Allylic amine isomerization

Remote olefins are maintained in BINAP-Rh(l)-catalyzed allylic amine isomerizations 1. (CH3)2CO, aq. NaOH (aldol condensatlon/dehydratlon) 2. H2, Pt/C... 

Remote hydroxyl groups are compatible with BINAP-Rh(l)-catalyzed allylic amine isomerizations... 

In the Rh-BINAP-catalyzed allyl amine isomerization step used in Takasago s Menthol process, the catalyst is inhibited by water through the formation of a hydroxyl-bridged rhodium trinuclear complex [ Rh(BINAP) i(/<2-0H)2]C104 [61]. 

Allylic amide isomerization, 117 Allylic amine isomerization ab initio calculations, 110 catalytic cycle, 104 cobalt-catalyzed, 98 double-bond migration, 104 isotope-labeling experiments, 103 kinetics, 103 mechanism, 103 model system, 110 NMR study, 104 rhodium-catalyzed, 9, 98 Allylnickel halides, 170 Allylpalladium intermediates, 193 Allylsilane protodesilylation, 305 Aluminum, chiral catalysts, 216, 234, 310 Amide dimers, NMR spectra, 282, 284 Amines ... 

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). 

Perhaps the most successful industrial process for the synthesis of menthol is employed by the Takasago Corporation in Japan.4 The elegant Takasago Process uses a most effective catalytic asymmetric reaction - the (S)-BINAP-Rh(i)-catalyzed asymmetric isomerization of an allylic amine to an enamine - and furnishes approximately 30% of the annual world supply of menthol. The asymmetric isomerization of an allylic amine is one of a large and growing number of catalytic asymmetric processes. Collectively, these catalytic asymmetric reactions have dramatically increased the power and scope of organic synthesis. Indeed, the discovery that certain chiral transition metal catalysts can dictate the stereo-... 

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... 

Scheme 7. Stereochemical outcome of BINAP-Rh(i)-catalyzed asymmetric isomerization of allylic amines.

We now turn to the Takasago Process for the commercial synthesis of (-)-menthol (1),4 one of the most successful industrial applications of catalytic asymmetric synthesis. This exquisite synthesis is based on the BINAP-Rh(i)-catalyzed enantioselecdve isomerization of allylic amines, and has been in operation for the commercial production of (-)-menthol since 1984. 

Rh/(5)-BINAP Isomerization of allylic amine /.-Menthol Aroma and flavour chemical 96-98... 

Morpholine also gives the allyhc amine in high yield. The reaction is thought to involve a known hydridopaUadium-catalyzed isomerization of alkynes to aUenes followed by reaction of the latter with the hydridopalladium complex to give 1-phenyl-substituted q -allylpalladium complexes. These complexes react with amines affording the allylic amines. Primary amines give the diallylic amines. An intramolecular version has been developed for the synthesis of 2-(2-phenyl)-pyrroUdines and -piperidines [319]. 

Allyl groups attached directly to amine or amide nitrogen can be removed by isomerization and hydrolysis.228 These reactions are analogous to those used to cleave allylic ethers (see p. 266). Catalysts that have been found to be effective include Wilkinson s catalyst,229 other rhodium catalysts,230 and iron pentacarbonyl.45 Treatment of /V-allyl amines with Pd(PPh3)4 and (V,(V -dimethylbarbi Lurie acid also cleaves the allyl group.231... 

Takasago A catalytic process for the enantioselective isomerization of allylic amines. The catalyst is a chiral rhodium complex. Used in the manufacture of (-)menthol. Named after Takasago International Corporation, the Japanese company which commercialized the process in 1983. 

When the reaction temperature is increased to 80°C, all amines convert to product in less than 10 h. Typical examples and yields (unoptimized) are shown in Fig. 5. It is interesting that the allyl amine double bond does not isomerize in the first example. 

Isomerization of allylic amines is another example of the application of the BINAP complex. Rh BINAP complex catalyzes the isomerization of N,N-diethylnerylamine 40 generated from myrcene 39 with 76-96% optical yield. Compound (R)-citronellal (R)-42. prepared through hydrolysis of (R)-41, is then cyclized by zinc bromide treatment.49 Catalytic hydrogenation then completes the synthesis of (—)-menthol. This enantioselective catalysis allows the annual production of about 1500 tons of menthol and other terpenic substances by Takasago International Corporation.50... 

When the reaction of a triethylsilyl-substituted derivative 42 is examined, an allylic alcohol 43 is isolated albeit in low yield. This result suggests that in the presence of a tertiary amine isomerization of the cyclopropanol to an allylic al-... 

The commercialization in 1983 of the process illustrated in Eq. (1) is undoubtedly one of the most significant triumphs of asymmetric catalysis to date [2]. Takasago Chemical Company produced more than 22 000 tons of menthol by this route during the period 1983-1996, consuming only 125 kg of the chiral Hgand in the process. Rh(I)/Tol-BINAP-catalyzed isomerizations of allylic amines are beheved to proceed through the pathway outlined in Eq. (2) [3]. 

For Rh(I)/BINAP-catalyzed isomerizations of allylic amines, the mechanistic scheme outlined in Eq. (2) has been proposed. The available data are consistent with the notion that Rh(I)/PF-P(o-Tol)2-catalyzed isomerizations of allylic alcohols follow a related pathway [11]. For example, the only deuterium-containing product of the reaction depicted in Eq. (9) is the l,3-dideuterated aldehyde, which estabhshes that the isomerization involves a clean intramolecular 1,3-migration. The data illustrated in Eqs. (10) and (11) reveal that the catalyst selectively abstracts one of the enantiotopic hydrogens/ deuteriums alpha to the hydroxyl group. 

One of the landmark achievements in the area of enantioselective catalysis has been the development of a large-scale commercial application of the Rh(I)/BINAP-catalyzed asymmetric isomerization of allylic amines to enamines. Unfortunately, methods for the isomerization of other families of olefins have not yet reached a comparable level of sophistication. However, since the early 1990s promising catalyst systems have been described for enantioselective isomerizations of allylic alcohols and aUylic ethers. In view of the utility of catalytic asymmetric olefin isomerization reactions, I have no doubt that the coming years will witness additional exciting progress in the development of highly effective catalysts for these and related substrates. 

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). 

Ar = 2-(n-C4H,0)-5-(t-C4H9)C5H3 Rh(I)-cataIyzed isomerization of allylic amines... 

RHODIUM-CATALYZED ENANTIOSELECTIVE ISOMERIZATION OF ALLYLIC AMINES... 

Isocyanophosphonates, aldol reactions, 227 Isoquinoline synthesis, enamide reactions, 33 Isomerization allylic amines, 9, 95 olefins, 118, 171 see also specific compounds Isopulegol, 102 Isotactic polymers, 174 chloral, 182 photoirradiation, 347 methacrylates, 181 propylene, 174 Isotacticity, 177... 

The Rh(I)-catalyzed isomerization of prochiral allylic amines to optically active enamines is used for the giant-scale synthesis of citronellal, citronellol, menthol, and other fragrances (18)(Chapter 3). 7-Meth-oxydihydrocitronellal, thus prepared, is an insect growth regulator. All of these processes can be carried out economically and with extremely high optical yields. 

RHODIUM-CATALYZED enantioselective isomerization of ALLYLIC AMINES 103... 

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