Tris(trimethylsilyl)silane: an unprecedented enhancement in the diastereoselectivity of radical cyclisations to give 2,4-disubstituted piperidines

Cyclisation of bromides 4a-f mediated by tributyltin hydride affords predominantly the trans piperidines 5a-f with modest diastereomeric ratios, while cyclisation with tris(trimethylsilyl)silane affords the same products with diastereomeric ratios of up to 99 : 1.     

Stereoselective synthesis of 2,4,5-trisubstituted piperidines via radical cyclization

A novel approach to 2,4,5-trisubstituted piperidines is reported, involving the 6-exo cyclization of stabilized radicals onto α,β-unsaturated esters. Only two of the four possible diastereoisomers are observed, with diastereomeric ratios ranging from 3:2 to 40:1 when the radical stabilizing group is vinyl or phenyl. Cyclization of a (triethylsilyl)vinyl-stabilized radical gives the corresponding piperidine radical as a single diastereoisomer that may either be trapped by tributyltin hydride to afford the 2,4,5-trisubstituted piperidine or undergo a second 5-endo cyclization onto the (triethylsilyl)vinyl substituent to produce the 3,5,7-trisubstituted octahydro[2]pyrindene as a single diastereoisomer.     

Novel intramolecular (4 + 1) and (4 + 2) annulations of halopolyenes by cascade radical reaction

Free radical reaction of vinyl iodides having dinenoate function in the presence of tributyltin hydride or tris(trimethylsilyl)silane caused a sequential cyclization reaction to produce (4 + 1) and (4 + 2) annulated compounds by means of a cascade radical reaction. Stereogenic centers of the cascade reaction were highly controlled. On the contrary, the cathodic electrolysis of the vinyl iodides afforded monocyclic compounds.     

Synthesis of 3,4-disubstituted piperidines by carbonyl ene and Prins cyclizations: a switch in diastereoselectivity between Lewis and Brønsted acid catalysts

[reaction: see text] A novel diastereoselective approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 6a-e catalyzed by the Lewis acid methyl aluminum dichloride in refluxing chloroform affords trans piperidines 8a-e with diastereomeric ratios of up to 93:7. By contrast, Prins cyclization of 6a-e catalyzed by hydrochloric acid at low temperatures affords cis products 7a-e with diastereomeric ratios of up to 98:2.     

Synthesis of 3,4-disubstituted piperidines by carbonyl ene and prins cyclizations: switching between kinetic and thermodynamic control with Brønsted and Lewis acid catalysts

A novel approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 4a-e catalyzed by MeAlCl(2) in refluxing chloroform afforded the trans piperidines 7a-e with diastereomeric ratios of up to 93:7, while aldehyde 4f afforded solely the cis product 6f, which was resistant to isomerization to the trans isomer. It was demonstrated for 4a that the cyclization catalyzed by a variety of Lewis acids at low temperature proceeded under kinetic control to afford predominantly the cis piperidine 6a, and this isomerized to the thermodynamically more stable trans piperidine 7a on warming. In contrast, Prins cyclization of 4a-e catalyzed by concentrated hydrochloric acid in CH2Cl2 at low temperature afforded cis piperidines 6a-e with diastereomeric ratios of up to >98:2. The yield and diastereoselectivity of these cyclizations could be improved by using HCl-saturated CH2Cl2 to form the corresponding chloride, followed by elimination of HCl effected by ammonia. Aldehydes 4f and 4galso cyclized in good yield under the latter conditions. Mechanistic studies supported by DFT calculations (B3LYP/6-31G(d)) suggest that the cyclizations proceed via a mechanism with significant carbocationic character, with the cis carbocation being more stable than the trans carbocation. DFT calculations (B3LYP/6-31G(d)) of the transition state energies for concerted cyclization show that the cis piperidine is also the favored product from cyclization through a more concerted mechanism.     

Novel intramolecular [4 + 1] and [4 + 2] annulation reactions employing cascade radical cyclizations

Tributyltin hydride and tris(trimethylsilyl)silane promote sequential/cascade free radical cyclization reactions of dienoate tethered vinyliodides or alkynes. These processes produce [4 + 1] and [4 + 2] annulated products. In contrast, the electrochemical reductions of the vinyliodides afford monocyclic compounds. Both the regiochemical and stereochemical courses of the sequential radical cyclizations strongly depend on substrate structure. Especially important is the balance between steric and stereoelectronic (Baldwin's rules) factors that serve to control cyclization regiochemistry.     

Cyclopropyl alkynes as mechanistic probes to distinguish between vinyl radical and ionic intermediates

[reaction: see text] The reactions of (trans-2-phenylcyclopropyl)ethyne, 1a, (trans,trans-2-methoxy-3-phenylcyclopropyl)ethyne, 1b, and (trans,trans-2-methoxy-1-methyl-3-phenylcyclopropyl)ethyne, 1c, with either aqueous sulfuric acid or tris(trimethylsilyl)silane (or tributyltin hydride) and AIBN have been investigated. Protonation and addition of the silyl (or stannyl) radical occurred at the terminal position of the alkyne giving an alpha-cyclopropyl-substituted vinyl cation or radical, respectively. Under both reaction conditions, 1a yielded products derived from ring opening toward the phenyl substituent. Alkynes 1b and 1c, however, gave different products depending on whether radical or cationic conditions were used. When radical conditions were employed, products derived from regioselective ring opening toward the phenyl substituent were obtained. In contrast, when cationic conditions were employed, products derived from selective ring opening toward the methoxy substituent were isolated. The corresponding alpha-cyclopropyl-substituted vinyllithium derivatives were also synthesized and were found to be stable toward rearrangement. An estimate of the rate constants for ring opening of the alpha-cyclopropylvinyl cations was also made: values of 10(10)-10(12) s(-1) were found for the vinyl cations derived from protonation of the terminal carbon of alkynes 1a-c. Based on these results, cyclopropyl alkynes 1a-c can be classified as hypersensitive mechanistic probes for the detection of vinyl radical or cationic intermediates generated adjacent to the cyclopropyl ring and, in the case of 1b and 1c, the distinction between a radical or cationic intermediate is possible.     

Stereoselective synthesis of 2,4,5-trisubstituted piperidines by carbonyl ene and Prins cyclisations

Cyclisation of aldehydes 3-e catalysed by concentrated hydrochloric acid affords predominantly the all cis 2,4,5-trisubstituted piperidines 4a-ewhen the 2-substituent is small, while catalysis by MeAlCl2 in refluxing chloroform gives the trans piperidines 5a-e with diastereomeric ratios of up to 99:1.     

Synthesis of 3-substituted 4-piperidinones via a one-pot tandem oxidation-cyclization-oxidation process: stereodivergent reduction to 3,4-disubstituted piperidines

A novel approach to 3-substituted 4-piperidinones is described. The one-pot tandem oxidation-cyclization-oxidation of unsaturated alcohols 1a-e by PCC or PCC and trifluoromethanesulfonic acid affords piperidinones 2a-e in good yield. Reduction of 2a-e by L-Selectride gives the corresponding cis 3,4-disubstituted piperidines with diastereomeric ratios of >99:1. By contrast, reduction of 2a-e by Al-isopropoxydiisobutylalane gives the trans products with diastereomeric ratios of up to 99:1.     

Radical ring closures of 4-isocyanato carbon-centered radicals

The 2-(2-isocyanatophenyl)ethyl radical was generated from the corresponding bromide with tributyltin and tris(trimethylsilyl)silyl radicals and shown to ring close in the 6-endo-mode to afford 3,4-dihydro-1H-quinolin-2-one as the major product. Cyclization in the 5-exo-mode to produce 2,3-dihydroindole-1-carbaldehyde, after hydrogen abstraction, was a minor reaction. Rate constants for the two processes were estimated and compared with reaction enthalpies computed by the DFT method.     

Thiophenol-mediated hydrogen atom abstraction: an efficient tin-free procedure for the preparation of cyclopentane derivatives

[reaction: see text] An efficient procedure for running a cascade reaction involving 1,5-abstraction of a hydrogen atom followed by a radical cyclization is reported. Alkenyl radicals are generated from easily available terminal alkynes and thiophenol. This procedure eliminates the need of using the toxic tributyltin hydride and gives a greater amount of radical translocation products.     

Enantioselective cyclization of alkene radical cations

[reaction: see text] Enantiomerically enriched beta-(diphenylphosphatoxy)nitroalkanes undergo radical ionic fragmentation, induced by tributyltin hydride and AIBN in benzene at reflux, to give alkene radical cations in contact radical ion pairs. These contact ion pairs are trapped intramolecularly by amines to give pyrrolidines and piperidines with significant enantioselectivity ( approximately 60% ee), indicative of cyclization competing effectively with equilibration within the ion pairs. Use of an intramolecular N-propargylamine as a nucleophile provides an enantiomerically enriched pyrrolizidine skeleton via a tandem polar/radical crossover sequence.     

Free-radical cyclizations onto differently substituted 1,2,3-triazoles installed in sugar templates

The synthesis and manipulation of differently substituted 1,2,3-triazoles (7-11 and 12-16) installed in sugar templates gave compounds 29-34 and 44-50, after reaction with tributyltin hydride or tris(trimethylsilyl)silane. Following standard procedures compound 44 was transformed into piperidinose derivative 54. These compounds are chiral, useful building blocks for the synthesis of glycosidase inhibitors of the fused-azole piperidinose type.     

Total Synthesis of (−)‐Histrionicotoxin through a Stereoselective Radical Translocation–Cyclization Reaction

Stereoselective total syntheses of (−)‐histrionicotoxin and (−)‐histrionicotoxin 235A are described. The 1‐azaspiro[5.5]undecane skeleton was constructed diastereoselectively by a radical translocation–cyclization reaction involving a chiral cyclic acetal; the use of tris(trimethylsilyl)silane was crucial for the high diastereoselectivity. The cyclization product was converted into (−)‐histrionicotoxin 235A through a one‐pot partial‐reduction–allylation reaction of a derivative containing an unprotected lactam. Finally, two terminal alkenes were transformed into enynes with the 1,3‐amino alcohol protected as an oxathiazolidine oxide to complete the total synthesis of (−)‐histrionicotoxin.     

A tandem radical cyclization approach to 3-(2-oxopyrrolidin-3-yl)indolin-2-ones, potential intermediates toward complex indole-heterocycles

A series of substituted 3-(2-oxopyrrolidin-3-yl)indolin-2-one derivatives have been synthesized by tris(trimethylsilyl)silane (TTMSS) induced tandem radical cyclization as key step.     

Novel diastereoselective synthesis of bicyclic beta-lactams through radical cyclization and their reduction toward 2-(1-alkoxy-2-hydroxyethyl)piperidines and 2-(1-alkoxy-2-hydroxyethyl)azepanes

1-Allyl- and 1-(3-phenylallyl)-substituted 4-(2-bromo-1,1-dimethylethyl)azetidin-2-ones were transformed into 3-substituted 7-alkoxy-5,5-dimethyl-1-azabicyclo[4.2.0]octane-8-ones through radical cyclization by means of n-tributyltin hydride and AIBN in toluene with excellent diastereocontrol (>or=99%). The radical cyclization of 4-(2-bromo-1,1-dimethylethyl)-1-(2-methylallyl)azetidin-2-ones afforded 8-alkoxy-3,6,6-trimethyl-1-azabicyclo[5.2.0]nonan-9-ones in good diastereomeric excess (75-78%). The reductive ring opening of 1-azabicyclo[4.2.0]octane-8-ones and 1-azabicyclo[5.2.0]nonan-9-ones with lithium aluminum hydride resulted in novel 2-(1-alkoxy-2-hydroxyethyl)piperidines and -azepanes, which were isolated as single isomers.     

Photochemical intramolecular cyclization of o-alkynylaryl isocyanides with organic dichalcogenides leading to 2,4-bischalcogenated quinolines

When a mixture of o-alkynylaryl isocyanides and organic dichalcogenides such as diselenides or ditellurides was irradiated with light of wavelength over 300 or 400 nm, the intramolecular cyclization of the isocyanides took place to afford the corresponding 2,4-bischalcogenated quinolines selectively. The photochemical cyclization of 2-(phenylethynyl)phenyl isocyanide could also proceed in the presence of hydrogen transfer reagents such as tris(trimethylsilyl)silane, tributylgermyl hydride, alkanethiols, and benzeneselenol, providing the corresponding 3-phenylquinoline as the result of 2,4-dihydrogenation.     

Intramolecular radical additions to pyridines

Intramolecular 6-exolendo-trig and 5-exo-trig cyclisations of aryl radical intermediates to the alpha-, beta- and gamma-carbons of pyridine have been shown to be facile processes at neutral pH. The tether conjoining the radical donor to the pyridine plays an important role in determining the outcome of the reaction. When a Z-alkene is used as a tether, ortho-cyclisation proceeds in good yield. A more complex course is followed when a saturated two carbon tether is employed, leading to products derived from hydrogen atom abstraction, ipso-cyclisation and ortho-cyclisation pathways. All attempts to effect 5-exolendo-trig cyclisations failed. Tributyltin hydride, tris(trimethylsilyl)silane, tris(trimethylsilyl)germane and, in part, samarium(II) iodide can each be employed as mediators of the reaction.     

Intramolecular cyclization of beta-amino and beta-ammonio radicals: a new synthetic route to the 1-azabicyclo

Treatment of 1-(2-phenylselenoethyl)-1,2,5,6-tetrahydropyridine (15) with tributyltin hydride affords only the product of reduction, demonstrating the reluctance of the 5-hexenyl radical 9 to undergo ring closure. When the nature of the radical is modified, either by introduction of an ester group at C4 or via its quaternary ammonium salt, cyclization occurs readily; while the radical 52 gives an excellent yield of 1-methyl-1-azoniabicyclo[3.2.1.]octyl bromide (55) uncontaminated with the product of reduction, the bicyclic product from 21 is accompanied by some reduced material. Production of the unwanted alkene can be eliminated in the latter by recourse to the quaternary ammonium ester 1-(2-bromoethyl)-4-carbethoxy-1-methyl-1,2,5,6-tetrahydropyridinium bromide (35) which, when exposed to tributyltin hydride, affords a 1:1 endo/exo mixture of 4-carbethoxy-1-methyl-1-azoniabicyclo[3.2.1]octyl bromide (37) exclusively. These results support the demonstration of the powerful polar effect of an ester function when attached to the double bond of a 5-hexenyl system, a property which can be exploited in the case of the radical 58. Treatment of the precursor, 1-(2-bromoethyl)-3-carbethoxy-1-methyl-3-pyrrolinium bromide (60), with tributyltin hydride generates 58 which is found to cyclize with high regioselectivity, affording a convenient high-yielding synthesis of the endo/exo isomers of 3-carbethoxy-1-methyl-1-azoniabicyclo[2.2.1]heptyl bromide 57. The isomeric bicyclo[2.2.1]heptyl ester 63 was not detected. These observations are in accordance with predictions based upon frontier molecular orbital considerations.     

Decarbonylative radical cyclization of alpha-amino selenoesters upon electrophilic alkenes. A general method for the 6-azabicyclo[3.2.1]octane synthesis

alpha-Amino selenoester-tethered electronically poor alkenes on treatment with tributyltin hydride or TTMSS undergo intramolecular radical cyclization to provide 6-azabicyclo[3.2.1]octanes through 1-aminomethyl radical intermediates.