Allylic amines, diene

Addition of several organomercury compounds (methyl, aryl, and benzyl) to conjugated dienes in the presence of Pd(II) salts generates the ir-allylpalladium complex 422, which is subjected to further transformations. A secondary amine reacts to give the tertiary allylic amine 423 in a modest yield along with diene 424 and reduced product 425[382,383]. Even the unconjugated diene 426 is converted into the 7r-allyllic palladium complex 427 by the reaction of PhHgCI via the elimination and reverse readdition of H—Pd—Cl[383]. 

Selenium diimides react in a manner similar to SeOa with unsaturated organic compounds. The first report of BuN=Sc=N Bu described its use as an in situ reagent for allylic amination of olefins and acetylenes. Improved procedures for this process (Eq. 10.5) and for the diamination of 1,3-dienes (Eq. 10.6) have been developed using the reagents RN=Se=NR [R = para-toluenesulfonyl (Ts), ort/io-nitrobenzenesulfonyl (Ns)]. ... 

The reductive coupling of of dienes containing amine groups in the backbones allows for the production of alkaloid skeletons in relatively few steps [36,46,47]. Epilupinine 80 was formed in 51% yield after oxidation by treatment of the tertiary amine 81 with PhMeSiEh in the presence of catalytic 70 [46]. Notably, none of the trans isomer was observed in the product mixture (Eq. 11). The Cp fuMcTIIF was found to catalyze cyclization of unsubstituted allyl amine 82 to provide 83. This reaction proceeded in shorter time and with increased yield relative to the same reaction with 70 (Eq. 12) [47]. Substitution of either alkene prevented cyclization, possibly due to competitive intramolecular stabilization of the metal by nitrogen preventing coordination of the substituted olefin, and resulted in hydrosilylation of the less substituted olefin. 

Amino alkenols have been prepared by palladium-catalyzed chloroacetoxylation and allylic amination of 1,3-dienes. 1,4-Acetoxychlorination is stereospecific and cyclic dienes give an overall cis- 1,4-addition12. Acetoxychlorination of 6-acetoxy-l,3-cycloheptadiene afforded only one isomer as shown in equation 8. Sequential substitution of the allylic chloro group can occur with either retention or inversion, thereby allowing complete control of the 1,4-relative stereochemistry (equation 9). 

Employing iminophosphoranes to protect a group labile under alkaline conditions can lead to a dramatic increase in yield. This is exemplified by the transformation of allylic azide 31 into the corresponding iminophos-phorane 32 shown in Scheme 16. Hydrolysis under basic conditions leads finally to 4-amino-3-hydroxycyclohexa-l,5-diene-l-carboxyclic acid (33) in 80% yield. However, when the same azide (31) is converted with a Lindlar catalyst, via allylic amine 34 into carboxylic acid 33, only 0-30% yields are found as a consequence of the low stability of the allylic amine [93JCR(S)148]. 

The combination of allylic amination, ring-closing metathesis, and a free radical cyclization provides a convenient approach to the dihydrobenzo[b]indoline skeleton, as illustrated in Scheme 10.10. The rhodium-catalyzed aUylic amination of 43 with the lithium anion of 2-iodo-(N-4-methoxybenzenesulfonyl)arrihne furnished the corresponding N-(arylsulfonyl)aniline 44. The diene 44 was then subjected to ring-closing metathesis and subsequently treated with tris(trimethylsilyl)silane and triethylborane to afford the dihydrobenzojhjindole derivative 46a in 85% yield [14, 43]. 

For the synthesis of protected allylic amines, a variety of synthetically useful carbamates and sulfonamides can be used, added to conjugated dienes [65]. Scheme 8.7 shows the proposed mechanism for these reactions. 

Polystyrene-bound secondary aliphatic amines and /V-alkyl amino acids can be ally-lated by treatment with a diene and an aryl iodide or bromide in the presence of palla-dium(II) acetate (Entry 14, Table 10.3). As the diene, 1,3-, 1,4-, and 1,5-dienes can be used, and, besides aryl halides, heteroaryl bromides have also been successfully used [63], This remarkable reaction is likely to proceed via the formation of an aryl palladium complex, with subsequent insertion of an alkene into the C-Pd bond. The resulting organopalladium compound does not undergo ( -elimination (as in the Heck reaction), but isomerizes to an allyl palladium complex, which reacts with the amine to give the observed allyl amines. 

Imido selenium compounds Se(NR)2, where R = Bu or Ts, were first noted to give allylic amination of alkenes and alkynes.232 Formally the NR function is inserted into the allylic C—H bond yielding the C—NHR moiety. Related reactivity was also found for the sulfur imides, S(NR)2.233 Reactions between 1,3-dienes and Se(NTs)2 give [4 + 2] adducts which, in the presence of TsNH2, react to generate 1,2-disulfonamides.234... 

Conjugated dienes afford either allylic amines or saturated diamines (equation 159).204,219 When mer-cury(II) oxide plus tetrafluoroboric acid is employed, dihydropyrroles are formed instead (equation 160).220... 

Vinyl substitution occurs with conjugated dienes as well as with alkenes, employing aryl-, vinyl-, methyl-, alkoxycarbonyl- or benzyl-mercury reagents and lithium tetrachloropalladate(II), but the products are usually rr-allylpalladium complexes if the reactions are carried out under mild conditions (equation 8).24,25 The ir-allylic complexes may be decomposed thermally to substituted dienes26 or reacted with nucleophiles to form allylic derivatives of the nucleophile. Secondary amines, for example, react to give tertiary allylic amines in modest yields, along with dienes and reduced dienes (equation 9).25... 

The reaction proceeds well with unhindered secondary amines as both nucleophiles and bases. The yield of allylic amine formed depends upon how easily palladium hydride elimination occurs from the intermediate. In cases such as the phenylation of 2,4-pentadienoic acid, elimination is very facile and no allylic amines are formed with secondary amine nucleophiles, while phenylation of isoprene in the presence of piperidine gives 29% phenylated diene and 69% phenylated allylic amine (equation 30).84 Arylation occurs at the least-substituted and least-hindered terminal diene carbon and the amine attacks the least-hindered terminal ir-allyl carbon. If one of the terminal ir-allyl carbons is substituted with two methyl groups, however, then amine substitution takes place at this carbon. The reasons for this unexpected result are not clear but perhaps the intermediate reacts in a a- rather than a ir-form and the tertiary center is more accessible to the nucleophile. Primary amines have been used in this reaction also, but yields are only low to moderate.85 A cyclic version occurs with o-iodoaniline and isoprene.85... 

Vinyl substitutions on alkenes not having their double bonds conjugated with carbonyl groups often proceed more rapidly and give better product yields when the reactions are conducted in the presence of an unhindered secondary amine. Conjugated and nonconjugated dienes are usually only minor products in these cases. The major products normally are allylic amines obtained by nucleophilic attack of the secondary amine upon the ir-allylpalladium intermediates. Since allylic amines may be quatemized and subjected to the Hoffmann elimination, this is a two-step alternative to the direct vinyl substitution reaction.90... 

Palladium acetate triarylphosphine complexes catalyze the addition of vinylic groups from vinylic halides to olefinic compounds in the presence of amines. Conjugated dienes are major products from 0,/3-unsaturated acids, esters, or nitriles while unactivated olefinic compounds react best in the presence of secondary amines where allylic amines are major products. The reactions are usually regio- and stereospecific. The synthetic utility of the reaction is illustrated with a wide variety of examples. 

The choice as to which fragment of the molecule to be synthesized should be the vinylic halide and which should be the olefin will depend on several factors. In the cases where elimination to form conjugated dienes is the favored reaction, either possible combination of vinylic halide and olefin may produce the same diene however, different intermediates are involved and in some instances different products may be formed. The situation is more complex when allylic amines are produced since these products always will be different from the two different combinations of reactants. For example, Z-... 

It is interesting and of preparative value that although 1-bromo-2-methyl-l-propene and similar halides add to 1-hexene at both double-bond carbons, only one of the two 7r-allylic intermediates reacts with the amine. The result is that a mixture of six isomeric dienes is formed, but only one allylic amine is produced. Therefore the reaction is useful since the dienes and the amine are separated easily (2). 

Four-carbon-chain extensions have been very successful with conjugated dienes as the functionalized olefins. We have used a few other compounds also, but they are of limited value, such as N-3-butenylphthalimide. The last compound is only useful with aromatic or certain vinyl halides where mixtures of allylic amines would not be formed. A typical diene example is the reaction of vinyl bromide with butadiene and piperidine which gives E-N-(2,5-hexadienyl)-piper-idine in 70% yield (7). The product of this reaction can be reacted again and used to extend the carbon chains by six atoms (see below). The reactions of conjugated dienes can be used to produce conjugated trienes also (4). 

Intramolecular hydroamination of cyclohexa-2,5-dienes has afforded the corresponding bicyclic allylic amines with high selectivity (Scheme 13).80 The reaction does not proceed through a direct hydroamination of one of the diastereotopic alkenes but more likely involves a diastereoselective protonation of a pentadienyl anion, followed by addition of a lithium amide across the double bond of the resulting 1,3-diene and a highly regioselective protonation of the final allylic anion. 

The Bi(OTf)3-Cu(CH3CN)4PF6 system has been reported to promote efficiently an intermolecular 1 1 hydroamination of 1,3-dienes R1CH=CHCH=CHR2 with various carbamates, sulfonamides, and carboxamides to afford allylic amines in Markovnikov... 

Intramolecular hydroamination of cyclohexa-2,5-dienes (204) mediated by Bu"Li has been reported to produce the corresponding bicyclic allylic amines (205) with high... 

This palladium-catalyzed three-component coupling reaction leading to the formation of aryl-substituted allylic amines was recently adapted to solid-phase synthesis (Scheme 8.23). Amines were chosen to attach to a solid support (Rink resin) in this three-component coupling process and were reacted with a variety of aryl halides and linear or cyclic non-conjugated dienes, the reaction being carried out at 100 °C for two days in the presence of palladium acetate and diisopropylethyl-amine. A wide variety of aryl-substituted allylic amines were then obtained after cleavage from the solid support by trifluoroacetic acid [60],... 

When 1,2-diene (allene) derivative 60 is treated with aryl halide in the presence of Pd(0), the aryl group is introduced at the central carbon by the insertion of one of the allenic double bonds to form the 7i-allylpalladium intermediate 61, which is attacked by an amine to give the allylic amine 62. A good ligand for the reaction is dppe [30]. 

Allylic amines are difficult to cleave, but they can be cleaved by using a cationic Pd complex and DPPB as a ligand. As an example, N, /V-dicthylgcranylamine (348) is converted 349, and its regioselective dehydropalladation affords the myrcene-type conjugated diene 350, and the reaction is applied to commercial production of the fragrant compound 351, called kovanol [166]. 1,4-Elimination of allylic amines is also possible as their amine salts using AcOH as a solvent [167],... 

The basic Markovnikov selectivity pattern is partially or fully overrun in the presence of neighboring coordinating groups within the olefin substrate (Section 2.2.2). Known functionalities where inversed selectivity can occur include 3-alke-noylamides (e.g. 17 reacts to give a mixture of 18 and 19, Table 3) [43], homoallyl esters and alcohols, allyl ethers (but not necessarily allyl alcohols) [44], allyl amines, allyl amides, or carbamates (cf. 20 to 21) [45], allyl sulfides [46] or 1,5-dienes [47]. As a matter of fact, aldehyde by-products are quite normal in Wacker reactions, but tend to be overlooked. 

Several catalytic systems have been investigated for hydroamination of unsaturated bonds [16]. Takahashi et al. reported the telomerization of 1,3-dienes in the presence of an amine leading to octadienylamine or allylic amines when palladium catalysts are used in association with monodentate or bidentate phosphine ligands, respectively [17]. Dieck et al. demonstrated the beneficial effect of addition of an amine hydroiodic salt in the hydroamination reaction of 1,3-dienes in which the allylic amines are produced via an intermediate Jt-allyl palladium complex [18]. Coulson reported the Pd-catalyzed addition of amines to allenes where dimerization is incorporated [4]. This reaction presumably proceeds via a cyclic palladium intermediate in which the Pd activates the olefinic bond for nucleophilic attack the reactions are therefore different from pronucleophilic additions. 

But it is not this step that makes the synthesis remarkable, but rather Takasago s route focitronel lal. Pinene is another terpene that is produced in only low enantiomeric excess by pine trees (and indeed, which is the major enantiomer depends on whether it is a European or a North Americar pine tree). But in the menthol process none of this matters, and cheap, enantiomerically impure pinene can be used, because the first step is to convert it to an achiral terpene, myrcene. Lithium diethylamide adds to this diene to give an allylic amine. 

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