Imino-ene

Carbonyl- and imino-ene reactions were also catalyzed by the bis(oxazo-line)-copper complexes of ligands 6a, 6b and 11b supported on zeoHte Y (Scheme 13) [69]. The enantioselectivities obtained with the supported catalysts were similar or better than those obtained in homogeneous phase with the same ligands. Some relevant examples are shown in Table 12. 

In the presence of In powder 2-cycIohexen-l-one is converted by allyl iodide and Me3SiCI 14, in 63% yield, into the 1,4-addition product 2179 [84], which is also obtained in 73% yield by Sakurai 1,4-addition ofallyltrimethylsilane 82 to 2-cyclohexene-l-one in the presence of excess Me3SiCl 14 and catalytic amounts of InCl3 [85] (Scheme 13.25). Ytterbium] 111) triflate-catalyzed imino-ene reactions of N-tosylaldimines with a-methylstyrene are dramatically accelerated on addition of Me3SiCl 14 [85 a]. 

The imino-ene reaction has been recently reviewed thus, this work only consists of research done since that time.26 During the past decade there has been some expansion of the scope of the imino-ene reaction (vide infra) however, much of the work done in this area has involved its application to the synthesis of biologically relevant compounds (see Section 10.12.7). 

An enantioselective imino-ene reaction was developed by Lectka to provide ct-amino acid derivatives.27 Aryl alkenes (cr-methyl styrene, tetralene), aliphatic alkenes (methylene cyclohexane), and heteroatom-containing enes, all gave high yields and high ee s of the homoallylic amides (Equation (17)). The mechanism of this reaction has been proposed to proceed through a concerted pathway. This mechanism is evidenced by a large kinetic isotope effect observed in the transfer of H(D). 

Racemic fluorinated tryptophan derivatives 31 were obtained from 3-methylene indole 29 and fluorinated imines 30 using the imino-ene reaction (Equation (18)).28 The highest yields were obtained for the more electrophilic imines (R2 = SC>2Ph, Ts, SC Me). Moreover, these reactions took place at ambient temperature. 

Ytterbium triflate [Yb(OTf)3] combined with TMSG1 or TMSOTf are excellent reagents for the conversion of a-methyl styrene and tosyl-imines into homoallylic amides 32 (Equation (19)) (TMS = trimethylsilyl).29 These conditions produce the first examples of intermolecular imino-ene reactions with less reactive imines. Typically, glyoxalate imines are necessary. A comprehensive examination of the lanthanoid metal triflates was done and the activity was shown to directly correlate with the oxophilicity scale. The first report used preformed imines, and subsequently it was found that a three-component coupling reaction could be effected, bypassing the isolation of the intermediate imine.30 Particularly noteworthy was the successful participation of aliphatic aldehydes to yield homoallylic amines. 

Ketenimines have been observed to participate in imino-ene reactions.32 Conversion of 34 into 35 could be controlled by ortho-substitution on the aryl rings (Scheme 4). For example, if Ar = 2,6-(CH3)2-C6H3, only 35 was obtained in 70% yield and none of the [2 + 2]-cycloadduct 36 was observed. 

Weinreb et al86 have also studied the participation of allenes in imino-ene and carbonyl-ene reactions. Gycloisomerization of imine 133 in the presence of stannic chloride gave exclusively the m-substituted cyclopentyl isomer 135 (Scheme 27). The thermal imino-ene reaction of 136 was equally effective. More highly substituted... 

An intramolecular imino-ene reaction was used as the key step in the synthesis of the non-natural perhydrohis-trionicotoxin.90 The spirocycle 147 was obtained as a single diastereomer upon exposure of 145 to TiGl2(01Pr)2 (Scheme 31). The transition structure 146 was proposed to explain the high diastereoselectivity of this reaction. 

A stereospecific intramolecular imino-ene reaction was used by Weinreb and co-workers92 to provide the enantio-selective total syntheses of (-)-montanine, (-)-coccinine, and (-)-pancracine. Refluxing the imine resulting from the condensation of 151 and 152 in mesitylene produces the amine 153 (Scheme 33) as a single stereoisomer in 63% yield after removal of the silyl group from the alkyne. The high stereoselectivity is thought to arise from a concerted ene process. 

In conclusion, the ene reaction has undergone a synthetic renaissance with the advent of Lewis acid and transition metal-catalyzed protocols. The carbonyl-ene, imino-ene, and Alder-ene reactions have all experienced tremendous growth due to the mild conditions in which these reactions can be performed, the high functional group compatibility and high stereoselectivity. As a confirmation of the synthetic utility of the ene reaction, there are many applications to natural product synthesis, and some of these are highlighted in Section 10.12.6. Finally, it should be mentioned that these catalyzed ene reactions are still in their infancy, so much remains to be learned. 

Lectka and co-workers (252) subsequently extended this system to the catalysis of the imino ene reaction. This reaction proceeds in low conversion albeit good selectivity in dichloromethane. The optimal solvent proved to be benzotrifluoride (BTF), possessing solubility properties similar to dichloromethane while accelerating the rate of the ene reaction presumably due to its aromaticity. A variety of 1,1-disubstituted alkenes participated in the ene reaction, providing amino acid derivatives in high yields and selectivities (85-99% ee). Evidence for the concerted nature of this reaction was provided by a high primary kinetic isotope effect (ku/kr) = 4.4). 

The possibility of using C-nucleophiles in chiral ion pair catalysis encouraged us to investigate an enantioselective Brpnsted acid catalyzed imino ene reaction (Rueping et al. 2007a Scheme 5). The reaction consists of a new BINOL-phosphate catalyzed addition of methylene-hydrazines 22 to A-Boc-protected aldimines 23 to afford chiral amino-hydrazones 24. 

Imines behave like aldehydes. This imino-ene reaction has been reviewed [408,409]. The following examples (Eqs (164) [409] and (165) [413]) are intramolecular reactions of an aldimine and a ketimine. It should be noted that in the former reaction a small amount of the unusual product (benzimine, the right) was formed and that in the latter reaction the MOM ether was eliminated during the reaction. 

Weinreb, S. M. Synthetic applications of a novel pericyclic imino ene reaction of allenyi siianes. J. Heterocyd. Chem. 1996, 33, 1429-1436. 

The zeolite Y-supported, heterogeneous catalyst (54-CuHY) was also used by Hutchings et al. [61] for the enantioselective carbonyl- and imino-ene reactions. In a carbonyl-ene reaction of methylene cyclopentane with ethyl glyoxylate, the heterogeneous catalyst 54-CuHY exhibited superior enantioselectivity (93% ee) compared to the homogeneous catalyst 54-Cu(OTf)2 (57% ee) (Scheme 2.30), due to the confinement effect of the zeolite pores. 

Jia et al. [396] have recently disclosed an example of a solid-phase application of their ytterbium] 111) triflate-mediated cyclization of glyoxylate-derived unsaturated imines. Instead of the expected imino-ene products, the authors observed the sole formation of y-lactones, in good to high yields and with good trans stereoselectivity. An explanation of both the mechanism and the observed preferred trans selectivity was presented. The importance of using the lanthanide triflate in its hydrated form in order to fadhtate a catalytic process is also in accordance with the proposed mechanism, in which water plays a role in attacking the oxonium ion intermediate. 

Mukaiyama-aldol [45] (8.3) and Diels-Alder [46] (8.4) reactions. Lectka and coworkers [47] reported an efficient catalytic enantioselective imino-ene reaction using a copper catalyst in BTF (8.5), which gave better results in BTF compared to traditional solvents like THF or dichloromethane. They suggested that the aromatic character of BTF has a favorable influence for the enantiosel-ectivity. Trimethylaluminum and dimethylaluminum-perfluorophenolate were successfully used for the cleavage of acetals derived from C2-symmetric diols... 

Intramolecular imino ene reaction of an allenylsilane has recently been found to generate cyclohexyl systems with adjacent cis-amino and -alkynyl moieties. This enantioselective ene cyclization was developed for the enantio-selective total syntheses of (—)-montanine (338), (-)-coccinine (351), (-)-pancracine (339), and (-)-brunsvigine (356) (a formal total synthesis) by the same research group (181) (Schemes 40 and 41). A precursor allenylsilane-aldehyde 370 for the enantioselective ene cyclization was synthesized from scalemic epoxy alcohol 369 in nine steps. The allenylsilane-aldehyde 370 thus obtained reacted with A -triphenylphosphinyl-(2-bromo-4,5-methy-lenedioxy)phenylmethylimine in boiling mesitylene to lead to a cyclized product 371 in 63% yield after protodesilylation. Hydrogenation of 371... 

It was also discovered that these reactions can be conducted intramolecular-ly and that they remain stereospecific. For example, imino ene reaction of the N-sulfonyl imine derived from 246 produced two cis <5-lactones 248 and 250 as a 9 1 mixture (Scheme 44). The formation of the major (E)-product 248 can be rationalized by invoking the more favorable pericydic endo ene transition state 247. The minor (Z)-product 250 would arise from endo ene transition state 249, which suffers from A1,3 strain between the allylic methyl substituent and the cis vinyl hydrogen. Rather surprisingly, the Z -olefin isomer corresponding to 246 gave the same 9 1 mixture as did the E isomer. Based on the related loss of stereoselectivity with Z-2-butene (vide supra) it was again postulated that the... 

Z-alkene may be isomerizing to the E isomer prior to the imino ene cyclization. It was also reported that a y-lactone can be prepared stereospecifically by the imino ene procedure. Thus, thermolysis of 251 gave exclusively the cis product 253, presumably via N-tosyl aldimine 252 [Eq. (59)]. 

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