Efficient enantiomeric synthesis of pyrrolidine and piperidine alkaloids from tobacco

An enantiomeric synthesis of six piperidine and pyrrolidine alkaloids, (S)-nornicotine 1, (S)-nicotine 2, (S)-anatabine 3, (S)-N-methylanatabine 4, (S)-anabasine 5, and (S)-N-methylanabasine 6, known as natural products in tobacco, was established from a common chiral homoallylic (S)-3-(1-azido-but-3-enyl)-pyridine 15. An intramolecular hydroboration-cycloalkylation of the homoallylic azide intermediate 15 served as the key step in the pyrrolidine ring formation. A ring closing metathesis reaction (RCM) of a diethylenic amine intermediate (S)-allyl-(1-pyridin-3-yl-but-3-enyl)-carbamic acid benzyl ester 20 served as the key step in the piperidine ring formation. From the commercially available 3-pyridinecarboxaldehyde 13, a short and convenient enantiomeric synthesis of tobacco alkaloids is described: (S)-nornicotine 1 (5 steps, with an overall yield of 70%), (S)-nicotine 2 (6 steps, 65%), (S)-anatabine 3 (8 steps, 30%), (S)-N-methylanatabine 4 (8 steps, 25%), (S)-anabasine 5 (8 steps, 35%), and (S)-N-methylanabasine 6 (8 steps, 25%).     

Process development and large-scale synthesis of NK1 antagonist

A scaleable synthetic route is described to obtain 2-(4-acetylpiperadin-1-yl)-6-[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (1, KRP-103) as a neurokinin (NK)(1) antagonist. The key step in the synthesis is the intramolecular cyclization of N-[3,5-bis(trifluoromethyl)phenylmethyl]-N-(3-hydroxypropyl)-4-chloro-6-(2-methylphenyl)-2-methylthiopyrimidine-5-carboxamide (15) which was obtained by amide formation between 4-(2-methylphenyl)-2-methylthio-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (8) and 3-[3,5-bis(trifluoromethyl)phenylmethylamino]-1-propanol (3). Treatment of 15 with 1,8-diazabicyclo[5,4,0]undec-7-ene provided 6-[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl)-2-methylthio-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (6). This intermediate (6) is transformed into the candidate compound (1) by two steps; oxidation, and substitution reaction of the resultant sulfone (7) with 1-acetylpiperazine. This synthetic method is free of chromatographic purification and is amenable to large scale synthesis.     

1,N6-Etheno-7-deaza-2,8-diazaadenosine: syntheses, properties and conversion to 7-deaza-2,8-diazaadenosine

1,N6-Etheno-7-deaza-2,8-diazaadenosine (4) was synthesized from 8-aza-7-deazaadenosine (6) in 64% overall yield. The starting material 6 was obtained by the direct glycosylation of 8-aza-7-deazaadenine (7) with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-d-ribofuranose (8) (NO2 CH3, BF3 x Et2O; 77% yield). Compound 4 was transformed into 7-deaza-2,8-diazaadenosine (5). The fluorescence of compound 4 shows an emission maximum at 531 nm (phosphate buffer; pH 7.0), which is bathochromically shifted compared to 1,N(6)-etheno-2-azaadenosine (3a) (495 nm). A conformational analysis was performed in the solid state and in solution.     

Photostable, amino reactive and water-soluble fluorescent labels based on sulfonated rhodamine with a rigidized xanthene fragment

Highly water soluble fluorescent dyes were synthesized and transformed into new amino reactive fluorescent labels for biological microscopy. To this end, rhodamine 8 (prepared from 7-hydroxy-1,2,3,4-tetrahydroquinoline (7) and phthalic anhydride in 85 % aq. H(3)PO(4)) was sulfonated with 30 % SO(3) in H(2)SO(4) and afforded the water soluble disulfonic acid 3 a (64 %). Amidation of the carboxy group in 3 a with 2-(methylamino)ethanol in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumPF(6) (-) (HATU) led to alcohol 3 b (66 %), which was transformed into the amino reactive mixed carbonate 3 d with di(N-succinimidyl)carbonate and Et(3)N. Reaction of the carboxy group in 3 a with MeNH(CH(2))(2)CO(2)Me and N,N,N',N'-tetramethyl-O-(N-succinimidyl)-uroniumBF(4) (-) (TSTU) yielded methyl ester 13. After saponification of the aliphatic carboxy group in 13, the compound was converted into NHS-ester 3 e (using HATU and Et(3)N). Heating of 7 with trimellitic anhydride in H(3)PO(4) gave a mixture of dicarboxylic acids 14 and 15 (1:1). Regioisomer 15 was isolated, sulfonated with 30 % SO(3) in H(2)SO(4), and disulfonic acid 3 f was used for the synthesis of the mono NHS-ester 3 g, in which the sterically unhindered carboxy group was selectively activated (with N-hydroxysuccinimide, HATU, and Et(3)N). The sulfonated rhodamines 3 b, c and f are soluble in water (up to 0.1 M), have excellent photostabilities and large fluorescence quantum yields. Subdiffraction resolution images of tubulin filaments of mammalian cells stained with these dyes illustrate their applicability as labels for stimulated emission depletion microscopy and other fluorescence techniques.     

A new route to trans-2,6-disubstituted piperidine-related alkaloids using a novel C2-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester

A novel C2-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester 1 was prepared by the double asymmetric allylboration of glutaldehyde followed by an aminocyclization and carbamation. On the basis of desymmetrization of 1 using iodocarbamation, one allyl group of 1 was protected and monofunctionalizations of the resulting oxazolidinone 11 were performed. The reaction of the N-methoxycarbonyl piperidine 25 employing decarbamation reagent (n-PrSLi or TMSI) as a key step gave oxazolidinone 26 or 17 including an intramolecular ring formation, which was transformed in a few steps into (-)-porantheridine (2) and (-)-2-epi-porantheridine (3), respectively. In addition, the expedient synthesis of (+)-epi-dihydropinidine (4), (2R,6R)-trans-solenopsin A (5), and precoccinelline (6), starting from 11 is described.     

First total synthesis of rhodexin A

An efficient total synthesis of rhodexin A (1) is reported. An initial inverse-electron-demand Diels-Alder reaction of the acyldiene 6 with the silyl enol ether 7 gave the cycloadduct 8 with the required 4 contiguous stereocenters in a single step. This compound was then transformed into the tetracyclic enone 16, which was converted to rhodexin A (1).     

Total synthesis of the tricyclic marine alkaloids (-)-lepadiformine, (+)-cylindricine c, and (-)-fasicularin via a common intermediate formed by formic acid-induced intramolecular conjugate azaspirocyclization

A very short and efficient enantioselective total synthesis of the tricyclic marine alkaloids (-)-lepadiformine (3), (+)-cylindricine C (1c), and (-)-fasicularin (4) has been developed utilizing the formyloxy 1-azaspiro[4.5]decane 5 as a common intermediate. The key strategic element for the synthesis was the formic acid-induced intramolecular conjugate azaspirocyclization, which proved to be a highly efficient and stereoselective way to rapid construction of the 1-azaspirocyclic substructure of these natural products in a single operation. Thus, the common intermediate 5, synthesized in two steps with 70% overall yield starting from the known (S)-N-Boc-2-pyrrolidinone 7 via the conjugate spirocyclization using an acyclic ketoamide 6, was utilized for the concise and stereoselective total synthesis of (-)-lepadiformine (3), which was accomplished in seven steps with 45% overall yield from 5 (31% yield from 7). The developed strategy based on the conjugate spirocyclization was also applied to the stereoselective total synthesis of (+)-cylindricine C (1c), which was achieved in 10 steps from 5 in 18% overall yield (12% yield from 7). Further application of this approach using 5 led to the synthesis of (-)-fasicularin (4), wherein an extremely efficient method for the introduction of the thiocyanato group via an aziridinium intermediate at the last step was developed. Thus, the highly efficient first enantioselective total synthesis of (-)-fasicularin was accomplished in nine steps with an overall yield of 41% from 5 (28% yield from 7).     

First stereospecific synthesis of (E)- or (Z)-alpha-fluoroenones via a kinetically controlled Negishi coupling reaction

A highly stereospecific synthesis of (E)- or (Z)-alpha-fluoro-alpha,beta-unsaturated ketones 4, via a kinetically controlled Negishi palladium-catalyzed coupling reaction, was developed, providing an easy and general access to valuable fluorinated intermediates (pharmaceutical, peptide mimic, and so on). The synthesis involved a reaction between E/Z gem-bromofluoroolefins 2 and alkoxyvinylzinc species 6 under controlled reaction temperature. At 10 degrees C, (Z)-4 (70 to 99% yields) was obtained along with unreacted (Z)-2 (66 to 99% yields). At THF reflux, the recovered olefin was transformed into (E)-4 (up to 98% yield).     

Synthesis of Chiral Bicyclic Bis-lactam Components for the controlled self-assembly of hydrogen-bonded arrays

The chiral biyclic bis-lactams of structures 3 and 4 were synthesized from the key intermediate 2′b , the N,N′-bis(4-methoxybenzyl) derivative of 2 (X = MeO) (Scheme 6). The synthesis of this intermediate involved two key steps: (1) a double condensation of glyoxylic acid/anisamide (= oxoacetic acid/4-methoxybenzamide) adduct 11c with veratrole (1,2-dimethoxybenzene; 10 ) allowed the introduction of two glycine units at the 4,5-positions of the veratrole ring to give 18c (Schemes 3 and 4); (2) in order to circumvent the hydrolysis of 4-methoxybenzoyl protective groups which proved to be unfeasible, these groups were transformed into 4-methoxybenzyl groups through a sequence involving thiocarbonylation followed by reduction (Scheme 5). Thereafter, the double intramolecular cyclization of the resulting diamino diester 22c proceeded easily to afford 2′b. This intermediate may be transformed via the tetrol 2′g or the diol 2′h into the N-protected derivatives of 2 (X = OR) and of 3 (X = OCOR). Cleavage of the 4-alkuxybenzyl groups was achieved by ceric ammonium nitrate. However, when the aromatic ring bore ether functions (N-protected 2 ), this normal reaction was accompanied by the oxidative ring cleavage to give the diene-diester structure 4 (Schemes 5 and 6).     

Enantioefficient synthesis of alpha-ergocryptine: first direct synthesis of (+)-lysergic acid

The first direct synthesis of (+)-lysergic acid (2a) suitable for scale-up has been achieved by the following reaction sequence. Bromoketones 4d or 4g were allowed to react with amine 5 followed by deprotection, and the resulting diketone 6c was transformed into the unsaturated ketone (+/-)-7 by the LiBr/Et(3)N system. Resolution afforded (+)-7, which was further transformed by Sch?llkopf's method into the mixture of esters 2e and 2f. Upon hydrolysis the latter mixture afforded (+)-2a. The peptide part of alpha-ergocryptine (1) was prepared according to the Sandoz method; the stereoefficiency, however, has been significantly improved by applying a new resolution method and recycling the undesired enantiomer. Coupling the peptide part with lysergic acid afforded 1. Having synthetic (+)-7 in hand, we can claim the total synthesis of all the alkaloids which were prepared earlier from (+)-7 that had been obtained through degradation of natural lysergic acid.     

Amine mediated proton transfer reaction and C-Cl bond activation of solvent chloroform by a trinuclear copper(II) complex of a glucopyranosylamine derived ligand

An amine mediated C-Cl bond activation process of the solvent chloroform has been explored by a coordinatively labile trinuclear Cu(II) complex, [Cu3(L1)2(MeOH)(H2O)] (1), derived from N-(3-tert-butyl-2-hydroxybenzylidene)-4,6-O-ethylidene--D-glucopyranosylamine (H3L1). The effect of activation is extremely high with methylamine, resulting in the formation of [Cu(MeNH2)5]Cl2 (2) and [Cu(L2)2] (3; HL2 = 2-tert-butyl-6-[(methylimino)methyl]phenol), however, under identical conditions it is moderate with ethylamine resulting in the isolation of crystals of the intermediate amine bound trinuclear copper(II) complex, [Cu3(L1)2(EtNH2)2(MeOH)2] (5), which was further converted into the mononuclear complex, [Cu(HL1)(EtNH2)] (6), in a novel crystal-to-crystal transformation. The successive isolation of the ethylamine-bound tri- and mononuclear complexes, 5 and 6, supported the occurrence of proton transfer reactions, which might be a key step in C-Cl bond activation. The primary and secondary amines, 2-aminomethylpyridine, N,N-dimethylethylenediamine, and 1,4,7-triazacyclononane, also having chelating features further enhance the rate of activation. No activation has been noted in the case of triethylamine and N,N,N,N-tetramethylethylenediamine. Formation of a carbene-trapped compound, 2,6-xylyl isocyanide, was confirmed in the reaction of complex 1 with 1,4,7-triazacyclononane and 2,6-xylidine in CHCl3, suggesting that the C-Cl bond cleavage led to the generation of dichlorocarbene. In addition, the mononuclear complex 6 has been transformed into a homotrinuclear complex [Cu3(L1)2(MeOH)2] by treatment with Cu(II) ions in MeOH/CHCl3, suggesting the possibility that the former could be regarded as a suitable metalloligand for heterotrimetallic complex synthesis.     

Aromatic nucleophilic substitution or CuI-catalyzed coupling route to martinellic acid

Condensation of beta-amino ester 8b with triflate 7 gives N-aryl amino ester 11, which is converted into 2-substituted 4-oxoquinoline 4 using an intramolecular Dieckmann reaction as the key step. CuI-mediated coupling of beta-amino ester 8a with 1,4-diiodobenzene followed by an intramolecular acylation and Pd-catalyzed carbonylation provide another manner to 4. Alkylation of 4 and subsequent reductive amination deliver the cyclic imine 14, which is transformed into triamine 3 by ordinary operations. Guanylation of 3 under mild condition followed by deprotection results in the synthesis of martinellic acid 1.     

Preparation of perhydroisoquinolines via the intramolecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates: a formal synthesis of (+/-)-reserpine

The intramolecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates provides an efficient method for the synthesis of cis-fused hexahydroisoquinolones. As a demonstration of the stereochemical control offered by this cycloaddition, two approaches to the construction of the DE rings of reserpine are reported. In the second entry, N-((4-(trimethylsilyl)ethoxymethoxy)methyl-6-benzyloxy-3Z,5E-hexadienoyl)-1-aza-2-ethoxy-1,3-butadiene (40) undergoes cycloaddition to produce as the major product (4aS,7R,8aS)-7-benzyloxy-5-((2-trimethylsilyl)ethoxymethoxy)methyl-3,4,4a,7,8,8a-hexahydroisoquinol-3-one (41). Cycloadduct 41 is then stereospecifically elaborated to (4aS,5S,6R,7R,8aR)-6-methoxy-5-methoxycarbonyl-7-(3,4,5-trimethoxy)benzoyldecahydroisoquinoline-2-carboxylic acid methyl ester (3), a key intermediate previously transformed to reserpine.     

1-苯基-3-甲基-6-N,N-二正丁基胺-2(1H)-喹喔啉-2-酮的全合成

报道了2(1H)-喹喔啉类衍生物——1-苯基-3-甲基-6-N,N-二正丁基胺-2(1H)-喹喔啉-2-酮的全合成.该化合物及其中间体1-苯基-3-甲基-6-胺基-2(1H)-喹喔啉-2-酮和1-苯基-3-甲基-6-硝基-2(1H)-喹喔啉-2-酮均为新化合物,文中给出了它们的重要的分析数据,简要讨论了溶剂在关环反应以及N-烷基化反应中的重要影响,偶然发现以水作溶剂时关环主产物为1-苯基-3-甲基-5-硝基-苯并咪唑.这类化合物可应用于药物,如用作N-甲基-D-天冬氨酸(NMDA)受体及α-氨基羟甲基异噁唑丙酸(AMMPA)受体拮抗剂、杀菌剂等;还可用作植物生长抑制剂、荧光探针以及作为新型功能染料中间体等诸多领域.     

Convenient synthesis of epimeric indolizidines by the intramolecular 1,3-dipolar cycloaddition of a sugar derived N-(3-alkenyl)nitrone

The stereoselective synthesis of two epimeric penta-hydroxylated indolizidines was accomplished from 2,3:5,6-di-O-isopropylidene-α-d-mannofuranose and N-(2-methylpent-4-en-2-yl)hydroxylamine. The transformation of these substrates into the corresponding 7-oxa-1-azabicyclo[2.2.1]heptane by the intramolecular 1,3-dipolar cycloaddition was the key step of the synthesis. The adduct was transformed into the tricyclic ammonium salt by intramolecular N-alkylation. The tricyclic ammonium salt was converted to the target compounds by: (route 1) the catalytic hydrogenation; or (route 2) the reaction with sodium azide, followed by the enantioselective reduction of the resulting indolizidinone.     

Syntheses and experimental studies on the relative stabilities of spiro, ansa, and bridged derivatives of cyclic tetrameric fluorophosphazene

Reactions of (CF2CH2OSiMe3)2 and CF2(CF2CH2OSiMe3)2 with N4P4F8 (1) in a 1:2.5 molar ratio resulted in the formation of monospiro compounds [(CF2CH2O)2PN](F2PN)3 (2) and [CF2(CF2)CH2O)2PN](F2PN)3 (4) as well as the intermolecular bridged compounds F7N4P4OCH2CF2CF2CH2OP4N4)F7 (3) and F7N4P4OCH2CF2CF2CF2CH2OP4N4F7 (5). An equimolar reaction of dilithiated 1,3-propanediol with 1 resulted in the 1,3-ansa-substituted compound CH2(CH2O)2[P(F)N]2(F2PN)2 (6) as the major product in good yield. However, an analogous reaction of the dilithiated 1,3-propanedithiol with 1 gave only the spirocyclic compound CH2(CH2S)2(PN)(F2PN)3 (8). The molecular structures of 2 and 6 were determined by single-crystal X-ray diffraction. In the presence of catalytic amounts of CsF in THF, the bridged compound 3 was converted to the spirocyclic compound 2 while the 1,3-ansa compound 6 under similar conditions transformed into the monospiro-substituted compound CH2(CH2O)2 (PN)(F2PN)3 (7). These transformations were monitored by time-dependent 19F and 31P NMR studies.     

Synthesis and structural characterization of a series of lanthanide(II) amides: steric effect of amido ligand

The synthesis and structures of a series of lanthanide(II) and lanthanide(III) complexes supported by the amido ligand N(SiMe3)Ar were described. Several lanthanide(III) amide chlorides were synthesized by a metathesis reaction of LnCl3 with lithium amide, including {[(C6H5)(Me3Si)N]2YbCl(THF)}2.PhCH3 (1), [(C6H3-iPr2-2,6)(SiMe3)N]2YbCl(mu-Cl)Li(THF)3.PhCH3 (4), [(C6H3-iPr2-2,6)(SiMe3)N]YbCl2(THF)3 (6), and [(C6H3-iPr2-2,6)(SiMe3)N]2SmCl3Li2(THF)4 (7). The reduction reaction of 1 with Na-K alloy afforded bisamide ytterbium(II) complex [(C6H5)(Me3Si)N]2Yb(DME)2 (2). The same reaction for Sm gave an insoluble black powder. An analogous samarium(II) complex [(C6H5)(Me3Si)N]2Sm(DME)2 (3) was prepared by the metathesis reaction of SmI2 with NaN(C6H5)(SiMe3). The reduction reaction of ytterbium chloride 4 with Na-K alloy afforded monoamide chloride {[(C6H3-iPr2-2,6)(SiMe3)N]Yb(mu-Cl)(THF)2}2 (5), which is the first example of ytterbium(II) amide chloride, formed via the cleavage of the Yb-N bond. The same reduction reaction of 7 gave a normal bisamide complex [(C6H3-iPr2-2,6)(SiMe3)N]2Sm(THF)2 (8) via Sm-Cl bond cleavage. This is the first example for the steric effect on the outcome of the reduction reaction in lanthanide(II) chemistry. 5 can also be synthesized by the Na/K alloy reduction reaction of 6. All of the complexes were fully characterized including X-ray diffraction for 1-7.     

The Synthesis of 12-Methyl-1, 2, 3, 4, 6, 7, 12, 12B-Octahydroindolo [2,3-A]Quinolizine (1), 1-Benzoyl-1, 2, 3, 4, 6, 7, 12, 12B-Octahydroindolo[2, 3-A]Quinolizine (2), and 1-Phenylcarbinol-1, 2, 3, 4, 6, 7, 12, 12B-Octahydroindolo[2, 3-A]Quinolizine (3)

12-Methyl-l, 2, 3, 4, 6, 7, 12, 12b-octahydroindolo[2, 3-a]quinolizine (1) is synthesized through a new route developed in our laboratory. The most important step in this synthesis is the condensation of I-methyltryptophyl bromide (4) with 2-piperidone (5) to give N -(2-(1-methylidol)-3-ylethyl)-2-piperidone (6) in good yield (70%). The synthesis of 1-benzoyl-1, 2, 3, 4, 6, 7, 12, 12b-octahydroindolo(2, 3-a]quinolizine (2) and 1-phenylcarbinol-1, 2, 3, 4, 6, 7, 12, 12b-octahydroindolo[2, 3-a]quinolizine (3) follow the method developed by Wenkert. But the yield of tetrahydropyridine 9 from partial hydrogenation of pyridinum bromide 8 with 10% palladium-charcoal is 84% which is much higher than the best yield (40%) in the literature, since the phenyl group contribute additional stability.     

Alternative reaction pathways in domino reactions of hydrazinediidozirconium complexes with alkynes

Reaction of [Zr{(NAr)(2)N(py)}(NMe(2))(2)] (Ar=3,5-xylyl: 2?a, mesityl: 2?b) with one or two molar equivalents of 1,1-diphenylhydrazine gave the mixed amido/hydrazido(1-) complex [Zr{(NMes)(2)N(py)}(HNNPh(2))(NMe(2))] (3), the bis-hydrazido complex [Zr{(NMes)(2)N(py)}(HNNPh(2))(2)] (4), and, in the presence of excess 4-dimethylaminopyridine (DMAP), hexacoordinate hydrazinediidozirconium complexes [Zr{(NXyl)(2)N(py)}(=NN(Me)Ph)(dmap)(2)] (5) and [Zr{(NXyl)(2)N(py)}(=NNPh(2))(dmap)(2)] (6). The reaction of one equivalent of the zirconium-hydrazinediide [Zr{(NTBS)(2)N(py)}(NNPh(2))(py)] (1) with disubstituted alkynes at RT for 16?h led to the formation of seven-membered diazazirconacycles 7?a-7?e in high yields. Similar reactivity was observed by reacting bis-amido complex 2?b with one molar equivalent of the corresponding alkyne and diphenylhydrazine. The formation of the seven-membered zirconacycles implied a key coupling step that involved the alkyne and one of the aryl rings of the diphenylhydrazinediido ligand. In some cases, such as the reaction with 2-butyne, the corresponding metallacycle was only obtained in modest yields (45?% for the reaction with 2-butyne) and a second major product, vinylimido complex 9, was formed in almost equal amounts (42?%) by 1,2-amination (formal insertion of the alkyne). The formation of compounds 7?a and 9 followed in part the same sequence of reaction steps and a key intermediate, an azirinido complex, represented a "bifurcation point" in the reaction network. Reaction of 1.2?equivalents of several diarylhydrazines and various substituted alkynes (1?equiv) at ambient temperature (or at 80?°C) in the presence of 10?mol?% [Zr{(NXyl)(2)N(py)}(NMe(2))(2)] (2?a) gave the corresponding indole derivatives. On the other hand, the replacement of 1,1-diarylhydrazines by 1-methyl-1-phenyl hydrazine led to head-to-head cis-1,3-enynes in good yields.     

One pot solid phase synthesis of 2-substituted 2,3-dihydropyridin-4(1H)-ones on Rinkamide-resin

A novel solid phase synthesis of 2-substituted 2,3-dihydropyridin-4(1H)-ones using Rinkamide-polystyrene-resin is described. The key step involves a hetero-Diels-Alder reaction of Danishefsky's diene with solid phase bound imines, which was carefully optimized. Using this method even ketones are transformed into 2,2-disubstituted dihydropyridones.