Piperidine reaction with

A recent synthesis of racemic conhydrine (163) was reported in which lithiation of A-BOC piperidine, reaction with DMF, and then reaction with ethyl magnesium chloride gave the protected diastereomeric conhydrines. Chromatographic separation followed by hydrolysis of the BOC group gave 163 [436],... 

Like butadiene, allene undergoes dimerization and addition of nucleophiles to give 1-substituted 3-methyl-2-methylene-3-butenyl compounds. Dimerization-hydration of allene is catalyzed by Pd(0) in the presence of CO2 to give 3-methyl-2-methylene-3-buten-l-ol (1). An addition reaction with. MleOH proceeds without CO2 to give 2-methyl-4-methoxy-3-inethylene-1-butene (2)[1]. Similarly, piperidine reacts with allene to give the dimeric amine 3, and the reaction of malonate affords 4 in good yields. Pd(0) coordinated by maleic anhydride (MA) IS used as a catalyst[2]. 

Pyrylium perchlorate, 2,4,6-triphenyl-hydrolysis, 3, 741 nitration, 3, 649 reactions with alkali, 3, 652 with methoxides, 3, 652 with piperidine, 3, 655 synthesis, 3, 869... 

The dimethyl acetal (94) is readily prepared from the 22-aldehyde (93) by direct reaction with methanol in the presence of hydrogen chloride. Ena-mines (95) are formed without a catalyst even with the poorly reactive piperidine and morpholine.Enol acetates (96) are prepared by refluxing with acetic anhydride-sodium acetate or by exchange with isopropenyl acetate in pyridine.Reaction with acetic anhydride catalyzed by boron trifluoride-etherate or perchloric acid gives the aldehyde diacetate. 

Other secondary amines such as pyrrolidine, di- -butylamine, tetrahydro-quinoline, n-benzylamine, and piperidine were also found to be capable of effecting this reduction. Interestingly, morpholine does not reduce enamines as readily (47) and its acid-catalyzed reaction with norbornanone was reported (45) to give only the corresponding enamine (93), although trace amounts of the reduction product were detected when cyclohexanone was treated with morpholine under these conditions (47a). The yield of morpholine reduction product was increased by using higher temperatures. 

Steroidal a,j8-unsaturated ketones such as /l -3-ketones undergo a facile reaction with pyrrolidine to give the corresponding, d - -dienamines (111) (40,53). The reaction is much slower with morpholine and piperidine, which is undoubtedly due to the generation of the double bond exocyclic to the six-membered hetero rings in the step involving the dehydration of the intermediate carbinolamine (112) to the corresponding iminium ion (113). 

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

Cleavage at A or G If the DNA is first treated with acid, dimethyl sulfate methylates adenine at the 3-position as well as guanine at the 7-position (not shown). Subsequent reaction with OH and piperidine triggers degradation and displacement of the methylated A or G purine base and strand scission, essentially as indicated here for reaction of dimethyl sulfate with guanine. 

An indole protected by a Mannich reaction with formaldehyde and dimethyl-amine is stable to lithiation. The protective group is removed with NaBH4 (EtOH, THE, reflux). The related piperidine analogue has been used similarly for the protection of a triazole. ... 

Marazano and co-workers have used the Zincke reaction extensively to prepare chiral templates for elaboration to substituted piperidine and tetrahydropyridine natural products and medicinal agents. For example, 3-picoline was converted to Zincke salt 40 by reaction with 2,4-dinitrochlorobenzene in refluxing acetone, and treatment with R- -)-phenylglycinol in refluxing n-butanol generated the chiral pyridinium 77. Reduction to... 

The same amino compounds also underwent reactions with a series of 3-cyano-4-imino- and 3-cyano-4-oxo-piperidines to yield 4-amino-5,0,7,8-tetrahydropyrido[4,3-d]pyrimidines. . A tetra-hydropyTido[4,3-prepared from 4-amino-l-henzyl-3-cyano-d -piperidine (134) hy a simple one-step preparation. This method is of general application for the preparation of fused pyrimidines and previous papers in this field are listed by Taylor. ... 

The incompleteness of the other data precludes generalization. However, a few apparent inconsistencies may be indicated to stimulate further research. Insertion of another aza group into 2-chloroquinoline causes the reactivity sequence o >m (reaction with piperidine) or, even, o reaction with CgHsO"), involving only relatively small factors and, in any case, in sharp contrast with the above-mentioned effects on 2-chloropyridine as a substrate. Further, meta-aza activation in all cases involving the ethoxide ion is fairly strong suggest-... 

From the standpoint of geometrical considerations, the major difference is in the far greater steric requirements of the nitro group. This could result in either primary or secondary steric effects. Nevertheless, primary steric effects do not seem to be necessarily distinguishable by direct kinetic comparison. A classic example is the puzzling similarity of the activation parameters of 2-chloropyrimidine and 2,6-dinitrochlorobenzene (reaction with piperidine in ethanol), which has been described by Chapman and Rees as fortuitous. However, that nitro groups do cause (retarding) primary steric effects has been neatly shown at peri positions in the reaction with alkoxides (see Section IV,C, l,c). 

Secondary steric effects of nitro groups are more easily detected by comparing the reactivities with those of aza derivatives. For example, in structure 20 the rate depression on passing from methyl to -butyl is only 2.5-fold and can be attributed to an inductive effect, whereas in structure 21 a similar change involves the factor 16, which can be attributed in part to steric inhibition of resonance (S.I.R.) of thep-N02 group (reaction with piperidine). 

Okamoto et al. found that A-oxidation activates 4-halogeno-quinolines in the reaction with piperidine in aqueous alcohol by kinetic factors of 9 to 25, at 100°. This rate-enhancing effect is accompanied by a fairly large decrease in the enthalpy of activation (up to 10 kcal/mole in the chloro compounds), the effect of which is partly offset by a decrease in the entropy of activation. 

In non-polar solvents, the reaction with piperidine is best represented by a two-term kinetic form indicating a mixed 2nd- and 3rd-order reaction. Also, base catalysis by tri-ri-butylamine was observed. This kinetic pattern is strongly reminiscent of the results obtained with nitro-activated benzenes.Another interesting result is that stepwise replacement of chlorine atoms by amino groups results in marked... 

The para direct deactivation (toward excess piperidine, 45°) by a 4-methyl substituent on 2-nitrobromobenzene (164) is greater than para indirect deactivation by a 5-methyl group (rate of displacement equivalent to absence of a methyl group). A similar result was obtained with 2-nitrochlorobenzenes substituted by methyl or methoxy groups in the reaction with piperidine in benzene. 

The effect of the leaving group is illustrated in the comparison of fluoro- and chloro-nitrobenzenes (Table VIII) in their reactions with ethoxide ion (lines 5 and 8) and with piperidine (lines 7 and 9). Rate ratios F Cl are 23 1 (opposing and entropy of activation changes) and 201 1 (E effect), respectively, for the two nucleophiles. For the reasons discussed in Section II, D, 1, a fluorine substituent produces a lower energy of repulsion of the nucleophile and thus facilitates reaction. 

The work of Okamoto et on quinoline and quinoline-l-oxides (Table XI) provides the following relation of solvent to the rate of reaction with piperidine A 7oo/ aic. = 1.5-2.5 x = 80-200 x A benzene-... 

The relations 4- > 2-position in rate and 4- < 2-position in will apparently apply to reactions with anions, but the reverse relation is observed in piperidination, presumably due to 2-substitution being favored by hydrogen bonding in the zwitterionic transition state (cf. 47, 59, and 277) or by solvent-assisted proton removal from the intermediate complex (235). Substitutions of polychloroquino-lines (in which there is a combined effect of azine-nitrogen and unequal mutual activation of the chlorine substituents) also show 4- > 2-position in reactivity contrary statements are documented by these same references. Examples are cited below of the relation 2- > 4-position when a protonated substrate or a cyclic transition state is involved. 

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