Tandem carbon-carbon bond-forming radical addition-cyclization reaction of oxime ether and hydrazone

The novel tandem radical addition-cyclization of oxime ethers and hydrazones intramolecularly connected with the alpha,beta-unsaturated carbonyl group is described. The radical reaction of oxime ethers 1, 2, and 4 connected with acryloyl and methacryloyl moieties proceeded smoothly to give the heterocycles via a tandem C-C bond-forming process. The tandem reaction of hydrazone 5 took place in the presence of Zn(OTf)(2) as a Lewis acid to give the trans-cyclic product 17 without the formation of the cis-isomer. The diastereoselective radical addition-cyclization reaction of chiral oxime ether 19 was also studied. The tandem reaction of 19 proceeded smoothly even in aqueous media, providing the novel method for asymmetric synthesis of gamma-butyrolactones and beta-amino acid derivatives.     

Solid-phase tandem radical addition-cyclization reaction: triethylborane-induced reaction of oxime ethers anchored to polymer support

Tandem radical addition-cyclization of oxime ethers anchored to polymer support was studied. The reaction of oxime ethers with stannyl radical proceeded effectively by the use of triethylborane as a radical initiator. The alkyl radical addition-cyclization reactions of oxime ether connected with alpha,beta-unsaturated carbonyl group proceeded under iodine atom-transfer reaction conditions to give the functionalized azacycles via two carbon-carbon bonds-forming process.     

Zinc-mediated carbon radical addition to glyoxylic imines in aqueous media for the synthesis of alpha-amino acids

The addition of carbon radicals to glyoxylic imines was studied using zinc dust as a radical initiator. The zinc-mediated radical reaction of glyoxylic oxime ethers and hydrazones proceeded smoothly to give the alkylated products via a carbon-carbon bond-forming process in aqueous media. The reaction of the oxime ethers and hydrazones having an Oppolzer's camphorsultam group provided the corresponding alkylated products, which could be converted into enantiomerically pure alpha-amino acids. The diastereoselectivities observed in the reaction of hydrazones were better than those obtained in the reaction of oxime ethers.     

Stereocontrol in solid-phase radical reactions: radical addition to oxime ether anchored to polymer support

A high degree of stereocontrol in solid-phase radical reactions was achieved by using triethylborane and diethylzinc as a radical initiator at low reaction temperature. Alkyl radical addition to Oppolzer's camphorsultam derivatives of oxime ether anchored to polymer support proceeded smoothly to give the alpha-amino acid derivatives with excellent diastereoselectivities.     

Carbon-carbon bond construction on solid support: triethylborane-induced radical reactions of oxime ethers

The triethylborane-induced solid-phase radical reaction was studied. The solid-phase radical reaction of oxime ether anchored to Wang resin proceeded smoothly to give the α-amino acid derivatives. The carbon-carbon bond-forming radical reaction of TentaGel OH resin-bound glyoxylic oxime ether proceeded even in aqueous media.     

Novel synthesis of substituted pyrrolidines and piperidines via radical addition-ionic cyclization reaction of oxime ethers

We have developed a novel synthetic route to nitrogen-containing heterocycles via radical addition-ionic cyclization reaction. Treatment of oxime ethers carrying the tosyloxy group with Et₃B and alkyl iodide in the presence of Lewis acid gave the substituted pyrrolidines and piperidines. The reaction of oxime ethers carrying the methoxycarbonyl group proceeded under the same conditions to give the amino esters, which were easily converted into the corresponding lactams by the treatment with concd HCl. On the other hand, the oxime ether bearing the phenoxycarbonyl group afforded directly alkylated lactams under the radical reaction conditions. The utility of this domino reaction was demonstrated by the synthesis of (±)-bgugaine and the formal synthesis of 5,8-disubstituted indolizidine alkaloids.     

Radical cyclization in heterocycle synthesis 15. Relationship between a Radical species and radical acceptors of three different types of double bond in radical addition-cyclization

Relationship between a radical species and radical acceptors of three different types of double bond in radical addition-cyclization was systematically investigated. Substrates carrying alpha,beta-unsaturated amide, isolated olefin, and oxime ether moieties underwent radical addition-cyclization to give differently substituted lactams depending upon the radicals used. The sulfanyl radical addition-cyclization of the substrate proceeded smoothly to give the 5-membered lactam having an alkoxyamino group as a result of preferable addition of an intermediary alpha-carbonyl radical to the oxime ether. On the other hand, the triethylborane-mediated radical addition-cyclization gave the lactam bearing an iodomethyl group as a result of addition to an intermediary alpha-carbonyl radical to isolated olefin. The different regioselectivity was explained by the stability of the intermediary radical and the interaction between SOMO and HOMO.     

Stannyl radical addition-cyclization of oxime ethers connected with olefins

Stannyl radical addition-cyclization of oxime ethers connected with olefin moieties was studied. The radical reactions proceeded effectively by the use of triethylborane as a radical initiator to provide the functionalized pyrrolidines via a carbon-carbon bond-forming process.     

Addition of electrophilic and heterocyclic carbon-centered radicals to glyoxylic oxime ethers

[reaction: see text] Stabilized primary radicals can be formed from alkyl halides in an atom transfer process with Et(3)B. This process depends on the strength of the carbon-halogen bond and the stability of the resulting primary radical. Radicals formed from benzyl iodide and ethyl iodoacetate add to glyoxylic oxime ethers; however, more electrophilic radicals do not. Glyoxylic oxime ethers are also good radical acceptors for heterocyclic carbon-centered secondary radicals, giving novel alpha-amino acid derivatives.     

Enantioselective radical cyclizations: a new approach to stereocontrol of cascade reactions

Stereocontrol in a cascade radical addition-cyclization-trapping reaction was achieved by a new approach, which utilizes a hydroxamate ester moiety as a coordinating chiral Lewis acid tether between two radical acceptors. A remarkable feature of this reaction is the construction of three bonds and tertiary and quaternary stereogenic centers through both inter- and intramolecular carbon-carbon bond-forming processes. The chiral Lewis acid mediated reaction of oxime ethers also proceeded smoothly with good enantio- and diastereoselectivities, indicating the usefulness of the cascade approach for the asymmetric synthesis of various gamma-lactams.     

Asymmetric synthesis of alpha-amino acids based on carbon radical addition to glyoxylic oxime ether

The first asymmetric synthesis of alpha-amino acids based on diastereoselective carbon radical addition to glyoxylic imine derivatives is reported. The addition of an isopropyl radical, generated from i-PrI, Bu(3)SnH, and Et(3)B in CH(2)Cl(2) at 25 degrees C, to achiral glyoxylic oxime ether 1 proceeded regioselectively at the imino carbon atom of the oxime ether group to give an excellent yield of the C-isopropylated product 2. The competitive reaction using glyoxylic oxime ether 1 and aldoxime ether 4 showed that the reactivity of the glyoxylic oxime ether toward nucleophilic carbon radicals was enhanced by the presence of a neighboring electron-withdrawing substituent. Thus, the alkyl radical addition to glyoxylic oxime ether 1 proceeded smoothly even at -78 degrees C, in contrast to the unactivated aldoxime ether 4. A high degree of stereocontrol in the carbon radical addition to the glyoxylic oxime ether was achieved by using Oppolzer's camphorsultam as a chiral auxiliary. The stannyl radical-mediated reaction of the camphorsultam derivative 6 with an isopropyl radical at -78 degrees C afforded a 96:4 diastereomeric mixture, 7a, of the C-isopropylated product. The reductive removal of the benzyloxy group of the major diastereomer (R)-7a, by treatment with Mo(CO)(6) and the subsequent removal of the sultam auxiliary by standard hydrolysis, afforded the enantiomerically pure D-valine (R)-12 without any loss of stereochemical purity. To evaluate the new methodology, a variety of alkyl radicals were employed in the addition reaction which gave the alkylated products 7 with excellent diastereoselectivity, allowing access to a wide range of enantiomerically pure natural and unnatural alpha-amino acids. Even in the absence of Bu(3)SnH, treatment of 6 with alkyl iodide and Et(3)B at 20 degrees C gave the C-alkylated products 7 with moderate diastereoselectivities. The use of Et(2)Zn as a radical initiator, instead of Et(3)B, was also effective for the radical reaction. The enantioselective isopropyl radical addition to 1 using (R)-(+)-2, 2'-isopropylidenebis(4-phenyl-2-oxazoline) and MgBr(2) gave excellent chemical yield of the valine derivative 2 in 52% ee.     

Chiral Brønsted acid-catalyzed inverse electron-demand aza Diels-Alder reaction

Inverse electron-demand aza Diels-Alder reaction of aldimine with enol ethers proceeded under the influence of a phosphoric acid diester, derived from (R)-BINOL, to give tetrahydroquinoline derivatives with excellent enantioselectivity.     

A novel synthesis of amino-1,2-oxazinones as a versatile synthon for beta-amino acid derivatives

The radical addition-cyclisation of alpha, beta-unsaturated hydroxamates containing an oxime ether provides a novel method for the stereoselective synthesis of amino-1,2-oxazinones. Its synthetic utility is demonstrated by a stereoselective synthesis of beta-amino acid derivatives, such as alpha-alkyl-beta-amino-gamma-lactone and alpha,beta-disubstituted beta-lactam.     

Novel polycyclic heterocyeles. XIII. Derivatives of the oxime and carbinol derived from 1,2-dihydro-11-(trifluoromethyl)-3H,7H-quino[8,1-cd] [1,5]benzoxazepin-3-one

The anions derived from the oxime, 2 , and the carbinol, 3 , generated by reaction with sodium hydride, were reacted with aminoalkyl chlorides and an aroyl chloride to give a number of amino-alkyl ethers and an aroyl ester. In addition, 2 and 3 were reacted with phenylisocyanate to yield O-phenylcarbamoyl derivatives. The pmr spectra of several of these compounds are discussed.     

Photosensitized reactions of oxime ethers: a steady-state and laser flash photolysis study

The mechanistic aspects of the photosensitized reactions of a series of oxime ethers were studied by steady-state (product studies) and laser flash photolysis methods. Nanosecond laser flash photolysis studies have shown that chloranil-sensitized reactions of the oxime ethers result in the formation of the corresponding radical cations. The radical cation species react with nucleophiles such as MeOH by clean second-order kinetics with rate constants of (0.7-1.4) x 10(6) M(-1) s(-1). Only a small steric effect is observed in these reactions, which is taken as an indication that the reaction center is not the O-alkyl moiety, but rather somewhere else in the molecule. Product studies in a polar nonnucleophilic solvent (MeCN) revealed that in order for the oxime ether radical cation to react more readily, alpha-protons must be available on the alkyl group. The O-methyl (1), O-ethyl (2), and O-benzyl (3) acetophenone oximes all reacted readily to give acetophenone oxime as the major product (as well as an aldehyde derived from the O-alkyl group), whereas O-tert-butyl acetophenone oxime (4) did not. The product formation can be explained by a mechanism that involves electron transfer followed by proton transfer (alpha to the oxygen) and subsequent beta-cleavage. When using 3 in MeOH, a change in the product formation is observed, the most important difference being the presence of benzyl alcohol rather than benzaldehyde as the major product. On the basis of the data from LFP and steady-state experiments, it is suggested that the competing mechanism under these conditions involves electron transfer, followed by a nucleophilic attack on the nitrogen, a MeOH-assisted [1,3]-proton transfer, and subsequent loss of benzyl alcohol. This mechanism is supported by DFT (B3LYP/6-31G) and AM1 calculations.     

Development of radical addition-cyclization-elimination reaction of oxime ether and its application to formal synthesis of (±)-martinelline

Radical addition-cyclization-elimination (RACE) reaction of oxime ether carrying unsaturated ester provides a novel method for the construction of pyrroloquinoline. Treatment of oxime ethers with Bu₃SnH and AIBN gave N-norpyrroloquinoline as a major product, which was also obtained by the radical reaction of the corresponding hydrazone and imine. The radical reaction of aldehyde and ketone carrying unsaturated ester proceeded stereoselectively to give cis-furoquinolines and cis-hydroxyesters. The RACE reactions by using each of Bu₃SnNMe₂, Bu₃SnD, and/or D₂O were also examined in order to propose a reaction pathway to N-norpyrroloquinoline. Furthermore, the synthetic utility of RACE reaction is demonstrated by preparation of a key intermediate for the synthesis of (±)-martinelline.     

Iodine atom transfer [3 + 2] cycloaddition reaction with electron-rich alkenes using N-tosyliodoaziridine derivatives as novel azahomoallyl radical precursors

Treatment of N-tosyliodoaziridine derivatives with Et(3)B efficiently produces various azahomoallyl radical (2-akenylamidyl radical) species which give oxygen-functionalized pyrrolidine derivatives through iodine atom transfer [3 + 2] cycloaddition with electron-rich alkenes such as enol ethers and ketene acetal. The present cycloaddition reaction proceeds regioselectively via C-N bond cleavage of an aziridinylalkyl radical intermediate and addition of the resulting azahomoallyl radicals to the terminal carbon of an alkene. The reaction of alkenes with the cyclohexenylamidyl radical generated from an optically active bicyclic iodoaziridine [(1S,2S,6S)-2-iodo-7-(p-toluenesulfonyl)-7-azabicyclo[4.1.0]heptane, 94% ee] also proceeds to give optically active octahydroindole derivatives (84-93% ee).     

Utility of the iridium complex of the pybox ligand in regio- and enantioselective allylic substitution

The viability of the iridium complex of pybox as chiral catalyst in allylic substitutions and the enantioselective synthesis of branched products was studied. Among several chiral ligands evaluated, the iridium complex of pybox having a phenyl group catalyzed the reaction with high activity to form the branched amines with good enantioselectivities when hydroxylamine, amine, and aniline were employed as a nucleophile. The allylic substitution with oximes proceeded smoothly to give the branched oxime ethers with good enantioselectivities. [reaction: see text]     

Thermal decomposition of O-benzyl ketoximes; role of reverse radical disproportionation

Thermolyses of seven dialkyl, two alkyl-aryl and two diaryl O-benzyl ketoxime ethers, R(1)R(2)C[double bond, length as m-dash]NOCH(2)Ph, have been examined in three hydrogen donor solvents: tetralin, 9,10-dihydrophenanthrene, and 9,10-dihydroanthracene. All the oxime ethers gave the products expected from homolytic scission of both the O-C bond (viz., R(1)R(2)C[double bond, length as m-dash]NOH and PhCH(3)) and N-O bond (viz., R(1)R(2)C[double bond, length as m-dash]NH and PhCH(2)OH). The yields of these products depended on which solvent was used and the rates of decomposition of the O-benzyl oxime ethers were greater in 9,10-dihydrophenanthrene and 9,10-dihydroanthracene than in tetralin. These results indicated that a reverse radical disproportionation reaction in which a hydrogen atom was transferred from the solvent to the oxime ether, followed by [small beta]-scission of the resultant aminoalkyl radical, must be important in the latter two solvents. Benzaldehyde was found to be an additional product from thermolyses conducted in tetralin. This, and other evidence, indicated that another induced decomposition mode involving abstraction of a benzylic hydrogen atom, followed by [small beta]-scission of the resulting benzyl radical, became important for some substrates. Participation by minor amounts of enamine tautomers of the oxime ethers was shown to be negligible by comparison of thermolysis data for the O-benzyloxime of bicyclo[3.3.1]nonan-9-one, which cannot give an enamine tautomer, with that of the O-benzyloxime of cyclohexanone.     

Metal‐Free 2,2,6,6‐Tetramethylpiperidin‐1‐yloxy Radical (TEMPO) Catalyzed Aerobic Oxidation of Hydroxylamines and Alkoxyamines to Oximes and Oxime Ethers

TEMPO‐Mediated oxidation of hydroxylamines (=hydroxyamines) and alkoxyamines to the corresponding oxime derivatives is reported (TEMPO=2,2,6,6‐tetramethylpiperidin‐1‐yloxy radical; Scheme 2). These environmentally benign oxidations proceed in good to excellent yields (Table 1). For alkoxyamines, oxidation to the corresponding oxime ethers can be performed by using dioxygen as a terminal oxidant in the presence of 5–10 mol‐% of TEMPO or 4‐substituted derivatives thereof as a catalyst (Scheme 3 and Table 2). Importantly, benzyl bromides can directly be transformed to oxime ethers via in situ alkoxyamine formation by a nucleophilic substitution followed by TEMPO‐mediated oxidation (Scheme 4 and Table 3).