Synthesis of substituted tetrahydropyridines by cyclizations of silicon-containing iminium ions

Trans-2,6-disubstituted-1,2,5,6-tetrahydropyridines are formed stereoselectively from the cyclization of silicon-containing iminium cations 5 if the nitrogen substituent R¹ is an alkyl group. In contrast, cyclization of the corresponding NH or N-acyl iminium ions occurs in a stereorandom fashion. Nonracemic tetrahydropyridines cannot be prepared in this way, since both iminium ion and N-acyliminium ion intermediates racemize prior to cyclization.     

Cationic carbohydroxylation of alkenes and alkynes using the cation pool method

The reactions of an N-acyliminium ion pool with alkenes and alkynes gave gamma-amino alcohols and beta-amino carbonyl compounds, respectively, after treatment with H(2)O/Et(3)N. The present reaction serves as an efficient method for cationic carbohydroxylation of alkenes and alkynes. When vinyltrimethylsilane was used as an alkene, the reaction was highly diastereoselective and served as an access to an enantiomerically pure alpha-silyl-gamma-amino alcohol. [reaction: see text]     

Allylation of exocyclic N-Acyliminium ions generated from chiral N-[1-(phenylsulfonyl)alkyl]oxazolidin-2-ones

N-[1-(Phenylsulfonyl)alkyl]oxazolidin-2-ones are successfully prepared by condensation of the corresponding optically active oxazolidin-2-ones with aldehydes and benzenesulfinic acid. At low temperature, in the presence of titanium tetrachloride, these sulfones are converted into N-acyliminium ions, which react with allyltrimethylsilane with a variable degree of stereoselectivity. The best results are obtained with (R)-5,5-dimethyl-4-phenyloxazolidin-2-one as a chiral auxiliary. Cleavage of the oxazolidin-2-one ring with lithium/ammonia affords the corresponding homoallylamines, which reveal an absolute configuration opposite that expected on the basis of the usual steric effects. A complexation of the Lewis acid with the N-acyliminium ion may be responsible of this rather unusual stereochemical outcome.     

Acyclic stereoselection in the reaction of nucleophilic reagents with chiral N-acyliminium ions generated from N-

Optically active N-[1-(phenylsulfonyl)alkyl]imidazolidin-2-ones react at low temperature in the presence of tin tetrachloride to give acyclic N-acyliminium ions. These electrophilic substrates give addition products upon reaction with pi-nucleophiles. Allyltrimethylsilane affords the corresponding allylated products in good yields and high diastereoselectivity. The stereochemical outcome of this process can be rationalized by taking into account the preference of the intermediate N-acyliminium ion for an E configuration that favors the attack of the nucleophile from the si-si face. Disappointing results are obtained using silyl ketene acetals; conversely trimethylsilyl enol ether of acetophenone gives the corresponding adducts in high diastereoselectivity. The utilization of trimethylsilyl enol ether of 2-acetylfuran is particularly interesting since the corresponding adducts are obtained with good diastereoselectivity and the furan ring could be amenable of further synthetic transformations.     

Three-component coupling based on the "cation pool" method

Sequential one-pot three-component coupling reactions have been developed based on the "cation pool" method. An N-acyliminium ion generated by the "cation pool" method adds to an electron-rich carbon-carbon double bond, such as enamine derivatives and vinyl sulfides, to form the second "cation pool". The addition of nucleophiles such as allylsilanes, enol silyl ethers, Grignard reagents, and organoaluminum compounds led to the formation of the corresponding three-component coupling products.     

Stereochemical memory effects in alkene radical cation/anion contact ion pairs: effect of substituents, and models for diastereoselectivity

A series of 12 stereochemically defined 2,m-dimethyl- and 2,m,n-trimethyl-6-benzylamino-2-nitro-3-(diphenylphosphatoxy)hexanes have been synthesized and their cyclization reactions leading to di- and trisubstituted N-benzyl pyrrolidines examined in the presence of tributyltin hydride and azoisobutyronitrile in benzene at reflux. The cyclizations are interpreted in terms of generation of an alkyl radical by abstraction of the nitro group with a stannyl radical. The phosphate leaving group is then expelled in a heterolytic cleavage to give a contact alkene radical cation/phosphate anion pair. For the majority of the examples studied, the cyclizations are best understood in terms of nucleophilic attack by the amine on the opposite face of the alkene radical cation to the one shielded by the leaving group, within the confines of the initial contact ion pair, resulting in overall cyclization with inversion of configuration. Dependent on the relative stereochemistry of the substituents, the cyclization is envisaged as taking place through either chair-like or twist-boat-like transition states with the maximum number of substituents pseudo-equatorial. The model breaks down when cyclization on the initial contact ion pair would engender significant destabilizing steric interactions, especially (1,3)A strain in the alkene radical cation. In these cases a fully equilibrated Beckwith-Houk-type transition state provides a satisfactory model. Interesting examples of matching and mismatching in the Corey-type oxazaborolidine-mediated reduction of alkyl (methyl-1-nitroethyl) ketones by a beta-methyl group in the alkyl chain are reported, and the mismatching is attributed to a developing syn-pentane interaction in the transition state.     

Pi-aromatic and sulfur nucleophilic partners in cationic pi-cyclizations: intramolecular amidoalkylation and thioamidoalkylation cyclization via omega-carbinol lactams(1, 2).

NaBH(4) reduction of imides 1 and 6a,b,c followed by a pi-cyclization of the resultant N-acyliminium ions, generated in trifluoroacetic acid conditions, afforded two positional isomers, isoindolobenzothiazolinones 4 and 8, respectively. These ring closures proceeded via an intramolecular alpha-amidoalkylation with the classical pi-aromatic or the atypical sulfur atom as an internal nucleophile. A ready access to the related six-membered N,S-heterocyclic compounds such as isoindolobenzothiazinones 20a and 21a is also described. During this reaction, we have shown that omega-carbinol lactam precursor 14a led to endocyclic and exocyclic N-acyliminium ions 18a and 19a in equilibrium via the cyclic aza-sulfonium ion A. The latter furnished the expected products 20a and 21a in good yields. Similarly, different omega-carbinol lactams 14b-e substituted at C-angular position afforded the corresponding isoindolobenzothiazinones 20b-e and 21b-e bearing an angular alkyl, aralkyl, or aryl group. In the case of methyl 14b and benzyl 14e groups, an additional amount of the dehydration products 16b and 31 was isolated. These results indicate that the isomerization-pi-cyclization takes place via the cleavage of the thioether linkage in acidic medium.     

Stereoselective formation of N-acyliminium ion via chiral N,O-acetal TMS ether and its application to the synthesis of beta-amino acids

[reaction: see text] The highly stereoselective synthesis of beta-amino acids via the chiral 4-phenyloxazolidinone-controlled linear N-acyliminium ion reaction has been achieved by employing chiral N,O-acetal TMS ethers. In addition, the mechanism of the excellent stereochemical outcome has been elucidated. The oxazolidinone auxiliary plays a dual role in stereocontrol: the E/Z geometry control of the N-acyliminium ion induced by an initial stereoselective amide reduction, leading to the chiral N,O-acetal TMS ether, and face control of the nucleophile attack in the N-acyliminium ion reaction.     

Polymer-supported stereoselective synthesis of benzimidazolinopiperazinones

We describe the efficient synthesis of 4,7,8,10-tetrasubstituted-(((4S,10aS)-3-oxo-3,4,10,10a-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)alkyl)amides on solid phase via tandem N-acyliminium ion cyclization-nucleophilic addition reactions. The synthesis proceeded with complete stereocontrol of a newly formed stereogenic center, provided crude material of high purity, and used commercially available building blocks under mild reaction conditions.     

Tandem polar/radical crossover sequences for the formation of fused and bridged bicyclic nitrogen heterocycles involving radical ionic chain reactions,and alkene radical cation intermediates,performed under reducing conditions: scope and limitations

It is demonstrated that phosphorylated forms of beta-nitro alcohols provide an excellent means of entry into beta-(phosphatoxy)alkyl radicals on exposure to tributyltin hydride and AIBN in benzene at reflux. These radicals then undergo heterolytic cleavage of the phosphate group to yield alkene radical cation/phosphate anion contact ion pairs which are trapped intramolecularly in a tandem polar/radical crossover sequence involving radical ionic chain reactions by allylic and propargylic amines. The substitution pattern of the alkene radical cation dictates the cyclization mode, and this may be engineered to form fused ring systems by an initial exo-mode nucleophilic cyclization or bridged bicyclic systems when the nucleophilic attack takes place in the endo-mode.     

Building addressable libraries: site-selective formation of an N-acyliminium ion intermediate

A strategy for site-selectively generating reactive N-acyliminium ion intermediates on a microelectrode array has been developed. The route capitalizes on the use of an electroauxiliary for building a methoxylated amino acid substrate, and then the electrochemical generation and solution phase confinement of acid in order to form the N-acyliminium ion. Keys to this strategy were the stability of an N-alpha-methoxyalkyl amide to basic reaction conditions and the generality of the electrogenerated acid conditions for conducting microelectrode array reactions in a site-selective fashion.     

Distannane mediated reaction of N-acyliminium ion pools with alkyl halides. A chain mechanism involving radical addition followed by electron transfer

Hexabutyldistannane was found to be an effective mediator allowing the reaction of N-acyliminium ion pools with alkyl halides. A chain mechanism involving the addition of an alkyl radical generated from an alkyl halide to an N-acyliminium ion followed by the one-electron reduction of the resulting radical-cation by distannane was proposed.     

A stable radical-substituted radical cation with strongly ferromagnetic interaction: nitronyl nitroxide-substituted 5,10-diphenyl-5,10-dihydrophenazine radical cation

A stable radical-substituted radical ion with strongly ferromagnetic intramolecular interaction (J) between the radical and radical ion sites is an attractive spin building block of organic magnets. We prepared 2-nitronyl nitroxide-substituted 5,10-diphenyl-5,10-dihydrophenazine radical cation, 1+. The 1+ salt was stable under aerated conditions at room temperature and had a large J/kB value (>/=+700 K).     

Identification of esters by collisional charge inversion of their enolate ions

The collisional charge inversion and neutralization-reionization (^?NR) mass spectra of the enolate ions of m/z 115 derived from the four butyl acetates, the two propyl propionates, ethyl butyrate, ethyl isobutyrate, methyl valerate, methyl 2-methylbutyrate and methyl 3-methylbutyrate were recorded. The major primary fragmentation reactions of the unstable carbenium ion formed by charge inversion involve elimination of an alkoxy radical to form a ketene or alkylketene molecular ion and formation of an alkyl ion consisting of the R¹ group of RCOOR¹. A minor fragmentation reaction involves elimination of an alkyl radical by cleavage of a C? C bond α to the ether oxygen. The alkylketene ions fragment by β-cleavage eliminating an alkyl radical to form an olefinic acylium ion. In most cases the charge inversion mass spectra of the enolate ions allow identification of the ester.     

A formal total synthesis of (+/-)-cephalotaxine using sequential N-acyliminium ion reactions

[reaction: see text] Novel synthesis of cephalotaxine 1 based on tertiary N-acyliminium ion chemistry starting from alkynylamide 2 was achieved. The key steps include the preparation of pyrroloisoquinoline 4 from alkynylamide 2, the ring expansion of pyrroloisoquinoline 4 to pyrrolobenzazepine 12, and the construction of cyclopentapyrrolobenzazepine ring system 6, all of which are derived from N-acyliminium ion intermediates.     

Synthesis and antibacterial activity of hydroxylated 2-arylbenzothiazole derivatives

Abstract

N-acyliminium reagents formed in situ from benzothiazole and alkyl chloroformates react with hydroxyarenes in a Friedel-Crafts manner, providing access to 2-(hydroxyaryl)-benzothiazolines with antibacterial properties.     

由N-苯基[1,3]苯并噁嗪正离子与烯烃[4+2]反应合成喹啉并[1,2-c][1,3]苯并噁嗪-6-酮衍生物

以BF3·OEt2 为催化剂, 在室温下通过4-羟基-N-苯基[1,3]苯并噁嗪-2-酮的脱羟基产生N-苯基[1,3]苯并噁嗪正离子, 然后与富电子烯烃发生Diels-Alder反应, 合成出了一系列喹啉并[1,2-c][1,3]苯并噁嗪-6-酮和喹啉并[1,2-c][1,3]萘并噁嗪-6-酮衍生物.     

Novel approach to trans-fused carbobicycles

The combination of a silicon directed N-acyliminium ion cyclization reaction and a subsequent S_N2′ substitution of an imide nitrogen with lithium dimethyl cuprate constitutes a novel approach to functionalized transfused carbobicycles.     

Mannich-type reactions in the gas-phase: the addition of enol silanes to cyclic N-acyliminium ions

The intrinsic gas-phase reactivity of cyclic N-acyliminium ions in Mannich-type reactions with the parent enol silane, vinyloxytrimethylsilane, has been investigated by double- and triple-stage pentaquadrupole mass spectrometric experiments. Remarkably distinct reactivities are observed for cyclic N-acyliminium ions bearing either endocyclic or exocyclic carbonyl groups. NH-Acyliminium ions with endocyclic carbonyl groups locked in s-trans forms participate in a novel tandem N-acyliminium ion reaction: the nascent adduct formed by simple addition is unstable and rearranges by intramolecular trimethylsilyl cation shift to the ring nitrogen, and an acetaldehyde enol molecule is eliminated. An NSi(CH(3))(3)-acyliminium ion is formed, and this intermediate ion reacts with a second molecule of vinyloxytrimethylsilane by simple addition to form a stable acyclic adduct. N-Acyl and N,N-diacyliminium ions with endocyclic carbonyl groups, for which the s-cis conformation is favored, react distinctively by mono polar [4(+) + 2] cycloaddition yielding stable, ressonance-stabilized cycloadducts. Product ions were isolated via mass-selection and structurally characterized by triple-stage mass spectrometric experiments. B3LYP/6-311G(d,p) calculations corroborate the proposed reaction mechanisms.     

Stereoselective total syntheses of the racemic form and the natural enantiomer of the marine alkaloid lepadiformine via a novel N-acyliminium ion/allylsilane spirocyclization strategy

Stereoselective total syntheses of the racemic form and the natural enantiomer of the tricyclic marine alkaloid lepadiformine (6) have been accomplished using a novel intramolecular spirocyclization of an N-acyliminium ion with an allylsilane to form the A/C rings as the key step. Introduction of the hydroxymethyl group at C-13 of the racemic spirocycle 11 was achieved using our methodology for oxidative radical-based remote functionalization of o-aminobenzamides, followed by copper-catalyzed addition of Grignard reagent 16 to the N-acyliminium ion intermediate derived from 15. Subsequent Tamao oxidation of silane 17 then afforded the requisite hydroxymethyl compound 19, which was converted to the dimethyl acetal 25 via hydroformylation followed by aldehyde protection. Hydrolysis of the benzamide moiety of 25 and subsequent protection of the primary alcohol gave amino acetal 27. The synthesis was concluded from 27 by a four-step procedure: acid-catalyzed ring closure, amino nitrile formation, introduction of the hexyl chain by a Grignard reaction to an iminium salt, and removal of the O-benzyl protecting group to give (+/-)-lepadiformine (6). The enantioselective total synthesis of 6 started from known optically pure bromide 37, derived from (S)-pyroglutamic acid, and followed a similar sequence involving the key spirocyclization of N-acyliminium ion 42. This synthesis has established the absolute configuration of naturally occurring lepadiformine to be 2(R),5(S),10(S),13(S).