Amines homoallylic, formation

Whereas THF and DME were suitable solvents, Lewis basic additives such as HMPA, DMSO or TMEDA hampered the reaction.82 These results point towards an intramolecular assistance of the zinc coordinated by the nitrogen atom. A related effect was evidenced in the additions of Grignard reagents to allylic alcohols83-87. Two mechanisms were proposed for the allylzincation of homoallylic amines involving formation of a complex with the... 

Scheme 1). Introduction of a jt bond into the molecular structure of 1 furnishes homoallylic amine 2 and satisfies the structural prerequisite for an aza-Prins transform.4 Thus, disconnection of the bond between C-2 and C-3 affords intermediate 3 as a viable precursor. In the forward sense, a cation ji-type cyclization, or aza-Prins reaction, could achieve the formation of the C2-C3 bond and complete the assembly of the complex pentacyclic skeleton of the target molecule (1). Reduction of the residual n bond in 2, hydro-genolysis of the benzyl ether, and adjustment of the oxidation state at the side-chain terminus would then complete the synthesis of 1. 

The addition of allylboronates 1 to the chiral oxime 2 results in the formation of a hydroxyl-amine. This is a general method for the subsequent reductive generation of primary homoallyl-amines, but with poor diastereoselectivity in the case of 3 and 4. A diastereomeric ratio of 90 10 is achieved in the addition reaction, using the chiral allylboronate 59 (double stcrcodifferenti-ation). 

Homoallylic amine formation resulting from a change in the mode of addition of reagents. 

The approach to polyketide synthesis described in Scheme 5.2 requires the relatively nontrivial synthesis of acid-sensitive enol acetals 1. An alternative can be envisioned wherein hemiacetals derived from homoallylic alcohols and aldehydes undergo dia-stereoselective oxymercuration. Transmetallation to rhodium could then intercept the hydroformylation pathway and lead to formylation to produce aldehydes 2. This proposal has been reduced to practice as shown in Scheme 5.6. For example, Yb(OTf)3-cata-lyzed oxymercuration of the illustrated homoallyhc alcohol provided organomercurial 14 [6]. Rhodium(l)-catalyzed hydroformylation of 14 proved successful, giving aldehyde 15, but was highly dependent on the use of exactly 0.5 equiv of DABCO as an additive [7]. Several other amines and diamines were examined with variation of the stoichiometry and none proved nearly as effective in promoting the reaction. This remarkable effect has been ascribed to the facilitation of transmetallation by formation of a 2 1 R-HgCl DABCO complex and the unique properties of DABCO when both amines are complexed/protonated. 

Reaction of a homoallylic Grignard reagent with la resulted in formation of the expected amine as well as the amination product of the rearranged Grignard reagent . 

In summary, we have found that allylation of in situ prepared imines proceeds smoothly with allyltrimethylsilane and a catalytic amount of Bi(0Tf)3-4H20. This method offers several advantages including mild reaction conditions, low quantity of the catalyst (1 mol%), and no formation of by-products. Moreover, our protocol does not require prior isolation of the imine. The homoallylic amine is directly obtained as a Cbz-protected group in a one-pot process. 

We were particularly interested to see whether a regio- and stereoselective hy-droxyalkylation and amrnoalkylation of 1 and 2 with aldehydes and imino esters, perhaps by choice of the substituent X at the Ti atom, with formation of the corresponding sulfonimidoyl-substituted homoallyl alcohols 4-7 and the homoallyl amines 8-11 (Fig. 1.3.3) could be achieved. Reggelin et al. had already demonstrated that the sulfonimidoyl-substituted mono(allyl)titanium complexes 3, the... 

Solvolytic rearrangement of formic acid gave quantitatively the most stable product of the homoallyl rearrangement, e.vu-bicyclo[3.2.1]oct-2-en-7-yl formate (10). In 70% aqueous dioxane buffered with triethyl-amine at 80°C, the same tricyclic dinitrobenzoate 9 furnished a mixture of 78% tricy-clo[3.2.1.02 7]octan-3-ol (11) and 22% c.w-bicyclo[3.2.1]oct-2-en-7-ol (12).21... 

When either an alcohol or an amine function is present in the alkene, the possibility for lactone or lactam formation exists. Cobalt or rhodium catalysts convert 2,2-dimethyl-3-buten-l-ol to 2,3,3-trimethyl- y-butyrolactone, with minor amounts of the 8-lactone being formed (equation 51).2 In this case, isomerization of the double bond is not possible. The reaction of allyl alcohols catalyzed by cobalt or rhodium is carried out under reaction conditions that are severe, so isomerization to propanal occurs rapidly. Running the reaction in acetonitrile provides a 60% yield of lactone, while a rhodium carbonyl catalyst in the presence of an amine gives butane-1,4-diol in 60-70% (equation 52).8 A mild method of converting allyl and homoallyl alcohols to lactones utilizes the palladium chloride/copper chloride catalyst system (Table 6).79,82 83... 

The conventional procedure for the synthesis of homoallylic amines involves the allylboration of imines (generated in situ from the partial reduction of expensive and toxic nitriles). Recently, a practical and operationally simple protocol has been developed for the stereoselective formation of homoallylic amines starting directly from the... 

An asymmetric version of aminoallylation has been developed via a transfer aminoallylation protocol. This methodology involves the initial aminoallylation of camphorquinone 207 with 5-allylpinacol boronate 177 in alcoholic ammonia, furnishing the a-aminoketone 208 stereoselectively, which upon treatment with an aldehyde 209 and achiral allyl boronate 177 leads to the in situ formation of chiral imine 210 followed by allylation to yield the homoallylic amines 212 (Scheme 35) <2006JA11038>. Excellent levels of enantio- and diastereo control were observed for the allylation of a wide array of aldehyde substrates. 

A regio- and stereoselective formation of homoallylic alcohols and amines has been realized by the reaction of easily available allylic acetates 213 and 217 with bispinacolatodiboron 149 in the presence of palladium catalysts followed by the addition of aldehydes/imines (Scheme 36) <2005EJO2539>. The mechanism involves the formation of an 7]3-allyl-Pd complex, which inserts between B-B bond, and subsequent reductive elimination to yield the allyl... 

Synthesis of homoallylic amines has been reported by a three-component coupling of aldimines, diiodomethane, and alkenylzirconocenes, in the presence of dimethylzinc (Scheme 28).296,296a The formation of homoallylic products is rationalized by the mechanism shown in Scheme 29. The //////-relationship of the final product is explained by a cyclic chair-like transition state. This type of homologation was used to form f, -dicyclop ropy I ruethylamines by a double C,C-cr-bond insertion into bicyclobutanes (Scheme 30).297 During the course of this cascade process, 10 C,C-bonds are formed, and the final product is isolated in one step with a high diastereoselectivity. 

The allylation of imines with allylindium reagents in organic solvents gives the corresponding homoallylic amines.251-253 Under solvent-free conditions, the indium-mediated reaction of iV-benzylideneaniline furnishes a mixture of mono-allylated 79 and bis-allylated products 80 (Equation (56)). The bis-allylated product 80 presumably arises via a formation of an iminium salt, which is subsequently attacked by the allylindium nucleophiles. Formation of 80 is entirely suppressed by addition of allyl bromide to indium metal prior to any addition of the imine (Grignard-type reaction).254... 

Allylation of aldimines and sulfonimines with indium powder in poly(propylene) glycol (MW 1000), a benign and recyclable reaction medium, results in the formation of the corresponding homoallylic amines and sulfonamides in high yields (Equation (62)).265... 

When a bis-homoallylic amine containing a nucleophilic ester group 5 undergoes iodocycliza-tion, formation of a frara.v-2,5-disubstituted pyrrolidine ring is favored, followed by conversion of the iodoamine to an aziridine. The intramolecular capture of the intermediate aziridinium salt by participation of the proximate ester results in a net retention of carbon configuration and total stereoselectivity123. 

Asymmetric selenoxide elimination of the optically active vinyl selenoxides affords optically active allenes and cyclohexylidenes. On the other hand, asymmetric [2,3]sigmatropic rearrangement of allylic selenoxides, selenimides, and selenium ylides leads to the formation of the corresponding optically active allylic alcohols, amines, and homoallylic selenides, respectively. 

Azo-ene reactions. The ene reaction provides a powerful method for C-C bond formation with concomitant activation of an allylic C-H bond. A variety of functionalized carbon skeletons can be constructed due to the range of enophiles which can be used. For example, carbonyl compounds give homoallylic alcohols and imino derivatives of aldehydes afford homoallylic amines. The azo-ene reaction offers a method for effecting allylic amination by treatment of an alkene with an azo-diester to afford a diacyl hydrazine which upon N-N cleavage furnishes a carbamate. Subsequent hydrolysis of the carbamate provides an allylic amine. Use of chiral diazenedicarboxylates provides a method for effecting stereoselective electrophilic amination. 

Three-component reactions of aldehydes, amines, and allyltributyltin also proceeded smoothly in micellar systems with Sc(OTf)3 as Lewis acid catalyst, to afford the corresponding homoallylic amines in high yields (Eq. 19) [68]. Not only aromatic aldehydes but also aliphatic, unsaturated, and heterocyclic aldehydes worked well. The procedure is very simple—merely mixing an aldehyde, an amine, and allyltributyltin in the presence of Sc(OTf)3 and SDS in water no homoallylic alcohol (an adduct between an aldehyde and allyltributyltin) was produced. It was suggested that imine formation from aldehydes and amines was very fast under these conditions, and that the selective activation of imines rather than aldehydes was achieved. 

The regio- and stereoselective zirconocene-catalyzed addition of alkylmagnesium halides to alkenes, a process which has been described previously (see Section 7.5.2, Scheme 7-79) was investigated with ethylene-l,2-bis( M,5,6,7-tetrahydroind-l-enyl)zirconium dichloride [(EBTHI)ZrCl2l) [118] as chiral zirconocene. Thus, treatment of the latter with alkylmagnesium halides leads to the formation of the derived zirconocene-alkene complex 88, characterized by NMR [119], which reacts with cyclic ethers or amines to lead to the corresponding homoallylic alcohol or amine, respectively, in > 95% ee and good overall yield [120] (Scheme 7-103). 

In combination with the incremental advances concerning reaction conditions in recent years, especially for low-pressure carbonylations, there is a trend toward increasing use of this chemistry to synthesize advanced building blocks. In this respect carboxylation of alkenes with an appropriate alcohol or amine function leads to the formation of lactones or lactams. Thus, cobalt, rhodium, or palladium chloride/copper chloride catalysts convert allyl and homoallyl alcohols or amines to the corresponding butyrolactones or butyrolactams, respectively [15]. 

More unexpected was the formation of cyclopropane during the indium-mediated reaction of dibenzylidene acetone with allyl bromide which gave l,l-distyryl-2-(but-3-enyl)cyclopropane as a mixture of four isotopomers (Scheme 31) [158]. In a related reaction, a simple and efficient one-pot method was developed to give chiral homoallylic amines and amino acids from the respective aldehydes with high stereoselectivity [159]. 

Another series of -alkyl-metal complexes that owe their stabilities to the formation of a five-membered chelate ring is those produced in the reaction of allylic and, homoallylic amine and sulfide complexes of Pd(II) with nucleophiles. Lithium tetra-chloropalladate reacts with N,N-dimethylallylamine in methanol to produce the methoxy- kalkylPd complex ... 

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