Facile and General Synthesis of 2‐, 3‐, or 4‐[(Dialkylamino)alkyl]pyridines and ‐piperidines

Abstract

Reaction of (dialky1amino)alkyl chloride with picolyllithiums provides the corresponding pyridine derivatives from which the piperidines are obtained by catalytic hydrogenation.[(Dialkylamino)alkyl]pyridines and -pipendines are compounds of considerable importance in organic synthesis. Many drugs contain [(dialkylamino)alkyl]piperidines. A number of synthetic methods have been developed for the preparation of these compounds but most of them are not totally satisfactory and lack generality. Examples are the reaction of respective pyridylalkyl alcohol with hydrogen bromide and treatment of the resulting bromine derivative with secondary amine ['-3], addition of primary or secondary amina to ~inylpyridine[~-~I, or reduction and decomposition of We now report on an efficient and straightforward synthesis of pyridines 2 and piperidines 3 from 2-, 3-, or 4-picolyllithium 1 as shown in Scheme 1. Thus, reaction of alkylaminoalkyl chlorides with 1 provides derivatives 2 in good yields. These intermediates were transformed into the corresponding piperidines 3 by catalytic reduction (platinum oxide).This work was supported in part by grant NS22215 from the National Institute of Health and DE FG0582ER60649 from the Department of Energy. Experimental'H-NMR spectra: Bruker AC-300, TMS as internal standard. Picolines, 3-(diethylamino)-l-propanol, 3-(dimethylamino)-l-pro-panol, 2-(diethylamino)ethyl chloride hydrochloride, 2-(dimethylamino)ethyl chloride hydrochloride, 3-(dimethy1amino)propyl chloride hydrochloride, diisopropylamine, hexamethylphosphorous triamide (HMPT), n-butyllithium, platinum(1V) oxide, thionyl chloride, and THF were obtained from Aldrich. 4-(Dimethylamino)-1-butanol was purchased from American Tokyo Kasaei, Inc. (Tables 1 and 2). -4-[4-(Diethylamino) butyllpyridine (2g): The procedure described by Kaiser et a1.[I0] was followed. To a solution of 10.12 g (0.1 mol) of diisopropylamine in THF (100 ml) -with stirring at 0°C -a solution of n-butyllithium in hexane (0.1 mol, 2.5 M in hexane, 40 ml), was added by a syringe gradually. The mixture was then stirred for 15 min at 0°C. Hexamethylphosphoric triamide (17.92 g, 0.1 mol) in THF (40 ml) was added and the resulting solution was stirred for 15 min at 0°C. The bright yellow solution was then treated during 20 min with a solution of 4-methylpyridine (9.31 g, 0.1 mol) in THF (40 ml). Stirring was continued at 0°C for 30 min, and 3-(diethy1amino)propyl 2-(Ethylamino)ethyl

C(8) Substituted 1-Azabicyclo[3.3.1]non-3-enes and C(8) Substituted 1-Azabicyclo[3.3.1]nonan-4-ones: Novel Muscarinic Receptor Antagonists

“…The overall yield of 13c from 12c was 57% compared to the 13% yield obtained in Scheme 1. 13 C NMR analysis indicated that the ratio of cis-to trans-13c was approximately 0.16:1, respectively. Dieckmann cyclization of the cis-and trans-mixture 13c gave 3 and 4 (69% yield) in an approximate 1:1 ratio.…”

“…We are unaware of other general methods for this ring system. Accordingly, we adopted the Dieckmann route − and first coupled it with a more recent procedure for the synthesis of 2,5-disubstituted piperidines from the corresponding pyridine − (Scheme ).

1 Synthesis of Aza-Bridged [3.3.1]-Bicyclic Amines

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“…Several pyridine-reductive methods have been reported. − , For C(2) substituted methylene pyridines, piperidine formation is accompanied by competitive reduction of the C(2) methylene substituent. We examined several methods and found, for 12c and 12e , that PtO 2 , H 2 , and acid 12-14 provided the desired piperidines.…”

“…The catalytic reduction of 12c and 12e proceeded stereoselectively to give 13c and 13e as a single diastereomer after the Michael addition with ethyl acrylate while the C(2) methyl piperidine 15 byproduct was generated as an approximate 1:1 diastereomeric mixture. The 13 C NMR provided information concerning piperidine 13 and 15 structures. For 15, we observed diagnostic signals for the C(2) (δ 53.5, 55.1) and the C(5) (δ 41.2, 42.2) carbons in the cis-and trans-products.…”

“…In this investigation, we combined older, more recent, and new synthetic methodologies for the preparation of 1. X-ray and 13 C NMR spectroscopic studies are coupled to provide useful structural tools for the stereochemical assignments of [3.3.1]-bicyclic amine ring substituents. We report the pharmacological activity of these compounds against the human M 1 -M 5 muscarinic receptors and document their potent activity against these receptors.…”