2-Amino-3,4,5,6-tetrahydropyridine, reaction

With Af-acyl or Af-sulfonyl hydrazines as nucleophiles, Zincke salts serve as sources of iminopyridinium ylides and ylide precursors.Reaction of the nicotinamide-derived Zincke salt 8 with ethyl hydrazino urethane 42 provided salt 43, while the tosyl hydrazine gave ylide 44 (Scheme 8.4.14). ° Benzoyl hydrazines have also been used in reactions with Zincke salts under similar conditions.Af-amino-1,2,3,6-tetrahydropyridine derivatives such as 47 (Scheme 8.4.15), which showed antiinflammatory activity, are also accessible via this route, with borohydride reduction of the initially formed ylide 46. ... 

More recently, Menendez et al. reported a closely related four-component access to tetrahydropyridines, the amino alcohol being replaced by a primary amine and an alcohol. Thus, the cerium(IV) ammonium nitrate (CAN)-catalyzed reaction between primary aliphatic amines, 1,3-dicarbonyls, cx,p-unsaturated aldehydes, and alcohols resulted in the formation of 6-aUcoxy-2-methyl-l,4,5,6-tetrahydropyridines with... 

Reaction of methyl 4-amino-l-benzyl-l,2,5>6-tetrahydropyridine-3-carboxylate 601 with ethyl isothiocyanoacetate in refluxing pyridine or ethyl iV-[bis(methylthio)methylene]glycinate (BMMA reagent) in AcOH at reflux temperature gave the pyrido[4,3-r7 pyrimidines 603 and 604, respectively, via intermediate 602 (Equation 50) <2001H(55)115>. 

Diels-Alder reactions of a,fi-unsaturatedN,N-dimethylhydrazones.1 These readily available hydrazones can function as 1-amino-l-aza-l,3-dienes in Diels-Alder reactions. Thus, 1 undergoes regioselective cycloaddition with various electrophilic dienophiles to give tetrahydropyridines such as 2 and 3. Unfortunately, removal of the dimethylamino group with zinc and acetic acid (or other reagents) also effects reduction of the double bond. The initial adduct from cycloaddition of 1 with naphthoquinone is unstable and undergoes spontaneous elimination of the elements of dimethylamine to give the aromatic adduct 4. 

Bis(2,4,6-trichlorophenyl) malonate reacted smoothly with 2-[(cyclo-hexylmethyl)amino]pyridine at 160-175°C under nitrogen to yield pyr-ido[l, 2- ]pyrimidinone 112 (81JMC1284). Reaction of an equimolar mixture of bis(2,4,6-trichlorophenyl) 2-substituted malonates and 2-(phen-ylamino)-, 2-(3-pyridylamino)-, and 2-(3-trifluorophenyl)amino]pyridines at 160-180°C gave cardiotonic mesoionic pyrido[l,2-a]pyrimidinones 113 (91AP863). Mesoionic tetrahydropyridopyrimidinones 114 were obtained in the reaction of 2-(phenylamino)-3,4,5,6-tetrahydropyridine and bis(2,4,6-trichlorophenyl) 2-substituted malonates (85CB4567 86CC687). 

The 4 + 2-cycloaddition of 2-substituted 1,2-dihydropyridines with nitrosoben-zene produces [2.2.2]bicycloadducts, which are readily reduced by alane to trans-2-substituted 3-amino-l,2,3,6-tetrahydropyridines stereospeciflcally.123 The intramolec- (g) ular nitroso-Diels-Alder reaction of a-acetoxynitroso derivatives in aqueous medium produces 3,6-dihydro-l,2-oxazines in high yield.124 The nitroso-Diels-Alder reaction of acyclic OTIPS-dienes (115) and 6-methyl-2-nitrosopyridine (114) in the presence of (g) [Cu(MeCN)4(difluorosegphos)]PF6 yielded the dihydro 1,2-oxazine cycloadduct (116) with high yield and enantioselectivity (Scheme 33). 125 (Fe)... 

Tetrahydropyridines are endocyclic enamines and can react readily with numerous electrophiles at the 5-position and nucleophiles at the 6-position. An example of this reactivity is a three-component reaction of iV-benzyloxycarbonyl-l,2,3,4-tetrahydropyridine 185, which reacts with primary carbamates in the presence of iodine to give 2-amino-3-iodopiperidines 186, with a toor-relationship between the substituents (Scheme 49). Tetrahydropyridine 185 also reacts with sodium azide in methanol in the presence of ceric ammonium nitrate to give 3-azido-2-methoxypiperidine 187, which can be isolated or reacted with nucleophiles in the presence of BF3-OEt2 to give 3-azido-2-alkylpiperidines 188 in which the relationship between the substituents is cis <2005T1221>. 

An intramolecular aza Diels-Alder reaction of as well electronically neutral N-aryl imines useful for the synthesis of novel tetrahydropyridine derivatives has been introduced by our group [268]. The reactive intermediate 3-43 exhibiting the 2-aza-l,3-butadiene subunit was generated in situ from the aldehyde 3-41 and the amino isoxazole 3-42 and led directly to the diastereomerically pure cycloadduct 3-44 (Fig. 3-14). In contrast to the reactions studied by Barlu-enga, the 2-aza-1,3-butadiene acts as electron-deficient component in this case. 

Simple double aza-Michael reaction of divinyl ketones with primary amines was utilized to generate TV-substituted 3-phenyl-4-piperidones in good yields <07EJO4376>. In a somewhat similar mode, the diastereoselective synthesis of cyclic (3-amino esters by an Sn2 substitution-cyclization of an iodo-a,(3-unsaturated ester with (.Sj-u-mcthy 1 benzylamine was described <07OBC3614>. A combination intramolecular Michael-type addition followed by retro-Michael elimination was exploited in the generation of a phosphoryl dihydropyridone intermediate in the synthesis of /m .v-2,6-disubstitutcd 1,2,5,6-tetrahydropyridines <07JOC2046>. 

A formal total synthesis of ( )-morphine has been achieved by adopting the above synthetic route (Scheme 18). The tetrahydropyridine 91, prepared from the reaction of A/ -methyl-4-piperidone with 2,3-dimethoxy-phenyllithium, followed by dehydration, was converted to the bicyclic en-amine 92 by treatment with the ylic dibromide. Kinetic protonation of 92 with perchloric acid gave the trans-fused immonium salt, which upon dissolution in methanol equilibrated to the thermodynamically prefered cis isomer 93. Treatment of 93 with diazomethane brought about the formation of the aziridinium salt 94, which was readily transformed into the a-amino aldehyde 95 by its oxidation with dimethyl sulfoxide. It is also worth noting that the Komblum oxidation of aziridinium salts leads to the construction of a-amino aldehydes efficiently. Lewis-acid-catalyzed cyclization of 95 afforded the morphinan carbinol 96 in 80% yield. Successive mesylation and reduction of the mesylate derived from 96 with LiBEtjH afforded morphinan (97) in excellent yield. In this instance, direct conversion of 93 to 97 by treatment with diazomethane gave approximately 1 % of the desired product. Lemieux-Johnson oxidation of 97 under acidic conditions furnished the ketone 98, which was previously transformed into ( )-morphine by Gates. In order to confirm the structure of 98, its conversion to the known... 

A reported50 yield of 52% of 5,6,7,8-tetrahydropyrido[4,3-r/]pyrimidine-2,4-diamine by reaction of 4-amino-l,2.5,6-tetrahydropyridine-3-carbonitrile with guanidine carbonate could not be duplicated even with a better solvent, only 19% resulted.502... 

Santamaria et al [42] for synthesizing a-amino nitriles in the alkaloid field and also for preparing 6-cyano-l,2,3,6-tetrahydropyridine from corresponding pyridine nucleus. A similar approach has also been used by Sundberg et al. [43a,43b] for the cyanation of Catharanthine alkaloids. In situ trapping of the iminium cation (37) by allyltrimethylsilanes or silyl enol ethers is also shown [44] recently as a direct —C-C— bond formation methodology at the a-posi-tion of tertiary amines (Scheme 8). The success of this reaction is based on the comparative correlation of ion-pair yield with the AGg, values from amines and enol ethers. 

Formation of azetidines and tetrahydropyridines is expected by the reaction of 3,4-pentadienylamines with alkenyl halides. The ratio of the two products was found to change depending on the substrates. The reaction of the amino acid ester 412 with the triflate 413 afforded the azetidine 414 with high selectivity and the six-membered ring 415 as tlie minor product. On the other hand, the pipecolic ester 416 was obtained as the sole product of the reaction of 412 with iodobenzene [159]. 

Aznar, et al. reported a proline-catalyzed imino-Diels-Alder reactions of acyclic a,p-unsaturated ketones 96 with imines 92 for the synthesis of mc50-2,5-diaryl-4-piperidones 98, Scheme 3.35 [50], The 2-amino-1,3-butadiene was generated in situ by the reaction of a,p-unsaturated ketones 96 with L-proline, followed by Diels-Alder cycloaddition with imine 92 to provide tetrahydropyridine adduct which was then hydrolyzed to the 4-piperidone 98. 

More exotic procedures are the Raney Nickel-catalyzed hydrogenation of the nicotinic hydroxamic acid to X-ISO, and a sequence of reactions starting with 4-amino-3-cyano-l,2,3,6-tetrahydropyridine pC-151). This compound is hydrolyzed to l-acetyl-4-oxohexahydronicotinamide (X-1S2), which is reduced and... 

Aspartate 4-semialdehyde, seen, for example, in Scheme 12.13, which provided a pathway for the biosynthesis of the essential amino acid methionine (Met, M) and in Scheme 12.14, which holds a representation of the biosynthesis of threonine (Thr, T), is also a place to begin to describe a pathway to lysine (Lys, K). As shown in Scheme 12.19, aspartate 4-semialdehyde undergoes an aldol-type reaction with pyruvate (CHsCOCO ") in the presence of dihydropicoUnate synthase (EC 4.2.1.52) to produce a series of intermediates that, it is presumed, lead to (5)-23-dihydropyridine-2,6-dicarboxylate. Then, dihydrodipicolinate reductase (EC 1.3.1.26) working with NADPH produces the tetrahydropyridine, (S)-2,3,4,5-tetrahydropyridine-2,6-dicarboxylate.This heterocycle, in the presence of glutamate (Glu, E) and water, is capable of transamination directly to 2-oxoglutarate and (2S, 6S)-2,3-diaminopimelate in the presence of LL-diaminopimelate aminotransferase (EC 2.6.1.83), while the latter, in the presence of the pyridoxal dependent racemase... 

Dihydropyridinium salt 31 was initially selected to check the viability of the proposal. This salt was prepared from tetrahydropyridine 30, which was accessible in six steps from methyl nicotinate, by treatment of the corresponding N-oxide derivative (mixture of two diastereoisomers) under Polonovski-Potier reaction conditions (Scheme 11). Reaction of the crude salt 31 with the sodium salt of diethyl 1,3-acetonedicarboxylate gave a mixture of two diastereoisomeric adducts 32 (two isolable enol forms) and 33 in 87% overall yield, the undesired stereoisomers 32 (axial amino-methyl chain) predominating (69 31 ratio). 

Ethyl 1 -(4-methoxyphenyl)-4-((4-methoxyphenyl) amino)-2,6-di-p-tolyl-l,2,5,6-tetrahydropyridine-3-carboxylate (4c) Yellow solid, mp 221-224 °C reaction time 22 h yield 81%... 

A catalytic asymmetric intramolecular hydroamination of aminoallenes has been carried out in the presence of titanium complexes prepared by the in situ reaction of Ti(NMe3)4 with chiral amino alcohols [319]. The ring-closing reaction of hepta-4,5-dienylamine at 110 °C with 5 mol% catalyst gives a mixture of 6-ethyl-2,3,4,5-tetrahydropyridine (14-33%) and both Z- and T-2-propenylpyrroli-dine (67-86%), whereas the same reaction with 6-methylhepta-4,5-dienylamine under similar conditions gives exclusively 2-(2-methylpropenyl)pyrrolidine with modest enantiomeric excess values (<16%) (Scheme 14.139). 

Monoaminomonocarboxylic a-amino acids with a primary amino group produce sensory active aldehydes called Strecker aldehydes. Strecker degradation of P-amino acids yields alkan-2-ones known as methylketones (see Section 8.2.4.1.2). By analogy, alkane-3-ones (ethylketones) are formed from y-amino acids. The general reaction is schematically indicated in Figure 2.43. The reaction mechanism, however, varies considerably depending on the type of oxidant and amino acid. 2-Imino acids and 2-oxoacids can in some cases apparently form as intermediates, analogous to enzymatically catalysed transamination and oxidative deamination of amino acids (see Section 2.5.1.3.2). Some Strecker aldehydes readily decompose, such as methional, or yield cyclic products, such as 5-aminopentanal, which dehydrates to 2,3,4,5-tetrahydropyridine. 

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