Allylamines enamines

Isomerization is a frequent side-reaction of catalytic transformations of olefins, however, it can be a very useful synthetic method, as well. One of the best-known examples is the enantioselective allylamine enamine isomerization catalyzed by [Rh (jR)-or(S)-BINAP (COD)] which is the crucial step in the industrial synthesis of L-menthol by Takasago [42]... 

A further highlight was introduced by R. Noyori in the 1980s when an efficient stereoselective hydrogen migration (allylamine —> enamine) was found to occur with Rh catalysts containing the BINAP diphosphine ligand of axial chirality (see Scheme 3 and Section 2.9). An L-menthol synthesis with an annual production of 2000 tons was the first commercial result of this development at Takasago Perfumery Co. Ltd. in Japan [66]. 

Rivire and Lattes used LiNH2 and NaNHj in liquid ammonia at — 70°C, in hexamethylphosphortriamide at room temperature or t-BuOK/HMPA at room temperature for allylamine enamine isomerizations. An anion formed by deprotonation of the allylamine at C was considered to be the intermediate species in the isomerization. Intramolecular transfer of hydrogen in the transition state of the isomerization was suggested to explain both the kinetic formation of the Z-enamine and the absence of exchange with deuteriated base during the isomerization. Quantum chemical calculations showed that the Z-carbanion (61) is actually more stable than the -carbanion (62). 

Allylic amines are coupled to halides giving either allylic amines or enamines depending on the reaction condition. Reaction of steroidal dienyl triflate with Boc-diprotected allylamine affords allylamine. Use of AcOK as a base is crucial for the clean coupling[102]. The tert-allylic amine 123 reacts with an aryl halide to give the enamine 125 in DMF and allylic amine 124 in nonpolar solvents[103]. 

Allylamines have been used as nitrogen protective groups. They can be removed by isomerization to the enamine (t-BuOK, DMSO) or by rhodium-catalyzed isomerization. ... 

Treatment of allylamines with potassium amide on alumina causes their isomerization to enamines in good yields (124b). When allylamines are heated to about 55° the same type of isomerization takes place (I24c). 

Rhodium-catalyzed isomerization. Ru(cod)(cot) has been used to convert an allylamine into an enamine."... 

Radical cyclization is compatible with the presence of other functional groups. Treatment of XCH2CON(R)-C(R )=CH2 derivatives (X = Cl, Br, 1) with Ph3SnH and AIBN led to formation of a lactam via radical cyclization. " Cyclization of N-iodoethyl-5-vinyl-2-pyrrolidinone led to the corresponding bicyclic lactam, " and there are other examples of radical cyclization with molecules containing a lactam unit " or an amide unit. Radical cyclization occurs with enamines as well. Photochemical irradiation of A,A-dialIyl acrylamide leads to formation of a lactam ring, and in this case thiophenol was added to generate the phenylthio derivative. Phenylseleno N-allylamines lead to cyclic amines. co-Iodo acrylate esters cyclize to form lactones. " ... 

The thermal [1] or photochemical [5] isomerization of N-silylated allylamine in the presence of Fe(CO)5 provides the corresponding N-silylated enamines 7a and 7b. Z-enamine 7b does not react in any of the examined cycloadditions. The cyclopropanation of E-enamine 7a with methyl diazoacetate under copper(I) catalysis provides the donor-acceptor-substituted cyclopropane 9 [1], which can be converted in good yield into the interesting dipeptide 10 [6]. 

The synthesis of a variety of chiral aliphatic aldehydes of high optical purity through the enantioselective isomerization of allylamines found many applications in organic synthesis. The enantioselective isomerization of diethylgeranylamine, which was prepared from myrcene, furnished (R, )-diethylenamine in >98% yield with >98% ee. This enamine is converted to (—(-menthol stereospecifically in high chemical yield (yield of each step >92%, Scheme 4).9 11... 

Although the asymmetric isomerization of allylamines has been successfully accomplished by the use of a cationic rhodium(l)/BINAP complex, the corresponding reaction starting from allylic alcohols has had a limited success. In principle, the enantioselective isomerization of allylic alcohols to optically active aldehydes is more advantageous because of its high atom economy, which can eliminate the hydrolysis step of the corresponding enamines obtained by the isomerization of allylamines (Scheme 26). 

The nudeophile is activated by the formation of a titanium(IV)-imido complex 19. The next step is a [2 + 2] cydoaddition with one of the jt-bonds of the allene, depending on the regioselectivity leading to either 20 or 22. Compound 20 then delivers 21 by twofold stepwise proto-demetallation and the latter enamine tau-tomerizes to the imine 24 (Scheme 15.3). Compound 22, on the other hand, should provide allylamines 23, but as we shall see, there are no examples of that mode of reaction known so far. 

Phosphorylated allenes 195 (R1 = H or Me) are a source of secondary ( )-allylamines. The allenes are treated with an amine R2NH2 (R2 = t-Bu or 4-MeCgH4 and the products, which exist as equilibrium mixtures of enamines 196 and imines 197, are olefinated by successive reaction with methyllithium and an aldehyde R3CHO (R = i-Bu, 4-MeCgH4, PhCH2CH2 etc). Reduction with sodium borohydride finally yields the... 

The synthesis of menthol is given in the reaction scheme, Figure 5. 6. The key reaction [2] is the enantioselective isomerisation of the allylamine to the asymmetric enamine. It is proposed that this reaction proceeds via an allylic intermediate, but it is not known whether the allyl formation is accompanied by a base-mediated proton abstraction or hydride formation. 

When the secondary amine 33 was used instead of a primary amine, a different type of three-component coupling reaction took place with aldehyde 34 and 1-alkynes 35 to afford the corresponding allylamines (36 and 37) [22]. In this reaction, Ir-hydride generated by amine (33) with Ir, would be a key intermediate. The reaction may proceed by addition of the Ir-hydride to the enamine derived from amine 33 and alkyne 34, followed by insertion of aldehyde and dehydration to give the coupling product (36 and 37). 

Ring-closing metathesis seems particularly well suited to be combined with Passerini and Ugi reactions, due to the low reactivity of the needed additional olefin functions, which avoid any interference with the MCR reaction. However, some limitations are present. First of all, it is not easy to embed diversity into the two olefinic components, because this leads in most cases to chiral substrates whose obtainment in enantiomerically pure form may not be trivial. Second, some unsaturated substrates, such as enamines, acrolein and p,y-unsaturated aldehydes cannot be used as component for the IMCR, whereas a,p-unsaturated amides are not ideal for RCM processes. Finally, the introduction of the double bond into the isocyanide component is possible only if 9-membered or larger rings are to be synthesized (see below). The smallest ring that has been synthesized to date is the 6-membered one represented by dihydropyridones 167, obtained starting with allylamine and bute-noic acid [133] (Fig. 33). Note that, for the reasons explained earlier, compounds... 

The enantioselective BINAP-Rh +-catalyzed isomerization of an achiral allylamine, such as diethylgeranylamine, to give an optically active enamine (e. g., 2) (for configurational assignment, see p 436)56. 

Aminoallyl carbanions, obtained by deprotonation of enamines or allylamines, are well-known homoenolate equivalents, since electrophilic attack occurs, in most cases, highly regiose-lectively to give the 3-substituted enamines, hydrolysis of which leads to the corresponding carbonyl compounds15 24,25. 

The conditions for the deprotonation of chiral allylamine 8 depend on the substituent. For the phenyl compound only butyllithium is needed, however, with the alkyl compounds potassium /err-butoxide/tert-butyllithium must be used, giving access to the potassium salts 9 in these cases only. Alkylation with iodoalkanes afforded the unstable enamines, which were hydrolyzed either by water alone but preferably with dilute acid to afford the chiral 3-phenylalkanones. 

The chiral a-cyano allylamines prepared from ( )-3-phenylpropenal, potassium cyanide and (L)-ephcdrinc [(17 ,2S )-2-methylamino-l-phenylpropanol] hydrochloride as a mixture (1 1) of C-l epimers, were deprotonated using 2 equivalents of LDA in THF to give the dilithio compound37. Alkylation at C-3 afforded regioselectively a mixture of (E)- and (Z)-enamines in variable amounts depending on reaction conditions. Diastereoselectivity varied from moderate to excellent. Addition of HMPA and especially lithium iodide improved the diastereoselectivity. De-aggregation is proposed to be the reason for the effect of these additives. 

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