Tetrahydropyridines => imines

Amines undergo aminopalladation to alkynes. The intramolecular addition of amines to alkynes yields cyclic imines. The 3-alkynylamine 273 was cyclized to the 1-pyrroline 274, and the 5-alkynylamine 275 was converted into the 2,3,4,5-tetrahydropyridine 276[137]. Cyclization of o-(l-hexynyl)aniline (277)... 

The regioselectivity is an issue in substrates 141. With two alkyl substituents on the distal position, tetrahydropyridines 142 are the product. With only one alkyl substituent, the cyclic imine 143 was isolated for these rearrangement products it is unknown whether they stem from the enamine generated from a 5-endo-trig or 5-exo-digcydization (Scheme 15.44) [98]. 

The cycloaddition of dienes to imines to form tetrahydropyridines (equation 46) has been investigated extensively40. Ordinary imines are not sufficiently reactive to add to dienes they have to be activated by the presence of electron-withdrawing substituents. Thus the triester 70 adds to cyclopentadiene under atmospheric pressure to form 71 (equation 47). The reactions with other dienes (cyclohexadiene, isoprene or 2,3-dimethylbuta-l,3-diene) require high pressures41. 

Electron transfer reduction of pyridines in both acid and alkaline solution generates the protonated radical-anion. This rapidly accepts a further electron and a proton to give a mixture of dihydropyridines. Enamine structures in these dihydro-pyridines can tautomerise to the imine, which is more readily reduced than the original pyridine molecule. Further reaction of the 1,4-dihydropyridine leads to piperidine while reduction of the t, 2-dihydropyridine leads to a tetrahydropyridine in which the alkene group cannot tautomerise to the imine and which is not therefore reduced to the piperidine stage. The reaction sequence is illustrated for 2,6-dimethyl-pyridine 18 which yields the thermodynamically favoured cis-2,6-dimethylpiperidine in which the two alkyl substituents occupy equatorial conformations. 

Imines can be photoreduced by hydrogen donors such as propan-2-ol, but in some cases it is clear that a small amount of carbonyl compound (arising from hydrolysis of the imine) is necessary to initiate the process. For example, N-alkytirnines of benzaldehyde give elhane-1.2-diamine derivatives on irradiation in 95% ethanol (5.6). but they are inert when irradiated in a perfectly dry alcohol. The C=N chromophore is capable of abstracting a hydrogen atom, and both the photoreduclion of a tetrahydropyridine (5.7) and the photoaddition of p-xylene to an isoxazoline (5.6) occur by such a direct reaction. 

The photochemistry of certain A-substituted heterocycles has also been studied. As part of a continuing investigation of the photolysis of A-nitroso compounds in solution, the conversion of A-nitroso-3-azabicyclo[3.2.2]nonane (65) into the oxime (66) by photolysis in the presence of acid was reported.58 N-Nitrosopyrrolidine is similarly transformed. The mechanism of this reaction is said58 to involve elimination of NOH with the formation of an imine as intermediate, and, in fact, in the photolysis of 2-ethyl-A-nitrosopiperidine (67), the tetrahydropyridine (68) is the major product. This mechanism certainly does not operate in the photolysis of iV-nitroso-2-azacyclo-octanone, which can be rationalized on the basis of an intramolecular hydrogen transfer [Eq. (16)].59 Acyclic iV-nitrosoamides behave in a similar fashion to IV-nitrosoamines.60... 

Several cyclic imines were reduced with phenylsilane as a reducing agent in the presence of the chiral titanocene catalyst 11 followed by a workup process to give the corresponding cyclic amines in excellent ee [26]. The hydrosilylation of 2-propyl-3,4,5,6-tetrahydropyridine with (R)-ll (substrate Ti=100 l) in THF at room temperature was completed in about 6 h (Scheme 14) [29]. The reaction mixture was treated with an acid and then with an aqueous base to afford (S)-coniine, the poisonous hemlock alkaloid, in 99% ee. 

Accepting the enthalpies of formation given by Jackman and Packam150 for all three imines results in a value of 40 14 kJ mol 1, considerably lower than experiment148. In principle, clarification of this discrepancy could be achieved by related studies on other 1-azacycloalkenes. However, except for an unsuccessful attempt148 for the corresponding 1-azacyclohexene (alternatively, A1-piperideine or 3,4,5,6-tetrahydropyridine) 65—its trimer fails to monomerize—we do not know of any such study. 

Panek et al. employed the optically active amines 252 and 254 [57]. Their condensation with various aldehydes in the presence of MgS04 probably afforded the corresponding imines, which were treated with TiCl4. The resulting substituted 1,2,5,6-tetrahydro pyridines were finally protected, affording the corresponding tri-fluoroacetamides 253 and 255. In all cases, the desired tetrahydropyridines 253 and 255 could be isolated in excellent yields. The IMSC condensation also displays a high diastereoselectivity (Scheme 13.93). 

A novel route to unsymmetrical /ra t-2-allyl-6-alkyl(akyl)-l,2,3,6-tetrahydropyridines 127 was developed using the known 1,2-addition of RLi to pyridine followed by an allylboration of an intermediate imine formed on addition of methanol (Equation 46) <1996TL1317>. 

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. 

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. 

Substituted tetrahydropyridines 134 have been recently prepared via an interesting one-pot transformation involving the Aza Diels-Alder reaction of imines 132 with enamines 133 (Scheme 26) [62]. The enamine adducts were prepared from the reaction of anilines 129 with the Knoevenagel products of 130 and 131. 

In this chapter, we describe our effort to develop GGTIs with novel scaffolds [13,14]. Our approach commenced with the constrnction of a novel library of dihydropyrroles and tetrahydropyridines derived from the phosphine-catalyzed annulation of resin-bound allenoates and A-sulfonyl imines. Derivatization of one of the initial hits, dihydropyrrole-carboxyhc... 

In the presence of 10 mol % Sc(OTf)3, A-benzylideneaniline reacts with 2-trans-l-methoxy-3-trimethylsiloxy-l, 3-butadiene (Danishefsky s diene) [23] to afford the corresponding aza Diels-Alder adduct, a tetrahydropyridine derivative, quantitatively (Eq. 7) [24]. In the reaction of A -benzylideneaniline with cyclopentadiene under the same conditions, on the other hand, the reaction course ehanged and a tetrahydroqui-noline derivative was obtained (Eq. 8). In this reaction, the imine aeted as an azadiene toward one of the double bonds of cyclopentadiene as a dienophile [25]. In the reaction with 2,3-dimethylbutadiene a mixture of tetrahydropyridine and tetrahydroqui-noline derivatives was obtained. A vinyl sulfide, a vinyl ether, and a silyl enol ether worked well as dienophiles to afford the tetrahydroquinoline derivatives in high yields [26,27]. 

That worked rather well Though reduction is needed to get the enamine, the final product must The same reduction of pyridinium be oxidized back to a pyridine again so there is no overall oxidation or reduction. Let s try adding s lts to tetrahydropyridines with a the same enamine to nicotinic acid as an electrophile. Now we need decarboxylation of both rings, oxidation of the left-hand ring, and reduction of the right-hand ring, all easily achieved with imines or enamines. 

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