2-Alkyl-6-methylpiperidines

Venoms from the fire ants Solenopsis invicta and 5. geminata are free of detectable histamine but possess histamine-release activity. This activity can account for the edema, itch, redness, warmth, and possibly the pain and burning sensations resulting from fire ant stings. And it can be attributed to the piperidines which constitute the major component of the venom. It has actually been proved that 6-methyl-2-n-undecylpiperidines (Ic and Id), components of S. geminata, possess the histamine-release activity (75). Due to some of the above-mentioned various activities the piperidine alkaloids play roles as defensive compounds. In addition to 2-alkyl-6-methylpiperidines, their N-methyl derivatives (3) are found in S. pergandei, S. carolinensis, and S. conjurata, and 1-piperideine derivatives (6 and 7) in S. sp. A (Puerto Rico) and S. xyloni (Table I). 

Alkyl-6-methylpiperidines have only been detected in the venoms of Solenopsis workers and their queens (16, 17, 18). These compounds, which are sometimes referred to as solenopsins, are consistent poison gland products of Solenopsis species in the subgenus Solenopsis, the fire ants ( T7, 3J3J. In addition, some species in the subgenus Diplorhoptrum (thief... 

The cis-trans isomers of four 2-alkyl-6-methylpiperidines, in which the alkyl groups consist of relatively long alkyl chains (C9-Ci5), have been identified in fire ant venoms (XI) (15, 17) members of each Solenopsis (Solenopsis) species group appear to produce characteristic alkaloids. The presence of a fifth 2-alkyl-6-methylpiperidine, 2-hepytl-6-methylpiperidine, in the venom of queens of S. richteri is indicated by mass spectral data (20). ... 

These results emphasize the broad spectrum activities of 2-alkyl-6-methylpiperidines which offer novel probes for identifying and exposing target sites for new classes of insect neurotoxins (33). ... 

A nitrogen atom at X results in a variable downfield shift of the a carbons, depending in its extent on what else is attached to the nitrogen. In piperidine (45 X = NH) the a carbon signal is shifted by about 20 p.p.m., to ca. S 47.7, while in A-methylpiperidine (45 X = Me) it appears at S 56.7. Quaternization at nitrogen produces further effects similar to replacement of NH by A-alkyl, but simple protonation has only a small effect. A-Acylpiperidines show two distinct a carbon atoms, because of restricted rotation about the amide bond. The chemical shift separation is about 6 p.p.m., and the mean shift is close to that of the unsubstituted amine (45 X=NH). The nitroso compound (45 X = N—NO) is similar, but the shift separation of the two a carbons is somewhat greater (ca. 12 p.p.m.). The (3 and y carbon atoms of piperidines. A- acylpiperidines and piperidinium salts are all upfield of the cyclohexane resonance, by 0-7 p.p.m. 

One obvious way in which to attach a nitroxide group to B12 is to simple alkylate Cob(I)aiamin with a suitable nitroxide derivative. This would result in having the nitroxide covalently bound to the corrinoid at the upper axial coordination position of the cobalt. Such a procedure is outlined in Fig. 19. In this reaction 4-bromoacetamido 2,2,6,6-tetra-methylpiperidine-N-oxyl is used to alkylate Cob(I)alamin. This results in a Co(III)-nitroxalkylcobalamin. The corresponding cobinamide can then be produced by hydrolyzing the ribose-phosphate linkage (119). 

Alkylation of pyrrohdine and piperidine heterocycles was investigated extensively by Gawley and coworkers. The initial evaluation of 2-lithio-A-methylpiperidine and 2-lithio-A-methylpyrrolidine as nucleophiles was conducted on racemic material, but... 

Thioridazine Thioridazine, 10-[2-(l-methyl-2-piperidyl)ethyl]-2-(methylthio)phenoth-iazine (6.1.9), is synthesized in an analogous manner by alkylating 2-methylthiophenoth-iazine with 2-(2-chloroethyl)-l-methylpiperidine [29,30]. 

Mesoridazine Mesoridazine, I0-[2-(I-methyI-2-piperidyI)ethyI]-2-(methyIsnfmyI)phe-nothiazine (6.1.13), is synthesized by an analogons scheme, however, it is also synthesized by alkylating the acidic form of 2-methylthiphenothiazine—methylsnlfonylphenothiazine — using 2-(2-chlorethyl)-l-methylpiperidine. 

Diphenylpyraline Diphenylpyraline, 4-diphenylmethoxy-l-methylpiperidine (16.1.32), is synthesized by alkylating 4-hydroxy-1-methylpiperidine with benzhydrylbromide [49,50]. 

The difference in conformational free energy of the N-Me group in N-methylpiperidine (2.7 kcal mol-1, favoring N-Meeq) and in N-methyltetra-hydro-l,3-thiazine (0.7 kcal mol-1, favoring lV-Meax at -120°C) suggests the predominance of the lV-Meax conformer 463 of 5-methyldihydro-1,3,5-dithiazine (462 R = Me). Indeed, H-NMR spectra and dipole-moment data show that NR axial is the predominant conformer for a series of AT-alkyl-dihydro-l,3,5-dithiazines (462 R = Me, Et, iPr, -Bu).356 This even applies to the Af-tert-butyl compound, which possesses an unconstrained axial tert-butyl group.357... 

Aryl)thioindoxyls undergo both C- (in the 2-position) and O-alkylation in the presence of potassium terf-butoxide.609 The C-alkylated products (237) react with A-methylpiperidine-4-magnesium chloride to give compounds (238) (as mixtures of a- and /3-racemates), which lose water on treatment with hydrogen bromide to give 239. 

As expected, macroscale reduction gave products corresponding to those from reduction of the parent pyridine, that is, piperideines and piperidines. Electrolysis of a series of N-alkyl-substituted 2-pyridones, for example N-methyl-(79), yielded a mixture of A-methylpiperidine and -piperideine 80.126 Reduction of the methyl ether of 2-pyridone gave piperidine only.127... 

Gawley, R. E. Zhang, Q. Alkylation of 2-lithio-N-methylpiperidines and -pyrrolidines scope, 534 limitations, and stereochemistry. J. Org. Chem. 

Cyanopiperidines are useful reagents that allow stereoselective alkylation at the 2-position and can be decya-nated with predictable outcomes. Alkylation of 2,4-/ra .r-iV-phenyl-2-cyano-4-methylpiperidine 268 results in formation of the 2,4-m-dialkyl product 269 (Scheme 65) <2002SL895>. A wide variety of alkyl halides can be employed... 

Hydroxy-3-methylpyridine was hydrogenated to 3-methyl-2-piperidone in an 80% yield over Raney Ni in methanol at 200-240°C and 12 MPa H2 (eq. 12.28).40 At 280°C, hydrogenolysis to give 3-methylpiperidine and A-alkylation to give 1,3-di-methylpiperidine took place. In contrast, l-methyl-2-pyridone is hydrogenated under much milder conditions to the corresponding 2-piperidone over Raney Ni in ethanol (eq. 12.29).41... 

No comparison between trialkyloxonium fluoroborates and dialkyl sulfates has been made, but analysis of available data shows that oxonium salts are more generally applicable reagents for the preparation of lactim ethers. The alkylation of 3-carbethoxypiperid-2-one (7)25 and morpholin-3-one (8)32 with dimethyl sulfate failed, but with triethyloxonium fluoroborate these compounds gave 2-ethoxy-3-carbethoxy-3,4,5,6-tetrahydropyridine (9) and 3-ethoxy-3,4-dehydro-morpholine (10) in excellent yield. The selective character of triethyloxonium fluoroborate is shown in its reaction with 3,3-diethyl-5-methylpiperidine-2,4-dione (11 ).25 Reaction of 11 with the calculated quantity of dimethyl sulfate resulted in alkylation of the carbonyl group in position 4 with formation of 12, but reaction of 11 with triethyloxonium fluoroborate gave the lactim ether (13). 

CK-6-Alkyl-l-methylpiperidines. Reductive aminocyclization of 2.6-diones (I) affords c7. v-2,6-dialkylpiperidines (2) exclusively. 

Alkyl- and 2,6-dialkyl-piperidine alkaloids have been synthesized by the alkylation of cyclic a-ami-nonitriles such asN-benzyl-2-cyano-6-methylpiperidine or l-benzyl-2,6-dicyanopiperidine. 29... 

The deprotonation of an jp -hydrogen a to nitrogen has been developed into a highly useful synthetic tool in recent years. - Although some authors have suggested that this type of reactivity is a reversal of the normal reactivity adjacent to nitrogen, we submit that this notion is inappropriate and should be discontinued. The a-deprotonation of dimethyldodecylamine and triethylamine was reported over 20 years ago. In 1984, Ahlbrecht reported that j-butylpotassium readily deprotonates N-methylpiperidine, N-methylpyrrolidine and triethylamine, and that the derived organometallics add readily to aldehydes, ketones and alkyl halides. An example is shown in Scheme 1. 

Racemic sedaminone (180) was synthesized in the same manner as reported for N-methylpelletierine (170), via alkylation of an S-methylthioamidium salt generated from N-methylpiperidine-2-thione [444]. 

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