Allylation of imines

Enamines derived from ketones are allylated[79]. The intramolecular asymmetric allylation (chirality transfer) of cyclohexanone via its 5-proline ally ester enamine 120 proceeds to give o-allylcyclohexanone (121) with 98% ee[80,8l]. Low ee was observed in intermolecular allylation. Similarly, the asymmetric allylation of imines and hydrazones of aldehydes and ketones has been carried out[82]. 

More recently, catalytic asymmetric allylations of imines and imine derivatives in aqueous media have been studied. An /V-spiro C2-symmetrical chiral quaternary ammonium salt (5,5)-I-Br (,S, .S )-()-Np-NAS-Br] has been evaluated in the allylation of glycine tert-Bu ester benzophenone Schiff base [Ph2C=NCH2COOCMe3] for synthesis of both natural and unnatural a-amino acids (Eq. 11,45).76... 

Catalytic amounts of I fCl4-AgC104 and Hf(OTf)4 are used for activation of acid halides and acid anhydrides for Friedel -Crafts acylation (Scheme 42) 178 the reactions of both reactive and unreactive aromatic substrates proceed smoothly in the presence of Hf(OTf)4. Furthermore, the Fries rearrangement179,180 and direct C-acylation of phenolic compounds181,182 take place using Hf(OTf)4. Formation of esters and Mannich-type reactions and allylation of imines have been also reported.152... 

Table 3 Allylation of imines with allylytterbium bromide...

These authors also found that the addition of excess MgO during the in situ preparation of allyltantalum species improved reaction outcomes, even allowing for the first example of allylation of imines derived from aliphatic amines and aliphatic aldehydes (prepared in situ at room temperature in the presence of molecular sieves) (Equation (18)). The selective addition to imines permitted three-component reactions. 

Accordingly, chiral 7r-allylpalladium complex 204 was found to catalyze enantioselective allylation of imines with good to high selectivity (Equation (98)).4S7c 457e 457g 4S71... 

The first example of allylation of imines using dialkyl 2-allyl-l, 3-dioxaborolane-4,5-dicarboxylates 110 or fi-allyldiisopinocamphcnyl borane 154 was reported in 1995." After hydrolysis of the reaction product, homoallyl primary amine was obtained in 54-90% yield and up to 73% ee (Scheme 3-52). 

Allylation of imines using this type of reagent has been extensively studied, and this transformation has become important for the synthesis of acyclic and cyclic amine derivatives. 

Nakamura et al.100 found that in the presence of palladium catalysts imines undergo allylation readily, providing the corresponding homoallylamines with high yields. Thus, chiral palladium complex 157 has been synthesized and applied in the asymmetric allylation of imines using allyl tributyltin as the allylation reagent. In Scheme 3-54, moderate yield and up to 82% ee have been obtained with 157 as the chiral catalyst.101... 

Park et al.102 demonstrated an interesting intramolecular asymmetric allylation of imine based on a substrate-controlled mode. 

This chapter has introduced the aldol and related allylation reactions of carbonyl compounds, the allylation of imine compounds, and Mannich-type reactions. Double asymmetric synthesis creates two chiral centers in one step and is regarded as one of the most efficient synthetic strategies in organic synthesis. The aldol and related reactions discussed in this chapter are very important reactions in organic synthesis because the reaction products constitute the backbone of many important antibiotics, anticancer drugs, and other bioactive molecules. Indeed, study of the aldol reaction is still actively pursued in order to improve reaction conditions, enhance stereoselectivity, and widen the scope of applicability of this type of reaction. 

Scheme 151 Barbier-type allylation of imines with electrogenerated lead(O).

A new electrolysis system comprising two metal redox couples, Bi(0)/Bi(III) and A1(0)/A1(III), has been shown to be effective for electroreductive Barbier-type allylation of imines [533]. The electrode surface structure has been correlated with the activity towards the electroreduction of hydrogen peroxide for Bi monolayers on Au(III) [578], Electroreductive cycliza-tion of the 4-(phenylsulfonylthio)azetidin-2-one derivative (502) as well as the allenecarboxylate (505) leading to the corresponding cycKzed compounds (504) and (506) has been achieved with the aid of bimetallic metal salt/metal redox systems, for example, BiCh/Sn and BiCh /Zn (Scheme 175) [579]. The electrolysis of (502) is carried out in a DMF-BiCh/Py-(Sn/Sn) system in an undivided cell by changing the current direction every 30 s, giving the product (504)in 67% yield. 

A combination of dissolving aluminium and titanium tetrachloride in tetrahycko-furan promotes the allylation of imines. Here titanium is reduced to titaniumfo),... 

In 1998, Yamamoto et al. reported the first catalytic enantioselective allylation of imines with allyltributylstannane in the presence of a chiral 7i-allylpalladium complex 23 (Scheme 9) [15]. The imines derived from aromatic aldehydes underwent the allylation with high ee values. Unfortunately, the allylation reaction of aliphatic imines resulted in modest enantioselectivities. They proposed that a bis-Jt-allylpalladium complex is a reactive intermediate for the allylation and reacts with imines as a nucleophile. The bis-Jt-allylpalladium complex seemed the most likely candidate for the Stille coupling [16]. Indeed, the Stille coupling reaction takes place in the presence of triphenylphosphine even if imines are present, whereas the allylation of imines occurs in the absence of the phosphine [17]. They suggested the phosphine ligand played a key role in controlling the... 

Kobayashi and colleagues developed a catalytic enantioselective method for the allylation of imines 24 by substituted allylstannanes 25 with chiral zirconium catalysts 26 and 27 prepared from zirconium alkoxides and l,l -bi-2-naph-thol derivatives (Scheme 10) [19]. The allylation of aromatic imines 24 with 25 afforded the corresponding homoallylic amines 28 in good yields (71-85%) with high stereoselectivities (87-99% ee). 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

Allylation of imines.1 A low-valent Ti(0) species generated by reduction of TiCl4 with aluminum foil in THF can effect allylation of imines with allyl bromide, even when used in catalytic amounts (0.05 equiv.). This combination of a catalytic amount of TiCU with 1 equiv. of aluminum presumably generates Al(III) and Ti(0), which reacts with the allyl halide to form an allyltitanium, the reactive species. 

In this chapter, recent applications of (W)-phcnylglycine amide (1) in asymmetric synthesis are presented (Figure 25.2). The first section deals with diastereoselective Strecker reactions for the preparation of a-amino acids and derivatives, whereas the second section focuses on diastereoselective allylation of imines for preparation of enantiomerically pure homoallylamines. This latter class of compounds is a well-known intermediate for the synthesis of, for example, many types of amines, amino alcohols, and P-amino acids. The final section describes reduction of imines providing enantiomerically pure amines. (S)-3,3-Dimethyl-2-butylamine and (S)-l-aminoindane will be presented as leading examples. The results described in this chapter originate from a longstanding cooperation in the field of chiral technology development between DSM Pharma Chemicals and Syncom B.V. 

Chiral homoallylamines are valuable intermediates for the preparation of compounds such as amines, P-amino acids, 1-amino-3,4-epoxides, and 1,3-amino alcohols.24 High 1,3-asymmetric induction has been achieved during the allylation of imines derived from chiral auxiliaries such as P-amino alcohols and a-amino acid esters.25 Drawbacks of these methods are the limited availability... 

Intramolecular allylation of imines with allylsilanes is useful for the synthesis of substituted piperidines.123... 

The first catalytic asymmetric allylation of imines has been reported using allyltri- -butyltin in the presence of a chiral 7r-allylpalladium complex.179 Zirconium is also demonstrated as a metal center for the design of chiral Lewis acid catalysts that are suitable for the activation of bidentate imino compounds.180 Jprgensen reports high enantio-selective allylation of ct-imino esters (Equation (52)).181... 

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... 

Diastereoselective Barbier-type allylation of chiral imines bearing a hydroxyl group on the chiral auxiliary has been achieved in DMF (Equation (59)).257-259 The chelation between the nitrogen and the hydroxyl group of the imine with indium is crucial for the high stereoselectivity. The palladium-catalyzed indium-mediated allylation of imines also proceeds well with Ini prepared in situ from In and I2.259... 

PPG 425 has been used in the preparation of a range of benzaldehydes that were subsequently used in the solvent free synthesis of calix[4]resorcinarenes. The aldehydes are isolated in near quantitative yields by distillation from the PPG, which can be recycled. PPG has also been used in the indium metal mediated allylation of imines and sulfonylimines. Ultrasound was used for two reasons to clean the metal surface and to increase the solubility of the imine in PPG. The solvent was recycled three times, but a desire to develop an easier drying and recycling method was indicated. 

Although allylation of imines with allylsilanes is encountered less frequently, that with allylstannanes seems more common, probably because of the enhanced nucleo-philicity of the tin reagent compared with the silyl counterpart. Equations (109) [292] and (110) [293,294] illustrate the allylation of imines. In the former reaction, a catalytic amount of the L wis acid, TiCl(OTf)3, is sufficient to bring the reaction to completion. Intramolecular allylation of imines [295] or hydrazones [296] led to the stereoselective construction of amino-cyclic structures, as shown in Eq. (HI) [296]. 

Hf(OTf)4 [or Zr(OTf)4] also acts as a catalyst in the allylation of imines with allyltri-butylstannane (Eq. 19) [23], Extension to the three-eomponent condensation of aldehyde, amine, and allyltin was made possible by use of these catalysts in the presence of a dehydrating agent, MgS04 (Eq. 20). Other Lewis acids were ineffective, because they deeompose or become deactivated by the amine and/or the water produced during imine formation. 

Asymmetric intramolecular allylation of imine 39, with a chiral auxiliary on the imino nitrogen, was attempted with 2 equiv. Lewis acids (Eq. 17) [18]. When ZrCU was employed as a Lewis acid, of four possible diastereomers of /3-aminotetrahydro-furan (40), the only isomer obtained was that with trans substituents on the tetrahy-dropyran ring. 

Sc(OTf)3 promoted allylation reactions of carbonyl compounds were reported, (a) Tetraallylger-manium T. Akiyama, J. Iwai, Tetrahedron Lett. 1997, 38, 853-856. (b) Allyltrimethylsilane V. K. Aggarwal, G. P. Vennall, Tetrahedron Lett. 1996,37, 3745-3746. Sc(OTf)3 is also an effective catalyst for the allylation of imines with allyltributyltin. (c) C. Bellucci, P. G. Cozzi, A. Umani-Ronchi, Tetrahedron Lett. 1995,36,7289-1292. 

Chiral allylation of imines by an allylstannane is promoted by a bis-Ji-allylpalladium complex based on the pinane skeleton, while using triallylborane to supply the allyl group a polymer-supported arenesulfonaminoisobomeol can provide a proper environment. The chirality of alkenyl sulfoxides imposes the approach of methyl lithioacetate, and therefore it enables the generation of optically active P-amino acids. ... 

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