Imines with dienes

As in the case of Diels-Alder reactions, aqueous aza-Diels-Alder reactions are also catalyzed by various Lewis acids such as lanthanide triflates.113 Lanthanide triflate-catalyzed imino Diels-Alder reactions of imines with dienes or alkenes were developed. Three-component aza-Diels-Alder reactions, starting from aldehyde, aniline, and Danishefsky s diene, took place smoothly under the influence of HBL4 in aqueous media to afford dihydro-4-pyridone derivatives in high yields (Eq. 12.46).114... 

Enantiomerically pure pipecolic acid (6) is accessible essentially by two well-established synthetic routes (i) cyclization of l- or D-lysine by reaction with disodium nitrosyl-pentacyanoferrate(II) with preservation of configuration at C2 215 216 (ii) ring closure of A ,Ae-bis(A-nitroso-A-tosyl) derivatives of l- or D-lysine, again with retention of chirality at C2. 217 Stereoselective synthesis of pipecolic acid derivatives, substituted in position 4, is achieved using the aza-Diels-Alder reaction of imines with dienes 218-220 or via an ene-iminium cyclization. 221 222 ... 

Thus, a new type of Lewis acid, lanthanide triflates, is quite effective for the catalytic activation of imines, and has achieved imino Diels-Alder reactions of imines with dienes or alkenes. The unique reactivities of imines which work as both dienophiles and azadienes under certain conditions were also revealed. Three-component coupling reactions between aldehydes, amines, and dienes or alkenes were successfully carried out by using Ln(OTf)3 as catalysts to afford pyridine and quinoline derivatives in high yields. The triflates were stable and kept their activity even in the presence of water and amines. According to these reactions, many substituted pyridines and quinolines can be prepared directly from aldehydes, amines, and dienes or alkenes. A stepwise reaction mechanism in these reactions was suggested from the experimental results. 

Thus, this new type of Lewis acid, the Ln(OTf)3, is quite effective for the catalytic activation of imines, and has achieved aza Diels-Alder reactions of imines with dienes or alkenes. The unique reactivities of imines which work as both dienophiles and azadienes under certain conditions were also revealed. Three-component coupling reactions between... 

Danishefsky reported some years ago that acyclic, unactlvated imines undergo Lewis acid catalysed cycloaddition with siloxydienes to give six-membered nitrogen heterocycles. Two reports have now extended these observations to include the reaction of cyclic imines with dienes. Danishefsky s group has also described the cycloaddition of dihydro-B-carbolines with three siloxydienes to... 

The aza-Diels-Alder reaction of imines with diene of Danishefsky is an important route to 2,3-dihydro-4-pyridones. A number of Lewis acids have been used to catalyze the reaction in organic solvents. In water the reaction was realized by acid catalysis via iminium salts or by Bronsted acids. The montmorillonite K-10 catalyzed this cycloaddition in water or in aqueous acetonitrile in excellent yield. Recently Kobayashi has performed the reaction in water at room temperature under neutral conditions in two (imine - - diene) or three (aldehyde -b amine -b diene) component versions by using sodium triflate as catalyst. Imine intermediates from the indium-mediated reaction, in aqueous medium at 50° C, between aromatic nitro compounds and 2,3-dihydrofuran undergo aza-Diels-Alder cycloadditions to give tetrahydroquinoline derivatives in good overall yields. ... 

On the basis of these findings, the reaction of acyl imines with methanesulfony 1 chloride-triethylamine is not expected to proceed via a sulfene intermediate as previously proposed [99]. Again, a carbanion intermediate accounts nicely for the experimental facts. The electrophihcity of the hetero-l,3-diene is exdemely high, therefore the carbanion, formed on reaction of triethylamme with methanesulfonyl chloride, should undergo nucleophilic attack at C-4 of the hetero-1,3-diene faster than sulfene formabon by chloride elimination. 

Other advances include the construction of seven- and nine-membered rings via the analogous [4-1-3] and [6-1-3] cycloadditions with dienes and trienes respectively. Heterocycles, such as tetrahydrofurans and pyrrolidines, are accessible using carbonyl compounds and imines as substrates. The following discussion is organized around these recent discoveries. It serves to illustrate the versatility and the high degree of selectivity which are some of the distinctive features of the Pd-TMM chemistry. 

The assumed transition state for this reaction is shown in Scheme 5.5. The two bulky t-butoxy groups are expected to locate at the two apical positions. One of the 3,3 -phenyl groups would effectively shield one face of an imine, and consequently, a diene attacks from the opposite side. Judging from this model, similar selectivities were expected in the Mannich-type reactions of imines with silyl eno-lates. Actually, when ligand 10 was used in the reaction of imine la with S-ethyl-thio-l-trimethylsiloxyethene, the corresponding / -amino thioester was obtained in 84% ee (Scheme 5.6). As expected, the sense of the chiral induction in this case was the reverse of that observed when using catalyst 6 [12, 25]. 

The use of chiral bis(oxazoline) copper catalysts has also been often reported as an efficient and economic way to perform asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imines with conjugated dienes [81], with the main focus on the application of this methodology towards the preparation of biologically valuable synthons [82]. Only some representative examples are listed below. For example, the copper complex 54 (Scheme 26) has been successfully involved in the catalytic hetero Diels-Alder reaction of a substituted cyclohexadiene with ethyl glyoxylate [83], a key step in the total synthesis of (i )-dihydroactinidiolide (Scheme 30). 

In addition, the same group has used copper complexes of these ligands as efficient catalysts for enantioselective Cu-catalysed aza-Diels-Alder reactions of A-sulfonyl imines with Danishefsky s dienes, providing the corresponding six-membered heterocycles with enantioselectivities of up to 80% ee. ... 

Table 9 Ni-catalyzed homoallylation of 2-furfural-p-anisidine imine with a variety of dienes...

In this context, also mentionable are several publications by the groups of Dlaz-de-Villegas [242], Guarna [243], Kunz [244] and Waldmann [245], which describe the formation of six-membered azaheterocycles via treatment of an imine with an appropriate substituted diene. For instance, as described by Waldmann and coworkers, reaction of the enantiopure amino acid-derived imines 2-452 with Danishefsky s diene 2-453 in the presence of equimolar amounts of a Lewis acid provided diastereomeric enaminones 2-456 and 2-457 (Scheme 2.105) [245a]. 

Formation of nitrones can be achieved in the first stage of a Krohnke type reaction in which p-n trosodi methy 1 an dine reacts with 2-oo-bromoacetylphenoxathiin in alkaline medium (336). The synthesis of a series of cyclic nitrones of structure (182) has been achieved by regioselective, and by an unusual [3 + 2] cycloaddition of a-nitrosostyrenes (181) to 1,3-diazabuta-l,3-dienes (180) (Scheme 2.64) (337a). Theoretical studies of the substitution effect at the imine nitrogen on the competitive [3 + 2] and [4 + 2] mechanisms of cycloaddition of simple acyclic imines with nitrosoalkenes have been reported (337b). 

Ab initio calculations on aza-Diels-Alder reactions of electron-deficient imines with buta-l,3-diene show that these reactions are HOMO (diene)-LUMO(dienophile)-controlled and that electron-deficient imines should be more reactive than alkyl-or aryl-imines. The Diels-Alder reaction of r-butyl 2//-azirine-3-carboxylate (80) proceeds with high diastereoselectivity with electron-rich dienes (81) (Scheme 28). The hetero-Diels-Alder additions of imines with sterically demanding dienes yield perhydroquinolines bearing an angular methyl group. The asymmetric hetero-Diels-Alder reaction between alkenyloxazolines and isocyanates produces diastereometri-cally pure oxazolo[3,2-c]pyrimidines. °... 

The aza-Diels-Alder reaction is an important and versatile tool for the preparation of nitrogen-containing heterocycles present in numerous natural products and drug candidates. It involves the [4 + 2] cycloaddition of either an imine with an electron-rich diene or an azabutadiene with an electron-rich alkene (inverse electron demand). Catalytic asymmetric variants employing not only metal complexes, but also organic molecules were disclosed over the last few years. 

Although several Lewis acids are known to catalyze the hetero-Diels-Alder reaction involving imino-dienes or imino-dienophiles (aza-Diels-Alder reaction), a large amount of the catalyst is often necessary. Bi(0Tf)3-xH20 showed higher activity than lanthanide triflates in catalyzing the reactions of imines with Danishefsky s diene (Scheme 15) [72]. 

The reaction of aromatic imines with [Cp(PPh3)2Ru=C=C=C=CH2] gave two types of products, either l-azabuta-l,3-diene-2-ethynyl complexes or 4-ethynylquino-line complexes [52, 53]. The azabutadiene-2-ethynyl complexes were thought to be... 

The reaction of carbohydrate-derived imines with the Danishefsky diene, ( )-1 -methoxy-3-(trimethylsilyloxy)butadiene, to form heterocycles via the open-chain adducts (for assignment, see pp 456 and 478)130. 

Imines derived from aniline and glyoxylic acid esters can be regarded as electron-poor 2-azadienes, in which an aromatic carbon—carbon double bond takes part of the diene system. In this context, Prato and Scorrano et al. were able to achieve the [4 + 2] cycloaddition of ethyl N-phenyl glyoxylate imines with dihydrofuran and indene leading to hexahydrof-uro[3,2-c]- and tetrahydro-7//-indeno[2,l-c]quinolines, respectively, in moderate to good yields (88JHC1831). Similarly, tetrahydroquinoline derivatives were formed by [4 + 2] cycloaddition of 1,2-bis(trimethylsily-... 

Hetero-Diels-Alder reactions provide an attractive means of rapidly constructing complex heterocyclic ring systems. Cycloaddition of pyrazolyl imines with a variety of electron-deficient dienophiles has been used to assemble pyrazolo[3,4,1 ]pyridines in a focused microwave reactor under solvent-free conditions53. The reactions proceeded in modest to excellent yield, depending upon the choice of diene and dienophile (Scheme 3.32). 

Fig. 2.3 shows the core structures of the most important 1,3-dipoles, and what they are all called. As with dienes, they can have electron-donating or withdrawing substituents attached at any of the atoms with a hydrogen atom in the core structure, and these modify the reactivity and selectivity that the dipoles show for different dipolarophiles. Some of the dipoles are stable compounds like ozone and diazomethane, or, suitably substituted, like azides, nitrones, and nitrile oxides. Others, like the ylids, imines, and carbonyl oxides, are reactive intermediates that have to be made in situ. Fig. 2.4 shows some examples of some common 1,3-dipolar cycloadditions, and Fig. 2.5 illustrates two of the many ways in which unstable dipoles can be prepared. 

Cyclocondensation with imines. The diene (1) undergoes a similar [2 + 4] cycloaddition with imines, even nonactivated imines. Use of a three- or fourfold excess of the diene improves the yield of 5,6-dihydro-y-pyridones (equation l).4... 

OT w-2,6-Diaryl-4-piperidones were produced in a [4+2] cycloaddition reaction using aryl-iV-allylimines and a diene in the presence of Cu(OTf)2 in high yield and de (>99%) (Scheme 87) <2004TL4357>. Reaction of imines with /3,7-unsaturated a-bromoketenes yields dihydro-2-pyridones some of which were reacted with allylamines producing aziridines with 99% de in generally high yield <2004TL5031>. 

Binary regiocontrolled pentadienylation of imines with a pentadienyltin reagent has been achieved. While A-phenylimines affords e-adducts (1,3-dienes) exclusively under Lewis-acidic conditions, the combination of A-tosylimines and indium chloride or zinc chloride as a Lewis acid gives y-adducts (1,4-dienes) preferentially (Scheme 65).266... 

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