiary allylic amines with vinylic halides are related closely to the allylic alcohol reactions since enamines are often major products. We have just begun work in this area and have few results to report yet. We have seen some significant differences in the products formed from tertiary allylic amines and from the related allylic alcohols. A typical example is the reaction of 2-bromopropene with N-allyl piperidine and piperdine where a 42% yield of a single enamine is obtained (6). The related reaction with allyl alcohol gives a mixture of regioisomeric enamines. 

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... 

Like the synthesis of L-DOPA by asymmetric hydrogenation, the manufacture of L-menthol hy Takasago Company is also one of the early examples of an industrial process where asymmetric isomerization is a key step. The desired isomerization reaction is one of the steps of the overall synthetic scheme. The synthesis of L-menthol from diethyl geranylamine is shown by 9.2. The formal electron pair pushing mechanism for the isomerization of the allylic amine to the enamine proceeds according to reaction 9.3. 

Further application of the Torgov reaction has been made in the synthesis of oestrone, the 3,16-dimethylether of oestriol, and a series of 4-halogeno-oestrogens. A novel modification involves the use of allylic amine (412) (readily prepared from the enamine of m-methoxytetralone) in place of the usual alcohol... 

The key step of the synthesis is the isomerisation of the allylic amine to the corresponding enamine. This is a simple reaction in which a hydrogen atom is moved from the first carbon to the third of the geranyl skeleton. The ingenious feature of this particular case is that the hydrogen atom is added to that third carbon atom from one face only and therefore results in the formation of a single enantiomer of the enamine. When this is hydrolysed, the citronellal produced, is entirely in the dextrorotatory form. The catalyst which performs this transformation is a complex of the Group VIII metal, rhodium. The catalyst which... 

Enamines are made from secondary amines and aldehydes or ketones via the iminium salt you met them in Chapter 11 and have seen them in action in Chapters 20 and 25. In Chapter 25 we saw that reliable C-alkylation of enamines occurs with reactive allyl halides and... 

Synthetic highlight Diastereoselective production of rac-menthol from its aromatic precursor is achieved by site-selective isopropylation and diastereoselective hydrogenation to the all-trans racemate. Enantioselective allylic amine-enamine-imine rearrangement of an acyclic diene-allylic amine, catalyzed by an Rh(I)-(—)-BINAP complex, affords (—)-menthol the process has been scaled-up to production of 1,000 tons/year. 

Noyori has achieved the asymmetric catalytic isomerization of allylic amines to optically active enamines using his Rh -BINAP complex (see Chap. 14). This reaction, isomerization of geranyldiethylamine to ( )-enamine of (/f)-citronellal, is used in Japan as a key step in the synthesis of 1500 tons per year of (-)menthol starting from myrcene. The catalyst is recycled, which still increases its efficiency, and the total chiral multiplication reaches 400,000 mol product per mol catalyst. The optical purity of citronellal obtained (96-99%) is far larger than that of natural citronellal (82%). ... 

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