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An unprecedented application of tributyltin hydride (TBTH) as a reagent for the reductive ionic 1,5-cyclization of 3-azamuconoates (3-azahexa-2,4-dienedioates) is described. A novel 1,5-exo-trig-cyclization of 5-chloro-3-azamuconoates was used as a base for the development of an effective two-step method for the preparation of 4-hydroxy-1H-pyrrole-3-carboxylic and 3-hydroxy-1H-pyrrole-2,4-dicarboxylic acids derivatives from readily available diazo esters and 2-chloro-2H-azirines or 4-chloroisoxazoles. The experimental results, as well as the DFT calculations of the pyrroles formation, are in good agreement with the ionic mechanism involving the initial hydride attack at the CN bond of the azamuconoate followed by tin-promoted 1,5-cyclization.

A α-cross-coupling aldol type addition reaction activated olefins with isatins has been described in the presence of ruthenium(III) chloride and tributyltin hydride (TBTH) at room temperature. This method is found to work consistently for the delivering of ene-carbonyl coupled products in good to excellent yields with moderate to acceptable selectivity. The substrate scope of the present method was briefly discussed.

An efficient and asymmetric synthetic approach towards one of the biologically interesting 4(S)-11-diHDHA derivatives was developed. This process mainly relied on two reactions, one is the copper-catalyzed mild cross-coupling that allows for the efficient construction of a chiral α-alkynyl α-hydroxy motif and another is the synthesis of chiral α-hydroxy α-stannanes that has previously been developed by our group featuring the asymmetric stannylation using the well-established tributyltin hydride/diethyl zinc system from an aldehyde.

Free-radical mediated cyclizative carbonylations of azaenynes were carried out using TTMSS as a radical mediator to compare the efficiency and the stereochemistry with those using tributyltin hydride. Using a substrate concentration of 0.1 M, the reactions gave good yields of alpha-silylmethylene lactams having four to seven-membered rings. The observed E-diastereoselectivity of the resulting vinylsilane moiety is in sharp contrast to the Z-selectivity observed during the analogous carbonylation using tributyltin hydride. When hexanethiol was used as the radical mediator, alpha-thiomethylene lactams were formed with E-favoring stereoselectivity again. Ab initio and DFT molecular orbital calculations on the stability of E and Z products were carried out for a set of five-membered methylene lactams bearing SnH3, SiH3, and SMe groups. The distinct thermodynamic preference for the Z-isomer was only predicted for the Sn-bearing lactam. A steric effect due to the bulky (TMS)3Si group is proposed for the E-selectivity observed in the TTMSS-mediated reaction.

The tributyltin hydride-mediated cyclisation of unsaturated ethers and amines bearing an aldehyde or α,β-unsaturated ketone group is reported. Cyclisation proceeds via reversible addition of the tributyltin radical to the carbonyl double bond to form an intermediate O-stannyl ketyl. This nucleophilic radical can add intramolecularly to electron-rich double bonds to form substituted 5- or 6-membered rings. The efficiency of the cyclisation to form, for example, hydroxytetrahydrofurans, chromanols or quinolones, is shown to depend on the nature of the acceptor double bond and also on the stability of the intermediate O-stannyl ketyl. Thus, resonance-stabilised allylic or benzylic O-stannyl ketyl radicals have been shown, for the first time, to have a particular application in slow radical cyclisations leading to butyrolactones or pyrans.

The 2-[4-(trimethylsilyl)but-3-ynyl]piperidines 16a–c, upon treatment with tributyltin hydride in the presence of azoisobutyronitrile in refluxing toluene, gave the 9-azabicyclo[3.3.1]nonanes 17a–c in high yields, respectively. Compound 17c was subjected to desilylation, ozonolysis, and subsequent 1,2-transposition of the resulting carbonyl group to give 9-benzoyl-1-methyl-9-azabicyclo[3.3.1]nonan-3-one, a potential precursor for the synthesis of (±)-euphococcinine.

A simple chiral synthesis of cis- and trans-furo[3,2-c][2]benzoxocines 8a–d and 9a–d through a regioselective 8-endo-trig aryl radical cyclisation of the respective 5,6-dideoxy-D-xylo-hex-5-enofuranosides 6a–d and 5,6-dideoxy-D-ribo-hex-5-enofuranosides 7a–d with tributyltin hydride is described.

PolyHIPE-supported tin hydride and thiol are synthesized to reduce alkyl bromides under free-radical conditions, taking advantage of the fully interconnected polyHIPE structure. Radical reduction of 1-bromoadamantane, 6-bromohex-1-ene and 1-allyloxy-2-bromobenzene are performed using two methodologies: one using supported tin hydride as reducing agent, and another using supported thiol as polarity-reversal catalyst in the presence of triethylsilane as reducing agent. The polyHIPE-supported tin hydride is used either in catalytic or stoichiometric amounts depending on the bromo compound to be reduced. In the case of unsaturated bromides, both methodologies lead to reductive cyclization, thus enabling radical rearrangement before hydrogen transfer. PolyHIPE-supported organotin hydride is a good alternative to tributyltin hydride to prevent tin contamination and facilitate product separation. PolyHIPE-supported thiol, in the presence of an excess of triethylsilane, shows good activity and selectivity toward reductive cyclization products. Results obtained by the two methodologies are compared and discussed.

Polysubstituted cyclopentane rings can be synthesized with good to high stereocontrol by radical cyclization using tributyltin hydride and a radical initiator, triethylborane–O2 in anhydrous xylene at room temperature. We have demonstrated that the nature (protected or unprotected) of the hydroxy functions in position 2 and 4 is responsible for the stereochemical cyclization outcome of acyclic 1-substituted-2,4-dihydroxylated hex-5-enyl compounds. The presence of a 2,4-diol leads to the all-syn precursor of isoprostanes while the diprotected diol affords the diastereoisomer syn-anti-syn precursor.

Synthesis of 3-norcephalosporin 1 was performed successfully by reaction of either 3-trifluoromethylsulfonyloxy-Δ3-cephem 2, allenecarboxylate 3 or 3,4-disubstitued but-2-enoates 4 with copper(I) chloride and tributyltin hydride in N-methylpyrrolidin-2-one (NMP). Generation and reactions of a copper(I) hydride species in the copper(I) chloride–tributyltin hydride–NMP or N,N-dimethylformamide (DMF) system are discussed.

The γ-dissociations of 3-substituted bicyclo[1.1.1]pent-1-yl radicals and cyclobutyl radicals were investigated by abinitio SCF MO (HF, MP2, MP3 and MP4/6–31G*) and density functional methods (B3LYP/6–31G*). The transition states were found to resemble the product alkyl radical and [1.1.1]propellane or bicyclo[1.1.0]butane. Calculated endothermicities and energy barriers were comparatively low for loss of the t-butyl radical from the 3-t-butylbicyclo[1.1.1]pent-1-yl radical, which suggested that this dissociation would be significant under laboratory conditions. The dissociation was verified experimentally by means of the reaction of 1-iodo-3-t-butylbicyclo[1.1.1]pentane with tributyltin hydride. Arrhenius parameters for this dissociation were determined by end product analysis. The SCF MO and density functional calculations resulted in much higher endothermicities and energy barriers for γ-dissociations of cyclobutyl radicals, hence neither the formation of bicyclo[1.1.0]butane nor alkyl radical addition to this bicyclic compound was predicted to be important.

On treatment with tributyltin hydride, the vinyl bromide 11 and the vinyl iodide 26 cyclize to give mixtures of the (E)- and (Z)-4-(alkoxycarbonylmethylene)tetrahydropyrans 12/13 and 27/28 in which the (E)-isomers 12 and 27 are the major components accounting for 80% of the products. Addition of triphenyltin hydride to the alkyne 34 similarly initiates cyclization giving a mixture of products 35–37, the composition of the mixture depending upon the concentration of the tin hydride. These results are consistent with faster cyclization of the (Z)-vinyl radical with kinetic formation of five-membered ring containing products which are either trapped by hydrogen transfer from the tin hydride or which rearrange to form a 4-methylenetetrahydropyran. This chemistry was applied to prepare the cis-2,6-disubstituted 4-(methoxycarbonylmethylene)tetrahydropyran 50 which may be useful for the introduction of the C(10)–C(16) fragment into the bryostatins. Cyclization of the p-methoxybenzyl protected vinyl iodide 58 is less stereoselective, perhaps because of intramolecular hydrogen transfer from the p-methoxybenzyl group.

A range of 1-alkylcyclohexa-2,5-diene-1-carboxylic acids were prepared by Birch reduction–alkylation of benzoic acid and their efficiency as mediators of alkyl radical chain addition and cyclisation processes was investigated. Reductive alkylations were respectably successful, even with only one or two equivalents of alkene, for secondary, tertiary and benzylic radicals. Reaction of 1-[2-(cyclohex-2-enyloxy)ethyl]cyclohexa-2,5-diene-1-carboxylic acid yielded the product of exo-trig-cyclisation, i.e. 7-oxabicyclo[4.3.0]nonane, in a yield comparable to that obtained from the tributyltin hydride induced cyclisation of 3-(2′-iodoethoxy)cyclohexene. This, together with the isolation of both exo- and endo-cyclisation products from 1-[2-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-ylmethoxy)ethyl]cyclohexa-2,5-diene-1-carboxylic acid established that ring closures could also be satisfactorily mediated with these reagents. Preparations were completely free of metal contaminants and direct reduction of the alkyl radicals, prior to addition or cyclisation, was completely absent. However, the desired products were accompanied by alkylbenzenes, together with by-products from the initiator decompositions, and this complicated work-up. Failure to obtain 1-[2-(prop-2-yn-1-yloxy)cyclohexyl]cyclohexa-2,5-diene-1-carboxylic acid in Birch reductive alkylations with trans-1-iodo-2-(prop-2-yn-1-yloxy)cyclohexane (and the corresponding bromide) indicated a limitation on precursor synthesis. The Birch reduction–alkylation was not of universal applicability and was suppressed for alkyl halides having β-substituents.

Thiols catalyse the radical-chain addition of primary aliphatic aldehydes R1CH2CHO to terminal alkenes H2CCR2R3 to give ketonic adducts R1CH2C(O)CH2C(H)R2R3 in moderate to good yields. The reaction takes place under mild conditions (dioxane solvent, 60 °C) and is initiated by di-tert-butyl hyponitrite (TBHN). Thiol catalysis is effective for hydroacylation of electron-rich, -neutral and -deficient alkenes, but is most efficient for addition to electron-rich double bonds. For example, the addition of butanal (2 equiv.) to isopropenyl acetate [H2CC(Me)OAc] in the presence of TBHN (2 × 2.5 mol%) and methyl thioglycolate (MeO2CCH2SH; 2 × 5 mol%) gives the adduct in 80% yield, whilst a similar reaction in the absence of thiol catalyst affords only an 8% yield. Other enol acetates, silyl enol ethers, an enol phosphate and butyl vinyl ether react similarly. For comparison, the reaction of butanoyl phenyl selenide with isopropenyl acetate, in the presence of tributyltin hydride and azoisobutyronitrile initiator in benzene at 80 °C, gives the adduct in only 7% yield. Methyl thioglycolate is generally the most efficient catalyst for hydroacylation of electron-rich alkenes, whilst tert-dodecanethiol is more effective for addition of aldehydes to electron-deficient alkenes. Triorganosilanethiols also function as catalysts, as does the arenethiol 2,4,6-tris(trifluoromethyl)thiophenol. The role of the thiol is to act as a polarity-reversal catalyst that promotes the overall hydrogen-atom transfer from the aldehyde to the carbon-centred radical produced by addition of the acyl radical to the alkene. Intramolecular hydroacylation is also subject to thiol catalysis and the radical-chain cyclisation of citronellal to a mixture of menthone and isomenthone is effectively promoted in the presence of triphenylsilanethiol.

Bu3SnH-mediated radical translocations/cyclisations of methyl 2-alkynyl-1-(o-iodobenzoyl)pyrrolidine-2-carboxylates have been examined. The 2-[3-(trimethylsilyl)prop-2-ynyl]-8,2-[4-(trimethylsilyl)but-3-ynyl]- 14, and 2-[5-(trimethylsilyl)pent-4-ynyl]-pyrrolidine derivatives 18, upon treatment with tributyltin hydride in the presence of azoisobutyronitrile in boiling toluene gave, regioselectively, the 7-azabicyclo[2.2.1]heptane 19, 8-azabicyclo[3.2.1]octane 23, and 9-azabicyclo[4.2.1]nonane 26, respectively. The method has been applied to a formal total synthesis of (±)-epibatidine.

Synthesis of chiral tricyclo[3.2.1.02,7]octanes by efficient and exclusive 3-exo-trig radical cyclisation of either a bicyclo[3.2.1]oct-6-en-2-yl radical or a bicyclo[2.2.2]oct-5-en-2-yl radical is described. Reaction of the methoxy enones 7a–c with boron tribromide at low temperature furnishes the bicyclo[3.2.1]octenyl bromides 9a–c and 10a–c along with varying amounts of 8a–c, whereas the methoxy enone 7d provides the unrearranged bicyclo[2.2.2]octenyl bromide 8d. Treatment of the homoallyl bromides 9a–c and 10a–c and 8d with tributyltin hydride and AIBN generates, exclusively, the tricyclic ketones 15a–d.

Nitrate esters, prepared by treatment of β-hydroxy-α-amino acid derivatives with nitric acid, react with tributyltin hydride to give the corresponding alkoxyl radicals. These radicals readily undergo β-scission, providing a convenient route for the regiocontrolled production of α-carbon-centred amino acid radicals. By examining the partitioning of the alkoxyl radicals between the β-scission process and the competing hydrogen transfer reaction, it has been possible to evaluate the influence of electronic and steric effects on the β-scission reaction and the formation of the carbon-centred radicals.

Treatment of the 1-(ω-iodoalkyl)indole-3-carbaldehydes 8–13 with tributyltin hydride and AIBN results in radical cyclisation to give the 1,2-fused indoles 14–19 containing five-, six- and seven-membered rings. The tetrahydropyridoindole 18 is converted into the indolequinone 23.

A simple convergent synthesis of trans- and cis-octahydro-1H-dibenzo[a,d] cycloheptenes 15a–c and 16a–c and 20a–c and 21a–c through implementation of a regioselective 7-endo-trig-aryl radical cyclisation of the respective 2-(o-bromoarylethyl)-1-methylenecyclohexanes 6a–c and 8a–c with tributyltin hydride is described. The scope of the 7-endo aryl radical cyclisation has been further demonstrated by the synthesis of (2SR,4aRS,11aSR)-methyl 1,1-dimethyl-2,3,4,4a,5,10,11,11a-octahydro-1H-dibenzo[a ,d]cycloheptene-2-carboxylate 29.

α-Diazo ketones RC(O)CHN2 react with tributyltin hydride at 60 °C in benzene to give the corresponding α-stannyl ketones RC(O)CH2SnBu3, which exist in equilibrium with the stannyl enol ether tautomers R(Bu3SnO)CCH2. The reactions are initiated by di-tert-butyl hyponitrite and follow a freeradical chain mechanism. Triphenyltin hydride and tris(trimethylsilyl)silane [(TMS)3SiH] react similarly, the latter to yield the α-silyl ketone RC(O)CH2Si(TMS)3 which does not isomerise to the more stable silyl enol ether R[(TMS)3SiO]CCH2 under the reaction conditions. This result indicates that TMS3Si˙ reacts at the α-carbon atom of the α-diazo ketone to give R(CO)ĊHSiTMS3, probably via an initial diazenyl radical adduct; triorganotin radicals are assumed to react in the same way. When the group R in the α-diazo ketone is but-3-enyl, the intermediate α-metalloalkyl radical undergoes 5-exo-cyclisation. Allyltributylstannane reacts with α-diazo ketones and with ethyl α-diazoacetate in refluxing benzene, in the presence of 2,2′-azo(2-methylpropionitrile) as initiator, to give butenyl ketones RC(O)CH2CH2CHCH2 and ethyl pent-4-enoate, respectively, after a hydrolytic work-up.

Cyclisation of the O-stannyl ketyl, generated from the aldehyde 17 by reaction with tributyltin hydride in the presence of AIBN, gives the 5-benzyloxymethyl-7-hydroxypyrrolooxazolidin-2-ones as a diastereoisomeric mixture of 7α-ol 18 and 7β-ol 19 (2 : 1), with high diastereoselectivity with respect to the 5,7a positions. (+)-Bulgecinine 8 is enantioselectively synthesised by stereospecific reduction of the ketone 20, derived from compounds 18 and 19. In a similar way, cyclisation of compound 40 gives a 2 : 1 mixture of compounds 41 and 42. Conversion of compound 41 into (–)-desoxoprosopinine 9 is successfully achieved.

The method used for a general synthesis of macrocyclic ketones based on a ring expansion involving a selective β-scission of alkoxyl radicals devised by Suginome and Yamada was extended and modified. Thus, cycloalkanones was transformed into the corresponding α-(ω-iodoalkyl)-cycloalkanones by alkylation of the corresponding lithium enolates with either 1,3-diiodopropane or 1,4-diiodobutane. Treatment of these α-iodoalkyl cyclic ketones with samarium iodide gave bicyclic tertiary alcohols. The generation of the alkoxyl radicals from the bicyclic alcohols by irradiation of the corresponding hypoiodites generated with mercury(II) oxide–iodine–pyridine in benzene resulted in a selective β-scission of their ring-junction bond to give high yields of macrocyclic ketones carrying an iodine which can be removed with tributyltin hydride. The method was then applied to new syntheses of (±)-isocaryophyllene and (±)-caryophyllene. Thus, ω-iodopropylation of ethyl 7,7-dimethyl-2-oxobicyclo[4.2.0]octane-3-carboxylate, followed by cyclization of the resulting α-(ω-iodoalkyl)cycloalkanone with samarium diiodide, gave cis-transoid-cis-ethyl 1-hydroxy-4,4-dimethyltricyclo[6.3.0.02,5]undecane-8-carboxylate (69%). The ethoxycarbonyl group of this tricyclic alcohol was transformed into a methyl group by the standard method. Irradiation of a solution of the hypoiodite, prepared by the method mentioned above, with Pyrex-filtered light gave the corresponding cis-bicyclo[7.2.0]undecenone (15%), its exomethylene isomer (

Et3B-Induced hydrostannation of ethyl propiolate with tributyltin hydride afforded a mixture of ethyl (Z)- and (E)-3-(tributylstannyl)propenoate which, after purification, could be used as such in radical carbon–carbon bond-forming reactions with iodides as the sources of the carbon radicals. The radical-coupling reactions took place without significant loss of yield or stereoselectivity when compared with the same reactions carried out with the pure (Z)-stannylacrylate. Use of ethyl (Z)-3-(phenylsulfanyl)propenoate in the presence of carbon-centred radicals, generated with Bu3SnH from alkyl iodides, resulted in the formation of reduced and coupled products where the intermediate β-phenylsulfanyl radicals had experienced hydrogen transfer from Bu3SnH rather than 1,2-elimination of phenylsulfanyl radicals.

The tributyltin hydride mediated radical Cyclisation of N-(α-chloroacetamido)dehydroalanine derivatives prepared from serine proceeds regioselectively to give pyroglutamates in 47–74% yield– the cyclisation of the intermediate carbamoylmethyl radical proceeds in a ‘disfavoured’ 5-endo-trig manner.

Thebaine 3 has been converted in an improved yield (72%), with tetranitromethane, oxygen and ammonia, into the 14β-nitro 8α, 10α-epidioxide 4, which reacted with base to give the known 14β-nitro-10-oxo compound 7. Reduction of this nitro compound with tributyltin hydride gave the 8β-hydroxy-10-oxodihydrothebaine 8, which was dehydrated with phosphorus oxychloride to give 10-oxothebaine 9. As expected, this conjugated diene reacted with but-3-en-2-one to form a Diels–Alder cycloadduct 10, the 10-oxo derivative of thevinone 11, the precursor of a well known series of opiate analgesics. Unexpectedly, the epidioxide 4 was found to isomerise cleanly on activated alumina to give the 8α, 10α-epoxy acetal 5, in which a peroxide oxygen has been inserted into the 7,8-bond of the bridged peroxide 4.

On treatment with tributyltin hydride and azoisobutyronitrile in benzene at reflux α-aryl-β-bromoalkyl vinyl ethers rearrange in moderate yield to δ-aryl ketones: possible mechanistic rationales are discussed for this novel C–C bond-forming process.

Conjugated addition of benzenethiol, under mild conditions, to carbohydrate derived hex-2-enono-δ-lactones, substituted at C-6 or C-7 with an electron-rich insaturation, affords 3-phenylthio derivatives that, on treatment with tributyltin hydride and AIBN (azoisobutyronitrile), undergo an efficient radical cyclization to give highly functionalized cyclohexanes and cyclopentanes.

Reaction of the 3,5-bis-(S-methyl dithiocarbonate) of 1,2-O-isopropylidene-α-D-xylose with tributyltin hydride gives not the expected 3-deoxygenated xylo-furanose but instead the 3-thio-α-D-xylo-furanose derivative 4 resulting from radical cyclization. The structure of compound 4 was confirmed by X-ray crystallography. The absolute configuration has been established.

Several α,β-epoxy ketones were converted to aldols in good yields upon irradiation or heating with azoisobutyronitrile in the presence of tributyltin hydride in benzene; the reactions involve selective Cα–O bond cleavage of the oxiranylmethyl radicals derived from these substances.

Free-radical carbonylation of omega-alkynylamines with tributyltin hydride gives a mixture of alpha-methylene lactams and alpha-stannylmethylene lactams. Nucleophilic addition of an internal amino group to the carbonyl group of alpha-ketenyl radicals is proposed as the cyclization step. The subsequent unusual 1,4-H shift from the resulting 1-hydroxyallyl radical, followed by elimination of the beta-tributyltin radical leads to the formation of alpha-methylene lactams.

Through the simple expedient of using a mixture of KF and silica as the stationary phase in column chromatography, levels of organotin impurities from tributyltin hydride mediated reductions have been reduced from stoichiometric levels to approximately 30 ppm.

The nBu(3)SnH-mediated cyclisation reactions of allylic-allylic alkylation products of alpha,alpha-dicyanoalkenes and Morita-Baylis-Hillman (MBH) carbonates of methyl vinyl ketone (MVK) have been investigated. Cyclopentane derivatives bearing multiple substituents were efficiently prepared with moderate to excellent diastereoselectivity.

A number of alkynes 5, allene 11 and alkene 13 smoothly underwent hydrostannation with tributyltin hydride 1, prepared in situ from tributylchlorostannane 6 and triethylsilane 7 in the presence of catalytic amounts of Lewis acids.

Glyoxylic acid diphenylhydrazone (2, Y = NPh 2 ) and the corresponding O-benzyloxime (2, Y = OBn) are easily esterified in high yield by β-bromo alcohols, and the resulting esters undergo radical cyclization to α-(2,2-diphenylhydrazino) or α-(benzyloxyamino) lactones on treatment with tributyltin hydride; the initial radical can be formed by homolysis of a carbon–selenium bond as well as a carbon–bromine bond and, when applied to appropriate alcohols, the esterification–radical closure sequence can also be used to make six- or seven-membered lactones.

A sequential reductive 1,2-elimination and hydride addition process for 3,4-disubstituted butenoates derived from penicillin is successfully performed with the aid of a combination of tributyltin hydride and copper(I) chloride in N-methyl-2-pyrrolidinone (NMP) to afford 3-norcephalosporin.

Tributylgermanium hydride (Bu3GeH) can be used as an alternative to tributyltin hydride (Bu3SnH) as a radical generating reagent with a wide range of radical substrates. Tributylgermanium hydride has several practical advantages over tributyltin hydride, e.g. low toxicity, good stability and much easier work-up of reactions. The reagent can be easily prepared in good yield and stored indefinitely. Suitable substrates include iodides, bromides, activated chlorides, phenyl selenides, tert-nitroalkanes, thiocarbonylimidazolides and Barton esters. Alkyl, vinyl and aryl radicals can be generated in radical reactions including reduction and cyclisation processes. Common radical initiators such as ACCN and triethylborane can be used. The slower rate of hydrogen abstraction by carbon-centred radicals from Bu3GeH as compared to Bu3SnH facilitates improved cyclisation yields. Polarity reversal catalysis (PRC) with phenylthiol can be used in reactions which generate stable radical intermediates which will not abstract hydrogen from Bu3GeH.

The idea that ring closures of C-centred radicals onto isocyanates could be made permanent by designing the cyclised radical to undergo a rapid onward beta-scission, was investigated for the 2-(2-isocyanato)cyclopropylphenyl and 2-(2-isocyanato)oxiranylphenyl radicals. The radical precursors, trans- and cis-1-bromo-(2-isocyanatocyclopropyl)benzene and (2-bromophenyl)-3-isocyanatooxirane, were prepared from the corresponding bromophenylcyclopropane and bromophenyloxirane carboxylic acids via Curtius rearrangements of the derived azides. The structure of the trans-2-(2-isocyanato)cyclopropylphenyl radical prevents cyclization, however, it was shown that isomerisation to the analogous cis-radical occurred, probably by scission of the disubstituted cyclopropane bond followed by internal rotation of the resulting resonance stabilised diradical. It was found, however, that the main product from homolytic reactions of both trans- and cis-isocyanatocyclopropyl compounds, with tributyltin hydride and tris(trimethylsilyl)silane, was the direct reduction product, trans-(2-isocyanatocyclopropyl)benzene. Only traces of cyclised products, that were probably 4,5-dihydrobenzo[c]azepin-1-one from the cyclopropane precursor and 5H-6-oxa-8-azabenzocyclohepten-9-one from the oxirane precursor, were detected. We conclude, therefore, that the rate of cyclization onto isocyanate acceptor groups must be slower in these systems than hex-5-enyl cyclization or that the reverse ring-opening process must be faster than for analogous radicals.

Enantioselective radical-mediated reduction of α-methoxymethyl-α-iododihydrocoumarin 1 using tributyltin hydride is realized in up to 62% enantiomeric excess (e.e.)(88% chemical yield) by combination of chiral diamine 2 and magnesium iodide.

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.

An approach to 1α, 25-dihydroxyvitamin D3 involving the preparation of the vinyl selenide 8, its cyclization to 9 with tributyltin hydride and the conversion of the latter into the known isomeric dienes 3 and 10 is described.

119 Sn and 125Te NMR spectroscopies reveal that methyl, primary and secondary alkyl radicals, generated by reaction of phenyltelluroalkanes 4, 6, 7 with tributyltin hydride (benzene, AIBN initiator), are capable of displacing tributylstannyl radicals from (4-fluorophenyltelluro)tributylstannane to afford the 4-fluorophenyltelluroalkanes 3, 8, 9.

(±)-3-Methylmuconolactone (±)-4 is resolved by fractional crystallisation of the (S)-(–)-1-phenylethylammonium salts. The X-ray crystal structures of both salts are determined. Salt A (Fig. 1) gives (S)-(–)-3-methylmuconolactone 4, which is identical to the lactone from fungi. The lactone is converted with bromine into the bromo dilactone 5 and thence with tributyltin hydride into the (–)-1-methylmuconodilactone 6. This dilactone with aqueous sodium hydroxide gives (S)-(+)-4-methylmuconolactone 3, which is identical to the lactone from bacteria, together with (S)-(–)-3-methylmuconolactone 4. The X-ray structure of the bromo dilactone 5 (Fig. 3) confirms the absolute configurations of both the fungal and bacterial muconolactones. (S)-(+)-4-Methylmuconolactone 3 gives the corresponding (–)-bromo dilactone 9, which is also reduced with tributyltin hydride to yield the (–)-1-methylmuconodilactone 6. The isomeric bromo dilactones (±)-5 and 9 are similarly converted into the dibromo dilactones (±)-8 and 11, via the corresponding 2-bromomuconolactones (±)-7 and 10, respectively.Disodium 3-methyl-cis,cis-muconate 17 is prepared non-enzymically by treatment of 3-methylmuconic anhydride 16 with 2 mol equiv. of aqueous sodium hydroxide. Unexpectedly, the salt 17 rapidly gives 3-methyl-2-cis,-4-trans-muconate even in weakly alkaline solutions. Contrary to an earlier report, at pD 6.5 the salt 17 is converted at approximately equal rates into 3-methyl-2-cis-4-trans-muconic acid 18 and (±)-3-methylmuconolactone (±)-4.

Methyl 1-(o-bromobenzoyl)-2-(prop-2-enyl)piperidine-2-carboxylate 8a, upon treatment with tributyltin hydride in the presence of azoisobutyronitrile in boiling toluene gave regioselectively the 8-azabicyclo[3.2.1]octane 14a (a 5-exo cyclisation product) in quantitative yield as a diastereomeric mixture (66:34). 1-(o-Bromobenzoyl)-2-(prop-2-enyl)piperidine 13 also gave the 8-azabicyclo[3.2.1]octane 16(75% as a diastereomeric mixture), along with the pyrido[2,1-a]isoindolone 17(10%) and the simple reduction product 18(5%). 1-(o-Iodobenzoyl)-2-[3-(trimethylsilyl)prop-2-ynyl]piperidine 23 afforded, in addition to the pyrido[2,1-a]isoindolone 25(18%), the 8-azabicyclo[3.2.1]octane 24(75%) which was converted into the 6-oxo derivative 27. For comparison, the behaviour of the azetidine congener 31 was also examined.

A series of N-methyl-N-(1-substituted or 1,2-disubstituted vinyl)-2,2-bis(phenylsulfanyl)acetamides, upon treatment with tributyltin hydride in the presence of a catalytic amount of AIBN in boiling toluene, underwent smooth cyclisation in a 5-endo-trig manner to give the corresponding pyrrolidin-2-ones. In contrast, the N-(1-unsubstituted 2-phenylvinyl) congener gave predominantly the reduction product. These results imply that, for the 5-endo cyclisation to proceed effectively, the developing α-acylamino radicals in the transition state of the 5-endo cyclisation must be stabilised by an aryl or an alkyl group. An application of this method to a synthesis of (±)-continine is also described.

[(4S)-5-(tert-Butyldimethylsilyloxy)-4-hydroxypent-2-enyl](tributyl)stannane 18 has been prepared from di-O-isopropylidene-D-mannitol 8. Oxidative cleavage of the mannitol derivative followed by condensation with triethyl phosphonoacetate and reduction gave the alcohol 10 which was converted into the xanthate 11. Deprotection gave the dihydroxy xanthate 12 which was protected as its bis-tert-butyldimethylsilyl ether 13. This rearranged on heating in toluene to give the dithiocarbonate 15 which reacted with tributyltin hydride under free radical conditions to give the [(4S)-4,5-bis(tert-butyldimethylsilyloxy)pent-2-enyl](tributyl)stannane 16 as an approximately 9:1 mixture of E- and Z-isomers. Deprotection and selective protection of the primary hydroxy group provided the [(4S)-5-(tert-butyldimethylsilyloxy)-4-hydroxypent-2-enyl]stannane 18. As a shorter route, the primary hydroxy group of the dihydroxy xanthate 12 was protected as its tert-butyldimethylsilyl ether 14 which underwent clean rearrangement into the dithiocarbonate 19 when heated in toluene. Reaction with tributyltin hydride under free radical conditions then gave the (5-tert-butyldimethylsilyloxy-4-hydroxypent-2-enyl)stannane 18. Treatment of this 4,5-disubstituted pentenylstannane with tin(IV) chloride generated an allyltin trichloride which reacted with aldehydes with excellent 1,5-asymmetric induction to give 1,5-syn-products, e.g. 20, 29–31 and 41. The stereoselectivity of these reactions would appear to be controlled by the 4-hydroxy substituent rather than by the 5-tert-butyldimethylsilyl group. Aspects of the chemistry of these products, in particular their conversion into 2,6-disubstituted 5,6-dihydro-2H-pyrans, was investigated.

Thermal reduction of 1-methylquinolinium ion by tributyltin hydride occurs via a polar mechanism to yield 1-methyl-1,2-dihydroquinoline selectively, while the photoreduction of 1-methylquinolinium ion derivatives by tributyltin hydride and tris(trimethylsilyl)silane proceeds via photoinduced electron transfer from the metal hydrides to the singlet excited states of 1-methylquinolinium ion derivatives to yield the corresponding 1,4-dihydroquinolines exclusively.

Chiral, non-racemic N-(2-iodoethyl)-5-vinylpyrrolidin-2-ones have been synthesized and then cyclized with tributyltin hydride and azoisobutyronitrile (AIBN) to produce chiral, non-racemic pyrrolizidin-2-ones, with high diastereoselectivity. Reduction of the lactam moiety provides a facile route to naturally occurring pyrrolizidine alkaloids.

Trimethylsilyl trifluoromethanesulfonate promoted chemoselective reactions of acyclic acetals with allyltrimethylsilane, allyltributyltin, a silyl enol ether, tributyltin hydride, trimethylsilyl azide and trimethylsilyl cyanide have been achieved in the presence of cyclic acetals.

Reaction of the aldehyde 11 with tributyltin hydride in the presence of AIBN gave a mixture of 12 and 13, which successfully led to (+)-bulgecinine 3.

5′-Deoxyjuglomycin A 3 and 5′-methoxyjuglomycin A 4 have been synthesized via oxidative fragmentation of furo[3,2-b]naphtho[2,1-d]furans 9 and 10 respectively. Addition of 2-trimethylsiloxyfuran 5 to naphthoquinone sulfides 7, 8 afforded the key adducts 9, 10 which then underwent fragmentation to the quinone sulfides 11, 14 using ceric ammonium nitrate. Treatment of the trimethylsilyl derivatives 13, 15 of the sulfides 11, 14 with meta-chloroperoxybenzoic acid effected conversion into the sulfoxides 16, 18 which then underwent smooth desulfurization using tributyltin hydride to the quinones 21, 23. Finally, hydrolysis of the trimethylsilyl group completed the synthesis of 5′-deoxyjuglomycin A 3 and 5′-methoxyjuglomycin A 4.