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

By reacting 2-amino-3,4,5,6-tetrahydropyridine (118) with ethyl aceto-acetate or ethyl benzoyl acetate in pyridine, Wamhofif and Lichtenthaler178 obtained 1 4 equilibrium mixtures of the tautomers 119 and 120. 

Amino-3,4,5,6-tetrahydropyridine and diethyl malonate in ethanolic sodium ethoxide yielded the 6,7.8.9-tetrahydro derivative of 63 (R = H)179-180 whereas the carbethoxy-substituted derivative (118) gave the pyrido[l,2- ]-... 

Amino-3,4,5,6-tetrahydropyridines were usually reacted with /3-oxo esters in the absence or presence of a base to give 6,7,8,9-tetrahydro-4//-pyrido[ 1,2-a ]pyrimidin-4-ones [83JHC393 85EUP132375, 85JOC166 88JCS(P1)2653]. In these cases the formation of the isomeric 6,7,8,9-tetrahydro-2Z/-pyrido[ 1,2-a]pyrimidin-2-one must also be considered (see Section II, C). 

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. ... 

Eda and Kurth applied a similar solid-phase combinatorial strategy for synthesis of pyridinium, tetrahydropyridine, and piperidine frameworks as potential inhibitors of vesicular acetylcholine transporter. One member of the small library produced was prepared from amino-functionalized trityl resin reacting with a 4-phenyl Zincke salt to give resin-bound product 62 (Scheme 8.4.21). After ion exchange and cleavage from the resin, pyridinium 63 was isolated. Alternatively, borohydride reduction of 62 led to the 1,2,3,6-tetrahydropyridine 64, which could be hydrogenated to the corresponding piperidine 65. 

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... 

Efforts have been made to find stereoselective routes which provide disubstituted azetidines. Palladium catalysed cyclization of an enantiomer of allene-substituted amines and amino acids gives the azetidine ester 2 and a tetrahydropyridine in variable yield and ratio, depending on the substituents and conditions <990L717>. The (TRIS)- and (253I )-isomeis of the substituted azetidine-2-carboxylic acids 3 (R = COjH) are obtained in several steps from the corresponding 3 (R = CHjOSiMejBu ) which, in turn, is produced in high yield by photochemical intramolecular cyclization <98HCA1803>. 

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>. 

Macrocyclic 2-pyrones (113) and (114) are prepared from enamine (115) and ketene (75HCA2409). Reduction of cyano ketone (116) with LAH affords an amino ketone which spontaneously cyclizes to generate a tetrahydropyridine (117) dehydrogenation by palladium on charcoal produces the aromatized phane (118) (71TL671). 

Cyclocondensation of 6-methylthio-5-cyano-l,2,3,4-tetrahydropyridine-2,4-dione with arylidenemalononitrile (174) in the presence of piperidine in boiling ethanol gave 2-amino-4-aryl-6-methylthio-8-oxo-4,8-dihydropyr-ido[2,l-h][l,3]oxazine-3,7-dicarbonitrile (175) (92MI4). 

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)... 

The [4+2] cycloaddition of 2-substituted-l,2-dihydropyridines 109 with heterodienophile nitrosobenzene gives unstable cycloadducts 110 as single diastereomers in 98% ee. Adducts 110 can be reduced with alane to give 3-aminosubstituted-l,2,3,6-tetrahydropyridines 111 with a /razw-relationship between the 2-substituent and 3-amino group (Scheme 30) <2005JOC2368>. 

Tetrahydropyridine Ar-oxidc 174 undergoes 1,3-dipolar cycloaddition with (Z)-vinyl sulfoxides 178 to give isoxazolidines 179, which can be desulfurized to give amino alcohols 180 with high enantiomeric selectivity (Scheme 47) <1997TA109>. 

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. 

The N-protected 1,4,5,6-tetrahydropyridine 560 reacts as an enamine, the immediate iminium product being trapped by a nucleophile, for example, with primary carbamates in the presence of iodine 2-amino-3-iodopiperidines 561, with a trans relationship between the substituents being formed <2005T1221>. A -Benzyl-1,4,5,6-tetrahydropyridine 562 can be coupled with alkynes giving products 563 <2002AGE2535>. 

Intermolecular trapping of PET generated iminium cations by Me3SiCN have been recently reported by Santamaria et al. [95] for synthesizing a-amino nitriles (e.g. 95-96) in the alkaloid field and also for preparing 6-cyano 1,2,3,6-tetrahydropyridine (98) [96] from 1,2,3,6-tetrahydropyridine (97). Similar cyan-ation of catharanthine alkaloids has also been reported by Sundberg recently... 

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>. 

---