Hydrogenations ethyl nicotinate

From ethyl l-methylpiperidine-3-carboxylate (which was prepared by hydrogenation of ethyl nicotinate with Ni-catalyst and then by methylation by action dimethyl sulfate) and 2-thienyl magnesium bromide was synthesized l,l-di(thiophen-2-yl)-2-(3 -N-methylpiperidine), 3-(di-2-thienylmethylene)-l-methylpiperidine was obtained by dehydration of l,l-di(thiophen-2-yl)-2-(3 -N-methylpiperidine) by action of base. 

The initial step in the reaction could be the addition of a Ti-Si species across the C=N bond of the pyridine to give an /V-silyldi hydropyridine. An additional two hydrogen atoms can be transferred to produce the tetrahydropyridine, but complete reduction only occurs in the presence of H2. On the other hand, electron-donating substituents and electron-withdrawing substituents on pyridine derivatives affect the reactions in different ways. 3-Picoline with electron-donating substituents gives two hydrogenation-hydrosilation isomers in a 3 2 ratio in 85% yield [Eq. (24)] whereas ethyl nicotinate with... 

Partial hydrogenation of ethyl nicotinate under heterogeneous catalytic conditions in EtOH, or in THF/AC2O, affords the corresponding vinylogous amides 191 and 192, respectively. This method can also be applied to 3-acetyl-and 3-benzoylpyridine (Scheme 33) <2006EJO4343>. 

Somewhat surprisingly, the Pd-bppfa complex 24 tethered to a macroporous silica was shown to be moderately active for the enantioselective hydrogenation of ethyl nicotinate (25) (a rare example of a homogeneous Pd-catalyzed hydrogenation), but ee s were very low (Scheme 15.1).10a... 

When ethyl nicotinate (3-ethoxycarbonylpyridine) was hydrogenated over Raney Ni in ethanol at 165°C, the product contained 20% of ethyl iV-ethylnipecotate (1-ethyl-3-ethoxycarbonylpiperidine). The /V-elhylalion could be avoided when ether, methylcyclohexane, or dioxane was used as the solvent (eq. 12.14).18 The formation of 3-methyl-2-piperidone, which amounted to a considerable amount with Ni-kiesel-guhr in ethanol,21 was also never higher than 5% under these conditions. The yields of other high-boiling materials, which amounted to 15-20% in ethanol, were about 5% in methylcyclohexane or ether. 

An interesting application of the Fujiwara-Moritani/oxidative Heck reaction for the synthesis of benzo furans was recently reported by the Stoltz lab [31]. A variety of allyl phenyl ethers (all containing electron-rich aryl components) react with 10 mol% palladium acetate, 20 mol% ethyl nicotinate, 20 mol% sodium acetate, and one equivalent of benzoquinone at 100°C to provide benzofurans in 52-79% yield (e.g. 16—>17). The mechanism of this transformation begins with arene palladation of Pd(II) followed by olefin insertion, p-hydrogen elimination, and olefin isomerization to the thermodynamically favored benzofuran product. The resulting Pd(0) species is then oxidized to Pd(ll) thus regenerating the active catalyst. 

Scheme 6.7 Net enantioselective hydrogenation of ethyl nicotinate by (a) direct asymmetric reduction, (b) achiral partial hydrogenation followed by asymmetric hydrogenation, and (c) achiral partial hydrogenation followed by functionalization and then asymmetric hydrogenation.

Scheme 10.33 Two step hydrogenation of ethyl nicotinate by Studer.

Thomas and Johnson described a direct asymmetric hydrogenation of ethyl nicotinate using Pd ferrocenyl catalyst anchored within MCM 41 [48]. The confined catalyst (5%) displayed a good activity (TON = 291), but no increase in enantioselec tivity (17% ee) was observed compared to the corresponding homogeneous catalyst (Scheme 10.35). 

Scheme 10.3S Hydrogenation of ethyl nicotinate using a chiral heterogeneous catalyst.

The hydrogenation of the methiodide of ethyl nicotinate in alcohol in the presence of Raney nickel and triethylamine, at 120° and 120 atm for eight hours gave over 80 % of ethyl-1 -methylpiperidine-3-carboxylate (106). When the reduction was run for 4 hr at 80° and the same pressure, 54% of the hexahydro compound and 38% of a tetrahydro product were obtained. 

The influence of acid on these additions is considerable. In ethanol, for example, ethyl nicotinate is converted into the corresponding 6a-hydroxyethylpyridine, whereas in acidified solution the 6-ethylpyridine derivative is obtained.147 The function of the acid may, of course, simply be to promote dehydration of the intermediate 6a-hydroxyethyldihydropyridine. Phthalazine and quinoxaline are converted by irradiation in acidified methanol into 1-methylphthalazine and 2-methylquinoxaline, respectively.148 In this case, however, there is evidence to suggest that the alkylations proceed by way of electron transfer from the solvent to an excited state of the protonated diazines in neutral solution, a hydrogen... 

Picolinic acid, 3,6-dichloro-. See Clopyralid Picolinic acid ethyl ester. See Ethyl nicotinate P-Picolyl alcohol. See Pyridine-3-methanol PicoPure . See Hydrogen peroxide Picramic acid. See 2-Amino-4,6-dinitrophenol Picramic acid, sodium salt. See Sodium picramate... 

Condensation of ethyl acetoacetate with phenyl hydrazine gives the pyrazolone, 58. Methylation by means of methyl iodide affords the prototype of this series, antipyrine (59). Reaction of that compound with nitrous acid gives the product of substitution at the only available position, the nitroso derivative (60) reduction affords another antiinflammatory agent, aminopyrine (61). Reductive alkylation of 61 with acetone in the presence of hydrogen and platinum gives isopyrine (62). Acylation of 61 with the acid chloride from nicotinic acid affords nifenazone (63). Acylation of 61 with 2-chloropropionyl chloride gives the amide, 64 displacement of the halogen with dimethylamine leads to aminopropylon (65). ... 

Hydroxycynnclidine (14.1.17) is synthesized from the methyl ester of wo-nicotinic acid, which is reacted with the ethyl ester of bromoacetic acid to give the piridinium salt (14.1.14). This is rednced by hydrogen nsing a platinnm catalyst, giving 1-carbethoxymethyl-... 

Nomicotine, in which the N-methyl is replaced by hydrogen, is somewhat less potent and active than nicotine in most assays (102). R- and S-nomicotine are equipotent with R-(+)-nicotine,the less active, unnatural enantiomer, in a rat brain membrane-binding assay (103). In that study, S-(-)-nicotinewas 13 times more potent than its R- enantiomer. Replacement of the N-methyl of nicotine with ethyl or n-propyl eauses an exponential loss of peripheral nicotinic effect (102). Anabasine (51), a relatively minor alkaloidal constituent of tobacco, demonstrated approximately 1/10 the affinity of nicotine in a binding assay (104). A synthetic azetidine congener (52) of nicotine binds with the same affinity as nicotine to rat brain membrane tissue, and it displayed a greater potency than nicotine in a rat behavioral assay (105). Evaluation of a series of 6-substituted nicotine derivatives (53) led to the conclusion that affinity for rat brain... 

An acyl-lactone rearrangement has been utilized in synthesizing nicotine (94), myosmine (94), and iV-methylanabasine (95). Ethyl nico-tinate and 1-methyl-2-pyrrolidone treated with potassium in dry ether gave 3-nicotinoyl-l-methyl-2-pyrrolidone (LXIII). LXIII was hydrolyzed with acid to LXIV which on hydrogenation gave dLnicotine. 

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