Reactions of 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... 

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. ... 

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]. 

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]. 

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>. 

The Brpnsted acid-assisted chiral Lewis acid (BLA) 28, prepared from a 1 2 molar ratio mixture of a trialkylborate and optically pure binaphthol, is also an excellent chiral promoter for the aza Diels-Alder reaction of imines with Danishefsky dienes (Eqs 44 and 45). Enantioselectivity and double diastereodifferentiation in reactions employing chiral 28 are slightly better than those using chiral 27 [41]. 

A general synthesis of 3,5-disubstituted pyridines is based on the uncatalysed thermal reaction of imines with enamines which yields 1-aza-1,3-dienes. The dienes afford the pyridines by a further reaction with the same or a different enamine. For example, methylene A- -butylimine (304) and 1-piperidinobutene give the diene 307, accompanied by 3,5-diethylpyridine (309 = Et) Heating the diene with 1-piperidinopropene gives... 

A review of formal aza-Diels-Alder reactions of imines with e-rich dienes and enones, in the presence of Lewis acids/Brpnsted acids/organocatalysts, has been presented. Bifunctional A-acyl aminophosphine catalysts (75) are effective asymmetric organocatalysts in the hetero-4- -2-cycloaddition of a-substituted allenoates with tosylaldimines to produce optically active tetrahydropyridines. The Brpnsted acid-catalysed aza-Diels-Alder reactions of cyclopentadiene with iminoacetates possessing two chiral auxiliaries yielded 2-azabicyclo[2.2.1]hept-5-ene cycloadducts with high exo-selectivities. ... 

Thus, we have developed catalytic asymmetric aza Diels-Alder reactions of imines with alkenes using a chiral lanthanide Lewis acid, to afford 8-hydroxyquinoline derivatives in high yields with high diastereo- and enan-tioselectivities. The characteristic points of this reaction are as follows, (i) Asymmetric aza Diels-Alder reactions between achiral azadienes and dienophiles have been achieved using a catalytic amount of a chiral source, (ii) The unique reaction pathway, in which the chiral Lewis acid activates not dienophiles but dienes, is revealed. In most asymmetric Diels-Alder reactions reported using chiral Lewis acids, the Lewis acids activate dienophiles [64, 65]. However, inverse electron-demand asymmetric Diels-Alder reactions of 2-pyrone derivatives have been reported [72]. (iii) A unique lanthanide complex including an azadiene and an additive, which is quite different from the conventional chiral Lewis acids, has been developed. 

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. 

Polymer-supported BINOLs thus prepared were treated with Zr(Ot-Bu)4 to form polymer-supported zirconium 20. In the presence of 20 mol% of various zirconium 20, the model aza Diels-Alder reactions of imine Id with Danishefsky s diene (7a) were performed results from selected examples are shown in Table 5.8. Whereas the 4-t-butylphenyl group resulted in lower enantiomeric excess (ee), higher ee were obtained when 3,5-xylyl, 4-biphenyl, 4-fluorophenyl, and 3-tri-... 

Lanthanide triflates catalyze the Diels-Alder reaction of imines, generated from anilines and aldehydes, with both dienes and alkenes [26]. Thus N-benzyl-ideneaniline in the presence of Yb(OTf)3 (Scheme 6.16) reacts in organic solvent with open-chain dienes, such as Danishefsky s diene, to give tetrahy-dropyridine derivatives, while with cyclopentadiene and vinylethers and vinylthioethers it works like azadiene in both organic solvent and aqueous medium, affording tetrahydroquinoline derivatives. 

Similar aza-Diels-Alder reactions of Danishefsky s diene with imines or aldehydes and amines in water took place smoothly under neutral conditions in the presence of a catalytic amount of an alkaline salt such as sodium triflate or sodium tetraphenylborate to afford dihydro-4-pyridones in high yields (Eq. 12.49).117 Antibodies have also been found to catalyze hetero-Diels-Alder reactions.118... 

In the reaction of benzylideneaniline with cyclopentadiene, the imine functions as an azadiene to yield the rearranged Diels-Alder adduct 77 (equation SI)44,453. In a study of the effect of various Lewis acids (ZnCl2, TiCU, Et2AlCl and SnCU) on diastereoselective cycloadditions of Danishefsky s diene to the imines 79, obtained from the chiral aldehydes 78 (R = MeO or Cl), it was found that SnCLj was the most effective, giving the optically active products in high yields and excellent ee values (equation 52)46. 

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. °... 

Reactions of germylenes with 1,3-dienes, vinyl ketones, ot-diketones, vinyl imines, and a-diimines gave corresponding [4 - - 1] cycloadducts (Scheme 14.55). ... 

One approach to tetrahydropyridinones is the Lewis acid mediated hetero-Diels-Alder reaction of electron-rich dienes with polystyrene-bound imines (Entries 3 and 4, Table 15.23). The Ugi reaction of 5-oxo carboxylic acids and primary amines with support-bound isonitriles has been used to prepare piperidinones on insoluble supports (Entry 5, Table 15.23). Entry 6 in Table 15.23 is an example of the preparation of a 4-piperidinone by amine-induced 3-elimination of a resin-bound sulfinate followed by Michael addition of the amine to the newly generated divinyl ketone. The intramolecular Pauson-Khand reaction of propargyl(3-butenyl)amines, which yields cyclopenta[c]pyridin-6-ones, is depicted in Table 12.4. 

The aza-Diels-Alder reaction of Danishefsky s diene with imines provides a convenient method for the synthesis of 2-substituted 2,3-dihydro-4-pyridones, a compound class that has important synthetic applications. Kobayashi and co-workers have studied the reaction in detail using ytterbium (III) triflate as the Lewis acid30. Although the reaction is often run at low temperature (—78°C to 0°C) for a number of hours, we have found that the reaction also worked well at elevated temperatures (150°C) in the microwave for a few minutes (J. Westman and A. Hurynowics, unpublished results) (see Scheme 5.15). The imines could either be preformed prior to the addition of the Danishefsky s diene or the reaction could be performed as a multi-component protocol, where all components were added at once. 

The chiral boron complex prepared in situ from chiral binaphthol and B(OPh)3 is utilized for the asymmetric aza-Diels-Alder reaction of Danishefsky s diene and imines [67] (Eq. 8A.43). Although the asymmetric reaction of prochiral imine affords products with up to 90% ee, the double asymmetric induction with chiral imine by using oc-benzylamine as a chiral auxiliary has achieved almost complete diastereoselectivity for both aliphatic and aromatic aldimines. This method has been successfully applied to the efficient asymmetric synthesis of anabasine and coniine of piperidine alkaloides. 

Regiospecific addition took place affording good yields of thietanes 143503 and, with alkynes, diene systems were formed504. Fischer has also described the reactions of thioketones with (CO)sW=NPh which undergo metathesis with these substrates to yield N-phenyl imines 144505 as shown in equation 154. 

Further studies revealed that a 10 mol% loading of AgOTf was sufficient to catalyze the reaction of Danishefsky s diene (195) with a variety of aromatic phenylimines bearing electron-withdrawing/donating substituents, in 57-92% yield within 2-3 h. These studies were carried out in water. Electron-poor imines generally required the use of 3 equiv of diene 195 to obtain satisfactory yields. The method was extended to a one-pot three-component protocol with in situ formation of the imine from the aniline and 1.5 equiv of the aldehyde (Scheme 2.51, Table 2.13). Because of... 

Aza-1,3-dienes. The reaction of imines (1) of aldehydes obtained from bis(trimethylsilyl)methylamine with aldehydes catalyzed by Bu4NF (Peterson alkenylation) provides 2-aza-l,3-dienes in 65-78% yield. 

In the field of [4 + 2]-cycloadditions, silver catalysts have been used mainly for aza-Diels-Alder reactions of Danishefsky s diene 447 with various imines. Kobayashi and co-workers364 have recently shown that this transformation can be carried out with catalytic amounts of silver(i) triflate in water (Scheme 133). Various aryl- or alkenyl-substituted pyridone derivatives 448 were obtained in high yields. A survey of other silver catalysts revealed that... 

The formation of tetrahydropyridines by reaction of a suitable diene with an imino dienophile is a reaction known since more than half a century [177] and has been intensively studied. In general, the imines react as the electron-deficient component and their reactivity strongly depends on the electron density which may be tuned by activating or deactivating moieties. However, exceptions from this rule are possible as found by Padwa et al. [178]. They described cycloadditions of imines to bis(phenylsulfonyl)-1,3-butadienes. 

A similar approach to the synthesis of tetracyclic indole alkaloid derivatives has been described [182], and the use of reactive chiral iminium ions allows the realisation of stereoselective aza Diels-Alder reactions even in aqueous solution [183,184]. Nevertheless it should be noted that reactions of electron-rich dienes with imines e. g. derived from amino acids do not necessarily proceed via a Diels-Alder mechanism. They may as well undergo a domino-Mannich-Michael sequence which also efficiently leads to useful nitrogen heterocycles [185-188]. 

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