Synthesis of 1-benzyl-3,6-diazahomoadamantane

By condensation of 4-phenylbutan-2-one with tetramethylenediethylenetetramine 1-benzyl-3,6-diazahomoadamantan-9-one was synthesized. Further nitration of 1-benzyl-3,6-diazahomoadamantan-9-one yielded 1-(4-nitrobenzyl)-3,6-dia?ahomoadamantan-9-one. The modification of the nitro and carbonyl groups resulted in the formation of 1-benzyl-3,6-diazahomoadamantane and its derivatives with functional groups in the benzene ring and at the bridge carbon atom C⁹.     

4‐(Piperidin‐1‐yl)pyridinium hexafluorophosphate at 150 K

Structural characterization of the title compound, C₁₀H₁₅N₂⁺·PF₆⁻, shows it to be ionic, with the pyridine rather than the piperidine N atom being protonated and forming hydrogen bonds to the counter‐ions, resulting in two independent ion pairs. A number of unusual features are noted, in particular the remarkably close inter‐ring hydrogen contacts [1.97 (3)–2.00 (3) Å] and the considerable differences in the pair of cations, in respect of the torsion angles within the piperidine ring involving the bonds to either side of the N atom.     

Development of two diastereoselective routes towards trans-4-aminomethyl-piperidin-3-ol building blocks

Two diastereoselective, scaleable routes towards trans-3,4-disubstituted piperidines with a 4-hydroxymethyl-3-hydroxy or 4-aminomethyl-3-hydroxy substitution pattern are being described. In the first route, the 3,4-trans configuration was introduced regio- and diastereoselectively via a hydroboration/oxidation sequence starting from 4-hydroxymethylpyridine. In the second route, regioselective epoxide ring opening of N-benzyl-3,4-epoxy-piperidine was achieved with LiCN, in situ generated from acetocyanohydrin and LiNH₂. The regioselectivity of both the hydroboration and the epoxide ring opening was positively influenced by the presence of the basic piperidine nitrogen. Both routes have been optimized to be performed at large scale.     

Amination of <Emphasis Type="Italic">meso</Emphasis>-bromophenyl(polyalkyl)porphyrins: Synthesis of porphyrins containing a hydroxypiperidine fragment

5,15-Bis(4-bromophenyl)-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin and 5-(4-bromophenyl)-13,17-dibutyl-2,3,7,8,12,18-hexamethylporphyrin were synthesized, and their palladium-catalyzed amination with a number of cyclic secondary amines, including hydroxypiperidines, was studied [Pd(OAc)₂, ligand, THF or dioxane, t-BuONa, 80–100°C]. The reactions of the meso-bromophenylporphyrins with piperidine and morpholine gave the corresponding amination products in quantitative yield. The amination with hydroxypiperidines required excess amine (3 equiv per bromine atom) and excess base (6–8 equiv) and was accompanied by formation of hydrodebromination products; in the reactions with the bis(bromophenyl)derivative, mixed products resulting from amination at one phenyl group and reductive debromination at the other were also formed. The yields of the amination products varied from good {75–50% in the reactions with 4-hydroxypiperidine and trans-3-hydroxy-4-[4-(2-fluorophenyl)piperazin-1-yl]piperidine} to moderate (20–50%, 3-hydroxypiperidine) and poor [11–25%, trans-3,4-dihydroxypiperidine and trans-3-hydroxy-4-(4-hydroxypiperidin-1-yl)piperidine].     

Some reactions of 5-benzyl-2,3,5-trichloro-4,4-dimethoxy-cyclopent-2-en-1-one and its derivatives

5-Benzyl-2,3,5-trichloro-4,4-dimethoxycyclopent-2-en-1-one and 2-benzyl-2,4,5-trichlorocyclopent-4-ene-1,3-dione were subjected to dehydrochlorination by the action of 1,4-diazabicyclo[2.2.2]octane, selective dechlorination at C⁵ by the action of CrCl₂, and Ad_NE replacement of the chlorine atom at C³ by the action of secondary amines. The reduction of 2-benzyl-2,4-dichloro-5-morpholinocyclopent-4-ene-1,3-dione with sodium tetrahydridoborate in methanol and ethanol gave different products.     

Synthesis,structural, conformational and biochemical study of some 3β-acyloxytropan-3α-carboxylic acid hydrochlorides

A series of 3β-acyloxytropan-3α-carboxylic acid hydrochlorides have been synthesized and studied by ¹H and ¹³C nmr spectroscopy, and the crystal structure of 3β-(3,4,5-trimethoxybenzoyloxy)tropan-3α-carboxylic acid hydrochloride 4c has been determined by X-ray diffraction. The compounds studied display in methanol-d₄ the same preferred conformation. The pyrrolidine and piperidine rings adopt a flattened N8 envelope and distorted chair conformation; puckered at N8 and flattened at C3 respectively with the N-substituent in equatorial position with respect to the piperidine ring. In all cases, there is only one mode (axial) of proton uptake at the piperidine nitrogen atom. These results are in close agreement with that found for compound 4c in the crystalline state. The inhibitory ability of the title compounds upon ³ H -GABA binding to sinaptosomal brain membranes is also reported.     

t‐3‐Iso­propyl‐1‐methyl‐r‐2,c‐6‐di­phenyl­piperidin‐4‐one thio­semi­carbazone

The piperidine ring in the title compound, C₂₂H₂₈N₄S, exhibits a chair conformation. The thio­semicarbazone moiety adopts an extended conformation, and the planar phenyl rings are oriented equatorially with respect to the piperidine ring. Two intermol­ecular hydrogen bonds involving the S atom form molecular pairs, and the crystal structure is stabilized by weak C—H⃛π interactions in addition to van der Waals forces.     

Convenient synthesis of trans-3-amino-1-benzylpiperidin-4-ols using regiospecific cleavage of 1-benzyl-3,4-epoxypiperidine with diisobutylaluminum amides (DIBAL-NR1R2)

The report presents a first example of a regio- and stereospecific Lewis acid-catalyzed aminolysis of 1-benzyl-3,4-epoxypiperidine leading to trans-3-amino-1-benzylpiperidin-4-ols, in contrast with other Lewis acid-catalyzed reactions leading to trans-4-amino-1-benzylpiperidin-3-ols. The reaction is performed at room temperature using the reagents prepared by interaction of a hard Lewis acid – diisobutylaluminum hydride (DIBAL-H) with primary and secondary amines. The obtained products are potential intermediates on the way to stereochemical analogues of the antitumor piperidine alkaloid pseudodistomin D.     

Tetra‐μ2‐acetato‐diacetatodi‐μ3‐hydroxido‐tetrakis[piperidinecopper(II)] dihydrate

The title complex, [Cu₄(C₂H₃O₂)₆(OH)₂(C₅H₁₁N)₄]·2H₂O, possesses an unusual inversion‐symmetric tetranuclear copper framework, with each Cu^II atom displaying a square‐pyramidal geometry and one additional long Cu...O contact. The four piperidine ligands are terminal, one at each Cu^II atom, and the two hydroxide ligands are triply bridging. The six acetate ligands exhibit two distinct coordination modes, namely as two monodentate acetates and four bridging acetates that bridge the two inequivalent copper centres. The noncoordinating acetate O atom is involved in intramolecular hydrogen bonding with H atoms from the hydroxide and one piperidine ligand. In addition, extensive intermolecular hydrogen bonding involving the solvent water molecules is observed.     

Effect of Through‐Bond Interaction on Conformation and Structure in Rod‐Shaped Donor–Acceptor Systems. Part 2.

The crystal structures of seven N‐aryltropan‐3‐one (=8‐aryl‐8‐azabicyclo[3.2.1]octan‐3‐one) derivatives 1T1, 2T1, 2T2, 3T2, 5T2, 2T3 , and 3T3 are presented (Fig. 2 and Tables 1–5) and discussed together with the derivatives 1T2 and 4T2 published previously. The piperidine ring adopts a chair conformation. In all structures, the aryl group is in the axial position, with the plane through the aryl C‐atoms nearly perpendicular to the mirror plane of the piperidine ring. The through‐bond interaction between the piperidine ring N‐atom (one‐electron donor) and the substituted exocyclic C?C bond (acceptor) not only elongates the central C? C bonds of the piperidine ring but also increases the pyrimidalization at C(4) of the piperidine ring. Flattening of the C(2)–C(6) part of the piperidine ring decreases the through‐bond interaction.     

Effect of Through‐Bond Interaction on Conformation and Structure in Rod‐Shaped Donor–Acceptor Systems. Part 1

The crystal structures of five N‐arylpiperidin‐4‐one derivatives 2P2, 3P2, 5P2, 1P3 , and 2P3 are presented (Fig. 2 and Tables 1–5) and discussed together with the derivatives 1P2 and 4P2 published previously. In all but one structure, 1P2 , the aryl group is in an equatorial position. The piperidine ring adopts a normal chair conformation. In 1P2 , the piperidine ring central C? C bonds are significantly elongated, which is consistent with the idea that through‐bond interaction is more pronounced in the axial conformation. Through‐bond interaction also influences the pyramidalization at the piperidine C(4)‐atom in such a way that a strong interaction is directing the ethylene C‐atom C(9) into the axial direction.     

The interaction of 3-methyl-4-nitro-3-thiolene-1,1-dioxide with aliphatic amines

The reactions of 3-methyl-4-nitro-3-thiolene-1,1-dioxide with highly basic amines (pK _a of HB⁺ = 8.97–13.27), morpholine, piperazine, piperidine, cyclohexylamine, diphenylguanidine, and guanidine, proceed via deprotonation of methylene group at the C² atom of sulfolene ring with formation of ammonium thiolene nitronates. The products were characterized by IR, UV, and NMR (¹H, ¹³C, ²D) spectroscopy methods.     

7,8‐Dihydr­oxy‐4‐propyl‐1,2,3,4,4a,5,6,10b‐octa­hydro­benzo[f]quinolinium bromide monohydrate,a dopamine agonist

In the crystal structure of the title dopamine­rgic compound, C₁₆H₂₄NO₂⁺·Br⁻·H₂O, protonation occurs at the piperidine N atom. The piperidine ring adopts a chair conformation and the cyclo­hexene ring adopts a half‐chair conformation; together with the planar benzene ring, this results in a relatively planar shape for the whole mol­ecule. Classical hydrogen bonds (N—H⋯Br, O—H⋯Br and O—H⋯O) produce an infinite three‐dimensional network. Hydrogen bonds between water ­mol­ecules and Br⁻ anions create centrosymmetric rings throughout the crystal structure. Structural comparison of the mol­ecule with the ergoline dopamine agonist pergolide shows that it is the hydrogen‐bond‐forming hydr­oxy or imino group that is necessary for dopamine­rgic activity, rather than the presence of a phenyl or a pyrrole ring per se.     

1‐(2‐{4‐[6‐Hydro­xy‐2‐(4‐hydroxy­phenyl)­benzo­[b]­thiol‐3‐yl­carbonyl]­phenoxy}ethyl)­piperidinium chloride

The title compound, raloxifene hydro­chloride, C₂₈H₂₈NO₄S⁺·Cl^?, belongs to the benzo­thio­phene class of antiosteoporotic drugs. In the molecular cation, the 2‐phenol ring sustains a dihedral angle of 45.3 (1)° relative to the benzo­[b]­thio­phene system. The benzo­[b]­thio­phene and phenyl ring planes are twisted with respect to the carbonyl plane, with the smallest twist component occurring between the phenyl and carbonyl planes. The N atom bears the positive charge in the molecular cation and the piperidine ring adopts an almost perfect chair conformation. The Cl^? anion is involved in the formation of N—H?Cl and O—H?Cl intermolecular hydrogen bonds, which lead to the formation of a layer of molecular cations.     

Zwitterionic 5‐(1‐piperidiniomethyl)‐1H‐tetrazolide

The title compound, C₇H₁₃N₅, a tetrazole analogue of betaines, exists as a zwitterion, with the H atom of the tetrazole ring being transferred to the piperidine ring N atom. The tetrazole ring symmetry is close to C_2v, which suggests strong charge delocalization in the N—C—N fragment of the ring. There are classical hydrogen bonds in the structure which are responsible for the formation of two‐membered aggregates.     

2‐(2‐Naphthyloxy)acetate derivatives. I. A new class of antiamnesic agents

The title compounds 1‐(2‐naphthyloxymethylcarbonyl)piperidine, C₁₇H₁₉NO₂, (I), and 3‐methyl‐1‐(2‐naphthyl­oxy­methyl­carbonyl)­piperidine, C₁₈H₂₁NO₂, (II), are potential antiamnesics. In (II), the methyl‐substituted piperidine ring is disordered over two conformations. The piperidine ring has a chair conformation in both compounds. In (I), the mol­ecules are linked by weak intermolecular C—H⃛O interactions to give networks represented by C(4), C(6) and (18) graph‐set motifs, while in (II), weak intermolecular C—H⃛O interactions generate (5), C(4) and C(7) graph‐set motifs. The dihedral angle between the naphthalene moiety and the piperidine ring is 33.83 (7)° in (I), while it is 31.78 (11) and 19.38 (19)° for the major and minor conformations, respectively, in (II).     

1H Nmr structural analysis of azabicyclospirohydantoins

Based on the data from ¹H nmr spectra, the structure and spatial configuration of the ahove mentioned hydantoins are established. In the 3-alkyl-3-azabicyelo[3.3.f ]nonane-9-spiro-5′-hydantoins analyzed, we confirm the chair-chair configuration and the presence of only one stereoisomer at the spiro carbon atom (with the C₄′=() group axial with regard to the piperidine ring). In the 3,7-dialkyl-3,7-diazabieyclo[3.3.1 ]nonane-9-spiro-5′-hydantoins analyzed, we also confirm the chair-chair configuration and we calculate the percentage of the two stereoisomers when they exist.     

Intermolecular C—H...O and C—H...X interactions in substituted spiroacenaphthylene structures

In the three spiroacenaphthylene structures 5′′‐[(E)‐2,3‐dichlorobenzylidene]‐7′‐(2,3‐dichlorophenyl)‐1′′‐methyldispiro[acenaphthylene‐1,5′‐pyrrolo[1,2‐c][1,3]thiazole‐6′,3′′‐piperidine]‐2,4′′‐dione, C₃₅H₂₆Cl₄N₂O₂S, (I), 5′′‐[(E)‐4‐fluorobenzylidene]‐7′‐(4‐fluorophenyl)‐1′′‐methyldispiro[acenaphthylene‐1,5′‐pyrrolo[1,2‐c][1,3]thiazole‐6′,3′′‐piperidine]‐2,4′′‐dione, C₃₅H₂₈F₂N₂O₂S, (II), and 5′′‐[(E)‐4‐bromobenzylidene]‐7′‐(4‐bromophenyl)‐1′′‐methyldispiro[acenaphthylene‐1,5′‐pyrrolo[1,2‐c][1,3]thiazole‐6′,3′′‐piperidine]‐2,4′′‐dione, C₃₅H₂₈Br₂N₂O₂S, (III), the substituted aryl groups are 2,3‐dichloro‐, 4‐fluoro‐ and 4‐bromophenyl, respectively. The six‐membered piperidine ring in all three structures adopts a half‐chair conformation, the thiazolidine ring adopts a slightly twisted envelope and the pyrrolidine ring an envelope conformation; in each case, the C atom linking the rings is the flap atom. In all three structures, weak intramolecular C—H...O interactions are present. The crystal packing is stabilized through a number of intermolecular C—H...O and C—H...X interactions, where X = Cl in (I) and F or S in (II), and C—H...O interactions are observed predominantly in (III). In all three structures, molecules are linked through centrosymmetric ring motifs, further tailored through a relay of C—H...X [Cl in (I), Br in (II) and O in (III)] interactions.     

Chemo-, regio-, and stereoselectivity in acid-catalyzed hydromethoxylation of tricyclo[4.1.0.0<Superscript>2,7</Superscript>]hept-1-yl and 7-methyltricyclo[4.1.0.0<Superscript>2,7</Superscript>]hept-1-yl phenyl sulfones

Hydromethoxylation of tricyclo[4.1.0.0^2,7]hept-1-yl and 7-methyltricyclo[4.1.0.0^2,7]hept-1-yl phenyl sulfones with methanol at 20°C in the presence of a catalytic amount of perchloric acid is initiated by the endo attack of proton at the C¹ atom, and the subsequent cleavage of the side C¹–C² bond leads to formation of mixtures of diastereoisomeric exo-7-phenylsulfonyl-2-methoxybicyclo[4.1.0]heptanes, the endo-2 isomer prevailing. Probable factors responsible for the observed chemo-, regio-, and stereoselectivity of the addition are discussed.     

Two isomers of 2,4‐di­benzyl‐8‐azabicyclo­[3.2.1]­octan‐3‐ol

The crystal structures of the title compounds, 2α,4α‐di­benzyl‐3α‐tropanol (2α,4α‐di­benzyl‐8‐methyl‐8‐aza­bi­cyclo­[3.2.1]­octan‐3α‐ol), C₂₂H₂₇NO, (I), and 2α,4α‐di­benzyl‐3β‐tropanol (2α,4α‐di­benzyl‐8‐methyl‐8‐aza­bi­cyclo­[3.2.1]­octan‐3β‐ol), C₂₂H₂₇NO, (II), show that both compounds have a piperidine ring in a chair conformation and a pyrrolidine ring in an envelope conformation. Isomer (I) is asymmetric, the benzyl groups having different orientations, whereas isomer (II) is mirror symmetric, and the N and O atoms, the C atom attached to the hydroxy group, and the methyl C atom attached to the N atom lie on the mirror plane. In the crystal structures of both (I) and (II), the mol­ecules are linked together by intermolecular O—H⋯N hydrogen bonds to form chains that run parallel to the a direction in (I) and parallel to b in (II).