Allylic substitutions

Palladium-catalyzed allylic substitution may be regarded as a special case of cross-coupling with jr-allylpalladium complexes. First developed as a stoichiometric technique, this reaction was later realized in a catalytic mode, and became a valuable tool of organic synthesis, as it allows for a broad variation of both allylic substrates and nucleophiles. 

Pd(0) generated by the action of TPPTS may react in oxidative addition across the C-H bond of CH-acids, and the resulting hydridopalladium intermediate reacts with allylating agent with the formation of either a- or Jt-allyl-palladium intermediate. It is quite noteworthy that the use of aqueous solvent may help the formation of allylpalladium intermediate in an Snl-like process. 

The reaction with sterically unhindered primary amines and hydroxyl-amine often leads to bisallylation occurring with remarkable ease. Again note that hydroxylamine is used as the hydrochloride salt, and the liberation of hydrochloric acid must not have interfered with double allylation in near-quantitative yield  

Monoallylation of hydroxylamine can only be achieved with a diprotected derivative BocNH-OBoc. 

It is to be noted that allylic rearrangement occurs only in rare cases, one of which is the reaction of ethyl acetoacetate with butadiene monoepoxide  

To explain the stereochemistry of the allylic substitution reaction, a simple stereoelectronic model based on frontier molecular orbital considerations has been proposed (155, Fig. 6.2). Organocopper reagents, unlike C-nucleophiles, possess filled d-orbitals (d configuration), which can interact both with the 7t -(C=C) orbital at the y-carbon and to a minor extent with the o- -(C-X) orbital, as depicted 

When the non-coordinating mesitoate system 156 was treated with lithium di-methylcuprate, formation of the anti-S 2 substitution product 157 was observed. Notably, the exclusive formation of the y-substitution product is the result of severe steric hindrance at the a-position, originating from the adjacent isopropyl group [78]. Conversely, the corresponding carbamate 158 was reported, on treatment with a higher order cuprate, to form the syn-SN2 product 159 exclusively [74]. The lithi-ated carbamate is assumed to coordinate the cuprate reagent (see 160), which forces the syn attack and gives trans-menthene (159). 

6 Copper-mediated Diastereoselective Conjugate Addition and AHyiic Substitution Reactions 

As already noted, lower order cyanocuprates are more SN2 -selective reagents. On treatment with acetate 163, however, a mixture of the two regioisomers was obtained (entry 2) [81]. In addition, y-alkylation had taken place with ca. 25% loss of double bond configuration [82]. 

As a consequence of this model, it should be foreseeable that increasing allylic A strain - arising from employment of a Z alkene system, for example - should favor transition state 167 even more, giving higher levels of E selectivity for the 

Catalytic reactions of allylic electrophiles with carbon or heteroatom nucleophiles to form the products of formal S 2 or S 2 substitutions (Equation 20.1) are called catalytic allylic substitution reactions. Tliese reactions have become classic processes catalyzed by transition metal complexes and are often conducted in an asymmetric fashion. The aUylic electrophile is typically an allylic chloride, acetate, carbonate, or other t)q e of ester derived from an allylic alcohol. The nucleophile is most commonly a so-called soft nucleophile, such as the anion of a p-dicarbonyl compound, or it is a heteroatom nucleophile, such as an amine or the anion of an imide. The reactions with carbon nucleophiles are often called allylic alkylations. 

Much effort has been devoted to developing catalysts that control the enantioselectiv-ity of these substitution reactions, as well as the regioselectivity of reactions that proceed through unsymmetrical allylic intermediates. A majority of this effort has been spent on developing palladium complexes as catalysts. Increasingly, however, complexes of molybdenum, tungsten, ruthenium, rhodium, and iridium have been studied as catalysts for enantioselective and regioselective processes. In parallel with these studies of allylic substitution catalyzed by complexes of transition metals, studies on allylic substitution catalyzed by complexes of copper have been conducted. These reactions often occur to form products of Sj 2 substitution. As catalylic allylic substitution has been developed, this process has been applied in many different ways to the synthesis of natural products.  

Many transition metal complexes catalyse the reaction but palladium systems are the most widely used. Allylic substitution can be used to create C-C as well as C-X (X = heteroatom) bonds under very mild conditions, which are compatible with many functional groups. The allylic substitution reaction is unique in the sense that there are many mechanisms that can be responsible for asymmetric induction and because chiral elements can be placed at the nucleophile, the electrophile or both. 

After alkene coordination to Pd(0) species and ionisation, a Pd(II) 7t-allylic intermediate is formed. This intermediate undergoes nucleophilic attack at either terminal carbon. In special cases, the nucleophile can attack the central allylic position, leading to substituted cyclopropanes (see Section 8.10). 

The reaction was discovered more than 40 years ago, and since then a huge number of publications on allylic substitution have appeared. Some of them deal with P-stereogenic ligands. 

Treatment of allylic substrates ISO, possessing suitable leaving groups X in tlieir allylic positions, witli organocopper reagents may result eitlier in an S 2-type process fa-attack) or alternatively in an S 2 one fy-attack), giving tlie substitution products 151 and 152, respectively fSclieme G.30) [Ij]. 

2 [73]. To adiieve optimal orbital overlap, tlie fl- -orbital of tlie C X 

2 j tJ Coppe -medloteci Dloste eoselectlve Conjt gote Addition and Allylic tscib MagCujUt, EtaO M sCu,Lij. EtaO 

Scli ir 6.33. Different ctereochemical and regiochemical reciihc with acetate (— 157) and carbamate (—162) leaving grcpiipc on allylic cubctitution of 161 with a higher order methylcii prate. 

RSC Catalysis Series No. 2 Chiral Sulfur Ligands Asymmetric Catalysis By Helene Pellissier Helene Pellissier 2009 

L = mono- or bidentate ligand S = solvent or vacant LG = leaving group Nu = nucleophile 

In 2004, Shi et al. reported Pd-catalysed asymmetric allylic substitutions using axially chiral S/S- and S/O-heterodonor ligands based on the binaphthalene backbone. The test reaction was performed in the presence of 

The preparation of BINAP reported in 1980 has marked a landmark in asymmetric catalysis and has illustrated the peculiar stereorecognitive properties inherent with the axially chiral 1,1 -binaphthalene framework. Since then, a great deal of work has been devoted to the preparation of binaphthalene-templated ligands of related design. These efforts have resulted in the 

Since carbohydrates constitute an inexpensive and highly modular chiral source for preparing chiral ligands, Claver et al. have reported the use of a series of thioether-phosphite and thioether-phosphinite furanoside ligands in the test palladium-catalysed allylic substitution reaction. In the first type of ligand, a systematic variation of the donor group attached to the carbon atom C5 indicated that the presence of a bulky phosphite functionality had a positive effect on the enantioselectivity. Indeed, the enantioselectivity was controlled mainly by the phosphite moiety. This was confirmed by the use of a ligand 

---

Complete reactions are obtained by the combination of these unit exchanges into composite reactions. Figure 3-11 gives the example of an allylic substitution. 

Figure 3-11. Allylic substitution as a composite reaction in Hendrickson s scheme.

The allyl-substituted cyclopentadiene 122 was prepared by the reaction of cyclopentadiene anion with allylic acetates[83], Allyl chloride reacts with carbon nucleophiles without Pd catalyst, but sometimes Pd catalyst accelerates the reaction of allylic chlorides and gives higher selectivity. As an example, allylation of the anion of 6,6-dimethylfulvene 123 with allyl chloride proceeded regioselectively at the methyl group, yielding 124[84]. The uncatalyzed reaction was not selective. 

The lactone A was also used as starting material in the synthesis of the primary prostaglandins via an allylic substitution-semi-pinacolic rearrangement sequence (Ref. 2). 

Both conjugated and isolated dienes are usually accessible by extension of the methods suitable for mono-olefins. Allylic functions for ehmination may be produced by double bond introduction a to a functional group or by allylic substitution of an olefin. Both reduction of allylic systems to mono-olefins and elimination to give dienes, may involve rearrangement. 

Another useful modification of this reagent is the reaction of CF3CCI3 with zinc and DMF in the presence of AICI3 [60, 63] (equation 53). The alcohol product can be treated subsequently with DAST, thionyl chloride, or phosphorus chlorides to afford the allyl substitution product regio- and stereoselectively [66] (equation 54). 

Wlien tlie diiral molybdenum -K-allyl-substituted enone 147 was treated witli litliium dimetliylciiptate, formation of adduct 148 witli fait selectivity was observed tSdieme 6.29) [69], Interestingly, bigber selectivities were obtained in tlie presetice of boron ttlbuotlde etlierate. It is assumed tliat Lewis acid coordination induces tlie s-trans reactive conformation 149 [64], Consequently, nudeopb de attack anti to tlie molybdetiLim ftagmetit sbould afford tlie major diastereomer 148. 

To acliieve diastereoselectivity in tlie course of allylic substitution, tlie cnnitoliing cliital inforniation may not only reside in tlie substtate skeleton but may also be pan of tlie allylic leaving group. Tlius, a cliital carbamate bas been developed as a... 

Depending on the substrate and the other reaction parameters, very higli re-gioselectivilies towards either a or y suhstilution can he obtained. In cetLain cases, the regioselectivity can easily he switclied between the two modes by changing the reaction conditions [11]. Compared to, for example, palladiumiO)-catalyzed allylic substitution reactions, the possibility of switching between S j2 and S j2 selectivity... 

S ]2 -selective reactions between primary allylic substrates and otganocoppet reagents testiU in the creation of new Chirality in previously aChital molecules, and it is tempting to try to take advantage of this for the development of enantioselective allylic substitution reactions. 

Denniatk and co-wotkets teporied tlie brst example in 1990 [16], using substrates 1, s7ntliesized Grom adiital allylic alcohols and tead dy ava dable optically active amine auxdiaries. Substrates 1 were tlien employed in coppet-niediaied allylic substitution reactions, as shown in Sdienie 8.4. 

A result equivalent to an allylic substitution reaction with a chiral leaving group can also be achieved by a two-step procedure involving a conjugate addition reaction and a subsequent elimination reaction, as demonstrated by Tamura et al., wbo studied the reaction shown in Scheme 8.15 [27]. 

Hie use of tlie cliiral catalyst 19b for asymmetric allylic substitution of allylic substrates bas been studied in some deta d fSdieme 8.18) and, under ji-selective reaction conditions, asymmetric induction was indeed obtained [28, 34]. 

It may be concluded from die different examples sliown here tiiat die enantio-selective copper-catalyzed allylic substitution reaction needs ftirdier improvemetiL High enantioselectivities can be obtained if diirality is present in tiie leaving group of die substrate, but widi external diiral ligands, enantioselectivities in excess of 9096 ee have only been obtained in one system, limited to die introduction of die sterically hindered neopeatyl group. 

Nabilone (37) is a synthetic 9-ketocannabinoid with antiemetic properties. One of the best of the various published routes to nabilone starts with the enolacetate of nopinone (33), which on short heating with lead tetraacetate undergoes allylic substitution to give Treatment with p-toluene-... 

Allyl Substitution using Trialkyl- or Triaryltin Reagents... 

A variety of routes are available for the preparation of allylsilanes (/) with the simplest and most direct being the silylation of allyl-metal species. Other routes exemplified in this chapter include Wittig methodology, the use of silyl anions/anionoids in allylic substitution, and hydrometallation of... 

Nanaomycin A 103 and deoxyfrenolicin 108 are members of a group of naphthoquinone antibiotics based on the isochroman skeleton. The therapeutic potential of these natural products has attracted considerable attention, and different approaches towards their synthesis have been reported [65,66]. The key step in the total synthesis of racemic nanaomycin A 103 is the chemo-and regioselective benzannulation reaction of carbene complex 101 and allylacety-lene 100 to give allyl-substituted naphthoquinone 102 after oxidative workup in 52% yield [65] (Scheme 47). The allyl functionality is crucial for a subsequent intramolecular alkoxycarbonylation to build up the isochroman structure. However, modest yields and the long sequence required to introduce the... 

The other bromine atom comes from another bromine-containing molecule or ion. This is clearly not a problem in reactions with benzylic species since the benzene ring is not prone to such addition reactions. If the concentration is sufficiently low, there is a low probability that the proper species will be in the vicinity once the intermediate forms. The intermediate in either case reverts to the initial species and the allylic substitution competes successfully. If this is true, it should be possible to brominate an alkene in the allylic position without competition from addition, even in the absence of NBS or a similar compound, if a very low concentration of bromine is used and if the HBr is removed as it is formed so that it is not available to complete the addition step. This has indeed been demonstrated. ... 

Alkynes react with indium reagents such as (allyl)3ln2l3 to form dienes (allyl substituted alkenes from the alkyne). Allyltin reagents add to alkynes in a similar manner in the presence of ZrCU Alkylzinc reagents add to alkynes to give substituted alkenes in the presence of a palladium catalyst. ... 

Allylic silanes react with aldehydes, in the presence of Lewis acids, to give an allyl-substituted alcohol. In the case of benzylic silanes, this addition reaction has been induced with Mg(C104)2 under photochemical conditions. The addition of chiral additives leads to the alcohol with good asymmetric induction. In a related reaction, allylic silanes react with acyl halides to produce the corresponding carbonyl derivative. The reaction of phenyl chloroformate, trimethylallylsilane, and AICI3, for example, gave phenyl but-3-enoate. ... 

Yamano T, Taya N, Kawada M, Huang T, Imamoto T (1999) Tetrahedron Lett 40 2577 Brunner H, Nishiyama H, Itoh K (1993) Asymmetric hydrosilylation. In Ojima I (ed) Catalytic asymmetric synthesis. Wiley-VCH, New York, chap 6 Sawamura M, Kuwano R, Ito Y (1994) Angew Chem, Int Ed Engl 33 111 Kuwano R, Uemura T, Saitoh M, Ito Y (1999) Tetrahedron Lett 40 1327 Hayashi T (1993) Asymmetric allylic substitution and grignard cross-coupling. In Ojima I (ed) Catalytic asymmetric synthesis. WUey-VCH, New York, chap 7-1 Trost BM, Vranken DLV (1996) Chem Rev 96 395 Consiglio G,Waymouth RM (1989) Chem Rev 89 257... 

---